One-Pot Synthesis of Metalated Pyridines from Two Acetylenes, a Nitrile, and a Titanium(II) Alkoxide

Abstract

Four-component coupling process involving two acetylenes, a nitrile, and a divalent titanium alkoxide reagent, Ti(O-i-Pr)(4)/2i-PrMgCl, directly yielded titanated pyridines in a highly selective manner. The reaction can be classified into four categories: (i) a combination of an internal acetylene, a terminal acetylene, sulfonylnitrile, and the titanium reagent to yield alpha-titanated pyridines, (ii) a combination of an internal acetylene, a (sulfonylamino)acetylene, a nitrile, and the titanium reagent to yield alternative alpha-titanated pyridines, (iii) a combination of an internal acetylene, a (sulfonylamino)acetylene, a nitrile, and the titanium reagent to yield titanated aminopyridines, and (iv) a combination of an acetylenic amide, a terminal acetylene, a nitrile, and the titanium reagent to yield pyridineamides with their side chain titanated. Some of these reactions enabled virtually completely regioselective coupling of two different, unsymmetrical acetylenes and a nitrile to form a single pyridine. Synthetic applications of these reactions have been illustrated in the preparation of optically active pyridines and medicinally useful compounds.

Transition metals in organic synthesis: Highlights for the year 2005

“…(327)) [1425]. Zirconium mediated a cyclization-elimination of 2-heterosubstituted 1,6-dienes and 1,6-enynes (Eq.…”

5.34 Early Transition Metal Mediated Reductive Coupling Reactions

“…150 Ti-mediated [2 þ 2 þ 2] annulation has emerged as a powerful approach to the synthesis of substituted pyridines. 100,151,152 As illustrated in Scheme 67B, the collection of reactions defined for [2 þ 2 þ 2]-based entry to substituted pyridines employ two carbon-based p-systems (alkynes) and one C-N-based p-system (nitrile). Although a variety of distinct approaches to this aromatic heterocycle has been described, they proceed by one of two general pathways.…”

Solid‐Supported [2+2+2] Cyclotrimerizations

“…[11] The development of several catalyst systems based on Ni, Co, Ru, and Rh have led to mild reaction conditions applicable to organic synthesis. [12][13][14][15][16][17][18][19] However, various problems are still associated with these reactions, including chemo-and regioselectivity issues. [20] The crossed solution-phase reaction of diynes and alkynes often results in only moderate yields and contamination with side products, due to the participation of the diyne in competing cycloadditions.…”