THE JOURYAL of Organic Chemistry

THE JOURYAL OF Organic Chemistry 0 Copyright 1980 VOLUME45, NUMBE~R1 by the American Chemical Societ) JANUARY4, 1980 Selective Reductions. 26. Lithium Triethylborohydride as an Exceptionally Powerful and Selective Reducing Agent in Organic Synthesis. Exploration of the Reactions with Selected Organic Compounds Containing Representative Functional Groups1r2 Herbert C. Brown,* S. C. Kim,3 and S. Krishnamurthy Richard B. Wetherill Laboratory, Purdue University, West Lafayette, Indiana 47907 Received July 2, 1979 The approximate rates, stoichiometry, and products of the reaction of lithium triethylborohydride (LiEt,BH) with selected organic compounds containing representative functional groups under standard conditions (tetrahydrofuran, 0 "C)were examined in order to explore the reducing characteristics of this reagent and to establish the utility of the reagent as a selective reducing agent. Primary and secondary alcohols, phenols, and thiols evolve hydrogen rapidly and quantitatively, whereas the reaction with 3-ethyl-3-pentanol is slow. n-Hexylamine is inert to this reagent. Aldehydes and ketones are reduced rapidly and quantitatively to the corresponding alcohols. Even the highly hindered ketone 2,2,4,4-tetramethyl-3-pentanoneis reduced within 30 min. The stereoselectivities achieved with this reagent in the reduction of mono- and bicyclic ketones are better than those realized with lithium aluminum hydride, lithium alkoxyaluminohydrides and lithium borohydride; thus norcamphor is reduced to 1% ezo- and 99% endo-2-norbornanol. The reagent rapidly reduces cinnamaldehyde to the cinnamyl alcohol stage, with further addition to the double bond being sluggish. Anthraquinone is cleanly reduced to 9,lO-di- hydro-9,lO-dihydroxyanthracene.The diol was isolated in 77% yield. Carboxylic acids evolve hydrogen rapidly and quantitatively (1 equiv); further reduction is very slow. Acyclic anhydrides utilize 2 equiv of hydride to give an equimolar mixture of acid and alcohol after hydrolysis. Utilizing this procedure, we converted phthalic anhydride to phthalide in 90% yield. Acid chlorides, esters, and lactones are rapidly and quantitatively reduced to the corresponding carbinols. Epoxides undergo rapid reduction with the uptake of 1 equiv of hydride. In the case of unsymmetrical epoxides, exclusive Markovnikov ring opening was observed. Acetals, ketals, and ortho esters are inert to this reagent. Primary amides evolve 1 equiv of hydrogen rapidly. Further reduction of caproamide is slow, whereas benzamide is not reduced. Tertiary amides are rapidly and quantitatively reduced by LiEt3BH exclusively to the corresponding alcohols. Such a clean transformation has not been observed with any other hydride reagent currently available. Benzonitrile rapidly utilizes 2 equiv of hydride to go to the amine stage, whereas capronitrile takes only 1 equiv. Hydrolysis of the latter reaction mixture did not give the expected caproaldehyde, but n-hexylamine and the starting material were obtained in equal amounts. It appears possible to selectively reduce tertiary amides and aromatic nitriles to aldehydes in excellent yields by utilizing stoichiometric quantities of the reagent. 1-Nitropropane utilizes only 1 equiv of hydride for hydrogen evolution without any reduction. Nitrobenzene, azobenzene, and azoxybenzene are rapidly reduced. Cyclohexanone oxime rapidly evolves hydrogen but no reduction is observed. Phenyl isocyanate readily consumes 1 equiv of hydride in going to the formanilide stage. Pyridine is rapidly reduced to the tetrahydropyridine stage, followed by further slow reduction. Pyridine N-oxide also undergoes rapid reaction with this reagent. Disulfides are rapidly reduced to the thiol stage, whereas sulfoxide, sulfonic acid, and sulfides are practically inert toward this reagent. Cyclohexyl tosylate is slowly reduced to give a mixture of cyclohexane (80%)and cyclohexene (20%). Diphenyl sulfone slowly reacts to give an unexpected product, ethylbenzene, in excellent yield. The nature of the intermediates of representative reactions was also studied. Products of the reaction of the reagent with simple primary and secondary alcohols, tert-butyl alcohol, and most ketones exist as weak triethylborane complexes, whereas those of 3-ethyl-3-pentano1, phenols, carboxylic acids, thiols, and 1-nitropropane exist as their lithium salts without coordinating with the triethylborane formed. The discovery4 of the exceptional characteristics of study of the carbonylation of organoboranes aroused lithium trialkylborshydrides in 1972 in the course of a considerable interest in the exploration of their utility for (?) Based upon a thesis submitted by S.C. Kim in December 1976 in partial fulfillment of the requirements for the degree of Doctor of Phi- (2) Presented at the 168th National Meeting of the American Chem- losophy. ical Society, Atlantic City, NJ, Sept 1974. 0022-3263/80/1945-0001$01.00/00 1980 American Chemical Society 2 J. Org. Chem., Vol. 45, No. 1, 1980 Brown, Kim, and Krishnamurthy organic functional-group reductions. As a result of such 9-BBN26all in tetrahydrofuran (THF) solution at 0 “C explorations, a number of trialkylborohydrides have (with one exception, 9-BBN, which was carried out at 25 emerged in recent years as highly attractive reducing “C) with a standard list of organic compounds repre- agents to achieve chemo-, regio-, and stereoselective sentative of the more common functional groups. Because transformations in organic synthesis!v6 Unlike the parent of the commercial availabilityn and the easier method of compound, lithium borohydride, trialkylborohydrides are preparation, lithium triethylborohydride (Super-Hydride exceptionally powerful nucleophilic reducing agents ca- 1 M, LiEt3BH) was chosen as the reagent of choice in the pable of cleaving cyclic ethers’ and reducing hindered present study. halides? epoxides? p-toluenesulfonate esters of hindered We undertook a detailed study of the rate, stoichiome- and cyclic alcoho1s,l0J1quaternary ammonium salts,12ac- try, and products of the reaction of LiEt3BH with repre- tivated olefins,13 etc., rapidly and cleanly to the desired sentative functional groups and its applicability for se- products. They have been recognized as the most powerful lective reductions in organic synthesis. The results of these simple nucleophiles available for SN2displacements. Even investigations are reported in the present paper. more important, hindered and highly hindered trialkylborohydrides possess the remarkable ability to introduce Results and Discussion major steric control into the reduction of cyclic and bicyclic Preparation of Standard Solutions of Lithium ketones.”16 In this respect, these reagents are unequalled Triethylborohydride in THF. Solutions of lithium by any other reagents currently available. Many of these triethylborohydride in THF were conveniently prepared reagents are finding attractive applications in the stereo- by stirring at 25 “C 1equiv of triethylborane with an excess selective synthesis of pro~tag1andins.l~ Further, tri- of finely divided lithium hydride (usually in moderate alkylborohydrides containing an asymmetric alkyl group excess) in THF for approximately 24 h, followed by re- reduce unsymmetrical ketones to optically active secondary fluxing for 2-3 h. Filtration removed the excess lithium alcohols.18 hydride and gave crystal clear solutions. The concentration In view of these remarkable properties, it was desirable was determined by hydrolyzing a known aliquot of the to undertake a systematic exploration of the reducing solution with a water-glycerine-THF (1:l:l)mixture at 25 characteristics of trialkylborohydrides. We have recently “C and measuring the hydrogen evolved. The yields were described such systematic studies of the approximate rates, quantitative (eq 1). stoichiometry, and products of the reactions of lithium THF aluminum hydride,lg lithium trimethoxyaluminohydride,m LiH + Et3B -LiEt3BH (1) 100% lithium tri-tert-butoxyaluminohydride,21 aluminum hydride,22dib~rane,~~ di~iamylborane,~~ thexylb~rane,~~ and Under an inert atmosphere, solutions of lithium triethylborohydride in THF appear to be stable indefinitely-with no change observed in months at room temperature and in days at 65 “C. (3)Graduate research assistant on Research Grant No. DA-ARO-D- 31-124-73-G148,supported by the US.Army Research Office (Durham, Procedure for Rate and Stoichiometry Studies. The NC). general procedure adopted was to add 10 mmol of the (4)For extensive review of the discovery and applications of tri- organic compound under investigation to 40 mmol of alkylborohydrides, see: Krishnamurthy, S. Aldrichimica Acta 1974, 7, lithium triethylborohydride in sufficient tetrahydrofuran 55 and references cited therein. (5)Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567. to give 40 mL of solution. The mixtures were maintained (6)Brown, H. C.; Krishnamurthy, S. Aldrichimica Acta 1979, 12, 3. at 0 “C (ice bath). This made the reaction mixture 1.0 M (7) (a) Brown, H. C.; Krishnamurthy, S.; Coleman, R. A. J. Am. Chem. in LiEt3BH and 0.25 M in compound. Any hydrogen SOC.1972,94,1750. (b) Brown, H. C.; Krishnamurthy, S. J. Chem. SOC., evolved was noted. Aliquots were then removed at ap- Chem. Commun. 1972,868. (c) Brown, H. C.; Krishnamurthy, S.; Hub- bard, J. L.; Coleman, R. A. J. Organomet. Chem. 1979, 166, 281. (d) propriate intervals of time and analyzed for “residual Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1979, 44, 3678. hydride” by hydrolysis.28 Simultaneously, a

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