Ammonium Chloride-Mediated Trifluoromethylthiolation of p-Quinone Methides

Article abstract of DOI:10.1021/acs.joc.0c01752

Ammonium chloride-mediated trifluoromethylthiolation of p-quinone methides is reported using inexpensive and bench stable AgSCF3 as a nucleophilic trifluoromethylthiolating (-SCF3) reagent. This method is an efficient strategy for the construction of the benzylic C(sp3)-SCF3 bond to synthesize trifluoromethylthio-diarylmethane derivatives by 1,6-conjugate addition/aromatization under mild reaction conditions without any metal catalyst, oxidants, or additives. This is the first report of trifluoromethylthiolation of p-quinone methides. In addition, di-trifluoromethylthiolation of δ-chloro-p-quinone methide and scalability are demonstrated.

Full text of DOI:10.1021/acs.joc.0c01752

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Ammonium Chloride-Mediated Trifluoromethylthiolation of
p‑Quinone Methides
Debabrata Das, Krishna Gopal Ghosh, Palasetty Chandu, and Devarajulu Sureshkumar*
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ABSTRACT: Ammonium chloride-mediated trifluoromethylthiolation of p-quinone methides is reported using inexpensive and
bench stable AgSCF3 as a nucleophilic trifluoromethylthiolating (-SCF3) reagent. This method is an efficient strategy for the
construction of the benzylic C(sp3)−SCF3 bond to synthesize trifluoromethylthio-diarylmethane derivatives by 1,6-conjugate
addition/aromatization under mild reaction conditions without any metal catalyst, oxidants, or additives. This is the first report of
trifluoromethylthiolation of p-quinone methides. In addition, di-trifluoromethylthiolation of δ-chloro-p-quinone methide and
scalability are demonstrated.
n recent years, fluorinated functionalities (like -SCF3, -CF3,
-CF2CO2Et, etc.) are of considerable interest in pharma-
natural products and drug molecules.6 p-QMs consist of a
zwitterionic resonance structure of a cyclohexadiene moiety in
para conjugation with a carbonyl group that enhances the
electrophilic character at the δ position and facilitates 1,6-
conjugate addition reactions.7 Different 1,6-conjugate addi-
tions of p-QMs, for example, transition metal-based Lewis acid-
catalyzed borylation, bismuth-catalyzed allylation, and NHC/
Lewis acid-catalyzed cyanation of p-QMs, have been
described.8 Asymmetric 1,6-conjugate additions of p-QM
derivatives have also been well studied using various
nucleophiles.5b,6a,9 The Sunliang group demonstrated both
transition metal-catalyzed and metal-free approaches for the
alkylation of p-QM derivatives (Scheme 1).10
Liu and our group have successively developed a visible-
light-mediated Ir-based and organo-photocatalyst for alkylation
and trifluoromethylation of p-QMs by a photoredox method-
ology.11 Recently, we have reported visible-light-mediated
trifluoromethylation of p-QMs by 1,6-conjugate addition using
a pyrylium salt as the organic photocatalyst (Scheme 1b).11c
I
ceuticals, agrochemicals, and materials research fields.1 Being
part of bioactive motifs, these groups improve transmembrane
permeability and metabolic stability.2 Also, the presence of a
highly electronegative fluorine and a heavy sulfur atom in SCF3
balance electron-withdrawing (Hammett constants σp = 0.50
and σm = 0.40) and lipophilic (Hansch parameter π = 1.43)
properties.3 Although there is immense value and interest in
trifluoromethylthiolation of organic molecules, a suitable
strategy for direct trifluoromethylthiolation under milder
reaction conditions with good functional group tolerance is
challenging. In the early era of SCF3 chemistry, trifluorome-
thylthiolation was carried out either by H−F exchange on
thioethers or trifluoromethylation of thiols and disulfides.
Recently, direct trifluoromethylthiolation using electrophilic
and nucleophilic trifluoromethylthiolating reagents by various
activation strategies has been reported.3,4 However, trifluor-
omethylthiolation of electron-deficient unsaturated alkene or
Michael acceptors has been less explored due a lack of
trifluoromethylthiolating reagents.
The 1,4/1,6-conjugate addition of various nucleophiles to an
electron-deficient unsaturated alkene or Michael acceptor is
one of the most studied, versatile reactions for C−C/C−
heteroatom bond construction in organic chemistry.5 In this
respect, p-quinone methides (p-QMs) are well-known reaction
intermediates for the synthesis of diarylmethane derivatives by
1,6-conjugate addition reactions and are also present in various
Received: July 23, 2020
https://dx.doi.org/10.1021/acs.joc.0c01752
© XXXX American Chemical Society
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A

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a
Scheme 1. Different Types of Nucleophilic Addition
Reactions of p-Quinone Methides
Table 1. Optimization of Reaction Conditions
b
entry
mediator
CuBr2
AlCl3
Zn(OTf)2
FeCl3
FeCl3, NH4Cl
NH4Cl
HN4OAc
HCO2NH4
HCl
HNO3
H2SO4
−
NH4Cl
NH4Cl
NMe4Cl
NEt4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
solvent
yield (%)
c
1
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
7
33
13
35
85
98
0
0
91
0
0
0
82
91
0
c
2
c
3
c
4
d
5
6
7
8
9
10
11
12
e
13
f
14
15
16
17
18
19
20
21
22
0
85
81
45
17
21
12
toluene
CH3CN
DME
dioxane
CHCl3
a
Reaction conditions: 1a (0.15 mmol), 2 (0.23 mmol), solvent (2.0
b
mL), 0.45 mmol of mediator, room temperature, 24 h. 1H NMR
yields using tetrachloroethane as the internal standard. With 20 mol
% mediator. With 20 mol % FeCl3 and 0.15 mmol of NH4Cl. With
0.15 mmol of NH4Cl. With 0.30 mmol of NH4Cl.
c
However, to date trifluoromethylthiolation of p-QM
derivatives has not been described due to challenges associated
with the limited trifluoromethylthiolating agents and their
stability. Here, we report the first efficient route for direct
trifluoromethylthiolation of p-QM derivatives using readily
available AgSCF3 and very cheap NH4Cl as reaction mediator
under mild and ambient conditions (Scheme 1c).
We began with testing of suitable Lewis acid catalysts to
activate the p-QMs for trifluoromethylthiolation by 1,6-
conjugate addition reaction. For this, p-QM derivative 1a
was used as a model substrate and readily available, cheap,
bench stable AgSCF3 was employed as the trifluoromethylth-
iolating agent. Reaction was optimized with screening of
different Lewis acids using 1.5 equiv of AgSCF3 in 2 mL of
DCM under an aerial atmosphere at room temperature. After
screening, Lewis acids such as CuBr2, AlCl3, and Zn(OTf)2
gave trifluoromethylthio-diarylmethane derivative 3a in 7%,
33%, and 13% yields, respectively, based on 1H NMR (Table 1,
entries 1−3, respectively). The yield increased to 35% when
FeCl3 (20 mol %) was used as a catalyst after 24 h. To further
improve the yield, we investigated the effect of protic solvents
using FeCl3 as a catalyst. Instead of improving the yield of
desired product 3a, protic solvents underwent 1,6-nucleophilic
addition/aromatization reactions and furnished solvent-added
d
e
f
for 24 h, desired product 3a was isolated in 82% yield. Next,
the required amount of ammonium salts (Table 1, entries 6,
13, and 14), AgSCF3 equivalents (see the Supporting
Information), and different solvents (see Table 1 and the
Supporting Information) were screened and optimized. The
most optimized conditions for this reaction are 0.15 mmol of
1a, 3 equiv of NH4Cl, and 1.5 equiv of AgSCF3 in 2 mL of
DCM under an aerial atmosphere at rt for 24 h. With these
optimized conditions, product 3a was obtained in 95% yield
1
and confirmed by H NMR, 13C NMR, and 19F NMR.
Next, a wide variety of p-QMs were explored for the
trifluoromethylthiolation reaction (Scheme 2). The electron-
donating substituents on the benzene ring afforded the
corresponding trifluoromethylthiolated diarylmethane deriva-
tives (3a−3c) in excellent isolated yields (79−95%). Simple
substituents on the phenyl ring furnished the expected
products 3d and 3e in good yield of 83% and 87%,
respectively. Then, we performed this reaction with different
p-QMs derived from benzaldehyde, 2-naphthaldehyde, and 1-
pyrenecarboxaldehyde, which offered the desired products
(3f−3h, respectively) in moderate to good yields (70−86%).
The solid state structure of compound 3h was confirmed by
single-crystal X-ray analysis (see the Supporting Information).
When p-QMs with a halogen substitution on the phenyl ring
were subjected to this reaction, the respective products (3i−
3n) were isolated (71−87% yields). Electron-withdrawing
̈
products. Next, we used 1 equiv of weak Bronsted acid NH4Cl
as an additive with 20 mol % FeCl3 under the same reaction
conditions, and this gave desired product 3a in85% yield.
Interestingly, when the reaction was carried out in the absence
of Lewis acid FeCl3 using only 1 equiv of NH4Cl and 1.5 equiv
of AgSCF3 in 2 mL of DCM under an aerial atmosphere at rt
B
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a
Scheme 2. Substrate Scope for Trifluoromethylthiolation of δ-Aryl-p-quinone Methides
a
Reaction conditions: 1 (0.15 mmol), 2 (0.23 mmol), DCM (2.0 mL), 0.45 mmol of NH4Cl, room temperature, 24 h.
groups such as p-CF3, p-CO2Me, p-NO2, and m-CN on the
phenyl ring also yielded the corresponding products in isolated
yields of 81%, 85%, 81%, and 72%, respectively (3o−3r,
respectively).
was tested. δ-tert-Butyl-p-QM derived from pivalaldehyde and
p-QM from isobutyraldehyde offered trifluoromethylthiolated
products (3x and 3y, respectively) in 77% and 80% yields,
respectively (Scheme 3).
The corresponding p-QMs of pyridine-3-carboxaldehyde
and thiophane-2-carboxaldehyde produced the expected
products (3s and 3t, respectively) with isolated yields of
81% and 76%, respectively. More interestingly, the p-QMs
derived from 2-tert-butyl-6-methyl phenol, 2,6-diisopropyl
phenol, and 2,6-dimethyl phenol gave the desired products
(3u−3w, respectively) in moderate to excellent yields (81%,
71%, and 65%, respectively). Next, the scope of δ-alkyl-p-QMs
Surprisingly, when δ-chloro-p-QM 1aa was subjected to our
optimized reaction conditions, di-trifluoromethylthiolated
product 4 was obtained in an isolated yield of 62% (Scheme
1
4) and the product was characterized by H NMR, 13C NMR,
and 19F NMR. First, trifluoromethylthiolation of 1aa generates
phenolate intermediate M, which loses a chloride anion by an
addition−elimination mechanism to form trifluoromethylthio-
p-QM intermediate N. Then, the second trifluoromethylth-
C
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AgSCF3. After vigorously stirring the mixture for 2 h, we
filtered the reaction mixture, and 0.15 mmol of 1a was added
to both the filtrate and the residue (here, an additional 2 mL of
DCM was added); the mixture was stirred for 24 h. In the case
of the residue, expected product 3a was obtained and
confirmed by 19F NMR whereas the filtrate failed to furnish
this product, which clearly indicates that the reactive species
NH4SCF3 must be insoluble or sparingly soluble in the DCM
reaction medium (Scheme 6).
Scheme 3. Substrate Scope for Trifluoromethylthiolation of
δ-Alkyl-p-quinone Methides
a
a
Reaction conditions: 1 (0.15 mmol), 2 (0.23 mmol), DCM (2.0
mL), 0.45 mmol of NH4Cl, room temperature, 24 h.
Scheme 6. Probable Mechanism for
Trifluoromethylthiolation of p-Quinone Methides
Scheme 4. Di-trifluoromethylthiolation of δ-Chloro-p-
quinone Methides 1aa
a
a
Reaction conditions: 1aa (0.15 mmol), 2 (0.38 mmol), DCM (2.0
mL), 0.75 mmol of NH4Cl, room temperature, 24 h.
iolation of intermediate N furnished di-trifluoromethylthio-
lated product 4 in tandem one-pot fashion. To test the
scalability of this protocol, a gram-scale synthesis was
performed using 3 mmol of 1a, under our standard optimized
conditions. This resulted in 3a in an 89% isolated yield
(Scheme 5).
Lewis acid-catalyzed 1,6-conjugate addition to p-QMs is
well-established,8d,f and the catalytic behavior of Ag+ as a Lewis
acid has been described in the literature.12 Here, because Ag+ is
present at levels higher than (∼1.5 times) that of the p-QM in
the reaction medium, its influence should be considered
important. Moreover, the involvement of the Lewis acid for
enhancing the δ nucleophilicity of p-QMs is supported well by
previous reports.5b,6a,7 To deduce p-QM’s reactivity in our
protocol, we consider two simultaneous possibilities, which can
enhance its δ nucleophilicity. (a) Participation of a Lewis
acidic Ag+ species: Silver is well-known for its affinity for
carbonyl oxygen; as a result, Ag+ can coordinate with the
oxygen atom of the p-QM and enhances the δ nucleophilicity.8f
a
Scheme 5. Gram-Scale Synthesis of 3a
+
a
(b) Participation of NH4 : Hydrogen from an ammonium ion
Reaction conditions: 1a (3 mmol), 2 (4.5 mmol), DCM (30 mL), 9
is a good hydrogen bond donor, so there is a high likelihood of
a successive hydrogen bond formation with the carbonyl
oxygen of p-QMs. This hydrogen bond formation could
enhance the δ nucleophilicity of p-QMs. Also, protons from
mmol of NH4Cl, room temperature, 24 h.
The mechanism of nucleophilic 1,6-conjugate addition to p-
QM is known;5−8 here, we aim to understand the reactive
nature of both NH4Cl and AgSCF3 in our reaction. We
hypothesized an in situ generation of NH4SCF3, which reacts
with p-QM. To test this, we performed a reaction using 0.23
mmol of AgSCF3 and 0.45 mmol of NH4Cl in 2 mL of DCM
at room temperature. As the reaction progressed, we clearly
observed formation of the white AgCl precipitate that
confirmed the ongoing reaction between NH4Cl and
+
NH4 would furnish the desired product by protonating
intermediate X.8f In addition, another interesting factor that
plays a crucial role in this reaction would be the precipitation
of AgCl, which provides an entropy boost to generate the
reacting nucleophile (-SCF3) or reactive species NH4SCF3. On
the basis of these preliminary experimental observations, we
propose a plausible mechanism for this trifluoromethylthiola-
tion reaction as depicted in Scheme 6.
D
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diethyl ether and kept at −20 °C for crystallization for 24 h by being
covered with aluminum foil. Then white crystalline solid was collected
by filtration, dried in vacuum, and stored in a refrigerator (7.3 g, 89%
yield).
In summary, a direct and efficient method for trifluor-
omethylthiolation of p-QMs is demonstrated using cheap
ammonium chloride as a reaction mediator and commercially
available, bench stable AgSCF3 as a nucleophilic trifluorome-
thylthiolating reagent. This is the first study of trifluorome-
thylthiolation of p-QMs. Our strategy is benign without the use
of any peroxide, while most of the reported nucleophilic
trifluoromethylthiolations require sacrificial amounts of per-
oxides and transition metal catalysts or more equivalents of
alkylammonium halides. In addition, this method is successful
under ambient reaction conditions and has a good substrate
scope with a wide range of functional group tolerance. Given
these advantages, this strategy could be applicable in late stage
trifluoromethylthiolation for the preparation of biologically
active molecules and drugs.
Experimental Procedure for the Synthesis of Compounds 3
and 4. To an oven-dried 20 mL reaction tube equipped with a
magnetic stir bar were added p-QMs (0.15 mmol, 1.0 equiv), AgSCF3
(0.225 mmol, 1.5 equiv), and NH4Cl (0.45 mmol, 3.0 equiv). The
reaction tube was sealed with a septum. Then, 2 mL of dry DCM was
added through the septum using a syringe, and the reaction mixture
stirred at room temperature. After 24 h, the reaction mixture was
diluted with 15 mL of DCM and dried over Na2SO4 and the solvent
was removed under reduced pressure at 45 °C in a water bath. To
purify the crude product, 230−400 mesh silica gel was used. Before
purification, the column was washed with 200 mL of a 2% AcOH/
hexane mixture and then the excess of AcOH was washed using 100
mL of hexane. Then, the crude product dissolved in hexane was
loaded into the column and purified by flash column chromatography
using an EtOAc/hexane mixture as the eluent. Solvent evaporation
under reduced pressure at 45 °C afforded product 3, and compounds
3(a−y) and 4 were stored in a refrigerator at 0 °C.
EXPERIMENTAL SECTION
■
General Information. Commercial reagents and solvents were
purified prior to their use following the guidelines of Chai and
Armarego.13a All NMR spectra were recorded on 400 MHz Jeol and
To synthesize 4 from 1aa, 2.5 equiv of AgSCF3 and 5.0 equiv of
NH4Cl were used, keeping all other conditions the same as mentioned
above.
1
500 MHz Bruker spectrometers. H, 13C, and 19F NMR spectral data
are reported as chemical shifts (δ) in parts per million relative to the
solvent residual peak using the Jeol internal referencing procedure
(edlock). Chemical shifts (δ) are quoted in parts per million, and
coupling constants (J) are measured in hertz. The following
abbreviations are used to describe multiplicities: s, singlet; d, doublet;
t, triplet; q, quartet; pent, pentet; br, broad; m, multiplet; dd, doublet
of doublets. High-resolution mass spectra (HRMS, m/z) were
recorded on a Bruker MicroTOF instrument. IR spectra were
recorded on a Bruker ATR spectrometer. All reactions for
trifluoromethylthiolation of p-QMs were conducted in dried glassware
with magnetic stirring under ambient atmosphere, unless otherwise
noted. Thin layer chromatography (TLC) was performed using Silica
gel 60 F254 and visualized under ultraviolet light and an iodine
chamber. Flash column chromatography was performed over Merck
silica gel (230−400 mesh). Silver fluoride was purchased from
Fluorochem. AgSCF3 was prepared by the reported literature
procedure. Other reagents were obtained from commercial suppliers
Alfa Aesar, Merck, and Spectrochem and used without further
purification, unless otherwise specified.
Gram-Scale Synthesis of 3a. To an oven-dried 100 mL round-
bottom flask equipped with a magnetic stirring bar were added p-QM
1a (3 mmol, 1.0 equiv), AgSCF3 (4.5 mmol, 1.5 equiv), and NH4Cl
(9 mmol, 3.0 equiv), and the flask was closed with a septum. Then, 30
mL of dry DCM was added, and the reaction mixture was stirred at
room temperature. After 24 h, the reaction mixture was diluted with
30 mL of DCM and dried over Na2SO4 and the solvent was removed
under reduced pressure at 45 °C in a water bath. To purify the crude
product, 230−400 mesh silica gel was used. First, a 2% AcOH/hexane
mixture was passed through the silica gel to make it acidic, and the
excess AcOH was washed with 100 mL of hexane. Then, the crude
product was dissolved in hexane, applied to the column, and purified
by flash column chromatography using hexane as an eluent to afford
1.14 g of yellow solid product 3a in 89% yield.
Characterization of Compounds 3 and 4. 2,6-Di-tert-butyl-4-
{(4-methoxyphenyl)[(trifluoromethyl)thio]methyl}phenol (3a).
Compound 3a was purified by flash column chromatography on
silica gel using hexane as the eluent: yellow solid; 95% yield (60.7
1
mg); H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.6 Hz, 2H), 7.17
Synthesis of p-Quinone Methides 1. In an oven-dried 250 mL
round-bottom flask fitted with a Dean-Stark apparatus, phenol (25
mmol) and the appropriate aldehyde (25 mmol) were placed. To this
was added toluene (100 mL), and the mixture was heated using an oil
bath to reflux followed by dropwise addition of the piperidine (50
mmol) over a period of 1 h. The reaction mixture was allowed to
continue to reflux overnight. After that, it was cooled just below the
boiling point of the reaction mixture and acetic anhydride (50 mmol)
was added and refluxed for 30 min. It was then poured into 500 mL of
ice-cold water and extracted with CH2Cl2 (2 × 250 mL). The
combined organic phase was dried over Na2SO4, and the solvent was
removed under reduced pressure using a rotary evaporator. The
product was finally purified using column chromatography to afford
the corresponding p-QMs (1a−1t and 1v).13b
(s, 2H), 6.90 (d, J = 8.6 Hz, 2H), 5.63 (s, 1H), 5.22 (s, 1H), 3.81 (s,
3H), 1.42 (s, 18H); 13C{1H} NMR (126 MHz, CDCl3) δ 159.2,
153.5, 136.2, 132.2, 130.2 (q, JC−F = 310.0 Hz), 129.7, 129.5, 125.0,
114.1, 55.4, 53.8, 34.6, 30.4; 19F NMR (471 MHz, CDCl3) δ −40.73
(s); FT-IR (thin film, neat) 3591, 2919, 2884, 2835, 1592, 1493,
1442, 1415, 1376, 1349, 1303, 1288, 1261, 1237, 1162, 1123, 1089,
1026, 942, 879, 845, 826, 799, 769, 741, 627, 609 cm−1; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C23H30F3O2S 427.1919, found
427.1936.
2,6-Di-tert-butyl-4-{(3,4-dimethoxyphenyl)[(trifluoromethyl)-
thio]methyl}phenol (3b). Compound 3b was purified by flash
column chromatography on silica gel using an EtOAc/hexane (1/
1
19) mixture as the eluent: orange oil; 79% yield (54 mg); H NMR
(400 MHz, CDCl3) δ 7.18 (s, 2H), 7.02−6.96 (m, 2H), 6.84 (d, J =
8.1 Hz, 1H), 5.62 (s, 1H), 5.22 (s, 1H), 3.89 (s, 3H), 3.88 (s, 3H),
1.41 (s, 18H); 13C{1H} NMR (126 MHz, CDCl3) δ 153.5, 149.1,
148.7, 136.2, 132.5, 130.2 (q, JC−F = 310.0 Hz), 129.5, 125.0, 120.7,
111.6, 111.2, 56.0, 54.0, 34.6, 30.3; 19F NMR (376 MHz, CDCl3) δ
−40.65 (s); FT-IR (thin film, neat) 3586, 2915, 2878, 2828, 1590,
1496, 1432, 1407, 1376, 1351, 1300, 1290, 1252, 1235, 1160, 1118,
1081, 1017, 940, 869, 837, 801, 758, 744, 635, 618 cm−1; HRMS
(ESI-TOF) m/z [M]+ calcd for C24H31F3O3S 456.1946, found
456.1946.
p-QMs 1u and 1w were prepared according to the literature
procedure.8a p-QM 1aa was also prepared on the basis of the
literature.13c
Synthesis of AgSCF3. The reagent AgSCF3 was prepared
following a previously reported procedure.14 Briefly, AgF (15 g, 118
mmol) was added under an argon atmosphere followed by CS2 (15
mL, 248 mmol, 2.1 equiv), and 75 mL of dry acetonitrile and the
reaction mixture were refluxed at 80 °C using an oil bath. After 14 h,
the reaction mixture was cooled to room temperature and excess CS2
and solvent were evaporated under reduced pressure in the dark.
Then the residue was dissolved in EtOAc and filtered through Celite,
and the filtrate was concentrated under reduced pressure in the dark.
After that, the yellow residue was dissolved in a minimum amount of
dry acetonitrile, and the yellow solution was layered with 60 mL of
2,6-Di-tert-butyl-4-({2-[(tert-butyldimethylsilyl)oxy]phenyl}-
[(trifluoromethyl)thio]methyl)phenol (3c). Compound 3c was
purified by flash column chromatography on silica gel using hexane
as the eluent: pale yellow solid; 86% yield (67.8 mg); 1H NMR (400
E
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MHz, CDCl3) δ 7.65 (dd, J = 9.3, 1.5 Hz, 1H), 7.23−7.18 (m, 3H),
7.04 (td, J = 7.6, 1.2 Hz, 1H), 6.89−6.87 (m, 1H), 6.17 (s, 1H), 5.20
(s, 1H), 1.43 (s, 18H), 1.01 (s, 9H), 0.29 (s, 3H), 0.20 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 153.3, 152.7, 136.0, 130.6, 130.6
(q, JC−F = 308.7 Hz), 130.0, 129.5, 128.7, 125.3, 121.2, 118.5, 47.5,
34.5, 30.3, 25.9, 18.4, −3.9, −4.0; 19F NMR (376 MHz, CDCl3) δ
−40.80 (s); FT-IR (thin film, neat) 3572, 2921, 2828, 1463, 1418,
1260, 1243, 1134, 1092, 1036, 996, 909, 876, 822, 793, 796, 741, 695
cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H42F3O2SSi
527.2627, found 527.2647.
2,6-Di-tert-butyl-4-{p-tolyl[(trifluoromethyl)thio]methyl}phenol
(3d). Compound 3d was purified by flash column chromatography on
silica gel using hexane as the eluent: pale yellow oil; 83% yield (51
mg); 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.1 Hz, 2H), 7.17 (t,
J = 4.0 Hz, 4H), 5.62 (s, 1H), 5.21 (s, 1H), 2.35 (s, 3H), 1.42 (s,
18H); 13C{1H} NMR (126 MHz, CDCl3) δ 153.5, 137.6, 137.3,
136.2, 130.3 (q, JC−F = 308.7 Hz), 129.7, 129.4, 128.2, 125.0, 54.0,
34.6, 30.4, 21.2; 19F NMR (376 MHz, CDCl3) δ −40.64 (s); FT-IR
(thin film, neat) 3703, 3628, 3596, 2925, 2886, 2836, 1492, 1415,
1378, 1347, 1298, 1227, 1125, 1091, 1006, 945, 878, 842, 820, 800,
765, 742, 726, 707, 628, 610, 569 cm−1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C23H30F3OS 411.1969, found 411.1955.
131.1, 130.8, 130.3 (q, JC−F = 310.0 Hz), 129.3, 128.4, 128.2, 127.8,
127.6, 126.9, 126.2, 125.7, 125.5, 125.5, 125.3, 125.0, 125.0, 123.8,
122.5, 50.8, 34.6, 30.3; 19F NMR (376 MHz, CDCl3) δ −40.66 (s);
FT-IR (thin film, neat) 3538, 2923, 2875, 2833, 1414, 1299, 1221,
1131, 1090, 959, 831, 746, 703, 671, 639, 615, 561 cm−1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C32H32F3OS 521.2126, found
521.2138.
2,6-Di-tert-butyl-4-{(2-fluorophenyl)[(trifluoromethyl)thio]-
methyl}phenol (3i). Compound 3i was purified by flash column
chromatography on silica gel using hexane as the eluent: pale yellow
oil; 87% yield (54 mg); 1H NMR (400 MHz, CDCl3) δ 7.63 (td, J =
7.7, 1.8 Hz, 1H), 7.29−7.24 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.16
(s, 2H), 7.08−7.02 (m, 1H), 5.97 (s, 1H), 5.23 (s, 1H), 1.40 (s,
18H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8 (d, JC−F = 244.4
Hz), 153.7, 136.3, 130.1 (q, JC−F = 310.1 Hz), 129.9 (d, JC−F = 2.0
Hz), 129.5 (q, JC−F = 8.1 Hz), 128.3, 127.8 (d, JC−F = 14.1 Hz), 125.0,
124.4 (d, JC−F = 4.0 Hz), 115.9 (d, JC−F = 22.2 Hz), 46.5, 34.6, 30.3;
19F NMR (376 MHz, CDCl3) δ −40.99 (s), −117.17 (s); FT-IR (thin
film, neat) 3577, 2926, 2881, 2840, 1565, 1468, 1436, 1414, 1380,
1348, 1299, 1262, 1238, 1213, 1191, 1128, 1093, 1020, 947, 922, 878,
839, 785, 746, 638, 599 cm−1; HRMS (ESI-TOF) m/z [M + H]+
calcd for C22H27F4OS 415.1719, found 415.1717.
2,6-Di-tert-butyl-4-{(4-ethylphenyl)[(trifluoromethyl)thio]-
methyl}phenol (3e). Compound 3e was purified by flash column
chromatography on silica gel using hexane as the eluent: pale yellow
oil; 87% yield (55.3 mg); 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J =
7.8 Hz, 2H), 7.25 (t, J = 3.8 Hz, 4H), 5.70 (s, 1H), 5.28 (s, 1H), 2.71
(q, J = 7.6 Hz, 2H), 1.49 (s, 18H), 1.30 (t, J = 7.6 Hz, 3H); 13C{1H}
NMR (126 MHz, CDCl3) δ 153.5, 143.9, 137.5, 136.2, 130.3 (q, JC−F
= 308.7 Hz), 129.8, 128.2, 128.2, 125.1, 54.1, 34.6, 30.4, 28.6, 15.5;
19F NMR (471 MHz, CDCl3) δ −40.20; FT-IR (thin film, neat) 3703,
3543, 2924, 2880, 2839, 1693, 1594, 1417, 1295, 1268, 1226, 1186,
1169, 1134, 1089, 1007, 950, 878, 856, 841, 806, 791, 761, 746, 727,
697, 610 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C24H32F3OS 425.2126, found 425.2132.
2,6-Di-tert-butyl-4-{(4-fluorophenyl)[(trifluoromethyl)thio]-
methyl}phenol (3j). Compound 3j was purified by flash column
chromatography on silica gel using hexane as the eluent: pale yellow
liquid; 79% yield (49 mg); 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J
= 8.7, 5.3 Hz, 2H), 7.12 (s, 2H), 7.06 (t, J = 8.7 Hz, 2H), 5.65 (s,
1H), 5.24 (s, 1H), 1.41 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3)
δ 162.3 (d, JC−F = 247.5 Hz), 153.7, 136.4, 136.0, 130.1 (q, JC−F
=
=
310.1 Hz), 130.0 (d, JC−F = 8.1 Hz), 129.1, 125.0, 115.6 (d, JC−F
21.2 Hz), 53.4, 34.6, 30.3; 19F NMR (376 MHz, CDCl3) δ −40.67
(s), −114.44 (s); FT-IR (thin film, neat) 3696, 3575, 2923, 2891,
2827, 1463, 1419, 1262, 1241, 1218, 1133, 1091, 908, 823, 769, 741
cm−1; HRMS (ESI-TOF) m/z [M + K]+ calcd for C22H26F4KOS
453.1278, found 453.1282.
2,6-Di-tert-butyl-4-{(4-chlorophenyl)[(trifluoromethyl)thio]-
methyl}phenol (3k). Compound 3k was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/49) mixture
as the eluent: pale yellow solid; 84% yield (54.2 mg); 1H NMR (400
MHz, CDCl3) δ 7.41 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H),
7.11 (s, 2H), 5.62 (s, 1H), 5.25 (s, 1H), 1.41 (s, 18H); 13C{1H}
NMR (100 MHz, CDCl3) δ 153.7, 138.9, 136.4, 133.7, 130.0 (q, JC−F
= 310.1 Hz), 129.7, 128.9, 128.8, 125.0, 53.5, 34.6, 30.3; 19F NMR
(376 MHz, CDCl3) δ −40.62 (s); FT-IR (thin film, neat) 3589, 2929,
2882, 2838, 1467, 1416, 1386, 1347, 1306, 1228, 1184, 1131, 1090,
1076, 1000, 945, 883, 842, 826, 801, 775, 741, 711, 679 cm−1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C22H27ClF3OS 431.1423, found
431.1437.
2,6-Di-tert-butyl-4-{(2-chlorophenyl)[(trifluoromethyl)thio]-
methyl}phenol (3l). Compound 3l was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/49) mixture
as the eluent: pale yellow solid; 71% yield (45.8 mg); 1H NMR (400
MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H),
7.35 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.22 (s, 2H), 6.24
(s, 1H), 5.27 (s, 1H), 1.45 (s, 18H); 13C{1H} NMR (126 MHz,
CDCl3) δ 153.7, 138.0, 136.3, 133.2, 130.1, 130.1 (q, JC−F = 308.7
Hz), 130.0, 129.0, 128.1, 127.2, 125.2, 50.0, 34.6, 30.3; 19F NMR
(376 MHz, CDCl3) δ −40.84 (s); FT-IR (thin film, neat) 3854, 3808,
3792, 3772, 3755, 3702, 3690, 3642, 3625, 3606, 3587, 3520, 2923,
2176, 2121, 2004, 1677, 1627, 1490, 1418, 1377, 1222, 1132, 1091,
1024, 823, 791, 740, 715, 685, 635 cm−1; HRMS (ESI-TOF) m/z [M
+ H]+ calcd for C22H27ClF3OS 431.1423, found 431.1415.
2,6-Di-tert-butyl-4-{phenyl[(trifluoromethyl)thio]methyl}phenol
(3f). Compound 3f was purified by flash column chromatography on
silica gel using hexane as the eluent: pale yellow oil; 86% yield (51.1
mg); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 2H), 7.39 (t,
J = 7.5 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 7.19 (s, 2H), 5.69 (s, 1H),
5.25 (s, 1H), 1.44 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ
153.6, 140.2, 136.3, 130.2 (q, JC−F = 310.0 Hz), 129.4, 128.7, 128.3,
127.8, 125.1, 54.2, 34.6, 30.3; 19F NMR (471 MHz, CDCl3) δ −40.73
(s); FT-IR (thin film, neat) 3629, 3590, 3569, 2925, 2881, 2834,
1523, 1455, 1434, 1415, 1378, 1348, 1303, 1226, 1186, 1089, 1014,
878, 836, 792, 729, 689, 645, 610 cm−1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C22H28F3OS 397.1813, found 397.1808.
2,6-Di-tert-butyl-4-{naphthalen-2-yl[(trifluoromethyl)thio]-
methyl}phenol (3g). Compound 3g was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/49) mixture
as the eluent: yellow solid; 85% yield (56.8 mg); 1H NMR (400 MHz,
CDCl3) δ 7.87 (dd, J = 16.6, 8.2 Hz, 4H), 7.65 (d, J = 10.1 Hz, 1H),
7.53−7.48 (m, 2H), 7.24 (s, 2H), 5.85 (s, 1H), 5.25 (s, 1H), 1.43 (s,
18H); 13C{1H} NMR (126 MHz, CDCl3) δ 153.6, 137.6, 136.4,
133.4, 133.0, 130.2 (q, JC−F = 308.7 Hz), 129.3, 128.6, 128.2, 127.8,
127.2, 126.5, 126.4, 126.2, 125.2, 54.4, 34.6, 30.3; 19F NMR (376
MHz, CDCl3) δ −40.51 (s); FT-IR (thin film, neat) 3851, 3809,
3776, 3756, 3701, 3684, 3648, 3626, 3606, 3575, 3517, 3447, 3183,
2921, 2879, 2851, 2821, 2224, 2002, 1494, 1414, 1347, 1220, 1188,
1128, 1087, 1008, 946, 879, 851, 808,795, 767, 739, 654 cm−1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C26H30F3OS 447.1969, found
447.1980.
2,6-Di-tert-butyl-4-{pyren-1-yl[(trifluoromethyl)thio]methyl}-
phenol (3h). Compound 3h was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/19) mixture
4-{(3-Bromophenyl)[(trifluoromethyl)thio]methyl}-2,6-di-tert-bu-
tylphenol (3m). Compound 3m was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/49) mixture
1
1
as the eluent: orange solid; 70% yield (54.6 mg); H NMR (400
as the eluent: yellow solid; 83% yield (59 mg); H NMR (400 MHz,
MHz, CDCl3) δ 8.41 (d, J = 9.3 Hz, 1H), 8.30 (d, J = 7.9 Hz, 1H),
8.20 (dd, J = 17.1, 9.7 Hz, 4H), 8.08 (d, J = 2.1 Hz, 2H), 8.02 (t, J =
7.6 Hz, 1H), 7.34 (s, 2H), 6.82 (s, 1H), 5.23 (s, 1H), 1.39 (s, 18H);
13C{1H} NMR (126 MHz, CDCl3) δ 153.5, 136.3, 132.9, 131.5,
CDCl3) δ 7.63 (t, J = 1.6 Hz, 1H), 7.43 (dd, J = 7.1, 4.9 Hz, 2H), 7.25
(t, J = 7.9 Hz, 1H), 7.13 (s, 2H), 5.60 (s, 1H), 5.27 (s, 1H), 1.42 (s,
18H); 13C{1H} NMR (126 MHz, CDCl3) δ 153.8, 142.6, 136.5,
131.4, 131.0, 130.3, 129.9 (q, JC−F = 310.0 Hz), 128.8, 126.9, 125.0,
F
https://dx.doi.org/10.1021/acs.joc.0c01752
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
122.8, 53.5, 34.5, 30.3; 19F NMR (376 MHz, CDCl3) δ −40.62 (s);
FT-IR (thin film, neat) 3586, 2921, 2877, 2838, 1573, 1546, 1453,
1411, 1377, 1348, 1299, 1223, 1132, 1091, 1013, 983, 878, 841, 792,
761, 741, 690, 660, 641, 602 cm−1; HRMS (ESI-TOF) m/z [M + H]+
calcd for C22H25BrF3OS 473.0761, found 473.0754.
4-{(4-Bromophenyl)[(trifluoromethyl)thio]methyl}-2,6-di-tert-bu-
tylphenol (3n). Compound 3n was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/49) mixture
as the eluent: yellow solid; 78% yield (55.5 mg); 1H NMR (400 MHz,
CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 7.15 (s,
2H), 5.64 (s, 1H), 5.28 (s, 1H), 1.44 (s, 18H); 13C{1H} NMR (126
MHz, CDCl3) δ 153.8, 139.4, 136.5, 131.9, 130.0 (q, JC−F = 308.7
Hz), 130.0, 128.8, 125.1, 125.0, 121.8, 53.5, 34.6, 30.3; 19F NMR
(376 MHz, CDCl3) δ −40.55 (s); FT-IR (thin film, neat) 3701, 3628,
3591, 3572, 3523, 2925, 2882, 2834, 1462, 1413, 1380, 1349, 1305,
1227, 1185, 1131, 1088, 1055, 994, 945, 881, 839, 822, 801, 775, 738,
709, 662, 608 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C22H27BrF3OS 475.0918, found 475.0917.
2,6-Di-tert-butyl-4-{[4-(trifluoromethyl)phenyl][(trifluoromethyl)-
thio]methyl}phenol (3o). Compound 3o was purified by flash
column chromatography on silica gel using hexane as the eluent:
pale yellow oil; 81% yield (56.4 mg); 1H NMR (400 MHz, CDCl3) δ
7.66−7.59 (m, 4H), 7.12 (s, 2H), 5.68 (s, 1H), 5.27 (s, 1H), 1.41 (s,
18H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.9, 144.4, 136.6,
130.1 (q, JC−F = 32.2 Hz), 130.0 (q, JC−F = 247.5 Hz), 128.7, 128.4,
125.8 (q, JC−F = 3.5 Hz), 125.0, 124.2 (q, JC−F = 272.7 Hz), 53.6, 34.6,
30.3; 19F NMR (376 MHz, CDCl3) δ −40.63 (s), −62.46 (s); FT-IR
(thin film, neat) 3592, 2920, 2889, 2836, 1600, 1417, 1306, 1228,
1151, 1090, 1001, 840, 790, 746 cm−1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C23H27F6OS 465.1687, found 465.1680.
2,6-Di-tert-butyl-4-{pyridin-3-yl[(trifluoromethyl)thio]methyl}-
phenol (3s). Compound 3s was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/19) mixture
1
as the eluent: pale yellow oil; 81% yield (48.2 mg); H NMR (400
MHz, CDCl3) δ 8.68 (s, 1H), 8.54 (d, J = 3.9 Hz, 1H), 7.84 (d, J =
8.0 Hz, 1H), 7.34−7.30 (m, 1H), 7.10 (s, 2H), 5.64 (s, 1H), 5.29 (s,
1H), 1.40 (s, 18H); 13C{1H} NMR (126 MHz, CDCl3) δ 153.9,
149.6, 149.1, 136.7, 136.2, 135.8, 129.9 (q, JC−F = 308.7 Hz), 128.2,
124.9, 123.6, 51.6, 34.6, 30.3; 19F NMR (376 MHz, CDCl3) δ −40.56
(s); FT-IR (thin film, neat) 3703, 3691, 2921, 2881, 2837, 1556,
1459, 1415, 1373, 1343, 1287, 1246, 1223, 1132, 1086, 1014, 922,
878, 843, 813, 799, 776, 730, 699, 665 cm−1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C21H27F3NOS 398.1765, found 398.1759.
2,6-Di-tert-butyl-4-{thiophen-2-yl[(trifluoromethyl)thio]methyl}-
phenol (3t). Compound 3t was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/49) mixture
1
as the eluent: pale yellow oil; 76% yield (45.8 mg); H NMR (400
MHz, CDCl3) δ 7.25 (d, J = 5.3 Hz, 1H), 7.22 (s, 2H), 7.02 (d, J =
3.3 Hz, 1H), 6.94−6.91 (m, 1H), 5.83 (s, 1H), 5.24 (s, 1H), 1.41 (s,
18H); 13C{1H} NMR (126 MHz, CDCl3) δ 153.9, 144.3, 136.4,
130.2 (q, JC−F = 310.0 Hz), 129.7, 126.8, 126.8, 126.1, 124.8, 49.7,
34.6, 30.4; 19F NMR (376 MHz, CDCl3) δ −40.85 (s); FT-IR (thin
film, neat) 3625, 2965, 2868, 1638, 1427, 1398, 1342, 1330, 1317,
1242, 1140, 1107, 852, 842, 769, 749, 699, 656, 601 cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C20H25F3NaOS2 425.1197,
found 425.1216.
2-(tert-Butyl)-6-methyl-4-{phenyl[(trifluoromethyl)thio]methyl}-
phenol (3u). Compound 3u was purified by flash column
chromatography on silica gel using hexane as the eluent: pale yellow
1
oil; 81% yield (43 mg); H NMR (400 MHz, CDCl3) δ 7.42 (d, J =
7.3 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.16
(d, J = 2.2 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 5.61 (s, 1H), 4.77 (s,
1H), 2.19 (s, 3H), 1.37 (s, 9H); 13C{1H} NMR (126 MHz, CDCl3) δ
152.5, 140.1, 136.1, 130.2, 130.2 (q, JC−F = 308.7 Hz), 128.8, 128.3,
128.2, 127.9, 125.3, 123.5, 53.7, 34.8, 29.8, 16.2; 19F NMR (376 MHz,
CDCl3) δ −40.70 (s); FT-IR (thin film, neat) 3564, 3537, 2922,
2888, 2837, 1581, 1462, 1436, 1416, 1375, 1346, 1307, 1280, 1263,
1237, 1205, 1183, 1130, 1091, 1018, 897, 875, 819, 785, 744, 688,
647, 615 cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for
C19H20F3OS 353.1187, found 353.1181.
2,6-Diisopropyl-4-{phenyl[(trifluoromethyl)thio]methyl}phenol
(3v). Compound 3v was purified by flash column chromatography on
silica gel using hexane as the eluent: pale yellow oil; 71% yield (39.2
mg); 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.5 Hz, 2H), 7.37 (t,
J = 7.5 Hz, 2H), 7.32−7.27 (m, 1H), 7.08 (s, 2H), 5.69 (s, 1H), 4.83
(s, 1H), 3.14 (hept, J = 6.8 Hz, 2H), 1.26 (d, J = 6.9 Hz, 12H);
13C{1H} NMR (126 MHz, CDCl3) δ 149.8, 140.0, 134.1, 130.8, 130.2
(q, JC−F = 308.7 Hz), 128.8, 128.4, 128.3, 127.9, 123.7, 54.0, 53.9,
27.5, 22.7; 19F NMR (376 MHz, CDCl3) δ −40.63 (s); FT-IR (thin
film, neat) 3625, 2960, 2935, 2868, 1623, 1501, 1461, 1407, 1357,
1259, 1189, 1148, 1100, 856, 752, 700, 656, 605 cm−1; HRMS (ESI-
TOF) m/z [M − H]− calcd for C20H22F3OS 367.1343, found
367.1331.
2,6-Dimethyl-4-{phenyl[(trifluoromethyl)thio]methyl}phenol
(3w). Compound 3w was purified by flash column chromatography
on silica gel using hexane as the eluent: colorless oil; 65% yield (30.4
mg); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.4 Hz, 2H), 7.35 (t,
J = 7.4 Hz, 2H), 7.30−7.26 (m, 1H), 6.99 (s, 2H), 5.59 (s, 1H), 4.65
(s, 1H), 2.22 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 152.0,
140.0, 130.8, 130.2 (q, JC−F = 308.7 Hz), 128.8, 128.5, 128.2, 127.9,
123.5, 53.3, 16.1; 19F NMR (376 MHz, CDCl3) δ −40.74 (s); FT-IR
(thin film, neat) 3447, 2917, 1627, 1489, 1400, 1259, 1187, 1145,
1102, 857, 753, 704, 649, 596 cm−1; HRMS (ESI-TOF) m/z [M −
H]− calcd for C16H14F3OS 311.0717, found 311.0707.
4-{(3,5-Di-tert-butyl-4-hydroxyphenyl)[(trifluoromethyl)thio]-
methyl}phenylacetate (3p). Compound 3p was purified by flash
column chromatography on silica gel using an EtOAc/hexane (1/19)
mixture as the eluent: yellow oil; 85% yield (57.9 mg); 1H NMR (400
MHz, CDCl3) δ 8.07 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H),
7.14 (s, 2H), 5.71 (s, 1H), 5.30 (s, 1H), 3.93 (s, 3H), 1.41 (s, 18H);
13C{1H} NMR (126 MHz, CDCl3) δ 166.8, 153.8, 145.4, 136.5,
130.1, 130.0 (q, JC−F = 308.7 Hz), 129.7, 128.5, 128.3, 125.1, 53.8,
52.2, 34.5, 30.3; 19F NMR (376 MHz, CDCl3) δ −40.58 (s); FT-IR
(thin film, neat) 3695, 3542, 2923, 2881, 2840, 1691, 1593, 1416,
1349, 1268, 1227, 1175, 1131, 1087, 1009, 949, 879, 850, 803, 754,
733, 700 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C24H30F3O3S 455.1867, found 455.1861.
2,6-Di-tert-butyl-4-{(4-nitrophenyl)[(trifluoromethyl)thio]-
methyl}phenol (3q). Compound 3q was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/19) mixture
1
as the eluent: yellow oil; 81% yield (53.6 mg); H NMR (400 MHz,
CDCl3) δ 8.23 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.07 (s,
2H), 5.70 (s, 1H), 5.28 (s, 1H), 1.39 (s, 18H); 13C{1H} NMR (126
MHz, CDCl3) δ 154.1, 147.7, 147.5, 136.9, 129.8 (q, JC−F = 310.0
Hz), 129.2, 127.7, 125.0, 124.1, 53.4, 34.6, 30.3; 19F NMR (376 MHz,
CDCl3) δ −40.58 (s); FT-IR (thin film, neat) 3575, 2921, 2886,
2819, 1576, 1499, 1417, 1328, 1308, 1241, 1226, 1189, 1161, 1128,
1091, 1002, 878, 848, 824, 785, 737, 693, 669, 608, 578 cm−1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C22H27F3NO3S 442.1664, found
442.1679.
3-{(3,5-Di-tert-butyl-4-hydroxyphenyl)[(trifluoromethyl)thio]-
methyl}benzonitrile (3r). Compound 3r was purified by flash column
chromatography on silica gel using an EtOAc/hexane (1/19) mixture
1
as the eluent: yellow oil; 72% yield (45.5 mg); H NMR (400 MHz,
CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 7.7 Hz, 1H), 7.50 (t, J
= 7.8 Hz, 1H), 7.08 (s, 2H), 5.66 (s, 1H), 5.30 (s, 1H), 1.41 (s, 18H);
13C{1H} NMR (126 MHz, CDCl3) δ 154.0, 142.1, 136.8, 132.7,
131.9, 131.5, 129.9 (q, JC−F = 310.0 Hz), 129.6, 127.9, 124.9, 118.6,
113.0, 53.2, 34.6, 30.2; 19F NMR (376 MHz, CDCl3) δ −40.58 (s);
FT-IR (thin film, neat) 3559, 2916, 2880, 2209, 1465, 1415, 1377,
1342, 1306, 1242, 1221, 1192, 1126, 1095, 1012, 948, 917, 889, 877,
794, 732, 682, 623, 592 cm−1; HRMS (ESI-TOF) m/z [M + H]+
calcd for C23H27F3NOS 422.1765, found 422.1758.
2,6-Di-tert-butyl-4-{2,2-dimethyl-1-[(trifluoromethyl)thio]-
propyl}phenol (3x). Compound 3x was purified by flash column
chromatography on silica gel using hexane as the eluent: pale yellow
1
oil; 77% yield (43.5 mg); H NMR (400 MHz, CDCl3) δ 7.06 (s,
2H), 5.16 (s, 1H), 4.04 (s, 1H), 1.46 (s, 18H), 1.02 (s, 9H); 13C{1H}
NMR (126 MHz, CDCl3) δ 153.1, 135.1, 131.4 (q, JC−F = 306.2 Hz),
G
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Note
130.7, 125.7, 62.1, 36.1, 34.5, 30.6, 28.3; 19F NMR (376 MHz,
CDCl3) δ −39.92 (s); FT-IR (thin film, neat) 3598, 2922, 2837,
1455, 1418, 1379, 1348, 1301, 1219, 1133, 1092, 1012, 920, 860, 796,
755, 636 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C20H32F3OS 377.2126, found 377.2127.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
D.S. thanks IISER Kolkata for a startup grant, SERB for an
Early Career Research Award (ECRA), and DST-SERB for a
Ramanujan Fellowship. D.D., K.G.G., and P.C. thank IISER-K,
DST, and UGC for their Ph.D. fellowships. The authors are
especially thankful to Dr. Biplab Maji, Assistant Professor, and
Mr. Surojit Bhunia, Ph.D., FleXtal Lab, Department of
Chemical Sciences, IISER Kolkata.
2,6-Di-tert-butyl-4-{2-methyl-1-[(trifluoromethyl)thio]propyl}-
phenol (3y). Compound 3y was purified by flash column
chromatography on silica gel using hexane as the eluent: pale yellow
1
oil; 80% yield (43.5 mg); H NMR (400 MHz, CDCl3) δ 7.04 (s,
2H), 5.17 (s, 1H), 4.09 (d, J = 6.9 Hz, 1H), 2.16 (dq, J = 13.5, 6.7 Hz,
1H), 1.45 (s, 18H), 1.04 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 153.2, 135.7, 131.2 (q, JC−F
=
307.4 Hz), 130.6, 124.8, 57.7, 34.5, 34.3, 30.5, 20.6, 20.2; 19F NMR
(376 MHz, CDCl3) δ −39.67 (s); FT-IR (thin film, neat) 3601, 2922,
2837, 1450, 1418, 1373, 1347, 1302, 1220, 1131, 1088, 1013, 317,
876, 801, 785, 760, 744, 726, 660, 633, 612 cm−1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C19H30F3OS 363.1969, found 363.1972.
4-{Bis[(trifluoromethyl)thio]methyl}-2,6-di-tert-butylphenol (4).
Compound 4 was purified by flash column chromatography on silica
gel using hexane as the eluent: pale yellow oil; 62% yield (39 mg); 1H
NMR (400 MHz, CDCl3) δ 7.21 (s, 2H), 5.74 (s, 1H), 5.38 (s, 1H),
1.44 (s, 18H); 13C{1H} NMR (126 MHz, CDCl3) δ 154.9, 136.9,
129.1 (q, JC−F = 310.0 Hz), 126.6, 124.2, 50.8, 34.6, 30.3; 19F NMR
(376 MHz, CDCl3) δ −41.05 (s); FT-IR (thin film, neat) 3595, 2923,
2884, 2843, 1416, 1349, 1305, 1232, 1078, 876, 743, 716, 614 cm−1;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H23F6OS2 421.1095,
found 421.1105.
DEDICATION
■
Dedicated to Professor Srinivasan Chandrasekaran on the
occasion of his 75th birthday.
REFERENCES
■
(1) (a) Song, H.-X.; Han, Q.-Y.; Zhao, C.-L.; Zhang, C.-P.
Fluoroalkylation Reactions in Aqueous Media: A Review. Green
Chem. 2018, 20, 1662−1731. (b) Tlili, A.; Toulgoat, F.; Billard, T.
Synthetic Approaches to Trifluoromethoxy-Substituted Compounds.
Angew. Chem., Int. Ed. 2016, 55, 11726−11735.
(2) (a) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J.
Med. Chem. 2015, 58, 8315−8359. (b) Jeschke, P. The Unique Role
of Fluorine in The Design of Active Ingredients for Modern Crop
Protection. ChemBioChem 2004, 5, 570−589.
(3) (a) Ismalaj, E. New Reagents for Fluoroalkylchalcogenations:
Applications to Hot Chemistry; Organic Chemistry. Thesis,
Universite de Lyon, Lyon, France, 2017. (b) Barata-Vallejo, S.;
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01752.
́
Bonesi, S.; Postigo, A. Late Stage Trifluoromethylthiolation Strategies
for Organic Compounds. Org. Biomol. Chem. 2016, 14, 7150−7182.
(4) (a) Xu, X.-H.; Matsuzaki, K.; Shibata, N. Synthetic Methods for
Compounds Having CF3-S Units on Carbon by Trifluoromethylation,
Trifluoromethylthiolation, Triflylation, and Related Reactions. Chem.
Rev. 2015, 115, 731−764. (b) Ni, C.; Hu, M.; Hu, J. Good
Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination
and Fluoroalkylation Reagents for Organic Synthesis. Chem. Rev.
2015, 115, 765−825. (c) Barthelemy, A.-L.; Magnier, E.; Dagousset,
G. Direct Trifluoromethylthiolation Reactions Involving Radical
Processes. Synthesis 2018, 50, 4765−4776. (d) Liu, J.-B.; Xu, X.-H.;
Chen, Z.-H.; Qing, F.-L. Direct Dehydroxytrifluoromethylthiolation
of Alcohols Using Silver(I) Trifluoromethanethiolate and Tetra-n-
butylammonium Iodide. Angew. Chem., Int. Ed. 2015, 54, 897−900.
(e) Li, C.; Zhang, K.; Xu, X.-H.; Qing, F.-L. Copper-Mediated
Oxidative Trifluoromethylthiolation of Quinones. Tetrahedron Lett.
2015, 56, 6273−6275.
(5) (a) Vicario, J. L.; Badia, D.; Carrillo, L.; Reyes, E. Organocatalytic
Enantioselective Conjugate Addition Reactions; Royal Society of
Chemistry: Cambridge, U.K., 2010. (b) Li, W.; Xu, X.; Zhang, P.;
Li, P. Recent Advances in the Catalytic Enantioselective Reactions of
para-Quinone Methides. Chem. - Asian J. 2018, 13, 2350−2359.
(c) Lima, C. G. S.; Pauli, F. P.; Costa, D. C. S.; de Souza, A. S.; Forezi,
L. S. M.; Ferreira, V. F.; de Carvalho da Silva, F. para-Quinone
Methides as Acceptors in 1,6-Nucleophilic Conjugate Addition
Reactions for the Synthesis of Structurally Diverse Molecules. Eur.
J. Org. Chem. 2020, 2020, 2650−2692. (d) Sun, M.; Ma, C.; Zhou, S.-
J.; Lou, S.- F.; Xiao, J.; Jiao, Y.; Shi, F. Catalytic Asymmetric (4 + 3)
Cyclizations of In Situ Generated ortho-Quinone Methides with 2-
Indolylmethanols. Angew. Chem., Int. Ed. 2019, 58, 8703−8708.
(e) Wu, S.-F.; Tu, M.-S.; Hang, Q.-Q.; Zhang, S.; Ding, H.; Zhang, Y.-
C.; Shi, F. Construction of Chiral Chroman Scaffolds via Catalytic
Asymmetric (4 + 2) Cyclizations of para-Quinone Methide
Derivatives with 3-Vinylindoles. Org. Biomol. Chem. 2020, 18,
5388−5399. (f) Wang, Y.-X.; Lu, Y.-N.; Xu, L.-L.; Sheng, F.-T.;
Zhang, J.-P.; Tan, W.; Shi, F. Application of Benzofuran-Derived
Azadienes as Two-Carbon Building Blocks in Annulations: Chemo-
Tables of the optimization of reaction conditions and
1
mechanistic studies, copies of H, 13C, and 19F NMR
spectra of all new compounds, crystal data of compound
3h, and X-ray crystallographic data (PDF)
Accession Codes
CCDC 2018273 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Devarajulu Sureshkumar − Department of Chemical Sciences,
Indian Institute of Science Education and Research, Kolkata
Mohanpur 741246, West Bengal, India; orcid.org/0000-
0002-6985-3496; Email: suresh@iiserkol.ac.in
Authors
Debabrata Das − Department of Chemical Sciences, Indian
Institute of Science Education and Research, Kolkata
Mohanpur 741246, West Bengal, India
Krishna Gopal Ghosh − Department of Chemical Sciences,
Indian Institute of Science Education and Research, Kolkata
Mohanpur 741246, West Bengal, India
Palasetty Chandu − Department of Chemical Sciences, Indian
Institute of Science Education and Research, Kolkata
Mohanpur 741246, West Bengal, India
Complete contact information is available at:
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J. Org. Chem. XXXX, XXX, XXX−XXX

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pubs.acs.org/joc
Note
and Diastereoselective Construction of Spiro-Benzofuran Scaffolds.
Synthesis 2020, DOI: 10.1055/s-0040-1707205.
Heterocyclic Carbene Complexes: Synthesis, Structure, and Applica-
tion. Chem. Rev. 2005, 105, 3978−4008.
(13) (a) Armarego, W. L. F.; Chai, C. L. L. Purification of Laboratory
Chemicals, 6th ed.; Elsevier Science: Amsterdam, 2009. (b) Huang, B.;
Shen, Y.; Mao, Z.; Liu, Y.; Cui, S. Metathesis Reaction of Diazo
Compounds and para-Quinone Methides for C-C Double Bond
Formation: Synthesis of Tetrasubstituted Alkenes and Quinolinones.
Org. Lett. 2016, 18, 4888−4891. (c) Inagaki, M.; Haga, N.; Kobayashi,
M.; Ohta, N.; Kamata, S.; Tsuri, T. Highly E-Selective and Effective
Synthesis of Antiarthritic Drug Candidate S-2474 using Quinone
Methide Derivatives. J. Org. Chem. 2002, 67, 125−128.
(6) (a) Lima, C. G. S.; Pauli, F. P.; Costa, D. C. S.; de Souza, A. S.;
Forezi, L. S. M.; Ferreira, V. F.; de Carvalho da Silva, F. para-Quinone
Methides as Acceptors in 1,6-Nucleophilic Conjugate Addition
Reactions for The Synthesis of Structurally Diverse Molecules. Eur.
J. Org. Chem. 2020, 2020, 2650−2692. (b) Turner, A. B. Quinone
methides. Q. Rev., Chem. Soc. 1964, 18, 347−360. (c) Lu, H.; Zhang,
H.-X.; Tan, C.-Y.; Liu, J.-Y.; Wei, H.; Xu, P.- F. One-Pot Asymmetric
Synthesis of Spiropyrazolone-Linked Cyclopropanes and Benzofurans
Through a General Michael Addition/Chlorination/Nucleophilic
Substitution Sequence. J. Org. Chem. 2019, 84, 10292−10305.
(d) Zhao, M.-X.; Xiang, J.; Zhao, Z.-Q.; Zhao, X.-L.; Shi, M.
Asymmetric Synthesis of Dihydrocoumarins via Catalytic Sequential
1,6-Addition/Transesterification of α-Isocyanoacetates with para-
Quinone Methides. Org. Biomol. Chem. 2020, 18, 1637−1646.
(e) Wang, D.; Ge, B.; Li, L.; Shan, J.; Ding, Y. Transition Metal-
Free Direct C-H Functionalization of Quinones and Naphthoqui-
nones with Diaryliodonium Salts: Synthesis of Aryl Naphthoquinones
as β-Secretase Inhibitors. J. Org. Chem. 2014, 79, 8607−8613.
(7) Richter, D.; Hampel, N.; Singer, T.; Ofial, A. R.; Mayr, H.
Synthesis and Characterization of Novel Quinone Methides:
Reference Electrophiles for The Construction of Nucleophilicity
Scales. Eur. J. Org. Chem. 2009, 2009, 3203−3211.
(14) Bohnen, C.; Bolm, C. N-Trifluoromethylthiolated Sulfoximines.
Org. Lett. 2015, 17, 3011−3013.
(8) (a) Jarava-Barrera, C.; Parra, A.; Lopez, A.; Cruz-Acosta, F.;
Collado-Sanz, D.; Cardenas, D. J.; Tortosa, M. Copper-Catalyzed
Borylative Aromatization of p-Quinone Methides: Enantioselective
Synthesis of Dibenzylic Boronates. ACS Catal. 2016, 6, 442−446.
(b) Sharma, B. M.; Shinde, D. R.; Jain, R.; Begari, E.; Satbhaiya, S.;
Gonnade, R. G.; Kumar, P. Unravelling the Nucleophilicity of
Butenolides for 1,6-Conjugate Addition to p-Quinone Methides: A
Direct Access to Diversely Substituted Butenolide-Derived Diaryl-
methanes. Org. Lett. 2018, 20, 2787−2791. (c) Goswami, P.; Singh,
G.; Vijaya Anand, R. N-Heterocyclic Carbene Catalyzed 1,6-
Conjugate Addition of Me3Si-CN to para-Quinone Methides and
Fuchsones: Access to α-Arylated Nitriles. Org. Lett. 2017, 19, 1982−
1985. (d) Shirsath, S. R.; Shinde, G. H.; Shaikh, A. C.;
Muthukrishnan, M. Accessing α-Arylated Nitriles via BF3·OEt2
Catalyzed Cyanation of para-Quinone Methides Using tert-Butyl
Isocyanide as A Cyanide Source. J. Org. Chem. 2018, 83, 12305−
12314. (e) Yu, J.; Sheng, H.; Wang, S.; Xu, Z.; Chen, S.-L.; Tang, S.
Copper-Catalyzed Radical Cascades of para-Quinone Methides with
AIBN and H2O via α-Cyanoalkylation by C-C Bond Cleavage: New
Access to Benzofuran-2(3H)-ones. Chem. Commun. 2019, 55, 4578−
4581. (f) Wang, J.-Y.; Hao, W.-J.; Tu, S.-J.; Jiang, B. Recent
Developments in 1,6-Addition Reactions of para-Quinone Methides
(p-QMs). Org. Chem. Front. 2020, 7, 1743−1778.
(9) Caruana, L.; Kniep, F.; Johansen, T. K.; Poulsen, P. H.;
Jørgensen, K. A. A New Organocatalytic Concept for Asymmetric α-
Alkylation of Aldehydes. J. Am. Chem. Soc. 2014, 136, 15929−15932.
(10) (a) Qi, J.; Deng, Z.; Huang, B.; Cui, S. Metal-Free α-Alkylation
of Alcohols with para-Quinone Methides. Org. Biomol. Chem. 2018,
16, 2762−2767. (b) Shen, Y.; Qi, J.; Mao, Z.; Cui, S. Fe-Catalyzed
Hydroalkylation of Olefins with para-Quinone Methides. Org. Lett.
2016, 18, 2722−2725.
(11) (a) Wu, Q.-Y.; Ao, G.-Z.; Liu, F. Redox-Neutral tri-/di-
Fluoromethylation of para-Quinone Methides with Sodium Sulfi-
nates. Org. Chem. Front. 2018, 5, 2061−2064. (b) Wu, Q.-Y.; Min, Q.-
Q.; Ao, G.-Z.; Liu, F. Radical Alkylation of para-Quinone Methides
with 4-Substituted Hantzsch Esters/Nitriles via Organic Photoredox
Catalysis. Org. Biomol. Chem. 2018, 16, 6391−6394. (c) Ghosh, K. G.;
Chandu, P.; Mondal, S.; Sureshkumar, D. Visible-light Mediated
Trifluoromethylation of p-Quinone Methides by 1,6-Conjugate
Addition using Pyrylium Salt as Organic Photocatalyst. Tetrahedron
2019, 75, 4471−4478.
(12) (a) Yanagisawa, A. In Lewis Acids in Organic Synthesis;
Yamamoto, H., Ed.; Wiley-VCH Verlag GmbH: Weinheim, Germany,
2000; pp 575−596. (b) Garrison, J. C.; Youngs, W. J. Ag(I) N-
I
https://dx.doi.org/10.1021/acs.joc.0c01752
J. Org. Chem. XXXX, XXX, XXX−XXX