Indolines 7-acylation

The stronger directing effects present in the indoline ring can sometimes be used to advantage to prepare C-substituted indoles. The aniline type of nitrogen present in indoline favours 5,7-substitution. After the substituent is introduced the indoline ring can be aromatized by dehydrogenation (see Section 15.2 for further discussion). A procedure for 7-acylation of indoline... 

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). 

Indolinines acylation, 4, 308 alkylation, 4, 308 reactivity, 4, 308 reduction, 4, 308 Indolinobenzospiropyrans photothermography, 1, 391 Indolin-3-one, l-acetoxy-5-hydroxy-reactions... 

The reaction of methane tricarboxylate with indoline 342 gave the tricyclic derivative 361 which can be transformed to the amide derivatives 362 (97JHC969). Alkylation of the iV-benzyl indoline 360 with pentafluor-oacetone gave 363 which upon debenzylation and subsequent acylation with diketene followed by cyclization gave 364. Other haloacetones were used to prepare different halogenated derivatives (79BEP872311) (Scheme 63). 

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]. 

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. 

The insertion of carbon monoxide into o-alkylpalladium(II) complexes followed by attack by either alcohols or amines is a powerful acylation method. This carbonylation reaction has been applied in several different ways to the reactions and syntheses of indoles. Hegedus and coworkers converted o-allylanilines to indoline esters 315 in yields up to 75% [293], In most of the examples in this section, CO at atmospheric pressure was employed. 

The Heck reaction on polymer-bound iodoarenes is assisted by the addition of a catalytic amount of tetra-n-butylammonium bromide and has been employed in the synthesis of 4-carboxycinnamic esters and amides [33], and 4-aminosulphonyl-cinnamic esters [34], It has also been reported that the presence of an equimolar equivalent of benzyltriethylammonium chloride aids the Pd(II)-mediated reaction of A -acyl-2-iodoanilines with vinylidene carbonate, which leads to A -acyl-2-hydroxy-indolines providing a convenient route to the indoles (80-90%) [35], The catalysed reaction of 2-hydroxy- and 2-tosylaminoiodobenzene with 1,2-dienes produces 1,2-dihydrobenzofurans and 1,2-dihydroindoles, respectively [36]. 

This acylating agent has also been used in the resolution of indolines see Gotor-Fernandez, V., Rebolledo, F. and Gotor, V., Chemoenzymatic preparation of optically active secondary amines a new efficient route to enantiomerically pure indolines. Tetrahedron Lett., 2006,17, 2558. 

Fu and co-workers expanded the scope of amine KR to include indolines [100], However, as the initial conditions developed for aryl alkyl i ec-amines were unsuc-cessfnl dne to the low nucleophilicity of the catalyst, a few structural modifications were introdnced. Hence, after screening varions catalysts and achiral acyl donors, the use of a bulky pentacyclopentadienyl-derived catalyst in conjunction with an... 

Indolines are produced in good yield from 1-benzenesulfonylindoles by reduction with sodium cyanoborohydride in TFA at 0°C (Equation 5) (89TL6833). If acyl groups are present at C-2 or C-3 in the substrate, they are reduced to alkyl groups. Indole is also reduced to 2,3-dihydroindole by sodium cyanoborohydride and acetic acid or triethylamineborane and hydrochloric acid. An alternative method for preparing indolines involves treatment of indoles with formic acid (or a mixture of formic acid and ammonium formate) and a palladium catalyst (82S785). Reduction of the heterocyclic ring under acidic conditions probably involves initial 3-protonation followed by reaction with hydride ion. 

The 2H-and 3//-pyrroles and -indoles are considerably more basic than the corresponding H-isomers and they readily undergo alkylation to give the quaternary salts, which are then highly susceptible to nucleophilic attack. Thus, for example, methylation of the trialkyl-3//-indole (507), followed by reaction with aqueous base, yields the indolin-2-ol (508). A similar reaction sequence results from the acylation of (507) under Schotten-Baumann conditions to give (509 X = OH). When the benzoylation is conducted in benzene in the absence of the base, the 2-chloroindoline (509 X = C1) is formed and acylation of (507) with a carboxylic acid anhydride produces the ester (509 X = OCOR) (79HC(25-3)l). 

Many early claims of having prepared simple 1-hydroxyindoles have proved to be unfounded, although the unusually stable l-hydroxy-2-phenylindole was obtained in 1895.1-Hydroxyindole itself polymerizes on attempted isolation, while O-acylation, O-alkylation, or the presence of substituents greatly stabilizes the molecule. One 1-hydroxyindole antibiotic has been identified and is the only 1-hydroxyindole derivative isolated from natural sources so far. In contrast, a substantial number of 1-methoxyindoles occurs in various plants, and some of these may inhibit tumor formation in mammals. The biochemistry of these compounds, which include 1-methoxy-indoles, -indolines and -2-oxindoles, has not been widely investigated and could be a very fruitful area for new research which might well lead to novel medicinal agents and other useful compounds. 

This reaction was exploited by Pass, Amit and Patchornik to directly couple two peptide fragments (Scheme 13.30) [117]. However, one of the main issues to date has been the preparation of such activable amino acids. Two approaches (which, unfortunately, are limited in their scope) are nitration of the parent indoline derivative after acylation with the amino acid, or use of the amino acid chloride prepared in situ. 

Trimethylindolenine and its 5-methyl-, 5-chloro- and 7-chloro derivatives react with phenyl isocyanate and various acyl isocyanates and isothiocyanates to give 75-97% of the corresponding l-carbamoyl-2-methyleneindolines (52), which isomerize to the 2-(carbamoylmethylene) indolines (53) (41-85% yield).52 Whether these Fischer s base derivatives after further N-alkylation will condense with salicylaldehydes to form spiropyrans is not known. 

M. A. GaTbershtam, N. N. Artamonova, and N. P. Samoilova, Synthesis of 3 -acyl-substituted indoline spiropyrans, Chem. Heterocycl. Cpds., 1975, 167-172. 

The first, and hitherto only, synthesis of lysergic acid was effected by the research group of Kornfeld et al. (50, 26). In this particular synthesis a X-acyl-2,3-dihydroindole derivative was used as starting material, thus allowing the formation of rings C and D by classical methods. Dehydrogenation of the 2,3-dihydroindole system to the indole system was only effected in the last stage so that the formation of the benz[c,d]-indoline system was prevented. 

Isatins fail to yield Knoevenagel condensation products with malonic acid419. However, malonic acid can be condensed with isatin in a mixture of ethanol and pyridine, in which the initial condensation product suffers decarboxylation, furnishing an acetic acid derivative. This can be converted to the acid chloride and submitted to a Friedel-Crafts acylation reaction, yielding acetophenone derivatives420. Alternatively the oxoindolinylidene acetic acid derivative can be treated with an arene in the presence of AICI3 to yield. sy />o[indoline-3,3 -indan]-2,l-dione derivatives. ... 

Cephalosporin derivatives containing a pyrrole ring in the A -acyl chain, such as compound 8, show significant antibacterial activity, similar to that of cefalexin <2000PHA568>. l-Butyl-4-(2-phenyl-17f-indol-3-yl)-2-azetidinones of the type 9 <2004HAC494> and several new spiro indoline-based heterocycles 10 <2004BMC2483> show interesting antibacterial activity. 

The synthesis of optically active substituted indolines 46 has been achieved via C. antarctica lipase A catalyzed resolution using 3 methoxyphenyl allyl carbonate 47 as the acylating agent (Figure 14.17) [23]. Indole and indoline cores are present in a variety of natural products, biologically active alkaloids, and pharmaceuticals. Ex cellent selectivity values ( > 200) were achieved. 

Under indole alkaloids we include naturally occurring bases or their derivatives which contain a true indole nucleus or a modification thereof, indoline (dihydroindole), N-acyl-indoline, indolenine, oxindole etc. 

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