Myers Birch Reduction Chem 115

Reviews:
Additivity of Substituent Effects:
Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334.
H3C OCH3 H3C OCH3
Mander, L. N. In Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I., Ed.; Na, NH3, MeOH
Pergamon: Oxford, 1991, Vol. 8, pp. 489-521.
44%
Hook, J. M.; Mander, L. N. Natural Prod. Rep. 1986, 3, 35-85.
Birch, A. J. J. Chem. Soc. 1944, 430-436.
Propects for Stereocontrol in the Reduction of Aromatic Compounds: Donohoe, T. J.; Garg, R.;
Stevenson, C. A. Tetrahedron: Asymmetry 1996, 7, 317-344. H3C CO2H 1. Na, NH3, MeOH H3C CO2H

2. NH4Cl
Mechanism:
94%
Electron-Donor Substituents (X):
Chapman, O. L.; Fitton, P. J. Am. Chem. Soc. 1963, 85, 41-47.
X X X X
H H Conditions:
M, NH3 ROH M, NH3
H H
– M –
M • Metals: Li, K, Na, occasionally Ca or Mg.
(rate-limiting
step) • Co-solvents: diethyl ether, THF, glymes.
(X = R, OR, NR2) meta
ortho protonation ROH • Proton sources (where appropriate): t-BuOH and EtOH are most common, also MeOH, NH4Cl,
protonation
and water.
• Reductions of alkyl benzenes and aryl ethers require a
Solubility in NH3 Normal reduction
stronger acid than ammonia; alcohols are typically employed. X
H Metal at –33 °C potential at –50 °C
H (mol Metal/mol NH3) in NH3 (V)
• Regioselectivity of protonation steps in the Birch reduction:
Zimmerman, H. E.; Wang, P. A. J. Am. Chem. Soc. 1993, H Li 0.26 –2.99
115, 2205-2216. H
Na 0.18 –2.59
• Protonation of cyclohexadienyl anions is kinetically controlled and occurs at the central carbon. K 0.21 –2.73

Electron-Withdrawing Substituents (W): From: Briner, K. In Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A., Ed.;
John Wiley and Sons: New York, 1995, Vol. 5, pp. 3003-3007.
W • Reduction in low molecular weight amines (Benkeser reduction):
ROH Na (excess), EtOH, NH3
M, NH3
W W W W H(R)
M, NH3 (Birch reduction)
H H NH4Cl
– M – M
Li, EtNH2
W or RX +
H H H H (Benkeser Reduction)
(W = CO2H, CO2R, ROH or
COR, CONR2, CN, Ar) M, NH3 2 – 2M NH3 • Reduction in low molecular weight amines (in the absence of alcohol additives) furnishes
more extensively reduced products than are obtained under Birch conditions (M, NH3, ROH).

• Aromatic carboxylic acids and carboxylates are readily reduced with Li/NH3 in the absence A Comparison of Methods Using Lithium/Amine and Birch Reduction Systems: Kaiser, E. M.
of alcohol additives. Synthesis 1972, 391-415.

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1
 Asymmetric Birch Reduction:
Reductive alkylation:
Reviews: Schultz, A. G. Acc. Chem. Res. 1990, 23, 207-213; Schultz, A. G. Chem. Commun.
• Enolates derived from 1,4-dihydrobenzoic acids are selectively alkylated at the !-carbon.
1999, 1263–1271.
CO2H HO2C CH3
1. KNH2, NH3 RX
O O
OM R
2. CH3I N M, NH3, THF RX N
H H
91% N
t-BuOH (1 equiv) –78 °C
O H O
Nelson, N. A.; Fassnacht, J. H.; Piper, J. U. J. Am. Chem. Soc. 1961, 83, 206-213. (M = Li, Na, or K) O
See also: Birch, A. J. J. Chem. Soc. 1950, 1551-1556.
(proposed convex attack)
• Loewenthal and co-workers first demonstrated single step reductive alkylation of
RX yield (%) de (%)
aromatic compounds:
MeI 67 60
CO2H HO2C CH3
1. Na, NH3 EtI 82 >98 opposite
CH2=CH2CH2Br 75 >96 facial
2. CH3I selectivity
PhCH2Br 73 >96
69% CH2=CH2CH2CH2Br 89 96
Bachi, M. D.; Epstein, J. W.; Herzberg-Minzly, Y.; Loewenthal, H. J. E. J. Org. Chem. 1969, ClCH2CH2CH2Br 91 (n.d.)
34, 126-135.

• Reductive alkylations of aromatic esters, amides, ketones, and nitriles typically are conducted H
OCH3 O
in the presence of one equivalent of an alcohol: O
N R
N M, NH3, THF RX N
O CH3 O
OCH3 CH3O –78 °C
1. K, NH3 CO2t-Bu H t-BuOH (1 equiv) M O H
CO2t-Bu O
t-BuOH (1 equiv) TFA CH3 OCH3 (M = Li, Na, or K) O OCH3
CH(CH3)2 CH3 CH3
2. i-PrI CH3
94% RX 70-88% yield,
>96% de
Hook, J. M.; Mander, L. N.; Woolias, M. Tetrahedron Lett. 1982, 23, 1095-1098. RX = MeI, EtI, PhCH2Br,

Br , Cl Br

CN 1. Li, NH3, THF CN

t-BuOH (1 equiv)
(CH2)3Cl • Transition state may be complex, viz., enolate aggregation and nitrogen pyramidalization.
OCH3 2. BrCH CH CH Cl
2 2 2 OCH3
85% • Schultz proposes that Birch reduction results in kinetically controlled formation of a dimeric
enolate aggregate wherein the metal is chelated by the aryl ether; the side chain of the chiral
Schultz, A. G.; Macielag, M. J. Org. Chem. 1986, 51, 4983-4987.
auxiliary is proposed to block the "-face of the enolate.
Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am. Chem. Soc.
1988, 110, 7828-7841.

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2
• 1,6-Dialkyl-1,4-cyclohexadienes are accessible by asymmetric Birch alkylation:
OCH3 OCH3
H3C O H3C O
CH3 PDC, t-BuOOH CH3 H2 (1 atm), CH2Cl2
OCH3 OCH3 N N
O O
Celite, PhH [Ir(cod)py(PCy3)]PF6
1. s-BuLi, THF, –78 °C O
N N
98% 98%
2. RX, –78 ! 25 °C OTBS OTBS
CH3
53–77% R
OCH3
H3C O
CH3I OCH3 CH3
OCH3 N
1. K (2.2 equiv), NH3,
OK H3C O
THF, t-BuOH (1 equiv) N N O

2. MeI, –78 °C OTBS

R R
Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614.

• Heterogenous hydrogenation with rhodium on alumina occurs anti to the bulky amide,
R yield (%) de (%) presumably due to steric factors.
H 90 > 98 OCH3
H3C O OCH3
H3C O
Me 66 93 CH3
N H2, Rh on Al2O3 CH3
Et 79 90 N
CH2CH=CH2 76 93 O EtOAc, 55 psi O
CH2CH2CH=CH2 69 90 OTBS 89% OTBS
CH2Ph 62 95
Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614.
CH2CH2Ph 77 93
• Dihydroxylation of 3-cyclohexen-1-ones obtained by Schultz's asymmetric Birch alkylation occurs
CH2OCH2CH2SiMe3 71 94 exclusively anti to the amido substituent:
CH2CH2OTBS 88 96
OCH3 OCH3 OCH3
HO
CH2CH2OMe 79 95 R' O R' O HO R' O
R H3O+ R OsO4, NMO
N N R N

OCH3 O H2O, acetone O

Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.
R R' yield (%)
Transformations of asymmetric Birch alkylation products:
H Me 91
• Amide-directed hydrogenation with Crabtree's catalyst:
H CH2Ph 86
OCH3 OCH3
H3C O H3C O H (CH2)3N3 88
N H2 (1 atm), CH2Cl2 N H (CH2)3Cl 94

[Ir(cod)py(PCy3)]PF6 CH2Ph Et 73
H
Ph Ph Me Et 76
89%
Schultz, A. G.; Dai, M.; Tham, F. S.; Zhang, X. Tetrahedron Lett. 1998, 39, 6663–6666.
Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.

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3
• Regio- and stereo-selective epoxidation has been demonstrated: • Iodolactonization:
OCH3 OCH3 O
OMOM O OMOM R2 O R2 O
H3 C O CH3 H3C O R1 R1 O
N 6 N aq. HCl N I2, THF, H2O
O CH3 N R2
N R1
OCH3 MeOH, 25 °C 75–98%
acetone O I O
CH3 CH3
68% O 89–100%

>13 : 1 diastereoselectivity Schultz, A. G.; Dai, M.; Khim, S.-K.; Pettus, L.; Thakkar, K. Tetrahedron Lett. 1998, 39, 4203–4206.

Schultz, A. G.; Harrington, R. E.; Tham, F. S. Tetrahedron Lett. 1992, 33, 6097–6100. • Addition of alkyllithium reagents:

Methods of cleavage of Schultz's chiral auxiliaries: OCH3

O O
• Acid catalyzed cleavage of the alkylation products requires harsh conditions: H3C H3C
N MeLi, THF CH3
OCH3 0 ! 23 °C
H3C O H3C O CH3 CH3
H H
N 6 N aq. HCl OH 58%

reflux, 7 h Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am. Chem. Soc.
Ph Ph 1988, 110, 7828-7841.
95%
Asymmetric synthesis of amino-substituted cyclohexenes:
Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.
R2 O R2 KO
• Olefinic substrates undergo protiolactonization under the conditions of acidic hydrolysis: R1 N R1 N
K (4.4 equiv), NH3
O
R O H H
N THF, t-BuOH (2 equiv) N
N O O H OK
18 N aq. H2SO4 H
H H R NH
N 100 °C 2
H O NH4Cl
H RX
R = Me, Et, Bn
62–82%
R2 O R2 O
Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502. H R
R1 N R1 N
• Lactonization can be effectively employed for amide cleavage:

OCH3 H H
N N
H3C O H3C O H O H O
1. BF3•OEt2 H H
N O
R1 RX yield (%) de (%)
2. H2O
H H H H MeI 54 70
SiMe3 82%
O H H EtI 68 82
H H NH4Cl 73 not reported
Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.
H Me MeI 53 > 88
OCH3 O
Me H NH4Cl 84 one diastereomer
H3C O H3C H3C O OCH3
CH3 O CH3 O Me H MeI 78 52
N m-CPBA NaOMe, MeOH;
N
O Me H EtI 87 78
O H+ O
82% Me H CH2=CHCH2Br 68 > 95 : 5
O 100%
OTBS OTBS CH3 Me H BnBr 78 > 95 : 5

Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614. Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502.
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4
Asymmetric Birch Reduction of heterocycles: Chiral substrates:

O 1. Li, NH3, THF O

t-BuOH (1 equiv) R
CH3 CH3
Ph CH3 1. Li, NH3, THF, –78 °C N –78 °C N
(CH3OCH2CH2)2NH R
O CH3 OR' CH3 2. RX CH3
N CH3 N
2. Isoprene >90% de
Boc O 3. RX Boc O
R = CH3 72%
91-96% (R' = (–)-8-phenylmenthol) R = CH2CH=CH2 66%
R = CH2Ph 68%
R yield(%) ee(%)
1. TFA Schultz, A. G.; Kirinich, S. J.; Rahm, R. Tetrahedron Lett. 1995, 36, 4551-4554.
R Me 79 78
N CO2H Et 71 86 H H
2. NaOH
3. (Boc)2O Boc i-Bu 70 90 1. Li, NH3, THF
CH2Ph 67 90
CH3O 2. CH3I CH3O
HO2C CO2H 51% HO2C CH3 CO2H
• Addition of the chelating amine (CH3OCH2CH2)2NH was found to increase yields; the anion derived
from this amine is less basic and less nucleophilic than LiNH2, suppressing byproduct formation. House, H. O.; Strickland, R. C.; Zaiko, E. J. J. Org. Chem. 1976, 41, 2401-2408.

Donohoe, T. J.; Guyo, P. M.; Helliwell, M. Tetrahedron Lett. 1999, 40, 435-438.

Dissolving metal reductions of conjugated alkenes:

CH3
OCH3 OCH3 • Styrenes, conjugated dienes, and enones are more readily reduced under dissolving metal
CH3 Na, NH3
OM CH3
OCH3 conditions than are aromatics; reduction occurs at low temperature without alcohol additives.
–78 °C O RX
N N
N –78 °C O
O R O
O 62-88% H3CO
OCH3 OCH3
RX O O O O
H3C H3C
(proposed TS geometry) K, NH3
THF, –70 °C H
H 62% H H
R yield(%) ee(%) H3CO H3CO
CH3
6 N HCl Me 86 >94
CO2H
100 °C Et 74 >94 Ananchenko, S. N.; Limanov, V. Y.; Leonov, V. N.; Rzheznikov, V. N.; Torgov, I. V.
O R
i-Bu 68 >94 Tetrahedron 1962, 18, 1355-1367.

• Trans-fused products are favored, carbon pyramidalization is proposed in the transition state.
Donohoe, T. J.; Helliwell, M.; Stevenson, C. A.Tetrahedron Lett. 1998, 39, 3071-3074.

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5
Stereochemical and/or regiochemical control by intramolecular protonation: Transformations of Birch Reduction products:

• Synthesis of !," or ",#-unsaturated cyclohexanones

H3C CH3 H3C CH3
H3C OH H3C OH H3C OH
H
H3C H3C H H H H
CH2OH CH2OH Li, NH3 aq HCl
Li, NH3
H H H H H H
H H CH3 H H CH3 EtOH
THF, –78 °C MeO MeO 77%
TBSO TBSO 90% O
H3C CH3 93% H3C CH3
aq oxalic acid 83%
• It is proposed that the stereochemical outcome is the result of intramolecular protonation
H3C OH
of the radical anion.
Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874. H

H H
O
H3C O H3C O
O O
H CH3 Nelson, N. A.; Wilds, A. L. J. Am. Chem. Soc. 1953, 75, 5366-5369.
! " CH3 Na, NH3,
CH2OH CH2OH
H H H
THF, –40 °C H CO • Reduction of aryl silyl ethers and synthesis of ",#-unsaturated cyclohexanones:
H3CO 3

100%
Li, NH3, THF TBAF
whereas:
H3C O H3C OTBS t-BuOH, –33 °C H3C OTBS H3C O
H3C O 96%
O
O H CH3
! CH3 Na, NH3, 92%
" H
H CH2OH Fuchs, P. L.; Donaldson, R. E. J. Org. Chem. 1977, 42, 2032-2034.
CH2OH H
THF, –40 °C
H3CO
H3CO
• Ozonolysis of Birch reduction products:
71%
• Initial intramolecular protonation at the "-position is proposed. OH Li, NH3, i-PrOH OH O3, CH2Cl2, MeOH,
Lin, Z.; Chen, J.; Valenta, Z. Tetrahedron Lett. 1997, 38, 3863-3866. CH3 CH3
H3CO –78 °C, 4 hr H3CO py, –78 °C; Me2S
OTIPS OTIPS 56% (two steps)
R Li, NH3, THF R H HO
H H Li, NH3, THF O O OH
t-BuOH t-BuOH H H
CH3
H3CO
(t1/2 ca. 10 h) Rapid OTIPS

R = H or R = OMe R = OH Evans, D. A.; Gauchet-Prunet, J. A.; Carreira, E. M.; Charette, A. B. J. Org. Chem. 1991, 56, 741-
750.
Cotsaris, E.; Paddon-Row, M. N. J. Chem. Soc., Chem. Commun. 1982, 1206-1208.

Kent Barbay

6
 Birch Reduction – Application in Synthesis:
• Reductive alkylation of aromatics without electron-withdrawing groups is unsuccessful.
(±)-Gibberellic Acid:
• Directed metalation of Birch products is possible:
CH3O
CH3 CH3O
Li, NH3, THF,–33 °C; PPA

HO2C OCH3 CH3O OCH3

CH3 CH3 1. n-BuLi, HMPA CO H
CO2CH3 2
Birch –70 °C I
H3CO
Reduction 2. RBr CO2CH3
O O 3. H+
NEt2 NEt2 O 88% H
H t-BuOK, THF;
K, NH3, –78 °C;
Amupitan, J.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1978, 852-853. OMOM
CH3O O
Bishop, P. M.; Pearson, J. R.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1983, 123-124. CH3O O CH3I, –33 °C
CH3O2C CO2H
CO2CH3 O 84%
H
• Diels-Alder cycloaddition by isomerization of 1,3-dienes in situ: O H

Cl Cl OMOM CO
CH3O OH
O HO
OCH3 OCH3 CN CH3O2C CH3 CO2H H
OCH3 O H3C COOH
O O O
CN
(±)-Gibberellic Acid
0.1 mole %
80–90 °C Hook, J. M.; Mander, L. N.; Urech, R. J. Org. Chem. 1984, 49, 3250-3260.
75%
(+)-Lycorine:
• Isomerization is proposed to occur through a charge-transfer complex.
Birch, A. J.; Dastur, K. P. Tetrahedron Lett. 1972, 41,4195-4196. OH
OCH3 K, NH , t-BuOH, OCH3 1. DEAD, PPh3,
O 3 O
–78 °C; (PhO)2P(O)N3
• Silyl substituents can be used to modify the regiochemistry of Birch reduction: N N
BrCH2CH2OAc 2. HCl, MeOH
CH3 CH3 CH3 OCH3 –78 " 25 °C; OCH3 3. I2, THF, H2O
KOH, MeOH
M, NH3 TBAF 96%, single diastereomer

O I O I
SiMe3 SiMe3 80% (two steps)
O 1. Ph3P Br O 1. BnOH, THF, n-BuLi
Rabideau, P. W.; Karrick, G. L. Tetrahedron Lett. 1987, 28, 2481-2484. O
• In the absence of competing factors, allylic silanes are generally produced from Birch reduction O 2. ArCOCl, Et3N N 2. AIBN, Bu3SnH
O
of aryl silanes; this is attributed to stabilization of negative charge at the !-carbon by silicon. N3
≥ 99% ee O
But:
CH3 CH3 O OH
Li, NH3
HO
H CO2Bn H
O O
EtOH, –70 °C H
N H
SiMe3 58% SiMe3 O O N
O O
Eaborn, C.; Jackson, R. A.; Pearce, R. J. Chem. Soc., Perkin Trans. I 1975, 470-474.
(single diastereomer) (+)-Lycorine

Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118, 6210-6219.
Kent Barbay