Highly regioselective synthesis of chiral diamines via a Buchwald–Hartwig amination from camphoric acid and their application in the Henry reaction

Abstract

In this work the synthesis of new asymmetric diamine ligands from camphoric acid is described. The new diamines can be directly prepared in a regioselective arylation of the less hindered primary amine group of (+)-cis-1,2,2-trimethylcyclopentane-1,3-diamine via a Buchwald-Hartwig amination in high yields. The resulting diamines incorporate a secondary and primary amine group and were successfully applied as ligands in a copper-catalyzed Henry reaction.

Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin

“…11 This paucity is likely attributable to the requirement for a high catalyst loading to effect the desired transformation, and/or limited availability of certain chiral ligands. 12 Given these known challenges, we focused our initial efforts on identifying a practical ligand for the asymmetric Henry reaction. Using 2,5-difluorobenzaldehyde ( 15 ) as substrate, a variety of commercially available chiral ligands were surveyed utilizing high-throughput experimentation tools and techniques.…”

Straightforward Diastereoselective Synthesis of P-Chirogenic (1R)-1,8,8-Trimethyl-2,4-diaza-3-phosphabicyclo[3.2.1]octane 3-Oxides: Application as Chiral NMR Solvating Agents

“…The symmetrical substituted diamines 7 and 8 were prepared according to a literature procedure . Thereafter, a series of enantiopure secondary diamines 26 with two differently substituted nitrogen atoms were synthesized via an alkylation of monoarylated diamines with mesitylmethylene chloride in the presence of triethylamine in acetonitrile under reflux (Scheme ). The corresponding diamines 9 – 15 were obtained in yields between 50% and 70% as shown in Table .…”

“…(+)‐ cis ‐(1 R ,3 S )‐1,2,2‐Trimethylcyclopentane‐1,3‐diamine ( 25 ) was synthesized according to the literature from (+)‐camphoric acid, which was purchased from commercial sources. Diamines 7 and 8 and monoarylated diamines were prepared according to the literature.…”

Synthesis of New Camphor-Based Carbene Ligands and Their Application in a Copper-Catalyzed Michael Addition with B2Pin2

“…9i However, although they investigated their complexes in several reactions, no significant enantiomeric excess has so far been reported with these types of carbene complexes. 9i-m Here we report a straightforward synthesis of new derivatives of these types of carbenes by incorporating at the less hindered nitrogen atom an arene substituent via a Buchwald-Hartwig amination 15 and on the other nitrogen atom an aliphatic or benzylic substituent. This gave a set of different enantiopure C 1 -symmetric carbene ligands with different sterical and electronic substituents in the amidinium fragment and resulted in the successful application of these new ligands in an asymmetric copper-catalyzed B 2 Pin 2 addition to an unsaturated ester.…”

“…The syntheses of the desired carbene precursors started by treating diamine 7 with different bromoarenes under Buchwald-Hartwig amination conditions resulting in the selective arylation of the less hindered amine function of diamine 7 (Scheme 1). 15 These diamines were transformed into cyclic amidines using trimethyl orthoformate in the presence of acetic acid in acetonitrile under reflux. The cyclic amidines were thereafter treated with various benzylic bromides and chlorides resulting in quaternization to give differently substituted amidinium chloride and bromide salts.…”