Rapid and efficient synthesis of 2-substituted-tetrahydropyrido[3,4-b] quinoxalines using TDAE strategy

Article abstract of DOI:10.1016/j.tetlet.2012.02.119

We report herein an original and rapid synthesis of substituted 2-tosyl-1,2,3,4-tetrahydropyrido[3,4-b]quinoxaline derivatives by TDAE strategy from 2,3-bis(bromomethyl)quinoxaline and N-(toluenesulfonyl)benzylimines.

Full text of DOI:10.1016/j.tetlet.2012.02.119

Tetrahedron Letters 53 (2012) 2410–2413
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Tetrahedron Letters
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Rapid and efficient synthesis of 2-substituted-tetrahydropyrido[3,4-b]
quinoxalines using TDAE strategy
⇑
Omar Khoumeri, Marc Montana, Thierry Terme, Patrice Vanelle
Aix-Marseille Univ, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin,
13385 Marseille Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein an original and rapid synthesis of substituted 2-tosyl-1,2,3,4-tetrahydropyrido[3,4-
b]quinoxaline derivatives by TDAE strategy from 2,3-bis(bromomethyl)quinoxaline and N-
(toluenesulfonyl)benzylimines.
Received 30 January 2012
Revised 21 February 2012
Accepted 29 February 2012
Available online 7 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
TDAE
Quinoxaline
N-(Toluenesulfonyl)benzylimine
Pyrido[3,4-b]quinoxaline
The quinoxaline derivatives show very interesting biological
properties,1 such as antibacterial,1b antiviral,2 anticancer,3
antifungal, antihelmintic, antileishmanial,4 anti-HIV,4 insecticidal,
and anti-inflammatory activites,5 and their interest in medicinal
chemistry is far from coming to an end.6 Many drug candidates
bearing quinoxaline core structures are in clinical trials in antiviral,7
anticancer, antibacterial,1d and CNS (central nervous system)
therapeutic areas. Among them, the XK469 (( )-2-[4-(7-chloro-2-
quinoxaliny)oxy]phenoxy propionic acid) (Fig. 1) was known as anti
neoplastic quinoxaline topoisomerase II inhibitor and possesses
antitumor activity especially against murine and human solid
tumors.8–10
On the other hand, the tetra- and dihydropyrido[3,4-b]pyrazine
derivatives exhibited interesting biological activity as anticancer
agents.11 In spite of the great interest that could represent
combined structures presenting the quinoxaline and the tetrahy-
dropyridine nucleus, few synthesis of tetra-hydropyrido[3,4-b]
quinoxaline derivatives have been reported.12
N
N
O
COOH
CH3
XK469
Cl
O
Figure 1. Structure of XK469.
etones based on TDAE strategy from the reaction between 2-(tri-
chloromethyl)-quinoxaline and aromatic aldehydes.15
In continuation of our program directed toward the study of
single electron transfer reactions of bioreductive alkylating
agents16 and the preparation of new potentially bioactive com-
pounds as anticancer agents,17 we report herein an original and
efficient synthesis of new substituted 2-tosyl-1,2,3,4-tetrahydro-
pyrido[3,4-b]quinoxalines based on the TDAE strategy from the
reaction
sulfonimine.
between
2,3-bis(bromomethyl)quinoxaline
and
The reaction of 2,3-bis(bromomethyl)quinoxaline
1
with
3 equiv of sulfonimine 2a in the presence of TDAE at À20 °C for
1 h, led to the 2-tosyl-1,2,3,4-tetrahydropyrido[3,4-b]quinoxaline
3a. The reaction of 2,3-bis(bromomethyl)quinoxaline 1 with sul-
fonimine 2a was studied (Scheme 1) under various conditions (Ta-
ble 1). The best yield in product 3a (60%) is obtained using 1 equiv
of TDAE in THF at À20 °C for 1 h.
Since 2003, we have shown that from o- and p-nitrobenzyl chlo-
ride, tetrakis(dimethylamino)ethylene (TDAE)13 could generate a
nitrobenzyl carbanion which is able to react with various electro-
philes as aromatic aldehydes,
a-ketoester, ketomalonate, a-keto-
lactam and sulfonimine derivatives.14 In quinoxaline series, we
have reported the reaction of 2-(dibromomethyl)quinoxaline with
aromatic aldehydes in the presence of TDAE furnished a mixture of
We have generalized this reaction with other sulfonimines 2b–
k to prepare a new series of 2-tosyl-1,2,3,4-tetrahydropyrido[3,4-
b]quinoxalines 3b–k18 in moderate to good yields (56–67%) as
shown in Scheme 2 and reported in Table 2.
cis/trans isomers of oxiranes14 and the synthesis of new
a-chlorok-
⇑
Corresponding author. Tel.: +33 49183 5580.
E-mail addresses: patrice.vanelle@univ-amu.fr, patrice.vanelle@pharmacie.
The formation of these pyrido[3,4-b]quinoxaline derivatives
3a–k could be explained by two mechanisms, the first one would
univ-mrs.fr (P. Vanelle).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.02.119

O. Khoumeri et al. / Tetrahedron Letters 53 (2012) 2410–2413
2411
Table 2
Ts
N
N
N
N
Ts
N
TDAE
Reaction of 2,3-bis(bromomethyl)quinoxaline 1 with substituted N-(toluenesulfo-
Br
Br
N
+
nyl)benzylimine 2b–k using TDAE strategya
Sulfonimine
Product
Yieldb
(%)
1
2a
3a
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Scheme 1. Reaction of 2,3-bis(bromomethyl)quinoxaline 1 with N-(toluenesulfo-
nyl)benzylimine 2a.
Cl
N
N
N
N
N
N
N
N
N
Ts
Ts
1
2
3
4
5
6
7
8
3b
59
65
56
66
61
58
64
63
Br
N
Br
3c
3d
3e
3f
Table 1
Optimization of the reaction of 2,3-bis(bromomethyl)quinoxaline 1 with N-(toluene-
sulfonyl)benzylimine 2a using TDAE strategya
H3C
H3CO
N
CH3
OCH3
Ts
Entry
Solvent
Equiv of TDAE
Yieldb (%)
1
2
3
4
THF
THF
THF
DMF
1.05
1.05
1.5
46c
60
29
41
N
Ts
1.05
a
All the reactions are performed using 3 equiv of N-(toluenesulfonyl)benzyli-
mine 2a, 1 equiv of 2,3-bis(bromomethyl)quinoxaline 1 and 1 equiv of TDAE in
anhydrous THF stirred at À20 °C for 1 h.
N
Ts
b
CF3
All yields refer to chromatographically isolated pure products and are relative
F3C
F
to 2,3-bis(bromomethyl)quinoxaline 1.
c
The reaction mixture was stirred at À20 °C for 1 h and then warmed up to room
N
temperature for 0.5 h.
Ts
F
3g
3h
3i
N
Ts
Ts
N
N
N
N
Ts
N
Br
TDAE
THF
Br
Br
N
Br
+
X
X
N
1
Ts
2b-k
3b-k
OCH3
H3CO
Scheme 2. Reaction of 2,3-bis(bromomethyl)quinoxaline 1 with substituted N-
(toluenesulfonyl)benzylimine 2b–k.
N
Ts
9
3j
67
64
occur by a nucleophilic addition of carbanion formed by the action
of TDAE with 2,3-bis(bromomethyl)quinoxaline, on the imine
group of sulfonimine 2a–k followed by an intramolecular nucleo-
philic substitution with the second bromomethyl group. The sec-
ond pathway would envisage the formation of the biradical of
2,3-bis(bromomethyl)quinoxaline which reacts with imine as sug-
gested by Nishiyama in benzene series.19
CH3
H3C
N
N
N
Ts
N
Ts
10
3k
OCH3
H3CO
a
All the reactions are performed using 3 equiv of substituted N-(toluenesulfo-
In the absence of intermediates or by-products in this reaction
and in order to clarify this mechanism, we envisage the reaction
of 2,3-bis(bromomethyl)quinoxaline 1 with another kind of unsat-
urated compound such as benzaldehyde 4 under the optimal con-
ditions (Scheme 3).
nyl)benzylimines 2b–k, 1 equiv of 2,3-bis(bromomethyl)quinoxaline 1 and 1 equiv
of TDAE in anhydrous THF stirred at À20 °C for 1 h.
b
All yields refer to chromatographically isolated pure products and are relative
to 2,3-bis(bromomethyl)quinoxaline 1.
This reaction has not furnished the expected 3-phenyl-3,4-dihy-
dro-1H-pyrano[3,4-b]quinoxaline, but traces of 2-[3-(bromo-
methyl)quinoxalin-2-yl]-1-phenylethanol 5 have been identified.
The formation of this product may be explained by an ionic addition
of carbanion, formed by the action of TDAE with 2,3-bis(bromo-
methyl)quinoxaline, on the carbonyl group of benzaldehyde.
However, the alcoholate intermediate is not enough nucleophile
to cyclize by an intramolecular nucleophilic substitution explaining
the absence of the formation of 3-phenyl-3,4-dihydro-1H-pyr-
ano[3,4-b]quinoxaline.
Br
O
N
N
N
N
TDAE
THF
OH
Br
Br
H
+
1
4
5
Scheme 3. Reaction of 1 with benzaldehyde 4.
methyl)quinoxaline 1 and sulfonimines 2a–k. The anti-plasmodial
and cytotoxic activities of all synthesized compounds are under ac-
tive investigation.
These results with benzaldehyde would seem to confirm an
ionic pathway for the formation of these pyrido[3,4-b] quinoxaline
derivatives 3a–k.
Acknowledgments
In conclusion, we have developed in this work the synthesis of
new substituted pyrido[3,4-b]quinoxalines by an easy, original,
and mild procedure using TDAE methodology from 2,3-bis(bromo-
This work supported by the Centre National de la Recherche Sci-
entifique. We express our thanks to Vincent Remusat for 1H and
13C NMR spectra recording.

2412
O. Khoumeri et al. / Tetrahedron Letters 53 (2012) 2410–2413
Giraud, L.; Sabuco, J. F.; Vanelle, P.; Barreau, M. Tetrahedron Lett. 1991, 32,
References and notes
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18. General procedure for TDAE reaction of 1 with 2a–k. Into a two-necked flask
equipped with a drying tube (silica gel) and a nitrogen inlet was added 100 mL
of anhydrous THF solution of 2,3-bis(bromomethyl)quinoxaline (1) (0.3 g,
0.95 mmol) and corresponding N-(benzenesulfonyl)benzylimine 2a–k
(3 equiv). The solution was stirred and maintained at this temperature for
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30 min and then was added dropwise (via
1.42 mmol). The solution was vigorously stirred at À20 °C for 1 h. After this
time, TLC analysis (CH2Cl2) clearly showed that compound was totally
a syringe) the TDAE (0.28 g,
1
consumed. The solution was filtered (to remove the octamethyl-oxamidinium
dibromide). The filtrate was concentrated in vacuo, diluted with
dichloromethane, washed with H2O (3 Â 40 mL) and dried over MgSO4. After
evaporation, the crude product was purified by silica gel chromatography
(CH2Cl2) and recrystallized from isopropanol, gave corresponding 2-
substituted-tetrahydropyrido[3,4-b]quinoxaline derivatives (3a–k). New
products: 3a: white solid; mp 182 °C; 1H NMR (200 MHz, CDCl3) d 2.30 (s,
3H, CH3); 3.44 (dd, 1H, J = 17.5 Hz, J = 6.1 Hz, CH2); 3.63 (dd, 1H, J = 17.5 Hz,
J = 5.2 Hz, CH2); 4.31 (d, 1H, J = 18.4 Hz, CH2); 5.80 (d, 1H, J = 18.4 Hz, CH2);
5.75 (dd, 1H, J = 6.1 Hz, J = 5.2 Hz, CH); 7.14–7.35 (m, 7H, Ar); 7.72 (d, 4H,
J = 7.1 Hz, Ar); 7.92–8.00 (m, 2H, Ar). 13C NMR (50 MHz, CDCl3) d 21.4 (CH3);
34.7 (CH2); 46.0 (CH2); 54.3 (CH); 127.0 (2 Â CH); 127.1 (2 Â CH); 127.9 (CH);
128.5 CH); 128.6 (CH); 128.8 (2 Â CH); 129.7 (CH); 129.8 (2 Â CH); 129.9 (CH);
136.9 (C); 137.6 (C); 141.1 (C); 141.7 (C); 143.7 (C); 148.4 (C); 149.5 (C). Anal.
Calcd for C24H21N3O2S: C, 69.37; H, 5.09; N, 10.11; S, 7.72. Found: C, 69.31; H,
5.21; N, 10.18; S, 7.61. Compound 3b: white solid; mp 200 °C; 1H NMR
(200 MHz, CDCl3) d 2.18 (s, 3H, CH3); 3.34 (dd, 1H, J = 16.6 Hz, J = 5.3 Hz, CH2);
3.70 (dd, 1H, J = 16.6 Hz, J = 6.7 Hz, CH2); 4.68 (d, 1H, J = 17.1 Hz, CH2); 4.98 (d,
1H, J = 17.1 Hz, CH2); 5.87 (dd, 1H, J = 6.7 Hz, J = 5.3 Hz, CH); 7.06 (d, 3H,
J = 8.2 Hz, Ar); 7.10–7.22 (m, 2H, Ar); 7.31–7.40 (m, 1H, Ar); 7.63 (m, 2H, Ar);
7.70–7.75 (m, 2H, Ar); 7.93–8.02 (m, 2H, Ar). 13C NMR (50 MHz, CDCl3) d 21.2
(CH3); 36.6 (CH2); 48.3 (CH2); 53.9 (CH); 127.0 (CH); 127.6 (2 Â CH); 127.7
(CH); 128.6 (CH); 128.7 (CH); 129.1 (CH); 129.4 (2 Â CH); 129.8 (CH); 129.9
(CH); 130.2 (CH); 132.6 (C); 135.1 (C); 138.1 (C); 141.1 (C); 141.9 (C); 143.7
(C); 149.1 (C); 150.0 (C). Anal. Calcd for C24H20ClN3O2S: C, 64.06; H, 4.48; Cl,
7.88; N, 9.34; S, 7.13. Found: C, 63.85; H, 4.59; N, 9.33; S, 7.03. Compound 3c:
white solid; mp 201 °C; 1H NMR (200 MHz, CDCl3) d 2.15 (s, 3H, CH3); 3.30 (dd,
1H, J = 16.4 Hz, J = 5.7 Hz, CH2); 3.67 (dd, 1H, J = 16.4 Hz, J = 6.6 Hz, CH2); 4.74
(d, 1H, J = 16.9 Hz, CH2); 4.99 (d, 1H, J = 16.9 Hz, CH2); 5.70 (dd, 1H, J = 6.6 Hz,
J = 5.7 Hz, CH); 7.01 (d, 2H, J = 8.2 Hz, Ar); 7.05–7.07 (m, 3H, Ar); 7.52–7.56 (m,
1H, Ar); 7.62 (d, 2H, J = 8.2 Hz, Ar); 7.68–7.76 (m, 2H, Ar); 7.91–8.01 (m, 2H,
Ar). 13C NMR (50 MHz, CDCl3) d 21.2 (CH3); 37.0 (CH2); 48.6 (CH2); 56.3 (CH);
122.4 (C); 127.5 (2 Â CH); 127.6 (CH); 127.7 (CH); 128.6 (CH); 128.7 (CH);
129.2 (CH); 129.3 (2 Â CH); 129.7 (CH); 129.8 (CH); 133.3 (CH); 134.8 (C);
140.0 (C); 141.1 (C); 141.9 (C); 143.7 (C); 149.1 (C); 149.9 (C). Anal. Calcd for
C
24H20BrN3O2S: C, 58.30; H, 4.08; N, 8.50; S, 6.49. Found: C, 58.11; H, 4.07; N,
8.41; S, 6.25. Compound 3d: white solid; mp 186 °C; 1H NMR (200 MHz, CDCl3)
d 2.17 (s, 3H, CH3); 2.60 (s, 3H, CH3); 3.41 (dd, 1H, J = 18.0 Hz, J = 2.6 Hz, CH2);
3.59 (dd, 1H, J = 18.0 Hz, J = 6.9 Hz, CH2); 4.28 (d, 1H, J = 18.3 Hz, CH2); 4.94 (d,
1H, J = 18.3 Hz, CH2); 5.85 (dd, 1H, J = 6.9 Hz, J = 2.6 Hz, CH); 6.76–6.94 (m, 2H,
Ar); 7.00 (d, 2H, J = 8.2 Hz, Ar); 7.11–7.24 (m, 2H, Ar); 7.62 (d, 2H, J = 8.2 Hz,
Ar); 7.71–7.76 (m, 2H, Ar); 7.93–8.01 (m, 2H, Ar). 13C NMR (50 MHz, CDCl3) d
19.6 (CH3); 21.2 (CH3); 34.7 (CH2); 46.7 (CH2); 52.6 (CH); 125.9 (CH); 126.2
(CH); 127.5 (2 Â CH); 128.3 (CH); 128.4 (CH); 128.6 (CH); 129.4 (2 Â CH);
129.7 (CH); 129.8 (CH); 131.4 (CH); 136.0 (C); 136.6 (C); 137.3 (C); 141.1 (C);
141.7 (C); 143.8 (C); 148.9 (C); 150.2 (C). Anal. Calcd for C25H23N3O2S: C, 69.91;
H, 5.40; N, 9.78; S, 7.47. Found: C, 69.56; H, 5.49; N, 9.78; S, 7.33. Compound
3e: white solid; mp 184 °C; 1H NMR (200 MHz, CDCl3) d 2.19 (s, 3H, CH3); 3.39
(dd, 1H, J = 16.4 Hz, J = 4.8 Hz, CH2); 3.67 (dd, 1H, J = 16.4 Hz, J = 6.9 Hz, CH2);
3.77 (s, 3H, OCH3); 4.64 (d, 1H, J = 17.3 Hz, CH2); 5.03 (d, 1H, J = 17.3 Hz, CH2);
5.86 (dd, 1H, J = 6.9 Hz, J = 4.8 Hz, CH); 6.70–6.86 (m, 2H, Ar); 7.02 (d, 2H,
J = 8.2 Hz, Ar); 7.16–7.27 (m, 2H, Ar); 7.59 (d, 2H, J = 8.2 Hz, Ar); 7.68–7.75 (m,
2H, Ar); 7.93–8.00 (m, 2H, Ar). 13C NMR (50 MHz, CDCl3) d 21.2 (CH3); 36.5
(CH2); 47.7 (CH2); 52.1 (CH); 55.1 (OCH3); 110.7 (CH); 120.4 (CH); 127.2
(2 Â CH); 127.6 (CH); 128.1 (C); 128.5 (CH); 128.7 (CH); 129.1 (CH); 129.2
(2 Â CH); 129.5 (CH); 129.6 (CH); 136.2 (C); 140.9 (C); 141.7 (C); 143.2 (C);
149.4 (C); 151.0 (C); 156.4 (C). Anal. Calcd for C25H23N3O3S: C, 67.40; H, 5.20;
N, 9.43; S, 7.20. Found: C, 66.86; H, 5.24; N, 9.37; S, 7.02. Compound 3f: white
solid; mp 136 °C; 1H NMR (200 MHz, CDCl3) d 2.30 (s, 3H, CH3); 3.51 (dd, 1H,
J = 17.4 Hz, J = 5.6 Hz, CH2); 3.61 (dd, 1H, J = 17.4 Hz, J = 3.3 Hz, CH2); 4.35 (d,
1H, J = 18.2 Hz, CH2); 5.15 (d, 1H, J = 18.2 Hz, CH2); 5.74 (dd, 1H, J = 5.6 Hz,
J = 3.3 Hz, CH); 7.17 (d, 2H, J = 7.9 Hz, Ar); 7.33–7.48 (m, 4H, Ar); 7.68–7.75 (m,
4H, Ar); 7.93–8.00 (m, 2H, Ar). 13C NMR (50 MHz, CDCl3) d 21.4 (CH3); 35.3
(CH2); 46.3 (CH2); 54.4 (CH); 123.6 (q, J = 272.6 Hz, CF3); 124.0 (q, J = 4.0 Hz,
CH); 124.9 (q, J = 3.6 Hz, CH); 127.0 (2 Â CH); 128.6 (CH); 128.7 (CH); 129.4
(CH); 129.9 (2 Â CH); 130.0 (CH); 130.1 (CH); 131.0 (CH); 131.6 (q, J = 3.6 Hz,
C); 136.5 (C); 139.2 (C); 141.3 (C); 141.8 (C); 144.1 (C); 148.0 (C); 148.9 (C).
Anal. Calcd for C25H20F3N3O2S: C, 62.10; H, 4.17; N, 8.69; S, 6.63. Found: C,
61.87; H, 4.36; N, 8.62; S, 6.42. Compound 3g: white solid; mp 184 °C; 1H NMR
(200 MHz, CDCl3) d 2.30 (s, 3H, CH3); 3.44 (dd, 1H, J = 17.6 Hz, J = 5.8 Hz, CH2);
3.57 (dd, 1H, J = 17.6 Hz, J = 2.6 Hz, H2); 4.35 (d, 1H, J = 18.3 Hz, CH2); 5.09 (d,
1H, J = 18.3 Hz, CH2); 5.71 (dd, 1H, J = 5.8 Hz, J = 2.6 Hz, CH); 6.80–7.04 (m, 3H,
Ar); 7.15–7.21 (m, 3H, Ar); 7.69–7.75 (m, 4H, Ar); 7.93–8.00 (m, 2H, Ar). 13C
NMR (50 MHz, CDCl3) d 21.3 (CH3); 34.9 (CH2); 46.1 (CH2); 54.1 (CH); 114.3 (d,
J = 22.3 Hz, CH); 114.9 (d, J = 20.8 Hz, CH); 122.6 (d, J = 2.9 Hz, CH); 127.0
(2 Â CH); 128.5 (CH); 128.6 (CH); 129.8 (3 Â CH); 129.9 (CH); 130.4 (d,
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O. Khoumeri et al. / Tetrahedron Letters 53 (2012) 2410–2413
2413
J = 8.0 Hz, CH); 136.6 (C); 140.5 (d, J = 6.6 Hz, C); 141.2 (C); 141.7 (C); 143.9 (C);
148.1 (C); 149.0 (C); 162.6 (d, J = 247.4 Hz, C). Anal. Calcd for C24H20FN3O2S: C,
66.50; H, 4.65; N, 9.69; S, 7.40. Found: C, 66.69; H, 4.79; N, 9.75; S, 7.36.
Compound 3h: white solid; mp 162 °C; 1H NMR (200 MHz, CDCl3) d 2.30 (s, 3H,
CH3); 3.43 (dd, 1H, J = 17.5 Hz, J = 6.1 Hz, CH2); 3.60 (dd, 1H, J = 17.5 Hz,
J = 2.9 Hz, CH2); 4.36 (d, 1H, J = 18.2 Hz, CH2); 5.12 (d, 1H, J = 18.2 Hz, CH2);
5.67 (dd, 1H, J = 6.1 Hz, J = 2.9 Hz, CH); 7.02–7.19 (m, 4H, Ar); 7.27–7.50 (m, 4H,
Ar); 7.68–7.77 (m, 2H, Ar); 7.93–8.00 (m, 2H, Ar). 13C NMR (50 MHz, CDCl3) d
21.4 (CH3); 35.0 (CH2); 46.2 (CH2); 54.1 (CH); 123.1 (C); 125.5 (CH); 127.0
(2 Â CH); 128.5 (CH); 128.7 (CH); 129.9 (3 Â CH); 130.0 (CH); 130.3 (CH);
130.4 (CH); 131.2 (CH); 136.6 (C); 140.3 (C); 141.2 (C); 141.7 (C); 144.0 (C);
148.1 (C); 149.0 (C). Anal. Calcd for C24H20BrN3O2S: C, 58.30; H, 4.08; N, 8.50; S,
6.49. Found: C, 58.29; H, 4.08; N, 8.50; S, 6.41. Compound 3i: white solid; mp
174 °C; 1H NMR (200 MHz, CDCl3) d 2.30 (s, 3H, CH3); 3.43 (dd, 1H, J = 17.7 Hz,
J = 6.4 Hz, CH2); 3.59 (dd, 1H, J = 17.7 Hz, J = 2.3 Hz, CH2); 3.67 (s, 3H, OCH3);
4.32 (d, 1H, J = 18.3 Hz, CH2); 5.07 (d, 1H, J = 18.3 Hz, CH2); 5.71 (dd, 1H,
J = 6.4 Hz, J = 2.3 Hz, CH); 6.70–6.78 (m, 3H, Ar); 7.07–7.18 (m, 3H, Ar); 7.68–
7.74 (m, 4H, Ar); 7.92–7.99 (m, 2H, Ar). 13C NMR (50 MHz, CDCl3) d 21.4 (CH3);
34.8 (CH2); 46.0 (CH2); 54.3 (CH); 55.1 (OCH3); 113.0 (CH); 113.4 (CH); 119.2
(CH); 126.4 (CH); 127.1 (2 Â CH); 128.5 (CH); 128.6 (CH); 129.7 (CH); 129.8
(3 Â CH); 136.9 (C); 139.3 (C); 141.1 (C); 141.6 (C); 143.7 (C); 148.4 (C); 149.5
(C); 159.9 (C). Anal. Calcd for C25H23N3O3S: C, 67.40; H, 5.20; N, 9.43; S, 7.20.
Found: C, 67.26; H, 5.27; N, 9.43; S, 7.14. Compound 3j: white solid; mp 158 °C;
1H NMR (200 MHz, CDCl3) d 2.24 (s, 3H, CH3); 2.30 (s, 3H, CH3); 3.42 (dd, 1H,
J = 17.7 Hz, J = 6.4 Hz, CH2); 3.61 (dd, 1H, J = 17.7 Hz, J = 2.0 Hz, CH2); 4.29 (d,
1H, J = 18.5 Hz, CH2); 5.06 (d, 1H, J = 18.5 Hz, CH2); 5.71 (dd, 1H, J = 6.4 Hz,
J = 2.0 Hz, CH); 6.99–7.18 (m, 6H, Ar); 7.69–7.74 (m, 4H, Ar); 7.92–7.98 (m, 2H,
Ar). 13C NMR (50 MHz, CDCl3) d 20.9 (CH3); 21.4 (CH3); 34.7 (CH2); 45.8 (CH2);
54.1 (CH); 127.0 (2 Â CH); 127.1 (2 Â CH); 128.4 (CH); 128.6 (CH); 129.4 (CH);
129.5 (2 Â CH); 129.7 (CH); 129.8 (2 Â CH); 134.5 (C); 137.0 (C); 137.7 (C);
141.1 (C); 141.6 (C); 143.7 (C); 148.5 (C); 149.7 (C). Anal. Calcd for
C25H23N3O2S: C, 69.91; H, 5.40; N, 9.78; S, 7.47. Found: C, 69.69; H, 5.49; N,
9.79; S, 7.25. Compound 3k: white solid; mp 160 °C; 1H NMR (200 MHz, CDCl3)
d 2.31 (s, 3H, CH3); 3.42 (dd, 1H, J = 17.7 Hz, J = 5.5 Hz, CH2); 3.59 (dd, 1H,
J = 17.7 Hz, J = 2.0 Hz, CH2); 3.71 (s, 3H, OCH3); 4.28 (d, 1H, J = 18.5 Hz, CH2);
5.06 (d, 1H, J = 18.5 Hz, CH2); 5.72 (dd, 1H, J = 6.5 Hz, J = 2.0 Hz, CH); 6.73 (d,
2H, J = 8.7 Hz, Ar); 7.13 (d, 2H, J = 8.4 Hz, Ar); 7.17 (d, 2H, J = 8.0 Hz, Ar); 7.70–
7.74 (m, 4H, Ar); 7.93–8.01 (m, 2H, Ar). 13C NMR (50 MHz, CDCl3) d 21.4 (CH3);
34.8 (CH2); 45.8 (CH2); 53.8 (CH); 55.2 (OCH3); 114.1 (2 Â CH); 127.0 (2 Â CH);
128.4 (CH); 128.5 (2 Â CH); 128.6 (CH); 129.4 (CH); 129.7 (CH); 129.8
(2 Â CH); 130.0 (C); 137.0 (C); 141.1 (C); 141.6 (C); 143.7 (C); 148.5 (C);
149.7 (C); 159.1 (C). Anal. Calcd for C25H23N3O3S: C, 67.40; H, 5.20; N, 9.43; S,
7.20. Found: C, 67.54; H, 5.30; N, 9.47; S, 7.13.
19. Nishiyama, Y.; Kawabata, H.; Kobayashi, A.; Nishino, T.; Sonoda, N. Tetrahedron
Lett. 2005, 46, 867–869.