A convenient procedure for the N-alkylation of compounds containing multiple benzimidazole functionalities

Tetrahedron Letters,Vol.29,No.25,pp Printed in Great Britain

3033-3036,1988

0040-4039/88 $3.00 + .OO Peryamon Press plc

A CONVENIENT PROCEDURE FOR THE N-ALKYLATION OF COMPOUNDS CONTAINING MULTIPLE BENZIMIDAZOLE FUNCTIONALITIES David R Chapman and Christopher A. Reed* Department of Chemistry University of Southern California Los Angeles, California 90089-0744

SUWSY:

A facile and efficient method for the N-alkylaticn of ligand systenm containing mul-

tiple benzimidazole groups has been developed, involving a basic media of pcwdered RI=Hin dimathylsulfoxide andalkylhalides

as alkylatiny agents.

In the course of our work an the synthesis of binucleatiny liyands for bidtic

studies on

dinuclear copper proteins' we have found a need to N-alkylate a variety of ligands containing up to four 2-substituted banzimidazole groups (1).

Although several efficient methods have been reported for the N-alkylation of simple benzimidazoles,2-4 we have found that these methods are generally unsuitable for the alkylation of our sore ccqlex systems because of (a) poor solubility of the starting materials in the solvents ccsmonly used, (b) incomplete alkylation, despite the use of excess alkylatiny agent, and subsequent

separation difficulties, and (c) overreaction to formquatemary

at the elevated temperatures often required.5,6 This probablyexplainswhy

aratrniumsalts

there are several

reports of nnilti-benzimidazole ligands' but only sporadic exarqles of successful alkylation. Mathylation in 77% yield of the tetra-benzimidazole1 with Y = -CH2CH2- has been reported8 usinypowdered~

in acetone andethylaticn oflwith

Y=

-CH2CH(CH)CH2- in basictetrahy-

1 drofuran proceeds in 83% yield. powdered KC&iin dimathylsulfoxidehas been shown tobe a successfulmsdium for the Nalkylation of a variety of functicr& groups' including indoles and pyrro1es.l' Alkyl halides aretheallqlating

agents. We have foundthatthis

procedwe canbeadaptedtoaran~of

tetrabenzimidazoleliyands (Table I) using a variety of al.&1 halides (Table II):

3033

3034

BE reactionis extrmly

facile,king ccmpletewithin 1 hr at room temperature, and no

slpcialprecauticmsare nesdedtoensure drynessof the reagents. Wderatetoexcellentisolated yieldswere consistentlyobtainedobviatingthe need for yield optimization.me yields and sccpe of the reactioninvestigated to date are listedin the followingtables. In additicm,me l&and systemwith 5,6-~~y~z~~zoles mathylatedin 64% yield. We expect the n&h&

Table

(Y = ~C6H4~2-)

will have wide generality.

I. IGIWL- andEZXYLWIONOF TEIT(ABENzIMIDAzms Y

Rx

II

42-0

Yield (%)

Me1

63

EXI

40

MI

44

Me1

72

Et1

50

Me1

68

p-i II

@

has been

3035

Table II. ALKYT_ATIoNOF1wHEREY=-CH2CH2-

Rx

Yield (%)

Me1

81

EXI

92

n-PrBr

100

n-BuBr

93

cH2=cHcH2Br

86

BZBr

87

TYPICALPRCmxJm lb a stirred suspension of powdered K(xI (1.2 g, 19 ml) benztidazole

(1.6 ml)

follmed inmsdiately by ethyl

reactionwas stirred.atroamtemp.

forlhrand

in ENSO (30 Ki.)was added the

iodide (1.4 g, 9.6 mml).

thenpoured intowater

(80 ml).

Ihe 'Iheresul-

tantflccculantprecipitatewas

extractedinto chloroform (3 x 80ml) andthe cmGnedorganic

extractswerewashadwithwater

(5 x 4Oml) toremvethebulkofthem,

dried (Mgso4),

and the solvent remxed under reduced pressure. The residue was titmatedwitham armmtofacetone

and the product collectedby filtrationandvacuumdried.

Productswere

characterized by 'H i%lRand ISINS.

1.

V. WKee, M. Zvagulis, J. V. Dagdigian, M. A. Patch & C. A. Reed, J. Am. Chm. (1984).

2. A. F. Pozharski & A. M. Shmov,

J. Gen. C&m.

(USSR), 33, 172, (1963).

3.

S. Trofimnko, J. Am. Chein.Sm.,

4.

Y. Kikugawa, Synthetic Canmn., 124, (1981).

5.

L. J. Mathias & D. Burkett, Tetiahedxon I.&t., 4709, (1979).

92, 5118, (1970).

6. M. Haring, Helv. Chim. Acrta,42, 1845, (1959).

Sot., 106,

3036

7.

See for exanple M. Suzuki & A. Uehara, Inorg. Chim. Acta, 87, L29, (1984); Y. Nishida, K. Takahshi, H. Kuramto & S. Kida, Inorg.Chim. Acta, 54, L103, (1981); L. K. ?hcmpson, B. S. Rimaswang & R. D. Da=,

8.

Can. J. C&m.,

56, 1311, (1978).

H. M. J. Hendriks, P. J. M. W. L. Birker, J. van Rijn, G. C. Verschxx & J. Reedijk, 3. Am. c&em. Sot., 104, 3607, (1982).

9.

R. A. W. Johnston@ & M. E. mse,

Tetrahedron, 35, 2169, (1979).

10. H. Heaney & S. V. Levy, J. Chem. See., Chem. Camun., 499, (1973). m.

This wxk

was suppxted by the National Institutes of Health (DK30801 to

C.A.R.) with rfassspectra obtained at the Bio-organic, BiomzdicalMass SpactnmetryF&saure of U.C. San F'rancisco(RRO1614).

(Received

in USA 21 December

1987)