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
–
M
(X = R, OR, NR2)
X
H
H
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
• 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
K
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):
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
M
(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
1
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, 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.
O
R
OM
M, NH3, THF
N
t-BuOH (1 equiv)
(M = Li, Na, or K)
N
RX
H
–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
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
O
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
N
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.
N
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
2
• 1,6-Dialkyl-1,4-cyclohexadienes are accessible by asymmetric Birch alkylation:
OCH3
O
OCH3
O
1. s-BuLi, THF, –78 °C
N
CH3
Celite, PhH
N
H2 (1 atm), CH2Cl2
N
[Ir(cod)py(PCy3)]PF6
O
98%
OTBS
R
CH3I
OCH3
OK
1. K (2.2 equiv), NH3,
THF, t-BuOH (1 equiv)
OCH3
H3C O
98%
OTBS
53–77%
CH3
PDC, t-BuOOH
N
2. RX, –78 ! 25 °C
CH3
OCH3
H3C O
OCH3
H3C O
CH3
N
O
N
N
OCH3
H3C O
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
CH2Ph
62
95
CH2CH2Ph
77
93
CH2OCH2CH2SiMe3
71
94
CH2CH2OTBS
88
96
CH2CH2OMe
79
95
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,
presumably due to steric factors.
Ph
89%
H2 (1 atm), CH2Cl2
OCH3
N
H
OCH3
R' O
N
H3O+
R
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
N
Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614.
Transformations of asymmetric Birch alkylation products:
N
EtOAc, 55 psi
OTBS
R
OCH3
N
OCH3
H3C O
H2, Rh on Al2O3 CH3
O
Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.
H3C O
OCH3
H3C O
CH3
Ph
Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936.
OCH3
R' O
N
O
OsO4, NMO
H2O, acetone
HO
R
HO
OCH3
R' O
N
O
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.
Kent Barbay
3
• Regio- and stereo-selective epoxidation has been demonstrated:
OMOM O
O
H3 C O
N
OMOM
H3C O
CH3
CH3
R1
O
OCH3
R2 O
CH3
H3C
• Acid catalyzed cleavage of the alkylation products requires harsh conditions:
OCH3
O
H3C O
H
6 N aq. HCl
O
O
CH3
0 ! 23 °C
CH3
H
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
N
Ph
I
• Addition of alkyllithium reagents:
Methods of cleavage of Schultz's chiral auxiliaries:
N
R2
R1
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.
OCH3
75–98%
O
89–100%
>13 : 1 diastereoselectivity
H3C O
O
I2, THF, H2O
N
MeOH, 25 °C
OCH3
O
OCH3
R2 O
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.
R
H
O
R1
N
O
N
H
N
H
O
R NH
H
100 °C
2
NH4Cl
R1
• Lactonization can be effectively employed for amide cleavage:
OCH3
1. BF3•OEt2
N
2. H2O
O
SiMe3
H
O
R1
H
82%
CH3
OCH3
N
O
H3C
m-CPBA
O
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, 4931–4936.
H3C O
H
NaOMe, MeOH;
H+
100%
O CH3
O
CH3
Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614.
O
R1
N
N
H
N
H
OK
RX
R = Me, Et, Bn
Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502.
H
N
THF, t-BuOH (2 equiv)
O
62–82%
H3C O
R1
K (4.4 equiv), NH3
H
N
H
O
18 N aq. H2SO4
R2 KO
R2 O
• Olefinic substrates undergo protiolactonization under the conditions of acidic hydrolysis:
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
4
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)
R
R
CH3 2. RX
yield(%) ee(%)
R
1. TFA
N
CH3
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, 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
O
62-88%
H3CO
OCH3
N
N
O
Dissolving metal reductions of conjugated alkenes:
CH3
CH3
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
–78 °C
O
OCH3
N
R O
OCH3
RX
H3C
(proposed TS geometry)
O O
H
CH3
6 N HCl
100 °C
CO2H
O
R
R
yield(%) ee(%)
Me
86
>94
Et
74
>94
i-Bu
68
>94
H3CO
H3C
K, NH3
THF, –70 °C
O O
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 pyramidalization is proposed in the transition state.
Donohoe, T. J.; Helliwell, M.; Stevenson, C. A.Tetrahedron Lett. 1998, 39, 3071-3074.
Kent Barbay
5
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
H
TBSO
H3C CH3
H
CH2OH
H
H
CH3
THF, –78 °C
TBSO
93%
H3C CH3
H3C OH
H3C OH
H
H
Li, NH3
H
EtOH
90%
MeO
H
H
77%
MeO
Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874.
H
H
"
H
O
CH3
CH2OH
H3CO
H
THF, –40 °C H CO
3
H
H
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.
H
(t1/2 ca. 10 h)
R = H or R = OMe
H Li, NH3, THF
t-BuOH
O
H3CO
H HO
H
Rapid
R = OH
O
H
H3CO
O
–78 °C, 4 hr
O3, CH2Cl2, MeOH,
OH
Li, NH3, i-PrOH
CH3
OTIPS
R
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%
R
TBAF
Li, NH3, THF
H3C O
H3CO
H
• Reduction of aryl silyl ethers and synthesis of ",#-unsaturated cyclohexanones:
100%
!
H
Nelson, N. A.; Wilds, A. L. J. Am. Chem. Soc. 1953, 75, 5366-5369.
whereas:
H3C O
H
O
O
H3C O
Na, NH3,
H
83%
aq oxalic acid
H3C OH
!
H
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
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:
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
O
O
OCH3
CN
O
0.1 mole %
80–90 °C
BrCH2CH2OAc
–78 " 25 °C;
KOH, MeOH
OCH3
O
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
O
≥ 99% ee
CH3
EtOH, –70 °C
2. HCl, MeOH
3. I2, THF, H2O
96%, single diastereomer
O
N3
1. DEAD, PPh3,
(PhO)2P(O)N3
OCH3
O
Li, NH3
SiMe3
COOH
N
I
Rabideau, P. W.; Karrick, G. L. Tetrahedron Lett. 1987, 28, 2481-2484.
CH3
OH
H
OCH3
O
–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
N
CH3
SiMe3
H3C
O
OCH3 K, NH , t-BuOH,
3
O
• 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%
H
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
H
Cl
t-BuOK, THF;
K, NH3, –78 °C;
OMOM
O
CH3O
CH3O2C
O
• Diels-Alder cycloaddition by isomerization of 1,3-dienes in situ:
OCH3
H
88%
CO2CH3
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
H
O
HO
CO2Bn
N
O
(single diastereomer)
H
O
H
O
N
O
(+)-Lycorine
Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118, 6210-6219.
Kent Barbay
7