Diels or no Diels? A bifunctional organic catalyst based on the thiourea motif is able to coordinate both diene and dienophile in an unprecedented asymmetric Diels–Alder reaction of 3-vinylindole derivatives, giving a rapid access to optically active tetra- and hexahydrocarbazoles with excellent results in terms of yields, diastereoselectivities, and enantioselectivities
Trifluoromethylsulfonate (triflate) and bis(trifluoromethylsulfonyl)imide (triflimide) salts, well-known Lewis acid catalysts, present some difficulty in their characterization. By using nitromethane as the solvent, useful electrospray mass spectra in positive and negative ion mode were obtained for salts of metals in oxidation states +2 and +3. In positive mode, addition of a strong Lewis base (triphenylphosphine oxide, TPPO), capable of displacing a triflate (TfO(-)) or a triflimide (Tf(2)N(-)) anion, is necessary for obtaining useful spectra. Under these conditions of solvent and added ligand, the most abundant ions were [M(2+)(A(-))(TPPO)(2)](+) or [M(3+)(A(-))(2)(TPPO)(2)](+) with A(-) = TfO(-) or Tf(2)N(-). The MS/MS spectra of these diagnostic ions provide additional analytical information. The breakdown curves, in the form of % dissociated as a function of the ion activation energy, offer a mean for investigating the bonding in these ions.
Diels-Alder type reactions are amongst the most useful transformations in organic chemistry for the construction of cyclohexene structures, often containing multiple stereocenters. Catalytic asymmetric variants of these [4+2] cycloadditions have been reported for different diene-dienophile combinations, [1] showing in several instances outstanding synthetic utility. Herein, we present the development of an unprecedented catalytic asymmetric Diels-Alder reaction of 3-vinylindoles 1 with different representative dienophiles 2 (Scheme 1). Our studies were motivated by the stunning directness and versatility of this approach for the [b]anellation (at the C2ÀC3 bond) of the indole nucleus, giving partially saturated, optically active carbazoles 3. Standard manipulations of these cycloadducts give access to tricyclic indolines 4 and tetrahydrocarbazoles 5 (Scheme 1), which are common scaffolds in a variety of natural and/or biologically active alkaloids.[2] It has long been recognized that 3-vinylindoles can participate in frontier-molecular-orbital-controlled Diels-Alder reactions with the HOMO of their electronrich diene systems.[3] Control of the relative stereochemistry in the thus-formed hydrogenated carbazoles is often excellent, owing to the concerted mechanism and to secondary molecular orbital interactions, favoring an endo approach. However, no catalytic asymmetric variants of these useful transformations have been reported to date. [4] To find a suitable catalytic system, we envisioned a scenario where a bifunctional acid-base organic catalyst coordinates through hydrogen-bond interactions to both the diene 1 and the dienophile 2, [5] resulting in a highly organized transition state, potentially giving rise to the cycloadduct with good levels of stereoselectivity. The mild acidic nature of many commonly employed organic catalysts, often based on urea or thiourea motifs, should be compatible even with the acid-sensitive 3-vinylindoles. The asymmetric Friedel-Crafts reactions of 1-H-indole derivatives, [6] wherein the catalysts operate through a hydrogen-bonding network involving the indole N À H, as well as the cycloaddition reaction of 3-hydroxy-2-pyrones, [7] wherein the double activation of a diene and a dienophile by an organic catalyst was realized with great success, were both of great encouragement and inspiration.We initially investigated the catalytic reaction between 3-vinylindole 1 a and N-phenylmaleimide 2 a (Scheme 2). Carrying out the reaction at À25 8C in dichloromethane, screening of bifunctional organic catalysts [8] suggested 6 a, derived from (1S,2R)-1-aminoindanol, and 6 b and c, both derived from quinine, [9] as the most promising structures. Having identified dichloromethane as the solvent of choice for this transformation, [8] optimum selectivity (98 % ee) was reached using catalyst 6 d, derived from hydroquinine, at À55 8C (Scheme 2). Derivatization with trifluoroacetic anhydride (TFAA) after the reaction gave additional stability to the cycloadduct, thus facilitating its isolation b...
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