Indole macrocycles formed by diindolylmethane ring closure

Indole containing macrocyclic compounds can be formed from suitable diindolyl diesters and diamides by acid-catalysed reaction with formaldehyde to generate a 2,2’ -linkage in the ring closure step. The alternative protocol in which macrocyclisation is attempted by la ctone or lactam formation from starting 2,2’ - diindolylmethane systems was unsuccessful in our examples


Introduction
Macrocyclic compounds in general are of increasing interest because of their applications in supramolecular chemistry. 1,2 Indoles can be incorporated into a wide range of macrocyclic ring systems, 3 and some of the resulting macrocycles, such as the bis(indolyl)maleimides, show potent biological and antibiotic activity. [4][5][6][7][8] Most commonly the resulting macrocycles are imines and the ring closure step is carried out by the reaction of indole carbaldehydes with primary amines. [9][10][11][12][13] Another major approach to indole containing macrocycles involves the construction of indolylmethylene cyclic oligomers, the calixindoles, formed by acid-catalysed reactions of activated indoles with aryl aldehydes, 14,15 activated indoles with hydroxymethylindoles, 16,17 or hydroxymethylindoles alone with extrusion of formaldehyde. 18 In special circumstances, direct oxidative dimerization of 2,7'-biindolyl compounds can generate macrocyclic tetraindolyls, the indorphyrins. 19

Synthesis of macrocycle precursors
We have previously shown that indolylesters can be prepared by the reaction of trichloroacetylindoles with alcohols. 20 Suitable precursors for macrocyclic compounds would be diindolyl diesters or diamides. Therefore two equivalents of the 7-trichloroacetylindole 1 21 were reacted with one equivalent of ethylene glycol in acetone containing potassium carbonate to give the diindolyl diester 2 in 75% yield (Scheme 1). We have also shown that 2,2'-diindolylmethanes can be readily prepared from 3,7-disubstituted-4,6-dimethoxyindoles by the acid-catalysed reaction with formaldehyde or aryl aldehydes. 10,15,20,22 In general, alkyl aldehydes either fail to react or follow other paths. Consequently the diindolyl diester 2 was heated under reflux with formaldehyde in methanol containing concentrated hydrochloric acid, but no reaction occurred and the starting material remained intact. The failure to form the macrocycle 3 was presumably caused by the necessity for the normal hydrogen bonding between the indole NH and the 7-carbonyl oxygen atom to be broken. This hydrogen bonding would have an effect on the orientation of the ester 2, which would discourage macrocyclisation. This result indicates that a longer linkage between the two ester groups is required for macrocyclisation. Therefore, indole 1 was reacted with tetraethylene glycol in acetone containing potassium carbonate to give the diindolyl diester 4 in 56% yield (Scheme 2). While in our hands this compound could not be obtained analytically pure, it was nevertheless reacted with formaldehyde to give the 24-membered macrocyclic diindolylmethane 5 in 82% yield. Furthermore, a similar reaction with 4-chlorobenzaldehyde gave the related macrocycle 6 in 53% yield. These results indicate that the length of the ether linker is an important factor to achieve a suitable distance between each indole C2 position and to take into account the presence of hydrogen bonding between the indole NH and the 7-carbonyl O atom. In contrast to the success of macrocyclization through diindolylmethane formation, reaction of the preformed 2,2'-diindolylmethane-7,7'-di(trichloroacetyl) compound 7 21 with tetraethylene glycol failed to generate any macrocyclic product 5 in a complex reaction mixture. Tentatively, the failed ring closure could be attributed to a lack of sufficient flexibility in the diindolylmethane linkage. Therefore, this route cannot be recommended for macrocyclization.
The diindolylmethane macrocyclization protocol was extended to an investigation of diindolyl diamides. Treatment of two equivalents of 7-trichloroacetylindole 1 with one equivalent of diethylenetriamine in acetonitrile at room temperature gave the diindolyl diamide 8 in 95% yield. Reaction of compound 8 with formaldehyde in methanol containing concentrated hydrochloric acid then afforded the 18-membered macrocyclic diindolylmethane 11 in 74% yield (Scheme 3).

Scheme 3. Formation of diamide 8 and macrocyclic diindolylmethane 11.
A similar reaction of indole 1 with triethylenetriamine gave diamide 9 in 60% yield and subsequent reaction of this product with formaldehyde in methanol containing concentrated hydrochloric acid afforded the 21-membered macrocyclic diindolylmethane 12 in 80% yield (Scheme 4). However, in contrast to the synthesis of the macrocyclic diester 6, attempts to obtain the arylmethine linked macrocycle 14 by reaction of the diindolyl diamide 9 with 4-chlorobenzaldehyde failed, and only complex product mixtures were obtained. Several factors could be responsible for the failure to form the macrocycle 14. 4-Chlorobenzaldehyde is less reactive than formaldehyde and also has a greater steric presence. Also formation of a 21-membered ring in the case of compound 14 would be less accessible than formation of a 24-membered ring in the case of compound 6.

Conclusions
The synthesis of the macrocyclic diindolylmethanes 5, 6, 11, 12 and 13 indicates that diindolylmethane formation is an effective protocol for macrocyclization, as 18-, 21-, and 24-membered rings were formed. However, attempts to generate similar macrocyclic structures by ester and amide formation from diindolylmethane 7 were unsuccessful.

Experimental Section
General. 1