Cyclization of 4-phenylthiosemicarbazide with phenacylbromide revisited. Formation of 1,3,4-thiadiazines and of isomeric 1,3-thiazoles

Article abstract of DOI:10.1002/jhet.2007

The cyclization of 4-phenylthiosemicarbazide with phenacylbromide, carried out in refluxing ethanol, afforded 1,3,4-thiadiazine 1 as the major product. In contrast to a previous report, 2-phenylimino-4-phenyl-2,3-dihydro-1,3-thiazol-3- amine (2) and not 2

Full text of DOI:10.1002/jhet.2007

Month 2014
Cyclization of 4-Phenylthiosemicarbazide with Phenacylbromide
Revisited. Formation of 1,3,4-Thiadiazines and of Isomeric 1,3-Thiazoles
Wolf-Diethard Pfeiffer,a Dieter Junghans,a Ashot S. Saghyan,b,c,f and Peter Langerd,e
*
aInstitut für Biochemie, Universität Greifswald, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
bScientific and Production Center “Armbiotechnology” of NAS RA 14 Gyurjyan Str., 0056 Yerevan, Armenia
cDepartment of Pharmaceutical Chemistry, Yerevan State University Alex Manoogian Str., 1, 0025 Yerevan, Armenia
dInstitut für Chemie, Universität Rostock Albert-Einstein-Str. 3a, 18059 Rostock, Germany
eLeibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
fFelix-Hausdorff-Str. 4, 17487 Greifswald, Germany
*
E-mail: peter.langer@uni-rostock.de
Received February 6, 2013
DOI 10.1002/jhet.2007
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
The cyclization of 4-phenylthiosemicarbazide with phenacylbromide, carried out in refluxing ethanol,
afforded 1,3,4-thiadiazine 1 as the major product. In contrast to a previous report, 2-phenylimino-4-phenyl-
2,3-dihydro-1,3-thiazol-3-amine (2) and not 2-hydrazono-3,4-diphenyl-2,3-dihydro-1,3-thiazole (8) was formed
as a side-product. This product is the main product when the reaction is carried out in concentrated hydrochloric
acid. Our findings were independently confirmed by independent syntheses of the isomeric products and by a
thorough study of their reactivity. It is important to note that the product distribution of the cyclization of
thiosemicarbazides with haloketones strongly depends on the substitution pattern and on the reaction conditions.
J. Heterocyclic Chem., 00, 00 (2014).
1,3,4-Thiadiazines are of considerable biochemical and
pharmacological relevance. Many 1,3,4-thiadiazin-2-yl-
amine derivatives show metalloproteinase inhibitory activity
[1,2]. 2-Alkylimino-1,3,4-thiadiazines and 2-alkyamino-
1,3,4-thiadiazines are used as cardiotonic and spasmolytic
agents [3–8]. 1,3,4-Thiadiazin-2-ones also represent
cardiotonica with calcium sensitizing activity [9–11].
3-Phenylazo-1H-4,2,1-thiadiazine has been used for the
treatment of 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 and can be used for
treatment of tumors and AIDS [13,14]. 2-Nitrosimino-3,
6-dihydro-2H-1,3,4-thiadiazines [15], N-morpholinyl-1,3,
4-thiadiazines, N-thiomorpholinyl-1,3,4-thiadiazines or
N-piperidinyl-1,3,4-thiadiazines [16] exhibit antithrombotic
activities. In the context of our studies related to the chemistry
of 1,3,4-thiadiazines [3–8,17], we studied the cyclization of
4-substituted thiosemicarbazides with phenacylhalogenides.
In this context, we realized a discrepancy between results
reported in the literature and our own observations. We
reinvestigated the work reported in the literature and
herein report that the previously assigned structures have to
be revised.
RESULTS AND DISCUSSION
The cyclization of thiosemicarbazides with phenacylhalo-
genides can, in principle, result in three isomeric products,
namely, 2-aryl(alkyl)amino-5-phenyl-1,3,4-thiadiazines, 2-
alkyl(aryl)imino-4-phenyl-2,3-dihydro-1,3-thiazol-3-amines,
and 2-hydrazono-3-alkyl(aryl)-4-phenyl-2,3-dihydro-1,3-
thiazoles. Because of a number of discrepancies between
the results reported by Bose [18] related to the cyclization
of thiosemicarbazides with phenacylhalogenides with our
own work, we decided to repeat the work of this author.
© 2013 HeteroCorporation

W-D. Pfeiffer, D. Junghans, A. S. Saghyan, and P. Langer
Vol 000
Scheme 2. Synthesis of 3, 4, and 6.
We have found that, as reported by Bose [18], reflux of
an ethanol solution of 4-phenylthiosemicarbazide and
phenacylbromide afforded 1,3,4-thiadiazine 1 as the major
product (Scheme 1). Bose also reported the formation of
the isomeric side-product 8, which, however, was assigned
to a wrong structure and has to be revised. According
to our own investigations, the structure of the product is
2-phenylimino-4-phenyl-2,3-dihydro-1,3-thiazol-3-amine
(2) and not 2-hydrazono-3,4-diphenyl-2,3-dihydro-1,
3-thiazole (8). We have also found that product 2
was selectively formed as the single isomer when the
reaction was carried out in concentrated hydrochloric
acid (reflux for 3 h). It is interesting to note that the
cyclization of phenacylbromide with 4-methylthio-
semicarbazide and 4-ethylthiosemicarbazide (instead of
4-phenylthiosemicarbazide) in concentrated hydrochloric
acid exclusively afforded the 1,3,4-thiadiazines [19].
The reaction of 2 with 4-nitrobenzaldehyde afforded
2-phenylimino-3-(4-nitrobenzylideneamino)-2,3-dihydro-
1,3-thiazole 3 (Scheme 2). Treatment of 2 with nitrous acid
resulted in deamination at position 3 and subsequent
nitrosylation at position 5 to give 2-phenylamino-5-nitroso-
1,3-thiadiazole 4. The same product is formed from 2-
phenylamino-5-phenyl-1,3-thiazole 5. The structure of 4
was confirmed by reduction with zinc dust in glacial acetic
acid and subsequent reaction with benzaldehyde to give 2-
phenylamino-4-phenyl-5-benzylideneamino-1,3-thiazole 6
2-Hydrazono-3,4-diphenyl-2,3-dihydro-1,3-thiazole
Scheme 3. Synthesis of 8, 9a, and 9b.
8 (Scheme 3) was isolated by careful acidic hydrolysis
of 2-isopropylidenehydrazono-3,4-diphenyl-2,3-dihydro-
1,3-thiazole 7 in 2 M hydrochloric acid. Hydrolysis of 7
in concentrated hydrochloric acid gave phenylimide 2. At
the same time, we have observed that the reaction of con-
centrated hydrochloric acid with 8 also afforded product
2. The structure of 8 was independently confirmed by its
reaction with benzaldehyde and 4-nitrobenzaldehyde to
give 2-(benzylidenehydrazono)-3,4-diphenyl-2,3-dihydro-
1,3-thiazole 9a and 2-(4-nitrobenzylidenehydrazono)-
3,4-diphenyl-2,3-dihydro-1,3-thiazole 9b, respectively. These
Scheme 1. Synthesis of 1 and 2.
products are independently available by condensation of
phenacylbromide with the thiosemicarbazones derived from
benzaldehyde and 4-nitrobenzaldehyde. The structure of 9b
is identical with the structure of the product obtained by change
of the hydrazone moiety of 2-(isopropylidenehydrazono)-
3,4-diphenyl-2,3-dihydro-1,3-thiazole 7. Product 9b is
obtained, depending on the reaction conditions, in the form
of two different modifications. One modification appears in
the form of orange to red needles; the other one appears as
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Cyclization of 4-Phenylthiosemicarbazide with Phenacylbromide Revisited
8 (2.67 g, 10mmol) in a solution of concentrated hydrochloric
acid was refluxed for 2 h. The work-up was carried out
as described for Method A. Yield: 1.75 g (66%). IR (KBr, cmÀ1):
red plates. Both modifications show the same melting point
of the mixture. However, at temperatures higher than
180ꢀC, the orange needles start to undergo a solid phase
reaction to give red plates. This transformation of the two
modifications can also be initiated by increase of the pressure.
In conclusion, we have reinvestigated the cyclization of
4-phenylthiosemicarbazide and phenacylbromide carried
out in refluxing ethanol. This reaction afforded, in accor-
dance to previous reports, 1,3,4-thiadiazine 1 as the major
product. However, we have found that, in contrast to a
previous report by Bose [18], 2-phenylimino-4-phenyl-
2,3-dihydro-1,3-thiazol-3-amine (2) and not 2-hydrazono-
3,4-diphenyl-2,3-dihydro-1,3-thiazole (8) is formed as a
side-product. In addition, we have observed that this prod-
uct is the main product when the reaction is carried out in
concentrated hydrochloric acid. Our findings were inde-
pendently confirmed by independent syntheses of the
isomeric products and by a thorough study of their reactiv-
ity. It is important to note that the product distribution of
the cyclization of thiosemicarbazides with haloketones
strongly depends on the substitution pattern and on the
reaction conditions.
e
n = 493 (w), 580 (m), 638 (m), 695 (s), 765 (m), 842 (m),
917 (m), 1074 (w), 1205 (m), 1289 (m), 1407 (w), 1445 (w),
1493 (m), 1562 (s), 1579 (s), 1606 (s), 1618 (s), 2918 (m), 3060
8 m), 3169 (m). 1H NMR (300MHz, CDCl3) d = 4.53 (s, 2H,
NH2), 5.80 (s, 1H, 5-H, Hetar), 6.98–7.57 (m, 10H, ArH).
13C NMR (75 MHz, DMSO-d6) d = 120.80 (C-5), 122.60 (CH,
Ar), 125.87 (CH, Ar), 127.72 (CH, Ar), 128.39 (CH, Ar),
129.13 (CH, Ar), 129.13 (CH, Ar), 130.74 (Ar), 135.07 (Ar),
140.10 (C-4), 150.57 (C-2). MS (EI, 70eV): m/z = 267 (M+, 100),
252 (4), 136 (12), 103 (12), 77 (16), 51 (3), 44 (14), 32 (13),
28 (74). Anal. Calcd for C15H13N3S (267.35): C, 67.39; H, 4.90;
N, 15.72. Found: C, 67.49; H, 4.92; N, 15.81.
2-Phenylimino-3-(4-nitrobenzylideneamino)-2,3-dihydro-
1,3-thiazole (3).
A mixture of 2 (1.34g, 5 mmol) and 4-
nitrobenzaldehyde (0.75 g, 5 mmol) in EtOH (30 mL) was
refluxed for 15min. After cooling, a red crystalline precipitate
formed. Yield: 1.6 g (80%); red needles (n-BuOH); mp 171ꢀC. IR
(KBr, cmÀ1): n = 694 (m), 1172 (m), 1259 (m), 1340 (s), 1490
(w), 1517 (m), 1563 (s), 1582 (s), 1617 (m), 3440 (m). H NMR
e
1
(300 MHz, CDCl3) d = 6.04 (s, 1H, 5-H, Hetar), 7.61–8.19
(m, 14H, ArH), 10.62 (s, 1H, CH). 13C NMR (75MHz, DMSO-
d6) = 120.79 (C-5), 123.96 (CH, Ar), 126.0 (CH, Ar), 128.10 (CH,
Ar), 128.53 (CH, Ar),, 128.55 (CH, ArH), 128.74 (CH, ArH),
129.36 (CH, Ar), 129.60 (CH, Ar), 130.87 (Ar), 139.49 (Ar),
140.84 (Ar), 148.13 (NCH), 149.51 (Ar), 150.05 (C-4), 155.49
(C-2). MS (EI, 70eV): m/z = 400 (M+, 8), 389 (16), 388 (100),
386 (91), 357 (43), 355 (42), (308 (64), 278 (11), 277 (62), 276
(33), 252 (21), 251 (10), 118 (22), 217 (13), 113 (15),104 (70), 91
(30), 77 (92), 51 (29), 28 (6). Anal. Calcd for C22H16N4O2S
(400.46): C, 65.98; H, 4.03; N, 13.99. Found: C, 65.91; H, 4.00;
N, 13.95. Yield:1.6 g (80%), F 171ꢀC, red needles (n-BuOH).
2-Phenylamino-4-phenyl-5-nitroso-1,3-thiazole (4). Method A:
A mixture of 2 (2.67 g, 10 mmol) was suspended in a solution of
hydrochloric acid (10%, 50mL). Under stirring, a solution of
NaNO2 (1.38 g, 20mmol) was added in H2O (10 mL) at 5ꢀC. An
orange precipitate formed, which was washed with H2O. Yield:
2.6 g (93%); yellow lamella (EtOH); mp 197ꢀC. Method B: 5
(2.52 g, 10 mmol) in 1 M HCl (15 mL) and H2O (30 mL) was
suspended. A solution of NaNO2 (0.69g, 10mmol) in H2O (5ml)
was added dropwise at 5ꢀC. An orange precipitate formed. After
3 h, the precipitate was separated under suction filtration, washed
with H2O, and recrystallized from EtOH. Yield: 2.7 g (96%); mp
197ꢀC. IR (KBr, cmÀ1): en = 695 (s), 744 (s), 769 (m), 1161 (w),
1492 (m), 1534 (m), 1578 (s), 1616 (s), 3060 (m), 3120 (m).
1H NMR (300 MHz, DMSO-d6) d = 7.06–8.29 (m, 10H, ArH),
13.59 (s, 1H, NH). MS (EI, 70eV): m/z = 281 (M+, 40), 265 (15),
207 (11), 147 (30), 146 (10), 135 (25), 133 (15), 121 (13), 119
(31), 118 (19), 115 (15), 105 (13), 104 (40), 103 (81), 91 (16), 89
(17), 77 (1000), 71 (29), 51 (19). Anal. Calcd for C15H11N3OS
(281.34): C, 64.04; H, 3.94; N, 14.94. Found: C, 64.11; H, 3.94;
N, 14.98.
EXPERIMENTAL
2-Phenylamino-5-phenyl-6H-1,3,4-thiadiazine
(1).
A
mixture of 4-phenylthiosemicarbazide (1.67 g, 10 mmol) and
phenacylbromide (1.99 g, 10 mmol) in EtOH (20 mL) was
refluxed 30 min. After cooling and addition of an NH3 solution,
a crystalline precipitate formed. Yield: 2.35 g (88%); colorless
À1
needles (pyridine/EtOH); mp 176ꢀC. IR (KBr, cm ): n = 581
e
(w), 638 (w), 693 (m), 765 (m), 842 (w), 918 (w), 1187 (w),
1205 (m), 1289 (m), 1495 (m), 1561 (s), 1580 (s), 1620 (m),
2919 (m), 3060 (m), 3167 (m), 3428 (m). 1H NMR
(300 MHz, CDCl3): d = 3.74 (s, 2H, 6-CH2), 6.98–7.77 (m, 10H,
ArH), 8.90 (s, br, 1H, NH). 13C NMR (75 MHz, DMSO-d6)
d = 22.17 (C-6), 121.08, 122.74, 125.98, 128.55, 129.35, 135.12
(C-2). MS (EI, 70 eV): m/z = 267 (M+, 100), 164 (12), 146 (2),
136 (97), 135 (29), 104 (32), 103 (85), 91 (12), 78 (12),
77 (74), 51 (25), 28 (8). Anal. Calcd for C15H N3S (267.35):
C, 67.39; H, 4.90; N, 15.72. Found: C, 67.41; H, 4.92; N 15.81.
2-Phenylimino-4-phenyl-2,3-dihydro-1,3-thiazol-3-amine
(2). Method A: 1 (2.67 g, 10mmol) in a solution of concentrated
hydrochloric acid (20 mL) was refluxed for 3 h. The hot solution
was filtered to remove resinous products. After cooling, to the
mixture was added an aqueous solution of Na2CO3 (to give
pH8), and the precipitate formed was filtered with the help of
vacuum; yield: 1.10 g (41%). The crude product was crystallized
from benzene and subsequently from n-PrOH to give colorless
lamella; mp 200ꢀC. Method B:
7 (3.07g, 10mmol) in
2-Phenylamino-4-phenyl-1,3-thiazole (5).
An EtOH
concentrated HCl (30mL) was refluxed for 3 h. The work-up was
carried out as described for Method A. Yield: 0.32g (12%).
Method C: 4-phenylthiosemicarbazide (3.34 g, 20mmol) was
dissolved in a hot solution of concentrated hydrochloric acid
(50 mL). An EtOH solution (10 mL) of phenacylchloride (1.55 g,
10mmol) was added dropwise within 15min to the boiling
mixture of 4-phenylthiosemicarbazide. The work-up was carried
out as described for Method A. Yield: 3.5 g (66%). Method D:
solution (10 mL) of phenylthioureas (1.52 g, 10 mmol) and
phenacylbromide (1.99 g, 10 mmol) was refluxed for 30 min.
After cooling and addition of an aq NH3 solution, a crystalline
precipitate formed; yield: 2.2 g (87%); colorless needles (Et2O);
À1
mp 140ꢀC [20]. IR (KBr, cm ): n = 498 (m) ,698 (s), 751 (s),
e
771 (m), 1070 (m), 1214 (m), 1282 (m), 1315 (m), 1342 (m),
1427 (s), 1463 (s), 1501 (s), 1567 (s), 1603 (s), 2960 (m), 3068
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W-D. Pfeiffer, D. Junghans, A. S. Saghyan, and P. Langer
Vol 000
1
32 (9), 28 (41). Anal. Calcd for C15H13N3S1 (267.08): C, 67.39;
H, 4.90; N, 15.72. Found: C, 67.41; H, 4.92; N, 15.81.
(m), 3229 (m). H NMR (300 MHz, DMSO-d6) d = 6.96 (s, 1H,
5-H, Hetar), 7.31–7.93 (m, 10H, ArH), 10.62 (s, 1H, CH). MS
(EI, 70 eV): m/z = 252 (M+, 100), 251 (38), 134 (23), 104 (13),
90 (7), 89 (7), 32 (2), 28 (11). Anal. Calcd for C15H12N2S
(252.34): C, 71.40; H, 4.79; N, 11.10. Found: C, 71.51; H,
Benzaldehyde-4-phenylthiosemicarbazone. A mixture of
4-phenylthiosemicarbazide (3.34 g, 20 mmol) and freshly
distilled benzaldehyde (2.33 g, 22 mmol) in EtOH (35 mL) was
refluxed for 1 h. After cooling, a crystalline precipitate formed.
Yield: 3.6 g (71%); yellow lamella (EtOH); mp 185ꢀC. IR (KBr,
cmÀ1): en = 551 (m), 623 (m), 653 (m), 692 (s), 745 (m),
943 (m), 1064 (m), 1201 (s), 1227 (m), 1270 (s), 1308 (m),
1335 (m), 1397 (m), 1445 (s), 1507 (s), 1541 (s), 1595 (m),
2992 (m), 3162 (m), 3305 (s), 3436 (m). 1H NMR (300 MHz,
CDCl3) d = 7.36–7.71 (m, 10H, ArH), 7.98 (s, 1H, CH), 9.22
(s, 1H, NH), 10.32 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6)
d = 125.12 (CH, ArH), 125.55 (CH, ArH), 127.47 (CH, ArH),
127.89 (CH, ArH), 128.49 (CH, ArH), 129.87 (CH, ArH),
133.90 (Ar), 138.96 (Ar), 142.81 (NCH), 175.97 (CS). MS (EI,
70 eV): m/z = 255 (M+, 61), 178 (4), 162 (14), 152 (26),150
(96), 136 (29), 120 (30), 119 (72), 118 (14), 104 (25), 103 (10),
93 (100), 78 (11), 77 (82), 66 (22), 51 825), 39 (8), 28 (2).
Anal. Calcd for C14H13N3S (255.34): C, 65.85; H, 5.13; N,
16.46. Found: C, 65.81; H, 5.20; N, 16.51.
4.82; N, 11.15.
2-Phenylamino-4-phenyl-5-(benzylideneamino)-1,3-
thiazole (6). To a suspension of 4 (2.81 g, 10 mmol) in glacial
acetic acid (30mL) and EtOH (20mL), zinc dust (2.5g) was
added in portions. After 12h, the solution was filtered, and freshly
distilled benzaldehyde was added. After 3 days, a precipitate was
separated by filtration. The crude product was washed with H2O.
Yield: 2.8 g (79%); gold-colored lamella (EtOH); mp 172ꢀC. IR
(KBr, cmÀ1): en = 621 (m), 693 (s), 752 (m), 1022 (m), 1337 (s),
1403 (s), 1424 (s), 1452 (s), 1559 (s), 2857 (m),3122 (s), 3387
(m). 1H NMR (300 MHz, DMSO-d6) d = 7.04–8.23 (m, 15H,
ArH; s, 1H, CH), 10.50 (s, 1H, NH). 13C NMR (75 MHz, DMSO-
d6) d = 117.82, 122.05, 127.84, 128.10, 128.17, 128.90, 129.03,
129.05, 130.66, 134.46, 136.27, 140.58, 145.27, 154.05, 157.76,
176.81. MS (EI, 70eV): m/z = 355 (M+, 100), 278 (3), 136 (8),
117 (40), 104 (23), 102 (4), 77 (27), 45 (20), 43 (26), 28 (12).
Anal. Calcd for C22H17N3OS (355.46): C, 74.34; H, 4.82; N
11.82. Found: C, 74.42; H, 4.81; N, 11.83.
2-Benzylidenehydrazono-3,4-diphenyl-2,3-dihydro-1,3-
thiazole (9a).
Method A: A mixture of benzaldehyd-4-
phenylthiosemicarbazone (2.55 g, 10mmol) and phenacylbromide
(1.99 g, 10mmol) was refluxed in EtOH (30 mL) for 30min. A
solution of sodium acetate was added to the reaction mixture.
After cooling, a yellow precipitate crystallised. Yield: 1.9 g (54%);
yellow lamella (n-PrOH); mp 196ꢀC. Method B: An EtOH
solution (10 mL) of 8 (0.27g, 1 mmol) and 0.106 g, 1 mmol)
benzaldehyde was refluxed for 10 min. YÀie1ld: 0.33g (93%);
yellow lamella (n-PrOH); 196ꢀC. IR (KBr, cm ): n =513 (m), 559
(m), 578 (m), 694 (s), 729 (m), 760 (s), 1020 (m), 1290 (m), 1343
(m), 1448 (s), 1490 (s), 1527 (s), 1576 (s), 1609 (s), 3031 (m),
2-Isopropylidenehydrazono-3,4-diphenyl-2,3-dihydro-1,3-
thiazole (7). A mixture of acetone-4-phenylthiosemicarbazone
(2.07 g, 10mmol) and phenacylbromide (1.99g, 10mmol) in
acetone 10 (mL) was refluxed for 30 min. The solvent was
removed under reduced pressure. The crude product was
dissolved in EtOH, and an NH3 solution was added. A yellow
precipitate was separated. Yield: 2.70g (88%); yellow needles
(EtOH); mp 165ꢀC. IR (KBr, cmÀ1): en = 556 (w), 695 (m),
711 (m), 769 (m), 815 (w), 1080 (m), 1303 (m), 1359 (s), 1449
(m), 1495 (s), 1549 (s),1570 (s), 1596 (s), 1628 (s), 3066 (w),
e
1
1
3058 (m), 3437 (m). H NMR (300 MHz, CDCl3) d =6.16 (s, 1H,
3427 (w), 3442 (w). H NMR (300 MHz, CDCl3): 1.90 (s, 3H,
5H, Hetar), 7.07–7.72 (m, 10H, ArH), 8.22 (s, 1H, NCH).
13C NMR (75 MHz, DMSO-d6) d = 101.6 (C-5), 126.49 (CH, ArH),
127.29 (CH, ArH), 127.66 (CH, Ar), 127.73 (CH, Ar), 127.87 (CH,
Ar), 128.10 (CH, Ar),128.26 (CH, Ar), 128.30 (CH, Ar), 128.89
(CH, Ar), 130.43 (Ar), 134.87 (Ar), 137.34 (Ar), 139.35 (C-4),
151.14 (NCH), 169.51 (C-2). MS (EI, 70 eV): m/z= 355 (M+, 39),
326 (15), 238 (42), 135 (16), 134 (19), 91 (11), 90 (23), 77 (51),
51 (13), 28 (100). Anal. Calcd for C22H17N3S (355.46): C, 74.34; H,
4.82; N, 11.82. Found: C, 74.35; H, 4.81; N, 11.83.
Me), 2.01 (s, 3H, Me), 6.07 (s, 1H, 5-H, Hetar), 7.08–7.26
(m, 10H, ArH). 13C NMR (75 MHz, DMSO-d6) d = 18.07 (Me),
24.20 (Me), 100.84 (C-5), 127.13 (CH, Ar), 127.81 (CH, Ar),
128.05 (CH, Ar), 128.09 (CH, Ar), 128.23 (CH, Ar), 128.42 (CH,
Ar), 130.99 (Ar), 138.02 (Ar), 139.02 (C-4), 158.74 (NC), 165.82
(C-2). MS (EI, 70eV): m/z = 307 (M+, 100), 251 (35), 238 (11),
181 (10), 180 (80), 135 (45), 134 (67), 102 (5), 91 (10), 77 (64),
32 (18), 28 (93). Anal. Calcd for C18H17N3S (307.41): C, 70.33;
H, 5.57; N, 13.67. Found: C, 70.30; H, 5.61; N 13.72.
4-Nitrobenzaldehyde-4-phenylthiosemicarbazone.
A
2-Hydrazono-3,4-diphenyl-2,3-dihydro-1,3-thiazole
(8).
mixture of 4-phenylthiosemicarbazide (3.34 g, 20 mmol) and 4-
nitrobenzaldehyde (3.02 g, 20 mmol) in EtOH (50 mL) was
refluxed for 15 min. A crystalline precipitate formed. Yield:
5.7 g (95%); yellow needles (n-BuOH); mp 219ꢀC. IR (KBr,
cmÀ1): en = 508 (w), 693 (m), 748 (m), 843 (m), 1091 (m), 1107
(m), 1192 (s), 1262 (s), 1340 (s), 1448 (m), 1516 (s), 1541 (s),
1580 (m), 1598 (m), 2989 (m),3139 (m), 3340 (m). 1H NMR
(300 MHz, DMSO-d6) d = 7.21–7.56 (m, 9H, ArH), 8.27 (s, 1H,
CH), 10.33 (s, br, 1H, NH), 12.10 (s, br, 1H, NH). MS (EI,
70 eV): m/z = 300 (M+, 51), 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). Anal. Calcd for C14H12N4O2S (300.34): C, 55.99; H,
4.03; N, 18.65. Found: C, 55.90; H, 4.05; N, 18.70.
Compound 7 (3.07 g, 10mmol), dissolved in EtOH (15 mL) and
2 M HCl (5mL), 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 ether. The pH was adjusted to 4–5 by addition of an
NH3 solution and then by addition of an aqueous solution of
Na2CO3 with vigorous shaking. The ether layer was separated,
dried, filtered worked, and concentrated to give 8. Yield:
0.9 g, (34%); yellow lamella (EtOH); mp 176ꢀC. IR (KBr, cmÀ1):
en = 554 (w), 572 (m), 699 (s), 762 (s), 920 (w), 1079 (m), 1195
(w), 1298 (m), 1363 (s), 1447 (w), 1493 (s), 1551 (m), 1561 (m),
1594 (m), 1645 (s), 3291 (m), 3426 (m). 1H NMR
(300MHz, CDCl3) d = 3.70 (s, br, 2H, NH2), 6.03 (s, 1H, 5-H,
Hetar), 7.05–7.33 (m, 10H, ArH). 13C NMR (75 MHz, DMSO-d6)
d = 98.36 (C-5), 126.71 (CH, ArH), 127.55 (CH, Ar), 127.91
(CH, Ar), 128.10 (CH, Ar), 128.43 (CH, Ar), 131.34 (Ar), 138.77
(Ar), 139.43 (C-4), 157.84 (C-2). MS (EI, 70eV): m/z = 267 (M+,
100), 250 (22), 180 (18), 134 (8), 93 (5), 91 (6), 77 (39), 51 (10),
2-(4-Nitrobenzylidenehydrazono)-3,4-diphenyl-2,3-dihydro-
1,3-thiazole (9b). Method A: A mixture of 4-nitrobenzaldehyde-
4-phenylthiosemicarbazone (3.0g, 10mmol) and phenacylbromide
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Cyclization of 4-Phenylthiosemicarbazide with Phenacylbromide Revisited
[5] Pfeiffer, W. D.; Bulka, E.. Ger. (East) Pat. 1985 220 311
(Chem. Abstr. 1986, 104, 68891).
[6] 1990EGP280760, Pfeiffer, W. D.; Bulka, E. Ger. (East) Pat.
1990 280 760 (Chem. Abstr. 1991, 114, 81896).
[7] Pfeiffer, W. D.; Bulka, E. Ger. (East) Pat. 1991 289 272
(Chem. Abstr. 1991, 115, 232298).
[8] Pfeiffer, W. D.; Bulka, E., Ger.(East) Pat. 1991 293 351
(Chem. Abstr. 1992, 116, 41490).
[9] Ravens, U.; Fluss, M. O.; Li, Q.; Himmel, H. M.; Wettwer, E.;
Klockow, M.; Lues, I.. Naunyn-Schmiedeberg’s Arch. Pharma. 1997,
355, 733 (Chem. Abstr. 1997, 127, 104094).
[10] Sugawara, H.; Endoh, M.. Jpn J Pharmacol 1999, 80, 55
(Chem. Abstr. 1999, 131, 111182).
[11] Himmel, M. H.; Amos, G. J.; Wettwer, E.; Ravens, U. J.
Cardiovas. Pharmacol. 1999, 33, 301 (Chem. Abstr. 1999, 131, 443).
[12] Petrie, C.; Orme, M. W.; Baindur, N.; Robbins, K. G.;
Harris, S. M.; Kontoyianni, M.; Hurley, L. H.; Kerwin, S. M.;
Mundy, G. R. PCT Int. Appl. WO 9 715 308 (1997) (Chem. Abstr.
1997, 127, 17703).
[13] Eggenweiler, H. M.; Wolf, M.; Ger. Pat. 2003 10 150 517
(Chem. Abstr. 2003, 138, 297702).
[14] Warner, J. M.. PCT Int. Appl. WO 2004 2 004 067 006
(Chem. Abstr. 2004, 141, 185092).
[15] Rese, R.; Brümmer, U.; Unsöld, E.. Pharmazie 1998, 53, 820.
[16] Chupakhin, O. N.; Sidorova, L. P.; Perova, N. M.; Charushin,
V. N.; Rusinov, V. L.; Mulyar, A. G. Russ. Pat. 2005 2259371 (Chem.
Abstr. 2005, 143, 229887).
[17] (a) Pfeiffer, W. D.; Dilk, E.; Roßberg, H.; Langer, P.
Synlett 2003, 2392, (b) Bodtke, A.; Pfeiffer, W. D.; Ahrens, N.;
Langer, P. Tetrahedron 2005, 61, 10926, (c) Bodtke, A.; Pfeiffer,
W. D.; Ahrens, N.; Langer, P. Bioorg Med Chem Lett 2004, 1509,
(d) Pfeiffer, W. D.; Dilk, E.; Rossberg, H.; Langer, P. Synlett 2003,
2392, (e) Pfeiffer, W. D. Houben-Weyl, Methoden der Organischen
Chemie, Hetarene IV, E9c; Schaumann, E.,Ed.; Thieme-Verlag:
Stuttgart, 1998, pp 488–529, (f) Jira, T.; Stelzer, A.; Pfeiffer, W.
D.; Schopplich, C.; Siegert, S.; Kindermann, M.. Pharmazie 1997,
52, 11, (g) Jira, T.; Pfeiffer, W. D.; Lachmann, K.; Epperlein, U.
Pharmazie 1994, 49, 401, (h) Szulzewsky, K.; Pfeiffer, W. D.; Bulka,
E.; Rossberg, H.; Schulz, B. Acta Chem Scand 1993, 47, 302,
(i) Pfeiffer, W. D.; Dilk, E.; Bulka, E. Wiss. Zeitschrift der Ernst-
Moritz-Arndt-Universität Greifswald 1978, 27, 135, (j) Pfeiffer, W.
D.; Buhrow, J.; Bulka, E. Wiss. Zeitschrift der Ernst-Moritz-
Arndt-Universität Greifswald 1988, 37, 38, (k) Bulka, E.; Pfeiffer,
W. D.; Tröltsch, C.; Dilk, E.; Gärtner, H.; Daniel, D. Collect.
Czech. Chem. Commun. 1978, 28, 577.
(1.99 g, 10mmol) was refluxed in EtOH (120 mL) for 1 h. A red to
orange precipitate formed. Yield: 3.00g (75%); modification 1:
long orange needles (n-BuOH); mp 209ꢀC; modification 2: rubin
red-colored prisms (n-PrOH), mp 209ꢀC. The orange needles
were converted into the red prisms after repeated recrystallization
from n-PrOH. Method B: An EtOH solution (75mL) of 7
(3.07 g,10mmol) and 4-nitrobenzaldehyde (1.51 g, 10mmol), in
the presence of three drops of concentrated HCl, was refluxed for
10min. Yield. 1.87g (47%); orange needles (n-BuOH);
mp 209ꢀC. Method C: A Mixture of 8 (0.27 g, 1 mmol) and
4-nitrobenzaldehyde (0.15 g, 1 mmol) in EtOH (10 mL) was
briefly heating. An orange precipitate formed. Yield: 0.39 g,
(97%), orange needles (n-BuOH), mp 209ꢀC. IR (KBr, cmÀ1):
e
n = 556 (m), 696 (m), 711 (s), 769 (s), 815 (m), 926 (m), 985
(m), 1029 (w), 1080 (s), 1256 (m), 1303 (s), 1359 (s), 1449
(m), 1495 (s), 1548 (s), 1569 (s), 1596 (s), 1627 (s), 2907 (m),
3040 (m), 3433 (m). 1H NMR (300 MHz, CDCl3) d = 6.10
(s, 1H, 5H, Hetar), 7.11–7.30 (m, 14H, ArH, s, 1H, CH).
13C NMR (75 MHz, DMSO-d6) d = 100.84 (C-5), 127.13 (CH,
Ar), 127.81 (CH, Ar), 128.05 (CH, Ar), 128.09 (CH, Ar), 128.23
(CH, Ar), 128.42 (CH, ArH), 130.99 (Ar), 138.02 (Ar), 139.02
(C-4), 158.74 (Ar), 165.82 (C-2). MS (EI, 70eV): m/z = 399
(M+, 17), 370 (3), 307 (33), 292 (16), 291 (64), 251 (11), 238
(11), 185 (27), 183 (28), 180 (14), 135 (20), 93 (31), 77 (33),
57 (18), 51 (12), 44 (38), 43 (35), 36 (62), 28 (100). Anal.
Calcd for C22H16N4O2S (400.46): C, 65.98; H, 4.03; N, 13.99.
Found: C, 65.90; H, 4.01; N, 13.89.
Acknowledgments. Financial support by the Volkswagenstiftung
(Az86223) and by the State of Mecklenburg-Vorpommern is
gratefully acknowledged. We are gratefully to Prof. Dr. E. Bulka
(late) for his support.
REFERENCES AND NOTES
[1] Tschesche, H.; Schröder J. Eur. Pat. 2002, 1191024 (Chem.
Abstr. 2002, 136, 263179).
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Stammler, H. G.; Stammler, A.; Pfeiffer, W. D.; Tschesche, H.; J Med
Chem 2001, 44, 3231.
[18] Bose, P. K.. Indian Chem. Soc. 1925, 2, 95.
[19] Pfeiffer, W. D; Ahlers, K.-D.; Villinger, A.; Langer, P.
unpublished results.
[3] Pfeiffer, W. D.; Dilk, E.; Bulka, E.. Ger. (East) Pat. 1983 204
092 (Chem. Abstr. 1984, 101, 7216).
[4] Pfeiffer, W. D.; Bulka, E.; Fermum, R. Ger. (East) Pat. 1984
209 196 (Chem. Abstr. 1984, 101, 191974).
[20] Beyer, H.; Ruhlig, G.; Chem Ber, 1955, 89, 107.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet