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Synthesis of 2-(2-Thienyl)benzimidazolesby the Reaction of 2-(Mercaptomethyl)benzimidazoleWith β-Electrophilic EstersTamás Kálai a b , Péter Sáska b , Zoltán Szabó c ,József Jek[otilde] c , Olga H. Hankovszky a & KálmánHideg a ba Central Research Laboratory, Chemistry ,University of Pécs , H-7643, Pécs, P.O. Box 99,Hungaryb Chemistry and Biochemistry Department , JanusPannonius University , H-7601, Pécs, Hungaryc Alkaloida Chemical Company Ltd. , H-4440,Tiszavasvári, HungaryPublished online: 22 Aug 2006.

To cite this article: Tamás Kálai , Péter Sáska , Zoltán Szabó , József Jek[otilde] ,Olga H. Hankovszky & Kálmán Hideg (1997) Synthesis of 2-(2-Thienyl)benzimidazolesby the Reaction of 2-(Mercaptomethyl)benzimidazole With β-Electrophilic Esters,Synthetic Communications: An International Journal for Rapid Communication ofSynthetic Organic Chemistry, 27:12, 2041-2050, DOI: 10.1080/00397919708006808

To link to this article: http://dx.doi.org/10.1080/00397919708006808

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SYNTHETIC COMMUNICATIONS, 27( 12). 2041-2050 (1997)

SYNTHESIS OF 2-(2-THIENYL)BENZIMIDMOLES BY THE

REACTION OF 2-(MERCAPTOMETHYL)BENZIMIDMOLE

WITH P-ELECTROPHILIC ESTERS

Tamas Kalai,a,b Peter Saska,b Zoltan Szab6,c Jozsef Jek6,c

Olga H. Hankovszky,a Kalman Hidega>b*

a Central Research Laboratory, Chemistry, University of Pecs, H-7643 Pecs, P.O. Box 99, Hungary

b Chemistry and Biochemistry Department, Janus Pannonius University, H-760 1 Pecs, Hungary

C Alkaloida Chemical Company Ltd., H-4440 Tiszavasvari, Hungary

Abstract: New 2-(2-di- and tetrahydrothieny1)benzimidazole compounds were prepared by the ring closure reactions of 2-(mer~aptornethyl)benzimidazole~~~ (1) and a,P-unsaturated compounds activated with electron-withdrawing groups.

It is known that the reaction of 2-mercaptobenzimidazole with a-haloketones

results the formation of 3-hydroxy-2,3-dihydrothiazolo[3,2-a]benzimidazoles

which exist in an equilibrium with their open-chain aminoketone t au t~mers .~

* To whom correspondence should be addressed

204 1

Copyright 0 1997 by Marcel Dekker, Inc.

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2042 a L A I ET AL.

b

The cyclisation could not be carried out under above conditions in a single step

neither from P-haloketones or a,P-unsaturated ketone^.^ However the ring closure

reaction of 2-(mercaptornethyl)benzimidazole (1) with either P-haloketones or

a,P-unsaturated esters taken place not with imidazole nitrogen but with the

activated methylen group and resulted in the formation of benzimidazolyl

tetrahydr~thiophenes.~.~ Here we report reactions of the three possible

nucleophilic sites of 2-(mercaptomethyl)benzimidazole (1) with alkenes or alkynes

activated by ester, nitril and 0x0 electron-withdrawing groups.

0

H H C 0 2 - p

BivSyPh B i y S , , ,,Ph L B i y s l .,Ph

Ho 5 EtOOC

3 6

l a t H

1

1. 2 4

2 1 R R Q

a I H H COZEt

Scheme 1 Reagents and conditions: (a) 2a, TMG, acetone, reflux, 1 h; (b) 2b, TMG, acetone, reflux, 1 h; (c) NaBH4, EtOH, reflux, 5 h. (d) Pyridine, A g o , reflux, 4 h; (e) 2c, TMG, acetone, reflux, 1 h.

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2-(2-THIENY L)BENZIMIDAZOLES 2043

The conjugate addition of the SH group of 1 with ethyl trans-cinnamate (2a) in

the presence of tetramethylguanidine (TMG) catalyst led to an open chain adduct

(3) and no cyclisation occured. The cyclisation could be achieved with an activated

ester, the N-succinimidyl frum-cinnamate (2b) which could be obtained from

trans-cinnamic acid and N-hydroxy~uccinimide.~ The cyclic enolized ketone (4)

was reduced further with NaE3H4 and gave the tetrahydrothiophene alcohol (5)

which could be dehydrated to dihydrothiophene (6). The same readiness for

conjugate addition and cyclisation reaction was also observed with acetylenic

activated ester, the N-succinimidyl phenylpropiolate (2c) to give dihydrothiophene

derivative (7) which exists in enol form supported by IR and N M R spectra and

which exhibits fluorescence. Compound 1 cyclised with the readily available ethyl

benzylideneacetoacetate8 (2d) to 8 by participation of carbonyl group in the ring

closure. The indicated geometry of tetrasubstituted tetrahydrothiophene (8) was

determinated by NOE measurements. Irradiation of methyl protons resulted

enhancement peaks of 2-CH and 4-CH, while irradiation of 4-CH gave stronger

enhancement of peak in case of 2-CH than in case of 5-CH. Elimination reaction

of compound 8 gave dihydrothiophene (9). The reaction of 1 with ethyl (a-cyano-

P-pheny1)acrylate (2e), obtained conveniently from benzaldehyde and ethyl

cyanoacetate,g can take place on two different ways. Firstly SH could react with

C=C group in 1,Caddition followed by addition of the methylen group (CH2) to

nitrile group, in a Thrope-Ziegler type cyclisation9 or alternatively as we observed,

by 1,2-addition of SH to nitrile group followed by the addition of CH2 group to

the electrophilic P-carbon atom to compound 10 according to MS and lH-NMR

measurements. However the reaction of 1 with activated ester, N-succinimidyl

(a-cyano-P-pheny1)acrylate (20 took place in different way, because the SH group

attacked the P-carbon of the double bond, then the anion of methylene group

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2044 U L A I ET AL.

reacted with the activated ester to give compound 11 in a Dieckmann type of

cyclisation.

9

YPh - B ? i T Y p h

2

NC COzEt HN COzEt

Scheme 2 Reagents and conditions: (a) 2d, TMG, acetone, reflux, 1 h; (b) Ac20, reflux, 2 h, satd. aq. NaHCO3, 4 h; (c) t e , TMG, acetone, reflux, 1 h; (d) 2f, TMG, acetone, reflux, 1 h.

In conclusion, reactions of nucleophilic centres of 2-(mercaptomethyl)benzi-

midazole (1) by chosen activating electron-withdrawing groups of a,P-unsaturated

active esters, ketones and nitriles can be used in designing the synthesis of

polysubstitued 2-benzimidazolyl-2-thiophenes. We hope, these observations will

also be applicable in designing other polysubstitued thiophenes from CH2SH group

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2-(2-THIENY L)BENZIMIDAZOLES 2045

containing compounds and a#-unsaturated compounds activated by electron-

withdrawing groups.

Experimental

Melting points were determined on a Boetius micro melting point apparatus and

are uncorrected. Elemental analyses (C, H, N) were performed on Heraeus Micro

U/E apparatus or (S) analyses were carried out titrimetrically by Schoniger’s

method. IR (Zeiss Specord 75) spectra of the compounds were in each case

consistent with the assigned structures. lH-NMR spectra were recorded on Varian

- Gemini 200 spectrometer using DMSO-d6 as solvent. In NOE measurements

standard Varian NOEDIF sequence was used with a saturation delay of 6 s. Mass

spectra were recorded on a VG TRIO-2 instrument in the EI mode (70 eV, direct

inlet). Flash chromatography was performed on Merck Kieselgel 60 (0.040-0.063

mm). Qualitative TLC was carried out on commercially preparad plates (20 x 20 x

0.02 cm) coated with Merck Kieselgel GF 254. N-succinimidyl esters 2b, 2c, 2f

were prepared from the corresponding carboxylic acids according to literature.’

Ethyl (3-(2-Benzimidazo~l-methylthio)-3-phe~~~propionate (3): The mixture of

1 (1.64 g, 10 mmol), 2a (1.76 g, 10 mmol) and TMG (0.1 mL, 0.8 mrnol) in

anhydr. acetone (25 d) was refluxed till the reaction was complete, monitoring

the reaction by TLC (CHCI3Et20, 2/1). After cooling, the precipitated crystals

were filtered, washed with water (15 mL), Et2O (5 mL) and dried at r.t. to give 3

as off-white crystals; yield: 2.66 g (78%); Rf 0.38 (Et20KHC13, 2/1); mp 154-

156°C; Anal. calcd. for C19H20N202S (340.44); C 67.03; H 5.95; N 8.27;

S 9.47; Found: C 66.92; H 5.82; N 8.33; S 9.60 %. IR : 1725, 1580 cm-1. 1H-

NMR (6 / ppm): 0.95 (t, J=8.5, 3H), 2.95 (9, 2H), 3.6-4.0 (m, 4H), 4.38 (dd,

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2046 ~ L A I ET AL.

J1=7.5, J ~ ~ 7 . 5 , lH), 7.15 (m, 2H), 7.2-7.5 (m, SH), 7.55 (m, 2H), 12.3 (broad,

1H). MS m/z (%): 340 (M+*, I), 295 (2), 163 (1 l), 132 (100).

General procediire for yiiihesis of 2-(2-ihienyl)benzimidazole derivatives (4, 7 , 8,

10, 11): Mixture of 1 (1.64 g, 10 mmol), and 2 (10 mmol) and TMG (0.1 mL, 0.8

mmol) in anhydr. acetone (40 mL) was refluxed for 1 h. After cooling to r.t. the

precipitated crystals were filtered off, washed with Et20 (10 mL).

b(3-Hydroxy-5-phenyl-4, 5-dihydro-2-thienyl) benzimidazole (4) :

Compound 4 7.0 g (79 YO) was obtained from 1 (4.92 g, 30 mmol), and 2b (7.35

g, 30 mmol). Rf 0.55 (CHCkjMeOH, 9/1); mp 203-205 "C; Anal. calcd. for

C17H14N20S (294.37); C 69.36; H 4.79; N 9.52; S 10.89; Found: C 69.40; H

4.82; N 9.43; S 10.81 %. IR : 1580 cm-l. 1H-NMR (6 / ppm): 3.35 (dd, J1=17.5,

Jz=11.5, lH), 3.60 (dd, J1=17.5, Jz=8.5, lH), 5.17 (dd, lH), 7.2-7.6 (m, 9H). MS

m/z (%): 294 (M", 60), 261 (8), 235 (7), 162 (100).

2-(3-Hydroxy&pheny1-2-ihienyl) benzimidnrole (7):

Mixture of 1 (1.64 g, 10 mmol) and active ester 2c (2.43 g, 10 mmol) gave

800 mg (27 %) compound 7, Rf 0.6 (CHC13/MeOH, 9/1); mp 157-160 "C; Anal.

calcd. for C17H12N20S (292.36); C 69.84; H 4.14; N 9.58; S 10.97;

Found: C 69.91; H 4.25; N 9.62; S 11.10. IR: 1620, 1580 cm-1. lH-NMR (6 I

ppm): 7.18 (m, 2H), 7.28 (s, lH), 7.3-7.6 (m, SH), 7.70 (m, 2H). MS m/z (YO): 292

(M+*, l), 173 (12), 129 (52), 105 (100).

2-(3-Hydroxy-3-meihyl-4-carbeihoxy-5-phenyl-2~ 3,4,5-tetrahydro-2-thienyl) ben-

rimidmole (8): Compound 8 2.46 g (32 %) was obtained from 1 (3.28 g, 20 mmol)

and 2d (4.36 g, 20 mmol). Rf0.46 (CHC13Et20, 211); mp 192-194 "C. Anal. calcd

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2-(2-THIENY L)BENZIMIDAZOLES 2047

for C21H22N203S (382.48); C 65.95; H 5.80; N 7.32; S 8.38; Found: C 65.98; H

5.92; N 7.40; S 8.50. IR: 3200, 1730, 1590 cm-l. lH-NMR (6 / ppm): 1.09 (t, J=8.5,

3H), 1.46 (s, 3H), 3.53 (d, J=11.4, lH), 4.00 (q, 2H), 5.2 (s, lH), 5.26 (d, lH), 5.77

(s, lH), 7.15 (m, 2H), 7.2-7.4 (m, 3H), 7.5-7.6 (m, 4H), 12.2 (broad, 1H). MS m/z

(%): 382 @I+*, l l ) , 291 (14), 163 (83), 131 (100).

2-(3-Phenyl-l-carbethoxy-5-amino-2,3-dihydro-2-thienyl) benzimidazole (1 0):

Compound 10 1.53 g (21 %) was obtained from 1 (3.28 g, 20 mmol) and 2e (4.02

g, 20 mmol). Rf 0.59 (CHC13/MeOH, 9/1) mp 238-239 "C. Anal. calcd. for

C20H19N302S (365.45); C 65.73; H 5.24; N 11.50; S 8.77; Found: C 65.92; H

5.33; N 11.43; S 8.80. IR: 3380, 3260, 1640, 1590 cm-l. lH-NMR (6 / pprn):

0.95 (t, J=8.5, 3H), 3.90 (q, 2H), 4.74 (d, J=8.0, lH), 5.76 (d, lH), 6.9-7.1 (m,

SH), 7.15 (m, 2H), 7.35 (m, 2H), 7.70 (s, 2H), 12.2 (broad, 1H) MS m/z (%): 365

(M", 8), 332 (83), 286 (37), 164 (100).

2- (3-Hydroxy-4-cyano-5-phenyl-4,5-dihydro-2-rhienyZ)benzimidazoZe (1 1) :

Compound 11 1.55 g (24 %) was obtained from 1 (3.28 g, 20 mmol) and 2f

(5.08 g, 20 mmol). Rf 0.71 (CHC13/MeOH, 2/1) mp 272-274 "C (dec). Anal.

calcd. for C18H13N30S (319.38); C 67.69; H 4.10; N 13.16; S 10.04; C

67.81; H 4.20; N 13.02; S 10.16. IR: 3240, 2215, 1625, 1595 cm-l. lH-NMR

(6 / ppm): 4.69 (d, J=12.0, lH), 5.10 (d, lH), 7.1-7.2 (m, 2H), 7.2-7.5 (m,

3H), 7.5-7.6 (m, 4H), 12.0 (broad, 1H). MS m/z (%): 319 (M+*, 281,287 (23).

210 (23), 162 (100).

2-(3-Hydroxy-5-phenyl-2,3,4,5-tetrahydro-2-thienyl)benzimidazole (5) :

Compound 4 (6.00 g, 20 mmol) was dissolved in EtOH (50 mL) and NaBH4 (4.53

g, 0.12 mol) was added at 0 "C. The mixture was stirred and refluxed for 5 h , then

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2048 d L A I ET AL.

allowed to stand for overnight. Water (50 mL) was added to the solution to afford 5

as white precipitate, which was filtered off, washed with water (40 mL) and Et2O

(20 mL). The mother liquor was concentrated in vacuo and the residue was allowed

to stand overnight to give a second crop of 5. Yield: 5.16 g (87 %); Rf 0.51

(CHC13/MeOH, 9/1); mp 214-216 "C. Anal. calcd. for C17H16N20S (296.39); C

68.89; H 5.44; N 9.45; S 10.82; Found C 68.83; H 5.36; N 9.60; S 11.00. IR:

1580 cm-1. lH-NMR@/ppm): 2.27 (ddd, J1=12.2, J2=11.2, J3=10.5, lH), 2.69

(ddd, JI=12.2, J2=6.8, J3=5.2, lH), 4.7 (d, J=7.9, lH), 4.80 (dd,lH), 4.91 (m,

lH), 5.80 (broad, lH), 7.15 (m, 2H), 7.2-7.4 (m, 3H), 7.4-7.6 (m, 4H). MS m/z

(%): 296 (M+., 151,237 (8), 161 (100).

2-(5-Phenyl-4,5-dihydro-2-thienyl)bcnzimidazole (6):

To a solution of 5 (2.96 g, 10 mmol) in anhydr. pyridine (15 mL) acetic anhydride

(3.06 g, 30 mmol) was added and the mixture was refluxed for 4 h. The mixture

was poured onto crushed ice (300 g), the precipitated yellow crystals were filtered

off, dried at r.t. and recrystallised from EtOH to obtain the title compound 6, 1.86

g (67 %); Rf 0.6 (CHC13/Et20, 2/1); mp 195-198 "C. Anal. calcd. for

C17H14N2S (278.37); C 73.35; H 5.07; N 10.06; S 11.52. Found: C 73.42; H

5.10; N 10.25; S 11.70. IR: 1620, 1580 cm-1. lH-NMR (6 / ppm): 3.15 (ddd,

J1=17.9, J2=7.4, J3=3.2, lH), 3.47 (ddd, J 1 ~ 1 7 . 9 , J2~9 .5 , J3=3.3, lH), 5.13

(dd,lH), 6.56 (dd, lH), 7.20 (m, 2H), 7.2-7.4 (m, 3H), 7.4-7.6 (m, 4H). MS m/z

(%): 278 (M+', 93), 245 (22), 201 (100).

2-(3-Methyl-4-carbethoxy-5-phenyl-4.5-dihydro-2-thienyl)be~imidazole (9) :

Compound 7 (3.82 g, 10 mmol) was suspended in acetic anhydride (30 mL),

stirred and refluxed for 2 h then poured onto crushed ice (200 g). The precipitated

solid was filtered, dissolved in CHC13 (30 mL) and vigorously stirred for 3-4 h at r.

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2-(2-THIENY L)BENZIMIDAZOLES 2049

t. with saturated NaHCO3 (30 mL) solution to remove N-acetyl group. The organic

layer was separated, dried (MgS04), filtered and evaporated in vacuo. The residue

was purified by flash chromatography (CHC13 / Et20) to give 2.62 g (72%) 8; Rf

0.29 (hexane/EtOAc, 2/1) mp 136-138 "C. Anal. calcd. for C ~ ~ H ~ J N ~ @ S

(364.46) C 69.21; H 5.53; N 7.69; S 8.80; Found: C 69.09; H 5.65; N 7.83; S

8.90. IR: 1725, 1640, 1590 cm-l. IH-NMR (6 / ppm): 0.85 (t, J=7.5, 3H), 2.22

(s, 3H), 4.00 (9, 2H), 5.53 (d, J=4.6, lH), 6.10 (d, lH), 7.1-7.6 (m, 9H). MS

m/z (96): 364 (M+*, 16), 291 (13), 163 (14), 132 (100).

Acknowledgement: This work was supported by grants from the Hungarian

National Research Foundation (TO1 7842) and the Ministry of Public Education and

Culture (MKM 46/94). The authors wish to express their thankr to M. J . Lovas, B.

Rozsnyai for technical assistance, and to J. Ott for microanalyses.

References

1.

2.

Franzen, H.; Furst, B. Annalen, 1916, 412, 28.

For a review of benzimidazoles see: Preston, P. N. "Benzimidazoles and

Congeneric Tricyclic Compounds," Vol. 1-2; Wiley, New York, 1981.

Alper, H.; Lipshutz, B. H. J. Org. Chem., 1973,38, 3742.

Hankovszky, H. 0.; Hideg, K. Acta Chim. Acad. Sci. Hung., 1970, 63, 447.

Hankovszky, H. 0.; Hideg, K.; Lex, L.; Foldesi, A.; Sohk, P. J. Chem.

SOC. Perkin 1, 1980, 699.

SohAr, P.; MAnyai, Gy.; Hideg, K.; Hankovszky, H. 0.; Lex, L. Org.

Magn. Reson., 1980, 14, 125.

Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. J. Am. Chem. Soc..

1964, 86, 1839.

3.

4.

5.

6.

7.

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2050 KALAI ET AL.

8. Jones, G . Organic Reactions, 1st ed., Vol. 15, Wiley, New York, 1967; pp

204-599.

9. Schaefer, J. P.; Bloomfield, J. J. Organic Reacfiom, 1st ed., Vol. 15, Wiley,

New York, 1967; pp 1-203.

(Received in The Netherlands 23 January 1997)

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