Iodine catalyzed one-pot synthesis of highly substituted N-methyl pyrroles via [3 + 2] annulation and their in vitro evaluation as antibacterial agents

Abstract

A new class of highly substituted pyrroles have been synthesized via a simple, fast, and efficient method using environmentally friendly iodine catalyzed [3 + 2] annulation. N-Methyl-N-[(E)-1-(methylsulfanyl)-2-nitro-1-ethenyl]amine (NMSM) 1 and β-nitrostyrenes 3 underwent cycloaddition to afford the desired products 4 in excellent yields under solvent and metal free conditions. All the pyrrole derivatives were evaluated for their in vitro anti-bacterial activity. Among the synthesized pyrrole derivatives, 4b, 4c, 4e, 4g, 4i, 4j, 4l, 4m and 4n displayed good inhibitory properties against a panel of Gram positive and negative infectious pathogens.

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Introduction

Over the past decades, the design and synthesis of substituted pyrroles has been important for obtaining building blocks for organic synthesis. This key heterocyclic core is found in a large number of natural and unnatural compounds, which has significant importance in pharmacology and materials science. Besides the natural products and their analogues, unnatural pyrroles show attractive biological activities, and are present in many bioactive compounds like HIV fusion inhibitors,^1a antitubercular compounds,^1b–c non-steroidal anti-inflammatory compound tolmetin and cholesterol-lowering agent atorvastatin, which is one of the top selling drugs worldwide (Fig. 1).^1d,e Substituted pyrrole derivatives show more biological activities² like antioxidant,³ anti-inflammatory,⁴ antibacterial,⁵ antifungal⁶ and antitumor⁷ activities etc. N-Methyl substituted heterocycles are significant synthetic targets owing to their wide range of applications as medicinal compounds and they can also modulate the physical and biological properties of the molecule. Methyl homologation increases the inhibitory potency of HMG-COA_R inhibitors.^8a–d S-Methyl substituted pyrrole derivatives and their analogues are useful precursors for synthesizing H₂ receptor histamine antagonists.^8e–g As a result, methods for the preparation of N- and S-methyl substituted heterocycle-containing structural scaffolds are in high demand.

Fig. 1 Pyrrole based biologically important compounds.

In general, the standard methods to synthesise pyrrole are the Hantzsch,⁹ Knorr & Paal–Knorr¹⁰ methods, and multi-component synthesis,¹¹ tandem reactions,²¹ transition-metal-catalyzed cyclization reactions¹³ etc. These methods allow the efficient construction of pyrroles with various substitution patterns, atom economy and regioselectivity. Despite the number of available synthetic strategies and their advantages, modern methodologies are focused on the solvent and metal free synthesis of substituted pyrroles due to lower energy consumption, increased selectivity, and minimized waste, hazards, toxicity and cost.¹⁴ Recently, iodine catalyzed reactions have been of considerable interest for various organic transformations due to its low toxicity to the environment, ready availability and inexpensiveness. Therefore, it is worth contributing to the creation of environmentally benign processes.¹⁵ In light of literature precedent,^1–15 it would be interesting to develop a useful and efficient approach to the synthesis of N- and S-methyl substituted pyrrole derivatives, which have a major effect on the partitioning into biological membranes^16a,b for example, methyl thio-ethers and their sulfoxides and sulfones are commonly occurring components in biologically active molecules.^16c,d N-Methyl-N-[(E)-1-(methylsulfanyl)-2-nitro-1-ethenyl]amine (NMSM) 1 is used on an industrial scale for the manufacture of anti-ulcer (histamine H₂ receptor antagonist) bulk drugs ranitidine¹⁷ and nizatidine.^18a NMSM 1 (ref. 18b and c) is a multi-faceted building block in organic synthesis.

The methyl sulfanyl group is an electron donor as well as a good leaving group and it could be replaced with a variety of nucleophiles following a nucleophilic vinylic substitution (S_NV) mechanism.¹⁹ In the current study, we report the synthesis of highly functionalized N-methyl substituted pyrrole derivatives 4 via one-pot [3 + 2] cycloaddition of NMSM 1 and β-nitrostyrenes 3 under solvent free conditions.

Results and discussion

To commence our study, the model reaction of NMSM 1, benzaldehyde 2a and nitromethane was performed in the absence of catalyst in a multi-component fashion. Eventually, we ended up with very little conversion to 4a and a 5% yield (Table 1, entry 1). Then, the reaction was carried out in the presence of solvents like DMSO and DMF, which was found to be counterproductive, under catalyst free conditions at reflux (Table 1, entry 2 & 3). For further optimization of the reaction conditions, the reaction was conducted in the presence of an iodine catalyst in DMF solvent and the results showed that the compounds obtained were in trace amounts (Table 1, entry 4). To improve the yield of 4a, different Lewis acids such as FeCl₃, Yb(OTf)₃ and CuI were used as catalysts to afford 4a in 15–25% yield (Table 1, entries 6–9). However, when molecular iodine was used as the catalyst (10 mol%), the target product 4a was obtained in 30% yield (Table 1 entry 5). Unfortunately, there was no significant improvement in the cycloaddition after increasing the temperature and amount of catalyst.

Table 1 Optimization of the reaction conditions for the three component synthesis of 4a^a

Entry	Catalyst	Temp (°C)	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), nitromethane (1 ml) catalyst (10 mol%).b Isolated yields after column chromatography.c Starting material 1 was recovered.
1	—	90		9	5^c
2	—	180	DMSO	12	Traces
3	—	145	DMF	12	Traces
4	Iodine	145	DMF	12	Traces
5	Iodine	90	—	9	30
6	FeCl3	90	—	9	20^c
7	Yb(OTf)3	90	—	9	25
8	AcOH	95	—	9	15^c
9	CuI	90	—	9	17^c

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In order to improve the yield of 4a, the nitrostyrene^20a was prepared separately and subjected to cycloaddition with NMSM 1 by manual grinding using mortar and pestle at room temperature. Initially, we tried a catalytic amount of anhydrous FeCl₃ with 1 and 3a in a grinding method to afford 4a in 63% yield (Table 2, entry 1). We repeated the cycloaddition using metal catalysts such as AlCl₃, CuI, ZnCl₂, CuCl₂·2H₂O, and Yb(OTf)₃ using the grinding method at RT, however, there was not much improvement in the yield of 4a (Table 2, entries 2–6).

Table 2 Optimization of the reaction conditions for the synthesis of 4a using a manual grinding method (solvent free conditions)^a

Entry	Catalyst	Time (min)	Yield^b (%)
a Reaction conditions: 1 (1 mmol), 3a (1 mmol), catalyst (10 mol%).b Isolated yields after column chromatography.c Starting material 1 was recovered.
1	FeCl3	30	63
2	AlCl3	30	52
3	CuI	30	50^c
4	ZnCl2	30	53
5	CuCl2·2H2O	30	49^c
6	Yb(OTf)3	30	65
7	Iodine	30	70
8	Acetic acid	30	65

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Interestingly, the cycloaddition product 4a was obtained in 70% yield in the presence of an iodine catalyst (Table 2, entry 7). Using acetic acid, 4a was obtained in moderate yield (Table 2, entry 8).

We then tried an alternative method to study the tolerance of 3a and 1 in affording 4a, using different reaction conditions with various solvents and catalysts. The cycloaddition was conducted with NMSM 1 and 3a at 65 °C for 6 h under catalyst and solvent free conditions (Table 3, entry 1). However the yield was reduced to 25% on increasing the temperature from 65 °C to 90 °C (Table 3, entry 2). The yield of 4a was considerably increased to 54–62% yield, when the solvent was varied from water to ethanol under reflux conditions (Table 3, entries 4–8). When other Lewis acids were used as the catalyst under solvent free conditions, the desired product 4a was obtained in moderate yields (Table 3, entries 9–14). The compound 4a was obtained in 50% yield, when a catalytic amount of acetic acid was used (Table 3, entry 15). The solvent effect had not much influence on improving the product yield. Furthermore, to design an environmentally benign procedure, a model cycloaddition reaction was performed with 1 and 3a at 55 °C in the presence of iodine as the catalyst. Interestingly, the cycloaddition product 4a was obtained in 82% yield under solvent free conditions in 5 min (Table 3, entry 16). The yield of 4a decreased to 67% when reaction was carried out at 90 °C (Table 3 entry 17). Similarly, the yield of 4a decreased to 66% when the cycloaddition was performed in MeOH at reflux for 6 h (Table 3 entry 18) along with the iodine catalyst. Overall, iodine catalyzed cycloaddition (Tables 1–3) was found to be the better method for the synthesis of 4a.

Table 3 Optimization of the reaction conditions for the two component synthesis of 4a^a

Entry	Catalyst	Solvent	Temp (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 1 (1 mmol), 3a (1 mmol), catalyst (10 mol%).b Isolated yields after column chromatography.c Starting material 1 was recovered.
1	—	—	65	6	32^c
2	—	—	90	5	25^c
3	—	MeOH	RT	48	10^c
4	—	H2O	Reflux	9	54
5	—	MeOH	Reflux	8	59
6	—	EtOH	Reflux	8	60
7	FeCl3	EtOH	Reflux	8	60
8	FeCl3	MeOH	Reflux	8	62
9	FeCl3	—	50	30 min	67
10	AlCl3	—	55	30 min	60
11	CuI	—	55	30 min	61
12	ZnCl2	—	55	30 min	65
13	CuCl2·2H2O	—	55	30 min	55
14	Yb(OTf)3	—	55	45	72
15	AcOH	—	55	30 min	50
16	Iodine	—	55	5 min	82
17	Iodine	—	90	5 min	67
18	Iodine	MeOH	Reflux	6	66

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Among the above reactions, [3 + 2] cycloaddition under solvent free conditions at 55 °C was found to be the ideal method for the synthesis of tetra substituted pyrrole 4a in good yield (Table 3, entry 16). The NMR spectral data support the structure of 4a.

Following optimization of the reaction conditions, we investigated the scope of the reaction between NMSM 1 and a β-nitrostyrene 3 via [3 + 2] cycloaddition to afford 4a–n (Table 4). The starting materials containing electron-donating and -withdrawing groups on the β-nitrostyrene (3) were well tolerated under the optimized reaction conditions to afford 4a–n in moderate to good yields (65–90%). Temperature plays a significant effect in the reaction because the yields were improved to 65–90% at 55 °C (Table 4). Whether the aryl group of β-nitrostyrene 3 contains an electron-donating group or an electron-withdrawing group present at the ortho or meta positions, this shows little influence to afford 4c, 4f, 4h, 4j in similarly lower yields. Whereas, the products with the para substituents 4a, 4g, 4i, and 4k were obtained in high yield. An electron withdrawing group such as –NO₂ was well tolerated under the optimized conditions and gave a moderate yield of 65% of the desired product 4m (Table 4). A halogen substituted phenyl group of the β-nitrostyrene 3 leads to the formation of pyrroles 4g and 4i in 83% yield. A naphthyl substituted β-nitrostyrene works well for the formation of pyrrole 4n and gave the highest yield 90% (Table 4). In conclusion all types of β-nitrostyrenes could be successfully applied in this reaction providing N-methylated pyrroles 4a–4n in good yield.

Table 4 One-pot two-component synthesis of 4a–n via [3 + 2] cycloaddition^a

a Reaction conditions: 1 (1 mmol), 3 (1 mmol), catalyst (10 mol%). Isolated yields after column chromatography.

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Interestingly, nitro- and thioether linkage-containing structural scaffolds are able to undergo further coupling reactions.^20b–f In our present report, the synthesis of tetra substituted pyrroles (4) is assumed to get more attention as they are important intermediates in organic, biological, as well as materials chemistry. All the synthesized compounds (4) were well characterized using their IR and NMR (¹H, ¹³C, DEPT-135) spectra. The ¹H NMR spectrum of 4a is explained as an example. The ¹H NMR spectrum shows two doublets at δ 7.28 ppm (d, J = 9.0 Hz, 2H) and 6.91 ppm (d, J = 8.6 Hz, 2H) for the para methoxy substituted phenyl group and the aromatic proton of the substituted pyrrole (C5, H) appears as a singlet at 6.67 ppm. The N-methyl, S-methyl and methoxy protons appear as singlets at 3.83 ppm, 2.49 ppm and 3.79 ppm respectively. The singlet at δ = 6.67 ppm (C-5 proton) is the diagnostic signal for 4a.

On the basis of previous literature reports,²¹ a plausible mechanism was proposed for the iodine catalyzed cycloaddition of 1 and 3 to yield 4 (Scheme 1). Here, iodine acts as a mild Lewis acid, which increases the nucleophilicity of NMSM 1. In the first step, due to the polarized push–pull alkene of NMSM 1, it undergoes Michael addition with 3 to form a new C–C single bond to form B. Then, the lone pair of the sulphur atom of the methyl sulfanyl group shifts its electrons towards the nitrogen, which causes intramolecular nucleophilic attack of the nitrogen and formation of new N–C bond to give C. Intermediate C undergoes elimination of H₂O to give intermediate D, which on further elimination of nitrosyl hydride (HNO) leads to the formation of product 4.

Scheme 1 Plausible reaction mechanism for the formation of 4.

Biological data

Disc diffusion method

Based on a biological literature survey, the synthesized compounds (4a–n) were evaluated for their anti-bacterial activity against selected Gram positive and negative bacteria, which are individually responsible for various infections and disorders, by using the standard disk diffusion assay²² described by Murray et al. in 1995. The Gram negative bacteria such as Salmonella typhi, Escherichia coli and Pseudomonas aeruginosa cause typhoid fever,²³ haemolytic uremic syndrome,²⁴ and nosocomial infections,²⁵ respectively. The Gram positive bacteria Streptococcus pneumoniae is responsible for bronchitis, rhinitis, acute sinusitis, otitis media, conjunctivitis, meningitis, bacteraemia, sepsis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis, and brain abscesses.²⁶ Bacillus subtilis, a Gram positive model organism, causes food poisoning.²⁷ Bacillus cereus causes food borne illnesses, causing severe nausea, vomiting, and diarrhoea and is responsible for “fried rice syndrome”.²⁸ Stock solutions of the synthesized compounds were prepared in DMSO and filter sterilized using a 0.45 μm syringe filter. Briefly, cultures grown overnight containing 108 CFU ml⁻¹ were spread on Mueller Hinton agar plates. Sterile paper discs (Himedia lab) were impregnated with the filter sterilized compounds, approximately 20 μL per disc. The paper discs were placed on the agar plates and incubated at 30 °C for 24 h. After 24 h of incubation, the zone of inhibition around the discs was observed and measured (Table 5). The values presented in the table are the average of two independent tests.

Table 5 Antibacterial activity screening for compounds 4a–4n

Entry	Compound code	Gram negative^a			Gram positive^a
		S. typhi	E. coli	P. aeruginosa	S. pneumonia	B. subtilis	B. cereus
a The values represent the activity of the compounds against the bacteria (with a 0.01 M solution), and show the zone of inhibition by diameter (mm). –: no inhibition.b Streptomycin
1	4a	—	—	—	—	—	—
2	4b	—	—	—	—	6	9
3	4c	—	—	—	9	9	—
4	4d	—	—	—	—	—	—
5	4e	7	8	7	9	9	8
6	4f	—	—	—	—	—	—
7	4g	—	—	—	8	11	—
8	4h	—	—	—	—	—	—
9	4i	7	—	—	—	—	—
10	4j	8	—	—	—	—	—
11	4k	—	—	—	—	—	—
12	4l	6	—	9	11	8	8
13	4m	9	—	—	—	—	—
14	4n	—	—	—	7	7	8
15	Cont. l	—	—	—	—	—	—
16	Std^b	14	10	15	14	18	16

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The results of the initial antibacterial activity screening revealed that among the pyrrole derivatives the compounds 4b, 4c, 4e, 4g, 4i, 4j, 4l, 4m and 4n displayed activity against the Gram-positive bacteria and Gram-negative bacteria, inhibitory zones (6–11 mm) are shown in Table 5. The compounds 4e and 4l showed good activity against almost all bacteria. Whereas the compound 4g displayed good activity against Gram-positive bacteria (Table 5, entry 7). These results provoked considerable interest to find the minimum inhibitory concentration (MIC).

Minimum inhibitory concentration (MIC)

The compounds which showed sensitivity to the bacteria were selected for the determination of the MIC (Fig. 2).²⁹ The cultures grown overnight were adjusted to an OD of 0.1. Stock solutions of the synthesized compounds and standards were serially diluted to achieve a concentration between 10 mM to 0.001 mM and 1 to 10 μg ml⁻¹ respectively. The MIC values of the compounds were determined by adopting the micro-well dilution method (Zgoda and Porter, 2001).³⁰ Briefly, each well of the 96 well plates was seeded with the serially diluted compound, the bacterial culture and nutrient broth to a final volume of 200 μL per well. A well containing the cells and nutrient broth served as a negative control. Similarly a well seeded with DMSO, the cells and nutrient broth served as a solvent control. The plates were sealed tightly with a sterile plate sealer and incubated for 24 h in an orbital shaker at 90 rpm. Bacterial growth was measured using the optical density (OD) at 600 nm using 96 well plate readers (ELISA Plate reader) and also using the visual appearance of turbidity. Further confirmation was obtained by plating 10 μL of the samples from the clear wells on nutrient agar.

Fig. 2 Minimum inhibitory concentration of the selected compounds.

MIC values are defined as the lowest concentration that completely inhibits visible growth of a microorganism. Compound 4b displayed activity against Bacillus cereus and Bacillus subtilis (Gram-positive bacteria) due the presence of the phenyl substituent on the pyrrole ring (Table 6, entry 1). Moreover, the 3-methoxy substituted aryl group of pyrrole 4c showed considerable activity against Streptococcus pneumoniae and Bacillus subtilis (Table 6, entry 2). Whereas the 3,4,5-trimethoxy compound 4e displayed activity against both the Gram-positive bacteria and Gram-negative bacteria (Table 6, entry 3). The halogen substituted phenyl derivatives of 4 showed good antibacterial activities. Among the halogens, the 4-fluoro derivative (4g) was the most effective for Bacillus subtilis and has considerable activity against Streptococcus pneumoniae (Table 6, entry 4). Whereas 4i (4-chloro) and 4j (2-bromo) showed moderate activities for the Gram-negative bacteria Salmonella typhi (Table 6, entry 5 and 6).

Table 6 MIC values (μg ml⁻¹) against the infectious pathogens

Entry	Compound code	Gram negative^a			Gram positive^a
		S. typhi	E. coli	P. aeruginosa	S. pneumonia	B. subtilis	B. cereus
a The values show considerable activity, and the quantity in μg ml^−1 required to confine the bacterial growth. –: no inhibition.b Streptomycin
1	4b	—	—			5.0	5.0
2	4c	—	—	—	5.5	5.5	—
3	4e	33.8	6.7	6.7	6.7	6.7	6.7
4	4g	—	—	—	26.6	5.3	—
5	4i	28.2	—	—	—	—	—
6	4j	6.5	—	—	—	—	—
7	4l	5.3	—	26.4	5.3	26.4	5.3
8	4m	5.8	—	—	—	—	—
9	4n	—	—	—	—	29.8	5.9
10	Std^b	2.0	5.0	2.0	3.0	1.0	2.0

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Interestingly the 3-hydroxy substituted aryl group of 4l showed a wide range of activity (Table 6, entry 7), but the 4-nitro substituted aryl group of 4m was weakly effective against Salmonella typhi (Table 6, entry 8). The compound 4n with naphthyl substitution displayed activity against Bacillus cereus and Bacillus subtilis (Gram-positive bacteria) (Table 6, entry 9). Due to the strong resistance of the pathogens towards the anti-bacterial agent, some of the pyrrole derivatives did not show inhibitory properties against Gram negative and positive bacteria (Tables 5 and 6). The obtained results show that different substituents influence the activity of the N-methyl substituted pyrrole compounds.

Conclusion

Hence we have developed a simple, fast, and efficient method for the synthesis of tetra substituted pyrroles in the presence of a catalytic amount of iodine under metal and solvent free conditions. In comparison with reported procedures, the present one affords an environmentally benign approach for the synthesis of pyrrole derivatives 4a–n. In this procedure new C–C and C–N bonds were effectively constructed. The presence of nitro and sulphur groups enables further construction of complex derivatives. The synthesized compounds 4a–n were evaluated for their anti-bacterial activity against selected bacteria. Most of the synthesized compounds have good antibacterial activity.

Experimental section

General considerations

Melting points were determined using open capillary tubes and were uncorrected. IR spectra were obtained on a Jasco FT-IR instrument using KBr pellets and the data are reported in cm⁻¹. Mass spectra were obtained with an Agilent mass spectrometer and recorded in positive and negative mode with an ESI source. The ¹H and ¹³C NMR spectra of the new compounds were measured at 300 MHz and 75 MHz in CDCl₃ and DMSO-d₆ with TMS as the internal standard. The chemical shifts are expressed in ppm, the coupling constants (J values) are given in Hertz (Hz) and the spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), td (triplet of doublets). Elemental analyses were carried out with a Perkin Elmer 2400 Series II analyzer. Silica gel-G plates (Merck) were used for TLC analysis with a mixture of petroleum ether (60–80 °C) and ethyl acetate as the eluent. All chemicals were purchased and used without further purification. The starting material β-nitrostyrenes 3 were prepared according to the previous literature methods. Nitroketene-N,S-acetal (NMSM) 1 is commercially available and was used without further purification.

General procedure for the preparation of the β-nitrostyrenes (3)

Aldehyde (0.05 mmol), nitromethane (0.05 mmol), and MeOH (10–20 ml) were added to a round-bottom flask and then stirred vigorously. NaOH solution (10.5 M, 10 ml) was added dropwise to the mixture in an ice bath; a large amount of yellow solid precipitated, and the stirring was continued for 15 min. Distilled H₂O was added until the solution became clear, and then the solution was added dropwise to concentrated HCl (30 ml), and a yellow solid precipitated. The yellow solid was filtered and washed with H₂O, then the solvent was evaporated in a vacuum drying oven. After recrystallization (EtOH), yellow needle-like crystals were obtained. 4-OMe-β-nitrostyrene (3a): isolated yield of 93%; yellow solid; mp 86–88 °C; ¹H NMR (300 MHz, CDCl3): δ, 7.98 (d, J = 13.6 Hz, 1H), 7.52 (m, 3H), 6.96 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 162.88, 138.97, 134.91, 131.11, 122.44, 114.84, and 55.45. The other β-nitrostyrene derivatives were prepared using a similar procedure and characterized by ¹H and ¹³C NMR.

General procedure for the synthesis of the substituted pyrroles (4)

NMSM 1 (1.0 mmol), β-nitrostyrene 3 (1.0 mmol) and molecular iodine (10 mol%) were charged into a 25 ml glass vial equipped with a stirring bar. The reaction mixture was heated in an oil bath at 55 °C for 5–10 min (monitored by TLC). After cooling down to room temperature, the resulting mixture was extracted with ethyl acetate (3 × 7 ml), and then washed with water (2 × 10 ml) followed by brine solution (1 × 15 ml). The organic phases were collected and dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified using column chromatography on silica gel (petroleum ether/EtOAc) to afford the corresponding product 4.

Experimental procedure for the three component one pot synthesis of the substituted pyrrole (Table 1)

Aldehyde (1.0 mmol), nitromethane (1 ml), and molecular iodine (10 mol%) were charged into a 25 ml glass vial equipped with a stirring bar. The reaction mixture was allowed to reflux at 90 °C for 50–60 min, then after cooling down to room temperature, NMSM 1 (1.0 mmol) was added by sequential addition and the refluxing was continued for 9 h (monitored by TLC). The resulting mixture was extracted with ethyl acetate (3 × 7 ml), and then washed with water (2 × 10 ml) followed by brine solution (1 × 15 ml). The organic phases were collected and dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified using column chromatography on silica gel (petroleum ether/EtOAc) to afford the corresponding product 4a.

Experimental procedure for the one pot synthesis of the substituted pyrrole using a manual grinding method (Table 2)

NMSM 1 (1.0 mmol), β-nitrostyrene 3a (1.0 mmol) and the catalyst (10 mol%) were subjected to manual grinding for 30 min (monitored by TLC) at RT using a mortar and pestle. The resulting mixture was extracted with ethyl acetate (3 × 7 ml), and then washed with water (2 × 10 ml) followed by brine solution (1 × 15 ml). The organic phases were collected and dried with anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified using column chromatography on silica gel (petroleum ether/EtOAc) to afford the corresponding product 4a.

4-(4-Methoxyphenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4a)

Yellow solid; mp 128–130 °C; yield: 0.153 g (82%); ¹H NMR (300 MHz, CDCl₃): δ, 7.28 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.67 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 2.49 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 158.88, 136.99, 129.74, 126.09, 124.47, 122.17, 121.76, 113.55, 55.14, 34.87, 19.38; IR (ATR KBr cell, cm⁻¹): 791, 1327, 1495, 3741, 3840; anal. calcd for C₁₃H₁₄N₂O₃S: C, 56.10; H, 5.07; N, 10.06; found: C, 56.01; H, 5.03; N, 10.02; LC-MS (ESI) calcd m/z: 278, found 279 [(M + H)]⁺.

1-Methyl-2-(methylthio)-3-nitro-4-phenyl-1H-pyrrole (4b)

Yellow solid; mp 129–131 °C; yield: 0.120 g (72%); ¹H NMR (300 MHz, CDCl₃): δ, 7.35 (s, 5H), 6.71 (s, 1H), 3.80 (s, 3H), 2.50 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ, 137.00, 132.06, 128.46, 128.06, 127.20, 126.30, 122.32, 122.06, 34.88, 19.38; IR (ATR KBr cell, cm⁻¹): 691, 756, 1322, 1479, 2348, 3728. Anal. calcd for C₁₂H₁₂N₂O₂S: C, 58.05; H, 4.87; N, 11.28; found: C, 58.03; H, 4.86; N, 11.26; LC-MS (ESI) calcd. m/z: 248, found 249 [(M + H)]⁺.

4-(3-Methoxyphenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4c)

Yellow solid; mp 127–129 °C; yield: 0.150 g (80%); ¹H NMR (300 MHz, CDCl₃): δ, 7.27 (s, 1H), 6.91 (m 3H), 6.72 (s, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 159.38, 137.30, 133.46, 129.11, 126.24, 122.41, 121.96, 121.00, 114.25, 113.01, 55.18, 34.89, 19.46; IR (ATR KBr cell, cm⁻¹): 688, 784, 1321, 1477, 2349, 2930; anal. calcd for C₁₃H₁₄N₂O₃S: C, 56.10; H, 5.07; N, 10.06; found: C, 56.01; H, 5.03; N, 10.02; LC-MS (ESI) calcd. m/z: 278, found 279 [(M + H)]⁺.

4-(3,4-Dimethoxyphenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4d)

Yellow solid; mp 118–120 °C; yield: 0.174 g (84%); ¹H NMR (300 MHz, CDCl₃): δ, 6.93–6.85 (m, 3H), 6.70 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.80 (s, 3H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 148.63, 137.22, 126.10, 124.91, 122.23, 121.97, 121.02, 112.53, 111.13, 110.89, 55.90, 55.86, 34.85, 19.42; IR (ATR KBr cell, cm⁻¹): 804, 1240, 1504, 3741, 3840; anal. calcd for C₁₄H₁₆N₂O₄S: C, 54.53; H, 5.23; N, 9.08; found: C, 54.50; H, 5.21; N, 9.05; LC-MS (ESI) calcd. m/z: 308, found 309 [(M + H)]⁺.

1-Methyl-2-(methylthio)-3-nitro-4-(3,4,5-trimethoxyphenyl)-1H-pyrrole (4e)

Yellow solid; mp 132–134 °C; yield: 0.198 g (87%); ¹H NMR (300 MHz, CDCl₃): δ, 6.73 (s, 1H), 6.57 (s, 2H), 3.88 (s, 3H), 3.86 (s, 6H), 3.80 (s, 3H), 2.51 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 152.85, 137.43, 137.04, 127.68, 126.42, 122.44, 122.06, 105.96, 60.77, 56.04, 34.93, 19.44; IR (ATR KBr cell, cm⁻¹): 698, 820, 1105, 1339, 1497, 3741, 3840; anal. calcd for C₁₅H₁₈N₂O₅S: C, 53.24; H, 5.36; N, 8.28; found: C, 53.22; H, 5.34; N, 8.25; LC-MS (ESI) calcd. m/z: 338, found 339 [(M + H)]⁺.

4-(2-Fluorophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4f)

Yellow solid; mp 218–220 °C; yield: 0.138 g (77%); ¹H NMR (300 MHz, CDCl₃): δ, 7.38–7.24 (m, 2H), 7.20–7.04 (m, 2H), 6.76 (s, 1H), 3.81 (s, 3H), 2.51 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 161.60, 158.32, 130.60, 129.37, 129.26, 126.49, 123.97, 122.98, 120.49, 120.29, 115.64, 115.34, 35.12, 19.48; IR (ATR KBr cell, cm⁻¹): 636, 767, 1329, 1480, 2348, 3728; anal. calcd for C₁₂H₁₁FN₂O₂S: C, 54.12; H, 4.16; N, 10.52; found: C, 54.11; H, 4.14; N, 10.51; LC-MS (ESI) calcd. m/z: 266, found 267 [(M + H)]⁺.

4-(4-Fluorophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4g)

Yellow solid; mp 168–170 °C; yield: 0.149 g (83%); ¹H NMR (300 MHz, CDCl₃): δ, 7.32 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.69 (s, 1H), 3.80 (s, 3H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 163.84, 160.58, 130.45, 130.34, 128.24, 126.70, 122.42, 121.27, 115.23, 114.94, 35.03, 19.42; IR (ATR KBr cell, cm⁻¹): 793, 829, 1210, 1322, 1489, 3741, 3840; anal. calcd for C₁₂H₁₁FN₂O₂S: C, 54.12; H, 4.16; N, 10.52; found: C, 54.10; H, 4.13; N, 10.50; LC-MS (ESI) calcd. m/z: 266, found 267 [(M + H)]⁺.

4-(3-Chlorophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4h)

Yellow solid; mp 96–98 °C; yield: 0.142 g (75%); ¹H NMR (300 MHz, CDCl₃): δ, 7.33 (s, 1H), 7.27 (m, 3H), 6.72 (s, 1H), 3.80, (s, 3H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 136.64, 133.98, 133.62, 129.21, 128.41, 127.11, 126.94, 126.79, 122.74, 120.47, 34.93, 19.26; IR (ATR KBr cell, cm⁻¹): 778, 1312, 1478, 3741, 3840; anal. calcd for C₁₂H₁₁ClN₂O₂S: C, 50.97; H, 3.92; N, 9.91; found: C, 50.95; H, 3.91; N, 9.90; LC-MS (ESI) calcd. m/z: 282, found 283 [(M + H)]⁺.

4-(4-Chlorophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4i)

Yellow solid; mp 76–78 °C; yield: 0.158 g (83%); ¹H NMR (300 MHz, CDCl₃): δ, 7.34 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 7.1 Hz, 2H), 6.70 (s, 1H), 3.80 (s, 3H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 136.89, 133.25, 130.72, 129.95, 128.30, 126.94, 122.48, 121.02, 35.05, 19.42; IR (ATR KBr cell, cm⁻¹): 832, 1320, 1487, 3741, 3840; anal. calcd for C₁₂H₁₁ClN₂O₂S: C, 50.97; H, 3.92; N, 9.91; found: C, 50.95; H, 3.91; N, 9.90; LC-MS (ESI) calcd. m/z: 282, found 283 [(M + H)]⁺.

4-(2-Bromophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4j)

Yellow solid; mp 188–190 °C; yield: 0.170 g (77%); ¹H NMR (300 MHz, CDCl₃): δ, 7.63 (d, J = 7.9 Hz, 1H), 7.39–7.13 (m, 3H), 6.68 (s, 1H), 3.82 (s, 3H), 2.52 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 134.01, 132.46, 131.24, 129.08, 127.05*, 126.45, 124.60, 122.87, 121.15, 35.15, 19.34; IR (ATR KBr cell, cm⁻¹): 764, 1325, 1479, 2347, 3615, 3728; anal. calcd for C₁₂H₁₁BrN₂O₂S: C, 44.05; H, 3.39; N, 8.56; found: C, 44.03; H, 3.36; N, 8.55; LC-MS (ESI) calcd. m/z: 327, found 328 [(M + H)]⁺ [* – two carbon signals have merged together].

4-(4-Bromophenyl)-1-methyl-2-(methylthio)-3-nitro-1H-pyrrole (4k)

Yellow solid; mp 102–104 °C; yield: 0.174 g (79%); ¹H NMR (300 MHz, CDCl₃): δ, 7.49 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 6.70 (s, 1H), 3.80 (s, 3H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 136.83, 131.23, 131.19, 130.25, 126.99, 122.45, 121.40, 121.00, 35.07, 19.42; IR (ATR KBr cell, cm⁻¹): 617, 781, 1320, 1439, 3741, 3839; anal. calcd for C₁₂H₁₁BrN₂O₂S: C, 44.05; H, 3.39; N, 8.56; found: C, 44.02; H, 3.37; N, 8.54; LC-MS (ESI) calcd. m/z: 327, found 328 [(M + H)]⁺.

3-(1-Methyl-5-(methylthio)-4-nitro-1H-pyrrol-3-yl)phenol (4l)

Yellow solid; mp 140–142 °C; yield: 0.151 g (85%); ¹H NMR (300 MHz, CDCl₃): δ, 7.33–7.15 (m, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 11.8 Hz, 1H), 6.70 (s, 1H), 5.01 (s, 1H), 3.79 (s, 3H), 2.49 (s, 3H); ¹³C NMR (75 MHz, DMSO): δ, 157.38, 136.71, 133.46, 129.44, 125.70, 123.91, 120.59, 118.98, 115.17, 114.30, 35.11, 19.33; IR (ATR KBr cell, cm⁻¹): 774, 1306, 1472, 3447, 3741, 3840; anal. calcd for C₁₂H₁₂N₂O₃S: C, 54.53; H, 4.58; N, 10.60; found: C, 54.51; H, 4.56; N, 10.58; LC-MS (ESI) calcd. m/z: 264, found 265 [(M + H)]⁺.

1-Methyl-2-(methylthio)-3-nitro-4-(4-nitrophenyl)-1H-pyrrole (4m)

Yellow solid; mp 258–260 °C; yield: 0.128 g (65%); ¹H NMR (300 MHz, CDCl₃): δ, 8.23 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 6.82 (s, 1H), 3.84 (s, 3H), 2.53 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 146.83, 139.15, 136.85, 129.31, 128.23, 123.45, 123.09, 120.09, 35.29, 19.44; IR (ATR KBr cell, cm⁻¹): 807, 1321, 1493, 2348, 3729; anal. calcd for C₁₂H₁₁N₃O₄S: C, 49.14; H, 3.78; N, 14.33; found: C, 49.13; H, 3.76; N, 14.34; LC-MS (ESI) calcd. m/z: 293, found 294 [(M + H)]⁺.

1-Methyl-2-(methylthio)-4-(naphthalen-1-yl)-3-nitro-1H-pyrrole (4n)

Orange solid; mp 168–170 °C; yield: 0.181 g (90%); ¹H NMR (300 MHz, CDCl₃): δ, 7.91–7.82 (m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.52–7.34 (m, 4H), 6.74 (s, 1H), 3.86 (s, 3H), 2.56 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): δ, 138.20, 133.35, 132.45, 130.58, 128.25, 128.15, 127.31, 126.28, 126.12, 125.71, 125.29, 125.07, 123.46, 120.24, 35.05, 19.31; IR (ATR KBr cell, cm⁻¹): 780, 1324, 1481, 3741, 3840; anal. calcd for C₁₆H₁₄N₂O₂S: C, 64.41; H, 4.73; N, 9.39; found: C, 64.40; H, 4.71; N, 9.37; LC-MS (ESI) calcd. m/z: 298, found 299 [(M + H)]⁺.

Acknowledgements

SS thanks DST and UGC-MRP, New Delhi, for financial assistance. We thank DST-IRHPA for funding towards a high resolution NMR spectrometer. BBC thanks the University Grants Commission, New Delhi, for the award of Senior Research Fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: All the ¹H & ¹³C NMR and mass spectra of 4a–n are available. See DOI: 10.1039/c5ra11094g

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