A facile four-component Gewald reaction under organocatalyzed aqueous conditions

In the presence of water and triethylamine, a four-component process involving ethyl cyanoacetate, an α -methylene carbonyl compound, a primary or a secondary amine, and elemental sulfur leads to efficient room-temperature formation of 2-amino-3-carboxamide derivatives of thiophene in short time periods. The products, which precipitate from the reaction mixtures, are easily obtained by simple filtration and recrystallization from ethyl acetate/hexanes.


Introduction
A multicomponent reaction (MCR) is defined as a process that causes combination of three or more reactants to form a product, exclusively or in adequate yield, in a one-pot operation. 1,2In an ideal case the process would take place highly selectively and a single product would form which retains all or the majority of the atoms of the reactants.These features have overwhelmingly led to numerous applications of MCRs in synthetic organic chemistry in recent years because MCRs allow direct access to complex target molecules and chemical libraries in a much more efficient and economical fashion. 3,4ne of the best studied MCRs in recent decades has been the one-pot cyclocondensation of α-methylene carbonyl compounds and β-substituted acetonitriles with elemental sulfur, 5,6 a process which is named after its discoverer: the Gewald reaction. 7The 2-aminothiophene products of the reaction exhibit agrochemical, 8 pharmaceutical, 9 mesogenic, 10 and dye 11 properties.In several cases they are also the key substructure of organic structures [12][13][14] and biologically active compounds. 15,16The original two-component Gewald reaction between α-mercaptoketones and cyanoacetate proceeds under basic catalysis. 7][22][23] Another interesting feature of the Gewald reaction is the use of the 2-aminothiophene products in other organic transformations. 24,25The growing use of MCRs in synthesis led us to examine the possibility of employing more than three components in the reaction so that we can access derivatized Gewald products in a one-pot operation.In the framework of our investigations on the development of one-pot synthetic procedures, [26][27][28] we herein report a simple method for conducting a four-component Gewald reaction under inexpensive and benign aqueous triethylamine conditions.As a result of this method, reactions proceed within relatively short time periods and 2-aminothiophene-N-alkyl products precipitate spontaneously, perhaps because of high polarity of the medium, allowing their solvent-free separation from the reaction mixtures.The overall process is exemplified in Scheme 1 for the reaction of 3-phenylpropanal (1a) with methyl cyanoacetate (2), cyclohexanamine (3a), and elemental sulfur.It is noteworthy that a literature survey shows little precedent for a four-component strategy in the Gewald reaction. 29heme 1. Four-component synthesis of 4.

Results and Discussion
We first optimized the conditions by studying the reaction of 1a with 2, 3a, and sulfur at room temperature (Table 1).Among various secondary or tertiary amines used in the reaction (entries 1-5), Et 3 N caused a higher conversion of the reactants into 4.In addition, the use of Et 3 N led to precipitation of the product at the end of the process (entry 1).Conversely, hexyl-1-amine gave negligible quantities of the product (entry 6).In the absence of the amine (entry 7) or water (entry 8) no formation of product was noticed, even after a longer time period, illustrating the promoting effect of both additives.
From a mechanistic point of view, when a reaction rate is enhanced under aqueous conditions, the acceleration is attributed to either the repulsive forces arising from hydrophobicity of the reactants 30 or to activation of electron donating functional groups through H-bonding with water molecules. 31To study the role of these effects in the present work, we next altered the composition of the aqueous medium to investigate the effect of different additives on the progress of the reaction (entries 9-14).In these cases, an early work-up procedure was used (after 0.5 h) so that a better comparison of the results could be concluded.Therefore, under optimum conditions (H 2 O/Et 3 N), 65% of 4 was formed after 0.5 h (entry 9).When solutions of LiCl (entry 10) or NaCl (entry 11) were used, yields increased, suggesting that hydrophobic forces are responsible for the rate enhancement in this Gewald reaction.This was further confirmed by observing a greater rate increase at a higher concentration of NaCl (entry 12).In contrast, a descending pattern was noticed for a similar reaction conducted in the presence of guanidinium chloride (GnCl) (entry 13) or LiClO 4 (entry 14).This excluded intervention of hydrogen-bonds as being a driving force for the reaction.Thus, one can conclude that hydrophobic behavior of the reactants in water provides the driving force of the reaction.On this basis, it can also be justified that why Et 3 N, which has the lowest solubility among the amines examined, causes a greater rate increase under the conditions, governed by hydrophobic effects.Next, the generality of the method was investigated (Table 2).The optimum conditions under which 4 was formed in 95% yield and within 1 h (entry 1) were applied to the reactions of aldehydes 1a-b with various amines, 2, and sulfur.Thus, 92-97% of products 5, 6, and 7 were formed after 1-2 h (entries 2-4).Then, the conditions were used for similar reactions of cyclohexanone 1c (entries 5-7).As a result, good to high yields of the respective products were obtained.For these entries, reaction times were relatively longer presumably due to lower reactivity of the starting ketone.Because of our interest in developing the chemistry of the thiopyran-4-one system, 32,33 we subjected 1d to the reaction conditions and obtained the expected products as shown in entries 8-10.Based on these results, a mechanism, as depicted in Figure 1, can be suggested for the process.The starting amine, which is first mixed with 2, forms the corresponding amide.This amide then produces an α,β-unsaturated nitrile intermediate via a Knoevenagel The Knoevenagel intermediate then reacts with sulfur to produce the final thiophene skeleton, after a ring closure and an aromatization rearrangement.

Conclusions
In summary, we have reported a general and efficient protocol for the preparation of various 2aminothiophene-3-carboxamide derivatives resulted from a four-component Gewald reaction.Thus, various ketones can combine with methyl cyanoacetate, an amine, and sulfur at room temperature in a one-pot process.Reactions occur using the H 2 O/Et 3 N environmentally safe medium, single products are rapidly formed in high yields, no complex operation or handling is required, and use of toxic organic solvents is avoided.These features make the present method an attractive addition to the present literature archive.

Experimental Section
General.Reactions were monitored by TLC using silica-gel coated plates and ethyl acetate/hexanes solutions as the mobile phase.Melting points are uncorrected.FT-IR spectra were recorded using KBr disks on a Bruker Vector-22 infrared spectrometer and absorptions are reported as wave numbers (cm -1 ). 1 H NMR and 13 C NMR spectra were obtained on a FT-NMR Bruker Ultra Shield TM (500 MHz) instrument as CDCl 3 solutions and the chemical shifts are expressed as δ units with Me 4 Si as the internal standard.Mass spectra were obtained on a Finnigan MAT 8430 apparatus at ionization potential of 70 eV.Elemental analyses were performed using a Thermo Finnigan Flash EA 1112 instrument.Compound 1d was prepared using available methods. 34All other chemicals were purchased from commercial sources and were used after being freshly purified by standard procedures.Products 4, 7, 10, 35 and 9 16 are known.Other products were new and were characterized based on their spectral and physical data.
Typical procedure.A mixture of methyl cyanoacetate (2) (297 mg, 3 mmol) and cyclohexylamine (3a) (343 µL, 3 mmol) was stirred at room temperature for 15 minutes.To this mixture was added 3-phenylpropionaldehyde (1a) (400 µL, 3 mmol), sulfur (96 mg, 3 mmol), water (1.0 mL), and Et 3 N (418 µL, 3.0 mmol) sequentially and stirring was continued at room temperature for another 45 minutes or until TLC showed complete disappearance of the starting materials.The product which solidified at the end of the reaction was separated by filtration and recrystallized from EtOAc/hexanes mixture.Product 4 was obtained in 95% yield (895 mg).The product was identified based on its physical and spectral characteristics.

Table 1 .
Optimization of the Gewald reaction for the synthesis of 4 a isolated yields

Table 2 .
Continued a isolated yields.