phản ứng Reduction phản ứng Reduction

Myers Mark G. Charest Reduction Chem 215 General References Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry Part B, Plenum Press: New York, 1 990, p. 61 5664. Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical Society Monograph 1 88: Washington DC, 1 996, p. 1 930. Brown, H. C.; Ramachandran, P. V. In Reductions in Organic Synthesis: Recent Advances and Practical Applications, AbdelMagid, A. F. Ed.; American Chemical Society: Washington DC, 1 996, p. 1 30. SeydenPenne, J. In Reductions by the Alumino and Borohydrides in Organic Synthesis, 2nd Ed., WileyVCH: New York, 1 997, 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% PdC 5% Pd(BaSO4) PtO2 5% PdC Raney Ni CatalystCompound Ratio (wt%) 51 0% 2% + 2% quinoline 24% 1 1 5%, KOH 330% Pressure (atm) 1 3 1 3570 Adapted from: Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical Society Monograph 1 88: Washington DC, 1 996, 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 DiazeneMediated 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 LiAlH 4 DIBAL NaAlH(OtBu)3 AlH 3 NaBH4 NaCNBH3 Na(AcO)3BH B 2H6 Li(Et)3BH H 2 (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 – αalkoxy 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 NH CO2CH3 O CH3 OTES TESO CH3O LiAlH 4, ether –78 °C O CH3O O H H N O CH3 OH CH3O O H H N CH3 LiAlH 4 THF H 3C CO2H H O H CH3O2C CH3O2C C(CH3)3 O H 3C H OH H HOCH2 HOCH2 OH LiAlH 4, THF reflux N N Ts O H H LiAlH 4 THF H CH3 CH3 HC H 3 OH TsO H 3C LiAlH4 THF (CH3)2N O H 3C CH3 O H O LiAlH 4 ether (CH3)2N HO O H 3C CH3 H HO N N H H H H CH3 CH3 H H 3C H 3C OH N O NH CH2OH O CH3 OTES TESO CH3O Acid Alcohol Mark G. Charest Lithium Aluminum Hydride (LAH): LiAlH4 • LAH is a powerful and rather nonselective hydridetransfer 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 workup procedures for LAH reductions are available that avoid the difficulties of separating byproducts of the reduction. In the Fieser workup, following reduction with n grams of LAH, careful successive dropwise addition of n mL of water, n mL of 1 5% NaOH solution, and 3n mL of water provides a granular inorganic precipitate that is easy to rinse and filter. For moisturesensitive 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. •P aquette, L. A. In HandbookofReagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1 999, p. 1 99204. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis 1 967, 581 595. White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1 999, 64, 7871 7884. (+)codeine 70% 72% Bergner, E. J.; Helmchen, G. J. Org. Chem. 2000, 65, 50725074. 72% Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1 992, 114, 94349453. 88% (+)aloperine Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1 999, 121, 700709. • • In the following example, rearrangement accompanied reduction. Bates, R. B.; Büchi, G.; Matsuura, T.; Shaffer, R. R. J. Am. Chem. Soc. 1 960, 82, 23272337. 60% • Examples 8995% Heathcock, C. H.; Ruggeri, R. B.; McClure, K. F. J. Org. Chem. 1 992, 57, 25852599. HN NH O F CH3 CH3 O CO2CH3 OTBS O2N O OC H 3 Br CO2H H CH3O2C CO2H HO CH3 HN NH OC H 3 CH3 O OTBS O2N OH F CO2H HO CH3 HOCH2 CO2H HN SO2 LiBH 4 HO2C CO2Et HOCH2 CO2Et CH2OH HN SO2 O OC H 3 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 > 2propanol. 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. •N ystrom, R. F.; Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1 949, 71, 32453246. Banfi, L.; Narisano, E.; Riva, R. In HandbookofReagents for Organic Synthesis: Oxidizing and Reducing Reagents, Burke, S. D.; Danheiser, R. L., Eds., John Wiley and Sons: New York, 1 999, p. 20921 2. Corey, E. J.; Sachdev, H. S. J. Org. Chem. 1 975, 40, 579581 . 1 . BH 3•THF, 0 °C 2. dihydropyran, THF TsOH, 0 °C 86% NaBH4, BF3•Et2O THF, 1 5 °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, 1 3991 406. LiBH 4, CH3OH THF, Et2O, 0 °C 83% Laïb, T.; Zhu, J. Synlett. 2000, 1 3631 365. • 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. 1 975, 97, 41 4441 45. 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 boranedimethylsulfide complex exhibits improved stability and solubility compared to the boraneTHF complex. Competing hydroboration of carboncarbon double bonds can limit the usefulness of boraneTHF as a reducing agent. •Y oon, N. M.; Pak, C. S.; Brown, H. C.; Krishnamurthy, S.; Stocky, T. P. J. Org. Chem. 1 973, 38, 27862792. Lane, C. F. Chem. Rev. 1 976, 76, 773799. Brown, H. C.; Stocky, T. P. J. Am. Chem. Soc. 1 977, 99, 821 88226. BH 3•THF 0 → 25 °C 67% Kende, A. S.; Fludzinski, P. Org. Synth. 1 986, 64, 1 041 07. • Examples • Examples • I CO2Et N O CO2CH3 Boc H 3C CH3 TBSO N O CH3 OCH3 Cl N O CHO Boc H 3C CH3 TBSO H Cl O I CHO O NC HO C(CH3)3 O OMOM HNC H 3 OMOM MOMO H 3C O O O TMS CH3 OAc CH3 CH3 CO2CH3 O O H 3C CH3 CH3 CH3OAc O O O OHC HO C(CH3)3 Ester Aldehyde Mark G. Charest Garner, P.; Park, J. M. Org. Synth. 1 991 , 70, 1 828. Diisobutylaluminum Hydride (DIBAL): iBu2AlH 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. 1 996, 74, 1 94204. DIBAL, toluene CH2Cl2, –78 °C 82% Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1 999, 38, 35423545. DIBAL, ether –78 °C 56% Crimmins, M. T.; Jung, D. K.; Gray, J. L. J. Am. Chem. Soc. 1 993, 115, 31 4631 55. R = CH2OH, 62% Swern, 82% R = CHO, 1 6% (+)damavaricin D Roush, W. R.; Coffey, D. S.; Madar, D. J. J. Am. Chem. Soc. 1 997, 119, 1 1 331 1 1 332. • 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. •M iller, A. E. G.; Biss, J. W.; Schwartzman, L. H. J. Org. Chem. 1 959, 24, 627630. Zakharkin, L. I.; Khorlina, I. M. Tetrahedron Lett. 1 962, 3, 61 9620. • Examples DIBAL, THF –1 00 → –78 °C • Nitriles are reduced to imines, which hydrolyze upon workup to furnish aldehydes. O OMOM HNC H 3 OMOM MOMO H 3C O O O TMS CH3 OAc CH3 CH3 R O O H 3C CH3 CH3 CH3OAc O O Reduction of NmethoxyNmethyl 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 H CH3 COCl ClOC COCl NH O COCl OCF 3 F 3C H PhtN CHO CH3 H CH3 CHO H NH O OCF 3 F 3C CHO OHC CHO Mark G. Charest Lithium Triethoxyaluminohydride (LTEAH): Li(EtO)3AlH Johnson, R. L. J. Med. Chem. 1 982, 25, 60561 0. • LTEAH selectively reduces aromatic and aliphatic nitriles to the corresponding aldehydes (after aqueous workup) in yields of 7090%. 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. LiAlH 4 + 3 EtOH LiAlH 4 + 1 .5 CH3CO2Et Li(EtO)3AlH + 3H2 Et2O 0 °C Et2O 0 °C • Examples Brown, H. C.; Shoaf, C. J. J. Am. Chem. Soc. 1 964, 86, 1 0791 085. Brown, H. C.; Garg, C. P. J. Am. Chem. Soc. 1 964, 86, 1 0851 089. Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1 964, 86, 1 0891 095. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1 997, 119, 6496651 1 . 1 . LTEAH, hexanes, THF, 0 °C 2. TFA, 1 N HCl >99% de 77% (94% ee) 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. Overreduction 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. •R osemund, K. W.; Zetzsche, F. Chem. Ber. 1 921 , 54, 425437. Mosetting, E.; Mozingo, R. Org. React. 1 948, 4, 362377. • Examples 1 . SOCl2 2. H 2, PdBaSO4 64% H 2, PdBaSO4 64% Winkler, D.; Burger, K. Synthesis 1 996, 1 41 91 421 . Sodium tritertbutoxyaluminohydride (STBA), generated by the reaction of sodium aluminum hydride with 3 equivalents of tertbutyl alcohol, reduces aliphatic and aromatic acid chlorides to the corresponding aldehydes in high yields. STBA, diglyme THF, –78 °C STBA, diglyme THF, –78 °C 1 00% 93% Cha, J. S.; Brown, H. C. J. Org. Chem. 1 993, 58, 47324734. • 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 1 979, 35, 567607. R R N NH Ts H+ R R N NH Ts R R HN NH Ts H+ NaBH3CN R R N N Ts R H R HN NH Ts HNa BH 3CN R R HN NH Ts H R R N NH H –N 2 R R H H H 3C CH3 CH3 CH3 NNHTs O OtBu CH3O2C OAc 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 –N 2 O OtBu CH3O2C OH H 3C CH3 CH3 CH3 Y X 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, electronpoor aryl carbonyls prove to be resistant to reduction. • + –TsH α, βUnsaturated 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 ,5sigmatropic rearrangement. • However, reduction of an azohydrazine is proposed when inductive effects andor 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. 1 973, 95, 36623668. Kabalka, G. W.; Baker, J. D., Jr. J. Org. Chem. 1 975, 40, 1 8341 835. Kabalka, G. W.; Chandler, J. H. Synth. Commun. 1 979, 9, 275279. Miller, V. P.; Yang, D.y.; Weigel, T. M.; Han, O.; Liu, H.w. J. Org. Chem. 1 989, 54, 41 7541 88. Hutchins, R. O.; Kacher, M.; Rua, L. J. Org. Chem. 1 975, 40, 923926. Kabalka, G. W.; Yang, D. T. C.; Baker, J. D., Jr. J. Org. Chem. 1 976, 41, 574575. Boeckman, R. K., Jr.; Arvanitis, A.; Voss, M. E. J. Am. Chem. Soc. 1 989, 111, 27372739. ZnCl2, NaBH3CN CH3OH, 90 °C ~50% (±)ceroplastol I Hutchins, R. O.; Natale, N. R. J. Org. Chem. 1 978, 43, 22992301 . 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. 1 991 , 56, 29472949. 68% overall • Examples In the following example, exchange of the tosylhydrazone NH proton is evidently faster than reduction and hydride transfer. • Conditions Product (Yield) O O H N(CHO)CH3 OCH3 O H SEt SEt N O Cl Cl Cl Cl N O H N(CHO)CH3 OCH3 O H Piers, E.; Zbozny, M. Can. J. Chem. 1 979, 57, 1 0641 074. Woodward, R. B.; Brehm, W. J. J. Am. Chem. Soc. 1 948, 70, 21 0721 1 5. Mark G. Charest, Jason Brubaker 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. The two principal side reactions associated with the Wolff–Kishner reduction are azine formation and alcohol formation. •T odd, D. Org. React. 1 948, 4, 378423. Hutchins, R. O.; Hutchins, M. K. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., Eds., Pergamon Press: New York, 1 991 , Vol. 8, p. 327362. • 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 H 2NNH2, 21 0 °C 90% Vedejs, E. Org. React. 1 975, 22, 401 41 5. Yamamura, S.; Ueda, S.; Hirata, Y. J. Chem. Soc., Chem. Commun. 1 967, 1 0491 050. Toda, M.; Hayashi, M.; Hirata, Y.; Yamamura, S. Bull. Chem. Soc. Jpn. 1 972, 45, 264266. Zn(Hg), HCl 56% Marchand, A. P.; Weimer, W. R., Jr. J. Org. Chem. 1 969, 34, 1 1 091 1 1 2. • 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. •P ettit, G. R.; Tamelen, E. E. Org. React. 1 962, 12, 356521 . • Example Raney Ni, H2 ~50% H H • Ntertbutyldimethylsilylhydrazone (TBSH) derivatives serve as superior alternatives to hydrazones. • TBSH derivatives of aliphatic carbonyl compounds undergo WolffKishnertype reduction at 23 °C; derivatives of aromatic carbonyl undergo reduction at 1 00 °C. ReducedTemperature WolffKisherType Reduction O CH3O CH3O CH3O CH3O Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436. CH3 O CH3O CH3 CH3O N N TBS H HT BS , cat. Sc(OTf)3; KOtBu, HOtBu, DMSO 23 °C, 24 h N N TBS H HT BS , cat. Sc(OTf)3; KOtBu, HOtBu, DMSO 1 00 °C, 24 h 93% 92% CH3O NEt 2 OC HO I O CH3 OPiv O O O CH3 O H 3C CH3O H 3C H Ph CH3O O O O O CH3 O H 3C CH3O H 3C H Ph HO I O CH3 OPiv HO H H NH N O CH3O2C H O O O CH3 OBOM H OH OH NH N OH CH3O2C H H H O TIPSO CH3 OBOM H Aldehyde or Ketone Alcohol NaBH4, CH3OH 0 °C ~1 00% 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). ••C haikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1 949, 71, 1 221 25. Brown, H. C.; Krishnamurthy, S. Tetrahedron 1 979, 35, 567607. 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. 1 992, 114, 31 6231 64. 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. 1 993, 115, 71 5271 65. + 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. 1 993, 72, 1 631 72. >81 % • Examples Luche Reduction Sodium borohydride in combination with cerium (III) chloride (CeCl3) selectively reduces α , βunsaturated carbonyl compounds to the corresponding allylic alcohols. Typically, a stoichiometric quantity of cerium (III) chloride and sodium borohydride is added to an α , βunsaturated carbonyl substrate in methanol at 0 °C. Control experiments reveal the dramatic influence of the lanthanide on the regiochemistry of the reduction. •L uche, J.L. J. Am. Chem. Soc. 1 978, 100, 22262227. NaBH4 NaBH4, CeCl3 51 % 99% 49% trace • Examples Binns, F.; Brown, R. T.; Dauda, B. E. N. Tetrahedron Lett. 2000, 41, 5631 5635. NaBH4, CeCl3 CH3CN, CH3OH 78% 1 . NaBH4, CeCl3•7H2O CH3OH, 0 °C 2. TIPSCl, Im Meng, D.; Bertinato, P.; Balog, A.; Su, D.S.; Kamenecka, T.; Sorensen, E. K.; Danishefsky, S. J. J. Am. Chem. Soc. 1 997, 119, 1 00731 0092. 87% Reductant O HN O CH3N OH tBu2Si(H)O CH3 CH H 3 OCH3 CH3 H O H 3C H Si H tBu CF3CO2– tBu O HN O CH3N HO CH3 CH H 3 CO2CH3 O CH3 OTBS O O H CH3 O CH3 H H H CH3 DEIPSO PMBO O O H CH3 OH CH3 H H H CH3 DEIPSO PMBO CO2CH3 CH3 OTBS HO H Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1 990, 112, 7001 7031 . Mark G. Charest Ionic Hydrogenation • Ionic hydrogenation refers to the general class of reactions involving the reduction of a carbonium ion intermediate, often generated by protonation of a ketone, alkene, or a lactol, with a hydride donor. Generally, ionic hydrogenations are conducted with a proton donor in combination with a hydride donor. These components must react with the substrate faster than with each other. Organosilanes and trifluoroacetic acid have proven to be one of the most useful reagent combinations for the ionic hydrogenation reaction. Carboxylic acids, esters, amides, and nitriles do not react with organosilanes and trifluoroacetic acid. Alcohols, ethers, alkyl halides, and olefins are sometimes reduced. •M cCombie, S. W.; Cox, B.; Lin, S.I.; Ganguly, A. K.; McPhail, A. T. Tetrahedron Lett. 1 991 , 32, 20832086. CF3CO2H; nBu4N+F– 6575% >95% isomeric purity + Et 3SiH, CF3CO2H CH2Cl2, reflux Madin, A.; ODonnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem., Int. Ed. Engl. 1 999, 38, 29342936. >65% (±)gelsemine Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1 974, 633651 . • Examples • The ionic hydrogenation has been used to prepare ethers from the corresponding lactols. • Intramolecular ionic hydrogenation reactions have been used in stereoselective reductions. Samarium Iodide: SmI2 • Samarium iodide effectively reduces aldehydes, ketones, and alkyl halides in the presence of carboxylic acids and esters. Aldehydes are often reduced much more rapidly than ketones. Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1 980, 102, 26932698. Molander, G. A. Chem. Rev. 1 992, 92, 2968. Soderquist, J. A. Aldrichimica Acta. 1 991 , 24, 1 523. •S ingh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1 987, 109, 61 8761 89. SmI2 THF, H2O 97% (86% de) SmI2 iPrOH, THF 98% • Examples In the following example, a samariumcatalyzed Meerwein–Ponndorf–Verley reduction successfully reduced the ketone to the alcohol where many other reductants failed. • O O O CH3 OH CH3 CH2CHO CH3 Et OCH2 HO O CH3O N(CH3)2 O CH3 OH CH3 OH O OO CH3 CH3O HO H 3C NaBH3CN CH3OH, HN O O O O CH3 OH CH3 CH3 Et OCH2 HO O CH3O N(CH3)2 O CH3 OH CH3 OH O OO CH3 CH3O HO H 3C N O CH3 CHO AcO CH3 NH O H OTBS N H O OTBS AcO CH3 CH3 NaBH3CN CH3OH N OTHP CO2Bn CO2Bn CO2tBu H H N CO2Bn OHC H N OTHP CO2Bn CO2Bn CO2tBu H H NH•TFA CO2Bn H ONH CH3 Ph Ph H ON CH3 Ph Ph H CH3 NaBH3CN CH2O NH OH H CO2H H CO2H N CO2H H Mark G. Charest Reductive Amination • The reductive amination of aldehydes and ketones is an important method for the synthesis of primary, secondary, and tertiary amines. Iminium ions can be reduced selectively in the presence of their carbonyl precursors. Reductive aminations are often conducted by in situ generation of the imine (iminium ion) intermediate in the presence of a mild acid. Reagents such as sodium cyanoborohydride and sodium triacetoxyborohydride react selectively with iminium ions and are frequently used for reductive aminations. •H osokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.; Kobayashi, S. Tetrahedron Lett. 2000, 41, 64356439. 66% Na(AcO)3BH, Sn(OTf)2 4 Å MS, ClCH2CH2Cl, 0 °C Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1 971 , 93, 28972904. AbdelMagid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron 1 990, 31, 55955598. AbdelMagid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1 996, 61, 38493862. • Examples + Matsubara, H.; Inokoshi, J.; Nakagawa, A.; Tanaka, H.; Omura, S. J. Antibiotics 1 983, 36, 1 71 31 721 . 79% 59% 2deoxymugineic acid Ohfune, Y.; Tomita, M.; Nomoto, K. J. Am. Chem. Soc. 1 981 , 103, 2409241 0. 84% Jacobsen, E. J.; Levin, J.; Overman, L. E. J. Am. Chem. Soc. 1 988, 110, 43294336. tylosin + 1 . H 2, PdC, EtOH, H 2O, HCl 2. TFA RO R S (nBu)3Sn RO R S Sn(nBu)3 R O R S Sn(nBu)3 H 3C OH H CH3 CH3 OH N PhO O O CO2H OH H OH HO HO O O O H Im S O SO H HO O O H 3C H H iPr N O H PhO O H 3C H iPr H Alcohol Alkane Mark G. Charest, Jason Brubaker Barton Deoxygenation • Radicalinduced deoxygenation of Othiocarbonate derivatives of alcohols in the presence of hydrogenatom donors is a versatile and widelyused method for the preparation of an alkane from the corresponding alcohol. The Barton deoxygenation is a twostep process. In the initial step, the alcohol is acylated to generate an Othiocarbonate derivative, which is then typically reduced by heating in an aprotic solvent in the presence of a hydrogenatom donor. The method has been adapted for the deoxygenation of primary, secondary, and tertiary alcohols. In addition, monodeoxygenation of 1 ,2 and 1 ,3diols has been achieved. The accepted mechanism of reduction proceeds by attack of a tin radical on the thiocarbonyl sulfur atom. Subsequent fragmentation of this intermediate generates an alkyl radical which propagates the chain. •B arton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. I 1 975, 1 5741 585. Barton, D. H. R.; Motherwell, W. B.; Stange, A. Synthesis 1 981 , 743745. Barton, D. H. R.; Hartwig, W.; HayMotherwell, R. S.; Motherwell, W. B.; Stange, A. Tetrahedron Lett. 1 982, 23, 201 92022. Barton, D. H. R.; Zard, S. Z. Pure Appl. Chem. 1 986, 58, 675684. Barton, D. H. R.; Jaszberenyi, J. C. Tetrahedron Lett. 1 989, 30, 261 92622. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett. 1 990, 31, 3991 3994. Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett. 1 990, 31, 4681 4684. Barton, D. H. R.; Blundell, P.; Dorchak, J.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron 1 991 , 47, 89698984. + • Examples AIBN, Bu3SnH xylenes, 1 40 °C 40% Nicolaou, K. C.; Hwang, C.K.; Smith, A. L.; Wendeborn, S. V. J. Am. Chem. Soc. 1 990, 112, 741 6 741 8. 1 . 1 ,1 thiocarbonyldiimidazole, DMAP, CH2Cl2, reflux 2. AIBN, Bu3SnH, toluene, 70 °C 46% (1 : 1 mixture) βylangene βcopaene Kulkarni, Y. S.; Niwa, M.; Ron, E.; Snider, B. B. J. Org. Chem. 1 987, 52, 1 5681 576. Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1 988, 29, 281 284. quinic acid In the following example, the radical generated during the deoxygenation reaction undergoes 6 exotrig radical cyclization. + • 1 . 1 ,1 thiocarbonyldiimidazole, DMAP, CH2Cl2 2. AIBN, Bu3SnH, toluene, 75 °C 75% TinFree BartonType Reduction Employing Water as a Hydrogen Atom Source: • Simple concentration of the reaction mixture provides products in high purity. • Trialkylborane acts as both the radical initiator and an activator of water prior to hydrogen atom abstraction. O O O O O CH3 CH3 CH3 H CH3 O SCH3 S O O O O O CH3 CH3 CH3 H CH3 B(CH3)3, H2O benzene, 23 °C 91 % Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J. Am. Chem. Soc. 2005, ASAP. RCH2OH N CH3O CH3 OH O Cl CH3 N O OH RCH2N(NH2)SO2Ar RCH2N=NH CH3 N O OH N CH3O CH3 CH3 O Cl –N 2 RCH3 R H N N tBuSi(CH3)2 SO2Ar CH3O OCH3 I CH3 C4H9 OO O OO H N N SO2Ar H CH3 CH3 CH3 CH3 Ph H CH3 N N H SO2Ar R N N tBuSi(CH3)2 SO2Ar R H Li Li CH3 H 3C CH3 Li Ph CH3 CH3 CH3 CH3O OCH3 OMOM CH3 C4H9 NN(TBS)Ts CH2OH R N HNH ROO O OO CH3 CH3 CH3 CH3 CH3 CH3 CH3 Ph CH3 CH3 CH3 Ph CH3 CH3O OCH3 CH3 C4H9 CH3O OCH3 HO CH3 C4H9 –N 2 R R H H Mark G. Charest • Deoxygenation proceeds by Mitsunobu displacement of the alcohol with onitrobenzenesulfonylhydrazine (NBSH) followed by in situ elimination of onitrobenzene sulfinic acid. The resulting monoalkyl diazene is proposed to decompose by a freeradical mechanism to form deoxygenated products. The deoxygenation is carried out in a single step without using metal hydride reagents. The method is found to work well for unhindered alcohols, but sterically encumbered and β oxygenated alcohols fail to undergo the Mitsunobu displacement and are recovered unchanged from the reaction mixture. • 87% Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1 997, 119, 85728573. 84% RLi –78 °C AcOH, TFE –78 → 23 °C Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1 998, 120, 8891 8892. 94% Ar = 2,4,6triisopropylbenzene 1 . TBSOTf, Et3N, THF, –78 °C 2. 1 . tBuLi, ether 2. 3. HCl, CH3OH, THF 73% (–)cylindrocyclophane F 1 . TBSOTf, Et3N, THF, –78 °C 2. 87% PPh 3, DEAD, NBSH NMM, –35 °C 65% PPh 3, DEAD, NBSH THF, –30 °C ≥ 0 °C PPh 3, DEAD, NBSH THF, –30 °C PPh 3, DEAD, NBSH, THF, –30 °C; O2; DMS • Examples Ar = 2O2NC6H4 In related studies, it was shown that alkyllithium reagents add to Ntertbutyldimethylsilyl aldehyde tosylhydrazones at –78 °C and that the resulting adducts can be made to extrude dinitrogen in a freeradical process. • Examples 3. AcOH, CF3CH2OH, –78 → 23 °C 3. AcOH, CF3CH2OH, –78 → 23 °C Smith, A. B., III; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 1 999, 121, 74237424. • DiazeneMediated Deoxygenation Monoalkyl diazenes will undergo concerted sigmatropic elimination of dinitrogen in preference to radical decomposition where this is possible. In the following example, the radical generated from decomposition of the diazene intermediate underwent a rapid 5exotrig radical cyclization. This generated a second radical that was trapped with oxygen to provide the cyclic carbinol shown after workup with methyl sulfide. • R 3 R1 R 2 R 4 HO H HO CH3 CO2CH3 OH O O R 3 R1 R 2 R 4 N N H H ArSO2NHNH2, Ph 3P, DEAD –N 2 R 3 R1 R 2 R 4 N H2N SO2Ar H R 3 R1 R 2 R 4 H H CH3 CO2CH3 OH O O OTs OH BnO CH3 CH2OTs R 2 R 1 H OH R 2 R 1 N N H H ArSO2NHNH2, Ph 3P, DEAD –N 2 R 2 R 1 H N H 2N SO2Ar R 1 H R 2 H ArSO2NHNH2, Ph 3P, DEAD EtO CH3 H OH OEt CH3 CH3 CH3 H EtO EtO H OH BnO CH3 CH3 OH Mark G. Charest • Reductive 1 ,3transposition of allylic alcohols proceeds with excellent regio and stereochemical control. Myers, A. G.; Zheng, B. Tetrahedron Lett. 1 996, 37, 4841 4844. 23 °C 66% Ph 3P , DEAD NBSH, NMM 0.32 h • Example Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1 996, 118, 44924493. 23 °C 1 8 h In addition, allenes can be prepared stereospecifically from propargylic alcohols. • Example 74% Reduction of Alkyl Tosylates pToluenesulfonate ester derivatives of alcohols are reduced to the corresponding alkanes with certain powerful metal hydrides. Among hydride sources, lithium triethylborohydride (Super Hydride, LiEt3BH) has been shown to rapidly reduce alkyl tosylates efficiently, even thoes derived from hindered alcohols. LAH LiEt 3BH + + 54% 80% 25% 20% 1 9% 0% Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1 976, 41, 30643066. Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1 990, 112, 5290531 3. 92% LiEt 3BH, THF; H 2O2, NaOH (aq) CH3OH • Examples O O H H CH3 CH3 H OSO2iPr O O H H CH3 CH3 H H Hua, D. H.; Venkataraman, S.; Ostrander, R. A.; Sinai, G.Z.; McCann, P. J.; Coulter, M. J.; Xu, M. R. J. Org. Chem. 1 988, 53, 50751 5. 72% LiEt 3BH, toluene 90 °C In the following example, selective CO bond cleavage by LiEt3BH could only be achieved with a 2propanesulfonate ester. The corresponding mesylate and tosylate underwent SO bond cleavage when treated with LiEt3BH. • Reductant –30 °C, 0.56 h –1 5 °C, 1 2 h –1 5 °C O O CH3 OAc AcO H H H H Br OAc O O CH3 H O O OTIPS CH3 OPMB TIPSO H OPMB H CH3 HO OTIPS H Cl CH3O I O O OTIPS CH3 OPMB TIPSO H OPMB H CH3 HO OTIPS H Cl CH3O O O CH3 OH HO H H H H OH O O CH3 H Br CH3 CH3 CH3 H OI BzO O O O O I I O CH3 Bz O OI O IO Bz OI BzO IO CH3 O OTBS O HO O O O O H H3C 3C HO CH3 O O OH HO O 3C HO H O 3C CH3 O OH H 3C H CH3 CH3 H Mark G. Charest Radical Dehalogenation • Alkyl bromides and iodides are reduced efficiently to the corresponding alkanes in a freeradical chain mechanism with trinbutyltin hydride. The reduction of chlorides usually requires more forcing reaction conditions and alkyl fluorides are practically unreactive. The reactivity of alkyl halides parallels the thermodynamic stability of the radical produced and follows the order: tertiary > secondary > primary. Triethylboronoxygen is a highly effective freeradical initiator. Reduction of bromides and iodides can occur at –78 °C with this initiator. •G uo, J.; Duffy, K. J.; Stevens, K. L.; Dalko, P. I.; Roth, R. M.; Hayward, M. M.; Kishi, Y. Angew. Chem., Int. Ed. Engl. 1 998, 37, 1 871 96. altohyrtin A 5 7 5 7 Bu 3SnH, AIBN, THF PhBr, 80 °C 70% 1 . Bu 3SnH, AIBN, PhCH3 2. CH3OH, CH3COCl 64% parviflorin Trost, B. M.; Calkins, T. L.; Bochet, C. G. Angew. Chem., Int. Ed. Engl. 1 997, 36, 26322635. Neumann, W. P. Synthesis 1 987, 665683. Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1 989, 62, 1 431 47. Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 2000, 122, 61 2461 25. (±)capnellene Curran, D. E.; Chen, M.H. Tetrahedron Lett. 1 985, 26, 4991 4994. 1 . Bu 3SnH, Et3B, O2 2. K 2CO3, THF, CH3OH 3. Bu4N+F–, AcOH, THF 61 % In the following example, the radical generated during the dehalogenation reaction undergoes a tandem radical cyclization. • Bu 3SnH, AIBN benzene, 80 °C 61 % HO2C O N NH O O O O CH3 CH3 O N NH O O O O CH3 CH3 H 2NOC SPy H CO2Bn CbzNH R O N S O N O COCl Sn(nBu)3 O O N O O N S S RCO2 N SSn(nBu)3 –CO2 N OH S R (nBu)3SnH NH O RH + (nBu)3Sn NH N HO H H CO2H O CH3 CONH2 CO2Bn CbzNH H N O–Na+ S N O–Na+ S NH N HO H H O CH3 NH N HO H H O CH3 Acid Alkane Mark G. Charest Barton Decarboxylation • AIBN, Bu3SnH THF, reflux ~1 00% Eaton, P. E. Angew. Chem., Int. Ed. Engl. 1 992, 31, 1 421 1 436. OEsters of thiohydroxamic acids are reduced in a radical chain reaction by tin hydride reagents. These are typically prepared by the reaction of commercial Nhydroxypyridine2thione with activated carboxylic esters. • + + Barton, D. H. R.; Circh, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1 983, 939941 . Barton, D. H. R.; Bridon, D.; FernandezPicot, I.; Zard, S. Z. Tetrahedron 1 987, 43, 27332740. • Examples 2. tBuSH, toluene, 80 °C 65% Diedrichs, N.; Westermann, B. Synlett. 1 999, 1 1 271 1 29. (–)tetrahydroalstonine 1 . iBuOCOCl, NMM 2. Martin, S. F.; Clark, C. W.; Corbett, J. W. J. Org. Chem. 1 995, 60, 32363242. 3. h ν Barton, D. H. R.; Géro, S. D.; Lawrence, F.; RobertGero, M.; QuicletSire, B.; Samadi, M. J. Med. Chem. 1 992, 35, 6367. sinefungin analogs 1 . 3. tBuSH, h ν 1 . iBuOCOCl, NMM 2. In the following example, the alkyl radical generated from the decarboxylation reaction was trapped with an electrondeficient olefin. This produced a second radical intermediate that continued the chain to give the stereoisomeric mixture of products shown. • cubane • The Barton decarboxylation is known to be stereoselective in rigid bicycles. + Diol Olefin Jason Brubaker General Reference: Block, E. Org. React. 1 984, 30, 457. CoreyWinter Olefination: HO OH CO2 (CH3O)3P S S N N toluene, reflux O O S P(OEt)3 (solvent) 1 1 0 °C Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1 963, 85, 2677. HO OH CO2 CHCl3, 25 °C, 3 h R2 R3 2540 °C R R1 4 R 2 R3 R R1 4 O O S N P CH3 N CH3 Ph (3 equiv, neat) R 2 R 3 R 4 R 1 N P CH3 N CH3 Ph S + + ++ • This is a twostep procedure. The diol is converted to a thionocarbonate by addition of thiocarbonyldiimidazole in refluxing toluene. The intermediate thionocarbonate is then desulfurized (with concomitant loss of carbon dioxide) upon heating in the presence of a trialkylphophite. O OH CH3 HO CH3 CH3 O O CH3 Et O CH3 OH CH3 CH3 CH3 O CH3 CH3 O O CH3 Et O CH3 OH CH3 CH3 CH3 CH3 1 . Cl2C S, DMAP 2. 40 °C 61 % Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1 982, 23, 1 979. • Original report: • Milder conditions have been reported for both the formation of the thiocarbonate intermediate and the subsequent decomposition to the desired olefin. O O • These milder conditions have been used effectively for the olefination of highly functionalized diols: N P CH3 N CH3 Ph (3 equiv, neat) Cl2C S CH2Cl2 0 °C, 1 h DMAP • This method has been useful in the preparation of highly strained transcycloalkenes: OH OH (+)1 ,2cyclooctanediol Im 1 . 2C S 2. (iC8H1 7)3P 1 30 °C (–)transcylooctene 84% Corey, E. J.; Shulman, J. I. Tetrahedron Lett. 1 968, 8, 3655. • The elimination is stereospecific. P O h Ph H O Ph Ph O S P(OEt)3 (solvent) 1 1 0 °C + • In an initial attempt to prepare transcycloheptene, the only product observed was the cisisomer. Performing the olefination reaction in the presence of 2,5diphenyl3,4isobenzofuran traps the highly strained olefin before isomerization to the cisisomer can occur: Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1 965, 87, 934. N O O Et N O O Et O O CH3O CH3 S O CH3 OCH3 P(OCH3)3 O 1 20 °C • Synthesis examples: Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 1 5284. • Preparation of Unsaturated Sugars: O O O CH3 CH3 CH3O O S O O O O CH3 CH3 CH3O P(OCH3)3 1 20 °C 85% 66% Barton, D. H. R.; Stick, R. V. J. Chem. Soc., Perkin Trans. 1, 1 975, 1 773. Jason Brubaker Eastwood Deoxygenation: • A vicinal diol is treated with ethyl orthoformate at high temperature (1 401 80 °C), followed by pyrolysis of the resulting cyclic orthoformate (1 60220 °C) in the presence of a carboxylic acid (typically acetic acid). • The elimination is stereospecific. H O H O H Ph LDA, tBuOK THF, reflux O HO OH OH O HO O O OEt O HC(OEt)3 HO CH3CO2H Crank, G.; Eastwood, F. W. Aust. J. Chem. 1 964, 17, 1 385. • Not suitable for functionalized substrates. 200 °C 72% Fleet, G. W. J.; Gough, M. J. Tetrahedron Lett. 1 982, 23, 4509. Base Induced Decomposition of Benzylidene Acetals: Hines, J. N.; Peagram, M. J.; Whitham, G. H.; Wright, M. J. Chem. Soc., Chem. Commun. 1 968, 1 593. 90% Pu, L.; Grubbs, R. H.; J. Org. Chem. 1 994, 59, 1 351 . 75% O Ph nBuLi, THF 20 °C, 1 4 h • The elimination is stereospecific. • Long reaction times and high temperatures under extremely basic conditions make this an unsuitable method for functionalized substrates. α, βUnsaturated Carbonyl Carbonyl Catalytic Hydrogenation: Stryker Reduction: • The carboncarbon double bond of α, βunsaturated carbonyl compounds can be reduced selectively by catalytic hydrogenation, affording the corresponding carbonyl compounds. • This method is not compatible with olefins, alkynes, and halides. • α, βUnsaturated carbonyl compounds undergo selective 1 ,4reduction with (Ph3P)CuH6. • (Ph3P)CuH6 is stable indefinitely, provided that the reagent is stored under an inert atmosphere. The reagent can be weighed quickly in the air, but the reaction solutions must be deoxygenated. The reaction is unaffected by the presence of water (in fact, deoxygenated water is often added as a proton source). • α, βUnsaturated ketones, esters, aldehydes, nitriles, sulfones, and sulfonates are all suitable substrates. • This method is compatible with isolated olefins, halides, and carbonyl groups (in contrast to reduction by catalytic hydrogenation). • Each of the six hydrides of the copper cluster can be transferred. O CH3 CH3 O CH3 CH3 O CH3 CH3 +88 % >1 00:1 1 0 equiv H2O benzene, 23 °C, 1 h 0.24 (Ph3P)CuH6 • The reduction is highly steroselective, with addition occuring to the less hindered face of the olefin: O I O I 30 equiv H2O THF, 23 °C, 7 h 0.32 (Ph3P)CuH6 83 % Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M. Tetrahedron Lett. 1 990, 31, 3237. Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1 988, 110, 291 . • TBSCl is often added during the reduction of α, βunsaturated aldehydes to suppress side reactions arising from aldol condensation of the copper enolate intermediates.

Myers Chem 215 Reduction 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 • 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 Catalyst/Compound Substrate Product Catalyst Ratio (wt%) Pressure (atm) Seyden-Penne, J In Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd Ed., Wiley-VCH: New York, 1997, p 1-36 Reactivity Trends Alkene Alkane 5% Pd/C 5-10% 1-3 Alkyne Alkene 5% Pd(BaSO4) 2% + 2% quinoline Aldehyde (Ketone) Alcohol PtO2 2-4% Halide Alkane 5% Pd/C 1-15%, KOH Nitrile Amine Raney Ni 3-30% 35-70 • Following are general guidelines concerning the reactivities of various reducing agents Substrates, Reduction Products Iminium Ion Acid Halide Aldehyde Ester Amide Carboxylate Salt Amine Alcohol Alcohol Alcohol Amine Alcohol Hydride Donors LiAlH4 Adapted from: Hudlicky, M In Reductions in Organic Chemistry 2nd Ed., American Chemical Society Monograph 188: Washington DC, 1996, p Summary of Reagents for Reductive Functional Group Interconversions: Acid DIBAL – Alcohol Alcohol Alcohol or Aldehyde Amine or Aldehyde Alcohol NaAlH(O-t-Bu)3 – Aldehyde Alcohol Alcohol (slow) Amine (slow) – Lithium Aluminum Hydride (LAH) Ester – Alcohol Alcohol Alcohol Amine Alcohol NaBH4 Amine – Alcohol –** – – NaCNBH3 Amine – Alcohol (slow) – – – Na(AcO)3BH Amine – Alcohol (slow) Alcohol (slow) Amine (slow) – B2H6 – – Alcohol Alcohol (slow) Amine (slow) Alcohol Li(Et)3BH – Alcohol Alcohol Alcohol Alcohol (tertiary amide) – H2 (catalyst) Amine Alcohol Alcohol Alcohol Amine – α-alkoxy esters are reduced to the corresponding alcohols – indicates no reaction or no productive reaction (alcohols are deprotonated in many instances, e.g.) Lithium Borohydride Borane Complexes Aldehyde Diisobutylaluminum Hydride (DIBAL) AlH3 ** Alcohol Reduction of Acid Chlorides, Amides, and Nitriles Lithium Triethoxyaluminohydride (LTEAH) Aldehyde Alcohol Reductive Amination Luche Reduction Sodium Borohydride Ionic Hydrogenation Aldehyde Samarium Iodide Alkane Deoxygenation of Tosylhydrazones Desulfurization with Raney Nickel Wolff–Kishner Reduction Clemmensen Reduction Alcohol Alkane Barton Deoxygenation Diazene-Mediated Deoxygenation Reduction of Alkyl Tosylates Radical Dehalogenation Acid Alkane Barton Decarboxylation Mark G Charest Acid Alcohol TESO CH3O (CH3)2N Lithium Aluminum Hydride (LAH): LiAlH4 O CH3 TESO O N H OTES N –78 °C CO2CH3 • 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 LiAlH4, ether CH3O (CH3)2N O CH3 O N H OTES N CH2OH 72% Evans, D A.; Gage, J R.; Leighton, J L J Am Chem Soc 1992, 114, 9434-9453 • 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 H H LiAlH4 N N H Ts O N THF 88% N H H (+)-aloperine • 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 Brosius, A D.; Overman, L E.; Schwink, L J Am Chem Soc 1999, 121, 700-709 Fieser, L F.; Fieser, M Reagents for Organic Synthesis 1967, 581-595 • Examples O H O O LiAlH4 CH3O O H H THF O 70% ether O N CH3 N CH3 H3C CH3O O H OH 89-95% CH3 H HO LiAlH4 H O HO H3C CH3 Heathcock, C H.; Ruggeri, R B.; McClure, K F J Org Chem 1992, 57, 2585-2599 (+)-codeine • In the following example, rearrangement accompanied reduction White, J D.; Hrnciar, P.; Stappenbeck, F J Org Chem 1999, 64, 7871-7884 CH3O2C O CH3O2C H HOCH2 OH HOCH2 C(CH3)3 O LiAlH4, THF H H3C H reflux H H3C CO2H 72% Bergner, E J.; Helmchen, G J Org Chem 2000, 65, 5072-5074 H H3C OH TsO HH CH3 OH CH3 CH3 H LiAlH4 H3C HH OH THF 60% CH3 CH3 H3C Bates, R B.; Büchi, G.; Matsuura, T.; Shaffer, R R J Am Chem Soc 1960, 82, 2327-2337 Mark G Charest Borane Complexes: BH3•L 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 • 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 • Examples • Examples F O2N H N O CH3 O N H CH3 H CO2CH3 OTBS O O BH3•THF, °C CH3 dihydropyran, THF LiBH4, CH3OH O H O CH3 TsOH, °C Br THF, Et2O, °C CO2H Br CH2OTHP 86% 83% Corey, E J.; Sachdev, H S J Org Chem 1975, 40, 579-581 F O2N H N Laïb, T.; Zhu, J Synlett 2000, 1363-1365 O CH3 O N H CH3 OH HO2C BH3•THF CO2Et → 25 °C HOCH2 CO2Et OTBS 67% Kende, A S.; Fludzinski, P Org Synth 1986, 64, 104-107 • The combination of boron trifluoride etherate and sodium borohydride has been used to generate diborane in situ HO CH3 CH3O2C CO2H LiBH4 81% HO CH3 CO2H NaBH4, BF3•Et2O HOCH2 CO2H THF, 15 °C HN 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 CH2OH SO2 95% HN SO2 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 Mark G Charest Ester Aldehyde O Diisobutylaluminum Hydride (DIBAL): i-Bu2AlH H3C • 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 MOMO O OMOM H N O TMS O CH3 H3C CH3 OMOM CH3 OAc OAc O O DIBAL, THF –100 → –78 °C employed, including dichloromethane Miller, A E G.; Biss, J W.; Schwartzman, L H J Org Chem 1959, 24, 627-630 CH3 Zakharkin, L I.; Khorlina, I M Tetrahedron Lett 1962, 3, 619-620 CH3 O O CH3 CH3 CO2CH3 • Examples CO2CH3 O H3C N Boc CHO DIBAL, toluene O –78 °C H3C CH3 N O H3C Boc CH3 (+)-damavaricin D O Garner, P.; Park, J M Org Synth 1991, 70, 18-28 O TMS O CH3 H3C CH3 OMOM CH3 OAc OAc O O MOMO 76% OMOM H N CH3 DIBAL, CH2Cl2, –78 °C CH3 O O CH3 CH3 R CH3OH, –80 °C I CO2Et I potassium sodium tartrate CHO Swern, 82% R = CH2OH, 62% R = CHO, 16% 88% Marek, I.; Meyer, C.; Normant, J.-F Org Synth 1996, 74, 194-204 Roush, W R.; Coffey, D S.; Madar, D J J Am Chem Soc 1997, 119, 11331-11332 • Reduction of N-methoxy-N-methyl amides, also known as Weinreb amides, is one of the • Nitriles are reduced to imines, which hydrolyze upon work-up to furnish aldehydes most frequent means of converting a carboxylic acid to an aldehyde Cl TBSO O CH3 N OCH3 Cl DIBAL, toluene CH2Cl2, –78 °C TBSO O O H 82% Trauner, D.; Schwarz, J B.; Danishefsky, S J Angew Chem., Int Ed Engl 1999, 38, 3542-3545 O DIBAL, ether NC HO C(CH3)3 –78 °C OHC HO C(CH3)3 56% Crimmins, M T.; Jung, D K.; Gray, J L J Am Chem Soc 1993, 115, 3146-3155 Mark G Charest Lithium Triethoxyaluminohydride (LTEAH): Li(EtO)3AlH Reduction of Acid Chlorides • LTEAH selectively reduces aromatic and aliphatic nitriles to the corresponding aldehydes (after aqueous workup) in yields of 70-90% • The Rosemund reduction is a classic method for the preparation of aldehydes from carboxylic acids by the selective hydrogenation of the corresponding acid chloride • Tertiary amides are efficiently reduced to the corresponding aldehydes with LTEAH • Over-reduction and decarbonylation of the aldehyde product can limit the usefulness of the Rosemund protocol • LTEAH is formed by the reaction of mole of LAH solution in ethyl ether with moles of ethyl alcohol or 1.5 moles of ethyl acetate LiAlH4 + Et2O EtOH °C Li(EtO)3AlH + 3H2 • 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 LiAlH4 + Et2O 1.5 CH3CO2Et °C Li(EtO)3AlH • Examples PhtN H 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 CO2H SOCl2 CH3 CHO CH3 H2, Pd/BaSO4 CH3 CH3 64% Brown, H C.; Tsukamoto, A J Am Chem Soc 1964, 86, 1089-1095 • Examples PhtN H Johnson, R L J Med Chem 1982, 25, 605-610 CON(CH3)2 Cl CHO O Cl LTEAH, ether, °C F3C 80% CON(CH3)2 CHO LTEAH, ether, °C H2, Pd/BaSO4 NH F3C CF3 H CHO O 64% NH CF3 Winkler, D.; Burger, K Synthesis 1996, 1419-1421 • Sodium tri-tert-butoxyaluminohydride (STBA), generated by the reaction of sodium aluminum hydride with equivalents of tert-butyl alcohol, reduces aliphatic and aromatic acid chlorides to the corresponding aldehydes in high yields H+ NO2 COCl O H+ O H NO2 75% STBA, diglyme COCl CHO THF, –78 °C Brown, H C.; Krishnamurthy, S Tetrahedron 1979, 35, 567-607 100% LTEAH, hexanes, CH3 O Bn OH N CH3 CH3 >99% de O THF, °C TFA, N HCl H Bn CH3 77% (94% ee) Myers, A G.; Yang, B H.; Chen, H.; McKinstry, L.; Kopecky, D J.; Gleason, J L J Am Chem Soc 1997, 119, 6496-6511 ClOC COCl STBA, diglyme THF, –78 °C OHC CHO 93% diglyme = (CH3OCH2CH2)2O Cha, J S.; Brown, H C J Org Chem 1993, 58, 4732-4734 Mark G Charest Aldehyde or Ketone Alkane • Examples • In the following example, exchange of the tosylhydrazone N-H proton is evidently faster than reduction and hydride transfer 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 NNHTs H3C CH3 H3C CH3Y X CH3 • Esters, amides, nitriles, nitro groups, and alkyl halides are compatible with the reaction conditions CH3 • Most hindered carbonyl groups are readily reduced to the corresponding hydrocarbon CH3 CH3 Conditions Product (Yield) • However, electron-poor aryl carbonyls prove to be resistant to reduction NaBD4, AcOH X = D, Y = H (75%) Hutchins, R O.; Milewski, C A.; Maryanoff, B E J Am Chem Soc 1973, 95, 3662-3668 NaBH4, AcOD X = H, Y = D (72%) NaBD4, AcOD X = Y = D (81%) 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 Hutchins, R O.; Natale, N R J Org Chem 1978, 43, 2299-2301 • 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 N R Ts NH R' H+ + HN R Ts NH NaBH3CN R' Ts NH HN H R R' N R H+ R' Ts N N H R R' OH CH3 N –TsH R NH H R' –N2 R R' NaBH3CN H CH3 H ZnCl2, NaBH3CN CH3OH, 90 °C H CH H CH3 Ts NH HN H R R' Miller, V P.; Yang, D.-y.; Weigel, T M.; Han, O.; Liu, H.-w J Org Chem 1989, 54, 4175-4188 CH3 NNHTs H H • However, reduction of an azohydrazine is proposed when inductive effects and/or conformational constraints favor tautomerization of the hydrazone to an azohydrazine Ts NH OH CH3 H CH H CH3 ~50% (±)-ceroplastol I Boeckman, R K., Jr.; Arvanitis, A.; Voss, M E J Am Chem Soc 1989, 111, 2737-2739 • 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 H R N N H R' R OAc TsNHNH2, EtOH CH3O2C OH NaBH3CN O H –N2 CH3O2C O Ot-Bu NaOAc, H2O, EtOH CH3O–Na+, CH3OH O Ot-Bu R' 68% overall 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 Hanessian, S.; Faucher, A.-M J Org Chem 1991, 56, 2947-2949 Mark G Charest Wolff–Kishner Reduction Desulfurization With Raney Nickel • 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 • The two principal side reactions associated with the Wolff–Kishner reduction are azine formation and alcohol formation • 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 OCH3 N(CHO)CH3 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 SEt SEt H N • Examples H O diethylene glycol, Na metal OCH3 N(CHO)CH3 Raney Ni, H2 H N H H O ~50% H O H H O H2NNH2, 210 °C O Woodward, R B.; Brehm, W J J Am Chem Soc 1948, 70, 2107-2115 90% Clemmensen Reduction Piers, E.; Zbozny, M Can J Chem 1979, 57, 1064-1074 • 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 Reduced-Temperature Wolff-Kisher-Type Reduction • Typically, the classic Clemmensen reduction involves refluxing a carbonyl substrate with • N-tert-butyldimethylsilylhydrazone (TBSH) derivatives serve as superior alternatives to hydrazones • TBSH derivatives of aliphatic carbonyl compounds undergo Wolff-Kishner-type reduction at 23 °C; derivatives of aromatic carbonyl undergo reduction at 100 °C H N N H TBS , cat Sc(OTf)3; Vedejs, E Org React 1975, 22, 401-415 CH3 CH3 KOt-Bu, HOt-Bu, DMSO 23 °C, 24 h CH3O • Anhydrous hydrogen chloride and zinc dust in organic solvents has been used as a milder alternative to the classic Clemmensen reduction conditions TBS O 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 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 CH3O 93% • Example O TBS O CH3O H N N H TBS , cat Sc(OTf)3; Cl CH3O Cl CH3O KOt-Bu, HOt-Bu, DMSO 100 °C, 24 h Cl Zn(Hg), HCl CH3O 92% 56% Cl Marchand, A P.; Weimer, W R., Jr J Org Chem 1969, 34, 1109-1112 Furrow, M E.; Myers, A G J Am Chem Soc 2004, 126, 5436 Mark G Charest, Jason Brubaker Aldehyde or Ketone Alcohol Luche Reduction • Sodium borohydride in combination with cerium (III) chloride (CeCl3) selectively reduces 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 α,β-unsaturated carbonyl compounds to the corresponding allylic alcohols • Typically, a stoichiometric quantity of cerium (III) chloride and sodium borohydride is added to an α,β-unsaturated carbonyl substrate in methanol at °C • Control experiments reveal the dramatic influence of the lanthanide on the regiochemistry of the reduction • Typically, sodium borohydride reductions are performed in ethanol or methanol, often OH O 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 Reductant Brown, H C.; Krishnamurthy, S Tetrahedron 1979, 35, 567-607 NaBH4 NaBH4, CeCl3 • Examples O I HO O Luche, J.-L J Am Chem Soc 1978, 100, 2226-2227 CH3 • Examples O °C OPiv 49% trace 51% 99% I NaBH4, CH3OH CH3 OH OPiv ~100% CH3 CH3O H3C H3C O H Ph O O OsO4 (cat), CH3 CH3O aq NMO NaIO4 NaBH4 HO H3C H3C O H Ph N N H H 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 H CH3CN, CH3OH H CH3O2C O 78% N N H H NaBH4, CeCl3 H H CH3O2C OH O O Binns, F.; Brown, R T.; Dauda, B E N Tetrahedron Lett 2000, 41, 5631-5635 90% Ireland, R E.; Armstrong, J D., III; Lebreton, J.; Meissner, R S.; Rizzacasa, M A J Am Chem Soc 1993, 115, 7152-7165 O CH3O O NaBH4, CH3OH NEt2 M HCl CH3O O H CH3 OBOM O NaBH4, CeCl3•7H2O CH3OH, °C TIPSCl, Im TIPSO H CH3 OBOM O O CHO >81% Wang, X.; de Silva, S O.; Reed, J N.; Billadeau, R.; Griffen, E J.; Chan, A.; Snieckus, V Org Synth 1993, 72, 163-172 87% Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E K.; Danishefsky, S J J Am Chem Soc 1997, 119, 10073-10092 Mark G Charest Ionic Hydrogenation Samarium Iodide: SmI2 • Ionic hydrogenation refers to the general class of reactions involving the reduction of a carbonium ion intermediate, often generated by protonation of a ketone, alkene, or a lactol, with a hydride donor • Samarium iodide effectively reduces aldehydes, ketones, and alkyl halides in the presence of carboxylic acids and esters • Aldehydes are often reduced much more rapidly than ketones • Generally, ionic hydrogenations are conducted with a proton donor in combination with a hydride donor These components must react with the substrate faster than with each other Girard, P.; Namy, J L.; Kagan, H B J Am Chem Soc 1980, 102, 2693-2698 Molander, G A Chem Rev 1992, 92, 29-68 • Organosilanes and trifluoroacetic acid have proven to be one of the most useful reagent combinations for the ionic hydrogenation reaction Soderquist, J A Aldrichimica Acta 1991, 24, 15-23 • Examples • Carboxylic acids, esters, amides, and nitriles not react with organosilanes and trifluoroacetic acid Alcohols, ethers, alkyl halides, and olefins are sometimes reduced Kursanov, D N.; Parnes, Z N.; Loim, N M Synthesis 1974, 633-651 • Examples O CH3 SmI2 THF, H2O • The ionic hydrogenation has been used to prepare ethers from the corresponding lactols HO OTBS OTBS CO2CH3 H N O O CH3 H CO2CH3 97% (86% de) H N Et3SiH, CF3CO2H CH2Cl2, reflux CH3N O OH CH3N Singh, A K.; Bakshi, R K.; Corey, E J J Am Chem Soc 1987, 109, 6187-6189 O • In the following example, a samarium-catalyzed Meerwein–Ponndorf–Verley reduction (±)-gelsemine >65% successfully reduced the ketone to the alcohol where many other reductants failed Madin, A.; O'Donnell, C J.; Oh, T.; Old, D W.; Overman, L E.; Sharp, M J Angew Chem., Int Ed Engl 1999, 38, 2934-2936 CH3 • Intramolecular ionic hydrogenation reactions have been used in stereoselective reductions CH3 DEIPSO t-Bu2Si(H)O CH3 H CF3CO2– CF3CO2H; + – n-Bu4N F H H3C H CH3 65-75% t-Bu O Si t-Bu H + CH3 OCH3 HO CH3 H H H H PMBO H O O CH3 O DEIPSO CH3 SmI2 i-PrOH, THF PMBO H 98% H H H CH3 O O CH3 OH CH3 >95% isomeric purity McCombie, S W.; Cox, B.; Lin, S.-I.; Ganguly, A K.; McPhail, A T Tetrahedron Lett 1991, 32, 2083-2086 Evans, D A.; Kaldor, S W.; Jones, T K.; Clardy, J.; Stout, T J J Am Chem Soc 1990, 112, 7001-7031 Mark G Charest Reductive Amination O • The reductive amination of aldehydes and ketones is an important method for the CH3 synthesis of primary, secondary, and tertiary amines H3C • Iminium ions can be reduced selectively in the presence of their carbonyl precursors Reductive aminations are often conducted by in situ generation of the imine (iminium ion) intermediate in the presence of a mild acid • Reagents such as sodium cyanoborohydride and sodium triacetoxyborohydride react HO CH3O CH3 CH2CHO O HO O CH3 O OCH2 OCH3 Et O O N(CH3)2 O CH3 NaBH3CN O OH OH CH3 OH CH3 CH3OH, HN O selectively with iminium ions and are frequently used for reductive aminations tylosin Borch, R F.; Bernstein, M D.; Durst, H D J Am Chem Soc 1971, 93, 2897-2904 79% Abdel-Magid, A F.; Maryanoff, C A.; Carson, K G Tetrahedron 1990, 31, 5595-5598 O Abdel-Magid, A F.; Carson, K G.; Harris, B D.; Maryanoff, C A.; Shah, R D J Org Chem 1996, 61, 3849-3862 • Examples H3C HO CH3O OTBS AcO N H H + CH3 O CH3 CHO Na(AcO)3BH, Sn(OTf)2 AcO CH3 OTBS CH3 N H CO2Bn H CO2Bn OHC O N CO2t-Bu OTHP + N H Ph Ph NaBH3CN H CH3 CH2O OCH2 OCH3 Et HO O CH3 O O O N(CH3)2 O CH3 O OH OH CH3 OH CH3 Matsubara, H.; Inokoshi, J.; Nakagawa, A.; Tanaka, H.; Omura, S J Antibiotics 1983, 36, 1713-1721 H O CH3 O Å MS, ClCH2CH2Cl, °C 66% Hosokawa, S.; Sekiguchi, K.; Hayase, K.; Hirukawa, Y.; Kobayashi, S Tetrahedron Lett 2000, 41, 6435-6439 O CH3 N O Ph Ph H NaBH3CN H CO2Bn N CH3OH N CO2t-Bu OTHP 59% H2, Pd/C, EtOH, H2O, HCl TFA CO2Bn NH•TFA H N CH CH3 84% H CO2Bn H CO2Bn Ohfune, Y.; Tomita, M.; Nomoto, K J Am Chem Soc 1981, 103, 2409-2410 H CO2H N H CO2H H CO2H N H OH 2'-deoxymugineic acid Jacobsen, E J.; Levin, J.; Overman, L E J Am Chem Soc 1988, 110, 4329-4336 Mark G Charest Alcohol Alkane O Barton Deoxygenation PhO • Radical-induced deoxygenation of O-thiocarbonate derivatives of alcohols in the presence of hydrogen-atom donors is a versatile and widely-used method for the preparation of an alkane from the corresponding alcohol O 1,1'-thiocarbonyl-diimidazole, N DMAP, CH2Cl2 O PhO N O AIBN, Bu3SnH, toluene, 75 °C OH • The Barton deoxygenation is a two-step process In the initial step, the alcohol is acylated to generate an O-thiocarbonate derivative, which is then typically reduced by heating in an aprotic solvent in the presence of a hydrogen-atom donor H 75% • The method has been adapted for the deoxygenation of primary, secondary, and tertiary alcohols In addition, monodeoxygenation of 1,2- and 1,3-diols has been achieved Nicolaou, K C.; Hwang, C.-K.; Smith, A L.; Wendeborn, S V J Am Chem Soc 1990, 112, 74167418 • The accepted mechanism of reduction proceeds by attack of a tin radical on the thiocarbonyl sulfur atom Subsequent fragmentation of this intermediate generates an alkyl radical which propagates the chain • In the following example, the radical generated during the deoxygenation reaction undergoes 6exo-trig radical cyclization S RO S (n-Bu)3Sn R' RO Sn(n-Bu)3 S R R' + O Sn(n-Bu)3 CH3 1,1'-thiocarbonyl-diimidazole, H3C R' OH CH3 i-Pr H 46% (1 : mixture) Barton, D H R.; Motherwell, W B.; Stange, A Synthesis 1981, 743-745 Barton, D H R.; Hartwig, W.; Hay-Motherwell, R S.; Motherwell, W B.; Stange, A Tetrahedron Lett 1982, 23, 2019-2022 H3C AIBN, Bu3SnH, toluene, 70 °C H Barton, D H R.; McCombie, S W J Chem Soc., Perkin Trans I 1975, 1574-1585 H3C DMAP, CH2Cl2, reflux H + H H i-Pr β-copaene β-ylangene Kulkarni, Y S.; Niwa, M.; Ron, E.; Snider, B B J Org Chem 1987, 52, 1568-1576 Barton, D H R.; Zard, S Z Pure Appl Chem 1986, 58, 675-684 Tin-Free Barton-Type Reduction Employing Water as a Hydrogen Atom Source: Barton, D H R.; Jaszberenyi, J C Tetrahedron Lett 1989, 30, 2619-2622 • Trialkylborane acts as both the radical initiator and an activator of water prior to hydrogen atom abstraction Barton, D H R.; Jang, D O.; Jaszberenyi, J C Tetrahedron Lett 1990, 31, 3991-3994 • Simple concentration of the reaction mixture provides products in high purity Barton, D H R.; Jang, D O.; Jaszberenyi, J C Tetrahedron Lett 1990, 31, 4681-4684 S Barton, D H R.; Blundell, P.; Dorchak, J.; Jang, D O.; Jaszberenyi, J C Tetrahedron 1991, 47, 8969-8984 O • Examples S O O OH H O HO H OH HO CO2H quinic acid AIBN, Bu3SnH H O O Im xylenes, 140 °C O S O HO CH3 CH3 O H O O 40% SCH3 B(CH3)3, H2O O O CH3 CH3 benzene, 23 °C O H O O O CH3 CH3 O CH3 CH3 91% Spiegel, D A.; Wiberg, K B.; Schacherer, L N.; Medeiros, M R.; Wood, J L J Am Chem Soc 2005, ASAP Mills, S.; Desmond, R.; Reamer, R A.; Volante, R P.; Shinkai, I Tetrahedron Lett 1988, 29, 281284 Mark G Charest, Jason Brubaker Diazene-Mediated Deoxygenation • Deoxygenation proceeds by Mitsunobu displacement of the alcohol with onitrobenzenesulfonylhydrazine (NBSH) followed by in situ elimination of o-nitrobenzene sulfinic acid The resulting monoalkyl diazene is proposed to decompose by a free-radical mechanism to form deoxygenated products • The deoxygenation is carried out in a single step without using metal hydride reagents • The method is found to work well for unhindered alcohols, but sterically encumbered and βoxygenated alcohols fail to undergo the Mitsunobu displacement and are recovered unchanged from the reaction mixture RCH2OH PPh3, DEAD, NBSH THF, –30 °C RCH2N(NH2)SO2Ar ≥ °C • In related studies, it was shown that alkyllithium reagents add to N-tert-butyldimethylsilyl aldehyde tosylhydrazones at –78 °C and that the resulting adducts can be made to extrude dinitrogen in a free-radical process t-BuSi(CH3)2 N N SO2Ar R t-BuSi(CH3)2 N N SO2Ar H R R' Li R'Li –78 °C H RCH3 –N2 Ph • Examples H AcOH, CF3CH2OH, –78 → 23 °C CH3 OH CH3 N PPh3, DEAD, NBSH CH3 Cl R R' CH3 CH3 CH3 Ph Ph CH3 94% CH3O N THF, –30 °C O R –N2 TBSOTf, Et3N, THF, –78 °C CH3 CH3 CH3 Li Ph SO2Ar N N H Ar = 2-O2NC6H4 CH3O H H H R' Ar = 2,4,6-triisopropylbenzene • Examples RCH2N=NH N AcOH, TFE –78 → 23 °C H N CH3 O 87% SO2Ar N N H Cl CH3 CH3 • In the following example, the radical generated from decomposition of the diazene intermediate underwent a rapid 5-exo-trig radical cyclization This generated a second radical that was trapped with oxygen to provide the cyclic carbinol shown after work-up with methyl sulfide O O O H3C CH3 H O O TBSOTf, Et3N, THF, –78 °C Li CH3 CH3 CH3 AcOH, CF3CH2OH, –78 → 23 °C O O CH3 CH3 CH3 CH3 CH3 O O O 87% CH3 CH3 Myers, A G.; Movassaghi, M J Am Chem Soc 1998, 120, 8891-8892 N O PPh3, DEAD, NBSH, CH3 OH N O t-BuLi, ether CH3 CH3 THF, –30 °C; OMOM O2; DMS CH3 84% OH • Monoalkyl diazenes will undergo concerted sigmatropic elimination of dinitrogen in preference to radical decomposition where this is possible CH2OH CH3 I CH3O C4H9 CH3O OCH3 CH3O NN(TBS)Ts HCl, CH3OH, THF C4H9 PPh3, DEAD, NBSH C4H9 OCH3 CH3O C4H9 73% OCH3 OCH3 HO CH3 NMM, –35 °C 65% Myers, A G.; Movassaghi, M.; Zheng, B J Am Chem Soc 1997, 119, 8572-8573 (–)-cylindrocyclophane F Smith, A B., III; Kozmin, S A.; Paone, D V J Am Chem Soc 1999, 121, 7423-7424 Mark G Charest • Reductive 1,3-transposition of allylic alcohols proceeds with excellent regio- and stereochemical control ArSO2NHNH2, R4 HO H R3 H2N SO2Ar R4 N H R3 R1 R2 Ph3P, DEAD R1 –30 °C, 0.5-6 h R2 23 °C 0.3-2 h Reduction of Alkyl Tosylates • p-Toluenesulfonate ester derivatives of alcohols are reduced to the corresponding alkanes with certain powerful metal hydrides • Among hydride sources, lithium triethylborohydride (Super Hydride, LiEt3BH) has been shown to rapidly reduce alkyl tosylates efficiently, even thoes derived from hindered alcohols OTs H N R4 N H R3 R1 R2 H R3 –N2 O Reductant R2 LAH LiEt3BH O O Ph3P , DEAD OH OH NBSH, NMM CH3 CO2CH3 O + + R1 • Example HO CH3 OH H R4 54% 80% 25% 20% 19% 0% Krishnamurthy, S.; Brown, H C J Org Chem 1976, 41, 3064-3066 • Examples CO2CH3 66% CH3 CH2OTs Myers, A G.; Zheng, B Tetrahedron Lett 1996, 37, 4841-4844 BnO • In addition, allenes can be prepared stereospecifically from propargylic alcohols H OH R1 R2 Ph3P, DEAD N N H H R1 R2 23 °C 1-8 h R2 R1 R2 Evans, D A.; Dow, R L.; Shih, T L.; Takacs, J M.; Zahler, R J Am Chem Soc 1990, 112, 5290-5313 • In the following example, selective C-O bond cleavage by LiEt3BH could only be achieved with a 2-propanesulfonate ester The corresponding mesylate and tosylate underwent S-O bond cleavage when treated with LiEt3BH H –N2 H HO CH3 • Example O CH3 ArSO2NHNH2, H OH CH3 EtO CH3 OEt OH 92% R1 –15 °C, 1-2 h CH3 CH3 BnO CH3OH OH SO2Ar H2N N H ArSO2NHNH2, LiEt3BH, THF; H2O2, NaOH (aq) Ph3P, DEAD –15 °C CH3 EtO 74% H H EtO H H OSO2i-Pr LiEt3BH, toluene CH3 90 °C CH3 HO H 72% O H H CH3 Hua, D H.; Venkataraman, S.; Ostrander, R A.; Sinai, G.-Z.; McCann, P J.; Coulter, M J.; Xu, M R J Org Chem 1988, 53, 507-515 Myers, A G.; Zheng, B J Am Chem Soc 1996, 118, 4492-4493 Mark G Charest Radical Dehalogenation I BzO O • Alkyl bromides and iodides are reduced efficiently to the corresponding alkanes in a free-radical chain mechanism with tri-n-butyltin hydride • The reduction of chlorides usually requires more forcing reaction conditions and alkyl fluorides are practically unreactive • The reactivity of alkyl halides parallels the thermodynamic stability of the radical produced and follows the order: tertiary > secondary > primary I BzO O CH3 O I O CH3 O O I I O Bz O Bu3SnH, Et3B, O2 K2CO3, THF, CH3OH Neumann, W P Synthesis 1987, 665-683 Bu4N+F–, AcOH, THF Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.; Utimoto, K Bull Chem Soc Jpn 1989, 62, 143-147 TIPSO OTIPS H CH3 H3C HO O Bu3SnH, AIBN, THF PhBr, 80 °C H3C HO O 70% OPMB OPMB Cl 61% OTIPS CH3 O CH3 OTIPS CH3 CH3O HO H O H TIPSO altohyrtin A O AcO H O H Br H O H Bu3SnH, AIBN, PhCH3 H O H 64% OAc CH3 O O • In the following example, the radical generated during the dehalogenation reaction undergoes a tandem radical cyclization O O HO CH3OH, CH3COCl H O H CH3 CH3 O O O Roush, W R.; Bennett, C E J Am Chem Soc 2000, 122, 6124-6125 OH H CH3 H3C O HO H3C O HO OTIPS H CH3 Guo, J.; Duffy, K J.; Stevens, K L.; Dalko, P I.; Roth, R M.; Hayward, M M.; Kishi, Y Angew Chem., Int Ed Engl 1998, 37, 187-196 O O O OH OPMB OPMB Cl O OAc O O OTBS • Triethylboron-oxygen is a highly effective free-radical initiator Reduction of bromides and iodides can occur at –78 °C with this initiator I CH3O HO H O H I O I Bz O O CH3 H CH3 CH3 Br Bu3SnH, AIBN benzene, 80 °C CH3 H H3C 61% parviflorin CH3 CH3 H H (±)-capnellene Curran, D E.; Chen, M.-H Tetrahedron Lett 1985, 26, 4991-4994 OH Trost, B M.; Calkins, T L.; Bochet, C G Angew Chem., Int Ed Engl 1997, 36, 2632-2635 Mark G Charest Acid Alkane CO2H • O-Esters of thiohydroxamic acids are reduced in a radical chain reaction by tin hydride reagents O H N N HH Barton Decarboxylation H CH3 i-BuOCOCl, NMM S N O–Na+ H O • These are typically prepared by the reaction of commercial N-hydroxypyridine-2-thione with activated carboxylic esters O H N N HH t-BuSH, hν CH3 O O R O RCO2 + N + S + (n-Bu)3SnH R N –CO2 RH + (n-Bu)3Sn SSn(n-Bu)3 Sn(n-Bu)3 O H N N HH Martin, S F.; Clark, C W.; Corbett, J W J Org Chem 1995, 60, 3236-3242 H Barton, D H R.; Circh, D.; Motherwell, W B J Chem Soc., Chem Commun 1983, 939-941 CH3 O (–)-tetrahydroalstonine Barton, D H R.; Bridon, D.; Fernandez-Picot, I.; Zard, S Z Tetrahedron 1987, 43, 2733-2740 • Examples • In the following example, the alkyl radical generated from the decarboxylation reaction was trapped with an electron-deficient olefin This produced a second radical intermediate that continued the chain to give the stereoisomeric mixture of products shown O S AIBN, Bu3SnH O N N O THF, reflux O S O cubane ~100% NH Eaton, P E Angew Chem., Int Ed Engl 1992, 31, 1421-1436 HO2C N O O i-BuOCOCl, NMM S N O–Na+ O N S CONH2 N OH O CH3 CH3 O NH H2NOC SPy N O hν • The Barton decarboxylation is known to be stereoselective in rigid bicycles O O CbzNH H CO2Bn O CbzNH O O CH3 CH3 H CO2Bn N t-BuSH, toluene, 80 °C H COCl sinefungin analogs 65% Diedrichs, N.; Westermann, B Synlett 1999, 1127-1129 Barton, D H R.; Géro, S D.; Lawrence, F.; Robert-Gero, M.; Quiclet-Sire, B.; Samadi, M J Med Chem 1992, 35, 63-67 Mark G Charest Diol Olefin • This method has been useful in the preparation of highly strained trans-cycloalkenes: General Reference: OH Im2C S Block, E Org React 1984, 30, 457 OH (i-C8H17)3P 130 °C (+)-1,2-cyclooctanediol Corey-Winter Olefination: • This is a two-step procedure The diol is converted to a thionocarbonate by addition of thiocarbonyldiimidazole in refluxing toluene The intermediate thionocarbonate is then desulfurized (with concomitant loss of carbon dioxide) upon heating in the presence of a trialkylphophite • Original report: S S OH N O N O CH3 S O (3 equiv, neat) R4 R1 R2 Ph P N N CH3 R3 R1 25-40 °C R3 R2 CO2 + Ph S + CH3 N P N CH3 • These milder conditions have been used effectively for the olefination of highly functionalized diols: O Et O CH3 CH3 HO CH3 OH CH3 O O CH3 OH O O CH3 CH3 CH3 CHCl3, 25 °C, h CH3 CH3 CH3 Cl2C S, DMAP CH3 OH CH3 Ph P N N CH3 (3 equiv, neat) 40 °C Corey, E J.; Hopkins, P B Tetrahedron Lett 1982, 23, 1979 O 110 °C Ph H O Ph H • Synthesis examples: CH3 CH3O R4 O P(OEt)3 (solvent) Corey, E J.; Winter, R A E J Am Chem Soc 1965, 87, 934 • Milder conditions have been reported for both the formation of the thiocarbonate intermediate and the subsequent decomposition to the desired olefin CH2Cl2 °C, h O + S O Ph Corey, E J.; Winter, R A E J Am Chem Soc 1963, 85, 2677 OH R4 R3 Ph 110 °C toluene, reflux HO R1 R2 Corey, E J.; Shulman, J I Tetrahedron Lett 1968, 8, 3655 CO2 + (CH3O)3P S + P(OEt)3 (solvent) Cl2C S DMAP 84% • In an initial attempt to prepare trans-cycloheptene, the only product observed was the cis-isomer Performing the olefination reaction in the presence of 2,5-diphenyl-3,4-isobenzofuran traps the highly strained olefin before isomerization to the cis-isomer can occur: • The elimination is stereospecific HO (–)-trans-cylooctene CH3 O Et O 61% CH3 CH3 P(OCH3)3 O S N O O Et CH3 O OCH3 N O O 120 °C Et O O 66% Bruggemann, M.; McDonald, A I.; Overman, L E.; Rosen, M D.; Schwink, L.; Scott, J P J Am Chem Soc 2003, 125, 15284 • Preparation of Unsaturated Sugars: O O O CH3 O S O O CH3O O O P(OCH3)3 O CH3 CH3 120 °C O O CH3O CH3 CH3 85% Barton, D H R.; Stick, R V J Chem Soc., Perkin Trans 1, 1975, 1773 Jason Brubaker α,β-Unsaturated Carbonyl Eastwood Deoxygenation: Crank, G.; Eastwood, F W Aust J Chem 1964, 17, 1385 • A vicinal diol is treated with ethyl orthoformate at high temperature (140-180 °C), followed by pyrolysis of the resulting cyclic orthoformate (160-220 °C) in the presence of a carboxylic acid (typically acetic acid) • The elimination is stereospecific Carbonyl Catalytic Hydrogenation: • The carbon-carbon double bond of α,β-unsaturated carbonyl compounds can be reduced selectively by catalytic hydrogenation, affording the corresponding carbonyl compounds • This method is not compatible with olefins, alkynes, and halides • Not suitable for functionalized substrates Stryker Reduction: OEt OH HO OH HC(OEt)3 CH3CO2H O O O HO 200 °C O • α,β-Unsaturated carbonyl compounds undergo selective 1,4-reduction with [(Ph3P)CuH]6 HO O 72% Fleet, G W J.; Gough, M J Tetrahedron Lett 1982, 23, 4509 • [(Ph3P)CuH]6 is stable indefinitely, provided that the reagent is stored under an inert atmosphere The reagent can be weighed quickly in the air, but the reaction solutions must be deoxygenated The reaction is unaffected by the presence of water (in fact, deoxygenated water is often added as a proton source) • α,β-Unsaturated ketones, esters, aldehydes, nitriles, sulfones, and sulfonates are all suitable substrates Base Induced Decomposition of Benzylidene Acetals: • This method is compatible with isolated olefins, halides, and carbonyl groups (in contrast to reduction by catalytic hydrogenation) • The elimination is stereospecific • Long reaction times and high temperatures under extremely basic conditions make this an unsuitable method for functionalized substrates O Ph O • Each of the six hydrides of the copper cluster can be transferred • TBS-Cl is often added during the reduction of α,β-unsaturated aldehydes to suppress side reactions arising from aldol condensation of the copper enolate intermediates O n-BuLi, THF I O I 0.32 [(Ph3P)CuH]6 20 °C, 14 h 30 equiv H2O THF, 23 °C, h 75% Hines, J N.; Peagram, M J.; Whitham, G H.; Wright, M J Chem Soc., Chem Commun 1968, 1593 83 % Koenig, T M.; Daeuble, J F.; Brestensky, D M.; Stryker, J M Tetrahedron Lett 1990, 31, 3237 • The reduction is highly steroselective, with addition occuring to the less hindered face of the olefin: H Ph O O 0.24 [(Ph3P)CuH]6 LDA, t-BuOK THF, reflux CH3 90% Pu, L.; Grubbs, R H.; J Org Chem 1994, 59, 1351 O O O H H CH3 10 equiv H2O benzene, 23 °C, h + CH3 CH3 CH3 CH3 >100:1 88% Mahoney, W S.; Brestensky, D M.; Stryker, J M J Am Chem Soc 1988, 110, 291 Jason Brubaker