Myers

Birch Reduction

Reviews:

Chem 115

Additivity of Substituent Effects:

Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334.

H3C

Mander, L. N. In Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I., Ed.;

Pergamon: Oxford, 1991, Vol. 8, pp. 489-521.

OCH3

H3C

Na, NH3, MeOH

OCH3

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.

CO2H 1. Na, NH3, MeOH

H3C

H3C

CO2H

2. NH4Cl

Mechanism:

94%
Electron-Donor Substituents (X):
X

Chapman, O. L.; Fitton, P. J. Am. Chem. Soc. 1963, 85, 41-47.

X

X
M, NH3

ROH

(X = R, OR, NR2)

X
H
H

M, NH3

Conditions:

H
H

Metals: Li, K, Na, occasionally Ca or Mg.

(rate-limiting
step)

Co-solvents: diethyl ether, THF, glymes.

ortho protonation

Reductions of alkyl benzenes and aryl ethers require a

stronger acid than ammonia; alcohols are typically employed.

H
H

Protonation of cyclohexadienyl anions is kinetically controlled and occurs at the central carbon.

W
ROH

M
W

(W = CO2H, CO2R,
COR, CONR2, CN, Ar)

M, NH3

Li

0.26

2.99

Na

0.18

2.59

0.21

2.73

Na (excess), EtOH, NH3

W

W H(R)

NH4Cl

H H

Normal reduction
potential at 50 C
in NH3 (V)

Reduction in low molecular weight amines (Benkeser reduction):

M, NH3

W
M, NH3

Solubility in NH3
at 33 C
(mol Metal/mol NH3)

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.

Electron-Withdrawing Substituents (W):

Proton sources (where appropriate): t-BuOH and EtOH are most common, also MeOH, NH4Cl,
and water.
Metal

H
H

Regioselectivity of protonation steps in the Birch reduction:

Zimmerman, H. E.; Wang, P. A. J. Am. Chem. Soc. 1993,
115, 2205-2216.

meta
protonation

ROH

2 2M

H H

(Birch reduction)
Li, EtNH2

or RX
H H

ROH or
NH3

Aromatic carboxylic acids and carboxylates are readily reduced with Li/NH3 in the absence
of alcohol additives.

(Benkeser Reduction)

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).
A Comparison of Methods Using Lithium/Amine and Birch Reduction Systems: Kaiser, E. M.
Synthesis 1972, 391-415.
Kent Barbay

Asymmetric Birch Reduction:

Reductive alkylation:
Enolates derived from 1,4-dihydrobenzoic acids are selectively alkylated at the !-carbon.
CO2H

Reviews: Schultz, A. G. Acc. Chem. Res. 1990, 23, 207-213; Schultz, A. G. Chem. Commun.
1999, 12631271.

HO2C CH3

1. KNH2, NH3

RX

O
N

2. CH3I
91%

H
O

Nelson, N. A.; Fassnacht, J. H.; Piper, J. U. J. Am. Chem. Soc. 1961, 83, 206-213.
See also: Birch, A. J. J. Chem. Soc. 1950, 1551-1556.

O
R

OM

M, NH3, THF

t-BuOH (1 equiv)
(M = Li, Na, or K)

RX
H

78 C

O
(proposed convex attack)

Loewenthal and co-workers first demonstrated single step reductive alkylation of

aromatic compounds:
CO2H

1. Na, NH3

HO2C CH3

2. CH3I
69%
Bachi, M. D.; Epstein, J. W.; Herzberg-Minzly, Y.; Loewenthal, H. J. E. J. Org. Chem. 1969,
34, 126-135.

Reductive alkylations of aromatic esters, amides, ketones, and nitriles typically are conducted
in the presence of one equivalent of an alcohol:

CO2t-Bu
TFA
CH(CH3)2

2. i-PrI
94%

CH3
CH3

MeI

67

60

EtI

82

>98

CH2=CH2CH2Br

75

>96

PhCH2Br

73

>96

CH2=CH2CH2CH2Br

89

96

ClCH2CH2CH2Br

91

(n.d.)

H
O
N

OCH3
CH3O
1. K, NH3
CO2t-Bu
t-BuOH (1 equiv)

yield (%) de (%)

RX

OCH3

O
R

RX

M, NH3, THF

O
M

t-BuOH (1 equiv)
H
O
OCH3 (M = Li, Na, or K)
CH3

78 C

70-88% yield,
>96% de
RX = MeI, EtI, PhCH2Br,
Br , Cl

1. Li, NH3, THF

t-BuOH (1 equiv)

OCH3 2. BrCH CH CH Cl
2
2
2

85%
Schultz, A. G.; Macielag, M. J. Org. Chem. 1986, 51, 4983-4987.

H
O
OCH3
CH3

O
CH3

RX

Hook, J. M.; Mander, L. N.; Woolias, M. Tetrahedron Lett. 1982, 23, 1095-1098.

CN

opposite
facial
selectivity

Br

CN
(CH2)3Cl
OCH3

Transition state may be complex, viz., enolate aggregation and nitrogen pyramidalization.
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
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.

Kent Barbay

 1,6-Dialkyl-1,4-cyclohexadienes are accessible by asymmetric Birch alkylation:

OCH3

OCH3

O
1. s-BuLi, THF, 78 C

CH3

Celite, PhH

H2 (1 atm), CH2Cl2

[Ir(cod)py(PCy3)]PF6

98%

OTBS

CH3I

OCH3

OK

1. K (2.2 equiv), NH3,

THF, t-BuOH (1 equiv)

OCH3

H3C O

98%

OTBS

5377%

CH3

PDC, t-BuOOH

2. RX, 78 ! 25 C

CH3

OCH3

H3C O

OCH3

H3C O

CH3

OCH3

H3C O

OTBS

2. MeI, 78 C

yield (%)

de (%)

90

> 98

Me

66

93

Et

79

90

CH2CH=CH2

76

93

CH2CH2CH=CH2

69

90

CH2Ph

62

95

CH2CH2Ph

77

93

CH2OCH2CH2SiMe3

71

94

CH2CH2OTBS

88

96

CH2CH2OMe

79

95

Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 66116614.
Heterogenous hydrogenation with rhodium on alumina occurs anti to the bulky amide,
presumably due to steric factors.

Ph

89%

H2 (1 atm), CH2Cl2

OCH3
N

OCH3

R' O
N

H3O+

OCH3

H3C O

89%

O
OTBS

Dihydroxylation of 3-cyclohexen-1-ones obtained by Schultz's asymmetric Birch alkylation occurs

exclusively anti to the amido substituent:

Amide-directed hydrogenation with Crabtree's catalyst:

[Ir(cod)py(PCy3)]PF6

Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 66116614.

Transformations of asymmetric Birch alkylation products:

EtOAc, 55 psi

OTBS

OCH3

OCH3

H3C O

H2, Rh on Al2O3 CH3

Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 49314936.

H3C O

OCH3

H3C O

CH3

Ph

Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 49314936.

OCH3

R' O
N
O

OsO4, NMO
H2O, acetone

HO
R

HO

OCH3

R' O
N
O

yield (%)

R'

Me

91

CH2Ph

86

(CH2)3N3

88

(CH2)3Cl

94

CH2Ph

Et

73

Me

Et

76

Schultz, A. G.; Dai, M.; Tham, F. S.; Zhang, X. Tetrahedron Lett. 1998, 39, 66636666.

Kent Barbay

 Regio- and stereo-selective epoxidation has been demonstrated:

OMOM O
O

H3 C O
N

OMOM

H3C O

CH3
CH3

R1

OCH3

R2 O

CH3

H3C

Acid catalyzed cleavage of the alkylation products requires harsh conditions:

OCH3

H3C O

6 N aq. HCl

O
CH3

0 ! 23 C

CH3

58%

OH

CH3

Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am. Chem. Soc.
1988, 110, 7828-7841.

reflux, 7 h
Ph

95%

H3C

MeLi, THF

Ph

Addition of alkyllithium reagents:

Methods of cleavage of Schultz's chiral auxiliaries:

R2

R1

Schultz, A. G.; Dai, M.; Khim, S.-K.; Pettus, L.; Thakkar, K. Tetrahedron Lett. 1998, 39, 42034206.

Schultz, A. G.; Harrington, R. E.; Tham, F. S. Tetrahedron Lett. 1992, 33, 60976100.

OCH3

7598%

89100%

>13 : 1 diastereoselectivity

H3C O

I2, THF, H2O

MeOH, 25 C

OCH3

OCH3

R2 O

R1

6 N aq. HCl

acetone
68%

CH3

Iodolactonization:

Asymmetric synthesis of amino-substituted cyclohexenes:

Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 49314936.

R1

O
N
H

N
H

R NH

100 C

NH4Cl

R1

Lactonization can be effectively employed for amide cleavage:

OCH3
1. BF3OEt2

2. H2O
O

SiMe3

H
O

R1

82%

CH3

OCH3
N

O
H3C

m-CPBA
O

82%
OTBS

H3C O

OCH3
N

O
OTBS

R2 O
H

H3C O

Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 49314936.

H3C O

NaOMe, MeOH;
H+
100%

O CH3
O
CH3

Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 66116614.

R1

N
H

H
OK

RX

R = Me, Et, Bn

Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 64936502.

THF, t-BuOH (2 equiv)

6282%

H3C O

R1

K (4.4 equiv), NH3

H

N
H

18 N aq. H2SO4

R2 KO

R2 O

Olefinic substrates undergo protiolactonization under the conditions of acidic hydrolysis:

R2 O
R

H
H

RX

yield (%)

H
N
O
H
de (%)

MeI

54

70

EtI

68

82

NH4Cl

73

not reported

Me

MeI

53

> 88

Me

NH4Cl

84

one diastereomer

Me

MeI

78

52

Me

EtI

87

78

Me

CH2=CHCH2Br

68

> 95 : 5

Me

BnBr

78

> 95 : 5

Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 64936502.
Kent Barbay

Chiral substrates:

Asymmetric Birch Reduction of heterocycles:

O
Ph CH3
O
N
CH3
Boc O

CH3

1. Li, NH3, THF, 78 C

(CH3OCH2CH2)2NH
2. Isoprene
3. RX
91-96%

2. NaOH
3. (Boc)2O

R
OR'
N
Boc O

1. Li, NH3, THF

t-BuOH (1 equiv)
78 C

Me

79

78

N CO2H
Boc

Et

71

86

i-Bu

70

90

CH2Ph

67

90

O
N

CH3
CH3

>90% de
R = CH3
72%
R = CH2CH=CH2 66%
R = CH2Ph
68%

(R' = ()-8-phenylmenthol)

CH3 2. RX

yield(%) ee(%)

R
1. TFA

CH3

Schultz, A. G.; Kirinich, S. J.; Rahm, R. Tetrahedron Lett. 1995, 36, 4551-4554.

H
1. Li, NH3, THF

CH3O
HO2C

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.

CO2H

2. CH3I
51%

CH3O
HO2C CH3 CO2H

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.

CH3

OCH3

OM

Na, NH3
78 C

62-88%

H3CO

OCH3

Dissolving metal reductions of conjugated alkenes:

CH3
CH3

OCH3

Styrenes, conjugated dienes, and enones are more readily reduced under dissolving metal
conditions than are aromatics; reduction occurs at low temperature without alcohol additives.

RX
78 C

OCH3
N

R O
OCH3

RX

H3C

(proposed TS geometry)

O O

H
CH3

6 N HCl
100 C

CO2H
O

yield(%) ee(%)

Me

86

>94

Et

74

>94

i-Bu

68

>94

H3CO

H3C

K, NH3
THF, 70 C

O O

H
H

62%

H3CO

Ananchenko, S. N.; Limanov, V. Y.; Leonov, V. N.; Rzheznikov, V. N.; Torgov, I. V.

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.

Kent Barbay

Transformations of Birch Reduction products:

Stereochemical and/or regiochemical control by intramolecular protonation:

H3C CH3

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

H3C CH3

H3C
H

CH2OH
H

CH3

H3C

Li, NH3

TBSO
H3C CH3

CH2OH
H

CH3

THF, 78 C
TBSO
93%
H3C CH3

H3C OH

H3C OH

Li, NH3

EtOH
90%

MeO

H
77%

MeO

Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874.

H
H

"
H

O
CH3
CH2OH

H3CO

THF, 40 C H CO
3

O
CH3
CH2OH

"

O
CH3
H
CH2OH

H3C

O
H
CH3
H
CH2OH
H

Na, NH3,
THF, 40 C

OTBS t-BuOH, 33 C H3C

H3CO

OH

Lin, Z.; Chen, J.; Valenta, Z. Tetrahedron Lett. 1997, 38, 3863-3866.

(t1/2 ca. 10 h)
R = H or R = OMe

H Li, NH3, THF

t-BuOH

H3CO
H HO
H

Rapid
R = OH

H3CO

78 C, 4 hr

O3, CH2Cl2, MeOH,

OH

Li, NH3, i-PrOH

CH3
OTIPS

H3C

96%

Ozonolysis of Birch reduction products:

Initial intramolecular protonation at the "-position is proposed.

Li, NH3, THF

t-BuOH

OTBS

92%
Fuchs, P. L.; Donaldson, R. E. J. Org. Chem. 1977, 42, 2032-2034.

71%

TBAF

Li, NH3, THF

H3C O

H3CO

Reduction of aryl silyl ethers and synthesis of ",#-unsaturated cyclohexanones:

100%

Nelson, N. A.; Wilds, A. L. J. Am. Chem. Soc. 1953, 75, 5366-5369.

whereas:

H3C O

H
O

H3C O
Na, NH3,

83%

aq oxalic acid

H3C OH

aq HCl

It is proposed that the stereochemical outcome is the result of intramolecular protonation

of the radical anion.

H3C O

H3C OH

H3CO

CH3
OTIPS

py, 78 C; Me2S
56% (two steps)

OH
CH3
OTIPS

Evans, D. A.; Gauchet-Prunet, J. A.; Carreira, E. M.; Charette, A. B. J. Org. Chem. 1991, 56, 741750.

Cotsaris, E.; Paddon-Row, M. N. J. Chem. Soc., Chem. Commun. 1982, 1206-1208.

Kent Barbay

Birch Reduction Application in Synthesis:

Reductive alkylation of aromatics without electron-withdrawing groups is unsuccessful.

()-Gibberellic Acid:

Directed metalation of Birch products is possible:

CH3
CH3

CH3

Birch

NEt2

NEt2

CH3O

OCH3

CO2CH3
O

Amupitan, J.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1978, 852-853.

Bishop, P. M.; Pearson, J. R.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1983, 123-124.

H
CH3O

OCH3
CN

0.1 mole %
8090 C

BrCH2CH2OAc
78 " 25 C;
KOH, MeOH

OCH3

80% (two steps)

But:

1. Ph3P

O
O

2. ArCOCl, Et3N

58%

Eaborn, C.; Jackson, R. A.; Pearce, R. J. Chem. Soc., Perkin Trans. I 1975, 470-474.

I
O 1. BnOH, THF, n-BuLi
2. AIBN, Bu3SnH

N
O

OH

O
H

O
SiMe3

Br

99% ee

CH3

EtOH, 70 C

2. HCl, MeOH
3. I2, THF, H2O

96%, single diastereomer

N3

1. DEAD, PPh3,
(PhO)2P(O)N3

OCH3

Li, NH3

SiMe3

COOH

Rabideau, P. W.; Karrick, G. L. Tetrahedron Lett. 1987, 28, 2481-2484.

CH3

OH

OCH3

78 C;

TBAF

In the absence of competing factors, allylic silanes are generally produced from Birch reduction
of aryl silanes; this is attributed to stabilization of negative charge at the !-carbon by silicon.

OH

CH3

SiMe3

H3C

OCH3 K, NH , t-BuOH,
3

Silyl substituents can be used to modify the regiochemistry of Birch reduction:

SiMe3

HO

()-Gibberellic Acid

Birch, A. J.; Dastur, K. P. Tetrahedron Lett. 1972, 41,4195-4196.

M, NH3

CO

OMOM
O

(+)-Lycorine:

Isomerization is proposed to occur through a charge-transfer complex.

CH3

84%

Hook, J. M.; Mander, L. N.; Urech, R. J. Org. Chem. 1984, 49, 3250-3260.

75%

CH3

CH3I, 33 C

O
O

CH3O
CH3O2C CH3 CO2H

CN

OCH3

CO2H

Cl

t-BuOK, THF;
K, NH3, 78 C;

OMOM
O

CH3O
CH3O2C

Diels-Alder cycloaddition by isomerization of 1,3-dienes in situ:

OCH3

88%

CO2CH3

Cl

OCH3

CO H
CO2CH3 2

H3CO

2. RBr
3. H+

PPA

Li, NH3, THF,33 C;

HO2C

1. n-BuLi, HMPA
70 C

Reduction

CH3O

CH3O

H
O

HO
CO2Bn

O
(single diastereomer)

O
H
O

O
(+)-Lycorine

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