The development of a mild and general method for the alkylation of amides with relatively unreactive alkyl halides (i.e., poor substrates for S N 2 reactions) is an ongoing challenge in organic synthesis. We describe herein a versatile transition-metal-catalyzed approach: in particular, a photoinduced, copper-catalyzed monoalkylation of primary amides. A broad array of alkyl and aryl amides (as well as a lactam and a 2-oxazolidinone) couple with unactivated secondary (and hindered primary) alkyl bromides and iodides using a single set of comparatively simple and mild conditions: inexpensive CuI as the catalyst, no separate added ligand, and C−N bond formation at room temperature. The method is compatible with a variety of functional groups, such as an olefin, a carbamate, a thiophene, and a pyridine, and it has been applied to the synthesis of an opioid receptor antagonist. A range of mechanistic observations, including reactivity and stereochemical studies, are consistent with a coupling pathway that includes photoexcitation of a copper−amidate complex, followed by electron transfer to form an alkyl radical.

We have recently reported that, in the presence of light and a copper catalyst, nitrogen nucleophiles such as carbazoles and primary amides undergo C–N coupling with alkyl halides under mild conditions. In the present study, we establish that photoinduced, copper-catalyzed alkylation can also be applied to C–C bond formation, specifically, that the cyanation of unactivated secondary alkyl chlorides can be achieved at room temperature to afford nitriles, an important class of target molecules. Thus, in the presence of an inexpensive copper catalyst (CuI; no ligand co-additive) and a readily available light source (UVC compact fluorescent light bulb), a wide array of alkyl halides undergo cyanation in good yield. Our initial mechanistic studies are consistent with the hypothesis that an excited state of [Cu(CN)2]− may play a role, via single electron transfer, in this process. This investigation provides a rare example of a transition metal-catalyzed cyanation of an alkyl halide, as well as the first illustrations of photoinduced, copper-catalyzed alkylation with either a carbon nucleophile or a secondary alkyl chloride.

Nickel‐catalyzed cross‐coupling has emerged as the most versatile approach to date for achieving enantioconvergent carbon–carbon bond formation using racemic alkyl halides as electrophiles. In contrast, there have not yet been reports of the application of chiral nickel catalysts to the corresponding reactions with heteroatom nucleophiles to produce carbon–heteroatom bonds with good enantioselectivity. Herein, we establish that a chiral nickel/pybox catalyst can borylate racemic secondary benzylic chlorides to provide enantioenriched benzylic boronic esters, a highly useful family of compounds in organic synthesis. The method displays good functional group compatibility (e.g., being unimpeded by the presence of an indole, a ketone, a tertiary amine, or an unactivated alkyl bromide), and both of the catalyst components (NiCl2⋅glyme and the pybox ligand) are commercially available.

Reported is the first nickel-catalyzed enantioselective allylic alkylation of lactones and lactams to provide products bearing an all-carbon quaternary stereocenter.

A new strategy for the catalytic enantioselective C-acylation to generate α-quaternary substituted lactams is reported. Ni-catalyzed three-component coupling of lactam enolates, benzonitriles, and aryl halides produce β-imino lactams that then afford β-keto lactams by acid hydrolysis. Use of a readily available Mandyphos- ype ligand and the addition of LiBr enables the construction of quaternary stereocenters on α-substituted lactams to form β-keto lactams in up to 94% ee.

Herein, we report the first Pd‐catalyzed enantioselective arylation of α‐substituted γ‐lactams. Two sets of conditions were developed for this transformation, allowing for the use of either aryl chlorides or bromides as electrophiles. Utilizing a highly electron‐rich dialkylphosphine ligand we have been able to construct α‐quaternary centers in good yields (up to 91 % yield) and high enantioselectivities (up to 97 % ee).

Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, or KMnO 4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40-63 nm) was used for flash chromatography. 1 H NMR spectra were recorded on a Bruker Avance HD 400 MHz or Varian Mercury 300 MHz spectrometers and are reported relative to residual CHCl 3 (δ 7.26 ppm). 13 C NMR spectra were recorded on a Bruker Avance HD 400 MHz spectrometer (100 MHz) and are reported relative to residual CHCl 3 (δ 77.36 ppm). 19 F NMR spectra were recorded on a Varian Mercury 300 MHz spectrometer (282 MHz). Data for 1 H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet, app = apparent. Data for 13 C NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell and are reported as: [α] D T (concentration in 10 mg/1 mL, solvent). Analytical SFC was performed with a Mettler SFC supercritical CO 2 analytical chromatography system utilizing Chiralpak (AD-H) or Chiralcel (OD-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A S3 Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). Reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. List of Abbreviations ee-enantiomeric excess, SFC-supercritical fluid chromatography, TLC-thin-layer chromatography, IPA-isopropanol, MTBE-methyl tert-butyl ether, PE-petroleum ether, DMAP-4-dimethylaminopyridine, EtOAc-ethyl acetate, LiHMDS-lithium bis(trimethylsilyl)amide, NaHMDS-sodium bis(trimethylsilyl)amide, PMPp-methoxy phenyl, pmdba-4,4'-dimethoxydibenzylideneacetone, THF-tetrahydrofuran, DMEDA-1,2-dimethylethylenediamine.

The synthesis of a variety of enantioenriched 1,3-diketospiranes from the corresponding racemic allyl β-ketoesters via an interrupted asymmetric allylic alkylation is disclosed.