Reduction of Imines with Zinc Borohydride Supported on Silica Gel. Highly Stereoselective Synthesis of Substituted Cyclohexylamines

Full text of DOI:10.1021/jo961736a

J . Org. Chem. 1997, 62, 1841-1842
1841
Notes
Sch em e 1
Red u ction of Im in es w ith Zin c Bor oh yd r id e
Su p p or ted on Silica Gel. High ly
Ster eoselective Syn th esis of Su bstitu ted
Cycloh exyla m in es
Brindaban C. Ranu,* Arunkanti Sarkar, and
Adinath Majee
Department of Organic Chemistry,
Indian Association for the Cultivation of Science,
J adavpur, Calcutta 700 032, India
Ta ble 1. Red u ction of Im in es w ith Zin c Bor oh yd r id e
Su p p or ted on Silica Gel
Received September 10, 1996
The reduction of imines to the corresponding amines
is a very useful transformation in organic synthesis since
amines constitute important precursors to compounds
that are of much interest in pharmaceutical and agri-
cultural industries.1 The stereochemistry of such carbon-
nitrogen π bond reduction is also of great importance in
synthetic applications; unfortunately, only a few reports
are available in the literature dealing with this aspect.2
In general, it has been postulated that smaller reducing
agents such as sodium borohydride2c,i and sodium
cyanoborohydride2g,h provide stereoselective conversion
to equatorial secondary amines, although mixtures usu-
ally result. On the other hand, bulky trialkylborohy-
drides reduce imines to the corresponding axial amines
with excellent stereoselectivity.2c Thus, although axial
amines are obtained in high purity, an efficient method
to produce equatorial amines through simple operation
is still appreciated. Our recent endeavor of utilizing zinc
borohydride3 for selective reduction of various sensitive
entry
R1
R2
R3
time (h) yielda (%) ref
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
c-C6H11
CH2Ph
CH(CH3)Ph
12
8
92
90
92
90
95
91
94
92
91
94
2e
2e
2f
2f
2e
4
10
12
12
10
8
CH3 CH2Ph
CH3 c-C6H11
CH3 CH(CH3)Ph
H
H
H
H
n-C7H15
n-C7H15
n-C7H15
C2H5
CH2Ph
CH(CH3)Ph
c-C6H11
5
8
6
8
7
10
CH(CH3)Ph
10
8
a
All yields refer to pure isolated products, fully characterized
by IR and 1H NMR.
functionalities including the carbon-nitrogen bond31
prompted us to study this important transformation. We
have discovered that zinc borohydride supported on silica
gel reduces imines to the corresponding secondary amines
very efficiently (Scheme 1).
(1) Worbel, J . E.; Ganem, B. Tetrahedron Lett. 1981, 22, 3447 and
references cited therein.
In a simple procedure, the imine was stirred with a
suspension of silica gel-supported zinc borohydride in
THF at 0 °C under nitrogen for a certain period of time
as required to complete the reaction (TLC). Usual
workup and purification through a column of basic
alumina furnished the corresponding amine. Several
structurally varied aldimines and ketimines underwent
reductions by this procedure to produce the corresponding
secondary amines in high yields. Zinc borohydride
without silica gel can also induce reduction,2e but in the
case of aliphatic amines this requires treatment of the
initially formed amine-borane complex with HCl in
refluxing THF overnight to generate the free amine. On
the other hand, reductions with silica gel-supported zinc
borohydride directly lead to amines, avoiding this ad-
ditional step of HCl treatment, and are comparatively
clean and high yielding. Presumably, silica gel moder-
ates the reactivity of zinc borohydride, making the
process rather slow but cleaner compared to that with
zinc borohydride alone. As is evident from the results
summarized in Table 1, reductions of CdN by this
reagent are uniform irrespective of the nature of sub-
stituents at N and C. The reductions of substituted
(2) (a) Hutchins, R. O.; Hutchins, M. K. Comprehensive Organic
Synthesis; Trost, B., Ed.; Pergamon: New York, 1991; Vol. 8, Chapter
1.2, p 25. (b) Zhu, Q.-C.; Hutchins, R. O.; Hutchins, M. K. Org. Prep.
Proced. Int. 1994, 26, 193. (c) Hutchins, R. O.; Su, W.-Y.; Sivakumar,
R.; Cistone, F.; Stercho, Y. P. J . Org. Chem. 1983, 48, 3412. (d)
Hutchins, R. O.; Su, W.-Y. Tetrahedron Lett. 1984, 25, 695. (e) Kotsuki,
H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi, M. Synthesis 1990, 401.
(f) Willoughby, C. A.; Butchwald, S. L. J . Am. Chem. Soc. 1992, 114,
7562. (g) Lane, C. F. Synthesis 1975, 135. (h) Hutchins, R. O.; Natale,
N. R. Org. Prep. Proced. Int. 1979, 11, 201. (i) Bolton, R.; Danks, T.
N.; Paul, J . M. Tetrahedron Lett. 1994, 35, 3411.
(3) (a) Sarkar, D. C.; Das, A. R.; Ranu, B. C. J . Org. Chem. 1990,
55, 5799. (b) Ranu, B. C.; Das, A. R. J . Chem. Soc., Chem. Commun.
1990, 1334. (c) Ranu, B. C.; Chakraborty, R. Tetrahedron Lett. 1990,
31, 7663. (d) Ranu, B. C.; Basu, M. K. Tetrahedron Lett. 1991, 32, 3243.
(e) Ranu, B. C.; Chakraborty, R. Tetrahedron Lett. 1991, 32, 3579. (f)
Ranu, B. C.; Das, A. R. J . Org. Chem. 1991, 56, 4796. (g) Ranu, B. C.;
Das, A. R. Tetrahedron Lett. 1992, 33, 2361. (h) Ranu, B. C.; Das, A.
R. J . Chem. Soc., Perkin Trans. 1 1992, 1561. (i) Ranu, B. C.; Das, A.
R. J . Chem. Soc., Perkin Trans. 1 1992, 1881. (j) Ranu, B. C.;
Chakraborty, R.; Saha, M. Tetrahedron Lett. 1993, 34, 4659. (k) Ranu,
B. C. Synlett 1993, 885. (l) Ranu, B. C.; Sarkar, A.: Chakraborty, R.
J . Org. Chem. 1994, 59, 4114.
(4) (a) Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins,
N. S. Tetrahedron 1990, 46, 523. (b) Rossiter, B. E.; Eguchi, M.
Tetrahedron Lett. 1990, 31, 965.
(5) Katrizky, A. R.; Latif, M.; Urogdi, L. J . Chem. Soc., Perkin Trans.
1 1990, 667.
(6) Experimental data: 1H NMR δ 0.87 (3H, t, J ) 6.6 Hz), 1.01-
1.58 (12H, m), 1.34 (3H, d, J ) 6.5 Hz), 2.46 (2H, m), 3.74 (1H, q, J )
6.6 Hz), 7.19-7.36 (5H, m); 13C NMR δ 13.95, 22.53, 24.22, 27.27, 29.14,
29.40, 30.19, 31.71, 47.78, 58.31, 126.42, 127.51, 128.24, 145.82. Anal.
Calcd for C16H27N: C, 72.33; H, 8.22. Found: C, 72.46; H, 8.16.
(7) Kabalka, G. W.; Want, Z. Synth. Commun. 1990, 20, 231.
(8) Duhamel, L.; Ravard, A.; Plaque, V. J . C.; Pleg, D. D. Bull. Soc.
Chim. Fr. 1990, 787.
(9) McGill, J . M.; Labell, E. S.; Williams, M. A. Tetrahedron Lett.
1996, 37, 3977.
(10) Knupp, G.; Frahm, A. W. Chem. Abstr. 1985, 103, 160124S.
(11) Adachi, M.; Sasakura, K.; Sugasawa, T. Chem. Pharm. Bull.
1985, 33, 1826.
S0022-3263(96)01736-7 CCC: $14.00 © 1997 American Chemical Society

1842 J . Org. Chem., Vol. 62, No. 6, 1997
Notes
Ta ble 2. Red u ction of Cycloh exylim in es w ith Zin c
Bor oh yd r id e Su p p or ted on Silica Gel
selectivity make this procedure extremely attractive and
a practical alternative to the existing methods,2 and we
believe this will find general acceptance in organic
synthesis.
Exp er im en ta l Section
Gen er a l Meth od s. General information regarding instru-
ments and techniques used are the same as mentioned in our
previous paper.3b
The aldimines and cyclohexylimines were prepared by treat-
ment of the corresponding aldehydes and cyclohexanones with
the appropriate amines in ether in the presence of sodium sulfate
following a reported procedure.13 However, the corresponding
imines from acetophenone and comphor were obtained by
reactions catalyzed with p-toluenesulfonic acid/molecular sieves14
and zinc chloride,15 respectively.
Zinc borohydride in DME was prepared from zinc chloride and
sodium borohydride according to a reported procedure,16 and the
crude solution was used without any purification. Silica gel-
supported zinc borohydride was obtained3b by adding activated
(heated at 200 °C for 4 h at reduced pressure) silica gel HF 254
(1 g) to the crude solution of Zn(BH4)2 (3 mmol) in DME (3 mL)
followed by stirring at room temperature for 30 min. Solvent
was evaporated under reduced pressure at room temperature
to give the reagent, which was used on the same or next day.
Gen er a l P r oced u r e for Red u ction . Rep r esen ta tive P r o-
ced u r e. 4-(Methylcyclohexyl)phenylimine (187 mg, 1 mmol) in
THF (3 mL) was added to the silica gel-supported zinc borohy-
dride (1.3 g, 3 mmol) at 0 °C under nitrogen, and stirring was
then continued at room temperature for a certain period of time
(Tables 1 and 2) as required to complete the reaction (TLC). The
reaction mixture was then decomposed by careful dropwise
addition of water and extracted with ether (3 × 10 mL). The
extract was washed with brine, dried (Na2SO4), and evaporated
to leave the crude product, which was purified by column
chromatography over basic alumina to provide the pure (>99%;
TLC, 1H and 13C NMR) trans amine (174 mg, 92%) as an oil.
This procedure is followed for reduction of all imines. The
products (Table 1 and Table 2) are all known compounds and
have been easily characterized by their spectral (1H and 13C
NMR) and other physical data.
a
All yields refer to pure isolated products, fully characterized
by IR, H NMR, 13C NMR, mp, and mp of derivatives. The ratio
of isomers has been determined by GC and NMR.
1
b
cyclohexylimines (Table 2) are highly stereoselective,
providing exclusively (Table 2, entries 4 and 6-9) or
predominantly (Table 2, entries 1-3 and 5) trans amine
products. N-Benzylbornimine (Table 2, entry 10) also
undergoes stereoselective reduction to produce the cor-
responding endo bornamine.12 Evidently, in analogy with
small reducing agents,2c axial hydride attack is preferred,
in general, for substituted cyclohexylimines. Steric fac-
tors do seem to influence the stereochemistry as mixtures
of trans and cis product are formed when certain 2- or
3-substituted cyclohexylimines (Table 2, entries 2, 3, and
5) are reduced. This is possibly because of the steric
hindrance imposed by the combination of the particular
alkyl substituent present and its proximity to the imino
group.
Although the results reported in Tables 1 and 2 were based
on mmol-scale reactions, gram-scale reactions also afforded the
corresponding products in analogously excellent yields.
Ack n ow led gm en t. We are pleased to acknowledge
financial support from CSIR, New Delhi (Grant No. 01-
(1364)/95), for this investigation. A.S. and A.M. are
thankful to CSIR for their fellowships.
In conclusion, zinc borohydride supported on silica gel
thus appears to be a very efficient reagent for the
reduction of imines to the corresponding amines in high
yields. Moreover, the easy availability of the reagent,
operational simplicity, generality, and superior stereo-
J O961736A
(13) Savoia, D.; Trombini, C.; Ronchi, A. U. J . Org. Chem. 1978,
43, 2907.
(14) Vanniel, J . C. G.; Pandit, U. K. Tetrahedron Lett. 1985, 41, 6005.
(15) Bolton R.; Danks, T. N.; Paul, J . M. Tetrahedron Lett. 1994,35,
3411.
(16) Crabbe, P.; Garcia, G. A.; Rius, C. J . J . Chem. Soc., Perkin
Trans. 1 1973, 810.
(12) A similar stereochemical outcome was also observed in the
reduction of N-benzyl bornimine by NaBH4/NiCl2 in MeOH: J ian, L.;
Aiqiao, M.; Guishu, Y.; Yaozhong, J . Synth. Commun. 1992, 22, 1497.