A novel approach to pyrrolo[2,1-b][1,3]benzothiazines

Article abstract of DOI:10.1055/s-2008-1067214

Alkylation of (3,4-dihydro-4-oxo-2H-1,3-benzothiazin-2-ylidene)acetic acid ethyl ester and (3,4-dihydro-4-oxo-2H-1,3-benzothiazin-2-ylidene)acetonitrile with phenacyl chlorides in the presence of potassium carbonate was shown to occur at the nitrogen atom yielding the corresponding N-phenacyl derivatives. The latter, upon treatment with DMF·POCl₃ complex, were converted into 1-aroyl-9-oxo-9H-pyrrolo[2,1 b][1,3]benzothiazine-3-carboxylic acid ethyl esters and -3-carbonitriles. The structure of the obtained pyrrolobenzothiazine derivatives was confirmed unambiguously by X-ray crystallographic study. Reaction of these pyrrolo[2,1-b][1,3]benzothiazines with aliphatic primary amines resulted in the thiazine ring cleavage and formation of 2-[(5-aroyl-3-cyano(or ethoxycarbonyl)-1H-pyrrol-2-yl)thio]-N- alkylbenzamides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067214

PAPER
2701
A Novel Approach to Pyrrolo[2,1-b][1,3]benzothiazines
P
yrrolo[2,1-
b
][1,3
n
]
benzothiazin
t
e
s
on V. Tverdokhlebov,*a Alexander P. Andrushko,a Andrey A. Tolmachev,a,b Svitlana V. Shishkina,c
Oleg V. Shishkinc
a
Enamine Ltd., Alexandra Matrosova Street 23, 01103 Kiev, Ukraine
Fax +380(44)5373253; E-mail: atver@univ.kiev.ua
Kiev National Taras Shevchenko University, Volodimirska Street 62, 01033 Kiev, Ukraine
STC ‘Institute for Single Crystals’, NAS of Ukraine, 60 Lenina Avenue, 61001 Khar’kiv, Ukraine
b
c
Received 7 April 2008; revised 6 May 2008
R
Abstract: Alkylation of (3,4-dihydro-4-oxo-2H-1,3-benzothiazin-
S
2-ylidene)acetic acid ethyl ester and (3,4-dihydro-4-oxo-2H-1,3-
benzothiazin-2-ylidene)acetonitrile with phenacyl chlorides in the
X
X
S
N
presence of potassium carbonate was shown to occur at the nitrogen
atom yielding the corresponding N-phenacyl derivatives. The latter,
upon treatment with DMF·POCl3 complex, were converted into
1-aroyl-9-oxo-9H-pyrrolo[2,1-b][1,3]benzothiazine-3-carboxylic
acid ethyl esters and -3-carbonitriles. The structure of the obtained
pyrrolobenzothiazine derivatives was confirmed unambiguously by
X-ray crystallographic study. Reaction of these pyrrolo[2,1-
b][1,3]benzothiazines with aliphatic primary amines resulted in the
thiazine ring cleavage and formation of 2-[(5-aroyl-3-cyano(or
ethoxycarbonyl)-1H-pyrrol-2-yl)thio]-N-alkylbenzamides.
O
N
O
H
O
Ar
1
2
Figure 1 X = CN, CO2Et, SO2Ar; Ar = Ph or substituted Ph;
R = NMe2, Ph or substituted Ph
thio)benzoic acid derivatives represents another method
for the thiazine ring closure4 during the synthesis of the
title system. Finally, a free-radical cyclization of certain
N-[2-bromo(iodo)benzyl]pyrrolidine derivatives bearing
suitable sulfur substituents into pyrrolobenzothiazines
was described.5 However, all these methods1–5 predomi-
nantly afford the singular derivatives of the target core
with unique substitution pattern and for different reasons
are inapplicable for the preparation of the series of diverse
compounds. Moreover, some of the mentioned reactions
gave pyrrolobenzothiazines in the mixtures with isomers
and side products,2c,3b,c,5 necessitating a separation proce-
dure. Thus, the current achievements in the synthesis of
pyrrolo[2,1-b][1,3]benzothiazines are rather limited, and
therefore, elaboration of new general approaches to this
system is required.
Key words: alkylations, cleavage, cyclizations, heterocycles, pyr-
roles
Pyrrolo[2,1-b][1,3]benzothiazine is a rare heterocyclic
core. To the best of our knowledge only 15 derivatives of
this system have been described to date. Apparently, this
is because of the lack of good and general procedures for
their preparation. Among the known methods, only a sin-
gle example of pyrrole ring annulation to the benzothiaz-
ine moiety was reported.1 The rest of the published
approaches were based on construction of the thiazine
ring.2–5 Most of them included 3aC–S bond formation.2,3
At this step both possible polarities, that is, either the in-
tramolecular attack of electrophilic carbon atom on the
sulfur2 or the intramolecular capture of electrophilic sul-
fur species produced by Pummerer rearrangement of sul-
foxides with electron-rich carbon,3 were realized.
Furthermore, the thermal- or base-induced intramolecular
acylation of the nitrogen in the 2-(1H-pyrrol-2-yl-
In our recent work,6 we have prepared pyrrolo[2,1-b]thia-
zoles of type 1 by a two-step pyrrole annulation to the thi-
azole precursors 2 (Figure 1). Since the closely related
benzothiazine derivatives 3,4 (Scheme 1) are readily
available from 2-mercaptobenzoic ester and ethyl cy-
anoacetate or malononitrile, respectively,7 it would be
O
O
N
Ar
O
O
O
Ar
O
S
Cl
NH
Ar
DMF⋅POCl3
N
K2CO3, DMF
S
S
X
X
7a–c
8a–c
X
5a–c
6a–c
3,4
Scheme 1 X = CO2Et (3, 5, 7), X = CN (4, 6, 8); Ar = Ph (a), 4-ClC6H4 (b), 4-BrC6H4 (c)
SYNTHESIS 2008, No. 17, pp 2701–2706
x
x.
x
x
.
2
0
0
8
Advanced online publication: 06.08.2008
DOI: 10.1055/s-2008-1067214; Art ID: P04908SS
© Georg Thieme Verlag Stuttgart · New York

2702
A. V. Tverdokhlebov et al.
PAPER
Figure 2 X-ray molecular structures of compound 7a with the atom numbering used in the crystallographic analysis
reasonable to extend the method to these compounds. both A and B while the typical length is 1.35 Å;9 and the
Moreover, the alternative route to pyrrolo[2,1-b][1,3]ben- distance N(1)–C(9) is 1.41 and 1.42 Å in A and B, respec-
zothiazines based on the pyrrole ring formation seems to tively, whereas the standard value is 1.37 Å.9 Further-
be more promising because the previous thiazine ring clo- more, in both the molecules the ester group is disordered.
sure approaches2–5 revealed their inaptitude providing In molecule A the whole ethoxycarbonyl substituent is
only 15 derivatives over the last 45 years since the first disordered over two positions E and C with a population
report1 of the core synthesis.
70:30% owing to the rotation around C(11)–C(12) bond.
In molecule B, only the ethyl group is disordered over two
positions F and D with a population of 62:38% at the ex-
pense of rotation around C(12)–O(3) bond.
Compounds 3,4 undergo N-alkylation with simple alkyl
halides under basic conditions.7 Indeed, their reaction
with phenacyl chlorides in the presence of K2CO3 pro-
ceeded smoothly leading to derivatives 5a–c, 6a–c in sat- Certain condensed heterocycles containing the N-acylpyr-
isfactory yields. Alkylation of the enamine carbon atom role moiety were reported to undergo cleavage at the CO–
was not observed, similar to the case of thiazole analogues N bond upon treatment with highly nucleophilic amines or
2.6 In the next step, the benzothiazines 5,6 were treated hydrolysis.10 Moreover, the two examples of such a cleav-
with a 2.5-fold excess Vilsmeier’s complex according to age were noted for 9-oxo derivatives of the title sys-
our method6 to afford the pyrrolobenzothiazines 7a–c, tem.3b,4a Thus, the reaction of compounds 7,8 also
8a–c in good yields. Compounds 7,8 were assumed to be containing the N-acylpyrrole fragment with aliphatic pri-
formed through initial formylation of the enamine moiety mary amines was examined. It was found that heating de-
and further intramolecular condensation of the introduced rivatives 7a,c, 8c with amines in DMF furnished 2-(2-
formyl group with the methylene. Compared to the prep- pyrrolylthio)benzamides 9a–g in nearly quantitative
aration of the pyrrolothiazoles 1 the present reaction oc- yields (Scheme 2, Table 1). The CO–N bond of pyr-
curred slightly faster, but the final yields of the isolated rolobenzothiazines 7,8 is really reactive towards nucleo-
products 7, 8 were comparable with that of 1.
philes and compounds 7,8 can be used as mild acylating
agents giving access to unique pyrrole derivatives. The
observed reactivity agrees completely with the elongation
of the N(1)–C(8) bond revealed by the crystal data.
The structure of the obtained compounds 7,8 was initially
deduced from their 1H and 13C NMR spectra and then con-
firmed unambiguously by X-ray crystallographic study
carried out on the derivative 7a (Figure 2). According to
the crystal data, the asymmetric part of crystal unit cell
contains the two molecules A and B differed by certain
geometric parameters. In both molecules, the thiazine ring
adopts a twist-boat conformation. Deviations of the S(1)
and C(8) atoms from the least-squared plane of the rest of
the atoms of the ring are +0.15 and +0.19 Å for molecule
A or –0.12 and –0.19 Å for B, respectively. The following
puckering parameters8 have been calculated: S = 0.27,
Q = 72.9°, y = 24.6° for molecule A and S = 0.28,
Q = 68.0°, y = 29.1° for B. A repulsion between the
neighboring carbonyls of the thiazine moiety and the ben-
zoyl substituent results in considerable elongation of the
bonds N(1)–C(8) and N(1)–C(9) compared with their
standard values. Thus, the distance N(1)–C(8) is 1.42 Å in
Ar
O
HN
X
H2N
DMF
R
S
7a,c, 8c
O
NH
R
9a–g
Scheme 2 For yields and assignments of the groups X, R, Ar, see
Table 1
Synthesis 2008, No. 17, 2701–2706 © Thieme Stuttgart · New York

PAPER
Pyrrolo[2,1-b][1,3]benzothiazines
2703
Benzothiazines 5a–c and 6a–c; General Procedure
Table 1 Compounds 9a–g Prepared
Powdered K2CO3 (0.76 g, 5.5 mmol) was added to a solution of
compound 3,4 (5.0 mmol) in DMF (10 mL) and the mixture was
stirred at r.t. for 0.5 h. Then an appropriate phenacyl chloride (5.0
mmol) was added in one portion and the stirring was continued for
5–6 h. The mixture was poured into H2O (20 mL) and the separated
solid was filtered and recrystallized from a suitable solvent to give
derivatives 5a–c and 6a–c.
Product
9a
X
Ar
R
Yield (%)
CO2Et
CO2Et
CO2Et
CO2Et
CN
Ph
Ph
96
89
96
93
91
91
95
9b
Ph
2-furyl
Ph
9c
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
[3,4-Dihydro-4-oxo-3-(2-oxo-2-phenylethyl)-2H-1,3-benzothi-
azin-2-ylidene]acetic Acid Ethyl Ester (5a)
Yield: 0.88 g (48%); mp 177 °C (EtOH).
1H NMR: d = 1.16 (t, J = 7.0 Hz, 3 H, CH3), 4.07 (q, J = 7.0 Hz, 2
H, OCH2), 5.57 (s, 1 H, CHCOO), 5.71 (s, 2 H, NCH2), 7.43 (t,
J = 7.5 Hz, 1 H, 6-H), 7.57–7.62 (m, 3 H, 3,5-HAr, 8-H), 7.68 (t,
J = 7.5 Hz, 1 H, 7-H), 7.73 (t, J = 7.0 Hz, 1 H, 4-HAr), 8.09 (m, 3 H,
5-H, 2,6-HAr).
9d
2-furyl
Ph
9e
9f
CN
2-furyl
Bn
9g
CO2Et
The structures of compounds 9a–g were confirmed by 1H
and 13C NMR data. For selected samples the sets of 2D
NMR experiments (COSY, NOESY, HSQC, HMBC)
were performed to facilitate the signal assignments and to
ensure the 2-(2-pyrrolylthio)benzamide structure. As for
the spectral data, the downfield shift of the carbonyl signal
from 157–158 ppm (9-C) in the starting materials 7,8 to
167–168 ppm (CONH) in the products 9 in the 13C NMR
spectra as well as appearance of the both pyrrole (12.7–
13.5 ppm) and amide (8.6–9.1 ppm) NH signals in the 1H
NMR spectra of derivatives 9 deserve to be mentioned as
the most remarkable attributes of the thiazine ring cleav-
age.
13C NMR: d = 14.7 (CH3), 54.3 (NCH2), 60.0 (OCH2), 96.3
(CHCOO), 122.3 (4a-C), 125.7 (5-C), 127.6 (8-C), 128.8 (3,5-CAr),
129.4 (2,6-CAr), 130.4 (6-C), 134.0 (1-CAr), 134.6 (4-CAr), 134.7 (7-
C), 134.9 (8a-C), 150.6 (2-C), 160.6 (4-CO), 166.4 (COO), 192.6
(COAr).
Anal. Calcd for C20H17NO4S: C, 65.38; H, 4.66; N, 3.81; S, 8.73.
Found: C, 65.56; H, 4.73; N, 3.80; S, 8.89.
{3-[2-(4-Chlorophenyl)-2-oxoethyl]-3,4-dihydro-4-oxo-2H-1,3-
benzothiazin-2-ylidene}acetic Acid Ethyl Ester (5b)
Yield: 1.08 g (54%); mp 190 °C (EtOH).
1H NMR: d = 1.16 (t, J = 7.5 Hz, 3 H, CH3), 4.06 (q, J = 7.5 Hz, 2
H, OCH2), 5.61 (s, 1 H, CHCOO), 5.70 (s, 2 H, NCH2), 7.43 (t,
J = 8.0 Hz, 1 H, 6-H), 7.58 (d, J = 8.0 Hz, 1 H, 8-H), 7.68 (m, 3 H,
7-H, 3,5-HAr), 8.09 (m, 3 H, 5-H, 2,6-HAr).
13C NMR: d = 14.7 (CH3), 54.3 (NCH2), 60.0 (OCH2), 96.4
(CHCOO), 122.2 (4a-C), 125.7 (5-C), 127.6 (8-C), 129.5 (3,5-CAr),
130.4 (6-C), 130.7 (2,6-CAr), 133.6 (1-CAr), 134.0 (7-C), 134.7 (8a-
C), 139.5 (4-CAr), 150.6 (2-C), 160.6 (4-CO), 166.4 (COO), 191.8
(COAr).
In summary, the present research has resulted in a novel
and convenient approach to pyrrolo[2,1-b][1,3]benzothi-
azines. Contrary to the known procedures1–5 it allows for
the preparation of a diverse series of compounds 7,8 with
at least two points of substituent variation. For the first
time, the precise crystallographic data about structure and
conformation of pyrrolo[2,1-b][1,3]benzothiazine core
have been obtained. Furthermore, the possibility of easy
nucleophilic cleavage of derivatives 7,8 into benzamides
9 has been demonstrated, thus confirming a few previous
observations.3b,4a In view of our preceding work6 the two-
step pyrrole annulation to heterocyclic enamides of type
2–4 is believed to be general. Further studies in the field
are in progress.
Anal. Calcd for C20H16ClNO4S: C, 59.78; H, 4.01; N, 3.49; Cl, 8.82;
S, 7.98. Found: C, 59.84; H, 3.86; N, 3.70; Cl, 8.80; S, 7.76.
{3-[2-(4-Bromophenyl)-2-oxoethyl]-3,4-dihydro-4-oxo-2H-1,3-
benzothiazin-2-ylidene}acetic Acid Ethyl Ester (5c)
Yield: 1.13 g (51%); mp 183 °C (EtOH).
1H NMR: d = 1.12 (t, J = 7.0 Hz, 3 H, CH3), 4.04 (q, J = 7.0 Hz, 2
H, OCH2), 5.49 (s, 1 H, CHCOO), 5.74 (s, 2 H, NCH2), 7.51 (t,
J = 7.5 Hz, 1 H, 6-H), 7.58 (d, J = 7.5 Hz, 1 H, 8-H), 7.69 (m, 3 H,
7-H, 3,5-HAr), 8.05 (m, 3 H, 2,6-HAr, 5-H).
The starting compounds 3,4 were prepared as described.7 Phenacyl
chlorides were either commercially available or obtained according
to the reported procedures.11 Commercial DMF was kept over P2O5
overnight and then distilled under reduced pressure. Other reagents
were commercially available and were used without additional pu-
rification. All melting points were determined in open capillary
13C NMR: d = 12.1 (CH3), 55.5 (NCH2), 60.6 (OCH2), 97.8
(CHCOO), 122.5 (4a-C), 126.5 (5-C), 127.2 (8-C), 130.2 (4-CAr),
130.4 (6-C), 130.9 (3,5-CAr), 132.5 (7-C), 133.5 (2,6-CAr), 134.4 (1-
CAr), 134.6 (8a-C), 150.3 (2-C), 163.3 (4-CO), 166.3 (COO), 191.5
(COAr).
Anal. Calcd for C20H16BrNO4S: C, 53.82; H, 3.61; N, 3.14; Br,
17.90; S, 7.18. Found: C, 53.66; H, 3.64; N, 3.18; Br, 17.71; S, 7.35.
1
tubes in a Thiele apparatus and are uncorrected. H and 13C NMR
spectra were recorded on a Varian Unity plus 400 spectrometer (400
MHz for 1H and 100 MHz for 13C) in DMSO-d6. 2D NMR experi-
ments were performed on a Bruker Avance 500 spectrometer (500
MHz for 1H and 125 MHz for 13C). Chemical shifts (d) are given in
ppm downfield from internal Me4Si. J values are in Hz. The purity
of all compounds obtained was checked by 1H NMR and LC/MS on
an Agilent 1100 instrument.
[3,4-Dihydro-4-oxo-3-(2-oxo-2-phenylethyl)-2H-1,3-benzothi-
azin-2-ylidene]acetonitrile (6a)
Yield: 1.02 g (64%); mp 153 °C (MeCN).
1H NMR: d = 5.24 (s, 1 H, CHCN), 5.55 (s, 2 H, NCH2), 7.37 (t,
J = 7.5 Hz, 1 H, 6-H), 7.57 (d, J = 7.5 Hz, 1 H, 8-H), 7.63–7.68 (m,
3 H, 7-H, 3,5-HAr), 7.71 (t, J = 7.0 Hz, 1 H, 4-HAr), 8.05 (d, J = 7.0
Hz, 2 H, 2,6-HAr), 8.13 (d, J = 7.5 Hz, 1 H, 5-H).
Synthesis 2008, No. 17, 2701–2706 © Thieme Stuttgart · New York

2704
A. V. Tverdokhlebov et al.
PAPER
13C NMR: d = 53.9 (NCH2), 74.7 (CHCN), 115.5 (CN), 121.6 (4a-
C), 125.2 (5-C), 128.1 (3,5-CAr), 128.2 (8-C), 131.4 (2,6-CAr), 132.8
(6-C), 133.5 (7-C), 134.1 (1-CAr), 134.3 (4-CAr), 135.4 (8a-C),
153.8 (2-C), 160.5 (4-CO), 193.1 (COAr).
1-(4-Chlorobenzoyl)-9-oxo-9H-pyrrolo[2,1-b][1,3]benzothiaz-
ine-3-carboxylic Acid Ethyl Ester (7b)
Yield: 0.76 g (62%); mp 196 °C (DMF–H2O).
1H NMR: d = 1.32 (t, J = 7.5 Hz, 3 H, CH3), 4.32 (q, J = 7.5 Hz, 2
H, OCH2), 7.28 (s, 1 H, 2-H), 7.56 (m, 3 H, 7-H, 3,5-HAr), 7.82 (m,
3 H, 6-H, 2,6-HAr), 7.92 (d, J = 7.5 Hz, 1 H, 5-H), 8.23 (d, J = 7.5
Hz, 1 H, 8-H).
Anal. Calcd for C18H12N2O2S: C, 67.48; H, 3.78; N, 8.74; S, 10.01.
Found: C, 67.47; H, 3.72; N, 8.61; S, 9.97.
{3-[2-(4-Chlorophenyl)-2-oxoethyl]-3,4-dihydro-4-oxo-2H-1,3-
benzothiazin-2-ylidene}acetonitrile (6b)
Yield: 0.80 g (45%); mp 184 °C (MeCN).
13C NMR: d = 14.7 (CH3), 61.1 (OCH2), 113.0 (3-C), 118.9 (2-C),
121.9 (8a-C), 126.9 (8-C), 128.0 (5-C), 129.3 (3,5-CAr), 130.8 (7-
C), 131.2 (2,6-CAr), 131.8 (6-C), 133.9 (4a-C), 134.8 (1-CAr), 134.9
(1-C), 136.7 (3a-C), 138.6 (4-CAr), 157.9 (9-CO), 162.9 (COO),
184.9 (COAr).
1H NMR: d = 5.28 (s, 1 H, CHCN), 5.55 (s, 2 H, NCH2), 7.38 (t,
J = 7.5 Hz, 1 H, 6-H), 7.46 (d, J = 7.5 Hz, 1 H, 8-H), 7.53 (d, J = 8.5
Hz, 2 H, 3,5-HAr), 7.61 (t, J = 7.5 Hz, 1 H, 7-H), 8.06 (d, J = 8.5 Hz,
2 H, 2,6-HAr), 8.14 (d, J = 7.5 Hz, 1 H, 5-H).
13C NMR: d = 53.5 (NCH2), 75.8 (CHCN), 117.2 (CN), 122.3 (4a-
C), 125.7 (5-C), 128.1 (8-C), 129.5 (3,5-CAr), 130.7 (2,6-CAr), 131.1
(6-C), 131.2 (7-C), 133.5 (1-CAr), 135.0 (8a-C), 139.6 (4-CAr),
152.2 (2-C), 160.2 (4-CO), 191.1 (COAr).
Anal. Calcd for C21H14ClNO4S: C, 61.24; H, 3.43; N, 3.40; Cl, 8.61;
S, 7.79. Found: C, 61.30; H, 3.21; N, 3.30; Cl, 8.60; S, 7.64.
1-(4-Bromobenzoyl)-9-oxo-9H-pyrrolo[2,1-b][1,3]benzothiaz-
ine-3-carboxylic Acid Ethyl Ester (7c)
Yield: 0.85 g (62%); mp 190–191 °C (DMF–H2O).
Anal. Calcd for C18H11ClN2O2S: C, 60.93; H, 3.12; N, 7.90; Cl,
9.99; S, 9.04. Found: C, 60.84; H, 3.20; N, 7.80; Cl, 10.01; S, 8.95.
1H NMR: d = 1.32 (t, J = 7.0 Hz, 3 H, CH3), 4.32 (q, J = 7.0 Hz, 2
H, OCH2), 7.29 (s, 1 H, 2-H), 7.57 (t, J = 7.5 Hz, 1 H, 7-H), 7.71 (m,
4 HAr), 7.83 (t, J = 7.5 Hz, 1 H, 6-H), 7.94 (d, J = 7.5 Hz, 1 H, 5-H),
8.24 (d, J = 7.5 Hz, 1 H, 8-H).
13C NMR: d = 14.7 (CH3), 61.1 (OCH2), 112.9 (3-C), 119.0 (2-C),
121.8 (8a-C), 126.9 (8-C), 127.8 (4-CAr), 128.0 (5-C), 130.8 (7-C),
131.3 (2,6-CAr), 131.8 (6-C), 132.3 (3,5-CAr), 133.9 (4a-C), 134.7
(1-CAr), 134.8 (1-C), 136.9 (3a-C), 157.9 (9-CO), 162.9 (COO),
185.1 (COAr).
{3-[2-(4-Bromophenyl)-2-oxoethyl]-3,4-dihydro-4-oxo-2H-1,3-
benzothiazin-2-ylidene}acetonitrile (6c)
Yield: 0.92 g (46%); mp 185 °C (MeCN).
1H NMR: d = 5.52 (s, 1 H, CHCN), 5.58 (s, 2 H, NCH2), 7.47 (t,
J = 8.0 Hz, 1 H, 6-H), 7.65 (d, J = 8.0 Hz, 1 H, 8-H), 7.71 (t, J = 8.0
Hz, 1 H, 7-H), 7.82 (d, J = 7.0 Hz, 2 H, 3,5-HAr), 8.00 (d, J = 7.0 Hz,
2 H, 2,6-HAr), 8.09 (d, J = 8.0 Hz, 1 H, 5-H).
13C NMR: d = 53.4 (NCH2), 75.8 (CHCN), 117.2 (CN), 122.3 (4a-
C), 125.7 (5-C), 128.1 (8-C), 128.8 (4-CAr), 130.8 (3,5-CAr), 131.1
(6-C), 131.2 (7-C), 132.4 (2,6-CAr), 133.8 (1-CAr), 135.0 (8a-C),
152.2 (2-C), 160.2 (4-CO), 191.4 (COAr).
Anal. Calcd for C21H14BrNO4S: C, 55.28; H, 3.09; N, 3.07; Br,
17.51; S, 7.03. Found: C, 55.30; H, 3.16; N, 3.10; Br, 17.50; S, 7.13.
1-Benzoyl-9-oxo-9H-pyrrolo[2,1-b][1,3]benzothiazine-3-carbo-
nitrile (8a)
Yield: 0.66 g (67%); mp 208–209 °C (DMF–H2O).
Anal. Calcd for C18H11BrN2O2S: C, 54.15; H, 2.78; N, 7.02; Br,
20.01; S, 8.03. Found: C, 53.93; H, 2.74; N, 7.17; Br, 19.98; S, 7.87.
1H NMR: d = 7.50 (m, 3 H, 2-H, 3,5-HAr), 7.59 (t, J = 8.0 Hz, 1 H,
7-H), 7.65 (t, J = 7.0 Hz, 1 H, 4-HAr), 7.81–7.88 (m, 3 H, 6-H, 2,6-
HAr), 7.96 (d, J = 8.0 Hz, 1 H, 5-H), 8.25 (d, J = 8.0 Hz, 1 H, 8-H).
13C NMR: d = 91.4 (3-C), 113.9 (CN), 119.6 (2-C), 121.8 (8a-C),
126.9 (8-C), 128.3 (5-C), 129.2 (3,5-CAr), 129.7 (2,6-CAr), 131.3 (7-
C), 132.0 (4-CAr), 132.5 (6-C), 134.1 (1-CAr), 135.1 (1-C), 135.6
(4a-C), 137.4 (3a-C), 157.4 (9-CO), 185.8 (COAr).
Pyrrolo[2,1-b][1,3]benzothiazines 7a–c and 8a–c; General Pro-
cedure
The appropriate compound 5a–c, 6a–c (3.0 mmol) was added to a
cold solution of POCl3 (1.15 g, 7.5 mmol) in DMF (10 mL) and the
mixture was gently warmed to dissolve the starting material and
then heated at 60–70 °C for 1–1.5 h. After cooling, the mixture was
diluted with H2O (20 mL) and the precipitate formed was filtered
and recrystallized from aq DMF yielding derivatives 7a–c and
8a–c.
Anal. Calcd for C19H10N2O2S: C, 69.08; H, 3.05; N, 8.48; S, 9.71.
Found: C, 69.15; H, 3.16; N, 8.62; S, 9.89.
1-(4-Chlorobenzoyl)-9-oxo-9H-pyrrolo[2,1-b][1,3]benzothiaz-
ine-3-carbonitrile (8b)
Yield: 0.68 g (62%); mp 184 °C (DMF–H2O).
1-Benzoyl-9-oxo-9H-pyrrolo[2,1-b][1,3]benzothiazine-3-car-
boxylic Acid Ethyl Ester (7a)
1H NMR: d = 7.53 (s, 1 H, 2-H), 7.55 (d, J = 8.5 Hz, 2 H, 3,5-HAr),
7.60 (t, J = 8.0 Hz, 1 H, 7-H), 7.83 (d, J = 8.5 Hz, 2 H, 2,6-HAr),
7.86 (t, J = 8.0 Hz, 1 H, 6-H), 7.96 (d, J = 8.0 Hz, 1 H, 5-H), 8.26
(d, J = 8.0 Hz, 1 H, 8-H).
13C NMR: d = 91.5 (3-C), 113.8 (CN), 119.9 (2-C), 121.8 (8a-C),
126.9 (8-C), 128.4 (5-C), 129.4 (3,5-CAr), 131.3 (7-C), 131.4 (2,6-
CAr), 131.6 (1-CAr), 132.5 (6-C), 135.1 (1-C), 135.9 (4a-C), 136.3
(3a-C), 138.9 (4-CAr), 157.5 (9-CO), 184.7 (COAr).
Yield: 0.88 g (78%); mp 153 °C (DMF–H2O).
1H NMR: d = 1.32 (t, J = 7.0 Hz, 3 H, CH3), 4.31 (q, J = 7.0 Hz, 2
H, OCH2), 7.23 (s, 1 H, 2-H), 7.50 (t, J = 7.5 Hz, 2 H, 3,5-HAr), 7.55
(t, J = 8.0 Hz, 1 H, 7-H), 7.63 (t, J = 7.5 Hz, 1 H, 4-HAr), 7.81 (m, 3
H, 6-H, 2,6-HAr), 7.91 (d, J = 8.0 Hz, 1 H, 5-H), 8.22 (d, J = 8.0 Hz,
1 H, 8-H).
13C NMR: d = 14.8 (CH3), 61.1 (OCH2), 112.8 (3-C), 118.7 (2-C),
121.9 (8a-C), 126.9 (8-C), 128.0 (5-C), 129.2 (3,5-CAr), 129.5 (2,6-
CAr), 130.8 (7-C), 132.3 (6-C), 133.7 (4a-C), 133.8 (4-CAr), 134.8
(1-CAr), 134.9 (1-C), 137.7 (3a-C), 157.8 (9-CO), 162.9 (COO),
186.0 (COAr).
Anal. Calcd for C19H9ClN2O2S: C, 62.56; H, 2.49; N, 7.68; Cl, 9.72;
S, 8.79. Found: C, 62.77; H, 2.68; N, 7.60; Cl, 9.70; S, 8.70.
1-(4-Bromobenzoyl)-9-oxo-9H-pyrrolo[2,1-b][1,3]benzothiaz-
ine-3-carbonitrile (8c)
Yield: 0.92 g (75%); mp 189–190 °C (DMF–H2O).
Anal. Calcd for C21H15NO4S: C, 66.83; H, 4.01; N, 3.71; S, 8.50.
Found: C, 66.91; H, 4.10; N, 3.72; S, 8.28.
1H NMR: d = 7.52 (s, 1 H, 2-H), 7.59 (t, J = 7.5 Hz, 1 H, 7-H), 7.69
(d, J = 8.5 Hz, 2 H, 3,5-HAr), 7.74 (d, J = 8.5 Hz, 2 H, 2,6-HAr), 7.86
Synthesis 2008, No. 17, 2701–2706 © Thieme Stuttgart · New York

PAPER
Pyrrolo[2,1-b][1,3]benzothiazines
2705
(t, J = 7.5 Hz, 1 H, 6-H), 7.95 (d, J = 7.5 Hz, 1 H, 5-H), 8.25 (d,
J = 7.5 Hz, 1 H, 8-H).
Hz, 1 H, Ho-phenylene), 7.78 (m, 4 H, HAr), 9.10 (t, J = 5.5 Hz, 1 H,
CONH), 12.89 (br s, 1 H, NH).
13C NMR: d = 91.5 (3-C), 113.8 (CN), 119.9 (2-C), 121.8 (8a-C),
126.9 (8-C), 128.2 (4-CAr), 128.4 (5-C), 131.3 (7-C), 131.4 (3,5-
CAr), 131.5 (1-CAr), 132.3 (2,6-CAr), 132.6 (6-C), 135.1 (1-C), 135.9
(4a-C), 136.6 (3a-C), 157.5 (9-CO), 185.0 (COAr).
13C NMR: d = 14.6 (CH3), 43.1 (NCH2), 60.2 (OCH2), 120.2 (4-
CPy), 121.5 (3-CPy), 126.2 (4-Co-phenylene), 126.8 (4-CAr), 127.3 (4-
CR), 127.7 (2,6-CR), 128.4 (6-Co-phenylene), 128.7 (3,5-CR), 128.8 (5-
Co-phenylene), 131.2 (3,5-CAr), 131.3 (3-Co-phenylene), 132.2 (2,6-CAr),
132.3 (1-Co-phenylene), 133.1 (1-CR), 134.6 (2-Co-phenylene), 136.9 (1-
CAr), 137.1 (5-CPy), 139.8 (2-CPy), 162.7 (COO), 167.7 (CONH),
183.1 (COAr).
Anal. Calcd for C19H9BrN2O2S: C, 55.76; H, 2.22; N, 6.84; Br,
19.52; S, 7.83. Found: C, 55.70; H, 2.30; N, 6.80; Br, 19.52; S, 7.75.
2-(2-Pyrrolylthio)benzamides 9a–g; General Procedure
An appropriate amine (1.8 mmol) was added to a solution of com-
pound 7a,c, 8c (1.5 mmol) in DMF (5 mL) and the mixture was re-
fluxed for 2 h. Upon cooling, the mixture was poured into H2O (15
mL) to give an oily precipitate, which slowly solidified overnight.
The solid was filtered and recrystallized from an appropriate solvent
affording derivatives 9a–g (Table 1).
Anal. Calcd for C28H23BrN2O4S: C, 59.69; H, 4.11; N, 4.97; Br,
14.18; S, 5.69. Found: C, 59.52; H, 4.11; N, 5.09; Br, 14.15; S, 5.53.
5-(4-Bromobenzoyl)-2-[(2-{[(2-furanylmethyl)amino]carbon-
yl}phenyl)thio]-1H-pyrrole-3-carboxylic Acid Ethyl Ester (9d)
Mp 172 °C (i-PrOH).
1H NMR: d = 1.07 (t, J = 7.5 Hz, 3 H, CH3), 4.07 (q, J = 7.5 Hz, 2
H, OCH2), 4.48 (d, J = 5.5 Hz, 2 H, NCH2), 6.33 (dd, J = 2.5, 1.5
Hz, 1 H, 4-HR), 6.40 (d, J = 1.5 Hz, 1 H, 3-HR), 6.82 (d, J = 8.0 Hz,
1 H, Ho-phenylene), 7.16 (s, 1 H, 4-H), 7.25 (t, J = 8.0 Hz, 1 H,
5-Benzoyl-2-({2-[(benzylamino)carbonyl]phenyl}thio)-1H-pyr-
role-3-carboxylic Acid Ethyl Ester (9a)
Mp 119 °C (i-PrOH–H2O).
Ho-phenylene), 7.32 (t, J = 8.0 Hz, 1 H, Ho-phenylene), 7.58 (d, J = 2.5 Hz,
1H NMR: d = 1.20 (t, J = 7.0 Hz, 3 H, CH3), 4.13 (q, J = 7.0 Hz, 2
H, OCH2), 4.53 (d, J = 5.0 Hz, 2 H, NCH2), 6.99 (d, J = 7.0 Hz,
1 H, Ho-phenylene), 7.12 (s, 1 H, 4-H), 7.22–7.30 (m, 5 H, 3 HR,
2 Ho-phenylene), 2.47 (d, J = 6.5 Hz, 2 H, 2 HR), 7.52 (t, J = 7.0 Hz,
2 H, 3,5-HAr), 7.59 (m, 2 H, 4-HAr, Ho-phenylene), 7.82 (d, J = 7.0 Hz,
2 H, 2,6-HAr), 8.92 (t, J = 5.0 Hz, 1 H, CONH), 12.73 (br s, 1 H,
NH).
13C NMR: d = 14.6 (CH3), 43.1 (NCH2), 60.2 (OCH2), 120.1 (4-
CPy), 121.4 (3-CPy), 126.2 (4-Co-phenylene), 127.3 (4-CR), 127.7 (2,6-
CR), 128.4 (6-Co-phenylene), 128.8 (3,5-CR), 128.9 (5-Co-phenylene),
129.1 (3,5-CAr), 129.2 (2,6-CAr), 131.3 (3-Co-phenylene), 132.6
(1-Co-phenylene), 132.7 (1-CR), 132.8 (4-CAr), 134.7 (2-Co-phenylene),
137.1 (1-CAr), 137.9 (5-CPy), 139.8 (2-CPy), 162.8 (COO), 167.8
(CONH), 184.2 (COAr).
1 H, 5-HR), 7.62 (d, J = 8.0 Hz, 1 H, Ho-phenylene), 7.78, (m, 4 H, HAr),
9.03 (t, J = 5.5 Hz, 1 H, CONH), 13.01 (br s, 1 H, NH).
13C NMR: d = 14.5 (CH3), 36.7 (NCH2), 60.2 (OCH2), 107.4 (3-CR),
111.0 (4-CR), 120.3 (4-CPy), 121.5 (3-CPy), 126.1 (4-Co-phenylene),
126.7 (4-CAr), 128.5 (6-Co-phenylene), 128.7 (5-Co-phenylene), 131.2 (3,5-
CAr), 131.4 (3-Co-phenylene), 132.2 (2,6-CAr), 132.3 (1-Co-phenylene),
133.0 (5-CR), 134.2 (2-Co-phenylene), 136.9 (1-CAr), 137.2 (5-CPy),
142.6 (2-CPy), 152.6 (1-CR), 162.7 (COO), 167.7 (CONH), 183.1
(COAr).
Anal. Calcd for C26H21BrN2O5S: C, 56.43; H, 3.82; N, 5.06; Br,
14.44; S, 5.79. Found: C, 56.59; H, 3.65; N, 4.96; Br, 14.60; S, 5.70.
2-{[5-(4-Bromobenzoyl)-3-cyano-1H-pyrrol-2-yl]thio}-N-ben-
zylbenzamide (9e)
Anal. Calcd for C28H24N2O4S: C, 69.40; H, 4.99; N, 5.78; S, 6.62.
Found: C, 69.29; H, 4.86; N, 5.75; S, 6.77.
Mp 115–116 °C (i-PrOH).
1H NMR: d = 4.54 (d, J = 5.0 Hz, 2 H, NCH2), 6.91 (d, J = 7.5 Hz,
1 H, Ho-phenylene), 7.19 (s, 1 H, HPy), 7.22 (t, J = 7.5 Hz, 1 H,
5-Benzoyl-2-[(2-{[(2-furanylmethyl)amino]carbonyl}phe-
nyl)thio]-1H-pyrrole-3-carboxylic Acid Ethyl Ester (9b)
Mp 134 °C (i-PrOH–H2O).
1H NMR: d = 1.21 (t, J = 4.5 Hz, 3 H, CH3), 4.13 (q, J = 4.5 Hz, 2
H, OCH2), 4.51 (d, J = 3.0 Hz, 2 H, NCH2), 6.33 (m, 2 H, HR), 6.97
(d, J = 7.0 Hz, 1 H, Ho-phenylene), 7.13 (s, 1 H, 4-H), 7.27 (m, 2 H, 2
Ho-phenylene), 7.27–7.32 (m, 4 H, 3,4,5-HR, Ho-phenylene), 7.39 (d,
J = 6.5 Hz, 2,6-HR), 7.67 (m, 3 H, 3,5-HAr, Ho-phenylene), 7.79 (d,
J = 7.5 Hz, 2 H, 2,6-HAr), 9.02 (t, J = 5.0 Hz, 1 H, CONH), 13.48
(br s, 1 H, NH).
13C NMR: d = 43.2 (NCH2), 102.1 (3-CPy), 115.2 (CN), 122.9 (4-
CPy), 126.4 (5-C), 127.2 (4-CAr), 127.3 (4-CR), 127.7 (2,6-CR),
127.8 (1-CR), 127.9 (3-C), 128.7 (4-C), 128.8 (3,5-CR), 131.5 (3,5-
CAr), 131.8 (6-C), 132.2 (2,6-CAr), 133.5 (2-C), 134.8 (1-C), 136.4
(1-CAr), 136.9 (5-CPy), 139.7 (2-CPy), 167.4 (CONH), 182.9
(COAr).
Ho-phenylene), 7.45 (d, J = 0.5 Hz, 1 H, HR), 7.52–7.61 (m, 4 H, 3,4,5-
HAr, Ho-phenylene), 7.83 (d, J = 6.5 Hz, 2,6-HAr), 8.87 (t, J = 3.0 Hz, 1
H, CONH), 12.75 (s, 1 H, NH).
13C NMR: d = 14.5 (CH3), 36.7 (NCH2), 60.2 (OCH2), 107.4 (3-CR),
111.0 (4-CR), 120.2 (4-CPy), 121.4 (3-CPy), 126.1 (4-Co-phenylene),
128.5 (6-Co-phenylene), 128.7 (5-Co-phenylene), 129.1 (3,5-CAr), 129.2
(2,6-CAr), 131.4 (3-Co-phenylene), 132.5 (1-Co-phenylene), 132.6 (5-CR),
132.8 (4-CAr), 134.3 (2-Co-Phenylene), 137.2 (1-CAr), 137.9 (5-CPy),
142.6 (2-CPy), 152.6 (2-CR), 162.8 (COO), 167.6 (CONH), 184.2
(COAr).
Anal. Calcd for C26H18BrN3O2S: C, 60.47; H, 3.51; N, 8.14; Br,
15.47; S, 6.21. Found: C, 60.52; H, 3.37; N, 8.20; Br, 15.68; S, 6.24.
2-{[5-(4-Bromobenzoyl)-3-cyano-1H-pyrrol-2-yl]thio}-N-(2-
furanylmethyl)benzamide (9f)
Mp 85 °C (i-PrOH).
Anal. Calcd for C26H22N2O5S: C, 65.81; H, 4.67; N, 5.90; S, 6.76.
Found: C, 65.80; H, 4.58; N, 6.08; S, 6.59.
1H NMR: d = 4.51 (d, J = 5.5 Hz, 2 H, NCH2), 6.32 (m, 2 H, 3,4-
HR), 6.87 (d, J = 8.0 Hz, 1 H, Ho-phenylene), 7.19 (s, 1 H, HPy), 7.26 (t,
J = 8.0 Hz, 1 H, Ho-phenylene), 7.32 (t, J = 8.0 Hz, 1 H, Ho-phenylene),
7.43 (d, J = 1.0 Hz, 1 H, 5-HR), 7.62 (d, J = 8.0 Hz, 1 H, Ho-phenylene),
7.67 (d, J = 8.5 Hz, 2 H, 3,5-HAr), 7.79 (d, J = 8.5 Hz, 2 H, 2,6-HAr),
8.96 (t, J = 5.5 Hz, 1 H, CONH), 13.48 (s, 1 H, NH).
13C NMR: d = 45.3 (NCH2), 102.8 (3-CPy), 105.1 (3-CR), 111.6 (4-
CR), 115.9 (CN), 121.4 (4-CPy), 126.4 (5-C), 127.7 (3-C), 128.4 (4-
CAr), 128.7 (4-C), 130.5 (3,5-CAr), 130.6 (2,6-CAr), 131.8 (5-CR),
5-(4-Bromobenzoyl)-2-({2-[(benzylamino)carbonyl]phe-
nyl}thio)-1H-pyrrole-3-carboxylic Acid Ethyl Ester (9c)
Mp 186–187 °C (i-PrOH).
1H NMR: d = 1.07 (t, J = 7.0 Hz, 3 H, CH3), 4.07 (q, J = 7.0 Hz, 2
H, OCH2), 4.50 (d, J = 5.5 Hz, 2 H, NCH2), 6.84 (d, J = 8.0 Hz, 1
H, Ho-phenylene), 7.16 (s, 1 H, 4-H), 7.25 (m, 2 H, Ho-phenylene), 7.33 (m,
3 H, 3,4,5-HR), 7.37 (d, J = 7.0 Hz, 2 H, 2,6-HR), 7.66 (d, J = 7.5
Synthesis 2008, No. 17, 2701–2706 © Thieme Stuttgart · New York

2706
A. V. Tverdokhlebov et al.
PAPER
(2) (a) Hucher, N.; Daich, A.; Netchitailo, P.; Decroix, B.
132.5 (6-C), 134.9 (2-C), 135.7 (1-C), 137.1 (5-CPy), 137.2 (1-CAr),
139.3 (2-CPy), 151.9 (1-CR), 167.8 (CONH), 182.6 (COAr).
Tetrahedron Lett. 1999, 40, 3363. (b) Hucher, N.; Decroix,
B.; Daich, A. J. Org. Chem. 2001, 66, 4695. (c) Hucher, N.;
Pesquet, A.; Netchitailo, P.; Daich, A. Eur. J. Org. Chem.
2005, 2758. (d) Rothe, M.; Steinberger, R. Tetrahedron Lett.
1970, 649. (e) Rothe, M.; Steinberger, R. Tetrahedron Lett.
1970, 2467.
Anal. Calcd for C24H16BrN3O3S: C, 56.93; H, 3.18; N, 8.30; Br,
15.78; S, 6.33. Found: C, 57.04; H, 3.04; N, 8.39; Br, 15.72; S, 6.48.
5-(4-Bromobenzoyl)-2-[(2-{[(2-phenylethyl)amino]carbon-
yl}phenyl)thio]-1H-pyrrole-3-carboxylic Acid Ethyl Ester (9g)
Mp 133 °C (i-PrOH–H2O).
1H NMR: d = 1.08 (t, J = 6.5 Hz, 3 H, CH3), 2.87 (t, J = 6.5 Hz, 2
H, CH2), 3.50 (m, 2 H, NCH2), 4.07 (q, J = 6.5 Hz, 2 H, OCH2), 6.85
(d, J = 7.5 Hz, 1 H, Ho-phenylene), 7.16 (s, 1 H, 4-H), 7.19 (t, J = 7.5
Hz, 1 H, Ho-phenylene), 7.27 (m, 6 H, 5 HR, Ho-phenylene), 7.52 (d, J = 7.5
Hz, 1 H, Ho-phenylene), 7.78 (m, 4 H, HAr), 8.63 (t, J = 5.5 Hz, 1 H,
CONH), 12.99 (s, 1 H, NH).
13C NMR: d = 14.6 (CH3), 35.5 (CH2), 41.3 (NCH2), 60.2 (OCH2),
120.1 (4-CPy), 121.5 (3-CPy), 126.3 (4-Co-phenylene), 126.6 (4-CR),
126.7 (4-CAr), 128.3 (6-Co-phenylene), 128.8 (2,6-CR), 129.0
(5-Co-phenylene), 129.2 (3,5-CR), 131.1 (3-Co-phenylene), 131.2 (3,5-CAr),
132.2 (2,6-CAr), 132.3 (1-Co-phenylene), 133.3 (1-CR), 135.1
(2-Co-phenylene), 136.7 (1-CAr), 136.9 (5-CPy), 139.9 (2-CPy), 162.7
(COO), 167.7 (CONH), 183.0 (COAr).
(3) (a) Garofalo, A.; Campiani, G.; Nacci, V.; Fiorini, I.
Heterocycles 1992, 34, 51. (b) Tafel, K. A.; Bates, D. K.
J. Org. Chem. 1992, 57, 3676. (c) Bates, D. K.; Tafel, K. A.
J. Org. Chem. 1994, 59, 8076.
(4) (a) Duncia, J. V.; Santella, J. B.; Higley, C. A.; Pitts, W. J.;
Wityak, J.; Frietze, W. E.; Rankin, F. W.; Sun, J.-H.; Earl, R.
A.; Tabaka, A. C.; Teleha, C. A.; Blom, K. F.; Favata, M. F.;
Manos, E. J.; Daulerio, A. J.; Stradley, D. A.; Horiuchi, K.;
Copeland, R. A.; Scherle, P. A.; Trzaskos, J. M.; Magolda,
R. L.; Trainor, G. L.; Wexler, R. R.; Hobbs, F. W.; Olson, R.
E. Bioorg. Med. Chem. Lett. 1998, 8, 2839. (b) Beveridge,
S.; Harris, R. L. N. Aust. J. Chem. 1971, 24, 1229.
(5) Beckwith, A. L. J.; Boate, D. R. J. Org. Chem. 1988, 53,
4339.
(6) (a) Tverdokhlebov, A. V.; Andrushko, A. P.; Tolmachev, A.
A. Synthesis 2006, 1433. (b) Tverdokhlebov, A. V.;
Andrushko, A. P.; Tolmachev, A. A.; Kostyuk, A. N.;
Chernega, A. N.; Rusanov, E. B. Monatsh. Chem. 2005, 136,
1781. (c) Tverdokhlebov, A. V.; Resnyanska, E. V.;
Tolmachev, A. A.; Andrushko, A. P. Synthesis 2003, 2632.
(7) Satzinger, G. Liebigs Ann. Chem. 1978, 473.
(8) Zefirov, N. S.; Palyulin, V. A.; Dashevskaya, E. E. J. Phys.
Org. Chem. 1990, 3, 147.
Anal. Calcd for C29H25BrN2O4S: C, 60.32; H, 4.36; N, 4.85; Br,
13.84; S, 5.55. Found: C, 60.30; H, 4.46; N, 4.71; Br, 13.64; S, 5.51.
X-ray Crystal Structure Determination of Compound 7a
Colorless single crystals of 7a were obtained from DMF. Intensities
of 18956 reflections (6131 independent, Rint = 0.044) were mea-
sured with ‘Xcalibur-3’ diffractometer operating in the w-2q scan
mode, 2qmax = 50°, and using graphite monochromated MoKa radi-
ation (l = 0.71073 Å). Crystal data: C21H15O4NS, Mr = 377.40,
monoclinic, a = 21.977(1), b = 10.833(1), c = 15.888(1) Å,
β = 110.08(1)°, V = 3552.8(3) Å3, T = 293 K, space group P21/c,
Z = 8, m(MoKa) = 0.210 mm–1. The structure was solved by direct
method with the SHELXTL program package.12,13 Hydrogen atoms
were placed geometrically and refined by riding model with
Uiso = nUeq of nonhydrogen atom bonded with the hydrogen atom
given (n = 1.5 for methyl group and n = 1.2 for the rest of hydro-
gens). During the refinement the following restraints were placed
on the bonds length of the disordered fragments: C=O 1.21 Å, Csp2–
O 1.32 Å, Csp3–O 1.43 Å, Csp3–Csp3 1.53 Å. Full-matrix least-
squares refinement against F2 in anisotropic approximation using
5902 reflections was converged to wR2 = 0.112, R1 = 0.079 [for
4078 reflections with F>4s(F)], S = 1.041.
(9) Burgi, H.-B.; Dunitz, J. D. Structure Correlation, Vol. 2;
VCH: Weinheim, 1994, 741.
(10) (a) Tverdokhlebov, A. V.; Andrushko, A. P.; Resnyanska, E.
V.; Tolmachev, A. A. Synthesis 2004, 2317.
(b) Guillaumel, J.; Leonce, S.; Pierre, A.; Renard, P.;
Pfeiffer, B.; Arimondo, P. B.; Monneret, C. Eur. J. Med.
Chem. 2006, 41, 379. (c) Flitsch, W.; Niehoff, A. Liebigs
Ann. Chem. 1989, 239. (d) Black, D. St. C.; Bowyer, M. C.;
Catalano, M. M.; Ivory, A. J.; Keller, P. A.; Kumar, N.;
Nugent, S. J. Tetrahedron 1994, 50, 10497. (e) Haynes, H.
F.; Nelson, E. R.; Price, J. R. Aust. J. Sci. Res. 1952, A5,
563. (f) Fabris, F.; Sopkova de Oliveira Santos, J.; Fouchet-
Jolivet, S.; Rault, S. Tetrahedron Lett. 2001, 42, 5183.
(11) (a) Kamal, A.; Sandbhor, M.; Ahmed, K.; Adil, S. F.; Ahaik,
A. A. Tetrahedron: Asymmetry 2003, 14, 3861. (b) Rao, V.
S.; Gupta, S. V. S. A. K.; Gupta, C. N. V. H. B. Synth.
Commun. 2000, 30, 2763.
Acknowledgment
(12) Sheldrick, G. M. SHELXTL PLUS. PC Version. A System of
Computer Programs for the Determination of Crystal
Structure from X-ray Diffraction Data. Rev. 5.1; University
of Göttingen: Göttingen, 1998.
The authors wish to thank Dr. Vitaliy V. Polovinko (Enamine Ltd.)
for his support in recording the 1H, 13C, and 2D NMR spectra.
(13) Full crystallographic parameters have been deposited at
Cambridge Crystallographic Data Center under reference
number CCDC 681250. Copies of the data may be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: +44 1223 33603 or e-mail:
deposit@ccdc.cam.ac.uk).
References
(1) Boehme, H.; Boeing, H. Arch. Pharm. (Weinheim, Ger.)
1961, 294, 556.
Synthesis 2008, No. 17, 2701–2706 © Thieme Stuttgart · New York