Copper-catalyzed dearomative 1,4-carboxylate rearrangement of 2-carbonateindoles

Abstract

A novel dearomative 1,4-rearrangement reaction of 2-carbonateindoles with aryl diazoacetates has been developed in the presence of a copper catalyst, which might proceed through a tandem formation of a zwitterionic intermediate, intramolecular cyclization and ring-opening reaction to give the final rearrangement products containing an all-carbon quaternary center with two newly formed C–C bonds. In this sequence, the disruption of the aromaticity of indole has been realized, associated with 1,4-carboxylate rearrangements.

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Introduction

Rearrangement reactions are one of the most important methods to increase molecular complexity in organic synthesis.¹ In particular, the rearrangements involving onium ylides that originate from the decomposition of diazo compounds have attracted much attention, and versatile transformations have been developed to prepare structurally diverse and complicated compounds.² Among them, [2,3]- and [1,2]-sigmatropic rearrangements remain the most common ones in the field of carbene-mediated rearrangement reactions,^3,4 in which a metal-bound ylide or a free ylide is responsible for the subsequential sigmatropic rearrangements.⁵ Despite the great achievements that have been made,⁶ these reports mainly focused on the rearrangement of aliphatic systems. In sharp contrast, the dearomative rearrangement reactions are rare due to the difficulty in disrupting the aromaticity of arenes and heterocycles.⁷ Recently, we reported a rhodium-catalyzed dearomative 1,4-acyl rearrangement by the reaction of 2-oxypyridines and diazo compounds (Scheme 1b).⁸ A density functional theory calculation indicates the sequential formation of a metal-bound pyridinium ylide and a free ylide, which undergo intramolecular cyclization and ring-opening to give the final dearomative rearrangement products. Later, using triazoles, pyridotriazoles and cyclopropenes as the carbene precursors, such types of dearomative rearrangements have been developed.⁹ After that, we wanted to extend this rearrangement to heterocycles rather than 2-oxypyridines. Herein, we wish to report our endeavour to find a novel dearomative 1,4-rearrangement of indoles under copper catalysis. As shown in Scheme 1c, the reaction of 2-carbonateindole with a diazo compound in the presence of a copper salt might generate the metal-bound zwitterionic intermediate I, which may form the metal-free intermediate II with the release of the copper catalyst. Intramolecular cyclization either from I or II will give the zwitterionic intermediate III, which undergoes a ring-opening reaction to give the dearomative product with two newly formed C–C bonds.

Scheme 1 Previous reports and our strategy.

Results and discussion

We started our studies by using indole 1a and phenyl diazoacetate 2a as the model substrates in dichloromethane at room temperature to optimize the reaction conditions (Table 1). Unfortunately, the use of rhodium complexes led to unsatisfactory results. For example, when Rh₂(OAc)₄ was used as the catalyst, only 30% yield of 3aa was isolated in 30 min (entry 1) and Rh₂(esp)₂ gave a much lower yield (entry 2). Palladium catalysts, such as Pd(OAc)₂, did not work at all (entry 3). Then a series of copper salts were screened. Gratifyingly, 65% yield of 3aa was obtained by using copper(I) thiophene-2-carboxylate (CuTc) as the catalyst, although with a longer reaction time (entry 4). In contrast, CuOTf·Tol_1/2 and Cu(MeCN)₄PF₆ afforded 3a in 45% and 41% yields, respectively (entries 5 and 6). Next, a screening of solvents was conducted. It was found that chloroform, 1,2-dichloroethane, and toluene gave moderate yields of 3aa (entries 8–10). However, no 3aa was formed when acetonitrile was used (entry 11). Next, the influence of substrate 2a at different ratios was examined. Using 1.5 equiv. of 2a delivered 3aa in 69% yield (entry 12), which was further improved to 78% when 1.8 equiv. of 2a was used (entry 13). Next, on performing the reaction at 40 °C, the reaction could reach completion in 12 h with a yield of 77% (entry 14), and the reaction time could be reduced to 6 h at 60 °C (entry 15). As a result, we chose entry 15 as the best conditions for further investigation.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (X mol%)	Solvent	Time (h)	Yield of 3aa^b (%)
DCE: 1,2-dichloroethane.a Unless otherwise noted, the reactions were carried out with 1a (0.2 mmol), 2a (0.24 mmol), and catalyst (1–5 mol%) in solvent (4 mL) at rt.b Isolated yields.c 1a : 2a = 1 : 1.5.d 1a : 2a = 1 : 1.8.e Reaction temperature is 40 °C.f Reaction temperature is 60 °C.
1	Rh2(OAc)4 (1 mol%)	CH2Cl2	0.5	30
2	Rh2(esp)2 (1 mol%)	CH2Cl2	0.5	17
3	Pd(OAc)2 (5 mol%)	CH2Cl2	24	0
4	Cu(OTf)2 (5 mol%)	CH2Cl2	0.5	40
5	CuTc (5 mol%)	CH2Cl2	24	65
6	CuOTf·Tol1/2 (5 mol%)	CH2Cl2	0.5	45
7	Cu(MeCN)4PF6 (5 mol%)	CH2Cl2	0.5	41
8	CuTc (5 mol%)	CHCl3	24	49
9	CuTc (5 mol%)	DCE	48	36
10	CuTc (5 mol%)	Toluene	48	31
11	CuTc (5 mol%)	MeCN	24	0
12^c	CuTc (5 mol%)	CH2Cl2	24	69
13^d	CuTc (5 mol%)	CH2Cl2	24	75
14^e	CuTc (5 mol%)	CH2Cl2	12	77
15^f	CuTc (5 mol%)	CH2Cl2	6	77

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With the optimal reaction conditions in hand, we next explored the scope of diazoacetates in this dearomative 1,4-methyl carbonate rearrangement reaction (Scheme 2). para-Substituted electron-rich and electron-deficient phenyl diazoacetates all worked well in this reaction, providing the corresponding products (3ab–3ag) in 59–81% yields. Aryl diazoacetates containing a chloro or a methyl group on the benzene ring also reacted well, affording 3ah–3aj in 72–78% yields. In the case of sterically hindered 2-chloro phenyl diazoacetate, a moderate yield of the desired product was observed (3ak, 50%). The reaction of 2-naphthyl diazoacetate with 1a delivered 3al in 92% yield. The simple methyl 2-diazoacetate was tolerated, providing the corresponding product 3am in 66% yield. It should be noted that alkyl diazoacetates and donor–donor diazo compounds did not work in this reaction.

Scheme 2 Substrate scope for diazo compounds. The reactions were carried out with 1a (0.2 mmol), 2 (0.36 mmol), and CuTc (5 mol%) in CH₂Cl₂ (4 mL) at 60 °C for 6 h. Isolated yields.

Next, the scope of indole substrates 1 was examined using phenyl diazoacetate 2a as the reaction partner (Scheme 3). In the case of indoles containing different N-substituents, the benzyl substituted indole gave the corresponding product 3ba in 68% yield, and the indole with the N-isopropyl group afforded 75% yield of 3ca. We next investigated the influence of substituents on the phenyl ring of the indoles. The use of the 4-bromo indole substrate led to 85% yield of 3da. Indoles bearing functional groups such as methyl, methoxy, fluoro, and bromo at the C5 position all worked well in this reaction, furnishing the corresponding products 3ea–3ha in 72–83% yields. The 6-bromo and 6-methoxy indole substrates also reacted well, providing 3ia and 3ja in 74% and 67% yields, respectively. Indoles containing a substituent at the C7 position were tolerated in this reaction, affording the desired products (3ka and 3la) in good yields. Different ester groups at the C2 position of the indole led to different results, for example, ethyl ester led to 76% yield of 3mn and isopropyl ester gave 3no in 53% yield. Typically, the reaction of N-methyl ethyl carbonate with 2a gave 3ma in 80% yield with 1 : 1 dr. The structure of 3ma (one isomer) was confirmed by X-ray diffraction.

Scheme 3 Substrate scope for indoles. The reactions were carried out with 1 (0.2 mmol), 2 (0.36 mmol), and CuTc (5 mol%) in CH₂Cl₂ (4 mL) at 60 °C for 6 h. Isolated yields.

Gram-scale reaction and further elaboration were then conducted (Scheme 4). The reaction of 4 mmol of 1a with 7.2 mmol of 2a afforded 1.03 g of 3aa (Scheme 4a). The Suzuki coupling reaction of 3ha with aryl boronic acid delivered 4 in 84% yield (Scheme 4b). The treatment of 3aa with iodomethane provided compound 5 bearing an all-carbon quaternary center in 87% yield, providing an effective approach for the construction of heterocycles containing two adjacent all-carbon quaternary centers (Scheme 4c).

Scheme 4 Gram-scale reaction and further exploration.

Conclusions

In summary, a novel rearrangement that originated from the reaction of 2-carbonateindoles with diazo compounds has been developed in the presence of a copper catalyst under mild reaction conditions. In this reaction, the disruption of aromaticity of indoles has been realized associated with the 1,4-rearrangement of a carboxylate group, affording indolin-2-ones containing an all-carbon quaternary center in acceptable yields.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (21971026 and 22171028) and the Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (BM2012110) for financial support. The Analysis and Testing Center, NERC Biomass of Changzhou University is also acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2213330. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2qo01647h

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