An efficient, three-component synthesis and molecular structure of derivatives of 2-amino-3-R-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide spirocombined with a 2-oxindole nucleus

Article abstract of DOI:10.1016/j.tet.2014.09.005

Spiro[(2-amino-3-R-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide)-4,3′-(1′-R′-5′-R″-indolin-2′-one)] compounds were synthesized based on the three-component interaction of benzo[c][2,1]thiazin-4-on 2,2-dioxide with corresponding isatins a

Full text of DOI:10.1016/j.tet.2014.09.005

Accepted Manuscript
An efficient, three-component synthesis and molecular structure of derivatives
of 2-amino-3-r-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide
spirocombined with a 2-oxindole nucleus
Leonid A. Shemchuk, Prof. Dmitry A. Lega, Ruslan Gr. Redkin, Valentine P.
Chernykh, Oleg V. Shishkin, Svetlana V. Shishkina
PII:
S0040-4020(14)01284-8
10.1016/j.tet.2014.09.005
TET 25979
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 May 2014
Revised Date: 22 August 2014
Accepted Date: 2 September 2014
Please cite this article as: Shemchuk LA, Lega DA, Redkin RG, Chernykh VP, Shishkin OV, Shishkina
SV, An efficient, three-component synthesis and molecular structure of derivatives of 2-amino-3-r-6-
ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide spirocombined with a 2-oxindole nucleus,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.09.005.
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1
ACCEPTED MANUSCRIPT
Graphical Abstracts
An efficient, three-component synthesis and molecular structure of derivatives of 2-amino-
3-r-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide spirocombined with a
2-oxindole nucleus
Leonid A. Shemchuk,a * Dmitry A. Lega,a Ruslan Gr. Redkin,a Valentine P. Chernykh,a Oleg V.
Shishkin, b Svetlana V. Shishkinab
O
NH2
O
R
R''
+
CN
Method A
O
O
N
O
+
S
R'
N
O
R
N
N
O
O
46-83%
R'
O
S
O
NC
R''
R
R''
O
+
S
Method B
40-77%
N
O
N
O
R'
*
Corresponding author. Tel. +38(0572) 67-93-70; Fax: +38(0572) 67-93-72; e-mail:
dr_shemchuk@mail.ru (Prof. Leonid A.Shemchuk)

2
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AN EFFICIENT, THREE-COMPONENT SYNTHESIS AND MOLECULAR
STRUCTURE OF DERIVATIVES OF 2-AMINO-3-R-6-ETHYL-4,6-
DIHYDROPYRANO[3,2-C][2,1]BENZOTHIAZINE-5,5-DIOXIDE SPIROCOMBINED
WITH A 2-OXINDOLE NUCLEUS
Leonid A. Shemchuk,a † Dmitry A. Lega,a Ruslan Gr. Redkin,a Valentine P. Chernykh,a Oleg V.
Shishkin, b Svetlana V. Shishkinab
aNational University of Pharmacy, Pushkinska Str. 53, Kharkiv, 61001, Ukraine
bSTC Institute for Single Crystals, National Academy of Sciences of Ukraine, Lenin Ave. 60,
Kharkiv, 61001, Ukraine
Abstract — Spiro[(2-amino-3-R-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-
dioxide)-4,3'-(1'-R'-5'-R''-indolin-2'-one)] compounds were synthesized based on the three-
component interaction of benzo[c][2,1]thiazin-4-on 2,2-dioxide with corresponding isatins and
appropriate methylene active nitriles in the presence of a base as a catalyst. The molecular
structures of the target compounds were proved uniquely by the X-ray diffraction analysis
method.
Keywords: benzo[c][2,1]thiazine, 2-oxindoles, methylene active nitriles, spirocyclic
compounds, 4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide, X-ray diffraction
analysis.
1. Introduction
Currently, synthetic organic chemistry provides medicine with new and effective
heterocyclic compounds for treating a variety of diseases. In this regard, derivatives of
benzothiazinone S,S-dioxide occupy a special place, since they are very perspective compounds
to create new drugs. This is associated with their fairly wide range of biological activities.
Sedative, anticonvulsant, hypnotic, hypoglycemic, muscle relaxant, anti-arrhythmic hypotensive
and other activities are the most typical for them.1,2
Among ten possible structural isomers of benzothiazinone S,S-dioxide,3,4
benzo[c][2,1]thiazin-4-on 2,2-dioxide attracted our attention, due to insufficient studies of the
biological activity spectra for different derivatives of this benzothiazinone and insufficient
studies of its chemical properties.
Derivatives of 3,4-dihydro-2,1-benzothiazine-2,2-dioxide are characterized by such
biological activities as IL-8 receptor antagonism,5 selective inhibition of focal adhesion kinase,6
antiviral (reverse transcriptase inhibitory activities),7 anticancer8 and antibacterial activities.9
†
Corresponding author. Tel. +38(0572)67-93-70; Fax: +38(0572)67-93-72; e-mail:
dr_shemchuk@mail.ru (Prof. Leonid A.Shemchuk)

3
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Also, they demonstrate potent biological activities such as lipoxygenase inhibition and are
applied as agents for heart diseases.10 On the other hand, being structural isomers, the
benzo[c][2,1]thiazine-4(3H)-on 2,2-dioxide core is bioisosteric to the benzo[e][1,2]thiazine one.
It serves as a base for such drugs as piroxicam®, droxicam® and meloxicam® (Fig. 1), which
one to efficient analgesic and anti-inflammatory agents.11 Some of these compounds showed
anti-bacterial activity.12
O
N
N
OH
O
O
OH
O
CH3
O
S
N
S
N
N
N
H
H
O
N
S
O
N
S
CH3
N
R
S
CH3
N
O
O
O
O
O
CH3
O
O
Pyroxicam
Droxicam
Meloxicam
Figure 1. Initial benzo[c][2,1]thiazin-4-on 2,2-dioxide and bioisosteric biologically
active benzothiazine derivatives
Benzo[c][2,1]thiazine-4(3H)-on 2,2-dioxide represents the methylene active CH-acid. Its
structure is an analogue of a cyclic methyleneactive 1,3-dicarbonyl compound, which makes it a
very convenient and promising intermediate for building new heterocyclic systems based on it.
Although this compound, unlike its carbonyl analogue, exists entirely in the 4-oxo form,13,14 it
exhibits a number of specific properties that are not characteristic for carbonyl compounds. In
particular, it is not reduced in 4-hydroxy derivatives by the direct route and does not form
enamines with secondary amines. The carbonyl group of the given heterocycle is distinguished
by a high propensity for enolization in when of introducing alkyl or acyl groups into position
3.15,16 This property opens up great opportunities for the synthesis of condensed heterocyclic
systems using СН2СО-group in this compound in particular using multi-component reactions.
Multicomponent reactions of enol-nucloephilic compounds, carbonyl compounds and the
appropriate active nitriles have recently attracted the interest of the synthetic community,
because the formation of diverse condensation products can be expected depending on the
specific conditions and structure of the building blocks. This interaction is the direct route for
construction of the 2-amino-4H-pyrane core.17 The mechanism of this coupling is based on a
domino Knoevenagel/Michael cyclization sequence between carbonyl compounds, appropriate
nitriles and carbonyl CH-acids.18 There are no data about these interactions for
benzo[c][2,1]thiazine-4(3H)-on 2,2-dioxide. No information is available about the synthesis of
the condensed heterocyclic systems including benzo[c][2,1]thiazine-4(3H)-on 2,2-dioxide and
the 4Н-pyranic ring as well.
Using isatins in this reaction as the carbonyl component allows construction of the
spiro[4H-pyran-oxindole] core19 in a one-pot synthesis. For example, a three-component reaction

4
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of isatins, ethylcyanoacetate or malononitrile, and 3-methylpyrazol-5-one in the presence of base
catalysts20 or under ultrasound irradiation,21 or in the presence of NaHCO3 under grinding,22
leads to the spiro[pyrano[2,3-c]pyrazolo-2-oxindoles] with good yields. The same principle was
used by us in the preparation and study of the previously reported 4-hydroxy-2-quinolones
annelated by a spiro[indole-3,4'-pyran] ring.23
In this aspect, N-ethyl-1H-2,1-benzothiazin-4(3H)-on-2,2-dioxide is new synthon for the
one-step three-component synthesis of condensed system of 2-amino-6-ethyl-3-R-4-R'-4-R''-4,6-
dihydropyrano[3,2-c][2,1]benzothiazine 5,5-dioxide.
This article is devoted to a new spirocyclic system of spiro[(2-amino-3-R-6-ethyl-4,6-
dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide)-4,3'-(2'-oxindole)]. Experiments carried
out by us have shown that exchange of the 4-hydroxycoumarin or 4-hydroxy-2-oxo-1,2-
dihydroquinoline for heteroanalog, in particular, N-ethyl-1H-2,1-benzothiazin-4(3H)-on-2,2-
dioxide 4, does not have any kind of effect on the course of the reaction and thus, it gives
spiro[(2-amino-3-R-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide)-4,3'-(2'-
oxindole)] 10-11.
2. Results and discussion
The synthesis of the initial N-ethyl-1H-2,1-benzothiazin-4(3H)-on-2,2-dioxide 4 was
described in the literature,24 and included esters of anthranilic acids 1 as initial compounds
(Scheme 1). Different authors used different conditions for the synthesis of compound 2, such as
THF(dioxane)-triethylamine, methylenechloride/pyridine, pyridine, etc. We found that using the
DMF/N-methylmorpholine system in this reaction allows pure compound 2 to be obtained with
excellent yields in a short time. Moreover, all authors21,24 used only NaH in DMF for
heterocyclization of alkylated compound 3. We also found that replacement of NaH with tBuOK
increases the yield of compound 4, obtaining it in analytically pure form, which did not need
further purification.
O
O
N
O
O
OMe
t-BuOK
OMe
Et-Br
OMe
CH3SO2Cl
O
K2CO3
DMF
DMF
DMF/N-methylmorpholine
SO2Me
S
SO2Me
NH2
N
N
H
O
1
2
3
4
Scheme 1. Synthesis of N-ethyl-1H-2,1-benzothiazin-4(3H)-on-2,2-dioxide 4
The synthesis of target compounds 10a-e and 11a-e was carried out according to
transformations presented on Scheme 2.

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A three-component one-pot reaction of equimolar quantities of benzothiazinone 4,
malonodinitrile and the appropriate isatins 5a-e in the presence of triethanolamine under reflux
for 30 min in ethanol, gave to derivatives of 2-amino-3-R-6-ethyl-4,6-dihydropyrano[3,2-
c][2,1]benzothiazine-5,5-dioxide 10a-e spiricombined with a 2-oxindole core with the yields of
64-83% (Scheme 2, Table 1).
Using ethylcyanoacetate in the three-component condensation as the methyleneactive
nitrile increases the time of interaction to about 2 h. The yields of target compounds 11a-e were
46-63% (Scheme 2, Table 1).
It was possible to carry out a two-step synthesis of target compounds 10a-e and 11a-e
using the corresponding Knoevenagel condensation products, namely 2-oxoindolinilidenes 8a-e
and 9a-e, in accordance with the mechanism of the reaction. Synthesis of compounds 8a-e and
9a-e was carried out pursuant to a procedure presented in our previous work.20 Interaction of
benzothiazinone 4 with 3-cyanomethylidene-2-oxindoles 8a-e and 9a-e proceeded by reflux in
ethanol in the presence of a base. In the case of compounds 8a-e, heating continued for 1 h; as a
result, compounds 10a-e were formed with the yields of 53-77%. For 2-oxoindolinilidenes 9a-e,
the duration of heating was 3-4 h, and the yields of target compounds were 40-52% (Scheme 2,
Table 1).
Compounds 10 a-e and 11 a-e were obtained in the form of stable, refractory, fine
colourless powders, which, if necessary, were recrystallized from a ethanol/DMF mixture (1:1).
NH2
CN
NC
O
O
N
O
N
R'
R''
+
CH2(CN)2
6
CN
N
EtOH
O
O
N(CH2CH2OH)3
EtOH
S
S
N(CH2CH2OH)3
O
N
O
O
O
N
R'
O
R''
R''
4
8 a-e
10 a-e
Method A
Method B
+
O
S
N
O
NH2
O
COOEt
O
R'
NC
O
N
O
R''
COOEt
NCCH2CO2Et
R'
N
7
EtOH
4
5 a-e
+
O
N(CH2CH2OH)3
EtOH
N(CH2CH2OH)3
S
O
N
O
S
O
N
R'
R''
O
R'
a
H
H
H
H
R''
11 a-e
4
9 a-e
b
Me
Bn
c
d
e
Allyl
H
H
Br
Scheme 2.
Table 1. Yields for the compounds 10a-e and 11a-e synthesized by two methods
Compound
R'
R''
Yield, %

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Method A
Method B
H
Me
Bn
Allyl
H
H
H
H
H
Br
H
H
H
H
Br
83
70
65
81
64
63
55
58
57
46
77
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
61
53
73
56
52
49
41
52
40
H
Me
Bn
Allyl
H
Using cyanoacetamide 8 as methyleneactive nitrile in the three-component reaction, we
did not obtain the expected 3-carbamide derivatives. In the case of N-methylisatin 5b, 3-
ethoxycarbonyl derivative 11b was a product of the reaction, which can be explained by
alcoholysis of the amide group.
The infrared spectrum of the compounds features absorption bands of valence and
deformation oscillations of amino, cyano groups for 10a-e or amino, carbethoxy groups for 11a-
e.
1
The H NMR spectra of 10a-e and 11a-e compounds feature a characteristic set of
signals: an extended high-intensity singlet of the α-amino group of the pyran ring at 7.6-7.7
ppm for 3-cyano derivatives 10a-e and at 7.8-8.1 ppm for 3-ethoxycarbonyl derivatives
11a-e. The corresponding non-alkylated compounds 10-11a,e, (R' = H) also feature a
proton singlet from the NH group of the 2-oxindole ring in a higher field at 10.45-10.85
ppm. A triplet can be observed in all of the compounds at 0.9-1.1 ppm and at 0.6-0.7 ppm
for 11c corresponding to the methyl group of the N-ethyl function. Protons from the NH
group of the 2-oxindole rings as well as of the α-amino group of the pyran ring can be
easily exchanged in the presence of D2O in DMSO-D6 solution.
The 13C NMR spectra also confirmed the structures of the synthesized compounds.
Furthermore, full assignment of the 13C NMR data confirmed structures 10,11a-e, where the key
signals at δ175─178 ppm was assigned to the 2-oxindolic carbonyl group; at δ57 ppm for 10a-e
and at δ59 ppm for 11a-e was assigned to the quaternary sp3 carbon.20,25 The signal at δ118 ppm
was assigned to the nitrile carbon in the pyran ring for compounds 10a-e and the signal at δ167
ppm was assigned to the carbonyl carbon of the ester group for compounds 11a-e. Full spectral
data for all new compounds are presented in Section 4.

7
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The structures of the compounds 10c and 11e have been confirmed by X-ray diffraction
study (Fig. 2)
10d
11f
Figure 2. Molecular structure of the compounds 10c and 11e according to the X-ray diffraction
study.
The molecules 10c and 11e differ from each other by substituents at the C18, C5 and N1
atoms and details of molecular and crystal structures as consequence. The benzothiazine ring
adopts a twist-boat conformation in both molecules (the puckering parameters26 are S = 0.64, Θ
= 51.8°, Ψ = 27.2° for 10c and S = 0.66, Θ = 50.9°, Ψ = 21.3° for 11e). However, the S1 and C9
atoms deviate from the mean plane of the remaining atoms of the ring in opposite directions with
respect to the indolone fragment. In the case of molecule 10c both atoms are shifted toward the
benzene ring of indolone (deviations are -0.89 Å and -0.30 Å for the S1 and C9 atoms,
respectively) while both atoms in molecule 11e deviate in the opposite direction by 0.90 Å and
0.26 Å, respectively. Such a difference in conformation of the benzothiazine ring results in
appearance of steric repulsion between atoms of the sulfonyl group and bicyclic fragment in the
molecule 10c in contrast to the molecule 11e (the shortened intramolecular contacts O3…C3
2.96 and S1…C4 3.44 Å as compared with van der Waals radii sum27 3.00 Å and 3.55 Å,
respectively). This leads to slightly non-planar conformation of the five-membered heterocycle
of bicyclic fragment in 10c (deviation of the C1 atom from the mean plane of the remaining
atoms of the ring is 0.11 Å), some bending of the bicyclic fragment (the angle between the -N-
C(=O)-C- planar fragment and aromatic ring is 11.6°) and deviation from the orthogonal
orientation of the spiro-joined fragments to each other (the angle between mean planes of the
dihydroindolone fragment and pyran ring is 84.1°). In contrast to 10c, the bicyclic fragment in
11e is planar within 0.03 Å, and the angle between the bicyclic fragment and planar within 0.01

8
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Å pyran ring is 92.0°. It can be noted that the pyran ring in 10c is slightly non-planar and adopts
a flattened boat conformation (the puckering parameters are S = 0.25, Θ = 69.6°, Ψ = 0.0°) with
the deviations of the O2 and C2 atoms by 0.10 Å and 0.22 Å, respectively.
3. Conclusion
In conclusion, we have demonstrated that the original spiro-joined heterocyclic system
containing the spiro[(4,6-dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide)-4,3'-(indolin-2'-
one)] core 10-11 was synthesized based on the domino Knoevenagel/Michael cyclization
sequence between benzo[c][2,1]thiazin-4-on-2,2-dioxide with corresponding isatins and
appropriate methylene active nitriles in the presence of an organic base as a catalyst.
Experiments carried out by us have shown that N-ethyl-1H-2,1-benzothiazin-4(3H)-on-2,2-
dioxide 4 is a proper analogue of cyclic methyleneactive 1,3-dicarbonyl compounds in this
reaction. The isolated yields in this one-pot protocol were moderate to high (46–83%) and
provided the desired target compounds with a high purity after a simple filtration or
recrystallization from an ethanol/DMF mixture (1:1).
4. Experimental section
4.1. General
Starting isatins and methylenactive nitriles were obtained from commercial sources and
used without further purification. Dry solvents were prepared in accordance with standard
methods. Melting points were obtained on a Gallenkamp melting point apparatus, Model MFB-
1
595 in open capillary tubes. H NMR spectra were recorded on a Varian WXR-400 (200 MHz)
spectrometer in DMSO-d6 using TMS as an internal standard (chemical shifts in parts per
million). 13C NMR spectra were recorded on a Bruker Avance II 400 MHz, the references at the
signal of the solvent 39.5 ppm for DMSO-d6. IR spectra were taken on a Perkin–Elmer 298
spectrophotometer in KBr pellets. Elemental analyses were carried out using Carlo Erba CHNS-
O EA 1108 analyzer. Mass spectra were taken on a Varian 1200L DIP (EI, 70 eV).
4.2. X-ray diffraction study
The crystals of 10c (C28H22N4O4S) are monoclinic. At 100 K a = 13.9801(5), b =
18.7160(7), c = 9.4293(3) Å, β = 99.037(4)°, V = 2436.6(2) Å3, Mr = 510.56, Z = 4, space group
P21/c, dcalc= 1.392 g/cm3, µ(MoKα) = 0.177 mm-1, F(000) = 1,064. Intensities of 24,624
reflections (7,111 independent, Rint = 0.052) were measured on the Xcalibur-3 diffractometer
(graphite monochromated MoKα radiation, CCD detector, ω-scaning, 2Θmax = 60°).
The crystals of 11e (C23H20N3O6BrS) are triclinic. At 293 K a = 9.7567(5), b = 11.2376(5), c
= 12.0580(6) Å, α = 99.984(4)°, β = 94.389(4)°, γ = 112.110(4)°, V = 1191.6(1) Å3, Mr =

9
ACCEPTED MANUSCRIPT
546.39, Z = 2, space group P
1
, dcalc= 1.523 g/cm3,
µ
(MoK
α
) = 1.857 mm-1, F(000) = 556.
Intensities of 11080 reflections (6931 independent, Rint = 0.022) were measured on the«Xcalibur-
3» diffractometer (graphite monochromated MoKα radiation, CCD detector, -scaning, 2Θmax
60 ).
ω
=
°
The structures were solved by the direct method using the SHELXTL package.28 The
restrictions on the bond lengths in the disordered fragments for the 11e were applied (Csp3-Csp3
1.54 Å). The absorption correction was performed using the multi-scan method (Tmin = 0.708,
Tmax = 0.913). Position of the hydrogen atoms were located from electron density difference
maps and refined by “riding” model with Uiso = nUeq of the carrier atom (n = 1.5 for methyl and
hydroxyl groups and for water molecule and n = 1.2 for other hydrogen atoms) in the case of the
structure 11e. The hydrogen atoms of the molecule 10c and the hydrogen atoms of 11e taking
part in the formation of the hydrogen bonds are refined in isotropic approximation. Full-matrix
least-squares refinement of the structures against F2 in anisotropic approximation for non-
hydrogen atoms using 7090 (10c), 6877 (11e) reflections was converged to: wR2 = 0.111 (R1 =
0.049 for 5188 reflections with F>4
σ
(F), S = 1.038) for structure 10c and wR2 = 0.197 (R1 =
(F), S = 1.051) for structure 11e. The final atomic
0.070 for 4381 reflections with F>4
σ
coordinates, and crystallographic data for molecules 10c and 11e have been deposited to with the
Cambridge Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK (fax: +44-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk) and are available on request quoting the deposition
numbers CCDC (1002460 for 10c and CCDC 1002461 for 11e).
4.3. Procedure for the synthesis of N-ethyl-benzo[c][2,1]thiazin-4-on 2,2-dioxide. Starting
methylanthranilate (13 mL, 0.1 mol) was added to a mixture of DMF (25 mL) and
N-methylmorpholine (0.1 mol, 11 mL). After that methansulphonylchloride (0.1 mol, 7.7 mL)
was added to the solution dropwise, while cooling the reaction mixture with ice. The resulting
suspension was mixed using a magnetical stirrer for 10 min at room temperature, then the
temperature was gradually increased to 50-60°C and the suspension was mixed for 1.5 h. Next,
was added water (100 mL) to the resulting suspension. The resulting precipitate was filtered off,
washed with water and dried in air, giving pure product
Product (0.1 mol, 22.9 g) was dissolved in DMF (80 mL) and potassium carbonate (0.205 mol,
2
(m.p. 80-83oC) in a yield of 80-85%.
2
29 g) was added to this solution. The resulting suspension was stirred for 30 min and
ethylbromide (0.128 mol, 9.6 mL) was added dropwise. This mixture was stirred at 80oC for 8-
10 h, cooled down and poured on to water. The obtained precipitate was filtered off and dried in
air. Recrystallisation from i-PrOH gave pure product
magnetically stirred suspension of potassium tert-butoxide (90 mmol) in dry DMF (15 mL), a
3
(m.p. 58-60oC) in a yield of 77-80%. To a

10
ACCEPTED MANUSCRIPT
solution of methyl 2-ethylmethylsulfonylamidobenzoate 3 (60 mmol) in dry DMF (25 mL) was
added at room temperature, and then the suspension was stirred for 4 hours at 70oC. When
mixing was completed, diluted hydrochloric acid was added to the resulting suspension. The
precipitate was filtered off, washed with water and dried. As a result, analytically pure product 4
was obtained (m.p. 84-86oC) in a yield of 85-90%.
4.4. General procedure for the synthesis of spiro[(2-amino-3-R-6-ethyl-4,6-
dihydropyrano[3,2-c][2,1]benzothiazine-5,5-dioxide)-4,3'-(1'-R'-5'-R''-indolin-2'-one)]
(10a-e, 11a-e).
Method A. Three-component one-pot procedure. To a solution of the respective isatins 5a–e
(0.001 mol) in ethanol (5.0 mL), triethanolamine (0.13 mL, 0.001 mol) and malonodinitrile 6
(0.066 g, 0.001 mol) or cyanoacetic acid ethyl ester 7 (0.11 mL, 0.001 mol) were added. After
that the N-ethyl-1H-2,1-benzothiazin-4(3H)-one-2,2-dioxide 4 (0,23 g, 0.001 mol) was added to
the resulting solution. When compound 6 was used, the reaction mixture was heated until the
precipitate of compounds 10a–e was observed (usually about 30 min). When compound 7 was
used, the resulting reaction mixture was refluxed for 2 h and cooled down to room temperature.
After cooling, the mixture was allowed to form the precipitate of 11a–e. The resulting
precipitates of compounds 10a–e and 11a-e were filtered, washed with ethanol and then dried.
When necessary, the precipitates were recrystallized from an ethanol and DMF mixture.
Method B. Synthesis using 3-cyanomethyliden-2-oxindoles. A solution of 3-cyanomethyliden-2-
oxindoles 8a–e or 9a–e (0.001 mol), compound 4 (0.225 g, 0.001 mol), and triethanolamine
(0.13 mL, 0.001 mol) was refluxed in ethanol (10.0 mL). When 8a–e was used, the reaction
mixture was refluxed for 1 h and in the case of synthesis with 9a–e nitriles – for 3-4 h. The
resulting precipitates of 10a–e and 11a-e were treated as mentioned in method A.
The yields for the synthesized compounds 10a–e and 11a-e are presented in Table 1.
4.4.1. Spiro[(2-amino-3-cyano-6-ethyl-4,6-dihydropyrano[3,2-c][2,1] benzothiazine-5,5-
dioxide)-4,3'-(indolin-2'-one)] (10a).
Beige powder; mp 232–234oC (decomp.); νmax (KBr) 3583, 3411, 3371, 3324, 3212, 2198, 1721,
1670, 1598, 1469, 1384, 1320 cm-1; 1H NMR (200 MHz, DMSO-d6): δ (ppm) 10.69 (s, 1H), 7.98
(d, J=7.6 Hz, 1H), 7.79 - 7.56 (m, 4H), 7.47 (t, J=7.3 Hz 1H), 7.35-7.20 (m, 2H), 7.01 (t, J=7.3,
13
1H), 6.87 (d, J=7.6, 1H), 3.86 (br. q, J=7.2 Hz, 2H), 1.06 (t, J=7.0, 3H);δ C NMR (100 MHz,
DMSO-d6): δ (ppm) 176.49, 159.34, 148.00, 142.12, 137.86, 132.75, 131.22, 129.63, 124.57,
124.38, 122.21, 120.57, 117.86, 116.79, 112.02, 109.87, 57.26, 56.06, 48.64, 43.96, 18.58,
13.19; EI-MS (m/z) = 420 ([M]+). Anal. Calcd for C21H16N4O4S: C, 59.99; H, 3.84; N, 13.33; S,
7.63. Found: C, 60.19; H, 3.79; N, 13.26; S, 7.65.

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4.4.2. Spiro[(2-amino-3-cyano-6-ethyl-4,6-dihydropyrano[3,2-c][2,1] benzothiazine-5,5-
dioxide)-4,3'-(1'-methyl-indolin-2'-one)] (10b).
Light gray crystalline powder; mp 224-225oC (decomp.); νmax (KBr) 3397, 3318, 3210, 3129,
1
2204, 1706, 1673, 1609, 1490, 1470, 1417, 1325, 1169 cm-1; H NMR (200 MHz, DMSO-d6): δ
(ppm) 7.96 (d, J=7.63 Hz, 1H), 7.78-7.54 (m, 4H), 7.53-7.31 (m, 3H), 7.19-7.01 (m, 2H), 3.82
13
(q, J=7.12 Hz, 2H), 3.20 (s, 3H), 0.99 (t, J=7.02 Hz, 3H); C NMR (100 MHz, DMSO-d6): δ
(ppm) 175.39, 159.85, 148.46, 143.95, 138.30, 133.26, 130.89, 130.27, 125.78, 124.86, 123.39,
121.03, 118.25, 117.11, 112.33, 109.30, 57.23, 44.40, 27.19, 13.65; EI-MS (m/z) = 434 ([M]+).
Anal. Calcd for C22H18N4O4S: C, 60.82; H, 4.18; N, 12.90; S, 7.38. Found: C, 61.01; H, 4.25; N,
12.81; S, 7.33.
4.4.3. Spiro[(2-amino-3-cyano-6-ethyl-4,6-dihydropyrano[3,2-c][2,1] benzothiazine-5,5-
dioxide)-4,3'-(1'-benzyl-indolin-2'-one)] (10c).
Light brown crystalline powder; mp 230-232oC (decomp.); νmax (KBr) 3595, 3392, 3308, 3197,
1
2202, 1707, 1667, 1591, 1488, 1466, 1410, 1326 cm-1; H NMR (200 MHz, DMSO-d6): δ (ppm)
7.99 (d, J=7.63 Hz, 1H), 7.78-7.56 (m, 4H), 7.53-7.18 (m, 8H), 7.06 (t, J=7.5 Hz, 1H), 6.87 (d,
J=7.63 Hz, 1H), 4.94 (dd, J=34, 16 Hz, 2H), 3.84 (q, J=7.83 Hz, 2H), 1.00 (t, J=6.87 Hz, 3H);
13C NMR (100 MHz, DMSO-d6): δ (ppm) 175.76, 160.02, 148.72, 143.16, 138.34, 136.19,
133.33, 130.87, 130.17, 128.86, 127.65, 125.96, 125.11, 123.49, 121.08, 118.28, 117.29, 112.16,
109.94, 57.03, 44.49, 44.07, 13.68; EI-MS (m/z) = 510 ([M]+). Anal. Calcd for C28H22N4O4S: C,
65.87; H, 4.34; N, 10.97; S, 6.28. Found: C, 65.93; H, 4.37; N, 11.01; S, 6.23.
4.4.4. Spiro[(2-amino-3-cyano-6-ethyl-4,6-dihydropyrano[3,2-c][2,1] benzothiazine-5,5-
dioxide)-4,3'-(1'-allyl-indolin-2'-one)] (10d).
Beige crystalline powder; mp>250oC; νmax (KBr) 3534, 3457, 3296, 3131, 2203, 1649, 1610,
1
1487, 1320, 1175, 1148, 1108 cm-1; H NMR (200 MHz, DMSO-d6): δ (ppm) 7.97 (d, J=6.71
Hz, 1H), 7.77-7.54 (m, 4H), 7.54-7.27 (m, 3H), 7.07 (t, J=7.50 Hz, 1H), 6.98 (d, J=7.63 Hz, 1H),
5.93-5.75 (m, 1H), 5.34 (d, J=17.09 Hz, 1H), 5.16 (d, J=10.68 Hz, 1H), 4.34 (q, J=14.5, 2H),
13
3.82 (q, J=7.3 Hz, 2H), 0.99 (t, J=6.87 Hz, 3H); C NMR (100 MHz, DMSO-d6): δ (ppm)
175.23, 159.90, 148.63, 143.06, 138.32, 133.31, 131.86, 130.85, 130.14, 125.87, 124.85, 123.38,
120.99, 118.21, 117.22, 112.17, 109.95, 57.37, 48.70, 44.41, 42.68, 13.67; EI-MS (m/z) = 460
([M]+). Anal. Calcd for C24H20N4O4S: C, 62.60; H, 4.38; N, 12.17; S, 6.96. Found: C, 62.56; H,
4.42; N, 12.23; S, 6.91.
4.4.5. Spiro[(2-amino-3-cyano-6-ethyl-4,6-dihydropyrano[3,2-c][2,1] benzothiazine-5,5-
dioxide)-4,3'-(5'-bromo-indolin-2'-one)] (10e).
Light gray crystalline powder; mp>250oC; ν
1667, 1591, 1471, 1411, 1328, 1206, 1178 cm-1; H NMR (200 MHz, DMSO-d6): δ (ppm) 10.85
(KBr) 3421, 3285, 3194, 2204, 1740, 1710,
max
1

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(s, 1H), 7.94 (d, J=7.63 Hz, 1H), 7.79-7.34 (m, 7H), 6.83 (d, J=8.55 Hz, 1H), 3.85 (q, J=7.02 Hz,
13
2H), 1.00 (t, J=6.80, 3H); C NMR (100 MHz, DMSO-d6): δ (ppm) 176.61, 159.84, 148.70,
141.91, 138.24, 133.99, 133.28, 128.95, 124.86, 121.03, 118.29, 117.22, 114.22, 112.29, 111.62,
56.97, 44.42, 13.62; EI-MS (m/z) = 499 ([M]+). Anal. Calcd for C21H15BrN4O4S: C, 50.51; H,
3.03; N, 11.22; S, 6.42. Found: C, 50.47; H, 3.08; N, 11.25; S, 6.46.
4.4.6. Spiro[(2-amino-3-ethoxycarbonyl-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]
benzothiazine-5,5-dioxide)-4,3'-(indolin-2'-one)] (11a).
Green-gray crystalline powder; mp>250oC; νmax (KBr) 3349, 3249, 2987, 1716, 1687, 1646,
1
1533, 1325, 1278, 1175, 1150, 1104 cm-1; H NMR (200 MHz, DMSO-d6): δ (ppm) 10.45 (br.
s., 1H), 8.13-7.93 (m, 3H), 7.67-7.35 (m, 3H), 7.22-7.03 (m, 2H), 6.86 (d, J=7.32, 1H), 6.74 (d,
J=7.63 Hz, 1H), 3.89-3.59 (m, 4H), 0.95 (t, J=6.87, 3H), 0.74 (t, J=7.17 Hz, 3H); 13C NMR (100
MHz, DMSO-d6): δ (ppm) 178.17, 167.38, 159.66, 147.09, 144.10, 138.46, 134.31, 132.81,
128.85, 125.11, 124.68, 121.63, 120.94, 118.66, 115,59, 109.33, 76.22, 59.46, 49.16, 44.59,
13.56; EI-MS (m/z) = 467 ([M]+). Anal. Calcd for C23H21N3O6S: C, 59.09; H, 4.53; N, 8.99; S,
6.86. Found: C, 59.03; H, 4.48; N, 9.06; S, 6.93.
4.4.7. Spiro[(2-amino-3-ethoxycarbonyl-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]
benzothiazine-5,5-dioxide)-4,3'-(1'-methyl-indolin-2'-one)] (11b).
Light green crystalline powder; mp 230-232oC (decomp.); νmax (KBr) 3325, 2933, 1689, 1608,
1
1528, 1468, 1322, 1279, 1176, 1102 cm-1; H NMR (200 MHz, DMSO-d6): δ (ppm) 8.20-7.98
(m, 3H), 7.71-7.49 (m, 2H), 7.43 (t, J=7.50, 1H), 7.26 (t, J=7.70 Hz, 1H), 7.15 (d, J=7.50 Hz,
1H), 7.04-6.87 (m, 2H), 3.90-3.59 (m, 4H), 3.14 (s, 3H), 0.95 (t, J=6.87 Hz, 3H), 0.68 (t, J=7.17
13
Hz, 3H); C NMR (100 MHz, DMSO-d6): δ (ppm) 176.53, 167.23, 159.75, 147.13, 145.18,
138.43, 133.44, 132.93, 129.13, 125.13, 124.87, 122.44, 120.95, 118.57, 115.40, 108.17, 75.78,
59.39, 44.58, 26.92, 13.60; EI-MS (m/z) = 481 ([M]+). Anal. Calcd for C24H23N3O6S: C, 59.87;
H, 4.81; N, 8.73; S, 6.65. Found: C, 59.82; H, 4.86; N, 8.77; S, 6.53.
4.4.8. Spiro[(2-amino-3-ethoxycarbonyl-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]
benzothiazine-5,5-dioxide)-4,3'-(1'-benzyl-indolin-2'-one)] (11c).
Yellow-green crystalline powder; mp 226-228oC (decomp.); νmax (KBr) 3366, 3258, 1688, 1608,
1
1529, 1487, 1328, 1283, 1171, 1106 cm-1; H NMR (200 MHz, DMSO-d6): δ (ppm) 7.96-7.67
(m, 3H), 7.40-6.79 (m, 10H), 6.68-6.49 (m, 2H), 4.53 (s, 2H), 3.61-3.30 (m, 4H), 0.65 (t, J=7.02
13
Hz, 3H), 0.04 (t, J=7.02 Hz, 3H); C NMR (100 MHz, DMSO-d6): δ (ppm) 176.95, 167.18,
159.86, 147.34, 144.84, 138.47, 137.03, 133.66, 132.96, 128.89, 128.70, 127.79, 125.21, 124.77,
124.56, 122.52, 121.02, 118.61, 115.10, 108.83, 75.94, 59.09, 44.69, 13.78, 13.59; EI-MS (m/z)
= 557 ([M]+). Anal. Calcd for C30H27N3O6S: C, 64.62; H, 4.88; N, 7.54; S, 5.75. Found: C,
64.48; H, 4.97; N, 7.42; S, 5.86.

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4.4.9. Spiro[(2-amino-3-ethoxycarbonyl-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]
benzothiazine-5,5-dioxide)-4,3'-(1'-allyl-indolin-2'-one)] (11d).
Gray powder; mp 225-226oC (decomp.); νmax (KBr) 3354, 3197, 2976, 1693, 1644, 1613, 1532,
1
1341, 1282, 1171, 1103 cm-1; H NMR (200 MHz, DMSO-d6): δ (ppm) 8.11 (s, 2H), 8.04 (d,
J=7.90, 1H), 7.73-7.50 (m, 2H), 7.43 (t, J=7.30 Hz, 1H), 7.31-7.10 (m, 2H), 7.01-6.82 (m, 2H),
5.99-5.73 (m, 1H), 5.51 (d, J=17.50 Hz, 1H), 5.23 (d, J=10.07 Hz, 1H), 4.52-4.08 (m, 2H), 3.87 -
3.53 (m, 4H), 0.94 (t, J=7.00 Hz, 3H), 0.64 (t, J=7.02 Hz, 3H); 13C NMR (100 MHz, DMSO-d6):
δ (ppm) 176.31, 167.17, 159.79, 147.29, 144.58, 138.45, 133.54, 132.85, 128.93, 125.18, 124.60,
122.41, 120.93, 118.40, 115.20, 108.80, 75.98, 59.24, 48.62, 44.59, 43.33, 14.05, 13.59; EI-MS
(m/z) = 507 ([M]+). Anal. Calcd for C26H25N3O6S: C, 61.53; H, 4.96; N, 8.28; S, 6.32. Found: C,
61.65; H, 5.07; N, 8.36; S, 6.15.
4.4.10. Spiro[(2-amino-3-ethoxycarbonyl-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]
benzothiazine-5,5-dioxide)-4,3'-(5'-bromo-indolin-2'-one)] (11e).
Light broun crystalline powder; mp>250oC; νmax (KBr) 3322, 2981, 1715, 1698, 1645, 1531,
1473, 1326, 1281, 1171, 1103 cm-1; 1H NMR (200 MHz, DMSO-d6): δ (ppm) 10.61 (s, 1H), 8.11
(s, 2H), 8.02 (d, J=7.63 Hz, 1H), 7.73-7.51 (m, 2H), 7.43 (t, J=7.20, 1H), 7.37-7.26 (m, 2H), 6.71
13
(d, J=7.94 Hz, 1H), 3.94-3.65 (m, 4H), 0.96 (t, J=7.02 Hz, 3H), 0.78 (t, J=7.32 Hz, 3H); C
NMR (100 MHz, DMSO-d6): δ (ppm) 177.86, 167.18, 159.78, 147.40, 143.50, 138.40, 136.70,
132.94, 131.63, 127.66. 124.91, 124.71, 120.94, 118.61, 114.79, 113.15, 111.27, 75.60, 59.61,
49.28, 44.61, 13.53; EI-MS (m/z) = 546 ([M]+). Anal. Calcd for C23H20BrN3O6S: C, 50.56; H,
3.69; N, 7.69; S, 5.87; Found: C, 50.70; H, 3.54; N, 7.81; S, 5.75.

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Acknowledgements
We acknowledge Prof. Dr. M.V. Savoskin (Lytvynenko Institute for Physical and Organic
Chemistry and Coal Fuel Chemistry of NAS of Ukraine) for assisting in the 13C NMR
spectroscopic analysis of compounds.
References and notes
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