3.3- disubstituted oxindole synthesis

Colegate and co-workers (98P437) isolated (-)-coerulescine (120b) from Phalaris coemlescens and determined that its structure has a 3,3-disubstituted oxindole nucleus (Scheme 18). The synthesis of ( )-coerulescine (120b) was... 

The utility of the neutral pathway is highlighted in the synthesis of chiral 3,3-disubstituted oxindoles from the corresponding acyclic Z iodide substrates, which can be realized with enantioselectivities as high as 97% ee under neutral conditions (Scheme 8G.18, Table 8G.1)... 

The asymmetric Heck reaction can be used to synthesise quaternary carbon centres. During studies towards the synthesis of 3,3-disubstituted oxindoles. Overman and coworkers have shown how the use of silver salts can change the sense of asymmetric induction of the cyclised product. Thus, the iodide (10.131) can be converted into the product (10.132) with the (S)-enantiomer predominating, when the reaction is run in the presence of silver salts. In the absence of silver salts, the (J )-enantiomer is the major product. 

Overman and coworkers have extensively developed the utility of asymmetric Mizoroki-Heck reactions for constructing quaternary carbon stereocentres through various alkaloid total synthesis endeavours. A particular focus of these studies has been the catalytic asymmetric synthesis of enantioenriched 3,3-disubstituted oxindoles, because oxindoles of this type are versatile precursors of many natural alkaloids, hi an early, unanticipated discovery, it was found that either enantiomer of spirocychc oxindole 103 could be formed with moderate selectivity using a single enantiomer of a chiral diphosphine ligand (Scheme 16.24) [13]. Specifically, the use of Ag3P04 as an HI scavenger in the cyclization of 102 produced (S)-103 in 71% ee, whereas use of the amine base PMP under otherwise identical reaction conditions yielded (7 )-103 in 66% ee. 

Recently, Trapp and coworkers presented a series of six-membered NHC-Pd complexes 69 [63]. Steric demand increases from 69a to 69c while retaining natural rf-(+)-camphor as the chiral motif. The complexes showed different catalytic profiles in the intramolecular asymmetric a-arylation of amides (Scheme 3.38). Whereas catalyst 69a showed no enantiodiscrimination and 69c gave dehaloge-nation products in attempted oxindole synthesis, 69b proved to be more effective producing the 3,3-disubstituted oxindoles in high yields (up to 98%) and moderate enantioselectivities (68% ee). 

Yasui Y, Kamisaki H, Takemoto Y (2008) Enantioselective synthesis of 3,3-disubstituted oxindoles through Pd-catalyzed cyanoamidation. Org Lett 10(15) 3303-3306. doi 10.1021/ ol801168j... 

The reaction of A-arylacrylamides and simple alcohols in the presence of 70% aqueous solution of TBHP leads to metal-free synthesis of 3,3-disubstituted oxindoles. A series of hydroxyl-containing oxindole derivatives could be prepared using this method. The reaction is proposed to proceed through an oxidative radical cyclization mechanism and shows excellent functional group tolerance." ... 

The intramolecular synthesis of 3,3-disubstituted oxindoles through C(sp )-H and Ar-H coupling of anilides using potassium t-butoxide as base and stoichiometric Cu(0Ac)2 H20 in DMF (N,N-Dimethylformamide) was reported by Taylor et /.[66]. This reaction also could be conducted under catalytic Cu(0Ac)2-H20 in toluene or mesitylene with atmospheric oxygen as the reoxidant without an additional base. A range of substrates including several... 

Scheme 8.30 The intramolecular synthesis of 3,3-disubstituted oxindoles through C(sp )-H...

Synthesis of 3,3-disubstituted oxindoles from arylation- and vinylation-carbocycUzation of electron-deficient alkenes with diaryliodonium salts catalyzed by CuCl catalyst was reported by Zhou, Li, and coworkers. A wide range of diaryl and vinyl(aryl)iodonium triflates and various substitutions on phenylacrylamides are compatible for this reaction. Both ( )-physostigmine and ( )-physovenine have been synthesized successfully in 41 and 36% overall yield using this vinyl addition/cyclization method [71]. Fu and coworkers developed a Cul-catalyzed synthesis of oxindole derivatives from readily available Af-alkyl-Af-phenylacrylamides and diaryliodonium triflates [72] (Scheme 8.34). 

Scheme 8.34 Synthesis of 3,3-disubstituted oxindoles from arylation- and vinylation-carbocydization of electron-deficient alkenes with diaryliodonium salts.

In 2010, Taylor and co-workers described an intramolecular CDC reaction between an aryl sp C-H bond and an enolizable sp C-H bond to produce 3,3-disubstituted oxindoles. The generality of this copper-catalyzed process was demonstrated with a broad substrate scope and illustrated with the efficient synthesis of a biologically active alkaloid precursor (Scheme 9.30). 

Very recently, the total synthesis of marine alkaloids ent-flustramines A and B and c t-flustramides has been achieved using a Pd-catalyzed asymmetric prenylation of oxindoles. Initially, Trost and co-workers investigated the regioselective and enantioselective prenylation of a variety of oxindoles for the preparation of prenylated or reversed-prenylated 3,3 -disubstituted oxindole derivatives. The... 

After copper and palladium, rhodium is the third most important transition metal for the synthesis of the indole ring. For a 2007 review on this reaction, see Patil and Paiil [1], Some early examples (Scheme 1) are Alper s rhodium reaction of 2-aryl-2/7-azirines to give 2-styiylindoles (equation 1) [2], Watanabe s Rh-catalyzed Fischer indole synthesis (equation 2) [3], Ucciani s 3-methylindole synthesis via the hydroformylation of o-nitrostyrene (equation 3) [4], and Burst s preparation of 3-acetyl-2-hydrox-yindoles from the Rh-catalyzed decomposition and carbenoid aromatic C-H bond insertion (equation 4) [5]. Narasaka extended Alper s 2-aryl-2//-azirine reaction to a Rh(II)-catalyzed synthesis of 2,3-disubstituted indoles [6], and both Cenini [7] and Alper [8] stretched the deoxygenation of o-nitrostyrenes to give indoles. Burst s Rh-catalyzed decomposition of a-diazo carbonyl compounds was used by Bauban [9] and Jha [10] in the synthesis of substituted oxindoles. 

The synthesis of 3,3-disubstituted 2-oxindoles by palladium-catalyzed a-arylation/alkylation sequences in a biphasic flow system has been achieved by Buchwald et al. [44]. The reaction sequence consisted of two steps, the arylation followed by the alkylation. The first reaction system contains the substrate and aryl halide in toluene in one solution, the second the pre-catalyst in toluene, and a third solution containing potassium hydroxide and tetrabutyl ammonium bromide (TBAB) (Scheme 8.11). This is then mixed in a packed-bed mixer and heated to 100 °C for arylation. This system is then fed into a second T-piece where the alkyl halide is introduced, further mixing is applied in the second packed-bed reactor for the alkylation. This product mixture is then quenched with monosodium phosphate and extracted with ethyl acetate. The overall reaction proceeded in a 93% yield and could also be stopped at the arylation step by the addition of a switch valve before the alkylation step. Palladium-catalyzed hydrogenations have also been investigated under organic/aqueous biphasic conditions and an enhancement has been observed when using polymeric encapsulation [45]. 

The synthesis commences with alkylation of oxindole 120 with spiroaziri-dinium triflate 109, providing the 3,3-disubstituted 121 in 53% yield (cf. Scheme 2.17). Treatment of 121 with boron trifluoride etherate at 100°C in toluene initiates the tandem retro Diels-Alder/intramolecular aza Diels-Alder process, leading to spiro-tetracyclic oxindoles 122 and 123 (1.5/1) in 61% yield. Addition of 2-lithio-l,l-diethoxy-2-propene to oxindole 122 provides carbinolamine 124 (95%). Exposure of 124 to p-toluenesulfonic acid in acetone-water followed by treatment with excess triethylamine in acetonitrile at 80°C effects the biomimetic transformation to adduct 126, which possesses the pentacyclic carbon framework of pseudotabersonine. This unique two-step one-pot transformation generates the inherently unstable dihydropyridine portion of dehydrosecodine 125, which participates in an intramolecular reverse electron-demand Diels-Alder reaction, providing 126 in 50% yield. The total synthesis is completed by transformation of the formyl group into the requisite carbomethoxy unit followed by N-benzyl deprotection (Scheme 2.19). 

A f-BuONa-mediated synthesis of 3,3-disubstituted aza-oxindoles via a Truce-Smiles rearrangement-cyclization pathway has been reported (Scheme 181). ... 

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