ChemInform Abstract: Highly Regio‐, Diastereo‐, and Enantioselective C—H Insertions of Methyl Aryldiazoacetates into Cyclic N‐Boc‐Protected Amines. Asymmetric Synthesis of Novel C₂‐Symmetric Amines and threo‐Methylphenidate.

Abstract

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Undirected, Homogeneous C–H Bond Functionalization: Challenges and Opportunities

“…The reactions also occur preferentially at the C−H bonds located alpha to alkoxy, siloxy, and amino groups. 78 Thus, the reactions occur with high regioselectivity at the C−H bonds of cycloalkanes, 78 cyclic ethers, 78 and cyclic amine derivatives, 79 and these reactions occur with high enantioselectivity (eq 11). The reactions also occur alpha to oxygen in linear, allylic silyl ethers 80 to form products that are equivalent to those from aldol reactions.…”

Lewis Base Promoted Delayed Copper Catalysis: Borylative α-C-H Allylation of Alicyclic Amines

“…bearing contiguous quaternary and tertiary stereocentres. Gratifyingly, this method could be extended to other alicyclic amine frameworks such as piperidine (15,16), piperazine (17), pyrrolidine (18) and azepine (19), obtaining in all cases the product in good yield with perfect regio-and diastereoselectivity. Of note is the reaction with 4methylpiperidin-1-yl benzoate which afforded 16 bearing three new stereocentres which were generated with total stereocontrol.…”

“…4,5,6,7 Other strategies based on protecting-groups have relied on transition metal-catalyzed direct C-H arylation reactions, 8,9,10 photoredox catalysis, 11,12,13 intramolecular hydride transfer 14 and C-H insertions via metal carbenoids. 15 An alternative strategy to generate α-substituted saturated nitrogen heterocycles is the generation of a cyclic imine and its engagement with a nucleophile. However, alicyclic imines are unstable, and they tend to undergo trimerization, resulting in non-reactive compounds.…”

Generation of Tosyl Azide in Continuous Flow Using an Azide Resin, and Telescoping with Diazo Transfer and Rhodium Acetate-Catalyzed O–H Insertion

“…32 α-Aryl-α-diazoacetates have been shown to have potential as intermediates in the synthesis of active pharmaceutical ingredients (APIs), albeit demonstrated at lab scale only to the best of our knowledge. 33,34 Indeed, interest in the use of these compounds has prompted recent investigation and review of their thermal stability and associated hazard. 5 For example, enantioselective palladium mediated O−H insertion of a phenyl-α-diazoacetate 1 has been employed in the synthesis of a key intermediate 3, 98% ee, for atomoxetine 4 (Eli Lilly) in Scheme 1, 33 while rhodium-mediated C−H insertion has led to methylphenidate 7 (Novartis) in 86% ee (Scheme 2), both of which are used to treat ADHD (Attention Deficit Hyperactivity Disorder), albeit prepared at scale by other routes.…”

“…5 For example, enantioselective palladium mediated O−H insertion of a phenyl-α-diazoacetate 1 has been employed in the synthesis of a key intermediate 3, 98% ee, for atomoxetine 4 (Eli Lilly) in Scheme 1, 33 while rhodium-mediated C−H insertion has led to methylphenidate 7 (Novartis) in 86% ee (Scheme 2), both of which are used to treat ADHD (Attention Deficit Hyperactivity Disorder), albeit prepared at scale by other routes. 34 A report from Zhou et al 35 associated with the Regitz diazo transfer currently are likely to render this route unattractive at scale. Accordingly, exploration of a flow process to provide the key intermediate, methyl 2-hydroxy-2-chlorophenylacetate (10), used in the synthesis of the antiplatelet drug clopidogrel 11 was undertaken.…”