The discovery of indazapyroxamet: a novel 3-pyridinyl insecticide targeting piercing/sucking insectsa.

In recent years, the registrations for a number of commercial insecticides utilized for piercing/sucking insects have been cancelled or restricted. To meet this growing need for new hemipteran controlling agrochemicals, we discovered a 2-(pyridin-3-yl)-thiazole compound, with limited insecticidal activity against cotton/melon aphid (Aphis gossypii). The 2-(pyridin-3-yl)-thiazole moiety offered us a basis to pursue the bicyclic 2-(pyridin-3-yl)-2H-indazole carboxamides. Evaluation of such 2-(pyridin-3-yl)-2H-indazole carboxamides revealed that even analogs containing only simple alkyl amides attached at the 4 or 5 positions possess promising insecticidal activity. Extensive optimization of this novel class of 2-(pyridin-3-yl)-2H-indazole carboxamides led to identifying indazapyroxamet for commercial development. © 2024 Society of Chemical Industry.

Palladium-Catalyzed N-Arylation of Cyclopropylamines.

A general method has been developed for the previously challenging arylation of cyclopropylamine and N-arylcyclopropylamines. Highly active, air-stable, and commercially available R-allylpalladium precatalysts provide access to a wide range of (hetero)arylated cyclopropylanilines in high yields. Precatalysts [(tBuBrettPhos)Pd(allyl)]OTf and [(BrettPhos)Pd(crotyl)]OTf, deliver monoarylated products, while (PtBu3)Pd(crotyl)Cl is suited for preparing unsymmetrical diarylated products. The developed conditions tolerate a range of functional groups and heterocycles, allowing access to an array of arylated cyclopropylamines, a motif present in prominent drug molecules.

Rh-Catalyzed Intermolecular Reactions of α-Alkyl-α-Diazo Carbonyl Compounds with Selectivity over ß-Hydride Migration.

Rh-carbenes derived from α-diazocarbonyl compounds have found broad utility across a remarkable range of reactivity, including cyclopropanation, cyclopropenation, C-H insertions, heteroatom-hydrogen insertions, and ylide forming reactions. However, in contrast to α-aryl or α-vinyl-α-diazocarbonyl compounds, the utility of α-alkyl-α-diazocarbonyl compounds had been moderated by the propensity of such compounds to undergo intramolecular ß-hydride migration to give alkene products. Especially challenging had been intermolecular reactions involving α-alkyl-α-diazocarbonyl compounds. This Account discusses the historical context and prior limitations of Rh-catalyzed reactions involving α-alkyl-α-diazocarbonyl compounds. Early studies demonstrated that ligand and temperature effects could influence chemoselectivity over ß-hydride migration. However, effects were modest and conflicting conclusions had been drawn about the influence of sterically demanding ligands on ß-hydride migration. More recent advances have led to a more detailed understanding of the reaction conditions that can promote intermolecular reactivity in preference to ß-hydride migration. In particular, the use of bulky carboxylate ligands and low reaction temperatures have been key to enabling intermolecular cyclopropenation, cyclopropanation, carbonyl ylide formation/dipolar cycloaddition, indole C-H functionalization, and intramolecular bicyclobutanation with high chemoselectivity over ß-hydride migration. Cyclic α-diazocarbonyl compounds have been shown to be particularly resilient toward ß-hydride migration and are the first class of compounds that can engage in intermolecular reactivity in the presence of tertiary ß-hydrogens. DFT calculations were used to propose that for cyclic α-diazocarbonyl compounds, ring constraints relieve steric interaction for intermolecular reactions and thereby accelerate the rate of intermolecular reactivity relative to intramolecular ß-hydride migration. Enantioselective reactions of α-alkyl-α-diazocarbonyl compounds have been developed using bimetallic N-imido-tert-leucinate-derived complexes. The most effective complexes were found by computation and X-ray crystallography to adopt a "chiral crown" conformation in which all of the imido groups are presented on one face of the paddlewheel complex in a chiral arrangement. Insight from computational studies guided the design and synthesis of a mixed ligand paddlewheel complex, Rh2(S-PTTL)3TPA, the structure of which bears similarity to the chiral crown complex Rh2(S-PTTL)4. Rh2(S-PTTL)3TPA engages substrate classes (aliphatic alkynes, silylacetylenes, α-olefins) that are especially challenging in intermolecular reactions of α-alkyl-α-diazoesters and catalyzes enantioselective cyclopropanation, cyclopropenation, and indole C-H functionalization with yields and enantioselectivities that are comparable or superior to Rh2(S-PTTL)4. The work detailed in this Account describes progress toward enabling a more general utility for α-alkyl-α-diazo compounds in Rh-catalyzed carbene reactions. Further studies on ligand design and synthesis will continue to broaden the scope of their selective reactions.

Rh-catalyzed intermolecular reactions of cyclic α-diazocarbonyl compounds with selectivity over tertiary C-H bond migration.

Intermolecular Rh-catalyzed reactions of cyclic α-diazocarbonyl compounds with chemoselectivity over ß-hydride elimination are described. These methods represent the first general intermolecular reactions of Rh-carbenoids that are selective over tertiary ß-C-H bond migration. Successful transformations include cyclopropanation, cyclopropenation, and various X-H insertion reactions with a broad scope of substrates. We propose that the intermolecular approach of substrates to carbenes from acyclic diazo precursors may be relatively slow due to a steric interaction with the ester function, which is perpendicular to the π-system of the carbene. For carbenes derived from five- and six-membered cyclic α-diazocarbonyls, it is proposed that the carbene is constrained to be more conjugated with the carbonyl, thereby relieving the steric interaction for intermolecular reactions, and accelerating the rate of intermolecular reactivity relative to intramolecular ß-hydride migration. However, attempts to use α-diazo-ß-ethylcaprolactone in intermolecular cyclopropanation with styrene were unsuccessful. It is proposed that the conformational flexibility of the seven-membered ring allows the carbonyl to be oriented perpendicular to Rh-carbene. The significant intermolecular interaction between the carbonyl and approaching substrate is in agreement with the poor ability of α-diazo-ß-ethylcaprolactone to participate in intermolecular cyclopropanation reactions. DFT calculations provide support for the mechanistic proposals that are described.

Rhodium(II)-catalyzed enantioselective C-H functionalization of indoles.

A catalytic, enantioselective method for the C-H functionalization of indoles by diazo compounds has been achieved. With catalytic amounts of Rh(2)(S-NTTL)(4), the putative Rh-carbene intermediates from α-alkyl-α-diazoesters react with indoles at C(3) to provide α-alkyl-α-indolylacetates in high yield and enantioselectivity. From DFT calculations, a mechanism is proposed that involves a Rh-ylide intermediate with oxocarbenium character.

Total Synthesis of Hyacinthacine A2: Stereocontrolled 5-aza-cyclooctene Photoisomerization and Transannular Hydroamination with Planar-to-Point Chirality Transfer.

The total synthesis of hyacinthacine A2 is reported via a novel transannular hydroamination in which planar chirality of a 5-aza-trans-cyclooctene precursor is transferred to point chirality in the product. Key to the success of this strategy was the development of a method for establishing absolute planar chirality via stereocontrolled photoisomerization of a 5-aza-cis-cyclooctene. This was accomplished by constructing a 5-aza-cis-cyclooctene precursor with a trans-fused acetonide. The improved diastereoselectivity observed upon photoisomerization of this derivative is attributed to the conformational strain of the eight-membered ring in the minor diastereomer.

The chiral crown conformation in paddlewheel complexes.

Bimetallic paddlewheel complexes derived from imides of (S)-tert-leucine adopt 'chiral crown' configurations in which the four imide groups are projected in a chiral arrangement on one face, and the four tert-butyl groups are projected on the opposite face. In this contribution, the generality of the chiral crown conformation is examined through crystallographic studies where the metal and the nature of the chiral ligands are altered. Based upon these observations, a model is proposed to explain the factors which create bias for the chiral crown configuration.

Chiral crown conformation of Rh(2)(S-PTTL)(4): enantioselective cyclopropanation with alpha-alkyl-alpha-diazoesters.

Herein, we provide crystallographic and computational evidence that Hashimoto's Rh(2)(S-PTTL)(4) catalyst adopts a "chiral crown" conformation with a reactive chiral face and an unreactive achiral face. In Rh(2)(S-PTTL)(4), all four tert-butyl groups are aligned on the same face of the catalyst, and each C-(t-Bu) bond is roughly parallel to the central Rh-Rh bond. This orients the four phthalimido groups on the opposite face of the catalyst. Also described is an enantioselective and diastereoselective protocol for intermolecular Rh(2)(S-PTTL)(4)-catalyzed cyclopropanation using alpha-alkyl-alpha-diazoesters. Intermolecular cyclopropanation is selective over two competing intramolecular pathways: C-H insertion and beta-hydride elimination. On the basis of density functional theory calculations and the Davies-Singleton model for cyclopropanation, a model for asymmetric induction is proposed.

Unusually reactive and selective carbonyl ylides for three-component cycloaddition reactions.

Conditions are described for the Rh-catalyzed formation of highly functionalized dihydro- and tetrahydrofuran products via three-component reactions of aldehydes, alpha-alkyl-alpha-diazoesters, and dipolarophiles. The alkyl-substituted carbonyl ylides that are generated in this fashion are highly reactive in cycloaddition reactions and display a scope of reactivity that is much broader than the three-component reactions of carbonyl ylides derived from ethyl diazoacetate or alpha-aryl-alpha-diazoesters. The reactions of alkyl-substituted carbonyl ylides proceed with high regioselectivity and diastereoselectivity that are rationalized in terms of an asynchronous, endo-selective transition state.

Rh-catalyzed intermolecular cyclopropanation with alpha-alkyl-alpha-diazoesters: catalyst-dependent chemo- and diastereoselectivity.

A Rh-catalyzed procedure for the cyclopropanation of alkenes with alpha-alkyl-alpha-diazoesters is described. With dirhodium tetraoctanoate, the predominant pathway is beta-hydride elimination. While a number of sterically demanding carboxylate ligands serve to avoid beta-hydride elimination, it was found that triphenylacetate (TPA) also imparts high diastereoselectivity.

Rh-catalyzed formation of dioxolanes from alpha-alkyl diazoesters: diastereoselective cycloadditions of carbonyl ylides with selectivity over beta-hydride elimination.

Described here is a diastereoselective Rh-catalyzed method for the preparation of dioxolanes from alpha-alkyl-alpha-diazoesters. This represents the first general method for generating carbonyl ylides from alpha-diazoesters that possess beta-hydrogens, as such diazo compounds typically give rise to alkenes via beta-hydride elimination. Subsequent cycloaddition with aromatic aldehydes gives tetrasubstituted dioxolanes with unusually high diastereoselectivity. A model is set forth to explain the diastereoselectivity of the cycloaddition.

Development of a chipscale integrated microelectrode/microelectronic device for brain implantable neuroengineering applications.

An ultralow power analog CMOS chip and a silicon based microelectrode array have been fully integrated to a microminiaturized "neuroport" for brain implantable neuroengineering applications. The CMOS integrated circuit (IC) includes preamplifier and multiplexing circuitry, and a hybrid flip-chip bonding technique was developed to fabricate a functional, encapsulated microminiaturized neuroprobe device. Our neuroport has been evaluated using various methods, including pseudospike detection and local excitation measurement, and showed suitable characteristics for recording neural activities. As a proof-of-concept demonstration, we have measured local field potentials from thalamocortical brain slices of rats, suggesting that the new neuroport can form a prime platform for the development of a microminiaturized neural interface to the brain in a single implantable unit. An alternative power delivery scheme using photovoltaic power converter, and an encapsulation strategy for chronic implantation are also discussed.