Abstract
Alkylamino coupling reactions at the C4 positions of 4-halo-1H-1-tritylpyrazoles were investigated using palladium or copper catalysts. The Pd(dba)2 catalyzed C-N coupling reaction of aryl- or alkylamines, lacking a β-hydrogen atom, proceeded smoothly using tBuDavePhos as a ligand. As a substrate, 4-Bromo-1-tritylpyrazole was more effective than 4-iodo or chloro-1-tritylpyrazoles. Meanwhile, the CuI mediated C-N coupling reactions of 4-iodo-1H-1-tritylpyrazole were effective for alkylamines possessing a β-hydrogen atom.
Highlights
Synthetic methodologies towards a range of substituted pyrazoles have been developed, as they commonly exhibit bioactivities such as antitumor, antiviral, and antifungal activities
Introduction of various functional groups at specific positions on a pyrazole ring is an important and attractive endeavor inMsoylencutlhese2t0ic20o, 2r5g, axnFOicRcPhEeEmR RisEtVryIE.WIn particular, the synthesis of C4-aminated pyrazoles has be2coof 1m2 e a prominent research topic, due to the important bioactivities exhibited by this compound class, as shcoawtanlyisntsF, pigruecreat1a.lysts, and bulky ligands
Numerous combinations of catalysts and ligands exist that are suitable for specific coupling reactions [11,12,13,14,15,16,17,18]
Summary
Synthetic methodologies towards a range of substituted pyrazoles have been developed, as they commonly exhibit bioactivities such as antitumor, antiviral, and antifungal activities. In the case of commonly used bidentate ligands, namely 1,1’-bis(diphenylphosphino)ferrocene (dppf, L1), 1,2-bis(diphenylphosphino)ethane (dppe, L2), and 2,2’-bis(diphenylphosphino)diphenyl ether (DPEPhos, L3), the reaction did not proceed (entries 1–3), while with the use of the bulky tBuDavePhos ligand (L4) the desired coupled product 2a was obtained in 21% yield; L4 was Molecules 2020, 25, 4634 the experimental process. Reactions with aromatic amines (anilines and 1-naphtylamine) gave the corresponding 2o (94%), 2p (91%), and 2q (85%) in high yields (entries 15–17) as being analogous to Buchwald’s findings [21]. Reactions of 1Br with pyrrolidine, allylamine, or primary amines bearing a β-hydrogen atom resulted in low yields (entries 3–12), while amines lacking a β-hydrogen afforded good yields (entries 13–18) These contrasting results are likely due to β-elimination occurring in the palladium complex during the coupling process. Entries 13–18 were performed with 1.1 equivalents of amine
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