Temhedmn Letters. Vol.31. No.39. pp 5595-5598, 1990 oo404039/90 53.00 + .

oo
Printed in Glut Britain Pcrgamm Press plc

REDUCTIVE AMINATION OF ALDEHYDES AND KETONES BY USING

SODIUM TRIACETOXYBOROHYDRIDE

Ahmed F. Abdel-Magid*, Cynthia A. Mayano@ and Kenneth G. Carson

R. W. Johnson Pkrmaceutical Research Institute, Deparbnent of Chemical Development
Spring House, PA 19477

Summary: Sodium triacetoxyborohydride is a reagent of choice in the reductive amination

of aldehydes and saturated aliphatic ketones with primary and secondary amines.

The reductive amination of aldehydes and ketones is one of the most useful reactions in the
synthesis of primary, secondary and tertiary amines. * The Borch reduction,3 using sodium
cyanoborohydride [NaBHsCN] has been the most popular method to carry out this transformation in
recent years. However, in our work. we desired a hydride alternative to this toxic reagent to eliminate
any risk of residual cyanide in the product or in the workup waste stream. We selected sodium
triacetoxyborohydride [NaBH(OAc)s],4 a very mild and selective reducing agent.5 The reagent
reduces aldehydes selectively over ketones,-5.6 Gribble had previously shown the potential for its use
in reductive amination.7 In this paper, we report our preliminary work on the scope and limitations of
sodium triacetoxyborohydride in the reductive amination of aldehydes and ketones.

Table I shows that a wide variety of aliphatic and cyclic saturated ketones and aldehydes
were reductively aminated with primary and secondary amines under the standard conditions in
good to excellent yields.6 The reductive aminations were carried out in either 1,2-dichloroethane
(DCE) or tetrahydrofuran (THF). In general, the mixture of the carbonyl compound (10 mmol) and the
amine (IO-1 1 mmol) in DCE or THF (30-40 mL) was treated with sodium triacetoxyborohydride (14-
15 mmol) under a nitrogen atmosphere at room temperature. With most ketones and with some
aldehydes, acetic acid (10 mmol) was added to the mixture. The progress of the reaction was
followed by GC and GClMS analysis. In general, most of the reactions carried out in DCE were
faster than those carried out in THF, and in both solvents, addition of one (or more) equivalent (s) of
acetic acid (AcOH) accelerated the reaction.9

Generally, with the same ketone, primary aliphatic amines reacted faster than primary
aromatic and secondary aliphatic amines (Table I, entries 2 vs. 3 and 11 vs. 15). Among the
secondary amines, cyclic amines such as morpholine reacted faster than acyclic amines such as
diethylamine (Table I, entry 5 vs. 6) while sterically hindered diisopropylamine did not react even
after days (Table I, entry 7). Aromatic and a&unsaturated ketones, on the other hand, reacted very
slowly (Table I, entries 24, 25 and 26).

In competition experiments, we found that an aliphatic ketone reacted, selectively and

quantitatively, in the presence of an aromatic or a&unsaturated ketone. Thus, competitive reaction

5595
 5596

TABLE I: REDUCTIVE AMINATION OF ALDEHYDES AND KETONES

USING SODIUM TRIACETOXYBOROHYDRIDE

Rl -H,O RI, Q/b NaBH(OAc)3 Rl\

NR, P3
R2>=0 + HN\R, W
/=NLR4 - R,2/cH-NLR,

entry &bony1 Compound Amine methoda time product

1 Cycloheptanone 1-Pmpylamine III 3 88 wa

2 ZHeptanone Cyclohexylamine II 24 84 (ox)b
3 ZHeptanone Aniline Iv 96 89 (ox)b
4 ZHeptanone Aniline I 96 74
5 2-Heptanone Mapholine I 27 73 @ICI)
6 2-Heptanone Dithylamine I 192 44 Wl)
7 Cycloheptanone Diisopropylamine I, II 96 NRC
8 Cyclohexanedione monoketal d Piperidine III 1.25 85
9 Qclohexanedione monoketal d Benzylamine. III 0.3 92
11 Norcamphor Benzyiamine Iv 6 9se
12 Benzaklehyde enab-2-Aminonorbamane Iv 0.5 85 (HCl)e
13 Norcamphor Aniline I 48 75 (Hc!l)e
14 Norcamphor Aniline III 6 76 (HCW
15 Norcamphor Diethylamine III 96 79 (0x)e
16 4-t-Butylcyclohexa Pyrrolidine Iv 0.17 98f
17 4-r-Butylcyclohexanone Isopropylamine III 0.5 988
18 Cyclohexane carboxaldehyde Morpholine II 2 74
19 Cyclohexane carboxaldehyde Diethylamine Iv 0.5 84 WC0
20 Cyclohexane carboxaldehyde Diisopropylamine III 3 410-w
21 Benzak-lehyde t-Butylamine III 3 95
22 m-Anisaldehyde Aniline III 0.3 95 @ICI)
23 m-Anisaldehyde Moipholine II 6 88
24 Acetophenone Beruylamine III 240 55h
2s Acetophenone Cyclohexylamine I, III 24 15”
26 I-Acetylcyclohexene Morpholine II 96 lob

a) methods; I: THF, AcOH (I equiv.). NoBH(OAc)3 (1.3-I 5 equiv.); II: THF. NaBH(OAc)3 (1.3-I ..5 equiv.);
III: DCE, AcOH (I equiv.), No.BH(OAc)j (I .3-l 5 equiv.), IV: DCE, NaBH(OAc)j (I .3-l J equiv.).
b) ox = oxalate. c) no reaction . d) I,4-cyclohtxanedione monoethylene ketal. e) endo product fi about 3 : I
ratlo of axlallequatorial. g) about 4 : 1 ratio of axiaUequatorial. h) yleld was determined by CC.
of 1-acetylcyclohexene and acetylcyclohexane (1 :l) with benzylamine for 1h led to a 98% yield of
N-(1 -cyclohexylethyl)benzylamine and recovered 1-acetylcyclohexene; competitive reaction of
acetophenone and cyclohexanone (1:l) with benzyl amine for 4h led to a 85% isolated yield of N-
cyclohexyl benzylamine and unreacted acetophenone. In these cases, there was no detectable
reaction with the aromatic or unsaturated ketone, except for the formation of trace amounts of their
imines.

The reaction conditions tolerate the presence of an acid sensitive group such as a ketal.
Thus, the reductive amination of cyclohexanedione monoethylene ketal with benzylamine and
piperidine in the presence of one mole of acetic acid afforded isolated yields of 92% and 85% of the
corresponding amines (Table I, entries 8 and 9).

The reductive amination of norcamphor led to the exclusive formation of the endo products,
probably from an exe attack by the hydride reagent on an intermediate imine. The predominance of
the endo product was confirmed by reductive amination of benzaldehyde with endo-2-
aminonorbornane (Table I, entry 11) which produced a product identical to that obtained from
reductive amination of norcamphor with benzylamine (Table I, entry 12). Reductive amination of 4-
tert-butyl cyclohexanone with pyrrolidine and isopropylamine occurred with a moderate
diastereoselectivity towards the thermodynamically less favored cis products resulting from
equatorial attack by the hydride reagent on the intermediate iminelo (Table I, entries 18 and 17).

Unlike ketones, aldehydes can-be reduced with sodium triacetoxyborohydride.4 However, in

only one case was the aldehyde reduction noticeable: Table I, entry 20 which involved a reaction
with the very sterfcally hindered diisopropylamine. All others (Table I, entries 12, 18, 19, 21, 22 and
23) resulted in fast and efficient reductive aminations with both primary and secondary amines in
reaction times ranging from 20 minutes to 8 hours. In the reactions between aldehydes and primary
amines, formation of dialkylated amines can be suppressed by addition of a 10% molar excess of the
primary amine.

In representative comparison reactions, sodium triacetoxyborohydride in 1,Pdichloroethane

reacted consistently faster, gave better yields and produced fewer side products than sodium
cyanoborohydrtde in methanol when used in reductive amination reactions.9 So, in conclusion,
sodium triacetoxyborohydride is a good alternative to sodium cyanoborohydride; its use eliminates
the problem of the residual cyanide in the product and in the waste stream.

Acknowledgement: The authors wish to thank Professor Robert 0. Hutchins (Drexel University)
for helpful discussions and for supplying some authentic samples. We also thank our spectroscopy
group: D. A. Gauthier, G. C. Leo, J. Masucci, W. J. Jones and G. Caldwell.
5598

References and Notes:

1. Abdel-Magid, A. F.; Maryanoff, C. A.; Sorgi, K. L.; Carson, K. G. Presented in part at the 198th
ACS National Meeting, Miami Beach, FL, September 1989; paper ORGN 154 and at the
1989 lntemational Chemical Congress of Pacific Basin Societies, Honolulu, HI, December
1989; paper ORGN 409.
2. For reviews on reductive aminations see: (a) Emerson, W. S. Organic Reactions, Wiley: New
York, 1948, vol.1 4, chapter 3, p 174, (b) Hutchins, Ft. 0.; Natale, N. Org. Prep. Pmced. Int.
1979, 11 (5), 20, (c) Lane, C. F. Synthesis 1975, 135.
3. Borch. R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Sot. 1971, 93, 2897.
4. Gribble, G. W.; Ferguson, D. C. J. C. S. Chem. Commun. 1975,535.
5. The mildness of the reagent was attributed to both the steric and the electron withdrawing
effects of the acetoxy groups which stabilize the boron-hydrogen bond. Gribble, G. W.
Eastman Organic Chemical Bulletin 1979, 51, No. 1.
6. Triacetoxyborohydrides do not usually reduce aliphatic and aromatic ketones4 but do reduce
8-hydroxyketones selectively to the Vans 1,3-dials. See for example:
(a) Saksena, A. K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24, 273, (b) Evans, D. A.;
Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939, (c) Evans, D. A.; Chapman, K. T.; Carreira,
E. M. J. Am. Chem. Sot. 1968, 1IO, 3560.
7. Earlier work by Gribble et al., demonstrated the potential of triacyloxyborohydrides generated
from NaBH4 in neat liquid carboxylic acids in reductive aminations involving aromatic amines:
(a) Gribble, G. W.; Lord, P. D.; Skotnicki, J.; Dietz, S. E.; Eaton, J. T.; Johnson, J. L. J. Am.
Chem. Sot. 1974, 96,7812, (b) Gribble, G. W.; Jasinski, J. M.; Pellicone, J. T.; Panetta, J. A.
Synthesis 1978, 766.
8. All products showed spectroscopic properties and elemental analyses consistent with their
structures.
9. A more detailed account of the comparative rates of reductive aminations with NaBH(OAc)s in
DCE vs. THF, the effect of acetic acid as well as comparisons between NaBH(OAc)s/DCE and
NaBHsCN/MeOH reactions will be reported.
10. This result is consistent with an earlier study on reduction of 4-substituted cyclohexanone
imines which concluded that bulky hydride reagents attack preferentially from the equatorial
side in contrast to small hydride reagents such as NaBH4 and NaBH3CN which favor the axial
approach. See Hutchins, R. 0.; Su, W. Y.; Sivakumar, R.; Cistone, F.; Stercho, Y. P. J. Org.
Chem. 1983, 43, 3412.

(Receivedin USA 2 July 1990)