New 2-functionalized 2H-3,4-dihydro-1,4-benzothiazin-3-ones and their application in the synthesis of spiro heterocycles

Article abstract of DOI:10.1016/j.tet.2007.04.084

The reaction of 2-chloro-3,4-dihydro-2H-1,4-benzothiazin-3-ones 1 with enamines is an efficient synthetic method to produce 2-substituted derivatives. The resulting bifunctional compounds such as 6a,b, 7c,d and 8b react with hydrazines to furnish the spir

Full text of DOI:10.1016/j.tet.2007.04.084

Tetrahedron 63 (2007) 7727–7732
New 2-functionalized 2H-3,4-dihydro-1,4-benzothiazin-3-ones and
their application in the synthesis of spiro heterocycles
a
b
K. G. Nazarenko,a N. A. Shtil,a, M. O. Lozinskii and A. A. Tolmachev
*
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, Kyiv, 02094, Ukraine
bResearch and Development Center for Chemistry and Biology, National Taras Shevchenko University,
62 Volodymyrska st., Kyiv, 01033, Ukraine
Received 12 December 2006; revised 6 April 2007; accepted 26 April 2007
Available online 3 May 2007
Abstract—The reaction of 2-chloro-3,4-dihydro-2H-1,4-benzothiazin-3-ones 1 with enamines is an efficient synthetic method to produce 2-
substituted derivatives. The resulting bifunctional compounds such as 6a,b, 7c,d and 8b react with hydrazines to furnish the spiro derivatives
of N-aminopyrrole or 3-pyridazinone depending on the direction of the primary nucleophilic attack and the nature of the nucleophile. Under
the reaction conditions, spiro pyridazinones 13 are converted into the 3-pyridazinone-4-carboxylic acid derivatives 9 via the 1,4-thiazine ring
opening.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The carbethoxy group at the c-2 position in compound
1b greatly extends its synthetic potential, especially in the
molecular design of the various spiro derivatives of 2H-
1,4-benzothiazin-3-one. It is noteworthy that although spiro
heterocycles have been a subject of a large number of publi-
cations,6 only few syntheses of 2H-1,4-benzothiazin-3-one
spiro derivatives have been reported hitherto.5,7 For instance,
one of the present authors has previously described the
synthesis of 1,4-benzothiazin-2-spiro-(20-aryliminothiazol-
idin-50-3-ones) (2) by the amine-induced cyclization of
isothiocyanates readily obtained from compound 1b.7b As
we found in our preceding study on the synthesis of 2-hetero-
aryl-2H-1,4-benzothiazin-3-ones, the reaction between 1b
and 6-aminouracils involves the C-5 atom of the pyrimidine
ring and likewise results in the intramolecular spirocycliza-
tion to provide spiro[1,4-benzothiazine-2,70-pyrrolo[3,2-
d]pyrimidine] (3) derivatives (Fig. 1).5
Many 2H-1,4-benzothiazin-3-one derivatives exhibit a broad
spectrum of biological activities, so that the purposeful
modification of their structure attracts great interest in phar-
macology and other related fields.1 Generally methods for
preparing these compounds rely on condensation of 2-ami-
nothiophenols with a,b-unsaturated acids or a-haloacetic
acids (or esters).2 The limited availability of such acids is
the major disadvantage of the method. As an alternative
method, one can use 2-chloro-2H-1,4-benzothiazin-3-ones
(1), easily accessible starting materials, in the synthesis
of various 2-substituted 1,4-benzothiazin-3-ones. Like any
a-halogeno sulfides, compounds 1 are distinguished by an
extremely easy nucleophilic substitution of the chlorine
atom. For instance, they react with alcohols, primary and
secondary amines and triethyl phosphite.3 An efficient syn-
thetic route to 2-aryl-2H-1,4-benzothiazin-3-ones (useful as
Ca2+ antagonists, blood platelet aggregation inhibitors and
vascular agents) is offered by the Friedel–Crafts reaction
of compounds 1 with aromatics.4 Recently we have prepared
2-heteroaryl-2H-1,4-benzothiazin-3-ones by the reaction of
1 with electron-rich heterocycles.5 The research work
presented here is a part of the program aimed at the develop-
ment of methods for synthesis of 2-heteroaryl and 2-spiro
derivatives of 1,4-benzothiazin-3-one.
A remarkably high reactivity of 1a and b towards electron-
rich heterocycles suggests that these compounds can be
reacted in a similar manner with other C-nucleophiles to
form a new C–C bond. The present work addresses the reac-
tion of compounds 1a and b with enamines 4a,b and 5 as
R2
N
H
N
S
R
O
N
O
S
Ar
R
S
O
Cl
S
N
H
N
N
H
O
R1
N
H
O
N
H
O
O
1 a R= H
1 b R= CO2Et
2 R= Me, Cl
3
Keywords: Chloro derivatives; Enamines; Electrophilic substitution; Cycli-
zation; Spiro heterocycles.
* Corresponding author. E-mail: shnataliya@ukr.net
Figure 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.084

7728
K. G. Nazarenko et al. / Tetrahedron 63 (2007) 7727–7732
Me
a synthetic entry into 2-functionalized 2H-1,4-benzothiazin-
3-ones and also describes their further use as starting com-
pounds in the synthesis of 1,4-benzothiazin-3-one spiro
derivatives.
Me
Me
Me
O
R
S
Et3N
1 a, b +
CH2Cl2
N
Me
N
N
H
Me
8 a R= H
8 b R= CO2Et
5
2. Results and discussion
Scheme 2.
Compounds 1a,b and 4a,b were reacted in methylene chlo-
ride at room temperature in the presence of a slight excess of
triethylamine (see Scheme 1). Under these conditions, no
notable distinctions are observed in the reactivity of the sec-
ondary and tertiary chloro derivatives 1a and b, in contrast to
the case when they are reacted with electron-rich hetero-
cycles. If morpholinocycloalkenes 4a and b are replaced
with their more reactive 1-pyrrolidinyl-substituted counter-
parts, pronounced resinification of the reaction mixture
occurs and the yields of the target products drop. If the reac-
tion is conducted with 1a, treatment of the resulting reaction
mixture with water immediately affords the hydrolysis prod-
ucts, ketones 7a and b, in high yields, since the initially
formed enamines are too labile to be isolated. Intermediate
enamines 6a and b containing a carbethoxy group proved
to be more stable towards hydrolysis and were both isolated
as a mixture of two diastereomers. On heating in 10% hydro-
chloric acid, these compounds are readily hydrolyzed to fur-
nish g-ketoesters 7c and d in nearly quantitative yields.
and b and, on the other hand, to their sterically hindered re-
action centre precluding polysubstitution of the enamines.8
The prepared g-ketoesters 7c and d as well as enamines 6a,b
and 8b are 1,4-biselectrophiles and show promise in the syn-
thesis of 2H-1,4-benzothiazin-3-one spiro derivatives. Here
we study the reaction of these compounds with the simplest
1,2-bisnucleophiles, hydrazine and methylhydrazine, in an
effort to synthesize the 1,4-benzothiazin-3-one-2-spiro-41-
31-oxopyridazine derivatives 13. On boiling 6a and b or 7c
and d in ethanol with a slight excess of hydrazine hydrate
or methylhydrazine, we isolated, in moderate yields, high-
melting yellow solids that was recrystallized from DMF or
1
DMSO (see Scheme 3). The H, 13C NMR, IR and mass
spectroscopic data led us to infer that the compounds formed
were disulfides 9a–d, 3-pyridazinone-4-carboxylic acid de-
rivatives, rather than the desired spiro systems 13.
For unequivocal structural determination of compounds
9a–d, one of them was obtained by alternate synthesis.
Following the known procedure,9 we started from diethyl
mesoxalate and cyclohexanone, and thus came, in three
stages, to 3-oxo-2,3,5,6,7,8-hexahydro-4-cinnoline carboxy-
lic acid 10 (see Scheme 4). Acylation of ortho-aminophenol
11 with acid 10 (CDI, DMF) resulted in a product identical
with compound 9b as judged from the melting point and
spectral characteristics.
(CH2)n
(CH2)n
(CH2)n
O
R
R
S
S
Et3N
CH2Cl2
H3O+
1 a, b +
N
O
N
O
N
H
O
N
H
O
6 a R= CO2Et n= 1
6 b R= CO2Et n= 2
7 a R= H n= 1
4 a n= 1
4 b n= 2
7 b R= H n= 2
7 c R= CO2Et n= 1
7 d R= CO2Et n= 2
Scheme 1.
H
N
O
Heterocyclic enamine 5 likewise smoothly reacts with com-
pounds 1a and b under the same conditions to produce
monosubstituted indolines 8a and b (see Scheme 2). The
readiness and equally good yields of the reaction with 4a
and b (70–90%) and 5 (70–75%) are attributable, on the
one hand, to the high electrophilic reactivity of reagents 1a
SH
N
CDI
9 b
+
COOH
DMF
NH2
10
11
Scheme 4.
R
N
NHR
N
O
S
EtO2C
S
N
H2NNHR
EtOH
(CH2)n
6 a, b or 7 c, d
(CH2)n
N
H
O
O
N
H
12
R
N
SH
NH
O
S
NH
(CH2)n
O
[O]
O
n(CH2)
N
H
R
N
N
O
O
N
H
S
N
N
R
O
13
(CH2)n
2
9 a R= H n= 1
9 b R= H n= 2
9 c R= Me n= 1
9 d R= Me n= 2
Scheme 3.

K. G. Nazarenko et al. / Tetrahedron 63 (2007) 7727–7732
7729
Formation of products 9 in the reaction of 7c,d and 6a,b with
hydrazine can be accounted for the following reaction
pathway: the primary nucleophilic attack on the carbonyl
group of the cyclic ketone (in 7c,d) or on the a-enamine car-
bon atom (in 6a,b) leads to hydrazones 12, which then cyclize
to spiro derivatives 13. The next stage represents quite an un-
usual 1,4-thiazine ring opening via the C–S bond cleavage
and the formation of the stable 3-pyridazinone system, the
latter appearing to be a driving force for the process.
The structural determination of compounds 15a and b was
1
based on the H and 13C NMR spectra as well as on the
HMQC and HMBC data (see Fig. 2).
It is also noteworthy that the C-acyl derivatives of enamine 5
act as 1,3-biselectrophiles and are known to react with hy-
drazine and hydroxylamine affording the spiro derivatives
of 1,2-azoles such as pyrazole and isoxazole.10 However,
they readily undergo the indoline ring opening, i.e., a despiro
conversion, to release pyrazole and isoxazole during the
course of the reaction or on the treatment with hydrochloric
acid. On the contrary, the bis-spiro system in compounds 15a
and b proved unexpectedly stable. For instance, these com-
pounds remain unchanged even after extended heating in
DMF. Boiling 15a in hydrochloric acid results only in hydro-
chloride formation rather than in the cleavage of the spiro
structure.
Though the indoline derivative 8b also reacts smoothly with
hydrazine, the reaction proceeds differently than described
above. In the first stage, hydrazide 14 is formed (see
Scheme 5), which further undergoes the 5-endo-trig type
cyclization to produce 1-amino-1,3,3-trimethyl-1,3-di-
hydro-5H-dispiro[1,4-benzothiazine-2,4-pyrrolidine-2,2-in-
dole]-3,5(4H)-dione 15a via the intramolecular nucleophilic
attack of the amide nitrogen atom on the C-2 atom of the
indoline ring. The yield of product 15a amounts to 88%. In-
terestingly, the reaction of enamine 8b with hydroxylamine
under analogous conditions provides a mixture of two prod-
ucts, spiro compound 15b and hydroxamic acid derivative
14 (X¼OH); only boiling in ethanol for 8 h brings the
cyclization to completion.
When methylhydrazine instead of hydrazine was used in the
reaction with enamine 8b, a mixture of products was formed
from which the 3-pyridazinone-4-carboxylic acid derivative
19 was isolated in 40% yield (see Scheme 6). Evidently, in
this case the primary nucleophilic attack occurs on the carb-
ethoxy group, just as in the reaction of 8b with hydrazine,
and the N-1 atom of methylhydrazine acts as a nucleophile.
However, the resulting hydrazide cannot cyclize to N-amino-
pyrrole derivative like 15. An alternative reaction pathway is
therefore realized, which implies that the formation of inter-
mediate spiro pyridazinone 16 is followed by the indoline
ring opening and the conversion of intermediate 17 into di-
sulfide 19 (similar to the 6/9 conversion described above).
X
X Me
N
Me
NH
Me
O
S
O
S
Me
H2N-X
8b
N
OMe
X= NH2, OH
N
Me
O
N
H
N
H
1
The structure of compound 19 is supported by H and 13C
14
15 a X=NH2
15 b X= OH
NMR spectroscopies including the HH COSY experiments.
Scheme 5.
Me
3. Conclusions
Me
H2N
S
N
O
91.82
To conclude, the studied reaction between chloro derivatives
1 and enamines appears as an efficient synthetic method to
produce 2-substituted 3,4-dihydro-2H-1,4-benzothiazin-3-
ones. The resulting bifunctional compounds such as 6a,b,
7c,d and 8b react with hydrazines to furnish the spiro deriv-
ativesof N-aminopyrrole or 3-pyridazinone depending on the
direction of the primary nucleophilic attack and the nature of
N
HMe
H
N
H
O
1.97 and 3.54 (AB system, 2JHH= 15 Hz)
46.87
HMBC correlations
Figure 2.
Me
Me
N
O
S
N
Me
Me
NH
O
S
NH
Me
Me
H2NNHMe
8 b
N
Me
N
H
O
N
H
O
N
Me
16
17
SH
O
O
Me
N
H
N
N
HN
Me
Me
[O]
Me
NH
S
O
Me
Me
Me
N
O
N
Me
N
H
2
18
19
Scheme 6.

7730
K. G. Nazarenko et al. / Tetrahedron 63 (2007) 7727–7732
the nucleophile. Under the reaction conditions, spiro pyrid-
azinones 13 are converted into the 3-pyridazinone-4-carb-
oxylic acid derivatives 9 via the 1,4-thiazine ring opening.
C20H24N2O4S: C 61.84; H 6.23; N 7.21; found C 61.86; H
6.26; N 7.24; yield (solvent): 76% (EtOH).
4.1.1.2. Ethyl 2-(2-morpholin-4-ylcyclohex-2-en-1-yl)-
3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2-carboxylate
(6b).y Colourless solid, mp 151–152 ꢀC; dH 10.61 (1H, s),
7.29 (1H, d, J 7.5 Hz), 7.14 (1H, t, J 7.7 Hz), 6.98–6.91
(2H, m), 5.23 (1H, s), 4.02–3.95 (2H, m), 3.77 (1H, br s),
3.59–3.49 (2H, m), 3.48–3.38 (2H, m), 2.94 (2H, br s),
2.31 (2H, br s), 2.17–1.93 (2H, m), 1.88–1.68 (2H, m),
1.60–1.37 (2H, m), 0.94 (3H, t, J 7.0 Hz); dC 167.70,
163.80, 147.52, 136.17, 127.23, 126.87, 122.70, 118.68,
116.10, 114.05, 66.39, 61.64, 60.97, 51.35, 35.56, 26.10,
24.05, 19.57, 13.63; MS [m/z (%)]: 402 (M+) (6.78), 252
(9.45), 167 (8.00), 166 (100), 41 (4.25); IR (cmꢂ1): 1670,
1710, 2980; Anal. Calcd for C21H26N2O4S: C 62.66; H
6.51; N 6.96; found C 62.88; H 6.53; N 6.96; yield (solvent):
78% (EtOH).
4. Experimental
4.1. General
CH2Cl2 and DMF for the reactions were freshly distilled and
dried bystandard methods. All solvents for the crystallization
were used without additional purification. The H and 13C
1
NMR (500 and 125 MHz, respectively) were recorded on
a Bruker Avance DRX 500 with DMSO-d6 as the solvent
and TMS as an internal standard. EIMS were recorded on
a mass spectrometer MX-1321 using direct sample insertion
into the ion source with an ionizing electron accelerating
voltage of 70 V and an ionization chamber temperature of
150 ꢀC. LC/MS spectra were recorded using chromato-
graphy/mass spectrometric system that consists of high-
performance liquid chromatograph ‘Agilent 1100 Series’
equipped with diode-matrix and mass-selectivedetector ‘Ali-
gent LCMSD SL’. The parameters of chromatography-mass
analysis: Column: Zorbax SB-C18, 1.8 mmꢁ4.6 mmꢁ
15 mm. Solvents: A—acetonitrile/water (95:5), 0.1% TFA,
B—water (0.1% of TFA). Eluent flow: 3 mL sꢂ1. The
volume of injected sample: 1 mL. UV-detectors operate at
215, 254 and 265 nm. Ionization method: chemical ioniza-
tion under atmospheric pressure (APCI). Ionization mode: si-
multaneous scanning of positive and negative ions in the
mass range of 80–1000 MHz. Microanalyses were per-
formed in the Microanalytical Laboratory of the Institute of
Organic Chemistry, National Academy of Sciences of Uk-
raine. IR spectra were recorded on a Nexus-470 spectrometer
for samples in KBr disks. Melting points (mp) were deter-
mined with electrothermal capillary melting point apparatus
and are uncorrected.
4.1.1.3. 2-(2-Oxocyclopentyl)-2H-1,4-benzothiazin-
3(4H)-one (7a). Colourless solid, mp 207–208 ꢀC; dH
10.52 (1H, s), 7.25 (1H, d, J 7.5 Hz), 7.13 (1H, t, J 7.7 Hz),
6.98–6.91 (2H, m), 3.93 (1H, d, J 3.9 Hz), 2.52–1.72 (7H,
m); dC 216.36, 165.49, 137.38, 127.76, 127.61, 123.49,
119.70, 117.55, 47.45, 41.90, 37.61, 25.84, 20.60; MS [m/z
(%)]: 247 (M+) (100.00), 191 (93.80), 164 (24.20), 136
(25.68), 55 (25.50); IR (cmꢂ1): 1680, 1720, 2980; Anal.
Calcd for C13H13NO2S: C 63.14; H 5.30; N 5.66; found C
63.16; H 5.31; N 5.68; yield (solvent): 75% (MeOH).
4.1.1.4.
2-(2-Oxocyclohexyl)-2H-1,4-benzothiazin-
3(4H)-one (7b). Colourless solid, mp 168–169 ꢀC; dH
10.57 (1H, s), 7.21 (1H, d, J 7.2 Hz), 7.10 (1H, t, J 7.2 Hz),
6.97–6.75 (2H, m), 3.93 (1H, d, J 5.4 Hz), 2.55–2.30 (3H,
m), 2.10–1.60 (6H, m); dC 209.10, 166.28, 137.21, 127.75,
127.49, 123.47, 119.37, 117.44, 49.49, 41.39, 40.99, 29.68,
27.43, 23.89; MS [m/z (%)]: 261 (M+) (100.00), 233
(25.21), 136 (30.09), 132 (16.81), 109 (18.63); IR (cmꢂ1):
1670, 1700, 2940; Anal. Calcd for C14H15NO2S: C 64.34;
H 5.79; N 5.36; found C 64.32; H 5.78; N 5.35; yield (sol-
vent): 84% (C6H5CH3).
4.1.1. General procedure for the synthesis of 6a,b, 7a,b
and 8a,b. To a stirred solution of the appropriate enamine
(5 mmol) and Et3N (0.72 mL, 5.1 mmol) in anhydrous
CH2Cl2 (30 mL), 1a (5 mmol) or 1b (5 mmol) was added.
The reaction mixture was boiled with a reflux condenser for
2 h, cooled and washed with water (2ꢁ30 mL). The organic
phase was dried over Na2SO4 and evaporated in vacuo. The
crude product was crystallized from the appropriate solvent.
4.1.1.5. 2-[(1,3,3-Trimethyl-1,3-dihydro-2H-indol-2-
ylidene)methyl]-2H-1,4-benzothiazin-3(4H)-one
(8a).
Colourless solid, mp 212–213 ꢀC; dH 10.52 (1H, s), 7.32
(1H, d, J 7.8 Hz), 7.22–6.96 (5H, m), 6.74 (1H, t, J 7.5 Hz),
6.64 (1H, d, J 8.0 Hz), 4.69 (1H, d, J 11 Hz), 4.23 (1H, d,
J 11 Hz), 2.85 (1H, s), 1.50 (6H, s); dC 165.75, 156.79,
145.04, 137.68, 136.91, 127.80, 127.63, 126.82, 122.91,
121.35, 118.68, 118.47, 116.84, 105.49, 85.79, 44.52,
32.00, 29.13, 28.61, 28.05; MS [m/z (%)]: 336 (M+)
(96.91), 184 (100.00), 170 (63.65); IR (cmꢂ1): 1670, 2980;
Anal. Calcd for C20H20N2OS: C 71.40; H 5.99; N 8.33; found
C 71.37; H 5.96; N 8.32; yield (solvent): 71% (EtOH).
4.1.1.1. Ethyl 2-(2-morpholin-4-ylcyclopent-2-en-1-
yl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2-carboxyl-
ate (6a).y Colourless solid, mp 146–147 ꢀC; dH (CDCl3)
8.75 (1H, br s), 7.34 (1H, d, J 7.2 Hz), 7.12 (1H, t, J
8.3 Hz), 7.00 (1H, t, J 7.7 Hz), 6.80 (1H, d, J 7.8 Hz), 5.00
(1H, s), 4.37–4.29 (1H, m), 4.02–3.93 (2H, m), 3.68–3.56
(4H, m), 2.99–2.93 (2H, m), 2.58–2.11 (6H, m), 0.86 (3H,
t, J 7.2 Hz); dC 167.37, 163.01, 151.51, 136.01, 127.80,
127.12, 123.56, 120.11, 116.96, 109.23, 66.36, 62.65,
61.90, 50.83, 45.58, 29.82, 28.14, 13.77; MS [m/z (%)]:
388 (M+) (28.20), 237 (61.14), 191 (49.73), 152 (100.00),
151 (59.22); IR (cmꢂ1): 1665, 1738, 2980; Anal. Calcd for
4.1.1.6. Ethyl 3-oxo-2-[(1,3,3-trimethyl-1,3-dihydro-
2H-indol-2-ylidene)methyl]-3,4-dihydro-2H-1,4-benzo-
thiazine-2-carboxylate (8b). Colourless solid, mp 187–
188 ꢀC; dH 10.82 (1H, s), 7.21–7.02 (5H, m), 6.91 (1H, t,
J 8.1 Hz), 6.76 (1H, t, J 7.1 Hz), 6.64 (1H, d, J 7.8 Hz),
4.18 (1H, s), 4.10–4.02 (2H, m), 3.39 (3H, s), 1.20 (3H, s),
1.06 (3H, s), 1.01 (3H, t, J 7.2 Hz); dC 169.78, 166.86,
158.78, 147.13, 138.13, 137.3, 128.19, 127.90, 123.47,
y
The compounds were obtained as a mixture of two diastereomers (10:1)
and 1H NMR signals of major diastereomers are given. 13C NMR spectra
exhibited signals of only one diastereomer.

K. G. Nazarenko et al. / Tetrahedron 63 (2007) 7727–7732
7731
122.21, 120.18, 119.58, 117.06, 107.05, 83.61, 62.73,
55.01, 46.77, 33.85, 30.37, 14.16; MS [m/z (%)]: 408 (M+)
(17.65), 335 (100.00), 158 (21.72); IR (cmꢂ1): 1680, 1740,
2980; Anal. Calcd for C23H24N2O3S: C 67.62; H 5.92; N
6.86; found C 67.65; H 5.96; N 6.89; yield (solvent): 75%
(EtOH).
t, J 7.7 Hz), 7.16 (1H, t, J 7.7 Hz), 2.96 (2H, t, J 6 Hz),
2.71 (2H, t, J 6.5 Hz), 1.80–1.59 (4H, m); dC 162.48,
159.12, 145.85, 144.13, 136.89, 131.68, 129.86, 129.24,
129.03, 125.87, 124.07, 29.24, 26.86, 21.30, 21.07; MS
APCI: 601 (M+H+); IR (cmꢂ1): 1630, 1680, 2890, 2955;
Anal. Calcd for C30H28N6O4S2: C 59.98; H 4.70; N 13.99;
found C 59.95; H 4.69; N 13.96; yield: 62%.
4.1.2. Procedure for the synthesis of 7c and d. To a stirred
solution of HCl (10%, 30 mL) 6a and b (1.8 mmol) was
added and heated at 60 ꢀC for 30 min. The precipitate was
filtered and recrystallized from EtOH.
4.1.3.3. N,N0-[Dithiobis(2,1-phenylene)]bis(2-methyl-
3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridazine-4-
carboxamide) (9c). Yellow solid, mp 251–252 ꢀC; dH
(CF3COOD) 7.99 (1H, d, J 7.8 Hz), 7.59 (1H, d, J 8.1 Hz),
7.37 (1H, t, J 7.5 Hz), 7.21 (1H, t, J 7.7 Hz), 4.09 (3H, s),
3.62 (2H, t, J 7.5 Hz), 3.16 (2H, t, J 7.5 Hz), 2.44–2.32
(2H, m); dC (CF3COOD) 163.25, 160.52, 160.26, 156.63,
137.02, 136.05, 130.93, 128.90, 127.37, 123.96, 122.76,
40.89, 33.23, 29.92, 22.96; MS APCI: 601 (M+H+); IR
(cmꢂ1): 1630, 1680, 2950; Anal. Calcd for C30H28N6O4S2:
C 59.98; H 4.70; N 13.99; found C 59.96; H 4.67; N
13.95; yield: 57%.
4.1.2.1. Ethyl 3-oxo-2-(2-oxocyclopentyl)-3,4-dihydro-
2H-1,4-benzothiazine-2-carboxylate (7c). Colourless
solid, mp 205–206 ꢀC; dH 10.86 (1H, s), 7.25 (1H, d,
J 7.5 Hz), 7.19 (1H, t, J 7.8 Hz), 7.02 (1H, d, J 8.1 Hz),
6.96 (1H, t, J 8.0 Hz), 4.08–3.90 (2H, m), 2.88 (1H, t,
J 9.5 Hz), 2.45–2.36 (1H, m), 2.30–2.14 (2H, m), 2.08–
1.98 (1H, m), 1.92–1.76 (2H, m), 0.95 (3H, t, J 7.2 Hz); dC
214.91, 168.81, 163.90, 137.64, 128.41, 127.99, 123.73,
117.28, 116.33, 61.97, 55.83, 49.99, 37.76, 26.54, 20.49,
14.09; MS [m/z (%)]: 319 (M+) (53.97), 247 (34.97), 246
(100.00), 191 (26.89), 55 (41.13); IR (cmꢂ1): 1590,
1680, 1730, 2950; Anal. Calcd for C16H17NO4S: C 60.17;
H 5.37; N 4.39; found C 60.15; H 5.35; N 4.37; yield:
91%.
4.1.3.4. N,N0-[Dithiobis(2,1-phenylene)]bis(2-methyl-
3-oxo-2,3,5,6,7,8-hexahydrocinnoline-4-carboxamide)
(9d). Yellow solid, mp 213–214 ꢀC, dH (CF3COOD) 8.03
(1H, d, J 8.1 Hz), 7.55–7.44 (2H, m), 7.27 (1H, t,
J 8.0 Hz), 4.01 (3H, s), 3.17 (2H, t, J 6.0 Hz), 3.04 (2H,
t, J 6.5 Hz), 2.06–1.91 (4H, m); dC (CF3COOD) 164.41,
159.29, 151.87, 147.26, 135.52, 135.20, 131.14, 129.91,
128.83, 127.87, 124.75, 40.56, 28.74, 27.16, 20.42, 20.25;
MS APCI: 601 (M+H+); IR (cmꢂ1): 1630, 1680, 2980;
Anal. Calcd for C32H32N6O4S2: C 61.13; H 5.13; N 13.37;
found C 61.11; H 5.12; N 13.34; yield: 59%.
4.1.2.2. Ethyl 3-oxo-2-(2-oxocyclohexyl)-3,4-dihydro-
2H-1,4-benzothiazine-2-carboxylate (7d). Colourless
solid, mp 154–155 ꢀC; dH 10.81 (1H, s), 7.16–7.33 (2H,
m), 7.03–6.92 (2H, m), 3.99–3.85 (2H, m), 3.14–3.06 (1H,
m), 2.38–2.12 (3H, m), 2.11–1.51 (5H, m), 0.86 (3H, t,
J 6.9 Hz); dC 205.98, 167.84, 163.02, 137.13, 127.61,
127.54, 126.93, 123.03, 116.42, 116.38, 61.15, 54.05, 40.79,
30.35, 27.32, 24.57, 23.81, 13.50; MS [m/z (%)]: 333 (M+)
(97.59), 260 (100.00), 243 (26.66), 232 (40.41), 164 (35.87);
IR (cmꢂ1): 1590, 1680, 1720, 2990; Anal. Calcd for
C17H19NO4S: C 61.24; H 5.74; N 4.20; found C 61.26; H
5.76; N 4.22; yield: 92%.
4.1.4. Procedure for acylation of 2-aminothiophenol (9b).
To a stirred solution of 11 (0.50 g, 2.6 mmol) in anhydrous
DMF (15 mL), CDI (0.42 g, 2.6 mmol) was added. The mix-
ture was stirred for 30 min and 2-aminothiophenol (0.33 g,
2.6 mmol) was added. The reaction mixture was stirred for
4 h and poured in water (50 mL). The precipitate was filtered
and crystallized from DMF (yield 64%).
4.1.3. General procedure for the synthesis of 9a–d, 15a,b
and 19. To a solution of 6a and b or 7c and d or 8b (5 mmol)
in EtOH (30 mL), hydrazine hydrate (or methylhydrazine)
(1 mL) was added. The mixture was boiled with a reflux
condenser for 4 h. The EtOH was evaporated in vacuo and
the precipitate was recrystallized from DMF.
4.1.4.1. 1-Amino-1,3,3-trimethyl-1,3-dihydro-5H-
dispiro[1,4-benzothiazine-2,4-pyrrolidine-2,2-indole]-
3,5(4H)-dione (15a).
5"
Me 4"
Me
H2N
3a"
N,N0-[Dithiobis(2,1-phenylene)]bis(3-oxo-
6"
4.1.3.1.
3"
2"
N
O
7a"
N
1'
5'
1"
7"
3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridazine-4-carbox-
amide) (9a). Yellow solid, mp 315–317 ꢀC; dH 13.36 (1H, s),
12.52 (1H, s), 8.29 (1H, d, J 8.1 Hz), 7.32 (1H, t, J 8.3 Hz),
7.24 (1H, d, J 7.2 Hz), 6.98 (1H, t, J 7.4 Hz), 2.91–2.70 (4H,
m), 2.15–2.01 (2H, m); dC 161.24, 160.56, 155.77, 154.50,
139.78, 135.58, 130.84, 124.42, 124.17, 122.49, 121.39,
32.49, 29.49, 23.35; MS APCI: 573 (M+H+); IR (cmꢂ1):
1635, 1695, 2900, 2985; Anal. Calcd for C28H24N6O4S2: C
58.73; H 4.22; N 14.68; found C 58.70; H 4.19; N 14.66;
yield: 64%.
2'
4' 3'
8
5
S
7
6
8a
4a
1
2
3
Me
H
H
4
O
N
H
Colourless solid, mp 284–285 ꢀC. The signals of 1H and 13C
NMR were assigned on the basis of HMQC and HMBC ex-
periments. dH 11.03 (1H, s, NH-4), 7.30 (1H, d, J 10.0 Hz,
CH-5), 7.18 (1H, t, J 5.0 Hz, CH-6), 7.10–6.96 (4H, m),
6.61 (1H, t, J 5.0 Hz, CH-500), 6.42 (1H, d, J 10.0 Hz, CH-
400), 4.15 (2H, s, NH2), 3.54 (1H, d, J 15.0 Hz, CH2-30),
2.72 (3H, s, 1-NMe), 1.97 (1H, d, J 15.0 Hz, CH2-30), 1.24
(3H, s, C300–Me), 1.17 (3H, s, C300–Me); dC 166.94 (CO-
50), 165.09 (CO-3), 150.14 (C-7a00), 137.75 (C-3a00),
4.1.3.2.
2,3,5,6,7,8-hexahydrocinnoline-4-carboxamide)
N,N0-[Dithiobis(2,1-phenylene)]bis(3-oxo-
(9b).
Yellow solid, mp 282–283 ꢀC; dH 13.29 (1H, s), 11.18 (1H,
s), 7.75 (1H, d, J 7.5 Hz), 7.55 (1H, d, J 7.5 Hz), 7.33 (1H,

7732
K. G. Nazarenko et al. / Tetrahedron 63 (2007) 7727–7732
137.68 (C-4a), 127.62 (CH-6), 127.30 (CH-5), 127.22 (CH-
700), 123.53 (C-8), 120.51 (C-600), 118.27 (C-500), 117.97
(C-8a), 116.97 (CH-7), 105.65 (CH-400), 91.82 (C-200), 46.87
(C-200), 46.71 (C-2), 32.01 (CH2-30), 28.75 (1-NCH3),
28.67 (CH3-1), 19.50 (CH3-1); MS [m/z (%)]: 394 (M+)
(33.86), 336 (11.56), 159 (100.00); IR (cmꢂ1): 1590, 1695,
2980, 3158, 3220; Anal. Calcd for C21H22N4O2S: C 63.94;
H 5.62; N 14.20; found C 63.92; H 5.60; N 14.18; yield:
88%.
Acknowledgements
We thank Enamine Co., Ukraine for the financial support of
this work.
References and notes
1. (a) Campiani, G.; Garofalo, A.; Fiorini, I.; Botta, M.; Nacci, V.;
Tafi, A.; Chiari, A.; Budriesi, R.; Bruni, G.; Romeo, M. J. Med.
Chem. 1995, 38, 4393–4410; (b) Brown, C.; Davidson, R. M.
Adv. Heterocycl. Chem. 1985, 38, 135–176; (c) Tomita, K.;
Araya, M. Jpn. Kokai Tokkyo Koho 08,319,237, 1996; Chem.
Abstr. 1997, 126, 126916s; (d) Kawashima, Y.; Ota, A.;
Araki, Y.; Shii, D. Jpn. Kokai Tokkyo Koho 09,100,418,
1997; Chem. Abstr. 1997, 127, 34231g; (e) Lozinskii, M. O.;
Demchenko, A. M.; Shivanyuk, A. F. Advanced Methods of
Synthesis and Modifications of Heterocycles; Karcev, V. G.,
Ed.; JBS: Moscow, 2003; Vol. 2.
2. (a) Krapcho, J.; Szabo, A.; Williams, J. J. Med. Chem. 1963,
214; (b) Teulon, J.-M. European Patent Appl. EP 1163, 1984;
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Chem. Soc. 1959, 81, 1721; (d) Koz’minykh, E. N.; Igidov,
N. M.; Koz’minykh, V. O.; Shavkunova, G. A.; Sof’ina,
O. A. Zh. Org. Khim. 2000, 36, 1381.
3. (a) Shivanyuk, A. F.; Lozinskii, M. O.; Kalinin, V. N.;
Sokolova, Y. A.; Atovmyan, L. O.; Dyachenko, O. A. Zh.
Org. Khim. 1990, 26, 1345–1351; (b) Konishi, H.; Takishita,
M.; Koketsu, H.; Okano, T.; Kiji, J. Heterocycles 1986, 24,
1557–1560; (c) Chihara, Y.; Setoguchi, S.; Yaoka, O. PCT
Int. Appl. WO 8,403,700, 1984; Chem. Abstr. 1985, 103,
54090t; (d) Worley, J. W.; Wayne Ratts, K.; Cammack, K. L.
J. Org. Chem. 1975, 40, 1731.
4. (a) Fujita, M.; Ota, A.; Ito, S.; Yamamoto, K.; Kawashima, Y.
Synthesis 1988, 599–604; (b) Iwao, J.; Iso, T.; Oya, M. Jpn.
Kokai Tokkyo Koho 60,166,674, 1985; Chem. Abstr. 1986,
104, 109666p.
4.1.4.2. N,N0-[Dithiobis(2,1-phenylene)]bis(2-methyl-
6-{1-methyl-1-[2-(methylamino)phenyl]-ethyl}-3-oxo-2,3-
dihydropyridazine-4-carboxamide) (19).
5
4
6
3
1
Me
1
2
1
HN
Me
2
Me 5'
NH
S
2"
4'
1
O
6'
1"
6"
3"
4"
N
3'
1'
O
2'N
Me
5"
2
1
Orange solid, mp 236–237 ꢀC. The signals of 1H NMR were
assigned on the basis of HH COSY experiments. dH 12.20
(1H, s, NH), 8.14 (1H, d, J 5.0 Hz, CH-6), 7.56 (1H, s,
CH-50), 7.41 (1H, d, J 10.0 Hz, CH-300), 7.29 (1H, d,
J 5.0 Hz, CH-3), 7.20 (1H, t, J 7.5 Hz, CH-500), 7.07 (1H,
t, J 7.5 Hz, CH-5), 6.88 (1H, t, J 7.5 Hz, CH-4), 6.77 (1H,
t, J 7.5 Hz, CH-400), 6.59 (1H, d, J 5.0 Hz, CH-600), 3.84
(1H, d, J 5.0 Hz, NHMe), 3.70 (3H, s, NMe), 2.66 (3H, d,
J 5.0 Hz, NHMe), 1.66 (6H, s, C(Me)2); dC 159.64, 159.44,
154.10, 147.14, 140.41, 136.75, 132.73, 131.63, 128.96,
128.90, 128.57, 126.81, 125.08; MS APCI: 815 (M+H+);
IR (cmꢂ1): 1630, 1690, 2990, 3460; Anal. Calcd for
C44H46N8O4S2: C 64.84; H 5.69; N 13.75; found C 64.86;
H 5.71; N 13.79; yield: 42%.
5. Nazarenko, K. G.; Shtil, N. A.; Chernega, A. N.; Lozinskii,
M. O.; Tolmachev, A. A. Synthesis 2004, 1195–1202.
6. (a) Fokas, D.; Ryan, W.; Casebier, D.; Coffen, D.
Tetrahedron Lett. 1998, 39, 2235–2238; (b) Cossy, J.;
Cases, M.; Pardo, D. Tetrahedron Lett. 1998, 39, 2331–
2332; (c) Suchy, M.; Kutschy, P.; Monde, K.; Goto, H.;
Harada, N.; Takasugi, M.; Dzurilla, M.; Balentova, E.
J. Org. Chem. 2001, 66, 3940–3947; (d) Risitano, F.;
Grasii, G.; Foti, F.; Nicolo, F.; Condello, M. Tetrahedron
2002, 58, 191–195; (e) Nair, V.; Biju, A.; Vinod, A.;
Suresh, E. Org. Lett. 2005, 23, 5139–5142.
7. (a) Chimichi, S.; Nesi, R.; Sio, F.; Pepino, R.; Degl‘Innocenti, A.
Gazz. Chim. Ital. 1982, 112, 249–254; (b) Shivanyuk, A. F.;
Sereda,S. V.;Lozinskii, M.O. Ukr. Khim. Zh. 1992, 58, 682–685.
8. Hickmott, P. W. Electrophilic and Nucleophilic Substitution
and Addition Reactions of Enamines; Rappoport, Z., Ed.;
John Wiley & Sons: Chichester, UK, 1994; Chapter 14,
pp 727–871.
4.1.5. Procedure for synthesis of 15b. To a stirred suspen-
sion of hydroxylamine hydrochloride (0.26 g, 3.75 mmol) in
EtOH (30 mL) NaOH (0.12 g, 3.00 mmol) and 8b (1.02 g,
2.50 mmol) were added. The mixture was boiled with a re-
flux condenser for 8 h. The EtOH was evaporated in vacuo
to dryness and the precipitate was washed with water and re-
crystallized from DMF.
4.1.5.1. 10-Hydroxy-100,300,300-trimethyl-100,300-dihydro-
50H-dispiro[1,4-benzothiazine-2,40-pyrrolidine-20,200-in-
dole]-3,50(4H)-dione (15b). Colourless solid, mp 282–
283 ꢀC; dH 11.02 (1H, s), 9.68 (1H, s), 7.25 (1H, d,
J 7.5 Hz), 7.17 (1H, t, J 7.7 Hz), 7.10–6.88 (4H, m), 6.63
(1H, t, J 7.1 Hz), 6.42 (1H, d, J 8.1 Hz), 3.57 (1H, d,
J 16.2 Hz), 2.77 (1H, s), 1.95 (1H, d, J 16.2 Hz), 1.30 (3H,
s), 1.20 (3H, s); dC 164.42, 162.83, 149.19, 137.19,
136.95, 127.27, 126.99, 126.75, 123.16, 120.17, 118.16,
117.35, 116.58, 105.57, 90.71, 46.24, 45.13, 30.91, 28.45,
27.03, 19.65; MS [m/z (%)]: 395 (M+) (36.61), 336
(18.20), 159 (100.00); IR (cmꢂ1): 1590, 1695, 2990, 3080;
Anal. Calcd for C21H21N3O3S: C 63.78; H 5.35; N 10.62;
found C 63.77; H 5.33; N 10.57; yield: 65%.
9. Daunis, J.; Jacquier, R.; Rigail, M. Bull. Soc. Chim. Fr. 1970,
11, 4011–4017.
10. (a) Bailey, A. S.; Ellis, J. H.; Peach, J. M. J. Chem. Res., Synop.
1993, 202–206; (b) Tolmachev, A. A.; Babichenko, I. N.;
Sheinkman, A. K. Khim. Geterotsikl. Soed. 1993, 523–528.