Revisiting the Chemistry of Vinylpyrazoles: Properties, Synthesis, and Reactivity

Vinylpyrazoles, also known as pyrazolyl olefins, are interesting motifs in organic chemistry but have been overlooked. This review describes the properties and synthetic routes of vinylpyrazoles and highlights their versatility as building blocks for the construction of more complex organic molecules. Concerning the reactivity of vinylpyrazoles, the topics surveyed herein include their use in cycloaddition reactions, free-radical polymerizations, halogenation and hydrohalogenation reactions, and more recently in transition-metal-catalyzed reactions, among other transformations. The current state of the art about vinylpyrazoles is presented with an eye to future developments regarding the chemistry of these interesting compounds. Styrylpyrazoles were not considered in this review, as they were the subject of a previous review article published in 2020.


Introduction
Pyrazoles have attracted increased attention in recent years owing to their widespread applications in medicine [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], agriculture, [16] materials science [17][18][19][20], and catalysis [21,22]. In this review, the chemistry of a particular kind of pyrazoles, the vinylpyrazoles, is revisited. Vinylpyrazoles (vinyl-1H-pyrazoles), also known as pyrazolyl olefins, are characterized by the presence of a vinyl group linked at one of the pyrazoles' ring positions (N-1, C-3, C-4, C-5) (Figure 1). There are few examples of vinylpyrazoles despite their interesting properties. These compounds are interesting building blocks for the synthesis of more complex pyrazoles endowed with biological activities and for other advanced structures, such as indazoles, among others. For example, some 5-vinylpyrazoles were found to be potent DNA gyrase inhibitors with antibacterial activity against Gram-(+) bacteria [23], while others have been used as additives in the production of rubbers [24][25][26]. Furthermore, these compounds present interesting physicochemical properties, such as tautomerism and isomerism, owing to the presence of the vinyl group. Consequently, several spectroscopic studies on vinylpyrazoles have been reported [27][28][29][30][31][32][33][34][35]. For example, Skvortsova and coworkers performed several 1 H-and 13 C-NMR spectral analyses for evaluation of electronic and steric effects in 1-vinylpyrazoles [28]. They showed that the substituents on the pyrazole ring had an effect on the conformation of the vinyl group; 5-methyl-1vinylpyrazoles had predominantly S-cis-N 2 orientation, while 1-vinylpyrazoles without substituents at C-5 were a mixture of conformers. These observations were confirmed six years later by Vashchenko and Afonin [35]. Despite their interesting structural features and chemistry, vinylpyrazoles have been overlooked, and their reactivity has not been much explored. However, the discovery of several tools in modern organic synthesis in the last decades, mainly related to metathesis, transition-metal-catalyzed and C-H activation reactions, and visible light-driven and green organometallic transformations, among others, may open novel opportunities towards the investigation of the vinylpyrazoles reactivity and versatility in organic synthesis. This review intends to show the current state of the art with an eye to future perspectives concerning the chemistry and reactivity studies of vinylpyrazoles. For sake of simplicity, throughout the manuscript, the nomenclature 1-vinylpyrazole is adopted instead of 1-vinyl-1H-pyrazole.

Synthesis of Vinylpyrazoles
One of the first methods described in the literature for the synthesis of 1-vinylpyrazoles, namely 3,5-dimethyl-1-vinylpyrazole and 3-methyl-5-phenyl-1-vinylpyrazole, was the reaction of acetylene with 3,5-dimethylpyrazole and 3-methyl-5-phenylpyrazole using high pressure [36]. The compounds 1-vinylpyrazole and 3,5-dimethyl-1-vinylpyrazole were also prepared by dehydration of the corresponding alcohols, 1-(β-hydroxyethyl)pyrazole and 3,5-dimethyl-1-(β-hydroxyethyl)pyrazole. These alcohols were obtained by condensing 1,1,3,3-tetraethoxypropane and acetylacetone, respectively, with β-hydroxyethyl hydrazine [36]. Later, 1-vinylpyrazoles were prepared starting from pyrazoles with free NH and different substituents at C-4 by reaction with boiling vinyl acetate in the presence of mercuric(II) sulfate as a catalyst for 1-7 h. The catalyst was directly produced in the reaction medium from mercuric(II) acetate and sulfuric acid added dropwise [37]. The 1-vinylpyrazoles were obtained in very good yields (70-86%). Electron-acceptor groups at C-4 of the pyrazole nucleus increased the acidity of the NH group and accelerated the reaction. In 1970, Trofimenko reported the synthesis of 1-vinylpyrazoles and their analogs containing alkyl substituents on the vinyl group by acid-catalyzed cracking of geminal bis(1-pyrazolyl)alkanes 1, obtained from the reaction of pyrazole with acetals or ketals [38]. At around 200 • C and in the presence of an acid such as p-toluenesulfonic acid, the bis(1pyrazolyl)alkanes 1 containing β-hydrogens underwent fragmentation to 1-vinylpyrazole 2 and pyrazole 3 (Scheme 1). to show the current state of the art with an eye to future perspectives concerning the chemistry and reactivity studies of vinylpyrazoles. For sake of simplicity, throughout the manuscript, the nomenclature 1-vinylpyrazole is adopted instead of 1-vinyl-1H-pyrazole.
Another interesting method that allowed the formation of 1-vinylpyrazoles used water as solvent under phase transfer catalysis conditions (PTC). This method involved the Nalkylation of pyrazole 4 with dichloroethane (DCE) followed by dehydrochlorination of Only a few examples of the synthesis of 3-and 5-vinylpyrazoles are known, especially when one of the nitrogens bears a proton. In 1976, Sharp reported the synthesis of 3-vinylpyrazoles by thermolysis and rearrangement of 3H-1,2-diazepines [42]. Later, Ponticello demonstrated that the cracking of the adducts 12, prepared by a condensationcyclization reaction of a β-ketoaldehyde 10 (R 1 = H) or a β-diketone 11 (R 1 = Me) with hydrazine or its derivatives, afforded 3(5)-vinylpyrazoles 13 in good yield (Scheme 4) [43]. When R 1 = H, the two tautomers corresponding to the 3-and 5-vinylpyrazoles are indistinguishable, since very easy interconversion might be expected through ions formed by addition and loss of a proton. As expected, condensation of methyl hydrazine with βketoaldehyde or β-diketone each gave two isomeric pyrazoles. Substitution on nitrogen prevents tautomerism; thus, the two isomers were not identical. Scheme 2. Synthesis of 1-vinylpyrazoles 6 by dehydrochlorination of 1-(2-chloroethyl)pyrazoles 5 [40].
Only a few examples of the synthesis of 3-and 5-vinylpyrazoles are known, especially when one of the nitrogens bears a proton. In 1976, Sharp reported the synthesis of 3-vinylpyrazoles by thermolysis and rearrangement of 3H-1,2-diazepines [42]. Later, Ponticello demonstrated that the cracking of the adducts 12, prepared by a condensationcyclization reaction of a β-ketoaldehyde 10 (R 1 = H) or a β-diketone 11 (R 1 = Me) with hydrazine or its derivatives, afforded 3(5)-vinylpyrazoles 13 in good yield (Scheme 4) [43]. When R 1 = H, the two tautomers corresponding to the 3-and 5-vinylpyrazoles are indistinguishable, since very easy interconversion might be expected through ions formed by addition and loss of a proton. As expected, condensation of methyl hydrazine with β-ketoaldehyde or β-diketone each gave two isomeric pyrazoles. Substitution on nitrogen prevents tautomerism; thus, the two isomers were not identical.
Furthermore, 5-vinylpyrazoles 16 could be obtained by aromatization of 5-vinylpyra zolines 15 generated from N-sulfonyl,C-homoallyl-hydrazones 14 via Pd-catalyzed C-H oxidative C,N-cyclization through a 5-exo-trig process from a π-allyl complex intermediate when the Pd(II) center is associated to noncoordinating anions such as tosylates or triflates. Indeed, 5-vinylpyrazolines with electron-active substituents at the p-position of the phenyl ring and hindered pyrazolines could be converted to the corresponding pyrazoles in moderate-to-high yields through a base-induced eliminative aromatization process (Scheme 5) [44]. Furthermore, 5-vinylpyrazoles 16 could be obtained by aromatization of 5-vinylpyrazolines 15 generated from N-sulfonyl,C-homoallyl-hydrazones 14 via Pd-catalyzed C-H oxidative C,N-cyclization through a 5-exo-trig process from a π-allyl complex intermediate when the Pd(II) center is associated to noncoordinating anions such as tosylates or triflates. Indeed, 5-vinylpyrazolines with electron-active substituents at the p-position of the phenyl ring and hindered pyrazolines could be converted to the corresponding pyrazoles in moderate-to-high yields through a base-induced eliminative aromatization process (Scheme 5) [44]. Mohanan and coworkers developed a rapid synthesis of 5(3)-vinylpyrazoles under mild conditions. The reaction was based on the versatility and dual reactivity of Bestmann-Ohira reagent (BOR) 18 as a homologation reagent and cycloaddition reactant in a domino reaction with a cinnamaldehyde 17 (Scheme 6) [45]. The sequence involved a formal 1,3-dipolar cycloaddition/Horner-Wadsworth-Emmons (HWE) homologation of the resulting pyrazoline carbaldehydes followed by a 1,3-H shift to give the 5(3)-vinylpyrazoles.  Furthermore, 5-vinylpyrazoles 16 could be obtained by aromatization of 5-vinylpyrazolines 15 generated from N-sulfonyl,C-homoallyl-hydrazones 14 via Pd-catalyzed C-H oxidative C,N-cyclization through a 5-exo-trig process from a π-allyl complex intermediate when the Pd(II) center is associated to noncoordinating anions such as tosylates or triflates. Indeed, 5-vinylpyrazolines with electron-active substituents at the p-position of the phenyl ring and hindered pyrazolines could be converted to the corresponding pyrazoles in moderate-to-high yields through a base-induced eliminative aromatization process (Scheme 5) [44]. Mohanan and coworkers developed a rapid synthesis of 5(3)-vinylpyrazoles under mild conditions. The reaction was based on the versatility and dual reactivity of Bestmann-Ohira reagent (BOR) 18 as a homologation reagent and cycloaddition reactant in a domino reaction with a cinnamaldehyde 17 (Scheme 6) [45]. The sequence involved a formal 1,3-dipolar cycloaddition/Horner-Wadsworth-Emmons (HWE) homologation of the resulting pyrazoline carbaldehydes followed by a 1,3-H shift to give the 5(3)-vinylpyrazoles. The reaction mechanism started with the methanolysis of BOR and generation of a diazomethyl anion I. Then, a 1,3-dipolar cycloaddition of I to cinnamaldehydes gave pyrazoline carbaldehydes II. Reaction of pyrazolines II with another molecule of BOR generated pyrazoline alkyne intermediates III, which after a 1,3-H shift followed by aromatization produced 5(3)-vinylpyrazoles 19 (Scheme 7). The reaction mechanism started with the methanolysis of BOR and generation of a diazomethyl anion I. Then, a 1,3-dipolar cycloaddition of I to cinnamaldehydes gave pyrazoline carbaldehydes II. Reaction of pyrazolines II with another molecule of BOR generated pyrazoline alkyne intermediates III, which after a 1,3-H shift followed by aromatization produced 5(3)-vinylpyrazoles 19 (Scheme 7). mann-Ohira reagent 18 [45].
The reaction mechanism started with the methanolysis of BOR and generation of a diazomethyl anion I. Then, a 1,3-dipolar cycloaddition of I to cinnamaldehydes gave pyrazoline carbaldehydes II. Reaction of pyrazolines II with another molecule of BOR generated pyrazoline alkyne intermediates III, which after a 1,3-H shift followed by aromatization produced 5(3)-vinylpyrazoles 19 (Scheme 7).
The reaction mechanism started with the methanolysis of BOR and generation of a diazomethyl anion I. Then, a 1,3-dipolar cycloaddition of I to cinnamaldehydes gave pyrazoline carbaldehydes II. Reaction of pyrazolines II with another molecule of BOR generated pyrazoline alkyne intermediates III, which after a 1,3-H shift followed by aromatization produced 5(3)-vinylpyrazoles 19 (Scheme 7).

Reactivity of Vinylpyrazoles
Vinylpyrazole and substituted vinylpyrazoles do not resemble enamines in reactivity. This is in accord with the nonavailability of electrons from the N-1 to stabilize dipolar structures of transition states such as those commonly invoked to account for the reactivity of enamines. Vinylpyrazoles coexist with pyrazole and show no tendency to add it back. The shelf life of vinylpyrazoles is good, and no polymerization in the neat liquid is observed even after 2 years [27][28][29][30][31][32][33][34][35]. Some reactions with vinylpyrazoles have been described in the literature. However, the reactivity of these scaffolds has been barely ex-Scheme 9. Synthesis of 4-vinylpyrazoles 24 from tetrahydropyrazolo [3,4-d] [1,2]diazepines 23 [49].

Reactivity of Vinylpyrazoles
Vinylpyrazole and substituted vinylpyrazoles do not resemble enamines in reactivity. This is in accord with the nonavailability of electrons from the N-1 to stabilize dipolar structures of transition states such as those commonly invoked to account for the reactivity The shelf life of vinylpyrazoles is good, and no polymerization in the neat liquid is observed even after 2 years [27][28][29][30][31][32][33][34][35]. Some reactions with vinylpyrazoles have been described in the literature. However, the reactivity of these scaffolds has been barely explored. Some examples of vinylpyrazoles' transformations are described in the following subsections.

Cycloaddition Reactions
Diels-Alder (DA) cycloadditions are amongst the most elegant reactions for rapidly building complex cyclic compounds. Vinylpyrazoles are very reluctant to react as dienes in DA cycloadditions because of the loss of aromaticity of the pyrazole ring on [4 + 2] cycloadduct formation being much less reactive than vinylpyrroles and vinylindoles. Harsh reaction conditions are required, such as sealed vessels and high pressures (8-10 atm) and temperatures (120-140 • C) for long reaction times (several days), to obtain very low or moderate yields [50,51]. So far, the vinylpyrazoles have been used as dienes in Diels-Alder reactions for the preparation of compounds with medicinal interest, being these ones of the most described reactions of vinylpyrazoles in literature. In 1996, Díaz-Ortiz et al. studied the effect of microwaves in solvent-free conditions in the improvement of the reactivity of vinylpyrazoles. They found that 4-vinylpyrazoles 26 reacted with dienophiles, such as methyl and ethyl propiolate, dimethyl acetylenedicarboxylate, N-phenylmaleimide, or tetracyanoethene, to form 1:1 adducts [52]. The cycloaddition occurred rapidly (6-30 min), and the yields, while generally fair, were superior to those of conventional methods. Moreover, with microwave activation, it was possible to use low-reactive dienophiles such as ethyl phenylpropiolate, and other intermediate products not observed in conventional methods were isolated and characterized. This type of reaction also occurred with 3-and 5-vinylpyrazoles [53]. Since DA reactions of vinylpyrazoles have been the subject of several publications, only some examples are provided for the reaction of 4-and 5-vinylpyrazoles 26 and 27 with some common dienophiles (Schemes 10 and 11) [53]. Few data on the reactivity of 3-and 5-methyl-1-vinylpyrazoles 28 and 29 as dienophiles are available in the literature. Asratyan and coworkers studied the behavior of these pyrazoles as dienophiles in the reaction with cyclohexa-1,3-diene (Scheme 12) [55]. Although 1 H-and 13 C-NMR data showed that 5-methyl-1-vinylpyrazole 29 existed mainly as the S-cis-N 2 isomer, while 3-methyl-1-vinylpyrazole 28 was a roughly equimolar mixture of steric isomers [28], no characteristic differences were found in the behavior of these compounds in the cycloaddition. The reaction with the diene proceeded only at 180 °C to give the product in low yields. When reaction temperature is increased to 220 °C, fast polymerization of the diene and dienophile occurred. The authors suggested that the spatial location of the vinyl group in 1-vinylpyrazoles 28 and 29 with respect to N-2 took no part in the Diels-Alder reaction. The obtained products 30 and 31 went through a hydrogenation reaction to afford compounds 32 and 33. Scheme 11. Diels-Alder reactions of 1-phenyl-5-vinylpyrazole 27 with different dienophiles [53].
Sepúlveda-Arques et al. investigated the effects of the presence of substituents either on the pyrazole ring nitrogen or in the vinyl group on the improvement of the yields of the cycloadducts obtained from the Diels-Alder reactions. They showed that the reactivity was not limited to one kind of substituent on the nitrogen ring but was nonetheless limited and that it failed with small changes by substitution on the vinyl group [54].
Few data on the reactivity of 3-and 5-methyl-1-vinylpyrazoles 28 and 29 as dienophiles are available in the literature. Asratyan and coworkers studied the behavior of these pyrazoles as dienophiles in the reaction with cyclohexa-1,3-diene (Scheme 12) [55]. Although 1 Hand 13 C-NMR data showed that 5-methyl-1-vinylpyrazole 29 existed mainly as the S-cis-N 2 isomer, while 3-methyl-1-vinylpyrazole 28 was a roughly equimolar mixture of steric isomers [28], no characteristic differences were found in the behavior of these compounds in the cycloaddition. The reaction with the diene proceeded only at 180 • C to give the product in low yields. When reaction temperature is increased to 220 • C, fast polymerization of the diene and dienophile occurred. The authors suggested that the spatial location of the vinyl group in 1-vinylpyrazoles 28 and 29 with respect to N-2 took no part in the Diels-Alder reaction. The obtained products 30 and 31 went through a hydrogenation reaction to afford compounds 32 and 33. In aprotic solvents, 1-vinylpyrazoles 34 reacted with tetracyanoethylene. The reaction gave mainly l-(2,2,3,3-tetracyano-l-cyclobutyl)pyrazoles 35 as a result of a [2 + 2] cycloaddition involving the formation of a π-π complex at the first stage (Scheme 13) [56]. The reaction occurred in benzene at room temperature for 1-vinylpyrazole but required heating at 80 °C for its 3-methyl and 5-methyl derivatives, while 2-5% of the product was Scheme 12. Diels-Alder reaction of 3-and 5-methyl-1-vinylpyrazoles 28 and 29 with cyclohexa-1,3diene [55].

Polymerization Reactions
Polymerization of vinylpyrazoles has been performed with azo initiators [38]. The rate and extent of polymerization depends on the nature of the substituents on the vinyl group. For example, neat 1-vinylpyrazole polymerizes almost explosively, while 1-(propen-2-yl)pyrazole polymerizes to a lesser extent, and the more heavily substituted the analogs are, the slower the polymerization is. In dilute benzene, 1-vinylpyrazole solution was cleanly polymerized to polymers of molecular weight 150.000-330.000. Furthermore, 1-vinylpyrazole polymerized under free-radical initiation to a high polymer. In this case, the same trend was observed; the extent of polymerization diminished with increasing substitution on the vinyl group. Nikitenko and coworkers studied the free-radical polymerization of 3-methyl-1-vinylpyrazole and 5-methyl-1-vinylpyrazole separately, as individual substances and not as a mixture of isomers [57]. In both cases, the rate of polymerization was proportional to 0.5 order with respect to the initiator azobisisobutyronitrile (AIBN) concentration. When the concentration of monomer was low (≤3M), the reaction followed first-order kinetics, but for higher initial concentrations, the order was lower than the unit. The overall rate of polymerization was found to be higher for 5-methyl-1-vinylpyrazole.

Polymerization Reactions
Polymerization of vinylpyrazoles has been performed with azo initiators [38]. The rate and extent of polymerization depends on the nature of the substituents on the vinyl group. For example, neat 1-vinylpyrazole polymerizes almost explosively, while 1-(propen-2-yl)pyrazole polymerizes to a lesser extent, and the more heavily substituted the analogs are, the slower the polymerization is. In dilute benzene, 1-vinylpyrazole solution was cleanly polymerized to polymers of molecular weight 150.000-330.000. Furthermore, 1vinylpyrazole polymerized under free-radical initiation to a high polymer. In this case, the same trend was observed; the extent of polymerization diminished with increasing substitution on the vinyl group. Nikitenko and coworkers studied the free-radical polymerization of 3-methyl-1-vinylpyrazole and 5-methyl-1-vinylpyrazole separately, as individual substances and not as a mixture of isomers [57]. In both cases, the rate of polymerization was proportional to 0.5 order with respect to the initiator azobisisobutyronitrile (AIBN) concentration. When the concentration of monomer was low (≤3M), the reaction followed first-order kinetics, but for higher initial concentrations, the order was lower than the unit. The overall rate of polymerization was found to be higher for 5-methyl-1-vinylpyrazole.

Halogenation and Hydrohalogenation Reactions
Compared with 1-vinylimidazoles and 1-vinyltriazoles, 1-vinylpyrazoles show a different behavior in bromination reactions [58]. With 1-vinylimidazoles, the formation of a complex with the halogen occurs, while with 1-vinyltriazoles, addition of bromine to the double bond of the vinyl group occurs. Notably, 1-vinylpyrazoles 6 do not form complexes with bromine. The bromination in carbon tetrachloride at −20 • C affords a complex mixture of products that is difficult to separate. The main reaction products are 1-(1',2'-dibromo)ethylpyrazoles 36 and the product of electrophilic substitution at C-4 37; however, the coordination of the released hydrogen bromide with the pyrazoles present in the reaction mixture also produces hydrohalides 38 (Scheme 14). Higher percentages of 36 can be obtained by increasing the temperature, by adding the vinylpyrazole to a solution of bromine, and by using an excess of bromine, but the stability of the bromination products depends on the position and number of substituents in the pyrazole ring, especially methyl groups. dibromo)ethylpyrazoles 36 and the product of electrophilic substitution at C-4 37; however, the coordination of the released hydrogen bromide with the pyrazoles present in the reaction mixture also produces hydrohalides 38 (Scheme 14). Higher percentages of 36 can be obtained by increasing the temperature, by adding the vinylpyrazole to a solution of bromine, and by using an excess of bromine, but the stability of the bromination products depends on the position and number of substituents in the pyrazole ring, especially methyl groups.
The products of the hydrohalogenation of vinylpyrazoles depend on the structure of the pyrazole itself and the nature of the hydrogen halide. Skvortsova and coworkers investigated the hydrohalogenation of a series of vinylpyrazoles 39, (l-vinylpyrazole, 4bromo-l-vinylpyrazole, 3-methyl-l-vinylpyrazole, 5-methyl-l-vinylpyrazole, 3,5-dimethyl-l-vinylpyrazole, and 4-nitro-3,5-dimethyl-l-vinylpyrazole) (Scheme 15) [59]. At −150 °C, addition of hydrogen halides to all l-vinylpyrazoles occurred only at the N-2 with formation of salts 40. However, the hydrohalides of the less basic vinylpyrazoles (l-vinylpyrazole, 4-bromo-l-vinylpyrazole, and 4-nitro-3,5-dimethyl-l-vinylpyrazole) decomposed rapidly. On the other hand, at 20-25 °C, l-vinylpyrazole and 4-bromo-l-vinylpyrazole added predominantly hydrogen halides at the double bond of the vinyl group, with formation of l-(l′-haloethyl)pyrazoles 41, which was in accordance with Markovnikov's rule. Then, the resulting compounds 41 underwent further hydrohalogenation at the N-2 to give compounds 42. Under these conditions, the more basic alkyl-substituted l-vinylpyrazoles produced the corresponding hydrohalides. Addition of hydrogen halides to the double bond of the vinyl group of 4-nitro-3,5-dimethyl-l-vinylpyrazole was more difficult, since the nitro group decreased the nucleophilicity not only of the N-2 but of the double bond of the vinyl group. The reaction of 4-bromo-l-vinylpyrazole with HBr formed a mixture of products, whereas the reaction with HCl proceeded most specifically [59]. Under these conditions, the more basic alkyl-substituted l-vinylpyrazoles produced the corresponding hydrohalides. Addition of hydrogen halides to the double bond of the vinyl group of 4-nitro-3,5-dimethyl-l-vinylpyrazole was more difficult, since the nitro group decreased the nucleophilicity not only of the N-2 but of the double bond of the vinyl group. The reaction of 4-bromo-l-vinylpyrazole with HBr formed a mixture of products, whereas the reaction with HCl proceeded most specifically [59]. ever, the coordination of the released hydrogen bromide with the pyrazoles present in the reaction mixture also produces hydrohalides 38 (Scheme 14). Higher percentages of 36 can be obtained by increasing the temperature, by adding the vinylpyrazole to a solution of bromine, and by using an excess of bromine, but the stability of the bromination products depends on the position and number of substituents in the pyrazole ring, especially methyl groups.
The products of the hydrohalogenation of vinylpyrazoles depend on the structure of the pyrazole itself and the nature of the hydrogen halide. Skvortsova and coworkers investigated the hydrohalogenation of a series of vinylpyrazoles 39, (l-vinylpyrazole, 4bromo-l-vinylpyrazole, 3-methyl-l-vinylpyrazole, 5-methyl-l-vinylpyrazole, 3,5-dimethyl-l-vinylpyrazole, and 4-nitro-3,5-dimethyl-l-vinylpyrazole) (Scheme 15) [59]. At −150 °C, addition of hydrogen halides to all l-vinylpyrazoles occurred only at the N-2 with formation of salts 40. However, the hydrohalides of the less basic vinylpyrazoles (l-vinylpyrazole, 4-bromo-l-vinylpyrazole, and 4-nitro-3,5-dimethyl-l-vinylpyrazole) decomposed rapidly. On the other hand, at 20-25 °C, l-vinylpyrazole and 4-bromo-l-vinylpyrazole added predominantly hydrogen halides at the double bond of the vinyl group, with formation of l-(l′-haloethyl)pyrazoles 41, which was in accordance with Markovnikov's rule. Then, the resulting compounds 41 underwent further hydrohalogenation at the N-2 to give compounds 42. Under these conditions, the more basic alkyl-substituted l-vinylpyrazoles produced the corresponding hydrohalides. Addition of hydrogen halides to the double bond of the vinyl group of 4-nitro-3,5-dimethyl-l-vinylpyrazole was more difficult, since the nitro group decreased the nucleophilicity not only of the N-2 but of the double bond of the vinyl group. The reaction of 4-bromo-l-vinylpyrazole with HBr formed a mixture of products, whereas the reaction with HCl proceeded most specifically [59]. Scheme 15. Main products formed in the hydrohalogenation of 1-vinylpyrazoles 39 [59]. Scheme 15. Main products formed in the hydrohalogenation of 1-vinylpyrazoles 39 [59].

Difluorocyclopropanation Reactions
Fluorinated cyclopropanes have become extraordinary structural motifs with huge importance in organic synthesis, drug discovery, and agrochemistry. In fact, highly potent compounds bearing a gem-difluorocyclopropyl group were disclosed in recent patents [60][61][62][63]. In most of the compounds reported in the literature, the gem-difluorocyclop ropyl is attached to a carbon atom, while the corresponding N-linked analogues are less common. N-vinylpyrazoles 43 and 45 undergo difluorocyclopropanation with CF 3 SiMe 3 -NaI system with formation of the corresponding N-difluorocyclopropyl derivatives 44 and 46 in very good yield (Scheme 16). These compounds are stable and undergo further regioselective functionalization to afford gem-difluorocyclopropylpyrazole amines, carboxylic acids, aldehydes, bromides, and boronic derivatives [64]. It is noteworthy that this method is not successful for the preparation of other azole derivatives, such as imidazoles, triazoles, and tetrazoles, possibly because of the presence of a nucleophilic nitrogen atom (in the case of the imidazole) or electronic effects for the other representatives. system with formation of the corresponding N-difluorocyclopropyl derivatives 44 and 46 in very good yield (Scheme 16). These compounds are stable and undergo further regioselective functionalization to afford gem-difluorocyclopropylpyrazole amines, carboxylic acids, aldehydes, bromides, and boronic derivatives [64]. It is noteworthy that this method is not successful for the preparation of other azole derivatives, such as imidazoles, triazoles, and tetrazoles, possibly because of the presence of a nucleophilic nitrogen atom (in the case of the imidazole) or electronic effects for the other representatives.

Phosphorylation Reactions
The phosphorylation of 1-vinylpyrazole 2 with phosphorus pentachloride afforded phosphorylated azoles 47 and 48 (Scheme 17) [65]. Krivdin and coworkers studied the effects of intramolecular and intermolecular coordination on 31 P nuclear shielding both experimentally and theoretically, with a special emphasis on the calculation of 31 P shielding constants. They noticed dramatic 31 P nuclear shielding to approximately 150 ppm on changing the phosphorus coordination number by one (+(90-120) ppm for tetracoordinated phosphorus, −(20-40) ppm for pentacoordinated phosphorus, and −(200-220) ppm for hexacoordinated phosphorus) and suggested that 31 P-NMR chemical shifts could serve as an unambiguous criterion of intra-or intermolecular coordination involving phosphorus.

Phosphorylation Reactions
The phosphorylation of 1-vinylpyrazole 2 with phosphorus pentachloride afforded phosphorylated azoles 47 and 48 (Scheme 17) [65]. Krivdin and coworkers studied the effects of intramolecular and intermolecular coordination on 31 P nuclear shielding both experimentally and theoretically, with a special emphasis on the calculation of 31 P shielding constants. They noticed dramatic 31 P nuclear shielding to approximately 150 ppm on changing the phosphorus coordination number by one (+(90-120) ppm for tetracoordinated phosphorus, −(20-40) ppm for pentacoordinated phosphorus, and −(200-220) ppm for hexacoordinated phosphorus) and suggested that 31 P-NMR chemical shifts could serve as an unambiguous criterion of intra-or intermolecular coordination involving phosphorus. lective functionalization to afford gem-difluorocyclopropylpyrazole amines, carboxylic acids, aldehydes, bromides, and boronic derivatives [64]. It is noteworthy that this method is not successful for the preparation of other azole derivatives, such as imidazoles, triazoles, and tetrazoles, possibly because of the presence of a nucleophilic nitrogen atom (in the case of the imidazole) or electronic effects for the other representatives.

Phosphorylation Reactions
The phosphorylation of 1-vinylpyrazole 2 with phosphorus pentachloride afforded phosphorylated azoles 47 and 48 (Scheme 17) [65]. Krivdin and coworkers studied the effects of intramolecular and intermolecular coordination on 31 P nuclear shielding both experimentally and theoretically, with a special emphasis on the calculation of 31 P shielding constants. They noticed dramatic 31 P nuclear shielding to approximately 150 ppm on changing the phosphorus coordination number by one (+(90-120) ppm for tetracoordinated phosphorus, −(20-40) ppm for pentacoordinated phosphorus, and −(200-220) ppm for hexacoordinated phosphorus) and suggested that 31 P-NMR chemical shifts could serve as an unambiguous criterion of intra-or intermolecular coordination involving phosphorus.

Organomettalic Reactions
The vinyl group is a stable and versatile N-protection group for bromine-lithium exchange reactions in pyrazoles that can be removed easily under mild conditions. Begtrup

Organomettalic Reactions
The vinyl group is a stable and versatile N-protection group for bromine-lithium exchange reactions in pyrazoles that can be removed easily under mild conditions. Begtrup and coworkers demonstrated that 3,4,5-tribromo-1-vinylpyrazole 8, underwent regioselective bromine-lithium exchange at the 5-position. Subsequent addition of an electrophile gave 5-substituted 3,4-dibromo-1-vinylpyrazoles 51 (Scheme 19) [41]. A range of electrophiles can be introduced at the 5-position. Longer lithiation time (10-15 min) led to lower yields of the 5-substituted product because of the low stability of the pyrazole anion. NH4Cl  H  80  Cl6C2  Cl  82  MeI  Me  78  DMF  CHO  66  Ph2CO  CHPh2OH  81  TsCN  CN  26  TBDMSCl  TBDMS  77  Me2S2  SMe  84  All2S2  SAll  77  Ph2PCl  PPh2  59  Bu3SnCl SnBu3 77 The 5-substituted 3,4-dibromo-1-vinylpyrazoles 51 can undergo subsequent brominelithium or bromine-magnesium exchange using n-BuLi or i-PrMgCl together with protons from methanol as the electrophile, affording compounds 52 and 53. The reaction occurred preferentially at C-4, with the regioselectivity between C-3-and C-4 being influenced by the nature of the metal and the 5-substituent (Scheme 20) [41]. Begtrup and coworkers found that bromine-lithium exchange took place with higher regioselectivity than brominemagnesium exchange. occurred preferentially at C-4, with the regioselectivity between C-3-and C-4 being influenced by the nature of the metal and the 5-substituent (Scheme 20) [41]. Begtrup and coworkers found that bromine-lithium exchange took place with higher regioselectivity than bromine-magnesium exchange.
The vinyl group can be removed from the 5-substituted compounds 51 by mild treatment with KMnO4, affording the corresponding NH-pyrazoles 54. Depending on the substituents, slightly different conditions may be required (Scheme 21) [41]. For example, the vinyl group of 3,4,5-tribromo-1-vinylpyrazole (E = Br) and 3,4-dibromo-5-methyl-1-vinylpyrazole (E = Me) could be removed smoothly in excellent yield (96% for both) by treatment with a 2% solution of KMnO4 at room temperature and at 10 °C. When oxidation sensitive groups such as SMe (E = SMe) are present, the devinylation should be performed at −20 to −10 °C to avoid concurrent oxidation of SMe to SO2Me.

Transition-Metal-Catalyzed Reactions
Transition-metal-catalyzed reactions have gained increasing interest in organic chemistry over the last years because of their versatility and high levels of chemo-, regio-, and stereoselectivity. Many transition-metal complexes of Pd, Au, Zn, Co, Rh, Ru, Mo, Ni, Cu, and Fe have been developed as catalysts to accelerate these organic reactions. One of the hottest topics in transition metal catalysis is the development of highly efficient catalysts for direct C-H bond functionalization reactions. Preferentially, these reactions should be performed in mild conditions (room temperature, weak base, air atmosphere) to allow easy access to nitrogen-containing compounds such as pyrazoles frequently found in pharmaceuticals, crop-protection chemicals, and products for material sciences.

C-H Activation Reactions
Among the transition-metal-catalyzed reactions, C-C bond formation via C-H activation has gaining increasing interest as a very powerful, selective, and atom-economical tool in organic synthesis [71]. Aromatic protons have been commonly involved in this process, but functionalization of the vinyl C-H bond is more challenging because of competitive polymerization or Michael addition reactions, and electron-rich olefins are much less reactive [72]. The 1-vinylpyrazoles 2 and 6 underwent coupling with alkynes via C-H activation to afford Markovnikov-selective butadienylpyrazole derivatives 55 and 57 under mild conditions [73]. This reaction was efficiently catalyzed by the rhodium(I)-N-Scheme 21. Cleavage of the vinyl group of 5-substituted 1-vinylpyrazoles 51 [41].

Transition-Metal-Catalyzed Reactions
Transition-metal-catalyzed reactions have gained increasing interest in organic chemistry over the last years because of their versatility and high levels of chemo-, regio-, and stereoselectivity. Many transition-metal complexes of Pd, Au, Zn, Co, Rh, Ru, Mo, Ni, Cu, and Fe have been developed as catalysts to accelerate these organic reactions. One of the hottest topics in transition metal catalysis is the development of highly efficient catalysts for direct C-H bond functionalization reactions. Preferentially, these reactions should be performed in mild conditions (room temperature, weak base, air atmosphere) to allow easy access to nitrogen-containing compounds such as pyrazoles frequently found in pharmaceuticals, crop-protection chemicals, and products for material sciences.

C-H Activation Reactions
Among the transition-metal-catalyzed reactions, C-C bond formation via C-H activation has gaining increasing interest as a very powerful, selective, and atom-economical tool in organic synthesis [71]. Aromatic protons have been commonly involved in this process, but functionalization of the vinyl C-H bond is more challenging because of competitive polymerization or Michael addition reactions, and electron-rich olefins are much less reactive [72]. The 1-vinylpyrazoles 2 and 6 underwent coupling with alkynes via C-H activation to afford Markovnikov-selective butadienylpyrazole derivatives 55 and 57 under mild conditions [73]. This reaction was efficiently catalyzed by the rhodium(I)-N-heterocyclic carbene catalyst A (A = [Rh(µ-Cl) (IPr) (η 2 -coe)] 2 ) (Rh-NHC). The reaction occurred both with terminal or internal alkynes (Scheme 22) and with terminal diynes (Scheme 23) in mild conditions. With terminal diynes, a mixture of monohydrovinylated Z/gem product 59 and the doubly coupled derivatives bis-Z/gem 60 and Z/gem Z/E 61 was obtained (Scheme 23). The presence of the carbene ligand in the rhodium catalyst was found to be essential for the catalytic coupling and C-H activation of the electron-rich pyrazolyl olefin. Moreover, 1-vinylpyrazole 2 (R 1 = R 2 = H) was more reactive than 3,5-dimethyl-1-vinylpyrazole 6 (R 1 = R 2 = Me), but the reaction with the former presented slightly lower selectivity. It is worth mentioning that even with the diynes, the selectivity trend towards Markovnikov addition products was maintained, with disubstituted pyrazole 6 being slightly more selective than 2. Contrarily to aromatic alkynes, aliphatic terminal alkynes were preferentially hydrovinylated without dimerization, cyclotrimerization, or polymerization of the alkyne.
thyl-1-vinylpyrazole 6 (R 1 = R 2 = Me), but the reaction with the former presented slightly lower selectivity. It is worth mentioning that even with the diynes, the selectivity trend towards Markovnikov addition products was maintained, with disubstituted pyrazole 6 being slightly more selective than 2. Contrarily to aromatic alkynes, aliphatic terminal alkynes were preferentially hydrovinylated without dimerization, cyclotrimerization, or polymerization of the alkyne.
The reaction mechanism started with the C-H activation of the vinylpyrazole assisted by nitrogen coordination to the metallic center. Then, alkyne coordination, insertion, and reductive elimination took place to afford the coupling product (Scheme 24) [73]. The reaction mechanism started with the C-H activation of the vinylpyrazole assisted by nitrogen coordination to the metallic center. Then, alkyne coordination, insertion, and reductive elimination took place to afford the coupling product (Scheme 24) [73].

Reaction with Ethyl N-Trichloroethylidenecarbamate
The reaction of vinylpyrazoles 26, 62, and 27 with N-trichloroethylidenecarbamate, which participates in cycloaddition reactions as a dienophile, as a dipolarophile, and even as a heterodiene, did not afford any cycloaddition product. Under microwave heating, the result of the reaction was found to depend on the nature of the diene and the substitution of the pyrazole ring. In fact, an electrophilic substitution reaction occurred through the exocyclic double bond, which was activated by conjugation with the pyrazole ring, to give Michael addition to the conjugated imine system (Scheme 25) [74]. Even in the 3-and 5substituted pyrazoles 62 and 27, the reaction occurred at the double bond and not in the activated C-4 of the pyrazole ring. A mixture of trans-63 and cis-64 isomers was otained with pyrazole 26 (although the cis was obtained in 15% yield), while the thermodynamic trans isomer 65 and 66 was the only product observed in the reactions of pyrazoles 62 and 27, respectively. Under conventional heating in an oil bath, no reaction occurred under similar conditions of temperature and time, and the starting vinylpyrazoles were not recovered because of dimerization in these conditions.

Reaction with Ethyl N-Trichloroethylidenecarbamate
The reaction of vinylpyrazoles 26, 62, and 27 with N-trichloroethylidenecarbamate, which participates in cycloaddition reactions as a dienophile, as a dipolarophile, and even as a heterodiene, did not afford any cycloaddition product. Under microwave heating, the result of the reaction was found to depend on the nature of the diene and the substitution of the pyrazole ring. In fact, an electrophilic substitution reaction occurred through the exocyclic double bond, which was activated by conjugation with the pyrazole ring, to give Michael addition to the conjugated imine system (Scheme 25) [74]. Even in the 3-and 5-substituted pyrazoles 62 and 27, the reaction occurred at the double bond and not in the activated C-4 of the pyrazole ring. A mixture of trans-63 and cis-64 isomers was otained with pyrazole 26 (although the cis was obtained in 15% yield), while the thermodynamic trans isomer 65 and 66 was the only product observed in the reactions of pyrazoles 62 and 27, respectively. Under conventional heating in an oil bath, no reaction occurred under similar conditions of temperature and time, and the starting vinylpyrazoles were not recovered because of dimerization in these conditions.

Reaction with Alkanethiols
Pyrazoles containing sulfur atoms have interesting biological activities and are used as drugs [75]. This type of pyrazoles can be prepared from vinylpyrazoles and their alkyl derivatives, which are known to react with thiols via either ionic or free radical mechanisms, with the formation of αand β-addition products, depending on whether the addition follows the Markovnikov rule or not, respectively [76].
The method of radical thiylation yields more stable products and is easily and rapidly conducted not only with heating, catalysts, and irradiation with UV light but at 20 • C without special initiation, being a more convenient method of synthesis of pyrazoles with sulfur-containing substituents.

Reaction with Alkanethiols
Pyrazoles containing sulfur atoms have interesting biological activities and are used as drugs [75]. This type of pyrazoles can be prepared from vinylpyrazoles and their alkyl derivatives, which are known to react with thiols via either ionic or free radical mechanisms, with the formation of α-and β-addition products, depending on whether the addition follows the Markovnikov rule or not, respectively [76].
The method of radical thiylation yields more stable products and is easily and rapidly conducted not only with heating, catalysts, and irradiation with UV light but at 20 °C without special initiation, being a more convenient method of synthesis of pyrazoles with sulfur-containing substituents.