Jason Williams

We report a general preparation of arylated bicyclo[1.1.1]pentanes through the opening of [1.1.1]propellane with various arylmagnesium halides. After transmetalation with ZnCl₂ and Negishi cross-coupling with aryl and heteroaryl halides, bis-arylated bicyclo[1.1.1]pentanes are obtained. These bis-arylated bicyclo[1.1.1]pentanes may be considered as bioisosteres of internal alkynes. Bioisosteres of tazarotene and the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine were prepared and their physicochemical properties were evaluated.

BCPs have the right profile! The opening of [1.1.1]propellane with various arylmagnesium halides proceeds smoothly in sealed tubes to provide bicyclo[1.1.1]pentylmagnesium (BCP magnesium) derivatives. After transmetalation with ZnCl₂, these undergo Negishi cross-coupling with various aryl and heteroaryl halides to provide bis-arylated BCPs, which represent a useful class of bioisosteres of alkynes or 1,4-disubstituted arenes.

A new class of palladium catalysts, based on heterocyclic diphosphines, was rationally designed and synthesized. Application of one of these catalysts allows novel Markovnikov-selective carbonylation of non-activated alkynes with heteroarenes to give the corresponding branched α,β-unsaturated ketones in excellent yields (up to 97 %) and regioselectivities (b/l up to 99:1). In addition to heteroarenes, other common nucloephiles (alcohol, phenol, amine, and amide) furnish the desired carbonylation products smoothly in high yields.

Cool cat: The ligand L1 [bis(2-(diphenylphosphanyl)-1H-pyrrol-1-yl)methane] allows a general palladium-catalyzed carbonylation of unactivated alkynes with heteroarenes. The reaction proceeds smoothly to give the corresponding branched α,β-unsaturated ketones in good yields and often with high Markovnikov selectivity. b=branched, l=linear.

The ubiquitous use of π-rich five-membered heterocycles has driven the development of new methods for their synthesis for more than a century. Here, we disclose a general and reliable reaction manifold for the construction of highly substituted heterocycles through a facile Lewis-acid-catalyzed oxetane rearrangement. Notably, this methodology employs a keto-oxetane motif as a 1,4-dicarbonyl surrogate, which can be synthesized using robust alkylation or alkenylation reactions, and thus obviates the need to access 1,4-dicarbonyl compounds via umpoled starting materials. We harnessed this reactivity to generate a broad range of substituted furans and pyrroles, and extended this methodology to produce benzo-fused versions thereof.

Upon alkenylation or addition to the keto function of inexpensive 3-oxetanone, the strained oxetane ring is poised for a facile and general rearrangement to make important heterocycles.

α-Amino nitriles tethered to alkenes through a urea linkage undergo intramolecular C-alkenylation on treatment with base by attack of the lithionitrile derivatives on the N′-alkenyl group. A geometry-retentive alkene shift affords stereospecifically the E or Z isomer of the 5-alkenyl-4-iminohydantoin products from the corresponding starting E- or Z-N′-alkenyl urea, each of which may be formed from the same N-allyl precursor by stereodivergent alkene isomerization. The reaction, formally a nucleophilic substitution at an sp² carbon atom, allows the direct regioselective incorporation of mono-, di-, tri-, and tetrasubstituted olefins at the α-carbon of amino acid derivatives. The initially formed 5-alkenyl iminohydantoins may be hydrolyzed and oxidatively deprotected to yield hydantoins and unsaturated α-quaternary amino acids.

E- or Z-alkenylurea derivatives of aminonitriles undergo stereospecific N-to-C alkenyl migration on treatment with base. Alkenyl hydantoins or (upon hydrolysis) alkenyl amino acids of biological and pharmaceutical utility are thus formed. PMP=4-methoxyphenyl.

We present an automated microfluidic platform for in-flow studies of visible-light photoredox catalysis in liquid or gas–liquid reactions at the 15 μL scale. An oscillatory flow strategy enables a flexible residence time while preserving the mixing and heat transfer advantages of flow systems. The adjustable photon flux made possible with the platform is characterized using actinometry. Case studies of oxidative hydroxylation of phenylboronic acids and dimerization of thiophenol demonstrate the capabilities and advantages of the system. Reaction conditions identified through droplet screening translate directly to continuous synthesis with minor platform modifications.

Glow with the flow: An automated photochemistry platform built around a microfluidic oscillatory flow reactor enables efficient investigation of photocatalyzed liquid and gas–liquid reactions in individual 15 μL droplets. The conditions identified through screening are directly adapted to continuous flow synthesis.

We report the first direct catalytic method for formyl-selective deuterium labeling of aromatic aldehydes under mild conditions, using an iridium-based catalyst designed to favor formyl over aromatic C−H activation. A good range of aromatic aldehydes is selectively labeled, and a one-pot labeling/olefination method is also described. Computational studies support kinetic product control over competing aromatic labeling and decarbonylation pathways.

Al(D)hydes: An iridium catalyst system was designed to effect formyl over aryl C−H activation of aromatic aldehydes. Computational studies support kinetic product control over competing aromatic labeling and decarbonylation pathways.

Disclosed herein is the first general chemo- and site-selective alkylation of C−Br bonds in the presence of COTf, C−Cl and other potentially reactive functional groups, using the air-, moisture-, and thermally stable dinuclear Pd^I catalyst, [Pd(μ-I)PtBu₃]₂. The bromo-selectivity is independent of the substrate and the relative positioning of the competing reaction sites, and as such fully predictable. Primary and secondary alkyl chains were introduced with extremely high speed (<5 min reaction time) at room temperature and under open-flask reaction conditions.

Pick me! A method for cross-coupling bromo groups with Grignard or organozinc reagents mediated by a dinuclear Pd^I catalyst was developed. The reactions were highly selective for C−Br and were tolerant of both C−OTf and C−Cl functionalities. The transformations proceeded under open-flask conditions at room temperature, and were complete within 5 min.

Much contemporary organic synthesis relies on transformations that are driven by the intrinsic, so-called “natural”, polarity of chemical bonds and reactive centers. The design of unconventionally polarized synthons is a highly desirable strategy, as it generally enables unprecedented retrosynthetic disconnections for the synthesis of complex substances. Whereas the umpolung of carbonyl centers is a well-known strategy, polarity reversal at the α-position of a carbonyl group is much rarer. Herein, we report the design of a novel electrophilic enolonium species and its application in efficient and chemoselective, metal-free oxidative C−C coupling.

Umpole me: The design of unconventionally polarized synthons is a highly desirable strategy in synthesis. While the umpolung of carbonyl centers is a well-known strategy, polarity reversal at the α-position to a carbonyl group is much rarer. The design of a novel electrophilic enolonium species for chemoselective, metal-free oxidative C−C coupling is now reported.

The first transition metal catalyzed hydrophosphination of isocyanates is presented. The use of low-coordinate iron(II) precatalysts leads to an unprecedented catalytic double insertion of isocyanates into the P−H bond of diphenylphosphine to yield phosphinodicarboxamides [Ph₂PC(=O)N(R)C(=O)N(H)R], a new family of derivatized organophosphorus compounds. This remarkable result can be attributed to the low-coordinate nature of the iron(II) centers whose inherent electron deficiency enables a Lewis-acid mechanism in which a combination of the steric pocket of the metal center and substrate size determines the reaction products and regioselectivity.

Seeing double: Low-coordinate iron(II) complexes have been used in the hydrophosphination of isocyanates to produce mono- and/or diinsertion products yielding phosphinodicarboxamides, a new family of derivatized organophosphorus compounds. Small changes in reaction conditions drastically alter the product selectivity.

The treatment of various N-morpholino amides with TMPZnCl⋅LiCl (TMP=2,2,6,6-tetramethylpiperidyl) and Mg(OPiv)₂ in THF at 25 °C provides solid zinc enolates with enhanced air and moisture stability (t_1/2 in air: 1–3 h) after solvent evaporation. These enolates undergo Pd- and Cu-catalyzed cross-couplings with (hetero)aryl bromides as well as allylic and benzylic halides. The arylated N-morpholino amides were converted into various ketones by LaCl₃⋅2 LiCl mediated acylation with Grignard reagents. The new, solid enolates were used to prepare a potent anti-breast-cancer drug candidate in six steps and 23 % overall yield.

Solid chemistry: A convenient method for the preparation of solid zinc enolates with enhanced air and moisture stability is described. These enolates undergo Pd- and Cu-catalyzed cross-couplings. The reactive N-morpholino amides can be readily converted into aldehydes or various ketones. These new zinc enolates were employed in the short synthesis of a 3-formylindole derivative that is a potent inhibitor of tubulin polymerization.