i. basic principles i-q. reductionsccc.chem.pitt.edu/wipf/courses//2320_07_files/reductions_i.pdf-...

1 I-Q. Reductions I. Basic Principles The most important practical difference between oxidation and reduction is that the reduction of unsymmetrical ketones generates chiral secondary alcohols. Reduction is treated extensively in most organic text and reference books. More thorough treatises can be found in: - Comprehensive Organic Synthesis (Trost, B. M.; Fleming, I.; Eds.); Pergamon Press, Oxford 1991, volume 8. - Paderes, G. D.; Metivier, P.; Jorgensen, W. L. J. Org. Chem. 1991, 56, 4718. - Sinclair, S.; Jorgensen, W. L. J. Org. Chem. 1994, 59, 762. - Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis.; VCH: New York, 1991. -Reductions in Organic Synthesis; Abdel-Magid, A. F., Ed.; ACS: Washington, DC, 1996. - Daverio, P.; Zanda, M., "Enantioselective reductions by chirally modified alumino- and borohydrides." Tetrahedron: Asymmetry 2001, 12, 2225-2259. Hydrogen/Metal catalysts H 2 , Raney-Ni H 2 , PtO 2 H 2 , Rh H 2 , Pd/C H 2 , Lindlar-Catalyst Hydrides and Mixed Hydrides AlH 3 (LAH+AlCl 3 ) LAH DIBAL-H Li(OMe) 3 AlH (LTMA) Li(O-t-Bu) 3 AlH (LTBA) NaH 2 Al(O(CH 2 ) 2 OMe) 2 (Red-Al, vitride, SMEAH; with CuBr→1,4-reductions) B 2 H 6 ; BH 3 SMe 2 , BH 3 •THF, BH 3 • NH 3 LiBH 4 (LBH) LiEt 3 BH (super hydride) K(i- PrO) 3 BH (KIPBH) Li, Na, K, LS-Selectride Dr. P. Wipf Chem 2320 3/20/2007

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I-Q. Reductions

I. Basic Principles

The most important practical difference between oxidation and reduction is thatthe reduction of unsymmetrical ketones generates chiral secondary alcohols.Reduction is treated extensively in most organic text and reference books. Morethorough treatises can be found in:

- Comprehensive Organic Synthesis (Trost, B. M.; Fleming, I.; Eds.); Pergamon Press, Oxford1991, volume 8.- Paderes, G. D.; Metivier, P.; Jorgensen, W. L. J. Org. Chem. 1991, 56, 4718.- Sinclair, S.; Jorgensen, W. L. J. Org. Chem. 1994, 59, 762.- Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis.;VCH: New York, 1991.-Reductions in Organic Synthesis; Abdel-Magid, A. F., Ed.; ACS: Washington, DC, 1996.- Daverio, P.; Zanda, M., "Enantioselective reductions by chirally modified alumino- andborohydrides." Tetrahedron: Asymmetry 2001, 12, 2225-2259.

Hydrogen/Metal catalystsH2, Raney-NiH2, PtO2

H2, RhH2, Pd/CH2, Lindlar-Catalyst

Hydrides and Mixed HydridesAlH3 (LAH+AlCl3)LAHDIBAL-HLi(OMe)3AlH (LTMA)Li(O-t-Bu)3AlH (LTBA)NaH2Al(O(CH2)2OMe)2 (Red-Al, vitride, SMEAH; with CuBr→1,4-reductions)B2H6; BH3SMe2, BH3•THF, BH3 • NH3

LiBH4 (LBH)LiEt3BH (super hydride)K(i- PrO)3BH (KIPBH)Li, Na, K, LS-Selectride

Dr. P. Wipf Chem 2320 3/20/2007

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Hydrides and Mixed Hydrides (cont.)NaBH4 (SBH)NaCNBH3 (stable at pH 3-4)NaBH4, CeCl3 (Luche reagent, 1,2-reduction of enones)NaBH(OAc)3Zn(BH4)2Sia2BHBu3SnH

Dissolving Metal ReagentsNa/NH3/ROH (Birch)Li/NH3/ROHLi/NH3Zn/HOAcZn/HCl (Clemmensen)Na/HgZn/Hg

Miscellaneous ReductantsNH2NH2/KOHMeerwein-Ponndorf-Verley, i-PrOH, Al(i-Pro)3Diimide (H-N=N-H, prepared in situ from KOCON=NCOOK; adds to nonpolarized

double bonds)Et3SiH/BF3

The reduction of hindered halides with LAH proceeds predominantly by a single electrontransfer pathway (Ashby, E. C.; Welder, C. O. J. Org. Chem. 1997, 62, 3542).

Dr. P. Wipf Chem 2320 3/20/2007

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Diastereoselectivity of Reductions

Dr. P. Wipf Chem 2320 3/20/2007

Page 4: I. Basic Principles I-Q. Reductionsccc.chem.pitt.edu/wipf/Courses//2320_07_files/Reductions_I.pdf- Daverio, P.; Zanda, M., "Enantioselective reductions by chirally modified alumino-

Acid to Alcohol [LAH]

Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195.

Acid to Alcohol [BH3]

Dymock, B. W.; Kocienski, P. J.; Pons, J.-M., "A synthesis of the hypocholesterolemic agent1233A via asymmetric [2+2] cycloaddition." Synthesis 1998, 1655.

Dr. P. Wipf Chem 2320 3/20/2007

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Ester to Alcohol [LiBH4]

Hamada, Y.; Shibata, M.; Sugiura, T.; Kato, S.; Shioiri, T. J. Org. Chem. 1987, 52,1252.

Wipf, P.; Xu, W. J. Org.Chem. 1996, 61, 6556.

Lactone to Lactol

Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc.1969, 91, 5675.

Wipf, P.; Kim, Y.; Fritch, P. C. J. Org. Chem. 1993, 58, 7195.

Dr. P. Wipf Chem 2320 3/20/2007

Page 6: I. Basic Principles I-Q. Reductionsccc.chem.pitt.edu/wipf/Courses//2320_07_files/Reductions_I.pdf- Daverio, P.; Zanda, M., "Enantioselective reductions by chirally modified alumino-

Amide to Amine

Armstrong, J. D.; Keller, J. L.; Lynch, J.; Liu, T.; Hartner, F. W.; Ohtake, N.; Ikada,S.; Imai, Y.; Okamoto, O.; Ushijima, R.; Nakagawa, S.; Volante, R. P. TetrahedronLett. 1997, 38, 3203.

Godjoian, G.; Singaram, B. Tetrahedron Lett. 1997, 38, 1717.

Tertiary amides require two equivalents of 9-BBN to give tertiary amines. Sterically morehindered dialkylboranes react in a 1:1 stoichiometry to give aldehydes.

Amide to Amine [Raney-Nickel]

Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106.

Tian, X.; Hudlicky, T.; Königsberger, K. J. Am. Chem. Soc. 1995, 117, 3643.

Amide to Aldehyde

Dr. P. Wipf Chem 2320 3/20/2007

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