5
006
Q. P. B. Nguyen, T. H. Kim / Tetrahedron Letters 52 (2011) 5004–5007
Table 4
Recovery of the catalyst
Table 2 (continued)
Entry Aldehydes 1
Product amines 3
Yield (%)
87
O
EtO
2
C
2
CO Et
H
O
N
H
(1.2 eq)
1
6
3p
H
+
NH
NH
2
O
1p
Cl
S
(
1 eq)
(1.1 eq)
a
Toluene, 70 °C.
H
2
N
NH
2
1a
2b
(0.1 eq)
3q
2
rt, CH Cl2, overnight
Table 3
Scope of amines
Recycle
st
2nd
3rd
Yield of recovered catalyst (%)
Yield of product 3q (%)
2
EtO C
CO
2
Et
O
1
96
95
96
97
99
97
98
95
N
H
(1.2 eq)
H
+
NH
R
2
NH
2
R
2
4th
(1 eq)
Cl
S
(
1.1 eq)
3
1a
2
H
2
N
NH
2
(0.1 eq)
rt, CH
2
Cl
2
, overnight
Conclusions
In summary, S-benzyl isothiouronium chloride was explored as
an effective organocatalyst for the direct reductive amination of
aldehydes. A mild and operationally simple fragment coupling pro-
cedure was developed, which functions with a wide range of alde-
hydes as well as amines in good to excellent yield. The S-benzyl
isothiouronium chloride catalyst can be easily recovered by simple
filtration and reused with no drop in its efficiency. Compared with
the same model based on thiourea, the isothiouronium catalyst
showed higher yield and milder reaction conditions, as well as eas-
ier recovery and reuse.
Entry
1
Amines 2
Product amines 3
Yield (%)
99
NH
2
3q
2
2
b
NH
2
2
3
3r
3s
92
93
2
c
NH
2
d
Cl
NH
2
Acknowledgments
4
5
6
3t
97
92
99
2
e
HO
NH
This study was financially supported by the Sabbatical Research
Program of Chonnam National University, 2010. We wish to thank
the Korea Basic Science Institute Gwang-ju center for analysis of
LC–MS/MS Spectrometry.
2
3u
3va
2
f
CF
3
NH
2
2
g
Supplementary data
2
O N
NH
2
Supplementary data (typical reaction procedure, spectral data
7
8
3w
3xa
94
92
2
h
HOOC
NH
2
2
i
a
Toluene, 70 °C.
References and notes
1
2
.
.
Tararov, V. I.; Borner, A. Synlett 2005, 203.
8
, and 13) also proceeded in good yield. Pleasingly, all of the
(a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J.
Org. Chem. 1996, 61, 3849; (b) Itoh, T.; Nagata, K.; Kurihara, A.; Miyazaki, M.;
Ohsawa, A. Tetrahedron Lett. 2002, 43, 3105; (c) Itoh, T.; Nagata, K.; Miyazaki,
M.; Ishikawa, H.; Kurihara, A.; Ohsawa, A. Tetrahedron 2004, 60, 6649; (d)
Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
amines listed in Table 3 functioned successfully, thus demonstrat-
ing the wide range of functional groups that can be used with our
protocol. In addition, one remarkable point that should be men-
tioned here is that high selectivity is obtained in this reaction. Only
the carbonyl group of the aldehyde was reduced in the presence of
a ketone, ester, and acid (entries 15 and 16 in Table 2 and entry 7 in
Table 3). Finally, the S-benzyl isothiouronium chloride catalyst can
be easily recovered by simple filtration and reused with no signif-
8
4; (e) Byun, E.; Hong, B.; De Castro, K. A.; Lim, M.; Rhee, H. J. Org. Chem. 2007,
72, 9815; (f) Liu, Z. G.; Li, N.; Yang, L.; Liu, Z. L.; Yu, W. Chin. Chem. Lett. 2007, 18,
58; (g) Kumar, A.; Sharma, S.; Maurya, R. A. Adv. Synth. Catal. 2010, 352, 2227;
h) Apodaca, R.; Xiao, W. Org. Lett. 2001, 11, 1745; (i) Sato, S.; Sakamoto, T.;
Miyazawa, E.; Kikugawa, Y. Tetrahedron 2004, 60, 7899.
4
(
3. (a) Menche, D.; Arikan, F. Synlett 2006, 0841; (b) Hoffmann, S.; Nicoletti, M.;
List, B. J. Am. Chem. Soc. 2006, 128, 13074; (c) Zhang, Z.; Schreiner, P. R. Synlett
2007, 1455; (d) Huang, Y.-B.; Cai, Y. J. Chem. Res. 2009, 11, 686.
icant change in its efficiency (Table 4). Compared with the same
model based on thiourea,3a the isothiouronium catalyst showed a
4
.
Menche, D.; Hassfeld, J.; Li, J.; Menche, G.; Ritter, A.; Rudolph, S. Org. Lett. 2006,
8, 741.
higher yield and milder reaction conditions, for example, from
7
0 °C to room temperature, as well as easier recovery and reuse.
5. (a) Connon, S. J. Synlett 2009, 0354; (b) Breuzard, J. A. J.; Christ-Tommasino, M.
L.; Lemaire, M. Top. Organomet. Chem. 2005, 15, 231.
The extension of the scope of the S-benzyl isothiouronium chloride
catalyst to other reactions, for example, the direct reductive ami-
nation of ketones, is currently under our consideration.13
6.
For the syntheses of the isothiouronium derivatives and the more hydrogen
bond of them as compared with that of the corresponding thioureas, see: (a)
Kubo, Y.; Ishihara, S.; Tsukahara, M.; Tokita, S. J. Chem. Soc., Perkin Trans. 2 2002,