Umpolung Reactions of α-Tosyloximino Esters in a Flow System

Kazuki Ota; Shinya Fukumoto; Taiki Iwase; Isao Mizota; Makoto Shimizu; Iwao Hachiya

doi:10.1055/s-0040-1707265

Synlett, Table of Contents

Synlett 2020; 31(19): 1930-1936
DOI: 10.1055/s-0040-1707265

cluster

Integrated Synthesis Using Continuous-Flow Technologies

Umpolung Reactions of α-Tosyloximino Esters in a Flow System

Kazuki Ota

^aDepartment of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan Email: hachiya@chem.mie-u.ac.jp

,

Shinya Fukumoto

^aDepartment of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan Email: hachiya@chem.mie-u.ac.jp

,

Taiki Iwase

^aDepartment of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan Email: hachiya@chem.mie-u.ac.jp

,

Isao Mizota

^aDepartment of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan Email: hachiya@chem.mie-u.ac.jp

,

Makoto Shimizu∗

^aDepartment of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan Email: hachiya@chem.mie-u.ac.jp

^bSchool of Energy Science and Engineering, Nanjing Tech University, Nanjing 211816, Jiangsu Province, P. R. of China Email: mshimizu@chem.mie-u.ac.jp

,

Iwao Hachiya∗

^aDepartment of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan Email: hachiya@chem.mie-u.ac.jp

› Author Affiliations

Abstract

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Abstract

An umpolung reaction of α-tosyloximino esters in a flow system is disclosed. Tandem N,N-dialkylations with two different Grignard reagents gave the desired N,N-dialkylated products in moderate to good yields. In addition, a tandem N,N,C-trialkylation of an α-tosyloximino ester with three different Grignard reagents has been successfully achieved to afford the desired N,N,C-trialkylated product in moderate yield.

Key words

umpolung - tosyloximino esters - tandem - alkylation - Grignard reagents - flow reactor

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References

References and Notes

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9 See the Supporting Information for details.
10 Results with other acids as additives are summarized in Table S1 of the Supporting Information.
11 Ethyl [Ethyl(propyl)amino](phenyl)acetate (3b) ⁴; Typical ProcedureA flow-microreactor system consisting of two connected Comet X-01 micromixers (M1), a Comet X-01 micromixer (M2), two pre-cooling units (P1: inner diameter = 2000 μm, length = 100 cm; P2: inner diameter: 2 mm, length = 100 cm), and two Teflon tube reactors (R1: inner diameter = 2 mm, length = 5 cm; R2: inner diameter = 2 mm, length = 20 cm) was used. The first flow-microreactor system consisting of the two connected Comet X-01 micromixers together with P1 and P2 was immersed in a magnetically stirred constant-temperature bath at –40 °C. The remainder of the system was at rt. A solution of α-tosyloxyimino ester 1a (0.02 M) and BzOH (0.01 M) in toluene (9.5 mL/min) [prepared from α-tosyloximino ester (E)-1a (138.9 mg, 0.40 mmol), BzOH (24.4 mg, 0.20 mmol), and toluene (20 mL)] was introduced into M1 by using a syringe pump. A 0.04 M solution of EtMgBr in toluene–Et₂O (9.5 mL/min) [prepared from a 0.93 M solution of EtMgBr (0.86 mL, 0.80 mmol) in Et₂O and toluene (19.14 mL)] was also introduced into M1 by using a syringe pump, and the mixed solution was passed through R1. A 0.04 M solution of PrMgBr in DME–Et₂O (9.5 mL/min), prepared from a 0.82 M solution of PrMgBr (0.98 mL, 0.80 mmol) in Et₂O and DME (19.02 mL), was introduced into M2 by using a syringe pump, and the resulting solution was passed through R2. Once a steady state was reached, the resulting solution (30 mL) was poured into sat. aq NaHCO₃ (10 mL) to quench the reaction. The resulting mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (15 mL), dried (Na₂SO₄), and filtered. The solvents were evaporated in vacuo, and the residue was purified by preparative TLC [silica gel, hexane–Et₂O (20:1)] three times to give the desired product 3b [yield: 35.5 mg (71%)], together with the N,N-diethyl product 3a [yield: 3.0 mg (6%)].3bYellow oil. IR (neat): 1737, 1453, 1372, 1154, 1067 1029, 728, 696 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.42–7.40 (m, 2 H), 7.34–7.25 (m, 3 H), 4.51 (s, 1 H), 4.25–4.13 (m, 2 H), 2.63 (q, J = 7.3 Hz, 2 H), 2.55–2.44 (m, 2 H), 1.52–1.35 (m, 2 H), 1.24 (t, J = 7.3 Hz, 3 H), 0.98 (t, J = 7.3 Hz, 3 H), 0.81 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ = 172.4, 137.4, 128.7, 128.2, 127.7, 69.1, 60.4, 52.0, 44.3, 20.4, 14.2, 12.3, 11.7. HRMS (EI): m/z [M – C₃H₅O₂]⁺ calcd for C₁₂H₁₈N: 176.1434; found: 176.1434.

Supplementary Material

Supporting Information