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Aerobic Copper-Catalyzed Organic Reactions

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This paper explores the rich chemistry of copper as a catalyst, emphasizing its capability to adopt various oxidation states and catalyze reactions with molecular oxygen. The introduction highlights the advantages of using oxygen as an oxidant, due to its atom-economical and environmentally friendly properties, as well as the associated challenges in reaction conditions. The text discusses alternative approaches to safely utilize oxidation chemistry involving copper catalysts across different environments, including innovative reactor designs and the application of supercritical carbon dioxide.

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seen for alkane or arene oxidation. Oxidation occurs through two primary mechanisms. In acidic or activated substrates, deprotonation can occur, followed by single-electron oxidation to form the key radical species that then reacts with molecular oxygen. As demonstrated below, these processes can be highly efficient but are inherently limited in scope. In unactivated substrates, the benzylic radical species is formed directly via hydrogen abstraction. These operations typically require more forcing conditions, and efficiency and selectivity remain significant obstacles. For both modes of oxidation, controlling the degree of oxygenation is critical since the acid, aldehyde, or alcohol can be produced. As of yet there is no general catalyst available for a broad range of substrates. However, a variety of different copper catalysts have been devised that operate on electron-poor or electron-rich substrates.
seen for alkane or arene oxidation. Oxidation occurs through two primary mechanisms. In acidic or activated substrates, deprotonation can occur, followed by single-electron oxidation to form the key radical species that then reacts with molecular oxygen. As demonstrated below, these processes can be highly efficient but are inherently limited in scope. In unactivated substrates, the benzylic radical species is formed directly via hydrogen abstraction. These operations typically require more forcing conditions, and efficiency and selectivity remain significant obstacles. For both modes of oxidation, controlling the degree of oxygenation is critical since the acid, aldehyde, or alcohol can be produced. As of yet there is no general catalyst available for a broad range of substrates. However, a variety of different copper catalysts have been devised that operate on electron-poor or electron-rich substrates.
Scheme 2. Selected Oxidations of Nitrotoluene demonstrated in the presence of sodium hydroxide and a copper phthalocyanine catalyst under 2 MPa of oxygen.'* High selectivity was observed, with only trace amounts of the alcohol and the aldehyde formed. The process was later demonstrated to proceed in an ionic solvent (Scheme 2b).’? Although slightly higher temperature was necessary, simple acidification of the aqueous layer conveniently provided the pure product and allowed recycling of the ionic liquid solvent, making the process
Scheme 2. Selected Oxidations of Nitrotoluene demonstrated in the presence of sodium hydroxide and a copper phthalocyanine catalyst under 2 MPa of oxygen.'* High selectivity was observed, with only trace amounts of the alcohol and the aldehyde formed. The process was later demonstrated to proceed in an ionic solvent (Scheme 2b).’? Although slightly higher temperature was necessary, simple acidification of the aqueous layer conveniently provided the pure product and allowed recycling of the ionic liquid solvent, making the process
Scheme 5. Cu;(TBC),-catalyzed Oxidation of Xanthene and Fluorene Garcia and co-workers tested the oxidation of xanthene, another doubly benzylic system, using a metal—organic framework composed of 1,3,5-benzenetricarboxylate (BTC).”° Although the most selective metal was found to be Fe”, Cu,(BTC), also provided the ketone product at 70 °C in good yield and usable selectivity (Scheme 5). Under the same conditions, fluorene could also be converted to fluorenone in moderate conversion but excellent selectivity. The catalysts were easily recovered and could be reused after drying with minimal loss in activity.
Scheme 5. Cu;(TBC),-catalyzed Oxidation of Xanthene and Fluorene Garcia and co-workers tested the oxidation of xanthene, another doubly benzylic system, using a metal—organic framework composed of 1,3,5-benzenetricarboxylate (BTC).”° Although the most selective metal was found to be Fe”, Cu,(BTC), also provided the ketone product at 70 °C in good yield and usable selectivity (Scheme 5). Under the same conditions, fluorene could also be converted to fluorenone in moderate conversion but excellent selectivity. The catalysts were easily recovered and could be reused after drying with minimal loss in activity.
Scheme 3. Copper(II)-Catalyzed Oxygenation of Fluorene mechanism proceeds through oxidation of the fluorenyl anion by copper, coupling of the radical with molecular oxygen, and decomposition of the resulting peroxide by base deprotonation to give the ketone product. Kinetic studies using 9,9’- dideuterofluorene indicated that the rate-limiting step was deprotonation of the substrate. Although the oxidation proceeded in the presence of base (NaOMe) and oxygen, the addition of copper catalyst increased the rate by ~500-fold. In an early report by Allara,”° fluorene was readily oxidized to fluorenone at room temperature using Cu(OBz)(OMe) with triethylenetetraamine (trine) as a ligand and pyridine/MeOH as solvent. Despite only moderate conversion, excellent selectivity (200:1) of corresponding ketone to homocoupled 9,9'-bifluorene was observed (Scheme 3). The proposed
Scheme 3. Copper(II)-Catalyzed Oxygenation of Fluorene mechanism proceeds through oxidation of the fluorenyl anion by copper, coupling of the radical with molecular oxygen, and decomposition of the resulting peroxide by base deprotonation to give the ketone product. Kinetic studies using 9,9’- dideuterofluorene indicated that the rate-limiting step was deprotonation of the substrate. Although the oxidation proceeded in the presence of base (NaOMe) and oxygen, the addition of copper catalyst increased the rate by ~500-fold. In an early report by Allara,”° fluorene was readily oxidized to fluorenone at room temperature using Cu(OBz)(OMe) with triethylenetetraamine (trine) as a ligand and pyridine/MeOH as solvent. Despite only moderate conversion, excellent selectivity (200:1) of corresponding ketone to homocoupled 9,9'-bifluorene was observed (Scheme 3). The proposed
“See Chart 1 for ligand structures. »Benzaldehyde/benzoic acid 4:94. “Acid and diaryls were the other major products. “Includes oxidation products at other positions of the cyclohexyl ring. Table 1. Benzylic Oxidation of Unactivated Hydrocarbons
“See Chart 1 for ligand structures. »Benzaldehyde/benzoic acid 4:94. “Acid and diaryls were the other major products. “Includes oxidation products at other positions of the cyclohexyl ring. Table 1. Benzylic Oxidation of Unactivated Hydrocarbons
Scheme 6. General Mechanism for Benzylic Oxidation of Unactivated Substrates several modes. In some cases, reaction occurs in the absence of an obvious radical initiator. The high temperatures and long
Scheme 6. General Mechanism for Benzylic Oxidation of Unactivated Substrates several modes. In some cases, reaction occurs in the absence of an obvious radical initiator. The high temperatures and long
Chart 1. Ligands Utilized in Table 1 cumene in the presence of a variety of metals, a radical initiator, and NHPI (Table 1, entry 13— 14).° Interestingly, NHPI in the absence of a metal cocatalyst afforded cumyl hydroperoxide in moderate conversions but excellent selectivity (>99%). Addition of metal salts changed the product distribution, presumably from catalyzing the decomposition of the initial hydroperoxide adduct. Copper was found to be the most effective, affording either the alcohol or rearranged ketone as the major product depending on solvent and temperature. Notably, much higher conversion but poorer selectivity was observed in the oxygenation of cumene when NHPI, radical initiator, and Cu(acac), were employed in comparison to the heterogeneous Cu(OAc), on Chelex system (Table 1, entry 12-13). conditions, and toluene was converted almost exclusively to benzyl bromide. Oxidation of cumene to cumyl hydroperoxide represents an industrially significant process that accounts for the majority of the global production of both phenol and acetone.” A selective oxidation of cumene was reported by Cheng and co-workers, in which Cu(OAc), on Chelex was used as a heterogeneous catalyst in the absence of a radical initiator (Table 1, entry 12).** Although only minor conversion is observed, the hydroperoxide is formed in almost perfect selectivity, with only trace (<1%) alcohol detected (Scheme 7).
Chart 1. Ligands Utilized in Table 1 cumene in the presence of a variety of metals, a radical initiator, and NHPI (Table 1, entry 13— 14).° Interestingly, NHPI in the absence of a metal cocatalyst afforded cumyl hydroperoxide in moderate conversions but excellent selectivity (>99%). Addition of metal salts changed the product distribution, presumably from catalyzing the decomposition of the initial hydroperoxide adduct. Copper was found to be the most effective, affording either the alcohol or rearranged ketone as the major product depending on solvent and temperature. Notably, much higher conversion but poorer selectivity was observed in the oxygenation of cumene when NHPI, radical initiator, and Cu(acac), were employed in comparison to the heterogeneous Cu(OAc), on Chelex system (Table 1, entry 12-13). conditions, and toluene was converted almost exclusively to benzyl bromide. Oxidation of cumene to cumyl hydroperoxide represents an industrially significant process that accounts for the majority of the global production of both phenol and acetone.” A selective oxidation of cumene was reported by Cheng and co-workers, in which Cu(OAc), on Chelex was used as a heterogeneous catalyst in the absence of a radical initiator (Table 1, entry 12).** Although only minor conversion is observed, the hydroperoxide is formed in almost perfect selectivity, with only trace (<1%) alcohol detected (Scheme 7).
(one-pot) or isoindolines (two-pot). Interestingly, subjecting 2- cyclohexylbenzonitrile to the reaction conditions afforded an aminoperoxide product in good yield, and the structure was secured by X-ray crystallographic analysis (Scheme 11).
(one-pot) or isoindolines (two-pot). Interestingly, subjecting 2- cyclohexylbenzonitrile to the reaction conditions afforded an aminoperoxide product in good yield, and the structure was secured by X-ray crystallographic analysis (Scheme 11).
Scheme 14. Ammoxidation Using CuNa-ZSM-5
Scheme 14. Ammoxidation Using CuNa-ZSM-5
Scheme 12. Mechanism for Imine-Directed Benzylic Oxidation
Scheme 12. Mechanism for Imine-Directed Benzylic Oxidation
to increase conversion while only slightly modifying selectivity. However, even at 350 °C, only slight conversion was observed with an 85% selectivity of oxidation at the benzylic position. The process afforded a mixture of products, with significant amounts of both the aldehyde and nitrile forming. In accord with the proposed mechanism involving an aldehyde intermediate (see below), formation of nitrile products was only observed when aldehydes were also detected.
to increase conversion while only slightly modifying selectivity. However, even at 350 °C, only slight conversion was observed with an 85% selectivity of oxidation at the benzylic position. The process afforded a mixture of products, with significant amounts of both the aldehyde and nitrile forming. In accord with the proposed mechanism involving an aldehyde intermediate (see below), formation of nitrile products was only observed when aldehydes were also detected.
Table 2. Alkane Oxidation with Copper Catalysts
Table 2. Alkane Oxidation with Copper Catalysts
Scheme 16. General Mechanism for Alkane Oxidation
Scheme 16. General Mechanism for Alkane Oxidation
conditions than those for the corresponding alkyl or benzylic substrates (see sections 2.1 and 2.2). As for the oxidations in the preceding sections, selective formation of the potential oxygenation products (alcohol, carbonyl, peroxide) remains challenging, although copper catalysts have been identified that give good conversion and high levels of selectivity. A key substrate for allylic oxidation is propylene, which is employed in the current process for acrolein production using various multicomponent mixed metal catalysts.°° Studies of copper oxides in a flow reactor for this transformation indicate competing combustion, particularly when the catalyst was oxidized before use.°”* Even without preoxidation, a ratio of ~52:44 acrolein/CO, was observed, with small amounts of acetaldehyde and propionaldehyde also detected.®* A copper phthalocyanine catalyst on a silica matrix at low loading (<0.1 wt %) has been reported to catalyze the conversion of propene
conditions than those for the corresponding alkyl or benzylic substrates (see sections 2.1 and 2.2). As for the oxidations in the preceding sections, selective formation of the potential oxygenation products (alcohol, carbonyl, peroxide) remains challenging, although copper catalysts have been identified that give good conversion and high levels of selectivity. A key substrate for allylic oxidation is propylene, which is employed in the current process for acrolein production using various multicomponent mixed metal catalysts.°° Studies of copper oxides in a flow reactor for this transformation indicate competing combustion, particularly when the catalyst was oxidized before use.°”* Even without preoxidation, a ratio of ~52:44 acrolein/CO, was observed, with small amounts of acetaldehyde and propionaldehyde also detected.®* A copper phthalocyanine catalyst on a silica matrix at low loading (<0.1 wt %) has been reported to catalyze the conversion of propene
Scheme 19. Oxidation of Cycloalkanes with Copper- Modified Ceramic and oxygen to acrolein at 475— 500 °C with approximately 50% selectivity and 10% yield.” A more highly studied substrate is cyclohexene, the oxidation products of which are precursors to many commodity chemicals. Table 3 contains a summary of this transformation with copper catalysts using oxygen.
Scheme 19. Oxidation of Cycloalkanes with Copper- Modified Ceramic and oxygen to acrolein at 475— 500 °C with approximately 50% selectivity and 10% yield.” A more highly studied substrate is cyclohexene, the oxidation products of which are precursors to many commodity chemicals. Table 3 contains a summary of this transformation with copper catalysts using oxygen.
Scheme 17. Oxidation of Cyclooctane under Various Atmospheres Scheme 18. Copper—Crown Ether Catalyzed Oxygenation of Alkanes
Scheme 17. Oxidation of Cyclooctane under Various Atmospheres Scheme 18. Copper—Crown Ether Catalyzed Oxygenation of Alkanes
A report by Quici and co-workers explored the fluorous biphasic oxidation of hydrocarbons using a copper catalyst prepared by N-perfluoroalkylation of the commercially available 1,4,8,11-tetraazacyclotetradecane (Table 3, entry 1).”° In this reaction, the metal catalyst is soluble in perfluorohexane solvent, while the cyclohexene substrate and oxygenated products are immiscible, allowing convenient recycling of the
A report by Quici and co-workers explored the fluorous biphasic oxidation of hydrocarbons using a copper catalyst prepared by N-perfluoroalkylation of the commercially available 1,4,8,11-tetraazacyclotetradecane (Table 3, entry 1).”° In this reaction, the metal catalyst is soluble in perfluorohexane solvent, while the cyclohexene substrate and oxygenated products are immiscible, allowing convenient recycling of the
Table 3. Allylic Oxidation of Cyclohexene
Table 3. Allylic Oxidation of Cyclohexene
“See Chart 3 for ligand structures. Diol (5%) observed. “Exact conversion and distribution not reported. At lower temperatures, hydroperoxide is the major product, with alcohol and ketone principally forming as the temperature is increased. The alcohol entry typically represents the sum of peroxide and alcohol product generation in the reaction. @Approximately 95% allylic selectivity. “Peroxide (24%) observed. Peroxide (87%) observed. catalytic system. Use of 1 mol % TBHP as an initiator provided a 3:1 mixture of cyclohexenone to cyclohexenol in 6% conversion at ambient temperature (Scheme 21). Notably, no Copper—salen complexes attached to various mesoporous or amorphous silica supports have been tested in the oxidation of cyclohexene (Table 3, entry 3).’” These catalysts provided high conversions at 60 °C with a peroxide initiator and oxygen atmosphere. However, the alcohol and ketone products were produced in a nearly 1:1 ratio for all copper catalysts tested. Interestingly, high allylic selectivity was achieved even using stoichiometric H,O, initiator.
“See Chart 3 for ligand structures. Diol (5%) observed. “Exact conversion and distribution not reported. At lower temperatures, hydroperoxide is the major product, with alcohol and ketone principally forming as the temperature is increased. The alcohol entry typically represents the sum of peroxide and alcohol product generation in the reaction. @Approximately 95% allylic selectivity. “Peroxide (24%) observed. Peroxide (87%) observed. catalytic system. Use of 1 mol % TBHP as an initiator provided a 3:1 mixture of cyclohexenone to cyclohexenol in 6% conversion at ambient temperature (Scheme 21). Notably, no Copper—salen complexes attached to various mesoporous or amorphous silica supports have been tested in the oxidation of cyclohexene (Table 3, entry 3).’” These catalysts provided high conversions at 60 °C with a peroxide initiator and oxygen atmosphere. However, the alcohol and ketone products were produced in a nearly 1:1 ratio for all copper catalysts tested. Interestingly, high allylic selectivity was achieved even using stoichiometric H,O, initiator.
Scheme 22. Allylic Alkene Oxidation with an Oxyhemocyanin/Oxytyrosinase Model Compound
Scheme 22. Allylic Alkene Oxidation with an Oxyhemocyanin/Oxytyrosinase Model Compound
“See Chart 4 for ligand structures. ’Based on GLC yield of epoxide. Table 4. Copper-Catalyzed Epoxidation of Alkenes
“See Chart 4 for ligand structures. ’Based on GLC yield of epoxide. Table 4. Copper-Catalyzed Epoxidation of Alkenes
case, ketone is the predominant product, with smaller amounts of alcohol also forming. Notably, no competitive alkene reactivity (epoxide formation) was reported for cyclohexene, and very high ketone selectivity was observed for ethylbenzene. The conversions are expectedly dissimilar, with a general reactivity trend of allylic > benzylic >> alkyl observed. The
case, ketone is the predominant product, with smaller amounts of alcohol also forming. Notably, no competitive alkene reactivity (epoxide formation) was reported for cyclohexene, and very high ketone selectivity was observed for ethylbenzene. The conversions are expectedly dissimilar, with a general reactivity trend of allylic > benzylic >> alkyl observed. The
Scheme 24. Epoxidation of Alkenes with a Copper Catalyst
Scheme 24. Epoxidation of Alkenes with a Copper Catalyst
inantly the trans-epoxide, again similar to MCPBA (Scheme 26). Both peroxy acids and radical species appear to form under the reaction conditions, with the former accounting for product formation except when the substrates can stabilize radical intermediates (i.e., the stilbenes, Scheme 24).
inantly the trans-epoxide, again similar to MCPBA (Scheme 26). Both peroxy acids and radical species appear to form under the reaction conditions, with the former accounting for product formation except when the substrates can stabilize radical intermediates (i.e., the stilbenes, Scheme 24).
With copper and oxygen, the aldehyde co-oxidant is believed to form peroxy acids. The epoxidation mechanism appears to involve both peroxy acids and radical species (Scheme 25). The latter is consistent with the formation of mixtures of epoxide diastereomers when cis alkenes are used as subststrates (Scheme 24). The high ratio of hydroxyl-directed cis- epoxidation seen with the copper catalyst, however, is very similar to that observed with MCPBA (meta-chloroperox-
With copper and oxygen, the aldehyde co-oxidant is believed to form peroxy acids. The epoxidation mechanism appears to involve both peroxy acids and radical species (Scheme 25). The latter is consistent with the formation of mixtures of epoxide diastereomers when cis alkenes are used as subststrates (Scheme 24). The high ratio of hydroxyl-directed cis- epoxidation seen with the copper catalyst, however, is very similar to that observed with MCPBA (meta-chloroperox-
Scheme 25. Mechanism of Epoxidation of Alkenes with a Copper Catalyst ybenzoic acid) supporting the intervention of a peroxy acid (Scheme 26). The acetate-protected version gives predom-
Scheme 25. Mechanism of Epoxidation of Alkenes with a Copper Catalyst ybenzoic acid) supporting the intervention of a peroxy acid (Scheme 26). The acetate-protected version gives predom-
as a peracid precursor. In an interesting departure from this pattern, the epoxidation of norbornene with a copper amidrazone catalyst and oxygen has been reported in the absence of aldehyde or peroxide (Scheme 28).°° Complete
as a peracid precursor. In an interesting departure from this pattern, the epoxidation of norbornene with a copper amidrazone catalyst and oxygen has been reported in the absence of aldehyde or peroxide (Scheme 28).°° Complete
Scheme 29. Selective Epoxidation of Tetrahydropyridines
Scheme 29. Selective Epoxidation of Tetrahydropyridines
Scheme 28. Epoxidation of Norbornene in the Absence of Aldehyde or Peroxide selectivity to the exo product is reported in high conversion as detected by GC. Due to the bicyclic structure, the corresponding allylic radical cannot undergo resonance stabilization; as a consequence, allylic oxidation is not competitive. Hypothetically, the higher temperatures in this reaction might allow formation of a copper—oxo species, which acts as the oxygenating source in the absence of typical peracid.
Scheme 28. Epoxidation of Norbornene in the Absence of Aldehyde or Peroxide selectivity to the exo product is reported in high conversion as detected by GC. Due to the bicyclic structure, the corresponding allylic radical cannot undergo resonance stabilization; as a consequence, allylic oxidation is not competitive. Hypothetically, the higher temperatures in this reaction might allow formation of a copper—oxo species, which acts as the oxygenating source in the absence of typical peracid.
Scheme 34. Aminoxygenation of Alkenes with Stoichiometric Copper
Scheme 34. Aminoxygenation of Alkenes with Stoichiometric Copper
with (PhS), was attempted under a nitrogen atmosphere, only trace amount of product was observed.
with (PhS), was attempted under a nitrogen atmosphere, only trace amount of product was observed.
Scheme 31. Acetoxysulfenylation of Alkenes
Scheme 31. Acetoxysulfenylation of Alkenes
Scheme 33. Oxidative Sulfonylation of Alkenes
Scheme 33. Oxidative Sulfonylation of Alkenes
homolytic cleavage of the Cu—C bond affords a Cu(1) species and a primary radical, which is readily trapped with TEMPO. Reoxidation of the Cu(I) to Cu(II) by oxygen regenerates the active catalyst.
homolytic cleavage of the Cu—C bond affords a Cu(1) species and a primary radical, which is readily trapped with TEMPO. Reoxidation of the Cu(I) to Cu(II) by oxygen regenerates the active catalyst.
TEMPO alone could trap the proposed alkyl—copper intermediate in addition to acting as the terminal oxidant, performing the reaction under oxygen was necessary for complete conversion to the pyrrolidine products.
TEMPO alone could trap the proposed alkyl—copper intermediate in addition to acting as the terminal oxidant, performing the reaction under oxygen was necessary for complete conversion to the pyrrolidine products.
Scheme 36. Catalytic Aminooxygenation of Alkenes To Form Cyclic Ureas Scheme 37. Catalytic Asymmetric Desymmetrization via Aminooxygenation
Scheme 36. Catalytic Aminooxygenation of Alkenes To Form Cyclic Ureas Scheme 37. Catalytic Asymmetric Desymmetrization via Aminooxygenation
Scheme 35. Aminooxygenation of Alkenes with Catalytic Copper and Oxygen
Scheme 35. Aminooxygenation of Alkenes with Catalytic Copper and Oxygen
Scheme 38. Mechanism for the Catalytic Aminooxygenation of Alkenes
Scheme 38. Mechanism for the Catalytic Aminooxygenation of Alkenes
Scheme 41. Potential Mechanism for the Carboacetoxylation of Alkenes reaction, lending evidence to a nonradical pathway. A potential mechanism for the reaction involves initial oxycupration via attack of the enolate form of the anhydride with the alkene. In this instance, the carbocuprate then undergoes carbometalation of a second alkene to generate the cyclic system. Oxidative decomposition generates the product and regenerates the catalytic copper species.
Scheme 41. Potential Mechanism for the Carboacetoxylation of Alkenes reaction, lending evidence to a nonradical pathway. A potential mechanism for the reaction involves initial oxycupration via attack of the enolate form of the anhydride with the alkene. In this instance, the carbocuprate then undergoes carbometalation of a second alkene to generate the cyclic system. Oxidative decomposition generates the product and regenerates the catalytic copper species.
Scheme 42. Cyclopropanation of N-Allyl Enamine Carboxylates
Scheme 42. Cyclopropanation of N-Allyl Enamine Carboxylates
Scheme 46. Carbooxygenation Mechanism for N-Allyl Enamine Carboxylates
Scheme 46. Carbooxygenation Mechanism for N-Allyl Enamine Carboxylates
Scheme 48. Aminooxygenation of N-Allyl-2-aminopyridines and N-Allylamidines
Scheme 48. Aminooxygenation of N-Allyl-2-aminopyridines and N-Allylamidines
Scheme 45. Carbooxygenation of N-Allyl Enamine Carboxylates To Afford 4-Formylpyrroles substitution of the allyl moiety was not tolerated, affording complex mixtures. However, a variety of 4-benzoylpyrroles could be formed from substituted N-propargyl enamine carboxylates via alkyne carbooxygenation (see section 2.4.4).
Scheme 45. Carbooxygenation of N-Allyl Enamine Carboxylates To Afford 4-Formylpyrroles substitution of the allyl moiety was not tolerated, affording complex mixtures. However, a variety of 4-benzoylpyrroles could be formed from substituted N-propargyl enamine carboxylates via alkyne carbooxygenation (see section 2.4.4).
Recently, Zhu and co-workers treated N-(1-phenylallyl)-2- aminopyrazine with a copper(II) species and oxygen, anticipating a copper-promoted C— H amination of the double bond and oxidative aromatization."°’ However, a heterocyclic aldehyde was formed instead via an aminooxygenation process. This reaction was found to be general for a wide range of N- allyl-2-aminopyradines, providing the aldehyde products in good to moderate yields (Scheme 48). Under slightly different conditions, N-allylamidines provided the imidizolyl aldehyde products in more modest yields.
Recently, Zhu and co-workers treated N-(1-phenylallyl)-2- aminopyrazine with a copper(II) species and oxygen, anticipating a copper-promoted C— H amination of the double bond and oxidative aromatization."°’ However, a heterocyclic aldehyde was formed instead via an aminooxygenation process. This reaction was found to be general for a wide range of N- allyl-2-aminopyradines, providing the aldehyde products in good to moderate yields (Scheme 48). Under slightly different conditions, N-allylamidines provided the imidizolyl aldehyde products in more modest yields.
Scheme $2. Oxidative Diacetoxylation of Butadiene
Scheme $2. Oxidative Diacetoxylation of Butadiene
Scheme 49. Aminooxygenation Mechanism of N-Allyl-2- aminopyridines substrate and the requirement of several equivalents of pivalic acid.
Scheme 49. Aminooxygenation Mechanism of N-Allyl-2- aminopyridines substrate and the requirement of several equivalents of pivalic acid.
Scheme 56. Evolution of the Glaser—Hay Process The bidentate tertiary amine ligand N,N,N’,N’-tetramethyle- thylenediamine (TMEDA) provides enhanced solubility to the reactive copper intermediate, and the classical Hay conditions (CuCl, TMEDA, and oxygen) continue to be widely used. These mild conditions typically provide high yields. The reaction conditions permit many functional groups to be employed including unprotected hydroxyls (see Scheme 56, above). The poor ability of alkynes to transfer from copper in conjugate addition means that enones and carbonyls are also compatible. Homocoupling predominates even with mixtures of alkynes. The appearance of an Organic Syntheses description is a manifestation of the high reliability of the process (Scheme eae
Scheme 56. Evolution of the Glaser—Hay Process The bidentate tertiary amine ligand N,N,N’,N’-tetramethyle- thylenediamine (TMEDA) provides enhanced solubility to the reactive copper intermediate, and the classical Hay conditions (CuCl, TMEDA, and oxygen) continue to be widely used. These mild conditions typically provide high yields. The reaction conditions permit many functional groups to be employed including unprotected hydroxyls (see Scheme 56, above). The poor ability of alkynes to transfer from copper in conjugate addition means that enones and carbonyls are also compatible. Homocoupling predominates even with mixtures of alkynes. The appearance of an Organic Syntheses description is a manifestation of the high reliability of the process (Scheme eae
Scheme 55. Oxygenation of Alkynes to a,f-Acetylenic Ketones While NHPI alone can catalyze the reaction of certain substrates, the addition of the copper catalyst significantly enhances reactivity, allowing for lower reaction temperatures, as well as playing a key role in the final oxidation of the initial propargylic alcohol to the ketone product. Presumably, the mechanism proceeds via formation of the NHPI radical (for example, see Scheme 6). 2.4.1. Propargylic Oxidation. Aerobic oxidation of propargylic substrates is complicated by competitive alkyne reaction pathways, as well as potential overoxidation to carboxylic acid products. One system that overcomes these challenges utilizes NHPI in conjunction with a copper(II) catalyst to selectively oxidize propargylic substrates to the corresponding conjugated carbonyl products (Scheme i
Scheme 55. Oxygenation of Alkynes to a,f-Acetylenic Ketones While NHPI alone can catalyze the reaction of certain substrates, the addition of the copper catalyst significantly enhances reactivity, allowing for lower reaction temperatures, as well as playing a key role in the final oxidation of the initial propargylic alcohol to the ketone product. Presumably, the mechanism proceeds via formation of the NHPI radical (for example, see Scheme 6). 2.4.1. Propargylic Oxidation. Aerobic oxidation of propargylic substrates is complicated by competitive alkyne reaction pathways, as well as potential overoxidation to carboxylic acid products. One system that overcomes these challenges utilizes NHPI in conjunction with a copper(II) catalyst to selectively oxidize propargylic substrates to the corresponding conjugated carbonyl products (Scheme i
Table 5. Glaser Hay Dimerization Reactions
Table 5. Glaser Hay Dimerization Reactions
Table 5. continued
Table 5. continued
Table 5. continued
Table 5. continued
Table 5. continued
Table 5. continued
Table 5. continued “Substrate coupled directly after deprotection from silyl-protected precursor. For cyclodimerization of a similar substrate with excess copper catalyst, see ref 210.
Table 5. continued “Substrate coupled directly after deprotection from silyl-protected precursor. For cyclodimerization of a similar substrate with excess copper catalyst, see ref 210.
Perhaps more than any other area, the Glaser—Hay coupling has become a critical process in supermolecular chemistry. The controlled formation of diacetylene linkages allows access to an array of well-defined molecular architectures such as molecular rods, macrocycles, and extended z-conjugated systems, '7* Possible applications of such advanced materials include nonlinear optical devices and molecular photochemical switches. Tykwinski and co-workers have explored extended m-conjugated materials based on the iso-polydiacetylene and iso- polytriacetylene linkages.” These unique systems, which lack Numerous dimerizations via Glaser—Hay coupling have been implemented (see Table 5). In the context of natural product synthesis, the method proved key in approaching the caryoynencins, which contain 1,3,5,7-octatetraynes and show potent antibacterial activity. Specifically, the conjugated polyynes are highly unstable, polymerizing readily, and present a significant synthetic challenge. The mild nature of Hay alkyne dimerization afforded the requisite tetrayne in high yield en route to the caryoynencins (Scheme $9).'*”
Perhaps more than any other area, the Glaser—Hay coupling has become a critical process in supermolecular chemistry. The controlled formation of diacetylene linkages allows access to an array of well-defined molecular architectures such as molecular rods, macrocycles, and extended z-conjugated systems, '7* Possible applications of such advanced materials include nonlinear optical devices and molecular photochemical switches. Tykwinski and co-workers have explored extended m-conjugated materials based on the iso-polydiacetylene and iso- polytriacetylene linkages.” These unique systems, which lack Numerous dimerizations via Glaser—Hay coupling have been implemented (see Table 5). In the context of natural product synthesis, the method proved key in approaching the caryoynencins, which contain 1,3,5,7-octatetraynes and show potent antibacterial activity. Specifically, the conjugated polyynes are highly unstable, polymerizing readily, and present a significant synthetic challenge. The mild nature of Hay alkyne dimerization afforded the requisite tetrayne in high yield en route to the caryoynencins (Scheme $9).'*”
methanolic cleavage of the more labile silyl-protecting group and ensuing Glaser—Hay cross-coupling with TMS-acetylene (see section 2.4.3). Treatment of the resulting TMS—diyne under similar deprotection/oxidation conditions affords the extended thiafulvene structure in good yield. Extended tetrathiafulvene-based molecules have received considerable attention due to their unique redox properties and potential use as organic conducting and nonlinear optical materials.'*’ An iterative Glaser—Hay process has been used to synthesize thiafulvene units with polyacetylene linkers (Scheme 61).'** The method first extends the initial monoalkyne by
methanolic cleavage of the more labile silyl-protecting group and ensuing Glaser—Hay cross-coupling with TMS-acetylene (see section 2.4.3). Treatment of the resulting TMS—diyne under similar deprotection/oxidation conditions affords the extended thiafulvene structure in good yield. Extended tetrathiafulvene-based molecules have received considerable attention due to their unique redox properties and potential use as organic conducting and nonlinear optical materials.'*’ An iterative Glaser—Hay process has been used to synthesize thiafulvene units with polyacetylene linkers (Scheme 61).'** The method first extends the initial monoalkyne by
More recently, the dibrominated iso-polytriacetylene has been used in studies toward the realization of carbyne.'*° Treatment with 2 equiv of n-BuLi triggers a Fritsch— Buttenberg—Wiechell rearrangement to form the silyl-protected triacetylene intermediate (Scheme 60). Subsequent silyl arene linkers, are assembled by Sonagashira coupling of vinyl triflates with 1-silylalkynes and Hay dimerization upon strategic silyl group removal. The products possess interesting structural, optical, and electronic properties.
More recently, the dibrominated iso-polytriacetylene has been used in studies toward the realization of carbyne.'*° Treatment with 2 equiv of n-BuLi triggers a Fritsch— Buttenberg—Wiechell rearrangement to form the silyl-protected triacetylene intermediate (Scheme 60). Subsequent silyl arene linkers, are assembled by Sonagashira coupling of vinyl triflates with 1-silylalkynes and Hay dimerization upon strategic silyl group removal. The products possess interesting structural, optical, and electronic properties.
Scheme 63. Substrates Used in Desilylation—Hay Intramolecular Macrocyclization
Scheme 63. Substrates Used in Desilylation—Hay Intramolecular Macrocyclization
“Substrate coupled directly after deprotection from silyl-protected precursor.
“Substrate coupled directly after deprotection from silyl-protected precursor.
Scheme 64. Hay Coupling of Stable Organometallic Adducts To Form Polymers Scheme 65. Copolymerization with Biphasic Glaser—Hay Conditions
Scheme 64. Hay Coupling of Stable Organometallic Adducts To Form Polymers Scheme 65. Copolymerization with Biphasic Glaser—Hay Conditions
“Unless noted, a vast excess (10—90 equiv) of the end-cap alkyne was used. ’Substrate coupled directly after deprotection from silyl-protected precursor. “Performing the reaction with 1 equiv of phenylacetylene afforded nearly equal amounts of end-capped monomer, dimer, and trimer. “For related examples of enediyne oligomerization in lower yields, see ref 214. Table 7. Glaser—Hay Cross-Coupling Reactions with End-Caps
“Unless noted, a vast excess (10—90 equiv) of the end-cap alkyne was used. ’Substrate coupled directly after deprotection from silyl-protected precursor. “Performing the reaction with 1 equiv of phenylacetylene afforded nearly equal amounts of end-capped monomer, dimer, and trimer. “For related examples of enediyne oligomerization in lower yields, see ref 214. Table 7. Glaser—Hay Cross-Coupling Reactions with End-Caps
Scheme 68. Tandem Asymmetric Oxidative Biaryl Coupling/ Glaser—Hay Coupling Scheme 69. Mechanism of the Hay Version of Alkyne Dimerization
Scheme 68. Tandem Asymmetric Oxidative Biaryl Coupling/ Glaser—Hay Coupling Scheme 69. Mechanism of the Hay Version of Alkyne Dimerization
Scheme 67. Oligomerization and End-Capping of a Platinum Octayne via Hay Coupling stoichiometry. Many reports have exploited this concept by employing a vast excess of a less costly alkyne component (see Table 7).''17° A general method for the cross-coupling of arylacetylenes was recently studied by Kesavan and Balara- man.” After screening a variety of copper catalysts and bases for the homocoupling of phenylacetylene, the optimized conditions were tested on the cross-coupling of a series of simple aryl and alkyl acetyelenes (Scheme 71). Good to excellent yields of the cross-coupled diynes were afforded using Cu(OAc),-H,O, piperidine, and air at room temperature. However, a 5-fold excess of one of the alkyne partners was required, and as expected, large amounts of homodimer were also formed. a * ae am: pr
Scheme 67. Oligomerization and End-Capping of a Platinum Octayne via Hay Coupling stoichiometry. Many reports have exploited this concept by employing a vast excess of a less costly alkyne component (see Table 7).''17° A general method for the cross-coupling of arylacetylenes was recently studied by Kesavan and Balara- man.” After screening a variety of copper catalysts and bases for the homocoupling of phenylacetylene, the optimized conditions were tested on the cross-coupling of a series of simple aryl and alkyl acetyelenes (Scheme 71). Good to excellent yields of the cross-coupled diynes were afforded using Cu(OAc),-H,O, piperidine, and air at room temperature. However, a 5-fold excess of one of the alkyne partners was required, and as expected, large amounts of homodimer were also formed. a * ae am: pr
Scheme 70. General Example of Cadiot—Chodkiewicz Heterocoupling
Scheme 70. General Example of Cadiot—Chodkiewicz Heterocoupling
terminal alkyne unit with a variety of functionalized alkynes via copper-catalyzed coupling. Specifically, alkynyl-modified fluo- rescein, biotin, and anthroquinone tags were coupled with the resin-bound substrate and subsequently deprotected with concentrated ammonium hydroxide (Scheme 73).
terminal alkyne unit with a variety of functionalized alkynes via copper-catalyzed coupling. Specifically, alkynyl-modified fluo- rescein, biotin, and anthroquinone tags were coupled with the resin-bound substrate and subsequently deprotected with concentrated ammonium hydroxide (Scheme 73).
Scheme 76. Oxidative Amination of Terminal Alkynes
Scheme 76. Oxidative Amination of Terminal Alkynes
homodimer proved to be highly favorable and was suppressed by slow addition of the alkyne to the trifluoromethyl anion, “CuCF;”, which was generated in situ by combining TMS-CF, with Cul/phenanthroline and KF. The phenanthroline profoundly affects the product distribution. Its role may include stabilization of the CuCF, adduct by chelation and increasing the electron density at copper to promote Cu(II) or Cu(II) formation. In this case, the replacement of air with O, shifted the outcome to the homodimer entirely. While some oxygen is required for the oxidation portion, a high concentration appears to quench the “CuCF,” intermediate.
homodimer proved to be highly favorable and was suppressed by slow addition of the alkyne to the trifluoromethyl anion, “CuCF;”, which was generated in situ by combining TMS-CF, with Cul/phenanthroline and KF. The phenanthroline profoundly affects the product distribution. Its role may include stabilization of the CuCF, adduct by chelation and increasing the electron density at copper to promote Cu(II) or Cu(II) formation. In this case, the replacement of air with O, shifted the outcome to the homodimer entirely. While some oxygen is required for the oxidation portion, a high concentration appears to quench the “CuCF,” intermediate.
For the direct cross-coupling of alkynes, the strategy of using an excess of one partner is the state of the art. However, coupling of alkynyl acids and terminal alkynes via a copper- catalyzed decarboxylative cross-coupling also leads to unsym- metric diynes with high efficiency (Scheme 74).7*! In
For the direct cross-coupling of alkynes, the strategy of using an excess of one partner is the state of the art. However, coupling of alkynyl acids and terminal alkynes via a copper- catalyzed decarboxylative cross-coupling also leads to unsym- metric diynes with high efficiency (Scheme 74).7*! In
Scheme 74. Decarboxylative Cross-Coupling of Alkynyl Acids and Alkynes
Scheme 74. Decarboxylative Cross-Coupling of Alkynyl Acids and Alkynes
Scheme 77. Oxidative Cross-Coupling of Alkynes with H- Phosphonates found to facilitate the reaction. A large variety of aryl and alkyl alkynes are tolerated under the reaction conditions. Similarly, complex phosphonates were incorporated in good yield; secondary phosphine oxides, however, were oxidized to the phosphinic acid. Notably, an excess of one of the coupling partners is not necessary in the reaction.
Scheme 77. Oxidative Cross-Coupling of Alkynes with H- Phosphonates found to facilitate the reaction. A large variety of aryl and alkyl alkynes are tolerated under the reaction conditions. Similarly, complex phosphonates were incorporated in good yield; secondary phosphine oxides, however, were oxidized to the phosphinic acid. Notably, an excess of one of the coupling partners is not necessary in the reaction.
Scheme 78. Possible Alkyne—Anion Coupling Mechanisms
Scheme 78. Possible Alkyne—Anion Coupling Mechanisms
Scheme 79. Halosulfenylation of Alkenes
Scheme 79. Halosulfenylation of Alkenes
Scheme 83. Tandem Copper-Catalyzed Cycloisomerization, Oxidation of Bispropargylic Esters
Scheme 83. Tandem Copper-Catalyzed Cycloisomerization, Oxidation of Bispropargylic Esters
Scheme 84. Oxidative Formation of 2-Acylfurans from Bispropargylic Esters Scheme 85. Intermolecular Oxidative Formation of 2- Acylfurans
Scheme 84. Oxidative Formation of 2-Acylfurans from Bispropargylic Esters Scheme 85. Intermolecular Oxidative Formation of 2- Acylfurans
Scheme 82. Oxidative Halosulfonylation of Alkynes
Scheme 82. Oxidative Halosulfonylation of Alkynes
Scheme 89. Carbooxygenation of N-Propargyl Enamine Carboxylates To Afford 4-Benzoylpyrroles Scheme 90. Tandem Oxycupration/Oxadiazole Coupling with Superstoichiometric Copper
Scheme 89. Carbooxygenation of N-Propargyl Enamine Carboxylates To Afford 4-Benzoylpyrroles Scheme 90. Tandem Oxycupration/Oxadiazole Coupling with Superstoichiometric Copper
Scheme 88. Mechanism for the Oxidative Formation of 1,4- Naphthoquinones
Scheme 88. Mechanism for the Oxidative Formation of 1,4- Naphthoquinones
stoichiometric copper, the use of catalytic copper has been demonstrated to provide products in slightly lower yield when using MnO, as a co-oxidant (Scheme 90b). Even with MnO,,
stoichiometric copper, the use of catalytic copper has been demonstrated to provide products in slightly lower yield when using MnO, as a co-oxidant (Scheme 90b). Even with MnO,,
Scheme 86. Possible Mechanism of the Intermolecular Oxidative Formation of 2-Acylfurans Scheme 87. Oxidative Cyclization To Form 1,4- Naphthoquinones
Scheme 86. Possible Mechanism of the Intermolecular Oxidative Formation of 2-Acylfurans Scheme 87. Oxidative Cyclization To Form 1,4- Naphthoquinones
Scheme 92. Tandem Oxidative Amination/Diketonization of Primary Anilines and Terminal Alkynes
Scheme 92. Tandem Oxidative Amination/Diketonization of Primary Anilines and Terminal Alkynes
Scheme 93. Possible Mechanism for Oxidative Amination/ Diketonization
Scheme 93. Possible Mechanism for Oxidative Amination/ Diketonization
Scheme 95. Postulated Mechanism for the Copper-Mediated Oxygenation of Benzene oxidation and rearomatization affords the phenol product. Alternatively, formation of hydroquinone byproduct can occur through reaction of the radical intermediate with molecular oxygen, as observed in an '8O, labeling study.**° Additional support for this mechanism was found in the high selectivity of phenol in the absence of oxygen and using hydrogen peroxide as the hydroxyl radical precursor.
Scheme 95. Postulated Mechanism for the Copper-Mediated Oxygenation of Benzene oxidation and rearomatization affords the phenol product. Alternatively, formation of hydroquinone byproduct can occur through reaction of the radical intermediate with molecular oxygen, as observed in an '8O, labeling study.**° Additional support for this mechanism was found in the high selectivity of phenol in the absence of oxygen and using hydrogen peroxide as the hydroxyl radical precursor.
nucleophilic arene onto Cu(OCOCF;), to form an aryl— copper(II) species and an equivalent of CF;CO,H. Trans- metalation with the arylboronic acid followed by oxidatively induced reductive elimination then affords the biaryl product and a reduced copper species. Stoichiometric amounts of copper were necessary for useful yields, as low turnover was observed with catalytic copper. Other copper salts, including very electrophilic Cu(OTf),, were found to be ineffective for the transformation. Interestingly, no homocoupling of either arene or boronic acid substrates were detected (for homocoupling of arylboronic acids, see section 3.3.5.). A range of biaryl products was afforded through this method in moderate to good yields. Notably, multiple C—H bond arylations were possible when indoles or pyrroles were used as the arene nucleophile (right half of Scheme 97).
nucleophilic arene onto Cu(OCOCF;), to form an aryl— copper(II) species and an equivalent of CF;CO,H. Trans- metalation with the arylboronic acid followed by oxidatively induced reductive elimination then affords the biaryl product and a reduced copper species. Stoichiometric amounts of copper were necessary for useful yields, as low turnover was observed with catalytic copper. Other copper salts, including very electrophilic Cu(OTf),, were found to be ineffective for the transformation. Interestingly, no homocoupling of either arene or boronic acid substrates were detected (for homocoupling of arylboronic acids, see section 3.3.5.). A range of biaryl products was afforded through this method in moderate to good yields. Notably, multiple C—H bond arylations were possible when indoles or pyrroles were used as the arene nucleophile (right half of Scheme 97).
Scheme 98. Copper-Catalyzed Oxidative Halogenation of Non-phenols Notably, both LiBr and LiCl can be utilized to regioselectively afford the corresponding aryl bromide or chloride, although more forcing conditions are required in the latter case. As previously described, the mechanism for bromination is believed to operate through formation of Br, and electrophilic aromatic substitution. Alternatively, chlorination is postulated to occur through a single-electron oxidation of the arene and subsequent reaction with a chlorine source. In both cases, the possibility of a copper(III) intermediate cannot be definitively ruled out. A more recent report by Stahl and co-workers reports the efficient substitution of electron-rich arenes with halides using catalytic copper(II) halides and oxygen (Scheme 98).”
Scheme 98. Copper-Catalyzed Oxidative Halogenation of Non-phenols Notably, both LiBr and LiCl can be utilized to regioselectively afford the corresponding aryl bromide or chloride, although more forcing conditions are required in the latter case. As previously described, the mechanism for bromination is believed to operate through formation of Br, and electrophilic aromatic substitution. Alternatively, chlorination is postulated to occur through a single-electron oxidation of the arene and subsequent reaction with a chlorine source. In both cases, the possibility of a copper(III) intermediate cannot be definitively ruled out. A more recent report by Stahl and co-workers reports the efficient substitution of electron-rich arenes with halides using catalytic copper(II) halides and oxygen (Scheme 98).”
Scheme 99. Aqueous Copper-Catalyzed Oxidative Bromination of Non-phenols under the mild reaction conditions, whereas arenes containing electron-withdrawing substituents, such as chlorobenzene or nitrobenzene, were unreactive. The reported method offers an environmentally benign and atom-economical approach for halogenation of arenes.
Scheme 99. Aqueous Copper-Catalyzed Oxidative Bromination of Non-phenols under the mild reaction conditions, whereas arenes containing electron-withdrawing substituents, such as chlorobenzene or nitrobenzene, were unreactive. The reported method offers an environmentally benign and atom-economical approach for halogenation of arenes.
Scheme 103. Arene Hydroxylation of a Bis(s-oxo)dicopper Complex precedent of directed oxidative functionalization of arenes using a 2-pyridyl moiety.
Scheme 103. Arene Hydroxylation of a Bis(s-oxo)dicopper Complex precedent of directed oxidative functionalization of arenes using a 2-pyridyl moiety.
Scheme 102. Proposed Mechanism for Arene Thiolation
Scheme 102. Proposed Mechanism for Arene Thiolation
Scheme 101. Copper-Catalyzed Oxidative Thiolation of Electron-Rich Arenes
Scheme 101. Copper-Catalyzed Oxidative Thiolation of Electron-Rich Arenes
Scheme 104. Copper-Catalyzed Directed Chlorination of 2- Pyridylarenes
Scheme 104. Copper-Catalyzed Directed Chlorination of 2- Pyridylarenes
the nearby CuCl, accounts for the regioselection as well as the fact that biphenyl does not react under these conditions. The reaction is first order in substrate and copper catalyst, consistent with rate-determining formation of a radical cation if formation of the pyridyl complex is not highly favorable, a likely event since the reaction is conducted under acidic conditions (HCI produced from dichloroethane). Additional evidence for the proposed mechanism is found in the absence of an isotope effect when using an ortho-deuterated substrate as well as the slower reactivity of electron-poor arenes.
the nearby CuCl, accounts for the regioselection as well as the fact that biphenyl does not react under these conditions. The reaction is first order in substrate and copper catalyst, consistent with rate-determining formation of a radical cation if formation of the pyridyl complex is not highly favorable, a likely event since the reaction is conducted under acidic conditions (HCI produced from dichloroethane). Additional evidence for the proposed mechanism is found in the absence of an isotope effect when using an ortho-deuterated substrate as well as the slower reactivity of electron-poor arenes.
Catalytic amidation of 2-phenylpyridine has been described with a variety of nitrogen nucleophiles using Cu(OAc), and oxygen (Scheme 110). 66 Notably, the reaction is completely regioselective as well as selective for the monosubstituted products. Solvent was observed to be critical to achieving catalytic turnover, with a mixture of anisole and small amounts of DMSO able to overcome product inhibition. Sulfonamides, carboxamides, and p-nitroaniline were found to serve as
Catalytic amidation of 2-phenylpyridine has been described with a variety of nitrogen nucleophiles using Cu(OAc), and oxygen (Scheme 110). 66 Notably, the reaction is completely regioselective as well as selective for the monosubstituted products. Solvent was observed to be critical to achieving catalytic turnover, with a mixture of anisole and small amounts of DMSO able to overcome product inhibition. Sulfonamides, carboxamides, and p-nitroaniline were found to serve as
Scheme 108. Directed Oxidative Acyloxylation Using Acyl Chlorides authors observed high ortho-chlorination yields when the added base was changed from ¢-BuOK to Li,CO, (Scheme 109). This change in reactivity is not yet fully understood.
Scheme 108. Directed Oxidative Acyloxylation Using Acyl Chlorides authors observed high ortho-chlorination yields when the added base was changed from ¢-BuOK to Li,CO, (Scheme 109). This change in reactivity is not yet fully understood.
Scheme 107. Directed Oxidative Acyloxylation of 2- Pyridylarenes
Scheme 107. Directed Oxidative Acyloxylation of 2- Pyridylarenes
Scheme 113. Proposed Mechanism for Directed ortho- Nitration with a Pyridyl Directing Group then proceed through a four-centered transition state involving aryl C-NO, bond formation with concomitant generation of a Cu(II)(OH)(OAc) species. The proposed process, however, starts and ends with copper(II) and does not account for the necessity of dioxygen even though a different product distribution is seen under a nitrogen atmosphere. Further mechanistic studies are needed to elucidate the exact role of dioxygen as well as the significant solvent effects.
Scheme 113. Proposed Mechanism for Directed ortho- Nitration with a Pyridyl Directing Group then proceed through a four-centered transition state involving aryl C-NO, bond formation with concomitant generation of a Cu(II)(OH)(OAc) species. The proposed process, however, starts and ends with copper(II) and does not account for the necessity of dioxygen even though a different product distribution is seen under a nitrogen atmosphere. Further mechanistic studies are needed to elucidate the exact role of dioxygen as well as the significant solvent effects.
successful amidating reagents. Variation of the arylpyridine substrate was not reported. A similar mechanism to that outlined in Scheme 106 is proposed.
successful amidating reagents. Variation of the arylpyridine substrate was not reported. A similar mechanism to that outlined in Scheme 106 is proposed.
Scheme 114. Copper-Catalyzed Oxidative Formation of Phenanthridines
Scheme 114. Copper-Catalyzed Oxidative Formation of Phenanthridines
Scheme 111. Directed ortho-Nitration Using a Pyridyl Directing Group was found to be critical in developing a catalytic process. Examination of nitrating sources showed AgNO, to be nearly as effective, whereas Fe(NO;), provided no product, and NaNO, instead gave rise to the ortho-hydroxylated product. Mono- ortho-nitrated products were afforded in moderate to excellent yield for a variety of substrates using this method. Replacement of the 2-pyridyl group with pyrimidine, pyrazole, and thiazole did provide the ortho-nitration product but in lower efficiencies (Scheme 112). In contrast, 3-pyridyl- and 4-pyridylarenes did not yield any of the product, demonstrating the necessity for a proximal nitrogen directing group.
Scheme 111. Directed ortho-Nitration Using a Pyridyl Directing Group was found to be critical in developing a catalytic process. Examination of nitrating sources showed AgNO, to be nearly as effective, whereas Fe(NO;), provided no product, and NaNO, instead gave rise to the ortho-hydroxylated product. Mono- ortho-nitrated products were afforded in moderate to excellent yield for a variety of substrates using this method. Replacement of the 2-pyridyl group with pyrimidine, pyrazole, and thiazole did provide the ortho-nitration product but in lower efficiencies (Scheme 112). In contrast, 3-pyridyl- and 4-pyridylarenes did not yield any of the product, demonstrating the necessity for a proximal nitrogen directing group.
electron oxidation of the aryl ring to form a radical cation. Attack of the radical on copper can form a metallocyclic copper(II) species, as shown in pathway A. Reductive elimination then affords product and a reduced copper. In pathway B, the radical cation directly reacts with the nitrogen of the amidine to displace Cu(I)OAc and benzimidazole product upon rearomatization. Finally, pathway C invokes a copper
electron oxidation of the aryl ring to form a radical cation. Attack of the radical on copper can form a metallocyclic copper(II) species, as shown in pathway A. Reductive elimination then affords product and a reduced copper. In pathway B, the radical cation directly reacts with the nitrogen of the amidine to displace Cu(I)OAc and benzimidazole product upon rearomatization. Finally, pathway C invokes a copper
copper(II) species with the resulting N-H imine, intramolecular electrophilic aromatic substitution can ultimately form a copper(II) metallocycle. Molecular oxygen may help facilitate reductive elimination of the cyclized product, in addition to reoxidation of the copper species to close the catalytic cycle.
copper(II) species with the resulting N-H imine, intramolecular electrophilic aromatic substitution can ultimately form a copper(II) metallocycle. Molecular oxygen may help facilitate reductive elimination of the cyclized product, in addition to reoxidation of the copper species to close the catalytic cycle.
Scheme 117. Amidine-Directed Oxidative Intramolecular C-H Insertion into Arenes this case, aryl amidines serve as effective directing groups for oxidative formation of the aryl! C—N bond. Successful cyclization was only observed with amidines containing hindered R’ substituents. The described method employs inexpensive reagents and produces only water as byproduct.
Scheme 117. Amidine-Directed Oxidative Intramolecular C-H Insertion into Arenes this case, aryl amidines serve as effective directing groups for oxidative formation of the aryl! C—N bond. Successful cyclization was only observed with amidines containing hindered R’ substituents. The described method employs inexpensive reagents and produces only water as byproduct.
Electronic effects from substituents on the starting anilide greatly affected the rate and yield, with electron-rich substrates reacting much faster. In line with this observation, the authors propose initial coordination of the copper catalyst to the amide and subsequent electrophilic aromatic substitution to form a cyclometalated copper(II) species (see Scheme 118, path A). Reductive elimination and reoxidation of the copper provides the cyclized product and closes the catalytic cycle.
Electronic effects from substituents on the starting anilide greatly affected the rate and yield, with electron-rich substrates reacting much faster. In line with this observation, the authors propose initial coordination of the copper catalyst to the amide and subsequent electrophilic aromatic substitution to form a cyclometalated copper(II) species (see Scheme 118, path A). Reductive elimination and reoxidation of the copper provides the cyclized product and closes the catalytic cycle.
Scheme 122. Arene Functionalization of a Copper(III)— Azacalix[1]arene[3]pyridine Complex
Scheme 122. Arene Functionalization of a Copper(III)— Azacalix[1]arene[3]pyridine Complex
azacalixaromatics using a variety of nucleophiles including halide, cyanide, thiocyanide, carboxylate, alkoxide, and phen- oxide (Scheme 122).7”*
azacalixaromatics using a variety of nucleophiles including halide, cyanide, thiocyanide, carboxylate, alkoxide, and phen- oxide (Scheme 122).7”*
Scheme 123. Catalytic C-N and C—O Functionalization of a Triazamacrocyclic Arene
Scheme 123. Catalytic C-N and C—O Functionalization of a Triazamacrocyclic Arene
Scheme 119. Directed Oxidative Cyclization of Acylanilines Coordinating groups at the meta-position, such as acetate, 2- pyrrolidinone, or pyrazole groups, also direct the C—H insertion and selectively provide the more hindered 2,7- substituted benzoxazoles (Scheme 120); the observed selectivity is attributed to the formation of a doubly coordinated copper intermediate.
Scheme 119. Directed Oxidative Cyclization of Acylanilines Coordinating groups at the meta-position, such as acetate, 2- pyrrolidinone, or pyrazole groups, also direct the C—H insertion and selectively provide the more hindered 2,7- substituted benzoxazoles (Scheme 120); the observed selectivity is attributed to the formation of a doubly coordinated copper intermediate.
Scheme 128. ortho-Hydroxylation of Toluic Acid Isomers
Scheme 128. ortho-Hydroxylation of Toluic Acid Isomers
affords a copper(III) arene intermediate, as well as a copper(I) species that can be oxidized by oxygen to reenter the cycle. After ligand exchange with the nucleophile, the copper(IIL) species undergoes reductive elimination to afford the function- alized arene product. In these transformations, oxygen acts as the terminal oxidant to regenerate copper(II) from copper(I) produced from both disproportionation and reductive elimi- nation processes.
affords a copper(III) arene intermediate, as well as a copper(I) species that can be oxidized by oxygen to reenter the cycle. After ligand exchange with the nucleophile, the copper(IIL) species undergoes reductive elimination to afford the function- alized arene product. In these transformations, oxygen acts as the terminal oxidant to regenerate copper(II) from copper(I) produced from both disproportionation and reductive elimi- nation processes.
Scheme 127. Oxidation of Benzoic Acids To Form Salicylic Acids Application of the process to toluic acids also led to the expected phenolic products (Scheme 128).?°°? Slightly lower yields are observed due to competitive oxidation of the benzylic position and formation of ester products. Significantly, both
Scheme 127. Oxidation of Benzoic Acids To Form Salicylic Acids Application of the process to toluic acids also led to the expected phenolic products (Scheme 128).?°°? Slightly lower yields are observed due to competitive oxidation of the benzylic position and formation of ester products. Significantly, both
Scheme 126. Oxidative Decarboxylation in a High- Temperature Water Continuous Flow System Under stringent aprotic conditions, the process could be conducted without decarboxylation to afford the salicylic acid intermediate (Scheme 127).’** However, conversions were low, and only one example was shown to perform with catalytic copper in the presence of oxygen.
Scheme 126. Oxidative Decarboxylation in a High- Temperature Water Continuous Flow System Under stringent aprotic conditions, the process could be conducted without decarboxylation to afford the salicylic acid intermediate (Scheme 127).’** However, conversions were low, and only one example was shown to perform with catalytic copper in the presence of oxygen.
Scheme 130. ortho-Hydroxylation of N-Methylalanine Benzamides
Scheme 130. ortho-Hydroxylation of N-Methylalanine Benzamides
Scheme 133. Copper-Catalyzed Coupling of Azoles with Acidic Nitrogen Nucleophiles this process was suppressed by addition of 5 equiv of coupling partner. In addition, the coupling of a small number of tetrafluorobenzenes with 2-pyrrolidinone was achieved in modest yield (Scheme 134).
Scheme 133. Copper-Catalyzed Coupling of Azoles with Acidic Nitrogen Nucleophiles this process was suppressed by addition of 5 equiv of coupling partner. In addition, the coupling of a small number of tetrafluorobenzenes with 2-pyrrolidinone was achieved in modest yield (Scheme 134).
Scheme 135. Copper-Catalyzed Sulfoximination of Azoles contrast to the preceding reactions, the present transformation is conducted at room temperature, and the nitrogen nucleophile is used as the limiting reagent. Other copper salts such as Cu(OTf), or Cul could be used with similar results, while addition of amine ligands such as TMEDA showed a deleterious effect. Good yields were achieved with 1,3,4- oxadiazoles, benzoxazoles, and benzothiazoles, but other
Scheme 135. Copper-Catalyzed Sulfoximination of Azoles contrast to the preceding reactions, the present transformation is conducted at room temperature, and the nitrogen nucleophile is used as the limiting reagent. Other copper salts such as Cu(OTf), or Cul could be used with similar results, while addition of amine ligands such as TMEDA showed a deleterious effect. Good yields were achieved with 1,3,4- oxadiazoles, benzoxazoles, and benzothiazoles, but other
Scheme 132. Copper-Catalyzed Coupling of Azoles with Amine Nucleophiles
Scheme 132. Copper-Catalyzed Coupling of Azoles with Amine Nucleophiles
Scheme 134. Copper-Mediated Coupling of Polyfluoroarenes with 2-Pyrrolidinone Coupling of azoles with sulfoximines using catalytic copper catalyst under air has been reported (Scheme 135).””° In sharp
Scheme 134. Copper-Mediated Coupling of Polyfluoroarenes with 2-Pyrrolidinone Coupling of azoles with sulfoximines using catalytic copper catalyst under air has been reported (Scheme 135).””° In sharp
Scheme 131. Possible Mechanism for ortho-Hydroxylation of N-Benzoyl-2-methylalanine classes: nitrogen nucleophiles (amines, anilines, amides, sulfonamides, and sulfoximines; see also sections 8 and 9), thiols (see also section 12), and alkynes (see also section 2.4.3). Alternately, homocoupling can occur to yield biaryl compounds via C—C bond formation. To date, arenes able to undergo this type of reactivity are largely limited to azoles and polyfluor- arenes, with the majority of reports focusing on the former.
Scheme 131. Possible Mechanism for ortho-Hydroxylation of N-Benzoyl-2-methylalanine classes: nitrogen nucleophiles (amines, anilines, amides, sulfonamides, and sulfoximines; see also sections 8 and 9), thiols (see also section 12), and alkynes (see also section 2.4.3). Alternately, homocoupling can occur to yield biaryl compounds via C—C bond formation. To date, arenes able to undergo this type of reactivity are largely limited to azoles and polyfluor- arenes, with the majority of reports focusing on the former.
Scheme 136. Copper-Catalyzed Sulfoximination of Polyfluoroarenes The coupling of benzoxazoles with secondary amines has recently been described to occur under acidic conditions (Scheme 137).””’ The reaction uses Cu(OAc), and oxygen and
Scheme 136. Copper-Catalyzed Sulfoximination of Polyfluoroarenes The coupling of benzoxazoles with secondary amines has recently been described to occur under acidic conditions (Scheme 137).””’ The reaction uses Cu(OAc), and oxygen and
Scheme 137. Coupling of Benzoxazoles and Secondary Amines under Acidic Conditions relatively mild heating to afford the coupled products in good yield. Other heteroarenes or nitrogen nucleophiles were unsuccessful. While an acid additive was not crucial for reaction efficiency, addition of 2 equiv of acetic acid slightly increased the yield rather than having any deleterious effect.
Scheme 137. Coupling of Benzoxazoles and Secondary Amines under Acidic Conditions relatively mild heating to afford the coupled products in good yield. Other heteroarenes or nitrogen nucleophiles were unsuccessful. While an acid additive was not crucial for reaction efficiency, addition of 2 equiv of acetic acid slightly increased the yield rather than having any deleterious effect.
Scheme 138. Decarbonylation and Oxidative Coupling of Benzoxazoles with Formamides
Scheme 138. Decarbonylation and Oxidative Coupling of Benzoxazoles with Formamides
Scheme 142. Catalytic Oxidative Thiolation of Benzoxazoles with Disulfides
Scheme 142. Catalytic Oxidative Thiolation of Benzoxazoles with Disulfides
Scheme 140. Copper/TEMPO Catalyzed C—H Insertion into Perhaloarenes Scheme 141. Catalytic Oxidative Thiolation of Benzoxazoles with Thiophenols sulfide nucleophilicity and oxidizability as important consid- erations.
Scheme 140. Copper/TEMPO Catalyzed C—H Insertion into Perhaloarenes Scheme 141. Catalytic Oxidative Thiolation of Benzoxazoles with Thiophenols sulfide nucleophilicity and oxidizability as important consid- erations.
Scheme 144. Cul/Bipyridyl-Mediated Thiolation of Azoles with Alkyl and Aryl Thiols indoles also successfully afforded the thioether products. Similar to the method in Scheme 143, an oxygen atmosphere decreased reaction efficiency. However, use of oxygen/nitrogen mixes with oxygen percentages lower than that of air gave significantly less product. The particular sensitivity to oxygen was attributed to facile disulfide byproduct formation.
Scheme 144. Cul/Bipyridyl-Mediated Thiolation of Azoles with Alkyl and Aryl Thiols indoles also successfully afforded the thioether products. Similar to the method in Scheme 143, an oxygen atmosphere decreased reaction efficiency. However, use of oxygen/nitrogen mixes with oxygen percentages lower than that of air gave significantly less product. The particular sensitivity to oxygen was attributed to facile disulfide byproduct formation.
Scheme 148. Cross-Coupling of Alkynes with 5- Aryloxadiazoles
Scheme 148. Cross-Coupling of Alkynes with 5- Aryloxadiazoles
Scheme 145. Oxidative Coupling of Polyfluoroarenes with Aryl and Heteroaryl Alkynes
Scheme 145. Oxidative Coupling of Polyfluoroarenes with Aryl and Heteroaryl Alkynes
Scheme 147. Cross-Coupling of Alkynes with 1,3,4- Oxadiazoles although more forcing conditions were necessary and the products were formed in more modest yields (Scheme 148). In both cases, the alkyne was slowly added to an excess of heteroarene to minimize the favored Hay product. Use of
Scheme 147. Cross-Coupling of Alkynes with 1,3,4- Oxadiazoles although more forcing conditions were necessary and the products were formed in more modest yields (Scheme 148). In both cases, the alkyne was slowly added to an excess of heteroarene to minimize the favored Hay product. Use of
alkynes, with electron-rich substrates performing better than electron-poor substrates. Similar to the method in Scheme 145, an excess of polyfluoroarene is employed to promote cross- coupling over the Hay process.
alkynes, with electron-rich substrates performing better than electron-poor substrates. Similar to the method in Scheme 145, an excess of polyfluoroarene is employed to promote cross- coupling over the Hay process.
yields are observed for a variety of heteroarenes including benzimidazoles, thiazoles, benzothiazoles, oxazoles, and ben- zoxazoles with as little as 1 mol % CuCl with 2 mol % ligand. A screen of ligand structure revealed electron-donating groups on the pyridonate structure to be the most active. No cross- coupling of the ligand to afford the C—-N or C—O coupled products is reported.
yields are observed for a variety of heteroarenes including benzimidazoles, thiazoles, benzothiazoles, oxazoles, and ben- zoxazoles with as little as 1 mol % CuCl with 2 mol % ligand. A screen of ligand structure revealed electron-donating groups on the pyridonate structure to be the most active. No cross- coupling of the ligand to afford the C—-N or C—O coupled products is reported.
Scheme 153. Deprotonative Mechanism for the Copper- Catalyzed Coupling of Acidic Arenes with Nucleophiles
Scheme 153. Deprotonative Mechanism for the Copper- Catalyzed Coupling of Acidic Arenes with Nucleophiles
salt is unknown, the authors speculate that it serves as a base to form the bisazole—copper(II) species. Substitution at the 1- position of benzimidazoles proved important, because electron- withdrawing groups were not tolerated. This trend may suggest that coordination through the 3-nitrogen is necessary for reactivity.
salt is unknown, the authors speculate that it serves as a base to form the bisazole—copper(II) species. Substitution at the 1- position of benzimidazoles proved important, because electron- withdrawing groups were not tolerated. This trend may suggest that coordination through the 3-nitrogen is necessary for reactivity.
Scheme 151. Oxidative Dimerization of Azoles with Cu(OAc),
Scheme 151. Oxidative Dimerization of Azoles with Cu(OAc),
Scheme 149. Catalytic Cross-Coupling of Alkynes with 1,3,4- Oxadiazoles In the absence of other coupling partners, the formation of C-H insertion intermediates with copper and acidic arenes can occur twice. The resulting diaryl copper species can undergo reductive elimination to afford the corresponding homocou- pling product. For an example of the same reaction using strong base (ie., i-PrMgCl), see section 3.1.2.
Scheme 149. Catalytic Cross-Coupling of Alkynes with 1,3,4- Oxadiazoles In the absence of other coupling partners, the formation of C-H insertion intermediates with copper and acidic arenes can occur twice. The resulting diaryl copper species can undergo reductive elimination to afford the corresponding homocou- pling product. For an example of the same reaction using strong base (ie., i-PrMgCl), see section 3.1.2.
Scheme 154. Mechanistic Pathways for the Coupling of Polyfluoroarenes with Alkynes alkyne then forms the key aryl—copper(II)—alkyne complex, which undergoes reductive elimination to afford the product. Alternatively, copper(II)—alkyne formation may occur first. Ensuing deprotonation and coordination of either additional alkyne or perfluoroarene can afford the Glaser—Hay diyne or heterocoupled product, respectively. In certain cases, initial coordination of the nucleophile to copper may occur prior to arene. For example, in the coupling of azoles with thiols (Scheme 144), mechanistic investigations as well as DFT studies revealed the initial reactive species to be a copper— thiolate complex, rather than a copper—azole species.°°! A specific example of this ambivalent mode of reactivity can be seen in the heterocoupling of polyfluoroarenes with alkynes (Scheme 145). The reaction presumably proceeds via initial copper-facilitated deprotonation of the polyfluoroar- ene and formation of an aryl—copper(II) species (Scheme 154). Subsequent deprotonation and ligand exchange with the
Scheme 154. Mechanistic Pathways for the Coupling of Polyfluoroarenes with Alkynes alkyne then forms the key aryl—copper(II)—alkyne complex, which undergoes reductive elimination to afford the product. Alternatively, copper(II)—alkyne formation may occur first. Ensuing deprotonation and coordination of either additional alkyne or perfluoroarene can afford the Glaser—Hay diyne or heterocoupled product, respectively. In certain cases, initial coordination of the nucleophile to copper may occur prior to arene. For example, in the coupling of azoles with thiols (Scheme 144), mechanistic investigations as well as DFT studies revealed the initial reactive species to be a copper— thiolate complex, rather than a copper—azole species.°°! A specific example of this ambivalent mode of reactivity can be seen in the heterocoupling of polyfluoroarenes with alkynes (Scheme 145). The reaction presumably proceeds via initial copper-facilitated deprotonation of the polyfluoroar- ene and formation of an aryl—copper(II) species (Scheme 154). Subsequent deprotonation and ligand exchange with the
3.1.1. Anion Couplings Using Stoichiometric Copper. A seminal report by Whitesides and co-workers established that organolithiums readily undergo homocoupling after formation of a copper(I)—ate complex and oxidation with O, (eq 1).3"" In this instance, coupling of mixed ate complexes gave a mixture of products (eq 2). However, the homocoupling proved preparatively useful for the coupling of primary and secondary alkyl, vinyl, alkynyl, and aryl groups, while Grignard reagents and tertiary alkyl groups gave poorer yields (Scheme 157).
3.1.1. Anion Couplings Using Stoichiometric Copper. A seminal report by Whitesides and co-workers established that organolithiums readily undergo homocoupling after formation of a copper(I)—ate complex and oxidation with O, (eq 1).3"" In this instance, coupling of mixed ate complexes gave a mixture of products (eq 2). However, the homocoupling proved preparatively useful for the coupling of primary and secondary alkyl, vinyl, alkynyl, and aryl groups, while Grignard reagents and tertiary alkyl groups gave poorer yields (Scheme 157).
Scheme 159. Coupling of Tethered Diarylcyanocuprates Using Oxygen
Scheme 159. Coupling of Tethered Diarylcyanocuprates Using Oxygen
Scheme 164. Aryl Zinc Coupling with Catalytic Copper and a Co-oxidant
Scheme 164. Aryl Zinc Coupling with Catalytic Copper and a Co-oxidant
Scheme 161. Oxidative Diarylcyanocuprate Coupling en Route to Calphostin A
Scheme 161. Oxidative Diarylcyanocuprate Coupling en Route to Calphostin A
Scheme 162. Copper-Catalyzed Reaction of Aryl and Alkenyl Zincs with Oxygen
Scheme 162. Copper-Catalyzed Reaction of Aryl and Alkenyl Zincs with Oxygen
Scheme 167. Copper-Catalyzed Reaction of an Allyl Zinc with Oxygen Scheme 168. Boronic Acids in Copper-Catalyzed Oxidative Bond Formation with Oxygen, Nitrogen, and Sulfur Nucleophilic Substrates
Scheme 167. Copper-Catalyzed Reaction of an Allyl Zinc with Oxygen Scheme 168. Boronic Acids in Copper-Catalyzed Oxidative Bond Formation with Oxygen, Nitrogen, and Sulfur Nucleophilic Substrates
Scheme 169. Copper-Catalyzed Coupling of Arylboronic Acids with Azaheterocycles and optimized for the cross-coupling reaction of aryl boronic acids with imidazoles. While the copper-catalyzed N-arylations with the related aryl—lead species had been reported earlier, the reactions of the boronic acids proceeded under milder conditions and without the use of toxic lead species.*”* 3.3.1. C-N Bond Formation. A major advance in the field of oxidative coupling with boronic acids was reported by Collman and co-workers.**! Recognizing that the readily available Cu(OH)CI(TMEDA) catalyst had been successfully employed in aerobic oxidative coupling of 2-naphthols,”” the authors employed this same catalyst in this oxidative trans- formation leading to a copper-catalyzed modified Ullmann reaction (Scheme 169). This system was successfully employed
Scheme 169. Copper-Catalyzed Coupling of Arylboronic Acids with Azaheterocycles and optimized for the cross-coupling reaction of aryl boronic acids with imidazoles. While the copper-catalyzed N-arylations with the related aryl—lead species had been reported earlier, the reactions of the boronic acids proceeded under milder conditions and without the use of toxic lead species.*”* 3.3.1. C-N Bond Formation. A major advance in the field of oxidative coupling with boronic acids was reported by Collman and co-workers.**! Recognizing that the readily available Cu(OH)CI(TMEDA) catalyst had been successfully employed in aerobic oxidative coupling of 2-naphthols,”” the authors employed this same catalyst in this oxidative trans- formation leading to a copper-catalyzed modified Ullmann reaction (Scheme 169). This system was successfully employed
See also section 2.5.4 for functionalization of acidic arenes under less basic conditions (conjugate acid pK, < 18). In these cases, similar mechanisms are proposed to those outlined there except that the aryl anion is not preformed. Rather, deprotonation is closely coupled to copper coordination. Reasoning that this phenol arose from trapping of the in situ formed aryl lithium with oxygen, other bases were investigated. Ultimately, it was found that hindered amide anions with LiCl and/or ZnCl, additives gave rise to an aryl anion species that was less prone to oxygenation and more likely to form a copper adduct that would undergo oxidative coupling (Scheme 166).°17
See also section 2.5.4 for functionalization of acidic arenes under less basic conditions (conjugate acid pK, < 18). In these cases, similar mechanisms are proposed to those outlined there except that the aryl anion is not preformed. Rather, deprotonation is closely coupled to copper coordination. Reasoning that this phenol arose from trapping of the in situ formed aryl lithium with oxygen, other bases were investigated. Ultimately, it was found that hindered amide anions with LiCl and/or ZnCl, additives gave rise to an aryl anion species that was less prone to oxygenation and more likely to form a copper adduct that would undergo oxidative coupling (Scheme 166).°17
Table 8. N-Arylation Conditions
Table 8. N-Arylation Conditions
“Microwave (MW), molecular sieves (MS), N-heterocyclic carbene (NHC), 2,2,6,6,-tetramethylpiperidinooxy (TEMPO), tetrabutylammonium fluoride (TBAF), dimethyl formamide (DMF), dichloroethane (DCE), N,N,N’,N’-tetramethylethylenediamine (TMEDA). Table 8. continued
“Microwave (MW), molecular sieves (MS), N-heterocyclic carbene (NHC), 2,2,6,6,-tetramethylpiperidinooxy (TEMPO), tetrabutylammonium fluoride (TBAF), dimethyl formamide (DMF), dichloroethane (DCE), N,N,N’,N’-tetramethylethylenediamine (TMEDA). Table 8. continued
Scheme 174. Alternate Mechanism for the Copper-Catalyzed N-Arylation
Scheme 174. Alternate Mechanism for the Copper-Catalyzed N-Arylation
Table 9. O-Arylation with Aryl Boronic Acid Derivatives*
Table 9. O-Arylation with Aryl Boronic Acid Derivatives*
Scheme 180. O-Arylation of Benzoic Acid with Various Aryl Boronic Acids Scheme 181. O-Arylation of Various Benzoic Acids with Phenyl Boronic Acids
Scheme 180. O-Arylation of Benzoic Acid with Various Aryl Boronic Acids Scheme 181. O-Arylation of Various Benzoic Acids with Phenyl Boronic Acids
Scheme 178. Outline of Proposed Mechanism for Oxidative Hydroxylation of Arylboronic Acids reactivity. The reaction rate decreased significantly under air, and no product formed under an argon atmosphere. A wide range of functional groups including alkoxycarbonyl, acetyl, cyano, and halogens (Scheme 179) can be incorporated. Using H,'%O as the solvent revealed that the phenolic oxygen arises from water, not oxygen, consistent with observations made by Evans and et al.°’ and Lam et al.*”°
Scheme 178. Outline of Proposed Mechanism for Oxidative Hydroxylation of Arylboronic Acids reactivity. The reaction rate decreased significantly under air, and no product formed under an argon atmosphere. A wide range of functional groups including alkoxycarbonyl, acetyl, cyano, and halogens (Scheme 179) can be incorporated. Using H,'%O as the solvent revealed that the phenolic oxygen arises from water, not oxygen, consistent with observations made by Evans and et al.°’ and Lam et al.*”°
Scheme 179. Substrate Scope Oxidative Hydroxylation of Various Arylboronic Acids
Scheme 179. Substrate Scope Oxidative Hydroxylation of Various Arylboronic Acids
Scheme 177. Oxidative Hydroxylation of Aryl Boronic Acids
Scheme 177. Oxidative Hydroxylation of Aryl Boronic Acids
avoiding the need for added oxidant such as air, this work will be described since it is preparatively useful for the synthesis of vinyl ether substrates. In contrast to other previously reported C—O bond-forming reactions, vinyl pinacol boronate coupling partners were optimal while other boronate esters, boronic acids, boroxines, and boranes were sluggish (19-59% yield). Only 1.0 equiv of coupling partner is required, and water was found to be detrimental. These conditions are compatible with acidic, basic, nucleophilic, oxidative, and radical conditions. The addition of triethylamine improves the yield by quenching acetic acid minimizing protodeboronation of the pinacol vinyl boronate (Scheme 182). A mechanism is proposed based on the works of Evans et al.°'? and Stahl and co-workers*”® (Scheme 183). Transmetalation of the pinacol boronate to aliphatic alcohols using Cu(OAc), at ambient temperature (Scheme 182).*°° Although the method employs excess copper
avoiding the need for added oxidant such as air, this work will be described since it is preparatively useful for the synthesis of vinyl ether substrates. In contrast to other previously reported C—O bond-forming reactions, vinyl pinacol boronate coupling partners were optimal while other boronate esters, boronic acids, boroxines, and boranes were sluggish (19-59% yield). Only 1.0 equiv of coupling partner is required, and water was found to be detrimental. These conditions are compatible with acidic, basic, nucleophilic, oxidative, and radical conditions. The addition of triethylamine improves the yield by quenching acetic acid minimizing protodeboronation of the pinacol vinyl boronate (Scheme 182). A mechanism is proposed based on the works of Evans et al.°'? and Stahl and co-workers*”® (Scheme 183). Transmetalation of the pinacol boronate to aliphatic alcohols using Cu(OAc), at ambient temperature (Scheme 182).*°° Although the method employs excess copper
Scheme 185. Formation of Silyl Enol Ethers from Vinyl Boronates classical enol ether synthesis in that a C—O bond is formed rather than a Si-O bond via O-silylation of carbonyl derivatives. The importance of pyridine N-oxide and oxygen is unclear, and removing either reagent leads to poor yields. Substrates with acid and base labile functional groups could also be coupled in moderate yields. Notably, the coupling of vinylboronate containing both an alcohol and ketone functional groups was silylated selectively in 43% and 44% yield, respectively (no evidence of alcohol coupling was observed). Aryl silyl ethers could also be synthesized from the corresponding silanols and aryl pinacol boronate (65% yield). The authors speculate that the mechanism may be analogous to the mechanism of copper-based couplings with alcohols.
Scheme 185. Formation of Silyl Enol Ethers from Vinyl Boronates classical enol ether synthesis in that a C—O bond is formed rather than a Si-O bond via O-silylation of carbonyl derivatives. The importance of pyridine N-oxide and oxygen is unclear, and removing either reagent leads to poor yields. Substrates with acid and base labile functional groups could also be coupled in moderate yields. Notably, the coupling of vinylboronate containing both an alcohol and ketone functional groups was silylated selectively in 43% and 44% yield, respectively (no evidence of alcohol coupling was observed). Aryl silyl ethers could also be synthesized from the corresponding silanols and aryl pinacol boronate (65% yield). The authors speculate that the mechanism may be analogous to the mechanism of copper-based couplings with alcohols.
Scheme 186. Proposed Mechanism of Copper-Catalyzed Etherification with Boronic Acids Stahl and co-workers have also examined C—O bond formation between oxygen nucleophiles (carboxylic acids, phenols, and alcohols) and a well-defined macrocyclic aryl— Cu(II) complex.””? The order of reactivity observed for the stoichiometric reactions of the oxygen nucleophiles with the macrocyclic aryl—Cu(III) complex was carboxylic acids > phenols > alcohols. Studies examining the dependence of the reaction rate on the concentration of the nucleophile, evaluating of the effect of pK,, and identifying the Cu(III)— nucleophile adducts are outlined. A positive slope was observed for the Bronsted correlation of carboxylic acids indicating that less acidic acids react faster, and a negative slope was observed for para-substituted phenols except for p-nitrophenol, which behaved similarly to carboxylic acid nucleophiles. Lastly, UV— visible spectroscopy data suggested the presence of a ground- state interaction between the macrocyclic aryl—Cu(III) complex and the more acidic carboxylic acids and phenols. Based on the findings outlined above, a pre-equilibrium of the carboxylic acid nucleophile and Cu(III)—aryl macrocycle is proposed, which can be stabilized by hydrogen bonding of the acidic H to the acetonitrile solvent, intermediate II (Scheme
Scheme 186. Proposed Mechanism of Copper-Catalyzed Etherification with Boronic Acids Stahl and co-workers have also examined C—O bond formation between oxygen nucleophiles (carboxylic acids, phenols, and alcohols) and a well-defined macrocyclic aryl— Cu(II) complex.””? The order of reactivity observed for the stoichiometric reactions of the oxygen nucleophiles with the macrocyclic aryl—Cu(III) complex was carboxylic acids > phenols > alcohols. Studies examining the dependence of the reaction rate on the concentration of the nucleophile, evaluating of the effect of pK,, and identifying the Cu(III)— nucleophile adducts are outlined. A positive slope was observed for the Bronsted correlation of carboxylic acids indicating that less acidic acids react faster, and a negative slope was observed for para-substituted phenols except for p-nitrophenol, which behaved similarly to carboxylic acid nucleophiles. Lastly, UV— visible spectroscopy data suggested the presence of a ground- state interaction between the macrocyclic aryl—Cu(III) complex and the more acidic carboxylic acids and phenols. Based on the findings outlined above, a pre-equilibrium of the carboxylic acid nucleophile and Cu(III)—aryl macrocycle is proposed, which can be stabilized by hydrogen bonding of the acidic H to the acetonitrile solvent, intermediate II (Scheme
Scheme 187. Mechanism Proposed for Alkoxylation of a Cu(III)—Aryl Species
Scheme 187. Mechanism Proposed for Alkoxylation of a Cu(III)—Aryl Species
To gain an understanding of the mechanism, PhSCu was treated with 4-MePhB(OH), (experiment A, Scheme 192); the
To gain an understanding of the mechanism, PhSCu was treated with 4-MePhB(OH), (experiment A, Scheme 192); the
“Arrow indicates the bond formed.
“Arrow indicates the bond formed.
Scheme 193. Mechanisms for Copper-Catalyzed Thiolation of Disulfides with Aryl Boronic Acids Cu(II) (IV), which then undergoes transmetalation with a second equivalent of arylboronic acid to form Cu(II)R'R’ species V. This species undergoes oxidative expulsion of the disulfide product and regenerates the Cu(I)L, species (I) catalyst. For cycle B, the disulfide coordinates to the Cu(I)L, species I and undergoes transmetalation to form 1.0 equiv of R'SR’ species VII, as well as R'SCu(I)L species II, which intersects the catalytic cycle A. The formation of discrete Cu(IIL) intermediates is not proposed for the formation of the C-S bond.
Scheme 193. Mechanisms for Copper-Catalyzed Thiolation of Disulfides with Aryl Boronic Acids Cu(II) (IV), which then undergoes transmetalation with a second equivalent of arylboronic acid to form Cu(II)R'R’ species V. This species undergoes oxidative expulsion of the disulfide product and regenerates the Cu(I)L, species (I) catalyst. For cycle B, the disulfide coordinates to the Cu(I)L, species I and undergoes transmetalation to form 1.0 equiv of R'SR’ species VII, as well as R'SCu(I)L species II, which intersects the catalytic cycle A. The formation of discrete Cu(IIL) intermediates is not proposed for the formation of the C-S bond.
Scheme 194. S-Arylation in the Presence of an Amino Group
Scheme 194. S-Arylation in the Presence of an Amino Group
Scheme 196. Byproducts in the Cross-Coupling of Dibenzyl Disulfide with Aryl Boroxine
Scheme 196. Byproducts in the Cross-Coupling of Dibenzyl Disulfide with Aryl Boroxine
Scheme 199. Oxidative Dimerization of Arylboronic Acids
Scheme 199. Oxidative Dimerization of Arylboronic Acids
Scheme 200. Oxidative Dimerization of Arylboronic Acids with a Copper(II) Bis-#-hydroxo Catalyst
Scheme 200. Oxidative Dimerization of Arylboronic Acids with a Copper(II) Bis-#-hydroxo Catalyst
discovery that a C—P bond can also be formed under oxidative conditions. Zhuang and co-workers have reported the first example of cross-coupling secondary H-phosphonate diesters using catalytic amounts of copper(II) oxide and phenanthroline catalyst in the presence of excess amine base under an oxygen atmosphere to afford aryl phosphonates.*'* Phenol and diaryl ether side products arising from competing oxidation of the
discovery that a C—P bond can also be formed under oxidative conditions. Zhuang and co-workers have reported the first example of cross-coupling secondary H-phosphonate diesters using catalytic amounts of copper(II) oxide and phenanthroline catalyst in the presence of excess amine base under an oxygen atmosphere to afford aryl phosphonates.*'* Phenol and diaryl ether side products arising from competing oxidation of the
Scheme 206. Oxidative Coupling of Ester- and Aryl- Substituted Terminal Alkynes with Aryl Boronic Acids Scheme 205. Possible Mechanism for Tandem Copper- Catalyzed C—C and C-—S Bond Formation
Scheme 206. Oxidative Coupling of Ester- and Aryl- Substituted Terminal Alkynes with Aryl Boronic Acids Scheme 205. Possible Mechanism for Tandem Copper- Catalyzed C—C and C-—S Bond Formation
mechanistic studies to elucidate the nature of this interesting transformation remain to be undertaken, information from studies on the processes described above suggests the catalytic cycle outlined in Scheme 205, which is in accord with all the data described.
mechanistic studies to elucidate the nature of this interesting transformation remain to be undertaken, information from studies on the processes described above suggests the catalytic cycle outlined in Scheme 205, which is in accord with all the data described.
Scheme 207. Oxidative Coupling of Hydroxyl- and Amino- Functionalized Terminal Alkynes with Aryl Boronic Acids Scheme 208. Cross-Coupling of Alkynes with Aryl Boronic Acids
Scheme 207. Oxidative Coupling of Hydroxyl- and Amino- Functionalized Terminal Alkynes with Aryl Boronic Acids Scheme 208. Cross-Coupling of Alkynes with Aryl Boronic Acids
Scheme 210. C—P Bond Formation with Various Boronic Acids
Scheme 210. C—P Bond Formation with Various Boronic Acids
copper(II) and molecular oxygen, which is well covered in a recent review by Stack and co-workers.’””* Mechanism type II, pioneered by Semmelhack,*’” features a hydrogen radical acceptor, often TEMPO or one of its analogues, as a cofactor. In mechanism type III, largely developed by Marké,”*"* a hydrogen anion acceptor serves as a cofactor. Mechanism type IV is the most analogous to that of galactose oxidase, in which an oxy radical on the ligand itself abstracts a hydrogen radical.
copper(II) and molecular oxygen, which is well covered in a recent review by Stack and co-workers.’””* Mechanism type II, pioneered by Semmelhack,*’” features a hydrogen radical acceptor, often TEMPO or one of its analogues, as a cofactor. In mechanism type III, largely developed by Marké,”*"* a hydrogen anion acceptor serves as a cofactor. Mechanism type IV is the most analogous to that of galactose oxidase, in which an oxy radical on the ligand itself abstracts a hydrogen radical.
Scheme 212. The Mechanism of the Aerobic Alcohol Oxidation without Cocatalyst and proton abstraction results in formation of the aldehyde and regeneration of the catalyst. However, other mechanistic studies indicate the presence of H,O, as a byproduct of the oxidation process.*** This reaction is inhibited by water, a byproduct of the oxidation reaction,*”> as well as by tertiary phosphine ligands, likely due to competitive binding at the copper center.’”® The oxidation reaction is most effective at pH of 12.6—13.3, indicating that the alcohol must be deprotonated prior to binding to the copper complex.*”” Highly oxidized copper(III) complexes have also been shown to mediate the oxidation of benzyl alcohol to benzaldehyde, suggesting that these complexes may play a role depending on reaction conditions (Scheme 213).‘”*
Scheme 212. The Mechanism of the Aerobic Alcohol Oxidation without Cocatalyst and proton abstraction results in formation of the aldehyde and regeneration of the catalyst. However, other mechanistic studies indicate the presence of H,O, as a byproduct of the oxidation process.*** This reaction is inhibited by water, a byproduct of the oxidation reaction,*”> as well as by tertiary phosphine ligands, likely due to competitive binding at the copper center.’”® The oxidation reaction is most effective at pH of 12.6—13.3, indicating that the alcohol must be deprotonated prior to binding to the copper complex.*”” Highly oxidized copper(III) complexes have also been shown to mediate the oxidation of benzyl alcohol to benzaldehyde, suggesting that these complexes may play a role depending on reaction conditions (Scheme 213).‘”*
Table 10. Oxidation of Alcohols with Copper Catalysts Using Oxygen Scheme 214. Oxidation of Benzylic Alcohols Catalyzed by CuClL,-CsCO,
Table 10. Oxidation of Alcohols with Copper Catalysts Using Oxygen Scheme 214. Oxidation of Benzylic Alcohols Catalyzed by CuClL,-CsCO,
Scheme 215. Aerobic Oxidation of Propargylic Alcohols Using Copper Nanoparticles involving oxidative arene C—H insertion with a Cu(II) to Cu(III) redox couple raises the possibility of an alternate mechanism (path B), in which a Friedel—Crafts reaction is followed by copper-catalyzed oxidation of the alkoxy intermediate. The authors noted that in the absence of oxygen, significant amounts of the anticipated Friedel—Crafts adduct are formed. A rate-determining copper-catalyzed oxidation of this intermediate would account for the isotope effects and is also consistent with the mass values and IR stretches reported.
Scheme 215. Aerobic Oxidation of Propargylic Alcohols Using Copper Nanoparticles involving oxidative arene C—H insertion with a Cu(II) to Cu(III) redox couple raises the possibility of an alternate mechanism (path B), in which a Friedel—Crafts reaction is followed by copper-catalyzed oxidation of the alkoxy intermediate. The authors noted that in the absence of oxygen, significant amounts of the anticipated Friedel—Crafts adduct are formed. A rate-determining copper-catalyzed oxidation of this intermediate would account for the isotope effects and is also consistent with the mass values and IR stretches reported.
indoline-2,3-diones (isatins) in good to excellent yield (Scheme 216). Secondary amides failed to provide more than trace amounts of product, and substrates with a strongly electron- withdrawing group at the para-position also gave poor yields. meta-Substituted substrates afforded regioisomeric product mixtures.
indoline-2,3-diones (isatins) in good to excellent yield (Scheme 216). Secondary amides failed to provide more than trace amounts of product, and substrates with a strongly electron- withdrawing group at the para-position also gave poor yields. meta-Substituted substrates afforded regioisomeric product mixtures.
Table 11. continued
Table 11. continued
Table 11. continued
Table 11. continued
Scheme 218. Oxidation of Primary Alcohols Using CuCl and TEMPO
Scheme 218. Oxidation of Primary Alcohols Using CuCl and TEMPO
An aerobic Cu/TEMPO-catalyzed alcohol oxidation was employed in the synthesis of a simplified analog of the FGH ring of rubrifloradilactone C (Scheme 234)."”’ Here, the primary allylic alcohol is oxidized to the aldehyde in the presence of a secondary allylic alcohol. The resultant hemiacetal is then oxidized to the lactone. Notably, other oxidants such as MnO), did not give the desired selectivity. A similar method, Scheme 223. Preference for Unhindered Alcohols and Overoxidation by CuOTf in the Cu/TEMPO/NMI- Catalyzed Alcohol Oxidation
An aerobic Cu/TEMPO-catalyzed alcohol oxidation was employed in the synthesis of a simplified analog of the FGH ring of rubrifloradilactone C (Scheme 234)."”’ Here, the primary allylic alcohol is oxidized to the aldehyde in the presence of a secondary allylic alcohol. The resultant hemiacetal is then oxidized to the lactone. Notably, other oxidants such as MnO), did not give the desired selectivity. A similar method, Scheme 223. Preference for Unhindered Alcohols and Overoxidation by CuOTf in the Cu/TEMPO/NMI- Catalyzed Alcohol Oxidation
Scheme 222. Selected Examples in the Cu/TEMPO/NMI- Catalyzed Aerobic Alcohol Oxidation
Scheme 222. Selected Examples in the Cu/TEMPO/NMI- Catalyzed Aerobic Alcohol Oxidation
oxidation to the aldehyde followed by oxidation of the hemiacetal, was also employed by Nonappa and Maitra in the total synthesis of 16-a-hydroxycholic acid, a component in bile of the shoebill stork (Scheme 235). Cleavage of the lactone with potassium hydroxide furnished the natural product.*”* Aitken and co-workers tested a number of oxidants in their studies toward the synthesis of the southern region of cyclotheonamide C. An aerobic Cu/TEMPO-catalyzed oxida- tion of the primary allylic alcohol followed by Horner—
oxidation to the aldehyde followed by oxidation of the hemiacetal, was also employed by Nonappa and Maitra in the total synthesis of 16-a-hydroxycholic acid, a component in bile of the shoebill stork (Scheme 235). Cleavage of the lactone with potassium hydroxide furnished the natural product.*”* Aitken and co-workers tested a number of oxidants in their studies toward the synthesis of the southern region of cyclotheonamide C. An aerobic Cu/TEMPO-catalyzed oxida- tion of the primary allylic alcohol followed by Horner—
Scheme 225. Synthesis of a Tetrahydroazapane Using the Light-Activated Cu/TEMPO-Catalyzed Aerobic Alcohol Oxidation Scheme 226. The Cu/TEMPO-Catalyzed Aerobic Oxidation of Alcohols Using a Fluorous Biphasic System
Scheme 225. Synthesis of a Tetrahydroazapane Using the Light-Activated Cu/TEMPO-Catalyzed Aerobic Alcohol Oxidation Scheme 226. The Cu/TEMPO-Catalyzed Aerobic Oxidation of Alcohols Using a Fluorous Biphasic System
Scheme 227. Application of the Chemoselective Cu/ TEMPO-Catalyzed Alcohol Oxidation
Scheme 227. Application of the Chemoselective Cu/ TEMPO-Catalyzed Alcohol Oxidation
Scheme 228. The Cu/TEMPO-Catalyzed Alcohol Oxidation in the Synthesis of Epoxyquinol A Scheme 229. The Use of Cu/TEMPO in Mechanism Elucidation
Scheme 228. The Cu/TEMPO-Catalyzed Alcohol Oxidation in the Synthesis of Epoxyquinol A Scheme 229. The Use of Cu/TEMPO in Mechanism Elucidation
Scheme 232. The Application of the Cu/TEMPO-Catalyzed Alcohol Oxidation to an Intermediate in the Total Synthesis of Torreyanic Acid
Scheme 232. The Application of the Cu/TEMPO-Catalyzed Alcohol Oxidation to an Intermediate in the Total Synthesis of Torreyanic Acid
Scheme 235. Selective Oxidation of a Primary Alcohol in the Presence of Secondary Alcohols in the Synthesis of Bile Acids Scheme 236. Application of the Cu/TEMPO-Catalyzed Alcohol Oxidation in the Studies toward the Synthesis of Cyclotheonamide C
Scheme 235. Selective Oxidation of a Primary Alcohol in the Presence of Secondary Alcohols in the Synthesis of Bile Acids Scheme 236. Application of the Cu/TEMPO-Catalyzed Alcohol Oxidation in the Studies toward the Synthesis of Cyclotheonamide C
Scheme 234. Selective Alcohol Oxidation in Studies toward the Synthesis of Rubrifloradilactone C
Scheme 234. Selective Alcohol Oxidation in Studies toward the Synthesis of Rubrifloradilactone C
Scheme 237. A Mild and Chemoselective Cu/TEMPO- Catalyzed Aerobic Alcohol Oxidation in Studies toward th Synthesis of Iejimalide B
Scheme 237. A Mild and Chemoselective Cu/TEMPO- Catalyzed Aerobic Alcohol Oxidation in Studies toward th Synthesis of Iejimalide B
Table 12. Aerobic Alcohol Oxidations Employing the Copper and Diazodicarboxylate Cocatalytic System
Table 12. Aerobic Alcohol Oxidations Employing the Copper and Diazodicarboxylate Cocatalytic System
Scheme 238. Aerobic Cu/TEMPO-Catalyzed Alcohol Oxidation in the Synthesis and Determination of Absolute Configuration of (+)-(S,S)-Canangone developing this method was performed by Marko and co- workers (Scheme 239).*1%
Scheme 238. Aerobic Cu/TEMPO-Catalyzed Alcohol Oxidation in the Synthesis and Determination of Absolute Configuration of (+)-(S,S)-Canangone developing this method was performed by Marko and co- workers (Scheme 239).*1%
Scheme 241. Proposed Mechanism of the Galactose Oxidase-Catalyzed Alcohol Oxidation
Scheme 241. Proposed Mechanism of the Galactose Oxidase-Catalyzed Alcohol Oxidation
Scheme 240. Mechanism of the Copper—Diazodicarboxylate Aerobic Alcohol Oxidation
Scheme 240. Mechanism of the Copper—Diazodicarboxylate Aerobic Alcohol Oxidation
Scheme 239. Aerobic Copper-Catalyzed Alcohol Oxidations Using a Diazodicarboxylate as a Cocatalyst
Scheme 239. Aerobic Copper-Catalyzed Alcohol Oxidations Using a Diazodicarboxylate as a Cocatalyst
1.2. Oxidation of Diols and a-Hydroxycarbonyls reaction time, but product ratios are correspondingly more
1.2. Oxidation of Diols and a-Hydroxycarbonyls reaction time, but product ratios are correspondingly more
Scheme 242. Mechanism of a Small Molecule Galactose Oxidase Mimic Scheme 243. Asymmetric Oxidative Kinetic Resolution of Diarylmethanols
Scheme 242. Mechanism of a Small Molecule Galactose Oxidase Mimic Scheme 243. Asymmetric Oxidative Kinetic Resolution of Diarylmethanols
Scheme 244. Asymmetric Oxidative Kinetic Resolution of Benzils
Scheme 244. Asymmetric Oxidative Kinetic Resolution of Benzils
Table 14. continued
Table 14. continued
Table 14. continued Scheme 247. Oxidation of a Hydroxy Ketone in the Synthesis of Ouabain Derivatives
Table 14. continued Scheme 247. Oxidation of a Hydroxy Ketone in the Synthesis of Ouabain Derivatives
Scheme 248. Oxidative Cleavage of a-Methylbenzoin with CuCl and Molecular Oxygen
Scheme 248. Oxidative Cleavage of a-Methylbenzoin with CuCl and Molecular Oxygen
the secondary radicals obtained from isopropanol and diphenylmethanol.
the secondary radicals obtained from isopropanol and diphenylmethanol.
Scheme 245. Mechanism of the Copper-Catalyzed Aerobic Oxidation of Benzoins and Hydroxymethylketones Scheme 246. Oxidation of a Steroid Followed by Intramolecular Hydride Transfer Reaction
Scheme 245. Mechanism of the Copper-Catalyzed Aerobic Oxidation of Benzoins and Hydroxymethylketones Scheme 246. Oxidation of a Steroid Followed by Intramolecular Hydride Transfer Reaction
Scheme 253. Tandem Alcohol Oxidation and Passerini Three-Component Coupling
Scheme 253. Tandem Alcohol Oxidation and Passerini Three-Component Coupling
Scheme 254. Copper(II), TEMPO, and NaNO, Cocatalyzed Oxidation of Aldehydes Leading to a Multicomponent Coupling
Scheme 254. Copper(II), TEMPO, and NaNO, Cocatalyzed Oxidation of Aldehydes Leading to a Multicomponent Coupling
Scheme 257. Mechanism for the Copper-Catalyzed Tandem Cyclization—Hemiacetal Oxidation Reaction Scheme 256. Copper-Catalyzed Tandem Reaction To Generate Substituted Furocoumarins
Scheme 257. Mechanism for the Copper-Catalyzed Tandem Cyclization—Hemiacetal Oxidation Reaction Scheme 256. Copper-Catalyzed Tandem Reaction To Generate Substituted Furocoumarins
vinylogous ester is activated for nucleophilic attack by coordination of copper(I). Addition of the oxycuprate across the alkyne generates a furan and a proton displaces the copper. It is highly likely that the final oxidation of the hemiacetal is facilitated by trace copper(II) that will form in air.
vinylogous ester is activated for nucleophilic attack by coordination of copper(I). Addition of the oxycuprate across the alkyne generates a furan and a proton displaces the copper. It is highly likely that the final oxidation of the hemiacetal is facilitated by trace copper(II) that will form in air.
Scheme 255. One-Pot Aerobic Oxidation and Methylenation of Alcohols
Scheme 255. One-Pot Aerobic Oxidation and Methylenation of Alcohols
Scheme 260. Formation of an Unexpected Naphthofuran Product from CuCl under Air
Scheme 260. Formation of an Unexpected Naphthofuran Product from CuCl under Air
analogous to that seen in the oxidative cleavage reactions seen in section 5.3.2. Scheme 261. Two Possible Reaction Paths in the Tandem Cyclization—Oxidative Cleavage Formation of Naphthofurans Scheme 261. Two Possible Reaction Paths in the Tandem Cyclization—Oxidative Cleavage Formation of Naphthofurans
analogous to that seen in the oxidative cleavage reactions seen in section 5.3.2. Scheme 261. Two Possible Reaction Paths in the Tandem Cyclization—Oxidative Cleavage Formation of Naphthofurans Scheme 261. Two Possible Reaction Paths in the Tandem Cyclization—Oxidative Cleavage Formation of Naphthofurans
Scheme 264. New Mechanism Proposed for the Oxidative N- Alkylation of Sulfonamides
Scheme 264. New Mechanism Proposed for the Oxidative N- Alkylation of Sulfonamides
Scheme 263. Selected Substrate Scope in the Copper and Oxygen Cocatalyzed Amination of Benzyl Alcohols borrowing reaction requires an excess of the benzyl alcohol. A similar reaction using aluminum hydrotalcite-supported catalyst has been reported.°*” An alternate mechanism that does not require a copper-hydride, which is not stable in the presence of molecular oxygen,** is described for the next transformation below.
Scheme 263. Selected Substrate Scope in the Copper and Oxygen Cocatalyzed Amination of Benzyl Alcohols borrowing reaction requires an excess of the benzyl alcohol. A similar reaction using aluminum hydrotalcite-supported catalyst has been reported.°*” An alternate mechanism that does not require a copper-hydride, which is not stable in the presence of molecular oxygen,** is described for the next transformation below.
Scheme 262. “Hydrogen-Borrowing” N-Alkylation of Sulfamides and Its Dependency on Atmosphere addition of a secondary oxidant like molecular oxygen when the metal is Ru or Ir. However, Deng and co-workers have determined that the copper-catalyzed N-alkylation of sulfona- mides is improved by the use of an air atmosphere (Scheme 262, left). Presumably, oxygen facilitates the oxidation of benzyl alcohol, determined to be the rate-determining step." ° On the other hand, too much oxygen (up to 70% with respect to sulfonamide) shuts down the reaction by degrading the copper- hydride and thereby inhibiting the transfer hydrogenation. The reaction shows very little substituent dependence on the benzyl
Scheme 262. “Hydrogen-Borrowing” N-Alkylation of Sulfamides and Its Dependency on Atmosphere addition of a secondary oxidant like molecular oxygen when the metal is Ru or Ir. However, Deng and co-workers have determined that the copper-catalyzed N-alkylation of sulfona- mides is improved by the use of an air atmosphere (Scheme 262, left). Presumably, oxygen facilitates the oxidation of benzyl alcohol, determined to be the rate-determining step." ° On the other hand, too much oxygen (up to 70% with respect to sulfonamide) shuts down the reaction by degrading the copper- hydride and thereby inhibiting the transfer hydrogenation. The reaction shows very little substituent dependence on the benzyl
Scheme 269. Copper-Catalyzed Oxidation of Aldehydes to Carboxylic Acids
Scheme 269. Copper-Catalyzed Oxidation of Aldehydes to Carboxylic Acids
Scheme 266. Copper-Catalyzed Hydroxamide Oxidation and Intermolecular Ene Reaction
Scheme 266. Copper-Catalyzed Hydroxamide Oxidation and Intermolecular Ene Reaction
Scheme 265. Mechanism and Scope of the Intramolecular Ene Reaction
Scheme 265. Mechanism and Scope of the Intramolecular Ene Reaction
Scheme 268. Oxidative Rearrangement of Tertiary Alcohols
Scheme 268. Oxidative Rearrangement of Tertiary Alcohols
5. REACTIONS OF CARBONYLS AND CARBONYL EQUIVALENTS
5. REACTIONS OF CARBONYLS AND CARBONYL EQUIVALENTS
Scheme 270. Putative Mechanism of Aldehyde Oxidation with Copper and Oxygen generates a peracid,°* which reacts with another aldehyde equivalent to form two molecules of carboxylic acid. This method of peracid generation utilizing an aldehyde as a transfer oxidant is used in many alkane and alkene oxidation reactions (cf., sections 2.2 and 2.3). Despite the great potential of such a transformation, little further work has been done with the bulk of efforts focusing on peroxide as the oxidant.°°*
Scheme 270. Putative Mechanism of Aldehyde Oxidation with Copper and Oxygen generates a peracid,°* which reacts with another aldehyde equivalent to form two molecules of carboxylic acid. This method of peracid generation utilizing an aldehyde as a transfer oxidant is used in many alkane and alkene oxidation reactions (cf., sections 2.2 and 2.3). Despite the great potential of such a transformation, little further work has been done with the bulk of efforts focusing on peroxide as the oxidant.°°*
Scheme 273. Mechanism of the Copper and Oxygen Catalyzed Oxidation of Aldimines to Nitriles Maumy and co-workers have improved the yields and expanded the substrate scope to include a host of arenes anc heterocycles (Scheme 274)? CuCl, and ammonia are
Scheme 273. Mechanism of the Copper and Oxygen Catalyzed Oxidation of Aldimines to Nitriles Maumy and co-workers have improved the yields and expanded the substrate scope to include a host of arenes anc heterocycles (Scheme 274)? CuCl, and ammonia are
both a Lewis acid and an oxidant. (Scheme 273). Formation of the nitrile can result from oxidation by the copper or by a disproportionation reaction (not illustrated), which also yields an equivalent of starting material.°°*
both a Lewis acid and an oxidant. (Scheme 273). Formation of the nitrile can result from oxidation by the copper or by a disproportionation reaction (not illustrated), which also yields an equivalent of starting material.°°*
generated in situ from the metal corrosion of metallic copper by ammonium chloride in the presence of oxygen. Though the copper catalyzes the reaction, a full equivalent is needed to generate the necessary ammonia. The reaction works well with aryl aldehydes, but aliphatic aldehydes give lower yields due to competing enolization under the basic conditions, and halogenated arenes tend to exchange with the chloride ligands on the copper.
generated in situ from the metal corrosion of metallic copper by ammonium chloride in the presence of oxygen. Though the copper catalyzes the reaction, a full equivalent is needed to generate the necessary ammonia. The reaction works well with aryl aldehydes, but aliphatic aldehydes give lower yields due to competing enolization under the basic conditions, and halogenated arenes tend to exchange with the chloride ligands on the copper.
Scheme 276. Mechanism for the Oxidative Coupling of a- Haloketones Scheme 277. Oxidative Enolate Coupling of a-Cyanoesters
Scheme 276. Mechanism for the Oxidative Coupling of a- Haloketones Scheme 277. Oxidative Enolate Coupling of a-Cyanoesters
Scheme 275. Copper-Catalyzed Reaction of Zinc Enolates with Oxygen
Scheme 275. Copper-Catalyzed Reaction of Zinc Enolates with Oxygen
Scheme 280. Postulated Mechanism for the Oxidative Aerobic Coupling of Alkynes and f-Diketones
Scheme 280. Postulated Mechanism for the Oxidative Aerobic Coupling of Alkynes and f-Diketones
Scheme 279. Oxidative Coupling of Alkynoates and 1,3- Diketones Using Copper and Molecular Oxygen
Scheme 279. Oxidative Coupling of Alkynoates and 1,3- Diketones Using Copper and Molecular Oxygen
Scheme 286. Mechanism of the Catalytic Oxidative Cleavage of Cycloalkane-1,3-diones
Scheme 286. Mechanism of the Catalytic Oxidative Cleavage of Cycloalkane-1,3-diones
Scheme 285. Oxidative Cleavage of Cycloalkane-1,3-diones Using Copper and Oxygen
Scheme 285. Oxidative Cleavage of Cycloalkane-1,3-diones Using Copper and Oxygen
Scheme 283. Oxidative Cleavage of Cycloalkanones witl Copper and Oxygen
Scheme 283. Oxidative Cleavage of Cycloalkanones witl Copper and Oxygen
Scheme 289. A Possible Mechanism for Synthesis of Imidazoles from Ketone
Scheme 289. A Possible Mechanism for Synthesis of Imidazoles from Ketone
Scheme 295. Stepwise Degradation of Aliphatic Aldehydes
Scheme 295. Stepwise Degradation of Aliphatic Aldehydes
Scheme 292. Mechanism for the Oxidative Deprotection of Phenacyl Esters partner through rapid formation of the desired alkynyl cuprate (see section 2.4.3).
Scheme 292. Mechanism for the Oxidative Deprotection of Phenacyl Esters partner through rapid formation of the desired alkynyl cuprate (see section 2.4.3).
DABCO and zero order in oxygen and copper, indicating that the rate-determining step is likely enolization. The reaction does proceed in the absence of copper, though at a retarded rate; ketones are known to oxygenate under strong enolizing conditions. The mechanism of the degradation is shown in Scheme 294. After DABCO-mediated deprotonation of the aldehyde, copper(II) oxidizes the enolate to the radical, which is trapped by oxygen. Abstraction of the aldehydic hydrogen gives a hydroperoxide species that is reduced by copper(I) to release carbon monoxide and the ketone.
DABCO and zero order in oxygen and copper, indicating that the rate-determining step is likely enolization. The reaction does proceed in the absence of copper, though at a retarded rate; ketones are known to oxygenate under strong enolizing conditions. The mechanism of the degradation is shown in Scheme 294. After DABCO-mediated deprotonation of the aldehyde, copper(II) oxidizes the enolate to the radical, which is trapped by oxygen. Abstraction of the aldehydic hydrogen gives a hydroperoxide species that is reduced by copper(I) to release carbon monoxide and the ketone.
Scheme 300. Photooxidation of Dypnone in the Presence of Copper and Molecular Oxygen
Scheme 300. Photooxidation of Dypnone in the Presence of Copper and Molecular Oxygen
Scheme 299. Formation of Lactone Dimer from the Dypnone Oxidation Product
Scheme 299. Formation of Lactone Dimer from the Dypnone Oxidation Product
Scheme 296. Mechanism of the Oxidative Degradation of Linear Aliphatic Aldehydes Scheme 297. Copper-Catalyzed Oxygenation of Crotonaldehyde and Dypnone
Scheme 296. Mechanism of the Oxidative Degradation of Linear Aliphatic Aldehydes Scheme 297. Copper-Catalyzed Oxygenation of Crotonaldehyde and Dypnone
Scheme 308. Mechanism of the Copper-Catalyzed Oxidative Cleavage of 1,2-Diketones Scheme 309. Mononuclear Mechanism for the Oxidative Cleavage of 1,2-Diketones
Scheme 308. Mechanism of the Copper-Catalyzed Oxidative Cleavage of 1,2-Diketones Scheme 309. Mononuclear Mechanism for the Oxidative Cleavage of 1,2-Diketones
than between the two ketones (Scheme 310), similar to the oxidative cleavage of unsaturated carbonyls seen in section
than between the two ketones (Scheme 310), similar to the oxidative cleavage of unsaturated carbonyls seen in section
substrate provided the product with the excellent enantiomeric excess of 91%, whereas the simple /-substituted cyclobutanone afforded poorer asymmetric induction (44% ee). This disparity suggests that the very hindered tricycle undergoes greater interaction with the catalyst, permitting better differentiation of the two prochiral substrate enantiomers. The same catalyst has been used to effect desymmetrization of achiral cyclobutanones (Scheme 306).°*° The complex meso
substrate provided the product with the excellent enantiomeric excess of 91%, whereas the simple /-substituted cyclobutanone afforded poorer asymmetric induction (44% ee). This disparity suggests that the very hindered tricycle undergoes greater interaction with the catalyst, permitting better differentiation of the two prochiral substrate enantiomers. The same catalyst has been used to effect desymmetrization of achiral cyclobutanones (Scheme 306).°*° The complex meso
Scheme 310. Oxidative Cleavage of Enolizable 1,2-Diketones
Scheme 310. Oxidative Cleavage of Enolizable 1,2-Diketones
Notably, the generation of an enamine analog in situ by use of morpholine allows control of the oxidative cleavage such that a carbon is not excised (see section 6.1.3, Scheme 354). However, oxidative cleavage with carbon excision does proceed in the absence of the morpholine (Scheme 312). The last degradation step was accomplished utilizing catalytic amounts of DABCO base and a Cu(OAc) —2,2'-bipyridyl complex and afforded the desired ketone in 95% (Scheme 312).
Notably, the generation of an enamine analog in situ by use of morpholine allows control of the oxidative cleavage such that a carbon is not excised (see section 6.1.3, Scheme 354). However, oxidative cleavage with carbon excision does proceed in the absence of the morpholine (Scheme 312). The last degradation step was accomplished utilizing catalytic amounts of DABCO base and a Cu(OAc) —2,2'-bipyridyl complex and afforded the desired ketone in 95% (Scheme 312).
Scheme 313. Biomimetic Oxidative Cleavage of Flavonols Using a Copper Complex and Molecular Oxygen which required higher temperature and increased reaction time. The addition of a nitrogen-containing ligand allows for a much lower catalyst loading, though high reaction temperatures are still needed (Scheme 314).°”
Scheme 313. Biomimetic Oxidative Cleavage of Flavonols Using a Copper Complex and Molecular Oxygen which required higher temperature and increased reaction time. The addition of a nitrogen-containing ligand allows for a much lower catalyst loading, though high reaction temperatures are still needed (Scheme 314).°”
Flavonols are 1,2-diketones of particular commercial interest, because they are found in a wide variety of plants and are key components in a number of herbal remedies.°’' The enzyme flavonol-2,4-dioxygenase (quercetinase), which contains a copper(II) atom at the active site, has been shown to catalyze the oxidative cleavage of the diketone in the presence of molecular oxygen, with release of an equivalent of carbon monoxide.”
Flavonols are 1,2-diketones of particular commercial interest, because they are found in a wide variety of plants and are key components in a number of herbal remedies.°’' The enzyme flavonol-2,4-dioxygenase (quercetinase), which contains a copper(II) atom at the active site, has been shown to catalyze the oxidative cleavage of the diketone in the presence of molecular oxygen, with release of an equivalent of carbon monoxide.”
Scheme 315. Oxidative Ring Contraction of 3- Hydroxyflavonol with an Excess of CuCl,
Scheme 315. Oxidative Ring Contraction of 3- Hydroxyflavonol with an Excess of CuCl,
Scheme 316. Mechanism of the Oxidative Ring Contraction of 3-Hydroxyflavonol When treated with copper and oxygen in the presence of ammonia, a-ketoamides undergo condensation followed by oxidative cleavage to generate nitriles and amides (Scheme 317). The latter undergo decarboxylation to reveal the free
Scheme 316. Mechanism of the Oxidative Ring Contraction of 3-Hydroxyflavonol When treated with copper and oxygen in the presence of ammonia, a-ketoamides undergo condensation followed by oxidative cleavage to generate nitriles and amides (Scheme 317). The latter undergo decarboxylation to reveal the free
Scheme 320. Proposed Mechanism for a-Hydroxylation of N-Salicyloylglycine 5.6. Reactions of Imines
Scheme 320. Proposed Mechanism for a-Hydroxylation of N-Salicyloylglycine 5.6. Reactions of Imines
Scheme 318. Proposed Mechanism for the Oxidative Amination of an a-Ketoamide
Scheme 318. Proposed Mechanism for the Oxidative Amination of an a-Ketoamide
“TMAO, trimethylamine oxide.
“TMAO, trimethylamine oxide.
ketones and secondary amines (Scheme 325).°° Both electron- rich and electron-poor substitution on the aryl ring is tolerated, Scheme 324. Proposed Mechanism for the Formation of Ketones, Isocyanates, and Isonitriles from Ketenimines
ketones and secondary amines (Scheme 325).°° Both electron- rich and electron-poor substitution on the aryl ring is tolerated, Scheme 324. Proposed Mechanism for the Formation of Ketones, Isocyanates, and Isonitriles from Ketenimines
Scheme 321. Oxidative Cyclization of Iminophenols with Copper and Molecular Oxygen
Scheme 321. Oxidative Cyclization of Iminophenols with Copper and Molecular Oxygen
Scheme 325. Tandem Enamine Oxidation-Aminal Oxidation toward the Synthesis of A-Ketoamides
Scheme 325. Tandem Enamine Oxidation-Aminal Oxidation toward the Synthesis of A-Ketoamides
Scheme 323. Oxygenolysis of Ketenimines by Copper and Oxygen
Scheme 323. Oxygenolysis of Ketenimines by Copper and Oxygen
Scheme 329. Possible Mechanism for the Tandem Cycloaddition—Aerobic Oxidation Reaction
Scheme 329. Possible Mechanism for the Tandem Cycloaddition—Aerobic Oxidation Reaction
Scheme 326. Proposed Mechanism in the Copper-Catalyzed Aerobic Synthesis of @-Ketoamides A similar condensation—oxidation reaction generates a- ketoamides from phenylacetaldehydes combined with primary and secondary anilines (Scheme 327).°” The reaction proceeds
Scheme 326. Proposed Mechanism in the Copper-Catalyzed Aerobic Synthesis of @-Ketoamides A similar condensation—oxidation reaction generates a- ketoamides from phenylacetaldehydes combined with primary and secondary anilines (Scheme 327).°” The reaction proceeds
Scheme 327. One-Pot Copper-Catalyzed Oxidative Synthesis of N-Aryl a-Ketoamides best with 2 equiv of pyridine, generating N-aryl ketoamides in moderate to good yield. The method was applied to the synthesis of a known orexin receptor antagonist, generating the desired product in one step and in 40% yield. The reaction likely follows a mechanism similar to that seen in Scheme 326.
Scheme 327. One-Pot Copper-Catalyzed Oxidative Synthesis of N-Aryl a-Ketoamides best with 2 equiv of pyridine, generating N-aryl ketoamides in moderate to good yield. The method was applied to the synthesis of a known orexin receptor antagonist, generating the desired product in one step and in 40% yield. The reaction likely follows a mechanism similar to that seen in Scheme 326.
Scheme 333. Oxidative Coupling of Diarylhydrazines To Yield Diaryldiazabutadienes The hydrazone can also be formed via condensation of the aldehyde with hydrazine; this intermediate can then be oxidized by Cu(acac), and oxygen to form azines in quantitative yields (Scheme 334).°” The authors again propose that the resulting
Scheme 333. Oxidative Coupling of Diarylhydrazines To Yield Diaryldiazabutadienes The hydrazone can also be formed via condensation of the aldehyde with hydrazine; this intermediate can then be oxidized by Cu(acac), and oxygen to form azines in quantitative yields (Scheme 334).°” The authors again propose that the resulting
Scheme 331. Oxidation of Ketohydrazones Using Cu(acac), and Oxygen The authors propose that the copper acetoacetonate first oxidizes the hydrazone to the diazoketone, which can be isolated under mild reaction conditions. However, warmer reaction conditions lead to copper-mediated decomposition of the diazo compound to a carbenoid that can be trapped by a second diazoketone to furnish the azine product (Scheme 332).
Scheme 331. Oxidation of Ketohydrazones Using Cu(acac), and Oxygen The authors propose that the copper acetoacetonate first oxidizes the hydrazone to the diazoketone, which can be isolated under mild reaction conditions. However, warmer reaction conditions lead to copper-mediated decomposition of the diazo compound to a carbenoid that can be trapped by a second diazoketone to furnish the azine product (Scheme 332).
Scheme 334. Oxidation of in Situ-Generated Hydrazones To Yield Azines hydrazone is oxidized to the diazo compound, which decomposes under the reaction conditions (Scheme 332). In this case, no diazo compound could be isolated, which the authors attribute to rapid decomposition of this intermediate under the reaction conditions. Though a Lewis acid catalyzed condensation mechanism may be proposed, the short reaction times and mild conditions relative to what is needed for acid- catalyzed condensation,°'* the known tendency for Cu(acac), to form carbenoid species,°'* and the isolation of the diazo compound in the case of the ketohydrazones®'” suggest that a simple condensation is not occurring.
Scheme 334. Oxidation of in Situ-Generated Hydrazones To Yield Azines hydrazone is oxidized to the diazo compound, which decomposes under the reaction conditions (Scheme 332). In this case, no diazo compound could be isolated, which the authors attribute to rapid decomposition of this intermediate under the reaction conditions. Though a Lewis acid catalyzed condensation mechanism may be proposed, the short reaction times and mild conditions relative to what is needed for acid- catalyzed condensation,°'* the known tendency for Cu(acac), to form carbenoid species,°'* and the isolation of the diazo compound in the case of the ketohydrazones®'” suggest that a simple condensation is not occurring.
hydrogen peroxide formed from the first reaction. The first cycle of this proposed mechanism is outlined in (Scheme 344). For related reactions of amines, see section 9.1. Table 15. Oxidative Deamination of 1,2-Dihydrazones Using Copper and Oxygen
hydrogen peroxide formed from the first reaction. The first cycle of this proposed mechanism is outlined in (Scheme 344). For related reactions of amines, see section 9.1. Table 15. Oxidative Deamination of 1,2-Dihydrazones Using Copper and Oxygen
Scheme 337. Oxidation of 1,2-Dihydrazones in the Total Synthesis of cis-Civetone formation was not detected by EPR spectroscopy. The dehydrogenation reaction with oxygen-containing Cu(II) species formed the desired indole product along with water as the byproduct suggesting a four-electron reduction of dioxygen. The authors speculate that the dehydrogenation occurs in two reactions, one with oxygen and the second with
Scheme 337. Oxidation of 1,2-Dihydrazones in the Total Synthesis of cis-Civetone formation was not detected by EPR spectroscopy. The dehydrogenation reaction with oxygen-containing Cu(II) species formed the desired indole product along with water as the byproduct suggesting a four-electron reduction of dioxygen. The authors speculate that the dehydrogenation occurs in two reactions, one with oxygen and the second with
Scheme 343. Proposed Mechanism for the Oxidation of Thioamides to Oxazolines and Amidines enamine to the copper salt. Based on the predominance of the dicarbonyl products over the a-hydroxy ketone, it appears that elimination of the peroxo intermediate occurs more readily than reductive cleavage. In addition, the hydroxy group can also
Scheme 343. Proposed Mechanism for the Oxidation of Thioamides to Oxazolines and Amidines enamine to the copper salt. Based on the predominance of the dicarbonyl products over the a-hydroxy ketone, it appears that elimination of the peroxo intermediate occurs more readily than reductive cleavage. In addition, the hydroxy group can also
Scheme 340. '*O Labeling of Amides by Oxidation of the Thioamide
Scheme 340. '*O Labeling of Amides by Oxidation of the Thioamide
Scheme 338. Oxidative Cyclization through the Copper- Mediated Oxidation of 1,2-Dihydrazones
Scheme 338. Oxidative Cyclization through the Copper- Mediated Oxidation of 1,2-Dihydrazones
Scheme 342. Copper-Catalyzed Oxidation of Thioamides to Oxazolines and Amidines Scheme 341. Proposed Mechanism of the Oxidation of Thioamides to Amides
Scheme 342. Copper-Catalyzed Oxidation of Thioamides to Oxazolines and Amidines Scheme 341. Proposed Mechanism of the Oxidation of Thioamides to Amides
Scheme 346. Mechanism of the a-Oxygenation
Scheme 346. Mechanism of the a-Oxygenation
bearing f-vinylic hydrogens. Copper(II) sources with polya- tomic counterions were inefficient for this process; on the other hand, trace amounts of halogenated byproducts were observed with copper halide sources. enamines in 1969.°° Sterically hindered and cyclic enamines afforded ketone and amide products in good yields (Scheme 348). Diketone formation was problematic for enamines A few years later, Baloghergovich and co-workers reported similar conditions for the oxidative cleavage of enamines (Scheme 349).°° The authors suggested that a binuclear copper species with a bridging oxygen atom could be the catalytically active species.
bearing f-vinylic hydrogens. Copper(II) sources with polya- tomic counterions were inefficient for this process; on the other hand, trace amounts of halogenated byproducts were observed with copper halide sources. enamines in 1969.°° Sterically hindered and cyclic enamines afforded ketone and amide products in good yields (Scheme 348). Diketone formation was problematic for enamines A few years later, Baloghergovich and co-workers reported similar conditions for the oxidative cleavage of enamines (Scheme 349).°° The authors suggested that a binuclear copper species with a bridging oxygen atom could be the catalytically active species.
Scheme 350. Oxidative Cleavage of Acyclic Enamines Scheme 351. Substrate Scope Oxidative Cleavage of Enamines
Scheme 350. Oxidative Cleavage of Acyclic Enamines Scheme 351. Substrate Scope Oxidative Cleavage of Enamines
correlated with the ionization potential rather than nucleophil- icity of the enamine. A mechanism has been outlined by Kaneda and co-workers®”’ (Scheme 352). Alternately, the initial oxygenation products (Scheme 346) may form and then undergo further oxidative cleavage via enolic intermediates. More recently, exploration of the catalytic abilities of zeolite X-encapsulated copper(II) chloride complexes were examined for liquid-phase oxygenation of enamines under an oxygen atmosphere (Scheme 353).°°° The oxygenation rate was slower for bulky enamines compared with the homogeneous system. The difference in reactivity between the heterogeneous system
correlated with the ionization potential rather than nucleophil- icity of the enamine. A mechanism has been outlined by Kaneda and co-workers®”’ (Scheme 352). Alternately, the initial oxygenation products (Scheme 346) may form and then undergo further oxidative cleavage via enolic intermediates. More recently, exploration of the catalytic abilities of zeolite X-encapsulated copper(II) chloride complexes were examined for liquid-phase oxygenation of enamines under an oxygen atmosphere (Scheme 353).°°° The oxygenation rate was slower for bulky enamines compared with the homogeneous system. The difference in reactivity between the heterogeneous system
Scheme 353. Oxidative Cleavage of Enamines Catalyzed by Cu—X Zeolite Complexes
Scheme 353. Oxidative Cleavage of Enamines Catalyzed by Cu—X Zeolite Complexes
and the homogeneous system could be attributed to the shape- selective effect of Cu™* species within the 3-D zeolite pores. The catalyst could be recovered without appreciable loss of activity.
and the homogeneous system could be attributed to the shape- selective effect of Cu™* species within the 3-D zeolite pores. The catalyst could be recovered without appreciable loss of activity.
carbo-carbonylation of unactivated alkenes with enamines promoted by an organocatalyst and a copper catalyst to afford y-diketones and y-carbonyl aldehydes under air.°** The use of a co-oxdiant (MnO,) was required to increase the yields.
carbo-carbonylation of unactivated alkenes with enamines promoted by an organocatalyst and a copper catalyst to afford y-diketones and y-carbonyl aldehydes under air.°** The use of a co-oxdiant (MnO,) was required to increase the yields.
Scheme 356. Oxidative Cleavage of 3-Methylindole
Scheme 356. Oxidative Cleavage of 3-Methylindole
Scheme 354. Oxidative Cleavage of an a-Ketoester Derivative Scheme 355. Oxidative Cleavage of Isoquinolone
Scheme 354. Oxidative Cleavage of an a-Ketoester Derivative Scheme 355. Oxidative Cleavage of Isoquinolone
Electron-rich and electron-deficient aryl alkenes reacted smoothly except for strongly electron-deficient aryl alkenes (Scheme 360). The pyrrolidine was proposed to act as an organocatalyst, and no experimental evidence was provided to support the proposed mechanism outlined below (Scheme 261).
Electron-rich and electron-deficient aryl alkenes reacted smoothly except for strongly electron-deficient aryl alkenes (Scheme 360). The pyrrolidine was proposed to act as an organocatalyst, and no experimental evidence was provided to support the proposed mechanism outlined below (Scheme 261).
conditions from the corresponding aldehyde, which can form the enolate in situ, provide the oxidative cleavage product with only 5% yield. The authors propose a mechanism involving a superoxide anion, but Scheme 365 outlines a mechanism similar to those invoked in the oxidative cleavage of enolates (see section 5.3.2).
conditions from the corresponding aldehyde, which can form the enolate in situ, provide the oxidative cleavage product with only 5% yield. The authors propose a mechanism involving a superoxide anion, but Scheme 365 outlines a mechanism similar to those invoked in the oxidative cleavage of enolates (see section 5.3.2).
Scheme 361. Proposed Mechanism for Cascade Carbo- carbonylation of Unactivated Alkenes with Enamines Scheme 362. Substrate Scope for Synthesis of Polysubstituted Pyrroles*
Scheme 361. Proposed Mechanism for Cascade Carbo- carbonylation of Unactivated Alkenes with Enamines Scheme 362. Substrate Scope for Synthesis of Polysubstituted Pyrroles*
“Reaction conditions: A 0.3 mmol, B 0.3 mmol, O, 1 atm, DMF 2 mL, 80 °C, 4h.
“Reaction conditions: A 0.3 mmol, B 0.3 mmol, O, 1 atm, DMF 2 mL, 80 °C, 4h.
Scheme 365. Proposed Mechanism for Oxidative Cleavage of Enol Ethers
Scheme 365. Proposed Mechanism for Oxidative Cleavage of Enol Ethers
Scheme 364. Oxidative Cleavage of Various Enol Ethers under an Oxygen Atmosphere “GC yield. "Isolated yield.
Scheme 364. Oxidative Cleavage of Various Enol Ethers under an Oxygen Atmosphere “GC yield. "Isolated yield.
Scheme 366. Radicals Arising from Phenols, 2-Naphthols, and 1-Naphthols
Scheme 366. Radicals Arising from Phenols, 2-Naphthols, and 1-Naphthols
Scheme 369. Copper-Catalyzed Aerobic Dimerization of Naphthalene Catechol and Hydroquinone Sakamoto and co-workers reported the discovery of a copper catalyst system supported on alumina. No reaction was seen without the alumina support. Furthermore, the premixing and coevaporation of the copper sulfate and alumina was required. This supported catalyst couples both electron-rich and halogen- substituted 2-naphthols but is not successful with the more difficult to oxidize substrates containing electron-withdrawing groups (Scheme 370).
Scheme 369. Copper-Catalyzed Aerobic Dimerization of Naphthalene Catechol and Hydroquinone Sakamoto and co-workers reported the discovery of a copper catalyst system supported on alumina. No reaction was seen without the alumina support. Furthermore, the premixing and coevaporation of the copper sulfate and alumina was required. This supported catalyst couples both electron-rich and halogen- substituted 2-naphthols but is not successful with the more difficult to oxidize substrates containing electron-withdrawing groups (Scheme 370).
Scheme 367. Different Coupling Patterns for Phenols stoichiometric transition metal oxidants in 2-naphthol coupling is well established.““* The use of catalytic copper, however, required identification of an appropriate terminal oxidant, a role in which oxygen has proved particularly effective. Initial studies of naphthol oxidation by Brackman and Havinga found that copper nitrate and 2,4,6-trimethylpyridine (collidine) were effective in catalyzing the oxidation reaction (Scheme 368).°? However, the product distribution varied greatly depending on substrate structure. 2~-Naphthol gave biaryl products, but further oxidation also occurs to give a complex mixture.
Scheme 367. Different Coupling Patterns for Phenols stoichiometric transition metal oxidants in 2-naphthol coupling is well established.““* The use of catalytic copper, however, required identification of an appropriate terminal oxidant, a role in which oxygen has proved particularly effective. Initial studies of naphthol oxidation by Brackman and Havinga found that copper nitrate and 2,4,6-trimethylpyridine (collidine) were effective in catalyzing the oxidation reaction (Scheme 368).°? However, the product distribution varied greatly depending on substrate structure. 2~-Naphthol gave biaryl products, but further oxidation also occurs to give a complex mixture.
Scheme 370. Oxidative Dimerization of 2-Naphthols with Alumina-Supported Catalyst
Scheme 370. Oxidative Dimerization of 2-Naphthols with Alumina-Supported Catalyst
Scheme 368. Early Studies on the Aerobic Copper-Catalyzed Oxidative Coupling of 2-Naphthol
Scheme 368. Early Studies on the Aerobic Copper-Catalyzed Oxidative Coupling of 2-Naphthol
Scheme 375. Formation of Binaphthols and Related Compounds Using Cu(OH)CI(TMEDA) complex
Scheme 375. Formation of Binaphthols and Related Compounds Using Cu(OH)CI(TMEDA) complex
Scheme 378. Total Synthesis of Bioxanthracene (—)-ES-242. 4 via Oxidative Naphthol Coupling Scheme 379. Oxidative Coupling and Diastereomeric Resolution en Route to Binaphthol Oligomers
Scheme 378. Total Synthesis of Bioxanthracene (—)-ES-242. 4 via Oxidative Naphthol Coupling Scheme 379. Oxidative Coupling and Diastereomeric Resolution en Route to Binaphthol Oligomers
Scheme 382. Aerobic Synthesis of Helical Binaphthyls Using Stoichiometric Copper whether the initial coupling proceeds with selectivity or whether a resolution of the resultant binaphthol occurs in . 670b situ. Nakajima and co-workers reported the first catalytic asymmetric oxidative coupling of 2-naphthols. Building on their work using molecular oxygen with racemic copper catalysts,” they employed a chiral copper catalyst derived from proline (Scheme 385). The selectivity could be improved by decreasing the temperature to ambient, but the coordinating group at the 3-position was needed for selectivity, a pattern that persists through much of the copper-catalyzed aerobic biaryl
Scheme 382. Aerobic Synthesis of Helical Binaphthyls Using Stoichiometric Copper whether the initial coupling proceeds with selectivity or whether a resolution of the resultant binaphthol occurs in . 670b situ. Nakajima and co-workers reported the first catalytic asymmetric oxidative coupling of 2-naphthols. Building on their work using molecular oxygen with racemic copper catalysts,” they employed a chiral copper catalyst derived from proline (Scheme 385). The selectivity could be improved by decreasing the temperature to ambient, but the coordinating group at the 3-position was needed for selectivity, a pattern that persists through much of the copper-catalyzed aerobic biaryl
Stoichiometric copper-catalyzed anaerobic asymmetric biaryl couplings are known,°°”-°” though it is not always clear
Stoichiometric copper-catalyzed anaerobic asymmetric biaryl couplings are known,°°”-°” though it is not always clear
Scheme 380. Synthesis of Axially Chiral Phosphine Ligands via Racemic Coupling and Resolution of Binaphthols
Scheme 380. Synthesis of Axially Chiral Phosphine Ligands via Racemic Coupling and Resolution of Binaphthols
enantiomers of the diaza-cis-decalin ligand could be isolated via a simple resolution, allowing for the selective synthesis of either biaryl enantiomer. Though the coordinating group at the 3-position was still needed, substantial variation in that group was tolerated (Scheme 387), allowing for the synthesis of sulfonyl- and phosphonyl-substituted BINOL compounds. Highly substituted substrates could be coupled effectively (Scheme 388), although very electron-rich substrates under-
enantiomers of the diaza-cis-decalin ligand could be isolated via a simple resolution, allowing for the selective synthesis of either biaryl enantiomer. Though the coordinating group at the 3-position was still needed, substantial variation in that group was tolerated (Scheme 387), allowing for the synthesis of sulfonyl- and phosphonyl-substituted BINOL compounds. Highly substituted substrates could be coupled effectively (Scheme 388), although very electron-rich substrates under-
Scheme 385. The First Copper-Catalyzed Enantioselective Naphthol Coupling coupling studies. It was proposed that the copper binds through a chelated adduct (Scheme 386), because substrates without this coordinating group (e.g,, 2-naphthol) gave no selectivity.°”!
Scheme 385. The First Copper-Catalyzed Enantioselective Naphthol Coupling coupling studies. It was proposed that the copper binds through a chelated adduct (Scheme 386), because substrates without this coordinating group (e.g,, 2-naphthol) gave no selectivity.°”!
Scheme 384. Diastereoselective Coupling Using a Prolyl Chiral Auxiliary
Scheme 384. Diastereoselective Coupling Using a Prolyl Chiral Auxiliary
Scheme 387. Scope of Coordinating Group in Diaza-cis- decalin-Catalyzed Asymmetric Naphthol Coupling
Scheme 387. Scope of Coordinating Group in Diaza-cis- decalin-Catalyzed Asymmetric Naphthol Coupling
Scheme 390. Asymmetric Naphthol Coupling in the Synthesis of Perylenequinone Natural Products metric coupling could provide either enantiomer of the axial chiral bisiodide shown in Scheme 390, from which a biscuprate could be generated and added to either enantiomer of propylene oxide. This allowed for selective synthesis of the diastereomeric series leading to cercosporin, calphostin D, and phleichrome.*”®
Scheme 390. Asymmetric Naphthol Coupling in the Synthesis of Perylenequinone Natural Products metric coupling could provide either enantiomer of the axial chiral bisiodide shown in Scheme 390, from which a biscuprate could be generated and added to either enantiomer of propylene oxide. This allowed for selective synthesis of the diastereomeric series leading to cercosporin, calphostin D, and phleichrome.*”®
Scheme 389. Asymmetric Naphthol Coupling in the Synthesis of Nigerone
Scheme 389. Asymmetric Naphthol Coupling in the Synthesis of Nigerone
of the diamine is to support the dimeric clustering of copper and to weaken the Cu—OAr naphtholic bond, facilitating C—C bond formation.°” Further infrared multiphoton disassociation (IRMPD) spectroscopy and DFT calculations showed that the driving force for the coupling is the keto—enol tautomerization, which may occur while the initial adduct is still bound to copper. The DFT calculations showed that the C-O and O-O
of the diamine is to support the dimeric clustering of copper and to weaken the Cu—OAr naphtholic bond, facilitating C—C bond formation.°” Further infrared multiphoton disassociation (IRMPD) spectroscopy and DFT calculations showed that the driving force for the coupling is the keto—enol tautomerization, which may occur while the initial adduct is still bound to copper. The DFT calculations showed that the C-O and O-O
A gas-phase study by Roithova and co-workers showed that the CuCl(OH)TMEDA-catalyzed biaryl coupling occurs in clusters containing two copper atoms (Scheme 394). The role
A gas-phase study by Roithova and co-workers showed that the CuCl(OH)TMEDA-catalyzed biaryl coupling occurs in clusters containing two copper atoms (Scheme 394). The role
Scheme 391. Asymmetric Biaryl Coupling and Dynamic Aldol Reaction in the Synthesis of Hypocrellin A Scheme 392. The First Total Synthesis of (S)-Bisoranjidiol
Scheme 391. Asymmetric Biaryl Coupling and Dynamic Aldol Reaction in the Synthesis of Hypocrellin A Scheme 392. The First Total Synthesis of (S)-Bisoranjidiol
Scheme 396. Dynamic Thermodynamic Resolution of BINOL and Vaulted Biaryls
Scheme 396. Dynamic Thermodynamic Resolution of BINOL and Vaulted Biaryls
Scheme 402. Product Distributions on the Copper-Catalyzed Aerobic Oxidative Dimerization of Phenols
Scheme 402. Product Distributions on the Copper-Catalyzed Aerobic Oxidative Dimerization of Phenols
Scheme 399. Mechanism of Cross-Coupling with Lewis Acid Scheme 400. Oxidative Aerobic Cross-Coupling of Linked Naphthol Units
Scheme 399. Mechanism of Cross-Coupling with Lewis Acid Scheme 400. Oxidative Aerobic Cross-Coupling of Linked Naphthol Units
Scheme 401. Asymmetric Oxidative Cross-Coupling of an Electron-Rich Capped 2,6-Naphthalene Diol with a Linked Electron-Poor Monomer
Scheme 401. Asymmetric Oxidative Cross-Coupling of an Electron-Rich Capped 2,6-Naphthalene Diol with a Linked Electron-Poor Monomer
(Scheme 403).’"* Note that the peroxide-bridged diradical species is unstable and likely undergoes rapid fragmentation to the copper(II) complex. However, the nature of the rate- determining step can be catalyst-dependent.’””° In the presence of protic solvents the dimer formed initially undergoes further reaction, generating either an oxetane’'' or a furan tricycle’'* (Scheme 404). Interestingly, substitution at the meta-position prevents this additional oxidation step.””” Treatment of the ortho—ortho-coupled product with CuCl, and pyridine in the presence of oxygen and KOH in methanol also leads only to the benzooxetane product.’ only one reactive site, multiple products can still arise from C— C or C—O coupling depending on the reaction conditions. Phenols with multiple reactive sites typically generate complex mixtures of products. Notably, phenol dimerization competes with phenol oxygenation under many conditions using copper catalysts with oxygen (see section 7.4).
(Scheme 403).’"* Note that the peroxide-bridged diradical species is unstable and likely undergoes rapid fragmentation to the copper(II) complex. However, the nature of the rate- determining step can be catalyst-dependent.’””° In the presence of protic solvents the dimer formed initially undergoes further reaction, generating either an oxetane’'' or a furan tricycle’'* (Scheme 404). Interestingly, substitution at the meta-position prevents this additional oxidation step.””” Treatment of the ortho—ortho-coupled product with CuCl, and pyridine in the presence of oxygen and KOH in methanol also leads only to the benzooxetane product.’ only one reactive site, multiple products can still arise from C— C or C—O coupling depending on the reaction conditions. Phenols with multiple reactive sites typically generate complex mixtures of products. Notably, phenol dimerization competes with phenol oxygenation under many conditions using copper catalysts with oxygen (see section 7.4).
Scheme 404. Formation of a Furan Tricycle and Oxetane from the ortho-Coupled Product of 2,4-Di-tert-butylphenol Barton and co-workers," the first application of aerobic copper-catalyzed intramolecular coupling was reported by Kametani et al. in 1976.’”’ The treatment of (+)-reticuline perchlorate with cuprous chloride and pyridine under O, yielded (+)-corytuberine in 28% yield (Scheme 408). Use of the free base of (+)-reticuline resulted in an intractable tarry mixture.
Scheme 404. Formation of a Furan Tricycle and Oxetane from the ortho-Coupled Product of 2,4-Di-tert-butylphenol Barton and co-workers," the first application of aerobic copper-catalyzed intramolecular coupling was reported by Kametani et al. in 1976.’”’ The treatment of (+)-reticuline perchlorate with cuprous chloride and pyridine under O, yielded (+)-corytuberine in 28% yield (Scheme 408). Use of the free base of (+)-reticuline resulted in an intractable tarry mixture.
Scheme 406. Proposed Mechanism for the Formation of Unsaturated Lactams from Benzooxetanes
Scheme 406. Proposed Mechanism for the Formation of Unsaturated Lactams from Benzooxetanes
Scheme 403. Proposed Reaction Mechanism to Bisphenol
Scheme 403. Proposed Reaction Mechanism to Bisphenol
Scheme 409. Intramolecular Phenol Coupling in the Total Synthesis of TMC-66
Scheme 409. Intramolecular Phenol Coupling in the Total Synthesis of TMC-66
7.3.1.2. Diastereoselective Naphthol Polymerization. The availability of enantiopure BINOL derivatives has led to the development of methods for diastereoselective naphthol polymerization. Okamoto and co-workers found that for optimum stereocontrol of the resulting polymer, the stereo- chemistry of the monomer and amine ligand must be properly matched. While a matched case can give up to 84:16 (R)/(S) ratio of axial stereocenters in the product, a mismatched case can drop the ratio to nearly 1:1 (Scheme 411).’** However, using the PhBox ligand completely overrides the stereo- chemistry of the monomer, resulting in complete ligand control (Scheme 412), an effect seen both with both binaphthol and trinaphthol monomers,°**””? as well as dihydroxyquater- naphthyl derivatives (Scheme 413). 730 cae Hh we —_ 6Uele OU - oe ‘aac
7.3.1.2. Diastereoselective Naphthol Polymerization. The availability of enantiopure BINOL derivatives has led to the development of methods for diastereoselective naphthol polymerization. Okamoto and co-workers found that for optimum stereocontrol of the resulting polymer, the stereo- chemistry of the monomer and amine ligand must be properly matched. While a matched case can give up to 84:16 (R)/(S) ratio of axial stereocenters in the product, a mismatched case can drop the ratio to nearly 1:1 (Scheme 411).’** However, using the PhBox ligand completely overrides the stereo- chemistry of the monomer, resulting in complete ligand control (Scheme 412), an effect seen both with both binaphthol and trinaphthol monomers,°**””? as well as dihydroxyquater- naphthyl derivatives (Scheme 413). 730 cae Hh we —_ 6Uele OU - oe ‘aac
Scheme 407. Trapping of the 6-Amino-2,4-dieneone Intermediates with Secondary Amines
Scheme 407. Trapping of the 6-Amino-2,4-dieneone Intermediates with Secondary Amines
Scheme 408. Intramolecular Biomimetic Phenol Coupling to (+)-Corytuberine with Copper and Oxygen
Scheme 408. Intramolecular Biomimetic Phenol Coupling to (+)-Corytuberine with Copper and Oxygen
Table 17. Racemic Copper-Catalyzed Aerobic Oxidative Polymerization of Naphthols Scheme 411. Matched and Mismatched Cases in the Diastereoselective Asymmetric Oxidative Coupling Polymerization (AOCP)
Table 17. Racemic Copper-Catalyzed Aerobic Oxidative Polymerization of Naphthols Scheme 411. Matched and Mismatched Cases in the Diastereoselective Asymmetric Oxidative Coupling Polymerization (AOCP)
Scheme 412. PhBox Ligand Overrides the Stereochemistry of Monomer in Diastereoselective AOCP
Scheme 412. PhBox Ligand Overrides the Stereochemistry of Monomer in Diastereoselective AOCP
catalyst to the tandem polymerization reaction. Starting from an achiral alkynyl 2-naphthol, the resulting polymer formed in 83% yield with approximately 73% ee at each biaryl bond,
catalyst to the tandem polymerization reaction. Starting from an achiral alkynyl 2-naphthol, the resulting polymer formed in 83% yield with approximately 73% ee at each biaryl bond,
bonds are formed, diastereoselection becomes relevant. Here, the diastereoselection is poor, and the enantioselection in the chiral C, diastereomer is moderate.
bonds are formed, diastereoselection becomes relevant. Here, the diastereoselection is poor, and the enantioselection in the chiral C, diastereomer is moderate.
7.3.1.4. Heterocoupling Naphthol Polymerization. The combined utility of the PhBox diamine ligand for the asymmetric oxidative biaryl heterocoupling (section 7.1.4) and for oxidative polymerization (above) has led to its application in cross-coupling polymerization reactions. Again, the combination of an electron-rich and electron-poor substrate is crucial. As seen in Scheme 416, a very chemoselective (80%) oxidative coupling can arise.*** Since multiple axial chiral
7.3.1.4. Heterocoupling Naphthol Polymerization. The combined utility of the PhBox diamine ligand for the asymmetric oxidative biaryl heterocoupling (section 7.1.4) and for oxidative polymerization (above) has led to its application in cross-coupling polymerization reactions. Again, the combination of an electron-rich and electron-poor substrate is crucial. As seen in Scheme 416, a very chemoselective (80%) oxidative coupling can arise.*** Since multiple axial chiral
Scheme 417. Heteropolymerization of a Heterodimeric Monomer Using Copper and Molecular Oxygen
Scheme 417. Heteropolymerization of a Heterodimeric Monomer Using Copper and Molecular Oxygen
demonstrating a useful approach for the organized assembly of multifunctional substrates in a single operation (Scheme 415),”3"
demonstrating a useful approach for the organized assembly of multifunctional substrates in a single operation (Scheme 415),”3"
Scheme 413. Polymerization of Dihydroxyquaternaphthyl Derivatives
Scheme 413. Polymerization of Dihydroxyquaternaphthyl Derivatives
Scheme 420. Oxidative Polymerization of Methyl 3,6- Dihydroxy-2-naphthoate substrates lacking a chelating group in the C3-position (Scheme 421).’3
Scheme 420. Oxidative Polymerization of Methyl 3,6- Dihydroxy-2-naphthoate substrates lacking a chelating group in the C3-position (Scheme 421).’3
As in the case of copper—bisoxazoline heterodimerizations (section 7.1.4), the addition of the Lewis acid Yb(OTf); improves the chemoselectivity and stereoselectivity at the expense of yield and degree of polymerization (Scheme 422).”*4
As in the case of copper—bisoxazoline heterodimerizations (section 7.1.4), the addition of the Lewis acid Yb(OTf); improves the chemoselectivity and stereoselectivity at the expense of yield and degree of polymerization (Scheme 422).”*4
amount of enantioselectivity was seen with higher copper loading and 2 full equivalent of (—)-sparteine with respect to monomer.°”! A series of hyperbranched polymers were also synthesized using this method. Interestingly, the stereo- selectivity in the polymerization was much lower with
amount of enantioselectivity was seen with higher copper loading and 2 full equivalent of (—)-sparteine with respect to monomer.°”! A series of hyperbranched polymers were also synthesized using this method. Interestingly, the stereo- selectivity in the polymerization was much lower with
Scheme 418. Heterocoupled Polymerization of Two 6,6’- Homodimeric Monomers Scheme 419. Crosspolymerization of 2,6- Dihydroxynaphthalene with a Homodimeric 6,6’-Linked Chelating Monomer
Scheme 418. Heterocoupled Polymerization of Two 6,6’- Homodimeric Monomers Scheme 419. Crosspolymerization of 2,6- Dihydroxynaphthalene with a Homodimeric 6,6’-Linked Chelating Monomer
consisting of two phenols linked through a biphenyl group (Scheme 423).”°° Alternatively, two phenols can be linked through an ether. Upon subjection to oxidative polymerization conditions with stoichiometric copper, a polymer consisting of diphenoquinone linkages was formed. The diphenoquinone polymers can be used as oxidizing agents, and treatment of these polymers with hydrazine hydrate yields the C— -c linked polyphenols, which have applications as antioxidants.”*
consisting of two phenols linked through a biphenyl group (Scheme 423).”°° Alternatively, two phenols can be linked through an ether. Upon subjection to oxidative polymerization conditions with stoichiometric copper, a polymer consisting of diphenoquinone linkages was formed. The diphenoquinone polymers can be used as oxidizing agents, and treatment of these polymers with hydrazine hydrate yields the C— -c linked polyphenols, which have applications as antioxidants.”*
Two products are possible in the initial oxidative coupling of two molecules of 2,6-dimethylphenol using Cu(I)Cl under oxygen (Scheme 425).°” Diphenylene ether, is formed by Scheme 423. Polymerization by Formation of Diphenoquinones 7.3.3. C-O Naphthol and Phenol Polymers. In 1959, Alan Hay reported the first copper-catalyzed C—O polymer- ization of 2,6-dimethylphenol to form poly(phenylene ether), or PPE,” * using cuprous chloride in pyridine under an oxygen atmosphere.” The polymer thus formed is heat-resistant and durable, especially when combined with polystyrene or other polymers in postprocessing. PPE and its derivatives are found in everything from printer cartridges’ to automobile fend- ers.’*° Given its broad commercial utility, much work has been done to elucidate the mechanism of polymerization, improve the conditions for the polymerization process, and develop new substrates and catalysts for the oxidative polymerization product. This review covers only the copper-catalyzed aerobic oxidative polymerization of phenols. Commercial applications of polymer products, including postproduction functionaliza- tion and the blending of polymer products, such as the formation of Noryl, are covered elsewhere,’”*' as are reactions that use other metals.”*”
Two products are possible in the initial oxidative coupling of two molecules of 2,6-dimethylphenol using Cu(I)Cl under oxygen (Scheme 425).°” Diphenylene ether, is formed by Scheme 423. Polymerization by Formation of Diphenoquinones 7.3.3. C-O Naphthol and Phenol Polymers. In 1959, Alan Hay reported the first copper-catalyzed C—O polymer- ization of 2,6-dimethylphenol to form poly(phenylene ether), or PPE,” * using cuprous chloride in pyridine under an oxygen atmosphere.” The polymer thus formed is heat-resistant and durable, especially when combined with polystyrene or other polymers in postprocessing. PPE and its derivatives are found in everything from printer cartridges’ to automobile fend- ers.’*° Given its broad commercial utility, much work has been done to elucidate the mechanism of polymerization, improve the conditions for the polymerization process, and develop new substrates and catalysts for the oxidative polymerization product. This review covers only the copper-catalyzed aerobic oxidative polymerization of phenols. Commercial applications of polymer products, including postproduction functionaliza- tion and the blending of polymer products, such as the formation of Noryl, are covered elsewhere,’”*' as are reactions that use other metals.”*”
ketal intermediate.” Historically, the radical pathway has been accepted,’* though the ionic mechanism has gained significant ; 743,752 ground in the past 15 years. attack of the phenolic oxygen of one monomer on the para position of another monomer. This C—O-coupled dimer can react further to ultimately lead to polymer. Recent studies have suggested that this process is likely ionic rather than radical,’*? but a consensus has not yet been reached. Diphenoquinone arises from the para—para coupling of two monomers, followed by two-electron oxidation, and is the major contaminant resulting from the polymerization process. The amount of diphenoquinone can be reduced significantly by using a large excess of amine or hydroxide base with respect to the copper catalyst. aaa
ketal intermediate.” Historically, the radical pathway has been accepted,’* though the ionic mechanism has gained significant ; 743,752 ground in the past 15 years. attack of the phenolic oxygen of one monomer on the para position of another monomer. This C—O-coupled dimer can react further to ultimately lead to polymer. Recent studies have suggested that this process is likely ionic rather than radical,’*? but a consensus has not yet been reached. Diphenoquinone arises from the para—para coupling of two monomers, followed by two-electron oxidation, and is the major contaminant resulting from the polymerization process. The amount of diphenoquinone can be reduced significantly by using a large excess of amine or hydroxide base with respect to the copper catalyst. aaa
Much work has been performed to control the polymer- ization reaction, including the examination of the effect of copper source, oxygen amount, amine ligand, and additive on the yield, reaction rate, and intrinsic viscosity (IV) of the resultant polymer. graces eex Scheme 428. Dendrimeric Ligand PAMAMG3 Used in the Aerobic Copper-Catalyzed Oxidative Polymerization of 2,6- Dimethylphenol
Much work has been performed to control the polymer- ization reaction, including the examination of the effect of copper source, oxygen amount, amine ligand, and additive on the yield, reaction rate, and intrinsic viscosity (IV) of the resultant polymer. graces eex Scheme 428. Dendrimeric Ligand PAMAMG3 Used in the Aerobic Copper-Catalyzed Oxidative Polymerization of 2,6- Dimethylphenol
oxidation of 2,4,6-trimethylphenol also results in a polymer consisting of 2,6-dimethylphenol units. One equivalent of formaldehyde is ejected for every equivalent of phenol that is incorporated into the polymer (Scheme 430).
oxidation of 2,4,6-trimethylphenol also results in a polymer consisting of 2,6-dimethylphenol units. One equivalent of formaldehyde is ejected for every equivalent of phenol that is incorporated into the polymer (Scheme 430).
Scheme 430. Formation of PPE from Oxidative Degradative Polymerization of 2,4,6-Trimethylphenol
Scheme 430. Formation of PPE from Oxidative Degradative Polymerization of 2,4,6-Trimethylphenol
Table 18. continued
Table 18. continued
Similarly, 98% of the double bonds in the polymer made from 2-methyl-6-geranylphenol underwent dibromination.**” identity of the alkyl substituent had little effect on the electronic character of the resulting polymer.**°
Similarly, 98% of the double bonds in the polymer made from 2-methyl-6-geranylphenol underwent dibromination.**” identity of the alkyl substituent had little effect on the electronic character of the resulting polymer.**°
Scheme 431. Synthesis of a Bifunctional Polymer Linked through a Hydroquinone Heitz and Risse determined that a bifunctional polymer can be synthesized in one step if 0.25 equiv of a dimethyl- methylene-linked dimer of 2,6-dimethylphenol is included in the reaction as a comonomer (Scheme 432) using standard
Scheme 431. Synthesis of a Bifunctional Polymer Linked through a Hydroquinone Heitz and Risse determined that a bifunctional polymer can be synthesized in one step if 0.25 equiv of a dimethyl- methylene-linked dimer of 2,6-dimethylphenol is included in the reaction as a comonomer (Scheme 432) using standard
Scheme 434. Oxidative Polymerization of para-Substituted Phenols To Obtain Predominantly C—O Coupled Product Scheme 433. Oxidative Polymerization of a Silicon-Tethered para-Substituted Phenol
Scheme 434. Oxidative Polymerization of para-Substituted Phenols To Obtain Predominantly C—O Coupled Product Scheme 433. Oxidative Polymerization of a Silicon-Tethered para-Substituted Phenol
Scheme 432. Synthesis of a Bifunctional Polymer Linked via a Linked Dimer of 2,6-Dimethylphenol
Scheme 432. Synthesis of a Bifunctional Polymer Linked via a Linked Dimer of 2,6-Dimethylphenol
Scheme 435. Radical Intermediates in the Oxidation of 1- Naphthol
Scheme 435. Radical Intermediates in the Oxidation of 1- Naphthol
Scheme 438. Copper-Catalyzed Aerobic Oxygenation of Naphthols and Phenols Scheme 439. Proposed Mechanism for the Oxygenation of Phenols and Naphthols by Copper and Morpholine
Scheme 438. Copper-Catalyzed Aerobic Oxygenation of Naphthols and Phenols Scheme 439. Proposed Mechanism for the Oxygenation of Phenols and Naphthols by Copper and Morpholine
Scheme 436. Oxidative Polymerization of 1-Naphthol
Scheme 436. Oxidative Polymerization of 1-Naphthol
Table 20. Copper-Catalyzed Oxygenation of Phenols to ortho-Quinones Scheme 443. Mechanism for the Copper-Catalyzed Oxidation of para-Methoxyphenol to a Vinylogous Ester
Table 20. Copper-Catalyzed Oxygenation of Phenols to ortho-Quinones Scheme 443. Mechanism for the Copper-Catalyzed Oxidation of para-Methoxyphenol to a Vinylogous Ester
the y-hydroxide groups in the enzyme. In general, binuclear copper(II) complexes show stronger catecholase activity, with an optimum Cu—Cu interatomic distance of 3 APE 980288 91 The utility of binuclear metal complexes suggests that both copper centers are involved in the formation of one ortho- quinone. This mechanism depends on catalyst structure, and smaller ligands such as TMEDA appear to react through a mononuclear species.””* The reaction is promoted by high pH, in the form of either added amine base or aqueous buffer solution.”** The rate order of the reaction varies across catalyst structures.’ Das reported the most efficient catalyst, a binuclear salen ligand, in 2008.78
the y-hydroxide groups in the enzyme. In general, binuclear copper(II) complexes show stronger catecholase activity, with an optimum Cu—Cu interatomic distance of 3 APE 980288 91 The utility of binuclear metal complexes suggests that both copper centers are involved in the formation of one ortho- quinone. This mechanism depends on catalyst structure, and smaller ligands such as TMEDA appear to react through a mononuclear species.””* The reaction is promoted by high pH, in the form of either added amine base or aqueous buffer solution.”** The rate order of the reaction varies across catalyst structures.’ Das reported the most efficient catalyst, a binuclear salen ligand, in 2008.78
Scheme 442. Copper-Catalyzed Aerobic Phenol Oxidation in the Total Synthesis of Dihydromaesanin
Scheme 442. Copper-Catalyzed Aerobic Phenol Oxidation in the Total Synthesis of Dihydromaesanin
Scheme 446. Synthesis of 2H-1-Benzopyran-5,8-quinones from para-Methoxyphenol Scheme 447. Mechanism of the Tandem Saucy—Marbet— Claisen, [1,5]-Hydride Shift, and 6-7 Electrocyclization
Scheme 446. Synthesis of 2H-1-Benzopyran-5,8-quinones from para-Methoxyphenol Scheme 447. Mechanism of the Tandem Saucy—Marbet— Claisen, [1,5]-Hydride Shift, and 6-7 Electrocyclization
Scheme 444. Synthesis of Substituted Benzoquinones from para-Methoxyphenol via a Dimeric ortho-Quinone Scheme 445. Synthesis of Dihydroardisiaquinone A via an ortho-Quinone Derived from para-Methoxyphenol
Scheme 444. Synthesis of Substituted Benzoquinones from para-Methoxyphenol via a Dimeric ortho-Quinone Scheme 445. Synthesis of Dihydroardisiaquinone A via an ortho-Quinone Derived from para-Methoxyphenol
comparable to that of the standard luminol substrate hemin, an iron-containing porphyrin.
comparable to that of the standard luminol substrate hemin, an iron-containing porphyrin.
Scheme 450. Proposed Mechanism for the Observed Alkyl Migration
Scheme 450. Proposed Mechanism for the Observed Alkyl Migration
Scheme 448. Synthesis of Amino ortho-Quinones from para- Methoxyphenol via a Dimeric ortho-Quinone
Scheme 448. Synthesis of Amino ortho-Quinones from para- Methoxyphenol via a Dimeric ortho-Quinone
Scheme 451. Catechol Oxidation to an ortho-Quinone Myers and co-workers applied a very mild copper-mediated aerobic oxidation of hydroquinones to para-quinones in the total synthesis of the sensitive enediyne (+)-dynemicin A (Scheme 463). Treatment of a Diels—Alder adduct model system with 4 equiv of CuCl in the presence of HF—pyridine under an oxygen atmosphere resulted in selective cleavage of phenolic silyl ethers with concurrent oxidation to the para- ; 1027 quinone.
Scheme 451. Catechol Oxidation to an ortho-Quinone Myers and co-workers applied a very mild copper-mediated aerobic oxidation of hydroquinones to para-quinones in the total synthesis of the sensitive enediyne (+)-dynemicin A (Scheme 463). Treatment of a Diels—Alder adduct model system with 4 equiv of CuCl in the presence of HF—pyridine under an oxygen atmosphere resulted in selective cleavage of phenolic silyl ethers with concurrent oxidation to the para- ; 1027 quinone.
Table 22. continued
Table 22. continued
Table 22. continued
Table 22. continued
Table 22. continued
Table 22. continued
Table 22. continued The same type of transformation occurs with other nucleophiles, such as amines. Treatment of hydroquinone with two equivalents of a primary or a secondary amine in the presence of catalytic copper nanoparticle-embedded aluminum oxyhydroxide under an oxygen atmosphere yields the bisaminoquinone product in excellent yield (Scheme 467).'°* ment of a naphthoquinone with an a-bromocarbonyl and 3 equiv of pyridine results in incorporation of one pyridine into a fused tetracycle.'°** A representative sample of the substrate scope is shown in Scheme 472. The reaction tolerates pyridine, 4-alkylpyridine, and isoquinoline nucleophiles. The a-bromo- carbonyl cannot have any other enolizable positions; for R’, both alkoxy groups and sterically unencumbered arenes work well.
Table 22. continued The same type of transformation occurs with other nucleophiles, such as amines. Treatment of hydroquinone with two equivalents of a primary or a secondary amine in the presence of catalytic copper nanoparticle-embedded aluminum oxyhydroxide under an oxygen atmosphere yields the bisaminoquinone product in excellent yield (Scheme 467).'°* ment of a naphthoquinone with an a-bromocarbonyl and 3 equiv of pyridine results in incorporation of one pyridine into a fused tetracycle.'°** A representative sample of the substrate scope is shown in Scheme 472. The reaction tolerates pyridine, 4-alkylpyridine, and isoquinoline nucleophiles. The a-bromo- carbonyl cannot have any other enolizable positions; for R’, both alkoxy groups and sterically unencumbered arenes work well.
Scheme 453. Mechanism of the Oxidation of Ascorbic Acid with Concurrent Luminol Chemiluminescence
Scheme 453. Mechanism of the Oxidation of Ascorbic Acid with Concurrent Luminol Chemiluminescence
Table 23. continued The substrate scope can be improved considerably through the use of a polymer-supported bipyridyl ligand (Scheme 483). The polymer catalyst can be recovered and reused at least 3 times without appreciable loss of activity.'°* controlled by moderation of the reaction time (Scheme 481).° The reaction is believed to proceed via an ortho- quinone methide that undergoes nucleophilic attack by the alcohol solvent (Scheme 482). A second oxidation/addition sequence gives an acetal that can be hydrolyzed to give the aldehyde product. Further oxidation of this compound gives a radical that captures molecular oxygen. Elimination of formic acid gives the observed para-quinone product. Alternatively, the para-quinone can be formed from protonation of the initial peroxy radical followed by rearrangement to expel methanol.
Table 23. continued The substrate scope can be improved considerably through the use of a polymer-supported bipyridyl ligand (Scheme 483). The polymer catalyst can be recovered and reused at least 3 times without appreciable loss of activity.'°* controlled by moderation of the reaction time (Scheme 481).° The reaction is believed to proceed via an ortho- quinone methide that undergoes nucleophilic attack by the alcohol solvent (Scheme 482). A second oxidation/addition sequence gives an acetal that can be hydrolyzed to give the aldehyde product. Further oxidation of this compound gives a radical that captures molecular oxygen. Elimination of formic acid gives the observed para-quinone product. Alternatively, the para-quinone can be formed from protonation of the initial peroxy radical followed by rearrangement to expel methanol.
Scheme 456. In situ Trapping of the Quinone Product with 3-Methyl-2-benzothiazoline Hydrazone (MBTH) major product is the formylated benzopyran (S-FTD). On the other hand, when sodium dodecyl sulfate is used, the major product is the ring-opened quinone (a-tocoquinone).'°** Both products are proposed to come from the same phenol radical intermediate (Scheme 485).
Scheme 456. In situ Trapping of the Quinone Product with 3-Methyl-2-benzothiazoline Hydrazone (MBTH) major product is the formylated benzopyran (S-FTD). On the other hand, when sodium dodecyl sulfate is used, the major product is the ring-opened quinone (a-tocoquinone).'°** Both products are proposed to come from the same phenol radical intermediate (Scheme 485).
Scheme 459. Oxidative Cleavage of Catechols by Stoichiometric Copper under Oxygen Scheme 458. Effect of Temperature on the k,,; of a Diastereoselective Aerobic Oxidation of t-Dopamine with a Chiral Copper Complex
Scheme 459. Oxidative Cleavage of Catechols by Stoichiometric Copper under Oxygen Scheme 458. Effect of Temperature on the k,,; of a Diastereoselective Aerobic Oxidation of t-Dopamine with a Chiral Copper Complex
Scheme 460. Possible Mechanism for the Copper-Mediated Oxidative Cleavage of Catechols under Oxygen Atmosphere
Scheme 460. Possible Mechanism for the Copper-Mediated Oxidative Cleavage of Catechols under Oxygen Atmosphere
Scheme 454. The First Oxidative Kinetic Resolution o: Dopamine Using Copper and Molecular Oxygen Scheme 455. Oxidative Kinetic Resolution of Dopamine Methyl Ester
Scheme 454. The First Oxidative Kinetic Resolution o: Dopamine Using Copper and Molecular Oxygen Scheme 455. Oxidative Kinetic Resolution of Dopamine Methyl Ester
Scheme 463. Copper-Mediated Aerobic Oxidation to a para- Quinone in the Total Synthesis of (+)-Dynemicin A
Scheme 463. Copper-Mediated Aerobic Oxidation to a para- Quinone in the Total Synthesis of (+)-Dynemicin A
Scheme 466. Mechanism for the Sequential Oxidation, Nucleophilic Addition, And Oxidation
Scheme 466. Mechanism for the Sequential Oxidation, Nucleophilic Addition, And Oxidation
Scheme 464. Quinone Oxidation in the Total Synthesis of Oosporein Scheme 465. Preparation of 2-Acyl-3-alkyoxy-para-quinones via Oxidation, Nucleophilic Addition, and Oxidation
Scheme 464. Quinone Oxidation in the Total Synthesis of Oosporein Scheme 465. Preparation of 2-Acyl-3-alkyoxy-para-quinones via Oxidation, Nucleophilic Addition, and Oxidation
Scheme 461. Substrate Scope in the Oxidative Cleavage of Catechols
Scheme 461. Substrate Scope in the Oxidative Cleavage of Catechols
Scheme 467. Oxidative Bisamination of Hydroquinones to 2,5-Diamino-para-quinones Scheme 468. Substrate Scope of the Nucleophilic Addition of Dialkyl Amines to Quinones under Oxidizing Conditions
Scheme 467. Oxidative Bisamination of Hydroquinones to 2,5-Diamino-para-quinones Scheme 468. Substrate Scope of the Nucleophilic Addition of Dialkyl Amines to Quinones under Oxidizing Conditions
Scheme 472. Multicomponent Coupling via Oxidative Addition to 1,4-Naphthoquinone (Scheme 488). The oxidation of 2,4,6-tri-tert-butylphenol yields the same para-quinone product with low catalyst loading and high temperatures, though the yield was not reported.‘
Scheme 472. Multicomponent Coupling via Oxidative Addition to 1,4-Naphthoquinone (Scheme 488). The oxidation of 2,4,6-tri-tert-butylphenol yields the same para-quinone product with low catalyst loading and high temperatures, though the yield was not reported.‘
Scheme 469. Amine Addition to Unsymmetrically Substituted Quinones under Oxidative Conditions
Scheme 469. Amine Addition to Unsymmetrically Substituted Quinones under Oxidative Conditions
Scheme 470. Oxidative Bisamination in the Synthesis of Functionalized Helicenes
Scheme 470. Oxidative Bisamination in the Synthesis of Functionalized Helicenes
The oxidation of 2,6-di-tert-butyl-4-methylphenol with copper(I) is less clean, with six identified products formed with 5.5 mol % CuCl in 4 hours.'°*” The major product of this reaction is 2,6-dimethyl-para-quione, formed in 27% yield
The oxidation of 2,6-di-tert-butyl-4-methylphenol with copper(I) is less clean, with six identified products formed with 5.5 mol % CuCl in 4 hours.'°*” The major product of this reaction is 2,6-dimethyl-para-quione, formed in 27% yield
Scheme 471. Oxidative Addition of Anilines to Naphthoquinone
Scheme 471. Oxidative Addition of Anilines to Naphthoquinone
Scheme 474. Unexpected Ring Contraction in the Aerobic Copper-Catalyzed Oxidation of Phenol Scheme 475. Screening Various Alcohols in the Oxidative Ring Contraction of Phenols
Scheme 474. Unexpected Ring Contraction in the Aerobic Copper-Catalyzed Oxidation of Phenol Scheme 475. Screening Various Alcohols in the Oxidative Ring Contraction of Phenols
Scheme 476. The Effect of Substitution Pattern on the Oxidation of Aminophenol Scheme 477. Mechanism for the Formation of an Oxidized Dimer of ortho-Aminophenol
Scheme 476. The Effect of Substitution Pattern on the Oxidation of Aminophenol Scheme 477. Mechanism for the Formation of an Oxidized Dimer of ortho-Aminophenol
Scheme 473. Proposed Mechanism for the Oxidative Multicomponent Coupling of Naphthoquinone, Pyridine, and a@-Bromoacetophenone Scheme 473. Proposed Mechanism for the Oxidative Multicomponent Coupling of Naphthoquinone, Pyridine, and a@-Bromoacetophenone
Scheme 473. Proposed Mechanism for the Oxidative Multicomponent Coupling of Naphthoquinone, Pyridine, and a@-Bromoacetophenone Scheme 473. Proposed Mechanism for the Oxidative Multicomponent Coupling of Naphthoquinone, Pyridine, and a@-Bromoacetophenone
Scheme 478. Oxidative Halogenation of Phenols
Scheme 478. Oxidative Halogenation of Phenols
Scheme 482. Mechanism for the Oxidation of 2,4,6- Trimethylphenol to a Benzaldehyde and a para-Quinone
Scheme 482. Mechanism for the Oxidation of 2,4,6- Trimethylphenol to a Benzaldehyde and a para-Quinone
Scheme 483. Oxidative Benzylic C-O Coupling of a Phenol Using a Supported Catalyst
Scheme 483. Oxidative Benzylic C-O Coupling of a Phenol Using a Supported Catalyst
Scheme 484. Oxidation of a-Tocopherol in the Presence of Solubilizing Agents
Scheme 484. Oxidation of a-Tocopherol in the Presence of Solubilizing Agents
Scheme 480. Oxidative Nitration of a Phenol
Scheme 480. Oxidative Nitration of a Phenol
Scheme 485. A Common Intermediate in the Oxidation of a- Tocopherol to S-FTD and a@-Tocoquinone Scheme 486. Oxidation of 2,4,6-Trimethylphenol To Yield Stilbenequinone in the Absence of Alcohol
Scheme 485. A Common Intermediate in the Oxidation of a- Tocopherol to S-FTD and a@-Tocoquinone Scheme 486. Oxidation of 2,4,6-Trimethylphenol To Yield Stilbenequinone in the Absence of Alcohol
Scheme 489. Oxidative Alkenylphenol Coupling to Carpanone
Scheme 489. Oxidative Alkenylphenol Coupling to Carpanone
Scheme 487. Oxidation of Two Isomers of Di-tert-butyl- methylphenol
Scheme 487. Oxidation of Two Isomers of Di-tert-butyl- methylphenol
Scheme 491. Oxidative Dearomatization of Dialkyl- monomethoxyphenols Scheme 492. Oxidative Dearomatization by Addition of Solvent to the Least Hindered Position
Scheme 491. Oxidative Dearomatization of Dialkyl- monomethoxyphenols Scheme 492. Oxidative Dearomatization by Addition of Solvent to the Least Hindered Position
Scheme 494. Asymmetric Dearomatization of Bisphenols en Route to Azaphilones Scheme 495. Total Syntheses Using Asymmetric Dearomatization As a Key Step
Scheme 494. Asymmetric Dearomatization of Bisphenols en Route to Azaphilones Scheme 495. Total Syntheses Using Asymmetric Dearomatization As a Key Step
Scheme 496. Utilization of a (+)-Sparteine Surrogate in an Oxidative Dearomatization
Scheme 496. Utilization of a (+)-Sparteine Surrogate in an Oxidative Dearomatization
Scheme 493. (—)-Sparteine-Derived Tyrosinase Mimic
Scheme 493. (—)-Sparteine-Derived Tyrosinase Mimic
8.1. C—-C Couplings of Anilines
8.1. C—-C Couplings of Anilines
Scheme 500. Potential Oxidation Pathways of Anilines
Scheme 500. Potential Oxidation Pathways of Anilines
Scheme 498. Total Synthesis of Aquaticol via Asymmetric Dearomatization
Scheme 498. Total Synthesis of Aquaticol via Asymmetric Dearomatization
Scheme 505. Effect of ortho-Substitution on Azo Formation from Anilines
Scheme 505. Effect of ortho-Substitution on Azo Formation from Anilines
Scheme 501. Oxidative Coupling of 2-Naphthylamine with a Benzylamine—Copper Catalyst
Scheme 501. Oxidative Coupling of 2-Naphthylamine with a Benzylamine—Copper Catalyst
Scheme 504. Early Example of Copper-Catalyzed Azo Formation Concurrent work by Kinoshita described a similar system, also utilizing CuCl and pyridine in air to form azo compounds in high yield (Scheme 505).°8619° Several key features of the
Scheme 504. Early Example of Copper-Catalyzed Azo Formation Concurrent work by Kinoshita described a similar system, also utilizing CuCl and pyridine in air to form azo compounds in high yield (Scheme 505).°8619° Several key features of the
A mechanistic proposal for the formation of azo compounds from anilines proceeds through initial oxidation of the substrate with copper to produce an aniline radical. Subsequent reaction with molecular oxygen could then afford nitrosobenzene after further oxidation. Condensation with unreacted aniline substrate then affords the azo product. However, subjecting nitrosobenzene and ethyl 4-aminobenzoate to typical coupling conditions did not afford any of the heterocoupled product (Scheme 511). Thus, intervention of a nitroso intermediate does not appear to be consistent with empirical data.
A mechanistic proposal for the formation of azo compounds from anilines proceeds through initial oxidation of the substrate with copper to produce an aniline radical. Subsequent reaction with molecular oxygen could then afford nitrosobenzene after further oxidation. Condensation with unreacted aniline substrate then affords the azo product. However, subjecting nitrosobenzene and ethyl 4-aminobenzoate to typical coupling conditions did not afford any of the heterocoupled product (Scheme 511). Thus, intervention of a nitroso intermediate does not appear to be consistent with empirical data.
Scheme 509. Copper-Catalyzed Formation of Unsymmetric Azobenzenes The use of Grignard reagents as strong bases has been reported in the copper-catalyzed formation of azo com- pounds.'°” The process utilizes catalytic CuCl, at rt, and a coordinating ligand, such as pyridine, is not required. Although only a limited substrate scope was explored, the described method afforded the desired azo compounds in excellent yield from even ortho-substituted substrates (Scheme 510). A nitroaniline, however, afforded no product, instead undergoing nucleophilic aromatic substitution with the Grignard reagent.
Scheme 509. Copper-Catalyzed Formation of Unsymmetric Azobenzenes The use of Grignard reagents as strong bases has been reported in the copper-catalyzed formation of azo com- pounds.'°” The process utilizes catalytic CuCl, at rt, and a coordinating ligand, such as pyridine, is not required. Although only a limited substrate scope was explored, the described method afforded the desired azo compounds in excellent yield from even ortho-substituted substrates (Scheme 510). A nitroaniline, however, afforded no product, instead undergoing nucleophilic aromatic substitution with the Grignard reagent.
Scheme 507. Substrate Effect on Copper-Mediated Oxidative Diazo Formation
Scheme 507. Substrate Effect on Copper-Mediated Oxidative Diazo Formation
A later report by Terent’ev and Mogilyanskii further established the effects of substrate substitution on azo formation (Scheme 507).'°% Poor yields were observed with
A later report by Terent’ev and Mogilyanskii further established the effects of substrate substitution on azo formation (Scheme 507).'°% Poor yields were observed with
Scheme 514. Copper-Catalyzed Formation of Hydrazines from Secondary Anilines Electron-rich substrates exhibited enhanced reactivity and yields, while substrates possessing strong electron-withdrawing groups, such as para-nitroaniline, did not undergo coupling under the reaction conditions. Steric hindrance, such as ortho- substitution or use of N-isopropylaniline, also inhibited reaction. Interestingly, when anilines possessing ethers at the para-position were employed, none of the anticipated N—N coupled product was formed. Instead, coupling occurred at the ortho-position, affording the C—N coupling products in high yields (Scheme 515). It is unclear at this time, why the para- alkyoxy anilines behave differently. Later work by Huang and co-workers showed that addition of TMEDA as a ligand greatly expanded the scope of secondary aniline couplings using oxygen and CuBr as catalyst.'°’* The use of CuO as a cocatalyst was also found to greatly enhance product yields. Reaction under a nitrogen atmosphere yielded trace product, and other oxidants, including TBHP and DDQ, also afforded poor yields. Under the optimized conditions, an array of N-alkylanilines containing alkyl, ether, and halogen substitution could be coupled in good yields (Scheme $14).
Scheme 514. Copper-Catalyzed Formation of Hydrazines from Secondary Anilines Electron-rich substrates exhibited enhanced reactivity and yields, while substrates possessing strong electron-withdrawing groups, such as para-nitroaniline, did not undergo coupling under the reaction conditions. Steric hindrance, such as ortho- substitution or use of N-isopropylaniline, also inhibited reaction. Interestingly, when anilines possessing ethers at the para-position were employed, none of the anticipated N—N coupled product was formed. Instead, coupling occurred at the ortho-position, affording the C—N coupling products in high yields (Scheme 515). It is unclear at this time, why the para- alkyoxy anilines behave differently. Later work by Huang and co-workers showed that addition of TMEDA as a ligand greatly expanded the scope of secondary aniline couplings using oxygen and CuBr as catalyst.'°’* The use of CuO as a cocatalyst was also found to greatly enhance product yields. Reaction under a nitrogen atmosphere yielded trace product, and other oxidants, including TBHP and DDQ, also afforded poor yields. Under the optimized conditions, an array of N-alkylanilines containing alkyl, ether, and halogen substitution could be coupled in good yields (Scheme $14).
Scheme 515. Oxidative Formation of ortho-Semidines from Secondary Anilines As first noted by Terent’ev during mechanistic studies on azo formation,'°® phenylhydroxylamine undergoes oxidation with copper and oxygen to afford azoxybenzene in high yield. A report by Hall and co-workers described the same process using small amounts of CuCl in pyridine with two N-hydroxyanilines. (Scheme 516).'°”
Scheme 515. Oxidative Formation of ortho-Semidines from Secondary Anilines As first noted by Terent’ev during mechanistic studies on azo formation,'°® phenylhydroxylamine undergoes oxidation with copper and oxygen to afford azoxybenzene in high yield. A report by Hall and co-workers described the same process using small amounts of CuCl in pyridine with two N-hydroxyanilines. (Scheme 516).'°”
Scheme 511. Postulated Formation of Azo Compounds from Nitroso Intermediates In an alternate approach, support for the intermediacy of a nitrosobenzyl radical, which could form directly from aniline radical and oxygen, has been reported through EPR studies of the reaction.'°”” This species is postulated to then dimerize and subsequently expel dioxygen after two-electron reduction from copper. In this mechanism, the role of oxygen is formation of the nitrosobenzyl radical as opposed to oxidation of a reduced copper species.
Scheme 511. Postulated Formation of Azo Compounds from Nitroso Intermediates In an alternate approach, support for the intermediacy of a nitrosobenzyl radical, which could form directly from aniline radical and oxygen, has been reported through EPR studies of the reaction.'°”” This species is postulated to then dimerize and subsequently expel dioxygen after two-electron reduction from copper. In this mechanism, the role of oxygen is formation of the nitrosobenzyl radical as opposed to oxidation of a reduced copper species.
Scheme 520. Oxidative Polymerization To Form Polyaniline
Scheme 520. Oxidative Polymerization To Form Polyaniline
Scheme 519. Oxidative Polymerization of Aniline under Biphasic Conditions
Scheme 519. Oxidative Polymerization of Aniline under Biphasic Conditions
Scheme 516. Copper-Catalyzed Formation of Azoxyarenes from N-Hydroxyanilines process have not been reported. Presumably, the process proceeds via an aniline radical similar to azo formation. After N-N bond formation, dehydration can afford the azoxy product. Alternatively, initial oxidation of the substrate could afford a nitroso compound that can undergo dehydration with unreacted starting material to directly afford the product. Further studies are needed to confirm the exact mechanism for this transformation.
Scheme 516. Copper-Catalyzed Formation of Azoxyarenes from N-Hydroxyanilines process have not been reported. Presumably, the process proceeds via an aniline radical similar to azo formation. After N-N bond formation, dehydration can afford the azoxy product. Alternatively, initial oxidation of the substrate could afford a nitroso compound that can undergo dehydration with unreacted starting material to directly afford the product. Further studies are needed to confirm the exact mechanism for this transformation.
Scheme 523. Copper-Mediated Oxidative Dimerization To Afford 1,1’-Bibenzimidazoles Scheme 524. Benzimidazoles Not Productive Intermediates under the Copper Oxidation Conditions
Scheme 523. Copper-Mediated Oxidative Dimerization To Afford 1,1’-Bibenzimidazoles Scheme 524. Benzimidazoles Not Productive Intermediates under the Copper Oxidation Conditions
Scheme 521. Oxidative Polymerization To Form a Poly(azoxyarelene) N,N'-dihydroxyl-1,4-phenylenediamine to the oxidation con- ditions failed to afford any polymerized material. 8.4. Heterocvcle Formation from Anilines
Scheme 521. Oxidative Polymerization To Form a Poly(azoxyarelene) N,N'-dihydroxyl-1,4-phenylenediamine to the oxidation con- ditions failed to afford any polymerized material. 8.4. Heterocvcle Formation from Anilines
Scheme 522. Copper-Mediated Oxidative Cyclization To Afford Benzimidazoles
Scheme 522. Copper-Mediated Oxidative Cyclization To Afford Benzimidazoles
Scheme 530. Copper-Catalyzed Oxygenative Dimerization of Aniline
Scheme 530. Copper-Catalyzed Oxygenative Dimerization of Aniline
Scheme 528. Copper-Catalyzed Oxidative Cyclization To Afford Triazoles
Scheme 528. Copper-Catalyzed Oxidative Cyclization To Afford Triazoles
Scheme 529. Potential Mechanism for the Oxidative Cyclization To Afford Triazoles and an aniline radical. After intramolecular cyclization, another single-electron oxidation affords the triazole product. Oxidation by molecular oxygen regenerates the active copper species and closes the catalytic cycle.
Scheme 529. Potential Mechanism for the Oxidative Cyclization To Afford Triazoles and an aniline radical. After intramolecular cyclization, another single-electron oxidation affords the triazole product. Oxidation by molecular oxygen regenerates the active copper species and closes the catalytic cycle.
Scheme 535. Copper-Catalyzed Oxidative Dimerization To Construct Phenazine-Containing Heterocycles Simple anilines were noted to form azo compounds under these conditions (see section 8.2, Scheme 504). However, the absence of azo byproducts here makes a mechanism proceeding through initial N—-N coupling and subsequent [3,3]-sigma- tropic rearrangement unlikely. The reaction is proposed to occur through initial oxidation of the aniline to the radical and dimerization to form the ortho C—N bond. A series of subsequent oxidations via copper can occur with concomitant cyclization to afford the phenazine-containing product. Alternately, the compound may dimerize via an iminoquinone (see Scheme 533). Mechanistic studies are needed to clarify the reaction pathways here.
Scheme 535. Copper-Catalyzed Oxidative Dimerization To Construct Phenazine-Containing Heterocycles Simple anilines were noted to form azo compounds under these conditions (see section 8.2, Scheme 504). However, the absence of azo byproducts here makes a mechanism proceeding through initial N—-N coupling and subsequent [3,3]-sigma- tropic rearrangement unlikely. The reaction is proposed to occur through initial oxidation of the aniline to the radical and dimerization to form the ortho C—N bond. A series of subsequent oxidations via copper can occur with concomitant cyclization to afford the phenazine-containing product. Alternately, the compound may dimerize via an iminoquinone (see Scheme 533). Mechanistic studies are needed to clarify the reaction pathways here.
Scheme 531. Iminoquinone Formation from 2,6- Dialkylanilines aminophenol to various copper catalysts under oxygen (Scheme 532).'°” With catalytic CuCl, ortho-aminophenol
Scheme 531. Iminoquinone Formation from 2,6- Dialkylanilines aminophenol to various copper catalysts under oxygen (Scheme 532).'°” With catalytic CuCl, ortho-aminophenol
Scheme 533. Possible Mechanism for Phenoxazine Formation from o-Aminophenol Scheme 534. Possible Mechanism for Quinone Formation from meta-Aminophenol
Scheme 533. Possible Mechanism for Phenoxazine Formation from o-Aminophenol Scheme 534. Possible Mechanism for Quinone Formation from meta-Aminophenol
Scheme 532. Copper-Catalyzed Oxidation of Aminophenol Isomers
Scheme 532. Copper-Catalyzed Oxidation of Aminophenol Isomers
to afford a bisindolophenazine product. The process was found to be applicable to a variety of 3-aminocarbazole and S- aminoindole substrates through treatment with catalytic CuBr in DMSO under air (Scheme 535).
to afford a bisindolophenazine product. The process was found to be applicable to a variety of 3-aminocarbazole and S- aminoindole substrates through treatment with catalytic CuBr in DMSO under air (Scheme 535).
Scheme 537. Proposed Mechanism of Copper-Catalyzed Azaspirocyclohexadienone Formation
Scheme 537. Proposed Mechanism of Copper-Catalyzed Azaspirocyclohexadienone Formation
scheme 541. Oxidative Cleavage of ortho- ~*henylenediamines amine also afforded the corresponding bis-nitrile product in good yield.
scheme 541. Oxidative Cleavage of ortho- ~*henylenediamines amine also afforded the corresponding bis-nitrile product in good yield.
Scheme 538. Oxybromination of Primary Anilines
Scheme 538. Oxybromination of Primary Anilines
formation can also take place in ionic liquids with the benefit that the ionic liquid and copper catalyst could be recycled nine times before loss in activity was observed.'””” Experiments were conducted to verify that the oxidative coupling could be done electrochemically. The reaction of tetrahydroisoquinolines and anilines with nitroalkanes is illustrative (Scheme 5$45).'°’° This trans-
formation can also take place in ionic liquids with the benefit that the ionic liquid and copper catalyst could be recycled nine times before loss in activity was observed.'””” Experiments were conducted to verify that the oxidative coupling could be done electrochemically. The reaction of tetrahydroisoquinolines and anilines with nitroalkanes is illustrative (Scheme 5$45).'°’° This trans-
Scheme 544. Oxidative Coupling of Amines with Alkynes Seminal work on this type of reaction was described by Miura and co-workers who showed that N,N-dimethylanilines would couple with alkynes in the presence of oxygen and a copper(I) chloride catalyst.'°°°'°°* While formation of other byproducts was problematic (Scheme 544), this work firmly established that copper and oxygen are a functional pair for this type of transformation. The use of less acidic nucleophiles such as ketones has also been documented (Scheme 547).'°”* Slightly higher yields were obtained using O, vs TBHP with acetone, but only O, was effective with butanone. The addition of 3 equiv of acetic acid and molecular sieves increased yields even further to 72%. Interestingly, CoCl, and RuCl, could also be used as catalysts, but the reactions were less efficient. For the methyl alkyl ketones, there was a general downward trend in the product yield as the alkyl chain became longer. Even with oxygen, diethyl ketone gave poor yield (24%) and poor diastereose- lection (1.1:1).
Scheme 544. Oxidative Coupling of Amines with Alkynes Seminal work on this type of reaction was described by Miura and co-workers who showed that N,N-dimethylanilines would couple with alkynes in the presence of oxygen and a copper(I) chloride catalyst.'°°°'°°* While formation of other byproducts was problematic (Scheme 544), this work firmly established that copper and oxygen are a functional pair for this type of transformation. The use of less acidic nucleophiles such as ketones has also been documented (Scheme 547).'°”* Slightly higher yields were obtained using O, vs TBHP with acetone, but only O, was effective with butanone. The addition of 3 equiv of acetic acid and molecular sieves increased yields even further to 72%. Interestingly, CoCl, and RuCl, could also be used as catalysts, but the reactions were less efficient. For the methyl alkyl ketones, there was a general downward trend in the product yield as the alkyl chain became longer. Even with oxygen, diethyl ketone gave poor yield (24%) and poor diastereose- lection (1.1:1).
Scheme 548. Oxidative Coupling of Amines and Silyl Ketene Acetals
Scheme 548. Oxidative Coupling of Amines and Silyl Ketene Acetals
Scheme 547. Oxidative Coupling of Amines and Ketones Highly nucleophilic silyl ketene acetals, for which in situ deprotonation was not required, were also highly effective nucleophiles in this type of transformation (Scheme 548).107? In contrast to the direct coupling of the ketones outlined above (Scheme 547), no acid was needed for the transformation. In this case, the reduction product from O, must be a silanol instead of water.
Scheme 547. Oxidative Coupling of Amines and Ketones Highly nucleophilic silyl ketene acetals, for which in situ deprotonation was not required, were also highly effective nucleophiles in this type of transformation (Scheme 548).107? In contrast to the direct coupling of the ketones outlined above (Scheme 547), no acid was needed for the transformation. In this case, the reduction product from O, must be a silanol instead of water.
Scheme 549. Oxidative Coupling of Amines with Silyl Enol Ethers and Silyl Ketene Acetals
Scheme 549. Oxidative Coupling of Amines with Silyl Enol Ethers and Silyl Ketene Acetals
Scheme 552. Substrate Scope for Copper-Catalyzed Aerobic Phosphination
Scheme 552. Substrate Scope for Copper-Catalyzed Aerobic Phosphination
Scheme 551. Copper-Catalyzed Oxidative Coupling of an Amine with an Aryl Boronic Acid
Scheme 551. Copper-Catalyzed Oxidative Coupling of an Amine with an Aryl Boronic Acid
Scheme 557. Proposed Mechanism of the Copper-Catalyzed Amine to Iminium Oxidation
Scheme 557. Proposed Mechanism of the Copper-Catalyzed Amine to Iminium Oxidation
Scheme 554. Copper-Catalyzed Oxidation of an Amine to an Iminium Using Oxygen Followed by Nucleophilic Trapping
Scheme 554. Copper-Catalyzed Oxidation of an Amine to an Iminium Using Oxygen Followed by Nucleophilic Trapping
Scheme 563. Proposed Mechanism I for Vitamin Bg Catalyzed Oxidative Deamination was more challenging affording the products in good to excellent yields and moderate selectivity (Scheme 570).'!'? As would be expected, poorly nucleophilic amines, such as the heteroaromatic amines and benzylamines with strong electron-
Scheme 563. Proposed Mechanism I for Vitamin Bg Catalyzed Oxidative Deamination was more challenging affording the products in good to excellent yields and moderate selectivity (Scheme 570).'!'? As would be expected, poorly nucleophilic amines, such as the heteroaromatic amines and benzylamines with strong electron-
Scheme 562. Proposed Mechanism for Primary Aliphatic Amines by Copper(I) Species under Acidic Conditions
Scheme 562. Proposed Mechanism for Primary Aliphatic Amines by Copper(I) Species under Acidic Conditions
Scheme 560. Oxidation of Primary Aliphatic Amines by Copper in Acidic Medium 2,2-biquinolyl or 2,2'-quinolyl pyridine ligand fragments in the polymer backbone were examined for the oxidation of primary and secondary amines. A mechanism similar to that of amine oxidase is proposed for this transformation (Scheme 568).
Scheme 560. Oxidation of Primary Aliphatic Amines by Copper in Acidic Medium 2,2-biquinolyl or 2,2'-quinolyl pyridine ligand fragments in the polymer backbone were examined for the oxidation of primary and secondary amines. A mechanism similar to that of amine oxidase is proposed for this transformation (Scheme 568).
Scheme 558. Oxidation of Tetrahydroisoquinolines to Dihydroisoquinolines Scheme 559. Oxidation of Acyclic and Cyclic Amines to Imines
Scheme 558. Oxidation of Tetrahydroisoquinolines to Dihydroisoquinolines Scheme 559. Oxidation of Acyclic and Cyclic Amines to Imines
Scheme 565. Oxidative Deamination of Amines Scheme 567. Oxidation of Primary and Secondary Amines Using Polymer-Bound Copper Catalyst Scheme 564. Proposed Mechanism II for Vitamin B, Catalyzed Oxidative Deamination
Scheme 565. Oxidative Deamination of Amines Scheme 567. Oxidation of Primary and Secondary Amines Using Polymer-Bound Copper Catalyst Scheme 564. Proposed Mechanism II for Vitamin B, Catalyzed Oxidative Deamination
withdrawing groups, did not compete favorably with the starting primary amine in adding to the imine intermediate.
withdrawing groups, did not compete favorably with the starting primary amine in adding to the imine intermediate.
The authors proposed that the imine forms by /-hydride elimination of a copper—amine adduct accompanied by two- electron oxygen-mediated reoxidation of the copper.'’'* An alternate mechanism in agreement with the mechanistic data described earlier in this section (see Schemes 554—557) is
The authors proposed that the imine forms by /-hydride elimination of a copper—amine adduct accompanied by two- electron oxygen-mediated reoxidation of the copper.'’'* An alternate mechanism in agreement with the mechanistic data described earlier in this section (see Schemes 554—557) is
Scheme 569. Oxidation of Primary Amines in the Synthesis of Symmetrical Imines
Scheme 569. Oxidation of Primary Amines in the Synthesis of Symmetrical Imines
Scheme 572. Proposed Mechanism for Copper-Catalyzed Oxidation of Amine to Imines with TEMPO Scheme 573. Dehydroascorbic Acid-Mediated, Copper- Catalyzed Oxidation of Amines
Scheme 572. Proposed Mechanism for Copper-Catalyzed Oxidation of Amine to Imines with TEMPO Scheme 573. Dehydroascorbic Acid-Mediated, Copper- Catalyzed Oxidation of Amines
Scheme 575. Chemoselectivity of the Dehydroascorbic Acid- Mediated Oxidation 9.1.4. Nitriles from Primary Amines. Section 9.1.3 illustrated that imines or aldehydes can be formed from primary amines by copper-initiated oxidation to the iminyl radical cation. Further reaction of the imine to the nitrile is also possible but is complicated by a competing hydrolysis of the imine intermediate to the aldehyde. Kametani and co-workers reported the oxidation of amines to nitriles using copper and oxygen in 1977.'1!° Oxidation of amines to nitriles or aldehydes was achieved using copper(I) chloride in pyridine under an oxygen atmosphere. This method suffered from poor yields ranging in 22—35% yields (Scheme 576).
Scheme 575. Chemoselectivity of the Dehydroascorbic Acid- Mediated Oxidation 9.1.4. Nitriles from Primary Amines. Section 9.1.3 illustrated that imines or aldehydes can be formed from primary amines by copper-initiated oxidation to the iminyl radical cation. Further reaction of the imine to the nitrile is also possible but is complicated by a competing hydrolysis of the imine intermediate to the aldehyde. Kametani and co-workers reported the oxidation of amines to nitriles using copper and oxygen in 1977.'1!° Oxidation of amines to nitriles or aldehydes was achieved using copper(I) chloride in pyridine under an oxygen atmosphere. This method suffered from poor yields ranging in 22—35% yields (Scheme 576).
Scheme 574. Mechanism of the Dehydroascorbic Acid- Mediated Oxidation of Amines
Scheme 574. Mechanism of the Dehydroascorbic Acid- Mediated Oxidation of Amines
Scheme 576. Oxidation of Various Alkyl Amines to Aryl Nitriles Efforts for further developing this type of chemistry lapsec for 12 years before a new report appeared. Capdevielle and co- workers in 1989 reported an improved method based on Kametani’s earlier work for oxidation of primary amine te nitriles using copper(I) salt and pyridine under an oxyger atmosphere.'''’ The improved protocol differs from Kameta- ni’s work in that the reaction is carried out at higher temperatures and 4 A molecular sieves were added to minimize hydrolysis of the imine. Catalytic amounts of copper could alse be employed; however, stoichiometric amounts of copper were preferred to push the reaction to completion. The method has < broad substrate scope providing a diverse array of nitriles in nearly quantitative yield (Scheme 577). However, the oxidatior of 2-phenylethylamine was problematic, affording a mixture ot products.
Scheme 576. Oxidation of Various Alkyl Amines to Aryl Nitriles Efforts for further developing this type of chemistry lapsec for 12 years before a new report appeared. Capdevielle and co- workers in 1989 reported an improved method based on Kametani’s earlier work for oxidation of primary amine te nitriles using copper(I) salt and pyridine under an oxyger atmosphere.'''’ The improved protocol differs from Kameta- ni’s work in that the reaction is carried out at higher temperatures and 4 A molecular sieves were added to minimize hydrolysis of the imine. Catalytic amounts of copper could alse be employed; however, stoichiometric amounts of copper were preferred to push the reaction to completion. The method has < broad substrate scope providing a diverse array of nitriles in nearly quantitative yield (Scheme 577). However, the oxidatior of 2-phenylethylamine was problematic, affording a mixture ot products.
Scheme 580. Catalytic Oxidation of Primary Amines to Nitriles
Scheme 580. Catalytic Oxidation of Primary Amines to Nitriles
Scheme 578. Proposed Mechanism of Primary Aliphatic Amine Oxidation to Nitriles
Scheme 578. Proposed Mechanism of Primary Aliphatic Amine Oxidation to Nitriles
9.1.6. Amide Anion Generation and Reactions. Aerobic oxidation of amines has also been exploited to generate a source of a copper amide in situ. For example, Guo and co- workers demonstrated that an iminium ion, derived from oxidation of a tertiary amine, can undergo C—N bond cleavage via hydrolysis to afford a copper amide species (LnCu— NR'R’), which can react further with benzoxazole via a copper- mediated C—H insertion to afford the desired aminated product.'!** Alkyl tertiary amines bearing a-hydrogens reacted efficiently, while amines without an a-H failed to react. An
9.1.6. Amide Anion Generation and Reactions. Aerobic oxidation of amines has also been exploited to generate a source of a copper amide in situ. For example, Guo and co- workers demonstrated that an iminium ion, derived from oxidation of a tertiary amine, can undergo C—N bond cleavage via hydrolysis to afford a copper amide species (LnCu— NR'R’), which can react further with benzoxazole via a copper- mediated C—H insertion to afford the desired aminated product.'!** Alkyl tertiary amines bearing a-hydrogens reacted efficiently, while amines without an a-H failed to react. An
Scheme 583. Substrate Scope for Various Substituted Azoles with Triethylamine A gram scale reaction of 4-benzylmorpholine and benzox- azole was explored to gain an understanding of the mechanism. Isolation of benzaldehyde in 87% yield and the aminated product in 75% yield suggest that C—N bond cleavage may occur prior to the C—N bond formation step between the amine and benzoxazole. A free radical pathway was ruled out since the product formed in a 62% and 82% yield in the presence of TEMPO and 1,1-diphenylethylene, respectively. Isotope labeling experiments with 'SO, and H,'%O revealed that the aldehyde oxygen comes from the water produced during hydrolysis leading to C—N bond cleavage. Cleavage of the C— H bond of the azole was determined not to be involved in the rate-limiting step based on the kinetic isotope effect of 1.4 in a competition experiment for 5S-methylbenzoxazole and 2- deutero-5-methylbenzoxazole. In the case of 4-benzylmorpho- line, a value of 2.7 for the kinetic isotope effect indicates the C— H bond cleavage of the tertiary amine may be rate-limiting. A mechanism with modifications for forming the amide—copper intermediate is outlined in Scheme 584. The proposal that the reduced copper species remains bound to the iminium ion via a nitrogen coordination is unlikely based on the X-ray crystal structure obtained by Klussman and co-workers. An alternative pathway for iminium hydrolysis involves nucleophilic attack by water to afford a hemiaminal II’. Coordination of the CuL,, to the nitrogen of the hemiaminal facilitates the C—N bond cleavage for elimination of the copper—amide intermediate IV’ and the corresponding aldehyde. Deprotonation of the C-H bond of the benzoxazole followed by a copper-mediated rearrangement affords intermediate V’, which undergoes a one- electron oxidation to afford a Cu(III) intermediate VIII’.
Scheme 583. Substrate Scope for Various Substituted Azoles with Triethylamine A gram scale reaction of 4-benzylmorpholine and benzox- azole was explored to gain an understanding of the mechanism. Isolation of benzaldehyde in 87% yield and the aminated product in 75% yield suggest that C—N bond cleavage may occur prior to the C—N bond formation step between the amine and benzoxazole. A free radical pathway was ruled out since the product formed in a 62% and 82% yield in the presence of TEMPO and 1,1-diphenylethylene, respectively. Isotope labeling experiments with 'SO, and H,'%O revealed that the aldehyde oxygen comes from the water produced during hydrolysis leading to C—N bond cleavage. Cleavage of the C— H bond of the azole was determined not to be involved in the rate-limiting step based on the kinetic isotope effect of 1.4 in a competition experiment for 5S-methylbenzoxazole and 2- deutero-5-methylbenzoxazole. In the case of 4-benzylmorpho- line, a value of 2.7 for the kinetic isotope effect indicates the C— H bond cleavage of the tertiary amine may be rate-limiting. A mechanism with modifications for forming the amide—copper intermediate is outlined in Scheme 584. The proposal that the reduced copper species remains bound to the iminium ion via a nitrogen coordination is unlikely based on the X-ray crystal structure obtained by Klussman and co-workers. An alternative pathway for iminium hydrolysis involves nucleophilic attack by water to afford a hemiaminal II’. Coordination of the CuL,, to the nitrogen of the hemiaminal facilitates the C—N bond cleavage for elimination of the copper—amide intermediate IV’ and the corresponding aldehyde. Deprotonation of the C-H bond of the benzoxazole followed by a copper-mediated rearrangement affords intermediate V’, which undergoes a one- electron oxidation to afford a Cu(III) intermediate VIII’.
Scheme 581. Substrate Scope for the Three-Component Reaction Scheme 582. Proposed Mechanism for Silver(I)-Catalyzed Intramolecular Cyclization and Copper(II)-Catalyzed Oxidation of Tertiary Amines
Scheme 581. Substrate Scope for the Three-Component Reaction Scheme 582. Proposed Mechanism for Silver(I)-Catalyzed Intramolecular Cyclization and Copper(II)-Catalyzed Oxidation of Tertiary Amines
Scheme 586. Mechanism of the Synthesis of Complex Heterocycles from Benzylic Amines Scheme 587. Substrate Scope Oxidative Rearrangement of Tertiary Amines
Scheme 586. Mechanism of the Synthesis of Complex Heterocycles from Benzylic Amines Scheme 587. Substrate Scope Oxidative Rearrangement of Tertiary Amines
Scheme 585. Substrate Scope for Synthesis of Complex Heterocycles from Benzylic Amines
Scheme 585. Substrate Scope for Synthesis of Complex Heterocycles from Benzylic Amines
Scheme 584. Proposed Mechanism for Oxidative C-H Amination
Scheme 584. Proposed Mechanism for Oxidative C-H Amination
Scheme 588. Proposed Mechanism for Oxidative Rearrangement of Tertiary Amines
Scheme 588. Proposed Mechanism for Oxidative Rearrangement of Tertiary Amines
Scheme 590. Mechanism of the Copper-Catalyzed Domino Synthesis of Pyrroles
Scheme 590. Mechanism of the Copper-Catalyzed Domino Synthesis of Pyrroles
the fragmentation leading to iminium ion radical II, which is trapped by dioxygen forming a 1,2-dioxolane intermediate V. Intermediate V then undergoes an O—O bond cleavage and hydrolysis to form the corresponding epoxy ketone VII. An alternate pathway proceeds through /-bond cleavage (Scheme 594, B), affording a primary iminium radical I’. Upon oxygenation of intermediate III’ an oxaspiro epoxy ketone IV’ can form. The authors speculate it is unlikely that /-bond cleavage occurs due to exclusive formation of the ring-expanded epoxy ketone VII. Furthermore, the cation radical III’ is speculated to be less stable than cation radical III formed from the a-cleavage pathway. Interestingly, the oxygen atoms are proposed to arise from dioxygen. However, further experiments were not conducted to support this hypothesis.
the fragmentation leading to iminium ion radical II, which is trapped by dioxygen forming a 1,2-dioxolane intermediate V. Intermediate V then undergoes an O—O bond cleavage and hydrolysis to form the corresponding epoxy ketone VII. An alternate pathway proceeds through /-bond cleavage (Scheme 594, B), affording a primary iminium radical I’. Upon oxygenation of intermediate III’ an oxaspiro epoxy ketone IV’ can form. The authors speculate it is unlikely that /-bond cleavage occurs due to exclusive formation of the ring-expanded epoxy ketone VII. Furthermore, the cation radical III’ is speculated to be less stable than cation radical III formed from the a-cleavage pathway. Interestingly, the oxygen atoms are proposed to arise from dioxygen. However, further experiments were not conducted to support this hypothesis.
Scheme 592. Mechanism for the Tandem Cyclization— Oxidation Scheme 593. Oxygenolysis of Cyclopropylamines to Epoxy Ketones
Scheme 592. Mechanism for the Tandem Cyclization— Oxidation Scheme 593. Oxygenolysis of Cyclopropylamines to Epoxy Ketones
Scheme 591. Tandem Copper-Catalyzed Cyclization— Aerobic Oxidation to Pyrazolidinones
Scheme 591. Tandem Copper-Catalyzed Cyclization— Aerobic Oxidation to Pyrazolidinones
The mechanism (Scheme 594) is proposed to involve the iminyl radical, which initiates fragmentation of the cyclo- propane ring. a-Bond cleavage (Scheme 594A) is proposed for
The mechanism (Scheme 594) is proposed to involve the iminyl radical, which initiates fragmentation of the cyclo- propane ring. a-Bond cleavage (Scheme 594A) is proposed for
Scheme 595. Oxidative Cyclization of Iminyl Radicals with Alkenes broad array of tetrahydroquinolines could be generated in moderate to good yields (Scheme 596). The process only works for tertiary anilines with at least one N-methyl group; attempts to couple N-methyl-3,4-dimethylaniline or N,N- diethylaniline were unsuccessful. This process has been proposed to proceed via the radical cation intermediate (II, Scheme 597) instead of an iminium intermediate (VIII). Experimental evidence supporting this mechanism is the regioselectivity observed for preferential coupling at the ortho- position of the arene (I). The authors speculate trapping of II occurs faster than the second one-electron oxidation to form
Scheme 595. Oxidative Cyclization of Iminyl Radicals with Alkenes broad array of tetrahydroquinolines could be generated in moderate to good yields (Scheme 596). The process only works for tertiary anilines with at least one N-methyl group; attempts to couple N-methyl-3,4-dimethylaniline or N,N- diethylaniline were unsuccessful. This process has been proposed to proceed via the radical cation intermediate (II, Scheme 597) instead of an iminium intermediate (VIII). Experimental evidence supporting this mechanism is the regioselectivity observed for preferential coupling at the ortho- position of the arene (I). The authors speculate trapping of II occurs faster than the second one-electron oxidation to form
Scheme 597. Mechanism of the Oxidative Cyclization of Iminyl Radicals with Alkenes iminium ion VIII (Scheme 596) even though secondary and benzyl radicals are more stable.
Scheme 597. Mechanism of the Oxidative Cyclization of Iminyl Radicals with Alkenes iminium ion VIII (Scheme 596) even though secondary and benzyl radicals are more stable.
Scheme 596. Substrate Scope of the Oxidative Cyclization of Iminyl Radicals with Alkenes
Scheme 596. Substrate Scope of the Oxidative Cyclization of Iminyl Radicals with Alkenes
intermediate. The desired sulfenamide was obtaind in a 59% isolateld yield suggesting that PhSCu forms in the course of the reaction. A decrease in yield was observed in the absence of oxygen. The authors speculate that the copper acts as a Lewis acid and co-oxidant with air. A mechanism was proposed based on these findings (Scheme 600).
intermediate. The desired sulfenamide was obtaind in a 59% isolateld yield suggesting that PhSCu forms in the course of the reaction. A decrease in yield was observed in the absence of oxygen. The authors speculate that the copper acts as a Lewis acid and co-oxidant with air. A mechanism was proposed based on these findings (Scheme 600).
scheme 598. Copper-Catalyzed Coupling of Diphenyl Disulfide with Various Alkyl Amines Scheme 599. Copper-Catalyzed Coupling of Various Aryl Disulfides with Alkyl Amines
scheme 598. Copper-Catalyzed Coupling of Diphenyl Disulfide with Various Alkyl Amines Scheme 599. Copper-Catalyzed Coupling of Various Aryl Disulfides with Alkyl Amines
Scheme 600. Proposed Mechanism of the Sulfonylation Reaction Scheme 601. Oxidation of a Hydrazine to an Azo Compound
Scheme 600. Proposed Mechanism of the Sulfonylation Reaction Scheme 601. Oxidation of a Hydrazine to an Azo Compound
Scheme 604. Synthesis of Benzoic Acid from Phenyl Hydrazide
Scheme 604. Synthesis of Benzoic Acid from Phenyl Hydrazide
Scheme 602. Copper-Mediated Oxidation of Hydrazides
Scheme 602. Copper-Mediated Oxidation of Hydrazides
Scheme 605. Synthesis of Various Aromatic Carboxylic Acids and Esters
Scheme 605. Synthesis of Various Aromatic Carboxylic Acids and Esters
603).'"°° The choice of copper source is important for promoting oxidative cleavage of the hydrazide, and excess amounts of copper are used. Cu(NO3)5, CuCl, and copper oxide showed no activity, while Cu(acac), was similar in reactivity to Cu(OAc),. Benzoic acid was synthesized selectively, while the synthesis of esters required in situ formation of Cu(OMe) by treatment of CuCl with sodium methoxide to achieve good selectivity. A mixture of products was obtained for ester synthesis when pyridine and methanol was used. An amine solution of Cu(OAc), was required for the synthesis of amides. The authors speculate that a stepwise oxidation of the hydrazide to form an acyl cation with liberation of nitrogen water occurs. The acyl cation can then be trapped by the alcohol, amine, or water nucleophile to afford the desired product.
603).'"°° The choice of copper source is important for promoting oxidative cleavage of the hydrazide, and excess amounts of copper are used. Cu(NO3)5, CuCl, and copper oxide showed no activity, while Cu(acac), was similar in reactivity to Cu(OAc),. Benzoic acid was synthesized selectively, while the synthesis of esters required in situ formation of Cu(OMe) by treatment of CuCl with sodium methoxide to achieve good selectivity. A mixture of products was obtained for ester synthesis when pyridine and methanol was used. An amine solution of Cu(OAc), was required for the synthesis of amides. The authors speculate that a stepwise oxidation of the hydrazide to form an acyl cation with liberation of nitrogen water occurs. The acyl cation can then be trapped by the alcohol, amine, or water nucleophile to afford the desired product.
Scheme 606. Mechanism of Copper-Catalyzed Conversion of Hydrazides to Carboxylic Acids excess copper was reported by Kajimoto (Scheme 607).11°? Secondary amines such as di-2-naphthylamine and N-ethyl-
Scheme 606. Mechanism of Copper-Catalyzed Conversion of Hydrazides to Carboxylic Acids excess copper was reported by Kajimoto (Scheme 607).11°? Secondary amines such as di-2-naphthylamine and N-ethyl-
Scheme 609. Tandem Amidine Formation and Oxidative Cyclization To Afford Triazolopyridines stoichiometric copper to give similar yields as the catalytic process. With these results, a mechanistic proposal is suggested with initial copper activation of the nitrile and nucleophilic attack by the aniline nitrogen (Scheme 610). Oxidation of the
Scheme 609. Tandem Amidine Formation and Oxidative Cyclization To Afford Triazolopyridines stoichiometric copper to give similar yields as the catalytic process. With these results, a mechanistic proposal is suggested with initial copper activation of the nitrile and nucleophilic attack by the aniline nitrogen (Scheme 610). Oxidation of the
Scheme 614. Proposed Mechanisms for the Synthesis of Nitriles from Azidoesters accounting for the increased rate observed under aerobic conditions.
Scheme 614. Proposed Mechanisms for the Synthesis of Nitriles from Azidoesters accounting for the increased rate observed under aerobic conditions.
Scheme 613. Substrate Scope for Synthesis of Nitriles from Azidoesters A proposed mechanism based on these observations is shown in Scheme 614.
Scheme 613. Substrate Scope for Synthesis of Nitriles from Azidoesters A proposed mechanism based on these observations is shown in Scheme 614.
Scheme 615. Orthogonal Oxidation Products of a-Azido Amides aryl amide to the reaction conditions formed an unexpected azaspirocyclohexadienone product instead of the anticipated aryl nitrile (Scheme 615b). The process was found to be general for a variety of substrates, affording moderate to good yields when aryl substituents containing electron-donating and electron-withdrawing groups were installed at the a-position (see section 8.5 for complete discussion, substrate scope, and mechanistic proposal).
Scheme 615. Orthogonal Oxidation Products of a-Azido Amides aryl amide to the reaction conditions formed an unexpected azaspirocyclohexadienone product instead of the anticipated aryl nitrile (Scheme 615b). The process was found to be general for a variety of substrates, affording moderate to good yields when aryl substituents containing electron-donating and electron-withdrawing groups were installed at the a-position (see section 8.5 for complete discussion, substrate scope, and mechanistic proposal).
Scheme 612. Metal-Catalyzed 6-Carbon Elimination of Iminyl Metal Species
Scheme 612. Metal-Catalyzed 6-Carbon Elimination of Iminyl Metal Species
Scheme 619. Control Experiments Investigated To Elucidate Mechanism of Pyrazinone Formation benzylamide to afford bicyclic intermediate B, which undergoes rapid denitrogenation. The desired pyrazinone was formed in 46% yield upon exposure of the aziridine to the optimized reaction conditions.
Scheme 619. Control Experiments Investigated To Elucidate Mechanism of Pyrazinone Formation benzylamide to afford bicyclic intermediate B, which undergoes rapid denitrogenation. The desired pyrazinone was formed in 46% yield upon exposure of the aziridine to the optimized reaction conditions.
Scheme 618. Substrate Scope for Synthesis of Pyrazinones from @-Azido-N-allylamides To determine whether an iminyl species intermediate is involved in the reaction mechanism, a transient N—H imine species A was synthesized using basic conditions and subjected to the optimized reaction conditions (Scheme 619a). Only a- keto amides were isolated indicating that a copper iminyl species was not formed. Subsequently, a-azido-N-ally-N- benzylamide was heated at reflux under toluene in the absence of copper catalyst to afford an aziridine product (Scheme 619b). The formation of the aziridine product was proposed to arise from 1,3-dipolar cycloaddition of the a-azido-N-allyl-N-
Scheme 618. Substrate Scope for Synthesis of Pyrazinones from @-Azido-N-allylamides To determine whether an iminyl species intermediate is involved in the reaction mechanism, a transient N—H imine species A was synthesized using basic conditions and subjected to the optimized reaction conditions (Scheme 619a). Only a- keto amides were isolated indicating that a copper iminyl species was not formed. Subsequently, a-azido-N-ally-N- benzylamide was heated at reflux under toluene in the absence of copper catalyst to afford an aziridine product (Scheme 619b). The formation of the aziridine product was proposed to arise from 1,3-dipolar cycloaddition of the a-azido-N-allyl-N-
Scheme 620. Proposed Mechanism for the Synthesis of Pyrazinones from a-Azido-N-allylamides mide undergoes a 1,3-dipolar cycloaddition to afford II, which undergoes rapid denitrogenation to form III. Single-electron oxidation of III affords a radical cation intermediate IV. Deprotonation of IV and subsequent opening of the aziridine ring forms a primary radical intermediate V. A copper peroxy species then traps the primary radical to afford VI, which is further oxidized to form the formyl group. Copper-mediated oxidation of VII affords the desired pyrazinone.
Scheme 620. Proposed Mechanism for the Synthesis of Pyrazinones from a-Azido-N-allylamides mide undergoes a 1,3-dipolar cycloaddition to afford II, which undergoes rapid denitrogenation to form III. Single-electron oxidation of III affords a radical cation intermediate IV. Deprotonation of IV and subsequent opening of the aziridine ring forms a primary radical intermediate V. A copper peroxy species then traps the primary radical to afford VI, which is further oxidized to form the formyl group. Copper-mediated oxidation of VII affords the desired pyrazinone.
Scheme 616. Reaction of N-Allyl-N-phenylamide with «a-azido-N-allyl-N-benzylamide provided the 2-formyl pyrazinone in 62% isolated yield. Under an inert atmosphere, none of this material was detected; instead, a dihydropyr- azinone byproduct was isolated in 14% yield suggesting that oxygen is critical for this transformation (Scheme 617).
Scheme 616. Reaction of N-Allyl-N-phenylamide with «a-azido-N-allyl-N-benzylamide provided the 2-formyl pyrazinone in 62% isolated yield. Under an inert atmosphere, none of this material was detected; instead, a dihydropyr- azinone byproduct was isolated in 14% yield suggesting that oxygen is critical for this transformation (Scheme 617).
substituents (tertiary > secondary > primary) implying that coordination of the ether to copper species is not crucial to oxidation.
substituents (tertiary > secondary > primary) implying that coordination of the ether to copper species is not crucial to oxidation.
In an effort to further understand the effects of ligand tuning on the equilibrium of copper bishydroxo species, Zhang and co- workers synthesized several Cu(I) complexes containing tridentate bis[2-(2-pyridyl)ethyl]methyl amine ligands. Varying the electronics of these ligands by modification of the 4- substituent influenced the reactivity of the copper complexes in the two-electron oxidations of tetrahydrofuran, N-methylani- line, and primary alcohols (Scheme 622).''*” Notably, these reactions are not catalytic. Experiments employing 80, indicated that hydroxylation of tetrahydrofuran involves transfer of an oxygen atom from the copper bishydroxo complex.
In an effort to further understand the effects of ligand tuning on the equilibrium of copper bishydroxo species, Zhang and co- workers synthesized several Cu(I) complexes containing tridentate bis[2-(2-pyridyl)ethyl]methyl amine ligands. Varying the electronics of these ligands by modification of the 4- substituent influenced the reactivity of the copper complexes in the two-electron oxidations of tetrahydrofuran, N-methylani- line, and primary alcohols (Scheme 622).''*” Notably, these reactions are not catalytic. Experiments employing 80, indicated that hydroxylation of tetrahydrofuran involves transfer of an oxygen atom from the copper bishydroxo complex.
Scheme 623. Oxidative Coupling of Ethers and Ketones Using the Co-oxidant NHPI Scheme 624. Mechanism of the Oxidative Coupling of Ethers and Ketones
Scheme 623. Oxidative Coupling of Ethers and Ketones Using the Co-oxidant NHPI Scheme 624. Mechanism of the Oxidative Coupling of Ethers and Ketones
section 9.1). Key differences include a single-electron oxidation catalyzed by NHPI, which is in turn reoxidized by dioxygen. The resultant radical traps oxygen to form a peroxyketal, which is then reduced by the copper or indium to provide a hemiketal. The oxocarbenium formed from the hemiketal can then trap a nucleophile. The copper/indium plays an additional role as a Lewis acid to facilitate deprotonation of the nucleophile.
section 9.1). Key differences include a single-electron oxidation catalyzed by NHPI, which is in turn reoxidized by dioxygen. The resultant radical traps oxygen to form a peroxyketal, which is then reduced by the copper or indium to provide a hemiketal. The oxocarbenium formed from the hemiketal can then trap a nucleophile. The copper/indium plays an additional role as a Lewis acid to facilitate deprotonation of the nucleophile.
Scheme 625. Oxidative Coupling of Ethers and Alkenes
Scheme 625. Oxidative Coupling of Ethers and Alkenes
When oxygen instead of air and larger amounts of the copper catalyst (10 mol % vs 5 mol %) were employed, it was possible to initiate further oxygenation of the sulfur center to generate the sulfonamides (Scheme 630, top). The reaction could be controlled by using of 30 mol % PdCl, 5 mol % Cul, and air resulting in mono-oxygenation to the sulfinamides (Scheme 630, bottom). Product formation was not observed under an inert atmosphere, indicating that oxygen is integral to the reaction. A mechanism for the first step in these trans- formations, N—S bond formation, is outlined in Scheme 631.
When oxygen instead of air and larger amounts of the copper catalyst (10 mol % vs 5 mol %) were employed, it was possible to initiate further oxygenation of the sulfur center to generate the sulfonamides (Scheme 630, top). The reaction could be controlled by using of 30 mol % PdCl, 5 mol % Cul, and air resulting in mono-oxygenation to the sulfinamides (Scheme 630, bottom). Product formation was not observed under an inert atmosphere, indicating that oxygen is integral to the reaction. A mechanism for the first step in these trans- formations, N—S bond formation, is outlined in Scheme 631.
sulfenamides from diaryl disulfides (see Schemes 598 and 599 in section ok aia Later, Taniguchi reported the copper-mediated coupling of thiols with amines for the preparation of sulfenamides, sulfinamides, and sulfonamides. Under very mild conditions using air, dehydrocoupling occurred to provide the sulfena- mides in good yields with a variety of amine donors (Scheme 629).''45 Aryl amines afforded slightly lower yields in this process due to competing oxidation of the anilines.
sulfenamides from diaryl disulfides (see Schemes 598 and 599 in section ok aia Later, Taniguchi reported the copper-mediated coupling of thiols with amines for the preparation of sulfenamides, sulfinamides, and sulfonamides. Under very mild conditions using air, dehydrocoupling occurred to provide the sulfena- mides in good yields with a variety of amine donors (Scheme 629).''45 Aryl amines afforded slightly lower yields in this process due to competing oxidation of the anilines.
12. REACTIONS OF THIOLS 12.1. Sulfoxidation Sulfoxides are key intermediates in organic synthesis and medicinal chemistry, and many methods have been reported for their synthesis. Even so, the majority use peroxide or peracid oxidants. For example, copper-catalyzed oxidations of sulfides to sulfoxides with tert-butyl hydroperoxide (TBHP) have been reported as highly effective.''*’ However, the corresponding reaction with oxygen has lagged due to overoxidation of the sulfides. Some progress has been made as shown in Scheme 627 suggesting that a general aerobic copper-catalyzed oxidation is viable 421143
12. REACTIONS OF THIOLS 12.1. Sulfoxidation Sulfoxides are key intermediates in organic synthesis and medicinal chemistry, and many methods have been reported for their synthesis. Even so, the majority use peroxide or peracid oxidants. For example, copper-catalyzed oxidations of sulfides to sulfoxides with tert-butyl hydroperoxide (TBHP) have been reported as highly effective.''*’ However, the corresponding reaction with oxygen has lagged due to overoxidation of the sulfides. Some progress has been made as shown in Scheme 627 suggesting that a general aerobic copper-catalyzed oxidation is viable 421143
Scheme 630. Sulfonamides and Sulfinamides by Coupling of Amines and Thiols Followed by Sulfur Oxygenation
Scheme 630. Sulfonamides and Sulfinamides by Coupling of Amines and Thiols Followed by Sulfur Oxygenation
Scheme 631. Mechanism for Formation of the N—S Bond
Scheme 631. Mechanism for Formation of the N—S Bond
associate. Ryan R. Walvoord was born in 1986 in the small town of Williamson,
associate. Ryan R. Walvoord was born in 1986 in the small town of Williamson,
Biographies Scott E. Allen was born in 1984 in Kutztown, Pennsylvania. He
Biographies Scott E. Allen was born in 1984 in Kutztown, Pennsylvania. He
Rosaura Padilla-Salinas was born in Piedras Negras, Coahuila, Mexico. In 2003, she was awarded a Gates Millennium Scholarship. She obtained her B.Sc. in Chemistry and B.A. Biology from the University of Colorado at Colorado Springs, where she conducted undergraduate research in the laboratory of Professor Allen M. Schoffstall. In 2008, she continued on to graduate studies at the University of Pennsylvania in the laboratory of Professor Marisa C. Kozlowski. Her research in the group has focused on the development of new asymmetric oxidative C-—N bond-forming reactions for the synthesis of novel C—N biaryls and natural products. Marisa Kozlowski received an A.B. in Chemistry from Cornell University in 1989 and a Ph.D. under the direction of Paul Bartlett from the University of California at Berkeley in 1994. After a NSF postdoctoral fellowship with David A. Evans at Harvard University, she joined the faculty at the University of Pennsylvania in 1997 and is currently Professor of Chemistry. The Kozlowski group research focuses on the design of new catalysts and transformations. She has also coauthored “Fundamentals of Asymmetric Catalysis” with Patrick Walsh.
Rosaura Padilla-Salinas was born in Piedras Negras, Coahuila, Mexico. In 2003, she was awarded a Gates Millennium Scholarship. She obtained her B.Sc. in Chemistry and B.A. Biology from the University of Colorado at Colorado Springs, where she conducted undergraduate research in the laboratory of Professor Allen M. Schoffstall. In 2008, she continued on to graduate studies at the University of Pennsylvania in the laboratory of Professor Marisa C. Kozlowski. Her research in the group has focused on the development of new asymmetric oxidative C-—N bond-forming reactions for the synthesis of novel C—N biaryls and natural products. Marisa Kozlowski received an A.B. in Chemistry from Cornell University in 1989 and a Ph.D. under the direction of Paul Bartlett from the University of California at Berkeley in 1994. After a NSF postdoctoral fellowship with David A. Evans at Harvard University, she joined the faculty at the University of Pennsylvania in 1997 and is currently Professor of Chemistry. The Kozlowski group research focuses on the design of new catalysts and transformations. She has also coauthored “Fundamentals of Asymmetric Catalysis” with Patrick Walsh.

Key takeaways

  • The copper source for this reaction was important because not all copper sources promoted the reaction.
  • 512,512, Oxidation to the alcohol is concurrent with reduction of the copper center and is followed by the oxidation of the copper and ligand by molecular oxygen to regenerate the active catalyst.
  • Both a copper and oxygen are required for this transformation to occur.
  • Later studies showed that the reaction can be performed using excess copper(II) under a nitrogen atmosphere, suggesting that the oxygen is only required to oxidize the copper(I) to copper(II) and that the incorporated oxygen comes from that initial catalyst oxidation.
  • However, under these conditions, it is highly probable that much of the copper is in the copper(II) oxidation state.

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