Transition metal catalyzed Sonogashira cross-coupling of terminal alkynes with aryl(vinyl) (pseudo)halides has been successfully extended to alkyl halides for the synthesis of functionalized internal alkynes. The direct alkynylation of remote unfunctionalized sp 3 carbon by terminal alkynes remains difficult to realize. We report herein an approach to this synthetic challenge by developing two catalytic remote sp 3 carbon alkynylation protocols. In the presence of a catalytic amount of Cu(I) salt and a tridentate ligand (tBu 3-terpyridine), O-acyloximes derived from cycloalkanones and acyclic ketones are efficiently coupled with terminal alkynes to afford a variety of γand δ-alkynyl nitriles and γ-alkynyl ketones, respectively. These reactions proceed through a domino sequence involving copper-catalyzed reductive generation of iminyl radical followed by radical translocation via either β-scission or 1,5hydrogen atom transfer (1,5-HAT) and copper-catalyzed alkynylation of the resulting translocated carbon radicals. The protocols are applicable to complex natural products.

A novel heteroannulation reaction between α-amino imides and in situ generated arynes has been developed for the synthesis of 2,2-disubstituted indolin-3-ones. An enantioselective total synthesis of the marine alkaloid (+)-hinckdentine A was subsequently accomplished using this reaction as a key step. A catalytic enantioselective Michael addition of an α-aryl-α-isocyanoacetate to phenyl vinyl selenone was employed for the construction of the enantioenriched α-quaternary α-amino ester.

In the presence of ac atalytic amount of iron(III) acetylacetonate [Fe(acac) 3 ], the reaction of structurally diverse ketoxime esters with trimethylsilyl azide (TMSN 3 )a fforded g-azido ketones in good to excellent yields. This unprecedented distal g-C(sp 3 )ÀHb ond azidation reaction went through as equence of reductiveg eneration of an iminyl radical, 1,5-hydrogen atom transfer (1,5-HAT) and iron-mediated redox azido transfert ot he translocated carbon radical. TMSN 3 served not only as an itrogen source to functionalise the unactivated C(sp 3 )ÀHb ond, but also as ar eductant to generate the catalytically active Fe II species in situ. Based on the same principle, an ovel b-C(sp 3 )ÀHf unctionalisation of alcohols via N-acyloxy imidates was subsequently realised, leading, after hydrolysis of the resulting ester,t ob-azido alcohols, which are important building blocks in organic and medicinal chemistry.

Caulerpin (1a), a bis-indole alkaloid from the marine algal Caulerpa sp., was synthesized in three reaction steps with an overall yield of 11%. The caulerpin analogues (1b–1g) were prepared using the same synthetic pathway with overall yields between 3% and 8%. The key reaction involved a radical oxidative aromatic substitution involving xanthate (3) and 3-formylindole compounds (4a–4g). All bis-indole compounds synthesized were evaluated against the Mycobacterium tuberculosis strain H37Rv, and 1a was found to display excellent activity (IC50 0.24 µM).

Nitrogen-substituted alkynes, such as ynamines and ynamides, are versatile synthetic building blocks. Ynimines bearing additional nucleophilic and electrophilic centers relative to ynamines and ynamides are expected to have high synthetic potential. However, their chemical reactivity remains unexplored owing mainly to the lack of synthetic accessibility. We report herein a versatile copper-catalyzed synthesis of ynimines from readily available O-acetyl ketoximes and terminal alkynes. A wide range of O-acetyl ketoximes derived from diaryl ketones, aryl alkyl ketones and dialkyl ketones underwent cross-coupling with a diverse set of terminal alkynes to afford the ynimines in good to excellent yields. An unprecedented [5+1] heteroannulation reaction exploiting the reactivity of the ynimine generated in situ was subsequently developed for the synthesis of medicinally important heterocycles, including isoquinolines, azaindoles, azabenzofurans, azabenzothiophenes and carbolines.Scheme 1. Ynimines: structure and synthesis.