Gold-Catalyzed Annulations with Nucleophilic Nitrenoids Enabled by Heteroatom-Substituted Alkynes
1School of Chemistry, University of Birmingham Edgbaston, Birmingham, B15 2TT, UK.
Abstract:
The combination of a nucleophilic nitrene equivalent, a triple bond and a π-acid catalyst has underpinned numerous efficient transformations for the preparation of azacycles. This personal account details our efforts in developing an annulation strategy. Adding a nucleophilic nitrenoid to an activated alkyne can generate carbenoid character that is then quenched by a cyclisation onto the nitrenoid substituent. The use and development of N-acyl and N-heterocyclic pyridinium-N-aminides as 1,3-N,O and 1,3-N,N-dipole equivalents is discussed in the context of oxazole and heterocycle-fused imidazole formation, respectively. The resulting processes are highly efficient, practically straightforward, and tolerate considerable structural and functional group variation. Our use of heteroatom-substituted alkynes as enabling tools for reaction discovery is discussed. The reactivity accessed from the strong donor-like properties of ynamides is complemented by that obtained from alkynyl thioethers, which are emerging as interesting substrates for π-acid catalysis.
Related Concept Videos
02:24Reduction of Alkynes to cis-Alkenes: Catalytic Hydrogenation
Like alkenes, alkynes can be reduced to alkanes in the presence of transition metal catalysts such as Pt, Pd, or Ni. The reaction involves two sequential syn additions of hydrogen via a cis-alkene intermediate.
02:27Preparation of Alkynes: Alkylation Reaction
Alkylation of terminal alkynes with primary alkyl halides in the presence of a strong base like sodium amide is one of the common methods for the synthesis of longer carbon-chain alkynes. For example, treatment of 1-propyne with sodium amide followed by reaction with ethyl bromide yields 2-pentyne.
02:47Alkynes to Aldehydes and Ketones: Hydroboration-Oxidation
One of the convenient methods for the preparation of aldehydes and ketones is via hydration of alkynes. Hydroboration-oxidation of alkynes is an indirect hydration reaction in which an alkyne is treated with borane followed by oxidation with alkaline peroxide to form an enol that rapidly converts into an aldehyde or a ketone. Terminal alkynes form aldehydes, whereas internal alkynes give ketones as the final product.
01:26Synthesis of α-Substituted Carbonyl Compounds: The Stork Enamine Reaction
02:38Electrophilic Addition to Alkynes: Halogenation
Halogenation is another class of electrophilic addition reactions where a halogen molecule gets added across a π bond. In alkynes, the presence of two π bonds allows for the addition of two equivalents of halogens (bromine or chlorine). The addition of the first halogen molecule forms a trans-dihaloalkene as the major product and the cis isomer as the minor product. Subsequent addition of the second equivalent yields the tetrahalide.
02:34Preparation of Alkynes: Dehydrohalogenation
Alkynes can be prepared by dehydrohalogenation of vicinal or geminal dihalides in the presence of a strong base like sodium amide in liquid ammonia. The reaction proceeds with the loss of two equivalents of hydrogen halide (HX) via two successive E2 elimination reactions.