Synthesis and reactivity of 2-pyrrolidino-, 2-N-methylpiperazino-, 2-piperidino-, and 2-morpholino-1,3,4-thiadiazines

Article abstract of DOI:10.1002/jhet.2072

A variety of 2-pyrrolidino-, 2-N-methylpiperazino-, 2-piperidino-, and 2-morpholino-1,3,4-thiadiazines were prepared by cyclocondensation of phenacyl halides with thiosemicarbazides. Heating of the products resulted in desulfurization and formation of pyrazoles. The rate of this process strongly depends on the substitution pattern of the 1,3,4-thiadiazines.

Full text of DOI:10.1002/jhet.2072

Month 2014
Synthesis and Reactivity of 2-Pyrrolidino-, 2-N-Methylpiperazino-,
2-Piperidino-, and 2-Morpholino-1,3,4-thiadiazines
Stefanie Knak,a Wolf-Diethard Pfeiffer,a Horst Dollingerb and Peter Langerc,d
*
aInstitut für Biochemie, Universität Greifswald, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
bBoehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach/Riss, Germany
cInstitut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
dLeibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
*
E-mail: peter.langer@uni-rostock.de
Received March 7, 2013
DOI 10.1002/jhet.2072
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
R3
N
R3
R4
O
H2N
S
N
NH
+
R1
R1
R4
S
N
N
Br
R2
R2
A variety of 2-pyrrolidino-, 2-N-methylpiperazino-, 2-piperidino-, and 2-morpholino-1,3,4-thiadiazines
were prepared by cyclocondensation of phenacyl halides with thiosemicarbazides. Heating of the products
resulted in desulfurization and formation of pyrazoles. The rate of this process strongly depends on the
substitution pattern of the 1,3,4-thiadiazines.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
exclusively result in the formation of 1,3,4-thiadiazines,
because of the double substituted amino group [24]. In
our present study, we investigated the cyclization of novel
4,4-disubstituted thiosemicarbazides with α-haloketones.
In this context, we were interested in the influence of the
substitution pattern on the stability of the 1,3,4-
thiadiazines. As novel building blocks, we chose, for the
first time, pyrrolidino-thiocarbonyl-hydrazine (2a) and N-
methyl-piperazino-thiocarbonyl-hydrazine (2b). Pyrrolidino-
thiocarbonyl-hydrazine (2a) was prepared from S-
(pyrrolidino-thiocarbonyl)-thioglycolic acid and hydrazine
hydrate (100%) in an alkaline solution (heating for 1 h). S-
(Pyrrolidino-thiocarbonyl)-thioglycolic acid was prepared
from pyrrolidine and CS2 and subsequent alkylation with
chloroacetic acid. N-Methyl-piperazino-thiocarbonyl-hydra-
zine (2b) was prepared, in analogy to 2a, from S-(N-methyl-
piperazino-thiocarbonyl)-thioglycolic acid and hydrazine
hydrate. S-(N-Methyl-piperazino-thiocarbonyl)-thioglycolic
acid was prepared from N-methyl-piperazine, CS2, and
chloroacetic acid. Thiocarbonylhydrazines 2c,d were
previously mentioned in the literature, but without NMR-
spectroscopic data. We have prepared these compounds in
analogy to 2a,b and provide a comprehensive characterization
(Scheme 1).
1,3,4-Thiadiazines are of considerable biological and
pharmacological relevance. 1,3,4-Thiadiazine derivatives
have attracted considerable interest in medicinal chemistry
because of their high pharmacological activity and low
toxicity. Many 2-amino-1,3,4-thiadiazine derivatives have
been shown to act as matrix metalloproteinase inhibitors
[1,2]. 2-Alkylimino- and 2-alkyamino-1,3,4-thiadiazines
are used as cardiotonic and spasmolytic agents [3–8]. In
addition, it has been reported that 1,3,4-thiadiazin-2-ones
act as cardiotonic with calcium sensitizing activity [9–11].
3-Phenylazo-1H-4,2,1-thiadiazines are active against
deficient bone growth [12]. 3-Nitrobenzyl-5-aryl-1,3,4-
thiadiazin-2-ones
and
1,3,4-thiadiazin-2-ones
are
phosphodiesterase IV inhibitors that can be used for the
treatment of tumours and AIDS [13,14]. 2-Nitrosimino-3,6-
dihydro-2H-1,3,4-thiadiazines [15], N-morpholinyl-, N-
thiomorpholinyl-, and N-piperidinyl-1,3,4-thiadiazines [16]
exhibit antithrombotic activities. 2-(N-Methylpiperazino)-
1,3,4-thiadiazine dihydrobromides display antiarrhythmic
activity [17]. Some 1,3,4-thiadiazin-2-ones can be used for
the treatment of erectile dysfunction [18]. 1,3,4-Thiadiazines
may be used in agricultural chemistry as herbicides [19], fun-
gicides [20], insecticides [21], and plant-growth agents [22].
RESULTS AND DISCUSSION
The reaction of 2a–d with α-bromo- and α-
chloroacetophenones 1a–g proceeded already by gentle
heating of an EtOH solution of the starting materials to give
2-pyrrolidino-5-phenyl-6H-1,3,4-thiadiazines 3a–g, 2-(N-
Dependent on the reaction conditions and substitution
pattern, the cyclocondensation of α-haloketones with 4-
alkylthiosemicarbazides can result in the formation of
thiazolo-2-hydrazones, thiazolon-2-imides, or 1,3,4-
thiadiazines. The latter may undergo desulfurization to
give pyrazoles [23]. In contrast, the cyclocondensation of
4,4-dimethylthiosemicarbazides with α-haloketones can
methyl-piperazino)-5-phenyl-6H-1,3,4-thiadiazins
3h–m,
and the 2-piperidino- and 2-morpholino-5-(4-fluorophenyl)-
1,3,4-thiadiazines 3o,p in the form of their hydrochlorides
and hydrobromides. Analogous products, that is, 2-
© 2014 HeteroCorporation

S. Knak, W.-D. Pfeiffer, H. Dollinger, and P. Langer
Vol 000
solution of sodium ethanolate was added. After heating
for a short period of time and cooling, yellow crystals
precipitated, that is, 2-pyrrolidino-5,6-diphenyl-6H-1,3,4-
thiadiazine 4g and 2-(N-methyl-piperazino)-5,6-diphenyl-
6H-1,3,4-thiadiazine 4m. Treatment of an ethanol solution
of the free base 4m with ethanolic hydrochloric acid yielded
the hydrochloride 3n. It proved to be important to keep the
solution with a neutral pH during the addition of sodium
ethanolate in order to avoid that the products undergo a
base-mediated desulfurization and formation of pyrazoles.
This type of transformation has been previously noted for
several thiadiazines. In addition, the reaction time must be
short, because prolonged heating also resulted in the formation
of pyrazoles.
The reaction of 4a,b with 4-nitrobenzaldehyde (p-
NBA) afforded 6-(4-nitrobenzylidene)-1,3,4-thiadiazines
5a,b. The reactions proceeded by aldol-type
condensation of position 6 with the aldehyde. Analo-
gous reactions of 2-dimethylamino-, 2-piperidino-, and
2-morpholino-5-phenyl-6H-1,3,4-thiadiazines have been
previously reported [23,24]. The stability of products
5a,b is remarkable, as, under identical conditions,
2-amino- and 2-alkyl(aryl)amino-5-phenyl-6H-1,3,4-
thiadiazines are cleaved to give ω-(4-nitrobenzylidene)-
acetophenone-semicarbazones [25]. These semicarbazones
were hydrolyzed by hydrochloric acid to the corresponding
semicarbazides and ω-(4-nitrobenzylidene)-acetophenones
(Scheme 3).
dimethylamino-, 2-piperidino-, and 2-morpholino-5-
phenyl-6H-1,3,4-thiadiazines, have been previously
reported [23,24]. To avoid desulfurization, it proved to
be important to keep the reaction time short (5–10 min
). The hydrobromides and hydrochlorides were purified
by recrystallization from EtOH. The free bases 4a–f and
4h–l were obtained by addition of ammonia that was
isolated as highly viscous oil that became solid upon
standing (Scheme 2; Table 1).
The NMR-spectroscopic data confirm the structures of
1,3,4-thiadiazines 3a–p and 4a–m. The presence of the
6-CH2 signals confirms that the products reside in their
6H tautomeric form. The signals of the hydrogen halides
3a–m and 3o,p are observed in the range of 3.90 to
4.40 ppm (DMSO-d6). In case of the free bases 4a–f and
4h–m, the values are in the range of 3.47 and 3.59 ppm
(CDCl3). To study the influence of a phenyl group located
at position 6 on the stability of the 1,3,4-thiadiazine
system, we carried out the cyclocondensation of
2-bromo-1,2-diphenylethan-1-one 1h with pyrrolidino-
thiocarbonyl-hydrazine (2a) and 1-methyl-piperazino-
thiocarbonyl-hydrazine (2b). The starting materials were
stirred for 1 h in dry ethanol, and subsequently, an aq.
Scheme 1. Synthesis of thiocarbonylhydrazines (2a–d).
R1
S
CS2
R1
R2
Heating of 2-pyrrolidino-6H-1,3,4-thiadiazines 4a–c with
2-(N-methyl-piperazino)-6H-1,3,4-thiadiazine 4i in the pres-
ence of acetic anhydride resulted in the formation of 1-ace-
N
R2
N
H
K+
S-
KOH,
EtOH
tyl-3-pyrrolidino-4-acetylmercapto-5-aryl-pyrazoles
6a–c
Cl
CO2H
and of 1-acetyl-3-(N-methylpyrrolidino)-4-acetylmercapto-5-
(4-bromophenyl)-pyrazole 6d. Their formation can be
explained by ring transformation and acetylation. It has been
previously reported that related products were prepared by
reaction of acetic anhydride with 2-methylamino-, 2-
dimethylamino-, 2-piperidino-, and morpholino-5-phenyl-
6H-1,3,4-thiadiazines (Schemes 4 and 5) [23,24].
R1
S
R1
S
+ H2N-NH2
N
R2
N
R2
HN NH2
S
2a-d
COOH
An overview of the reactions carried out by heating in
conc. hydrochloric acid, dilute hydrochloric acid (2M),
and dilute aq. NaOH (2M) is given in Table 2. In contrast
to the reaction of 1-acetyl-3-acetylmethylamino-4-
acetylmercapto-5-phenyl-pyrazole with conc. HCl, the analo-
gous reactions of 1-acetyl-3-pyrrolidino-4-acetylmercapto-5-
phenyl-pyrazoles 6a–c afforded the sulfur-free 3-pyrrolidino-
5-phenyl-pyrazoles 7a–c. Disulfides were not formed. The
basic hydrolysis of diacetyl-pyrazoles 6a–c resulted in the
formation of dipyrazolyl-(4,4′)-disulfides 8a–c. Likewise,
heating of acylated 3-piperidino-, 3-morpholino-, and
3-dimethylamino-5-aryl-pyrazoles in a 2M aq. solution
of NaOH afforded disulfides B [23,24]. Disulfides B are
also obtained when 2-methylamino- and 2-phenylamino-
5-phenyl-1,3,4-thiadiazines were heated in toluene
(Tables 3–6) [23].
Scheme 2. Synthesis of 1,3,4-thiadiazines 3a–p, 4a–m: conditions: i,
reflux, EtOH; ii, aq. ammonia.
R3
N
R3
O
i
H2N
.
HX
N
NH
+
R1
R1
R4
S
N
-HX, -H2O
R4
Br
S
N
R2
R2
3a-p
1a-h
2a-d
ii
R3
R4
N
N
R1
S
N
R2
4a-m
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Thiadiazines
Table 1
Synthesis of hydrohalogenides of 1,3,4-thiadiazines 3a–p and free bases of 4a–m.
α-Haloketones
R1
R2
R3
R4
%a hydrobromide
%a free base
1a
1b
1c
1d
1e
1f
1g
1h
1a
1b
1c
1d
1f
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
C6H5
H
H
H
H
H
H
H
C6H5
H
H
H
H
H
H
C6H5
H
H
3a
3b
3c
3d
3e
3f
3 g
–
3h
3i
73
72
71
73
78
74
72
–
68
75
70
79
74
80
73 b
72
76
4a
4b
4c
4d
4e
–
4f
4g
4h
4i
4j
–
4 k
4 l
4 m
–
75
75
69
72
76
–
69
72
66
73
70
–
4-BrC6H4
4-ClC6H4
4-FC6H4
4-CH3C6H4
4-CH3OC6H4
4-NO2C6H4
C6H5
–(CH2)2–(NCH3)–(CH2)2–
–(CH2)2–(NCH3)–(CH2)2–
–(CH2)2–(NCH3)–(CH2)2–
–(CH2)2–(NCH3)–(CH2)2–
–(CH2)2–(NCH3)–(CH2)2–
–(CH2)2–(NCH3)–(CH2)2–
–(CH2)2–(NCH3)–(CH2)2–
–(CH2)5–
C6H5
4-BrC6H4
4-ClC6H4
4-FC6H4
4-(MeO)C6H4
4-(O2N)C6H4
C6H5
3j
3 k
3 l
3 m
3n
3o
3p
73
77
69
–
1g
1h
1d
1d
4-FC6H4
4-FC6H4
–(CH2)2–O–CH2)2–
–
–
aIsolated yields.
bIsolated in the form of its hydrochloride.
Scheme 3. Synthesis of 2-pyrrolidino-5-aryl-(4-nitrophenylbenzylidene)-
1,3,4-thiadiazines 5a,b.
Scheme 5. Hydrolysis of 1-acetyl-4-acetylmethylthio-5-aryl-pyrazoles
6a–d; conditions: i by 6a–c, ii by 6a–c.
pNBA
Ar
N
Ar
N
Ac
N
N
H
N
N
- H2O
(H+ resp OH- )
R
R
S
N
N
N
O2N
S
N
5a,b
4a,b
AcS
HS
N
N
6a-c
Scheme 4. Synthesis of 1-acetyl-4-acetylmethylthio-5-aryl-pyrazole 6a–d.
Ac
(H+)
R2
N
S
N
R2
(OH-)
ii
1/2 O2 -H2O
N
(CH3CO)2O
N
i
R1
-S
R1
-H2O
AcS
Ac
H
N
N
6a-d
4a-c, 4i
H
N
N
R
R
N
R
N
N
S
S
N
N
7a-c
8a-c
Hydrolysis of acylated 3-piperidino-, 3-morpholino-, and
3-dimethylamino-5-aryl-pyrazoles in 2M HCl afforded the
sulfur-free pyrazoles A in 62–64% yield. Disulfides B are
formed in 20–24% yields. The use of conc. HCl did not re-
sult in a considerable change of the ratio of A and B [23,24].
3-Methylamino-4-methylthio-5-phenyl-pyrazole, formed
by acidic hydrolysis of 3-methylamino-5-phenyl-pyrazole,
was less easily desulfurized. The use of 2M hydrochloric
acid afforded exclusively disulfides B. Employment of
conc. HCl gave a mixture of disulfides B (60%) and of
sulfur-free pyrazoles A (35%) [24].
7a, 8a: R = C6H5 7b, 8b: R = 4-BrC6H4 7c, 8c: R = 4-ClC6H4
Table 2
Synthesis of 5a,b.
Ar
Yield (%)a
5a
5b
C6H5
4-BrC6H4
73
71
Heating of 1,3,4-thiadiazines in glacial acetic acid also
resulted in desulfurization and formation of pyrazoles.
aIsolated yields.
Journal of Heterocyclic Chemistry
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S. Knak, W.-D. Pfeiffer, H. Dollinger, and P. Langer
Vol 000
Table 3
acetic acid resulted in the formation of 3-pyrrolidino-
and 2-N-methylpiperazino-5-aryl-pyrazoles 7a–f, 7h,i
and of 3-piperidino- and 3-morpholino-4-aryl-pyrazoles
9a,b, respectively. Treatment of an ethanol solution of
the free base of 7d,g, 9a,b with ethanolic hydrochloric
acid or hydrobromic acid (48%) yielded the hydrochlo-
rides and hydrobromides, respectively. A completely
different reaction was observed when 2-phenyl-, 2-benzyl-,
and 2-methylthio-5-aryl-1,3,4-thiadiazines were heated in
glacial acetic acid [23]. These compounds underwent a ring
contraction to give 4-mercapto-5-aryl-pyrazoles [23].
Prolonged heating in glacial acetic acid did not result in
desulfurization and formation of sulfur-free pyrazoles.
Heating of the mercapto-pyrazoles in ethanol for 10–24 h
resulted in the formation of disulfides. The reaction time
was decreased to 30min by addition of iodine (Scheme 6).
The stability of the 1,3,4-thiadiazines depends of the
substituents located at positions 2, 5, and 6. The substituent
located at position 6 has the highest influence on the rate of
desulfurization.
Synthesis of 6a–d.
R1
R2
Yield (%)a
64
6a
6b
C6H5
4-BrC6H4
69
6c
4-ClC6H4
4-BrC6H4
67
71
6d
aYields of isolated products.
Table 4
Synthesis of sulfur-free 5-phenyl-pyrazoles A and of disulfides B.
The cyclocondensation of ethyl 2-chloro-acetoacetate 1i
with
pyrrolidino-,
piperidino-,
and
morpholino-
thiocarbonylhydrazines 2a,c,d resulted in direct formation of
pyrazoles 10a–c via the corresponding 1,3,4-thiadiazines that
could not be isolated. Likewise, the reaction of morpholino-
thiocarbonyl-hydrazine with 2-chloro-acetylacetone 1j
(EtOH, gentle heating) resulted in cyclization and subse-
quent desulfurization to give 3-morpholino-4-acetyl-5-
methyl-pyrazole hydrochloride 10d (Scheme 7).
R
Conditions
Yield (%)a
In conclusion, we have reported the synthesis of a
variety of novel 1,3,4-thiadiazines. The presence of a
phenyl group located at position 5 has a stabilizing
effect on the 1,3,4-thiadiazine moiety. The presence of
an electron-withdrawing group located at position 6
and the presence of the twofold alkylated amino group
result in a destabilization of the 1,3,4-thiadiazine moiety
and desulfurization.
2N NaOH,15 min reflux
Conc. HCl, 1 h reflux
B (8a) 70
A (7a) 71
2N NaOH,15 min reflux
2N HCl, 30 min reflux
B 93 [23a]
A 62 [23a]
B 20 [23a]
2N NaOH,15 min reflux
2N HCl, 30 min reflux
B 92 [23a]
A 64 [23a]
B 24 [23a]
NMe2
2N NaOH,1 h reflux
2N HCl, 1 h reflux
B 96 [24]
A 64 [24]
EXPERIMENTAL
B 23 [24]
NHMe
2N HCl, 1 h reflux
B 91 [24]
A 35 [24]
General procedure for the synthesis of thiocarbonylhydrazines
2a–d. (a) Synthesis of thiocarbamoylthioacetic acids: A solution of
55 g (1 mole) of potassium hydroxide in 50 mL of water (for 2a: 40g
sodium hydroxide) and of 1 mole of the secondary amine in 150 mL
of ethanol was mixed with 76 g (1 mole) of carbon disulfide with ice
cooling, keeping the temperature below 20°C. After 1 h, a solution of
95 g (1 mole) of chloroacetic acid in 300 mL water, neutralized with
56 g of sodium carbonate, was added, and the mixture was kept for
about 12 h. The acid was isolated by addition of 70 mL of conc.
hydrochloric acid to the filtrate.
Conc. HCl, 1 h reflux
B 60 [24]
aIsolated yield of product A or B.
The rate of desulfurization was particularly high in case of 5,6-
diphenyl-6H-1,3,4-thiadiazines 4g and 4m. Although the iso-
lation of these compounds was possible, they were
rapidly transformed into pyrazoles 7g and 9c by heating in
glacial acetic acid, respectively. Heating of 6-unsubstituted
2-pyrrolidino- and 2-(N-methylpiperazino)-5-aryl-6H-1,3,4-
thiadiazines 3f and 4a–d, 4f,i,j and of 2-piperidino- and 2-
morpholino-5-aryl-1,3,4-thiadiazines 3o,p for 2 h in glacial
(b) Synthesis of thiocarbonylhydrazine:
A solution of
0.76 mole of thiocarbamoylthioacetic acid in 190 mL of 2M
sodium hydroxide (2b: 2M potassium hydroxide) and of 50 mL
of hydrazine hydrate was refluxed for 15 min. After cooling, the
thiocarbonyl hydrazide crystallized, and the precipitate was
filtered off.
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Thiadiazines
Table 5
3-Pyrrolidino- and 3-N-methylpiperazino-5-aryl-pyrazoles 7a–i and 9a–c.
R1
R2
R3
H
Starting material
%a hydrochloride
%a free base
73
7a
7b
7c
7d
7e
7f
C6H5
4a
–
4BrC6H5
4ClC6H5
4FC6H5
H
H
4b
4c
4d
3f
–
–
71
76
–
H
68b
–
4CH3OC6H5
4NO2C6H5
C6H5
H
69
73
71
73
71
H
4f
–
7g
7h
7i
C6H5
H
4g
3
71c
–
4FC6H5
4FC6H5
H
3p
–
9a
9b
9c
4BrC6H5
4ClC6H5
C6H5
H
H
4i
4j
72b
72b
–
–
–
C6H5
4m
68
aIsolated yields.
bAddition of ethanolic HCl.
cHydrobromide, addition of HBr (48%).
Pyrrolidino-thiocarbonyl-hydrazine (2a).
S-(Pyrrolidino-
Anal. Calcd. for C5H11N3S (145.23): C, 41.35; H, 7.63; N, 28.93.
thiocarbonyl)-thioglycolic acid: prepared from 71g (1mole) of
pyrrolidine in 150 mL of ethanol and 76 g (1mole) of carbon
disulfide. Yield: 81.68 g (74%), colourless needles (EtOH), mp
180°C. Pyrrolidino-thiocarbonyl-hydrazine: 156 g (0.76 mole) S-
(pyrrolidino-thiocarbonyl)-thioglycol acid in 190 mL of 2M
sodium hydroxide solution and 50mL of hydrazine hydrate was
refluxed for 1 h; ir (KBr, cmÀ1): 3201 (m), 3161 (m), 3137 (m),
2968 (m), 2949 (m), 2875 (m), 1557 (s), 1431 (s), 1368 (s), 1354
Found: C, 41.34; H, 7.61; N, 28.91.
N-Methyl-piperazino-thiocarbonyl-hydrazine (2b). Synthesis
of N-(Methyl-piperazino-thiocarbonyl)-thioglycolic acid: prepared
from 99.7g (1mole) of N-methyl-piperazine and 76g (1mole) of
carbon disulfide. N-(Methyl-piperazino-thiocarbonyl)-thioglycolic
acid was not isolated. The solution of N-(methyl-piperazino-
thiocarbonyl)-thioglycolic acid was neutralized with HCl and then
refluxed with 60mL of hydrazine hydrate for 1 h. The reaction
yielded the N-methyl-piperazino-thiocarbonyl-hydrazine (2b).
Yield: 123.73 g (71%), colourless lamella (EtOH), mp 139°C; ir
(KBr, cmÀ1): 3250 (m), 3214 (m), 3131 (m), 2929 (m), 1557 (m),
1428 (m), 1365 (m), 1298 (m), 1255 (m), 1222 (m), 1146 (m),
1
(m), 1289 (m); H nmr (DMSO-d6, 300MHz): δ = 1.88 (s, 2H,
NH2), 3.78–3.41 (m, 8H, H-pyrrolidine), 8.54 (s, 1H, NH); 13C
nmr (DMSO-d6, 75MHz): δ = 24.94 (CH2), 49.62 (CH2), 179.76
(C=S); ms (EI, 70eV): m/z (%)= 28 (32), 41 (34), 55 (75), 73
(100), 86 (5), 97 (3), 102 (3), 113 (61), 128 (44), 145 (M+, 77).
1
1002 (m); H nmr (DMSO-d6, 300 MHz): δ = 2.32 (s, 3H, Me),
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1
Table 6
(m), 1428 (m), 1363 (m), 1252 (m), 1219 (m), 1001 (m); H nmr
(CDCl3, 300 MHz): δ =1.59–1.75 (m, 6H, 3xCH2), 3.54–3.60 (t,
4H, 2xN-CH2), 4.90 (s, br, 2H, NH2), 9.21 (s, 1H, NH); ms (El,
70 eV): m/z (%) = 28 (53), 41 (81), 56 (54), 70 (61), 84 (100), 96
(8), 113 (6), 128 (49), 142 (32), 159 (M+, 71). Anal. Calcd. for
C6H13N3S (159.25): C, 45.25; H, 8.23; N, 26.39. Found: C, 45.25;
H, 8.24; N, 26.39.
Synthesis of 3-pyrrolidino-, 3-piperidino-, and
3-morpholino-4-ethoxycarbonyl- resp. 4-acetyl-pyrazoles 10a–d.
R1
R2
mp (°C)
122
Yield (%)
76
10a
10b
10c
10d
C2H5OCO
Morpholino-thiocarbonyl-hydrazine (2d).
S-(Morpholino-
thiocarbonyl)-thioglycolic acid: prepared from 87g (1mole) of
morpholine, 68g (0.76mole), and 76g (1mole) of carbon
disulfide. Morpholino-thiocarbonyl-hydrazine: prepared from S-
(morpholino-thiocarbonyl)-thioglycolic acid in 190mL of 2M
sodium hydroxide solution and 50mL of hydrazine hydrate
(reflux, 15min). Yield: 109.06 g (89%), colourless needles (H2O),
mp 176°C; ir (KBr, cmÀ1): 3263 (s), 3217 (s), 3139 (s), 3038 (m),
2894 (m), 2865 (m), 1548 (s), 1423 (s), 1384 (s), 1359 (s), 1299
(m), 1278 (s), 1228 (s), 1205 (s), 1122 (s), 1049 (m), 1016 (m);
1H nmr (DMSO-d6, 300 MHz): δ = 3.55–3.58 (m, 4H, 2xCH2),
3.68–3.70 (m, 4H, 2xCH2), 4.81 (s, 2H, NH2), 9.12 (s, br, 1H,
NH); ms (El, 70eV): m/z (%) = 28 (31), 45 (16), 61 (25), 73 (7),
86 (100), 117 (2), 130 (47), 144 (18), 161 (M+, 82). Anal. Calcd.
for C5H11N3OS (161.23): C, 37.25; H, 6.88; N, 26.06. Found: C,
C2H5OCO
C2H5OCO
CH3CO
159
139
116
77
74
73
aIsolated yields.
37.22; H, 6.86; N, 26.01.
Scheme 6. Synthesis of 3-pyrrolidino- and 3-(N-metylpiperazino)-5-aryl-
pyrazoles 7a-i, 9a–c.
General procedure for the synthesis of 3a–m, 3o,p and 4a–f,
4h–l. An ethanol solution (15 mL) of 10 mmol of 1a–d and of
10mmol of phenacylbromides or phenacylchlorides was refluxed
for 10 min. The hot solution was filtered, and the filtrate was
cooled and slowly added to ether (400mL) with stirring and
scratching the glass surface. A precipitate formed. In some cases,
the precipitate already formed when the reaction mixture was
cooled. The solid was filtered off, washed with ether/EtOH (9:1)
and recrystallized. Free bases: To an EtOH solution of the
hydrobromide was added a dilute aqueous solution of ammonia
until pH= 8 was reached. A precipitate formed that was filtered
H
CH3COOH
R2
N
N
R2
R3
N
N
-S
R3
S
R1
R1
7a-i
9a-c
3f,o,p 4a-d,f,g,i,j,m
off and recrystallized from EtOH.
Scheme 7. Synthesis of 3-pyrrolidino-, 3-piperidino-, and 3-morpholino-
5-aryl-pyrazoles 10a–d.
2-Pyrrolidino-5-phenyl-6H-1,3,4-thiadiazine. Hydrobromide
3a: prepared from 1.45 g (10 mmol) of 2a and 1.99 g (10 mmol) of
phenacylbromide 1a. Yield: 2.38 g (73%), colourless prisms
(EtOH), mp.: 218°C; ir (KBr, cmÀ1): 3406 (m), 2979 (m), 2877
(m), 2826 (m), 1614 (m), 1586 (s), 1449 (m), 1316 (m), 776 (m),
694 (m); 1H nmr (DMSO-d6, 300 MHz): δ = 2.04 (m, 4H,
2xCH2), 3.71–3.75 (t, 4H, 2xN-CH2), 4.36 (s, 2H, 6-CH2,
thiadiazine), 7.54–7.96 (m, 5H, ArH); 13C nmr (DMSO-d6,
75MHz): δ = 22.30 (6-CH2, thiadiazine) 24.79 (CH2), 53.1 (CH2),
124 (ArH), 126.40 (ArH), 139.40 (Ar), 148.46 (Ar), 149.0 (5-C,
thiadiazine), 158 (2-C, thiadiazine); ms (EI, 70eV): m/z (%) = 28
(14), 55 (24), 73 (51), 113 (100), 116 (2), 147 (1), 216 (6), 245
(M+, 58). Anal. Calcd. for C13H16BrN3S (326,26): C, 47.86; H,
4.94; N, 12.88. Found: C, 47.75; H, 4.76; N, 12.73. Free base 4a:
Yield: 1.84g (75%), yellow prisms (EtOH), mp 112°C; ir (KBr,
cmÀ1): 2970 (m), 2871 (m), 1509 (s), 1483 (s), 1473 (m), 1459
(s), 1449 (m), 1396 (m), 1368 (m), 1362 (m), 1323 (m), 1190 (m),
EtOH, reflux
Me
R2
N
S
H2N
Me
R2
O
N
NH
+
-HCl, -H2O
R1
S
R1
Cl
2a,c,d
1i,j
H
N
Me
N
R2
R1
10a-d
2.44–2.47 (t, 4H, 2xN-CH2), 3.80–3.83 (t, 4H, 2xN-CH2), 7.28 (s,
1H, NH); ms (El, 70eV): m/z (%) = 42 (75), 59 (38), 71 (89), 99
(9), 128 (10), 143 (24), 174 (M+, 100), 192 (4). Anal. Calcd. for
C6H14N4S (174.27): C, 41.35; H, 8.10; N, 32.15. Found: C,
41.39; H, 8.12; N, 32.10.
1
914 (m), 761 (m), 697 (m), 588 (m); H nmr (CDCl3, 300MHz):
δ = 1.96–2.01 (m, 4H, 2xCH2), 3.56–3.68 (s, 2H, 6-CH2,
thiadiazine), 3.64–3.68 (t, 4H, 2xN-CH2), 7.38–7.91 (m, 5H,
ArH); 13C nmr (CDCl3, 75MHz): δ = 21.60 (6-CH2, thiadiazine)
24.93 (CH2), 48.08 (CH2), 126.31 (ArH), 128.48 (ArH), 129.15
(Ar), 136.10 (Ar), 145.26 (5-C, thiadiazine), 148.42 (2-C,
thiadiazine); ms (EI, 70eV): m/z (%) = 28 (9), 55 (32), 731 (47),
113 (100), 115 (5), 146 (3), 184 (1), 185 (1), 216 (7), 245 (M+,
41). Anal. Calcd. for C13H15N3S (245, 34): C, 63.64; H, 6.16; N,
17.13. Found: C, 63.43; H, 5.81; N, 16.94.
Piperidino-thiocarbonyl-hydrazine
(2c).
S-(Piperidino-
thiocarbonyl)-thioglycolic acid: prepared from 87 g (1 mole) of
piperidine and 76 g (1 mole) of carbon disulfide. Piperidino-
thiocarbonyl-hydrazine: prepared from 166 g (0.76 mole) of S-
(piperidino-thiocarbonyl)-thioglycolic acid in 190 mL of 2M
sodium hydroxide solution and 50 mL of hydrazine hydrate. Yield:
95.61 g (79%), colourless lamella (EtOH), mp 94°C; ir (KBr,
cmÀ1): 3199 (m), 3165 (m), 2931 (m), 2853 (m), 1550 (m), 1512
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Thiadiazines
2-Pyrrolidino-5-(4-bromophenyl)-6H-1,3,4-thiadiazine.
Hydrobromide 3b: prepared from 1.45g (10 mmol) of 2a and
2.78 g (10mmol) of 4-bromo-phenacylbromide 1b. Yield: 2.92 g
(72%), yellow prisms (EtOH), mp 129°C; ir (KBr, cmÀ1): 3093
(m), 3050 (m), 2972 (m), 2843 (m), 1619 (m), 1584 (s), 1448 (m),
1412 (m), 1317 (m), 852 (m), 811 (m); 1H nmr (DMSO-d6,
300 MHz): δ = 2.04 (m, 4H, 2xCH2), 3.41–3.45 (t, 4H, 2xN-CH2),
4.31 (s, 2H, 6-CH2, thiadiazine), 7.64–7.88 (m, 4H, ArH), 13.00
(s, 1H, NH+); 13C nmr (DMSO-d6, 75MHz): δ = 27.18, 125.34
(ArH), 129.12 (ArH), 132.38 (Ar), 149.37 (5-C, thiadiazine),
158.84 (2-C, thiadiazine); ms (El, 70eV): m/z (%) = 28 (49), 73
(39), 102 (15), 113 (100), 141 (2), 183 (2), 279 (4), 323/325 (M+,
10/10). Anal. Calcd. for C13H15Br2N3S (405.15): C, 38.54 H, 3.73
N, 10.37. Found: C, 38.87, H, 3.98 N, 10.27. Free base 4b:
Yield: 2.43g (75%), yellow prisms (EtOH), mp 157°C; ir (KBr,
cmÀ1): 2968 (m), 2868 (m), 1586 (m), 1531 (m), 1502 (s), 1482
(s), 1457 (m), 1409 (m), 1368 (m), 1330 (m), 1069 (m), 1002 (m),
2872 (m), 1597 (m), 1505 (s), 1484 (5), 1458 (s), 1371 (m),
1319 (m), 1222 (m), 1170 (m), 1156 (m), 918 (m), 841 (m), 572
(m); H nmr (CDCl3, 300 MHz): δ = 1.96–2.00 (m, 4H, 2xCH2),
1
3.53 (s, 2H, 6-CH2, thiadiazine), 3.63–3.68 (t, 4H, 2xN-CH2),
7.07–7.89 (m, 4H, ArH); 13C nmr (CDCl3, 50MHz): δ = 21.58
(6-CH2, thiadiazine), 24.92 (2xCH2), 48.16 (2xCH2), 115.75
(d, J(C,F) = 21.2, ArH), 128.24 (d, J(C,F) = 8.1, ArH), 132.26
(d, J(C,F) = 3.3, Ar), 148.51 (5-C, thiadiazine), 160.898(d, J(C,
F) = 247.3, Ar), 165.85 (2-C, thiadiazine); ms (El, 70 eV): m/z
(%) = 41 (1), 55 (14), 73 (29), 113 (100), 121 (16), 141 (4),
165 (2), 203 (3), 230 (6), 231 (9), 263 (M+, 17). Anal. Calcd.
for C13H14FN3S (263.33): C, 59.29; H, 5.36; N, 15.96. Found:
C, 59.12; H, 5.32; N, 15.91.
2-Pyrrolidino-5-(4-tolyl)-6H-1,3,4-thiadiazine. Hydrochloride
3e: prepared from 1.45 g (10 mmol) 2a and 2.13 g (10 mmol) of
4-methyl-phenacylbromide 1e. Yield: 2.3 g (78%), yellow
prisms (EtOH), mp 175°C; ir (KBr, cmÀ1): 3036 (m), 2969 (s),
2875 (m), 2813 (s), 1584 (s), 1447 (m), 1413 (m), 1324 (m),
1183 (m), 1153 (m), 915 (m), 807 (m), 742 (m); 1H nmr
(DMSO-d6, 300 MHz): δ = 2.04 (s, 3H, Me), 2.46–2.52 (m, 4H,
2xCH2), 3.70–3.74 (t, 4H, 2xN-CH2), 4.31 (s, 2H, 6-CH2,
thiadiazine) 7.36–7.84 (m, 4H, ArH), 12.92 (s, 1H, NH+);
ms (El, 70 eV): m/z (%) = 36 (53), 55 (22), 73 (42), 113
(100), 117 (16), 161 (4), 162 (1), 230 (6), 259 (M+, 72).
Anal. Calcd. for C14H18Cl N3S (295,83): C, 56.84; H, 6.13;
N, 14.20. Found: C, 52.43; H, 5.62; N, 10.84. Free base
4e: Yield: 1.97 g (76%), yellow prisms (EtOH), mp. 142°C;
ir (KBr, cmÀ1): 3030 (m), 2966 (m), 2921 (m), 2874 (m),
1503 (s), 1474 (s), 1455 (s), 1416 (m), 1366 (s), 1322 (s),
1226 (m), 1193 (m), 913 (m), 815 (m), 574 (m); 1H nmr
(CDCl3, 300 MHz): δ = 1.95–1.99 (m, 4H, 2xCH2), 2.38 (s,
3H, Me), 3.53 (s, 2H, 6-CH2, thiadiazine), 3.60–3.67 (t, 4H,
2xN-CH2), 7.77–7.80 (m, 4H, ArH); 13C nmr (DMSO-d6,
50 MHz) δ = 21.22 (Me), 21.58 (6-CH2, thiadiazine), 24.92
(2xCH2), 48.05 (2xCH2), 126.22 (ArH), 129.19 (ArH),
133.21 (Ar), 139.27 (Ar), 145.29 (5-C, thiadiazine), 148.37
(2-C, thiadiazine); ms (El, 70 eV): m/z (%) = 28 (42), 55
(25), 73 (41), 113 (100), 117 (15), 161 (3), 230 (5), 259
(M+, 79). Anal. Calcd. for C14H17N3S (259.37): C, 64.83;
H, 6.61; N, 16.20. Found: C, 64.53; H, 6.59; N, 16.18.
2-Pyrrolidino-5-(4-methoxyphenyl)-6H-1,3,4-thiadiazine.
Hydrochloride 3f: prepared from 1.45g (10 mmol) of 2a and
2.29g (10 mmol) of p-methoxy-phenacylbromide 1f. Yield:
2.30g (74%), yellow prisms (EtOH), mp 171°C; ir (KBr, cmÀ1):
3419 (m), 2978 (m), 2836 (m), 1603 (s), 1582 (s), 1514 (m),
1460 (m), 1447 (m), 1424 (m), 1315 (s), 1255 (s), 1181 (m),
1009 (m), 847 (m), 587 (m); 1H nmr (DMSO-d6, 300MHz):
δ = 2.03 (m, 4H, 2xCH2), 3.73 (t, 4H, 2xN-CH2), 3.85 (s, 3H,
MeO), 4.29 (s, 2H, 6-CH2, thiadiazine), 7.10–7.91 (m, 4H, ArH),
13.12 (s, 1H, NH+); 13C nmr (DMSO-d6, 50 MHz): δ = 22.16
(6-CH2, thiadiazine), 24.61 (2xCH2), 51.19 (2xCH2), 114.39
(ArH), 125.07 (Ar), 128.67 (ArH), 150.21 (5-C, thiadiazine), 158.58
(2-C, thiadiazine), 161.74 (OAr); ms (El, 70eV): m/z (%) = 28
(7), 55 (23), 73 (47), 113 (100), 133 (49), 177 (4), 215 (1), 243
(6), 275 (M+, 57). Anal. Calcd. for C14H18ClN3OS (311,83): C,
53.92; H, 5.82; N, 13.48. Found: C, 53.79; H, 5.81; N, 13.47.
2-Pyrrolidino-5-(4-nitrophenyl)-6H-1,3,4-thiadiazine.
Hydrobromide 3g: prepared from 1.45 g (10 mmol) of 2a and
2.44 g (10 mmol) of p-nitro-phenacylbromide 1g. Yield: 2.67g
(72%), yellow prisms (EtOH), mp 211°C; ir (KBr, cmÀ1): 2974
(m), 2822 (m), 1620 (m), 1598 (m), 1575 (s), 1521 (s), 1449
(m), 1415 (m), 1348 (s), 1313 (m), 860 (m), 751 (m); 1H nmr
1
915 (m), 943 (m); H nmr (CDCl3, 300 MHz): δ = 1.96–2.00 (m,
4H, 2xCH2), 3.52 (s, 2H, 6-CH2), 3.63–3.68 (t, 4H, 2xN-CH2),
7.52–7.77 (m, 4H, ArH); ms (El, 70eV): m/z (%) = 28 (23), 55
(46), 102 (21), 113 (100), 142 (2), 183 (7), 293 (1), 323/325 (M+,
15/16). Anal. Calcd. for C13H14BrN3S (324,24): C, 48.16; H,
4.35; N, 12.96. Found: C, 48.42; H, 4.56; N, 13.06.
2-Pyrrolidino-5-(4-chlorophenyl)-6H-1,3,4-thiadiazine.
Hydrobromide 3c: prepared from 1.45g (10 mmol) 2a and 1.89 g
(10 mmol) of 4-chloro-phenacylbromide 1c. Yield: 2.56g (71%),
yellow prisms (EtOH), mp 223°C; ir (KBr, cmÀ1): 3050 (m),
2973 (m), 2841 (m), 1620 (m), 1584 (s), 1449 (m), 1413 (m),
1317 (m), 1093 (m), 854 (m), 815 (m), 707 (m); 1H nmr
(DMSO-d6, 300MHz): δ = 2.04 (m, 4H, 2xCH2), 3.70–3.74 (t,
4H, 2xN-CH2), 4.31 (s, 2H, 6-CH2, thiadiazine), 7.64–7.95 (m,
4H, ArH), 13.02 (s, 1H, NH+); ms (El, 70eV): m/z (%)= 41 (24),
55 (32), 73 (47), 113 (100), 137 (8), 148 (5), 193 (1), 250 (3),
279 (M+, 28). Anal. Calcd. for C13H15BrClN3S (360.70): C,
43.29 H, 4.19 N, 11.65. Found: C, 43.53 H,4.29,N, 11.63. Free
base 4c: Yield: 1.93 g (69%), yellow prisms (EtOH), mp 139°C;
ir (KBr, cmÀ1): 2967 (m), 2874 (m), 1536 (m), 1507 (s), 1473
(s), 1454 (s), 1412 (m), 1366 (s), 1325 (m), 1218 (m), 1191 (m),
1089 (m), 915 (m), 836 (m), 812 (m); 1H nmr (CDCl3,
300 MHz): δ = 1.96–2.01 (m, 4H, 2xCH2), 3.52 (s, 2H, 6-CH2,
thiadiazine), 3.63–3.68 (t, 4H, 2xN-CH2), 7.37–7.84 (m, 4H,
ArH); 13C nmr (CDCl3, 75MHz): δ = 21.48 (6-CH2, thiadiazine)
25.01 (CH2), 48.21 (CH2), 127.59 (ArH), 134.66 (ArH), 135.66
(Ar), 144.19 (5-C, thiadiazine), 148.51 (2-C, thiadiazine); ms (El,
70er): m/z (%) = 28 (7), 55 (26), 73 (48), 113 (100), 137 (9), 139
(3), 181 (1), 250 (3), 279 (M+, 26). Anal. Calcd. for
C13H14ClN3S (279.79): C, 55.81; H, 5.04; N, 15.02. Found: C,
55.92; H, 5.03; N, 14.97.
2-Pyrrolidino-5-(4-fluorophenyl)-6H-1,3,4-thiadiazine.
Hydrobromide 3d: prepared from 1.45 g (10 mmol) of 2a and
2.17 g (10mmol) of 4-fluoro-phenacylbromide 1d. Yield: 2.51 g
(73%), yellow prisms (EtOH), mp 224°C; ir (RBr, cmÀ1): 3038
(m), 2978 (m), 2833 (m), 1621 (m), 1595 (s), 1513 (m), 1449
(m), 1416 (m), 1320 (m), 1232 (m), 1158 (m), 854 (m), 812 (m),
735 (m), 577 (m); 1H nmr (DMSO-d6, 300MHz): δ = 2.04 (m,
4H, 2xCH2), 3.38–3.45 (t, 4H, 2xN-CH2), 4.30 (s, 2H, 6-CH2,
thiadiazine), 7.39–8.00 (m, 4H, ArH), 12.93 (s, 1H, NH+); ms
(El, 70eV): m/z (%) = 51 (6), 76 (13), 102 (35), 137 (17), 160
(21), 187 (51), 290 (3), 325 (M+, 100). Anal. Calcd. for
C15H15BrFN3S (344.25): C, 45.36; H, 4.39; N, 12.21. Found: C,
45.29; H, 4.37; N, 12.20. Free base 4d: Yield: 1.89 g (72%),
colourless prisms (EtOH), mp 214°C. IR (KBr, cmÀ1): 2986 (m),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Knak, W.-D. Pfeiffer, H. Dollinger, and P. Langer
Vol 000
1
(DMSO-d6, 300 MHz): δ = 2.05 (m, 4H, 2xCH2), 3.39–3.75
(t, 4H, 2xN-CH2), 4.39 (s, 2H, 6-CH2, thiadiazine), 8.15–8.42 (m,
4H, ArH), 13.1 (s, 1H, NH+); 13C nmr (DMSO-d6, 50MHz):
δ = 22.19 (6-CH2, thiadiazine) 24.34 (CH2), 51.22 (CH2), 123.99
(ArH), 127.97 (ArH), 138.90 (Ar), 148.10 (Ar), 148.56 (5-C,
thiadiazine), 158.29 (2-C, thiadiazine); ms (El, 70eV): m/z
(%) = 28 (43), 55 (24), 73 (48), 113 (100), 118 (3), 141 (1), 191
(4), 260 (4), 290 (M+, 31). Anal. Calcd. for C13H15BrN4O2S
(371,25): C, 42.06; H, 4.07; N, 15.09. Found: C, 42.99; H, 4.27;
N, 14.67. Free base 4f: Yield: 2,0 g (69%), yellow prisms
(EtOH), mp 164°C; ir (KBr, cmÀ1): 1598 (m), 1497 (s), 1456 (s),
1410 (m), 1367 (m), 1340 (s), 1319 (m), 1222 (m), 1191 (m), 917
(m), 699 (m); H nmr (CDCl3, 300 MHz): δ = 2.34 (s, 3H, Me),
2.48–2.52 (t, 4H, 2xN-CH2), 3.56 (s, 2H, 6-CH2), 3.79–3.82 (t,
4H, 2xN-CH2), 7.41–7.91 (m, 5H, ArH); ms (El, 70 eV): m/z
(%) = 42 (20), 59 (6), 71 (23), 104 (4), 143 (2), 172 (6), 204
(27), 217 (29), 242 (18), 274 (M+, 100). Anal. Calcd. for
C14H18N4 S (274,39): C, 61.28; H, 6.61; N, 20.42. Found: C,
61.30; H, 6.60; N, 20.45.
2-(N-Methyl-piperazino)-5-(4-bromophenyl)-6H-1,3,4-
thiadiazine.
Hydrobromide 3i: prepared from 1.74 g
(10 mmol) of 2b and 1.99 g (10 mmol) of 4-bromo-
phenacylbromide 1b. Yield: 3.26 g (75%), yellow prisms (EtOH),
mp 131°C; ir (KBr, cmÀ1): 2938 (m), 2797 (m), 1586 (m), 1493
(m), 1447 (m), 1372 (m), 1290 (m), 1248 (m), 1229 (m), 1144 (m),
1
(m), 857 (m); H nmr (CDCl3, 300MHz): δ = 1.99–2.03 (m. 4H,
1
2xCH2), 3.59 (s, 2H, 6-CH2, thiadiazine), 3.65–3.69 (t, 4H,
2xN-CH2), 8.02–8.24 (m, 4H, ArH); 13C nmr(CDCl3, 50 MHz):
δ = 21.10 (6-CH2, thiadiazine), 24.88 (2xCH2), 48.31 (2xCH2),
123.75 (ArH), 126.75 (ArH), 142.14 (Ar), 142.74 (Ar), 147.70
(5-C, thiadiazine), 148.72 (2-C, thiadiazine); ms (El, 70 eV):
m/z (%) = 28 (71), 55 (49), 73 (62), 113 (100), 115 (8), 141 (4),
183 (5), 185 (4), 261 (2), 290 (M+, 17). Anal. Calcd. for
C13H14N4O2S (290.34): C, 53.78; H, 4.86; N, 19.30. Found: C,
53.71; H, 4.85; N, 19.32.
1071 (m), 1005 (m); H nmr (DMSO-d6, 300 MHz): δ = 2.82 (s,
3H, Me), 3.43–3.45 (m, 8H, 4xN-CH2), 3.90 (s, 2H, 6-CH2), 7.69–
7.91 (m, 4H, ArH), 10.63 (s, 1H, NH+); ms (El, 70 eV): m/z
(%) = 28 (51), 42 (46), 71 (100), 113 (19), 143 (9), 183 (9), 185 (2),
250 (4), 295 (8), 320 (4), 353(M+, 8). Anal. Calcd. for
C14H18Br2N4S (434.19): C, 38.73 H, 4.18 N, 12.90. Found: C,
38.59 H, 4.17 N, 12.87. Free base 4i: Yield: 2.58 g (73%), yellow
prisms (CHCl3, precipitated with petroleum ether), mp 142°C. IR
(KBr, cmÀ1): 2938 (m), 2846 (m), 2796 (m), 1586 (m), 1493
(s), 1447 (m), 1408 (m), 1372 (m), 1351 (m), 1290 (m), 1249
2-Pyrrolidino-5,6-diphenyl-6H-1,3,4-thiadiazine. Free base
4g: 1.45 g (10mmol) of 2a and 2.75 g (10mmol) of 2-bromo-1,2-
diphenyl- ethan-1-one 1h in ethanol were stirred at 20°C for 1 h.
A sodium ethanolate solution (0.23g; 10mmol sodium and 10mL
of ethanol) was added. The solution was refluxed for 5 min. After
cooling, the mixture was poured into ice water. Scratching of the
flask resulted in crystallization of the products. Yield: 2.31 g
(72%), yellow prisms (EtOH), mp 159°C; ir (KBr, cmÀ1): 2970
(m), 2950 (m), 1501 (s), 1477 (s), 1457 (m), 1367 (m), 1320 (m),
1
(m), 1229 (m), 1144 (m), 1071 (m), 1004 (m); H nmr (CDCl3,
300 MHz): δ = 2.33 (s, 3H, Me), 2.47–2.50 (t, 4H, 2xN-CH2),
3.52 (s, 2H, 6-CH2, thiadiazine), 3.78–2.81 (t, 4H, 2xN-CH2),
7.53–7.78 (m, 4H, ArH); 13C nmr (CDCl3, 50MHz): δ = 22.21
(6-CH2, thiadiazine), 46.01 (Me), 47.22 (CH2), 54.60 (CH2),
123.97 (Ar), 128.01 (ArH), 131.77 (ArH), 134.47 (Ar), 146.12
(5-C, thiadiazine), 151.56 (2-C, thiadiazine); ms (El, 70 eV): m/z
(%) = 28 (34), 42 (37), 71 (100), 102 (20), 143 (10), 183 (3),
295 (9), 353 (M+, 5). Anal. Calcd. for C14H17BrN4S (353.28):
C, 47.60; H, 4.85; N, 1586. Found: C, 47.57; H, 4.82; N, 15.87.
2-(N-Methyl-piperazino)-5-(4-chlorophenyl)-6H-1,3,4-
1
1191 (m), 918 (m), 764 (m), 725 (m), 694 (m), 600 (m); H nmr
(CDCl3, 300MHz): δ = 1.87–1.94 (m, 4H, 2xCH2), 3.60–3.65 (t,
4H, 2xN-CH2), 5.17 (s, 1H, 6-CH, thiadiazine), 8.02–8.24 (m,
10H, 2xArH); 13C NMR (CDCl3, 50MHz) δ = 24.75 (2xCH2),
37.86 (6-CH2, thiadiazine), 47.73 (2xCH2), 126.14 (ArH), 127.46
(ArH), 127.90 (ArH), 128.46 (ArH), 128.75 (ArH), 129.09 (ArH)
136.67 (Ar), 137.18 (Ar), 144.64 (5-C, thiadiazine), 145.45 (2-C,
thiadiazine); ms (El, 70 eV): m/z = 28 (40), 73 (39), 105 (3), 113
(100), 151 (2), 178 (20), 191 (3), 223 (15), 260 (8), 289 (41), 321
(M+, 27), 329 (1). Anal. Calcd. for C19H19N3S (321.44): C, 70.99;
H, 5.96; N, 13.07. Found: C, 70.89; H, 5.94; N, 12.98.
thiadiazine.
Hydrobromide 3j: prepared from 1.74 g
(10 mmol) of 2b and 2.34 g (10 mmol) of 4-chloro-
phenacylbromide 1c. Yield: 2.73g (70%), yellow prisms (EtOH),
mp 184°C; ir (KBr, cmÀ1): 2937 (m), 2799 (m), 1489 (s), 1446
(m), 1352 (m), 1291 (m), 1251 (m), 1145 (m), 1006 (m); 1H nmr
(DMSO-d6, 300 MHz): δ = 2.84 (s, 3H, Me), 3.40–3.47 (t, 4H,
2xN-CH2), 3.80 (t, 4H, 2xN-CH2), 4.41 (s, 2H, 6-CH2,
thiadiazine), 7.44–7.98 (m, 4H, ArH), 9.97 (s, 1H, NH+); 13C nmr
(DMSO-d6, 50MHz): δ = 21.50 (6-CH2, thiadiazine), 42.08 (Me),
43.99 (CH2), 51.71 (CH2), 128.38 (ArH), 128.61 (ArH), 134 (Ar),
134.43 (Ar), 147.25 (5-C, thiadiazine), 151.14 (2-C, thiadiazine);
ms (El, 70eV): m/z (%) = 28 (45), 71 (100), 83 (42), 113 (29),
143 (10), 206 (2), 216 (11), 251 (15), 276 (2), 308 (M+, 14).
Anal. Calcd. for C14H18BrClN4S (389.74): C, 43.14; H, 4.66; N,
14.38. Found: C, 43.09; H, 4.63; N, 14.37. Free base 4j: Yield:
2.16g (70%), yellow prisms (EtOH), mp 142°C; ir (KBr,
cmÀ1): 2937 (m), 2797 (m), 1491 (s), 1447 (m), 1374 (m),
1352 (m), 1291 (m), 1250 (m), 1230 (m), 1145 (m), 1005
(m); 1H nmr (CDCl3, 300 MHz): δ = 2.29 (s, 3H, Me), 2.43–
2.46 (t, 4H, 2xN-CH2), 3.47 (s, 2H, 6-CH2, thiadiazine),
3.73–3.77 (t, 4H, 2xN-CH2), 7.33–7.79 (m, 4H, ArH); ms
2-(N-Methyl-piperazino)-5-phenyl-6H-1,3,4-thiadiazine.
Hydrobromide 3h: prepared from 1.74 g (10 mmol) of 2b and
1.99 g (10mmol) of phenacylbromide 1a. Yield: 2.41 g (68%),
yellow prisms (EtOH), mp.: 176°C; ir (KBr, cmÀ1): 3129 (m),
3025 (m), 3003 (m), 2939 (m), 2657 (m), 2592 (m), 2475 (m),
1496 (s), 1466 (m), 1446 (m), 1422 (m), 1399 (s), 1367 (m), 1244
1
(m), 974 (m), 692 (m); H nmr (DMSO-d6, 300 MHz): δ = 2.82
(s, 3H, Me), 3.28–3.41 (t, 4H, 2xN-CH2), 3.75–3.79 (t, 4H,
2xN-CH2) 4.40 (s, 2H, 6-CH2, thiadiazine), 7.46–7.96 (m, 5H,
-ArH), 10.85 (s, 1H, NH+); 13C nmr (DMSO-d6, 50 MHz):
δ = 21.69 (6-CH2, thiadiazine), 42.17 (Me), 44.10 (CH2), 51.77
(CH2), 126.66 (ArH), 128.56 (ArH), 129.70 (ArH), 135.18
(Ar), 148.18 (5-C, thiadiazine), 150.95 (2-C, thiadiazine); ms
(El, 70 eV): m/z = 28 (50), 56 (18), 71 (100), 103 (26), 124 (5),
143 (19), 172 (10), 204 (66), 217 (50), 242 (9), 274 (M+, 19).
Anal. Calcd. for C14H19BrN4S (355.30): C, 47.33; H, 5.39; N,
15.77. Found: C, 47.33; H, 5.38; N, 15.72. Free base 4h:
Yield: 1.81 g (66%), yellow prisms (EtOH), mp 100°C; ir
(KBr, cmÀ1): 2935 (m), 2790 (m), 1488 (m), 1453 (m), 1372
(m), 1345 (m), 1289 (m), 1251 (m), 1230 (m), 1145 (m), 1003
(El, 70 eV):
m/z % = 42 (44), 71 (100), 83 (41), 110 (4),
143 (15), 238 (17), 251 (20), 276 (1), 308 (M+, 13). Anal.
Calcd. for C14H17Cl N4S (308.83): C, 54.45; H, 5.55; N,
18.14. Found: C, 54.50; H, 5.55; N, 18.13.
2-(N-Methyl-piperazino)-5-(4-fluorophenyl)-6H-1,3,4-
thiadiazine. Hydrobromide 3k: prepared from 1.74 g (10 mmol)
of 2b and 2.17 g (10 mmol) of 4-fluoro-phenacylbromide 1d. Yield:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Thiadiazines
2.95 g (79%), yellow prisms (EtOH), mp 175°C; ir (KBr, cmÀ1):
2593 (m), 1499 (m), 1423 (m), 1241 (m); 1H nmr (DMSO-d6,
300 MHz): δ =2.82 (s, 3H, Me), 3.33–3.45 (m, 8H, 4xN-CH2),
3.79 (s, 2H, 6-CH2, thiadiazine), 7.29–8.02 (m, 4H, ArH),
4.83 (s, 1H, NH2); 13C nmr (DMSO, 50 MHz): δ = 21.66
(6-CH2, thiadiazine), 42.13 (Me), 44.07 (CH2), 51.83 (CH2),
115.30 (d, J(C,F) = 21.4, ArH), 128.86 (d, J(C,F) = 8.0, ArH),
131.74 (d, J(C,F) = 3.3, Ar), 150.95 (5-C, thiadiazine), 160,50
(d, J(C,F) = 247.4, Ar) 165.63 (2-C, thiadiazine); ms (El,
70 eV): m/z (%) = 28 (24), 57 (1), 80 (16), 95 (2), 122 (19), 146
(2), 162 (27), 189 (55), 216 (11), 247 (M+, 100) 279 (4). Anal.
Calcd. for C14H18BrFN4S (373.29): C, 45.05; H, 4.86; N,
15.01. Found: C, 45.10; H, 4.83; N, 14.98.
47.15 (CH2), 54.57 (CH2), 123.88 (ArH), 127.11 (ArH),
141.61 (Ar), 144.70 (Ar), 148.07 (5-C, Hetar), 151.67 (2-C,
thiadiazine); ms (El, 70 eV): m/z (%) = 28 (62), 71 (100), 83
(26), 133 (3), 149 (4), 165 (1), 217 (2), 262 (13), 287 (3), 319
(M+, 13). Anal. Calcd. for C14H17N5O2S (319.38): C, 52.65; H,
5.37; N, 21.93. Found: C, 52.63; H, 3.36; N, 21.95.
2-(N-Methyl-piperazino)-5,6-diphenyl-6H-1,3,4-thiadiazine.
Free base 4m: The title compound was prepared starting from
1.74 g (10 mmol) of 2b and 2.75 g (10 mmol) of 2-bromo-1,2-
diphenylethan-1-one 1h as described for 4g. Yield: 2.42 g
(69%), orange prisms (EtOH), mp 176°C; ir (KBr, cmÀ1): 3420
(m), 3212 (m), 2935 (m), 2798 (m), 1495 (s), 1469 (m), 1446
(m), 1293 (m), 1269 (m), 1157 (m), 1010 (m), 770 (m), 698
(s); 1H nmr (CDCl3, 300 MHz): δ = 2.32 (s, 3H, Me), 2.43–2.47
(t, 4H, 2xN-CH2), 3.05–3.08 (t, 4H, 2xN-CH2), 3.62 (s, 1H,
6-CH, thiadiazine); 13C nmr (DMSO-d6, 50 MHz): δ = 22.1
(6-CH2, thiadiazine), 45.59 (Me), 48.97 (CH2), 54.32 (CH2),
126.19 (ArH), 127.51 (ArH), 127.76 (ArH), 128.23 (ArH),
128.30 (ArH), 128.45 (ArH), 129.24 (ArH), 137.70 (Ar),
148.18 (5-C, thiadiazine), 150.95 (2-C, thiadiazine); ms (El,
70 eV): m/z (%) = 28 (18), 43 (34), 77 (29), 105 (46), 143
(3), 178 (5), 192 (2), 234 (5), 248 (81), 303 (40), 318 (M+,
100). Anal. Calcd. for C20H22N4S (350.48): C, 68.54; H,
6.33; N, 15.99. Found: C, 68.52; H, 6.19; N, 16.01.
Hydrochloride 3n: Treatment of an ethanol solution of the
free base 4m with ethanolic hydrochloric acid yielded the
hydrochlorides. Yield: 3.15 g (73%), orange prisms (EtOH),
mp 285°C; ir (KBr, cmÀ1): 3197 (m), 3023 (m), 2923 (m),
2845 (m), 2698 (m), 2654 (s), 2586 (s), 2517 (m), 2470
(m), 2445 (m), 1593 (m), 1497 (m), 1448 (m), 696 (m); 1H
nmr (DMSO-d6, 300 MHz): δ = 2.77 (s, 3H, Me), 2.99–3.05
(t, 8H, 4xN-CH2), 3.48 (s, 2H, 6-CH2, thiadiazine), 7.24–7.35
(m, 10H, ArH); ms (El, 70 eV): m/z (%) = 28 (5), 43 (46), 72
(37), 116 (7), 151 (1), 178 (7), 191 (4), 217 (10), 248 (100),
303 (59), 318 (73), 350 (M+, 2). Anal. Calcd. for
C20H23BrN4S (431.39): C, 55.68, H, 5.37; N, 12.99. Found: C,
55.64; H, 5.36; N, 13.01.
2-(N-Methyl-piperazino)-5-(4-methoxyphenyl)-6H-1,3,4-
thiadiazine.
Hydrobromide 3l: prepared from 1.74 g
(10 mmol) of 2b and 2.29 g (10 mmol) of 4-methoxy-
phenacylbromide 1f. Yield: 2.85 g (74%), yellow prisms (EtOH),
mp 166°C; ir (KBr, cmÀ1): 2928 (m), 2653 (m), 2602 (m), 2581
(m), 1604 (m), 1501 (s), 1467 (m), 1420 (m), 1379 (m), 1325 (m),
1253 (m), 1186 (m), 1022 (m), 975 (m); 1H nmr (DMSO-d6,
300 MHz): δ = 2.84 (s, 3H, Me), 3.39–3.43 (t, 4H, 2xN-CH2),
3.77 (s, 2H, 6-CH2, thiadiazine), 3.80–3.81 (t, 4H, 2xN-CH2),
7.02–7.92 (m, 4H, ArH), 9.90 (s, 1H, NH+); 13C nmr (DMSO-
d6, 50MHz) δ = 21.62 (6-CH2, thiadiazine), 42.09 (Me), 44.10
(CH2), 51.71 (CH2), 55.22 (MeO), 113.99 (ArH), 127.38 (Ar),
128.23 (ArH), 147.80 (OAr), 150.79 (5-C, thiadiazine), 160.61
(2-C, thiadiazine); ms (El, 70 eV): m/z (%) = 28 (100), 71 (63),
91 (29), 119 (42), 135 (46), 202 (57), 234 (32), 247 (16), 275
(98), 304 (M+, 19). Anal. Calcd. for C15H21Br N4OS (385.32):
C, 46.76; H, 5.49; N, 14.54. Found: C, 46.69; H, 5.47; N,
19.52. Free base 4k: Yield: 2,22 g (73%), yellow prisms
(EtOH), mp 117°C; ir (KBr, cmÀ1): 1606 (m), 1498 (m), 1451
(m), 1291 (m), 1252 (m), 1223 (m), 1179 (m), 1027 (m); 1H
nmr (CDCl3, 300MHz): δ = 2.35 (s, 3H, Me), 2.49–2.52 (t, 4H,
2xN-CH2), 3.53 (s, 2H, 6-CH2, thiadiazine), 3.79 (s, 3H, Me),
3.85–3.87 (t, 4H, 2xN-CH2), 6.94–7.87 (m, 4H, ArH); ms (El,
70 eV): m/z (%) = 28 (82), 71 (100), 83 (57), 133 (44), 135 (61),
185 (2), 213 (16), 234 (95), 247 (35), 272 (10), 304 (M+, 97).
Anal. Calcd. for C15H20N4OS (304.41): C, 59.18; H, 6.62; N,
18.40. Found: C, 58.99; H, 6.64; N, 18.35.
2-Piperidino-5-(4-fluorphenyl)-6H-1,3,4-thiadiazine.
Hydrobromide 3o: prepared from 1.59g (10 mmol) of 1c and
2.17g (10 mmol) of 4-fluoro-phenacylbromide 1d. Yield: 2.58 g
(72%), yellow prisms (EtOH), mp 182°C; ir (KBr, cmÀ1): 3038
(m), 2946 (m), 2897 (m), 2858 (m), 1595 (m), 1568 (s), 1513 (m),
1443 (m), 1361 (m), 1328 (m), 1228 (m), 854 (m); 1H nmr
(DMSO-d6, 300 MHz): δ = 1.70 (m, 6H, 3xCH2), 3.42–3.47 (t,
4H, 2xN-CH2), 4.37 (s, 2H, 6-CH2, thiadiazine), 7.39–8.03 (m,
4H, ArH), 13.07 (s, 1H, NH+); 13C NMR (DMSO-d6, 50MHz):
δ = 22.79 (6-CH2, thiadiazine), 23.90 (CH2), 49.23 (CH2), 115.77
(d, J(C,F)= 21.1, ArH), 124.00 (d, J(C,F)= 3.2, Ar), 128.51 (d, J
(C,F) = 8.1, ArH), 153.32 (5-C, thiadiazine), 160.39 (d, J(C,
F)= 247.3, Ar), 165.32 (2-C, thiadiazine); ms (El, 70eV): m/
z = 28 (80), 55 (21), 70 (89), 101 (22), 128 (100), 155 (7), 245
(11), 277 (M+, 59). Anal. Calcd. for C14H17BrFN3S (358,27): C,
46.93; H, 4.78; N, 11.73. Found: C, 46.79; H, 4.77; N. 11.74.
2-Morpholino-5-(4-fluorophenyl)-6H-1,3,4-thiadiazine.
Hydrobromide 3p: prepared from 1.61 g (10 mmol) of 2d and 2.17 g
(10 mmol) of 4-fluoro-phenacylbromide 1d. Yield: 2.74 g (76%),
yellow prisms (EtOH), mp 121°C; ir (KBr, cmÀ1): 1601 (m), 1501
(m), 1448 (m), 1373 (m), 1350 (m), 1324 (m), 1269 (m), 1232 (m),
2-(N-Methyl-piperazino)-5-(4-nitrophenyl)-6H-1,3,4-
thiadiazine. Hydrobromide 3m: prepared from 1.74 g (10 mmol)
of 2b and 2.44 g (10 mmol) of 4-nitro-phenacylbromide 1g. Yield:
3.2 g (80%), yellow lamella (EtOH), mp 202°C; ir (KBr, cmÀ1):
2923 (m), 1600 (m), 1519 (m), 1499 (m), 1346 (s), 1109 (m), 1090
1
(m), 1022 (m), 856 (m).; H nmr (DMSO-d6, 300 MHz): δ =2.84
(s, 3H, Me), 3.44 (m, 8H, 4xN-CH2), 3.94 (s, 2H, 6-CH2),
8.19–8.35 (m, 4H, ArH); 13C nmr (DMSO-d6, 50 MHz):
δ = 21.83 (6-CH2, thiadiazine), 42.01 (Me), 44.47 (CH2), 51.51
(CH2), 123.79 (ArH), 127.91 (ArH), 140.64 (Ar), 147.76 (Ar),
148.02 (5-C, thiadiazine), 154.18 (2-C, thiadiazine); ms (El,
70 eV): m/z (%) = 28 (67), 71 (100), 82 (30), 124 (3), 143 (13),
171 (4), 196 (3), 217 (14), 262 (35), 287 (25), 319 (M+, 26),
338 (6). Anal. Calcd. for C14H18Br N5O2S (400.30): C, 42.01;
H, 4.53; N, 17.50. Found: C, 42.02; H, 4.51; N, 17.53. Free
base 4l: Yield: 2.46 g (77%), yellow lamella (EtOH), mp 149°
C; ir (KBr, cmÀ1): 1598 (m), 1514 (s), 1496 (s), 1445 (m),
1376 (m), 1345 (s), 1290 (m), 1250 (m), 1233 (m), 1144 (m),
859 (m); 1H NMR (CDCl3, 300 MHz): δ = 2.35 (s, 3H,Me),
2.49–2.54 (t, 4H, 2xN-CH2), 3.59 (s, 2H, 6-CH2, thiadiazine) ,
3.83–3.86 (t, 4H, 2xN-CH2), 8.04–8.30 (m, 4H, ArH); 13C nmr
(CDCl3, 50 MHz): δ = 22.07 (6-CH2, thiadiazine), 45.97 (Me),
1
1114 (m), 887 (m); H nmr (DMSO-d6, 300 MHz): δ =3.78–3.81
(t, 4H, 2xCH2), 3.86–3.90 (t, 4H, 2xN-CH2), 4.36 (s, 2H, 6-CH2,
thiadiazine), 7.39–8.01 (m, 4H, ArH); 13C nmr (DMSO-d6,
50 MHz): δ = 22.95 (6-CH2, thiadiazine), 49.48 (CH2), 64.94
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Knak, W.-D. Pfeiffer, H. Dollinger, and P. Langer
Vol 000
(CH2), 116.28 (d, J(C,F) = 21.2, ArH), 129.04 (d, J(C,F) = 3.2, Ar),
129.58 (d, J(C,F) = 8.1, ArH), 151.41 (5-C, thiadiazine), 161.80 (d,
J(C,F) = 247.4, Ar), 166.42 (2-C, thiadiazine); ms (El, 70 eV): m/z
(%) = 28 (29), 61 (13), 86 (89), 101 (20), 130 (100), 157 (2), 165
(3), 195 (4), 233 (3), 279 (M+, 53). Anal. Calcd. for
C13H15BrFN3OS (360.25): C, 43.34; H, 4.20; N, 11.66. Found: C,
70eV): m/z (%)= 28 (31), 71 (9), 104 (6), 121 (1), 148 (3), 204
(11), 216 (2), 245 (100), 287 (32), 329 (M+, 43). Anal. Calcd. for
C17H19N3O2S (329.42): C, 61.98; H, 5.81; N, 12.76. Found: C,
61,79; H, 5,83; N, 12.73.
1-Acetyl-3-pyrrolidino-4-acetylmercapto-5-(4-bromophenyl)-
pyrazole (6b).
From 3.24 g (10 mmol) of 4b. Yield: 2.82 g
(69%), colourless prisms (EtOH), mp 134°C; ir (KBr, cmÀ1):
1729 (s), 1705 (s), 1564 (s), 1530 (s), 1421 (s), 1365 (s), 1347
(m), 1316 (s), 1282 (s), 1107 (m), 932 (m), 617 (m); 1H nmr
(CDCl3, 300 MHz): δ = 1.90–1.94 (m, 4H, 2xCH2), 2.27 (s, 3H,
Me), 2.59 (s, 3H, Me), 3.49–3.53 (t, 4H, 2xN-CH2), 7.13–7.35
(m, 4H, ArH); ms (El, 70 eV): m/z (%) = 28 (7), 43 (40), 71 (17),
138 (7), 140 (3), 183 (5), 238 (16), 244 (16), 279 (100), 321
(37), 363 (43), 408 (M+, 3). Anal. Calcd. for C17H18BrN3O2S
(408.31): C, 50.01; H, 4.44; N, 10.29. Found: C, 50.01; H, 4.43;
N, 10.28.
43.21; H, 4.19; N, 11.66.
General procedure for the synthesis of 2-pyrrolidino-5-aryl-6-
(4-nitrobenzylidene)-6H-1,3,4-thiadiazines 5a,b. The free base
of the thiadiazines 4a,b (10 mmol) and 1.5 g (10 mmol) of 4-
nitrobenzaldehyde in 20 mL of ethanol was refluxed for 10 min.
The precipitated product was separated by filtration. The residue
was extracted with boiling ethanol and recrystallized from pyridine.
2-Pyrrolidino-5-phenyl-6-(4-nitrobenzylidene)-6H-1,3,4-
thiadiazine (5a).
From 2.45 g (10 mmol) of 4a and 1.5 g
(10 mmol) of 4-nitrobenzaldehyde. Yield: 3.32 g (73%), yellow
prisms (EtOH), mp 186°C; ir (KBr, cmÀ1): 3420 (m), 3168 (m),
3072 (m), 2869 (m), 1515 (s), 1481 (m), 1458 (m), 1396 (m),
1344 (s), 853 (m), 695 (m); 1H nmr (DMSO-d6, 300 MHz):
δ = 1.88–1.90 (m, 4H, 2xCH2), 3.41–3.46 (t, 4H, 2xN-CH2),
7.43–8.20 (m, 9H, ArH), 9.7 (s, 1H, CH); 13C nmr (DMSO-d6,
50MHz): δ = 24.27 (CH2), 40.01 (6-C, thiadiazine), 47.29 (CH2),
70.11 (CH), 122.61 (ArH), 126.59 (ArH), 128.14 (ArH), 128.24
(ArH), 128.62 (ArH), 137.0 (Ar), 143.74 (Ar), 144.26 (Ar),
146.94 (5-C, thiadiazine), 149.06 (2-C, thiadiazine); ms (El,
70eV): m/z (%)= 28 (100), 55 (35), 77 (39), 113 (76), 150 (46),
176 (67), 199 (14), 245 (38), 296 (20), 378 (M+, 8). Anal. Calcd.
for C26H22N4O2S (454.54): C, 68.70; H, 4.88; N, 12.33. Found:
C, 68.74; H, 4.8;9 N, 12.31.
2-Pyrrolidino-5-(4-bromophenyl)-6-(4-nitrobenzylidene)-6H-
1,3,4-thiadiazine (5b). Prepared from 3.24 g (10 mmol) of 4b
and 1.5 g (10 mmol) of 4-nitrobenzaldehyde. Yield: 3.24 g
(71%), orange prisms (EtOH), mp 174°C; ir (KBr, cmÀ1): 3421
(m), 1517 (s), 1481 (m), 1456 (m), 1369 (m), 1345 (m), 1322
(m), 1073 (m), 835 (m); 1H NMR (DMSO-d6, 300 MHz):
δ = 1.88–1.90 (m, 4H, 2xCH2), 4.67–4.69 (t, 4H, 2xN-CH2),
7.47–8.23 (m, 8H, ArH), 9.7 (s, 1H, CH); 13C nmr (DMSO-d6,
50 MHz): δ = 25.4 (CH2), 46.64 (6-C, thiadiazine); 47.65 (CH2),
122.31 (CH), 122.73 (ArH), 128.34 (ArH), 128.65 (ArH),
131.15 (ArH), 136.13 (Ar), 143.92 (Ar), 147.03 (Ar), 148.94
(5-C, thiadiazine), 154.36 (2-C, thiadiazine); ms (El, 70 eV): m/z
(%) = 323 (2), 345 (9), 347 (3), 442 (2), 444 (1), 458 (M+, 1).
Anal. Calcd. for C20H17BrN4O2S (457.34): C, 52.52; H, 3.75;
1-Acetyl-3-pyrrolidino-4-acetylmercapto-5-(4-chlorophenyl)-
pyrazole (6c). From 2.8 g (10 mmol) of 4c. Yield: 2.44 g (67%),
colourless prisms (EtOH), mp 131°C; ir (KBr, cmÀ1): 1730 (s),
1703 (s), 1561 (s), 1531 (m), 1422 (s), 1365 (s), 1344 (m), 1317
(s), 1301 (m), 1282 (m), 1105 (m), 1091 (m), 934 (m), 840 (m),
618 (m); 1H nmr (CDCl3, 300 MHz): δ = 1.90–1.94 (m, 4H,
2xCH2), 2.27 (s, 3H, Me), 2.59 (s, 3H, Me), 3.50–3.52 (t, 4H,
2xN-CH2), 7.13–7.35 (m, 4H, ArH); 13C nmr (CDCl3, 50 MHz):
δ = 23.23 (Me), 25.36 (CH2), 29.44 (Me), 48.42 (CH2), 99.62
(4-C, Hetar), 128.05 (ArH), 128.79 (Ar), 130.41 (ArH), 134.91
(Ar), 149.33 (5-C, Hetar), 156.91 (3-C, Hetar), 169.33 (C=O),
194.57 (C=O); ms (El, 70 eV): m/z (%) = 28 (39), 43 (40), 71
(13), 113 (1), 138 (5), 183 (3), 204 (1), 238 (12), 247 (3), 279
(100), 321 (34), 363/365 (M+, 40/13). Anal. Calcd. for
C17H18ClN3O2S (363.86): C, 56.12; H, 4.99; N, 11.55. Found:
C, 56.14; H, 4.97; N, 11.54.
1-Acetyl-3-(N-methyl-piperazino)-4-acetylmercapto-5-(4-
bromophenyl)-pyrazole (6d).
From 3.53 g (10 mmol) of 4i.
Yield: 3.10 g (71%), colourless prisms (washed with H2O), mp
154°C; ir (KBr, cmÀ1): 2938 (m), 2841 (m), 2798 (m), 1561 (m),
1504 (m), 1451 (m), 1369 (m), 1324 (m), 1283 (m), 1008 (m),
828 (m); 1H nmr (DMSO-d6, 300MHz): δ = 0.89 (s, 3H, Me),
1.05 (s, 3H, Me), 2.31 (s, 3H, N-CH3), 3.22–3.36 (m, 8H, 4xN-
CH2), 7.43–7.63 (m, 4H, ArH); 13C nmr (CDCl3, 50MHz):
δ = 46.10 (Me), 48.23 (CH2), 54.53 (CH2), 129.41 (ArH), 131.06
(ArH), 131.40 (ArH); ms (El, 70 eV): m/z (%) = 28 (84), 43 (100),
83 (17), 129 (7), 182 (7), 252 (21), 282 (17), 320 (16), 352 (13),
394 (22), 439 (M+, 2). Anal. Calcd. for C18H21Br N4O2S (437.36):
N, 12.25. Found: C, 52.49; H, 3.72; N, 12.22.
General procedure for the synthesis of 1-acetyl-3-
pyrrolidino-4-acetylmercapto-5-aryl-pyrazoles (6a–c) and
C, 49.43; H, 4.84; N, 12.81. Found: C, 49.41; H, 4.82; N, 12.83.
General procedure for the synthesis of 3-pyrrolidino-,
3-piperidino, and 3-morpholino-5-aryl-pyrazoles 7a–i and 9a–
c. The free base of the 1,3,4-thiadiazine (10 mmol) in 15 mL of
glacial acetic acid was refluxed for 2 h. The hot solution was
filtered. The precipitated product was recrystallized from ethanol.
Treatment of an ethanol solution of the free base of 7a–i with
ethanolic hydrochloric acid or hydrobromic acid (48%) yielded the
hydrochlorides and hydrobromides, respectively. In case of 9a–c,
the solvent was evaporated in vacuo. Standing of the oil in the
refrigerator for several days resulted in crystallization. The
pyrazoles 9a–c were recrystallized from ethanol.
1-Acetyl-3-(N-methyl-piperazino)-4-acetylmercapto-5-(4-
bromophenyl)-pyrazole (6d).
The free base of the 1,3,4-
thiadiazine (10mmol) in 6 mL acetic acid was refluxed for 1 h.
The mixture was concentrated in vacuo to afford oil. The product
was washed with water and recrystallized from ethanol.
1-Acetyl-3-pyrrolidino-4-acetylmercapto-5-phenyl-pyrazole (6a).
Prepared from 2.45 g (10 mmol) of 4a. Yield: 2.11 g (64%),
colourless prisms (EtOH), mp 99°C; ir (KBr, cmÀ1): 1732 (s),
1701 (s), 1562 (s), 1528 (m), 1423 (s), 1464 (s), 1346 (m), 1315
(s), 1284 (s), 1133 (m), 1109 (m), 932 (m), 621 (m); 1H nmr
(CDCl3; 300 MHz): δ = 1.90–1.94 (m, 4H, 2xCH2), 2.25 (s, 3H,
Me), 2.59 (s, 3H, Me), 3.50–3.55 (t, 4H, 2xN-CH2), 7.19–7.39
(m, 4H, ArH); 13C NMR (CDCl3, 50MHz): δ = 23.28 (Me),
25.37 (CH2), 29.40 (Me), 99.42 (4-C, Hetar), 127.71 (ArH),
128.81 (ArH), 128.95 (ArH), 130.37 (Ar), 150.56 (5-C, Hetar),
156.95 (3-C, Hetar), 169.22 (C=O), 194.93 (C=O); ms (El,
3-Pyrrolidino-5-phenyl-pyrazole (7a).
Free base: From
2.45g (10 mmol) of 4a in glacial acetic acid. Yield: 1.55 g (73%),
colourless prisms (CHCl3/petroleum ether), mp 183°C.
Hydrochloride: 3.29 g (10 mmol) of 6a was refluxed in conc. aq.
HCl for 1 h. Yield: 1.49 g (71%); ir (KBr, cmÀ1): 3430 (m), 3250
(m), 2967 (m), 2873 (m), 2849 (m), 1603 (m), 1572 (m), 1542
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Thiadiazines
(m), 1482 (m), 1461 (m), 736 (m), 695 (m), 539 (m); 1H nmr
(CDCl3, 300MHz): δ = 1.95–1.99 (m, 4H, 2xCH2), 3.30–3.35 (t,
4H, 2xN-CH2), 5.77 (s, 1H, NH), 7.31–7.92 (m, 6H, ArH, Hetar),
7.31–7.92 (m, 5H, ArH), 5.77 (s, 1H, NH), 7.31–7.92 (m, 5H,
ArH); 13C nmr (CDCl3, 50MHz): δ = 25.23 (CH2), 48.29 (CH2),
86.14 (4-C, Hetar), 125.33 (ArH), 127.50 (ArH), 128.49 (ArH),
131.24 (Ar), 145.78 (5-C, Hetar), 156.27 (3-C, Hetar); ms (El,
70eV): m/z (%) = 28 (13), 41 (4), 71 (12), 77 (8), 104 (6), 115 (4),
144 (9), 158 (8), 185 (35), 213 (M+, 100). Anal. Calcd. for
C13H15N3 (213.28): C, 73.21; H, 7.09; N, 19.70. Found: C, 73.23;
H, 7.07; N, 19.68.
2xN-CH2), 4.29 (s, 3H, MeO), 7.05–7.92 (m, 5H, ArH, Hetar);
ms (El, 70 eV): m/z (%) = 28 (38), 55 (7), 73 (6), 113 (20), 133
(10), 146 (1), 174 (7), 188 (5), 215 (26), 243 (M+, 100). Anal.
Calcd. for C14H18ClN3O (279.77): C, 60.10; H, 6.49; N, 15.02.
Found: C, 59.98; H, 6.42; N, 15.02.
3-Pyrrolidino-5-(4-nitrophenyl)-pyrazole (7f).
Free base:
From 2.90 g (10 mmol) of 4f in glacial acetic acid. Yield: 1.88 g
(73%), colourless rods (EtOH), mp 154°C; ir (KBr, cmÀ1): 2954
(m), 2869 (m), 2361 (m), 1600 (m), 1577 (m), 1551 (m), 1517
(s), 1496 (s), 1456 (m), 1338 (s), 855 (m); 1H nmr (CDCl3,
300 MHz): δ = 1.97–2.05 (t, 4H, 2xCH2), 3.30–3.35 (t, 4H,
2xN-CH2), 5.75 (s, 1H, NH), 7.82–8.29 (m, 5H, ArH, Hetar);
ms (El, 70 eV): m/z (%) = 28 (63), 65 (47), 71 (19), 96 (7), 128
(21), 160 (14), 183 (3), 192 (6), 230 (12), 258 (M+, 100).
Anal. Calcd. for C13H14N4O2 (258.28): C, 60.45; H, 5.46; N,
21.69. Found: C, 60.45; H, 5.45; N, 21.67.
3-Pyrrolidino-5-(4-bromophenyl)-pyrazole (7b).
Free base:
From 3.24 g (10mmol) of 4b in glacial acetic acid. Yield: 2.07 g
(71%), colourless prisms (EtOH), mp 217°C. Hydrochloride:
4.08 g (10 mmol) of 6b was refluxed in con. HCl for 1 h. Yield
2.16 g (74%); ir (KBr, cmÀ1): 3163 (m), 3136 (m), 3063 (m),
3000 (m), 2966 (m), 2931 (m), 2896 (m), 2848 (m), 1606 (m),
1547 (s), 1486 (m), 1467 (m), 827 (m), 742 (m); 1H nmr (CDCl3,
300 MHz): δ = 1.93–1.98 (m, 4H, 2xCH2), 3.24–3.26 (t, 4H,
2xN-CH2), 5.64 (s, 1H, NH), 7.47–7.49 (m, 5H, ArH, H-Hetar);
13C NMR (DMSO–d6, 50 MHz): δ = 24.43 (CH2), 48.29 (CH2),
84.2 (4-C, Hetar), 119.86 (Ar), 126.55 (ArH), 131.14 (ArH),
145.78 (5-C, Hetar), 156.3 (3-C, Hetar), ms (El, 70eV): m/z
(%) = 28 (91), 71 (6), 263 (10), 291/293 (M+, 100/85). Anal.
Calcd. for C13H14Br N3 (292,17): C, 53.44; H, 4.83; N, 14.38.
3-Pyrrolidino-4.5-diphenyl-pyrazole (7g).
Hydrobromide:
From 3.21g (10 mmol) 4g as described by general procedure in
glacial acetic acid. Treatment of an ethanol solution of the free
base with hydrobromic acid (48%) yielded the hydrobromides.
Yield: 2.63 g (71%), colourless prisms (EtOH), mp 202°C; ir
(KBr, cmÀ1): 3425 (m), 3219 (m), 3064 (m), 2964 (m), 1507 (s),
1480 (m), 1443 (m), 775 (m), 700 (m); 1H nmr (CDCl3,
300 MHz): δ = 1.79–1.83 (m, 4H, 2xCH2), 3.09–3.14 (t, 4H, 2xN-
CH2), 7.21–7.31 (m, 10H, 2xArH); 13C nmr (DMSO-d6,
50MHz): δ = 24.28 (CH2), 49.28 (CH2), 104.1 (4-C, Hetar),
126.22 (ArH), 127.05 (ArH), 127.29 (ArH), 127.83 (ArH), 128.10
(ArH), 130 (ArH), 134.52 (Ar), 145.7 (5-C, Hetar), 156.41 (3-C,
Hetar); ms (El, 70 eV): m/z (%)= 51 (11), 77 (20), 95 (1), 128 (1),
151 (8), 183 (12), 201 (15), 260 (1), 277 (100), 289 (M+/7). Anal.
Calcd. for C19H20Br N3 (370,29): C, 61.63; H, 5.44; N, 11.35.
Found: C, 61.62; H, 5.44 N, 11.38. Free base: (a) To an EtOH
solution of 3.70 g (10 mmol) of hydrobromide 7g was added a
dilute aqueous solution of ammonia until pH = 8 was reached.
Yield: 2.05 g (71%), colourless prisms, mp 211°C; (b) 3.21 g
(10 mmol) of 2 h in an ethanol solution of sodium ethanolate
(prepared from 0.23 g, 10 mmol, of sodium and 10 mL of ethanol)
was refluxed for 1 h. Yield: 2.17g (75 %); ir (KBr, cmÀ1): 3217
(m), 3098 (m), 3065 (m), 2965 (m), 2860 (m), 1581 (m), 1505 (s),
1480 (m), 1443 (m), 1353 (m), 1294 (m), 1151 (m), 775 (m), 739
Found: C, 53.42; H, 4.82; N, 14.39.
3-Pyrrolodino-5-(4-chlorophenyl)-pyrazole (7c). Free base:
From 2.80g (10 mmol) of 4c in glacial acetic acid. Yield: 1.88g
(76%), colourless prisms (EtOH), mp 215°C. Hydrochloride:
3.63 g (10mmol) of 6c was refluxed in conc. HCl for 1 h. Yield:
1.80 g (73%); ir (KBr, cmÀ1): 3166 (m), 3143 (m), 3085 (m),
3064 (m), 3007 (m), 2958 (m), 2844 (m), 1607 (m), 1546 (s),
1489 (m), 1459 (m), 1092 (m), 831 (m); 1H nmr (CDCl3,
300 MHz): δ = 1.96–2.01 (m, 4H, 2xCH2), 3.28–3.33 (t, 4H,
2xN-CH2), 5.69 (s, 1H, NH), 7.31–7.58 (m, 5H, ArH, H-Hetar);
13C nmr (DMSO-d6, 50MHz): δ = 24.66 (CH2), 48.65 (CH2),
86.1 (4-C, Hetar), 126.38 (ArH), 138.48 (ArH), 131.58 (Ar),
145.7 (5-C, Hetar), 156.3 (3-C, Hetar); ms (El, 70 eV): m/z
(%) = 28 (34), 91 (4), 248 (M+, 19). Anal. Calcd. for C13H14ClN3
(247.72): C, 63.03; H, 5.70; N, 16.96. Found: C, 62.99; H, 5.68;
N, 16.97.
1
(m), 701 (s), 621 (m); H nmr (CDCl3, 300MHz): δ = 1.78–1.83
3-Pyrrolidino-5-(4-fluorophenyl)-pyrazole (7d). Hydrochloride:
(m, 4H, 2xCH2), 3.09–3.12 (t, 4H, 2xN-CH2) 5.00 (s, 1H, NH),
7.24–7.31 (m, 10H, 2xArH); 13C nmr (DMSO-d6, 50MHz):
δ = 24.28 (CH2), 49.25 (CH2), 104.84 (4-C), 126.23 (ArH),
127.04 (ArH), 127.29 (ArH), 127.84 (ArH), 128.11 (ArH), 130.82
(ArH), 131.26 (Ar), 134.52 (Ar), 145.7 (5-C, Hetar), 156.41 (3-C,
Hetar); ms (El, 70eV): m/z (%) = 28 (54), 65 (40), 91 (10), 128
(12), 160 (14), 178 (3), 192 (5), 220 (4), 260 (19), 289 (M+, 100),
297 (5). Anal. Calcd. for C19H19N3 (289.37): C, 78.86; H, 6.62;
N, 14.52. Found: C, 78.79; H, 6.63; N, 14.53.
From 2.63 g (10 mmol) of 4d in glacial acetic acid. Treatment of an
ethanol solution of the free base with ethanolic hydrochloric acid
yielded the hydrochlorides. Yield: 1.82g (68%), colourless
prisms (EtOH), mp 169°C, ir (KBr, cmÀ1): 3423 (m), 3106 (m),
2976 (m), 2932 (m), 2877 (m), 2770 (m), 1636 (s), 1596 (m),
1574 (m), 1503 (m), 1460 (m), 1234 (m); 1H nmr (DMSO-d6,
300 MHz): δ = 1.94–1.98 (m, 4H, 2xCH2), 3.35–3.39 (t, 4H,
2xN-CH2), 6.36 (s, 1H, NH), 7.35–8.02 (m, 5H, ArH, H-Hetar);
ms (El, 70eV): m/z (%)= 28 (23), 55 (3), 71 (5), 113 (5), 120
(5), 146 (1), 162 (6), 203 (21), 230 (43), 231 (M+, 100). Anal.
Calcd. for C13H15ClFN3 (267.73): C, 58.32; H, 5.65; N, 15.70.
3-Piperidino-5-(4-fluorophenyl)-pyrazole hydrochloride
(7h). From 3.58g (10 mmol) of 3o in glacial acetic acid. Yield:
2.06g (73%), colourless prisms (EtOH), mp 172°C; ir (KBr,
cmÀ1): 3053 (m), 2937 (m), 2854 (s), 2743 (s), 2691 (m), 1614
Found: C, 58.35; H, 5.63; N, 15.72.
3-Pyrrolidino-5-(4-methoxyphenyl)-pyrazole (7e). Free base:
1
(s), 1564 (m), 1502 (m), 1454 (m), 1234 (m), 1170 (m); H nmr
From 3.12 g (10mmol) of 3f in glacial acetic acid. To an EtOH
solution of the reaction product was added a dilute aqueous
solution of ammonia until pH = 8 was reached. Yield: 1.93 g
(69%), colourless prisms (EtOH), mp 183°C; ir (KBr, cmÀ1):
2977 (m), 2837 (m), 2744 (m), 1632 (m), 1605 (m), 1580 (s),
1463 (m), 1316 (m), 1256 (m), 1182 (m); 1H nmr (DMSO-d6,
300 MHz): δ = 1.96–2.01 (m, 4H, 2xCH2), 3.60–3.74 (t, 4H,
(CDCl3, 300 MHz): δ = 1.65–1.73 (m, 6H, 3xCH2), 3.46–3.50 (t,
4H, 2xN-CH2), 5.58 (s, 1H, NH), 7.13–7.96 (m, 5H, ArH, Hetar);
ms (El, 70eV): m/z (%) = 36 (23), 68 (7), 84 (4), 128 (s), 162 (4),
190 (5), 216 (25), 245 (M+, 100). Anal. Calcd. for C14H17ClFN3
(281.76): C, 59.68; H, 6.08; N, 14.91. Found: C, 59.66; H, 6.09;
N, 14.93.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Knak, W.-D. Pfeiffer, H. Dollinger, and P. Langer
Vol 000
3-Morpholino-5-(4-fluorophenyl)-pyrazole
(7i). The title compound was prepared starting from 3.60 g
hydrochloride
(5-C, Hetar), 157.57 (3-C, Hetar); ms (El, 70 eV): m/z (%) = 72
(17), 83 (3), 114 (3), 143 (1), 182 (3), 195 (1), 224 (1), 250
(15), 320 (12), 321 (M+, 2). Anal. Calcd. for C14H18BrClN4
(357.68): C, 47.01; H, 5.07; N, 15.66. Found: C, 46.96; H,
5.02; N, 15.63.
(10 mmol) of 3p in glacial acetic acid. Yield: 2.33 g (71%),
colourless prisms (EtOH), mp 264°C; ir (KBr, cmÀ1): 3022
(m), 2964 (m), 2891 (m), 2858 (m), 2756 (m), 1618 (s), 1563
(m), 1501 (m), 1467 (m), 1449 (m), 1236 (m), 1119 (m), 904
3-(N-Methyl-piperazino)-5-(4-chlorphenyl)-pyrazol (9b).
Hydrochloride: From 3.08 g (10 mmol) of 4j in glacial acetic
acid. Yield: 2.25 g (72%), colourless prisms (EtOH), mp
181°C; ir (KBr, cmÀ1): 3426 (m), 3135 (m), 3015 (m), 2962
(m), 2924 (m), 2674 (m), 1630 (m), 1451 (m), 1402 (s); 1H
nmr (DMSO-d6, 300 MHz): δ = 2.98 (s, 3H, Me), 3.14–3.23
(t, 4H, 2xN-CH2), 3.82–3.87 (t, 4H, 2xN-CH2), 7.36–7.77
(m, 5H, ArH, H-Hetar), 11.3 (s, 1H, NH); 13C nmr (DMSO-d6,
50 MHz): δ = 41.98 (Me), 44.77 (CH2), 51.21 (CH2), 89.28
(4-C, Hetar), 127.16 (ArH), 127.48 (Ar), 127.95 (Ar),
128.92 (ArH), 146.31 (5-C, Hetar), 157.55 (3-C, Hetar); ms
(El, 70 eV): m/z (%) = 28 (48), 51 (12), 77 (19), 107 (8),
151 (10), 183 (38), 201 (14), 213 (4), 262 (42), 277 (M+,
100). Anal. Calcd. for C14H18Cl2N4 (313,23): C, 53.68; H,
5.79; N, 17.89. Found: C, 53.67; H, 5.81; N, 17.88.
3-(N-Methyl-piperazino)-4.5-diphenyl-pyrazole (9c). Free base:
(a) From 3.5 g (10mmol) of free base 4m. Reaction time: 45min.
Yield: 2.16 g (68%), colourless needles (EtOH), mp 199°C; (b)
3.5 g (10 mmol) of 3g and an ethanol solution of sodium
ethanolate (prepared from 0.23g, 10mmol, of sodium and 10 mL
of ethanol) was refluxed for 1 h. Yield: 2.42 g (76%); ir (KBr,
cmÀ1): 3421 (s), 3232 (m), 3066 (m), 2935 (m), 2838 (m), 2805
(m), 1494 (m), 1472 (m), 1447 (m), 1010 (m), 771 (m), 698 (s);
1H nmr (CDCl3, 300 MHz): δ = 2.29 (s, 3H, N-Me), 2.42–2.45 (t,
4H, 2xN-CH2), 3.04–3.07 (t, 4H, 2xN-CH2), 7.25–7.39 (m, 10H,
2xArH); 13C nmr (DMSO-d6, 50MHz): δ = 45.68 (Me), 49.05
(CH2), 54.39 (CH2), 107.2 (4-C, Hetar), 126.16 (ArH), 127.50
(ArH), 127.71 (ArH), 128.20 (ArH), 128.26 (ArH), 129.27 (ArH),
133.75 (Ar), 145.7 (5-C, Hetar), 156.42 (3-C, Hetar); ms (El,
70eV): m/z (%)= 43 (28), 72 (33), 84 (5), 116 (3), 159 (2), 178
(3), 191 (2), 234 (7), 248 (100), 274 (2), 318 (M+, 88). Anal.
Calcd. for C20H22N4 (318.42): C, 75.44; H, 6.96; N, 17.60.
Found: C, 75.45; H, 7.01; N, 17.60.
1
(m), 772 (m); H nmr (DMSO-d6, 300 MHz): δ = 3.11–3.14 (t,
4H, 2xN-CH2), 3.70–3.75 (t, 4H, 2xO-CH2), 4.21 (s, br, 1H,
NH+), 7.32–7.87 (m, 5H, ArH, Hetar); 13C nmr (DMSO-d6,
50 MHz): δ = 47.53 (CH2), 65.17 (CH2), 88.53 (4-C, Hetar),
115.78 (ArH), 129.44 (ArH), 140.43 (Ar), 155.43 (5-C, Hetar),
160.22 (Ar), 165.17 (3-C, Hetar); ms (El, 70 eV): m/z (%) = 28
(24), 57 (1), 80 (16), 95 (7), 122 (19), 146 (2), 162 (27), 189
(55), 216 (11), 247 (M+, 100), 279 (4). Anal. Calcd. for
C13H15BrFN3O (328.18): C, 47.58; H, 4.61; N, 12.80. Found:
C, 47.51; H, 4.58; N, 12.79.
General procedure for the synthesis of 3,3-bis(pyrrolidino)-
5,5-diaryl-pyrazolyl-(4,4′)-disulfide (8a–c).
diacetyl-pyrazole (10 mmol) 6a–c was refluxed in 20 mL of a 2M aq.
The respective
solution of sodium hydroxide for 15 min. The product was filtered,
washed thoroughly with water, and recrystallized from ethanol.
3,3-Bis(pyrrolidino)-5,5-diphenyl-pyrazolyl-(4,4′)-disulfide
(8a).
From 3.29 g (10 mmol) of 6a. Yield: 1.71 g (70%),
yellow prisms (EtOH), mp 115°C; ir (KBr, cmÀ1): 1732 (s), 1702
(s), 1562 (s), 1528 (m), 1423 (m), 1365 (s), 1346 (m), 1315 (s),
1284 (m), 1133 (m), 1109 (m), 932 (m), 620 (m); 1H nmr
(CDCl3, 300 MHz): δ = 1.85–1.90 (m, 8H, 4xCH2), 3.40 (t, 8H,
4xN-CH2), 7.16–7.58 (m, 10H, 2xArH); 13C nmr (CDCl3,
50MHz): δ = 25.36 (CH2), 48.40 (CH2), 99.41 (4-C, Hetar),
127.71 (ArH), 128.94 (ArH), 130.36 (Ar), 150.56 (5-C, Hetar),
156.95 (2-C, Hetar); ms (El, 70eV): m/z (%) = 28 (29), 71 (12),
104 (13), 148 (8), 185 (2), 202 (17), 244 (100), 275 (1), 488 (M+,
1). Anal. Calcd. for C26H28N6S2 (488,68): C, 127.8; H, 11.56; N,
34.40. Found: C, 126.9; H, 11.51; N, 34.12.
3,3-Bis(pyrrolidino)-5,5-bromophenyl-pyrazolyl-(4,4′)-disulfide
(8b). From 4.08 g (10 mmol) of 6b. Yield: 2.10 g (65%), yellow
prisms (EtOH), mp 227°C; ir (KBr, cmÀ1): 3207 (m), 2970 (m),
2869 (m), 1588 (m), 1570 (m), 1542 (m), 1486 (m), 1460 (m),
1438 (m); 1H nmr (DMSO-d6, 300 MHz): δ = 1.81 (t, 4H, 2xCH2),
5.7 (s, br, 2H, 2xNH), 7.40–7.73 (m, 8H, ArH). Anal. Calcd. for
C26H26Br2N6S2 (646.46): C, 96.62; H, 8.10; N, 26.00. Found: C,
General procedure for the synthesis of 3-pyrrolidino-,
3-piperidino-, and 3-morpholino-4-ethoxycarbonyl-5-methyl-
pyrazole hydrochlorides 10a–c and 3-morpholino-4-acetyl-5-
96.65; H, 8.03; N, 26.31.
3,3-Bis(pyrrolidino)-5,5-chlorophenyl-pyrazolyl-(4,4′)-disulfide
methyl-pyrazole hydrochloride 10d.
4,4-Disubstituted
thiosemicarbazides 2a,c,d (10mmol) and 1.65g (10 mmol) of
ethyl α-chloro-acetoacetate 1i or 1.3 g (10mmol) of α-chloro-
acetylacetone 1j in 10mL of ethanol were refluxed for 1 h (10d:
5 min). After cooling and rapid filtration, the product was
(8c).
From 3.64 g (10 mmol) of 6c. Yield: 1.79 g (64%),
yellow prisms (EtOH), mp 229°C; ir (KBr, cmÀ1): 3204 (m),
2970 (m), 1588 (m), 1541 (m), 1484 (m), 1460 (m), 1438 (m);
1H nmr (CDCl3, 300 MHz): δ = 1.89–2.03 (t, 4H, 2xCH2),
3.69–3.76 (m, 4H, 2xCH2), 7.40–7.60 (m, 10H, ArH); ms
(El, 70 eV): m/z (%) = 28 (61), 77 (100), 93 (26), 146 (31),
189 (46), 248 (100), 279 (47), 336 (13), 395 (11), 557 (M+,
1). Anal. Calcd. for C26H26Cl2N6S2 (557.56): C, 112.02; H,
recrystallized from ethanol.
3-Pyrrolidino-4-ethoxycarbonyl-5-methyl-pyrazole (10a).
Hydrochloride: From 1.45 g (10 mmol) of 2a. Yield: 1.98 g
(76%), colourless prisms (EtOH), mp 122°C; ir (KBr, cmÀ1):
2988 (m), 2937 (s), 2860 (s), 2798 (s), 2757 (s), 2708 (s), 2680
(s), 1712 (s), 1600 (s), 1518 (m), 1457 (s), 1326 (s), 1132 (s),
9.40; N, 30.14. Found: C, 112.13; H, 9.35; N, 30.08.
3-(N-Methyl-piperazino)-5-(4-bromophenyl)-pyrazole (9a).
1
1112 (m); H nmr (DMSO-d6, 300 MHz): δ = 1.25–1.30 (t, 3H,
Hydrochloride: From 3.53 g (10 mmol) of 4i in glacial acetic acid.
Yield: 2.57 g (72%). 6d was refluxed in conc. aq. HCl for 1 h.
Yield from 6d: 2.61g (73%), colourless prisms (EtOH), mp 178°
C; ir (KBr, cmÀ1): 3415 (s), 3142 (m), 2915 (m), 2852 (m), 2686
(s), 2604 (m), 2476 (m), 1619 (s), 1557 (m), 1455 (m), 1401 (m);
1H nmr (DMSO-d6, 300 MHz): δ = 2.98 (s, 3H, N-Me), 3.14–3.18
(t, 4H, 2xN-CH2), 3.83–3.91 (t, 4H, 2xN-CH2), 5.28 (s, 1H, NH),
7.41–7.74 (m, 5H, ArH, Hetar); 13C nmr (DMSO-d6, 50MHz):
δ = 41.96 (Me), 44.72 (CH2), 51.14 (CH2), 89.32 (4-C, Hetar),
127.53 (ArH), 127.93 (Ar), 131.99 (ArH), 149.11 (Ar), 146.43
Me), 1.89–1.94 (m, 4H, 2xCH2), 2.39 (s, 3H, Me), 3.42–3.47
(t, 4H, 2xN-CH2), 4.17–4.24 (t, 2H, CH2-O), 11.47 (s, 1H,
NH+); 13C nmr (DMSO-d6, 50 MHz): δ = 12.10 (Me), 14.02
(Me), 24.64 (CH2), 51.48 (CH2), 59.87 (CH2), 97.42 (4-C,
Hetar), 147.97 (5-C, Hetar), 150.38 (3-C, Hetar), 161.68
(C=O); ms (El, 70 eV): m/z (%) = 36 (78), 76 (5), 91 (28), 107
(9), 136 (5), 148 (49), 176 (82), 194 (69), 223 (M+, 100). Anal.
Calcd. for C11H18ClN3O2 (259,73): C, 50.87; H, 6.99; N,
16.18. Found: C, 50.83; H, 6.98; N, 16.21.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Thiadiazines
REFERENCES AND NOTES
3-Piperidino-4-ethoxycarbonyl-5-methyl-pyrazole (10b).
Hydrochloride: From 1.59 g (10 mmol) of 2c. To the mixture was
added, after 10min, 1 mL of ethanolic hydrochloric acid. The
hydrochloride precipitated when the solution was added dropwise
to 100 mL of ether. Yield: 2.11g (77%), colourless rod (EtOH),
mp 159°C; ir (KBr, cmÀ1): 3059 (m), 2954 (m), 2932 (m), 2866
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1
(m), 1725 (s), 1587 (m), 1443 (m), 1278 (m), 1106 (m); H nmr
(CDCl3, 300MHz): δ = 1.39–1.41 (t, 3H, Me), 1.67–1.75 (m, 6H,
3xCH2), 2.03 (s, 3H, Me), 3.65–3.80 (t, 4H, 2xN-CH2), 4.33–4.40
(t, 2H, CH2O), 8.56 (s, 1H, NH), 9.26 (s, 1H, NH+); 13C nmr
(DMSO-d6, 50MHz): δ = 11.72 (Me), 13.92 (Me), 22.02 (CH2),
27.56 (CH2), 53.37 (CH2), 59.92 (CH2), 100.89 (4-C, Hetar),
146.50 (5-C, Hetar), 152.24 (3-C, Hetar), 161.91 (C=O); ms (El,
70eV): m/z (%) = 42 (20), 55 (11), 84 (20), 97 (9), 136 (21), 151
(6), 162 (29), 190 (92), 208 (93), 237 (M+, 100). Anal. Calcd. for
C12H20ClN3O2 (273.76): C, 52.65; H, 7.36; N, 15.35. Found: C,
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52.63; H, 7.39; N, 15.36.
3-Morpholino-4-ethoxycarbonyl-5-methyl-pyrazole (10c).
Hydrochloride: From 1.61 g (10 mmol) of 2d. To the mixture
was added, after 10 min, 1 mL of ethanolic hydrochloric acid.
After 1 h, the solvent was evaporated in vacuo. Yield: 2.04 g
(74%), colourless needles (EtOH), mp 139°C; ir (KBr,
cmÀ1): 2970 (m), 2921 (m), 2864 (m), 2782 (m), 2762 (m),
2695 (m), 2581 (m), 1707 (s), 1587 (m), 1521 (m), 1464
(m), 1442 (m), 1332 (m), 1261 (m), 1116 (s); 1H nmr
(CDCl3, 300 MHz): δ = 1.22–1.27 (t, 3H, Me), 2.36 (s, 3H,
Me), 3.14–3.17 (t, 4H, 2xCH2), 3.68–3.71 (t, 4H, 2xCH2),
4.12–4.19 (t, 2H, CH2-O), 8.08 (s, br, 1H, NH+); 13C nmr
(DMSO-d6, 50 MHz): δ = 12.34 (Me), 14.11 (Me), 50.34
(CH2), 59.30 (CH2), 65.65 (CH2), 99.32 (4-C, Hetar),
146.35 (5-C, Hetar), 156.83 (3-C, Hetar), 162.54 (C=O); ms
(El, 70 eV): m/z (%) = 36 (77), 60 (6), 79 (15), 108 (39), 136
(65), 151 (100), 166 (48), 196 (39), 208 (30), 239 (M+, 91).
Anal. Calcd. for C11H18ClN3O3 (275.73): C, 47.92; H, 6.58;
N, 15.24. Found: C, 48.01; H, 6.5;7 N, 15.14.
3-Morpholino-4-acetyl-5-methyl-pyrazole (10d). Hydrochloride:
1.61 g (10 mmol) of morpholino-thiocarbonyl-hydrazine 1d and
1.3 g (10 mmol) of α-chloro-acetylacetone in 5 mL of ethanol were
refluxed for 5 min. Yield: 1.80 g (73%), colourless prisms (EtOH),
mp 116°C; ir (KBr, cmÀ1): 3229 (m), 3097 (m), 3053 (m), 2968
(m), 2921 (m), 1664 (s), 1627 (s), 1512 (s), 1475 (m), 1456 (m),
1441 (m), 1415 (m), 1118 (m); 13C NMR (DMSO-d6, 50MHz):
δ = 12.64 (Me), 29.13 (Me), 51.48 (CH2), 65.79 (CH2), 110.15 (4-C,
Hetar), 144.90 (5-C, Hetar), 157.65 (3-C, Hetar), 192.10 (C=O); ms
(El, 70 eV): m/z (%) = 28 (22), 43 (31), 67 (11), 79 (14), 108 (53),
123 (60), 136 (98), 166 (79), 178 (100), 209 (M+, 62). Anal. Calcd.
for C10H16ClN3O2 (245.71): C, 48.88; H, 6.56; N, 17.10. Found: C,
48.87; H, 6.56; N, 17.08.
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741, 45.
Acknowledgment. We are grateful to Boehringer Ingelheim
Pharma GmbH & Co. KG for financial support.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet