Please inquire for pricing and availability of listed products to our local sales representatives. 1 Reducing Agents Reduction is a chemical reaction in which the target substances ● Reduction of Carbonyl Groups and receive electrons, and is one of the most fundamental reactions Imino Group in organic chemistry. Reduction reactions include the deoxygenation The table below shows the reactivities of each reducing agent reaction and the hydrogenation reaction. Well-known reducing toward carbonyl compounds and imines. Please make use of this agents include metal hydrides1) such as lithium aluminum hydride table as a standard for reactions. (= LiAlH4) [L0203], boranes for hydride reduction, and hydrazine [H0172] used in the Wolff-Kishner reduction. A disconnection Reactions NR O O O O O reaction of a disulfide moiety into two thiols is also considered a R H R H R R R OR R NR2 R OH Carboxylic reduction. Imine Aldehyde Ketone Ester Amide Acid O OH OH R R N R OH R OH R NR2 R OH R1 R2 R1 R2 H R R Reagents Amine Alcohol Alcohol Alcohol Amine Alcohol O H H NaBH3CN 1 2 R R R1 R2 [S0396] 3 3 NR NHR NaBH(OAc)3 [S0394] R1 R2 R1 R2 H H R2 R2 NaBH4 R1 R1 [S0480] H H R1 SH R1 SSR2 + 2 HS R LiBH4 [L0186] This brochure introduces a variety of reducing agents and catalysts for reduction. We hope that this brochure will be useful for your research in organic synthesis. Catalysts for hydrogenation are introduced in another brochure, “Hydrogenation Catalysts”. LiAIH4 [L0170] Caution: Many reducing agents may spontaneously ignite on contact with air, or may react violently with water to produce flammable gases. Sufficient safety measures, such as using THF・BH3 [T2346] safety shields, wearing protective equipment, and using extreme Me2S・BH3 caution should be taken when working with these reagents as [D1843] well as in their disposal. PhNEt2・BH3 [D2581] Reactivity : High Middle Low 2 Please inquire for pricing and availability of listed products to our local sales representatives. Reducing Agents Sodium tris(1,1,1,3,3,3-hexafluoroisopropoxy)borohydride ● Luche Reduction (= NaBH(HFIP)3) [S0810] is a selective reducing agent developed When a,b-unsaturated ketones are reduced with sodium borohydride by Toshima et al. Aldehydes are selectively reduced in the [B0480], 1,4-reduction, not 1,2-reduction, preferentially occurs. presence of ketones and other reducible functions using S0810 However, Luche et al. have found that 1,2-reduction preferentially to afford the corresponding primary alcohols in high yields.2) occurred by adding cerium(III) chloride [C2058].7) The difference in reactivity can be explained with HSAB theory. A “hard” nucleophile is OCH(CF3)2 required for 1,2-reduction, whereas a hydride of S0480 is originally H B OCH(CF3)2 Na regarded as a “soft” nucleophile, resulting in 1,4-reduction. However, OCH(CF3)2 it is considered that the nucleophile turns “hard” in the presence of NaBH(HFIP)3 and alcohol. In addition, since the cerium cation works as a [S0810] C2058 Lewis acid, which promotes the electrophilicity of the carbonyl O OTBS group, the 1,2-addition preferentially occurs. Incidentally, an S0810 H aldehyde is not reduced under this method because it forms an CH 3 THF,HFIP[H0424] O acetal, which is inert under these conditions. O OTBS OH O O OH CH3 NaBH4 H CH3OH H 1,4-reduction ● Reductive Amination Reductive amination is a synthetic method that converts O NaBH4 OH aldehydes and ketones into an amino group with an amine and a CeCl3 [C2058] reducing agent. First, carbonyl groups and an amine form imines CH3OH or iminium salts and subsequent nucleophilic attack by a reducing 1,2-reduction agent gives the amine moiety. The Leuckart reaction3) and Eschweiler-Clarke reaction4) are known as classical methods and formic acid [F0513] is used as a reducing agent in these reactions. Recently, sodium cyanoborohydride [S0396] has been frequently ● Silane Reduction used for reductive amination, in what is called the Borch reaction.5) Hydrosilanes are utilized in reduction as a hydride or a hydrogen However, this method has a problem in that S0396 has strong radical source since the hydrogen atom has lower electronegativity toxicity due to the cyano group. Meanwhile, Kikukawa et al. have than silicon. For instance, triethylsilane [T0662] is known as a reported a new method using 2-picoline borane [B3018].6) B3018 reducing agent in the presence of a metal catalyst8) and Lewis is less toxic than S0396 and can be applied in both aqueous and acid9) and can reduce carbonyl groups and hydroxy groups into neat conditions. methylene moieties. T0662 is also used in the dehalogenation10) reaction and in the reduction of olefins.11) Tris(trimethylsilyl)silane (= TTMSS) [T1463] is mainly used as a 12) . BH hydrogen radical source in the dehalogenation reaction. In this NaBH3CN 3 N CH3 manner, hydrosilanes and tin hydrides are currently used [S0396] [B3018] complementarily. Leuckart reaction + - NH2 O NH4 HCOO CH2CH3 Si(CH3)3 1 2 1 2 + R R CH3CH2 Si H (CH3)3Si Si H R R thenH H CH2CH3 Si(CH3)3 Triethylsilane TTMSS Eschweiler-Clarke reaction [T0662] [T1463] CH2O 9) CH3 HCO2H[F0513] NO 2 T0662 NO2 RNH2 RN BF3·OEt2[B0527] CH3 CH2Cl2 O H H Borch reaction S0396 12) or T1463 NaBH(OAc)3[S0394] Cl or 3 4 O R3 R R h B3018 N + HN R1 R2 4 R R1 R2 Please inquire for pricing and availability of listed products to our local sales representatives. 3 Reducing Agents ● Wolff-Kishner Reduction ● Meerwein-Ponndolf-Verley Reduction and Clemensen Reduction In the Meerwein-Ponndolf-Verley (MPV) reduction, ketones and Both Wolff-Kishner reduction13) and Clemensen reduction14) are aldehydes can be reduced to alcohols by the treatment of known as reactions to convert carbonyl groups into methylene aluminum isopropoxide [A0246] in isopropyl alcohol [I0163] groups. The Wolff-Kishner reduction can reduce carbonyl groups solvent with heat.17) This reaction is an equilibrium reaction, so an to methylene moieties in the presence of hydrazine [H0172], excess amount of A0246 is needed to bias the reaction toward the strong base, and alcohol. This reaction conventionally requires desired alcohol. This reaction has an advantage in that it does not strong base and intense heat conditions, but an improved method affect other functional groups. Following the first report, a modified to use a Lewis acid catalyst and a silylhydrazine derivative (Myers method using a catalytic amount of samarium(II) iodide18) [S0494] modification) has been developed,15) which proceeds at room instead of an excess amount of A0246 and asymmetric MPV temperature. reactions19) was reported. Incidentally, the Oppenauer oxidation20) The Clemensen reduction is operated by the treatment of zinc is regarded as an opposite reaction of MPV reduction and it under acidic conditions. Zinc amalgam had been used at first, but proceeds under acetone solvent to oxidize alcohols to carbonyl a non-aqueous modification using zinc powder and hydrogen groups. chloride in organic solvent has been developed16) and is utilized widely since mercury in amalgam is highly harmful. MPV reduction The Wolff-Kishner reduction and Clemensen reduction are Al(OiPr)3 [A0246] O OH operated under basic and acidic conditions, respectively, so the iPrOH, reflux O + 1 2 R R R1 R2 CH CH two reactions can be used complementarily. Al(OiPr)3 [A0246] H 3 3 ketone or acetone, reflux aldehyde Oppenauer oxidation Wolff-Kishner reduction NH2NH2·H2O[H0172] O KOH NNH2 H H SmI2-catalyzed MPV reduction 1 2 R1 R2 R1 R2 or R R DMSO cat. SmI [S0494] O 2 OH ketoneor tBuOK[P1008] iPrOH aldehyde 1 2 tBuOH,rt 1 2 R R R R H Myers modification ketone or aldehyde TBSHN-NHTBS cat.Sc(OTf)3[T1663] O CH2Cl2 H H R1 R2 then R1 R2 DMSO ketoneor tBuOK[P1008] aldehyde ● Staudinger Reaction tBuOH,rt The Staudinger reaction is utilized to convert an azide to an 21) Clemensen reduction amine and can be regarded as a reduction in the sense of the Zn(Hg) addition of a hydrogen atom. When an azide is treated with conc.aq.HCl triphenylphosphine [T0519], an iminophosphorane is formed with O organicsolvent, H H 1 2 the elimination of a nitrogen molecule. The iminophosphorane is R1 R2 or R R Znpowder ketoneor hydrolyzed to give the amine moiety. In contrast, the HClinorganicsolvent aldehyde rt iminophosphorane gives an imine via the aza-Wittig reaction when treated with aldehydes or ketones.22) Ph3P [T0519] H2O R1 N N N 1 1 R N PPh3 R NH2 O R2 H N R2 R1 4 Please inquire for pricing and availability of listed products to our local sales representatives. Reducing Agents ● Reducing Agent to Disconnect Disulfide References Bond Tris(2-carboxyethyl)phosphine hydrochloride [T1656] can reduce 1) Review: J. Málek, M. Černý, Synthesis 1972, 217. a disulfide bond to give two thiols.23) In addition, T1656 can remove 2) Y. Kuroiwa, S. Matsumura, K. Toshima, Synlett 2008, 16, 2523. the oxygen atom on N-oxides and sulfoxides and can be applied to 3) R. Leuckart, Ber. 1885, 18, 2341. the Staudinger reaction.24) In this manner, T1656 shows interesting 4) a) W. Eschweiler, Ber. 1905, 38, 880. effects in the reductions of heteroatoms. b) H. T. Clarke, H. B. Gillespie, S. Z. Weisshaus, J. Am. Chem. Soc. 1933, 55, 4571. 5) a) R. F. Borch, M. D. Bernstein, H. D. Durst, J. Am. Chem. Soc. 1971, 93, 2897. b) R. F. Borch, A. I. Hassid, J. Org. Chem. 1972, 37, 1673. CO2H P . HCl 6) S. Sato, T. Sakamoto, E. Miyazawa, Y. Kikugawa, Tetrahedron 2004, 60, 7899.