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

NaAlH(O-t-Bu)3 – Aldehyde Alcohol Alcohol Amine – R OH R H

R OR' R H
(slow) (slow)
ester aldehyde alcohol alkane
AlH3 – Alcohol Alcohol Alcohol Amine Alcohol
Diisobutylaluminum Hydride Sodium Borohydride
NaBH4 Amine – Alcohol – – – (DIBAL) Luche Reduction Barton Deoxygenation
(NaBH4, CeCl3)
Lithium Triethoxyaluminohydride
** Reduction of Alkyl Tosylates
NaCNBH3 Amine – Alcohol – – – (LTEAH) Ionic Hydrogenation
(slow) (Et3SiH, TFA) Diazene-Mediated Deoxygenation
Reduction of Acid Chlorides,
Amides, and Nitriles Samarium Iodide
Na(AcO)3BH Amine – Alcohol Alcohol Amine –
(slow) (slow) (slow)

B2H6 – – Alcohol Alcohol Amine Alcohol O 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

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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
addition of n mL of water, n mL of 15% NaOH solution, and 3n mL of water provides a N OEt N
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.

• Examples H H
O O HO O
O CH3 LiAlH4
O HO
N CH3 N ether
H3C H3C
CH3 89-95% CH3
CH3O LiAlH4 CH3O
H H
O THF O
H H
O 70% OH
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
CH3O2C HOCH2 OCH3 LiAlH4 OH
CH3O2C O C(CH3)3 HOCH2 OH OCH3 OH
THF, 0 ºC
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

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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 (B2H6) is available.
order: ether > THF > 2-propanol. This is attributed to the availability of the lithium counterion
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 O
1. BH3•THF, 0 °C
O O
H CH3 2. dihydropyran, THF H CH3
F TsOH, 0 °C
O2N Br CO2H Br CH2OTHP
O CO2CH3
H LiBH4, CH3OH 86%
N OTBS
N THF, Et2O, 0 °C Corey, E. J.; Sachdev, H. S. J. Org. Chem. 1975, 40, 579-581.
H
O
H3C CH3
SO2CH3 SO2CH3
83%
O HO
F
HO BH3•THF, 0 °C
O2N OH
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 H 3C OH
CO2H 15 ºC, 100% CO2H NaBH4, BF3•Et2O
450 g THF, 15 °C
HN SO2 HN SO2
95%

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

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Myers Reduction Chem 115
O O

R OR' R H O OMOM
H
Ester Aldehyde H3C N O
TMS
O
Diisobutylaluminum Hydride (DIBAL): i-Bu2AlH MOMO CH3
H3C CH3 DIBAL, THF
OMOM
• At low temperatures, DIBAL reduces esters to the corresponding aldehydes, and lactones to CH3 –100 ! –78 °C
O OAc OAc O O
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
CO2CH3 CHO H3C N O
DIBAL, toluene TMS
O O
N –78 °C N O
H3C Boc H3C Boc MOMO CH3
O OMOM OMOM H3C CH3
CH3 CH3
H CH3
76% H3C N O O OAc OAc O O
TMS
Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18-28. O +
MOMO CH3
OMOM H3C CH3 CH3 CH3 CH3 CH3 CHO
CH3 O O
O OAc OAc O O
O 1. DIBAL, CH2Cl2, –78 °C OH
F F
O 2. CH3OH, –78 °C O 16%
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 1. DIBAL, ether O
Cl O Cl O
DIBAL, toluene –78 °C
CH3 NC OHC
TBSO N CH2Cl2, –78 °C TBSO H
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

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Myers Reduction Chem 115
Reduction of Acid Chlorides
Lithium Triethoxyaluminohydride (LTEAH): Li(EtO)3AlH

• LTEAH selectively reduces aromatic and aliphatic nitriles to the corresponding aldehydes • The Rosemund reduction is a classic method for the preparation of aldehydes from carboxylic
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:
Et2O O OH 1. (COCl)2, DMF O H
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 N
cat. thioanisole
Brown, H. C.; Garg, C. P. J. Am. Chem. Soc. 1964, 86, 1085-1089. (7.89 kg) Cbz Cbz
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
2. H2, Pd/BaSO4
H
H3C H3C
80% CH3 CH3
64%
CON(CH3)2 CHO
Johnson, R. L. J. Med. Chem. 1982, 25, 605-610.
1. LTEAH, ether, 0 °C
O O
2. H+ H H
COCl H2, Pd/BaSO4 O CHO
NO2 NO2 O
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 CH3 CH3 CH3
STBA, diglyme
COCl CHO
THF, –78 °C
>99% de 77% (94% ee)

diglyme = (CH3OCH2CH2)2O
Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am.
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 Selective Amide Reduction:
R'
R' R N
R N • Amides can be activated by Tf2O to form a highly electrophilic iminium intermediate that can be
R'
R' reduced by mild reductants known as Hantzsch esters:
Amide Amine

Lithium Aluminum Hydride (LAH): LiAlH4 O 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 86%
H H O
Ph N LiAlH4 Ph N
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 Et3SiH, CH2Cl2 96%
H H
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
Et3SiH, CH2Cl2 NH
opened products:
2. 1, CH2Cl2
H3C CH3 AlH3 H3C CH3
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

CH3 O CH3 TsNHNH2, AcOH
Aldehyde or Ketone Alkane
CH2Cl2, 23 ºC
BocO OPMB
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, CHCl3, 65 ºC 0 # 23 ºC
• Even many hindered carbonyl groups can be readily reduced to the corresponding hydrocarbon.

• 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–
been suggested. Direct hydride attack by sodium cyanoborohydride on an iminium ion is 6351.
proposed in most cases.
Ts Ts Ts H OH OH
NH + NH NH N CH3 CH3
N H+ HN NaBH3CN HN N H H NNHTs

R R' R R' R R' –TsH R R' –N2 R R' CH3 CH3

H ZnCl2, NaBH3CN H
• However, reduction of an azohydrazine is proposed when inductive effects and/or CH3OH, 90 °C
conformational constraints favor tautomerization of the hydrazone to an azohydrazine. H CH H CH
3 3
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, H2O, EtOH O
N O
H N H 4. CH3ONa, CH3OH
Ot-Bu 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

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 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)CH3 N(CHO)CH3
• The two principal side reactions associated with the Wolff–Kishner reduction are azine formation
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 NiCl2•H2O, NaBH4 BnO
diethylene glycol, Na metal
N THF, H2O, –20 ºC N
H2NNH2, 210 °C O Bn 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 Zn(Hg), HCl Cl
TBS H
O N N
, cat. Sc(OTf)3; CH3 56%
H TBS Cl
CH3 Cl
KOt-Bu, HOt-Bu, DMSO CH3O
CH3O Marchand, A. P.; Weimer, W. R., Jr. J. Org. Chem. 1969, 34, 1109-1112.
23 ºC, 24 h 93%
• 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
, cat. Sc(OTf)3; CH3O Br Br
CH3O H TBS
Zn, Ac2O, TFA
KOt-Bu, HOt-Bu, DMSO N Cl N Cl
CH3O
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
O Luche Reduction – NaBH4, CeCl3
OH
• 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%
NaBH4, CeCl3 99% trace
Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567-607.

• Examples
Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
I I
O HO
• Examples
CH3 NaBH4, CH3OH CH3
O 0 °C O
OPiv OPiv
~100%, dr = 1 : 1 N N
N NaBH4, CeCl3 N
H H H 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 NaBH4 O
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. NaBH4,
Diederich, A. M.; Ryckman, D. M.; Tetrahedron Lett. 1993, 34, 6169–6172. CH3 CH3
H CeCl3•7H2O H
O TIPSO
OBOM OBOM
CH3OH, 0 °C
O O
2. TIPSCl, Im
CH3O O CH3O O
1. NaBH4, CH3OH
NEt2 2. 6 M HCl 87%
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, H2O
• Ionic hydrogenation has been used to prepare ethers from the corresponding lactols.
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
H3C H3C CH3 CH3
O OH O H H
F3C F3C H O SmI2 O
Et3SiH, CF3CO2H H
PMBO i-PrOH, THF PMBO
CH2Cl2, 23 ºC O O
H H
88% CH3 O 98% CH3 OH
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 H3C CH3 1. 1,1'-thiocarbonyl-diimidazole, H3C
propagates the chain. H3C
DMAP, CH2Cl2, reflux i-Pr H
OH CH3 +
2. AIBN, Bu3SnH, toluene, 70 °C H i-Pr
H H H
Sn(n-Bu)3 Sn(n-Bu)3
S S S
(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
HO O HO B(CH3)3, H2O H CH3
AIBN, Bu3SnH O O O CH3
H OH O
H O Im H H CH3 benzene, 23 ºC
xylenes, 140 °C H3C
HO CO2H O O O O CH3
H3C O
O S O H3C
quinic acid 40% H3C O 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 !- R H –78 °C R –78 " 23 °C R –N2 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 SO2Ar THF, –78 °C
OH 2. CH3 CH3 CH3
N CH3 CH3 CH3
N H Li Ph
CH3
Ph
CH3O CH3O Ph H Ph
PPh3, DEAD, NBSH 3. AcOH, CF3CH2OH, CH3
CH3 CH3 CH3 –78 " 23 °C
N THF, –30 °C N
94%
O Cl O Cl
87%

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.
O CH3 PPh3, DEAD, NBSH, O CH3 OMOM
THF, –30 °C;
OH CH3 CH3
O2; DMS
CH3O OCH3 C4H9
I
OH CH3O OCH3
84% C4H9 NN(TBS)Ts

CH3O OCH3 3. HCl, CH3OH, THF CH3O OCH3

• Monoalkyl diazenes will undergo concerted sigmatropic elimination of dinitrogen in preference to
radical decomposition where this is possible. HO
C4H9 C4H9
CH2OH 73% CH3

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
CH3 HO OH OH
O H ArO2S NBSH, NMM
OH N O H3C CO2CH3 H3C CO2CH3
O ArSO2 N CH3 N O O
O O NH2
Ph (IPNBSH) 66%
O Ph
H3C
H3C
CH3 PPh3, DEAD 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
H H NCO2Et H H NCO2Et
NH H H
O 60%
O HO
O N
O H O
Ph O
H3C Ph
H3C Magnus, P.; Ghavimi, B.; Coe, J. Bioorg. Med. Chem. Lett. 2013, 23, 4870-4874.
CH3 71%
CH3
CH3 dr = 3 : 1
CH3
OBn OBn
Ar = 2-O2NC6H4 H3C O H3C O
1. NaBH4, CeCl3
O CH3 CH3
Movassaghi, M.; Piizzi, G.; Siegel, D.; Piersanti, G. Angew. Chem. Int. Ed. 2006, 45, 5859-5863. O O
O 2. Ph3P , DEAD O
Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838–1841.
p-NO2C6H4 NBSH, NMM p-NO2C6H4
O O
• 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, H2N SO2Ar
HO H N 23 °C
Ph3P, DEAD H
BnO Et BnO Et 0.5 h
–30 °C, 1 h H3C CH3 H3C CH3
N Ph3P , DEAD N
H H
O toluene; NBSH O
N N
HO 74%
H N O OBn O OBn
N TBSO H O TBSO H O
H BnO
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 ArSO2NHNH2, H2N N H • Among hydride sources, lithium triethylborohydride (Super Hydride, LiEt3BH) has been shown to
23 °C rapidly reduce alkyl tosylates efficiently, even those derived from hindered alcohols.
R1 Ph3P, DEAD R1
R2 –15 °C, 1-2 h R2 1-8 h
OTs OH

N N H H + +
H R2 •
R1 R1 Reductant
–N2
R2 LAH 54% 25% 19%
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 CH3 CH2OTs CH3 CH3
CH3 CH3
Ph3P, DEAD • H2O2, NaOH (aq)
EtO BnO BnO
CH3 EtO CH3OH
–15 °C CH3
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
NBSH H H3C HO O
H3C HO O
Br O Br LiEt3BH, toluene
Ph3P, DEAD H3C H3C
• NTs 90 °C
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
• The reduction of chlorides usually requires more forcing reaction conditions and alkyl fluorides I Bz O
I H3C O
are practically unreactive. O I
BzO O
O O O
• The reactivity of alkyl halides parallels the thermodynamic stability of the radical produced and O
I Bz
follows the order: tertiary > secondary > primary. H 3C 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 CH3 H3C
O H3C
CH3O HO O
HO Bu3SnH, AIBN, THF O O
O OTIPS HO
H H PhBr, 80 °C H 3C H3C O
CH3 O H3C
TIPSO O HO O
H O O O
70% HO
OPMB H3C O
OTIPS
Cl OPMB
CH3 OH
CH3O
HO
O OTIPS
H H
CH3 Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 2000, 122, 6124-6125.
TIPSO O
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
H3C H3C CH3
Br
O O Bu3SnH, AIBN
OAc O OH O H
H H benzene, 80 °C
AcO HO H3C H H3C H
CH3 CH3
5 5
H Br H
61% (±)-capnellene
O O
1. Bu3SnH, AIBN, PhCH3
H H
H 2. CH3OH, CH3COCl H
O O
H 64% H parviflorin Curran, D. E.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991-4994.
H3C H3C
OAc 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 SO2Ph
H3C 3 2. S
Acid Alkane (–1C) O
O N O–Na+
O H
Barton Decarboxylation
O
• O-Esters of thiohydroxamic acids are reduced in a radical chain reaction by tin hydride reagents. 3. t-BuSH, h!
HO2C
CH3 86%
• These are typically prepared by the reaction of commercial N-hydroxypyridine-2-thione with H
O
activated carboxylic esters.
OPiv CH3 H CO
H3C 3 SO2Ph
O
O O
N RCO2 + R + (n-Bu)3SnH RH + (n-Bu)3Sn O H
R O N –CO2 O
S
+ SSn(n-Bu)3 CH3
H
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:

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

1. (COCl)2, DMF
H H
O 2. S O
OAc OAc
O OAc O OAc O
H N OH H
O OAc , 89% O OAc
H H
CO2H
O 3. t-BuSH, THF, h! O
OAc 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. Cl2C S
OH
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
CH3O O H3C
• Original report: OCH3
CO2 O
O OCH P(OCH3)3 H3C
S + 3 O N
S N
(H3CO)3P S S O Et
O O Et 110 ºC
HO OH N N O O +
N N P(OEt)3 O
(solvent) O
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
and the subsequent decomposition to the desired olefin. S P(OCH3)3 O
O O
O O
Ph 120 ºC CH3
CH3
CO2 O
S H3C N P N CH3 + CH3O O CH3 CH3O CH3
Cl2C S Ph S
HO OH O O R1 R4 85%
DMAP (3 equiv, neat)
+ H3C N P N CH3
R1 R4 R1 R4
R2 R3 CH2Cl2 R2 R3 25–40 ºC R2 R3
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 PPh3, I2 H3C
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
CH3 CH3 OH
O O O O
CH3 CH3
CH3 (3 equiv, neat) 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 HC(OEt)3 O
HO OH CH3CO2H HO O 200 ºC HO
H3C OH H3C OH

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
THF, reflux H3C CH3 H3C CH3 H3C CH3
benzene, 23 ºC, 1h

>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

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