Tandem one-pot synthesis of polysubstituted 1,3-thiazine derivatives

Article abstract of DOI:10.1002/cjoc.201100067

A tandem one-pot synthesis of polysubstituted 1,3-thiazines has been developed by reacting with cyanoacetamide and isothiocyanate derivatives to give rise to 2-cyano-3-mercaptoacrylamides, which are trapped in situ by various aldehydes or diversely substi

Full text of DOI:10.1002/cjoc.201100067

FULL PAPER
Tandem One-pot Synthesis of Polysubstituted 1,3-Thiazine
Derivatives
Wang, Shuliang(王树良)
Wang, Xiang(王翔)
Tu, Mansu(屠蔓苏)
Jiang, Bo*(姜波)
Tu, Shujiang*(屠树江)
Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, School of Chemistry and Chemical
Engineering, Xuzhou Normal University, Xuzhou, Jiangsu 221116, China
A tandem one-pot synthesis of polysubstituted 1,3-thiazines has been developed by reacting with
cyanoacetamide and isothiocyanate derivatives to give rise to 2-cyano-3-mercaptoacrylamides, which are trapped in
situ by various aldehydes or diversely substituted ketones through intermolecular cyclization, providing polysubsti-
tuted 1,3-thiazine derivatives in short reaction times with good to excellent yields. The salient features of this novel
protocol are operational simplicity, accessing the desired products from the readily available starting materials and
easy of product isolation and may find wide spread applications in medicinal chemistry.
Keywords one-pot synthesis, polysubstituted 1,3-thiazines, tandem reaction
Introduction
cyanates and cycloketones in one-pot manner.10 To
thoroughly investigate the substrate scope of the reac-
tion system, in this paper aldehydes or chain ketones
were subjected to this reaction. A series of new poly-
substituted 1,3-thiazines were synthesized through a
one-pot two-step tandem reaction of cyanoacetamide,
isothiocyanates and aldehydes or straight-chain ketones,
(Scheme 1).
The development of efficient approaches to chemi-
cally and biologically important products from readily
available inexpensive starting materials has been an ac-
tive topic in modern organic chemistry.1 Great efforts
have been focused on synthesizing libraries of small
heterocyclic molecules because of their high degree of
structural diversity and extensive utility as therapeutic
agents.2
Scheme 1 One-pot tandem synthesis of 1,3-thiazine derivatives
The rapid assembly of molecular diversity utilizing
multicomponent tandem reactions has received a great
deal of attention, most notably for the construction of
heterocyclic drug-like libraries.3 These methodologies
are of particularly great utility when they lead to the
formation of privileged medicinal scaffolds.4 Such
chemistry can avoid time-consuming and energy-cost-
ing processes that involve multi-step syntheses, protec-
tion-deprotection, tedious work-up and purifications,
which greatly facilitates the development of pharmaceu-
tical agents for diverse applications.
Thiazine is one of the most important heterocyclic
skeletons in many natural products and synthesized
compounds. Its derivatives have a series of bioactivities
such as COX-1 inhibition,5 anti-inflammatory,6 antipro-
liferative,7 antihistaminic,8 and anti-HIV activities.9
Therefore, much attention has been paid to the synthesis
and biological evaluation of 1,3-thiazine derivatives.
Recently, we have reported an efficient synthesis of
spiro-substituted 1,3-thiazine library. The syntheses
were achieved by reacting cyanoacetamide with isothio-
4
CN
H
Ar
H2N
O
N
O
1) NaOH, DMF
2) HOAc, MW
N
O
Ar
+
+
R2
R1
C
S
NH
R2
R1
CN
S
1
2
3
4
Results and discussion
An attempted reaction of isothiocyanatobenzene (1.0
mmol) with cyanoacetamide (1.0 equiv.) was performed
in DMF catalyzed by sodium-hydroxide (0.2 equiv.) for
30 min at room temperature, and then HOAc (1.0 mL)
and acetone (1.1 equiv.) were added into reaction sys-
tem, respectively. Subsequently, the mixture was heated
under microwave irradiation at 60 ℃. Pleasedly, the
pale yellow solid was obtained in 68% chemical yield.
The polysubstituted 1,3-thiazine 4a was fully confirmed
1
13
by H NMR, C NMR and IR spectra, and its structure
was also determined by single-crystal X-ray diffraction
*
E-mail: jiangchem@xznu.edu.cn, laotu2001@263.net; Tel.: 0086-0516-83500065; Fax: 0086-0516-83500065
Received June 26, 2011; revised August 13, 2011; accepted August 14, 2011.
Project supported by the National Natural Science Foundation of China (Nos. 21072163, 21002083 and 21110102002), the Science Foundation in
Interdisciplinary Major Research Project of Xuzhou Normal University (No. 09XKXK01), the Priority Academic Program Development of Jiangsu
Higher Education Institutions, and the Doctoral Research Foundation of Xuzhou Normal University (No. 10XLR20).
Chin. J. Chem. 2011, 29, 2411— 2415
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wang et al.
FULL PAPER
(Figure 1).11 During this reaction process, tedious
work-up procedure can be avoided since the products
directly precipitate out after the reaction is finished and
when its mixtures are diluted with cold water.
Table 1 Synthesis of products 4
R1
Time/ Yield/
Entry 4
Ar
R2
min
7
%
85
87
88
86
84
85
84
87
86
87
88
87
1
2
3
4
5
6
7
8
9
4a Phenyl
Me
Me
Me
Me
H
4b 4-Chlorophenyl Me
4c 4-Bromophenyl Me
5
5
4d Phenyl
4e Phenyl
4f Phenyl
4g Phenyl
4h Phenyl
4i Phenyl
Cyclohexyl
4-Tolyl
4-Methoxyphenyl
7
H
9
H
8
2,3-Dimethoxyphenyl H
3,4-Dimethoxyphenyl H
9
8
Phenyl
H
H
H
H
9
10 4j Phenyl
11 4k Phenyl
12 4l Phenyl
4-Chlorophenyl
4-Bromophenyl
3-Nitrophenyl
5
5
7
4-Hydroxy-3-nitro-
phenyl
Figure 1 X-ray crystallography structure of product 4a.
13 4mPhenyl
H
7
86
Encouraged by the above interesting result, we next
screened for the practical temperature for the synthesis.
The similar reaction was conducted at 80 and 100 ℃,
respectively. The acetone was converted to product 4a
in 85% yield when the reaction temperature was in-
creased from 60 ℃ to 80 ℃. Increasing reaction tem-
perature to 100 ℃ did not improve chemical yields.
Under the above optimized conditions, the substrate
scope of this reaction was examined by using various
chain ketones or aldehydes. As revealed in Table 1, a
range of isothiocyanates are suitable for this synthesis.
In addition, electron-neutral, electron-deficient, and
electron-rich groups on the phenyl ring gave good to
excellent yields (4d—4o). Moreover, the straight-chain
aldehyde such as cyclohexanecarbaldehyde (Table 1,
Entry 4) and the heterocyclic aldehyde such as thio-
phene-2-carbaldehyde (Table 1, Entry 15) still displayed
high reactivity under this standard condition. Gratify-
ingly, functional groups like bromide and chloride were
well tolerated. These functional groups provide ample
opportunity for further functional group manipulations,
for example, by modern cross-coupling reactions.
Additionally, to demonstrate the purely nonthermal
microwave effects, the same temperature was applied to
synthesize some of products under classical heating (CH)
conditions. The results listed in Table 2 showed the spe-
cific activation of this reaction by microwave heating.
Simultaneously, the reaction times were strikingly
shortened to minutes from hours required in traditional
heating condition, and the yields were increased too.
The difference in yields (MW＞CH) may be a conse-
quence of both thermal effects and specific effects in-
duced by the microwave field.12
14 4n Phenyl
15 4o Phenyl
2,4-Dichlorophenyl
Thiophen-2-yl
H
H
6
8
87
93
Table 2 Synthesis of some compounds 4 using conventional
heating
Entry
Product
Time/h
Yield/%
1
2
3
4
4a
4d
4f
1.0
1.5
2.0
1.5
82
79
80
84
4k
Scheme 2 Mechanism of the formation of polysubstituted
1,3-thiazines 4
NH2
Ar
H2N
O
O
SH
NH
Base
N
O
+
C
H+
NC
CN
S
Ar
5
1
2
H2O
NH2
CN
H
N
O
Ar
O
S
S
NH
NC
NH
Ar
4
sation, intermolecular nucleophilic addition, and in-
tramolecular nucleophilic substitution.
Conclusions
In conclusion, we have developed a one-pot two-step
tandem reaction for the efficient synthesis of 1,3-thiaz-
ine derivatives by using different isothiocyanates with
cyanoacetamide and aldehydes or straight-chain ketones.
The reactions proceed in mild conditions and give the
products in good yields. The separation and purification
On the basis of all the above results, a possible
mechanism has been proposed for the formation of
polysubstituted 1,3-thiazine derivatives as shown in
Scheme 2. The formation of products 4 involves a ring
closure cascade process that consists of initial conden-
2412
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2411— 2415

Synthesis of Polysubstituted 1,3-Thiazine Derivatives
process are very simple and convenient, only needing
recrystallization.
2H-1,3-thiazine-5-carbonitrile (4d) Pale yellow solid,
1
m.p. 235—236 ℃; H NMR (400 MHz, DMSO-d6) δ:
10.12 (s, 1H, NH), 8.16 (s, 1H, NH), 7.40 (t, J＝8.0 Hz,
2H, ArH), 7.28 (d, J＝7.6 Hz, 1H, ArH), 7.24 (d, J＝8.0
Hz, 2H, ArH), 4.77 (d, J＝4.4 Hz, 1H, CH), 1.56—1.75
(m, 6H, CH2), 1.19—1.01 (m, 5H, CH2 and CH); IR
(KBr) ν: 3168, 3039, 2203,－ 1641, 1593, 1540, 1447,
Experimental
Microwave irradiation was carried out with Biotage
from Personal Chemistry, Uppsala, Sweden. Melting
points were determined in open capillaries and were
uncorrected. IR spectra were taken on a FT-IR-Tensor
1
1407, 1348, 1279, 12－12 cm ; HRMS (ESI) calcd for
C17H18N3OS ([M－H] ) 312.1165, found 312.1132.
3,4-Dihydro-4-oxo-6-(phenylamino)-2-p-tolyl-2H-
1,3-thiazine-5-carbonitrile (4e) Pale yellow solid,
1
27 spectrometer in KBr pellets. H NMR spectra were
measured on a Bruker DPX 400 MHz spectrometer in
DMSO-d6 with chemical shift (δ) relative to TMS as
internal standard. HRMS (ESI) was determined by using
a microTOF-QII HRMS/MS instrument (BRUKER).
X-ray crystallographic analysis was performed with a
Siemens SMART CCD and a Siemens P4 diffractome-
ter.
1
m.p. 253—254 ℃; H NMR (400 MHz, DMSO-d6) δ:
10.21 (s, 1H, NH), 8.49 (s, 1H, NH), 7.38 (d, J＝8.0 Hz,
2H, ArH), 7.34 (d, J＝8.0 Hz, 2H, ArH), 7.25 (d, J＝8.0
Hz, 1H, ArH), 7.20 (d, J＝8.0 Hz, 4H, ArH), 6.08 (d,
J＝2.8 Hz, 1H, CH), 2.29 (s, 3H, CH3); IR (KBr) ν:
3228, 3134, 2210, 1652, 1600, 1577, 1559, 1495, 1460,
－1
1404, 1349, 1331, 1269, 1235 cm ; HRMS (ESI) calcd
for C18H14N3OS ([M－H]－) 320.0852, found 320.0856.
General procedure for the synthesis of compound 4a
In a 10-mL reaction vial, isothiocyanatobenzene (1.0
mmol) with cyanoacetamide (1.0 mmol) was performed
in DMF catalyzed by sodium-hydroxide (0.2 mmol) for
30 min at room temperature, and then HOAc (1.0 mL,
excess) and acetone (1.1 mmol) were added into reac-
tion system, respectively. Subsequently, the mixture
was conducted by microwave heat at 80 ℃ for 7 min.
Upon completion, monitored by TLC, the reaction mix-
ture was cooled to room temperature and filtered to give
the crude products, which were further purified by
recrystallization from 95% EtOH as pale yellow solid.
3,4-Dihydro-2,2-dimethyl-4-oxo-6-(phenylamino)-
2H-1,3-thiazine-5-carbonitrile (4a) Pale yellow solid,
3,4-Dihydro-2-(4-methoxyphenyl)-4-oxo-6-(phen-
ylamino)-2H-1,3-thiazine-5-carbonitrile (4f)
Pale
1
yellow solid, m.p. 244—245 ℃; H NMR (400 MHz,
DMSO-d6) δ: 10.21 (s, 1H, NH), 8.46 (d, J＝3.2 Hz, 1H,
NH), 7.39 (d, J＝8.4 Hz, 2H, ArH), 7.36 (d, J＝7.6 Hz,
2H, ArH), 7.26 (d, J＝6.8 Hz, 1H, ArH), 7.21 (d, J＝8.0
Hz, 2H, ArH), 6.95 (d, J＝8.4 Hz, 2H, ArH), 6.08 (d,
J＝2.4 Hz, 1H, CH), 3.75 (s, 3H, OCH3); IR (KBr) ν:
3220, 3156, 2208, 16－55, 1589, 1560, 1498, 1465, 1398,
1
1342, 1257, 1221 cm ; HRMS (ESI) calcd for C18H14-
N3O2S ([M－H]－) 336.0801, found 336.0829.
3,4-Dihydro-2-(2,3-dimethoxyphenyl)-4-oxo-6-
(phenylamino)-2H-1,3-thiazine-5-carbonitrile
(4g)
1
1
m.p. 235—236 ℃; H NMR (400 MHz, DMSO-d6) δ:
Pale yellow solid, m.p. 242—243 ℃; H NMR (400
MHz, DMSO-d6) δ: 10.22 (s, 1H, NH), 8.35 (d, J＝3.2
Hz, 1H, NH), 7.36 (t, J＝7.6 Hz, 2H, ArH), 7.26 (d, J＝
7.6 Hz, 1H, ArH), 7.22 (t, J＝8.0 Hz, 2H, ArH), 7.13 (t,
J＝8.4 Hz, 1H, ArH), 7.11—7.08 (m, 1H, ArH), 7.02 (d,
J＝7.2 Hz, 1H, ArH), 6.17 (d, J＝2.8 Hz, 1H, CH), 3.80
(s, 3H, OCH3), 3.72 (s, 3H, OCH3); IR (KBr) ν: 3226,
3165, 2212, 1652, 1590, 1573, 1489, 1463, 1378, 1348,
10.13 (s, 1H, NH), 8.17 (s, 1H, NH), 7.38 (d, J＝8.8 Hz,
2H, ArH), 7.28 (d, J＝8.8 Hz, 2H, ArH), 7.24 (d, J＝8.8
Hz, 2H, ArH), 1.60 (s, 6H, CH3); IR (KBr) ν: 3195,
3128, 2206, 1647, 1589, 1538, 1508, 1452, 1423, 1371,
－1
1215 cm ; HRMS (ESI) calcd for C13H12N3OS ([M－
H]－) 258.0696, found 258.0701.
6-(4-Chlorophenylamino)-3,4-dihydro-2,2-dime-
thyl-4-oxo-2H-1,3-thiazine-5-carbonitrile (4b) Pale
－1
1276, 1245 cm ; HRMS (ESI) calcd for C19H16N3O3S
([M－H]－) 366.0907, found 336.0925.
1
yellow solid, m.p. 234—235 ℃; H NMR (400 MHz,
DMSO-d6) δ: 10.16 (s, 1H, NH), 8.24 (s, 1H, NH), 7.45
(d, J＝8.8 Hz, 2H, ArH), 7.26 (d, J＝8.8 Hz, 2H, ArH),
1.61 (s, 6H, CH3); IR (KBr) ν: 3222, 2932, 2212, 1653,
3,4-Dihydro-2-(3,4-dimethoxyphenyl)-4-oxo-6-
(phenylamino)-2H-1,3-thiazine-5-carbonitrile
(4h)
1
Pale yellow solid, m.p. 230—231 ℃; H NMR (400
MHz, DMSO-d6) δ: 3.74 (s, 3H, OCH3), 3.75 (s, 3H,
OCH3), 6.06 (d, J＝2.8 Hz, 1H, CH), 6.95 (d, J＝8.0 Hz,
1H, ArH), 7.00 (d, J＝8.4 Hz, 1H, ArH), 7.07 (d, J＝8.0
Hz, 1H, ArH), 7.22 (t, J＝7.2 Hz, 2H, ArH), 7.27 (d,
J＝7.6 Hz, 1H, ArH), 7.37 (t, J＝7.6 Hz, 2H, ArH),
8.46 (d, J＝2.4 Hz, 1H, NH), 10.23 (s, 1H, NH); IR
(KBr) ν: 3236, 3174, 2210, 1655, 1587, 1576, 1503,
－1
1592, 1508, 1499, 1385, 1364, 1321, 1295, 1246 cm－ ;
HRMS (ESI) calcd for C13H11ClN3OS ([M － H] )
292.0385, found 292.0399.
6-(4-Bromophenylamino)-3,4-dihydro-2,2-dime-
thyl-4-oxo-2H-1,3-thiazine-5-carbonitrile (4c) Pale
1
yellow solid, m.p. 251—252 ℃; H NMR (400 MHz,
DMSO-d6) δ: 10.15 (s, 1H, NH), 8.24 (s, 1H, NH), 7.58
(d, J＝8.8 Hz, 2H, ArH), 7.19 (d, J＝8.8 Hz, 2H, ArH),
1.61 (s, 6H, CH3); IR (KBr) ν: 3250, 3130, 2210, 1651,
1593, 155－3, 1494, 1477, 1450, 1406, 1389, 1303, 1273,
1242 cm 1; HRMS (ESI) calcd for C13H11BrN3OS
([M－H]－) 335.9801, found 335.9820.
－1
1457, 1356, 1345, 1275, 1250, 1201 cm ; HRMS (ESI)
calcd for C19H16N3O3S ([M－H]－ ) 366.0907, found
336.0909.
3,4-Dihydro-4-oxo-2-phenyl-6-(phenylamino)-2H-
1,3-thiazine-5-carbonitrile (4i) Pale yellow solid,
1
2-Cyclohexyl-3,4-dihydro-4-oxo-6-(phenylamino)-
m.p. 245—246 ℃; H NMR (400 MHz, DMSO-d6) δ:
Chin. J. Chem. 2011, 29, 2411— 2415
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Wang et al.
FULL PAPER
10.23 (s, 1H, NH), 8.54 (d, J＝2.8 Hz, 1H, NH), 7.46 (d,
J＝8.0 Hz, 2H, ArH), 7.40 (t, J＝7.2 Hz, 3H, ArH),
7.36 (d, J＝8.0 Hz, 2H, ArH), 7.26 (t, J＝7.6 Hz, 1H,
ArH), 7.20 (d, J＝7.6 Hz, 2H, ArH), 6.13 (d, J＝2.8 Hz,
1H, CH); IR (KBr) ν: 3200, 3046, 2212, 1654, 1567,
J＝7.2 Hz, 2H, ArH), 6.23 (d, J＝3.6 Hz, 1H, CH); IR
(KBr) ν: 3213, 3083, 2208,－ 1663, 1548, 1507, 1470,
1
1410, 1365, 1347, 1247 －cm ; HRMS (ESI) calcd for
C17H10Cl2N3OS ([M－H] ) 373.9916, found 373.9951.
3,4-Dihydro-4-oxo-6-(phenylamino)-2-(thiophen-
－1
1470, 1417, 1355, 1297, 1211 cm ; HRMS (ESI) calcd
2-yl)-2H-1,3-thiazine-5-carbonitrile (4o)
Pale
for C17H12N3OS ([M＋] 307.0774, found 307.0777.
1
yellow solid, m.p. 229—230 ℃; H NMR (400 MHz,
DMSO-d6) δ: 10.25 (s, 1H, NH), 8.72 (d, J＝4.0 Hz, 1H,
NH), 7.55 (t, J＝4.8 Hz, 1H, ArH), 7.40 (t, J＝8.0 Hz,
2H, ArH), 7.28 (t, J＝7.6 Hz, 1H, ArH), 7.22 (d, J＝7.6
Hz, 2H, ArH), 7.11 (d, J＝3.6 Hz, 1H, ArH), 7.00 (d, J
＝4.8 Hz, 1H, ArH), 6.36 (d, J＝4.4 Hz, 1H, CH); IR
(KBr) ν: 3193, 3094, 2207,－ 1640, 1595, 1583, 1494,
2-(4-Chlorophenyl)-3,4-dihydro-4-oxo-6-(phenyl-
amino)-2H-1,3-thiazine-5-carbonitrile (4j)
Pale
1
yellow solid, m.p. 254—255 ℃; H NMR (400 MHz,
DMSO-d6) δ: 6.15 (d, J＝3.2 Hz, 1H, CH), 7.20 (d, J＝
8.0 Hz, 2H, ArH), 7.27 (t, J＝8.0 Hz, 1H, ArH), 7.38 (d,
J＝8.0 Hz, 2H, ArH), 7.48 (s, 4H, ArH), 8.58 (d, J＝3.2
Hz, 1H, NH), 10.23 (s, 1H, NH); IR (KBr) ν: 3225,
3161, 2213, 1662, 1591, －1545, 1494, 1461, 1413, 1356,
1285, 1248, 1223 cm－ 1; HRMS (ESI) calcd for
C17H11ClN3OS ([M－H] ) 340.0305, found 340.0302.
2-(4-Bromophenyl)-3,4-dihydro-4-oxo-6-(phenyl-
1
1417, 1353, 1265, 1210 cm ; HRMS (ESI) calcd for
C15H10N3OS2 ([M－H]－) 312.0259, found 312.0232.
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Pale
1
yellow solid, m.p. 261—262 ℃; H NMR (400 MHz,
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1
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Allen, S.; Newhouse, B.; Anderson, A. S.; Fauber, B.; Allen,
A.; Chantry, D.; Eberhardt, C.; Odingo, J.; Burgess, L. E.
Bioorg. Med. Chem. Lett. 2004, 14, 1619.
(a) Ottana, R.; Carotti, S.; Maccari, R.; Landini, I.;
Chiricosta, G.; Caciagli, B.; Vigorita, M. G.; Mini, E.
Bioorg. Med. Chem. Lett. 2005, 15, 3930.
(b) Gududuru, V.; Hurh, E.; Dalton, J. T.; Miller, D. D.
Bioorg. Med. Chem. Lett. 2004, 14, 5289.
Diurno, M. V.; Mazzoni, O.; Piscopo, E.; Calignano, A.;
Giordano, F.; Bolognese, A. J. Med. Chem. 1992, 35, 2910.
(a) Rawal, R. K.; Tripathi, R.; Katti, S. B.; Pannecouque, C.;
DeClercq, E. Bioorg. Med. Chem. 2007, 15, 1725.
4
－1
1496, 1446, 1408, 1354, 1266, 1180 cm ; HRMS (ESI)
calcd for C17H11N4O3S ([M－H]－ ) 351.0546, found
351.0553.
3,4-Dihydro-2-(4-hydroxy-3-nitrophenyl)-4-oxo-
6-(phenylamino)-2H-1,3-thiazine-5-carbonitrile (4m)
1
Pale yellow solid, m.p. 262—263 ℃; H NMR (400
MHz, DMSO-d6) δ: 11.34 (s, 1H, OH), 10.28 (s, 1H,
NH), 8.57 (d, J＝3.2 Hz, 1H, NH), 7.97 (d, J＝2.4 Hz,
1H, ArH), 7.61 (d, J＝8.4 Hz, 1H, ArH), 7.38 (t, J＝8.0
Hz, 2H, ArH), 7.28 (t, J＝7.6 Hz, 1H, ArH), 7.21 (t, J＝
7.2 Hz, 1H, ArH), 7.16 (d, J＝8.8 Hz, 1H, ArH), 6.14 (d,
J＝3.2 Hz, 1H, CH); IR (KBr) ν: 3220, 3175, 2218,
1653, 15－96, 1556, 1505, 1489, 1461, 1401, 1338, 1298,
5
6
7
1
1254 cm ; HRMS (ESI) calcd for C17H11N4O4S ([M－
H]－) 367.0495, found 367.0529.
2-(2,4-Dichlorophenyl)-3,4-dihydro-4-oxo-6-(phe-
nylamino)-2H-1,3-thiazine-5-carbonitrile (4n) Pale
1
8
9
yellow solid, m.p. 258—259 ℃; H NMR (400 MHz,
DMSO-d6) δ: 10.36 (s, 1H, NH), 8.56 (d, J＝3.2 Hz, 1H,
NH), 7.71 (s, 1H, ArH), 7.56 (s, 2H, ArH), 7.37 (t, J＝
7.6 Hz, 2H, ArH), 7.27 (t, J＝7.6 Hz, 1H, ArH), 7.19 (d,
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2411— 2415

Synthesis of Polysubstituted 1,3-Thiazine Derivatives
(b) Rawal, R. K.; Prabhakar, Y. S.; Katti, S. B.; De Clercq,
E. Bioorg. Med. Chem. 2005, 13, 6771.
10 Zhuang, Q.-Y.; Wang, X.; Gao, Y.; Shi, F.; Jiang, B.; Tu,
S.-J. ACS Comb. Sci. 2011, 13, 84.
Å3, Mr＝ 275.38, Z＝ 4, Dc＝ 1.343 Mg/m3, λ＝ 0.71073 Å,
μ(Mo Kα)＝ 0.376 mm , F(000)＝ 576, R＝ 0.0427, wR2＝
0.1123, S＝ 1. 007, largest differential peak and hole: 0.303
and － 0.213 e/Å3.
－
1
11 Crystal data for 4a: C13H13N3S2, pale yellow, crystal dimen-
sion 1 mm× 0.28 mm× 0.07 mm, monoclinic, space group
P2(1)/c, a ＝ 13.6208(14) Å, b ＝ 9.5590(8) Å, c ＝
10.9676(11) Å, α＝ β＝ 90°, γ＝ 107.5260(10)°, V＝ 1361.7(2)
12 (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
(b) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199.
(c) Kappe, C. O.; Dallinger, D. Mol. Divers. 2009, 13, 71.
(d) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563.
(CJOC201100067 Li, L.)
Chin. J. Chem. 2011, 29, 2411— 2415
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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