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

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.

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.
We have paid a ention 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-1,2dihydropyridine-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 sp 3 -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. 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.
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-1,2dihydropyridine-4-carboxylates in the reaction of 3,3-diaminoacrylonitriles with diethyl 1,2-acetylenedicarboxylate (Scheme 1, Path C). Here, we present the formation of NHand 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 3,3diaminoacrylonitriles 3 with 1,2-dibenzoylacetylene (2) leading to novel pyrrole derivatives 5, bearing an exocyclic C=C bond and an sp 3 -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.
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, 1 H and 13 C 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. 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 1 H 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-2oxopyrrolidenes 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, 1 H and 13 C 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 R 3 = H) or 1-substituted pyrrole 5 (in the case when R 3 ≠ 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.

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 Nsubstituted 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, 1 H and 13 C 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 sp 3 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. 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.

Synthesis of 5-Hydroxypyrroles
Similar to the reaction of DMAD (1), the reaction of 3,3-diaminoacrylonitriles 3 with 1,2dibenzoylacetylene (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, 1 H and 13 C 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 sp 3 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.
3.1.2. 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.

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 ( 1 H NMR) and 100 MHz ( 13 C NMR) in CDCl 3 and DMSO-d 6  . 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.
3.1.2. 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.