Indoles 3- -. intramolecular 4-acylation

Bennasar et al. reported a new radical-based route for the synthesis of calothrixin B (378) (869). This synthesis starts from the 2,3-disubstituted N-Boc indole 1558 and uses a regioselective intramolecular acylation of a quinoline ring as the key step for the construction of the calothrixin pentacyclic framework. Chemoselective reaction of in s/fM-generated 3-lithio-2-bromoquinoline [from 2-bromoquinoline 1559 with LDA] with the 3-formylindole 1558 followed by triethylsilane reduction of the... 

The thermal cyclization of the indol-3-yldienamines 360 (R = H, Ph, or OH), which gave the 4-cyanocarbazoles 361, are presumably driven to completion by the loss of dimethylamine. Intramolecular indole a-acylation using ester acids (362 R = H or Me) produced by Stobbe condensation gave... 

A novel tandem carbonyiation/cyclization radical process has been developed for the intramolecular acylation of l-(2-iodoethyl)indoles and pyrroles <99TL7153>. In this process, an acyl radical is formed when CO is trapped by an alkyl radical formed from the AIBN-induced radical reaction of l-(2-iodoethyl)indoles 104 with BusSnH. Intramolecular addition of the acyl radical to the C-2 position of the heteroaromatic system presumably affords a benzylic radical which undergoes in situ oxidative rearomatization to the bicycloketones 105. 

Intramolecular acylation of l-benzyl-2-(2-carboxybenzoyl)pyrrole under Friedel-Crafts conditions yields l//-benz[/]indole-4,9-dione (79KGS1564). When the 1-position is unsubstituted, cyclization occurs to that position (B-77MI30502). 

Indole, 2-acyl-1-benzenesulfonyl-intramolecular nucleophilic reactions, 4, 244 Indole, 1-acyloxy-synthesis, 4, 364 Indole, alkoxy-synthesis, 4, 367 Indole, 1-alkoxy-synthesis, 4, 364 Indole, 4-alkoxy-synthesis, 4, 328 Indole, 2-alkoxycarbonyl synthesis, 4, 337 Indole, alkyl-... 

Whereas intramolecular acylation of indole 88 takes place only in moderate yield, the analogous alkylation of indole 101 gives the dihydrodibenzpyrrol-izine (102) in excellent yield. The reaction conditions for conversion of acid 88 to the tosylate (101) are, however, critical.23 A conversion of tosylate 103 to dihydropyrrolizine 104 was reported.69... 

Intramolecular acylations of pyrroles and indoles are useful synthetically, for example, A-glutamyl-substituted pyrrole 94 gives 95, regioselectively, with retention of configuration, on brief treatment with methanolic hydrogen chloride or boron tribromide. A seven-membered ketone 97 was produced from 96 no cyclization onto the indole 4-position was observed <1999T4341>. 

Reaction of enaminones and carboxylic acids is mainly interesting as a route for cyclization of suitable substituted enaminoketones to N-heterocycles45. In this way iV-cyclohexenylglycines can cyclize to indoxyl derivatives (equation 30). By a similar intramolecular acylation at the / -carbon of enaminones, fused indoles or pyrrole derivatives are obtained46-48. 

Acylation of 3-substituted indoles is more difficult, however 2-acetylation can be effected with the aid of boron trifluoride catalysis." " Indoles, with a carboxyl-containing side-chain acid at C-3, undergo intramolecular acylation forming cyclic 2-acylindoles." Intramolecular Vilsmeier processes, using tryptamine amides, have been used extensively for the synthesis of 3,4-dihydro-p-carbolines, a sub-structure found in many indole alkaloids (P-carboline is the widely used, trivial name for pyrido[3,4-fc]indole). Note that it is the imine, rather than a ketone, that is the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone as in the standard Vilsmeier sequence " this ring closure is analogous to the Bischler-Napieralski synthesis of 3,4-dihydro-isoquinolines (9.15.1.7). 

Intramolecular acylations of the Bischler-Napieralski type have been used as crucial steps in the synthesis of indole alkaloids of the yohimbine class <94JCS(Pl)299, 94TL1071>. Also, the aluminum chloride-catalysed reaction of the indolosuccinic anhydride (46) gave the bridged cyclic product (47) rather than the cyclopentanone (49), presiunably because the reaction involves initial acylation at C-3 and reaction via the less strained intermediate is favored. Formation of the cyclopentanone (49) can be achieved using the polyphosphate ester cyclodehydration of the modified intermediate (48) (Scheme 13) <90JCS(Pi)2487>. 

The formation of indole thioethers can be carried out at C-4 by a process involving migration from C-3. An intramolecular acylation of 2-(3-indolylthio)propionic acid undergoes reaction at C-3, with rearrangement of the sidfur moiety and substitution at C-4 via a sulfenyl chloride there is also good optical retention in a chiral substrate (Scheme 51) <92TL47I7>. 

New conditions for intramolecular acylation of indoles have been found in the course of exploration of intramolecular Friedel-Crafts acylation of 3- and... 

Meldrum s acid derivatives have been introduced as readily available precursors for intramolecular acylation. 5-Substituted A -(arylsulfonyl)indoles cycUze to C-5 in the presence of Bp3-OEt2 [395], Similar cyclizations can also be effected using... 

The importance of radical processes in the chemistry of pyrroles and indoles remain vital in expanding the repertoire of reaction processes available to these heterocycles. For example, Allin and Mclnally have devised a novel approach lo (l,2-a -fused pyrroles 76 via intramolecular acyl radical cyclization of Al-(oi-acyl)-radicals 75 generated from acyl-selenide precursors 74 <01TL7887>. This reaction can be conducted even in the absence of CO and has also been shown feasible on electron rich pyrrole rings. 

Isatins are indole derivatives with broad use in synthetic dye production and are intermediates in the synthesis of other heterocyclic molecules/ They also possess a variety of biological activities/ Aksenov et al. reported a one-pot synthesis of isatins using ethyl nitroacetate with substituted benzenes such as anisole (159) in polyphosphoric acid fScheme 5.38)/ The process for isatin formation likely includes a hybrid between the Nef and Vilsmeier reactions of anisole 159 and nitro ester 160 to form the oxime intermediate 161, which then undergoes a Beckmann rearrangement to give the anilide 162. Subsequent intramolecular acylation yields isatin 163. 

Regioselectivity is also critical in the acylation of electron-rich heterocycles other than substituted benzenes. High regioselectivity (94 6 C-4 versus C-2 acylation) observed in the AICI3 promoted intramolecular acylation of 28 a 3-(indol-3-yl)propionyl chloride analogue, to adduct 29, a precursor in the synthesis of Uhle s ketone 30. A donor-acceptor complex between AICI3 and chloroacetyl chloride was proposed to drive the acylation reaction. A sodium methoxide mediated cleavage of the A-BOC moiety of 29 completed the synthesis of 30 in 95% yield. 

Under ruthenium-catalyzed ortho-C-H activation and intramolecular C-N bond formation, the condensation of iminophosphoranes (in situ generated from acyl azides and triphenylphosphine) with internal alkynes afforded a variety of isoquinolinone derivatives (Eq. (7.43)) [53]. The regioselective insertion of unsymmetrical alkynes led to an (aryl)C-N bond formation. Thiophene and indole-based acyl azides were also compatible for this transformation. A domino reaction sequence via coordination of ruthenium with Af-atom of iminophosphoranes, ort/zo-cyclometalation, alkyne insertion, protonation, and reductive elimination was proposed for the catalytic cycle. Based on and NMR experiments, the involvement of benzamide during the reaction process was ruled out. 

As was the case with reactions of vinylindoles, the most elaborate synthetic targets approached by the indole-2,3-quinodimethane route have been alka-loids[18]. The route has been applied to aspidospenna[l9 ] and kopsine[20] structures. The fundamental reaction pattern is illustrated in equation 16.7. An indole-2,3-quinodimethane is generated by W-acylation of an Ai-(pent-4-enyl)-imine of a 2-methyl-3-formylindole. Intramolecular 2 -P 4 cydoaddition then occurs. 

The intramolecular cyclization of A -acylated-o-alkylanilines in the presence of a strong base at elevated temperatures is known as the Madelung indole synthesis. ... 

A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. 

A new synthetic method of benzofuran was reported (equation 39). The [3,31-sigma-tropic rearrangement of Af-trifluoroacetyl enehydroxylamines 136 obtained in situ by acylation of oxime ethers 135 in the presence of trifluoroacetic anhydride lead to the synthesis of cyclic or acyclic dihydrobenzofurans 138. The effects of base and temperature on the reaction products were studied. A similar pathway to that of Fisher indolization was proposed. The acylimine formed by the [3,3]-sigmatropic rearrangement of the V-trifluoroacetyl enehydroxylamine 136 gave the dihydrobenzofuran 137 by an intramolecular cyclization or the benzofuran 138 after elimination. 

An alternate step-wise cyclization strategy to form 3-carboline 22 is shown in Scheme 7. Acylation of D-tryptophan (21) with piperonyloyl chloride afforded amide 25, which was converted to thioamide 26 with Lawesson s reagent. Thioamide 26 was treated with methyl iodide in refluxing CH2CI2 to give a a-thiomethylimmonium ion, which was trapped by the intramolecular addition of indole. The thiomethyl group was... 

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