Myers

Chem 215

Birch Reduction

Reviews:

Additivity of Substituent Effects:

Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334.
OCH3

H3C

Mander, L. N. In Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I., Ed.;
Pergamon: Oxford, 1991, Vol. 8, pp. 489-521.

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

X
M, NH3

H
H

ROH


–

M

(X = R, OR, NR2)

M, NH3

Conditions:

H
H

–

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

M

(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.


X

H

H

W
ROH

M, NH3

0.26

–2.99

Na

0.18

–2.59

K

0.21

–2.73

Na (excess), EtOH, NH3
W


W H(R)

–

2 – 2M

(Birch reduction)

NH4Cl

H H
M

M

Li, EtNH2

or RX

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

Li

Normal reduction
potential at –50 °C
in NH3 (V)

• Reduction in low molecular weight amines (Benkeser reduction):

M, NH3

W

–

Solubility in NH3
at –33 °C
(g-atom M/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):

M, NH3

Metal

H

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

W

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

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

H H

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 α-carbon.
CO2H

Reviews: Schultz, A. G. Acc. Chem. Res. 1990, 23, 207-213; Schultz, A. G. Chem. Commun.
1999, 1263–1271.

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.

R

OM
M, NH3, THF


O
N

RX
H

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

–78 °C

H

O

O
(proposed convex attack)

• Loewenthal and co-workers first demonstrated single step reductive alkylation of
aromatic compounds:
CO2H

1. Na, NH3

HO2C CH3

MeI


67

60

EtI

82
75

>98

PhCH2Br
CH2=CH2CH2CH2Br

73
89

>96
96

ClCH2CH2CH2Br

91

(n.d.)

CH2=CH2CH2Br

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:

H
O
N

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

yield (%) de (%)

RX

CO2t-Bu
CH(CH3)2

O
TFA

2. i-PrI
94%

CH3

CH3

OCH3
R

N
M, NH3, THF

H
t-BuOH (1 equiv)
O
(M = Li, Na, or K)
OCH
3
CH3

–78 °C

OCH3

2. BrCH2CH2CH2Cl
85%

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

N
H
O
CH3 OCH3


O
CH3

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

1. Li, NH3, THF
t-BuOH (1 equiv)

O

RX
O
M

RX

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

CN

opposite
facial
selectivity

>96

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 β-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

O

OCH3

O

H3C

H3C

H2 (1 atm), CH2Cl2


N

[Ir(cod)py(PCy3)]PF6

98%

OTBS

OCH3

O

O

N

53–77%

98%

OTBS

R

CH3I

OCH3

OK


1. K (2.2 equiv), NH3,
THF, t-BuOH (1 equiv)

CH3

PDC, t-BuOOH

N

2. RX, –78 → 25 °C

CH3

OCH3

O

Celite, PhH

1. s-BuLi, THF, –78 °C

N

CH3

H3C

OCH3


O

CH3

OCH3

O
N

O

N

N

H3C

OTBS

2. MeI, –78 °C

R

R

yield (%)

de (%)

H


90

> 98

Me

66

93

Et

79

90

CH2CH=CH2

76

93

CH2CH2CH=CH2

69

90

62


95

77

93

71

94

88

96

79

95

69

96

R

CH2Ph
CH2CH2Ph
CH2OCH2CH2SiMe3
CH2CH2OTBS
CH2CH2OMe


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,
presumably due to steric factors.

H3C

CH3

OCH3

O

H3C

H2, Rh on Al2O3 CH3

N

O

EtOAc, 55 psi

OTBS

OCH3

O
N


O
OTBS

89%

Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614.
• Dihydroxylation of 3-cyclohexen-1-ones obtained by Schultz's asymmetric Birch alkylation occurs
exclusively anti to the amido substiuent:

R

Ph

R'

OCH3

O
N

H3O+

R

OCH3

R'

OCH3


O
N
O

OsO4, NMO

HO
R

OCH3

OH O
R'

H2O, acetone

N
O

Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.
Transformations of asymmetric Birch alkylation products:
• Amide-directed hydrogenation with Crabtree's catalyst:

H3C

OCH3

O
N


H2 (1 atm), CH2Cl2
[Ir(cod)py(PCy3)]PF6

Ph

H3C

OCH3

O
N

H

89%

Ph

yield (%)

R

R'

H

Me

91


H

CH2Ph

86

H

(CH2)3N3

88

H

(CH2)3Cl

94

CH2Ph

Et

73

Me

Et

76


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.
Kent Barbay


• Regio- and stereo-selective epoxidation has been demonstrated:

H3C

OMOM O
O

O
N

CH3

H3C

CH3

OMOM

O

R1

R2

O


OCH3

O

H3C

O

H3C

H

6 N aq. HCl

OCH3

O
N

MeLi, THF

CH3

0 → 23 °C

OH

O


CH3
CH3

H

58%

Ph

95%

O

H3C

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

reflux, 7 h
Ph

I

75–98%

• Addition of alkyllithium reagents:

• Acid catalyzed cleavage of the alkylation products requires harsh conditions:

N


R2

R1
O

Methods of cleavage of Schultz's chiral auxiliaries:

OCH3

I2, THF, H2O

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.

O

O

89–100%

>13 : 1 diastereoselectivity

H3C

O

OCH3


O
N

MeOH, 25 °C

OCH3

CH3

R2

R1

6 N aq. HCl

N

N

acetone
68%

CH3

• Iodolactonization:

Asymmetric synthesis of amino-substituted cyclohexenes:
Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.

O


H

R1

N

O

R

N
H
O

N
H

THF, t-BuOH (2 equiv)

O

R NH

H

100 °C

2


NH4Cl

62–82%
R1

• Lactonization can be effectively employed for amide cleavage:
H3C

OCH3

O

1. BF3•OEt2

N

2. H2O
H
O

SiMe3

H3C

O

H
O

R1


H

82%

Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.

H3C

OCH3

O
N

O
H3C

m-CPBA
O

O

82%
OTBS

H3C

O

OCH3

N

O
OTBS

R2 O
H

RX

O CH
3

NaOMe, MeOH;
H+
100%

O
CH3

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

O

N

N
H

H

OK

N

H

R = Me, Et, Bn

Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502.

CH3

N

K (4.4 equiv), NH3
H

N
H

O

18 N aq. H2SO4

KO

R2 O

• Olefinic substrates undergo protiolactonization under the conditions of acidic hydrolysis:


R1

R2 O
R

H
H

O

RX

yield (%)

N

H
N
O
H
de (%)

H

H

MeI

54


70

H

H

EtI

68

82

H

H

NH4Cl

73

not reported

H

Me

MeI

53


> 88

Me

H

NH4Cl

84

one diastereomer

Me

H

MeI

78

52

Me

H

EtI

87


78

Me

H

CH2=CHCH2Br

68

> 95 : 5

Me

H

BnBr

78

> 95 : 5

Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502.
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

Me

N CO H
2
Boc

R
OR'
N
Boc O


1. Li, NH3, THF
t-BuOH (1 equiv)
–78 °C

CH3 2. RX

Et

79
71

78
86

i-Bu

70

90

CH2Ph

67

90

R

O

CH3

N

CH3
>90% de
R = CH3
R = CH2CH=CH2
R = CH2Ph

(R' = (–)-8-phenylmenthol)

yield(%) ee(%)

R
1. TFA

N

CH3

72%
66%
68%

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

H

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, supressing byproduct formation.

CO2H

2. CH3I
51%

CH3O
HO2C CH3CO2H

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

O


N

O

Dissolving metal reductions of conjugated alkenes:

CH3
OCH3

CH3

O

H3CO

OCH3

O

• 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

N
–78 °C

62-88%


OCH3

N
R O
OCH3

RX

O O
H3C

(proposed TS geometry)

H
CH3

6 N HCl
100 °C

CO2H
O

R

R

yield(%)

ee(%)


Me
Et

86

>94

74

>94

i-Bu

68

>94

H3CO

O O
H3C

K, NH3
THF, –70 °C

H
H

62%


H

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 proposed pyramidalized 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 α,β or β,γ-unsaturated cyclohexanones

H3C CH3

CH2OH
H

H

H

CH3


THF, –78 °C
TBSO
H
93%
H3C CH3

TBSO
H
H3C CH3

H

CH2OH

Li, NH3

CH3

H3C OH

H3C OH

H

H

Li, NH3
H


H
EtOH

MeO

90%

aq HCl
H

H
H

H

O
CH3
CH2OH

H3CO

H
H

THF, –40 °C

H

O
CH3

CH2OH

100%

β

O
CH3
H
CH2OH

H3C

O
H
CH3
H
CH2OH
H

Na, NH3,
THF, –40 °C

OTBS t-BuOH, –33 °C H3C

• Ozonolysis of Birch reduction products:

OH

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


H3CO

–78 °C, 4 hr

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

R

H Li, NH3, THF
t-BuOH

H HO
H

Rapid
R = OH

O

H

H3CO

O

O3, CH2Cl2, MeOH,

OH


Li, NH3, i-PrOH

CH3
OTIPS

Li, NH3, THF
t-BuOH

O

96%

H3CO

• Initial intramolecular protonation at the β-position is proposed.

H

H3C

OTBS

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

71%

R


TBAF

Li, NH3, THF

H3C O

H3CO

H

• Reduction of aryl silyl ethers and synthesis of β,γ-unsaturated cyclohexanones:

whereas:

α

OH

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

H3CO

H3C O

H

O

H3C O
Na, NH3,


H

83%

aq oxalic acid

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

β

H

O

H3C

α

H

77%

MeO

• 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,
741-750.

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

O

O

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

H

88%


OMOM
O

CH3O
CH3O2C

O
CO2CH3

CO2H

H
Cl

OCH3

OCH3
O

O

OCH3
CN

O

0.1 mole %
80–90 °C


H3C

O

OCH3 K, NH , t-BuOH,
3

O

–78 °C;

O

80% (two steps)

But:

1. Ph3P

O

O

2. ArCOCl, Et3N

O
≥ 99% ee

58%


H
H

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

OH

O
O

SiMe3

2. AIBN, Bu3SnH

N
O

Li, NH3

SiMe3

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

O 1. BnOH, THF, n-BuLi

Br

O


N3

CH3

EtOH, –70 °C

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

O I

I

Rabideau, P. W.; Karrick, G. L. Tetrahedron Lett. 1987, 28, 2481-2484.
• 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 α-carbon by silicon.

OCH3

O
N

TBAF

CH3

COOH

BrCH2CH2OAc
OCH3

–78 → 25 °C;
KOH, MeOH
96%, single diastereomer

OCH3

CH3

SiMe3

OH

N

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

SiMe3

OH

H

(±)-Gibberellic Acid

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

M, NH3

HO


(+)-Lycorine:

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

CH3

CO

OMOM
O

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

75%

CH3

CH3I, –33 °C
84%

H

O

CH3O
CH3O2C CH3 CO2H

CN

t-BuOK, THF;

K, NH3, –78 °C;

O

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

Cl

OCH3

CO H
CO2CH3 2

I

H3CO

2. RBr
3. H+

PPA

Li, NH3, THF,–33 °C;

HO2C

1. n-BuLi, HMPA
–70 °C

Reduction


CH3O

CH3O

O

HO
CO2Bn

H
O

N

O
(single diastereomer)

H
O

N

O
(+)-Lycorine

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

Kent Barbay