Yun-He Xu

Palladium‐Catalyzed Direct CH Arylation of Enamides with Simple Arenes

The realm of transition-metal-catalyzed cross-coupling reactions has traditionally depended on prefunctionalized substrates for both reactivity and selectivity. The quest for improved atom economy and efficiency has brought forward revolutionary changes and important advances especially in the palladium-catalyzed direct C H functionalization where one or ideally both coupling partners could be replaced with simple arenes/alkenes. A vast majority of these tandem C H activation reactions are devoted on the synthesis of biaryl motifs. Direct oxidative coupling of unactivated arenes with olefins, the Fujiwara–Moritani reactions are comparatively under-explored in terms of the olefinic substrate scope and selectivity. Given the synthetic and economic potential of these reactions, development of new olefin functionalities that could be coupled with simple arenes is much warranted. Enamides are stable enamine surrogates and important synthetic intermediates having tunable reactivity and potential usage in various transformations. Development of effective and direct olefin functionalization of these compounds is highly desirable, because it provides access to multisubstituted amines and olefins, which are scaffolds that are pivotal in natural products as well as in molecular materials. Absolute stereocontrol of the double bond in these type of transformations is quite challenging, particularly when Z-enamides are required. Herein we present our results on the palladium-catalyzed direct arylation of enamides by using unactivated arenes through double C H functionalization. To our knowledge, this is the first report on the catalytic direct arylation of enamides and provides cost-effective and efficient access to highly substituted enamides with perfect Z selectivity. The initial screening studies were carried out using the enamide substrate 1 (Table 1, entry 1). Benzene was chosen as the model arene partner and used as the solvent, too. Sodium acetate was employed as a base and a stoichiometric amount of palladium acetate was used for the initial studies to avoid any side reactions that may happen with a terminal oxidant. Enamide 1 decomposed to the corresponding ketone under the reaction temperature of 80 8C (no reaction was observed at room temperature). We assumed that protecting the nitrogen atom of the enamide would increase the chemical stability of the enamide under the reaction conditions, and accordingly the N-methylated substrate 2 (Table 1, entry 2) was tested next. Significantly the substrate underwent a clean conversion and 59% of the desired arylated product 2a was isolated as a single stereoisomer (Z configuration as evidenced by NOESY, see the Supporting Information). The doubly acylated enimide 3 responded poorly under the reaction conditions (Table 1, entry 3). We reasoned that the electron density of the double bond is crucial for the coupling reaction and switched to the benzyl-protected substrate 4. Gratifyingly the product 4a was isolated in 91% yield in 26 h solely as the Z isomer (Table 1, entry 4, see the Supporting Information for the NMR proof for the Z configuration). Further increase of the electron density through a p-methoxy benzyl protection (enamide 5) did not alter the reaction profile (Table 1, entry 5). The carbonyl ligand on the nitrogen atom was also modified (enamide 6), but an E/Z mixture of the product 6a was isolated in a yield of 78% (Table 1, entry 6). Table 1: Effect of various nitrogen-protecting groups on the reactivity of enamides towards direct arylation.

Synthesis of multi-substituted pyrroles using enamides and alkynes catalyzed by Pd(OAc)2 with molecular oxygen as an oxidant

A cyclization reaction between enamides and alkynes catalyzed by palladium(II) acetate is described. In this method, the molecular oxygen serves as an efficient oxidant for the Pd(II)/Pd(0) catalytic cycle. The simple reaction conditions permit this methodology to be used as a general tool for the preparation of multi-substituted pyrroles.

Palladium(II)-catalyzed cross-coupling of simple alkenes with acrylates: a direct approach to 1,3-dienes through C–H activation

The results from a direct palladium-catalyzed cross-coupling reaction between a variety of olefins with acrylate through vinylic C–H activation that give the corresponding butadienes in moderate to good yields and stereoselectivities are reported. Given the reactions ability to tolerate a wide range of styrenes, aliphatic alkenes and acrylates, this atom- and step-economical methodology offers a straightforward method to forge new C–C bonds of the valuable diene products from readily available starting materials under very mild reaction conditions.

Direct coupling of sp3 carbon of alkanes with α,β-unsaturated carbonyl compounds using a copper/hydroperoxide system

A new methodology for the monovalent copper-initiated direct coupling of alkanes and hydroperoxides with unsaturated carbonyl compounds is developed. In this work, α,β-unsaturated carbonyl compounds underwent alkylation and peroxidation to give synthetically useful α-peroxy ketones with wide functional group tolerance. The resulting α-peroxy ketones could be easily transformed into very useful α-hydroxy ketones.

Chelation versus Non-Chelation Control in the Stereoselective Alkenyl sp2 C-H Bond Functionalization Reaction

A hydroxy group chelation-assisted stereospecific oxidative cross-coupling reaction between alkenes was developed under mild reaction conditions. In the presence of palladium catalyst, the alkenes tethered with hydroxy functionality can couple efficiently with electron-deficient alkenes to form the corresponding multi-substituted olefin products. The hydroxy group on the substrate could play dual roles in reaction, acting as the directing group for alkenyl C-H bond activation and controlling the stereoselectivity of the products.

Macrolide Synthesis through Intramolecular Oxidative Cross-Coupling of Alkenes

A RhIII -catalyzed intramolecular oxidative cross-coupling between double bonds for the synthesis of macrolides is described. Under the optimized reaction conditions, macrocycles containing a diene moiety can be formed in reasonable yields and with excellent chemo- and stereoselectivity. This method provides an efficient approach to synthesize macrocyclic compounds containing a 1,3-conjugated diene structure.

Copper-catalyzed enantioselective conjugate addition of grignard reagents to methyl 4,4,4-trifluorocrotonate: synthesis of enantioenriched trifluoromethylated compounds.

Copper-catalyzed enantioselective 1,4-conjugate addition of methyl 4,4,4-trifluorocrotonate with aliphatic Grignard reagents to access an asymmetric tertiary carbon center attached with a trifluoromethyl group was achieved under mild reaction conditions. The desired products could be obtained in reasonable yields and good enantioselectivities.

Copper-Catalyzed Dehydrogenative Diels–Alder Reaction

A practical and effective copper-catalyzed dehydrogenative Diels-Alder reaction of gem-diesters and ketone with dienes has been established. The active dienophiles were generated in situ via a radical-based dehydrogenation process, which reacted with a wide variety of dienes to afford various polysubstituted cyclohexene derivatives in good to excellent yields.

Palladium-Catalyzed One-Pot Highly Regioselective 6-Endo Cyclization and Alkylation of Enynoates: Synthesis of 2-Alkanone Pyrones

The Pd(II)-catalyzed one-pot tandem cyclization/alkylation reactions of enynoates with allylic alcohols have been demonstrated. In this reaction, an innovative protocol proceeded well through Pd-catalyzed intramolecular selective 6- endo cyclization, insertion of allylic alcohols into the Pd-C bond of vinylpalladium species generated in situ, and β-hydrogen elimination processes. This conversion provides a convenient and efficient methodology for the synthesis of 2-alkanone pyrones in moderate to good yields.

Palladium-Catalyzed Regioselective Olefination of O-Acetyl Cyanohydrins

A practical palladium-catalyzed ortho-olefination of O-acetyl cyanohydrins assisted by synergetic directing groups has been developed. Thus, a range of olefinated O-acetyl cyanohydrins were synthesized in moderate to good yields. The reaction occurs efficiently with high regioselectivity and with a satisfactory tolerance of functional groups.