The French connecTion CHIMIA 2016, 70, No. 1/2 67 doi:10.2533/chimia.2016.67 Chimia 70 (2016) 67–76 © Swiss Chemical Society Tin-free Alternatives to the Barton- McCombie Deoxygenation of Alcohols to Alkanes Involving Reductive Electron Transfer Ludwig Chenneberg and Cyril Ollivier* Abstract: Echoing the recent celebration of the fortieth anniversary of the Barton-McCombie reaction, this review aims to explore another facet of radical processes for deoxygenation of alcohols by considering SET (single electron transfer) reduction of carboxylic ester, thiocarbonate and thiocarbamate derivatives. Various protocols have been developed relying on the use of organic and organometallic SET reagents, electrochemi- cal conditions, photoinduced electron transfer processes and visible-light photoredox catalysis. Applications to the synthesis of molecules of interest provide a glimpse into the scope of these different approaches. Keywords: Alcohols · Deoxygenation · Electron transfer · Radicals · Reduction 1. Introduction phorus derivatives and less toxic metals.[1] secondary and tertiary alcohols.[7] In 2015, Interesting perspectives have opened up the radical community celebrated the 40th Radical chemistry has witnessed an ex- with the use of organoboranes[4] and com- anniversary of the discovery of the Barton- plosive growth over the last three decades. pounds responsible for electron-transfer McCombie deoxygenation reaction, unan- Owing to their mildness and high com- reactions have been increasingly seen as imously considered as the most common patibility with functional groups, radical valuable alternatives to tin radical chem- and important process to perform such a reactions have been firmly established as istry.[5] However, mild and sustainable transformation.[8] Originally, this approach reliable and versatile tools for organic syn- preparative redox processes limiting the was based first on the activation of a sec- thesis.[1] But the main drawback is associ- utilization of substoichiometric amounts ondary or tertiary alcohol as a thiocarbon- ated with the overuse of tin mediators to of metal complexes are still needed. Re- ate or thiocarbamate precursor including propagate chain reactions. These reagents cently, visible-light photoredox catalysis the well-known xanthate followed by its are known for being toxic and purification has emerged as a valuable and efficient subsequent reduction to alkane through of reaction products is a non-trivial task. tool for the generation of radicals by sin- a nBu SnH/AIBN(cat)-mediated radical 3 Thus, tin residues are often detected in gle electron transfer (SET) reactions from chain process under thermal conditions traces eliminating any possibility of radi- an appropriate photocatalyst that absorbs (Scheme 1, Eqn. 1). Several improvements cal reactions being used in industry. As light in the visible region. These conditions have been achieved by replacing the tin pointed out by J. Walton,[2] it is time to es- have demonstrated their high synthetic po- mediator with silicon hydrides,[3,9] cyclo- cape from ‘the tyranny of tin’ and to devise tential in various organic redox processes hexadienyl compounds,[10] phosphorous valuable alternatives for the generation of for fine chemical synthesis and contributed reagents,[11] organoboranes[4,12] or DLP/ radicals. One option consists in using stan- at the same time to the development of a isopropanol.[13] In parallel, a great deal nane derivatives in a catalytic fashion or greener radical chemistry.[6] of effort has been devoted to the devel- as supported reagents.[3] Another has dealt Among the mainstream transforma- opment of single electron transfer (SET) with the development of tin-free media- tions present in the synthetic toolbox of processes whose major advances will be tors based for instance on silanes, phos- organic chemists, reduction of alcohols to highlighted in this brief review and will alkanes has gained a place of choice. Hy- complement a former review published by droxyl functional groups can indeed par- Hartwig in 1983.[14] Specific focus will be ticipate in the construction of elaborated placed on reduction of alcohols to alkanes molecular structures and be removed in with emphasis on Barton-McCombie-type due course. However, the hydroxide anion deoxygenations of alcohol derivatives in- is known as a poor leaving group, homo- volving SET reduction of carbonyl and lytic scission of non-activated carbon–hy- thiocarbonyl-based functional groups. For droxyl bonds is not thermodynamically that purpose, different methods using or- feasible and direct electron transfer reduc- ganic and organometallic SET reagents, tion of alcohols requires very low nega- electrochemical conditions and photoin- tive potentials. A proposed solution was duced electron transfer (PET) processes *Correspondence: Dr. C. Ollivier to convert the hydroxyl group to a good under UV light irradiation or by visible- Institut Parisien de Chimie Moléculaire leaving group or to a suitable radical pre- light photoredox catalysis will be present- (UMR CNRS 8232) cursor. Yet, limitations of deoxygenation ed (Scheme 1, Eqn. 2). Applications to the UPMC Univ-Paris 06, Sorbonne Universités 4 Place Jussieu, C. 229, 75005 Paris, France by ionic processes were encountered with synthesis of molecules of interest such as E-mail:[email protected] sterically hindered and/or non-activated natural products will also be discussed. 68 CHIMIA 2016, 70, No. 1/2 The French connecTion Scheme 1. SET re- the bulk of the acyl substituent from methyl Classical Barton-McCombie-type Radical Deoxygenation duction of carbonyl to isopropyl, to tert-butyl and to adamantyl and thiocarbonyl- S(O) Init., [H] enhances the yield in deoxygenation prod- ROH R RH (Eqn. 1) based functional O X ucts (Scheme 2, Eqn. 1). Running reactions groups: Tin-free alter- in tert-butylamine or 1,2-dimethoxyethane Derivatization Chain reaction natives to the classi- X=Alkyl, Ph, SMe, cal Barton-McCombie with THF as a co-solvent is more suitable OMe, OPh, Imidazolyl, aryl deoxygenation reac- than in a nucleophilic solvent such as di- tion of alcohols to ethylamine for impeding competitive ami- The topic of this review SET reagents alkanes. dolysis of acetates and regeneration of the Electrochemistry S(O) PET,photocatalysis starting alcohol. Moreover, deacylation R OH R RH (Eqn. 2) may also be caused by the presence of ‘ad- O X +1e- ventitious’ water and by crown ether-de- Derivatization SET reduction rived nucleophiles generated by degrada- tion along the process. Thus, a new reduc- tion system based on the use of a eutectic 2. Metal-promoted Deoxygenation (Scheme 2, Eqn. 1).[20] This methodology potassium/sodium alloy solubilized by aza was applied to the synthesis of various 18-crown-6 1,4,7,10,13,16-hexamethyl- Low-valent metals such as alkali met- natural products such as (–)-trichodiene[21] 1,4,7,10,13,16-hexaazacyclooctadecane using the Li/EtNH system (Scheme 2, als behave as good electron donors towards 2 in tert-butylamine/THF was developed organic compounds. Owing to their high Eqn. 2), (–)-cladiella-6,11-dien-3-ol and and allowed the reduction of both hin- negative potential, these have been widely its derivatives[22] (Scheme 2, Eqn. 3) and dered and non-hindered esters including (±)-tormesol with K/18-C-6 in tBuNH / exploited in organic synthesis for electron 2 primary esters. As examples, reduction transfer reduction of a range of functional THF[23] (Scheme 2, Eqn. 4). A modified of 5α-cholestan-3β-yl and octadecyl ada- groups including carbonyl moieties. The protocol with lithium/t-BuOH in liquid mantane-1-carboxylates gave the products earliest observations date back to the be- ammonia was used by Mander et al. in the of deoxygenation in 90% and 74% yields ginning of the nineteenth century with suc- synthesis of C20 gibberellins.[24] respectively, but in the former case a Bou- cessively the so-called Bouveault-Blanc Further optimization of the reaction veault-Blanc reduction predominates at reduction of carboxylic esters to alcohols conditions and mechanistic studies were lower temperature (Scheme 3). by excess of sodium in ethanol (or amyl undertaken by Barrett, Barton et al.[25] These experiments are fully consis- alcohol)[15] and their bimolecular reduc- They particularly showed that increasing tent with a mechanism that involves one- tive coupling in refluxing aprotic solvents, better known as acyloin condensation.[16] Both involved formation of a common ke- tyl-like radical anion intermediate subse- quent to electron transfer. Over the years, some other unexpected reactivities have Conditions H (Eqn. 1) 3 6 been observed. In the nineteen-sixties, two O H H Li/EtNH reflux different groups reported independently O R 2 R=Me, 40% O R HO the uncanny ability of allylic-[17] and K, 18-crown-6 H O R=Me, 62% [18] tBuNH /THF,rt β-keto acetates to be reduced to alkanes 2 R=iPr,71% by dissolving metals (Li or Ca) in liquid R=tBu, 79% ammonia). Later, Stetter and Lehmann R=adamantyl, 27% and 45% 5α-cholestane examined the behavior of allyl and benzyl benzoates upon reductive treatment with sodium. In this case, the transient radical anion of benzoates was assumed to under- Li (Eqn. 2) go a β-fragmentation and expel an allyl or + benzyl radical which should dimerize.[19] OAc EtNH2/THF, −78 °C Along the same lines, Boar, Barton et (−)-Trichodiene 86% 2:1 al. designed a selective method of deoxy- genation of sterically hindered secondary and tertiary alcohols to alkanes relying H H H H on the reduction of the corresponding ac- 1-Ac2O, DMAP H H O Et3N,CH2Cl2,rt etates by alkali metals dissolved in amines. O O (Eqn. 3) Two protocols involving either lithium in H 2-K,18-crown-6 H H H H H H OTr diethylamine or potassium solubilized by OH tBuNH2/THF,rt H OH Me OH 18-crown-6 ether in tert-butylamine have (−)-Cladiella-6,11-dien-3-ol been established and, applied for instance 62% to the chemoselective cleavage of 6β and AcO 12α acetates in 3β,6β-diacetoxy-5α- K, 18-crown-6 cholestane and 3β,12α-diacetoxy-13α- (Eqn.