Enantioselective organocatalytic transfer hydrogenation of α-imino esters by utilization of benzothiazoline as highly efficient reducing agent

Article abstract of DOI:10.1002/adsc.201000328

Benzothiazoline was employed as an efficient and versatile reducing agent for the chiral phosphoric acid-catalyzed transfer hydrogenation of α-imino esters. The corresponding α-amino esters were furnished with excellent enantioselectivities. Novel and rea

Full text of DOI:10.1002/adsc.201000328

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DOI: 10.1002/adsc.201000328
Enantioselective Organocatalytic Transfer Hydrogenation of a-
Imino Esters by Utilization of Benzothiazoline as Highly Efficient
Reducing Agent
Chen Zhua and Takahiko Akiyamaa,*
a
Department of Chemistry, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax : (+81)-3-5992-1029; e-mail: takahiko.akiyama@gakushuin.ac.jp
Received: April 28, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000328.
Abstract: Benzothiazoline was employed as an effi-
cient and versatile reducing agent for the chiral
phosphoric acid-catalyzed transfer hydrogenation of
a-imino esters. The corresponding a-amino esters
were furnished with excellent enantioselectivities.
Novel and readily removable benzothiazolines bear-
ing a hydroxy group were also investigated.
acid-catalyzed asymmetric transfer hydrogenation of
a-imino esters using benzothiazoline as the reducing
agent.
Preliminary experiments were carried out with the
combination of ethyl imino ester 2a and benzothiazo-
line 4 (Table 1). We examined the effects of a variety
Table 1. Enantioselective transfer hydrogenation of a-imino
ester mediated by benzothiazoline.
Keywords: amino esters; benzothiazolines; imino
esters; organocatalysis; transfer hydrogenation
a-Amino acids are found widely in natural products
and biological systems. They are broadly utilized in
biochemistry and pharmaceutical chemistry because
of their intriguing biological activities.[1] The synthesis
of a-amino acids and their derivatives in the optically
pure form has attracted much attention in the last
decade.[2] The reduction of a-imino esters is one of
the most direct approaches to afford the a-amino
esters. In addition to the transition metal-catalyzed
method reported by Zhang,[3] Antilla and You inde-
pendently reported the asymmetric reduction of a-
imino esters by means of a chiral Brønsted acid cata-
lyst[4] and Hantzsch esters,[5] which are the most well-
used cofactors in biochemical hydrogenation reac-
tions. Although Hantzsch esters have been extensively
employed as a hydrogen source, in asymmetric orga-
nocatalyzed reactions lately,[6,7] the development of
novel hydrogen sources has been expected. We have
recently reported that benzothiazoline[8] functioned as
a novel reducing agent in the asymmetric transfer hy-
drogenation of ketimines,[9] giving rise to the corre-
sponding amines with excellent enantioselectivities.
As a result of our continuing efforts towards the de-
velopment of chiral Brønsted acid-catalyzed reac-
tions,[10,11,12] we wish to report herein the phosphoric
Entry
2
Catalyst Time [h] Yield [%][a] ee [%][c]
1
2
3
4
5
6
7
2a 1a
2a 1b
2a 1c
2a 1d
2a 1e
2a 1f
2b 1e
21
24
21
24
20
20
24
60
86
83
57
0
À10
48
34
58
44
93
99
99
99 (92)[b]
[a]
1
Determined by H NMR.
Isolated yield.
Determined by chiral HPLC analysis.
[b]
[c]
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Adv. Synth. Catal. 2010, 352, 1846 – 1850

Enantioselective Organocatalytic Transfer Hydrogenation of a-Imino Esters
Table 3. Substrate scope of the asymmetric transfer hydroge-
nation of a-imino esters.
of chiral phosphoric acids and found that catalyst 1e,
bearing the 2,4,6-triisopropylphenyl substituent exhib-
ited the highest catalytic activity (entry 5). Gratifying-
ly, the ee value rose to 93% when methyl ester 2b was
used in place of ethyl ester 2a (entry 7).
Then we tried to optimize the reaction conditions.
The investigation of different benzothiazolines dem-
onstrated that benzothiazoline 4, bearing a 2-phenyl
group was the hydrogen source of choice with respect
to the enantioselectivity.[13] Although no remarkable
solvent effect was observed, mesitylene gave slightly
higher enantioselectivity than the other solvents
(Table 2, entries 1–4). It is noted that lowering the
catalyst loading of 1e to 1 mol% improved ee to 98%
(entry 5). The catalyst loading could be reduced to as
little as 0.5 mol% without sacrificing both chemical
yield and enantioselectivity (entry 6).
With the optimized reaction conditions in hand, we
set out to define the scope of the transfer hydrogena-
tion reaction. Excellent enantioselectivities (93–99%
ee) as well as high chemical yields were realized in all
the cases examined (Table 3).[14] A range of a-imino
esters bearing electron-donating, electron-withdraw-
ing, and bulky aromatic groups as R1 furnished the
corresponding a-amino esters 3 with excellent yields
and enantioselectivities (entries 1–7). Remarkably,
even the transfer hydrogenation of an aliphatic imino
ester proceeded smoothly without compromising the
enantioselectivity (entry 8). Both N-phenyl- and N-4-
chlorophenylimines also proved to be suitable sub-
strates (entries 9 and 10).
Entry
1
3
Time Yield
[h]
ee
[%][a]
[%][b]
3b
3c
3d
3e
24
95
98
97
96
94
2
3
4
24
25
28
99
97
96
To expand the practicality of the current method,
benzothiazoline was generated in situ and subjected
to the transfer hydrogenation reaction. Then, we ex-
amined a gram-scale reaction using 0.5 mol% of phos-
5
6
3f
3g
24
24
98
97
94
93
Table 2. Examination of solvents and catalyst loading.
7
8
9
3h
3i
24
27
22
97
93
90
96
99
97
Entry
Solvent
(CH2Cl)2
benzene
toluene
mesitylene
mesitylene
mesitylene
X
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
G
10
10
10
10
1
96
93
92
97
95
94
94
92
93
95
98
96
3j
0.5
[a]
Isolated yield.
Determined by chiral HPLC analysis.
[b]
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In order to overcome the difficulties associated with
the purification of the compounds from benzothiazole
generated as the by-product, we introduced a hydroxy
group onto the 2-aryl group of the benzothiazoline. A
screening experiment of hydroxy group-substituted
benzothiazolines 5a–5d revealed that 5c was the most
effective in terms of enantioselectivity (Scheme 2).
The substrate scope of the transfer hydrogenation re-
action with 5c is shown in Scheme 3. Cyclohexylimino
as well as arylimino esters proved to be suitable sub-
strates. The advantage of 5c is three-fold: (i) the ben-
zothiazole by-product appears as a precipitate in the
reaction and is readily removable by filtration, (ii) fur-
Table 3. (Continued)
Entry
3
Time Yield
[h]
ee
[%][a]
[%][b]
10
3k
23
96
96
[a]
Isolated yield.
Determined by chiral HPLC analysis.
[b]
phoric acid 1e. The three-component reaction starting ther purification by chromatography is facilitated due
from a-imino ester 2b, benzaldehyde, and 2-amino- to the presence of polar hydroxy group, and (iii) ap-
thiophenol furnished the corresponding a-amino ester
3b in high yield along with excellent enantioselectivity
(Scheme 1).
One of the disadvantages of the transfer hydroge-
nation reaction that used the Hantzsch ester lies in
the difficulty of separating the product from the pyri-
dine derivatives generated by dehydrogenation. The
present transfer hydrogenation reaction that used
benzothiazoline also faced similar isolation problems.
Scheme 1. Transfer hydrogenation reaction by use of in-situ
generated benzothiazoline.
Scheme 2. Survey of hydroxy group-substituted benzothiazo-
lines.
Scheme 3. Transfer hydrogenation by use of hydroxy group-
substituted benzothiazoline 5c.
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Adv. Synth. Catal. 2010, 352, 1846 – 1850

Enantioselective Organocatalytic Transfer Hydrogenation of a-Imino Esters
[4] a) G.-L. Li, Y.-X. Liang, J. C. Antilla, J. Am. Chem.
plication of the polymer-supported benzothiazoline is
anticipated due to the facile modification of the hy-
droxy group.
Soc. 2007, 129, 5830–5831; b) Q. Kang, Z. A. Zhao,
S. L. You, Adv. Synth. Catal. 2007, 349, 1657–1660, cor-
rigendum: Adv. Synth. Catal. 2007, 349, 2075; c) Q.
Kang, Z.-A. Zhao, S.-L. You, Org. Lett. 2008, 10, 2031–
2034.
In summary, we have described the first example of
the use of benzothiazoline as the hydrogen source in
the asymmetric transfer hydrogenation of a-imino
esters. The use of hydroxy group-substituted benzo-
thiazoline as the hydrogen source significantly facili-
tated the purification procedure. This is a simple and
complementary approach that may widen the scope
of catalytic transfer hydrogenation chemistry in gener-
al. Mechanistic studies and further applications are
ongoing.
[5] For reviews, see: a) S. G. Ouellet, A. M. Walji, D. W. C.
MacMillan, Acc. Chem. Res. 2007, 40, 1327–1339;
b) S.-L. You, Chem. Asian J. 2007, 2, 820–827; c) S. J.
Connon, Org. Biomol. Chem. 2007, 5, 3407–3417;
d) M. Rueping, E. Sugiono, F. R. Schoepke, Synlett
2010, 852–865.
[6] For the asymmetric reduction of C=N bond, see: a) M.
Rueping, E. Sugiono, C. Azap, T. Theissmann, M.
Bolte, Org. Lett. 2005, 7, 3781–3783; b) S. Hoffmann,
A. M. Swayad, B. List, Angew. Chem. 2005, 117, 7590–
7593; Angew. Chem. Int. Ed. 2005, 44, 7424–7427;
c) R. I. Storer, D. E. Carrere, Y. Ni, D. W. C. MacMil-
lan, J. Am. Chem. Soc. 2006, 128, 84–86; d) S. Hoff-
mann, M. Nicoletti, B. List, J. Am. Chem. Soc. 2006,
128, 13074–13075; e) M. Rueping, A. P. Antonchick, T.
Theissmann, Angew. Chem. 2006, 118, 3765–3768;
Angew. Chem. Int. Ed. 2006, 45, 3683–3686; f) M.
Rueping, A. P. Antonchick, T. Theissmann, Angew.
Chem. 2006, 118, 6903–6907; Angew. Chem. Int. Ed.
2006, 45, 6751–6755; g) G. Li, J. C. Antilla, Org. Lett.
2009, 11, 1075–1078; h) Z.-Y. Han, H. Xiao, X.-H.
Chen, L.-Z. Gong, J. Am. Chem. Soc. 2009, 131, 9182–
9183; i) Z.-Y. Han, H. Xiao, L.-Z. Gong, Bioorg. Med.
Chem. Lett. 2009, 19, 3729–3732; j) X.-Y. Liu, C.-M.
Che, Org. Lett. 2009, 11, 4204–4207.
Experimental Section
Typical Procedure for the Transfer Hydrogenation of
2b
A 10-mL dry Schlenk flask was charged with 0.1 mmol
imino ester 2b (26.9 mg), 0.16 mmol benzothiazoline 4
(34 mg) and 0.001 mmol phosphoric acid 1e (0.8 mg,
1 mol%). After the addition of 1 mL of mesitylene, the reac-
tion mixture was heated to 508C under nitrogen for 24 h.
Upon completion of the reaction, amino ester 3b was puri-
fied by flash column chromatography (hexane/ethyl ace-
tate=14/1) in 95% yield with 98% ee.
[7] For the asymmetric reduction of the C=C bond, see:
a) S. G. Ouellet, J. B. Tuttle, D. W. C. MacMillan, J.
Am. Chem. Soc. 2005, 127, 32–33; b) J. B. Tuttle, S. G.
Ouellet, D. W. C. MacMillan, J. Am. Chem. Soc. 2006,
128, 12662–12663; c) J. W. Yang, M. T. H. Fonseca, B.
List, Angew. Chem. 2004, 116, 6829–6832; Angew.
Chem. Int. Ed. 2004, 43, 6660–6662; d) J. W. Yang,
M. T. H. Fonseca, N. Vignola, B. List, Angew. Chem.
2005, 117, 110–112; Angew. Chem. Int. Ed. 2005, 44,
108–110; e) J. W. Yang, M. T. H. Fonseca, B. List, J.
Am. Chem. Soc. 2005, 127, 15036–15037; f) S. Mayer,
B. List, Angew. Chem. 2006, 118, 4299–4301; Angew.
Chem. Int. Ed. 2006, 45, 4193–4195; g) N. J. A. Martin,
B. List, J. Am. Chem. Soc. 2006, 128, 13368–13369;
h) J. W. Yang, B. List, Org. Lett. 2006, 8, 5653–5655;
i) G.-L. Zhao, A. Cꢂrdova, Tetrahedron Lett. 2006, 47,
7417–7421; j) J. Zhou, B. List, J. Am. Chem. Soc. 2007,
129, 7498–7499; k) M. Rueping, T. Theissmann, S.
Raja, J. W. Bats, Adv. Synth. Catal. 2008, 350, 1001–
1006; l) M. Rueping, A. P. Antonchick, Angew. Chem.
2008, 120, 5920–5922; Angew. Chem. Int. Ed. 2008, 47,
5836–5838; m) N. J. A. Martin, X. Cheng, B. List, J.
Am. Chem. Soc. 2008, 130, 13862–13863.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Sci-
entific Research from the Japan Society for the Promotion of
Science.
References
[1] a) G. C. Barrett, Chemistry and Biochemistry of the
Amino Acids, Chapman and Hall, London, 1985;
b) R. M. Williams, Synthesis of Optically Active Amino
Acids, Pergamon Press, Oxford, 1989; c) R. M. Wil-
liams, J. A. Hendrix, Chem. Rev. 1992, 92, 889–917;
d) J.-A. Ma, Angew. Chem. 2003, 115, 4426–4435;
Angew. Chem. Int. Ed. 2003, 42, 4290–4299.
[2] For selected reviews, see: a) J. M. Brown, in: Compre-
hensive Asymmetric Catalysis, Vol. 1, (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin,
1999, chap. 5.1; b) R. Noyori, Asymmetric Catalysis in
Organic Synthesis Wiley, New York, 1994; c) W. Tang,
X. Zhang, Chem. Rev. 2003, 103, 3029–3070; d) H.
Grçger, Chem. Rev. 2003, 103, 2795–2827; e) K. Mar-
uoka, T. Ooi, Chem. Rev. 2003, 103, 3013–3028; f) M. J.
OꢁDonnell, Acc. Chem. Res. 2004, 37, 506–517; g) B.
Lygo, B. I. Andrews, Acc. Chem. Res. 2004, 37, 518–
525.
[8] a) H. Chikashita, M. Miyazaki, K. Itoh, Synthesis 1984,
308–310; b) H. Chikashita, M. Miyazaki, K. Itoh, J.
Chem. Soc. Perkin Trans. 1 1987, 699–706.
[9] C. Zhu, T. Akiyama, Org. Lett. 2009, 11, 4180–4183.
[10] Our reports, see: a) T. Akiyama, J. Itoh, K. Yokota, K.
Fuchibe, Angew. Chem. 2004, 116, 1592–1594; Angew.
Chem. Int. Ed. 2004, 43, 1566–1568; b) T. Akiyama, H.
Morita, J. Itoh, K. Fuchibe, Org. Lett. 2005, 7, 2583–
[3] G. Shang, Q. Yang, X. Zhang, Angew. Chem. 2006, 118,
6508–6510; Angew. Chem. Int. Ed. 2006, 45, 6360–
6362.
Adv. Synth. Catal. 2010, 352, 1846 – 1850
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1849

Chen Zhu and Takahiko Akiyama
COMMUNICATIONS
2585; c) T. Akiyama, Y. Saitoh, H. Morita, K. Fuchibe,
Adv. Synth. Catal. 2005, 347, 1523–1526; d) T. Akiya-
ma, Y. Tamura, J. Itoh, H. Morita, K. Fuchibe, Synlett
2006, 141–143; e) J. Itoh, T. Akiyama, K. Fuchibe,
Angew. Chem. 2006, 118, 4914–4916; Angew. Chem.
Int. Ed. 2006, 45, 4796–4798; f) T. Akiyama, H. Morita,
K. Fuchibe, J. Am. Chem. Soc. 2006, 128, 13070–13071;
g) M. Yamanaka, J. Itoh, K. Fuchibe, T. Akiyama, J.
Am. Chem. Soc. 2007, 129, 6756–6764; h) T. Akiyama,
Y. Honma, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2008,
350, 399–402; i) J. Itoh, K. Fuchibe, T. Akiyama,
Angew. Chem. 2008, 120, 4080–4082; Angew. Chem.
Int. Ed. 2008, 47, 4016–4018; j) T. Akiyama, T. Suzuki,
K. Mori, Org. Lett. 2009, 11, 2445–2447; k) T. Akiya-
ma, T. Kato, K. Mori, Angew. Chem. 2009, 121, 4290–
4292; Angew. Chem. Int. Ed. 2009, 48, 4226–4228; l) T.
Akiyama, H. Morita, P. Bachu, K. Mori, M. Yamanaka,
T. Hirata, Tetrahedron 2009, 65, 4950–4956; m) T.
Akiyama, T. Katoh, K. Mori, K. Kanno, Synlett 2009,
1664–1666; n) K. Mori, T. Katoh, T. Suzuki, T. Noji, T.
Akiyama, Angew. Chem. 2009, 121, 9832–9834; Angew.
Chem. Int. Ed. 2009, 48, 9652–9654; o) W. Kashikura,
J. Itoh, K. Mori, T. Akiyama, Chem. Asian J. 2010, 5,
470–472; p) P. Bachu, T. Akiyama, Chem. Commun.
2010, 46, 4112–4114.
shima, H. Yamamoto, J. Am. Chem. Soc. 2006, 128,
9626–9627; c) M. J. Wanner, R. N. S. van der Haas,
K. R. de Cuba, J. H. van Maarseveen, H. Hiemstra,
Angew. Chem. 2007, 119, 7629–7631; Angew. Chem.
Int. Ed. 2007, 46, 7485–7487; d) E. B. Rowland, G. B.
Rowland, E. Rivera-Otero, J. C. Antilla, J. Am. Chem.
Soc. 2007, 129, 12084–12085; e) X.-H. Chen, W.-Q.
Zhang, L.-Z. Gong, J. Am. Chem. Soc. 2008, 130, 5652–
5653; f) X. Wang, C. M. Reisinger, B. List, J. Am.
Chem. Soc. 2008, 130, 6070–6071; g) S. Xu, Z. Wang,
X. Zhang, X. Zhang, K. Ding, Angew. Chem. 2008, 120,
2882–2885; Angew. Chem. Int. Ed. 2008, 47, 2840–
2843; h) D. Enders, A. A. Narine, F. Toulgoat, T. Bis-
schops, Angew. Chem. 2008, 120, 5744–5748; Angew.
Chem. Int. Ed. 2008, 47, 5661–5665; i) M. Rueping,
A. P. Antonchick, E. Sugiono, K. Grenader, Angew.
Chem. 2009, 121, 925–927; Angew. Chem. Int. Ed.
2009, 48, 908–910; j) W. Schrader, P. P. Handayani, J.
Zhou, B. List, Angew. Chem. 2009, 121, 1491–1494;
Angew. Chem. Int. Ed. 2009, 48, 1463–1466; k) M.
Terada, H. Tanaka, K. Sorimachi, J. Am. Chem. Soc.
2009, 131, 3430–3431; l) M. Lu, D. Zhu, Y. Lu, X.
Zeng, B. Tan, Z. Xu, G. Zhong, J. Am. Chem. Soc.
2009, 131, 4562–4563; m) H. Liu, G. Dagousset, G.
Masson, P. Retailleau, J. Zhu, J. Am. Chem. Soc. 2009,
131, 4598–4599; n) X. Zeng, Z. Xu, M. Lu, G. Zhong,
Org. Lett. 2009, 11, 3036–3039; o) Q.-W. Zhang, C.-A.
Fan, H.-J. Zhang, Y.-Q. Tu, Y.-M. Zhao, P. Gu, Z.-M.
Chen, Angew. Chem. 2009, 121, 8724–8726; Angew.
Chem. Int. Ed. 2009, 48, 8572–8574; p) M. Rueping,
M.-Y. Lin, Chem. Eur. J. 2010, 16, 4169–4172; q) S. Xu,
Z. Wang, Y. Li, X. Zhang, H. Wang, K. Ding, Chem.
Eur. J. 2010, 16, 3021–3035.
[11] For reviews on Brønsted acid catalysis, see: a) T.
Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006,
348, 999–1010; b) T. Akiyama, Chem. Rev. 2007, 107,
5744–5758; c) S. J. Connon, Angew. Chem. 2006, 118,
4013–4016; Angew. Chem. Int. Ed. 2006, 45, 3909–
3912; d) T. Akiyama, in: Acid Catalysis in Modern Or-
ganic Synthesis, Vol. 1, (Eds.: H. Yamamoto, K. Ishi-
hara), Wiley-VCH, Weinheim, 2008, pp 62–107; e) M.
Terada, Chem. Commun. 2008, 4097–4112; f) M.
Terada, Synthesis 2010, 1929–1982 and references cited
therein.
[13] For details, see Supporting Information.
[14] The absolute configuration was determined by compar-
ing the optical rotation of 3 with those of reports of
Antilla[4a] and You.[4b]
[12] For selected examples, see: a) D. Uraguchi, M. Terada,
J. Am. Chem. Soc. 2004, 126, 5356–5357; b) D. Naka-
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