Conventional approaches for Pd‐catalyzed ring‐opening cross‐couplings of gem‐difluorocyclopropanes with nucleophiles predominantly deliver the β‐fluoroalkene scaffolds (linear selectivity). Herein, ...we report a cooperative strategy that can completely switch the reaction selectivity to give the alkylated α‐fluoroalkene skeletons (branched selectivity). The unique reactivity of hydrazones that enables analogous inner‐sphere 3,3′‐reductive elimination driven by denitrogenation, as well as the assistance of steric‐embedded N‐heterocyclic carbene ligand, are the key to switch the regioselectivity. A wide range of hydrazones derived from naturally abundant aryl and alkyl aldehydes are well applicable, and various gem‐difluorocyclopropanes, including modified pharmaceutical and biological molecules, can be efficiently functionalized with high value alkylated α‐fluorinated alkene motifs under mild conditions.
A highly effective Pd‐catalyzed defluorinative alkylation of gem‐difluorocyclopropane with branched selectivity was achieved by using a cooperative strategy that integrated the unique trifunctional character of hydrazones with Pd/NHC catalysis.
Employing phenols and phenol derivatives as electrophiles for cross-coupling reactions has numerous advantages over commonly used aryl halides in terms of environmental-friendliness and ...sustainability. In the early stage of discovering such transformations, most efforts have been devoted to utilizing highly activated sulfonate types of phenol derivatives (e.g., OTf, OTs, etc.), which have similar reactivities to the corresponding aryl halides. However, a continuing scientific challenge is how to achieve the direct C–O functionalizations of relatively less-activated phenol derivatives more efficiently. In this review, we will focus on the recent updates on the C–O functionalizations of less-activated phenol derivatives, from aryl carboxylates (e.g., pivalates, acetates, etc.), aryl carbamates and carbonates, to aryl ethers (anisoles, diaryl ethers, aryl pyridyl ethers, aryl silyl ethers), to phenolate salts, and ultimately to simply unprotected phenols, sorted by the types of bond formations. Both transition-metal-catalyzed and transition-metal-free protocols will be covered and discussed in detail. Instead, the C–O functionalizations of aryl sulfonates will not be covered extensively unless they are closely related, due to their high reactivity. Since aryl ethers and phenols represent the main linkages or units in lignin biomass, the successes of such transformations will potentially make major contributions to the direct lignin biomass upgrading and depolymerization.
Synthetic chemists aspire both to develop novel chemical reactions and to improve reaction conditions to maximize resource efficiency, energy efficiency, product selectivity, operational simplicity, ...and environmental health and safety. Carbon−carbon bond formation is a central part of many chemical syntheses, and innovations in these types of reactions will profoundly improve overall synthetic efficiency. This Account describes our work over the past several years to form carbon−carbon bonds directly from two different C−H bonds under oxidative conditions, cross-dehydrogenative coupling (CDC). We have focused most of our efforts on carbon−carbon bonds formed via the functionalization of sp3 C−H bonds with other C−H bonds. In the presence of simple and cheap catalysts such as copper and iron salts and oxidants such as hydrogen peroxide, dioxygen, tert-butylhydroperoxide, and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), we can directly functionalize various sp3 C−H bonds by other C−H bonds without requiring preactivation. We demonstrate (1) reaction of α-C−H bonds of nitrogen in amines, (2) reaction of α-C−H bonds of oxygen in ethers, (3) reaction of allylic and benzylic C−H bonds, and (4) reaction of alkane C−H bonds. These CDC reactions can tolerate a variety of functional groups, and some can occur under aqueous conditions. Depending on the specific transformation, we propose the in situ generation of different intermediates. These methods provide an alternative to the separate steps of prefunctionalization and defunctionalization that have traditionally been part of synthetic design. As a result, these methods will increase synthetic efficiencies at the most fundamental level. On an intellectual level, the development of C−C bond formations based on the reaction of only C−H bonds (possibly in water) challenges us to rethink some of the most fundamental concepts and theories regarding chemical reactivities. A successful reaction requires the conventionally and theoretically less reactive C−H bonds to react selectively in the presence of a variety of functional groups. With further investigation, we expect that C−C bond formations based on cross-dehydrogenative coupling will have a positive economic and ecological impact on the next generation of chemical syntheses.
Abstract
Hydrogen atom abstraction (HAT) from C(
sp
3
)–H bonds of naturally abundant alkanes for alkyl radical generation represents a promising yet underexplored strategy in the alkylation reaction ...designs since involving stoichiometric oxidants, excessive alkane loading, and limited scope are common drawbacks. Here we report a photo-induced and chemical oxidant-free cross-dehydrogenative coupling (CDC) between alkanes and heteroarenes using catalytic chloride and cobalt catalyst. Couplings of strong C(
sp
3
)–H bond-containing substrates and complex heteroarenes, have been achieved with satisfactory yields. This dual catalytic platform features the in situ engendered chlorine radical for alkyl radical generation and exploits the cobaloxime catalyst to enable the hydrogen evolution for catalytic turnover. The practical value of this protocol was demonstrated by the gram-scale synthesis of alkylated heteroarene with merely 3 equiv. alkane loading.
Despite their impressive capacity to access diverse functional groups and to synthesize structurally complex molecules, the majority of the organic reactions suffers from harsh conditions, low atom ...economy, and hazardous waste production. The goal of our research is geared towards developing efficient methods to minimize the adverse environmental impact and contributing to chemical sustainability. Herein, we illustrate three distinct green approaches, studying the novel reactivities with environmentally innocuous reagents to improve the synthetic efficiency, utilization of natural feedstocks, and employment of green energy to facilitate various important chemical transformations. From this perspective article, we hope to provide an overview of green synthetic chemistry and inspire the expansion of the field in the future.
Green synthesis and catalysis play key roles in future chemical sustainability. Various examples drawn from our lab are used to discuss potential chemistry tools to convert resources prevalent in nature more efficiently into valuable products. Display omitted
The first example of homogeneous copper‐catalyzed aerobic oxidation of aldehydes is reported. This method utilizes atmospheric oxygen as the sole oxidant, proceeds under extremely mild aqueous ...conditions, and covers a wide range of various functionalized aldehydes. Chromatography is generally not necessary for product purification.
Without ‘Fehl ’: The first example of homogeneous copper‐catalyzed aerobic oxidation of aldehydes is reported. This method utilizes atmospheric oxygen as the sole oxidant, proceeds under extremely mild aqueous conditions, and covers a wide range of various functionalized aldehydes. Chromatography is generally not necessary for product purification.
Phenols are common precursors and core structures of a variety of industrial chemicals ranging from pharmaceuticals to polymers. However, the synthesis of site‐specifically substituted phenols is ...challenging, and thus the development of new methods for this purpose would be highly desirable. Reported here is a protocol for palladium‐catalyzed ortho‐selective alkylation reactions of phenols with primary alcohols by a dearomatization‐rearomatization strategy, with water as the sole by‐product. Various substituted phenols and primary alcohols were compatible with the standard reaction conditions. The detailed mechanism of this transformation was also investigated.
A dearomatization‐rearomatization strategy was developed for palladium‐catalyzed cross‐coupling reactions of phenols and inexpensive primary alcohols to site‐specifically generate ortho‐alkyl‐substituted phenols. Water was the sole by‐product of the reaction, making it a green method for site‐specific synthesis of these phenols.
The simple and efficient conversion of carbonyl compounds into functionalized alkanes via deoxygenation is highly enabling in chemical synthesis. This Review covers the recent methodology development ...in carbonyl and carboxyl deoxygenative functionalizations, highlighting some representative and significant contributions in this field. These advances are categorized based on the reactivity patterns of some oxygenated feedstock compounds, including aldehydes, ketones and carboxylic acids. Four types of reactive intermediates arising from aldehydes and ketones during the deoxygenation, namely, bis‐electrophiles, carbenoids, bis‐nucleophiles and alkyl radical equivalents, are presented, while the carboxylic acids mainly behave as tris‐electrophiles when deoxygenated. In each subcategory, selected examples are organized according to the type of bond formation and discussed from a generalized mechanistic perspective.
This Review recaps the development of selected deoxygenation methodologies for aldehydes, ketones and carboxylic acids, which take full advantage of the tremendous yet underexplored synthetic potential of carbonyl and carboxyl groups. Representative literature examples are discussed and their general features summarized, including characteristic reaction intermediates, typical reactivity patterns and commonly used conditions.
Lignin is the second most abundant organic matter on Earth, and is an underutilized renewable source for valuable aromatic chemicals. For future sustainable production of aromatic compounds, it is ...highly desirable to convert lignin into value‐added platform chemicals instead of using fossil‐based resources. Lignins are aromatic polymers linked by three types of ether bonds (α‐O‐4, β‐O‐4, and 4‐O‐5 linkages) and other C−C bonds. Among the ether bonds, the bond dissociation energy of the 4‐O‐5 linkage is the highest and the most challenging to cleave. To date, 4‐O‐5 ether linkage model compounds have been cleaved to obtain phenol, cyclohexane, cyclohexanone, and cyclohexanol. The first example of direct formal cross‐coupling of diaryl ether 4‐O‐5 linkage models with amines is reported, in which dual C(Ar)−O bond cleavages form valuable nitrogen‐containing derivatives.
From waste to value: A strategy for converting renewable lignin biomass into value‐added nitrogen‐containing chemicals is reported. Model compounds of lignin containing a 4‐O‐5 linker were cross‐coupled with amines by dual C(Ar)−O bond cleavages to generate valuable nitrogen‐containing derivatives.
One of the major research endeavors in synthetic chemistry over the past two decades is the exploration of synthetic methods that work under ambient atmosphere with benign solvents, that maximize ...atom utilization, and that directly transform natural resources, such as renewable biomass, from their native states into useful chemical products, thus avoiding the need for protecting groups. The nucleophilic addition of terminal alkynes to various unsaturated electrophiles is a classical (textbook) reaction in organic chemistry, allowing the formation of a C−C bond while simultaneously introducing the alkyne functionality. A prerequisite of this classical reaction is the stoichiometric generation of highly reactive metal acetylides. Over the past decade, our laboratory and others have been exploring an alternative, the catalytic and direct nucleophilic addition of terminal alkynes to unsaturated electrophiles in water. We found that various terminal alkynes can react efficiently with a wide range of such electrophiles in water (or organic solvent) in the presence of simple and readily available catalysts, such as copper, silver, gold, iron, palladium, and others. In this Account, we describe the development of these synthetic methods, focusing primarily on results from our laboratory. Our studies include the following: (i) catalytic reaction of terminal alkynes with acid chloride, (ii) catalytic addition of terminal alkynes to aldehydes and ketones, (iii) catalytic addition of alkynes to CN bonds, and (iv) catalytic conjugate additions. Most importantly, these reactions can tolerate various functional groups and, in many cases, perform better in water than in organic solvents, clearly defying classical reactivities predicated on the relative acidities of water, alcohols, and terminal alkynes. We further discuss multicomponent and enantioselective reactions that were developed. These methods provide an alternative to the traditional requirement of separate steps in classical alkyne reactions, including the pregeneration of metal acetylides with stoichiometric, highly basic reagents and the preprotection of sensitive functional groups. Accordingly, these techniques have greatly enhanced overall synthetic efficiencies and furthered our long-term objective of developing Grignard-type reactions in water.
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