Indium ( III )-Catalyzed Synthesis of N-Substituted Pyrroles under Solvent-Free Conditions

Vários pirróis N-substituídos foram sintetizados pela reação de -dicetonas (RC(O) CH 2 CH 2 C(O)R: R, R = Me, Ph) com aminas (RNH 2 : R = Alkyl, Aryl, TsNH) ou diaminas (1,6-diaminohexano and 1,2-diaminoetano) na presença de tribrometo de índio, tricloreto de índio ou trifluorometanossulfonato de índio a temperatura ambiente e sem solventes. O protocolo envolve operações simples e os produtos são isolados em excelentes rendimentos (81-98%).


Introduction
Heterocyclic small molecules play an important role in the search for new therapeutic and drug candidates. 1 Pyrroles are an important class of heterocyclic compounds and are structural units found in a vast array of natural products, synthetic materials, and bioactive molecules, such as heme, vitamin B12, and cytochromes. 2Pyrroles also play crucial roles in nonlinear optical materials as well as in supramolecular chemistry. 3Therefore, the enormous number of procedures have been developed for the construction of pyrroles.][8][9][10][11][12][13][14][15][16] Among these methods, the most commonly used and straightforward approach for the preparation of pyrroles is the direct condensation of -diketones and amines (Paal-Knorr reaction) in the presence of protonic acids such as AcOH, 6 p-TsOH. 7ome improved procedures were reported to utilize Lewis acids such as Bi(NO 3 ) 3  .5H 2 O, 8 Sc(OTf) 3 , 9 SnCl 2 10 and heterogeneous catalyst like montmorillonite (KSF, 11 K10 12 and Fe(III) 13 ), zirconium compounds. 14Recently, this condensation reaction has also been performed under microwave technology 15 and in ionic liquid medium. 16wever, there are some limitations with these methodologies such as prolonged reaction times, 11,14,16 elevated temperatures, 7 use of volatile organic solvents, 8,11 the requirement of excess reagents or catalysts, 10 moisture sensitive/hazardous catalysts, 10 use of an additional microwave oven, 15 use of costly solvent (ionic liquids), 16 unsatisfactory and yields 14 .Thus, the development of new reagents with great efficiency, environmentally friendly, convenient procedure, and delivery of better yields methods for the synthesis of pyrroles is of great interest.
During the last decade particularly after the review by Cintas, 17 indium(III) based carbon-carbon bond formation and other organic transformations have gained much attention.In accordance with the recent surge of interest in indium(III) salts has emerged as a promising catalyst for various types of organic transformations.Particularly, indium tribromide, 18 indium trichloride 19 and indium trifluoromethanesulfonate 20 as a novel type of water-tolerant green Lewis acid catalyst have received considerable attention for various transformations, because they have advantages of water stability, operational simplicity, recyclability, strong tolerance to oxygen and nitrogencontaining reaction substrates and functional groups, and it can often be used in just catalytic amounts.Recently, Zhang 21 reported a few examples of InBr 3 -catalyzed organic reactions.Ghosh and coworkers 22 reviewed systematically In(OTf) 3 -catalyzed organic syntheses.
In continuation of our interest in Lewis acid-catalyzed and green chemistry organic reactions, 23 we herein wish to report a simple, practical and efficient method for the synthesis of pyrroles from -diketones and amines using indium(III) salt as catalyst at room temperature under solvent-free conditions (Scheme 1).

Results and Discussion
Initially, the efficacy of various catalysts was tested in the model reaction under solvent-free condition at room temperature (Table 1).The results showed that InCl 3 , InBr 3 and In(OTf) 3 were superior to other Lewis acids with respect to reaction times and product yields.Entry 1 showed the blank reaction without addition of any catalyst, in this case only 29% 2,5-dimethyl-1phenyl-1H-pyrrole (3a) was obtained after 24 h.For the sake of comparison, the reaction was carried out using other anhydrous chloride, such as ZnCl 2 , NiCl 2 , SrCl 2 and CuCl 2 under solvent free conditions (Entries 2-8).However, these chlorides showed lower activity than InCl 3 under same reaction conditions.We examined influence of solvents on the reaction yields.It was found that the reactions gave lower yields of the desired product in solvents such as CH 2 Cl 2 , H 2 O, CH 3 NO 2 after prolonged reaction time.(Entries 10-13, 15-18, 20-23).We also checked the reusability of the catalyst by separation and reloading in a new run and found that the catalyst could be reused three times without any decrease in the yield (Entry 19).In light of these good results, subsequent studies were carried out under the following optimized conditions: with 5 mol% InBr 3 , InCl 3 or In(OTf) 3 at room temperature under solvent-free conditions.
To evaluate the scope of catalyst's application, various -diketones were treated with amines under the above conditions and the results presented in Table 2.The desired products were characterized by NMR, IR and mass spectrometry and also by comparison with authentic samples.
The Indium(III)-catalyzed reactions were found to be dependent on electronic and steric factors of amines.
Anilines with electron-donating groups gave a high yield (up to 98%) due to the increased electron density of the aromatic system (entries 2 and 6).Whereas anilines with strongly electron-withdrawing group (NO 2 ) afforded in moderate yield (71%) after 40 min (entry 7), which showed electronic effect.ortho-substituted anilines whatever the Scheme 1. character of the substituted groups required longer reaction times.It was revealed that yields were significantly decreased when the sizes of the ortho-substituent groups were large.For example, 2,6-dimethylaniline or 2,6-diisopropylaniline (entries 4-5) were found to be less active and gave mild yields after 1 h.This may be due to the steric hindrance exhibited by the 2,6-diisopropyl and 2,6-dimethyl groups of the aniline towards the approaching acetonylacetone.Moreover, we also examined the condensation reaction of aliphatic amines with acetonylacetone (entries 8-18).The corresponding products (3h-3r) were obtained with excellent yields.In the case of 1,6-diaminohexane or 1,2-diaminoethane, two equivalents of acetonylacetone were used giving products with dipyrryl groups 3n or 3o (entries 14-15).On the other hand, it was found that heterocyclic amines (2-aminopyridine) and less nucleophilic aromatic amine ( -naphthalenamine) did not make any difference in this reaction (entries 19 and 20).It is noteworthy that optically active amines were converted into the products (3p-3q) without any racemization or inversion (entries 16 and 17).We also investigated the reaction of various -diketones such as 1,4-diphenylbutane-1,4-dione and 1-phenylpentane-1,4dione with amines.Similarly, the corresponding pyrroles (3u, 3v) were obtained in high yields in the presence of InCl 3 , InBr 3 or In(OTf) 3 at 50 °C.
Finally, we examined the condensation reactions of -diketones with p-toluenesulfonylhydrazide (Scheme 2).N-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methylbenzenesulfonamide (4a) were obtained with good yields (87-91%) when the reaction was performed at 70 °C in the presence of Indium(III) salts.It is found that this condensation reaction gave 4a in moderate yield (53%) under solvent-free conditions due to poor solubility of p-toluenesulfonylhydrazide in -diketones and the yields showed significant improvement in CH 3 NO 2 .Nevertheless, trace product was obtained in the absence of catalysts, which also further proved that Indium(III) salts do play an important role in this reaction.
The reaction proceeds very cleanly without the formation of any by-products except water.Because the reaction can be performed using a solvent-free procedure, at the end of the reaction, the crude mixture can be directly charged on a chromatographic column to obtain the pure product, avoiding any tedious work up.
In summary, we have developed a facile and efficient method for the synthesis of N-substituted pyrroles using Indium(III) salts.The advantages of the method include (i) absence of a solvent, (ii) short reaction times, (iii) high yields, (iv) no work-up, and (v) use of trace amounts of a catalyst that could be recovered and re-used.

Experimental
Melting points were recorded on Digital Melting Point Apparatus WRS-1B and are uncorrected. 1H NMR and 13 C NMR spectra were taken with a VARIAN Mercury plus-400 instrument using CDCl 3 as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature.Chemical shifts are given in relative to TMS, the coupling constants J are given in Hz.IR spectra was recorded on a AVATAR 370 FI-Infrared Spectrophotometer.Mass spectra were recorded on Finnigan Trace DSQ (EI, CI) or Thermo Finnigan LCQ-Advantage (ESI).

Table 1 .
The condensation reaction of acetonylacetone with aniline under various reaction conditions a a General reaction conditions: acetonylacetone (5 mmol), aniline (5 mmol), catalyst (5 mol%), rt.b In(OTf) 3 was reused for three times.c Isolated yield.d 10 mol% was used.e 2 mL of CH 2 Cl 2 were used.f 2 mL of H 2 O were used.g 2 mL of CH 3 NO 2 were used.