Synthesis of new N-[3-(Benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene] substituted benzamides

Article abstract of DOI:10.3906/kim-1212-26

A series of novel N -[3-(2-benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)- ylidene] substituted benzamides (2a-k) were efficiently synthesized by heterocyclization of the corresponding 1-(benzo[d]thiazol-2-yl)-3-aroylthioureas (1a{k). The cyclization was achieved by the reaction of α-bromoacteone produced in situ using bromine in dry acetone in the presence of triethylamine. TUeBITAK.

Full text of DOI:10.3906/kim-1212-26

Turk J Chem
Turkish Journal of Chemistry
(2013) 37: 909 – 916
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1212-26
Research Article
Synthesis of new N -[3-(Benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]
substituted benzamides
Aamer SAEED,∗ Hummera RAFIQUE
Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan
Received: 09.12.2012
•
Accepted: 15.05.2013
•
Published Online: 04.11.2013
•
Printed: 29.11.2013
Abstract:A series of novel N -[3-(2-benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene] substituted benzamides (2a–k)
were efficiently synthesized by heterocyclization of the corresponding 1-(benzo[d]thiazol-2-yl)-3-aroylthioureas (1a–k).
The cyclization was achieved by the reaction of α-bromoacteone produced in situ using bromine in dry acetone in the
presence of triethylamine.
Key words: N -[3-(2-Benzothiazolyl)-4-methylthiazol-2(3H)-ylidene] substituted benzamides, 1-(benzo[d] thiazol-2-yl)-
3-aroylthioureas, 2-aminobenzothiazoles
1. Introduction
The 2-iminothiazoline scaffold is found in many bioactive heterocycles, which have a wide variety of phar-
maceutical applications such as analgesic, antipyretic, antirheumatic,1 anti-Schistosomiasis,2 and anti-HIV
activities.3−5 Bis-thiazoline derivatives are potent antitumor,6,7 antihistaminic,8 antihypertensive,9 hypnotic,10
and antimycobacterial and potent antibacterial agents.11,12 Coumarin derivatives of thiazolines display sig-
nificant anticonvulsant activities against PTZ-induced seizures.13,14 Thiazoline analogues also inhibit the
enzyme indoleamine-N -methyltransferase and are useful for the treatment of schizophrenia.15 Pifithrin-α
(PFT-α), a reversible inhibitor of p53-mediated apoptosis and p53-dependent gene transcription, is an-
other well-known iminothiazoline derivative.16 N ’-[3,4-disubstituted-1,3-thiazol-2(3H)-ylidene]-2-(pyrazin-2-
yloxy)acetohydrazide derivatives exhibit remarkable activity against the (H37 Rv) strain of Mycobacterium
tuberculosis.17
Similarly, 2-aminobenzothiazole is a privileged structure and different derivatives have been used for the
treatment of diabetes,18 epilepsy,19 inflammation,20 amyotrophic lateral sclerosis,21 analgesia,22 tuberculosis,23
and viral infections,24 and as central muscle relaxants.25 6-(Trifluoromethoxy)-2-benzothiazolamine (Riluzole)
possesses potent anticonvulsant and neuroprotective effects (Figure).26,27
In view of the above observations, in this study, we report an efficient synthesis of some new N -(4-
methyl-3-tolylthiazol-2(3H)-ylidene) substituted benzamides containing these 2 important heterocycles in a
single molecule. We envisioned 2 points of structural diversity in our target molecule (R and R’ on aromatic
rings) for systematic evaluation of biological activities and establishment of the structure–activity relationship
(SAR) in depth.
∗Correspondence: aamersaeed@yahoo.com
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SAEED and RAFIQUE/Turk J Chem
O
MeO
NH
O
N
HOOC
S
N
N
H
S
NH
NH2
N
F
Me
N
O
Me
PS028
Me
KHG22394
OCF3
S
N
S
N
OAc
NH
H2N
O
AcO
AcO
H
N
H
N
Riluzole
OAc
O
CH3
N
S
S
PFT-a
R
Glucopyranosyl benzothiazolyl thioureas
Figure. Structures of some pharmacologically important iminothiazolines and aminothiazoles reported in the literature.
2. Experimental
Melting points were recorded using a digital Gallenkamp (SANYO) model MPD.BM 3.5 apparatus and are
uncorrected. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) spectra were recorded using a Bruker AM-300
spectrophotometer. FTIR spectra were recorded on an FTS 3000 MX spectrophotometer. Mass spectra (EI,
70 eV) were recorded on a GC-MS instrument (Agilent Technologies) and elemental analyses were conducted
using a LECO-183 CHNS analyzer. Thin layer chromatography (TLC) was conducted on 0.25-mm silica gel
plates (60 F254, Merck). Visualization of chromatograms was performed with UV at 365 and 254 nm.
1-(Benzo[d]thiazol-2-yl)-3-aroyl thioureas were prepared according to a method reported earlier.28
2.1. General procedures for the synthesis of N-[3-(benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-
ylidene] substituted benzamides (2a–k)
A solution of 1-(benzo[d]thiazol-2-yl)-3-aroyl thioureas (1a–k) (3 mmol) in 20 mL of dry acetone was stirred
under inert atmosphere. Triethylamine (3 mmol) was added dropwise through the rubber septum using a syringe
(3 mL), and then a solution of bromine (3 mmol) in dry acetone (10 mL) was added slowly. The reaction mixture
was allowed to stir for 3–4 h. After completion (monitored by TLC), the reaction mixture was filtered and the
filtrate was concentrated to get crude N -[3-(benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene] substituted
benzamides (2a–k), which were then recrystallized from ethanol to afford pure products.
N-[3-(Benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene] benzamide (2a)
(Yield: 70%). Rf. 0.4 (ethyl acetate/hexane, 2:8). mp 97–98 ◦ C. IR (KBr) νmax : 2926 (C=C-H), 2832
(-CH3), 1678 (amide C=O), 1582 (C=N), 1558 (C=C), 1461 (C-N), 1168 (C-S) cm−1
.
1 H NMR (300 MHz,
CDCl3)δ (ppm): 8.12 (1H, d, J = 7.6 Hz, H-4’), 8.06 (1H, d, J = 7.6 Hz, H-7’), 7.61–7.94 (5H, m, Ar), 7.57
(1H, dd, J = 7.2, 7.4 Hz, H-5’), 7.34 (1H, dd, J = 7.1, 7.4 Hz, H-6’), 6.44 (1H, s, C=C-H , ring H-5), 2.23
(-CH3). 13 C NMR (75 MHz, CDCl3)δ (ppm): 166.5 (C-2’), 165.3 (amide C=O), 162.4 (C-2), 151.3 (C-4),
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SAEED and RAFIQUE/Turk J Chem
146.3 (C-9’), 136.7 (C-1”), 134.5 (C-2”, C-6”), 133.4 (C-3”, C-5”), 128.2 (C-4”), 127.4 (C-6’), 125.6 (C-5’),
124.3 (C-8’), 123.7 (C-4’), 122.5 (C-7’), 101.6 (C-5), 15.4 (-CH3). Anal. calcd. for C18 H13 N3 OS2 (351.45);
C, 61.53; H, 3.70; N, 11.96; S, 18.23. Found: C, 61.47; H, 3.51; N, 11.83; S, 18.14. MS (70 eV): m/z(%), 351
(M+. 54), 274 (30), 140 (100), 134 (36), 112 (25), 96 (13), 77 (19).
N-[3-(Benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]-2-methoxybenzamide (2b)
(Yield: 74%). Rf. 0.45 (ethyl acetate/hexane, 2:8). mp 76–77 ◦ C. IR (KBr) νmax : 2931 (C=C-H), 2834
(-CH3), 1674 (amide C=O), 1586 (C=N), 1553 (C=C), 1466 (C-N), 1171 (C-S) cm−1
.
1 H NMR (300 MHz,
CDCl3)δ (ppm): 8.14 (1H, d, J = 7.6 Hz, H-4’), 8.08 (1H, d, J = 7.6 Hz, H-7’), 7.91 (1H, d, J = 7.1 Hz,
H-6”), 7.84 (1H, dd, J = 7.4,7.6, Hz, H-5’), 7.76 (1H, dd, J = 7.6, 7.4, Hz, H-6’), 7.61 (1H, dd, J = 7.1, 7.2
Hz, H-5”), 7.47 (1H, dd, J = 7.3, 7.2, Hz, H-4”), 7.38 (1H, d, J = 7.3 Hz, H-3”), 6.45 (1H, s, C=C-H , ring
H-5), 3.76 (3H, s, -OCH3), 2.24 (3H, s, -CH3). 13 C-NMR (75 MHz, CDCl3) δ (ppm): 166.7 (C-2’), 165.5
(amide C=O), 162.7 (C-2), 151.6 (C-4), 146.4 (C-9’), 137.5 (C-1”), 136.4 (C-2”), 135.7 (C-6”), 134.6 (C-3”),
133.2 (C-5”), 128.6 (C-4”), 127.4 (C-6’), 126.3 (C-5’), 125.7 (C-8’), 124.6 (C-4’), 123.4 (C-7’), 101.5 (C-5), 54.3
(-OCH3), 15.8 (-CH3). MS (70 eV): m/z(%), 381 (M+. 67), 274 (36), 140 (100), 134 (29), 112 (20), 107 (41),
96 (21), 77 (14). Anal. calcd. for C19 H15 N3 O2 S2 (381.46); C, 59.84; H, 3.94; N, 11.02; S, 16.78. Found: C,
59.77; H, 3.82; N, 10.93; S, 16.67.
N-[3-(Benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]-4-methylbenzamide (2c)
(Yield: 71%) Rf. 0.5 (ethyl acetate/hexane, 2:8). mp 84–85 ◦ C. IR (KBr) νmax : 2935 (C=C-H), 2826
(-CH3), 1676 (amide C=O), 1588 (C=N), 1555 (C=C), 1464 (C-N), 1173 (C-S) cm−1
.
1 H NMR (300 MHz,
CDCl3)δ (ppm): 8.11 (1H, d, J = 7.6 Hz, H-4’), 8.05 (1H, d,J = 7.6 Hz, H-6’), 7.84 (1H, d, J = 7.2 Hz,
H-2”, H-6”). 7.73 (1H, d, J = 7.2 Hz, H-3”, H-5”), 7.66 (1H, dd, J = 7.2, 7.4 Hz, H-7’), 7.57 (1H, dd,J =
7.2, 7.4 Hz, H-5’), 6.43 (1H, s, C=C-H , ring H-5), 2.56 (3H, s, Ar-CH3), 2.22 (3H, s, -CH3). 13 C NMR (75
MHz, CDCl3)δ (ppm): 166.6 (C-2’), 165.4 (amide C=O), 162.6 (C-2), 151.3 (C-4), 146.8 (C-9’), 134.4 (C-1”),
132.7 (C-2”, C-6”), 131.5 (C-3”, C-5”), 127.4 (C-4”), 126.3 (C-6’), 125.5 (C-5’), 124.7 (C-8’), 123.6 (C-4’), 122.4
(C-7’), 101.6 (C-2), 21.3 (Ar-CH3), 15.6 (-CH3). Anal. calcd. for C19 H15 N3 OS2 (365.47); C, 62.47; H, 4.11;
N, 11.51; S, 17.53. Found: C, 62.34; H, 3.97; N, 11.38; S, 17.42. MS (70 eV): m/z(%), 365 (M+. 49), 274 (71),
140 (100), 134 (50), 112 (30), 107 (38), 96 (24), 91 (45), 77 (20).
N-[3-(6-Bromobenzo[d]thiazol-2-yl)-3-methylthiazol-2(3H)-ylidene]-3-chlorobenzamide (2d)
(Yield: 73%). Rf. 0.5 (ethyl acetate/hexane, 2:8). mp 89–90 ◦ C. IR (KBr) νmax : 2955 (C=C-H), 2841
(-CH3), 1685 (amide C=O), 1576 (C=N), 1563 (C=C), 1462 (C-N), 1172 (C-S) cm−1
.
1 H NMR (300 MHz,
CDCl3)δ (ppm): 8.26 (1H, d, J = 7.4 Hz, H-7’), 8.14 (1H, d,J = 2.3 Hz, H-4’), 7.83 (1H, d, J = 2.4 Hz,
H-2”), 7.75 (1H, d, J = 7.4 Hz, H-5’), 7.71 (1H, d, J = 7.2 Hz, H-6”), 7.54 (1H, dd, J = 7.2, 2.2 Hz, H-4”),
7.42 (1H, d, J = 7.2, 7.1 Hz, H-5’), 6.44 (1H, s, C=C-H , ring H-5), 2.26 (3H, s, -CH3). 13 C NMR (75 MHz,
CDCl3) δ (ppm): 166.4 (C-2’), 165.2 (amide C=O), 162.5 (C-2), 152.3 (C-4), 146.5 (C-9’), 136.7 (C-1”), 135.6
(C-3”), 134.5 (C-4”), 130.6 (C-5”), 130.3 (C-2”), 128.3 (C-6”), 128.5 (C-5’), 126.7 (C-8’), 124.5 (C-7’), 124.2
(C-4’), 117.4 (C-6’), 101.6 (C-5), 16.4 (-CH3). Anal. calcd. for C18 H11 N3 OBrS2 Cl (363.78); C, 46.52; H,
2.38; N, 9.05; S, 13.78. Found: C, 46.36; H, 2.26; N, 8.93; S, 13.64. MS (70 eV): m/z(%), 463.5 (M+. 45), 352
(64), 212 (56), 140 (100), 134 (24), 112 (10), 111.5 (22), 96 (19) 77 (28).
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SAEED and RAFIQUE/Turk J Chem
N-[3-(6-Bromobenzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]-2-fluorobenzamide (2e)
(Yield: 68%). Rf. 0.55 (ethyl acetate/hexane, 2:8). mp 78–79 ◦ C. IR (KBr) νmax : 3021 (C=C-H), 2863
(-CH3), 1684 (amide C=O), 1585 (C=N), 1568 (C=C), 1485 (C-N), 1187 (C-S) cm−1
.
1 H NMR (300 MHz,
CDCl3)δ (ppm): 8.17 (1H, d, J = 7.6 Hz, H-7’), 8.11 (1H, d, J = 2.3 Hz, H-4’), 7.81 (1H, d, J = 7.4 Hz,
H-5’), 7.73 (1H, d, J = 7.1 Hz, H-3”), 7.64 (1H, dd, J = 7.1, 7.3 Hz, H-5”), 7.52 (1H, dd, J = 7.4, 7.1 Hz,
H-4”), 7.32 (1H, d, J = 7.4 Hz, H-6”), 6.46 (1H, s, C=C-H , ring H-5), 2.27 (3H, s, -CH3). 13 C NMR (75
MHz, CDCl3) δ (ppm): 166.7 (C-2’), 165.8 (amide C=O), 162.7 (C-2), 151.6 (C-4), 146.8 (C-9’), 141.6 (C-2”),
137.3 (C-1”), 136.4 (C-6”), 134.6 (C-4”), 132.5 (C-5’), 128.7 (C-5”), 127.5 (C-3”), 126.4 (C-8’), 125.6 (C-4’),
124.7 (C-7’), 121.6 (C-6’), 101.7 (C-5), 15.6 (-CH3). Anal. calcd. for C18 H11 N3 OS2 BrF (448.33); C, 48.21;
H, 2.46; N, 9.37; S, 14.28. Found: C, 48.13; H, 2.35; N, 9.23; S, 14.17. MS (70 eV): m/z(%), 448 (M+. 37),
351 (61), 211 (48), 140 (100), 112 (26), 95 (31), 77 (22).
N-[3-(6-Methylbenzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]-3-chlorobenzamide (2f)
(Yield: 72%). Rf. 0.45 (ethyl acetate/hexane, 2:8). mp 86–87 ◦ C. IR (KBr) νmax : 2965 (C=C-H),
2839 (-CH3), 1683 (amide C=O), 1576 (C=N), 1561 (C=C), 1463 (C-N), 1165 (C-S) cm−1
.
1 H NMR (300
MHz, CDCl3)δ (ppm): 8.12 (1H, d, J = 7.4 Hz, H-4’), 8.07 (1H, d,J = 2.3 Hz, H-7’), 7.76 (1H, d, J = 7.4
Hz, H-5’), 7.65 (1H, d, J = 7.2 Hz, H-6”), 7.56 (1H, d, J = 2.2 Hz, H-2”), 7.34 (1H, dd, J = 7.2, 2.2 Hz,
H-5”), 7.28 (1H, d, J = 7.2, 7.1 Hz, H-4”), 6.45 (1H, s, C=C-H , ring H-5), 2.55 (3H, s, Ar-CH3), 2.25 (3H,
s, -CH3). 13 C NMR (75 MHz, CDCl3)δ (ppm): 166.5 (C-2’), 165.7 (amide C=O), 162.6 (C-2), 151.7 (C-4),
146.8 (C-9’), 138.7 (C-1”), 137.6 (C-3”), 136.5 (C-6”), 135.4 (C-4”), 134.2 (C-6’), 133.6 (C-5”), 128.3 (C-2”),
126.5 (C-5’), 124.4 (C-8’), 122.5 (C-4’), 121.6 (C-7’), 101.8 (C-5), 22.7 (Ar-CH3), 15.5 (-CH3). Anal. calcd.
for C19 H14 N3 OS2 Cl (399.92); C, 57.07; H, 3.50; N, 10.51; S, 16.02. Found: C, 56.96; H, 3.31; N, 10.43; S,
15.84. MS (70 eV): m/z(%), 399.5 (M+. 45), 288 (64), 148 (53), 140 (100), 134 (26), 112 (30), 111.5 (32), 96
(29) 77 (18).
2-Bromo-N-[4-methyl-3-(6-methylbenzo[d]thiazol-2-yl)thiazol-2(3H)-ylidene]benzamide (2g)
(Yield: 77%). Rf. 0.35 (ethyl acetate/hexane, 2:8). mp 90–91 ◦ C. IR (KBr) νmax : 2956 (C=C-H),
2835 (-CH3), 1677 (amide C=O), 1570 (C=N), 1554 (C=C), 1454 (C-N), 1157 (C-S) cm−1
.
1 H NMR (300
MHz, CDCl3)δ (ppm): 8.13 (1H, d, J = 7.6 Hz, H-4’), 8.09 (1H, d,J = 2.4 Hz, H-7’), 7.74 (1H, d, J = 7.6
Hz, H-5’), 7.65 (1H, d, J = 7.1 Hz, H-6”), 7.52 (1H, dd, J = 7.1, 7.2 Hz, H-5”), 7.43 (1H, dd, J = 7.4, 7.1
Hz, H-4”), 7.23 (1H, d, J = 7.4 Hz, H-3”), 6.42 (1H, s, C=C-H , ring H-5), 2.57 (3H, s, Ar-CH3), 2.26 (3H,
s, -CH3). 13 C NMR (75 MHz, CDCl3)δ (ppm): 166.3 (C-2’), 165.4 (amide C=O), 162.5 (C-2), 151.5 (C-4),
146.4 (C-9’), 138.3 (C-1”), 137.4 (C-6”), 136.5 (C-4”), 135.4 (C-3”), 134.6 (C-5”), 133.5 (C-6’), 128.7 (C-2”),
127.5 (C-5’), 125.4 (C-8’), 123.6 (C-4’), 122.7 (C-7’), 101.6 (C-5), 22.4 (Ar-CH3), 15.2 (-CH3). Anal. calcd.
for C19 H14 N3 OS2 Br (444.37); C, 51.35; H, 3.15; N, 9.46; S, 14.41. Found: C, 51.24; H, 3.09; N, 9.32; S, 14.27.
MS (70 eV): m/z(%), 444 (M+. 57), 288 (49), 154 (63), 140 (100), 134 (38), 112 (20), 96 (21) 77 (25).
N-[3-(6-Methoxybenzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]benzamide (2h)
(Yield: 71%). Rf. 0.35 (ethyl acetate/hexane, 2:8). mp 82–83 ◦ C. IR (KBr) νmax : 2943 (C=C-H),
2843 (-CH3), 1675 (amide C=O), 1572 (C=N), 1556 (C=C), 1453 (C-N), 1162 (C-S) cm−1
.
1 H NMR (300
MHz, CDCl3)δ (ppm): 8.11 (1H, d, J = 7.6 Hz, H-4’), 8.06 (1H, d, J = 2.4 Hz, H-7’), 7.82 (1H, d, J = 7.6
Hz, H-5’), 7.38–7.78 (5H, m, Ar), 6.43 (1H, s, C=C-H , ring H-5), 3.78 (3H, s, -OCH3), 2.24 (3H, s, -CH3).
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SAEED and RAFIQUE/Turk J Chem
13 C NMR (75 MHz, CDCl3)δ (ppm): 166.5 (C-2’), 165.3 (amide C=O), 162.4 (C-2), 151.3 (C-4), 146.3 (C-9’),
127.4 (C-6’), 135.6 (C-1”), 134.3 (C-2”, C-6”), 132.8 (C-3”, C-5”), 128.5 (C-4”), 127.6 (C-8’), 126.3 (C-4’), 124.2
(C-5’), 122.4 (C-7’), 101.7 (C-5), 54.7 (-OCH3), 15.6 (-CH3). Anal. calcd. for C19 H15 N3 O2 S2 (381.47); C,
59.84; H, 3.94; N, 11.02; S, 16.78. Found: C, 59.75; H, 3.81; N, 10.93; S, 16.64. MS (70 eV): m/z(%), 381 (M+.
68), 217 (41), 164 (53), 140 (100), 134 (28), 112 (40), 96 (19) 77 (35).
2,4-Dichloro-N-[3-(6-methoxybenzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]beza-mide
(2i)
(Yield: 76%). Rf. 0.4 (ethyl acetate/hexane, 2:8). mp 79–80 ◦ C. IR (KBr) νmax : 3027 (C=C-H), 2857
(-CH3), 1687 (amide C=O), 1584 (C=N), 1564 (C=C), 1471 (C-N), 1181 (C-S) cm−1
.
1 H NMR (300 MHz,
CDCl3)δ (ppm): 8.16 (1H, d, J = 7.6 Hz, H-4’), 8.08 (1H, d, J = 2.4 Hz, H-7’), 7.84 (1H, d, J = 7.6 Hz, H-5’),
7.73 (1H, d, J = 7.4 Hz, H-6”), 7.64 (1H, d, J = 2.4 Hz, H-3”), 7.48 (1H, d, J = 7.4 Hz, H-5”), 6.46 (1H,
s, C=C-H , ring H-5), 3.83 (3H, s, -OCH3), 2.27 (3H, s, -CH3). 13 C NMR (75 MHz, CDCl3)δ (ppm): 167.2
(C-2’), 166.2 (amide C=O), 162.8 (C-2), 152.3 (C-4), 147.5 (C-9’), 138.6 (C-6’), 137.5 (C-1”), 136.3 (C-2”),
134.7 (C-4”), 133.6 (C-6”), 132.5 (C-3”), 131.8 (C-5”), 128.4 (C-8’), 126.4 (C-4’), 124.6 (C-5’), 121.8 (C-7’),
102.6 (C-5), 54.6 (-OCH3), 15.4 (-CH3). Anal. calcd. for C19 H13 N3 O2 S2 Cl2 (450.36); C, 50.67; H, 2.88; N,
9.33; S, 14.22. Found: C, 50.44; H, 2.73; N, 9.18; S, 14.13. MS (70 eV): m/z(%), 450 (M+. 58), 284 (34), 164
(73), 144 (35), 140 (100), 112 (20), 96 (23) 77 (13).
2,4-Dichloro-N-[3-(4,6-dichlorobenzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene] benz-
amide (2j)
(Yield: 75%). Rf. 0.6 (ethyl acetate/hexane, 2:8). mp 74–76 ◦ C. IR (KBr) νmax : 2963 (C=C-H), 2846
(-CH3), 1691 (amide C=O), 1587 (C=N), 1568 (C=C), 1477 (C-N), 1186 (C-S) cm−1
.
1 H NMR (300 MHz,
CDCl3)δ (ppm): 8.24 (1H, d, J = 2.2 Hz, H-7’), 8.17 (1H, d, J = 2.2 Hz, H-5’), 7.96 (1H, d, J = 7.6 Hz,
H-6”), 7.87 (1H, d, J = 2.3 Hz, H-3”), 7.78 (1H, d, J = 7.6 Hz, H-5”), 6.48 (1H, s, C= C-H , ring H-5),
2.31 (3H, s, -CH3). 13 C NMR (75 MHz, CDCl3) δ (ppm): 167.4 (C-2’), 166.5 (amide C=O), 163.1 (C-2),
152.5 (C-4), 147.7 (C-9’), 138.4 (C-1”), 137.6 (C-2”), 136.5 (C-4”), 134.8 (C-6”), 133.4 (C-6’), 132.3 (C-4’),
131.8 (C-3”), 128.2 (C-5”), 125.1 (C-8’), 124.6 (C-5’), 123.7 (C-7’), 102.8 (C-5), 15.7 (-CH3). Anal. calcd. for
C18 H9 N3 OS2 Cl4 (489.23); C, 44.17; H, 1.84; N, 8.58; S, 13.08. Found: C, 44.09; H, 1.61; N, 8.43; S, 13.01.
MS (70 eV): m/z(%), 489 (M+. 58), 284 (65), 201 (52), 167 (46), 144 (65), 140 (100), 134 (42), 112 (31), 111.5
(34), 96 (26), 77 (18).
N-[3-(4,6-Dichlorobenzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]benzamide (2k)
(Yield: 78%). Rf. 0.4 (ethyl acetate/hexane, 2:8). mp 70–71 ◦ C. IR (KBr) νmax : 3031 (C=C-H), 2855
(-CH3), 1686 (amide C=O), 1583 (C=N), 1565 (C=C), 1474 (C-N), 1183 (C-S) cm−1
.
1 H NMR (300 MHz,
CDCl3)δ (ppm): 8.21 (1H, d, J = 2.3 Hz, H-7’), 8.16 (1H, d, J = 2.3 Hz, H-5’), 7.63–7.91 (5H, m, Ar), 6.47
(1H, s, C = C-H , ring H-5), 2.28 (3H, s, -CH3). 13 C NMR (75 MHz, CDCl3)δ (ppm): 167.3 (C-2’), 166.1
(amide C=O), 162.6 (C-2), 152.3 (C-4), 147.3 (C-9’), 136.5 (C-1”), 134.7 (C-6’), 133.8 (C-4’), 132.6 (C-2”,
C-6”), 131.5 (C-3”, C-5”), 127.4 (C-4”), 124.6 (C-8’), 123.8 (C-5’), 122.7 (C-7’), 102.3 (C-5), 15.3 (ring -CH3).
Anal. calcd. for C18 H11 N3 OS2 Cl2 (420.34); C, 51.42; H, 2.62; N, 10.01; S, 15.24. Found: C, 51.37; H, 2.43;
N, 9.92; S, 15.14. MS (70 eV): m/z(%), 420 (M+. 46), 274 (52), 201 (36), 167 (40), 144 (65), 140 (100), 134
(33), 112 (23), 96 (16), 77 (24).
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SAEED and RAFIQUE/Turk J Chem
3. Results and discussion
The synthesis of the title compounds (2a–k) was carried out according to the synthetic route sketched in
the Scheme. Thus suitably substituted anilines were converted into the requisite benzo[d]thiazol-2-amines by
reaction with thiocyanogen generated in situ from bromine and potassium thiocyanate in acidic medium. The
2-aminobenzothiazoles showed characteristic peaks at 3390–3460 (NH), 1630–1650 (C=N), 2723–2734 (C–S),
and 1527–1542 cm−1 for (C–N) in the FTIR spectral data. The 1 H NMR shows a broad singlet at 5.4 ppm
due to –NH2 protons besides those for aromatic protons in the region 6.92–7.47 ppm.
O
COOH
COCl
C
N C S
NH2
S
N
SOCl2
KSCN
AcOH
NH2
R
R
2–3
dry acetone
h re
flu
x
Br2 + KSCN
R'
R'
R'
1 h reflux
R'
1''
O
C
N
2''
7'
1'
R
Br2 / dry acetone
Et3N/ under N2
S
C
O
C
8'
S
S
N
R'
2
1
H
N
2'
S
NH
N
3
R
(2a–k)
5
H
N
9'
4
(1a–k)
4'
3'
H3C
2a: R = R' = H,
2b: R = H, R' = 2-OCH3
2d: R = 6-Br, R' = 3-Cl
2f: R = 6-CH3, R' = 3-Cl
2h: R = 6-OCH3, R' = H
2c: R = H, R' = 4-CH3
2e: R = 6-Br, R' = 2-F
2g: R = 6-CH3, R' = 2-Br,
2i: R = 6-OCH3, R' = 2,4-di-Cl 2j: R = 4,6-di-Cl, R' = 2,4-di-Cl
2k: R = 4,6-di-Cl, R' = H
Scheme. Synthetic route to N-[3-(2-benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene] substituted benzamides
(2a–k).
1-(Benzo[d]thiazol-2-yl)-3-(substituted) thioureas (1a–k) were synthesized by treating suitably substi-
tuted acid chlorides with potassium thiocyanate, followed by their reaction with benzo[d]thiazol-2-amines pre-
pared above.28 The FTIR spectra of thioureas showed peaks at 3150–3382 (N–H) and 1627–1720 and 1230–1250
cm−1 for carbonyl and thiocarbonyl groups, respectively, in addition to those at 1235–1278, (C–N), 1211–1173
(C=N), and 1517–1558 (C=C) cm−1 . The 1 H NMR spectral data show 2 characteristic singlets of NH protons
at δ 11.38 and 10.09 ppm for HN(1) and HN(3) in the 1 H NMR spectra, respectively.
Base-catalyzed cyclization of benzothiazolyl thioureas with 2-bromoacetone produced in situ by the reac-
tion of bromine with dry acetone afforded the title N -[3-(benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene]
substituted benzamides (2a–k) in good yields (Scheme).
TLC analysis was carried out to authenticate the purity of the compounds. Iminothiazoline derivatives
have Rf values lower than those of the corresponding benzothiazolyl thioureas.29 Analytical and spectral data
(IR and 1 H NMR) of all the newly synthesized compounds were found in full conformity with the proposed
structures. In the 1 H NMR spectra the signals of the particular proton of the compounds were established on
the basis of their chemical shifts and multiplicities. The FTIR spectra of compounds revealed the disappearance
914

SAEED and RAFIQUE/Turk J Chem
of N-H peaks around 3200–3400 cm−1 and the appearance of characteristic strong absorption peaks of C=N in
the range of 1660–1680 cm−1 for the iminothiazoline moiety besides C-S absorptions at 1250–1275 cm−1 , C-N
at 1420–1465 cm−1 , and the aromatic C=C at 1565–1600 cm−1 . In 1 H NMR the characteristic singlet was
observed at δ 6.42–6.48 for thiazoline proton and the singlet for -CH3 protons of the thiazoline moiety appeared
in CDCl3 at δ 2.22–2.31 ppm. In 13 C NMR the characteristic signals for olefinic carbon appeared at δ 101.5–
102.8, for methyl carbon at δ 15.2–16.4, and for imino carbon at δ 166.3–167.4 ppm. In the EIMS, in addition
to the molecular ions, the base peaks were observed at m/z 140, corresponding to fragment [C5 H4 N2 SO]+
.
4. Conclusion
Synthesis of a number of iminothiazol–benzothiazole hybrid molecules has been carried out; they can potentially
be used as new lead compounds in drug discovery.
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