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Method Article
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.
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.
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 (Πx = 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, efforts to address this challenge led to the development of a handful of transformations for the synthesis of trifluoromethoxylated arenes.5-7,9-11 These include (i) chlorine/fluorine exchange on trichlorinated precursors;1,12-17 (ii) deoxyfluorination of fluoroformates;18 (iii) oxidative fluorodesulfurization;19-21 (iv) electrophilic trifluoromethylation of alcohols;22-25 (v) nucleophilic trifluoromethoxylation;26-30, (vi) transition metal-mediated trifluoromethoxylation of aryl borates and stannanes;31 and (vii) radical trifluoromethoxylation.32,33 Nevertheless, many of these approaches either suffer from poor substrate scope or require use of highly toxic and/or thermally labile reagents. Therefore, due to the lack of a general and user-friendly method to synthesize OCF3-containing compounds, the potential of the OCF3 group has not been fully exploited in chemistry.
As part of our interest in trifluoromethoxylation reactions,34 we describe herein a two-step protocol (i.e., radical O-trifluoromethylation and thermally induced OCF3-migration) for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) from methyl 4-(N-hydroxyacetamido)benzoate (1a). The strategy is easy-to-operate and applicable to the synthesis of a wide range of ortho-trifluoromethoxylated aniline derivatives.
1. Precursor Preparation: Synthesis of Methyl 4-(N-hydroxyacetamido)benzoate (1a)
2. Synthesis of Methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a)
3. Synthesis of Methyl 4-Acetamido-3-(trifluoromethoxy)benzoate via OCF3-migration (3a)
4. Characterization of New Products
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<...
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...
The authors declare no competing financial interests.
We acknowledge generous start-up funds from the State University of New York at Stony Brook in support of this work. We also thank TOSOH F-Tech, Inc. for providing us TMSCF3 reagent for the synthesis of Togni reagent II.
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 |
nitro methane | Alfa Aesar | J03z053 | Dried over CaSO4 and distilled |
Silica gel | SILICYCLE | 60514 | 40-63 µm (230-400 mesh) |
Cilite | EMD | 2012040674 | Not acid washed |
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