Indoline intermediates

With Pd(0) generated in situ, the oxidative addition of aryl bromide 102 to Pd(0) proceeds to form Pd(II) intermediate 104. Migratory insertion of 104 then occurs to furnish the cyclized indoline intermediate 105. Subsequent reductive elimination of 105 takes place in a cis fashion, giving rise to exo-cyclic olefin 107, which then tautomerizes spontaneously to the thermodynamically more stable indole 103. The reductive elimination by-product as a palladium hydride species 106 reacts with base, regenerating Pd(0) to close the catalytic cycle. 

A soln. of 5-nitro-N-acetylindoline-3-acetic acid in aq. NaOH treated at ca. 20° with sufficient Raney-Ni to supply the required Hg, heated slowly to boiling, and refluxed 16 hrs. 5-aminoindole-3-acetic acid. Y 93% as the monohydrate. —Certain aminoindoles can best be prepared via indoline intermediates. F. e. s. H. E. Johnson and D. G. Crosby, J. Org. Chem. 28, 2794 (1963). 

Friedel-Crafts acylation of 3,3-dimethyl-2-indolinone by succinic anhydride gives 3,3-dimethyl-5-(3-catboxyptopionyl)-2-indoline, which is used as an intermediate in the preparation of inotropic agents for treatment of heart failure (94). Antibacterial phlotophenone derivatives have been prepared by Friedel-Crafts acylation with ptopanoyl chlotide (95). 

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

Buchwald has developed a route to indolines by the Pd-catalyzed intramolecular amination of aryl halides <96T7525> and applied this method to the synthesis of natural products. Thus, cyclization of tetrahydroquinoline 70 provided 71 which was elaborated to a key intermediate in syntheses of damirones A and B and makuluvamine <96JA1028>. 

A novel approach to 3-substituted indolines and indoles via the anionic cyclization of 2-bromo-lV,lV-diallyanilines has been developed simultaneously by Bailey <96JOC2596> and Liebeskind <96JOC2594>. Thus, treatment of 2-bromo-lV,lV-diallylanilines 78 with 2 equivalents of BuLi at -78 °C leads to the formation of the intermediate 79 which may be trapped with an electrophile to afford 3-substituted indolines 80. Aside from ease of preparation, an additional benefit of the intramolecular carbolithiation of <7-lithio-W,Al-diallyl-anilines is the production of Al-allyl-protected indolines, which are easily deprotected using... 

The unexpected formation of cyclopenta[b]indole 3-339 and cyclohepta[b]indole derivatives has been observed by Bennasar and coworkers when a mixture of 2-in-dolylselenoester 3-333 and different alkene acceptors (e. g., 3-335) was subjected to nonreductive radical conditions (hexabutylditin, benzene, irradiation or TTMSS, AIBN) [132]. The process can be explained by considering the initial formation of acyl radical 3-334, which carries out an intermolecular radical addition onto the alkene 3-335, generating intermediate 3-336 (Scheme 3.81). Subsequent 5-erafo-trig cyclization leads to the formation of indoline radical 3-337, which finally is oxidized via an unknown mechanism (the involvement of AIBN with 3-338 as intermediate is proposed) to give the indole derivative 3-339. 

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-A,-allylanilines in the presence of (-)-sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of /BuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent. 

Nitrogen-containing heterocyclic compounds, including 1,2,3,4-tetrahydroqui-noline, piperidine, pyrrolidine and indoline, are also popular hydrogen donors for the reduction of aldehydes, alkenes, and alkynes [75, 76]. With piperidine as hydrogen donor, the highly reactive 1-piperidene intermediate undergoes trimer-ization or, in the presence of amines, an addition reaction [77]. Pyridine was not observed as a reaction product. 

Alkali metal borohydrides are frequently used for the reduction of rc-electron-deficient heteroaromatic systems, but reduction of jt-electron-excessive arenes is generally possible only after protonation of the systems [e.g. 35-37]. The use of tetra-n-butylammonium borohydride under neutral conditions for the conversion of alkylindoles into indolines [38] is therefore somewhat unusual. Reduction of indoles by diborane under strongly alkaline conditions involves the initial interaction of the indolyl anion with the diborane to form an amino-borane which, under the basic conditions, reacts with a second molecule of diborane to produce the indoline [39]. The reaction of tetra-n-butylammonium borohydride with indoles could also proceed via the intermediate formation of diborane. 

Palladium complexes have been used for the electroreductive cycliza-tion of Ai-alkenyl-2-bromoanilines to the corresponding indoline derivatives (Scheme 69) [101]. The postulated carban-ion intermediate undergoes a reaction with the electrophiles (H+, CO2). 

The psychoactive constituents of rauwolfia are alkaloids classified in three groups (1) weakly basic indole alkaloids, (2) intermediate basic indoline alkaloids, and (3) strong anhydronium bases. Approximately 50 alkaloids have been identified, but the principal indole alkaloids... 

Intramolecular C-N bond coupling in arylazides via C-H bond activation catalyzed by [Ir(COD)(OMe)]2 was recently reported [131]. The intermediate iridium nitrenoid complex (50) formed after the extrusion of dinitrogen is proposed as a reactive species, which can cleave the benzylic C-H bond to yield indoline derivatives (31). 

The synthetic scheme for functionalized indolines shown in equation 83 assumes formation of a doubly metallated intermediate (335), derived from V,iV-diallyl-2,6-dibromo-p-toluidine, that may be quenched to the dehalogenated toluidine 336, or may undergo cyclization to 337. Quenching of 337 with trimethylchlorosilane in the presence of TMEDA leads to formation of indoline derivatives 338 and 339. Apparently a second cyclization of intermediate 337 to compound 340 is hard to accomplish . 

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... 

Brassilexin 48 and sinalexin 49 are among the most potent phytoalexins produced by economically important cruciferous plants. The most efficient preparation of brassilexin 48, sinalexin 49, and analogues 52 reported uses a Vilsmeier formylation-amination of readily available indoline-2-thiones 50 followed by an aqueous ammonia work-up procedure with subsequent oxidation of the 3-(amino)methyleneindoline-2-thione intermediates 51 using iodine in pyridine (Scheme 10) <20010L1213, 2005JOC1828>. The reaction yields are dictated by the efficiency of the... 

Perindopril (A), an orally active pharmaceutical for the treatment of hypertension, is an important commercial target compound that has a cyclic a-amino acid as an intermediate in its synthetic route. The bicyclic a-amino acid building block is synthesized by reduction of the chiral indoline-2-carboxylic acid (B, R=R =H) shown in Figure 1.4. This chiral cyclic amino acid has so far proven very difficult to synthesize in a highly enantioselective manner using chiral hydrogenation. 

Therefore better methods for the chiral reduction of indole-2-carboxylic acid derivatives would provide an elegant synthesis of this intermediate. A study by Kuwano and Kashiwabara of the reduction of indole derivatives into the corresponding indohnes found that a range of the more common ligand systems gave almost no enantioselectivity but the TRAP ligand gave the chiral indolines in up to 95 % ee for reduction of the methyl ester (B, R=Me, R =H). Further developments are awaited. 

As part of a study of the reactions of arenesulfonyl azides with indoles, Bailey et al.lu obtained a compound from the action of tosyl azide on indoline-2-thione to which they ascribed structure 114 (R = H). In contrast, N-methylindoline-2-thione gave only a low yield of 114 (R = Me) under the same conditions. Diazo-transfer via an intermediate 115 is thought to be involved when R = H, facile loss of toluene-p-sulfonamide leads to 114a, but when R = Me, loss of the same fragment leads mainly to other products. 

A number of claims have been made that this type of oxidation can be effected by chemical means, but all have been discounted [65M11 68JCS(C)504] except perhaps one. l-Hydroxy-2-phenylindole has been detected (74CC677) as an intermediate in the oxidation of 2-phenylindoline by 3-chloroperbenzoic acid to 2-phenylisatogen (321), but even here it is possible that N-oxidation of the indoline takes place and is followed by aromatization. The formation of a few l-hydroxyindoles not possessing an... 

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