Regioselective One‐Step Synthesis of Pyrazoles from Alkynes and N‐Tosylhydrazones: [3+2] Dipolar Cycloaddition/[1,5] Sigmatropic Rearrangement Cascade

Synthesis of Chiral Pyrazoles: A 1,3‐Dipolar Cycloaddition/[1,5] Sigmatropic Rearrangement with Stereoretentive Migration of a Stereogenic Group

“…Nevertheless, the conditions developed in our previous work (K2CO3, 1,4-dioxane, 110 ºC) turned out to be appropriate again. As expected, the 1,3,5-trisubstitued pyrazole 4a turned out to be the major isomer (6: 1 , 4a: 5a ratio as determined by 1 H NMR on the reaction crude and GC/MS), [18] which could be very easily obtained in pure form after chromatography, due to the very different eluting properties of both regioisomers. The same reaction was then conducted with the tosylhydrazone obtained from the enantiomerically pure carboxylic acid (R)-(−)-2-phenylpropionic acid.…”

“…In our previous communication, [18] we had reported that tosylhydrazones derived from -N-azole substituted ketones, led to the 1,3,5-trisubstituted pyrazoles with high yields and total regioselectivity. Therefore, we decided to explore the same reaction with the analogous chiral derivatives.…”

“…[18] The mechanism proposed for these cascade processes involves the following steps: 1) decomposition of the tosylhydrazone to produce a diazo compound IV, 2) 1,3-dipolar cycloaddition of the diazo compound with the terminal alkyne to form a 3H-pyrazole V, [19,20] 3) 1,5-sigmatropic rearrangement which may lead to 1,3,5-substituted 1H-pyrazole II or to a new 4H-pyrazole VI. The latter will undergo additional [1,5]-sigmatropic shifts to provide the aromatic 3,4,5-pyrazole III (Scheme 1).…”

“…[18,19] Thus, in the examples above, the presence of the methoxy group is essential to drive the reaction towards the formation of the pyrazoles 13. Importantly, determination of the enantiomeric purity on the products derived from the enantiomerically pure tosylhydrazone revealed an enantiomeric ratio > 99:1, indicating that the whole process had proceeded again with complete preservation of the chiral information.…”

Cooperative Iodide Pd(0)‐Catalysed Coupling of Alkoxyallenes and N‐Tosylhydrazones: A Selective Synthesis of Conjugated and Skipped Dienes

“…Moreover, thanks to the very short reactiont ime, this coupling is compatible with acetylenes without producing any pyrazolef rom [3+ +2] dipolar cycloaddition (entry 21). [33] Finally the reactionw as extended to different protected alkoxyallenes (1b, c)w ithout remarkable changes with respectt ob enzyl group (entries [16][17][18][19][20]. In all cases isomer E was predominant with the E/Z ratio determined by 1 HNMR spectroscopy and gas chromotography.T races of the regioisomerd erived from the carbene a-additionw ere detected in some cases (see the Supporting Information).…”