Chiral cinchona alkaloid-derived thiourea catalyst for enantioselective synthesis of novel β-amino esters by Mannich reaction

Article abstract of DOI:10.1002/chir.21986

A cinchona alkaloid-derived thiourea catalyst has been designed to access new asymmetric β-amino esters bearing benzothiazole moiety by utilizing a Mannich reaction between an imine and a malonate. A simultaneous activation of the two imine functionalitie

Full text of DOI:10.1002/chir.21986

CHIRALITY 24:223–231 (2012)
Chiral Cinchona Alkaloid-Derived Thiourea Catalyst
for Enantioselective Synthesis of Novel b-Amino Esters
by Mannich Reaction
*
WEIHUA LI, BAOAN SONG, PINAKI S. BHADURY, LIANG LI, ZHENCHAO WANG, XIAOYAN ZHANG, DEYU HU,
*
ZHUO CHEN, YUPING ZHANG, SONG BAI, JIAN WU, AND SONG YANG
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Center for Research and Development of Fine Chemicals, Guizhou University, Guiyang 550025,
People’s Republic of China
ABSTRACT
A cinchona alkaloid-derived thiourea catalyst has been designed to access new
asymmetric b-amino esters bearing benzothiazole moiety by utilizing a Mannich reaction
between an imine and a malonate. A simultaneous activation of the two imine functionalities and
malonate by the bifunctional chiral organocatalyst is proposed to account for the good yields
(71–91%) and high enantiomeric excess (89.4–98.5%) under mild conditions. Chirality 24:223–
C
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231, 2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: asymmetric b-amino esters; benzothiazole moiety; chiral cinchona alkaloid-
derived thiourea; enantiomeric excess
INTRODUCTION
attacked by the nucleophilic enolsilane,26,35 1,3-diketones,36 or
malonates which in turn could be activated by the Bronsted
basic part of the bifunctional organocatalyst through a con-
certed pathway.16,37,38 Thus, appropriate positioning of a
bifunctional catalyst containing a thiourea (capable to provide
activation through hydrogen bond) and a cinchona alkaloid
bearing tertiary amine component in a chiral scaffold could
result in potential catalysts for asymmetric Mannich transfor-
mations. Based on this concept, we explored the possibility to
utilize a series of cinchona alkaloid-derived thiourea catalysts
in the preparation of enantioenriched b-amino esters from
imines containing a benzothiazole unit and diethyl malonate.
Some novel structural catalysts were also designed by making
subtle variation in the nature of substituents linked to thiourea
group. The final structure in the product still retains the bio-
active component of heterocyclic benzothiazole. The stereo-
chemical outcome of the reaction can be controlled through
double hydrogen bond activation of two imine groups by thio-
urea, while the malonate is activated by the basic nitrogen
atom of cinchona alkaloid. The method was found to be suita-
ble with different imine and good yields and high ee values of
the target compounds were obtained. To the best of our
knowledge, this is the first report for the preparation of enan-
tioselective b-amino esters bearing benzothiazole moiety
Enantiomerically pure b-amino acid derivatives are
extremely useful in life sciences as part of biologically active
molecules and small molecule pharmaceuticals.1–4 Some of
these compounds can also serve as valuable intermediates in
routes to novel molecules with biological and pharmacologi-
cal activities. The synthetic requirement emanates from the
fact that barring the only example of b-alanine, other b-amino
acids and b-peptides in general do not occur in nature. Most
of the reported methods predominantly rely upon classical
resolution, stoichiometric use of chiral auxiliaries, or homolo-
gation of a-amino acids.5–10 In fact, chemical synthesis of b-
amino acid derivatives offers great challenge due to the wide
diversity of functional groups that can be bonded to the b
carbon and the necessity of preserving chirality or creating
the same via stereospecific addition of reagents across flat
substrates. To access optically active b-amino acid deriva-
tives through the later method, various organocatalytic tech-
niques promoted by small chiral organic molecules ranging
from simple proline and related chiral amine derivatives to
axially chiral binaphthyl-derived Bronsted acids, thioureas,
and cinchona alkaloids have been reviewed.11–21 In this con-
text, asymmetric organocatalytic Mannich reactions, at least
in principle, are perhaps one of the most powerful modern
techniques that represent a direct entry into optically active
b-amino carbonyl compounds.22–25 Jacobsen’s group
reported organocatalytic asymmetric Mannich reaction to
prepare enantioenriched b-amino acid derivatives,26 whereas
various other workers obtained similar class of compounds
by cinchona alkaloid induced Mannich reaction.27–31 Despite
these reports, a reliable route to access optically active b-
amino acid derivatives bearing heterocyclic pharmacophores
by organocatalytic Mannich reaction still needs to be devel-
oped. Multifunctional organocatalysts having hydrogen-bond
donor ability and a secondary interaction site, are able to cat-
alyze a vast number of reactions with high enantioselectiv-
ity.32–34 Acidic sites of chiral thioureas and phosphoric acids
often bind with the nitrogen atom of the Schiff’s base making
the electrophilic imine susceptible to be stereoselectively
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: National Key Program for Basic Research;
Contract grant numbers: 2010CB 126105, 2010CB134504.
Contract grant sponsor: Key Technologies R&D Program; Contract grant
number: 2011BAE06B05.
Contract grant sponsor: National Natural Science Foundation of China;
Contract grant number: 20872021.
*Correspondence to: Baoan Song or Song Yang, Center for Research and De-
velopment of Fine Chemicals, State Key Laboratory Breeding Base of Green
Pesticide and Agricultural Bioengineering, Key Laboratory of Green
Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou
University, Guiyang 550025, People’s Republic of China. Fax: 10086-851-
3622211. E-mail: songbaoan22@yahoo.com or jhzx.mxm@gmail.com
Received for publication 2 October 2011; Accepted 2 November 2011
DOI: 10.1002/chir.21986
Published online 25 January 2012 in Wiley Online Library
(wileyonlinelibrary.com).
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2012 Wiley Periodicals, Inc.

224
LI ET AL.
Scheme 1. Synthetic route to chiral b-amino esters 3.
phy to afford the corresponding product. The optical purity was deter-
mined by HPLC analysis using a chiral column.
through simultaneous activation of two imines and malonate
by the catalyst (Scheme 1).
MATERIALS AND METHODS
General
Diethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(phenyl)methyl)-
malonate (3a).
The melting points of the products were determined on a XT-4 binocu-
lar microscope (Beijing Tech Instrument Co., China) and were not cor-
rected. The IR spectra were recorded on a Bruker VECTOR22 spectrome-
ter in KBr disks. NMR spectra were recorded on a JEOL-ECX 500 instru-
ment (500 MHz for 1H, 125 MHz for 13C, 200 MHz for 31P, 470 MHz for
19F) using CDCl3 as a solvent, unless otherwise mentioned. Tetramethylsi-
lane (d 5 0) served as an internal standard for 1H-NMR and CDCl3 was
used as an internal standard (d 5 77.0) for 13C-NMR. H3PO4 was used as
an internal standard (d 5 0) for 31P-NMR. CF3COOD was used as an
external standard (d 5 76.5) for 19F-NMR. Elemental analysis was per-
formed on an Elementar Vario-III CHN analyzer. The reagents were all of
analytical grade or chemically pure. Analytical thin layer chromatography
(TLC) was performed on silica gel GF254. Organic solvents used were
dried by standard methods when necessary. Purification of the products
was performed by chromatographic operation on silica gel Qingdao GF254
under normal pressure. Reaction experiments were performed under ar-
gon atmosphere using standard double-line pipe. Catalysts Q-1, QD-1,
andQ-3 were prepared according to the literature procedures.39,40 Cata-
lysts Q-2, Q-4, and Q-5 and benzothiazol-2-yl-benzylidene imines 1 were
prepared as given in the Supporting Information.
The analytical high-performance liquid chromatography (HPLC) of the
compounds was performed on Agilent 1100 series Apparatus composed of
a quaternary pump, an auto sampler, a diode array detector (DAD) a vac-
uum degasser, a column oven, and Agilent Chemstation software. The
two columns employed were Chiralpak AD-H-amylose tri-(3,5-dimethyl-
phenylcarbamate) coated on 5-lm silica-gel and Chiralpak IA-amylose tri-
(3,5-dimethylphenylcarbamate) immobilized on silica-gel (each of 250 mm
3 4.6 mm i.d., Daicel Chemical Industries Ltd).
(R)-(2)-3a, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 72 h; yield (92.8
mg, 90%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 5/
1); 95.8% ee as determined by HPLC [Daicel Chiralpak IA, hexane/iso-
propyl alcohol (IPA) 5 95/5, 1.0 ml min21, k 5 254 nm, tr (major) 5 7.85
min, tr (minor) 5 14.81 min]; [a]2D5 5 222.7 (c 5 1.10, CHCl3). IR (KBr)
m: 3387, 2978, 1732, 1539, 1452, 1236, 1157, 759, 700, 480 cm21. 1H-NMR
(500 MHz,CDCl3) d: 1.13–1.14 (m, 6H), 2.52 (s, 3H), 4.01 (d, J 5 5.7 Hz,
1H), 4.09–4.19 (m, 4H), 5.65 (brs, 1H), 6.95 (t, J 5 14.9 Hz, 2H), 7.06 (d, J
5 7.4 Hz, 1H), 7.22–7.25 (m, 1H), 7.30 (t, J 5 14.9 Hz, 2H), 7.35 (d, J 5
7.4 Hz, 1H), 7.41 (d, J 5 7.4 Hz, 2H). 13C-NMR (125 MHz, CDCl3) d:
168.0, 167.0, 165.5, 151.3, 138.7, 130.8, 129.2, 128.8, 126.8, 126.7, 121.7,
118.3, 62.3, 62.0, 58.4, 57.3, 18.5, 14.0. Analysis calculated for
C22H24N2O4S: C, 64.06; H, 5.86; N, 6.79. Found: C, 63.99; H, 5.77; N, 6.53.
(S)-(1)-3a, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 72 h; yield (80%); 89.4%
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 70/30,
1.0 ml min21, k 5 270 nm, tr (major) 5 5.05 min, tr (minor) 5 4.33 min].
Diethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(2-fluorophenyl)-
methyl)malonate (3b).
General Procedure for Enantioenriched 3a–l by
Organocatalytic Mannich Reaction of Benzothiazolyl Imine
1a–l with Diethyl Malonate 2b or Dimethyl Malonate 2a
Diethyl malonate 2b (0.30 mmol) in dichloromethane (DCM) (2.0–3.0
ml) was added in one shot to a mixture of imine 1a–l (0.25 mmol) and chi-
ral catalyst (10 mol %) at room temperature and stirred for 72–96 h. After
the completion of the reaction (as observed by TLC), the solvent was
evaporated and the product was purified by silica gel column chromatogra-
(R)-(2)-3b, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 72 h; yield (97.8 mg,
Chirality DOI 10.1002/chir

CINCHONA ALKALOID-DERIVED THIOUREA CATALYST
225
91%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 5/1);
96.0% ee as determined by HPLC [Daicel Chiralpak IA, hexane/IPA 5 90/
10, 1.0 ml min21, k 5 254 nm, tr (major) 5 7.09 min, tr (minor) 5 10.61
min]; [a]2D5 5 220.0 (c 5 1.50, CHCl3). IR (KBr) m: 3387, 2980, 1734,
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 70/30,
1.0 ml min21, k 5 270 nm, tr (major) 5 5.85 min, tr (minor) 5 4.32 min].
Diethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(4-chlorophenyl)-
methyl)malonate (3e).
1539, 1373, 1240, 1151, 1039, 759 cm21 1H-NMR (500 MHz, CDCl3) d:
.
1.15–1.19 (m, 6H), 2.52 (s, 3H), 4.10–4.15 (m, 5H), 5.83–5.85 (m, 1H), 6.84
(d, J 5 9.8 Hz, 1H), 6.97 (t, J 5 7.4 Hz, 1H), 7.05–7.10 (m, 3H), 7.24–7.28
(m, 1H), 7.38 (d, J 5 8.0 Hz, 1H), 7.44–7.47 (m, 1H); 13C-NMR (125 MHz,
CDCl3) d: 167.9, 166.7, 165.1, 161.5, 159.5, 151.3, 129.4, 129.0, 126.7, 124.4,
121.8, 118.3, 115.6, 62.3, 62.0, 55.7, 53.7, 18.4, 14.0. 19F-NMR (470 MHz,
CDCl3) d: 2117.7. Analysis calculated for C22H23N2O4FS: C, 61.38; H,
5.39; N, 6.51; Found: C, 61.36; H, 5.25; N, 6.56.
(S)-(1)-3b, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 72 h; yield (85%); 90.0%
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 70/30,
1.0 ml min21, k 5 270 nm, tr (major) 5 4.90 min, tr (minor) 5 4.27 min].
(R)-(2)-3e, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 72 h; yield (100.0 mg,
89%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 5/1);
95.2% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
95/5, 1.0 ml min21, k 5 270 nm, tr (major) 5 8.72 min, tr (minor) 5 15.41
min]; [a]2D5 5 27.2 (c 5 0.77, CHCl3). IR (KBr) m: 3361, 2980, 1743, 1533,
1489, 1344, 1238, 1149, 1039, 756, 744 cm21. 1H-NMR (500 MHz, CDCl3) d:
1.18 (s, 6H), 2.51 (s, 3H), 3.96 (d, J 5 5.2 Hz, 1H), 4.09–4.23 (m, 4H), 5.65
(brs, 1H), 6.88 (brs, 1H), 6.98 (t, J 5 7.4 Hz, 1H), 7.08 (d, J 5 6.8 Hz, 1H),
7.30 (d, J 5 8.6 Hz, 2H), 7.36–7.39 (m, 3H); 13C-NMR (125 MHz, CDCl3) d:
168.0, 166.8, 165.0, 151.2, 137.4, 133.9, 129.3, 128.9, 128.2, 126.7, 121.8,
118.3, 62.4, 62.1, 57.6, 57.0, 18.4, 14.0. Analysis calculated for C22H23N2O4
ClS: C, 59.12; H, 5.19; N, 6.27; Found: C, 59.01; H, 5.08; N, 6.17.
Diethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(2-chlorophenyl)-
methyl)malonate (3c).
(S)-(1)-3e, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 72 h; yield (80%); 85.9%
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 70/30,
1.0 ml min21, k 5 270 nm, tr (major) 5 6.11 min, tr (minor) 5 4.42 min].
(R)-(2)-3c, this product was obtained as a white solid from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 72 h; yield (99.4 mg,
89%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 5/1);
94.8% ee as determined by HPLC [Daicel Chiralpak IA, hexane/IPA 5 95/
5, 1.0 ml min21, k 5 254 nm, tr (major) 5 10.36 min, tr (minor) 5 16.63
min]; [a]2D5 5 2120.4 (c 5 1.00, CHCl3). IR (KBr) m: 3383, 2922, 1732,
Diethyl
2-((6-methoxybenzo[d]thiazol-2-ylamino)(phenyl)
methyl)malonate (3f).
1535, 1373, 1238, 1155, 756 cm21 1H-NMR (500 MHz, CDCl3) d: 1.14–
.
1.22 (m, 6H), 2.52 (s, 3H), 4.05–4.12 (m, 1H), 4.14–4.28 (m, 4H), 5.93
(brs, 1H), 6.96 (t, J 5 15.4 Hz, 1H), 7.06 (d,J 5 7.4 Hz, 1H), 7.19–7.24 (m,
3H), 7.36–7.40 (m, 2H), 7.49–7.51 (m, 1H); 13C-NMR (125 MHz, CDCl3) d:
168.1, 166.8, 165.2, 151.3, 135.8, 129.9, 129.4, 129.3, 128.5, 127.3, 126.7,
121.7, 118.3, 62.4, 61.9, 55.9, 54.4, 18.4, 14.0. Analysis calculated for C22
H23N2O4ClS: C, 59.12; H, 5.19; N, 6.27; Found: C, 59.24; H, 5.11; N, 6.08.
(S)-(1)-3c, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 72 h; yield (85%); 90.0%
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 70/30,
1.0 ml min21, k 5 270 nm, tr (major) 5 4.92 min, tr (minor) 5 4.14 min].
(R)-(2)-3f, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (86.8
mg, 81%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/
1); 98.5% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH
5 70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 8.35 min, tr (minor) 5
10.23 min]; [a]2D5 5 213.8 (c 5 1.40, CHCl3). IR (KBr) m: 3371, 2980,
1734, 1604, 1545, 1471, 1222, 1157, 1028, 833, 700 cm21 1H-NMR (500
.
Diethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(4-fluorophenyl)-
methyl)malonate (3d).
MHz, CDCl3) d: 1.14–1.16 (m, 6H), 3.78 (s, 3H), 4.00 (d, J 5 4.6 Hz,1H),
4.14–4.16 (m, 4H), 5.69 (brs, 1H), 6.84–6.90 (m, 2H), 7.08 (d, J 5 2.8
Hz,1H), 7.24–7.26 (m, 1H), 7.32 (t, J 5 14.8 Hz, 2H), 7.39–7.42 (m, 3H).
13C-NMR (125 MHz, CDCl3) d: 168.2, 167.0, 164.6, 155.3, 146.4, 138.7,
131.8, 128.8, 128.0, 126.6, 119.7, 113.6, 105.3, 62.3, 61.9, 57.9, 57.2, 55.9,
14.0, 13.9. Analysis calculated for C22H24N2O5S: C, 61.67; H, 5.65; N,
6.54. Found: C, 61.55; H, 5.48; N, 6.66.
(S)-(1)-3f, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 96 h; yield (72%); 95.8%
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 70/30,
1.0 ml min21, k 5 270 nm, tr (major) 5 10.20 min, tr (minor) 5 8.35 min].
(R)-(2)-3d, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 72 h; yield (95.6 mg,
89%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 5/1);
95.0% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
95/5, 1.0 ml min21, k 5 270 nm, tr (major) 5 8.41 min, tr (minor) 5 14.97
min]; [a]2D5 5 222.6 (c 5 0.73, CHCl3). IR (KBr) m: 3373, 2993, 1747,
1539, 1506, 1301, 1261, 1145, 1024, 769 cm21. 1H-NMR (500 MHz, CDCl3)
d: 1.17–1.18 (m, 6H), 2.52 (s, 3H), 3.96 (d, J 5 5.2 Hz, 1H), 4.14–4.17 (m,
4H), 5.63–5.65 (m, 1H), 6.88 (d, J 5 8.6 Hz, 1H), 6.96–7.03 (m, 3H), 7.08
(d, J 5 7.4 Hz, 1H), 7.38–7.42 (m, 3H); 13C-NMR (125 MHz, CDCl3) d:
168.0, 166.8, 165.1, 163.4, 161.4, 151.2, 130.6, 129.3, 128.6, 126.7, 121.8,
118.3, 115.8, 115.6, 62.3, 62.1, 57.6, 57.2, 18.4, 14.0. 19F-NMR (470 MHz,
CDCl3) d: 2114.0. Analysis calculated for C22H23N2O4FS: C, 61.38; H,
5.39; N, 6.51; Found: C, 61.20; H, 5.26; N, 6.41.
Diethyl
2-((6-methoxybenzo[d]thiazol-2-ylamino)(2-fluorophe-
nyl)methyl)malonate (3g).
(R)-(2)-3g, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (95.5 mg,
86%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/1);
98.2% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
(S)-(1)-3d, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 72 h; yield (80%); 90.2%
Chirality DOI 10.1002/chir

226
LI ET AL.
70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 8.64 min, tr (minor) 5 7.02
min]; [a]2D5 5 215.2 (c 5 1.00, CHCl3). IR (KBr) m: 3383, 1741, 1606,
Diethyl
2-((6-methoxybenzo[d]thiazol-2-ylamino)(4-chlorophe-
nyl)methyl)malonate (3j).
1548, 1489, 1219, 1155, 1037, 763 cm21 1H-NMR (500 MHz, CDCl3) d:
.
1.13–1.17 (m, 6H), 3.79 (s, 3H), 4.10–4.16 (m, 5H), 5.86–5.88 (m, 1H), 6.78
(brs, 1H), 6.86 (dd, J 5 2.3 Hz, J 5 2.8 Hz, 1H), 7.05–7.10 (m, 3H), 7.24–
7.28 (m, 1H), 7.40–7.44 (m, 2H). 13C-NMR (125 MHz, CDCl3) d: 168.1,
166.8, 164.2, 161.4, 159.4, 146.4, 131.8, 129.4, 129.9, 128.7, 124.4, 119.9,
115.9, 115.6, 113.6, 105.3, 62.3, 61.9, 55.9, 55.6, 53.4, 14.0, 13.9. 19F-NMR
(470 MHz, CDCl3) d: 2117.4. Analysis calculated for C22H23N2FO5S: C,
59.18; H, 5.19; N, 6.27; Found: C, 59.04; H, 5.19; N, 6.28.
(S)-(1)-3g, this product was obtained as a colorless oil from a reaction
catalyzed by QD-1 (10 mol %) at room temperature for 96 h; yield (74%);
96.0% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 8.65 min, tr (minor) 5
7.12 min].
(R)-(2)-3j, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (93.6
mg, 81%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/
1); 98.1% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH
5 70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 7.98 min, tr (minor) 5
12.40 min]; [a]2D5 5 215.0 (c 5 1.25, CHCl3). 1H-NMR (500 MHz,
CDCl3) d: (ppm) 1.21 (s, 6H), 3.81 (s, 3H), 3.96 (s, 1H), 4.15–4.18 (m,
4H), 5.69 (brs, 1H), 6.87 (s, 1H), 7.28 (s, 1H), 7.30–7.41 (m, 5H); 13C-
NMR (125 MHz, CDCl3) d (ppm): 168.0, 166.8, 164.2, 155.4, 146.3, 137.4,
133.8, 131.8, 128.9, 128.1, 119.9, 113.6, 105.3, 62.0, 57.2, 57.0, 55.9, 54.3,
14.1, 13.9; IR(KBr, cm21) m: 3364, 2980, 1734, 1605, 1498, 1476, 1223,
1091, 1028, 829. Analysis calculated for C22H23N2ClO5S: C, 57.08; H,
5.01; N, 6.05. Found: C, 57.00; H, 5.18; N, 5.99.
Diethyl 2-((6-methoxybenzo[d]thiazol-2-ylamino)(2-chlorophenyl)
methyl)malonate (3h).
(S)-(1)-3j, this product was obtained as a colorless oil from a reaction
catalyzed by QD-1 (10 mol %) at room temperature for 96 h; yield (65%);
95.6% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 12.39 min, tr (minor) 5
8.11 min].
R)-(2)-3h, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (99.2 mg,
86%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/1);
97.9% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 6.51 min, tr (minor) 5 7.79
min]; [a]2D5 5 2106.5 (c 5 0.90, CHCl3). IR (KBr) m: 3387, 2974, 1749,
1604, 1533, 1473, 1226, 1151, 1031, 765 cm21. 1H-NMR (500 MHz, CDCl3)
d: 1.13 (t, J 5 38.4 Hz, 3H), 1.20 (t, J 5 13.8 Hz, 3H), 3.78 (s, 3H), 4.03–
4.09 (m, 1H), 4.12–4.28 (m, 4H), 5.90–5.91 (m, 1H), 6.85 (dd, J 5 2.3 Hz, J
5 2.2 Hz, 1H), 7.07 (d, J 5 2.3 Hz, 1H), 7.14–7.24 (m, 3H), 7.38–7.48 (m,
3H). 13C-NMR (125 MHz, CDCl3) d: 168.2, 166.9, 164.3, 155.3, 146.5,
135.8, 132.8, 131.9, 129.4, 129.9, 129.5, 128.4, 127.3, 119.9, 105.3, 62.4,
61.9, 55.9, 55.8, 54.3, 14.1, 13.9. Analysis calculated for C22H23N2ClO5S: C,
57.08; H, 5.01; N, 6.05; Found: C, 57.07; H, 4.99; N, 6.01.
Diethyl 2-((6-methoxybenzo[d]thiazol-2-ylamino)(p-tolyl)methyl)-
malonate (3k).
(R)-(2)-3k, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (77.5 mg,
70%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/1);
98.4% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 7.93 min, tr (minor) 5 10.85
min]; [a]2D5 5 214.7 (c 5 1.40, CHCl3). IR (KBr) m: 3366, 2980, 1732, 1604,
1548,1469, 1223, 1157, 1029, 814, 563 cm21. 1H-NMR (500 MHz, CDCl3) d:
1.13–1.16 (m, 3H), 2.28 (m, 3H), 3.77 (s, 3H), 3.96 (d, J 5 5.2 Hz, 1H),
4.09–4.18 (m, 4H), 5.61 (brs, 1H), 6.83–6.87 (m, 2H), 7.06–7.12 (m, 3H),
7.25–7.28 (m, 2H), 7.39 (d, J 5 9.2 Hz, 1H). 13C-NMR (125 MHz, CDCl3) d:
168.2, 167.0, 164.8, 155.3, 146.5, 137.8, 135.6, 131.8, 129.5, 126.5, 119.7,
113.5, 105.3, 62.2, 61.9, 57.3, 55.9, 21.2, 14.1, 13.9. Analysis calculated for
C23H26N2O5S: C, 62.42; H, 5.92; N, 6.33. Found: C, 62.50; H, 5.87; N, 6.25.
(S)-(1)-3k, this product was obtained as a colorless oil from a reaction
catalyzed by QD-1 (10 mol %) at room temperature for 96 h; yield (66%);
97.7% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 9.34 min, tr (minor) 5
7.14 min].
(S)-(1)-3h, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 96 h; yield (73%); 96.3%
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 70/30,
1.0 ml min21, k 5 270 nm, tr (major) 5 7.88 min, tr (minor) 5 7.07 min].
Diethyl
2-((6-methoxybenzo[d]thiazol-2-ylamino)(4-fluorophe-
nyl)methyl)malonate (3i).
(R)-(2)-3i, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (90.3 mg,
81%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/1);
98.5% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 11.55 min, tr (minor) 5
7.80 min]; [a]2D5 5 220.1 (c 5 1.30, CHCl3). IR (KBr) m: 3371, 2993, 1751,
Diethyl 2-((6-methoxybenzo[d]thiazol-2-ylamino)(2-methoxyphe-
nyl)methyl)malonate (3l).
1604, 1548, 1474, 1263, 1159, 1022, 817, 567 cm21 1H-NMR (500 MHz,
.
CDCl3) d: 1.15–1.16 (m, 6H), 3.79 (s, 3H), 3.96 (d, J 5 5.2 Hz, 1H), 4.09–
4.19 (m, 4H), 5.68 (brs, 1H), 6.85–6.91 (m, 2H), 6.99–7.02 (m, 2H), 7.08
(d, J 5 2.8 Hz, 1H), 7.37–7.42 (m, 3H); 13C-NMR (125 MHz, CDCl3) d:
168.1, 166.8, 164.3, 163.4, 161.4, 155.4, 146.4, 134.5, 131.8, 128.4, 128.3,
119.8, 115.8, 115.6, 113.6, 105.3, 62.3, 62.0, 57.2, 55.9, 14.1, 13.9; 19F-NMR
(470 MHz, CDCl3) d: 2114.2; Analysis calculated for C22H23N2FO5S: C,
59.18; H, 5.19; N, 6.27. Found: C, 59.30; H, 5.27; N, 6.27.
(S)-(1)-3i, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 96 h; yield (66%); 91.5%
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 70/30,
1.0 ml min21, k 5 270 nm, tr (major) 5 11.50 min, tr (minor) 5 7.89 min].
R)-(2)-3l, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (81.3 mg,
71%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/1);
89.4% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
95/5, 1.0 ml min21, k 5 270 nm, tr (major) 5 22.01 min, tr (minor) 5
24.44 min]; [a]2D55 259.2 (c 5 0.80, CHCl3). IR (KBr) m: 3200, 2982, 1726,
1
1605, 1554, 1475, 1230, 1030, 815, 760 cm21. H-NMR (500 MHz, CDCl3)
d: 1.12–1.14 (m, 6H), 3.78 (s, 3H), 3.94 (m, 3H), 4.10–4.11 (m, 4H), 4.26
Chirality DOI 10.1002/chir

CINCHONA ALKALOID-DERIVED THIOUREA CATALYST
227
Fig. 1. Cinchona alkaloid-derived thiourea catalysts and commercial quinine and quinidine.
(d, J 5 6.9 Hz, 1H), 5.62–5.64 (m, 1H), 6.77 (d, J 5 10.3 Hz, 1H), 6.84–
6.90 (m, 3H), 7.08 (d, J 5 2.8 Hz, 1H), 7.23–7.25 (m, 1H) 7.34–7.36 (m,
1H), 7.40 (d, J 5 9.2 Hz, 1H). 13C-NMR (125 MHz, CDCl3) d: 168.1, 167.2,
165.2, 156.8, 155.2, 146.5, 131.8, 129.4, 128.9, 125.8, 120.7, 119.6, 113.5,
110.6, 105.3, 61.9, 61.8, 55.9, 55.6, 55.3, 14.0. Analysis calculated for
EtOH 5 80/20, 1.0 ml min21, k 5 270 nm, tr (major) 5 5.20 min, tr
(minor) 5 5.76 min]; [a]2D5 5 221.8 (c 5 1.47, CHCl3). IR (KBr) m: 3334,
2949, 1720, 1539, 1340, 1267, 1024, 769, 700 cm21 1H-NMR (500 MHz,
.
CDCl3) d: 2.52 (s, 3H), 3.68 (s, 6H), 4.03–4.04 (m, 1H), 5.63–5.64 (m,
1H), 6.86 (br, 1H), 6.96 (t, J 5 7.4 Hz, 1H), 7.07 (d, J 5 6.9 Hz, 1H), 7.27
(t, J 5 12.6 Hz, 1H), 7.33 (t, J 5 15.5 Hz, 2H), 7.31–7.41 (m,3H). 13C-
NMR (125 MHz, CDCl3) d: 168.3, 167.3, 165.4, 151.2, 138.6, 129.2, 128.9,
128.2, 126.7, 126.6, 121.7, 118.3, 58.4, 57.0, 53.2, 52.9, 18.4. Analysis cal-
culated for C20H20N2O4S: C, 62.48; H, 5.24; N, 7.29. Found: C, 62.43; H,
5.27; N, 7.40.
C23H26N2SO6: C, 60.25; H, 5.72; N, 6.11. Found: C, 60.31; H, 5.35; N, 6.17.
(S)-(1)-3l, this product was obtained as a colorless oil from a reaction cat-
alyzed by QD-1 (10 mol %) at room temperature for 96 h; yield (65%); 98.2%
ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5 95/5, 1.0
ml min21, k 5 270 nm, tr (major) 5 23.86 min, tr (minor) 5 22.06 min].
General Procedure for Enantioenriched 3m–r by
Organocatalytic Mannich Reaction of Benzothiazolyl Imine
with dimethyl Malonate 2a
TABLE 1. Catalyst screeninga
Similar procedure as described with diethyl malonate 2a was adopted.
The enantioenriched 3m–r was obtained by reaction of diethyl malonate
2a and benzothiazolyl imine 1a–c and 1i–k catalyzed by Q-1 (10 mol %)
at room temperature for 72–96 h.
Entry
Cat.
Temp (8C)
Yieldb
eec
1
2
3
4
5
6
7
8
Quinine
Quinidine
Q-1
QD-1
Q-2
rt
rt
rt
rt
rt
rt
rt
rt
85%
85%
90%
85%
85%
90%
30%
85%
79.1%
76.0%
95.7%
90.0%
88.8%
95.1%
21.2%
92.6%
Dimethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(phenyl)methyl)
malonate (3m).
Q-3
Q-4d
Q-5
aUnless otherwise noted, reactions were carried out with 0.25 mmol of 1b,
0.30 mmol of 2b in 2.0 ml of methylene chloride using 10 mol % of catalyst at
room temperature for 72 h.
bIsolated yield after chromatographic purification.
cDetermined by HPLC analysis (Chiralpak IA).
(R)-(2)-3m, this product was obtained as a colorless oil from a reac-
tion catalyzed by Q-1 (10 mol %) at room temperature for 72 h; yield
(71.0 mg, 74%) by preparative TLC (GF254 silica gel: hexane/ethyl ether
5 5/1); 95.3% ee as determined by HPLC [Daicel Chiralpak IA, hexane/
dReaction was carried out with 10 mol % of catalyst at room temperature for
96 h.
Chirality DOI 10.1002/chir

228
LI ET AL.
Fig. 2. Catalyst screening.
Dimethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(2-fluorophenyl)
methyl)malonate (3n).
1); 97.1% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH
5 70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 7.96 min, tr (minor) 5
10.17 min]; [a]2D5 5 217.7 (c 5 0.90, CHCl3). IR (KBr) m: 3373, 2953,
1755, 1602, 1539, 1438, 1222, 1157, 844, 812, 584 cm21 1H-NMR (500
.
MHz, CDCl3) d: 3.67 (s, 3H), 3.70 (s, 3H), 3.78 (m, 3H), 3.98 (d, J 5 5.2
Hz, 1H), 5.64–5.67 (m, 1H), 6.84–6.87 (m, 2H), 7.00 (t, J 5 8.6 Hz, 2H),
7.08 (d, J 5 2.9 Hz, 1H), 7.35–7.41 (m, 3H); 13C-NMR (125 MHz, CDCl3)
d: 168.4, 167.2, 164.3, 163.4, 161.4, 155.5, 146.3, 134.4, 131.8, 128.4, 128.3,
119.8, 115.9, 115.7, 113.7, 105.3, 57.0, 56.0, 53.2, 52.9; 19F-NMR (470 MHz,
CDCl3) d: 2113.9. Analysis calculated for C20H19FN2SO5: C, 57.41; H,
4.58; N, 6.69. Found: C, 57.45; H, 4.57; N, 6.79.
(R)-(2)-3n, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 72 h; yield (85.4
mg, 85%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 5/
1); 95.3% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH
5 80 /20, 1.0 ml min21, k 5 270 nm, tr (major) 5 5.04 min, tr (minor) 5
5.47 min]; [a]2D5 5 217.5 (c 5 1.29, CHCl3). IR (KBr) m: 3360, 2955,
Dimethyl 2-((6-methoxybenzo[d]thiazol-2-ylamino)(4-chlorophe-
nyl)methyl)malonate (3q).
1745, 1593, 1535, 1360, 1165, 762, 744, 525 cm21 1H-NMR (500 MHz,
.
CDCl3) d: 2.52 (s, 3H), 3.68 (s, 3H), 3.70 (m, 3H), 4.14 (d, J 5 5.7 Hz,
1H), 5.83–5.85 (m, 1H), 6.81 (d, J 5 9.2 Hz, 1H), 6.97 (t, J 5 8.0 Hz, 1H),
7.08 (q, J 5 7.4 Hz, 3H), 7.24–7.28 (m, 1H), 7.38 (m, J 5 7.8 Hz, 1H),
7.44 (t, J 5 7.4 Hz, 1H). 13C-NMR (125 MHz, CDCl3) d: 168.3, 167.1,
165.0, 161.5, 159.5, 151.2, 128.9, 126.7, 124.5, 121.9, 118.3, 115.8, 115.6,
53.6, 53.2, 18.4; 19F-NMR (470 MHz, CDCl3) d: 2117.8. Analysis calcu-
lated for C20H19 FN2SO4: C, 59.69; H, 4.76; N, 6.96. Found: C, 59.59; H,
4.52; N, 6.91.
(R)-(2)-3q, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (85.8 mg,
79%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/1);
97.4% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 8.16 min, tr (minor) 5
11.11 min]; [a]2D5 5 221.9 (c 5 0.99, CHCl3). IR (KBr) m: 3346, 2951,
Dimethyl 2-((4-methylbenzo[d]thiazol-2-ylamino)(2-chlorophe-
nyl)methyl)malonate (3o).
1747, 1607, 1543, 1435, 1151, 837, 825, 549 cm21 1H-NMR (500 MHz,
.
CDCl3) d: 3.67 (s, 3H), 3.70 (s, 3H), 3.78 (s, 3H), 3.98 (d, J 5 5.2 Hz, 1H),
5.66 (br, 1H), 5.85 (dd, J 5 2.8 Hz, J 5 1.5 Hz, 2H), 7.08 (d, J 5 2.9 Hz,
1H), 7.25–7.34 (m, 4H), 7.40 (d, J 5 8.6 Hz, 1H). 13C-NMR (125 MHz,
CDCl3) d: 168.4, 167.2, 164.2, 155.5, 146.3, 137.2, 134.0, 131.8, 129.0, 128.0,
113.7, 105.3, 56.8, 55.6, 56.0, 53.2. Analysis calculated for C20H19ClN2O5S:
C, 55.24; H, 4.40; N, 6.44. Found: C, 55.12; H, 4.36; N, 6.29.
Dimethyl
2-((6-methoxybenzo[d]thiazol-2-ylamino)(p-tolyl)
(R)-(2)-3o, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 72 h; yield (85.8 mg,
82%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 5/1);
96.9% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH 5
80/20, 1.0 ml min21, k 5 270 nm, tr (major) 5 4.78 min, tr (minor) 5 5.44
min]; [a]2D5 5 2122.7 (c 5 1.34, CHCl3). IR (KBr) m: 3367, 2951, 1745,
1539, 1492, 1355, 1251, 761, 586 cm21. 1H-NMR (500 MHz, CDCl3) d: 2.52
(s, 3H), 3.66 (s, 3H), 3.76 (m, 3H), 4.18 (d, J 5 4.6 Hz, 1H), 5.92 (q, J 5
4.6 Hz, 1H), 6.96 (t, J 5 7.4 H z, 1H), 7.06 (d, J 5 7.4 Hz, 1H), 7.20–7.25
(m, 3H), 7.36–7.40 (m, 2H), 7.40–7.48 (m, 1H); 13C-NMR (125 MHz,
CDCl3) d: 168.5, 167.2, 165.1, 151.3, 129.9, 129.5, 128.3, 127.3, 126.7, 121.8,
118.3, 55.9, 54.1, 52.8, 18.4. Analysis calculated for C20H19ClN2SO4: C,
57.34; H, 4.57; N, 6.69. Found: C, 57.29; H, 4.46; N, 6.69.
methyl)malonate (3r).
TABLE 2. Optimization of reaction conditions using catalyst
Q-1a
Entry Q-1 (xmol %) Temp (8C) Solvent Yieldb (%) eec (%)
1
2
3
4
10
10
5
10
20
10
rt
rt
rt
rt
rt
THF
Acetone
DCM
DCM
DCM
60
90
85
90
90
90
80.5
91.9
95.9
95.7
96.4
96.2
Dimethyl 2-((6-methoxybenzo[d]thiazol-2-ylamino)(4-fluorophe-
nyl)methyl)malonate (3p).
5
d 6
220
DCM
aUnless noted, reactions were run with 0.25 mmol of 1b, 0.30 mmol of 2b in
2.0 ml of solvent using 10 mol % of catalyst at room temperature for 60–72 h.
bIsolated yield after chromatographic purification.
(R)-(2)-3p, this product can be obtained as a colorless oil from a reac-
tion catalyzed by Q-1(10 mol %) at room temperature for 96 h; yield (84.6
mg, 81%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/
cDetermined by HPLC analysis (Chiralpak IA).
dReaction was carried out for 72 h.
Chirality DOI 10.1002/chir

CINCHONA ALKALOID-DERIVED THIOUREA CATALYST
229
Fig. 3. Optimization of reaction condition using catalyst Q-1.
(R)-(2)-3r, this product was obtained as a colorless oil from a reaction
catalyzed by Q-1 (10 mol %) at room temperature for 96 h; yield (77.6
mg, 75%) by preparative TLC (GF254 silica gel: hexane/ethyl ether 5 3/
1); 97.1% ee as determined by HPLC [Daicel Chiralpak IA, hexane/EtOH
5 70/30, 1.0 ml min21, k 5 270 nm, tr (major) 5 7.92 min, tr (minor) 5
9.52 min]; [a]2D5 5 218.6 (c 5 1.00, CHCl3). IR (KBr) m: 3346, 2999,
1747, 1607, 1541, 1494, 1149, 827, 561 cm21. 1H-NMR (500 MHz, CDCl3)
d: 2.28 (s, 3H), 3.64 (s, 3H), 3.67 (s, 3H), 3.78 (s, 3H), 4.00 (br, 1H), 5.59
(s, 1H), 6.84–6.85 (m, 1H), 7.06–7.11 (m, 3H), 7.26 (d, J 5 8.0 Hz, 2H),
7.40 (d, J 5 8.6 Hz, 1H); 13C-NMR (125 MHz, CDCl3) d: 168.4, 167.4,
164.8, 155.3, 146.4, 137.9, 135.5, 131.8, 129.5, 126.5, 119.7, 113.6, 105.3,
58.0, 55.9, 53.1, 52.8, 21.2. Analysis calculated for C21H22N2O5S: C, 60.85;
H, 5.35; N, 6.76. Found: C, 60.75; H, 5.22; N, 6.79.
nich reaction of the imine 1b with diethyl malonate 2b to
obtain b-amino ester 3b (Table 1, Fig. 2) . The reason for
employing imines derived from benzothiazole was to gener-
ate enantioenriched Mannich adducts with potent anti-plant
viral activity. The importance of the heterocyclic benzothia-
zole unit in agricultural application was brought out explicitly
in our recently written book in this field.41 It may clearly be
noted that presence of strong electron withdrawing substitu-
ent in the phenyl ring of the catalysts is a prerequisite to
achieve high enantioselectivity through H-bond activation of
the substrate. Thus, the newly prepared electron deficient
catalysts (entries 5 and 8) and all the previously known cata-
lysts (entries 3, 4, and 6) afforded high enantiomeric excess
of the target ester with a slightly improved value being
recorded for Q-1. The catalyst Q-4 (entry 7), where the thio-
urea is not directly conjugated to the phenyl ring, offered
much lower yield and enantioselectivity. Quite expectedly,
both quinine and qunidine (entries 1 and 2), bearing single
H-bond donor part, displayed inferior results compared to thi-
ourea-derived catalysts Q-1,32QD-1,32 Q-2–Q-3, and Q-5.
The catalyst Q-1 was selected for further investigation to
optimize the reaction temperature, solvent, and catalyst load-
ing and the results are provided in Table 2 and Figure 3.
Out of the three solvents (THF, acetone, and DCM)
selected for the study, DCM afforded better selectivity and
yield to the product. The optimal result could be achieved at
room temperature with 10 mol % catalyst loading. The reac-
tion at lower temperature took much longer reaction time
without significant gain on enantioselectivity.
Having established the proper reaction conditions, differ-
ent imines 1a–l bearing benzothiazole moiety were reacted
with diethyl malonate by using 10 mol % of Q-1 or QD-1 as
chiral catalyst in methylene chloride at room temperature for
72–96 h to provide the title b-amino esters 3a–l in excellent
yields and high enantioselectivity (Table 3 and Fig. 4) . Simi-
lar to our observation with the pair of enantiomers quinine
and quinidine (Table 1, entries 1 and 2), Q-1 was found
more effective compared to QD-1 in terms of yield and ee
values. The enantioenriched b-amino esters can easily be
converted into their corresponding b-amino acids without
any significant loss of enantioselectivity by following stand-
ard procedures.19,21
RESULTS AND DISCUSSION
For the initial exploration, we studied the role of various
cinchona alkaloid-derived thiourea catalysts and commercial
quinine and quinidine (Fig. 1) in a model asymmetric Man-
TABLE 3. Asymmetric Mannich reaction of diethyl malonate
2b with benzothiazol-2-yl-benzylidene imines 1a-l catalyzed by
Q-1 and QD-1a
Entry
R1
R2
Adduct Time (h) Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
H
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
6-OCH3
6-OCH3
6-OCH3
6-OCH3
6-OCH3
3a
3bd
3c
3d
3e
3f
3g
3h
3i
72
72
72
72
72
96
96
96
96
96
96
96
90(80)
91(85)
89(85)
89(80)
85(80)
81(72)
86(74)
86(73)
81(66)
81(65)
70(66)
71(65)
95.8(89.4)
96.0(90.0)
94.8(90.0)
95.0(90.2)
95.2(85.9)
98.5(95.8)
98.2(96.0)
97.9(96.3)
98.5(91.5)
98.1(95.6)
98.4(97.7)
89.4(98.2)
o-F
o-Cl
p-F
p-Cl
H
o-F
o-Cl
p-F
p-Cl
9
10
11
12
3j
3k
3l
p-CH3 6-OCH3
o-OCH3 6-OCH3
aUnless otherwise stated, reactions were conducted with 0.25 mmol of 1a–l
and 0.30 mmol of 2b in 2.0–3.0 ml of DCM in the presence of 10 mol % cata-
lyst at room temperature for 72–96 h. The results (ee and yield) in parenthe-
ses were obtained with QD-1.
bIsolated yields after chromatographic purification.
cDetermined by chiral HPLC analysis (Chiralpak IA).
dAbsolute configuration of (2)-3b obtained in presence of Q-1 was deter-
mined to be R by single crystal X-Ray structure analysis.
Fig. 4. Asymmetric Mannich reaction of diethyl malonate 2b with benzothiazol-2-yl-benzylidene imines 1a–l catalyzed by Q-1 and QD-1.
Chirality DOI 10.1002/chir

230
TABLE 4. Enantioselective Mannich reaction of dimethyl
LI ET AL.
malonate 2a with heterocyclic imines (1a-c, 1i-k) catalyzed by
Q-1a
Entry
R1
R2
Adduct Time (h) Yield (%)b ee (%)c
1
2
3
4
5
6
H
4-CH3
4-CH3
4-CH3
6-OCH3
6-OCH3
3m
3n
3o
3p
3q
3r
72
72
72
96
96
96
74
85
82
81
79
75
95.3
95.3
96.9
97.1
97.4
97.1
o-F
o-Cl
p-F
p-Cl
p-CH3 6-OCH3
aUnless otherwise noted, reactions were run with 0.25 mmol of 1a–c, 1i–k,
and 0.30 mmol of 2a in 2.0–3.0 ml of DCM in the presence of 10 mol % cata-
lyst Q-1 at room temperature for 72–96 h.
bIsolated yields after chromatographic purification.
cDetermined by chiral HPLC analysis (Chiralpak IA).
Fig. 6. Proposed stereochemical mode. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
Fig. 5. Enantioselective Mannich reaction of dimethyl malonate 2a with heterocyclic imines (1a–c, 1i–k) catalyzed by Q-1.
Substituent effects of different groups (R1) in the aromatic
ring of the aldehydic part of the imine were usually insignifi-
cant on enantioselectivity, whereas imines derived from 2-
amino-4-methylbenzothiazole displayed slightly higher reac-
tivity compared to the one obtained from 2-amino-6-methoxy-
benzothiazole.
Six different benzothiazol-2-yl-benzylidene imines (1a–c,
1i–k) were then subjected to catalytic Mannich reaction with
dimethyl malonate 2a affording 3m–r in excellent yields
(74–85%) and high enantiomeric excess (95.3–97.4%) as
shown in Table 4 and Figure 5. The chiral HPLC chromato-
grams of the title a-aminophosphonates are provided in Sup-
porting Information.
Furthermore, the absolute configuration of the Mannich
reaction product (2)-3b was unambiguously confirmed as R
by X-ray crystallographic, which was reported in our Previ-
ous work.42 Crystallographic data for the structure reported
in this article have been deposited with the Cambridge Crys-
tallographic Data Centre (CCDC-781779).
lidene imines with malonates. The resulting novel b-amino
esters bearing benzothiazole moiety are obtained in high
yields and excellent enantioselectivities (up to 98% ee). The
reaction itself features simple experimental procedures
under benign conditions and is completely atom-economic in
character. We believe that this method provides an efficient
route for the preparation of chiral b-amino esters derivatives,
and the availability of these compounds should facilitate me-
dicinal chemical studies in various fields. Simultaneous acti-
vation of both the imine groups and malonate by the bifunc-
tional catalyst seems to control the sterochemical outcome.
Further studies on the scope of new catalyst Q-5 in other
asymmetric transformations and anti-plant viral activities of
the Mannich products are currently underway.
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Chirality DOI 10.1002/chir