Route Evaluation and Ritter Reaction Based Synthesis of Oxazoline Acaricide Candidates FET-II-L and NK-12

Abstract

Clean synthetic processes are essential for industrial production of bioactive molecules. In this study, we explored several routes for the synthesis of acaricide candidates FET-II-L and NK-12 with the goal of developing a rapid route that is suitable for industrial production. Our results led us to adopt a Ritter reaction based aminohalogenation strategy that features fewer steps, simpler operation, and greatly increased overall yields relative to those of previously reported syntheses. After further optimization, the route reported herein is likely to be applicable for large scale production of these molecules.

Highly Efficient Synthesis and Acaricidal and Insecticidal Activities of Novel Oxazolines with N-Heterocyclic Substituents

“…To efficiently synthesize the target compounds, we prepared crucial intermediate 4 by means of a new route that was an improvement over the previous route . The first step in the new route was a modified sulfuric-acid-catalyzed Ritter reaction of p -chloromethylstyrene, 2,6-difluorobenzonitrile, and N -bromosuccinimide, which afforded intermediate 3 in 86% isolated yield (Scheme ).…”

“…N -(2-Bromo-1-(4-(chloromethyl)­phenyl)­ethyl)-2,6-difluorobenzamide ( 3 ) and 4-(4-(chloromethyl)­phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole ( 4 ) were prepared according our published literature …”

“…N-(2-Bromo-1-(4-(chloromethyl)phenyl)ethyl)-2,6-difluorobenzamide (3) and 4-(4-(chloromethyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole (4) were prepared according our published literature. 17 Synthesis of 3-(4-(2-(2,6-Difluorophenyl)-4,5-dihydrooxazol-4-yl)benzyl)pentane-2,4-dione (5a). 18 To a solution of compound 4 (1.84 g, 6.0 mmol), pentane-2,4-dione (0.72 g, 7.2 mmol), and potassium iodide (1.10 g, 6.6 mmol) in acetonitrile (15 mL), sodium hydroxide (0.26 g, 6.6 mmol) was added, and then the mixture was stirred at room temperature for 8 h. When the reaction was complete indicated by thin-layer chromatography (TLC), acetonitrile was removed in vacuo and dichloromethane (25 mL) was added.…”

Potential Safety Hazards Associated with Using N,N-Dimethylformamide in Chemical Reactions

“…The Vilsmeier–Haack reaction has found wide applications in chemical industry, including the preparation of pharmaceutical ingredients and crop protection products . Commercially available Vilsmeier–Haack reagent 21 has been used in the large-scale preparation of pharmaceutical ingredients However, the potential safety hazards associated with the Vilsmeier–Haack reaction are well-documented in the literature.…”

The serendipitous effect of KF in Ritter reaction: Photo-induced amino-alkylation of alkenes

“…This two-component protocol usually involves the generation of carbocation intermediates from tertiary, secondary, and benzylic alcohols under acidic conditions ( Kürti and Czakó, 2005 ). As basic feedstock chemicals, simple alkenes have also been widely used as carbocation precursors in Ritter reaction ( Eren and Kusefoglu, 2005 ; Huang et al., 2012 ; Jiang and Studer, 2020 ; Nandy et al., 2020 ; Park et al., 2018 ; Shi et al., 2015 ; Subba Reddy et al., 2010 ; Welniak, 1996 ; Williams et al., 2017 ; Xu et al., 2017 ; Yang et al., 2018 ; Yasuda and Obora, 2015 ; Zhang et al., 2020 ). Of particular interest is the three-component Ritter reaction, which can efficiently incorporate two distinct functional groups onto the carbon-carbon double bonds in one-step ( Abe et al., 2010 , 2017 ; Ahmed et al., 2020 ; Ai et al., 2015 ; Bao et al., 2019 ; Chen et al., 2016 ; Feng et al., 2018 ; Liu and Klussmann, 2020 ; Qian et al., 2017 ; Zhu et al., 2017 ).…”