Synthesis of IAN-type N,N-Ligands via Dynamic Kinetic Asymmetric Buchwald–Hartwig Amination

Abstract

The Pd 0 -catalyzed coupling of racemic heterobiaryl bromides, triflates or nonaflates with aryl/alkyl primary amines using QUINAP as the ligand provides the corresponding axially chiral heterobiaryl amines with excellent yields and enantioselectivities. Reactivity and structural studies of neutral and cationic oxidative addition intermediates support a dynamic kinetic asymmetric amination mechanism based on the labilization of the stereogenic axis in the latter, and suggest that coordination of the amine to the Pd center is the stereodetermining step.In recent years, significant advances have been achieved in the field of asymmetric cross-coupling, in particular for the synthesis of axially chiral biaryls.1 In sharp contrast, the direct asymmetric heteroaryl-aryl cross-coupling remains as an unmet challenge, 2 limiting the access to functionalized heterobiaryls with appealing structures for their use as ligands in asymmetric catalysis. As a remarkable example, the use Isoquinoline-Amino Naphthalene (IAN) and related derivatives, which can be seen as N(sp 2 ),N(sp 3 ) analogues of QUINAP, have been scarcely investigated.3 A plausible explanation is the poor availability: there are no commercially available representatives and their synthesis still requires chromatographic separation of diastereomeric mixtures (Scheme 1, eq. 1), 4 while the lack of a general and practical method of synthesis has also limited the structural diversity of known ligands of this type. Recently, we have reported a novel strategy for the synthesis of functionalized heterobiaryls based on dynamic kinetic asymmetric C-C 5 and C-P 6 bond formations starting from heterobiaryl triflates to ensure the formations of cationic oxidative addition intermediates (Scheme 1, eq. 2). Stimulated by the growing potential of related axially chiral heterobidentate ligands, 7 we decided to focus on the development of dynamic kinetic Buchwald-Hartwig (DYKAT: Dynamic Kinetic Asymmetric Transformation) amination of heterobiaryl electrophiles for the asymmetric synthesis of axially chiral IAN-type diamines (Scheme 1, eq. 3).The unprecedented asymmetric amination of heterobiaryls is a particularly challenging goal due to the specific conditions required. First, a strong base is generally needed to achieve good reactivities, so that compatibility issues might arise with the heteroScheme 1. Synthetic approaches to IAN amines biaryl triflates used in previous DYKAT processes. Second, the racemization barriers for IAN amines are significantly lower than those of arylated products I or QUINAP-type products II, 8 making necessary to work under exceptionally mild conditions. 9 In order to minimize the hydrolysis of the starting material, we started using the coupling between nonaflate (±)-1A 10 and aniline 5a as a model reaction for the synthesis of IAN 6Aa, using NaOtBu as the base, dry toluene as the solvent at 60 °C and 10 mol% Pd(dba)2/12 mol% ligand as the catalyst system (Scheme 2).Ligands that showed a good performance in related processes were select...

NNB-Type Tridentate Boryl Ligands Enabling a Highly Active Iridium Catalyst for C–H Borylation

“…For preligand NNB-L1 , heating a neat mixture of 2-chloro-4,4’-di-tert-butyl bipyridine with a 10.0 equivalent of o-phenylenediamine [43,44,45] gave preL 1 in a 48% isolated yield. The treatment of preL 1 with a 1.05 equivalent of B–Si reagent [46,47,48,49,50] at 120 °C in toluene cleanly gave the new NNB-L 1 in excellent yield. As for the other two preligands, preL 2 and preL 3 were synthesized through Buchwald–Hartwig amination [51,52,53] in a Pd/BINAP catalytic system in moderate yield; the second step is identical to that previously mentioned.…”

Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc‐Catalyzed Asymmetric Hydrosilylation

“…A unique class of the chiral N , N ‐ligand ( R a , S )‐ 8 was prepared by copper(I)‐catalyzed cycloaddition reaction of ( R a , S )‐ 7 with phenylacetylene in good yield under mild reaction conditions. Moreover, Staudinger reduction of ( R a , S )‐ 7 furnished the amine ( R a , S )‐ 9 , an appealing homologue of the ligand IAN, but incorporating an additional stereocenter. Finally, a novel class of bifunctional thiourea catalysts, ( R a , S )‐ 10 , was easily obtained by condensation of ( R a , S )‐ 9 and 1‐isothiocyanato‐3,5‐ bis(trifluoromethyl)benzene.…”

Design and Atroposelective Construction of IAN analogues by Organocatalytic Asymmetric Heteroannulation of Alkynes

“…[6] This type of heteroaryl atropisomers ordinarily formed a chelate ring with metal atom through the coordination of nitrogen and other donor atoms, such as phosphorus, nitrogen, oxygen, and sulfur, providing the asymmetric induction in various metal‐catalyzed enantioselective transformations (Figure 2 a). [7] Conventionally, synthetic approaches for enantioenriched 2‐arylpyridine/isoquinoline skeletons depend mainly on transition‐metal mediated patterns, such as cross‐coupling, [6i,r] (dynamic) kinetic resolution/transformation, [6a,g,h,j–q,s] and de novo construction of a (hetero)aromatic ring [6c,e,f] . However, as the number of this type of axially chiral ligands and catalysts in asymmetric catalysis grows, a highly efficient organocatalytic approach to corresponding axially chiral heterobiaryl skeletons becomes an urgent need.…”