Arylation of α‐Chiral Ketones by Palladium‐Catalyzed Cross‐Coupling Reactions of Tosylhydrazones with Aryl Halides

Abstract

The carbonyl group is probably the most versatile functional group in organic synthesis, owing to its rich and highly developed chemistry. In particular, carbonyl compounds are extraordinary sources of enantiomerically pure compounds, that can be obtained from the chiral pool from terpenes, carbohydrates, and amino acids, and also through asymmetric catalysis [1] and organocatalysis.[2] However, carbonyl compounds bearing chirality at the a carbon can be difficult to manipulate owing to their configurational instability through enolization. Moreover, the typical formation of alkenes by nucleophilic-addition/elimination sequences usually affords the more-substituted olefin, [3] with loss of the chiral information (Figure 1 a), and the reactions that proceed through the formation of enolates, such as cross-coupling reactions through enol sulfonates, require tightly controlled kinetic conditions to avoid the equilibration of the chiral center (Figure 1 c). [4,5] For these reasons, the development of methodologies that allow the manipulation of the carbonyl functionality with preservation of the a chirality are highly desirable.The palladium-catalyzed cross-coupling between tosylhydrazones and aryl halides, recently developed by our group, [6] constitutes an efficient method to manipulate the carbonyl functionality. The overall transformation is equivalent to a nucleophilic addition/elimination sequence. However, as we will show herein, in many cases the reaction gives the lesssubstituted alkene, and importantly, with no erosion of the chirality of the stereogenic center at the a position (Figure 1 d); thus, we report the implementation of this new methodology for the manipulation of a-chiral ketones.The catalytic cycle proposed for the palladium-catalyzed cross-coupling between tosylhydrazones and aryl halides is presented in Figure 2. The characteristic steps are formation of the palladium-carbene complex VII, migratory insertion of the aryl to give the alkylpalladium complex VIII, [7,8] and synb-hydride elimination, that releases the coupling product. For tosylhydrazones derived from ketones with two enolizable positions, such as I, two regioisomers II and III can be obtained that differ in the position of the double bond. [6a,c, 8] Cross-coupling reactions of tosylhydrazones derived from ketones with two enolizable positions and aryl halides: the regioselectivity in the formation of the double bond is determined by the syn-bhydride-elimination step on alkylpalladium complex VIII. xphos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

Palladium‐Catalyzed/Norbornene‐Mediated CH Activation/ N‐Tosylhydrazone Insertion Reaction: A Route to Highly Functionalized Vinylarenes

“…The use of 1.5 equiv of NEt 3 as co-base did not improve the yield (data not shown). For the palladium catalysts, various Pd II and Pd 0 were investigated, however, they were less efficient than Pd(OAc) 2 ( Table 1, entries [16][17][18][19][20]. Employing dppb as the ligand gave moderate yields (Table 1, entry 15).…”

Stereoselective Csp3–Csp2 Bond‐Forming Reactions by Transition‐Metal‐Free Reductive Coupling of Cyclic Tosylhydrazones with Boronic Acids

“…Chem.E ur.J.2016, 22,6253 -6257 www.chemeurj.org carbon atom, [13] we selected the tosylhydrazone 11,t hat can be readily obtained as au nique enantiomer from (À)-menthol (Scheme 4). Both menthone and its tosylhydrazone 11 have been reported to undergo easy partial epimerization of the acarbon atom, [14] but nevertheless 11 has been successfully employed for the synthesis of sterochemically pure menthol derivatives through Shapiror eactions.…”

Base‐Promoted/Gold‐Catalyzed Intramolecular Highly Selective and Controllable Detosylative Cyclization

“…[1] Since the diazo compounds are usually unstable, the in situ generation of diazo intermediates from readily available N-tosylhydrazones, via af ormal Bamford-Stevens process, [2] has been alternativelye mployed. [3] Nevertheless, the N-tosylhydrazone chemistry has some unique characteristics,p articularly in the absence of metalc atalysts, andv ariety of related transformations, [4] such as XÀHi nsertions (X = N, O, etc. ), [5] cross-couplings [6] and carbonylations, [7] have been carriedo ut with high efficiency.The intermolecular dimerization of diazo compounds to produce alkenes has been known for decades, [8] but, in comparison, the intramolecular couplingh as been less investigated.…”