Lithium borohydride: a reagent of choice for the selective reductive amination of cyclohexanones

Article abstract of DOI:10.1016/j.tetlet.2007.07.217

Traditional reductive amination of substituted cyclohexanones are either selective toward the formation of cis-products or show low selectivity. Herein we report a selective procedure for the reductive amination of substituted cyclohexanones with primary

Full text of DOI:10.1016/j.tetlet.2007.07.217

Tetrahedron Letters 48 (2007) 7134–7136
Lithium borohydride: a reagent of choice for the selective
reductive amination of cyclohexanones
Shawn Cabral,a,* Bernard Hulina and Makoto Kawaib
aDepartment of Cardiovascular and Metabolic Diseases, Groton, United States
bDepartment of Medicinal Chemistry-2 G3, Nagoya, United States
Received 3 May 2007; revised 27 July 2007; accepted 31 July 2007
Available online 6 August 2007
Abstract—Traditional reductive amination of substituted cyclohexanones are either selective toward the formation of cis-products
or show low selectivity. Herein we report a selective procedure for the reductive amination of substituted cyclohexanones with pri-
mary amines using lithium borohydride that is selective toward formation of trans-products.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Carbon–nitrogen bond forming reactions are critical to
the synthesis of natural products and biologically active
compounds. Of these reactions, the reductive amination
of ketones to amines of known configurations is partic-
ularly useful. As our drug discovery program was
confronted with the necessity to generate trans-4-substi-
tuted cyclohexylamine intermediate 2, we decided to
explore the possibility of selectively producing these
isomers from the corresponding ketones. In the analo-
gous reduction of substituted cyclohexanones to cyclo-
hexanols, bulky hydride reagents provide axial
alcohols and, in the absence of steric factors, small re-
agents such as sodium borohydride or lithium aluminum
hydride give the more stable equatorial isomers.1 In the
reductive amination of substituted cyclohexanones, the
axial attack of the imino group to give the equatorial
amine has not been as successful.2 Sodium borohydride
is selective toward the formation of equatorial isomers
but competes with reduction of the ketone to the alco-
hol,3 a problem that can be avoided by the prior forma-
tion and isolation of the imine.4 However, the reported
selectivity from reduction of these imines has been mod-
erate.2 The use of other reagents such as sodium cyano-
borohydride results in moderate equatorial selectivity2
or may give the reverse selectivity toward the axial
amines in a similar manner as bulkier hydride reagants
such as sodium triacetoxyborohydride.5 The reduction
of substituted cyclohexanone oximes with sodium metal
in ethanol is selective toward the equatorial isomers but
it is not practical on large scale.1 Herein, we report a
convenient and selective procedure for the reductive
amination of substituted cyclohexanones to the equato-
rial amines, suitable for development scale.
Sodium borohydride afforded the best conditions for a
scaleable reaction. In order to avoid the cumbersome
removal of water and the isolation of the intermediate
imine, we increased the number of equivalents of benzyl-
amine relative to ketone 1 as a means of shifting the
equilibrium toward the formation of the imine. Thus,
the reductive amination of the substituted cyclohexa-
none 1 using 3 equiv of benzylamine and sodium boro-
hydride in methanol produced the desired secondary
amine 2 with no detectable reduction of 1 to alcohol 3.
Lesser equivalents of benzylamine resulted in the forma-
tion of the alcohol by-product in varying amounts,
which made purification difficult. In addition, perform-
ing the reduction with sodium borohydride at À30ꢁC
resulted in a better trans-selectivity than previously re-
ported1 (Scheme 1). The poor solubility of sodium boro-
hydride in methanol at low temperatures prompted us to
try lithium borohydride. Lithium borohydride solution
in THF was added to the mixture of substituted cyclo-
hexanone and the primary amine in methanol at
À78 ꢁC and the reaction mixture was allowed to slowly
warm to room temperature.6 The results show superior
ratios of equatorial to axial amine products to those
obtained using other reagents.7
The results from reductive amination of several substi-
tuted cyclohexanones with a variety of primary amines
are summarized in Table 1. Lithium borohydride
*
Corresponding author. Tel.: +1 860 715 1383; e-mail: shawn.
cabral@pfizer.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.217

S. Cabral et al. / Tetrahedron Letters 48 (2007) 7134–7136
7135
H
N
OH
O
BnNH2 (2 equiv);
NaBH4, -30º C, MeOH
+
N
N
N
BnO
BnO
BnO
2
3
14%
1
89: 11 trans/cis
H
N
O
BnNH2 (3 equiv);
NaBH4,-30º C, MeOH
N
N
BnO
BnO
2
1
89: 11 trans/cis
Scheme 1.
Table 1. Reductive amination selectivity using various borohydrides
NHR
O
R'
R'
NHR
+
+
RNH2
R'
Ketone
Amine
Products
Product ratioa (yield, %)
Equatorial amine
Axial amine
LiBH4,
NaBH4,
NaBH3CN, NaBH(OAc)3,
À78 ꢁC
À30 ꢁC
0 ꢁC
0 ꢁC
O
NHBn
NHBn
BnNH2
92:8 (90)
92:8 (65)
83:17 (84) 73:17 (82)
83:17 (85) 76:24 (95)
31:69 (98)
Allylamine
23:77 (99)
24:76 (85)
NH
NH
MeNH2
91:9 (76)
93:7 (84)
87:13 (77) 78:22 (75)
75:25 (95) 69:31 (83)
NHMe
NHMe
O
Ph
Ph
Cyclobutyl-amine
Allylamine
N
N
25:75 (96)
33:67 (42)
H
H
Ph
H
N
H
N
O
84:16 (73) 87:13 (36) 80:20 (68)
78:22 (81) 67:33 (91) 63:37 (86)
BnNH2
15:85 (82)
O
NHBn
NHBn
a Ratios determined by H NMR and GC–MS.
consistently gave better trans-selectivity than sodium
cyanoborohydride.8 It was also slightly more selective
than sodium borohydride, the one exception being
3-methyl-cyclohexanone, where sodium and lithium
borohydride reagents gave equivalent results. The
lower selectivity with sodium cyanoborohydride and
the cis-selectivity from sodium triacetoxyborohydride
are consistent with the size of the hydride reagent
being a controlling factor for the direction of hydride
delivery.
The reductive amination procedure of substituted cyclo-
hexanones with primary amines described herein for the
synthesis of substituted cyclohexylamines provides
better trans-selectivity than other methods previously
reported. The use of excess amine shifts the ketone-
imine equilibrium toward the imine, so that the presence
of a dehydrating agent is not necessary. The boro-
hydride preferentially adds from the axial direction
particularly at low temperature. Lithium borohydride
has the advantage over sodium borohydride in that

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S. Cabral et al. / Tetrahedron Letters 48 (2007) 7134–7136
with a 2 M solution of lithium borohydride in tetrahydro-
furan (0.55 mL, 1.1 equiv). After stirring at À78 ꢁC for 1 h,
the mixture was slowly warmed to room temperature and
stirred for 16 h. It was then partitioned between ethyl
acetate (10 mL) and saturated sodium bicarbonate (2 mL).
The aqueous layer was extracted with ethyl acetate
(2 · 10 mL). The combined organic phases were washed
with brine (5 mL), dried over magnesium sulfate, filtered,
concentrated, and the residue was dried under high
vacuum. The product was isolated as a colorless solid.
the reaction can be performed at À78 ꢁC due to its better
solubility in THF.
References and notes
1. Wu, Y.-D.; Houk, K. J. Am. Chem. Soc. 1987, 109, 908,
and references therein.
2. Hutchins, R. O.; Su, W.; Sivakumar, R.; Cistone, F.;
Stercho, Y. P. J. Org. Chem. 1983, 48, 3412–3422.
3. Wigfield, D. C. Tetrahedron 1979, 35, 449.
4. Wrobel, J. E.; Ganem, B. Tetrahedron Lett. 1981, 22, 3447–
3450.
5. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849–3862.
1
(222 mg, 90%) H NMR (CDCl3) 7.37–7.22 (m, 5H), 3.83
(s, 2H), 2.45 (m, 1H), 2.05 (d, 2H), 1.75 (d, 2H), 1.15 (m,
2H), 1.00 (m, 3H), 0.82 (s, 9H).
7. The reducing agent in these reactions is probably borohy-
dride itself rather than mono-, di-, or trimethoxyborohy-
dride, since borohydride reacts slowly with methanol at low
temperatures: Schlesinger, H. I.; Brown, H. C.; Hoekstra,
H. R.; Rapp, L. J. Am. Chem. Soc. 1953, 75, 199–204,
Switching the solvent to ethanol had no effect on the isomer
ratio.
6. Representative procedure for trans-N-benzyl-4-tert-butylcyclo-
hexanamine: Benzylamine (322 mg, 3.0 mmol) was added
to
a solution of 4-tert-butylcyclohexanone (154 mg,
1.0 mmol) in methanol (2 mL). The mixture was stirred at
room temperature for 1 h, cooled to À78 ꢁC, and treated
8. In most cases the ratio of trans-isomer was improved
further upon formation of the hydrochloride salt.