Indoline scaffolds

Fig. 17.5 First- and second-generation functionalized indoline scaffolds.

Fig. 17.6 Solution and solid phase synthesis from the racemic first-generation indoline scaffold to obtain a 100-membered library using an intramolecular Mitsunobu approach.

Nicolaou [67, 68] and Fukase [69] have also reported the use of radical cyclization and solid phase methodology to synthesize indoline scaffolds and indol-2-ones. 

Almost at the same time as the first report of the Kiindig group in 2011, Kagan and co-workers realized an asymmetric synthesis of chiral indoline scaffolds via Pd°/bisphosphine catalyzed C(sp )—H bond functionalization. They briefly investigated a number of chiral ligands (R,R)-L16 gave the cyclization product in best results (Scheme 5.35). They also employed this method to synthesize cyclohexyl fused indolines in promising yields (up to 97%) and enantioselectivity (up to 93% ee). 

The transformation proceeds through initial intramolecular N-arylation, generating the indoline scaffold. Subsequent carboamination across the double bond provides the product exclusively as the cis isomer. 

Scheme 13.91 Intramolecular C-N cross-coupling to access indoline scaffolds [137].

A series of diamine amides based on the phenoxypropyl amine scaffold was reported. Amide 26 displayed an hH3 Ki of 1 nM and was selective versus other histamine receptors [73]. The chirality was removed via cyclic diamines to produce tetrahydroisoquinolines, tetrahydroquinolines, benzazepines and indolines [74]. The benzazepine 27 displayed picomolar hH3 binding affinity. Pharmacokinetic issues were also identified with this diamine series, with i.v. half-lives of 10-12 h in the rat. A strategy to remove the diamine skeleton and prepare new H3... 

With the goal of producing different indoline-based functionalized polycyclic architectures and using such architectures in library generation, we developed a practical, enantio-controlled synthesis of an aminoindoline scaffold, (14) (Figure 17.7) [26]. This scaffold has several attractive features that make it extremely... 

The treatment of 4,6-dichloro-5-aminopyrimidine 1198 with indoline 1197 gave 4-chloro-6-(2,3-dihydro-l//-indol-l-yl)-5-pyrimidinamine 1199 in 79% yield (Scheme 230) <2005JC0813>. Subsequent oxidation of the indoline moiety to the corresponding indole was achieved with DDQ in refluxing benzene to yield the indole-substituted pyrimidine 1200, the key compound in the cyclization reactions with various aldehydes and ketones leading to a novel heterocyclic scaffold consisting of indole-fused pteridines. 

Lactam 243 was thus proposed to be a versatile intermediate which could possibly permit entry to echitamine or akuammiline type scaffolds. No further work was described by this group toward these ends. This work, however, can be considered as the first late stage construction of the C6—C7 bond to form the indoline quaternary center of the akuammiline core. 

Moreover, two indoline-Uke libraries were prepared (Scheme 1.6). A hydroxyindoline-derived scaffold 26 was used to prepare a tricyclic indoline-based library 27 by an IRORl split-and-mix approach on solid-support." A later indoline-alkaloid-like polycyclic library incorporated additional diversity, and the stereochemistry at the ring junction was controlled." ... 

The same authors disclosed a convergent three-component access to the indolone scaffold by a sequentially Pd-catalyzed N-arylation-carbopalladation-CH activation-cyclization process [53]. Without further addition of catalyst or ligands after the AT-arylation of the secondary propiolamide, a second aryliodide concludes the synthesis of 3-(diarylmethylene)indolin-2-ones 32 in moderate to good yields via an intermolecular carbopalladation-CH activation - arylation (Scheme 12.21). 

Keywords Indoles, istains/acenaphthaquinone, sulfamic acid, ethanol-water (1 1), room temperature, one-pot pseudo-multicomponent reaction, functionalized 3,3-f>A(indol-3-yl) indolin-2-one scaffolds / 2,2-W5(indol-3-yl)acenaphthylen-l(2/f)-one derivatives... 

Gan Z, Reddy PT, Quevillon S, Couve-Bonnaire S, Arya P. Stereocontrolled solid-phase synthesis of a 90-membered library of indoline-alkaloid-like polycycles from an enan-tioenriched aminoindoline scaffold. Angew. Chem. Int. Ed. 2005 44 1366-1368. 

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