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Synlett 2020; 31(19): 1930-1936
DOI: 10.1055/s-0040-1707265
DOI: 10.1055/s-0040-1707265
cluster
Integrated Synthesis Using Continuous-Flow Technologies
Umpolung Reactions of α-Tosyloximino Esters in a Flow System
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant No. JP18H04402 in Middle Molecular Strategy and JP17K05860.
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.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1707265.
- Supporting Information
Publication History
Received: 20 July 2020
Accepted after revision: 03 August 2020
Article published online:
03 September 2020
© 2020. Thieme. All rights reserved
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- 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.
For reviews on α,α-disubstituted α-amino acids and their peptides, see:
For representative N-alkylations of α-imino esters by our group, see:
For representative reviews on flow-microreactor syntheses, see:
For some selected recent examples of flow-microreactor syntheses, see:
For representative examples of flow-microreactor syntheses using Comet X-01, see: