The Diels-Alder reaction is not limited to 1,3-dienes. Many cycloadditions of enynes and a smaller number of examples with 1,3-diynes have been reported. These "dehydro"-Diels-Alder cycloadditions are one class of dehydropericyclic reactions which have long been used to generate strained cyclic allenes and other novel structures. CCSD(T)//M05-2X computational results are reported for the cycloadditions of vinylacetylene and butadiyne with ethylene and acetylene. Both concerted and stepwise diradical routes have been explored for each reaction, with location of relevant stationary points. Relative to 1,3-dienes, replacement of one double bond by a triple bond adds 6-6.5 kcal/mol to the activation barrier; a second triple bond adds 4.3-4.5 kcal/mol to the barrier. Product strain decreases the predicted exothermicity. In every case, a concerted reaction is favored energetically. The difference between concerted and stepwise reactions is 5.2-6.6 kcal/mol for enynes but diminishes to 0.5-2 kcal/mol for diynes. Experimental studies on intramolecular diyne + ene cycloadditions show two distinct reaction pathways, providing evidence for competing concerted and stepwise mechanisms. Diyne + yne cycloadditions connect with arynes and ethynyl-1,3-cyclobutadiene. This potential energy surface appears to be flat, with only a minute advantage for a concerted process; many diyne cycloadditions or aryne cycloreversions will proceed by a stepwise mechanism.

Pd-catalyzed ortho-C–H iodination directed by a weakly coordinating amide auxiliary using I2 as the sole oxidant was developed. This reaction is compatible with a wide range of heterocycles including pyridines, imidazoles, oxazoles, thiazoles, isoxazoles and pyrazoles.

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It has recently been proposed that plasma levels of 4β-hydroxycholesterol (4βHC) may be indicative of cytochrome P450 3A4 (P450 3A) activity and therefore could be used to probe for P450 3A-mediated drug-drug interactions. With this in mind, we describe a highly sensitive and precise liquid chromatography-electrospray ionization-tandem mass spectrometry method for the measurement of 4βHC in human plasma with a lower limit of quantification established at 2 ng/mL using 50 μL of plasma. The entire sample preparation scheme including saponification and derivatization of 4βHC to the corresponding dipicolinyl ester (DPE) was completed in less than 8 h using an automated sample preparation scheme enabling higher-throughput capabilities. Chromatographic resolution of 4βHC from 4α-hydroxycholesterol and other endogenous isobaric species was achieved in 11-min using an isocratic gradient on a C18 column. Because of endogenous concentrations of 4βHC in plasma, a stable isotope labeled (SIL) analogue, d7-4βHC, was used as a surrogate analyte and measured in the standard curve and quality control samples prepared in plasma. A second SIL analogue, d4-4βHC, was used as the internal standard. The intraday and interday accuracy for the assay was within 6% of nominal concentrations, and the precision for these measurements was less than 5% relative standard deviation. Rigorous stability assessments demonstrated adequate stability of endogenous 4βHC in plasma and the corresponding DPE derivative for the analysis of clinical study samples. The results from clinical samples following treatment with a potent P450 3A inducer (rifampin) or inhibitor (ketoconazole) are reported and demonstrate the potential future application for this highly precise and robust analytical assay.

Kinetic studies of the thermal isomerization and fragmentation reactions exhibited by cis- and trans-1-(E)-propenyl-2-methylcyclobutanes at 275 degrees C in the gas phase have provided first-order rate constants for cis,trans interconversions of the cyclobutanes, 1,3-carbon migrations leading to 3,4- and 3,6-dimethylcyclohexenes, isomerizations providing directly and indirectly four acyclic dienes, and fragmentations to ethylene, propene, and mixtures of pentadienes and hexadienes. Both cis and trans isomers of 1-(E)-propenyl-2-methylcyclobutane form trans-3,4-dimethylcyclohexene faster than they are converted to cis-3,4-dimethylcyclohexene; the trans reactant gives rise to cis-3,6-dimethylcyclohexene in preference to its trans isomer, while the cis starting material gives neither at measurable rates; both form the relatively minor product 1,6-(Z)-octadiene. The rate constants derived from 35 kinetic runs starting with four distinct 1-(E)-propenyl-2-methylcyclobutane samples are consistent to within narrow error limits. The stereomutations, isomerizations, and fragmentations of the 1-(E)-propenyl-2-methylcyclobutanes are interpreted in terms of competitive processes involving conformationally flexible short-lived 2-(E)-octene-4,7-diyl and 3-methyl-5-(E)-heptene-1,4-diyl diradicals.