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

Abstract

Abstract:The reactions between terminal alkynes and -chiral tosylhydrazones lead to the obtention of chiral pyrazoles with a stereogenic group directly attached at a nitrogen atom, through cascade reactions that include decomposition of the hydrazone into a diazocompound, 1,3-dipolar cycloaddition of the diazo compound with the alkyne and 1,5-sigmatropic rearrangement with migration of the stereogenic group. This strategy have been succesfully applied to the synthesis of structurally diverse chiral pyrazoles from -chiral tosylhydrazones obtained from -phenylpropionic acid, -aminoacids and 2-methoxycyclohexanone. Noteworthy, the stereoretentive 1,5-sigmatropic rearrangements represent very rare examples of this stereospecific transformation.The pyrazole ring is a five-membered heterocycle present in a large number of molecules with biological activity.[1] Compounds containing substituted pyrazoles find widespread as antimicrobials, analgesics, anti-inflamatory agents, CNS and oncology drugs. [2][3][4][5] Indeed, pyrazoles are constantly employed as building blocks in drug discovery programs. [6,7] Moreover, structures built around the pyrazole scaffold are also found as key constituents of ligands for transition metals with biological or catalytic activity, [8] receptors in supramolecular chemistry, [9] and functional organic materials.[10] For these reasons, and in spite of the variety of existing methods, the development of new methodologies for the efficient regioselective synthesis of polysubstituted pyrazoles is still an area of very active research. [11,12] A particularly challenging type of pyrazoles are chiral pyrazoles with a stereogenic carbon attached at N-position. Limited examples of this type of chiral pyrazoles with biological activity have been reported, [13] but their usefulness have been hampered by the lack of general methods for their preparation. Chiral pyrazoles with a sterogenic center attached at the nitrogen have been synthesized from chiral amines, [14] and also by alkylation of the corresponding N-H pyrazole through Mitsunobu reactions of chiral alcohols, [13,15] ring opening of chiral or meso epoxides, [16] and organocatalytic aza-Michael reactions. [17] Nevertheless, these methods are far from general and have been mostly employed on unsubstituted pyrazole.We have recently reported the regioselective synthesis of 1,3,5-trisubstituted pyrazoles II and 3,4,5-pyrazoles III from the reaction of tosylhydrazones I and terminal alkynes by a 1,3-dipolar cycloaddition/1,5-sigmatropic rearrangement sequence (Scheme 1).[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 ...

Luxury of N‐Tosylhydrazones in Transition‐Metal‐Free Transformations

“…In subsequent work, an asymmetric variant of this methodology was employed by the same research group for the synthesis of N ‐chiral pyrazoles 102 from α‐chiral tosylhydrazones 101 and terminal alkynes under similar reaction conditions (Scheme ) . This chemo‐, regio‐ and stereoselective cascade proceeds via diazo formation/1,3‐dipolar cycloaddition/[1,5]‐sigmatropic rearrangement.…”

Hydrazones as Substrates in the Synthesis of Isoxazolidines via a KOH-Promoted One-Pot Three-Component Cycloaddition with Nitroso Compounds and Olefins

“…The design of environmentally friendly multicomponent cycloaddition reactions, which use cheap and readily available starting materials bearing a wider substrate range for the rapid assembly of complex molecules, is generally preferred in the context of sustainable chemistry. Hydrazones, as an important class of synthetic intermediates, have been widely applied in many cycloadditions with a broad scope . However, their applications in multicomponent cycloaddition for the preparation of highly functionalized target molecules are scarcely observed …”