Enantioselective synthesis of β-amino esters bearing a benzothiazole moiety via a Mannich-type reaction catalyzed by a cinchona alkaloid derivative

Article abstract of DOI:10.1002/ejoc.201100351

Novel β-amino esters bearing a bioactive benzothiazole moiety were obtained with high enantioselectivities (up to 95 % ee) through a Mannich-type reaction of different imines with malonate in the presence of a new chiral cinchona alkaloid thiourea catalys

Full text of DOI:10.1002/ejoc.201100351

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100351
Enantioselective Synthesis of β-Amino Esters Bearing a Benzothiazole Moiety
via a Mannich-Type Reaction Catalyzed by a Cinchona Alkaloid Derivative
Liang Li,[a] Bao-An Song,*[a] Pinaki S. Bhadury,[a] Yu-Ping Zhang,[a] De-Yu Hu,[a] and
Song Yang*[a]
Keywords: β-Amino esters / Enantioselectivity / Asymmetric catalysis / Alkaloids / Organocatalysis
Novel β-amino esters bearing a bioactive benzothiazole moi-
ety were obtained with high enantioselectivities (up to
95%ee) through a Mannich-type reaction of different imines
with malonate in the presence of a new chiral cinchona alka-
loid thiourea catalyst. Imines derived from both aromatic and
heterocyclic aldehydes were found useful in this conversion.
metal ions. This makes them easy to synthesize, easy to
handle, cheap, and less toxic than their metal-ion counter-
parts. In addition to employing proline and its derivatives
in direct three-component Mannich reactions for preparing
chiral β-amino carbonyl compounds,[9] some other metal-
free bifunctional organocatalysts such as Brønsted acids,[10]
chiral thioureas,[11] and cinchona alkaloids[12] may also be
employed in asymmetric Mannich reactions. These asym-
metric catalysts, by virtue of their intrinsic chemical nature,
often affiliate with flat substrates and prevent or promote,
to some extent, an addition reaction of a reagent to one or
to other faces of the double bond. These transformations
are usually targeted to reach high levels of efficiencies and
widen the substrate scope in the Mannich reaction.
Similar to enzyme catalysis characterized by selective
substrate recognition and activation, hydrogen bonding in-
duced by synthetic chiral bifunctional organocatalysts plays
an important role in asymmetric catalysis.[13] The weak in-
teractions of small, metal-free compounds with electron-
rich binding sites have been investigated in detail and fur-
ther extended by other researchers to study the hydrogen-
bonding ability of various chiral thiourea derivatives in
asymmetric Mannich reactions. These purely organic com-
pounds effectively accelerate simple organic reactions, be-
have like weak Lewis acid catalysts, but act through explicit
double hydrogen bonding instead of covalent binding
known for traditional-metal-ion-mediated catalysis.
Introduction
The importance for the enrichment of a single enantio-
mer, often as the bioactive chiral component, has grown
sharply in recent years, driven not only by the demands of
the pharmaceutical industry, but also by other applications
in the field of agriculture and materials science.[1] Optically
active enantiopure β-amino acids and their derivatives have
extensive biological, pharmacological and plant-regulatory
activities. They are encountered in numerous compounds
and are part of crucial building blocks of many natural
products.[2] Because of their role in various key industries,
enantioselective synthesis of these compounds has attracted
considerable attention in recent times.[3] On the other hand,
benzothiazole derivatives have been studied extensively and
found to have a broad spectrum of biological activities
which include antiviral,[4] antiallergic,[5] antimicrobial,[6]
and anticancer.[7] So, based on our technical competence in
the field of plant virology,[1d] we prepared herein a series of
novel asymmetric β-amino esters incorporating a benzothi-
azole moiety to obtain potent environmentally friendly
antiviral agents for plants. Enantioenriched β-amino esters
from achiral precursors of imines and different nucleophilic
donor components were obtained in the past through asym-
metric Mannich reactions in the presence of chiral bifunc-
tional organocatalysts. Unlike many other efficient chiral
catalysts in the literature, asymmetric organocatalysis[8]
benefits from purely organic materials and is free from
It is generally believed that appropriate positioning of
a typical bifunctional organocatalyst containing a thiourea
(capable of providing activation through hydrogen bonding)
and a basic amine in a chiral scaffold could result in a new
type of organocatalyst. Based on this idea, the organocata-
lytic asymmetric Mannich addition of malonates to N-Boc-
protected aromatic aldimines was developed in the presence
of base-compatible cinchona-based chiral bifunctional or-
ganocatalysts (Figure 1, a) to access β-amino acid ester de-
rivatives in high yield with high ee (up to 99%).[12a] It was
[a] State Key Laboratory Breeding Base of Green Pesticide and
Agricultural Bioengineering, Key Laboratory of Green Pesti-
cide and Agricultural Bioengineering, Ministry of Education,
Center for Research and Development of Fine Chemicals,
Guizhou University,
Guiyang 550025, P. R. China
Fax: +86-851-3622211
E-mail: basong@gzu.edu.cn
fcc.syang@gzu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100351.
Eur. J. Org. Chem. 2011, 4743–4746
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4743

L. Li, B.-A. Song, P. S. Bhadury, Y.-P. Zhang, D.-Y. Hu, S. Yang
A similar thiourea–cinchonine alkaloid catalyst (Fig-
SHORT COMMUNICATION
proposed that the thiourea group of the bifunctional cata-
lyst activates and directs the electrophilic imine through H- ure 1, b) was also successfully used for the asymmetric ad-
bonding, whereas the tertiary nitrogen atom of the quinine dition of malonates to N-Boc- and N-Cbz-protected aldimi-
moiety activates the nucleophile. Upon hydrogenation, the nes.[12b] The β-amino esters were obtained as Mannich ad-
benzyl ester was deprotected and subsequent decarboxyl- ducts of dimethyl malonate and the protected aromatic ald-
ation provided the N-protected β-amino acid (Scheme 1).
imines with high ee values (Scheme 2).
Fascinated by these reports, we prepared new cinchona-
based thiourea Q-1 from 2,6-dichloro-4-(trifluoromethyl)-
aniline. The selection of this amine, which serves as a useful
precursor to some commercial insecticides[14] and pesti-
cides, was governed by several factors such as its low price
and easy availability. The asymmetric Mannich reaction of
malonate with different imines in the presence of Q-1 af-
forded β-amino esters with good to high enantioselectivities
(80–95%ee) under mild conditions. Under similar condi-
tions, catalyst a, prepared from more-expensive 3,5-bis(tri-
fluoromethyl)aniline, afforded similar result in terms of
enantioselectivity and yield. To the best of our knowledge,
this is the first report on the preparation of asymmetric β-
amino esters bearing a bioactive benzothiazole moiety.
Figure 1. Some potential cinchona alkaloid thiourea catalysts for
asymmetric transformations.
Results and Discussion
New cinchona-based thiourea Q-1 was prepared as out-
lined in Scheme 3. N-(2-Fluorobenzylidene)-4-methyl-
benzo[d]thiazol-2-amine (1a) and diethyl malonate (2a)
were adopted as the starting materials for the initial explo-
Scheme 1. Asymmetric Mannich addition of malonate to N-Boc-
protected aromatic aldimines catalyzed by a.
Scheme 2. Asymmetric Mannich addition using chiral catalyst b.
Figure 2. X-ray crystal structure of adduct 3a.
Scheme 3. Synthesis of Q-1.
4744
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4743–4746

Enantioselective Synthesis of β-Amino Esters
ration of the asymmetric Mannich reaction. The reaction Table 2. Asymmetric Mannich reaction of diethyl malonate (2a)
with imines catalyzed by Q-1.[a]
was carried out in various solvents in the presence of the
catalyst (10 mol-%) at room temperature for 72 h. In DCM,
product 3a (Figure 2) was obtained in 84%ee (Table 1, En-
try 1). Another catalyst, quinine, although it appeared supe-
rior in terms of yield (85%), afforded the product with
lower enantioselectivity (79%ee; Table 1, Entry 2) in the
same solvent. Higher ee values were obtained in chloroform
and toluene (87 and 89%ee; Table 1, Entries 3 and 6,
respectively); however, the yields were lower. Both yields
and enantioselectivities were found to be poor in acetone
and THF (Table 1, Entries 4 and 5). Of all the five solvents
selected for the screening (Table 1), xylene gave a better
yield and enantioselectivity (91%ee) of product 3a (Table 1,
Entry 7). As mentioned earlier, similar results were ob-
tained with catalyst a (Table 1, Entry 8).
Entry
R1
R2
Time
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
2-FC6H4
4-FC6H4
2-ClC6H4
4-ClC6H4
C6H5
72
72
72
72
72
96
96
96
96
96
96
96
96
96
3a[d], 88
3b, 85
3c, 88
3d, 78
3e, 75
3f, 56
3g, 67
3h, 73
3i, 65
3j, 77
3k, 67
3l, 63
3m, 60
3n, 57
91
90
93
90
89
80
88
82
85
84
84
86
85
89
thiophen-2-yl
4-CH3 naphthalen-1-yl
6-OCH3
6-OCH3
6-OCH3
6-OCH3
6-OCH3
6-OCH3
6-OCH3
2-FC6H4
4-FC6H4
2-ClC6H4
4-ClC6H4
C6H5
4-CH3C6H4
thiophen-2-yl
9
10
11
12
13
14
Table 1. Optimization studies.[a]
[a] Unless otherwise indicated, all reactions were conducted with
imine (0.3 mmol), 2a (0.36 mmol), and catalyst Q-1 (10 mol-%,
0.03 mmol) in xylene (3 mL) at room temperature for 72–96 h.
[b] Isolated yield after chromatographic purification. [c] Deter-
mined by HPLC analysis (Chiralpak IA). [d] Absolute configura-
tion of 3a obtained in the presence of Q-1 was determined to be
(R) by single-crystal X-ray structure analysis (Figure 2).[15]
Entry
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Q-1
quinine
Q-1
Q-1
Q-1
Q-1
Q-1
a
DCM
DCM
CHCl3
acetone
THF
toluene
xylene
xylene
77
85
58
70
73
75
88
87
84
79[d]
87
67
17
89
91
90
achieved with N-(furan-2-ylmethylene)-6-methoxybenzo[d]-
thiazol-2-amine and dimethyl malonate in the presence of
10 mol-% of catalyst Q-1 (95%ee; Table 3, Entry 10).
Table 3. Asymmetric Mannich reaction of diethyl malonate (2b)
with imines catalyzed by Q-1.[a]
[a] Unless otherwise indicated, all reactions were conducted with
1a (0.3 mmol), 2a (0.36 mmol), and the catalyst (10 mol-%,
0.03 mmol) in the specified solvent (3 mL) at room temperature for
72 h. [b] Isolated yield after chromatographic purification. [c] De-
termined by HPLC analysis (Chiralpak IA). [d] The configuration
of the Mannich adduct is different from those of the other adducts
obtained in other entries.
Entry
R1
R2
Time
[h]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
2-FC6H4
2-ClC6H4
C6H5
72
72
72
72
72
96
96
96
96
96
96
3o, 80
3p, 77
3q, 73
3r, 50
3s, 49
3t, 65
3u, 75
3v, 70
3w, 73
3x, 50
3y, 47
89
92
90
91
86
91
86
87
85
95
88
Various imines and diethyl malonate were then reacted
under the optimized conditions, and the results are col-
lected in Table 2. All the synthesized imines afforded the
desired β-amino esters with good to high ee values (80–
93%).
furan-2-yl
thiophen-2-yl
naphthalen-1-yl
4-FC6H4
4-CH3
6-OCH3
6-OCH3
6-OCH3
6-OCH3
6-OCH3
4-ClC6H4
Substituent effects usually have a significant impact of
the yield and enantioselectivity. Almost all of the desired
products derived from 2-amino-4-methylbenzothiazole were
obtained in higher yields and with higher ee values com-
pared to those derived from 2-amino-6-methoxybenzothi-
azole. With R1 = 4-CH3, better enantioselectivities were
achieved with an ortho substituent in the aryl ring (Table 2,
Entries 1–4), whereas a para substituent usually gave better
results with R1 = 6-OCH3 (Table 2, Entries 8–11).
9
10
11
4-CH3C6H4
furan-2-yl
thiophen-2-yl
[a] Unless otherwise noted, all reactions were conducted with imine
(0.3 mmol), 2b (0.36 mmol), and catalyst Q-1(10 mol-%,
0.03 mmol) in xylene (3 mL) at room temperature for 72–96 h.
[b] Isolated yield after chromatographic purification. [c] Deter-
mined by HPLC analysis (Chiralpak IA).
Selected imines were treated with dimethyl malonate to
broaden the scope of the Mannich reaction, and the results
are listed in Table 3. All of the desired products were ob-
Conclusions
In summary, we have developed for the first time an
tained with high ee values; the most promising result was enantioselective synthesis of β-amino esters bearing a
Eur. J. Org. Chem. 2011, 4743–4746
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4745

L. Li, B.-A. Song, P. S. Bhadury, Y.-P. Zhang, D.-Y. Hu, S. Yang
SHORT COMMUNICATION
[4]
F. Gualtieri, G. Brody, A. H. Fieldsteel, W. A. Skinner, J. Med.
Chem. 1971, 14, 546–549.
M. Ban, H. Taguchi, T. Katsushima, M. Takahashi, K. Shin-
oda, A. Watanabe, T. Tominaga, Bioorg. Med. Chem. 1998, 6,
1069–1076.
benzothiazole moiety by employing a Mannich reaction
catalyzed by a new and cheap quinine-derived thiourea cat-
alyst. The desired products were obtained with high
enantioselectivities (80–95%).
[5]
[6]
[7]
Y. Cho, T. R. Ioerger, J. C. Sacchettini, J. Med. Chem. 2008,
51, 5984–5992.
a) I. Caleta, M. Kralj, M. Marjanovic´, B. Bertosˇa, S. Tomic´,
Experimental Section
´
Typical Procedure for the Organocatalytic Asymmetric Mannich-
Type Reaction: To a solution of imine 1a (0.3 mol) and chiral cata-
lyst (10 mol-%) in dimethylbenzene (3.0 mL) at room temperature
was added diethyl malonate (2b, 0.36 mmol) in one portion. After
stirring for 72–96 h, the mixture was concentrated, and the residue
was purified directly by preparative thin-layer chromatography
(hexane/diethyl ether, 9:1–3:1) to afford products 3a. The enantio-
meric excess was determined by HPLC with a Chiralpak IA column
(hexane/ethanol = 70:30; 1.0 mL/min; λ = 270 nm): tR = 4.29
(major), 4.82 (minor) min.
G. Pavlovic´, K. Pavelic´, G. Karminski-Zamola, J. Med. Chem.
2009, 52, 1744–1756; b) S. Aiello, G. Wells, E. L. Stone, H.
Kadri, R. Bazzi, D. R. Bell, M. F. G. Stevens, C. S. Matthews,
T. D. Bradshaw, A. D. Westwell, J. Med. Chem. 2008, 51, 5135–
5139; c) M. Yoshida, I. Hayakawa, N. Hayashi, T. Agatsuma,
Y. Oda, F. Tanzawa, S. Iwasaki, K. Koyama, H. Furukawa, S.
Kurakata, Y. Sugano, Bioorg. Med. Chem. Lett. 2005, 15, 3328–
3332; d) L. H. Jin, B. A. Song, G. P. Zhang, R. Q. Xu, S. M.
Zhang, X. W. Gao, D. Y. Hu, S. Yang, Bioorg. Med. Chem.
Lett. 2006, 16, 1537–1543.
L. S. Hegedus, J. Am. Chem. Soc. 2009, 131, 17995–17997 and
references cited therein.
a) B. List, J. Am. Chem. Soc. 2000, 122, 9336–9337; b) B. List,
P. Pojarliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002,
124, 827–833; c) J. W. Yang, M. Stadler, B. List, Angew. Chem.
2007, 119, 615–617; Angew. Chem. Int. Ed. 2007, 46, 609–611;
d) J. W. Yang, C. Chandler, M. Stadler, D. Kampen, B. List,
[8]
[9]
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, characterization data of the
prepared compounds, 1H and 13C NMR spectra, and HPLC analy-
sis data.
ˇ
Nature 2008, 452, 453–455; e) E. Veverková, J. Strasserová, R.
Acknowledgments
ˇ
ˇ
Sebesta, S. Toma, Tetrahedron: Asymmetry 2010, 21, 58–61; f)
P. S. Bhadury, B. A. Song, Curr. Org. Chem. 2010, 14, 1989–
2003; g) W. Notz, K. Sakthivel, T. Bui, G. F. Zhong, C. F.
Barbas III, Tetrahedron Lett. 2001, 42, 199–201; h) W. Notz, F.
Tanaka, C. F. Barbas III, Acc. Chem. Res. 2004, 37, 580–591.
The authors are grateful for the financial support of the National
Key Program for Basic Research (No. 2010CB126105,
2010CB134504), Key Technologies R&D Program (No.
2011BAE06B05), and the National Natural Science Foundation of
China (No. 20872021).
[10] a) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356–
5357; b) T. Akiyama, Y. Saitoh, H. Morita, K. Fuchibe, Adv.
Synth. Catal. 2005, 347, 1523–1526; c) Q. X. Guo, H. Liu, C.
Guo, S. W. Luo, Y. G, L. Z. Gong, J. Am. Chem. Soc. 2007,
129, 3790–3791; d) M. Yamanaka, J. Itoh, K. Fuchibe, T. Aki-
yama, J. Am. Chem. Soc. 2007, 129, 6756–6764.
[11] a) X. Han, J. Kwiatkowski, F. Xue, K. W. Huang, Y. X. Lu,
Angew. Chem. 2009, 121, 7740–7743; Angew. Chem. Int. Ed.
2009, 48, 7604–7607; b) A. G. Wenzel, E. N. Jacobsen, J. Am.
Chem. Soc. 2002, 124, 12964–12965.
[1] a) R. Crossley, Chirality and the Biological Activity of Drugs,
CRC, Boca Raton, 1995; b) M. Eichelbaum, A. S. Gross, Adv.
Drug Res. 1996, 28, 1–64; c) W. P. Liu, J. Ye, M. Q. Jin, J. Agric.
Food Chem. 2009, 57, 2087–2095; d) B. A. Song, S. Yang, L. H.
Jin, P. S. Bhadury, Environment-Friendly Anti-Plant Viral
Agent, Chemical Industry Press (Beijing) & Springer Press,
2009.
[2] a) D. A. Evans, L. D. Wu, J. J. M. Wiener, J. S. Johnson, [12] a) J. Song, Y. Wang, L. Deng, J. Am. Chem. Soc. 2006, 128,
D. H. B. Ripin, J. S. J. Tedrow, Org. Chem. 1999, 64, 6411–
6417; b) H. M. L. Davies, C. Venkataramani, Angew. Chem.
2002, 114, 2301–2303; Angew. Chem. Int. Ed. 2002, 41, 2197–
2199; c) R. P. Cheng, S. H. Gellman, W. F. DeGrado, Chem.
Rev. 2001, 101, 3219–3232; d) A. H. Berks, Tetrahedron 1996,
52, 331–375; e) S. Kosemura, T. Ogawa, K. Totsuka, Tetrahe-
dron Lett. 1993, 34, 1291–1294; f) M. Arend, B. Westermann,
N. Risch, Angew. Chem. 1998, 110, 1096–1122; Angew. Chem.
Int. Ed. 1998, 37, 1044–1070; g) F. V. Nussbaum, P. Spiteller in
Highlights in Bioorganic Chemistry: Methods and Application
(Eds.: C. Schmuck, H. Wennemers), Wiley-VCH, Weinheim,
2004, vol. 63, pp. 10–20; h) I. Ojima, S. N. Lin, T. Wang, Curr.
Med. Chem. 1999, 6, 927–954.
6048–6049; b) A. L. Tillman, J. X. Ye, D. J. Dixon, Chem. Com-
mun. 2006, 1191–1193; c) J. Song, H. W. Shih, L. Deng, Org.
Lett. 2007, 9, 603–606; d) H. L. Zhang, S. Syed, C. F.
Barbas III, Org. Lett. 2010, 12, 708–711; e) C. M. Bode, A.
Ting, S. E. Schaus, Tetrahedron 2006, 62, 11499–11505; f) T. B.
Poulsen, C. Alemparte, S. Saaby, M. Bella, K. A. Jørgensen,
Angew. Chem. 2005, 117, 2956–2959; Angew. Chem. Int. Ed.
2005, 44, 2896–2899.
[13] For reviews, see: a) M. S. Taylor, E. N. Jacobsen, Angew. Chem.
2006, 118, 1550–1573; Angew. Chem. Int. Ed. 2006, 45, 1520–
1543; b) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713–5743.
[14] I. G. Buntain, L. R. Hatton, D. W. Hawkins, C. J. Pearson,
D. A. Roberts, EP 295117, 1988.
[15] Crystal data of 3a: C22H23FN2O4S, Mr = 430.48, triclinic,
space group P1, a = 9.1694(12) Å, b = 9.2368(11) Å, c =
13.6139(17) Å, α = 79.486(5)°, β = 72.968 (5)°, γ = 79.460(5)°,
V = 1073.6(2) Å3, Dcalcd. = 1.329 Mg/m3, T = 293(2) K, Z =
2, 11437 reflections collected, 3717 independent (Rint = 0.0426),
final R indices [IϾ2σ(I)]: R1 = 0.0775, wR2 = 0.1031, R indices
(all data): R1 = 0.1031, wR2 = 0.2541, absolute structure pa-
rameter: 0.008(4), GOF = 0.974. CCDC-781779 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: March 12, 2011
[3] a) W. J. Tang, X. M. Zhang, Org. Lett. 2002, 4, 4159–4161; b)
J. A. Ma, Angew. Chem. 2003, 115, 4426–4435; Angew. Chem.
Int. Ed. 2003, 42, 4290–4299; c) M. P. Sibi, N. Prabagaran,
S. G. Ghorpade, C. P. Jasperse, J. Am. Chem. Soc. 2003, 125,
11796–11797; d) M. K. Edmonds, F. H. M. Graichen, J. Gardi-
ner, A. D. Abell, Org. Lett. 2008, 10, 885–887; e) C. Agami, S.
Cheramy, L. Dechoux, M. Melaimi, Tetrahedron 2001, 57, 195–
200; f) J. Vesely, R. Rios, I. Ibrahem, A. Córdova, Tetrahedron
Lett. 2007, 48, 421–425; g) E. Juaristi, V. A. Soloshonok, Enan-
tioselective Synthesis of β-Amino Acids, 2nd ed., Wiley-VCH,
New York, 2005; h) T. Y. Liu, J. Long, B. J. Li, L. Jiang, R. Li,
Y. Wu, L. S. Ding, Y. C. Chen, Org. Biomol. Chem. 2006, 4,
2097–2099; i) T. Y. Liu, R. Li, Q. Chai, J. Long, B. J. Li, Y.
Wu, L. S. Ding, Y. C. Chen, Chem. Eur. J. 2007, 13, 319–327.
Published Online: July 18, 2011
4746
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4743–4746