Synthesis of 5,6,7,8-Tetrahydro-1,6-naphthyridines and Related Heterocycles by Cobalt-Catalyzed [2 + 2 + 2] Cyclizations

Abstract

[reaction: see text] Microwave-promoted, cobalt-catalyzed intramolecular [2 + 2 + 2] cyclizations of dialkynylnitriles successfully gave 5,6,7,8-tetrahydro-1,6-naphthyridines. The efficient synthesis of these relatively simple, yet rarely addressed heterocycles enabled the preparation of a collection of these compounds.

A General Approach to Chemo‐ and Regioselective Cyclotrimerization Reactions

“…The cyclotrimerization was performed in nonpolar toluene as the solvent at 110 8C with 10 mol % [CpCo(CO) 2 ] under microwave irradiation (300 W) for 10 min. After removal of the protecting group with TFA, 3 was obtained in 46 % yield (similar results have recently been observed by others [9,10] ). When the same cyclotrimerization was conducted without microwave irradiation, only 9 % product formation was observed, even after a prolonged reaction time of 24 h at 110 8C.…”

“…Cyclotrimerization of 14 to 15, followed by acid-mediated cleavage from the resin, afforded pyridines 16-23 in high yields (73-91 %), excellent purities (> 90 %), and as single regioisomers (Scheme 3). These yields are significantly higher than in previous solution-phase reactions (especially in the case of reactive terminal alkynes) [9,19] as competing sidereactions are completely suppressed through the spatial separation on the solid support. The cyclotrimerization of alkynes and isocyanates is an effective means of generating pyridones, and catalyst systems based on Ni, Co, Rh, and Ru have been employed.…”

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

“…After 12 h, the reaction mixture was quenched with strd aq. NH 4 Step g: The product obtained after step f (0.103 g, 0.289 mmol) and PTSA·H 2 O (3.7 mg, 0.019 mmol) were stirred in MeOH (10 mL) for 20 h. The reaction mixture was quenched with strd aq. NaHCO 3 Step j: BuLi (1.9 m in hexanes, 330 mL, 0.633 mmol) was added to a solution of the product obtained after step i (0.270 g, 0.634 mmol) in THF (12 mL) at À78 8C under Ar in a Schlenk tube.…”

“…After a further 12 h, the reaction mixture was quenched with strd aq. NH 4 Step g: The product obtained after step f (0.212 g, 0.564 mmol) and tetrabutyl ammonium fluoride (TBAF) ( …”

“…[2,3] In principle, this atom-and-step economy procedure, which is tolerant to a wide range of functional groups, should enable the direct formation of polycyclic functionalized pyridines, or at least inherently functionalizable ones owing to the presence of heteroatoms. The incorporation of an heteroatom at C2 has been achieved frequently by [2 + 2 + 2] cycloaddition reactions with silicon (Scheme 1, Y = Si), [4] and rarely with phosphorus (Y = P). [5] On the other hand, very few examples of pyridines heterosubstituted at C2 and/or C3 can be found, and they are strictly restricted to silicon (X = Si or X = Y = Si).…”