Crafts alkylation of aromatic compounds is one of the important organic transformations. A report (Org. Lett. 2013, 15, 5912) described an intramolecular Friedel−Crafts reaction of aziridinium ions for the synthesis of 4-substituted tetrahydroquinolines. Treatment of enantiopure β-haloamines with AlCl 3 provided, via aziridinium ion intermediates, enantiomerically enriched 4-substituted tetrahydroisoquinolines. Both the formation and ring-opening of aziridinium ions are identified as key steps in these transformations. The bromide in β-bromoamines proved to be the leaving group of choice as using the β-chloroor β-iodoamine substrates led to a lower yield and ee. In addition this intramolecular Friedel−Crafts reaction was quite sensitive to the N-substitution.■ PALLADIUM-CATALYZED AZIRIDINE RING-OPENING Aziridine ring-opening by carbon nucleophiles requires, in general, organometallic nucleophiles in the presence of strong Lewis acid. Those reaction conditions are poorly compatible with functional groups. A mild Pd-catalyzed aziridine ringopening reaction with aryl boronic acid as the nucleophile was developed (J. Am. Chem. Soc. 2013, 135, 18347). Exposure of the aziridine to a mixture of arylboronic acid, Pd(dba) 2 , P(Np) 3 , and Cs 2 CO 3 in the presence of m-chlorophenol (4 equiv) as an additive gave the desired β-aryl-substituted amine product. This ring-opening is highly regioselective and compatible with diverse functionality in the aryl boronic acids, including alkyl, alkoxy, ketone, amide, hydroxyl, nitro, etc. The reaction is hypothesized to proceed through three intermediates, A, B, and C. As the ring-opened intermediates, B and C, are susceptible to the β-hydride elimination, the use of an m-chlorophenol additive is critical for the success of the transformation in preventing the β-hydride elimination side reaction. The key role of the m-chlorophenol additive is presumably to minimize the lifetime of these two species by careful control of the protonolytic equilibrium and the rate of transmetalation.
The preparation of new RSV inhibitors required an efficient synthesis of (R)-2-methylazepane ((R)-1) amenable to large-scale production to support preclinical studies. After consideration of different options, an efficient five-step synthesis relying on the preparation of the racemic N-Boc precursor and its purification by chiral SFC was developed and successfully implemented on a 400 g scale.
Metrics & More Article Recommendations ■ N-HYDROXYPHTHALIMIDE-CATALYZED AEROBIC OXIDATION OF ALDEHYDES UNDER CONTINUOUS FLOW CONDITIONS Oxidation of aldehydes to carboxylic acids is a common organic transformation for which a wide array of stochiometric and catalytic methods are known. Kappe and co-workers recently disclosed an improvement of aerobic oxidation of aldehydes catalyzed by N-hydroxyphthalimide (NHPI) through recourse to flow chemistry (Adv. Synth. Catal.
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