Hydroxyketones in the thiadiazine cycle formation

Article abstract of DOI:10.1007/s11172-016-1609-3

Cyclocondensation of 1-hydroxyketones with thiosemicarbazide resulted in thiadiazines. Nitrate ester of 1-hydroxyketone reacted under similar conditions to give the corresponding thiosemicarbazone. In the case of bromoacetyl-substituted nitrate ester of 1-hydroxyketone, condensation proceeded via intramolecular reaction between the thiol and bromomethyl groups.

Full text of DOI:10.1007/s11172-016-1609-3

Russian Chemical Bulletin, International Edition, Vol. 65, No. 10, pp. 2475—2478, October, 2016
2475
Hydroxyketones in the thiadiazine cycle formation
E. Kh. Pulatov, M. J. Isobaev, and B. G. Mavlonov
V. I. Nikitin Institute of Chemistry, Academy of Sciences of the Republic of Tajikistan,
299/2 ul. Aini, 734063 Dushanbe, Tajikistan
.
Fax: +992 (37) 225 8095. Eꢀmail: coordin@yandex.ru
Cyclocondensation of 1ꢀhydroxyketones with thiosemicarbazide resulted in thiadiazines.
Nitrate ester of 1ꢀhydroxyketone reacted under similar conditions to give the corresponding
thiosemicarbazone. In the case of bromoacetylꢀsubstituted nitrate ester of 1ꢀhydroxyketone, conꢀ
densation proceeded via intramolecular reaction between the thiol and bromomethyl groups.
Key words: cyclocondensation, thiosemicarbazones, 1ꢀhydroxyketones, aminothiadiazine ring.
One of the modern approaches towards fiveꢀ and sixꢀ
membered heterocycles is a condensation of thiosemiꢀ
carbazide (TSC) with carbonyl compounds. The main
advantages in this filed are summarized in the review.1
It has been shown that the reaction course depends on the
reaction conditions to give either fiveꢀmembered thiazoꢀ
lidines or sixꢀmembered 1,2,4ꢀtriazines and 1,3,4ꢀthiaꢀ
diazines as the major products.
cyclohexyl)ethanone (5) to give thiadiazines 6 and 7 can
be enabled by catalytic amounts of sulfuric acid (Scheme 1).
Note that thiosemicarbazone 8 (Scheme 2) bearing proꢀ
tected hydroxy group is stable under these conditions.
Apparently, the reaction is initiated by protonation of
the hydroxy group as described,8 leading to a water molꢀ
ecule elimination and subsequent bonding of the thiol
group to the adjacent carbon atom.
For instance, reaction of TSC with acetylenedicarꢀ
boxylates in anhydrous dichloromethane gives the correꢀ
sponding thiazolidines in high yields,2 while the same
reaction carried out either solventꢀfree under microwave
irradiation or in refluxing low alcohols produces sixꢀ
membered triazinones.3
Formation of sixꢀmembered thiadiazine ring of 6 was
also confirmed by the counter synthesis, namely, by the
reaction of TSC with isopropenyl methyl ketone (9).
Compound 9 was prepared from dimethylacetylcarbinol
by dehydration with phosphorous anhydride in anhyꢀ
drous chloroform as earlier described.9
Reaction of TSC with aromatic carbonyl compounds
in acidic alcohol solutions leads to the corresponding
thiosemicarbazones, which undergo condensation with
αꢀhalocarboxylic acids to yield fiveꢀmembered thiazoliꢀ
dinones.4
1,3,4ꢀThiadiazines can be also synthesized by the reꢀ
action of TSC with αꢀhalocarbonyl compounds.5—7
Synthesis of vicinal 2ꢀaminoꢀ1,3,4ꢀthiadiazines by
the reaction of acyloins with thiosemicarbazides in TFA
has been described earlier.8 The thiadiazine ring system
is formed via an intermediate carbocation.
In the present work, we report on the reactions of
TSC with 3ꢀhydroxyꢀ3ꢀmethylbutanꢀ2ꢀone (1), 1ꢀ(1ꢀhydꢀ
roxycyclohexyl)ethanone (2), and 3ꢀmethylꢀ3ꢀnitroꢀ
oxybutanꢀ2ꢀone (3). Analysis of the reaction products
indicates that in all cases compounds of the Schiff
base type are initially formed. This conclusion is based
on a comparison of the reactivity of structural analogs of
1ꢀhydroxy ketones and directions of their reactions
with TSC.
Total similarity of the cyclizations involving comꢀ
pound 1 and its dehydrated derivative 9 suggests that in
the case of compound 1 the water molecule elimination
at the intermediate stage is essential for finalizing the
cyclization.
1H NMR spectra of compounds 6 and 7 lack the
proton signals at δ 6.30 characteristic of the OH groups
of the starting thiosemicabazones of 3ꢀhydroxyꢀ3ꢀmethylꢀ
butanꢀ2ꢀone (4) and 1ꢀ(1ꢀhydroxycyclohexyl)ethanone (5).
In the case of 3ꢀmethylꢀ3ꢀnitrooxybutanꢀ2ꢀone (3),
the nitro ester group apparently impedes the cyclization
and the Schiff base becomes the major reaction product
(see Scheme 2).
IR spectrum of 3ꢀmethylꢀ3ꢀnitrooxobutanꢀ2ꢀone (8)
exhibits new absorptions at 1170, 1275, 1650, 1520, and
3200 cm–1 attributed to the N—C(S)—N, О—NO2,
C=N, N—N, and NH2 groups, respectively.
It has been shown previously10 that the activated meꢀ
thyl group bonded to the carbonyl group is rather readily
undergoes bromination and the products of cycloconꢀ
densation of these αꢀbromo derivatives with 4ꢀsubstitutꢀ
ed thiosemicarbazides inhibit human platelet aggregaꢀ
Thus, cyclization of thiosemicarbazones of 3ꢀhydrꢀ
oxyꢀ3ꢀmethylbutanꢀ2ꢀone (4) and 1ꢀ(1ꢀhydroxyꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2475—2478, October, 2016.
1066ꢀ5285/16/6510ꢀ2475 © 2016 Springer Science+Business Media, Inc.

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Pulatov et al.
Scheme 1
R1 = R2 = Ме (1, 4, 6), R1 + R2 = (CH2)5 ( 2, 5, 7)
Scheme 2
we studied the reactions of bromo ketones 10—12 with
TSC in refluxing ethanol (Scheme 4).
It was found that these reactions produce 2ꢀaminothiꢀ
adiazines 13a—c. This indicates that intramolecular atꢀ
tack on the thiol group is directed on the C atom of the
bromomethyl group.
Formation of sixꢀmembered aminothiadiazines 13a—c
was confirmed by IR and 1H NMR spectroscopy.
IR spectra of compounds 13a—c lack the absorptions
characteristic of the C—Br bonds. This spectral change
can be attributed to the involvement of the Br atom in the
cyclization. New bands at 1325—1175, 1425, 3250, and
760, 675, 1520, 1650 cm–1 were ascribed to the vibraꢀ
tions of the exocyclic (C—C, C—N, C—О) and endocyꢀ
clic (C—S, N—N, C=N) bonds, respectively.
tion induced by ADP. Taking these facts into account, we
synthesized the corresponding bifunctional brominated
derivatives 10—12 from 3ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀ
butanone (1) and 1ꢀ(1ꢀhydroxycyclohexyl)ꢀ2ꢀethanone
(2) (Scheme 3).
Scheme 3
We believed that bromoꢀsubstituted 1ꢀhydroxy keꢀ
tones 10 and 11 can serve as the starting material in the
synthesis of sixꢀmembered aminothiadiazines since the
C atom of the bromomethyl group will participate in the
reaction.
3ꢀHydroxyꢀ3ꢀmethylbutanꢀ2ꢀone (1) was treated oneꢀ
pot with acetyl nitrate (AcONO2) and bromine in AcОH
to give 1ꢀbromoꢀ3ꢀmethylꢀ3ꢀnitrooxybutanꢀ2ꢀone (12)
in 75% yield (see Scheme 3).
To determine, which one of two possible directions of
the attack of the thiol group on the C atom is realized
(C—ОH (intermediate A) or C—Br (intermediate B)),
R1 = R2 = Me (1, 10), R1 + R2 = (CH2)5 (2, 11)

Hydroxyketones in the thiadiazine cycle formation Russ.Chem.Bull., Int.Ed., Vol. 65, No. 10, October, 2016
2477
Scheme 4
R1 = R2 = Me, X = H (10, 13a); R1 = R2 = Me, X= NO2 (12, 13c); R1 + R2 = (CH2)5, X = H (11, 13b)
1
1H NMR spectra of compounds 13a—c show two
singlets at δ 4.42 and 4.82 with the 4 H integral intensity.
These signals were assigned to the protons at the 6ꢀposiꢀ
tion and the exocyclic amino group, respectively. Note
that in the 1H NMR spectrum of compound 13a a singlet
signal of the OH group proton of the starting bromo
derivative 10 is retained and appeared at δ 6.30.
(N—N); 1645 (C=N); 3245—3065 (NH2). H NMR (CDCl3),
δ: 0.96 (s, 6 H, 2 Me); 1.80 (s, 3 H, Me); 6.30 (s, 1 H, ОH); 7.26
(s, 2 H, NH2); 8.54 (s, 1 H, NH).
Thiosemicarbazones 5 and 8 were synthesized similarly.
1ꢀ(1ꢀHydroxycyclohexyl)ethanone thiosemicarbazone (5). Yield
1.63 g (76%), m.p. 164 °C (from EtOH). Found (%): C, 50.16;
H, 7.85; N, 19.48; S, 14.81. C9H17N3ОS. Calculated (%): C, 50.23;
H, 7.90; N, 19.53; S, 14.88. IR (KBr), ν/cm–1: 1165 (N—C(S)—N);
3365 (ОH); 1515 (N—N); 1640 (C=N); 3240—3060 (NH2).
1H NMR (CDCl3), δ: 1.62 (s, 3 H, Me); 0.92—2.25 (m, 10 H,
C(CH2)5); 6.32 (s, 1 H, ОH); 7.30 (s, 2 H, NH2); 8.60 (s, 1 H, NH).
3ꢀMethylꢀ3ꢀnitrooxybutanꢀ2ꢀone thiosemicarbazone (8). Yield
1.78 g (81%), m.p. 187 °C (from EtOH). Found (%): C, 32.68;
H, 5.38; N, 25.37; S, 14.48. C6H12N4О3S. Calculated (%):
C, 32.72; H, 5.45; N, 25.45; S, 14.54. IR (KBr), ν/cm–1: 1170
(N—C(S)—N); 1275 (О—NО2); 1520 (N—N); 1650 (C=N);
Experimental
1
H NMR spectra were recorded on a XTIPC VARIAN
MRꢀ400 instrument with the working frequency of 400 MHz. The
chemical shifts are given in the δ scale relative to SiMe4 (internal
standard).
IR spectra were recoded with a Perkin—Elmer Spectrumꢀ65
spectrophotometer. Elemental analysis was performed with a Perꢀ
kin—Elmer 2400 analyzer. Melting points were measured on a
1
3240—3060 (NH2). H NMR (CDCl3), δ: 0.98 (s, 6 H, 2 Me);
1.90 (s, 3 H, Me); 7.38 (s, 2 H, NH2); 8.72 (s, 1 H, NH).
Boetius apparatus; heating range was 4 °C min–1
.
2ꢀAminoꢀ5,6,6ꢀtrimethylꢀ1,3,4ꢀthiadiazine (6). Thiosemicarꢀ
bazone 4 (1.75 g, 0.01 mol) was dissolved in concentrated sulfuric
acid (10 mL) with heating at 60—70 °C and the mixture was kept at
room temperature for 24 h. Then the reaction mixture was poured
by portions into iceꢀwater (100 mL) and carefully neutralized with
25% aqueous ammonia until low basic mixture was obtained. The
precipitate formed was collected by filtration, washed and purified
by refluxing in EtOH with activated charcoal. Recrystallization from
aqueous EtOH afforded the title product in the yield of 1.16 g
(74%), m.p. 196 °C (from EtOH). Found (%): C, 41.31; H, 5.69;
N, 16.02; S, 36.71. C6H11N3S. Calculated (%): C, 41.38; H, 5.75;
N, 16.09; S, 36.78. IR (KBr), ν/cm–1: 1325, 1170 (C—C); 1425
(C—N); 1520 (N—N); 1650 (C=N); 750 (C—S); 3240—3060
3ꢀHydroxyꢀ3ꢀmethylbutanꢀ2ꢀone (1) and 1ꢀ(1ꢀhydrꢀ
oxycyclohexyl)ethanone (2) were synthesized by the Kucherov
reaction from the corresponding acetylene alcohols.11 Isopropenyl
methyl ketone (9) was synthesized following the known proceꢀ
dure.9 1ꢀBromoꢀ3ꢀhydroxyꢀ3ꢀmethylbutanꢀ2ꢀone (10) and 2ꢀbroꢀ
moꢀ1ꢀ(1ꢀhydroxycyclohexyl)ethanone (11) were synthesized by
the described procedure.10.
3ꢀMethylꢀ3ꢀnitrooxybutanꢀ2ꢀone (3). To a stirred solution of
dimethyl acetyl carbinol (1) (10.2 g, 0.1 mol) in a mixture of Ac2О
(10.2 g, 0.1 mol) and glacial AcOH (20 mL), a solution of 98%
HNO3 (6.5 g, 0.1 mol) in glacial AcOH (10 mL) was added
dropwise at –5 °C. The reaction mixture was stirred for 2 h with
cooling and then Ac2O was distilled off at 70 °C (water bath) under
vacuum. The product was purified by vacuum distillation at 45 °C
(20 Torr). Yield 10 g (68%), nD20 = 1.4580.
Synthesis of 3ꢀhydroxyꢀ3ꢀmethylbutanꢀ2ꢀone thiosemicarbaꢀ
zone (4). To a stirred suspension of TSC (0.91 g, 0.01 mol) in
H2O—EtOH (60 mL, 2 : 1), 3ꢀhydroxyꢀ3ꢀmethylbutanꢀ2ꢀone (1)
(1.02 g, 0.01 mol) was added and the clear solution was formed
(thiosemicarbazide completely dissolved). After 10—15 min, a white
precipitate was formed. The precipitate was collected by filtration,
dried and recrystallized from aqueous EtOH. Yield 1.43 g (82%),
m.p. 179 °C (from EtOH). Found (%): C, 41.08; H, 7.35; N, 23.92;
S, 18.21. C6H13N3ОS. Calculated (%): C, 41.14; H, 7.42; N, 24.00;
S, 18.28. IR (KBr), ν/cm–1: 1160 (N—C(S)—N); 3370 (ОH); 1520
1
(NH2). H NMR (CDCl3), δ: 1.39 (s, 6 H, 2 Me); 2.16 (s, 3 H,
Me); 4.80 (s, 2 H, NH2).
2ꢀAminoꢀ5ꢀmethylꢀ1ꢀthiaꢀ3,4ꢀdiazaspiro[5.5]undecaꢀ2,4ꢀdiꢀ
ene (7) was synthesized similarly. Yield 1.53 g (78%), m.p. 169 °C
(from EtOH). Found (%): C, 50.16; H, 7.85; N, 19.48; S, 14.81.
C9H15N3S. Calculated (%): C, 50.23; H, 7.90; N, 19.53; S, 14.88.
IR (KBr), ν/cm–1: 1065, 1290 (C—C); 1440 (C—N); 1500
(N—N); 1600 (C=N); 740 (C—S); 2850 (О—C); 3185 (NH2).
1H NMR (CDCl3), δ: 1.62 (t, 3 H, Me); 0.95—2.30 (m, 10 H,
C(CH2)5); 4.75 (s, 2 H, NH2).
1ꢀBromoꢀ3ꢀmethylꢀ3ꢀnitrooxybutanꢀ2ꢀone (12). To a stirred
solution of compound 1 (10.2 g, 0.1 mol) in a mixture of Ac2O
(10.2 g, 0.1 mmol) and glacial AcOH (20 mL), a solution of 98%

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Pulatov et al.
HNO3 (6.5 g, 0.1 mol) in glacial AcOH (10 mL) was added dropꢀ
wise at –5 °C. The reaction mixture was stirred for 2 h with cooling,
treated dropwise with bromine (9.6 g, 0.06 mol), and stirred for 2 h.
Then the reaction mixture was heated at 60 °C (water bath) for 4 h,
cooled down, and poured into cold water (300 mL). Precipitated
heavy liquid was separated and subjected to vacuum distillation at 55
°C (20 Torr). Yield 9.9 g (73%, based on nitro ester 3), nD20 = 1.4500.
2ꢀAminoꢀ5ꢀ(1ꢀhydroxyꢀ1ꢀmethylethyl)ꢀ6Hꢀ1,3,4ꢀthiadiazine
(13a). To a stirred solution of 1ꢀbromoꢀ3ꢀhydroxyꢀ3ꢀmethylbuꢀ
tanꢀ2ꢀone (10) (3.62 g, 0.02 mol) in 96% EtOH (30 mL), a
solution of TSC (1.82 g, 0.02 mol) in aqueous EtOH (150 mL) was
added followed by addition of concentrated HBr (1 mL). The
mixture was heated for 2 h and concentrated to 1/4 of the initial
volume. The residue was neutralized with NH4OH. The precipitate
was recrystallized from EtOH (70 mL per 1 g of the compound)
with activated charcoal, washed with aqueous EtOH, and dried at
40—50 °C. Yield 2.45 g (70.8%), m.p. 125 °C (from EtOH). Found
(%): C, 41.55; H, 6.27; N, 24.20; S, 18.41. C6H11N3ОS. Calculated
(C—S); 3200 (NH2). 1H NMR (CDCl3), δ: 1.06 (s, 6 H, 2 Me);
4.46 (s, 2 H, CH2); 4.92 (s, 2 H, NH2).
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(%): C, 41.62; H, 6.35; N, 24.27; S, 18.49. IR (KBr), ν/cm–1
:
1059, 1284 (C—C); 1438 (C—N); 1508 (N—N); 1607 (C=N); 739
(C—S); 3200 (NH2), 3360 (ОH). 1H NMR (CDCl3), δ: 0.98 (s, 6 H,
2 Me); 4.42 (s, 2 H, CH2); 4.82 (s, 2 H, NH2); 6.30 (s, 1 H, ОH).
Thiadiazines 13b,c were synthesized similarly.
2ꢀAminoꢀ5ꢀ(1ꢀhydroxycyclohexyl)ꢀ6Hꢀ1,3,4ꢀthiadiazine
(13b). Yield 2.81 g (66%), m.p. 66 °C (from EtOH). Found (%):
C, 50.63; H, 6.96; N, 19.65; S, 14.95. C9H15N3ОS. Calculated (%):
C, 50.70; H, 7.04; N, 19.72; S, 15.02. IR (KBr), ν/cm–1: 1063,
1288 (C—C); 1441 (C—N); 1510 (N—N); 1610 (C=N); 740
(C—S); 3200 (NH2). 1H NMR (CDCl3), δ 0.94—2.26 (m, 10 H,
C(CH2)5); 4.40 (s, 2 H, CH2); 4.80 (s, 2 H, NH2); 6.34 (s, 1 H, ОH).
2ꢀAminoꢀ5ꢀ[1ꢀmethylꢀ1ꢀ(nitrooxy)ethyl]ꢀ6Hꢀ1,3,4ꢀthiadiazine
(13c). Yield 3.4 g (78%), m.p. 198—99 °C (from EtOH). Found (%):
C, 32.96; H, 4.51; N, 25.61; S, 14.62. C6H10N4О3S. Calculated
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1065, 1290 (C—C); 1443 (C—N); 1513 (N—N); 1611 (C=N); 741
:
Received August 4, 2015;
in revised form February 5, 2016