Cyclocondensations of substituted thiosemicarbazides with 2-bromo-1,2-diphenylethan-1-one

Article abstract of DOI:10.5560/ZNB.2013-3036

The cyclocondensation of 4-methylthiosemicarbazide with 2-bromo-1,2-diphenylethan-1-one in ethanol afforded isomeric 2-methylamino-5,6-diphenyl-6H-3,4-thiadiazine and 2-hydrazono-3- methyl-4,5-diphenyl-2,3-dihydro-1,3-thiazole. A pyrazole was obtained by cyclocondensation and subsequent desulfurization of the thiadiazine when the reaction was carried out in concentrated hydrochloric acid. A chemical proof of the structures has been provided. The product distribution of the cyclizations strongly depends on the substitution pattern of the starting materials, and the cyclizations of methylthiosemicarbazide with 2-bromo-1,2-diphenylethan-1-one behaved considerably different from that of the analogous reactions of α-bromoacetophenone.

Full text of DOI:10.5560/ZNB.2013-3036

Cyclocondensations of Substituted Thiosemicarbazides with 2-Bromo-
1,2-diphenylethan-1-one
Wolf-Diethard Pfeiffera, Helmut Gillea, Ehrenfried Bulkaa, Ashot Saghyanb,c, and
Peter Langerd,e
a
Institut fu¨r Biochemie, Universita¨t Greifswald, Felix-Hausdorff-Str. 4, 17487 Greifswald,
Germany
b
Scientific and Production Center “Armbiotechnology” of NAS RA, 14 Gyurjyan Str., 0056
Yerevan, Armenia
c
Department of Pharmaceutical Chemistry, Yerevan State University, Alex Manoogian Str. 1,
0025 Yerevan, Armenia
Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059
d
e
Rostock, Germany
Reprint requests to Prof. Dr. Peter Langer. Fax: +381 4986412, E-mail: peter.langer@uni-rostock.de
Z. Naturforsch. 2013, 68b, 823 – 830 / DOI: 10.5560/ZNB.2013-3036
Received February 6, 2013
The cyclocondensation of 4-methylthiosemicarbazide with 2-bromo-1,2-diphenylethan-1-one
in ethanol afforded isomeric 2-methylamino-5,6-diphenyl-6H-3,4-thiadiazine and 2-hydrazono-3-
methyl-4,5-diphenyl-2,3-dihydro-1,3-thiazole. A pyrazole was obtained by cyclocondensation and
subsequent desulfurization of the thiadiazine when the reaction was carried out in concentrated hy-
drochloric acid. A chemical proof of the structures has been provided. The product distribution of
the cyclizations strongly depends on the substitution pattern of the starting materials, and the cy-
clizations of methylthiosemicarbazide with 2-bromo-1,2-diphenylethan-1-one behaved considerably
different from that of the analogous reactions of α-bromoacetophenone.
Key words: Cyclizations, Heterocycles, Thiadiazines, Regioselectivity, Thiazoles, Rearrangement
Introduction
1,3,4-Thiadiazines are of considerable bio-
Results and Discussion
In continuation of our studies related to the
chemical and pharmacological relevance. Many synthesis of 1,3,4-thiadiazines [17 – 27], we have
1,3,4-thiadiazine-2-yl-amine derivatives are im- studied the cyclocondensation of 4-methyl- and 4-
portant matrix metalloproteinase inhibitors [1, 2]. phenylthiosemicarbazide with 2-bromo-1,2-diphenyl-
2-Alkylimino- and 2-alkyamino-1,3,4-thiadiazines are ethan-1-one. In principle, the cyclization of 4-alkyl-
used as cardiotonic and spasmolytic agents [3 – 8]. (aryl)-thiosemicarbazides with α-haloketones can
1,3,4-Thiadiazin-2-ones are cardiotonica with cal- result in the formation of three isomeric products,
cium sensitizing activity [9 – 11]. 3-Phenylazo-1H- namely, 2-alkyl(aryl)amino-1,3,4-thiadiazines, 2-hy-
4,2,1-thiadiazine is an agent for treating deficient drazono-3-alkyl(aryl)-2,3-dihydro-1,3-thiazoles and
bone growth [12]. 3-Nitrobenzyl-5-aryl-1,3,4-thia- 2-alkyl(aryl)imino-2,3- dihydro-1,3- thiazol-3-amines.
diazin-2-ones and 1,3,4-thiadiazin-2-ones are phos- The reaction of 4-methylthiosemicarbazide with
phodiesterase IV inhibitors and can be used for 2-bromo-1,2-diphenylethan-1-one in ethanol afforded,
the treatment of tumors and AIDS [13, 14]. 2- via unstable, open-chained S-(1,2-diphenyl-2-oxo-
Nitrosimino-3,6-dihydro-2H-1,3,4-thiadiazines [15], ethyl)-isothiosemicarbazide hydrobromide, two iso-
and N-morpholinyl-, N-thiomorpholinyl- or N- meric products, i.e. 2-methylamino-5,6-diphenyl-6H-
piperidinyl-1,3,4-thiadiazines [16] exhibit antithrom- 1,3,4-thiadiazine (1) and 2-hydrazono-3-methyl-4,5-
botic activities.
diphenyl-2,3-dihydro-1,3-thiazole (2) in 59% and
© 2013 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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W.-D. Pfeiffer et al. · Cyclocondensations of Substituted Thiosemicarbazides
Ph
Ph
O
Me
Ph
O
Me
HN
HN
+
+
NH2
N
R
Br
S
N
H
Ph
Br
S
N
H
R = 4-NO2C6H4
EtOH, r. t.
Ph
Ph
Me
Me
RCHO
N
N
Ph
Ph
O
S
Me
R
HN
NH2
N
Ph
Ph
N
N
NH2
S
S
Br
N
H
2
4
H, RCHO
H
reflux
Ph
Me
N
Me
N
Ph
N
S
Me
5
Ph
Ph
Me
Ph
NH2
Ph
Ph
N
Scheme 2. Chemical proof of the structure of 2.
N
N
N
NH2
Ph
N
NMe
S
NHMe
S
S
phenylethan-1-one. Besides the direct condensation,
product 2 is also formed by acidic steam distillation
of 2-isopropylidenehydrazono-3-methyl-4,5-diphenyl-
2,3-dihydro-1,3-thiazol (5). When the reaction
of 4-methylthiosemicarbazone with 2-bromo-1,2-
1
2
3
59 %
40 %
Scheme 1. Synthesis of 1 and 2.
40% isolated yields, respectively (Scheme 1). The diphenylethan-1-one was carried out in a diluted
formation of isomer 3 was not observed. solution of HCl in ethanol, 1,3,4-thiadiazine 1 was
The combined yield of 1 and 2 is nearly quan- formed as the major product. In contrast to the
titative. Product 1 resides in its 6H-form as indi- analogous reaction of α-bromoacetophenone [30], the
cated by 1H NMR. It is important to note that hydrazono isomer 2 is still formed in 10% yield. The
the cyclization of 4-methylthiosemicarbazide with α- formation of isomer 3 could not be detected.
bromoacetophenone afforded the corresponding thia-
The cyclocondensation of 4-methylthiosemi-
diazine along with a small amount (8.5%) of the hy- carbazide with 2-bromo-1,2-diphenylethan-1-one,
drazono isomer [28 – 30]. In the cyclization reported carried out in concentrated hydrochloric acid, re-
herein, where 2-bromo-1,2-diphenyl-ethan-1-one in- quired a long reaction time at elevated temperature.
stead of α-bromoacetophenone was employed under The main product proved to be 1,3,4-thiadiazine 1
otherwise identical conditions, a different result was which, however, was unstable under these condi-
obtained as the hydrazono isomer 2 was isolated in tions and underwent desulfurization to give pyrazol
a considerable amount (40%). This result suggests that 6a (Scheme 3). Heating of the crude product with
the structure of the electrophile has a strong influence 4-nitrobenzaldehyde allowed for the isolation of
on the product distribution.
The structure of
a small amount of the orange compound 7, which
was unambigously con- is an isomer of 4 and represents a derivative of
2
firmed by reaction with 4-nitrobenzaldehyde to 3-amino-4,5-diphenyl-2,3-dihydro-1,3-thiazole 3.
give 2-(4-nitrobenzylidenhydrazono)-3-methyl-4,5- The cyclocondensation of 4-phenylthiosemicarba-
diphenyl-2,3-dihydro-1,3-thiazole (4) (Scheme 2). zide with 2-bromo-1,2-diphenylethan-1-one afforded
This compound proved to be identical with the product 2-phenylamino-5,6-diphenyl-6H-1,3,4-thiadiazine hy-
obtained from the reaction of 4-nitro-benzaldehyde- drobromide (8) which crystallized as the major product
4-methylthiosemicarbazone with 2-bromo-1,2-di- (Scheme 4). The solution contains 2- phenylimino-
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W.-D. Pfeiffer et al. · Cyclocondensations of Substituted Thiosemicarbazides
825
Ph
Ph
O
Ph
Ph
O
Me
HN
HN
+
+
NH2
NH
2
Ph
Br
S
N
H
S
Br
N
H
conc. HCl
EtO H
Ph
NH2
Ph
NH
2
Ph
Ph
N
Ph
Ph
N
N
N
N
N
Ph
NMe
S
S
NHMe
Ph
NPh
S
S
NHPh
82 %
1
3
8
9
13 %
RCHO
R
R
Ph
N
H
Ph
Ph
N
N
R = 4-NO
C H
6 5
2
N
Ph
N
N
Ph
NMe
S
NPh
Ph
NHMe
S
R = 4-NO2C6H4
7
6a
10
Scheme 3. Cyclocondensation in concentrated hydrochloric
acid.
Scheme 4. Cyclocondensation of 4-phenylthiosemicarbazide
with 2-bromo-1,2-diphenylethan-1-one.
4,5- diphenyl- 2,3- dihydro- 1,3- thiazol- 3- amine (9)
which was reacted with 4-nitrobenzaldehyde to
give 2-phenylimino-3-(4-nitrobenzylidenamino)-2,3-
dihydro-1,3-thiazole (10).
Ph
NH2
Ph
HNO2
N
N
NO
Ph
Ph
NPh
N
S
S
Ph
The reaction of the 2-phenylimide 9 with ni-
trous acid resulted in deamination and nitrosylation
(Scheme 5). The attempt to transform this product into
the corresponding hydrazine derivative by treatment
with zinc in glacial acetic acid failed and resulted in
the cleavage of the nitrosyl group to give known 2-
phenylamino-4,5-diphenyl-1,3-thiazole (11) [29].
The third isomer of this series, 2-hydrazono-3,4,5-
triphenyl-2,3-dihydro-1,3-thiazole (13), is not avail-
able by direct cyclocondensation. However, it can
be obtained in good yield via the 2-isopropylidene-
9
Zn, AcOH
Ph
N
Ph
NHPh
S
11
Scheme 5. Nitrosylation and reduction of 9.
hydrazono derivative 12 (Scheme 6). Compound 12 is which underwent hydrolysis to give hydrazono deriva-
a weak base which is stable in a 2 M aqueous solu- tive 13. The acetone formed has to be removed from
tion of HCl. The addition of conc. hydrochloric acid the equilibrium by steam distillation. The reaction of
resulted in the formation of a soluble hydrobromide 13 with benzaldehyde or 4-nitrobenzaldehyde afforded
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W.-D. Pfeiffer et al. · Cyclocondensations of Substituted Thiosemicarbazides
Ph
Ph
heating in glacial acetic acid (Scheme 7, Table 1). The
kinetic data reveal that 2-phenylamino-5,6-diphenyl-
thiadiazine 8 is much more prone towards desulfur-
ization than the corresponding 2-methylamino deriva-
tive 1.
N
Me
Me
N
Ph
N
S
12
H
Experimental Section
Ph
Ph
Ph
Ph
2-Methylamino-5,6-diphenyl-6H-1,3,4-thiadiazine (1)
RCHO
N
N
R
N
NH2
Method A: 4-Methylthiosemicarbazide (2.1 g, 20 mmol)
was dissolved in hot EtOH (20 mL) and conc. HCl (5 mL).
Ph
Ph
N
N
S
S
2-Bromo-1,2-diphenylethan-1-one was added to this mixture
in portions, and the mixture was refluxed for 5 min. Subse-
quently, the mixture was diluted with H2O (500 mL) and
filtered after addition of active carbon. The free base was
obtained from the filtrate by addition of a conc. solution of
NH3. The crude product contains 2. Fractional crystallization
from benzene yielded 1 (3.4 g, 60.5%); colorless lamella;
m. p. 125 ◦C and 2 (0.56 g, 10%).
Method B: A mixture of thiosemicarbazide (2.1 g
20 mmol) and 2-bromo-1,2-diphenylethan-1-one in EtOH
(20 mL) was stirred with cooling in cold H2O for 1 h.
A precipitate formed which was separated, washed with
EtOH−EtO2 (1 : 1) and dissolved in EtOH (40 mL) and
conc. HCl (5 mL). The mixture was refluxed for 10 min.
Subsequently, the solution was neutralized by a solution of
NH3 and cautiously diluted with H2O (100 mL). The col-
orless crystals formed were filtered off. Yield: 5.0 g (89%);
colorless lamella (benzene); m. p. 125 ◦C. Addition of NH3
to the filtrate gave 2 (0.5 g, 9%).
13
14a, b
R = Ph, 4-NO2C6H4
Scheme 6. Transformation of 12 into 13 and 14.
H
N
AcOH
Heat
Ph
N
N
Ph
N
Ph
S
NHR
S
Ph
NHR
6a
b
1, 8
,
Scheme 7. Desulfurization of 1 and 8.
Table 1. Kinetic parameters for the desulfurization of 1 and 8
to pyrazoles 6a, b in glacial acetic acid.
EA (kJ mol−1
ln k0
)
k80 (s−1
)
t1/2 (min)
◦
R
C
1
8
6a Me 95.2
24.3
6b Ph
2.95·10−4
3.81·10−3
39.1
69.5
18.1
3
Method C: From the filtrate of 2 (Method A) by addition
of a solution of NH3 and H2O. Yield: 3.4 g (61%); colorless
lamella (benzene); m. p. 125 ◦C. – IR ( KBr, cm−1): ν = 572
˜
(m), 694 (s), 728 (m), 764 (m), 973 (m), 1060 (m), 1169 (m),
1262 (m), 1354 (m), 1400 (s), 1441 (m), 1514 (s), 1538 (s),
1639 (m), 2941 (m), 3031 (m), 3262 (m), 3416 (m). – 1H
NMR (300 MHz, CDCl3): δ = 2.98 (s, 3H, Me), 5.30 (s,
1H, 6-CH), 5.70 (s, br, 1H, NH), 7.22–7.84 (m, 10H, ArH).
the corresponding benzylidene-hydrazono derivatives
14a, b.
The reaction of 4-phenylthiosemicarbazide with 2-
bromo-1,2-diphenylethan-1-one in conc. hydrochloric
acid-EtOH (1 : 1) only proceeded at elevated tem-
perature and afforded 3-phenylamino-4,5-diphenyl-
pyrazole (6b) by desulfurization of 1,3,4-thiadiazine
8. The phenylimide isomer was only formed in 0.6%
yield. While the reaction of 4-phenylthiosemicarbazide
with 2-bromo-1,2-diphenylethan-1-one in ethanol pro-
ceeds similarly to the analogous reaction of bromoace-
tophenone [31], the reaction proceeds differently in hy-
drochloric acid. This can be explained by the strong in-
fluence of the substitution pattern of the thiadiazine on
the stability towards acid. To shed further light on this
observation, we compared the rate of desulfurization of
–
13C NMR (75 MHz, CDCl3): δ = 39.26 (Me), 126.48,
127.30, 128.32, 128.61, 128.79, 128.96, 129.57, 129.83,
135.83, 136.15, 147.26. – MS (EI, 70 eV): m/z(%) = 281(4)
[M]+, 252 (52), 207 (3), 154 (4), 104 (2), 82 (11), 28 (100).
– Anal. for C16H15N3S (281.38): calcd. C 68.30, H 5.37, N
14.93; found C 68.31, H 5.39, N, 14.95.
3-Methyl-4,5-diphenyl-thiazolone-(2)-hydrazone (2)
Hydrobromide:
4-Methylthiosemicarbazide
(2.1 g,
20 mmol) and 2-bromo-1,2-diphenylethan-1-one (5.5 g,
20 mmol) in EtOH (20 mL) was stirred for 15 min at 20 ◦C,
and the mixture was refluxed for 5 min. After cooling, the
crystalline precipitate was filtered off. Yield: 2.9 g 2. HBr
1,3,4-thiadiazines 1 and 8 (to give pyrazoles 6a, b) by (40%); colorless needles ( EtOH); m. p. 180 ◦C. The work
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W.-D. Pfeiffer et al. · Cyclocondensations of Substituted Thiosemicarbazides
827
up of the filtrate followed the procedure as given for 1. – HCl (1 mL) was refluxed 2 h. Yield: 3.23 g, (78%); red nee-
IR ( KBr, cm−1): ν = 507 (w), 697 (m), 762 (m), 782 (m), dles (ethyl acetate); m. p. 198 ◦C. – IR ( KBr, cm−1): ν = 694
938 (m), 1084 (m), 1100 (w), 1356 (s), 1420 (m), 1443 (m), (m), 841 (m), 924 (m), 1018 (m), 1065 (s), 1106 (m), 1334
1493 (m),1565 (s), 1642 (s), 3058 (m), 3173 (m), 3299 (s), (s), 1420 (m), 1507 (s), 1588 (s). – 1H NMR (300 MHz,
3427 (m). – 1H NMR (300 MHz, [D6]DMSO): δ = 3.12 (s, [D6]DMSO): δ = 3.41 (s, 3H, Me), 7.04–8.30 (m, 14H,
3H, Me) 4.52 (s, br, 2H, NH2) 6.99–7.54 (m, 10H, ArH). ArH), 8.45 (s, 1H, CH). – MS (EI, 70 eV): m/z(%) = 415 (2)
˜
˜
–
13C NMR (75 MHz, [D6]DMSO): δ = 30.84 (C, Me), [M]+, 226 (2), 178 (2), 148 (2), 122 (3), 102 (4), 56 (3), 43
108.74 (C-5), 126.86 (CH, Ar), 127.70 (CH, Ar), 128.00 (9), 32 (32), 28 (100). – Anal. for C23H18N4O2S (414.48):
(CH, Ar), 128.78 (CH, Ar), 128.90 (CH, Ar), 129.13 (CH, calcd. C 66.65, H 4.38, N 13.52; found C 66.38, H 4.40, N
Ar), 129.39 (Ar), 130.58 (Ar), 131.42 (C-4), 136.47 (C-2). 13.53.
– MS (EI, 70 eV): m/z(%) = 281 (100) [M]+, 266 (8), 225
(4), 178 (16), 118 (7), 103 (8), 77 (8), 52 (4), 28 (29). –
Acetone-[3-methyl-4,5-diphenyl-thiazolon-(2)]-azine (5)
Anal. for C16H16N3SBr (362.29): calcd. C 53.04, H 4.45 N
11.60; found C 53.24, H 4.78 N, 11.20.
Free base (Method A): The free base of 2 was obtained
quantitatively from a hot EtOH solution of the hydrobromide
by addition of conc. NH3. Yield: 3.32 g (100%); yellow nee-
dles ( EtOH); m. p. 178 ◦C.
Method B: 5 (3.21 g, 10 mmol) in EtOH (30 mL) and
2 M HCl (5 mL) was subjected to steam distillation for
30 min. The distillation residue was filtered to remove impu-
rities. NH3 solution was added to the filtrate and a precipitate
formed. Yield: 2.5 g (89%).
A mixture of acetone-4-methylthiosemicarbazone (2.9 g,
20 mmol) and 2-bromo-1,2-diphenylethan-1-one (5.5 g,
20 mmol) in acetone (20 mL) was refluxed for 2 h. After
cooling, the solution was neutralized with NH3. Yield: 5.6 g
(87%); yellow lamella ( EtOH); m. p. 126 ◦C. – IR ( KBr,
cm−1): ν = 701 (m), 744 (m), 792 (m), 1065 (w), 1251 (w),
˜
1345 (m), 1357 (m), 1420 (m), 1494 (w), 1557 (s), 1625
(s), 2910 (w), 3024 (w), 3432 (w). – 1H NMR (300 MHz,
CDCl3): δ = 2.08 (s, 3H, Me) 2.10 (s, 3H, Me) 3.19 (s,
3H, Me) 6.99–7.44 (m, 10H, ArH). – 13C NMR (75 MHz,
[D6]DMSO): δ = 17.90 (Me), 24.93 (Me), 32.62 (Me, N-
3, Hetar), 112.03 (C-5), 126.53 (CH, ArH), 127.07 (CH,
ArH), 128.34 (CH, ArH), 129.09 (CH, Ar), 129.38 (CH, Ar),
130.31 (CH, ArH), 130.37 (Ar), 132.18 (Ar), 135.17 (N=C),
157.55 (C-5), 163.62 (C-2). – MS (EI, 70 eV): m/z(%) = 321
(100) [M]+, 265 (17), 250 (6), 225 (9), 178 (17), 118 (28),
77 (10), 36 (24), 28 (16). – Anal. for C19H19N3S (321.44):
calcd. C 70.99, H 5.96, N 13.07: found C 70.91, H 5.92, N
13.08.
Method C: From the mother liquor of 1 (Method A), yield:
0.56 g (10%). – IR ( KBr, cm−1): ν = 508 (w), 697 (m), 725
˜
(m), 761 (m), 938 (w), 1083 (m), 1099 (m), 1356 (s), 1420
(m), 1443 (m), 1493 (m), 1565 (s), 1590 (s), 1642 (s), 3173
(w), 3299 (m), 3427 (m). – 1H NMR (300 MHz, CDCl3):
δ = 3.08 (s, 3H, Me) 4.40 (s, br, 2H, NH2) 6.97–7.44 (m,
10H, ArH). – 13C NMR (75 MHz, [D6]DMSO): δ = 32.14
(C, Me), 108.74 (C-5), 126.06 (CH, Ar), 126.79 (CH, Ar),
128.29 (CH, Ar), 129.08 (CH, Ar), 129.28 (CH, Ar), 130.16
(CH, Ar), 130.72 (Ar), 132.70 (Ar), 135.79 (C-4), 156.30 (C-
2). – MS (EI, 70 eV): m/z(%) = 281 (100) [M]+, 266 (8),
225 (4), 178 (16), 118 (7), 103 (8), 77 (8), 52 (4), 28 (29). –
Anal. for C16H15N3S1 (281.38): calcd. C 68.30, H 5.37, N
14.93; found C 68.32, H 5.40, N 14.95.
3-Methylamino-4,5-diphenyl-pyrazole (6a)
Method A: 1 (2.81 g, 10 mmol) in glacial acetic acid
(20 mL) was refluxed for 30 min. After cooling, the solu-
tion was filtered to remove sulfur. Concentrated hydrochloric
acid (1 mL) was added to the filtrate. The solution was di-
luted with H2O (200 mL). After addition of active carbon,
the mixture was heated, and the hot solution was filtered.
On basification with NH3, a precipitate was obtained. Yield:
4-Nitrobenzaldehyde-[(3-methyl-4,5-diphenyl-1,3-
thiazolon-(2)]-azine (4)
Method A: A mixture of 2 (2.81 g, 10 mmol) and 4- 2.3 g (92.5%); colorless lamella ( EtOH); m. p. 176 ◦C.
nitrobenzaldehyde (1.51 g, 10 mmol) in EtOH (30 mL) was Method B: A mixture of 4-methylthiosemicarbazide
refluxed briefly. Yield: 4.06 g (98%); red needles (ethyl ac- (2.1 g, 20 mmol) in conc. hydrochloric acid (15 mL) and
etate); m. p. 198 ◦C.
EtOH 10 mL) was heated under reflux, and 2-bromo-1,2-
Method B: A mixture of 4-nitrobenzaldehyde-4- diphenylethan-1-one (2.75 g, 10 mmol) was added. The so-
methylthiosemicarbazone (2.38 g, 10 mmol) and 2-bromo- lution was refluxed for 2 h and then diluted with H2O
1,2-diphenylethan-1-one (2.75 g, 10 mmol) in EtOH (200 mL). Active carbon was added to the solution, the latter
(100 mL) was refluxed for 2 h. After cooling, the mixture was heated briefly, and the hot solution was filtered. The mix-
was neutralized with NH3. Yield: 3.52 g, 85%); red needles ture was neutralized by addition of a aqueous NH3 solution.
(ethyl acetate); m. p. 198 ◦C.
A crystalline precipitate was separated. Yield: 3.2 g (64%).
Method C: A mixture of 5 (3.21 g, 10 mmol) and 4- The mother solution was worked up accordingly to give 7
nitrobenzaldehyde (1.51 g, 10 mmol) in EtOH (100 mL) and (0.37 g, 4.5%; m. p. 173 ◦C. – IR ( KBr, cm−1): ν = 698
˜
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W.-D. Pfeiffer et al. · Cyclocondensations of Substituted Thiosemicarbazides
(s), 735 (m), 771 (s), 1413 (w), 1441 (w), 1488 (m), 1532 NMR (75 MHz, [D6]DMSO): δ = 115.43, 116.62, 126.59,
(s), 1601 (m), 2952 (m), 3054 (m), 3244 (s), 3404 (m). – 126.69, 127.47, 127.62, 128.15, 128.48, 128.67, 129.68,
1H NMR (300 MHz, CDCl3): δ = 2.73 (s, 3H, Me), 7.16– 129.71, 131.14, 131.96, 144.35, 146.49. – MS (EI, 70 eV):
7.33 (m, 10H, ArH), 12.01 (s, br, 1H, NH). – 13C NMR m/z(%) = 343 (13) [M]+, 311 (100), 310 (25), 256 (3), 192
(75 MHz, [D6]DMSO): δ = 30.59 (Me), 125.66, 127.20, (6), 179 (9), 178 (10), 160 8(5), 105 (6), 82 (20), 80 (21),
127.52, 128.29, 128.43, 129.27, 133.38. – MS (EI, 70 eV): 77 (12), 65 (19), 32 (14), 28 (49). – Anal. for C21H18BrN3S
m/z(%) = 249 (42) [M]+, 248 (13) 173 (4), 104 (16), 77 (3), (424.36): calcd. C 59.44, H 4.28 N 9.40; found C 59.54, H
44 (18), 32 (19), 28 (100). – Anal. for C16H15N3 (249.31): 4.31, N 9.92.
calcd. C 77.08, H 6.06, N 16.86; found C 77.09, H 6.08, N,
16.91.
Free base: The hydrobromide was dissolved in EtOH and
an aqueous NH3 solution was carefully added. Purification
of 8 (4.2 g, 10 mmol) was performed by mild heating in pyri-
dine and addition of EtOH to give a precipitate. Yield: 2.74 g
(80%); colorless prisms (pyridine- EtOH); m. p. 207 ◦C. – IR
3-Anilino-4,5-diphenyl-pyrazole (6b)
Method A: A mixture of 8 (3.43 g, 10 mmol) with glacial
acetic acid (50 mL) was refluxed for 10 min. The solution
was filtered and diluted with H2O (200 mL). The precipitate
was filtered rapidly using vacuum. Yield: 3.08 g (99%); col-
orless needles (benzene); m. p. 182 ◦C.
( KBr, cm−1): ν = 563 (m), 637 (m), 694 (s), 720 (m), 767
˜
(s), 852 (m), 914 (m), 1005 (m), 1074 (w), 1142 (m), 1176
(m), 1205 (m), 1281 (m), 1310 (m), 1447 (m), 1495 (s), 1578
(s), 2914 (s), 3064 (m), 3179 (m). – 1H NMR (300 MHz,
CDCl3): δ = 5.30 (s, 1H, 6-CH) 6.99–7.76 (m, 15H, ArH)
8.70 (s, br, 2H, NH2). – 13C NMR (75 MHz, [D6]DMSO):
δ = 120.54, 122.53, 123.78, 126.01, 126.69, 127.26, 127.84,
128.06, 128.17, 128.52, 128.76, 129.46, 135.54, 137.64,
149.51. – MS (EI, 70 eV): m/z(%) = 343 (47) [M]+, 311 (3),
207 (4), 179 (31), 178 (22), 151 (4), 91 84), 77 (10), 43 (7),
32 (19), 28 (100). – Anal. for C21H17N3S (343.45): calcd. C
73.44, H 4.99, N 12.23; found C 73.50, H 5.02, N 12.35.
Method B: 4-Phenylthiosemicarbazide (1.67 g, 10 mmol)
in EtOH (20 mL) and conc. HCl (20 mL) was heated un-
der reflux, and 2-bromo-1,2-diphenylethan-1-one (2.75 g,
10 mmol) was added. The solution was refluxed for 1 h,
and the hot solution was filtered. The mixture was allowed
to settle at −10 ◦C (refrigerator). The resultant precipitate
was suspended in EtOH (10 mL), an aqueous NH3 solu-
tion was added, and the solution was diluted with H2O
(100 mL). Yield: 1.7 g (55%), colorless needles (benzene);
m. p. 182 ◦C. The mother solution was worked up accord-
2-Phenylimino-3-amino-4,5-diphenyl-2,3-dihydro-1,3-
thiazole (9)
ingly to give 10. – IR ( KBr, cm−1): ν = 696 (s), 749 (s), 769
˜
(m), 1016 (w), 1240 (m), 1312 (m), 1442 (m),1463 (m), 1497
(s), 1537 (s), 1572 (m), 1602 (s), 3031 (m), 3056 (m), 3189
(m), 3426 (m). – 1H NMR (300 MHz, CDCl3): δ = 5.88 (s,
br, 1H, NH), 6.87 (s, br, 1H, NH) 7.30–7.42 (m, 15H, ArH).
The filtrate of 8 was neutralized with NH3 and a precipi-
tate was formed. Yield: 2.0 g (13%); yellow needles ( EtOH);
m. p. 162 ◦C. – IR ( KBr, cm−1): ν = 694 (s), 725 (w), 765
˜
(m), 913 (m), 1203 (w), 1291 (w), 1446 (m), 1492 (m), 1517
(w), 1576 (s), 2919 (w), 3059 (w), 3433 (m). – 1H NMR
(300 MHz, CDCl3): δ = 4.56 (s, br, 2H, NH2) 6.99–7.76 (m,
15H, ArH). – 13C NMR (50 MHz, [D6]DMSO): δ = 105.66
(C-5), 120.96 (CH, Ar), 122.59 (CH, Ar), 126.78 (CH, Ar),
127.50 (CH, Ar), 128.12 (CH, Ar), 128.42 (CH, Ar), 128.68
(CH, Ar), 129.35 (CH, Ar), 130.45 (Ar), 130.61 (Ar, CH),
131.95 (Ar), 136.18 (Ar), 150.56 (C-4), 156.07 (C-2). –
MS (EI, 70 eV): m/z(%) = 343 (100) [M]+, 328 (40), 327
(11), 251 (11), 223 (9), 211 (4), 210 (21), 179 (16) 178 (30),
165 (24), 121 (15), 77 (33), 28 (20). – Anal. for C21H17N3S
(343.45): calcd. C 73.44, H 4.99, N 12.23; found C 73.30, H
5.01, N 12.33.
–
13C NMR (75 MHz, [D6]DMSO): δ = 114.47, 117.68,
126.32, 127.31, 127.81, 128.35, 128.48, 129.59, 132.50.
MS (EI, 70 eV): m/z(%) = 311, (100) [M]+, 218 (5), 207
(2), 178 (4), 155 (2), 104 (3), 77 (7), 28 (16). – Anal. for
C21H17N3 (311.38): calcd. C 81.00, H 5.50, N 13.49; found
C 81.04, H 5.53, N 13.51.
2-Anilino-5,6-diphenyl-1,3,4-thiadiazine (8)
Hydrobromide: A solution of 4-phenylthiosemicarbazide
(13.75 g, 50 mmol) and 2-bromo-1,2-diphenylethan-1-one
(13.75 g, 50 mmol) in EtOH (70 mL) was stirred for 20 min
with cooling by cold H2O. The product was isolated by cool-
ing of the mixture and filtration of the precipitate. Yield:
17.4 g (82%); yellow prisms; m. p. 164 ◦C. Partial desulfu-
rization of 8. HBr occured during the recrystallization. – IR
( KBr, cm−1): 574 (w), 637 (w), 693 (m), 763 (m), 1225 (w),
1329 (m), 1383 (m), 1449 (m), 1494 (s), 1538 (s), 1571 (s),
3-[(4-Nitrobenzylideneamino)-4,5-diphenyl-1,3-thiazolon-
(2)]phenylimide (10)
Method A: A mixture of 9 (343 mg, 1 mmol) and 4-
1602 (s), 2774 (m), 2912 (m), 2979 8m), 3161 (m), 3410 nitrobenzaldehyde (151 mg, 1 mmol) in EtOH (10 mL) was
(m). – 1H NMR (300 MHz, [D6]DMSO): δ = 5.35 (s, 1H, 6- refluxed for 15 min. Yield: 460 mg (97%); orange needles
CH) 6.95–7.72 (m, 15H, ArH) 8.72 (s, br, 2H, NH2). – 13C (ethyl acetate); m. p. 193 ◦C.
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W.-D. Pfeiffer et al. · Cyclocondensations of Substituted Thiosemicarbazides
829
Method B: The mother liquor of the recrystallization of 6b 156.00 (C-2). – MS (EI, 70 eV): m/z(%) = 343 (100) [M]+,
(Method B) and 4-nitrobenzaldehyde (10 mg, 0.066 mmol) 334 (15), 333 (14), 318 (13), 317 (66), 257 (20), 256 (51),
were refluxed briefly to give a precipitate. Yield: 28.6 mg 198 (10), 197 (83), 180 (18), 165 (22), 151 (30), 121 (20),
(0.6%). – IR ( KBr, cm−1): ν = 509 (w), 568 (w), 694 119 (16), 114 (13), 91 (50), 77 (35), 28 (56). – Anal. for
˜
(m), 752 (m), 753 (m), 838 (m), 1108 (w), 1188 (m), C21H17N3S (343.45): calcd. C 73.44, H 4.99, N 12.23; found
1267 (m), 1341 (s), 1446 (w), 1493 (m), 1516 (s), 1582 C 73.46, H 5.01, N 12.28.
(s), 1606 (s), 1630 (m), 3435 (m). – 1H NMR (300 MHz,
2-Benzylidenehydrazono-3,4,5-triphenyl-2,3-dihydro-1,3-
thiazole (14a)
[D6]DMSO): δ = 7.15 – 8.27 (m, 19H, ArH), 8.87 (s, 1H
CH). – 13C NMR (75 MHz, [D6]DMSO): δ = 123.63 (CH,
Ar), 125.5 (CH, Ar), 126.0 (CH, Ar), 128.02 (CH, Ar),
128.37, 138.86, 140.07, 140.45, 147.65 (C-4), 176.50 (C-2).
– MS (EI, 70 eV): m/z(%) = 476 (14) [M]+, 328 (100), 300
(35), 207 (19), 165 (42), 150 (56), 93 (62), 51 (20), 28 (28).
– Anal. for C28H20N4O2S (476.56): calcd. C 70.57, H 4.23,
N 11.76; found C 70.58, H 4.25, N 11.81.
A mixture of 13 (3.43 g, 10 mmol) and benzaldehyde
(1.06 g, 10 mmol) in EtOH (20 mL) was refluxed briefly
to give a precipitate. Yield: 4.09 g (95%); yellow needles
( PrOH); m. p. 207 ◦C. – IR ( KBr, cm−1): ν = 514 (w),
˜
593 (w), 694 (m), 732 (w), 756 (m), 1023 (w), 1336 (m),
1360 (w), 1447 (w), 1491 (s), 1525 (s), 1574 (m), 1611
(m), 3027, (w), 3433m). – 1H NMR (300 MHz, CDCl3):
δ = 7.03 – 7.75 (m, 20H, ArH), 8.30 (s, 1H, CH). – 13C
Acetone-[3,4,5-triphenyl-thiazolon-(2)]-azine (12)
A mixture of acetone-4-methylthiosemicarbazone (20.7 g, NMR (75 MHz, [D6]DMSO): δ = 114.34 (CH, Ar), 126.88
100 mmol) and 2-bromo-1,2-diphenylethan-1-one (27.5 g, (CH, Ar), 127.19 (CH, Ar), 127.54 (CH, Ar), 127.64 (CH,
10 mmol) in acetone (100 mL) was refluxed for 2 h. A precip- Ar), 127.82 (CH, Ar), 127.98 (CH, Ar), 128.29 (CH, Ar),
itate formed. Yield: 35.3 g (92%); grey bright needles (ethyl 128.48 (CH, Ar), 128.56 (CH, Ar), 128.79 (CH, Ar), 129.41
acetate); m. p. 205 ◦C. – IR ( KBr, cm−1): ν = 591 (w), 694 (CH, Ar), 130.02 (Ar), 130.68 (CH, Ar), 131.68 (Ar), 135.02
˜
(s), 734 (m), 764 (m), 801 (w), 817 (w), 1028 (w), 1078 (m), (Ar), 135.13 (Ar), 137.14 (C-4), 151.53 (HC=N), 167.70 (C-
1261 (m), 1344 (s), 1443 (m), 1492 (s), 1559 (s), 1594 (s), 2). – MS (EI, 70 eV): m/z(%) = 432 (37) [M]+, 314 (4), 178
1628 (s), 3053 (w). – 1H NMR (300 MHz, CDCl3): δ = 1.88 (3), 77 (9), 44 (6), 32 (21), 28 (100). – Anal. for C28H21N3S
(s, 3H, Me), 2.02 (s, 3H, Me), 7.03 – 7.26 (m, 15H, ArH). (431.56): calcd. C 77.93, H 4.90, N 9.74; found C 77.95, H
–
13C NMR (75 MHz, [D6]DMSO): δ = 17.50 (Me), 23.70 4.92, N, 9.93.
(Me), 113.0 (C-5), 126.51 (CH, Ar), 126.94 (CH, Ar), 127.26
(CH, Ar), 127.77 (CH, Ar), 127.91 (CH, Ar), 128.11 (CH,
Ar), 128.49 ( CH, Ar), 130.23 (CH, Ar), 131.92 (Ar), 135.12
(Ar), 137.47 (C-4), 158.27 (N=C), 163.82 (C-2). – MS (EI,
70 eV): m/z(%) = 383 (100) [M]+, 328 (7), 327 (20), 326
(6), 210 (12), 180 (30), 178 (12), 165 (12), 77 (20), 44 (6),
28 (22). – Anal. for C24H21N3S (383.51): calcd. C 75.1, H
5.52 N 10.96; found C 75.20, H, 5.61, N 10.91.
4-Nitrobenzaldehyde-[3,4,5-triphenyl-thiazolone-(2)]-azine
(14b)
Method A: A mixture of 13 (3.43 g, 10 mmol) and 4-
nitrobenzaldehyde (1.51 g, 10 mmol) in EtOH (30 mL) was
refluxed briefly. Yield: 4.57 g (96%); red lamella (dioxane-
EtOH); m. p. 222 ◦C.
Method B: A mixture of 4-nitrobenzaldehyde-4-
phenylthiosemicarbazone (3.0 g, 10 mmol) and 2-bromo-
1,2-diphenylethan-1-one (2.75 g, 10 mmol) in EtOH
3,4,5-Triphenyl-thiazolone-(2)-hydrazone (13)
Compound 12 (11.4 g, 30 mmol) in hydrochloric acid (100 mL) was refluxed for 2 h. Yield: 4.05 g, 85%); red
(18%, 150 mL) was subjected to steam distillation for 1 h. lamella (dioxane- EtOH); m. p. 222 ◦C.
The distillation residue was filtered. After cooling an oil pre-
Method C: A mixture of 12 (3.83 g, 10 mmol) and 4-
cipitated which, on basification with a NH3 solution, gave nitrobenzaldehyde (1.51 g, 10 mmol) in EtOH (100 mL) and
the free base as a solid. Yield: 9.8 g (95%); yellow prisms HCl (1 mL) was refluxed 2 h. Yield: 3.57 g, (75%). – IR
(pyridine); m. p. 210 ◦C. – IR ( KBr, cm−1): ν = 590 (w), (KBr, cm−1): ν = 513 (w), 595 (m), 695 (s), 735 (m),
695 (m), 725 (m), 757 (m), 1074 (m), 1232 (m), 1353 (s), 755 (m), 830 (m), 848 (m), 873 (m), 1026 (m), 1047 (s),
1401 (m), 1446 (m), 1493 (s), 1564 (m), 1593 (m), 1642 1106 (m), 1175 (w), 1335 (s), 1482 (s), 1497 (s), 1590 (s),
(s), 3180 (m), 3299 (m), 3428 (m). – 1H NMR (300 MHz, 3062 (w), 3434 (m). – 1H NMR (300 MHz, [D6]DMSO):
CDCl3): δ = 3.70 (s, br, 2H, NH2) 7.14 – 7.24 (m, 15H, δ = 7.11 – 7.95 (m, 15H, ArH), 8.30 (s, 1H, CH). – 13C
ArH). – 13C NMR (50 MHz, [D6]DMSO): δ = 110.40 (C- NMR (50 MHz, [D6]DMSO): δ = 115.31 (C-5), 123.94
5), 126.55 (CH, Ar), 127.17 (CH, Ar), 127.29 (CH, Ar), ( CH−Ar), 127.46 (CH, Ar), 127.61 (CH, Ar), 128.23 (CH,
127.29 (CH, Ar), 128.26 (CH, Ar), 128.35 (CH, Ar), 128.42 Ar), 128.32 (CH, Ar), 128.57 (CH, Ar), 128.75 (CH, Ar),
(CH, Ar), 128.50 (CH, Ar), 129.22 (CH, Ar), 130.40 (CH, 128.95 (CH, Ar), 129.04 (CH, Ar), 129.76 (Ar), 130.75
Ar), 130.65 (Ar), 132.55 (Ar), 135.18 (Ar), 137.99 (C-4), (CH, Ar), 131.36 (Ar), 135.45 (Ar), 136.93 (Ar), 141.42
˜
˜
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830
W.-D. Pfeiffer et al. · Cyclocondensations of Substituted Thiosemicarbazides
(Ar), 147.27 (C-4), 149.00 (N=CH), 169.69 (C-2). – MS (EI, (m), 1516 (s), 1541 (s), 1580 (m), 1598 (m), 2989 (m), 3139
70 eV): m/z(%) = 476 (100) [M]+, 447 (4), 314 (4), 312 (3), (m), 3340 (m). – 1H NMR (300 MHz, [D6]DMSO): δ =
210 (1), 178 (6), 77 (4), 28 (4). – Anal. for C28H20N4O2S 7.21 – 7.56 (m, 9H, ArH), 8.27 (s, 1H, CH), 10.33 (s, br, 1H,
(476.55): calcd. C 70.57, H 4.73, N 11.76; found C 70.50, H NH), 12.10 (s, br, 1H, NH). – MS (EI, 70 eV): m/z(%) = 300
4.21, 11.82.
(51) [M]+, 207 (26), 176 (26), 150 (48), 149 (18), 148 (18),
136 (19), 135 (30), 119 (17), 118 (16), 104 (14), 103 (31),
93 (100), 92 (20), 91 (12), 89 (16), 77 (62), 51, 76 (42), 75
(20), 66 (31), 64 (19), 51 (27), 50 (26), 32 (22), (27), 28 (83).
4-Nitrobenzaldehyde-4-phenylthiosemicarbazone
IR ( KBr, cm−1): ν = 508 (w), 693 (m), 748 (m), 843 – Anal. C14H12N4O2S (300.34): calcd. C 55.99, H 4.03, N
(m), 1091 (m), 1107 (m), 1192 (s), 1262 (s), 1340 (s), 1448 18.65; found C 55.90, H 4.05, N 18.70.
˜
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