Hypervalent iodine(III) catalyzed oxidative C–N bond formation in water: synthesis of benzimidazole-fused heterocycles

Abstract

An iodine(III) catalyzed C(sp²)–H functionalization–intramolecular amination reaction of N-aryl-2-amino-N-heterocycles has been developed in water and under ambient conditions. This metal-free open-flask chemistry is general and successfully applied in synthesizing the benzimidazole-fused heterocycles pyrido[1,2-a]benzimidazole, benzimidazo[1,2-a]quinoline and benzimidazo[2,1-a]isoquinoline derivatives.

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Direct cross-dehydrogenative amination of inert C(sp²)–H bonds has become a valuable tool in organic synthesis.¹ Over the years, numerous protocols for intramolecular direct C–N bond formation have been developed, and most of these methods involve the catalytic use of Pd complexes² or Cu salts.³ Generally, transition metal catalyzed carbon–heteroatom bond formation reactions require elevated temperatures and high loading of the catalyst and/or metal oxidant. Furthermore, the presence of heavy metal contaminants in the final products restricts their application in the bulk synthesis of active pharmaceutical ingredients (APIs) for commercial use. Hence, reaction protocols that enable the preparation of nitrogen containing compounds through C–N cross-coupling reactions in the absence of transition metals are attractive and considered greener.⁴ In this context, hypervalent iodine reagents that promote oxidative C–N bond formation have received much attention due to their low toxicity, comparable reactivity with transition-metals and availability.^5,6 However, in most cases of iodine(III) mediated cross-coupling chemistry, fluorinated solvents^6a,e,h,i are still preferred, which severely impedes application, particularly in large scale synthesis. Therefore a new, more efficient and environmentally benign metal-free catalytic system for oxidative C–H amination is highly desirable.

The benzimidazole-fused heterocyclic scaffold exists in a wide range of biologically active compounds (Fig. 1).⁷ Consequently, substantial synthetic methods have been developed for the preparation of this class of molecules.^8–10

Fig. 1 Medicinally interesting compounds containing benzimidazole-fused heterocycles.

Synthesis of pyrido[1,2-a]benzimidazoles by copper(II) catalyzed intramolecular C–H amination of N-aryl-2-aminopyridines in acidic media has been reported by Zhu^8d and Maes^8e independently. However, both of the approaches require a high reaction temperature (120 °C), and the substrate scope is limited in terms of substituents on the pyridine moiety. An alternative approach mediated by iodine(III) has also been reported by Zhu recently.⁶ⁱ However, this methodology failed in terms of regioselectivity and the use of expensive fluorinated alcohol remains the drawback of this synthesis. To overcome these issues, herein, we report oxidative C–N bond formation using a catalytic amount of in situ generated hypervalent iodine(III) reagent [hydroxy(tosyloxy)iodo]benzene (Koser's reagent, HTIB)¹¹ in water^12,13 and under ambient conditions (Scheme 1).

Scheme 1 Formation of benzimidazole-fused heterocycles.

This protocol is general, regioselective and has been successfully utilized in synthesizing medicinally important heterocycles such as pyrido[1,2-a]benzimidazole, benzimidazo[1,2-a]quinoline and benzimidazo[2,1-a]isoquinoline derivatives.

First, N-phenyl-2-aminopyridine¹⁴ 1a was selected as a model compound to explore the optimized reaction conditions with iodine(III) in water at room temperature (Table 1). It was found that the reaction of 1a with phenyliodine diacetate (PIDA, 1 equiv.) in water at room temperature was unsuccessful (entry 1, Table 1). The product was not formed even at an elevated temperature, 100 °C (entry 2, Table 1). To our delight when we performed the reaction with PIDA (1 equiv.) in the presence of p-toluenesulphonic acid monohydrate (PTSA·H₂O) (2 equiv.) as an additive, the desired product was isolated in a 90% yield (entry 3, Table 1).^11a When methane sulphonic acid (2 equiv.) was combined with PIDA a poor yield (15%) was obtained (entry 4, Table 1). When we reduced the amount of PIDA from 1 to 0.5 equiv., the yield of the isolated product dropped to 30% (entry 5, Table 1). The yield also decreased when the amount of PTSA·H₂O was reduced from 2 equiv. to 1 equiv. (entry 6, Table 1). Next we turned our attention to making the reaction catalytic and performed the reaction using PIDA with several oxidants (entries 7–9, Table 1). It was observed that a combination of PIDA (0.2 equiv.) with PTSA·H₂O (2 equiv.) and m-CPBA (1 equiv.) in water gave 2a in the best yield (90%) (entry 7, Table 1). Oxidants like tert-butyl hydroperoxide (TBHP) (entry 8, Table 1) and H₂O₂ (entry 9, Table 1) remained ineffective. The use of 10 mol% PIDA gave the desired product only in a 60% isolated yield (entry 10, Table 1). When we tried to promote the cyclization by in situ generated HTIB by using PhI (0.2 equiv.) as an iodine source^11b with PTSA·H₂O and m-CPBA as an oxidant in water, an annulated product was obtained in a 75% yield (entry 11, Table 1).

Table 1 Optimization of the reaction conditions^a

Entry	Precat.	Amount	Additive	Oxidant	t (h)	Yield^b (%)
a Reaction conditions: 1a (1.0 equiv.), PIDA (0.2 equiv.), PTSA·H2O (2 equiv.), m-CPBA (1 equiv.) and H2O (1 mL); rt.b Isolated yields.c Reaction carried out at 100 °C.d 1.0 equiv. used.e 70 vol% in water.f 30 vol% in water; n. r. = no reaction.
1	PIDA	1 equiv.	—	—	24	n. r.
2^c	PIDA	1 equiv.	—	—	24	n. r.
3	PIDA	1 equiv.	PTSA·H2O	—	4	90
4	PIDA	1 equiv.	CH3SO3H	—	8	15
5	PIDA	0.5 equiv.	PTSA·H2O	—	8	30
6	PIDA	1 equiv.	PTSA·H2O^d	—	8	40
7	PIDA	0.2 equiv.	PTSA·H2O	m-CPBA	4	90
8	PIDA	0.2 equiv.	PTSA·H2O	TBHP^e	8	n. r.
9	PIDA	0.2 equiv.	PTSA·H2O	H2O2^f	8	n. r.
10	PIDA	0.1 equiv.	PTSA·H2O	m-CPBA	4	60
11	PhI	0.2 equiv.	PTSA·H2O	m-CPBA	4	75
12	HTIB	1 equiv.	—	—	4	85

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When we used Koser's reagent (HTIB) (1.0 equiv.) in the absence of m-CPBA and PTSA, 2a was isolated in an 85% yield, which indicates that Koser's reagent is the active species (entry 12, Table 1).

Reactions of a variety of N-arylated-2-aminopyridines¹⁴ were investigated under the optimized reaction conditions (Table 2). As depicted in Table 2, reactions involving N-aryl-2-aminopyridines bearing electron-donating (Me and t-Bu) or electron-withdrawing groups (F, Cl, Br, CF₃) at the para position of the aniline moiety proceeded to give almost quantitative yields (2b–g). A high yield was also obtained with ortho substitution as compound 2h was isolated in an 89% yield. Reactions involving both electron donating (OMe) and electron withdrawing (F, Cl, CF₃, NO₂) substituents at the meta-position of the aniline of the N-aryl-2-aminopyridine derivatives proceeded in a highly regioselective manner to afford exclusively C-7 substituted pyrido[1,2-a]benzimidazoles (2i–m).^8d,e Interestingly, no other regioisomers i.e. C-9 substituted pyrido[1,2-a]benzimidazoles were detected. In this context, a disubstituted derivative has been tested under these optimized conditions and the product 2n was isolated in an 82% yield with complete regioselectivity. To further enhance the generality of the reaction, substitution on the pyridine ring was also investigated. 5-Bromo and 2-methyl derivatives reacted efficiently to give the corresponding products 2o and p, and 2q, respectively in excellent yields (90–94%). Cyclization of N-napthyl-2-aminopyridine was also performed under the optimized conditions and a novel pyridine annulated naptho imidazo product (2r) was isolated in an 82% yield. By applying these optimized conditions the benzo[d][1,3]dioxole annulated pyridoimidazo compound (2s) has been synthesized in a 94% yield.

Table 2 Synthesis of pyrido[1,2-a]benzimidazole derivatives^a

a Reaction conditions: N-arylpyridine-2-amine (0.29 mmol), Phl(OAc)₂ (0.058 mmol), m-CPBA(0.29 mmol), PTSA·H₂O (0.58 mmol) and H₂O (1 mL); rt; air.

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Next we turned our attention to applying the present protocol for the synthesis of another important complex heterocyclic system, benzimidazo[1,2-a]quinoline (Table 3). Under the optimized conditions, N-aryl-2-aminoquinolines¹⁴ bearing electron donating (3a) or electron withdrawing groups (3b–d) produced the desired heterocycles in high yields (92–95%). Here also the reaction was highly regioselective as substrates with substituents at the meta-position of the aniline ring gave exclusively C-9 substituted products (3e–g) in good yields (72–75%). We have further applied the optimized conditions in the synthesis of benzimidazo[2,1-a]isoquinolines (Table 3).

Table 3 Synthesis of benzimidazo[1,2-a]quinoline and benzimidazo[2,1-a]isoquinoline derivatives^a

a Reaction conditions: N-arylquinolin-2-amine/N-arylisoquinolin-1-amine (0.29 mmol), Phl(OAc)₂ (0.058 mmol), m-CPBA (0.29 mmol), PTSA·H₂O (0.58 mmol) and H₂O (1 mL); rt; air.

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We were pleased to find that the iodine(III) promoted C–H amination of N-arylisoquinoline-1-amine derivatives¹⁴ was facile and the cyclic compounds were isolated in excellent yields (84–85%) (Table 3). The electronic nature of the substituents at the para-position (3h–j) had no effect on the cycloamination reaction. In this case also the reaction remained completely regioselective and only the C-10 substituted product (3k) was isolated in a 72% yield.

The scalability of this reaction was tested by performing the reaction of 1a on a gram scale (5.8 mmol) under the optimized conditions (Scheme 2).

Scheme 2 Gram scale synthesis of pyrido[1,2-a]benzimidazole.

Based on these findings and previous literature reports^15,6c,h,i we put forward a plausible mechanism for the amination of 1a. We suggest that the operating mechanism for this reaction starts from an interaction between the in situ generated PhI(OH)OTs (Koser's reagent) and N-phenyl-2-aminopyridine (1a) (Scheme 3), to result in the electrophilic N-iodo species A. In the subsequent steps the electrophilic annulation on the pyridine nitrogen of A generates intermediate B, which upon deprotonation forms 2a (eqn (1), Scheme 3). The eliminated PhI enters the catalytic cycle upon oxidation by m-CPBA in the presence of PTSA·H₂O to generate reactive iodine(III) PhI(OH)OTs and complete the catalytic cycle. An explanation for the high regioselectivity can be put forward, where the intermediate AA is favoured over AB due to steric effects (eqn (2), Scheme 3), in order to give one regioisomer exclusively.

Scheme 3 A plausible reaction mechanism.

In conclusion, we have developed a practical method for the synthesis of benzimidazole-fused heterocycles from readily available N-aryl-2-amino-N-heterocycles under metal-free conditions. The reaction is catalyzed by in situ generated hypervalent iodine(III) at room temperature. Use of water as a solvent and open-flask chemistry makes this process greener and more attractive for large scale synthesis. To the best of our knowledge, this is one of the rare examples in which water has been used as a solvent in hypervalent iodine(III) catalyzed oxidative C–N bond formation. More significantly, complete control of the regioselectivity was achieved in this C–H cycloamination process. In view of the growing understanding of hypervalent iodine C–H activation–functionalization processes, the reaction described herein showcased a reactivity profile that is notably different to those previously reported.^6h,i,8c It is believed that the new hypervalent iodine(III) promoted protocol will add value in developing a number of efficient and practical methods for C–N bond construction from unactivated C–H bonds.

Acknowledgements

D. N. R and Sk. R. thank UGC and CSIR-New Delhi for research fellowship, respectively. This research work is financially supported by CSIR-New Delhi (BSC 0108). IIIM communication no 1491.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and spectroscopic data for all compounds. See DOI: 10.1039/c4ra02279c

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