Synthesis of spirocyclic dihydropyrazoles from tosylhydrazones and electron-deficient alkenes

Abstract

Spirocyclic heterocycles are highly three-dimensional scaffolds with significant utility in medicinal chemistry. This report demonstrates a procedurally simple method for the synthesis of a range of medicinally relevant spirocyclic dihydropyrazoles.

Photogenerated donor–donor diazo compounds enable facile access to spirocyclopropanes

“…19 Although this method was initially applied only to benzylic tosylhydrazones, in the following years several groups developed protocols that also enabled aliphatic hydrazones to initiate intra-and intermolecular cycloadditions. [20][21][22][23][24] An early example combining both the tosylhydrazone based cycloaddition and the extrusion of nitrogen from D 1 -pyrazolines to form cyclopropanes was published by Taber and Guo. 24 They utilized tethered substrates that formed annulated D 1 -pyrazolines intramolecularly which, upon irradiation with UV-light, produced the desired cyclopropanes in moderate yields over two steps (Scheme 1).…”

“…Allwood and co-workers developed an intermolecular synthesis of spiropyrazoline motifs from aliphatic tosylhydrazones under thermal conditions. 21,23 Similar to other previously developed thermal protocols, refluxing the mixture of tosylhydrazone and base for long times was necessary to achieve adequate yields. We are pleased to report that when similar substrates are employed under our photochemical reaction conditions, we observe the formation of the desired structures within 60 minutes under very mild conditions.…”

Automated multistep synthesis of 2-pyrazolines in continuous flow

“…40 A photochemical method was recently reported for the synthesis of spiro-Δ 2 -pyrazolines. 41 This approach involved the cycloaddition of a diazo compound with an electron-deficient alkene, and, unlike previous studies that required refluxing of tosylhydrazones and base for longer times, 42,43 achieved the desired reaction under mild conditions.…”

Synthesis and drug development of small molecule inhibitors of PTP1B

“…Scheme 37: Failed functionalised reactions of hit compound 30a. Scheme 37 145,148,149,159,161,167,168 shows two-alternative attempted methods for the synthesis of compound 52a. In both cases only starting material was recovered, implying conditions were insufficient for reactivity.…”

“…This was reason why the prior optimised synthesis of spirocyclic dihydropyrazoles was used for the formation of a compound library for PTP1B inhibition testing, the synthesis of which was originally conducted for an unrelated publication cited here. 167 The predominant reason for the interest in investigating 5,6-spirocyclic dihydropyrazoles as potential PTP inhibitors was the active site example hit 3 from Chapter 2 (section 2.3.2) which closely resembles that of a 5,6 -spirocycle dihydropyrazoles. Specifically, because the two-step linear synthesis of which was mostly investigated and optimised during prior work conducted during a master's level research project.…”