Regioselective Thermal [3+2]‐Dipolar Cycloadditions of α‐Diazoacetates with α‐Sulfenyl/Sulfinyl/Sulfonyl‐β‐Chloroacrylamide Derivatives to Form Densely Functionalised Pyrazoles

Abstract

Highly regioselective synthetic methodology leading to densely functionalised C(3), C(4) and C(5) substituted pyrazoles 10a–q, 14a‐i and 16a–g via thermal [3+2]‐dipolar cycloaddition, of α‐diazoacetates and α‐thio‐β‐chloroacrylamides, at the sulfide, sulfoxide and sulfone levels of oxidation, is described. This method allows access to C(4)‐sulfenyl or sulfonyl pyrazoles, through migration of the sulfur substituent at the sulfide and sulfone oxidation levels, while elimination of the sulfinyl group leading to 3,5‐disubstituted pyrazoles, is observed. While the sulfide migration is readily rationalised, the carbon to carbon 1,2‐sulfonyl migration is unprecedented and mechanistically intriguing. The synthetically versatile generation of densely functionalised pyrazoles containing substituents amenable to further modification offers advantages over alternative synthetic routes. Isolation of the N‐alkylated pyrazoles 11a and 12a as by‐products from the cycloaddition through further reaction of the pyrazoles 10 with excess α‐diazoacetate, proved useful in rationalising the tautomeric behaviour evident in the NMR spectra of the pyrazoles, with the position of tautomeric equilibrium influenced by solvent and substituents.

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

“…To assign the regiochemistry of isolated N-1 and N-2 substituted indazole isomers, a combination of one and two-dimensional NMR experiments (particularly, heteronuclear multiple bond correlation (HMBC)) was employed [27]. For example, ( 1 H-13 C) HMBC analysis of N-1 regioisomer 10 shows a 1 H- 13 C correlation between the C-7a carbon of the indazole ring and the n-pentyl CH 2 proton pair proximal to the indazole N-1 atom (Figure 2).…”

Synthesis of Pyrazoles by 1,3‐Dipolar Cycloaddition under Aqueous Micellar Catalysis

“…Ethyl 5‐(benzylcarbamoyl)‐1 H ‐pyrazole‐3‐carboxylate 25 a [27] . White solid, 136.0 mg (yield: 31 %).…”

“…13 Ethyl 5-(benzylcarbamoyl)-1H-pyrazole-3-carboxylate 25 a. [27] White solid, 136.0 mg (yield: 31 %). 1 1 H NMR (600 MHz, CDCl 3 ) δ 7.35 (h, J = 6.6, 6.1, 5H), 7.16 (d, J = 5.8, 1H), 4.64 (d, J = 5.9, 2H), 4.45 (q, J = 7.1, 2H), 1.42 (t, J = 7.1, 3H).…”

Transition Metal‐ and Oxidant‐Free Regioselective Synthesis of 3,4,5‐Trisubstituted Pyrazoles by Means of [3+2] Cycloaddition Reactions

“…The 13 C NMR showed a peak at δ 163.28 corresponds À C=O carbon of the amide group. [37] The molecular weight of the compound was determined by the peak at m/z 308.1397 corresponds [M + H] + in HRMS spectrum.…”