Synthesis, physico-chemical properties and microsomal stability of compounds bearing aliphatic trifluoromethoxy group

Article abstract of DOI:10.1016/j.jfluchem.2020.109461

Effects of the trifluoromethoxy substituent on physico-chemical properties of compounds, such as kinetic solubility, lipophilicity and microsomal clearance, was studied in a series of aliphatic derivatives. It was found that kinetic solubility of the CF₃O-containing compounds was comparable to that of analogs, i.e. compounds bearing CH₃O and CF₃ moieties. The CF₃O-substituted compounds had higher lipophilicity as compared to methoxy analogues, and nearly the same like CF₃-bearing compounds. Microsomal stability studies indicated that the trifluoromethoxy group typically decreased metabolic stability of the corresponding derivatives as compared to either CH₃O- or CF₃-substituted counterparts, except for N-alkoxy(sulfon)amide series.

Full text of DOI:10.1016/j.jfluchem.2020.109461

Journal Pre-proof
Synthesis, physico-chemical properties and microsomal stability of
compounds bearing aliphatic trifluoromethoxy group
Ivan G. Logvinenko, Yevheniia Markushyna, Ivan S. Kondratov,
Bohdan V. Vashchenko, Maria Kliachyna, Yuliya Tokaryeva,
Valentyna Pivnytska, Oleksandr O. Grygorenko, Gu¨nter Haufe
PII:
S0022-1139(20)30012-9
DOI:
https://doi.org/10.1016/j.jfluchem.2020.109461
FLUOR 109461
Reference:
To appear in:
Journal of Fluorine Chemistry
Received Date:
Revised Date:
Accepted Date:
29 November 2019
8 January 2020
8 January 2020
Please cite this article as: Logvinenko IG, Markushyna Y, Kondratov IS, Vashchenko BV,
Kliachyna M, Tokaryeva Y, Pivnytska V, Grygorenko OO, Haufe G, Synthesis,
physico-chemical properties and microsomal stability of compounds bearing aliphatic
trifluoromethoxy group, Journal of Fluorine Chemistry (2020),
doi: https://doi.org/10.1016/j.jfluchem.2020.109461
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Synthesis, physico-chemical properties and microsomal stability of compounds
bearing aliphatic trifluoromethoxy group
Ivan G. Logvinenko,a,b Yevheniia Markushyna,a,c‡ Ivan S. Kondratov,a,b* Bohdan V. Vashchenko,a,d
Maria Kliachyna,e Yuliya Tokaryeva,e Valentyna Pivnytska,e Oleksandr O. Grygorenko,a,d* Günter Haufef,g
a Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
b V.P. Kukhar Institute of Bioorganic Chemistry & Petrochemistry, NAS of Ukraine, Murmanska Street 1, Kyiv 02660, Ukraine
c National Technical University of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute", Prospect Peremogy 37, Kyiv 03056, Ukraine
d Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine
e Bienta/Enamine Ltd. (www.bienta.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine
f Organisch-Chemisches Institut Westfälische, Wilhelms-Universität Münster, Corrensstr. 40, D-48149, Münster, Germany
g Cells-in-Motion Cluster of Excellence, Universität Münster, Waldeyerstraße 15, 48149 Münster, Germany
–––––––––––––––––––––
Corresponding authors. Tel.: +38-044-239-33-15; fax: +38-044-537-32-53; e-mail: gregor@univ.kiev.ua (O.O.G.); kondratov@mail.enamine.net
(I.S.K.)
‡Current address: Max-Planck Institute of Colloids and Interfaces, Department of Colloid Chemistry, Research Campus Golm, 14476 Potsdam,
Germany
Highlights




Effect of CF3O group on physico-chemical properties and metabolic stability of aliphatic compounds was evaluated.
Kinetic solubility of all derivatives in aqueous buffer was similar; the effect of the CF3O substituent was not significant.
OCF3 group increased liphophilicity by 0.7–1.4 LogD units as compared to OCH3 substituent similarly to the CF3 group.
Decreased metabolic stability was observed for most of the CF3O compounds in comparison to either CH3O or CF3 analogues.
ABSTRACT
Effects of the trifluoromethoxy substituent on physico-chemical properties of compounds, such as kinetic solubility, lipophilicity and microsomal
clearance, was studied in a series of aliphatic derivatives. It was found that kinetic solubility of the CF3O-containing compounds was comparable to that
of analogs, i.e. compounds bearing CH3O and CF3 moieties. The CF3O-substituted compounds had higher lipophilicity as compared to methoxy
analogues, and nearly the same like CF3-bearing compounds. Microsomal stability studies indicated that the trifluoromethoxy group typically decreased
metabolic stability of the corresponding derivatives as compared to either CH3O- or CF3-substituted counterparts, except for N-alkoxy(sulfon)amide
series.
Keywords: Aliphatic compounds, Trifluoromethoxy group, Lipophilicity, Microsomal stability
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1. Introduction
While compounds bearing fluorinated alkyl substituents attached to the carbon atom were widely used in organic synthesis [1–7],
drug discovery [8–15], and agricultural chemistry [16] over decades, fluoroalkoxy moieties were considered exotic for a long time but
have attracted significant interest in recent years. It was found that electronic properties of the CxFyO groups relied on delocalization of
n-electron pairs of oxygen atom into the σ*-orbitals of the adjacent C–F bonds [16–18]. In turn, fluoroalkoxy moieties were found to be
thermally stable, chemically resistant towards acids and bases, common oxidating or reducing agents, as well as organometallic species
[19,20].
To date, application of aromatic CF3O-containing derivatives has been predominating [17,18,21–23]; a number of pharmaceuticals
and agrochemicals bearing this structural motif were introduced into the market, i.e. antituberculosis drug Delamanid (1), anti-
amyotrophic lateral sclerosis agent Riluzole (2), fungicide Thifluzamide (3), insecticide Triflumuron (4), and plant growth regulator
Flurprimidol (5) (Figure 1).
Figure 1. Useful representatives of F3CO-containing aromatic derivatives
In contrast, compounds bearing aliphatic trifluoromethoxy groups are much less abundant [16–18,24]. Common methods for their
synthesis included: oxidative desulfurization-fluorination of xanthates using an oxidant and a fluoride source [25–31] (Scheme 1,
pathway A), trifluoromethylation of alcohols with the Ruppert–Prakash [21,24,32], Togni [33–35], or Umemoto reagents [36] etc.
[20,37,38] (pathway B), trifluoromethoxylation of alkyl halides [39–45], triflates [43,46], or triethoxyalkyl silanes [47] with CF3O
anion source (pathway C), silver-mediated trifluoromethoxylation of α-diazo esters [48] (pathway D), deoxofluorination of
fluoroformates [20] (pathway E); silver-catalyzed oxidative benzylic C-H trifluoromethoxylation [49] (pathway F), addition of CF3OF
to alkenes [50–52] and aziridines [53], or Pd-catalysed oxidative trifluoromethoxylation of allylic C-H bonds [54,55] (pathway G).

Scheme 1. Common approaches to aliphatic CF3O-substituted derivatives
In this work, we aimed to evaluate the effect of introducing a CF3O group into aliphatic compounds on their physico-chemical
properties, e.g. lipophilicity (measured by logarithm of the distribution coefficient between n-octanol and aq buffer, LogP) and kinetic
solubility (precipitation concentration of the compound upon addition of its DMSO solution into aq buffer), and microsomal stability
(the rate of disappearance of the compound in aq buffer over time upon incubation to microsomal liver fraction). It should be noted that
to date, such studies were available only for aromatic CF3O-containing compounds [56]. To achieve the aforementioned goal, we
synthesized simple aliphatic CF3O-containing building blocks 6a–8a (Figure 2) using either known (for 6a) or newly developed (for 7a
and 8a) methods. The obtained building blocks, as well as their CH3O- (6b–8b) and CF3-substituted (6c–8c) counterparts, were used to
synthesize a compound library by standard modifications at the functional groups present in these molecules. Finally, kinetic solubility
in a phosphate buffer, lipophilicity, and microsomal stability were evaluated for the synthesized derivatives.
Figure 2. Simple building blocks 6a–8c studied in this work
2. Results and discussion
Initially, synthesis of the primary amine 7a was attempted to start by alkylation of potassium phthalimide with the commercially
available bromide 9 to form 11. Surprisingly, instead of bromide the trifluoromethoxy group acted as a leaving group, so that instead of
11 derivative 10 was obtained in 52% yield in a mixture with remaining starting bromide 9 (Scheme 2).
Scheme 2. Attempted preparation of phtalimide 11
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Therefore, the required 2-[3-(trifluoromethoxy)propyl]phthalimide (11) was prepared from alcohol 12 analogous to a known
procedure [28] (81% yield), then transformed into 7a via phtalimide hydrazinolysis and isolated as hydrochloride in 61% yield after
recrystallization from MeCN in up to 15 g scale in one run (Scheme 3).
Scheme 3. Synthesis of primary amine 7aHCl
Synthesis of O-alkylhydroxylamine derivative 8a included NaH-mediated alkylation of N-hydroxyphthalimide with commercially
available triflate 13 in DMF at 100 °C to form 14 and subsequent N-deprotection with hydrazine hydrate, leading to the target product
8a as hydrochloride in 51% yield for two steps after recrystallization from MeCN (Scheme 4).
Scheme 4. Synthesis of O-alkyl hydroxylamine 8aHCl
Building blocks 6a–8a, as well as their CF3- and CH3O-substituted counterparts 6b–8b and 6c–8c, respectively, were used to
synthesize a series of model derivatives 15–22 using standard acylation/sulfonylation protocols (see experimental part for details)
(Figure 3). Kinetic solubility [57–59] of all library members in phosphate buffered saline (PBS) was measured at 26.5 °C and pH = 7.4
(Figure 4). The solubility of all synthesized derivatives was found to be approximately 0.4 mM, and influence of the corresponding
substituents was not significant.
Figure 3. Structures of derivatives 15–22

Figure 4. Kinetic solubility of compounds 15–22 in PBS (26.5 °C, pH = 7.4)
Lipophilicity of compounds 15–22 was measured as logarithm of the distribution coefficient between n-octanol and PBS at pH = 7.4
(LogD7.4). According to the obtained results, CF3O-substituted derivatives were significantly (by 0.7–1.4 LogD units) more lipophilic
than the corresponding methoxy-substituted analogues and had nearly equal LogD7.4 values to those of CF3-substituted counterparts
(Figure 5). Similar trends were observed for aromatic CF3O-containing compounds, which were by 0.3–1.3 logD units more lipophilic
as compared to the corresponding anisoles [56].
Figure 5. Logarithm of the distribution coefficient between n-octanol and PBS at pH = 7.4 (LogD7.4) for compounds 15–22.
Microsomal stability of compounds 15–22 was determined by standard method using mouse liver microsomes; the relative parent
compound depletion over 40 min was monitored by high performance liquid chromatography – mass spectrometry (HPLC-MS/MS)
analysis; the results were obtained as percentages of parent compound remaining (Figure 6), half-life times (t1/2) (Figure 7) and intrinsic
clearance (Clint, see the supporting information). The metabolic pathways for the compounds studied are not clear; possible
transformations might include nucleophilic substitution of CF3O moiety (analogously to Scheme 2), as well as microsomal oxidation at
the  or  position to the CF3O group. It was found that the trifluoromethoxy group considerably decreased microsomal stability for
most of the studied compounds (as compared to CH3O- and CF3-substituted counterparts), except N-substituted derivatives of the
corresponding O-alkylhydroxylamines 8 (compounds 19 and 22). This is contrary to stability of the aromatic counterparts where
trifluoromethoxy derivatives had comparable microsomal stability to that of their methoxy analogues [56].
The data of control samples without cofactors indicate that instability of compound 15b is determined by cytochrome P450 enzymes
activity. p-Fluoro-substituted derivatives 16a, 16b, and 16c demonstrated improved microsomal stability as compared to phenyl-
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substituted counterparts 15a–c; therefore, metabolism of the latter might include (at least partial) hydroxylation at the para-position of
the aromatic ring. The data for the control samples without cofactors showed that microsomal degradation of compounds 19a–c and
20a–c bearing N–O bonds proceeded through some non-CYP450 enzymatic activity, possibly hydrolysis and/or reduction.
Figure 6. Amount of compounds 15–22 (%) remaining after incubation for 40 min
3. Conclusions
In this work, effects of the CF3O substituent on the physico-chemical and microsomal properties of aliphatic compounds, namely
kinetic solubility, lipophilicity, and microsomal stability were evaluated and compared to those of CF3 and CH3O groups. Little impact
of the CF3O group was found on the solubility in phosphate buffer at pH = 7.4. On the other hand, this group increased liphophilicity
significantly as compared to methoxy substituent, so that LogD7.4 values of the corresponding derivatives were close to that of CF3-
substituted counterparts. Finally, decreased half-life times were observed for the aliphatic CF3O-substituted compounds in the presence
of rat liver microsomes as compared to both CH3O- and CF3-substituted analogues (except derivatives of O-alkylhydroxylamines); this
is contrary to their aromatic counterparts, which were superior over the corresponding anisoles in terms of microsomal stability.
4. Experimental
4.1. General
The solvents were purified according to standard procedures [60]. All starting materials were purchased from commercial sources.
Analytical TLC was performed using Polychrom SI F254 plates. Column chromatography was performed using silica gel as the
stationary phase. 1H, 13C, and 19F NMR spectra were recorded on a Varian Unity Plus 400 spectrometer (at 400 MHz for Protons, 101
MHz for Carbon-13, and 376 MHz for Fluorine-19). Elemental analyses were performed at the Laboratory of Organic Analysis,
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, their results were found to be in good agreement (±0.4%)
with the calculated values. Mass spectra were recorded on an Agilent 1200 LCMSD SL instrument (chemical ionization (APCI),
electrospray ionization (ESI)) or Agilent 7820A gas chromatograph system (electron impact ionization (EI), ionization energy – 70 eV).
Compounds 6a–c, 7b,7c. 8b and 8c are commercially available and compound 11 was synthesized according to known protocol [19].
Compound 13 was obtained from Enamine Ltd. Kinetic solubility, lipophilicity (LogD7.4), and microsomal stability for the synthesized
derivatives were measured according to the previously published protocols [61,62].

4.2. 3-(Trifluoromethoxy)propan-1-amine hydrochloride (7a)
2-[3-(Trifluoromethoxy)propyl]isoindoline-1,3-dione (11) [28] (32.8 g, 120 mmol) was dissolved in EtOH (300 mL), and hydrazine
hydrate (18.0 g, 360 mmol) was added. The resulting mixture was stirred at 60 °С for 12 h, then cooled to rt, and the precipitate was
filtered off. The filtrate was acidified with 4 M HCl – 1,4-dioxane to pH = 1, and the resulting solution was evaporated in vacuo. The
precipitate was dried in vacuo. Yield: 13.1 g (61% for two steps); yellowish solid; mp 110–112 °C. 1H NMR (400 MHz, DMSO-d6) δ
8.29 (s, 3H), 4.19 (t, J = 6.4 Hz, 2H), 2.91 – 2.78 (m, 2H), 2.00 (quint, J = 6.7 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 121.7 (q, J =
253 Hz), 66.0 (q, J = 3.1 Hz), 35.8, 26.8. 19F NMR (376 MHz, DMSO-d6) δ –59.4 (s). LC/MS (CI): m/z = 144 [M–HCl+H]+. Anal.
Calcd. for C4H9ClF3NO: C 26.76; H 5.05; N 7.80; Cl 19.74. Found: C 26.87; H 4.85; N 7.78; Cl 19.69.
4.3. O-[2-(Trifluoromethoxy)ethyl]hydroxylamine hydrochloride (8a)
NaH (60%, 4.60 g, 115 mmol) was suspended in DMF (200 mL), and the mixture was cooled to 0 °С. N-Hydroxyphtalimide (15.3 g,
94.0 mmol) was added at 0 °С, and the resulting mixture was stirred at rt for 2 h. Then, triflate 13 (26.2 g, 100 mmol) solution in DMF
(50 mL) was added, the resulting mixture was stirred at 100°С for 10 h, then cooled to rt and poured onto H2O (300 mL), and extracted
with t-BuOMe (3150 mL). Combined organic layer was washed with brine (100 mL), H2O (100 mL), dried over Na2SO4 and
evaporated in vacuo. The crude compound was purified by column chromatography using gradient hexanes – EtOAc as eluent to give
14 (24.0 g, 87.2 mmol), which was dissolved in EtOH (250 mL), and hydrazine hydrate (4.36 g, 77.0 mmol) was added. The resulting
mixture was stirred at 70 °С for 4 h, then cooled to rt, and the precipitate was filtered off. Filtrate was acidified with 4M HCl – 1,4-
dioxane to pH = 1, and the resulting solution was evaporated in vacuo. The crude compound was crystallized from MeCN (50 mL).
Yield: 8.70 g (51% for two steps); yellowish solid; mp 165–168 °C. 1H NMR (400 MHz, D2O) δ 4.21 (t, J = 6.1 Hz, 2H), 4.19 (t, J =
6.1 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 121.2 (q, J = 254 Hz), 71.6, 65.4 (q, J = 3.1 Hz). 19F NMR (376 MHz, D2O) δ –61.4 (s).
LC/MS (CI): m/z = 146 [M–HCl+H]+. Anal. Calcd. for C3H7ClF3NO2: C 19.85; H 3.89; N 7.72; Cl 19.53. Found: C 19.94; H 4.24; N
7.70; Cl 19.40.
4.4. General procedure for the preparation of amides 15–17
DCC (1.08 g, 5.25 mmol) was added at 10 °С to a solution of the corresponding aniline (5.00 mmol) in CH2Cl2 (5 mL). Then, the
corresponding acid 7a–7c (5.00 mmol) in CH2Cl2 (2 mL) was added dropwise, and the resulting mixture was astirred at rt for 12 h. The
precipitate was filtered off, and filtrate was evaporated in vacuo. If necessary, amides 15–17 were purified by column chromatography
using gradient t-BuOMe – MeOH as eluent (unless otherwise specified).
4.4.1. N-Phenyl-2-(trifluoromethoxy)acetamide (15a)
Crude compound 15a was purified by HPLC (0.5–6.5 min; MeOH; flow rate: 30 mL / min). Yield: 252 mg (23%); orange solid. 1H
NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 4.58 (s, 2H). 13
C
NMR (151 MHz, CDCl3) δ 162.9, 136.2, 129.1, 125.4, 121.0 (q, J = 258 Hz), 120.3, 65.0 (q, J = 3.2 Hz). 19F NMR (376 MHz, CDCl3)
δ –61.8 (s). LC/MS (CI): m/z = 220 [M+H]+. Anal. Calcd. for C9H8F3NO2: C 49.32; H 3.68; N 6.39. Found: C 48.99; H 3.49; N 6.07.
4.4.2. 3,3,3-Trifluoro-N-phenylpropanamide (15b)
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Yield: 934 mg (92%); white powder. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.37 – 7.25 (m, 2H), 7.15
(t, J = 7.6 Hz, 1H), 3.22 (q, J = 10.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 161.1, 136.3, 128.6, 124.9, 123.5 (q, J = 277 Hz), 120.3,
41.6 (q, J = 29.6 Hz). 19F NMR (376 MHz, CDCl3) δ –63.4 (s). LC/MS (CI): m/z = 204 [M+H]+. Anal. Calcd. for C9H8F3NO: C 53.21;
H 3.97; N 6.89. Found: C 52.82; H 3.64; N 7.01.
4.4.3. 2-Methoxy-N-phenylacetamide (15c)
Yield: 743 mg (90%); reddish oil. 1H NMR (500 MHz, CDCl3) δ 8.25 (s, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.9 Hz, 2H), 7.15
– 7.11 (m, 1H), 4.02 (s, 2H), 3.51 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 167.0, 136.6, 128.5, 124.0, 119.3, 71.6, 58.8. LC/MS (CI):
m/z = 166 [M+H]+. Anal. Calcd. for C9H11NO2: C 65.44; H 6.71; N 8.48. Found: C 65.09; H 6.59; N 8.80.
4.4.4. N-(4-Fluorophenyl)-2-(trifluoromethoxy)acetamide (16a)
Yield: 960 mg (81%); colorless powder. 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.52 (dd, J = 8.5, 4.3 Hz, 2H), 7.06 (t, J = 8.5
Hz, 2H), 4.57 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 162.5, 159.5 (d, J = 245 Hz), 131.7, 121.8 (d, J = 8.0 Hz), 120.4 (q, J = 258 Hz),
115.4 (d, J = 22.7 Hz), 64.5. 19F NMR (376 MHz, CDCl3) δ –61.8 (s, 3F), –116.9 (s, 1F). LC/MS (CI): m/z = 238 [M+H]+. Anal. Calcd.
for C9H7F4NO2: C 45.58; H 2.98; N 5.91. Found: C 45.45; H 3.16; N 6.23.
4.4.5. 3,3,3-Trifluoro-N-(4-fluorophenyl)propanamide (16b)
Yield: 984 mg (89%); colorless powder. 1H NMR (500 MHz, CDCl3) δ 7.55 (s, 1H), 7.44 (dd, J = 8.5, 4.8 Hz, 2H), 7.03 (t, J = 8.5
Hz, 2H), 3.23 (q, J = 10.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 160.3 (q, J = 3.2 Hz), 159.5 (d, J = 245 Hz), 132.2 (d, J = 3.0 Hz),
123.4 (d, J = 277 Hz), 122.0 (d, J = 8.5 Hz), 115.4 (d, J = 22.7 Hz), 42.0 (q, J = 29.7 Hz). 19F NMR (470 MHz, CDCl3) δ –62.8 (t, J =
10.4 Hz, 3F), –116.30 (ddd, J = 13.9, 8.5, 4.8 Hz, 1F). LC/MS (CI): m/z = 222 [M+H]+. Anal. Calcd. for C9H7F4NO: C 48.88; H 3.19; N
6.33. Found: C 49.02; H 3.33; N 6.27.
4.4.6. N-(4-fluorophenyl)-2-methoxyacetamide (16c)
Yield: 797 mg (87%); colorless powder. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.53 (dd, J = 8.8, 4.4 Hz, 2H), 7.02 (t, J = 8.8
Hz, 2H), 4.01 (s, 2H), 3.50 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 166.9, 159.0 (d, J = 244 Hz), 132.6, 121.0 (d, J = 7.9 Hz), 115.2 (d,
J = 22.5 Hz), 71.5, 58.8. 19F NMR (376 MHz, CDCl3) δ –118.3 (s). LC/MS (CI): m/z = 184 [M+H]+. Anal. Calcd. for C9H10FNO2: C
59.01; H 5.50; N 7.65. Found: C 59.34; H 5.16; N 7.91.
4.4.7. N-Methyl-N-phenyl-2-(trifluoromethoxy)acetamide (17a)
Yield: 641 mg (55%); orange oil. 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.37 (m, 3H), 7.20 (d, J = 6.9 Hz, 2H), 4.25 (s, 2H), 3.31 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 164.0, 141.0, 129.8, 128.4, 126.5, 120.9 (q, J = 256 Hz), 63.3, 37.1. 19F NMR (376 MHz, CDCl3) δ
–61.6 (s). LC/MS (CI): m/z = 234 [M+H]+. Anal. Calcd. for C10H10F3NO2: C 51.51; H 4.32; N 6.01. Found: C 51.14; H 4.54; N 6.06.
4.4.8. 3,3,3-Trifluoro-N-methyl-N-phenylpropanamide (17b)
Yield: 880 mg (81%); colorless powder. 1H NMR (500 MHz, CDCl3) δ 7.47 (t, J = 7.5 Hz, 2H), 7.44 – 7.36 (m, 1H), 7.21 (d, J = 7.5
Hz, 2H), 3.31 (s, 3H), 2.96 (q, J = 10.1 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 163.1, 142.9, 130.2, 128.6, 127.2, 123.9 (q, J = 276

Hz), 38.1 (q, J = 29.2 Hz), 37.5. 19F NMR (376 MHz, CDCl3) δ –63.1 (s). LC/MS (CI): m/z = 218 [M+H]+. Anal. Calcd. for
C10H10F3NO: C 55.30; H 4.64; N 6.45. Found: C 55.22; H 4.75; N 6.41.
4.4.9. 2-Methoxy-N-methyl-N-phenylacetamide (17c)
Yield: 699 mg (78%); greyish solid. 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.32 (m, 3H), 7.18 (d, J = 7.6 Hz, 2H), 3.77 (s, 2H), 3.32
(s, 3H), 3.27 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.5, 142.0, 129.4, 127.7, 126.6, 70.0, 58.7, 36.8. LC/MS (CI): m/z = 180
[M+H]+. Anal. Calcd. for C10H13NO2: C 67.02; H 7.31; N 7.82. Found: C 67.01; H 6.91; N 7.73.
4.5. General procedure for the preparation of benzamides 18–20
Et3N (767 μL, 556 mg, 5.50 mmol) was added to a solution of the corresponding amine 7 or hydroxylamine 8 (5.00 mmol) in CH2Cl2
(5 mL), and the corresponding chloroanhydride (5.00 mmol) was added dropwise at 10 °С. The resulting mixture was stirred at rt for 10
h, then H2O (10 mL) was added, and organic phase was separated. Aqueous phase was extracted with CH2Cl2 (210 mL), combined
organic layers were washed with brine (10 mL), H2O (10 mL) , dried over Na2SO4 and evaporated in vacuo. If necessary, amides 18–20
were purified by column chromatography using gradient CH2Cl2 – MeOH as eluent (unless otherwise specified).
4.5.1. N-[3-(Trifluoromethoxy)propyl]benzamide (18a)
Yield: 1.01 g (82%); orange powder. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.1 Hz, 2H), 7.54 – 7.47 (m, 1H), 7.44 (t, J = 7.1
Hz, 2H), 6.42 (s, 1H), 4.10 (t, J = 6.0 Hz, 2H), 3.59 (q, J = 6.4 Hz, 2H), 2.05 (p, J = 6.4 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 167.2,
133.8, 131.1, 128.1, 126.3, 121.1 (q, J = 255 Hz), 65.0, 36.4, 28.1. 19F NMR (376 MHz, CDCl3) δ –61.3 (s). LC/MS (CI): m/z = 248
[M+H]+. Anal. Calcd. for C11H12F3NO2: C 53.44; H 4.89; N 5.67. Found: C 53.42; H 4.76; N 5.81.
4.5.2. N-(4,4,4-Trifluorobutyl)benzamide (18b)
Yield: 809 mg (70%); yellowish powder. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.6 Hz, 2H), 7.54 – 7.44 (m, 1H), 7.40 (t, J =
7.6 Hz, 2H), 6.61 (s, 1H), 3.50 (q, J = 6.7 Hz, 2H), 2.25 – 2.07 (m, 2H), 1.87 (p, J = 7.3 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 167.4,
133.8, 131.1, 128.1, 126.5 (q, J = 276 Hz), 126.4, 38.3, 30.8 (q, J = 29.1 Hz), 22.0 (d, J = 2.9 Hz). 19F NMR (376 MHz, CDCl3) δ –66.7
(s). LC/MS (CI): m/z = 232 [M+H]+. Anal. Calcd. for C11H12F3NO: C 57.14; H 5.23; N 6.06. Found: C 57.47; H 4.87; N 6.28.
4.5.3. N-(3-Methoxypropyl)benzamide (18c)
Yield: 879 mg (91%); yellowish oil. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.2 Hz, 2H), 7.51 – 7.45 (m, 1H), 7.41 (t, J = 7.2 Hz,
2H), 6.98 (s, 1H), 3.58 – 3.54 (m, 4H), 3.37 (s, 3H), 1.88 (p, J = 5.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 167.2, 134.8, 131.2, 128.5,
126.8, 72.3, 58.9, 39.1, 28.9. LC/MS (CI): m/z = 194 [M+H]+. Anal. Calcd. for C11H15NO2: C 68.37; H 7.82; N 7.25. Found: C 68.68; H
7.66; N 7.14.
4.5.4. N-[2-(Trifluoromethoxy)ethoxy]benzamide (19a)
Crude compound 19a was purified by HPLC (0.5–6.5 min; MeOH; flow rate: 30 mL / min). Yield: 411 mg (33%); white powder. 1H
NMR (500 MHz, CDCl3) δ 9.19 (s, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 4.32 – 4.28 (m, 2H),
4.27 – 4.24 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 167.0, 132.2, 128.7,127.0, 126.9, 121.5 (q, J = 255 Hz), 73.4, 65.0 (q, J = 3.6 Hz).
9

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Journal of Fluorine Chemistry
19F NMR (376 MHz, CDCl3) δ –61.5 (s). LC/MS (CI): m/z = 250 [M+H]+. Anal. Calcd. for C10H10F3NO3: C 48.20; H 4.05; N 5.62.
Found: C 48.12; H 4.20; N 6.01.
4.5.5. N-(3,3,3-Trifluoropropoxy)benzamide (19b)
Yield: 734 mg (63%); colorless powder. 1H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.2 Hz,
1H), 7.45 (t, J = 7.6 Hz, 2H), 4.28 (t, J = 6.5 Hz, 2H), 2.59 (qt, J = 10.7, 6.5 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 167.2, 132.4,
131.4, 128.8, 127.0, 125.8 (q, J = 276 Hz), 69.4, 33.0 (q, J = 29.4 Hz). 19F NMR (470 MHz, CDCl3) δ –64.6 (t, J = 10.7 Hz, s). LC/MS
(CI): m/z = 234 [M+H]+. Anal. Calcd. for C10H10F3NO2: C 51.51; H 4.32; N 6.01. Found: C 51.42; H 4.65; N 5.68.
4.5.6. N-(2-Methoxyethoxy)benzamide (19c)
Yield: 673 mg (69%); colorless powder. 1H NMR (500 MHz, CDCl3) δ 9.19 (s, 1H), 7.74 (d, J = 7.7 Hz, 2H), 7.56 – 7.49 (m, 1H),
7.44 (t, J = 7.7 Hz, 2H), 4.28 – 4.13 (m, 2H), 3.76 – 3.66 (m, 2H), 3.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 132.0, 132.0, 128.7,
127.0, 75.3, 71.4, 59.1. LC/MS (CI): m/z = 196 [M+H]+. Anal. Calcd. for C10H13NO3: C 61.53; H 6.71; N 7.18. Found: C 61.77; H 6.51;
N 6.97.
4.5.7. 4-Fluoro-N-[2-(trifluoromethoxy)ethoxy]benzamide (20a)
Yield: 347 mg (26%); colorless powder. 1H NMR (500 MHz, CDCl3) δ 9.04 (s, 1H), 7.78 (dd, J = 8.4, 5.2 Hz, 2H), 7.13 (t, J = 8.4
Hz, 2H), 4.33 – 4.28 (m, 2H), 4.28 – 4.24 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 165.1 (d, J = 259 Hz), 129.5 (d, J = 19.3 Hz), 127.5,
121.5 (q, J = 255 Hz), 115.9 (d, J = 22.0 Hz), 73.7, 65.0. 19F NMR (376 MHz, CDCl3) δ –61.5 (s, 3F), –106.7 (s, 1F). LC/MS (CI): m/z
= 268 [M+H]+. Anal. Calcd. for C10H9F4NO3: C 44.95; H 3.40; N 5.24. Found: C 44.91; H 3.44; N 4.84.
4.5.8. 4-Fluoro-N-(3,3,3-trifluoropropoxy)benzamide (20b)
Yield: 1.13 g (90%); yellowish solid. 1H NMR (500 MHz, CDCl3) δ 8.72 (s, 1H), 7.76 (dd, J = 8.7, 5.2 Hz, 2H), 7.14 (t, J = 8.7 Hz,
2H), 4.27 (t, J = 6.6 Hz, 2H), 2.59 (qt, J = 10.7, 6.6 Hz, 2H). 13C NMR (126 MHz, CDCl3) δ 162.8 (d, J = 253 Hz), 129.0 (d, J = 9.1
Hz), 127.5 (d, J = 8.7 Hz), 122.9 – 120.6 (m), 115.5 (d, J = 22.0 Hz), 69.0, 32.5 (q, J = 29.4 Hz). 19F NMR (470 MHz, CDCl3) δ –64.6
(t, J = 10.7 Hz, 3F), –106.0 (s, 1F). LC/MS (CI): m/z = 252 [M+H]+. Anal. Calcd. for C10H9F4NO2: C 47.82; H 3.61; N 5.58. Found: C
48.16; H 3.23; N 5.75.
4.5.9. 4-Fluoro-N-(2-methoxyethoxy)benzamide (20c)
Yield: 565 mg (53%); colorless powder. 1H NMR (500 MHz, CDCl3) δ 9.54 (s, 1H), 7.76 (dd, J = 8.6, 5.4 Hz, 2H), 7.08 (t, J = 8.6
Hz, 2H), 4.21 – 4.15 (m, 2H), 3.72 – 3.67 (m, 2H), 3.38 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 164.4 (d, J = 253 Hz), 129.0 (d, J = 6.8
Hz), 127.5 (d, J = 8.6 Hz), 115.2 (d, J = 21.9 Hz), 74.6, 70.7, 58.5. 19F NMR (376 MHz, CDCl3) δ –107.6 (s). LC/MS (CI): m/z = 214
[M+H]+. Anal. Calcd. for C10H12FNO3: C 56.33; H 5.67; N 6.57. Found: C 56.32; H 5.79; N 6.30.
4.6. General procedure for the preparation of sulfonamides 21 and 22
PhSO2Cl (883 mg, 5.00 mmol) was added to a solution of the corresponding amine 7 or hydroxylamine 8 (5.00 mmol) in pyridine (5
mL). The resulting mixture was stirred at 60 °C for 2 h, then cooled to rt and evaporated in vacuo. Then, H2O (10 mL) was added to the

residue, aqueous phase was extracted with EtOAc (210 mL), and combined organic layers were washed with brine (10 mL), H2O (10
mL) , dried over Na2SO4 and evaporated in vacuo. If necessary, sulfonamides 21 and 22 were purified by column chromatography using
gradient CH2Cl2 – MeOH as eluent (unless otherwise specified).
4.6.1. N-[3-(Trifluoromethoxy)propyl]benzenesulfonamide (21a)
Crude compound 21a was purified by HPLC (0.5–6.5 min; MeOH; flow rate: 30 mL / min). Yield: 524 mg (37%); white solid. 1H
NMR (500 MHz, CDCl3) δ 7.89 (d, J = 7.4 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.4 Hz, 2H), 4.93 (t, J = 6.3 Hz, 1H), 4.01 (t, J
= 6.0 Hz, 2H), 3.10 (q, J = 6.5 Hz, 2H), 1.89 (p, J = 6.3 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 139.6, 132.8, 129.2, 127.0, 121.4 (q, J
= 255 Hz), 64.4 (q, J = 3.2 Hz), 39.6, 28.9. 19F NMR (376 MHz, CDCl3) δ –61.4 (s). LC/MS (CI): m/z = 284 [M+H]+. Anal. Calcd. for
C10H12F3NO3S: C 42.40; H 4.27; N 4.94; S 11.32. Found: C 42.47; H 4.32; N 4.60; S 11.70.
4.6.2. N-(4,4,4-Trifluorobutyl)benzenesulfonamide (21b)
Yield: 1.08 g (81%); orange powder. 1H NMR (400 MHz, CDCl3) δ 7.89 – 7.81 (m, 2H), 7.64 – 7.55 (m, 1H), 7.54 – 7.47 (m, 2H),
4.93 (s, 1H), 3.03 – 2.99 (m, 2H), 2.15 – 2.07 (m, 2H), 1.72 (p, J = 6.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 139.6, 132.9, 129.3,
126.9, 126.8 (d, J = 276 Hz), 41.9, 30.8 (q, J = 29.2 Hz), 22.5 (q, J = 2.8 Hz). 19F NMR (376 MHz, CDCl3) δ –66.7 (s). LC/MS (CI):
m/z = 268 [M+H]+. Anal. Calcd. for C10H12F3NO2S: C 44.94; H 4.53; N 5.24; S 12.00. Found: C 45.34; H 4.57; N 5.02; S 12.14.
4.6.3. N-(3-Methoxypropyl)benzenesulfonamide (21c)
Yield: 929 mg (81%); yellowish oil.1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.3 Hz, 2H), 7.65 – 7.54 (m, 1H), 7.51 (t, J = 7.3 Hz,
2H), 5.22 (t, J = 5.6 Hz, 1H), 3.39 (t, J = 5.6 Hz, 2H), 3.27 (s, 3H), 3.07 (q, J = 6.0 Hz, 2H), 1.70 (p, J = 6.0 Hz, 2H). 13C NMR (126
MHz, CDCl3) δ 139.5, 132.0, 128.5, 126.5, 71.0, 58.3, 41.6, 28.4. LC/MS (CI): m/z = 230 [M+H]+. Anal. Calcd. for C10H15NO3S: C
52.38; H 6.59; N 6.11; S 13.98. Found: C 51.98; H 6.76; N 6.02; S 13.98.
4.6.4. N-[2-(Trifluoromethoxy)ethoxy]benzenesulfonamide (22a)
Yield: 970 mg (68%); brownish solid. 1H NMR (500 MHz, CDCl3) δ 8.02 – 7.89 (m, 2H), 7.72 – 7.67 (m, 1H), 7.59 (t, J = 7.6 Hz,
2H), 7.04 (s, 1H), 4.29 – 4.25 (m, 2H), 4.22 – 4.18 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 135.6, 133.6, 128.7, 128.1, 121.0 (q, J =
255 Hz), 73.6, 63.7 (q, J = 3.0 Hz). 19F NMR (470 MHz, CDCl3) δ –61.0 (s). LC/MS (CI): m/z = 286 [M+H]+. Anal. Calcd. for
C9H10F3NO4S: C 37.90; H 3.53; N 4.91; S 11.24. Found: C 38.16; H 3.91; N 5.03; S 11.49.
4.6.5. N-(3,3,3-Trifluoropropoxy)benzenesulfonamide (22b)
Yield: 1.01 g (75%); yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 2H), 7.70 – 7.63 (m, 1H), 7.55 (t, J = 7.7 Hz,
2H), 7.04 (s, 1H), 4.22 (td, J = 6.2, 1.5 Hz, 2H), 2.54 – 2.42 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 136.2, 134.1, 129.2, 128.5, 125.7
(q, J = 277 Hz), 69.8 (q, J = 3.1 Hz), 32.7 (q, J = 28.9 Hz). 19F NMR (376 MHz, CDCl3) δ –65.1 (s). LC/MS (CI): m/z = 268 [M–H]–.
Anal. Calcd. for C9H10F3NO3S: C 40.15; H 3.74; N 5.20; S 11.91. Found: C 40.49; H 3.70; N 5.44; S 11.95.
11

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Journal of Fluorine Chemistry
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
Acknowledgements
This work has been supported by the Deutsche Forschungsgemeinschaft (Ha 2145/9-2; AOBJ: 560896). O.O.G. was also funded by
Ministry of Education and Science of Ukraine (Grant No. 19BF037-03). The authors thank Mr. Yurii Kheylik for measurements of
microsomal stability, Dr. Sergey Zozulya and Dr. Volodymyr Iurchenko for management of ADME services, and Prof. Andrey
Tolmachev for his encouragement and support.

References and notes
[1]
[2]
R.D. Chambers, Fluorine in Organic Chemistry, Blackwell Publishing Ltd., Oxford, UK, 2004. doi:10.1002/9781444305371.
B.A. Chalyk, K. V. Hrebeniuk, Y. V. Fil, K.S. Gavrilenko, A.B. Rozhenko, B. V. Vashchenko, O. V. Borysov, A. V. Biitseva, P.S. Lebed, I.
Bakanovych, Y.S. Moroz, O.O. Grygorenko, Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized
Halogenoximes, J. Org. Chem. 84 (2019) 15877–15899. doi:10.1021/acs.joc.9b02264.
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
O. V. Geraschenko, V. V. Solomin, B. V. Vashchenko, P. Khodakivskyi, A.A. Tolmachev, O.O. Grygorenko, Synthesis and chemical transformations
of diazolyl α,α-difluoroacetates, J. Fluorine Chem. 229 (2020) 109407. doi:10.1016/j.jfluchem.2019.109407.
P.S. Nosik, S. V. Ryabukhin, O.O. Grygorenko, D.M. Volochnyuk, Transition Metal-free gem-difluorocyclopropanation of Alkenes with CF3SiMe3
−NaI System: a Recipe for Electron-deficient Substrates, Adv. Synth. Catal. 360 (2018) 4104–4114. doi:10.1002/adsc.201801006.
P.S. Nosik, S. V Ryabukhin, M.O. Pashko, G.P. Grabchuk, O.O. Grygorenko, D.M. Volochnyuk, Synthesis of 1-hetaryl-2,2-difluorocyclopropane-
derived building blocks: The case of pyrazoles, J. Fluorine Chem. 217 (2019) 80–89. doi:10.1016/j.jfluchem.2018.11.006.
P.S. Nosik, A.O. Gerasov, R.O. Boiko, E. Rusanov, S. V. Ryabukhin, O.O. Grygorenko, D.M. Volochnyuk, Gram-Scale Synthesis of Amines Bearing
a gem-Difluorocyclopropane Moiety, Adv. Synth. Catal. 359 (2017) 3126–3136. doi:10.1002/adsc.201700857.
K. Melnykov, D. Granat, D. Volochnyuk, S. Ryabukhin, O. Grygorenko, Multigram Synthesis of C4/C5 3,3-Difluorocyclobutyl-Substituted Building
Blocks, Synthesis. 50 (2018) 4949–4957. doi:10.1055/s-0037-1610237.
W. Zhu, J. Wang, S. Wang, Z. Gu, J.L. Aceña, K. Izawa, H. Liu, V.A. Soloshonok, Recent advances in the trifluoromethylation methodology and new
CF3-containing drugs, J. Fluorine Chem. 167 (2014) 37–54. doi:10.1016/j.jfluchem.2014.06.026.
H. Mei, J. Han, K.D. Klika, K. Izawa, T. Sato, N.A. Meanwell, V.A. Soloshonok, Applications of fluorine-containing amino acids for drug design, Eur.
J. Med. Chem. 186 (2020) 111826. doi:10.1016/j.ejmech.2019.111826.
H. Mei, J. Han, S. Fustero, M. Medio‐Simon, D.M. Sedgwick, C. Santi, R. Ruzziconi, V.A. Soloshonok, Fluorine‐Containing Drugs Approved by the
FDA in 2018, Chem. – A Eur. J. 25 (2019) 11797–11819. doi:10.1002/chem.201901840.
G. Haufe, F.R. Leroux, Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals, Progress in Fluorine Science Series,
2019.
[12]
[13]
S. Swallow, Fluorine in Medicinal Chemistry, in: Prog. Med. Chem., 1st ed., Elsevier B.V., 2015: pp. 65–133. doi:10.1016/bs.pmch.2014.11.001.
E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, Applications of Fluorine in Medicinal Chemistry, J. Med. Chem. 58 (2015) 8315–
8359. doi:10.1021/acs.jmedchem.5b00258.
[14]
[15]
S. Swallow, Fluorine in medicinal chemistry, Prog. Med. Chem. 54 (2015) 65–133. doi:10.1016/bs.pmch.2014.11.001.
J. Wang, M. Sánchez-Roselló, J.L. Aceña, C. Del Pozo, A.E. Sorochinsky, S. Fustero, V.A. Soloshonok, H. Liu, Fluorine in pharmaceutical industry:
Fluorine-containing drugs introduced to the market in the last decade (2001-2011), Chem. Rev. 114 (2014) 2432–2506. doi:10.1021/cr4002879.
P. Jeschke, E. Baston, F.R. Leroux, Alpha-Fluorinated Ethers As “Exotic” Entity in Medicinal Chemistry., Mini Rev. Med. Chem. 7 (2007) 1027–
1034. doi:10.2174/138955707782110150.
[16]
[17]
[18]
F. Leroux, P. Jeschke, M. Schlosser, α-Fluorinated ethers, thioethers, and amines: Anomerically biased species, Chem. Rev. 105 (2005) 827–856.
doi:10.1021/cr040075b.
F.R. Leroux, B. Manteau, J.P. Vors, S. Pazenok, Trifluoromethyl ethers - Synthesis and properties of an unusual substituent, Beilstein J. Org. Chem. 4
(2008). doi:10.3762/bjoc.4.13.
[19]
[20]
[21]
W.A. Sheppard, α-Fluorinated Ethers. I. Aryl Fluoroalkyl Ethers 1, J. Org. Chem. 29 (1964) 1–11. doi:10.1021/jo01024a001.
P.E. Aldrich, W.A. Sheppard, α-Fluorinated Ethers. II. Alkyl Fluoroalkyl Ethers 1, J. Org. Chem. 29 (1964) 11–15. doi:10.1021/jo01024a002.
T. Besset, P. Jubault, X. Pannecoucke, T. Poisson, New entries toward the synthesis of OCF3-containing molecules, Org. Chem. Front. 3 (2016) 1004–
13

14
Journal of Fluorine Chemistry
1010. doi:10.1039/c6qo00164e.
[22]
[23]
[24]
G.A. Olah, T. Yamato, T. Hashimoto, J.G. Shih, N. Trivedi, B.P. Singh, M. Piteau, J.A. Olah, Electrophilic Nitration, Halogenation, Acylation, and
Alkylation of α,α,α-Trifluoromethoxybenzenela, J. Am. Chem. Soc. 109 (1987) 3708–3713. doi:10.1021/ja00246a030.
A. Liang, S. Han, Z. Liu, L. Wang, J. Li, D. Zou, Y. Wu, Y. Wu, Regioselective Synthesis of N-Heteroaromatic Trifluoromethoxy Compounds by
Direct O-CF3 Bond Formation, Chem. Eur. J. 22 (2016) 5102–5106. doi:10.1002/chem.201505181.
Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J.L. Acenã, V.A. Soloshonok, K. Izawa, H. Liu, Next Generation of Fluorine-Containing Pharmaceuticals,
Compounds Currently in Phase II-III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas, Chem. Rev.
116 (2016) 422–518. doi:10.1021/acs.chemrev.5b00392.
[25]
[26]
T. Inoue, C. Fuse, S. Hara, Synthesis of trifluoromethyl ethers and difluoro(methylthio)methyl ethers by the reaction of dithiocarbonates with IF5-
pyridine-HF, J. Fluorine Chem. 179 (2015) 48–52. doi:10.1016/j.jfluchem.2015.04.016.
I. S. Kondratov, I.G. Logvinenko, N.A. Tolmachova, R.N. Morev, M.A. Kliachyna, F. Clausen, C.G. Daniliuc, G. Haufe, Synthesis and physical
chemical properties of 2-amino-4-(trifluoromethoxy)butanoic acid-a CF3O-containing analogue of natural lipophilic amino acids, Org. Biomol. Chem.
15 (2017) 672–679. doi:10.1039/c6ob02436j.
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
J.C. Blazejewski, E. Anselmi, C. Wakselman, 2-Trifluoromethoxyethyl triflate: A versatile trifluoromethoxyethyl carrier, J. Org. Chem. 66 (2001)
1061–1063. doi:10.1021/jo005701t.
T.M. Sokolenko, M.I. Dronkina, E. Magnier, L.M. Yagupolskii, Y.L. Yagupolskii, Evaluation of efficient and practical methods for the preparation of
functionalized aliphatic trifluoromethyl ethers, Molecules. 22 (2017). doi:10.3390/molecules22050804.
R. Zriba, E. Magnier, J.C. Blazejewski, Preparation and reactivity of some new keto- and styrene-based trifluoromethoxylated synthons, Synlett. (2009)
1131–1135. doi:10.1055/s-0028-1088155.
K. Kanie, Y. Tanaka, K. Suzuki, M. Kuroboshi, T. Hiyama, A convenient synthesis of trifluoromethyl ethers by oxidative desulfurization-fluorination
of dithiocarbonates, Bull. Chem. Soc. Jpn. 73 (2000) 471–484. doi:10.1246/bcsj.73.471.
I. Ben-David, D. Rechavi, E. Mishani, S. Rozen, A novel synthesis of trifluoromethyl ethers via xanthates, utilizing BrF3, J. Fluorine Chem. 97 (1999)
75–78. doi:10.1016/S0022-1139(99)00031-7.
J.B. Liu, C. Chen, L. Chu, Z.H. Chen, X.H. Xu, F.L. Qing, Silver-Mediated Oxidative Trifluoromethylation of Phenols: Direct Synthesis of Aryl
Trifluoromethyl Ethers, Angew. Chem. Int. Ed. 54 (2015) 11839–11842. doi:10.1002/anie.201506329.
J. Charpentier, N. Fru, A. Togni, Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents, Chem. Rev. 115 (2015) 650−682.
doi:10.1021/cr500223h.
K. Stanek, R. Koller, A. Togni, Reactivity of a 10-I-3 hypervalent iodine trifluoromethylation reagent with phenols, J. Org. Chem. 73 (2008) 7678–
7685. doi:10.1021/jo8014825.
R. Koller, K. Stanek, D. Stolz, R. Aardoom, K. Niedermann, A. Togni, Zinc-mediated formation of trifluoromethyl ethers from alcohols and
hypervalent iodine trifluoromethylation reagents, Angew. Chem. Int. Ed. 48 (2009) 4332–4336. doi:10.1002/anie.200900974.
T. Umemoto, K. Adachi, S. Ishihara, CF3 Oxonium Salts, O-(Trifluoromethyl)dibenzofuranium Salts: In Situ Synthesis, Properties, and Application as
a Real CF3+ Species Reagent, J. Org. Chem. 72 (2007) 6905–6917. doi:10.1021/jo070896r.
S. Chen, Y. Huang, X. Fang, H. Li, Z. Zhang, T.S.A. Hor, Z. Weng, Aryl-BIAN-ligated silver(i) trifluoromethoxide complex, Dalt. Trans. 44 (2015)
19682–19686. doi:10.1039/c5dt02078f.
X. Jiang, Z. Deng, P. Tang, Direct Dehydroxytrifluoromethoxylation of Alcohols, Angew. Chem. Int. Ed. 57 (2018) 292–295.
doi:10.1002/anie.201711050.
O. Marrec, T. Billard, J.P. Vors, S. Pazenok, B.R. Langlois, A new and direct trifluoromethoxylation of aliphatic substrates with 2,4-
dinitro(trifluoromethoxy)benzene, Adv. Synth. Catal. 352 (2010) 2831–2837. doi:10.1002/adsc.201000488.

[40]
[41]
[42]
[43]
[44]
[45]
[46]
O. Marrec, T. Billard, J.P. Vors, S. Pazenok, B.R. Langlois, A deeper insight into direct trifluoromethoxylation with trifluoromethyl triflate, J. Fluorine
Chem. 131 (2010) 200–207. doi:10.1016/j.jfluchem.2009.11.006.
T.M. Sokolenko, Y.A. Davydova, Y.L. Yagupolskii, Efficient synthesis of 5′-fluoroalkoxythiazoles via α-bromo-α-fluoroalkoxyacetophenones
Hantzsch type cyclization with thioureas or thioamides, J. Fluorine Chem. 136 (2012) 20–25. doi:10.1016/j.jfluchem.2012.01.005.
J. Barbion, S. Pazenok, J.P. Vors, B.R. Langlois, T. Billard, Multigram laboratory scale synthesis of α-trifluoromethoxy carbonyl compounds, Org.
Process Res. Dev. 18 (2014) 1037–1040. doi:10.1021/op500118r.
A.A. Kolomeitsev, M. Vorobyev, H. Gillandt, Versatile application of trifluoromethyl triflate, Tetrahedron Lett. 49 (2008) 449–454.
doi:10.1016/j.tetlet.2007.11.105.
W. Huang, X. Wan, Q. Shen, Enantioselective Construction of Trifluoromethoxylated Stereogenic Centers by a Nickel-Catalyzed Asymmetric Suzuki–
Miyaura Coupling of Secondary Benzyl Bromides, Angew. Chem. Int. Ed. 56 (2017) 11986–11989. doi:10.1002/anie.201706868.
M. Zhou, C. Ni, Y. Zeng, J. Hu, Trifluoromethyl Benzoate: A Versatile Trifluoromethoxylation Reagent, J. Am. Chem. Soc. 140 (2018) 6801–6805.
doi:10.1021/jacs.8b04000.
N.A. Powell, F.L. Ciske, C. Cai, D.D. Holsworth, K. Mennen, C.A. Van Huis, M. Jalaie, J. Day, M. Mastronardi, P. McConnell, I. Mochalkin, E.
Zhang, M.J. Ryan, J. Bryant, W. Collard, S. Ferreira, C. Gu, R. Collins, J.J. Edmunds, Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-
3-ones as small molecule renin inhibitors, Bioorg. Med. Chem. 15 (2007) 5912–5949. doi:10.1016/j.bmc.2007.05.069.
F. Wang, P. Xu, F. Cong, P. Tang, Silver-mediated oxidative functionalization of alkylsilanes, Chem. Sci. 9 (2018) 8836–8841.
doi:10.1039/c8sc03730b.
[47]
[48]
[49]
G.F. Zha, J. Bin Han, X.Q. Hu, H.L. Qin, W.Y. Fang, C.P. Zhang, Silver-mediated direct trifluoromethoxylation of α-diazo esters: via the-OCF3 anion,
Chem. Commun. 52 (2016) 7458–7461. doi:10.1039/c6cc03040h.
H. Yang, F. Wang, X. Jiang, Y. Zhou, X. Xu, P. Tang, Silver-Promoted Oxidative Benzylic C−H Trifluoromethoxylation, Angew. Chem. Int. Ed. 57
(2018) 13266–13270. doi:10.1002/anie.201807144.
[50]
[51]
A. Sekiya, K. Ueda, Synthesis of Perfluoroethylmethylether by Direct Fluorination, Chem. Lett. 19 (1990) 609–612. doi:10.1246/cl.1990.609.
J.A.C. Allison, G.H. Cady, Reactions of Trifluoromethyl Hypofluorite with Organic Compounds, J. Am. Chem. Soc. 81 (1959) 1089–1091.
doi:10.1021/ja01514a018.
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
K.K. Johri, D.D. DesMarteau, Comparison of the Reactivity of CF3OX (X = Cl, F) with Some Simple Alkenes, J. Org. Chem. 48 (1983) 242–250.
doi:10.1021/jo00150a019.
M. Seguin, J.C. Adenis, C. Michaud, J.J. Basselier, Action de CF3OF sur des aziridines N-substituees, J. Fluorine Chem. 15 (1980) 201–211.
doi:10.1016/S0022-1139(00)82576-2.
X. Qi, P. Chen, G. Liu, Catalytic Oxidative Trifluoromethoxylation of Allylic C−H Bonds Using a Palladium Catalyst, Angew. Chem. Int. Ed. 56
(2017) 9517–9521. doi:10.1002/anie.201703841.
C. Chen, Y. Luo, L. Fu, P. Chen, Y. Lan, G. Liu, Palladium-Catalyzed Intermolecular Ditrifluoromethoxylation of Unactivated Alkenes: CF3O-
Palladation Initiated by Pd(IV), J. Am. Chem. Soc. 140 (2018) 1207–1210. doi:10.1021/jacs.7b11470.
L. Xing, D.C. Blakemore, A. Narayanan, R. Unwalla, F. Lovering, R.A. Denny, H. Zhou, M.E. Bunnage, Fluorine in drug design: A case study with
fluoroanisoles, ChemMedChem. 10 (2015) 715–726. doi:10.1002/cmdc.201402555.
X. Jiang, Z. Deng, P. Tang, Direct Dehydroxytrifluoromethoxylation of Alcohols, Angew. Chem. Int. Ed. 57 (2018) 292–295.
doi:10.1002/anie.201711050.
E. Maes, V. Nikolaev, M. Patek, Kinetic Solubility: Measurement and Data Processing, (2017). http://www.virscidian.com/workflows/medicinal-
chemistry/automated-compound-qc/.
C. Saal, A.C. Petereit, Optimizing solubility: Kinetic versus thermodynamic solubility temptations and risks, Eur. J. Pharm. Sci. 47 (2012) 589–595.
doi:10.1016/j.ejps.2012.07.019.
15

16
Journal of Fluorine Chemistry
[60]
[61]
W.L.F. Armarego, Purification of Laboratory Chemicals Eighth Edition, 2008.
M. Krasavin, A. Lukin, D. Bagnyukova, N. Zhurilo, I. Zahanich, S. Zozulya, J. Ihalainen, M.M. Forsberg, M. Lehtonen, J. Rautio, D. Moore, I.G.
Tikhonova, Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835, Bioorg. Med. Chem. 24 (2016)
5481–5494. doi:10.1016/J.BMC.2016.09.004.
[62]
M. Krasavin, A. Lukin, N. Zhurilo, A. Kovalenko, I. Zahanich, S. Zozulya, D. Moore, I.G. Tikhonova, Novel free fatty acid receptor 1 (GPR40)
agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold, Bioorg. Med. Chem. 24 (2016) 2954–2963. doi:10.1016/J.BMC.2016.04.065.