Basic Ionic Liquid [bmIm]OH–Mediated Gewald Reaction as Green Protocol for the Synthesis of 2-Aminothiophenes

Abstract A simple, efficient, and environmental friendly procedure was developed based on the Gewald reaction for the synthesis of 2-aminothiophenes using a basic ionic liquid [bmIm]OH as both catalyst and solvent. Besides being a green protocol, the method offers advantages of successful synthesis of a variety of alkyl, aryl, alkoxy, and alkylamino-2-aminothiophenes in good yields. GRAPHICAL ABSTRACT


INTRODUCTION
Ionic liquids (ILs) have attracted growing interest in the context of green organic synthesis. Initially they were introduced as alternative green reaction media because of their unique chemical and physical properties of nonvolatility, nonflammability, thermal stability, and controlled miscibility. [1] They are also referred to as ''designer solvents'' because their physical and chemical properties could be tailor-made by a careful choice of cation and anion. Recently, the development of task-specific ionic liquids (TSILs) with special functions to suit the specific requirements of a reaction has become an attractive field. Besides their inherent advantages as reusable homogenous supports, reagents, and catalysts with green credentials, the additional enabling tunable features made them more popular. These TSILs often serve the dual role of catalyst as well as reaction media. [2] Multisubstituted 2-aminothiophene scaffolds derived from Gewald reaction (GR) attracted considerable attention in the design of several biologically active molecules. [3] Ample data has been accumulated, highlighting their biological utility as synthons in the development of atypical antipsychotic agents (Fig.1, 1), [4] antiinflammatory agents (2), allosteric enhancers of adenosine A 1 receptor (3,5), [5][6][7] IjB kinase b (IKKb) inhibitors (4), [8] and antitubercular agents (6). [9] A typical GR involves base-catalyzed condensation of a ketone with an activated nitrile in the presence of sulfur to obtain functionalized 2-aminothiophenes. [10] The majority of GR applications include use of organic bases such as morpholine, [11,12] triethylamine, [13,14] piperidine, [15] and pyridine and diethylamine, [16] making it environmentally unfriendly. This caused us to investigate GR using TSILs. Surprisingly, very few such attempts were reported in the literature. The application of an IL ester, prepared by coupling of N,N 0 -dicyclohexylcarbodiimide (DCC) with cyanoacetic acid and an imidazolium-based IL as soluble support in GR was studied by Hu et al.; however, this methodology lacks versatility. [17,18] For instance, IL ester cannot be prepared with activated nitriles such as malononitrile and ethylcyanoacetate. Further product isolation by base-catalyzed hydrolysis and recovery of IL from alkoxide solution is prohibitively tedious process. A basic ionic liquid, [TMG] [Lac]  (1,1,3,3-tetramethylguanidine lactate), has been explored as solvent and catalyst in the synthesis of 4,5-dialkyl-2-aminothiophenes, but the utility of the method has not been studied for 4-aryl and 4-alkoxy-2-aminothiophenes. [19] Hence the development of a versatile and robust protocol involving TSIL was felt as an urgent need for the synthesis of functionalized 2-aminothiophenes. Recently a TSIL [bmIm]OH has been successfully utilized to catalyze Michael addition of active methylene compounds to conjugated ketones, carboxylic esters, and nitriles [20] and Markovnikov addition of N-heterocycles to vinyl esters. [21] The versatility of this TSIL as green reaction media and catalyst prompted us to study its utility in GR to get 2-aminothiophenes.

RESULTS AND DISCUSSION
As our key interest is to develop a multicomponent, one-pot, green protocol, different alkylketones, activated nitrile, and sulfur were condensed in one pot using [bmIm]OH as catalyst and solvent (Scheme 1). Interestingly, the yields of 2-aminothiophenes (2a-2j, Table 1) are better than the reported procedures. [22][23][24] For example, in the literature 2a was obtained in 61% yield after 8 h using calcined Mg-Al hydrotalcite as the base at 60 C in EtOH, [22] whereas 2a was obtained in 88% yield in the present method. Similarly, 2g-2j were also obtained in good yields. Several reviews and papers on the Gewald reaction and its improvements propose that a 2-aminothiophene ring is formed from the aliphatic ketones such as 1a-j during the multistep reaction sequence: condensation, base-promoted activation, and addition of sulfur and ring closure. Hence it can be presumed that [bmIm]OH is efficient to catalyze condensation as well as sulfur addition process in the synthesis of 4,5-alkyl-2-aminothiophenes. The additional advantage of this green methodology is that the final products are pure enough (>90%) for spectral analysis and to proceed to further reactions.
Remarkably, [bmIm]OH is very promising for the synthesis of 4-alkoxy-2-aminothiophenes (Scheme 3) in good yields. In our previous experiments, [27] use of organic bases for sulfur addition and cyclization of ylidenes 7a-i resulted in black masses, which consequently necessitated tedious column purification. With aqueous inorganic bases (aqueous KOH or NaOH), nucleophilic displacement of 7a occurred with hydroxyl and subsequently formed 2-amino-4-hydroxythiophene (9) as the major product. Using [bmIm]OH no such side products were observed. The final compounds are separated from the IL simply by washing with diethyl ether or ethyl acetate. The residual ionic liquid was washed with diethyl ether and dried under vacuum at 90 C for 2 h to eliminate any water trapped from moisture. Weight of the ionic liquid lost in the washings was adjusted and reused for subsequent reactions. The ionic liquid has been reused in three runs without loss of activity (Table 1, 2k-l), making it a greener approach.    [bmIm]OH-MEDIATED SYNTHESIS OF 2-AMINOTHIOPHENES In conclusion, the present study highlights the task-specific basic ionic liquid [bmIm]OH as an useful environmentally friendly solvent and catalyst in GR. The results delineated in Tables 1-3  For the synthesis of 4,5-alkyl-2-aminothiophenes (2a-2j), the general procedures are the same as those of compound 2i.
A mixture of N-benzyl-4-piperidone (1i, 380 mg, 2 mmol), malononitrile (132 mg, 2 mmol), sulfur (64 mg, 2 mmol), and basic ionic liquid (bmIm)OH (380 mg, 2.4 equiv.) was heated to 60 C for 2 h. The reaction mixture was cooled to room temperature and washed with diethyl ether or ethyl acetate (3 Â 40 mL), and the organic layers were concentrated under vacuum to obtain an oily crude product. The crude product was dissolved in ether=hexane (3:1, 50 mL) mixture, insoluble material was decanted, and the organic layer was concentrated to 1=4 of the volume and kept in a refrigerator. The precipitate that formed was filtered and dried.
A mixture of 2-(1-ethoxyethylidene)malononitrile [27] (7b, 272 mg, 2 mmol), sulfur (64 mg, 2 mmol), and basic ionic liquid (bmIm)OH (380 mg, 2.4 mmol) was allowed to stir at 60 C for 4 h. The reaction mixture was cooled to room temperature and washed with diethyl ether or ethyl acetate (3 Â 30 mL), and organic layers were concentrated to 1=4 of the volume and kept in a refrigerator. The precipitate that formed was filtered and dried.