Direct reductive amination of carbonyl compounds using bis(triphenylphosphine) copper(I) tetrahydroborate

Article abstract of DOI:10.1016/j.tetlet.2006.12.037

A direct reductive amination protocol for aldehydes/ketones using bis(triphenylphosphine) copper(I) tetrahydroborate as a novel reducing agent in the presence of sulfamic acid has been developed. The reagent chemoselectively reduces the imine moiety and does not affect other reducible functionalities such as chloro, nitro, cyano and methoxy.

Full text of DOI:10.1016/j.tetlet.2006.12.037

Tetrahedron Letters 48 (2007) 1273–1276
Direct reductive amination of carbonyl compounds
using bis(triphenylphosphine) copper(I) tetrahydroborate
Mayur J. Bhanushali, Nitin S. Nandurkar, Malhari D. Bhor and
Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, N.Parekh Marg, Matunga, Mumbai 400 019, India
Received 17 October 2006; revised 24 November 2006; accepted 8 December 2006
Abstract—A direct reductive amination protocol for aldehydes/ketones using bis(triphenylphosphine) copper(I) tetrahydroborate as
a novel reducing agent in the presence of sulfamic acid has been developed. The reagent chemoselectively reduces the imine moiety
and does not affect other reducible functionalities such as chloro, nitro, cyano and methoxy.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Amines and their derivatives are important functional-
ities in various natural products and unnatural synthetic
targets. Due to its unique biological properties the
amine moiety has played a central role in the chemother-
apeutics of numerous diseases.1 Lower aliphatic amines
are used as organic intermediates for the synthesis of
drugs, bactericides, herbicides, rubber accelerators,
corrosion inhibitors and surface-active agents.2–4 Con-
sidering their significant applications in the fields of
medicinal, bioorganic, industrial and synthetic organic
chemistry, there has been tremendous interest in devel-
oping efficient methods for the synthesis of amines.
hydride–magnesium perchlorate,10 ZnBH4–ZnCl2,11
NaBH(OAc)3,12 silica gel–ZnBH4,13 dibutyltin chloride
hydride14 and NaBH3CN15 have been developed for this
conversion. However, most of these reagents have one
or other disadvantages. The use of NaBH3CN carries
the risk of having residual cyanide in the product, while
pyridine–borane is thermally unstable and must be han-
dled with extreme care. Also, catalytic hydrogenation
protocols are incompatible with a number of other
reducible functional groups such as nitro, cyano and
C–C multiple bonds. Therefore, the search for a milder
and more efficient system for performing direct reduc-
tive amination has been the subject of recent focus.
The reductive amination of aldehydes and ketones is one
of the most useful methods for the synthesis of second-
ary and tertiary amines. The importance of reductive
amination procedures is exemplified by the enormous
number of its synthetic uses.5 Direct reductive amina-
tion (DRA) procedures, where the carbonyl compound
is treated in a one-pot fashion with the amine and a
reducing agent is an extremely useful method. The two
commonly used DRA processes are based either on a
hydride reagent or catalytic hydrogenation. Hydride re-
In an effort to develop a convenient system for the DRA
reaction, we focussed our attention on the use of
complex hydrides. The size of the complex transition
metal borohydrides, together with their solubility in
non-hydroxylic organic solvents, makes them ideal for
studies on selective reduction. An example of one such
reagent is bis(triphenylphosphine) copper(I) tetrahydro-
borate (1) which has been used in the reduction of acid
chlorides to aldehydes.16,17 Unlike NaBH4, 1 provides
only one hydride equivalent per mole and the reagent
appears to tolerate a variety of functional groups such
as nitro, cyano, ester and C–C multiple bonds. As a
result of its unique features, 1 has found applicability
in many natural product syntheses. The ease of prepara-
tion of 1, compatibility with various functional groups,
indefinite shelf life and stability towards air and mois-
ture prompted us to investigate its activity in direct
reductive amination reactions.
6
agents such as NaBH4 borane–pyridine,7 borohydride
exchange resin (BER),8 zinc–acetic acid,9 sodium boro-
Keywords: Reductive amination; Bis(triphenylphosphine) copper(I)
tetrahydroborate; Carbonyl compounds; Amines.
*
Corresponding author. Tel.: +91 22 24145616; fax: +91 22
24145614; e-mail addresses: bhalchandrabhanage@rediffmail.com;
bhalchandra_bhanage@yahoo.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.037

1274
M. J. Bhanushali et al. / Tetrahedron Letters 48 (2007) 1273–1276
H
H
1:1.2:1 mol ratio of aniline, benzaldehyde and
Ph3P
Ph3P
H
H
Cu
B
Cu(PPh3)2BH4 in methanol at room temperature. Under
neutral conditions, no substantial reduction of the corre-
sponding imine was observed. We then turned our atten-
tion towards the use of additives to promote the
reaction. Since most DRA reactions are favoured under
acidic conditions, the addition of 1 equiv of sulfamic
acid led to higher yields of the desired product. Sulfamic
acid was used because of its mild acidity, non-volatility,
non-corrosive nature and cheap commercial availability.
Bis(triphenylphosphine) copper(I) tetrahydroborate (1)
Herein, we report bis(triphenylphosphine) copper(I)
tetrahydroborate18 as a complex transition metal boro-
hydride for the direct reductive amination of aldehydes
and ketones in the presence of sulfamic acid. The reac-
tion was carried out in methanol under mild operating
conditions (Scheme 1).
The influence of solvents on the DRA of aldehydes and
ketones was also investigated (Table 1). Solvents such as
chloroform and THF led to no conversion due to the
Initially, the condensation of benzaldehyde with aniline
was chosen as the model reaction, to examine the effect
of the reductant. The reaction was carried out in a
Table 1. Influence of solvent on the DRA of carbonyl compounds
Entry
Solvent
Time (h)
Yielda (%)
NHR3
O
1
2
3
4
5
Chloroform
Tetrahydrofuran
Methanol
Ethanol
Toluene
6
6
1.5
4
6
—
—
96
92
92
H2NR3
Cu(PPh3)2BH4, MeOH
+
C
NH2SO3H, R.T
R1
R2
R1
R2
R1, R3 = alkyl, aryl
2 = H, alkyl, aryl
R
a Reaction conditions: benzaldehyde = 1.2 mmol, aniline = 1 mmol,
sulfamic acid = 1 mmol, complex 1 = 1 mmol, solvent = 5 ml. Yields
based on GC analysis.
Scheme 1. DRA of aldehydes and ketones with primary and secondary
amines.
Table 2. Reductive amination of aldehydes and ketonesa
Entry
Carbonyl compound
Amine
Time (h)
1.5
Product
Isolated yieldb
94
CHO
H N
2
1
N
H
CHO
CHO
H2N
H2N
N
H
2
3
2
92
93
1.5
N
H
Cl
Cl
CHO
H N
2
4
1.5
90
N
H
NC
CN
CHO
H N
2
5
6
2
4
88
83
N
H
H3CO
OCH
3
H2N
NO2
CHO
N
H
NO2
H N
2
OCH
3
CHO
CHO
7
8
3
2
91
92
N
H
OCH
3
O
N
H
O
N

M. J. Bhanushali et al. / Tetrahedron Letters 48 (2007) 1273–1276
1275
Table 2 (continued)
Entry
Carbonyl compound
Amine
Time (h)
3
Product
Isolated yieldb
93
CHO
9
N
H
N
Bz
N
CHO
CHO
CHO
10
1.5
3
94
92
87
89
88
Bz N
N
N
H
11
12
13
14
N
H
N
(CH2)5CH3
N
CH3(CH2)5NH2
4
H
H2N
NH(CH ) CH
CHO
CHO
2 4
3
1.5
1.5
H N
2
H
N
CHO
H N
2
15
16
2
84
88
N
H
H N
H
2
O
C
Me
Me
N
1.5
Me
Me
Et
O
C
H N
2
H
N
Et
17
18
19
20
2
3
4
4
88
82
92
91
Me
Et
Me
Et
O
C
H N
2
H
N
Et
Et
O
H N
2
H
N
O
O
O
H N
2
H
N
O
21
22
4
4
90
87
O
N
N
H
CH3(CH2)5NH2
NH(CH ) CH
2 5
3
a Reaction conditions: carbonyl compound = 6 mmol, amine = 5 mmol, sulfamic acid = 5 mmol, 1 = 5 mmol, solvent = methanol (15 ml).
b Isolated yields.
good solubility of complex 1 in the respective solvent.
However, when methanol, ethanol and toluene were
employed, better results were obtained, which was in
agreement with literature reports,16a suggesting that
complex 1 is highly active when the reactions are carried
out in a medium in which 1 is insoluble.

1276
M. J. Bhanushali et al. / Tetrahedron Letters 48 (2007) 1273–1276
5. (a) Emerson, W. S. In Org. React.; Wiley, 1948; Vol. 4, p.
174; (b) Lane, C. F. Synthesis 1975, 135; (c) Hutchins, R.
O.; Hutchins, M. K. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 8, pp 25–78; (d) Tarasevich, V. A.; Kozlov, N. G.
Russ. Chem. Rev. 1999, 68, 55; (e) Baxter, E. W.; Reitz, A.
B. In Org. React.; Wiley, 2002; Vol. 59, p 1 and references
cited therein.
To evaluate the general applicability of this reagent,
a variety of aldehydes and ketones were reductively
aminated with aliphatic and aromatic amines (Table 2,
entries 1–22).19 The reaction of aniline with benzalde-
hyde (entry 1) gave a 94% yield of N-benzylaniline with-
in 1.5 h. Similarly, primary and secondary aliphatic
amines (entries 2, 8–12) when reacted with benzaldehyde
afforded the corresponding N-benzyl derivatives in
excellent yields. Another important feature of this
protocol was the survival of a variety of reducible func-
tional groups such as chloro, cyano, nitro and methoxy
(entries 3–7). The system also allowed the DRA of cin-
namaldehyde, to N-cinnamyl aniline in an excellent yield
without affecting the double bond (entry 15). Similarly
aliphatic aldehydes such as valeraldehyde and isobutyr-
aldehyde were also aminated effectively (entries 13–14).
6. Hutchins, R. O.; Natale, N. R. Org. Prep. Proced. Int.
1979, 11, 201.
7. (a) Pelter, A.; Rosser, R. M.; Mills, S. J. Chem. Soc.,
Perkin Trans. 1 1984, 717; (b) Bomann, M. D.; Guch,
I. C.; DiMare, M. J. Org. Chem. 1995, 60, 5995; (c)
Moorman, A. E. Synth. Commun. 1993, 23, 789.
8. Yoon, N. M.; Kim, E. G.; Son, H. S.; Choi, J. Synth.
Commun. 1993, 23, 1595.
9. Micovic, I. V.; Ivanovic, M. D.; Paitak, D. M.; Bojic, V.
Dj. Synthesis 1991, 1043.
10. Brussee, J. R.; van Benthem, A. T. M.; Kruse, C. G.; van
der Gen, A. Tetrahedron: Asymmetry 1990, 1, 163.
11. Bhattacharyya, S.; Chatterjee, A.; Duttachowdhury, S. K.
J. Chem. Soc., Perkin Trans. 1 1994, 1.
12. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
13. Ranu, B. C.; Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63,
370.
14. (a) Shibata, I.; Suwa, T.; Sugiyama, E.; Baba, A. Synlett
1998, 1081; (b) Shibata, I.; Moriuchi-Kawakami, T.;
Tanizawa, D.; Suwa, T.; Sugiyama, E.; Matsuda, H.;
Baba, A. J. Org. Chem. 1998, 63, 383.
15. Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
Soc. 1971, 93, 2897.
To check the overall compatibility of this protocol, the
direct reductive amination of ketones was also carried
out. A variety of ketones such as acetone, butan-2-one
and cyclohexanone were efficiently aminated with
various aliphatic and aromatic amines under mild condi-
tions to afford the corresponding amines (entries 16–22)
in good to excellent yields.
In summary, bis(triphenylphosphine) copper(l) tetra-
hydroborate has proved to be an excellent reagent for
direct reductive amination of both aldehydes and
ketones having different steric and electronic properties.
The ease of making, handling, storing and using 1,
together with its compatibility with a large number of
functional groups, makes this reagent an attractive and
general alternative to the present range of methods for
the direct reductive amination procedures. There is also
considerable scope for modifying the reagent with a
chiral phosphine ligand with the prospect of asymmetric
induction.
16. (a) Fleet, G. W. J.; Harding, P. J. C. Tetrahedron Lett.
1979, 20, 975; (b) Sorrell, T. N.; Pearlman, P. S. J. Org.
Chem. 1980, 45, 3449.
17. Fleet, G. W. J.; Harding, P. J. C.; Whitcombe, M. J.
Tetrahedron Lett. 1980, 21, 4031.
18. Preparation of bis (triphenylphosphine) copper(I) tetra-
hydroborate: Finely powdered copper(I) chloride (10 g,
0.1 mol) was added to a stirred solution of triphenylphos-
phine (54 g, 0.205 mol) in chloroform (375 ml) over 5 min.
The reaction mixture was stirred until the copper chloride
had dissolved (15 min), then treated with a suspension of
sodium tetrahydroborate (3.8 g, 0.1 mol) in ethanol
(40 ml) and stirred for a further 15 min, and then added
to water (75 ml). The chloroform layer was washed with
water (2 · 65 ml), dried (magnesium sulphate) and treated
with diethyl ether (500 ml). Bis(triphenylphosphine) cop-
per(I) tetrahydroborate precipitated immediately and was
collected by filtration and washed with ether to give white
needles of 1, mp 172–174 ꢁC.
Acknowledgement
Financial assistance from TEQIP—Government of
India is kindly acknowledged.
References and notes
19. Typical procedure for DRA of aldehydes and ketones: To a
solution of carbonyl compound (6 mmol), amine (5 mmol)
and sulfamic acid (5 mmol) in 15 ml of methanol was
added Cu(PPh3)2BH4 (5 mmol) over a period of 5 min.
The reaction mixture was magnetically stirred at room
temperature. After completion of the reaction (monitored
by TLC), the reaction mixture was filtered and the filtrate
was evaporated to yield a crude product, which was
purified using silica gel (60–120 mesh) column chroma-
tography with petroleum ether–ethyl acetate as the eluent
to afford the pure amine.
1. Bradshaw, J. S.; Krakowiak, K. E.; Izatt, R. M. Tetra-
hedron 1992, 48, 4475.
2. (a) Merla, B.; Risch, N. Synthesis 2002, 1365; (b) Gordon,
E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.;
Gallop, M. A. J. Med. Chem. 1994, 37, 1385.
3. Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. In
Pharmaceutical Substances, 3rd ed.; Thieme: Stuttgart,
1999.
4. Henkel, T.; Brunni, R. M.; Mueller, H.; Reichel, F.
Angew. Chem., Int. Ed. Engl. 1993, 38, 643.