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An exploration of the scope and limitations of Pd(0)-catalyzed intramolecular coupling reactions of amino-tethered aryl halides and ketones has been conducted. Two different and competitive reaction pathways starting from omega-(2-haloanilino) alkanones, enolate arylation and addition to the carbonyl group, have been observed, while omega-(2-halobenzylamino) alkanones exclusively underwent the enolate arylation process. The dichotomy between ketone alpha-arylation and carbonyl-addition in the reactions of omega-(2-haloanilino) alkanones has been rationalized by the intermediacy of unprecedented four-membered azapalladacycles, from which X-ray data and chemical behavior are reported.

N-Acylated 2-substituted anilines undergo slow Ar-N bond rotation, allowing in some cases isolation of enantiomeric or diastereoisomeric atropisomers and in others the determination of the rate of Ar-N bond rotation by NMR. 2-Iodoanilides bearing a branched N-substituent demonstrate sufficient enantiomeric stability to be resolvable, either by HPLC or by formation of diastereoisomeric lactanilide derivatives. For the first time, the rates of Ar-N rotation in 2-substituted N,N'-diarylureas have been established: they mainly fall in the region of 50-70 kJ mol(-1) with a relatively weak dependence on substituent size.

A general strategy for the synthesis of pentacyclic Strychnos alkaloids with the curan skeleton has been developed. It utilizes 3a-(2-nitrophenyl)hexahydroindol-4-one (23), which was prepared from 2-allyl-2-(2-nitrophenyl)-1,3-cyclohexanedione (15), as the common, pivotal intermediate. Three different procedures have been employed for the closure of the bridged piperidine D ring from 23:  (i) an intramolecular Michael-type conjugate addition; (ii) a Ni(COD)2-promoted biscyclization that assembles B and D rings in a single synthetic step, and (iii) an intramolecular cyclization of an enone−propargylic silane system. When necessary, depending on the procedure used, introduction of the oxidized one-carbon substituent at C-16, closure of the indole ring, and/or adjustment of the functionality of the C-20 two-carbon chain constitute the last stages of the synthetic route to the title alkaloids. The procedure involving the cyclization of a propargylic silane has been successfully extended to the enantiospecific synthesis of (−)-tubifolidine starting from the enantiopure 3a-(2-nitrophenyl)hexahydroindolone (−)-51, which was prepared taking advantage of the prochiral character of cyclohexanedione 15.

Vinyl halides undergo intramolecular coupling with amino-tethered ketones, esters, and nitriles in the presence of a palladium catalyst and potassium phenoxide as the base. This reaction constitutes a useful methodology for the synthesis of monocyclic, bridged, and spirocyclic nitrogen-containing compounds.Keywords: alkenylation; enolates; homogeneous catalysis; nitrogen heterocycles; palladium During the past decade there has been a growing interest in the palladium-catalyzed coupling reactions of aryl and vinyl halides with enolates and related anions. However, while the reactions of aryl halides have been extensively studied, and it is now possible to introduce an aromatic unit to a broad range of enolate-type nucleophiles, [1] the coupling reactions involving vinyl halides have received little attention and deal almost exclusively with the a-alkenylation of ketone enolates.The first examples of such palladium-catalyzed coupling reactions involving vinyl halides were reported by Piers at the beginning of the 1990s, when he described the intramolecular alkenylation of ketone enolates and then applied the reaction to the synthesis of the diterpenoid crinipellin B.[2] Some years later, another example of this coupling process was reported by Cook in the context of the total synthesis of the alkaloid (þ)-vellosimine, [3] and we reported our studies on the synthesis of nitrogen heterocycles by the Pd(0)-catalyzed intramolecular coupling of amino-tethered vinyl halides and ketone enolates.[4] Later on, Buchwald described the intermolecular vinylation of ketone enolates. [5] Finally, it is worth mentioning that isolated examples of the alkenylation reaction have also been reported in the studies of the Pd(0)-catalyzed intermolecular arylation of ester [6] and alanine-derived azlactone [7] enolates.In our previous work, we established that the use of Pd(PPh 3 ) 4 (0.2 equivs.) and KO-t-Bu (1.5 equivs.) in THF at reflux effectively promotes the intramolecular coupling of amino-tethered vinyl halides and ketones to afford bridged, condensed, and monocyclic nitrogen-containing compounds.[4] However, for some substrates side reactions such as the elimination of HX leading to alkynes which may undergo subsequent coupling with the starting vinyl halides to afford dimeric compounds, and dealkylation at the nitrogen, resulted in low or moderate yields of the cyclization products.[4b]As these side reactions can mainly be attributed to the use of a strong base, a more general protocol for the intramolecular a-alkenylation of ketones could be found if, instead of KO-t-Bu, a milder base was used. In this context, it should be noted that the intramolecular coupling of amino-tethered vinyl halides and ketones was also accomplished in some cases by using Cs 2 CO 3 as the base, although these reaction conditions were only suitable for the construction of five-membered ring systems and afforded moderate or low yields. [4b] Continuing our studies on this palladium chemistry, [8] we have recently reported that both vinyl an...