Tin-Free Alternatives to the Barton-McCombie Deoxygenation of Alcohols to Alkanes Involving Reductive Electron Transfer

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Metal-Promoted Deoxygenation

Low valent metals such as alkali metals behave as good electron donors towards organic compounds. Owing to their high negative potential, these have been widely exploited in Organic Synthesis for electron transfer reduction of a range of functional groups including carbonyl moieties. The earliest observations date back to the beginning of the nineteen century with successively the so-called Bouveault-Blanc reduction of carboxylic esters to alcohols by excess of sodium in ethanol (or amyl alcohol)15 and their bimolecular reductive coupling in refluxing aprotic solvents, better known as acyloin condensation.16 Both involved formation of a common ketyl-like radical anion intermediate subsequent to electron transfer. Over the years, some other unexpected reactivities have been observed. In the sixties, two different groups reported independently the uncanny ability of allylic-17 and -keto acetates18 to be reduced to alkanes by dissolving metals (Li or Ca in liquid ammonia). Later, Stetter and Lehmann examined the behaviour of allyl and benzyl benzoates upon reductive treatment with sodium. In this case, the transient radical anion of benzoates was supposed to undergo a -fragmentation and expel an allyl or benzyl radical which should dimerize.19 In the same line, Boar, Barton et al. designed a selective method of deoxygenation of sterically hindered of secondary and tertiary alcohols to alkanes relying on the reduction of the corresponding acetates by alkali metals dissolved in amines. Two protocols involving either lithium in diethylamine or potassium solubilized by 18-crown-6 ether in tertbutylamine have been established and, applied for instance to the chemoselective cleavage of 6 and 12 acetates in 3,6-diacetoxy-5-cholestane and 3,12-diacetoxy-13-oleanane respectively. Conversely, less hindered acetates such as these at the 3 position are more likely to regenerate the original hydroxyl groups. It means that the degree of selectivity is strongly related to the difference of steric environments (Scheme 2, eq. 1).20 This methodology was applied to the synthesis of various natural products such as (-)-trichodiene21 using the Li/EtNH2 system (Scheme 2, eq. 2), (-)-cladiella-6,11-dien-3-ol and its derivatives22 (Scheme 2, eq. 3) and (±)-Tormesol with K/18-C-6 in tBuNH2/THF23 (Scheme 2, eq. 4). A modified protocol with lithium/t-BuOH in liquid ammonia was used by Mander et al. in the synthesis of C20 gibberellins.

Electrochemical Deoxygenation

Electrochemical processes have proven to be some of the most economical and ecofriendly methods of achieving redox synthetic transformations since the unique source of electron is the current.39 In particular, electroreduction of organic halides and carbonyl compounds has been widely studied compared to the reductive cleavage of alcohols which required high negative potential. To realize such deoxygenation processes, alcohols have been converted into acetates, oxalates or toluates prior being electrochemically reduced.
Early research studies on this subject began in 1960 with the polarographic reduction of 2-acetoxyacetophenone to acetophenone by Henning Lund.40 Ten years after, Utley et al. have been interested in the reductive electrolysis of para-methoxycarbonyl benzylacetate at a lead cathode in a methanol solution of tetra-n-butylammonium acetate as the supporting electrolyte. When a potential of -1.8 V vs. SCE is applied, the corresponding methyl paratoluate was obtained in 95% yield and with a good current efficiency. It is worthy of note that under these conditions, the cathodic reduction of acetoxyacetophenone is not chemoselective and leads to a mixture of acetophenone (20%) and 1-phenylethanol (54%), which results fromthe cleavage of the benzylic carbon-oxygen bond and the subsequent reduction of the carbonyl group.41 Logically, the behavior of allylic acetates was then examined. A preparative electrolysis of vitamin A acetate at a mercury pool cathode was performed in an acetonitrile solution of tetra-n-butylammonium acetate and acetic acid as a proton source at a controlled potential (-1.35V vs. Ag/AgI) and delivered axerophtene in 71% yield after the passage of  2 F/mol of current.42 Also, as shown by Tsujimoto et al., electrochemical reduction of 3-(2- naphthyl)-2-butenyl acetate at a platinum cathode gave (E)-2-(2-naphthyl)-2-butene in 73% yield.43 In 2002, Frontana-Uribe et al. explored the ability of the electrogenerated tetrabutylammonium-mercury amalgam to reduce aliphatic acetates. For instance, electroreduction of diosgenin acetate under a constant current (5 mA, 2.1 F/mol) gave rise to a ca. 1:1 ratio of alkane and alcohol, and the deoxygenated product could be isolated in 53% yield. These results are comparable with those obtained using alkaline metals and a similar mechanism involving a ketyl-like radical-anion formation and fragmentation can be proposed (vide supra).

Electron Transfer Deoxygenation from Carbon Dioxide Radical Anion

The chemical system (Bu4N)2S2O8/HCO2Na has aroused keen interest for its ability to generate carbon dioxide radical anion CO2:
•- by oxidation with sulfate radical anion SO4.
•- and then promote one-electron reductive processes. In 1991, Hu and Qing took advantage of this reactivity to carry out per(poly)fluoroakylation of olefins by reduction of per(poly)fluoroalkyl chlorides.49 Based on this seminal work, Kim et al. developed a new method for the radical deoxygenation of alcohols from thiocarbonyl derivatives. Using a mixture of (Bu4N)2S2O8 (3 equiv.)/HCO2Na (6 equiv.)/Na2CO3 (8 equiv.) in DMF at 50°C, good to excellent yields in alkane (up to 98%) were reached whatever the nature of the radical precursor (xanthate, phenyl thionocarbonate or (thiocarbonyl)imidazolide) and the functional groups present in the substrate. A SET mechanism was proposed involving electron transfer from carbon dioxide radical anion CO2.
•to the thiocarbonyl function and  -scission of the tetrahedral radical anion intermediate. Deuterium labeling experiments then indicated that the expelled radical can abstract a hydrogen atom from the formate anion, the tetrabutylammonium cation and DMF to form the deoxygenated product.50 This transformation has been applied to the synthesis of Platencin51 and a 3-des-hydroxyl analogue of ()-clausenamide.


Visible Light-induced Photodeoxygenation Reactions

More appealing routes to perform photoreductive deoxygenations under milder conditions were recently reported with the rebirth of photoredox catalysis using visible light irradiation.6 These photoinduced SET processes require the presence of photocatalysts (Pcat ) that absorbs light in the visible range, which can be polypyridine transition metal complexes.
We developed notably a photocatalytic alternative of the classical Barton-McCombie deoxygenation of aliphatic secondary and tertiary alcohols based on photoreduction of the corresponding imidazole O-thiocarbamates. Upon treatment with fac-Ir(ppy)3 and diisopropylethylamine (DIPEA, Hünig’s base) in acetonitrile under LED lights at room temperature, products of reduction were obtained in good to moderate yields (Scheme 18).
Excellent functional group compatibility was observed with sulfonamide and tertbutoxycarbonyl protecting groups, aromatics, alkenes, acetals, alkyl esters, lactones. By comparison, this transformation performed under standard tin hydride conditions gave the same results. However, photoreduction of the benzhydrol derivative furnished a mixture of 1,1-diphenylmethane (21%) and dimer 1,1,2,2-tetraphenylethane (37%). To gain insights into the mechanism, fluorescence quenching experiments and comparison of reduction potentials of a set of thiocarbamates (-1.11 to -1.73 V) with the Ir(IV)/Ir(III)* redox system (–1.73 V) established that photoactivated fac-Ir(ppy)3* reduce the O-thiocarbamates. These informations allowed to propose a reasonable mechanism where fac-Ir(ppy)3* can transfer an electron to the thiocarbamate moiety and the photocatalyst is regenerate in the presence of DIPEA. Then, the generated thiocarbamate radical anion fragments and affords the intermediate carboncentered radical which can abstract an hydrogen to the amine radical cation (Scheme 18).77

Table of contents :

Résumé détaillé en Français
Chapter I Green Radical Chemistry and Photoredox Catalysis
I.A. Green Radical Chemistry
I.A.1. Introduction to Radical Synthesis
I.A.2. To a Greener Radical Synthesis
I.B. Visible-Light Photoredox Catalysis
I.B.1. Photophysical properties of Ru(bpy)3 complexes and other photocatalysts
I.B.2. Basic of photoredox catalysis
I.B.3. Photocatalytic Generation of C-Centered Radicals
I.B.3.a. Formation involving photoreductive processes
I.B.3.b. Formation involving photooxidative processes
I.C. Conclusion
Chapter II Barton-McCombie Deoxygenation of Alcohols to Alkanes
II.A. Tin-Free Alternatives to the Barton-McCombie Deoxygenation of Alcohols to Alkanes Involving Reductive Electron Transfer
II.A.1. Abstract
II.A.2. Introduction
II.A.3. Metal-Promoted Deoxygenation
II.A.4. Electrochemical Deoxygenation
II.A.5. Electron Transfer Deoxygenation from Carbon Dioxide Radical Anion
II.A.6. Photoinduced-Electron Transfer Deoxygenation
II.A.6.a. UV Light-Induced Photodeoxygenation Reactions
II.A.6.b. Visible Light-induced Photodeoxygenation Reactions
II.A.7. Conclusion
II.B. Results: Visible-Light Photocatalytic Reduction of O-Thiocarbamates: Development of A Tin- Free Barton-McCombie Deoxygenation Reaction
II.B.1. Objectives of the Project
II.B.2. Barton-McCombie Deoxygenation – State of the Art
II.B.3. O-Thiocarbamates as New Class of Substrates for Visible-Light Triggered Generation of Radicals
II.B.3.a Optimization of the photocatalyzed deoxygenation of alcohols
II.B.3.b. Influence of the leaving groupII.B.3.c. Synthesis of other O-thiocarbamates from the corresponding alcohols
II.B.3.d. Scope and limitations of the photoreductive deoxygenation of alcohols
II.B.4. Mechanistic Studies of the Photoredox Catalyzed
II.B.5. Miscellaneous Studies
II.B.6. Conclusion
Experimental Section – Chapter II
II.B.7. Experimental Section
II.B.7.a. General remarks
II.B.7.b. General procedures
II.B.7.c. Compound characterizations
Chapter III Visible Light-induced Photooxidative Generation of Radicals from Hypervalent Species and Development of a New Dual Photoredox/Nickel Catalysis Process
III.A. Bibliographical Background: When Photoredox Catalysis Merged with Organometallic Catalysis: Rising of Dual Catalysis Process
III.A.1. Introduction
III.A.2. Merging of Visible-light Photoredox/Transition-Metal Catalysis
III.A.3. Photoredox/Nickel Dual Catalysis
III.A.3.a. Development of the nickel catalysis
III.A.3.b. The birth of visible-light photoredox/nickel dual catalysis
III.A.3.c. Molander’s research
III.A.3.d. MacMillan and Doyle’s research
III.A.3.e. Development of the photoredox/nickel dual catalysis
III.A.4. Conclusion
III.B. Results: Alkyl Bis-Catecholato Silicates in Dual Photoredox/Nickel Catalysis: Aryl- and Heteroaryl-Alkyl Cross Coupling Reactions
III.B.1. Introduction and Objectives
III.B.2. Synthesis of Alkyl Silicates Precursors
III.B.3. Photoredox/Nickel dual catalysis process
III.B.4. Conclusion
III.C. Results: Photooxidative Generation of Alkyl Radicals by a Metal Free Catalytic Process: Applications to Radical Synthesis and Dual Catalysis
III.C.1. Introduction and objectives
III.C.2. Generation of radicals by organic oxidants
III.C.2.a. Stoichiometric oxidation
III.C.2.b. Photocatalytic oxidation
III.C.2.c. New generation of organic dyes
III.C.3. Conclusion
Experimental Section – Chapter III
III.C.4. Experimental Section
III.C.4.a. General informations
III.C.4.b. General procedures
III.C.4.c. Compound characterizations
General Conclusion 


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