Regio‐ and Enantioselective Synthesis of N‐Substituted Pyrazoles by Rhodium‐Catalyzed Asymmetric Addition to Allenes

Abstract

The rhodium-catalyzed asymmetric N-selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)-ruxolitinib.

Palladium‐ and Rhodium‐Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes Towards Chiral Pyrazoles

“…[5] In the presence of asuitable chiral rhodium catalyst these reactions proceed with perfect branched regioselectivity and in many cases with excellent control of enantioselectivity. [6] However, most of these reactions furnish allylic products with amonosubstituted terminal alkene functionality.H owever,i tw ould be synthetically very attractive to access also disubstituted allylic alkene moieties,w hich might be accessible upon addition of pronucleophiles to 1,3-disubstituted allenes possessing axial chirality. [7] An ideal asymmetric transformation would start from racemic 1,3-disubstituted allenes and transform them into the corresponding allylation products in a dynamic kinetic resolution (DKR) [8,9] process.T his would demand ac atalyst allowing for fast allene racemization relative to pronucleophile addition as well as as ignificantly enhanced catalyst activity since 1,3-disubstituted allenes have shown to be significantly less reactive.A sp articularly attractive pronucleophiles we selected pyrazoles since many a-chiral N-alkylated pyrazoles have shown to have impressive medicinal properties such as BMS-394136 (Ikur inhibitor), [10] ibrutinib (Brutonstyrosine kinase inhibitor) [11] or ruxolitinib (JAK1/2 kinase inhibitor;Scheme 1).…”

“…[15] Scheme 1. Several functional groups were tolerated such as halogens (3)(4)(5)(6), esters (10,(22)(23), nitriles (11,20), and pinacolboranes (12), which in turn allow further modifications by Suzuki-Miyaura cross-coupling reactions. With the optimal reaction conditions in hand, first the substrate scope of the palladium system was studied.…”

Enantioselective, Stereodivergent Hydroazidation and Hydroamination of Allenes Catalyzed by Acyclic Diaminocarbene (ADC) Gold(I) Complexes

“…[7] Fewer still are enantioselective hydroazidation reactions, which have only been reported in a formal sense via conjugate addition to activated double bonds (Scheme 1). [8–10] In light of recent examples of transition-metal catalysed asymmetric additions of nitrogen nucleophiles to allenes [11] and the growing utility of organic azides, we sought to develop a gold(I)-catalyzed enantioselective hydroazidation of allenes. Cognizant of potential regioselectivity issues from the Winstein rearrangement [12] of the product allylic azides, we initiated our studies using aryl allene 3a .…”

Enantioselective C−H Activation with Earth‐Abundant 3d Transition Metals

“…[38] Essential to the success was the use of the JoSPOphos [39] pre-ligand 30,whose applications had until then been restricted to rhodium(I)catalyzed hydrofunctionalizations. [40] Remarkably,w hile all other investigated catalysts required AlMe 3 as the additive, the transformation was found to occur efficiently in the absence of pyrophoric organoaluminium reagents.V arious substituted benzimidazoles,including electron-rich, electronpoor,and chlorinated derivatives,aswell as abroad variety of bioactive heterocyclic motifs,h ighly functionalized purines and theophylline derivatives,p erformed well. Furthermore, the reaction was found to be highly chemoselective with respect to several different olefinic motifs present on the same substrate.…”