Synthesis of C2-tetrasubstituted indolin-3-ones via Cu-catalyzed oxidative dimerization of 2-aryl indoles and cross-addition with indoles

An efficient protocol for the synthesis of 2,2-disubstituted indolin-3-ones under mild conditions has been developed. This reaction involves the copper-catalyzed in situ oxidative de-aromatization of 2-arylindoles to indol-3-one, followed by self-dimerization as well as cross-addition with indoles under mild conditions. The result generates a wide variety of C2-tetrasubstituted indolin-3-ones with good to high yields (62–82%).


Introduction
Indolin-3-ones are privileged scaffolds that function as intermediates for the synthesis of medicinally important compounds. 1 In particular, 2,2-disubstituted 1,2-dihydro-3Hindol-3-one, also known as pseudoindoxyls bearing C2 stereocenters have continually appeared in natural products such as austamide (I), strobilanthoside A (II), isatisine A (III), and halichrome A (IV), as well as in many other bioactive synthetic compounds (Fig. 1). 2 Moreover, compounds with this skeleton have also exhibited exciting applications in the areas of uorescence labeling and optoelectronic materials in recent years. 3 Owing to the wide utility of 2,2-disubstituted indolin-3-ones, several methods had been developed in the past few years which include; transition-metal catalyzed annulation reactions, 4 the cascade Fischer indolization/Claisen rearrangement, 5 and photooxidative rearrangements, 6 along with other methods. 7 Besides these methods, chemoselective addition of various nucleophiles to 2-aryl-indol-3-one, an activated cyclic Cacylimine, is another exciting way to access 2,2-disubstituted indolin-3-one derivatives. 8 However, the synthesis of 2-aryl-3Hindol-3-ones requires troublesome multistep syntheses and are not easily accessible. 9 To overcome this problem, some attention has recently been given to the chemistry of dearomative cascade reactions of 2-substituted indoles for the direct construction of C2-quaternary indolin-3-ones (Scheme 1a). In this context, self-dimerization of 2-substituted indoles have been explored either through Cu-catalysis (Scheme 1a(i)) 10 or other metal-catalysis (Scheme 1a(ii)). 11 However, these methods required high temperature and sometimes hazardous components. Likewise, oxidative cross-addition of indole to 2substituted indole could be another way to achieve C2quaternary indolin-3-ones; however, that is a difficult task to accomplish in terms of selectivity. Guchhait and coworkers developed an exciting and the very rst protocol for the crossaddition of indoles to 2-substituted indoles to access 2,2disubstituted indolin-3-ones with a chiral center under Pdcatalysis in a chemoselective fashion (Scheme 1a(iii)). 12 Very recently, Yu and coworkers developed a metal-free approach for the cross-addition of indoles with a series of 2-substituted

Results and discussion
Copper-catalyzed transformations are one of the most studied methods in synthetic chemistry due to their efficiency, good functional group tolerance. 14 In this context, Cu-catalyzed tandem oxidative reactions of 2-aryl indol-3-ones, in situ generated from 2-arylindoles, have been explored to synthesize 2-arylbenzoxazinone, 15 and polyhydropyrido[1,2-a]indoles/ tetracyclic quinazolinones. 16 Encouraged by these relevant precedents, we envisaged that a general copper-catalyzed method could be developed for the self-dimerization of 2substituted indoles and cross-addition with indoles through the in situ generations of indol-3-ones under mild conditions. Herein, we describe the successful implementation of our protocol.
We begin this study for the oxidative cross-dimerization of 2phenyl indole 1a as model substrate to prepare 2-phenyl-2-(2-phenyl-1H-indol-3-yl)indolin-3-one 2a. In this context, optimization of the reaction conditions was carried out by employing several bases, oxidizing agents, catalysts and solvents, and the results are shown in Table 1. Initially, reaction failed to work, when 1a was treated with catalysts CuCl (30 mol%), pyridine with; K 2 S 2 O 8 (entry 1, Table 1), oxone (entry 2, Table 1). Trace amount (<10%) of the product was obtained with air as oxidants in toluene (entry 3, Table 1) and DMSO (entry 4, Table 1) as solvents, respectively. However, product 2a was obtained with low yield (34%), when the reaction was carried out with CuCl (cat.), pyridine, and TBHP (tert-butyl hydroperoxide) in CH 3 CN (entry 5, Table 1) at room temperature. Additional efforts were made to improve the reaction yields either by changing the oxidants, base, and catalysts (entries 6-11, Table 1). An improvement in the reaction yields was observed by employing lutidine, in place of pyridine, with TBHP (45%) (entry 8, Table  1), and with m-CPBA (meta-chloro perbenzoic acid) (52%) (entry 10, Table 1). The dimerized product 2a was obtained with moderate yield (63%) when Cu(OAc) 2 (entry 11, Table 1) was employed in place of CuCl as a catalyst with TBHP as oxidant, which was again improved to 75% yield by using m-CPBA as oxidant (entry 12, Table 1). Any additional change in the reaction conditions either; by changing oxidant (entry 12, Table 1) or lowering the catalyst loading (entry 14, Table 1) failed to improve the reaction yield. The reaction failed to produce any dimerization product in the absence of catalyst (entry 15, Table  1), and base (entry 16, Table 1). Thus, we preferred to perform this reaction to yield cross-dimerized product 2a under the standardized conditions (entry 12, Table 1). Moreover, reaction Scheme 1 Synthetic approaches from 2-aryl indoles to access 2,2disubstituted indolin-3-ones. only furnished 2-indoles substituted 3-oxindole 2a through the addition of indole as a nucleophile at the C2-position of in situ generated indol-3-one in a chemoselective fashion. Next, we explored the generality of our developed crossdimerization protocol with variously substituted 2-aryl indoles 1a-k under standardized conditions, and results are shown in Table 2. The reaction was found to be quite general concerning the substituents on both the aryl-rings of 2-aryl-indole 1 and accomplished within 14-22 h at room temperature to the furnish corresponding cross-dimerized product, i.e., 2-indoles substituted 3-oxindoles 2 in good to high yields (68-82%).
The practical use of this method was also demonstrated to access both cross-dimerization of 2-arylindole and crossaddition of indole with 2-arylindole products on a gram-scale without much variation in yield, as shown in Scheme 2. Pleasingly, the gram-scale reaction successfully afforded 2g with a higher yield (81%) (Scheme 2a) as compared to the small-scale response ( Table 2). The single-crystal X-ray diffraction analysis conrmed the structure of cross-dimerized product 2g. 17 Moreover, 2,2-disubstituted indole-3-one 4bb was isolated with 78% yield, when cross-addition of 2-substituted indole 1b was performed with 4-methoxy indole 3b, under standardized conditions (Scheme 2b).

Conclusions
In summary, we have developed an efficient and general protocol for the synthesis of 2,2-disubstituted indolin-3-ones through the self-dimerization of 2-aryl indoles and crossaddition of 2-aryl indoles with indoles. This reaction proceeds with in situ generation of indol-3-one, followed by chemoselective nucleophilic addition under mild copper-catalyzed conditions. This simple strategy provides convenient and either way to access indolin-3-ones bearing C2-quaternary center in good to high yields. The developed protocol utilized nontoxic, readily available materials, and practically viable at the gram-scale synthesis.

General remarks
All reactions were observed using thin-layer chromatography (on SiO 2 gel F254 plates) under standard condition. The desired compounds were puried through ash column chromatography packed with silica gel (100-200 meshes size) as the stationary phase and eluting solvent, hexane-ethyl acetate solvent mixture was used as mobile phase. Melting points were determined in open capillary tubes on an EZ-Melt Automated melting point apparatus and are uncorrected. NMR spectra were recorded on a Bruker AV 400 spectrometer. Chemical shis were reported in parts per million (ppm) using deuterated solvent or tetramethylsilane (TMS) as an internal standard. High-resolution mass spectra (HRMS-ESI) were recorded using quadrupole time-of-ight (Q-TOF) mass spectrometer (Applied Biosystem). All the chemicals were obtained from the commercial supplier and were used without purication.
Typical procedure for the synthesis of oxidative dimerized product 2 To a stirred solution of 2-phenylindole 1 (0.5 mmol) in CH 3 CN (3.0 mL) was added lutidine (1.0 mmol), Cu(OAc) 2 (30 mol%) and m-CPBA (meta-chloroperoxybenzoic acid, 0.3 mmol) successively at room temperature. The combined reaction mixture was stirred at the same temperature until TLC conrmed the complete consumption of starting material. Subsequently, the reaction was quenched with H 2 O (3.0 mL) and stirred with EtOAc (10 mL). The organic layer was separated, and the aqueous layer was again extracted with EtOAc (5.0 mL). The combined organic extracts were washed with brine, dried over Na 2 SO 4 anhydrous, and concentrated under reduced pressure. Column chromatography purication through silica gel by eluting the mixture of hexane/EtOAc gave corresponding dimerized product 2 as mainly yellow solid with 64-82% yields.

Conflicts of interest
There are no conicts to declare.