Transfer hydrogenation of imines with carboxyl-tailed benzothiazoline as readily removable hydrogen donor

Article abstract of DOI:10.1016/j.tetlet.2011.11.061

A benzothiazoline bearing 4-carboxyphenyl group at 2-position was developed as an efficient hydrogen donor for the transfer hydrogenation reaction. Introduction of the carboxyl group significantly facilitated the removal of the residual benzothiazoline an

Full text of DOI:10.1016/j.tetlet.2011.11.061

Tetrahedron Letters 53 (2012) 416–418
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Tetrahedron Letters
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Transfer hydrogenation of imines with carboxyl-tailed benzothiazoline
as readily removable hydrogen donor
⇑
Chen Zhu, Takahiko Akiyama
Department of Chemistry, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A benzothiazoline bearing 4-carboxyphenyl group at 2-position was developed as an efficient hydrogen
donor for the transfer hydrogenation reaction. Introduction of the carboxyl group significantly facilitated
the removal of the residual benzothiazoline and benzothiazole by washing with aqueous basic solution.
The present approach provides a convenient and straightforward access to various amines with broad
substrate scope and in good yields.
Received 13 October 2011
Revised 7 November 2011
Accepted 11 November 2011
Available online 18 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Transfer hydrogenation
Reduction
Imine
Benzothiazoline
Reductive amination
NPMP EtO C
CO Et
NHPMP
+
2
2
EtO C
CO Et
2
2
The reduction of imines, including the direct hydrogenation and
transfer hydrogenation pathways, is an important reaction for the
+
N
N
1
H
preparation of amines. In addition to several known methods that
2
employ metal catalysts, a biomimetic approach that relies on the
Rf value (EtOAc:Hexane = 1:4) :
utilization of Hantzsch esters as the hydrogen source has been
established in the fields of asymmetric synthesis, inspired by nat-
0.45
0.10
0.38
0.35
3
urally occurring hydrogenation processes. As the most prevalent
mimic of NADH, Hantzsch esters are efficiently applied in the
NPMP
NHPMP
H
N
4–6
N
S
reduction of C@N and C@C bonds.
We have recently reported
+
+
Ph
the first example of the use of benzothiazoline7 as the hydrogen
Ph
S
source in the transfer hydrogenation of ketimines and
esters, which furnished a variety of chiral amines and
a
-imino
a
-amino
f
R value (EtOAc:Hexane = 1:4) :
esters with excellent enantioselectivities, respectively.8 Enders
,9
0.45
0.43
0.38
0.50
et al. successfully used benzothiazoline in the reductive amination
of ketones to construct tetrahydroisoquinolines.10 The process of
Scheme 1. R values of the components in the transfer hydrogenation of aldimine.
f
transfer hydrogenation involving Hantzsch esters or benzothiazo-
lines, however, is accompanied by difficulties in the purification
as the amine product is mixed with the byproducts because of their
washing with an aqueous basic solution, allowing us to simplify
the purification process significantly.
f
similar R values. This inconvenience in the purification procedure
clearly limits the application of the hydrogen source in both indus-
try and academia. Thus, the development of a readily removable
hydrogen source is strongly desired from a practical point of view.
We wish to report herein an environment-friendly approach to the
transfer hydrogenation of imines with carboxyl-tailed benzothiaz-
oline 1 as the hydrogen source, which can be easily removed by
Fueled by our continued interests in the transfer hydrogenation
reaction, we examined the reduction of imines with a range of
reducing agents, including Hantzsch esters and benzothiazoline.
f
The measured R values of all the components in the reaction are
shown in Scheme 1. Separation of the generated amine from the
reaction mixture by column chromatography is not a trivial issue
8
f
due to the similar R values. Nevertheless, the ease of tuning of
the reactivity and chemical properties by changing the 2-substitu-
ent on the backbone of benzothiazoline is a significant advantage.
⇑
Corresponding author. Tel.: +81 3 3986 0221; fax: +81 3 5992 1029.
E-mail address: takahiko.akiyama@gakushuin.ac.jp (T. Akiyama).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.061

C. Zhu, T. Akiyama / Tetrahedron Letters 53 (2012) 416–418
417
Thus, we designed a benzothiazoline with a carboxyl moiety,
Table 2
a
The scope of substrates in the transfer hydrogenation of imines
which was envisaged to be readily removable from the reaction
mixture by washing with an aqueous basic solution (Scheme 2).
A mixture of o-aminothiophenol with p-formylbenzoic acid in
ethanol was stirred for a few hours to give benzothiazoline 1 as a
white precipitate in excellent chemical yield. Benzothiazoline 1 is
sufficiently stable to allow storage in a refrigerator for several
months without decomposition. An initial screening of the solvent
effect on the transfer hydrogenation reaction of aldimine 2a,
derived from benzaldehyde and p-anisidine, with benzothiazoline
1 (1.2 equiv)
TFA (20 mol %)
NR2
NHR2
R1
R1
MeCN
r.t.
2
3
Entry
1
R1
R2
Product
Time (h)
22
Yieldb (%)
PMP
3a
3b
87
90
1
in the presence of TFA revealed that polar solvents were more
2
3
4
PMP
PMP
PMP
25
21
23
efficient than nonpolar solvents, and acetonitrile gave the best
result (Table 1). It is noted that the use of 20 mol % TFA as an acid
and acetonitrile as the solvent gave the highest yield, whereas an
increase in the loading of TFA to 50 mol % diminished the chemical
yield because of the decomposition of imine.
MeO
O2N
3c
92
95
3d
With the optimized reaction conditions in hand, we set out to
Cl
Cl
define the substrate scope of the transfer hydrogenation reaction
1
(
Table 2). Both R and R2 functional groups were well tolerated.
5
6
PMP
PMP
3e
3f
23
22
94
96
Aldimines bearing a variety of substituents with different steric
and electronic effects on the aromatic ring underwent the transfer
hydrogenation smoothly to give 3 in high chemical yields (entries
NO2
1
–6). Aldimines derived from heteroaromatic aldehyde, cinnamal-
dehyde, and aliphatic aldehyde also gave the corresponding
amines in good yields (entries 7–9). Not only N-PMP imine but also
other N-aryl imines proved to be suitable substrates (entries 10
and 11).
Remarkably, the work-up procedures became easy due to the
ease of removal of the reducing agent. After the completion of
the transfer hydrogenation, both the excess of benzothiazoline
and the corresponding benzothiazole were eliminated by simply
washing with 10% aqueous NaOH.
7
8
9
PMP
PMP
PMP
Ph
3g
3h
3i
80
26
40
22
23
79
75
60
93
92
N
1
0
1
3j
1
p-Cl-Ph
3k
a
Reactions were performed with imine 2 and benzothiazoline 1 (1.2 equiv) at
S
S
removed by washing
with basic solution
0.1 M concentration.
R
COOH
b
Isolated yield.
N
H
N
H
SH
S
EtOH
COOH
+
OHC
COOH
N
H
Encouraged by the above results, we further studied the reduc-
NH2
r.t., 3 h
tive amination with benzothiazoline 1 as the hydrogen source
1
92% yield
(
Table 3). In the presence of benzothiazoline 1, the one-pot mixture
0
Scheme 2. Synthesis of 2-(4 -carboxyl)phenyl benzothiazoline.
of aldehydes 4 and p-anisidine (5) afforded amines 3 in good chem-
ical yields. A range of aromatic substrates bearing electron-rich
and electron-deficient substituents proved to be compatible with
the reductive amination conditions.
Furthermore, the transfer hydrogenation of a-imino esters was
Table 1
also investigated (Scheme 3). Using the previous optimized reac-
tion conditions, we found that raising the temperature to 50 °C en-
hanced the reaction rate. The reduction of imino ester 6a furnished
Examination of various solvents
NPMP
1 (1.2 equiv)
TFA (20 mol %)
NHPMP
the corresponding a-amino ester 7a in an 84% yield in 26 h. Replac-
1
2
ing R with a naphthyl group, changing R from PMP to phenyl or
replacing methyl ester with ethyl ester did not lead to any loss of
reactivity.
solvent
r.t.
2
a
3a
Yielda (%)
In summary, we have developed a novel hydrogen donor for the
acid-catalyzed transfer hydrogenation of imines. Benzothiazoline
bearing a carboxylic acid moiety proved to be practically useful be-
cause the corresponding benzothiazole as well as the recovered
benzothiazoline were readily removable by simple phase separa-
tion. Undoubtedly, this environment-friendly approach reduces
the volume of organic solvents used for the purification process
and offers a convenient and straightforward access to various
amines with a broad substrate scope and in high chemical yields.
Studies of other applications of the asymmetric transfer hydroge-
nation are ongoing.
Entry
Solvent
Time (h)
1
2
3
4
5
6
7
THF
24
25
24
24
24
24
22
12
33
47
53
68
19
85
87
55
Toluene
MeOH
EtOAc
DMF
CH Cl
2 2
MeCN
MeCN
b
8
a
Isolated yield.
b
5
0 mol % TFA.

4
18
C. Zhu, T. Akiyama / Tetrahedron Letters 53 (2012) 416–418
Table 3
Supplementary data
Reductive aminationa
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.061.
1
(1.4 equiv)
OMe
TFA (20 mol %)
NHPMP
RCHO +
MeCN
r.t.
R
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5
0 °C
6
7
7
.
.
1
2
3
6
a: R = Ph, R = PMP, R = Me
26 h, 7a: 84%
8
1
2
3
6
b: R = 2-Naphthyl, R = PMP, R = Me 28 h, 7b: 87%
1
2
3
6
c: R = Ph, R = Ph, R = Me
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1
2
3
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6
d: R = Ph, R = PMP, R = Et
1
Scheme 3. Transfer hydrogenation of
a-imino esters.
Acknowledgment
This work was partially supported by a Grant-in Aid for
Scientific Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.