Reduction Chem 115

Home , Aldehyde, Amide, Amide (functional group), Azine, Borane, Borohydride

Myers Reduction Chem 115

General References • 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 Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry Part B, Springer: New York, 2007, execute a desired reduction. p. 396–431. • A brief list of recommended reaction conditions for catalytic hydrogenations of selected functional Brown, H. C.; Ramachandran, P. V. In Reductions in Organic Synthesis: Recent Advances and groups is given below. Practical Applications, Abdel-Magid, A. F. Ed.; American Chemical Society: Washington DC, 1996, p. 1-30. Catalyst/Compound Substrate Product Catalyst Ratio (wt%) Pressure (atm) Ripin, D. H. B. Oxidation. In Practical Synthetic Organic Chemistry; Caron, S., Ed.; John Wiley & Sons: New Jersey, 2011. Alkene Alkane 5% Pd/C 5-10% 1-3

Reactivity Trends Alkyne Alkene 5% Pd(BaSO4) 2% + 2% quinoline 1

• Following are general guidelines concerning the reactivities of various reducing agents. Aldehyde Alcohol PtO2 2-4% 1 (Ketone) Substrates, Reduction Products Halide Alkane 5% Pd/C 1-15%, KOH 1 Iminium Ion Acid Halide Aldehyde Ester Amide Carboxylate Salt Nitrile Amine Raney Ni 3-30% 35-70 Hydride Donors Adapted from: Hudlicky, M. In Reductions in Organic Chemistry 2nd Ed., American Chemical LiAlH4 Amine Alcohol Alcohol Alcohol Amine Alcohol Society Monograph 188: Washington DC, 1996, p. 8.

Summary of Reagents for Reductive Functional Group Interconversions: DIBAL – Alcohol Alcohol Alcohol or Amine or Alcohol Aldehyde Aldehyde O O R OH R H NaAlH(O-t-Bu)3 – Aldehyde Alcohol Alcohol Amine – R OR' R H (slow) (slow) ester aldehyde alcohol alkane AlH3 – Alcohol Alcohol Alcohol Amine Alcohol Diisobutylaluminum Hydride Sodium Borohydride (DIBAL) NaBH4 Amine – Alcohol – – – Luche Reduction Barton Deoxygenation (NaBH , CeCl ) Lithium Triethoxyaluminohydride 4 3 Reduction of Alkyl Tosylates ** (LTEAH) NaCNBH3 Amine – Alcohol – – – Ionic Hydrogenation (slow) (Et SiH, TFA) Diazene-Mediated Deoxygenation Reduction of Acid Chlorides, 3 Amides, and Nitriles Samarium Iodide Na(AcO)3BH Amine – Alcohol Alcohol Amine – (slow) (slow) (slow) O B2H6 – – Alcohol Alcohol Amine Alcohol O O (slow) (slow) R CH3 R H R OH R OH R H R OH Li(Et)3BH – Alcohol Alcohol Alcohol Alcohol – (tertiary amide) acid alcohol aldehyde alkane acid alkane (–1C)

H2 (catalyst) Amine Alcohol Alcohol Alcohol Amine – Lithium Aluminum Hydride (LAH) Wolff–Kishner Reduction Barton Decarboxylation

Lithium Borohydride Reduction of Tosylhydrazones LAB – – Alcohol Alcohol Alcohol – Borane Complexes Desulfurization with Raney ** !-alkoxy esters are reduced to the corresponding alcohols. Nickel via 1,3-dithiane (BH3•L) – indicates no reaction or no productive reaction (alcohols are deprotonated in many instances, Clemmensen Reduction e.g.) Mark G. Charest, Fan Liu

1 Myers Reduction Chem 115

O R OH TESO O CH3 TESO O CH3 R OH O LiAlH4, ether O Acid Alcohol CH3O N CH3O N H –78 °C H (CH3)2N OTES N (CH3)2N OTES N Lithium Aluminum Hydride (LAH): LiAlH4 CO2CH3 CH2OH

• LAH is a powerful and rather nonselective hydride-transfer reagent that readily reduces 72% 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. Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453. • 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. O • Several work-up procedures for LAH reductions are available that avoid the difficulties of Ph Ph separating by-products of the reduction and minimize the possibility of ignition of liberated H2. OH LiAlH4, THF OH In the Fieser work-up, following reduction with n grams of LAH, careful successive dropwise N OEt N addition of n mL of water, n mL of 15% NaOH solution, and 3n mL of water provides a H 0 ! 65 ºC H H 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 O product, ethanol, is unlikely to interfere with product isolation. 8.93 g 98%

• Although, in theory, one equivalent of LAH provides four equivalents of hydride, an excess of the reagent is typically used. Becker, C. W.; Dembofsky, B. T.; Hall, J. E.; Jacobs, R. T.; Pivonka, D. E.; Ohnmacht, C. J. 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. Synthesis 2005, 2549-2561. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis 1967, 581-595.

H H • Examples O O HO O O CH3 LiAlH4 O HO N N CH3 ether H3C H3C 89-95% CH O LiAlH4 CH3O CH3 CH3 3 H H O THF O H H 70% OH O Heathcock, C. H.; Ruggeri, R. B.; McClure, K. F. J. Org. Chem. 1992, 57, 2585-2599. (+)-codeine

White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64, 7871-7884. O

H3C H3C HOCH OCH LiAlH4 OH CH3O2C 2 3 O C(CH3)3 OH CH3O2C HOCH2 OCH3 THF, 0 ºC OH H3C H3C H O H TIPSO O >99% TIPSO LiAlH4, THF reﬂux 102 g H H OH H3C CO2H 72% H3C Yamaguchi, J.; Seiple, I.; Young, I. S.; O'Malley, D. P.; Maue, M.; Baran, P. S. Angew. Chem., Int. Bergner, E. J.; Helmchen, G. J. Org. Chem. 2000, 65, 5072-5074. Ed. Engl. 2008, 47, 3578–3580. Mark G. Charest, Fan Liu

2 Myers Reduction Chem 115

Lithium Borohydride: LiBH4 Borane Complexes: BH3•L • Lithium borohydride is commonly used for the selective reduction of esters and lactones to the • Borane is commonly used for the reduction of carboxylic acids in the presence of esters, corresponding alcohols in the presence of carboxylic acids, tertiary amides, and nitriles. lactones, amides, halides and other functional groups. In addition, borane rapidly reduces Aldehydes, ketones, epoxides, and several other functional groups can also be reduced by aldehydes, ketones, and alkenes. lithium borohydride. • Borane is commercially available as a complex with tetrahydrofuran (THF) or dimethysulfide in • The reactivity of lithium borohydride is dependent on the reaction medium and follows the solution. In addition, though highly flammable, gaseous diborane (B H ) is available. order: ether > THF > 2-propanol. This is attributed to the availability of the lithium counterion 2 6 for coordination to the substrate, promoting reduction. • The borane-dimethylsulfide complex exhibits improved stability and solubility compared to the • Lithium borohydride is commercially available in solid form and as solutions in many organic borane-THF complex. solvents (e.g., THF). Both are inflammable and should be stored protected from moisture. • Competing hydroboration of carbon-carbon double bonds can limit the usefulness of borane- THF as a reducing agent. Nystrom, R. F.; Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1949, 71, 3245-3246. Lane, C. F. Chem. Rev. 1976, 76, 773-799. 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, Brown, H. C.; Stocky, T. P. J. Am. Chem. Soc. 1977, 99, 8218-8226. 1999, p. 209-212. • Examples • Examples O 1. BH3•THF, 0 °C O O O H CH3 2. dihydropyran, THF H CH3 F TsOH, 0 °C O2N Br CO2H Br CH2OTHP O CO2CH3 H LiBH , CH OH 86% N OTBS 4 3 N THF, Et O, 0 °C H 2 Corey, E. J.; Sachdev, H. S. J. Org. Chem. 1975, 40, 579-581. O H C CH 3 3 SO CH SO CH 83% 2 3 2 3 O HO F HO BH •THF, 0 °C O2N OH 3 O EtO2C EtO2C H THF, 98% Laïb, T.; Zhu, J. Synlett. 2000, 1363-1365. N OTBS N H O 500 g Br Br H3C CH3 Lobben, P. C.; Leung, S. S.-W.; Tummala, S. Org. Process Res. Dev. 2004, 8, 1072–1075.

• The combination of boron triﬂuoride etherate and sodium borohydride has been used to generate diborane in situ.

O LiBH4 THF, i-PrOH CO2H CH2OH H3C OEt H3C OH 15 ºC, 100% CO2H CO2H NaBH4, BF3•Et2O 450 g THF, 15 °C HN SO 2 95% HN SO2

Hu, B.; Prashad, M.; Har, D.; Prasad, K.; Repic, O.; Blacklock, T. J. Org. Process Rev. Dev. 2007, 11, 90–93. 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. Brown, H. C.; Tierney, P. A. J. Am. Chem. Soc. 1980, 80, 1552–1558. Mark G. Charest, Fan Liu

3 Myers Reduction Chem 115

O O

R OR' R H O OMOM H Ester Aldehyde H C N O 3 TMS O MOMO Diisobutylaluminum Hydride (DIBAL): i-Bu2AlH CH3 DIBAL, THF OMOM H3C CH3 CH • At low temperatures, DIBAL reduces esters to the corresponding aldehydes, and lactones to O 3OAc OAc O O –100 ! –78 °C lactols.

• Typically, toluene is used as the reaction solvent, but other solvents have also been employed, including dichloromethane. CH3 CH3 CH3 CH3 CO2CH3 O O 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 O OMOM H CO CH CHO H C N O 2 3 3 TMS O DIBAL, toluene O N –78 °C N O Boc Boc MOMO CH3 H3C H3C O OMOM H3C CH3 CH3 CH3 OMOM H CH 76% H C N O O 3OAc OAc O O 3 TMS O Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18-28. MOMO CH + 3 H C CH OMOM 3 3 CH3 CH3 CH3 CH3 CHO CH O O O 3OAc OAc O O O 1. DIBAL, CH2Cl2, –78 °C OH F F 16% O 2. CH3OH, –78 °C O CH3 CH3 CH3 CH3 3. potassium sodium tartrate O O OH 1 kg >99% 62% Swern, 82%

Cai, X.; Chorghade, M.; Fura, A.; Grewal, G. S.; Jauregui, K. A.; Lounsbury, H. A.; Scannell, R.; Yeh, C. G.; Young, M. A.; Yu, S. Org. Process Res. Dev. 1999, 3, 73–76. 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 most • Nitriles are reduced to imines, which hydrolyze upon work-up to furnish aldehydes. frequent means of converting a carboxylic acid to an aldehyde.

O O Cl O Cl O 1. DIBAL, ether DIBAL, toluene CH –78 °C TBSO N 3 TBSO H NC OHC CH2Cl2, –78 °C HO C(CH3)3 2. 5% H2SO4 HO C(CH3)3 OCH3

82% 56%

Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1999, 38, 3542-3545. Crimmins, M. T.; Jung, D. K.; Gray, J. L. J. Am. Chem. Soc. 1993, 115, 3146-3155.

Mark G. Charest, Fan Liu

4 Myers Reduction Chem 115 Reduction of Acid Chlorides Lithium Triethoxyaluminohydride (LTEAH): Li(EtO)3AlH • The Rosemund reduction is a classic method for the preparation of aldehydes from carboxylic • LTEAH selectively reduces aromatic and aliphatic nitriles to the corresponding aldehydes acids by the selective hydrogenation of the corresponding acid chloride. (after aqueous workup) in yields of 70-90%. • Over-reduction and decarbonylation of the aldehyde product can limit the usefulness of the • Tertiary amides are efﬁciently reduced to the corresponding aldehydes with LTEAH. Rosemund protocol.

• LTEAH is formed by the reaction of 1 mole of LAH solution in ethyl ether with 3 moles of ethyl • The reduction is carried out by bubbling hydrogen through a hot solution of the acid chloride in alcohol or 1.5 moles of ethyl acetate. which the catalyst, usually palladium on barium sulfate, is suspended. Rosemund, K. W.; Zetzsche, F. Chem. Ber. 1921, 54, 425-437. Et2O LiAlH4 + 3 EtOH Li(EtO)3AlH + 3H2 Mosetting, E.; Mozingo, R. Org. React. 1948, 4, 362-377. 0 °C • Examples: O OH O H Et2O 1. (COCl)2, DMF LiAlH4 + 1.5 CH3CO2Et Li(EtO)3AlH 0 °C toluene

2. H2, Pd/C, DIPEA Brown, H. C.; Shoaf, C. J. J. Am. Chem. Soc. 1964, 86, 1079-1085. N cat. thioanisole N (7.89 kg) Cbz Cbz Brown, H. C.; Garg, C. P. J. Am. Chem. Soc. 1964, 86, 1085-1089. 94% Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089-1095. Maligres, P. E.; Houpis, I.; Rossen, K.; Molina, A.; Sager, J.; Upadhyay, V.; Wells, K. M.; Reamer, • Examples R. A.; Lynch, J. E.; Askin, D.; Volante, R. P.; Reider, P. J.; Houghton, P. Tetrahedron 1997, 53, 10983–10992. CON(CH3)2 CHO Cl 1. LTEAH, ether, 0 °C Cl PhtN CO2H PhtN CHO 1. SOCl2 2. H+ H H 2. H2, Pd/BaSO4 H3C H3C 80% CH CH 3 64% 3 CON(CH ) CHO 3 2 Johnson, R. L. J. Med. Chem. 1982, 25, 605-610. 1. LTEAH, ether, 0 °C O O 2. H+ H H H , Pd/BaSO O COCl 2 4 O CHO NO2 NO2 75% NH NH F3C F3C CF3 64% CF3 Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567-607. Winkler, D.; Burger, K. Synthesis 1996, 1419-1421.

1. LTEAH, hexanes, • Sodium tri-tert-butoxyaluminohydride (STBA), generated by the reaction of sodium aluminum CH3 O O hydride with 3 equivalents of tert-butyl alcohol, reduces aliphatic and aromatic acid chlorides to Bn THF, 0 °C Bn the corresponding aldehydes in high yields. N H 2. TFA, 1 N HCl OH CH CH CH 3 3 3 STBA, diglyme COCl CHO THF, –78 °C >99% de 77% (94% ee) diglyme = (CH OCH CH ) O Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am. 3 2 2 2 Chem. Soc. 1997, 119, 6496-6511. Cha, J. S.; Brown, H. C. J. Org. Chem. 1993, 58, 4732-4734. Mark G. Charest, Fan Liu

5 Myers Reduction Chem 115

O R' Selective Amide Reduction: R' R N R N R' • Amides can be activated by Tf2O to form a highly electrophilic iminium intermediate that can be R' reduced by mild reductants known as Hantzsch esters: Amide Amine

O Lithium Aluminum Hydride (LAH): LiAlH4 R OTf Tf2O • Reduction of amides is commonly employed for the synthesis of amines. N Ph N Ph CH2Cl2 1, CH2Cl2 O Ph Ph OTf H H O 86% Ph Ph N N LiAlH4 N N THF, 60 ºC H H EtO2C CO2Et O 92%

H3C N CH3 H N Ph Watson, T. J.; Ayers, T. A.; Shah, N.; Wenstrup, D.; Webster, M.; Freund, D.; Horgan, S.; Carey, Hantzsch ester (1) J. P. Org. Process Res. Dev. 2003, 7, 521-532. Note: ketone is preserved

Aluminum Hydride (Alane): AlH3 Barbe, G.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 18–19. • Alane is another powerful reducing agent that reduces carboxylic acids, esters, lactones, amides and nitriles to the corresponding alcohols or amines. In addition, aldehydes, ketones, acid • Similar activation of secondary amides followed by reduction provides amines, imines, or aldehydes: chlorides, quinones and many other functional groups are reduced by AlH3. • under carefully controlled conditions, the selective reduction of a lactam can be achieved in the presence of an ester functionality:

H O Bn Bn O N H N H N O N Tf2O AlH3 2-ﬂuoropyridine citric acid, THF O THF, –78 ºC O Et SiH, CH Cl 96% H H 3 2 2 Et Et H3CO2C O N 89% H3CO2C O N 96% OBn n-Bu OBn n-Bu CO2Et CO2Et CO2Et

Martin, S. F.; Rüeger, H.; Williamson, S. A. J. Am. Chem. Soc. 1987, 109, 6124–6134.

1. Tf2O • With the following substrate, attempted use of alternative hydride reducing agents led to ring- 2-ﬂuoropyridine NH opened products: Et3SiH, CH2Cl2 2. 1, CH2Cl2

H3C CH3 H3C CH3 AlH3 H3C CH3 H3C CH3 71% THF N N Bn O Bn 80% CO2Et

Jackson, M. B.; Mander, L N.; Spotswood, T. M. Aust. J. Chem. 1983, 36, 779–788. Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am. Chem. Soc. 2010, 132, 12817–12819. Fan Liu

6 Myers Reduction Chem 115

O • Examples:

R R' R R' TBSO CH O CH TsNHNH2, AcOH Aldehyde or Ketone Alkane 3 3 CH Cl , 23 ºC BocO OPMB 2 2 Deoxygenation of Tosylhydrazones 70% OTBS OBn Ts • Reduction of tosylhydrazones to hydrocarbons with moderately reactive hydride donors such as sodium cyanoborohydride, sodium triacetoxyborohydride, or catecholborane, is a mild and 1. O TBSO NH selective method for carbonyl deoxygenation. B H CH3 N CH3 O • Esters, amides, nitriles, nitro groups, and alkyl halides are typically not reduced under the reaction BocO OPMB conditions. 2. Na2S2O3, H2O CHCl3, SiO2 OTBS OBn 3. NaOAc, CHCl , 65 ºC • Even many hindered carbonyl groups can be readily reduced to the corresponding hydrocarbon. 3 0 # 23 ºC

• However, electron-poor aryl carbonyl groups prove to be resistant to reduction. TBSO CH3 CH3 Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am. Chem. Soc. 1973, 95, 3662-3668. BocO OPMB Kabalka, G. W.; Baker, J. D., Jr. J. Org. Chem. 1975, 40, 1834-1835. OTBS OBn 75% Kabalka, G. W.; Chandler, J. H. Synth. Commun. 1979, 9, 275-279.

• Two possible mechanisms for reduction of tosylhydrazones by sodium cyanoborohydride have Hutchinson, J. M.; Gibson, A. S.; Williams, D. T.; McIntosh, M. C. Tetrahedron Lett. 2011, 52, 6349– 6351. been suggested. Direct hydride attack by sodium cyanoborohydride on an iminium ion is proposed in most cases. Ts Ts Ts H OH OH CH CH NH + + NH NH N 3 3 N H HN NaBH3CN HN N H H NNHTs

–TsH –N CH3 CH R R' R R' R R' R R' 2 R R' H H 3 ZnCl2, NaBH3CN • However, reduction of an azohydrazine is proposed when inductive effects and/or CH OH, 90 °C H 3 H conformational constraints favor tautomerization of the hydrazone to an azohydrazine. CH3 CH3 H H Ts Ts Ts CH3 ~50% CH3 NH H+ N NH N N NaBH3CN HN (±)-ceroplastol I

R R' R R' R R' Boeckman, R. K., Jr.; Arvanitis, A.; Voss, M. E. J. Am. Chem. Soc. 1989, 111, 2737-2739. Miller, V. P.; Yang, D.-y.; Weigel, T. M.; Han, O.; Liu, H.-w. J. Org. Chem. 1989, 54, 4175-4188.

• !,"-Unsaturated carbonyl compounds are reduced with concomitant migration of the conjugated alkene.

• The mechanism for this "alkene walk" reaction apparently proceeds through a diazene CH3O2C OAc 1. TsNHNH2, EtOH CH3O2C OH intermediate which transfers hydride by 1,5-sigmatropic rearrangement. 2. NaBH3CN O 3. NaOAc, H O, EtOH O N O 2 H N H 4. CH ONa, CH OH Ot-Bu 3 3 Ot-Bu R R' –N2 R 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, Fan Liu

7 Myers Reduction Chem 115 Desulfurization With Raney Nickel Wolff–Kishner Reduction • Thioacetal (or thioketal) reduction with Raney nickel and hydrogen is a classic method to prepare • The Wolff–Kishner reduction is a classic method for the conversion of the carbonyl group in a methylene group from a carbonyl compound. 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. • The most common limitation of the desulfurization method occurs when the substrate contains an alkene; hydrogenation of the alkene group may be competitive. • 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 • Examples: removal of water, and by the use of high concentrations of hydrazine. OCH3 OCH3 N(CHO)CH N(CHO)CH • The two principal side reactions associated with the Wolff–Kishner reduction are azine formation 3 3 and alcohol formation. SEt H SEt Raney Ni, H2 H Todd, D. Org. React. 1948, 4, 378-423. N N H H ~50% H H Hutchins, R. O.; Hutchins, M. K. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, I., O O O O Eds., Pergamon Press: New York, 1991, Vol. 8, p. 327-362. H H

• Examples Woodward, R. B.; Brehm, W. J. J. Am. Chem. Soc. 1948, 70, 2107-2115.

H3C SCH3 H3C BnO SCH3 NiCl •H O, NaBH BnO diethylene glycol, Na metal 2 2 4 N THF, H O, –20 ºC N H2NNH2, 210 °C O Bn 2 O Bn O 70 %

90% Alcaide, B.; Casarrubios, L.; Dominguez, G.; Sierra, M. A. J. Org. Chem. 1994, 59, 7934–7936.

Piers, E.; Zbozny, M. Can. J. Chem. 1979, 57, 1064-1074. Clemmensen Reduction • The Clemmensen reduction of ketones and aldehydes with zinc and hydrochloric acid is a classic method for converting a carbonyl group into a methylene group. Reduced-Temperature Wolff-Kisher-Type Reduction • N-tert-butyldimethylsilylhydrazone (TBSH) intermediates provide superior alternatives to hydrazones. • Typically, the classic Clemmensen reduction involves reﬂuxing a carbonyl substrate with 40% aqueous hydrochloric acid, amalgamated zinc, and an organic solvent such as toluene. • TBSH derivatives of aliphatic carbonyl compounds undergo Wolff-Kishner-type reduction at 23 °C; • Examples: aromatic carbonyl groups undergo reduction at 100 °C. O Cl TBS H Cl Zn(Hg), HCl O N N , cat. Sc(OTf)3; CH 56% H TBS 3 Cl CH3 Cl KOt-Bu, HOt-Bu, DMSO CH3O CH O 3 23 ºC, 24 h 93% Marchand, A. P.; Weimer, W. R., Jr. J. Org. Chem. 1969, 34, 1109-1112. • Anhydrous acid and zinc dust in organic solvents has been used as a milder alternative to the classic Clemmensen reduction conditions: TBS H O N N CH O Br Br , cat. Sc(OTf)3; 3 CH3O H TBS Zn, Ac2O, TFA Cl Cl KOt-Bu, HOt-Bu, DMSO CH3O N N CH3O THF, –28 ºC 100 ºC, 24 h O 92% 200 g Br 80% Br

Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436. Kuo, S.-C.; Chen, F.; Hou, D.; Kim-Meade, A.; Bernard, C.; Liu, J.; Levy, S.; Wu, G. G. J. Org. Chem. 2003, 68, 4984–4987. Mark G. Charest, Fan Liu

8 Myers Reduction Chem 115

Luche Reduction – NaBH , CeCl O OH 4 3

• Sodium borohydride in combination with cerium (III) chloride (CeCl3) selectively reduces !,"- R R R R' unsaturated carbonyl compounds to the corresponding allylic alcohols. Aldehyde or Ketone Alcohol • Typically, a stoichiometric quantity of cerium (III) chloride and sodium borohydride is added to an Sodium Borohydride: NaBH4 !,"-unsaturated carbonyl substrate in methanol at 0 °C.

• Sodium borohydride reduces aldehydes and ketones to the corresponding alcohols at or below • The regiochemistry of the reduction is dramatically inﬂuenced by the presence of the lanthanide in 25 °C. Under these conditions, esters, epoxides, lactones, carboxylic acids, nitro groups, and nitriles are not reduced. the reaction.

• Sodium borohydride is commercially available as a solid, in powder or pellets, or as a solution in various solvents. O OH OH

• 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). Reductant Chaikin, S. W.; Brown, W. G. J. Am. Chem. Soc. 1949, 71, 122-125. NaBH4 51% 49% NaBH , CeCl 99% trace Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567-607. 4 3

• Examples Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227. I I O HO • Examples NaBH , CH OH CH3 4 3 CH3 O 0 °C O OPiv OPiv ~100%, dr = 1 : 1 N N N NaBH , CeCl N H H H 4 3 H H H CH3CN, CH3OH Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; H H Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162-3164. CH3O2C 78%, dr = 4 : 1 CH3O2C O OH

Ph Ph O O NaBH4 Binns, F.; Brown, R. T.; Dauda, B. E. N. Tetrahedron Lett. 2000, 41, 5631-5635. Bn2N O CH3OH, 0 ºC Bn2N O O 95%, dr = 27 : 1 OH

1. NaBH , CH 4 CH Diederich, A. M.; Ryckman, D. M.; Tetrahedron Lett. 1993, 34, 6169–6172. H 3 H 3 O CeCl3•7H2O TIPSO OBOM OBOM CH3OH, 0 °C O O 2. TIPSCl, Im CH3O O CH3O O 1. NaBH4, CH3OH NEt 87% 2 2. 6 M HCl O CHO >81% Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. K.; Danishefsky, S. J. Wang, X.; de Silva, S. O.; Reed, J. N.; Billadeau, R.; Griffen, E. J.; Chan, A.; Snieckus, V. Org. J. Am. Chem. Soc. 1997, 119, 10073-10092. Synth. 1993, 72, 163-172. Mark G. Charest, Fan Liu

9 Myers Reduction Chem 115

Ionic Hydrogenation Samarium Iodide: SmI2

• Ionic hydrogenation refers to the general class of reactions involving the reduction of a • Samarium iodide effectively reduces aldehydes, ketones, and alkyl halides in the presence of carbonium ion intermediate, often generated by protonation of a ketone, alkene, or a lactol, with carboxylic acids and esters. a hydride donor. • 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. • Organosilanes and triﬂuoroacetic acid have proven to be one of the most useful reagent combinations for the ionic hydrogenation reaction. Molander, G. A. Chem. Rev. 1992, 92, 29-68.

• Carboxylic acids, esters, amides, and nitriles do not react with organosilanes and triﬂuoroacetic Soderquist, J. A. Aldrichimica Acta. 1991, 24, 15-23. acid. Alcohols, ethers, alkyl halides, and oleﬁns are sometimes reduced. • Examples

Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 633-651.

H3C HO H3C Examples: O SmI2 H THF, H O • Ionic hydrogenation has been used to prepare ethers from the corresponding lactols. 2 OTBS OTBS

CO2CH3 CO2CH3 97% (86% de) H H O N O N Et3SiH, CF3CO2H

CH2Cl2, reﬂux CH3N CH3N Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1987, 109, 6187-6189. O >65% O OH • In the following example, a samarium-catalyzed Meerwein–Ponndorf–Verley reduction (±)-gelsemine 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. H3C H3C

DEIPSO DEIPSO H H H C H C 3 O OH 3 O H CH3 CH3 SmI H F3C F3C H O 2 H O Et3SiH, CF3CO2H PMBO i-PrOH, THF PMBO O O CH2Cl2, 23 ºC H H O OH 88% CH3 98% CH3 OCH3 OCH3

Caron, S.; Do, N. M.; Sieser, J. E.; Arpin, P.; Vazquez, E. Org. Process Res. Dev. 2007, 11, Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 1015–1024. 7001-7031.

Mark G. Charest, Fan Liu

10 Myers Reduction Chem 115

R OH R CH3 O 1. 1,1'-thiocarbonyl-diimidazole, O Alcohol Alkane PhO N DMAP, CH2Cl2 PhO N O O 2. AIBN, Bu3SnH, toluene, 75 °C Barton Deoxygenation OH H 75% • Radical-induced deoxygenation of O-thiocarbonate derivatives of alcohols in the presence of hydrogen-atom donors is a widely-used method for the preparation of an alkane from the corresponding alcohol. Nicolaou, K. C.; Hwang, C.-K.; Smith, A. L.; Wendeborn, S. V. J. Am. Chem. Soc. 1990, 112, 7416- • The Barton deoxygenation is a two-step process. In the initial step, the alcohol is acylated to 7418. generate an O-thiocarbonate derivative, which is then typically reduced by heating in an aprotic solvent in the presence of a hydrogen-atom donor. • In the following example, the radical generated during the deoxygenation reaction undergoes 6- exo-trig radical cyclization. • 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.

• 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 H C CH 1. 1,1'-thiocarbonyl-diimidazole, H C propagates the chain. 3 3 3 H3C DMAP, CH2Cl2, reﬂux i-Pr H OH CH3 + 2. AIBN, Bu SnH, toluene, 70 °C 3 H i-Pr H H H Sn(n-Bu) Sn(n-Bu) S S 3 S 3 (n-Bu)3Sn R + 46% (1 : 1 mixture) !-ylangene !-copaene RO R' RO R' O R'

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.

Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett. 1990, 31, 4681-4684. Tin-Free Barton-Type Reduction Employing Water as a Hydrogen Atom Source: Barton, D. H. R.; Blundell, P.; Dorchak, J.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron 1991, 47, 8969-8984. • Trialkylborane acts as both the radical initiator and an activator of water prior to hydrogen atom abstraction. • Simple concentration of the reaction mixture provides products in high purity. • Examples S S OH O O SCH3 O O O HO HO B(CH3)3, H2O H CH3 AIBN, Bu SnH O O 3 O O CH H OH H O Im CH 3 xylenes, 140 °C H H 3 benzene, 23 ºC H C O 3 HO CO2H O O O CH3 O S H3C O O H3C O quinic acid 40% H3C 91%

Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J. Am. Chem. Soc. Mills, S.; Desmond, R.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1988, 29, 281- 2005, 127, 12513–12515. 284. Mark G. Charest, Jason Brubaker

11 Myers Reduction Chem 115

Diazene-Mediated Deoxygenation • Alkyllithium reagents add to N-tert-butyldimethylsilyl aldehyde tosylhydrazones at –78 °C. The resulting adducts can be made to extrude dinitrogen in a free-radical process. • Deoxygenation proceeds by Mitsunobu displacement of an alcohol with o- nitrobenzenesulfonylhydrazine (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. t-BuSi(CH3)2 t-BuSi(CH3)2 H N Li N N • The deoxygenation is carried out in a single step without using metal hydride reagents. N SO2Ar R'Li N SO2Ar AcOH, TFE N H H H H The method is found to work well for unhindered alcohols, but sterically encumbered and - –78 °C –78 " 23 °C –N2 • ! R H R R' R R' R R' oxygenated alcohols fail to undergo the Mitsunobu displacement and are recovered unchanged from the reaction mixture. Ar = 2,4,6-triisopropylbenzene

PPh3, DEAD, NBSH ≥ 0 °C RCH2OH RCH2N(NH2)SO2Ar RCH2N=NH RCH3 THF, –30 °C –N2 • Examples

Ar = 2-O2NC6H4 1. TBSOTf, Et3N, • Examples THF, –78 °C SO2Ar 2. OH N CH3 CH3 CH3 N H CH3 CH3 CH3 CH Li Ph 3 Ph CH3O CH3O Ph H Ph PPh , DEAD, NBSH 3. AcOH, CF3CH2OH, CH 3 CH CH CH3 3 3 3 –78 " 23 °C N THF, –30 °C N 94% O O Cl 87% Cl

Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120, 8891-8892. • 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.

1. t-BuLi, ether CH3 N N 2. PPh , DEAD, NBSH, O CH3 3 O CH3 OMOM THF, –30 °C; OH CH3 CH3 O2; DMS C4H9 I CH3O OCH3 OH CH3O OCH3 84% C4H9 NN(TBS)Ts

CH O OCH 3. HCl, CH OH, THF CH O OCH • Monoalkyl diazenes will undergo concerted sigmatropic elimination of dinitrogen in preference to 3 3 3 3 3 radical decomposition where this is possible. HO C4H9 C4H9 73% CH3 CH2OH

PPh3, DEAD, NBSH NMM, –35 °C (–)-cylindrocyclophane F

65%

Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572-8573. Smith, A. B., III; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 1999, 121, 7423-7424. Mark G. Charest, Fan Liu

12 Myers Reduction Chem 115

• N-isopropylidene-N'-o-nitrobenzenesulfonyl hydrazine (IPNBSH), exhibits higher stability • Examples: compared to NBSH and provides greater ﬂexibility with respect to deoxygenation conditions. In situ hydrolysis furnishes the hydrazine intermediate which liberates dinitrogen.

O Ph3P , DEAD O CH HO OH OH O H 3 ArO2S NBSH, NMM OH N O H3C CO CH H3C CO CH O ArSO N CH N O 2 3 O 2 3 2 3 O NH O Ph 2 66% (IPNBSH) O H C Ph 3 H C PPh , DEAD 3 CH3 3 Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841-4844. CH3 CH3 THF, 0 ! 23 °C; CH3 TFE, H2O CH3O CH3O

Ph3P , DEAD O O NBSH, NMM NCO Et NCO Et H H H 2 H H H 2 O NH O 60% O N HO H O O Ph O Ph H3C H3C Magnus, P.; Ghavimi, B.; Coe, J. Bioorg. Med. Chem. Lett. 2013, 23, 4870-4874. CH 71% 3 CH CH dr = 3 : 1 3 3 CH 3 OBn OBn Ar = 2-O NC H O O 2 6 4 H3C H3C

1. NaBH4, CeCl3 O CH3 CH3 Movassaghi, M.; Piizzi, G.; Siegel, D.; Piersanti, G. Angew. Chem. Int. Ed. 2006, 45, 5859-5863. O O 2. Ph P , DEAD Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838–1841. O 3 O p-NO C H NBSH, NMM p-NO C H O 2 6 4 O 2 6 4 • Reductive 1,3-transposition of allylic alcohols can proceed with regio- and stereochemical control: 83% over 2 steps

Zhou, M.; O'Doherty, G. A. Org. Lett. 2008, 10, 2283–2286.

ArSO2NHNH2, H N SO Ar HO H 2 N 2 23 °C Ph3P, DEAD H BnO Et 0.5 h –30 °C, 1 h BnO Et H C CH H C CH 3 N 3 3 N 3 H Ph3P , DEAD H O toluene; NBSH O N N HO 74% H N O O TBSO H O OBn TBSO H O OBn N BnO H Et BnO Et –N2 77%, E:Z > 99:1 Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D. R.; Myers, A. G. Science 2005, 308, 395–398. Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841-4844. Mark G. Charest, Fan Liu

13 Myers Reduction Chem 115

Reduction of Alkyl Tosylates • Allenes can be prepared stereospeciﬁcally from propargylic alcohols. • p-Toluenesulfonate ester derivatives of alcohols are reduced to the corresponding alkanes with certain powerful metal hydrides. SO2Ar H OH H N N H • Among hydride sources, lithium triethylborohydride (Super Hydride, LiEt3BH) has been shown to ArSO2NHNH2, 2 23 °C rapidly reduce alkyl tosylates efﬁciently, even those derived from hindered alcohols. R1 Ph3P, DEAD R1 1-8 h R2 –15 °C, 1-2 h R 2 OTs OH

N N H H + + H R R 2 • R1 1 –N Reductant 2 LAH 54% 25% 19% R2 H LiEt3BH 80% 20% 0%

• Examples: Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976, 41, 3064-3066.

• Examples

H OH H LiEt3BH, THF; NBSH, EtO CH CH OTs CH CH CH3 3 2 3 3 CH3 H2O2, NaOH (aq) Ph3P, DEAD • BnO BnO EtO EtO CH3 CH OH –15 °C CH3 3 OEt H OH OH 74% 92%

Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-4493. 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 derivatives underwent S-O bond cleavage when treated with LiEt3BH. Ts N Ph O O O O NBSH H H C H H C H Br O Br 3 LiEt3BH, toluene 3 Ph3P, DEAD • NTs H3C 90 °C H3C THF, –15 °C H H OH H O Ph H OSO2i-Pr H H N 77%, dr = 94 : 6 N 72% Ts Ts

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. Inuki, S.; Iwata, A.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 2072–2083.

Mark G. Charest, Fan Liu

14 Myers Reduction Chem 115

Radical Dehalogenation • Alkyl bromides and iodides are reduced efﬁciently to the corresponding alkanes in a free-radical I O I chain mechanism with tri-n-butyltin hydride. BzO O O O O • The reduction of chlorides usually requires more forcing reaction conditions and alkyl ﬂuorides I I H3C O Bz are practically unreactive. O I BzO O O O • The reactivity of alkyl halides parallels the thermodynamic stability of the radical produced and O O I Bz follows the order: tertiary > secondary > primary. H3C O I

• Triethylboron-oxygen is a highly effective free-radical initiator. Reduction of bromides and OTBS iodides can occur at –78 °C with this initiator. 1. Bu3SnH, Et3B, O2

Neumann, W. P. Synthesis 1987, 665-683. 2. K2CO3, THF, CH3OH + – Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 3. Bu4N F , AcOH, THF 1989, 62, 143-147. 61% OTIPS I CH H C 3 3 H C CH O HO O 3 3 O O HO Bu3SnH, AIBN, THF O O OTIPS HO H H PhBr, 80 °C H3C H3C O CH3 O H3C TIPSO O HO O H O O O 70% HO OPMB H C O OTIPS 3 Cl OPMB CH3 OH CH3O HO O OTIPS H H CH Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 2000, 122, 6124-6125. TIPSO O 3 H • In the following example, the radical generated during the dehalogenation reaction undergoes a OPMB tandem radical cyclization. Cl OPMB

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. CH3 H C H3C CH3 3 Br O O Bu3SnH, AIBN OAc O OH O H H H benzene, 80 °C AcO HO CH CH H3C H H3C H 5 3 5 3 H Br H (±)-capnellene O O 61% 1. Bu SnH, AIBN, PhCH H 3 3 H H 2. CH3OH, CH3COCl H O O H 64% H parviﬂorin Curran, D. E.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991-4994. H C H C 3 OAc 3 OH 7 7

Trost, B. M.; Calkins, T. L.; Bochet, C. G. Angew. Chem., Int. Ed. Engl. 1997, 36, 2632-2635. Mark G. Charest

15 Myers Reduction Chem 115

O R H 1. 2,4,6-Cl3PhCOCl R OH CH3 H CO SO Ph H3C 3 2 2. S Acid Alkane (–1C) O O N O–Na+ O Barton Decarboxylation H O 3. t-BuSH, h! • O-Esters of thiohydroxamic acids are reduced in a radical chain reaction by tin hydride reagents. HO C 2 CH H 3 86% • These are typically prepared by the reaction of commercial N-hydroxypyridine-2-thione with O activated carboxylic esters. OPiv CH3 H C H3CO SO2Ph 3 O O O O N RCO2 + R + (n-Bu) SnH RH + (n-Bu)3Sn H R O N 3 –CO2 O S + SSn(n-Bu)3 CH H 3 Sn(n-Bu)3 O OPiv Barton, D. H. R.; Circh, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939-941.

Barton, D. H. R.; Bridon, D.; Fernandez-Picot, I.; Zard, S. Z. Tetrahedron 1987, 43, 2733-2740. Dong, C.-G.; Henderson, J. A.; Kaburagi, Y.; Sasaki, T.; Kim, D.-S.; Kim, J. T.; Urabe, D.; Guo, H.; Kishi, Y. J. Am. Chem. Soc. 2009, 131, 15642–15646. • Examples:

• In the following example, the alkyl radical generated from the decarboxylation reaction was S O trapped with BrCCl3. O N AIBN, Bu3SnH N O THF, reﬂux 1. (COCl) S O 2 O O O ~100% cubane 2. S OH Br – + CH O N O Na CH O 3 N 3 N Eaton, P. E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1421-1436. O O AIBN, BrCCl CH3O 3 CH3O 105 ºC, 75%

1. (COCl) , DMF H 2 H O O OAc 2. S OAc OAc OAc O H N OH O H O O OAc O OAc H , 89% H CO H 2 O O OAc 3. t-BuSH, THF, h! OAc CH3O OAc OAc N 97% O CH3O

Larsen, D. S.; Lins, R. J.; Stoodley, R. J.; Trotter, N. S. Org. Biomol. Chem. 2004, 2, 1934–1942. Wang, Q.; Padwa, A. Org. Lett. 2006, 8, 601-604. Mark G. Charest, Fan Liu

16 Myers Reduction Chem 115 • This method has been useful in the preparation of highly strained trans-cycloalkenes: HO OH 1. Cl C S OH 2 Diol Oleﬁn 2. (i-C8H17)3P OH General Reference: 130 ºC

Block, E. Org. React. 1984, 30, 457. (+)-1,2-cyclooctanediol (–)-trans-cylooctene 84% Corey-Winter Olefination: Corey, E. J.; Shulman, J. I. Tetrahedron Lett. 1968, 8, 3655. • This is a two-step procedure. The diol is first converted to a thionocarbonate by addition of thiocarbonyldiimidazole in refluxing toluene. The intermediate thionocarbonate is then desulfurized • Examples in synthesis: (with concomitant loss of carbon dioxide) upon heating in the presence of a trialkylphosphite. • The elimination is stereospecific. CH3 CH O H C • Original report: 3 O 3 OCH CO O 3 2 O H C + O P(OCH3)3 3 S S CH3 O N (H CO) P S S N Et 3 3 O Et 110 ºC O HO OH N N O O + O N N P(OEt)3 O O (solvent) 66% toluene, reflux 110 ºC Bruggemann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.; Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284. Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963, 85, 2677.

• Milder conditions have been reported for both the formation of the thionocarbonate intermediate O P(OCH ) and the subsequent decomposition to the desired oleﬁn. S O 3 3 O O O O Ph CH 120 ºC CH3 CO 3 O S H C P CH 2 O CH3O CH3 3 N N 3 + CH3O CH3 Cl2C S Ph S HO OH O O R R 85% DMAP (3 equiv, neat) 1 4 P + H3C N N CH3 R1 R4 R1 R4 R R R R 25–40 ºC R R 2 3 CH2Cl2 2 3 2 3 Barton, D. H. R.; Stick, R. V. J. Chem. Soc., Perkin Trans. 1, 1975, 1773. 0 ºC, 1 h

• Trans-Diol ! Alkene • These milder conditions have been used effectively for the oleﬁnation of highly functionalized diols: O O CH3 H3C CH3 1. Cl2C S, DMAP H3C CH3 H3C CH3 O H3C PPh3, I2 HO CH3 CHCl3, 25 ºC, 3 h CH3 O H3C O OBz H3C OH OH OH O OBz 2. Ph imidazole, H3C H3C toluene, 110 ºC Et O O P Et O O BzO OH H3C N N CH3 BzO CH CH OH O O 3 O O 3 CH CH 3 (3 equiv, neat) 3 CH3 CH3 40 ºC 61% Garegg, P. J.; Samuelsson, B. Synthesis. 1979, 469–470. Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 1979. Kwon, Y-U.; Lee. C.; Chung, S-K. J. Org. Chem. 2002, 67, 332–3338. Jason Brubaker, Fan Liu

17 Myers Reduction Chem 115

Eastwood Deoxygenation: O O Crank, G.; Eastwood, F. W. Aust. J. Chem. 1964, 17, 1385. R' R R' R !,"-Unsaturated Carbonyl Carbonyl • 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). Catalytic Hydrogenation: • The elimination is stereospecific. • The carbon-carbon double bond of !,"-unsaturated carbonyl compounds can be reduced selectively by catalytic hydrogenation, affording the corresponding carbonyl compounds. • Not suitable for highly functionalized substrates. • This method is not compatible with olefins, alkynes, and halides. OEt • The stereochemistry of reduction can be influenced by functional groups capable of chelation: OH O HC(OEt)3 HO OH CH CO H HO O HO 3 2 200 ºC OH OH H3C H3C O O O [Ir(cod)Py2]PF6

72% O H2, CH2Cl2 O H Fleet, G. W. J.; Gough, M. J. Tetrahedron Lett. 1982, 23, 4509. >90%, dr = 96 : 4

Base Induced Decomposition of Benzylidene Acetals: Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072–1073.

• The elimination is stereospeciﬁc. Stryker Reduction: • Long reaction times and high temperatures under extremely basic conditions make this an unsuitable method for highly functionalized substrates. • !,"-Unsaturated carbonyl compounds undergo selective 1,4-reduction with [(Ph3P)CuH]6.

• [(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 O n-BuLi, THF a proton source). Ph O 20 ºC, 14 h • !,"-Unsaturated ketones, esters, aldehydes, nitriles, sulfones, and sulfonates are all suitable substrates. 75% • This method is compatible with isolated oleﬁns, halides, and carbonyl groups.

• TBS-Cl is often added during the reduction of !,"-unsaturated aldehydes to suppress side reactions arising from aldol condensation of the copper enolate intermediates. Hines, J. N.; Peagram, M. J.; Whitham, G. H.; Wright, M. J. Chem. Soc., Chem. Commun. 1968, 1593. • The reduction is highly steroselective, with addition occuring to the less hindered face of the oleﬁn:

H O O O O Ph H 0.24 [(Ph3P)CuH]6 O H LDA, t-BuOK + 10 equiv H2O H C CH H C CH H C CH THF, reﬂux 3 3 benzene, 23 ºC, 1h 3 3 3 3 >100:1 90% 88%

Pu, L.; Grubbs, R. H.; J. Org. Chem. 1994, 59, 1351. Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110, 291. Jason Brubaker, Fan Liu