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Article

Functionalized 2,3′-Bipyrroles and Pyrrolo[1,2-c]imidazoles from Acylethynylpyrroles and Tosylmethylisocyanide

by
Maxim D. Gotsko
,
Ivan V. Saliy
,
Igor A. Ushakov
,
Lyubov N. Sobenina
and
Boris A. Trofimov
*
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(4), 885; https://doi.org/10.3390/molecules29040885
Submission received: 15 December 2023 / Revised: 14 February 2024 / Accepted: 15 February 2024 / Published: 17 February 2024
(This article belongs to the Special Issue Synthesis, Functionalization and Applications of Nitrogen-Containing Compounds)
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Abstract

An efficient method for the synthesis of pharmaceutically prospective but still rare functionalized 2,3′-bipyrroles (in up to 80% yield) by the cycloaddition of easily available acylethynylpyrroles with tosylmethylisocyanide (TosMIC) has been developed. The reaction proceeds under reflux (1 h) in the KOH/THF system. In the t-BuONa/THF system, TosMIC acts in two directions: along with 2,3′-bipyrroles, the unexpected formation of pyrrolo[1,2-c]imidazoles is also observed (products ratio~1:1).

1. Introduction

The widespread applications of pyrroles, including their assemblies and the functionalized fused derivatives, in such fields as pharmacology, medicinal chemistry and materials science as well as their significance as precursors in the synthesis of many natural products have made this class of compounds one of the most important in heterocyclic chemistry [1,2,3,4,5,6,7,8,9,10,11,12].
Many products containing the pyrrole moiety exhibit a broad range of biological activities such as anticancer, antimicrobial, antiviral, anti-inflammatory, antipsychotic, antimalarial, insecticidal, etc. [1,2,3,4,5,6,7,8,9,10,11,12]. Based on pyrroles, anti-hyperlipidemic atorvastatin, anti-tumor agents sunitinib, vemurafenib, ruxolinitib and pemetrexed, vonoprazan used for the treatment of gastroduodenal ulcers, and nonsteroidal anti-inflammatory agents tolmetin, zomepirac and ketorolac were created.
In the light of the foregoing, it is clear that the synthesis of new pyrrole derivatives as potential drugs or that of their precursors is an important synthetic challenge.
Among the most promising precursors suitable for the synthesis of various pyrrole derivatives, acylethynylpyrroles are readily available products of the mechanochemical reaction of pyrroles with acylbromoacetylenes, which occurs by simple grinding the reagents in a mortar in the solid Al2O3 medium [13]. On the platform of these compounds, a wide range of pyrrole assemblies, such as pyrrolyl-oxazoles [14], pyrrolyl-pyrazoles [14], pyrrolyl-pyridines [14], pyrrolyl-pyrones [14] and pyrrolyl-pyridones [14], and condensed pyrrole compounds, such as pyrrolopyrazines [14], pyrrolizines [14] and pyrroloimidazoles [15], have already been obtained.
In this paper, we report on the methods for the synthesis of such important representatives of pyrrole assemblies and fused pyrroles as 2,3′-bipyrroles and pyrrolo[1,2-c]imidazoles via the reaction of 2-acylethynylpyrroles with tosylmethylisocyanide (TosMIC).
It is known that readily available 2,2′-bipyrroles are widely used as key building blocks in the synthesis of pyrrole macrocycles with different pharmacological activities [16]. Investigations of 2,3′-bipyrroles are still restricted by the absence of suitable facile approaches to these unique molecules. Only a few preparative significant methods for the synthesis of these assemblies are known. Among them are 1,3-dipolar cycloaddition of unsymmetrical münchnones and nitrovinylheterocycles in the presence of N,N′-diisopropylcarbodiimide (DIPC) (Scheme 1a) [17] and cycloaddition of acylethynylpyrroles with diethyl aminomalonate hydrochloride (Scheme 1b) [18].
Pyrrolo[1,2-c]imidazoles are an important structural motif frequently found in a number of natural products and bioactive molecules. For instance, some derivatives of pyrrolo[1,2-c]imidazole are capable of inhibiting aldose reductase [19], heparanase [20], glucosamine deacetylase (LpxC) [21], and ERK (extracellular signal-regulated kinases) [22].
Compounds of this class are antagonists of the 5-HT3 receptor with antiemetic activity especially effective in chemotherapy [23], the neuropeptide S receptor associated with biological processes such as appetite and food intake, movement, wakefulness, activation and anxiety [24], and the TNF receptor widely employed for the treatment of rheumatoid arthritis [25]. Pyrrolo[1,2-c]imidazoles also exhibit anticancer [26,27], antioxidant, antibacterial [28], anti-inflammatory and neuroprotective [29] activities.
Despite the insufficient knowledge of the biological activity of 2,3′-bipyrroles, there is information about the prospects of their use as anticancer drugs[30,31] and EGFR inhibitor [32] (Figure 1).
It should be underlined that almost all pyrrolo[1,2-c]imidazoles studied to date contain an exocyclic carbonyl group or a thione function [19,20,21,22,23,24,25,26,27,28,29], which is probably explained by the inaccessibility of representatives of this class of compounds by other substituents.
Recently, based on the [3+2]-cycloaddition of acylethynylpyrroles to 1-pyrrolines, a method for the synthesis of pyrrolo[1,2-c]imidazoles with an exocyclic acylmethylidene group was developed (Scheme 2) [15].

2. Results and Discussion

In this paper, we share the results concerning the synthesis of 2,3′-bipyrroles and pyrrolo[1,2-c]imidazoles via the reaction of 2-acylethynylpyrroles 1a–o with TosMIC, which is a versatile and powerful synthetic tool in heterocyclization reactions used to build five-membered heterocycles and heterofused systems [33].
It is known that activated acetylenes such as acetylenic esters or propiolic aldehydes react with TosMIC to afford pyrroles [34,35,36] or oxazoles [34,37], respectively, and carbonyl compounds can form oxazoles [34,38] or undergo reductive cyanation in nitriles [34,39].
At the same time, it was found that the reaction of 2-acylethynylpyrroles with TosMIC, depending on its conditions and substituents in the pyrrole ring, can deliver either pyrrolyl vinyl sulfones [40] or tosyl/pyrrolyl-capped 1,3-enynes [41]. In the former case, the reaction proceeds under a long reflux (120 h) in the Et3N/MeCN catalytic system, whereas for the easy and rapid (reflux, 1 h) synthesis of tosyl/pyrrolyl-capped 1,3-enynes, the t-BuOK/THF system is employed.
From these results, it follows that the optimal temperature for the reaction studied is that of reflux in THF, and the search for optimal conditions for the reaction of acylethynylpyrroles with TosMIC was carried out via reflux in THF at the molar ratio of acylethynylpyrroles:TosMIC:base = 1:2:2.
To commence the reaction of 2-acylethynylpyrroles 1a–o with TosMIC, 2-benzoylethynylpyrrole (1a, 1 equiv) was refluxed with TosMIC (2 equiv) in THF in the presence of Et3N (2 equiv) for 24 h (Table 1, entry 1). However, under these conditions, not even traces of any products were found in the reaction mixture. Other organic catalysts, such as DBU (entry 2) and DABCO (entry 3), also did not promote the reaction: in all cases, the starting reagents were completely returned from the reaction.
Carrying out a reaction of 2-benzoylethynylpyrrole 1a with TosMIC in the K2CO3/THF system (reflux, 24 h, entry 4), we were encountered, to our surprise, with a new reaction of this popular reagent: along with the expected 2,3′-bipyrrole 2a (15% isolated yield), pyrrolo[1,2-c]imidazole, which functionalized with acyl and tosyl substituents, (E)-1-phenyl-2-(1H-pyrrolo[1,2-c]imidazol-1-ylidene)-3-tosylpropan-1-one (3a), was formed (isolated yield is 10%).
When other bases, e.g., Cs2CO3, NaOH, KOH, t-BuONa, t-BuOK (entries 5–9, 11), were employed in the reaction of TosMIC with ethynylpyrrole 1a, the complete conversion of the latter was achieved after 1 h of reflux in THF.
The highest yield of bipyrrole 2a (80%) was reached when the reaction was carried out in the presence of KOH (entry 7) or in the presence of t-BuOK (entry 11). Under these conditions, pyrroloimidazole 3a was detected only in traces. In preparative quantities, pyrroloimidazole 3a was formed only in the t-BuONa/THF system: in this case, bipyrrole 2a and pyrroloimidazole 3a were obtained in almost equal ratios (1H NMR data), with their isolated yields being 27 and 37%, respectively (entry 9).
The selective formation of pyrroloimidazole 3a was observed when the reaction was carried out in the presence of NaH (molar ratio 1a:TosMIC:NaH = 1:1:1 and 1:2:2). However, in this case, the reaction was accompanied by strong tarring, and the target product was isolated in a yield of 39–45% (Table 1, entries 13, 14).
As follows from the data in Table 1, the selectivity of the reaction and yields of the products depend both on the nature and ratio of bases. This can be rationalized from the points of strength of bases and their softness (hardness) according to Pearson’s HSAB principle [42,43]. Indeed, in the reaction mixture, two different acids, namely CH-acid (TosMIC) and NH-acid (the pyrrole moiety), compete with each other for a base.
In the real process, the strengths of bases and their softness (hardness) as well as those of the acids depend not only on the nature of the base/alkali metal cation but also on the solvation effects, which are different for Na and K cations—i.e., the selectivity of the reaction and yields of the products are complex functions of several mutually depended variables.
Next, given the better convenience of working with KOH than with t-BuOK and its lower cost, we evaluated the substrate scope of the synthesis of bipyrroles 2a–o in the presence of KOH (Scheme 3).
The experiments showed that the reaction of 2-acylethynylpyrroles 1a–o with TosMIC under these conditions proceeded efficiently and selectively, thus providing a short route to 2,3-dipyrroles 2a–o, which are still rare and poorly studied compounds, in good yields up to 80%.
As follows from Scheme 3, the reaction is tolerant to different acylethynylpyrroles with aliphatic and aromatic substituents in the pyrrole ring as well as 2-acylethynyl-4,5,6,7-tetrohydroindoles; i.e., the synthesis has quite a general character.
Next, a range of acylethynylpyrroles (acylethynylpyrroles 1a,b,d,h–n) were involved in the reaction with TosMIC in the t-BuONa/THF system to evaluate the scope of the novel cyclization giving hitherto unknown pyrrolo[1,2-c]imidazoles 3a–j.
Unfortunately, in contrast to the KOH/THF system, which selectively catalyzed the formation of 2,3′-bipyrroles, the t-BuONa/THF system c promoted the formation of both 2,3′-bipyrroles and pyrrolo[1,2-c]imidazoles from all the studied acylethynylpyrroles 1a,b,d,h–n (Scheme 4). The reaction products were easily separated via column chromatography (SiO2, n-hexane:diethyl ether, 5:1).
As can be seen from Scheme 4, this reaction, like the formation of 2,3′-bipyrroles, also tolerates different acylethynylpyrroles with aliphatic and aromatic substituents in the pyrrole ring as well as 2-acylethynyl-4,5,6,7-tetrohydroindoles—i.e., it also has quite a general character.
The structures of compounds 2a and 3a were proved by 1H and 13C NMR spectroscopy using also 2D COSY, NOESY, HMBC and HSQC techniques. The 1H NMR spectra of 2,3′-bipyrroles contain broad singlets of 2 NH groups at 10.23–11.77 and 9.84–10.77 ppm, while the spectra of pyrroloimidazole 3a show singlets of a proton at the C=N bond at 8.51–8.91 ppm and methylene group at 5.05–5.20 ppm.
Apparently, the formation of 2,3′-bipyrroles 2 starts with proton abstraction from the CH2-group of TosMIC followed by a nucleophilic attack of carbanion A, thus generated as a C-nucleophile, on the triple bond of acylethynylpyrroles 1 to afford intermediate anion B. This anion then undergoes intramolecular cyclization with the participation of an anionic center and a carbene carbon atom to form the cyclic anion C that is further quenched by a proton of the medium. The aromatization of the intermediate bipyrrole D, as a result of the [1,3]-H shift finishes the process (Scheme 5).
The assembly of pyrrolo[1,2-c]imidazoles 3 likely involves the formation of the pyrrolate anion E in the first stage due to the greater deprotonating ability of the t-BuONa/THF super-base system compared to the KOH/THF system. The anion E attacks the carbene carbon atom of TosMIC, and the forming carbanion F is neutralized with t-BuOH to give intermediate imine G. The latter undergoes intramolecular cyclization to pyrroloimidazole via the four-membered transition state H, wherein the cleavage of the N and CH2-Ts bond occurs accompanied by simultaneous C1-N and C2-CH2Ts bonding (Scheme 6).

3. Materials and Methods

3.1. General Information

IR spectra were obtained with a Vertex 70 spectrometer (Bruker, Billerica, MA, USA, 400–4000 cm–1, films). 1H (400.13 MHz) and 13C (100.6 MHz) spectra were recorded on a DPX-400 spectrometer (Bruker, Chicago, IL, USA) at ambient temperatures in CDCl3 and DMSO-d6 solutions and referenced to CDCl3 (residual protons of CDCl3 in 1H NMR δ = 7.26 ppm; 13C NMR δ = 77.1 ppm) and DMSO-d6 (residual protons of CDCl3 in 1H NMR δ = 2.50 ppm; 13C NMR δ = 39.52 ppm).
The C, H, N microanalyses were performed on a Flash EA 1112 CHNS-O/MAS analyzer (CHN Analyzer, Thermo Fisher Scientific, Monza, Italy). Sulfur was determined via complexometric titration with Chlorasenazo III. Fluorine content was determined on a SPECOL 11 (Carl Zeiss, Jena, Germany) spectrophotometer. Clorine was determined using mercurimetric titration. The melting point (uncorrected) was determined through a Kofler micro hot-stage apparatus (Antwerpen, Belgium). High-resolution mass spectral analyses were performed on an acetonitrile solution with 0.1% HFBA on an HPLC Agilent 1200/Agilent 6210 TOF instrument equipped with an electrospray ionization (ESI) source (Agilent, Santa Clara, CA, USA).
All reactions were carried out in air.
Acylethynylpyrroles 1a–o were prepared from corresponding pyrroles and acylbromoacetylenes in the presence of Al2O3 according to the reported procedure [13], and TosMIC, t-BuONa, KOH, NaH and THF were the commercial products.

3.2. The Reaction of Acylethynylpyrroles 1a–o with TosMIC in the Presence of KOH: Synthesis of 2,3′-Bipyrroles (2a–o) (General Procedure)

A solution of acylethynylpyrrole 1a–o (1 mmol) and TosMIC (395 mg, 2 mmol) in THF (10 mL) was heated to reflux. Then, under reflux, a suspension of KOH·0.5H2O (130 mg, 2 mmol) in THF (10 mL) was added dropwise to the reaction mixture for 1 h. The residue, after removal of the solvent, was fractionated using column chromatography (SiO2, n-hexane:diethyl ether, 5:1) to afford the 2,3′-bipyrrole 2a–o.

3.3. The Reaction of Acylethynylpyrroles 1a,b,d,h–n with TosMIC in the Presence of t-BuONa: Synthesis of 2,3′-Bipyrroles (2a,b,d,h–n) and Pyrrolo[1,2-c]imidazoles 3a–j (General Procedure)

A solution of acylethynylpyrrole 1b,d,h–n (1 mmol) and TosMIC (395 mg, 2 mmol) in THF (10 mL) was heated to reflux. Then, under reflux, a solution of t-BuONa (224 mg, 2 mmol) in THF (10 mL) was added dropwise to the reaction mixture for 1 h. The residue, after removal of the solvent, was fractionated using column chromatography (SiO2, n-hexane:diethyl ether, 5:1) to afford the 2,3′-bipyrrole 2a,b,d,h–n (SiO2, n-hexane:diethyl ether, 5:1) pyrrolo[1,2-c]imidazoles 3a–j. Yields of 2,3′-bipyrrole 2a,b,d,h–n, thus obtained, are as follows: 2a—27%; 2b—32%; 2d—32%; 2h—24%; 2i—29%, 2j—24%; 2k—30%; 2l—22%; 2m—26%; and 2n—24%.

3.4. Characterization Data of 2,3-Bipyrroles 2a–o and Pyrrolo[1,2-c]imidazoles 3a–j

Phenyl(2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)methanone (2a).
Yield 312 mg (80%). Yellow crystals, mp 163–165 °C. IR (KBr, cm−1): 3295 (NH), 3148, 3063 (=CH), 2920 (CH), 1636 (CO), 1597, 1517 (C=C), 1354, 1140 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 10.89 (br.s, 1H, NH, CO-pyrrole), 9.92 (br.s, 1H, NH, pyrrole), 7.75–7.73 (m, 2H, Ph), 7.59–7.57 (m, 2H, Ph), 7.54–7.52 (m, 1H, Ph), 7.44–7.40 (m, 2H, Ph), 7.24 (d, J = 3.5 Hz, 1H, H-5, CO-pyrrole), 7.16–7.14 (m, 2H, Ph), 6.84–6.83 (m, 2H, H-5, H-3, pyrrole), 6.20–6.18 (m, 1H, H-4, pyrrole), 2.34 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 192.4, 144.7, 139.3, 137.5, 132.7, 129.8 (2C), 129.7 (2C), 129.3, 128.4 (2C), 127.2 (2C), 125.2, 124.3, 123.0, 121.4, 119.2, 113.1, 109.5, 21.7. Anal. Calcd for C22H18N2O3S: C, 67.68; H, 4.65; N, 7.17; S, 8.21%. Found: C, 67.84; H, 4.78; N, 7.32; S, 8.01%. HRMS (ESI-TOF): found 391,1116. Calcd. for [C22H18N2O4S+H]+ 391,1121.
Furan-2-yl(2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)methanone (2b).
Yield 282 mg (74%). Yellow crystals, mp 95–97 °C. IR (KBr, cm−1): 3293 (NH), 3131 (=CH), 2923, 2859 (CH), 1620 (CO), 1563, 1520 (C=C), 1354, 1140 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 10.71 (br.s, 1H, NH, CO-pyrrole), 9.94 (br.s, 1H, NH, pyrrole), 7.68 (d, J = 3.3 Hz, 1H, H-5, CO-pyrrole), 7.62–7.61 (m, 1H, H-5, furan), 7.57–7.55 (m, 2H, Ph), 7.16–7.14 (m, 3H, H-3, furan, Ph), 6.86–6.84 (m, 2H, H-3, H-5, pyrrole), 6.54 (dd, J = 3.3, 1.4 Hz, 1H, H-4, furan), 6.22–6.20 (m, 1H, H-4, pyrrole), 2.33 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 177.8, 153.4, 146.9, 144.7, 137.9, 129.7 (2C), 127.5, 127.3 (2C), 125.7, 123.3, 123.0, 121.4, 119.8, 119.3, 113.2, 112.5, 109.5, 21.6. Anal. Calcd for C20H16N2O4S: C, 63.15; H, 4.24; N, 7.36; S, 8.43%. Found: C, 63.27; H, 4.42; N, 7.53; S, 8.3%.
Thiophen-2-yl(2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)methanone (2c).
Yield 274 mg (69%). Yellow crystals, mp 175–177 °C. IR (KBr, cm−1): 3351 (NH), 3137, 3110 (=CH), 2922 (CH), 1614 (CO), 1569, 1520, 1484, 1458 (C=C), 1359, 1136 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 10.64 (br.s, 1H, NH, CO-pyrrole), 10.16 (br.s, 1H, NH, pyrrole), 7.65 (d, J = 4.9 Hz, 1H, H-5, thiophene), 7.57 (d, J = 8.1 Hz, 2H, Ph), 7.54 (d, J = 3.5 Hz, 1H, H-3, thiophene), 7.46 (d, J = 3.3 Hz, 1H, H-3, pyrrole), 7.14 (d, J = 8.1 Hz, 2H, Ph), 7.09–7.07 (m, 1H, H-4, thiophene), 6.85–6.83 (m, 1H, H-4, pyrrole), 6.83–6.82 (m, 1H, H-3, pyrrole), 6.21–6.20 (m, 1H, H-5, pyrrole), 2.32 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 183.5, 145.0, 144.8, 137.5, 134.6, 134.4, 129.7 (2C), 128.2, 127.4, 127.2 (2C), 125.4, 124.1, 122.5, 121.4, 119.3, 113.0, 109.4, 21.7. Anal. Calcd for C20H16N2O3S2: C, 60.59; H, 4.07; N, 7.07; S, 16.17%. Found: C, 60.73; H, 4.27; N, 7.18; S, 15.99%. HRMS (ESI-TOF): found 397,0681. Calcd. for [C20H16N2O3S2+H]+ 397,0685.
(4-Ethyl-5-propyl-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)(phenyl)methanone (2d).
Yield 203 mg (44%). Yellow crystals, mp 170–172 °C. IR (KBr, cm−1): 3285 (NH), 3160 (=CH), 2958, 2927, 2869 (CH), 1630 (CO), 1596, 1575, 1519, 1495, 1461 (C=C), 1351, 1142, (SO2). 1H NMR (400.13 MHz, CDCl3): δ 10.63 (br.s, 1H, NH, CO-pyrrole), 9.84 (br.s, 1H, NH, pyrrole), 7.72–7.70 (m, 2H, Ph), 7.63–7.61 (m, 2H, Ph), 7.54–7.51 (m, 1H, Ph), 7.43–7.39 (m, 2H, Ph), 7.22 (d, J = 3.5 Hz, 1H, H-5, CO-pyrrole), 7.16–7.14 (m, 2H, Ph), 6.67–6.65 (m, 1H, pyrrole), 2.55–2.53 (m, 2H, CH2), 2.51–2.53 (m, 2H, CH2), 2.37 (s, 3H, CH3), 1.67–1.57 (m, 2H CH2), 1.12 (t, J = 7.6 Hz, 3H, CH3), 0.90 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 192.5, 144.5, 139.8, 137.7, 132.4, 130.1, 129.7 (2C), 129.6 (2C), 129.5, 128.4 (2C), 127.3 (2C), 124.1, 124.0, 123.8, 123.2, 118.7, 113.5, 28.0, 23.1, 21.7, 19.0, 16.1, 13.9. Anal. Calcd for C27H28N2O3S: C, 70.41; H, 6.13; N, 6.08; S, 6.96%. Found: C, 70.6; H, 6.28; N, 6.25; S, 6.84%. HRMS (ESI-TOF): found 461,1899. Calcd. for [C27H28N2O3S +H]+ 461,1902.
Phenyl(4-(4,5,6,7-tetrahydro-1H-indol-2-yl)-5-tosyl-1H-pyrrol-3-yl)methanone (2e).
Yield 311 mg (70%). Yellow crystals, mp 235–237 °C. IR (KBr, cm−1): 3342 (NH), 3171 (=CH), 2922, 2851 (CH), 1633 (CO), 1594, 1574, 1521, 1495 (C=C), 1351, 1126 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 10.60 (br.s, 1H, NH, CO-pyrrole), 9.89 (br.s, 1H, NH, pyrrole), 7.73–7.71 (m, 2H, Ph), 7.65–7.63 (m, 2H, Ph), 7.56–7.52 (m, 1H, Ph), 7.44–7.40 (m, 2H, Ph), 7.20–7.19 (m, 2H, Ph), 7.17–7.15 (m, 1H, H-2, CO-pyrrole), 6.68–6.67 (m, 1H, H-3, pyrrole), 2.61–2.59 (m, 2H, CH2–7), 2.51–2.48 (m, 2H, CH2–4), 2.36 (s, 3H, CH3), 1.79–1.78 (m, 2H, CH2–5), 1.73–1.71 (m, 2H, CH2–6). 13C NMR (100.61 MHz, CDCl3): δ 192.5, 144.5, 139.8, 137.7, 132.5, 129.7 (3C), 129.6 (2C), 129.2, 128.4 (2C), 127.2 (2C), 124.1, 123.9, 121.3, 119.5, 118.8, 112.4, 24.0, 23.6, 23.1, 23.1, 21.7. Anal. Calcd for C26H24N2O3S: C, 70.25; H, 5.44; N, 6.30; S, 7.21%. Found: C, 70.40; H, 5.25; N, 6.44; S, 7.04%. HRMS (ESI-TOF): found 445,1586. Calcd. for [C26H24N2O3S+H]+ 445,1589.
Furan-2-yl(4-(4,5,6,7-tetrahydro-1H-indol-2-yl)-5-tosyl-1H-pyrrol-3-yl)methanone (2f).
Yield 291 mg (67%). Yellow crystals, mp 173–175 °C. IR (KBr, cm−1): 3278 (NH), 3019 (=CH), 2924, 2850 (CH), 1618 (CO), 1609, 1524, 1464 (C=C), 1351, 1138 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 10.39 (br.s, 1H, NH, CO-pyrrole), 10.27 (br.s, 1H, NH, pyrrole), 7.65–7.64 (m, 2H, Ph), 7.62–7.61 (m, 2H, H-5, H-3, furan), 7.16–7.14 (m, 2H, Ph), 7.12 (d, J = 3.5 Hz, 1H, H-2, CO-pyrrole), 6.64 (d, J = 2.2 Hz, 1H, H-3, pyrrole), 6.52 (dd, J = 3.5, 1.6 Hz, 1H, H-4, furan), 2.60–2.57 (m, 2H, CH2–7), 2.51–2.48 (m, 2H, CH2–4), 2.33 (s, 3H, CH3), 1.81–1.75 (m, 2H, CH2–5), 1.74–1.70 (m, 2H, CH2–6). 13C NMR (100.6 MHz, CDCl3): δ 177.9, 153.2, 147.0, 144.5, 137.7, 129.6 (2C), 129.1, 128.5, 127.2 (2C), 124.0, 123.8, 122.4, 119.9, 119.3, 118.6, 112.4, 112.3, 24.0, 23.5, 23.1, 23.0, 21.7. Anal. Calcd for C24H22N2O4S: C, 66.34; H, 5.10; N, 6.45; S, 7.38%. Found: C, 66.41; H, 5.87; N, 6.18; S, 7.22%. HRMS (ESI-TOF): found 435,1379. Calcd. for [C24H22N2O4S+H]+ 435,1383.
(4-(4,5,6,7-Tetrahydro-1H-indol-2-yl)-5-tosyl-1H-pyrrol-3-yl)(thiophen-2-yl)methanone (2g).
Yield 293 mg (65%). Yellow crystals, mp 198–200 °C. IR (KBr, cm−1): 3289 (NH), 3131 (=CH), 2924, 2851 (CH), 1613 (CO), 1595, 1514 (C=C), 1358, 1140 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 10.23 (br.s, 1H, NH, CO-pyrrole), 10.02 (br.s, 1H, NH, pyrrole), 7.66–7.62 (m, 3H, Ph, H-5, thiophene), 7.56–7.55 (m, 1H, H-3, thiophene), 7.43 (d, J = 3.4 Hz, 1H, H-2, CO-pyrrole), 7.17–7.15 (m, 2H, Ph), 7.10–7.08 (m, 1H, H-4 thiophene), 6.63–6.60 (m, 1H, H-3, pyrrole), 2.60–2.57 (m, 2H, CH2–7), 2.51–2.48 (m, 2H, CH2–4), 2.35 (s, 3H, CH3), 1.84–1.76 (m, 2H, CH2–5), 1.74–1.69(m, 2H, CH2–6). 13C NMR (100.61 MHz, CDCl3): δ 183.5, 145.3, 144.5, 137.7, 134.3, 134.1, 129.6 (2C), 129.2, 128.1, 127.8, 127.3 (2C), 124.3, 123.7, 123.4, 119.4, 118.6, 112.3, 24.0, 23.6, 23.1, 23.0, 21.7. Anal. Calcd for C24H22N2O3S2: C, 63.98; H, 4.92; N, 6.22; S, 14.23%. Found: C, 63.75; H, 5.07; N, 6.08; S, 14.12%. HRMS (ESI-TOF): found 451,1150. Calcd. for [C24H22N2O3S2+H]+ 451,1154.
Phenyl(5-phenyl-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)methanone (2h).
Yield 247 mg (53%). Yellow crystals, mp 205–207 °C. IR (KBr, cm−1): 3281 (NH), 3147 (=CH), 2923 (CH), 1629 (CO), 1597, 1677, 1508, 1477 (C=C), 1349, 1139 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 11.77 (br.s, 1H, NH, CO-pyrrole), 9.89 (br.s, 1H, NH, pyrrole), 7.78–7.76 (m, 2H, Ph), 7.68–7.66 (m, 2H, Ph), 7.65–7.63 (m, 2H, Ph), 7.58–7.54 (m, 1H, Ph), 7.46–7.43 (m, 2H, Ph), 7.40–7.36 (m, 2H, Ph), 7.28 (d, J = 3.2 Hz, 1H, H-5, CO-pyrrole), 7.21–7.19 (m, 1H, Ph), 7.18–7.16 (m, 2H, Ph), 7.04–7.02 (m, 1H, H-4, pyrrole), 6.56–6.55 (m, 1H, H-3, pyrrole), 2.32 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 192.7, 144.9, 139.6, 137.4, 133.1, 132.7, 132.6, 129.9 (2C), 129.8 (2C), 129.0 (2C), 128.5 (2C), 127.2 (2C), 126.4, 125.1, 124.2, 123.9 (2C), 122.8, 122.8, 122.7, 120.2, 114.9, 107.4, 21.7. Anal. Calcd for C28H22N2O3S: C, 72.08; H, 4.75; N, 6.00; S, 6.87%. Found: C, 71.81; H, 4.85; N, 5.89; S, 6.75%. HRMS (ESI-TOF): found 467,1429. Calcd. for [C28H22N2O3S+H]+ 467,1431.
Furan-2-yl(5-phenyl-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)methanone (2i).
Yield 215 mg (47%). Yellow crystals, mp 90–92 °C. IR (KBr, cm−1): 3278 (NH), 3150 (=CH), 2923 (CH), 1619 (CO), 1519, 1561, 1531, 1509 (C=C), 1351, 1140 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 11.58 (br.s, 1H, NH of CO-pyrrole), 7.70–7.66 (m, 2H, H-5, furan, H-5, CO-pyrrole), 7.64–7.62 (m, 4H, Ph), 7.39–7.35 (m, 2H, Ph), 7.21–7.17 (m, 1H, Ph), 7.15–7.12 (m, 3H, H-3, furan, Ph), 7.05–7.03 (m, 1H, H-3, pyrrole), 6.57–5.55 (m, 1H, H-4, pyrrole), 6.52 (dd, J = 3.4, 1.5 Hz, 1H, H-4, furan), 2.29 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 178.0, 153.0, 147.2, 144.8, 137.4, 132.9, 132.5, 129.8 (2C), 129.1, 129.0 (2C), 127.1 (2C), 126.3, 125.1, 123.8 (2C), 122.8 (2C), 122.6, 120.4, 114.7, 112.5, 107.3, 21.6. Anal. Calcd for C26H20N2O4S: C, 68.41; H, 4.42; N, 6.14; S, 7.02%. Found: C, 68.11; H, 4.29; N, 6.22; S, 6.91%. HRMS (ESI-TOF): found 457,1222. Calcd. for [C26H20N2O4S+H]+ 457,1220.
(5-Phenyl-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)(thiophen-2-yl)methanone (2j).
Yield 198 mg (42%). Yellow crystals, mp 105–107 °C. IR (KBr, cm−1): 3295 (NH), 3137 (=CH), 2922, 2853 (CH), 1613 (CO), 1582, 1562, 1511 (C=C), 1359, 1140 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 11.26 (br.s, 1H, NH, CO-pyrrole), 9.72 (br.s, 1H, NH, pyrrole), 7.68–7.67 (m, 1H, H-5 of thiophene), 7.65–7.60 (m, 5H, Ph, H-3, thiophene), 7.50–7.49 (m, 1H, H-5, CO-pyrrole), 7.40–7.36 (m, 2H, Ph), 7.22–7.18 (m, 1H, Ph), 7.16–7.14 (m, 2H, Ph), 7.12–7.10 (m, 1H, H-4, thiophene), 6.97 (dd, J = 3.6, 2.5 Hz, 1H, H-3, pyrrole), 6.55–6.54 (m, 1 7.2, 134.5, 134.3, 132.9, 132.4, 129.7 (2C), 128.9 (2C), 128.0, 127.6, 127.0 (2C), 126.2, 125.1, 123.9, 123.7 (2C), 122.5, 122.1, 114.5, 107.1, 21.5. Anal. Calcd for C26H20N2O3S2: C, 66.08; H, 4.27; N, 5.93; S, 13.57%. Found: C, 66.25; H, 4.46; N, 6.07; S, 13.38%. HRMS (ESI-TOF): found 473,0994. Calcd. for [C26H20N2O3S2+H]+ 473,0998.
(5-(4-(Dimethylamino)phenyl)-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)(phenyl)methanone (2k).
Yield 270 mg (53%). Yellow crystals, mp 213–215 °C. IR (KBr, cm−1): 3240 (NH), 2924, 2853 (CH), 1613 (CO), 1512, 1491 (C=C), 1350, 1141 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 11.58 (br.s, 1H, NH, CO-pyrrole), 10.03 (br.s, 1H, NH, pyrrole), 7.75–7.73 (m, 2H, Ph), 7.67–6.65 (m, 2H, Ph), 7.54–7.52 (m, 3H, Ph), 7.44–7.40 (m, 2H, Ph), 7.24–7.19 (m, 1H, H-5, CO-pyrrole), 7.16–7.14 (m, 2H, Ph), 6.98–6.96 (m, 1H, H-4, pyrrole), 6.78–6.76 (m, 2H, Ph), 6.40–6.38 (m, 1H, H-3 pyrrole), 2.96 (s, 6H, N(CH3)2), 2.31 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 192.6, 149.4, 144.7, 139.7, 137.6, 133.9, 132.5, 130.0, 129.8 (2C), 129.7 (2C), 128.4 (2C), 127.1 (3C), 125.0 (2C), 124.3, 123.9, 123.2, 121.6, 121.3, 114.9, 113.2, 105.6, 40.8 (2C), 21.7. Anal. Calcd for C30H27N3O3S: C, 70.71; H, 5.34; N, 8.25; S, 6.29%. Found: C, 70.82; H, 5.48; N, 8.38; S, 6.18%. HRMS (ESI-TOF): found 510,1851. Calcd. for [C30H27N3O3S+H]+ 510,1848.
(5-(4-Fluorophenyl)-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)(phenyl)methanone (2l).
Yield 252 mg (52%). Yellow crystals, mp 130–132 °C. IR (KBr, cm−1): 3233 (NH), 3063 (=CH), 2969 (CH), 1613 (CO), 1597, 1486 (C=C), 1351, 1145 (SO2). 1H NMR (400.13 MHz, DMSO-d6): δ 11.79 (br.s, 1H, NH, CO-pyrrole), 9.94 (br.s, 1H, NH, pyrrole), 7.77–7.75 (m, 2H, Ph), 7.68–7.66 (m, 2H, Ph), 7.60–7.55 (m, 3H, Ph), 7.47–7.43 (m, 2H, Ph), 7.28 (d, J = 3.5 Hz, 1H, H-5, CO-pyrrole), 7.19–7.17 (m, 2H, Ph), 7.09–7.03 (m, 3H, H-4, pyrrole, Ph), 6.49–6.47 (m, 1H, H-3, pyrrole), 2.33 (s, 3H, CH3). 13C NMR (100.6 MHz DMSO-d6): δ 190.4, 160.5 (d, J = 242.4 Hz), 144.1, 138.8 (d, J = 29.4 Hz, 2C), 131.9, 130.9, 130.1, 129.8 (2C), 129.3 (d, J = 2.8 Hz), 129.0 (2C), 128.1 (2C), 126.7, 126.5 (2C), 125.3 (d, J = 7.8 Hz, 2C), 123.6, 122.5, 121.7, 115.6, 115.4, 112.7, 106.2, 21.0. Anal. Calcd for C28H21FN2O3S: C, 69.41; H, 4.37; F, 3.92; N, 5.78; S, 6.62%. Found: C, 69.56; H, 4.50; N, 5.95; S, 6.51; F, 4.04%.
(5-(4-Fluorophenyl)-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)(furan-2-yl)methanone (2m).
Yield 228 mg (48%). Yellow crystals, mp 118–120 °C. IR (KBr, cm−1): 3281 (NH), 3152 (=CH), 2923, 2856 (CH), 1621 (CO), 1602, 1561, 1512, 1488 (C=C), 1351, 1141 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 11.58 (br.s, 1H, NH, CO-pyrrole), 7.72–7.70 (m, 1H, H-5, furan), 7.67–7.65 (m, 2H, Ph), 7.64–7.62 (m, 1H, H-3, furan), 7.59–7.55 (m, 2H, Ph), 7.17 (d, J = 3.6 Hz, 1H, H-5, CO-pyrrole), 7.16–7.14 (m, 2H, Ph), 7.08–7.03 (m, 3H, H-3 pyrrole, Ph), 6.54 (dd, J = 3.3, 1.5 Hz, 1H, H-4, furan), 6.49–6.48 (m, 1H, H-4 pyrrole), 2.31 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 178.0, 161.7 (d, J = 245.4 Hz), 153.1, 147.3, 144.9, 137.5, 132.2, 129.8 (2C), 129.0, 128.9 (d, J = 2.8 Hz), 127.2 (2C), 125.5 (d, J = 7.9 Hz, 2C), 125.1, 122.8, 122.7, 122.7, 120.5, 115.9 (d, J = 21.8 Hz, 2C), 114.8, 112.6, 107.1, 21.7. Anal. Calcd for C26H19FN2O4S: C, 65.81; H, 4.04; F, 4.00; N, 5.90; S, 6.76%. Found: C, 65.99; H, 4.21; F, 4.18; N, 6.09; S, 6.66%. HRMS (ESI-TOF): found 475,1128. Calcd. for [C26H19FN2O4S+H]+ 475,1133.
(5-(4-Chlorophenyl)-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)(phenyl)methanone (2n).
Yield 225 mg (45%). Yellow crystals, mp 218–220 °C. IR (KBr, cm−1): 3275 (NH), 3118, 3092 (=CH), 1630 (CO), 1596, 1576, 1505, 1477 (C=C), 1351, 1145 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 11.83 (br.s, 1H, NH, CO-pyrrole), 9.89 (br.s, 1H, NH, pyrrole), 7.78–7.76 (m, 2H, Ph), 7.68–7.66 (m, 2H, Ph), 7.59–7.54 (m, 3H, Ph), 7.47–7.43 (m, 2H, Ph), 7.34–7.32 (m, 2H, Ph), 7.29 (d, J = 3.5 Hz, 1H, H-5, CO-pyrrole), 7.19–7.17 (m, 2H, Ph), 7.05 (dd, J = 3.6, 2.4 Hz, 1H, H-4, pyrrole), 6.54–6.52 (m, 1H, H-3, pyrrole), 2.33 (s, 3H, CH3). 13C NMR (100.61 MHz, CDCl3): δ 192.8, 144.9, 139.6, 137.4, 132.7, 131.8, 131.7, 131.1, 130.3, 129.9 (2C), 129.8 (2C), 129.2 (2C), 128.5 (2C), 127.1 (2C), 125.1, 125.0 (2C), 124.0, 123.2, 122.6, 114.9, 107.8, 21.7. Anal. Calcd for C28H21ClN2O3S: C, 67.13; H, 4.23; Cl, 7.08; N, 5.59; S, 6.40%. Found: C, 67.33; H, 4.38; N, 5.70; S, 6.29%. HRMS (ESI-TOF): found 501,1040. Calcd. for [C28H21ClN2O3S+H]+ 501,1044.
(4,5-Diphenyl-2′-tosyl-1H,1′H-[2,3′-bipyrrol]-4′-yl)(phenyl)methanone (2o).
Yield 250 mg (46%). Yellow crystals, mp 203–205 °C. IR (KBr, cm−1): 3296 (NH), 3059 (=CH), 2923 (CH), 1632 (CO), 1599, 1508, 1477 (C=C), 1351, 1132 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 11.36 (br.s, 1H, NH, CO-pyrrole), 9.82 (br.s, 1H, NH, pyrrole), 7.80–7.77 (m, 2H, Ph), 7.73–7.70 (m, 2H, Ph), 7.61–7.55 (m, 1H, H-5, CO-pyrrole), 7.48–7.45 (m, 4H, Ph), 7.36–7.27 (m, 7H, Ph), 7.24–7.20 (m, 4H, Ph), 7.05–7.03 (m, 1H, pyrrole), 2.36 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 192.6, 144.9, 139.6, 137.4, 137.0, 133.2, 132.7, 129.8 (3C), 129.6, 129.2, 128.8 (2C), 128.7 (2C), 128.5 (2C), 128.4 (2C), 127.4 (2C), 127.1 (2C), 126.8, 126.0, 125.5, 124.4, 123.6, 122.4, 121.8, 120.8, 115.7, 21.7. Anal. Calcd for C34H26N2O3S: C, 74.95; H, 4.68; N, 5.13; S, 5.91%. Found: C, 75.45; H, 4.98; N, 5.30; S, 5.79%. HRMS (ESI-TOF): found 543,1742. Calcd. for [C34H26N2O3S+H]+ 543,1739.
(E)-1-Phenyl-2-(1H-pyrrolo[1,2-c]imidazol-1-ylidene)-3-tosylpropan-1-one (3a).
Yield 144 mg (37%). Yellow crystals, mp 183–185°C. IR (KBr, cm−1): 3063 (=CH), 2923, 1689 (CO), 1596, 1581, 1523, 1493 (C=C), 1320, 1153 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.64 (s, 1H, H-3, pyrroloimidazole), 8.14–8,12 (m, 2H, Ph), 7.90–7.88 (m, 2H, Ph), 7.66–7.62 (m, 1H, Ph), 7.56–7.53 (m, 2H, Ph), 7.44–7.43 (m, 1H, H-5, pyrroloimidazole), 7.29–7.27 (m, 2H, Ph), 6.94–6.93 (m, 1H, H-6, pyrroloimidazole), 6.67–6.65 (m, 1H, H-7, pyrroloimidazole, 5.17 (s, 2H, CH2), 2.39 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 195.2, 144.4, 138.3, 137.6, 136.9, 136.8, 133.7, 132.1, 129.6 (2C), 128.9 (2C), 128.8 (2C), 128.5 (2C), 124.2, 118.3, 114.2, 104.8, 38.1, 21.8. Anal. Calcd for C22H18N2O3S: C, 67.68; H, 4.65; N, 7.17; S, 8.21%. Found: C, 67.80; H, 4.83; N, 7.30; S, 8.09%. HRMS (ESI-TOF): found 391,1116. Calcd. for [C22H18O3SN2+H]+ 391,1120.
(E)-1-(Furan-2-yl)-2-(1H-pyrrolo[1,2-c]imidazol-1-ylidene)-3-tosylpropan-1-one (3b).
Yield 133 mg (35%). Yellow crystals, mp 90–92 °C. IR (KBr, cm−1): 3132 (=CH), 2923, 2853 (CH), 1679 (CO), 1621, 1595, 1521, 1467 (C=C), 1320, 1153 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.63 (s, 1H, H-3, pyrroloimidazole), 7.93–7.91 (m, 2H, Ph), 7.66–7.67 (m, 1H, H-5, furan), 7.43–7.41 (m, 1H, H-3, furan), 7.38–7.37 (m, 1H, H-5, pyrroloimidazole), 7.30–7.28 (m, 2H, Ph), 6.94–6.92 (m, 1H, H-6, pyrroloimidazole), 6.72–6.71 (m, 1H, H-7, pyrroloimidazole), 6.62 (dd, J = 3.4, 1.5 Hz, 1H, H-4, furan), 5.05 (s, 2H, CH2), 2.40 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 184.1, 152.4, 146.8, 144.4, 138.5, 137.6, 136.9, 132.0, 129.6 (2C), 128.9 (2C), 123.2, 118.4, 117.8, 114.2, 112.7, 104.9, 37.6, 21.8. Anal. Calcd for C20H16N2O4S: C, 63.30; H, 4.24; N, 7.21; S, 8.43%. Found: C, 63.30; H, 4.39; N, 7.48; S, 8.31%. HRMS (ESI-TOF): found 381,0909. Calcd. for [C20H16N2O4S+H]+ 381,0911.
(E)-2-(6-Ethyl-5-propyl-1H-pyrrolo[1,2-c]imidazol-1-ylidene)-1-phenyl-3-tosylpropan-1-one (3c).
Yield 147 mg (32%). Yellow crystals, mp 153–155 °C. IR (KBr, cm−1): 3129 (=CH), 2963, 2932, 2872 (CH), 1690 (CO), 1597, 1581, 1495 (C=C), 1318, 1129 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.51 (s, 1H, H-3, pyrroloimidazole), 8.15–8,13 (m, 2H, Ph), 7.90–7.88 (m, 2H, Ph), 7.65–7.61 (m, 1H, Ph), 7.56–7.52 (m, 2H, Ph), 7.28–7.26 (m, 2H, Ph), 6.55–6.53 (m, 1H, H-6, pyrroloimidazole), 5.13 (s, 2H, CH2), 2.85–2.81 (m, 2H, CH2), 2.62–2.57 (m, 2H, CH2), 2.38 (s, 3H, CH3), 1.63–1.57 (m, 2H, CH2), 1.19 (t, J =7.5 Hz, 3H, CH3), 0.94 (t, J = 7.3 Hz, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 195.5, 144.1, 137.9, 136.9, 136.6, 133.9, 133.8, 133.5, 130.9, 129.5 (2C), 128.9 (2C), 128.7 (2C), 128.5 (2C), 124.3, 123.1, 103.9, 38.2, 25.6, 21.7, 21.6, 19.5, 15.2, 14.0. Anal. Calcd for C27H28N2O3S: C, 70.41; H, 6.13; N, 6.08; S, 6.96%. Found: C, 70.14; H, 6.15; N, 6.98; S, 6.77%. HRMS (ESI-TOF): found 461,1899. Calcd. for [C27H28N2O3S+H]+ 461,1900.
(E)-1-Phenyl-2-(5-phenyl-1H-pyrrolo[1,2-c]imidazol-1-ylidene)-3-tosylpropan-1-one (3d).
Yield 149 mg (32%). Yellow crystals, mp 165–167 °C. IR (KBr, cm−1): 3134, 3061 (=CH), 2923, 2853 (CH), 1688 (CO), 1596, 1455 (C=C), 1318, 1145 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.91 (s, 1H, H-3, pyrroloimidazole), 8.17–8.15 (m, 2H, Ph), 7.90–7.88 (m, 2H, Ph), 7.68–7.64 (m, 1H, Ph), 7.58–7.55 (m, 2H, Ph), 7.49–7.48 (m, 4H, Ph), 7.43–7.39 (m, 1H, Ph), 7.29–7.27 (m, 2H, Ph), 6.98 (d, J = 3.7 Hz, 1H, H-6, pyrroloimidazole), 6.76 (d, J = 3.7 Hz, 1H, H-7, pyrroloimidazole), 5.20 (s, 2H, CH2), 2.39 (s, 3H, CH3). 13C NMR (100.61 MHz, CDCl3): δ 195.4, 144.4, 138.3, 137.6, 136.9, 135.1, 133.7, 132.8, 130.1, 129.5 (2C), 129.4 (2C), 129.0 (2C), 128.9 (2C), 128.8, 128.6 (3C), 128.5 (2C), 124.2, 118.2, 105.2, 38.1, 21.8. Anal. Calcd for C28H22N2O3S: C, 72.08; H, 4.75; N, 6.00; S, 6.87%. Found: C, 72.24; H, 4.94; N, 6.15; S, 6.74%. HRMS (ESI-TOF): found 467,1429. Calcd. for [C28H22N2O3S+H]+ 467,1435.
(E)-1-(Furan-2-yl)-2-(5-phenyl-1H-pyrrolo[1,2-c]imidazol-1-ylidene)-3-tosylpropan-1-one (3e).
Yield 160 mg (35%). Yellow crystals, mp 183–185 °C. IR (KBr, cm−1): 3133, 3063 (=CH), 2924 (CH), 1680 (CO), 1596, 1589, 1537 (C=C), 1317, 1145 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.90 (s, 1H, H-3, pyrroloimidazole), 7.95–7.93 (m, 2H, Ph), 7.70–7.69 (m, 1H, H-5, furan), 7.52–7.48 (m, 4H, Ph), 7.42–7.41 (m, 2H, p-Ph, H-3, furan), 7.31–7.29 (m, 2H, Ph), 6.99 (d, J = 4.1 Hz, 1H, H-6, pyrroloimidazole), 6.82 (d, J = 4.1 Hz, 1H, H-7, pyrroloimidazole), 6.64 (dd, J = 3.6, 1.7 Hz, 1H, H-4, furan), 5.09 (s, 2H, CH2), 2.40 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 184.0, 152.2, 146.6, 144.2, 138.3, 137.4, 134.9, 132.5, 129.8, 129.3 (2C), 129.2 (2C), 128.8 (2C), 128.7, 128.6, 128.4 (2C), 123.0, 118.0, 117.6, 112.5, 105.1, 37.5, 21.6. Anal. Calcd for C26H20N2O4S: C, 68.04; H, 4.42; N, 6.14; S, 7.02%. Found: C, 68.54; H, 4.56; N, 6.27; S, 6.88%. HRMS (ESI-TOF): found 457,1222. Calcd. for [C26H20N2O4S+H]+ 457,1229.
(E)-2-(5-Phenyl-1H-pyrrolo[1,2-c]imidazol-1-ylidene)-1-(thiophen-2-yl)-3-tosylpropan-1-one (3f).
Yield 175 mg (37%). Yellow crystals, mp 155–157 °C. IR (KBr, cm−1): 3120, 3097 (=CH), 2861 (CH), 1663 (CO), 1595, 1518, 1494 (C=C), 1318, 1122 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.87 (s, 1H, H-3, pyrroloimidazole), 7.99–7.98 (m, 1H, H-5, thiophene), 7.90–7.87 (m, 2H, Ph), 7.70–7.68 (m, 1H, H-3, thiophene), 7.45–7.40 (m, 4H, Ph), 7.39–7.34 (m, 1H, Ph), 7.27–7.25 (m, 2H, Ph), 7.21-.7.18 (m, 1H, H-3, thiophene), 6.94–6.93 (m, 1H, H-6, pyrroloimidazole), 6.78–6.77 (m, 1H, H-7, pyrroloimidazole), 5.12 (s, 2H, CH2), 2.35 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 187.9, 144.4, 143.5, 138.3, 137.5, 135.1, 134.2, 132.8, 132.6, 129.9, 129.5 (2C), 129.4 (2C), 128.9, 128.8 (2C), 128.6, 128.5 (2C), 128.4, 123.4, 118.2, 105.4, 38.4, 21.7. Anal. Calcd for C26H20N2O3S2: C, 66.08; H, 4.27; N, 5.93; S, 13.57%. Found: C, 65.91; H, 4.05; N, 6.11; S, 13.39%. HRMS (ESI-TOF): found 473,0994. Calcd. for [C26H20N2O3S2+H]+ 473,0995.
(E)-2-(5-(4-(Dimethylamino)phenyl)-1H-pyrrolo[1,2-c]imidazol-1-ylidene)-1-phenyl-3-tosylpropan-1-one (3g).
Yield 143 mg (28%). Yellow crystals, mp 108–110 °C. IR (KBr, cm−1): 3018 (=CH), 2924 (CH), 1688 (CO), 1612, 1597 (C=C), 1318, 1145 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.89 (s, 1H, H-3, pyrroloimidazole), 8.17–8.15 (m, 2H, Ph), 7.90–7.88 (m, 2H, Ph), 7.67–7.62 (m, 1H, Ph), 7.57–7.54 (m, 2H, Ph), 7.35–7.33 (m, 2H, Ph), 7.28–7.26 (m, 2H, Ph), 6.87 (d, J = 3.9 Hz, 1H, H-6, pyrroloimidazole), 6.79–6.77 (m, 2H, Ph), 6.73 (d, J = 3.9 Hz, 1H, H-7, pyrroloimidazole), 5.18 (s, 2H, CH2), 3.02 (s, 6H, N(CH3)2), 2.39 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 195.5, 150.6, 144.2, 137.8, 137.4, 136.9, 135.3, 133.6, 132.0, 130.5, 129.8, 129.6 (3C), 129.5 (2C), 128.9 (2C), 128.8 (2C), 128.5 (3C), 124.2, 117.3, 112.6, 105.1, 38.1 (2C), 21.8. Anal. Calcd for C30H27N3O3S: C, 70.71; H, 5.34; N, 8.25; S, 6.29%. Found: C, 70.85; H, 5.53; N, 8.39; S, 6.12%. HRMS (ESI-TOF): found 510,1851. Calcd. for [C30H27N3O3S+H]+ 510,1856.
(E)-2-(5-(4-Fluorophenyl)-1H-pyrrolo[1,2-c]imidazol-1-ylidene)-1-phenyl-3-tosylpropan-1-one (3h).
Yield 184 mg (38%). Yellow crystals, mp 95–97 °C. IR (KBr, cm−1): 3131, 3063 (=CH), 2923 (CH), 1689 (CO), 1596, 1539, 1510, 1493 (C=C), 1316, 1146 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.81 (s, 1H, H-3, pyrroloimidazole), 8.16–8,14 (m, 2H, Ph), 7.90–7.88 (m, 2H, Ph), 7.67–7.63 (m, 1H, Ph), 7.58–7.54 (m, 2H, Ph), 7.47–7.44 (m, 2H, Ph), 7.29–7.27 (m, 2H, Ph), 7.20–7.16 (m, 2H, Ph), 6.93 (d, J = 4.0 Hz, 1H, H-6, pyrroloimidazole), 6.75 (d, J = 4.0 Hz, 1H, H-7, pyrroloimidazole), 5.20 (s, 2H, CH2), 2.39 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 195.3, 162.9 (d, 1JCF = 250.5 Hz, C4, 4F-C6H4), 144.4, 138.3, 137.5, 136.8, 134.8, 133.7, 132.7, 130.6 (d, 3JCF = 8.3 Hz, C-2,6 4F-C6H4, 2C), 129.5 (2C), 129.0 (2C), 128.9 (2C), 128.5 (2C), 127.4, 126.1 (d, 4JCF = 3.3 Hz, C-1 4F-C6H4), 124.2, 118.2, 116.6 (d, 2JCF = 21.8 Hz, C-3,5 4F-C6H4, 2C), 105.1, 38.1, 21.8. Anal. Calcd for C28H21FN2O3S: C, 69.41; H, 4.37; F, 3.92; N, 5.78; S, 6.62%. Found: C, 69.52; H, 4.51; N, 5.97; S, 6.47; F, 4.04%. HRMS (ESI-TOF): found 485,1335. Calcd. for [C28H21FN2O3S+H]+ 485,1339.
(E)-2-(5-(4-Fluorophenyl)-1H-pyrrolo[1,2-c]imidazol-1-ylidene)-1-(furan-2-yl)-3-tosylpropan-1-one (3i).
Yield 157 mg (33%). Yellow crystals, mp 188–190 °C. IR (KBr, cm−1): 3131, 3056 (=CH), 2925 (CH), 1680 (CO), 1602, 1561, 1570, 1540, 1513 (C=C), 1317, 1161 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.80 (s, 1H, H-3, pyrroloimidazole), 7.93–7,91 (m, 2H, Ph), 7.68–7.67 (m, 1H, H-5, furan), 7.46–7.43 (m, 2H, H-3, furan), 7.41–7.40 (m, 1H, Ph), 7.30–7.28 (m, 2H, Ph), 7.19–7.15 (m, 2H, Ph), 6.93 (d, J = 4.0 Hz, 1H, H-6, pyrroloimidazole), 6.79 (d, J = 4.0 Hz, 1H, H-7, pyrroloimidazole), 6.63 (dd, J = 2.5, 1.4 Hz, 1H, H-4, furan), 5.08 (s, 2H, CH2), 2.39 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 184.1, 162.9 (d, 1JCF = 249.8 Hz, C4, 4F-C6H4), 152.3, 146.8, 144.4, 138.5, 137.5, 134.9, 132.6, 130.5 (d, 3JCF = 8.3 Hz, C-2,6 4F-C6H4, 2C), 129.5 (2C), 128.9 (2C), 127.4, 126.1 (d, 4JCF = 3.4 Hz, C-1 4F-C6H4), 123.2, 118.2, 117, 116.6 (d, 2JCF = 21.8 Hz, C-3,5 4F-C6H4, 2C), 112.7, 105.3, 37.6, 21.7. Anal. Calcd for C26H19FN2O4S: C, 65.81; H, 4.04; F, 4.00; N, 5.90; S, 6.76%. Found: C, 65.99; H, 4.19; N, 6.10; S, 6.60; F, 4.12%. HRMS (ESI-TOF): found 475,1128. Calcd. for [C26H19FN2O4S+H]+ 475,1128.
(E)-2-(5-(4-chlorophenyl)-1H-pyrrolo[1,2-c]imidazol-1-ylidene)-1-phenyl-3-tosylpropan-1-one (3j).
Yield 160 mg (32%). Yellow crystals, mp 135–137 °C. IR (KBr, cm−1): 3056 (=CH), 2924 (CH), 1688 (CO), 1596, 1581, 1532, 1494 (C=C), 1315, 1145 (SO2). 1H NMR (400.13 MHz, CDCl3): δ 8.84 (s, 1H, H-3, pyrroloimidazole), 8.16–8,14 (m, 2H, Ph), 7.90–7.88 (m, 2H, Ph), 7.67–7.64 (m, 1H, Ph), 7.58–7.54 (m, 2H, Ph), 7.47–7.41 (m, 4H, Ph), 7.29–7.27 (m, 2H, Ph), 6.96 (d, J = 4.1 Hz, 1H, H-6, pyrroloimidazole), 6.76 (d, J = 4.1 Hz, 1H, H-7, pyrroloimidazole), 5.20 (s, 2H, CH2), 2.39 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3): δ 194.7, 143.8, 137.9, 136.8, 136.1, 134.3, 134.2, 133.1, 132.4, 129.1 (2C), 129.0 (2C), 128.9 (2C), 128.3 (2C), 128.2 (2C), 127.9 (2C), 127.8, 126.6, 123.6, 117.7, 104.6, 37.4, 21.1. Anal. Calcd for C28H21ClN2O3S: C, 67.13; H, 4.23; Cl, 7.08; N, 5.59; S, 6.40%. Found: C, 67.25; H, 4.39; N, 5.78; S, 6.25%.

4. Conclusions

In summary, the base-catalyzed cycloaddition of readily available acylethynylpyrroles with TosMIC was studied to develop a feasible one-pot syntheses, which is pharmaceutically prospective, but still rare functionalized 2,3′-bipyrroles and previously unknown pyrrolo[1,2-c]imidazoles have exocyclic double bonds with tosyl and acyl substituents. The elaborated methods are easy to operate and demonstrate good substrate coverage. The synthesized compounds represent a promising rewarding platform for drug design and materials science.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29040885/s1. File S1: The synthesis of detailed procedures and physicochemical characterization of products: 2,3′-bipyrroles (2a–o) and pyrrolo[1,2-c]imidazoles (3a–j); 1H NMR and 13C NMR spectra of compounds 2a–o and 3a–j.

Author Contributions

Conceptualization, B.A.T.; investigation, M.D.G. and I.V.S.; writing—review and editing, L.N.S. and B.A.T.; writing—original draft preparation, L.N.S.; formal analysis, I.A.U. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the Supplementary Materials.

Acknowledgments

The authors thank the Baikal Analytical Centre of collective use and Shared Research Facilities for Physical and Chemical Ultramicroanalysis, Limnological Institute, SB RAS.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 00885 sch001
Scheme 1. Synthetic approaches toward 2,3′-bipyrroles. (a) 1,3-Dipolar cycloaddition of unsymmetrical münchnones and nitrovinylheterocycles [17]; (b) Cycloaddition of acylethynylpyrroles with diethyl aminomalonate hydrochloride [18]. Previous works.
Scheme 1. Synthetic approaches toward 2,3′-bipyrroles. (a) 1,3-Dipolar cycloaddition of unsymmetrical münchnones and nitrovinylheterocycles [17]; (b) Cycloaddition of acylethynylpyrroles with diethyl aminomalonate hydrochloride [18]. Previous works.
Molecules 29 00885 sch001
Molecules 29 00885 g001
Figure 1. Some biological active compounds containing 2,3′-bipyrroles or pyrrolo[1,2-c]imidazoles moieties [24,26,28,30,31,32].
Figure 1. Some biological active compounds containing 2,3′-bipyrroles or pyrrolo[1,2-c]imidazoles moieties [24,26,28,30,31,32].
Molecules 29 00885 g001
Molecules 29 00885 sch002
Scheme 2. Synthesis of pyrrolo[1,2-c]imidazoles from acylethynylpyrroles and 1-pyrrolines.
Scheme 2. Synthesis of pyrrolo[1,2-c]imidazoles from acylethynylpyrroles and 1-pyrrolines.
Molecules 29 00885 sch002
Molecules 29 00885 sch003
Scheme 3. The synthesis of 2,3′-bipyrroles 2a–o from 2-(acylethynyl)pyrroles 1a–o and TosMIC (scope of the reaction) a. a Reagents and conditions: acylethynylpyrrole 1a–o (1 mmol), TosMIC (2 mmol), KOH (2 mmol), THF (10 mL) and reflux, 1 h.
Scheme 3. The synthesis of 2,3′-bipyrroles 2a–o from 2-(acylethynyl)pyrroles 1a–o and TosMIC (scope of the reaction) a. a Reagents and conditions: acylethynylpyrrole 1a–o (1 mmol), TosMIC (2 mmol), KOH (2 mmol), THF (10 mL) and reflux, 1 h.
Molecules 29 00885 sch003
Molecules 29 00885 sch004
Scheme 4. The synthesis of pyrrolo[1,2-c]imidazoles 3a–j from 2-(acylethynyl)pyrroles 1a,b,d,h–n and TosMIC (scope of the reaction) a. a Reagents and conditions: acylethynylpyrrole 1a,b,d,h–n (1 mmol), TosMIC (2 mmol), t-BuONa (2 mmol), THF (10 mL) and reflux, 1 h; b The yield of the corresponding bipyrrole is presented in parentheses.
Scheme 4. The synthesis of pyrrolo[1,2-c]imidazoles 3a–j from 2-(acylethynyl)pyrroles 1a,b,d,h–n and TosMIC (scope of the reaction) a. a Reagents and conditions: acylethynylpyrrole 1a,b,d,h–n (1 mmol), TosMIC (2 mmol), t-BuONa (2 mmol), THF (10 mL) and reflux, 1 h; b The yield of the corresponding bipyrrole is presented in parentheses.
Molecules 29 00885 sch004
Molecules 29 00885 sch005
Scheme 5. Proposed route of 2,3′-bipyrroles 2 formation.
Scheme 5. Proposed route of 2,3′-bipyrroles 2 formation.
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Molecules 29 00885 sch006
Scheme 6. Proposed route of pyrrolo[1,2-c]imidazoles 3 formation.
Scheme 6. Proposed route of pyrrolo[1,2-c]imidazoles 3 formation.
Molecules 29 00885 sch006
Table 1. Effects of reaction conditions on the synthesis of 2,3′-bipyrroles 2a and pyrroloimidazole 3a from 2-benzoylethynylpyrrole 1a and TosMIC.
Table 1. Effects of reaction conditions on the synthesis of 2,3′-bipyrroles 2a and pyrroloimidazole 3a from 2-benzoylethynylpyrrole 1a and TosMIC.
Molecules 29 00885 i001
Entry aBaseTime,
h		Conversion
of 1a, %		Yield of 2a, % bYield of
3a, % b
1NEt324000
2DBU24000
3DABCO24000
4K2CO324451510
5Cs2CO31100560
6NaOH110072traces
7KOH110080traces
8 ct-BuONa11001523
9t-BuONa11002737
10 ct-BuOK17543traces
11t-BuOK110080traces
12 dNaH1901731
13 cNaH190traces39
14NaH1100traces45
15 eNaH1100traces42
a The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:2:2, 20 mL THF; b Isolated yield; c The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:1:1; d The reactions were carried out at a molar ratio of 1a:TosMIC:base = 1:1:0.5; e 1 eq. t-BuOH was added.
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Gotsko, M.D.; Saliy, I.V.; Ushakov, I.A.; Sobenina, L.N.; Trofimov, B.A. Functionalized 2,3′-Bipyrroles and Pyrrolo[1,2-c]imidazoles from Acylethynylpyrroles and Tosylmethylisocyanide. Molecules 2024, 29, 885. https://doi.org/10.3390/molecules29040885

AMA Style

Gotsko MD, Saliy IV, Ushakov IA, Sobenina LN, Trofimov BA. Functionalized 2,3′-Bipyrroles and Pyrrolo[1,2-c]imidazoles from Acylethynylpyrroles and Tosylmethylisocyanide. Molecules. 2024; 29(4):885. https://doi.org/10.3390/molecules29040885

Chicago/Turabian Style

Gotsko, Maxim D., Ivan V. Saliy, Igor A. Ushakov, Lyubov N. Sobenina, and Boris A. Trofimov. 2024. "Functionalized 2,3′-Bipyrroles and Pyrrolo[1,2-c]imidazoles from Acylethynylpyrroles and Tosylmethylisocyanide" Molecules 29, no. 4: 885. https://doi.org/10.3390/molecules29040885

APA Style

Gotsko, M. D., Saliy, I. V., Ushakov, I. A., Sobenina, L. N., & Trofimov, B. A. (2024). Functionalized 2,3′-Bipyrroles and Pyrrolo[1,2-c]imidazoles from Acylethynylpyrroles and Tosylmethylisocyanide. Molecules, 29(4), 885. https://doi.org/10.3390/molecules29040885

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