One-pot syntheses of 2-(2-sulfanyl-4H-3,1-benzothiazin-4-yl)acetic acid derivatives via reactions of 3-(2-isothiocyanatophenyl)prop-2-enoic acid derivatives with thiols or sodium sulfide

Article abstract of DOI:10.1002/hlca.201000340

Two efficient methods for the preparation of 2-(2-sulfanyl-4H-3,1- benzothiazin-4-yl)acetic acid derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3-(2- isothiocyanatophenyl)prop-2-enoates 1a-1c with thi

Full text of DOI:10.1002/hlca.201000340

Helvetica Chimica Acta – Vol. 94 (2011)
111
One-Pot Syntheses of 2-(2-Sulfanyl-4H-3,1-benzothiazin-4-yl)acetic Acid
Derivatives via Reactions of 3-(2-Isothiocyanatophenyl)prop-2-enoic Acid
Derivatives with Thiols or Sodium Sulfide
by Shuhei Fukamachi, Hisatoshi Konishi, and Kazuhiro Kobayashi*
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
Two efficient methods for the preparation of 2-(2-sulfanyl-4H-3,1-benzothiazin-4-yl)acetic acid
derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3-
(2-isothiocyanatophenyl)prop-2-enoates 1a – 1c with thiols in the presence of Et3N in THF at room
temperature, leading to the corresponding dithiocarbamate intermediates 2, which underwent sponta-
neous cyclization at the same temperature by an attack of the S-atom at the prop-2-enoyl moiety in a 1,4-
addition manner (Michael addition) to give 2-(2-sulfanyl-4H-3,1-benzothiazin-4-yl)acetates in one pot.
The second method involves treatment of 3-(2-isothiocyanatophenyl)prop-2-enoic acid derivatives 1b –
1d with Na2S leading to the formation of 2-(2-sodiosulfanyl-4H-3,1-benzothiazin-4-yl)acetic acid
intermediates 5 by a similar addition/cyclization sequence, which are then allowed to react with alkyl or
aryl halides to afford derivatives 3. 2-(2-Thioxo-4H-3,1-benzothiazin-4-yl)acetic acid derivatives 6 can be
obtained by omitting the addition of halides.
Introduction. – Compounds with the 4H-3,1-benzothiazine skeleton have recently
attracted much attention because of their biological activities [1], and a number of
efficient methods for their preparation have been reported [2]. We have recently
described a synthesis of 2-[2-(dialkylamino)-4H-3,1-benzothiazin-4-yl]acetic acids by
the reaction of 3-(2-isothiocyanatophenyl)prop-2-enoic acids with secondary amines
[3]. As a continuation of this work, we became interested in investigating the possibility
of preparation of 4H-3,1-benzothiazines with a sulfanyl group at C(2) by reacting 3-(2-
isothiocyanatophenyl)prop-2-enoic acid derivatives with thiols. We now report the
results of our investigation, which offer a facile one-pot procedure for the synthesis of
2-(2-sulfanyl-4H-3,1-benzothiazin-4-yl)acetic acid derivatives from 3-(2-isothiocyana-
tophenyl)prop-2-enoates via cyclization of the corresponding dithiocarbamates. The 2-
sulfanyl-4H-3,1-benzothiazine skeleton has attracted much attention because of the
biological activities of some derivatives [2b][4], and some efficient methods for their
preparation have been reported [5]. We also found that the use of Na2S in place of
thiols generated 2-[2-(sodiosulfanyl)-4H-3,1-benzothiazin-4-yl]acetic acid intermedi-
ates, which were then allowed to react with alkyl or aryl halides to afford 2-(2-sulfanyl-
4H-3,1-benzothiazin-4-yl)acetic acid derivatives. Moreover, we found that 2-(2-thioxo-
4H-3,1-benzothiazin-4-yl)acetic acid derivatives were obtained, when the reactions of
2-[2-(sodiosulfanyl)-4H-3,1-benzothiazin-4-yl]acetic acid intermediates were quenched
with aqueous acidic solutions. The 2-thioxo-4H-3,1-benzothiazine skeleton is found in
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
some biologically active compounds [6]. However, few practical methods for the
preparation of this class of 4H-3,1-benzothiazine derivatives have been reported so far
´
[6b][7]. Although Tarraga et al. have reported the synthesis of methyl 2-(2-thioxo-4H-
3,1-benzothiazin-4-yl)acetate by the reaction of methyl (E)-3-{2-[(triphenylphosphor-
anylidene)amino]phenyl}prop-2-enoate with CS2, this method suffers from low yield
and limited generality [7].
Results and Discussion. – First, a one-pot synthesis of 2-(2-sulfanyl-4H-3,1-
benzothiazin-4-yl)acetates 3 was performed by the process illustrated in Scheme 1.
Thus, 3-(2-isothiocyanatophenyl)prop-2-enoates 1 [3] were treated with thiols in the
presence of Et3N in THF at room temperature to generate the corresponding
dithiocarbamate intermediates 2, which, at the same temperature, underwent cycliza-
tion by an attack of the S-atom at the prop-2-enoyl moiety in a 1,4-addition manner.
The usual aqueous workup and subsequent purification by column chromatography on
silica gel afforded the desired products 3. The results are summarized in Table 1, which
indicates that the yields are generally good-to-excellent. It should be noted that the use
of 3-(2-isothiocyanatophenyl)-N,N-dimethylprop-2-enamide in stead of 1 resulted in
the formation of complex mixtures of products, in which no trace of the desired
products could be detected (data not shown).
Scheme 1
Table 1. Preparation of 2-(2-Sulfanyl-4H-3,1-benzothiazin-4-yl)acetates 3 via 2
Entry
Starting material
R2
3
Yielda) [%]
1
2
3
4
5
6
7
8
9
1a (R1 ¼ H, Y¼ MeO)
HOCH2CH2
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
75
88
84
76
78
74
95
93
93
1a
1a
4-ClꢀC6H4
1b (R1 ¼ H, Y¼ t-BuO)
Hexyl
1b
1b
1b
Bn
t-Bu
Ph
1c (R1 ¼ Cl, Y¼ t-BuO)
4-MeꢀC6H4
1c
Naphthalen-2-yl
a) Yields of isolated products.
Next, we found that 2-(2-sulfanyl-4H-3,1-benzothiazin-4-yl)acetates 3 could be
prepared by using Na2S · 9 H2O in place of thiols, as depicted in Scheme 2. Thus, 3-(2-
isothiocyanatophenyl)prop-2-enoates 1b and 1c were treated with Na2S · 9 H2O in
DMF at room temperature to generate the corresponding sodium dithiocarbamate

Helvetica Chimica Acta – Vol. 94 (2011)
113
Scheme 2
intermediates 4, which underwent cyclization in the same manner as that mentioned
above at the same temperature. These reactive intermediates 5 were allowed to react
with an equimolar amount of alkyl or aryl halides at the same temperature. The usual
aqueous workup and subsequent purification by column chromatography on silica gel
afforded the desired products 3. The results are compiled in Table 2, which indicates
that the yields are generally fair-to-good. It can be seen from Entries 8 and 9 that 3-(2-
isothiocyanatophenyl)-N,N-dimethylpropenamide (1d) also provided the correspond-
ing benzothiazine products. Moreover, we found that 2-(2-thioxo-4H-3,1-benzothiazin-
4-yl)acetic acid derivatives 6 were obtained, when the reactions of the 2-[2-
(sodiosulfanyl)-4H-3,1-benzothiazin-4-yl]acetic acid intermediates 5 were quenched
with an aqueous acidic solution, as shown in Scheme 2 as well. Preparation of products 3
Table 2. Preparation of 2-(2-Sulfanyl-4H-3,1-benzothiazin-4-yl)acetic Acid Derivatives 3 via 4 and 5
Entry
1
R2X
3
Yielda) [%]
1
2
3
4
5
6
7
8
9
1b (R1 ¼ H, Y¼ t-BuO)
MeI
BnBr
BrCH2CN
EtBr
4-NO2ꢀC6H4CH2Br
4-CNꢀC6H4CH2Br
PhCOCH2Br
CH2¼CHCH2Br
2,4-(NO2)2ꢀC6H3F
3j
72
74
77
65
59
57
52
60
64
1b
3e
3k
3l
3m
3n
3o
3p
3q
1b
1c (R1 ¼ Cl, Y¼ t-BuO)
1c
1c
1c
1d (R1 ¼ H, Y¼ Me2N)
1d
a) Yields of isolated products.

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Helvetica Chimica Acta – Vol. 94 (2011)
or 6 carrying a COOMe function was attempted under the same conditions. However,
each of the reactions resulted in the formation of an intractable mixture of products.
This may be ascribed to the sensitivity of the COOMe function to saponification.
In conclusion, we have demonstrated that 2-(2-sulfanyl-4H-3,1-benzothiazin-4-
yl)acetic acid derivatives 3 could be efficiently prepared by one-pot addition/
cyclization sequences between 3-(2-isothiocyanatophenyl)prop-2-enoic acid deriva-
tives 1, and thiols or Na2S. The procedure with Na2S has been applied to the synthesis of
2-(2-thioxo-4H-3,1-benzothiazin-4-yl)acetic acid derivatives 6. Notable advantages of
all of the present syntheses are: i) simplicity of the procedure, ii) mild reaction
conditions, and iii) easy availability of the starting materials.
Experimental Part
General. All of the org. solvents were dried on appropriate drying agents and distilled prior to use.
All chemicals were commercially available. TLC: Merck Kieselgel 60 PF254. Column chromatography
(CC): Wako Gel C-200E. M.p.: Laboratory Devices MEL-TEMP II melting-point apparatus;
1
uncorrected. IR Spectra: Shimadzu FTIR-8300 spectrophotometer. H- and 13C-NMR spectra: JEOL
ECP500 FT NMR spectrometer, at 500 (1H) and 125 (13C) MHz; TMS as an internal reference. Low-
resolution (LR) MS spectra (EI; 70 eV): JEOL JMS AX505 HA spectrometer.
(E)-3-(2-Isothiocyanatophenyl)prop-2-enoates 1 were prepared from the corresponding N-(2-
iodophenyl)formamides, according to the procedure reported by us in [3]. The physical, spectral, and
anal. data for the new compounds are given below.
tert-Butyl (2E)-3-[5-Chloro-2-(formylamino)phenyl]prop-2-enoate. Yield: 78%. White solid. M.p.
154 – 1558 (hexane/CH2Cl2). IR (KBr): 3231, 1707, 1665, 1632. 1H-NMR (CDCl3): 1.53 (s, 9 H); 6.34 – 6.38
(m, 1 H); 7.14 – 8.49 (m, 6 H). Anal. calc. for C14H16ClNO3 (281.73): C 59.68, H 5.72, N 4.97; found: C
59.65, H 5.76, N, 5.01.
tert-Butyl (2E)-3-(5-Chloro-2-isocyanatophenyl)prop-2-enoate. Yield: 73%. White solid. M.p. 105 –
1078 (hexane/Et2O). IR (KBr): 2128, 1703, 1626. 1H-NMR (CDCl3): 1.54 (s, 9 H); 6.47 (d, J ¼ 15.6, 1 H);
7.36 – 7.37 (m, 2 H); 7.63 (d, J ¼ 0.9, 1 H); 7.80 (d, J ¼ 15.6, 1 H). Anal. calc. for C14H14ClNO2 (263.72): C
63.76, H 5.35, N 5.31; found: C 63.65, H 5.36, N 5.05.
tert-Butyl (2E)-3-(5-Chloro-2-isothiocyanatophenyl)prop-2-enoate (1c). Yield: 95%. Pale-yellow
crystal. M.p. 55 – 568 (hexane). IR (KBr): 2074, 1709, 1638. 1H-NMR (CDCl3): 1.55 (s, 9 H); 6.40 (d, J ¼
16.0, 1 H); 7.24 (d, J ¼ 8.7, 1 H); 7.31 (dd, J ¼ 8.7, 2.3, 1 H); 7.56 (d, J ¼ 2.3, 1 H); 7.76 (d, J ¼ 16.0, 1 H).
Anal. calc. for C14H14ClNO2S (295.78): C 56.85, H 4.77, N 4.74; found: C 56.63, H 4.81, N 4.52.
Methyl {2-[(2-Hydroxyethyl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetate (3a; Typical Procedure). A
mixture of 1a (0.14 g, 0.64 mmol), HSCH2CH2OH (0.10 g, 1.28 mmol), and Et3N (65 mg, 0.64 mmol) in
THF (3 ml) was stirred at r.t. for 5 h, then sat. aq. NaHCO3 (10 ml) was added. The org. materials were
extracted with AcOEt (3 ꢁ 10 ml), and the combined extracts were washed with brine (10 ml), dried
(anh. Na2SO4), and concentrated by evaporation. The residue was purified by CC (SiO2; AcOEt/hexane,
1:2) to afford 3a (0.14 g, 75%). White solid. M.p. 135 – 1378 (hexane/CH2Cl2). IR (KBr): 3387, 1734, 1537.
1H-NMR (CDCl3): 2.64 (dd, J ¼ 16.0, 6.4, 1 H); 2.74 (dd, J ¼ 16.0, 8.7, 1 H); 3.16 – 3.20 (m, 1 H); 3.46 –
3.51 (m, 1 H); 3.68 (s, 3 H); 3.88 – 3.93 (m, 1 H); 4.08 – 4.14 (m, 1 H); 4.49 (dd, J ¼ 8.7, 6.4, 1 H); 4.80
(dd, J ¼ 6.4, 4.1, 1 H); 7.18 (dd, J ¼ 7.8, 1.4, 1 H); 7.25 (td, J ¼ 7.8, 1.4, 1 H); 7.32 (dd, J ¼ 7.8, 1.4, 1 H); 7.36
(td, J ¼ 7.8, 1.4, 1 H). 13C-NMR (CDCl3): 36.27; 40.14; 41.07; 51.97; 63.12; 122.86; 125.81; 126.87; 127.41;
128.97; 141.99; 161.31; 170.32. MS: 297 (80, Mþ), 224 (100). Anal. calc. for C13H15NO3S2 (297.39): C 52.50,
H 5.08, N 4.71; found: C 52.45, H 5.35, N 4.69.
Methyl [2-(Phenylsulfanyl)-4H-3,1-benzothiazin-4-yl]acetate (3b). Colorless oil. Rf (THF/hexane
1
1:5) 0.41. IR (neat): 1738, 1539. H-NMR (CDCl3): 2.64 (dd, J ¼ 16.0, 6.4, 1 H); 2.70 (dd, J ¼ 16.0, 8.7,
1 H); 3.65 (s, 3 H); 4.46 (dd, J ¼ 8.7, 6.4, 1 H); 7.13 (d, J ¼ 7.3, 1 H); 7.18 (d, J ¼ 7.3, 1 H); 7.21 (t, J ¼ 7.3,
1 H); 7.30 (t, J ¼ 7.3, 1 H); 7.39 – 7.44 (m, 3 H); 7.62 – 7.63 (m, 2 H). 13C-NMR (CDCl3): 40.27; 41.21; 51.90;
122.39; 126.49; 126.61; 127.25; 128.46; 129.05; 129.38; 129.51; 135.11; 142.79; 159.89; 170.35. MS: 329 (82,

Helvetica Chimica Acta – Vol. 94 (2011)
115
Mþ), 256 (100). Anal. calc. for C17H15NO2S2 (329.44): C 61.98, H 4.59, N 4.25; found: C 62.05, H 4.54, N
4.30.
Methyl {2-[(4-Chlorophenyl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetate (3c). Colorless crystals.
1
M.p. 115 – 1178 (hexane/Et2O). IR (KBr): 1738, 1541. H-NMR (CDCl3): 2.62 (dd, J ¼ 16.0, 6.4, 1 H);
2.71 (dd, J ¼ 16.0, 8.7, 1 H); 3.66 (s, 3 H); 4.47 (dd, J ¼ 8.7, 6.4, 1 H); 7.14 (dd, J ¼ 7.8, 1.4, 1 H); 7.18 (dd,
J ¼ 7.8, 1.4, 1 H); 7.22 (td, J ¼ 7.8, 1.4, 1 H); 7.31 (td, J ¼ 7.8, 1.4, 1 H); 7.39 (d, J ¼ 8.2, 2 H); 7.55 (d, J ¼ 8.2,
2 H). 13C-NMR (CDCl3): 40.30; 41.21; 51.91; 122.37; 126.19; 126.64; 127.42; 127.87; 128.83; 129.25;
135.90; 136.23; 142.62; 158.89; 170.26. MS: 363 (79, Mþ), 290 (100). Anal. calc. for C17H14ClNO2S2
(363.88): C 56.11, H 3.88, N 3.85; found: C 55.82, H 3.92, N 3.63.
tert-Butyl [2-(Hexylsulfanyl)-4H-3,1-benzothiazin-4-yl]acetate (3d). Pale-yellow oil. Rf (Et2O/
1
hexane 1:10) 0.58. IR (neat): 1730, 1537. H-NMR (CDCl3): 0.90 (distorted t, J ¼ 7.3, 3 H); 1.31 – 1.33
(m, 5 H); 1.40 – 1.44 (m, including s at 1.41, 10 H); 1.68 – 1.75 (m, 2 H); 2.58 (dd, J ¼ 16.0, 6.8, 1 H); 2.66
(dd, J ¼ 16.0, 8.2, 1 H); 3.11 (dt, J ¼ 13.4, 7.3, 1 H); 3.37 (dt, J ¼ 13.4, 7.3, 1 H); 4.38 (dd, J ¼ 8.2, 6.8, 1 H);
7.16 (dd, J ¼ 7.3, 1.4, 1 H); 7.19 (td, J ¼ 7.3, 1.4, 1 H); 7.28 (dd, J ¼ 7.3, 1.4, 1 H); 7.33 (td, J ¼ 7.3, 1.4, 1 H).
13C-NMR (CDCl3: 14.00; 22.49; 28.04; 28.47; 29.23; 31.29; 31.47; 40.34; 42.39; 81.37; 123.17; 123.97:
126.03; 126.53; 126.81; 128.59; 158.6; 169.25. MS: 379 (29, Mþ), 323 (81), 264 (100). Anal. calc. for
C20H29NO2S2 (379.58): C 63.28, H 7.70, N 3.69; found: C 63.04, H 7.74, N 3.58.
tert-Butyl {2-[(Phenylmethyl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetate (3e). White solid. M.p. 55 –
1
588 (hexane). IR (KBr): 1728, 1537. H-NMR (CDCl3): 1.41 (s, 9 H); 2.56 (dd, J ¼ 15.6, 6.8, 1 H); 2.61
(dd, J ¼ 15.6, 8.2, 1 H); 4.37 – 4.42 (m, 2 H); 4.63 (d, J ¼ 13.3, 1 H); 7.16 (d, J ¼ 7.3, 1 H); 7.19 – 7.25 (m,
2 H); 7.31 (t, J ¼ 7.3, 2 H); 7.34 – 7.35 (m, 2 H); 7.41 (d, J ¼ 7.3, 2 H). 13C-NMR (CDCl3): 28.04; 35.61;
40.39; 42.43; 81.44; 123.21; 126.07; 126.74; 126.86; 127.32; 128.58; 128.69; 129.14; 137.11; 142.59; 157.98;
169.19. MS: 385 (28, Mþ), 329 (80), 270 (100). Anal. calc. for C21H23NO2S2 (385.54): C 65.42, H 6.01, N
3.63; found: C 65.27, H 6.02, N 3.79.
tert-Butyl {2-[(tert-Butyl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetate (3f). Colorless oil. Rf (Et2O/
hexane 1:14) 0.46. IR (neat): 1730, 1537. 1H-NMR (CDCl3): 1.41 (s, 9 H); 1.62 (s, 9 H); 2.55 (dd, J ¼ 16.0,
7.3, 1 H); 2.78 (dd, J ¼ 16.0, 7.8, 1 H); 4.57 (dd, J ¼ 7.8, 7.3, 1 H); 7.15 (dd, J ¼ 7.8, 1.4, 1 H); 7.20 (td, J ¼ 7.8,
2.3, 1 H), 7.30 – 7.35 (m, 2 H). 13C-NMR (CDCl3): 8.92; 28.05; 30.68; 40.59; 42.30; 51.15; 81.35; 126.09;
126.68; 126.93; 128.48; 157.82; 168.94; 178.85. MS: 351 (23, Mþ), 295 (31), 239 (76), 180 (100). Anal. calc.
for C18H25NO2S2 (351.53): C 61.50, H 7.17, N 3.98; found: C 61.45, H 7.30, N 3.96.
tert-Butyl [2-(Phenylsulfanyl)-4H-3,1-benzothiazin-4-yl]acetate (3g). White solid. M.p. 70 – 728
(hexane). IR (KBr): 1728, 1541. 1H-NMR (CDCl3): 1.39 (s, 9 H); 2.57 (dd, J ¼ 15.6, 6.9, 1 H); 2.61 (dd,
J ¼ 15.6, 8.2, 1 H); 4.64 (dd, J ¼ 8.2, 6.9, 1 H); 7.13 (dd, J ¼ 7.3, 1.4, 1 H); 7.18 (dd, J ¼ 7.3, 1.8, 1 H); 7.20
(td, J ¼ 7.3, 1.4, 1 H); 7.29 (td, J ¼ 7.3, 1.8, 1 H); 7.40 – 7.43 (m, 3 H); 7.62 – 7.64 (m, 2 H). 13C-NMR
(CDCl3): 28.03; 40.55; 42.61; 81.40; 122.53; 126.42; 126.69; 127.10; 128.62; 129.08; 129.31; 129.51; 135.16;
142.83; 160.16; 169.03. MS: 371 (29, Mþ), 315 (77), 256 (100). Anal. calc. for C20H21NO2S2 (371.52): C
64.66, H 5.70, N 3.77; found: C 64.52, H 5.70, N 3.69.
tert-Butyl {6-Chloro-2-[(4-methylphenyl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetate (3h). White
1
solid. M.p. 117 – 1188 (hexane). IR (KBr): 1721, 1526. H-NMR (CDCl3): 1.39 (s, 9 H); 2.40 (s, 3 H);
2.54 (dd, J ¼ 15.6, 7.3, 1 H); 2.57 (dd, J ¼ 15.6, 8.2, 1 H); 4.34 (dd, J ¼ 8.2, 7.3, 1 H); 7.12 (d, J ¼ 8.7, 1 H);
7.13 (d, J ¼ 2.3, 1 H); 7.22 (d, J ¼ 8.2, 2 H); 7.25 (dd, J ¼ 8.7, 2.3, 1 H); 7.49 (d, J ¼ 8.2, 2 H). 13C-NMR
(CDCl3) 21.36; 24.98; 40.11; 42.46; 81.64; 123.84; 125.27; 126.66; 127.68; 128.62; 129.94; 131.79; 135.37;
140.13; 141.46; 161.63; 168.67. MS: 419 (25, Mþ), 363 (75), 304 (100). Anal. calc. for C21H22ClNO2S2
(419.99): C 60.06, H 5.28, N 3.34; found: C 60.07, H 5.38, N 3.22.
tert-Butyl {6-Chloro-2-[(naphthalen-2-yl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetate (3i). Colorless
crystals. M.p. 131 – 1328 (hexane/Et2O). IR (KBr): 1722, 1537. 1H-NMR (CDCl3): 1.36 (s, 9 H); 2.56 (dd,
J ¼ 15.6, 7.3, 1 H); 2.62 (dd, J ¼ 15.6, 7.8, 1 H); 4.36 (dd, J ¼ 7.8, 7.3, 1 H); 7.08 (d, J ¼ 8.7, 1 H); 7.14 (d, J ¼
2.3, 1 H); 7.24 (dd, J ¼ 8.7, 2.3, 1 H); 7.53 (td, J ¼ 6.9, 1.4, 1 H), 7.56 (td, J ¼ 6.9, 1.4, 1 H), 7.62 (dd, J ¼ 8.2,
1.4, 1 H), 7.85 – 7.88 (m, 3 H), 8.15 (s, 1 H). 13C-NMR (CDCl3): 27.97; 40.20; 42.33; 81.70; 123.92; 126.36;
126.70 (two overlapped Cs); 127.36; 127.71; 127.77; 128.09; 128.67 (two overlapped Cs); 131.48; 131.95;
133.43; 133.47; 134.94; 141.39; 160.79; 168.63. MS: 455 (20, Mþ), 399 (69), 340 (100). Anal. calc. for
C24H22ClNO2S2 (456.02): C 63.21, H 4.86, N 3.07; found: C 63.35, H 4.86, N 3.04.

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Helvetica Chimica Acta – Vol. 94 (2011)
tert-Butyl [2-(Methylsulfanyl)-4H-3,1-benzothiazin-4-yl]acetate (3j; Typical Procedure). A mixture
of 1b (0.12 g, 0.45 mmol) and Na2S · 9 H2O (0.11 g, 1.1 mmol) in DMF (3 ml) was stirred at r.t. for 30 min.
The resulting mixture was then treated with MeI (64 mg, 0.45 mmol) and stirred for a further 5 min
before sat. aq. NH4Cl (10 ml) was added. The org. materials were extracted with AcOEt (3 ꢁ 10 ml), and
the combined extracts were washed with brine (10 ml), dried (anh. Na2SO4), and concentrated by
evaporation. The residue was purified by CC (SiO2; Et2O/hexane 1:10) to afford 3j (0.10 g, 72%). White
1
solid. M.p. 69 – 718 (hexane). IR (KBr): 1728, 1537. H-NMR (CDCl3): 1.41 (s, 9 H); 2.55 (dd, J ¼ 15.6,
7.3, 1 H); 2.61 (dd, J ¼ 15.6, 8.2, 1 H); 2.62 (s, 3 H), 4.40 (dd, J ¼ 8.2, 7.3, 1 H); 7.16 (dd, J ¼ 7.8, 1.4, 1 H);
7.19 (td, J ¼ 7.8, 2.3, 1 H); 7.31 (dd, J ¼ 7.8, 2.3, 1 H); 7.33 (td, J ¼ 7.8, 1.4, 1 H). 13C-NMR (CDCl3): 14.39;
28.06; 40.34; 42.42; 81.41; 123.17; 126.10; 126.60; 126.82; 128.65; 142.65; 159.01; 169.22. MS: 309 (17, Mþ),
253 (68), 194 (100). Anal. calc. for C15H19NO2S2 (309.45): C 58.22, H 6.19, N 4.53; found: C 58.17, H 6.34,
N 4.44.
tert-Butyl {2-[(Cyanomethyl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetate (3k). Pale-yellow oil. Rf
(Et2O/hexane 1:3) 0.29. IR (neat): 2249, 1726, 1545. 1H-NMR (CDCl3): 1.42 (s, 9 H); 2.57 (dd, J ¼
16.0, 6.8, 1 H); 2.62 (dd, J ¼ 16.0, 8.7, 1 H); 3.91 (d, J ¼ 16.5, 1 H); 4.17 (d, J ¼ 16.5, 1 H); 4.47 (dd, J ¼
8.7, 6.8, 1 H); 7.18 (d, J ¼ 7.3, 1 H); 7.24 – 7.28 (m, 1 H); 7.37 – 7.38 (m, 2 H). 13C-NMR (CDCl3): 16.02;
28.05; 40.58; 42.46; 81.71; 115.90; 122.79; 126.45; 126.82; 127.66; 129.03; 141.85; 168.89; 172.75. MS: 334
(20, Mþ), 278 (69), 219 (100). Anal. calc. for C16H18N2O2S2 (334.46): C 57.46, H 5.42, N 8.38; found: C
57.31, H 5.59, N 8.19.
tert-Butyl [6-Chloro-2-(ethylsulfanyl)-4H-3,1-benzothiazin-4-yl]acetate (3l). Pale-yellow oil. Rf
1
(Et2O/hexane 1:10) 0.38. IR (neat): 1728, 1535. H-NMR (CDCl3): 1.38 (t, J ¼ 7.3, 3 H); 1.42 (s, 9 H);
2.54 (dd, J ¼ 15.6, 7.3, 1 H); 2.60 (dd, J ¼ 15.6, 7.8, 1 H); 3.08 – 3.16 (m, 1 H); 3.31 – 3.38 (m, 1 H); 4.34 (dd,
J ¼ 7.8, 7.3, 1 H); 7.16 (d, J ¼ 2.3, 1 H); 7.22 (d, J ¼ 8.2, 1 H); 7.29 (dd, J ¼ 8.2, 2.3, 1 H). 13C-NMR
(CDCl3): 14.43; 26.05; 28.03; 39.95; 42.24; 81.69; 124.46; 126.79; 127.35; 128.64; 131.38; 141.26; 157.54;
168.86. MS: 357 (19, Mþ), 301 (72), 242 (100). Anal. calc. for C16H20ClNO2S2 (357.92): C 53.69, H 5.63, N
3.91; found: C 53.63, H 5.85, N 3.94.
tert-Butyl (6-Chloro-2-{[(4-nitrophenyl)methyl]sulfanyl}-4H-3,1-benzothiazin-4-yl)acetate (3m).
Pale-yellow needle. M.p. 103 – 1048 (hexane/Et2O). IR (KBr): 1724, 1599, 1520, 1344. 1H-NMR (CDCl3):
1.42 (s, 9 H); 2.54 (dd, J ¼ 15.6, 7.3, 1 H); 2.94 (dd, J ¼ 15.6, 7.8, 1 H); 4.63 (dd, J ¼ 7.8, 7.3, 1 H); 4.39 (d,
J ¼ 14.2, 1 H); 4.65 (d, J ¼ 14.2, 1 H); 7.17 (d, J ¼ 2.3, 1 H); 7.23 (d, J ¼ 8.7, 1 H); 7.32 (dd, J ¼ 8.7, 2.3, 1 H);
7.58 (d, J ¼ 8.7, 2 H); 8.17 (d, J ¼ 8.7, 2 H). 13C-NMR (CDCl3): 28.02; 34.66; 40.04; 42.30; 81.88; 123.79;
124.39; 126.93; 127.23; 128.88; 129.91; 132.01; 140.83; 145.11; 147.16; 157.63; 168.61. MS: 464 (20, Mþ), 408
(75), 349 (100). Anal. calc. for C21H21ClN2O4S2 (464.99): C 54.24, H 4.55, N 6.02; found: C 54.22, H 4.58,
N 5.94.
tert-Butyl (6-Chloro-2-{[(4-cyanophenyl)methyl]sulfanyl}-4H-3,1-benzothiazin-4-yl)acetate (3n).
1
Pale-yellow oil. Rf (AcOEt/hexane 1:5) 0.29. IR (neat): 2230, 1728, 1537. H-NMR (CDCl3): 1.42 (s,
9 H); 2.54 (dd, J ¼ 15.6, 7.3, 1 H); 2.58 (dd, J ¼ 15.6, 7.8, 1 H); 4.35 (d, J ¼ 14.2, 1 H); 4.36 (dd, J ¼ 7.8, 7.3,
1 H); 4.62 (d, J ¼ 14.2, 1 H); 7.17 (d, J ¼ 2.3, 1 H); 7.22 (d, J ¼ 8.7, 1 H); 7.32 (dd, J ¼ 8.7, 2.3, 1 H); 7.51 (d,
J ¼ 8.2, 2 H); 7.60 (d, J ¼ 8.2, 2 H). 13C-NMR (CDCl3): 28.03; 34.98; 40.04; 42.30; 81.87; 111.24; 118.63;
124.41; 126.92; 127.24; 128.86; 129.80; 131.97; 132.35; 140.86; 143.00; 157.76; 168.63. MS: 444 (24, Mþ),
388 (75), 329 (100). Anal. calc. for C22H21ClN2O2S2 (445.00): C 59.38, H 4.76, N 6.30; found: C 59.45, H
4.95, N 6.05.
tert-Butyl {6-Chloro-2-[(2-oxo-2-phenylethyl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetate (3o) Pale-
yellow oil. Rf (AcOEt/hexane 1:5) 0.44. IR (neat): 1728, 1694, 1537. 1H-NMR (CDCl3): 1.42 (s, 9 H); 2.52
(dd, J ¼ 16.0, 7.3, 1 H); 2.58 (dd, J ¼ 16.0, 7.8, 1 H); 4.36 (dd, J ¼ 7.8, 7.3, 1 H); 4.63 (d, J ¼ 16.0, 1 H); 4.68
(d, J ¼ 16.0, 1 H); 6.97 (d, J ¼ 8.2, 1 H); 7.15 (d, J ¼ 2.3, 1 H); 7.22 (dd, J ¼ 8.2, 2.3, 1 H); 7.51 (t, J ¼ 7.8,
2 H); 7.62 (t, J ¼ 7.8, 1 H); 8.05 (d, J ¼ 7.8, 2 H). 13C-NMR (CDCl3): 28.02; 38.11; 39.97; 42.30; 81.81;
124.34; 126.81; 127.18; 128.52; 128.71; 128.75; 131.75; 133.63; 135.95; 140.82; 157.85; 168.72; 193.43. MS:
447 (22, Mþ), 391 (74), 332 (100). Anal. calc. for C22H22ClNO3S2 (448.00): C 58.98, H 4.95, N 3.13; found:
C 58.88, H 5.04, N 3.12.
N,N-Dimethyl-2-{2-[(prop-2-en-1-yl)sulfanyl]-4H-3,1-benzothiazin-4-yl}acetamide (3p). Pale-yel-
1
low oil. Rf (AcOEt/hexane 1:3) 0.31. IR (neat): 1647, 1537. H-NMR (CDCl3): 2.57 (dd, J ¼ 15.6, 6.0,
1 H); 2.76 (dd, J ¼ 15.6, 8.6, 1 H); 2.80 (s, 3 H); 2.92 (s, 3 H), 3.74 – 3.78 (m, 1 H); 4.07 (dd, J ¼ 13.8, 8.2,

Helvetica Chimica Acta – Vol. 94 (2011)
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1 H); 4.63 (dd, J ¼ 8.6, 6.0, 1 H); 5.14 (dd, J ¼ 10.0, 1.4, 1 H); 5.29 – 5.33 (m, 1 H); 5.91 – 5.99 (m, 1 H);
7.19 (dd, J ¼ 7.8, 2.3, 1 H); 7.22 (td, J ¼ 7.8, 1.4, 1 H); 7.30 (dd, J ¼ 7.8, 1.4, 1 H); 7.34 (td, J ¼ 7.8, 2.3, 1 H).
13C-NMR (CDCl3): 31.32; 35.51; 37.17; 39.77; 40.73; 118.39; 123.58; 125.97; 126.94; 127.08; 128.59; 133.03;
142.68; 158.56; 169.17. MS: 306 (100, Mþ). Anal. calc. for C15H18N2OS2 (306.45): C 58.79, H 5.92, N 9.14;
found: C 58.77, H 6.01, N 9.02.
2-{2-[(2,4-Dinitrophenyl)sulfanyl]-4H-3,1-benzothiazin-4-yl}-N,N-dimethylacetamide (3q). Yellow
solid. M.p. 194 – 1968 (hexane/AcOEt). IR (KBr): 1643, 1593, 1524, 1333. 1H-NMR ((D6)DMSO): 2.64
(dd, J ¼ 16.4, 5.0, 1 H); 2.80 – 2.85 (m including s at 2.80 and s at 2.83, 7 H); 2.84 (dd, J ¼ 9.1, 5.0, 1 H); 7.12
(d, J ¼ 7.3, 1 H); 7.32 – 7.39 (m, 3 H); 8.22 (d, J ¼ 8.7, 1 H); 8.51 (dd, J ¼ 8.7, 2.7, 1 H); 8.88 (d, J ¼ 2.7, 1 H).
13C-NMR: ((D6)DMSO): 34.94; 36.46; 39.61; 40.42; 120.84; 123.20; 126.09; 127.41; 127.73; 128.57; 128.75;
134.30; 135.62; 146.92; 148.54; 155.47; 165.83; 168.12. MS: 432 (100, Mþ). Anal. calc. for C18H16N4O5S2
(432.47): C 49.99, H 3.73, N 12.95; found: C 49.91, H 4.03, N 13.04.
Omission of the addition of halides before aqueous workup in the procedure for the preparation of 3
afforded 2-(2-thioxo-4H-3,1-benzothiazin-4-yl)acetic acid derivatives 6.
tert-Butyl (1,4-Dihydro-2-thioxo-2H-3,1-benzothiazin-4-yl)acetate (6a). Yellow solid. M.p. 136 – 1388
(hexane/Et2O). IR (KBr): 3130, 1721, 1150. 1H-NMR (CDCl3): 1.42 (s, 9 H); 2.70 (dd, J ¼ 16.0, 7.3, 1 H);
2.85 (dd, J ¼ 16.0, 7.8, 1 H); 4.42 (dd, J ¼ 7.8, 7.3, 1 H); 7.02 (d, J ¼ 7.8, 1 H); 7.18 (t, J ¼ 7.8, 1 H); 7.26 (d,
J ¼ 7.8, 1 H); 7.32 (t, J ¼ 7.8, 1 H); 10.18 (s, 1 H). 13C-NMR (CDCl3): 28.01; 42.30; 43.54; 81.92; 117.23;
121.92; 125.77; 127.71; 129.07; 135.97; 168.77; 193.02. MS: 295 (20, Mþ), 239 (72), 180 (100). Anal. calc.
for C14H17NO2S2 (295.42): C 56.92, H 5.80, N 4.74; found: C 56.81, H 5.82, N 4.74.
2-(1,4-Dihydro-2-thioxo-2H-3,1-benzothiazin-4-yl)-N,N-dimethylacetamide (6b). Pale-yellow solid.
M.p. 173 – 1748 (hexane/CH3Cl). IR (KBr): 3153, 1628, 1148. 1H-NMR (CDCl3): 2.71 (dd, J ¼ 16.0, 6.0,
1 H); 2.86 (s, 3 H); 2.95 (s, 3 H); 2.99 (dd, J ¼ 16.0, 8.7, 1 H); 4.67 (dd, J ¼ 8.7, 6.0, 1 H); 6.99 (d, J ¼ 7.3,
1 H); 7.18 (t, J ¼ 7.3, 1 H); 7.32 (t, J ¼ 7.3, 1 H); 7.33 (d, J ¼ 7.3, 1 H); 9.87 (s, 1 H). 13C-NMR (CDCl3):
35.64; 37.12; 41.40; 42.66; 117.23; 122.33; 125.90; 128.00; 128.93; 136.15; 168.80; 193.47. MS: 266 (100,
Mþ). Anal. calc. for C12H14N2OS2 (266.38): C 54.11, H 5.30, N 10.52; found: C 53.97, H 5.57, N 10.32.
tert-Butyl (6-Chloro-1,4-dihydro-2-thioxo-2H-3,1-benzothiazin-4-yl)acetate (6c). Pale-yellow solid.
1
M.p. 126 – 1288 (hexane/Et2O). IR (KBr): 3154, 1726, 1150. H-NMR (CDCl3): 1.43 (s, 9 H); 2.70 (dd,
J ¼ 16.0, 7.8, 1 H); 2.84 (dd, J ¼ 16.0, 7.8, 1 H); 4.38 (t, J ¼ 7.8, 1 H); 6.98 (d, J ¼ 8.2, 1 H); 7.27 (d, J ¼ 2.3,
1 H); 7.29 (dd, J ¼ 8.2, 2.3 Hz, 1 H); 10.17 (s, 1 H); 13C-NMR (CDCl3): 28.00; 42.01; 43.33; 82.26; 118.40;
123.53; 127.74; 129.09; 130.67; 134.59; 168.43; 192.70. MS: 329 (20, Mþ), 273 (72), 214 (100). Anal. calc.
for C14H16ClNO2S2 (329.87): C 50.98, H 4.89, N 4.25; found: C 50.94, H 5.03, N 4.13.
This work was partially supported by a Grant-in-Aid for Scientific Research (C) No. 22550035 from
Japan Society for the Promotion of Science. We thank Mrs. Miyuki Tanmatsu of this university for
recording mass spectra and performing combustion analyses.
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Received September 6, 2010