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

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) ų, 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) ų, 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) ų, 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: [email protected]).

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.