Rh(III)-Catalyzed Synthesis of 2-Alkylbenzimidazoles from Imidamides

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Rh(III)-Catalyzed Synthesis of 2‑Alkylbenzimidazoles from Imidamides and N‑Hydroxycarbamates Yanlin Li, Chunqi Jia, Huan Li, Linhua Xu, Lianhui Wang, and Xiuling Cui* Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen 361021, P. R. China

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ABSTRACT: An efficient tandem reaction of imidamides and N-hydroxycarbamates has been developed. Valuable 2alkylbenzimidazoles could be easily obtained in up to 97% yield for more than 20 examples. The products would further streamline the synthesis of molecules, which are essential building blocks in organic synthesis and drug discovery. This protocol features high regioselectivity, efficiency, good tolerance of functional groups, and mild reaction conditions.

However, for the synthesis of heterocycles with multiple nitrogen atoms using an N−H imine as a directing group, it is necessary to introduce an external amine reagent.8 Organic azide has been recently widely utilized as an elegant amine source and internal oxidant, and various C−H amidations have been realized by following this strategy.9 The construction of azacycles using this nitrogen source had been reported by the groups of Glorius9c and Jiao.9d The products are limited to indazoles and quinazolines. Very recently, our group developed an efficient synthesis of 2-arylbenzimidazoles using imidamides and sulfonyl azides as the nitrogen source via [Cp*IrCl2]2catalyzed cleavage of C−N bonds and the regeneration of C− N bonds.10 Good functional group tolerance, high atom efficiency, and moderate to high yields under relatively mild conditions made this protocol useful in preparing various substituted benzimidazole derivatives. However, our previous report was limited to N-arylbenzimidamides and showed low reaction activity with N-phenylalkylimidamides. To solve this limitation, herein, we developed a convenient, efficient, and straightforward approach to 2-alkyl-substituted benzimidazole via Rh-catalyzed annulation of N-phenylalkylimidamides with N-hydroxycarbamates. We initially started our investigation by employing easily available N-phenylalkylimidamide and N-hydroxycarbamate as the model substrates to screen various reaction parameters (Table 1). As a result, the desired benzimidazole 3aa was obtained in 45% isolated yield in the presence of [Cp*RhCl2]2 (2.5 mol %), AgOAc (1 equiv), t-BuOK (50 mol %), and PivOH (2 equiv) in DCE at 100 °C (Table 1, entry 1). Then other oxidants were investigated (entries 2−4). To our delight, the yield of 3aa was largely enhanced up to 91%, and Ag2CO3 was the ideal oxidant for the reaction (entry 4). Control experiments showed that the oxidant and base were necessary (entries 5 and 6). The reaction could be conducted in the

2-Alkyl-substituted benzimidazoles represent an important class of benzimidazoles widely observed in pharmaceuticals and natural products.1 Therefore, tremendous effort has been put into the synthesis of such scaffolds. The conventional methods to build 2-alkyl-substituted benzimidazole are confined to the coupling of benzene-1,2diamine with a C1 synthon and the cascade arylamination/ condensation catalyzed by a transition metal, such as Cu, Co, and Pd. These procedures can suffer from limitations, such as a requirement for functionalized starting materials and multiple steps.2 In the past decade, metal-catalyzed C−H activation has become established as a straightforward and step-economic process for the construction of 2-alkyl-substituted benzimidazoles. In 2010, Nakao, Hiyama, and co-workers reported a Nicatalyzed C2−H alkylation of benzimidazoles with vinylarenes.3 Subsequently, Ellman’s group4 demonstrated a direct C−H alkylation of C2-unsubstituted benzimidazoles with alkenes based on a system that used Rh(I) as a precatalyst combined with the electron-poor ligand dArFpe and K3PO4. In the meantime, the use of directing groups is an efficient way to improve reactivity and selectivity.5 Recently, Li’s6 group reported the synthesis of benzimidazoles by annulation of aniline derivatives with dioxazolones based on C−H activation. Here, the aminopyridyl group was not a removable directing group, and the products were limited to 2-phenylbenzimidazoles. Other nitrogen-containing functional groups, especially the N−H imine, have been widely explored as directing groups and allow expedient access to various azacycles in a highly efficient manner through C−H activation. The amino moiety could work as both a directing group and an amine source of azacycles. Via this strategy, the groups of Wang,7a Glorius,7b and others reported Cp*Rh(III)-, Cp*Co(III)-, and [MnBr(CO)5]-catalyzed cyclizations of N−H imines with alkene, alkyne, or diazo compounds.7 In these procedures, the N−H imine serves as a directing group for C−H bond functionalization, and the nucleophilicity of the N−H triggers a subsequent tandem cyclization and thus provides a powerful strategy for the synthesis of mononitrogen heterocycles. © 2018 American Chemical Society

Received: July 1, 2018 Published: August 9, 2018 4930

DOI: 10.1021/acs.orglett.8b02057 Org. Lett. 2018, 20, 4930−4933

Letter

Organic Letters

Scheme 1. Scope of N-Phenylalkylimidamides and NHydroxycarbamatesa

Table 1. Screening of Various Parameters for the Reaction of N-Phenylalkylimidamides and N-Hydroxycarbamatesa

entry

cat. (mol %)

oxidant

base

1 2 3 4c 5 6 7 8 9 10 11 12 13 14 15

[Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [CpRh*Cl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [CpRh*Cl2]2 [Cp*RhCl2]2 [Cp*IrCl2]2 Pd(OAc)2

AgOAc Ag2O K2S2O8 Ag2CO3

t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK

Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3

LiOAc K3PO4 Et3N t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK

acid PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH HOAc benzoic acid TFA PivOH PivOH

yieldb (%) 45 58 33 91 18 trace 51 67 47 trace 31 52 NR trace NR

a

Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (2.5 mol %), AgOAc (1 equiv), acid (2 equiv), base (50 mol %), solvent (1.5 mL), 12 h, under air, 100 °C. bIsolated yields. c36 h.

presence of a series of bases, including the organic base, Et3N, in spite of its somewhat lower efficiency (entries 6−9). Next, the acid was evaluated. Clearly, the control experiment showed that the acidity had a great effect on the reaction (entry 10). No reaction was observed in the presence of strong acids, such as trifluoroacetic acid (TFA) (entry 13). The addition of benzoic acid led to the product in 52% yield (entry 12). A trace amount of 3aa was detected when [Cp*IrCl2]2 was used as the catalyst (entry 14). On the other hand, Pd(OAc)2 inhibited the progress of the reaction (entry 15). With the optimized reaction conditions in hand, we investigated the generality and scope of this reaction (Scheme 1). N-Phenylalkylimidamides bearing various electron-donating and halide groups at the para position all coupled smoothly with 2a to afford the target products in generally good yields (3ba−ia). Among them, the yield of the methyl-substituted Nphenylalkylimidamides 3ba was the highest and reached up to 93%. Derivatives substituted by a halogen atom on the para position gave moderate to good yields (3ca−fa). Introduction of a substituent at the meta position of N-phenylalkylimidamides was also tolerated. When the meta substituent was halogen (3ka chloro, 3la bromo, 3ma iodo), C−H functionalization occurred exclusively at the less hindered ortho site and made further functionalization possible. We next employed N-phenylalkylimidamides bearing ortho substituents (Cl, Br, and Me) as arene substrates (3na−pa). A methyl substituent at the ortho position of the benzene (3na) resulted in the highest yield up to 97%, thus indicating high steric tolerance in this system, which is different from our previous work.10 In addition, N-naphthylalkylimidamide was a suitable substrate, giving the corresponding benzimidazole (3qa) in 68% yield through selective reaction at the C2-position rather than the C8-position.

a

Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [Cp*RhCl2]2 (2.5 mol %), Ag2CO3 (1 equiv), PivOH (2 equiv), t-BuOK (50 mol %), DCE (1.5 mL), 36 h, under air, 100 °C.

Moreover, the imine substrate was not limited to Nphenylpivalimidamide. The reaction proceeded smoothly to afford the annulated products in moderate to good yields when an alkyl substituent was introduced to the α-position of the N−H imine group. N-Phenylalkylimidamides substituted by isobutyl and cyclopropyl on the imine carbon led to good yields of 75% (3sa) and 90% (3ta). Introduction of benzyl led to a moderate yield of 56% (3ra). To our delight, other substituted hydroxylamines could be installed by this amidation reaction in a slightly lower yield of 77% (3ab), which perhaps results from a weaker coordinating ability compared to that of N-Cbz hydroxylamines. 4931

DOI: 10.1021/acs.orglett.8b02057 Org. Lett. 2018, 20, 4930−4933

Letter

Organic Letters According to these literature precedents,11 a plausible reaction mechanism is given in Scheme 2. First, [Cp*RhCl2]2

ORCID

Xiuling Cui: 0000-0001-5759-766X Notes

Scheme 2. Plausible Reaction Mechanism

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the NSF of China (Nos. 21572072 and 21602064), the Xiamen Southern Oceanographic Center (15PYY052SF01), and the Science and Technology Bureau of Xiamen City (3502Z20150054).

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was transformed to [Cp*Rh(OPiv)2] as an active catalyst by treatment with t-BuOK/PivOH. Then, the six-membered rhodacycle A was formed through the coordination of Nphenylalkylimidamides to the rhodium center and a subsequent ortho C−H bond activation. Coordination of E, which was generated from oxidation of 2a in situ, gave intermediate B. The thus formed B underwent migratory insertion or nucleophilic addition to give the intermediate C. Subsequently, intramolecular nucleophilic attack at the N atom with the concomitant N−O cleavage afforded amide species D. βHydride elimination gave rise to the product 3aa with one molecule of NH3 and H2O from D upon intramolecular protonolysis, while the catalytically active rhodium(III) was regenerated under the acidic conditions. In summary, we have developed a novel method to synthesize 2-alkylbenzimidazole and its derivatives through the direct C−H amination of imidamides with hydroxylamines catalyzed by Cp*Rh(III), employing readily available Nhydroxycarbamates as a nitrogen source. Various 2-alkylbenzimidazoles were conveniently afforded in good to excellent yields under relatively mild conditions. Further mechanistic studies and other novel transformations of imidamides are underway in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02057. General procedures, relevant NMR spectra, and catalytic experiments (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. 4932

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DOI: 10.1021/acs.orglett.8b02057 Org. Lett. 2018, 20, 4930−4933