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 β-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.

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We report a general visible-light-mediated strategy that enables the construction of complex C(sp 3)rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C(sp 3)-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.

The study of a selective palladium(ii)-catalyzed C(sp3)–H acetoxylation reaction on a class of cyclic alkyl amines is reported.

Chloromethylvinyl alanes (E)-ClMeAl(CHQ Q QCHR) prepared directly from terminal alkynes undergo 1,4-addition to cyclohexenone and 3-methylcyclohexenone in moderate to good yield (30-70%) and good to excellent stereoselectivity (80-98% ee) using readily available copper(I) sources and chiral ligands.Asymmetric conjugate addition (ACA) has become a mainstay of contemporary chiral synthesis in the last 10 years. 1 Sublime levels of enantioselectivity are realised in 1,4-additions of simple alkyl groups to various Michael acceptors, but the situation for C(sp 2 ) vinyl-based nucleophiles is not so clear cut. Rhodium-diphosphine catalysts are normally preferred for additions of C(sp 2 ) nucleophiles, especially aryls, to mono substituted enones 2 but these fail to elicit any reaction for b,b-substituted enones -where copper(I)/phosphorus-ligand catalysts are required. 1,3 The choice of C(sp 2 ) nucleophile also has issues: vinyl boronic acids, and their derivatives, are rather more susceptible to hydrolytic deboronation compared to their aryl cousins -causing lower yields or the need for excess reagents. Alkenylalanes, used with Cu I catalysts, are often prepared from RCCH and DIBAL-H (either through heating, 4 or Ni-catalysis 5 ) have issues: (i) deprotonation by-products are common under thermal DIBAL-H procedures except for alkyl substituted cases; (ii) b-aryl Bu i 2 AlCHQCHAr, prepared by Ni-catalysis, are normally contaminated with B5% of the a-aryl isomer; finally (iii) the bulky Bu i substituents can cause problems in the subsequent ACA catalysis leading to low yields and slow reactions. Alternative hydroalumination-ACA approaches are desirable, particularly if they use simple reagents catalysts and conditions to deliver high ee values for 1,4-additions to both mono and b,b-disubstituted enones.

The ability of alkali metal complexes bearing chiral BINOL-derived ligands to catalyse the enantioselective hydroboration of ketones was explored.

ReactIR studies of mixtures of AlEt3 (A) and cyclohex-2-en-1-one (CX) in Et2O indicate immediate formation of the Lewis acid–base complex CX·A at −40 °C (K = 12.0 M–1, ΔG°react = −1.1 kcal mol–1). Copper­(I) catalysts, derived from precatalytic Cu­(OAc)2 (up to 5 mol %) and (R,S,S)-P­(binaphtholate)­{N­(CHMePh)2} (Feringa’s ligand (L), up to 5 mol %) convert CX·A (0.04–0.3 M) into its 1,4-addition product enolate (E) within 2000 s at −40 °C. Kinetic studies (ReactIR and chiral GC) of CX·A, CX, and (R)-3-ethylcyclohexanone (P, the H+ quenching product of enolate E) show that the true catalyst is formed in the first 300 s and this subsequently provides P in 82% ee. This true catalyst converts CX·A to E with the rate law [Cu]1.5[L]0.66[CX·A]1 when [L]/[Cu] ≤ 3.5. Above this ligand ratio inhibition by added ligand with order [L]−2.5 is observed. A rate-determining step (rds) of Cu3 L 2(CX·A)2 stoichiometry is shown to be most consistent with the rate law. The presence of the enolate in the active catalyst best accounts for the reaction’s induction period and molecularity as [E] ≡ [CX·A]. Catalysis proceeds through a “shuttling mechanism” between two C 2 symmetry related ground state intermediates. Each turnover consumes 1 equiv of CX·A, expels one molecule of E, and forms the new Cu–Et bond needed for the next cycle. The observed ligand (L) inhibition and a nonlinear ligand L ee effect on the ee of P are well simulated by the kinetic model. DFT studies (ωB97X-D/SRSC) support coordination of CX·A to the groundstate Cu trimer and its rapid conversion to E.

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