Synthesis of Tricyclic Fused 3‐Aminopyridines through Intramolecular Co^I‐Catalyzed [2+2+2] Cycloaddition between Ynamides, Nitriles, and Alkynes

Abstract

Three-ring circus: An expedient route to tricyclic fused 2-trimethylsilyl-3-aminopyridines exhibiting unprecedented skeletons is described. The key step is a very efficient cobalt-catalyzed [2+2+2] cycloaddition of a polyunsaturated compound displaying an ynamide, an alkyne, and a nitrile functionality (see picture). The first [2+2+2] cocyclizations between ynamides, nitriles, and alkynes are reported. They open a new access to unprecedented nitrogen-containing heterocycles of type 2-trimethylsilyl-3-aminopyridines. Such frameworks, which can be found in various compounds of biological interest, are very difficult to prepare by conventional methods. However, using [CpCo(C(2)H(4))(2)] (Cp=cyclopentadienyl) as catalyst, the intramolecular cyclizations could be achieved in up to 100 % yield. The presence of the trimethylsilyl group allowed a rare type of Hiyama cross-coupling: one of the silylated pyridines could be coupled with p-iodoanisole to give a new type of biaryl system.

Ynamides: Versatile Tools in Organic Synthesis

“…Nitriles can also participate in cyclotrimerization reactions with ynamides, as recently shown by Aubert and co‐workers: starting from acyclic precursors 129 , which contains a nitrile, an internal alkyne, and an ynamide, a cobalt‐catalyzed [2+2+2] cocyclization leads to tricyclic fused 3‐aminopyridines 130 in excellent yields (Scheme ) 85. An especially elegant intermolecular titanium‐mediated reaction between a nitrile, a terminal ynamide, and an alkyne was reported by Sato and Urabe.…”

[2+2+2] Cycloadditions of Alkynylynamides – A Total Synthesis of Perlolyrine and the First Total Synthesis of “Isoperlolyrine”

“…The use of tethered 1,6-diynes [14] or 5-cyanoalkynes [15] allows the synthesis of annulated pyridines. Malacria et al [16] proved that tethered ω-cyano alkynylynamides can undergo intramolecular cyclization to bisannulated pyridines.…”

CHAPTER 5. Cobalt-Catalyzed Heterocycle Synthesis

“…81,82 In 2009, the first [2 þ 2 þ 2] co-cyclizations between ynamides, nitriles and alkynes were reported by Aubert, Malacria and co-workers. 83 They opened up a new access route to unprecedented nitrogen-containing heterocycles of the type 2-trimethylsilyl-3-aminopyridines. Using [CpCo(C 2 H 4 ) 2 ] (Cp ¼ cyclopentadienyl) as the catalyst, intramolecular cyclizations could be achieved in up to 100% yield.…”