Br?nsted acid catalyzed reductive amination with benzothiazoline as a highly efficient hydrogen donor

Article abstract of DOI:10.1055/s-0030-1260539

Reductive amination of aldehyde and amine proceeded smoothly in the presence of benzothiazoline as efficient hydrogen source by means of 20 mol% trifluoroacetic acid to give the corresponding amines in excellent yields. Hydrogen-donor abilities of benzothiazoline, benzimidazoline, and benzoxazoline were compared. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260539

CLUSTER
1251
Brønsted Acid Catalyzed Reductive Amination with Benzothiazoline as a
Highly Efficient Hydrogen Donor
R
eductive Amina
h
tion by Use
e
of Benzothi
n
a
zoline as
a
H
ydro
Z
gen
D
onor hu, Takahiko Akiyama*
Department of Chemistry, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax +81(3)59921029; E-mail: takahiko.akiyama@gakushuin.ac.jp
Received 7 February 2011
dehyde, amine, and benzothiazoline with acid catalyst, al-
dimine is generated in situ and reduced by
benzothiazoline to give amine 2. Aromatization of ben-
Abstract: Reductive amination of aldehyde and amine proceeded
smoothly in the presence of benzothiazoline as efficient hydrogen
source by means of 20 mol% trifluoroacetic acid to give the corre-
sponding amines in excellent yields. Hydrogen-donor abilities of
1
zothiazoline proceeded concurrently to give benzothiaz-
benzothiazoline, benzimidazoline, and benzoxazoline were com- ole 4. Brønsted acid worked twofold: generation of
pared.
aldimine and transfer hydrogenation.
Key words: reduction, reductive amination, benzothiazoline, trans-
fer hydrogenation, phosphoric acid
R2
R2
H
O
N
HN
R1
H+
R1
H
R1
H
+
1
2
The preparation of amines by constructing a novel car-
bon–nitrogen bond is one of the most fundamental syn-
thetic methods. The reductive amination, in which
carbonyl compounds and amines are treated with hydro-
gen source in the presence of catalyst, is an expedient
method for the preparation of amines, enabling the rapid
access to primary and secondary amines.1–3 It has been
successfully employed both in academia and industry. A
H+
R2NH2
H
N
N
R3
R3
S
S
3
4
biomimetic approach that relies on the utilization of a hy- Scheme 1 Reductive amination with benzothiazoline
drogen source has been developed, inspired by naturally
occurring hydrogenation processes. As the most prevalent
At the outset, we studied the reductive amination of p-ni-
trobenzaldehyde (5a) and p-anisidine (6a) with 1.2 equiv-
alents of benzothiazoline 3a as hydrogen source
(Table 1). Although the reduction did not proceed in the
absence of acid (Table 1, entry 1), the addition of Brøn-
sted acid (10 mol%) promoted the reductive amination to
give 2. Biphenyl phosphoric acid (BPP), acetic acid, and
p-toluenesulfonic acid were less efficient (Table 1, entries
2–4), whereas use of trifluoroacetic acid (TFA) signifi-
cantly improved the chemical yield (Table 1, entry 5). In-
creasing the amount of TFA to 20 mol% furnished 2a in
an excellent yield (Table 1, entry 6). Further screening of
solvents revealed that use of CH2Cl2 as a solvent furnished
2a quantitatively (Table 1, entry 7). Moreover, increasing
the concentration of 5a to 0.2 M significantly accelerated
the reaction (Table 1, entry 8).
analogue of NADH, Hantzsch esters4,5 are efficiently em-
ployed in the reductive amination as well as reduction of
imines under the catalysis of Lewis acid6 and Brønsted ac-
id.7 A highly enantioselective version of the Brønsted acid
catalyzed reductive amination has been reported lately.8,9
Furthermore, Hantzsch ester has been broadly applied to
other hydrogenation reactions.10–12 One weakness of
Hantzsch esters, however, is difficulties in the structural
modification and/or introduction of additional substitu-
ents. Thus, the search for novel biomimetic hydrogen
source remains to be elusive.
We focused on benzothiazolines, which have been recog-
nized to be efficient antioxidants13 with potent reducing
ability,14 and envisioned that they might be employed as
hydrogen source in the Brønsted acid catalyzed reductive
amination with concurrent generation of benzothiazole.
Based on the consideration, we reported chiral phosphoric
acid catalyzed enantioselective transfer hydrogenation of
ketimines by use of benzothiazoline as a novel hydrogen
donor.15 We wish to report herein Brønsted acid catalyzed
reductive amination using benzothiazoline as a hydrogen
donor. The strategy is shown in Scheme 1. Exposure of al-
We examined the scope of the reductive amination of al-
dehydes and amines under the optimal reaction conditions
[5 (0.2 M, 1.0 equiv), 6 (1.2 equiv), TFA (20 mol%),
CH2Cl2, r.t.], and the results are shown in Table 2. A range
of aromatic aldehydes, bearing electron-withdrawing,
electron-donating, and steric groups proved to be suitable
substrates (Table 2, entries 1–6). An aldimine derived
from cinnamaldehyde exclusively underwent 1,2-reduc-
tion (Table 2, entry 7). In addition, heteroaromatic alde-
hyde and aliphatic aldehyde also gave 2 in good chemical
yield by prolonging the reaction time (Table 2, entries 8
SYNLETT 2011, No. 9, pp 1251–1254
x
x.
x
x.
2
0
1
1
Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260539; Art ID: Y03711ST
© Georg Thieme Verlag Stuttgart · New York

1252
C. Zhu, T. Akiyama
CLUSTER
Table 1 Examination of Brønsted Acids and Solvents for the Re-
Table 2 Substrate Scope of the Reductive Amination
ductive Amination
3a (1.2 equiv )
NHR2
O
TFA (20 mol%)
O
NHPMP
R2NH2
3a (1.2 equiv)
+
CH2Cl2
r.t.
R1
catalyst
R1
2
+
PMPNH2
5
6
solvent
r.t.
O2N
O2N
5a
6a
2a
Entrya
R1
R2
Time (h) Yield (%)b
H
N
1
2
Ph
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
Ph
5
4
93
91
99
95
90
93
82
87
66
87
84
77
OMe
2-naphthyl
4-O2NC6H4
4-MeOC6H4
3-ClC6H4
4-ClC6H4
C6H5CH=CH
4-pyridyl
c-Hex
S
3a
3
5
Entrya
Catalyst (mol%) Solvent
Time (h) Yield (%)b
4
6
1
2
3
4
5
6
7
8c
–
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
20
24
24
24
24
24
14
5
0
47
30
29
70
93
99
99
5
5
BPP (10)
AcOH (10)
TsOH (10)
TFA (10)
TFA (20)
TFA (20)
TFA (20)
6
5
7
9
8
48
40
14
15
24
9
10
11
12
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-ClC6H4
4-O2NC6H4
a Reactions were performed with aldehyde 5a and p-MeOC6H4NH2
(1.2 equiv) at 0.07 M concentration.
b Isolated yield.
a Reactions were performed with aldehyde 5 and amine 6 (1.2 equiv)
at 0.2 M concentration.
b Isolated yield.
c Concentration was 0.2 M.
and 9). Other aniline derivatives also participated in the ticipate in the transfer hydrogenation. We tried the three-
reductive amination,16 giving the corresponding amines in component reaction starting from aldehyde 5, aniline 6,
good yields (Table 2, entries 10–12).
and ortho-substituted aniline 7, in which aldehyde 5
played two roles under the standard reaction conditions:
CH2Cl2 as solvent and 20 mol% TFA as a catalyst
(Table 3).
One of the advantages of benzothiazoline resides in its
ease of tuning of the 2-substituents on the backbone of
benzothiazoline. Thus, we investigated the effect of the 2-
substituents on the reactivity in the reductive amination of Initially, we examined different ortho-substituted
5a and 6a with 3a, 3b, and 3c under the standard condi- anilines, which could be converted to the corresponding
tions, and the results are shown in Figure 1.17 It was found benzoxazoline, benzimidazoline, and benzothiazoline.
that reductive amination proceeded smoothly even when While o-aminophenol and o-phenylenediamine did not
benzothiazolines, bearing electron-rich or electron-defi- give satisfactory results (Table 3, entries 1 and 2), o-ami-
cient substituent, were employed to give 2a in excellent nothiophenol furnished 2 in an excellent yield (Table 3,
yields with slight difference of reaction rate.
entry 3). Benzothiazoline proved to be more efficient hy-
drogen donor in this reductive amination than other anal-
ogous heterocycles. Using o-aminothiophenol as the
precursor of reducing agent, a variety of aromatic alde-
hydes were surveyed and furnished the corresponding
amines 2 in high yields (Table 3, entries 4–8). It is noted
that aliphatic aldehydes also gave the corresponding
amines in good yields (Table 3, entry 9 and 10). Practica-
bly, extending the one-pot approach to gramscale, the re-
action proceeded smoothly without compromising the
excellent chemical yield (Table 3, entry 11). These results
clearly show the order of the reactivity to be as follows:
benzothiazoline > benzimidazoline >> benzoxazoline
(Figure 2). Because benzimidazolines automatically gen-
erate hydrogen to form benzimidazole on standing, ben-
zothiazoline is the most efficient and useful hydrogen
donor from a practical point of view.
Because the 2-substituents on the benzothiazolines did not
influence the reactivity in the reductive amination, we
supposed a novel one-pot reduction process in which both
benzothiazoline and imine were generated in situ to par-
H
N
H
N
OMe
S
S
3a
14 h, yield 99%
3b
16 h, yield 99%
H
N
NO2
S
3c
20 h, yield 96%
Figure 1 Comparison of the hydrogen donor ability
Synlett 2011, No. 9, 1251–1254 © Thieme Stuttgart · New York

CLUSTER
Reductive Amination by Use of Benzothiazoline as a Hydrogen Donor
1253
Typical Experimental Procedure for the Reductive Amination
Under nitrogen, a mixture of aldehyde, amine (0.24 mmol), ben-
zothiazole (0.24 mmol) in CH2Cl2 (1 mL), was added TFA (0.04
mmol). The reaction was stirred at r.t. until the aldehyde was con-
sumed monitoring by TLC. The product was purified by flash col-
umn chromatography on SiO2.
Table 3 One-Pot Reductive Amination with Generation of Reduc-
ing Agents in situ
H
NH2
X
N
N
X
O
R1
R1
+
R1
X
5
7
NHR2
O
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
R2NH2
+
R1
R1
TFA (20 mol%)
CH2Cl2, r.t.
5
6
2
Entrya
X
R1
R2
Time (h) Yield(%)b
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science.
1
2
OH
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
Ph
PMP
24
24
20
15
trace
56
96
99
99
97
86
78
83
64
94
NH2
SH
SH
SH
SH
SH
SH
SH
SH
SH
PMP
3
PMP
References and Notes
(1) For general reviews of metal-catalyzed asymmetric
reductive amination, see: (a) Ohkuma, T.; Noyori, R. In
Comprehensive Asymmetric Catalysis, Suppl. 1; Jacobsen,
E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York,
2004. (b) Gomez, S.; Peters, J. A.; Maschmeyer, T. Adv.
Synth. Catal. 2002, 344, 1037. (c) Tararov, V. I.; Börner, A.
Synlett 2005, 203.
(2) For asymmetric synthesis, see: (a) Blaser, H.-U.; Buser,
H.-P.; Jalett, H.-P.; Pugin, B.; Spindler, F. Synlett 1999,
867. (b) Kadyrov, R.; Riermeier, T. H. Angew. Chem. Int.
Ed. 2003, 42, 5472. (c) Li, C.; Villa-Marcos, B.; Xiao, J. J.
Am. Chem. Soc. 2009, 131, 6967. (d) Steinhuebel, D.; Sun,
Y.; Matsumura, K.; Sayo, N.; Saito, T. J. Am. Chem. Soc.
2009, 131, 11316. (e) Steinhuebel, D.; Sun, Y.; Matsumura,
K.; Sayo, N.; Saito, T. J. Am. Chem. Soc. 2009, 131, 11316.
For biocatalysis, see: (f) Koszelewski, D.; Lavandera, I.;
Clay, D.; Guebitz, G. M.; Rozzell, D.; Kroutil, W. Angew.
Chem. Int. Ed. 2008, 47, 9337.
(3) For achiral reactions, see: (a) Chandrasekhar, S.; Reddy,
C. R.; Ahmed, M. Synlett 2000, 1655. (b) Apodaca, R.;
Xiao, W. Org. Lett. 2001, 3, 1745. (c) Gross, T.; Seayad, A.
M.; Ahmad, M.; Beller, M. Org. Lett. 2002, 4, 2055.
(4) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1.
(5) For representative reviews on Hantzsch esters, see:
(a) Ouellet, S. G.; Walji, A. M.; MacMillan, D. W. C. Acc.
Chem. Res. 2007, 40, 1327. (b) You, S.-L. Chem. Asian J.
2007, 2, 820. (c) Connon, S. J. Org. Biomol. Chem. 2007, 5,
3407. (d) Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett
2010, 852.
(6) (a) Steevens, J. B.; Pandit, U. K. Tetrahedron 1983, 39,
1395. (b) Fujii, M.; Aida, T.; Yoshihara, M.; Ohno, A. Bull.
Chem. Soc. Jpn. 1989, 62, 3845. (c) Itoh, T.; Nagata, K.;
Kurihara, A.; Miyazaki, M.; Ohsawa, A. Tetrahedron Lett.
2002, 43, 3105. See also: (d) Che, J.; Lam, Y. Synlett 2010,
2415.
4
4-ClC6H4
5
4-O2NC6H4 19
6
PMP
PMP
17
19
20
22
43
17
7
4-O2NC6H4
8
C6H5CH=CH PMP
9
c-Hex
i-Pr
PMP
PMP
PMP
10
11c
Ph
a The one-pot reactions were performed with aldehyde 5 (2.2 equiv),
amine 6 (1.0 equiv), and 7 (1.2 equiv) at 0.2 M concentration.
b Isolated yield.
c Aldehyde 5 (2.33 g), amine 6 (1.23 g), and 7 (1.50 g) at 0.2 M con-
centration.
H
N
H
N
H
N
>
>>
R
R
R
N
H
S
O
Figure 2 The order of reactivity of the hydrogen donor
In summary, we have described an efficient and novel ap-
proach of utilizing benzothiazolines as reducing agents
for the reductive amination of aldehydes. A range of alde-
hydes, including aromatic aldehyde, heteroaromatic alde-
hyde, cinnamaldehyde, and aliphatic aldehyde,
participated in the reductive amination to give the corre-
sponding amines in high yields. Several functional groups
such as nitro, halide survived under the mild conditions.
Benzothiazoline possesses many advantages, including:
1) one-step or in situ preparation from inexpensive mate-
rials in excellent yield; 2) convenient structural modifica-
tion. It is believed that the development of
benzothiazolines would find wide applications also in
asymmetric transfer hydrogenation.
(7) (a) Menche, D.; Arikan, F. Synlett 2006, 841. (b) Zhang, Z.;
Schreiner, P. R. Synlett 2007, 1455. (c) Rueping, M.; Azap,
C.; Sugiono, E.; Theissmann, T. Synlett 2005, 2367.
(d) Wakchaure, V. N.; Nicoletti, M.; Ratjen, L.; List, B.
Synlett 2010, 2708. See also: (e) Menche, D.; Hassfeld, J.;
Li, J.; Menche, G.; Ritter, A.; Rudolph, S. Org. Lett. 2006,
8, 741.
(8) (a) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2006, 128, 84. (b) Hoffmann, S.;
Nicoletti, M.; List, B. J. Am Chem. Soc. 2006, 128, 13074.
(c) Wakchaure, V. N.; Zhou, J.; Hoffmann, S.; List, B.
Angew. Chem. Int. Ed. 2010, 49, 4612.
Synlett 2011, No. 9, 1251–1254 © Thieme Stuttgart · New York

1254
C. Zhu, T. Akiyama
CLUSTER
Chem. Soc. 2009, 131, 9182. (k) Liu, X.-Y.; Che, C.-M.
(9) For reviews on chiral Brønsted acid catalysis, see:
(a) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal.
2006, 348, 999. (b) Akiyama, T. Chem. Rev. 2007, 107,
5744. (c) Connon, S. J. Angew. Chem. Int. Ed. 2006, 45,
3909. (d) Terada, M. Chem. Commun. 2008, 4097.
(e) Terada, M. Synthesis 2010, 1929. (f) Zamfir, A.;
Schenker, S.; Freund, M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2010, 8, 5262.
(10) For reduction of imines, see: (a) Hoffmann, S.; Seayad,
A. M.; List, B. Angew. Chem. Int. Ed. 2005, 44, 7424.
(b) Rueping, M.; Sugiono, E.; Azap, C.; Theissmann, T.;
Bolte, M. Org. Lett. 2005, 7, 3781. (c) Li, G. L.; Liang,
Y. X.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830.
(d) Kang, Q.; Zhao, Z. A.; You, S. L. Adv. Synth. Catal.
2007, 349, 1657; Corrigendum: Adv. Synth. Catal. 2007,
349, 2075. (e) Kang, Q.; Zhao, Z. A.; You, S. L. Org. Lett.
2008, 10, 2031. (f) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem. Int. Ed. 2006, 45, 3683.
(g) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew.
Chem. Int. Ed. 2006, 45, 6751. (h) Rueping, M.; Merino, E.;
Koenigs, R. M. Adv. Synth. Catal. 2010, 352, 2629 . See
also: (i) Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 1075.
(j) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am.
Org. Lett. 2009, 11, 4204.
(11) For reduction by menas of iminium catalysis, see:
(a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 32. (b) Tuttle, J. B.; Ouellet, S. G.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 12662.
(12) For the study on the hydride donor ability, see: Richter, D.;
Mayr, H. Angew. Chem. Int. Ed. 2009, 48, 1958.
(13) Davies, P. R.; Askew, H. F. US 4708810, 1987.
(14) (a) Chikashita, H.; Miyazaki, M.; Itoh, K. Synthesis 1984,
308. (b) Chikashita, H.; Miyazaki, M.; Itoh, K. J. Chem.
Soc., Perkin Trans. 1 1987, 699.
(15) For chiral Brønsted acid catalyzed enantioselective transfer
hydrogenation of imines employing benzothiazoline as a
hydrogen donor, see: (a) Zhu, C.; Akiyama, T. Org. Lett.
2009, 11, 4180. (b) Zhu, C.; Akiyama, T. Adv. Synth. Catal.
2010, 352, 1846 . See also: (c) Enders, D.; Liebich, J. X.;
Raabe, G. Chem. Eur. J. 2010, 16, 9763.
(16) Aliphatic amines such as benzylamine and n-pentylamine
did not give the reduction products.
(17) The reactions were performed with 20 mol% TFA in CH2Cl2
at 0.07 M concentration.
Synlett 2011, No. 9, 1251–1254 © Thieme Stuttgart · New York