Copper‐Mediated Coupling of 1,1‐Dibromo‐1‐alkenes with Nitrogen Nucleophiles: A General Method for the Synthesis of Ynamides

Abstract

Mild reaction conditions are the advantage of the title reaction, which allows straightforward entry to a variety of ynamides starting from readily available 1,1-dibromo-1-alkenes, which act as attractive alkynylating agents (see scheme; EWG = electron-withdrawing group, DMF = N,N-dimethylformamide).

Diamine ligands in copper-catalyzed reactions

“…Recently Evano has documented a new method for the synthesis of ynamides from 1,1-dibromo-1-alkenes and sulfonamides or carbamates using a copper-diamine catalyst (Scheme 5). 90 …”

Intramolecular carbolithiation of N-allyl-ynamides: an efficient entry to 1,4-dihydropyridines and pyridines – application to a formal synthesis of sarizotan

“…Among all the methods evaluated, Hsung’s second-generation synthesis based on the copper-mediated cross-coupling between bromoalkynes 9 and nitrogen nucleophiles [42] turned out to be the most convenient one, the use of terminal alkynes [43], gem -dibromoalkenes [7], potassium alkynyltrifluoroborates [8] or copper acetylides [12] being less efficient when bulky N -Boc-allylamines 10 were used as nucleophiles. By using a slightly modified Hsung’s procedure, a series of N -allyl-ynamides 1 could be readily prepared in acceptable yields using a combination of copper(II) sulfate pentahydrate (40 mol %) and 1,10-phenanthroline (80 mol %) with potassium phosphate in refluxing toluene, the major side reaction observed in all cases being the competitive dimerization of the starting bromoalkynes (Scheme 3).…”

“…Based on our recent interest in the chemistry of ynamides [7–18] and inspired by recent reports from Meyer and Cossy [19–21], Marek [22–24] and Lam [25–26] on their carbopalladation, carbocupration and carbozincation, respectively, we decided to study the intramolecular carbolithiation of ynamides, which may provide an interesting entry to highly functionalized 1,4-dihydropyridines [27–29] and pyridines [30–33], most useful building blocks in organic synthesis and medicinal chemistry as well. Our strategy is summarized in Scheme 1 and is based on the following assumptions: According to the remarkable work of the Beak group on the α-lithiation of Boc-protected amines [34–38], N -allyl-ynamides 1 should be readily deprotonated to afford a transient chelation-stabilized allyllithium 2 and, provided that a metallotropic equilibrium exists between this intermediate and the less-stable allyllithium 3 , an intramolecular carbometallation may then occur to yield a chelation-stabilized vinyllithium 4 and drive the overall process to the formation of the heterocyclic ring system.…”

Ynamides: A Modern Functional Group for the New Millennium

“…More recently, Evano61 documented the direct synthesis of ynamides 114 from 1,1-dibromo-1-alkenes 113 . A combination of CuI and DMEDA was found to be the best catalyst system for the reaction between 96 and 113 , and Cs 2 CO 3 was the optimal base (Scheme 31).…”