Synthetic access to some new benzothiazole-based 1,3,4-thiadiazole and 1,3-thiazole derivatives

Article abstract of DOI:10.3906/kim-1503-75

1-(Benzothiazol-2-yl)-3-phenylthiourea 2 was prepared and treated with hydrazonoyl chlorides 3a-e to yield the corresponding 5-(benzothiazol-2-ylimino)-1,3,4-thiadiazole derivatives 6a-e, respectively. Reaction of the thiourea derivative 2 with ethyl 2-ch

Full text of DOI:10.3906/kim-1503-75

Turk J Chem
Turkish Journal of Chemistry
(2016) 40: 277 – 282
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http://journals.tubitak.gov.tr/chem/
˙
c
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doi:10.3906/kim-1503-75
Research Article
Synthetic access to some new benzothiazole-based 1,3,4-thiadiazole and
1,3-thiazole derivatives
Kamal M. DAWOOD1,∗, Eman A. RAGAB1, Korany A. ALI2
1Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
2Department of Applied Organic Chemistry,Center of Excellence for Advanced Science, National Research Centre,
Dokki, Giza, Egypt
Received: 22.03.2015
•
Accepted/Published Online: 08.08.2015
•
Final Version: 02.03.2016
Abstract: 1-(Benzothiazol-2-yl)-3-phenylthiourea 2 was prepared and treated with hydrazonoyl chlorides 3a–e to
yield the corresponding 5-(benzothiazol-2-ylimino)-1,3,4-thiadiazole derivatives 6a–e, respectively. Reaction of the
thiourea derivative 2 with ethyl 2-chloro-3-oxobutanoate 9 afforded the corresponding 2-(benzothiazol-2-ylimino)thiazole-
5-carboxylate derivative 11. The newly synthesized heterocyclic derivatives were confirmed from their elemental and
spectral analyses.
Key words: Benzothiazole, thiazole, thiadiazole, thiourea, hydrazonoyl chlorides
1. Introduction
1,3,4-Thiadiazoles are among the most common heterocyclic pharmacophores. They display a broad spectrum
of biological activities including antimicrobial,1 anticancer,2,3 antioxidant,4 antidepressant,5 anticonvulsant,6,7
and antihypertensive activity,8 as well as acetylcholinesterase inhibitors for the treatment of Alzheimer disease.9,10
In addition, thiourea derivatives are key synthons for the synthesis of biologically active heterocycles with a
broad spectrum of medicinal applications.11 In particular, the most significant thiourea derivatives demon-
strated antiviral,12 anti-HIV,13 antifungal,14 and anticancer activities.15 Benzothiazolyl thiourea derivatives
have also attracted continuing interest due to their valuable biological activities such as antiinflammatory,16
antibacterial,17 and cytotoxic activities.18,19 As part of our research projects aimed at the synthesis of po-
tent biologically active 1,3,4-thiadiazole-based heterocycles,20−32 the aim of this work was the synthesis of
some new benzothiazole-based 1,3,4-thiadiazole and 1,3-thiazole derivatives utilizing 1-(benzothiazol-2-yl)-3-
phenylthiourea 2 as a key starting synthon.
2. Results and discussion
1-(Benzothiazol-2-yl)-3-phenylthiourea 2 was prepared from the reaction of 2-aminobenzothiazole 1 with phenyl
isothiocyanate in dimethylformamide in the presence of potassium hydroxide at room temperature according to
literature procedures.33,34 First, the reaction of 1-(benzothiazol-2-yl)-3-phenylthiourea 2 with the hydrazonoyl
chloride esters 3a–c was performed. The reaction of 2 with 3a was carried out in refluxing ethanol in the
presence of Et3 N to afford only one isolable product. There are two possible structures, 6a and 8a, for the
∗Correspondence: dr dawood@yahoo.com
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DAWOOD et al./Turk J Chem
reaction product either via loss of aniline from intermediate 5a or via loss of ethanol from the intermediate 7a,
respectively (Scheme 1). The spectral data of the isolated product were completely compatible with structure
6a and not 8a. For example, the IR spectrum of 6a showed a carbonyl absorption band at 1741 cm−1 . Its
1 H NMR showed characteristic quartet and triplet signals at δ 1.37 and 4.45 (J = 7.2 Hz) due to ethyl-ester
protons in addition to the aromatic protons in the region δ 7.31–7.94. The mass spectrum of 6a showed the
molecular ion at m/z 382. In a similar way, treatment of 2 with the hydrazonoyl chloride esters 3b,c conducted
in refluxing ethanol in the presence of Et3 N afforded the corresponding ethyl 1,3,4-thiadiazole-2-carboxylate
derivatives 6b,c in high yield as shown in Scheme 1.
Next, reaction of the thiourea derivative 2 with the acetyl hydrazonoyl chloride 3d,e in refluxing ethanol
in the presence of triethylamine resulted, similarly, in the formation of only one isolable product as examined
by TLC. Structures of the obtained products were established as 5-acetyl-2-(benzothiazol-2-ylimino)-4-aryl-4,5-
dihydro-1,3,4-thiadiazoles 6d,e on the basis of their elemental analyses and spectral data. As outlined in Scheme
1, the loss of aniline molecule from the intermediates 5d,e led to the formation of compounds 6d,e. Their IR
spectra showed, in each case, an absorption band around 1680 cm−1 due to C=O function. The 1 H NMR
spectrum of 6e exhibited two singlet signals at δ 2.22 and 2.52 due to methyl and acetyl protons in addition
to the aromatic signals. The mass spectra of 6d,e showed, in each case, a peak due to their molecular ions.
Finally, treatment of compound 2 with ethyl 2-chloro-3-oxobutanoate (9) in refluxing ethanol in the
presence of triethylamine yielded a single product for which the structure 5-acetyl-2-(5-acetyl-4-methylthiazol-
2-ylimino)-4-methyl-3-phenyl-1,3-thiazole (11) was assigned based on its elemental and spectral data. Formation
of 11 proceeded via loss of HCl followed by water during an intramolecular cyclization of the intermediate 10.
The presence of only one carbonyl absorption band at 1686 cm−1 in the IR spectrum and the presence of three
signals at δ 1.33, 2.24, and 4.33 assignable to the CH3 and CO2 CH2 CH3 protons in the 1 H NMR spectrum
of the reaction product supported structure 11 and ruled out the other possible product 13 (Scheme 2). In
addition, the mass spectrum of 11 showed a peak at m/z 395 due to its molecular ion.
3. Experimental
Melting points were determined on a Gallenkamp apparatus and are uncorrected. The IR spectra were recorded
on Shimadzu FT-IR 8101 PC infrared spectrophotometer. The 1 H NMR spectra were determined in DMSO-d6
at 300 MHz (1 H NMR) and at 75.46 MHz (13 C NMR) on a Varian Mercury VX 300 NMR spectrometer using
TMS as an internal standard. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 ev.
Elemental analyses were carried out at the Microanalytical Center of Cairo University. Benzothiazolylthiourea
233 and hydrazonoyl chlorides 3a–c,35 and 3d,e36,37 were prepared according to procedures reported in the
literature.
4. Synthesis of 5-(benzothiazol-2-ylimino)-4-aryl-1,3,4-thiadiazole derivatives 6a–e
General Procedure. To a stirred solution of 1-(benzolthiazol-2-yl)-3-phenylthiourea 2 (0.57 g, 2 mmol) in ethanol
(30 ml) was added the appropriate hydrazonoyl chloride 3a–c or 3d,e (2 mmol) followed by addition of Et3 N
(0.2 mL). The reaction mixture was heated at reflux for 4∼7 h, during which the starting substrates were
dissolved and completely consumed and a colored product was precipitated. The solid product that formed
was filtered off, washed with water and ethanol, dried, and finally recrystallized from the appropriate solvent
to afford the corresponding 1,3,4-thiadiazole derivatives 6a–e, respectively.
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DAWOOD et al./Turk J Chem
S
N
S
NH
NHPh
O
2
N
Ar
Ar
3a-e
R
N
H
NH
Cl
R
S
O
N
O
S
N
N
N
R
NH
S
S
N
NH
Ph
NH
N
Ar
4
Ph
Ar
COR
N
NH
N
S
S
R
N
N
S
NH
N
S
N
N
NH
OH
Ph
Ar
Ph
7a-e
5a-e
-PhNH2
S
(R = Me)
-H2O
(R = OEt)
-EtOH
N
Ar
COR
N
S
N
N
NHAr
O
N
N
S
S
N
N
N
Me
6a-e
S
S
Ar
N
N
N
N
Ph
Ph
R
Ar
6-8
a
8d,e
8a-c
OEt
OEt
OEt
Me
C6H5
4-ClC6H4
b
4-MeC6H4
C6H5
c
d
Me
4-MeC6H4
e
Scheme 1. Synthesis of (benzothiazolyl)imino-1,3,4-thiadiazole derivatives 6a–e.
5. Ethyl 5-(benzothiazol-2-ylimino)-4,5-dihydro-4-phenyl-1,3,4-thiadiazole-2-carboxylate (6a)
Yield (0.49 g, 64%), orange solid, mp 210–212 ◦ C (EtOH/DMF); IR (KBr) ν (cm−1): 1741 (C=O), 1592
(C=N), 1530 (C=C); 1 H NMR (DMSO-d6 , 300 MHz) δ 1.37 (t, 3H, CH2 CH 3 , J = 7.2 Hz), 4.45 (q, 2H,
CH 2 CH3 , J = 7.2 Hz), 7.31 (t, 1H, ArH, J = 7.8 Hz), 7.45 (t, 1H, ArH, J = 7.8 Hz), 7.52–7.66 (m, 3H,
ArH), 7.80–7.94 (m, 4H, ArH); MS m/z (%): 382 (M+ , 92.6), 251 (21.0), 225 (20.4), 198 (18.8), 108 (21.6), 91
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DAWOOD et al./Turk J Chem
S
S
N
H
Ph
N
H
N
2
COCH3
CO2Et
EtOH, Et3N
reflux
Cl
9
COCH3
O
CO2Et
O
S
S
S
S
OEt
NH
Me
N
N
N
NH
Ph
N
10
12
Ph
- EtOH
-H2O
COCH3
CO2Et
Me
S
S
S
S
N
N
O
N
N
N
N
13
Ph
11
Ph
Scheme 2. Synthesis of (benzothiazolyl)imino-1,3-thiazolidine derivative 11.
(100), 77 (76.7). Anal. Calcd. for C18 H14 N4 O2 S2 (382.46): C, 56.53; H, 3.69; N, 14.65; S, 16.77. Found: C,
56.27; H, 3.57; N, 14.80; S, 16.72.
6. Ethyl 5-(benzothiazol-2-ylimino)-4,5-dihydro-4-(4-chlorophenyl)-1,3,4-thiadiazole-2-carboxylate
(6b)
Yield (0.63 g, 75%), yellow powder, mp 219–221 ◦ C (EtOH/DMF); IR (KBr) ν (cm−1): 1742 (C=O), 1590
(C=N), 1532 (C=C); 1 H NMR (DMSO-d6 , 300 MHz) δ 1.37 (t, 3H, CH2 CH 3 , J = 7.2 Hz), 4.44 (q, 2H,
CH 2 CH3 , J = 7.2 Hz), 7.32 (t, 1H, ArH, J = 7.8 Hz), 7.46 (t, 1H, ArH, J = 7.8 Hz), 7.70 (d, 2H, ArH, J
= 8.7 Hz), 7.87–7.95 (m, 4H, ArH); MS m/z(%): 418 (M+ +2, 41.6), 417 (M+ +1, 22.9) 416 (M+ , 96.0) 285
(21.6), 258 (10.2), 192 (8.9), 127 (33.1), 125 (100), 111 (17.2), 90 (24.8), 74 (14.9), 68 (10.2). Anal. Calcd for
C18 H13 ClN4 O2 S2 (416.90): C, 51.86; H, 3.14; N, 13.44; S, 15.38. Found: C, 52.08; H, 3.11; N, 13.16; S, 15.42.
7. Ethyl 5-(benzothiazol-2-ylimino)-4,5-dihydro-4-(4-tolyl)-1,3,4-thiadiazole-2-carboxylate (6c)
Yield (0.61 g, 77%), yellowish-orange solid, mp 202–204 ◦ C (EtOH/DMF); IR (KBr) ν (cm−1): 1742 (C=O),
1611, 1590 (C=N), 1519 (C=C); 1 H NMR (DMSO-d6 , 300 MHz) δ 1.34 (t, 3H, CH2 CH 3 , J = 7.2 Hz), 2.42
280

DAWOOD et al./Turk J Chem
(s, 3H, CH3), 4.45 (q, 2H, CH 2 CH3 , J = 7.2 Hz), 7.24–7.47 (m, 4H, ArH), 7.67 (d, 2H, ArH, J = 8.1 Hz),
7.86–7.93 (m, 2H, ArH); MS m/z(%): 396 (M+ , 100), 297 (4.9), 265 (22.1), 239 (14.6), 184 (4.8), 148 (7.2),
105 (97.5), 91 (26.9), 78 (21.6), 65 (18.4). Anal. Calcd for C19 H16 N4 O2 S2 (396.49): C, 57.56; H, 4.07; N,
14.13; S, 16.17. Found: C, 57.77; H, 4.16; N, 14.01; S, 16.13.
8. 2-Acetyl-5-(benzothiazol-2-ylimino)-4,5-dihydro-4-phenyl-1,3,4-thiadiazole (6d)
Yield (0.51 g, 72%), yellow solid, mp 222–224 ◦ C (EtOH/DMF); IR (KBr) ν (cm−1): 1686 (C=O), 1595
(C=N), 1534 (C=C); 1 H NMR (DMSO-d6 , 300 MHz) δ 2.64 (s, 3H, COCH 3), 7.32 (t, 1H, ArH, J = 7.8 Hz),
7.46 (t, 1H, ArH, J = 8.1 Hz), 7.53–7.68 (m, 3H, ArH), 7.86–7.95 (m, 4H, ArH); MS m/z (%): 352 (M+ ,
100), 251 (15.1), 225 (10.7), 193 (19.1), 118 (58.1), 117 (14.3), 108 (12.6), 91 (73.2), 77 (47.9). Anal. Calcd for
C17 H12 N4 OS2 (352.43): C, 57.93; H, 3.43; N, 15.90; S, 18.20. Found: C, 57.77; H, 3.32; N, 15.66; S, 18.28.
9. 2-Acetyl-5-(benzothiazol-2-ylimino)-4,5-dihydro-4-(4-tolyl)-1,3,4-thiadiazole (6e)
Yield (0.51 g, 70%), yellow solid, mp 233–235 ◦ C (EtOH/DMF); IR (KBr) ν (cm−1): 1679 (C=O), 1586
(C=N), 1541 (C=C); 1 H NMR (DMSO-d6 , 300 MHz) δ 2.22 (s, 3H, p-CH3), 2.52 (s, 3H, COCH 3), 7.23 (t,
1H, ArH, J = 7.2 Hz), 7.39 (t, 1H, ArH, J = 7.5 Hz), 7.57 (d, 2H, ArH, J = 8.8 Hz), 7.65 (d, 2H, ArH, J =
8.5 Hz), 7.78–7.84 (m, 2H, ArH); MS m/z (%): 366 (M+ , 7.1), 287 (13.7), 194 (26.1), 132 (27.5), 104 (11.8),
85 (100). Anal. Calcd for C18 H14 N4 OS2 (366.46): C, 58.99; H, 3.85; N, 15.29; S, 17.50. Found: C, 58.78; H,
3.77; N, 15.12; S, 17.54.
10. Ethyl 2-(benzothiazol-2-ylimino)-4-methyl-3-phenyl-2,3-dihydrothiazole-5-carboxylate (11)
To a stirred solution of 1-(benzolthiazol-2-yl)-3-phenylthiourea 2 (0.57 g, 2 mmol) in ethanol (30 mL), ethyl
2-chloro-3-oxobutanoate (9) (2 mmol) was added followed by adding Et3 N (0.2 mL) and the mixture was then
heated at reflux for 4 h. The solvent was removed under reduced pressure and the residue was treated with
crushed ice; then the precipitate was filtered off, washed with water and ethanol, dried, and finally recrystallized
from DMF to give the corresponding 1,3-thiazole-5-carboxylate derivative 11. Yield (0.55 g, 69%), yellowish-
green solid, mp 206–208 ◦ C (DMF); IR (KBr), νg(cm−1): 1686 (C=O), 1594 (C=N), 1506 (C=C); 1 H NMR
(DMSO-d6 , 300 MHz) δ 1.33 (t, 3H, CH2 CH 3 , J = 7.2 Hz), 2.24 (s, 3H, CH3), 4.33 (q, 2H, CH 2 CH3 , J =
7.2 Hz), 7.23 (t, 1H, ArH, J = 7.8 Hz), 7.39 (t, 1H, ArH, J = 7.8 Hz), 7.51–7.64 (m, 5H, ArH), 7.78–7.84 (m,
2H, ArH). 13 C NMR (DMSO-d6 , 75.46 MHz) δ 13.9, 14.4, 32.4, 61.0, 64.8, 118.1, 120.6, 121.2, 121.8, 122.8,
124.6, 128.5, 129.4, 138.0, 146.9, 155.9, 168.6, 172.6. MS m/z(%): 395 (M+ , 51.5), 323 (12.5), 253 (20.7), 225
(10.8), 135 (12.9), 118 (66.7), 77 (100). Anal. Calcd for C20 H17 N3 O2 S2 (395.49): C, 60.74; H, 4.33; N, 10.62;
S, 16.22. Found: C, 60.65; H, 4.29; N, 10.39; S, 16.27%.
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