Reductive amination of aldehydes and ketones with 2-(Tributylamino)- ethoxyborohydride

Article abstract of DOI:10.1007/s00706-007-0750-y

A new ionic liquid is presented as a medium and reducing agent for the reductive amination of aldehydes and ketones.

Full text of DOI:10.1007/s00706-007-0750-y

Monatshefte fu¨r Chemie 138, 1187–1189 (2007)
DOI 10.1007/s00706-007-0750-y
Printed in The Netherlands
Reductive Amination of Aldehydes and Ketones with 2-(Tributylamino)-
ethoxyborohydride
Farajollah Mohanazadeh1;ꢀ, Mehdi Forozani2, and Azam Taheri2
1
Institute of Industrial Chemistry, Iranian Research Organization for Science and Technology, Tehran, Iran
2
Department of Chemistry, PayamNour, Sari, Iran
Received June 16, 2007; accepted June 23, 2007; published online September 12, 2007
# Springer-Verlag 2007
Summary. A new ionic liquid is presented as a medium and
reducing agent for the reductive amination of aldehydes and
ketones.
opment of an efficient, safe, and environmentally
friendly method to accomplishing the reductive ami-
nation is an important challenge.
Room temperature ionic liquids (RTILs) are rec-
Keywords. Reductions; Ionic liquids; Alcohols; Hydrides.
ognized as green recyclable alternatives to the tra-
ditional volatile organic solvents because of their
unique chemical and physical properties [16]. They
have emerged as alternative reaction media for the
immobilization of transition metal based catalysts,
Lewis acids, and enzymes [17]. They are referred
to as ‘‘designer solvents’’ as their properties such as
hydrophilicity, hydrophobicity, Lewis acidity, viscos-
ity, and density can be altered by changing the cation
and the counter anions. Their high polarity and abil-
ity to solubilize both organic and inorganic com-
pounds can result in enhanced reaction rates and
can provide higher selectivity compared to conven-
tional solvents. As results of their green credentials
and potential to enhance rates and selectivity ionic
liquids are finding increasing applications in organic
synthesis [18].
Introduction
An important method of preparing amines is to treat
ammonia or an amine with aldehyde or ketone in the
presence of a suitable reducing agent. These reduc-
ing agents are usually hydrogen and a catalyst [1] or
a hydride reducing agent, particularly sodium cyano-
borohydride (NaBH3CN) [2]. Other reported reduc-
tive amination reagents include borone-pyridine [3],
Ti(O-i-Pr)4=NaBH3CN [4], borohydride exchange
resin [5], Zn=AcOH [6], NaBH4=Mg(ClO4)2 [7],
NaBH(OAc)3 [8], Et3SiH=CF3COOH [9], Bu3SnH=
DMF [10], ZnCl2=NaBH4 [11], silica gel=Zn(BH4)2
[12], ZrCl4=NaBH4 [13], NiCl2=NaBH4 [14], and
H2SO4=NaBH4 [15]. Though some of the above-
mentioned reagents provide good yields of amines,
they also involve the use of hazardous reagents or
organic solvents. Reductive amination with NaBH4
and Lewis acids requires an excess of the amine (up
to five-fold) in order to drive the reaction to comple-
tion, since carbonyl compounds themselves are also
reduced under the conditions used. Thus, the devel-
Results and Discussion
However, we discovered that a task-specific ionic
liquid, 2-(tributylamino)ethoxyborohydride (1), effi-
ciently promotes the reductive amination of alde-
hydes and ketones with amines without requiring
any other catalyst and solvent. 2-Hydroxy-N,N,N-
tributylethanaminium bromide (Scheme 1, 1) was
ꢀ
Corresponding author. E-mail: mohannazadeh@irost.org

1188
F. Mohanazadeh et al.
generated by mixing the separated ionic liquid with
5% HBr for 20 min, decanting, and heating at 80ꢁC
under vacuum for 30 min.
The reaction condition is very mild and can toler-
ate the presence of acid sensitive functional groups
such as ketals. For example, the reductive amination
of cyclohexanedione monoethylene ketal with pri-
mary and secondary amines afforded good isolated
yields of the corresponding amines (Table 1, entries
11, 12).
Scheme 1
In conclusion, the present procedure using an easi-
ly accessible and inexpensive ionic liquid as reagent
for the reductive amination of amines with aldehydes
or ketones provides a novel protocol for the synthesis
of amines. This procedure offers marked improve-
ments with regard to operational simplicity, isolated
yields of products, considerably faster reaction times
(20–30min), and mild and neutral conditions.
obtained from reaction of tributylamine and 2-bro-
moethanol at 120ꢁC for 6 h. 2-(Tributylamino)ethox-
yborohydride (Scheme 1, 1) was prepared from 2 by
reaction with sodium borohydride in water. This
reagent is soluble in chloroform, dichloromethane,
acetone, and ethanol. It is insoluble in water, diethyl
ether, and n-hexane. The resulting ionic liquid is
very stable at room temperature and could be stored
as a bench-top reagent for months without appreci-
able change in its reactivity.
Experimental
In a typical procedure the aldehyde or ketone and
amine are mixed with the ionic liquid at room tem-
perature for the time specified in Table 1. At the end
of the reaction, ether was added. The organic layer
was separated, washed with water, dried with Na2SO4,
and filtered. The filtrate was evaporated to leave the
crude product. It was purified on a short column of
silica gel. The bromide salt of ionic liquid 2 was
2-Hydroxy-N,N,N-tributylethanaminium bromide
(2, C14H32BrNO)
In a round bottomed 50cm3 flask equipped with a condenser
and magnetic stirrer, 9.25 g tributylamine (0.05 mol) and 6.25 g
2-bromoethanol (0.05 mol) were mixed at 120ꢁC for 6 h. The
reaction mixture was washed with 2ꢂ30cm3 diethyl ether.
After drying in vacuum for 30min, 10.8g (70%) of product
were isolated as a pure oily liquid. 1H NMR (90 MHz, DMSO-
Table 1. Reductive amination of aldehydes and ketones
Ref.b
Yielda
Time
Entry
Aldehyde=ketone
Amine
min
%
1
2
3
4
5
6
7
8
9
benzaldehyde
benzaldehyde
benzaldehyde
4-chlorobenzaldehyde
4-nitrobenzaldehyde
3-chlorobenzaldehyde
propanal
acetophenone
cyclohexanone
cyclohexanone
cyclohexanedionemonoethylene ketal
cyclohexanedionemonoethylene ketal
aniline
30
20
30
30
20
30
20
90
45
45
45
60
92
93
85
93
93
83
91
75
85
88
85
87
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[8]
benzylamine
o-toluidine
aniline
benzylamine
o-toluidine
aniline
aniline
aniline
morpholine
benzylamine
piperidine
10
11
12
[8]
a
Comparison of spectral data (IR, NMR) and thin layer chromatography with an authentic sample also confirmed structure and
b
purity of the reported amines. References for products

Reductive Amination of Aldehydes and Ketones
1189
d6): ꢀ ¼ 6.1 (s, 1H), 3.8–4.1 (t, 2H), 3.1–3.7 (m, 8H), 1.2–1.9
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Trans I: 717
(m, 12H), 0.86–1.1 (br, d, 9H) ppm.
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Trans I: 503
2-(Tributylamino)ethoxyborohydride (1, C14H34BNO)
In a round bottomed 100 cm3 flask, 15.5 g compound 2
(0.05 mol), 40 cm3 H2O, and 2.28g sodium borohydride
(0.06 mol) were mixed at room temperature. The mixture
was stirred rapidly for 2 min and extracted with 3ꢂ50cm3
CH2Cl2. The organic layer was dried (Na2SO4) and the solvent
was evaporated in reduced pressure. After drying in vacuum
for 2 h, 11.3g (93%) 1 were obtained as a colorless oily liquid.
1H NMR (90 MHz, DMSO-d6): ꢀ ¼ 3.4–4.0 (t, 2H), 2.9–3.4
(m, 8H), 1.2–1.9 (m, 12H), 0.8–1.1 (br. d, 9H) ppm; Anal.
calcd (%) for C14H34BNO (234.24): C, 69.13; N, 5.758; B,
4.444; Htotal, 14.08; Hactive, 1.243; O, 6.577; found: C, 68.01;
N, 6.27; B, 4.41; Htotal, 13.88; Hactive, 1.22; B=Hactive1=3.
Active hydrogen was determined by a standard method [19]
and nitrogen by the Dumas method.
Reductive Amination of Benzaldehyde and Aniline,
Typical Procedure
[15] Verado G, Giumanin AG, Strazzolini P, Poiana M (1993)
Synthesis: 121
Benzaldehyde (1.06 g, 0.01 mol) and aniline (0.93 g, 0.01mol)
are mixed in 5.13 g (0.015 mol) ionic liquid 1, at room tem-
perature for 30 min. At the end of the reaction, 20cm3 diethyl
ether were added. The organic layer was separated, washed
with water, dried (Na2SO4), and filtered. The filtrate was evap-
orated to leave the product. Crystallization from ethanol af-
forded 1.68g (62%) benzylaniline. Mp 36.5–37.5ꢁC (Ref. [20]
36–37.2ꢁC).
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[18] Jain N, Kumar A, Chauhan S, Chauhan SMS (2005)
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[21] Mason T (1893) J Chem Soc Trans: 1311
[22] Miyano S, Abe N, Uno A (1966) Chem Pharm Bull 14:
731
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