Alkyl indole-2-carboxylates, synthesis

Stanovnik, B., Tisler, M. and Carlock, J.T. (1976) Heterocycles, CLIX. A novel synthesis of alkyl indole-3-carboxylates. Synthesis, (11), 754—755. 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

Additional communications deal with the synthesis of pyrrolo[l,2-cjquinazolines by treatment of methyl 3-alkyl-l,3-dihydro-2-oxo-3-(triphenylphosphoranylidenamino)-2//-indole-l-carboxylates (275) with ketones to afford A -pyrrolin-4-ones (276). As Scheme 100 shows, 276 can... 

The Barton-Zard pyrrole synthesis <1990T7587> was applied in the syntheses of pyrrolo[3,4- ]indoles 423 from 3-nitroindoles 422. Treatment of appropriate alkyl 3-nitroindole-l-carboxylates 422a-c with ethyl isocyanoacetate and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave the corresponding pyrrolo[3,4- ]indole 423a-c (Equation 12) <1997CC1873, 1999S1117>. 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

Enantioselective additions of a,f)-unsaturated 2-acyl imidazoles, catalyzed by bis(oxazolinyl)pyridine-scandium(III)triflate complex, were used for the asymmetric synthesis of 3-substituted indoles. The complex 114 was one of the most promising catalysts. The choice of acetonitrile as the solvent and the use of 4 A molecular sieves were also found to be advantageous. The 2-acyl imidazole residue in the alkylation products of u,(i-unsaturated 2-acyl imidazoles could be transformed into synthetically useful amides, esters, carboxylic acid, ketones, and aldehydes (Scheme 32) [105]. Moreover, the catalyst 114 produced both the intramolecular indole alkylation and the 2-substituted indoles in good yield and enantioselectivity (Scheme 33) [106]. The complex... 

In a Nenintzescu indole synthesis with 2-alkyl-l,4-benzoquinones (3) and 3-aminocrotonates (4) (Scheme 1), two isomeric products (5) and (6) were formed. The compound 5 was already identified as 5-hydroxy-6-alkylindole-3-carboxylic ester. For compound 6, there was ambiguity as to whether there was 4- or 7- alkyl substitution. The following solution was obtained ... 

More recently, Langlois and co-workers have adapted this methodology to total synthesis of some complex indole alkaloids.56 Cyclic imines (Scheme 2-IX) reacted thermally in good yields with methylbutadiene-1-carboxylate to afford a mixture of Diels-Alder adducts. Alkylation of the enolate derived from the mixture of isomers gave a /3, y-unsaturated ester stereospecifically. This type of compound was coverted to vindoline (28, R = OMe) and vindorosine (28, R = H). These workers found that 1-cyanobutadiene is also useful in this sort of cycloaddition [Eq. (13)]... 

Indole-2-carboxylic esters.- Benzs he mates followed by addition of alkyl oxalau indole-2-carboxylic ester synthesis on treain... 

Amino Acids and Peptides. - Wasserman s method of one-carbon homologation of carboxylic acids to give a-ketocarboxylates involves reaction with cyanomethylenetriphenyl-phosphorane followed by ozone (Scheme 24) and has been used as a key step in a chemo-enzymatic synthesis of isotopically labelled L-valine, L-isoleucine, and o/fo-isoleucine. Alkylation of the carbanion derived from the imino-substituted methylphosphonate diphenyl ester (186) with indol-3-ylmethyl bromide followed by appropriate deprotection has been used to prepare the phosphonate analogue (187) of tryptophan (Scheme 25). The deprotected analogue (188) and derived peptides show activity as inhibitors of chymotrypsin. Two approaches to solid phase Wadsworth-Enunons reactions which have applications in combinatorial chemistry have been reported. In one diethylphosphonoacetamide is bound to PEG-PAL resin via a peptide link, while... 

For the retrosynthesis of indole (see Fig. 5.8), two routes (I/II) are proposed, as for pyrrole (see p 94). Route I suggests o-aminobenzyl ketone 1 or 6>-alkyl-A -acylaniline 2 as starting material on the basis of operations a - c. Their retroanalysis (d,e) in turn leads to 2-alkylaniline 5 and carboxylic acid derivative 6. Construction of the indole system should thus occur by N- or C-acylation of 5 (utilizing the o-nitrotoluene derivative 4) followed by cyclodehydration of 1/2. The alternative route n, based on retrosynthetic analysis g-i, leads to aniline via the a-(A -phenylamino)ketones 3 and to a-halo ketones 7 as possible precursors for the indole synthesis. 

Both 1-methylpyrrole and 1-methylindole can be easily lithiated and the resulting intermediates have been used extensively in synthesis. The range of electrophiles which can be used with lithiated pyrroles and indoles is quite broad. Aldehydes and ketones give carbinols. A,A-Disubstituted formamides give aldehydes. Carbon dioxide and alkyl chloroformates have been used to make carboxylic acid derivatives. Alkyl halides, sulfates and sulfonates can be used to introduce alkyl groups. Interestingly, even t-butyl bromide has been used successfully for alkylation (see entry 3, Table 7). Some examples are given in Table 7. 

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