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

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To a Greener Radical Synthesis

Green chemistry is a new paradigm for chemistry emerged in the 90s which provides pollution prevention related to chemical activities. This benign chemistry to the environment aims to develop products and chemical processes that reduce or eliminate the use and synthesis of hazardous substances. It applies to both the preparation of new products or processes more environmentally friendly and the search for alternative solutions or to the improvement of existing approaches. This new concept was made popular in the scientific community by the American chemists Paul Anastas , director of the Green Chemistry Institute in Washington DC, and John Warner with the publication in 1998 of the 12 principles of Green Chemistry as cited Table 1.3.

Visible-Light Photoredox Catalysis

Millions of years of evolution have allowed nature to implement chemical and biological processes in order to preserve life by maintaining a sustainable balance. For plants, the energy required for creation of organic matter comes from a virtually inexhaustible source: the sun. The light, absorbed by chlorophyll, promotes activation of ATP production which then allows carbon sequestration provided by the CO2, thereby transforming solar energy into chemical energy.
Inspired by such a process the radical chemistry community participated over the last years to the use of visible light, to carry out original, selective and efficient chemical transformations involving redox processes for the generation of radical species. Visible light photoredox catalysis has recently established itself as one of the most versatile methods to conduct radical chemistry. It is also one of the most productive fields of activity in contemporary organic chemistry. As chlorophyll is fundamental in photoredox processes involved in photosynthesis, the envisaged chemical transformations require the intervention of an appropriate photocatalyst which absorbs light in the visible range. For that purpose, the photoactive complexe Ru(bpy)32+ was introduced in catalytic quantity. Well known in the inorganic chemistry community as a photoredox catalyst for diverse applications such as hydrogen and oxygen production from water, methane evolution from carbon dioxide and reduction of carbon dioxide to formate, 9,10 it has witnessed only sporadic uses in organic synthesis by the groups of Kellog,11 Pac12 and Deronzier,13 until recently in 2008 when David MacMillan (Princeton University) used it to merge organocatalysis with photoredox catalysis and provide an asymmetric-alkylation of aldehydes.14 Since this renaissance, two other teams, the groups of Corey Stephenson (Boston University) and Tehshik P. Yoon (University of Wisconsin, Madison) have published very interesting contributions on dehalogenative cyclization reactions15 and photocatalytic [2+2] cycloadditions of enones.

Photophysical properties of Ru(bpy)3 complexes and other photocatalysts

Known for many years for its photochemical properties and its activity in photoredox catalysis, the complex Ru(bpy)3Cl2,9 discovered by Burstall in 1936,17 has recently shown great potential in various organic redox processes used for synthetic purposes.18 If we consider the photochemical properties of such complex, the UV/Visible spectrum shows us three different bands of absorption which correspond to three different types of electronic transitions: one is the LC (Ligand Centered) transfer, the second MC (Metal Centered) and the most interesting is the MLCT (Metal-to-Ligand Charge-Transfer) that absorbs in the visible region. The characteristic absorption band at 452 nm, as shown in scheme 1, is responsible for the visible-light excitation of the complex of Ru(bpy)3Cl2.9 A tuning of ligands around the ruthenium metal center, can promote a red shift of the MLCT band which induces a modification of physical properties of the complex.

Basic of photoredox catalysis

Upon visible light irradiation at wavelength λmax, the photocatalyst PCat reaches its excited state PCat*. Two scenarios can take place: In the first one, a sacrificial electron donor is present in the reaction medium with adequate reduction potential (Scheme 2, green path) which can act as a reductive quencher (Qred) of PCat* and generate PCat-. The reduced complex then transfers an electron to the substrate R which regenerates PCat in a so-called “reductive quenching cycle”. The resulting radical anion R·- then undergoes subsequent transformations. Similarly, if the photoexcited complex PCat* reacts with a sacrificial electron acceptor acting, as an oxidative quencher (Qox), it gets oxidized to PCat+ and can be reduced by a substrate R to regenerate the starting catalytic species (oxidative quenching cycle) and liberate the radical cation R·+ (Scheme 2, orange path).

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 tert-butylamine 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

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Electrochemical processes have proven to be some of the most economical and eco-friendly 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 para-toluate 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 from the 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).
In that vein, oxalate esters exhibit a propensity to undergo reductive cleavage of carbon-oxygen bond from alcohols at lower negative potentials (ca -1.2 vs. Ag/AgI). Electron transfer from cathode to oxalates was first highlighted by Voss with the formation of a stable semidione radical anion intermediate, evidenced by EPR experiments. This reduction turned out to be reversible for diethyl oxalate and irreversible for diallyl and dibenzyl oxalates in aprotic solution.45 Utley et al. suggested this irreversibility comes from a rapid fragmentation of the radical anion, as already observed with acetate (vide supra), which can be accelerated in protic conditions. Studies on benzyl oxalates supported a mechanism whereby transient radical anions collapse to benzyl radicals and oxalate anions and not the reverse. However, the process was hampered by competing hydrolysis of preformed oxalates, particularly of benzylic alcohols. The solution was found by generating in situ the reactive oxalate prior to be reduced via a co-electrolysis between benzylic (or allylic) alcohols and diethyl oxalate. For instance, reduction of diphenylmethanol under these conditions (mercury cathode, DMF-Bu4NClO4, -1.6 V vs. Ag/AgI, 1 F/mol) gave diphenylmethane in 70% yield. Of interest, controlled potential electrolysis of oxalate of vicinal diols gave rise to olefinic adducts. As reported by Markó et al., aromatic esters such as toluates can also be regarded as valuable substrates for electrochemical deoxygenation of alcohols. A series was electrolyzed at 130°C in a H-type cell equipped with a carbon graphic cathode and filled with tetrabutylammonium tetrafluoroborate and N-methylpyrrolidone (NMP) under a constant current (15 mA.cm-2). Secondary and tertiary toluate esters were efficiently reduced to the desired alkanes and addition of a protic co-solvent such as isopropanol improved the yields. These conditions were found to be tolerant to a number of functional groups, including alkyl esters, amides, silyl ethers, ketones and free-alcohols (Scheme 9, eq. 1).38b,47 In contrast, primary toluates gave only moderate yields but by analogy with oxalates, a co-electrolysis between primary alcohols and methyl toluate provided an effective solution to that issue (Scheme 9, eq. 2).

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 group
II.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
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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