One-pot synthesis of 1,2-diphenyl-1H-benzo[d]imidazole derivatives by a Pd-catalyzed N-arylation and Cu-catalyzed C–H functionalization/C–N bond formation process

Abstract

A one-pot synthesis of 1,2-diphenyl-1H-benzo[d]imidazole derivatives starting from N-phenylbenzimidamides and iodobenzenes or bromobenzenes has been introduced. The process consisted of a Pd-catalyzed N-arylation and a Cu-catalyzed C–H functionalization/C–N bond formation.

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Metal-catalyzed C–H functionalization, because of its atom economy and environmental benefits, has been intensively investigated in the past decade.¹ C–H functionalization/C–N bond formation has been a promising strategy to prepare N-heterocycles from simple precursors,² which exist as fundamental motifs in the scaffold of more than half of the biological molecules and pharmaceutical products. Recently, more concise cascade, tandem, and domino reactions involving C–H functionalization/C–N bond formation attract chemists of increasing interest,³ because these processes avoid the tedious step by step separations and purifications of intermediates and reduce the amount of pollutant waste. Amidine is a type of easily obtainable compound and often used as synthetic precursor. Tandem reactions starting from amidines have been reported by many groups to synthesize diverse benzimidazoles,^12–15 quinazolinones,⁴ quinazoline,⁵ pyrimidines⁶ and imidazoles.⁷ On the other hand, a broad variety of Pd-catalyzed coupling reactions of N–H nucleophiles with C–X (X = Br, I) bonds,^8,14b and Cu-catalyzed oxidative cross-dehydrogenative-couplings (CDC) of C–H bonds with N–H bonds^9,12a have also been reported. Obviously, a process of Pd-catalyzed N-arylation and Cu-catalyzed C–H functionalization/C–N bond formation in one-pot starting from amidines is more concise.

Benzimidazole motif is often found in commercial medicine.¹⁰ Therefore, it is not surprising that the efficient synthesis of benzimidazoles is always in high demand for organic and medicinal chemistry.¹¹ In the past decade, some interesting literatures using amidines to synthesize benzimidazoles have been reported. Buchwald, Shi and Zhu groups reported the synthesis of 1-H-2-substituted benzimidazoles through intramolecular-cyclization of N-phenylbenzimidamides.¹² Brain, Deng and Punniyamurthy groups reported the synthesis of 1,2-disubstituted benzimidazoles through intramolecular aryl-amination of N′-(2-halophenyl)-N-phenylbenzimidamides.¹³ Deng and You groups reported the synthesis of 1,2-disubstituted benzimidazoles through intermolecular tandem amination, starting from 1,2-dihaloarenes and 1,2-disubstituted amidines.¹⁴ Zhu group reported an one-pot synthesis of 1,2-disubstituted benzimidazoles by a Chan–Lam–Evans N-arylation and C–H activation/C–N bond forming process, starting from organoboronic acids and 1,2-disubstituted amidines.¹⁵ In this paper, we report a more efficient and economic one-pot synthesis of 1,2-diphenyl-1H-benzo[d]imidazole derivatives from N-phenylbenzimidamides and iodo- or bromobenzenes. The 1,2-diphenyl-1H-benzo[d]imidazole derivatives have been used as cyclometalated ligands or important components to prepare iridium(III) or platinum(II) complexes that exhibit improved luminescence properties and stability for applications.¹⁶

Firstly, we studied the reaction stepwise (Scheme 1). Initially, equivalent N-phenylbenzimidamide 1a and iodobenzene 2a were examined to form the coupling product A. When Pd(OAc)₂ (5 mol%), xantphos (5 mol%) and Cs₂CO₃ (1.0 equiv.) were added, and the mixture was reacted in xylene under nitrogen atmosphere at 140 °C for 18 h, nearly equivalent product A was isolated (Scheme 1(1), 94% yield). Then the A was further examined to synthesize the final cyclized product 3a. When Pd(OAc)₂ (5 mol%) was catalyst and Cu(OAc)₂ (1.2 equiv.)/O₂ was oxidant, the desired product 3a was obtained in 56% yield after reacted in xylene at 140 °C for 18 h (Scheme 1(2)). Excitingly, when no Pd(OAc)₂ was added, Cu(OAc)₂ was reduced to 0.3 equiv. and O₂ was the final oxidant, the desired product 3a was obtained in satisfactory yield of 88% after 6 h in xylene at 140 °C (Scheme 1(3)). Therefore, we obtained the best reaction condition for stepwise process. Based on these conditions, the one-pot reaction condition was optimized as follows (Table 1).

Scheme 1 Two-step synthesis of 1,2-diphenyl-1H-benzo[d]imidazole 3a.

Table 1 Optimization of one-pot synthesis conditions of 3a^a

Entry	(i)		(ii)		Yield^b (%)
	Ligand (5 mol%)	Temp (°C)	Catalyst (equiv.)/oxidant	Temp (°C)
a Reaction conditions: (i) 1a (0.3 mmol), 2a (0.3 mmol), Pd(OAc)2 (5 mol%, 0.015 mmol), ligand (5 mol%, 0.015 mmol), Cs2CO3 (0.3 mmol) in solvent under N2 for 18 h, then (ii) catalyst/oxidant was added for 8 h.b Isolated yield of 3a.c Xantphos = 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.d 2a was 1.5 equiv. and the reaction time of step (ii) was 30 hourse dppp = 1,3-bis(diphenyphosphino)propane.f dppf = 1,1′-bis(diphenyphosphino)ferrocene.g NMP was solvent.h DMSO was solvent.
1	Xantphos^c	140	Cu(OAc)2 (0.3)/O2	140	82
2	Xantphos	140	Cu(OAc)2 (1.2)/air	140	54
3	Xantphos	140	O2	140	10
4	Xantphos	140	Cu(OTf)2 (0.3)/O2	140	50
5	Xantphos	140	FeCl3 (0.3)/O2	140	5
6	Xantphos	140	FeBr3 (0.3)/O2	140	10
7	Xantphos	120	Cu(OAc)2 (0.3)/O2	120	31
8	Xantphos	120	Cu(OAc)2 (0.3)/O2	140	55
9^d	Xantphos	140	Cu(OAc)2 (0.3)/O2	140	67
10	PPh3	140	Cu(OAc)2 (0.3)/O2	140	Trace
11	dppp^e	140	Cu(OAc)2 (0.3)/O2	140	Trace
12	dppf^f	140	Cu(OAc)2 (0.3)/O2	140	Trace
13^g	Xantphos	140	Cu(OAc)2 (0.3)/O2	140	31
14^h	Xantphos	140	Cu(OAc)2 (0.3)/O2	140	Trace

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Equivalent N-phenylbenzimidamide 1a and iodobenzene 2a, Pd(OAc)₂ (5 mol%), xantphos (5 mol%) and Cs₂CO₃ (1.0 equiv.) were mixed in an over-dried Schlenk tube, and the mixture was reacted in xylene under nitrogen atmosphere at 140 °C for 18 h, then Cu(OAc)₂ (0.3 equiv.)/O₂ was added. The desired product 3a was obtained in exciting yield of 82% (Table 1, entry 1). To increase the yield of 3a, we examined the condition of step (ii) firstly. When 1.2 equiv. Cu(OAc)₂ was added as oxidant, and the reaction of step (ii) was conducted in air, the yield of 3a was 54% (Table 1, entry 2). When only O₂ atmosphere was applied to the reaction step (ii), few of 3a was obtained (Table 1, entry 3). So as a catalyst, Cu²⁺ may be necessary, and O₂ may be a final oxidant. Unfortunately, after testing other copper sources and iron sources, no better system was obtained than Cu(OAc)₂/O₂ (Table 1, entries 4–6). Reducing the temperature of step (i) or step (ii) caused diminution in the yield (Table 1, entries 7 and 8). When the proportion of 2a was raised to 1.5 equiv., the reaction time of step (ii) should be extended to 30 hours, and the yield of 3a was decreased to 67% (Table 1, entry 9). Then three phosphate ligands and two solvents were screened, xantphos and xylene were found to be superior (Table 1, entries 10–14). Eventually, the conditions described in entry 1 were selected as the optimal conditions.

With the optimized reaction conditions in hand, a variety of substituted N-phenylbenzimidamides and iodobenzenes were tested to explore the scope and the generality of the one-pot reaction (Scheme 2). From the scheme, it could be seen that if substituted groups R¹ and R³ were different, there would be two benzimidazole isomers produced. When R¹ or R³ was p-electron-donating group, such as –CH₃, –C₂H₅, –OMe or –OCF₃, excellent yield was obtained, and the main isomer was 6-substituted-1,2-diphenyl-1H-benzo[d]imidazole 3b, 3c, 3d or 3e. When R¹ or R³ was moderate p-electron-withdrawing group, such as –F, –Cl or –Br, the yield was a little less than the yield of electron-donating substrate. However, the main isomer was also 6-substituted-1,2-diphenyl-1H-benzo[d]imidazole 3g, 3h or 3i. Maybe there were two tautomeric isomers in intermediate A. When intermediate A underwent the cyclization reaction in the second step, two factors influenced it. In p-electron-donating substituted intermediate A, electron-rich phenyl ring was easier to cyclize with nitrogen.¹⁷ In p-halogen substituted intermediate A, the halogens may stabilize the positive metallacycle IV, just like in aromatic electronic substitutions. When R³ was –COOMe, the main isomer was methyl 4-(2-phenyl-1H-benzo[d]imidazol-1-yl)benzoate 3j with moderate yield, cyclization took place on electron-rich phenyl ring. When R¹ was –NO₂, no desired product was obtained. 4-Nitro-N-phenylaniline was formed instead of the intermediate A. When R³ was –NO₂, the final product 3k could be obtained, but the yield was very low. In this instance, the intermediate A could be formed, but a lot of 4-nitro-N-phenylaniline was also formed, so the yield was low. The mainly produced isomer was also 1-(4-nitrophenyl)-2-phenyl-1H-benzo[d]imidazole 3k, cyclization also took place on electron-rich phenyl ring. When R¹ and R³ were the same, no isomer was generated. However, comparing 3n with 3o, and 3p with 3q, it could be seen that the yields of o-substituted products were lower than p-substituted and m-substituted products. It directly showed the steric hindrance. This steric effect could also be seen in the reaction of N-(2-methoxyphenyl)benzimidamide 1f with 2a. In this reaction, not only the yield was obviously decreased, but also main isomer was changed to 1-(2-methoxyphenyl)-2-phenyl-1H-benzo[d]imidazole 3f′.

Scheme 2 One-pot synthesis of diversely substituted benzimidazoles 3 and 3′.

Taking economic factor into account, bromobenzene 2f and 1-bromo-4-methylbenzene 2g were reacted with 1a, 1b or 1m under the optimized reaction conditions in Scheme 3. To our delight, these reactions could also be well conducted with acceptable yields, though a little less than the corresponding yields with iodobenzenes.

Scheme 3 One-pot synthesis of benzimidazoles with bromobenzenes.

According to all the above results, a plausible mechanism was proposed as shown in Scheme 4. Firstly the oxidative addition of iodobenzene 2a to Pd⁰ generated aryl palladium iodine complex I. Then the amidine 1g was coordinated to I, and then an amido complex II was formed. Subsequent reductive elimination of II released the intermediate aryl amidine A and regenerated the Pd⁰ catalyst. A existed in a mixture of two isomers. The mechanical route of one isomer was described as follows. Under the action of Cu(OAc)₂, a Cu–N adduct III was formed. Then the N-phenyl ring attacked the copper center in III to give a metallacycle IV. Subsequent re-aromatization and elimination processes produced the major product 3g. Copper was released in the Cu(I) state and oxidized by O₂ to Cu(II).

Scheme 4 A plausible mechanism.

Conclusions

In summary, we have introduced a method that Pd-catalyzed N-arylation and Cu-catalyzed C–H functionalization/C–N bond formation in one-pot. This method provides an efficient and concise approach to 1,2-diphenyl-1H-benzo[d]imidazole derivatives in moderate to excellent yields, starting from N-phenylbenzimidamides and iodobenzenes or bromobenzenes.

Acknowledgements

This work is financially supported by the Natural Science Foundation of China (no. 21072168).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, NMR spectra and characterizations for all new compounds. See DOI: 10.1039/c4ra09542a

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