Synthesis of bis(indolyl)methanes under catalyst-free and solvent-free conditions

Abstract

Condensation of indole with aromatic aldehydes has been carried out without using any catalyst and solvent to give bis(indolyl)methanes.

Keywords:

• bis(indolyl)methanes
• solventless
• catalyst free
• grinding
• multicomponent reaction

Introduction

The focus of green chemistry lies on reducing environmental pollution by designing benign reaction processes, avoiding waste generation, and saving energy by reducing number of chemical steps. Multicomponent reactions 1–3 and domino reactions 4–15 are the fascinating offshoots of the search for reducing chemical steps. Solventless or when solvent is a must, water as a preferred medium and use of catalyst or catalyst-free reaction conditions are some of the solutions to avoid waste. Bis(indolyl)methanes (BIMs) have been attractive targets to develop green methodologies because of their wide range of biological, industrial, and synthetic applications 16. (See Supporting information in 16).

The reaction of indole with aldehydes or ketones produces azafulven, which then undergo further addition with another indole molecule to give BIM and water (Scheme 1). Both protic and Lewis acids are known to promote this reaction. However, many Lewis acids are prone to undergo change in the presence of nitrogen containing reactants and this necessitates the use of excess and sometimes stoichiometric amount of Lewis acid catalyst. The various strategies adopted for the synthesis of BIMs and tris(indolyl)methanes (TIMs) have recently been comprehensively reviewed 16. There is continuing interest for the development of a new, practical, economical, and environmental friendly protocol for the synthesis of BIMs. Recent catalysts used for this propose are FeCl₃.6H₂O 17, CuBr 18, CeCl₃.7H₂O 19, silica-bonded S-sulfonic acid 20, N,N,N′,N′–tetrabromobenzene-1,3-disulfonamide (TBBDA) and poly(N-bromobenzene-1,3-disulfonamide) (PBBS) 21, cellulose sulfuric acid 22 and ionic liquid 3-methyl-1-sulfonic acid imidazolium chloride 23, polystyrene-supported aluminum chloride (PS–AlCl₃) 24, heteropoly acids 25 26, etc.

short-legendScheme 1. Probable mechanism for the formation of bis(indolyl)methanes.

A perfectly matching green chemistry protocol would be to carry out the synthesis successfully without the use of any catalyst and solvent. To our knowledge, there are no such reports for the synthesis of BIMs. The only report of catalyst free formation of BIMs is in glycerol 27 at 90 °C. We disclose herein our findings of solventless and catalyst free synthesis of BIMs.

Results and discussion

The propensity with which indole undergoes electrophilic substitution made us to envisage that, for many of the BIMs reported particularly with aryl aldehydes having electron withdrawing groups, there may not be any need of assistance from promoters like protic acids or catalyst. To check this hypothesis, in the first experiment, we mixed o-chlorobenzaldehyde and indole (1:2 mole ratio) and kept at ambient temperature in a test tube (Method 1). To our expectation, the reaction was found to complete within 45 min Thin Layer Chromatography (TLC). In another experiment a mixture of o-chlorobenzaldehyde and indole (1:2 mole ratio) was ground using mortar and pestle (Method 2) (mechanochemical synthesis) 28 29. The reaction was found to complete within 15 min TLC, in shorter time than that in the above mixing experiment. Similar procedure was followed for other aryl aldehydes. Aryl aldehyde with an electron donating group at meta position (Entry f) also underwent reaction. Heterocyclic aldehydes (Entry g, h) also reacted successfully. Expectedly, anisaldehyde with electron donating group at para position and heptaldehyde failed to react completely. Ketones did not react at all, while 2-methylindole reacted rapidly to give corresponding BIMs (Entry i–p). Even anisaldehyde which failed to give significant product with parent indole gave corresponding BIM product with 2-methylindole (Entry p). To check whether the byproduct water (Scheme 1) was promoting the reaction, deliberately 2–4 drops of water were added to the mixture. However, no enhancement was observed in the rate of reaction, product formation or yield. Another possibility of catalysis by the trace amount of carboxylic acid formed by aerial oxidation of aryl aldehydes cannot be ruled out.

Experimental

Method 1

Aryl aldehyde (1 eqiv.) and indole (2 eqiv.) were mixed thoroughly in a test tube and kept at ambient temperature in a test tube for a certain period as stipulated in Table 1. The crude product obtained was recrystallized with chloroform-ethyl acetate mixture.

Table 1. Synthesis of bis(indolyl)methanes

				Method 1		Method 2
Entry	R^1	R	Product	Reaction time	Yields^a (%)	Reaction time	Yields^a (%)
A	4-NO2C6H4	H	3a	6 days	58	8 h	60
B	2-NO2C6H4	H	3b	18 h	61	6 h	61
C	4-ClC6H4	H	3c	5 days	92	23 h	95
D	2-ClC6H4	H	3d	45 min	96	15 min	96
E	C6H5	H	3e	48 h	61	2 h	86
F	3-MeOC6H4	H	3f	5 days	57	13 h	86
G	2-furyl	H	3g	24 h	62	90 min	87
H	2-pyridyl	H	3h	13 h	59	10 h	94
I	4-NO2C6H4	Me	3i	7 h	51	105 min	60
J	4-ClC6H4	Me	3j	3 h	77	100 min	97
K	2-ClC6H4	Me	3k	3 min	97	2 min	98
L	C6H5	Me	3l	3 days	69	7 min	90
M	3-MeOC6H4	Me	3m	3 days	63	2 h	87
N	2-furyl	Me	3n	10 min	77	5 min	85
O	4-MeOC6H4	Me	3o	5 days	53	2 days	83
P	2-pyridyl	Me	3p	7 h	63	15 min	96
^aYield of isolated product.

Method 2

Aryl aldehyde (1 eqiv.) and indole (2 eqiv.) were mixed and ground using mortar and pestle. For compounds having reaction time of more than 15 min, the initial grinding was done for 15 min and the reaction mixture was kept at ambient temperature. The mixture was ground periodically for a short time after every 30 min till the reaction completed as stipulated in Table 1. The crude product obtained was recrystallized with chloroform-ethyl acetate mixture.

Conclusion

In conclusion, we have accomplished a green protocol for solvent free and catalyst free synthesis of BIMs from indole/2-methylindole and aryl adehydes.

Acknowledgements

The authors thank DST, New Delhi for financial assistance. One of us (KLD) thanks CSIR, New Delhi for award of JRF.

Supporting information

Table

Table of contents:
General information	2
General Procedure for the formation of bis(indolyl)methane	2
Characterisation data for compounds	2
Copy of ^1H NMR and ^13C NMR spectra of compounds	7
HRMS and LC-MS of selected compounds	40

General methods. Commercial reagents were used without further purification. 1H NMR (300 and 400 MHz) and 13C NMR (300 and 400 MHz) were recorded using CDCl3 and DMSO-d6 as solvent and TMS as an internal standard. IR spectra's were recorded in KBr. Melting points are uncorrected.

General procedure; Method-1; Indole (1) (2 mmol)/2-methyl indole (2) (2 mmol), aryl aldehydes (1a-1p) (1 mmol) were mixed thoroughly in a test tube and kept at ambient temprature. The reaction was monitored using TLC. The crude product was recrystallised using chloroform and ethyla cetate mixture.

Method-2; Indole (1) (2 mmol)/2-methyl indole (2) (2 mmol), aryl aldehydes (1a-1p) (1 mmol) was ground using mortar and pastle. The reaction was monitored by TLC. For compounds requiring more than 15 min, the grinding was done intermittently after every 30 min. The crude product was then recrystallised using chloroform and EtOAc.