Synthesis of 6- and 7-acyl-4H-benzothiazin-3-ones

Article abstract of DOI:10.1016/j.tet.2006.07.006

Synthesis of 6- and 7-substituted benzoxazin-3-ones was already described in the literature by acylation of the corresponding benzoxazin-3-ones or cyclization of the corresponding 4- or 5-acyl-2-aminophenols. This paper describes original synthetic pathwa

Full text of DOI:10.1016/j.tet.2006.07.006

Tetrahedron 62 (2006) 9054–9058
Synthesis of 6- and 7-acyl-4H-benzothiazin-3-ones
b
a
a
Pascal Carato,a, Ziaeddine Moussavi, Ahmed Sabaouni, Nicolas Lebegue,
*
a
Pascal Berthelot and Saıd Yous
a
€
a
´
Laboratoire de Chimie Therapeutique, Faculte de Pharmacie, EA 1043, 3, rue du Professeur Laguesse,
´
BP 83, 59006 Lille Cedex, France
bFaculty of Pharmacy, Salman Street, Sari, Iran
Received 24 March 2006; revised 30 June 2006; accepted 1 July 2006
Available online 28 July 2006
Abstract—Synthesis of 6- and 7-substituted benzoxazin-3-ones was already described in the literature by acylation of the corresponding
benzoxazin-3-ones or cyclization of the corresponding 4- or 5-acyl-2-aminophenols. This paper describes original synthetic pathways to
afford the 6- and 7-acyl products in the benzothiazin-3-one series, respectively, via Stille coupling reaction and by acylation.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
benzothiazin-3-one or benzoxazin-3-one, of the amide and
the sulfur or oxygen are quite identical. However, the elec-
tronegativities, implicated in the inductive effect, of oxygen
and sulfur atoms are strongly different (S: 2.5, N: 3.0, O:
3.5). Therefore, the electrophile group could be introduced
at the para position of the nitrogen affording the correspond-
ing 7-acylbenzothiazin-3-ones.
The chemistry of benzoxazin-3-one and benzothiazin-3-one
heterocycles has been offering for years an attractive
pathway to lots of new synthetic methods and transforma-
tions. Benzothiazin-3-ones, in fact, have gained substantial
interest in the scientific community not only due to their
meaningful biological activity, but also as reactive inter-
mediates and as starting materials in a wide range of
synthesis.1–3
The obvious disagreement between literature and theoreti-
cal electronic effects has prompted us to study the acylation
of the benzothiazinonic ring. In the first attempt, we acyl-
ated this heterocycle directly, according to different
methods, in polyphosphoric acid (PPA) and in the mixture
AlCl3–DMF with the corresponding carboxylic acid or
acid chloride, respectively; the structures of obtained com-
pounds 2a–d (Scheme 1) were confirmed by full spectral
data. In the second attempt, we have realized two unequiv-
ocal syntheses to afford 6- or 7-acylbenzothiazin-3-ones
(Schemes 2 and 3) in order to have a reference of each
position isomer.
Direct acylation of the benzoxazin-3-one heterocycle at the
C-6 position is well described in the literature4–7 and leads to
products in accordance with theoretical study of the elec-
tronic effects.8 Indeed, two distinct electronic effects were
generated by a substituent: the mesomeric and the inductive
effects. The basis of the inductive effect is probably complex
but originates in part from differences in electronegativity.
For the benzoxazin-3-one heterocycle, not only the with-
drawing effect of the amide but also the donating and the in-
ductive effects of the oxygen allowed the introduction of the
electrophile group logically towards the para position of
the oxygen to give 6-acylbenzoxazin-3-ones. However, the
direct acylation of benzothiazin-3-one at the C-6 position
is less described in the literature. We have only found
some patents9–11 describing results that are not consistent
with the expected electronic effects-related reactivity.8 In
Friedel–Crafts conditions, the mesomeric effects, with
R
N
R
N
O
O
a or b
R1
S
S
O
1a-b
2a : R= H
2b : R= CH3 R1= C3H7
2a-e
R1= C3H7
2c : R= H
R1= C6H5
2d : R= CH3 R1= C6H5
2e : R= H R1= CH2CH2CO2H
Keywords: Benzothiazin-3-one; Friedel–Crafts acylation; Stille coupling.
* Corresponding author. Tel.: +33 320964040; fax: +33 320964913; e-mail:
pascal.carato@univ-lille2.fr
Scheme 1. Synthesis of 7-acylbenzothiazin-3-ones 2a–e by direct acylation.
(a) PPA, R1CO2H; (b) AlCl3–DMF, R1COCl.
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.07.006

P. Carato et al. / Tetrahedron 62 (2006) 9054–9058
9055
R
corresponding 5-acyl-2-aminothiophenols 5a–d followed
by cyclization using ethyl bromoacetate and sodium ethylate
in DMSO,13 which supplied compounds 2a–d (Scheme 2)
with identical physico-chemical characteristics as com-
pounds obtained by direct acylation (Scheme 1).
R
N
R
N
HN
a or b
c
O
O
R1
R1
S
S
HS
O
O
,b
3a
4a-d
5a-d
d
6-Acylbenzothiazin-3-ones were described in the literature
by cyclization of the corresponding 4-chloro-3-nitrophenyl-
acyl derivatives.14,15 A new approach was developed in two
steps to afford original 6-acylbenzothiazin-3-ones 8a–c
(Scheme 3).
R
N
R1 : C3H7, C6H5
R : H, CH3
O
R1
S
O
2a-d
2.3. Synthesis of 6-acylbenzothiazin-3-ones 8a–c
Scheme 2. Synthesis of 7-acylbenzothiazin-3-ones 2a–d by cyclization of
the 5-acyl-2-aminothiophenols 5a–d. (a) PPA, C6H5CO2H; (b) AlCl3–
DMF, C3H7CO2Cl; (c) (i) KOH, (ii) HCl, (iii) NaHCO3; (d) EtONa,
BrCH2CO2C2H5, DMSO.
6-Bromobenzothiazin-3-one16 (6)wastreatedwithPd(PPh3)4
and (Bu3Sn)2 in toluene under argon to afford 6-tributyltin-
benzothiazin-3-one (7). Reaction of derivative 7 with the
corresponding acid chloride was then performed in toluene
under argon with PdCl2(PPh3)2 to give the 6-acylbenzothia-
zin-3-ones 8a–c. This synthetic pathway developed, in two
steps, allows access to various 6-acylbenzothiazin-3-ones
(Scheme 3).
H
N
H
N
SnBu3
O
Br
O
a
S
S
6
7
b
Spectral data of compounds 8a and b obtained in Scheme 3
were strongly different from those found for compounds 2a
and c obtained by direct acylation (Scheme 1). Melting
points differed for compounds 8a, 2a and for compounds
2c, 8b from 20 to 30 ꢀC.
O
R
H
N
8a: R= C3H7
8b: R= C6H5
8c: R= CH2CH2CO2Et
8d: R= CH2CH2CO2H
O
c
S
Combs9,10 described the synthesis of 6-(4-oxobutyric)ben-
zothiazin-3-one (8d) by acylation of the corresponding ben-
zothiazin-3-ones in the mixture AlCl3–DMF with succinic
anhydride, which was not in agreement with our results.
We have realized the acylation of the benzothiazin-3-one
in the Combs conditions, who used ethylsuccinyl chloride
and obtained derivative 2e (Scheme 1). Full NMR spectral
data confirmed that the substitution occurred at the C-7
position of the benzothiazin-3-one, as in all derivatives
2a–d synthesized in Schemes 1 and 2. (4-Oxobutyric)benzo-
thiazin-3-one substituted at the C-6 position was also syn-
thesized by the unequivocal way described in Scheme 3,
starting from the stannic intermediate 7 and ethylsuccinyl
chloride. The 6-(ethyl-4-oxobutyrate) intermediate 8c was
obtained, followed by hydrolysis in a solution of ethanol/
water with KOH leading to acid 8d whose physico-chemical
characteristics were strongly different from those for 7-(4-
oxobutyric)benzothiazin-3-one 2e.
8a-d
Scheme 3. Synthesis of 6-acylbenzothiazin-3-one 8a–d via 6-tributyltin
benzothiazin-3-one 7. (a) (Bu3Sn)2, Pd(PPh3)4, toluene under argon; (b)
RCOCl, PdCl2(PPh3)2, toluene under argon; (c) (i) KOH, EtOH, H2O,
(ii) HCl.
2. Results and discussion
2.1. Synthesis of 7-acylbenzothiazin-3-ones by direct
acylation
Benzothiazin-3-one derivatives 1a and b were acylated by
using either acyl chloride in the mixture AlCl3–DMF or car-
boxylic acid in PPA to give the corresponding 7-acylbenzo-
thiazin-3-one derivatives 2a–d (Scheme 1). It was confirmed
by full NMR spectral data (2H COESY, ROESY, HMBC,
HSQC) that compounds 2a–d obtained by Friedel–Crafts
conditions were not substituted in the C-6 position but in
the C-7 position, in accordance with theoretical study of
the electronic effects.
3. Conclusion
2.2. Synthesis of 7-acylbenzothiazin-3-ones 2a–d by
unequivocal way
Friedel–Crafts acylations of benzothiazin-3-ones using ei-
ther AlCl3–DMF mixture or PPA led to the 7-acyl derivatives
2a–d, in accordance with the theoretical study of the elec-
tronic effects. It was confirmed by full NMR spectral data
and unambiguous synthesis. In order to access 6-acylbenzo-
thiazin-3-ones 8a–c, we have developed a new synthetic
pathway using Stille coupling with 6-tributyltinbenzothia-
zin-3-one intermediate. This work proves that synthesis of
6-acylbenzothiazin-3-ones from direct acylation of benzo-
thiazin-3-one, as Combs described in the literature,9,10 is
not in agreement with our results and the electronic effect
rules on this heterocycle ring.
In order to confirm these structural data, we have realized the
unequivocal synthesis of 7-acylbenzothiazin-3-ones 2a–d
by cyclization of the corresponding 5-acyl-2-aminothiophe-
nols 5a–d (Scheme 2).
6-Acylbenzothiazolin-2-ones 4a–d were prepared according
to literature procedure12 from the corresponding benzothia-
zolin-2-ones 3a and b. Ring opening under strong basic con-
ditions of 6-acylbenzothiazolin-2-ones 4a–d afforded the

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P. Carato et al. / Tetrahedron 62 (2006) 9054–9058
4. Experimental
(CO); 1H NMR (300 MHz, DMSO-d6): d¼3.50 (s, 2H,
CH2), 7.10 (d, 1H, J¼8.30 Hz, H5), 7.50–7.60 (m, 3H, H6,
HAr), 7.70–7.80 (m, 4H, H8, HAr), 10.50 (s, 1H, NH,
exchangeable with D2O). Anal. Calcd for C15H11NO2S:
C, 66.91; H, 4.12; N, 5.20; S, 11.88. Found: C, 66.81; H,
4.27; N, 5.06; S, 11.23.
4.1. General
All compounds were purified by recrystallization in different
solvents and their purity was determined by TLC. Melting
€
points were determined by a Buchi 510 capillary apparatus
and are uncorrected. Elemental analyses were performed
at C.N.R.S centre Vernaison, France and were within
ꢁ0.4% of the theoretical values. Infrared spectra were
obtained on a Nicolet 550-FT spectrometer on KBr paths.
1H and 2H NMR proton spectra were recorded on a Bruker
FT-80 spectrometer and chemical shifts are in parts per
million with TMS as internal standard.
4.2.4. 7-Benzoyl-4-methyl-4H-benzothiazin-3-one (2d).
Recrystallization from ethanol gave 2d in 75% yield; mp
1
130–132 ꢀC; IR (KBr, n cmꢂ1) 1670 and 1640 (CO); H
NMR (300 MHz, CDCl3): d¼3.40 (s, 3H, CH3), 3.50 (s,
2H, CH2), 7.10 (d, 1H, J¼8.20 Hz, H5), 7.50–7.80 (m, 7H,
H6, H8, HAr). Anal. Calcd for C16H13NO2S: C, 66.44; H,
4.84; N, 5.16; S, 11.79. Found: C, 66.61; H, 4.70; N, 5.52;
S, 11.70.
4.2. General procedure for the synthesis of 7-acyl-4H-
benzothiazin-3-one derivatives (2a–e)
4.2.5. 7-(4-Oxobutyric)-4H-benzothiazin-3-one (2e). Re-
crystallization from ethanol gave 2e in 63% yield; mp
173–174 ꢀC; IR (KBr, n cmꢂ1) 3189 (NH), 1701 (COO),
1678 (CON), 1647 (CO); 1H NMR (300 MHz, CDCl3):
d¼2.60 (t, 2H, J¼7.00 Hz, CH2COO), 3.20 (t, 2H,
J¼7.00 Hz, CH2CO), 2.55 (s, 2H, CH2), 7.45 (d, 1H,
J¼8.20 Hz, H5), 7.55 (d, 1H, J¼1.75 Hz, H8), 7.60 (d, 1H,
J¼8.20 Hz, J¼1.75 Hz, H6), 11.75 (s, 1H, NH, exchange-
able with D2O), 12.30 (br s, 1H, OH, exchangeable with
D2O). Anal. Calcd for C12H11NO4S: C, 54.33; H, 4.18;
N, 5.28; S, 12.09. Found: C, 54.64; H, 4.41; N, 5.14;
S, 12.35.
The method adopted for the synthesis of 7-acyl-4H-benzo-
thiazin-3-ones (2a–e) is described in PPA and in the mixture
AlCl3–DMF. Under mechanical stirring, to a mixture of
benzothiazin-3-one 1a (16.4 g, 100 mmol) in 100 g of poly-
phosphoric acid was added portionwise the corresponding
acid (130 mmol). The resulting mixture was heated at
110 ꢀC for 4 h. After cooling, the reaction mixture was
poured into ice-water (1 L), and the resulting precipitate
was filtered, washed with water, dried and recrystallized.
Reaction with AlCl3–DMF: to 112 g of AlCl3 (53.5 g,
400 mmol) was added dropwise anhydrous DMF
(17.2 mL, 230 mmol) under stirring. To the mixture heated
at 50 ꢀC, benzothiazin-3-one 1a (16.4 g, 100 mmol) and
the corresponding acid chloride (130 mmol) were added.
The mixture was heated at 90 ꢀC for 4 h, poured into ice-
water (1 L), and the resulting precipitate was filtered,
washed with water, dried and recrystallized.
4.3. General procedure for the synthesis of 5-acyl-2-
aminothiophenol derivatives (5a–d)
6-Acyl-2(3H)-benzothiazolone (4a–d) (20 mmol) and KOH
powder (5.6 g, 100 mmol) were heated at fusion during 1 h
under nitrogen. The residue was poured into 100 mL of
cold water and filtered. The aqueous solution was extracted
with diethyl ether, acidified (pH¼3) by 12 M HCl solution,
then the pH adjusted to 8 with aqueous solution of sodium
hydrogen carbonate. The precipitate was filtered, washed
with water and recrystallized.
4.2.1. 7-Butyryl-4H-benzothiazin-3-one (2a). Recrystalli-
zation from acetone gave 2a in 81% yield; mp 191–
193 ꢀC; IR (KBr, n cmꢂ1) 3200 (NH), 1670 and 1645
(CO); 1H NMR (300 MHz, DMSO-d6): d¼0.95 (t, 3H,
J¼5.90 Hz, CH3), 1.55 (m, 2H, CH2), 2.75 (t, 2H, J¼
6.05 Hz, CH2), 3.50 (s, 2H, CH2), 6.95 (d, 1H, J¼8.15 Hz,
H5), 7.55 (d, 1H, J¼1.25 Hz, H8), 7.70 (dd, 1H, J¼
8.15 Hz, J¼1.25 Hz, H6), 10.50 (s, 1H, NH, exchangeable
with D2O). Anal. Calcd for C12H13NO2S: C, 61.27; H,
5.57; N, 5.91; S, 13.61. Found: C, 61.03; H, 5.54; N, 5.74;
S, 13.84.
4.3.1. 5-Butyryl-2-aminothiophenol (5a). Recrystalliza-
tion from acetone gave 5a in 60% yield; mp 187–188 ꢀC;
IR (KBr, n cmꢂ1) 3410 (NH), 3350 (SH), 1645 (CO); H
1
NMR (300 MHz, DMSO-d6): d¼0.90 (t, 3H, CH3), 1.50
(m, 2H, CH2), 2.60 (t, 2H, CH2), 6.25 (br s, 3H, NH2 and
SH, exchangeable with D2O), 6.75 (d, 1H, J¼7.80 Hz,
H3), 7.40 (d, 1H, J¼1.10 Hz, H6), 7.70 (dd, 1H,
J¼7.80 Hz, J¼1.10 Hz, H4). Anal. Calcd for C10H13NOS:
C, 60.14; H, 6.81; N, 7.10; S, 16.02. Found: C, 60.42;
H, 6.41; N, 6.92; S, 16.33.
4.2.2. 7-Butyryl-4-methyl-4H-benzothiazin-3-one (2b).
Recrystallization from ethanol gave 2b in 80% yield; mp
1
109–111 ꢀC; IR (KBr, n cmꢂ1) 1670 and 1640 (CO); H
NMR (300 MHz, CDCl3): d¼1.00 (t, 3H, J¼5.50 Hz,
CH3), 1.50 (m, 2H, CH2), 2.80 (t, 2H, J¼6.50 Hz, CH2),
3.40 (s, 3H, CH3), 3.50 (s, 2H, CH2), 7.10 (d, 1H,
J¼8.00 Hz, H5), 7.60 (d, 1H, J¼1.40 Hz, H8), 7.75 (dd,
1H, J¼8.00 Hz, J¼1.40 Hz, H6). Anal. Calcd for
C13H15NO2S: C, 62.64; H, 6.07; N, 5.62; S, 13.61. Found:
C, 62.90; H, 6.02; N, 5.67; S, 12.93.
4.3.2. 5-Butyryl-2-methylaminothiophenol (5b). Recrys-
tallization from ethanol gave 5b in 70% yield; mp 117–
118 ꢀC; IR (KBr, n cmꢂ1) 3400 (NH), 3350 (SH), 1640
1
(CO), 1580 (C]C); H NMR (300 MHz, CDCl3): d¼0.90
(t, 3H, J¼6.20 Hz, CH3), 2.45 (m, 2H, CH2), 2.65 (t, 2H,
J¼6.05 Hz, CH2), 2.95 (s, 3H, CH3), 4.20–3.80 (br s, 2H,
NH and SH, exchangeable with D2O), 6.60 (d, 1H,
J¼8.00 Hz, H3), 7.70 (d, 1H, J¼1.20 Hz, H6), 7.90 (dd,
1H, J¼8.00 Hz, J¼1.20 Hz, H4). Anal. Calcd for
C11H15NOS: C, 63.14; H, 6.71; N, 6.69; S, 15.29. Found:
C, 63.50; H, 6.71; N, 6.55; S, 15.35.
4.2.3. 7-Benzoyl-4H-benzothiazin-3-one (2c). Recrystalli-
zation from acetone gave 2c in 55% yield; mp 210–
212 ꢀC; IR (KBr, n cmꢂ1) 3196 (NH), 1694 and 1645

P. Carato et al. / Tetrahedron 62 (2006) 9054–9058
9057
4.3.3. 5-Benzoyl-2-aminothiophenol (5c). Recrystalliza-
tion from acetone gave 5c in 60% yield; mp 208–210 ꢀC;
IR (KBr, n cmꢂ1) 3500 (NH), 3300 (SH), 1650 (CO), 1590
The residue was purified by flash column chromatography
with dichloromethane/EtOAc (9/1) and recrystallized.
1
(C]C); H NMR (300 MHz, DMSO-d6): d¼6.25 (br s,
4.6.1. 6-Butyryl-4H-benzothiazin-3-one (8a). Recrystalli-
zation from ethanol gave 8a in 40% yield; mp 214–
215 ꢀC; IR (KBr, n cmꢂ1) 3194 (NH), 1672 (CO); 1H
NMR (300 MHz, CDCl3): d¼0.90 (t, 3H, J¼7.00 Hz,
CH3), 1.60 (m, 2H, CH2), 2.90 (t, 2H, J¼7.00 Hz,
CH2CO), 3.55 (s, 2H, CH2S), 7.45 (d, 1H, J¼8.20 Hz, H8),
7.50 (s, 1H, H5), 7.55 (dd, 1H, J¼8.20 Hz, J¼1.75 Hz,
H7), 10.60 (br s, 1H, NH, exchangeable with D2O). Anal.
Calcd for C12H13NO2S: C, 61.25; H, 5.57; N, 5.95; S,
13.63. Found: C, 61.05; H, 5.70; N, 5.68; S, 13.50.
3H, NH2 and SH, exchangeable with D2O), 6.75 (d, 1H,
J¼8.30 Hz, H3), 7.45–7.60 (m, 6H, H6, HAr), 7.80 (dd, 1H,
J¼8.30 Hz, J¼1.05 Hz, H4). Anal. Calcd for C13H11NOS:
C, 68.41; H, 4.83; N, 6.13; S, 14.02. Found: C, 68.32; H,
4.52; N, 6.02; S, 14.12.
4.3.4. 5-Benzoyl-2-methylaminothiophenol (5d). Recrys-
tallization from ethanol gave 5d in 60% yield; mp 70–
71 ꢀC; IR (KBr, n cmꢂ1) 3400 (NH), 3350 (SH), 1650
(CO); 1H NMR (300 MHz, DMSO-d6): d¼2.95 (s, 1H,
NH, exchangeable with D2O), 3.20 (s, 3H, CH3), 6.75 (s,
1H, SH, exchangeable with D2O), 7.20 (d, 1H, J¼8.15 Hz,
H3), 7.50 (m, 6H, H6, HAr), 7.80 (dd, 1H, J¼8.15 Hz,
J¼1.30 Hz, H4). Anal. Calcd for C14H13NOS: C, 69.12; H,
5.38; N, 5.75; S, 13.15. Found: C, 69.01; H, 5.55; N, 5.92;
S, 13.02.
4.6.2. 6-Benzoyl-4H-benzothiazin-3-one (8b). Recrystalli-
zation from ethanol gave 8b in 69% yield, mp 180–181 ꢀC;
IR (KBr, n cmꢂ1) 3140 (NH), 1678 and 1640 (CO); 1H NMR
(300 MHz, DMSO-d6): d¼3.35 (s, 2H, CH2CO), 7.30 (dd,
1H, J¼7.90 Hz, J¼1.50 Hz, H7), 7.40 (d, 1H, J¼1.50 Hz,
H5), 7.50 (d, 1H, J¼7.90 Hz, H8), 7.60 (m, 2H, HAr),
7.65–7.75 (m, 3H, HAr), 10.75 (br s, 1H, NH, exchangeable
with D2O). Anal. Calcd for C15H11NO2S: C, 66.89; H, 4.12;
N, 5.20; S, 11.91. Found: C, 66.74; H, 4.24; N, 5.03; S,
12.13.
4.4. General procedure for the synthesis of 7-acyl-
4H-benzothiazin-3-one derivatives (2a–d) from
compounds 5a–d
The method adopted for the synthesis of 7-butyryl-4H-ben-
zothiazin-3-one (2a) is described. To a solution of compound
5a (3.9 g, 20 mmol) in DMSO was added sodium ethylate
(1.36 g, 20 mmol). After 1 h, ethyl bromoacetate (2.45
mL, 22 mmol) was added and the mixture was stirred for
2 h at room temperature. The solution was poured into
cold water and acidified with 6 M HCl solution (pH¼5), fil-
tered, washed with water and recrystallized from acetone to
give 2a in 65% yield (2b–d: 56–76% yield).
4.6.3. 6-(Ethyl-4-oxobutyrate)-4H-benzothiazin-3-one
(8c). Recrystallization from ethanol gave 8c in 57% yield;
mp 162–163 ꢀC; IR (KBr, n cmꢂ1) 3315 (NH), 1723
(COO), 1672 (CON); 1H NMR (300 MHz, CDCl3):
d¼1.30 (t, 3H, J¼7.00 Hz, CH3), 2.80 (t, 2H, J¼6.45 Hz,
CH2CO), 3.30 (t, 2H, J¼6.45 Hz, CH2COO), 3.50 (s, 2H,
CH2S), 4.20 (q, 2H, J¼7.00 Hz, CH3), 7.40 (d, 1H,
J¼8.20 Hz, H7), 7.50 (d, 1H, J¼1.75 Hz, H4), 7.65 (dd,
1H, J¼8.20 Hz, J¼1.75 Hz, H6), 8.50 (br s, 1H, NH,
exchangeable with D2O). Anal. Calcd for C14H15NO4S: C,
57.32; H, 5.15; N, 4.77; S, 10.93. Found: C, 57.15; H,
5.28; N, 4.63; S, 10.78.
4.5. 6-Tributyltin-4H-benzothiazin-3-one (7)
To a mixture of 6-bromo-3-methyl-4H-benzothiazin-3-one
(6) (4.4 g, 18 mmol) in toluene (20 mL) under argon, tetra-
kis(triphenyl phosphine) palladium (1.86 g, 1.8 mmol) and
bis(tributyltin) (11.80 mL, 27 mmol) were added. The reac-
tion mixture was stirred at reflux for 6 h. The solution was
evaporated under reduced pressure. The oily residue was
purified by flash column chromatography with petroleum
ether/EtOAc (9/1) to give an oily product. Yield 53%; IR
(KBr, n cmꢂ1) 3211 (NH), 2852–2956 (CH), 1679 (CO);
1H NMR (300 MHz, CDCl3): d¼0.80 (t, 9H, J¼5.70 Hz,
(CH3)3), 1.05 (t, 6H, J¼6.00 Hz, (COCH2)3), 1.30 (m, 6H,
(CH2)3), 1.50 (m, 6H, (CH2)3), 3.45 (s, 2H, CH2CO), 6.90
(d, 1H, J¼0.95 Hz, H5), 7.10 (dd, 1H, J¼7.30 Hz,
J¼0.95 Hz, H7), 7.30 (d, 1H, J¼7.30 Hz, H8), 8.50 (br s,
1H, NH, exchangeable with D2O). Anal. Calcd for
C20H33NOSSn: C, 52.88; H, 7.32; N, 3.08; S, 7.06. Found:
C, 52.63; H, 7.50; N, 2.86; S, 7.32.
4.7. 6-(4-Oxobutyric)-4H-benzothiazin-3-one (8d)
To sodium hydroxide (0.21 g, 5.13 mmol) dissolved in a so-
lution of ethanol/water (15/15 mL) was added compound 8c
(0.50 g, 1.71 mmol). The reaction mixture was refluxed for
2 h and then evaporated under reduced pressure. The residue
was dissolved in water (30 mL). The solution was acidified
with 6 N HCl to pH¼1, and extracted with dichloromethane.
The organic layer was dried over magnesium sulfate and
evaporated under reduced pressure. The compound was
recrystallized from ethanol to give 8d in 65% yield; mp
189–190 ꢀC; IR (KBr, n cmꢂ1) 3254 (NH), 1701 (COO),
1669 (CON), 1650 (CO); 1H NMR (300 MHz, CDCl3):
d¼2.60 (m, 2H, CH2CO), 3.15 (m, 2H, CH2COO), 3.60 (s,
2H, CH2S), 7.40–7.60 (m, 3H, H4, H6, H7), 10.60 (br s,
1H, NH, exchangeable with D2O), 12.10 (br s, 1H, OH,
exchangeable with D2O). Anal. Calcd for C12H11NO4S: C,
54.33; H, 4.18; N, 5.28; S, 12.09. Found: C, 54.57; H,
4.35; N, 5.08; S, 12.24.
4.6. General procedure for the synthesis of 6-acyl-4H-
benzothiazin-3-one derivatives (8a–c)
Compound 7 (1.04 g, 2.3 mmol) in toluene (10 mL) was
placed under argon, dichlorobis(triphenyl phosphine) palla-
dium (0.16 g, 0.23 mmol) and the corresponding acid chlo-
ride (4.6 mmol) were added. The reaction was refluxed for
2 h. The solution was evaporated under reduced pressure.
References and notes
1. Moussavi, Z.; Lesieur, D.; Lespagnol, C.; Sauzieres, J.; Olivier,
P. Eur. J. Med. Chem. 1989, 24, 55–60.

9058
P. Carato et al. / Tetrahedron 62 (2006) 9054–9058
2. Moussavi, Z.; Depreux, P.; Lesieur, D.; Cotelle, N.; Sauzieres,
J.; Plancke, M. O.; Fruchart, J. C. Il Farmaco 1991, 46, 339–
355.
3. Depreux, P.; Moussavi, Z.; Lesieur, D.; Sauzieres, J. Il Farmaco
1993, 48, 1079–1089.
9. Combs, D. W. Eur. Pat. EP 0272914, 1988; Chem. Abstr. 1988,
109, 190436m.
10. Combs, D. W. Eur. Pat. EP 509845, 1992.
11. Chihiro, M.; Komatsu, H.; Tominaga, M.; Yabuuchi, Y. Inter.
Patent WO 9209586, 1992.
4. Krishnan, V. S. H.; Chowdary, K. S.; Dubey, P. K.; Naidu, A.;
Vijaya, S. Indian J. Chem., Sect. B 2001, 40, 603–607.
5. Reddy Sastry, C. V.; Bansal, O. P.; Srinivasa Rao, K.; Rao, P.;
Jain, M. L.; Shridhar, D. R. Indian J. Chem., Sect. B 1987,
26, 662–665.
6. Reddy Sastry, C. V.; Srinivasa Rao, K.; Krishnan, V. S. H.;
Rastogi, K.; Jain, M. L. Indian J. Chem., Sect. B 1989, 28,
882–884.
12. Yous, S.; Poupaert, J.-H.; Lesieur, I.; Depreux, P.; Lesieur, D.
J. Org. Chem. 1994, 56, 1574–1576.
13. Moussavi, Z.; Plancke, M. O.; Olivier, P.; Lesieur, D.; Fruchart,
J. C.; Sauzieres, J. Clin. Chim. Acta 1989, 180, 35–44.
14. Shridhar, D. R.; Reddy Sastry, C. V.; Bansal, O. P.; Rao, P.;
Singh, P. P.; Tripathi, R. M.; Seshagiri Rao, C.; Junnarkar,
A. Y.; Thomas, G. P. Indian J. Chem., Sect. B 1983, 22,
1236–1242.
7. Combs, D. W.; Rampulla, M. S.; Bell, S. C.; Klaubert, D. H.;
Tobia, A. J.; Falotico, R.; Haertlein, B.; Lakas-Weiss, C.;
Moore, J. B. J. Med. Chem. 1990, 33, 380–386.
8. Issacs, N. Physical Organic Chemistry, 2nd ed.; Addison
Wesley Longman: New York, NY, 1995; pp 149–159.
15. Davies, D. T.; Jones, G. E.; Markwell, R. E.; Pearson, N. D.
Inter. Patent WO 010138, 2003.
16. Cecchetti, V.; Calderone, V.; Tabarrini, O.; Sabatini, S.;
Filipponi, E.; Testai, L.; Spogli, R.; Martinotti, E.; Fravolini,
A. J. Med. Chem. 2003, 46, 3670–3679.