Oxindole enolates

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]. 

Asymmetric addition of an oxindole enolate to nitroalkenes has been observed by Matsunaga, Shibasaki, and coworkers [25]. As illustrated in Scheme 9, chiral oxindole 35 was prepared with good diastereoselective and enantioselective control (30 1 dr, 97% ee) upon treatment of oxindole 32 with nitroalkene 33 in the presence of the bimetallic (Mn2) Schiff Base complex 34. Control experiments with various heterobimetallic complexes (Cu/Mn or Pd/Mn with organic catalyst 34) and a mononuclear complex of Mn with organic catalyst 34 led to decreased selectivity, highlighting the importance of the homodinuclear Mn2-34 complex for promoting the stereoselective transformation. 

An all organic catalyst system 38 has been reported by the Maruoka group for directing asymmetric additions of oxindole enolates derived from 36 to nitro-aUcenes 37 under phase-transfer conditions [26] (Scheme 10). The methodology was extended to the synthesis of a tetrahydropyrroloindole scaffold bearing two chiral centers. Asymmetric Michael and Mannich reactions of 3-aryloxindoles directed by chiral phosphonium salt phase-transfer catalysts have been described by the same group [27]. 

Isatins have served as valuable precursors for the preparation of oxindoles bearing amino functionality at stereodefined C3. In a report from the Emiua group, isatin derived oxime 91 (Scheme 25) was transformed to the urea derivative 92 which underwent a diastereoselective alkylation at C3 to afford the /-menthol adduct 93 (94 6 dr) [59]. Lithium counterions proved to be more effective than potassium ions for achieving diastereocontrol of the enolate alkylation a mechanism has been suggested involving lithium ion chelation between the oxindole enolate of 92, the carbonyl of the urea fimctionality at C3, and the carbonyl of the menthyl ester electrophile. 

Emura, T. Esaki, T. Tachihana, K. Shimizu M. Efficient asymmetric synthesis of novel gastrin receptor antagonist AG-041R via highly stereoselective alkylation of oxindole enolates. J. Org. Chem. 2006, 71, 8559-8564. 

The isolation of calycanthine (9) in 1888 by Eccles [28] and the subsequent proposition for its origins in the oxidative dimerization of tryptamine by Woodward [29] and Robinson [30] had prompted several key synthetic studies based on a biomimetic approach. Hendrickson was the first to experimentally verify the plausibility of forming the C3-C3 linked dimers through an oxidative radical dimerization strategy (Scheme 9.2a). He demonstrated that the sodium enolate of a tryptamine-derived oxindole could be oxidized with iodine to afford a mixture of three possible stereoisomers. The racemic product was isolated in 13 % yield, while the meso product was isolated in 8 % yield. Global reduction of the oxindole and carbamates afforded the first synthetic samples of chimonanthine (7) [9a],... 

Spirocyclic oxindole 60 was synthesized by [3,3]-sigmatropic rearrangement of the Af-phenyl-O-acylhydroxamic acid 58 (equation 19). The potassium enolate formed by treatment of 58 with potassium hexamethyldisilazide at low temperature rearranged to 59, which easily cyclized to the spirocyclic oxindole 60. Spirooxindoles were previously synthesized by Wolff and Taddei. The spirooxindole 60 was formed in 51% yield from cyclohexanecarboxylic acid after heating the preformed lithium salts of phenyl hydrazide 61 to 205-210 °C. 

Taylor and colleagues discovered recently that IV-aryl malonamides or cyanoacetamides 312 cyclized in 53-92% yield to oxindole-3-carboxylates 313 in the presence of 5 mol% of Cu(OAc)2 using air as the stoichiometric reoxidant for the catalyst (Fig. 83) [412]. The reactions occur likely by initial formation of a copper enolate of 312. SET oxidation with elimination of CuOAc gives radical 312A, which undergoes a 5-exo cyclization to the aryl unit. A final oxidative... 

When A-acyl-ochloroaniline (314) is treated with LDA in THF-hexane solution, it forms the enolate ions which undergo cyclization to afford oxindoles 315. When R, R = Me, Ph, -Bu, the yield of 315 are 63-82%. When R = PhCH2, R = H the yield is 32% (equation 188)336. 

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]. 

Iniino ethers. Harley-Mason and Leeney found that triethyloxonium fluoroborate converts oxindole (1) into the enol ether (2, m.p. 110°) and that (2) on being heated in vacuum is isomerized to the imino ether (3, m.p. 63°). If (3) is heated above its... 

This group continuously enlarged the scope of substrate to allylsilane, silyl enol ether 113 and oxindoles 115 for enantioselective catalytic a-fluorination (Scheme 6.34) [62]. They employed N-fluorobenzenesulfonimide (NFSI) as a fluorinating reagent with bis-cinchona alkaloid catalysts and excess base to provide the corresponding fluorinated compounds 114,115 in excellent enantioselectivities up to 95% ee. 

Mirroring oxindoles, aldol-type condensation at the 2-position in indoxyls can be accomplished either using the acetate of the enol form and base catalysis,or with indoxyl itself, in either acid or basic condi-tions. Borohydride redaction and dehydration allows these aUcylidene condensation prodncts to be converted into 2-substituted indoles. 

Oxindoles can also be prepared by palladium-catalysed enolate cyclisation of orl/to-halo-anilides. ... 

ArykUion. Oxindole and ester enolates are arylated by ArX, with (dba)2Pd and a bulky phosphine ligand present,although in the case dealing with the esters [t-BusP PdBr]2 is equally effective. ... 

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]. 

Chiral indole-2-sulfoxides have been employed by Feldman and Karatjas for asymmetric spirooxindole synthesis [70]. In one example, treatment of 115 with triflic anhydride initiated a Pummerer-type cyclization of the silyl enol ether side chain onto C3 (Scheme 30). Sequential hydrolysis of the resulting thioimidate intermediate with aqueous HgCl2 afforded the spirocyclohexanone functionalized oxindole 116 in modest yield and enantioselectivity at —78°C (33, 67% ee). Improved selectivity (58, 86% ee) was observed at lower reaction temperature (-110°C). 

---