Synthesis of N-alkoxy-substituted 2H-benzimidazoles

Abstract

Treatment of 2-nitro-N-(2-methyl-1-propen-1-yl)benzenamines with potassium tert-butoxide in tert-butanol followed by the addition of an electrophile affords N-alkoxy-2H-benzimidazoles. Electrophiles including methyl iodide, allylic bromides, propargylic bromides, benzyl bromide, and acetyl chloride gave good to excellent yields of product while 1-iodo- and 2-iodo-butane afforded very low yields.

Graphical Abstract

1. Introduction

N-alkoxy- and N-hydroxy-benzimidazoles have been shown to exhibit a number of biological activities such as, acting as a growth inhibitor of Lactobacillus leichmanii¹ and influenza virus,² inhibition of bacterial transcriptase factors,³ and anti-HIV-1 activity.⁴ Only two general methods for the preparation of N-alkoxybenzimidazoles can be found in the literature. The first method involves a direct alkylation of N-hydroxybenzimidazole, or its tautomer 1H-benzimidazole-3-oxide, and this procedure has been used to prepare, for example, N-methoxy, N-ethoxy and N-allyloxybenzimidazole.⁵ The second method reported by Gardiner et al is perhaps the most versatile synthesis of N-alkoxybenzimidazoles and it involves a base-mediated reaction of 2-nitroanilines in the presence of an alkyl halide (Scheme 1).⁶ A potential drawback is the formation of mixtures of N-alkylated anilines and N-alkoxybenzimidazoles observed in many cases. In addition, only a single case of an N-alkoxy-2H-benzimidazole was described.

Scheme 1.

Gardiner et al synthesis of 1-methoxy-4-methylbenzimidazole.

We have recently developed a base-mediated cyclization-alkylation of 2-nitroaniline-derived enamines to afford N-alkoxy-substituted benzimidazoles having an oxygenate side chain in the 2-position.⁷ By simply changing the amount of base and electrophile used, either a hydroxy or an alkoxy substituent could be introduced on the side chain. For example, treatment of enamine 1 with 2.0 equivalents of sodium hydride (NaH) in DMSO at ambient temperature followed by addition of 1.05 equivalents of methyl iodide (MeI) gave after purification N-methoxybenzimidazole 2 (Scheme 2). When the amounts of both NaH and MeI were increased to 3.15 equivalents, N-methoxybenzimidazole 3 was isolated in good yield. In both reactions a very minor amount of N-methoxy-2H-benzimidazole 4 was either isolated or observed in the crude reaction mixture. While optimizing the reaction conditions for a divergent synthesis of either 2 or 3, we found conditions wherein 4 was selectively formed (Scheme 2). Thus, reaction of 1 with potassium tert-butoxide in tert-butanol for 24 h followed by addition of methyl iodide gave 4 in 76% yield after chromatographic purification.

Scheme 2.

Cyclization of enamine 1 to give either N-methoxybenzimidazole 2 or 3.

Herein we report the scope and limitations of the formation of N-alkoxy-2H-benzimidazoles from reactions of enamines, derived from condensation of 2-nitroanilines with α-branched aldehydes, with reactive carbon-centered electrophiles.

2. Results and Discussion

Fifteen enamines (1, 5–18, Table 1) were prepared via condensation of 4- and 5-substututed 2-nitroanilines with 2-methylpropanal, 2-phenylpropanal, 2-cyclohexylethanal, and 2,2-diphenylethanal in the presence of 4 Å molecular sieves, as previously described.⁷ The base-mediated transformation of enamines to afford N-alkoxy-2H-benzimidazoles is limited by the availability of the starting material. It should be noted that we were unable to prepare enamines in synthetically useful yields from 3- or 6-substituted 2-nitroanilines even under more forced reaction conditions.

Table 1.

Formation of N-methoxybenzimidazoles from 2-nitro-N-(2-methyl-1-propen-1-yl)benzenamines and methyl iodide.

Entry	Enaminea	Methoxybenzimidazoleb
1	5 (R=H)	19 (100%)
2	1 (R=4-OMe)	4 (76%)
3	6 (R=4-Me)	20 (76%)
4	7 (R=4-Cl)	21 (92%)
5	8 (R=4-Br)	22 (85%)
6	9 (R=4-F)	23 (67%)
7	10 (R=4-CO2Me)	(not observed)
8	10c	24 (74%)
9	11 (R=4-NO2)	(not observed)
10	12 (R=5-OMe)	25 (85%)
11	13 (R=5-Me)	26 (71%)
12	14 (R=5-Cl)	27 (71%)
13	15 (R=5-Br)	28 (73%)
14	16	22 (94%)
15	17	4 (76%)
16	18	4 (78%)d

^aA solution of the enamine in tert-BuOH was treated with tert-BuOK (4 equiv.) stirred for 24 h then treated with MeI (3 equiv.)

^bIsolated yield of pure product after chromatography on silica gel.

^cA solution of 10 in DMSO was treated with NaH (5 equiv.) stirred for 24 h then treated with MeI (5 equiv.) as described in reference 7.

^dBenzophenone was also isolated in 97% yield.

All enamines were treated with tert-BuOK in tert-BuOH followed by the addition of MeI under the reaction conditions depicted in Scheme 2. The expected cyclization-alkylation products, N-methoxy-2H-benzimidazoles, were obtained in all but one case in 51–100% isolated yield. Cyclization-alkylation of both enamines having an electron-withdrawing ester (10) or nitro (11) group failed under the standard reaction conditions (entries 7 and 9). However, the ester-substituted enamine 10 was transformed to the corresponding N-methoxy-2H-benzimidazoles 24 in god isolated yield using sodium hydride – MeI in dimethylsulfoxide as described previously. No conditions were found for the cyclization of 11, neither the starting material nor any identifiable product was isolated.

The scope and limitation of the electrophile was examined next using enamine 1 as the substrate and the results are summarized in Table 2. For all entries in Table 2, 1 was treated with potassium tert-butoxide for 24 h followed by the addition of an electrophile. High yields of N-alkoxy-2H-benzimidazoles were obtained using benzyl bromide, allyl bromide and 2-methyl-3-bromopropene affording 29–31, respectively (entries 1–3). A 54% yield of N-acetoxy-2H-benzimidazole (34) was obtained using acetyl chloride while heptyl bromide, butyl iodide and 2-iodopropane gave cyclization products in low isolated yields. The two propargylic bromides employed in entries 4–5, 3-bromo-1-propyne and 3-bromo-1-butyne, afforded allenes by an S_N2′ reaction albeit, in low yields (entries 4–5). Based on the results shown in Tables 1–2, synthetically useful yields are obtained only from reactions of highly reactive alkylating reagents such as methyl iodide, benzyl bromide, and allylic bromides. Our observations parallels Gardiner’s results where lower yields of product were isolated from reactions with hindered and less reactive electrophiles such as 2-methyl-1-iodopropane compared to primary iodides, benzylic bromides, allyl bromide.⁶

Table 2.

Base mediated formation of N-alkoxy-2H-benzimidazoles from enamine 1.

Entry	Enaminea	Electrophile	Benzimidazoleb
1	1	Benzyl bromide	29 (82%)
2		Allyl bromide	30 (100%)
3		2-Methyl-3-bromopropene	31 (90%)
4		3-Bromo-1-propyne	32 (15%, R=-CH=C=CH2)
5		3-Bromo-1-butyne	33 (12%, R=-CH=C=CHCH3)
6		Acetyl chloride	34 (54%)
7		1-Bromoheptane	35 (16%)
8		1-Iodobutane	36 (15%)
9		2-Iodopropane	37 (8%)

^aA solution of the enamine in t-BuOH was treated with t-BuOK (4 equiv.), stirred for 24 h then treated with an electrophile (3 equiv.)

^bIsolated yield of pure product after chromatography on silica gel.

The transformation presented above affording N-alkoxy-2H-benzimidazoles can mechanistically be rationalized as follows. Deprotonation of 5 would afford 38, one of several possible resonance forms (Scheme 3). 1,7-Electrocyclization of 38 would furnish 39, followed by a ring opening to form the nitroso-imine 40. The two latter steps results in an overall intramolecular reduction – oxidation. 1,5-Electrocyclization of 40 to give 41 is plausible based on literature precedence.⁸ Aromatization of intermediate 41 via loss of acetone would furnish anion 42 which can finally be alkylated to give an N-alkoxy-2H-benzimidazole 43. The mechanism outlined in Scheme 3 is supported by a limited number of related transformations described in the literature.^9,10,11 Based on the mechanism outlined, not only is an N-alkoxy-2H-benzimidazole formed but also acetone as a biproduct. While acetone (entries 1–13), acetophenone (entry 14), or cyclohexanone (entry 15) were not isolated from the reactions depicted in Table 1, an almost quantitative yield of benzophenone was obtained from 19 (entry 16). Neither of the three former byproducts were recovered after chromatographic purification. This is probably due to evaporative loss upon removal of solvents.

Scheme 3.

Proposed mechanism for the formation of N-alkoxy-2H-benzimidazoles.

Summary

N-Alkoxy-2H-benzimidazoles can be prepared from enamines derived from condensation of 4- or 5-substituted 2-nitroanilines and α-branched aliphatic aldehydes via a base mediated cyclization-alkylation sequence using potassium tert-butoxide and a reactive electrophile.

Research highlights.

• A synthetic methodology to N-alkoxy-2H-benzimidazoles was developed.

• Enamines derived from condensation of 2-nitroanilines and aliphatic aldehydes were cyclized under basic conditions were used as starting materials.

• The alkoxy-group could be varied by the use of different reactive organic halides.