Oxindoles enol carbonates

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

Richards cobaltocene has also been used in the rearrangement of oxindole-derived enol carbonates, although with poor yields and enantioselectivities (Scheme 40.7) [15]. 

Scheme 40.7 Enantioselective rearrangement of oxindole-derived enol carbonate.

By converting the enol triflate 41 to the spiro-tricyclic dienone 42, Overman and co-workers had already shown in 1989 that the direct enantio-selective formation of quaternary chiral carbon centers ean be carried out through an intramolecular Heck reaction. While the enantioselectiv-ities were only moderate at the beginning [ 16], the same authors later succeeded in achieving the Pd(0)-BINAP-catalyzed cyclizalion of substrates of type 43 to spiro-oxindoles 44 with up to 95 % ee (Scheme 12) [17]. 

The first examples of asymmetric Heck cyclizations that form quatemaiy carbon centers with high enantioselectivity came from our development of an asymmetric synthesis of the pharmacologically important alkaloid (—)-physostigmine (184) and congeners (Scheme 6-31) [68]. In the pivotal reaction, (Z)-2-butenanilide iodide 182 was cyclized with Pd-(5)-BINAP to provide oxindole 183 in 84% yield and 95% ee after hydrolysis of the intermediate silyl enol ether. With substrates of this type, cyclizations in the presence of halide scavengers took place with much lower enantioselectivity [68]. 

A unique inversion on the theme of trapping an electrophile with enolate nucleophile has been reported by Krishnan and Stoltz who have installed all-carbon quaternary centers at oxindoles, e.g., 42, in racemic fashion through the treatment of electrophilic 3-halooxindoles with nucleophilic malonates, e.g., 40-41, using DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) for the deprotonation step (Scheme 11) [28]. An asymmetric variation of the chemistry in Scheme 11 has been reported by the same group who constructed enantioeiuiched oxindoles using catalytic Cu(ll)-Lewis acid and a chiral bis(oxazoline) ligand [29]. 

P,P-Disubstituted alkylidene derivatives of oxindole, azlactone, and y-butyrolactone are used as precursors of vinylogous enolates, which are highly stabilized owing to the heteroaromatic nature of the enolate components. Although these a,p-unsaturated carbonyl systems can act as electrophilic Michael acceptors, the presence of two p-substituents seems to suppress nucleophilic attack on the P-carbon. 

The best results were obtained by coupling the enolate of oxindole 79 with aryl and vinyl bromides. Arylated products 81, bearing an all-carbon quaternary stereocentre, were formed in good yield and excellent enantiomeric purity for several aryl and vinyl bromides. Interestingly, other binaphthyl-based phosphorus ligands without P-stereogenic centres led to inferior results. 

Hypervalent iodine reagents have successfully been employed in the oxidative functionalization of enolizable carbonyl compounds over the years [6]. This methodology has allowed the construction of diverse C-C bonds in the context of heterocychc synthesis and has enriched the otherwise rare repertoire of such chemistry. Zhao, Du, and coworkers [37] have recendy realized a metal-free PIFA-mediated synthesis of 3-hydroxy-2-oxindoles 34 and spirooxindoles 35 starting from anilide derivatives 33 (Scheme 8 (1)). These processes showcase an oxidative cross coupling between an aromatic carbon and a pendant aliphatic carbon, followed by further oxidative hydroxylation or spirocycUzation. Later, the authors extended the same concept to achieve C(sp )-C(sp ) bond formation, where anilide derivatives possessing terminal enol functionality underwent PIDA-... 

There has been a summary of computational and experimental studies of the use of palladium complexes with A -heterocyclic carbenes (NHCs) in the asymmetric coupling of -hybridized carbon-hydrogen bonds with aryl halides. It has been shown that the electronic and catalytic properties of NHCs fused to porphyrins may be modified by varying the inner metal in the porphyrin. A DPT study of the use of palladium-NHC complexes in the asymmetric intramolecular a-arylation of 2-bromoaryl amides to give 3,3-disubstituted oxindoles (101) has been reported. The likely pathway involves insertion of the palladium into the arene-bromine bond to form a palladacycle which deprotonates to give an (9-enolate. Conversion into the C-enolate followed by reductive elimination gives the product. The intramolecular reaction of 0 a cyclopropane carbon-hydrogen bond in a 2-bromoanilide derivative has been used to form cyclopropyloxindoles, (102), in a palladium-catalysed, silver-mediated reaction. 

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