Catalytic Asymmetric Cyclizative Rearrangement of Anilines and Vicinal Diketones to Access 2,2‐Disubstituted Indolin‐3‐ones

The efficient synthesis of chiral 2,2‐disubstituted indolin‐3‐ones is of great importance due to its significant synthetic and biological applications. However, catalytic enantioselective methods for de novo synthesis of such heterocycles remain scarce. Herein, a novel cyclizative rearrangement of readily available anilines and vicinal diketones for the one‐step construction of enantioenriched 2,2‐disubstituted indolin‐3‐ones is presented. The reaction proceeds through a self‐sorted [3+2] heteroannulation/regioselective dehydration/1,2‐ester shift process. Only chiral phosphoric acid is employed to promote the entire sequence and simplify the manipulation of this protocol. Various common aniline derivatives are successfully applied to asymmetric synthesis as 1,3‐binuclephiles for the first time. Remarkably, the observed stereoselectivity is proposed to originate from an amine‐directed regio‐ and enantioselective ortho‐Csp2‐H addition of the anilines to the ketones. A range of synthetic transformations of the resulting products are demonstrated as well.


Introduction
Chiral 2,2-disubstituted indolin-3-one represents an important class of the heterocyclic skeleton that occurs frequently in natural alkaloids, clinical drugs, and commercial dyes, such as (+)-Melokhanine, [1] (+)-Brevianamide A, [2] (+)-Austamide [3] and DOI: 10.1002/advs.202402532(+)-Aristotelone [4] (Scheme 1A).[7] Therefore, considerable effort has been dedicated to its catalytic asymmetric synthesis over the years.In this context, a strategy based on the derivation of the preconstructed indolin-3-one scaffolds, mainly centering on 2-aryl-3H-indol-3-ones and 2-mono-substituted indolin-3-ones, [8] has been widely adopted to access this important family of chiral N-heterocycles, but it relies heavily on the availability of the raw material 2-substituted indoles and the products are highly restricted to 2-aryl-or 2,2diaryl-substituted indolin-3-ones.On the other hand, however, there are very few reports dealing with the de novo synthesis of chiral 2,2-disubstituted indolin-3-ones from two achiral linear compounds.In this regard, representatively, Jia et al. reported an elegant synthesis of N-hydroxylated 2,2-diaryl-substituted indolin-3-ones via tandem formal heteroannulation/asymmetric Friedel-Crafts reaction under gold/chiral phosphoric acid dual catalysis (Scheme 1B). [9]Alternatively, asymmetric enzyme-catalyzed oxidative cross-coupling of indoles with different reaction partners, including ketones and indoles, was also documented. [10]Notably, all these examples featured either arylation or alkylation of the in situ formed 2-substituted indol-3-ones as the enantiodetermining step, and the resulting products were basically limited to 2-aryl-substituted indolin-3-ones as well.Undoubtedly, investigating the useful and general methods for the de novo construction of structurally diverse indolin-3-ones bearing quaternary stereocenters from readily available substrates is still highly interesting and desirable.
The asymmetric 1,2-rearrangement is a robust method for stereoselectively building carbon─carbon bonds. [11]Recently, on the basis of it, a range of important stereocenters and building blocks have been efficiently constructed.Despite these significant advances, however, catalytic asymmetric 1,2-rearrangements have rarely been successfully applied to the synthesis of enantioenriched heterocycles.Recently, we disclosed a novel strategy of catalytic asymmetric cyclizative rearrangement (CACR) which enabled the efficient construction of a series of synthetically challenging heterocycles bearing aza-quaternary stereocenters Scheme 1. Occurrence of 2,2-disubstituted indolin-3-ones and asymmetric catalytic de novo synthesis.
[14] Aimed toward a general and flexible strategy for the synthesis of enantiopure 2,2-disubstituted indolin-3-ones, we decided to pursue an alternative approach, that is, the development of a CACR of aniline derivatives and vicinal diketones.This strategy can in principle operate on diverse substituted substrates, and the resulting products are synthetically versatile due to the presence of functionalizable ester derivatives.It is worth noting that aniline is one of the most commonly used substrates in organic synthesis, but it has rarely been employed as a potential 1,3-binucleophile in the area of asymmetric catalysis due to various intrinsic difficulties, such as low nucleophilicity, multiple nucleophilic sites, preferred para-carbon-selectivity as well as compatibility issues of amine. [15]Among them, overriding aniline-inherent regioselectivities by means of catalyst control is undoubtedly the most challenging. [16]It is foreseeable that overcoming this formidable challenge would not only furnish direct access to more diverse building blocks but also significantly expand the synthetic utility of the anilines.On the other hand, as specific aromatic amines, the more nucleophilic and -naphthylamines with fixed ortho-nucleophilic-site have been used as 1,3-binucleophiles for few enantioselective cyclization reactions. [17,18]We report herein the successful realization of this endeavor via chiral phosphoric acid catalyzed CACR of diverse anilines and vicinal diketones using a simple procedure, which provides a modular and general synthesis of 2,2-disubstituted indolin-3-ones in a high level of yield and enantiopurity (Scheme 1D).Mechanistic studies as well as further synthetic transformations of the resulting products were also performed.

Results and Discussion
After a series of initial trials (Tables S1-S6, Supporting Information), we set out to optimize the model cyclizative rearrangement between meta-benzyloxy-substituted aniline 1a (1.0 equiv) [19] and 2,3-diketoester 2a (1.0 equiv) [20] under the catalysis of chiral phosphoric acid (CPA) [21] in methyl tert-butyl ether (TBME, c 0.1 m) at 60 °C with 4 Å molecular sieves (300 mg mmol −1 ) as dehydrating additive (Table 1).In the beginning, with the extensively used chiral acid 4a, the desired 2,2-disubstituted indolin-3-one 3a was successfully obtained in good yield and enantioselectivity (entry 1).Subsequently, the structure of the CPA was fine-tuned (entries 2-6), and chiral phosphoric acid 4f stood out as the best catalyst in terms of both yield and enantioselectivity (entry 6).With 4f (0.1 equiv) as a catalyst, other conditions were surveyed varying the additives, temperature, and solvent (entries 7-14), which gave no further improvement on the reaction outcome.Finally, the optimum conditions found consisted of performing the rearrangement of 1a and 2a in TBME (c 0.1 m) at 60 °C in the presence of 4f (0.1 equiv) and 4 Å molecular sieves.Under these conditions, the desired rearranged product 3a was isolated in 93% yield with 91% ee.Surprisingly, the product resulting from the competing para-carbon-alkylation of aniline 1a with 2,3-diketoester 2a was not observed under these conditions.
The scope of the aniline derivatives 1 was then examined and representative examples were displayed in Table 2.The cyclizative rearrangement of anilines with different meta-alkoxy residues, as methyl, isopropyl, p-methoxybenzyl (PMB), and p-fluorobenzyl, proceeded smoothly to provide the rearranged products 3ae-3ah in excellent yields and enantioselectivities.Moreover, aryloxyl as well as (tert-butyldimethylsilyl)oxy groups were also tolerated albeit with slightly diminished enantioselectivities (3ai-3aj).Remarkably, additional substituents, such as methoxyl, methyl, and chloro groups, at different positions of the benzene ring delivered the desired products in high enantiomeric excesses (3ak-3an).
In principle, the meta-electron donating substituents on anilines were capable of enhancing the nucleophilicity of the Csp 2 at 6-position.Indeed, other heteroatoms, such as nitrogen and sulfur, were able to play the same role in this reaction, providing the indolin-3-ones 3ao-3ap with high enantiopurities.Alternatively, a series of N-substituents, as benzyl, para-methoxybenzyl, 2,4-dimethoxybenzyl, methyl, and para-methoxyphenyl groups, were successfully engaged thus leading to structurally diverse products 3aq-3av in high yields with remarkable enantiocontrol.Notably, primary amine was also an applicable candidate to give the desired product 3aw in moderate yield with high enantiopurity.The lower yield of 3aw was due to the relatively messy reaction.Furthermore, a tricyclic compound 3ax could be also obtained in excellent yield with high enantiomeric excess when 5methoxy-1,2,3,4-tetrahydroquinoline was employed as a reaction partner.Notably, in all cases, no products originating from para-Friedel-Crafts addition of anilines 1 onto vicinal diketones 2 were observed.
To understand the possible reaction mechanism, a series of control experiments were performed (Scheme 2).Initially, 13 Clabeled 2,3-diketoester 2a' was synthesized to undergo this asymmetric cyclizative 1,2-rearrangement.Significantly, the isotopically labeled carbon exists as the aza-quaternary stereocenter rather than the carbonyl moiety in the product 13 C-3a (see Sup-porting Information for details), which suggests that the reaction proceeds via a 1,2-ester shift instead of a 1,2-phenyl migration (Scheme 2a).Importantly, it also implies that this CACR might be initiated by the nucleophilic 1,2-addition of C(sp 2 )-H to the central carbonyl group of 2,3-diketoester 2. Interestingly, N,Ndimethyl-substituted aniline 5 only delivered the para-carbon attack product 6 with a low level of yield and enantioselectivity (Scheme 2b), which indicated that the hydrogen bond between aniline derivative 1a and the chiral catalyst 4f is not only important for the stereoselectivity but also crucial for the regiocontrol.Interestingly, the simple N-methylaniline 7 featured lower nucleophilicity could also undergo this cyclizative rearrangement under the standard reaction conditions, affording the desired product 3ay with good enantioselectivity (74% ee, Scheme 2c).The low yield (26%) of 3ay due to the low conversion of the substrates 7 and 2a, and the product resulting from the para-Friedel-Crafts addition of aniline 7 to substrate 2a was not observed as well.Other achiral strong acids such as trifluoroacetic acid and p-toluenesulfonic acid, gave no reaction.These results suggest again that the hydrogen bond between the amine moiety and the bifunctional catalyst 4f is the key to the high regioselectivity rather than the orientation effect of the electron-donating groups at the meta-position of the anilines 1.Finally, we performed a set of experiments with ee-varied chiral phosphoric acid 4f, aniline 1a, and 2,3-diketoester 2a under the standard conditions (Scheme 2d).The results revealed the linear relationship between the ee value of 4f and the ee value of the indolin-3-one 3a, which suggested that a monomeric complex may work as a catalyst to promote the reaction. [23]On the basis of the mechanistic experiments, a possible reaction pathway is proposed in Scheme 2e.Initially, under our conditions, substrate 2 could readily dehydrate to the vicinal tricarbonyl compound 2* where the central carbonyl group is highly nucleophilic.Subsequently, the CPAcatalyzed regioselective and stereoselective catalytic ortho-carbonaddition of anilines 1 to 2,3-diketoesters 2 occurs through a key intermediate A, where the para-Csp 2 is too far to reach the central carbonyl group of 2 while ortho-Csp 2 attack is favored, leading to the formation of the enantioenriched tertiary alcohol B. A crucial -hydroxyl iminium intermediate C was then generated from the intramolecular cyclizative condensation of B in the presence of 4f.Finally, a stereospecific 1,2-ester shift [13,14] afforded the desired product 3 with the observed stereocontrol.
Further transformations of the enantioenriched indolin-3-one 3a were performed to illustrate the synthetic potential of our reaction (Scheme 3).Mono-bromination of 3a in the presence of N-bromosuccinimide (NBS, 1.2 equiv) delivered compound 8 with a high yield.Treatment of 3a with excessive 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at room temperature afforded the N-deprotection product 9 which could be further transformed to the O-deprotection product 10 in high yield.On the other hand, treatment of 9 with 2.8 equiv of NBS afforded the dibrominated product 11 that was armed for further functionalization (Scheme 3a).In the presence of the excessive BH 3 •DMS, the ester group of compound 9 could be easily reduced to the primary alcohol (12).Moreover, deprotection of 3a gave the product 13 bearing a hydroxyl group which provided a versatile handle for the functionalization of the rearranged products.As depicted in Scheme 3b, triflation of compound 13 delivered an important building block 14 in 84% yield.Reduction of 14 under the cataly-  sis of palladium complex combining with HCOOH as a reductant led to the formation of compound 15.Finally, Pd(II)-catalyzed Suzuki-Miyaura cross coupling of 14 with phenyl boronic acid gave the desired product 16 in excellent yield.

Conclusion
In conclusion, we have developed a CACR of aniline derivatives and vicinal diketones for the efficient synthesis of indolin-3-ones bearing quaternary stereocenters.An unusual amine-directed regio-and stereoselective ortho-Csp 2 -H addition of anilines to ketones is the key to the success of this CACR.Notably, aniline derivatives are employed as highly effective 1,3-binuclephiles in the field of asymmetric catalysis for the first time.This asymmetric tandem transformation, catalyzed by a single chiral phosphoric acid, exhibits excellent efficiency, simple procedure, good functional group compatibility, and broad substrate scope.The synthetic potential was also illustrated by the postfunctionalization of the resulting products.The development of cyclizative rearrangements is a fascinating research field, and further research on this topic is underway in our laboratory.

Table 1 .
Survey of reaction conditions.