A highly enantioselective catalytic Strecker reaction of cyclic (Z)-aldimines

Article abstract of DOI:10.1039/c2cc31001e

A range of 3H-indoles and 2H-benzo[b][1,4]thiazines smoothly undergo asymmetric Strecker reaction with ethyl cyanoformate in the presence of a Cinchona alkaloid-based thiourea catalyst at 10 °C to give structurally diverse nitrogen-containing heterocycles in good to excellent yields and with excellent ee.

Full text of DOI:10.1039/c2cc31001e

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A highly enantioselective catalytic Strecker reaction of cyclic (Z)-aldiminesw
You-Dong Shaoa and Shi-Kai Tian*ab
Received 11th February 2012, Accepted 20th March 2012
DOI: 10.1039/c2cc31001e
A range of 3H-indoles and 2H-benzo[b][1,4]thiazines smoothly
undergo asymmetric Strecker reaction with ethyl cyanoformate
in the presence of a Cinchona alkaloid-based thiourea catalyst
at 10 8C to give structurally diverse nitrogen-containing hetero-
cycles in good to excellent yields and with excellent ee.
low temperature.5b,c To our knowledge, there has been no
report on the catalytic asymmetric Strecker reaction of cyclic
(Z)-aldimines other than the three 3,4-dihydroisoquinolines.
The catalytic asymmetric Strecker reactions of cyclic
(Z)-aldimines are potentially useful for the construction of
optically active nitrogen-containing heterocycles, which are present
in many natural products, pharmaceutics, and catalysts. Although
3H-indoles are readily accessible cyclic (Z)-aldimines,6 they have
not been employed as carbon electrophiles in catalytic asymmetric
processes.7 In the course of transforming cyclic (Z)-aldimines,8 we
found that a Cinchona alkaloid-based thiourea9 could catalyze the
asymmetric Strecker reaction of 3H-indoles with a relatively safe
cyanide source at 10 1C to give various 2-cyanoindolines in a
highly enantioselective manner [Scheme 1(b)]. Moreover, this
chemistry was successfully extended to readily accessible
2H-benzo[b][1,4]thiazines.10
The Strecker reaction of imines with cyanide sources is extremely
useful for the formation of carbon–carbon bonds by providing
versatile a-amino nitriles that are widely employed as building
blocks in chemical synthesis.1 Ever since Lipton and coworkers
reported the first catalytic asymmetric Strecker reaction in 1996,2 a
number of protocols have been discovered for transforming acyclic
(E)-aldimines3 and ketimines4 into optically active a-amino nitriles.
In sharp contrast, much less attention has been paid to cyclic
(Z)-aldimines in catalytic asymmetric Strecker reactions. In 2000,
Jacobsen and coworkers disclosed that 3,4-dihydroisoquinoline
underwent hydrocyanation in 91% ee at ꢀ70 1C with a chiral
1,2-trans-diaminocyclohexane-based urea/Schiff base as the catalyst
[Scheme 1(a)].5a Several years later, two 3,4-dihydroisoquinoline
derivatives were reported to undergo catalytic asymmetric
cyanation with trimethylsilyl cyanide or acetyl cyanide at
While the Strecker reaction of 3H-indole 1a with ethyl
cyanoformate (2a, 1.2 equiv.) did not occur in the presence
of 10 mol% of catalyst QD-a, a quinidine-based thiourea, in
dry 1,2-dichloroethane at 10 1C (Table 1, entry 1), the addition
of 1.2 equiv. of methanol to the mixture resulted in the
formation of 2-cyanoindoline 3a in 97% yield and with 95% ee
(Table 1, entry 2). When the reaction was carried out in a common
organic solvent other than 1,2-dichloroethane, the enantio-
selectivity decreased significantly (Table 1, entries 3–8). The addi-
tion of 3 A molecular sieves to the reaction mixture led to higher
yield and enantioselectivity (99% yield and 96% ee), but inferior
enantioselectivity was observed with 4 A or 5 A molecular sieves
(Table 1, entries 9–11). Replacement of methanol with ethanol,
isopropanol, tert-butanol, or phenol led to deteriorated enantios-
electivity (Table 1, entries 12–15). A few other quinidine-based
catalysts were examined, and much lower enantioselectivity was
obtained (Table 1, entries 16–18). The use of trimethylsilyl cyanide
(2b) as the cyanide source slightly enhanced the enantioselectivity,
but reduced the yield significantly (Table 1, entry 19). In contrast,
the reaction with diethyl phosphorocyanidate (2c) gave inferior
enantioselectivity (Table 1, entry 20). It is noteworthy that the use
of catalyst Q-a, a quinine-based thiourea, resulted in the formation
of 2-cyanoindoline 3a0, the enantiomer of compound 3a, in 99%
yield and with 97% ee (Table 1, entry 21).
Scheme 1 Catalytic asymmetric Strecker reaction of cyclic (Z)-aldimines.
a Joint Laboratory of Green Synthetic Chemistry,
Department of Chemistry, University of Science and Technology
of China, Hefei, Anhui 230026, China. E-mail: tiansk@ustc.edu.cn;
Fax: +86 551-360-1592; Tel: +86 551-360-0871
b Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
In the presence of 10 mol% of catalyst QD-a, a range of
polysubstituted 3H-indoles smoothly underwent asymmetric
Strecker reaction with ethyl cyanoformate (2a) at 10 1C to give
structurally diverse 2-cyanoindolines in good to excellent
yields and with excellent ee (Table 2, entries 1–12). Halo, alkoxy,
carbamate, alkyl, and aryl groups were successfully introduced
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and copies of 1H NMR, 13C NMR,
and HPLC spectra for products. CCDC 832628 and 837035. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc31001e
c
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Chem. Commun., 2012, 48, 4899–4901 4899

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Table 1 Optimization of reaction conditionsa
ð1Þ
Table 2 Catalytic asymmetric Strecker reaction of cyclic (Z)-aldiminesa
QD-a, 3
Yieldb eec Yieldb eec
QD-a, 30
(%)
(%) (%)
(%)
Entry lmine
Entry 2, X
Catalyst ROH
None
Solvent Yieldb (%) eec (%)
1
2
1a, R = H
1b, R = Cl
1c, R = Br
99
73
83
96
97
98
97
97
99
80
90
99
99
97
97
96
98
97
1
2a, CO2Et
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-a
QD-b
QD-c
QD-d
QD-a
DCE
MeOH DCE
0
97
—
95
2
3
4
5
6
7
8
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
2a, CO2Et
3
4d
5d
1d, R = Me 99
1e, R = OMe 99
MeOH CH2Cl2 94
MeOH CHCl3 89
MeOH PhMe 65
MeOH Et2O
MeOH EtOAc 55
MeOH MeCN 43
MeOH DCE
MeOH DCE
MeOH DCE
EtOH DCE
i-PrOH DCE
t-BuOH DCE
PhOH DCE
MeOH DCE
MeOH DCE
MeOH DCE
MeOH DCE
MeOH DCE
MeOH DCE
92
87
78
86
86
54
96
92
91
94
93
64
6d
1f
99
99
98
95
99
99
97
97
9d
10e
11f
12d
13d
14d
15d
16d
17d
99
93
92
98
97
7d
1g
Trace
99
69
—
90
68
90
43
65
65
67
ꢀ10
18d,g 2a, CO2Et
8
9
1h, n = 1
1i, n = 8
93
99
92
93
83
99
98
94
19d
20d
2b, TMS
2c, PO(OEt)2 QD-a
Q-a
97
89
21d,g 2a, CO2Et
99
ꢀ97
a
Reaction conditions: 3H-indole 1a (0.10 mmol), cyanide source 2
b
(0.12 mmol), catalyst (10 mol%), solvent (1.0 mL), 10 1C, 60 h. Isolated
yield. c Determined by HPLC analysis on a chiral stationary phase. 3 A
d
10e
1j
99
91
99
98
molecular sieves (20 mg) were used. e 4 A molecular sieves (20 mg) were
used. f 5 A molecular sieves (20 mg) were used. 2-Cyanoindoline 3a0, the
enantiomer of compound 3a, was obtained as the major product.
g
to optically active 2-cyanoindolines. Replacement of catalyst
QD-a with its pseudoenantiomer Q-a led to the formation of
enantiomeric 2-cyanoindolines in comparable yields and ee. This
chemistry was further extended to 2H-benzo[b][1,4]thiazines, and
3-cyano-3,4-dihydro-2H-benzo[b][1,4]thiazines were obtained in
excellent yields and ee (Table 2, entries 13–14). The absolute
configuration of 2-cyanoindoline 3b and 3-cyano-3,4-dihydro-
2H-benzo[b][1,4]thiazine 3m was determined to be S and R,
respectively, by single-crystal X-ray analysis (see the ESIw).
In contrast to many other a-amino nitriles, transformation
of compounds 3 (or 30) into the corresponding a-amino acids
under acidic conditions was not successful.1a,c,g For example, a
complex mixture was obtained when a-amino nitrile 3a was
subjected to treatment with concentrated hydrochloric acid
at an elevated temperature. Gratifyingly, treatment of this
compound with lithium hydroxide and hydrogen peroxide
led to the formation of a-amino amide 4 in 70% yield (eqn (1)).
It is noteworthy that there was no loss of optical purity at all
during the reaction.
11
1k
1l
85
98
97
96
79
95
97
98
12
13
1m
1n
90
99
94
94
98
99
97
97
14
a
Reaction conditions: cyclic (Z)-aldimine
cyanoformate (2a, 0.12 mmol), QD-a or Q-a (10 mol%), DCE
1 (0.10 mmol), ethyl
b
c
(1.0 mL), 10 1C, 60 h. Isolated yield. Determined by HPLC
analysis on a chiral stationary phase. The reaction was run for 48 h.
d
e
The reaction was run for 72 h.
c
4900 Chem. Commun., 2012, 48, 4899–4901
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3 For recent examples, see: (a) S. C. Pan and B. List, Chem.–Asian J.,
2008, 3, 430; (b) S. Nakamura, H. Nakashima, H. Sugimoto,
H. Sano, M. Hattori, N. Shibata and T. Toru, Chem.–Eur. J.,
2008, 14, 2145; (c) Y. Wen, B. Gao, Y. Fu, S. Dong, X. Liu and
X. Feng, Chem.–Eur. J., 2008, 14, 6789; (d) S. Wunnemann,
¨
¨
R. Frohlich and D. Hoppe, Eur. J. Org. Chem., 2008, 684;
(e) S. J. Zuend, M. P. Coughlin, M. P. Lalonde and
E. N. Jacobsen, Nature, 2009, 461, 968; (f) J. P. Abell and
H. Yamamoto, J. Am. Chem. Soc., 2009, 131, 15118;
(g) J. Wang, W. Wang, W. Li, X. Hu, K. Shen, C. Tan, X. Liu
and X. Feng, Chem.–Eur. J., 2009, 15, 11642; (h) B. Karimi and
A. Maleki, Chem. Commun., 2009, 5180; (i) M. Hatano, Y. Hattori,
Y. Furuya and K. Ishihara, Org. Lett., 2009, 11, 2321;
(j) V. Banphavichit, W. Mansawat, W. Bhanthumnavin and
T. Vilaivan, Tetrahedron, 2009, 65, 5849; (k) R. Reingruber,
Fig. 1 Proposed catalytic model.
When benzyl alcohol was used as the additive in the
QD-a-catalyzed Strecker reaction of 3H-indole 1a with ethyl
cyanoformate (2a), EtOCO2CH2Ph was isolated in 99%
yield.11 This result clearly indicates that ethyl cyanoformate
(2a) undergoes alcoholysis to give the actual cyanating agent,
HCN,3f,g during the catalytic asymmetric Strecker reaction.
Hence, it is reasonable to conclude that catalyst QD-a and
HCN form an ammonium salt, in which the thiourea moiety
associates with the cyanide anion through noncovalent inter-
actions (Fig. 1).3e,12 This ammonium salt activates cyclic
(Z)-aldimine 1 through hydrogen bonding and provides a
chiral environment for the asymmetric addition of the cyanide
anion to cyclic (Z)-aldimine 1 to give optically active nitrogen-
containing heterocycle 3.
T. Baumann, S. Dahmen and S. Brase, Adv. Synth. Catal., 2009,
¨
351, 1019; (l) B. Karimi, A. Maleki, D. Elhamifar, J. H. Clark and
A. J. Hunt, Chem. Commun., 2010, 46, 6947; (m) A. M. Seayad,
B. Ramalingam, K. Yoshinaga, T. Nagata and C. L. L. Chai, Org.
Lett., 2010, 12, 264; (n) B. Ramalingam, A. M. Seayad, C. Li,
M. Garland, K. Yoshinaga, M. Wadamoto, T. Nagata and C. L.
L. Chai, Adv. Synth. Catal., 2010, 352, 2153; (o) N. H. Khan,
S. Saravanan, R. I. Kureshy, S. H. R. Abdi, A. Sadhukhan and
H. C. Bajaj, J. Organomet. Chem., 2010, 695, 1133; (p) N. H. Khan,
S. Saravanan, R. I. Kureshy, S. H. R. Abdi and H. C. Bajaj,
Tetrahedron: Asymmetry, 2010, 21, 2076; (q) P. Kaur, S. Pindi,
W. Wever, T. Rajale and G. Li, Chem. Commun., 2010, 46, 4330;
(r) P. Kaur, S. Pindi, W. Wever, T. Rajale and G. Li, J. Org.
Chem., 2010, 75, 5144.
In summary, we have developed a highly enantioselective cata-
lytic Strecker reaction of cyclic (Z)-aldimines with ethyl cyano-
formate at 10 1C. With a Cinchona alkaloid-based thiourea as the
catalyst, a range of polysubstituted 3H-indoles are transformed into
structurally diverse 2-cyanoindolines in good to excellent yields and
with excellent ee. Halo, alkoxy, carbamate, alkyl, and aryl groups
are successfully introduced to optically active 2-cyanoindolines.
Moreover, this chemistry is successfully extended to the synthesis
of 3-cyano-3,4-dihydro-2H-benzo[b][1,4]thiazines in excellent yields
and ee.
4 For recent examples, see: (a) Y.-J. Chen and C. Chen, Tetrahedron:
Asymmetry, 2008, 19, 2201; (b) Z. Hou, J. Wang, X. Liu and
X. Feng, Chem.–Eur. J., 2008, 14, 4484; (c) K. Shen, X. Liu,
Y. Cai, L. Lin and X. Feng, Chem.–Eur. J., 2009, 15, 6008;
(d) D. Enders, K. Gottfried and G. Raabe, Adv. Synth. Catal.,
2010, 352, 3147; (e) G.-W. Zhang, D.-H. Zheng, J. Nie, T. Wang
and J.-A. Ma, Org. Biomol. Chem., 2010, 8, 1399; (f) Y.-L. Liu,
F. Zhou, J.-J. Cao, C.-B. Ji, M. Ding and J. Zhou, Org. Biomol.
Chem., 2010, 8, 3847; (g) Y.-L. Liu, T.-D. Shi, F. Zhou,
X.-L. Zhao, X. Wang and J. Zhou, Org. Lett., 2011, 13, 3826.
5 (a) M. S. Sigman, P. Vachal and E. N. Jacobsen, Angew. Chem.,
Int. Ed., 2000, 39, 1279; (b) C. Becker, C. Hoben and H. Kunz,
Adv. Synth. Catal., 2007, 349, 417; (c) T. Kanemitsu,
E. Toyoshima, M. Miyazaki, K. Nagata and T. Itoh, Heterocycles,
2010, 81, 2781.
6 (a) J. G. Rodriguez, Y. Benito and F. Temprano, J. Heterocycl.
Chem., 1985, 22, 1207; (b) K. G. Liu and A. J. Robichaud,
Tetrahedron Lett., 2007, 48, 461.
7 For reviews, see: (a) S. Kobayashi and H. Ishitani, Chem. Rev.,
1999, 99, 1069; (b) D. Ferraris, Tetrahedron, 2007, 63, 9581;
(c) G. K. Friestad and A. K. Mathies, Tetrahedron, 2007,
63, 2541; (d) S. Kobayashi, Y. Mori, J. S. Fossey and
M. M. Salter, Chem. Rev., 2011, 111, 2626.
We are grateful for the financial support from the National
Natural Science Foundation of China (21172206 and 20972147),
the National Basic Research Program of China (973 Program
2010CB833300), and the Program for Changjiang Scholars and
Innovative Research Team in University (IRT1189).
Notes and references
1 For reviews, see: (a) D. Enders and J. P. Shilvock, Chem. Soc. Rev.,
2000, 29, 359; (b) L. Yet, Angew. Chem., Int. Ed., 2001, 40, 875;
8 Y.-D. Shao, X.-S. Wu and S.-K. Tian, Eur. J. Org. Chem., 2012,
1590.
9 For a review, see: S. J. Connon, Chem. Commun., 2008, 2499.
10 M. Watzke, K. Schulz, K. Johannes, P. Ullrich and J. Martens,
Eur. J. Org. Chem., 2008, 3859.
11 2-Cyanoindoline 3a was obtained in 90% yield and with 93% ee.
12 S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc., 2009,
131, 15358.
(c) H. Groger, Chem. Rev., 2003, 103, 2795; (d) C. Spino, Angew.
¨
Chem., Int. Ed., 2004, 43, 1764; (e) S. J. Connon, Angew. Chem.,
Int. Ed., 2008, 47, 1176; (f) P. Merino, E. Marques-Lopez,
´ ´
T. Tejero and R. P. Herrera, Tetrahedron, 2009, 65, 1219;
(g) J. Wang, X. Liu and X. Feng, Chem. Rev., 2011, 111, 6947.
2 M. S. Iyer, K. M. Gigstad, N. D. Namdev and M. Lipton, J. Am.
Chem. Soc., 1996, 118, 4910.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4899–4901 4901