Atanu Modak

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.

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.

Meta-selective arene C-H bond olefination of arylacetic acid using a nitrile-based directing group.

A nitrile-based template attached with a phenylacetic acid framework promoted meta-selective C-H bond olefination. This palladium-catalyzed protocol is applicable to a wide range of substituted phenylacetic acids and tolerates a variety of functional groups. The versatility of this operationally simple method has been demonstrated through drug diversification.

Palladium‐Catalyzed Directed para C−H Functionalization of Phenols

Various practical methods for the selective C-H functionalization of the ortho and recently also of the meta position of an arene have already been developed. Following our recent development of the directing-group-assisted para C-H functionalization of toluene derivatives, we herein report the first remote para C-H functionalization of phenol derivatives by using a recyclable silicon-containing biphenyl-based template. The effectiveness of this strategy was illustrated with different synthetic elaborations and by the synthesis of various phenol-based natural products.

Predictably Selective (sp3)C–O Bond Formation through Copper Catalyzed Dehydrogenative Coupling: Facile Synthesis of Dihydro-oxazinone Derivatives

An intramolecular dehydrogenative (sp(3))C-O bond formation in salicylamides can be initiated by an active Cu/O2 species to generate pharamaceutically relevant dihydro-oxazinones. Experimental findings suggest that stereoelectronic parameters in both coupling partners are controlling factors for site selectivity in bond formation. Mechanistic investigations including isotope labeling, kinetic studies helped to propose a catalytic cycle. The method provides a convenient synthesis of an investigational new medicine CX-614, which has potential in finding treatment for Parkinsons and Alzheimers diseases.

Iron-Catalyzed Regioselective Direct Arylation at the C-3 Position of N-Alkyl-2-pyridone

A number of pharmaceutical compounds possess an arylated 2-pyridone moiety. The existing reports using expensive starting materials and/or superstoichiometric metal salts have prompted us to explore a possible user-friendly method for their synthesis. In this report, we demonstrate an easy-to-handle reaction condition with an iron catalyst for the exclusive generation of C-3-arylated pyridone via C-H functionalization.

Nickel-catalyzed hydrogenolysis of unactivated carbon–cyano bonds

Selective hydrogenolysis of C-CN bonds can allow chemists to take advantage of ortho-directing ability, α-C-H acidity and electron withdrawing ability of the cyano group for synthetic manipulations. We have discovered hydrogenolysis of aryl and aliphatic cyanides under just 1 bar of hydrogen by using a nickel catalyst. This protocol was applied in the aryl cyanide directed functionalization reaction and α-substitution of benzyl cyanides.

Remote meta C–H bond functionalization of 2-phenethylsulphonic acid and 3-phenylpropanoic acid derivatives

This discovery illustrates selective meta C-H bond activation from multiple non-equivalent C-H bonds present in medicinally relevant arylethanesulfonic acid and the 2-arylpropanoic acid moiety using weakly coordinating nitrile as a directing group. Transformation of the meta olefinated compounds to important organic molecules has been demonstrated. Efforts were made to obtain mechanistic detail of the meta C-H bond functionalization reaction.

CHAPTER 12:Direct Arylation via C–H Activation

The realm of transition metal-catalyzed direct arylation via C–H activation has undergone significant advances in recent years. It has been established as a viable alternative to the standard cross-coupling reaction with organometallic reagents. The use of directing moieties, often through coordination to the catalytic metal, enhances the reactivity and regioselectivity of the C–H activation. In this chapter, the contribution of transition metals such as palladium, rhodium, ruthenium, iridium and copper is discussed. Mechanistic aspects, including the roles of the potential directing groups and of other additives, are emphasized. This chapter serves a concise summary along with essential information that could be beneficial for further understanding and development.