Visible-light mediated trifluoromethylation of p-quinone methides by 1,6-conjugate addition using pyrylium salt as organic photocatalyst

Article abstract of DOI:10.1016/j.tet.2019.06.029

A transition metal free visible light mediated organo photoredox catalyzed trifluoromethylation of p-quinone methides (p-QMs) to construct fluoro-analogs of dichlorodiphenyltrichloroethane (DDT) is reported using a bench stable, inexpensive Langlois reagent as a trifluoromethyl radical source. This protocol could generate a benzylic C(sp³)-CF₃ bond with excellent yield under mild reaction conditions using 1,6-conjugate addition/aromatization of trifluoromethyl radical in the absence of any external additives. Further, we demonstrate di-trifluoromethylation and gram scale synthesis of this reaction.

Full text of DOI:10.1016/j.tet.2019.06.029

Accepted Manuscript
Visible-light mediated trifluoromethylation of p-quinone methides by 1,6-conjugate
addition using pyrylium salt as organic photocatalyst
Krishna Gopal Ghosh, Palasetty Chandu, Santanu Mondal, Devarajulu Sureshkumar
PII:
S0040-4020(19)30691-X
https://doi.org/10.1016/j.tet.2019.06.029
TET 30421
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 May 2019
Revised Date: 8 June 2019
Accepted Date: 18 June 2019
Please cite this article as: Ghosh KG, 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), doi: https://doi.org/10.1016/j.tet.2019.06.029.
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ACCEPTED MANUSCRIPT
Organo photoredox catalyzed trifluoromethylation of p-quinone methides (p-QMs) to construct
fluoro-analogs of dichlorodiphenyltrichloroethane (DDT) is reported. This protocol could
generate a benzylic C(sp3)–CF3 bond with excellent yield. We also demonstrate the di-
trifluoromethylation of p-QM.
OH
OH
O
T(p-CH3)PPT (5 mol%)
T(p-CH3)PPT (5 mol%)
CF3SO2Na, CH3CN
CF3SO2Na, CH3CN
27 W blue LED, N2
35 °C, 6 h
27 W blue LED, N2
35 °C, 6 h
F3C
R = Cl; Yield: 68%
F3C
CF3
R
R
R = Aryl, alklyl; Yields: upto 97%

ACCEPTED MANUSCRIPT
Visible-light mediated trifluoromethylation of p-quinone methides by 1,6-
conjugate addition using pyrylium salt as organic photocatalyst
Krishna Gopal Ghosh,a Palasetty Chandu,a Santanu Mondalb and Devarajulu Sureshkumar *a
aDepartment of chemical sciences, Indian Institute of Science Education and Research Kolkata
b
Mohanpur-741246, West Bengal, India. Okinawa institute of Science and Technology (OIST), 1919-1,
Tancha, Onna-son, Okinawa, Japan
Abstract: A transition metal free visible light mediated organo photoredox catalyzed
trifluoromethylation of p-quinone methides (p-QMs) to construct fluoro-analogs of
dichlorodiphenyltrichloroethane (DDT) is reported using a bench stable, inexpensive Langlois
reagent as a trifluoromethyl radical source. This protocol could generate a benzylic C(sp3)-CF3
bond with excellent yield under mild reaction conditions using 1,6-conjugate
addition/aromatization of trifluoromethyl radical in the absence of any external additives.
Further, we demonstrate di-trifluoromethylation and gram scale synthesis of this reaction.
Keywords: Trifloromethylation, Photoredox Catalysis, p-Quinone Methides (p-QMs), 1,6-
Conjugate Addition, Organocatalysis
1. Introduction:
The selective introduction of trifluoromethyl group1 into organic structures is immensely
useful in advance functional materials, pharmaceutical, and agrochemical industry.2 The
advantage mainly arises due to the properties of fluorine such as high electronegativity,
enhanced metabolic stability, and lipophilicity leading to higher bioavailability of drug leads.3
These properties led to the development of numerous electrophilic,4 nucleophilic5 and radical
trifluoromethylation6 of organic molecules. Radical trifluoromethylation, in particular, has
received considerable attention due to chemoselective incorporation under mild reaction
conditions. Many reagents such as gaseous CF3I,6c low boiling CF3SO2Cl,6d expensive Togni4a,6e
or Umemoto reagent,6f Rupert-Prakash reagent (TMSCF3)6g and Langlois reagent (CF3SO2Na)7
have been used as trifluoromethyl radical sources. Among these, Langlois reagent (CF3SO2Na) is
a bench stable solid salt that is easy to handle, commercially available and inexpensive. It has
been widely used as a trifluoromethyl radical source particularly to construct C(sp3)-CF3 bonds.8
Many studies show the generation of trifluoromethyl group from Langlois reagent either by
1

ACCEPTED MANUSCRIPT
traditional transition metal catalysts such as Mn, Cu, Ag, etc.9 or with a strong oxidant like
peroxide8b,9c but these methods have limitations such as high cost, high temperature and use of
toxic and explosive peroxide as oxidant.
Visible light induced photoredox catalysts10 is an emerging alternative approach that avoids
expensive, toxic metal catalysts and strong oxidants. Such photocatalysts can activate a molecule
in a much greener way and under mild reaction condition.10c Although there are some reports on
visible light catalysis to construct C(sp3)-CF3 bond11 using expensive trifluoromethyl sources, till
date, only limited number of methods have been established for the generation of trifluoromethyl
radical from inexpensive Langlois reagent,8b,12 using organic photoredox catalysis.11b,13
The trifluoroethyl aromatics, the fluoro analogous of DDT is of interest in agriculture as they
are effective fungicides and insecticides (Figure 1).14 However, limited reports are known for the
synthesis of fluoroanalogous DDT due to many drawbacks like replacement of chlorine by
fluorine of 2,2,2-trichloroaromatics,14b reduction of diaryl trifluoroethyl aromatics14c or by
Friedel-Crafts reaction of a trifluoromethyl benzyl alcohol.14d But all these methods suffer from
toxic reagent, low yield or multistep procedure. Despite much progress in radical chemistry,
visible light photocatalyzed 1,6-conjugate addition to p-QMs is poorly studied. Recently,
difluoro alkylated diarylmethane was synthesized from p-QMs using copper16a and visible light
photocatalysts using fac-Ir(bpy)3 as photocatalyst .16b
Surya Prakash et al. reported BF3·H2O catalyzed Friedel-crafts reaction of arenes using
trifluoroacetaldehyde methyl hemiacetal (Scheme 1a).14e However, this method is applicable
only for the synthesis of symmetric fluoroanalogous. We are interested in synthesis of
unsymmetrical fluoroanalogous using pyrylium salt photocatalysis17 because it has higher
oxidation potentials, cheaper, and can be easily synthesized from commercially available
benzaldehyde and acetophenone in a single step as compared to acridinium salts which was
reported by Nicewicz and co-workers.11b Given the importance of radical trifluoromethylation,
there is a need for a simple, mild yet effective methodology to synthesize fluoroanalogs of DDT.
Herein, we are reporting a simple strategy for synthesizing unsymmetrical fluoroanalogous of
DDT using visible-light mediated trifluoromethylation of p-QMs by 1,6-conjugate addition using
Langlois reagent and pyrylium salt as an an organic photocatalyst. Due to its electrophilic nature
p-QMs act as a reactive Michael acceptor for various 1,6-conjugate addition/aromatization.15
2

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Despite the elegant work of Feng Liu and coworkers,16c our methodology shows pyrylium salt
catalyzed visible-light mediated trifluoromethylation of p-QMs with some improvements, such
as: cheaper pyrylium
Figure 1 Representative biologically active diarylmethane
(a) Surya Prakash’s Group: Synthesis of fluoroanalogous of DDT, a fluorinated
diarylmethane
(b) Feng Liu’s Group work and our strategy: Trifluoromethylation of
methides
p-quinone
salt as an efficient photocatalyst, shorter reaction times, additive free reactions conditions, highly
chemoselective, broad substrate scope, di-trifluoromethylation of p-QM and high chemical yield.
2. Result and discussion:
Our study began with the construction of new benzylic C(sp3)-CF3 bond using p-QMs
derivative 1a as a model substrate. From literature reports, it was known that
Ir[{dF(CF3)ppy}2(dtbbpy)]PF6 which has an excited state reduction potential [Ered1/2(*IrIII/IrII)]14a
of +1.21 V vs SCE in MeCN can generate trifluoromethyl radical by oxidizing the Langlois
reagent [Eox =1.05 V vs SCE in MeCN]18b under suitable visible light by single electron
1/2
transfer (SET). We performed the reaction of 1a with 2 equivalent of Langlois reagent and
2 mol% of Ir[{dF(CF3)ppy}2(dtbbpy)]PF6 photocatalyst in acetonitrile (0.05 M) solvent
3

ACCEPTED MANUSCRIPT
under nitrogen atmosphere. After irradiation for 6 h using 27 W blue LED, we observed
the desired product formation with 3% yield based on 19F NMR. Then we carried out the
Table 1 Optimization of reaction conditionsa
Entry Photocatalyst
Ir[(dFCF3ppy)2(dtbbpy)]PF6
Solvent
CH3CN
Yieldb
3%
1%
1c
2c
3
4
5
6
7
8
9
10
11
12
13
14d
15e
Ir[(ppy)2(dtbbpy)]PF6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
Dioxane
Acetone
DMSO
DME
–
Acr-mes+ClO4
82%
53%
26%
99%
24%
86%
35%
79%
0%
TPPT
T(p-F)PPT
T(p-CH3)PPT
T(p-Cl)PPT
T(p-CH3)PPT
T(p-CH3)PPT
T(p-CH3)PPT
T(p-CH3)PPT
T(p-CH3)PPT
-
76%
0%
0%
CH3CN
CH3CN
CH3CN
T(p-CH3)PPT
T(p-CH3)PPT
0%
aReaction condition: 1a (0.15 mmol), 2 (0.3 mmol), photocatalysts (5 mol%), solvent (3.0
mL), irradiation with 27 W Blue LED, 35 °C, 6 h, b19F NMR Yield using trifluorotolune
as internal standard. c2 mol% of photocatalysts was used, dwithout light, e2 eq. TEMPO
.
4

ACCEPTED MANUSCRIPT
reaction with a series of metal photoredox catalysts such as Ir[(ppy)2(dtbbpy)]PF6
[Ered1/2(*IrIII/IrII) = +0.66 V], (entry 2), fac-Ir(ppy)3 [Ered1/2(*IrIII/IrII) = +0.3 V],
Ru(bpy)3Cl2·6H2O [Ered1/2(*RuII/RuI) = +0.77 V], (see ESI), but as anticipated from their
redox potential values, none of them gave the expected product. The organic photo redox
–
catalysts, 9-mesityl-10-methyl-acridinium perchlorate (Acr- mes+ClO4 ) which has an
excited state redox potential of +2.06 V (vs SCE in MeCN) is also known to generate
trifluoromethyl radical from Langlois reagent. This catalyst gave the expected product in
82% yield at 5 mol% catalysts loading (Entry 3). Next, we screened different pyrylium
photocatalysts such as TPPT in MeCN), T(
CH3)PPT (+2.10 V vs SCE in MeCN), T( -Cl)PPT (+2.30 V vs SCE in MeCN) (+2.30 V
vs SCE (Entry 4-7), among which T( -CH3)PPT gave yield of 99% while other catalysts
p-F)PPT (+2.29 V vs SCE in MeCN), T(p-
p
p
either failed or gave a relatively lower yield (see ESI). We also checked other common
organic dyes (see ESI) but none of them led to the desired product. Then, we screened a
series of solvents using 5 mol% of T(
acetonitrile as the best solvent. Our results indicated that 2 equivalent of Langlois reagent,
5 mol% of T( -CH3)PPT photocatalyst in acetonitrile (0.05 M) solvent in nitrogen
p-CH3)PPT (Entry 8-12 and also see ESI) and found
p
atmosphere under irradiation of 27 W blue LED as best conditions for this reaction (Entry
6). No product was detected in control experiments in the absence of photocatalyst or
1
light. (Entry 13, 14). The product was confirmed by H NMR, 13C NMR, 19F NMR,
HRMS, and single crystal X-ray analysis.
Next, the substrate scope of the optimized reaction conditions was tested with a wide
variety of
afforded the corresponding trifluoromethylated diarylmethane derivatives (3a-3e) in
excellent isolated yields (86-97%). The phenyl ring of -QMs bearing halogen
p-QMs derivatives as depicted in Scheme 2. Simple substituents on phenyl ring
p
substituents produced the desired products (3f-3k) in good to excellent isolated yields
ranging from 77 to 94%. Presence of strong electron withdrawing groups on phenyl ring
such as p-NO2, p-CF3, m-CN, p-CO2Me delivered the corresponding products in 83%,
89%, 85%, and 94% (3l-3o) yields respectively. However, the electron donating
substituent on benzene ring
5

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OH
OH
OH
OH
OH
F3C
F3C
F3C
F3C
F3C
Ph
3c, 94%
3d, 86%
3a, 97%
3b, 96%
3e, 92%
OH
OH
OH
OH
OH
Cl
Br
F3C
F3C
F3C
F3C
F3C
Br
Cl
F
3f, 77%
3g, 88%
3h, 94%
3i, 80%
3j, 89%
OH
OH
OH
OH
OH
CN
F3C
F3C
F3C
F3C
F3C
NO2
CF3
CO2Me
F
3k, 87%
3l, 83%
3m, 89%
3n, 85%
3o, 94%
OH
OH
OH
OH
OH
OMe
OMe
S
F3C
F3C
F3C
F3C
F3C
OMe
N
3p, 73%
3q, 88%
3r, 90%
3s, 68%
3t, 59%
OH
OH
OH
OH
OH
F3C
F3C
F3C
F3C
F3C
3u, 86%
3v, 79%
3w, 88%
3x, 79%
3y, 93%
Scheme 2 Substrate scope for trifluoromethylation of p-quinone methide
6

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furnished the expected product (3p and 3q) with isolated yields of 73% and 88%
respectively but with longer reaction time (16 h). The p-QM derived from pyridine-3-
carboxaldehyde gave the trifluoromethylated product (3r) in excellent isolated yield of
Scheme 3 Ditrifluoromethylation of p-quinone methide 1aa
(a) Gram-scale reaction:
(b) Regeneration of p-quinone methide and de-tert butylation reaction:
Scheme 4 Synthetic application of trifluoromethylated p-quinone methide
90%. On the other hand,
naphthaldehyde gave the expected product (3s and 3t) in a lower isolated yield of 68%
and 59% respectively, possibly due to higher reactivity of -QM derived from thiophene-
2-carboxaldeyhde led to undesired side products formation. The steric effect could be one
p-QMs derived from thiophene-2-carbaxaldeyhde, and 3-
p
possible reason for the lower yield in the case of 3t. The corresponding
p-QMs of
7

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isobutyraldehyde and pivalaldehyde gave the trifluoromethylated products (3u and 3v
)
with isolated yield of 86% and 79% respectively Interestingly,
diisopropyl-phenol, 2,6-dimethyl-phenol and 2-tert-butyl-6-methyl phenol offered the
expected products 3w-3y in excellent yields (88%, 79% and 93%
respectively).Interestingly, when -QM 1aa was subjected to our optimized reaction
conditions, di-trifluoromethylated product was isolated in 68% yield (Scheme 3). To
p-QMs from 2,6-
(
)
p
4
show the synthetic utility and scalability of this methodology, we performed the reaction
in 5 mmol scale under the same optimized conditions (Scheme 4a) and desired product 3a
was obtained in excellent isolated yield of 84%. Further, we regenerated
(Scheme 4b) using 4 eq. of K3[Fe(CN)3] and 4.2 eq. of KOH in 1:1 mixture of H2O and
hexane at rt. Trifluoromethylated -QM was obtained as an orange solid with an
isolated yield of 83%. Also, we have demonstrated de-tertiary-butylation reaction of 3a
p-QM 5 from 3a
p
5
by treating with catalytic amount of H2SO4 at 120 °C to obtain
4b).
6 in 84% yield (Scheme
Figure 2 Proposed mechanism for trifluoromethylation of p-QMs
8

ACCEPTED MANUSCRIPT
To gain mechanistic insights, the reaction was performed in the presence of 2 eq. of
TEMPO (Table 1, Entry 15) using optimized reaction conditions. The reaction failed to
offer the desired product suggesting a radical mechanism. Based on this experimental
support and related literature reports18 a plausible mechanism is shown in Figure 2.
Initially, the photoexcited state of organic photocatalyst oxidizes the Langlois reagent by
abstracting a single electron to generate trifluoromethyl radical which adds to the
to generate the intermediate , and then the radical donates an electron to forming
intermediate to regenerate the catalytic cycle. Finally, protonation of produces 3a
p-QMs
A
C
A
B
B
.
3. Conclusions:
In summary, we have developed a mild and efficient method for radical
trifluoromethylation of -quinone methide under visible light organic photo-catalysis
p
using bench stable and inexpensive Langlois reagent as trifluoromethyl radical source.
We have used pyrylium catalysts for the first time for the generation of trifluoromethyl
radical from Langlois reagent. The reaction reported here has high functional group
tolerance and offers chemical yield > 80% in most of the cases. The synthetic utility has
been demonstrated by performing the reaction in large scale, regeneration of
trifluoromethyl-p-quinone methide and de-tertiary butylation reactions.
4. Experimental Section:
4.1. General Information:
Commercial reagents and solvents were purified prior to the use following the
guidelines of L.L Chai and Armarego. All NMR spectra were recorded on 400 MHz Jeol
1
13
19
spectrometers. H, C and F NMR spectral data are reported as chemical shifts (
parts per million (ppm) relative to the solvent residual peak using the Jeol internal
referencing procedure (edlock). Chemical shifts ( ) are quoted in parts per million (ppm)
δ) in
δ
and coupling constants (J) are measured in hertz (Hz). 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 doublet. High resolution mass spectra
(HRMS, m/z) were recorded on a Bruker MicroTOF. IR spectra were recorded on Perkin
9

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Elmer Frontier FT-IR spectrometer. All reactions for trifluoromethylation of p-quinone
methides were conducted in dried glassware with magnetic stirring under an inert
atmosphere, unless otherwise noted. Thin Layer Chromatography (TLC) were performed
using Silica gel 60 F254 and visualized under ultraviolet light. Flash column
chromatography was performed over Merck Silica gel (230−400 ꢀm). IrCl3·xH2O was
purchased from Souvenier chemicals, CF3SO2Na purchased from TCI chemical. All the
metal catalysts were either prepared by reported literature procedure19 or purchased from
the Sigmaldrich and used without further purification. Unless otherwise specified, other
reagents were obtained from commercial suppliers Alfa aesar, and Spectrochem. In a
general experiment, a 9 x 3 W blue LEDS were connected in series connection and used
as a visible light source with a cooling fan.
4.2. Synthesis of pyrylium salts:
BF3·Et2O (3.1 equiv.) was added dropwise under a N2 atmosphere to a solution of
appropriate benzaldehyde derivatives (1 equiv.) and appropriate acetophenone derivatives (3
equiv.) (3 mL toluene was added in case of solid). The mixture was heated to 80 ºC until the
reaction was completed, monitored by TLC (1 : 4 EtOAc–hexane). The residue was eventually
treated with EtOH or Et2O. Crystallization from acetone gave the corresponding pure pyrylium
tetrafluoroborate salts, which are identical to literature reports20.
4.3. Synthesis of p-quinone methides:
In an oven dried 250 mL round bottom fitted with a Dean-stark apparatus, the phenol (25
mmol) and the appropriate aldehyde (25 mmol) were taken. To this toluene (100 mL) was added
and heated to reflux followed by the dropwise addition of the piperidine (50 mmol) over a period
of 1 h. The reaction mixture was continued to reflux for overnight. After that it was cooled just
below the boiling point of the reaction mixture and acetic anhydride (50 mmol) was added and
continued for refluxing for 30 min. It was then poured into a 500 mL of ice-cooled water and
extracted with CH2Cl2 (2 x 250 mL). The combined organic phase was dried over Na2SO4 and
solvent was removed under reduced pressure using rotovac. The product was finally purified
using column chromatography to afford the corresponding p-quinone methides (1a-1w, 1z).
p-quinone methides 1aa, 1x and 1y were prepared according to the literature report.21,22
10

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4.4. Experimental procedure for Synthesis of 3:
To an oven dried borosilicate test tube equipped with a magnetic stir bar was added p-QMs
(0.15 mmol, 1 eq.), CF3SO2Na (0.30 mmol, 2 eq.) and 5 mol% photocatalyst T(p-CH3)PPT (3.3
mg, 0.05 equiv.). The reaction tube was vacuumed and backfilled with argon (3 times) and put a
septum over the reaction tube. Then 3 mL of CH3CN was added through the septum by a
syringe, and placed approximately 5 cm from light setup. After 6 h of the reaction 10 mL of
water was added and extracted with DCM (3 x 20 mL). The combined organic layer was dried
over Na2SO4 and solvent was removed under reduced pressure. The crude product was then
purified by Flash column chromatography on silica gel mesh 230-400 using hexane and DCM as
an eluent to afford the product 3. The reported data16c for compound 3a, 3b, 3d, 3g, 3h, 3i, 3j, 3l,
3o, 3q, 3r, 3s and 3x are well matched with our data.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-phenylethyl)phenol (3a): Rf
=
0.4 (hexane);
1
Colorless solid; Yield 97% (53.1 mg); H NMR (400 MHz, CDCl3)
δ 7.47 (d, J = 7.4 Hz, 2H),
7.40 (t, J = 7.3 Hz, 2H), 7.37 – 7.32 (m, 1H), 7.23 (s, 2H), 5.26 (s, 1H), 4.64 (q, J = 10.1 Hz,
1H), 1.48 (s, 18H); 13C NMR (101 MHz, CDCl3)
153.4, 136.1, 135.9, 129.0, 128.6, 127.7,
126.5 (q, JC-F = 280.4 Hz), 126.0, 125.8, 55.6 (q, JC-F = 27.1 Hz) , 34.4, 30.2; 19F NMR (376
MHz, CDCl3) -65.86 (d, J = 10.1 Hz); FT-IR (thin film, KBr): 3630, 2972, 1637, 1397, 1267,
δ
δ
1238, 1198, 1141, 1124, 1107, 863, 760, 701, 657, 641, 603 cm–1; HRMS (ESI): m/z calcd for
C22H26F3O [M–H]+ : 363.1936; found : 363.1947.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(p-tolyl)ethyl)phenol (3b): Rf = 0.4 (hexane);
Colorless solid; Yield 96% (54.5 mg); 1H NMR (400 MHz, CDCl3)
δ
7.31 (d, J = 7.9 Hz, 2H),
13
7.21 – 7.11 (m, 4H), 5.21 (s, 1H), 4.55 (q, J = 10.2 Hz, 1H), 2.36 (s, 3H), 1.44 (s, 18H); C
NMR (101 MHz, CDCl3)
δ
153.3, 137.4, 135.8, 133.1, 129.3, 128.9, 126.5 (q, JC-F = 280.4),
19
126.1, 125.7, 55.2 (q, JC-F = 27.1Hz), 34.3, 30.2, 21.0; F NMR (376 MHz, CDCl3)
δ -65.97 (d,
J = 10.2 Hz); FT-IR (thin film, KBr): 3614, 3008, 2966, 2923, 2873, 1435, 1259, 1237, 1154,
1104, 861, 811, 799, 725, 710, 641 cm–1; HRMS (ESI): m/z calcd for C23H29F3O [M–H]+ :
377.2092; found : 377.2101.
11

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2,6-Di-tert-butyl-4-(1-(4-(tert-butyl)phenyl)-2,2,2-trifluoroethyl)phenol (3c): Rf = 0.5
(hexane); Colorless solid; Yield 94% (59.4 mg); 1H NMR (400 MHz, CDCl3)
δ
7.41 – 7.32 (m,
13
4H), 7.20 (s, 2H), 5.21 (s, 1H), 4.55 (q, J = 10.2 Hz, 1H), 1.44 (s, 18H), 1.33 (s, 9H); C NMR
(101 MHz, CDCl3)
δ
153.4, 150.5, 135.8, 133.0, 128.6, 126.6 (q, JC-F = 280.6), 126.1, 125.8,
-65.92 (d,
125.5, 55.2 (q, JC-F = 27.3 Hz), 34.5, 34.4, 31.3, 30.2; 19F NMR (376 MHz, CDCl3)
δ
J = 9.9 Hz); FT-IR (thin film, KBr): 3618, 2972, 2866, 1639, 1519, 1438, 1399, 1364, 1329,
1316, 1267, 1252, 1237, 1193, 867, 815, 750, 702, 657, 647, 604 cm–1; HRMS (ESI): m/z calcd
for C26H35F3O [M–H]+ : 419.2562; found : 419.2573.
4-(1-([1,1'-)-2,6-Di-tert-butylphenolbiphenyl]-4-yl)-2,2,2-trifluoroethyl (3d): Rf =
1
0.5 (hexane); colorless solid; Yield 86% (56.8 mg); H NMR (400 MHz, CDCl3)
δ
7.62
(d,
J
= 8.2 Hz, 4H), 7.51 (d,
J
= 8.2 Hz, 2H), 7.46 (dd,
= 10.1 Hz, 1H), 1.46 (s, 18H); C NMR
J = 10.3, 4.7 Hz, 2H), 7.40 – 7.34
13
(m, 1H), 7.23 (s, 2H), 5.25 (s, 1H), 4.65 (q,
J
(101 MHz, CDCl3)
δ
153.5, 140.5,140.4, 135.9, 135.0, 129.4, 128.8, 127.4, 127.3, 127.1,
19
126.5 (q, JC-F = 280.5 Hz) 125.9, 125.8, 55.2 (q, JC-F = 27.0 Hz), 34.4, 30.2; F NMR
(376 MHz, CDCl3)
δ -65.80 (d, J = 10.1 Hz); FT-IR (thin film, KBr): 3614, 3007, 2964,
1637, 1401, 1247, 1191, 1146, 1122, 1103, 833, 761, 697, 658, 602 cm–1; HRMS (ESI):
m/z calcd for C28H31F3O [M–H]+ : 439.2249; found : 439.2260.
2,6-Di-tert-butyl-4-(1-(4-ethylphenyl)-2,2,2-trifluoroethyl)phenol (3e): Rf = 0.4
(hexane); colorless solid; Yield 92% (54.3 mg); 1H NMR (400 MHz, CDCl3)
= 7.9 Hz, 2H), 7.25 – 7.16 (m, 4H), 5.23 (s, 1H), 4.58 (q, = 10.2 Hz, 1H), 2.68 (q, J =
7.6 Hz, 2H), 1.46 (s, 18H), 1.27 (t, 153.4,
= 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 7.36 (d, J
J
J
δ
143.6, 135.8, 133.2, 128.9, 128.1, 126.6 (q, JC-F = 280.4 Hz), 126.1, 125.7, 55.2 (q, JC-F
=
19
27.2 Hz), 34.3, 30.2, 28.4, 15.4; F NMR (376 MHz, CDCl3)
δ -65.94 (d, J = 10.0 Hz);
FT-IR (thin film, KBr): 3616, 2970, 2870, 1634, 1513, 1434, 1402, 1362, 1267, 1192,
1146, 1101, 863, 814, 658, 643, 602 cm–1; HRMS (ESI): m/z calcd for C24H31F3O [M–
H]+ : 391.2249; found : 391.2259.
4-(1-(3-Bromophenyl)-2,2,2-trifluoroethyl)-2,6-di-tert-butylphenol (3f): Rf = 0.5
(hexane); Light yellow oil; Yield 77% (51.4 mg); 1H NMR (400 MHz, CDCl3)
1H), 7.50 (d, = 8.0 Hz, 1H), 7.40 (d, = 7.8 Hz, 1H), 7.29 (d, = 8.1 Hz, 1H), 7.18 (s,
2H), 5.29 (s, 1H), 4.58 (q,
δ 7.59 (s,
J
J
J
J
= 10.0 Hz, 1H), 1.48 (s, 18H); 13C NMR (101 MHz, CDCl3)
12

ACCEPTED MANUSCRIPT
δ
153.6, 138.2, 136.1, 132.2, 130.9, 130.1, 127.5, 126.1 (q, JC-F = 280.6 Hz), 125.7,
19
125.1, 122.6, 55.1 (q, JC-F = 27.6 Hz), 34.4, 30.2; F NMR (376 MHz, CDCl3)
δ -65.89
(d, J = 9.9 Hz); FT-IR (thin film, KBr): 3641, 2964, 2871, 1638, 1437, 1403, 1259, 1189,
1144, 1110, 780, 757, 701, 687, 657, 640, 603 cm–1; HRMS (ESI): m/z calcd for
C22H25BrF3O [M–H]+ : 441.1041; found : 441.1051.
4-(1-(4-Bromophenyl)-2,2,2-trifluoroethyl)-2,6-di-tert-butylphenol (3g): Rf = 0.5
(hexane); Light yellow oil; Yield 88% (58.7 mg); 1H NMR (400 MHz, CDCl3)
δ
7.48 (d,
= 7.6 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.11 (s, 2H), 5.23 (s, 1H), 4.53 (q, J = 10.0 Hz,
J
13
1H), 1.41 (s, 18H); C NMR (101 MHz, CDCl3)
δ
153.5, 136.0, 135.1, 131.7, 130.7,
19
126.1 (q, JC-F = 280.6 Hz), 125.6, 125.3, 121.8, 54.9 (q, JC-F = 27.5 Hz), 34.4, 30.2; F
NMR (376 MHz, CDCl3)
δ -66.00 (d, J = 10.0 Hz); FT-IR (thin film, KBr): 3627, 2970,
1637, 1491, 1436, 1399, 1258, 1155, 1108, 1011, 860, 807, 722, 655 cm–1; HRMS (ESI):
m/z calcd for C22H26BrF3O [M–H]+ : 441.1041; found : 441.1053.
2,6-Di-tert-butyl-4-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)phenol (3h): Rf = 0.4
1
(hexane); colorless solid; Yield 94% (56.1 mg); H NMR (400 MHz, CDCl3)
δ
7.37 –
13
7.29 (m, 4H), 7.11 (s, 2H), 5.22 (s, 1H), 4.55 (q,
J = 10.0 Hz, 1H), 1.41 (s, 18H); C
NMR (101 MHz, CDCl3)
δ
153.5, 136.0, 134.6, 133.7, 130.4, 128.8, 126.2 (q, JC-F =
19
280.5 Hz), 125.6, 125.4, 54.8 (q, JC-F = 27.4 Hz), 34.4, 30.2; F NMR (376 MHz,
CDCl3)
δ -66.02 (d, J = 10.0 Hz); FT-IR (thin film, KBr): 3628, 3002, 2965, 1633, 1400,
1258, 1191, 1138, 1102, 864, 757, 700, 656, 640, 603 cm–1; HRMS (ESI): m/z calcd for
C22H26ClF3O [M–H]+ : 397.1546; found : 397.1557.
2,6-Di-tert-butyl-4-(1-(2-chlorophenyl)-2,2,2-trifluoroethyl)phenol (3i): Rf = 0.4
(hexane); colorless solid; Yield 80% (47.7 mg); 1H NMR (400 MHz, CDCl3)
= 7.8 Hz, 1H), 7.41 (dd, = 7.7, 1.3 Hz, 1H), 7.31 (td, = 7.7, 1.2 Hz, 1H), 7.27 – 7.20
(m, 1H), 7.17 (s, 2H), 5.29 – 5.20 (m, 2H), 1.41 (s, 18H); 13C NMR (101 MHz, CDCl3)
δ 7.67 (d, J
J
J
δ
153.5, 135.8, 134.6, 134.1, 130.0, 129.1, 128.9, 127.0, 126.3 (q, JC-F = 280.7 Hz), 126.0,
19
124.7, 50.8 (q,
J = 27.9 Hz), 34.3, 30.2; F NMR (376 MHz, CDCl3) δ -65.35 (d, J =
10.1 Hz); FT-IR (thin film, KBr): 3631, 2962, 1638, 1400, 1259, 1193, 1148, 1106, 866,
757, 699, 656 cm–1; HRMS (ESI): m/z calcd for C22H26ClF3O [M–H]+ : 397.1546; found
: 397.1548.
13

ACCEPTED MANUSCRIPT
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)phenol (3j): Rf = 0.4
1
(hexane); Light yellow solid; Yield 89% (51.2 mg); H NMR (400 MHz, CDCl3)
δ 7.36
(dd,
J
= 8.2, 5.5 Hz, 2H), 7.12 (s, 2H), 7.04 (t,
J
= 8.7 Hz, 2H), 5.22 (s, 1H), 4.57 (q,
162.2 (d, JC-F = 246.6 Hz),
= 8.2 Hz), 126.3 (q, JC-F = 281.8 Hz), 125.7, 115.5 (d, JC-
= 21.4 Hz), 54.7 (q, JC-F = 27.5 Hz), 34.4, 30.2; 19F NMR (376 MHz, CDCl3)
-66.14
= 10.0 Hz), -114.58 – -114.70 (m); FT-IR (thin film, KBr): 3635, 2963, 2917, 2874,
J =
13
10.1 Hz, 1H), 1.42 (s, 18H); C NMR (101 MHz, CDCl3)
δ
153.5, 136.0, 131.9, 130.7 (d,
J
δ
F
(d,
J
1513, 1436, 1360, 1259, 1221, 1154, 1106, 1014, 868, 840, 809, 802, 773, 712, 641, 607,
507 cm–1; HRMS (ESI): m/z calcd for C22H26F4O [M–H]+ : 381.1842; found : 381.1851.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(2-fluorophenyl)ethyl)phenol (3k): Rf = 0.4
(hexane); colorless solid; Yield 87% (49.8 mg); 1H NMR (400 MHz, CDCl3)
= 7.6 Hz, 1H), 7.34 – 7.25 (m, 1H), 7.20 (s, 2H), 7.18 (d, = 6.5 Hz, 1H), 7.08 (t,
Hz, 1H), 5.24 (s, 1H), 5.04 (q, = 10.1 Hz, 1H), 1.43 (s, 18H); C NMR (101 MHz,
CDCl3) 160.5 (d, = 247.3 Hz), 153.6, 135.9, 129.4 (d, = 7.5 Hz), 129.3, 126.2 (q, JC-
δ
7.59 (t,
J
J
J
= 9.1
13
J
δ
J
J
F = 281.8 Hz), 125.9, 124.2 (d, JC-F = 3.4 Hz), 123.5 (d, JC-F = 13.6 Hz), 115.7 (d, JC-F
=
19
22.8 Hz), 47.4– 46.5 (m), 34.3, 30.2; F NMR (376 MHz, CDCl3)
δ -65.87 (dd, J = 9.8,
1.2 Hz), -116.92 – -117.06 (m); FT-IR (thin film, KBr): 3640, 2965, 1621, 1491, 1438,
1399, 1360, 1263, 1234, 1156, 1116, 867, 806, 758, 654 cm–1; HRMS (ESI): m/z calcd
for C22H26F4O [M–H]+ : 381.1842; found : 381.1851.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(4-nitrophenyl)ethyl)phenol (3l): Rf = 0.4
1
(10% DCM in hexane); Light yellow solid; Yield 83% (51.2 mg); H NMR (400 MHz,
CDCl3)
4.69 (q,
δ
8.22 (d,
J
= 8.8 Hz, 2H), 7.57 (d,
J
= 8.7 Hz, 2H), 7.09 (s, 2H), 5.27 (s, 1H),
13
J
= 9.7 Hz, 1H), 1.41 (s, 18H); C NMR (101 MHz, CDCl3) δ 153.9, 147.4,
143.2, 136.4, 130.0, 125.8 (q, JC-F = 281.8 Hz), 125.7, 124.5, 123.8, 55.2 (q, JC-F = 27.9
19
Hz), 34.3, 30.1; F NMR (376 MHz, CDCl3)
δ -65.72 (d, J = 9.8 Hz); FT-IR (thin film,
KBr): 3601, 2923, 1636, 1525, 1401, 1350, 1260, 1191, 1137, 1121, 1103, 850, 753, 656
cm–1; HRMS (ESI): m/z calcd for C22H26F3NO3 [M–H]+ : 408.1787; found : 408.1796.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)phenol
(3m): Rf = 0.5 (hexane); colorless solid; Yield 89% (57.5 mg);1H NMR (400 MHz,
CDCl3)
δ
7.62 (d,
J
= 8.2 Hz, 2H), 7.52 (d,
J
= 8.1 Hz, 2H), 7.13 (s, 2H), 5.25 (s, 1H),
14

ACCEPTED MANUSCRIPT
13
4.64 (q,
J
= 9.9 Hz, 1H), 1.42 (s, 18H); C NMR (101 MHz, CDCl3) δ 153.7, 140.0,
136.2, 130.0 (q, JC-F = 32.6 Hz), 129.4, 126.1 (q, JC-F = 280.4 Hz), 125.7, 125.6 (q, JC-F
3.7 Hz) 125.0, 124.0 (q, JC-F = 271.9 Hz), 55.3 (q, JC-F = 27.6 Hz); 34.4, 30.2; 19F NMR
(376 MHz, CDCl3) -62.58 (s), -65.81 (d, = 9.9 Hz); FT-IR (thin film, KBr): 3636,
=
δ
J
3018, 2977, 1633, 1400, 1327, 1262, 1191, 1156, 1110, 1067, 1018, 863, 847, 812, 751,
717, 657, 643 cm–1; HRMS (ESI): m/z calcd for C23H26F6O [M–H]+ : 431.1810; found :
431.1817.
3-(1-(3,5-Di-tert-butyl-4-hydroxyphenyl)-2,2,2-trifluoroethyl)benzonitrile (3n): Rf
1
= 0.3 (10% DCM in hexane); Light yellow solid; Yield 85% (49.8 mg); H NMR (400
MHz, CDCl3)
δ
7.67 (d,
J
= 9.7 Hz, 2H), 7.62 (d,
J
= 7.9 Hz, 1H), 7.49 (t, J = 7.8 Hz,
13
1H), 7.12 (s, 2H), 5.30 (s, 1H), 4.65 (q,
J
= 9.8 Hz, 1H), 1.44 (s, 18H); C NMR (101
MHz, CDCl3)
δ
153.8, 137.6, 136.3, 132.7, 131.4, 129.4, 125.9 (q, JC-F = 281.8 Hz),
19
125.6, 124.6, 118.5, 112.8, 54.9 (q, JC-F = 27.7 Hz), 34.3, 30.1; F NMR (376 MHz,
CDCl3)
δ -65.80 (d, J = 9.8 Hz); FT-IR (thin film, KBr): 3616, 3013, 2973, 2228, 1637,
1478, 1435, 1400, 1362, 1256. 1195, 1157, 1109, 857, 794, 745, 718, 697, 656, 602 cm–1;
HRMS (ESI): m/z calcd for C23H26F3NO [M–H]+ : 388.1888; found : 388.1899.
Methyl
4-(1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2,2-trifluoroethyl)benzoate
(3o): Rf = 0.3 (10% DCM in hexane); Light yellow solid; Yield 94% (59.5 mg);1H NMR
(400 MHz, CDCl3)
δ
8.04 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.13 (s, 2H), 5.25
13
(s, 1H), 4.65 (q, J = 10.0 Hz, 1H), 3.92 (s, 3H), 1.42 (s, 18H); C NMR (101 MHz,
CDCl3)
δ
166.7, 153.6, 141.0, 136.1, 129.9, 129.5, 129.0, 126.1 (q, JC-F = 281.8 Hz),
19
125.8, 125.2, 55.4 (q, JC-F = 27.6 Hz), 52.1, 34.3, 30.2; F NMR (376 MHz, CDCl3)
δ -
65.73 (d,
J = 9.9 Hz); FT-IR (thin film, KBr): 3628, 3022, 2940, 1715, 1628, 1400, 1194,
1139, 1124, 1100, 752, 658, 644, 603 cm–1; HRMS (ESI): m/z calcd for C24H29F3O3 [M–
H]+ : 421.1991; found : 421.2002.
2,6-Di-tert-butyl-4-(1-(3,4-dimethoxyphenyl)-2,2,2-trifluoroethyl)phenol (3p): Rf
1
= 0.3 (20% DCM in hexane); Colorless oil; Yield 73% (46.6 mg); H NMR (400 MHz,
CDCl3)
δ
7.18 (s, 2H), 6.97 – 6.91 (m, 2H), 6.85 (d,
J
= 8.3 Hz, 1H), 5.21 (s, 1H), 4.51 (q,
13
J
= 10.1 Hz, 1H), 3.87 (s, 6H), 1.42 (s, 18H); C NMR (101 MHz, CDCl3) δ 153.4,
148.7, 148.5, 135.9, 128.3, 126.1 (q, JC-F = 281.8 Hz), 126.0, 125.6, 121.5, 112.2, 111.1,
15

ACCEPTED MANUSCRIPT
19
55.8, 55.0 (q, JC-F = 27.2 Hz), 34.3, 30.2; F NMR (376 MHz, CDCl3)
δ -66.10 (d, J =
10.1 Hz); FT-IR (thin film, KBr): 3636, 2999, 2958, 2873, 2838, 1611, 1516, 1436, 1260,
1150, 1103, 1028, 887, 846, 808, 761, 712, 667, 633 cm–1; HRMS (ESI): m/z calcd for
C24H31F3O3 [M–H]+ : 423.2147; found : 421.2157.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)phenol (3q): Rf = 0.3
1
(10% DCM in hexane); Light yellow solid; Yield 88% (51.9 mg); H NMR (400 MHz,
CDCl3)
4.52 (q,
δ
7.31 (d,
J = 8.5 Hz, 2H), 7.15 (s, 2H), 6.89 (d, J = 8.8 Hz, 2H), 5.19 (s, 1H),
13
J
= 10.2 Hz, 1H), 3.80 (s, 3H), 1.42 (s, 18H); C NMR (101 MHz, CDCl3)
δ
159.0, 153.3, 135.8, 130.1, 128.1, 126.5 (q, JC-F = 281.8 Hz), 126.2, 125.6, 113.9, 55.2,
19
54.7 (q, JC-F = 27.0 Hz) 34.3, 30.2; F NMR (376 MHz, CDCl3)
δ -66.18 (d, J = 10.1
Hz); FT-IR (thin film, KBr): 3612, 3013, 2917, 1634, 1513, 1401, 1244, 1193, 1155,
1103, 1036, 837, 809, 753, 657, 604, 603 cm–1; HRMS (ESI): m/z calcd for C23H29F2O2
[M]+ : 394.2120; found : 394.2141.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(pyridin-3-yl)ethyl)phenol (3r):Rf = 0.5 (20%
1
DCM in hexane); colorless solid; Yield 90% (49.5 mg); H NMR (400 MHz, CDCl3)
δ
8.63 (d,
4.8 Hz, 1H), 7.12 (s, 2H), 5.28 (s, 1H), 4.60 (q,
(101 MHz, CDCl3) 153.7, 150.4, 149.0, 136.3, 136.2, 132.0, 126.1 (q, JC-F = 281.8 Hz),
125.6, 124.7, 123.4, 53.3 (q, JC-F = 27.9 Hz), 34.4, 30.2; 19F NMR (376 MHz, CDCl3)
66.00 (d, = 9.9 Hz); FT-IR (thin film, KBr): 3636, 2999, 2958, 2873, 2838, 1611, 1516,
J
= 1.3 Hz, 1H), 8.57 – 8.52 (m, 1H), 7.75 (d,
J = 8.0 Hz, 1H), 7.30 (dd, J = 8.0,
J
= 10.0 Hz, 1H), 1.41 (s, 18H); 13C NMR
δ
δ
-
J
1436, 1260, 1150, 1103, 1028, 887, 846 cm–1; HRMS (ESI): m/z calcd for C21H26F3NO
[M+H]+ : 366.2045; found : 366.2036.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(thiophen-2-yl)ethyl)phenol (3s): Rf = 0.4
(hexane); Colorless oil; Yield 68% (37.6 mg); 1H NMR (400 MHz, CDCl3)
(m, 1H), 7.23 (s, 2H), 7.08 (d, J = 3.3 Hz, 1H), 6.99 (dd, J = 5.1, 3.8 Hz, 1H), 5.25 (s,
1H), 4.80 (q, J = 9.6 Hz, 1H), 1.43 (s, 18H); 13C NMR (101 MHz, CDCl3)
153.8, 138.0,
δ 7.28 – 7.25
δ
136.0, 127.3, 126.7, 125.8, 125.7 (q, JC-F = 281.8 Hz), 125.5, 125.4,, 51.1 (q, JC-F = 28.7
19
Hz), 34.4, 30.2; F NMR (376 MHz, CDCl3)
δ -67.90 (d, J = 9.5 Hz); FT-IR (thin film,
KBr): 3625, 2961, 2872, 1633, 1433, 1401, 1342, 1327, 1311, 1247, 1138, 1104, 859,
16

ACCEPTED MANUSCRIPT
837, 771, 751, 702, 656, 602 cm–1; HRMS (ESI): m/z calcd for C20H25F3OS [M–H]+ :
369.1500; found : 369.1510.
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-(naphthalen-2-yl)ethyl)phenol (3t): Rf = 0.4
(hexane); Colorless solid; Yield 59% (36.4 mg); 1H NMR (400 MHz, CDCl3)
δ
7.85 (dd,
J
= 15.1, 9.1 Hz, 4H), 7.52 – 7.47 (m, 3H), 7.22 (s, 2H), 5.21 (s, 1H), 4.75 (q, JC-F = 10.1
Hz, 1H), 1.42 (s, 18H); 13C NMR (101 MHz, CDCl3)
δ 153.4, 135.9, 133.5, 133.2, 132.6,
128.3, 128.1, 128.1, 127.6, 126.7, 126.5 (q, JC-F = 281.8 Hz), 126.3, 126.2, 125.9, 55.6 (q,
JC-F = 26.5 Hz), 34.4, 30.2; 19F NMR (376 MHz, CDCl3)
-65.61 (d, = 10.1 Hz); FT-IR
δ
J
(thin film, KBr): 3622, 3010, 2967, 1633, 1401, 1260, 1193, 1151, 1107, 743, 655, 600
cm–1; HRMS (ESI): m/z calcd for C26H29F3O [M–H]+ : 413.2092; found : 413.2099.
2,6-Di-tert-butyl-4-(1,1,1-trifluoro-3-methylbutan-2-yl)phenol (3u): Rf = 0.5
1
(hexane); Colorless oil; Yield 86% (42.4 mg); H NMR (400 MHz, CDCl3)
δ
7.01 (s,
2H), 5.18 (s, 1H), 2.97 – 2.86 (m, 1H), 2.26 (dp,
J
= 13.8, 6.8 Hz, 1H), 1.45 (s, 18H), 1.08
13
(d,
135.9, 135.6, 127.6 (q, JC-F = 281.8 Hz), 125.7, 125.6, 124.9, 119.6, 56.3 (q, JC-F = 24.7
Hz), 34.3, 30.3, 29.0, 21.5, 20.7; 19F NMR (376 MHz, CDCl3)
-64.18 (d, = 10.2 Hz);
J = 6.5 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H); C NMR (101 MHz, CDCl3) δ 153.2,
δ
J
FT-IR (thin film, KBr): 3646, 2965, 2880, 1637, 1443, 1401, 1254, 1164, 1127, 1079,
859, 769, 710, 659, 646, 603 cm–1; HRMS (ESI): m/z calcd for C19H29F3O [M–H]+ :
329.2092; found : 329.2102.
2,6-Di-tert-butyl-4-(1,1,1-trifluoro-3,3-dimethylbutan-2-yl)phenol (3v): Rf = 0.5
1
(hexane); Colorless oil; Yield 79% (40.8 mg); H NMR (400 MHz, CDCl3)
δ 7.26 (s,
13
2H), 5.15 (s, 1H), 3.02 (q, J = 11.0 Hz, 1H), 1.43 (s, 18H), 1.01 (s, 9H); C NMR (101
MHz, CDCl3)
34.3, 33.5, 30.3, 29.1; 19F NMR (376 MHz, CDCl3)
δ
153.0, 135.0, 128.0 (q, JC-F = 283.8 Hz), 125.5, 59.4 (q, JC-F = 23.7 Hz),
-59.35 (d, = 11.0 Hz); FT-IR (thin
δ
J
film, KBr): 3646, 2961, 2916, 2873, 1639, 1438, 1400, 1258, 1194, 1139, 1098, 752, 657
cm–1;HRMS (ESI): m/z calcd for C20H31F3O [M–H]+ : 343.2249; found : 343.2256.
2,6-Diisopropyl-4-(2,2,2-trifluoro-1-phenylethyl)phenol (3w): Rf = 0.2 (hexane);
1
Colorless solid; Yield 88% (44.5 mg); H NMR (400 MHz, CDCl3)
δ
7.40 – 7.27 (m,
5H), 7.04 (s, 2H), 4.79 (s, 1H), 4.60 (q,
J = 10.1 Hz, 1H), 3.13 (hept, J = 6.8 Hz, 2H),
13
1.25 (d,
J
= 6.9 Hz, 12H); C NMR (101 MHz, CDCl3)
δ
149.7, 135.9, 133.8, 129.4,
17

ACCEPTED MANUSCRIPT
129.0, 128.6, 127.8, 127.2, 126.4 (q, JC-F = 281.8 Hz), 124.3, 55.3 (JC-F, J = 27.3 Hz),
19
27.3, 22.6; F NMR (376 MHz, CDCl3)
δ -65.89 (d, J = 10.1 Hz); FT-IR (thin film,
KBr): 2964, 2930, 2871, 1619, 1497, 1470, 1399, 1361, 1259, 1193, 1152, 1107, 862,
756, 700, 656, 601 cm–1; HRMS (ESI): m/z calcd for C20H23F3O [M–H]+ : 335.1623;
found : 335.1634.
2,6-Dimethyl-4-(2,2,2-trifluoro-1-phenylethyl)phenol (3x): Rf = 0.5 (5% DCM in
1
hexane); Colorless solid; Yield 79% (33.3 mg); H NMR (400 MHz, CDCl3)
δ 7.44 –
7.30 (m, 5H), 7.02 (s, 2H), 4.67 (s, 1H), 4.58 (q,
(101 MHz, CDCl3) 151.9, 135.9, 129.3, 128.9, 128.6, 127.7, 127.0, 126.3 (q, JC-F
281.8 Hz), 123.2, 54.8 (q, JC-F = 27.5 Hz), 15.9; 19F NMR (376 MHz, CDCl3)
-65.92 (d,
= 10.1 Hz); FT-IR (thin film, KBr): 3441, 2919, 1631, 1493, 1401, 1261, 1193, 1146,
J
= 10.1 Hz, 1H), 2.25 (s, 6H); 13C NMR
δ
=
δ
J
1105, 860, 755, 700, 656, 601 cm–1; HRMS (ESI): m/z calcd for C16H15F3O [M–H]+ :
279.0997; found : 279.1003.
2-(tert-Butyl)-6-methyl-4-(2,2,2-trifluoro-1-phenylethyl)phenol (3y): Rf = 0.3
(hexane); Colorless solid; Yield 93% (45.1 mg);1H NMR (400 MHz, CDCl3)
7.27 (m, 5H), 7.14 (s, 1H), 7.02 (s, 1H), 4.78 (s, 1H), 4.58 (q, = 10.1 Hz, 1H), 2.23 (s,
3H), 1.41 (s, 9H); 13C NMR (101 MHz, CDCl3)
152.3, 135.9, 135.7, 129.0, 128.9,
128.6, 127.8, 126.5, 126.4 (q, JC-F = 281.8 Hz), 126.2, 123.2, 55.1 (q, JC-F = 27.4 Hz),
34.5, 29.6, 16.1; 19F NMR (376 MHz, CDCl3)
-65.87 (d, = 10.1 Hz); FT-IR (thin film,
δ 7.43 –
J
δ
δ
J
KBr): 2966, 2871, 1632, 1605, 1484, 1435, 1401, 1361, 1261, 1192, 1153, 1104, 860,
754, 700, 656, 644, 602 cm–1; HRMS (ESI): m/z calcd for C19H21F3O [M–H]+ : 321.1466;
found : 321.1474.
4.5. Experimental procedure for Synthesis of 4:
To an oven dried borosilicate test tube equipped with a magnetic stir bar was added
QMs (0.15 mmol, 1 eq.), CF3SO2Na (0.30 mmol, 2 eq.) and 5 mol% photocatalyst T(
p
-
-
p
CH3)PPT (3.3 mg, 0.05 equiv.). The reaction tube was vacuumed and backfilled with
argon (3 times) and put a septum over the reaction tube. Then 3 mL of CH3CN was added
through the septum by a syringe, and placed approximately 5 cm from light setup. After 6
h of the reaction 10 mL of water was added and extracted with DCM (3 x 20 mL). The
combined organic layer was dried over Na2SO4 and solvent was removed under reduced
18

ACCEPTED MANUSCRIPT
pressure. The crude product was then purified by Flash column chromatography on silica
gel mesh 230-400 using hexane and DCM as an eluent to afford the product
68%).
4 (36.2 mg,
2,6-Di-tert-butyl-4-(1,1,1,3,3,3-hexafluoropropan-2-yl)phenol (4): Rf
=
0.5
1
(hexane); Colorless solid; Yield 68% (36.2 mg); H NMR (400 MHz, CDCl3)
δ 7.17 (s,
2H), 5.38 (s, 1H), 3.95 (hept,
J
= 8.5 Hz, 1H), 1.45 (s, 18H); 13C NMR (101 MHz,
CDCl3)
δ
155.0, 136.4, 126.5, 123.2 (q, JC-F = 280.5 Hz), 117.2, 54.2 (hept, JC-F = 28.9
19
Hz), 34.3, 33.8, 30.1; F NMR (376 MHz, CDCl3)
δ -65.43 (d, J = 8.5 Hz); FT-IR (thin
film, KBr): 3630, 3007, 1633, 1397, 1285, 1243, 1193, 1137, 1123, 1094, 982, 754, 703,
657, 643, 601 cm–1; HRMS (ESI): m/z calcd for C17H21F6O [M–H]+ : 355.1497; found :
355.1505.
4.6. Experimental procedure for synthesis of 5, 6:
K3[Fe(CN)6 (395 mg, 1.2 mmol) and KOH (71 mg, 1.26 mmol) in water (3 mL) were
added in one portion to a solution of 3a (109 mg, 0.3 mmol) in hexane (3 mL) under
argon in 25 mL round bottom flask. equipped with magnetic stir bar. The reaction mixture
was vigorously stirred at rt for 3 h. The aqueous layer was separated and extracted with
hexanes. The combined organic layer was washed with brine and dried over Na2SO4. The
solids were removed by filtration and the solution was concentrated by rotary
evaporation. The residue was purified by silica gel flash column chromatography using
hexane to afford 5 (90.1 mg, 83%).
A 20 mL sealed tube equipped with magnetic stir bar charged with 3a (109 mg, 0.3
mmol) in 3 mL of dry toluene. 1 drop of conc. H2SO4 was added to it and heated to 120
°C for 12 h. After cooling to room temperature 20 mL of water was poured to it and
extract with DCM (3 x 20 mL). The combined organic layer was dried over Na2SO4 and
solvent was removed under reduced pressure. The crude product was then purified by
Flash column chromatography on silica gel mesh 230-400 using hexane and EtOAc as an
eluent to afford the product
6 (63.4 mg, 84%).
2,6-Di-tert-butyl-4-(2,2,2-trifluoro-1-phenylethylidene)cyclohexa-2,5-dienone (5):
1
Rf = 0.6 (hexane); Orange solid; Yield 83% (90.1 mg); H NMR (400 MHz, CDCl3)
δ
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7.56 (dd,
J
= 4.2, 2.1 Hz, 1H), 7.48 – 7.42 (m, 3H), 7.26 (dd,
J
= 5.9, 3.1 Hz, 2H), 6.71
13
(d,
J
= 2.5 Hz, 1H), 1.33 (s, 9H), 1.11 (s, 9H); C NMR (101 MHz, CDCl3) δ 186.3,
150.5, 150.2, 137.2 (q, JC-F = 30.2 Hz), 134.8, 133.0, 130.1, 130.0, 129.3, 128.2, 127.0,
19
126.2 (q, JC-F = 276.0 Hz), 35.7, 35.4, 29.5, 29.3; F NMR (376 MHz, CDCl3)
δ -52.83
(s); FT-IR (thin film, KBr): 3064, 2999, 2962, 2915, 2868, 1627, 1374, 1280, 1202, 1160,
1113, 940, 910, 880, 821, 757, 705, 682, 650 cm–1; HRMS (ESI): m/z calcd for
C22H25F3O [M+H]+ : 363.1936; found : 363.1924.
4-(2,2,2 -Trifluoro-1-phenylethyl)phenol (6): Rf = 0.3 (20% DCM in hexane);
1
colorless oil, Yield 84% (63.4 mg); H NMR (400 MHz, CDCl3)
δ 7.42 – 7.29 (m, 5H),
7.24 (d, J = 8.5 Hz, 2H), 6.83 – 6.79 (m, 2H), 5.03 (brs, 1H), 4.63 (q, J = 10.0 Hz, 1H);
13C NMR (101 MHz, CDCl3)
δ
155.1, 135.6, 130.5, 128.9, 128.7, 127.8, 127.7, 126.2 (q,
19
JC-F = 280.3 Hz), 115.5, 54.7 (q, JC-F = 27.6 Hz); F NMR (376 MHz, CDCl3)
δ -66.00
(d, J = 10.0 Hz); FT-IR (thin film, KBr): 3371, 3033, 1616, 1597, 1514, 1452, 1399,
1253, 1147, 1096, 822, 753, 703, 653, 632, 603 cm–1; HRMS (ESI): m/z calcd for
C14H11F3O [M–H]+ : 251.0684; found : 251.0690.
4.7. Gram scale synthesis of 3a:
To an oven dried 100 mL round bottom flask equipped with a magnetic stir bar was
added
p-QMs (1.47 g, 5 mmol), CF3SO2Na (1.56 g, 10 mmol) and 5 mol% photocatalyst
T( -CH3)PPT (110 mg, 0.25 mmol). The reaction tube was vacuumed and backfilled with
p
argon (3 times) and put a septum over the reaction tube. Then 50 mL of CH3CN was
added through the septum by a syringe, and placed approximately 5 cm from light setup.
After 6 h of the reaction 50 mL of water was added and extracted with DCM (3 x 50 mL).
The combined organic Layer was dried over Na2SO4 and solvent was removed under
reduced pressure. The crude product was then purified by Flash column chromatography
on silica gel mesh 230-400 using hexane and DCM as an eluent to afford the product 3a
(1.53 g, 84%).
Conflicts of interest:
There are no conflicts to declare.
Acknowledgements:
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Financial support from the IISER Kolkata for startup Grant, SERB for Early Carrier
Research (ECR) Grant and DST-SERB for Ramanujan Fellowship are acknowledged.
KGG and PC thank DST and CSIR for their PhD fellowship.
Reference:
[1] (a) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev. 111 (2011) 455–529;
(b) A. Studer, Angew. Chem., Int. Ed. 51 (2012) 8950–8958;
(c) P. Jeschke, ChemBioChem. 5 (2004) 570–589;
(d) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S.
Fustero, V. A. Soloshonok, H. Liu, Chem. Rev. 114 (2014) 2432–2506;
(e) T. Furuya, A. S. Kamlet, T. Ritter, Nature 473 (2011) 470–477.
[2] (a) W. K. Hagmann, Med. Chem. 51 (2008) 4359–4369;
(b) T. Amazaki, T. Taguchi, I. Ojima, Fluorine in Medicinal Chemistry and Chemical
Biology (Wiley-Blackwell, 2009);
(c) T. Fujiwara, D. O’Hagan, J. Fluorine Chem. 167 (2014) 16–29;
(d) J.-P. Bégué, D. Bonnet-Delpon, J. Fluorine Chem. 127 (2006) 992–1012.
[3] (a) K. Müller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1886;
(b) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok, K. Izawa,
H. Liu, Chem. Rev. 116 (2016) 422–518;
(c) M. Hird, Chem. Soc. Rev. 36 (2007) 2070–2095;
(d) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008) 320–
330;
(e) E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem.
58 (2015) 8315–8359.
[4] (a) J. Charpentier, N. Früh, Togni, A. Chem. Rev. 115 (2015) 650–682;
(b) T. Umemoto, S. Ishihara, J. Am. Chem. Soc. 115 (1993) 2156–2164.
21

ACCEPTED MANUSCRIPT
[5] (a) X. Liu, C. Xu, M. Wang, Q. Liu, Chem. Rev. 115 (2015) 683–730;
(b) G. K. S. Prakash, A. K. Yudin, Chem. Rev. 97 (1997) 757–786.
[6] (a) Y. Fujiwara, J. A. Dixon, R. A. Rodrguez, R. D. Baxter, D. D. Dixon, M. R. Collins,
D. G. Blackmond, P. S. Baran, J. Am. Chem. Soc. 134 (2012) 1494–1497;
(b) Y. Ye, S. H. Lee, M. S. Sanford, Org. Lett. 13 (2011) 5464–5467;
(c) Y. Ye, M. S. Sanford, J. Am. Chem. Soc. 134 (2012) 9034–9037;
(d) D. B. Bagal, G. Kachkovskyi, M. Knorn, T. Rawner, B. M. Bhanage, O. Reiser,
Angew. Chem., Int. Ed. 54 (2015) 6999–7002;
(e) R. Tomita, Y. Yasu, T. Koike and M. Akita, Angew. Chem., Int. Ed., 53 (2014) 7144–
7148;
(f) J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, X. Lu, L. Liu, Y. Fu, J. Am. Chem.
Soc. 135 (2013) 8436–8439;
(g) Y.-F. Wang, G. H. Lonca, S. Chiba, Angew. Chem., Int. Ed. 53 (2014) 1067–1071.
[7] (a) B. Yang, X.-H. Xu, F.-L. Qing, Org. Lett. 17 (2015) 1906–1909;
(b) C. Zhang, Adv. Synth. Catal. 356 (2014) 2895–2906;
(c) M. Tordeux, B. R. Langlois, C. Wakselman, J. Org. Chem. 54 (1989) 2452–2453;
(d) Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su, D. G. Blackmond, P.
S. Baran, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 14411–14415.
[8] (a) W.-P. Mai, J.-T. Wang, L.-R. Yang, J.-W. Yuan, Y.-M. Xiao, P. Mao, L.-B. Qu,
Org. Lett. 16 (2014) 204–207;
(b) L. Shi, X. Yang, Y. Wang, H. Yang, H. Fu, Adv. Synth. Catal. 356 (2014) 1021–
1028;
(c) A. Deb, S. Manna, A. Modak, T. Patra, S. Maity, D. Maiti, Angew. Chem., Int. Ed. 52
(2013) 9747–9750.
[9] (a) Y. Ye, S. A. Künzi, M. S. Sanford, Org. Lett. 14 (2012) 4979–4981;
22

ACCEPTED MANUSCRIPT
(b) Y. Li, L. Wu, H. Neumann, M. Beller, Chem. Commun. 49 (2013) 2628–2630;
(c) H. Guyon, H, Chachignon, D. Cahard, Beilstein J. Org. Chem. 13 (2017) 2764–2799.
[10] (a) D. A. Nicewicz, D. W. C. MacMillan, Science 322 (2008) 77–80;
(b) N. A. Romero, D. A. Nicewicz, Chem. Rev. 17 (2016) 10075–10166;
(c) C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 113 (2013) 5322–5363.
[11] (a) S. Mizuta, S. Verhoog, K. M. Engle, T. Khotavivattana, M. O’Duill, K.
Wheelhouse, G. Rassias, M. Médebielle, V. Gouverneur, J. Am. Chem. Soc. 135 (2013)
2505–2508;
(b) D. J. Wilger, N. J. Gesmundo, D. A. Nicewicz, Chem. Sci. 4 (2013) 3160–3165.
[12] L. Zhu, L.-S. Wang, B. Li, B. Fu, C.-P. Zhang, W. Li, Chem. Commun. 52 (2016)
6371–
6374.
[13] Q. Lefebvre, N. Hoffmann, M. Rueping, Chem. Commun. 52 (2016) 2493–2496.
[14] (a) K. Uneyama, M. Momota, K. Hayashida, T. Itoh, J. Org. Chem. 55 (1990) 5364–
5368;
(b) C. H. DePuy, A. L. Schultz, J. Org. Chem. 39 (1974) 878–881;
(c) A. Kaluszyner, S. Reuter, E. D. Bergmann, J. Am. Chem. Soc. 77 (1955) 4164–4168;
(d) A. Jarczewski, G. Shroeder, W. Galezowski, Can. J. Chem. 63 (1985) 576–580;
(e) G. K. S. Prakash, F. Paknia, T. Mathew, G. Mlostoń, J. P. Joschek, G. A. Olah, Org.
Lett. 13 (2011) 4128–4131.
[15] (a) B. T. Ramanjaneyulu, S. Mahesh, R. V. Anand, Org. Lett., 17 (2015) 3952–3955;
(b) K. Gai, X. Fang, X. Li, J. Xu, X. Wu, A. Lin, H. Yao, Chem. Commun. 51 (2015)
15831–15834;
(c) W.-D. Chu, L.-F. Zhang, X. Bao, X.-H. Zhao, C. Zeng, J.-Y. Du, G.-B. Zhang, F.-X.
Wang, X.-Y. Ma, C.-A. Fan, Angew. Chem., Int. Ed. 52 (2013) 9229–9233;
23

ACCEPTED MANUSCRIPT
(d) C. Jarava-Barrera, A. Parra, A. López, F. Cruz-Acosta, D. Collado-Sanz, D. J.
Cárdenas , M. Tortosa, ACS Catal. 6 (2016) 442–446;
(e) F.-S. He, J.-H. Jin, Z.-T. Yang, X. Yu, J. S. Fossey, W.-P. Deng, ACS Catal. 6 (2016)
652–656;
(f) Y.-H. Deng, X.-Z. Zhang, K.-Y. Yu, X. Yan, J.-Y. Du, H. Huang, C.-A. Fan, Chem.
Commun. 52 (2016) 4183–4186;
(g) S. R. Angle, K. D. Turnbull, J. Am. Chem. Soc. 111 (1989) 1136–1138;
(h) V. Reddy, R. Vijaya Anand, Org. Lett. 17 (2015) 3390–3393;
(i) Y. Lou, P. Cao, T. Jia, Y. Zhang, M. Wang, J. Liao, Angew. Chem., Int. Ed. 54 (2015)
12134–12138;
(j) S. Gao, X. Xu, Z. Yuan, H. Zhou, H. Yao, A. Lin, Eur. J. Org. Chem. 2016 (2016),
3006–3012.
[16] (a) M. Ke , Q. Song, Adv. Synth. Catal. 359 (2017) 384–389;
(b) Y.-N. Zhao, Y.-C. Luo, Z.-Y. Wang, P.-G. Xu, Chem. Commun. 54 (2018) 3993–
3993;
(c) Q.-Y. Wu, G.-Z. Ao, F. Liu, Org. Chem. Front. 5 (2018) 2061–2064.
[17] F. Dufrasne, M. Gelbcke, J. Neve, R. Kiss, J.-L. Kraus, Curr. Med. Chem. 18 (2011)
3995–4011.
[18] (a) M. S. Lowry, J. I. Goldsmith, J. D. Slinker, R. Rohl, R. A. Pascal, G. G.
Malliaras, S. Bernhard, Chem. Mater. 17 (2015) 5712–5719;
(b) J.-B. Tommasino, A. Brondex, M. Médebielle, M. Thomalla, B. R. Langlois, T.
Billard, Synlett 10 (2002) 1697–1699.
[19] T. M. Monos, A. C. Sun, R. C. McAtee, J. J. Devery, C. R. J. Stephenson, J. Org. Chem. 81
(2016), 6988
–6994.
[20] Y. Zhao, B. Huang, C. Yang, B. Li, B. Gou, W. Xia, ACS Catal. 7 (2017) 2446–2451
.
24

ACCEPTED MANUSCRIPT
[21] C. Jarava-Barrera, A. Parra, A. López, F. Cruz-Acosta, D. Collado-Sanz, D. J. Cárdenas, M.
Tortosa,
ACS Catal. 6 (2015) 442–446.
[22] M. Inagaki, N. Haga, M. Kobayashi, N. Ohta, S. Kamata, T. Tsuri, J. Org. Chem. 1 (2002)
125–128.
25