Rhodium-Catalyzed (2+2+2) Cycloaddition of Oximes and Diynes To Give Pyridines

ward and efficient strategy for the generation of pyridines is a formidable challenge in this field. An alternative nitrogen source, oximes, can be easily accessed from hydroxylamine and carbonyl compounds (for example, aldehydes and ketones). The reactivity of the C=N bond makes oximes an alternative coupling partner for cycloaddition reactions; however, only the reaction of a,b-unsaturated oximes and alkynes has been reported to generate substituted pyridines (Scheme 1b). In these cases, either intramolecular [4+2] cycloaddition or C H bond functionalization was involved, both of which occurred using a rhodium catalyst. Although there are a few reports that show that imines bearing directing groups can undergo [2+2+2] cycloaddition to afford 1,2-dihydropyridines under conditions of high temperature (100 8C), the low reactivity of the C=N bond remains a challenging problem for simple oximes to participate in metal-catalyzed [2+2+2] cycloaddition (Scheme 1c). In addition, avoiding metal-catalyzed rearrangements and the Beckmann rearrangement of oximes to give the corresponding amides are challenges that need to be overcome. Furthermore, water, which would be generated in situ from the dehydration of the initial cycloadduct (for example, Nhydroxy-1,2-dihydropyridine) may greatly affect the efficiency of metal catalyzed cycloaddition reaction. Despite these challenges, we surmised that precious metals that could tolerate stoichiometric amounts of water could be used as catalysts for the effective activation of the oxime substrates. Herein, we report the first example of a rhodium-catalyzed cycloaddition of oximes and diynes that gives substituted pyridines (Scheme 1c). Moreover, the formation of pyridines from a one-pot reaction of an aldehyde, a hydroxylamine, and a diyne, as well as a possible reaction pathway are also discussed. Based on our previous work on [2+2+2] cycloaddition reactions, we used a combination of [Rh ACHTUNGTRENNUNG(cod)2]BF4 and binap as a catalyst system. Initially, the reaction of diyne 1a with (E)-benzaldehyde oxime 2a was conducted in the presence of a catalytic amount of [Rh ACHTUNGTRENNUNG(cod)2]BF4 and binap. The solvent is critical for this reaction. The use of MeOH and CF3CH2OH afforded 3aa in 26% and 31% yield, respectively (Table 1, entries 3 and 4). However, only a trace amount of 3aa was obtained when the reaction was conducted in either toluene, EtOH, dioxane, or DMF (Table 1, entries 1, 2, 5, and 6). Other bidentate phosphine ligands in combination with [Rh ACHTUNGTRENNUNG(cod)2]BF4 were screened for catalytic activity (Table 1). We were pleased to find that the use of dppf as a ligand led to the highest catalytic activity, and pyridine 3aa was obtained in moderate yield (Table 1, entry 8). Subsequently, we found that increasing the loading of [RhACHTUNGTRENNUNG(cod)2]BF4 and dppf to 10 mol% and then to 20 mol% led to a decrease in yield (Table 1, entries 13 and 14). Increasing the catalyst-to-ligand ratio from 1:1 to 1:1.2 resulted in a slight improvement in the yield (Table 1, entry 15). Importantly, the efficiency of the reaction could be drastically enhanced by increasing the amount of 2a from 2 to 4 equivalents (69% yield as determined using HPLC, Table 1, entries 15 and 16). Therefore, the optimized reaction conditions were as follows: [Rh ACHTUNGTRENNUNG(cod)2]BF4 (5 mol%), dppf (6 mol%), [a] F. Xu, C. Wang, Dr. D. Wang, Dr. X. Li, Prof. Dr. B. Wan Dalian Institute of Chemical Physics, Chinese Academy of Sciences 457 Zhongshan Road, Dalian 116023 (P. R. China) Fax: (+86)411-8437-9223 E-mail : bswan@dicp.ac.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201203909. Scheme 1. Synthesis of pyridines through either cycloaddition or C H bond functionalization.