Unexpected ring enlargement of 2-hydrazono-2,3-dihydro-1,3-thiazoles to 1,3,4-thiadiazines

Article abstract of DOI:10.1002/hlca.201300077

The cyclization of thiosemicarbazide with α-bromoacetophenone can result in the formation of isomeric 1,3,4-thiadiazines and two different thiazoles. We studied the use of 4-methyl- and 4-ethylthiosemicarbazide as dinucleophilic building blocks. In this c

Full text of DOI:10.1002/hlca.201300077

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Helvetica Chimica Acta – Vol. 97 (2014)
Unexpected Ring Enlargement of 2-Hydrazono-2,3-dihydro-1,3-thiazoles to
1,3,4-Thiadiazines
by Wolf-Diethard Pfeiffer*a), Klaus-Dieter Ahlersa), Ashot S. Saghyanb)c), Alexander Villingera), and
Peter Langer*d)e)
a) Institut fꢀr Biochemie, Universitꢁt Greifswald, Felix-Hausdorff-Straße 4, DE-17487 Greifswald
b) Scientific and Production Center ꢂArmbiotechnologyꢃ of NAS RA, 14 Gyurjyan Str., 0056 Yerevan,
Armenia
c) Department of Pharmaceutical Chemistry, Yerevan State University, Alex Manoogian Str. 1, 0025
Yerevan, Armenia
d) Institut fꢀr Chemie, Universitꢁt Rostock, Albert-Einstein-Straße 3a, DE-18059 Rostock
(fax: þ 49-381-4986412; e-mail: peter.langer@uni-rostock.de)
e) Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock, Albert-Einstein-Straße 29a, DE-18059
Rostock
In memoriam Prof. Dr. Ehrenfried Bulka
The cyclization of thiosemicarbazide with a-bromoacetophenone can result in the formation of
isomeric 1,3,4-thiadiazines and two different thiazoles. We studied the use of 4-methyl- and 4-
ethylthiosemicarbazide as dinucleophilic building blocks. In this context, we observed an unprecedented
rearrangement of a 2-hydrazono-2,3-dihydrothiazole to a 1,3,4-thiadiazine. While ring contractions of
1,3,4-thiadiazines to thiazoles are quite common, ring enlargements are new. The course of the reaction
depends on the substitution pattern of the substrate.
Introduction. – 1,3,4-Thiadiazines are of considerable biological and pharmaco-
logical relevance. Many 1,3,4-thiadiazin-2-amine derivatives are important matrix
metalloproteinase inhibitors [1]. 1,3,4-Thiadiazines exhibit cardiotonic [2] and
antithrombotic [3] activities. In continuation of our previous work on 1,3,4-thiadiazines
[4 – 16], we studied the use of 4-methyl- and 4-ethylthiosemicarbazide as dinucleophilic
building blocks in their reaction with a-bromoacetophenone. In this context, we
observed an unprecedented rearrangement of a 2-hydrazono-2,3-dihydrothiazole to a
1,3,4-thiadiazine. While ring contractions of 1,3,4-thiadiazines to thiazoles are quite
common, ring enlargements are new. The course of the reaction depends on the
substitution pattern of the substrate.
Results and Discussion. – The reaction of 4-methyl- and 4-ethylthiosemicarbazide,
2a and 2b, respectively, with a-bromoacetophenone (1a) resulted, as reported by Bose
[17], in the formation of 1,3,4-thiadiazines 3a and 3b (Scheme 1 and Table). The
cyclization involved the (more nucleophilic) NH2 group and the S-atom of the
thiosemicarbazide. We observed the formation of 2-hydrazono derivatives 8a and 8b as
side products. These compounds, which were formed by cyclization via the substituted
N- and the S-atom, were isolated in form of their benzylidenehydrazono derivatives 7a
ꢄ 2014 Verlag Helvetica Chimica Acta AG, Zꢀrich

Helvetica Chimica Acta – Vol. 97 (2014)
77
and 7b, respectively. This result prompted us to study the cyclization of a-
bromoacetophenones 1a and 1b with thiosemicarbazones 4a – 4e which can be
regarded as protected thiosemicarbazides. These reactions afforded the 2,3-dihydro-
2-(isopropylidenehydrazono)-1,3-thiazoles 5a – 5d and the 2,3-dihydro-2-(4-nitrobenz-
ylidenehydrazono)-1,3-thiazoles 6a – 6c, respectively. The structure of 6c was inde-
pendently established by X-ray crystal-structure analysis (Fig.). Hydrolysis of 2-
hydrazono-2,3-dihydro-5-methylthiazoles 5c and 5d with 2m HCl afforded the
deprotected 2-hydrazono-2,3-dihydrothiazoles 8c and 8d, respectively, by cleavage of
the hydrazone moiety.
Scheme 1. Cyclization of 1a with 2a and 2b
In contrast to the hydrolysis of 5c and 5d, all attempts to isolate 8a and 8b (R1 ¼ Me,
Et) by hydrolysis of 5-unsubstitituted 2-hydrazono-2,3-dihydrothiazoles 5a and 5b
failed. Interestingly, the 2-(alkylamino)-5-phenyl-6H-1,3,4-thiadiazines 3a and 3b,

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Helvetica Chimica Acta – Vol. 97 (2014)
Fig. 1. ORTEP Plot of 6c
Table 1. Yields of 1,3,4-Thiadiazines, Thiosemicarbazones, and 2,3-Dihydro-1,3-thiazoles
R1
R2
R3
R4
Yield [%]a)
3a
3b
4a
4b
4c
4d
4e
4f
4g
5a
5b
5c
5d
6a
6b
6c
7a
7b
8c
8d
Me
Et
73 (A), 95 (B), 58 (C) 88 (D), 70 (E)
50 (A), 95 (B), 50 (C) 85 (D), 66 (E)
98
97
81
57
97
97
94
96
95
82
Me
Et
iPr
Me
Et
Me
Et
Me
Et
Me
iPr
Me
Et
iPr
Me
Et
Me
Me
Me
4-NO2C6H4
4-NO2C6H4
Ph
Ph
Me
Me
Me
Me
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
Ph
Ph
–
Me
Me
Me
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
H
H
Me
Me
H
H
Me
H
H
Me
Me
84
30 (A), 71 (B)
39 (A), 91 (B), 1.1 (C)
83 (A), 71 (B)
86
94
44
82
Me
iPr
–
–
–
a) Yields of isolated products (in brackets, method of preparation, see the Exper. Part).
respectively, were formed when 2m HCl was employed (Scheme 2). 2-(Alkylimino)-3-
amino-2,3-dihydro-5-phenyl-1,3-thiazoles 9a and 9b were isolated as side-products.
Isomers 3 and 9 could be separated by extraction with Et2O. In addition, traces of 8b
were formed in case of 9b. Products 9a and 9b could be converted into thiadiazines 3a
and 3b, respectively, by reaction with concentrated HCl. The reaction of 5a and 5b with
concentrated HCl resulted in selective formation of thiadiazines 3a and 3b, respectively,
in high yields.

Helvetica Chimica Acta – Vol. 97 (2014)
Scheme 2. Ring Enlargements of 5a and 5b
79
The structures of 9a and 9b were elucidated as follows: the reaction of 9a and 9b
with 4-nitrobenzaldehyde afforded the 3-(4-nitrobenzylidene) derivatives 10a and 10b,
respectively, which are not identical with compounds 6a and 6b. In addition, 9a and 9b
were transformed into 2-(alkylamino)-4-phenyl-5-benzylideneamino-1,3-thiazoles 12a
and 12b by deamination, nitroslyation, reduction, and subsequent reaction with
benzaldehyde (Scheme 3). Products 12a and 12b, respectively, can also be prepared by
nitrosylation of 1,3-thiazoles 11a and 11b, respectively (Scheme 3). The formation of
benzaldehyde [N-alkyl-N-(1,3-thiazol-2-yl)]hydrazones 14a and 14b, which are isomers
of 12a and 12b, respectively, could not be detected. In contrast, products 14a and 14b
are available by condensation of benzaldehyde-2-alkyl-thiosemicarbazones 13a and
14b, respectively, with a-bromoacetophenone (Scheme 3).
In conclusion, we reported the cyclization of 4-methyl- and 4-ethylthiosemicarba-
zide with a-bromoacetophenone. In this context, we observed an unprecedented
rearrangement of a 2-hydrazono-2,3-dihydrothiazole to a 1,3,4-thiadiazine. While ring
contractions of 1,3,4-thiadiazines to thiazoles are quite common, ring enlargements are
new. The course of the reaction depends on the substitution pattern of the substrate.
Experimental Part
General. All reactions were carried out in oven-dried reaction pressure tubes under Ar. The
chemicals were purchased from Aldrich. Dry solvents (DMF, CH2Cl2) were purged with Ar before use.
TLC: Merck precoated aluminium plates (Si 60 F254). Column chromatography (CC): Merck silica gel 60
(SiO2; 0.043 – 0.06 mm). UV/VIS: Lambda 5 (PerkinElmer) spectrophotometer with a soln. concen-
tration of c ¼ 10ꢀ6 mol/l of the compounds. Fluorescence spectra: Hitachi F-4010 fluorescence
spectrophotometer using similar soln. concentrations in various solvents. IR Spectra: Nicolet 205 FT-
IR and Nicolet Protege 460 FT-IR instrument; as KBr pellets; n˜ in cmꢀ1. NMR data: Bruker ARX 300 and
1
Bruker ARX 400 spectrometers. H- and 13C-NMR chemical shifts referenced to signals of deuterated
solvents and residual protonated solvents, resp. GC/MS: Agilent HP-5890 instrument with an Agilent HP-
5973 mass-selective detector (EI) and HP-5 cap. column with He as carrier gas. HR-ESI-MS: Agilent
1969A TOF mass-spectrometer.

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Scheme 3. Chemical Establishment of the Structures of 9a and 9b
N-Methyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine (3a). Method A. 2,3-Dihydro-3-methyl-4-phenyl-2-
(propan-2-ylidenehydrazinylidene)-1,3-thiazole (5a; 24.5 g, 100.0 mmol) in 2m HCl (120 ml) was
subjected to steam distillation, until acetone was no longer detectable in the distillate. The distillation
residue was filtered to remove impurities and then placed in a separatory funnel with Et2O. The pH was
adjusted to 4 – 5 with aq. NH3 and then alkaline with aq. Na2CO3 under vigorous shaking. The Et2O phase
was worked up (distillation of Et2O) to give 9a. Yield: 4.1 g (20%). M.p. 1108. The precipitate formed in
the aq. phase was filtered under suction, dissolved in benzene, and reprecipitated by addition petroleum
ether (PE) to afford 3a. Yield: 15 g (73%). Pale-yellow rods (acetone). M.p. 1458. IR: 3217s, 3010s, 1542s,
1512s, 1440m, 1400s, 1326m, 1217s, 1167s, 1059m, 982m, 916w, 694s. 1H-NMR (300 MHz, CDCl3): 3.12 (s,
Me); 3.56 (s, CH2(6)); 5.05 (br. s, NH); 7.34 – 7.88 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 22.5
(Me); 30.6 (C(6)); 126.5 (arom. CH); 128.6 (arom. CH); 129.5 (arom. CH); 135.8 (arom. C); 147.5
(C(5)); 149.6 (C(2)). EI-MS (70 eV): 205 (19, Mþ), 164 (21), 103 (86), 91 (15), 75 (100), 51 (29), 28 (16).
Anal. calc. for C10H11N3S (205.28): C 58.51, H 5.40, N 20.47; found: C 58.62, H 5.51, N 20.61.
Method B. Hydrolysis of 5a (24.5 g, 100.0 mmol) in conc. HCl (120 ml) was performed as described
under Method A; the pH of the mixture was then adjusted to 4 – 5 with aq. NH3, and then alkaline with
aq. Na2CO3, and the precipitate was filtered under suction. Yield: 19.5 g (95%). Pale-yellow rods
(acetone). M.p. 1458.
Method C. 2-(Methylimino)-4-phenyl-1,3-thiazol-3(2H)-amine (9a; 0.5 g, 2.5 mmol) was refluxed in
conc. HCl (30 ml) for 30 min. The mixture was made alkaline with aq. Na2CO3, and the precipitate was
filtered under suction. Yield: 0.3 g (58%). Pale-yellow rods (acetone). M.p. 1458.
Method D. A mixture of 4-methylthiosemicarbazide (¼ N-methylhydrazinecarbothioamide; 2a; 2.1 g,
20.0 mmol) and phenacyl bromide (¼2-bromo-1-phenylethanone; 1a; 3.98 g, 20.0 mmol) in 5m HCl

Helvetica Chimica Acta – Vol. 97 (2014)
81
(30 ml) was refluxed briefly. The hot soln. was filtered. After cooling, aq. NH3 was added. A crystalline
precipitate was formed. Yield: 3.6 g (88%). Pale-yellow rods (acetone). M.p. 1458.
Method E. A mixture of 4-methylthiosemicarbazide (2a; 2.1 g, 20.0 mmol) and 1a (3.98 g,
20.0 mmol) in EtOH (30 ml) was refluxed 15 min. The hot soln. was filtered. After cooling, aq. NH3
was added. A crystalline precipitate formed. Yield: 2.87 g (70%). Pale-yellow rods (acetone). M.p. 1458.
N-Ethyl-5-phenyl-6H-1,3,4-thiadiazin-2-amine (3b). Method A. The product was obtained by
hydrolysis of 5b (13 g, 50.0 mmol) in 2m HCl (80 ml) as described for 3a under Method A. Yield: 5.5 g
(50%). Yellow needles (benzene). M.p. 1568. The workup of the Et2O soln. gave 3b. IR: 3172s, 2973s,
1555s, 1517s, 1468s, 1434m, 1410m, 1340m, 1266m, 1214m, 1152m, 1055w, 920w, 985w, 758m, 689m.
1H-NMR (300 MHz, CDCl3): 1.27 (t, J ¼ 8.0, Me); 3.54 – 3.57 (m, CH2); 3.61 (s, CH2(6)); 5.47 (br. s, NH);
7.38 – 7.86 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 15.4 (Me); 22.8 (CH2); 39.1 (C(6)); 126.8 (arom.
CH); 128.8 (arom. CH); 129.3 (arom. CH); 129.8 (arom.CH); 136 (arom. C); 147.7 (C(5)); 149.4 (C(2)).
EI-MS (70 eV): 219 (48, Mþ), 164 (55), 119 (7), 104 (49), 103 (100), 88 (96), 77 (49), 61 (46), 51 (17), 43
(5), 28 (14). Anal. calc. for C11H13N3S (219.31): C 60.24, H 5.97, N 19.16; found: C 59.85, H 6.22, N 18.98.
Method B. Hydrolysis of 5b (13 g, 50.0 mmol) in conc. HCl (80 ml) was performed as described for
3a under Method A. The mixture was made alkaline with aq. Na2CO3, and the precipitate formed under
suction. Yield: 10.4 g (95%). M.p. 1568.
Method C. 2-(Ethylimino)-5-phenyl-1,3-thiazol-3(2H)-amine (9b; 0.5 g, 2.5 mmol) was refluxed for
30 min in conc. HCl (10 ml). The mixture was made alkaline with aq. Na2CO3, and the precipitate formed
was filtered under suction. Yield: 0.25 g (50%). M.p. 1568.
Method D. 4-Ethylthiosemicarbazide (¼ N-ethylhydrazinecarbothioamide; 2b; 2.4 g, 20.0 mmol) and
1a (3.98 g, 20.0 mmol) in 5m HCl (30 ml) were refluxed briefly. The hot soln. was filtered to remove
impurities. The mixture was made alkaline with aq. NH3, and the precipitate formed was filtered under
suction. Yield: 3.7 g (85%). M.p. 1568.
Method E. A mixture of 2b (2.4 g, 20.0 mmol) and 1a (3.98 g, 20.0 mmol) in EtOH (30 ml) was
refluxed for 15 min. EtOH was evaporated by distillation to give an oil. The product and PhCHO (0.5 g)
was refluxed briefly in a water bath. Subsequently, acetone (50 ml) was added. A yellow precipitate
formed, which was filtered off. The product was dissolved in MeOH/H2O 1:1 and then placed in a
separatory funnel with Et2O. The pH was then adjusted to alkaline with aq. Na2CO3 under vigorous
shaking. The Et2O phase was worked up to give 9b. The precipitate formed in the aq. phase was filtered
under suction, dissolved in benzene, and reprecipitated by addition of PE to afford 3b. Yield: 2.9 g
(66%). Yellow needles (benzene). M.p. 1568.
N-Methyl-2-(propan-2-ylidene)hydrazinecarbothioamide (4a). Compound 2a (2.1 g, 20.0 mmol) was
refluxed in acetone (25 ml). Acetone was distilled off in vacuo. Yield: 2.85 g (98 %). Colorless lamella
(acetone). M.p. 116 – 1178. IR: 3390s, 3250s, 1556s, 1455s, 1479s, 1408s, 1343m, 1268s, 1226s, 1105m, 1059s,
1017s, 768m, 714m. 1H-NMR (300 MHz, CDCl3): 1.89 (s, Me); 2.0 (s, Me); 3.20 (s, Me); 7.52 (br. s, NH);
8.46 (br. s, NH). 13C-NMR (75 MHz, CDCl3): 16.5 (Me); 25.0 (Me); 30.8 (Me); 148.9 (C¼N); 178.6
(C¼S). EI-MS (70 eV): 145 (96, Mþ), 130 (54), 89 (23), 75 (69), 62 (14), 58 (75), 42 (52), 28 (100). Anal.
calc. for C5H11N3S (145.23): C 41.35, H 7.63, N 28.93; found: C 41.35, H 7.69, N 28.87.
N-Ethyl-2-(propan-2-ylidene)hydrazinecarbothioamide (4b). Compound 2b (2.4 g, 20.0 mmol) was
refluxed in acetone (25 ml) for 10 min, and acetone was distilled off in vacuo. Yield: 3.1 g (97%).
Colorless lamella (EtOH/H2O). M.p. 808. IR: 3273m, 3193s, 2978m, 1534s, 1490s, 1436m, 1363m, 1332m,
1363m, 1332m, 1263s, 1218s, 1218s, 1104s, 1062s, 796m. 1H-NMR (300 MHz, CDCl3): 1.27 (t, J ¼ 8.0, Me);
1.88 (s, Me); 2.00 (s, Me); 3.67 – 3.76 (m, CH2); 7.46 (br. s, NH); 8.33 (br. s, NH). 13C-NMR (75 MHz,
CDCl3): 14.3 (Me); 16.5 (Me); 25.0 (Me); 39.1 (CH2); 148.9 (C¼N)); 177.4 (C¼S). EI-MS (70 eV): 159
(50, Mþ), 144 (11), 103 (11), 73 (11), 72 (10), 61 (38), 59 (41), 28 (100). Anal. calc. for C6H13N3S (159.25):
C 45.25, H 8.23, N 26.39; found: C 45.30, H 8.29, N 26.64.
N-(Propan-2-yl)-2-(propan-2-ylidene)hydrazinecarbothioamide (4c). 4-Isopropylthiosemicarbazide
(¼ N-(propan-2-yl)hydrazinecarbothioamide; 2c; 1.33 g, 10 mmol) was refluxed in acetone (20 ml) for
15 min, and acetone was distilled off in vacuo.Yield: 1.4 g (81%). Colorless lamella (EtOH). M.p. 112.58.
Anal. calc. for C7H15N3S (173.28): C 48.52, H 8.73, N 24.25; found: C 48.50, H 8.79, N, 24.25.
N-Methyl-2-(4-nitrobenzylidene)hydrazinecarbothioamide (4d). A mixture of 2a (4.2 g, 40.0 mmol)
and 4-nitrobenzaldehyde (6 g, 40 mmol) in EtOH (70 ml) was refluxed for 30 min. Yellow crystals was

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Helvetica Chimica Acta – Vol. 97 (2014)
separated by boiling and recrystallized (BuOH). Yield: 5.5 g, (57%). Yellow needles. M.p. 2298. IR:
3376s, 3149s, 2994s, 1553s, 1523s, 1342s, 1219s, 1161m, 1100s, 1044s, 922m, 848s, 784m, 749m, 691m, 625m.
1H-NMR (300 MHz, CDCl3): 3.29 (s, Me); 7.79 – 8.28 (m, 4 arom. H); 7.50 (br. s, NH); 9.42 (s, CH).
13C-NMR (75 MHz, (D6)DMSO): 30.9 (Me); 123.8 (arom. CH); 128.0 (arom. CH); 139.0 (arom. C);
140.8 (arom. C); 147.5 (C¼N); 178.0 (C¼S). EI-MS (70 eV): 238 (13, Mþ), 165 (3), 112 (5), 103 (3), 91
(3), 90 (10), 75 (28), 57 (40), 28 (100). Anal. calc. for C9H10N4O2S (238.27): C 45.37, H 4.23, N 23.51;
found: C 45.47, H 4.51, N 23.81.
N-Ethyl-2-(4-nitrobenzylidene)hydrazinecarbothioamide (4e). Compound 2b (1.2 g, 10.0 mmol) and
4-nitrobenzaldehyde (1.5 g; 10 mmol) in EtOH (15 ml) were refluxed for 15 min. Yield: 2.4 g (97%).
Lemon yellow needles (EtOH). M.p. 259 – 2608. IR: 3365s, 3147s, 2984s, 1544s, 1510s, 1340s, 1240s, 1218s,
1102s, 1050m, 922m, 845m, 689m, 587m. 1H-NMR (300 MHz, CDCl3): 1.32 (t, J ¼ 8.0, Me); 3.78 – 3.81 (m,
CH2); 7.4 (br. s, NH); 7.79 – 8.30 (m, 4 arom. H); 9.27 (s, CH). 13C-NMR (75 MHz, (D6)DMSO): 14.4
(Me); 38.36 – 40.26 (CH2); 123.7 (arom. CH); 127.9 (arom. CH); 139.0 (arom C); 140.7 (arom. C); 147.4
(C¼N); 176.9 (C¼S). EI-MS (70 eV): 252 (19, Mþ), 150 (27), 118 (7), 103 (20), 88 (13), 77 (16), 61 (50),
44 (78), 28 (100). Anal. calc. for C10H12N4O2S (252.29): C 47.61, H 4.79, N 22.21; found: C 47.65, H 4.83, N
22.25.
2-Benzylidene-N-methylhydrazinecarbothioamide (4f). Compound 2a (4.7 g, 40.0 mmol) and
benzaldehyde (4.2 g, 40.0 mmol) in EtOH (30 ml) were refluxed briefly. Yield: 7.5 g (97%). Colorless
needles (EtOH). M.p. 1578. IR: 3366s, 3182m, 1553s, 1520s, 1450m, 1261s, 1097m, 1037m, 758m, 695m,
569m. 1H-NMR (300 MHz, CDCl3): 3.27 (d, J ¼ 8.0, Me); 7.38 – 7.89 (m, 5 arom. H); 9.97 (s, HC¼).
13C-NMR (75 MHz, CDCl3): 31.0 (Me); 127.2 (arom. CH); 128.7 (arom. CH); 130.3 (arom. C); 133.3
(arom. C); 142.7 (HC¼N); 178.0 (C¼S). EI-MS (70 eV): 193 (46, Mþ), 119 (25), 104 (17), 93 (17), 92
(15), 90 (36), 89 (20), 77 (37), 75 (67), 57 (100), 51 (38), 30 (30), 28 (27). Anal. calc. for C9H11N3S
(193.27): C 55.93, H 5.74, N 21.74; found: C 55.81, H 5.87, N 21.58.
2-Benzylidene-N-ethylhydrazinecarbothioamide (4g). Compound 2b (4.8 g, 40.0 mmol) and benzal-
dehyde (4.3 g, 40.0 mmol) in EtOH (30 ml) were refluxed briefly. After cooling, the precipitate was
filtered. Yield: 7.8 g (94%). Colorless lamella (EtOH/H2O). M.p. 1408. IR: 3327m, 3184m, 2975m, 1545s,
1308s, 1236s, 1098s, 942m, 757m, 691m, 624m. 1H-NMR (300 MHz, CDCl3): 1.32 (t, J ¼ 8.0, Me); 3.73 –
3.82 (m, CH2); 7.38 – 7.96 (m, 5 arom. H); 10.39 (s, HC¼). 13C-NMR (75 MHz, CDCl3): 14.5 (Me); 39.2
(CH2); 127.2 (arom. CH); 128.7 (arom. CH); 130.2 (arom. C); 133.3 (arom. C); 142.7 (HC¼N); 176.8
(C¼S). EI-MS (70 eV): 207 (57, Mþ), 120 (13), 119 (23), 106 (51), 104 (30), 103 (28), 93 (13), 88 (13), 77
(37), 72 (26), 66 (13), 61 (51), 51 (26), 44 (100), 28 (29). Anal. calc. for C10H13N3S (207.30): C 57.94, H
6.32, N 20.27; found C 57.97, H 6.51, N 20.10.
Compound 5a. A mixture of 4a (2.9 g, 20.0 mmol) and a-bromoacetophenone (1a; 3.98 g,
20.0 mmol) in acetone (30 ml) was refluxed for 15 min. Acetone was removed by distillation, and an
oil was formed. The product was dissolved in hot MeOH and neutralized with aq. NH3. A crystalline
product formed, which was filtered off and recrystallized (EtOH/H2O). Yield: 4.7 g (96%). Yellow
needles (EtOH/H2O). M.p. 888. IR: 2941m, 2909m, 1623s, 1551s, 1440m, 1418s, 1360s, 767s, 703s.
1H-NMR (300 MHz, CDCl3): 2.05 (s, Me); 2.08 (s, Me); 3.29 (s, Me); 5.84 (s, HꢀC(5)); 7.33 – 7.43 (m, 5
arom. H). 13C-NMR (75 MHz, CDCl3): 18.1 (Me); 24.9 (Me); 33.3 (Me); 98.4 (C(5)); 128.5 (arom. CH);
128.6 (arom. CH); 128.8 (arom. CH); 131.3 (arom. C); 140 (C¼N);158.7 (C(4)); 167.1 (C(2)). EI-MS
(70 eV): 246 (100, Mþ), 212 (7), 189 (39), 189 (39), 176 (22), 162 (34), 134 (42), 118 (79), 102 (78), 91
(24), 89 (15), 76 (30), 56 (19), 42 (50), 28 (36). Anal. calc. for C13H15N3S (245.34): C 63.64, H 6.16, N
17.13; found: C 63.75, H 6.18, N 17.34.
3-Ethyl-2,3-dihydro-4-phenyl-2-(propan-2-ylidenehydrazinylidene)-1,3-thiazole (5b). A mixture of
4b (3.18 g, 20.0 mmol) and 1a (3.98 g, 20.0 mmol) in acetone (30 ml) was refluxed for 15 min. Further
workup as described for 2a afforded 5b (5 g, 95%). Yellow needles (EtOH/H2O). M.p. 968. IR: 2932m,
1
1625s, 1557s, 1488m, 1441s, 1377s, 1330s, 1255s, 1167m, 1071s, 986m, 819m, 768s, 702s, 576m. H-NMR
(300 MHz, CDCl3): 1.18 (t, J ¼ 8.0, Me); 2.05 (s, Me); 2.07 (s, Me); 3.79 (q, J ¼ 8.0, CH2); 5.80 (s,
HꢀC(5)); 7.34 – 7.43 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 13.1 (Me); 18.2 (Me); 24.9 (Me); 40.8
(CH2); 98.6 (C(5)); 128.5 (arom. CH); 128.7 (arom. CH); 128.8 (arom. CH); 131.8 (arom. C); 140.3
(C¼N); 158.7 (C(4)); 166.1 (C(2)). EI-MS (70 eV): 259 (100, Mþ), 216 (29), 203 (42), 176 (28), 147 (59),

Helvetica Chimica Acta – Vol. 97 (2014)
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134 (37),103 (13), 91 (10), 56 (15), 29 (14), 28 (7). Anal. calc. for C14H17N3S (259.38): C 64.83, H 6.60, N
16.20; found: C 64.93, H 6.78, N 16.25.
2,3-Dihydro-3,5-dimethyl-4-phenyl-2-(propan-2-ylidenehydrazinylidene)-1,3-thiazole (5c). A ace-
tone soln. (20 ml) of 4a (3.04 g, 20 mmol) and a-bromopropiophenone (1b; 4.26 g, 20 mmol) was
refluxed for 2 h. After cooling to r.t. and addition of NH3, a crystalline precipitate formed. The product
was filtered off and recrystallized from EtOH to give 5c (4.30 g, 82%). Slightly-yellow needles. M.p. 1128.
IR: 2911m, 1626s, 1566s, 1413s, 1346s, 1259m, 1067m, 982m, 786m, 702m. 1H-NMR (CDCl3, 300 MHz):
1.98 (s, Me(5)); 2.05, 2.07 (2s, N¼CMe2); 3.15 (s, MeN); 5.94 (s, HꢀC(5)); 7.25 – 7.48 (m, 5 arom. H).
13C-NMR (CDCl3, 75 MHz): 12.7; 18.1; 25.0; 33.3; 109.2; 128.7; 128.7; 130.1; 130.6; 134.7; 158.0; 166.1.
Anal. calc. for C14H17N3S (259.37): C 64.83, H 6.61, N 16.20; found: C 65.00, H 6.78, N 15.96.
2,3-Dihydro-5-methyl-4-phenyl-3-(propan-2-yl)-2-(propan-2-ylidenehydrazinylidene)-1,3-thiazole
(5d). Reaction of 4c (1.73 g, 10 mmol) and 1b (2.13 g, 10 mmol) in acetone (20 ml) as described by 2c,
yielded 5d (2.41 g, 84%). Yellow lamella. M.p. 1318. IR: 2970m, 2928m, 2917m, 1645m, 1623m, 1558s,
1445m, 1369m, 1334s, 1303s, 1253m, 1109m, 1075m, 812m, 788 m, 735m, 703m. 1H-NMR (CDCl3,
300 MHz): 1.44, 1.46 (2d, J ¼ 8.0, Me2CH); 1.87 (s, Me(5)); 2.04, 2.06 (2s, N¼CMe2); 3.84 – 3.89 (m,
NCH); 5.95 (s, HꢀC(5)); 7.23 – 7.44 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 12.7; 18.4; 18.8; 24.6;
50.5; 108.4; 128.5; 130.0; 131.8; 134.8; 157.3; 164.2. Anal. calc. for C16H21N3S (287.42): C 66.86, H 7.36, N
14.62; found: C 66.82, H 7.46, N 14.58.
2,3-Dihydro-3-methyl-2-[(4-nitrobenzylidene)hydrazinylidene]-4-phenyl-1,3-thiazole (6a). Method
A. A mixture of 5a (1.23 g, 5.0 mmol) and 4-nitrobenzaldehyde (0.75 g, 5.0 mmol) in EtOH (10 ml) and
HCl (0.1 ml) was refluxed for 15 min. After cooling to 208, a crystalline precipitate formed, which was
filtered off and recrystallized from BuOH. Yield: 0.5 g (30%). Red lamella. M.p. 2028. IR: 2932m, 1589s,
1516m, 1421m, 1360m, 1333s, 1170m, 1107m, 1050m, 984m, 842m, 769m, 703m. 1H-NMR (300 MHz,
CDCl3): 3.14 (s, Me); 6.09 (s, HꢀC(5)); 7.38 – 8.35 (m, 9 arom. H). 13C-NMR (75 MHz, CDCl3): 35.7
(Me); 100.7 (C(5)); 123.9 (arom. C); 127.3 (arom. C); 128.8 (arom. C); 129.4 (arom. C); 130.5 (arom. C);
141.1, 147; 147.5, 147.7, 172.6 (C(2)). EI-MS (70 eV): 338 (98, Mþ), 307 (10), 292 (3), 244 (3), 189 (7), 177
(55), 135 (23), 118 (12), 102 (91), 89 (19), 77 (15), 64 (11), 30 (42), 28 (100). Anal. calc. for C17H14N4O2S
(338.38): C 60.34, H 4.17, N 16.56; found: C 60.44, H 4.18, N 16.47.
Method B. A mixture of 4d (1.19 g, 5.0 mmol) and 1a (1 g, 5.0 mmol) in EtOH (30 ml) was refluxed
for 30 min. After cooling, a red precipitate formed. Yield: 1.2 g (71%). M.p. 2028.
3-Ethyl-2,3-dihydro-2-[(4-nitrobenzylidene)hydrazinylidene]-4-phenyl-1,3-thiazole (6b). Method A.
The compound was obtained from 5b (1.3 g, 5.0 mmol) and 4-nitrobenzaldehyde, as described for 6a
under Method A. Yield: 0.6 g (39%). Red needles (dioxane). M.p. 2218. IR: 1625m, 1587s, 1502s, 1459m,
1
1407m, 1374m, 1336s, 1266w, 1166m, 1111m, 1062s, 1004m, 845m, 758m. H-NMR (300 MHz, CDCl3):
1.22 (t, J ¼ 8.0, Me); 3.87 – 3.94 (m, CH2); 6.04 (s, HꢀC(5)); 7.38 – 8.33 (m, 9 arom. H). 13C-NMR
(75 MHz, CDCl3): 13.7 (Me); 41.1 (CH2); 101.1 (C(5)); 127.9 (arom. C); 127.3 (arom. C); 128.8 (arom.
C); 129.1 (arom. C); 129.7 (arom. C); 130.9 (arom. C); 140.8 (arom. C); 142.5 (arom. C); 147.4, 147.5, 172
(C(2)). EI-MS (70 eV): 352 (100, Mþ), 322 (18), 203 (20), 190 (20), 177 (30), 176 (46), 134 (50), 104
(13), 102 (22), 91 (12), 89 (16), 77 (13), 28 (30). Anal. calc. for C18H16N4O2S (352.41): C 61.35, H 4.58, N
15.90; found: C 61.35, H 4.59, N 15.84.
Method B. Compounds 4e and 1a (1 g, 5.0 mmol) in EtOH (30 ml) was refluxed for 15 min. During
boiling, a red precipitate formed. Yield: 1.6 g (91%). Red needles (dioxane). M.p. 2218.
Method C. To the EtOH soln. of recrystallized 9b, 4-nitrobenzaldehyde (0.75 g, 5 mmol) was added,
and the mixture was refluxed briefly. A red precipitate formed, which filtered off. Yield: 0.2 g (1.1%).
M.p. 2218.
2,3-Dihydro-5-methyl-2-[(4-nitrobenzylidene)hydrazinylidene]-4-phenyl-3-(propan-2-yl)-1,3-thia-
zole (6c). Method A. A mixture of 5d (1.44 g, 5.0 mmol) and 4-nitrobenzaldehyde (0.75 g, 5.0 mmol) in
EtOH (20 ml) and HCl (0.1 ml) was refluxed for 2 h. After cooling to 208, a crystalline precipitate
formed, which was filtered off and recrystallized from BuOH. Yield: 1.8 g (83%). Green needles. M.p.
2328. Anal. calc. for C20H20N4O2S (380.46): C 63.14, H 5.30, N 14.73; found: C 63.10, H 5.40, N 14.54.
Method B. A mixture of 2-(4-nitrobenzylidene)-N-(propan-2-yl)hydrazinecarbothioamide (2.56 g,
10 mmol) and 1b (2.13 g, 10 mmol) in EtOH (30 ml) was refluxed for 3 h. After cooling, a green
precipitate formed. Yield: 3.6 g (95%). M.p. 2328.

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Helvetica Chimica Acta – Vol. 97 (2014)
2-(Benzylidenehydrazinylidene)-2,3-dihydro-3-methyl-4-phenyl-1,3-thiazole (7a). Hydrobromide.
Compound 4f (3.86 g, 20.0 mmol) and 1a (3.98 g, 20.0 mmol) in EtOH (40 ml) was refluxed for
10 min. During boiling, a precipitate formed. Yield: 6.4 g (86%). Colorless needles (MeOH). M.p. 2168.
Anal. calc. for C17H16BrN3S (374.30): C 54.55, H 4.31, N 11.23; found: C 54.58, H 4.30, N 11.32.
Free Base: Method A. The hydrobromide of 7a was converted into the free base by dissolation in
MeOH/H2O (3 :1) and addition of aq. Na2CO3 soln. Yellow lamella (EtOH). M.p. 1188. IR: 3084m,
1602s, 1571s, 1518s, 1487s, 1441m, 1420 m, 1358m, 1310m, 1185m, 1053m, 984s, 877m, 810m, 760s, 697s.
1H-NMR (300 MHz, CDCl3): 3.36 (s, Me); 5.97 (s, HꢀC(5)); 7.32 – 7.77 (m, 10 arom. H); 8.35 (s, HC¼N).
13C-NMR (75 MHz, CDCl3): 33.5 (Me); 99.7 (C(5)); 127.2 (arom. CH); 128.4 (arom. CH); 128.7 (arom.
CH); 129.1 (arom. CH); 130.9 (arom. C); 135.0 (arom. C); 140.8 (HC¼N); 151.0 (C(4)); 170.8 (C(2). EI-
MS (70 eV): 293 (100, Mþ), 264 (9), 176 (80), 174 (11), 147 (10), 134 (33), 118 (13), 102 (62), 90 (52), 77
(41), 51 (26), 44 (11), 28 (38). Anal. calc. for C17H15N3S (293.39): C 69.59, H 5.15, N 14.32; found: C
69.59, H 5.15, N 14.32.
Method B. Benzaldehyde (0.5 g) was added to the mother liquor of 3a (Method E) and refluxed
briefly. The solvent was distilled off in vacuo. Yield: 0.5 g (8.5%). Yellow lamella (EtOH/H2O). M.p.
1188.
2-[Benzylidenehydrazinylidene]-3-ethyl-2,3-dihydro-4-phenyl-1,3-thiazole (7b). Hydrobromide. A
mixture of 4g (4.14 g, 20.0 mmol) and 1a in acetone (25 ml) was refluxed for 15 min. After cooling to r.t.,
the product was suction-filtered. Yield: 7.3 g (94%). Colorless lamella (MeOH). M.p. 1708. Anal. calc.
for C18H18N3SBr (388.32): C 55.67, H 4.67, N 10.82; found: C 55.59, H 4.65, N 10.92.
Free Base: Method A. The EtOH soln. of the hydrobromide of 7b (3.88 g, 10 mmol) was treated with
aq. NH3, and a yellow precipitate formed. Yield: 3.41 g (88%). Yellow lamella (EtOH/H2O). M.p. 1078.
IR: 3094m, 2970m, 1604s, 1572s, 1517s, 1493s, 1441s, 1375m, 1273m, 1048m, 1003m, 944m, 760s, 695s.
1H-NMR (300 MHz, CDCl3): 1.19 (t, J ¼ 8.0, Me); 3.86 (q, J ¼ 8.0, CH2); 5.92 (s, HꢀC(5)); 7.31 – 7.77 (m,
10 arom. H); 8.34 (s, HC¼N). 13C-NMR (75 MHz, CDCl3): 13.6 (Me); 40.8 (CH2); 100.1 (C(5)); 127.1
(arom. CH); 128.0 (arom. CH); 128.4 (arom. CH); 128.6 (arom. CH); 129.0 (arom. CH); 131.6 (arom.
C); 135.0 (arom. C); 140.4 (HC¼N); 150.7 (C(2)). EI-MS (70 eV): 307 (100, Mþ), 203 (15), 190 (35), 176
(43), 132 (21), 118 (10), 104 (21), 102 (22), 90 (37), 77 (42), 52 (20), 28 (72). Anal. calc. for C18H17N3S
(307.41): C 70.33, H 5.57, N 13.67; found: C 70.38, H 5.61, N 13.47.
Method B. The Et2O soln. of 3b (Method E) was dried with CaCl2. The solvents was distilled in
vacuo. Yield: 0.6 g (10%). Yellow lamella (EtOH/H2O). M.p. 1078.
2-Hydrazinylidene-2,3-dihydro-3,5-dimethyl-4-phenyl-1,3-thiazole (8c). Hydrochloride. Compound
5c (7.80 g, 30 mmol) was dissolved in an aq. soln, of 18% HCl (200 ml). A steam distillation of the
mixture gave 5 – 6 l of an aq. soln. The hot soln. was filtered, cooled, and, subsequently, NH3 was added. A
yellow oil was separated, which was washed with H2O. The oil was dissolved in EtOH/HCl and treated
with Et2O, until the soln. became cloudy. After a few min, a colorless precipitate formed, which was
separated by filtration. The product was recrystallized from EtOH/Et2O to give hydrochloride of 8c as
colorless rods (3.40 g, 44%). M.p. 185 – 1878. IR: 3325m, 3242s, 3132s, 2984s, 2834s, 1665s, 1588s, 1459m,
1431m, 1124m, 787m, 709m. 1H-NMR (300 MHz, CDCl3): 2.13 (s, Me(5)); 3.58 (s, MeN); 3.69 – 3.79 (br.
s, NH2); 5.94 (s, HꢀC(5)); 7.24 – 7.56 (m, 5 arom. H); 11.98 (s, NHþ3 ). 13C-NMR (75 MHz, (D6)DMSO):
17.7, 18.5, 34.5, 55.9, 127.9, 129.0, 129.8, 130.3, 136.6. Anal. calc. for C11H14ClN3S (255.77): C 51.66, H 5.52,
N 16.43; found: C 51.83, H 5.71, N 16.24.
2-Hydrazinylidene-5-methyl-4-phenyl-3-(propan-2-yl)-2,3-dihydro-1,3-thiazole (8d). Hydrochloride.
The compound was obtained from 5d (2.87 g, 10 mmol) as described for 8c. Yield: 2.32 g (82%). M.p.
196 – 2048. Colorless prisms (EtOH, HCl, Et2O). IR: 3255m, 3162m, 2946m, 2817m, 1661s, 1567m,
1
1326m, 1316m, 1198s, 1125w, 730m, 809w, 699s. H-NMR (CDCl3, 300 MHz): 1.53 (d, Me2CH); 2.02 (s,
MeꢀC(5)); 4.39 – 4.44 (m, CH); 5.37 (br. s, NH2); 5.95 (s, HꢀC(5)); 7.26 – 7.57 (m, 5 arom. H); 11.67 (s,
NHþ3 ). 13C-NMR (CDCl3, 75 MHz): 11.8, 19.2, 53.2, 116.5, 128.5, 129.1, 130.2, 137.5, 169.7. Anal. calc. for
C13H18ClN3S (283.82): C 55.01, H 6.39, N 14.81; found: C 55.12, H 6.56, N 14.88.
2-(Methylimino)-4-phenyl-1,3-thiazol-3(2H)-amine (9a). The Et2O soln. of 3a (Method A) was
dried with CaCl2. The solvent was then distilled off in vacuo, the residue was boiled several times with
EtOH, and filtered hot. Upon addition of H2O, a precipitate formed. Yield: 4.1 g (20%). Light-yellow
needles (EtOH/H2O). M.p. 1108. IR: 3297m, 3149s, 2957m, 2845m, 1620m, 1567m, 1493m, 1493m,

Helvetica Chimica Acta – Vol. 97 (2014)
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1
1444m, 1399s, 957w, 850w, 758m, 688s, 495m. H-NMR (300 MHz, CDCl3): 3.09 (s, Me); 4.28 (s, NH2);
5.80 (s, HꢀC(5)); 7.38 – 7.53 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 48.5 (Me); 91.8 (C(5)); 128.2
(arom. CH); 128.5 (arom. CH); 128.8 (arom. CH); 131.2 (arom. C); 141.1 (C(4)); 159.4 (C(2)). EI-MS
(70 eV): 204.9 (100, Mþ), 188 (88), 163 (24), 146 (41), 134 (48) 131 (16), 119 (17), 103 (30), 102 (62), 91
(34), 77 (36), 42 (12), 28 (10). Anal. calc. for C10H11N3S (205.28): C 58.51, H 5.40, N 20.47; found: C
58.72, H 5.58, N 20.51.
2-(Ethylimino)-4-phenyl-1,3-thiazol-3(2H)-amine (9b).The Et2O soln. of 3b (Method A) was dried
with CaCl2. Et2O was distilled off under reduced pressure. The crude product was crystallized from
EtOH. Yield: 4.1 g (37%). Colorless needles. M.p. 1248. IR: 3278s, 3166m, 2953m, 1607s, 1492m, 1376m,
1350m, 1274m, 1173m, 1111m, 967m, 765s, 647s. 1H-NMR (300 MHz, CDCl3): 1.31 (t, J ¼ 8.0, Me); 3.22
(q, J ¼ 8.0, CH2); 4.29 (s, NH2); 5.76 (s, HꢀC(5)); 7.78 – 7.52 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3):
15.9 (Me); 48.4 (CH2); 91.6 (C(5)); 128.1 (arom. CH); 128.4 (arom. CH); 128.7 (arom. CH); 131.0 (arom.
C); 141.1 (C(4)); 159.0 (C(2)). EI-MS (70 eV): 219 (100, Mþ), 203 (33), 190 (18), 174 (22), 147 (11), 134
(38), 104 (11), 102 (32), 91 (33), 76 (21), 29 (23), 28 (7). Anal. calc. for C11H13N3S (219.31): C 60.24, H
5.97, N 19.16; found: C 59.95, H 6.21, N 18.99.
N-Methyl-3-[(4-nitrobenzylidene)amino]-4-phenyl-1,3-thiazol-2(3H)-imine (10a). Compound 9a
(1 g, 5.0 mmol) and 4-nitrobenzaldehyde (0.75 g, 5.0 mmol) in EtOH (10 ml) was refluxed briefly. After
cooling, a orange-red precipitate formed. Yield: 0.95 g (56%). Orange-red needles (EtOH). M.p. 1498.
IR: 1624s, 1608m, 1563m, 1512s, 1420w, 1420m, 1403m, 1341s, 1253s, 1108m, 695m. 1H-NMR (300 MHz,
CDCl3): 3.19 (s, Me); 6.09 (s, HꢀC(5)); 7.34 – 8.35 (m, 9 arom. H); 10.56 (s, HC¼N). 13C-NMR (75 MHz,
CDCl3): 15.9 (Me); 96.5 (C(5)); 123.8 (arom. CH); 127.1 (arom. CH); 127.5 (arom. CH); 128.3 (arom.
CH); 129.0 (arom. CH ); 131.8 (arom. C); 142.4 (arom. C); 143.3 (arom. C); 145.0 (HC¼N); 147.9 (C(4));
154.5 (C(2)). EI-MS (70 eV): 338 (79, Mþ), 292 (3), 190 (19), 176 (50), 162 (23), 134 (50), 118 (13), 102
(100), 90 (23), 77 (15), 64 (11), 28 (16). Anal. calc. for C17H14N4O2S (338.38): C 60.34, H 4.17, N 16.56;
found: C 60.24, H 4.28, N 16.57.
N-Ethyl-3-[(4-nitrobenzylidene)amino]-4-phenyl-1,3-thiazol-2(3H)-imine (10b). Compound 9b
(1.1 g, 5.0 mmol) and 4-nitrobenzaldehyde (0.75 g, 5.0 mmol) in EtOH (10 ml) was refluxed briefly.
After cooling, a crystalline product formed. Yield: 0.9 g (51%). Orange-red needles (EtOH). M.p. 1458.
IR: 2969m, 1622s, 1603s, 1563s, 1516s, 1446m, 1384m, 1340s, 1253s, 1180s, 1108m, 829m, 692m. 1H-NMR
(300 MHz, CDCl3): 1.40 (t, J ¼ 8.0, Me); 3.27 (q, J ¼ 8.0, CH2); 6.04 (s, HꢀC(5)); 7.37 – 8.32 (m, 9 arom.
H); 10.60 (s, HC¼). 13C-NMR (75 MHz, CDCl3): 15.9 (Me); 50.3 (CH2); 96.4 (C(5)); 123.9 (arom. CH);
123.9 (arom. CH); 127.5 (arom. CH); 127.9 (arom. CH); 128.7 (arom. CH); 131.8 (arom. C); 140.9 (arom.
C); 142.4 (arom. C); 145.0 (HC¼N); 147.9 (C(4)); 154.5 (C(2)). EI-MS (70 eV): 352 (46, Mþ), 322 (6),
229 (9), 204 (74), 176 (72), 134 (100), 104 (30), 102 (64), 91 (43), 89 (31), 77 (12), 28 (93). Anal. calc. for
C18H16N4O2S (352.42): C 61.35 H 4.58, N 15.90; found: C 61.27, H 4.73, N 15.86.
N-Methyl-4-phenyl-1,3-thiazol-2-amine (11a). N-Methylthiourea (¼1-(methylsulfanyl)urea; 0.9 g,
10.0 mmol) and 1a (1.99 g, 10.0 mmol) in EtOH (80 ml) was refluxed for 25 min. After cooling, a
precipitate of the hydrobromide was isolated. Yield: 2.4 g (89%). M.p. 1478. The EtOH soln. of the
hydrobromide was treated with aq. NH3, a crystalline precipitate formed, which was filtered off. Yield:
1.6 g (84%). Colorless prisms (EtOH). M.p. 1278. IR: 3226s, 3118s, 1588s, 1446w, 1404s, 1332m, 1058m,
1
776m, 712s. H-NMR (300 MHz, CDCl3): 2.87 (d, J ¼ 8.0, Me); 7.35 – 7.40 (m, 5 arom. H); 7.61 (br. s,
NH); 7.85 (s, HꢀC(5)). 13C-NMR (75 MHz, (D6)DMSO): 30.9 (Me); 100.7 (C(5)); 125.5 (arom. CH);
127.1 (arom. CH); 128.3 (arom. CH); 134.8 (arom. C); 150.0 (C(4)); 169.2 (C(2)). EI-MS (70 eV): 190
(100, Mþ), 162 (28), 134 (48), 102 (21), 89 (15), 70 (4), 64 (6), 42 (10), 30 (18), 28 (51). Anal. calc. for
C10H10N2S (190.26): C 63.13, H 5.30, N 14.72; found: C 63.38, H 5.35, N 14.66.
N-Ethyl-4-phenyl-1,3-thiazol-2-amine (11b). N-Ethylthiourea (¼1-(ethylsulfanyl)urea; 4.2 g,
40.0 mmol) and 1a (7.96 g, 40.0 mmol) in EtOH (80 ml) was refluxed for 25 min. After cooling, aq.
NH3 was added, and a crystalline product formed, which was filtered off. Yield: 7 g (86%). Colorless
prisms (EtOH/H2O). M.p. 788. IR: 3208m, 2973m, 1586s, 1480m, 1436m, 1379w, 1154w, 1333s, 1263w,
1
1058m, 773m, 705s. H-NMR (300 MHz, CDCl3): 1.31 (t, J ¼ 8.0, Me); 3.33 – 3.37 (m, CH2); 5.20 (br. s,
NH); 6.71 (s, HꢀC(5)); 7.29 – 7.81 (m, 5 arom. H). 13C-NMR (75 MHz, CDCl3): 14.5 (Me); 40.8 (CH2);
100.4 (C(5)); 126.0 (arom. CH); 127.5 (arom. CH); 128.4 (arom. CH); 134.9 (arom. C); 151.5 (C(4));
169.9 (C(2)). EI-MS (70 eV): 204 (40, Mþ), 189 (32), 176 (20), 134 (32), 102 (10), 89 (11), 77 (8), 44

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Helvetica Chimica Acta – Vol. 97 (2014)
(13), 32 (20), 28 (100). Anal. calc. for C11H12N2S (204.29): C 64.67, H 5.92, N, 13.71; found: C 64.88, H
5.95, N 13.65.
5-[Benzylideneamino]-N-methyl-4-phenyl-1,3-thiazol-2-amine (12a). Method A. Compound 9a (1 g,
5 mmol) in 2m HCl (30 ml) was suspended, and under stirring and cooling by 08 a soln. of NaNO2 (from
0.69 g (10.0 mmol) NaNO2 and 10 ml of H2O) was added dropwise. A yellow precipitate formed was
filtered off. The product was washed with 2m HCl and acetone. The precipitate was dissolved in AcOH
(20 ml) and EtOH (5 ml). The mixture was stirred. Zn (1 g) was added to the soln. After 20 min, PhCHO
(0.5 ml) was added to the soln. The mixture was allowed to stand overnight at 208 and poured into H2O
(40 ml). A precipitate formed, which was separated and recrystallized from acetone. Yield: 0.5 g (34%).
Yellow needles (acetone). M.p. 1828. IR: 3202s, 1671s, 1585s, 1559s, 1515s, 1480s, 1404m, 1330s, 1235w,
1185s, 1121m, 1075m, 819m, 768m, 704s, 685s. 1H-NMR (300 MHz, (D6)DMSO): 12.92 (t, J ¼ 8.0, Me);
7.32 – 8.06 (m, 10 arom. H); 8.29 (s, HC¼N); 11.81 (br. s, NH). 13C-NMR (75 MHz, (D6)DMSO): 30.29
(Me); 127.8 (arom. CH); 128.4 (arom. CH); 128.9 (arom. CH); 129.2 (arom. CH); 130.2 (arom. CH);
131.8 (arom. CH); 133.0 (arom. C); 134.5 (arom. C); 151.4; 163.5; 168.4; 177.2 (C(2)). EI-MS (70 eV):
293 (100, Mþ), 216 (7), 147 (3), 121 (10), 117 (29), 104 (20), 89 (13), 75 (24), 43 (6), 28 (18). Anal. calc.
for C17H15N3S (293.39): C 69.59, H 5.15, N 14.32; found: C 69.78, H 5.29, N 14.52.
Method B. Compound 11a (3.8 g, 20.0 mmol) was suspended in 2m HCl (60 ml). Under cooling and
stirring was added dropwise NaNO2 soln. (1.38 g, (20.0 mmol) in 10 ml of H2O). Workup was conducted
as described for Method A. Yield: 5.1 g (87%). Yellow prisms (EtOH). M.p. 1828.
5-[Benzylideneamino]-N-ethyl-4-phenyl-1,3-thiazol-2-amine (12b). Method A. The compound was
obtained from 9b (1.1 g, 5.0 mmol) as desribed for 12a. Yield: 0.8 g (52%). Yellow prisms (EtOH). M.p.
1218. IR: 3203s, 2973s, 1584 s, 1548s, 1480s, 1429m, 1334s, 1334s, 1309m, 1334s, 1191m, 1154m, 1071m,
761m, 776m, 692s. 1H-NMR (300 MHz, CDCl3): 1.20 (t, J ¼ 8.0, Me); 3.28 – 3.30 (m, CH2); 6.19 (s, NH);
7.32 – 7.98 (m, 10 arom. H); 8.24 (s, HC¼N). 13C-NMR (75 MHz, CDCl3): 14.9 (Me); 40.4 (CH2); 127.7
(arom. CH); 128.0 (arom. CH); 128.4 (arom. CH); 128.5 (arom. CH); 129.6 (arom. CH); 131.3 (arom.
CH); 133.6 (arom. C); 134.5 (arom. C); 147.1; 151.2; 169.2; 175.1 (C(2)). EI-MS (70 eV): 307 (100, Mþ),
147 (3), 121 (7), 117 (34), 104 (17), 77 (12), 28 (50). Anal. calc. for C18H17N3S (307.41): C 70.33, H 5.57, N
13.67; found: C 70.48, H 5.56, N 13.52.
Method B. Compound 11b (4.1 g, 20.0 mmol) was suspended in 2m HCl (60 ml). Under cooling and
stirring, a NaNO2 soln. (1.38 g, 20.0 mmol in 10 ml of H2O) was added dropwise. Workup was performed
as described for Method A. Yield: 4.2 g (68%). Yellow prisms (EtOH). M.p. 1218.
2-Benzylidene-1-methylhydrazinecarbothioamide (13a). A mixture of 2-methylthiosemicarbazide
(¼1-methylhydrazinecarbothioamide; 3.53 g, 30.0 mmol) and PhCHO (3.2 g, 30.0 mmol) in EtOH
(20 ml) was refluxed for 15 min. During boiling, a precipitate formed. The product was filtered off. Yield:
5.21 g (90%). Colorless rods (EtOH). M.p. 1678. IR: 3261s, 3122m, 1475s, 1452s, 1426s, 1365s, 1185m,
1001s, 908m, 759m, 627m, 512s. 1H-NMR (300 MHz, CDCl3): 3.88 (s, MeN); 6.54 (s, NH2); 7.40 – 7.70 (m,
5 arom. H); 7.80 (s, HC¼N). 13C-NMR (75 MHz, CDCl3): 32.9 (Me); 127.4 (arom. CH); 128.9 (arom.
CH); 130.4 (arom. CH); 133.7 (arom. C); 140.7 (HC¼N); 181.6 (C¼S). EI-MS (70 eV): 193 (86, Mþ), 133
(47), 118 (13), 116 (19), 106 (14) 104 (23), 90 (97), 107 (7), 77 (30), 61 (54), 57 (100), 30 (26), 28 (12).
Anal. calc. for C9H11N3S (193.27): C 55.93, H 5.74, N 21.74; found: C 55.84, H 5.62, N 21.63.
2-Benzylidene-1-ethylhydrazinecarbothioamide (13b). A mixture of 2-ethylthiosemicarbazide
(3.6 g, 30.0 mmol) and PhCHO (3.2 g, 30.0 mmol) in EtOH (20 ml) was refluxed for 15 min. During
boiling, a precipitate formed. The product was filtered off. Yield: 5.6 g (90%). Colorless rods (EtOH).
M.p. 1758. IR: 3251s, 3125m, 1572s, 1360s, 1237m, 1008s, 908m, 806m, 757m, 621m. 1H-NMR (300 MHz,
CDCl3): 1.31 (t, J ¼ 8.0, Me); 3.72 – 3.82 (m, CH2); 6.50 (s, NH2); 6.55 (s, HC¼N); 7.40 – 7.76 (m, 10 arom.
H). 13C-NMR (75 MHz, CDCl3): 14.5 (Me); 39.15 (CH2); 127.4 (arom. CH); 128.8 (arom. CH ); 130.4
(arom. CH); 133.8 (arom. C); 140.8 (HC¼N); 181.5 (C¼S). EI-MS (70 eV): 207 (90, Mþ), 145 (48), 132
(14), 130 (23), 120(15) 104 (23), 90 (90), 107 (7), 77 (32), 61 (55), 57 (100), 30 (28), 28 (15). Anal. calc.
for C10H13N3S (207.30): C 57.94, H 6.32, N 20.27; found: C 57.84, H 6.42, N 20.42.
2-(2-Benzylidene-1-methylhydrazinyl)-4-phenyl-1,3-thiazole (14a). Compound 13a (1.93 g,
10.0 mmol) and 1a (1.99 g, 10.0 mmol) in EtOH (40 ml) were refluxed for 10 min. After cooling, aq
NH3 was added. A precipitate formed, which was separated and recrystallized (EtOH) to give 14a. Yield:
2.64 g (90%). Yellow prisms (EtOH). M.p. 1918. IR: 695m, 722m, 755m, 955w, 1104s, 1194w, 1254m,

Helvetica Chimica Acta – Vol. 97 (2014)
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1335m, 1443m, 1486m, 1516s, 1537s, 1573m, 1597m, 3112w, 1H-NMR (300 MHz, CDCl3): 3.71 (s, MeN);
6.89 (s, HꢀC(5)); 7.30 – 7.71 (m, 10 arom. H); 7.88 (s, HC¼N). 13C-NMR (75 MHz, CDCl3): 32.2 (Me);
104.9 (C(5)); 125.8 (arom. C); 126.6 (arom. C); 127.5 (arom. C); 128.5 (arom. C); 128.7 (arom. C); 129
(arom. C); 134.9 (arom. C); 135.1 (arom. C); 135.8 (HC¼N); 151.1 (C(4)); 170.2 (C(2)). EI-MS (70 eV):
293 (44, Mþ), 215 (19), 190 (100), 162 (31), 147 (13), 134 (65), 121 (13), 104 (12), 107 (7), 77 (34), 51
(13), 28 (1). Anal. calc. for C17H15N3S (293.39): C 69.59, H 5.15, N 14.32; found: C 69.78, H 5.29, N 14.52.
2-(2-Benzylidene-1-ethylhydrazinyl)-4-phenyl-1,3-thiazole (14b). Compound 13b (2.07 g,
10.0 mmol) and 1a (1.99 g, 10.0 mmol) was refluxed for 15 min. Workup as described for 14a afforded
14b (2.55 g, 83%). Yellow lamella (EtOH). M.p. 142.5 – 143.08. IR: 3113w, 1598m, 1538s, 1445m, 1518 s,
1256m, 1105s, 756m, 724m, 696m. 1H-NMR (300 MHz, CDCl3): 1.28 (t, J ¼ 8.0, Me); 3.67 – 3.76 (m, CH2);
6.92 (s, HꢀC(5)); 7.32 – 7.70 (m, 10 arom. H); 7.81 (s, HC¼N). 13C-NMR (75 MHz, CDCl3): 32.2 (Me);
39.1 (CH2); 105.1 (C(5)); 125.8 (arom. C); 126.7 (arom. C); 127.6 (arom. C); 128.5 (arom. C); 128.7
(arom. C); 129 (arom. C); 134.9 (arom. C); 135.4 (arom. C); 137.1 (HC¼N ); 151.5 (C(4)); 170.5 (C(2)).
EI-MS (70 eV): 307 (100, Mþ), 121 (34), 104 (27), 77 (42), 28 (30). Anal. calc. for C18H17N3S (307.41): C
70.33, H 5.57, N 13.67; found: C 70.43, H 5.66, N 13.42.
Financial support from the State of Mecklenburg-Vorpommern is gratefully acknowledged.
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Received February 6, 2013