Visible light-mediated intramolecular C–H arylation of diazonium salts of N-(2-aminoaryl)benzoimines: a facile synthesis of 6-arylphenanthridines

Abstract

Utilizing [Ru(bpy)₃]Cl₂ as a photoredox catalyst and a blue LED as an irradiation source, moderate to good yields of 6-arylphenanthridines were obtained from aryl diazonium salts in situ formed from the reactions of N-(2-aminoaryl)benzoimines and tert-butyl nitrite (tBuONO). Although few visible light-mediated protocols are available for the synthesis of 6-arylphenanthridines, this work provides a new method to access them readily from inexpensive and environmentally benign starting materials.

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Introduction

The phenanthridine skeletons¹ are very important due to their pharmaceutical and biological properties including antibacterial, antifungal, antiseptic, antitumor, antiviral, cytotoxic, DNA intercalation and glutamic dehydrogenase inhibitory properties.^1b Thus, the development of new methods to access phenanthridine and its derivatives is of continuing interest to industry and academia.² The classical Pictet–Hubert condensation,³ Morgan–Walls cyclization,⁴ Diels–Alder cycloadditions,⁵ radical-mediated reactions,⁶ metal-catalyzed cross couplings,⁷ microwave-assisted reactions,⁸ cascade/tandem reactions⁹ and so on¹⁰ are some well-established synthetic protocols for phenanthridine syntheses. During the past few years, visible light-mediated syntheses have also emerged as viable strategies for the preparation of various organic compounds including phenanthridine and its derivatives.¹¹ For example, Yu et al.¹² reported that 6-alkylated phenanthridines could be synthesized by somophilic isocyanide insertion reactions, cf. Scheme 1a. Gu et al.¹³ reported a metal-free approach for the exclusive preparation of 6-arylphenanthridines from 2-isocyanobiphenyls and arylsulfonyl chlorides act as a radical source under visible light-irradiation conditions (Scheme 1b). Zhou et al.¹⁴ also reported a metal-free protocol for the synthesis of 6-substituted phenanthridines from 2-isocyanobiphenyls and various radicals. In this case, the authors generated functional radicals from hydrazines by visible light-irradiation (Scheme 1c). In 2014, Yu et al.¹⁵ again reported a new methodology for the synthesis of 6-substituted phenanthridines via intramolecular C–H arylation of iminyl-radicals produced from acyl oximes in the presence of visible light photoredox catalysis and irradiation, cf. Scheme 1d. They also disclosed a visible-light-mediated preparation of 6-trifluoromethyl phenanthridines (Scheme 1e) using the Umemoto reagent as a CF₃ radical precursor.¹⁶ Very recently, the same group once again reported a strategy for the synthesis of 6-mono- and difluoromethylated phenanthridines from 2-isocyanobiphenyls and ethyl bromofluoroacetate/ethyl bromodifluoroacetate (Scheme 1f and g).¹⁷ Of course, each of these methods has its own applications, but remains associated with some disadvantages such as low to moderate yields of products, use of toxic, expensive and unstable precursors, etc.¹⁸ As a consequence, extension of a visible light-induced method for the synthesis of phenanthridines utilizing readily available and environmentally benign starting compounds is very desirable and remains a challenging area for exploration.

Scheme 1 Visible light-mediated synthesis of 6-substituted phenanthridines reported in the literature (a–g) and this work (h).

Aryl diazonium salts¹⁹ have been employed as a source of aryl radicals under visible light-photocatalyzed conditions to synthesize arylboronates, arylsulfides, benzothiophenes, biaryls, biheteroaryls, phenanthrenes, α-phenylketones, stilbenes, trifluoroaryls as well as other compounds.²⁰ Moreover, the availability, stability and safety of diazonium salts are improved by an in situ strategy without being isolated.²¹ In these cases, the amino group (–NH₂) formally acts as a leaving group. To our surprise, there is still no report on the synthesis of 6-arylphenanthridines from aryl diazonium salts or anilines under visible light-photocatalyzed conditions.

Herein, we describe the visible light-mediated intramolecular C–H arylation of aryl diazonium salts to give 6-arylphenanthridines (PHE1–13, Scheme 1h) in good to excellent yields. Moreover, a tentative mechanism is described for the reaction, vide infra. It is worth noting that the various aryl diazonium salts used in this study were produced in situ from inexpensive and ecofriendly starting materials, i.e. N-(2-aminoaryl)benzoimines (IME1–13, Scheme 1h) and tert-butyl nitrite (tBuONO).

Results and discussion

At the outset of this investigation, a solution of N-(2-aminophenyl)benzoimine (IME1, 1.0 mmol.), tBuONO (1.0 mmol) and 1 mol% of Eosin Y in anhydrous acetonitrile under argon was irradiated with a 5 W blue LED lamp at room temperature. After about 24 h, we were pleased to find a desired 6-phenylphenanthridine (PHE1) in 26% yield (Table 1, entry 1). We then explored the influence of solvents on the formation of PHE1. Of the solvents tested (Table 1, entries 2–8), dry DMSO gave a moderate yield (Table 1, entry 7). After this, the amounts of tBuONO were inquired. 1.3 equiv. of tBuONO provided a satisfactory yield (64%, Table 1, entry 10). Further optimizations revealed that this reaction proceeded more efficiently (93%, Table 1, entry 13) in the presence of 1 mol% of [Ru(bpy)₃]Cl₂ (bpy = 2,2′-bipyridine), however other visible light-photoredox catalysts Eosin B and Rose bengal failed to produce satisfactory yields (Table 1, entries 14 and 15). We believe that the superior reduction capacity in the excited state of [Ru(bpy)₃]Cl₂ may be the reason for the higher yield of PHE1 (Table 1, entry 13).¹¹ Subsequently, the influence of the quantity of [Ru(bpy)₃]Cl₂ was investigated. With an increase in the catalyst amount from 1 mol% to 3 mol% and 5 mol%, the reaction time obviously shortened with 92–94% yield of PHE1 (Table 1, entries 16 and 17). A further increase in the catalyst amount showed a profound effect neither on the reaction time nor on the yield of the desired product (Table 1, entry 18). However, no product was observed in the absence of either [Ru(bpy)₃]Cl₂ or tBuONO or the irradiation source (Table 1, entries 19–21). Thus, the optimized conditions for this transformation (Scheme 1h) were 1.0 equiv. of N-(2-aminoaryl)benzoimines (IME), 1.3 equiv. of tBuONO and 1 mol% of [Ru(bpy)₃]Cl₂ in anhydrous DMSO at room temperature for 6 h, cf. ESI.†

Table 1 Selected results of screening the optimal conditions for the photocatalytic formation of 6-phenylphenanthridine (PHE1) from N-(2-aminophenyl)benzoimine (IME1) and tert-butyl nitrite (tBuONO)^a

Entry	Solvent^b	Catalyst^c	Time (h)	Yield^d (%)
a Unless stated otherwise all reactions were performed in a Schlenk tube with 1.0 equiv. of IME1, 1.0–2.0 equiv. of tBuONO and 1 mol% of photoredox catalyst in dry solvent under an inert atmosphere with a 5 W blue LED source. b Solvents were rigorously purified following the methods described in ref. 22. c All catalysts, in high quality, were purchased from the commercial source and used as such. d Isolated yields. e 1.1 equiv. of tBuONO were used. f 1.3 equiv. of tBuONO were used. g 1.5 equiv. of tBuONO were used. h 2.0 equiv. of tBuONO were used. i 3.0 mol% of [Ru(bpy)3]Cl2 were used. j 5.0 mol% of [Ru(bpy)3]Cl2 were used. k 10 mol% of [Ru(bpy)3]Cl2 were used. l No irradiation source was used. m No tBuONO was used. NR: no reaction.
1	CH3CN	Eosin Y	24	26
2	CH2Cl2	Eosin Y	24	<10
3	C2H4Cl2	Eosin Y	24	<10
4	Hexane	Eosin Y	24	<5
5	Heptane	Eosin Y	24	<5
6	Glyme	Eosin Y	24	18
7	DMSO	Eosin Y	24	43
8	DMF	Eosin Y	24	36
9	DMSO	Eosin Y	24	51^e
10	DMSO	Eosin Y	24	64^f
11	DMSO	Eosin Y	24	66^g
12	DMSO	Eosin Y	24	65^h
13	DMSO	[Ru(bpy)3]Cl2	6	93
14	DMSO	Eosin B	24	32
15	DMSO	Rose bengal	24	30
16	DMSO	[Ru(bpy)3]Cl2	4	92^i
17	DMSO	[Ru(bpy)3]Cl2	2	94^j
18	DMSO	[Ru(bpy)3]Cl2	2	93^k
19	DMSO	None	24	NR
20	DMSO	[Ru(bpy)3]Cl2	24	NR^l
21	DMSO	[Ru(bpy)3]Cl2	24	NR^m

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With the optimized reaction conditions in hand (Table 1), we next explored the scope of the reaction with a series of N-(2-aminoaryl)benzoimines²³ as shown in Table 2. Generally, the desired 6-arylphenanthridines were isolated in good to excellent yields (85–94%) irrespective of the position and electronic nature of substituents on the aniline moiety. For examples, the chloro and nitro groups were found to be compatible under these reaction conditions (Table 2, entries 6–9 and 12). Likewise, electron-donating substituents (methyl and methoxy groups) provided excellent yield of the products (Table 2, entries 2–5 and 11). Moreover, sterically hindered substrates, i.e.IME10, IME11, IME12 and IME13, also worked well in the present system affording the corresponding 6-arylphenanthridines in good yields (Table 2, entries 10–13). Thus, a wide range of electronically and structurally diverse 6-arylphenanthridines can be synthesized efficiently with the present methodology (ESI†).

Table 2 Substrate scope for the transformation of N-(2-aminoaryl)benzoimines into 6-arylphenanthridines^a

Entry	Substrate (N-(2-aminoaryl)benzoimines)	Product (6-arylphenanthridines)	Yield^b^,^c (%)
a Unless stated otherwise all reactions were performed in a Schlenk tube with 1.0 equiv. of IME, 1.3 equiv. of tBuONO and 1 mol% of [Ru(bpy)3]Cl2 in dry DMSO at room temperature in argon with the irradiation of a 5 W blue LED for 6 h. b Isolated yield. c All products were characterized by IR and NMR spectroscopy (ESI) in comparison with known compounds from literature data.
1			93
2			94
3			89
4			94
5			86
6			92
7			91
8			87
9			89
10			85
11			89
12			91
13			86

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A plausible reaction mechanism for the preparation of 6-arylphenanthridines from N-(2-aminoaryl)benzoimines is outlined in Scheme 2 on the basis of blank experiments and an earlier proposed mechanism.^11,24 It seems that reactions proceed through a visible light-induced single electron transfer mechanism as no product was observed without the photocatalyst or visible light-irradiation (Table 1, entries 19 and 20). Thus, the irradiation of [Ru(bpy)₃]Cl₂ with visible light generates the excited *[Ru(bpy)₃]Cl₂ species. A single electron transfer from the excited *[Ru(bpy)₃]Cl₂ to the diazonium salts, formed in situ from the reactions of N-(2-aminoaryl)benzoimine and tBuONO, affords [Ru(bpy)₃]³⁺ and the N-(o-phenyl radical)benzoimine (I, Scheme 2) by extrusion of N₂. Radical I undergoes intramolecular C–H aromatic coupling to form a cyclohexadienyl-type radical (II), which was then oxidized (path a) by [Ru(bpy)₃]³⁺ to form a cationic intermediate III and regenerate [Ru(bpy)₃]Cl₂ or collision with diazonium salts to produce radical I through path b. Ultimately, deprotonation of III by tBuO⁻ yields the desired 6-arylphenanthridines, cf. Scheme 2.

Scheme 2 A plausible mechanism for the visible light-induced preparation of 6-arylphenanthridines from N-(2-aminoaryl)benzoimines. SET, single electron transfer.

In summary, we have successfully developed a novel method for the synthesis of 6-arylphenanthridines from aryl diazonium salts, in situ formed from the reactions of N-(2-aminoaryl)benzoimines and tert-butyl nitrite, under visible light-photocatalyzed conditions. Mild reaction conditions, inexpensive reagents and non-polluting byproducts are few advantages of this method while compared to other visible light-mediated protocols reported yet for the synthesis of 6-arylphenanthridines. Currently, studies on the DNA intercalation and antibacterial properties of selected 6-arylphenanthridines are underway in our laboratories.

Acknowledgements

The authors are pleased to acknowledge the financial support from the Council of Scientific and Industrial Research (CSIR), New Delhi, vide project no.: 02(0246)/15/EMR-II. N. K. and M. S. thank the University Grant Commission (UGC), New Delhi for their junior research fellowships (JRF). Also, we thank anonymous reviewers for their insightful comments and suggestions.

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Footnote

† Electronic supplementary information (ESI) available: General aspects, experimental procedure, characterization data for products and references. See DOI: 10.1039/c6qo00275g

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