Synthesis of 1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives by the reaction of 2-chloro-1,4-benzothiazin-3-ones with 'push-pull' enamines

Article abstract of DOI:10.1016/j.tet.2008.02.049

The reaction of 2-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazines with 'push-pull' enamines was investigated. The reaction with the enamines occurs at the β-carbon atom in the presence of a small excess of triethylamine. As a result, a set of 3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives was prepared. On acidic hydrolysis of ethyl 2-ethyl-3-(methylimino)-2-(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)butanoate, a new rearrangement affording ethyl 11-ethyl-2,3-dimethyl-4-oxo-2,3,4,5-tetrahydro-1H-2,5-methano-6,1,3-benzothiadiazocine-11-carboxylate was discovered. A plausible mechanism and factors influencing the course of the reaction are discussed.

Full text of DOI:10.1016/j.tet.2008.02.049

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4478e4485
www.elsevier.com/locate/tet
Synthesis of 1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds
and benzothiazinone spiro derivatives by the reaction of 2-chloro-
1,4-benzothiazin-3-ones with ‘pushepull’ enamines
a
a
Konstantin G. Nazarenko a, Nataliya A. Shtil a, , Sergey A. Buth , Alexander N. Chernega ,
*
Miron O. Lozinskii a, Andrey A. Tolmachev b
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094, Ukraine
b Research and Development Center for Chemistry and Biology, National Taras Shevchenko University, 62 Volodymyrska St., Kyiv 01033, Ukraine
Received 17 October 2007; received in revised form 22 January 2008; accepted 14 February 2008
Available online 20 February 2008
Abstract
The reaction of 2-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazines with ‘pushepull’ enamines was investigated. The reaction with the
enamines occurs at the b-carbon atom in the presence of a small excess of triethylamine. As a result, a set of 3-oxo-3,4-dihydro-2H-1,4-benzo-
thiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives was prepared. On acidic hydrolysis of ethyl 2-ethyl-
3-(methylimino)-2-(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)butanoate, a new rearrangement affording ethyl 11-ethyl-2,3-dimethyl-4-oxo-
2,3,4,5-tetrahydro-1H-2,5-methano-6,1,3-benzothiadiazocine-11-carboxylate was discovered. A plausible mechanism and factors influencing
the course of the reaction are discussed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Chloro derivatives; Enamines; Electrophilic substitution; Spiro heterocycles; Rearrangement
1. Introduction
dihydro-2H-1,4-benzothiazin-3-one derivatives bearing a het-
erocyclic or ketonic residue at position 2. To systematically
study the reactivity of 1 towards C-nucleophiles, one needs
to explore the reaction between 1a,b and enamines containing
conjugated electron-acceptor groups (‘pushepull’ enamines) 2
(Fig. 1).
The enamines 2 are known to be attacked by electrophiles
at different nucleophilic centres depending on the nature of the
electrophile. For instance, acylation, alkylation and reactions
with isocyanates and isothiocyanates are directed to the
2-Chloro-2H-1,4-benzothiazin-3-one derivatives 1 are known
to be convenient intermediates in the synthesis of 2-functional-
ized 2H-1,4-benzothiazin-3-ones with biological activity.1 The
chlorine atom inthe molecules of1 is readily substitutable byvar-
iousnucleophilesthusofferingwidepossibilitiesformodification
of the 1,4-benzothiazin-3-one nucleus. Compounds 1 enter into
a number of reactions with amines, alcohols, and some other nu-
cleophilic reagents.2 The FriedeleCrafts reaction with 1 has been
extensively used to obtain 2-aryl-substituted 2H-1,4-benzothia-
zin-3-ones.3
EWG
R1
EWG
O
R
R
We have previously demonstrated that chloro derivatives 1
can react as electrophiles with C-nucleophiles such as elec-
tron-rich heterocycles4 and tertiary enamines derived from
cyclic ketones.5 This strategy provides a facile route to 3,4-
S
S
R
O
Me
R3
N
Cl
S
R2
EWG
N
H
O
Me
O
N
H
N
H
O
1 a R= H
b R= CO2Et
2a-f
3 R= H, CO2Et
4 R= H, CO2Et
EWG= COR', CO2Et EWG= COR', CO2Et
* Corresponding author. Tel./fax: þ380 44 573 26 43.
E-mail address: shnataliya@ukr.net (N.A. Shtil).
Figure 1.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.049

K.G. Nazarenko et al. / Tetrahedron 64 (2008) 4478e4485
4479
Table 1
The structures of starting ‘pushepull’ enamines 2aef
shifts suggest the configuration at which one of the protons
forms an intramolecular hydrogen bond with the ethoxycar-
bonyl group so that its signal is significantly shifted downfield
from that of the unchelated proton. In a similar manner,
secondary enamine 5b induces a rather downfield broadened
singlet at 9.66 ppm corresponding to the chelated NH-proton
of the methylamino group. Thus, enamines 5a,b resulting
from the reaction of 1a with 2a,b have the E configuration,
as was also corroborated by the NOESY experiment.
R1
R2
R3
EWG
2a
2b
2c
2d
2e
2f
H
H
Me
H
H
H
H
H
Et
CO2Et
CO2Et
CO2Et
COMe
COPh
CO2Et
H
(CH2)2O(CH2)2
(CH2)2O(CH2)2
(CH2)2O(CH2)2
H
Me
On boiling in 2 N HCl for a short time, compounds 5a,b read-
ily hydrolyzed to give the same product, ethyl 3-oxo-2-(3-oxo-
3,4-dihydro-2H-1,4-benzothiazin-2-yl)butyrate 3a, which was
isolated as a 3:2 mixture of two diastereomers.
Ethoxycarbonyl derivative 1b reacts with 2a,b similar to
1a, with the difference that the reaction is accompanied by
the intramolecular interaction between the ethoxycarbonyl
group and the amino group thus leading to spiro compounds
6a,b. It should be noted that the analogous spiro products
were obtained by us formerly by the reaction of 1b with 4-
aminouracils.4 Unlike compounds 5a,b, their spiro counter-
parts 6a,b proved to be hydrolytically stable even on boiling
in 2 N HCl for a long time.
The reaction of 1a,b with tertiary enamines also involves
the b-carbon atom, with the constitution and stability of the re-
action products governed by the starting compounds (Scheme
2). When 1a,b were reacted with the derivatives of acetoacetic
ester and acetylacetone (2c,d), the product mixtures were
formed, which hydrolyzed to quantitatively yield the corre-
sponding b-dicarbonyl compounds 3. Judging by the 1H
NMR spectra of unpurified products of the reaction between
1a,b and 2c,d isomeric enamines 7 and 8 are formed and
also diketones 3 resulting from their hydrolysis. Compound
7 exhibits two singlet peaks in the region of 4.1e4.2 ppm cor-
responding to the protons at the terminal double bond, whereas
8 is characterized by the signal at 5.15 ppm arising from the
H-2 atom of the benzothiazine ring. The attempts of separating
the reaction mixture by crystallization or chromatography on
silica gel resulted merely in an increased amount of hydrolysis
products 3, so that we failed to isolate compounds 7 and 8 in
the pure state. The reaction with 1b was often accompanied by
the elimination of the ethoxycarbonyl group from the C-2
atom of the benzothiazine ring. Thus, when reacted with 2c,
1b provided a complex mixture of inseparable products, which
was hydrolyzed by 2 N HCl to give compound 3a.
b-carbon atom,6 whereas carbonyl compounds, iminium salts,
and diazonium salts attack the methyl group of the enamine
molecule.7 Moreover, the primary amino group of 2 can also
8
be involved. Thus, one would expect that the reaction be-
tween 1 and 2 followed by hydrolysis of the initial products
can finally yield both derivatives 3 (as a result of the electro-
philic attack on the b-carbon atom) and 4 (arising from the
involvement of the methyl group as a nucleophilic centre).
The two possible products are both useful as intermediates
in the synthesis of 2-hetaryl and 2-spiro-substituted 3,4-dihy-
dro-2H-1,4-benzothiazin-3-ones. To establish the position of
the electrophilic attack and to reveal the key features of the
reaction in relation to the reagent and substrate constitution,
we have studied the condensation of secondary and tertiary
chloro derivatives 1a,b with various types of ‘pushepull’
enamines 2aef (Table 1).
2. Results and discussion
Compounds 1 and 2 were reacted in boiling methylene
chloride in the presence of a slight excess of triethylamine.
The reaction mixture was washed with water (to remove tri-
ethylammonium hydrochloride) and dried, followed by evapo-
ration of the solvent and analysis of the residue. As found,
the reaction of 1a with primary and secondary enamines
(2a,b) under the conditions indicated furnishes the 3-oxo-
3,4-dihydro-2H-1,4-benzothiazin-2-yl derivatives of 3-amino-
and 3-methylaminocrotonic acids (5a,b) in high yields (87
and 89%, respectively) (Scheme 1). The signals of a single
1
geometric isomer were detected in the H NMR spectra of
both unpurified products 5a and 5b. The amino group of 5a
gives rise to two proton resonances appearing as broadened
singlets at 8.61 and 7.24 ppm. The strongly differing chemical
R1
N
Benzoylacetone derivative 2e reacts with 1a,b to produce
solely enamines 7a,b containing a terminal double bond,
with only one of two possible diastereomers formed in both
cases; the products can be isolated in the pure state.
Me
H
Me
R
O
H3O+
H
S
Et3N
S
1 a, b + 2 a, b
CO2Et
CO2Et
N
H
O
N
H
O
Enamine 7a slowly isomerizes to 8 on standing in a DMSO
solution. A half-reaction period at room temperature is about
72 h. Pure product 8 was obtained by recrystallizing com-
pound 7a twice from a mixture of DMFeisopropanol. The
5 a R= R1= H (87 %)
3 a (~95 %)
b R= H, R1= Me (89 %)
R1
N
O
S
R= CO2Et
Me
1
structures of 7a and 8 were unambiguously confirmed by H
CO2Et
N
H
O
and 13C NMR spectra and no reconversion 8/7a was
observed, which, taken together, suggests that 7a and 8 are ki-
netically and thermodynamically controlled products, respec-
tively. Unlike compound 7a, its ethoxycarbonyl-substituted
6 a R1= H (85 %)
b R1= Me (89 %)
Scheme 1. Reactions of 1a,b with primary and secondary enamines.

4480
K.G. Nazarenko et al. / Tetrahedron 64 (2008) 4478e4485
H
O
O
EWG
R
N
Me
R
N
H
S
Et3N
H+
O
R
1 a, b + 2 c-e
S
S
EWG
EWG
Me
O
N
H
N
H
O
N
H
O
7 a R= H, EWG= COPh (88 %) 8 R= H, EWG= COPh (95 %) 3 a R= H, EWG= CO2Et (87 %)
b R= CO2Et, EWG=COPh (92 %)
b R= H, EWG= COMe (85 %)
c R= CO2Et, EWG= COMe (85 %)
d R= H, EWG= COPh (92 %)
e R= CO2Et, EWG= COPh (94 %)
Scheme 2. Reactions of 1a,b with tertiary enamines.
analogue 7b does not undergo isomerization to 8 even on long
standing in a DMSO solution or after repeated recrystalliza-
tion from DMF. Thus, it became possible to obtain a monocrys-
tal of 7b and to analyze it by X-ray diffraction, which provided
good evidence for the terminal double bond in this molecule
(Fig. 2).
Interestingly, compound 7b isolated as a single diastereo-
mer produces a 3:2 diastereomeric mixture of b-diketones
3d on boiling in 10% HCl. Formation of the second diastereo-
mer necessarily implies a configuration inversion at the C-2
atom of the enamine moiety, which would be impossible in
the hydrolysis of 7b containing a terminal double bond. One
can thus assume that the isomerization 7b/8 in acidic
medium precedes the hydrolysis of 8 finally affording two
diastereomers 3d.
There is scarce evidence in the literature on enamines de-
rived from b-dicarbonyl compounds and lacking conjugation
between the carbonyl group and the double bond.9 As a rule,
such compounds bear a N-acyl group stabilizing their mole-
cules. In our case, the preferential formation of enamines 7
is likely to result from the destabilization of the competing
enamine structure 8 by the bulky benzothiazinone residue.
The molecular stability of ‘pushepull’ enamines 8 is more
sensitive to the size of the substituent at the C-2 atom as com-
pared to isomeric compounds 7. Indeed, this substituent, if
bulky enough, causes significant steric hindrance in the former
structure because it is spatially close to the double bond, the
most rigid molecular unit. In contrast, the latter isomer is
less sterically strained even with a large-size group at the
C-2 atom, as it is relatively distant from the double bond.
We attempted to change the position of the electrophilic
attack using, as a substrate, secondary enamine 2f, which con-
tains an ethyl group at the b-C atom. Taking into consideration
the steric congestion of substituents at the C-2 atom of 1,4 one
might expect that the reaction would involve either the nitro-
gen atom or the C-4 atom of compound 2f, so as to avoid
enhanced steric interactions. It has been found that 1a and
2f react to produce, in 87% yield, a 10:1 diastereomeric mix-
ture of products; one of them was isolated in the pure state by
recrystallization from isopropanol (Scheme 3).
Me
N
Me
H
Me
N
H
S
Me
Et
Cl
S
Et3N
Et
CO2Et
H
+
N
H
O
N
H
O
CO2Et
1 a
2 f
9 (87 %)
Scheme 3.
The 1H and 13C NMR as well as IR spectral data suggest that
the compound obtained (9) is the a,a-disubstituted imine of
acetoacetic ester resulting from the electrophilic attack on the
b-C atom of enamine 2f. The 1H NMR spectrum displays a sin-
glet at 1.67 ppm assigned to the methyl group of acetoacetic
ester. At the same time, the 13C NMR spectrum lacks the signal
of the enaminic b-C atom in the region of 80e90 ppm, which
was observed for all the compounds bearing the enamine
moiety (5, 7 and 8), irrespective of the double bond position.
The assumed direction of the reaction is also supported by
the formation of spiro derivative 10 (Scheme 4), with its struc-
ture determined by X-ray diffraction analysis (Fig. 3).
C12
C13
C11
O2
N2
C10
S1
C19
C5
C3
C20
C21
C17
C15
C14
C4
N1
C16
C6
Product 10 was formed as a result of the electrophilic attack
on the b-C atom of enamine 2f accompanied by the intramo-
lecular cyclization, which leads to the only diastereomer of the
spiro heterocycle with a terminal double bond.
C9
C18
C22
C1
O5
C2
O1
C23
C7
C8
O3
Me
Me
O
HN
O4
EtO2C
S
N
S
Et3N
CH2
Et
CO2Et
CH2
CO2Et
1 b + 2 f
-EtOH
Et
N
H
N
H
O
O
C24
C25
Figure 2. X-ray structure of 7b.
10 (85 %)
Scheme 4.

K.G. Nazarenko et al. / Tetrahedron 64 (2008) 4478e4485
4481
C14
The rearrangement 9/11 is likely to proceed via a three-
step pathway (Scheme 6). At the first stage, the nitrogen atom
of the imino group is protonated to form iminium salt 12. Then
the intramolecular attack on the amide nitrogen atom (a vari-
ation of the Mannich reaction10) follows, which results in
intermediate 13. Bicyclic system 13 appearing as a so-called
twisted amide11 has a rigid geometry, which rules out the con-
jugation between the lone electron pair of the nitrogen atom
and the carbonyl group. Such amides normally act as acylating
agents towards nucleophiles,12 so that the further conversion
13/11 occurs easily as a result of intramolecular reacylation.
C15
N2
C18
C17
C10
C9
C1
O2
O3
C7
C4
S1
C6
C5
C8
C3
C11
C16
C12
O4
Me
C2
S
Me
H
Et
COOEt
Me
N
O
H
C13
H+
+
N1
S
O1
Et
COOEt
9
-H+
11
N
..
NH
..
Figure 3. X-ray structure of 10.
N
O
Me
13
H
12
On attempted acid hydrolysis of 9, we discovered a non-
trivial ring-extension rearrangement affording ethyl 11-ethyl-
2,3-dimethyl-4-oxo-2,3,4,5-tetrahydro-1H-2,5-methano-6,1,3-
benzothiadiazocine-11-carboxylate 11 in 82% yield (Scheme
5); it was with the X-ray diffraction method that we succeeded
in structural determination of the heterocycle obtained
(Fig. 4).
Scheme 6.
3. Conclusions
In summary, we have studied the reaction of 2-chloro-2H-
1,4-benzothiazin-3-ones with ‘pushepull’ enamines, which
offers a convenient synthetic access to a variety of b-dicar-
bonyl compounds containing the 3-oxo-3,4-dihydro-2H-ben-
zothiazin-2-yl moiety as well as to benzothiazinone spiro
derivatives. Further research in this line will be aimed at the
application of the newly synthesized b-dicarbonyl compounds
in the preparation of 2-hetaryl-substituted 2H-1,4-benzothia-
zin-3-ones.
Me
N
O
Me
H
Me
Et
H+
N
S
S
Et
COOEt
CO2Et
N
Me
N
H
O
H
9
11 (82 %)
Scheme 5.
4. Experimental
Further research on the rearrangement has revealed that im-
ine 9 is converted into 11 in the presence of catalytic acid
(10% HCl or CH3COOH) at room temperature, whereas the
reaction does not proceed at all in alkaline or neutral medium
even on heating for a long time. The conversion is completely
diastereoselective: the diastereomeric mixture has much the
same component ratio (10:1) for starting compound 9 and
product 11. Accordingly, a pure diastereomer of 9 gives rise
to a single diastereomer of 11.
4.1. General
CH2Cl2 for the reactions was freshly distilled and dried by
standard method. All solvents for the crystallization were used
without additional purification. The 1H and 13C NMR (500 and
125 MHz, respectively) were recorded on a Bruker Avance
DRX 500 with DMSO-d6 as the solvent and TMS as an inter-
nal 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 chromatography/mass spectrometric sys-
tem that consists of high-performance liquid chromatograph
‘Agilent 1100 Series’ equipped with diode-matrix and mass-
selective detector ‘Aligent LC/MSD SL’. The parameters of
chromatographyemass analysis: Column: Zorbax SB-C18,
C11
C12
C8
O1
N2
O2
C16
C10
N1
C5
C7
C4
C6
C17
C15
O3
1.8 mmꢁ4.6 mmꢁ15 mm. Solvents:
A acetonitrileewater
C9
C3
(95:5), 0.1% TFA, B water (0.1% of TFA). Eluent flow:
3 mL/s. The volume of injected sample: 1 mL. UV-detectors
operate at 215, 254 and 265 nm. Ionization method: chemical
ionization under atmospheric pressure (APCI). Ionization
mode: simultaneous scanning of positive and negative ions
in the mass range of m/z 80e1000. Microanalyses were
C1
C2
C13
S1
C14
Figure 4. X-ray structure of 11.

4482
K.G. Nazarenko et al. / Tetrahedron 64 (2008) 4478e4485
performed 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.
(50.49), 42 (60.50); IR (cmꢂ1): 3300, 3070, 3000, 1720,
1690 (br), 1625, 1595.
4.2.4. Ethyl 10,50-dimethyl-20,3-dioxo-10,20,3,4-
tetrahydrospiro[1,4-benzothiazine-2,30-pyrrole]-40-
carboxylate (6b)
4.2. General procedure for the synthesis of 5e10
Colourless solid, mp 191e192 ꢀC, yield (solvent): 1.48 g,
89% (EtOH); [Found: C, 57.83; H, 4.87; N, 8.45.
C16H16N2O4S requires C, 57.82; H, 4.85; N, 8.43%]; dH
10.88 (1H, s, CONH), 7.10e7.15 (2H, m, Ar), 6.92e6.98
(2H,m, Ar), 4.08 (2H, q, J 7.0 Hz, OCH2CH3), 3.02 (3H, s,
NMe), 2.52 (3H, s, Me), 1.16 (3H, t, J 7.0 Hz, OCH2CH3);
dC 173.3, 162.4, 161.9, 159.0, 136.9, 126.9, 126.8, 123.2,
116.5, 115.7, 104.2, 59.5, 52.0, 26.5, 14.1, 12.6; MS [m/z
(%)]: 332 (Mþ) (41.64), 286 (64.76), 244 (22.21), 169
(16.00), 81 (20.25), 56 (100.00); IR (cmꢂ1): 3000, 1720,
1690 (br), 1625, 1595.
To a stirred solution of an 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 4 h, cooled and
washed with water (2ꢁ30 mL). Organic phase was dried over
Na2SO4 and evaporated in vacuo. The crude product was crys-
tallized from an appropriate solvent.
4.2.1. Ethyl 3-amino-2-(3-oxo-3,4-dihydro-2H-1,4-
benzothiazin-2-yl)but-2-enoate (5a)
Colourless solid, mp 188e189 ꢀC, yield (solvent): 1.27 g,
87% (2-PrOH); [Found: C, 57.50; H, 5.50; N, 9.53.
C14H16N2O3S requires C, 57.52; H, 5.52; N, 9.58%]; dH
10.28 (1H, s, CONH), 8.61 (1H, br s, NH2), 7.24 (1H, br s,
NH2), 7.12 (1H, d, J 7.5 Hz, CH), 7.05 (1H, t, J 7.5 Hz, 1H,
CH), 6.85e6.92 (2H, m, Ar), 4.86 (1H, br s, SCH), 3.96
(2H, q, J 7.0 Hz, OCH2CH3,), 2.04 (3H, s, Me), 1.11 (3H, t,
J 7.0 Hz, OCH2CH3); dC 168.9, 168.4, 163.1, 137.7, 126.7,
126.4, 122.9, 121.7, 117.0, 86.5, 58.7, 41.1, 20.6, 14.8; MS
[m/z (%)] 292 (Mþ) (25.46), 246 (100), 218 (47.223), 91
(27.31), 44 (74.91); IR (cmꢂ1): 3420, 3310, 2950, 1680 (br),
1620 (br), 1595.
4.2.5. 2-(1-Benzoyl-2-morpholin-4-ylprop-2-en-1-yl)-2H-
1,4-benzothiazin-3(4H)-one (7a)
Yellow solid, mp 220e221 ꢀC, yield (solvent): 1.73 g, 88%
(2-PrOH); [Found: C, 67.00; H, 5.64; N, 7.13. C22H22N2O3S
requires C, 66.98; H, 5.62; N, 7.10%]; dH 10.66 (1H, s,
CONH), 8.04 (2H, d, J 7.5 Hz, Ar), 7.64 (1H, t, J 7.4 Hz,
CH), 7.53 (2H, t, J 7.2 Hz, Ar), 7.37 (1H, d, J 7.8 Hz, CH),
7.22 (1H, t, J 7.5 Hz, CH), 6.94e7.04 (2H, m, Ar), 4.76
(1H, d, J 10.2 Hz, CH), 4.28 (1H, d, J 10.2 Hz, SCH), 4.17
(1H, s, C]CH2), 4.19 (1H, s, C]CH2), 3.50e3.60 (4H, m,
O(CH2)2), 2.80e2.90 (4H, m, N(CH2)2); dC 196.5, 166.5,
150.3, 137.8, 137.4, 133.5, 129.1, 129.0, 128.4, 128.0,
127.7, 123.4, 121.1, 117.7, 94.6, 66.6, 49.2, 44.0, 40.1; MS
[m/z (%)]: 394 (Mþ) (3), 307 (86.78), 289 (100), 105
(57.04), 77 (46.02); IR (cmꢂ1): 3065, 2950 (br), 1720, 1680
(br), 1595.
4.2.2. Ethyl 3-(methylamino)-2-(3-oxo-3,4-dihydro-2H-1,4-
benzothiazin-2-yl)but-2-enoate (5b)
Colourless solid, mp 176e177 ꢀC, yield (solvent): 1.36 g,
89% (2-PrOH); [Found: C, 58.82; H, 5.93; N, 9.17.
C15H18N2O3S requires C, 58.80; H, 5.92; N, 9.14]; dH 10.41
(1H, s, CONH), 9.66 (1H, br s, NHMe), 7.19 (1H, d, J
7.8 Hz, CH), 7.12 (1H, t, J 7.5 Hz, CH), 6.90e6.96 (2H, m,
Ar), 5.08 (1H, br s, SCH), 3.94e3.99 (2H, q, J 7.2 Hz,
OCH2CH3), 2.92 (3H, d, J 4.8 Hz, NHMe), 2.08 (3H, s, Me),
1.09 (3H, t, J 7.2 Hz, OCH2CH3); dC 168.8, 168.2, 165.3,
137.2, 126.3, 126.2, 122.6, 121.4, 116.6, 79.2, 58.5, 40.6,
29.7, 18.5, 14.4; MS [m/z (%)]: 306 (Mþ) (29.05), 260
(49.76), 108 (62.04), 82 (56.57), 56 (100.00); IR (cmꢂ1):
3340 (w), 1680, 1640, 1595.
4.2.6. Ethyl 2-(1-benzoyl-2-morpholin-4-ylprop-2-en-1-yl)-
3-oxo-3,4-dihydro-2H-1,4-benzothiazine-2-carboxylate (7b)
Colourless solid, mp 167e168 ꢀC, yield (solvent): 2.14 g,
92% (MeOH); [Found: C, 64.38; H, 5.60; N, 5.97.
C25H26N2O5S requires C, 64.36; H, 5.62; N, 6.00%]; dH
10.82 (1H, s, CONH), 7.87 (2H, d, J 7.5 Hz, Ar), 7.59 (1H,
t, J 7.1 Hz, CH), 7.49 (2H, t, J 7.2 Hz, Ar), 7.16 (1H, d, J
7.5 Hz, CH), 7.06 (1H, t, J 7.4 Hz, CH), 6.88e6.96 (2H, m,
Ar), 5.44 (1H, s, CH), 4.17 (1H, s, C]CH2), 4.08 (1H, s,
C]CH2), 3.93e4.05 (2H, m, OCH2CH3), 3.60 (4H, br s,
O(CH2)2), 2.97e3.08 (2H, m, N(CH2)2), 2.34e2.42 (2H, m,
N(CH2)2), 0.97 (3H, t, J 7.1 Hz, OCH2CH3); dC 168.1,
163.8, 148.2, 136.3, 135.2, 133.0, 128.7, 128.2, 126.2,
126.1, 123.1, 117.9, 116.2, 99.9, 65.7, 61.8, 57.9, 51.4, 49.7,
13.4; MS [m/z (%)]: 466 (Mþ) (4.05), 379 (28.11), 315
(51.67), 105 (100), 77 (47.80); IR (cmꢂ1): 3070, 2950,
1740, 1680, 1620, 1595.
4.2.3. Ethyl 50-methyl-20,3-dioxo-10,20,3,4-tetrahydrospiro-
[1,4-benzothiazine-2,30-pyrrole]-40-carboxylate (6a)
Colourless solid, mp 242e243 ꢀC, yield (solvent): 1.35 g,
85% (EtOH); [Found: C, 56.57; H, 4.41; N, 8.77.
C15H14N2O4S requires C, 56.59; H, 4.43; N, 8.80%]; dH
10.81 (1H, s, CONH), 10.68 (1H, br s, NH), 7.09e7.15 (2H,
m, Ar), 6.92e6.96 (2H, m, Ar), 4.06 (2H, q, J 7.0 Hz,
OCH2CH3), 2.35 (3H, s, Me), 1.16 (3H, t, J 7.0 Hz,
OCH2CH3); dC 174.9, 162.9, 162.4, 157.7, 137.4, 127.3,
127.2, 123.6, 116.9, 116.3, 105.1, 59.8, 53.4, 14.6, 14.1; MS
[m/z (%)]: 318 (Mþ) (100.00), 272 (83.78), 244 (52.62), 155
4.2.7. 2-(1-Benzoyl-2-morpholin-4-ylprop-1-en-1-yl)-2H-
1,4-benzothiazin-3(4H)-one (8)
Yellow solid, mp 217e218 ꢀC, yield (solvent): 1.64 g, 95%
(2-PrOHeDMF 2:1); [Found: C, 66.97; H, 5.61; N, 7.09.

K.G. Nazarenko et al. / Tetrahedron 64 (2008) 4478e4485
4483
C22H22N2O3S requires C, 66.98; H, 5.62; N, 7.10%]; dH 10.46
(1H, s, CONH), 7.40e7.58 (5H, m, Ar), 7.21 (1H, d, J 7.8 Hz,
CH), 7.14 (1H, t, J 6.9 Hz, Ar), 6.90e6.99 (2H, m, Ar), 5.17
(1H, s, SCH), 3.23 (4H, br s, O(CH2)2), 2.81 (4H, br s,
N(CH2)2), 2.22 (3H, s, Me); dC 193.2, 166.9, 146.8, 141.0,
137.4, 130.4, 128.5, 128.0, 126.7, 126.7, 126.6, 122.7,
121.3, 116.9, 105.3, 65.7, 51.2, 42.9, 18.7; MS [m/z (%)]:
394 (Mþ) (100), 307 (86.78), 289 (56.46), 105 (54.56), 77
(46.02); IR (cmꢂ1): 3000, 1710, 1650, 1595.
1.27 g, 87% (2-PrOH); [Found: C, 57.34; H, 5.16; N, 4.80.
C14H15NO4S requires C, 57.32; H, 5.15; N, 4.77%]. The sig-
nals of major diastereomer: dH 10.73 (1H, s, CONH), 7.27
(1H, t, J 6.5 Hz, Ar), 7.19 (1H, t, J 7.8 Hz, Ar), 7.03e6.98
(2H, m, Ar), 4.18e4.04 (3H, m, OCH2CH3 and SCH), 3.92
(1H, d, J 10 Hz, CH), 2.29 (3H, s, Me), 1.24 (3H, t, J
7.0 Hz, OCH2CH3); dC 200.0, 166.8, 165.1, 137.2, 128.2,
128.0, 123.8, 118.9, 117.9, 62.1, 58.3, 41.1, 29.7, 14.3; the sig-
nals of minor diastereomer: dH 10.71 (1H, s, CONH), 7.27
(1H, t, J 6.5 Hz, Ar), 7.19 (1H, t, J 7.8 Hz, Ar), 7.00e6.95
(2H, m, Ar), 4.18e4.04 (3H, m, OCH2CH3 and SCH), 3.92
(1H, d, J 10 Hz, CH), 2.29 (3H, s, Me), 1.24 (3H, t, J
7.0 Hz, OCH2CH3); dC 200.6, 167.0, 165.0, 137.2, 128.2,
128.1, 123.7, 118.6, 117.8, 62.0, 58.3, 41.1, 30.0, 14.2; MS
[m/z (%)]: 293 (Mþ) (10.16), 250 (18.02), 204 (100.00), 99
(8.71), 43 (27.34); IR (cmꢂ1): 2950, 1730, 1710, 1670,
1595, 1670.
4.2.8. Ethyl 2-ethyl-3-(methylimino)-2-(3-oxo-3,4-dihydro-
2H-1,4-benzothiazin-2-yl)butanoate (9)
Colourless solid, mp 149e150 ꢀC, yield (solvent): 1.45 g,
87% (2-PrOH); [Found: C, 61.03; H, 6.65; N, 8.35.
C17H22N2O3S requires C, 61.05; H, 6.63; N, 8.38%]; dH
10.45 (1H, s, CONH), 7.22 (1H, d, J 6.9 Hz, CH), 7.08 (1H
t, J 7.7 Hz, CH), 6.86e6.93 (2H, m, Ar), 4.14 (1H, s, SCH),
4.05e4.14 (2H, m, OCH2CH3), 2.71 (3H, s, NMe), 2.06e
2.12 (1H, m, CH2CH3), 1.82e1.88 (1H, m, CH2CH3), 1.63
(3H, s, Me), 1.20 (3H, t, J 7.4 Hz, OCH2CH3), 0.82 (3H, t, J
7.4 Hz, CH2CH3); dC 171.4, 167.3, 163.8, 136.9, 126.6,
122.6, 118.7, 116.4, 61.1, 60.5, 44.6, 38.0, 28.0, 17.6, 13.8,
9.2; MS [m/z (%)]: 334 (Mþ) (14.92), 261 (61.33), 136
(12.58), 126 (12.65), 56 (100.00); IR (cmꢂ1): 3010, 1725,
1670 (br), 1585.
4.3.2. 3-(3-Oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-
pentane-2,4-dione (3b)
Colourless solid, mp 123e124 ꢀC, yield (solvent): 1.12 g,
85% (2-PrOH); [Found: C, 59.28; H, 4.97; N, 5.35.
C13H13NO3S requires C, 59.30; H, 4.98; N, 5.32%]; dH
10.75 (1H, s, CONH), 7.28 (1H, d, J 7.8 Hz, CH), 7.20 (1H,
t, J 8.0 Hz, CH), 6.96e7.04 (2H, m, Ar), 4.21 (1H, d, J
10.5 Hz, CH), 4.18 (1H, d, J 10.5 Hz, SCH), 2.26 (3H, s,
COMe), 2.23 (3H, s, COMe); dC 204.9, 201.5, 166.5, 137.4,
128.1, 127.7, 123.5, 119.1, 117.6, 65.8, 42.1, 36.7, 30.4; MS
[m/z (%)]: 263 (Mþ) (11.36), 221 (18.69), 220 (100.00), 178
(39.61), 43 (86.86); IR (cmꢂ1): 2950, 1710, 1670 (br), 1595.
4.2.9. Ethyl 40-ethyl-10-methyl-50-methylene-20,3-dioxo-3,4-
dihydrospiro[1,4-benzothiazine-2,30-pyrrolidine]-40-
carboxylate (10)
Colourless solid, mp 199e200 ꢀC, yield (solvent): 1.53 g,
85% (EtOH); [Found: C, 60.00; H, 5.60; N, 7.80.
C18H20N2O4S requires C, 59.98; H, 5.59; N, 7.77%]; dH
10.95 (1H, s, CONH), 7.24 (1H, d, J 7.8 Hz, CH), 7.16 (1H,
t, J 8.0 Hz, CH), 6.93e6.98 (2H, m, Ar), 4.53 (1H, d, J
2.6 Hz, C]CH2,), 4.42 (1H, d, J 2.6 Hz, C]CH2,), 3.88e
3.96 (2H, m, OCH2CH3), 2.09e2.20 (1H, m, CH2CH3),
1.67e1.79 (1H, m, CH2CH3), 0.96e1.09 (6H, m, OCH2CH3
and CH2CH3); dC 169.6, 168.2, 162.5, 147.3, 137.3, 127.9,
127.6, 123.6, 116.8, 116.3, 88.8, 61.4, 57.5, 56.6, 27.6, 26.2,
13.9, 9.7; MS [m/z (%)]: 360 (Mþ) (82.58), 287 (46.63), 286
(100.00), 164 (82.82), 56 (54.11); IR: (cmꢂ1): 3060, 2950
(br), 1720, 1660 (br), 1595.
4.3.3. Ethyl 2-(1-acetyl-2-oxopropyl)-3-oxo-3,4-dihydro-
2H-1,4-benzothiazine-2-carboxylate (3c)
Colourless solid, mp 154e5 ꢀC, yield (solvent): 1.20 g,
85% (2-PrOH); [Found: C, 57.28; H, 5.10; N, 4.15.
C16H17NO5S requires C, 57.30; H, 5.11; N, 4.18%]; dH
10.98 (1H, br s, CONH), 7.32 (1H, d, J 7.5 Hz, CH), 7.23
(1H, t, J 7.5 Hz, CH), 7.03e6.97 (2H, m, Ar), 4.56 (1H, s,
CH), 3.90e4.05 (2H, m, OCH2CH3), 2.32 (3H, s, COMe),
2.20 (3H, s, COMe), 0.91 (3H, t, J 7.2 Hz, OCH2CH3); dC
203.3, 192.0, 171.3, 164.8, 136.9, 128.0, 127.3, 123.5,
117.5, 116.8, 58.8, 54.4, 49.6, 31.5, 23.6, 14.9; MS [m/z
(%)]: 335 (Mþ) (14.45), 262 (100.00), 163 (17.00), 105
(80), 77 (38.60); IR (cmꢂ1): 2950, 1710, 1690, 1640, 1595.
4.3. General procedure for the synthesis of 3aec
To a stirred solution of an 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 4 h. CH2Cl2
was evaporated in vacuo to dryness. The residue was triturated
with acidified water (50 mL) and filtered. The crude product
was crystallized from an appropriate solvent.
4.4. General procedure for the synthesis of 3d, e, 11
To a stirred solution of HCl (2 N, 30 mL) 7a,b (0.5 g) or 8
(0.5 g), or 9 (0.5 g) was added and heated at 60 ꢀC for 30 min.
The precipitate was filtered and recrystallized from EtOH.
4.4.1. 2-(3-Oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)-1-
phenylbutane-1,3-dione (3d)
4.3.1. Ethyl 3-oxo-2-(3-oxo-3,4-dihydro-2H-1,4-
benzothiazin-2-yl)butanoate (3a)
Compound 3a was obtained as a mixture of two diastereo-
mers (3:2). Colourless solid, mp 159e160 ꢀC, yield (solvent):
Compound 3d was obtained as a mixture of two diastereo-
mers (3:2). Colourless solid, mp 207e208 ꢀC, yield (solvent):
0.38 g, 92% (EtOH); [Found: C, 66.46; H, 4.67; N, 4.33.
C18H15NO3S requires C, 66.44; H, 4.65; N, 4.30%]. The

4484
K.G. Nazarenko et al. / Tetrahedron 64 (2008) 4478e4485
signals of major diastereomer: dH 10.68 (1H, s, CONH), 8.03
(2H, t, J 7.5 Hz, Ar), 7.70e7.66 (1H, m, Ar), 7.56 (2H, t, J
7.5 Hz, Ar), 7.36 (1H, d, J 7.5 Hz, Ar), 7.21 (1H, t, J
7.5 Hz, Ar), 7.03e6.95 (2H, m, Ar), 5.24 (1H, d, J 10.0 Hz,
SCH), 4.40 (1H, d, J 10.0 Hz, CH), 2.21 (3H, s, Me); dC
201.2, 193.7, 165.1, 137.4, 136.4, 134.3, 129.4, 129.1,
128.2, 128.1, 123.7, 119.3, 117.9, 60.6, 42.0, 29.8; the signals
of minor diastereomer: dH 10.79 (1H, s, CONH), 8.03 (2H, t, J
7.5 Hz, Ar), 7.70e7.66 (1H, m, Ar), 7.56 (2H, t, J 7.5 Hz, Ar),
7.23e7.18 (2H, m, Ar), 7.00e6.92 (2H, m, Ar), 5.31 (1H, d, J
10 Hz, SCH), 4.37 (1H, d, J 10 Hz, CH), 2.23 (3H, s, Me); dC
200.3, 193.1, 165.6, 137.3, 136.6, 134.8, 129.6, 129.3, 128.0,
128.0, 123.7, 119.1, 117.9, 59.9, 42.2, 29.8; MS [m/z (%)]: 325
(Mþ) (10.79), 282 (74.69), 220 (100.00), 105 (85.41), 77
(42.59); IR (cmꢂ1): 2950, 1720, 1670 (br), 1595.
4.5. X-ray crystal structure determination of compounds 7b,
10 and 11
The crystallographic measurements for compounds 7b and
10 were performed at 18 ꢀC, for compound 11 at ꢂ70 ꢀC. All
data were corrected for Lorentz and polarization effects; em-
pirical absorption correction based on azimuthal scan data13
was applied for 7b and 10, absorption correction using the SA-
DABS procedure14 was applied for 11. All structures were
solved by direct methods. All atoms were refined on Fobs by
full-matrix least-squares technique in the anisotropic approxi-
mation. Chebushev weighting scheme15 was used. All struc-
tural calculations were carried out using CRYSTALS
program package.16 The hydrogen atoms for the all structures
were located in the difference Fourier maps and refined
isotropically.
The full crystallographic data sets (excluding structure fac-
tors) for the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 646354 for 7b and CCDC 603949
for 10 and CCDC 646353 for 11. Copies of data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: þ44(0) 1223 336033
or e-mail: deposit@ccdc.cam.ac.uk].
4.4.2. Ethyl 2-(1-benzoyl-2-oxopropyl)-3-oxo-3,4-dihydro-
2H-1,4-benzothiazine-2-carboxylate (3e)
Compound 3e was obtained as a mixture of two diastereo-
mers (3:2). Colourless solid, mp 157e158 ꢀC, yield (solvent):
0.40 g, 94% (EtOH); [Found: C, 63.47; H, 4.83; N, 3.55.
C21H19NO5S requires C, 63.46; H, 4.82; N, 3.52%]. The sig-
nals of major diastereomer: dH 10.99 (1H, s, CONH), 8.05
(2H, d, J 7.5 Hz, Ar), 7.70 (1H, t, J 7.0 Hz, Ar), 7.58 (2H, t,
J 7.8 Hz, Ar), 7.33 (1H, d, J 8.0 Hz, Ar), 7.22 (1H, t, J
7.8 Hz, Ar), 7.06e6.98 (2H, m, Ar), 5.55 (1H, s, CH),
3.95e3.75 (2H, m, OCH2CH3), 2.19 (3H, s, Me), 0.75 (3H,
t, J 7.0 Hz, OCH2CH3); dC 194.2, 167.3, 163.0, 136.3,
136.1, 133.6, 128.8, 128.4, 127.5, 127.2, 123.1, 116.5,
116.4, 61.8, 59.9, 54.9, 30.6, 13.0; the signals of minor diaste-
reomer: dH 11.08 (1H, s, CONH), 7.81 (2H, d, J 7.5 Hz, Ar),
7.65 (1H, t, J 7.0 Hz, Ar), 7.49 (2H, t, J 7.8 Hz, Ar), 7.22
(1H, t, J 7.8 Hz, Ar), 7.13 (1H, d, J 8.0 Hz, Ar), 7.02e6.93
(2H, m, Ar), 5.44 (1H, s, CH), 4.12e3.95 (2H, m, OCH2CH3),
2.23 (3H, s, Me), 1.00 (3H, t, J 7.0 Hz, OCH2CH3); dC 193.6,
166.5, 162.7, 136.7, 136.1, 133.6, 128.6, 128.2, 127.5 127.3,
123.1, 117.2, 116.8, 62.1, 59.3, 55.6, 30.6, 13.2; MS [m/z
(%)]: 397 (Mþ) (14.95), 351 (8.43), 282 (17.01), 105
(100.00), 77 (38.63); IR (cmꢂ1): 2950, 1710, 1690, 1640,
1595.
Acknowledgements
We thank Enamine Co, Ukraine for the financial support of
this work and Prof. Kostyuk, A. N. for his help in the prepara-
tion of this paper.
Supplementary data
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.02.049.
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