An Easy Synthesis of Monofluorinated Derivatives of Pyrroles from β-Fluoro-β-Nitrostyrenes

The catalyst-free conjugate addition of pyrroles to β-Fluoro-β-nitrostyrenes was investigated. The reaction was found to proceed under solvent-free conditions to form 2-(2-Fluoro-2-nitro-1-arylethyl)-1H-pyrroles. The effectiveness of this approach was demonstrated through the preparation of a series of the target products in a quantitative yield. The kinetics of a conjugate addition of pyrrole was studied in detail to reveal the substituent effect and activation parameters of the reaction. The subsequent base-induced elimination of nitrous acid afforded a series of novel 2-(2-Fluoro-1-arylvinyl)-1H-pyrroles prepared in up to an 85% isolated yield. The two-step sequence herein proposed is an indispensable alternative to a direct reaction with elusive and unstable 1-Fluoroacetylenes.


Introduction
The pyrrole ring is a constituent subunit of many naturally produced molecules and pharmaceutically active compounds [1]. Pyrrole and its derivatives are widely used as intermediates in the synthesis of pharmaceuticals, agrochemicals, dyes and other valuable organic compounds [2][3][4][5]. Many drugs containing a pyrrole moiety are available in the market or are currently undergoing clinical trials [6]. They exhibit a wide range of biological activities, such as antibacterial, anticoccidial, anti-inflammatory, antipsychotic, anticonvulsant, antifungal, antiviral, anticancer, etc. [7,8]. The conjugate addition of 2-unsubstituted pyrroles to Michael acceptors is a powerful tool used for their further functionalization [9][10][11][12]. Nitroalkenes are highly reactive and attractive Michael acceptors, giving useful compounds for the subsequent transformation of the nitro group [13]. Indeed, the introduction of a 2-Nitroalkyl moiety into the pyrrole nucleus has attracted much research interest. 2-(2-Nitroalkyl)pyrroles were demonstrated to be appealing intermediates for the synthesis of bioactive compounds [14].
On the other hand, the incorporation of a fluorine into a molecule can positively modulate a number of important pharmacokinetic and physicochemical properties of the drug, such as lipophilicity, electrophilicity, conformation, pKa, metabolic and chemical stability, membrane permeability and the binding affinity to a target protein [15][16][17][18]. Indeed, about one-fourth of the currently manufactured agrochemical and pharmaceutical products contain at least one fluorine atom, and their number tends to persistently rise [19]. In this respect, the development of new routes to fluorinated pyrrole derivatives is of great research interest and importance [20,21].
We recently reported an effective and stereoselective method for the preparation of β-Fluoro-β-nitrostyrenes based on the radical nitration of 2-Bromo-2-fluorostyrenes. This process takes place with the simultaneous elimination of bromine and gives the target structures solely as Z isomers in high yields (up to 92%) [22]. These molecules are very attractive building blocks for the construction of numerous monofluorinated molecules [23][24][25][26][27][28][29][30]. This paper is devoted to the development of routes to new classes of monofluorinated derivatives of pyrrole. We report a catalyst-free conjugate addition of pyrroles to β-Fluoro-β-nitrostyrenes, yielding a novel 2-(2-Fluoro-2-nitro-1-arylethyl)-1H-pyrroles 3. In turn, the latter prove to be effective precursors for the synthesis of novel 2-(2-Fluoro-1-arylvinyl)-1H-pyrroles 4 by the base-induced elimination of nitrous acid. This two-step sequence opens up a straightforward way to monofluorinated compounds not previously available. The approach reported herein is an indispensable alternative to the direct addition of pyrroles to elusive and unstable 1-Fluoroacetylenes (Scheme 1).
In turn, the latter prove to be effective precursors for the synthesis of novel 2-(2-Fluoro-1arylvinyl)-1H-pyrroles 4 by the base-induced elimination of nitrous acid. This two-step sequence opens up a straightforward way to monofluorinated compounds not previously available. The approach reported herein is an indispensable alternative to the direct addition of pyrroles to elusive and unstable 1-Fluoroacetylenes (Scheme 1).

Scheme 1.
Overview of this work.
In turn, the latter prove to be effective precursors for the synthesis of novel 2-(2-Fluoro-1arylvinyl)-1H-pyrroles 4 by the base-induced elimination of nitrous acid. This two-step sequence opens up a straightforward way to monofluorinated compounds not previously available. The approach reported herein is an indispensable alternative to the direct addition of pyrroles to elusive and unstable 1-Fluoroacetylenes (Scheme 1).

Scheme 1.
Overview of this work.
We found that the reaction proceeded very efficiently without any catalyst at room temperature. The reaction took place only at the α-position of pyrrole, affording the corresponding monofluorinated adducts 3 in a quantitative yield. The reaction demonstrated a broad scope in terms of nitrostyrenes 1 (Scheme 2). It can easily be scaled up to a gram scale without a loss of effectiveness. The NMR spectroscopic analysis showed the formation of a diastereoisomeric mixture of products 3 in a ratio of ca. 40:60. The formation of two diastereomers was probably caused by the high acidity of the proton on the carbon bearing the fluorine and nitro groups (the estimated pKa of CH 2 FNO 2 was around 9.5) [31]. We also studied the reaction with 1,3-bis((Z)-2-Fluoro-2-nitrovinyl)benzene 1o. The formation of bispyrrole adducts 3o proceeded in a quantitative yield, giving a mixture of four isomers. Due to the partial overlapping of the resonance signals of F, we did not estimate the molar ratio of all the isomers with 19 F NMR-spectroscopy. All the structures obtained were elucidated by a combination of NMR spectroscopy and HRMS (See Supplementary Materials).
To gain deeper insights into the reaction, we carried out some kinetic studies to estimate the activation parameters and substituent effect. All the kinetic runs were performed under pseudo-first order conditions using a 216-molar excess of 1H-pyrrole. Conversions (F) of 1 were measured by 19 F NMR spectroscopy. The total effective pseudo-first order rate constants k* were obtained by plotting the experimental values of ln (C 0 /C) versus time with good correlations (Tables 1 and 2). The overall second-order rate total constants k total were calculated from the effective k* and initial concentration of pyrrole (Tables 1 and 2). The individual constants for the minor and major isomers (k min and k maj ) were evaluated by the multiplication of k total with the molar fractions of the isomers (Tables 1 and 2). The reactions were found to proceed under the kinetic control, since the isomer ratio remained constant throughout the reactions course (Tables 1 and 2). First, the activation parameters were estimated for the reaction of nitrostyrene 1g with pyrrole. The kinetic studies were conducted in the temperature range of 30-90 • C ( Figure 1). The calculated rate constants are presented in Table 1. The activation parameters were estimated for both the reaction pathways (the formation of two diastereomers) by the Eyring equation [32] (1) from the plots of ln(k/T) versus 1/T (2-3). The activation enthalpies (∆H = ) and entropies (∆S = ) were found to be 51.72 kJ/mol and −183.45 J/mol K for the major isomer and 55.03 kJ/mol and −178.57 J/mol K for the minor isomer. under pseudo-first order conditions using a 216-molar excess of 1H-pyrrole. Conversions (F) of 1 were measured by 19 F NMR spectroscopy. The total effective pseudo-first order rate constants k* were obtained by plotting the experimental values of ln (C0/C) versus time with good correlations (Tables 1 and 2). The overall second-order rate total constants ktotal were calculated from the effective k* and initial concentration of pyrrole (Tables 1 and  2). The individual constants for the minor and major isomers (kmin and kmaj) were evaluated by the multiplication of ktotal with the molar fractions of the isomers (Tables 1 and 2). The  reactions were found to proceed under the kinetic control, since the isomer ratio remained  constant throughout the reactions course (Tables 1 and 2). First, the activation parameters were estimated for the reaction of nitrostyrene 1g with pyrrole. The kinetic studies were conducted in the temperature range of 30-90 °C ( Figure 1). The calculated rate constants are presented in Table 1.  Next, we studied the substituent effect. The kinetic curves were obtained for the reactions of pyrrole with differently para-position substituted nitrostyrenes 1 at 50 • C. The rate constants were calculated and summarized in Table 2. It was found that the reaction rate depended on the nature of a substituent on the benzene ring of the nitrostyrenes 1. The substituent effect was estimated first by plotting the log k against the Hammett constants σ p for the para-substituents ( Figure 2 The activation parameters were estimated for both the reaction pathways (the formation of two diastereomers) by the Eyring equation [32] (1) from the plots of ln(k/T) versus 1/T (2-3). The activation enthalpies (∆H ≠ ) and entropies (ΔS ≠ ) were found to be 51.72 kJ/mol and −183.45 J/mol K for the major isomer and 55.03 kJ/mol and −178.57 J/mol K for the minor isomer. ln(k/T) = ln(k /ħ) + ΔS ≠ /R − ∆H ≠ /RT (1) ln(kmaj/T) = 1.675 − 6222.5/T (R > 0.999) (2) ln(kmin/T) = 2.271 − 6622.7/T (R > 0.999) Next, we studied the substituent effect. The kinetic curves were obtained for the reactions of pyrrole with differently para-position substituted nitrostyrenes 1 at 50 °C. The rate constants were calculated and summarized in Table 2. It was found that the reaction rate depended on the nature of a substituent on the benzene ring of the nitrostyrenes 1 The substituent effect was estimated first by plotting the log k against the Hammett constants σp for the para-substituents ( Figure 2).  The following linear relationships were obtained: log k total = 0.33σ p − 5.00 (R = 0.889) log k min = 0.25σ p − 5.45 (R = 0.760) log k maj = 0.38σ p − 5.45 (R = 0.928) The positive value of the reaction constant ρ indicates that the reaction is favored by the withdrawal of electron pairs from the reaction site. However, the low value of ρ (0.3 ÷ 0.4) demonstrates a low sensitivity to the substituent influences. As a consequence, this leads to relatively low correlations of the linear relationships obtained (0.76 ÷ 0.93). Indeed, Molecules 2021, 26, 3515 5 of 28 the ratio of the maximum (p-NO 2 -substituted 1l) and minimum (p-OCH 3 -substituted 1b) values of k is around 3, whereas, for the Diels-Alder reaction of nitrostyrenes 1 with 2,3-dimethylbutadiene (ρ = 1.00), the same ratio is around 14 [24].
Another parameter frequently used for the estimation of reactivity is a global electrophilicity index (ω). This parameter is in good correlation with σ p . The ground-state geometries of nitrostyrenes 1 were optimized using the DFT B3LYP/6-31G* level of theory [24]. The values of ω were evaluated from the HOMO and LUMO energies of nitrostyrenes 1: Next, the linearization of the log k versus ω was made for the formation of both diastereomers ( Figure 3). However, the correlations of the linear relationships obtained were worse (8)(9)(10).
Another parameter frequently used for the estimation of reactivity is a global electr philicity index (ω). This parameter is in good correlation with σp. The ground-state geom etries of nitrostyrenes 1 were optimized using the DFT B3LYP/6-31G* level of theory [2 The values of ω were evaluated from the HOMO and LUMO energies of nitrostyrenes ω = μ 2 /2η = 1/8 (EHOMO + ELUMO) 2 /(ELUMO − EHOMO) ( Next, the linearization of the log k versus ω was made for the formation of both di stereomers ( Figure 3). However, the correlations of the linear relationships obtained we worse (8)(9)(10). Next, we selected a series of nitrostyrenes differing only in a substituent at the doub bond to evaluate the substituent effect at β-carbon (Scheme 3). The kinetics studies of r actions of pyrrole with nitrostyrenes bearing H, F, Cl and Me at the terminal carbon we conducted at 50 °C ( Figure 4). The data obtained are summarized in Table 3. In this cas a high sensitivity to the substituent influences was observed because of the near positio of the substituent to the reaction site. The least reactivity was demonstrated by β-methy ated nitrostyrene 1b′ (Table 3, Entry 1). Its conversion was only 17% after 4 h of the rea tion. Fluorinated nitrostyrene 1b showed a 6.5 times faster total reaction rate than that the methylated one 1b′. Next, we selected a series of nitrostyrenes differing only in a substituent at the double bond to evaluate the substituent effect at β-carbon (Scheme 3). The kinetics studies of reactions of pyrrole with nitrostyrenes bearing H, F, Cl and Me at the terminal carbon were conducted at 50 • C ( Figure 4). The data obtained are summarized in Table 3. In this case, a high sensitivity to the substituent influences was observed because of the near position of the substituent to the reaction site. The least reactivity was demonstrated by β-methylated nitrostyrene 1b (Table 3, Entry 1). Its conversion was only 17% after 4 h of the reaction. Fluorinated nitrostyrene 1b showed a 6.5 times faster total reaction rate than that of the methylated one 1b .  However, β-unsubstituted nitrostyrene 1b″ having the minimum sterical demand was about 18 times more reactive than 1b′. To our surprise, β-chlorinated nitrostyrene 1b‴ (Table 3, Entry 4) proved the most reactive one. Almost a full conversion was achieved only after 1 h. It was nearly 69 times more reactive than 1b′. Such an effect of the substituent at β-carbon can be explained by the combination of electronic and sterical effects. The novel 2-(2-Fluoro-2-nitro-1-arylethyl)-1H-pyrroles 3 obtained are interesting compounds due to their potential synthetic utility for the subsequent transformations. We proposed that they could be appropriate and effective precursors for novel 2-(2-Fluoro-1arylvinyl)-1H-pyrrole 4. C-Vinylpyrroles have attracted much research interest due to their synthetic utility as building blocks for pyrrole derivatives [33]. However, by now, 2-(2-Fluoro-vinyl)pyrroles have not been obtained yet. Apparently, this is related to the unavailability of suitable precursors. Indeed, 1-Fluoroacetylenes that could be potential precursors for the synthesis of such structures are elusive, unstable compounds. However, the use of β-fluoro-β-nitrostyrenes 1 as synthetic equivalents of 1-fluoroacetylenes is a promising way to overcome this synthetic problem. We applied this strategy based on the formation of a double bond in the final step by the base-induced elimination of nitrous acid from the adducts 3 (Scheme 4).  However, β-unsubstituted nitrostyrene 1b having the minimum sterical demand was about 18 times more reactive than 1b . To our surprise, β-chlorinated nitrostyrene 1b (Table 3, Entry 4) proved the most reactive one. Almost a full conversion was achieved only after 1 h. It was nearly 69 times more reactive than 1b . Such an effect of the substituent at β-carbon can be explained by the combination of electronic and sterical effects.
The novel 2-(2-Fluoro-2-nitro-1-arylethyl)-1H-pyrroles 3 obtained are interesting compounds due to their potential synthetic utility for the subsequent transformations. We proposed that they could be appropriate and effective precursors for novel 2-(2-Fluoro-1-arylvinyl)-1H-pyrrole 4. C-Vinylpyrroles have attracted much research interest due to their synthetic utility as building blocks for pyrrole derivatives [33]. However, by now, 2-(2-Fluoro-vinyl)pyrroles have not been obtained yet. Apparently, this is related to the unavailability of suitable precursors. Indeed, 1-Fluoroacetylenes that could be potential precursors for the synthesis of such structures are elusive, unstable compounds. However, the use of β-fluoro-β-nitrostyrenes 1 as synthetic equivalents of 1-fluoroacetylenes is a promising way to overcome this synthetic problem. We applied this strategy based on the formation of a double bond in the final step by the base-induced elimination of nitrous acid from the adducts 3 (Scheme 4).
The reactions were conducted in acetonitrile using DBU as a base at an ambient temperature (Scheme 4). In principle, the competitive elimination of either HNO 2 or HF can be expected, leading to the formation of either fluorine-substituted 4 or nitro-substituted 2-Vinylpyrrole 5. However, to our delight, the reaction demonstrated a high selectivity towards the desired 2-(2-Fluoro-1-arylvinyl)-1H-pyrroles 4. The reaction demonstrated a high effectiveness to furnish the desired products 4 in up to 85% yields, whereas the side products 5 did not exceed 15%. Somewhat lower yields (43-50%) were achieved in the case of the adducts 3b and 3l, having a strong electron-donating (EDG) methoxy-or a strong electron-withdrawing (EWG) nitro group at the para-position of the benzene ring, correspondingly. The presence of a nitro group at the ortho-position of the benzene substituent of 3n resulted in the decomposition of the reaction mixture under these reaction conditions. Only trace amounts of adduct 4n were detected. However, when the nitrogroup was posed at the meta-position, a high yield of product 4m (78%) was obtained. All the other adducts 3 were also successfully transformed into the corresponding 2vinylpyrroles 4.
perature (Scheme 4). In principle, the competitive elimination of either HNO2 or HF can be expected, leading to the formation of either fluorine-substituted 4 or nitro-substituted 2-Vinylpyrrole 5. However, to our delight, the reaction demonstrated a high selectivity towards the desired 2-(2-Fluoro-1-arylvinyl)-1H-pyrroles 4. The reaction demonstrated a high effectiveness to furnish the desired products 4 in up to 85% yields, whereas the side products 5 did not exceed 15%. Somewhat lower yields (43-50%) were achieved in the case of the adducts 3b and 3l, having a strong electron-donating (EDG) methoxy-or a strong electron-withdrawing (EWG) nitro group at the para-position of the benzene ring, correspondingly. The presence of a nitro group at the ortho-position of the benzene substituent of 3n resulted in the decomposition of the reaction mixture under these reaction conditions. Only trace amounts of adduct 4n were detected. However, when the nitrogroup was posed at the meta-position, a high yield of product 4m (78%) was obtained. All the other adducts 3 were also successfully transformed into the corresponding 2-vinylpyrroles 4.  The stereochemistry of the products 4 was unambiguously assigned with NMR spectroscopy. The 1 H NMR spectra displayed a significant downfield shift (ca. 1 ppm) of pyrrolic H5 in a Z-configuration in reference to that in the E-configuration ( Figure 5). Additionally, the splitting of the resonance signal of fluorine into a double doublet in the Z-configuration was observed with 19 F NMR spectroscopy ( Figure 5), whereas, in the E-configuration, the fluorine resonance signal was a doublet. Probably, this indicated the formation of an intermolecular hydrogen bond with fluorine. Indeed, a similar pattern was observed for the side nitro products 5. In this case, the downfield shift of the pyrrolic proton in the Z-configuration was much greater ca. 3.7 ppm. The difference in the frequencies of the NH vibrations regarding the Zand E-positions of fluorine observed with IR spectroscopy was about 20 cm −1 (Figure 6).
isomers have the same retention time and, therefore, are isolated together. We demonstrated the possibility of separation (Z)-and (E)-2-(2-Fluoro-1-phenylvinyl)-1H-pyrrole for a large number of examples and fully characterized them. As expected, the elimination of the bis-pyrrole adduct 3o resulted in the formation of the desired difluorinated product 4o as a mixture of three isomers, with the Z,Z-, E,Z-and E,E-configurations in a 24:48:28 ratio, correspondingly. The side products were monofluorinated nitro-derivatives 5o formed as a mixture of four isomers. We isolated two mixtures of isomers in the Z-NO2 and Z-F, along with E-NO2 and Z-F configurations and the Z-NO2 and E-F, along with E-NO2 and E-F configurations.
The stereochemistry of the products 4 was unambiguously assigned with NMR spectroscopy. The 1 H NMR spectra displayed a significant downfield shift (ca. 1 ppm) of pyrrolic H5 in a Z-configuration in reference to that in the E-configuration ( Figure 5). Additionally, the splitting of the resonance signal of fluorine into a double doublet in the Zconfiguration was observed with 19 F NMR spectroscopy ( Figure 5), whereas, in the E-configuration, the fluorine resonance signal was a doublet. Probably, this indicated the formation of an intermolecular hydrogen bond with fluorine. Indeed, a similar pattern was observed for the side nitro products 5. In this case, the downfield shift of the pyrrolic proton in the Z-configuration was much greater ca. 3.7 ppm. The difference in the frequencies of the NH vibrations regarding the Z-and E-positions of fluorine observed with IR spectroscopy was about 20 cm −1 ( Figure 6).  As expected, the resulting ratio of the diastereomers 4 remained similar to that of the precursors 3. However, the elimination of the 2,4-dichlorophenyl-substituted adduct 3b with dr = 48:52 led to the predominant formation of a Z-isomer 4 in high diastereomeric excess (90% de).
Next, we demonstrated the versatility of our methodology for N-substituted pyrroles. Due to the reduced nucleophilicity of N-aryl pyrroles and high steric demand of substituents, the conjugate addition required harsher conditions. Moreover, most of N-aryl pyrroles used are solid at room temperature (except for pyrrole 2g) and need heating to be melted. We applied catalyst-free conditions for the reactions of nitrostyrene 1g with N-substituted pyrroles (Scheme 5). The reactions were carried out under solvent-free conditions and microwave-activated at elevated temperatures (150-200 • C) for 16-20 h. This, in turn, intensified the undesirable side reactions and, as a consequence, in some cases, decreased the selectivity. Indeed, some amount of β-substituted adducts was observed along with the target products. The reaction with 1-methyl-1H-pyrrole 2b was completed at 150 • C with a good overall yield of 3p (76%). However, the formation of 13% of the β-substituted regioisomers was detected by 1 H and 19 F-NMR spectroscopy. The reactions of nitrostyrene 1g with 1-Phenyl-1H-pyrrole 2c and 1-(4-Ethylphenyl)-1H-pyrrole 2d demonstrated poor reactivity. Low yields of adducts 3q and 3r (28-35%) were obtained after the full conversion of 1g. However, the reaction with 1-(p-Tolyl)-1H-pyrrole 2e displayed a better reactivity to give adduct 3s in a 51% yield. It was also found that the reactivity of N-aryl-substituted pyrroles was increased in the presence of an electron-donating methoxy group in the benzene ring. For instance, the reaction with 1-(3-Methoxyphenyl)-1H-pyrrole 2g resulted in a good yield of adduct 3u (74%), whereas, in the case of the simultaneous presence of EDG (-OMe) and weak EWG (-Cl), the yield of the adduct 3t (46%) diminished compared to 3u. On the other hand, we failed to obtain the adducts based on pyrroles having only electron-withdrawing groups onthe aryl-substituent under these conditions. As expected, the resulting ratio of the diastereomers 4 remained similar to that of the precursors 3. However, the elimination of the 2,4-dichlorophenyl-substituted adduct 3b with dr = 48:52 led to the predominant formation of a Z-isomer 4 in high diastereomeric excess (90% de). Next, we demonstrated the versatility of our methodology for N-substituted pyrroles. Due to the reduced nucleophilicity of N-aryl pyrroles and high steric demand of substituents, the conjugate addition required harsher conditions. Moreover, most of Naryl pyrroles used are solid at room temperature (except for pyrrole 2g) and need heating to be melted. We applied catalyst-free conditions for the reactions of nitrostyrene 1g with N-substituted pyrroles (Scheme 5). The reactions were carried out under solvent-free conditions and microwave-activated at elevated temperatures (150-200 °C) for 16-20 h. This, in turn, intensified the undesirable side reactions and, as a consequence, in some cases, decreased the selectivity. Indeed, some amount of β-substituted adducts was observed along with the target products. The reaction with 1-methyl-1H-pyrrole 2b was completed at 150 °C with a good overall yield of 3p (76%). However, the formation of 13% of the βsubstituted regioisomers was detected by 1 H and 19 F-NMR spectroscopy. The reactions of nitrostyrene 1g with 1-Phenyl-1H-pyrrole 2c and 1-(4-Ethylphenyl)-1H-pyrrole 2d demonstrated poor reactivity. Low yields of adducts 3q and 3r (28-35%) were obtained after the full conversion of 1g. However, the reaction with 1-(p-Tolyl)-1H-pyrrole 2e displayed a better reactivity to give adduct 3s in a 51% yield. It was also found that the reactivity of N-aryl-substituted pyrroles was increased in the presence of an electron-donating methoxy group in the benzene ring. For instance, the reaction with 1-(3-Methoxyphenyl)-1Hpyrrole 2g resulted in a good yield of adduct 3u (74%), whereas, in the case of the simultaneous presence of EDG (-OMe) and weak EWG (-Cl), the yield of the adduct 3t (46%) diminished compared to 3u. On the other hand, we failed to obtain the adducts based on pyrroles having only electron-withdrawing groups onthe aryl-substituent under these conditions.
After, the subsequent elimination of nitrous acid from the adducts 3p-3u was conducted (Scheme 5). Similar to their N-unsubstituted analogs, these compounds also reacted smoothly. The corresponding 2-vinyl pyrroles 4p-4s were obtained in good yields (57-72%). The side nitro product 5 was isolated in the range of 10-18%. It was found that N-aryl-substituted 2-vinylpyrroles formed with a predominance of the Z-isomer. It can be After, the subsequent elimination of nitrous acid from the adducts 3p-3u was conducted (Scheme 5). Similar to their N-unsubstituted analogs, these compounds also reacted smoothly. The corresponding 2-vinyl pyrroles 4p-4s were obtained in good yields (57-72%). The side nitro product 5 was isolated in the range of 10-18%. It was found that N-arylsubstituted 2-vinylpyrroles formed with a predominance of the Z-isomer. It can be clearly explained by the steric demand of the aryl substituent with nitrogen compared to the hydrogen or methyl groups. Indeed, in the course of conjugate addition (Scheme 3), the orientation of the small fluorine near a bulky aryl is sterically more favorable.
The pyrrole derivatives are also of great importance for the modification at the free α-position. Therefore, we studied the reaction of adduct 3l with 4-Chlorobenzaldehyde to prepare the corresponding dipyrromethane 6 (Scheme 6). The reaction proceeded in the presence of trifluoroacetic acid (TFA) as the catalyst and gave 6 as a mixture of the diastereomers in a 48% yield. This transformation can open up the straightforward way to novel valuable classes of fluorinated pyrrole derivatives, such as dipyrromethanes and their boron difluoride complexes (BODIPYs).

Materials and Methods
All reagents were purchased from commercial sources and used without any further purification. All solvents were dried before use by the standard procedure [34]. Melting points (m.p.) were measured with a Büchi B-545 melting point apparatus (Büchi, Flawil, Switzerland). Microwave activated reactions were conducted in Monowave 200 (Anton Paar, Graz, Austria). NMR ( 1 H, 13 C and 19 F) spectra were obtained with the Bruker AVANCE 400 (Bruker Corp., Karlsruhe, Germany) and Agilent 400-MR spectrometers (Agilent Technologies, Santa Clara, CA, USA) using deuterated chloroform (CDCl3). Chemical shifts for the 1 H NMR spectroscopic data were referenced to the internal tetramethylsilane (δ = 0.0 ppm) and the residual solvent resonance (δ = 7.26 ppm); chemical Scheme 6. Synthesis of dipyrromethane 6.
In a typical experiment, β-fluoro-β-nitrostyrene (0.5 mmol) and pyrrole (0.5 mL) were successively loaded into a vial. The reaction mixture was stirred at room temperature for 25-30 h. After completion of the reaction (TLC monitoring), the excess of pyrrole was evaporated under vacuum. The desired product was isolated by column chromatography on silica gel as a mixture of diastereomers.     Fluoro-2-nitro-1-(2-nitrophenyl) General procedure for the conjugate addition of 1-substituted 1H-pyrroles to β-fluoroβ-nitrostyrenes.