Highly enantioselective Mannich reactions of imines with tert-butyl acetoacetate catalyzed by squaramide organocatalyst

Article abstract of DOI:10.1016/j.tetasy.2014.03.010

Highly enantioselective Mannich reactions of imines bearing a benzothiazole moiety with tert-butyl acetoacetate, catalyzed by a cinchona-based squaramide organocatalyst have been developed. The corresponding benzothiazole β-keto ester derivatives were obt

Full text of DOI:10.1016/j.tetasy.2014.03.010

Tetrahedron: Asymmetry 25 (2014) 637–643
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Highly enantioselective Mannich reactions of imines with tert-butyl
acetoacetate catalyzed by squaramide organocatalyst
⇑
Hai-Xiao He, Da-Ming Du
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 January 2014
Accepted 7 March 2014
Highly enantioselective Mannich reactions of imines bearing a benzothiazole moiety with tert-butyl ace-
toacetate, catalyzed by a cinchona-based squaramide organocatalyst have been developed. The corre-
sponding benzothiazole b-keto ester derivatives were obtained in high yields (up to 99%) and with
excellent enantioselectivities (up to 98% ee).
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
amines.12 Herein we report on an efficient direct enantioselective
Mannich reaction of imines bearing a benzothiazole moiety with
Chiral heterocyclic compounds are widely present in natural
products and organic materials.1 Compounds with a benzothiazole
moiety have been widely studied.2 It is well known that benzo-
thiazoles and their derivatives are synthetically and biologically
significant molecular structures. Many compounds containing a
benzothiazole ring system exhibit significant antidiabetic, antitu-
mor, anti-inflammatory, antimicrobial, anticonvulsant, antiviral,
antitubercular, antioxidant, antimalarial, antiasthmatic, anthelmin-
tic, and analgesic activities, and are diuretic.3 Chiral heterocyclic
compounds with a benzothiazole moiety can be obtained via reac-
tions of imines bearing a benzothiazole moiety with various types
of donors including nitroalkanes,4 malonates, etc.5,6 It is a challeng-
ing task to develop asymmetric Mannich reactions for synthesizing
these compounds with multiple stereogenic stereocenters.
tert-butyl acetoacetate catalyzed by a cinchona-based squaramide
organocatalyst; the corresponding products could be obtained
with excellent enantioselectivities (up to 98% ee).
2. Results and discussion
Our investigation began with the addition of tert-butyl acetoac-
etate 2a to imine 1a bearing a benzothiazole moiety using a cin-
chona-based squaramide as the catalyst. The reaction was
performed in the presence of 5 mol % catalyst I in CH2Cl2 for 24 h
at room temperature, and the corresponding products were ob-
tained in excellent yield (99%) and with high enantioselectivities
(91% and 89% ee) (Table 1, entry 1). However, the diastereoselectiv-
ity was low (60:40 dr) and the diastereomers could not be sepa-
rated by column chromatography. A series of acetoacetates were
evaluated under these reaction conditions. Ethyl benzoylacetate
2b gave low enantioselectivity (7% ee, the ee of the other isomer
cannot be determined), but the corresponding product 3ab was ob-
tained in 98% yield (Table 1, entry 2). Ethyl acetylacetate 2c and
ethyl-2-cyclohexanoncarboxylate 2e did not afford the corre-
sponding products (Table 1, entries 3 and 5). When ethyl 2-methy-
lacetoacetate 2d was used, compound 3ad was obtained in high
yield with low enantioselectivities (85% yield, 29%, and 48% ee),
while the diastereoselectivity ratio was only 37:63 (Table 2, entry
4). From the above results, the reaction of tert-butyl acetoacetate
2a with imines bearing a benzothiazole moiety was selected as
the optimal route.
In recent years, chiral squaramides7 have been successfully ap-
plied in various asymmetric reactions for the synthesis of com-
pounds with multiple stereogenic centers.8 Our group has
reported a series of efficient enantioselective reactions catalyzed
by squaramide organocatalysts.9 Organocatalysts containing a ter-
tiary amine group seem to be appropriate for substrate activation
and stereochemical control in the projected Mannich reaction. Un-
til now, the utilization of imimes bearing a benzothiazole moiety in
the reaction to synthesize these compounds with multiple chiral
stereocenters has not been reported on.
A
direct asymmetric Mannich reaction10 is an attractive
approach toward the construction of highly functionalized
amine-containing building blocks.11 In particular, the direct addi-
tion of b-keto esters to imines affords multifunctional secondary
In order to improve the enantioselectivity of product 3aa, other
four squaramide catalysts II–V (Fig. 1) were evaluated using
5 mol % catalyst loading in CH2Cl2 for 24 h at room temperature.
When mono-CF3 substituted quinine-based squaramide catalyst
⇑
Corresponding author. Tel./fax: +86 10 68914985.
E-mail address: dudm@bit.edu.cn (D.-M. Du).
http://dx.doi.org/10.1016/j.tetasy.2014.03.010
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

638
H.-X. He, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 637–643
Table 1
Asymmetric Mannich reaction of imine 1a with various acetoacetatesa
O
O
R1
OR3
*
*
R2
Ph
O
O
N
N
S
5 mol% catalyst I
Ph
N
N
H
+
R1
OR3
CH2Cl2, rt
S
R2
3aa-af
1a
2a-f
Entry
1
Acetoacetate
Time (h)
18
Product
Yieldb (%)
99
drc
eed (%)
91/89
O
O
3aa
60:40
OtBu
2a
2b
2c
O
O
2
3
18
24
3ab
3ac
98
90
51:49
—
7/nd
—
Ph
OEt
O
O
O
O
OEt
OEt
OEt
4
5
24
24
3ad
3ae
85
10
37:63
29/48
Me
2e
O
O
—
—
2f
a
b
c
Reaction conditions: imine 1a (47.6 mg, 0.2 mmol) and acetoacetates 2 (0.2 mmol) in CH2Cl2 (1 mL) at room temperature.
Isolated yield after column chromatography purification.
Determined by chiral HPLC analysis.
d
Enantiomeric excess was determined by chiral HPLC analysis using a Daicel Chiralpak IA or AD-H column. Nd: the ee cannot be determined.
Table 2
Screening of the organocatalysts for the enantioselective Mannich reaction of tert-butyl acetoacetate 2a with imine 1aa
O
O
*
*
OtBu
O
O
N
S
N
S
Ph
5 mol% I-V
N
H
Ph
N
+
OtBu
CH2Cl2, rt
1a
2a
3aa
drc
Entry
Catalyst
Yieldb (%)
eed (%)
1
2
3
4
5
I
99
99
97
96
99
60:40
57:43
54:46
49:51
49:51
91/89
81/79
85/83
59/53
86/82
II
III
IV
V
a
b
c
Reaction conditions: imine 1a (47.6 mg, 0.2 mmol) and tert-butyl acetoacetate 2a (0.2 mmol) in CH2Cl2 (1 mL) at room temperature.
Isolated yield after column chromatography purification.
Determined by chiral HPLC analysis.
d
Enantiomeric excess was determined by chiral HPLC analysis using Daicel Chiralpak IA column.
II was used in this reaction, the corresponding product 3aa was ob-
tained in excellent yield (99%) and with high enantioselectivities
(81% and 79% ee, 57:43 dr) (Table 2, entry 2). When C2-symmetric
quinine-based squaramide catalyst III was used, a high yield (97%
yield) was obtained, the enantioselectivities were better than
squaramide II (85% and 83% ee, 54:46 dr) (Table 2, entry 3).
Squaramide IV afforded the product in high yield, but the
enantioselectivities were very low (59% and 53% ee, 49:51 dr) (Ta-
ble 2, entry 4). The classical thiourea catalyst V was also evaluated
in this reaction and afforded high enantioselectivities (86% and 82%
ee, 49: 51 dr) (Table 2, entry 5). Squaramide I was chosen as the
best catalyst for further evaluation in this Mannich reaction of imi-
nes bearing a heterocycle moiety with tert-butyl acetoacetate 2a.
Next, the effect of the solvent, catalyst loading, and temperature
were evaluated to find the optimal reaction conditions. The results
are shown in Table 3. Five solvents were evaluated under the same
reaction conditions (Table 3, entries 1–5). In CHCl3 and PhCH3,
product 3aa was obtained in excellent yields (99% and 98%) and
with high enantioselectivities (84%, 82% ee, 58:42 dr and 86%,
80% ee, 57:43 dr) (Table 3, entries 2 and 3). When the reaction
was performed in THF, the product was obtained in the same yield
as with CH2Cl2 (99% yield), but the enantioselectivities were better

H.-X. He, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 637–643
639
CF3
O
O
O
F3C
H
H
N
N
H
HN
N
N
H
F3C
HN
OMe
OMe
N
N
I
II
O
O
CF3
O
O
H
N
N
NH HN
H
N
H
N
H
F3C
OMe
MeO
N
N
N
IV
III
H
H
N
H
N
N
F3C
OMe
S
CF3
N
V
Figure 1. Organocatalysts screened.
Table 3
Optimization of reaction conditions for the enantioselective Mannich reaction of tert-butyl acetoacetate 2a with imine 1aa
O
O
*
OtBu
O
O
N
S
catalyst I
N
S
Ph
N
N
H
Ph
*
+
solvent, 24 h
OtBu
3aa
2a
1a
Entry
Solvent
Time (h)
Product
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
PhMe
THF
ClCH2CH2Cl
THF
THF
THF
THF
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
5
5
5
5
5
2
1
10
15
20
10
99
99
98
99
99
98
96
99
99
99
0
60:40
58:42
57:43
57:43
56:44
54:46
55:45
58:42
52:48
56:44
—
91/89
84/82
86/80
97/96
70/67
94/93
80/79
98/98
98/98
98/98
—
10
11
rt
ꢀ15
THF
a
b
c
Reaction conditions: imine 1a (47.6 mg, 0.2 mmol) and tert-butyl acetoacetate 2a (0.2 mmol) in solvent (1 mL) for 24 h.
Isolated yield after column chromatography purification.
Determined by chiral HPLC analysis.
d
Enantiomeric excess was determined by chiral HPLC analysis using Daicel Chiralpak IA column.
(97% and 96% ee, 57:43 dr) (Table 3, entry 4). In ClCH2CH2Cl, the
product was obtained in 99% yield, but the enantioselectivities
were reduced to 70% and 67% ee (56:44 dr) (Table 3, entry 5).
Hence THF was selected as the best reaction medium. Catalyst
loadings of 1, 2, 5, 10, 15, and 20 mol % were evaluated in the same
reaction (Table 3, entries 4 and 6–10). The results indicated that
10 mol % catalyst loading was suitable for obtaining the best
enantioselectivities (98% and 98% ee) (Table 3, entry 8). When
the catalyst loading was enhanced to 15 and 20 mol %, the yields
and enantioselectivities remained the same (Table 3, entries 9
and 10). Increasing the catalyst loading further had no beneficial
effect on the enantioselectivity and diastereoselectivity. The cata-
lyst loading was reduced to 2 and 1 mol %, which led to a decrease
in the yields and enantioselectivities (Table 3, entries 6 and 7).
When the reaction was performed at ꢀ15 °C, the product was
not obtained. This suggests that the reaction temperature plays
an important role in this catalytic asymmetric reaction. From the
above evaluation, the optimal reaction conditions were deter-
mined as: 10 mol % catalyst I, in THF, at room temperature (Table 3,
entry 8).
We next investigated the scope of this direct Mannich reaction.
The results are shown in Table 4. Imines 1b, 1c, and 1d bear differ-

640
H.-X. He, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 637–643
Table 4
Substrate scope of the enantioselective Mannich reaction of tert-butyl acetoacetate 2a with imines 1a
O
O
*
*
OtBu
O
O
R2
N
S
N
S
10 mol% catalyst I
R1
R2
N
+
R1
N
H
OtBu
THF, rt
1a-j
2a
3aa-ja
Entry
R1
R2
Time (h)
Product
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
9
H
C6H5
C6H5
C6H5
C6H5
4-O2NC6H4
4-MeC6H4
4-BrC6H4
4-O2NC6H4
4-O2NC6H4
2-MeOC6H4
24
24
24
24
24
24
24
48
48
48
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
99
99
98
99
99
98
94
92
90
97
58:42
58:42
48:52
59:41
64:36
64:36
59:41
57:43
64:36
98:2
98/98
97/95
98/97
95/96
89/95
92/92
92/95
95/95
94/94
83/nd
6-Me
6-Cl
6-MeO
H
H
H
6-Cl
6-Me
6-MeO
10
3ja
a
b
c
Reaction conditions: imine 1a (47.6 mg, 0.2 mmol) and tert-butyl acetoacetate 2a (0.2 mmol) in THF (1 mL) at room temperature.
Isolated yield after column chromatography purification.
Determined by chiral HPLC analysis.
d
Enantiomeric excess was determined by chiral HPLC analysis.
HO
O
O
N
O
H
*
*
OtBu
OtBu
N
S
NH2OH·HCl
EtOH, H2O
N
S
N
H
N
H
H
Br
Br
3ga
4ga
96% yield
Scheme 1. The transformation of 3ga to oxime 4ga.
ent substituent (6-Me, 6-Cl, and 6-MeO) on the benzothiazole ring.
The desired products were obtained in excellent yields and with
excellent enantioselectivities (98–99% yield and 95–98% ee,
respectively) (Table 4, entries 2–4). Imines 1e–1g with various sub-
stituent groups (4-NO2, 4-Me, 4-Br) on the benzene ring, gave
slightly lower enantioselectivities compared with the imines
substituted on the benzothiazole ring (94–99% yield and 89–95%
ee, respectively) (Table 4, entries 5–7). Imines 1h and 1i have the
same substituent (4-NO2) on the benzene ring; the former gave
slightly better results than the latter (92% yield and 95% ee vs
90% yield and 94% ee) (Table 4, entries 8 and 9). When the benzo-
thiazole ring and benzene ring had the same substituent (MeO–),
the corresponding product was obtained in excellent yield (99%)
and with moderate enantioselectivities (83% ee, the ee of another
isomer could not be determined) (Table 4, entry 10). The excellent
diastereoselectivity (98:2 dr) may be ascribed to the steric hin-
drance of the 2-MeO substituent.
In order to ascertain the absolute configuration of these Man-
nich compounds with multiple stereogenic centers, product 3ga
was treated with hydroxylammonium chloride in aqueous EtOH
to afford the corresponding oxime 4ga (Scheme 1).13 The major
diastereomer of the product 4ga was separated directly by silica
gel column chromatography and its absolute configuration was
determined as (R,S) on the basis of X-ray crystal structure analysis
(Fig. 2).14
On the basis of the activation mode and previous related work
on this Mannich reaction, we have proposed a possible mechanism
for this reaction (Fig. 3). The enol form of tert-butyl acetoacetate 2a
is activated and deprotonated by the basic nitrogen atom of the
Figure 2. X-ray crystal structure of the major diastereomer of 4ga.
tertiary amine Lewis base in the squaramide organocatalyst I.
The heteroaromatic imine is activated through double hydrogen
bonding between the two N atoms in the imine and the two NH
group in the squaramide. The nucleophilic attack of the active
methylene of tert-butyl acetoacetate on imine 1a in the most fa-
vored direction via the following transition state, and product
3aa is obtained with excellent enantioselectivities.

H.-X. He, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 637–643
641
analyzed to determine the diastereoselectivity and enantioselec-
tivity of the reaction (58:42 dr, 98% ee (major), 98% ee (minor))
by HPLC (IA column, n-hexane-2-propanol 80:20, flow rate
OMe
N
N
H
1.0 mL/min, detection at 254 nm): major diastereomer: tmajor
=
O
10.6 min, tminor = 8.8 min; minor diastereomer: tmajor = 16.6 min,
tminor = 15.1 min; ½a D25
ꢁ
= +9.6 (c 1.03, CH2Cl2). 1H NMR (400 MHz,
O
O
N
H
O
CDCl3): d (major + minor) = 7.53 (d, J = 7.6 Hz, 1H, ArH), 7.50 (d,
J = 8.4 Hz, 1H, ArH), 7.42–7.38 (m, 2H, ArH), 7.30 (t, J = 7.4 Hz,
2H, ArH), 7.26–7.22 (m, 2H, ArH), 7.07–7.03 (m, 1H, ArH), 5.74
(d, J = 5.6 Hz, 0.5H, CH), 5.60 (d, J = 6.8 Hz, 0.5H, CH), 4.13 (d,
J = 5.6 Hz, 0.5H, CH), 3.98 (d, J = 5.6 Hz, 0.5H, CH), 2.27 (s, 1.5H,
CH3), 2.19 (s, 1.5H, CH3), 1.33 (s, 4.5H, CH3), 1.30 (s, 4.5H, CH3)
H
F3C
N
N
OtBu
H
Ph
N
S
CF3
ppm. 13C NMR (100 MHz, CDCl3):
d (major + minor) = 203.5,
Figure 3. Proposed transition state for the asymmetric Mannich reaction of tert-
butyl acetoacetate 2a with imine 1a.
200.9, 167.9, 166.5, 166.2, 165.9, 152.0, 138.8, 130.7, 128.6,
127.8, 126.9, 126.6, 125.8, 121.7, 121.6, 120.7, 119.2, 119.1, 83.1,
65.3, 64.5, 58.4, 57.3, 30.8, 29.1, 27.7, 27.6 ppm. IR (KBr):
3063, 2978, 2931, 1718, 1599, 1540, 1496, 1454, 1445, 1394,
1369, 1249, 1147, 1079, 1017, 883, 839, 753, 725, 699 cmꢀ1
m 3357,
3. Conclusion
.
In conclusion, a highly enantioselective Mannich reaction of
tert-butyl acetoacetate with imines bearing a benzothiazole has
been developed using a squaramide as organocatalyst. The corre-
sponding benzothiazole keto ester derivatives were obtained in
high to excellent yields and with high to excellent enantioselectiv-
ities in most cases. The squaramide catalyst proved to be better
than the corresponding thiourea catalyst for this reaction. Further
studies on squaramide-catalyzed asymmetric reactions are cur-
rently underway in our laboratory.
4.3.2. tert-Butyl 2-(((6-methylbenzo[d]thiazol-2-yl)amino)
(phenyl)methyl)-3-oxobutanoate 3ba
Compound 3ba was obtained according to the general proce-
dure as a yellow solid (81.1 mg, 99% yield); mp 53–55 °C. It was
analyzed to determine the diastereoselectivity and enantioselec-
tivity of the reaction (58:42 dr, 97% ee (major), 95% ee (minor))
by HPLC (AD-H column, n-hexane-2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): major diastereomer:
tmajor = 16.0 min,
tminor = 11.7 min;
minor
diastereomer:
tmajor = 27.8 min, tminor = 20.6 min; ½a D25
ꢁ
= +5.3 (c 1.28, CH2Cl2). 1H
NMR (400 MHz, CDCl3): d (major + minor) = 7.32 (t, J = 8.8 Hz, 3H,
ArH), 7.26–7.20 (m, 3H, ArH), 7.18–7.14 (m, 1H, ArH), 6.98 (d,
J = 8.0 Hz, 1H, ArH), 5.65 (d, J = 5.2 Hz, 0.5H, CH), 5.49 (d,
J = 6.4 Hz, 0.5H, CH), 4.05 (d, J = 6.4 Hz, 0.5H, CH), 3.90 (d,
J = 5.6 Hz, 0.5H, CH), 2.28 (s, 3H, CH3), 2.20 (s, 1.5H, CH3), 2.11 (s,
1.5H, CH3), 1.26 (s, 4.5H, CH3), 1.23 (s, 4.5H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): d (major + minor) = 203.6, 176.9, 168.0, 166.0,
165.7, 165.5, 162.3, 150.0, 139.0, 138.9, 131.5, 130.8, 128.6,
127.8, 127.1, 126.92, 126.82, 126.6, 120.8, 118.83, 118.75, 83.0,
4. Experimental
4.1. General methods
Commercially available compounds were used without further
purification. Solvents were dried according to standard procedures.
Column chromatography was carried out using silica gel (200–300
mesh). Melting points were measured with a XT-4 melting point
apparatus and are uncorrected. The 1H NMR spectra were recorded
with Varian Mercury-plus 400 or Bruker AVIII 400 MHz spectrom-
eters, while the 13C NMR spectra were recorded at 100 MHz. Infra-
red spectra were obtained with a Perkin Elmer Spectrum One FT-IR
spectrometer. Optical rotations were measured with a WZZ-3 or
Krüss P8000 polarimeter at the indicated concentration with unit
g/100 mL. The enantiomeric excesses (ee) of the products were
determined by chiral HPLC analysis using Aglient HP 1200 instru-
ment (n-hexane-2-propanol as eluent).
65.3, 64.4, 58.4, 57.3, 30.8, 29.1, 27.7, 27.6, 21.1 ppm. IR (KBr):
3404, 2966, 2922, 1713, 1608, 1572, 1540, 1470, 1454, 1369,
1261, 1146, 1096, 1028, 809, 698 cmꢀ1
m
.
4.3.3. tert-Butyl 2-(((6-chlorobenzo[d]thiazol-2-yl)amino)
(phenyl)methyl)-3-oxobutanoate 3ca
Compound 3ca was obtained according to the general proce-
dure as a yellow solid (84.2 mg, 98% yield); mp 44–46 °C. It was
analyzed to determine the diastereoselectivity and enantioselec-
tivity of the reaction (52:48 dr, 97% ee (major), 98% ee (minor))
by HPLC (AD-H column, n-hexane-2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): major diastereomer:
4.2. Materials
Squaramide catalysts I–III,9a IV9c were prepared according to
the literature.
tmajor = 21.0 min,
tminor = 18.2 min;
minor
diastereomer:
tmajor = 12.2 min, tminor = 11.7 min; ½a D25
ꢁ
= +11.5 (c 1.26, CH2Cl2).
1H NMR (400 MHz, CDCl3): d (major + minor) = 7.40–7.36 (m, 1H,
ArH), 7.33–7.28 (m, 3H, ArH), 7.22 (t, J = 7.4 Hz, 2H, ArH), 7.16 (t,
J = 7.2 Hz, 1H, ArH), 7.12–7.09 (m, 1H, ArH), 5.63 (d, J = 5.6 Hz,
0.5H, CH), 5.52 (d, J = 6.4 Hz, 0.5H, CH), 4.05 (d, J = 6.8 Hz, 0.5H,
CH), 3.89 (d, J = 6.0 Hz, 0.5H, CH), 2.19 (s, 1.5H, CH3), 2.12 (s,
1.5H, CH3), 1.26 (s, 4.5H, CH3), 1.22 (s, 4.5H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): d (major + minor) = 204.4, 200.7, 167.6, 166.7,
165.6, 138.4, 138.3, 128.64, 128.62, 128.1, 128.0, 127.0, 126.9,
126.7, 126.35, 126.27, 120.43, 120.40, 119.5, 119.2, 114.2, 83.21,
83.15, 65.3, 64.7, 58.6, 57.7, 30.6, 29.4, 27.9, 27.7, 27.5,
4.3. General procedure for the asymmetric Mannich reaction
Imine 1a (47.6 mg, 0.2 mmol), tert-butyl acetoacetate (31.6 mg,
0.2 mmol), and catalyst I (12.6 mg, 0.02 mmol) in THF (1 mL) were
stirred at room temperature for 24–48 h. After the reaction was
complete, the mixture was separated directly by silica gel column
chromatography with petroleum ether–ethyl acetate (5:1) as the
eluant, and a pure product was obtained.
4.3.1. tert-Butyl 2-((benzo[d]thiazol-2-ylamino)(phenyl)methyl)-
3-oxobutanoate 3aa
Compound 3aa was obtained according to the general proce-
dure as a yellow solid (78.0 mg, 99% yield); mp 42–43 °C. It was
21.5 ppm. IR (KBr):
1394, 1369, 1258, 1146, 1094, 1051, 1026, 969, 918, 813, 753,
699 cmꢀ1
m 3385, 2979, 1713, 1599, 1540, 1494, 1447,
.

642
H.-X. He, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 637–643
4.3.4. tert-Butyl 2-(((6-methoxybenzo[d]thiazol-2-yl)amino)
(phenyl)methyl)-3-oxobutanoate 3da
122.0, 121.7, 120.85, 120.81, 119.42, 119.35, 83.9, 64.6, 63.8, 57.2,
56.2, 30.8, 29.0, 27.72, 27.65 ppm. IR (KBr): 3369, 3066, 2978,
2931, 1713, 1599, 1532, 1480, 1456, 1444, 1369, 1350, 1284,
1249, 1146, 1098, 1017, 929, 901, 839, 806, 754, 726, 692 cmꢀ1
m
Compound 3da was obtained according to the general proce-
dure as a yellow solid (84.3 mg, 99% yield); mp 45–47 °C. It was
analyzed to determine the diastereoselectivity and enantioselec-
tivity of the reaction (59:41 dr, 95% ee (major), 96% ee (minor))
by HPLC (AD-H column, n-hexane-2-propanol 80:20, flow rate
.
4.3.7. tert-Butyl 2-((benzo[d]thiazol-2-ylamino)(4-bromophenyl)
methyl)-3-oxobutanoate 3ga
1.0 mL/min, detection at 254 nm): major diastereomer: tmajor
=
Compound 3ga was obtained according to the general proce-
dure as a yellow solid (89.3 mg, 94% yield); mp 68–70 °C. It was
analyzed to determine the diastereoselectivity and enantioselec-
tivity of the reaction (65:35 dr, 90% ee (major), 96% ee (minor))
by HPLC (IA column, n-hexane-2-propanol 80:20, flow rate
16.9 min, tminor = 14.4 min; minor diastereomer: tmajor = 39.9 min,
tminor = 36.3 min; ½a D25
ꢁ
= +11.3 (c 1.44, CH2Cl2). 1H NMR (400 MHz,
d (major + minor) = 7.34–7.30 (m, 3H, ArH), 7.23 (t,
CDCl3):
J = 7.4 Hz, 2H, ArH), 7.16 (t, J = 7.0 Hz, 1H, ArH), 7.00 (dd,
J1 = 5.2 Hz, J2 = 2.4 Hz, 1H, ArH), 6.77 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz,
1H, ArH), 5.63 (d, J = 5.6 Hz, 0.5H, CH), 5.47 (d, J = 6.8 Hz, 0.5H,
CH), 4.05 (d, J = 6.4 Hz, 0.5H, CH), 3.89 (d, J = 5.6 Hz, 0.5H, CH),
3.75–3.65 (m, 4H, CH and OCH3), 2.20 (s, 1.5H, CH3), 2.12 (s,
1.5H, CH3), 1.26 (s, 4.5H, CH3), 1.23 (s, 4.5H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): d (major + minor) = 203.3, 201.0, 167.9, 165.9,
165.1, 164.6, 155.3, 146.0, 138.8, 131.5, 128.6, 127.9, 127.8,
127.0, 126.6, 119.5, 119.2, 113.5, 105.2, 83.1, 65.3, 64.6, 58.5,
1.0 mL/min, detection at 254 nm): major diastereomer: tmajor
=
9.1 min, tminor = 10.7 min; minor diastereomer: tmajor = 20.4 min,
tminor = 22.4 min; ½a D25
ꢁ
= +29.4 (c 2.31, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d (major + minor) = 7.48–7.41 (m, 2H, ArH), 7.37–7.32 (m,
2H, ArH), 7.23–7.16 (m, 3H, ArH), 7.01–6.96 (m, 1H, ArH), 5.61
(d, J = 5.6 Hz, 0.5H, CH), 5.50 (d, J = 6.8 Hz, 0.4H, CH), 4.02 (d,
J = 6.8 Hz, 0.5H, CH), 3.86 (d, J = 5.2 Hz, 0.5H, CH), 2.19 (s, 1.5H,
CH3), 2.13 (s, 1.5H, CH3), 1.28 (s, 4.5H, CH3), 1.24 (s, 4.5H, CH3)
57.4, 55.8, 30.7, 29.2, 27.7, 27.6 ppm. IR (KBr):
2978, 2934, 2871, 1717, 1605, 1576, 1545, 1471, 1439, 1393,
1369, 1261, 1223, 1146, 1056, 1028, 833, 810, 754, 699 cmꢀ1
m
3366, 3063,
ppm. 13C NMR (100 MHz, CDCl3):
d (major + minor) = 203.3,
200.5, 167.7, 166.1, 165.9, 165.8, 151.9, 151.8, 138.1, 131.7,
128.7, 128.4, 125.9, 121.9, 121.8, 120.8, 119.2, 119.1, 83.4, 65.1,
.
64.3, 57.8, 56.8, 30.7, 29.2, 27.7, 27.6 ppm. IR (KBr):
2979, 2934, 1901, 1709, 1599, 1532, 1488, 1444, 1408, 1394,
1369, 1248, 1147, 1073, 1011, 829, 817, 755, 726, 668, 541 cmꢀ1
m 3362,
4.3.5. tert-Butyl 2-((benzo[d]thiazol-2-ylamino)(4-nitrophenyl)
methyl)-3-oxobutanoate 3ea
.
Compound 3ea was obtained according to the general proce-
dure as a yellow solid (87.3 mg, 99% yield); mp 54–55 °C. It was
analyzed to determine the diastereoselectivity and enantioselec-
tivity of the reaction (64:36 dr, 89% ee (major), 95% ee (minor))
by HPLC (AD-H column, n-hexane-2-propanol 80:20, flow rate
4.3.8. tert-Butyl 2-((6-chlorobenzo[d]thiazol-2-ylamino)(4-nitro-
phenyl)methyl)-3-oxobutanoate 3ha
Compound 3ha was obtained according to the general proce-
dure as a yellow solid (87.4 mg, 92% yield); mp 70–72 °C. It was
analyzed to determine the diastereoselectivity and enantioselec-
tivity of the reaction (57:43 dr, 95% ee (major), 95% ee (minor))
by HPLC (IA column, n-hexane-2-propanol 80:20, flow rate
1.0 mL/min, detection at 254 nm): major diastereomer: tmajor
=
18.9 min, tminor = 20.9 min; minor diastereomer: tmajor = 39.1 min,
tminor = 43.7 min; ½a D25
ꢁ
= +21.0 (c 2.50, CH2Cl2). 1H NMR (400 MHz,
CDCl3): d (major + minor) = 8.07 (d, J = 8.4 Hz, 2H, ArH), 7.54 (d,
J = 8.4 Hz, 1H, ArH), 7.51 (d, J = 8.4 Hz, 1H, ArH), 7.46 (t,
J = 8.0 Hz, 1H, ArH), 7.40 (d, J = 8.4 Hz, 1H, ArH), 7.17 (t,
J = 7.8 Hz, 1H, ArH), 7.02–6.98 (m, 1H, ArH), 5.83 (d, J = 5.6 Hz,
0.5H, CH), 5.73 (d, J = 6.4 Hz, 0.5H, CH), 4.12 (d, J = 6.4 Hz, 0.5H,
CH), 3.93 (d, J = 5.2 Hz, 0.5H, CH), 2.24 (s, 1.5H, CH3), 2.16 (s,
1.5H, CH3), 1.28 (s, 4.5H, CH3), 1.25 (s, 4.5H, CH3) ppm. 13C NMR
(100 MHz, CDCl3): d (major + minor) = 203.2, 200.1, 167.6, 165.6,
165.4, 151.7, 147.3, 146.6, 130.6, 128.0, 127.8, 125.9, 123.7,
122.2, 122.1, 120.8, 119.3, 119.2, 83.8, 64.6, 63.8, 57.4, 56.5, 30.7,
1.0 mL/min, detection at 254 nm): major diastereomer: tmajor =
13.4 min, tminor = 20.7 min; minor diastereomer: tmajor = 30.3 min,
tminor = 27.5 min; ½a D25
ꢁ
= +21.8 (c 2.34, CH2Cl2). 1H NMR (400 MHz,
CDCl3): (major + minor) = 8.17 (dd, J1 = 8.4 Hz, J2 = 4.0 Hz, 2H,
ArH), 7.60 (dd, J1 = 8.4 Hz, J2 = 5.6 Hz, 2H, ArH), 7.51–7.50 (m, 1H,
ArH), 7.36 (dd, J1 = 8.8 Hz, J2 = 4.0 Hz, 1H, ArH), 7.20 (d, J = 8.4 Hz,
1H, ArH), 5.91 (d, J = 4.8 Hz, 0.5H, CH), 5.84 (d, J = 5.6 Hz, 0.5H,
CH), 4.20 (d, J = 6.0 Hz, 0.5H, CH), 3.99 (d, J = 5.2 Hz, 0.5H, CH),
2.34 (s, 1.5H, CH3), 2.22 (s, 1.5H, CH3), 1.35 (s, 9H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): d (major + minor) = 203.6, 200.0, 167.8,
165.5, 165.4, 150.4, 147.4, 146.4, 131.9, 131.8, 127.8, 127.7,
127.3, 126.5, 126.4, 123.8, 120.4, 120.03, 119.95, 84.0, 77.2, 64.4,
29.1, 27.7, 27.6 ppm. IR (KBr):
1598, 1524, 1538, 1456, 1445, 1369, 1347, 1288, 1249, 1146,
1015, 841, 754, 726, 700 cmꢀ1
m 3369, 3063, 2978, 2933, 1713,
.
63.4, 57.3, 56.3, 31.0, 29.0, 28.1, 27.6 ppm. IR (KBr):
2979, 2934, 1713, 1598, 1540, 1492, 1447, 1394, 1369, 1347,
1252, 1146, 1052, 1014, 964, 855, 816, 767, 749, 700 cmꢀ1
m 3369,
4.3.6. tert-Butyl 2-((benzo[d]thiazol-2-ylamino)(p-tolyl)methyl)-
3-oxobutanoate 3fa
.
Compound 3fa was obtained according to the general procedure
as a yellow solid (80.3 mg, 98% yield); mp 54–56 °C. It was analyzed
to determine the diastereoselectivity and enantioselectivity of the
reaction (64:36 dr, 92% ee (major), 92% ee (minor)) by HPLC (AD-
H column, n-hexane-2-propanol 80:20, flow rate 1.0 mL/min, detec-
4.3.9. tert-Butyl 2-(((6-methylbenzo[d]thiazol-2-yl)amino)
(4-nitrophenyl)methyl)-3-oxobutanoate 3ia
Compound 3ia was obtained according to the general procedure
as a yellow solid (81.9 mg, 90% yield); mp 67–69 °C. It was analyzed
to determine the diastereoselectivity and enantioselectivity of the
reaction (64:36 dr, 94% ee (major), 94% ee (minor)) by HPLC (AD-
H column, n-hexane-2-propanol 80:20, flow rate 1.0 mL/min, detec-
tion at 254 nm): major diastereomer: tmajor = 12.4 min, tminor
=
11.2 min; minor diastereomer: tmajor = 19.2 min, tminor = 13.9 min;
½
a 2D5
ꢁ
= ꢀ9.7 (c 1.62, CH2Cl2). 1H NMR (400 MHz, CDCl3): d (major +
tion at 254 nm): major diastereomer: tmajor = 24.0 min, tminor
21.5 min; minor diastereomer: tmajor = 44.5 min, tminor = 35.7 min;
= +39.0 (c 1.18, CH2Cl2). 1H NMR (400 MHz, CDCl3): d (major +
=
minor) = 8.22 (d, J = 9.2 Hz, 1H, ArH), 8.04 (d, J = 6.0 Hz, 1H, ArH),
7.73 (t, J = 7.0 Hz, 1H, ArH), 7.49–7.41 (m, 3H, ArH), 7.20–7.16 (m,
1H, ArH), 7.01 (t, J = 7.6 Hz, 1H, ArH), 5.87 (d, J = 5.2 Hz, 0.5H, CH),
5.76 (d, J = 6.0 Hz, 0.5H, CH), 4.14 (d, J = 6.4 Hz, 0.5H, CH), 3.94 (d,
J = 5.2 Hz, 0.5H, CH), 2.26 (s, 1.5H, CH3), 2.16 (s, 1.5H, CH3), 1.29 (s,
4.5H, CH3), 1.26 (s, 4.5H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d
(major + minor) = 203.3, 200.2, 167.8, 165.7, 165.5, 165.4, 151.8,
148.3, 141.6, 141.5, 133.2, 129.6, 125.9, 122.9, 122.8, 122.2, 122.1,
½ ꢁ
a 2D5
minor) = 8.15 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 2H, ArH), 7.60 (t, J = 8.8 Hz,
2H, ArH), 7.38–7.34 (m, 2H, ArH), 7.06 (d, J = 8.4 Hz, 1H, ArH), 5.90
(d, J = 5.2 Hz, 0.5H, CH), 5.80 (d, J = 6.0 Hz, 0.5H, CH), 4.20 (d,
J = 6.4 Hz, 0.5H, CH), 4.00 (d, J = 5.6 Hz, 0.5H, CH), 2.36 (s, 3H, CH3),
2.32 (s, 1.5H, CH3), 2.22 (s, 1.5H, CH3), 1.35 and 1.34 (s, 9H, CH3)
ppm. 13C NMR (100 MHz, CDCl3): d (major + minor) = 203.1, 200.1,

H.-X. He, D.-M. Du / Tetrahedron: Asymmetry 25 (2014) 637–643
643
3. (a) Aiello, S.; Wells, G.; Stone, E. L.; Kadri, H.; Bazzi, R.; Bell, D. R.; Stevens, M. F.
G.; Matthews, C. S.; Bradshaw, T. D.; Westwell, A. D. J. Med. Chem. 2008, 51,
5135; (b) Cho, Y.; Ioerger, T. R.; Sacchettini, J. C. J. Med. Chem. 2008, 51, 5984; (c)
167.6, 165.6, 164.9, 164.7, 149.6, 147.3, 146.7, 132.0, 131.9, 128.0,
127.8, 127.1, 123.7, 120.8, 119.0, 118.9, 83.8, 64.6, 63.8, 57.4, 56.4,
30.7, 29.0, 27.72, 27.65, 21.1 ppm. IR (KBr):
2930, 1713, 1608, 1571, 1538, 1526, 1467, 1394, 1369, 1347,
1281, 1254, 1147, 1014, 964, 855, 815, 752, 738, 700 cmꢀ1
m 3369, 3203, 2979,
´
Caleta, I.; Kralj, M.; Marjanovic´, M.; Bertoša, B.; Tomic´, S.; Pavlovic´, G.; Pavelic´,
K.; Karminski-Zamola, G. J. Med. Chem. 2009, 52, 1744; (d) Kumbhare, R. M.;
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Bhadra, M. Bioorg. Med. Chem. Lett. 2012, 22, 5424; (e) Sharma, P. C.; Sinhmar,
A.; Sharma, A.; Rajak, H.; Pathak, D. P. J. Inhib. Med. Chem. 2013, 28, 240.
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5. He, H.-X.; Du, D.-M. RSC Adv. 2013, 3, 16349.
6. (a) Li, L.; Song, B.-A.; Bhadury, P. S.; Zhang, Y.-P.; Hu, D.-Y.; Yang, S. Eur. J. Org.
Chem. 2011, 25, 4743; (b) Bai, S.; Liang, X.-P.; Song, B.-A.; Bhadury, P. S.; Hu, D.-
Y.; Yang, S. Tetrahedron: Asymmetry 2011, 22, 518; (c) Li, W.-H.; Song, B.-A.;
Bhadury, P. S.; Li, L.; Wang, Z.; Zhang, X.; Hu, D.-Y.; Chen, Z.; Zhang, Y.; Bai, S.;
Wu, J.; Yang, S. Chiraliry 2012, 24, 223.
.
4.3.10. tert-Butyl 2-(((6-methoxybenzo[d]thiazol-2-yl)amino)
(2-methoxyphenyl)methyl)-3-oxobutanoate 3ja
Compound 3ja was obtained according to the general procedure
as a yellow solid (88.4 mg, 97% yield); mp 55–57 °C. It was ana-
lyzed to determine the diastereoselectivity and enantioselectivity
of the reaction (major 83% ee, the ee of minor diastereomer cannot
be determined) by HPLC (AD-H column, n-hexane-2-propanol
80:20, flow rate 1.0 mL/min, detection at 254 nm): major diaste-
reomer: tmajor = 14.7 min, tminor = 11.0 min; minor diastereomer:
7. For reviews of squaramides, see: (a) Storer, R. I.; Aciro, C.; Jones, L. H. Chem. Soc.
Rev. 2011, 40, 2330; (b) Aleman, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem.-
Eur. J. 2011, 17, 6890.
8. For selected examples of asymmetric reactions using squaramides, see: (a)
Hagihara, J. P. K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416; (b) Konishi,
H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2010, 12, 2028; (c) Zhu, Y.;
Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153; (d) Xu, D. Q.;
Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chem. Eur. J.
2010, 16, 4177; (e) Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao, J.; Rawal, V. H.
Chem. Commun. 2010, 3004; (f) Bae, H. Y.; Some, S.; Lee, J. H.; Kim, J.-Y.; Song,
M. J.; Lee, S.; Zhang, Y. J.; Song, C. E. Adv. Synth. Catal. 2011, 353, 3196; (g) Min,
C.; Han, X.; Liao, Z. Q.; Wu, X. F.; Zhou, H.-B.; Dong, C. Adv. Synth. Catal. 2011,
353, 2715; (h) Pansare, S. V.; Paul, E. K. Chem. Commun. 2011, 1027; (i) Fang, X.;
Li, Q.-H.; Tao, H.-Y.; Wang, C.-J. Adv. Synth. Catal. 2013, 355, 327.
9. For selected examples of asymmetric reactions using squaramides, see: (a)
Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450; (b) Yang, W.; Du, D.-M. Chem.
Commun. 2011, 12706; (c) Yang, W.; Du, D.-M. Adv. Synth. Catal. 2011, 353,
1241; (d) Yang, W.; Jia, Y.; Du, D.-M. Org. Biomol. Chem. 2012, 10, 332; (e) Yang,
W.; Yang, Y.; Du, D.-M. Org. Lett. 2013, 15, 1190; (f) Yang, W.; Du, D.-M. Chem.
Commun. 2013, 8842; (g) Yang, W.; He, H.-X.; Gao, Y.; Du, D.-M. Adv. Synth.
Catal. 2013, 355, 3670.
10. (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124,
827; (b) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003, 125, 338; (c) Marigo,
M.; Kjaersgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem.-Eur. J. 2003,
9, 2359; (d) Bernardi, L.; Gothelf, A. S.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 2003, 68, 2583; (e) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.;
Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677; (f) Matsunaga, S.;
Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 8777; (g) Zhuang, W.; Sabby, S.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2004, 43, 4476; (h) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
11. For selected reviews, see: (a) Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J. Org.
Chem. 2000, 4, 563; (b) Córdova, A. Acc. Chem. Res. 2004, 37, 102.
tR = 6.6 min; ½a 2D5
ꢁ
: +21.4 (c 1.02, CH2Cl2). 1H NMR (400 MHz,
d (major + minor) = 7.40–7.33 (m, 3H, ArH), 7.22 (t,
CDCl3):
J = 7.2 Hz, 1H, ArH), 7.04 (d, J = 7.6 Hz, 1H, ArH), 6.88 (t,
J = 7.6 Hz, 2H, ArH), 5.74 (t, J = 7.2 Hz, 0.5H, CH), 5.54 (t,
J = 8.0 Hz, 0.5H, CH), 4.35 (d, J = 8.0 Hz, 0.5H, CH), 4.21 (d,
J = 6.4 Hz, 0.5H, CH), 3.91 and 3.89 (s, 3H, OCH3), 2.34 (s, 3H,
OCH3), 2.24 (s, 1.5H, CH3), 2.22 (s, 1.5H, CH3), 1.32 (s, 4.5H, CH3),
1.25 (s, 4.5H, CH3) ppm. 13C NMR (100 MHz, CDCl3): d (major + mi-
nor) = 203.0, 201.3, 167.8, 166.1, 165.7, 156.8, 156.3, 150.0, 149.9,
131.2, 130.7, 129.8, 129.2, 129.0, 128.5, 126.8, 126.2, 125.9, 120.7,
120.6, 118.7, 110.7, 110.4, 82.6, 82.4, 63.4, 62.9, 57.1, 55.4, 54.8,
30.2, 28.9, 27.7, 27.5, 21.1 ppm. IR (KBr):
m 3377, 2977, 2930,
2839, 1713, 1607, 1571, 1543, 1491, 1466, 1394, 1369, 1281,
1245, 1147, 1024, 840, 814, 753, 563, 516 cmꢀ1
.
Acknowledgment
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21272024).
References
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R.; Meanwell, N. A. J. Heterocycl. Chem. 2009, 46, 432.
14. CCDC-978450 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
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