Cp*RuCl-Catalyzed [2 + 2 + 2] Cycloadditions of α,ω-Diynes with Electron-Deficient Carbon−Heteroatom Multiple Bonds Leading to Heterocycles

Abstract

In the presence of a catalytic amount of Cp*RuCl(cod), 1,6-diynes were allowed to react chemo- and regioselectively with electron-deficient nitriles and heterocumulenes at 60-90 degrees C to afford heterocyclic compounds. The mechanism of the ruthenium-catalyzed regioselective formations of bicyclic pyridines and pyridones were analyzed on the basis of density functional calculations. Cyclocotrimerizations of ethyl propiolate with ethyl cyanoformate or propyl isocyanate gave rise to two of the four possible pyridine or pyridone regioisomers.

Synthesis of 2‐Haloalkylpyridines via Cp*RuCl‐Catalyzed Cycloaddition of 1,6‐Diynes with α‐Halonitriles. Unusual Halide Effect in Catalytic Cyclocotrimerization

“…In striking contrast, chloroacetonitrile (3e; R ¼ Cl) underwent cycloaddition with 2a in the presence of 2 mol % 1 at ambient temperature for 2 h to give rise to chloromethylpyridine 4ae in 93% isolated yield. [7] This result was quite surprising because trichloroacetonitrile, which underwent cycloaddition with 2a at 60 8C in our previous study, [5] failed to react at ambient temperature. These facts indicate that the observed reactivity enhancement is not ascribed simply to the inductive activation of the cyano group by the chlorine atom.…”

“…In addition, novel intramolecular protocols were recently developed to synthesize pyridine-containing macrocycles or 2-aminopyridines. [4] We have also developed independently the Cp*RuClcatalyzed cycloadditions of a,w-diynes with carbon-heteroatom multiple bonds, [5] and found that the dicyanides are exceptional nitrile substrates capable of undergoing cycloaddition even at ambient temperature.[6] In fact, in the presence of 5 mol % Cp*RuCl(cod) 1 (Cp* ¼ h 5 -C 5 Me 5 , cod ¼ 1,5-cyclooctadiene), the cycloaddition of dimethyl dipropargylmalonate (2a) with malononitrile (3a; R¼ CN) proceeded even at room temperature for 2.5 h to afford bicyclic pyridine 4aa (R ¼ CN) in 95% yield (Scheme 1). Although one of the two cyano groups remained intact after the reaction, the complete incompetence of acetonitrile provides the possibility of one cyano moiety as a coordinating group.…”

“…[5,9] When diyne 2a and chloroacetonitrile (3e) were treated with 2 mol % of 1 as well as 5 mol % Et 3 NCl, the reaction was completed after 18 h to give rise to a dimer of 2a together with pyridine 4ae in 14% and 68% yields, respectively. This result suggests that the higher concentration of chloride ion partially suppressed the formation of the cationic species to result in the unfavorable dimerization of 2a.…”

Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library

“…In the diyne substrate series, Yamamoto et al's Ru(II)-catalyzed [2 þ 2 þ 2] cyclotrimerization reaction with benzyl isocyanate (26) was also translated effectively to solid-phase synthesis (27), using diyne substrates 4a,b,d. Some optimization of reaction conditions was required, because extended reaction times (12 h vs. 6 h) resulted in formation of an inseparable side product, apparently due to coupling of a second equivalent of benzyl isocyanate (M þ 133).…”

“…Accordingly, seven scaffolds (5,6,8,(26)(27)(28)(29) were produced with three variations at this position (amine, sulfinamide, sulfonamide). Three scaffolds required prior oxidation to the tertbutylsulfonamide to enable the cycloaddition reactions (7,9,10) and were limited to this functionality because it could not be cleaved effectively under a variety of conditions (e.g., PhSH, K 2 CO 3 ; TFA, anisole; TfOH, anisole).…”