Highly chemoselective reductive amination-coupling by one-pot reaction of aldehydes, HMDS and NaBH4

Article abstract of DOI:10.1016/j.tetlet.2008.09.048

An efficient and highly chemoselective synthesis of symmetrical secondary amines via reductive amination of aldehydes with inexpensive and commercially available HMDS and sodium borohydride in high to quantitative yields is reported.

Full text of DOI:10.1016/j.tetlet.2008.09.048

Tetrahedron Letters 49 (2008) 6682–6684
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly chemoselective reductive amination-coupling by one-pot
reaction of aldehydes, HMDS and NaBH4
Najmedin Azizi b, Elham Akbari a, Alireza Khejeh Amiri b, Mohammad R. Saidi a,
*
a Department of Chemistry, Sharif University of Technology, PO Box 11465-9516, Tehran 11365, Iran
b Chemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2008
Revised 31 August 2008
Accepted 10 September 2008
Available online 13 September 2008
An efficient and highly chemoselective synthesis of symmetrical secondary amines via reductive amina-
tion of aldehydes with inexpensive and commercially available HMDS and sodium borohydride in high to
quantitative yields is reported.
Ó 2008 Elsevier Ltd. All rights reserved.
Secondary amines and their derivatives exist in many biologi-
cally important molecules, and are important intermediates in
the synthesis of pharmaceutically active substances, dyes, and fine
chemicals.1 In addition, optically active secondary amines have
important applications in organic asymmetric synthesis as chiral
auxiliaries,2 catalysts,3 and resolving agents.4 Consequently, syn-
thesis of amines is an active field in medicinal chemistry and mod-
ern organic synthesis.
source of amine. This completely acid-free reaction was carried
out in the presence of catalytic amounts of lithium perchlorate as
a simple and readily available catalyst in a one-pot reaction with
NaBH4 in methanol as reducing agent. The general applicability
of this method for the direct and indirect synthesis of a wide vari-
ety of diverse amines is demonstrated in Scheme 1.
We initially examined indirect reductive amination of N,N-
bis(phenylmethylidene)phenylmethanediimine9 (1) with sodium
borohydride. After examining different procedures, it was deter-
mined that slow addition of a NaBH4 (3 equiv) to a cold solution
of 1 (1 equiv) in methanol at 0 °C resulted in formation of second-
ary amine 2. The reaction was carried out by mixing compound 1
with sodium borohydride in methanol under normal atmosphere,
until TLC showed complete disappearance of diimine 1.
To explore the generality and scope of this process, the reac-
tions of a range of diimines were studied, and the results are sum-
marized in Table 1. Generally, excellent yields of secondary amines
with different aryl groups were obtained under the optimized reac-
tion conditions, including those bearing electron-withdrawing- or
electron-donating groups, and the corresponding products were
obtained in excellent yields in all cases.10
The direct reductive amination of aldehydes and ketones with
metal hydride reagents is one of the most useful methods for the
synthesis of secondary and tertiary amines, and different methods
have been developed to carry out this transformation.5,6 However,
some of these procedures are complicated by the formation of ter-
tiary amines (when secondary amines are required) and by the
reduction of carbonyl compounds to alcohols. They often require
a large excess of nitrogen and hydrogen sources to achieve good
yields. Furthermore, in many of these procedures, primary amines,
as well as high pressure or precious metals, are used for reductive
amination. Recently, two Letters7 reported the first reductive ami-
nation of aldehydes with ammonia using molecular hydrogen and
water-soluble catalysts with excellent results. However, the reac-
tions were performed at high temperature and pressure. A litera-
ture survey shows that there are no reports on the selective
synthesis of secondary amines via reductive amination of alde-
hydes with inexpensive and commercially available hexamethyldi-
silazane, HMDS. Thus the development of a mild direct reductive
amination using HMDS as the source of amine is an important re-
search goal.
Ar
NaBH4
N
N
3
+
2
Ar
N
H
Ar NH3
MeOH, 0 oC-rt, 2 h
1
80-97%
Ar
Ar
2
Ar
N
LiClO4, 50 oC, 30 min
N
+
3 ArCHO
In continuation of our interest in developing organic transfor-
mations, using simple reagents, catalysts and reaction media,8
herein, we report the first direct reductive amination of aromatic
aldehydes with HMDS. In this procedure, HMDS is used as the
2 HMDS
1
Ar
Ar
MeOH, NaBH4, rt, 2 h
1
Ar
N
Ar
+
NH3
H
70-95%
* Corresponding author. Tel.: +98 2166 165303; fax: +98 2166 012983.
E-mail address: saidi@sharif.edu (M. R. Saidi).
Scheme 1. Reductive amination of aromatic aldehydes.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.048

N. Azizi et al. / Tetrahedron Letters 49 (2008) 6682–6684
6683
Table 1
Table 2
Synthesis of secondary amine from diimines
One-pot synthesis of secondary amines from an aldehyde and HMDS
Ar
1- LiClO4, 30 oC, 30 min
2- MeOH, NaBH4, rt, 2 h
NaBH4
Ar
N
H
Ar
Ar
N
Ar
ArCHO
+HMDS
Ar
N
N
Ar
MeOH, rt, 2 h
H
80-97%
2
(70-95%)
Entry
1
Aryl group
Products
N
H
Ar (yields)
97
97
97
95
80
Cl
Br
2a (95)
2b (92)
2c (90)
N
CHO
S
O
2
3
4
5
H
Cl
Cl
Cl
H3C
MeO
2e (70)
2d (92)
2f (80)
2g (78)
N
H
Br
Br
Br
Cl
N
H
Cl
2j (80)
H3C
CH3
H3C
2i (72)
2h (82)
N
H
MeO
Cl
MeO
OMe
and HMDS. Initially, the nucleophilic nitrogen in 3, generated from
reduction of the imine, adds to another molecule of diimine 1 to
form the intermediate 4, which can then undergo further reduction
and fragmentation to form the secondary amine 2 and intermedi-
ate 5. Although we have no direct evidence for this mechanistic
pathway, the detection of NH3 as a byproduct and the failure to de-
tect any deuterium in the secondary amines 2, when the reaction
was carried out in D2O instead of MeOH, may validate the pro-
posed mechanism in Scheme 2. Detection of ammonia was tested
qualitatively by HCl gas (formation of NH4Cl powder) and by pH
indicator paper.
In summary, we have described a novel, highly efficient and
simple protocol for the synthesis of secondary amines from alde-
hydes and HMDS in the presence of NaBH4. Furthermore, the pro-
cedure offers several advantages including improved yields,
cleaner reactions, simple experimental procedure, and use of read-
ily available and inexpensive starting materials, which make it a
useful and attractive strategy in multicomponent reactions in com-
binational chemistry.
N
H
6
7
85
92
Cl
Cl
Cl
Cl
Cl
N
H
N
8
9
80
88
84
H
O
S
N
H
O
O
S
N
H
10
S
Next, we explored the possibility of developing this new proto-
col into a one-pot three-component reaction, using an aldehyde,
HMDS, and NaBH4, Scheme 1. The reaction of benzaldehyde was
chosen as a model, and several sets of reaction conditions were
examined. The aldehyde (1.0 equiv) and HMDS (1.3 equiv) were
mixed at 50 °C in the presence of solid LiClO4 (1.0 equiv) as Lewis
acid for 30 min. Then the reaction mixture was cooled to room
temperature, and NaBH4 in methanol was added. The reaction mix-
ture was stirred at room temperature for 120 min to give the cor-
responding secondary amines in good to excellent yields. To show
the generality and scope of this method, various aromatic alde-
hydes were successfully transformed into their corresponding sec-
ondary amines in high yields. The results are summarized in Table
2. The presence of electron-withdrawing- or electron-donating
substituents on the aromatic ring was not effective on the reactiv-
ity. Sensitive aldehydes well tolerated under these reaction condi-
tions, which are very mild. Secondary amines formed exclusively
without the formation of reduced aldehyde.11 In most cases, after
the normal work-up, the crude products did not need any further
purification. However, aliphatic aldehydes, such as isobutyl alde-
hyde, did not give the desired products.
Ar
Ar
Ar
N
N
NaBH4
N
NH
N
N
Ar
Ar
1
3
Ar
Ar
Ar
Ar
1
_
H
Ar
Ar
Ar
HN
Ar
NH
Ar
HN
Ar
N
Ar
NaBH4
Ar
Ar
HN
N
Ar
Ar
Ar
N
N
Ar
4
NH2
Ar
-NH3
+NH3
Ar
N
Ar
N
H
Ar Ar
N
+
H
2
5
_
H
The following mechanistic postulate may be invoked to ratio-
nalize the formation of the secondary amines from the aldehyde
Scheme 2. Possible mechanism for the formation of secondary amine 2.

6684
N. Azizi et al. / Tetrahedron Letters 49 (2008) 6682–6684
3921; (j) Kobayashi, S.; Yasuda, M.; Hachiya, I. Chem. Lett. 1996, 407; (k)
Acknowledgments
Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745; (l) Suwa, T.; Sugiyama, E.;
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Baba, A. Org. Lett. 1999, 1, 1579; (n) Shibata, I.; Moriuchi-Kawakami, T.;
Tanizawa, D.; Suwa, T.; Sugiyama, E.; Matsuda, H.; Baba, A. J. Org. Chem. 1998,
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Financial support of this work by the Chemistry and Chemical
Research Center of Iran and Sharif University of Technology is
gratefully appreciated.
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10. General procedure for the one-pot preparation of a secondary amine: A mixture of
aldehyde (2 mmol), HMDS (4 mmol), and LiClO4 (2 mmol) was heated for
30 min at 50 °C. Then the reaction mixture was cooled to 0 °C, and methanol
(5 mL) and NaBH4 (6 mmol) were added over a period of 5 min. The reaction
mixture was warmed to room temperature and stirred for 120 min. Methanol
was removed under reduced pressure, and reaction mixture was quenched
with a saturated aqueous solution of NaHCO3 (10 mL) and extracted with
CH2Cl2 or ether (2 Â 5 mL). The combined organic extract was washed with
saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered, and
concentrated. The crude products were purified in some cases by a flash
column chromatography on silica gel (petroleum ether and ethyl acetate). All
compounds were characterized on the basis of their spectroscopic data (IR,
NMR) and by comparison with those reported in the literature.Caution:
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11. Indirect methods: N,N-Bis(phenylmethylidene)phenyl-methanediamine,9
1
(Ar = phenyl), (1 mmol) in MeOH (5 mL) was treated carefully with solid
NaBH4 (3 mmol) over a period of 5 min at 0 °C. The reaction mixture was
warmed to room temperature, stirred for 120 min, and quenched with 1 M
NaHCO3. The product was extracted with ether or CH2Cl2. The solvent extract
was washed with saturated aqueous NaCl and dried (Na2SO4). The solvent was
evaporated to give the crude product. Further, purification was carried out by
column chromatography on silica gel eluting with petroleum ether/ethyl
acetate, if needed.