Indian Journal of Chemi stry

Vol. 428 , April 2003, pp. 931-934

Note

Studies on syntheses of 1-alkyl-2- gave a product, which was found to be identical in

substitutedthiazolylbenzimidazoles m.p., m.m.p. and co-TLC with 4a 1 obtained above.
Compound 4a 1 could also be prepared by another
P K Dubey*, A Naidu & C Ravi Kumar route. Thus, reaction of 1 with p-methylphenyl-
Dept. of Chemi stry , College of Engg. , J. N. T . University , thiourea and iodine in iso-propanol under reflux for
Kukatpally , Hyderabad 500 072, India 2.5 hr followed by simple processing gave a product,
Received 4 July 2000; accepted (revised ) 1 May 2002 which was characterized as 2-(2'-p-methylphenyl-
amino-1,3-thiazolyl)benzimidazole Sa [i .e. , S, Ar =
Studies on syntheses of 1-alkyl-2-substitutedthiazolyl- C 6H4CH 3 (p)]. Its IR (KBr) showed peaks at 3308 and
benzimidazoles 4 starting from 2-acetylbe nzimidazoles 1 have 3260 (due to -NH- of imidazole and aminothiazole),
been reported. Alkylation of 1 leads to 1-alkyl -2-acetyl-
and absence of absorption at 1665 cm-1 which was
ben zimidazoles 2, which on bromination yield the known 1-alkyl-
2-(a-bromoacetyl)benzimidazoles 3 . The latter on treatment with
present in the starting material.
thioureas yield 4. Compound Sa was alkylated under phase-transfer
catalysed conditions using OMS in acetonitrile to ob-
Benzimidazoles are an important group of heterocyc- tain 4a 1 [i.e., 4, R=Me, R'=C 6H 4CH 3 (p)]. The m.p.,
lic compounds possessing a variety of biological ac- m.m.p., co-TLC and superimposable IR of 4a 1 were
tivities1. In continuation of our earlier work 2 on ben- found to be identical with those of the products ob-
zimidazoles, we wish to report herein syntheses of l- tained above using the two routes 2--73--74 and 3--74.
a\kyl-2-substitutedthiazolylbenzimidazoles. Furthermore, it has been found that 4a 1 obtained in
Alkylation of 2-acetylbenzimidazole3 1 under the route 2--73--74 gave the best product in terms of
phase-transfer catalysed conditions yields l-alkyl-2- m.p. and TLC. Therefore, the above reaction of 3a in
acetylbenzimidazoles4 2, which on bromination re- DMF has been extended to 3b (i.e., 3, R=Et) and 3c
sults in the formation of the known 5 1-alkyl- (i.e., 3, R=-CH 2 Ph) with various substituted thioureas
a-bromoacetylbenzimidazoles 3. Treatment of 3a and the products obtained have all been assigned
(i.e. , 3, R=Me) with p-methylphenylthiourea in DMF structure 4 on the basis of analytical and spectral data
at RT for 2 hr gave a product, which has been charac- (Tables I and II).
terized as 1-methyl-2-(2'-p-methylphenylamino-1 ,3- All the above reactions have been described in
thiazolyl)benzimidazole 4a 1 [i .e., 4a, R=Me, R' = Scheme I.
C6H4CH 3 (p)], on the basis of analytical and spectral
data. The yield of the product was found to be 75 %, Experimental Section
m.p. 234° C. Thus, its IR (KBr) spectrum showed Melting points are uncorrected and have been de-
peaks at 3242 (-NH-), 3117 (-CH-) , 1610 (-C=N-), termined in open capillary tubes in sulfuric acid bath .
1527 (-C=C-) with a shoulder at 1530 (s), 1460 (vw), TLC analyses were done on glass plates coated with
1 silicagel-G and spotting was done using iodine or UV
1380 (vs) cm· etc (series of absorption s due to vari -
ous C-C stretching and bending vibrations). Its light. IR spectra were recorded on JASCO FT-IR
1 1
H NMR (CDC1 3ffMS) showed signal s at 8 2.35 (s, 5300 spectrometer, H NMR spectra o n VARIAN 200
3H, -C6H4-CH 3 (p)), 4 .2 (s, 3H, -N-CH 3), 7.1-7.4 MHz spectrometer and mass spectra on Hewlett Pack-
(complex m, 8H, Ar-H) , 7.55 (s, 1H, -S-CH=), 7.75 ard Mass spectrometer operating at 70e V.
(br s, IH, -NH-). Its electron impact mass spectrum Preparation of 4 from 3 (General procedure). To
showed peaks at m/z (%I): 320 (100, M+·), 319 (6, M- a solution of 3 (10 m mole) in DMF (10 mL) was
1), 287 (9), 214 (54), 183 (31), 187 (19), 156 (41), added the respective thiourea (10 m mole) in DMF
107 (9), 77 (II) . (10 mL). The reaction mixture was stirred at RT for 2
The reaction of 2a (i.e., 2, R=Me) with p-methyl- hr and poured into ice-cold water. The separated solid
phenylthiourea in iso-propanol in the presence of io- was filtered, washed with water, suspended in water
dine under reflux for 3 hr and subsequent processing and neutralized with aq. NaHC0 3 . The product was
932 INDIAN J. CHEM ., SEC B, APRIL 2003

(1)
H2N-CS-NH-
12/ IPA I Ll.

f;l ~ 0
~Nret r(YN~Br
~N N N,-Ar ~N (3)

A~-CS-NH-Ar
( 2)

(S) A~ DMFI / 12/ IPA/.0.

( 4)

Scheme I

Table !- Characteri zati on data for compound 4

Starting Reagent Product Yi eld m.p. Mol. %N

material used obtain ed (% ) °C formul a Fou nd (Ca lcd)

3a H 2NCSNH - 4a, 75 234 C ,RHI 6N4S 17.46

PhCH3 (p) (R=M e, A r = p -MePh) ( 17 .48)
3a H 2NCSNH 2 4az 73 235 C ,,H IO N.S 24. 3 1
(R= M e, A r = H) (24. :'\4)
4 a _~ 74 220 C 17 H 14 N 4S 18.28
(R=Me, A r = C6 H 5 ) ( 18.28)
3a H 2NCSNH- 4a4 75 30 C 17H 13 N 4SCI 16.42
PhCI (p) (R=Me,Ar=p -CIPh) ( 16. 3)
3a H 2NCSNH - 4a5 68 24 1 C 17 H 13 N.SBr 14.53
PhBr (p) (R=Me, Ar=p -BrPh ) ( 14 ..'i4)
3b H 2NCSNH - 4b, 78 190 c, l) H , ~ N -~ s 16.73
PhCH3 (p) (R=Et, A r = p-MePh) ( 16:15)
3b H 2NCSNH 2 4hz 78 170 C ,2H1 2 N-1S 22.90
(R=Et, Ar = H) (22.92)
4b _1 75 160 C, xH1 r,N4S 17.40
(R=Et,Ar=C6 R5) ( 17.42)
3b H2 NCS ..J H- 4b 4 73 250 C 23 H 17 N 4 SCI 15.'74
PhCI (p) (R=Et.Ar=p-CIPh) ( i5.78)
3c H 2NCSNH - 4c 1 76 I 55 C24 H2oN4S 14.1JO
Ph-CH 3 (p ) (R=CH : Ph , Ar = p -M e- Ph ) ( 14.03)
3c H 2NCSN Hz 4c2 62 2 10 C 16HI 4 N4S 19.0 1
(R=CH 2Ph. Ar =H ) ( 19.1)4)
4c3 65 125 C 22 H 1x N 4S 15.1 2
(R=C H"Ph ,Ar=C6 H 5 ) ( 15. 15)
3c H 2NCSNH - 4c 4 61 132 C 22 H 17 N 4SC I 13.82
Ph-CI (p) (R=CH 2Ph , A r = p-Cl-Ph) ( I 3.86)
-------------------------------------------------- - -- - - - - - - - - - - -
 NOTES 933

Table 11-Spectra l c harac te ri st ics of compo und 4

1
Prod uc t I R (KBr) em·' H NMR (CDCI 3) M S m/z (% 1)
(8, ppm)
4a 2 3 150, 3297 (un equa l doublet,
m), 1614 (s, -C=N-), 1528 (vs)
with a shou lder at 1530 (s),
1455 (vw) . 138 1 (s) e tc.
3242 (vs, -N H- str) , 3 11 5 (s harp , 4.2 (t, 3 H, NCH 3), 7.2-7.5 (co mpl ex m, 9 H,
s, -C H- str), 1608 ( m, -C=N-), five phe ny l a nd fo ur ary l protons), 7.55
1524 (vs, with a shoulde r at (s, IH ,=CH-S-). 7.75(broads, IH , -NH- ).
1528), 1458 (vw), 1380 (vs) e tc .
3242 (vs, -NH-str), 3 105 (s harp, 4.22 (t, 3 H, NC H 3), 7.2-7.5 (compl ex m, 8 H,
s, -C H-str), 1605 (m, -C= N-), fo ur p-chlorophenyl a nd four a ry l proto ns),
1523 (vs, with a sho ulde r at 7.57(s,IH , =CH-S -). 7.79(broads, IH , -NH-).
1527), 1455 (vw), 1380 (vs) etc.
3230 (vs, -N H-str), 3 11 0 1.55 (t, 3H , NCH 2C H 3), 2.35 (s, 3H , -C 6H 4 - 335 (2 1, M+l ), 334 (84, M+), 306 (4),
(sha rp , s, -C H-str), 1608 (m, CH3(p)). 4.7-4.9 (q, 2 H, -N-C H2CH3), 7. 1-7.8 301 (24), 229 (80), 228 (100), 2 14 ( 14),
-C=N -), 1520 (vs, w ith a sho ul- (com pl ex m for IOH , fo ur p-methylphenyl and 20 I (39), 175 (34), 170 (76), 169 (37),
der at 1525), 1458 (vw), 1380 four ary l protons o ne -N H & o ne-C H protons). 157 ( 16), 13 1 (25), 11 8 ( 17), 107 (32),
(vs) etc. 9 1 (88), 77 (95), 65 (90).
3240 (vs, -NH- str), 3 11 8 1.55 (t, 3 H, N-CH 2C H 3), 2.37 (s, 3H,
(sharp , s, -C H- str), 1605 (m, -C6 H4C H3(p)), 4.75-4 .92 (q , 2 H, -N-C H2CH3),
-C=N- ). 1527 (vs) wi th a sho ul - 7. 15-7.82 (co mplex m for IOH , four p -c hl oro
der at 1528 (s), 1449 (vw), 1378 phenyl and four ary l protons, one -N H & one
(vs) etc. -C H protons).
3242 (vs, -NH-str), 3 11 5 (s ha rp, 2.35 (s, 3 H, -C 6 HrC H 3(p)),6.1 (s, 2 H, 396 (32, M+ I), 370 ( 16, M+ ), 368 ( 16) ,
s, -C H-str) . 1608 ( m, -C= N- ), -N-C H 2C 6 H 5 ) , 7.0-7.8 (complex m for ISH , 3 10 (24), 290 (25), 232 (39), I 07 (23),
1524 (vs) with a sho ulde r at four p-methylphen y l, fo ur arylproto ns a nd five 9 1 ( I 00), 77 ( II ), 65 (52), 51 (9).
1528 (s), 1458 (vw), 1380 (vs) phenyl o ne- H-a nd one -C H- proton) .
etc.
3244 (vs, -N H-str). 3 120 (s harp , 2 .35 (s. 3 H, -C 6 H4-C H 3(p)). 6. 1(s. 2 H,
s, -C H-s tr) , 1610 (m, -C=N-), CH 2C 6 H 5) , 7.0-7.8 (comp lex m, for ISH , fou r
1527 (vs) with a s houlder at p-chlorophe ny l, four a ryl proto ns and five
1529 (s), 1458 (vw), 1380 (vs) phenyl o ne - NH- and o ne -C H- proton)
e tc.

filtered and dried. The crude 4 thus obta ined was re- CH 3CN (15 mL) was added K 2C03 (0.7 g, 5 m mole)
crystalli zed from etha no l to obtain pure 4 (Tc.ble I ). and the mixture stirred at RT. To thi s, a so luti on of Sa
Preparation of Sa/4a 1 from 1/2a (General pro- ( 1.53 g, 5 m mo le) in CH 3CN (10 mL) was added
cedure). To a so luti on of 1/2a (I 0 m mole) in iso- with stirring followed by the alkyl ating agent (OMS)
propanol (20 mL) was added the p-methyl- (5 m mole) at RT. The mixture was stirred at RT for 3
pheny lthi ourea ( 1.66 g, I 0 m mo le ) and iod ine (2.53 hr and then fiitered. The CH 3CN filtrate was evapo-
g, 12 m mole) in iso-propano l (20 mL). Th e reaction rated to dryness y ielding a residue. The latter was
mixture was refl uxed for -3.5 hr. Th e co nte nts were treated with chloroform (20 mL), washed with water
reduced to half th e vo lume a nd separated so lid and evaporated to dryness y ie lding a second res idue.
(whi ch is the HI sa lt of Sa/4a 1) was filte red, washed The latter on trituratio n w ith hexane and recrysta lli za-
with iso-propan o l a nd dried . Th e so lid thu s o btained ti on from a suitable solvent gave pure 4a 1 (y ield 45 %,
was suspe nded in wa ter (50 mL' and ne utralized m.p. 233° C).
with aq. NaHC0 3 to obtain th e free base. The sepa-
rated co mpound , whi ch is crude Sa/4at was rec ry s- Acknowledgement
tallized from e th ano l to obta in pure Sa/4a 1 (y ie ld of The authors are hi ghl y indebted to UGC (Govt. of
Sa = 51 %, m.p. 170° C , y ield of 4a 1 = 45 %, m.p. Indi a), New Delhi for fin ancial support.
234° C).
Preparation of 4a 1 from Sa.To a so lu tion of References
triethylbenzylammonium c hloride (TEBAC) tn I Benzimidazole and congeneric lricyclic C01nf10unds, Part 2.
934 INDIAN J. CHEM. , SEC 8 , APRIL 2003

Chap.! 0, edited by P N Preston, (Wiley lnterseienee, 2 Dubey P K, Ramanatham J, Ramesh Kumar & Rav i Kum ar C,
New York ), 1980, p531; Preston P N, Ch em Rev, 74, 1974, Indian J Heterocyclic Chem, 9, 2000, 259.
279 ; Grimmett M R, Compreh ensive heterocyclic chemistry. 3 Ramaiah K, Dubey P K, Ramanatha m J, Grosser! J S &
Vol. 5, Chap-4 .08, K T Potts, A R Katrizky & C W Rees, Hooper D L, J Indian Chem Soc, 76, 1999, 140.
(Gene ral Editors) (Perga mon Pr ss, Oxford), 1984. 457; Hof- 4 Dubey P K, Ramanatham J, Ramesh Kumar. Grosser! J S &
man n K, Imida zole and its deri vati ves in th e chemistry of het- Hooper D L, Indian J Ch em, 398, 2000, 867.
erocyclic compounds, Part I (series Ed itor: A wei ssbergers) 5 Ramaiah K, Dubey P K, Ramanatham J, Grossert J S &
(Wiley lnterseienee, New York ), 1953, 247. Hooper D L , Indian J Chem, 388 , 1999, 302.