Selectivity control during the solid supported protic acids catalysed synthesis of 1,2-disubstituted benzimidazoles and mechanistic insight to rationalize selectivity

Abstract

Selectivity control during the formation of 1,2-disubstituted benzimidazoles has been achieved for the reaction of o-phenylenediamine with aldehydes in the presence of solid supported protic acids as catalysts and choosing an appropriate reaction medium. Perchloric acid adsorbed on silica-gel (HClO₄–SiO₂) was found to be the most effective catalyst system for the synthesis of 1,2-disubstituted benzimidazoles in EtOH at rt. Apart from the catalyst and solvent, the electronic and steric factors of the aldehyde and the electronic factor of the o-phenylenediamine are also significant contributory factors in dictating the selectivity. An understanding of the mechanistic course of the formation of the 1,2-disubstituted benzimidazoles has been outlined that would rationalise the origin of selectivity control under the set experimental parameters.

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Introduction

In view of the role of the 1,2-disubstituted benzimidazole scaffold as a versatile pharmacophore for the generation of new chemical entities in diverse therapeutic areas,¹ the formation of these privileged class of compounds has generated interest to develop newer synthetic methods.

The various synthetic strategies (Scheme 1) adopted for the generation of this heterocyclic framework can be summarized by the following distinct routes: (i) cyclodehydration of N-alkyl-N-acyl-o-phenylenediamine (route A),^1h,1i (ii) oxidative cyclocondensation of N-alkyl-o-phenylenediamine with aldehyde^1h,2 (route B), (iii) N-alkylation of 2-substituted benzimidazole^1b,d,g,k (route C), (iv) Suzuki coupling of aryl boronic acids with 1-iodo-2-alkyl benzimidazoles³ (route D), (v) copper-catalyzed amidation of o-halo N-alkylated anilines followed by cyclodehydration of the intermediately formed N-alkyl-N-acyl o-phenylenediamine⁴ (route E), (vi) copper/palladium-catalyzed amination of o-halo N-acylated anilines followed by cyclodehydration of the intermediately formed N-alkyl-N-acyl o-phenylenediamine⁵ (route F), (vii) palladium-catalysed intramolecular aryl-amination of (o-bromo/iodophenyl)amidines⁶ or bis(trifluoroacetoxy)iodobenzene mediated intramolecular cyclisation of N-alkyl-N′-arylamidines⁷ (route G). While the Buchwald and Suzuki chemistries (routes D–G) are used quite often by medicinal chemists, they require special efforts to prepare the desired starting materials.

Scheme 1 Synthetic strategies for the formation of 1,2-disubstituted benzimidazoles.

Thus, a direct one-pot cyclocondensation of o-phenylenediamine with aldehydes (route H, Scheme 1) to prepare 1,2-disubstituted⁸ benzimidazoles appears to be a straightforward approach and has received unabated attention from organic/medicinal chemists for the generation of new hits/leads for potential therapeutic applications that require a convenient, selective and high yielding synthetic method to meet the needs of the timely supply of designed molecules for biological evaluation.⁹

However, the synthetic design following route H poses a potential selectivity problem due to the possibility of competitive formation of the 1,2-disubstituted and the 2-substituted benzimidazoles, an issue that remains inadequately addressed so far. The present work aims to control the selectivity in the formation of 1,2-disubstituted benzimidazoles during the cyclocondensation of o-phenylenediamines with aldehydes and offer a mechanistic understanding that would rationalise the selectivity control.

In view of the considerable awareness that has been generated for chemical processes on solid surfaces¹⁰ and the implication of heterogeneous catalysts (solid acids) in devising greener synthetic processes/methods,¹¹ we describe herein a convenient and highly selective synthesis of 1,2-disubstituted benzimidazoles catalysed by solid acids such as HClO₄–SiO₂.¹²

Results and discussion

In a model study (Scheme 2), the cyclocondensation of o-phenylenediamine (1a) with two molar equivalents of 4-dimethylaminobenzaldehyde (2a) was performed separately in the presence of various catalyst systems. The use of HClO₄–SiO₂ (0.5 mol%) as the heterogeneous catalyst in EtOH at rt (25–30 °C) resulted in the formation of the desired 1,2-disubstituted benzimidazole 1-(4-N,N-dimethylaminophenylmethyl)-2-(4-N,N-dimethylphenyl)benzimidazole (3a) in 90% yield (Table 1).

Scheme 2 Selectivity of the formation of the 1,2-disubstituted benzimidazole 3a and the 2-substituted benzimidazole 4a during the reaction of 1a with 2a in the presence of various catalyst systems.

Table 1 The selectivity of the formation of 3a and 4a during the reaction of 1a with 2a (Scheme 2) in the presence of HClO₄–SiO₂ and various reported catalysts^a

Entry	Catalyst (mol%)	Time (h)	Yield (%)^b^,^c		Lit ref.
			3a	4a
a 1a (2.5 mmol) was treated with 2a (5 mmol, 2 equiv.) in the presence of the catalyst (except for entries 1 and 2) in EtOH (5 mL) (except for entries 1, 5, 8, 11, 12, 13, 14, 15, 16 and 17.) at rt (∼25–30 °C).b The isolated yield of 3a and 4a obtained after column chromatographic purification.c The products were characterised by NMR (^1H and ^13C) and MS (APCI).d The reaction was carried out at 130 °C (oil bath) under neat conditions in the absence of any catalyst.e The products 3a and 4a were obtained in 27 and 20% yield, respectively, on performing the reaction for 4 h.f The reaction was carried out at rt in EtOH in the absence of any catalyst.g The products 3a and 4a were obtained in 30 and 20% yield, respectively, on performing the reaction for 4 h.h A 10% w/w of the catalyst was used.i The reaction was carried out under microwave heating (600 W output) in a domestic microwave oven under neat conditions.j The products 3a and 4a were obtained in 65 and 25% yield, respectively, on performing the reaction for 1.5 h.k The products 3a and 4a were obtained in 75 and 15% yield, respectively, on performing the reaction for 7 h.l The reaction was carried out in CHCl3 instead of EtOH.m The products 3a and 4a were obtained in 70 and 18% yield, respectively, on performing the reaction for 7.5 h following a reported^9q procedure.n The reaction was carried out at rt under neat conditions.o The products 3a and 4a were obtained in 50 and 20% yield, respectively, on performing the reaction for 4 h at rt under neat conditions.p The reaction was carried out under neat conditions at 80 °C.q The reaction was carried out in water at 80 °C.r The products 3a and 4a were obtained in 65 and 20% yield, respectively, on performing the reaction for 3 h in water at 80 °C.s The reaction was carried out at rt.t The products 3a and 4a were obtained in 66 and 22% yield, respectively, on performing the reaction for 2 h at rt.u The products 3a and 4a were obtained in 73 and 10% yield, respectively, on performing the reaction for 5 h at rt.v The reaction was carried out in water at rt.w The products 3a and 4a were obtained in 72 and 16% yield, respectively, on performing the reaction in water at rt for 5 h.
1	none^d	1	trace	traces	this work^e
2	none^f	1	trace	traces	this work^g
3	HClO4–SiO2 (0.5)	1	90	00	this work
4	montmorillonite K-10 (10)^h	1	12	07	this work using the reported catalyst^8s
5	montmorillonite K-10 (10)^h	4	42	22	this work using reported catalyst^8s for the time reported therein
6	montmorillonite K-10 (10)^h^,^i	10 min	80	10	8s
7	H2SO4–SiO2 (10)	1	37	15	this work using the reported catalyst^j^8b
8	L-Proline (10)	1	15	traces	this work using the reported catalyst^k^8q
9	L-Proline (10)^l	1	12	traces	8q^m
10	oxalic acid (10)	1	26	traces	this work using the reported catalyst^8d
11	oxalic acid (10)	3	70	14	this work using reported catalyst^8d for the time reported therein
12	Fe(ClO4)3 (10)	1	25	traces	this work using the reported catalyst^8e
13	Fe(ClO4)3 (10)	3	72	10	this work using reported catalyst^8e for the time reported therein
14	Fe(ClO4)3 (10)^n	1	14	06	8e^o
15	Mg(HSO4)2 (30)^p	20 min	63	25	8p
16	Mg(HSO4)2 (30)^q	1	25	08	8p^r
17	SiO2/ZnCl2 (25)^n	1	trace	traces	8n
18	amberlite-IR-20 (0.1 g)^s	1	35	10	8m^t
19	Me3SiCl (50)^s	1	16	traces	8i^u
20	[Hmim][TFA] (10)^v	1	15	traces	8h^w

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The efficiency of HClO₄–SiO₂ was compared with the reported catalysts/processes. After the complete consumption of the starting materials, two new spots appeared in the TLC. The crude reaction mixtures were purified by column chromatography and the products eluted at different time intervals were identified as 3a and 2-(4-N,N-dimethylaminophenyl)benzimidazole (4a) (Scheme 2 and Table 1). However, when HClO₄–SiO₂ was used as the catalyst, the crude product mixtures exhibited a single spot in the TLC and 3a was obtained as the only product after purification either by crystallisation or column chromatography. The superiority of HClO₄–SiO₂ was clearly established both in terms of the product yields as well as the selectivity by comparing the results obtained for the reaction of 1a with 2a with those obtained using reported catalysts. While the use of HClO₄–SiO₂ afforded 3a as the sole product in 90% yield, the reported catalysts were found to be less effective and lacked selectivity affording 3a in 42–80% yields along with the formation of 4a in 10–25% yields. The use of a catalyst was found to be essential as inferior yields and selectivity were observed on performing the reaction in the absence of any catalyst (entries 1 and 2, Table 1).

The reaction medium appears to have a significant influence in controlling the selective formation of the 1,2-disubstituted benzimidazole as evidenced by the results (product yield and selectivity) during the HClO₄–SiO₂ catalysed cyclocondensation of 1a with 2a performed in various protic polar, aprotic polar, halogenated, weakly polar (ethereal), and non-polar (hydrocarbon) solvents as well as under neat conditions.¹³ The use of non polar, weakly polar, aprotic polar solvents and neat conditions decreased the selectivity and in each case 3a was associated with the formation of 4a. The best results were obtained in EtOH but the selectivity decreased when using other protic solvents such as MeOH, ⁱPrOH, ^tBuOH, ethylene glycol and water. Inferior results were also obtained with PEG-200, DCE and PhMe.

The efficiency of HClO₄–SiO₂, in comparison to that of other protic acids adsorbed on silica gel, is demonstrated by the results incorporated in Table 2. However, for this study for the reaction of 1a we took 4-methylbenzaldeheyde (2b) instead of 2a so as to avoid any influence of salt formation with the NMe₂ group of 2a on the selectivity and product yield (Scheme 3).

Scheme 3 Selectivity of the formation of the 1,2-disubstituted benzimidazole 3b and the 2-substituted benzimidazole 4b during the reaction of 1a with 2b in the presence of various catalysts.

Table 2 Comparison of the efficiency of HClO₄–SiO₂ with that of other protic acids adsorbed on SiO₂ for the selectivity in the formation of 3b and 4b during the reaction of 1a with 2b (Scheme 3)^a

Entry	Catalyst (mol%)	Yield (%)^b^,^c
		3b	4b
a 1a (2.5 mmol) was treated with 2b (5 mmol, 2 equiv.) in the presence of the catalyst in EtOH (5 mL except for entries 8–10) at rt (∼25–30 °C) for 1.5 h unless specified.b The isolated yield of 3b and 4b after column chromatographic purification.c The products were characterised by NMR (^1H and ^13C) and MS (APCI).d The reaction was carried out in water.e The reaction was carried out in 1 M (5 mL) aq LiCl.f The reaction was carried out in 1 M (5 mL) aq LiCl in the absence of any added catalyst.g A 10% w/w of the catalyst was used.
1	HClO4–SiO2 [230–400] (0.5)	80	5
2	HClO4–SiO2 [100–200] (0.5)	55	09
3	HClO4–SiO2 [60–120] (0.5)	18	10
4	TfOH–SiO2 (1)	61	12
5	TFA–SiO2 (1)	48	13
6	p-TsOH–SiO2 (1)	58	20
7	MSA–SiO2 (1)	55	12
8	HBr–SiO2 (1)	54	15
9	H2SO4–SiO2 (10)	40	08
10	H2SO4–SiO2 (10)^d	42	10^e
11	H2SO4–SiO2 (10)^e	38	08
12	—^f	trace	trace
13	HClO4–neutral Al2O3 (1)	45	12
14	HClO4–basic Al2O3 (1)	48	15
15	HClO4–acidic Al2O3 (1)	55	12
16	zeolite type Y (10)^g	25	10
17	zeolite K L^−1 (SAR 6.8)(10)^g	21	10
18	zeolite ZSM 5 (SAR 6.8) (10)^g	28	08
19	zeolite K L^−1 (for synthesis) (10)^g	21	08
20	zeolite Na/Fau(10)^g	20	08
21	zeolite NH4/Y(10)^g	24	13
22	montmorillonite K-10 (10)^g	15	09
23	montmorillonite KSF (10)^g	12	08
24	SiO2 [230–400] (10)^g	trace	trace
25	SiO2 [100–200] (10)^g	trace	trace
26	SiO2 [60–120] (10)^g	trace	trace
27	amberlite (10)^g	trace	trace

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The nature of the solid support was also found to be important in maintaining the selectivity as the use of neutral, basic or acidic alumina instead of silica-gel as the solid support decreased the selectivity inducing competitive formation of 4b in 18–30% yields (entries 16–21, Table 2). Amongst the different varieties of silica gel used as the support, the 230–400 mesh size (henceforth in the text SiO₂ refers to the 230–400 mesh size silica gel only) proved to be the most effective support (entries 1–3, Table 2). As silica and montmorillonite clays themselves have the ability to catalyse various organic reactions¹⁴ the catalytic efficiency of the solid support (various forms of silica gel) itself (without taking any protic acid) and other heterogeneous catalysts such as zeolites, clays, and amberlite (entries 16–27, Table 2) were tested and found to be inferior due to product yields and poor selectivity.

The efficiency of other inorganic and organic protic acids adsorbed on SiO₂ was compared with that of HClO₄–SiO₂ for the reaction of 1a with 4-methylbenzaldeheyde (2b) (Scheme 3). Although good to excellent cyclocondensation took place with organic (entries 4–7, Table 2), other inorganic protic acids (entries 8–11, Table 2), and aq LiCl (in the presence/absence of any protic acid), the selectivity was inferior as the 2-substituted product 4b was formed in 15–35% yields in addition to the 1,2-disubstituted product 3b (15–72%). The best performance in terms of the amount of the catalyst, reaction time, product yield and 3b : 4b selectivity was exhibited by HClO₄–SiO₂.¹³ The distinct advantage of using the supported protic acids instead of the protic acids as such was revealed during the reaction of 1a with 2b performed under the catalytic influence of the individual protic acids. In each case, the overall yield of the cyclocondensation products as well as the 3b : 4b selectivity was found to be inferior to the corresponding reactions performed using the protic acids supported on SiO₂.

The generality of the HClO₄–SiO₂ catalysed selective formation of 1,2-disubstituted benzimidazole is demonstrated through the reaction of 1a with various aromatic, heteroaromatic, alicyclic and aliphatic aldehydes (Table 3). The desired 1,2-disubstituted benzimidazoles were obtained in 70–90% yields. However, the steric and electronic nature of the substrate (aldehyde) exhibited a significant influence on the outcome of the selectivity. Sterically hindered (entries 9 and 20, Table 3) and electron deficient (entry 10, Table 3) aldehydes afforded exclusively the 2-substituted benzimidazole. The catalysts were easily separated from the products by filtration. The isolated products were purified by crystallisation from aq EtOH or by passing through a column of silica-gel and eluting with 10% EtOAc in heptane, wherever required.

Table 3 1,2-Disubstituted benzimidazole formation by HClO₄–SiO₂ catalysed reaction of 1a with various aldehydes^a

Entry	Substrate	Time (h)	Yield (%)^b^,^c
a 1a (2.5 mmol) was treated with the aldehyde (5 mmol, 2 equiv.) in EtOH (5 mL) separately in the presence of HClO4–SiO2 (0.5 mol%) at rt (∼25–30 °C).b The isolated yield of the corresponding 1,2-disubstituted benzimidazole after column chromatographic purification.c The products were characterised by NMR (^1H and ^13C) and MS (APCI).d The corresponding 2-substituted benzimidazole was the sole product.
1	R^1 = R^2 = R^3 = H	2	80
2	R^1 = R^3 = H; R^2 = Me	1.5	80
3	R^1 = R^3 = H; R^2 = OMe	1	90
4	R^1 = R^3 = H; R^2 = NMe2	1	90
5	R^1 = R^3 = H; R^2 = Cl	2	85
6	R^1 = R^3 = H; R^2 = Br	2	86
7	R^1 = R^3 = H; R^2 = CF3	2	85
8	R^1 = R^3 = H; R^2 = OCH2Ph	2	80
9	R^1 = R^2 = R^3 = Me	3	75^d
10	R^1 = R^3 = H; R^2 = NO2	2.5	86^d
11		1	90
12		2	90
13		2	75
14		1	80
15		2	75
16		3	75
17		2	80
18		2	75
19		2	78
20		3	75^d

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The recyclability of the catalyst was investigated during the reaction of 1a with 2b.¹³ After the completion of the reaction, the catalysts were recovered by filtration and reused for a subsequent fresh batch of the reaction after reactivation. The catalytic activity was found to be retained up to a fifth run in carrying out the reactions in 50, 40, 30, 20, and 10 mmol scale with respect to 1a affording 90, 90, 87, 85, and 85% yields with HClO₄–SiO₂. The feasibility for the large scale preparation of 1,2-disubstituted benzimidazole was demonstrated with 100 mmol scale reactions.

To rationalise the influence of the catalyst, solvent, and the steric and electronic nature of the substrate on the selectivity control, we set forth to understand the mechanistic course of the reaction. The cyclocondensation of o-phenylenediamines with aldehydes to form the 1,2-disubstituted benzimidazoles may proceed through two distinctly different pathways (Scheme 4): (i) a bis-imine-rearrangement route (path a)^{8a,d,e,i,k,n,o,u} and (ii) a mono-imine-cyclocondensation-aminal/immonium-rearrangement route (path b).^8l,m,p ‘Path a’, would involve the formation of the bis-imine IIa (this may arise in a stepwise fashion of mono-imine Ia formation followed by the formation of the bis-imine IIa), which may undergo rearrangement via intramolecular nucleophilic attack of the nitrogen electron lone pair of one of the imine groups to the C=N of the other imine group to from IIIa followed by a 1,3-hydride shift to generate the 1,2-disubstituted benzimidazole 3. In the alternative route ‘path b,’ the reaction may proceed through the formation of the mono-imine Ia, followed by intramolecular nucleophilic attack of the adjacent amino group on the imine to form the benzimidazolidine Ib, which would react with another molecule of the aldehyde to form the aminal/immonium species IIb/IIIb that on 1,3-hydrogen shift would lead to 3.

Scheme 4 Pathways of 1,2-disubstituted benzimidazole formation during the HClO₄–SiO₂ catalysed reaction of o-phenylenediamine with aldehyde.

The involvement of the 1,3-hydrogen shift was corroborated by the formation of 2-phenyl-1-α-d₂-phenylmethyl-1H-benzimidazole 3c–d⁸ⁱ during the reaction of deuterated benzaldehyde 2c–d (2 molar equiv.) with 1a (Scheme 5). However, the feasibility of the formation of 3 by ‘path a’ or ‘path b’ could not be distinguished.

Scheme 5 Evidence for the 1,3-hydrogen shift during the formation of 2-phenyl-1-α-d₂-methylphenyl-1H-benzimidazole by the HClO₄–SiO₂-catalysed reaction of o-phenylenediamine with deuterated benzaldehyde.

Thus, to demonstrate the mechanistic route for the progress of the formation of the 1,2-disubstituted benzimidazole, we planned to intercept the possible intermediates by various spectrometric studies. The formation of the 1,2-disubstituted benzimidazole via ‘path b’ seems unlikely as no ion peak corresponding to either of the aminal IIb or the immonium species IIIb (expected to be formed through the condensation of Ib with another molecule of the aldehyde) was detected (GCMS and LCMS) during the progress of the reaction of 1a with 2b (2 equiv.). The intermediate formation of Ib would further imply that the dehydrogenative conversion to the undesired product 2-substituted benzimidazole 4 would be accelerated under the presence of air/oxygen and on the other hand would be retarded under anaerobic conditions.^8l The treatment of 1a with 2b (2 equiv.) under the catalytic influence of HClO₄–SiO₂ afforded 3b in 78% yield using deoxygenated EtOH under nitrogen atmosphere compared to an 80% yield obtained in using EtOH in open air. Further, 3b was formed in 80% yield during the HClO₄–SiO₂ catalysed reaction of 1a with 2b (2 equiv.) in EtOH while oxygen gas was bubbled into the reaction mixture. Thus, the presence or the absence of air/oxygen did not have any significant influence on the overall outcome of the reaction. These ruled out the involvement of Ib (‘path b’) during 1,2-disubstituted benzimidazole formation for which the reaction follows ‘path a’.

To further demonstrate the progress of the reaction for 1,2-disubstituted benzimidazole formation via ‘path a,’ we tested the feasibility of imine formation under the adopted experimental procedure. Treatment of aniline with benzaldehyde 2c under the catalytic influence of HClO₄–SiO₂ under similar conditions formed the imine. Bis-imine formation also takes place when m-phenylenediamine is treated with two molar equivalents of 2c in the presence of HClO₄–SiO₂ under similar conditions. These suggested that the reaction might proceed via ‘path a’ involving the formation of the bis-imine IIa. As a direct proof, the progress of the reaction of 1a with 2c (2 equiv.) was monitored by GCMS at 10, 20, 30, 40, and 50 min time intervals to ‘fish out’ any relevant intermediate. In each case, the ion peak at m/z 312 was detected. However, it remained unclear whether this could be due to the bis-imine IIa (Ar = Ph) or the corresponding 1,2-disubstituted benzimidazole (1-phenylmethyl-2-phenyl-1H-benzimidazole 3c) as both are of the same molecular weight. Detailed MSⁿ studies also proved to be inconsequential with respect to the identity/authenticity of the species of m/z 312 as IIa (Ar = Ph) or 3c. However, when an aliquot of sample withdrawn from the reaction mixture of 1a with 2c (2 equiv.) was subjected to LCMS studies during a 5–60 min reaction period, the ion peak corresponding to the mono-imine of 1a and 2c could be detected. The height/area of this ion peak was found to decrease with time with a concomitant appearance of the peak at m/z 312 corresponding to the bis-imine with increasing intensity.

Finally, the formation of 1,2-disubstituted benzimidazole via ‘path a’ was validated by the isolation and characterisation (NMR) of N¹,N²-dibenzylbenzene-1,2-diamine (5) formed by the in situ reduction (NaBH₄) of the intermediately formed bis-imine (Scheme 4) during the course of the reaction between 1a and 2c providing for the first time crucial evidence that the reaction proceeds via path a.

Therefore, the selectivity of the 1,2-disubstituted and 2-substituted benzimidazole formation lies in the feasibility of the formation of the bis-imine under the prescribed set of experimental condition(s). A stronger catalyst (supported protic acid) and polar reaction medium should assist in bis-imine formation. Hence, EtOH (protic polar) is the most effective reaction medium for the 1,2-disubstituted benzimidazole formation. The intermediacy of the bis-imine IIa is the crucial and determining factor for 1,2-disubstituted benzimidazole formation and hence directing/controlling the 1,2-disubstituted vs. 2-substituted benzimidazole selectivity is demonstrated by the observation that the reaction of 1a with two molar equivalents of 2,4,6-trimethylbenzaldehyde 2d forms only the 2-(2,4,6-trimethyl)phenyl-1H-benzimidazole 4d in EtOH in the presence of HClO₄–SiO₂ (entry 9, Table 3). Due to the steric crowding surrounding the aldehyde group in 2d, the bis-imine is not feasible and the 2-substituted benzimidazole 4d is formed exclusively. To demonstrate that the reaction of 1a with 2d only forms the mono-imine (which on intramolecular nucleophilic attack by the adjacent amino group results in the formation of 4dvia the corresponding imidazoline), the reaction mixture was subjected to treatment with NaBH₄ (Scheme 6). The formation of 2-N-(2,4,6-trimethyl)aminomethylaniline 6 justified that the lack of formation of the expected 1,2-disubstituted benzimidazole from the reaction of 1a with 2d is due to the feasibility of only mono-imine formation. The implication of the steric factor in suppressing the bis-imine formation (and hence directing the selectivity towards the formation of 2-substituted benzimidazole) can also be realized with a sterically hindered aliphatic aldehyde. Thus, the reaction of 1a with pivalaldehyde (2 equiv.) under the catalytic influence of HClO₄–SiO₂ in EtOH forms exclusively the 2-substituted benzimidazole (entry 20, Table 3), as the steric effect of the ^tBu group in pivalaldehyde does not permit the bis-imine formation with 1a.

Scheme 6 Formation of 2-substituted benzimidazole during the HClO₄–SiO₂ catalysed reaction of 1a with 2d.

The selective formation of the 2-substituted benzimidazole from an electron deficient aldehyde such as 4-nitrobenzaldehyde 2e (entry 10, Table 3), under conditions conducive to form 1,2-disubstituted benzimidazole, could be due to the fact that because of the highly electrophilic character of the aldehyde carbonyl, rapid formation of the mono-imine takes place and before the second amino group of 1a is involved in imine formation with another molecule of 2e it undergoes an intramolecular nucleophilic attack on the C=N of the mono-imine (due its high electrophilic character owing to the 4-nitro group) leading to the formation of the intermediate imidazoline and subsequent dehydrogenation to the 2-substituted benzimidazole as the final/end product.

To assess the influence of the electronic effect of the o-phenylenediamine component on the selectivity of formation of the 1,2-disubstituted and 2-substituted benzimidazoles, 4-nitro-o-phenylenediamine 1b was treated separately with 2 equiv. each of benzaldehyde 2c, 4-nitrobenzaldehyde 2e, and 4-methoxybenzaldehyde 2f (Scheme 7) under conditions that would favour the formation of 1,2-disubstituted benzimidazole. However, in each case the corresponding 2-substituted benzimidazoles were obtained as the only product.

Scheme 7 HClO₄–SiO₂-catalysed reaction of 4-nitro-o-phenylenediamine with 2c, 2e, and 2f.

The origin of the selective formation of the 2-substituted benzimidazoles from the reactions of 1b could be due to its ability to form the mono-imine only as the electronic withdrawing effect of the nitro group makes the para amino group less nucleophilic. To prove that the reaction of 1b with an aldehyde can only form the mono-imine, the reaction mixture of 1b and 2c was treated with NaBH₄ to trap any intermediately formed imine by converting it to the corresponding reduced product which was found to be 4-nitro-2-methylphenylaminoaniline 7. The formation of the mono-N-benzylated product of 1b confirmed that only the mono-imine is formed although 2 molar equiv. of the aldehyde was used. That the 2-amino group (meta to the nitro group) in 1b undergoes imine formation was confirmed by comparison of the ¹H NMR (the benzylic protons being the probe nuclei) of the reductive alkylation product from the reaction of 1b and 2c with that of the N-benzylated 4- and 3-nitro anilines (prepared by reductive amination of 4- and 3- nitro anilines with benzaldehyde). The benzylic protons in N-benzyl-4-nitroaniline and N-benzyl-3-nitroaniline appear at δ 4.43 and 4.39, respectively. The benzyl protons of the reductive alkylation product obtained from the reaction of 1b with 2c appeared at δ 4.38 suggesting it to be 7 (Scheme 7). However, we realised that the tiny chemical shift difference between N-benzyl 4-nitro aniline and N-benzyl 3-nitro aniline cannot differentiate the regioisomers unambiguously. A recent literature report¹⁵ on the reductive amination of 1b and 2c came to our notice which, although, claimed the formation of 7, the ambiguity remains with respect to the identity of the product either as 7 or as 7a. In order to resolve this issue, we carried out various NMR experiments such as DEPT 135 and 2D (HSQC and NOESY) of 7 and confirmed its structure as 4-nitro-2-methylphenylaminoaniline (supporting information†).

Conclusions

This study provides an account on the issue of competitive formation of the 1,2-disubstituted and 2-substituted benzimidazoles during direct cyclocondensation of o-phenylenediamine aldehyde. The scope and limitation of various protic acids on a solid support as well as the reaction medium have been studied to derive that the best operative reaction conditions are the treatment of the o-phenylenediamine with two molar equiv. of an aldehyde in EtOH at rt in the presence of catalytic quantities of HClO₄–SiO₂ (0.5 mol%) to form exclusively/selectively the 1,2-disubstituted benzimidazoles. Other solid supports such as alumina (acidic/basic/neutral) gave inferior results both in terms of product yield and selectivity. The catalyst system HClO₄–SiO₂ is distinctly superior to the reported catalysts/procedures that are associated with the competitive formation of the 2-substituted benzimidazoles. A mechanistic outline has been derived for the HClO₄–SiO₂ catalysed formation of the 1,2-disubstituted benzimidazoles, which follows bis-imine formation, rearrangement, and a 1,3-hydride shift pathway. The origin/rationale of selectivity resides on furthering or suppressing the bis-imine formation using a judicial choice of the supported protic acid catalyst as well as an appropriate reaction medium. The steric and electronic factors of the aldehyde and the electronic factor of the o-phenylenediamine component also exhibit significant influence on the selectivity. Sterically hindered and electron deficient aldehydes and electron deficient o-phenylenediamine afforded the 2-substituted benzimidazoles under conditions that are conducive for 1,2-disubstituted benzimidazole formation.

Preparation of perchloric acid adsorbed on silica-gel (HClO₄–SiO₂)

The HClO₄–SiO₂ was prepared following the procedure first reported by its inventors.¹² To a suspension of silica gel (23.75 g, 230–400 mesh) in Et₂O (50 mL), was added HClO₄ (1.25 g, 12.5 mmol, 1.78 mL of a 70% aq solution of HClO₄) and the mixture was stirred magnetically for 30 min at rt. The Et₂O was removed under reduced pressure (rotary evaporator) and the residue heated at 100 °C for 72 h under vacuum (10 mm Hg) to afford HClO₄–SiO₂ (0.5 mmol g⁻¹) as a free flowing powder.

Typical experimental procedure for the synthesis of 2-aryl-1-arylmethyl-1H-1,3-benzimidazoles using HClO₄–SiO₂ (Entry 4, Table 3)

The mixture of o-phenylenediamine 1a (0.27 g, 2.5 mmol, 1 equiv.), 4-dimethylaminobenzaldehyde 2a (0.74 g, 5 mmol, 2 equiv.), and HClO₄–SiO₂ (25 mg, 0.012 mmol, 0.5 mol%) in EtOH (10 mL) was stirred magnetically at rt (∼25–30 °C). After completion of the reaction (TLC, 3 : 1 n-hexane–EtOAc), the mixture was filtered, washed with EtOH (2 × 5 mL), and the combined filtrates were concentrated under rotary vacuum evaporation. The crude product was purified by crystallisation from aq EtOH or passed through a column of silica gel and eluted with 10% EtOAc in hexane to afford 1-(4-dimethylaminophenylmethyl)-2-(4-dimethylaminophenyl)-1H-benzimidazole 3a (0.83 g, 90%) as a white solid; mp = 255–256 °C; IR (KBr) ν_max = 3038, 1610, 1562, 1482, 1251, 1168 cm⁻¹; ¹H NMR (300 MHz, 25 °C, CDCl₃): δ = 7.80 (d, J = 7.8 Hz, 2 H; Ar–H), 7.63 (d, J = 8.7 Hz, 2 H; Ar–H), 7.19 (t, J = 8.5 Hz, 3 H; Ar–H), 7.01 (d, J = 8.5 Hz, 2 H; Ar–H), 6.66–6.78 (m, 4 H; Ar–H), 5.37 (s, 2 H; CH₂), 3.00 (s, 3 H; CH₃), 2.92 (s, 3 H; CH₃); MS (APCI) m/z: 371 (M+H)⁺.^8c

Typical experimental procedures for mechanistic insights

Monitoring the progress of the reaction of 1a with two molar equivalents of 2b performed in EtOH at rt in the presence of HClO₄–SiO₂ by GCMS. The mixture of 1a (0.27 g, 2.5 mmol), 2b (0.6 g, 5 mmol, 2 equiv.), and HClO₄–SiO₂ (25 mg, 0.012 mmol, 0.5 mol%) in EtOH (5 mL) was stirred magnetically at 25–30 °C. Aliquot (0.5 mL) portions of the reaction mixture were taken out after 10, 20, 30, 40, 50 and 60 min and on each occasion was diluted with EtOH (1 mL). The resultant solution (1 μL) was subjected to GCMS to identify the ion peaks of any of the intermediates depicted in Scheme 4. In each case the ion peak at m/z 312 corresponding to the bis-imine (or the resultant 1,2-disubstituted benzimidazole 3b) was detected.

Monitoring the progress of the reaction of 1a with two molar equivalents of 2b performed in EtOH at rt in the presence of HClO₄–SiO₂ by APCI mass spectroscopy. The mixture of o-phenylenediamine 1a (0.27 g, 2.5 mmol), 4-methylbenzaldehyde 2b (0.6 g, 5 mmol, 2 equiv.), and HClO₄–SiO₂ (25 mg, 0.012 mmol, 0.5 mol%) in EtOH (5 mL) was stirred magnetically at 25–30 °C. Aliquot (20 μL) portions of the reaction mixture were taken out after 10, 20, 30, 40, 50 and 60 min and on each occasion was diluted with EtOH (1 mL). From the resultant solution an aliquot amount (10 μL) was subjected to +ve APCI-MS to identify the ion peaks of any of the intermediates depicted in Scheme 4. In the case of samples of the 10 and 20 min periods the ion peaks corresponding to the mono-imine along with the ion peak at m/z 312 were observed. The remaining samples showed only the presence of the ion peak at m/z 312.

Formation of N¹,N²-dibenzylbenzene-1,2-diamine 4 during the in situ reduction (with NaBH₄) of the presumably formed bis-imine during the synthesis of the 1,2-disubstituted benzimidazole from 1a with 2c. The mixture of o-phenylenediamine 1a (0.27 g, 2.5 mmol), benzaldehyde 2c (0.6 g, 2.5 mmol, 1 equiv.), and HClO₄–SiO₂ (25 mg, 0.012 mmol, 0.5 mol%) in EtOH (5 mL) was stirred magnetically at 25–30 °C. After 30 min, NaBH₄ (7.5 mmol, 3 equiv.) was added and the resultant mixture was stirred for further 30 min. The mixture was dissolved in EtOAc (5 mL), adsorbed on silica gel (1 g, 230–400 mesh) and concentrated under rotary vacuum evaporation. The resultant solid mass was charged on to flash chromatography column and eluted with hexane–EtOAc (85 : 15) to afford N¹, N²-dibenzylbenzene-1,2-diamine 5 (86 mg, 12%). Low melting solid; IR (KBr) ν_max = 3435, 2972, 1612, 1451, 1325, 1260 cm⁻¹; ¹H NMR (CDCl₃, 400 MHz, TMS) δ: 7.39–7.36 (m, 4H), 7.34–7.29 (m, 4H), 7.27–7.24 (m, 2H), 6.80–6.77 (m, 2H), 6.73–6.70 (m, 2H), 4.31 (s, 4H), 3.64 (brs, 2H); MS (EI) m/z: 289.4 (M+H)⁺.

Formation of 2-phenyl-1-α-d₂-phenylmethyl-1H-benzimidazole during the reaction of 1a and 2c-d₁ in the presence of HClO₄–SiO₂. The mixture of 1a (0.1 g, 1 mmol, 1 equiv.), 2c–d₁ (0.21 g, 2 mmol, 2 equiv.), and HClO₄–SiO₂ (10 mg, 0.005 mmol, 0.5 mol%) in EtOH (5 mL) was stirred magnetically at rt (∼25–30 °C). After completion of the reaction (TLC, 3 : 1 n-heptane–EtOAc), the mixture was filtered, washed with EtOH (2 × 5 mL), and the combined filtrates were concentrated under rotary vacuum evaporation. The crude product was purified by passing through a column of silica gel and eluting with 10% EtOAc in heptane to afford 2-phenyl-1-α-d₂-phenylmethyl-1H-benzimidazole 3c–d (0.20 g, 72%) as a white solid; ¹H NMR (400 MHz, 25 °C, CDCl₃): δ = 7.87 (d, J = 2 Hz, 1 H; Ar–H), 7.70–7.68 (m, 2 H; Ar–H), 7.48–7.42 (m, 3 H; Ar–H), 7.36–7.29 (m, 4 H; Ar–H), 7.24–7.20 (m, 2 H; Ar–H), 7.12–7.10 (m, 2 H; Ar–H); ¹³C NMR (100 MHz, CDCl₃): δ = 154.1, 143.2, 136.2, 136.0, 130.0, 129.9, 129.2, 129.0, 128.7, 127.8, 126.0, 123.0, 122.6, 120.0, 110.5; MS (APCI) m/z: 287.4 (M+H)⁺.⁸ⁱ

Formation of 2-(2,4,6-trimethyl)phenyl-1H-benzimidazole during the reaction of o-phenylenediamine and 2,4,6-trimethylbenzaldehyde in the presence of HClO₄–SiO₂. The mixture of o-phenylenediamine 1a (0.27 g, 2.5 mmol, 1 equiv.), 2, 4, 6-trimethylbenzaldehyde (0.74 g, 5 mmol, 2 equiv.), and HClO₄–SiO₂ (25 mg, 0.012 mmol, 0.5 mol%) in EtOH (10 mL) was stirred magnetically at rt (∼25–30 °C). After completion of the reaction, the mixture was filtered, washed with EtOH (2 × 5 mL), and the combined filtrates were concentrated under rotary vacuum evaporation. The crude product was purified by flash chromatography to afford 2-(2,4,6-trimethyl)phenyl 1H-benzimidazole 4d (0.44 g, 72%) as a white solid; mp = 282–284 °C; IR (KBr) ν_max = 1264, 1479, 1617, 1653, 3260 cm⁻¹; ¹H NMR (400 MHz, 25 °C, DMSO): 7.64 (d, J = 6.4 Hz, 1H; Ar–H), 7.47 (d, J = 7.64 Hz, 1H; Ar–H), 7.19 (s, 2H; Ar–H), 6.98 (s, 2H; Ar–H), 2.29 (s, 3H; CH₃), 2.04 (s, 6H; CH₃); ¹³C NMR (100 MHz, 25 °C, CDCl₃): 151.7, 143.8, 138.9, 134.9, 129.2, 128.4, 122.5, 121.6, 119.1, 111.6, 21.2, 20.1; MS (APCI) m/z: 237 (M+H)⁺; Anal. Calcd. For C₁₆H₁₆N₂: C, 81.32; H, 6.82; N, 11.85% Found: C, 81.35; H, 6.81; N, 11.86%.

Formation of N¹-benzyl-5-nitrobenzene-1,2-diamine 7 during the in situ reduction (with NaBH₄) of the presumably formed mono-imine during the reaction between from 1b and 2d. The mixture of 4-nitro o-phenylenediamine 1b (0.39 g, 2.5 mmol), benzaldehyde 2c (0.5 g, 5 mmol, 2 equiv.), and HClO₄–SiO₂ (25 mg, 0.012 mmol, 0.5 mol%) in EtOH (10 mL) was stirred magnetically at 25–30 °C. After 1 h, NaBH₄ (2 equiv.) was added and the resultant mixture was stirred for a further 2 h. The mixture was filtered to remove the catalyst, the filtrate was concentrated under rotary vacuum evaporation and the isolated crude product was purified by flash chromatography (15% EtOAc in hexane as eluent) to afford N¹-benzyl-5-nitrobenzene-1,2-diamine 7; ¹H NMR (400 MHz, 25 °C, CDCl₃): δ = 7.41 (dd, J = 8.7 Hz & J = 2.5 Hz, 1 H; Ar–H), 7.33–7.40 (m, 4H; Ar–H), 7.25 (t, J = 7.0 Hz, 1 H; Ar–H), 6.58 (d, J = 2.4 Hz, 1 H; Ar–H), 6.58 (d, J = 8.7 Hz, 1 H; Ar–H), 6.28 (d, J = 6.3 Hz, 1 H; NH), 5.72 (t, J = 5.5 Hz, 1 H; NH), 4.38 (t, J = 5.1 Hz, 2 H; PhCH₂); ¹³C NMR (100 MHz, 25 °C, CDCl₃): 14.3, 139.6, 137.5, 135.4, 128.9, 127.7, 127.4, 116.3, 111.5, 104.6, 47.2; MS (APCI) m/z: 244.2 (M+H)⁺.¹⁵

Representative procedure for the reductive amination (synthesis of N-benzyl-4-nitroaniline):^16a. To a stirred solution of 4-nitrobenzaldehyde (0.138 g, 1 mmol) and aniline (0.093 g, 1 mmol, 1 equiv.) in 1,2-dichloroethane (5 mL) was added the sodium triacetoxyborohydride (0.32 g, 1.5 mmol, 1.5 equiv.) under neutral conditions (pH 7). The mixture was stirred at rt under a N₂ atmosphere for 24 h. After completion of reaction, the reaction mixture was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over anhydrous MgSO₄ and the crude product was purified by silica gel column chromatography with n-hexane–EtOAc as the eluent to afford the desired product (0.19 g, 85%); ¹H NMR (400 MHz, 25 °C, CDCl₃): 8.05–8.09 (m, 2 H; Ar–H), 7.29–7.39 (m, 5 H; Ar–H), 6.55–6.58 (m, 2 H; Ar–H), 4.09 (bd, s, 1 H, NH), 4.42 (d, J = 5.6 Hz, 2 H; CH₂); MS (APCI) m/z: 229.3 (MH⁺).^16b The synthesis of N-benzyl-3-nitroaniline was carried out following a similar procedure (0.18 g, 81%): ¹H NMR (400 MHz, CDCl₃): 7.53 (d, J = 8.0 Hz, 1 H; Ar–H), 7.43 (s, 1 H; Ar–H), 7.24–7.37 (m, 6 H; Ar–H), 6.87 (d, J = 8.0 Hz, 1 H; Ar–H), 4.39 (bs, 3 H; NH); MS (APCI) m/z: 229.3 (M+H)⁺.^16c

Note added after first publication

This article replaces the version published on 6th November 2012, which contained errors in the title.

Acknowledgements

DK and DNK thank CSIR, New Delhi for RA and SRF respectively. RC and SKG thank UGC for SRF.

References

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Footnote

† Electronic Supplementary Information (ESI) available. See DOI: 10.1039/c2ra21994h

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