When Hydrazonoyl Chlorides Meet Allenes: a Site- and Regio-Selective Copper(I)-Catalysed Approach to 5-Substituted Pyrazoles

Abstract

The reaction between hydrazonoyl chlorides and monosubstituted allenes in the presence of catalytic amounts of copper(I) chloride gives 1,3,5-substituted pyrazoles under mild conditions and very short reaction times.This site-and regioselective process involves first the complexation of copper(I) on the external double bond of the allene moiety, followed by nucleophilic attack on the central carbon atom of the so-formed copper(I)-complexed allene by the terminal nitrogen of the hydrazonoyl chloride. Subsequent ring closure to the target pyrazole ring is possible in the presence of electron-attracting groups on the allene moiety. A catalytic cycle has been proposed on the basis of the experimental results.Allenes can undergo a wide variety of reactions 1 including the celebrated Diels-Alder 1,2 and 1,3-dipolar 3 cycloadditions. To this latter respect, allenes are particularly interesting dipolarophiles as they have two sites of addition, for each of which two different dipole-dipolarophile orientations are possible. Several years ago, one of us was engaged in the synthesis of highly-functionalised pyrazoles by cycloaddition between allenes and nitrilimines, 4 -C≡N + -N -, owing to the fact that variously functionalised pyrazoles are interesting targets in medicinal chemistry as analgesic, antifungal, anti-inflammatory, antibacterial and antiviral agents. 5 Unfortunately, it was found that the obtainment of complex reaction mixtures was often the rule, i.e. the cycloaddition showed poor site-and regio-selectivity. Furthermore, the reaction outcome was strongly dependent on the electronic nature of the 1,3-dipole: while electron-rich nitrilimines gave fair results, the cycloaddition pathway appeared impervious with electron-poor nitrilimines. Since the in situ generation of the labile nitrilimine intermediate was accomplished by dehydrohalogenation of the corresponding hydrazonoyl chloride -C(Cl)=N-NHwith stoichiometric amounts of silver carbonate, 4,6 it is apparent that a site-and regio-selective approach to the pyrazole ring

Advances in the Synthesis of Heterocycles with Two and Three Heteroatoms using Hydrazonoyl Halides

“…Subsequent nucleophilic attack of the central carbon atom of the resulting [allen – copper(I)] complex 203 by the terminal nitrogen atom of nitrilimine generated from hydrazonoyl chloride 201 is completed by closure into the target pyrazole ring 204 ( Scheme 62). [123] …”

“…Subsequent nucleophilic attack of the central carbon atom of the resulting [allen -copper(I)] complex 203 by the terminal nitrogen atom of nitrilimine generated from hydrazonoyl chloride 201 is completed by closure into the target pyrazole ring 204 (Scheme 62). [123] Double 1,3-dipolar cycloaddition of nitrilimines generated from hydrazonoyl chlorides 205 to 1,1disubstituted allenes 206 resulted in the formation of spirobidihydropyrazoles 207 in moderate to excellent yields and high diastereoselectivity (Scheme 63). The reaction takes place under mild conditions and two chiral centers are formed, one of which is a spirocarbon center.…”

Copper(I)-Catalysed Reaction of Hydrazonyl Chlorides with Homopropargylic Alcohols: Regioselective Synthesis of 5-Substituted Pyrazoles

“…This is an undoubtedly synthetic advantage that is the consequence of the reaction mechanism, which is well described by a catalytic cycle involving metallate intermediates. 7 8…”

“…This is an undoubtedly synthetic advantage that is the consequence of the reaction mechanism, which is well described by a catalytic cycle involving metallate intermediates. 7,8 Beyond the mechanistic features of the copper(I)-catalysed reaction between hydrazonoyl chlorides and terminal alkynes, the main interest in the synthesis of variously substituted pyrazoles lies in their pharmaco-clinical properties as analgesic, antifungal, anti-inflammatory, antibacterial, and antiviral agents. 9 Not by chance, hydrazonoyl halides have been defined as 'a bubbling fountain of biologically active compounds'.…”