JoVE Logo
Authors
Contact Us

Sign In

A subscription to JoVE is required to view this content. Sign in or start your free trial.

In This Article

  • Summary
  • Abstract
  • Introduction
  • Protocol
  • Results
  • Discussion
  • Disclosures
  • Acknowledgements
  • Materials
  • References
  • Reprints and Permissions

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 (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.

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 cycles (i.e., pumping the air out of the flask and replacing the resulting vacuum with nitrogen gas) to replace the air in the flask with nitrogen gas.
    3. Add 138 ml anhydrous tetrahydrofuran (THF, 0.200 M) to the reaction flask using airtight syringe. Cool and stir the reaction mixture at 0 °C for 15 min.
    4. Add 1.47 ml of hydrazine monohydrate (1.52 g, 30.4 mmol, 1.20 equiv) dropwise to the reaction mixture at 0 °C using an airtight syringe. Monitor the reaction using a thin layer chromatography (TLC). Use hexanes:ethyl acetate (EtOAc) (4:1 v/v, Rf = 0.23) as an eluent to develop the TLC.
    5. When methyl 4-nitrobenzoate is completely consumed, filter the reaction mixture through a short pad of diatomaceous earth (i.e., Celite, 5 g) in a 60 ml frit Buchner funnel using vacuum filtration. Wash the filter with EtOAc (20 ml x 3 times). Concentrate the filtrate in vacuo using a rotary evaporator to afford the crude methyl 4-(N-hydroxyamino)benzoate, which is used directly without further purification.
  2. Acetyl protection of methyl 4-(N-hydroxyamino)benzoate
    1. Add 2.55 g of sodium bicarbonate (NaHCO3, 30.4 mmol, 1.20 equiv), all the crude methyl 4-(N-hydroxyamino)benzoate obtained from the previous step, and a stir-bar into an oven-dried 500 ml two-neck round-bottom flask.
    2. Cap one neck with a septum and connect another neck to a nitrogen/vacuum manifold. Perform three vacuum-refill cycles to replace the air in the flask with nitrogen gas.
    3. Add 138 ml anhydrous diethyl ether (Et2O, 0.200 M) to the reaction flask using an airtight syringe. Cool and stir the reaction mixture at 0 °C for 15 min.
    4. Prepare a solution of acetyl chloride (2.17 ml, 2.39 g, 30.4 mmol, 1.20 equiv) in anhydrous Et2O (138 ml, 0.220 M). Add the solution to the reaction mixture at 0 °C using a syringe pump at a rate of 10.0 ml/hr.
    5. At the end of the addition, filter the reaction mixture through a short pad of diatomaceous earth (i.e., Celite, 5 g) in 60 ml frit Buchner funnel using vacuum filtration. Wash the filter with EtOAc (20 ml x 3 times). Concentrate the filtrate in vacuo using a rotary evaporator.
    6. Purify the crude product with flash column chromatography35 eluting with hexanes:EtOAc (4:1 to 1:1 (v/v)) (Rf = 0.13, hexanes:EtOAc (4:1 (v/v)) to afford 5.31 g of methyl 4-(N-hydroxyacetamido)benzoate as a light yellow solid (25.4 mmol, 92% yield).

2. Synthesis of Methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a)

  1. Add 2.00 g of methyl 4-(N-hydroxyacetamido) benzoate (1a) (9.56 mmol, 1.00 equiv), 311 mg of Cs2CO3 (0.956 mmol, 10.0 mol%), 3.63 g of Togni reagent II (11.5 mmol, 1.20 equiv), and a magnetic stir-bar into an oven-dried 250 ml round-bottom flask inside a glovebox (nitrogen atmosphere).
    NOTE: This reaction can also be performed using Schlenk techniques outside the glovebox.
    Caution: Pure Togni reagent II is impact and friction sensitive, open flames, sparks, and/or grinding should be avoided. Soft and polished tools should be used for manipulations. In addition, the reaction mixture should be stirred behind a safety shield.36
  2. Add 95.6 ml of dried and degassed chloroform (CHCl3, 0.100 M) to the reaction flask.
  3. Cap the flask with septum and stir the reaction mixture at 23 °C under N2 atmosphere either inside or outside of the glovebox for 16 hr.
  4. Filter the reaction mixture through a filter funnel to remove any solid residue. Concentrate the filtrate in vacuo using a rotary evaporator.
  5. Purify the crude product with flash column chromatography eluting with hexanes:dichloromethane (CH2Cl2) (7:3 to 0:1 (v/v)) (Rf = 0.44 (CH2Cl2) to afford 2.51 g of methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (9.05 mmol, 95% yield).
    NOTE: Togni reagent II is prepared according to the literature procedures37 and stored in the glovebox freezer at -35 °C to maintain its quality over a long period of time. This reaction is oxygen sensitive. Although all the reagents can be weighed out under ambient atmosphere at RT, removal of all oxygen from the reaction flask is critical. Dried and degassed CHCl3 is prepared by distilling it from CaH2 under nitrogen atmosphere followed by performing a three cycles of the freeze-pump-thaw procedure.

3. Synthesis of Methyl 4-Acetamido-3-(trifluoromethoxy)benzoate via OCF3-migration (3a)

  1. Add 2.51 g methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (9.05 mmol, 1.0 equiv), a magnetic stir-bar, and 9.05 ml of MeNO2 (1.00 M) into a 50 ml pressure vessel. Cap the vessel with a screw cap.
  2. Stir the reaction mixture at 120 °C behind the safety shield for 20 hr.
    Caution: Impure nitromethane is explosive, so the reaction mixture should be stirred behind the safety shield.
  3. Cool the reaction mixture to RT.
  4. Transfer the reaction mixture to a 100 ml round-bottom flask.
  5. Concentrate the reaction mixture in vacuo using a rotary evaporator.
  6. Purify the crude product with flash column chromatography eluting with hexanes:EtOAc (9:1 to 7:3 (v/v)) (Rf = 0.51 hexanes:EtOAc (4:1 (v/v)) to afford 2.13 g of methyl 4-acetamido-3-(trifluoromethoxy)benzoate (7.69 mmol, 85%).
    NOTE: This reaction can be carried out under ambient atmosphere. Nitrogen atmosphere is not required. A round-bottom flask equipped with a water condenser can be used as an alternative reaction apparatus.

4. Characterization of New Products

  1. Characterize all the new compounds by 1H, 13C NMR spectroscopy and high-resolution mass spectroscopy and use 19F NMR spectroscopy to characterize compounds containing fluorine atoms.34

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...

Disclosures

The authors declare no competing financial interests.

Acknowledgements

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.

Materials

NameCompanyCatalog NumberComments
5% Rhodium on carbonAspira Scientific3008355% wt% dry loading
Hydrazine monohydrateSigma-Alderich13696HMVReagent grade, 98%
Acetyl chlorideAlfa Aesar1017688798%
Sodium bicarbonateFisher Scientific134826Chemical pure
Cesium carbonateAlfa Aesar1288799.9%, metals basis
Togni Reagent IIPrepared 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).
TetrahydrofuranBDHBDH1149-4LGDistilled from deep purple sodium benzophenone ketyl.
Diethyl EtherFisher Scientific148221Distilled from deep purple sodium benzophenone ketyl.
ChloroformFisher Scientific141739Dried over CaH2 and distilled
NitromethaneAlfa AesarJ03z053Dried over CaSO4 and distilled
Silica gelSILICYCLE6051440-63 µm (230-400 mesh)
CeliteEMD2012040674Not acid washed

References

  1. Yagupolskii, L. M. Sintez proizvodnykh feniltriftormetilovogo efira. Dokl. Akad. Nauk SSSR. 105, 100-102 (1955).
  2. Booth, H. S., Burchfield, P. E. Fluorination of halogeno methyl ethers. I. Fluorination of trichlorodimethyl ether. J. Am. Chem. Soc. 57, 2070 (1935).
  3. McClinton, M. A., McClinton, D. A. Trifluoromethylations and related reactions in organic-chemistry. Tetrahedron. 48, 6555-6666 (1992).
  4. Hansch, C., Leo, A. . Substituent Constants for Correlation Analysis in Chemistry and Biology. , (1979).
  5. Leroux, F., Jeschke, P., Schlosser, M. Alpha-fluorinated ethers, thioethers, and amines: Anomerically biased species. Chem. Rev. 105, 827-856 (2005).
  6. Jeschke, P., Baston, E., Leroux, F. R. Alpha-fluorinated ethers as 'exotic' entity in medicinal chemistry. Mini-Rev. Med. Chem. 7, 1027-1034 (2007).
  7. Leroux, F. R., Manteau, B., Vors, J. P., Pazenok, S. Trifluoromethyl ethers - synthesis and properties of an unusual substituent. Beilstein J. Org. Chem. 4, (2008).
  8. Fantasia, S., Welch, J. M., Togni, A. Reactivity of a hypervalent iodine trifluoromethylating reagent toward THF: ring opening and formation of trifluoromethyl ethers. J. Org. Chem. 75, 1779-1782 (2010).
  9. Manteau, B., Pazenok, S., Vors, J. P., Leroux, F. R. New trends in the chemistry of alpha-fluorinated ethers, thioethers, amines and phosphines. J. Fluorine Chem. 131, 140-158 (2010).
  10. Landelle, G., Panossian, A., Leroux, F. R. Trifluoromethyl ethers and -thioethers as tools for medicinal chemistry and drug discovery. Curr. Top. Med. Chem. 14, 941-951 (2014).
  11. Liang, T., Neumann, C. N., Ritter, T. Introduction of fluorine and fluorine-containing functional groups. Angew. Chem. Int. Ed. 52, 8214-8264 (2013).
  12. Yarovenko, N. N., Vasileva, A. S. A new method for the introduction of trihalomethyl groups into organic molecules. Zh. Obshch. Khim. 28, 2502-2504 (1958).
  13. Yagupols, L., Troitskaya, V. I. Synthesis of phenyl trifluoromethyl ether derivatives. Zh. Obshch. Khim. 31, 915-924 (1961).
  14. Yagupolskii, L. M., Orda, V. V. Bis(triftormetoksi I triftormetilmerkapto)-proizvodnye benzola. Zh. Obshch. Khim. 34, 1979-1984 (1964).
  15. Louw, R., Franken, P. W. Selective side-chain chlorination of methoxybenzenes. Chem Ind-London. , 127-128 (1977).
  16. Feiring, A. E. Chemistry in hydrogen-fluoride. 7. Novel synthesis of aryl trifluoromethyl ethers. J. Org. Chem. 44, 2907-2910 (1979).
  17. Salome, J., Mauger, C., Brunet, S., Schanen, V. Synthesis conditions and activity of various Lewis acids for the fluorination of trichloromethoxy-benzene by HF in liquid phase. J. Fluorine Chem. 125, 1947-1950 (2004).
  18. Sheppard, W. A. Alpha-Fluorinated Ethers. I. Aryl Fluoroalkyl Ethers. J. Org. Chem. 29, 1-11 (1964).
  19. Kuroboshi, M., Suzuki, K., Hiyama, T. Oxidative desulfurization-fluorination of xanthates - a convenient synthesis of trifluoromethyl ethers and difluoro(methylthio)methyl ethers. Tetrahedron Lett. 33, 4173-4176 (1992).
  20. Kanie, K., Tanaka, Y., Suzuki, K., Kuroboshi, M., Hiyama, T. A convenient synthesis of trifluoromethyl ethers by oxidative desulfurization-fluorination of dithio carbonates. Bull. Chem. Soc. Jpn. 73, 471-484 (2000).
  21. Kuroboshi, M., Kanie, K., Hiyama, T. Oxidative desulfurization-fluorination: A facile entry to a wide variety of organofluorine compounds leading to novel liquid-crystalline materials. Adv. Synth. Catal. 343, 235-250 (2001).
  22. Umemoto, T. Electrophilic perfluoroalkylating agents. Chem. Rev. 96, 1757-1777 (1996).
  23. Umemoto, T., Adachi, K., Ishihara, S. CF3 oxonium salts, O-(trifluoromethyl)dibenzofuranium salts: in situ synthesis, properties, and application as a real CF3+ species reagent. J. Org. Chem. 72, 6905-6917 (2007).
  24. Stanek, K., Koller, R., Togni, A. Reactivity of a 10-I-3 hypervalent iodine trifluoromethylation reagent with phenols. J. Org. Chem. 73, 7678-7685 (2008).
  25. Koller, R., et al. Zinc-mediated formation of trifluoromethyl ethers from alcohols and hypervalent iodine trifluoromethylation reagents. Angew. Chem. Int. Ed. 48, 4332-4336 (2009).
  26. Trainor, G. L. The preparation of O-trifluoromethyl carbohydrates. J. Carbohydr. Chem. 4, 545-563 (1985).
  27. Nishida, M., Vij, A., Kirchmeier, R. L., Shreeve, J. M. Synthesis of polyfluoro aromatic ethers - a facile route using polyfluoroalkoxides generated from carbonyl and trimethysilyl compounds. Inorg. Chem. 34, 6085-6092 (1995).
  28. Kolomeitsev, A. A., Vorobyev, M., Gillandt, H. Versatile application of trifluoromethyl triflate. Tetrahedron Lett. 49, 449-454 (2008).
  29. Marrec, O., Billard, T., Vors, J. P., Pazenok, S., Langlois, B. R. A deeper insight into direct trifluoromethoxylation with trifluoromethyl triflate. J. Fluorine Chem. 131, 200-207 (2010).
  30. Marrec, O., Billard, T., Vors, J. P., Pazenok, S., Langlois, B. R. A new and direct trifluoromethoxylation of aliphatic substrates with 2,4-dinitro(trifluoromethoxy)benzene. Adv. Synth. Catal. 352, 2831-2837 (2010).
  31. Huang, C. H., Liang, T., Harada, S., Lee, E., Ritter, T. Silver-mediated trifluoromethoxylation of aryl stannanes and arylboronic acids. J. Am. Chem. Soc. 133, 13308-13310 (2011).
  32. Rozen, S. Selective fluorinations by reagents containing the OF group. Chem. Rev. 96, 1717-1736 (1996).
  33. Venturini, F., et al. Direct trifluoro-methoxylation of aromatics with perfluoro-methyl-hypofluorite. J. Fluorine Chem. 140, 43-48 (2012).
  34. Hojczyk, K. N., Feng, P., Zhan, C., Ngai, M. -. Y. Trifluoromethoxylation of arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF3 migration. Angew. Chem. Int. Ed. 53, 14559-14563 (2014).
  35. Still, W. C., Kahn, M., Mitra, A. Rapid chromatographic technique for preparative separations with moderate Resolution. J. Org. Chem. 43, 2923-2925 (1978).
  36. Fiederling, N., Haller, J., Schramm, H. Notification about the Explosive Properties of Togni's Reagent II and One of Its Precursors. Org. Process Res. Dev. 17, 318-319 (2013).
  37. Matousek, V., Pietrasiak, E., Schwenk, R., Togni, A. One-pot synthesis of hypervalent iodine reagents for electrophilic trifluoromethylation. J. Org. Chem. 78, 6763-6768 (2013).

Reprints and Permissions

Request permission to reuse the text or figures of this JoVE article

Request Permission

Explore More Articles

Ortho trifluoromethoxylated AnilineAniline DerivativesReductionHydrogenationAcetyl ProtectionRhodium CatalystCelite FiltrationTLC MonitoringAnhydrous SolventsNitrogen Atmosphere

This article has been published

Video Coming Soon

JoVE Logo

Privacy

Terms of Use

Policies

Contact Us

Recommend to library

JoVE NEWSLETTERS

Research

Education

Authors

Librarians

ABOUT JoVE

Copyright © 2025 MyJoVE Corporation. All rights reserved