Microwave-assisted catalyst-free synthesis of tetrasubstituted pyrroles using dialkyl acetylenedicarboxylates and monophenacylanilines

ABSTRACT An efficient catalyst-free microwave-assisted synthesis of tetrasubstituted pyrroles using dialkyl acetylenedicarboxylates and substituted monophenacylanilines has been developed. Axial chirality has been noticed in some N-(α-naphthyl/2-isopropylphenyl)-2,3-dicarbethoxy-4-arylpyrroles, but not with N-aryl-2,3-dicarbethoxy-4-(α-naphthyl)pyrrole. GRAPHICAL ABSTRACT


Results and discussion
We started our investigation with 1a as the model substrate and treated that with diethyl acetylenedicarboxylate (DEAD) in tetrahydrofuran (THF) without catalyst at room temperature. It must be admitted that a related reaction has been reported involving acidic reagent with limited substrate scope after isolating the intermediate. [25a] Our strategy involves no acidic reagent, no isolation of the intermediate, and a wide substrate scope. Similar work yielding 2-trifluoromethyl-substituted pyrrole has been reported very recently. [25b] After 16 h, 3a was formed in 50% yield (Table 1, entry 1) with 25% of starting material, the remaining being an unrecognizable mass. Increasing the reaction time had no impact on the yield of 3a. Carrying out the reaction in acetic acid also did not enhance the yield as expected, but resulted in additional by-products as evidenced by thin-layer chromatography (TLC). However, when the reaction was carried out in dimethylformamide (DMF) under reflux without any catalyst, the reaction was completed within 6 h (Table 1, entry 2) with 62% yield of 3a. When we investigated the reaction by applying microwave (MW) with varying power, temperature, and solvents (Table 1, entries 3-9), we found that 3a was obtained in good yield with DMF in 110 W at 110 °C (Table 1, entry 9) in 10 min. Increasing the reaction time beyond 10 min did not improve the yield; rather a slight decrease in the yield has been observed as evidenced by TLC. The yield was relatively good with solvents like ethanol, acetonitrile, and water (Table 1, entries 13-15), but it was relatively poor with the other solvents such as toluene, 1,4-dioxane, and 1,2-dichloroethane (Table 1, entries 10-12). The one-pot reaction of all three compounds, as reported in the previous study, [19] resulted in diethyl 1,5-diphenyl-1H-pyrrole-2,3-dicarboxylate. Here the reaction of aniline with the diethyl acetylenedicarboxylate was preferred over the formation of monophenacylaniline. The initial reaction between aniline to phenacyl bromide followed by the addition of DEAD could afford the desired product. When we attempted the one-pot synthesis through the addition of aniline to phenacyl bromide under MW for 1 min at 110 °C followed by the addition of DEAD, it resulted in lower yield of the dialkyl 1,4-diaryl-1H-pyrrole-2,3-dicarboxylate. This may be due to the initial formation of α,α'-amino ketones, preventing the formation of the pyrrole. After optimization we investigated the scope of the reaction and it worked well with variety of α-aminoketones and different acetylene esters ( Table 2). The structures of the products 3 has been unambiguously assigned by spectral and analytical data, and that of 3d has been confirmed by singlecrystal x-ray analysis as well (Fig. 2). [26] A closely related methodology employing gold catalyst has generated a similar skeleton, [23] whereas the present work uses no catalyst, generating a library of 18 compounds.
It is pertinent to note that this cyclization occurred successfully with both electronwithdrawing and electron-donating groups in the aryl ring ( Table 2). The presence of electron-withdrawing groups on the carbonyl attached phenyl ring and the electrondonating groups on the aniline ring of the monophenacylaniline promoted the formation of the product, enhancing the yield (Table 2, compounds 3d, 3e, 3i, and 3q). All the other monophenacylaniline derivatives differing from the aforementioned combination of electron-withdrawing and electron-donating groups afforded moderate yield (Table 2). Based on the observed results, a plausible mechanism is proposed (Scheme 2). Initially the reaction of α-amino ketones with electron-deficient alkynes afforded the enamine intermediate A. Then the nucleophilic attack of the enamine to the carbonyl group afforded intermediate B, followed by the elimination of water to provide the desired product 3.
One out of the two sets of methylene hydrogens in 3j, 3 l, and 3p is found to be diastereotopic, indicating that chirality has arisen due to the restricted rotation around the N-(α-naphthyl/N-(2-isopropylphenyl) bond in these cases. In the case of 3i, the diasterotopic behavior has been felt with the isopropyl methyls as well, both in the 1 H and 13 C NMR spectra. It must be noted that when a simple methyl is present in the 2-position of the N-phenyl ring, no chirality has been noticed. [22c] It is also interesting to note that the presence of α-naphthyl group in the 4th position of the pyrrole (3o) has not raised any chiral characteristics.

Experimental
All solvents were purchased from commercial sources and used without further purification. The melting points were measured in open capillary tubes and are uncorrected. A CEM Discover microwave synthesizer (model no. 908010) operating at 180/264 V and 50/60 Hz with maximum microwave power level of 300 W and microwave frequency of 2455 MHz was employed for the microwave-assisted experiments. Nuclear magnetic resonance ( 1 H and 13 C NMR) spectra were recorded on a 300-MHz spectrometer in CDCl 3 using tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported in parts per million (δ), coupling constants (J values) are reported in hertz (Hz), and spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), q (quatret), sept (septet), m (multiplet). 13 C NMR spectra were routinely run with broadband decoupling. Elemental analyses were performed on a Perkin-Elmer 2400 Series II Elemental CHNS analyzer.

General procedure for the synthesis of dialkyl 1,4-diaryl-1H-pyrrole-2, 3-dicarboxylate 3
A mixture of substituted monophenacylaniline 1 (1 mmol) and dialkyl acetylenedicarboxylate 2 (1.1 mmol) in DMF (1 mL) was sealed and subjected to microwave irradiation at 110 °C and 110 W for 10 min. The completion of the reaction was monitored by thin-layer Scheme 2. Plausible mechanism for the formation of 3. chromatography (TLC). The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The crude product was purified by column chromatography using petroleum etherÀ ethyl acetate (5:95) as the eluent to get 3.