Access to functionalized 4-benzylidene-4H-benzo[d][1,3]thiazines via tandem addition-cyclization/cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2012.03.098

Tandem addition-cyclization reactions of various 2-alkynylbenzenamines with CS₂ lead to the formation of 2-mercapto-4-benzylidene-4H-benzo[d][1, 3]thiazines under mild conditions. The reactions showed moderate to excellent yields and were highl

Full text of DOI:10.1016/j.tet.2012.03.098

Tetrahedron 68 (2012) 3937e3941
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Access to functionalized 4-benzylidene-4H-benzo[d][1,3]thiazines via tandem
addition-cyclization/cross-coupling reactions
,
a
a
b
a
a
a,
*
Qiuping Ding a , Xianjin Liu , Jinsheng Yu , Qiulan Zhang , Dan Wang , Banpeng Cao , Yiyuan Peng
*
a Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang,
Jiangxi 330022, China
b State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Tandem addition-cyclization reactions of various 2-alkynylbenzenamines with CS2 lead to the formation
of 2-mercapto-4-benzylidene-4H-benzo[d][1,3]thiazines under mild conditions. The reactions showed
moderate to excellent yields and were highly regiospecific, and only the six-membered ring was gen-
erated via 6-exo-dig S-cyclization. The reaction can be transferred to highly functionalized
4-benzylidene-4H-benzo[d][1,3]thiazines via CuI-catalyzed crossing-coupling and reductive coupling
reactions.
Received 11 December 2011
Received in revised form 16 March 2012
Accepted 22 March 2012
Available online 29 March 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
2-Alkynylbenzenamine
Crossing-coupling reaction
Reductive coupling reaction
Benzo[d][1,3]thiazine
1. Introduction
have been developed.6,9 As part of a continuing effort in our labo-
ratory toward the development of novel natural product-like
2-Alkynylbenzenamines are usefulsyntheticintermediates as they
possess two reactive sites, a nucleophile (ꢀNH2) and a triple bond. It is
well-known that alkynes possessing a nucleophile in proximity to the
triple bond can construct diverse heterocycles via transition metal- or
Lewis acid-catalyzed intramolecular annulation in an efficient way.
Based on 2-alkynylbenzenamines, various heterocycles have been
reported for the construction of privileged molecular entries, such as
indole,1 quinoline,2 quinazolinone,3 benzoxazine,4 4H-benzo[d][1,3]
thiazin-2-amine,5 and 1H-benzo[d] [1,3]thiazine.6 Moreover, 2-
alkynylbenzenamine can be easily prepared by classical Pd/Cu-
catalyzed Sonogashira reaction using 2-iodoaniline and terminal al-
kyne as readily available starting materials. Therefore, as a useful
synthetic intermediate, 2-alkynylbenzenamine has attracted consid-
erable attention in the fields of organic and medicinal chemistry.
Heterocycles having a privileged scaffold are systems of great
interest due to their promising biological activity and the applica-
tions in synthetic materials.7 As a privileged fragment, 4H-benzo[d]
[1,3]thiazine core can be found in many biologically active mole-
cules.8 The synthesis of 4H-benzo[d][1,3]thiazine has been a major
area of focus for synthetic organic chemists, and several efficient
synthetic routes for the preparation of 4H-benzo[d][1,3]thiazine
compounds,10 we recently reported the practical routes for
the generation of 2,4-dihydro-1H-benzo[d][1,3]thiazines via silica
gel-promoted6a or AgOTf-catalyzed6b tandem addition-cyclization
reactions of 2-alkynylbenzenamines with isothiocyanates. Very
recently, we described the synthesis of 4-methylene-4H-benzo[d]
[1,3]thiazine via a tandem reaction of 1-(2-alkynylphenyl)ketoxime
with Lawesson’s reagent catalyzed by InCl3 and cyanuric chloride.11
Herein, we would like to report the synthesis of 2-mercapto-
4-benzylidene-4H-benzo[d][1,3]thiazines starting from 2-alkynyl-
benzenamines with CS2, and the further transformation to highly
functionalized 4-benzylidene-4H-benzo[d][1,3]thiazines.
2. Results and discussions
Initially, we used 2-alkynylbenzenamine 1a with carbon disul-
fide as the starting materials and AgOTf as catalyst, DBU as base in
DMSO at room temperature. However, only trace 4-benzylidene-
4H-benzo[d][1,3]thiazine 2a was observed, most starting material
1a was recovered (Table 1, entry 1). Z-Configuration of the product
2a was verified by X-ray diffraction analysis. Then different sol-
vents, such as DMF, CH3CN, and CH2Cl2 were also tried in the re-
action, and DMF was demonstrated to be the best choice and gave
the desired product 2a as a single stereoisomer, characterized by 1H
NMR, in 56% yield (Table 1, entries 2e4). Next, the bases were ex-
amined in the reaction. The results demonstrated that the organic
* Corresponding authors. Tel./fax: þ86 791 88120380; e-mail addresses:
dqpjxnu@gmail.com (Q. Ding), yiyuanpeng@yahoo.com (Y. Peng).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.098

3938
Q. Ding et al. / Tetrahedron 68 (2012) 3937e3941
R0 group attached on the triple bond was an aryl group with electron-
withdrawing groups (such as F), moderate yields were observed
(Table 2, entries 2 and 3). The reaction of 1b with CS2 was completed
within 24 h to afford the desired product 2b as a single stereoisomer
in 65% yield. However, good results were displayed, when it was
replaced by electron-donating groups (Table 2, entries 4 and 5). For
instance, reaction of carbon disulfide with 2-alkynylbenzenamine 1d
afforded the desired product 2d in 80% yield (Table 2, entry 2), and
86% yield of product 2e was obtained when 2-alkynylbenzenamine
1e was employed in the reaction. As expected, other 2-alkynyl-
benzenamines 1feo, with electron-rich or electron-poor substituent
(Me, F, Cl) on aromatic ring all showed good tolerance (Table 2,
entries 6e13). For example, reaction of 4-fluoro-substituted 2-
alkynylbenzenamine 1i with CS2 gave rise to the corresponding
product 2i in 73% yield (Table 2, entry 9). A 76% yield was obtained
when4-methyl-substituted2-alkynylbenzenamine 1jwas utilized as
substrate (Table 2, entry 11). When R0 was replaced by aliphatic
group, such as cyclopropyl group, the reactions gave the corre-
sponding products in moderate yields (Table 2, entries 14 and 15).
Table 1
Conditions screening for Ag-catalyzed tandem reaction of 2-alkynylbenzenamine 1a
with CS2
a
Entry
Catalyst
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOAc
Ag2CO3
AgNO3
DBU
DBU
DBU
DBU
DMSO
DMF
CH3CN
CH2Cl2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Trace
56
Trace
Trace
65
67
11
15
35
30
54
73
86
95
95
62
50
Et3N
DABCO
Cs2CO3
Na2CO3
NaHCO3
NaOH
t-BuOK
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
9
10
11
12
13
14
15
16
17
Table 2
AgNO3-catalyzed tandem reactions of 2-alkynylbenzenamines 1 with CS2
c
AgNO3
AgNO3
d
d
NH2
N
H
S
(
5 mol
%
), DMF
AgNO3
R
CS2
R
a
S
Reaction conditions: 2-alkynylbenzenamine 1a (0.3 mol), CS2 (10.0 equiv), [Ag]
DABCO, N2, rt
(10 mol %), base (1.2 equiv), solvent (1 mL) rt, 24 h.
R'
1
b
2
Isolated yield based on 2-alkynylbenzenamine 1a.
AgNO3 (5 mol %).
AgNO3 (2 mol %).
R'
c
d
Entry
R/1
R0
Product 2
Yield (%)a (Z/E)b
bases were more efficient than inorganic bases, for example, Et3N
and DABCO increased the yield of product 2a to 65% and 67%, re-
spectively (Table 1, entries 5 and 6); however, inorganic bases, such
as Cs2CO3, Na2CO3, NaHCO3, and NaOH, most of them dramatically
decreased the yield of the product 2a (Table 1, entries 7e10). Other
silver salts, such as AgOAc, Ag2CO3, and AgNO3 were also screened
in the reaction, which revealed that AgNO3 provided the best yield
and just a single stereoisomer (Table 1, entries 12e14). The same
result was observed when the catalytic amount of AgNO3 was re-
duced to 5 mol % (Table 1, entry 15). The investigation showed that
further decreasing the amount of AgNO3 (2 mol %) gave moderate
(62%) isolated yield (Table 1, entry 16). Blank experiment showed
that Lewis acid AgNO3 was necessary in the reaction in order to
obtain good yield (Table 1, entry 17).Fig. 1.
1
2
3
4
5
6
7
8
H/1a
H/1b
H/1c
H/1d
C6H5
4-FC6H4
3-FC6H4
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
95
65
42 (75/25)
80 (87/13)
86 (82/18)
54
55 (82/18)
51
73
58 (91/9)
76
4-C2H5C6H4
4-MeOC6H4
C6H5
4-MeOC6H4
C6H5
4-MeOC6H4
4-FC6H4
C6H5
H/1e
4-Cl/1f
4-Cl/1g
4-F/1h
4-F/1i
4-F/1j
4-CH3/1k
4-CH3/1l
4-CH3/1m
H/1n
9
10
11
12
13
14
15
4-FC6H4
52
4-MeOC6H4
Cyclopropyl
Cyclopropyl
52 (81/19)
40 (83/17)
41 (72/28)
4-F/1o
a
Reaction conditions: 2-alkynylbenzenamine 1 (0.3 mol), CS2 (10.0 equiv), AgNO3
(5 mol %), DABCO (1.2 equiv), DMF (1 mL), rt. Isolated yield based on
2-alkynylbenzenamine 1.
b
Characterized the ratio of the stereoisomer 2 by 1H NMR.
After the successful generation of 2-mercapto-4-benzylidene-
4H-benzo[d][1,3]thiazine 2, we considered to introduce more di-
versity into the 2-mercapto-4-benzylidene-4H-benzo[d][1,3]thia-
zine scaffold via CuI-catalyzed crossing-coupling reactions. Thus,
we explored the possibility of the CuI-catalyzed cross-coupling
reactions of 2a with aryl iodides 3 for the synthesis of highly
functionalized 4-benzylidene-4H-benzo[d][1,3]thiazines 4. The re-
actions were performed at 110 ꢁC catalyzed by CuI (20 mol %) in
DMF in the presence of Cs2CO3 as base (Scheme 1). The results
showed that all reactions proceeded smoothly to generate the de-
sired products 4 in moderate to good yields. The limititation of the
protocol is that selective coupling of thiol and olefin couldn’t be
realized under the conditions.
Fig. 1. X-ray ORTEP illustration of compound 2a.
To evaluate the generalityof thismethod, thescopeof the reaction
was investigated under optimized conditions [AgNO3 (5 mol %) as
a catalyst, DABCO as a base, DMF as solvent, at room temperature
under N2], and the results are summarized in Table 2. Most reactions
proceeded smoothly to give rise to the corresponding products 2 in
moderate to good yields. The reactions of carbon disulfide with
various substituted 2-alkynylbenzenamines 1 were examined. When
Recently, we reported a metal-free procedure for the synthesis
of thioethers via base-promoted reductive coupling of tosylhy-
drazones with thiols.12 Therefore, the similar reductive coupling of
tosylhydrazones with 2-mercapto-4-benzylidene-4H-benzo[d][1,3]
thiazine 2a were also examined (Scheme 2). Under the optimized
conditions, the reductive coupling reactions proceeded well to
generate the intriguing target products 6 in moderate yields.

Q. Ding et al. / Tetrahedron 68 (2012) 3937e3941
3939
Scheme 1. Synthesis of highly functionalized 4-benzylidene-4H-benzo[d][1,3]thiazine 4 via CuI-catalyzed cross-coupling reactions.
Scheme 2. Metal-free reductive coupling between 4-benzylidene-4H-benzo[d][1,3]thiazine-2-thiol 2a and tosylhydrazones 5.
In summary, we have described a novel and efficient method for
the synthesis of 2-mercapto-4-benzylidene-4H-benzo[d][1,3]thia-
zines via AgNO3-catalyzed tandem reaction from readily available
starting materials, 2-alkynylbenzenamines and CS2. The reactions
showed moderate to excellent yields and were highly regiospecific,
and only the six-membered ring was generated via 6-exo-dig S-
cyclization. In addition, further transformation of 2-mercapto-4-
benzylidene-4H-benzo[d][1,3]thiazines to highly functionalized 4-
benzylidene-4H-benzo[d][1,3]thiazines has been developed via
crossing-coupling reaction and reductive coupling reaction in
moderate to good yields. Application of 2-alkynylbenzenamine in
other transformations is ongoing currently in our laboratory, and
the results will be reported in due course.
(100 MHz, CDCl3)
d
¼118.2, 120.5, 125.2, 125.6, 125.8, 127.9, 128.3,
129.1, 130.2, 134.8, 135.6, 187.2; HRMS (ESI) calcd for C15H12NS2
(MþH)þ 270.0411; found, 270.0385.
3.1.2. Crystal data and structure refinement for 2a. Empirical for-
mula: C15H11NS2 (Formula weight: 269.37); Temperature: 298(2) K;
Wavelength: 0.71073 A; Crystal system, space group Triclinic, P-1;
Unit cell dimensions: a¼8.1866(10) A,
a
¼83.049(2)ꢁ, b¼8.7350(10) A,
b
¼76.325(2)ꢁ, c¼10.0235(12) A,
g
¼67.924(2)ꢁ, Volume: 644.99(13)ꢁ
A3; Z¼2, Calculated density: 1.387 Mg/m3; Absorption coefficient:
0.392 mmꢀ1; F(000): 280; Crystal size: 0.28ꢂ0.25ꢂ0.22 mm;
Theta range for data collection: 2.52e25.50 deg.; Limiting
indices: ꢀ9<¼h<¼9, ꢀ10<¼k<¼10, ꢀ12<¼l<¼10; Reflections
collected/unique: 5391/2358 [R(int)¼0.0199]; Completeness to
theta¼25.50: 98.3%; Absorption correction: semi-empirical from
equivalents; max. and min. transmission: 0.9188 and 0.8983. Re-
finement method: full-matrix least-squares on F2. Data/restraints/
parameters: 2358/1/167; Goodness-of-fit on F2: 1.106, Final R indices
3. Experimental section
3.1. General
General experimental procedure for tandem addition-
cyclization of 2-alkynylbenzenamines (1) with CS2: A solution of
2-alkynylbenzenamines 1 (0.30 mmol), CS2 (3.0 mmol, 10 equiv),
AgNO3 (5 mol %), DABCO (1.2 equiv) in DMF (2.0 mL) was stirred at
room temperature. After completion of reaction as indicated by
TLC, the reaction was quenched with water (10 mL), extracted with
EtOAc (2ꢂ10 mL), and dried by anhydrous Na2SO4. Evaporation of
the solvent followed by purification on silica gel provided the
corresponding 4-benzylidene-4H-benzo[d][1,3]thiazine 2a.
[I>2
u
s
(I)]: R1¼0.0418, R2¼0.1479. R indices (all data): R1¼0.0489,
u
R2¼0.1820. Largest diff. peak and hole: 0.354 and ꢀ0.328 e Aꢀ3
3.1.3. 4-(4-Fluorobenzylidene)-4H-benzo[d][1,3]thiazine-2-thiol
(2b). Yield: 65%, 1H NMR (400 MHz, DMSO)
¼7.25 (s, 1H),
d
7.26e7.35 (m, 4H), 7.45 (t, J¼8.0 Hz, 1H), 7.51e7.54 (m, 2H), 7.77 (d,
J¼8.0 Hz, 1H), 12.88 (s, 1H); 13C NMR (100 MHz, DMSO)
¼115.2 (d,
d
2JCF¼22.0 Hz), 118.2, 120.5, 124.0, 125.1, 125.6, 125.8, 130.2, 131.3 (d,
3JCF¼8.0 Hz), 131.4, 135.6, 161.4 (d, 1JCF¼245.0 Hz), 187.0; HRMS (ESI)
calcd for C15H11FNS2 (MþH)þ: 288.0317; found, 288.0320.
3.1.1. 4-Benzylidene-4H-benzo[d][1,3]thiazine-2-thiol
(2a). Yield:
95%, 1H NMR (400 MHz, DMSO)
d
¼7.27e7.32 (m, 3H), 7.37e7.39 (m,
3.1.4. 4-(3-Fluorobenzylidene)-4H-benzo[d][1,3]thiazine-2-thiol
1H), 7.43e7.48 (m, 5H), 7.79 (d, J¼8.0 Hz,1H),12.92 (s, 1H); 13C NMR
(2c). Yield: 42%, 1H NMR (400 MHz, DMSO)
d¼7.00e7.03 (m, 1H),

3940
Q. Ding et al. / Tetrahedron 68 (2012) 3937e3941
7.21e7.34 (m, 5H), 7.44e7.53 (m, 2H), 7.80 (d, J¼8.0 Hz,1H),12.90 (s,
7.19e7.26 (m, 3H), 7.35e7.37 (m,1H), 7.42e7.47 (m, 4H), 7.61 (s, 1H),
12.81 (s, 1H); 13C NMR (100 MHz, DMSO)
125.3, 125.9, 127.9, 128.4, 129.2, 130.8, 133.5, 134.9, 135.3, 186.4;
HRMS (ESI) calcd for C16H14NS2 (MþH)þ: 284.0568; found,
284.0540.
1H); 13C NMR (100 MHz, DMSO)
d
¼114.8 (d, 2JCF¼21.0 Hz), 115.7 (d,
d
¼20.5, 118.2, 120.3, 124.7,
2JCF¼22.0 Hz), 118.3, 120.1, 123.6, 125.2, 125.3, 125.8, 127.2, 130.4 (d,
3
3
3JCF¼9.0 Hz), 130.5 (d, JCF¼9.0 Hz), 135.7, 137.2 (d, JCF¼8.0 Hz),
1
161.9 (d, JCF¼243.0 Hz), 186.6; HRMS (ESI) calcd for C15H11FNS2
(MþH)þ: 288.0317; found, 288.0326.
3.1.13. 4-(4-Fluorobenzylidene)-6-methyl-4H-benzo[d][1,3]thiazine-
3.1.5. 4-(4-Ethylbenzylidene)-4H-benzo[d][1,3]thiazine-2-thiol
2-thiol (2l). Yield: 52%, 1H NMR (400 MHz, DMSO)
d¼2.34 (s, 3H),
(2d). Yield: 80%, 1H NMR (400 MHz, DMSO)
d
¼1.20 (t, J¼8.0 Hz,
7.20 (d, J¼8.0 Hz, 1H), 7.25 (s, 1H), 7.26 (d, J¼8.0 Hz, 1H), 7.31 (t,
3H), 2.64 (q, J¼8.0 Hz, 2H), 7.12 (s, 1H), 7.26e7.35 (m, 4H), 7.37e7.45
J¼8.8 Hz, 2H), 7.50e7.54 (m, 2H), 7.60 (s, 1H), 12.89 (s, 1H); 13C NMR
(m, 3H), 7.76 (d, J¼8.0 Hz, 1H), 12.89 (s, 1H); 13C NMR (100 MHz,
(100 MHz, DMSO)
d
¼21.0, 115.9 (d, 2JCF¼21.0 Hz), 118.7, 120.7, 124.1,
DMSO)
d
¼15.4, 28.0, 118.2, 120.8, 124.8, 125.2, 125.3, 125.8, 127.8,
125.7, 126.3, 131.4, 131.8 (d, 3JCF¼8.0 Hz), 131.9, 134.0, 135.8, 161.9 (d,
1JCF¼245.0 Hz), 186.6; HRMS (ESI) calcd for C16H13FNS2 (MþH)þ:
302.0473; found, 302.0482.
129.3, 130.1, 132.3, 135.6, 143.9, 187.5; HRMS (ESI) calcd for
C17H16NS2 (MþH)þ: 298.0724; found, 298.0711.
3.1.6. 4-(4-Methoxybenzylidene)-4H-benzo[d][1,3]thiazine-2-thiol
3.1.14. 4-(4-Methoxybenzylidene)-6-methyl-4H-benzo[d][1,3]thia-
(2e). Yield: 86%, 1H NMR (400 MHz, DMSO)
d
¼3.81 (s, 3H), 7.04 (d,
zine-2-thiol (2m). Yield: 52%, 1H NMR (400 MHz, DMSO)
d
¼2.33
J¼8.0 Hz, 2H), 7.14 (d, J¼8.0 Hz, 1H), 7.19 (s, 1H), 7.25e7.31 (m, 2H),
(s, 3H), 3.81 (s, 3H), 6.86 (d, J¼8.0 Hz, 1H), 7.04 (d, J¼8.0 Hz, 2H),
7.43 (d, J¼8.0 Hz, 2H), 7.73 (d, J¼8.0 Hz, 1H), 12.88 (s, 1H); 13C NMR
7.14e7.24 (m, 3H), 7.43 (d, J¼8.4 Hz, 2H), 7.56 (s, 1H), 12.81 (s,
(100 MHz, DMSO)
d
¼54.6, 113.2, 117.6, 120.5, 122.7, 124.6, 124.7,
1H); 13C NMR (100 MHz, DMSO)
123.5, 124.8, 125.2, 127.5, 130.5, 130.8, 133.4, 135.3, 158.9, 186.5;
HRMS (ESI) calcd for C17H16NOS2 (MþH)þ: 314.0673; found,
314.0683.
d
¼20.5, 55.2, 113.8, 118.1, 120.8,
125.3, 126.9, 129.3, 130.2, 134.9, 158.3, 187.0; HRMS (ESI) calcd for
C16H14NOS2 (MþH)þ: 300.0517; found, 300.0530.
3.1.7. 4-Benzylidene-6-chloro-4H-benzo[d][1,3]thiazine-2-thiol
(2f). Yield: 54%, 1H NMR (400 MHz, DMSO)
d
¼7.29e7.34 (m, 2H),
7.37e7.39 (m, 2H), 7.47e7.52 (m, 4H), 7.89 (s, 1H), 13.01 (s, 1H); 13C
NMR (100 MHz, DMSO)
3.1.15. 4-(Cyclopropylmethylene)-4H-benzo[d][1,3]thiazine-2-thiol
(2n). Yield: 40%, 1H NMR (400 MHz, DMSO)
d
¼0.60e0.64 (m,
d
¼119.9, 122.3, 124.7, 126.6, 128.2, 128.3,
2H), 0.92e0.94 (m, 2H), 1.60e1.63 (m, 1H), 5.69 (d, J¼8.0 Hz, 1H),
7.16 (t, J¼8.0 Hz, 1H), 7.23 (d, J¼8.0 Hz, 1H), 7.32 (t, J¼8.0 Hz, 1H),
7.50 (d, J¼8.0 Hz, 1H), 12.56 (s, 1H); 13C NMR (100 MHz, DMSO)
128.4, 129.3, 129.8, 129.9, 134.5, 134.6, 187.28; HRMS (ESI) calcd for
C15H11ClNS2 (MþH)þ: 304.0021; found, 303.9997.
d
¼7.7, 11.5, 118.1, 120.3, 122.0, 124.1, 125.6, 129.2, 130.5, 135.2,
3.1.8. 4-(4-Methoxybenzylidene)-6-chloro-4H-benzo[d][1,3]thiazine-
188.5; HRMS (ESI) calcd for C12H12NS2 (MþH)þ: 234.0411; found,
2-thiol (2g). Yield: 55%, 1H NMR (400 MHz, DMSO)
d
¼3.81 (s, 3H),
7.04(d, J¼8.0 Hz, 2H), 7.27e7.29 (m, 2H), 7.44e7.49 (m, 3H), 7.82 (s,
1H), 12.97 (s, 1H); 13C NMR (100 MHz, DMSO)
234.0390.
d
¼55.2, 113.8, 119.8,
3.1.16. 4-(Cyclopropylmethylene)-6-fluoro-4H-benzo[d][1,3]thiazine-
121.7, 122.9, 124.6, 126.6, 127.2, 129.5, 129.7, 131.0, 134.3, 159.1,
187.64; HRMS (ESI) calcd for C16H13ClNOS2 (MþH)þ: 334.0127;
found, 334.0138.
2-thiol (2o). Yield: 41%, 1H NMR (400 MHz, DMSO)
d
¼0.62e0.64
(m, 2H), 0.90e0.95 (m, 2H), 1.59e1.62 (m, 1H), 5.79 (d, J¼10.0 Hz,
1H), 7.17e7.33 (m, 2H), 7.40 (dd, J¼10.0, 2.4 Hz, 1H), 12.69 (s, 1H);
2
13C NMR (100 MHz, DMSO)
d
¼8.3, 12.2, 111.1 (d, JCF¼25.0 Hz),
2
3
3.1.9. 4-Benzylidene-6-fluoro-4H-benzo[d][1,3]thiazine-2-thiol
116.8 (d, JCF¼23.0 Hz), 120.6 (d, JCF¼8.0 Hz), 121.2, 122.7
(2h). Yield: 51%, 1H NMR (400 MHz, DMSO)
d
¼7.34e7.40 (m, 4H),
(d, JCF¼7.0 Hz), 132.7, 140.4, 159.9 (d, JCF¼241.0 Hz), 188.3;
HRMS (ESI) calcd for C12H11FNS2 (MþH)þ: 252.0317; found,
252.0325.
3
1
7.47 (m, 3H), 7.71 (d, J¼8.0 Hz,1H),12.92 (s,1H); 13C NMR (100 MHz,
2
2
DMSO)
d
¼111.6 (d, JCF¼25.0 Hz), 117.2 (d, JCF¼25.0 Hz), 120.3 (d,
3JCF¼9.0 Hz), 122.4 (d, 3JCF¼9.0 Hz), 124.6, 126.3, 128.2, 128.4, 129.2,
General procedure for synthesis of highly functionalized 4H-
benzo[d][1,3]thiazines (4) via CuI-catalyzed crossing-coupling re-
actions: A solution of 4H-benzo[d][1,3]thiazines 2 (0.30 mmol), aryl
iodine (ArI) (0.9 mmol, 3.0 equiv), CuI catalyst (20 mol %), Cs2CO3
(0.6 mmol, 2.0 equiv) in DMF (2.0 mL) was stirred at 110 ꢁC under
N2 for overnight. After completion of reaction as indicated by TLC,
the reaction was cooled to room temperature and quenched with
water (10 mL), extracted with EtOAc (2ꢂ10 mL), and dried by an-
hydrous Na2SO4. Evaporation of the solvent followed by purifica-
tion on silica gel provided the corresponding functionalized 4H-
benzo[d][1,3]thiazines 4.
1
132.3, 134.6, 159.4 (d, JCF¼242.0 Hz), 186.5; HRMS (ESI) calcd for
C15H11FNS2 (MþH)þ: 288.0317; found, 288.0325.
3.1.10. 4-(4-Methoxybenzylidene)-6-fluoro-4H-benzo[d][1,3]thia-
zine-2-thiol (2i). Yield: 73%, 1H NMR (400 MHz, DMSO)
d¼3.81 (s,
3H), 7.05 (d, J¼8.4 Hz, 1H), 7.23 (s, 1H), 7.31 (d, J¼6 0.0 Hz, 4H), 7.45
(d, J¼8.4 Hz, 1H), 7.67 (d, J¼9.6 Hz, 1H), 12.93 (s, 1H); 13C NMR
2
(100 MHz, DMSO)
d
¼55.2, 111.5 (d, JCF¼24.0 Hz), 113.9, 114.2 (d,
2JCF¼27.0 Hz), 116.7, 120.2, 123.0 (d, 3JCF¼8.0 Hz), 126.3, 127.2, 130.9,
1
132.2, 159.1, 159.5 (d, JCF¼240.0 Hz), 186.8; HRMS (ESI) calcd for
C16H13FNOS2 (MþH)þ: 318.0423; found, 318.0438.
3.1.17. 4-(Phenyl(p-tolyl)methylene)-2-(p-tolylthio)-4H-benzo[d]
3.1.11. 4-(4-Fluorobenzylidene)-6-fluoro-4H-benzo[d][1,3]thiazine-2-
[1,3]thiazine (4a). Yield: 84%, 1H NMR (400 MHz, CDCl3)
d
¼2.21 (s,
thiol (2j). Yield: 58%, 1H NMR (400 MHz, DMSO)
d
¼7.26e7.33 (m,
3H), 2.38 (s, 3H), 6.79 (d, J¼8.4 Hz, 2H), 6.88 (d, J¼8.0 Hz, 2H), 7.20
(d, J¼8.0 Hz, 2H), 7.25e7.28 (m, 2H), 7.33 (t, J¼8.0 Hz,1H), 7.38e7.45
(m, 5H), 7.52 (t, J¼8.4 Hz, 1H), 7.72 (d, J¼8.4 Hz, 1H), 8.25 (d,
5H), 7.53e7.56 (m, 2H), 7.69 (d, J¼8.0 Hz,1H),12.95 (s,1H); 13C NMR
(100 MHz, DMSO)
d
¼111.6 (d, 2JCF¼25.0 Hz), 115.5 (d, 2JCF¼22.0 Hz),
117.4 (d, 2JCF¼24.0 Hz), 120.3(d, 3JCF¼9.0 Hz), 122.4 (d, 3JCF¼8.0 Hz),
J¼8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
¼20.5, 21.0, 125.7, 126.3,
d
2
124.5, 125.2, 131.2, 131.4 (d, JCF¼9.0 Hz), 132.3, 159.5 (d,
126.6, 127.8, 127.9, 128.5, 129.0, 129.1, 129.2, 129.5, 132.7, 134.8,
135.3, 136.4, 138.2, 138.3, 139.4, 147.4, 159.7; HRMS (ESI) calcd for
C29H24NS2 (MþH)þ: 450.1350; found, 450.1334.
1JCF¼242.0 Hz), 161.5 (d, 1JCF¼242.0 Hz), 186.3; HRMS (ESI) calcd for
C15H10F2NS2 (MþH)þ: 306.0223; found, 306.0220.
3.1.12. 4-Benzylidene-6-methyl-4H-benzo[d][1,3]thiazine-2-thiol
3.1.18. 4-(Phenyl(o-tolyl)methylene)-2-(o-tolylthio)-4H-benzo[d]
(2k). Yield: 76%, 1H NMR (400 MHz, DMSO)
d
¼2.34 (s, 3H),
[1,3]thiazine (4b). Yield: 85%, 1H NMR (400 MHz, CDCl3)
d
¼2.16 (s,

Q. Ding et al. / Tetrahedron 68 (2012) 3937e3941
3941
3H), 2.34 (s, 3H), 6.61 (d, J¼8.0 Hz, 1H), 6.85 (t, J¼7.6 Hz, 1H), 6.97 (t,
J¼7.6 Hz, 1H), 7.03 (d, J¼7.2 Hz, 1H), 7.19e7.25 (m, 3H), 7.32e7.42
(m, 6H), 7.51e7.55 (m, 2H), 7.69 (d, J¼8.4 Hz, 1H), 8.21 (d, J¼8.4 Hz,
HRMS (ESI) calcd for C23H19ClNS2 (MþH)þ: 408.0647; found,
408.0653.
1H); 13C NMR (100 MHz, CDCl3)
d
¼20.4, 21.0, 125.9, 126.3, 126.4,
3.1.24. 2-(4-Methoxybenzylthio)-4-benzylidene-4H-benzo[d][1,3]thi-
126.5, 126.6, 127.3, 128.2, 128.3, 128.5, 128.7, 129.1, 129.4, 129.6,
129.7, 130.0, 130.3, 130.4, 136.2, 136.4, 136.5, 137.0, 139.0, 140.3,
143.3, 148.0, 159.8; HRMS (ESI) calcd for C29H24NS2 (MþH)þ:
450.1350; found, 450.1303.
azine (6d). Yield: 62%, 1H NMR (400 MHz, CDCl3)
d
¼3.67 (s, 3H),
4.34 (s, 2H), 6.73 (d, J¼8.8 Hz, 2H), 6.97 (s, 1H), 7.17e7.25 (m, 4H),
7.26e7.35 (m, 6H), 7.44 (d, J¼8.0 Hz,1H); 13C NMR (100 MHz, CDCl3)
d
¼35.2, 55.2, 114.0, 122.9, 124.8, 126.1, 126.7, 127.4, 127.5, 127.7,
128.3, 129.0, 129.3, 129.7, 130.3, 135.4, 142.4, 157.9, 159.0; HRMS
3.1.19. 4-((4-Methoxyphenyl)(phenyl)methylene)-2-(4-
(ESI) calcd for C23H20NOS2 (MþH)þ: 390.0986; found, 390.0974.
methoxyphenylthio)-4H-benzo[d][1,3]thiazine (4c). Yield: 70%, 1H
NMR (400 MHz, CDCl3)
d
¼3.68 (s, 3H), 3.82 (s, 3H), 6.61 (d,
Acknowledgements
J¼8.8 Hz, 2H), 6.84 (d, J¼8.4 Hz, 2H), 6.92 (d, J¼8.4 Hz, 2H),
7.21e7.28 (m, 2H), 7.34e7.41 (m, 4H), 7.45 (d, J¼8.8 Hz, 2H), 7.52 (t,
J¼7.6 Hz, 1H), 7.71 (d, J¼8.4 Hz, 1H), 8.34 (d, J¼8.4 Hz, 1H); 13C NMR
Financial Supported from National Natural Science Foundation
of China (21002042), Natural Science Foundation of Jiangxi Prov-
ince of China (2009GQH0054), and Open Project Program of State
Key Laboratory of Food Science and Technology, Nanchang Uni-
versity (No. SKLF-KF-201004) is gratefully acknowledged.
(100 MHz, CDCl3)
d
¼55.3, 55.4,114.4,114.6,121.3,126.0,126.7,127.0,
127.1, 128.2, 128.3, 129.0, 129.5, 130.1, 131.0, 136.8, 137.1, 138.1, 141.0,
147.9, 158.4, 160.2, 160.6; HRMS (ESI) calcd for C29H24NO2S2
(MþH)þ, 482.1248; found, 482.1253.
3.1.20. 4-((4-Nitrophenyl)(phenyl)methylene)-2-(4-nitrophenylthio)-
Supplementary data
4H-benzo[d][1,3]thiazine (4d). Yield: 63%, 1H NMR (400 MHz,
CDCl3)
d
¼6.98 (d, J¼9.2 Hz, 2H), 7.25 (d, J¼7.6 Hz, 2H), 7.41e7.51 (m,
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.098.
4H), 7.68 (t, J¼7.6 Hz, 2H), 7.76 (d, J¼8.8 Hz, 2H), 7.83 (d, J¼8.4 Hz,
1H), 7.96 (d, J¼8.8 Hz, 2H), 8.17 (d, J¼8.4 Hz, 1H), 8.25 (d, J¼8.8 Hz,
2H); 13C NMR (100 MHz, CDCl3)
d
¼123.6, 124.1, 126.1, 127.0, 127.1,
References and notes
127.6,128.6,129.1,129.2,129.5,130.6,134.9,135.7,137.7,139.6,139.7,
145.6, 145.9, 147.7, 147.8, 158.1; HRMS (ESI) calcd for C27H18N3O4S2
(MþH)þ, 512.0739; found, 512.0750.
1. For some recent examples, see: (a) Nair, R. N.; Lee, P. J.; Grotjahn, D. B.;
Rheingold, A. L. Chem.dEur. J. 2010, 16, 7992; (b) Adriano, C.; Arianna, R.; Paolo,
S. Tetrahedron 2010, 66, 7169; (c) Bartolo, G.; Lucia, V.; Giuseppe, S.; Raffaella,
M.; Mirco, C. Adv. Synth. Catal. 2010, 352, 3355; (d) Praveen, C.; Karthikeyan, K.;
Perumal, P. T. Tetrahedron 2009, 65, 9244; (e) Guo, Y.-J.; Tang, R.-Y.; Li, J.-H.;
Zhong, P.; Zhang, X.-G. Adv. Synth. Catal. 2009, 351, 2615; (f) Adriano, C.;
Arianna, R. Tetrahedron Lett. 2009, 50, 6877; (g) Norio, S.; Kimiyoshi, A.; Akiko,
F.; Asuka, S.; Takeo, K. J. Org. Chem. 2008, 73, 4160; (h) Ye, S.; Ding, Q.; Wang, Z.;
Zhou, H.; Wu, J. Org. Biomol. Chem. 2008, 6, 4406.
2. (a) Zhao, J.; Peng, C.; Liu, L.; Wang, Y.; Zhu, Q. J. Org. Chem. 2010, 75, 7502; (b)
Peng, C.; Wang, Y.; Liu, L.; Wang, H.; Zhao, J.; Zhu, Q. Eur. J. Org. Chem. 2010, 818;
(c) Haruki, S.; Chao, P.; Mamoru, K.; Mao, M. Synthesis 2010, 3091; (d) Sakai, N.;
Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T. J. Org. Chem. 2008, 73, 4160; (e)
Du, W.; Dennis, P. C. Org. Lett. 2003, 5, 1765.
3. (a) Ana, G.; Mercedes, M.-S.; Carmen, R. C.; Gregorio, A.; Ana, B. C. Org. Lett.
2010, 12, 1900; (b) Wang, H.; Liu, L.; Wang, Y.; Zhang, J.; Zhu, Q. Tetrahedron Lett.
2009, 50, 6841.
4. Takao, S.; Shohel, O.; Naoya, T.; Noriki, K.; Takashi, O. Org. Lett. 2011, 13, 1098.
5. Tang, R.-Y.; Luo, P.-S.; Zhang, X.-G.; Li, J.-H.; Zhong, P. Synlett 2010, 1345.
6. (a) Ding, Q.; Cao, B.; Zong, Z.; Peng, Y. J. Comb. Chem. 2010, 12, 370; (b) Ding, Q.;
Wu, J. J. Comb. Chem. 2008, 10, 541.
7. Recent reviews for the synthesis of heterocycles: (a) Armstrong, A.; Collins, J. C.
Angew. Chem., Int. Ed. 2010, 49, 2282; (b) Katritzky, A. R.; Rachwal, S. Chem. Rev.
2010, 110, 1564; (c) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.;
Machado, P. Chem. Rev. 2009, 109, 4140; (d) Alvarez-Corral, M.; Munoz-Dorado,
M.; Rodrıguez-Garcıa, I. Chem. Rev. 2008, 108, 3174; (e) Minatti, A.; Muniz, K.
Chem. Soc. Rev. 2007, 36, 1142.
8. (a) Matysiak, J. Bioorg. Med. Chem. 2006, 14, 2613; (b) Su, Y.; Guo, Q.; Wang, G.;
Guo, S. Faming Zhuanli Shenqing Gongkai Shuomingshu Patent 1683349, 2005;
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Pharma. J. 2005, 57, 43; (d) Hsu, W.-C.; Tao, T.-M.; Chou, T.-C.; Ding, Y.-A.; Liu,
K.-C. Chin. Pharma. J. 2002, 54, 331; (e) Schmittel, M.; Mahajan, A.; Steffen, J.-P.
Synthesis 2004, 415.
General procedure for synthesis of functionalized 4H-benzo[d]
[1,3]thiazines (6) via metal-free reductive coupling reactions of 2-
mercapto-4H-benzo[d][1,3]thiazines (2) with tosylhydrazones (5):
a mixture of 2-mercapto-4H-benzo[d][1,3]thiazines 2 (0.3 mmol),
tosylhydrazone
5 (0.6 mmol, 2.0 equiv), K3PO4 (0.9 mmol,
3.0 equiv) in toluene (2.0 mL) was stirred at 110 ꢁC for 24 h under
N2. After completion of the reaction as indicated by TLC, the mix-
ture was cooled to room temperature. After adding ethyl acetate
(10 mL), the organic phase was washed with saturated brine, dried
with MgSO4, and concentrated under reduced vacuum. The residue
was then purified by flash chromatography on silica gel to afford
product 6.
3.1.21. 4-Benzylidene-2-(1-phenylethylthio)-4H-benzo[d][1,3]thia-
zine (6a). Yield: 68%, 1H NMR (400 MHz, CDCl3)
d¼1.77 (d, J¼7.2 Hz,
3H), 5.27 (q, J¼7.2 Hz, 1H), 7.06 (s, 1H), 7.28e7.33 (m, 5H), 7.37e7.45
(m, 8H), 7.54 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
¼22.0,
d
45.2, 122.9, 124.7, 126.2, 126.7, 127.3, 127.4, 127.5, 127.7, 128.2, 128.5,
129.3, 129.6, 135.4, 142.3, 142.5, 157.6; HRMS (ESI) calcd for
C23H20NS2 (MþH)þ: 374.1037; found, 374.1025.
3.1.22. 4-Benzylidene-2-(1-(4-methoxyphenyl)ethylthio)-4H-benzo
[d][1,3]thiazine (6b). Yield: 55%, 1H NMR (400 MHz, CDCl3)
d¼1.74
(d, J¼7.2 Hz, 3H), 3.77 (s, 3H), 5.22 (q, J¼7.2 Hz, 1H), 6.83 (d,
ꢀ
ꢀ
€
9. (a) Csomos, P.; Fodor, L.; Bernath, G.; Sinkkonen, J.; Salminen, J.; Wiinamaki, K.;
Pihlaja, K. Tetrahedron 2008, 64, 1002; (b) Abaev, V. T.; Tsiunchik, F. A.; Gutnov,
A. V.; Butin, A. V. Tetrahedron Lett. 2006, 47, 4029; (c) Fernandes, M. A.; Reid, D.
Synlett 2003, 2231; (d) Nishio, T.; Sekiguchi, H. Heterocycles 2002, 58, 203; (e)
Hari, A.; Miller, B. L. Org. Lett. 2000, 2, 3667; (f) El-Desoky, S. I.; Kandeel, E. M.;
Abd-el-Rahman, A. H.; Schmidt, R. R. J. Heterocycl. Chem. 1999, 36, 153; (g)
Nishio, T. J. Org. Chem. 1997, 62, 1106.
J¼8.4 Hz, 2H), 7.05 (s, 1H), 7.27e7.42 (m, 10H), 7.53 (d, J¼8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d¼22.1, 44.8, 55.2, 113.9, 122.9,
124.7, 126.3, 126.6, 127.3, 127.4, 127.7, 128.2, 128.6, 129.3, 129.6,
134.2, 135.5, 142.5, 157.7, 158.9; HRMS (ESI) calcd for C24H22NOS2,
(MþH)þ: 404.1143; found, 404.1150.
10. For some selected examples, see: (a) Ding, Q.; Liu, X.; Cao, B.; Zong, Z.; Peng, Y.
Tetrahedron Lett. 2011, 52, 1964; (b) Ding, Q.; Cao, B.; Zong, Z.; Peng, Y. Green.
Chem. 2010, 12, 1607; (c) Ding, Q.; Huang, X.; Wu, J. J. Comb. Chem. 2009, 11,
1047; (d) Ding, Q.; He, X.; Wu, J. J. Comb. Chem. 2009, 11, 587; (e) Ding, Q.;
Wang, Z.; Wu, J. J. Org. Chem. 2009, 74, 921; (f) Ding, Q.; Wu, J. Adv. Synth. Catal.
2008, 350, 1850; (g) Ding, Q.; Ye, Y.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 5439;
(h) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959.
3.1.23. 4-Benzylidene-2-(1-(4-chlorophenyl)ethylthio)-4H-benzo[d]
[1,3]thiazine (6c). Yield: 65%, 1H NMR (400 MHz, CDCl3)
d
¼1.63 (d,
J¼7.2 Hz, 3H), 5.13 (q, J¼7.2 Hz, 1H), 6.97 (s, 1H), 7.08e7.23 (m, 5H),
7.25e7.35 (m, 7H), 7.44 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
d
¼21.7, 44.4, 122.9, 124.7, 126.0, 126.8, 127.3, 127.5, 127.7,
11. Qiu, G.; Hu, Y.; Ding, Q.; Peng, Y.; Hu, X.; Wu, J. Chem. Commun. 2011, 9708.
12. Ding, Q.; Cao, B.; Yuan, J.; Liu, X.; Peng, Y. Org. Biomol. Chem. 2011, 9, 748.
128.2, 128.6, 128.8, 129.3, 129.6, 133.1, 135.4, 141.1, 142.3, 157.2;