Reductive amination of aldehydes using aminoboranes as iminium ion generators

Article abstract of DOI:10.1055/s-2006-939070

2-Dialkylamino-4H-1,3,2-benzodioxaborins, salicyl alcohol derived aminoboranes, serve as efficient and mild iminium ion generators in the reductive animation of aldehydes with NaBH₄. Using a diisopropylamino derivative, a variety of amines including secondary and primary amines, and ammonia can participate to the reductive amination in aprotic organic solvents without the use of acidic promoters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939070

LETTER
1047
Reductive Amination of Aldehydes Using Aminoboranes as Iminium Ion
Generators
Reductive Amination
o
i
f
A
lde
c
hydes
U
sing
h
A
minobor
a
i
ne
s
nori Suginome,* Yusuke Tanaka, Tomoaki Hasui
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University,
Katsura, Kyoto 615-8510, Japan
Fax +81(75)3832722; E-mail: suginome@sbchem.kyoto-u.ac.jp
Received 6 February 2006
Reaction of benzaldehyde with aminoborane 1a was car-
ried out in the presence of hydride sources with a catalytic
amount of 2-piperidinone, which had been proven to pro-
mote Mannich-type reactions using aminoboranes as an
Abstract: 2-Dialkylamino-4H-1,3,2-benzodioxaborins, salicyl al-
cohol derived aminoboranes, serve as efficient and mild iminium
ion generators in the reductive amination of aldehydes with NaBH4.
Using a diisopropylamino derivative, a variety of amines including
secondary and primary amines, and ammonia can participate to the iminium ion generator (Table 1).6c,7 In the reactions using
reductive amination in aprotic organic solvents without the use of
acidic promoters.
NaBH3CN as a reducing agent, diethylbenzylamine, a re-
ductive amination product, was obtained selectively albeit
Key words: reductions, aminations, boron, chemoselectivity, alde-
hydes
in moderate yields in NMP (N-methylpyrrolidinone) or in
DCE (1,2-dichloroethane, entries 1 and 2). The yield was
improved by using NaBH(OAc)3 as a reducing agent in
DCE (entry 3). Our interest was then focused on the use
Reductive amination of aldehydes is one of the most at- of more general reducing agents. Interestingly, we found
tractive methods for the synthesis of amine derivatives, that use of aminoborane 1a with NaBH4, which is capable
including highly functionalized ones.1,2 The attractiveness of reducing carbonyl groups, led to highly selective reduc-
of the protocol mainly arises from the availability of a tive amination with no formation of benzyl alcohol (en-
wide range of starting aldehydes and amines, as well as tries 4–8).8 Among the solvents tested for the reductive
the simplicity of the experimental procedures. Typically, amination, moderately polar aprotic organic solvents such
a mixture of an aldehyde and an amine is treated with a as 1,2-dichloroethane, THF, and dioxane gave almost
weak hydride donor, which only slowly reduces the alde- quantitative yields of diethylbenzylamine (entries 5–7). It
hyde directly. For this purpose, hydride sources such as should be noted that use of ethanol as a solvent resulted in
NaBH3CN3 and NaBH(OAc)3 have been developed.
From the mechanistic point of view, it has been widely
accepted that the reductive amination proceeds through
4
Table 1 Reactions of Benzaldehyde with Diethylaminoborane
Derivative 1a in the Presence of Reducing Agentsa
O
NEt2
generation of iminium ion intermediates. To facilitate imi-
nium ion formation, acid promoters are often added with
the hydride donors. Even with NaBH(OAc)3, which is
usually used without acid promoters in aprotic organic
solvents, certain aldehydes need the use of an acid to fa-
cilitate the generation of the iminium intermediates.5 Al-
though the acid-promoted reductive amination systems
have been used extensively, it seems to be highly desir-
able to develop alternative reductive amination systems
with non-acidic promoters to expand the reaction scope.
O
C
borohydrides
B
+
Ph
NEt2
O
Ph
H
2-piperidinone
(0.2 equiv)
3aa
solvent, r.t.
2a
1a (1 equiv)
Entry
Borohydride (equiv)
NaBH3CN (1.5)
NaBH3CN (1.5)
NaBH(OAc)3 (2.0)
NaBH4 (1.0)
Solvent
NMP
Yield (%)b
1
2
3
4
5
6
7
8
9
71
56
87
86
99
99
99
67
10
DCE
DCE
Recently, we reported an efficient reagent system for the
facile, mild generation of iminium ions.6 We found that
aminoborane derivatives served as non-acidic iminium
ion generators in Strecker-type and Mannich-type amina-
tive C–C bond forming reactions. The results prompted us
to apply the new iminium ion generators to other impor-
tant amination processes. Herein, we report a new reduc-
tive amination protocol, which utilizes the aminoborane
and NaBH4 in aprotic organic solvents under non-acidic
reaction conditions.
NMP
NaBH4 (1.0)
DCE
NaBH4 (1.0)
THF
NaBH4 (1.0)
Dioxane
Toluene
EtOH
NaBH4 (1.0)
NaBH4 (1.0)
a Benzaldehyde (0.24 mmol) and 1a (0.24 mol) were reacted with
borohydrides in the presence of 2-piperidinone (0.048 mmol) for 16 h
(entry 1), 2.5 h (entry 2), or 0.5 h (entries 3–9).
b GC yields.
SYNLETT 2006, No. 7, pp 1047–1050
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939070; Art ID: U01806ST
© Georg Thieme Verlag Stuttgart · New York

1048
M. Suginome et al.
LETTER
the formation of the amine only in 10% yield along with Reactions of various aldehydes with secondary amines
major formation of benzyl alcohol in 85% yield (entry 9). were then carried out (Equation 1, Table 3).9 Reactions of
para-substituted benzaldehydes afforded the correspond-
ing reductive amination products in good yields (entries
Following the successful reductive amination using ami-
noboranes 1a as the amino source, use of free secondary
1–3). Other aromatic aldehydes afforded the correspond-
amines as the amino source with iminium ion generator
ing diethylaminomethyl-substituted aromatic compounds
1b was examined (Table 2).6c
in good yields (entries 4 and 5). Reactions of aromatic
aldehydes with other secondary amines, including those
Table 2 Reactions of Benzaldehyde with Diethylamine in the
Presence of Aminoborane 1b with NaBH4
a
having benzyl or allyl protective groups, were also suc-
cessful (entries 6–11). An aliphatic aldehyde underwent
the reductive amination in good yields (entries 12 and 13).
O
NiPr2
B
O
O
C
O
NiPr2
1b
B
Et2NH
+
Ph
NEt2
Ph
H
NaBH4
O
2a
4a
2-piperidinone (0.2 equiv)
DCE, r.t., 30 min
3aa
R2
R1
R3
H
1b
R2
R3
O
C
N
C
(1.0 equiv)
N
+
H
Entry Equiv of 1b Equiv of Et2NH Equiv of NaBH4 Yield (%)b
R1
H
NaBH4
H
2-piperidinone (0.2 equiv)
DCE, r.t.
1
2
3
4
5d
6
7
8
1.0
1.0
1.0
1.0
1.0
0.5
0.33
0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
0.25
0.5
1.0
1.0
1.0
1.2
1.2
1.2
76
98
95c
99
90
66
59
0e
2
4
3
Equation 1
Table 3 Reductive Amination with Secondary Amines Using
a
Aminoborane 1b with NaBH4
Entry R1CHO
R2R3NH (equiv)
Et2NH (4a) (1.5)
4a (1.5)
Yield (%)b
96 (3ba)
95 (3ca)
84 (3da)
84 (3ea)
87 (3fa)
84 (3fb)
97 (3ac)
98 (3fd)
1
2
3
4
5
6
7
8
p-O2NC6H4CHO (2b)
p-BrC6H4CHO (2c)
p-MeOC6H4CHO (2d)
4a (1.5)
a Benzaldehyde (0.24 mmol), Et2NH, and 1b were reacted with
NaBH4 in the presence of 2-piperidinone (0.048 mmol) in DCE at r.t.
unless otherwise noted.
2,4-(MeO)2C6H3CHO (2e) 4a (1.0)
2-NapCHO (2f)
2-NapCHO (2f)
PhCHO (2a)
4a (1.0)
b GC yield based on the amount of benzaldehyde used.
c Diisopropylbenzylamine was also formed in <3% yield.
d No 2-piperidinone was added.
Me2NH (4b) (2.0)
Bn2NH (4c) (1.5)
e Benzyl alcohol was obtained in 78% yield.
2-NapCHO (2f)
NH
In the presence of 1b, benzaldehyde was reacted with var-
ied amounts of NaBH4 and diethylamine. Although a fair
yield was attained even with just stoichiometric amounts
of NaBH4 and diethylamine (entry 1), better yields were
obtained with use of excess amounts of the hydride. When
NaBH4 and the amine were used in a 1:1 molar ratio, mi-
nor formation (<3%) of diisopropylbenzylamine was de-
tectable (entry 3). Use of more diethylamine (entry 4) or
less borohydride (entry 2) suppressed the by-product for-
mation, leading to highly selective formation of diethyl-
benzylamine. It should be noted here that, in the absence
of 2-piperidinone, slightly lower yield was attained (entry
5). When less than one equivalent of the aminoborane was
used in the reaction, the reductive amination product was
obtained in much lower yields (entries 6 and 7), although
the aminoborane-based yields exceeded 100%. In the ab-
sence of the aminoborane, no reductive amination product
was formed, but benzyl alcohol was obtained in moderate
yield (entry 8).
(4d) (1.5)
9c 2-NapCHO (2f)
93 (3fe)
O
NH
O
(4e) (1.5)
10
2-NapCHO (2f)
2-NapCHO (2f)
(allyl)2NH (4f) (1.0) 84 (3ff)
11
92 (3fg)
O
NH
(4g) (1.0)
4a (1.0)
4d (1.5)
12
13
14
PhCH2CH2CHO (2g)
2g
83 (3ga)
93 (3gd)
2-NapCHO (2f)
PhMeNH (4h) (2.0) 80 (3fh)
a Aldehydes (0.24 mmol) were reacted with amines in the presence of
aminoborane 1b (0.24 mol), NaBH4 (0.26 mmol), and 2-piperidinone
(0.048 mmol) in DCE at r.t. for 1–3 h, unless otherwise noted.
b Isolated yield.
c 1.0 mmol scale.
Synlett 2006, No. 7, 1047–1050 © Thieme Stuttgart · New York

LETTER
Reductive Amination of Aldehydes Using Aminoboranes
1049
It should be remarked that an aniline derivative, which the amide, while lower yield was attained in the absence
generally shows low nucleophilicity, took part in the reac- of the amide (entry 3).
tion, leading to the formation of the corresponding aniline
Table 5 Reductive Amination of 2,4,6-Trimethoxybenzaldehyde
derivative in good yield (entry 14).
with Et2NHa
We found that not only secondary amines, but also prima-
OMe
OMe
ry amines and even ammonia gave the corresponding re-
ductive amination products selectively in good yields
(Table 4). Thus, reactions of p-methoxybenzylamine with
aromatic aldehydes under the reaction conditions identi-
cal to those for secondary amines gave the corresponding
p-methoxybenzylamine derivatives in good yields (entries
1 and 2). An aniline derivative (ArNH2) also afforded the
corresponding reductive amination product in good yield
in the reaction with benzaldehyde (entry 3). In the reaction
of an aliphatic aldehyde with primary amines, the corre-
sponding amines were obtained in moderate yields (en-
tries 4 and 5). In the reaction of 2g with 4i, formation of a
significant amount of an enamine, PhCH2CH=CHNH-
CH2C6H4-p-OMe, was responsible for the moderate yield
(entry 4). Reaction of 2-naphthaldehyde with 2 equiva-
lents of ammonia afforded 2-(aminomethyl)naphthalene
selectively in excellent yield (entry 6).
CHO
OMe
NEt2
OMe
+
Et2NH
MeO
MeO
4a
2h
3ha
Entry Reagent (equiv)
Conditions
Yield
(%)b
1
2
3
4
5
NaBH(OAc)3
(1.0)
DCE,
r.t., 12 h
40
55
48
NaBH3CN
(1.5)
AcOH (1.0 equiv), MeOH,
r.t., 10 h
1b (1.0), NaBH4 DCE,
(1.0) r.t., 18 h
1b (1.0), NaBH4 2-Piperidinone (0.2 equiv), DCE, 60
(1.0) r.t., 12 h
1b (1.0), NaBH4 2-Piperidinone (0.3 equiv), DCE, 88
(1.0) r.t., 0.5 h
Table 4 Reductive Amination with Primary Amines and Ammonia
a
Using Aminoborane 1b with NaBH4
a 2,4,6-Trimethoxybenzaldehyde (0.2 mmol) was reacted with
diethylamine (1.0 equiv).
Entry R1CHO
R2NH2
Yield (%)b
b GC yields (entries 1–3) or isolated yield (entry 4).
1
2
3
4
5
6
PhCHO (2a)
p-MeOC6H4CH2NH2 (4i) 92 (3ai)
2-NapCHO (2f)
PhCHO (2a)
4i
99 (3fi)
83 (3aj)
56 (3gi)
70 (3gj)
99 (3fk)
Throughout the study presented herein, we had almost no
success in the use of ketones as the carbonyl component.
In the reaction of acetophenone with diethylamine, for in-
stance, no reaction took place at room temperature, while
only carbonyl reduction proceeded at 50 °C. The only ex-
ception that we have so far experienced is the reaction of
cyclobutanone derivative 5, which afforded the corre-
sponding amine product 6 in good yield at room tempera-
ture (Equation 2).10 We then tested chemoselective
reductive amination in which formyl and keto groups are
discriminated. Reaction of 4-formylacetophenone (7)
with secondary amines in the presence of 0.50 equivalent
of NaBH4 with 1b afforded 4-(aminomethyl)acetophe-
none (8) in high yield (Equation 3). It should be remarked
that the keto group was left intact with no reduction.
p-MeC6H4NH2 (4j)
PhCH2CH2CHO (2g) 4i
PhCH2CH2CHO (2g) 4j
2-NapCHO (2f)
NH3 (4k) (2.0)
a Aldehydes (0.24 mmol) were reacted with amines (1.5 equiv unless
otherwise noted) in the presence of aminoborane 1b (0.24 mol),
NaBH4 (0.26 mmol), and 2-piperidinone (0.048 mmol) in DCE at r.t.
for 1–2 h.
b Isolated yield.
In the amination reaction using NaBH(OAc)3, it has been
reported that the use of electron-rich aromatic aldehydes
often meets with difficulty in attaining high yields.5 For
instance, reaction of 2,4,6-trimethoxybenzaldehyde (2h)
with diethylamine in the presence of NaBH(OAc)3 result-
ed in the production of the corresponding amine product
in moderate yield even after a prolonged reaction period
(12 h, Table 5, entry 1). Use of NaBH3CN with an acid
promoter in methanol also resulted in a moderate yield
(entry 2). In contrast, under the reaction conditions using
aminoborane 1b, the electron-rich aldehyde successfully
gave the reductive amination product in higher yields
(entries 4 and 5). In this particular reaction, the effect of
2-piperidinone as an additive was pronounced. Use of
0.3 equivalents of 2-piperidinone gave better yield than
the standard reaction conditions using 0.2 equivalents of
1b (1.0 equiv)
NaBH4 (1.2 equiv)
Ph
Ph
Ph
Ph
+
O
NEt2
Et2NH
2-piperidinone
(0.2 equiv)
DCE, r.t., 12 h
(2 equiv)
5
4a
6 (80%)
Equation 2
CHO
NEt2
1b (1.0 equiv)
Me
NaBH4 (0.5 equiv)
Me
Et2NH
+
2-piperidinone
(0.2 equiv)
O
(3 equiv)
O
8 (88%)
DCE, r.t., 30 min
7
4a
Equation 3
Synlett 2006, No. 7, 1047–1050 © Thieme Stuttgart · New York

1050
M. Suginome et al.
LETTER
(4) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
(5) Gutierrez, C. D.; Bavetsias, V.; McDonald, E. Tetrahedron
Lett. 2005, 46, 3595.
(6) (a) Suginome, M.; Yamamoto, A.; Ito, Y. Chem. Commun.
2002, 1392. (b) Suginome, M.; Uehlin, L.; Yamamoto, A.;
Murakami, M. Org. Lett. 2004, 6, 1167. (c) Suginome, M.;
Uehlin, L.; Murakami, M. J. Am. Chem. Soc. 2004, 126,
13196.
(7) Although the addition of 2-piperidinone is not crucial to
attain the reductive amination product, it moderately
accelerates the reaction and improves the yield to some
extent.
In summary, we have demonstrated reductive amination
of aldehydes using iminium ion generator 1 with NaBH4.
In certain reactions, we have found that the use of this new
reagent system is advantageous over some conventional
reaction systems, in which rather elaborated hydride
sources such as NaBH(OAc)3 and NaBH3CN are used. In
addition, the aminoborane’s capability for mild and selec-
tive iminium ion generation may offer new possibilities
for amine synthesis.
Acknowledgment
(8) (a) Sodium borohydride has rarely been utilized in reductive
aminations, unless imines are preformed in situ before the
reduction step, see ref. 1b. For reduction of preformed
imines by NaBH4, see: Schellenberg, K. A. J. Org. Chem.
1963, 28, 3259. (b) Very recently, a combination of NaBH4
and a solid acid, such as boric acid and p-TsOH, was
reported as an efficient reagent for reductive amination: Cho,
B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725.
(9) Typical Procedure for Reductive Amination Using 1b.
To a solution of 2-piperidinone (0.048 mmol) in 1,2-
dichloroethane (0.5 mL) were added 1b (57 mg, 0.24 mmol),
amines (0.24–0.48 mmol), aldehyde (0.24 mmol) and
NaBH4 (11 mg, 0.29 mmol) at r.t. After stirring for 0.5–3 h,
MeOH (0.5 mL) was added and the mixture was subjected
directly to column chromatography on silica gel pretreated
with 5% Et3N in hexane.
This work was supported by a Grant-in-Aid for Scientific Research
(No. 17655040) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
References and Notes
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Riermeier, T. H.; Börner, A. Chem. Commun. 2000, 1867.
(b) Apodaca, R.; Xiao, W. Org. Lett. 2001, 3, 1745.
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(10) 3,3-Diphenylcyclobutylamine derivatives have been
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E. J. Med. Chem. 1978, 21, 78.
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Synlett 2006, No. 7, 1047–1050 © Thieme Stuttgart · New York