Scalable Microwave-Assisted Johnson–Claisen Rearrangement with a Continuous Flow Microwave System

• Published in: Organic process research & development Vol. 22; no. 8; pp. 1029 - 1033
• Main Authors: Egami, Hiromichi, Tamaoki, Souma, Abe, Masato, Ohneda, Noriyuki, Yoshimura, Takeo, Okamoto, Tadashi, Odajima, Hiromichi, Mase, Nobuyuki, Takeda, Kazuhiro, Hamashima, Yoshitaka
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.08.2018; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Organic; Physical Sciences; Science & Technology; Johnson−Claisen rearrangement; γ,δ-unsaturated ester; microwave; flow chemistry; gamma,delta-unsaturated ester; NATURAL-PRODUCTS; Johnson-Claisen rearrangement; IMPACT; REACTOR; STEREOSELECTIVITY; CHEMISTRY; BATCH; APPLICATOR; ORGANIC-SYNTHESIS MACOS; TRANSFORMATIONS
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.8b00185

We demonstrated the rapid Johnson–Claisen rearrangement of allyl alcohol and triethyl orthoacetate with a continuous flow apparatus combined with a microwave reactor. The reaction could be carried out without solvent, and only a catalytic amount of acetic acid was sufficient to promote the reaction under microwave irradiation conditions. To confirm the optimal reaction conditions found experimentally, we performed Design of Experiments (DoE) by the Nelder–Mead method and a least-squares method regarding the amount of acetic acid and the flow rate. Consequently, the highest yield of the desired γ,δ-unsaturated ester was obtained, and the productivity at the reaction step of the continuous process was 89.5 g/h under the optimal conditions, suggesting that 2.1 kg of the product would be theoretically obtained in 1 day. We also investigated the Johnson–Claisen rearrangement using other allylic alcohols, and the corresponding products were obtained in good to high yields per unit of time.