Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Summary

An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF₃-migration is reported.

Abstract

Molecules bearing trifluoromethoxy (OCF₃) group often show desired pharmacological and biological properties. However, facile synthesis of trifluoromethoxylated aromatic compounds remains a formidable challenge in organic synthesis. Conventional approaches often suffer from poor substrate scope, or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Herein, we report a user-friendly protocol for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II). Treating methyl 4-(N-hydroxyacetamido)benzoate (1a) with Togni reagent II in the presence of a catalytic amount of cesium carbonate (Cs₂CO₃) in chloroform at RT afforded methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a). This intermediate was then converted to the final product methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in nitromethane at 120 °C. This procedure is general and can be applied to the synthesis of a broad spectrum of ortho-trifluoromethoxylated aniline derivatives, which could serve as useful synthetic building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and functional materials.

Introduction

The trifluoromethoxy (OCF₃) group has made a profound impact on life and materials science research since the first synthesis of trifluoromethyl ether in 1935.² Due to its unique combination of high electronegativity (χ = 3.7)³ and excellent lipophilicity (Π_x = 1.04),⁴ the trifluoromethoxy group has found broad applications in medicine, agriculture, and materials industry.^5-10 However, facile introduction of the OCF₃ group into organic molecules, especially aromatic compounds, remains a major challenge in synthetic chemistry.

Over the last few decades, ef....

Protocol

1. Precursor Preparation: Synthesis of Methyl 4-(N-hydroxyacetamido)benzoate (1a)

1. Reduction of methyl 4-nitrobenzoate.
   1. Add 5.00 g of methyl 4-nitrobenzoate (27.6 mmol, 1.00 equiv), 159 mg of 5% Rhodium on carbon (Rh/C, 0.300 mol% Rh), and a magnetic stir-bar into an oven-dried 250 ml two-neck round-bottom flask (dried at 150 °C for 18 hr).
      NOTE: Reagents can be weighed out under ambient atmosphere. However, the reaction needs to be carried out under nitrogen atmosphere.
   2. Connect one neck of the flask to a nitrogen/vacuum manifold and cap the other neck with a septum. Perform three vacuum-refill c....

Results

Methyl 4-(N-hydroxyacetamido)benzoate (1a) was synthesized in 92% isolated yield through a two-step procedure (i.e., reducing methyl 4-nitrobenzoate with hydrazine using 5% Rh/C as a catalyst to form methyl 4-(N-hydroxyamino)benzoate, followed by acetyl protection of the resulting hydroxylamine). O-Trifluoromethylation of 1a with Togni reagent II in the presence of catalytic amount of cesium carbonate (Cs₂CO<.......

Discussion

Due to the lack of a general and user-friendly procedure for the synthesis of trifluoromethoxylated arenes, many OCF₃-containing aromatic compounds are extremely expensive.³⁴ Our strategy displaces a broad functional group tolerance and provides an easy access to various trifluoromethoxylated arenes. These compounds could serve as valuable building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and materials.

Hydrazine was used as a hydrog.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
5% Rhodium on carbon	Aspira Scientific	300835	5% wt% dry loading
Hydrazine monohydrate	Sigma-Alderich	13696HMV	Reagent grade, 98%
Acetyl chloride	Alfa Aesar	10176887	98%
Sodium bicarbonate	Fisher Scientific	134826	Chemical pure
Cesium carbonate	Alfa Aesar	12887	99.9%, metals basis
Togni Reagent II			Prepared according to the literature procedure (ref 37). Caution: Pure Togni reagent II is impact and friction sensitive, treat it with great care (see ref. 36).
Tetrahydrofuran	BDH	BDH1149-4LG	Distilled from deep purple sodium benzophenone ketyl.
Diethyl Ether	Fisher Scientific	148221	Distilled from deep purple sodium benzophenone ketyl.
Chloroform	Fisher Scientific	141739	Dried over CaH2 and distilled
Nitromethane	Alfa Aesar	J03z053	Dried over CaSO4 and distilled
Silica gel	SILICYCLE	60514	40-63 µm (230-400 mesh)
Celite	EMD	2012040674	Not acid washed