Pergamon Tetrahedron Letters 39 (1998) 201-204

TETRAHEDRON

LETTERS

Solid Phase Synthesis of 1-Alkyl-2-alkylthio-5-carbamoylbenzimidazoles

Jung Lee,* Diane Gauthier, and Ralph A. Rivero

R.W. Johnson Pharmaceutical Research Institute

Spring House, PA 19447

Received 2 October 1997; revised 22 October 1997; accepted 24 October 1997

Abstract: The preparation of l-alkyl-2-alkylthio-5-carbamoylbenzimidazoles 7 is described. The cyclization of a resin bound o-phenylenediamine 4 with thiocarbonyldiimidazole (TCD) in THF provided a benzimidazole-2-thione 5. Treatment of 5 with benzylic halides in the presence of DIEA resulted in the resin bound l-alkyl-2-alkylthio-5- carbamoylbenzimidazoles 6. The final products were cleaved from the resin and obtained in from 74% to 99% yields. © 1997 Elsevier Science Ltd. All rights reserved.

In the past five years, solid phase synthesis of small organic molecules has emerged as an important

tool in drug discovery, j The synthetic method has helped in both expediting the preparation and increasing the

2 diversity of the molecules. The synthesis has also been used to optimize leads as well as generate them.

Therefore, the development of novel solid phase synthetic methods is an important aspect of the drug discovery

process. Our effort toward this end has been focused on developing solid phase synthesis of a variety of

heterocycles from common building blocks. 3 Herein we report the first solid phase synthesis of 1-alkyl-2-

alkylthio-5-carbamoylbenzimidazoles 7 from readily available starting materials.

Substituted-2-alkyhhiobenzimidazoles 1 represent an important heterocyclic structure in medicinal

chemistry. The 2-alkylthiobenzimidazoles and their corresponding sulfoxides have been shown to be proton-

pump inhibitors, 4 anti-ulcer compounds, 5 and antivirals. 6 Previously we demonstrated that 3,4-disubstituted-7-

carbamoyl-l,2,3,4-tetrahydroquinoxalin-2-ones could be prepared on the solid phase from resin bound o-

phenylenediamines. 3a The o-phenylenediamines were easily prepared from 4-fluoro-3-nitrobenzoic acid

attached to the resin at the carboxyl group. To further take advantage of the chemistry developed, we decided

to prepare the 2-alkylthiobenzimidazoles from resin bound o-phenylenediamines 4.

=2

i

R1

0040-4039/98/$19.00 © 1997 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(97) 10525-1

202

Scheme 1

~ N H2

Rink Amide Resin

O o ii

p

v N i l I

2 3 R1

iii O O

v NH = R1

R1 5 4

O O vi

R1 R1 7

6

(i) 4-F-3-NO2-PhCO~H, HATU, DIEA, DMF; (ii) R,NH:, DMF; (iii) SnCI2°H20, DMF; (iv) TCD, THF; (v) R2CH2Br, DIEA, DMF; (vi) TFA/H~O (95: 5)

The solid phase synthesis of l-alkyl-2-alkylthio-5-carbamoylbenzimidazoles 7 is illustrated in Scheme

1. The resin bound aryl fluoride 2 was prepared from Rink Amide resin, 4-fluoro-3-nitrobenzoic acid, 0-(7-

azabenzotriazol-l-yi)-N,N,N',N'-tetramethyluroniumhexa-fluorophosphate (HATU) and N,N-diisopropylethyl-

amine (DIEA) as before) ~ The fluoride on 2 was displaced with a primary amine to obtain the resin bound o-

nitroaniline 3. The aryl nitro group was then reduced to an aryl amine with SnCI2oH20 in DMF. Once the resin

bound o-phenylenediamine 4 was obtained, a variety of cyclization conditions to benzimidazole-2-thione was

examined. 7 The optimum result was attained when 4 was allowed to react with TCD (10 equiv.) in THF

overnight at room temperature. To verify the extent of cyclization, the thione was cleaved from the resin with a

solution of TFA/H20 (95 : 5). The crude cleavage solution containing 8 was then analyzed by MS, HPLC, and

~H NMR. The analysis indicated that the product was obtained in a quantitative yield, and >95% pure by both

HPLC and ~H NMR. 8

O O

(95: 5) H2 N S I "

I I

R1 R1 5 8

203

Table 1: 1-Alkyl-2-alkylthio-5-carbamoyibenzimidazoles

Entry R, R 2 Yield (%)" Purity (%)b

7a CH2Ph Ph 99 >95

7b CH2Ph 2-Naphthyl 76 84

7c CH2Ph (4-NO2)-Ph 76 >95

7d CH2Ph (4-CO:CH~)-Ph 82 86

7e CH2CH2CH(CH3) 2 Ph 99 91

7f CH2CH2CH(CH3) 2 2-Naphthyl 96 9 l

7g CHzCH2CH(CH3) 2 (4-NO2)-Ph 99 87

7h CH2CH2CH(CH3) 2 (4-CO:CH3)-Ph 84 91

7i CH2-(4-F)-Ph Ph 86 93

7j CH2-(4-F)-Ph 2-Naphthyl 85 82

7k CH2-(4-F)-Ph (4-NO2)-Ph 99 94

71 CH~-(4-F)-Ph (4-CO2CH 3)-Ph 93 90

7m CH2CH2OCH ~ Ph 86 >95

7n CH2CH2OCH 3 2-Naphthyl 96 >95

70 CH2CH2OCH ~ (4-NO 2)-Ph 99 >95

7p CH2CH2OCH 3 (4-CO2CH3)-Ph 74 >95

ayields based on the original loading of the Rink Amide Resin. b Purity of the compounds were based on the integration area on HPLC @220 nm.

To create a second point of diversity, the resin bound benzimidazole-2-thione 5 was treated with

benzylic halides in the presence of DIEA in DMF. Complete alkylations were observed after 16 hrs at room

temperature. The desired products were cleaved from the resins using the standard cleavage conditions. The

products were obtained in 74 - 99 % yields and 82 - >95% purity as shown in Table 1. Upon the alkylation, the

~3C NMR spectrum showed an upfield shift of the C-2 resonance from 172.7 ppm (C=S) of 8 compared to 154.9

ppm (C-S) of 7a. One and two-dimensional NMR experimental results confirmed the S-alkylated product over

the N-alkylated product. 9

In summary, we have demonstrated that 1-alkyl-2-alkylthio-5-carbamoylbenzimidazoles 7 can be

prepared from the resin bound o-phenylenediamine 4. The 2-thiobenzimidazoles were prepared in six steps and

204

74 - 94 % overall yields. In an efficient utilization of the solid phase chemistry developed, we have so far

shown that both quinoxalinones and 2-alkylthiobenzimidazoles could be prepared from the resin bound o-

phenylenediamine 4) 0 Further work expanding the utility of 4 will be reported in due course along with the

biological activity of the molecules.

References

1. (a) Gallop, M.A.; Barrett, R.W.; Dower, W.J.; Fodor, S.P.A.; Gordon, E.M.J. Med. Chem. 1994, 37, 1385-1401. (b) Martin, E.J.; Blaney, J.M.; Siani, M.A.; Spellmeyer, D.C.; Wong, A.K.; Moos, W.H.J. Med. Chem. 1995, 38, 1431- 1436. (c) Choong, I.C.; Ellman J.A. Annu. Rep. Med. Chem. 1996, 31,309-318. (d) Dolle, R.E. Molecular Diveristy 1996, 2, 223-236.

2. (a) Kim, R.M.; Manna, M.; Hutchins, S.M.; Griffin, P.R.; Yates, N.A.; Bemick, A.M.; Chapman, K.T. Proc. Natl. Acad. Sci. (USA) 1996, 93, 10012-10017. (b) Look, G.C.; Schullek, J.R.; Holmes, C.P.; Chinn, J.P.; Gordon, E.M.; Gallop, M.A. Bioorg. Med. Chem. Lett. 1996, 6, 707-712. (c) Wipf, P.; Cunningham, A.; Rich, R.L.; Lazo, J.S. Bioorg. Med. Chem. 1997, 5, 165-177.

3. (a) Lee, J.; Murray, W.V.; Rivero, R.A.J. Org. Chem. 1997, 62, 3874-3879. (b) Matthews, J.; Rivero, R.A.J. Org. Chem. 1997, 62, 6090-6092.

4. Kugishima, H.; Horie, T.; Imafuku, K.J. Heterocyclic Chem. 1994, 31, 1557-1559.

5. Cereda, E.; Turconi, M.; Ezhaya, A.; Bellora, E.; Brambilla, A.; Pagani, F.; Donetti, A. Eur. J. Med. Chem. 1987, 22, 527-537.

6. Salluja, S.; Zou, R.; Drach, J.C.; Townsend, L.B.J. Med. Chem. 1996, 39, 881-891.

7. The cyclization was attempted with thiophosgene, triphosgene, and thiocarbonyldiimidazole using a variety of reaction conditions. Only the reaction with thiocarbonyldiimidazole in THF resulted in a satisfactory cyclization.

8. 8 (R~ = CH2Ph): 'H NMR (300 MHz, CD3OD) 8 7.74 (IH, s), 7.66 (IH, d, J = 8.7 Hz), 7.40 - 7.20 (5H, m), 7.16 (1H, d, J = 8.7 Hz), 5.55 (2H, s); ~3C NMR (75 MHz, CD3OD) 8 172.7, 171.9, 137.3, 136.5, 132.4, 130.3, 129.8, 128.9, 128.7, 123.5, 110.6, 49.2; mass spectrum (ESI) m/z 294.3 (M + IT).

9. 7a (R, = CH2Ph, R 2 = Ph): 'H NMR (300 MHz, CD3OD ) fi 8.25 (1H, s), 7.91 (IH, d, J = 8.7 Hz), 7.59 (1H, d, J = 8.7 Hz), 7.40 - 7.10 (10H, m), 5.50 (2H, s), 4.67 (2H, s); ~3C NMR (75 MHz, CD3OD ) ~ 172.1,154.9, 141.3, 138.7, 137.4, 136.3, 130.6, 130.1, 130.0, 129.9, 129.3, 129.1, 128.9, 128.6, 128.2, 124.4, 117.7, 111.7, 110.5, 49.2, 38.8; mass spectrum (ESI) m/z 374.3 (M + H*). NOE was observed between H7 and Hl l and absent between H4 and H10, indicative of S-alkylation rather than N-alkylation. Furthermore, a three bond connectivity was shown between C8 and HI 1 and absent between C9 and H10 in the heteronuclear multiple bond correlation (HMBC) experiment. If the product 7a was N,N'-dialkylated, a three bond connectivity would have been observed between C9 and HI0.

O II 4 3 10

6 t~.,,.,~8 N 2

10. Previously, another heteroeycle, benzimidazole, has been prepared from o-phenylenediamine on a solid support; see Phillips, G.B.; Wei, G.P. Tetrahedron Lett. l ~ , 37, 4887-4890.