Enantioselective Aza-Henry Reaction of Imines Bearing a Benzothiazole Moiety Catalyzed by a Cinchona-Based Squaramide

Article abstract of DOI:10.1002/adsc.201200957

An efficient enantioselective aza-Henry reaction of nitroalkanes to imines bearing a benzothiazole moiety catalyzed by a Cinchona-based squaramide has been developed. In the reaction of imines, the corresponding products were obtained in good to excellent

Full text of DOI:10.1002/adsc.201200957

FULL PAPERS
DOI: 10.1002/adsc.201200957
Enantioselective Aza-Henry Reaction of Imines Bearing a Benzo-
thiazole Moiety Catalyzed by a Cinchona-Based Squaramide
a
a
a,
Hai-Xiao He, Wen Yang, and Da-Ming Du *
a
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, Peopleꢀs Republic of
China
Fax : (+86)-010-6891-4985; e-mail: dudm@bit.edu.cn
Received: October 31, 2012; Revised: January 24, 2013; Published online: March 20, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200957.
Abstract: An efficient enantioselective aza-Henry re- Moreover, a one-pot three-component enantioselec-
action of nitroalkanes to imines bearing a benzothia- tive aza-Henry reaction using 2-aminobenzothia-
zole moiety catalyzed by a Cinchona-based squar- zoles, aldehydes, and nitromethane was also devel-
ACHTUNGTRENNUNGa mide has been developed. In the reaction of imines, oped. Moderate to good yields and high enantiose-
the corresponding products were obtained in good to lectivities were obtained in the one-pot cases (up to
excellent yields (up to 99%) with excellent enantio- 98% ee).
selectivities (up to >99% ee) for most of the aromat-
ic substituted imines. The imines with electron-with-
drawing groups gave better yields than those bearing Keywords: asymmetric catalysis; aza-Henry reaction;
electron-donating groups in the aza-Henry reaction. benzothiazoles; imines; organocatalysis; squaramides
Introduction
heterocyclic amino counterparts has been rarely re-
ported. Among the heterocyclic compounds, benzo-
[
12]
The aza-Henry reaction is an important and efficient thiazole is an important heterocyclic moiety found in
method for carbon-carbon bond formation in organic many natural products and medically important syn-
[1]
[13]
chemistry. The resulting b-nitro amines are useful thetic molecules.
Benzothiazole derivatives often
synthetic intermidiates, which can be conveniently exhibit a wide spectrum of significant biological activ-
[
14]
converted to vicinal diamines by reduction of the ities.
In this context, the syntheses of these com-
nitro group, or to a-amino acids derivatives through pounds have attracted more attation, but only a few
[2]
[15]
Nef reactions. In recent years, many studies on the catalytic asymmetric approaches were reported.
catalytic asymmetric aza-Henry reaction have been Despite the successful catalytic systems reported,
reported. Shibasaki et al. reported that heterobimetal- the development of new and efficient ones for aza-
lic complexes with lanthanide BINOL systems pro- Henry reactions is still in demand. Chiral squaramide
moted the aza-Henry reaction to give b-nitro amines catalysts like thiourea catalysts have great potential in
[
3]
with high enantioselectivity. Jørgensen et al. also de- catalytic asymmetric reactions. These molecules ex-
veloped a catalytic asymmetric version of this reaction hibit a dual donor-acceptor hydrogen bonding abili-
[
4]
[16]
with bisoxazoline copper(II) complexes. Trost et al. ty. Chiral squaramides as a novel type of good hy-
used dinuclear Zn as a novel catalyst in the addition drogen-bonding organocatalysts have been successful-
[
17]
of nitroalkanes to carbamate-protected imines and ly applied in various asymmetric reactions. Recent-
a,b-unsaturated imines giving a-amino products in ly, our group also reported the chiral squaramide-cat-
[
5]
high enantiomeric excess. Various types of organo- alyzed asymmetric Michael addition of nitroalkanes
[
17g]
catalysts have also been developed in recent years, to nitroalkenes.
In spite of the progress in this
[
6]
such as chiral thioureas, chiral phase-transfer cata- area, the application of this class of organocatalysts in
lysts, chiral proton catalysts, chiral phosphoric aza-Henry reactions has never been reported. We en-
[7]
[8]
[9]
[10]
acid and other types of catalysts.
However, the visioned that Cinchona alkaloid-based squaramides as
substrates of most reports are limited to aldimines or bifunctional organocatalysts can be used to catalyze
[
11]
ketoimines using simple amino counterparts.
The the aza-Henry reaction, because both the electrophilic
utilization of heterocyclic imines or imines containing and nucleophilic components in this reaction can be
Adv. Synth. Catal. 2013, 355, 1137 – 1148
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Hai-Xiao He et al.
FULL PAPERS
8% ee) (Table 1, entry 2). Next, several quinine-based
organocatalysts were prepared and their capacity to
promote the enantioselective aza-Henry reaction was
evaluated. Squaramide catalysts III–V all gave prod-
uct 3a in high yields and excellent enantioselectivities
(
99% ee). When the C -symmetrical quinine-based
2
squaramide catalyst VI was used, high yield and enan-
tioselectivity (91% yield, 94% ee) were obtained
(
Table 1, entry 6). In addition, a control experiment
with quinine-based thiourea catalyst VII was per-
formed for comparing the catalytic activity. Under
otherwise identical conditions, thiourea VII gave the
Figure 1. Activation mode of Cinchona alkaloid-squaramide.
activated by Brønsted acid and Lewis base functional- corresponding adduct 3a in 90% yield with 97% ee
ities of squaramide organocatalysts simultaneously (Table 1, entry 7). This result indicates that the squar-
[18]
(
Figure 1). The match of these two backbones em- amide catalyst exhibits a slightly higher reactivity and
bedded in the squaramide catalysts is critical for pro- enantioselectivity than the corresponding thiourea.
moting the enantioselectivity. Based on the activation From the above evaluation, squaramide III was iden-
mode and previous related work, the application of tified as the optimal catalyst.
Cinchona-based squaramides in this reaction was in-
With the optimal catalyst in hand, we investigated
vestigated. Herein we would like to report the first the effects of solvent, catalyst loading, and tempera-
highly enantioselective aza-Henry reaction catalyzed ture in a search for the optimal conditions. The results
by
a Cinchona-based squaramide organocatalyst are shown in Table 2. Variation of the solvents had
(
Figure 2).
a very limited effect on the reaction process. The
common solvents such as PhMe, THF, ClCH CH Cl,
2
2
CHCl , and CCl all afforded high yields (87–92%)
3
4
Results and Discussion
and excellent enantioselectivities (99% ee) (Table 2,
entries 2–6). This observation demonstrates that the
Initially, we selected the addition of nitromethane 2a catalytic system for the aza-Henry reaction is well tol-
to imine 1a bearing a benzothiazole moiety as erant towrds solvent variation. The solvent CH Cl2
2
a model reaction. The model reaction proceeded well was still the best reaction medium. Noticeably, when
in CH Cl in the presence of 5 mol% catalyst I for the reaction was carried out in neat nitromethane, the
2
2
48 h at room temperature to furnish the correspond- product 3a in high yield with excellent enantioselec-
ing adduct 3a with very low enantioselectivity (9% tivity (80% yield, 99% ee) was achieved (Table 2,
ee) albeit with good yield (70%) (Table 1, entry 1). entry 7). Subsequently, the effect of catalyst loading
The primary amine catalyst II derived from quinine I was investigated. We chose the amount of catalyst III
also afforded very low enantioselectivity (10% yield, with the four gradients (10 mol%, 5 mol%, 2 mol%,
Figure 2. The screened organocatalysts.
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Enantioselective Aza-Henry Reaction of Imines Bearing a Benzothiazole Moiety
[a]
Table 1. Screening of organocatalysts for the enantioselective aza-Henry of nitromethane 2a to imine 1a.
[b]
[c]
Entry
Catalyst
Time [h]
Yield [%]
ee [%]
1
2
3
4
5
6
7
I
II
III
IV
V
VI
VII
48
72
48
48
48
48
48
70
10
95
92
94
91
90
9
8
99
99
99
94
97
[
a]
Unless noted otherwise, reactions were carried out with imine 1a (47.6 mg, 0.2 mmol) and nitromethane 2a (122 mg,
.0 mmol) in CH Cl (2 mL) at room temperature.
Isolated yield after column chromatographic purification.
2
2
2
[
[
b]
c]
Determined by HPLC analysis using a Daicel Chiralpak IB column.
[a]
Table 2. Optimization of reaction conditions for the enantioselective aza-Henry of nitromethane 2a to imine 1a.
o
[b]
[c]
Entry
Solvent
CH Cl
PhMe
THF
Temperarture [ C]
Time [h]
Loading [mol%]
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
48
48
48
48
72
48
48
48
48
48
72
72
5
5
5
5
5
5
5
10
2
1
5
5
95
92
87
90
92
91
80
94
67
60
88
90
99
99
99
99
99
99
99
99
98
96
94
98
2
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH Cl)
2
2
CHCl3
CCl4
MeNO2
CH Cl
2
2
2
2
2
2
CH Cl
2
10
11
12
CH Cl
2
CH Cl
2
CH Cl
40
2
[
[
[
a]
Reactions were carried out with imine 1a (47.6 mg, 0.2 mmol) and nitromethane 2a (122 mg, 2.0 mmol) in CH Cl (2 mL).
Isolated yield after column chromatographic purification.
Determined by HPLC analysis using a Daicel Chiralpak IB column
2
2
b]
c]
and 1 mol%) (Table 2, entries 8–10). The presence of than the one at room temperature (Table 2, entries 11
0 mol% or 5 mol% catalyst almost gave the same re- and 12). Neither high nor low temperature is favoura-
1
sults (Table 2, entry 8). When 2 mol% catalysts were ble for this reaction. So we identified that the optimal
used, the enantioselectivity was decreased to 98% ee. reaction conditions were: CH Cl , in the presence of
2
2
On further reduction of the catalyst loading the enan- 5 mol% catalyst III, and at room temperature.
tioselectivity was decreased to 96% ee. At the same With the optimal reaction conditions established,
time the yields also decreased obviously (67% and we explored the scope of this aza-Henry reaction. The
0% yield, respectively) (Table 2, entries 9 and 10). In results are shown in Table 3. Imines 1a–1f derived
6
the asymmetric reaction, the influence of the temper- from aromatic aldehydes bearing electron-neutral,
ature cannot be ignored. So the aza-Henry reactions electron-withdrawing or electron-donating substitu-
were conducted at 08C and 408C, respectively. How- tions reacted smoothly with nitromethane to afford
ever, the enantioselectivity at 08C or 408C was lower the corresponding adducts in good-to-high yields with
Adv. Synth. Catal. 2013, 355, 1137 – 1148
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Hai-Xiao He et al.
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[a]
Table 3. Substrate scope of the enantioselective aza-Henry of nitromethane 2a to imines 1.
1
2
[b]
[c]
Entry
R
R
Time [h]
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
H
H
H
H
H
H
H
H
C H
4-FC H
4-ClC H
6 4
4-BrC H
3-O NC H
2 6 4
2-MeOC H
5-Cl-2-HOC H
4-(Me) NC H
48
48
48
48
24
48
48
48
48
48
48
48
24
24
24
24
24
48
48
48
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
95
80
94
86
99
80
97
70
91
95
90
94
90
91
98
92
89
97
90
92
>99
99
99
98
>99
99
51
87
80
99
98
99
99
99
99
99
97
99
99
99
6
5
6 4
6 4
6 4
6
3
2
6
4
H
H
H
3,5-Cl -2-HOC H
3-pyridinyl
2
6
2
0
1
2
3
4
5
6
7
8
9
0
2-furanyl
C H
6-Me
6-MeO
6-Cl
6-Me
6-MeO
6-Cl
6-Me
6-MeO
6-Cl
6
5
5
5
C H
6
C H
6
3-O NC H
2
6
4
4
4
3-O NC H
2
6
3-O NC H
2
6
2-MeOC H
2-MeOeC H
2-MeOC H
6
4
3s
3t
6
4
6
4
[
[
[
a]
Reactions were carried out with imine 1 (0.2 mmol) and nitromethane 2a (122 mg, 2.0 mmol) in CH Cl (2 mL).
Isolated yield after column chromatographic purification.
Determined by HPLC analysis.
2
2
b]
c]
excellent enantioselectivities (99% ee) (Table 3, en-
To get a general sense of what this catalyst can do
tries 1–6). The electronic property of the substituent for the aza-Henry reaction, other imines with more
has a certain effect on the yield. Generally, imines typical N-substituents were investigated. The imines
with electron-withdrawing substituents gave higher derived from benzaldehyde and aniline or p-chloroa-
yields than those with electron-donating substituents. niline cannot undergo this aza-Henry reaction, Ts-
When reactions were performed with imines 1g and 1i imine 4a gave very low enantioselectivity (15% ee)
bearing a hydroxy group, the desired products were and Boc-imine 4b afforded the corresponding product
obtained with moderate enantioselectivities (51% ee 5b in 90% yield with 31% ee. This result indicates
and 80% ee, respectively) (Table 3, entries 7 and 9). that the presence of the N-heterocycle in the imine is
Imine 1h bearing strong electron-donating substitu- necessary for high enantioselectivity. Other nitroal-
tion, N(Me) , afforded the corresponding product in kanes were further investigated. The reaction of nitro-
2
70% yield with 87% ee (Table 3, entry 9). A signifi- ethane 2b and imine 1a catalyzed by 5 mol% catalyst
cant decrease on the enantioselectivity can be attrib- III was also effective to provide the corresponding
uted to strong hydrogen bond interaction between the product 6 in 96% yield with excellent enantioselectivi-
OH or N(Me) group and squaramide catalyst III. ties for both diastereomers (99% ee and 99% ee, re-
2
Imines 1j and 1k derived from heteroaromatic alde- spectively), albeit with low diastereoselectivity
hydes were also good substrates, and the desired (Scheme 1). When nitropropane 2c was used, the aza-
products were obtained in high yields with excellent Henry product 7 was obtained in 92% yield with ex-
enantioselectivities (95% yield, 99% ee and 90% cellent enantioselectivities for one diastereomer (99%
yield, 98% ee, respectively) (Table 3, entries 10 and ee). The enantioselectivity of another diastereomer
11). Imines 1l–1t with variations (6-Me, 6-MeO, and cannot be determined owing to the fact that the cor-
6-Cl) on the benzothiazole ring were examined, and responding two enantiomers cannot be separated with
excellent yields and excellent enantioselectivities (97– the series of columns in hand.
99% ee) were achieved (Table 3, entries 12–20).
To determine the absolute configuration of the aza-
Henry products, a single crystal of the product 3d
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Enantioselective Aza-Henry Reaction of Imines Bearing a Benzothiazole Moiety
Scheme 1. Further substrate scope of imines and nitroalkanes.
at room temperature. The desired product 3a was ob-
tained with excellent enantioselectivity but in low
yield (20% yield, 98% ee) (Table 4, entry 1). For im-
proving the yield, the reaction conditions such as sol-
vent, temperature and additives were simply reopti-
mized (Table 4, entries 2–8). When the reaction tem-
perature was increased to 608C, the yield was en-
hanced but with reduction of the enantioselectivity
(
Table 4, entries 2–4). No good result was obtained
when the reaction was performed at 908C in PhMe
Table 4, entry 5). Then, we tried to evaluate the
(
effect of additives. When 4ꢂ molecular sieve, anhy-
drous Na SO or MgSO was used as additive, the
2
4
4
product was obtained with higher yield but lower
enantioselectivity (Table 4, entries 6–8). The result
(
55% yield, 89% ee) achieved in toluene at 608C was
found to be acceptable in consideration of both yield
and enantioselectivity (Table 4, entry 2). Under the
new optimal conditions, the scope of the one-pot
three-component asymmetric aza-Henry reaction was
further explored. Aromatic aldehydes 9 with electron-
withdrawing or electron-donating substitutions were
Figure 3. X-ray crystal structure of product 3d.
suitable for X-ray crystallographic analysis was ob- examined, and moderate to good yields with high
tained by crystallization from ethanol. As shown in enantioselectivies were obtained (Table 4, entries 9–
Figure 3, the absolute configuration of 3d was deter- 11). 2-Aminobenzothiazoles with different substitu-
[
19]
mined to be (S).
The absolute configurations of tions (6-Me, 6-MeO, and 6-Cl) on the benzothiazole
ring also gave comparable results (Table 4, entries 12–
other products were assigned by analogy.
Encouraged by the above excellent results, we tried 14). When the aza-Henry reaction with 2-amino-5-
to develop a one-pot three-component enantioselec- chlorobenzothiazole, 2-methoxybenzaldehyde, and ni-
[
20]
tive aza-Henry reaction. Following the two-compo- tromethane was performed in toluene in the presence
nent reaction conditions, the asymmetric one-pot aza- of 5 mol% catalyst III at 60 8C for 90 h, the product
Henry reaction was performed with 2-aminobenzo- 3t was obtained with high yield and excellent enantio-
thiazole, benzaldehyde, and nitromethane in CH Cl
selectivity (90% yield, 94% ee) (Table 4, entry 15).
2
2
Adv. Synth. Catal. 2013, 355, 1137 – 1148
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Hai-Xiao He et al.
FULL PAPERS
[a]
Table 4. One-pot three-component enantioselective aza-Henry reaction.
1
2
o
[b]
[c]
Entry
R
R
Temperature [ C]
Solvent
CH Cl
PhMe
CHCl3
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
H
H
H
H
H
H
H
H
H
H
H
6-Me
6-MeO
6-Cl
6-Cl
C H
r.t.
60
60
60
90
60
60
60
60
60
60
60
60
60
60
3a
3a
3a
3a
3a
3a
3a
3a
3c
3e
3f
3 L
3 m
3n
3t
20
55
43
36
57
90
65
75
57
50
71
61
46
46
90
98
89
59
73
52
76
80
79
86
94
91
83
87
94
94
6
5
5
5
5
5
5
5
5
2
2
C H
6
C H
6
C H
ACHTUNGTNRENUNG( CH Cl)
6
2 2
C H
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
6
[
[
[
d,e]
e,f]
C H
6
C H
6
e,g]
C H
6
4-ClC H
3-O NC H
4
2-MeOC H
6 4
0
1
2
3
4
5
2
6
6
4
4
C H
6
5
5
5
C H
6
C H
6
[
h]
2-MeOC H
6
[
a]
Reactions were carried out with 2-aminobenzothiazole 8 (0.2 mmol), aldehyde 9 (0.3 mmol), and nitromethane 2a
(122 mg, 2.0 mmol) for 48 h.
b]
[
[
[
[
[
[
[
Isolated yield after column chromatographic purification.
Determined by HPLC analysis.
c]
d]
e]
f]
4
ꢂ molecular sieves (30 mg) were used as additive.
The reaction time was 72 h.
Anhydrous Na SO (30 mg) was used as additive.
2
4
g]
h]
Anhydrous MgSO (30 mg) was used as additive.
4
The reaction time was 90 h.
After obtaining products that are important inter- Conclusions
mediates for organic synthesis, we paid more atten-
tion to their derivatization. Product 10 was obtained In summary, we have developed an efficient Cincho-
from 3a by palladium-catalyzed hydrogen reduction. na-based squaramide-catalyzed efficient enantioselec-
Next, glutaraldehyde was added to product 10 tive aza-Henry of imines bearing a benzothiazole
(
Scheme 2), and the novel compound 11 bearing two moiety with nitromethane. The corresponding prod-
biologically active heterocycles was obtained in good ucts were obtained in good to excellent yields with ex-
yield (76%) with retained excellent enantioselectivity cellent enantioselectivities in most cases. In addition,
(
99% ee). This demonstrates the synthetic utility of a one-pot three-component enantioselective aza-
the present asymmetric methodology.
Henry reaction using 2-aminobenzothiazoles, alde-
hydes, and nitromethane was also developed. Moder-
ate to good yields and high enantioselectivities were
obtained in one-pot cases. Further studies on squara-
mide-catalyzed asymmetric reactions and the enantio-
selective synthesis of other functional chiral molecules
are currently underway in our laboratory.
Experimental Section
General Remarks
Commercially available compounds were used without fur-
ther purification. Solvents were dried according to standard
Scheme 2. The synthetic transformation of 3a.
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Adv. Synth. Catal. 2013, 355, 1137 – 1148

Enantioselective Aza-Henry Reaction of Imines Bearing a Benzothiazole Moiety
À1
procedures. Column chromatography was carried out using
silica gel (200–300 mesh). Melting points were measured on
an XT-4 melting point apparatus and are uncorrected. The
752, 726 cm ; HR-MS (ESI): m/z=318.07127, calcd. for
+
C H FN O S [M+H] : 318.08012.
1
5
13
3
2
Benzothiazol-2-yl-[1-(4-chlorophenyl)-2-nitroethyl]amine
(3c): Compound 3c was obtained according to the general
procedure as a white solid: yield: 62.4 mg (94%); mp 142–
1448C. The enantiomeric excess was determined by HPLC
[Daicel Chiralpak IB column (n-hexane-2-propanol 90:10),
flow rate 1.0 mLmin , detection at 254 nm]: minor enantio-
mer t =23.7 min, major enantiomer t =30.8 min, 99% ee;
[a] : +99.7 (c 0.61, CH Cl ). H NMR (400 MHz, CDCl ):
d=7.57 (dd, J =14.0 Hz, J =8.0 Hz, 2H, ArH), 7.35–7.29
1
H NMR spectra were recorded with Varian Mercury-plus
1
3
4
00 MHz spectrometers, while the C NMR spectra were re-
corded at 100 MHz. Infrared spectra were obtained with
a Perkin–Elmer Spectrum One FT-IR spectrometer. Mass
spectra were obtained on a VG-ZAB-HS (EI) mass spec-
trometer. The HR-MS (ESI) spectra were obtained with
a Bruker APEX IV mass spectrometer. Optical rotations
were measured on a WZZ-3 polarimeter at the indicated
concentration with units g/100 mL. The enatiomeric excesses
À1
R
R
2
D
5
1
2
2
3
1
2
(m, 5H, ArH), 7.14 (t, J=7.4 Hz, 1H, ArH), 6.31 (s, 1H,
NH), 5.68 (t, J=5.8 Hz, 1H, CH), 5.06 (dd, J =13.0 Hz, J =
(
ee) of the products were determined by chiral HPLC analy-
1
2
sis using an Aglient HP 1200 instrument (n-hexane/2-propa-
nol as eluent). The squaramide catalysts III–VI were pre-
6
.6 Hz, 1H, CH ), 4.84 (dd, J =13.2 Hz, J =5.4 Hz, 1H,
2 1 2
13
CH ); C NMR (100 MHz, CDCl ): d=165.0, 151.5, 135.0,
2
3
[17f,21]
pared according to literature procedures.
1
5
1
1
34.7, 130.7, 129.5, 128.0, 126.2, 122.6, 121.0, 119.6, 78.1,
6.0; IR (KBr): n=3390, 3072, 2963, 2911, 1594, 1556, 1527,
502, 1457, 1442, 1431, 1379, 1335, 1271, 1247, 1226, 1185,
096, 1087, 1010, 918, 861, 823, 755, 740 cm ; HR-MS
(ESI): m/z=334.04145, calcd. for C H ClN O S [M+H] :
À1
Typical Procedure for the Asymmetric Aza-Henry of
Nitromethane to Imines
+
1
5
13
3
2
3
34.04115.
Benzothiazol-2-yl-[1-(4-bromophenyl)-2-nitroethyl]amine
3d): Compound 3d was obtained according to the general
procedure as a white solid: yield: 65 mg (86%); mp 133–
358C. The enantiomeric excess was determined by HPLC
The reaction was carried out with imine 1a (47.6 mg,
0.2 mmol), nitromethane 2a (122 mg, 2.0 mmol), and catalyst
(
III (6.3 mg, 0.01 mmol) in CH Cl (2 mL) at room tempera-
2
2
ture for 48 h. The mixture was separated directly by silica
gel column chromatography with petroleum ether-ethyl ace-
tate (5:1), and the product was obtained as pure form.
1
[
Daicel Chiralpak IB column (n-hexane-2-propanol 90:10),
À1
flow rate 1.0 mLmin , detection at 254 nm]: minor enantio-
mer t =30.4 min, major enantiomer t =36.5 min, 98% ee;
Benzothiazol-2-yl-[2-nitro-1-phenylethyl]amine
(3a):
R
R
Compound 3a was obtained according to the general proce-
dure as a white solid; yield: 57 mg (95%); mp 136–1388C.
The enantiomeric excess was determined by HPLC [Daicel
2
D
5
1
[a] : +24.4 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl ):
2
2
3
d=7.60–7.60 (m, 2H, ArH), 7.52 (d, J=8.4 Hz, 2H, ArH),
.34–7.29 (m, 3H, ArH), 7.14 (t, J=7.6 Hz, 1H, ArH),
7
Chiralpak IB column (n-hexane-2-propanol 95:5), flow rate
À1
6.05(s, 1H, NH), 5.69 (t, J=5.8 Hz, 1H, CH), 5.08 (dd, J =
13.2 Hz, J =6.4 Hz , 1H, CH ), 4.86 (dd, J =13.2 Hz, J =
5.6 Hz , 1H, CH ); C NMR (100 MHz, CDCl ): d=165.3,
1
1
1
1
1
1
5
+
.0 mLmin , detection at 254 nm]: minor enantiomer t =
R
2
5
2
2
1
2
4.8 min, major enantiomer t =59.2 min, >99% ee; [a] :
157.7 (c 0.35, CH Cl ). H NMR (400 MHz, CDCl ): d=
R
D
1
3
1
2
3
2
2
3
51.4, 135.2, 132.4, 130.5, 128.2, 126.2, 123.0, 122.5, 121.0,
19.4, 78.0, 56.2; IR (KBr): n=3383, 3070, 2923, 1632, 1594,
557, 1525, 1501, 1488, 1442, 1430, 1378, 1335, 1270, 1246,
7.57 (t, J=7.0 Hz, 2H, ArH), 7.43–7.36 (m, 5H, ArH), 7.31
(
(
1
t, J=8.0 Hz, 1H, ArH), 7.13 (t, J=7.8 Hz, 1H, ArH), 5.69
t, J=6.2 Hz, 1H, CH), 5.09 (dd, J =13.2 Hz, J =6.8 Hz,
1
2
À1
225, 1184, 1128, 1070, 1007, 918, 857, 821, 754, 730 cm ;
H, CH ), 4.86 (dd, J =12.8 Hz, J =5.8 Hz, 1H, CH );
2
1
2
2
1
3
HR-MS (ESI): m/z=377.99115, calcd. for C H BrN O S
15 13 3 2
+
C NMR (100 MHz, CDCl ): d=165.5, 151.6, 136.1, 130.7,
3
[
M+H] : 377.99064.
Benzothiazol-2-yl-[2-nitro-1-(3-nitrophenyl)ethyl]amine
129.3, 129.0, 126.5, 126.1, 122.4, 120.9 119.5, 76.3, 56.8; IR
(
1
KBr): n=3390, 3135, 3179, 2956, 2913, 2836, 1601, 1556,
À1
(3e): Compound 3e was obtained according to the general
procedure as a yellow solid; yield: 68.5 mg (99%); mp 50–
495, 1444, 1376, 1314, 1116, 1092, 753, 702 cm ; HR-MS
+
(
ESI): m/z=300.08051, calcd. for C H N O S [M+H] :
15 14 3 2
5
28C The enantiomeric excess was determined by HPLC
3
00.08012.
Benzothiazol-2-yl-[1-(4-fluorophenyl)-2-nitroethyl]amine
3b): Compound 3b was obtained according to the general
procedure as a white solid; yield: 50.7 mg (80%); mp 46–
88C.The enantiomeric excess was determined by HPLC
[
Daicel Chiralpak IB column (n-hexane-2-propanol 90:10),
À1
flow rate 0.8 mLmin , detection at 254 nm]: minor enantio-
mer t =44.3 min, major enantiomer t =48.9 min, >99% ee;
(
R
R
2
D
5
1
[a] : +28.0 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl ):
4
2
2
3
d=8.32 (s, 1H, ArH), 8.20 (d, J=8.0 Hz, 1H, ArH), 7.79 (d,
J=7.6 Hz, 1H, ArH), 7.60–7.53 (m, 3H, ArH), 7.31 (t, J=
7.4 Hz, 1H, ArH), 7.15 (t, J=7.2 Hz, 1H, ArH), 6.41 (s, 1H,
[
Daicel Chiralpak IB column (n-hexane-2-propanol 90:10),
À1
flow rate 1.0 mLmin , detection at 254 nm]: minor enantio-
mer t =22.5 min, major enantiomer t =28.1 min, 99% ee;
R
R
2
D
5
1
[a] : +54.2 (c 1.0, CH Cl ). H NMR (400 MHz, CDCl ):
NH), 5.90 (br s, 1H, CH), 5.13 (dd, J
1H, CH ), 4.94 (dd, J =13.4 Hz, J
C NMR (100 MHz, CDCl ): 164.6, 151.4, 148.6, 138.7,
1
=13.2 Hz, J
2
=5.6 Hz,
2
2
3
d=7.58 (t, J=8.8 Hz, 2H, ArH), 7.40 (dd, J =8.8 Hz, J =
5
7
NH), 5.69 (t, J=6.2 Hz, 1H, CH), 5.08 (dd, J =13.0 Hz, J =
6
2
1
2
=3.8 Hz, 1H, CH
);
2
1
2
1
3
.2 Hz , 2H, ArH), 7.32 (t, J=7.6 Hz, 1H, ArH), 7.14 (t, J=
.6 Hz, 1H, ArH), 7.08 (t, J=8.4 Hz, 2H, ArH), 6.30 (s, 1H,
3
132.8, 130.7, 130.3, 126.2, 123.9, 122.8, 121.6, 121.0, 119.7,
77.8, 55.6; IR (KBr): n=3377, 3071, 2962, 1711, 1613, 1598,
1562, 1525, 1455, 1443, 1376, 1347, 1262, 1206, 1099, 1017,
1
2
.6 Hz , 1H, CH ), 4.84 (dd, J =13.2 Hz, J =5.6 Hz , 1H,
2 1 2
13
À1
CH ); C NMR (100 MHz, CDCl ): d=165.3, 162.8 (d,
929, 896, 803, 754, 726, 686 cm ; HR-MS (ESI): m/z=
2
3
1
3
+
JC,F =246 Hz), 151.5, 132.0, 130.6, 128.5 (d, J =8.7 Hz),
345.06495, calcd. for C15
H
13
N
4
O
4
S [M+H] : 345.06520.
C.F
2
1
5
1
26.2, 122.5, 121.0, 119.5, 116.3 (d, JC.F =22.1 Hz), 78.2,
6.2; IR (KBr): n=3376, 3072, 2924, 1599, 1560, 1530, 1508,
456, 1444, 1375, 1339, 1224, 1160, 1125, 1016, 972, 919, 834,
Benzothiazol-2-yl-[(2-methoxyphenyl)-2-nitroethyl]amine
(3f): Compound 3f was obtained according to the general
procedure as a yellow solid; yield: 53.1 mg (80%); mp 46–
Adv. Synth. Catal. 2013, 355, 1137 – 1148
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1143

Hai-Xiao He et al.
FULL PAPERS
4
78C The enantiomeric excess was determined by HPLC
minor enantiomer t =10.3 min, major enantiomer t =
R
R
2
5
1
[Daicel Chiralpak IB column (n-hexane-2-propanol 90:10),
9.1 min, 80% ee; [a] : À113.4 (c 0.94, CH Cl ). H NMR
D
2
2
À1
flow rate 1.0 mLmin , detection at 254 nm]: minor enantio-
(400 MHz, CDCl ): d=7.60 (t, J=7.4 Hz, 2H, ArH), 7.36–
3
mer t =27.9 min, major enantiomer t =23.0 min, 99% ee;
7.31 (m, 2H, ArH), 7.19–7.15 (m, 2H, ArH), 5.94–5.88 (m,
R
R
2
5
1
[
a] : +121.5 (c 1.17, CH Cl ). H NMR (400 MHz, CDCl ):
1H, CH), 5.13 (dd, J =13.4 Hz, J =7.8 Hz , 1H, CH ), 4.89
D
2
2
3
1
2
2
1
3
d=7.57 (d, J=8.0 Hz, 2H, ArH), 7.36–7.27 (m, 3H, ArH),
(dd, J1 =13.2 Hz, J2 =4.8 Hz, 1H, CH );
C NMR
2
7
6
1
6
.10 (t, J=7.4 Hz, 1H, ArH), 6.95 (t, J=8.0 Hz, 2H, ArH),
(100 MHz, CDCl ): d=165.6, 150.3, 149.0, 129.9, 129.7,
3
.43 (s, 1H, NH) 5.80 (t, J=6.4 Hz, 1H, CH), 5.03 (dd, J =
126.6, 126.4, 125.7, 125.4, 123.1, 121.1, 119.5, 77.2, 53.2; IR
(KBr): n=3371, 3059, 2978, 1705, 1598, 1575, 1557, 1537,
1456, 1447, 1413, 1375, 1339, 1295, 1249, 1223, 1157, 1128,
1
2.4 Hz, J =7.2 Hz, 1H, CH ), 4.87 (dd, J =12.4 Hz, J =
2
2
1
2
1
3
.4 Hz, 1H, CH ), 3.93 (s, 3H, OCH ); C NMR (100 MHz,
2
3
À1
CDCl ): d=165.7, 156.9, 151.9, 130.7, 130.3, 129.2, 126.0,
1044, 1018, 930, 866, 752, 725 cm ; HR-MS (ESI): m/z=
3
+
123.5, 122.1, 121.2, 120.8, 119.4, 111.1, 77.2, 55.5, 55.4; IR
383.99747, calcd. for C H Cl N O S [M+H] : 383.99707.
1
5
12
2
3
3
(
1
9
KBr): n=3398, 3061, 2937, 2838, 1723, 1599, 1558, 1532,
Benzothiazol-2-yl-(2-nitro-1-pyridin-3-ylethyl)amine (3j):
Compound 3j was obtained according to the general proce-
dure as a yellow solid; yield: 57 mg (95%); mp 130–1338C.
The enantiomeric excess was determined by HPLC [Daicel
Chiralpak AD-H column (n-hexane:2-propanol 70:30), flow
490, 1456, 1444, 1376, 1338, 1286, 1245, 1208, 1123, 1020,
À1
30, 854, 790, 752, 726 cm ; HR-MS (ESI): m/z=330.09102,
+
calcd. for C H N O S [M+H] : 330.09069.
16
16
3
3
2-[1-(Benzothiazol-2-ylamino)-2-nitroethyl]-4-chlorophe-
À1
nol (3g): Compound 3g was obtained according to the gener-
al procedure as a yellow solid; yield: 67.7 mg (97%); mp
1
rate 1.0 mLmin , detection at 254 nm]: minor enantiomer
2
D
5
t =6.6 min, major enantiomer t =11.8 min, 99% ee; [a] :
R
R
1
05–1088C. The enantiomeric excess was determined by
+79.6 (c 0.5, CH Cl ). H NMR (400 MHz, CDCl ): d=8.73
2 2 3
HPLC [Daicel Chiralpak AD-H column (n-hexane-2-propa-
nol 70:30), flow rate 1.0 mLmin , detection at 254 nm]:
(d, J=2.0 Hz, 1H, pyridine-H), 8.60 (d, J=4.0 Hz , 1H, pyr-
idine-H), 7.78–7.76 (m, 1H, ArH), 7.59–7.55 (m, 2H, ArH),
7.34–7.29 (m, 2H, ArH), 7.16–7.12 (m, 1H, ArH), 6.48 (br s,
À1
minor enantiomer t =5.3 min, major enantiomer t =
R
R
2
5
1
6
.6 min, 51% ee; [a] : +46.9 (c 0.75, CH Cl ). H NMR
1H, NH), 5.84 (t, J=6.0 Hz, 1H, CH), 5.15 (dd, J =
D
2
2
1
(
(
400 MHz, CDCl ): d=7.65 (d, J=8.0 Hz, 1H, ArH), 7.50
d, J=8.0 Hz, 1H, ArH), 7.33 (t, J=7.8 Hz, 1H, ArH),
13.4 Hz, J =6.6 Hz, 1H, CH ), 4.93 (dd, J =13.2 Hz, J =
3
2
2
1
2
1
3
5.6 Hz , 1H, CH ); C NMR (100 MHz, CDCl ): d=164.6,
2
3
7
.22–7.16 (m, 2H, ArH), 7.13 (d, J=2.4 Hz, 1H, ArH), 6.80
151.5, 150.0, 148.3, 134.6, 132.5, 130.8, 126.1, 124.0, 122.6,
120.9, 119.7, 77.6, 54.2; IR (KBr): n=3197, 2961, 2759, 1598,
1565, 1534, 1476, 1455, 1443, 1424, 1377, 1338, 1316, 1240,
(
(
4
d, J=8.4 Hz, 1H, ArH), 6.31 (d, J=8.0 Hz, 1H, NH) 5.79
br s, 1H, CH), 5.12 (dd, J =13.2 Hz, J =7.6 Hz, 1H, CH ),
.96 (dd, J =13.2 Hz, J =3.6 Hz, 1H, CH ); C NMR
1
2
2
1
3
À1
1205, 1124, 1026, 911, 853, 754, 724, 709, 638 cm ; HR-MS
1
2
2
+
(100 MHz, CDCl ): d=167.0, 153.6, 149.5, 129.7, 129.4,
(ESI): m/z=301.07484, calcd. for C H N O S [M+H] :
3
14 13
4
2
1
5
2
1
8
26.7, 126.5, 124.3, 123.2, 122.9, 121.4, 118.4, 116.7, 76.8,
4.3; IR (KBr): n=3423, 3359, 3060, 3029, 2954, 2782, 2710,
572, 1706, 1603, 1570, 1558, 1539, 1522, 1499, 1490, 1449,
347, 1328, 1270, 1246, 1204, 1172, 1122, 1106, 1020, 931,
301.07537.
Benzothiazol-2-yl-(1-furan-2-yl-2-nitroethyl)amine (3k):
Compound 3k was obtained according to the general proce-
dure as a yellow solid; yield: 51.9 mg (90%); mp 130–1328C.
The enantiomeric excess was determined by HPLC with
a Daicel Chiralpak IB column (n-hexane-2-propanol 80:20),
À1
75, 818, 750, 725 cm ; HR-MS (ESI): m/z=350.03617,
+
calcd. for C H ClN O S [M+H] : 350.03607.
15
13
3
3
À1
Benzothiazol-2-yl-[1-(4-dimethylaminophenyl)-2-nitro-
ethyl]amine (3h): Compound 3h was obtained according to
the general procedure as a yellow solid; yield: 47.8 mg
flow rate 1.0 mLmin , detection at 254 nm]: minor enantio-
mer t =9.0 min, major enantiomer t =8.4 min, 98% ee;
R
R
2
5
1
[a] : +225.9 (c 1.95, CH Cl ). H NMR (400 MHz, CDCl ):
D
2
2
3
(
70%); mp 106–1088C. The enantiomeric excess was deter-
d=7.60–7.58 (m, 2H, ArH), 7.39 (d, J=1.6 Hz,1H, furan-
H), 7.32 (t, J=8.0 Hz,1H, ArH), 7.14 (t, J=7.0 Hz,1H,
mined by HPLC [Daicel Chiralpak IB column (n-hexane-2-
propanol 90:10), flow rate 0.8 mLmin , detection at
À1
ArH), 6.41 (d, J=3.2 Hz, 1H, furan-H), 6.36 (dd, J =
1
2
54 nm]: minor enantiomer t =37.3 min, major enantiomer
3.2 Hz, J =2.0 Hz, 1H, furan-H), 6.09 (br s, 1H, NH), 5.88
R
2
2
5
t =44.3 min, 87% ee; [a] : +111.3 (c 0.23, CH Cl );
(t, J=5.8 Hz, 1H, CH), 5.07 (dd, J =13.2 Hz, J =5.6 Hz,
R
D
2
2
1
2
1
H NMR (400 MHz, DMSO-d ): d=8.70 (d, J=7.2 Hz, 1H,
1H, CH ), 4.92 (dd, J =13.2 Hz, J =6.0 Hz, 1H, CH );
2 1 2 2
3
6
1
NH), 7.68 (d, J=7.2 Hz, 1H, ArH), 7.42 (d, J=8.0 Hz, 1H,
ArH), 7.30 (d, J=8.8 Hz, 2H, ArH), 7.25–7.21 (m, 1H,
ArH), 7.06–7.01 (m, 1H, ArH), 6.71 (d, J=8.8 Hz, 2H,
C NMR (100 MHz, CDCl ): d=164.7, 151.6, 148.8, 143.1,
3
130.8, 126.1, 122.5, 120.9, 119.7, 110.8, 108.6, 75.8, 50.6; IR
(KBr): n=3177, 3003, 2972, 2740, 1594, 1569, 1542, 1456,
1447, 1379, 1250, 1228, 1202, 1179, 1143, 1074, 1012, 965,
ArH), 5.65–5.59 (m, 1H, CH), 5.01–4.90 (m, 2H, CH ), 2.86
2
13
À1
(s, 6H, CH ); C NMR (100 MHz, DMSO-d ): d=165.0,
832, 821, 763, 751, 726, 692, 640 cm ; HR-MS (ESI): m/z=
3
6
+
1
1
1
1
51.9, 150.1, 132.0, 130.3, 127.6, 125.5, 124.5, 121.3, 120.9,
18.4, 112.2, 79.1, 78.6, 55.4; IR (KBr): n=3399, 3056, 2920,
722, 1643, 1597, 1530, 1484, 1446, 1379, 1319, 1295, 1267,
290.05895, calcd. for C H N O S [M+H] : 290.05939.
1
3
12
3
3
(6-Methylbenzothiazol-2-yl)-(2-nitro-1-phenylethyl)amine
(3l): Compound 3l was obtained according to the general
procedure as a white solid; yield: 58.7 mg (94%); mp 126–
1288C. The enantiomeric excess was determined by HPLC
[Daicel Chiralpak IB column (n-hexane-2-propanol 70:30),
À1
170, 1122, 1067, 968, 808, 741, 720 cm ; HR-MS (ESI): m/
+
z=343.12272, calcd. for C H N O S [M+H] : 343.12232.
1
7
19
4
2
2-[1-(Benzothiazol-2-ylamino)-2-nitroethyl]-4,6-dichloro-
À1
phenol (3i): Compound 3i was obtained according to the
general procedure as a yellow solid; yield: 69.7 mg (91%);
mp 83–858C. The enantiomeric excess was determined by
HPLC [Daicel Chiralpak AD-H column (n-hexane-2-propa-
flow rate 1.0 mLmin , detection at 254 nm]: minor enantio-
mer t =10.1 min, major enantiomer t =8.5 min, 99% ee;
R
R
2
D
5
1
[a] : +69.5 (c 2.29, CH Cl ). H NMR (400 MHz, CDCl ):
2
2
3
d=7.44 (d, J=8.2 Hz, 1H, ArH), 7.40–7.31 (m, 6H, ArH),
7.11 (d, J=8.0 Hz, 1H, ArH), 6.37 (s, 1H, NH), 5.66 (t, J=
À1
nol 85:15), flow rate 1.0 mLmin , detection at 254 nm]:
1144
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1137 – 1148

Enantioselective Aza-Henry Reaction of Imines Bearing a Benzothiazole Moiety
À1
6
.0 Hz, 1H, CH), 5.05 (dd, J =12.8 Hz, J =6.8 Hz, 1H,
1196, 1135, 1100, 1002, 928, 898, 814, 734, 688, 671 cm ;
1
2
CH ), 4.83 (dd, J =13.0 Hz, J =5.8 Hz, 1H, CH ), 2.38 (s,
HR-MS (ESI): m/z= 359.08098,calcd. for C H N O S [M+
H] : 359.08085.
2
1
2
2
16 15
4
4
13
+
3
1
7
1
H, CH ); C NMR (100 MHz, CDCl ): d=164.8, 149.5,
36.2, 132.1, 130.7, 129.2, 128.9, 127.2., 126.5, 120.9, 119.0,
3
3
(6-Methoxybenzothiazol-2-yl)-[2-nitro-1-(3-nitrophenyl)-
ethyl]amine (3p): Compound 3p was obtained according to
the general procedure as a yellow solid; yield: 68.7 mg
(92%); mp 48–508C. The enantiomeric excess was deter-
mined by HPLC [Daicel Chiralpak AD-H column (n-
8.3, 56.8, 21.2; IR (KBr): n=3195, 3013, 1719, 1605, 1542,
À1
467, 1384, 1233, 1196, 1074, 808, 760, 694 cm ; HR-MS
+
(
ESI): m/z=314.09591, calcd. for C H N O S [M+H] :
1
6
16
3
2
314.09557.
À1
(
6-Methoxybenzothiazol-2-yl)-(2-nitro-1-phenylethyl)am-
hexane-2-propanol 70:30 v/v), flow rate 1.0 mLmin , detec-
ine (3m): Compound 3m was obtained according to the gen-
eral procedure as a white solid; yield: 58.9 mg (90%); mp
tion at 254 nm]: minor enantiomer t =13.2 min, major enan-
R
2
5
tiomer t =14.6 min, 99% ee; [a] : +27.4 (c 1.93, CH Cl ).
R
D
2
2
1
45–478C. The enantiomeric excess was determined by
H NMR (400 MHz, CDCl ): d=8.32 (s, 1H, ArH), 8.20 (d,
3
HPLC [Daicel Chiralpak AD-H column (n-hexane-2-propa-
nol 70:30), flow rate 1.0 mLmin , detection at 254 nm]:
J=8.4 Hz, 1H, ArH), 7.79 (d, J=7.6 Hz, 1H, ArH), 7.58 (t,
J=8.0 Hz,1H, ArH), 7.44 (d, J=8.8 Hz, 1H, ArH), 7.12 (d,
J=1.6 Hz, 1H, ArH), 6.90 (dd, J =2.4 Hz, J =8.8 Hz,1H,
À1
minor enantiomer t =13.2 min, major enantiomer t =
R
R
1
2
2
5
1
2
0.2 min, 99% ee; [a] : +57.3 (c 0.45, CH Cl ). H NMR
ArH), 5.86 (t, J=5.6 Hz, 1H, CH), 5.12 (dd, J =13.6 Hz,
D
2
2
1
(
7
400 MHz, CDCl ): d=7.45 (d, J=8.8 Hz, 1H, ArH), 7.41–
.32 (m, 5H, ArH), 7.10 (d, J=2.4 Hz, 1H, ArH), 6.89 (dd,
J =6.8 Hz, 1H, CH ), 4.93 (dd, J =13.2 Hz, J =5.2 Hz, 1H,
3
2
2
1
2
1
3
CH ), 3.81 (s, 3H, OCH ); C NMR (100 MHz, CDCl ): d=
2
3
3
J =8.8 Hz, J =2.4 Hz, 1H, ArH), 5.64 (t, J=6.4 Hz, 1H,
163.2, 155.8, 148.5, 145.4, 138.7, 132.9, 131.8, 130.2, 123.7,
121.6, 120.0, 113.9, 105.3, 77.8, 55.8, 55.7; IR (KBr): n=
3462, 3385, 3088, 2925, 1619, 1597, 1561, 1526, 1446, 1376,
1350, 1271, 1245, 1206, 1098, 1051, 906, 858, 817, 733,
1
2
CH ), 5.05 (dd, J =13.0 Hz, J =7.0 Hz, 1H, CH ), 4.83 (dd,
2
1
2
2
J =13.0 Hz, J =5.8 Hz, 1H, CH ), 3.80 (s, 3H, OCH );
1
2
2
3
13
C NMR (100 MHz, CDCl ): d=163.9, 155.6, 145.7, 136.2,
3
À1
131.6, 129.2, 128.9, 126.5, 119.8, 113.7, 105.3, 78.3, 56.8, 55.8;
687 cm ; HR-MS (ESI): m/z=375.07562, calcd. for
+
IR (KBr): n=3412, 2917, 2738, 1626, 1602, 1556, 1487, 1441,
C H N O S [M+H] : 375.07577.
1
6
15
4
5
1
7
375, 1315, 1271, 1225, 1180, 1089, 1057, 1027, 927, 832, 765,
(6-Chlorobenzothiazol-2-yl)-[2-nitro-1-(3-nitrophenyl)-
ethyl]amine (3q): Compound 3q was obtained according to
the general procedure as a white solid; yield: 67.1 mg
(89%); mp 54–568C. The enantiomeric excess was deter-
mined by HPLC [Daicel Chiralpak IB column (n-hexane-2-
À1
01, 623, 602 cm ; HR-MS (ESI): m/z=330. 09091, calcd.
+
for C H N O S [M+H] : 330.09069.
16
16
3
3
(
6-Chlorobenzothiazol-2-yl)-(2-nitro-1-phenylethyl)amine
3n): Compound 3n was obtained according to the general
procedure as a white solid; yield: 60.9 mg (91%); mp 141–
428C. The enantiomeric excess was determined by HPLC
(
À1
propanol 80:20), flow rate 1.0 mLmin , detection at
1
254 nm]: minor enantiomer t =17.3 min, major enantiomer
R
2
D
5
[Daicel Chiralpak IB column (n-hexane-2-propanol 70:30),
t =15.5 min, 97% ee; [a] : +36.8 (c 1.88, CH Cl ).
R
1
2
2
À1
flow rate 1.0 mLmin , detection at 254 nm]: minor enantio-
H NMR (400 MHz, CDCl ): d=8.33 (s, 1H, ArH), 8.22 (d,
3
mer t =10.2 min, major enantiomer t =7.7 min, 99% ee;
J=7.2 Hz, 1H, ArH), 7.79 (d, J=7.6 Hz, 1H, ArH), 7.60 (t,
J=8.0 Hz, 2H, ArH), 7.55 (d, J=1.2 Hz, 1H, ArH), 7.44 (d,
J=8.8 Hz, 1H, ArH), 7.26 (d, J =2.6 Hz, J =8.6 Hz, 1H,
R
R
2
5
1
[
a] : +63.4 (c 2.72, CH Cl ). H NMR (400 MHz, CDCl ):
D
2
2
3
d=7.55–7.41 (m, 7H, ArH), 7.27 (d, J=6.4 Hz, 1H, ArH),
.80 (br s, 1H, NH), 5.70 (t, J=5.0 Hz, 1H, CH), 5.10 (dd,
J =13.0 Hz, J =6.2 Hz, 1H, CH ), 4.88 (dd, J =12.8 Hz,
1
2
5
ArH), 6.33 (br s, 1H, NH), 5.90 (t, J=5.6 Hz, 1H, CH), 5.13
(dd, J =13.8 Hz, J =6.6 Hz, 1H, CH ), 4.96 (dd, J =
1
2
2
1
1
2
2
1
1
3
13
J =5.6 Hz, 1H, CH ); C NMR (100 MHz, DMSO-d ): d=
2
13.4 Hz, J2 =5.4 Hz, 1H, CH );
C NMR (100 MHz,
2
6
2
1
1
1
1
3
65.6, 150.7, 137.4, 132.0, 128.6, 128.1, 126.9, 125.7, 125.2,
20.7, 119.4, 78.3, 55.5; IR (KBr): n=3375, 3062, 2977, 1597,
558, 1535, 1494, 1446, 1377, 1342, 1307, 1270, 1205, 1096,
CDCl ): d=164.7, 150.0, 148.6, 138.5, 132.9, 132.0, 130.4,
3
128.0, 126.7, 123.9, 121.6, 120.6, 120.4, 77.8, 55.5; IR (KBr):
n=3369, 3088, 2924, 1705, 1597, 1560, 1531, 1447, 1402,
1377, 1350, 1270, 1204, 1097, 1052, 904, 858, 816, 733,
À1
052, 967, 919, 816, 765, 700 cm ; HR-MS (ESI): m/z=
+
À1
34.04135, calcd. for C H Cl N O S [M+H] : 334.04115.
687 cm ; HR-MS (ESI): m/z=379.02622, calcd. for
1
5
13
3
2
+
(
6-Methylbenzothiazol-2-yl)-[2-nitro-1-(3-nitrophenyl)eth-
C H ClN O S [M+H] : 379.02623.
1
5
12
3
2
yl]amine (3o): Compound 3o was obtained according to the
general procedure as a yellow solid; yield: 70 mg (98%); mp
[1-(2-Methoxyphenyl)-2-nitroethyl]-(6-methylbenzothia-
zol-2-yl)amine (3r): Compound 3r was obtained according
to the general procedure as a white solid; yield: 66.5 mg
(97%); mp 45–478C. The enantiomeric excess was deter-
mined by HPLC [Daicel Chiralpak IB column (n-hexane-2-
131–1338C. The enantiomeric excess was determined by
HPLC [Daicel Chiralpak IA column (n-hexane-2-propanol
À1
8
0:20), flow rate 1.0 mLmin , detection at 254 nm]: minor
À1
enantiomer t =12.4 min, major enantiomer t =15.3 min,
propanol 70:30), flow rate 0.8 mLmin , detection at
R
R
2
D
5
1
9
9% ee; [a] : +48.4 (c 2.58, CH Cl ). H NMR (400 MHz,
254 nm]: minor enantiomer t =17.7 min, major enantiomer
2
2
R
2
5
CDCl ): d=8.33 (s, 1H, ArH), 8.21 (d, J=8.0 Hz, 1H,
t =13.6 min, 99% ee; [a] : +100.0 (c 0.68, CH Cl ).
3
R
D
2
2
1
ArH), 7.79 (d, J=7.6 Hz, 1H, ArH), 7.59 (t, J=8.0 Hz, 1H,
ArH), 7.44 (d, J=8.4 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.12
H NMR (400 MHz, CDCl ): d=7.45 (d, J=8.8 Hz, 1H,
3
ArH), 7.37–7.31 (m, 3H, ArH), 7.10 (d, J=8.0 Hz, 1H,
ArH), 6.95 (t, J=7.4 Hz, 2H, ArH), 6.26 (br s, 1H, NH),
5.77 (br s, 1H, CH), 5.03 (dd, J =12.4 Hz, J =7.2 Hz, 1H,
(
5
d, J=7.6 Hz, 1H, ArH), 6.09 (br s, 1H, NH), 5.89 (t, J=
.8 Hz, 1H, CH), 5.14 (dd, J =13.2 Hz, J =6.4 Hz, 1H,
1
2
1
2
CH ), 4.95 (dd, J =13.4 Hz, J =5.0 Hz, 1H, CH ), 2.39 (s,
CH ), 4.86 (dd, J =12.4 Hz, J =6.4 Hz, 1H, CH ), 3.94 (s,
3H, OCH ), 2.38 (s, 3H, CH ); C NMR (100 MHz,
3 3
2
1
2
2
2 1 2 2
13
13
3
1
1
1
H, CH ); C NMR (100 MHz, CDCl ): d=164.1, 149.2,
3
3
48.6, 138.7, 132.9, 132.6, 130.8, 130.3, 127.4, 123.8, 121.6,
21.0, 119.2, 77.9, 55.7, 21.2; IR (KBr): n=3374, 3201, 2922,
793, 1607, 1556, 1528, 1467, 1378, 1350, 1308, 1278, 1238,
CDCl ): d=165.0, 156.9, 149.8, 131.9, 130.7, 130.2, 129.3,
3
127.1, 123.6, 121.2, 120.8, 119.0, 111.1, 77.3, 55.5, 55.4, 21.2;
IR (KBr): n=3374, 3070, 2964, 2942,. 2836, 1604, 1550, 1541,
Adv. Synth. Catal. 2013, 355, 1137 – 1148
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1145

Hai-Xiao He et al.
FULL PAPERS
1
1
496, 1471, 1439, 1388, 1344, 1285, 1242, 1224, 1189, 1119,
056, 1030, 1015, 857, 829, 817, 768, 758, 737, 636, 627 cm ;
alpak OJ-H column (n-hexane-2-propanol 85:15), flow rate
À1
À1
1.0 mL·min , detection at 254 nm]: minor enantiomer t =
R
25
HR-MS (ESI): m/z=344.10657, calcd. for C H N O
S
13.6 min, major enantiomer t =11.4 min, 31% ee; [a] :
1
7
18
3
3
R
D
+
1
[M+H] : 344.10634.
+10.7 (c 1.5, CH
Cl
2
2
). H NMR (400 MHz, CDCl
3
): d=
(
6-Methoxybenzothiazol-2-yl)-[1-(2-methoxyphenyl)-2-ni-
7.40–7.27 (m, 5H), 5.38 (br s, 2H, CH+NH), 4.85 (br s, 1H,
CH), 4.70 (d, J=9.2, 1H, CH), 1.44 (s, 9H, CH ).
Benzothiazol-2-yl-(2-nitro-1-phenylpropyl)amine
troethyl]amine (3s): Compound 3s was obtained according
to the general procedure as a white solid; yield: 64.7 mg
3
(6):
(
90%); mp 50–528C. The enantiomeric excess was deter-
Compound 5 was obtained according to the general proce-
dure as a white solid; yield: 60.2 mg (96%); mp 55–578C.
The enantiomeric excess was determined by HPLC [Daicel
Chiralpak IA column (n-hexane-2-propanol 80:20), flow
mined by HPLC [Daicel Chiralpak IB column (n-hexane-2-
propanol 70:30 v/v), flow rate 0.8 mLmin , detection at
2
À1
54 nm]: minor enantiomer t =13.9 min, major enantiomer
R
2
D
5
À1
t =11.1 min, 99% ee; [a] : +133.1 (c 2.88, CH Cl ).
rate 1.0 mLmin , detection at 254 nm]: diastereomer A:
R
2
2
1
H NMR (400 MHz, CDCl ): d=7.46 (d, J=9.2 Hz, 1H,
t
minor =8.2 min, tmajor =11.1 min, 99% ee; diastereomer B:
3
25
tminor =13.7 min, t
CH Cl ). H NMR (400 MHz, CDCl ): d=7.56–7.50 (m, 2H,
=18.5 min, 99% ee; [a] : +36.9 (c 2.0,
D
ArH), 7.36–7.30 (m, 2H, ArH), 7.10 (d, J=2.4 Hz, 1H,
ArH), 6.97–6.92 (m, 2H, ArH), 6.89 (dd, J =2.6 Hz, J =
major
1
2
2
3
1
2
ArH), 7.34–7.25 (m, 6H, ArH), 7.12–7.06 (m, 1H, ArH),
8
5
1
3
1
1
1
1
.8 Hz, 1H, ArH), 6.32 (br s, 1H, NH), 5.77 (br s, 1H, CH),
6
1
.06 (br s, 1H, NH), 5.42–5.35 (m, 1H, CH), 5.14–5.07 (m,
.01 (dd, J =12.6 Hz, J =7.0 Hz, 1H, CH ), 4.85 (dd, J =
1
2
2
1
13
H, CH), 1.62–1.55 (m, 3H, CH ); C NMR (100 MHz,
2.6 Hz, J =6.2 Hz, 1H, CH ), 3.92 (s, 3H, OCH ) 3.80 (s,
3
2
2
3
13
CDCl ): d=166.3, 151.4, 136.3, 135.6, 129.1, 129.0, 128.9,
H, OCH ); C NMR (100 MHz, CDCl ): d=164.1, 156.8,
3
3
3
1
8
3
28.8, 127.0, 126.9, 126.0, 122.2, 122.1, 120.8, 119.2, 86.7,
5.3, 62.0, 61.8, 17.1, 15.2; IR (KBr): n=3369, 3195, 3062,
031, 2991, 2940, 2903, 1702, 1599, 1535, 1495, 1444, 1389,
55.4, 146.0, 131.6, 130.2, 129.1, 123.6, 121.1, 119.7, 113.6,
11.0, 105.2, 77.2, 55.8, 55.4, 55.3; IR (KBr): n=3310, 2921,
613, 1557, 1533, 1489, 1462, 1376, 1338, 1276, 1245, 1219,
À1
1358, 1310, 1287, 1262, 1247, 1204, 1157, 1069, 1028, 1017,
163, 1123, 1048, 1023, 907, 869, 816, 789, 753, 730 cm ;
À1
9
31, 883, 753, 725, 700 cm ; HR-MS (ESI): m/z=314.09570,
HR-MS (ESI): m/z=360.10126, calcd. for C H N O S [M+
H] : 360.10125.
1
7
18
3
4
+
+
calcd. for C H N O S [M+H] : 314.09577.
16 16 3 2
Benzothiazol-2-yl-(2-nitro-1-phenylbutyl)amine (7): Com-
pound 7 was obtained according to the general procedure as
a white solid; yield: 60.1 mg (92%); mp 60–628C. The enan-
tiomeric excess was determined by HPLC [Daicel Chiralpak
(
6-Chlorobenzothiazol-2-yl)-[1-(2-methoxyphenyl)-2-ni-
troethyl]amine (3t): Compound 3t was obtained according
to the general procedure as a white solid; yield: 66.9 mg
(
mined by HPLC [Daicel Chiralpak IB column (n-hexane-2-
propanol 70:30 v/v), flow rate 1.0 mLmin , detection at
2
92%); mp 59–628C. The enantiomeric excess was deter-
IA column (n-hexane-2-propanol 80:20), flow rate
À1
À1
1.0 mLmin , detection at 254 nm]: diastereomer C: t
=
minor
7
.3 min, tmajor =11.4 min, 99% ee; diastereomer D, t =
R
25
54 nm]: minor enantiomer t =15.9 min, major enantiomer
R
2
D
5
18.5 min, enantiomers cannot be separated; [a] : +26.3 (c
3.0, CH Cl ). H NMR (400 MHz, CDCl ): d=7.57–7.50 (m,
t =11.3 min, 99% ee; [a] : +161.8 (c 0.56, CH Cl ).
D
R
2
2
1
1
2
2
3
H NMR (400 MHz, CDCl ): d=7.54 (s, 1H, ArH), 7.46 (d,
3
2
H, ArH), 7.32–7.25 (m, 6H, ArH), 7.13–7.06 (m, 1H,
J=8.0 Hz, 2H, ArH),7.34 (t, J=7.4 Hz, 2H, ArH), 7.25 (d,
J=7.2 Hz, 1H, ArH), 6.96 (t, J=8.4 Hz, 2H, ArH), 5.79 (t,
J=6.4 Hz, 1H, CH), 5.02 (dd, J =12.6 Hz, J =7.4 Hz, 1H,
ArH), 6.44 (br s, 1H, NH), 5.40–5.31 (m, 1H, CH), 4.95–
4
1
.83 (m, 1H, CH), 2.17–1.99 (m, 2H, CH), 1.78–1.75 (m,
1
2
13
H, CH), 0.98–0.95 (m, 3H, CH ); C NMR (100 MHz,
3
CH ), 4.85 (dd, J =12.4 Hz, J =5.6 Hz, 1H, CH ), 3.94 (s,
2
1
2
2
13
CDCl
3
): d=166.3, 151.5, 136.6, 135.9, 130.4, 129.1, 129.0,
28.7, 127.0, 126.7, 126.1, 126.0, 122.2, 122.1, 120.9, 120.8,
19.2, 119.1, 93.7, 92.6, 61.4, 60.9, 24.9, 23.7, 10.3; IR (KBr):
3
1
1
2
1
H, OCH ); C NMR (100 MHz, CDCl ): d=165.7, 156.9,
3
3
1
1
50.6, 131.9, 130.4, 129.3, 127.3, 126.5, 123.3, 121.3, 120.5,
20.2, 111.2, 77.2, 55.6, 55.4; IR (KBr): n=3357, 3069, 2938,
840, 1717, 1596, 1550, 1534, 1489, 1447, 1419, 1376, 1336,
n=3366, 3211, 3026, 2975, 2937, 2879, 1701, 1598, 1552,
À1
1535, 1496, 1455, 1372, 1310, 1285, 1246, 1202, 1126, 1081,
306, 1250, 1216, 1119, 1021, 917, 859, 812, 798, 752 cm ;
À1
1
070, 1018, 930, 909, 884, 806, 754, 725, 698 cm ; HR-MS
HR-MS (ESI): m/z=364.05189, calcd. for C H ClN O S
1
6
15
3
3
+
+
(ESI): m/z=328.11128, calcd. for C17
H N O S [M+H] :
18 3 2
[M+H] : 364.05172.
3
28.11142.
4
-Methyl-N-(2-nitro-1-phenylethyl)benzenesulfonamide
[22]
(
5a): Compound 5a was obtained according to the general
procedure as a white solid; yield: 52.1 mg (80%); mp 154–
Synthesis of Benzolthiazol-2-yl-(1-phenyl-2-piperidin-
-ylethyl)-amine (11)
1568C. The enantiomeric excess was determined by HPLC
1
[
Daicel Chiralpak IB column (n-hexane-2-propanol 70:30),
À1
flow rate 1.0 mL·min , detection at 254 nm]: minor enantio-
To a solution of the adduct 3a (299 mg, 1 mmol, 99% ee) in
MeOH (25 mL) was added 10 wt% Pd-C (106 mg,
10 mol%). The mixture was placed under an atmosphere of
mer t =9.8 min, major enantiomer t =10.8 min, 15% ee;
R
R
2
D
5
1
[
a] : +12.3 (c 0.65, CH Cl ). H NMR (400 MHz, CDCl ):
2
2
3
d=7.64 (d, J=8.4 Hz, 2H, ArH), 7.26–7.21 (m, 5H, ArH),
.10–7.07 (m, 2H, ArH), 5.65 (d, J=7.6 Hz, 1H, NH), 5.00
dd, J =13.6 Hz, J =6.8 Hz , 1H, CH ), 4.82 (dd, J =
H in a rubber balloon and stirred for 12 h at room tempera-
2
7
(
ture. After filtration, the solvent was concentrated and the
residue was separated by silica gel column chromatography
with methanol-dichloromethane (1:10) as eluent, and the
product 10 was obtained as yellow liquid; yield: 200.2 mg
(74%).
1
2
2
1
1
6
3.2 Hz, J =6.8 Hz , 1H, CH ) , 4.66 (dd, J =13.2 Hz, J =
2 2 1 2
.4 Hz , 1H, CH ), 2.40 (s, 3H, CH ).
2
3
[
6j]
tert-Butyl 2-nitro-1-phenylethyl carbamate (5b): Com-
pound 5b was obtained according to the general procedure
as a white solid; yield: 47.8 mg (90%); mp 108–1108C. The
enantiomeric excess was determined by HPLC [Daicel Chir-
Glutaraldehyde (50 wt% in H O, 0.1 mL) was added drop-
wise into a mixture of 10 (80.7 mg, 0.3 mmol) and NaBH-
2
AHCTUNGTRNNEU(G OAc) (424 mg, 2 mmol) in ClCH CH Cl (3 mL) at room
3
2
2
1146
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 1137 – 1148

Enantioselective Aza-Henry Reaction of Imines Bearing a Benzothiazole Moiety
temperature. The resulting mixture was stirred at room tem-
perature for 13 h, and quenched with aqueous NaOH solu-
tion (10%, 5 mL). The organic layer was separated and the
aqueous layer was extracted with CH Cl (3 ꢃ10 mL). The
[2] a) R. Ballini, M. Petrini, Tetrahedron 2004, 60, 1017;
b) A. S. Kende, J. S. Mendoza, Tetrahedron Lett. 1991,
32, 1699; c) M. A. Sturgess, D. J. Yarberry, Tetrahedron
Lett. 1993, 34, 4743.
2
2
combined organic layers were concentrated. The residue
was dissolved in CH Cl (20 mL), washed with brine
[3] a) K. Yamada, S. J. Harwood, H. Groger, M. Shibasaki,
Angew. Chem. 1999, 111, 3713; Angew. Chem. Int. Ed.
1999, 38, 3504; b) K. Yamada, G. Moll, M. Shibasaki,
Synlett 2001, 980; c) N. Tsuritani, K. Yamada, N. Yoshi-
kawa, M. Shibasaki, Chem. Lett. 2002, 276; d) L. Yin,
M. Kanai, M. Shibasaki, Tetrahedron 2012, 68, 3497;
e) S. L. Shi, M. Kanai, M. Shibasaki, Angew. Chem.
2012, 124, 3998; Angew. Chem. Int. Ed. 2012, 51, 3932.
[4] a) N. Nishiwaki, K. R. Knudsen, K. V. Gothelf, K. A.
Jørgensen, Angew. Chem. 2001, 113, 3080; Angew.
Chem. Int. Ed. 2001, 40, 2992; b) K. R. Knudsen, T.
Risgaard, N. Nishiwaki, K. V. Gothelf, K. A. Jørgensen,
J. Am. Chem. Soc. 2001, 123, 5843.
2
2
(
10 mL), and dried over anhydrous Na SO . Then, the solu-
2 4
tion was filtered and concentrated, the residue was separat-
ed by silica gel column chromatography with methanol-di-
chloromethane (1:40) as eluent, and the product 11 was ob-
tained as a yellow liquid; yield: 76.8 mg (76%). The enantio-
meric excess was determined by HPLC [Daicel Chiralpak
IA column (n-hexane-2-propanol 75:25 v/v), flow rate
À1
1
4
(
(
2
6
1
6
2
1
9
.0 mLmin , detection at 254 nm]: minor enantiomer t =
R
2
5
.8 min, major enantiomer t =8.0 min, 99% ee; [a] : +37
R
D
1
c 1.0, CH Cl ). H NMR (400 MHz, CDCl ): d=7.54–7.26
2
2
3
m, 7H, ArH), 7.02–6.99 (m, 2H, ArH) 4.57 (s, 1H, CH),
.59–2.55 (m, 4H, CH ), 2.33 (s, 2H, CH ), 1.60–1.45 (m,
2
2
[5] B. M. Trost, D. W. Lupton, Org. Lett. 2007, 9, 2023.
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H, CH ); C NMR (100 MHz, CDCl ): d=167.8, 151.8,
2
3
40.2, 131.1, 128.7, 127.8, 126.9, 125.7, 121.3, 120.6, 118.9,
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À1
+
(
2
0
24
3
338.16854.
General Procedure for the One-Pot Asymmetric Aza-
Henry Reaction
The mixture of 2-aminobenzothiazole 8 (0.2 mmol), aromat-
2
008, 350, 1785; i) B. Han, Q. P. Liu, R. Li, X. Tian,
X. F. Xiong, J. G. Deng, Y. C. Chen, Chem. Eur. J. 2008,
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ic aldehyde
9 (0.3 mmol), and catalyst III (6.3 mg,
0.01 mmol) in toluene (2 mL) was stirred for 5 min, then ni-
1
tromethane 2a (122 mg, 104 mL, 2.0 mmol) was added. After
stirring at 608C for 48 h, the reaction mixture was separated
directly by silica gel column chromatography to afford the
corresponding product with petroleum ether-ethyl acetate
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Acknowledgements
[
We are grateful for financial support from the National Natu-
ral Science Foundation of China (Grant Nos. 21072020 and
3
466; c) A. Singh, J. N. Johnston, J. Am. Chem. Soc.
21272024), the Science and Technology Innovation Program
2
008, 130, 5866.
of Beijing Institute of Technology (Grant No. 2011CX01008)
and the Development Program for Distinguished Young and
Middle-aged Teachers of Beijing Institute of Technology.
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Adv. Synth. Catal. 2013, 355, 1137 – 1148