A convenient and efficient synthesis of heteroaromatic hydrazone derivatives via cyclization of thiosemicarbazone with ω-bromoacetophenone

Article abstract of DOI:10.1002/jhet.585

The synthesis of hydrazone derivatives containing thiazole unit was achieved with condensation of thiosemicarbazones and ω-bromoacetophenone at room temperature. This mild, convenient, and efficient method affords the desired products with good to excelle

Full text of DOI:10.1002/jhet.585

March 2011
A Convenient and Efficient Synthesis of Heteroaromatic
Hydrazone Derivatives via Cyclization of Thiosemicarbazone
with x-Bromoacetophenone
361
Weiwei Liu,a* Chuanzhou Tao,a Lijuan Tang,a Jie Li,a Yan Jin,a
Yueqiang Zhao,a and Hongwen Hub
aSchool of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, People’s
Republic of China
bDepartment of Chemistry, Nanjing University, Nanjing 210093, People’s Republic of China
*E-mail: liuww323@yahoo.com.cn
Received March 19, 2010
DOI 10.1002/jhet.585
Published online 22 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis of hydrazone derivatives containing thiazole unit was achieved with condensation of
thiosemicarbazones and x-bromoacetophenone at room temperature. This mild, convenient, and efficient
method affords the desired products with good to excellent yields. Their structures have been deter-
mined by X-ray diffractional analysis, 1H-NMR, MS, elemental analysis, and IR. Thiosemicarbazones
were prepared by the condensation of thiosemicarbazide with aldehydes or ketones.
J. Heterocyclic Chem., 48, 361 (2011).
INTRODUCTION
RESULTS AND DISCUSSION
Thiosemicarbazones and their derivatives are impor-
tant compounds in organic and medicinal chemistry
due to their biological properties including antitumor
[1], antifungal [2], antibacterial [3], antimalarial [4],
antifilarial [5], antiviral, and anti-HIV activities [6].
Thiosemicarbazones, especially those derived from het-
eroaromatic aldehydes or ketones have been exten-
sively studied. It is found that their structural pi-deloc-
alization of charge and configurational flexibility of
their molecular chain can give rise to a variety of reac-
tion manners.
Initially, thiosemicarbazones 2a were synthesized by
treating heterocyclic thioaldehydes 1a with potassium hy-
droxide and an equimolar quantity of thiosemicarbazide
in the cosolvent of anhydrous ethanol and dimethylsulf-
oxide (DMSO) [8]. The desired thiosemicarbazones 2b–
2e also can be readily formed under the acid or neutral
condition. The results are summarized in Table 1.
The structures of 2a–2e were unambiguously charac-
terized by spectroscopy (1H-NMR, IR, and MS), ele-
mental analysis, and further confirmed by X-ray diffrac-
tional analysis [9] of 2a. The Oak Ridge Thermal Ellip-
soid Plot (ORTEP) drawing and cell packing diagram
are given in Figure 1.
As part of our studies on thiocarbonyl chemistry [7],
the reactivity of heteroaromatic aldehyde- and ketone-
derived thiosemicarbazones were further investigated.
Chemical compounds with biological activity are often
derived from heterocyclic structures. Heterocycles are
an important class of scaffolds that are found in natural
products such as vitamins, hormones, antibiotics, as well
as pharmaceuticals, herbicides, and dyes. Herein, we
report an efficient and convenient method to synthesize
a new class of thiosemicarbazones that contain thiazole
heterocyclic ring. These novel compounds were
expected to exhibit biological activity in the near future.
The structures of products have also been fully charac-
Subsequently, we treat heteroaromatic thiosemicarba-
zones 2a with x-bromoacetophenone in anhydrous etha-
nol. To our surprise, a novel compound (3a) with thia-
zole scaffold was formed. The reaction proceeds
smoothly at room temperature and good yield (62%)
was obtained. Single-crystal X-ray diffraction analysis
[10] of 3a was measured, and the ORTEP drawing and
cell packing diagram are given in Figure 2.
Then, we examine whether the same reaction system
can be applied to other heteroaromatic thiosemicarba-
zones (entries 2–5). It is found that both heteroaromatic
aldehyde-derived and heteroaromatic ketone-derived thi-
osemicarbazones can be smoothly converted to the
desired products with good to excellent yields (61–
90%). The results were summarized in Table 2. It is
1
terized by infrared spectroscopy (IR), H nuclear mag-
netic resonance (1H-NMR), mass spectrometry (MS),
elemental analysis, and single-crystal X-ray diffraction
analysis.
C
V
2010 HeteroCorporation

362
W. Liu, C. Tao, L. Tang, J. Li, Y. Jin, Y. Zhao, and H. Hu
Vol 48
Table 1
Results of reactions of thiosemicarbazide with aldehydes, thioaldehydes, and ketones.
Entry
Ar
R
X
Solvent
Time (h)
Product
Yield (%)
1
2
3
4
5
2-Phenylindolizin-3-yl
Furan-2-yl
H
H
H
H
S
O
O
O
O
EtOH/DMSO
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH
6
2
5
3
4
2a
2b
2c
2d
2e
78
70
73
88
70
Thiophen-2-yl
Indol-3-yl
Phenyl
EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded on a
noteworthy that the present reaction was accomplished
under mild conditions and the method is operationally
simple with satisfactory yields. The structures of 3a,
4b–4e have been characterized by spectroscopic (1H-
NMR, IR, and MS) and elemental analysis.
Nicolet FTIR 5DX spectrometer in KBr with absorption in cmꢀ1
.
1H-NMR spectra were recorded on a Bruker ACF-300 spectrome-
ter, J values are in hertz. Chemical shifts are expressed in d down-
field from internal tetramethylsilane. Mass spectra were obtained
on a ZAB-HS mass spectrometer at 70 eV. Elemental analytical
were performed on a Foss Heraeus CHN-O-Rapid analyzer.
Preparation of 3-formyl-2-phenylindolizine thiosemicar-
bazone (2a). A solution of 2-phenyl-3-thioformylindolizine (1a;
0.24 g, 1 mmol) and thiosemicarbazide (0.09 g, 1 mmol) in anhy-
drous ethanol (50 mL) was stirred, after adding potassium hy-
droxide (0.06 g, 1.1 mmol), DMSO (5 mL) was added dropwise.
The mixture was refluxed at 80ꢁC for 6 h [monitored by thin
layer chromatography (TLC)], the resulting mixture was cooled
and poured into ice water, filtered, purified by alumina chroma-
tography eluted with the mixture of petroleum ether and ethyl ac-
etate in gradient to afford 2a.
A plausible mechanism was proposed in Scheme 1.
The bromine of x-bromoacetophenone was substituted
to form imide salt 5. The protolysis reaction of 5 gave 6
followed by cyclization leading to 4-hydroxyl-4,5-dihy-
drothiazole salt 7. The salt releases H2O to afford thia-
zole salt 3a and 4 followed by losing HBr to form
thiazole ring. Since indolizinyl moiety has the strong
conjugation ability, 3-formyl-2-phenylindolizine thiose-
micarbazone (2a) can react with x-bromoacetophenone
to afford thiazole salt 3a. When referred to other thiose-
micarbazone (2b–2e), the final step is to release HBr to
give products (4b–4e) with thiazole rings.
To conclude, in the present study, we report a conven-
ient and efficient method to synthesize a series of novel
thiosemicarbazone derivatives that contain thiazole heter-
ocyclic ring. Given the fact that many thiosemicarbazone
derivatives have exhibited biological activity, we antici-
pate that these new compounds described in the present
report would be valuable for pharmaceutical research.
General procedure for preparation of thiosemicarbazone
(2b–2d). ‘A solution of 2-formylfuran (1b; 0.29 g, 3 mmol) and
thiosemicarbazide (0.27 g, 3 mmol) in 50% ethanol (20 mL) was
stirred, 0.8-mL glacial acetic acid was added. The mixture was
refluxed at 80ꢁC for 2 h (monitored by TLC), the resulting mix-
ture was cooled and poured into ice water, filtered, purified by
recrystallization from anhydrous ethanol to afford 2b. Under
Figure 1. Molecular structure of 2a.
Figure 2. Molecular structure of 3a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
A Convenient and Efficient Synthesis of Heteroaromatic Hydrazone Derivatives via
Cyclization of Thiosemicarbazone with x-Bromoacetophenone
363
Table 2
Reactions of heteroaromatic thiosemicarbazones 2 with x-bromoacetophenone.
Entry
Ar
R
Time (min)
Product
Yield (%)
1
2
3
4
5
2-Phenylindolizin-3-yl
Furan-2-yl
H
H
H
H
12
30
20
30
30
3a
4b
4c
4d
4e
62
87
66
90
61
Thiophen-2-yl
Indol-3-yl
Phenyl
these conditions, reaction of 1b–1d was similarly conducted to
give the corresponding thiosemicarbazone 2b–2d.
¼ 7.7 Hz, 1H, indol-3-yl C5AH), 8.31(s, 1H, ¼¼CHA), 11.18
(s, 1H, ANHA), 11.61 (s, 1H, indol-3-yl nitrogen proton).
Anal. Calcd for C10H10N4S: C, 55.04; H, 4.59; N, 25.69.
Found: C, 55.10; H, 4.55; N, 25.62. MS (EI): m/z 218 (Mþ,
2.4), 201 (16), 143 (61.2), 142 (100), 115 (28.9), 89 (10.9).
1-Phenyl-2-[1,2,4]triazol-1-ylethanone thiosemicarbazone
(2e). Colorless crystals, yield 70%, m.p. 157–159ꢁC ; IR (KBr):
3373, 3264, 3173, 3073, 2986, 1644, 1619, 1603, 1510, 1492,
1-Phenyl-2-[1,2,4]triazol-1-ylethanone thiosemicarbazone
(2e). A solution of 1-phenyl-2-[1,2,4]triazol-1-ylethanone (0.56
g, 3 mmol) and thiosemicarbazide (0.27 g, 3 mmol) in anhy-
drous ethanol (20 mL) was stirred, 0.2-mL glacial acetic acid
and catalyst levels pyridine was added. The mixture was
refluxed at 80ꢁC for 4 h (monitored by TLC), the resulting
mixture was cooled and poured into ice water, filtered, purified
by recrystallization from anhydrous ethanol to afford 2e.
General procedure for the cyclization of 2 and x-bro-
moacetophenone to prepare 3a or 4b–4e. A solution of 2-
phenyl-3-thioformylindolizine thiosemicarbazone (2a; 0.12 g,
0.40 mmol), x-bromoacetophenone (0.085 g, 0.40 mmol) in
anhydrous ethanol (10 mL) was stirred at room temperature,
until all the thiosemicarbazone had disappeared (monitored by
TLC). The deposit was filtered, purified by recrystallization
from 95% ethanol to afford 3a. Under these conditions, reac-
tion of 2b–2e was similarly conducted to give the correspond-
ing cyclization compound 4b–4e.
1
1448, 1270, 844, 745, 676 cmꢀ1; H-NMR (300 MHz, DMSO-
d6): d 5.73 (s, 2H, ACH2A), 7.37–7.95 (m, 5H, PhH), 8.11 (s,
1H, ANH2), 8.52 (s, 1H, 1H-1, 2, 4-triazol-1-yl proton), 8.65 (s,
1H, ANH2), 8.68 (s, 1H, 1H-1, 2, 4-triazol-1-yl proton), 10.96
(s, 1H, ANHA). Anal. Calcd for C11H12N6S: C, 50.77; H, 4.62;
N, 32.31. Found: C, 50.85; H, 4.67; N, 32.30. ; MS (EI): m/z
243 (1.4), 178 (15.9), 103 (100), 77 (44.2), 69 (10.5).
N-(4-phenyl-thiazol-2-yl)-3-formyl-2-phenylindolizine hydra-
zone hydrobromic acid (3a). Green crystals, yield 62%, m.p.
122–124ꢁC; IR (KBr): 3333, 2853, 1625, 1590, 1533, 1496,
1
1456, 764, 697 cmꢀ1; H-NMR (300 MHz, CDCl3): d 6.72 (s,
1H, indolizin-3-yl C1AH), 6.90–7.01 (m, 1H, indolizin-3-yl
C6AH), 7.10–7.21 (m, 1H, indolizin-3-yl C7AH), 7.37–7.88 (m,
12H, indolizin-3-yl C8AH, phenyl and thiazole ring proton);
8.41 (s, 1H, ¼¼CAH), 9.31 (d, J ¼ 8.2 Hz, 1H, indolizin-3-yl
C5AH), 12.61 (s, 1H, ANHA), 13.87 (s, 1H, ANþHA). Anal.
Calcd for C24H21BrN4OS: C, 58.42; H, 4.26; N, 11.36. Found:
3-Formyl-2-phenylindolizine thiosemicarbazone (2a). Yellow
crystals, Yield 78%, m.p. 155ꢁC; IR (KBr): 3510, 3384, 3232,
3139, 3027.8, 1600, 1583, 1537, 1500, 1454, 1096, 834 cmꢀ1
;
1H-NMR (300 MHz, CDCl3): d 6.41 (br, s, 1H, ANH2), 6.67
(s, 1H, indolizin-3-yl C1AH), 6.86–6.90 (m, 2H, indolizin-3-yl
C6AH, ANH2), 7.04–7.10 (m, 1H, indolizin-3-yl C7AH),
7.44–7.58 (m, 6H, Ph, indolizin-3-yl C8AH), 8.10 (s, 1H,
¼¼CHA), 9.14 (s, 1H, ANHA), 9.21 (d, J ¼ 7.0 Hz, 1H, indo-
lizin-3-yl C5AH). Anal. Calcd for C16H14N4S: C, 65.31; H,
4.76; N, 19.05. Found: C, 65.45; H, 4.95; N, 19.10. MS (EI):
m/z 276 (58.9), 249 (24.7), 218 (51.3), 193 (100), 165 (35.3),
115 (29.6), 83 (30.8), 51 (28.9).
Scheme 1
2-Formylfuran thiosemicarbazone (2b). Yellowish brown
crystals, yield 70%, m.p. 154–156ꢁC (lit. 152–154ꢁC) [8].
2-Formylthiophene thiosemicarbazone (2c). Light brown
crystals, yield 73%, m.p. 184–186ꢁC (lit. 185–186ꢁC) [8].
3-Formyl-1H-indole thiosemicarbazone (2d). Light pink
crystals, yield 88%, m.p. 232–234ꢁC; IR (KBr): 3448, 3311,
3230, 3145, 3039, 1613, 1582, 1550, 1518, 1441, 1200, 751
;
cmꢀ1 1H-NMR (300 MHz, DMSO-d6): d 7.10–7.21 (m, 2H,
indol-3-yl C6-H, indol-3-yl C7AH), 7.42 (br, s, 1H, ANH2),
7.43 (d, J ¼ 7.9 Hz, 1H, indol-3-yl C8AH), 7.82 (d, J ¼ 2.7
Hz, 1H, indol-3-yl C2AH), 8.03 (br, s, 1H, ANH2), 8.23 (d, J
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

364
W. Liu, C. Tao, L. Tang, J. Li, Y. Jin, Y. Zhao, and H. Hu
Vol 48
C, 58.50; H, 4.42; N, 11.26. MS (EI): m/z 394 [(M-HBr-H2O)þ,
2.9], 219 (92), 218 (100), 192 (2.2), 176 (96.6), 134 (56.6).
N-(4-phenyl-thiazol-2-yl)-2-formylfuran hydrazone (4b). Brown-
ish yellow crystals, yield 87%, m.p. 136–138ꢁC; IR (KBr):
REFERENCES AND NOTES
[1] (a) Karki, S. S.; Thota, S.; Darj, S. Y.; Balzarini, J.; Clercq,
E. D. Bioorg Med Chem 2007, 15, 6632; (b) Gojo, I.; Tidwell, M. L.;
Greer, J.; Takebe, N.; Seiter, K.; Pochron, M. F.; Johnson, B.; Sznol,
M.; Karp, J. E. Leukemia Res 2007, 31, 1165.
3117, 3141, 3065, 1619, 1603, 1561, 1486, 760, 691 cmꢀ1
;
1H-NMR (300 MHz, DMSO-d6): d 6.59–6.62 (m, 1H, furan-2-
yl C4AH), 6.81 (d, J ¼ 3.3 Hz, 1H, furan-2-yl C3AH), 7.23–
7.93 (m, 9H, thiazole ring and phenyl proton, furan-2-yl
C5AH, ¼¼CAH, ANHA). Anal. Calcd for C14H11N3OS: C,
62.45; H, 4.09; N,15.61. Found: C, 62.53; H, 4.05; N,15.77.
MS (EI): m/z 269 (Mþ, 16.8), 176 (100), 134 (62.6).
[2] Wiles, D. M.; Suprunchuk, T. J Med Chem 1971, 14, 252.
[3] Gupta, M. K.; Sachan, A. K.; Pandeya, S. N. Asian J Chem
2007, 19, 5.
[4] Klayman, D. L.; Lin, A. J.; Hoch, J. M.; Scovill, J. P.;
Lambros, C.; Dobek, A. S. J Pharm Sci 1984, 73, 1763.
[5] Klayman, D. L.; Lin, A. J.; McCall, J. W.; Wang, S. Y.;
Townson, S.; Grogl, M.; Kinnamon, K. E. J Med Chem 1991, 34,
1422.
N-(4-phenyl-thiazol-2-yl)-2-formylthiophene hydrazone (4c).
Light brown crystals, yield 66%, m.p. 202–203ꢁC; IR (KBr):
3302, 3099, 3055, 1602, 1561, 1521, 1505, 1490, 768, 748,
[6] Kizilcikli, I.; Kurt, Y. D.; Akkurt, B.; Genel, A. Y.; Birtek-
1
740, 722, 706, 683 cmꢀ1; H-NMR (300 MHz, CDCl3): d 6.80
¨
¨
¨
¨
¨
soz, S.; Otuk, G.; Ulkuseven, B. Folia Microbiol 2007, 52, 15.
[7] (a) Liu, W. W.; Zhao, Y. Q.; Pu, Y. Q.; Xu, R. B.; Hu, H.
W. Chin J Org Chem 2005, 25, 838; (b) Liu, W. W.; Zhao, Y. Q.;
Xu, R. B.; Tang, L. J.; Hu, H. W. Chin J Chem 2006, 24, 1472; (c)
Liu, W. W.; Tang, L. J.; Zeng, Y. X.; Wang, L.; Zhao, Y. Q.; Chen,
K. Q.; Lu, Z. E. Chin J Org Chem 2007, 27, 1285; (d) Liu, W. W.;
Tu, S. J.; He, T.; Zhao, Y. Q.; Hu, H. W. J Heterocyclic Chem 2008,
45, 1311.
(s, 1H, thiazole ring proton), 7.00–7.90 (m, 8H, thiophen-2-yl
and phenyl proton), 7.97 (s, 1H, ACH¼¼NA), 8.20 (br, s, 1H,
ANHA). Anal. Calcd for C14H11N3S2: C, 58.95; H, 3.86; N,
14.74.Found: C, 59.01; H, 3.96; N, 14.65. MS (EI): m/z 285
(Mþ, 15.8), 176 (100), 134 (83.5), 110 (4.4), 77 (2.5).
N-(4-phenyl-thiazol-2-yl)-2-formyl-1H-indole hydrazone (4d).
Light purple crystals, yield 90%, m.p. 185–187ꢁC; IR (KBr):
3292, 3103, 2943, 1625, 1608, 1574, 1531, 1491, 749, 735
675 cmꢀ1 1H-NMR (300 MHz, DMSO-d6): d 7.15–7.52 (m,
;
8H, thiazole ring and phenyl proton, indol-3-yl C6AH, indol-3-
yl C7AH), 7.78 (s, 1H, ANHA), 7.85–7.95 (m, 2H, indol-3-yl
C8AH, indol-3-yl C2AH), 8.23–8.35 (m, 2H, indol-3-yl C5AH,
¼¼CHA), 11.61 (s, 1H, indol-3-yl nitrogen proton). Anal. Calcd
for C18H14N4S: C, 67.92; H, 4.40; N, 17.61. Found: C, 67.93;
H, 4.32; N, 17.66. MS (EI): m/z 318 (Mþ, 0.5), 176 (100), 142
(59.6), 134 (38.4), 115 (7.4), 89 (5.2).
[8] (a) Anderson, F. E.; Duca, C. J.; Scudi, J. V. J Am
Chem Soc 1951, 73, 4967; (b) Bernstein, J.; Yale, H. L.; Losee,
K.; Holsing, M.; Martins, J.; Lott, W. A. J Am Chem Soc 1951,
73, 906.
[9] Crystal data for 2a: 2(C16H14N4S)ꢂC2H6CO; M ¼ 646, Yel-
low single crystals, 0.20 ꢃ 0.20 ꢃ 0.30 mm3, triclinic, space group
˚
P1, a ¼ 11.572 (8), b ¼ 11.845 (8), c ¼ 13.173 (8) A, a ¼ 92.56 (3),
3
ꢁ
˚
b ¼ 110.61 (4), c ¼ 102.57 (4) , V ¼ 1635 (2) A , Z ¼ 2, Dc
¼
1.318 mg mꢀ3. F (000) ¼ 682, l (MoKa) ¼ 0.206 mmꢀ1. Intensity
data were collected on Bruker SMART APEX II with graphite mono-
˚
N-(4-phenyl-thiazol-2-yl)-x-(1, 2, 4-triazol-1-yl)acetophe-
none hydrazone (4e) Light yellow crystals, yield 61%, m.p.
212–214ꢁC; IR (KBr): 3165, 3096, 3081, 2656, 1598, 1583,
chromated MoKa radiation (k ¼ 0.71073 A) using x scan mode with
1.9ꢁ < y < 25.0ꢁ. 5671 unique reflections were measured and 4302
reflections with I > 2r(I) were used in the refinement. Structure
solved by direct methods and expanded using Fourier techniques. The
final cycle of full-matrix least squares technique to R ¼ 0.0533 and
wR ¼ 0.1168.
1
1503, 1444, 749, 688 cmꢀ1; H-NMR (300 MHz, DMSO-d6):
d 5.74 (s, 2H, ACH2A); 7.33–7.89 (m, 11H, thiazole ring and
phenyl proton), 7.97 (s, 1H, 1H-1, 2, 4-triazol-1-yl proton),
8.74 (s, 1H, 1H-1, 2, 4-triazol-1-yl proton). Anal. Calcd for
C19H16N6S: C, 58.95; H, 3.86; N, 14.74. Found: C, 59.01; H,
3.96; N, 14.65. MS (EI): m/z 291 (22.7), 262 (18.8), 176 (9.4),
134 (59.9), 103 (100), 77 (66.5), 69 (13.9).
[10] Crystal data for 3a: C24H21BrN4OS; M ¼ 493, Blackish
green single crystals, 0.42 ꢃ 0.36 ꢃ 0.20 mm3, monoclinic, space
˚
group P21/n, a ¼ 6.1679 (12), b ¼ 11.1657 (18), c ¼ 32.640 (4) A, a
3
ꢁ
˚
¼ 90, b ¼ 91.708 (2), c ¼ 90 , V ¼ 2246.9 (6) A , Z ¼ 4, Dx
¼
1.459 mg mꢀ3. F (000) ¼ 1008, l (MoKa) ¼ 1.946 mmꢀ1. Intensity
Acknowledgments. The authors are grateful to the National
Natural Science Foundation of China (No. 20672090), the Six
Kinds of Professional Elite Foundation of Jiangsu Province
(No. 07-A-024), the Science and Technology Critical Project
Foundation of Lianyungang Municipality (CG0803-2), and the
Natural Science Foundation of Jiangsu Education Department
(08KJB150002).
data were collected on Bruker SMART APEX II with graphite mono-
˚
chromated MoKa radiation (k ¼ 0.71073 A) using x scan mode with.
1.93ꢁ < y < 25.01ꢁ. 3904 unique reflections were measured and 2795
reflections with I > 2r(I) were used in the refinement. Structure
solved by direct methods and expanded using Fourier techniques. The
final cycle of full-matrix least squares technique to R ¼ 0.0661 and
wR ¼ 0.1554.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet