Oxindoles 3,3 -disubstituted

Another version of the o-aminobenzyl anion synthon is obtained by dilithi-ation of A-f-Boc-protected o-alkylanilines. These intermediates are C-acylated by DMF or A"-methoxy-At-melhyl carboxamides, leading to either 3- or 2,3-disubstituted indoles. In this procedure dehydration is not spontaneous but occurs on brief exposure of the cyelization product to acid[4]. Use of CO as the electrophile generates oxindoles. 

The mechanism of the rearrangement is explained as shown in Scheme 19. Protonation of the 9-hydroxy group followed by its elimination and subsequent chloride attack at the 4a-carbon generates a chloroindolenine 126. Addition of water to the 9a-imine carbon atom of 126 gives 127. Concerted elimination of the chloride with rearrangement of the alkyl side chain attached to the 9a carbon atom results in 3,3-disubstituted oxindole structure 120a. 

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 final, critical oxidative spirocyclization of the 2,3-disubstituted indole to the spiro oxindole was effected by treatment of 124 with tert-butyl hypochlorite in pyridine to provide the labile 125 [Fig. (34)]. The Pinacol-type rearrangement was conducted by treating compound 125 with p-toluenesulfonic acid in THF/water. It is assumed that the chlorination of 124 proceeds from the least hindered face of the indole, to give the a-chloroindolene 125. The hydration of the imine functionality must also occur from the same a-face that is syn to the relatively large chlorine atom furnishing the syn-chlorohydrin 126, that subsequently rearranges stereospecifically to the desired spiro oxindole 127. 

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)... 

Asymmetric Heck cyclizations to form chiral 3,3-disubstituted oxindoles were key strategic steps in enantioselective syntheses of the pyrroloindoline alkaloids (-)-phy sostigmine fl.l [39], (-)-physovenine (fl.2) [39], and complex dodecacyclic polyindolines such as fl.3 (Figure 8G. 1) [40],... 

NHCH2), which exhibits a typical dihydroindole UV-spectrum, and which, in contrast to mitraphylline, couples with diazotized sulfanilic acid. The formation of a dihydroindole derivative, and not an indole derivative, in this reduction is an indication, though not perhaps a conclusive one, that the molecule is a 3,3-disubstituted oxindole hence, structure V is invalidated (57). 

In the reaction of isatins with some cyclic ketones, such as 4-hydroxy-2H-benzopyran-2-one, the initial dioxindole formed reacts with a second equivalent of the ketone yielding a 3,3-disubstituted oxindole. 

An important issue with respect to the Knovenagel condensation is that a mixture of isomeric disubstituted 3-methyleneoxindoles can be obtained. NMR measurements, including nOe experiments, and quantum chemical calculations have also shown that 3-[cyano(ethoxycarbonyl)methylene]-2-oxindoles, which are obtained from the reaction of isatin or from 1-methylisatin with ethyl cyanoacetate, exist as a mixture of the E and Z isomers, and that the E isomer exists in an equilibrium between two conformers, trans-s-cis and (rans-s-/ram431 (Scheme 100). 

J-Oisubstitated SH-indoks. 3,3-Disubstituted 311-indoles (3) can be prepared readily by lithium aluminum hydride [or sodium bis-(2-mcthoxyethoxy)aluminum hydride, 3, 260-261 this volume] reduction of 3,3-disubstituted oxindoles (1), followed by oxidation of the indoline (2) with activated manganese dioxide or potassium permanganate in acetone. 

Several examples are known of the ring-expansion reactions that transform isatins into quinazolines. iV-Carbamoyl isatins rearrange in the presence of amines into derivatives of 4-carboxy-4-hydroxy-3,4-dihydroquinazolin-2(lH)-ones, and iV-carbamoyl-3-(dicyano)methylene oxindoles provided 4-(dicyano)methylene-3,4-dihydroquinazolin-2(l//)-ones. The two isomeric A-oxides 102 and 103 underwent ring expansion on photolysis and produced the same 1,3-disubstituted quinazoline-2,4-diones (104) among other products, which include isatins. The ratio of products was sensitive... 

With Ag3P04 as additive for an intramolecular Heck reaction to form 3,3-disubstituted oxindoles considerable variation of enantioselectivity and direction of asymmetric induction is observed. ... 

A novel gelsenicine-related oxindole alkaloid, named gelsemoxonine (55), was isolated from G. elegans (25). The UV absorption of 55 at 209.5 and 257.5 nm suggested a 3,3-disubstituted A(a-methoxyoxindole skeleton. The IH-NMR spectrum displayed a methyl group as a triplet at 5 1.07 (H-18), which was coupled to the H-19 methylene group multiplets. The COSY spectrum of 55 showed two methine doublets (5 3.78, d, H-3 and 5... 

An indium-mediated radical cyclization sequence has been used to synthesize stereoselectively 3-alkylideneoxindoles [65, 66]. The generation of predominantly the i -isomer, such as seen with 96 below, is attributed to the strong coordination of the indium to the carbonyl of the oxindole intermediate, and the transformation of various iodo-ynamides to the cyclized oxindoles occurred in good yield. Selective approaches to the E- and disubstituted 3-alkylideneoxindoles involving a tandem palladium-catalyzed cross coupling reaction were also highlighted in this report. 

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. 

In 2012, the Chi group demonstrated a diastereoselective NHC-catalyzed access to p-lactam fused spirocyclic oxindoles with an all-carbon quaternary stereogenic center, employing oxindole-derived p,p-disubstituted a,p-unsaturated imines and enals as substrates. The p-lactam products, stable at room temperature, were easily converted to cyclopentenes at 50 °C. An asymmetric example of the annulation reaction was presented with moderate enantioselectivity (89% yield and 51% ee by using the amino indanol derived catalyst), which is probably due to the sterical hindrance of p,p-disubstituted a,p-unsaturated imines (Scheme 7.58). 

Scheme 7.58 NHC-catal)rzed cross-annulation of enals with oxindole-derived P,P-disubstituted o,p-unsaturated imines reported by Chi.

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. 

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