Synthesis of Cyano Cyclic Olefins through Ring-Closing Metathesis

Abstract

Ring-closing metathesis has become a very powerful, versatile, and widely used method for the construction of cyclic ring systems in organic synthesis. The superior reactivity of Grubbs second generation catalyst 1, which has air-stability and thermal stability, is very important for the formation of triand tetra-substituted olefins having electron withdrawing groups. Recently, Weinreb, Salim, and Rutjes reported on the formation of carbocyclic and heterocyclic olefin by ring-closing metathesis of halogen (F, Cl, CF3) substituted olefins. Literature survey reveals that most of bisterminal olefins with electron withdrawing groups such as CO2Et, Br, and CN resulted in little to no yield of the RCM product under the condition of using the Grubbs first generation catalyst, but the microwave irradiation on olefin with carboxymethyl substituent (CO2Me) provided the desired product. As part of synthesis of a drug against Alzheimer disease, we became interested in the introduction of a nitrile group to huperzine B analog system. Monocyclic olefins with cyano group were prepared. Alkylations with 2-(bromoethyl)acrylonitrile were carried out to obtain several allylated substrates 3a-e from the carbon and heteroatom nucleophiles 2a-e in DMF in the presence of NaH as base. The RCM reaction of the bisterminal olefins 3a-e with a cyanide group has been explored for a variety of substrates, and some of the results are shown in Table 1. The substrates 3a-e reacted smoothly and furnished the olefinic cyanides containing six to seven membered cycles in high yields (Entry1-5). With successful outcome for the preparation of monocyclic cyanoolefins, we applied this method to the synthesis of tricyclic system of huperzine B analog (Scheme 3). Subjection of olefinic intermediate 6 to the standard condition (5 mol % catalyst 1 and 3 × 10−3 M substrate in CH2Cl2) provided a poor yield (5%) of cyclized product 6a despite the complete consumption of starting material. Thus, the reaction was performed at elevated temperature of 100 C under microwave irradiation with 5 mol % catalytic amount using the concentration of 0.05 M of the substrate in CH2Cl2. After 4 min of the irradiation, the RCM reaction provided an improved yield of 6a with no sign of other undesired reactions based on the recovered starting material. In conclusion, we have revealed an example of the ringScheme 1. Ring-Closing Metathesis (RCM) Reaction of Cyano Bisolefins.