The story of C-C bond formation includes several reactions, and surely Suzuki-Miyaura is among the most outstanding ones. Herein, a brief historical overview of insights regarding the reaction mechanism is provided. In particular, the formation of the catalytically active species is probably the main concern, thus the preactivation is in competition with, or even assumes the role of the rate determining step (rds) of the overall reaction. Computational chemistry is key in identifying the rds and thus leading to milder conditions on an experimental level by means of predictive catalysis.

Mechanistic Aspects of the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction.

Dipolar aprotic and ethereal solvents comprise just over 40% of all organic solvents utilized in synthetic organic, medicinal, and process chemistry. Unfortunately, many of the common “go-to” solvents are considered to be “less-preferable” for a number of environmental, health, and safety (EHS) reasons such as toxicity, mutagenicity, carcinogenicity, or for practical handling reasons such as flammability and volatility. Recent legislative changes have initiated the implementation of restrictions on the use of many of the commonly employed dipolar aprotic solvents such as dimethylformamide (DMF) and N-methyl-2-pyrrolidinone (NMP), and for ethers such as 1,4-dioxane. Thus, with growing legislative, EHS, and societal pressures, the need to identify and implement the use of alternative solvents that are greener, safer, and more sustainable has never been greater. Within this review, the ubiquitous nature of dipolar aprotic and ethereal solvents is discussed with respect to the physicochemical properties that have made them so appealing to synthetic chemists. An overview of the current legislative restrictions being imposed on the use of dipolar aprotic and ethereal solvents is discussed. A variety of alternative, safer, and more sustainable solvents that have garnered attention over the past decade are then examined, and case studies and examples where less-preferable solvents have been successfully replaced with a safer and more sustainable alternative are highlighted. Finally, a general overview and guidance for solvent selection and replacement are included in the Supporting Information of this review.

Replacement of Less-Preferred Dipolar Aprotic and Ethereal Solvents in Synthetic Organic Chemistry with More Sustainable Alternatives

The challenging transamidation of unactivated tertiary amides has been accomplished via cooperative acid/iodide catalysis. Most crucially, the method provides a novel manifold to re-route the reactivity of unactivated N,N-dialkyl amides through reactive acyl iodide intermediates, thus reverting the classical order of reactivity of carboxylic acid derivatives. This method provides a direct route to amide-to-amide bond interconversion with excellent chemoselectivity using equivalent amounts of amines. The combination of acid and iodide has been identified as the essential factor to activate the amide C-N bond through electrophilic catalytic activation, enabling the production of new desired transamidated products with wide substrate scope of both unactivated amides and amines, including late-stage functionalization of complex APIs (>80 examples). We anticipate that this powerful activation mode of unactivated amide bonds will find broad-ranging applications in chemical synthesis.

https://rss.onlinelibrary.wiley.com/doi/am-pdf/10.1002/anie.202202794

Highly Chemoselective Transamidation of Unactivated Tertiary Amides by Electrophilic N-C(O) Activation via Amide-to-Acyl Iodide Re-Routing.

Ground-state destabilization of the N-C(O) linkage represents a powerful tool to functionalize the historically inert amide bond. This burgeoning reaction manifold relies on the availability of amide bond precursors that participate in weakening of the nN → π*C=O conjugation through N-C twisting, N pyramidalization, and nN electronic delocalization. Since 2015, acyl N-C amide bond activation through ground-state destabilization of the amide bond has been achieved by transition-metal-catalyzed oxidative addition of the N-C(O) bond, generation of acyl radicals, and transition-metal-free acyl addition. This Perspective summarizes contributions of our laboratory in the development of new ground-state-destabilized amide precursors enabled by twist and electronic activation of the amide bond and synthetic utility of ground-state-destabilized amides in cross-coupling reactions and acyl addition reactions. The use of ground-state-destabilized amides as electrophiles enables a plethora of previously unknown transformations of the amide bond, such as acyl coupling, decarbonylative coupling, radical coupling, and transition-metal-free coupling to forge new C-C, C-N, C-O, C-S, C-P, and C-B bonds. Structural studies of activated amides and catalytic systems developed in the past decade enable the view of the amide bond to change from the "traditionally inert" to "readily modifiable" functional group with a continuum of reactivity dictated by ground-state destabilization.

Classes of Amides that Undergo Selective N-C Amide Bond Activation: The Emergence of Ground-State Destabilization.

Sonogashira cross-coupling protocol, typically showing the reaction between aryl/vinyl halide and terminal alkyne, has been a widely used protocol for constructing C(sp2)-C(sp) bond. The resulting internal alkynes are highly versatile for reaching differently functionalized alkyne-containing scaffolds or serving as valuable synthetic synthons to many other functional groups. It is worth noting that products originated from this coupling reaction are mostly applicable to be transformed into corresponding Z-alkene, alkane, or heterocyclic moieties in natural product syntheses. The reaction conditions and catalyst systems are able to be tweaked in order to facilitate the activation of steric hindered and/or electron-rich electrophiles. Pd-catalyzed copper-free Sonogashira coupling reaction has caught increasing attention as the improved method can be more environmentally friendly. What is more, the conditions of the coupling reaction can be readily amended to allow the fusion of other carbonylation or decarboxylation step in the catalytic cycle, and thus allow more complex yet versatile convergent synthesis to proceed in an operationally simple one-pot manner. 

Recent Expedition in Pd‐Catalyzed Sonogashira Coupling and Related Processes

A range of environmentally friendly solvents was evaluated in the Suzuki–Miyaura coupling of amides in an attempt to provide the first solvent selection guide for the powerful C–C coupling by amide...

Green Solvent Selection for Suzuki–Miyaura Coupling of Amides

Green-Solvent Selection for Acyl Buchwald–Hartwig Cross-Coupling of Amides (Transamidation)

Sonogashira Cross-Coupling of Aryl Ammonium Salts by Selective C-N Activation Catalyzed by Air- and Moisture-Stable, Highly Active [Pd(NHC)(3-CF3-An)Cl2] (An = Aniline) Precatalysts.

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Green Solvent Selection for Suzuki–Miyaura Coupling of Amides

Green-Solvent Selection for Acyl Buchwald–Hartwig Cross-Coupling of Amides (Transamidation)

Sonogashira Cross-Coupling of Aryl Ammonium Salts by Selective C-N Activation Catalyzed by Air- and Moisture-Stable, Highly Active [Pd(NHC)(3-CF3-An)Cl2] (An = Aniline) Precatalysts.