We report a denitrogenative dihalogenation reaction of phenyldiazomethanes in which the hypervalent iodine reagents PhICl2 and TolIF2 act as surrogates for elemental chlorine and fluorine. Halogen transfer from iodane to aryldiazomethane is described, as is a tandem oxidative dihalogenation reaction between iodane and hydrazone. This is the first use of non‐α‐stabilized diazo compounds in this reaction, which provided an efficient synthesis of aryldifluoromethane (ArCHF2) and aryldichloromethane (ArCHCl2) derivatives.magnified image

An operationally simple conversion of aromatic aldehyde hydrazones to monofluoromethylated arenes is reported. The hypervalent iodine reagent TolIF serves as an oxidant, converting the hydrazone to the corresponding diazo compounds. The by-product of the oxidation process, HF, is consumed in situ by a denitrogenative hydrofluorination reaction of the diazo group.

A formal enantioselective synthesis of (2)-aphanorphine (91% ee), that culminates with the preparation of (+)-O-methyl aphanorphine, was achieved. The methodology involves the diastereoselective synthesis of a key 3,5-disubstituted pyrrolidinone intermediate by the intramolecular oxidative amidation of a suitably functionalized a-hydroxy pentenoic acid derivative. A late-stage N-formyl protection, which functions as a latent N-methyl group, is utilized as a simple alternative to a protecting group switch and subsequent N-methylation strategy implemented in all other syntheses of aphanorphine related to the present approach.Aphanorphine (1) 1 is an alkaloid that shares structural features with the analgesic benzomorphan alkaloids eptazocine (3), pentazocine (4) and morphine (5, Fig. 1). This structural resemblance and the synthetically intriguing 3-benzazepine ring system and quaternary stereocenter have all contributed to significant interest in the synthesis of aphanorphine, 2-4 which continues to be a popular target for showcasing new methodology leading to the benzazepine motif. We describe here a synthesis of (+)-O-methyl aphanorphine (2), an immediate synthetic precursor of (2)-aphanorphine.Our interest in aphanorphine stems from our studies on the enantioselective synthesis and applications of a-alkyl a-hydroxy acid derivatives as intermediates to biologically relevant motifs and natural products. 5 We therefore envisaged an a-hydroxy acid based route to aphanorphine as detailed in Scheme 1. The strategy utilizes a stereoselective, intramolecular C-N bond formation as a pivotal step in the synthesis of a key pyrrolidine intermediate. A cyclative Friedel-Crafts alkylation in this pyrrolidine is used, as in previous aphanorphine syntheses, 2a,3a,4f for constructing the bridged benzazepine motif in aphanorphine. The precursor of the pyrrolidine is obtained by a cross metathesis reaction of an enantiomerically enriched a-hydroxy pentenoic acid derivative which, in turn, is obtained by asymmetric allylation of a chiral pyruvate (Scheme 1).Initially, we chose to explore the synthesis of a suitably substituted N-methyl pyrrolidinone as a precursor to the functionalized pyrrolidine motif in aphanorphine. The motivation for this approach was twofold: 1) several substituted N-methyl pyrrolidinones are natural products 6 or motifs in bioactive molecules, 7 and the present study could potentially provide methodology for their synthesis as well; and 2) the starting material for the pyrrolidinone based approach, the a-hydroxy N-methyl amide (R)-8 5f (Scheme 2) is directly obtained by our asymmetric allylation protocol 5f employing an ephedrine-derived chiral pyruvamide. Furthermore, the intramolecular Friedel-Crafts alkylation (Scheme 1) of the N-methyl pyrrolidine, obtained from the pyrrolidinone, could potentially provide the aphanorphine framework. Our studies therefore commenced with (R)-8 (92% ee) which was prepared by the asymmetric allylation of an ephedrine and pyruvic acidderived morpholinone 6 as shown in Sche...