Efficient Preparation of Cyclic α-Alkylidene β-Oxo Imides by Using a Flow Microreactor System

Katsuhiro Komuro; Aiichiro Nagaki; Hiroki Shimoda; Masahiro Uwamori; Jun-ichi Yoshida; Masahisa Nakada

doi:10.1055/s-0037-1610228

Synlett, Table of Contents

Synlett 2018; 29(15): 1989-1994
DOI: 10.1055/s-0037-1610228

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Efficient Preparation of Cyclic α-Alkylidene β-Oxo Imides by Using a Flow Microreactor System

Katsuhiro Komuro

^aDepartment of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan Email: mnakada@waseda.jp

,

Aiichiro Nagaki

^bDepartment of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto, 615-8510, Japan

,

Hiroki Shimoda

^aDepartment of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan Email: mnakada@waseda.jp

,

Masahiro Uwamori

^aDepartment of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan Email: mnakada@waseda.jp

,

Jun-ichi Yoshida

^bDepartment of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto, 615-8510, Japan

,

Masahisa Nakada*

^aDepartment of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan Email: mnakada@waseda.jp

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Abstract

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Abstract

Successful transformations of 3-iodo-1-methyl-5,6-dihydropyridin-2(1H)-one into its derivatives by a halogen–lithium exchange and subsequent reactions in a flow microreactor system are described. The methylation of the organolithium compound generated from 3-iodo-1-methyl-5,6-dihydropyridin-2(1H)-one in the flow microreactor system afforded the desired methylated product in 68% yield, whereas the yield of the corresponding batch reaction was 23%. This superiority of the flow microreactor system was further emphasized in the reaction of the organolithium compound with methoxycarbonyl isocyanate, which gave the desired imide in 78% yield by using the flow microreactor system whereas the yield of the corresponding batch reaction was only 2%. The established flow microreactor system was also effectively used for the reaction of the organolithium compound with phenyl isocyanate to afford the desired product in 52% yield.

Key words

flow microreactor system - halogen–lithium exchange reaction - lithiation - imides - isocyanates - methylation

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References

References and Notes
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11 1,3-Dimethyl-5,6-dihydropyridin-2(1H)-one (7); Typical Microflow Procedure A flow microreactor system consisting of two T-shaped micromixers (i.d. 250 μm), two microtube reactors (R1 and R2), and three pre-cooling units was used. The flow microreactor system was immersed in a cooling bath at –78 °C. A 0.25 M solution of 4 in THF (flow rate: 9.0 mL/min) and a 0.1125 M solution of PhLi in Et₂O–cyclohexane (8:1, flow rate: 3.0 mL/min) were introduced into the first mixer by syringe pumps. The resulting solution was passed through R1 (i.d. 1000 μm; length 2.6 cm; residence time 0.14 s) and mixed with a 0.75 M solution of MeOTf in Et₂O (flow rate: 9.0 mL/min) in the second micromixer. The resulting solution passed through R2–1 (i.d. 1000 μm, length 200 cm) at –78 °C and then through R2–2 (i.d. 1000 μm, length 200 cm) at r.t. When a steady state was reached, an aliquot of the product solution was collected in a flask containing Et₃N (0.5 mL) for 30 s. The yield was determined by GC analysis using an internal standard (hexadecane); R_f = 0.36 (hexane–EtOAc, 1:2). A colorless oil; yield: 68%. IR (ATR): 3468, 2924, 1670, 1627, 1492, 1361, 1310, 1225, 1063, 846 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.30–6.22 (m, 1 H), 3.37 (t, J = 7.2 Hz, 2 H), 2.99 (s, 3 H), 2.36–2.25 (m, 2 H), 1.87 (q, J = 2.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 166.3, 133.3, 131.5, 47.9, 34.7, 23.7, 17.3. HRMS (ESI): m/z [M + Na] calcd for C₇H₁₁NNaO: 148.0738; found: 148.0733.

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