Arghya Deb

Oxidative Trifluoromethylation of Unactivated Olefins: An Efficient and Practical Synthesis of α-Trifluoromethyl-Substituted Ketones†

The incorporation of a CF3 group in a compound of pharmacological relevance usually results in significant enhancement of its lipophilicity, binding selectivity, and metabolic stability. A number of highly effective methods for the incorporation of a CF3 moiety into commonly used synthetic scaffolds have been reported. In this context, the synthesis of a-CF3-substituted carbonyl compounds [10–14] has recently drawn significant attention, owing to their importance for both pharmaceutical and synthetic research. Generally, a-CF3-substituted carbonyl compounds are prepared from silyl enol ethers and enolates by using various radical and electrophilic trifluoromethylating agents (Scheme 1). Strong bases, such as lithium diisopropylamide (LDA), are often employed in the synthesis of these precursors, thus limiting the available methods by extra

Remote para-C–H Functionalization of Arenes by a D-Shaped Biphenyl Template-Based Assembly

Site-selective C-H functionalization has emerged as an efficient tool in simplifying the synthesis of complex molecules. Most often, directing group (DG)-assisted metallacycle formation serves as an efficient strategy to ensure promising regioselectivity. A wide variety of ortho- and meta-C-H functionalizations stand as examples in this regard. Yet despite this significant progress, DG-assisted selective para-C-H functionalization in arenes has remained unexplored, mainly because it involves the formation of a geometrically constrained metallacyclic transition state. Here we report an easily recyclable, novel Si-containing biphenyl-based template that directs efficient functionalization of the distal p-C-H bond of toluene by forming a D-shaped assembly. This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C-H activation. The applicability of this D-shaped biphenyl template-based strategy is demonstrated by synthesizing various complex molecules.

Palladium-Catalyzed Aryl C–H Olefination with Unactivated, Aliphatic Alkenes

Palladium-catalyzed coupling between aryl halides and alkenes (Mizoroki-Heck reaction) is one of the most popular reactions for synthesizing complex organic molecules. The limited availability, problematic synthesis, and higher cost of aryl halide precursors (or their equivalents) have encouraged exploration of direct olefination of aryl carbon-hydrogen (C-H) bonds (Fujiwara-Moritani reaction). Despite significant progress, the restricted substrate scope, in particular noncompliance of unactivated aliphatic olefins, has discouraged the use of this greener alternative. Overcoming this serious limitation, we report here a palladium-catalyzed chelation-assisted ortho C-H bond olefination of phenylacetic acid derivatives with unactivated, aliphatic alkenes in good to excellent yields with high regio- and stereoselectivities. The versatility of this operationally simple method has been demonstrated through drug diversification and sequential C-H olefination for synthesizing divinylbenzene derivatives.

A general and efficient aldehyde decarbonylation reaction by using a palladium catalyst

A facile decarbonylation reaction of aldehydes has been developed by employing Pd(OAc)(2). A wide variety of substrates are decarbonylated, without using any exogenous ligand for palladium as well as CO-scavenger.

Detailed Mechanistic Studies on Palladium-Catalyzed Selective C–H Olefination with Aliphatic Alkenes: A Significant Influence of Proton Shuttling

Directing group-assisted regioselective C-H olefination with electronically biased olefins is well studied. However, the incorporation of unactivated olefins has remained largely unsuccessful. A proper mechanistic understanding of olefination involving unactivated alkenes is therefore essential for enhancing their usage in future. In this Article, detailed experimental and computational mechanistic studies on palladium catalyzed C-H olefination with unactivated, aliphatic alkenes are described. The isolation of Pd(II) intermediates is shown to be effective for elucidating the elementary steps involved in catalytic olefination. Reaction rate and order determination, control experiments, isotopic labeling studies, and Hammett analysis have been used to understand the reaction mechanism. The results from these experimental studies implicate β-hydride elimination as the rate-determining step and that a mechanistic switch occurs between cationic and neutral pathway. Computational studies support this interpretation of the experimental evidence and are used to uncover the origins of selectivity.

Copper/P(tBu)3-Mediated Regiospecific Synthesis of Fused Furans and Naphthofurans

A novel [3+2] cycloaddition between a variety of cyclic ketones and diverse olefins or alkynes can be effectively promoted by copper in combination with the tri-tert-butylphosphine [P(tBu)3 ] ligand. This protocol exhibits excellent selectivity and provides an exemplary set of fused heterocycles in good to excellent yields. Present strategy also represents an extremely simple and atom-economic way to construct substituted fused furans and naphthofurans from readily available starting materials under mild reaction conditions. The utility of the method is further demonstrated by the synthesis of chiral furans from (R)-(-)-carvone and (S)-(+)-carvone. A plausible mechanism involving the oxidative radical cyclization has been suggested based on experimental observations.