Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls

Construction of C–C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C–C bonds in a tricomponent process.

α-Branched carboxylic acids and other carbonyls are readily accessed by a metal- and base-free deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls via boron enolates, resulting in a tricomponent coupling with unconventional electrophiles.     

Photo-induced copper-catalyzed alkynylation and amination of remote unactivated C(sp3)-H bonds

A method for remote radical C–H alkynylation and amination of diverse aliphatic alcohols has been developed. The reaction features a copper nucleophile complex formed in situ as a photocatalyst, which reduces the silicon-tethered aliphatic iodide to an alkyl radical to initiate 1,n-hydrogen atom transfer. Unactivated secondary and tertiary C–H bonds at β, γ, and δ positions can be functionalized in a predictable manner.

Remote C−H alkynylation and amination of aliphatic alcohols.     

Photoredox-enabled 1,2-dialkylation of α-substituted acrylates via Ireland–Claisen rearrangement

Herein, we report the 1,2-dialkylation of simple feedstock acrylates for the synthesis of valuable tertiary carboxylic acids by merging Giese-type radical addition with an Ireland–Claisen rearrangement. Key to success is the utilization of the reductive radical-polar crossover concept under photocatalytic reaction conditions to force the [3,3]-sigmatropic rearrangement after alkyl radical addition to allyl acrylates. Using readily available alkyl boronic acids as radical progenitors, this redox-neutral, transition-metal-free protocol allows the mild formation of two C(sp³)–C(sp³) bonds, thus providing rapid access to complex tertiary carboxylic acids in a single step. Moreover, this strategy enables the efficient synthesis of highly attractive α,α-dialkylated γ-amino butyric acids (GABAs) when α-silyl amines are used as radical precursors – a structural motif that was still inaccessible in related transformations. Depending on the nature of the radical precursors and their inherent oxidation potentials, either a photoredox-induced radical chain or a solely photoredox mechanism is proposed to be operative.

A photocatalytic 1,2-dialkylation of α-substituted acrylates is enabled by a reaction cascade combining reductive radical-polar crossover with the established Ireland–Claisen rearrangement for the synthesis of valuable tertiary carboxylic acids.     

Dynamic kinetic resolution of γ,γ-disubstituted indole 2-carboxaldehydes via NHC-Lewis acid cooperative catalysis for the synthesis of tetracyclic ε-lactones

The ubiquity of ε-lactones in various biologically active compounds inspired the development of efficient and enantioselective routes to these target compounds. Described herein is the enantioselective synthesis of indole-fused ε-lactones by the N-heterocyclic carbene (NHC)-Lewis acid cooperative catalyzed dynamic kinetic resolution (DKR) of in situ generated γ,γ-disubstituted indole 2-carboxaldehydes. The Bi(OTf)₃-catalyzed Friedel–Crafts reaction of indole-2-carboxaldehyde with 2-hydroxy phenyl p-quinone methides generates γ,γ-disubstituted indole 2-carboxaldehydes, which in the presence of NHC and Bi(OTf)₃ afforded the desired tetracyclic ε-lactones in up to 93% yield and >99 : 1 er. Moreover, preliminary studies on the mechanism of this formal [4 + 3] annulation are also provided.

NHC-Lewis acid cooperative catalyzed dynamic kinetic resolution (DKR) of transiently generated γ,γ-disubstituted indole 2-carboxaldehydes leading to the enantioselective synthesis of tetracyclic ε-lactones is reported.     

Arylation of gem-difluoroalkenes using a Pd/Cu Co-catalytic system that avoids β-fluoride elimination

Pd^II/Cu^I co-catalyze an arylation reaction of gem-difluoroalkenes using arylsulfonyl chlorides to deliver α,α-difluorobenzyl products. The reaction proceeds through a β,β-difluoroalkyl–Pd intermediate that typically undergoes unimolecular β-F elimination to deliver monofluorinated alkene products in a net C–F functionalization reaction. However to avoid β-F elimination, we offer the β,β-difluoroalkyl–Pd intermediate an alternate low-energy route involving β-H elimination to ultimately deliver difluorinated products in a net arylation/isomerization sequence. Overall, this reaction enables exploration of new reactivities of unstable fluorinated alkyl–metal species, while also providing new opportunities for transforming readily available fluorinated alkenes into more elaborate substructures.

Pd^II/Cu^I co-catalyze a desulfitative arylation of aliphatic gem-difluoroalkenes in a radical arylation/migratory insertion sequence that avoids β-F elimination.     

Merging C(sp3)–H activation with DNA-encoding

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp³)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp³)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp³) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

DNA-compatible C(sp³)–H activation reactions of aliphatic carboxylic acids, amides, and ketones were developed for efficient access to DEL synthesis.     

Organophotoredox/palladium dual catalytic decarboxylative Csp3–Csp3 coupling of carboxylic acids and π-electrophiles

A dual catalytic decarboxylative allylation and benzylation method for the construction of new C(sp³)–C(sp³) bonds between readily available carboxylic acids and functionally diverse carbonate electrophiles has been developed. The new process is mild, operationally simple, and has greatly improved upon the efficiency and generality of previous methodology. In addition, new insights into the reaction mechanism have been realized and provide further understanding of the harnessed reactivity.

A dual catalytic decarboxylative allylation and benzylation method for the construction of new C(sp³)–C(sp³) bonds between readily available carboxylic acids and functionally diverse carbonate electrophiles has been developed.     

A general method for site-selective Csp3–S bond formation via cooperative catalysis

Herein, we report a copper-catalysed site-selective thiolation of Csp³–H bonds of aliphatic amines. The method features a broad substrate scope and good functional group compatibility. Primary, secondary, and tertiary C–H bonds can be converted into C–S bonds with a high efficiency. The late-stage modification of biologically active compounds by this method was also demonstrated. Furthermore, the one-pot preparation of pyrrolidine or piperidine compounds via a domino process was achieved.

A copper-catalyzed site-selective thiolation of Csp³–H bonds of aliphatic amines was developed. The method features a broad substrate scope and good functional group tolerance.     

Asymmetric synthesis of γ-chiral borylalkanes via sequential reduction/hydroboration using a single copper catalyst

The synthesis of γ-chiral borylalkanes through copper-catalyzed enantioselective S_N2′-reduction of γ,γ-disubstituted allylic substrates and subsequent hydroboration was reported. A copper–DTBM-Segphos catalyst produced a range of γ-chiral alkylboronates from easily accessible allylic acetate or benzoate with high enantioselectivities up to 99% ee. Furthermore, selective organic transformations of the resulting γ-chiral alkylboronates generated the corresponding γ-chiral alcohol, arene and amine compounds.

Copper-catalyzed reductive hydroboration of γ,γ-disubstituted allylic substrates enables preparation of γ-chiral alkylboron compounds in a one-pot cascade manner.     

Diverse strategies for transition metal catalyzed distal C(sp3)–H functionalizations

Transition metal catalyzed C(sp³)–H functionalization is a rapidly growing field. Despite severe challenges, distal C–H functionalizations of aliphatic molecules by overriding proximal positions have witnessed tremendous progress. While usage of stoichiometric directing groups played a crucial role, reactions with catalytic transient directing groups or methods without any directing groups are gaining more attention due to their practicality. Various innovative strategies, slowly but steadily, circumvented issues related to remote functionalizations of aliphatic molecules. A systematic compilation has been presented here to provide insights into the recent developments and future challenges in the field. The Present perspective is expected to open up a new dimension and provide an avenue for deep insights into the distal C(sp³)–H functionalizations that could be applied routinely in various pharmaceutical and agrochemical industries.

Transition metal catalyzed C(sp³)–H functionalization is a rapidly growing field.     

Enantioselective iodolactonization to prepare ε-lactone rings using hypervalent iodine

Despite the rapid growth of enantioselective halolactonization reactions in recent years, most are effective only when forming smaller (6,5,4-membered) rings. Seven-membered ε-lactones, are rarely formed with high selectivity, and never without conformational bias. We describe the first highly enantioselective 7-exo-trig iodolactonizations of conformationally unbiased ε-unsaturated carboxylic acids, effected by an unusual combination of a bifunctional BAM catalyst, I₂, and I(iii) reagent (PhI(OAc)₂:PIDA).

We describe the first highly enantioselective 7-exo-trig iodolactonizations of conformationally unbiased ε-unsaturated carboxylic acids, effected by an unusual combination of a bifunctional BAM catalyst, I₂, and I(iii) reagent (PhI(OAc)₂:PIDA).     

Visible light driven deuteration of formyl C–H and hydridic C(sp3)–H bonds in feedstock chemicals and pharmaceutical molecules

Deuterium labelled compounds are of significant importance in chemical mechanism investigations, mass spectrometric studies, diagnoses of drug metabolisms, and pharmaceutical discovery. Herein, we report an efficient hydrogen deuterium exchange reaction using deuterium oxide (D₂O) as the deuterium source, enabled by merging a tetra-n-butylammonium decatungstate (TBADT) hydrogen atom transfer photocatalyst and a thiol catalyst under light irradiation at 390 nm. This deuteration protocol is effective with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds (e.g. α-oxy, α-thioxy, α-amino, benzylic, and unactivated tertiary C(sp³)–H bonds). It has been successfully applied to the high incorporation of deuterium in 38 feedstock chemicals, 15 pharmaceutical compounds, and 6 drug precursors. Sequential deuteration between formyl C–H bonds of aldehydes and other activated hydridic C(sp³)–H bonds can be achieved in a selective manner.

A selective hydrogen deuterium exchange reaction with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds has been achieved by merging tetra-n-butylammonium decatungstate photocatalyst and a thiol catalyst under 390 nm light irradiation.     

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar–Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp²) electrophile to the resultant Gly–Ni(i) intermediate gives a key Gly–Ni(iii)–Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly–Ni(i) intermediate.

We have developed Ni-catalyzed reductive coupling of N-carbonyl protected α-pivaloyloxy glycine with Csp²-electrophiles that enabled facile preparation of α-amino acids, including those bearing hindered branched vinyl groups.     

Selective α,δ-hydrocarboxylation of conjugated dienes utilizing CO2 and electrosynthesis

To date the majority of diene carboxylation processes afford the α,δ-dicarboxylated product, the selective mono-carboxylation of dienes is a significant challenge and the major product reported under transition metal catalysis arises from carboxylation at the α-carbon. Herein we report a new electrosynthetic approach, that does not rely on a sacrificial electrode, the reported method allows unprecedented direct access to carboxylic acids derived from dienes at the δ-position. In addition, the α,δ-dicarboxylic acid or the α,δ-reduced alkene can be easily accessed by simple modification of the reaction conditions.

Selective electrosynthetic α,δ-hydrocarboxylation of 1,3-dienes is reported, utilising non-sacrificial electrodes that provide access to the previously challenging δ-carboxylated regioisomer.     

Mangana(iii/iv)electro-catalyzed C(sp3)–H azidation

Manganaelectro-catalyzed azidation of otherwise inert C(sp³)–H bonds was accomplished using most user-friendly sodium azide as the nitrogen-source. The operationally simple, resource-economic C–H azidation strategy was characterized by mild reaction conditions, no directing group, traceless electrons as the sole redox-reagent, Earth-abundant manganese as the catalyst, high functional-group compatibility and high chemoselectivity, setting the stage for late-stage azidation of bioactive compounds. Detailed mechanistic studies by experiment, spectrophotometry and cyclic voltammetry provided strong support for metal-catalyzed aliphatic radical formation, along with subsequent azidyl radical transfer within a manganese(iii/iv) manifold.

The merger of manganese-catalyzed C–H functionalization with electrosynthesis enabled C(sp³)–H azidation devoid of chemical oxidants or photochemical irradiation. Detailed mechanistic studies are supportive of a manganese(iii/iv) electrocatalysis.     

Copper catalyzed borocarbonylation of benzylidenecyclopropanes through selective proximal C–C bond cleavage: synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds

A copper catalyzed borocarbonylation of BCPs via proximal C–C bond cleavage for the synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds has been developed. Using substituted benzylidenecyclopropanes (BCPs) and chloroformates as starting material, a broad range of γ-boryl-γ,δ-unsaturated esters were prepared in moderate to excellent yields with excellent regio- and stereoselectivity. Besides, when aliphatic acid chlorides were used in this reaction, γ-boryl-γ,δ-unsaturated ketones could be produced in excellent yields. When substituted BCPs were used as substrates, the borocarbonylation occurred predominantly at the proximal C–C bond trans to the phenyl group in a regio- and stereoselective manner, which leads to the Z-isomers as the products. This efficient methodology involves the cleavage of a C–C bond and the formation of a C–C bond as well as a C–B bond, and provides a new method for the proximal C–C bond difunctionalization of BCPs.

A copper catalyzed borocarbonylation of benzylidenecyclopropanes (BCPs) via proximal C–C bond cleavage for the synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds has been developed.     

Pd-catalyzed stereoselective tandem ring-opening amination/cyclization of vinyl γ-lactones: access to caprolactam diversity

A stereoselective amination/cyclization cascade process has been developed that allows for the preparation of a series of unsaturated and substituted caprolactam derivatives in good yields. This conceptually novel protocol takes advantage of the easy access and modular character of vinyl γ-lactones that can be prepared from simple precursors. Activation of the lactone substrate in the presence of a suitable Pd precursor and newly developed phosphoramidite ligand offers a stereocontrolled ring-opening/allylic amination manifold under ambient conditions. The intermediate (E)-configured ε-amino acid can be cyclized using a suitable dehydrating agent in an efficient one-pot, two-step sequence. This overall highly chemo-, stereo- and regio-selective transformation streamlines the production of a wide variety of modifiable and valuable caprolactam building blocks in an operationally attractive way.

A Pd-mediated stereoselective tandem process has been developed towards a large variety of functional caprolactam synthons.     

Modular synthesis of α-arylated carboxylic acids,esters and amides via photocatalyzed triple C–F bond cleavage of methyltrifluorides

α-Arylated carboxylic acids, esters and amides are widespread motifs in bioactive molecules and important building blocks in chemical synthesis. Thus, straightforward and rapid access to such structures is highly desirable. Here we report an organophotocatalytic multicomponent synthesis of α-arylated carboxylic acids, esters and amides from exhaustive defluorination of α-trifluoromethyl alkenes in the presence of alkyltrifluoroborates, water and nitrogen/oxygen nucleophiles. This operationally simple strategy features a unified access to functionally diverse α-arylated carboxylic acids, esters, and primary, secondary, and tertiary amides through backbone assembly from simple starting materials enabled by consecutive C–F bond functionalization at room temperature. Preliminary mechanistic investigations reveal that the reaction operates through a radical-triggered three-step cascade process, which involves distinct mechanisms for each defluorinative functionalization of the C–F bond.

Here we report an organophotocatalytic synthesis of α-arylated carboxylic acids, esters and amides from exhaustive defluorination of α-trifluoromethyl alkenes in the presence of alkyltrifluoroborates, water and nitrogen/oxygen nucleophiles.     

A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,β-unsaturated esters

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

The activation of both aromatic and aliphatic ureas as N-centered nucleophiles in intramolecular Michael addition reactions to α,β-unsaturated esters was achieved under bifunctional iminophosphorane squaramide superbase catalysis.