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 II...

C−H Bond Arylation of Pyrazoles at the β‐Position: General Conditions and Computational Elucidation for a High Regioselectivity

“…In recent years,s everal methods for the preparation of substituted pyrazoles have been reported such as addition-cyclization, [2+ +2+ +1] annulation or ringopening/cyclization. [2] However,t here is still an eed for simple and effectivemethods for the preparation of 4-arylpyrazoles.…”

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

“…Notably, however this reaction was carried out in toluene at 145 °C in a sealed tube. Recently, Valdés et al reported the synthesis of chiral pyrazoles through the [3+2]‐dipolar cycloaddition of α‐chiral tosylhydrazones with alkynes (Scheme , B) . Interestingly, they observed that the initial cycloadduct underwent [1,5]‐sigmatropic rearrangement with migration of the alkyl group.…”

“…[26] The authors rationalised the transformation through the formation of the enol intermediate which (Scheme 11, B). [27] Interestingly, they observed that the initial cycloadduct underwent [1,5]-sigmatropic rearrangement with migration of the alkyl group. Significantly in their study, they observed that the [1,5]-sigmatropic rearrangement, which has two regioisomeric outcomes, preferentially, but not exclusively, migrates to nitrogen rather than the C(4) carbon.…”

Regioconvergent and Enantioselective Rhodium‐Catalyzed Hydroamination of Internal and Terminal Alkynes: A Highly Flexible Access to Chiral Pyrazoles

“…For these purposes, versatile strategic approaches for the synthesis of aromatic and benzylic N‐substituted pyrazoles have been reported to proceed regioselectively . However, to date, only very limited examples have been documented accessing enantioenriched benzylic N‐substituted pyrazoles in a straightforward, regioselective fashion . The preparation of such chiral pyrazoles either requires multiple steps or is accompanied by the generation of stochiometric amounts of waste as well as strong limitations regarding the substrate variability…”