Indolines substitution reactions

The presence of an indoline nucleus was established by color reactions, substitution reactions, e.g., bromoajmaline, mp 192°, andUV-absorption spectroscopy. Upon catalytic hydrogenation, the benzene ring was reduced with remarkable ease to yield hexahydroajmaline, mp 149°—150°, [a]D + 92° (CHCI3) there was, however, no other unsaturation apart from this (1). 

Ajmaline. The presence of the indoline was established by colour reactions, substitution reactions, e.g. bromoajmaline, and by ultraviolet absorption spectroscopy. Its N-methyl was fixed onto the indoline nitrogen since potassium permanganate oxidation in acetone gave N-methylisatinacetone and soda lime or zinc dust distillation furnished N-methylharman. 

Spiro-(indoline-isoxazolidines) 137, exhibiting interesting biological activities, were prepared in modest yields, by the cycloaddition reaction between ethyl (3-indolylidene)-acetate 135 and various substituted a,N-diphenylnitrones 136 under solvent-free conditions (Scheme 48). The reaction conducted under conventional heating in an oil bath did not proceed even after 20 h, especially when it was carried out without solvent [87]. 

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

The formation of 2-(indolin-2-yl)indole dimers from indole-3-acetic acid and its propyl ester in trifluoroacetic acid and phosphoric acid has been studied." The reaction involves electrophilic attack of the protonated species (24) on the free substituted indole to give the trans stereochemistry at the C(2)-C(3) bond. 

The aryl radical cyclization has been successfully used for the preparation of substituted dihydrobenzo[Z)]indoline derivatives [59], An example is shown in Reaction (7.49). The diene 42 was preliminarly subjected to ring-closure metathesis using Grubbs catalyst and then treated with (TMS)3SiH and EtsB at -20 °C, in the presence of air, to provide the compound 43 with an excellent diastereoselectivity. 

When potassium amide, with added potassium metal in liquid ammonia, was substituted in the benzyne reaction, further cleavage of C—bonds of the intermediate dibenzopyrrocolines was often observed. The indoline 41 (32) and... 

Current studies43,44 show that a range of isatogens can now be prepared in good yield by the oxidation of 2-substituted 1-hydroxyindoles and 2-substituted indolines with perbenzoic acids. Until this work, 2-phenylisatogen was reported as only a minor product from a number of reactions of 2-phenylindole derivatives with a variety of oxidizing agents. 

The carbocyclic ring of substituted indolines can be constructed by intramolecular Diels-Alder reactions of 2-(Af-pent-3-ynylamino)pyridazines (Scheme 10) (84JOC2240). 

The extension of the use of lactams to include indolin-2-ones provides a Vilsmeier-type methodology for the construction of biindolyl systems, which are of considerable current interest.37,39-43 In this situation, the initially formed imines are indolenines, which readily isomerize to the related 2-indolyl derivatives.43 In view of our general interest in activated indoles, as well as a specific interest in continuing to synthesize structures containing indoles directly linked to each other, we investigated not only reactions with indolinone itself but also with substituted derivatives. These were variously methoxy-substituted at C-4 and C-6, and in some cases substituted also at C-3 with methyl, phenyl, or dithiolan groups. 

Early examples of intramolecular aryl radical addition reactions to heteroatom containing multiple bonds included cyclizations on N=N and C=S moieties [52, 53]. Recently, cyclizations to imines have been used as part of a new enantio-selective approach to indolines (Scheme 8). In the first step of the sequence, the required ketimines 19 were obtained by phase-transfer catalyzed alkylation of 2-bromobenzyl bromides 20 with glycinyl imines 21 in the presence of a cincho-nidinium salt [54], Due to the favorable substitution pattern on the imine moiety of 19, the tributyltin hydride mediated radical cyclization to 22 occurred exclusively in the 5-exo mode. The indoline synthesis can therefore also be classified as a radical amination. 

Recently Liu and coworkers used (porphyrin)iron(III) chloride complex 96 to promote 1,5-hydrogen transfer/SHi reactions of aryl azides 95, which provided indolines or tetrahydroquinolines 97 in 72-82% yield (Fig. 24) [148]. The reaction starts probably with the formation of iron nitrenoids 95A from 95. These diradicaloids undergo a 1,5- or 1,6-hydrogen transfer from the benzylic position of the ortho-side chain. The resulting benzylic radicals 95B react subsequently with the iron(IV) amide unit in an Sni reaction, which liberates the products 97 and regenerates the catalyst. /V,/V-Dialkyl-w// o-azidobenzamides reacted similarly in 63-83% yield. For hydroxy- or methoxy-substituted indolines 97 (R2=OH or OMe) elimination of water or methanol occurred from the initial products 97 under the reaction conditions giving indoles 98 in 74—78% yield. 

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