Jason Williams

Radical chemistry meets NHCs: NHC catalysis and single electron oxidants have been merged in several transformations, allowing the synthesis of useful β-hydroxy esters, cyclopentanones, and spirocyclic γ-lactones in a highly stereoselective manner. The key step is the oxidation of the NHC homoenolate equivalent to a radical species via a single-electron transfer process (see scheme).

We report a kinetic and spectroscopic analysis of alkyne-dependent chemoselectivity in the copper-catalyzed azide–alkyne click (CuAAC) reaction. Studies of six alkyne subtypes reveal that the rate-determining step (RDS) of an aromatic ynamine class is shifted from acetylide formation to the azide ligation/migratory insertion event allowing chemoselectivity independent of overall rate.

The old switcheroo: A kinetic and spectroscopic analysis of alkyne-dependent chemoselectivity in the copper-catalyzed azide–alkyne click (CuAAC) reaction is reported. Studies of six alkyne subtypes reveal that the rate-determining step (RDS) of an aromatic ynamine class is shifted from acetylide formation to the azide ligation/migratory insertion event allowing chemoselectivity independent of overall rate.

A change in reaction pathway was achieved for the first time by tuning the cyclopentadienyl (Cp) ligand used for the rhodium-catalyzed cyclization of benzamides with conjugated enynones. Depending on the Cp ligand, the reaction pathway switched between [4+2] and [4+1] annulation. Electronic effects turned out to be crucial for the product distribution. The dichotomy was attributed to the alteration of the Lewis acidity of the resultant Cp-bound rhodium species.

The choice is yours: A change in reaction pathway was achieved by tuning the cyclopentadienyl (Cp) ligand used for the rhodium-catalyzed cyclization of benzamides with conjugated enynones. Depending on the Cp ligand, the reaction pathway switched between [4+2] and [4+1] annulation. Electronic effects turned out to be crucial for the product distribution.

Traditional methods for the preparation of secondary alkyl-substituted aryl and heteroaryl chlorides challenge both selectivity and functional group tolerance. This contribution describes the use of statistical design of experiments to develop an effective procedure for the preparation of isopropyl-substituted (hetero)arenes with minimal isopropyl to n-propyl isomerization. The reaction tolerates electronically diverse aryl chloride coupling partners, with excellent conversion observed for strongly electron-deficient aromatic rings, such as esters and amides. Electron-rich systems, including methyl- and methoxy-substituted aryl chlorides, were found to be less reactive. Furthermore, the reaction was found to be most successful when heteroaryl chlorides were submitted to the cross-coupling protocol. By mapping substituent effects on reaction selectivity, we were able to show that electron-deficient aryl chlorides are essential for efficient coupling, and use electronic structure calculations to predict the likelihood of successful coupling through the estimation of the electron affinity of each aryl chloride. Moderate isolated yields were achieved with selected aryl chlorides, and moderate to good isolated yields were obtained for all the heteroaryl chlorides coupled. Excellent selectivity was observed when a 2,6-dichloroquinoline was used, allowing mono-substitution on a challenging substrate.

While chemoselectivities in Pd⁰-catalyzed coupling reactions are frequently non-intuitive and a result of a complex interplay of ligand/catalyst, substrate, and reaction conditions, we herein report a general method based on Pd^I that allows for an a priori predictable chemoselective C −C coupling at C−Br in preference to C−OTf and C−Cl bonds, regardless of the electronic or steric bias of the substrate. The C−C bond formations are extremely rapid (<5 min at RT) and are catalyzed by an air- and moisture-stable Pd^I dimer under open-flask conditions.

Open container: Reported herein is a general method based on Pd^I for the predictable chemoselective C −C coupling at C−Br in preference to C−OTf and C−Cl bonds, regardless of the electronic or steric bias of the substrate. The C−C bond formations are rapid (<5 min at RT) and can be conducted under open-flask conditions.

Three new visible-light-promoted functionalizations of benzotriazole substrates were discovered using a mechanism-based screening method. ortho-Thiolated, borylated, and alkylated N-arylbenzamide products were obtained under mild reaction conditions in a new denitrogenative synthetic approach to functionalized aniline derivatives. The functional group tolerance of the borylation reaction was further analyzed in the first application of an additive-based robustness screen in a photocatalytic transformation. All the functionalizations proceed via photocatalytically initiated chain mechanisms as indicated by determination of the reaction quantum yields and Stern–Volmer analyses.

Trinity! Three visible-light-promoted functionalization reactions of benzotriazole substrates were discovered using a mechanism-based screening method and provided ortho-thiolated, -borylated, and -alkylated N-arylbenzamide products. The functional group tolerance of the borylation reaction was further analyzed by the first application of an additive-based robustness screen in a photocatalytic transformation.

We report the development of a Pd-catalyzed process for the cross coupling of unactivated primary, secondary, and tertiary alkylcarbastannatrane nucleophiles with acyl electrophiles. Reactions involving optically active alkylcarbastannatranes occur with exceptional stereofidelity and with net retention of absolute configuration. Because the stereochemistry of the resulting products is entirely reagent-controlled, this process may be viewed as a general, alternative approach to the preparation of products typically accessed via asymmetric enolate methodologies. Additionally, we report a new method for the preparation of optically active alkylcarbastannatranes, which should facilitate their future use in stereospecific reactions.

Finding new ways: A Pd-catalyzed process for the cross-coupling of unactivated primary, secondary, and tertiary alkylcarbastannatrane nucleophiles with acyl electrophiles was developed. This reaction provides as a general, alternative approach to the preparation of products typically accessed via asymmetric enolate methodologies.

Chemoselective Suzuki–Miyaura cross-coupling generally requires a designed deactivation of one nucleophile towards transmetallation. Here we show that boronic acids can be chemoselectively reacted in the presence of ostensibly equivalently reactive boronic acid pinacol (BPin) esters by kinetic discrimination during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross-couplings in a single operation in the absence of protecting groups.

Set phases to stun: Chemoselective Suzuki–Miyaura cross-coupling can be achieved by kinetic discrimination of boronic acids and BPin esters during transmetallation. Simultaneous electrophile control allows sequential chemoselective cross-couplings in a single operation in the absence of protecting groups.

Demonstrated herein is a highly effective 3 starting materials–4 component reaction (3SM-4CR) strategy for the synthesis of pyrimidine carboxamides from amidines, styrene, and N,N-dimethylformamide (DMF) by a palladium-catalyzed oxidative process. This transformation represents the first example of employing DMF as a dual synthon, a one-carbon-atom synthon and amide synthon, and was proven by isotope-labeling experiments. Additionally, the combination of C−H bond functionalization and cross-dehydrogenative coupling processes affords four chemical bond formations. This sequential 3SM-4CR strategy features inexpensive, readily available starting materials, green oxidants, as well as atom and step economy. It leads to the preparation of pyrimidine carboxamides and has potential applications in the pharmaceutical industry.

Three to four to one: A palladium-catalyzed oxidative 3 starting materials–4 component reaction (3SM-4CR) strategy for the synthesis of pyrimidine carboxamides from amidines, styrene, and DMF. DMF serves as a dual synthon, a one-carbon-atom synthon and amide synthon. This is a fascinating protocol for the preparation of pyrimidine carboxamides and has potential applications in the pharmaceutical industry.

A general strategy for the cleavage and amination of C−C bonds of cycloalkanols has been achieved through visible-light-induced photoredox catalysis utilizing a cerium(III) chloride complex. This operationally simple methodology has been successfully applied to a wide array of unstrained cyclic alcohols, and represents the first example of catalytic C−C bond cleavage and functionalization of unstrained secondary cycloalkanols.

Breaking (D)BAD: A general strategy for the cleavage and amination of C−C bonds of cycloalkanols has been achieved through visible-light-induced photoredox catalysis utilizing a cerium(III) chloride complex. This method represents the first example of catalytic C−C bond cleavage and functionalization of unstrained secondary cycloalkanols. DBAD=di-tert-butyl azodicarboxylate, Boc=tert-butoxycarbonyl.

An aluminum-catalyzed hydroboration of alkynes using either the commercially available aluminum hydride DIBAL-H or bench-stable Et₃Al⋅DABCO as the catalyst and H-Bpin as both the boron reagent and stoichiometric hydride source has been developed. Mechanistic studies revealed a unique mode of reactivity in which the reaction is proposed to proceed through hydroalumination and σ-bond metathesis between the resultant alkenyl aluminum species and HBpin, which acts to drive turnover of the catalytic cycle.

Main-group catalysts: An aluminum-catalyzed hydroboration of alkynes using either the commercially available aluminum hydride DIBAL-H or bench-stable Et3Al⋅DABCO as the catalyst and H-Bpin as both the boron reagent and stoichiometric hydride source has been developed. Mechanistic studies revealed a unique mode of reactivity, in which the reaction is proposed to proceed through hydroalumination and σ-bond metathesis between the resultant alkenyl aluminum species and HBpin.

A nickel-catalyzed alkylation of polycyclic aromatic methyl ethers as well as methyl enol ethers with B-alkyl 9-BBN and trialkylborane reagents that involves the cleavage of stable C(sp²)−OMe bonds is described. The transformation has a wide substrate scope and good chemoselectivity profile while proceeding under mild reaction conditions; it provides a versatile way to form C(sp²)−C(sp³) bonds that does not suffer from β-hydride elimination. Furthermore, a selective and sequential alkylation process by cleavage of inert C−O bonds is presented to demonstrate the advantage of this method.

No side reactions: A nickel-catalyzed Suzuki-type alkylation of aryl methyl ethers and methyl enol ethers with B-alkyl 9-BBN and trialkylborane reagents has been developed, which involves the cleavage of highly inert C(sp²)−OMe bonds. This transformation provides a versatile way to build C(sp²)−C(sp³) bonds that does not suffer from β-hydride elimination.

Radical style: Several breakthroughs have recently been achieved in enantioselective C(sp³)−H functionalization through radical activation. These new strategies show how radical chemistry can be used to convert alkanes into functionalized chiral molecules (see scheme; HAT=hydrogen atom transfer).

An easy access to highly versatile gem-silylboronate synthons is achieved by means of a new olefination reagent, HC(Bpin)₂(SiMe₃). Subsequent silicon or boron-based selective functionalization allows for the modular and stereocontrolled synthesis of all-carbon tetrasubstituted alkenes. A particular attraction of this approach is the iododesilylation reaction, which becomes a pivotal tool for C−Si functionalization.

Stereo-power with silylborylation: The stereocontrolled synthesis of all-carbon tetrasubstituted alkenes was achieved with gem-silylborylated structures that perform selective silicon- or boron-based cross coupling. The access to gem-silylborylated olefins from ketones and HC(Bpin)₂(SiMe₃) is based on B−O olefination. Selective iododesilylation accomplishes target C−Si mediated cross coupling, and hence the stereoselective preparation of tetra-substituted olefins (see example for Tamoxifen).

The first examples of 3,3-diaryloxetanes are prepared in a lithium-catalyzed and substrate dependent divergent Friedel–Crafts reaction. para-Selective Friedel–Crafts reactions of phenols using oxetan-3-ols afford 3,3-diaryloxetanes by displacement of the hydroxy group. These constitute new isosteres for benzophenones and diarylmethanes. Conversely, ortho-selective Friedel–Crafts reactions of phenols afford 3-aryl-3-hydroxymethyl-dihydrobenzofurans by tandem alkylation–ring-opening reactions; the outcome of the reaction diverging to structurally distinct products dependent on the substrate regioselectivity. Further reactivity of the oxetane products is demonstrated, suitable for incorporation into drug discovery efforts.

Double the benefit: 3,3-Diaryloxetanes are prepared as isosteres of benzophenones and diarylmethanes, through inexpensive lithium catalyzed Friedel–Crafts reaction (see figure). Complementary dihydrobenzofurans are also prepared, highly selectively, with the product dependent on the substrate regioselectivity. The oxetane products are stable to further derivatization reactions, suitable for incorporation into drug discovery efforts.