Dearomative C–C and C–N bond cleavage of 2-arylindoles: transition-metal-free access to 2-aminoarylphenones

Abstract

A transition-metal-free conversion of 2-arylindoles to 2-aminoarylphenones, using environmentally benign O₂ as the sole oxidant, has been developed. This novel oxidative dearomatization process involves cleavage of both C–C and C–N bonds followed by new C–C and C–O bond formation. The C2 carbon of an indole scaffold was released in the form of CO₂.

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In recent years, much attention has been paid to chemoselective C–C bond cleavage followed by new C–C and/or C–heteroatom bond formation; since it enables a great number of readily available substances in chemical transformations.¹ In general, certain classes of molecules such as carbonyl derivatives, restrained small rings, alkenes or alkynes, etc., in combination with transition-metal catalysts are applied in this process due to the relatively high energy barrier for C–C bond dissociation.² Meanwhile, dearomatization of aromatic compounds is also a thermodynamically unfavourable transformation in which transition-metal catalysts or hypervalent iodine reagents are normally required.³ Notably, in most of the reported dearomatization reactions, the frameworks of the starting material are maintained in the dearomatized products. Merging the two important classes of reactions together, that is cleavage of the C–C bond(s) inbuilt in an aromatic system in order to lead to dearomatized products, is scarce in the literature.

One major class of C–C bond cleavage reaction proceeds through one C–C bond activation followed by the introduction of a new group from another reactant (a, Scheme 1).^2h,j Thus, the part excised is unavoidably wasted. Another form of the reaction involves two bond cleavage including at least one C–C bond, and then two of the three resulting parts are reconnected. That is, a small portion of the substrate is extruded from the parent molecule (b, Scheme 1). For example, transition-metal-catalyzed decarboxylation and decarbonylation reactions are the representatives of this class, in which carbon dioxide and carbon monoxide are extruded from the substrates, respectively (c, Scheme 1).⁴ However, an extrusion reaction involving a non-carbonyl substrate is rare, especially under transition-metal-free conditions. In a related study, we reported an uncommon hypervalent iodine(III)-promoted tandem demethylenation/C–H cycloamination process of N-benzyl-2-aminopyridines via C–C and C–N bond cleavage.⁵ Recently, Laha et al. developed a novel conversion of 10,11-dihydro-5H-dibenzo[b,e][1,4]-diazepines to phenazines through transition-metal-free tandem oxidative extrusion of the benzylic methylene group.⁶ Cui et al. reported a metal-free synthesis of diaryl-1,2-diketones by the extrusion of a carbon atom of alkynones.⁷ Herein, we present a transformation of 2-arylindoles to unexpected products, which were identified as 2-aminoarylphenones, through dearomative C–C and C–N bond cleavage using environmentally benign oxygen as the sole oxidant (d, Scheme 1). In this process, three chemical bonds (2 C–C and 1 C–N) are cleaved and one new C–C bond and one C–O bond are generated in one step. It is well known that 2-aminoarylphenones are unique precursors for heterocyclic synthesis,⁸ and traditional methods for their syntheses include Friedel–Crafts acylation,⁹ palladium-catalyzed carbonylation reactions,¹⁰ and addition reactions of Grignard reagents to nitriles.¹¹ However, all of these presented procedures have some disadvantages, including lack of regio-selectivity, use of transition metals or poor functional group tolerance. The development of an efficient and general synthetic route is highly desirable.

Scheme 1 C–C bond cleavage reactions.

Initially, treatment of 2-phenylindole 1a in the presence of 2.0 equiv. of Cs₂CO₃ in DMSO (used as received) under an O₂ (1 atm) atmosphere at 120 °C afforded an unexpected product which was identified as 2-aminobenzophenone 2a (51% yield, entry 1, Table 1). When the reaction was performed in toluene, dioxane, DCE or acetonitrile, 1a was completely recovered (entries 2–5). However, 1a was decomposed in NMP and 2a could be obtained in only 10–20% yields in DMF or DMA, which indicated the crucial role played by DMSO (entries 6–8). Screening of bases demonstrated that Cs₂CO₃ was the most effective in promoting the reaction (entries 9–12). It is worth noting that the yield of 2a decreased significantly in anhydrous DMSO. The importance of H₂O was further proven by adding 10 equiv. of H₂O to anhydrous DMSO, which gave a comparable yield of 2a (see ESI† for details). Shortening the reaction time from 18 h to 16 h was beneficial (56%, entry 14). It was intriguing that when the reaction tube was sealed in air and then equipped with an oxygen balloon rather than pure O₂, 2a was isolated in an improved 69% yield (entry 15). Changing the reaction tube to a smaller one (10 mL) under the same procedure described in entry 15, the isolated yield of 2a finally improved to 73% (entry 16).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Base (2.0 eq.)	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), solvent (1 mL), base (2.0 equiv.), degassed with O2, 120 °C, 18 h, O2 balloon, in a 50 mL Schlenk tube. b NMR yields with CH2Br2 as an internal standard. Numbers in the parentheses are isolated yields. c Anhydrous DMSO with 100 mg of 4 Å MS. d 16 h. e Without degassing with O2. f Reaction was run in a 10 mL Schlenk tube.
1	DMSO	Cs2CO3	51
2	Toluene	Cs2CO3	nr
3	Dioxane	Cs2CO3	nr
4	DCE	Cs2CO3	nr
5	MeCN	Cs2CO3	nr
6	NMP	Cs2CO3	0
7	DMF	Cs2CO3	20
8	DMA	Cs2CO3	10
9	DMSO	K2CO3	0
10	DMSO	Na2CO3	nr
11	DMSO	CsOAc	nr
12	DMSO	LiOH	9
13^c	DMSO	Cs2CO3	38
14^d	DMSO	Cs2CO3	56
15^d^,^e	DMSO	Cs2CO3	73 (69)
16^d^,^e^,^f	DMSO	Cs2CO3	78 (73)

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With the optimal reaction conditions in hand, the substrate scope was then investigated as summarized in Scheme 2. Substrates with various substituents on the 2-phenyl group, regardless of their electron-donating (Me, ^tBu and OMe) or electron-withdrawing (F, Cl, Br and phenyl) properties, could undergo the transformation in moderate to good yields. In general, 2-arylindoles with meta substituents gave high yields than the same group in the para position (e.g., 71% for 2g and 40% for 2f, 70% for 2l and 60% for 2m). However, 2-arylindole bearing a strong electron-withdrawing CF₃ group (2k) was less compatible under reaction conditions. The substrate with an ortho Me group on the phenyl ring afforded 2b in 58% yield. Moreover, naphthyl and thienyl substituents were also tolerated under these oxidative conditions and provided the desired products in 57% and 55% yields, respectively (2o and 2p). Unfortunately, no product was obtained when 2-alkylindoles or 2-alkenylindoles were subjected to the reaction.

Scheme 2 Substrate scope. Reaction conditions: 1 (0.2 mmol), Cs₂CO₃ (0.4 mmol), DMSO (used as received, 1.0 mL), 10 mL Schlenk tube, sealed in air, O₂ balloon, 120 °C, 16 h.

Then, substrates with different functional groups on the indole ring were also investigated. The corresponding products were obtained in moderate to good yields irrespective of the electronic nature of the substituents on the 5- or 6-position of the indole ring (2q, 2r, 2t, 2u and 2v). However, a low yield of 24% was obtained when a methyl group was located at the 4-position of the indole ring, probably due to the steric hindrance (2s). The structures of products 2r and 2s clearly showed that the anilinic carbon linked to the carbonyl moiety was the one which was originally connected to C3 of indole.

To gain more insight into the reaction mechanism, a crossover experiment using a 1 : 1 mixture of 2-(m-tolyl)-1H-indole (1c) and 5-methyl-2-phenyl-1H-indole (1t) was conducted under the standard conditions. No crossover product was detected by NMR analysis of the reaction products, which indicated that an intramolecular pathway was involved (eqn (1)). To confirm which carbon atom (C2 or C3) was extruded during the reaction, 2-phenyl-2-[¹³C]indole (¹³C-1a) was prepared and subjected to the standard conditions. No ¹³C enriched 2a was isolated, demonstrating undoubtedly that the indole C2 carbon was extruded during the process (eqn (2)).

During the optimization of the reaction conditions, we found that when LiOH was used as a base, the desired product 2a was isolated in low yield (10%) along with a byproduct 3 (35% yield, eqn (3)). Subjecting compound 3 to the standard reaction led to the desired product 2a in 80% yield, which suggested that compound 3 might be a reaction intermediate (eqn (4)(a)). It was interesting to find out that compound 3 was stable in the absence of O₂ (eqn (4)(b)). In addition, CO₂ was generated by passing the gas through the reaction tube into clear limewater which turned cloudy during the test (see ESI† for details).⁷

Based on the results obtained, a plausible mechanistic pathway was proposed for this uncommon oxidative cleavage reaction (Scheme 3). A peroxy anion B is formed by the deprotonated substrate in the presence of a base and oxygen. Then intramolecular nucleophilic attack on the C–N double bond results in a four-membered ring C. Subsequently, intermediate D is formed by a homolytic cleavage of the peroxy bond, followed by the 1,3-H shift to give intermediate E, which can be protonated to afford 3. Then, C–N bond cleavage in the aminoacetal moiety of E generates a diaryl-1,2-diketone F, which undergoes nucleophilic attack by the in situ-formed peroxy anion to afford intermediate G. Finally, aryl group migration and subsequent elimination of carbon dioxide give intermediate I, which is protonated to afford the final product.

Scheme 3 Proposed reaction mechanism.

In summary, we have developed an unexpected, novel and environmentally benign method for the conversion of 2-arylindoles to 2-aminoarylphenones under transition-metal-free conditions using oxygen as the sole oxidant. The reaction proceeds through the cleavage of two C–C bonds and one C–N bond followed by new C–C and C–O bond formation. A reaction using ¹³C labeled 2-arylindole revealed that the C2 carbon of an indole scaffold was released in the form of CO₂.

Acknowledgements

We are grateful for the financial support of this work by National Science Foundation of China (21202167, 21402203, 21472190, and 21532009).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c5qo00394f

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