Alkylation of 1,3-benzothiazin-4-one 2-oxo-, 2-arylimino-, and 2-thioxo derivatives

Article abstract of DOI:10.1007/s10593-015-1709-2

[Figure not available: see fulltext.] Sodium salt of 3H -benzo[e][1,3]thiazine-2,4-dione is easily alkylated at position 3. In the case of 2-(arylimino)-2,3-dihydrobenzo[e][1,3]-thiazin-4-ones, the alkylation reaction at this position occurs regioselectively. Alkylation of 2-thioxo-2,3-dihydrobenzo[e][1,3]thiazin-4-one under the same conditions produced regioisomers, but S-alkylation at the exocyclic sulfur atom occurred in the presence of triethylamine. The reaction of 1-(4-oxo-3,4-dihydrobenzo[e][1,3]thiazin-2-ylidene)guanidine with methyl anthranilate led to the formation of tetracyclic quinazolino[2,1-b]quinazolinedione.

Full text of DOI:10.1007/s10593-015-1709-2

DOI 10.1007/s10593-015-1709-2
Chemistry of Heterocyclic Compounds 2015, 51(4), 370–376
Alkylation of 1,3-benzothiazin-4-one 2-oxo-, 2-arylimino-,
and 2-thioxo derivatives
Alexandr S. Shestakov1*, Mikhail A. Prezent2, Evgenia O. Zlatoustovskaya1,
Khidmet S. Shikhaliev1, Alexandr V. Falaleev1, Oleg E. Sidorenko1
1 Voronezh State University,
1 Universitetskaya Sq., Voronezh 394006, Russia;
е-mail: schas@vmail.ru
2 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(4), 370–376
Submitted February 2, 2015
Accepted March 17, 2015
O
S
O
S
O
O
S
R
O
1) MeONa
RHal, Et3N
NH
N
NH
N
R
2) RHal, DMF
70°C, 5–7 min
DMF, 70°C, 1 h
O
S
S
S
O
R1
O
S
R1
R
1) MeONa
N
N
2) RHal, DMF
70°C, 5–7 min
S
N
N
H
Sodium salt of 3Н-benzo[e][1,3]thiazine-2,4-dione is easily alkylated at position 3. In the case of 2-(arylimino)-2,3-dihydrobenzo[e][1,3]-
thiazin-4-ones, the alkylation reaction at this position occurs regioselectively. Alkylation of 2-thioxo-2,3-dihydrobenzo[e][1,3]thiazin-
4-one under the same conditions produced regioisomers, but S-alkylation at the exocyclic sulfur atom occurred in the presence of
triethylamine. The reaction of 1-(4-oxo-3,4-dihydrobenzo[e][1,3]thiazin-2-ylidene)guanidine with methyl anthranilate led to the formation of
tetracyclic quinazolinо[2,1-b]quinazolinedione.
Keywords: 2-(arylimino)-2,3-dihydrobenzo[e][1,3]thiazin-4-one, 3H-benzo[e][1,3]thiazine-2,4-dione, benzo[e][1,3]thiazin-4-one,
2-thioxo-2,3-dihydrobenzo[e][1,3]thiazin-4-one, alkylation.
Various types of physiological activity identified for
1,3-benzothiazin-4-one derivatives have caused an increas-
ing interest towards these compounds over the recent years.
For example, compounds based on 1,3-benzothiazin-4-one form
a new class of effective antituberculosis drugs.1,2 Substituted
2-thioxobenzothiazin-4-ones were discovered in the bark of
Bretschneidera sinensis evergreen tree, used in traditional
Chinese medicine for pain relief.3 The antimalarial activity
of 4-aminoquinolines is enhanced by the introduction of
2,3-dihydrobenzo[1,3]thiazin-4-one fragment.4
These recent advances motivate the search for new,
biologically active 1,3-benzothiazin-4-ones. We used 2-oxo-
(1), 2-imino- (2), and 2-thioxo (3) derivatives of 2,3-di-
hydrobenzo[e][1,3]thiazin-4-one as starting materials. The
presence of acidic hydrogen atoms in these structures
enabled the preparation of alkyl derivatives and the creation
of combinatorial libraries.
The acidity of SH hydrogen atom and its high reactivity
towards nitrile group allowed to use cyanic acid,
cyanamide, and thiocyanic acid for the preparation of
compounds 1–3, respectively. However, the low stability of
the aforementioned reagents is an obstacle to preparative
scale application of these procedures.
For the preparation of benzothiazinedione 1, we
designed a two-stage synthesis using cyanoguanidine,
involving the formation of intermediate guanidine 5.5 The
synthesis occurred in aqueous medium, and the products at
each stage formed precipitates. The total yield was 56%
(Scheme 1).
Derivatives of 1,3-benzothiazin-4-ones with a substituent at
position 3 have been described, but the selection of
The starting 1,3-benzothiazin-4-ones were obtained
from the commercially available 2-mercaptobenzoic acid (4).
0009-3122/15/5104-0370©2015 Springer Science+Business Media New York
370

Chemistry of Heterocyclic Compounds 2015, 51(4), 370–376
Scheme 1
substituents is limited by the range of available cyclization
reagents: alkylthiocarbamide,6 methyl isothiocyanate,7 isocya-
nate or carbamoyl chloride,8 and dicyclohexylcarbo-
diimide.9,10 Direct alkylation was found to be more
productive. This was most obvious for compound 1, taking
into account the acidic nature of the hydrogen atom at
also showed that Z-isomer is energetically more favored: its
energy is lower by 5.61 kJ/mol, compared to Е-isomer,
while its content in mixture is 6 times higher. The energy
barrier separating tautomers 7'a,b is not larger than 20 kJ/mol,
indicating that the isomers can freely interconvert.14,15 The
HPLC-MS data also confirmed that in this case both forms
do not exist as individual compounds, but are rapidly
interconverting: the same single HPLC peak with the
respective molecular ion mass was detected in both cases.
Compounds 7a,b were easily alkylated as sodium salts,
giving compounds 8а–с (Scheme 3). No thiazine ring
cleavage products were detected in the reaction mixture. At
the same time, 1H NMR spectra indicated that in the case of
compounds 8a,b the alkylation product isolated from the
reaction mixture contained 11% of the regioisomeric
impurities 8'a,b. This was also supported by HPLC. The
presence of impurity was apparently linked to the
aforementioned tautomerism of starting materials 7a,b. The
regioisomeric impurity could be removed by repeated
recrystallization.
Similarly to compounds 7a,b, compounds 8a–с also can
exist as Z- and Е-isomers. According to quantum-chemical
calculations, the energy of Z-isomers was lower by 33.9–
35.6 kJ/mol, compared to the energy of Е-isomers. This is a
substantial difference,14 sufficient to conclude that
compounds 8a–с should exist as Z-isomers only.
Methyl anthranilate, in contrast to aniline and m-tolu-
idine, did not react with guanidine 5 under the conditions
of acidic catalysis (Scheme 2), but heating of this mixture
in dimethyl acetamide for 1 h led to the formation of a
compound with strong (100%) mass spectral signal of
molecular ion with relative mass of 263, allowing to
propose structure 9 for this compound (Scheme 4).
Apparently, the nucleophilic guanidine group reacted in the
position 3. The N-alkylbenzothiazinediones
6 were
obtained in the presence of NaH11 or alcohol solution of
NaOH5. The method for alkylation followed our previously
developed procedure12 using sodium salts in DMF (the
sodium salts were usually soluble in this solvent and the
reaction mixture was homogeneous) (Scheme 1).
Iminobenzothiazinone 2 was obtained by reaction of
2-mercaptobenzoic acid (4) with cyanamide.5 The attempts
to obtain alkyl derivatives of compound 2 under alkaline
conditions led to destruction of heterocycle and the
formation of N-cyano-2-(alkylsulfanyl)benzamide, in
complete agreement with the literature data.13 It was found
that the use of compounds 7a,b, containing an aryl
substituent at the exocyclic nitrogen atom, allowed to
preserve the heterocyclic moiety during the alkylation
reaction.
The formation of compounds 7a,b occurred rapidly in
high yields upon heating the guanidine 5 with excess of
aniline in the presence of HCl (Scheme 2). 1Н NMR
spectra of compounds 7a,b in DMSO-d6 solution contained
two broadened signals corresponding to the NH proton,
apparently caused by tautomerism. According to quantum-
chemical calculations, the energy of tautomer 7а was lower
by 18.30 kJ/mol, compared to tautomer 7'а with proton at
the bridge nitrogen atom and lower by 43.04 kJ/mol,
compared to the respective 1,3-benzothiazin-4-ol 7'''а.
Compounds 7a,b can exist as Z- and Е-isomers (forms 7a,b
and 7''a,b, respectively). Quantum-chemical calculations
Scheme 2
371

Chemistry of Heterocyclic Compounds 2015, 51(4), 370–376
Scheme 3
absence of acid with the ester group of methyl anthranilate,
with subsequent formation of intermediates А and В. The
latter could be ionized, giving anions С and D, which, in
turn, reacted with the second methyl anthranilate molecule.
The determining factor in this case was the difference in bond
strength between the bridge nitrogen atom and the
quinazolinone or benzothiazinone fragments. The bond
between the nitrogen atom and benzothiazinone fragment
in the intermediate Е was stronger than the analogous bond
with quinazolinone fragment in intermediate F, therefore
even if the intermediate Е was formed, it did not undergo
further transformations. On the other hand, intermediate F
was transformed by intramolecular cyclization to
compound 9. This compound was previously obtained from
the isomeric 6Н-quinazolino[3,2-а]quinazoline-5,12-dione.
The study of the reaction between guanidine 5 and other
anilines in the absence of hydrochloric acid showed that
guanidines remained unchanged even during prolonged
heating.
attempting to apply our alkylation procedure to thione 3,
we observed that reactions of its sodium salt with alkyl
halides in DMF gave a mixture of products 10a–c and 11a–c
containing the S-alkyl derivatives 10а–с as major compo-
nents. The content of N-alkyl derivatives 11a–c was
1
approximately three times lower, as indicated by Н NMR
spectra of the mixture of alkylation products 10a–c and 11a–c.
The spectra contained two singlets corresponding to the
СН2 or СН3 groups in the alkyl derivative structure. The
upfield singlet (4.41–4.60 ppm for the СН2 group and 2.75
ppm for the СН3 group) corresponded to S-alkyl derivative
and its intensity was approximately three times higher than
the intensity of singlet at lower field (5.51–5.81 ppm for
the СН2 group and 3.85 ppm for the СН3 group). These
conclusions were also confirmed by HPLC analysis.
In cases when both N- and S-nucleophiles are present, the
alkylation of the latter is known to be favored,17,18 thus we
expected that a high degree of regioselectivity could be
achieved under certain conditions. Indeed, we were able to
perform selective S-alkylation of thioxobenzothiazinone 3
in the presence of soft base and obtained compounds 10с–е
in 26–62% yields (after purification). Triethylamine was
used to neutralize the hydrogen chloride produced in the
During further study we synthesized 2-thioxo-2,3-dihydro-
benzo[e][1,3]thiazin-4-one (3) by the reaction of 2-mercapto-
benzoic acid (4) with potassium thiocyanate in aqueous
pyridine in the presence of acid (Scheme 5). While
Scheme 4
O
O
N
O
N
O
N
O
OMe
–N
HN
HN
NH NH
NH2
N
NH3
N
N
NH
S
N
5
O
+
DMA, 150°C, 1 h
–MeOH
–NH4
–NH3
S
NH
S
N–
S
NH
H2N
O
O
O
A
B
C
D
O
O
O
N
O
OMe
NH2
OMe
O
O
N
NH2
N
NH2
–MeOH
N
N
O
N
O
N
H
S
NH
HN
NH
NH
NH2
N
9
–
O
N
S
F
S
O
O
E
372

Chemistry of Heterocyclic Compounds 2015, 51(4), 370–376
Scheme 5
reaction. The reaction in DMF was complete after 1 h at 70°С
(Scheme 5).
theory (B3LYP). Complete optimization of molecular
geometry was performed with the 3-21G* basis set. The
calculation of electronic structure was performed with the
6-31G* basis set.
Thus, we have studied the reactivity of 1,3-benzothiazin-
4-ones functionalized at position 2. The optimum
conditions were identified for alkylation of 2-oxo and
2-thioxo derivatives of 1,3-benzothiazin-4-one. A method
was developed for the synthesis of 2-(arylimino)-2,3-di-
hydrobenzo[e][1,3]thiazin-4-ones and their alkylation
reactions were investigated. Unusual polycondensation of
1,3-benzothiazin-4-one 2-guanidino derivative with methyl
anthranilate was found to produce a tetracyclic compound,
5H-quinazolino[2,3-b]quinazoline-11,13-dione.
2-Imino-2,3-dihydrobenzo[e][1,3]thiazin-4-one (2) was
obtained according to literature method.5
1-(4-Oxo-4H-benzo[e][1,3]thiazin-2-yl)guanidine (5). A
mixture of 2-mercaptobenzoic acid (4) (30.8 g, 0.2 mol) and
cyanoguanidine (16.8 g, 0.2 mol) in Н2О (100 ml) was
refluxed for 1 h. The contents of the flask were cooled, the
precipitated product was filtered off. Yield 29.5 g (67%).
Colorless crystals. Mp 238–239°C. IR spectrum, ν, cm–1:
3390 (NH2), 3320 (NH2), 3195 (NH), 3053 (NH), 1641
1
(C=O), 1612 (C=N). H NMR spectrum, δ, ppm (J, Hz):
Experimental
7.54 (1H, t, J = 7.8, Н-6); 7.62 (1H, d, J = 7.9, Н-8); 7.76
(1H, dt, J = 7.8, J = 0.9, Н-7); 8.27 (1H, dd, J = 7.9,
J = 0.9, Н-5); 8.50–10.00 (4H, br. s, NH). 13C NMR
spectrum, δ, ppm: 122.4; 125.4; 127.1; 129.6; 132.2; 136.4;
159.3; 168.2; 170.2. Found, %: C 48.97; H 3.69; N 25.51.
C9H8N4OS. Calculated, %: C 49.08; H 3.66; N 25.44.
3H-Benzo[e][1,3]thiazine-2,4-dione (1). A solution of
guanidine 5 (5.00 g, 23 mmol) in dilute HCl (50 ml) was
heated on a boiling water bath for 2 h, then the solution
was cooled; the precipitate that formed was filtered off,
washed with a warm NaHCO3 solution to remove the
starting acid, then washed with water. Yield 3.42 g (83%).
Colorless crystals. Mp 213–215°C. IR spectrum, ν, cm–1:
3134 (NH), 1650 (C=O). 1H NMR spectrum, δ, ppm (J, Hz):
7.37–7.47 (2H, m, Н-6,8); 7.63 (1H, t, J = 7.6, Н-7); 8.27 (1H,
d, J = 7.9, Н-5); 12.21 (1H, s, NH). 13C NMR spectrum, δ,
ppm: 122.4; 125.4; 127.4; 130.0; 133.4; 134.3; 163.5; 163.8.
Found, %: C 53.57; H 2.77; N 7.88. C8H5NO2S.
Calculated, %: C 53.62; H 2.81; N 7.82.
IR spectra were recorded on a Bruker Vertex 70 instru-
ment with ATR accessory. 1Н NMR spectra were acquired on
a Bruker AC-300 spectrometer (300 MHz) at 27°С in a 1:2
mixture of DMSO-d6 and CCl4 (compounds 6а–с, 7b, 8a,b)
or in DMSO-d6 (the rest of the compounds). The residual
solvent protons were used as internal standard (2.50 ppm).
13С NMR spectra were acquired on a Bruker DRX-500
instrument (125 MHz) in DMSO-d6 at 30°С, with solvent
carbon atoms as internal standard (39.5 ppm). Mass spectra
(EI ionization, 70 eV) were recorded on an MX-1321
spectrometer with direct introduction of sample at 100–
150°C. Elemental analysis was performed on a Carlo Erba
NA-1500 instrument. Melting points were determined on a
PTP-M apparatus. Chromatographic analysis of the
obtained compounds was performed on an Agilent 1260
Infinity chromatograph with UV detector or Agilent 6230
TOF LC/MS mass selective detector with electrospray
ionization. Chromatography conditions: a) Zorbax Extend
C18 column (2.1×50 mm); sorbent particle size 1.8 μm;
linear gradient elution; mobile phase: eluent А – Н2О,
eluent В – MeCN, 1 ml/min flow rate; column temperature
25°С; injection volume 1.0 μl (compounds 7а, 8а, mixture
of compounds 10с and 11с); b) Gemini C18 column
(4.6×50 mm); sorbent particle size 5 μm; linear gradient
elution; mobile phase: eluent А – MeCN–Н2О, 2.5:97.5,
0.1% CF3COOH, eluent В – MeCN, 0.1% CF3COOH,
3.75 ml/min flow rate; column temperature 40°С; injection
volume 1.5 μl (compounds 7b, 8b, 10d). The reaction
progress and the purity of the obtained compounds were
controlled by TLC on Merck UV-254 plates (eluent 20:1
CHCl3–MeOH). Quantum-chemical calculations were
performed with Gaussian 0919 using density functional
2-Thioxo-2,3-dihydrobenzo[e][1,3]thiazin-4-one (3).
The solution obtained by heating 2-mercaptobenzoic acid (4)
(3.85 g, 25 mmol) and KSCN (4.85 g, 50 mmol) in 50%
aqueous pyridine (10 ml) was treated by addition of conc. HCl
(4.5 ml, 50 mmol). The mixture was then heated on boiling
water bath for 1 h, neutralized with Na2CO3 to рН 8 and
diluted with water to 250 ml. The product that precipitated
during dilution and cooling was filtered off. Yield 1.07 g
(22%). Cream-colored crystals. Mp 230–231°C. IR
spectrum, ν, cm–1: 3068 (NH), 1672 (C=O), 1577 (NH),
1
1256 (C=S). H NMR spectrum, δ, ppm (J, Hz): 7.36 (1H,
d, J = 7.9, Н-8); 7.47 (1H, t, J = 7.6, Н-6); 7.67 (1H, t,
J = 7.6, Н-7); 8.25 (1H, d, J = 7.9, Н-5); 13.41 (1Н, s, NH).
13C NMR spectrum, δ, ppm: 122.3; 123.3; 128.3; 129.8;
373

Chemistry of Heterocyclic Compounds 2015, 51(4), 370–376
134.4; 136.8; 160.4; 192.7. Found, %: C 49.17; H 2.57; N 7.13.
C8H5NOS2. Calculated, %: C 49.21; H 2.58; N 7.17.
125.8; 125.9; 127.4; 129.3; 129.5; 129.6; 132.8; 133.3;
173.9; 202.4. HPLC: τR 1.77 min (the only component).
Mass spectrum, m/z: 255 [M+H]+. Found, %: C 66.17;
H 4.02; N 10.97. C14H10N2OS. Calculated, %: C 66.12;
H 3.96; N 11.02.
Preparation of 3-alkyl-3H-benzo[e][1,3]thiazine-2,4-diones
6a–c (General method). Benzothiazine-2,4-dione (1)
(0.45 g, 2.5 mmol) was added to a mixture of 1 M NaOMe
solution in МеОН (2.5 ml) and DMF (2.5 ml). Methanol
was removed from the obtained solution on rotary
evaporator. Alkyl halide (2.5 mmol) was then added, the
reaction mixture was heated at 70°С for 5–7 min and
poured into cooled distilled water. The precipitate that
formed was filtered off and recrystallized from 2-PrOH.
3-Ethyl-3H-benzo[e][1,3]thiazine-2,4-dione (6a). Yield
0.15 g (29%). Colorless crystals. Mp 97–98°C. IR
spectrum, ν, cm–1: 2970 (CH), 1681 (C=O), 1618 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 1.22 (3H, t, J = 7.0,
CH2CH3); 4.12 (2H, q, J = 7.0, CH2CH3); 7.45–7.53 (2H,
m, Н-6,8); 7.71 (1H, t, J = 7.9, Н-7); 8.29 (1H, d, J = 7.9,
Н 5). 13C NMR spectrum, δ, ppm: 12.7; 37.3; 122.2;
124.9; 127.5; 130.8; 131.5; 134.2; 162.3; 163.6. Found, %:
C 58.00; H 4.35; N 6.81. C10H9NO2S. Calculated, %:
C 57.95; H 4.38; N 6.76.
2-[(3-Methylphenyl)imino]-2,3-dihydrobenzo[e][1,3]-
thiazin-4-one (7b). Yield 2.14 g (80%). Colorless crystals.
Mp 159–160°C. IR spectrum, ν, cm–1: 3035 (NH), 1687
1
(C=O), 1618 (C=N). H NMR spectrum, δ, ppm (J, Hz):
2.36 (3H, s, CH3); 6.87–6.95 (overlapped with broadened NH
signal) (3H, m, Н Ar); 7.21 (1H, t, J = 7.7, H Ar); 7.31–
7.46 (2H, m, H Ar); 7.69 (1H, t, J = 7.8, Н-7); 8.20 (1H, d,
J = 7.9, Н-5); 11.40 (1H, br. s, NH). 13C NMR spectrum, δ,
ppm: 21.0; 118.5; 121.9; 122.6; 125.3; 125.8; 127.3; 127.6;
129.1; 129.5; 132.8; 133.3; 138.7. HPLC: τR 1.79 min (the
only component). Mass spectrum, m/z: 269 [M+H]+.
Found, %: C 67.13; H 4.50; N 10.37. C15H12N2OS.
Calculated, %: C 67.14; H 4.51; N 10.44.
(Z)-3-Alkyl-2-(arylimino)-2,3-dihydrobenzo[e][1,3]thi-
azine-4-ones 8a–с were obtained analogously to
compounds 6а–с from benzothiazinone 7a,b (2.5 mmol).
The crude product was recrystallized twice from 2-PrOH.
(Z)-3-Ethyl-2-(phenylimino)-2,3-dihydrobenzo[e][1,3]-
thiazin-4-one (8a). Yield 0.44 g (62%). Colorless crystals.
Mp 87–88°C. IR spectrum, ν, cm–1: 2996 (CH), 1664
3-(2-Oxo-2-phenylethyl)-3H-benzo[e][1,3]thiazine-
2,4-dione (6b). Yield 0.39 g (52%). Colorless crystals. Mp
120–122°C. IR spectrum, ν, cm–1: 3020 (CH), 1679 (C=O),
1
1631 (C=O). H NMR spectrum, δ, ppm (J, Hz): 5.59 (2H,
1
s, CH2); 7.52–7.62 (4H, m, Н Ar); 7.67 (1H, d, J = 7.9,
Н Ar); 7.73 (1H, t, J = 7.9, Н-7); 8.08–8.12 (2H, m, Н-2,6
Ph); 8.28 (1H, d, J = 7.9, Н-5). 13C NMR spectrum, δ, ppm:
48.4; 121.7; 125.3; 127.9; 128.1; 128.9; 129.0; 131.0;
131.3; 134.2; 134.8; 162.3; 163.8; 191.9. Found, %:
C 64.61; H 3.76; N 4.80. C16H11NO3S. Calculated, %:
C 64.63; H 3.73; N 4.71.
(C=O), 1583 (C=N). H NMR spectrum, δ, ppm (J, Hz):
1.33 (3H, t, J = 6.9, CH2CH3); 4.38 (2H, q, J = 6.9,
CH2CH3); 6.85 (2H, d, J = 7.6, Н-2,6 Ph); 7.11 (1H, t,
J = 7.6, H-4 Ph); 7.29 (1H, d, J = 7.6, H Ar); 7.35–7.46
(3H, m, Н Ar); 7.59 (1H, t, J = 7.3, Н-7); 8.22 (1H, d, J = 7.7,
Н-5). 13C NMR spectrum, δ, ppm: 12.3; 46.6; 120.5; 122.3;
124.2; 125.1; 127.0; 129.2; 129.3; 129.6; 129.7; 130.3;
131.0; 133.7; 147.2; 161.1. HPLC before the second
recrystallization: τR 2.03 min (11%, m/z 283 [M+H]+),
τR 13.54 min (89%, m/z 283 [M+H]+). Found, %: C 68.03;
H 5.05; N 9.84. C16H14N2OS. Calculated, %: C 68.06; H 5.00;
N 9.92.
N-(4-Methylphenyl)-2-(2,4-dioxo-2H-benzo[e][1,3]thi-
azin-3(4H)-yl)acetamide (6c). Yield 0.42 g (51%). Colorless
crystals. Mp 219–220°C. IR spectrum, ν, cm–1: 3253 (NH),
1
1679 (C=O), 1654 (C=O). H NMR spectrum, δ, ppm
(J, Hz): 3.11 (3H, s, CH3); 4.79 (2H, s, CH2); 7.07 (2H, d,
J = 7.6, Н-3,5 Ar); 7.41 (2H, d, J = 7.6, H-2,6 Ar); 7.52–
7.63 (2H, m, Н-6,8); 7.74 (1H, t, J = 7.8, Н-7); 8.29 (1H, d,
J = 7.9, Н-5); 10.11 (1H, s, NH). 13C NMR spectrum, δ,
ppm: 20.4; 44.5; 119.1; 121.9; 125.2; 126.7; 127.8; 129.1;
131.0; 131.4; 132.4; 134.6; 136.0; 162.5; 164.0; 164.4.
Found, %: C 62.62; H 4.30; N 8.62. C17H14N2O3S. Calculated,
%: C 62.56; H 4.32; N 8.58.
Preparation of 2-(arylimino)-2,3-dihydrobenzo[e][1,3]-
thiazin-4-ones 7a,b (General method). A mixture of
guanidine 5 (2.20 g, 0.01 mol), conc. HCl (0.90 ml), and
aniline or m-toluidine (10 ml) was heated at 150°С for
15 min. The reaction mixture was poured into water and
acidified with HCl to рН 5. The precipitate that formed was
filtered off and recrystallized from 2-PrOH.
(Z)-3-(4-Methylbenzyl)-2-[(3-methylphenyl)imino]-
2,3-dihydrobenzo[e][1,3]thiazin-4-one (8b). Yield 0.64 g
(69%). Colorless crystals. Mp 116–118°C. IR spectrum, ν,
1
cm–1: 3051 (CH), 1658 (C=O), 1585 (C=N). H NMR
spectrum, δ, ppm (J, Hz): 2.31 (3H, s, CH3); 2.33 (3H, s,
CH3); 5.48 (2H, s, CH2); 6.52–6.60 (2H, m, Н Ar); 6.92
(1H, d, J = 7.5, H-6 3-МеС6Н4); 7.11 (2H, d, J = 7.5, H-2,6
4-МеС6Н4); 7.22–7.43 (5H, m, Н Ar); 7.59 (1H, t, J = 7.4,
H-7); 8.22 (1H, d, J = 7.6, Н-5). 13C NMR spectrum, δ,
ppm: 20.7; 21.0; 46.2; 117.4; 120.8; 122.2; 125.0; 125.3;
127.1; 127.6; 128.1; 128.2; 129.0; 129.5; 130.5; 131.2; 133.9;
134.1; 136.1; 139.1; 147.0; 161.5. HPLC before the second
recrystallization: τR 2.17 min (21%, m/z 373 [M+H]+),
τR 2.41 min (79%, m/z 373 [M+H]+). Found, %: C 74.11;
H 5.42; N 7.52. C23H20N2OS. Calculated, %: C 74.16;
H 5.41; N 7.52.
2-(Phenylimino)-2,3-dihydrobenzo[e][1,3]thiazin-4-one
(7а). Yield 2.01 g (79%). Colorless crystals. Mp 180–181°C.
IR spectrum, ν, cm–1: 3020 (NH), 1689 (C=O), 1623
(Z)-2-{2-[(3-Methylphenyl)imino]-4-oxo-2H-benzo[e]-
[1,3]thiazin-3(4H)-yl}acetonitrile (8c). Yield 0.55 g (72%).
1
(C=N). H NMR spectrum, δ, ppm (J, Hz): 7.15 (2H, t,
1
J = 7.8, Н Ph); 7.36–7.56 (5H, m, Н Ar); 7.64 (1H, t,
J = 7.8, Н-7) (all three signals overlapped with broadened
NH signal); 8.20 (1H, d, J = 7.9, Н-5); 11.70 (br. s, NH).
13C NMR spectrum, δ, ppm: 121.3; 121.4; 122.6; 124.5;
Colorless crystals. Mp 181–182°C. H NMR spectrum, δ,
ppm (J, Hz): 2.34 (3H, s, CH3); 5.22 (2H, s, CH2); 6.69–
6.75 (2H, m, Н-2,6 Ar); 6.98 (1H, d, J = 7.5, Н-4 Ar); 7.28
(1H, t, J = 7.6, Н-5 Ar); 7.37 (1H, d, J = 7.9, Н-8); 7.45 (1H,
374

Chemistry of Heterocyclic Compounds 2015, 51(4), 370–376
t, J = 7.6, Н-6); 7.64 (1H, t, J = 7.3, Н-7); 8.28 (1H, d,
2-(4-Chlorobenzylsulfanyl)-4H-benzo[e][1,3]thiazin-
4-one (10c). Yield 0.09 g (26%). Colorless crystals. Mp 109–
110°C. IR spectrum, ν, cm–1: 3020 (CH), 1658 (C=O), 1585
J = 7.7, Н-5). 13C NMR spectrum, δ, ppm: 20.9; 31.6;
115.9; 117.4; 120.9; 121.7; 125.4; 127.2; 129.4; 130.4;
130.5; 131.0; 134.4; 139.1; 146.1; 146.2; 161.0. Found, %:
C 66.38; H 4.22; N 13.72. C17H13N3OS. Calculated, %:
C 66.43; H 4.26; N 13.67.
1
(C=N). H NMR spectrum, δ, ppm (J, Hz): 4.61 (2H, s,
CH2); 7.30 (2H, d, J = 8.3, Н-2,6 Ar); 7.46 (2H, d, J = 8.3,
Н-3,5 Ar); 7.51 (1H, d, J = 7.9, Н-8); 7.59 (1H, t, J = 7.5,
Н-6); 7.68 (1H, t, J = 7.2, Н-7); 8.29 (1H, d, J = 7.9, Н-5).
13C NMR spectrum, δ, ppm: 33.8; 122.2; 125.7; 128.3;
128.5; 129.1; 129.7; 130.0; 131.1; 132.3; 133.2; 134.4;
135.3; 164.8; 176.2. Found, %: C 56.36; H 3.10; N 4.41.
C15H10ClNOS2. Calculated, %: C 56.33; H 3.15; N 4.38.
2-(2-Chlorobenzylsulfanyl)-4H-benzo[e][1,3]thiazin-
4-one (10d). Yield 0.19 g (58%). Colorless crystals. Mp 111–
112°C. IR spectrum, ν, cm–1: 3012 (CH), 1664 (C=O), 1586
(C=N). 1H NMR spectrum, δ, ppm (J, Hz): 4.70 (2H, s, CH2);
7.26–7.32 (2H, m, Н Ar); 7.39–7.45 (1H, m, Н Ar); 7.50 (1H,
d, J = 7.7, Н-8); 7.59 (1H, t, J = 7.4, Н-6); 7.64–7.72 (2H, m,
Н Ar); 8.31 (1H, d, J = 7.7, Н-5). 13C NMR spectrum, δ, ppm:
32.7; 122.2; 125.7; 127.4; 127.5; 129.5; 129.7; 129.8; 130.0;
131.8; 133.3; 133.4; 134.3; 164.7; 176.0. HPLC: τR 2.16 min
(the only component). Mass spectrum, m/z: 320 [M+H]+. Found,
%: C 56.29; H 3.18; N 4.35. C15H10ClNOS2. Calculated, %:
C 56.33; H 3.15; N 4.38.
5H-Quinazolino[2,3-b]quinazoline-11,13-dione (9).
A
mixture of guanidine 5 (1.00 g, 4.5 mmol) and methyl
anthranilate (3.40 g, 22.5 mmol) with dimethyl acetamide
(10 ml) was heated at 150°С for 1 h. The precipitate formed
upon cooling was filtered off and recrystallized from a 2:1
mixture of DMF and 2-PrOH. Yield 0.52 g (44%). Cream-
colored crystals. Mp >300°C (mp 358–360°С).16 IR
spectrum, ν, cm–1: 3042 (NH), 1704 (C=O), 1629 (C=O).
1H NMR spectrum, δ, ppm (J, Hz): 7.40 (1H, t, J = 7.5,
Н Ar); 7.47 (1H, d, J = 8.2, Н Ar); 7.58 (1H, t, J = 7.5,
Н Ar); 7.75–7.87 (2H, m, Н Ar); 8.15–8.21 (2H, m, Н Ar);
9.20 (1H, d, J = 8.7, Н-10); 12.30 (1H, s, NH). 13C NMR
spectrum, δ, ppm: 118.5; 119.3; 121.0; 124.3; 124.4; 126.7;
126.9; 127.2; 133.8; 135.2; 137.1; 144.0; 145.8; 159.7;
161.5. Mass spectrum, m/z (Irel, %): 263 [M]+ (100), 238
[M–CN]+ (12), 235 [M–CO]+ (5), 207 [M–2CO]+ (7), 194 (4),
181 (4), 162 (3), 145 [M–C6H4CONH]+ (21), 117 (10), 101
(17), 90 (35). Found, %: C 68.52; H 3.45; N 16.01.
C15H9N3O2. Calculated, %: C 68.44; H 3.45; N 15.96.
Preparation of a mixture of compounds 10а–с and
11а–с by alkylation of 2-thioxo-2,3-dihydrobenzo[e]-
[1,3]thiazin-4-one (3) (General method). Methanol was
removed on a rotary evaporator from a mixture of 1 М
MeONa solution in МеОН (2.5 ml) and thione 3 (0.49 g,
2.5 mmol). A solution of alkyl halide (2.5 mmol) in DMF
(3 ml) was then added, the reaction mixture was heated at
70°С for 5–7 min and poured into cooled distilled water.
The precipitate that formed was filtered off.
2-(Ethylsulfanyl)-4H-benzo[e][1,3]thiazin-4-one
(10e).
Yield 0.14 g (62%). Colorless crystals. Mp 119–120°C. IR
spectrum, ν, cm–1: 2978 (CH), 1683 (C=O), 1583 (C=N).
1H NMR spectrum, δ, ppm (J, Hz): 1.32 (3H, t, J = 6.9,
CH2CH3); 4.68 (2H, q, J = 6.9, CH2CH3); 7.35 (1H, d,
J = 7.9, H-8); 7.49 (1H, t, J = 7.6, Н-6); 7.69 (1H, t, J = 7.3,
Н-7); 8.25 (1H, d, J = 7.9, Н-5). 13C NMR spectrum, δ, ppm:
11.6; 42.4; 122.3; 122.6; 128.3; 130.9; 134.3; 135.4; 159.3;
192.1. Found, %: C 53.83; H 4.11; N 6.21. C10H9NOS2.
Calculated, %: C 53.79; H 4.06; N 6.27.
This work was performed with financial support from
the Ministry of Education and Science of the Russian
Federation, within the framework of State Assgnment for
Universities scientific activity for years 2014–2016 (project
No. 4.2100.2014/K).
Mixture of 2-(methylsulfanyl)-4H-benzo[e][1,3]thi-
azin-4-one (10а) and 3-methyl-2-thioxo-2,3-dihydro-
1
benzo[e][1,3]thiazin-4-one (11а). H NMR spectrum, δ,
ppm: 2.75 (2.25H, s, CH3 (10а)); 3.85 (0.75H, s, CH3
(11а)); 7.45–7.78 (3Н, m, Н Ar); 8.20–8.35 (1Н, m, Н Ar).
Mixture of 2-(4-oxo-4H-benzo[e][1,3]thiazine-2-sulfanyl)
acetonitrile (10b) and 2-(4-oxo-2-thioxo-2H-benzo[e]-[1,3]
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