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

Abstract

In the presence of 2 -5 mol % Cp*RuCl (cod), various 1,6-diynes reacted with a-monohaloand a,a-dihalonitriles at ambient temperature to afford 2-haloalkylpyridines in 42 -93% isolated yields. The failure of acetonitrile, N,N-dimethylaminoacetonitrile, phenylthioacetonitrile, and methyl cyanoacetate as nitrile substrate clearly showed that the a halogen substitution is essential for the present cycloaddition under mild conditions. The cycloaddition of unsymmetrical diynes bearing a substituent on one alkyne terminal gave 2,3,4,6-substituted pyridines exclusively.Keywords: alkynes; cyanides; cyclotrimerization; pyridines; rutheniumThe transition-metal-mediated [2 þ 2 þ 2] cyclocotrimerization of two alkynes and a nitrile is a powerful and straightforward route to substituted pyridines.[1] Although the catalytic cyclocotrimerization is becoming increasingly important as an environmentally benign process, the pair-and regio-selectivity as well as reaction conditions have remained to be largely improved compared to stoichiometric protocols. [2] In this context, mild and selective catalytic cycloadditions of a,w-diynes with nitriles were recently achieved by means of a chiral indenylcobalt complex and a nickel N-heterocyclic carbene complex.[3] In particular, the former catalyst proved to be effective toward the asymmetric synthesis of axially chiral pyridines. 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. To expand the scope of the nitrile substrate, other nitriles possessing a coordinating group a to the cyano group were further screened (Figure 1). Consequently, methyl cyanoacetate (3b; R ¼ CO 2 Me), N,N-dimethylaminoacetonitrile (3c; R¼ NMe 2 ), and phenylthioacetonitrile (3d; R¼ SPh) were found to be totally ineffective. 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...

Iron-Catalyzed Formation of 2-Aminopyridines from Diynes and Cyanamides

“…17c Attempts to react (dimethylamino)acetonitrile with diyne 1b were unsuccessful, which may indicate that the inherent electronic structure of cyanamides, not a chelation effect, is the source of their high reactivity in this system. 21 To demonstrate the synthetic utility of this methodology, entry 1 was repeated on a 1 mmol scale leading to a comparable yield of 94 % (eq 5). …”

Multicomponent syntheses of 5- and 6-membered aromatic heterocycles using group 4–8 transition metal catalysts

“…Compared to other transition metals, Ru-based catalysts provide complementary access to pyridines with electron-decient nitriles, [80][81][82] which are oen challenging substrates for later transition metals like Co. 83 In contrast, cycloaddition using simple nitriles such as MeCN and PhCN is challenging with Ru due to oen endothermic nitrile insertion, 81 although examples of partially or fully intermolecular [2 + 2 + 2] cycloaddition with nitriles containing coordinating groups have been reported. 81,84,85 Detailed experimental and computational studies (both of [2 + 2 + 2] alkyne cyclotrimerization and pyridine formation) 22,86 have revealed that Cp*RuCl(COD)-catalyzed reactions of a,udiynes likely proceed rst through initial oxidative cyclization of the diyne to form ruthenacyclic biscarbenoid IM32. This intermediate, which related complexes have been structurally characterized via X-ray crystallography and NMR in several instances, 87 is shared between [2 + 2 + 2] pyridine formation, alkyne cyclotrimerization, and [2 + 2 + 1] pyrrole/furan/ thiophene synthesis (vide supra).…”

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

“…Notably, a number of the Ru-catalyzed [2+2+2] cycloaddition reactions for synthesis of pyridine were developed recently by Yamamoto and Itoh, 410,746 and Saá group. 747 In addition, Ni(0)-based catalytic systems for [2+2+2] synthesis of pyridines were recently reported.…”