Synthesis of 2-Alkyl-4,5-aryl-2H-[1λ6,2,3,6]- thiatriazine-1,1-dioxides

Article abstract of DOI:10.1002/jhet.5570450242

x(Chemical Equation Presented) Sulphamoyl chlorides and chlorosulphonyl isocyanate react with monosubstituted hydrazones and alkylhydrazonates to sulphamoyl hydrazones and sulphamoyl hydrazonates respectively. Reaction of benzil monoalkylhydrazones with c

Full text of DOI:10.1002/jhet.5570450242

Synthesis of 2-Alkyl-4,5-aryl-2H-[1λ6,2,3,6]-
thiatriazine-1,1-dioxides
Mar-Apr 2008
567
M. Hilp
Institute of Pharmaceutical Chemistry, Philipps-University, Marburg, Germany,
private address: Priv.-Doz. Dr. Manfred Hilp, Haselhecke 42, D-35041 Marburg, Germany
manfred@hilp.de
Received February 10, 2007
R2
C
R2
C
R2
R2
N
N
C
O
C
N
N
N
Cl SO2
N C O
+
R1
- CO2 - HCl
R1
H
S
O
O
R1 = alkyl
R2 = aryl
Sulphamoyl chlorides and chlorosulphonyl isocyanate react with monosubstituted hydrazones and
alkylhydrazonates to sulphamoyl hydrazones and sulphamoyl hydrazonates respectively. Reaction of
benzil monoalkylhydrazones with chlorosulphonyl isocyanate results in formation of 2-alkyl-4,5-aryl-2H-
[1λ6,2,3,6]-thiatriazine-1,1-dioxides.
J. Heterocyclic Chem., 45, 567 (2008).
oxidized analogue of 2H-1λ2,2,3,6-thiatriazines, have
hitherto been completely unknown. This as well as the
fact that the related isomeric benzo-1λ6,2,3,4-thiatriazine-
1,1-dioxides are known to exhibit diuretic activity [14]
prompted us to embark on the synthesis of novel thia-
azacycles such as the 1λ6,2,3,6-thiatriazine-1,1-dioxide
derivatives as putative biologically active compounds
utilizing differently substituted hydrazones as building
block.
INTRODUCTION
1,2,4,6-Thiatriazine and its derivatives are a well
investigated class of sulphur-containing azacycles and
have been described in several publications as well as
patents [1-7]. They mainly possess herbicidal activity but
in some cases have also been identified as pharma-
cologically active compounds [1,8-12]. However, only
few publications are found in the literature concerning the
isomeric 2H-1,2,3,6-thiatriazines. The 2H-1λ2,2,3,6
isomers were first synthesized by Spasov et al. via
reduction of dehydrophenylosazones with hydrogen
sulphide [13]. It turned out that these compounds are not
stable under acidic conditions thus giving rise to 1H-2,3-
triazoles through elimination of elemental sulphur [13].
2H-1λ6,2,3,6-Thiatriazine-1,1-dioxides, representing the
According to Scott and Barry [15], only benzoyl-
hydrazide and 2-hydrazinopyridine react with disub-
stituted sulphamoyl chlorides in the presence of triethyl-
amine to sulphamoyl hydrazide. The reaction of methyl-
or 1,1-dimethylhydrazine renders, according to a radical
mechanism, sulphonamides whereas phenylhydrazine
gives rise to benzenesulphonic acid hydrazide.
Scheme 1
R2
N
R1
R3
R4
R2
R1
H
R3
R4
C
N
N
SO2 Cl
N
N
C
N
SO2
+
- HCl
H
H
1
2
3
3
R1 R2 R3 R4
yield
a
CH3 CH3
89
90
47
H
H
H
Ph
Ph
Ph
b
c
d
e
CH3 Ph
H
CH3
Ph
CH3
Ph OCH3
18
9
CH3 Ph CH3
OC2H5
f
H
Ph
41
CH3 OC2H5

568
M. Hilp
Vol 45
Scheme 2
O
C
H3C
H
CH3
N
N
C
+
NH
Cl SO2
N
Cl SO2
C
O
N
H
N
C
H
4
2a
5
2a
+
- HCl
CH3
N
N
CH
O2S
N
H
C
O
N
N
CH
CH3
6
RESULTS AND DISCUSSION
blocks for the synthesis of novel five-membered
thiaazacyclic ring systems. However, under the applied
reaction conditions, the cyclic condensation to the desired
2,5-dihydro-1λ6,2,3,5-thiatriazole-1,1-dioxide did not
succeed.
We found that also hydrazones 2a-c [16] and
hydrazonates 2d-f are attacked by mono- and
unsubstituted sulphamoyl chlorides of type 1 thereby
resulting in crystalline and stable compounds representing
sulphamoyl hydrazones and sulphamoyl alkylhydrazon-
ates 3a-f* respectively. Alkylhydrazonates 3d-f were
obtained by the reaction of hydrazonates 2d-f with
sulphamoyl chlorides of type 1. Due to the fairly
susceptible imidoester functionality present in derivatives
3d-f, they could only be purified via their sodium-salts.
Therefore, the yields in this series are significantly lower.
Ethyl N-(aminosulphonyl)-N-phenylethanehydrazonoate
3f could additionally be converted into the analogous
methyl N-(aminosulphonyl)-N-phenylethanehydrazonoate
(see experimental for 3g) by standing it in methanol at
room temperature acidified with sulphuric acid. Due to
the presence of an imidoester function in products 3d-f,
these structures were first envisioned to serve as building
As an alternative to sulphamoyl chlorides 1, chloro-
sulphonyl isocyanate 4 was chosen as substrate to react
with hydrazone derivatives. Subjecting one equivalent of
1-benzylidene-2-methylhydrazine 2a to chlorosulphonyl
isocyanate resulted in formation of [(2-benzylidene-1-
methylhydrazino)-carbonyl]sulphamoyl chloride 5 via
nucleophilic addition of the mono-substituted hydrazone
2a to the highly reactive isocyanate function. The reaction
of a second equivalent of 2a in presence of triethylamine
as base gave 2-benzylidene-N-[(2-benzylidene-1-methyl-
hydrazino)-carbonyl]-1-methyl-hydrazinesulphonamide 6
(Scheme 2). Since intermediate 5 still bears reactive
functionalities, it can be considered as an interesting
synthon for further synthetic transformations.
Scheme 3
R2
C
R2
R2
R2
C
C
N
N
N
C
O
N
N
+
Cl SO2
C O
N
R1
R1
S
- CO2 - HCl
H
O
O
4
8
7
yield (%)
8
a
R1
R2
Ph
72
62
49
93
38
CH3
CH3
CH3
CH3
C2H5
b
c
d
e
2-Pyridine
4-PhOCH3
-PhCH
4
3
Ph

Mar-Apr 2008
Synthesis of 2-alkyl-4,5-aryl-2H-[1,2,3,6]-thiatriazine-1,1-dioxides
569
C, 47.56; H, 5.76; N, 18.49; S, 14.11. Found: C, 47.57; H, 5.87;
N, 18.28; S, 14.31.
The reaction of benzil monoalkylhydrazones of type 7,
which were obtained by reaction of aromatic diketones
with mono-substituted aliphatic hydrazines according to a
known procedure [17] (see experimental section for
compounds 7a-e), with chlorosulphonyl isocyanate finally
led to the stable 2-alkyl-4,5-aryl-2H-[1λ6,2,3,6]thia-
triazine-1,1-dioxides 8 in moderate to good yields
(Scheme 3). Interestingly, in this case the initial nucleo-
philic attack of hydrazones of type 7 happened to take
place at the sulphur atom of 4 thus leading after
subsequent intramolecular cyclization and concomitant
carbon dioxide extrusion to the title compounds of type 8.
The proposed structural constitution of this new class of
heterocycles could be confirmed by X-ray-analysis of 4,5-
diphenyl-2-methyl-2H-[1λ6,2,3,6]-thiatriazine-1,1-dioxide
8a [18].
Analogous to unsubstituted sulphamoyl hydrazones,
which are generally fairly unstable, reactions with
unsubstituted benzilhydrazones also did not form any
definite product. Benzilmonoarylhydrazones did not react
at all, which might either be due to its weaker
nucleophilicity or to steric effects. 1,2-Diphenyl-2-
(phenylhydrazono)ethanone (benzil-N-phenylhydrazone)
should exist as its E-isomer [19].
1-Phenyl-2-benzylidene-N-methylhydrazinesulphonamide*
[102276-33-5] (3b) [16]. To the stirred solution of 1-
benzylidene-2-phenylhydrazine (2b) [22] (19.3 g, 0.1 mol) and
triethylamine (10.1 g, 0.1 mol), dissolved in tetrahydrofuran
(75ml), was added dropwise a solution of methylsulphamoyl
chloride (1a) [21] (13.0 g. 0.1 mol) in the above solvent (75 ml)
under ice-cooling and protection of light. Through stirring over
night at room temperature, precipitated triethylammonium
chloride was removed by filtration. The filtrate was evaporated
giving a greenish black oil, which solidified after some hours.
After washing with water and drying, the product (3b) was
obtained as colorless to pale yellow crystals, yield: 90 %; mp
143 °C (ethanol, several times); ir 3356, 3067, 3040, 1603,
1592, 1585, 1488, 1447, 1433, 1414, 1348, 1218, 1155, 1136,
1081, 1070, 1010, 973, 948, 917, 860, 838, 779, 760, 723, 703,
695, 646 cm-1; 1H nmr (CDCl3) δ: = 2.72 (d, J = 6 Hz, 3H), 3.28
(s, 3H), 5.29 (q, J = 6 Hz, br, 1H), 7.17-7.84 (m, 6H). Anal.
Calcd. for C14H15N3O2S: C, 58.11; H, 5.22; N, 14.52; S, 11.08.
Found: C, 58.29; H, 5.19; N, 14.59; S, 10.97.
2-Benzylidene-1-methylhydrazinesulphonamide* [102276-
28-8] (3c) [16]. To the stirred solution of chlorosulphonyl
isocyanate (4) [23] (14.2 g, 0.1 mol) in anhydrous diethyl ether
(25 ml), a solution of water (1.8 g, 0.1 mol) in diethyl
ether/acetonitrile (35:15, 50 ml) was added dropwise at -40 °C.
Through warming up to room temperature and addition of
diethyl ether (25 ml), the solution was added dropwise within 90
min to a solution of 1-benzylidene-2-methylhydrazine (2a) [20]
(13.4 g, 0.1 mol) and triethylamine (10.1 g, 0.1 mol) in diethyl
ether (50 ml). After stirring over night at room temperature, the
resulting precipitate was filtered off and the filtrate evaporated.
The remaining residue was washed with benzene and dried. (3c)
was obtained as colorless to pale yellow-colored crystals; yield
47%; m.p. 153 °C (ethanol/water, 1:1); ir: 3367, 3279, 3135,
1575, 1466, 1451, 1416, 1366, 1314, 1295, 1236, 1200, 1164,
EXPERIMENTAL
Infrared spectra were obtained as potassium bromide pellets
from a Perkin–Elmer 257 spectrometer; H nmr spectra were
1
measured on a Varian T 60 spectrometer (60 MHz). The
chemical shift (δ) values are reported as parts per million (ppm)
relative to tetramethylsilane as internal standard, s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad; EI-MS
spectra were recorded on a Varian MAT 111 spectrometer,
Bremen; CH elemental analyses were performed according to F.
Salzer, CWH-Labormatic-Wösthoff; N by a CHN-Analyzer 185,
1
1151, 1116, 1022, 950, 932, 904, 882, 759, 695 cm-1; H nmr
(CD3CN): δ = 3.23 (s, 3H), 5.62 (s, br, 2H), 7.32-7.90 (m, 6H).
Anal. Calcd. for C8H11N3O2S: C, 45.06; H, 5.20; N, 19.70; S,
15.03. Found: C, 44.95; H, 5.20; N, 19.76; S, 14.83.
Hewlett-Packard;
S
according to the Schöniger method.
Methyl N-[(methylamino)sulphonyl]-N-phenylbenzenecar-
bohydrazonoate* (3d). To a stirred solution of methyl N-
phenylbenzenecarbohydrazonoate (2e) [24] (2.26 g, 0.01 mol) in
anhydrous pyridine (50 ml) was added dropwise a solution of
methylsulphamoyl chloride (1a) [21] (1.55 g, 0.012 mol) in
anhydrous acetonitrile (25 ml) within 10 min at 0°C. After
allowing the mixture to stand over night, water (1000 ml) was
added and the mixture acidified to a pH of 5 by addition of
diluted hydrochloric acid. The mixture was washed three times
with diethyl ether (25 ml each portion), the organic layer
separated and dried over calcium chloride. Through addition of a
solution of sodium methanolate (1.08 g, 0.02 mol) in methanol
(20 ml) and light petroleum (300 ml), the sodium salt (3dNa)
was precipitated and obtained after filtration; yield 23%.
Commercially available solvents and chemicals were used as
pure or synthetic grade without further purification; solvents
were dried according to general methods.
2-Benzylidene-N,1-dimethylhydrazinesulphonamide*
[102276-32-4] (3a) [16]. To the stirred solution of 1-
benzylidene-2-methylhydrazine (2a) [20] (26.8 g, 0.2 mol) and
triethylamine (20.2 g, 0.2 mol) dissolved in diethyl ether (150
ml) was added dropwise a solution of methylsulphamoyl
chloride (25.9 g, 0.2 mol) (1a) [21] dissolved in the same solvent
(150 ml) under ice-cooling. After stirring over night at room
temperature, the resulting precipitate was separated by filtration,
the filtrate set aside, and triethylammonium chloride removed by
washing the precipitate with water. Further product was obtained
by evaporation of the filtrate. Product (3a) was obtained as
colorless needles, yield: 89 %; m.p. 93 °C (benzene); soluble in
ethanol; sodium hydroxide forming an acid-labile salt; ir: 3300,
3003, 2994, 2933, 2825, 1475, 1456, 1427, 1422, 1414, 1364,
1333, 1319, 1229, 1195, 1166, 1159, 1133, 1103, 1070, 1022,
946, 921, 911, 874, 850, 772, 741, 700, 649 cm-1; 1H nmr
(CDCl3): δ = 2.71 (d, J = 6 Hz, 3H), 3.28 (s, 3H), 5.26 (q, J = 6
Hz, br, 1H), 7.15-7.78 (m, 6H). Anal. Calcd. for C9H13N3O2S:
(3dNa) (0.68 g, 2 mmol) was re-dissolved in 1 M sodium
hydroxide (20 ml) and acidified by addition of 2 M acetic acid at
0° C adjusting the mixture to pH 5. (3d) was obtained as nearly
colorless crystals after recrystallisation from ligroin (activated
1
carbon), yield 77%; H nmr (CCl4): δ = 2.56 (d, J = 5 Hz, 3H),
4.00 (s, 3H), 4.86 (q, J = 5 Hz, 1H), 6.93-7.57 (m, 10H). Anal.
Calcd. for C15H17N3O3S: C, 56.41; H, 5.36; N, 13.16; S; 10.04.
Found: C, 56.65; H, 5.43; N, 13.01; S, 9.90.

570
M. Hilp
Vol 45
Ethyl N-[(methylamino)sulphonyl]-N-phenylethanecarbo-
Methyl N-(aminosulphonyl)-N-phenylethanehydrazono-
ate* (3g). To the solution of ethyl-N-(aminosulphonyl)-N-
phenylethanehydrazonoate (3f) (1.29 g, 5 mmol) in methanol
(50 ml) was carefully added conc. sulphuric acid (0.05 ml, 0.9
mmol) at room temperature. After 20 min, the solution was
neutralized with a solution of sodium methanolate (49 mg, 0.9
mmol) in methanol (2 ml). The mixture was evaporated to
dryness and the remaining residue dissolved in diethyl ether (25
ml). The sodium salt (3gNa) was obtained by further addition of
a solution of sodium methanolate (270 mg, 5 mmol) in methanol
(25 ml); yield 51%. Applying an excess of sodium methanolate
resulted in a red-colored contamination of the product! Anal.
Calcd. for C9H12N3NaO3S: C, 40.75; H, 4.56; N, 15.84; S, 12.09.
Found: C, 40.58; H, 4.62; N, 15.65; S, 11.89.
hydrazonoate* (3e). To a solution of ethyl N-phenylethane-
hydrazonoate (2e) [24] (17.8 g, 0.1 mol) and triethylamine (10.1
g, 0.1 mol) in diethyl ether (75ml) was added dropwise a
solution of methylsulphamoyl chloride (1a) [21] (13.0 g, 0.1
mol) in anhydrous diethyl ether (75 ml) within 45 min at 0°.
Through stirring over night at room temperature, the precipitated
triethylammonium chloride was filtered and thoroughly washed
with diethyl ether (100ml). A solution of sodium ethanolate (6.8
g, 0.1 mol) in ethanol (50 ml) was added to the filtrate. After
evaporation to dryness, the remaining residue was dissolved in
hot cyclohexane and filtered. The sodium salt (3eNa) was
obtained after cooling the solution to room temperature
rendering colorless crystals (acetonitrile); yield 11%; 1H nmr
(CD3OH): δ = 1.29 (t, J = 8 Hz, 3H), 1.96 (s, 3H), 2.71 (s, 3H),
4.32 (q, J = 8Hz), 7.04-7.64 (m, 5H). Anal. Calcd. for
C11H16N3NaO3S: C, 45.04; H, 5.50; N, 14.33; S, 10.93. Found:
C, 44.95; H, 5.30; N, 14.26; S, 10.83.
The sodium salt of methyl N-(aminosulphonyl)-N-phenyl-
ethanehydrazonoate (3gNa) (0.53 g, 2 mmol) was re-dissolved
in water (20ml) and the solution slowly acidified with diluted
hydrochloric acid to pH 5. (3g) was obtained as colorless
1
crystals; yield 86%; H nmr (CDCl3): δ = 2.05 (s, 3H), 3.89 (s,
(3eNa) (2.93 g, 0.01 mol) was re-dissolved in water (20 ml)
and acidified with 0.1 M hydrochloric acid giving rise to (3e) as
3H), 4.71 (s, 2H), 7.13-7.73 (m, 5H). Anal. Calcd. for
C9H13N3O3S: C, 44.43; H, 5.39; N, 17.27; S, 13.18. Found: C,
44.23; H, 5.25; N, 17.15; S, 13.29.
1
colorless crystals; yield 78%; H nmr (CCl4): δ = 1.35 (t, J = 7
Hz, 3H), 2.01 (s, 3H), 2.63 (d, J = 5 Hz, 3H), 4.27 (q, J = 7 Hz,
2H), 4.82 (q, J = 5 Hz, 1H) 7.03-766 (m, 5H). Anal. Calcd. for
C11H17N3O3S: C, 48.69; H, 6.31; N, 15.49; S, 11.82. Found: C,
48.95; H, 6.20; N, 15.71; S, 11.70.
2-Benzylidene-N-[(2-benzylidene-1-methylhydrazino)car-
bonyl]-1-methylhydrazinesulphonamide* (6) To a solution of
1-benzylidene-2-methylhydrazine (2a) [20] (4.03 g, 0.03 mol) in
diethyl ether (25 ml) was added dropwise a solution of
chlorosulphonyl isocyanate (4) [23] (4.25 g, 0.03 mol) in diethyl
ether (25 ml) within 20 min at room temperature. A colorless
precipitate of [(2-benzylidene-1-methylhydrazino)carbonyl]-
sulphamoyl chloride (5) was immediately formed. After stirring
over night, the residue was dissolved in tetrahydrofuran (75 ml)
and further 1-benzylidene-2-methylhydrazine (2a) [20] (4.03 g,
0.03 mol) and triethylamine (3.04 g, 003 mol), dissolved in
tetrahydrofuran (25 ml), was added dropwise within 20 min.
Through stirring for 3 hours at room temperature, the mixture
was partially concentrated under vacuum giving rise to a
precipitate, which was separated by filtration and washed with
water. After drying under vacuum, analytically pure 2-
benzylidene-N-[(2-benzylidene-1-methylhydrazino)carbonyl]-1-
methylhydrazine-sulphonamide (6) was obtained as colorless
crystals, yield 25%; m.p. 200°C. When the filtrate was
Ethyl N-(aminosulphonyl)-N-phenylethanehydrazonoate*
(3f). To the solution of ethyl N-phenylethanehydrazonoate
(2e) [24] (17.8 g, 0.1 mol) and triethylamine (10.1 g, 0.1 mol)
in diethyl ether (50 ml) was added dropwise a solution of
sulphamoyl chloride (1c) (11.6 g, 0.1 mol) - preparation see
2-benzylidene-1-methylhydrazinesulphonamide (3c) - in a
mixture of acetonitrile and diethyl ether (3:17, 100 ml) within
1 hour at 0° C. Through stirring for 2 hours at room
temperature, the precipitated triethylammonium chloride was
filtered off and thoroughly washed with diethyl ether (100
ml). A solution of sodium ethanolate (6.8 g, 0.1 mol) in
ethanol (50 ml) and diethyl ether (50 ml) was added to the
filtrate thus precipitating the sodium salt (3fNa), which
subsequently was washed with light petroleum yielding 39%
of product. After evaporating the filtrate to dryness, the
remaining residue was extracted several times with small
quantities of acetone yielding a further amount of sodium salt
providing a total yield of 50% (3fNa); ir: 3448, 3311, 3236,
3058, 2994, 2941, 1637, 1595, 1582, 1488, 1451, 1397, 1379,
1353, 1300, 1258, 1212, 1170, 1148, 1134, 1117, 1078, 1053,
998, 971, 921, 907, 871, 841, 778, 739, 731, 698, 650 cm-1;
1H nmr (D2O): δ = 1.43 (t, J = 7 Hz, 3H), 2.10 (s, 3H), 4.42
(q, J = 7 Hz, 2H), 4.82 (s, 1H) 7.19-7. 76 (m, 5H). Anal.
Calcd. for C10H14N3 NaO3S: C, 43.01; H, 5.05; N, 15.05; S,
11.48. Found: C, 43.23; H, 5.15; N, 15.25; S, 11.69.
Sodium ethyl N-(aminosulphonyl)-N-phenylethanehydrazo-
noate (3fNa) (2.8 g, 0.01 mol) was re-dissolved in water (25 ml)
and slowly acidified by addition of diluted hydrochloric acid.
(3f) was obtained as nearly colorless crystals; m.p. 90 °C
(cyclohexane); yield 82%; ir: 3378, 3289, 3135, 3012, 2994,
2941, 2915, 1626, 1590, 1490, 1484, 1456, 1445, 1406, 1383,
1370, 1361, 1302, 1176, 1156, 1074, 1049, 1040, 1026, 1004,
929, 898, 843, 779, 760, 694, 657;1H nmr (CCl3D): δ = 1.35 (t, J
= 8 Hz, 3H), 2.05 (s, 3H ), 4.33 (q, J = 8 Hz, 2H), 4.65 (s, br,
2H), 7.21-7.77 (m, 5H). Anal. Calcd. for C10H15N3O3S: C,
46.68; H, 5.88; N, 16.33; S, 12.46. Found: C, 46.71; H, 5.75; N,
16.57; S, 12.69.
evaporated to dryness,
a smudgy, yellow-colored residue
remained. After dissolving it in acetone and addition of a
twofold amount of water, only significantly contaminated (6)
could be obtained; total yield 64%; ir: 3320, 3045, 3022, 3000,
2936, 1706, 1609, 1573, 1483, 1436, 1418, 1408, 1388, 1369,
1352, 1329, 1317, 1298, 1258, 1237, 1215, 1173, 1159, 1148,
1089, 1072, 1021, 998, 950, 945, 930, 908, 902, 881, 858, 762,
756, 748, 697, 690, 626 cm-1; 1H nmr (CD3CN): δ = 3.23 (s, 3H)
3.46 (s, 3H), 7.14-8.13 (m 13H). Anal. Calcd. for C17H19N5O3S:
C, 54.68; H, 5.13; N, 18.75; S, 8.59. Found: C, 54.47; H, 5.00;
N, 18.87; S, 8.74.
(2Z)-2-(Methylhydrazono)-1,2-diphenylethanone*, (Z)-
benzil-N-methylhydrazone [34289-86-6] (7a) [17]. Benzil
(42.0 g, 0.2 mol) was dissolved in ethanol (250 ml) through
heating. Methylhydrazine (9.21 g, 0.2 mol) was added to the
warmed solution. After allowing the mixture to stand over night,
(7a) precipitated yielding colorless crystals; yield 73%. Further
(7a) was obtained by concentrating the filtrate; total yield 84%;
m.p. 138 °C (benzene/light petroleum); ir: 3298, 3104, 3086,
3059, 3025, 3004, 2962, 2921, 2869, 2849, 2808, 1972, 1958,
1908, 1890, 1812, 1633, 1603, 1584, 1579, 1540, 1488, 1449,

Mar-Apr 2008
Synthesis of 2-alkyl-4,5-aryl-2H-[1,2,3,6]-thiatriazine-1,1-dioxides
571
1442, 1417, 1391, 1337, 1312, 1303, 1283, 1257, 1239, 1207,
1188, 1176, 1165, 1155, 1122, 1088, 1075, 1031, 1028, 995,
986, 968, 929, 924, 869, 854, 847, 802, 778, 733, 708, 698, 769,
(p-anisil) (0.68 g, 2.5 mmol) and methylhydrazine (0.23 g, 5
mmol) were dissolved in glacial acetic acid (12 g, 0.2 mol) and
ethanol (50 ml). After allowing the mixture to stand for 24 hours
at room temperature, water (50 ml) was added whereupon (7c)
precipitated as a yellow colored, smudgy solid; yield 70%; m.p.
119 °C (benzene/ligroin, nearly colorless crystals); ir: 3260,
3096, 3064, 3042, 3024, 3000, 2971, 2936, 2898, 2872, 2840,
2812, 2040, 1937, 1908, 1886, 1871, 1623, 1608, 1602, 1572,
1544, 1539, 1532, 1512, 1506, 1472, 1458, 1452, 1442, 1418,
1343, 1307, 1258, 1248, 1213, 1187, 1172, 1136, 1106, 1082,
1025, 1003, 942, 879, 841, 832, 824, 815, 807, 786, 773, 736,
718, 706, 655, 638; Anal. Calcd. for C17H18N2O3: C, 68.44; H,
6.08; N, 9.39. Found: C, 68.65; H, 6.21; N, 9.65.
1
625 cm-1; H nmr (CD3CN): δ = 3.03 (d, J = 4 Hz, 3H), 6.73 (s,
br, NH, 1H), 7.17-7.98 (m, 10 H). Anal. Calcd. for C15H14N2O:
C, 75.61; H, 5.92; N, 11.76. Found: C, 75.77; H, 5.88; N, 11.41.
2-Methyl-4,5-diphenyl-2H-[1,2,3,6]-thiatriazine-1,1-di-
oxide (8a). To a solution of (2Z)-2-(methylhydrazono)-1,2-
diphenylethanone (Z-benzil-N-methylhydrazone) (7a) [17] (2.38
g, 0.01 mol) in anhydrous pyridine (50 ml) was added dropwise
a solution of chlorosulphonyl isocyanate (4) [23] (1.70 g, 0.012
mol) in anhydrous acetonitrile (25 ml). within 10 min at 0° C.
After allowing the mixture to stand for 3 hours at room
temperature, water (750 ml) was added whereupon (8a)
precipitated as yellow crystals; yield 72%; m.p. 160 °C (1 x
benzene/cyclohexane through addition of Al2O3, acidified,
Woelm, activity I; 2 x ethanol); ir: 3112, 3092, 3064, 3033,
2965, 1976, 1925, 1903, 1822, 1772, 1720, 1675, 1600, 1588,
1536, 1499, 1463, 1450, 1434, 1407, 1350, 1317, 1314, 1297,
1289, 1224, 1196, 1171, 1159, 1107, 1092, 1080, 1030, 1006,
994, 972, 949, 926, 849, 843, 836, 793, 776, 742, 726, 702, 696,
2-Methyl-4,5-bis(4-methoxyphenyl)-2H-[1,2,3,6]-thiatria-
zine-1,1-dioxide (8c). To a solution of (2Z)-2-(methylhy-
drazono)-1,2-bis(4-methylphenyl)ethanone (2.98 g, 0.01 mol)
(7c) in anhydrou s pyridine (50 ml) was added dropwise
chlorosulphonyl isocyanate (4) [23] (1.70 g, 0.012 mol) in
anhydrous acetonitrile (25 ml) within 10 min at room
temperature. After allowing the mixture to stand for 3 days at
room temperature, water (2 l) was added whereupon (8c) was
obtained as a very amorphous precipitate; yield 49%; m.p. 101
°C, yellow crystals (benzene/cyclohexane, 1:1, addition of
1
667 cm-1; H-nmr (CD3COCD3): δ = 3.82 (s, 3H), 7.15-7.65 (m
10 H); ms: m/z (%) = 299 [M]+ (26), 192 (24), 132 (49), 131
(23), 112 (24), 95 (17), 82 (21), 80 (21), 79 (9), 69 (23), 61 (20),
53 (8), 48 (15), 47 (9), 43 (11), 42 (22), 41 (12), 40 (100), 39
(15). Anal. Calcd. for C15H13N3O2S: C, 60.19; H, 4.38; N, 14.04;
S, 10.71. Found: C, 60.29; H; 4.44; N, 13.94; S, 10.70.
1
Al2O3, acidified, Woelm, activity I); H nmr (CCl4): δ = 3.73 (s,
3H), 3.79 (s, 6H), 6.60-7.65 (m, 8 H). Anal. Calcd. for
C17H17N3O4S: C, 56.81; H, 4.77; N, 11.69; S, 8.92. Found: C,
56.91; H, 4.61; N, 11.60; S, 8.79.
(2Z)-2-(Methylhydrazono)-1,2-dipyridin-2-ylethanone*
(7b). 1,2-Dipyridin-2-ylethane-1,2-dione (α-pyridil) (10.6 g,
0.05 mol) was dissolved in ethanol (250 ml) through heating and
methylhydrazine (2.30 g, 0.05 mol) was added. After allowing
the mixture to stand over night at room temperature, (7b)
precipitated as pale, yellow crystals; yield 80%; m.p. 154-155
°C (ethanol or ligroin); ir: 3163, 3100, 3052, 3020, 2992, 2965,
2900, 1694, 1640, 1617, 1570, 1560, 1519, 1501, 1482, 1448,
1387, 1352, 1341, 1322, 1292, 1208, 1203, 1166, 1146, 1132,
1100, 1057, 1047, 1041, 1008, 948, 928, 869, 844, 812, 804,
(2Z)-2-(Methylhydrazono)-1,2-bis(4-methylphenyl)ethan-
one* (7d). 1,2-Bis(4-methylphenyl)ethane-1,2-dione (p-tolil)
(23.8 g, 0.1 mol), methylhydrazine (4.6 g, 0.1 mol) and glacial
acetic acid (6.0 g, 0.1 mol) were dissolved in ethanol (1 l).
Through heating the mixture to reflux, the resulting solution was
diluted with hot water (1 l). and allowed to cool down to room
temperature over night whereupon crude (7d) precipitated. After
washing with a mixture of ethanol and water (1:1, 200ml), (7d)
was obtained as long pale yellow crystals; yield 73%; m.p.98 °C.
ir: 3239, 3016, 2998, 2956, 2933, 2912, 2856, 2800, 1916, 1808,
1618, 1602, 1564, 1557, 1533, 1526, 1519, 1517, 1494, 1440,
1413, 1403, 1333, 1302, 1298, 1285, 1278, 1256, 1212, 1197,
1179, 1173, 1138, 1113, 1103, 1076, 1033, 1021, 1018, 1001,
968, 950, 944, 878, 842, 832, 822, 811, 779, 754, 728, 699, 638,
623. 1H nmr (CCl4): δ = 2.37 (d, J = 2 Hz, 6H), 3.06 (d, J = 8 Hz,
3H), 6.08 (s, br , NH, 1H) 6.93-7.97 (m, 8 H). Anal. Calcd. for
C17H18N2O: C, 76.66; H, 6.81; N, 10.52. Found: C, 76.53; H,
6.75; N, 10.39.
1
787, 768, 738, 688, 677, 667 cm-1; H nmr CCl4): δ = 3.12 (d, J
= 4 Hz, 3H), 6.73-8.67 (m, 8 H), 13.24 (s, br, NH, 1H). Anal.
Calcd. for C13H12N4O: C, 64.99; H, 5.03; N, 23.22. Found: C,
64.75; H, 4.94; N, 23.04.
2-Methyl-4,5-di-pyridin-2-yl-2H-[1,2,3,6]-thiatriazine-1,1-
dioxide (8b). To the solution of (2Z)-2-(methylhydrazono)-1,2-
dipyridin-2-ylethanone (7b) (2.40 g, 0.01 mol) in anhydrous
pyridine (50 ml) was added dropwise
a
solution of
chlorosulphonyl isocyanate (4) [23] (1.70 g, 0.012 mol) in
anhydrous acetonitrile (25 ml) within 10 min at room
temperature. Through allowing the mixture to stand for 3 days at
room temperature, the solvents were removed by evaporation.
The remaining residue was purified by column chromatography
using methylene dichloride for development and ethyl acetate as
eluent (Al2O3, acidified, Woelm, activity I). After evaporation of
the eluate, (8b) was obtained as brownish yellow crystals; yield
62%; m.p. 185 °C (1x benzene/cyclohexane (1:1), 1x acetone);
ir: 1592, 1556, 1462, 1438, 1360, 1345, 1318, 1290, 1229, 1192,
1177, 1162, 1153, 1109, 1098, 1055, 1003, 957, 847, 803, 787,
754, 748, 738, 713, 671; 1H nmr (CD3COCD3): δ = 3.85 (s, 3H),
7.12-8.38 (m, 8 H). Anal. Calcd. for C13H11N5O2S: C, 51.82; H,
3.68; N, 23.34; S, 10.64. Found: C, 51.95; H, 3.70; N, 23.50; S,
10.50.
2-Methyl-4,5-bis(4-methylphenyl)-2H-[1,2,3,6]-thiatriaz-
ine-1,1-dioxide (8d). To the solution of (2Z)-2-(methyl-
hydrazono)-1,2-bis(4-methylphenyl)ethanone (7d) (2.66 g,
0.01 mol) in anhydrous pyridine (50 ml) was added dropwise
a solution of chlorosulphonyl isocyanate (4) [23] (1.70 g,
0.012 mol) in anhydrous acetonitrile (25 ml). within 10 min at
0° C. After allowing the mixture to stand for 3 days at room
temperature, water (1 l) was added slowly while stirring
whereupon (8d) was obtained as yellow crystals; yield 93%;
m.p. 89 °C; ir: = 3088, 3054, 2954, 2930, 2854, 1612, 1578,
1548, 1517, 1482, 1450, 1403, 1358, 1344, 1309, 1304, 1285,
1219, 1212, 1187, 1184, 1168, 1118, 1082, 1038, 1024, 993,
969, 950, 854, 848, 841, 816, 791, 762, 727, 711, 702, 678,
648, 637 cm-1; 1H nmr (CCl4): δ = 2.33 (s, 6H), 3.72 (s, 3H),
6.80-7.47 (m, 8 H). Anal. Calcd. for C17H17N3O2S: C, 62.37;
H, 5.23; N, 12.83; S, 9.79. Found: C, 62.25; H, 5.19; N,
12.99; S 9.63.
(2Z)-1,2-Bis(4-methoxyphenyl)-2-(methylhydrazono)etha-
none* (7c). 1,2-Bis(4-methoxyphenyl)ethane-1,2-dione

572
M. Hilp
Vol 45
(2Z)-2-(Ethylhydrazono)-1,2-diphenylethanone*, (Z)-ben-
2H), 7.05-7.57 (m 10 H). Anal. Calcd. for C16H15N3O2S: C,
61.32; H, 4.82; N, 13.41; S, 10.23. Found: C, 61.48; H, 4.98; N,
13.37; S, 10.27.
zil-N-ethylhydrazone (7e). To a 50% aqueous ethylamine
solution in water (72 g, 0.8 mol) was added dropwise a solution
of potassium hydroxide (28 g, 0.5 mol) in water (80 ml). To
avoid loss of gaseous ethylamine, the reaction vessel was
equipped with a reflux condenser keeping the cooling liquid at 0
Acknowledgement. The author thanks Mr. H. - D. Gerber for
his correction of the manuscript.
°C. After heating the mixture to 60 °C,
a solution of
REFERENCES AND NOTES
hydroxylamine-O-sulphonic acid (22.6 g, 0.2 mol) in water (60
ml) was added dropwise within 30 min. The reaction mixture
was heated to reflux for 10 min and then acidified with glacial
acetic acid (52 ml, 0.9 mol). Benzil (10.5 g, 0.05 mol), dissolved
in ethanol (700 ml) and pyridine (100 ml), was added and the
*
Due to the formation of
a
hydrogen bridge,
benzilalkylhydrazones exist as Z-isomers [17] whereas all other
hydrazones could not be assigned as Z or E–isomers.
[1] Fischer, E. Sulfur Reports 1992, 11, 257.
[2] Stoller, A. D. J. Heterocyclic Chem. 2000, 37, 583.
[3] Stoller, A. D.; Kreuz, K.; Haake, M.; Wenger, J. Chimia
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[4] Peng, L.; Xiang, F.; Roberts, E.; Kawagoe, Y.; Greve, L. C.;
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[5] Stoller, A.; Haake, M.; Zondler, H. (Ciba-Geigy A.G.), WO
9601814-A1 (1997.07.07); Chem. Abstr. 1997, 127, 161840.
[6] Stoller, A.; Kunz, W. (Novartis AG), WO 9725319-A1
(1997.07.17); Chem. Abstr. 1997, 127, 161840.
[7] Stoller, A.; Kunz, W.; Zondler, H.; Luethy, Ch.; Wenger, J.
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mixture refluxed for
3 hours. The solidified potassium
hydrogensulphate was filtered off and the filtrate was
concentrated under vacuum to about half of its original volume.
The solution was diluted with hot water (500 ml) and cooled to
room temperature whereupon (7e) was obtained as tiny pale
yellow needles; yield 63%; m.p. 126 °C (cyclohexane); ir: 3270,
3075, 3052, 3019, 2983, 2969, 2931, 2916, 2876, 1983, 1963,
1918, 1897, 1815, 1775, 1623, 1597, 1575, 1526, 1520, 1491,
1460, 1444, 1378, 1369, 1332, 1306, 1291, 1255, 1244, 1200,
1175, 1152, 1089, 1076, 1027, 1024, 999, 990, 975, 966, 929,
924, 909, 856, 842, 807, 791, 770, 739, 724, 705, 695, 665, 631
1
cm-1; H nmr CDCl3): δ = 1.11 (t, J = 7.0 Hz, 3H), 3.43 (q, J =
[8] Palmer, C. J.; Casida, J. E. Toxicology Letters 1988, 42, 117.
[9] Tanaka, K.; Scott, J. G.; Matsumara, F. Pesticide
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(1986); Chem. Abstr. 1987, 106, 11894.
7.0 Hz, 2H), 6.48 (s, br, NH, 1H) 7.13-8.16 (m, 10 H). Anal.
Calcd. for C16H16N2O: C, 76.17; H, 6.39; N, 11.10. Found: C,
76.19; H, 6.26; N, 10.96.
2-Ethyl-4,5-phenyl-2H-[1,2,3,6]-thiatriazine-1,1-dioxide
(8e). To (2Z)-2-(ethylhydrazono)-1,2-diphenylethanone (Z-
benzil-N-ethylhydrazone) (7e) (2.52 g, 0.01 mol) in
anhydrou s pyridine (50 ml) was added within 10 min
dropwise at a temperature of about 0°C chlorosulphonyl
isocyanate (4) [23] (1.70 g, 0.012 mol) dissolved in
anhydrou s acetonitrile (25 ml). After 3 days at room
temperature water (1 l) was slowly added under stirring, whereas
(8e) was precipitated in smudgy form. Through washing with
water and drying the substance was dissolved in methylene
dichloride and purified by column chromatography (Al2O3,
acidified, Woelm, activity I). Methylene dichloride was applied
for development and ethyl acetate for elution. After evaporation
of the eluate (8e) was obtained as yellow crystals; yield 38%;
m.p.132 °C (cyclohexane); ir: 3090, 3070, 3060, 3028, 2997,
2984, 2972, 2953, 2940, 2931, 2872, 2851, 1604, 1590, 1556,
1498, 1470, 1449, 1443, 1357, 1349, 1338, 1309, 1288, 1196,
1184, 1162, 1156, 1137, 1092, 1082, 1078, 1032, 1008, 1002,
997, 992, 985, 981, 978, 972, 968, 964, 957, 932, 921, 848, 840,
801, 792, 787, 770, 738, 724, 700, 695, 688, 684, 653 cm-1; 1H
nmr (CCl4): δ = 1.55 (t, J = 6.6 Hz, 3H), 4.08 (q, J = 6.6 Hz,
[11] Allen, R. M.; Fletcher, S. R. (Hoechst, U. K., Ltd.), Brit. UK
Pat. Appl. GB 2,174,705 (1986); Chem. Abstr. 1987, 107, 39869.
[12] Ross, B. C.; Allen, R. M.; Cousins, S. J. (Hoechst U.K.,
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95470.
[13] Spasov, A.; Chemishev, B. Dokl. Bolg. Akad. Nauk. 1970,
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[18] Hilp, M.; Stubbs, M. unpublished.
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