Enol oxindole-derived

The utility of the alkylidene oxindole-derived vinylogous enolates was demonstrated in the y-selective asymmetric conjugate addition to nitroolefins (Scheme 38) [67, 68]. Dihydroquinine-derived thiourea 10 earned distinctirm as the most effective catalyst in terms of catalytic efficiency and stereocontroUing ability. The tertiary amine and the thiourea functionalities both appeared to be essential for ensuring catalytic activity. It should be noted that not only perfect y-selectivity but also very high /Z-selectivity were observed under the optimal conditions. A wide variety of nitroolefins and substituted alkylidene oxindoles were amenable to this protocol. 

In the same year, Durbin and Willis showed that potassium enolates of a variety of oxindole derivatives undergo efficient C3-arylation using Pd(dba)j and the bulky electron-rich phosphane ligand XPhos. Significant variation of the aryl coupling partner was possible, with both electron-rich and electron-poor substituents. Aryl bromides, chlorides, and triflates were all viable substrates in this intermolecular reaction (Scheme 8.48) [87],... 

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.

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],... 

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]. 

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. 

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. 

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. 

Silyl enol ethers and ketene silyl acetals add to aromatic nitro compounds in the presence of TASF(Me) to give intermediate dihydro aromatic nitronates which can be oxidized with bromine or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone to give a-nitroaryl carbonyl compounds the latter are precursors for indoles and oxindoles. The reaction is widely applicable to alkyl-, halo-, and alkoxy-substituted aromatic nitro confounds, including heterocyclic and polynuclear derivatives (eq 7). 

Scheme 5.50 Enantioselective palladium-catalyzed arylation of enolates derived from racemic oxindoles 152, mediated by the axially chiral and P-stereogenic ligand 153.

Intramolecular variants of the reaction were reported for the enolates of amides and aldehydes through the corresponding in situ generated enolates. The palladium-catalyzed conversion of ort/zo-bromoaniline-derived amides 157 into oxindoles 160 was first studied by Hartwig and Lee who noticed that... 

The ease of preparation and generality of fluorination make the [N-F] class of reagents an excellent choice for enantioselective electrophilic fluorination. Advantageously, enantioselective electrophilic fluorination was also achieved with silyl enol ethers and oxindoles as substrates using a catalytic amount of bis-cinchona alkaloids and NFSI in the presence of excess base (Scheme 44.14). Applications of these [N-F] reagents include the enantioselective syntheses of a-fluoro-a-amino acid derivatives (Scheme 44.15), a potent opener of maxi-K channels (BMS-204352, MaxiPost Xi an Unique Electronics Chemical Co., Ltd, Xi an, P.R. China), and 20-deoxy-20-fluorocamptothecin (see section 3). 

A vinylogous Michael addition of 3-alkylidene oxindoles (441), normally regarded as good Michel acceptors, to nitroalkenes, has been attained in the presence of the cinchona-derived thiourea catalyst (372). This rare example of organocatalytic umpol-ung, presumably proceeding via the hydrogen-binding stabilized enol (442), afforded the adducts (443) in a >99 1 y.a ratio with 10 1 to >20 1 Z/E) selectivity and 97 to >99%... 

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