Acylation pyrazole derivatives

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

Selective protection of 3-aminopyrazoles can lead to a variety of 3-acylaminopyrazole derivatives. 3-Aminopyrazole 317 could be selectively protected at N-2 giving BOC-protected pyrazole 318, which reacted with various acyl chlorides followed by BOG removal to provide 3-acylated pyrazoles 319 (Scheme 30) <2003TL4491>. Other protecting groups such as carbobenzyloxy (Cbz), benzyl (Bn), and SEM could be introduced at the N-2 position with biphasic conditions using potassium hydroxide as the base. A simple procedure for the BOG protection of H-1 of 3-aminopyrazoles has been described where 3-acylaminopyrazole derivatives could be prepared in good yields <2005TL933>. 

The synthesis and relative stability of 3,5-diacyl-4,5-dihydro-l//-pyrazoles prepared by dipolar cycloaddition of enones and a-diazoketones has been published <2004JOC9085>. 3-Acyl-4-aryl-2-pyrazolines have been synthesized by the reaction of a,/3-unsaturated ketones with diazomethane <1996IJB1091>. Ethyl diazoacetate added to 1,3-diarylpropenones in a regioselective fashion to give the intermediate 4,5-dihydto-3//-pyrazole derivative 1,3-hydride shift in the latter led to the formation of the isomeric ethyl 4-aryl-5-aroyl-4,5-dihydro-l//-pyrazole-3-carboxylate and ethyl 4-aryl-3-aroyl-4,5-dihydro-l/7-pyrazole-5-carboxylate in a ratio of 5 1 <2001RJ01517>. 1,3-Dipolar cycloaddition of 2-diazopropane with diarylideneacetones afforded diastereomeric bis-A -pyrazolines <1999T449>. 

Kashima et al. used 2-acyl-3-phenyl-l-menthopyrazoles 10 as chiral acylating agents, in the presence of 1 equiv AICI3 [40]. Interestingly, addition of 1 equiv of diisopropylamine reversed the sense of the enantioselectivity. Such a process shows the power of KR to access either enantiomer, either by using the pyrazole derived from the (-)-menthol or by modifying the experimental conditions. 

Startg. m. warmed at 35° product. Y ca. 100%. - Ring closure to these N-acyl-pyrazole and -indazole derivs. as well as their ring opening with nucleophiles proceeds with great ease. F. e. s. T. Yamazaki and H. Shechter, Tetrah. Let. 1972, 4533. 

Pyrazoles, isoxazoles and isothiazoles with a hydroxyl group in the 3-position (491 Z = NR, O, S) could isomerize to 3-azolinones (492). However, these compounds behave as true hydroxy derivatives and show phenolic properties. They give an intense violet color with iron(III) chloride and form a salt (493) with sodium hydroxide which can be O-alkylated by alkyl halides (to give 494 R = alkyl) and acylated by acid chlorides (to give 494 R = acyl). 

Acylindazoles are good acylating agents, particularly the 2-acetyl-7-nitro derivative (131). The acetylation of pyrazole by this compound proceeds quickly in chloroform and more slowly (about 15 min) in DMSO (66BSF3041). 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

Acyl-4,5-dihydro-pyrazole mit exo-cyclischer Carbonyl-Gruppe werden zu 1 -Alkyl-4,5 -dihydro-pyrazolen reduziert, mit Ausnahme der 1-Formyl-Derivate, die... 

In Scheme 7, ring-opening reactions of some fused pyrazoles are shown. Thus, Baraldi et al. <1999S453> described that the pyrazolo[l,5-<7][l,2,4]triazine-dione derivative 72 is sensitive toward nucleophiles its reaction with benzylamine at room temperature gives rise to the acyl semicarbazide 73 in high yield (78%). 

In pyrazolo[4,3-c]pyrazoles and pyrazolo[3,4-d]-t>-triazoles, acyl derivatives of the type 383, analogs of the stable NH tautomer (Section IV,A, 1) are formed.65,66b-66c-367... 

The acylation of a series of pyrazolo[3,4-c]pyridines has been studied.110 Acetic anhydride in refluxing benzene converted S-substituted derivatives to 1-acyl compounds (101 R2 = H), whereas the 7-methoxy derivative afforded the 2-substituted product 102 (R1 = H, R2 = OMe), attributed to peri interaction. In the absence of solvent, however, the latter reaction gave the 1-acyl isomer as the major product. Furthermore, benzoylation of the 5-chloro bicycle furnished a mixture of 101 and 102 (R1 = Cl, R2 = H). However, products benzoylated mainly at N-6 were obtained following introduction of a nitro group into the pyrazole ring. 

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