Alkylation pyrazol-5-ones

Although A-alkylation is one of the most important and most studied reactions of pyrazoles, its quantitative (orientation ratios) and qualitative (mechanism) aspects are still unclear. All the classical results are reported in (67HC(22)l, B-76MI40402) and can be summarized as follows. 

But when Begtrup (88BSB573) (Scheme 7) treated the pyrazol-3-one 19/pyrazole 20 tautomeric mixture with 4-methoxybenzyl chloride he obtained 5% of O-alkylated pyrazole derivative 21 and 70% of l-(4-methoxybenzyl)pyrazol-3-one 22. 

The use of sodium hydrogen carbonate under solvent-free conditions and microwave irradiation is best method for N-alkylating pyrazoles. The yields are good and the method is devoid of side reactions like quatemization, isomerization and hydrogen halide elimination. Solvent-free conditions are the only ones that allow the preparation of 1-substituted pyrazoles from secondary halides (Almena et al., 2009). 

Arylenamino)-5-ones were converted into a benzodiazepine by Pd/C and H2 while the alkyl counterpart produced a pyrazole and pyrazolone as shown in Scheme 71 <73CB332). 

Fused pyrazole compounds have been prepared from A-alkyl substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond were formed in one pot <060L2043>. A variety of highly substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from IV-bromoalkyl pyrazoles 57 and aryl iodides 58. 

The catalysed alkylation of l//,4//-pyrazol-5-ones is solvent dependent. In benzene, bis-alkylation occurs at the 4-position whereas, in a carbon disulphide benzene mixture, O-alkylation is observed, although the major product (4, Scheme 5.22) results from nucleophilic attack by the pyrazolone on the carbon disulphide, followed by alkylation of the dithiolate dianion [92]. The catalysed reaction of 2-thiono-3-aryl-thiazolidin-4-ones with alkylating agents under soliddiquid two-phase conditions results in alkylation at the 5-position (60-80%) [93]. The aldol condensation of the thiazolidinones with aryl aldehydes is also catalysed by quaternary ammonium salts. 

Carbon disulphide should not be used as the solvent for alkylation of fS-diketones, as the carbanion reacts preferentially with the solvent to generate the dithiocarboxyl-ate derivative, which undergoes mono- and dialkylation (Scheme 6.9) [95]. Ketene thioacetals have also been isolated from acetophenones (60-80%) and cyclopenta-diene (80%) using an ultrasound technique in carbon disulphide [96] and, in a similar manner, pyrazol-5-ones form pyrazole-4-dithiocarboxylic esters [97]. 

Further examples of alkylation of imidazole derivatives were recently reported by Galous et a/.145 The nature and importance of significant factors in phase transfer alkylation of pyrazole was studied by Elguero et al.146 Their conclusions are equivalent to those of Dehmlow and Lissel.147 The optimization method used by Elguero et al. (several parameters at a time) is different from the conventional procedure (one parameter at a time) and will probably find applications in the future for optimization of organic syntheses. 

Tarrago et al.149 have reported an interesting example of a change in selectivity induced by PT catalysis. In N-alkylation of pyrazoles (83), the ratio 84/85 is different under neutral or alkaline conditions, especially when a heteroatom with a lone pair is located ortho to one of the nitrogens of the... 

Alkyl- or aryl-substituted pyrazole 1-oxides 94 can be obtained in acceptable yields by oxidative cyclization of O-silylated 3-oximimines like 1 -tert-hutyldimethyIsilyloxy-4-methylamino-1 -azab nta-1,3-diene 93 using copper(II) sulfate as the oxidant and pyridine and acetonitrile as the solvent. The oximimines are prepared from 1,3-dicarbonyl compounds 92 in a one-pot process. The method also gives access to 2-alkyl and aryl-pyrazole 1-oxides R=H devoid of substituents at the ring carbon atoms (94 Ri = R2=H) (1995JCS(P1)2773) (Scheme 27). 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

---