One-pot reductive amination of aldehydes and ketones using N-methyl-piperidine zinc borohydride (ZBNMPP) as a new reducing agent

Article abstract of DOI:10.1055/s-2006-926230

A one-pot reductive amination of aldehydes and ketones using N-methyl piperidine zinc borohydride as a new and stable reducing agent is described. The reaction has been carried out in methanol at room temperature under neutral conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926230

LETTER
431
One-Pot Reductive Amination of Aldehydes and Ketones Using N-Methyl-
piperidine Zinc Borohydride (ZBNMPP) as a New Reducing Agent
O
ne-Pot Reductive
e
Amination
s
of
A
ldeh
h
yde
s
and
K
e
m
tones atollah Alinezhad,* Mahmoud Tajbakhsh,* Reza Zamani
Department of Chemistry, Mazandaran University, Babolsar, Iran
Fax +98(112)5242002; E-mail: heshmat@umz.ac.ir
Received 2 September 2005
N-Methylpiperidine zinc borohydride (ZBNMPP) is easi-
ly prepared by treating a freshly prepared ethereal solution
of zinc borohydride with N-methylpiperidine under a ni-
trogen atmosphere. ZBNMPP is a white powder, which
can be stored at room temperature in air. It decomposes at
250 °C. Based on the data obtained by atomic absorption
and borohydride content in an iodometric titration, togeth-
er with elemental analysis, showed within experimental
error that the reagent is in form of I. This reagent is an in-
expensive, stable and safe-to-handle reducing agent
(Figure 1).
Abstract: A one-pot reductive amination of aldehydes and ketones
using N-methyl piperidine zinc borohydride as a new and stable re-
ducing agent is described. The reaction has been carried out in
methanol at room temperature under neutral conditions.
Key words: ZBNMPP, reductive amination, aldehydes, ketones,
amines
Reductive amination of aldehydes and ketones, in which
a mixture of an aldehyde or ketone and an amine is treated
with a reductant in a one-pot fashion, is one of the most
useful methods for the preparation of secondary or tertiary
amines and related functional compounds in biological
and chemical systems1 (Scheme 1).
Zn(BH4)2
N
Me
I
NHR3
O
Figure 1
ZBNMPP
C
H2NR3
R1
+
R2
R1
R2
r.t., MeOH, 80–95%
Efficient and smooth reductive amination of a variety of
carbonyl compounds proceeded well in the presence of
amines using ZBNMPP under neutral conditions. The pH
of the media was adjusted to neutrality by addition of 10%
aqueous solution of HCl in methanol. Under such condi-
tions, ZBNMPP did not reduce the carbonyl compounds
in the reaction mixture, whereas the imine or iminium in-
termediate was converted easily to the corresponding
amine. Complete chemoselectivity is observed in reduc-
tive amination of a,b-unsaturated carbonyl compounds.
R1, R3 = alkyl, aryl
R2 = H, alkyl, aryl
Scheme 1
A variety of reducing agents, such as NaBH3CN,2
NaBH(OAC)3, borane–pyridine,4 tetrahydroborate ex-
3
change resin,5 ZnBH4,6a ZnBH4–ZnCl2,6b ZnBH4–SiO2,6c
Ti(Oi-Pr)4–NaBH4,7 decaborane,8 NaBH4–wet clay–mi-
crowave,9 PhSiH3–Bu2SnCl2,10 Bu3SnH,11 Bu3SnH–
SiO2,12 Zr(BH4)2Cl2(dabco)2,13 picoline–borane,14 and
solid acid-activated NaBH4 under solvent-free con-
ditions15 have been developed for this conversion. How-
ever, most of these reagents may have one drawback or
another. For example, the use of expensive and highly
toxic NaBH3CN that carries the risk of having residual
cyanide in the product as well as in the work upstream
makes this procedure less attractive. Clearly the use of
NaBH3CN is not acceptable in the context of green syn-
thesis, especially in industry.2b Tin hydride reagents are
also highly toxic and generate toxic organotin by-prod-
ucts.16 Herein, we introduce N-methylpiperidine zinc
borohydride (ZBNMPP) as a new stable reducing agent
for efficient and chemoselective reductive amination of
aldehydes and ketones.
In general, the reactions were carried out with four equiv-
alents of the primary amine or two equivalents of the sec-
ondary amine and one equivalent of ZBNMPP in MeOH
at room temperature. The reductive amination of a wide
variety of aldehydes and ketones with primary and sec-
ondary amines was successful and gave the desired prod-
ucts in good to excellent yields (80–95%), as shown in
Table 1. This method proves to be a clean, rapid and very
simple procedure for carrying out this type of transforma-
tion.
We initially examined a one-pot reductive amination reac-
tion of benzaldehyde (1 mmol) with aniline (4 mmol)
using ZBNMPP (1 mmol) in methanol (5 mL) and an
aqueous solution of HCl in methanol at room temperature
for two hours until TLC showed complete disappearance
of benzaldehyde. After usual work up, N-benzyl aniline
(91%) was obtained in high yield (entry 1). The same
reaction was conducted on larger scale [benzaldehyde
SYNLETT 2006, No. 3, pp 0431–0434
Advanced online publication: 06.02.2006
1
5.
0
2.
2
0
0
6
DOI: 10.1055/s-2006-926230; Art ID: D26605ST
© Georg Thieme Verlag Stuttgart · New York

432
H. Alinezhad et al.
LETTER
(10 mmol), aniline (40 mmol), ZBNMPP (10 mmol), that weakly acidic anilines like nitro and boromoanilines
MeOH (50 mL), r.t., 3.5 h] and a similar yield was ob- do not usually undergo clean reductive amination reac-
tained (93%).
tions. NaBH3CN, the most widely used reagent for the re-
ductive amination of aldehydes and ketones, is a sluggish
and inefficient reagent for this purpose.17 We have found
that both 4-nitro- and 4-boromoaniline react efficiently
with aromatic aldehydes within 3–4 hours in the presence
of ZBNMPP to produce their corresponding amines (en-
tries 6, 7). However, in order to examine a greater range
of amines to better illustrate the scope and limitation of
the method, we have investigated the reaction with allyl-
amine, benzylamine, propylamine, piperidine and pyrroli-
dine using PhCHO as a representative aldehyde, and
cyclohexanone as a representative ketone (Table 1, entries
11–14, 19–23). Reductive amination of aliphatic alde-
hydes such as butanal and hexanal with aniline also gives
excellent yield of the corresponding amines (Table 1,
entries 25, 26).
We also examined chemoselective reductive amination of
functionalized benzaldehydes bearing other reducible
functional groups employing the same methodology. As
shown in Table 1, aromatic aldehydes having nitro and
cyano groups underwent reductive amination to give the
corresponding N-phenyl amines in good yields without re-
duction of any other functional groups (entries 3, 4). In the
case of a,b-unsaturated aldehydes, such as cinnamalde-
hyde, reductive amination was successfully achieved in
excellent yield without reduction of the carbon–carbon
double bond (entry 27). Similarly aliphatic and cyclic ke-
tones underwent reductive amination successfully with
aniline to give the corresponding amines in high yield (en-
tries 16, 17), although the reaction with morpholine af-
forded the desired amine in lower yield (entry 24). But
under same conditions, however, reductive anilination of
acetophenone did not occur. It is interesting to mention
Table 1 Reductive Amination of Aldehydes and Ketones Using ZBNMPPa
Entry
1
Compound
Amine
Productb
Time (h)
2
Yield (%)c
9118
CHO
NH2
CH2NH
2
3
4
5
6
7
8
2.5
3
869
Cl
CHO
NH2
NH2
NH2
NH2
Cl
CH2NH
8519
8719
889
CHO
CH2NH
CH2NH
CH2NH
NC
NC
3.8
2.3
3
CHO
CHO
O2N
O2N
MeO
MeO
8620
8517
9325
CHO
CHO
CHO
Br
Br
NH2
CH2NH
4
NH2
NO2
O2N
CH2NH
1.2
Me
NH
Me
CH2N
9
1.5
1.2
9115
9014
CHO
CHO
CH2NH2
Me
CH2NHCH2
Me
10
CH
CH
NHCH2
NH2
11
12
13
1.5
0.5
1
8821
9214
8218
CH3–CH2–CH2–NH2
CH2=CH–CH2–NH2
CHO
CHO
CHO
CH2–NH–CH2–CH2–CH3
CH2–NH–CH2–CH=CH2
CH2
N
NH
Synlett 2006, No. 3, 431–434 © Thieme Stuttgart · New York

LETTER
One-Pot Reductive Amination of Aldehydes and Ketones
433
Table 1 Reductive Amination of Aldehydes and Ketones Using ZBNMPPa (continued)
Entry
14
Compound
Amine
Productb
Time (h)
0.8
Yield (%)c
8522
CHO
NH
N
CH2
15
16
17
3.8
1.2
2.5
8618
9323
9224
HN
CHO
O
O
O
N
CH2
NH
NH2
O
Me
NH2
NH2
CH3–(CH2)4 CH NH
CH3–(CH2)4
C
CH3
18
N.r.d
5
0
O
C
CH3
19
20
21
22
23
24
25
26
27
2
9115
9218
8022
9218
8322
8515
9318
9014
9519
CH2NH2
CH2NH
O
O
O
O
O
O
0.8
2.5
1.5
1
CH2=CH–CH2–NH2
CH3–CH2–CH2–NH2
NH–CH2–CH=CH2
NH–CH2–CH2–CH3
N
N
NH
NH
2
HN
O
N
O
O
1
NH2
NH2
NH2
CH3–CH2–CH2–CH2–NH
CH3–CH2–CH2 CH
1.2
1
O
CH3–(CH2)4 –CH2–HN
CH3–(CH2)4 –CH
O
CH
CH
CH2–NH
CH CH CH
a All reactions were carried out at r.t. and molar ratio of reagent–carbonyl compound–amine was 1:1:4 (primary amine) and 1:1:2 (secondary
amine).
b All products were characterized spectroscopically (1H NMR, IR) and showed physical and spectral data in accordance with their expected
structure and by comparison with authentic samples.
c Yields refer to pure isolated products.
d No reaction.
Preparation of N-Methylpiperidine Zinc Borohydride
(ZBNMPP)
Typical Procedure for Reductive Amination of Aldehydes and
Ketones with ZBNMPP
To a freshly prepared ethereal solution of zinc borohydride (200
mL, 0.03 mol), N-methylpiperidine (2.97 g, 0.03 mol) was added
dropwise over 20 min. Then the mixture stirred at r.t. for 1 h under
nitrogen atmosphere. The precipitate was filtered off, washed with
Et2O (10 mL), and the white powder was dried in vacuum desiccator
to produce 4.5 g (85% yield).
1H NMR (DMSO-d6): d = 2.43–2.55 (m, 4 H), 2.35 (s, 3 H), 1.55–
1.64 (m, 6 H), 0.86–1.42 (m, 8 H). MS: m/e = 41, 69, 96. Anal. Cal-
cd for: C, 37.13; H, 10.82; N, 7.21. Found: C, 37.08; H, 10.90; N,
7.23.
The preparation of N-cyclohexylaniline is representative. To a
stirred solution of cyclohexanone (0.098 g, 1 mmol) and aniline
(0.372 g, 4 mmol) in MeOH (5 mL) was added over 5 min the re-
ducing agent (0.194 g, 1 mmol) and the pH was adjusted to pH 7 by
addition of 10% aq soln of HCl in MeOH. The mixture was stirred
at r.t. (1.2 h), then silica gel (2 g) was added. The solvent was evap-
orated and the resulting material was applied on a silica gel column
and eluted with hexane–EtOAc (10:1, 100 mL). After evaporation
of the solvent, pure N-cyclohexylaniline was obtained (0.15 g, 93%
yield; Table, entry 16).
Synlett 2006, No. 3, 431–434 © Thieme Stuttgart · New York

434
H. Alinezhad et al.
LETTER
(8) Base, J. W.; Lee, S. H.; Cho, Y. J.; Yoon, C. M. J. Chem.
Soc., Perkin Trans. 1 2000, 145.
(9) Varma, R. S.; Dahiya, R. Tetrahedron 1998, 54, 6293.
(10) Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1754.
(11) Suwa, T.; Sugiyama, E.; Shibata, I.; Baba, A. Synlett 2000,
556.
(12) Hiror, R.; Miyoshi, N.; Wada, M. Chem. Lett. 2002, 274.
(13) Firouzabadi, H.; Iranpoor, N.; Alinezhad, H. Bull. Chem.
Soc. Jpn. 2003, 76, 143.
(14) Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y.
Tetrahedron 2004, 60, 7899.
(15) Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725.
(16) Pereyre, M.; Quintard, J. P.; Rahm, A. Tin in Organic
Synthesis; Butterworths: London, 1987, 6.
(17) Abdel-Magid, A. F.; Maryanoff, C. F. Synlett 1990, 537.
(18) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org.
Chem. 1985, 50, 1927.
(19) Cho, B. T.; Kang, S. K. Synlett 2004, 1484.
(20) Pin, L.; Jiangqing, L.; Gonghang, L.; Xunjun, Z. Youji
Huaxue 1986, 6, 447.
(21) Bumgardner, C. L.; Lawton, E. L.; Carver, J. G. J. Org.
Chem. 1972, 37, 407.
(22) Hutchines, R. O.; Markowitz, M. J. Org. Chem. 1981, 46,
3574.
Acknowledgment
Financial support of this work from the Research Council of
Mazandaran University gratefully acknowledged.
References
(1) (a) Baxter, E. W.; Reitz, A. B. Org. React. 2002, 59, 1.
(b) Hutchin, R. O.; Natale, N. R. Org. Prep. Proced. Int.
1979, 11, 201. (c) Lane, C. F. Synthesis 1975, 135.
(2) (a) Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673.
(b) Borch, R. F.; Bernstien, M. D.; Durst, H. D. J. Am. Chem.
Soc. 1971, 93, 2897.
(3) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849. (b) Beshore, D. C.; Dinsomere, C. J. Org. Lett. 2002,
4, 1201. (c) Zhang, J.; Blazecka, P. G.; Davidson, J. G. Org.
Lett. 2003, 5, 553.
(4) (a) Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem.
1995, 60, 5995. (b) Pelter, A.; Rosser, M.; Mills, S. J. Chem.
Soc., Perkin Trans. 1 1984, 717.
(5) Yoon, N. M.; Kim, E. G.; Son, H. S.; Choi, J. Synth.
Commun. 1993, 23, 1595.
(6) (a) Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi,
M. Synthesis 1990, 401. (b) Bhattacharyya, S.; Chatterjee,
A.; Williamson, J. S. Synth. Commun. 1997, 27, 4265.
(c) Ranu, B. C.; Majee, A.; Sakar, A. J. Org. Chem. 1998, 63,
370.
(7) (a) Miriyala, B.; Bhattacharyya, S.; Williamson, J. S.
Tetrahedron 2004, 60, 1463. (b) Kumpaty, H. J.;
Williamson, J. S.; Bhattacharyya, S. Synth. Commun. 2003,
33, 1411. (c) Neidigh, K. A.; Avery, M. A.; Williamson, J.
S.; Bhattacharyya, S. J. Chem. Soc., Perkin Trans. 1 1998,
2527. (d) Bhattacharyya, S. J. Org. Chem. 1995, 60, 4928.
(e) Bhattacharyya, S.; Chatterjee, A.; Williamson, J. S.
Synlett 1995, 1079.
(23) Gase, M. B.; Perie, J.; Lattes, A. Tetrahedron 1978, 34,
1943.
(24) Abdel-Magid, A. F.; Maryanoff, C. F.; Carson, K. C.
Tetrahedron Lett. 1990, 31, 5595.
(25) Gribble, G. W.; Nutaitis, C. F. Synthesis 1987, 709.
Synlett 2006, No. 3, 431–434 © Thieme Stuttgart · New York