Copper-catalyzed cascade syntheses of 2 H -benzo[ b ][1,4]thiazin-3(4 H)-ones and quinoxalin-2(1 H)-ones through capturing S and N atom respectively from AcSH and TsNH2

Article abstract of DOI:10.1021/jo101253a

A copper-catalyzed cascade method has been developed to synthesize the 2H-benzo[b][1,4]thiazin-3(4H)-ones from 2-halo-N-(2-halophenyl)-acetamides 1 and AcSH via the S_N2/deacetylation/coupling process, and to synthesize the quinoxalin-2(1H)-ones from 1 and TsNH₂ via the S _N2/coupling/desulfonation process. The target products were obtained with diversity at three positions on their scaffolds.

Full text of DOI:10.1021/jo101253a

pubs.acs.org/joc
3,4-dihydro-2H-1,4-benzoxazine, 1,4-benzodiazepin-3-one,
Copper-Catalyzed Cascade Syntheses of
2H-benzo[b][1,4]thiazin-3(4H)-ones and Quinoxalin-
2(1H)-ones through Capturing S and N Atom
Respectively from AcSH and TsNH2
etc.2 However, little report was found about the construction
of S-heterocycles via a one-pot copper-catalyzed S-arylation
process except for benzothiazole.3 The reason may be that
the thiols are prone to be oxidized dimerization or complexed
with metals, causing reduced catalytic efficiency. Therefore,
searching for a new sulfur reagent to apply it to the cascade
construction of S-heterocycles would be a research topic
worthy of study.
2H-Benzo[b][1,4]thiazin-3(4H)-one and quinoxalin-2(1H)-
one are important heterocycle scaffolds that display a wide
range of bioorganic and medicinal activities. For example,
2H-benzo[b][1,4]-thiazin-3(4H)-one derivatives act as anti-
microbial, anticancerous, immunostimulating, angiotensin
converting enzyme, aldose reductase inhibitors, and anti-
diabetic, antiarrhythmic inhibitors (Figure 1).4 Quinoxalin-
2(1H)-ones show antithrombotic, antitumor activity (Figure 1)
and are used as antimicrobial agents, kinases inhibitors,
benzodiazepine receptor agonist, etc.5
Dingben Chen,†,‡ Zhi-Jing Wang,† and Weiliang Bao*,†
†Department of Chemistry, Zhejiang University, Xi Xi
Campus, Hangzhou 310028, Zhejiang, People’s Republic of
China, and ‡College of Pharmaceutical and Chemical
Engineering, Taizhou University, Linhai 317000, Zhejiang,
People’s Republic of China
wlbao@css.zju.edu.cn
Received June 26, 2010
Some methods have been developed for the syntheses of
2H-benzo[b][1,4]thiazin-3(4H)-ones6 and quinoxalin-2(1H)-
ones.7 The classical synthesizing approaches of 2H-benzo[b]
[1,4]thiazin-3(4H)-ones are based on using 2-aminobenze-
nethiols or halonitrobenzenes as starting materials, which
are cyclized directly by reacting with acetyl halide, or sub-
stituted by thiol acetates and reduced to form a ring system.
Recently, Zuo and co-workers used 2-chlorobenzenthiols to
synthesize 2H-benzo[b][1,4]thiazin-3(4H)-ones via Smiles
A copper-catalyzed cascade method has been developed
to synthesize the 2H-benzo[b][1,4]thiazin-3(4H)-ones
from 2-halo-N-(2-halophenyl)-acetamides 1 and AcSH
via the SN2/deacetylation/coupling process, and to synthe-
size the quinoxalin-2(1H)-ones from 1 and TsNH2 via the
SN2/coupling/desulfonation process. The target products
were obtained with diversity at three positions on their
scaffolds.
(3) The examples for the synthesis of S-heterocycles via copper-catalyzed
one-pot strategies: (a) Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y.
Angew. Chem., Int. Ed. 2009, 48, 4222. (b) Muyyu, S.; Ghosh, H.; Sahoo,
S. K.; Patel, B. K. Org. Lett. 2009, 11, 4254. (c) Shen, G.; Lv, X.; Bao, W. Eur.
J. Org. Chem. 2009, 5897.
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Chem. 1986, 21, 455. (b) Gupta, R. R.; Dev, P. K.; Sharma, M. L.; Rajoria,
C. M.; Gupta, A.; Nyati, M. Anticancer Drugs 1993, 4, 589. (c) Todorov,
D. K.; Ilarionova, M. V.; Gupta, R. R.; Molna, J.; Motohashi, N. Hetero-
cycl. Commun. 1995, 1, 153. (d) Corona, L. D.; Signorelli, G.; Pinzetta, A.;
Coppi, G. Eur. J. Med. Chem. 1992, 27, 419. (e) Tawada, H.; Sugiyama, Y.;
Ikeda, H.; Yamamoto, Y.; Meguro, K. Chem. Pharm. Bull. 1990, 38, 1238.
(f) Matsui, T.; Nakamura, Y.; Ishikawa, H.; Matsuura, A.; Kobayashi, F.
Jpn. J. Pharmacol. 1994, 64, 115. (g) Fujita, M.; Ito, S.; Ota, A.; Kato, N.;
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(b) Lawrence, D. S.; Copper, J. E.; Smith, C. D. J. Med. Chem. 2001, 44, 594.
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D. B.; Im, H. K.; Im, W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander, P. F.;
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In the past few years, copper-mediated formation of aryl
C-N and C-S bonds via Ullmann-type coupling reaction
has drawn considerable attention for their efficiency and low
cost.1 Recently, the copper-catalyzed coupling has been
successfully applied to the assembly of various heterocyclic
compounds by one-pot strategies. Many Cu(I)-catalyzed
cascade methods involving N-arylation have been reported
for the synthesis of N-heterocycles, including pyrrole, indole,
benzimidazole, 1,3-dihydrobenzimidazol-2-one, isoquino-
line, isoquinolin-1(2H)-one, quininazoline, quinazolinone,
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5768 J. Org. Chem. 2010, 75, 5768–5771
Published on Web 07/28/2010
DOI: 10.1021/jo101253a
r
2010 American Chemical Society

Chen et al.
JOCNote
TABLE 1. Optimization of the Reaction Conditions for Synthesis
of 4-Benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one or 1-Benzylquinoxalin-
2(1H)-onea
entry
NuH
cat.
CuI
L
base
solvent yield (%)
FIGURE 1. Structures of some pharmaceutically important 2H-
benzo- [b][1,4]thiazin-3(4H)-one and quinoxalin-2(1H)-one deriva-
tives.
1
2
3
4
5
6
7
8
9
AcSH (2a)
AcSH
AcSH
AcSH
AcSH
TsNH2 (2b)
TsNH2
TsNH2
TsNH2
L1 Cs2CO3 dioxane
L1 K2CO3 dioxane
L1 Cs2CO3 toluene
L1 Cs2CO3 DMF
L1 Cs2CO3 dioxane
L1 Cs2CO3 dioxane
L2 Cs2CO3 dioxane
L3 Cs2CO3 dioxane
L4 Cs2CO3 dioxane
L1 Cs2CO3 dioxane
L1 Cs2CO3 dioxane
83
40
72
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
Cu2O
55
rearrangement. Quinoxalin-2(1H)-ones can be obtained
through condensing substituted o-phenylenediamine with
R-ketone acids, R-aldehyde acids, R-ketone acid esters,
or R-aldehyde acid esters. Although these methods for the
synthesis of the title heterocycles are feasible, they have two
common disadvantages: (i) The substituted group diversifi-
cation of products is limited, for example, it is difficult to
synthesize N-aryl substituted products. (ii) The substituted
products were obtained in low yields because of multistep
reaction or multiple byproduct. Therefore, it is highly desir-
able to search for more convenient and efficient approaches
for these two heterocycles.
AcSH and TsNH2 are the common nucleophilic reagents,
which are prone to SN2 reaction. Ac and Ts groups are also
the leaving groups. Therefore, they can provide S and imine
N atoms for building heterocycles. However, to the best of
our knowledge, there is no report about the formation of
N- or S-heterocycle via copper-catalyzed one-pot strategies
using this idea. As a part of our ongoing research in devel-
oping copper-catalyzed tandem reaction methods for the
syntheses of heterocycles,8 we were further interested in
developing new protocols for the syntheses of 2H-benzo[b]-
[1,4]thiazin-3(4H)-ones and quinoxalin-2(1H)-ones in one
pot. Herein, we report a Cu(I)-catalyzed domino strategy,
which employs 2-halo-N-(2-halophenyl)acetamides as pre-
cursors to react with AcSH to synthesize 2H-benzo[b]-
[1,4]thiazin-3(4H)-ones via the SN2/deacetylation/coupling
process, or to react with TsNH2 to synthesize quinoxalin-
2(1H)-ones via the SN2/coupling/desulfonation process. The
target products were obtained with diversity at three posi-
tions on their scaffold.
23b
89c
52c
73c
70c
83c
81c
62c
10 TsNH2
11 TsNH2
12 TsNH2
13 BocNH2 (2c)
14 PhCONH2 (2d) CuI
15 BnNH2 (2e) CuI
aReaction conditions: N-benzyl-2-chloro-N-(2-iodophenyl)acetamide
1a (0.5 mmol), 2a-e (0.6 mmol), copper source (0.05 mmol), ligand (0.1
mmol), and base (2.0 mmol) in solvent (2.0 mL) under N2 at 100 °C for 13 h.
b50 °C, 36 h. c18 h.
Cu(OAc)2 L1 Cs2CO3 dioxane
CuI
c
L1 Cs2CO3 dioxane
L1 Cs2CO3 dioxane
L1 Cs2CO3 dioxane
-
-
-
c
c
study the synthesis of 4-benzyl-2H-benzo[b][1,4]thiazin-
3(4H)-one 3a. Luckily, a satisfactory result was found, and
the yield of product 3a reached 83% (entry 1). Both base and
solvent were tested. The yield was decreased greatly as the
base K2CO3 was selected (entry 2). The other solvents,
toluene and DMF, were also inferior to dioxane. Subse-
quently, we investigated the optimum reaction condition for
the synthesis of 1-benzylquinoxalin-2(1H)-one 4a. Except
that the reaction time was extended to 18 h, the same reac-
tion condition also provides the highest yield of product 4a
(89%, entry 6). Despite the good result, three other ligands
(L2-L4), including N,N-dimethylglycine, DMEDA, and
ethyl 2-oxocyclohexanecarboxylate, were evaluated (entries
7-9), and 1,10-phenanthroline was proved to be the most
effective. Cu-catalysts were also examined (entries 10-12),
and the others (CuBr, Cu2O, Cu(OAc)2) were poorer than
CuI. Finally, the reactions between 1a and different NuH
reagents were investigated, but no target products were
observed (entries 13-15).
We then investigated the scope of copper-catalyzed cou-
pling of the substituted 2-halo-N-(2-halophenyl)acetamide
with AcSH for the synthesis of 2H-benzo[b][1,4]thiazin-
3(4H)-ones under the optimized conditions determined
above. As shown in Table 2, most of the substrates examined
provided good to excellent yields. For the variation of N-sub-
stituted group R2 in 2-chloro-N-(2-iodophenyl)acetamide, we
found allyl and methyl groups did not significantly affect the
yield of target products, compared with benzyl group (entries
1 and 2), but phenyl and H groups gave the corresponding
The reaction between N-benzyl-2-chloro-N-(2-iodophenyl)-
acetamide (1a) and AcSH (2a) or TsNH2 (2b) was investi-
gated to optimize the reaction conditions, including bases,
solvents, ligands, and catalysts. The results are summarized
in Table 1. Initially, according to our previously reported
experiment for the synthesis of 2H-1,4-benzoxazin-3-(4H)-
ones,8d we adopted the same reaction condition (10 mol %
CuI, 20 mol % 1,10- phenanthroline, Cs2CO3 in dioxane) to
(8) (a) Lv, X.; Liu, Y.; Qian, W.; Bao, W. Adv. Synth. Catal. 2008, 350,
2507. (b) Lv, X.; Bao, W. J. Org. Chem. 2009, 74, 5618. (c) Bao, W.; Liu, Y.;
Lv, X.; Qian, W. Org. Lett. 2008, 10, 3899. (d) Chen, D.; Shen, G.; Bao, W.
Org. Biomol. Chem. 2009, 7, 4067. (e) Chen, D.; Bao, W. Adv. Synth. Catal.
2010, 352, 955. (f) Shen, G.; Bao, W. Adv. Synth. Catal. 2010, 352, 981.
J. Org. Chem. Vol. 75, No. 16, 2010 5769

Chen et al.
JOCNote
TABLE 2. CuI-Catalyzed One-Pot Synthesis of 2H-Benzo[b][1,4]thiazin-
3(4H)-one from 2-Halo-N-(2-halophenyl)acetamide and AcSHa
TABLE 3. CuI-Catalyzed One-Pot Synthesis of Quinoxalin-2(1H)-ones
from 2-Halo- N-(2-halophenyl)acetamide and TsNH2
a
aReaction conditions: 2-halo-N-(2-halophenyl)acetamide 1 (0.5 mmol),
AcSH 2a (0.6 mmol), CuI (0.05 mmol), ligand (0.1 mmol), and Cs2CO3
(2.0 mmol) in dioxane (2.0 mL) under N2 at 100 °C for 13 h. bAt reflux.
aReaction conditions: 2-halo-N-(2-halophenyl)acetamide 1 (0.5 mmol),
TsNH2 2b(0.6 mmol), CuI (0.05 mmol), ligand (0.1 mmol), and Cs2CO3
(2.0 mmol) in dioxane (2.0 mL) under N2 at 100 °C for 18 h. bAt reflux
products in moderate yield (entries 3 and 4, 60% and 51%,
respectively). In the presence of R3 (Me, Et, i-Pr) groups, the
yields of 3f, 3g, and 3h were also excellent (entries 5-7). The
substrates with an electron-donating group on the phenyl ring
exhibited higher reactivity than the others with electron-with-
drawing groups (entries 8-10). In addition, N-benzyl-2-chloro-
N-(2-bromophenyl)acetamide 1l could react with AcSH to give
the product 3a in moderate yield.
The scope of the copper-catalyzed cascade synthesis of
quinoxalin-2(1H)-ones from substituted 2-halo-N-(2-halo-
phenyl)acetamide with TsNH2 was also investigated (Table 3,
entries 1-10). Most of the quinoxalin-2(1H)-ones could be
obtained in good yields under the optimized conditions (10 mol %
CuI, 20 mol % 1,10-phenanthroline, Cs2CO3 in dioxane,
100 °C, 18 h). Among the examination of the N-substituted
group of 2-chloro-N-(2-iodophenyl)acetamide, the N-allyl sub-
strate gave lower yield of product than the others (entries 1-3).
Comparing the yield of 4c with that of 4f and 4g, it was obvious
that the R3 group showed a little stereohindrance effect. The
electronic effect of the substituents on the aromatic rings of
2-halo-N-(2-halophenyl)acetamide was also investigated. The
presence of an electron-donating group provided better yield
5770 J. Org. Chem. Vol. 75, No. 16, 2010

Chen et al.
JOCNote
SCHEME 1. Proposed Reaction Pathways for the One-Pot
Syntheses of 2H-Benzo[b][1,4]thiazin-3(4H)-ones and
Quinoxalin-2(1H)-ones
to excellent yields of product. The method should be valuable for
the construction of these kinds of heterocycles with biological
and medicinal activities.
Experimental Section
General Experimental Procedures for the Cu(I)-Catalyzed
One-Pot Synthesis of 2H-Benzo[b][1,4]thiazin-3(4H)-ones or
Quinoxalin-2(1H)-ones. An oven-dried Schlenk tube equipped
with a Teflon valve was charged with a magnetic stir bar, CuI
(10 mg, 0.05 mmol, 10 mol %), Cs2CO3 (652 mg, 2.0 mmol),
1,10-phenanthroline (20 mg, 0.10 mmol, 20 mol %), and 2-halo-
N-(2-halophenyl)acetamide 1 (0.5 mmol). The tube was evac-
uated and backfilled with N2 (this procedure was repeated 3 times).
Under a counter flow of N2, AcSH (48 mg, 0.6 mmol) and dioxane
(2.0 mL) were added by syringe (TsNH2 was added before the tube
was capped), and the mixture was prestirred for about 15 min at
room temperature.Then the reaction was stirred at 100 °C. After the
reaction was completed, the mixture was directly passed through
Celite and rinsed with 30 mL of CH2Cl2. The combined filtrate was
concentrated and purified by column chromatography on silica gel
to give the pure product.
than the presence of electron-withdrawing groups (entries 7-9).
Additionally, 1-benzylquinoxanlin-2(1H)-one could be obtained
from the reaction of N-benzyl-2-chloro-N-(2-bromophenyl)-
acetamide 1l with TsNH2 in good yield (entry 10).
4-Benzyl-2H-benzo[b][1,4]thiazin-3(4H)-one(3a): yellow solid;10
mp 85-86 °C; IR (neat) vmax/cm-1 3065, 2918, 1660, 1579, 1476,
1377, 1145, 910, 749, 659 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.36-7.28 (m, 3H), 7.24-7.19 (m, 3H), 7.11-7.07 (m, 1H),
7.00-6.95 (m, 2H), 5.22 (s, 2H), 3.51 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 165.4, 139.7, 136.6, 128.7, 128.3, 127.2, 126.3,
123.7, 123.6, 118.2, 48.4, 31.5 ppm.
The possible formation pathways for 2H-benzo[b]-
[1,4]thiazin-3(4H)-ones and quinoxalin-2(1H)-ones are pro-
posed in Scheme 1 on the basis of the reported literature9 and
our previous reports for syntheses of 2H-1,4-benzoxazin-
3-(4H)-ones and quinoxalin-2(1H)-ones.8d,e First, the SN2reac-
tion happened between 2-halo-N-(2-halophenyl)acetamide 1
and AcSH or TsNH2, and the intermediates I or II would be
formed. Subsequently, 2H-benzo[b][1,4]-thiazin-3(4H)-ones
were achieved through the deacetylation and intramolecular
coupling process, while quinoxalin-2(1H)-ones were formed
through the intramolecular coupling and desulfonation process.
In summary, we have developed a domino method to
synthesize the 2H-benzo[b][1,4]thiazin-3(4H)-ones via the
SN2/deacetylation/coupling process, and to synthesize the
quinoxalin-2(1H)-ones via the SN2/coupling/desulfonation
process. The method could give the target products of diversi-
fying groups at three positions on their scaffold and obtain good
1-Benzylquinoxalin-2(1H)-one(4a): yellow solid;8e mp 120-
122 °C; IR (neat) vmax/cm-1 3061, 2979, 1649, 1596, 1448, 1365,
1072, 924, 756 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H),
7.88 (d, J = 8.0 Hz, 1H), 7.47-7.43 (m, 1H), 7.32-7.23 (m, 7H),
5.48 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 155.1, 150.2, 134.9,
133.6, 132.5, 131.0, 130.6, 128.9, 127.7, 126.8, 123.8, 114.6, 45.5 ppm.
Acknowledgment. This work was financially supported by
the Specialized Research Fund for the Doctoral Program of
Higher Education of China (20060335036)..
Supporting Information Available: Experimental proce-
dures along with copies of spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(9) Sarges, R.; Lyga, J. W. J. Heterocycl. Chem. 1988, 25, 1475.
(10) Prasad, R. N.; Tietje, K. Can. J. Chem. 1966, 44, 1247.
J. Org. Chem. Vol. 75, No. 16, 2010 5771