[reaction: see text] The intramolecular Friedel-Crafts acylation of aromatics with Meldrum's acid derivatives catalyzed by metal trifluoromethanesulfonates is reported. Meldrum's acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, while accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum's acids) and 5-benzyl-5-substituted Meldrum's acids (quaternized Meldrum's acids), forming 1-indanones and 2-substituted-1-indanones, respectively, are delineated. This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. Rate of cyclization as a function of ring size was established for various benzocyclic ketones via competition experiments: 1-tetralones form faster than both 1-indanones and 1-benzosuberones, and 1-benzosuberones cyclize faster than 1-indanones.

The ability to tune the reactiVity of palladium carbenes deriVed from diphenylketene, which is dependent on the oxidation state of the metal center, is presented. Competition experiments illustrated that Pd(0) catalysts faVor direct C-H functionalization of terminal alkynes and that Pd(II) catalysts lead to cyclopropanation of strained alkenes. In addition, a PdCl 2 -catalyzed cyclopropane isomerization of diphenylcyclopropanes and an unprecedented Pd(II)-catalyzed domino cyclopropanation/isomerization reaction are described.

A full account of the Pd-catalyzed intramolecular reactions of (E)-2,2-disubstituted 1-alkenyldimethylalanes with aryl triflates as an entry into polycarbocyclic structures displaying an ethyl−methyl-substituted all-carbon benzylic quaternary center is herein presented. It was found that the efficiency of the Pd-catalyzed carbon−carbon bond forming process is highly affected by the structure of the starting material, including tether length and aryl substitution pattern; substituting the position ortho to the triflate is mandatory to obtain a good yield of the carbocycle. Moreover, the formation of 1-ethyl-1-methylindanes is facile in comparison to the case for the analogous tetrahydronaphthalenes, for which the competing methyl cross-coupling reaction is equally competent. It was established through labeling studies that the carbon−carbon bond forming events are stereospecific and proceed though the intermediacy of a neopentylic sp3-gem-dimetallic palladio(II) dialkylaluminoalkane species, from which a 1,2-methyl migration from aluminum to carbon occurs. Intramolecular palladium-catalyzed reactions of 1-naphthyl triflates with (E)-2,2-disubstituted 1-alkenyldimethylalanes revealed two competing reaction pathways: arylation with sequential 1,2-alkyl migration from aluminum to carbon and intramolecular 1,2-diarylation, in which the catalytic cycle is terminated by direct arylation of the C(sp3)−Pd(II) bond. Factors such as tether length, additives, solvent polarity, and C−H···Pd interactions between the Pd(II) center and the hydrogen atom at the 8-position all influence not only the pathway taken by the (σ-aryl)palladium(II) complexes but also the subsequent reactivity of the (σ-alkyl)palladium(II) complexes.

The effects of kinetic vs thermodynamic control on endo/exo stereoisomer ratios can be observed in a simple Diels−Alder reaction between Nphenylmaleimide and furan. The use of microwave-promoted synthesis affords the cycloadducts in yields ranging from 65−100%, employing reaction times of 1−10 min at temperatures of 55−130 °C. Short reaction times enable screening of numerous reaction conditions (time and temperature) within a single lab period, where endo:exo product ratios follow the primary facets of kinetic and thermodynamic control. Analysis of product ratios obtained under kinetic control allows for the evaluation of activation parameters (ΔΔH ⧧ (≈ ΔE a ), ΔΔS ⧧ , and ΔΔG ⧧ ) by means of the Arrhenius and Eyring equations. Values of ΔΔH ⧧ , ΔΔS ⧧ , and ΔΔG ⧧ were found to be 6.4 ± 0.3 kJ mol −1 , 16.5 ± 0.9 J mol −1 K −1 , and 1.5 ± 0.4 kJ mol −1 (ΔΔ: exo − endo), respectively. Experimentally determined activation parameters correlate well with quantum-chemical calculations. Several key teaching points are also addressed, including frontier molecular orbital analysis, reversibility of the Diels−Alder reaction, column chromatography, and the use of 1 H nuclear magnetic resonance spectroscopy to assess both stereoisomeric yield and purity.

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