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. Author manuscript; available in PMC: 2013 Oct 8.
Published in final edited form as: Angew Chem Int Ed Engl. 2012 Sep 11;51(41):10364–10367. doi: 10.1002/anie.201204710

Catalyst-Controlled Chemoselective Arylation of 2-Aminobenzimidazoles

Satoshi Ueda 1, Stephen L Buchwald 1,✉
PMCID: PMC3517016  NIHMSID: NIHMS415537  PMID: 22969040

Abstract

The chemoselective and complementary Pd-and Cu-catalyzed N-arylation of 2-aminobenzimidazoles is described. Selective N-arylation of the amino-group was achieved with a Pd-catalyzed method, while selective N-arylation of azole nitrogen was achieved with a Cu-catalyzed procedure. The utility of these complementary sets of conditions is demonstrated in several two-step, selective syntheses of di-arylated aminoazoles.

Keywords: palladium, copper, C-N coupling, aminoazole, N-arylation

Transition-metal catalyzed heteroatom-arylation reactions are emerging as valuable tools in organic synthesis, fuelled by the identification of more efficient catalyst systems with increased substrate scopes.[1] The synthetic utility of these transformations is increased if catalysts are both highly reactive and selective. This is particularly important for substrates with multiple heteroatom sites capable of undergoing reaction. Furthermore, the development of complementary sets of catalysts or conditions for the selective arylation of substrates possessing multiple nucleophilic sites enables the rapid, protecting group-free generation of molecular complexity with minimal synthetic manipulations. In this context, we have developed sets of procedures for the Pd- and Cu-catalyzed chemoselective arylation of aminobenzamides,[2a] 5-aminoindole,[2a] 4-(2-aminoethyl)aniline,[2a] amino alcohols,[2b] oxindoles[2c] and aminophenols. [2d]

During our work on the N-arylation of nitrogen-containing heterocycles,[3] we became interested in the use of 2-aminobenzimidazoles as potential substrates for chemoselective N-arylation reactions. Both N1-aryl-2-aminobenzimidazoles and 2-arylaminobenzimidazoles are found in a variety of medicinally important compounds including integrin α4β1 antagonists,[4] mTOR inhibitors,[5] aurora kinase inhibitors,[6] Tie-2 kinase inhibitors,[7] Ca channel blockers,[8] and CXCR2 antagonists.[9 Thus, the selective syntheses of both of these isomers from a common core structure represent attractive alternatives to other previously-employed routes[10–11] and could provide rapid access to a diverse array of potentially bioactive 2-aminobenzimidazole derivatives (Scheme 1).

Scheme 1.

Scheme 1

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Chemoselective arylation of 2-aminobenzimidazole

While the efficient Cu-[12] and Pd-catalyzed[13] N1-arylations of some benzimidazole derivatives with aryl halides have been described, the chemoselective N-arylation of unprotected 2-aminobenzimidazoles with aryl halides has received little attention. [14–16] Potential challenges of such an approach include the formation of regioisomers and/or poly-arylated products due to the presence of three adjacent nucleophilic nitrogens (N1, N3 and C2-amino group), as well as the tautomeric nature of 2-aminobenzimidazoles. Herein, we report the successful development of an orthogonal set of Pd- and Cu-catalyzed chemoselective conditions for the N-arylation of unprotected 2-aminobenzimidazoles and related aminoazoles.

graphic file with name nihms415537u1.jpg

We initiated our investigation by examining the Pd-catalyzed coupling of 2-aminobenzimidazole and bromobenzene (Table 1). With Pd2(dba)3 (0.1 mol%), L1 (0.2 mol%), and K3PO4, the N-arylation went smoothly to give 2-anilinobenzimidazole 1a in 92% yield and without formation of regioisomer 1b or poly-arylated products (entry 1). The use of other biaryl phosphine ligands (L2–L4) provided low yields of product under these conditions. Replacing K3PO4 with other bases also resulted in lower yield of the product (entries 5–6).

Table 1.

Reaction optimization[a]

graphic file with name nihms415537u2.jpg
entry metal source (mol %) ligand (mol %) X base (1.5 eq.) yield (%)
1 Pd2(dba)3 (0.1) L1 (0.2) Br K3PO4 1a/92
2 Pd2(dba)3 (0.1) L2 (0.2) Br K3PO4 1a/<5
3 Pd2(dba)3 (0.1) L3 (0.2) Br K3PO4 1a/23
4 Pd2(dba)3 (0.1) L4 (0.2) Br K3PO4 1a/<5
5 Pd2(dba)3 (0.1) L1 (0.2) Br Cs2CO3 1a/14
6 Pd2(dba)3 (0.1) L1 (0.2) Br NaOt-Bu 1a/<5
7 CuI (10) L5 (15) I Cs2CO3 2a/89
8[b] CuI (10) L5 (15) Br Cs2CO3 2a/70
9 CuI (10) L6 (15) I Cs2CO3 2a/10
10 CuI (10) L7 (15) I Cs2CO3 2a/45
11 CuI (10) L8 (15) I Cs2CO3 2a/<5
12 CuI (10) L5 (15) I K2CO3 2a/45
13 CuI (10) L5 (15) I K3PO4 2a/39
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[a]

Conditions for entries 1–6: PhBr (1 mmol), 2-aminobenzimidazole (1.1 mmol), base (1.5 mmol), Pd2(dba)3 (0.1 mol%), ligand (0.2 mol%), t-BuOH (1.5 mL), 120 °C, 5 h. Conditions for entries 7–13: PhI or PhBr (1 mmol), 2-aminobenzimidazole (1.1 mmol), base (1.5 mmol), CuI (10 mol%), ligand (15 mol%), t-BuOH (1.5 mL), 90 °C, 16 h.

[b]

Reaction was performed at 120 °C.

Turning our attention to finding conditions for the selective formation of the the N1-arylated product (2a), we found that reactions with a Cu-catalyst system (iodobenzene/bromobenzene, CuI, L5,[17] and Cs2CO3) were completely chemoselective, providing no trace either of regioisomer 1a or of any poly-arylated products (entries 7–8). The use of other ligands (L6–L8) and bases did not alter this chemoselectivity, but rather gave lower yields of 1b (entries 9–13). Thus, complete selectivity and complementarity can be achieved using Pd- and Cu-based catalyst systems.

We next explored the scope of the Pd-catalyzed selective N-arylation of aminoazoles, and found that a variety of 2-aminobenzimidazoles and 2-aminoimidazole could be coupled chemoselectively with both electron-rich and electron-poor aryl halides, as well as with an ortho-substituted aryl halide (Table 2, 1b–1h).[18] For 3-amino-5-alkylpyrazoles the primary amino groups were also selectively and efficiently arylated using 0.2–0.5 mol% catalyst. Though the selective Pd-catalyzed N-arylation of 3-aminopyrazoles has been previously reported, relatively high catalyst loadings (5 mol% Pd and 10 mol% L4) and the use of a strong base (NaOtBu) were required.[13a]

Table 2.

Scope of the Pd-catalyzed N-arylation[a]

graphic file with name nihms415537f3.jpg
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[a]

aryl halide (1 mmol), aminoazole (1.1 mmol), K3PO4 (1.5 mmol), Pd2(dba)3 (0.1–0.5 mol%), L1 (0.2–1 mol%), t-BuOH (1.5 mL), 120 °C, 5 h. Yield of isolated product, average of two runs.

[b]

2-aminoimidazole sulfate (1.1 mmol), K3PO4 (2.5 mmol) and DMF were used.

The scope of the Cu-catalyzed N1-selective arylation was also investigated (Table 3). Reactions of 2-aminobenzimidazoles and 2-aminoimidazole with a variety of functionalized aryl iodides gave N1-arylated products 2b–2f and 2i selectively and in good yields. The N-arylation of unsymmetrical 2-amino-4-methylbenzimidazole reacted at the less sterically-hindered N1-position to provide 2g. Both electron-rich, 2e, g and electron-deficient aryl halides reacted smoothly to give products in high yield. Lastly, reactions of 2-alkylaminobenzimidazoles gave N1-arylated products 2j and 2k in good yields. Not surprisingly, the process showed good functional group compatibility.

Table 3.

Scope of the Cu-catalyzed N-arylation[a]

graphic file with name nihms415537f4.jpg
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[a]

aryl halide (1 mmol), aminoazole (1.1 mmol), Cs2CO3 (1.5 mmol), CuI (10 mol%), L5 (15 mol%), t-BuOH (1.5 mL), 90–110 °C, 16 h. Yield of isolated product, average of two runs.

[b]

0.5 mmol scale.

[c]

2-aminoimidazole sulfate (1.1 mmol), Cs2CO3 (2.5 mmol) were used.

Having established a complementary set of Pd- and Cu-catalyzed chemoselective arylation methods, we sought to apply our methods to selective two-step syntheses of diarylaminoazoles from unprotected aminoazoles using sequential Pd- and Cu-catalyzed reactions (or vice versa). Parent 2-aminobenzimidazole could be selectively arylated via an initial Pd-catalyzed N-arylation of 2-aminobenzimidazole, followed by a subsequent Cu-catalyzed arylation to give 3. Diarylated 3-aminoindazole 4 was prepared via a Cu-catalyzed reaction of 3-aminoindazole, followed by arylation via the Pd-catalyzed method. In both cases, the reaction order was important. In the first case, only a trace amount of 3 was obtained when the Pd-catalyzed system was used as the second step. For the synthesis of 4, the use of a Pd-catalyst for the first arylation of 3-amioindazole gave a mixture of mono- and di-arylated products.[19]

In summary, we have developed an orthogonal set of Pd- and Cu-catalyzed N-arylations of 2-aminobenzimidazoles and related aminoazoles. Selective N-arylation of the primary amino-group of 2-aminobenzimidazoles was achieved via Pd-catalyzed methods, while selective N-arylation of the azole nitrogen was achieved with Cu-catalysis. These general protocols are compatible with a variety of aryl halides and give facile access to an array of both isomers of N-arylaminoazoles from common aminoazole precursors.

Supplementary Material

Supporting Information

Scheme 2.

Scheme 2

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Selective syntheses of diarylaminoazoles

Acknowledgments

This work is supported by National Institutes of Health (GM58160). S.U. thanks the Japan Society for the Promotion of Sciences (JSPS) for a Postdoctral Fellowship for Research Abroad. We thank Dr. Meredeth A. McGowan for help with preparation of this manuscript.

Footnotes

Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author.

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  • 19.See supporting information for details.

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Supplementary Materials

Supporting Information
NIHMS415537-supplement-Supporting_Information.pdf (14.5MB, pdf)

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