Synthesis of [2,4-bis(arylamino)thiazol-5-yl](1-methyl-1h-benzimidazol-2- yl)methanones

Article abstract of DOI:10.1002/jhet.162

(Chemical Equation Presented) [2,4-Bis(arylamino)thiazol-5-yl]-(1-methyl- 1H-benzimidazol-2-yl)methanones, as the analogs of the cytotoxic marine alkaloid dendrodoine, are synthesized and characterized by elemental analysis, IR, NMR, and Mass spectral dat

Full text of DOI:10.1002/jhet.162

September 2009
Synthesis of [2,4-Bis(arylamino)thiazol-5-yl](1-methyl-1h-
benzimidazol-2-yl)methanones
1011
T. F. Abbs Fen Rejia* and Kallikat N. Rajasekharanb
aDepartment of Chemistry, Nesamony Memorial Christian College, Marthandam,
Tamil Nadu 629165, India
bDepartment of Chemistry, University of Kerala, Trivandrum, Kerala 695 581, India
*E-mail: abbsfen@gmail.com
Received June 17, 2008
DOI 10.1002/jhet.162
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
[2,4-Bis(arylamino)thiazol-5-yl]-(1-methyl-1H-benzimidazol-2-yl)methanones, as the analogs of the
cytotoxic marine alkaloid dendrodoine, are synthesized and characterized by elemental analysis, IR,
NMR, and Mass spectral data. The thiourea derivatives provide four ring atoms for the thiazole ring
construction and thus act as [CANACAS] synthons. The remaining carbon of the thiazole is sourced
from 2-(2-bromoacetyl)-1-methyl-1H-benzimidazole. This [4þ1] heterocyclization reaction is adopted
for the synthesis of novel 1-methyl-1H-benzimidazole derivatives.
J. Heterocyclic Chem., 46, 1011 (2009).
INTRODUCTION
logs of dendrodoine and the cancer cell cytotoxicity of the
indolyl derivative 2 at submicromolar concentration were
reported by us recently [4].
For a natural product, either from terrestrial or from
marine sources, dendrodoine 1, [3-(N,N-dimethylamino-
1,2,4-thiadiazol-5-yl]-indol-3-yl-methanone, isolated [1]
from the ‘‘baked bean ascidian’’ or Dendrodoa grossu-
laria, is unusual in that it incorporates a 1,2,4-thiadia-
zole ring. It has been shown to be cytotoxic in vitro
[1,2] and has been synthesized [3] by a 1,3-dipolar
cycloaddition of indoloyl cyanide to a nitrile sulfide
obtained by the thermolysis of a 1,3,4-oxathiazol-2-one
In this context, the 2-amino-5-ketothiazole synthesis
developed by us [5–7] appeared promising. A variety of
amino substituents could be placed on C-2 and C-4 car-
bons of the thiazole ring by choosing the appropriate thio-
urea synthon and the 5-keto substituent could be accessed
through a variety of a-haloketones. As typical examples,
[4-amino-2-(4-methoxyphenylamino)-thiazol-5-yl)]-phe-
nylmethanone 3 [8], [4-(4-chlorophenylamino)-2-(4-
methoxyphenylamino)thiazol-5-yl)]-1H-indol-3-yl-metha-
none 4, and 5-[4-amino-2-(4-methoxyphenylamino)-thia-
zol-5-yl)]-(1-methyl-1H-benzimidazol-2-yl)-methan-one 5
[9] were found to be cancer cell cytotoxic at submicromolar
levels. To broaden the scope of this study further, we now
report the synthesis of [2,4-bis(arylamino)thiazol-5-yl](1-
methyl-1H-benzoimidazol-2-yl)methanones as further ana-
logs of dendrodoine. Literature survey shows several exam-
ples of compounds having a 1H-benzimidazole ring which
exhibit remarkable bioactivity including anticancer activity
[10–14].
prepared from N,N-dimethylurea and chlorocarbonyl-
sulphenyl chloride. This route is rather inflexible as it is
confined solely to the preparation of 3-N,N-dialkylamino
derivatives. In addition, the hetaroyl cyanides are difficult
to access, thereby making the preparation of dendrodoine
analogs with a variety of substituents not easy. Moreover,
the scope of the substituent manipulation in 1 is restricted
due to the availability of only two carbons for substitution
or functionalization in the 1,2,4-thiadiazole ring. There-
fore, the exchange of a 2-aminothiazole unit for the 3-
amino-1,2,4-thiadiazole unit in dendrodoine seemed
attractive. Thus, the synthesis of several (2-N,N-dimethy-
laminothiazol-5-yl)-(hetaryl)-methanones as thiazole ana-
RESULTS AND DISCUSSION
The route adopted for the synthesis of these novel
analogs of dendrodoine was based on a retro synthetic
analysis as outlined in Scheme 1. The thiourea deriva-
tives [5–7] (6a–k) provide four ring atoms for the thia-
zole ring construction and thus act as [CANACAS]
C
V
2009 HeteroCorporation

1012
T. F. Abbs Fen Reji and K. N. Rajasekharan
Vol 46
1
synthons. The remaining carbon of the thiazole is
sourced from 2-(2-bromoacetyl)-1-methyl-1H-benzimid-
azole. This [4þ1]
The HNMR (300 MHz, DMSO-d6) spectrum shows
a three-hydrogen singlet at d 4.22, which has been
ascribed to the methyl group of 1-methyl-1H-benzimida-
zole ring. The spectrum consists of three multiplets in
the aromatic region. The first multiplet at d 7.06–7.18 is
due to two aromatic hydrogens. The H-5 and H-6 of the
1-methyl-1H-benzimidazole ring and the four other aro-
matic hydrogens give rise to the second multiplet at d
7.25–7.46. The third multiplet at d 7.64–7.78 arises
from H-4 and H-7 of the 1-methyl-1H-benzimidazole
ring and the remaining four aromatic hydrogens. The
two one-hydrogen singlets in the downfield region at d
11.19 and 11.85 are assignable to NH hydrogen of the
two NHAr groups.
The FAB MS confirms the molecular mass of the
compound as 425 in accordance with the elemental anal-
ysis data. The presence of 24 carbons in the compound
is confirmed from the 20 peaks observed in the
13CNMR spectrum. Based on these data, the structure of
the compound now obtained was assigned as [2,4-
bis(phenylamino)thiazol-5-yl](1-methyl-1H-benzim-ida-
zol-2-yl)methanone (8a). By following the similar pro-
cedure 10 additional [2,4-bis(arylamino)thia-zol-5-yl](1-
methyl-1H-benzimidazol-2-yl)methanones (8b–k) were
prepared and characterized.
EXPERIMENTAL
Melting points are uncorrected and were determined by
open capillary method using an immersion bath of silicon oil.
TLC was performed using silica gel-G (E. Merck, India)
coated on glass plates. The spots were visualized in iodine
vapor or under UV light. The spectra were recorded on: JEOL
Scheme 1
heterocyclization reaction is now selected for the
synthesis of novel 1-methyl-1H-benzimidazole deriva-
tives (Scheme 2). Thus, the reaction of 1-(N,N’-
diphenylamidino)-3-phenylthiourea (6a) in N,N-di-
methylformamide (DMF) with 2-(2-bromoacetyl)-1-
methyl-1H-benzimidazole (7) which was prepared from
2-(1-hydroxyethyl)-1H-benzimidazole [15,16], in DMF
in the presence of triethylamine afforded an orange,
crystalline compound which showed up in the thin layer
chromatogram (TLC) as a single fluorescent yellow
spot, indicating the formation of only one major
product.
The molecular composition of the compound (8a) was
found to be C24H19N5OS. The IR (KBr) spectrum shows
peaks at 3387, 3267, 3200, and 3117 cmꢀ1, which are
attributed to the mNAH vibration. The aromatic mCAH band
appears at 3050 cmꢀ1. The aliphatic mCAH band is
observed at 2928 cmꢀ1and 2861 cmꢀ1. The highly conju-
gated carbonyl group shows mC¼O vibration at 1607 cmꢀ1
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
Synthesis of [2,4-Bis(arylamino)thiazol-5-yl](1-
methyl-1H-benzimidazol-2-yl)methanones
1013
Scheme 2
[2,4-Bis(phenylamino)thiazol-5-oyl](1-methyl-1H-benzoimi-
dazol-2-yl)methanone (8a). Starting from 1-(N,N’-diphenyla-
midino)-3-phenylthiourea (6a), 2-(2-bromoacetyl)-1-methyl-
1H-benzimidazole (7), and following the general procedure
above, 8a was obtained as a deep orange solid. It was crys-
tallized from ethanol-water (3:1), m.p. 180–181ꢁC; IR (KBr)
m: 3387, 3267, 3200, 3117, 3050, 2928, 2861, 1607, 1573,
1517, 1483, 1445, 1350, 1217, 950, 900, 733, 690 cmꢀ1
;
1HNMR (300 MHz, DMSO-d6): d 4.22(s, 3H, NACH3),
7.06–7.18(m, 2H, 2ArH), 7.25–7.46(m, 6H, H-5, H-6,
4ArH), 7.64–7.78(m, 6H, H-4, H-7, 4ArH), 11.19(s, 1H,
NH), 11.85(s, 1H, NH); 13CNMR (75 MHz, DMSO-d6): d
32.4, 96.4, 111.2, 119.4, 120.0, 120.2, 123.2, 123.4, 124.0,
124.6, 129.2, 129.3, 136.8, 139.1, 139.3, 140.8, 147.2, 162.7,
171.7, 171.8; FABMS: m/z 426 (MHþ), 425 (Mþ). Anal.
Calcd for C24H19N5OS: C, 67.74; H, 4.50; N, 16.46%.
Found: C, 67.61; H, 4.58; 16.61%.
[2,4-Bis(4-chlorophenylamino)thiazol-5-oyl](1-methyl-1H-
benzoimidazol-2-yl)methanone (8b). The reaction of 1-
(N,N’-di(4-chlorophenyl)amidino)-3-(4-chlorophenyl)thiourea
(6b) with 7 afforded 8b as a deep orange solid. It was crys-
tallized from ethanol-water (3:1), m.p. 238–239ꢁC; IR (KBr)
m: 3449, 3238, 3189, 3111, 3032, 2933, 2867, 1627, 1576,
1493, 1455, 1411, 1356, 1210, 1093, 1023, 960, 822, 740,
674 cmꢀ1 1HNMR (300 MHz, DMSO-d6): d 4.20(s, 3H,
;
NACH3), 7.27–7.53(m, 6H, H-5, H-6, 4ArH), 7.60–7.78(m,
6H, H-4, H-7, 4ArH), 11.26(s, 1H, NH), 11.79(s, 1H, NH);
FABMS: m/z 494 (MHþ), 493 (Mþ). Anal. Calcd for
C24H17Cl2N5OS: C, 58.30; H, 3.47; N, 14.17%. Found: C,
58.53; H, 3.58; N, 14.02%.
[2,4-Bis(4-methylphenylamino)thiazol-5-oyl](1-methyl-1H-
benzoimidazol-2-yl)methanone (8c). 1-(N,N’-di(4-methylphe-
nyl)amidino)-3-(4-methylphenyl)thiourea (6c) and 7 on reac-
tion as above gave 8c a as a deep orange solid. It was crystal-
lized from ethanol-water (3:1), m.p. 208–209ꢁC; IR (KBr) m:
3312, 3200, 3117, 3050, 2928, 2850, 1607, 1597, 1550, 1519,
1450, 1350, 1216, 1167, 1117, 1017, 879, 825, 733, 683 cmꢀ1
;
1HNMR (300 MHz, DMSO-d6): d 2.29(s, 6H, 2CH3), 4.23(s,
3H, NACH3), 7.16–7.26(m, 4H, 4ArH), 7.28–7.43(m, 2H, H-5,
H-6), 7.54(d, J ¼ 8.1 Hz, 2H, 2ArH), 7.63(d, J ¼ 8.4 Hz, 2H,
2ArH), 7.69(d, J ¼ 8.1 Hz, 1H, H-7), 7.74(d, J ¼ 7.8 Hz, 1H,
H-4), 11.08(s, 1H, NH), 11.87(s, 1H, NH); 13CNMR (75 MHz,
DMSO-d6): d 20.86, 20.94, 32.27, 95.46, 97.76, 102.35,
110.09, 120.78, 120.92, 121.03, 123.00, 124.47, 129.47,
130.14, 133.20, 135.22, 135.62, 136.82, 141.48, 148.38,
163.25, 172.28; FABMS: m/z 454 (MHþ), 453 (Mþ). Anal.
Calcd for C26H23N5OS: C, 68.85; H, 5.11; N, 15.44%. Found:
C, 68.58; H, 5.01; N, 15.58%.
DRX 300 or DPX 300 NMR spectrometer (300 MHz for 1H
and 75 MHz for 13CNMR spectra), JEOL SX 102/DA-6000
mass spectrometer (using Argon/Xenon, 6 KV, 10 mA as the
FAB gas, and m-nitrobenzyl alcohol as the matrix) for FAB
mass spectra and Nicolet 400D FTIR spectrometer. All new
compounds gave satisfactory C, H, and N analysis (CDRI,
Lucknow).
General procedure for the synthesis of [2,4-bis(arylami-
no)thiazol-5-yl](1-methyl-1H-benzoimidazol-2-yl)methanones
(8a–k). A solution of 2-(2-bromoacetyl)-1-methyl-1H-benzim-
idazole (7) (0.254 g, 1 mmol) which was prepared from 2-(1-
hydroxyethyl)-1H-benzimidazole [15,16], in DMF (2 mL) was
added to a solution of 1-aryl-3-(N,N’-diarylamidino)thiourea (1
mmol) (6a–k) [5] in DMF (2 mL). Triethylamine (0.15 mL, 1
mmol) was added under stirring and the mixture was heated at
80–85ꢁC for 5 min. It was then cooled and poured into ice-
cold water with constant stirring. The yellow precipitate thus
obtained was filtered, washed with water, and dried. The crude
product was purified by crystallization.
[2-(4-Chlorophenylamino)-4-phenylaminothiazol-5-oyl](1-
methyl-1H-benzoimidazol-2-yl)methanone (8d). Using 1-
(N,N’-diphenylamidino)-3-(4-chlorophenyl)thiourea (6d), and
7, 8d was obtained as a deep orange solid. It was crystallized
from ethanol-water (3:1), m.p. 171–173ꢁC; IR (KBr) m: 3367,
3282, 3184, 3117, 2929, 2864, 1621, 1582, 1522, 1494, 1456,
1406, 1355, 1222, 1097, 963, 830, 752, 686 cmꢀ1 1HNMR
;
(300 MHz, DMSO-d6): d 4.22(s, 3H, NACH3), 7.11(t, J ¼ 9
Hz, 1H, 1ArH), 7.26–7.51(m, 6H, H-5, H-6, 4ArH), 7.59–
7.79(m, 6H, H-4, H-7, 4ArH), 11.27(s, 1H, NH), 11.80(s, 1H,
NH). FABMS: m/z 460 (MHþ). Anal. Calcd for
C24H18ClN5OS: C, 62.67; H, 3.94; N, 15.23%. Found: C,
62.57; H, 3.81; N, 15.48%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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T. F. Abbs Fen Reji and K. N. Rajasekharan
Vol 46
phenyl)thiourea (6i) with 7 afforded 8i as a deep orange solid
which was crystallized from ethanol-water (3:1), m.p. 218–
219ꢁC; IR (KBr) m: 3464, 3247, 3100, 3034, 2917, 2854,
1617, 1571, 1550, 1514, 1445, 1359, 1217, 1097, 958, 826,
[2-(4-Methylphenylamino)-4-phenylaminothiazol-5-oyl](1-
methyl-1H-benzoimidazol-2-yl)methanone (8e). The reac-
tion of 1-(N,N’-diphenylamidino)-3-(4-methylphenyl)th-
iourea (6e) with 7 afforded 8e as a deep orange solid. It
was crystallized from ethanol-water (3:1), m.p. 161–164ꢁC;
IR (KBr) m: 3384, 3272, 3200, 3117, 3059, 2931, 2850,
1619, 1580, 1506, 1448, 1418, 1357, 1205, 966, 825, 751
1
752, 673 cmꢀ1; HNMR (300 MHz, DMSO-d6): d 2.32(s, 3H,
CH3), 4.24(s, 3H, NACH3), 7.14–7.60(m, 8H, H-5, H-6,
6ArH), 7.61–7.88(m, 4H, H-4, H-7, 2ArH), 11.13(s, 1H, NH),
11.88(s, 1H, NH); FABMS: m/z 474 (MHþ), 473 (Mþ). Anal.
Calcd for C25H20ClN5OS: C, 63.35; H, 4.25; N, 14.78%.
Found: C, 63.50; H, 4.35; N, 14.95%.
cmꢀ1 1HNMR (300 MHz, DMSO-d6): d 2.31(s, 3H, CH3),
;
4.25(s, 3H, NACH3), 7.12(t, J ¼ 6.9 Hz, 1H, 1ArH),
7.24(d, J ¼ 7.8 Hz, 2H, 2ArH), 7.28–7.49(m, 4H, H-5, H-6,
2ArH), 7.56(d, J ¼ 7.5 Hz, 2H, 2ArH), 7.64–7.86(m, 4H,
H-4, H-7, 2ArH), 11.10(s, 1H, NH), 11.91(s, 1H, NH);
FABMS: m/z 440 (MHþ), 439 (Mþ). Anal. Calcd for
[4-(4-Chlorophenylamino)-2-(4-ethoxyphenylamino)thiazol-
5-oyl](1-methyl-1H-benzoimidazol-2-yl)methanone (8j). Upon
reacting with 7, 1-(N,N’-di(4-chlorophenyl)amidino)-3-(4-
ethoxyphenyl)thiourea (6j) afforded 8j as a deep orange solid,
which was crystallized from ethanol-water (3:1), m.p. 172–
173ꢁC; IR (KBr) m: 3440, 3299, 3200, 3080, 2975, 2917,
2867, 1625, 1600, 1560, 1518, 1490, 1438, 1354, 1249, 1217,
C25H21N5OS: C, 68.31; H, 4.82; N, 15.94%. Found: C,
68.53; H, 4.95; N, 16.07%.
[2-(4-Ethoxyphenylamino)-4-phenylaminothiazol-5-oyl](1-
methyl-1H-benzoimidazol-2-yl)methanone (8f). 1-(N,N’-diphe-
nylamidino)-3-(4-ethoxyphenyl)thiourea (6f) was reacted with
7 to obtain 8f as a deep orange solid, which was crystallized
from ethanol-water (3:1), m.p. 121–124ꢁC; IR (KBr) m: 3301,
3207, 3124, 3097, 2975, 2925, 2841, 1615, 1600, 1578, 1523,
1457, 1424, 1350, 1237, 1176, 1130, 1059, 949, 834, 747, 690
1205, 1181, 1093, 1051, 958, 821, 740, 617 cmꢀ1 1HNMR
;
(300 MHz, DMSO-d6): d 1.33(t, J ¼ 6.45 Hz, 3H, CH3),
4.02(quartet, J ¼ 6.9 Hz, 2H, CH2), 4.19(s, 3H, NACH3),
6.98(d, J ¼ 8.4 Hz, 2H, 2ArH), 7.21–7.82(m, 10H, H-4, H-5,
H-6, H-7, 6ArH), 11.00(s, 1H, NH), 11.91(s, 1H, NH). Anal.
Calcd for C26H22ClN5O2S: C, 61.96; H, 4.40; N, 13.90%.
Found: C, 62.08; H, 4.51; N, 13.74%.
1
cmꢀ1; HNMR (300 MHz, DMSO-d6): d 1.32(t, J ¼ 6 Hz, 3H,
CH3), 4.03(quartet, J ¼ 7 Hz, 2H, CH2), 4.22(s, 3H, NACH3),
6.99(d, J ¼ 8.7 Hz, 2H, 2ArH), 7.10(t, J ¼ 7.35 Hz, 1H,
1ArH), 7.28–7.46(m, 4H, H-5, H-6, 2ArH), 7.53(d, J ¼ 8.1
Hz, 2H, 2ArH), 7.68(d, J ¼ 8.1 Hz, 1H, H-7), 7.74(d, J ¼ 7.8
Hz, 3H, H-4, 2ArH), 11.04(s, 1H, NH), 11.92(s, 1H, NH);
FABMS: 470 (MHþ), 469 (Mþ). Anal. Calcd for
C26H23N5O2S: C, 66.50; H, 4.94; N, 14.92%. Found: C, 66.32;
H, 4.85, N, 14.81%.
[4-(4-Methylphenylamino)-2-phenylaminothiazol-5-oyl](1-
methyl-1H-benzoimidazol-2-yl)methanone (8k). The com-
pound 8k was obtained from 1-(N,N’-di-(4-methylphenyl)ami-
dino)-3-phenylthiourea (6k) and 7 as a deep orange solid. It
was crystallized from ethanol-water (3:1), m.p. 225–226ꢁC; IR
(KBr) m: 3306, 3051, 2928, 2859, 1607, 1567, 1538, 1499,
1411, 1364, 1337, 1204, 958, 877, 817, 751 cmꢀ1 1HNMR
;
(300 MHz, DMSO-d6): d 2.30(s, 3H, CH3), 4.23(s, 3H,
NACH3), 7.14(t, J ¼ 7.35 Hz, 1H, 1ArH), 7.21(d, J ¼ 8.4 Hz,
2H, 2ArH), 7.28–7.49(m, 4H, H-5, H-6, 2ArH), 7.58–7.82(m,
6H, H-4, H-7, 4ArH), 11.16(s, 1H, NH), 11.85(s, 1H, NH);
FABMS: m/z 440 (MHþ), 439 (Mþ). Anal. Calcd for
C25H21N5OS: C, 68.31; H, 4.82; N, 15.94%. Found: C, 68.58;
H, 4.92; N, 15.75%.
[4-(4-Chlorophenylamino)-2-phenylaminothiazol-5-oyl](1-
methyl-1H-benzoimidazol-2-yl)methanone (8g). Upon reac-
tion of 1-(N,N’-di(4-chlorophenyl)amidino)-3-phenylthiourea
(6g) with 7, 8g was obtained as a deep orange solid, which
was crystallized from ethanol-water (3:1), m.p. 193–198ꢁC; IR
(KBr) m: 3448, 3233, 3187, 3117, 3050, 2925, 2850, 1613,
1575, 1550, 1492, 1445, 1367, 1258, 1217, 1100, 1020, 958,
1
825, 767, 690 cmꢀ1; HNMR (300 MHz, DMSO-d6): d 4.21(s,
3H, NACH3), 7.15(t, J ¼ 7.2 Hz, 1H, 1ArH), 7.29–7.52(m,
6H, H-5, H-6, 4ArH), 7.59–7.80(m, 6H, H-4, H-7, 4ArH),
11.20(s, 1H, NH), 11.83(s, 1H, NH). Anal. Calcd for
C24H18ClN5OS: C, 62.67; H, 3.94; N, 15.23%. Found: C,
62.81; H, 4.00; N, 15.39.
Acknowledgment. T. F. A. F. Reji acknowledges University
Grants Commission, Govt. of India, New Delhi for financial sup-
port. The authors thank NIIST (RRL), Thiruvananthapuram and
CDRI, Lucknow for spectral and analytical data. They also thanks
Dr. D. Karunagran, IIT, Chennai for biological studies.
[4-(4-Chlorophenylamino)-2-(4-methoxyphenylamino)thiazol-
5-oyl](1-methyl-1H-benzoimidazol-2-yl)methanone (8h). Starting
REFERENCES AND NOTES
from
1-(N,N’-di(4-chlorophenyl)amidino)-3-(4-methoxy-
phenyl) thiourea (6h), and 7, 8h was obtained as a deep or-
ange solid, which was crystallized from ethanol-water (3:1),
m.p. 136–138ꢁC; IR (KBr) m: 3461, 3237, 3190, 3116, 3035,
2931, 2854, 1613, 1580, 1491, 1452, 1402, 1351, 1216,
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;
DMSO-d6): d 3.77(s, 3H, OCH3), 4.22(s, 3H, NACH3),
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4ArH), 7.60–7.83(m, 4H, H-4, H-7, 2ArH), 11.07(s, 1H,
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