Approaches to calix[3]indoles from activated indole carboxylic acids

Acid-catalyzed reactions of 3-substituted 4,6-dimethoxyindole-7-and -2-carboxylic acids with aryl aldehydes generate unsymmetrically-oriented calix[3]indoles, with one 2,2 ’ -linkage, one 2,7 ’ -linkage and one 7,7 ’ - linkage, in a wide range of yields. This behavior contrasts with similar reactions of the parent indoles, which more commonly yield the symmetrically-oriented calix[3]indoles, with three 2,7 ’ -linkages. The starting material carboxylic acids were prepared via the hydrolysis of trifluoroacetyl and trichloroacetyl substituents formed by acylation of the parent 3-substituted-4,6-dimethoxyindoles.


Introduction
2][3][4][5][6] Two direct methods have been used.The first involves the combination of a 3-substituted-4,6-dimethoxyindole with an aryl carbaldehyde under acidic conditions.The second requires the treatment of either 2-or 7-hydroxyalkyl-3-substituted-4,6-dimethoxyindoles with acid.Two different structural isomers of calix [3]indoles can be formed, depending on the reaction conditions.One has three 2,7'linkages (the so-called symmetrically-oriented isomer) and the other has one 2,2'-linkage, one 2,7'-linkage and one 7,7'-linkage (the so-called unsymmetrically-oriented isomer) (Scheme 1).The symmetrically-oriented isomer generally takes up a flattened partial cone conformation, but under certain circumstances a cone conformation can be achieved by the introduction of suitable hydrogen bonding. 4,5In addition, application of the second method can give rise to the formation of calix [4]indoles containing four 2,7'-linkages.There are four possible structural isomers of calix [4]indoles.A third method using a stepwise set of reactions can be applied to the synthesis of all possible calixindole isomers.In this paper we consider only the first two direct methods and the application of suitable indole carboxylic acids to the formation of calix [3]indoles, with concomitant decarboxylation.In general, we have found that in reactions of activated indoles with aryl aldehydes, under acidic reaction conditions involving phosphoryl chloride, the symmetrically-oriented isomer is selectively formed in rapid reactions with strongly electrophilic aldehydes, whereas the unsymmetricallyoriented isomer is preferred in slower reactions with weakly electrophilic aldehydes.We therefore decided to investigate reactions of the related less reactive indole carboxylic acids with aryl aldehydes, in the desire to achieve a simple, direct formation of unsymmetrically-oriented calix [3]indoles as a result of slower reactions.The 3-arylindole-7-carboxylic acid 15 was obtained by base hydrolysis of either the trifluoroacetylindole 3 or the trichloroacetylindole 9 (Scheme 3).The 3-arylindole-2-carboxylic acid 16 was similarly derived from the trichloroacetylindole 11, while the 3-methylindole-2-carboxylic acid 17 was derived from the trifluoroacetylindole 6. Base hydrolysis of the ditrifluoroacetylindole 8 gave the 3-methylindole-2,7dicarboxylic acid 18 (Scheme 3).Yields were generally high.The choice of sodium or potassium hydroxide relates to the solubility of the indoles.Conditions for the hydrolysis of trichloroacetyl compounds have been reported to use sodium hydroxide, so these were followed. 7Scheme 3. Formation of indole carboxylic and dicarboxylic acids 15-18.
The 2-hydroxymethylindole-7-carboxylic acid 21 was prepared in a sequence of reactions from the indole 9, involving formylation to give the 2-carbaldehyde 19, hydrolysis of the trichloroacetyl group to give the indole acid 20, followed by reduction of this compound with sodium borohydride to give the 2-hydroxymethylindole-7-carboxylic acid 21.In a corresponding reaction sequence, the indole 11 was formylated at C7 to give the carbaldehyde 22: this was hydrolysed to the indole acid 23, which was reduced by sodium borohydride to give the 7-hydroxymethylindole-2-carboxylic acid 24 (Scheme 4).Neither hydroxy acids 21 nor 24 could be fully purified, so were submitted directly to further reactions (see later).Scheme 4. Formation of hydroxymethylindole carboxylic acids 21 and 24.

Reactions of indole carboxylic acid 15 with aryl aldehydes
The indole-7-carboxylic acid 15 was heated under reflux with one equivalent of 4-chlorobenzaldehyde in ethanol containing concentrated hydrochloric acid and gave the unsymmetrically-oriented calix [3]indole 25 in 80% yield (Scheme 5).The structure of compound 25 was clear from NMR data, in particular with the application of 1 H- 13 C and 1 H-15 N correlations, which allowed a distinction between symmetrically-oriented and unsymmetrically-oriented structures.However, in this case, the calix [3]indole 25 was also synthesized using an unambiguous stepwise route.Indole 1 was reacted with 4-chloro-N,N-dimethylbenzamide and phosphoryl chloride to give a mixture of the 7-(4-chlorobenzoyl)indole 26 and the 2-(4-chlorobenzoyl)indole 27 in 62 and 13% yields, respectively.The 7-isomer 26 was reacted with 4-chlorobenzaldehyde in methanol containing concentrated hydrochloric acid to give the diindolylmethane 28 in 85% yield.Reaction of this compound with Scheme 5. Formation of calix [3]indoles 25 and 31.sodium borohydride gave the dialcohol 29, which was without purification directly combined with one equivalent of indole 1 in dichloromethane containing acetic acid to give the unsymmetrically-oriented calix [3]indole 25 in 30% yield (Scheme 5).Furthermore, the 2-isomer 27 was reduced by sodium borohydride to the alcohol 30, which without purification on treatment with ethanol containing concentrated hydrochloric acid was converted into the symmetrically-oriented calix [3]indole 31 in 60% yield (Scheme 5).Thus both calix [3]indole isomers were available for comparison and structural confirmation.
Similar treatment of the indole-7-carboxylic acid 15 with piperonal in ethanol containing concentrated hydrochloric acid gave the unsymmetrically-oriented calix [3]indole 34 in 50% yield (Scheme 7).In this case, the comparative reaction of the indole 1 with piperonal in phosphoryl chloride (conditions that usually favor formation of the symmetrically-oriented isomer) gave only the unsymmetrically-oriented calix [3]indole 34 in 84%.This result shows the effect of a relatively slower reaction because of the less electrophilic aldehyde.Scheme 7. Formation of calix [3]indole 34.

Reactions of indole carboxylic acids 16-18 with aryl aldehydes
To explore the situation with an indole-2-carboxylic acid, two starting materials were available, carboxylic acids 16 and 17, with the latter being the more accessible.Both underwent reaction with 4-chlorobenzaldehyde in ethanol containing concentrated hydrochloric acid and gave the unsymmetrically-oriented calix [3]indoles 25 and 35 in 16 and 62% yield, respectively (Scheme 8).These compounds were also formed respectively in 30 and 27% yield by reaction of the indoles 1 and 2 with 4-chlorobenzaldehyde catalyzed by chlorotrimethylsilane.Reaction of the indole-2,7-dicarboxylic acid 18 with 4-chlorobenzaldehyde in ethanol containing concentrated hydrochloric acid gave only a complex mixture.Scheme 8. Formation of calix [3]indoles 25 and 35.

Reaction of hydroxymethylindole carboxylic acids 21 and 24 with acid
The crude hydroxymethylindole carboxylic acids 21 and 24 were submitted to a wide variety of acidic conditions but failed to generate clean reactions and isolable products.However, there was no evidence for the formation of any calix [3]indoles or calix [4]indoles, as were obtained from the related hydroxymethylindoles without carboxyl substituents. 2

Conclusions
Acid-catalyzed reactions of 3-substituted 4,6-dimethoxyindole-7-and -2-carboxylic acids with aryl aldehydes generate unsymmetrically-oriented calix [3]indoles, with one 2,2'-linkage, one 2,7'-linkage and one 7,7'linkage, in a wide range of yields.This behavior contrasts with similar reactions of the parent indoles, which more commonly yield the symmetrically-oriented calix [3]indoles, with three 2,7'-linkages.The starting material carboxylic acids were prepared via the hydrolysis of trifluoroacetyl and trichloroacetyl substituents formed by acylation of the parent 3-substituted-4,6-dimethoxyindoles.These results expand the scope for the synthesis of calix [3]indoles by relatively simple one-pot acid-catalyzed reactions, and compliment other approaches involving linear sequences.The additional nucleophilic character of the 4,6-dimethoxyindoles leads to further new possibilities for synthesis of structurally diverse products.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded on a Bruker AC300F ( 1 H: 300 MHz, 13 C: 75.5 MHz) or a Bruker AM500 spectrometer.The chemical shifts (δ) and coupling constants (J) are expressed in ppm and hertz, respectively.Carbon attribution C, CH, CH2 and CH3 were determined by 13 C, DEPT and HMQC experiments.Infrared (IR) spectra were recorded on a Mattson Genesis Series FTIR spectrometer using potassium bromide disks, except where specified.Ultraviolet and visible (UV/Vis) spectra were recorded in tetrahydrofuran or methanol using a Carey 100 spectrometer.Mass spectra were recorded on a VG Quattro MS (EI) or a Finnigan MAT (MALDI).High resolution mass spectrometry (HRMS) was carried out at the Research School of Chemistry, Australian National University.Melting points were measured using a Mel-Temp melting point apparatus.Microanalyses were performed at the UNSW Microanalytical Unit and at the Campbell Microanalytical Laboratory, University of Otago, New Zealand.Column chromatography was carried out using Merck 230-400 mesh silica gel or Merck 70-230 mesh silica gel, whilst preparative TLC was performed using Merck 60GF254 silica gel.