Reductive amination using ammonia borane

Article abstract of DOI:10.1016/j.tetlet.2010.04.014

A variety of primary, secondary, and tertiary amines were prepared in 84-95% yields using ammonia borane for the reductive amination of aldehydes and ketones in the presence of titanium isopropoxide.

Full text of DOI:10.1016/j.tetlet.2010.04.014

Tetrahedron Letters 51 (2010) 3167–3169
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reductive amination using ammonia borane
a
a
b
P. Veeraraghavan Ramachandran a, , Pravin D. Gagare , Kaumba Sakavuyi , Paul Clark
*
a Department of Chemistry, 560 Oval Drive, Purdue University West Lafayette, IN 47907-2084, USA
b General Atomics, PO Box 85608, San Diego, CA 92186-5608, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 November 2009
Revised 5 April 2010
Accepted 6 April 2010
Available online 10 April 2010
A variety of primary, secondary, and tertiary amines were prepared in 84–95% yields using ammonia bor-
ane for the reductive amination of aldehydes and ketones in the presence of titanium isopropoxide.
Ó 2010 Elsevier Ltd. All rights reserved.
Reductive amination of carbonyls or reductive alkylation of
amines, the reaction of amines with aldehydes and ketones in the
presence of a reducing agent, is one of the widely used and funda-
mental reactions in organic chemistry.1,2 Catalytic hydrogenation,
sodium cyanoborohydride,3 sodium triacetoxyborohydride,4
sodium- or5 zinc borohydride6 in the presence of Brønsted or Lewis
acids, and amine boranes, such as pyridine–BH3,7 2-picoline–BH3,8
therefore, examined a selected series of Lewis acids such as ZnCl2,
NiCl2, SiO2, and Ti(OiPr)4 (Table 1) and carried out the reductive
amination reaction in tetrahydrofuran (THF) using AB as the reduc-
ing reagent. In the absence of Lewis acids, imine formation does
not occur and the aldehyde is reduced to benzyl alcohol.
In a typical reaction protocol, benzylamine (1.2 mmol) was
added to the solution of benzaldehyde (1 mmol) in THF (5 mL)
followed by the addition of the Lewis acid (1.2 mmol), and the
reaction mixture was stirred for 1 h at room temperature (rt).
Ammonia borane (1.5 mmol) was then added and stirring was
continued at the same temperature until the completion of the
reaction (disappearance of the carbonyl in thin layer chromato-
gram, 4 h). Utilization of ZnCl2 provided 80% yield of dibenzyl-
amine and increasing the equivalents of the amine had no
beneficial effect. NiCl2 failed to catalyze the reaction and the best
result, 94% yield of the product amine, was obtained with Ti(OiPr)4.
Under the optimized condition,23 the ratio of carbonyl/amine/
Ti(OiPr)4/AB is 1:1.2:1.2:1.5.
2,6-diborane–methanol,9 dimethylamine–BH3,10 t-BuMeiPrN–BH3,11
13
5-ethyl-2-methylpyridine–BH3,12 and benzylamine–BH3
have
been utilized to accomplish this transformation. However, most of
these reagents suffer from drawbacks. For example, NaBH3CN pro-
duces toxic by-products, such as NaCN and HCN.14 Catalytic hydro-
genation is unselective since it can also reduce other functional
groups such as alkenes, alkynes, and a nitro group.15 The amine bor-
anes are relatively expensive and have to be stored under optimal
conditions. For example, pyridine–borane16 undergoes an autocata-
lytic, highly exothermic hydroboration of the pyridine ring.17
The simplest amine borane, ammonia borane (AB), is a solid
with remarkable thermal and hydrolytic stability. Although the
use of AB for the reduction of carbonyls has been reported three
decades ago,18 to the best of our knowledge, its application for
reductive amination has not been reported, probably due to its rel-
atively high cost.19 Ammonia borane has recently received a lot of
attention as one of the promising materials for alternate energy.20
As part of our project involving AB as a hydrogen storage material,
we recently reported a large-scale synthesis of ammonia borane,21
which has been favorably received by the community.22 Our
project required the handling of large quantities of AB and we
observed that, indeed, AB is more convenient to handle in air than
sodium borohydride. This prompted us to examine AB for reduc-
tive amination and the results are described herein.
The reductive amination of a variety of aryl and alkyl aldehydes
and ketones with aryl and 1°- and 2°-alkyl amines of varying steric
Table 1
Reductive amination using ammonia borane: examination of Lewis acids
O
1. Lewis acid (1.2 eq)
THF, RT, 1 h
N
H
NH2
+
H
2. NH3BH3 (1.5 eq)
RT
Entry
Lewis acids
ZnCl2
ZnCl2
SiO2
Time (h)
Yielda (%)
A successful reductive amination procedure relies on the rapid
imine formation and selective reduction. Since imine formation is
usually the rate-determining step for in situ reductive aminations,
addition of mild Lewis acids as co-reactants is desirable. We,
1
2
3
4
5
10
8
11
24
4
80
78
75
b
NiCl2
Tracec
94
Ti(OiPr)4
a
b
c
Isolated yield.
1.5 equiv benzylamine was used.
Most of the starting material was recovered.
* Corresponding author. Tel.: +1 765 494 5303; fax: +1 765 494 0239.
E-mail address: chandran@purdue.edu (P. Veeraraghavan Ramachandran).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.014

3168
P. Veeraraghavan Ramachandran et al. / Tetrahedron Letters 51 (2010) 3167–3169
Table 2
Preparation of 2°- and 3°-amines via reductive amination using ABa
Entry
R1R2CO
R3R4NH
Time (h)
4
Product
Yieldb (%)
94
NH2
N
H
O
O
O
1
NH2
2
3
6
7
88
95
N
H
NH2
N
H
N
O
O
NH
4
5
5
3
84
85
N
O
NH
O
NH2
NH2
NH2
O
N
H
6
7
8
9
4
6
7
9
89
85
84
90
MeO
NC
MeO
NC
O
N
H
O
N
H
F C
F3C
N
3
NH2
NH2
NH2
O
N
H
N
CHO
N
H
10
11
4
2
91
91
CHO
N
H
CHO
NH2
H
N
12
8
87
CHO
NH2
NH2
NH2
N
H
13
14
15
5
6
94
92
90
CHO
N
H
H
CHO
O
N
10
NH2
N
H
16
17
8
8
86
84
O
O
O
NH
N
O
NH2
H
N
18
19
20
8
7
8
89
92
86
H
NH2
NH2
N
O
O
H
N
H
NH2
NH2
N
21
22
7
8
90
91
O
H
O
N
a
For the reaction conditions see footnote 23.
Isolated yields on the basis of the carbonyls.
b

P. Veeraraghavan Ramachandran et al. / Tetrahedron Letters 51 (2010) 3167–3169
3169
Table 3
References and notes
Preparation of 1°-amines via reductive amination using AB
1. For recent reviews see: (a) Margaretha, P. Sci. Synth. 2008, 40a, 65; (b) Tripathi,
R. P.; Verma, S. S.; Pandey, J.; Tiwari, V. K. Curr. Org. Chem. 2008, 12,
1093.
1. Ti(OiPr)4, Et3N, NH4Cl
O
NH2
THF, RT, 8 h
2. Abdel-Magid, A. F.; Carson, K. G.; Haris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org.
Chem. 1996, 61, 3849.
3. (a) Markey, M. D.; Fu, Y.; Kelly, T. R. Org. Lett. 2007, 9, 3255; (b) Baxter, E. W.;
Reitz, A. B. Org. React. 2002, 59, 1; (c) Lewin, G.; Schaeffer, C. Heterocycles 1998,
48, 171.
4. Abdel-Magid, A. F.; Mehrman, S. J. Org. Process Res. Dev. 2006, 10, 971.
5. (a) Alinezhad, H.; Ardestani, E. Lett. Org. Chem. 2007, 4, 473; (b) Saxena, I.;
Borah, R.; Sarma, J. C. J. Chem. Soc., Perkin Trans. 1 2000, 503; (c) Bhattacharyya,
S. J. Org. Chem. 1995, 60, 4928; (d) Verardo, G.; Giumanini, A. G.; Strazzolini, P.;
Poiana, M. Synthesis 1993, 121; (e) Itsuno, S.; Sakurai, Y.; Ito, K. Chem. Commun.
1988, 995.
R1
R1
2. NH3BH3
RT, 10 h
R2
R2
Entry
1
Ketone
R1R2CH2NH2
NH2
Yielda (%)
85
O
O
NH2
6. (a) Heydari, A.; Khaksar, S.; Esfandyari, M.; Tajbakhsh, M. Tetrahedron 2007, 63,
3363; (b) Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi, M. Synthesis
1990, 401; (c) Bhattacharyya, S.; Chatterjee, A.; Williamson, J. S. Synth.
Commun. 1997, 27, 4265; (d) Ranu, B. C.; Majee, A.; Sarkar, A. J. Org. Chem.
1998, 63, 370.
7. (a) Parker, J. S.; Bowden, S. A.; Firkin, C. R.; Moseley, J. D.; Murray, P. M.;
Welham, M. J.; Wisedale, R.; Young, M. J.; Moss, W. O. Org. Process Res. Dev.
2003, 7, 67; (b) Moseley, J. D.; Moss, W. O.; Welham, M. J. Org. Process Res. Dev.
2001, 5, 491; (c) Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60,
5995.
8. (a) Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Tetrahedron 2004, 60,
7899; (b) Uchiyama, S.; Inaba, Y.; Matsumoto, M.; Suzuki, G. Anal. Chem. 2009,
81, 485.
9. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1980, 34, 4817.
10. Heydari, A.; Tavakol, H.; Aslanzadeh, S.; Azarnia, J.; Ahmadi, N. Synthesis 2005,
627.
11. Brown, H. C.; Kanth, J. V. B.; Dalvi, P. V.; Zaidlewicz, M. J. Org. Chem. 1999, 64,
6263.
12. Bruckhardt, E. R.; Coleridge, B. M. Tetrahedron Lett. 2008, 49, 5152.
13. Peterson, M. A.; Bowman, A.; Morgan, S. Synth. Commun. 2002, 32, 443.
14. Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725.
15. (a) Roe, A.; Montgomery, J. A. J. Am. Chem. Soc. 1953, 74, 910; (b) Rylander, P. N.
Catalytic Hydrogenation over Platinum Metals, Academic Press, New York,
1967, p. 21.
16. (a) Brown, H. C.; Schlesinger, H. I. J. Am. Chem. Soc. 1942, 64, 328; (b) Taylor, M.
D.; Grant, L. R.; Sands, C. A. J. Am. Chem. Soc. 1955, 77, 1506; (c) Rychkewitsch,
G. E.; Birnbaum, E. R. Inorg. Chem. 1965, 4, 575.
2
3
83
75
MeO
MeO
O
NH2
O
NH2
4
5
72
74
O2N
O2N
NH2
O
a
Isolated yield.
requirements using AB as the reductant was accomplished within
2–10 h to obtain the desired 2°- or 3°-amines, respectively, in
80–94% yields (Table 2). The reactions were slower with increasing
steric requirements of the carbonyl or amine, and ketones were
slower to react than aldehydes.
17. (a) Baldwin, R. A.; Washburn, R. M. J. Org. Chem. 1961, 26, 3549; (b) Brown, H.
C.; Domash, L. J. Am. Chem. Soc. 1956, 78, 5384.
18. (a) Andrews, G. C.; Crawford, T. C. Tetrahedron Lett. 1980, 21, 693; (b) Andrews,
G. C. Tetrahedron Lett. 1980, 21, 697.
19. Aldrich: Borane–ammonia complex, 97% Tech. grade, $189.50/10 g.
20. (a) Davis, B. L.; Dixon, D. A.; Garner, E. B.; Gordon, J. C.; Matus, M. H.; Scott, B.;
Stephens, F. H. Angew. Chem., Int. Ed. 2009, 48, 6812; (b) Marder, T. B. Angew.
Chem., Int. Ed. 2007, 46, 8116.
21. Ramachandran, P. V.; Gagare, P. D. Inorg. Chem. 2007, 46, 7810.
22. http://www.hydrogen.energy.gov/pdfs/review09/st_20_linehan.pdf.
23. To the solution of carbonyl compound (1 mmol) in THF (4 mL), the 1°- or 2°-
amine (1.2 mmol) was added followed by the addition of Ti(OiPr)4 (1.2 mmol).
The reaction mixture was stirred for 1 h at rt. Ammonia borane (1.2 mmol) was
added and continued stirring at the same temperature. Upon completion of the
reaction, as revealed by TLC, the resulting mixture was treated with HCl (3 mL,
6 M) and stirred for an additional hour. The reaction mixture was diluted with
water (10 mL) and extracted with diethyl ether (3 Â 15 mL). The aqueous layer
was then treated with NaOH (2 M) until pH 10–12 and extracted with diethyl
ether (3 Â 15 mL). The combined organic extracts were washed with brine,
dried (Na2SO4), concentrated in vacuo, and purified by silica gel flash
chromatography to obtain the desired product.
24. Borch, R. F.; Dust, H. D. J. Am. Chem. Soc. 1969, 91, 3996.
25. Sharma, S. K.; Songster, M. F.; Colpitts, T. L.; Hegyes, P.; Barany, G.; Castellinoh,
F. J. J. Org. Chem. 1993, 58, 4993.
26. Garro-Helion, F.; Merzouk, A.; GuibB’J, F. J. Org. Chem. 1993, 58, 6109.
27. Bhattachyaryya, S.; Neidigh, K. A.; Avery, M. A.; Williamson, J. S. Synlett 1999,
1781.
Following the successful application of AB for the preparation of
2°- and 3°-amines, we focused on the synthesis of 1°-amines,
which remains a challenge due to over-alkylation reaction.24 Tri-
tylamine,25 diallylamine,26 and NH4Cl27 are often employed as sur-
rogates to prepare primary amines and we chose NH4Cl. In a
typical reaction,28 Ti(OiPr)4 was added to the solution of acetophe-
none, NH4Cl, and triethylamine in ethanol and stirred for 10 h at
ambient temperature. Ammonia borane was then added and stir-
red for an additional 8 h to obtain the desired primary amine in
83–85% yield (Table 3). Aryl and alkyl ketones furnished the 1°-
amine in 72–75% yields. However, the reaction of aldehydes re-
sulted in 2°-amines.
In conclusion, we have shown that ammonia borane is a versa-
tile and efficient reagent for the reductive amination of aldehydes
and ketones providing 2°- and 3°-amines in good to excellent
yields. The formation of primary amines was achieved in good
yield from ketones using Ti(OiPr)4/Et3N and NH4Cl as ammonia
source. We believe that this reductive amination process will find
applications in organic synthesis due to the stability and simple
preparation of AB.21
28. To the solution of the ketone (1 mmol), NH4Cl (1.5 mmol), and triethylamine
amine (1.5 mmol) in absolute ethanol (5 mL) was added Ti(OiPr)4 (1.5 mmol)
and stirred at rt for 10 h. Ammonia borane (1.5 mmol) was added and stirred
for an additional 8 h at the same temperature. Upon completion of the
reaction as revealed by TLC, the reaction was quenched with aq. ammonia
(1 M) and the reaction mixture was extracted with diethyl ether (3 Â 15 mL).
The combined organic extracts were washed with HCl (3 M, 10 mL). The
acidic aqueous solution was washed with diethyl ether, basified using NaOH
(2 M) to pH 10–12, and extracted with diethyl ether (3 Â 10 mL). The
combined organic extracts were washed with brine, dried (Na2SO4),
concentrated in vacuo, and purified by silica gel flash chromatography to
obtain the desired product.
Acknowledgment
Financial support from General Atomics/U.S. Army is gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.014.