Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Jun 15.
Published in final edited form as: Org Biomol Chem. 2016 Jun 15;14(24):5599–5605. doi: 10.1039/c6ob00132g

Mechanistic Studies on Intramolecular C-H Trifluoromethoxylation of (Hetero)arenes via OCF3-Migration

Katarzyna N Lee a,b, Zhen Lei a,b, Cristian A Morales-Rivera c, Peng Liu c, Ming-Yu Ngai a,b
PMCID: PMC4909548  NIHMSID: NIHMS775267  PMID: 27043815

Abstract

The one-pot two-step intramolecular aryl and heteroaryl C-H trifluoromethoxylation recently reported by our group has provided a general, scable, and operationally simple approach to access a wide range of unprecedented and valuable OCF3-containing building blocks. Herein we describe our investigations to elucidate its reaction mechanism. Experimental data indicates that the O-trifluoromethylation of N-(hetero)aryl-N-hydroxylamine derivatives is a radical process, whereas the OCF3-migration step proceeds via a heterolytic cleavage of the N–OCF3 bond followed by rapid recombination of a short-lived ion pair. Computational studies further support the proposed ion pair reaction pathway for the OCF3-migration process. We hope that the current study would provide useful insights for the development of new transformations using versatile N-(hetero)aryl-N-hydroxylamine synthons.

Introduction

Addition of fluorine atoms into organic molecules has a profound influence on their chemical, physical and biological properties. As a consequence, fluorine is frequently incorporated into drug molecules to enhance their lipophilicity, bioavailability, and metabolic stability.1 In recent years, there has been a significant progress towards development of synthetic methodologies that allow introduction of fluorine-containing functional groups into arenes and heteroarenes. Among fluorinated substituents, the trifluoromethoxy group (OCF3) has attracted increasing attention owing to its unique structural and electronic properties. In contrast to methoxybenzenes, which favor a planar conformation, trifluoromethoxybenzenes prefer to adopt a conformation in which the O–CF3 bond lies in a plane orthogonal to the aryl ring (Fig. 1a).2 This unique orientation, which results from the nO → σ*C–F hyperconjugative interaction (Fig. 1b) and the steric bulk of the CF3 group, provides additional conformational flexibility and renders the OCF3 group an electron–withdrawing substituent [χ (F) = 4.0, χ (OCF3) = 3.7].3 In addition, the OCF3 group has excellent lipophilicity as indicated by its Hansch-Leo parameter [πx (SF5) = +1.23, πx (OCF3) = +1.04, πx (CF3) = +0.88, πx (F) = +0.14, πx (OCH3) = −0.02].4 These properties of the OCF3 group are particularly beneficial in drug discovery and development as introduction of the OCF3 group into drug candidates may enhance their binding affinity, improve their metabolic stability and efficacy, promote their in vivo uptake and transport in biological systems, and minimize their side effects.5 Trifluoromethoxylated arenes are thus of great importance in medicinal chemistry and agrochemicals (Fig. 1c).5c, 5d, 6, 7 Moreover, incorporation of the OCF3 group into organic molecules increases their melting point and boiling point difference under ambient pressure, and lowers their surface tension, dielectric constant, and pour point.5e, 8 These properties are particularly useful in designing electronic devices and materials.9

Fig. 1.

Fig. 1

Open in a new tab

Properties and applications of OCF3-containing arenes.

Despite the prevalence of the OCF3 moiety in different areas of science, facile synthesis of (hetero)aryl trifluoromethyl ethers remains an unmet challenge in organic synthesis.10 Over the past few decades, there have been a number of synthetic routes towards trifluoromethoxylated (hetero)arenes: (i) chlorine-fluorine exchange on (hetero)aryl trichloromethyl ethers;11 (ii) deoxyfluorination of phenol fluoroformates;12 (iii) oxidative desulfurization-fluorination of aryl dithiocarbonates (xanthogenates);13 (iv) electrophilic trifluoromethylation of phenols;14 (v) nucleophilic trifluoromethoxylation of benzyne;15 (vi) silver-mediated trifluoromethoxylation of aryl stannanes and aryl boronic acids;16 (vii) radical trifluoromethoxylation;17 and (viii) silver-mediated trifluoromethylation of phenols.18 However, most of these approaches suffer from poor substrate scope and functional group tolerance, require the use of highly toxic, corrosive and/or temperature sensitive reagents, or impractical reaction conditions.

Our group has recently developed a new method for preparation of ortho-OCF3 (hetero)arylamine derivatives via a two-step process: O-trifluoromethylation of N-(hetero)aryl-N-hydroxylamine derivatives followed by OCF3-migration step (Fig. 2).19 Our approach is operationally simple and amenable to one pot as well as gram-scale synthesis, features a broad substrate scope and high functional group compatibility, and provides a wide range of valuable ortho-trifluoromethoxylated (hetero)arylamine scaffolds that would otherwise be difficult to synthesize. In view of its potential synthetic utility, an in-depth understanding of its mechanism is desirable. Herein, we report our mechanistic investigations to provide insights for this two-step transformation. Although the following studies were done using the N-aryl-N-hydroxylamine derivatives, the proposed mechanism is also applicable to the N-(hetero)aryl-N-hydroxylamine derivatives.

Fig. 2.

Fig. 2

Open in a new tab

Synthesis of (hetero)aryl trifluoromethyl ethers via O-trifluoromethylation of N-(hetero)aryl-N-hydroxylamine derivatives followed by OCF3-migration.19

Results and discussion

O-Trifluoromethylation of N-aryl-N-hydroxylamine derivatives

Treatment of protected N-aryl-N-hydroxylamines (1) with 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II, 1.2 equiv) in the presence of a catalytic amount of base (0.1 equiv Cs2CO3) in CHCl3 (0.1 M) at room temperature afforded the desired O-trifluoromethylation products (2) in high yields. These mild reaction conditions tolerate arenes with a wide variety of substitution patterns, electronic properties, and molecular complexities. To probe the nature of this reaction mechanism, we performed the O-trifluoromethylation reaction in the presence of radical traps: 2,6-di-tert-butyl-para-cresol (BHT) and 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) (Scheme 1a). It is known that Togni reagent II can be used to produce the CF3 radical in the presence of a one-electron donor through a single electron transfer (SET) process.20 If such a process takes place in our reaction, BHT and/or TEMPO would trap the CF3 radical and lower the reaction yields. Indeed, addition of a stoichiometric amount of either BHT or TEMPO to the reaction mixture under standard conditions had a detrimental effect on the formation of O-trifluoromethylated N-hydroxylamine – the yield of the desired product dropped from 97% to 28%, and 37%, respectively. The CF3 radical trapping products (BHT-CF3 and TEMPO-CF3) were detected by GC-MS and 19F NMR spectroscopy. We have also found that the O-trifluoromethylation reaction is oxygen sensitive and requires use of strictly degassed solvent. These results corroborate the intermediacy of trifluoromethyl radical in the reaction pathway, which is in agreement with literature precedents.20-21

Scheme 1.

Scheme 1

Open in a new tab

Radical trap experiments and proposed mechanism for the O-trifluoromethylation of N-(hetero)aryl-N-hydroxylamine derivatives. [a] 1 equiv.

Based on these studies and experimental observations, a plausible mechanism for the O-trifluoromethylation is depicted in Scheme 1b. Deprotonation of protected N-aryl-N-hydroxylamine (1) forms N-aryl-N-hydroxylamine anion I. Subsequent SET from I to Togni reagent II generates N-hydroxyl radical II and Togni II radical anion that collapses to liberate the electrophilic CF3 radical and 2-iodo-benzoate.22 Recombination of N-hydroxyl radical II with trifluoromethyl radical gives the desired O-trifluoromethylated hydroxylamine derivative (2).

OCF3-Migration of N-(trifluoromethoxy)-N-aniline derivatives (2)

Compounds 2 with an electron-deficient or -neutral N-aryl ring are stable at room temperature and could be purified through column chromatography. However, heating 2 in nitromethane (MeNO2, 1.0 M) cleaved the N–OCF3 bond and formed a new C–OCF3 bond to give ortho-OCF3 aniline derivatives (3) (Fig. 2). To gain mechanistic insights into the OCF3-migration step, we first examined whether the N–O bond is broken homo- or heterolytically. Homolytic cleavage of the N–OCF3 bond would generate N-amidyl and trifluoromethoxyl (˙OCF3) radicals; we envisioned that if these radicals are indeed being formed, the reaction yield should drop upon addition of a radical trap, which would disable radical recombination process. Thus, we performed the rearrangement reaction of 2b in the presence of a stoichiometric amount of BHT (Scheme 2). Similar yields were obtained regardless the presence or absence of BHT, which indicates that formation of long-lived radical species under the reaction conditions is unlikely.

Scheme 2.

Scheme 2

Open in a new tab

OCF3-Migration in the presence of radical trap. [a] 1 equiv.

In order to further shed light to the nature of the N–O bond cleavage, we performed linear free energy relationship analysis using Hammett plot. Relative rate constants were determined for the OCF3-migration with seven para/meta-substituted O-trifluoromethylated N-hydroxylamine derivatives, R-C6H4N(OCF3)C(O)Me (R = H (2b), m-OMe (2c), p-I (2d), p-Br (2e), m-F (2f), m-CO2Me (2g), and m-CF3 (2h)). The rearrangement reaction was conducted at 80°C and its rate was monitored by 19F NMR spectroscopy. For substrates with fast kinetics (R = H, m-OMe, p-I, and p-Br), the disappearance of the starting material peak was normalized against an internal standard (α,α,α-trifluorotoluene) and was measured for at least three half-lives. The kobs of each reaction was determined from a first-order plot of –ln[SM] versus time. For substrates with slow kinetics (R = m-F, m-CO2Me, and m-CF3), the rate of the appearance of the first 10-15% of product was measured. The kobs of each reaction was determined from a first-order plot of [P] versus time. The Hammett plot of log (kR/kH) versus σ showed a highly negative linear slope (ρ = −11.86; R2 = 0.99) (Fig. 3), which is commonly observed in organic reactions involving formation of a positive charge.23 Therefore, these results strongly suggest a heterolytic cleavage of the N–OCF3 bond, in which a nitrenium ion and trifluoromethoxide are generated.

Fig. 3.

Fig. 3

Open in a new tab

Hammett plot for OCF3-migration of R-C6H4N(OCF3)C(O)Me (R = m-OMe, p-I, p-Br, m-F, m-CO2Me, and m-CF3.

The formation of an intermediate nitrenium ion, whose stability is dependent on the electronic properties of nitrogen substituents, is further evidenced by the fact that the OCF3-migration is very slow at 80 °C for substrates bearing a strongly electron withdrawing group at the para-position of the N-aryl substituent (R = CO2Me (2a), σp = 0.45; COMe (2i), σp = 0.50).24 These substrates (2a and 2i) require a temperature of 120 °C for the rearrangement reaction to go to completion within a reasonable timeframe (24 h). When R = CN (2j, σp = 0.56),24 an even higher reaction temperature (140 °C) is required to thermally cleave the N–O bond. In an extreme case, no desired product is formed upon attempted rearrangement of N-(3,5-bis(trifluoromethyl)phenyl)-N-(trifluoromethoxy)acetamide (2k) due to the presence of two CF3 groups (σm = 0.43)24 on the aryl ring. In contrast, rearrangement takes place at room temperature when an electron-donating substituent, which can stabilize the positive charge, is present, e.g. R = Me (2l, σp = −0.17).24 While the presence of nitrenium ion was evidenced by the Hammett analysis, the intermediacy of trifluoromethoxide was corroborated by detection of fluorophosgene (decomposition product of trifluoromethoxide) and BF4− by 19F NMR spectroscopy (see the SI for details).25

Having investigated the N–OCF3 bond cleavage process, we then sought to determine if the final carbon–OCF3 bond forming step is an intramolecular reaction. We performed a cross-over experiment using N-(4-bromophenyl)-N-(trifluoromethoxy)acetamide (2e) and N-(4-chlorophenyl)-N-(perfluoroethoxy)acetamide (6), which was synthesized by treatment of N-(4-chlorophenyl)-hydroxamic acid with pentafluoroethyl analog of Togni reagent II.26 Heating 2e and 6 together either in MeNO2 or neat at 80 °C formed only non-crossover products (3e and 7) as monitored by GC-MS and 19F NMR (Scheme 3a). The lack of cross-over products suggests that the OCF3-migration is likely an intramolecular process and that the rate of recombination of an ion pair is much faster than an intermolecular OCF3-group transfer (see the SI for possible intermolecular mechanisms of OCF3-migration), which would require dissociation of two ions of opposite charge. The intramolecular mechanism is further corroborated by formation of benzoxazole 3m’ during the rearrangement reaction of methyl 4-(N-(trifluoromethoxy)benzamido)benzoate (2m) (Scheme 3b). This side product results from a competing intramolecular trapping of the nitrenium ion by an internal nucleophile, and its isolation further confirms that the nitrenium ion intermediates are very reactive and thus short lived.

Scheme 3.

Scheme 3

Open in a new tab

Crossover and trapping of carbocation intermediate experiments.

Computational Studies

Density functional theory (DFT) calculations were performed to investigate the mechanism of the OCF3 migration of compound 2b. The calculations were performed at the M06-2X/6-311++G(d,p)//M06-2X/6-31+G(d) level of theory with the SMD solvation model in MeNO2.27 The computed reaction energy profile of the stepwise OCF3 migration is shown in Fig. 4a.28 The heterolytic cleavage of the N–OCF3 bond of 2b to form the ion pair intermediate (10) requires an activation free energy of 27.6 kcal/mol (TS1),29 which is feasible under the experimental conditions (80 °C). The ion pair (10) is an anion-π complex30 between trifluoromethoxide and the highly electron-deficient phenyl ring. The relatively strong anion-π interaction is evidenced by the short O(OCF3)–C distances (Fig. 4b). The recombination of the ion pair (10) through O–C(ortho) bond formation to yield the dearomatized intermediate 11 requires a very low barrier and is highly exothermic. This indicates a very short lifetime of the ion pair intermediate, which is in agreement with the crossover experiments. The low barrier of the ion pair recombination is attributed to the structural similarity of 10 and TS2. The O(OCF3)–C(ortho) distance is only slightly shortened to 2.45 Å in the recombination transition state (TS2). The subsequent 1,3-hydrogen shift from the dearomatized intermediate 11 to the final product 3b occurs through a stepwise mechanism involving the autoionization of 11 to form 12a and 12b followed by the highly exothermic proton transfer from 12a to 12b to form 3b.31

Fig. 4.

Fig. 4

Open in a new tab

Computational investigations of the mechanism of OCF3-migration.

Altogether, these results are consistent with the proposed mechanism shown in Scheme 4. The N–O bond of 2 undergoes the thermally induced heterolytic cleavage to form a short-lived ion pair of a nitrenium ion and trifluoromethoxide. Rapid recombination of this ion pair affords intermediate IV, which then tautomerizes to restore aromaticity and generate the desired product 3. The ionic mechanism for the N–O bond cleavage of N-protected N-aryl-N-hydroxylamines is also well-precedented in the literature.32

Scheme 4.

Scheme 4

Open in a new tab

Proposed mechanism for the OCF3-migration process.

Conclusions

In summary, the experimental results obtained in this work delineate the mechanism of the two-step synthesis of ortho-OCF3 (hetero)arylamine derivatives. The radical trapping experiments with TEMPO and BHT indicate that O-trifluoromethylated hydroxylamine derivatives are formed via radical recombination reaction between N-hydroxyl radical and trifluoromethyl radical (˙CF3). The highly negative slope (ρ = −11.86) of the Hammett plot provides evidence for the generation of a positive charge in the course of the OCF3-migration reaction and strongly suggests that the N–OCF3 bond undergoes heterolytic cleavage. The intermediacy of a nitrenium ion and trifluoromethoxide is further verified by isolation of a benzoxazole side product and detection of trifluoromethoxide decomposition products by 19F NMR spectroscopy. The lack of cross-over products in a cross-over experiment supports intramolecular transfer of the OCF3 group. Computational studies further support the reaction pathway of a heterolytic cleavage of the N–OCF3 bond followed by rapid recombination of a short-lived ion pair. It is hoped that the deeper mechanistic insights stemming from the current study will be useful for the development of new transformations using versatile N-(hetero)aryl-N-hydroxylamine synthons.

Supplementary Material

Graphical Abstract
Supplementary Information

Acknowledgements

This paper is dedicated to Prof. Stephen L. Buchwald on the occasion of his 60th birthday. K.N.L., Z.L., and M.-Y.N. acknowledge generous start-up funds from Stony Brook University in support of this work. K.N.L. is grateful for the fellowship from the NIH Chemical-Biology training grant (T32GM092714). C.A.M.-R. and P.L. acknowledge generous start-up funds from University of Pittsburgh in support of this work. We thank TOSOH F-Tech, Inc. for their gift of TMSCF3 for the preparation of Togni reagents. Calculations were performed at the Center for Simulation and Modeling at the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the NSF (ACI-1053575).

Footnotes

Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be Included here]. See DOI: 10.1039/x0xx00000x

Notes and references

  • 1 (a).Thayer AM. Chem. Eng. News. 2006;84:15–24. [Google Scholar]; (b) Hagmann WK. J. Med. Chem. 2008;51:4359–4369. doi: 10.1021/jm800219f. [DOI] [PubMed] [Google Scholar]; (c) O'Hagan D. Chem. Soc. Rev. 2008;37:308–319. doi: 10.1039/b711844a. [DOI] [PubMed] [Google Scholar]; (d) Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008;37:320–330. doi: 10.1039/b610213c. [DOI] [PubMed] [Google Scholar]; (e) Ojima I. Fluorine in Medicinal Chemistry and Chemical Biology. Wiley-Blackwell; Chichester, U.K.: 2009. [Google Scholar]; (f) Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013;52:8214–8264. doi: 10.1002/anie.201206566. [DOI] [PubMed] [Google Scholar]; (g) Barnes-Seeman D, Beck J, Springer C. Curr. Top. Med. Chem. 2014;14:855–864. doi: 10.2174/1568026614666140202204242. [DOI] [PubMed] [Google Scholar]; (h) Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014;114:2432–2506. doi: 10.1021/cr4002879. [DOI] [PubMed] [Google Scholar]; (i) Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016;116 doi: 10.1021/acs.chemrev.5b00392. [DOI] [PubMed] [Google Scholar]
  • 2.Federsel D, Herrmann A, Christen D, Sander S, Willner H, Oberhammer H. J. Mol. Struct. 2001;567:127–136. [Google Scholar]
  • 3.Mcclinton MA, Mcclinton DA. Tetrahedron. 1992;48:6555–6666. [Google Scholar]
  • 4.Hansch C, Leo A. Substituent Constants for Correlation Analysis in Chemistry and Biology. Wiley; New York: 1979. [DOI] [PubMed] [Google Scholar]
  • 5 (a).Oreilly P, Kobayashi S, Yamane S, Phillips WG, Raymond P, Castanho B. Brighton Crop Prot. Conf.-Pest Dis. 1992:427–434. [Google Scholar]; (b) Bensimon G, Lacomblez L, Meininger V, Bouche P, Delwaide C, Couratier P, Blin O, Viader F, Peyrostpaul H, David J, Maloteaux JM, Hugon J, Laterre EC, Rascol A, Clanet M, Vallat JM, Dumas A, Serratrice G, Lechevallier B, Peuch AJ, Nguyen T, Shu C, Bastien P, Papillon C, Durrleman S, Louvel E, Guillet P, Ledoux L, Orvoenfrija E, Dib M. N. Engl. J. Med. 1994;330:585–591. doi: 10.1056/NEJM199403033300901. [DOI] [PubMed] [Google Scholar]; (c) Delorenzi FG. Pulm. Pharmacol. 1994;7:129–135. [Google Scholar]; (d) Santel HJ, Bowden BA, Sorensen VM, Mueller KH. 1999 Brighton Conference: Weeds. 1999;1-3:23–28. [Google Scholar]; (e) Leroux F, Jeschke P, Schlosser M. Chem. Rev. 2005;105:827–856. doi: 10.1021/cr040075b. [DOI] [PubMed] [Google Scholar]; (f) Jeschke P, Baston E, Leroux FR. Mini-Rev. Med. Chem. 2007;7:1027–1034. doi: 10.2174/138955707782110150. [DOI] [PubMed] [Google Scholar]; (g) Muller K, Faeh C, Diederich F. Science. 2007;317:1881–1886. doi: 10.1126/science.1131943. [DOI] [PubMed] [Google Scholar]; (h) Beria I, Valsasina B, Brasca MG, Ceccarelli W, Colombo M, Cribioli S, Fachin G, Ferguson RD, Fiorentini F, Gianellini LM, Giorgini ML, Moll JK, Posteri H, Pezzetta D, Roletto F, Sola F, Tesei D, Caruso M. Bioorg. Med. Chem. Lett. 2010;20:6489–6494. doi: 10.1016/j.bmcl.2010.09.060. [DOI] [PubMed] [Google Scholar]; (i) Beria I, Bossi RT, Brasca MG, Caruso M, Ceccarelli W, Fachin G, Fasolini M, Forte B, Fiorentini F, Pesenti E, Pezzetta D, Posteri H, Scolaro A, Depaolini SR, Valsasina B. Bioorg. Med. Chem. Lett. 2011;21:2969–2974. doi: 10.1016/j.bmcl.2011.03.054. [DOI] [PubMed] [Google Scholar]
  • 6 (a).Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, Anderson SW, Towell JA, Yuan Y, McMurray DN, Kreiswirth BN, Barry CE, Baker WR. Nature. 2000;405:962–966. doi: 10.1038/35016103. [DOI] [PubMed] [Google Scholar]; (b) Valsasina B, Beria I, Alli C, Alzani R, Avanzi N, Ballinari D, Cappella P, Caruso M, Casolaro A, Ciavolella A, Cucchi U, De Ponti A, Felder E, Fiorentini F, Galvani A, Gianellini LM, Giorgini ML, Isacchi A, Lansen J, Pesenti E, Rizzi S, Rocchetti M, Sola F, Moll J. Mol. Cancer Ther. 2012;11:1006–1016. doi: 10.1158/1535-7163.MCT-11-0765. [DOI] [PubMed] [Google Scholar]; (c) Landelle G, Panossian A, Leroux FR. Curr. Top. Med. Chem. 2014;14:941–951. doi: 10.2174/1568026614666140202210016. [DOI] [PubMed] [Google Scholar]; (d) Burness CB. Drugs. 2015;75:1559–1566. doi: 10.1007/s40265-015-0458-y. [DOI] [PubMed] [Google Scholar]
  • 7 (a).Howard J, Wall R. B. Entomol. Res. 1995;85:71–77. [Google Scholar]; (b) Amir OG, Peveling R. J. Appl. Entomol. 2004;128:242–249. [Google Scholar]; (c) Chen Y, Zhang AF, Wang WX, Zhang Y, Gao TC. Ann. Appl. Biol. 2012;161:247–254. [Google Scholar]; (d) Sagheer M, Yasir M, Mansoor-ul-Hasan, Ashfaq M. Pak. J. Agr. Sci. 2012;49:173–178. [Google Scholar]
  • 8 (a).Kirsch P. Modern Fluoroorganic Chemistry : Synthesis, Reactivity, Applications. Wiley-VCH; Weinheim: 2004. [Google Scholar]; (b) Siegemund G, Schwertfeger W, Feiring A, Smart B, Behr F, Vogel H, McKusick B. Ullmann's Encyclopedia of Industrial Chemistry. Wiley-VCH Verlag GmbH & Co. KGaA; 2000. [DOI] [Google Scholar]
  • 9 (a).Kirsch P, Bremer M. Angew. Chem. Int. Ed. 2000;39:4217–4235. doi: 10.1002/1521-3773(20001201)39:23<4216::AID-ANIE4216>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]; (b) Mamada M, Shima H, Yoneda Y, Shimano T, Yamada N, Kakita K, Machida T, Tanaka Y, Aotsuka S, Kumaki D, Tokito S. Chem. Mater. 2015;27:141–147. [Google Scholar]
  • 10 (a).Leroux FR, Manteau B, Vors JP, Pazenok S. Beilstein J. Org. Chem. 2008;4 doi: 10.3762/bjoc.4.13. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Lee KN, Lee JW, Ngai M-Y. Synlett. 2016 doi: 10.1055/s-0035-1560516. eFirst. [DOI] [Google Scholar]
  • 11 (a).Yagupolskii LM. Dokl. Akad. Nauk SSSR. 1955;105:100–102. [Google Scholar]; (b) Yarovenko NN, Vasileva AS. Zh. Obshch. Khim. 1958;28:2502–2504. [Google Scholar]; (c) Yagupolskii LM, Troitskaya VI. J. Gen. Chem. USSR. 1961;31:845–852. [Google Scholar]; (d) Yagupolskii LM, Orda VV. Zh. Obshch. Khim. 1964;34:1979–1984. [Google Scholar]; (e) Manteau B, Genix P, Brelot L, Vors JP, Pazenok S, Giornal F, Leuenberger C, Leroux FR. Eur. J. Org. Chem. 2010;2010:6043–6066. [Google Scholar]
  • 12.Sheppard WA. J. Org. Chem. 1964;29:1–11. [Google Scholar]
  • 13 (a).Kuroboshi M, Suzuki K, Hiyama T. Tetrahedron Lett. 1992;33:4173–4176. [Google Scholar]; (b) Kanie K, Tanaka Y, Suzuki K, Kuroboshi M, Hiyama T. Bull. Chem. Soc. Jpn. 2000;73:471–484. [Google Scholar]; (c) Kuroboshi M, Kanie K, Hiyama T. Adv. Synth. Catal. 2001;343:235–250. [Google Scholar]
  • 14 (a).Umemoto T, Adachi K, Ishihara S. J. Org. Chem. 2007;72:6905–6917. doi: 10.1021/jo070896r. [DOI] [PubMed] [Google Scholar]; (b) Stanek K, Koller R, Togni A. J. Org. Chem. 2008;73:7678–7685. doi: 10.1021/jo8014825. [DOI] [PubMed] [Google Scholar]
  • 15.Kolomeitsev AA, Vorobyev M, Gillandt H. Tetrahedron Lett. 2008;49:449–454. [Google Scholar]
  • 16.Huang C, Liang T, Harada S, Lee E, Ritter T. J. Am. Chem. Soc. 2011;133:13308–13310. doi: 10.1021/ja204861a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Venturini F, Navarrini W, Famulari A, Sansotera M, Dardani P, Tortelli V. J. Fluorine Chem. 2012;140:43–48. [Google Scholar]
  • 18.Liu JB, Chen C, Chu L, Chen ZH, Xu XH, Qing FL. Angew. Chem. Int. Ed. 2015;54:11839–11842. doi: 10.1002/anie.201506329. [DOI] [PubMed] [Google Scholar]
  • 19 (a).Hojczyk KN, Feng PJ, Zhan CB, Ngai MY. Angew. Chem. Int. Ed. 2014;53:14559–14563. doi: 10.1002/anie.201409375. [DOI] [PubMed] [Google Scholar]; (b) Feng PJ, Lee KN, Lee JW, Zhan CB, Ngai MY. Chem. Sci. 2016;7:424–429. doi: 10.1039/c5sc02983j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20 (a).Parsons AT, Buchwald SL. Angw. Chem. Int. Ed. 2011;50:9120–9123. doi: 10.1002/anie.201104053. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Wang X, Ye Y, Zhang S, Feng J, Xu Y, Zhang Y, Wang J. J. Am. Chem. Soc. 2011;133:16410–16413. doi: 10.1021/ja207775a. [DOI] [PubMed] [Google Scholar]; (c) Chen Z-M, Bai W, Wang S-H, Yang B-M, Tu Y-Q, Zhang F-M. Angw. Chem. Int. Ed. 2013;52:9781–9785. doi: 10.1002/anie.201304557. [DOI] [PubMed] [Google Scholar]; (d) Liu X, Xiong F, Huang X, Xu L, Li P, Wu X. Angw. Chem. Int. Ed. 2013;52:6962–6966. doi: 10.1002/anie.201302673. [DOI] [PubMed] [Google Scholar]; (e) Matoušek V, Pietrasiak E, Sigrist L, Czarniecki B, Togni A. Eur. J. Org. Chem. 2014;2014:3087–3092. [Google Scholar]
  • 21.Mizuta S, Engle KM, Verhoog S, Galicia-López O, O’Duill M, Médebielle M, Wheelhouse K, Rassias G, Thompson AL, Gouverneur V. Org. Lett. 2013;15:1250–1253. doi: 10.1021/ol400184t. [DOI] [PubMed] [Google Scholar]
  • 22 (a).Reduction potential (E1/2red) of Togni reagent II is between −1.10 and −0.94 V vs SCE in CH3CN, see Yasu Y, Koike T, Akita M. Angew. Chem. Int. Ed. 2012;124:9705–9709.; Mizuta S, Verhoog S, Wang X, Shibata N, Gouverneur V, Médebielle M. J. Fluorine Chem. 2013;155:124–131. Although E1/2red of I has not been measured, E1/2red of parent N-aryl-N-hydroxylamine derivatives (1) is around −0.48 V vs SCE, see, Xu F, Deussen HJW, Lopez B, Lam L, Li KC. Eur. J. Biochem. 2001;268:4169–4176. doi: 10.1046/j.1432-1327.2001.02328.x.
  • 23.Gassman PG, Granrud JE. J. Am. Chem. Soc. 1984;106:1498–1499. [Google Scholar]
  • 24.Hansch C, Leo A, Taft RW. Chem. Rev. 1991;91:165–195. [Google Scholar]
  • 25 (a).Seppelt K. Angew. Chem. Int. Ed. 1977;16:322–323. [Google Scholar]; (b) Christe KO, Hegge J, Hoge B, Haiges R. Angew. Chem. Int. Ed. 2007;46:6155–6158. doi: 10.1002/anie.200701823. [DOI] [PubMed] [Google Scholar]
  • 26.Li Y, Studer A. Angew. Chem. Int. Ed. 2012;51:8221–8224. doi: 10.1002/anie.201202623. [DOI] [PubMed] [Google Scholar]
  • 27.All calculations were performed using Gaussian 09, Revision D.01, Frisch MJ, et al. Gaussian, Inc.; Wallingford CT: 2009. See the Supporting Information for computational details.
  • 28.The concerted 1,3-OCF3 migration transition state that connects 2b and 11 cannot be located. Scan of the potential energy surface indicates that the concerted transition state, even if it exists, would have a much higher barrier than the stepwise transition state (TS1). This is also true for substrate 2a, see Supporting Information for details.
  • 29.This computed activation energy is comparable to the experimentally calculated value (30.8 kcal/mol). See supporting information for the detailed calculation.
  • 30 (a).Quinonero D, Garau C, Rotger C, Frontera A, Ballester P, Costa A, Deya PM. Angew. Chem. Int. Ed. 2002;41:3389–3392. doi: 10.1002/1521-3773(20020916)41:18<3389::AID-ANIE3389>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]; (b) Schottel BL, Chifotides HT, Dunbar KR. Chem. Soc. Rev. 2008;37:68–83. doi: 10.1039/b614208g. [DOI] [PubMed] [Google Scholar]
  • 31 (a).Although a thermal 1,3-hydrogen shift is symmetry-allowed according to the Woodward-Hoffmann rules, the requirement of the Mobius transition state geometry prohibits such a shift. Dedobbelaere JR, Vandijk JMF, Dehaan JW, Buck HM. J. Am. Chem. Soc. 1977;99:392–397.; Houk KN, Li Y, Evanseck JD. Angew. Chem. Int. Ed. 1992;31:682–708.
  • 32 (a).Kikugawa Y, Shimada M. J. Chem. Soc., Chem. Commun. 1989:1450–1451. [Google Scholar]; (b) Tabolin AA, Ioffe SL. Chem. Rev. 2014;114:5426–5476. doi: 10.1021/cr400196x. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Graphical Abstract
NIHMS775267-supplement-Graphical_Abstract.docx (250.7KB, docx)
Supplementary Information
NIHMS775267-supplement-Supplementary_Information.pdf (12.3MB, pdf)

RESOURCES