Substituent-Dependent Divergent Synthesis of 2-(3-Amino-2,4-dicyanophenyl)pyrroles, Pyrrolyldienols and 3-Amino-1-acylethylidene-2-cyanopyrrolizines via Reaction of Acylethynylpyrroles with Malononitrile

An efficient method for the synthesis of pharmaceutically and high-tech prospective 2-(3-amino-2,4-dicyanophenyl)pyrroles (in up to 88% yield) via the reaction of easily available substituted acylethynylpyrroles with malononitrile has been developed. The reaction proceeds in the KOH/MeCN system at 0 °C for 2 h. In the case of 2-acylethynylpyrroles without substituents in the pyrrole ring, the reaction changes direction: instead of the target 2-(3-amino-2,4-dicyanophenyl)pyrroles, the unexpected formation of pyrrolyldienols and products of their intramolecular cyclization, 3-amino-1-acylethylidene-2-cyanopyrrolizines, is observed.

The recent syntheses of arylpyrroles are based on the introduction of aryl moieties in the pyrrole ring [41][42][43][44][45][46][47] (for instance, the Suzuki-Miyaura coupling [44,47]) and construction of the pyrrole cycle from acyclic compounds with aryl substituents [48][49][50][51]. The reactions of alkylarylketoximes with acetylene [52] or its precursor, calcium carbide [50], which allow the obtainment of various 2-arylpyrroles, are considered to be of a general character. However, even these reactions do not enable the synthesis of pyrroles with some aryl substituents, (e.g., containing both amino and nitrile groups in the benzene ring, in particular, 2,6-dicyanoaniline). This is, probably, due to the inaccessibility of the starting reagents.
At the same time, the compounds containing 2,6-dicyanoaniline scaffold exhibit various biological activities [53][54][55], strong fluorescence [55][56][57][58][59] and may be used as nonlinear optical materials [55,60,61] and cell imaging agents [55,62] (Figure 1). Furthermore, they serve as building blocks for the synthesis of diverse biologically active compounds and In the light of the foregoing, the synthesis of arylpyrroles with amino and cyano substituents from readily available starting compounds is an important challenge.
Diverse methods for the preparation of 2,6-dicyanoanilines are summarized in review [55].
Diverse methods for the preparation of 2,6-dicyanoanilines are summarized in review [55].
Our attention was drawn to the methods based on the cyclization of acetylenic ketones with malononitrile, although they did not give 2,6-dicyanoanilines with heterocyclic substituents [56,63,64]. However, these methods have several shortcomings, such as low reaction selectivity or non-mild reaction conditions (reflux in toluene) and the large span of the yields (16-70%). Later [65], the conditions for the selective formation of 3,5-diaryl-2,6dicyanoanilines via the same reaction with a yield of up to 87% were found (KOH/MeCN, 40 • C, 6 h) (Scheme 1c). However, the substrate scope of this reaction is limited only to aryl and thienyl substituents. Perhaps this is due to the inaccessibility of acetylenic ketones with other substituents, such as, in particular, acylethynylpyrrolylketones.
Recently, thanks to the discovery and development of room temperature reaction of pyrroles with electrophilic haloacetylenes in the medium of solid metal oxides and salts, acetylenic ketones with pyrrole and aryl or hetaryl substituents in acyl moiety have become readily available [66][67][68][69][70] and widely used as a rewarding platform for design of polyfunctional pyrrole compounds [71,72]. Our attention was drawn to the methods based on the cyclization of acetylenic ketones with malononitrile, although they did not give 2,6-dicyanoanilines with heterocyclic substituents [56,63,64]. However, these methods have several shortcomings, such as low reaction selectivity or non-mild reaction conditions (reflux in toluene) and the large span of the yields (16-70%). Later [65], the conditions for the selective formation of 3,5-diaryl-2,6-dicyanoanilines via the same reaction with a yield of up to 87% were found (KOH/MeCN, 40 °C, 6 h) (Scheme 1c). However, the substrate scope of this reaction is limited only to aryl and thienyl substituents. Perhaps this is due to the inaccessibility of acetylenic ketones with other substituents, such as, in particular, acylethynylpyrrolylketones.
Recently, thanks to the discovery and development of room temperature reaction of pyrroles with electrophilic haloacetylenes in the medium of solid metal oxides and salts, acetylenic ketones with pyrrole and aryl or hetaryl substituents in acyl moiety have become readily available [66][67][68][69][70] and widely used as a rewarding platform for design of polyfunctional pyrrole compounds [71,72].

Results and Discussion
In the present paper, we describe the reaction of acylethynylpyrroles 1a-p, synthesized according to Scheme 2, with malononitrile 2. The study has been undertaken in order to develop an effective method for the synthesis of pyrroles with a 2,6-dicyanoaniline substituent.

Results and Discussion
In the present paper, we describe the reaction of acylethynylpyrroles 1a-p, synthesized according to Scheme 2, with malononitrile 2. The study has been undertaken in order to develop an effective method for the synthesis of pyrroles with a 2,6-dicyanoaniline substituent. According to our preliminary experiments, under the abovementioned conditions [65] (KOH/MeCN, 40 °C, 6 h), the reaction of 1-methyl-2-(benzoylethynyl)pyrrole 1a with malononitrile 2 (the ratio 1a : 2 : KOH is 1 : 2 : 2) did not afford the expected product, the process was accompanied by resinification. Therefore, in order to find suitable conditions for the construction of 1-methyl-2-(3-amino-2,4-dicyanophenyl)pyrrole 3a, we further car-Scheme 2. Synthesis of 2-acylethynylpyrroles 1a-p.
According to our preliminary experiments, under the abovementioned conditions [65] (KOH/MeCN, 40 • C, 6 h), the reaction of 1-methyl-2-(benzoylethynyl)pyrrole 1a with malononitrile 2 (the ratio 1a : 2 : KOH is 1 : 2 : 2) did not afford the expected product, the process was accompanied by resinification. Therefore, in order to find suitable conditions for the construction of 1-methyl-2-(3-amino-2,4-dicyanophenyl)pyrrole 3a, we further carried out the reaction of acylethynylpyrrole 1a with malononitrile 2 at room temperature. However, the tarring of the reaction mixture was also observed in this case. It was possible to obtain pyrrole 3a in 78% yield only at 0 • C for 2 h. It should be emphasized that the reaction is completely selective: no other products except for pyrrole 3a were found in the reaction mixture.
Since the conversion of the starting acylethynylpyrrole 1a was complete under the conditions employed, we used them for the reaction of malononitrile with other substituted acylethynylpyrroles 1b-1m. As a result, a number of previously unknown 2-(3-amino-2,4dicyanophenyl)pyrroles 3b-3m were synthesized in good to excellent yields (Table 1). According to our preliminary experiments, under the abovementioned conditions [65] (KOH/MeCN, 40 °C, 6 h), the reaction of 1-methyl-2-(benzoylethynyl)pyrrole 1a with malononitrile 2 (the ratio 1a : 2 : KOH is 1 : 2 : 2) did not afford the expected product, the process was accompanied by resinification. Therefore, in order to find suitable conditions for the construction of 1-methyl-2-(3-amino-2,4-dicyanophenyl)pyrrole 3a, we further carried out the reaction of acylethynylpyrrole 1a with malononitrile 2 at room temperature. However, the tarring of the reaction mixture was also observed in this case. It was possible to obtain pyrrole 3a in 78% yield only at 0 °C for 2 h. It should be emphasized that the reaction is completely selective: no other products except for pyrrole 3a were found in the reaction mixture.
Since the conversion of the starting acylethynylpyrrole 1a was complete under the conditions employed, we used them for the reaction of malononitrile with other substituted acylethynylpyrroles 1b-1m. As a result, a number of previously unknown 2-(3amino-2,4-dicyanophenyl)pyrroles 3b-3m were synthesized in good to excellent yields ( Table 1). - According to our preliminary experiments, under the abovementioned conditions [65] (KOH/MeCN, 40 °C, 6 h), the reaction of 1-methyl-2-(benzoylethynyl)pyrrole 1a with malononitrile 2 (the ratio 1a : 2 : KOH is 1 : 2 : 2) did not afford the expected product, the process was accompanied by resinification. Therefore, in order to find suitable conditions for the construction of 1-methyl-2-(3-amino-2,4-dicyanophenyl)pyrrole 3a, we further carried out the reaction of acylethynylpyrrole 1a with malononitrile 2 at room temperature. However, the tarring of the reaction mixture was also observed in this case. It was possible to obtain pyrrole 3a in 78% yield only at 0 °C for 2 h. It should be emphasized that the reaction is completely selective: no other products except for pyrrole 3a were found in the reaction mixture.
Since the conversion of the starting acylethynylpyrrole 1a was complete under the conditions employed, we used them for the reaction of malononitrile with other substituted acylethynylpyrroles 1b-1m. As a result, a number of previously unknown 2-(3amino-2,4-dicyanophenyl)pyrroles 3b-3m were synthesized in good to excellent yields ( Table 1). - According to our preliminary experiments, under the abovementioned conditions [65] (KOH/MeCN, 40 °C, 6 h), the reaction of 1-methyl-2-(benzoylethynyl)pyrrole 1a with malononitrile 2 (the ratio 1a : 2 : KOH is 1 : 2 : 2) did not afford the expected product, the process was accompanied by resinification. Therefore, in order to find suitable conditions for the construction of 1-methyl-2-(3-amino-2,4-dicyanophenyl)pyrrole 3a, we further carried out the reaction of acylethynylpyrrole 1a with malononitrile 2 at room temperature. However, the tarring of the reaction mixture was also observed in this case. It was possible to obtain pyrrole 3a in 78% yield only at 0 °C for 2 h. It should be emphasized that the reaction is completely selective: no other products except for pyrrole 3a were found in the reaction mixture.
Since the conversion of the starting acylethynylpyrrole 1a was complete under the conditions employed, we used them for the reaction of malononitrile with other substituted acylethynylpyrroles 1b-1m. As a result, a number of previously unknown 2-(3amino-2,4-dicyanophenyl)pyrroles 3b-3m were synthesized in good to excellent yields ( Table 1). - According to our preliminary experiments, under the abovementioned conditions [65] (KOH/MeCN, 40 °C, 6 h), the reaction of 1-methyl-2-(benzoylethynyl)pyrrole 1a with malononitrile 2 (the ratio 1a : 2 : KOH is 1 : 2 : 2) did not afford the expected product, the process was accompanied by resinification. Therefore, in order to find suitable conditions for the construction of 1-methyl-2-(3-amino-2,4-dicyanophenyl)pyrrole 3a, we further carried out the reaction of acylethynylpyrrole 1a with malononitrile 2 at room temperature. However, the tarring of the reaction mixture was also observed in this case. It was possible to obtain pyrrole 3a in 78% yield only at 0 °C for 2 h. It should be emphasized that the reaction is completely selective: no other products except for pyrrole 3a were found in the reaction mixture.
Since the conversion of the starting acylethynylpyrrole 1a was complete under the conditions employed, we used them for the reaction of malononitrile with other substituted acylethynylpyrroles 1b-1m. As a result, a number of previously unknown 2-(3amino-2,4-dicyanophenyl)pyrroles 3b-3m were synthesized in good to excellent yields ( Table 1). - According to our preliminary experiments, under the abovementioned conditions [65] (KOH/MeCN, 40 °C, 6 h), the reaction of 1-methyl-2-(benzoylethynyl)pyrrole 1a with malononitrile 2 (the ratio 1a : 2 : KOH is 1 : 2 : 2) did not afford the expected product, the process was accompanied by resinification. Therefore, in order to find suitable conditions for the construction of 1-methyl-2-(3-amino-2,4-dicyanophenyl)pyrrole 3a, we further carried out the reaction of acylethynylpyrrole 1a with malononitrile 2 at room temperature. However, the tarring of the reaction mixture was also observed in this case. It was possible to obtain pyrrole 3a in 78% yield only at 0 °C for 2 h. It should be emphasized that the reaction is completely selective: no other products except for pyrrole 3a were found in the reaction mixture.
Since the conversion of the starting acylethynylpyrrole 1a was complete under the conditions employed, we used them for the reaction of malononitrile with other substituted acylethynylpyrroles 1b-1m. As a result, a number of previously unknown 2-(3amino-2,4-dicyanophenyl)pyrroles 3b-3m were synthesized in good to excellent yields ( Table 1). - According to our preliminary experiments, under the abovementioned conditions [65] (KOH/MeCN, 40 °C, 6 h), the reaction of 1-methyl-2-(benzoylethynyl)pyrrole 1a with malononitrile 2 (the ratio 1a : 2 : KOH is 1 : 2 : 2) did not afford the expected product, the process was accompanied by resinification. Therefore, in order to find suitable conditions for the construction of 1-methyl-2-(3-amino-2,4-dicyanophenyl)pyrrole 3a, we further carried out the reaction of acylethynylpyrrole 1a with malononitrile 2 at room temperature. However, the tarring of the reaction mixture was also observed in this case. It was possible to obtain pyrrole 3a in 78% yield only at 0 °C for 2 h. It should be emphasized that the reaction is completely selective: no other products except for pyrrole 3a were found in the reaction mixture.
Since the conversion of the starting acylethynylpyrrole 1a was complete under the conditions employed, we used them for the reaction of malononitrile with other substituted acylethynylpyrroles 1b-1m. As a result, a number of previously unknown 2-(3amino-2,4-dicyanophenyl)pyrroles 3b-3m were synthesized in good to excellent yields ( Table 1). - As follows from Table 1, the reaction is equally effective for acylethynylpyrroles with alkyl and aryl substituents at carbon atoms in the pyrrole ring and also for 4,5,6,7-tetrahydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 °C, 2 h), instead of the expected 2-(3-amino-2,4-dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the case of enol 4a) or in the mixtures (in the case of enols 4b,c) with small amounts (10-14%) of their keto tautomers 5b,c (Scheme 3). As follows from Table 1, the reaction is equally effective for acylethynylpyrroles with alkyl and aryl substituents at carbon atoms in the pyrrole ring and also for 4,5,6,7-tetrahydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 °C, 2 h), instead of the expected 2-(3-amino-2,4-dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the case of enol 4a) or in the mixtures (in the case of enols 4b,c) with small amounts (10-14%) of their keto tautomers 5b,c (Scheme 3). As follows from Table 1, the reaction is equally effective for acylethynylpyrroles with alkyl and aryl substituents at carbon atoms in the pyrrole ring and also for 4,5,6,7-tetrahydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 °C, 2 h), instead of the expected 2-(3-amino-2,4-dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the case of enol 4a) or in the mixtures (in the case of enols 4b,c) with small amounts (10-14%) of their keto tautomers 5b,c (Scheme 3). As follows from Table 1, the reaction is equally effective for acylethynylpyrroles with alkyl and aryl substituents at carbon atoms in the pyrrole ring and also for 4,5,6,7-tetrahydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 °C, 2 h), instead of the expected 2-(3-amino-2,4-dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the case of enol 4a) or in the mixtures (in the case of enols 4b,c) with small amounts (10-14%) of their keto tautomers 5b,c (Scheme 3). As follows from Table 1, the reaction is equally effective for acylethynylpyrroles with alkyl and aryl substituents at carbon atoms in the pyrrole ring and also for 4,5,6,7-tetrahydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 °C, 2 h), instead of the expected 2-(3-amino-2,4-dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the case of enol 4a) or in the mixtures (in the case of enols 4b,c) with small amounts (10-14%) of their keto tautomers 5b,c (Scheme 3). As follows from Table 1, the reaction is equally effective for acylethynylpyrroles with alkyl and aryl substituents at carbon atoms in the pyrrole ring and also for 4,5,6,7-tetrahydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 °C, 2 h), instead of the expected 2-(3-amino-2,4-dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the case of enol 4a) or in the mixtures (in the case of enols 4b,c) with small amounts (10-14%) of their keto tautomers 5b,c (Scheme 3). As follows from Table 1, the reaction is equally effective for acylethynylpyrroles with alkyl and aryl substituents at carbon atoms in the pyrrole ring and also for 4,5,6,7tetrahydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 • C, 2 h), instead of the expected 2-(3-amino-2,4dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the hydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 °C, 2 h), instead of the expected 2-(3-amino-2,4-dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the case of enol 4a) or in the mixtures (in the case of enols 4b,c) with small amounts (10-14%) of their keto tautomers 5b,c (Scheme 3). It should be emphasized that, according to the 1 H NMR data, dienols 4a-c and ketones 5a-c are Z-isomers, the latter being stabilized by intramolecular hydrogen bond between the NH-proton and C = O group (δ NH-15.4 15.9 ppm).
During isolation and drying of the crude product (especially at elevated temperature), the mixture of tautomers 4b,c and 5b,c was selectively transformed to aminopyrrolizines 6b,c in 55 and 64% yields, respectively. The corresponding enol 4a turned out to be stable and was isolated in 75% yield without impurity of keto-tautomer and the corresponding pyrrolizine. Aminopyrrolizine 6a was prepared in 80% yield by refluxing enol 4a in ethanol in the presence of triethylamine (Scheme 4). The formation of aminopyrrolizines obviously °C curs as intramolecular addition of the NH pyrrole moiety to the cyano group followed by prototropic isomerization of the imino-group to NH2 substituent (Scheme 3). The formation of aminopyrrolizines is strictly It should be emphasized that, according to the 1 H NMR data, dienols 4a-c and ketones 5a-c are Z-isomers, the latter being stabilized by intramolecular hydrogen bond between the NH-proton and C = O group (δ NH-15.4 15.9 ppm).
During isolation and drying of the crude product (especially at elevated temperature), the mixture of tautomers 4b,c and 5b,c was selectively transformed to aminopyrrolizines 6b,c in 55 and 64% yields, respectively. The corresponding enol 4a turned out to be stable and was isolated in 75% yield without impurity of keto-tautomer and the corresponding pyrrolizine. Aminopyrrolizine 6a was prepared in 80% yield by refluxing enol 4a in ethanol in the presence of triethylamine (Scheme 4). hydroindole derivatives. The nature of the substituent at the acyl function (aryl or hetaryl), and at the nitrogen atom (H, methyl, benzyl or vinyl) almost does not affect the outcome of the reaction.
To our surprise, in the case of acylethynylpyrroles 1n-p with unsubstituted pyrrole ring, we encountered quite a different reaction: under the same conditions (KOH/MeCN, the ratio of 1 : 2 : base is 1 : 2 : 2, 0 °C, 2 h), instead of the expected 2-(3-amino-2,4-dicyanophenyl)pyrroles 3, the adducts of malononitrile and acylethynylpyrrole in the enol form, pyrrolyldienols 4a-c, were formed. The latter were isolated either in pure form (in the case of enol 4a) or in the mixtures (in the case of enols 4b,c) with small amounts (10-14%) of their keto tautomers 5b,c (Scheme 3). It should be emphasized that, according to the 1 H NMR data, dienols 4a-c and ketones 5a-c are Z-isomers, the latter being stabilized by intramolecular hydrogen bond between the NH-proton and C = O group (δ NH-15.4 15.9 ppm).
During isolation and drying of the crude product (especially at elevated temperature), the mixture of tautomers 4b,c and 5b,c was selectively transformed to aminopyrrolizines 6b,c in 55 and 64% yields, respectively. The corresponding enol 4a turned out to be stable and was isolated in 75% yield without impurity of keto-tautomer and the corresponding pyrrolizine. Aminopyrrolizine 6a was prepared in 80% yield by refluxing enol 4a in ethanol in the presence of triethylamine (Scheme 4). The formation of aminopyrrolizines obviously °C curs as intramolecular addition of the NH pyrrole moiety to the cyano group followed by prototropic isomerization of the imino-group to NH2 substituent (Scheme 3). The formation of aminopyrrolizines is strictly The formation of aminopyrrolizines obviously • C curs as intramolecular addition of the NH pyrrole moiety to the cyano group followed by prototropic isomerization of the imino-group to NH 2 substituent (Scheme 3). The formation of aminopyrrolizines is strictly stereoselective: the Z-isomers are formed exclusively with cis-position of the proton at the double bond and the ortho-proton of aryl group, which follows from the main NOESY ( The formation of aminopyrrolizines obviously °C curs as intramolecular addition of the NH pyrrole moiety to the cyano group followed by prototropic isomerization of the imino-group to NH2 substituent (Scheme 3). The formation of aminopyrrolizines is strictly stereoselective: the Z-isomers are formed exclusively with cis-position of the proton at the double bond and the ortho-proton of aryl group, which follows from the main NOESY ( ) and HMBC ( ) correlations in 2D NMR spectra ( Figure 2). 2M NMR spectra of aminopyrrolizine 6c confirm its the Z-form. Thus, the substituent-dependent divergent synthesis of three different products has been achieved: in the case of acylethynylpyrroles with substituents in the pyrrole ring, 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 are formed, while for substrate with unsubstituted pyrrole ring, pyrrolyldienols 4 and their keto-tautomers 5 are produced, which latter can be cyclized to aminopyrrolizines 6.
Apparently, the formation of 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 starts with proton abstraction from the CH2-group of malononitrile. The carbanion A, thus generated, adds to the triple bond of acylethynylpyrroles 1, followed by Knoevenagel condensation of the adduct B, thus formed, with second molecule of malononitrile. Otherwise, malononitrile first reacts with the carbonyl group, and its second molecule adds to the triple bond of the intermediate pyrrolylenyne D. Next, diadduct C undergoes intramolecular cyclization with the participation of carbanion E to give cyclic imine F. Hydrolysis of one of the nitrile groups followed by decarboxylation and aromatization of the intermediate G finishes the process (Scheme 5). The formation of aminopyrrolizines obviously °C curs as intramolecular addition of the NH pyrrole moiety to the cyano group followed by prototropic isomerization of the imino-group to NH2 substituent (Scheme 3). The formation of aminopyrrolizines is strictly stereoselective: the Z-isomers are formed exclusively with cis-position of the proton at the double bond and the ortho-proton of aryl group, which follows from the main NOESY ( ) and HMBC ( ) correlations in 2D NMR spectra ( Figure 2). 2M NMR spectra of aminopyrrolizine 6c confirm its the Z-form. Thus, the substituent-dependent divergent synthesis of three different products has been achieved: in the case of acylethynylpyrroles with substituents in the pyrrole ring, 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 are formed, while for substrate with unsubstituted pyrrole ring, pyrrolyldienols 4 and their keto-tautomers 5 are produced, which latter can be cyclized to aminopyrrolizines 6.
Apparently, the formation of 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 starts with proton abstraction from the CH2-group of malononitrile. The carbanion A, thus generated, adds to the triple bond of acylethynylpyrroles 1, followed by Knoevenagel condensation of the adduct B, thus formed, with second molecule of malononitrile. Otherwise, malononitrile first reacts with the carbonyl group, and its second molecule adds to the triple bond of the intermediate pyrrolylenyne D. Next, diadduct C undergoes intramolecular cyclization with the participation of carbanion E to give cyclic imine F. Hydrolysis of one of the nitrile groups followed by decarboxylation and aromatization of the intermediate G finishes the process (Scheme 5).
Molecules 2022, 27, x FOR PEER REVIEW 6 of 15 stereoselective: the Z-isomers are formed exclusively with cis-position of the proton at the double bond and the ortho-proton of aryl group, which follows from the main NOESY ( ) and HMBC ( ) correlations in 2D NMR spectra (Figure 2). 2M NMR spectra of aminopyrrolizine 6c confirm its the Z-form. Thus, the substituent-dependent divergent synthesis of three different products has been achieved: in the case of acylethynylpyrroles with substituents in the pyrrole ring, 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 are formed, while for substrate with unsubstituted pyrrole ring, pyrrolyldienols 4 and their keto-tautomers 5 are produced, which latter can be cyclized to aminopyrrolizines 6.
Apparently, the formation of 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 starts with The formation of aminopyrrolizines obviously °C curs as intramolecular addition of the NH pyrrole moiety to the cyano group followed by prototropic isomerization of the imino-group to NH2 substituent (Scheme 3). The formation of aminopyrrolizines is strictly stereoselective: the Z-isomers are formed exclusively with cis-position of the proton at the double bond and the ortho-proton of aryl group, which follows from the main NOESY ( ) and HMBC ( ) correlations in 2D NMR spectra (Figure 2). 2M NMR spectra of aminopyrrolizine 6c confirm its the Z-form. Thus, the substituent-dependent divergent synthesis of three different products has been achieved: in the case of acylethynylpyrroles with substituents in the pyrrole ring, 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 are formed, while for substrate with unsubstituted pyrrole ring, pyrrolyldienols 4 and their keto-tautomers 5 are produced, which latter can be cyclized to aminopyrrolizines 6.
Apparently, the formation of 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 starts with The formation of aminopyrrolizines obviously °C curs as intramolecular addition of the NH pyrrole moiety to the cyano group followed by prototropic isomerization of the imino-group to NH2 substituent (Scheme 3). The formation of aminopyrrolizines is strictly stereoselective: the Z-isomers are formed exclusively with cis-position of the proton at the double bond and the ortho-proton of aryl group, which follows from the main NOESY ( ) and HMBC ( ) correlations in 2D NMR spectra ( Figure 2). 2M NMR spectra of aminopyrrolizine 6c confirm its the Z-form. Thus, the substituent-dependent divergent synthesis of three different products has been achieved: in the case of acylethynylpyrroles with substituents in the pyrrole ring, 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 are formed, while for substrate with unsubstituted pyrrole ring, pyrrolyldienols 4 and their keto-tautomers 5 are produced, which latter can be cyclized to aminopyrrolizines 6.
Thus, the substituent-dependent divergent synthesis of three different products has been achieved: in the case of acylethynylpyrroles with substituents in the pyrrole ring, 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 are formed, while for substrate with unsubstituted pyrrole ring, pyrrolyldienols 4 and their keto-tautomers 5 are produced, which latter can be cyclized to aminopyrrolizines 6.
Apparently, the formation of 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 starts with proton abstraction from the CH 2 -group of malononitrile. The carbanion A, thus generated, adds to the triple bond of acylethynylpyrroles 1, followed by Knoevenagel condensation of the adduct B, thus formed, with second molecule of malononitrile. Otherwise, malononitrile first reacts with the carbonyl group, and its second molecule adds to the triple bond of the intermediate pyrrolylenyne D. Next, diadduct C undergoes intramolecular cyclization with the participation of carbanion E to give cyclic imine F. Hydrolysis of one of the nitrile groups followed by decarboxylation and aromatization of the intermediate G finishes the process (Scheme 5). Our assumption that one of the stages in the assembly of the aniline ring is the addition of acetonitrile to the carbonyl group, as we recently showed on the example of the formation of pyridines from acylethynylpyrroles [73], was not confirmed: when the reaction of acylethynylpyrrole 1d with malononitrile was carried out without acetonitrile in THF, the yield of pyrrole 3d was 38%.
In the framework of the above mechanism, the substituent-dependent divergence of the synthesis can be explained as follows. In the presence of KOH, monoadducts of malononitrle to acylethynylpyrroles 1n-p should exist mainly as pyrrolate-anions with the negative charge distributed over the whole molecules along the conjugated chain up to the carbonyl group, which accepts a part of the negative charge, as shown by the resonance forms in (Scheme 6). Our assumption that one of the stages in the assembly of the aniline ring is the addition of acetonitrile to the carbonyl group, as we recently showed on the example of the formation of pyridines from acylethynylpyrroles [73], was not confirmed: when the reaction of acylethynylpyrrole 1d with malononitrile was carried out without acetonitrile in THF, the yield of pyrrole 3d was 38%.
In the framework of the above mechanism, the substituent-dependent divergence of the synthesis can be explained as follows. In the presence of KOH, monoadducts of malononitrle to acylethynylpyrroles 1n-p should exist mainly as pyrrolate-anions with the negative charge distributed over the whole molecules along the conjugated chain up to the tion of acetonitrile to the carbonyl group, as we recently showed on the example of the formation of pyridines from acylethynylpyrroles [73], was not confirmed: when the reaction of acylethynylpyrrole 1d with malononitrile was carried out without acetonitrile in THF, the yield of pyrrole 3d was 38%.
In the framework of the above mechanism, the substituent-dependent divergence of the synthesis can be explained as follows. In the presence of KOH, monoadducts of malononitrle to acylethynylpyrroles 1n-p should exist mainly as pyrrolate-anions with the negative charge distributed over the whole molecules along the conjugated chain up to the carbonyl group, which accepts a part of the negative charge, as shown by the resonance forms in (Scheme 6). Scheme 6. The resonance forms of the deprotonated monoadducts. Scheme 6. The resonance forms of the deprotonated monoadducts.
Such a charge transfer should be mostly expressed for the substrates with unsubstituted pyrrole counterpart that results in the decreasing of electrophilicity of the carbonyl group, which loses the ability to add the second molecule of malononitrile. Alkyl substituents in the pyrrole ring disfavor the above charge transfer from the pyrrolateanions due to the reduction of the pyrrole moiety acidity. In the case of 5-arylsubstituted pyrrole structures, the negative charges of the pyrrolates are partially distributed over the aromatic substituents. N-substituted substrates do not form pyrrolate-anions at all. Thus, monoadducts with unsubstituted pyrrole counterparts 1n-p appear to be incapable of being attacked by the second molecule of malononitrile and hence of affording 2-(3amino-2,4-dicyanophenyl)pyrroles 3. Instead, they isomerize to dienols 4a-c, which in favorable conformation undergo the ring closure to pyrrolizines 6a-c. On the other hand, monoadducts having any substituents in the pyrrole ring are readily attacked by the second carbanion of malononitrile at their more electrophilic carbonyl group to construct dicyanoaniline structures.

General Information
IR spectra were obtained with a Bruker Vertex 70 spectrometer (400-4000 cm −1 , KBr). 1 H (400.13 MHz), 13 C (100.6 MHz) spectra were recorded on a Bruker DPX-400 spectrometer at ambient temperature in CDCl 3 solutions and referenced to CDCl 3 (residual protons of solvent in 1 H NMR δ = 7.27 ppm; 13 C NMR δ = 77.1 ppm) and DMSO-d 6 (residual protons of solvent in 1 H NMR δ = 2.50 ppm; 13 C NMR δ = 39.5 ppm). The assignment of signals in the 1 H NMR spectra was made using COSY and NOESY experiments. Resonance signals of carbon atoms were assigned based on 1 H- 13   The suspension of malononitrile 2 (132 mg, 2 mmol) and KOH·0.5H 2 O (130 mg, 2 mmol) in acetonitrile (15 mL) was stirred at 20-25 • C for 30 min. Then the reaction mixture was cooled to 0 • C, the 2-acylethynylpyrrole 1 (1 mmol) in acetonitrile (5 mL) was added dropwise to a reaction mixture within 10 min. Reaction mixture was stirred at 0 • C for 2 h and then was diluted with water (40 mL), extracted with diethyl ether (4 × 10 mL). Extracts were washed with water and dried over Na 2 SO 4 . The residue, after removing solvent, was fractionated by column chromatography (Al 2 O 3 , n-hexane: diethyl ether, 1 : 1) to afford the pyrroles 3a-m.
Under analogous conditions, pyrrolyldienols 4a-c are formed from 2-acylethynylpyrroles 1n-p and malononitrile 2. They are isolated by filtering the formed precipitates by diluting the reaction mixtures with water (1:3). Pyrrolyldienols 4b,c are formed with additive of the keto form. Products 4b,c were transformed in the corresponding pyrrolizines 6b,c in the course of isolation and drying.