Oxindoles 3-aryl

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

The selective constmction of all-carbon quaternary centers is a unique challenge within the realm of organic synthesis that has received significant attention in recent years. Many of the synthetic strategies for chiral oxindole synthesis described within this chapter rely on racemic 3-alkyl or 3-aryl oxindole precursors that are available through a manifold of well established synthetic protocols. Although the synthesis of C3 monosubstituted oxindoles will not be treated in detail within this... 

Given the variety of methods for accessing 3-alkyl or 3-aryl oxindoles in racemic form, the direct asymmetric hydroxylation of 3-substituted oxindoles represents a conceptually appealing strategy for controlled installation of hydroxyl-bound... 

Scheme 5.20 Enantioselective Michael reaction of 3-aryl oxindoles with enones catalyzed by phosphonium salt 110.

Finally, it should also be pointed out that enantioselective Michael reactions to enones under PTC conditions do not exclusively rely on the use of chiral ammonium salts as catalysts and, for example, chiral phosphonium salts can also be successfully employed in this context. This is the case of binaphthyl-containing phosphonium salt 110, which was demonstrated to be an outstanding catalyst in the conjugate addition of oxindoles to enones under PTC conditions (Scheme 5.20). The Michael adducts were obtained in excellent yields and enantioselectivities for a wide variety of differently substituted 3-aryl oxindoles tested as Michael donors. Remarkably, the high acidity of the 3-aryloxindoles employed as Michael donors allowed the use of a very mild base such as potassium benzoate for the activation of the nucleophile. 

Dounay, A.B., Hatanaka, K., Kodanko, J. et al. (2003) Catatytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective s3mthesis of 3-alkyl-3-aryl oxindoles by catalytic asymmetric intramolecular Heck reactions. J. Am. Chem. Soc., 125, 6261-71. 

In 2012, Dorta and coworkers reported other interesting chiral Pd-NHC complexes with naphthyl side chains, which are easily accessed as a single diastereomer from the NHC salt. The enantiose-lective construction of carbon-fluorine bonds via an asymmetric a-arylation is also a nice efficient approach to the direct synthesis of 3-flouro-3-aryl oxindoles (Scheme 8.46) [85]. 

Scheme 5.31 Enantioselective 107b-catalyzed Michael reaction of a-aryl oxindoles with nitroalkenes.

Cyclic P-ketoesters were converted to the corresponding products in high yields with up to 93% ee catalyzed by the combination of iron(II) chloride complex and silver carboxylate. 3-Azido aryl oxindoles were obtained with up to 94% ee using the catalyst prepared by iron(II) propionate and the ligand in situ (Scheme 15.10). 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

Intramolecular arylations are possible and several studies have examined the synthesis of biologically active compounds such as oxindoles.181 For example, a synthesis of physovenine has been reported using this methodology. 

Hartwig has reported an intramolecular/intermolecular process affording the 3-aryloxindoles 105 (Scheme 32).115 The intermolecular arylation of acetanilide derivative 104 is slower than the intramolecular arylation to form the oxindole. Thus, the overall transformation starts with cyclization followed by intermolecular arylation of indole. In order to slow down the intermolecular process and speed up the intramolecular reaction, chloroarene and bromine-substituted acetanilide precursors are used according to their respective reactivity with palladium(O) in the oxidative addition process. 

Anodic regioselective fluorination of a-phenylsulphenylated ethyl acetates, 1-naphthalene and 2-pyridine derivatives [80], l-aryl-3-(phenylthio)oxindoles and 2-substituted-3-oxo-4-(phenylthio)-l, 2, 3,4-tetrahydroisoquinolines [81], 2-benzo-thiazolyl and 5-chloro-2-benzothiazolyl sulfides [82], a-(phenylsulfenyl)lactams [83], as well as various heterocycles such as thiolanones, oxathiolanones, dithi-olanones, 3Fl-l,4-benzoxathian-2-ones [84] in Et3N-3HF or Etr NF- HF [n = 3,4), has been reported. 

Scheme 68 2-Oxindol derivatives by nickel-catalyzed cyclization of aryl halides.

The palladium catalyzed intramolecular coupling of aryl halides and classical carbanions, sometimes considered a variant of the Buchwald-Hartwig coupling, might also be used for the formation of heterocyclic systems. 7V-(2 -bromophenyl)-propionamides were converted in the presence of the appropriate palladium catalyst and lithium hexamethyldisilazide to oxindoles (3.2.). Under the applied conditions a series of electron deficient and electron rich aniline derivatives, including 2-chloroanilines were transformed successfully.2... 

In the other example CO insertion was used to introduced a nC-labelled amide function onto a series of aryl and hetaryl rings including oxindole and the y -carboline skeleton (8.35.), In the latter cast the trapping efficiency of 11 CO was 98% and the isolated yield of the labelled product was also good46... 

Makosza et al.115 have also reported similar reactions with a 3-substituted oxindol and an aryl halide. The reaction occurs only if the aryl halide is activated by an electron-withdrawing substituent. 

The analogous Z aryl triflate 19.1 reacts under the cationic manifold to give, ultimately, oxindole (/ )-17.3a in 72% yield and 43-48% ee (Scheme 8G.19) [38]. An important synthetic advance is the observation that Heck cyclization of this substrate could be diverted to the more selective neutral pathway by addition of halide salts. For example, Heck cyclization of triflate 19.1 in the presence of 1 equiv. of n-Bu4NI gave (/ )-17.3a in 62% yield and 90% ee, which is similar to the enantioselectivity obtained for cyclization of the corresponding iodide 18.1c under neutral conditions (see entry 6, Table 8G, 1). Conversely, cyclization of iodide 18.1c in the... 

With excess of Br2, further bromination products of the central ring were obtained. 3-iV-Aryl-2-oxindoles (55) undergo Hofmann-Martius rearrangement under acid-catalysed conditions, in contrast to their 3-0 analogues (Scheme 16).53 The thermal... 

Beckwith and Storey have developed a tandem translocation and homolytic aromatic substitution sequence en route to spiro-oxindoles [95CC977]. Treatment of the bromoaniline derivative 122 with tin hydride at 160 °C generated the aryl radical 123 which underwent a 1,5-hydrogen atom transfer to give intermediate 124. Intramolecular homolytic aromatic substitution and aromatization gave the spiro-oxindole 125. Intramolecular aryl radical cyclization on to a pyrrole nucleus has been used to prepare spirocyclic heterocycles [95TL6743]. 

Scheme 10 Preparation of AT-substituted oxindoles via a condensation-arylation sequence...

Turner and Poondra have described an efficient intramolecular one-pot and two-step Goldberg aryl amidation that gives access to useful AT-substituted oxindoles (Scheme 29) [96]. 

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