Jennifer Tsoung

One-Pot Synthesis of Chiral Dihydrobenzofuran Framework via Rh/Pd Catalysis

A one-pot synthesis of the chiral dihydrobenzofuran framework is described. The method utilizes Rh-catalyzed asymmetric ring opening (ARO) and Pd-catalyzed C-O coupling to furnish the product in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an indicator.

Multicomponent-multicatalyst reactions (MC)(2)R: efficient dibenzazepine synthesis.

A Rh(I)/Pd(0) catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.

Diastereoselective Friedel–Crafts Alkylation of Hydronaphthalenes

An efficient and versatile synthesis of chiral tetralins has been developed using both inter- and intramolecular Friedel-Crafts alkylation as a key step. The readily available hydronaphthalene substrates were prepared via a highly enantioselective metal-catalyzed ring opening of meso-oxabicyclic alkenes followed by hydrogenation. A wide variety of complex tetracyclic compounds have been isolated with high levels of regio-, diastereo-, and enantioselectivity.

Synthesis of Fused Pyrimidinone and Quinolone Derivatives in an Automated High-Temperature and High-Pressure Flow Reactor

Fused pyrimidinone and quinolone derivatives that are of potential interest to pharmaceutical research were synthesized within minutes in up to 96% yield in an automated Phoenix high-temperature and high-pressure continuous flow reactor. Heterocyclic scaffolds that are either hard to synthesize or require multisteps are readily accessible using a common set of reaction conditions. The use of low-boiling solvents along with the high conversions of these reactions allowed for facile workup and isolation. The methods reported herein are highly amenable for fast and efficient heterocycle synthesis as well as compound scale-ups.

Formation of Substituted Oxa- and Azarhodacyclobutanes

The preparation of substituted oxa- and azarhodacyclobutanes is reported. After exchange of ethylene with a variety of unsymmetrically and symmetrically substituted alkenes, the corresponding rhodium-olefin complexes were oxidized with H2O2 and PhINTs (Ts=p-toluenesulfonyl) to yield the substituted oxa- and azarhodacyclobutanes, respectively. Oxarhodacyclobutanes could be prepared with excellent selectivity for incorporation of the oxygen atom on the more substituted carbon atom of the alkene. At the same time, azarhodacyclobutanes showed good-to-excellent selectivity for heteroatom incorporation on the less substituted carbon. Furthermore, it was shown that steric modifications of the ancillary ligand have a significant influence on the selectivity of Rh-olefin complex formation as well as formation of the substituted azametallacycles.

Expedient Diels–Alder cycloadditions with ortho-quinodimethanes in a high temperature/pressure flow reactor

We describe herein Diels–Alder cycloadditions enabled by the efficient ring-opening of benzocyclobutenes and benzothiophene-2,2-dioxides using a high temperature/pressure flow reactor. The resultant ortho-quinodimethanes were generated and subsequently reacted with a wide range of dienophiles to provide complex heterocyclic ring systems. The use of flow technology allowed these reactions to be completed within minutes using conventional, readily removed solvents.

Synthesis of Pyridobenzazepines Using a One-Pot Rh/Pd-Catalyzed Process

In recent years, our group has been developing multicatalytic reactions for the synthesis of biologically relevant heterocyclic compounds. An efficient dual-metal catalyzed reaction of electron-deficient o-chlorovinylpyridines with o-aminophenylboronic esters to access pyridobenzazepines is described. Combining a RhI-catalyzed arylation followed by a Pd0-catalyzed C-N coupling, in a one-pot procedure, provides a simplified method to access heterocycles without workup and purification after each step. The substrate scope encompasses a variety of N-H and N-alkylated pyridobenzazepine variants with yields up to 93%.

C(sp3)–H Insertions with Donor Rhodium Carbenoids

Significance: The functionalization of unactivated C(sp3)–H bonds by insertion of transition-metal carbenoids is an attractive method of forming C–C bonds. However, while acceptor-substituted rhodium(II) carbenoids have been investigated, little is known on the reactivity of donor-substituted rhodium(II) carbenoids in C(sp3)–H insertions, due to the difficulty in handling the unstabilized diazo precursors. The authors report the facile generation of donor-substituted rhodium(II) carbenoids by ring opening of 3,3-dimethylcyclopropenylcarbinols, and their use in intramolecular C(sp3)–H insertions, which occur with high yield and diastereoselectivity. Comment: Donor-substituted rhodium carbenoids were found to trigger 1,5and 1,6-C–H insertions with high diastereoselectivity to generate a variety of functionalized carbocycles and oxygen heterocycles, which can be subsequently ozonolyzed to the corresponding ketones. Deuteriumlabelling studies suggest that the reaction involves a stereospecific process at the carbenoid carbon atom, and occurs in a concerted fashion with a late transition state. Furthermore, the C–H insertion process is selective for only one of two diastereotopic methylene groups, which the authors exploited to access various bicyclic compounds. Synthesis of donor rhodium carbenoids and their use in C(sp3)–H insertions

Cationic Gold-Catalyzed Cyclization of Diynamides

Significance: The authors report an enantioselective cycloisomerization of diynamides to methylene pyrrolidines catalyzed by cationic gold with optically active binol phosphates as counteranions. This work was inspired by Toste and coworkers’ application of chiral counterions in goldcatalyzed functionalization of allenes (Science 2007, 317, 462). The chiral pyrrolidine products formed are highly valuable as they contain an allcarbon-substituted quaternary stereocenter and are difficult to prepare in enantiomerically pure form by other conventional methods. Comment: Czekelius and co-workers had previously demonstrated that cationic gold complexes cyclize diynols and diynamides to the corresponding unsaturated heterocycles in good yield (Chem. Eur. J. 2009, 15, 13323). However, optically active phosphine and carbene ligands gave poor enantioselectivity due to the linear coordination geometry in gold(I)–alkyne complexes. The use commercially available binol phosphates as chiral counterions overcomes this problem and allows for high enantioselectivity in the cyclization. The best results were obtained in chlorinated solvents at low temperatures, which is in line with the contact ion pair model of the cationic gold–alkyne complex and the anionic chiral phosphate. R NHTs (t-Bu3P)AuTriP (5 mol%) NTs