Enantioselective Photoredox Catalysis Enabled by Proton-Coupled Electron Transfer: Development of an Asymmetric Aza-Pinacol Cyclization

The first highly enantioselective catalytic protocol for the reductive coupling of ketones and hydrazones is reported. These reactions proceed through neutral ketyl radical intermediates generated via a concerted proton-coupled electron transfer (PCET) event jointly mediated by a chiral phosphoric acid catalyst and the photoredox catalyst Ir­(ppy)₂(dtbpy)­PF₆. Remarkably, these neutral ketyl radicals appear to remain H-bonded to the chiral conjugate base of the Brønsted acid during the course of a subsequent C–C bond-forming step, furnishing <i>syn</i> 1,2-amino alcohol derivatives with excellent levels of diastereo- and enantioselectivity. This work provides the first demonstration of the feasibility and potential benefits of concerted PCET activation in asymmetric catalysis

Enantioselective Photoredox Catalysis Enabled by Proton-Coupled Electron Transfer: Development of an Asymmetric Aza-Pinacol Cyclization

The first highly enantioselective catalytic protocol for the reductive coupling of ketones and hydrazones is reported. These reactions proceed through neutral ketyl radical intermediates generated via a concerted proton-coupled electron transfer (PCET) event jointly mediated by a chiral phosphoric acid catalyst and the photoredox catalyst Ir­(ppy)₂(dtbpy)­PF₆. Remarkably, these neutral ketyl radicals appear to remain H-bonded to the chiral conjugate base of the Brønsted acid during the course of a subsequent C–C bond-forming step, furnishing <i>syn</i> 1,2-amino alcohol derivatives with excellent levels of diastereo- and enantioselectivity. This work provides the first demonstration of the feasibility and potential benefits of concerted PCET activation in asymmetric catalysis

Cleavage of Ether, Ester, and Tosylate C(sp³)–O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C–H Bonds. Experimental and Computational Studies

A pincer-ligated iridium complex, (PCP)Ir (PCP = κ³-C₆H₃-2,6-[CH₂P­(<i>t-</i>Bu)₂]₂), is found to undergo oxidative addition of C­(sp³)–O bonds of methyl esters (CH₃–O₂CR′), methyl tosylate (CH₃–OTs), and certain electron-poor methyl aryl ethers (CH₃–OAr). DFT calculations and mechanistic studies indicate that the reactions proceed via oxidative addition of C–H bonds followed by oxygenate migration, rather than by direct C–O addition. Thus, methyl aryl ethers react via addition of the methoxy C–H bond, followed by α-aryloxide migration to give <i>cis</i>-(PCP)­Ir­(H)­(CH₂)­(OAr), followed by iridium-to-methylidene hydride migration to give (PCP)­Ir­(CH₃)­(OAr). Methyl acetate undergoes C–H bond addition at the carbomethoxy group to give (PCP)­Ir­(H)­[κ²-CH₂OC­(O)­Me] which then affords (PCP-CH₂)­Ir­(H)­(κ²-O₂CMe) (<b>6-Me</b>) in which the methoxy C–O bond has been cleaved, and the methylene derived from the methoxy group has migrated into the PCP C_ipso–Ir bond. Thermolysis of <b>6-Me</b> ultimately gives (PCP)­Ir­(CH₃)­(κ²-O₂CR), the net product of methoxy group C–O oxidative addition. Reaction of (PCP)Ir with species of the type ROAr, RO₂CMe or ROTs, where R possesses β-C–H bonds (e.g., R = ethyl or isopropyl), results in formation of (PCP)­Ir­(H)­(OAr), (PCP)­Ir­(H)­(O₂CMe), or (PCP)­Ir­(H)­(OTs), respectively, along with the corresponding olefin or (PCP)­Ir­(olefin) complex. Like the C–O bond oxidative additions, these reactions also proceed via initial activation of a C–H bond; in this case, C–H addition at the β-position is followed by β-migration of the aryloxide, carboxylate, or tosylate group. Calculations indicate that the β-migration of the carboxylate group proceeds via an unusual six-membered cyclic transition state in which the alkoxy C–O bond is cleaved with no direct participation by the iridium center

Cleavage of Ether, Ester, and Tosylate C(sp³)–O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C–H Bonds. Experimental and Computational Studies

A pincer-ligated iridium complex, (PCP)Ir (PCP = κ³-C₆H₃-2,6-[CH₂P­(<i>t-</i>Bu)₂]₂), is found to undergo oxidative addition of C­(sp³)–O bonds of methyl esters (CH₃–O₂CR′), methyl tosylate (CH₃–OTs), and certain electron-poor methyl aryl ethers (CH₃–OAr). DFT calculations and mechanistic studies indicate that the reactions proceed via oxidative addition of C–H bonds followed by oxygenate migration, rather than by direct C–O addition. Thus, methyl aryl ethers react via addition of the methoxy C–H bond, followed by α-aryloxide migration to give <i>cis</i>-(PCP)­Ir­(H)­(CH₂)­(OAr), followed by iridium-to-methylidene hydride migration to give (PCP)­Ir­(CH₃)­(OAr). Methyl acetate undergoes C–H bond addition at the carbomethoxy group to give (PCP)­Ir­(H)­[κ²-CH₂OC­(O)­Me] which then affords (PCP-CH₂)­Ir­(H)­(κ²-O₂CMe) (<b>6-Me</b>) in which the methoxy C–O bond has been cleaved, and the methylene derived from the methoxy group has migrated into the PCP C_ipso–Ir bond. Thermolysis of <b>6-Me</b> ultimately gives (PCP)­Ir­(CH₃)­(κ²-O₂CR), the net product of methoxy group C–O oxidative addition. Reaction of (PCP)Ir with species of the type ROAr, RO₂CMe or ROTs, where R possesses β-C–H bonds (e.g., R = ethyl or isopropyl), results in formation of (PCP)­Ir­(H)­(OAr), (PCP)­Ir­(H)­(O₂CMe), or (PCP)­Ir­(H)­(OTs), respectively, along with the corresponding olefin or (PCP)­Ir­(olefin) complex. Like the C–O bond oxidative additions, these reactions also proceed via initial activation of a C–H bond; in this case, C–H addition at the β-position is followed by β-migration of the aryloxide, carboxylate, or tosylate group. Calculations indicate that the β-migration of the carboxylate group proceeds via an unusual six-membered cyclic transition state in which the alkoxy C–O bond is cleaved with no direct participation by the iridium center

Cleavage of Ether, Ester, and Tosylate C(sp³)–O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C–H Bonds. Experimental and Computational Studies

A pincer-ligated iridium complex, (PCP)Ir (PCP = κ³-C₆H₃-2,6-[CH₂P­(<i>t-</i>Bu)₂]₂), is found to undergo oxidative addition of C­(sp³)–O bonds of methyl esters (CH₃–O₂CR′), methyl tosylate (CH₃–OTs), and certain electron-poor methyl aryl ethers (CH₃–OAr). DFT calculations and mechanistic studies indicate that the reactions proceed via oxidative addition of C–H bonds followed by oxygenate migration, rather than by direct C–O addition. Thus, methyl aryl ethers react via addition of the methoxy C–H bond, followed by α-aryloxide migration to give <i>cis</i>-(PCP)­Ir­(H)­(CH₂)­(OAr), followed by iridium-to-methylidene hydride migration to give (PCP)­Ir­(CH₃)­(OAr). Methyl acetate undergoes C–H bond addition at the carbomethoxy group to give (PCP)­Ir­(H)­[κ²-CH₂OC­(O)­Me] which then affords (PCP-CH₂)­Ir­(H)­(κ²-O₂CMe) (<b>6-Me</b>) in which the methoxy C–O bond has been cleaved, and the methylene derived from the methoxy group has migrated into the PCP C_ipso–Ir bond. Thermolysis of <b>6-Me</b> ultimately gives (PCP)­Ir­(CH₃)­(κ²-O₂CR), the net product of methoxy group C–O oxidative addition. Reaction of (PCP)Ir with species of the type ROAr, RO₂CMe or ROTs, where R possesses β-C–H bonds (e.g., R = ethyl or isopropyl), results in formation of (PCP)­Ir­(H)­(OAr), (PCP)­Ir­(H)­(O₂CMe), or (PCP)­Ir­(H)­(OTs), respectively, along with the corresponding olefin or (PCP)­Ir­(olefin) complex. Like the C–O bond oxidative additions, these reactions also proceed via initial activation of a C–H bond; in this case, C–H addition at the β-position is followed by β-migration of the aryloxide, carboxylate, or tosylate group. Calculations indicate that the β-migration of the carboxylate group proceeds via an unusual six-membered cyclic transition state in which the alkoxy C–O bond is cleaved with no direct participation by the iridium center

Cleavage of Ether, Ester, and Tosylate C(sp³)–O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C–H Bonds. Experimental and Computational Studies

A pincer-ligated iridium complex, (PCP)Ir (PCP = κ³-C₆H₃-2,6-[CH₂P­(<i>t-</i>Bu)₂]₂), is found to undergo oxidative addition of C­(sp³)–O bonds of methyl esters (CH₃–O₂CR′), methyl tosylate (CH₃–OTs), and certain electron-poor methyl aryl ethers (CH₃–OAr). DFT calculations and mechanistic studies indicate that the reactions proceed via oxidative addition of C–H bonds followed by oxygenate migration, rather than by direct C–O addition. Thus, methyl aryl ethers react via addition of the methoxy C–H bond, followed by α-aryloxide migration to give <i>cis</i>-(PCP)­Ir­(H)­(CH₂)­(OAr), followed by iridium-to-methylidene hydride migration to give (PCP)­Ir­(CH₃)­(OAr). Methyl acetate undergoes C–H bond addition at the carbomethoxy group to give (PCP)­Ir­(H)­[κ²-CH₂OC­(O)­Me] which then affords (PCP-CH₂)­Ir­(H)­(κ²-O₂CMe) (<b>6-Me</b>) in which the methoxy C–O bond has been cleaved, and the methylene derived from the methoxy group has migrated into the PCP C_ipso–Ir bond. Thermolysis of <b>6-Me</b> ultimately gives (PCP)­Ir­(CH₃)­(κ²-O₂CR), the net product of methoxy group C–O oxidative addition. Reaction of (PCP)Ir with species of the type ROAr, RO₂CMe or ROTs, where R possesses β-C–H bonds (e.g., R = ethyl or isopropyl), results in formation of (PCP)­Ir­(H)­(OAr), (PCP)­Ir­(H)­(O₂CMe), or (PCP)­Ir­(H)­(OTs), respectively, along with the corresponding olefin or (PCP)­Ir­(olefin) complex. Like the C–O bond oxidative additions, these reactions also proceed via initial activation of a C–H bond; in this case, C–H addition at the β-position is followed by β-migration of the aryloxide, carboxylate, or tosylate group. Calculations indicate that the β-migration of the carboxylate group proceeds via an unusual six-membered cyclic transition state in which the alkoxy C–O bond is cleaved with no direct participation by the iridium center

Cleavage of Ether, Ester, and Tosylate C(sp³)–O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C–H Bonds. Experimental and Computational Studies

A pincer-ligated iridium complex, (PCP)Ir (PCP = κ³-C₆H₃-2,6-[CH₂P­(<i>t-</i>Bu)₂]₂), is found to undergo oxidative addition of C­(sp³)–O bonds of methyl esters (CH₃–O₂CR′), methyl tosylate (CH₃–OTs), and certain electron-poor methyl aryl ethers (CH₃–OAr). DFT calculations and mechanistic studies indicate that the reactions proceed via oxidative addition of C–H bonds followed by oxygenate migration, rather than by direct C–O addition. Thus, methyl aryl ethers react via addition of the methoxy C–H bond, followed by α-aryloxide migration to give <i>cis</i>-(PCP)­Ir­(H)­(CH₂)­(OAr), followed by iridium-to-methylidene hydride migration to give (PCP)­Ir­(CH₃)­(OAr). Methyl acetate undergoes C–H bond addition at the carbomethoxy group to give (PCP)­Ir­(H)­[κ²-CH₂OC­(O)­Me] which then affords (PCP-CH₂)­Ir­(H)­(κ²-O₂CMe) (<b>6-Me</b>) in which the methoxy C–O bond has been cleaved, and the methylene derived from the methoxy group has migrated into the PCP C_ipso–Ir bond. Thermolysis of <b>6-Me</b> ultimately gives (PCP)­Ir­(CH₃)­(κ²-O₂CR), the net product of methoxy group C–O oxidative addition. Reaction of (PCP)Ir with species of the type ROAr, RO₂CMe or ROTs, where R possesses β-C–H bonds (e.g., R = ethyl or isopropyl), results in formation of (PCP)­Ir­(H)­(OAr), (PCP)­Ir­(H)­(O₂CMe), or (PCP)­Ir­(H)­(OTs), respectively, along with the corresponding olefin or (PCP)­Ir­(olefin) complex. Like the C–O bond oxidative additions, these reactions also proceed via initial activation of a C–H bond; in this case, C–H addition at the β-position is followed by β-migration of the aryloxide, carboxylate, or tosylate group. Calculations indicate that the β-migration of the carboxylate group proceeds via an unusual six-membered cyclic transition state in which the alkoxy C–O bond is cleaved with no direct participation by the iridium center

Cleavage of Ether, Ester, and Tosylate C(sp³)–O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C–H Bonds. Experimental and Computational Studies

A pincer-ligated iridium complex, (PCP)Ir (PCP = κ³-C₆H₃-2,6-[CH₂P­(<i>t-</i>Bu)₂]₂), is found to undergo oxidative addition of C­(sp³)–O bonds of methyl esters (CH₃–O₂CR′), methyl tosylate (CH₃–OTs), and certain electron-poor methyl aryl ethers (CH₃–OAr). DFT calculations and mechanistic studies indicate that the reactions proceed via oxidative addition of C–H bonds followed by oxygenate migration, rather than by direct C–O addition. Thus, methyl aryl ethers react via addition of the methoxy C–H bond, followed by α-aryloxide migration to give <i>cis</i>-(PCP)­Ir­(H)­(CH₂)­(OAr), followed by iridium-to-methylidene hydride migration to give (PCP)­Ir­(CH₃)­(OAr). Methyl acetate undergoes C–H bond addition at the carbomethoxy group to give (PCP)­Ir­(H)­[κ²-CH₂OC­(O)­Me] which then affords (PCP-CH₂)­Ir­(H)­(κ²-O₂CMe) (<b>6-Me</b>) in which the methoxy C–O bond has been cleaved, and the methylene derived from the methoxy group has migrated into the PCP C_ipso–Ir bond. Thermolysis of <b>6-Me</b> ultimately gives (PCP)­Ir­(CH₃)­(κ²-O₂CR), the net product of methoxy group C–O oxidative addition. Reaction of (PCP)Ir with species of the type ROAr, RO₂CMe or ROTs, where R possesses β-C–H bonds (e.g., R = ethyl or isopropyl), results in formation of (PCP)­Ir­(H)­(OAr), (PCP)­Ir­(H)­(O₂CMe), or (PCP)­Ir­(H)­(OTs), respectively, along with the corresponding olefin or (PCP)­Ir­(olefin) complex. Like the C–O bond oxidative additions, these reactions also proceed via initial activation of a C–H bond; in this case, C–H addition at the β-position is followed by β-migration of the aryloxide, carboxylate, or tosylate group. Calculations indicate that the β-migration of the carboxylate group proceeds via an unusual six-membered cyclic transition state in which the alkoxy C–O bond is cleaved with no direct participation by the iridium center

Cleavage of Ether, Ester, and Tosylate C(sp³)–O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C–H Bonds. Experimental and Computational Studies

A pincer-ligated iridium complex, (PCP)Ir (PCP = κ³-C₆H₃-2,6-[CH₂P­(<i>t-</i>Bu)₂]₂), is found to undergo oxidative addition of C­(sp³)–O bonds of methyl esters (CH₃–O₂CR′), methyl tosylate (CH₃–OTs), and certain electron-poor methyl aryl ethers (CH₃–OAr). DFT calculations and mechanistic studies indicate that the reactions proceed via oxidative addition of C–H bonds followed by oxygenate migration, rather than by direct C–O addition. Thus, methyl aryl ethers react via addition of the methoxy C–H bond, followed by α-aryloxide migration to give <i>cis</i>-(PCP)­Ir­(H)­(CH₂)­(OAr), followed by iridium-to-methylidene hydride migration to give (PCP)­Ir­(CH₃)­(OAr). Methyl acetate undergoes C–H bond addition at the carbomethoxy group to give (PCP)­Ir­(H)­[κ²-CH₂OC­(O)­Me] which then affords (PCP-CH₂)­Ir­(H)­(κ²-O₂CMe) (<b>6-Me</b>) in which the methoxy C–O bond has been cleaved, and the methylene derived from the methoxy group has migrated into the PCP C_ipso–Ir bond. Thermolysis of <b>6-Me</b> ultimately gives (PCP)­Ir­(CH₃)­(κ²-O₂CR), the net product of methoxy group C–O oxidative addition. Reaction of (PCP)Ir with species of the type ROAr, RO₂CMe or ROTs, where R possesses β-C–H bonds (e.g., R = ethyl or isopropyl), results in formation of (PCP)­Ir­(H)­(OAr), (PCP)­Ir­(H)­(O₂CMe), or (PCP)­Ir­(H)­(OTs), respectively, along with the corresponding olefin or (PCP)­Ir­(olefin) complex. Like the C–O bond oxidative additions, these reactions also proceed via initial activation of a C–H bond; in this case, C–H addition at the β-position is followed by β-migration of the aryloxide, carboxylate, or tosylate group. Calculations indicate that the β-migration of the carboxylate group proceeds via an unusual six-membered cyclic transition state in which the alkoxy C–O bond is cleaved with no direct participation by the iridium center

Cleavage of Ether, Ester, and Tosylate C(sp³)–O Bonds by an Iridium Complex, Initiated by Oxidative Addition of C–H Bonds. Experimental and Computational Studies

A pincer-ligated iridium complex, (PCP)Ir (PCP = κ³-C₆H₃-2,6-[CH₂P­(<i>t-</i>Bu)₂]₂), is found to undergo oxidative addition of C­(sp³)–O bonds of methyl esters (CH₃–O₂CR′), methyl tosylate (CH₃–OTs), and certain electron-poor methyl aryl ethers (CH₃–OAr). DFT calculations and mechanistic studies indicate that the reactions proceed via oxidative addition of C–H bonds followed by oxygenate migration, rather than by direct C–O addition. Thus, methyl aryl ethers react via addition of the methoxy C–H bond, followed by α-aryloxide migration to give <i>cis</i>-(PCP)­Ir­(H)­(CH₂)­(OAr), followed by iridium-to-methylidene hydride migration to give (PCP)­Ir­(CH₃)­(OAr). Methyl acetate undergoes C–H bond addition at the carbomethoxy group to give (PCP)­Ir­(H)­[κ²-CH₂OC­(O)­Me] which then affords (PCP-CH₂)­Ir­(H)­(κ²-O₂CMe) (<b>6-Me</b>) in which the methoxy C–O bond has been cleaved, and the methylene derived from the methoxy group has migrated into the PCP C_ipso–Ir bond. Thermolysis of <b>6-Me</b> ultimately gives (PCP)­Ir­(CH₃)­(κ²-O₂CR), the net product of methoxy group C–O oxidative addition. Reaction of (PCP)Ir with species of the type ROAr, RO₂CMe or ROTs, where R possesses β-C–H bonds (e.g., R = ethyl or isopropyl), results in formation of (PCP)­Ir­(H)­(OAr), (PCP)­Ir­(H)­(O₂CMe), or (PCP)­Ir­(H)­(OTs), respectively, along with the corresponding olefin or (PCP)­Ir­(olefin) complex. Like the C–O bond oxidative additions, these reactions also proceed via initial activation of a C–H bond; in this case, C–H addition at the β-position is followed by β-migration of the aryloxide, carboxylate, or tosylate group. Calculations indicate that the β-migration of the carboxylate group proceeds via an unusual six-membered cyclic transition state in which the alkoxy C–O bond is cleaved with no direct participation by the iridium center