reduction

Myers Mark G. Charest Chem 115Reduction General References Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry Part B, Plenum Press: New York, 1990, p. 615-664. Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical Society Monograph 188: Washington DC, 1996, p. 19-30. Brown, H. C.; Ramachandran, P. V. In Reductions in Organic Synthesis: Recent Advances and Practical Applications, Abdel-Magid, A. F. Ed.; American Chemical Society: Washington DC, 1996, p. 1-30. Seyden-Penne, J. In Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd Ed., Wiley-VCH: New York, 1997, p. 1-36. Summary of Reagents for Reductive Functional Group Interconversions: Catalytic hydrogenation is used for the reduction of many organic functional groups. The reaction can be modified with respect to catalyst, hydrogen pressure, solvent, and temperature in order to execute a desired reduction. A brief list of recommended reaction conditions for catalytic hydrogenations of selected functional groups is given below. • • Substrate Alkene Alkyne Aldehyde (Ketone) Halide Nitrile Product Alkane Alkene Alcohol Alkane Amine Catalyst 5% Pd/C 5% Pd(BaSO4) PtO2 5% Pd/C Raney Ni Catalyst/Compound Ratio (wt%) 5-10% 2% + 2% quinoline 2-4% 1-15%, KOH 3-30% Pressure (atm) 1-3 1 1 1 35-70 Adapted from: Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical Society Monograph 188: Washington DC, 1996, p. 8. Acid Alcohol Ester Aldehyde Aldehyde Alcohol Aldehyde Alkane Alcohol Alkane Acid Alkane Lithium Aluminum Hydride (LAH) Borane Complexes Diisobutylaluminum Hydride (DIBAL) Lithium Triethoxyaluminohydride (LTEAH) Reduction of Acid Chlorides, Amides, and Nitriles Barton Decarboxylation Barton Deoxygenation Reduction of Alkyl Tosylates Diazene-Mediated Deoxygenation Radical Dehalogenation Deoxygenation of Tosylhydrazones Wolff–Kishner Reduction Desulfurization with Raney Nickel Clemmensen Reduction Reductive Amination Sodium Borohydride Luche Reduction Ionic Hydrogenation Samarium Iodide Lithium Borohydride Hydride Donors LiAlH4 DIBAL NaAlH(O-t-Bu)3 AlH3 NaBH4 NaCNBH3 Na(AcO)3BH B2H6 Li(Et)3BH H2 (catalyst) Substrates, Reduction Products Iminium Ion Amine – – – Amine Amine Amine – – Amine Acid Halide Alcohol Alcohol Aldehyde Alcohol – – – – Alcohol Alcohol Aldehyde Alcohol Alcohol Alcohol Alcohol Alcohol Alcohol (slow) Alcohol (slow) Alcohol Alcohol Alcohol Ester Alcohol Alcohol or Aldehyde Alcohol (slow) Alcohol –** – Alcohol (slow) Alcohol (slow) Alcohol Alcohol Amide Amine Amine or Aldehyde Amine (slow) Amine – – Amine (slow) Amine (slow) Alcohol (tertiary amide) Amine Carboxylate Salt Alcohol Alcohol – Alcohol – – – Alcohol – – ** α-alkoxy esters are reduced to the corresponding alcohols. – indicates no reaction or no productive reaction (alcohols are deprotonated in many instances, e.g.) Reactivity Trends Following are general guidelines concerning the reactivities of various reducing agents.• N O N H CO2CH3 CH3O OTES TESO CH3O LiAlH4, ether –78 °C O CH3O O H H N O CH3 OH CH3O O H H N CH3 LiAlH4 THF H3C CO2H H O H CH3O2C CH3O2C C(CH3)3 O H3C H OH H HOCH2 HOCH2 OH LiAlH4, THF reflux N N Ts O H H LiAlH4 THF H H CH3 CH3 H CH3 OH TsO H3C LiAlH4 THF (CH3)2N O H3C CH3 O O H LiAlH4 ether (CH3)2N HO O H3C CH3 H HO N N HH H H H CH3 CH3 H H3C H3C OH N O N H CH2OH CH3O OTES TESO CH3O Acid Alcohol Mark G. Charest Lithium Aluminum Hydride (LAH): LiAlH4 • LAH is a powerful and rather nonselective hydride-transfer reagent that readily reduces carboxylic acids, esters, lactones, anhydrides, amides and nitriles to the corresponding alcohols or amines. In addition, aldehydes, ketones, epoxides, alkyl halides, and many other functional groups are reduced readily by LAH. LAH is commercially available as a dry, grey solid or as a solution in a variety of organic solvents, e.g., ethyl ether. Both the solid and solution forms of LAH are highly flammable and should be stored protected from moisture. Several work-up procedures for LAH reductions are available that avoid the difficulties of separating by-products of the reduction. In the Fieser work-up, following reduction with n grams of LAH, careful successive dropwise addition of n mL of water, n mL of 15% NaOH solution, and 3n mL of water provides a granular inorganic precipitate that is easy to rinse and filter. For moisture-sensitive substrates, ethyl acetate can be added to consume any excess LAH and the reduction product, ethanol, is unlikely to interfere with product isolation. Although, in theory, one equivalent of LAH provides four equivalents of hydride, an excess of the reagent is typically used. • • Paquette, L. A. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, p. 199-204. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis 1967, 581-595. White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64, 7871-7884. (+)-codeine 70% 72% Bergner, E. J.; Helmchen, G. J. Org. Chem. 2000, 65, 5072-5074. 72% Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453. (+)-aloperine88% Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999, 121, 700-709. • In the following example, rearrangement accompanied reduction.• Bates, R. B.; Büchi, G.; Matsuura, T.; Shaffer, R. R. J. Am. Chem. Soc. 1960, 82, 2327-2337. 60% • Examples 89-95% Heathcock, C. H.; Ruggeri, R. B.; McClure, K. F. J. Org. Chem. 1992, 57, 2585-2599. H N N HO F H3C CH3 O CO2CH3 OTBS O2N O O CH3 Br CO2H H CO2HCH3O2C HO CH3 H N N HO H3C CH3 O OTBS OHO2N F CO2H HO CH3 HOCH2 CO2H HN SO2 LiBH4 HO2C CO2Et HOCH2 CO2Et CH2OH HN SO2 O O CH3 Br CH2OTHP H Mark G. Charest Lithium Borohydride: LiBH4 • Lithium borohydride is commonly used for the selective reduction of esters and lactones to the corresponding alcohols in the presence of carboxylic acids, tertiary amides, and nitriles. Aldehydes, ketones, epoxides, and several other functional groups can also be reduced by lithium borohydride. The reactivity of lithium borohydride is dependent on the reaction medium and follows the order: ether > THF > 2-propanol. This is attributed to the availability of the lithium counterion for coordination to the substrate, promoting reduction. Lithium borohydride is commercially available in solid form and as solutions in many organic solvents, e.g., THF. Both are inflammable and should be stored protected from moisture. • • Nystrom, R. F.; Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1949, 71, 3245-3246. Banfi, L.; Narisano, E.; Riva, R. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1999, p. 209-212. Corey, E. J.; Sachdev, H. S. J. Org. Chem. 1975, 40, 579-581. 1. BH3•THF, 0 °C 2. dihydropyran, THF TsOH, 0 °C 86% NaBH4, BF3•Et2O THF, 15 °C 95% Miller, R. A.; Humphrey, G. R.; Lieberman, D. R.; Ceglia, S. S.; Kennedy, D. J.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 2000, 65, 1399-1406. LiBH4, CH3OH THF, Et2O, 0 °C 83% Laïb, T.; Zhu, J. Synlett. 2000, 1363-1365. • The combination of boron trifluoride etherate and sodium borohydride has been used to generate diborane in situ. Huang, F.-C.; Lee, L. F.; Mittal, R. S. D.; Ravikumar, P. R.; Chan, J. A.; Sih, C. J. J. Am. Chem. Soc. 1975, 97, 4144-4145. 81% Borane Complexes: BH3•L • Borane is commonly used for the reduction of carboxylic acids in the presence of esters, lactones, amides, halides and other functional groups. In addition, borane rapidly reduces aldehydes, ketones, and alkenes. Borane is commercially available as a neat complex with tetrahydrofuran (THF) or dimethysulfide or in solution. In addition, gaseous diborane (B2H6) is available. The borane-dimethylsulfide complex exhibits improved stability and solubility compared to the borane-THF complex. Competing hydroboration of carbon-carbon double bonds can limit the usefulness of borane-THF as a reducing agent. • • Yoon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.; Stocky, T. P. J. Org. Chem. 1973, 38, 2786-2792. Lane, C. F. Chem. Rev. 1976, 76, 773-799. Brown, H. C.; Stocky, T. P. J. Am. Chem. Soc. 1977, 99, 8218-8226. BH3•THF 0 → 25 °C 67% Kende, A. S.; Fludzinski, P. Org. Synth. 1986, 64, 104-107. • Examples • Examples • CO2EtI NO CO2CH3 BocH3C CH3 TBSO N O CH3 OCH3 Cl NO CHO BocH3C CH3 TBSO H OCl CHOI O NC HO C(CH3)3 O OMOM H N CH3OMOM MOMO H3C O O O TMS CH3 OAc CH3 CH3 CO2CH3 OO H3C CH3 CH3 OAcCH3 OO O OHC HO C(CH3)3 Ester Aldehyde Mark G. Charest Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18-28. Diisobutylaluminum Hydride (DIBAL): i-Bu2AlH DIBAL, toluene –78 °C 1. DIBAL, CH2Cl2, –78 °C 2. CH3OH, –80 °C 3. potassium sodium tartrate 88% 76% Marek, I.; Meyer, C.; Normant, J.-F. Org. Synth. 1996, 74, 194-204. DIBAL, toluene CH2Cl2, –78 °C 82% Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 3542-3545. DIBAL, ether –78 °C 56% Crimmins, M. T.; Jung, D. K.; Gray, J. L. J. Am. Chem. Soc. 1993, 115, 3146-3155. R = CH2OH, 62% R = CHO, 16%Swern, 82% (+)-damavaricin D Roush, W. R.; Coffey, D. S.; Madar, D. J. J. Am. Chem. Soc. 1997, 119, 11331-11332. • At low temperatures, DIBAL reduces esters to the corresponding aldehydes, and lactones to lactols. Typically, toluene is used as the reaction solvent, but other solvents have also been employed, including dichloromethane. • Miller, A. E. G.; Biss, J. W.; Schwartzman, L. H. J. Org. Chem. 1959, 24, 627-630. Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1962, 3, 619-620. • Examples DIBAL, THF –100 → –78 °C Nitriles are reduced to imines, which hydrolyze upon work-up to furnish aldehydes.• O OMOM H N CH3OMOM MOMO H3C O O O TMS CH3 OAc CH3 CH3 R OO H3C CH3 CH3 OAcCH3 OO Reduction of N-methoxy-N-methyl amides, also known as Weinreb amides, is one of the most frequent means of converting a carboxylic acid to an aldehyde. • N Bn OH CH3 CH3 CH3 O CON(CH3)2 Cl CON(CH3)2 NO2 Li(EtO)3AlH CHO NO2 Bn CH3 O H CHO Cl PhtN CO2H CH3 CH3 H COCl ClOC COCl NH COClO O CF3 F3C H PhtN CHO CH3 CH3 H CHO H NH O O CF3 F3C CHO OHC CHO Mark G. Charest Lithium Triethoxyaluminohydride (LTEAH): Li(EtO)3AlH Johnson, R. L. J. Med. Chem. 1982, 25, 605-610. • LTEAH selectively reduces aromatic and aliphatic nitriles to the corresponding aldehydes (after aqueous workup) in yields of 70-90%. Tertiary amides are efficiently reduced to the corresponding aldehydes with LTEAH. LTEAH is formed by the reaction of 1 mole of LAH solution in ethyl ether with 3 moles of ethyl alcohol or 1.5 moles of ethyl acetate. LiAlH4 + 3 EtOH LiAlH4 + 1.5 CH3CO2Et Li(EtO)3AlH + 3H2 Et2O 0 °C Et2O 0 °C • • • Examples Brown, H. C.; Shoaf, C. J. J. Am. Chem. Soc. 1964, 86, 1079-1085. Brown, H. C.; Garg, C. P. J. Am. Chem. Soc. 1964, 86, 1085-1089. Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089-1095. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496-6511. 1. LTEAH, hexanes, THF, 0 °C 2. TFA, 1 N HCl 77% (94% ee)>99% de Reduction of Acid Chlorides The Rosemund reduction is a classic method for the preparation of aldehydes from carboxylic acids by the selective hydrogenation of the corresponding acid chloride. Over-reduction and decarbonylation of the aldehyde product can limit the usefulness of the Rosemund protocol. The reduction is carried out by bubbling hydrogen through a hot solution of the acid chloride in which the catalyst, usually palladium on barium sulfate, is suspended. • • • Rosemund, K. W.; Zetzsche, F. Chem. Ber. 1921, 54, 425-437. Mosetting, E.; Mozingo, R. Org. React. 1948, 4, 362-377. • Examples 1. SOCl2 2. H2, Pd/BaSO4 64% H2, Pd/BaSO4 64% Winkler, D.; Burger, K. Synthesis 1996, 1419-1421. Sodium tri-tert-butoxyaluminohydride (STBA), generated by the reaction of sodium aluminum hydride with 3 equivalents of tert-butyl alcohol, reduces aliphatic and aromatic acid chlorides to the corresponding aldehydes in high yields. STBA, diglyme THF, –78 °C STBA, diglyme THF, –78 °C 100% 93% Cha, J. S.; Brown, H. C. J. Org. Chem. 1993, 58, 4732-4734. • diglyme = (CH3OCH2CH2)2O 1. LTEAH, ether, 0 °C 2. H+ 1. LTEAH, ether, 0 °C 2. H+ 75% 80% Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567-607. R R' N NH Ts H+ R R' N NH Ts R R' HN NH Ts H+ NaBH3CN R R' N N Ts H R R' HN NH Ts H NaBH3CN R R' HN NH Ts H R R' N NHH –N2 R R' H H H3C CH3 CH3 CH3 NNHTs O Ot-Bu OAcCH3O2C O CH3 H CH3 NNHTs CH3 OH CH3 H H NaBD4, AcOH NaBH4, AcOD NaBD4, AcOD R R' N H N H R R' H –N2 O Ot-Bu OHCH3O2C H3C CH3 CH3 CH3 XY CH3 H CH3 CH3 OH CH3 H H Aldehyde or Ketone Alkane Mark G. Charest Deoxygenation of Tosylhydrazones • Reduction of tosylhydrazones to hydrocarbons with hydride donors, such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catecholborane, is a mild and selective method for carbonyl deoxygenation. Esters, amides, nitriles, nitro groups, and alkyl halides are compatible with the reaction conditions. Most hindered carbonyl groups are readily reduced to the corresponding hydrocarbon. However, electron-poor aryl carbonyls prove to be resistant to reduction. • • • • • + –TsH α,β-Unsaturated carbonyl compounds are reduced with concomitant migration of the conjugated alkene. The mechanism for this "alkene walk" reaction apparently proceeds through a diazene intermediate which transfers hydride by 1,5-sigmatropic rearrangement. • However, reduction of an azohydrazine is proposed when inductive effects and/or conformational constraints favor tautomerization of the hydrazone to an azohydrazine. • Two possible mechanisms for reduction of tosylhydrazones by sodium cyanoborohydride have been suggested. Direct hydride attack by sodium cyanoborohydride on an iminium ion is proposed in most cases. Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am. Chem. Soc. 1973, 95, 3662-3668. Kabalka, G. W.; Baker, J. D., Jr. J. Org. Chem. 1975, 40, 1834-1835. Kabalka, G. W.; Chandler, J. H. Synth. Commun. 1979, 9, 275-279. Miller, V. P.; Yang, D.-y.; Weigel, T. M.; Han, O.; Liu, H.-w. J. Org. Chem. 1989, 54, 4175-4188. Hutchins, R. O.; Kacher, M.; Rua, L. J. Org. Chem. 1975, 40, 923-926. Kabalka, G. W.; Yang, D. T. C.; Baker, J. D., Jr. J. Org. Chem. 1976, 41, 574-575. Boeckman, R. K., Jr.; Arvanitis, A.; Voss, M. E. J. Am. Chem. Soc. 1989, 111, 2737-2739. ZnCl2, NaBH3CN CH3OH, 90 °C ~50% (±)-ceroplastol I Hutchins, R. O.; Natale, N. R. J. Org. Chem. 1978, 43, 2299-2301. X = D, Y = H (75%) X = H, Y = D (72%) X = Y = D (81%) 1. TsNHNH2, EtOH 2. NaBH3CN 3. NaOAc, H2O, EtOH 4. CH3O–Na+, CH3OH Hanessian, S.; Faucher, A.-M. J. Org. Chem. 1991, 56, 2947-2949. 68% overall • Examples In the following example, exchange of the tosylhydrazone N-H proton is evidently faster than reduction and hydride transfer. • Conditions Product (Yield) O NH N NN O Cl CHO NH N NN O Cl CH3 O H N(CHO)CH3 OCH3 O H H SEt SEt N O Cl Cl Cl Cl N O H N(CHO)CH3 OCH3 O H H Piers, E.; Zbozny, M. Can. J. Chem. 1979, 57, 1064-1074. Coffen, D. L.; Fryer, R. I.; Katonak, D. A.; Wong, F. J. Org. Chem. 1975, 40, 894-897. Woodward, R. B.; Brehm, W. J. J. Am. Chem. Soc. 1948, 70, 2107-2115. Mark G. Charest Wolff–Kishner Reduction The Wolff–Kishner reduction is a classic method for the conversion of the carbonyl group in aldehydes or ketones to a methylene group. It is conducted by heating the corresponding hydrazone (or semicarbazone) derivative in the presence of an alkaline catalyst. Numerous modified procedures to the classic Wolff–Kishner reduction have been reported. In general, the improvements have focused on driving hydrazone formation to completion by removal of water, and by the use of high concentrations of hydrazine. In addition, attempts have been made to increase the rate of hydrazone decomposition, in some cases by increasing the reaction temperature. The two principal side reactions associated with the Wolff–Kishner reduction are azine formation and alcohol formation (proposed to occur by Meerwein–Ponndorf–Verley-like reduction of the carbonyl compound with sodium alkoxide). • • • Todd, D. Org. React. 1948, 4, 378-423. Hutchins, R. O.; Hutchins, M. K. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1991, Vol. 8, p. 327-362. • Examples Clemmensen Reduction The Clemmensen reduction of ketones and aldehydes using zinc and hydrochloric acid is a classic method for converting a carbonyl group into a methylene group. Typically, the classic Clemmensen reduction involves refluxing a carbonyl substrate with 40% aqueous hydrochloric acid, amalgamated zinc, and an organic solvent such as toluene. This reduction is rarely performed on polyfunctional molecules due to the harsh conditions employed. Anhydrous hydrogen chloride and zinc dust in organic solvents has been used as a milder alternative to the classic Clemmensen reduction conditions. diethylene glycol, Na metal H2NNH2, 210 °C 90% 91% H2NNH2, EtOH; KOt-Bu, reflux Vedejs, E. Org. React. 1975, 22, 401-415. Yamamura, S.; Ueda, S.; Hirata, Y. J. Chem. Soc., Chem. Commun. 1967, 1049-1050. Toda, M.; Hayashi, M.; Hirata, Y.; Yamamura, S. Bull. Chem. Soc. Jpn. 1972, 45, 264-266. Zn(Hg), HCl 56% Marchand, A. P.; Weimer, W. R., Jr. J. Org. Chem. 1969, 34, 1109-1112. • • • • Example Desulfurization With Raney Nickel Thioacetal (or thioketal) reduction with Raney nickel and hydrogen is a classic method to prepare a methylene group from a carbonyl compound. The most common limitation of the desulfurization method is the competitive hydrogenation of alkenes. • • Pettit, G. R.; Tamelen, E. E. Org. React. 1962, 12, 356-521. • Example Raney Ni, H2 ~50% H H CH3O NEt2 O CHO O I CH3 OPiv O O O OCH3 H3C CH3O H3C H Ph CH3O O O O O OCH3 H3C CH3O H3C H Ph HO O I CH3 OPiv HO H HNH N O CH3O2C H O O O CH3 OBOM H OH OH N H N OH CH3O2C H HH O TIPSO CH3 OBOM H Aldehyde or Ketone Alcohol NaBH4, CH3OH 0 °C ~100% Mark G. Charest Sodium Borohydride: NaBH4 • Sodium borohydride reduces aldehydes and ketones to the corresponding alcohols at or near 25 °C. Under these conditions, esters, epoxides, lactones, carboxylic acids, nitro groups, and nitriles are not reduced. Sodium borohydride is commercially available as a solid, in powder or pellets, or as a solution in various solvents. Typically, sodium borohydride reductions are performed in ethanol or methanol, often with an excess of reagent (to counter the consumption of the reagent by its reaction with the solvent). • • Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1949, 71, 122-125. Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567-607. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162-3164. 1. OsO4 (cat), aq. NMO 2. NaIO4 3. NaBH4 90% Ireland, R. E.; Armstrong, J. D., III; Lebreton, J.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc. 1993, 115, 7152-7165. + 1. NaBH4, CH3OH 2. 6 M HCl Wang, X.; de Silva, S. O.; Reed, J. N.; Billadeau, R.; Griffen, E. J.; Chan, A.; Snieckus, V. Org. Synth. 1993, 72, 163-172. >81% • E