Modular, automated synthesis of spirocyclic tetrahydronaphthyridines from primary alkylamines.

Spirocyclic tetrahydronaphthyridines (THNs) are valuable scaffolds for drug discovery campaigns, but access to this 3D chemical space is hampered by a lack of modular and scalable synthetic methods. We hereby report an automated, continuous flow synthesis of α-alkylated and spirocyclic 1,2,3,4-tetrahydro-1,8-naphthyridines ("1,8-THNs"), in addition to their regioisomeric 1,6-THN analogues, from abundant primary amine feedstocks. An annulative disconnection approach based on photoredox-catalysed hydroaminoalkylation (HAA) of halogenated vinylpyridines is sequenced in combination with intramolecular SNAr N-arylation. To access the remaining 1,7- and 1,5-THN isomers, a photoredox-catalysed HAA step is telescoped with a palladium-catalysed C-N bond formation. Altogether, this provides a highly modular access to four isomeric THN cores from a common set of unprotected primary amine starting materials, using the same bond disconnections. The simplifying power of the methodology is illustrated by a concise synthesis of the spirocyclic THN core of Pfizer's MC4R antagonist PF-07258669.

Palladium-Catalyzed Enantioselective C-H Activation of Aliphatic Amines Using Chiral Anionic BINOL-Phosphoric Acid Ligands.

The design of an enantioselective Pd(II)-catalyzed C-H amination reaction is described. The use of a chiral BINOL phosphoric acid ligand enables the conversion of readily available amines into synthetically valuable aziridines in high enantiomeric ratios. The aziridines can be derivatized to afford a range of chiral amine building blocks incorporating motifs readily encountered in pharmaceutically relevant molecules.

A general catalytic ß-C-H carbonylation of aliphatic amines to ß-lactams.

Methods for the synthesis and functionalization of amines are intrinsically important to a variety of chemical applications. We present a general carbon-hydrogen bond activation process that combines readily available aliphatic amines and the feedstock gas carbon monoxide to form synthetically versatile value-added amide products. The operationally straightforward palladium-catalyzed process exploits a distinct reaction pathway, wherein a sterically hindered carboxylate ligand orchestrates an amine attack on a palladium anhydride to transform aliphatic amines into ß-lactams. The reaction is successful with a wide range of secondary amines and can be used as a late-stage functionalization tactic to deliver advanced, highly functionalized amine products of utility for pharmaceutical research and other areas.

Continuous-Flow Synthesis and Derivatization of Aziridines through Palladium-Catalyzed C(sp(3) )-H Activation.

A continuous-flow synthesis of aziridines by palladium-catalyzed C(sp(3) )-H activation is described. The new flow reaction could be combined with an aziridine-ring-opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C-H activation flow process and illustrates an approach towards first-principles design based on novel catalytic reactions.

Mechanistic Insights into the Palladium-Catalyzed Aziridination of Aliphatic Amines by C-H Activation.

Detailed kinetic studies and computational investigations have been performed to elucidate the mechanism of a palladium-catalyzed C-H activation aziridination. A theoretical rate law has been derived that matches with experimental observations and has led to an improvement in the reaction conditions. Acetic acid was found to be beneficial in controlling the formation of an off-cycle intermediate, allowing a decrease in catalyst loading and improved yields. Density functional theory (DFT) studies were performed to examine the selectivities observed in the reaction. Evidence for electronic-controlled regioselectivity for the cyclopalladation step was obtained by a distortion-interaction analysis, whereas the aziridination product was justified through dissociation of acetic acid from the palladium(IV) intermediate preceding the product-forming reductive elimination step. The understanding of this reaction mechanism under the synthesis conditions should provide valuable assistance in the comprehension and design of palladium-catalyzed reactions on similar systems.

A family of simple benzene 1,3,5-tricarboxamide (BTA) aromatic carboxylic acid hydrogels.

We present the characterisation of a hydrogel forming family of benzene 1,3,5-tricarboxamide (BTA) aromatic carboxylic acid derivatives. The simple, easy to synthesise compounds presented here exhibit consistent gel formation at low concentrations through the use of a pH trigger.