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Article

Synthesis of Non-Aromatic Pyrroles Based on the Reaction of Carbonyl Derivatives of Acetylene with 3,3-Diaminoacrylonitriles

by
Pavel S. Silaichev
1,2,
Lidia N. Dianova
1,
Tetyana V. Beryozkina
1,
Vera S. Berseneva
1,
Andrey N. Maslivets
2 and
Vasiliy A. Bakulev
1,*
1
Technology of Organic Synthesis Department, Ural Federal University Named after the First President of Russia B. N. Yeltsin, 19 Mira Street, Yekaterinburg 620002, Russia
2
Department of Chemistry, Perm State University, 15 Bukireva Street, Perm 614990, Russia
*
Author to whom correspondence should be addressed.
Molecules 2023, 28(8), 3576; https://doi.org/10.3390/molecules28083576
Submission received: 27 March 2023 / Revised: 11 April 2023 / Accepted: 17 April 2023 / Published: 19 April 2023
(This article belongs to the Special Issue Novelties in N-Heterocycles Chemistry: From Synthesis to Application)
Browse Figures
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Abstract

:
The reaction of 3,3-diaminoacrylonitriles with DMAD and 1,2-dibenzoylacetylene was studied. It is shown that the direction of the reaction depends on the structure both of acetylene and of diaminoacrylonitrile. In the reaction of DMAD with acrylonitriles bearing a monosubstituted amidine group, 1-substituted 5-amino-2-oxo-pyrrole-3(2H)ylidenes are formed. On the other hand, a similar reaction of acrylonitriles containing the N,N-dialkylamidine group affords 1-NH-5-aminopyrroles. In both cases, pyrroles containing two exocyclic double bonds are formed in high yields. A radically different type of pyrroles containing one exocyclic C=C bond and sp3 hybrid carbon in the cycle is formed in reactions of 3,3-diaminoacrylonitriles with 1,2-diaroylacetylenes. As in reactions with DMAD, the interaction of 3,3-diaminoacrylonitriles with 1,2-dibenzoylacetylene can lead, depending on the structure of the amidine fragment, both to NH- and 1-substituted pyrroles. The formation of the obtained pyrrole derivatives is explained by the proposed mechanisms of the studied reactions.

1. Introduction

Esters of acetylenedicarboxylic acid, mostly dimethyl acetylenedicarboxylate (DMAD) (1), bearing highly electrophylic triple bond show a broad range of reactivity and are widely used in organic synthesis [1,2,3]. They serve as a two-electron component in formal [2+2]-cycloaddition to arylphosphine oxide to generate four-membered oxaphoshetene [1,2,3]. They can also react with azirines and aziridines as sources of azomethyne ylides to form 4-acylpyrroles [2]. 1,3-Dipolar cycloaddition of DMAD (1) to 1,3-dipoles such as azides [2], diazoalkanes [1], nitrile oxides [4], and azomethine ylides [5] affords 1,2,3-triazoles [2], pyrazoles [2], isoxazoles [4,5] and pyrroles [6,7,8]. They can be used in Diels–Alder reactions [9,10] and in reaction with thiolates [11], giving rise to 1:1 adducts and undergoing [8+2]-cycloaddition to form furanophane derivatives [12]. Therefore, DMAD (1) can also be involved in a three-component reaction with isocyanides and nucleophilic reagents [13,14,15] to furnish (a) a variety of acyclic and heterocyclic compounds, (b) hybrids of furans with quinolones, and (c) bis(4H-chromene)-3,4-dicarboxylate derivatives [15].
In 1998 we discovered that malonothioamides could react with DMAD (1) to form 2-oxoethylidene-4-oxothiazolidin-5-ylidenes (Scheme 1, path A) [16]. This reaction was also used to prepare various derivatives of 4-oxothiazolidin-5-ylidenes [1,2,3].
We have paid attention to the data of Taran and colleagues [17], who developed a method for the synthesis of 4-arylidene-5-imidazolones based on phosphine-catalyzed tandem umpolung addition and intramolecular cyclization of amidine pronucleophiles with arylpropiolates. Our earlier study of malonothioamides reaction with DMAD (1) [16] and the paper of Taran [17] inspired an idea to study the reaction of 3,3-diaminoacrylonitriles 3 with DMAD (1) and dibenzoylacetylene (2) (Scheme 1, Paths D, E).
Cocco and colleagues [18] have reported the formation of ethyl 5-cyano-2-oxo-1,2-dihydropyridine-4-carboxylates in the reaction of 3,3-diaminoacrylonitriles with diethyl 1,2-acetylenedicarboxylate (Scheme 1, Path C). Here, we present the formation of NH- and 1-substituted pyrrol-3(2)-ylidenes 4 in a similar reaction with DMAD (1) (Scheme 1, Path D). The present paper also contains the data on our study of the reaction of 3,3-diaminoacrylonitriles 3 with 1,2-dibenzoylacetylene (2) leading to novel pyrrole derivatives 5, bearing an exocyclic C=C bond and an sp3-hybride carbon atom (Scheme 1, Path E). It is worth noting that in the reactions in Scheme 1 (Paths A, B), two heteroatoms (S,N or N,N) of the starting compounds are involved in the structure of products, while in reactions in Paths C, D, E (Scheme 1), only one heteroatom of a reagent is incorporated in the product.

2. Results and Discussions

2.1. Reactions of DMAD (1) and 1,2-Dibenzoylacetylene (2) with 3,3-Diaminoacrylonitriles 3

2.1.1. Synthesis of 2-oxo-1H-pyrrol-3(2H)-ylidenes

To study the reactions of DMAD (1) and 1,2-dibenzoylacetylene (2) with 3,3-diaminoacrylonitriles (2-cyanoacetamidines, 3), the following starting reagents were used (Figure 1).
It is worth mentioning that Cocco and colleagues have already studied the reaction of 3,3-diaminoacrylonitriles with diethyl 1,2-acetylenedicarboxylates in ethanol and, based on IR and 1H NMR spectra, proposed the formation of 2(1H)-pyridones [18] (Scheme 1, Path C). We have found that DMAD (1) smoothly reacts with 3,3-diaminoacrylonitriles 3a m in DCM at room temperature to form sole products 4a–g or 5a–f at a 71–98% yield (Scheme 2).
We have shown the formation of NH-pyrroles 4a–g in the reaction of DMAD (1) with N,N-disubstituted 3,3-diaminoacrylonitriles 3a–f. On the other hand, in the reaction of compounds 3g–k,m bearing monosubstituted amidine group 1-substituted 5-amino-2-oxopyrrolidenes 5a–f are formed. Interestingly, the reaction of acrylonitrile 3l with DMAD affords 5-cyclohexylamino-NH-pyrrole 4g instead of 1-cyclohexylpyrrole 5g proposed [18]. Probably, the initially formed pyrrole 5g bearing bulky substituent in position 1 of the ring undergoes the Dimroth rearrangement to form NH-pyrrole 4g. It should be noted that the data of IR, 1H and 13C NMR spectra, including 2D NMR spectra obtained for compounds 4b and 5a, are in agreement with the structures of 2H(1H)-pyridones [18]. The final decision in favor of the pyrrole structure came from X-ray data analysis for compound 4e (Scheme 2). These data are in agreement with the formation of a rather 2-oxo-1H-pyrrol-3(2H)-ylidene acetate structure than of pyridine-2-one ring in this reaction [18]. Thus, we have first demonstrated the formation of 1H-pyrrol-3(2H)-ylidenes 4 and 5 bearing various primary and secondary amino groups and a variety of substituents (H, alkyl) in position 1 of the ring in the reaction of DMAD (1) with 3,3-diaminoacrylonitriles 3a–m.
Scheme 3 illustrates the plausible mechanism for the formation of pyrroles 4 and 5 in the reaction of 3,3-diaminoacrylonitriles 3 with DMAD (1).
It is reasonable to assume that the initial addition of a highly electrophilic alkyne group of DMAD (1) to position 2 of 2-cyanoacetamidine A results in the formation of intermediate B. The nucleophilicity of A is increased by the tert-amino effect of the amino group (Scheme 3). Then, the rotation around the single bond in the intermediate occurs. It is followed by an H-shift in C, generating key intermediate D. Interaction of ester and amino groups finalizes the process of formation of either NH-pyrrole 4 (when R3 = H) or 1-substituted pyrrole 5 (in the case when R3 ≠ H).
Pyrroles are important scaffolds due to their presence in various biologically active naturally occurring compounds (porphyrin, hemoglobin, chlorophyll, Vitamin B12). These compounds exhibit anti-inflammatory, antioxidant, and anticancer activities [19]. With the purpose of expanding the scope of pyrrole derivatives prepared from 3,3-diaminoacrylonitriles 3, we have also carried out a detailed study of the reactions of 3,3-diaminoacrylonitriles 3a–g, k, l with 1,2-dibenzoylacetylene (2). To the best of our knowledge, the reaction of 3,3-diaminoacrylonitriles 3 with 1,2-dibenzoylacetylene (2) was not studied so far.

2.1.2. Synthesis of 5-Hydroxypyrroles

Similar to the reaction of DMAD (1), the reaction of 3,3-diaminoacrylonitriles 3 with 1,2-dibenzoylacetylene (2) in DCM leads to the formation of two types of products (depending on the structure of amidine group), 1-nonsubstituted NH-pyrroles 6a–g or N-substituted pyrroles 7a,b in 83–98 and in 76–92% yield, respectively (Scheme 4). The structure of the prepared compounds is in good agreement with IR, 1H and 13C NMR spectra, including the data of HSQC and HMBC NMR spectra of compound 6b (Figures S37 and S38) and with the data of high-resolution mass spectrometry (HRMS). The final proof of the structure of compounds 6 and 7 came from X-ray data analysis for compounds 6e and 7a (Scheme 4). Thus, we have elaborated on an effective novel method of the synthesis of nonaromatic pyrroles bearing C=C bond and sp3 hybrid carbon atom in the ring.
The mechanism of formation of pyrroles 6 and 7 (Scheme 5) is similar to that of pyrroles 4 and 5 (Scheme 2). The first C–C bond in both compounds 6 and 7 is formed similarly to the formation of compounds 3 and 4 via the interaction of a negatively charged carbon atom of intermediate A with a triple bond of dibenzoylacetylene (2). The N–C bond of pyrroles 6 and 7 is formed via the addition of an amino group to the C=O bond in intermediate D. It is different from the mechanism depictured in Scheme 2, where the N–C bond is formed via the interaction of ester and amino groups.

3. Materials and Methods

All chemicals were purchased from commercial sources and were used without further purification. Analytical thin-layer chromatography was performed on aluminium foil plates Sorbfil UV-254 coated with 0.2 mm silica gel and visualized with UV-lamp 254 nm in an EtOAc/petroleum ether (PE) system (3:1, 2:1 or 1:2). Melting points were determined on a melting point apparatus Stuart SMP10 (Staffordshire, ST15 OSA, UK) and are uncorrected. All NMR spectra were recorded with a Bruker Avance II (Karlsruhe, Germany) spectrometer at 400 MHz, 600 MHz (1H NMR) and 100 MHz (13C NMR) in CDCl3 and DMSO-d6. The chemical shifts are given in ppm relative to the resonance of the solvents [1H: δ (CHCl3) = 7.26, 13C: δ (CDCl3) = 77.16 ppm; 1H: δ (DMSO-d5) = 2.50, 13C: δ (DMSO-d6) = 39.52 ppm]. Multiplicities were given as: s (singlet); br. s (broad singlet); d (doublet); t (triplet); dd (double of doublet); m (multiplet). Coupling constants are reported as J value in Hz. The minor isomer signal is highlighted with an asterisk (*). High-resolution mass spectra (HRMS) were recorded using ultrahigh resolution quadrupole time-of-flight mass spectrometer Bruker maXis impact HD (Billerica, MA, USA) with the electrospray ionization probe coupled with Agilent 1260 HPLC system. The Fourier-transform infrared (FT-IR) spectra were obtained using a Bruker Alpha (ATR, ZnSe) spectrometer (Ettlingen, Germany) in the 4000–500 cm–1 region.

3.1. Synthesis

3.1.1. Preparation of 3,3-Diaminoacrylonitriles 3

3,3-Diaminoacrylonitriles 3a–f, h, l were synthesized from ethyl 2-cyanoacetimidate and corresponding amines according to the literature procedures [20,21,22,23]; the compounds 3g, i–k, m are commercially available.

3.1.2. Synthesis of Pyrroles 4a–g, 5a–f. General Procedure

DMAD (1) (0.5 mmol, 71 mg) was added to the solution of corresponding 3,3-diaminoacrylonitryle 3 (0.5 mmol) in DCM (2 mL) at room temperature. The reaction mixture was stirred for 30 min at room temperature, then PE (10 mL) was added, and the resulting solution was stirred for 5 min more. The formed precipitate was filtered off, washed with DCM/PE (1:5) and dried.
Methyl (E)-2-(4-cyano-5-(dimethylamino)-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (4a). Compound 4a was obtained at a 98% yield (109 mg), according to the general procedure (amidine 3a: 56 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 241–243 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.29 (s, 6H), 3.64 (s, 3H), 5.71 (s, 1H), 11.27 (br. s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 40.7, 50.4, 60.7, 102.4, 117.4, 139.1, 161.5, 165.8, 168.3. IR (ATR, ZnSe, cm−1): ν, 3131, 3057, 2776, 2202, 1744, 1696, 1637, 1596, 1449, 1395, 1352, 1297, 1154, 1137, 1011. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C10H12N3O3 222.0873; Found: 222.0880.
Methyl (E)-2-(4-cyano-2-oxo-5-(pyrrolidin-1-yl)-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (4b). Compound 4b was obtained at a 79% yield (97 mg), according to the general procedure (amidine 3b: 69 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 254–255 °C. 1H NMR (400 MHz, DMSO-d6): δ 1.91–1.98 (m, 4H), 3.57 (br. s, 2H), 3.63 (s, 3H), 3.88 (br. s, 2H), 5.66 (s, 1H), 11.32 (br. s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 24.0, 25.2, 49.2, 50.4, 50.9, 60.9, 101.7, 117.5, 139.0, 158.8, 166.0, 168.5. IR (ATR, ZnSe, cm−1): ν, 3131, 3057, 2776, 2202, 1744, 1696, 1637, 1596, 1449, 1395, 1352, 1297, 1154, 1137, 1011. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C12H14N3O3 248.1030; Found: 248.1028.
Methyl (E)-2-(4-cyano-2-oxo-5-(piperidin-1-yl)-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (4c). Compound 4c was obtained at a 97% yield (128 mg), according to the general procedure (amidine 3c: 76 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 216–218 °C. 1H NMR (400 MHz, DMSO-d6): δ 1.66 (br. s, 6H), 3.64 (s, 3H), 3.76 (br. s, 4H), 5.71 (s, 1H), 11.34 (br. s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 23.1, 25.7, 49.4, 50.5, 60.7, 102.4, 117.2, 139.3, 160.2, 165.8, 168.4. IR (ATR, ZnSe, cm−1): ν, 3271, 3062, 2929, 2854, 2196, 1744, 1694, 1634, 1589, 1558, 1447, 1368, 1256, 1151, 1020. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C13H16N3O3 262.1186; Found: 262.1188.
Methyl (E)-2-(5-(4-benzylpiperidin-1-yl)-4-cyano-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (4d). Compound 4d was obtained at an 83% yield (146 mg), according to the general procedure (amidine 3d: 121 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 232–234 °C. 1H NMR (400 MHz, DMSO-d6): δ 1.27–1.37 (m, 2H), 1.70–1.73 (m, 2H), 1.86–1.97 (m, 1H), 2.53 (d, J = 8 Hz, 2H), 3.22–3.25 (m, 2H), 3.64 (s, 3H), 4.26 (br. s, 2H), 5.73 (s, 1H), 7.17–7.21 (m, 3H), 7.27–7.31 (m, 2H), 11.29 (br. s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 31.5, 36.2, 41.4, 48.4, 50.4, 60.8, 102.7, 117.0, 125.9, 128.1, 128.9, 139.1, 139.6, 160.2, 165.7, 168.3. IR (ATR, ZnSe, cm−1): ν 3149, 3083, 2918, 2200, 1718, 1688, 1627, 1597, 1493, 1452, 1375, 1281, 1185, 1153, 1111, 1091, 1072, 1040. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C20H21N3NaO3 374.1475; Found: 374.1472.
Methyl (E)-2-(5-(azepan-1-yl)-4-cyano-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (4e). Compound 4e was obtained at an 82% yield (113 mg), according to the general procedure (amidine 3e: 83 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 235–236 °C. 1H NMR (400 MHz, DMSO-d6): δ 1.55 (br. s, 4H), 1.64–1.80 (m, 4H), 3.64 (s, 3H), 3.68–3.95 (m, 4H), 5.72 (s, 1H), 11.25 (br. s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 25.7, 27.7, 50.4, 51.2, 60.1, 102.6, 117.1, 138.9, 160.4, 165.8, 168.3. IR (ATR, ZnSe, cm−1): ν 3159, 3089, 2923, 2857, 2184, 1725, 1688, 1631, 1585, 1451, 1403, 1355, 1261, 1158, 1097, 1045. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C14H18N3O3 276.1343; Found: 276.1347.
Methyl (E)-2-(4-cyano-5-morpholino-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (4f). Compound 4f was obtained at a 76% yield (100 mg), according to the general procedure (amidine 3f: 77 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 235–237 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.65 (s, 3H), 3.73–3.75 (m, 4H), 3.78–3.80 (m, 4H), 5.78 (s, 1H); 11.35 (br. s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 48.3, 50.5, 61.0, 65.5, 103.6, 117.0, 138.8, 160.8, 165.7, 168.1. IR (ATR, ZnSe, cm−1): ν 3184, 2981, 2875, 2187, 1755, 1713, 1700, 1575, 1461, 1432, 1357, 1297, 1266, 1202, 1145, 1114, 1066, 1002. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C12H13N3NaO4 286.0798; Found: 286.0800.
Methyl (E)-2-(4-cyano-5-(cyclohexylamino)-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (4g). Compound 4g was obtained at an 89% yield (122 mg), according to the general procedure (amidine 3l: 83 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 236–237 °C. 1H NMR (400 MHz, DMSO-d6): δ 1.04–1.11 (m, 1H), 1.21–1.31 (m, 2H), 1.41–1.49 (m, 2H), 1.57–1.60 (m, 1H), 1.70–1.82 (m, 4H), 3.53 (br. s, 1H), 3.63 (s, 3H), 5.60 (s, 1H), 8.78 (br. s, 1H), 11.45 (br. s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 24.4, 24.5, 32.1, 50.2, 53.5, 60.8, 100.1, 116.0, 138.0, 161.9, 166.3, 169.1. IR (ATR, ZnSe, cm−1): ν 3210, 3139, 3026, 2951, 2937, 2859, 2199, 1731, 1705, 1650, 1598, 1517, 1452, 1439, 1398, 1357, 1334, 1306, 1272, 1258, 1192, 1171, 1150, 1123, 1077, 1053, 1044. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C14H17N3NaO3 298.1162; Found: 298.1159.
Methyl (E)-2-(5-amino-1-benzyl-4-cyano-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (5a). Compound 5a was obtained at a 72% yield (102 mg), according to the general procedure (amidine 3g: 87 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 192–193 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.66 (s, 3H), 4.88 (s, 2H), 5.76 (s, 1H), 7.18–7.28 (m, 2H), 7.30–7.37 (m, 3H), 8.97 (br. s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 42.1, 50.5, 60.5, 102.7, 115.7, 126.7, 127.5, 128.6, 135.7, 136.6, 163.7, 166.1, 167.6. IR (ATR, ZnSe, cm−1): ν 3140, 3117, 2991, 2198, 1736, 1707, 1651, 1607, 1555, 1495, 1441, 1408, 1362, 1317, 1169, 1118, 1079, 1047, 1025. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C15H13N3NaO3 306.0849; Found: 306.0847.
Methyl (E)-2-(5-amino-4-cyano-1-(2,4-difluorobenzyl)-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (5b). Compound 5b was obtained at a 98% yield (78 mg), according to the general procedure (amidine 3h: 105 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 208–210 °C. 1H NMR (600 MHz, DMSO-d6): δ 3.66/3.61* (s, 3H), 4.89/4.82* (s, 2H), 5.74/5.69* (s, 1H), 7.03–7.07 (m, 1H), 7.13–7.19 (m, 1H), 7.24–7.29 (m, 1H), 8.97 (br. s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 37.1/37.0*, 50.5, 60.7, 102.7, 104.1 (t, J = 25.7 Hz), 111.5 (dd, J = 21.2, 3.5 Hz), 115.7, 118.9 (dd, J = 14.7, 3.6 Hz), 129.3 (dd, J = 10.0, 5.6 Hz), 136.5, 159.8 (dd, J = 248.4, 12.4 Hz), 161.7 (dd, J = 246.2, 12.2 Hz), 163.6, 166.1, 167.4. IR (ATR, ZnSe, cm−1): ν 3153, 2947, 2824, 2197, 1742, 1691, 1632, 1591, 1436, 1421, 1376, 1279, 1163, 1080, 1084, 1072, 1065, 1044. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C15H12F2N3O3 320.0841; Found: 320.0843.
Methyl (E)-2-(5-amino-4-cyano-2-oxo-1-propyl-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (5c). Compound 5c was obtained at a 71% yield (83 mg), according to the general procedure (amidine 3i: 63 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 182–183 °C. 1H NMR (400 MHz, DMSO-d6): δ 0.82/0.86* (t, J = 7.2 Hz, 3H), 1.46–1.51 (m, 2H), 3.56 (t, J = 7.2 Hz, 2H), 3.65/3.63* (s, 3H), 5.72 (s, 1H), 8.82 (br. s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 10.6, 21.2/22.7*, 40.5, 50.4/50.3*, 60.1, 102.2, 115.8, 136.8, 163.9, 166.1, 167.5. IR (ATR, ZnSe, cm−1): ν 3320, 3279, 3236, 3198, 3169, 2969, 2951, 2879, 2197, 1748, 1730, 1706, 1658,1614, 1561, 1499, 1451, 1412, 1385, 1348, 1318, 1277, 1199, 1177, 1115, 1051, 1042, 1025. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C11H14N3O3 236.1030; Found: 236.1027.
Methyl (E)-2-(1-allyl-5-amino-4-cyano-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (5d). Compound 5d was obtained at a 94% yield (110 mg), according to the general procedure (amidine 3j: 62 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 176–177 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.66/3.64* (s, 3H), 4.25–4.27 (m, 2H), 5.00–5.05 (m, 1H), 5.12–5.15 (m, 1H), 5.73–5.83 (m, 2H), 8.81 (br. s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 40.9, 50.4, 60.2, 102.5, 115.7, 116.3, 131.6/133.5*, 136.6, 163.6, 166.1, 167.2. IR (ATR, ZnSe, cm−1): ν 3395, 3316, 3279, 3238, 3199, 3169, 2950, 2197, 1749, 1730, 1706, 1697, 1657, 1613, 1562, 1494, 1448, 1411, 1385, 1319, 1201, 1183, 1136, 1116, 1050. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C11H12N3O3 234.0873; Found: 234.0853.
Methyl (E)-2-(5-amino-4-cyano-2-oxo-1-(prop-2-yn-1-yl)-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (5e). Compound 5e was obtained at a 96% yield (111 mg), according to the general procedure (amidine 3k: 61 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 202–203 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.66 (s, 3H), 4.47 (d, J = 2.2 Hz, 2H), 5.76 (s, 1H), 8.97 (br. s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 28.9, 50.5, 60.7, 74.8, 77.3, 103.0, 115.4, 136.3, 162.7, 165.9, 166.7. IR (ATR, ZnSe, cm−1): ν 3382, 3301, 3281, 3238, 3205, 3175, 2950, 2201, 2193, 2129, 1753, 1704, 1665, 1618, 1563, 1498, 1450, 1427, 1408, 1385, 1323, 1305, 1197, 1182, 1167, 1137, 1089. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C11H10N3O3 232.0717; Found: 232.0710.
Methyl (E)-2-(5-amino-4-cyano-1-(2,2-dimethoxyethyl)-2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)acetate (5f). Compound 5f was obtained at a 92% yield (129 mg), according to the general procedure (amidine 3m: 86 mg, 0.5 mmol; acetylene 1: 71 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 178–179 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.29 (s, 6H), 3.65 (s, 3H), 3.76 (d, J = 5.5 Hz, 2H), 4.50 (t, J = 5.5 Hz, 1H), 5.73 (s, 1H), 8.78 (br. s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 40.9, 50.4, 54.3, 60.4, 100.7, 102.4, 115.6, 136.5, 163.9, 166.1, 167.5. IR (ATR, ZnSe, cm−1): ν 3371, 3293, 3141, 3006, 2962, 2944, 2841, 2801, 2202, 1756, 1706, 1686, 1623, 1567, 1502, 1464, 1435, 1416, 1402, 1385, 1361, 1318, 1219, 1198, 1175, 1134, 1100, 1037, 1006. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C12H16N3O5 282.1084; Found: 282.1089.

3.1.3. Synthesis of Pyrroles 6a–g, 7a,b. General Procedure

Corresponding 3,3-diaminoacrylonitryle 3 (0.5 mmol) was added to the solution of dibenzoylacetylene 2 (0.5 mmol, 117 mg) in DCM (2 mL) at room temperature. The reaction mixture was stirred for 30 min at room temperature, then ethanol (4 mL) was added, and the resulting solution was stirred for 5 min more. The formed precipitate was filtered off, washed with cold ethanol (1:5) and dried.
(Z)-2-(Dimethylamino)-5-hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (6a). Compound 6a was obtained at a 96% yield (158 mg), according to the general procedure (amidine 3a: 56 mg, 0.5 mmol; acetylene 2: 117 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 162–164 °C. 1H NMR (400 MHz, CDCl3): δ 3.26 (br. s, 6H), 5.78 (br. s, 1H), 6.65 (s, 1H), 7.26–7.36 (m, 5H), 7.41–7.45 (m, 1H), 7.59 (d, J 8.0 Hz, 2H), 7.82 (d, J 8.0 Hz, 2H), 9.24 (br. s, 1H). 13C NMR (100 MHz, CDCl3): δ 40.2, 68.4, 92.0, 101.4, 117.4, 124.9, 128.3, 128.4, 128.6, 128.8, 132.0, 139.4, 141.4, 161.9, 169.6, 188.9. IR (ATR, ZnSe, cm−1): ν 3414, 3228, 3059, 3025, 2937, 2190, 1638, 1596, 1573, 1521, 1458, 1432, 1400, 1329, 1307, 1218, 1199, 1177, 1158, 1132, 1069, 1047, 1024, 1001. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C21H20N3O2 346.1550; Found: 346.1545.
(Z)-5-Hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-2-(pyrrolidin-1-yl)-4,5-dihydro-1H-pyrrole-3-carbonitrile (6b). Compound 6b was obtained at a 97% yield (170 mg), according to the general procedure (amidine 3b: 70 mg, 0.5 mmol; acetylene 2: 117 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 205–206 °C. 1H NMR (400 MHz, CDCl3): δ 1.88–1.94 (m, 4H), 3.18 (br. s, 1H), 3.35 (br. s, 1H), 3.90 (br. s, 2H), 6.44 (s, 1H), 6.51 (s, 1H), 7.19–7.27 (m, 5H), 7.34 (t, 1H, J = 7.2 Hz), 7.50 (d, 2H, J = 6.7 Hz), 7.71 (d, 2H, J = 7.4 Hz), 8.45 (br. s, 1H). 13C NMR (100 MHz, CDCl3): δ 24.8, 25.9, 49.2, 68.9, 92.4, 100.3, 117.4, 125.1, 128.2, 128.3, 128.4, 128.5, 131.8, 139.6, 141.5, 159.1, 170.2, 188.3. IR (ATR, ZnSe, cm−1): ν 3419, 3268, 3216, 3171, 3057, 2991, 2960, 2881, 2200, 1639, 1594, 1568, 1524, 1490, 1451, 1432, 1386, 1355, 1325, 1301, 1244, 1230, 1214, 1194, 1180, 1156, 1137, 1111, 1084, 1072, 1065, 1048, 1025. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C23H22N3O2 372.1707; Found: 372.1704.
(Z)-5-Hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-2-(piperidin-1-yl)-4,5-dihydro-1H-pyrrole-3-carbonitrile (6c). Compound 6c was obtained at a 98% yield (180 mg), according to the general procedure (amidine 3c: 76 mg, 0.5 mmol; acetylene 2: 117 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 148–150 °C. 1H NMR (400 MHz, CDCl3): δ 1.63 (s, 6H), 3.46–3.67 (m, 4H), 6.36 (s, 1H), 6.55 (br. s, 1H), 7.19–7.28 (m, 5H), 7.35 (t, J = 7.4 Hz, 1H), 7.51 (d, J 6.8 Hz, 2H), 7.73 (d, J = 7.2 Hz, 2H,), 8.48 (br. s, 1H). 13C NMR (100 MHz, CDCl3): δ 23.7, 25.9, 49.2, 68.6, 91.9, 100.6, 117.3, 125.0, 128.3, 128.3, 128.5, 128.7, 131.9, 139.5, 141.4, 160.5, 170.3, 188.5. IR (ATR, ZnSe, cm−1): ν 3418, 3195, 3061, 3031, 2941, 2858, 2189, 1622, 1595, 1569, 1519, 1491, 1450, 1435, 1400, 1385, 1355, 1326, 1300, 1232, 1219, 1198, 1178, 1131, 1085, 1071, 1051, 1022, 1004. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C24H24N3O2 386.1863; Found: 386.1861.
(Z)-2-(4-Benzylpiperidin-1-yl)-5-hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (6d). Compound 6d was obtained at an 83% yield (198 mg), according to the general procedure (amidine 3d: 120 mg, 0.5 mmol; acetylene 2: 117 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 143–145 °C. 1H NMR (400 MHz, CDCl3): δ 1.20–1.31 (m, 2H), 1.67–1.81 (m, 3H), 2.50 (d, J = 8.0 Hz, 2H), 2.92–3.01 (m, 2H), 4.02–4.25 (m, 2H), 6.32 (br. s, 1H), 6.56 (s, 1H), 7.04 (d, J = 7.4 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 7.18–7.28 (m, 7H), 7.36 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 6.9 Hz, 2H), 7.72 (d, J = 7.4 Hz, 2H), 8.69 (br. s, 1H). 13C NMR (100 MHz, CDCl3): δ 31.9, 32.0, 37.6, 42.7, 48.4, 48.5, 68.7, 91.9, 100.8, 117.2, 125.0, 126.5, 128.28, 128.34, 128.5, 128.6, 128.7, 129.2, 132.0, 139.2, 139.4, 141.4, 160.5, 170.1, 188.6. IR (ATR, ZnSe, cm−1): ν 3417, 3169, 3060, 3025, 2919, 2851, 2191, 1623, 1596, 1571, 1517, 1491, 1451, 1429, 1401, 1384, 1326, 1299, 1223, 1198, 1178, 1156, 1085, 1069, 1051, 1025, 1001. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C31H30N3O2 476.2332; Found: 476.2332.
(Z)-2-(Azepan-1-yl)-5-hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (6e). Compound 6e was obtained at a 92% yield (174 mg), according to the general procedure (amidine 3e: 82 mg, 0.5 mmol; acetylene 2: 117 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 212–214 °C. 1H NMR (400 MHz, CDCl3): δ 1.50–1.83 (m, 8H), 3.36–3.91 (m, 4H), 6.52 (s, 1H), 6.67 (br. s, 1H), 7.17–7.29 (m, 5H), 7.34 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 8.58 (br. s, 1H). 13C NMR (100 MHz, CDCl3): δ 26.9, 29.4, 50.6, 68.5, 91.9, 100.2, 117.3, 125.0, 128.2, 128.3, 128.4, 128.6, 131.8, 139.5, 141.3, 161.0, 170.6, 188.3. IR (ATR, ZnSe, cm−1): ν 3430, 3227, 3060, 2928, 2915, 2859, 2192, 1630, 1595, 1573, 1521, 1493, 1470, 1453, 1437, 1420, 1402, 1385, 1368, 1345, 1309, 1221, 1201, 1177, 1157, 1119, 1101, 1083, 1068, 1051, 1027, 1013. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C25H26N3O2 400.2020; Found: 400.2015.
5-(Z)-5-Hydroxy-2-morpholino-4-(2-oxo-2-phenylethylidene)-5-phenyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (6f). Compound 6f was obtained at an 86% yield (158 mg), according to the general procedure (amidine 3f: 76 mg, 0.5 mmol; acetylene 2: 117 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 207–209 °C. 1H NMR (400 MHz, CDCl3): δ 3.54–3.69 (m, 8H), 6.17 (br. s, 1H), 6.60 (s, 1H), 7.19–7.29 (m, 5H), 7.37 (t, J = 7.3 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 7.6 Hz, 2H), 8.88 (br. s, 1H). 13C NMR (100 MHz, CDCl3): δ 47.5, 66.1, 68.5, 91.9, 101.9, 117.1, 125.0, 128.3, 128.4, 128.6, 128.9, 132.2, 139.2, 141.2, 161.2, 169.4, 189.0. IR (ATR, ZnSe, cm−1): ν 3414, 3196, 3058, 2965, 2922, 2893, 2856, 2191, 1621, 1594, 1569, 1518, 1491, 1454, 1429, 1384, 1353, 1332, 1306, 1288, 1267, 1224, 1201, 1172, 1158, 1115, 1085, 1070, 1048, 1033, 1022, 1002. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C23H22N3O3 388.1656; Found: 388.1654.
(Z)-2-(Cyclohexylamino)-5-hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (6g). Compound 6g was obtained at a 95% yield (190 mg), according to the general procedure (amidine 3l: 82 mg, 0.5 mmol; acetylene 2: 118 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 216–218 °C. 1H NMR (400 MHz, CDCl3): 1.11–1.344 (m, 5H), 1.59 (br. s, 1H), 1.75 (br. s, 2H), 1.91–1.99 (m, 2H), 3.27–3.42 (m, 1H), 5.60 (d, J = 8.2 Hz, 1H), 6.48 (br. s, 1H), 7.30–7.36 (m, 2H), 7.41–7.44 (m, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 10.22 (br. s, 1H). 13C NMR (100 MHz, CDCl3): 24.6, 24.7, 25.0, 33.2, 33.5, 53.4, 68.2, 93.5, 115.9, 125.2, 128.2, 128.4, 128.5, 128.9, 132.0, 139.4, 140.6, 161.1, 183.4. IR (ATR, ZnSe, cm−1): ν 3298, 3229, 3182, 2185, 1638, 1575, 1484, 1359, 1325, 1298, 1247, 1117, 1044. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C25H26N3O2 400.2020; Found: 400.2018.
(Z)-2-Amino-1-benzyl-5-hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-4,5-dihydro-1H-pyrrole-3-carbonitrile (7a). Compound 7a was obtained at a 92% yield (94 mg), according to the general procedure (amidine 3g: 43 mg, 250 µmol; acetylene 2: 59 mg, 250 µmol; DCM (1 mL)) as a yellow solid, mp 230–232 °C. 1H NMR (400 MHz, CDCl3): 4.16 (d, J = 16.6 Hz, 1H), 4.49 (d, J = 16.6 Hz, 1H), 5.11 (br. s, 1H), 6.55 (s, 1H), 7.17 (d, J = 6.6 Hz, 2H), 7.29–7.36 (m, 8H), 7.41–7.46 (m, 1H), 7.66 (d, J = 7.4 Hz, 2H), 7.81 (d, J = 7.4 Hz, 2H), 9.40 (s, 1H). IR (ATR, ZnSe, cm−1): ν 3445, 3333, 3275, 3181, 3056, 3027, 2197, 1683, 1674, 1595, 1573, 1543, 1473, 1439, 1383, 1357, 1337, 1325, 1314, 1304, 1296, 1258, 1215, 1201, 1172, 1155, 1126, 1109, 1076, 1059, 1026, 1003. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C26H22N3O2 408.1707; Found: 408.1706.
5-(Z)-2-Amino-5-hydroxy-4-(2-oxo-2-phenylethylidene)-5-phenyl-1-(prop-2-yn-1-yl)-4,5-dihydro-1H-pyrrole-3-carbonitrile (7b). Compound 7b was obtained at a 76% yield (136 mg), according to the general procedure (amidine 3k: 60 mg, 0.5 mmol; acetylene 2: 117 mg, 0.5 mmol; DCM (2 mL)) as a yellow solid, mp 187–187 °C. 1H NMR (400 MHz, CDCl3): δ 2.29 (s, 1H), 3.85 (dd, J = 18.4, 2.5 Hz, 1H), 4.02 (dd, J = 18.4, 2.5 Hz, 1H,), 6.07 (br. s, 2H), 6.52 (s, 1H), 7.30–7.41 (m, 5H), 7.41–7.45 (m, 1H), 7.59 (d, J = 7.6 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H), 9.30 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 30.4, 68.1, 74.7, 76.0, 95.5, 100.8, 116.0, 125.8 128.2, 128.3, 129.1, 132.0, 138.3, 139.4, 162.6, 167.6, 188.7. IR (ATR, ZnSe, cm−1): ν 3432, 3340, 3288, 3263, 3195, 2190, 1663, 1613, 1597, 1576, 1546, 1498, 1477, 1450, 1423, 1385, 1343, 1322, 1304, 1297, 1235, 1211, 1175, 1156, 1106, 1078, 1059, 1033, 1025, 1017, 1003. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C22H18N3O2 356.1394; Found: 356.1391.

3.2. X-ray Structure Determination

4e: Crystal Data for C14H17N3O3 (M = 275.30 g/mol): monoclinic, space group P21/c (no. 14), a = 5.5382(12) Å, b = 23.708(6) Å, c = 10.245(2) Å, β = 91.08(2)°, V = 1344.9(5) Å3, Z = 4, T = 295(2) K, μ(MoKα) = 0.71073 mm−1, Dcalc = 1.360 g/cm3, 6120 reflections measured (2.166° ≤ Θ ≤ 29.683°), 3119 unique (Rint = 0.0719, Rsigma = 0.0942), which were used in all calculations. The final R1 was 0.0823 (I > 2σ(I)), and wR2 was 0.2489 (all data).
6e: Crystal Data for C25H25N3O2 (M = 399.48 g/mol): orthorhombic, space group Pna21 (no. 33), a = 13.549(3) Å, b = 19.212(6) Å, c = 8.2516(15) Å, V = 2147.8(9) Å3, Z = 4, T = 295(2) K, μ(MoKα) = 0.71073 mm−1, Dcalc = 1.235 g/cm3, 10,842 reflections measured (2.120° ≤ Θ ≤ 29.465°), 4991 unique (Rint = 0.0390, Rsigma = 0.0564), which were used in all calculations. The final R1 was 0.0494 (I > 2σ(I)), and wR2 was 0.1232 (all data).
7a: Crystal Data for C26H21N3O2 (M = 407.46 g/mol): monoclinic, space group P21/c (no. 14), a = 13.216(4) Å, b = 9.084(3) Å, c = 18.091(4) Å, β = 91.62(2)°, V = 2170.9(10) Å3, Z = 4, T = 295(2) K, μ(MoKα) = 0.71073 mm−1, Dcalc = 1.247 g/cm3, 11,891 reflections measured (2.766° ≤ Θ ≤ 29.723°), 5137 unique (Rint = 0.0590, Rsigma = 0.0946), which were used in all calculations. The final R1 was 0.0656 (I > 2σ(I)), and wR2 was 0.1904 (all data).
The experiment was accomplished on the automated X-ray diffractometer «Xcalibur 3» with CCD detector following standard procedures (MoKα-irradiation, graphite monochromator, ω-scans with 1o step at T = 295(2) K). Empirical absorption correction was applied. The structure was solved using the intrinsic phases in the ShelXT program [24] and refined by ShelXL [25] using a full-matrix least-squared method for non-hydrogen atoms. The H-atoms were placed in the calculated positions and were refined in isotropic approximation. The solution and refinement of the structures were accomplished with the Olex program package [26].
CCDC 2254801 (4e), 2254802 (6e), and 2244496 (7a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 17 April 2023) (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).

4. Conclusions

In order to develop an efficient method for the synthesis of aromatic pyrroles, the reaction of DMAD (1) and dibenzoylacetylene (2) with 3,3-diaminoacrylonitriles 3 was studied. It was shown that the reaction between these compounds proceeds smoothly in dichloromethane with the formation of functionalized nonaromatic pyrroles containing amino, cyano and hydroxy groups, as well as exocyclic C=C and C=O bonds, in high yields.
A revision of the structure of compounds obtained by Cocco and colleagues [18] in the reaction of DMAD (1) with 3,3-diaminoacrylonitriles 3a–m was carried out, and based on 2D HMBC NMR and HRMS spectroscopy data, it was concluded that in the studied reaction rather 2-oxo-1H-pyrrol-3(2H)-ylidenes than 2(1H)-pyridones are formed.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28083576/s1, 1H, 13C NMR spectra for compounds 4a–g, 5a–f, 6a–g, 7a,b, 2D HMBS and HSQC spectra for compounds 4a, 4b, 5a and 6b (Figures S1–S50).

Author Contributions

Conceptualization, V.A.B.; methodology, P.S.S. and A.N.M.; investigation, P.S.S., L.N.D. and T.V.B. (synthesis and spectral characterization); writing—original draft preparation, P.S.S., T.V.B. and V.A.B.; writing—review and editing, T.V.B. and V.A.B.; visualization, V.S.B.; supervision, V.A.B. All authors have read and agreed to the published version of the manuscript.

Funding

The research funding from the Ministry of Science and Higher Education of the Russian Federation (Ural Federal University Program of Development within the Priority-2030 Program, grant №4.71) is gratefully acknowledged.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

The authors are grateful to the Laboratory of Integrated Research and Expert Evaluation of Organic Materials of Ural Federal University for the registration of NMR spectra of compounds and Maxim V. Dmitriev, Department of Organic Chemistry of Perm State University for the X-ray investigations.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 4a–g, 5a–f, 6a–g, 7a,b are available from the authors.

References

  1. Neochoritis, C.G.; Zarganes-Tzitzikas, T.; Stephanidou-Stephanatou, J. Dimethyl Acetylenedicarboxylate: A Versatile Tool in Organic Synthesis. Synthesis 2014, 46, 537–585. [Google Scholar] [CrossRef]
  2. Heravi, M.M.; Alishiri, T. Dimethyl Acetylenedicarboxylate as a Building Block in Heterocyclic Synthesis. Adv. Heterocycl. Chem. 2014, 113, 1–66. [Google Scholar] [CrossRef]
  3. El-Sheref, E.M.; Brown, A.B. Utility of Acetylenedicarboxylate in Organic Synthesis. J. Heterocyclic Chem. 2017, 54, 825–843. [Google Scholar] [CrossRef]
  4. Chakraborty, B.; Luitel, G.P. An Efficient Ecofriendly Protocol for the Synthesis of Novel Fluoro Isoxazoline and Isoxazolidines Using N-benzyl Fluoro Nitrone via Cycloaddition Reactions. Tetrahedron Lett. 2013, 54, 765–770. [Google Scholar] [CrossRef]
  5. Mlostoń, G.; Jasiński, M.; Heimgartner, H. Straightforward Access to (Imidazol-2-yl)acetates by Reaction of 2-Unsubstituted Imidazole 3-Oxides with Dimethyl Acetylenedicarboxylate. Eur. J. Org. Chem. 2011, 2011, 2542–2547. [Google Scholar] [CrossRef]
  6. Caira, M.R.; Georgescu, E.; Barbu, L.; Georgescu, F.; Dumitrascu, F. New tri- and tetra-Substituted Pyrroles via Quinazolinium N1-ylides. ARKIVOC 2011, 10, 44–54. [Google Scholar] [CrossRef]
  7. Shang, Y.; Zhang, M.; Yu, S.; Ju, K.; Wang, C.; He, X. New Route Synthesis of Indolizines via 1,3-Dipolar Cycloaddition of Pyridiniums and Alkynes. Tetrahedron Lett. 2009, 50, 6981–6984. [Google Scholar] [CrossRef]
  8. Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.; Saha, P.; Paira, R.; Sahu, K.B.; Paira, P.; Ghosh, S.; Sinha, C.; et al. Amberlite–IRA-402 (OH) Ion Exchange Resin Mediated Synthesis of Indolizines, Pyrrolo[1,2-a]quinolines and Isoquinolines: Antibacterial and Antifungal Evaluation of the Products. Eur. J. Med. Chem. 2011, 46, 2132–2140. [Google Scholar] [CrossRef]
  9. Fodor, L.; Csomós, P.; Bernáth, G.; Sohár, P.; Holczbauer, T.; Kálmán, A. Reactions of 1,3-Benzothiazines and 1,4-Benzothiazepines with Dimethyl Acetylenedicarboxylate. Monatsh. Chem. 2010, 141, 431–436. [Google Scholar] [CrossRef]
  10. Imrich, J.; Tomaščiková, J.; Danihel, I.; Kristian, P.; Böhm, S.; Klika, K.D. Selective Formation of 5- or 6-Membered Rings, 1,3-Thiazolidin-4-one vs. 1,3-Thiazin-4-one, from Acridine Thiosemicarbazides by the Use of Ethyne Acid Esters. Heterocycles 2010, 80, 489–503. [Google Scholar] [CrossRef]
  11. Bakulev, V.A.; Berseneva, V.S.; Belskaia, N.P.; Morzherin, Y.Y.; Zaitsev, A.; Dehaen, W.; Luyten, I.; Toppet, S. Reactions of 5-Mercaptoazoles and Pyridine-2-thiones with Acetylenic Esters. Selectivity of the Formation of Novel Fused Thiazin-4-ones and Thiazolidin-4-ones. Org. Biomol. Chem. 2003, 1, 134–139. [Google Scholar] [CrossRef]
  12. Roy, P.; Ghorai, B.K. Annulation of Furan-bridged 10-Membered Rings on N-Heterocycles through [8+2] Cycloaddition of Dienylazaisobenzofurans and Dimethyl Acetylenedicarboxylate. Tetrahedron Lett. 2011, 52, 5668–5671. [Google Scholar] [CrossRef]
  13. Deng, J.-C.; Chan, F.-W.; Kuo, C.-W.; Cheng, C.-A.; Huang, C.-Y.; Chuang, S.-C. Assembly of Dimethyl Acetylenedicarboxylate and Phosphanes with Aldehydes Leading to γ-Lactones Bearing α-Phosphorus Ylides as Wittig Reagents. Eur. J. Org. Chem. 2012, 2012, 5738–5747. [Google Scholar] [CrossRef]
  14. Nair, V.; Vinod, A.U.; Abhilash, N.; Menon, R.S.; Santhi, V.; Varma, L.R.; Viji, S.; Mathew, S.; Srinivas, R. Multicomponent Reactions Involving Zwitterionic Intermediates for the Construction of Heterocyclic Systems: One Pot Synthesis of Aminofurans and Iminolactones. Tetrahedron 2003, 59, 10279–10286. [Google Scholar] [CrossRef]
  15. Shaabani, A.; Ghadari, R.; Sarvary, A.; Rezayan, A.H. Synthesis of Highly Functionalized Bis(4H-chromene) and 4H-Benzo[g]chromene Derivatives via an Isocyanide-Based Pseudo-Five-Component Reaction. J. Org. Chem. 2009, 74, 4372–4374. [Google Scholar] [CrossRef]
  16. Berseneva, V.S.; Tkachev, A.V.; Morzherin, Y.Y.; Dehaen, W.; Luyten, I.; Toppet, S.; Bakulev, V.A. Synthesis of Novel Thiazolidin-4-ones by Reaction of Malonthioamide Derivatives with Dimethyl Acetylenedicarboxylate. J. Chem. Soc. Perkin Trans 1 1998, 2133–2136. [Google Scholar] [CrossRef]
  17. Gabillet, S.; Loreau, O.; Specklin, S.; Rasalofonjatovo, E.; Taran, F. A Phosphine-Catalyzed Preparation of 4-Arylidene-5-imidazolones. J. Org. Chem. 2014, 79, 9894–9898. [Google Scholar] [CrossRef]
  18. Cocco, M.T.; Congiu, C.; Maccioni, A.; Onnis, V. Synthesis of Some New 2(1H)-Pyridones from 3-Amino-3-(dialkylamino)propenenitriles. Synthesis 1992, 1992, 371–373. [Google Scholar] [CrossRef]
  19. Fatahala, S.S.; Shalaby, E.A.; Kassab, S.E.; Mohamed, M.S. Promising Anti-Cancer and Anti-Oxidant Agents Based on the Pyrrole and Fused Pyrrole: Synthesis, Docking Studies and Biological Evaluation. Anti-Cancer Agents Med. Chem. 2015, 15, 523–532. [Google Scholar] [CrossRef]
  20. Cocco, M.T.; Congiu, C.; Onnis, V.; Maccioni, A. Synthesis of 2-Amino-5-pyrimidinecarbonitrile Derivatives. Synthesis 1991, 1991, 529–530. [Google Scholar] [CrossRef]
  21. Shafran, Y.M.; Silaichev, P.S.; Bakulev, V.A. β-(Cycloalkylamino)ethanesulfonyl Azides as Novel Water-soluble Reagents for the Synthesis of Diazo Compounds and Heterocycles. Chem. Heterocycl. Compds. 2019, 12, 1251–1261. [Google Scholar] [CrossRef]
  22. Silaichev, P.S.; Beryozkina, T.V.; Novikov, M.S.; Dehaen, W.; Bakulev, V.A. A Base-Controlled Reaction of 2-Cyanoacetamidines (3,3-Diaminoacrylonitriles) with Sulfonyl Azides as a Route to Nonaromatic 4-Methylene-1,2,3-triazole-5-imines. Eur. J. Org. Chem. 2020, 2020, 3688–3698. [Google Scholar] [CrossRef]
  23. Silaichev, P.S.; Beryozkina, T.V.; Ilkin, V.G.; Novikov, M.S.; Dehaen, W.; Bakulev, V.A. Tandem Cycloaddition of Azides to 3,3-Diaminoacrylonitriles (2-Cyanoacetamidines) and Cornforth Type Rearrangement as an Approach to 5-Amino-1,2,3-triazole-4-N-substituted Imidamides. J. Org. Chem. 2023. accepted to publication. [Google Scholar]
  24. Sheldrick, G.M. SHELXT-Integrated Space-group and Crystal-structure Determination. Acta Crystallogr. 2015, 71, 3–8. [Google Scholar] [CrossRef]
  25. Sheldrick, G.M. Crystal Structure Refinement with SHELXL. Acta Crystallogr. C Struct. Chem. 2015, 71, 3–8. [Google Scholar] [CrossRef]
  26. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J. Appl. Cryst. 2009, 42, 339–341. [Google Scholar] [CrossRef]
Molecules 28 03576 sch001 550
Scheme 1. Reaction of Carbonyl Derivatives of Acetylene with Thiocarbamoyl- and Amidine-Containing Compounds. See references [16] for path A, [17] for B and [18] for C.
Scheme 1. Reaction of Carbonyl Derivatives of Acetylene with Thiocarbamoyl- and Amidine-Containing Compounds. See references [16] for path A, [17] for B and [18] for C.
Molecules 28 03576 sch001
Molecules 28 03576 g001 550
Figure 1. Structures of Starting Materials 3.
Figure 1. Structures of Starting Materials 3.
Molecules 28 03576 g001
Molecules 28 03576 sch002 550
Scheme 2. Reaction of DMAD (1) with 3,3-Diaminoacrylonitriles 3a–m. Substrate Scope of 3,3-Diaminoacrylonitriles 3. Conditions: 1 (0.5 mmol), 3 (0.5 mmol), CH2Cl2 (2 mL), rt, 30 min.
Scheme 2. Reaction of DMAD (1) with 3,3-Diaminoacrylonitriles 3a–m. Substrate Scope of 3,3-Diaminoacrylonitriles 3. Conditions: 1 (0.5 mmol), 3 (0.5 mmol), CH2Cl2 (2 mL), rt, 30 min.
Molecules 28 03576 sch002
Molecules 28 03576 sch003 550
Scheme 3. Plausible Mechanism for the Formation of 1-Substituted- (4) and NH-Pyrroles 5.
Scheme 3. Plausible Mechanism for the Formation of 1-Substituted- (4) and NH-Pyrroles 5.
Molecules 28 03576 sch003
Molecules 28 03576 sch004 550
Scheme 4. Reaction of Dibenzoylacetylene (2) with 3,3-Diaminoacrylonitriles 3. Substrate Scope of 3,3-Diaminoacrylonitriles 3a–g, k, l. Conditions: 2 (0.5 mmol), 3 (0.5 mmol), CH2Cl2 (2 mL), rt, 30 min.
Scheme 4. Reaction of Dibenzoylacetylene (2) with 3,3-Diaminoacrylonitriles 3. Substrate Scope of 3,3-Diaminoacrylonitriles 3a–g, k, l. Conditions: 2 (0.5 mmol), 3 (0.5 mmol), CH2Cl2 (2 mL), rt, 30 min.
Molecules 28 03576 sch004
Molecules 28 03576 sch005 550
Scheme 5. Plausible Mechanism of the Formation of 1-Substituted- (6) and NH-Pyrroles 7.
Scheme 5. Plausible Mechanism of the Formation of 1-Substituted- (6) and NH-Pyrroles 7.
Molecules 28 03576 sch005
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MDPI and ACS Style

Silaichev, P.S.; Dianova, L.N.; Beryozkina, T.V.; Berseneva, V.S.; Maslivets, A.N.; Bakulev, V.A. Synthesis of Non-Aromatic Pyrroles Based on the Reaction of Carbonyl Derivatives of Acetylene with 3,3-Diaminoacrylonitriles. Molecules 2023, 28, 3576. https://doi.org/10.3390/molecules28083576

AMA Style

Silaichev PS, Dianova LN, Beryozkina TV, Berseneva VS, Maslivets AN, Bakulev VA. Synthesis of Non-Aromatic Pyrroles Based on the Reaction of Carbonyl Derivatives of Acetylene with 3,3-Diaminoacrylonitriles. Molecules. 2023; 28(8):3576. https://doi.org/10.3390/molecules28083576

Chicago/Turabian Style

Silaichev, Pavel S., Lidia N. Dianova, Tetyana V. Beryozkina, Vera S. Berseneva, Andrey N. Maslivets, and Vasiliy A. Bakulev. 2023. "Synthesis of Non-Aromatic Pyrroles Based on the Reaction of Carbonyl Derivatives of Acetylene with 3,3-Diaminoacrylonitriles" Molecules 28, no. 8: 3576. https://doi.org/10.3390/molecules28083576

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