3-Acylation, of indoles

Yoshino reports a novel and general method for the C-3 acylation of indoles with acyl chlorides in the presence of dialkylaluminium chloride which obviates the need for prior N-protection . Interestingly, as described in this preliminary communication, the unprotected indoles 147 are first treated with the Lewis acids prior to addition of the acid chlorides, yielding the desired 3-acyl derivatives 148. In reactions more typical of indoles under acidic conditions, Nakatsuka determined the structures of the dimers and trimers of 1-trimethylacetylindole produced in the presence of aluminium chloride . 

Negishi methodology can also be used to achieve the 3-acylation of indoles. Thus, Faul used this tactic to prepare a series of 3-acylindoles 83 from indole 82 [107], Indole 82 could also be iodinated cleanly at C-3 with iV-iodosuccinimide (78%). 

A regioselective Friedel-Crafts 3-acylation of indoles was reported that utilized diethyl aluminum chloride as a Lewis acid mediator <04S2277>. A facile, 3-cyanoacetylation of indoles has been reported <04S2760>. Treatment of indole substrates with cyanoacetic acid in acetic anhydride led to the formation of the corresponding 3-cyanoacetylindoles. This reaction was also investigated with pyrroles and anilines. 

Acylation of the highly reactive indolizines may be achieved at the 3-position and, less easily, at the 1-position using acid chlorides, anhydrides and even esters (48CRV(42)6ll). 3-Acetylation of indolizine, 1,3-diacetylation of indole and 2,5-diacetylation of pyrrole have been effected with acetic anhydride at 140-200 °C (see Section 3.02.2.4.8 for details). The indolizines (49) and (50) are formed with ethyl chloroformate and ethyl benzoylacetate respectively. 

N-Acylation of indole.1 Indole can be N-acylated by a carboxylic acid in the presence of boric acid (0.3 equiv.) in 45-80% yield. 

Azepines are frequently the products of ring transformation reactions. Thus 1-arylindoles have been converted into 57/-dibenz[/ /]azepines in an unusual acid-catalysed rearrangement <95T2091> and a number of 3-acyl-4-(indol-3-yl)-2-methyl-4,5-dihydro-l//- 1-benzazepines have... 

Several different methods for the acylation of lFf-pyrrolo[2,3-6]pyridine (1) have been reported <82JHC665> and the results are summarized in Table 40. When reaction conditions which gave a 90% yield for the acylation of indole were tested on compound (1), an excellent yield (91%) of 1-acetylpyrrolo[2,3-6]pyridine was obtained <52JCS3592>. Other acylation methods afforded the 3-acyl derivative as the major product. 

The direct and selective 3-acylation of both acid- and base-sensitive indoles 6 can be efficiently achieved using acyl chlorides and alkyl aluminum chlorides without NH protection (Scheme 2.3). When acyl chlorides are used for the acylation of indoles, liberation of hydrogen chloride is unavoidable, and the reaction results in the production of tar materials mainly due to polymerization of indole. Alkylaluminum compounds are utilized to scavenge the acid in the acylation with acyl chlorides. The reaction proceeds cleanly to give 3-acylindoles 7 without any by-product formation. The use of triethylaluminum leads to lower yields, probably because a nucleophilic attack of the alkyl group to acyl chloride occurs competitively. As expected, the use of aluminum... 

Okauchi, T., Itonaga, M., Minami, T., Owa, T., Kitoh, K., and Yoshino, H. 2000. A general method for acylation of indoles at the 3-position with acyl chlorides in the presence of dialkylaluminum chloride. Org. Lett. 2 1485-1487. 

Acylindoles Friedel-Crafts acylation of indoles at C-3 with acid chlorides is catalyzed by R2AICI (R = Me, Et). 

As noted in the introduction to this section, under UV light irradiation, carbonyl groups [42] and alkenes [43] will add photochemically in a 2 + 2 sense across the 2- and 3-positions of indole, but only if an acyl or aroyl group is present on the indole nitrogen atom. The photocycloaddition reaction of carbonyl compounds with acylindoles was first reported by Julian and Tringham in 1973 [42], They found that irradiation of N-acetylindole or N-para-chlorobenzoylindole with benzophenone, benzoyl-formamide, or methyl benzoylformate gave oxetane products, as shown in Scheme 12. The stereochemistry of the products was not reported. No products were obtained when the indoles were irradiated with acetophenone, benzaldehyde, acetone, or propionaldehyde. This observation... 

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

Historically, Friedel-Crafts acylations of N-unsubstituted indoles were found to provide a mixture of 3-acyl- and 1,3-diacylindoles. Last year, Yoshino disclosed a novel method for the regioselective C-3 acylation of N-unsubstituted indoles with acyl chlorides in the presence of dialkylaluminum chlorides in a process that obviated the need for prior N-protection . Intriguingly, despite the known susceptibility of ind(jles towards acid-catalyzed dimerization processes, Yoshino nevertheless pretreated the indoles 166 with the Lewis acid prior to addition of the acid chlorides, an artifice that in some way may account for the observed selectivity for the desired 3-acyl derivatives J67. Ottoni confirms the effectiveness of this sequence and also notes the importance of added nitromethane as cosolvent <010L1005>. 

Acylation of Amines. Acylation of amines is also faster in the presence of DMAP, as is acylation of indoles, phosphorylation of amines or hydrazines, and conversion of carboxylic acids into anilides by means of Phenyl Isocyanate /3-Lactam formation from /3-amino acids has been carried out with DCC-DMAP, but epimerization occurs. ... 

Murakami and coworkers reported the synthesis of indoles via the Pd-catalyzed cyclization of the 3-acylpyr-role 1 and the acetoxy derivative 2 (Scheme 1, equations 1 and 2) [1]. Once again, we encounter the selective C-3 acylation of a pyrrole with AICI3 as the Lewis acid. A complementary synthesis of 4-acetoxyindoles 3 was reported by Hidai and colleagues (equation 3) [2]. A dimer byproduct was also formed in lesser yield (up to 28%) when... 

If the 3-position of indole is substituted, the Houben-Hoesch acylation can proceed at other positions on the ring. As a representative example, dimethoxyindole 20 is reacted with benzylcyanide under acidic conditions to produce the indole 21, which has been acylated at the 7-position. ... 

Friedel-Crafts acylation of indole with acetic anhydride on tungstophosphoric acid modified H-BEA zeolite under microwave and conventional heating [179] showed better catalytic performance under microwave radiation. The reaction proceeded selectively to 3-acetylindole compared with conventional heating. 

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