Synlett 2020; 31(19): 1913-1918
DOI: 10.1055/s-0040-1706479
cluster
Integrated Synthesis Using Continuous-Flow Technologies

Trapping of Transient Thienyllithiums Generated by Deprotonation of 2,3- or 2,5-Dibromothiophene in a Flow Microreactor

a  Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan   Email: [email protected]
,
Yoshiki Yamane
a  Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan   Email: [email protected]
,
Aiichiro Nagaki
c  Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Kyoto 615-8510, Japan
,
Atsunori Mori
a  Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan   Email: [email protected]
b  Research Center for Membrane and Film Technology, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
› Author Affiliations
This work was financially supported by JSPS KAKENHI Grant Numbers JP16K05774 in Scientific Research (C), JP19H02717 in Scientific Research (B), JP16H01153 and JP18H04413 in the Middle Molecular Strategy.


In memory of Jun-ichi Yoshida

Abstract

Selective trapping of (4,5-dibromo-2-thienyl)lithium, known to undergo halogen dance, was achieved in a flow microreactor. This transient thienyllithium, generated by mixing 2,3-dibromothiophene and lithium diisopropylamide at –78 °C for 1.6 seconds, reacted with benzaldehyde. The reaction system is also applicable to other carbonyl compounds to afford the corresponding adducts in good yields. Moreover, the established conditions permit the conversion of 2,5-dibromothiophene into a mixture of the two constitutional isomers. The contrasting results are discussed on the basis of the reaction pathway.

Supporting Information



Publication History

Received: 30 July 2020

Accepted after revision: 28 August 2020

Publication Date:
15 October 2020 (online)

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • 14 Trapping of Transient Thienyllithium 4 in a Flow Microreactor; General Procedure The flow reactor system consisted of two micromixers [Mixer 1 (T-shaped micromixer; φ = 500 μm) and Mixer 2 (T-shaped micromixer; φ = 250 μm)], two microtube reactors [Microtube 1 (φ = 1000 μm, L = 25 cm) and Microtube 2 (φ = 1000 μm, L = 200 cm)], and three tube precooling units [Precooling Unit 1 (φ =1000 μm, L = 100 cm), Precooling Unit 2 (φ = 1000 μm, L = 50 cm), and Precooling Unit 3 (φ = 1000 μm, L = 50 cm)]. A 0.075 M solution of 2,3-dibromothiophene (1) in THF (flow rate: 6.00 mL min–1) and a 0.60 M solution of LDA in THF (flow rate: 1.50 mL min–1) were introduced into Mixer 1 by syringe pumps. The resulting mixture passed through Microtube 1 and was mixed with a 0.30 M solution of the appropriate electrophile in THF (flow rate: 3.00 mL min–1) in Mixer 2. The resulting solution then passed through Microtube 2. Once a steady state was reached (60 s), the product solution was collected for 240 s, while being quenched with sat. aq NH4Cl. The layers were separated, and the aqueous layer was extracted with Et2O. The combined organic extracts were washed with H2O and brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure to provide a crude product that was purified by column chromatography (silica gel).
  • 15 An NOE enhancement was observed between the aromatic proton on the thiophene ring and the methine proton.
  • 16 1-(4,5-Dibromo-2-thienyl)cyclohexanol (8c) Colorless prisms; yield: 475.6 mg (78%); mp 80–81 °C (hexane); Rf = 0.31 (hexane–CH2Cl2, 1:1). IR (ATR): 3348, 2927, 2854, 1445, 1305, 1158, 1131, 1000, 970, 814, 796 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.76 (s, 1 H), 2.03 (s, 1 H), 1.91–1.55 (m, 9 H), 1.36–1.23 (m, 1 H). 13C{1H} NMR (100 MHz, CDCl3): δ = 156.1, 124.8, 113.0, 109.5, 72.7, 39.6, 25.3, 22.2. Anal. calcd for C10H12Br2OS: C, 35.32; H, 3.50. Found: C, 35.29; H, 3.39.
  • 17 CCDC 2020290 contains the supplementary crystallographic data for compound 8c. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
  • 18 Chemical shifts of the 1H and 13C NMR spectra of the synthesized 8d were not consistent with those reported by Knochel (ref. 10).
  • 19 For details, see the Supporting Information.
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