Comparative reactivity of 5,7-dimethoxyindoles with aldehydes and ketones

This paper describes acid-catalysed reactions of 5,7-dimethoxy-1-methylindole and methyl 5,7-dimethoxy-indole-2-carboxylate with a range of aldehydes and ketones. The former indole reacts selectively at C3


Introduction
In an attempt to modify the reactivity of indoles to provide diverse substitution in the benzene ring, we have carried out extensive investigations on 4,6-dimethoxyindoles, 1-9 where the C7 position is strongly nucleophilic, and to a lesser extent on 5,7-dimethoxyindoles, 10 where the C4 position is strongly nucleophilic.The reactivity patterns also depend on the presence of other substituents, and also the fact that the methoxy groups increase the general reactivity of the whole indole framework to the extent that favoured reactivity sites can also be positions C2 and C3. 11We have previously reported a range of electrophilic substitution reactions on 5,7-dimethoxyindoles: 10 these include formylation, acylation, bromination and nitration.Depending on the structure of the starting indole, reactions can take place at C4 or C3.
We now report a range of acid-catalysed reactions of several 5,7-dimethoxyindoles with aldehydes and ketones, with an emphasis on the comparative behaviour resulting from the structure of the starting material. 10The two main starting indoles chosen were 5,7-dimethoxy-1-methylindole 1 and methyl 5,7dimethoxyindole-2-carboxylate 5: the former in general tends to favour reactions at C3 and the latter at C4.The N-methylindole 1 was chosen ahead of the simpler parent structure 2 because the electron-donating effect of the methyl group confers a more powerful nucleophilic reactivity at C3 (in the same way that Nmethylindole is a more effective C3 nucleophile than indole).The presence of the electron-withdrawing carboxylic ester at C2 in indole 5 has the effect of reducing nucleophilic reactivity at C3 and therefore leading to preferential reaction at C4.Some related indoles 2-4, 6 and indole carbaldehydes 7-12 participate in some individual reactions (Figure 1).The syntheses of indoles 1 and 5 use different methodology, and all the indoles 1-11 have already been described. 10The indole 12 was prepared by the reaction of indole 11 with di-t-butyl) carbonate.Several aspects of the following work have been mentioned in the report of a conference lecture.

Reactions with formaldehyde
The N-methylindole 1 failed to react with formaldehyde at room temperature but a complex mixture of products formed when the reaction mixture was heated.However, the less reactive 5,7-dimethoxy-1methylindole-3-carbaldehyde 7 reacted smoothly with formaldehyde in glacial acetic acid at room temperature to give the 4,4'-diindolylmethane 13 in 66% yield.The N-acetylindole 4 also combined with formaldehyde in glacial acetic acid to give the 4,4'-diindolylmethane 14 in 57% yield (Scheme 1).Presumably the C3 position is deactivated by the electron-withdrawing acetyl group.On the other hand, 5,7dimethoxyindole-4-carbaldehyde 10 and also its N-methyl derivative 9 gave complex mixtures under the same reaction conditions.Scheme 1. Formation of 4,4'-diindolylmethanes 13 and 14.
The indole-2-carboxylate 5 reacted slowly with formaldehyde in acetic acid over several days to give the 4,4'-diindolylmethane 15 in 85% yield (Scheme 2).An attempt to achieve a faster reaction using methanolic hydrochloric acid gave a yield of only 27%.The structures of the new 4,4'-diindolylmethanes 13, 14 and 15 were clear from their NMR spectra, and the linking methylene protons resonated at 4.99, 4.30 and 4.40 ppm respectively, and the linking carbon atoms resonated at 29.0, 22. 4  In any acid-catalysed addition of an indole to formaldehyde the initial intermediate would be a hydroxymethyl derivative.Therefore the indole-4-carbaldehyde 10 was reduced by sodium borohydride to give the 4-hydroxymethylindole 16 in 77% yield: treatment of this compound with acetic acid overnight gave a 73% yield of the 4,4'-diindolylmethane 15.The related 1-butyloxycarbonyl-4-hydroxymethylindole 17 was prepared by sodium borohydride reduction of the 1-butyloxycarbonylindole-4-carbaldehyde 12, and in an attempt to convert this by a standard procedure 13-14 into the related 4-bromomethyl derivative, instead it gave the 1-butyloxycarbonyl-4,4'-diindolylmethane 18 in 75% yield (Scheme 2).The structure was confirmed by almost quantitative conversion of the diindolylmethane 15 into compound 18 by reaction with di-t-butyl carbonate in acetonitrile.The precise mechanism for the formation of the diindolylmethane 18 is not clear.Presumably the intermediate bromomethyl compound undergoes further combination with the indole 17.However, many cases have been reported where 7-hydroxymethyl-4,6-dimethoxyindoles undergo acidcatalysed ipso-substitution reactions with elimination of formaldehyde to give 7,7'-diindolylmethanes, 8,9,15  (e.g. the conversion of indole 16 to diindolylmethane 15) so the two 4-hydroxymethylindoles 16 and 17 were further investigated.When 4-hydroxymethylindole 16 was stirred in methanol with concentrated hydrochloric acid at room temperature, the spiro-dienone 19 precipitated out as a highly pure white solid in 91% yield (Scheme 3).

Scheme 3. Formation of indolo-spiro-dienones 19 and 20.
A similar reaction with indole 17 gave a mixture of the spiro-dienone 20 (45%), the 4,4'-diindolylmethane 18 (30%), and the 4-methoxymethylindole 21 (12%).The structure of the dienone 19 was established by extensive 1D and 2D NMR spectroscopy: a suitable crystal for X-ray structure determination could not be obtained.The 1 H NMR spectrum showed the presence of two NH resonances and only five methoxy proton resonances, suggesting that the compound contains two indole moieties but that one methoxy group has been lost.The 13  The presence of methoxy groups at C5 and C7 did not change the normal regiochemistry for the formation of diindolylmethanes. 16,17The bond formation at C3 was established by 1 H NMR data showing the metacoupling between H4 and H6.The diindolylmethane 23 was also converted to the 4,4'-dicarbaldehyde 27 under Vilsmeier reaction conditions.Indole 1 also reacted with terephthaldialdehyde to yield the tetraindolyldimethane 28 in 71% yield.In contrast, the indole 5 combined with p-chloro-and p-methoxy-benzaldehydes under the improved conditions of concentrated hydrochloric acid in methanol to give the aryl-4,4'diindolylmethanes 29-30, which precipitated out of solution in high yields (Scheme 5).Trace amounts of the more soluble 3,4'-diindolylmethane isomers were detected but not isolated and characterized.When indole 5 was reacted with p-chlorobenzaldehyde under the more powerful conditions of phosphoryl chloride in chloroform, a complex mixture of products was formed: after extensive chromatography only the 3,4'- In an attempt to synthesise tri-indolylmethanes, the indoles 1 and 5 were reacted with several indole aldehydes.Indole 1 reacted in glacial acetic acid with indole-3-carbaldehyde 34 to give the 3,3',3"triindolylmethane 35 in only 25% yield.Slightly better yields of 37% and 47% were obtained in reactions with the 5,7-dimethoxyindole-4-carbaldehyde 10 and the N-methyl-3-carbaldehyde 7 to give the 3,3',4"triindolylmethane 36 and the 3,3',3"-triindolylmethane 37 respectively.However, since compound 37 is completely symmetrical, its yield was dramatically increased to 88% by the reaction of indole 1 with triethyl orthoformate in methanol in the presence of a catalytic amount of p-toluenesufonic acid. 18-24This reaction was more generally applied to the NH-indole 2 and the N-benzylindole 3 which yielded the respective 3,3'.3"triindolylmethanes38 and 39 in 37% and 77% yields (Scheme 6).Condensation of indole 5 with indole-3-carbaldehyde 34 in methanolic hydrochloric acid gave the 3,3',3"triindolylmethane 40 in 46% yield, and the corresponding reaction with the methyl 5,7-dimethoxyindole-4carbaldehyde 11 gave an 83% yield of a mixture of the 3,3',4"-triindolylmethane 41 and the 3,3',3"triindolylmethane 42 in a ratio of 88:12.This result contrasts with the reaction of indole 5 with 4chlorobenzaldehyde under the same conditions, which showed selective reaction at C4 (see Scheme 5).Presumably the greater steric bulk of the indole aldehydes 34 and 11 could be a factor in directing the reaction away from C4 to the more accessible C3.In comparison, the condensation of indole 5 with triethyl orthoformate gave an 80% yield of a mixture of the 3,3',4"-triindolylmethane 41 and the 3,3',3"- triindolylmethane 42 in a ratio of 98:2 (Scheme 7).The minor product 42 presumably arises as a result of reversible steps involved in the formation of the triindolylmethanes.Several triindolylmethanes have been reported as natural products from a marine bacterium 25 and also as products from reactions of indole with Nmethylindol-2-one or 1,3-dimethylimidazolidin-2-one and phosphoryl chloride. 26  Scheme 7. Formation of 3,3',4"-triindolylmethane 41 and 3,3',3"-triindolylmethanes 40 and 42.

Reactions with o-phthaldialdehyde
o-Phthaldialdehyde represents a special case in reactions of aldehydes with indoles.While terephthaldialdehyde behaves normally, o-phthaldialdehyde has the possibility to react at two adjacent positions of an indole if they are available.We have previously shown that 1-methyl-4,6-dimethoxyindole reacts regioselectively at C2 and C3 with o-phthaldialdehyde to give isomeric indolylbenzocarbazoles depending on the conditions. 27The indole 1 has positions C2, C3 and C4 available, so it was reacted with o-phthaldialdehyde in glacial acetic acid and found to give the 6-(3-indolyl)benzocarbazole 43 in 34% yield (Scheme 8).This is consistent with a slow reaction to give the thermodynamically more stable product, as previously described. 27  N H On the other hand, indole 5 only has availability for reaction at C3 and C4: it combined with ophthaldialdehyde in methanolic hydrochloric acid to give a very pure white precipitate of the heterotriptycene 44 in 90% yield (Scheme 8).Similarly high yields were obtained when the reaction was carried out in either phosphoryl chloride or p-toluenesulfonic acid.Scheme 8. Formation of indolobenzocarbazole 43 and indolotriptycenes 44 and 46.

MeO
The structure of compound 44 was established by extensive NMR spectroscopy and also by an X-ray crystal structure (Figure 2).The 1 H NMR spectrum showed only one NH, one H6 and three methoxy proton resonances, indicating that the two indole rings were in the same environment.A singlet at 6.90 ppm was assigned to the two bridging methines, thus establishing the presence of two 3,7'-diindolylmethane links, rather than the alternative possibility of one 3,3'-link and one 7,7'-link.The suggested mechanism proceeds via the intermediate 45 as a result of indole C7 attack on each formyl group (Scheme 8).The N-methylindole 6 also reacted with o-phthaldialdehyde to give the N-methylated triptycene 46 in 44% yield.The lower yield is thought to be a function of the greater solubility of the product, and no attempt was made to obtain a second crop from the filtrate after collecting the product.The characteristic triptycene structure has been put to use in a variety of applications, including materials chemistry, host-guest chemistry, and molecular motors.

Reactions with ketones
Neither indole 1 nor 5 underwent any reaction with a range of acetophenones.The N-methylindole 1 underwent reaction with acetone and acetic anhydride to give the 3,3'-diindolylmethane 47 in a yield of 18%.When glacial acetic acid was used as the solvent an even lower yield (10%) of the benzo[cd]indole 48 was obtained from a complex mixture.The acid-catalysed condensation of indole and acetone is known to give rise to multiple products. 17,29Indole 5 failed to react with acetone, but it did react when heated in 2,2dimethoxypropane in the presence of a catalytic amount of p-toluenesulfonic acid to give the benzo[cd]indole 49 in 34% yield (Scheme 9).The two benzoindoles 48 and 49 show different methyl substitution patterns, indicating that the initial attack for indole 1 takes place from C3, while that for indole 5 takes place from C4.The mechanism appears to be a stepwise intramolecular aldol-type, because neither indole 1 nor 5 showed any reaction with mesityl oxide.The structures of benzindoles 48 and 49 were established by extensive 1D and 2D NMR experiments.Other benz[cd]indole structures have been reported in similar reactions. 30 Scheme 9. Formation of benz [cd]indoles 48 and 49.
The indole 5 underwent reaction with two reactive ketones, ninhydrin and 1-pentanoylisatin.When indole 5 and ninhydrin were heated together in methanol with concentrated hydrochloric acid a yellow precipitate of the 1:1 adduct 50 was obtained in 91% yield, regardless of the stoichiometry.However, when Scheme 10.Formation of 2-(4-indolyl)indane-1,3-dione 50 and 2,2-di(4-indolyl)indane-1,3-dione 51. two equivalents of indole 5 and one of ninhydrin were heated together in toluene with a catalytic amount of p-toluenesulfonic acid, initial formation of the adduct 50 was observed, but continued heating for two days showed that this was converted into the 4,4'-diindolylmethane 51 in 98% yield (Scheme 10).Indole 5 failed to undergo any reaction with isatin but it reacted with the more reactive 1-pentanoylisatin 52 when heated in methanol with concentrated hydrochloric acid to give the 4,4'-diindolylmethane 53 in 75% yield (Scheme 11).Under these conditions it is known 31,32 that the 1-pentanoylisatin could undergo ringopening following attack at C2 by methanol to give the related methyl glyoxylate 54, which could then react with the indole 5. Subsequent hydrolysis of the amide and cyclisation, for which there is precedent, 33 would then generate the observed product 53.This possibility was checked and it was found that compound 53 was obtained in 79% yield when indole 5 and the methyl glyoxylate 54 were reacted together under the same conditions (Scheme 11).Some 3,3-diindolylindolin-2-ones are known where the indoles are linked through C3 and also C2: these compounds show interesting biological activity. 34  Scheme 11.Formation of 3,3-di(4-indolyl)oxindole 53.

Conclusions
A wide range of acid-catalysed reactions of 5,7-dimethoxyindoles with aldehydes and ketones has established many high yielding syntheses of diindolyl-and triindolyl-methanes, with linkages from C3 and C4.The reactions are most successful with formaldehyde, aryl aldehydes and highly reactive ketones.Aryl aldehydes give rise to aryldiindolylmethanes, while reactions with indole aldehydes yield triindolylmethanes.Reactions with o-phthalaldehyde generate triptycene analogs of novel structure.Unusual spiro-dienones can also be formed by double reaction at C4, and reactions with acetone give benzo[cd]indoles, although only in modest yield.
In summary: the positioning of methoxy groups at C5 and C7 on the indole framework greatly expands the synthetic potential of indole reactivity.