Pd-catalyzed efficient synthesis of benzo[4,5]imidazo[1,2-a]indoles with diaziridinone

Abstract

This work describes an efficient Pd-catalyzed synthesis of benzo[4,5]imidazo[1,2-a]indoles from readily available 1-(2-iodophenyl)-1H-indoles and di-t-butyldiaziridinone. A variety of benzo[4,5]imidazo[1,2-a]indoles can be obtained in up to 96% yield. The reaction likely proceeds via an intramolecular aryl C–H activation to form a pallada(II)cycle, which is subsequently bisaminated with di-t-butyldiaziridinone.

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Indoles are some of the most common nitrogen heterocycles. Indole fused N-heterocycles such as benzo[4,5]imidazo[1,2-a]indole (1) and its related derivatives widely exist in various natural products, biologically active molecules, and materials (Fig. 1).^1–3 Benzo[4,5]imidazo[1,2-a]indoles containing an indole and an imidazole have displayed unique properties and have great potential in organic light-emitting devices (OLEDs) as well as in drug development. The construction of structurally diverse benzo[4,5]imidazo[1,2-a]indoles and their related derivatives is of interest. A number of synthetic methods have been reported.⁴ In most cases, the reaction processes involve cyclization via C–C or C–N bond formation from precursors with all nitrogen atoms already being incorporated. In a few cases, only one example of benzo[4,5]imidazo[1,2-a]indole was reported.^4a,b,d There are several reports showing that benzo[4,5]imidazo[1,2-a]indoles can be oxidatively formed from 2-(1H-indol-1-yl)anilines with oxidants or via electrochemical oxidation (Scheme 1a).^4e–h It has also been reported that benzo[4,5]imidazo[1,2-a]indoles can be synthesized from bis(o-iodoaryl)carbodiimides and malonates via copper-catalyzed domino addition/double cyclization reaction processes (Scheme 1b).^4c Each method appears to have its own substrate scope and limitation. New and efficient reaction processes are still highly desirable. As part of our ongoing efforts in constructing nitrogen-heterocycles via bisamination of pallada(II)cycles with diaziridinone (Scheme 2),^5–7 we wish to report that benzo[4,5]imidazo[1,2-a]indoles 11 can be efficiently generated from 1-(2-iodophenyl)-1H-indoles 9 and di-t-butyldiaziridinone 6 with simultaneous formation of two C–N bonds⁸ (Scheme 3).

Fig. 1 Examples of benzo[4,5]imidazo[1,2-a]indole and its derivatives.

Scheme 1 Examples of reported methods for benzo[4,5]imidazo[1,2-a]indoles.

Scheme 2 Bisamination of pallada(II)cycles with diaziridinone.

Scheme 3 Synthesis of benzo[4,5]imidazo[1,2-a]indoles with diaziridinone.

Indole 9a was used as a test substrate. Various ligands were initially examined for the reaction with 5 mol% Pd(OAc)₂, di-t-butyldiaziridinone (6) (1.5 equiv.), and Cs₂CO₃ (2.0 equiv.) in dioxane at 85 °C for 12 h (Table 1, entries 1–16). To our delight, the desired benzo[4,5]imidazo[1,2-a]indoles 11a were obtained in all cases, with xantphos being the best, affording 11a in 75% yield as determined by ¹H NMR (Table 1, entry 16). A slightly higher yield (86%) was obtained when PdBr₂ was used as a catalyst (Table 1, entry 18). The yield increased to 96% when the reaction temperature was raised to 100 °C (Table 1, entry 23). 1,4-Dioxane appeared to be the best for the reaction among the solvents examined (Table 1, entry 23 vs. entries 26–30).

Table 1 Studies of reaction conditions^a

Entry	[Pd]	Ligand	Temperature	Solvent	Yield^b (%)
a All reactions were carried out with indole 9a (0.10 mmol), di-t-butyldiaziridinone 6 (0.15 mmol), Pd (0.0050 mmol), ligand (0.0050–0.010 mmol, Pd/P = 1/2), and Cs2CO3 (0.20 mmol) in 1,4-dioxane (0.5 mL) at 85 °C under N2 for 12 h unless otherwise stated. b The yield was determined by ^1H NMR analysis of the crude reaction mixture with BnOMe as the internal standard.
1	Pd(OAc)2	PPh3	85 °C	1,4-Dioxane	47
2	Pd(OAc)2	(o-Tolyl)3P	85 °C	1,4-Dioxane	21
3	Pd(OAc)2	(p-Tolyl)3P	85 °C	1,4-Dioxane	48
4	Pd(OAc)2	(p-MeOPh)3P	85 °C	1,4-Dioxane	26
5	Pd(OAc)2	(p-FPh)3P	85 °C	1,4-Dioxane	58
6	Pd(OAc)2	(p-CF3Ph)3P	85 °C	1,4-Dioxane	45
7	Pd(OAc)2	CyPPh2	85 °C	1,4-Dioxane	46
8	Pd(OAc)2	Cy2PPh	85 °C	1,4-Dioxane	46
9	Pd(OAc)2	Cy3P	85 °C	1,4-Dioxane	20
10	Pd(OAc)2	(2-Furyl)3P	85 °C	1,4-Dioxane	22
11	Pd(OAc)2	Dppm	85 °C	1,4-Dioxane	13
12	Pd(OAc)2	Dppe	85 °C	1,4-Dioxane	18
13	Pd(OAc)2	Dpph	85 °C	1,4-Dioxane	13
14	Pd(OAc)2	Dppf	85 °C	1,4-Dioxane	40
15	Pd(OAc)2	BINAP	85 °C	1,4-Dioxane	13
16	Pd(OAc)2	Xantphos	85 °C	1,4-Dioxane	75
17	PdCl2	Xantphos	85 °C	1,4-Dioxane	31
18	PdBr2	Xantphos	85 °C	1,4-Dioxane	86
19	PdI2	Xantphos	85 °C	1,4-Dioxane	64
20	Pd(TFA)2	Xantphos	85 °C	1,4-Dioxane	83
21	Pd(CH3CN)4(BF4)2	Xantphos	85 °C	1,4-Dioxane	28
22	Pd(dba)2	Xantphos	85 °C	1,4-Dioxane	34
23	PdBr2	Xantphos	100 °C	1,4-Dioxane	96
24	PdBr2	Xantphos	115 °C	1,4-Dioxane	95
25	PdBr2	Xantphos	130 °C	1,4-Dioxane	87
26	PdBr2	Xantphos	100 °C	DMF	87
27	PdBr2	Xantphos	100 °C	DMSO	83
28	PdBr2	Xantphos	100 °C	THF	94
29	PdBr2	Xantphos	100 °C	PhMe	78
30	PdBr2	Xantphos	100 °C	CH3CN	64

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Having the optimized reaction conditions in hand, the reaction generality was subsequently investigated with a range of 1-(2-iodophenyl)-1H-indoles 9. As shown in Table 2, the reaction can be extended to various 5-substituted indoles, affording the corresponding benzo[4,5]imidazo[1,2-a]indoles 11a–k in 39–96% yields (Table 2).⁹ The reaction was compatible with various substituents including Me (11b), OMe (11e), F (11f), Cl (11g), CHO (11h), CO₂Me (11i), CN (11j), and NO₂ (11k). Electron-withdrawing groups such as CN and CO₂Me appeared to be beneficial for the reaction, while a lower yield was obtained with an electron-donating OMe group. The reaction can also be applied to various 6-substituted (Table 2, 9l–q), 4-substituted (Table 2, 9r–t), and 7-substituted (Table 2, 9u) indoles, affording the corresponding benzo[4,5]imidazo[1,2-a]indoles 11l–u in 49–90% yields. When 3-methyl indole 9v was subjected to the reaction conditions, the corresponding product was obtained in only 29% yield, possibly due to the steric bulkiness of the 3-methyl group. The reaction was also effective for pyridine fused indole 9w and benzo[d]imidazole 9x, affording the corresponding products 11w and 11x in 88% and 81% yields, respectively. The reaction was also applicable to indoles bearing substituted N-phenyl rings 9y and 9z as well as N-pyridine ring 9aa, affording the corresponding benzo[4,5]imidazo[1,2-a]indoles 11y, 11z, and 11aa in 61%, 38% and 92% yields, respectively.^10,11

Table 2 The substrate scope^a,b

a All reactions were carried out with indole 9 (0.30 mmol), di-t-butyldiaziridinone 6 (0.45 mmol), PdBr₂ (0.015 mmol), xantphos (0.015 mmol), and Cs₂CO₃ (0.60 mmol) in 1,4-dioxane (1.0 mL) at 100 °C under N₂ for 12 h unless otherwise stated. b Isolated yield. c With PdBr₂ (0.030 mmol) and xantphos (0.030 mmol) at 120 °C. d For 24 h.

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As exemplified with 9a, the reaction can be carried out on a gram scale, affording benzo[4,5]imidazo[1,2-a]indole 11a in 82% yield (Scheme 4). Treating 11a with CF₃SO₃H/cyclohexane led to the formation of imidazole 12 in 70% yield (Scheme 5).^4h,5b

Scheme 4 Synthesis of 11a on a gram scale.

Scheme 5 Synthetic transformations of 11a.

The oxidation of 12 with O₂ gave 11H-benzo[4,5]imidazo[1,2-a]indol-11-one 13 in 82% yield (Scheme 5).^4h,12

A precise understanding of the reaction mechanism awaits further studies. A plausible catalytic cycle is outlined in Scheme 6.⁵ The oxidative addition of Pd(0) to iodophenyl indole 9a gave Pd(II) intermediate 14, which subsequently underwent intramolecular C–H activation to form pallada(II)cycle 15.¹³ The oxidative addition of di-t-butyldiaziridione (6) to 15 led to the formation of pallada(IV)cycle 16, which gave Pd(IV)-nitrene 17 upon release of t-butyl isocyanate. Benzo[4,5]imidazo[1,2-a]indole 11a was eventually formed from 17via two consecutive reductive elimination steps with regeneration of the Pd(0) catalyst.

Scheme 6 Plausible catalytic pathway.

Conclusions

In summary, we have developed an efficient synthesis of benzo[4,5]imidazo[1,2-a]indoles from readily available 1-(2-iodophenyl)-1H-indoles and di-t-butyldiaziridinone in the presence of a Pd(0) catalyst. A wide variety of benzo[4,5]imidazo[1,2-a]indoles bearing various functional groups can be obtained in up to 96% yields. The reaction can be performed on a gram scale, and the resulting benzo[4,5]imidazo[1,2-a]indoles can be further transformed into benzoimidazoles. The reaction was postulated to proceed via an intramolecular C–H activation to form the corresponding pallada(II)cycle, which was subsequently bisaminated with di-t-butyldiaziridinone to afford the benzo[4,5]imidazo[1,2-a]indole. The current amination process further illustrates the versatility of di-t-butyldiaziridinone for the synthesis of polycyclic heterocycles.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI): experimental details, NMR spectra of new compounds and X-ray crystallographic data for 11k. See DOI: https://doi.org/10.1039/d5ob01335f.

CCDC 2372228 contains the supplementary crystallographic data for this paper.¹⁴

Acknowledgements

The authors thank the National Natural Science Foundation of China (22271024 and 21632005) and Changzhou University for financial support.

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