The Parham cyclization-intermolecular α-amidoalkylation sequence results in the facile enantioselective synthesis of 12b-substituted isoindoloisoquinolines (ee up to 95%) using BINOL-derived Brønsted acids. α-Amidoalkylation of indole occurs through the formation of a chiral conjugate base/bicyclic quaternary N-acyliminium ion pair.

The intramolecular α-amidoalkylation reactions of aromatic and heteroaromatic ring systems constitute a versatile approach for the synthesis of nitrogen heterocyles in a diastereoselective or enantioselective fashion. On the other hand, the intramolecular reactions of aryllithium compounds have also been extensively used in the synthesis of carbocycles and heterocycles. The use of imides as internal electrophiles is particularly attractive because of the potential to introduce diverse functionality into the cyclized products by subjecting the resulting α-hydroxylactams to intermolecular IntroductionAryllithium compounds and N-acyliminium ions are extremely versatile intermediates for the formation of carboncarbon bonds in organic synthesis. Cyclization of aryllithium compounds generated by halogen/lithium exchange with internal electrophiles (Parham cyclization) has become a valuable protocol for the stereoselective construction of carbocyclic and heterocyclic systems.[1] Many electrophiles remain inert during halogen/metal exchange reaction at low temperature, but are reactive enough to participate in a subsequent cyclization reaction. Halides, epoxides, or alkenes [2] are thus among the different types of internal electrophiles used in the Parham cyclization. When the internal electrophile is a carboxylate derivative, this anionic cyclization could be considered an anionic Friedel-Crafts equivalent, with the advantage that it lacks the electronic requirements of the classical reaction. Although it is possible to use carboxylic acids [3] or esters, [4] carbamates have proven to be much more effective internal electrophiles in Parham cycliacylations.[5] Amides are also useful electrophiles in Parham cyclizations, and it has been reported that in some cases there is an influence of the natures of the substituents at the nitrogen atom on the course of the cyclization reaction. [6,7] [a] Departamento In connection with our interest in aromatic lithiation, we have developed an anionic cyclization approach directed towards the construction of the pyrrolo[1,2-b]isoquinolone core based on N-(o-halobenzyl)pyrrole-2-carboxamides, showing that Weinreb amides and morpholine amides function as excellent internal electrophiles.[8] This observation could be explained by assuming that halogen/lithium exchange could be favored by a complex-induced proximity effect (CIPE).[9] This concept has been invoked to explain other metal/metal, hydrogen/metal, or halogen/metal [10] exchange reactions. Lithium/halogen exchange would thus be favored first by coordination of the inducing organolithium compound with amide or carbamate groups, and then by stabilization of the resulting aryllithium compound. The better behavior of Weinreb and morpholine amides relative to N,N-diethyl amides could be attributed to the extra stabilization of the intermediate generated after cyclization through the formation of an internal chelate. The scope of these Parham-type cyclizations has been extended to the formation of seven-and eight-membered rings [8b] ...

A new multi-output PT-QSRR model to correlate and predict the enantioselectivity and yield of Heck–Heck cascade reactions has been developed.

Enamides with a free NH group have been evaluated as nucleophiles in chiral Brønsted acid‐catalyzed enantioselective α‐amidoalkylation reactions of bicyclic hydroxylactams for the generation of quaternary stereocenters. A quantitative structure–reactivity relationship (QSRR) method has been developed to find a useful tool to rationalize the enantioselectivity in this and related processes and to orient the catalyst choice. This correlative perturbation theory (PT)‐QSRR approach has been used to predict the effect of the structure of the substrate, nucleophile, and catalyst, as well as the experimental conditions, on the enantioselectivity. In this way, trends to improve the experimental results could be found without engaging in a long‐term empirical investigation.

An organolithium addition–intramolecular α-amidoalkylation sequence on N -phenethylimides has been developed for the synthesis of fused tetrahydroisoquinoline systems using 1,1′-bi-2-naphthol (binol)-derived Brønsted acids. This transformation is the first in which activated benzene derivatives are used as internal nucleophiles, instead of electron-rich heteroaromatics, generating a quaternary stereocenter. Phenolic substitution on the aromatic ring of the phenethylamino moiety and the use of binol-derived N -triflylphosphoramides as catalysts are determinants to achieve reasonable levels of enantioselection, that is, up to 75% enantiomeric excess, in the α-amidoalkylation step. The procedure is complementary to the intermolecular α-amidoalkylation process, as opposite enantiomers are formed, and to the Pictet–Spengler cyclization, which allows the formation of tertiary stereocenters.