Benzothiazoline: highly efficient reducing agent for the enantioselective organocatalytic transfer hydrogenation of ketimines

Article abstract of DOI:10.1021/ol901762g

Benzothiazoline proved to be an efficient reducing agent for the phosphoric acid-catalyzed enantloselectlve transfer hydrogenation reaction of imines. Corresponding amines were obtained with excellent enantioselectivities.

Full text of DOI:10.1021/ol901762g

ORGANIC
LETTERS
2
009
Vol. 11, No. 18
180-4183
Benzothiazoline: Highly Efficient
Reducing Agent for the Enantioselective
Organocatalytic Transfer Hydrogenation
of Ketimines
4
Chen Zhu and Takahiko Akiyama*
Department of Chemistry, Gakushuin UniVersity, 1-5-1 Mejiro, Toshima-ku,
Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
Received July 31, 2009
ABSTRACT
Benzothiazoline proved to be an efficient reducing agent for the phosphoric acid-catalyzed enantioselective transfer hydrogenation reaction
of imines. Corresponding amines were obtained with excellent enantioselectivities.
The asymmetric reduction of imines is an important reaction
for the preparation of amines in the optically pure form.
the development of a novel biomimetic hydrogen source is
strongly desired.
1
Although methods employing transition metal catalysts have
We focused on benzothiazolines, which are efficient
2
9
10
been reported, metal-free approaches that involve the
antioxidants with potent reducing ability, as the hydrogen
source. We hypothesized that the exposure of ketimine 1 to
benzothiazoline 3 in the presence of catalytic amounts of
chiral Brønsted acid would result in the formation of chiral
amine 2. Meanwhile, benzothiazoline 3 would be converted
into the corresponding more stable aromatic benzothiazole
3
4
5
reduction of ketimines, R-imino esters, etc., have been
developed only recently: in those cases, the reducing agent
is limited to Hantzsch esters, which are the most well-used
6
-8
cofactors in biochemical hydrogenation reactions.
Thus,
4
after liberating hydride (Scheme 1). Because of our
(
1) For general reviews, see: (a) Ohkuma, T.; Noyori, R. In Compre-
1
1-13
hensiVe Asymmetric Catalysis, Suppl. 1; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 2004; pp 43-53. (b) Tang, W.;
Zhang, X. Chem. ReV. 2003, 103, 3029–3070. (c) Blaser, H. U.; Malan,
C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M. AdV. Synth. Catal. 2003,
previous success in strong Brønsted acid catalysis,
studied the reduction of ketimine 1a by means of chiral
we
3
45, 103–151. (d) Tararov, V. I.; B o¨ rner, A. Synlett 2005, 203–211. (e)
Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006, 35, 226–236.
2) For recent examples, see: (a) Li, C.; Wang, C.; Villa-Marcos, B.;
(4) (a) Li, G. L.; Liang, Y. X.; Antilla, J. C. J. Am. Chem. Soc. 2007,
129, 5830–5831. (b) Kang, Q.; Zhao, Z. A.; You, S. L. AdV. Synth. Catal.
2007, 349, 1657–1660. Corrigendum: AdV. Synth. Catal. 2007, 349, 2075.
(c) Kang, Q.; Zhao, Z. A.; You, S. L. Org. Lett. 2008, 10, 2031–2031. See
also: (d) Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 1075–1078.
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A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 6751–6755.
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(
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1
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(
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10.1021/ol901762g CCC: $40.75
Published on Web 08/19/2009
 2009 American Chemical Society

Scheme 1
.
Hydrogen Transfer Reaction
Table 2. Survey of Benzothiazolines for the Asymmetric
Transfer Hydrogenation
a
b
entry
reducing agent
R
yield (%)
ee (%)
1
2
3
4
5
6
a
3a
3b
3c
3d
3e
3f
b
Ph
4-MeOC
6 4
4-NO C H
2-naphthyl
1-naphthyl
n-propyl
97
93
96
89
84
96
92
90
84
97
88
94
6
H
4
2
phosphoric acids. Herein, we reveal the first example of
utilizing benzothiazoline as a novel hydrogen source for the
asymmetric transfer hydrogenation of imines.
Although the exposure of ketimine 1a with 2-phenylben-
zothiazoline 3a (2 equiv) in the presence of phosphoric acid
Isolated yield. Enantiomeric excess was determined by chiral HPLC
analysis.
5
a furnished amine 2a with low enantioselectivity (Table 1,
entry 1), increasing the size of the substituents at 3,3′-
positions of the catalyts significantly improved both chemical
yields and enantioselectivities (entries 2-6). Gratifyingly,
phosphoric acid 5h gave the best result with 97% yield and
Further screening for the reaction conditions revealed that
the catalyst loading could be reduced to 2 mol % without
compromising the enantioselectivity. Thus, exposure of imine
1
a to 1.4 equiv of benzothiazoline 3d in the presence of 5h
9
2% ee (entry 8).
in mesitylene at 50 °C for 26 h provided reduction product
14
2
a in 90% yield with 98% ee. With the optimized reaction
conditions in hand, we set out to define the scope of the
Table 1. Enantioselective Transfer Hydrogenation Mediated by
Benzothiazoline
(
7) (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem.
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005, 44, 108–110. (e) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B.
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(
8) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc.
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009, 131, 9182–9183.
a
b
(9) Davies, P. R.; Askew, H. F. US Patent 4708810, 1987.
entry
catalyst
time (h)
yield (%)
ee (%)
(
10) (a) Chikashita, H.; Miyazaki, M.; Itoh, K. Synthesis 1984, 308–
310. (b) Chikashita, H.; Miyazaki, M.; Itoh, K. J. Chem. Soc., Perkin Trans.
1
2
3
4
5
6
7
8
a
5a
5b
5c
5d
5e
5f
5g
5h
b
22
21
22
21
21
24
22
21
63
67
91
93
96
53
94
97
11
79
75
62
84
84
84
92
1
1987, 699–706.
(11) For our reports, see: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe,
K. Angew. Chem., Int. Ed. 2004, 43, 1566–1568. (b) Akiyama, T.; Morita,
H.; Itoh, J.; Fuchibe, K. Org. Lett. 2005, 7, 2583–2585. (c) Akiyama, T.;
Saitoh, Y.; Morita, H.; Fuchibe, K. AdV. Synth. Catal. 2005, 347, 1523–
1
9
2
526. (d) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348,
99–1010. (e) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc.
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T.; Honma, Y.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2008, 350, 399–
Isolated yield. Enantiomeric excess was determined by chiral HPLC
analysis.
4
02. (i) Itoh, J.; Fuchibe, K.; Akiyama, T. Synthesis 2008, 1319–1322. (j)
Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016–
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8, 4226–4228. (m) Akiyama, T.; Morita, H.; Bachu, P.; Mori, K.;
4
We further examined a range of 2-substituted benzothia-
zolines in the asymmetric transfer hydrogenation reaction
by means of phosphoric acid 5h (Table 2). Gratifyingly, ee
could be increased to 97% by using 3d bearing a 2-naphthyl
group (entry 4). Conversely, replacement with a 1-naphthyl
group reduced the enantioselectivity (entry 5). Interestingly,
alkyl group substituted benzothiazoline 3f also exhibited high
reactivity without steric hindrance (entry 6).
4
Yamanaka, M.; Hirata, T. Tetrahedron 2009, 65, 4950–4956. (n) Akiyama,
T.; Katoh, T.; Mori, K.; Kanno, K. Synlett 2009, 1664–1666.
(
12) For reviews on Brønsted acid catalysis, see: (a) Akiyama, T.; Itoh,
J.; Fuchibe, K. AdV. Synth. Catal. 2006, 348, 999–1010. (b) Akiyama, T.
Chem. ReV. 2007, 107, 5744–5758. (c) Connon, S. J. Angew. Chem., Int.
Ed. 2006, 45, 3909–3912. (d) Akiyama, T. Acid Catalysis in Modern
Organic Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH: Wein-
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4097–4112See also references cited therein.
Org. Lett., Vol. 11, No. 18, 2009
4181

proceeded smoothly without any loss of enantioselectivity
entry 10). It is noted that the present protocol for the
(
Table 3. Substrate Scope of the Asymmetric Transfer
Hydrogenation
phosphoric acid-catalyzed reduction of ketimines uniformly
gave higher enantioselectivities than with the previous
3
reports, in which Hantzsch ester was employed as the
hydrogen source.
Benzothiazoline may be generated in situ and subjected
to the reduction reaction. Thus, three-component reaction
starting from ketimine 1b, 2-naphthalenecarbaldehyde, and
2
-aminothiophenol gave the corresponding reduction
product 2b in a high yield with excellent enantioselectivity
Scheme 2).
(
Scheme 2
. Hydrogen Transfer Reaction by Use of
Benzothiazoline Generated in Situ
According to the resulting R configuration of amines, we
1
5
speculated a ten-membered transition state wherein the
hydride was transferred from benzothiazoline to attack the
imine via Si-face (Figure 1).
Figure 1. Proposed transition state.
In summary, we have described the first example of the
use of benzothiazoline as the hydrogen source in the
(
13) For selected examples, see: (a) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356–5357. (b) Nakashima, D.; Yamamoto, H. J. Am.
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2
007, 129, 12084–12085. (f) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am.
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Enders, D.; Narine, A. A.; Toulgoat, F.; Bisschops, T. Angew. Chem., Int.
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a
b
Isolated yield. Enantiomeric excess was determined by chiral HPLC
analysis.
transfer hydrogenation reaction. Excellent ee values (95-98%
ee) as well as high chemical yields were obtained in all the
cases examined (Table 3).
1
2
463–1466. (m) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc.
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Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009,
1
2
Both R and R functional groups were well tolerated.
1
31, 4598–4599. (p) Zeng, X.; Zeng, X.; Xu, Z.; Lu, M.; Zhong, G. Org.
Significantly, even the reduction of aliphatic ketimine 1j
Lett. 2009, 11, 3036–3039.
4182
Org. Lett., Vol. 11, No. 18, 2009

asymmetric transfer hydrogenation of ketimines. This is a
simple and complementary approach that gives higher
enantioselectivity in the imine reduction and that may widen
the scope of catalytic transfer hydrogenation chemistry in
general. Mechanistic studies and further applications are
ongoing.
Acknowledgment. This work was partially supported by
a Grant-in Aid for Scientific Research from the Japan Society
for the Promotion of Science.
Supporting Information Available: Experimental pro-
cedures, characterization data, copies of NMR and HPLC
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
(
(
14) For details, see Supporting Information.
15) For the theoretical studies on the phosphoric acid-catalyzed
reduction of imines, see: (a) Sim o´ n, L.; Goodman, J. M. J. Am. Chem. Soc.
2
008, 130, 8741–8747. (b) Marcelli, T.; Hammar, P.; Himo, F. Chem.sEur.
J. 2008, 14, 8562–8571.
OL901762G
Org. Lett., Vol. 11, No. 18, 2009
4183