Microwave-assisted copper catalysis of α-difluorinated gem-diol toward difluoroalkyl radical for hydrodifluoroalkylation of para-quinone methides

Article abstract of DOI:10.1021/acs.joc.0c01686

Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated gemdiols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc)2 succeeds in the formation of transient difluoroalkyl radicals in situ, for the first time. The reaction features a simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology was also explored for the synthesis of difluoroalkylated spiro-cyclohexadienones, which is an important core structure in natural products and pharmaceuticals.

Full text of DOI:10.1021/acs.joc.0c01686

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Note
Microwave-Assisted Copper Catalysis of #-Difluorinated gem-Diol toward
Difluoroalkyl Radical for Hydrodifluoroalkylation of para-Quinone Methides
Chuan-Hua Qu, Gui-Ting Song, Dianyong Tang, Jing-
Wei Shao, Hong-yu Li, Zhi-Gang Xu, and Zhong-Zhu Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01686 • Publication Date (Web): 27 Aug 2020
Downloaded from pubs.acs.org on August 27, 2020
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The Journal of Organic Chemistry
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Microwave-Assisted Copper Catalysis of α-Difluorinated gem-
Diol toward Difluoroalkyl Radical for Hydrodifluoroalkylation
of para-Quinone Methides
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Chuan-Hua Qu,†,§ Gui-Ting Song,†,‡,§ Dian-Yong Tang,† Jing-Wei Shao,# Hong-yu Li,#,* Zhi-Gang Xu†,* and
Zhong-Zhu Chen†,*
†College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative
Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University
of Arts and Sciences, Chongqing 402160, China
‡Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing
Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
China
#Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences,
Little Rock, AR 72205, USA
*Corresponding author:
Email address: HLi2@uams. edu, xzg@cqwu.edu.cn, 18883138277@163.com
§These authors contributed equally to this work.
ABSTRACT
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O
OH
tBu
tBu
Microwave
1
2
3
4
tBu
tBu
O
Cu(OAc)2 (20 mol%),
DIPEA (2.0 equiv.)
HO OH
CF3
O
+
F
F
THF, 100 oC, 30 min
Ar
Ar
F
F
5
6
7
+
CF3COOH
short reaction time
ample acope
operationally simple
high yields
scalable
biologically relevant scaffolds
8
9
Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated
gem-diols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc)2
succeeds in the formation of transient difluoroalkyl radicals in situ, for the first time. The reaction features with
simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology
was also explored for the synthesis of difluoroalkylated spiro-cyclohexadienones, which is an important core
structure in natural products and pharmaceuticals.
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The selective incorporation of a difluoromethylene (CF2) group into organic compounds has gained a great
interest in contemporary organic synthesis due to its significant applications in the areas of nuclear imaging,
material science, agrochemical, and pharmaceutical.1 The CF2 group, which acts as a bioisostere for an oxygen
atom or a carbonyl group,1a, 2 can significantly change the electronic and chemical properties of target
molecules, thus improving biological activities and drug properties. Diarylmethane is the core structure of
various natural products and biologically active compounds such as tolterodine,3a latifolin,3b podophyllotoxin,3c
and kadangustin J3d (Scheme 1a), which have shown antimicrobial, antimuscarinic, anticancer, cytoprotectine,
and antidiabetic activities.3 The synthesis of natural products hybrid systems with varied biological and
pharmacological properties has received increasing attention in the past decade.4 Hence the introduction of a
CF2R into a diarylmethane motif to assemble the difluoroalkylated diarylmethane skeleton would enrich the
diversity of diarylmethanes which in turn could provide novel bioactivities for drug discovery campaign.
Carbon-carbon bond formation plays a pivotal role in synthetic organic and medicinal chemistry. One
of the unique protocols for catalytic C-C bond construction is 1,6-conjugate addition with para-quinone
methides (p-QMs).5 However, there are few reports on the use of other methods such as radical protocol
with p-QMs in this conversion.6 Recently, a radical or 1,6-conjugate addition strategy for the synthesis
of difluorinated diarylmethanes was reported,6b,6d,5g in which BrCF2COR or fluorinated silyl enol ethers
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were exploited as the difluoroalkyl precursor (Scheme 1b). In 2011, the Colby's group first disclosed
that difluoroenolates could be generated by α-difluorinated gem-diols in the presence of bases via the
trifluoroacetate-release strategy (Scheme 1c).7 The protocol is mild and versatile, and typically
produces difluoroenolates quickly at room temperature. Currently, Aldol, Mannich, halogenation,
sulfenylation, and amination reactions with the in situ generated difluoroenolates have been explored.8
Scheme 1. Bioactive Diarylmethanes and Reactions of Gem-difluoroenolates
1
2
3
4
5
6
7
8
9
10
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a) bioactive diarylmethanes
OH
OMe
O
Me
OMe
O
O
OMe
HO
H
O
Me
Me
OH
OMe
i-Pr
OH
N
OH
OMe
MeO
OMe
i-Pr
OMe
(-)-Kadangustin J
OMe
Podophyllotoxin
(-)-Latifolin
Tolterodine
b) difluoroalkylation of p-QMs (Xu, Song and Zhou)
F
F
O
OH
OEt
tBu
tBu
fac-Ir(ppy)3 (1 mol%) or
Cu(OAc)
(10 mol%)
tBu
tBu
Br
2·H2O
O
O
R
+
OTMs
Ph
Fe(OTf)3 (3 mol%)
F
F
F
F
existing difluoroalkylation with gem-difluoro-enolates (Common reaction patterns)
c)
O
O
HO OH
CF3
O
generation
E+
E
F
in situ
F
F
F
F
F
-CF3COOH
explored with carbonyls, imines, disufides,
halogen precursors, nitroso and azo compounds
difluorinated
gem-diols
gem-difluoro-enolate
-e- [O]
d) employ difluoroenolates as radical precursor ( this work)
O
H
O
tBu
tBu
tBu
tBu
O
radical
addition
F
+
O
F
Ar
difluoroalkyl radical
Ar
F
F
H
CF3COO
electrophilic radical
receptor
difluorinated diarylmethanes
hydrogen source
O
rapid process
ample scope
high yields
scalable
tBu
Ar
tBu
biologically relevant scaffolds
Ar
F
difluorinated spiroquinones
F
O
Our interest in radical fluoroalkylation chemistry9 led us to question whether this difluoroenolates could
proceed a single electron oxidation process using transition-metal salts, such that difluoroalkyl radicals could be
generated and radical difluoroalkylation can be realized with suitable radical receptors. Herein, we report an
unprecedented approach towards the synthesis of difluorinated diarylmethanes using α-difluorinated gem-diols
as ·CF2R source via a base-induced C-C cleavage followed by the copper-catalyzed radical reaction under
microwave irradiation (Scheme 1d). To the best of our knowledge, harnessing α-difluorinated gem-diols
as ·CF2R source for radical difluoroalkylation events has not been reported.
We chose to explore this idea through the difluoroalkylation of p-QM 1 (Scheme 2). We planned that α-
difluorinated gem-diol 2 could undergo base-induced trifluoroacetate-release process to a difluoroenolate I.
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Subsequently, difluoroenolate I proceeds single electron oxidation under Cu(II) affording difluoroalkyl radical
II and Cu(I). In fact, Cu(II)-catalyzed enolates formation of α-carbonyl radicals has been demonstrated by Su's
and Dong's groups.10 II can undergo regioselective Giese-addition to electron-deficient p-QM 1 furnishing
electrophilic allyl radical III.11 The resultant Cu(I) can easily reduce III to generate allyl anion IV and Cu (II).
Finally, the protonation of V by CF3COOH leads to the product 3a. Moreover, α-carbonyl anion I' could also
undergo a protonation process to form by-product 3'. To achieve this idea, one needs not only to meet the
thermodynamical requirement for difluoroalkyl radicals formation, but also to maintain the kinetic reactivity of
the generation difluoroalkyl radicals for subsequent transformation.
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Scheme 2. Reaction Design
Reaction design for the hydrodifluoroalkylation of p-QMs
tBu
OH
O
tBu
HO OH
CF3
[CuII], base
+
p-QMs
1
3
R
air, microwave
O
R
Ar
F
F
2
F
F
H+
O
O
-CF3COOH
O
tBu
tBu
tBu
tBu
+
R
CF2H
O
O
O
3'
O
F
F
CuII
R
R
R
R
Ar
F
IV
F
Ar
F
F
F
F
V
I'
I
CuI
O
O
tBu
tBu
Giese addition
F
R
p-QMs 1
F
O
II
R
Ar
F
F
III
With this mind, we initiated the study to generate difluoroalkyl radicals by cheap copper salts under
microwave irradiation. Herein, the reaction of p-QM 1a with α-difluorinated gem-diols 2a was chosen as a
model system to optimize the reaction conditions (Table 1). Irradiation of a mixture of 1a and 2a in
o
tetrahydrofuran (THF) with 20 mol% CuI under air in the presence of NEt3 at 100 C provided the desired
product 3a in 61% yield along with ketone 3a' that was generated via the protonation of the in situ formed gem-
difluoro-enolate (Table 1, entry 1). Because of this promising result, screening of various Lewis acids was
investigated (Table, entries 2-9), among which Cu(OAc)2 was found to be the best catalyst, delivering 88%
isolated yield at 100 oC under microwave irradiation. Solvent screening indicated that 1,4-dioxane, acetonitrile,
toluene, and DMF could not improve the isolated yield (Table 1, entries 10-13). The screening of bases showed
that DIPEA was the best with 91% yield (Table 1, entry 15). Other bases such as TMEDA and inorganic K2CO3
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were less effective (entries 14 and 16). Control experiments indicated that Cu(OAc)2 and microwave irradiation
were critical for this transformation ( Table 1, entries 17-19).
1
2
3
4
5
6
7
Table 1. Optimization of Reaction Conditions a
t-Bu
O
Me
OH
8
9
t-Bu
t-Bu
[Cu] (0.2 equiv.)
base (2.0 equiv.)
t-Bu
O
1a
H
O
+
+
O
solvent, 30 min,
F
F
HO OH
CF3
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MW, 100 o
C
F
F
3a'
Me
F
F
3a
2a
entry
[Cu]
base
solvent
yield of
3a (%)b
61c
1
CuI
Et3N
Et3N
Et3N
THF
THF
THF
THF
THF
THF
THF
THF
THF
1,4-
2
CuBr
CuOAc
64c
74c
47c
3
4
CuSO4·5H2 Et3N
c
5
CuCl2·2H2
Cu(OAc)2·
CuBr2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
-
6
85c
c
7
-
8
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
-
76c
88c
69c
71c
9
10
11
12
13
14
15
16
17
18
19e
MeCN
toluene
DMF
c
-
58c
46c
91
TMEDA THF
DIPEA
K2CO3
/
THF
THF
THF
THF
THF
d
-
79
c
DIPEA
DIPEA
-
d
Cu(OAc)2
-
aReaction were performed on a 0.2 mmol scale using 2.0 eq. of 2a and 2.0 eq. of base, MW, 100 C, 30 min. Yield are those of
o
b
c
d
products isolated by column chromatography. Decomposition of 2a was observed with the formation of 3a'. No reaction with the
recovery of 2a. eReaction performed at room temperature for two days. MW = microwave irradiation, Et3N = triethylamine, DIPEA =
N,N-diisopropylethylamine, TMEDA = tetramethylethylenediamine.
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With the optimized reaction conditions for the synthesis of difluorinated diarylmethanes in hand
(Table 1, entry 15), we examined the substrate scope of p-QMs 1 and α-difluorinated gem-diols 2. As
shown in Scheme 3, the presence of a substituent on the aryl ring of p-QMs 1 had no significant effect
for reaction yield. The reaction of p-QMs 1 with an electron-donating group or just hydrogen atom
furnished the corresponding products 3a-e with 77-92% yields. Gratifyingly, the p-QMs involving
para-N, N-dimethyl and trimethoxy groups on phenyl were suitable for this transformation, affording
the corresponding products 3f and 3g with 78 and 80% yield, respectively. Using the halo-substituted p-
QMs, the corresponding products 3h-k were obtained in excellent yields (86-95%). It was noteworthy
that heteroaryl derived p-QMs were also good substrates for this transformation (3l-3n). The reaction
was also examined with less bulky p-QMs with a di-ethyl and di-isopropyl substituents. The desired
products 3o and 3p were obtained in 76 and 86% yield, respectively.
1
2
3
4
5
6
7
8
9
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Scheme 3. Substrate Scope of p-QMs a,b
OH
O
R
R
O
Cu(OAc)2 (20 mol%)
DIPEA (2 equiv.), THF
MW, 100 oC, 30 min, air
O
R
R
HO OH
CF3
+
F
F
R
Ar
F
F
1
2a
3
OH
OH
OH
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
3a, 91%, R = 4-Me;
3b, 84%, R = 3-Me;
3c, 92%, R = H;
3d, 77%, R = 4-OMe;
3e, 80%, R = 4-t-Bu.
O
O
O
MeO
MeO
F F
F
F
R
Me
F
F
N
OMe
Me
3f, 78%
3g, 80%
OH
OH
OH
tBu
tBu
tBu
tBu
tBu
3h, 89%, R = 4-Cl;
3i, 95%, R = 4-F;
3g, 91%, R = 4-Br;
3k, 86%, R= 2-Br.
O
O
O
R
F
F
Br
F
F
S
F
F
S
3l, 71%
3m, 65%
OH
OH
OH
tBu
O
O
F
O
N
F
F
F
F
F
3n, 85%
3o, 76%
3p, 86%
aReaction conditions unless otherwise specified: 1 (0.2 mmol), 2a (0.4 mmol), Cu(OAc)2 (0.04 mmol), DIPEA (0.4 mmol), THF (4.0
mL), MW, 100 oC, 30 min. bYields are reported for the isolated products.
Next, the substrate scope of α-difluorinated gem-diols 2 was explored to examine their applicability in our
system (Scheme 4). α-Difluorinated gem-diols with different functional groups on the phenyl ring, either
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electron-donating methyl (4b), methoxyl (4c) or electron-withdrawing halo (4d-f) at the para position,
proceeded well with 1 to deliver the expected products 4a-f in 73% to 87% yields. However, an aliphatic α-
difluorinated gem-diol was not well tolerated; only 18% difluorinated diarylmethane 4g was obtained,
suggesting the redox potential is critical for these difluoroalkyl radicals generation. In general, this novel α-
diarylmethanation protocol demonstrated a broad substrate scope with high reaction yields (70-86%) and
accommodated versatile sensitive functional moieties, including olefin (4h) and heterocycles (4i-m). The
reaction also occurred smoothly with various substituted p-QMs to obtain products (4o-q).
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2
3
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Scheme 4. Scope of Cu-catalyzed Difluoroalkylation of p-QMs a,b
OH
O
tBu
tBu
tBu
tBu
O
HO OH
CF3
Cu(OAc)2 (20 mol%), DIPEA (2.0 equiv.)
THF, MW, 100 oC, 30 min, air
+
R
O
F
F
Ar
R
Ar
F
F
1
2
4
OH
OH
OH
4a
4b
4c
4d
4e
, 81%, R = H;
tBu
tBu
tBu
tBu
tBu
tBu
, 78%, R = 4-Me;
, 73%, R = 4-OMe;
, 87%, R = 4-F;
, 84%, R = 4-Cl;
O
O
O
Me
Me
4f
,
82%, R = 4-Br.
F
F
F
F
F
F
Me
Me
Me
R
4h
, 75%
4g
, 18%
OH
OH
OH
tBu
tBu
tBu
tBu
tBu
tBu
O
O
O
F
F
F F
S
O
F
F
S
O
Me
Me
4k
, 70%
4i
4j
, 71%
, 86%
OH
OH
OH
tBu
tBu
tBu
tBu
4n
4o
4p
4q
, 83%, R = H;
tBu
tBu
, 81%, R = 4-Br;
, 86%, R = 4-Cl;
, 72%, R = 4-tBu.
O
O
O
N
F
F
F
4l
F
O
O
R
N
F
F
, 79%
4m
, 72%
aReaction conditions unless otherwise specified: 1 (0.2 mmol), 2 (0.4 mmol), Cu(OAc)2 (0.04 mmol), DIPEA (0.4 mmol), THF (4.0
mL), MW, 100 oC, 30 min. bYields are reported for the isolated products.
Importantly, this transformation was scalable. The reaction of 1h (0.99 g) or 1j (1.12 g) with 2b (1.2 g) was
conducted under the standard conditions, providing 4p (1.1 g) and 4o (1.14 g) in the isolated yields of 75% and
72%, respectively (Scheme 5a). To expand the utility of this novel synthetic methodology, several
transformations of 4p were carried out in Scheme 5a. Compound 4p can be reduced by NaBH4 at room
temperature, furnishing diarylmethane 5 in excellent yield and moderate diastereoselectivity. However, the
AlCl3 mediated de-tert-butylation reaction via re-Friedel-Crafts alkylation was unsuccessful and a very fast
decomposition of the 4p was observed. The spiro-cyclohexadienone core, a privileged structure which was
found in many natural products and pharmaceuticals, exhibits unique characteristics and biological activities.12
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Notably, the difluorinated diarylmethane 4 can be converted into difluorinated spiro-quinones 6 and p-QMs 7,
1
2
3
thus pinpointing the synthetic applicability of this method.
4
5
6
7
8
Scheme 5. Gram Scale-up, Transformation of Products, Radical Trapping and Control Experiments
9
a) Gram scale reaction and synthetic application
O
OH
OH
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2b
, 4.5 mmol
tBu
tBu
tBu
tBu
tBu
tBu
Cu(OAc)2 (20 mol%)
DIPEA (2.0 equiv.)
NaBH4, THF
r.t., 16 h
O
OH
MW, 100 oC, 30 min
air, THF
F
F
F
F
R
R
R
5
R = Cl, , 95%
dr = 1.87/1.
1h
R = Cl, , 0.99 g, 3 mmol,
4p
R = Cl, , 1.10 g, 75%,
1j
, 1.12 g, 3 mmol.
4o
R = Br, , 1.14 g, 72%.
R = Br,
)
v.
equi
MnO2 (20 equiv.)
DCM, r.t., 16h
rt,1h
(3.0
,
N2
=
AlCl3
Beneze
,
Cl
O
O
R
tBu
tBu
tBu
tBu
R
+
O
F
F
F F
O
6a
R
7a
R = Cl, , 27%,
R = Br, , 24%.
R = Cl, , 38%,
6b
7b
R = Br, , 35%.
b) Radical trapping experiments
OH
O
tBu
tBu
tBu
tBu
Additive (2 equiv)
Cu(OAc)2 (20 mol%)
DIPEA (2.0 equiv.)
O
HO OH
CF3
O
+
MW, 100 oC, 30 min
air, THF
F
F
1a
F
F
2a
3a
Additive
3a
O
TEMPO
BHT
0%
trace
O
N
F
F
8
c) Control experiments
detected by ESI-HRMS
O
OH
tBu
tBu
tBu
tBu
O
Cu(OAc)2 (20 mol%)
DIPEA (2.0 equiv.)
HO OH
+
CF3
O
100 oC, air,24h
THF
oil bath
F
F
2a
F
F
1a
3a,
30% yield
O
OH
tBu
tBu
tBu
tBu
O
[M]
(20 mol%)
HO OH
CF3
DIPEA (2.0 equiv.)
+
O
MW, 100 oC, air, 30min
THF
F
F
2a
F
F
1a
3a
[M]
3a
Sc(OTf)3
MgCl2
AlCl3
0%
0%
0%
To verify that the difluoroalkyl radical was participated in the reaction, the radical trapping
experiment with two radical inhibitors, 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and 2,6-di-tert-
butyl-4-methylphenol (BHT) was conducted under the standard conditions (Scheme 5b). We found the
reaction was greatly suppressed and no desired product 3a was formed. Instead, the TEMPO-trapped
product 8 was detected by ESI-HRMS technique. These results indicated that the difluoroalkyl radical
was generated under the Cu(II)/microwave conditions. In contrast to those reported methods involving
non-radical nucleophilic difluoroenolates, the reaction didn't occur at room temperature8 (Table 1, entry
19), and it didn't proceed well by conventional heating with an oil bath for 24h (Scheme 5c). Moreover,
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The Journal of Organic Chemistry
the reaction couldn't occur if Cu(OAc)2 was replaced by other Lewis acids that have no redox activity,
such as Sc(OTf)3, MgCl2 and AlCl3 (Scheme 5c). These results demonstrate that copper salts and
microwave irradiation perfectly balance the thermodynamical requirement for difluoroalkyl radical
generation and the kinetic reactivity of the formed difluoroalkyl radical for following transformation,
and that the copper salt not only acts as a Lewis acid catalyst in this system, but also a redox catalyst
(see supporting information).
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CONCLUSIONS
In conclusion, an efficient methodology of the Cu(II)-catalyzed radical difluoroalkylation of p-QMs
via trifluoroacetate release and sequential radical addition has been developed. This method offers a
facile path to diverse substituted difluorinated diarylmethanes, which widely exist in biologically active
compounds and natural products. The synthesis proceeds rapidly under microwave irradiation and
demonstrated a broad substrate scope with high functional group compatibility. An additional synthetic
utility of this methodology was featured by the synthesis of spiro-cyclohexadienones. Further
applications of α-fluorinated gem-diols as fluoroalkyl radical source are underway in our laboratory.
EXPERIMENTAL SECTION
General information
19
13
1H NMR, F NMR and C{1H} NMR spectra were measured on 400 MHz spectrometer, using CDCl3 as the
solvent with tetramethylsilane (TMS) as the internal standard at room temperature. Chemical shifts (δ) are given
in ppm relative to TMS, the coupling constants J are given in Hz. HRMS were obtained in the ESI mode. All
reactions were carried out under air atmosphere unless otherwise noted. All solvents were obtained from
commercial suppliers. Reactions were monitored by TLC on silica gelplates (GF254), and the analytical thin-
layer chromatography (TLC) was performed on precoated, glass-backed silica gel plates. The products were
purified by Biotage Isolera™ Spektra Systems and Petroleum Ether/EtOAc solvent systems. All reagents and
solvents were obtained from commercial sources and used without further purification.
Microwave irradiation experiments
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All microwave irradiation experiments were carried out in a Biotage® Initiator Classic microwave apparatus
with continuous irradiation power from 0 to 400W with utilization of the standard absorbance level of 250W
maximum power. The reactions were carried out in 10 mL glass tubes, sealed with microwave cavity. The
reaction was irradiated at a required ceiling temperature using maximum power for the stipulated time. Then it
was cooled to 50 oC with gas jet cooling.
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General procedure for the preparation of compound 3 or 4.
In an oven-dried glass tubes p-QM 15e (0.2 mmol, 1.0 eq.), α-difluorinated gem-diols 27a (0.4 mmol, 2.0 eq.),
DIPEA (0.4 mmol, 2.0 eq.) were dissolved in THF (4 mL) and the reaction mixture was sealed and heated under
microwave irradiation at 100 °C for 30 min and monitored by TLC until starting material was consumed. Then
the reaction mixture was concentrated under reduced pressure followed by column chromatography over silica
gel using petroleum / EtOAc (0 to 30%) as eluent to afford the desired product 3 or 4.
Gram Scale-up Experiment of 4p
An oven-dried glass tube (25 mL) was equipped with a magnetic stir bar, 1h (3 mmol, 0.99 g), 2b (1.5 eq., 4.5
mmol, 1.20 g), DIPEA (2.0 eq., 6 mmol, 1.0 mL). 10 ml THF was added with syringe. The tube was placed in
Biotage® Initiator Classic microwave apparatus, and the resulting solution was stirred at microwave 100 oC for
30 min and monitored by TLC. After the reaction was finished, the mixture was concentrated under vacuum to
remove THF, and the residue was purified by chromatography on silica gel (EA/PE = 1/20) to afford the 4p 1.1
g, 75% yield, colorless oil.
Gram Scale-up Experiment of 4o
An oven-dried glass tube (25 mL) was equipped with a magnetic stir bar, 1j (3 mmol, 1.12 g), 2b (1.5 eq., 4.5
mmol, 1.2 g), DIPEA (2.0 eq., 6 mmol, 1.0 mL). 10 ml THF was added with syringe. The tube was placed in
Biotage® Initiator Classic microwave apparatus, and the resulting solution was stirred at microwave 100 oC for
30 min and monitored by TLC. After the reaction was finished, the mixture was concentrated under vacuum to
remove THF, and the residue was purified by chromatography on silica gel (EA/PE = 1/20) to afford the 4o
1.14 g, 72% yield, colorless oil.
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The Journal of Organic Chemistry
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)-3-(p-tolyl) propan-1-one (3a) slight
yellow oil, 93 mg, 91% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H),
7.90 – 7.78 (m, 4H), 7.60 (t, J = 7.1 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 5.8
1
2
3
4
5
6
13
Hz, 4H), 5.08 (s, 1H), 4.88 (dd, J = 19.6, 16.9 Hz, 1H), 2.30 (s, 3H), 1.30 (s, 18H) ppm; C{1H} NMR (100
7
8
9
MHz, CDCl3) δ 191.1 (t, J = 29.4 Hz), 153.2, 137.0, 135. 8, 135.6, 133.8, 132.2, 132.0, 130.9, 129.9, 129.5,
129.2, 129.0, 128.2, 127.7, 126.8, 126.6, 126.4, 124.8, 119.6 (t, J = 259.3 Hz), 55.20 (t, J = 21.6 Hz), 34.3, 30.2,
21.0 ppm; 19F NMR (376 MHz, CDCl3) δ -98.78 (dd, J = 267.7, 16.6 Hz, 1F), -102.37 (dd, J = 267.7, 19.8 Hz,
10
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60
+
1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C34H36F2NaO2 537.2576; found 537.2579.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)-3-(m-tolyl)propan-1-one (3b) colorless
oil, 86 mg, 84% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 7.90 –
7.77 (m, 4H), 7.60 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.33 – 7.25 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H),
7.13 (s, 2H), 7.06 (d, J = 7.5 Hz, 1H), 5.08 (s, 1H), 4.87 (dd, J = 19.9, 16.5 Hz, 1H), 2.31 (s, 3H), 1.31 (s, 18H)
13
ppm; C{1H} NMR (100 MHz, CDCl3) δ 191.1 (t, J = 29.5 Hz), 153.2, 138.1, 136.7, 135.8, 135.6, 132.2,
132.0, 130.9, 130.7, 129.9, 129.0, 128.4, 128.2 (d, J = 3.1 Hz), 127.7, 126.7 (t, J = 14.5 Hz), 126.3 (d, J = 5.0
Hz), 124.8, 119.6 (t, J = 259.4 Hz), 55.5 (t, J = 21.6 Hz), 34.3, 30.2, 21.5 ppm; 19F NMR (376 MHz, CDCl3) δ -
98.55 (dd, J = 267.6, 16.1 Hz, 1F), -102.31 (dd, J = 267.7, 20.2 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+
+
calcd for C34H36F2NaO2 537.2575; found 537.2575.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)-3-phenylpropan-1-one (3c) slight
yellow oil, 92 mg, 92% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H),
7.90 – 7.76 (m, 4H), 7.60 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.4
Hz, 2H), 7.24 (t, J = 3.5 Hz, 1H), 7.13 (s, 2H), 5.09 (s, 1H), 4.93 (dd, J = 19.9, 16.4 Hz, 1H), 1.30 (s, 18H)
13
ppm; C{1H} NMR (100 MHz, CDCl3) δ 191.0 (t, J = 29.6 Hz), 153.2, 136.9, 135.8, 135.6, 132.2, 132.0,
130.8, 129.9, 129.7, 129.0, 128.5, 128.2, 127.7, 127.4, 126.9, 126.6, 126.2, 124.7, 119.61 (t, J = 259.6 Hz),
19
55.51 (t, J = 21.6 Hz), 34.3, 30.2 ppm; F NMR (376 MHz, CDCl3) δ -98.55 (dd, J = 268.4, 16.1 Hz, 1F), -
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102.35 (dd, J = 268.4, 20.0 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C33H34F2NaO2 523.2419;
+
1
2
3
found 523.2419.
4
5
6
7
8
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-3-(4-methoxyphenyl)-1-(naphthalen-2-yl)propan-1-one
(3d) slight yellow oil, 82 mg, 77% yield, Rf = 0.4 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ
8.35 (s, 1H), 7.89 – 7.78 (m, 4H), 7.60 (t, J = 7.0 Hz, 1H), 7.53 (t, J = 7.1 Hz, 1H), 7.37 (d, J = 8.6 Hz, 2H),
7.12 (s, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.09 (s, 1H), 4.87 (dd, J = 19.0, 17.4 Hz, 1H), 3.77 (s, 3H), 1.31 (s, 18H)
9
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47
48
49
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54
55
56
57
58
59
60
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ppm; C{1H} NMR (100 MHz, CDCl3) δ 191.2 (t, J = 29.4 Hz), 158.8, 153.1, 135.8, 135.6, 132.2, 131.9,
130.8, 129.9, 129.0, 128.9, 128.2, 127.7, 126.8, 126.5, 124.8, 119.65 (t, J = 258.9 Hz), 113.9, 55.2, 54.8 (t, J =
21.7 Hz), 34.3, 30.2 ppm; 19F NMR (376 MHz, CDCl3) δ -99.18 (dd, J = 266.9, 18.8 Hz, 1F), -102.37 (dd, J =
+
267.1, 21.2 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C34H36F2NaO3 553.2525; found 553.2521.
3-(4-(tert-butyl)phenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)propan-1-one
(3e) slight yellow oil, 89 mg, 80% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ
8.32 (s, 1H), 7.88 – 7.76 (m, 4H), 7.60 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H),
7.32 (d, J = 8.4 Hz, 2H), 7.14 (s, 2H), 5.08 (s, 1H), 4.87 (dd, J = 20.1, 16.5 Hz, 1H), 1.31 (s, 18H), 1.27 (s, 9H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 191.2 (J = 28.7 Hz), 153.2, 150.2, 135.8, 135.6, 133.7, 132.2, 131.9,
131.0, 129.9, 129.4, 129.0, 128.1, 127.7, 126.8, 126.6, 126.4, 125.4, 124.7, 119.7 (t, J = 260.3 Hz), 55.3 (t, J =
21.3 Hz), 34.28 (t, J = 13.6 Hz), 31.3, 30.2 ppm; 19F NMR (376 MHz, CDCl3) δ -98.61 (dd, J = 265.8, 16.2 Hz,
+
1F), -102.95 (dd, J = 265.8, 20.2 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C37H42F2NaO2 579.3045;
found m/z 579.3043.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-(dimethylamino)phenyl)-2,2-difluoro-1-(naphthalen-2-yl)propan-
1-one (3f) brown oil, 85 mg, 78% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ
8.34 (s, 1H), 7.89 – 7.78 (m, 4H), 7.59 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H),
7.14 (s, 2H), 6.66 (d, J = 8.6 Hz, 2H), 5.06 (s, 1H), 4.80 (t, J = 18.4 Hz, 1H), 2.90 (s, 6H), 1.31 (s, 18H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 191.5 (t, J = 29.4 Hz), 153.0, 149.8, 135.6 (d, J = 12.9 Hz), 132.2, 131.8
(d, J = 4.7 Hz), 131.1, 130.4, 129.9, 128.9, 128.1, 127.7, 126.9, 126.8, 126.5, 124.8, 124.3 (d, J = 3.7 Hz), 119.8
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(t, J = 258.8 Hz), 112.5, 54.9 (t, J = 21.7 Hz), 40.5, 34.2, 30.2 ppm; 19F NMR (376 MHz, CDCl3) δ -99.49 (dd,
J = 264.1, 17.3 Hz, 1F), -102.31 (dd, J = 264.1, 19.4 Hz, 1F) ppm; HRMS (ESI) m/z: [M+H]+ calcd for
1
2
3
4
5
6
+
C35H40F2NO2 544.3022; found 544.3021.
7
8
9
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)-3-(3,4,5-trimethoxyphenyl)propan-1-
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1
one (3g) slight yellow oil, 94 mg, 80% yield, Rf = 0.3 (ethyl acetate/hexane = 20%); H NMR (400 MHz,
CDCl3) δ 8.32 (s, 1H), 7.88 – 7.77 (m, 4H), 7.61 (t, J = 7.1 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.18 (s, 2H), 6.69
(s, 2H), 5.12 (s, 1H), 4.82 (dd, J = 19.1, 16.8 Hz, 1H), 3.80 (s, 9H), 1.32 (s, 18H) ppm; C{1H} NMR (100
13
MHz, CDCl3) δ 191.3 (t, J = 29.1 Hz), 153.3, 153.0, 137.5, 135.8, 135.6, 132.2, 132.1 (d, J = 3.7 Hz), 131.9 (t,
J = 4.3 Hz), 130.9, 129.9, 129.1, 128.2, 127.7, 126.9, 126.6, 125.9 (d, J = 4.6 Hz), 124.7, 119.6 (t, J = 259.7
19
Hz), 107.2, 60.8, 56.1, 55.6 (t, J = 21.7 Hz), 34.3, 30.2 ppm; F NMR (376 MHz, CDCl3) δ -99.37 (dd, J =
265.6, 16.4 Hz, 1F), -102.10 (dd, J = 265.6, 19.4 Hz, 1F) ppm; HRMS (ESI) m/z: [M+H]+ calcd for
+
C36H41F2O5 591.2917; found 591.2916.
3-(4-chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)propan-1-one (3h)
slight yellow oil, 95 mg, 89% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.37
(s, 1H), 7.91 – 7.78 (m, 4H), 7.61 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.0 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.29 (d,
J = 8.2 Hz, 2H), 7.08 (s, 2H), 5.12 (s, 1H), 4.92 (t, J = 17.9 Hz, 1H), 1.30 (s, 18H) ppm; C{1H} NMR (100
13
MHz, CDCl3) δ 190.7 (t, J = 29.5 Hz), 153.3, 136.0, 135.6 (d, J = 3.5 Hz), 135.5, 133.3, 132.2, 132.1, 131.0,
130.6, 130.0, 129.2, 128.7, 128.3, 127.7, 126.9, 126.5, 125.8 (d, J = 4.9 Hz), 124.7, 119.4 (t, J = 259.5 Hz), 54.7
19
(t, J = 21.6 Hz), 34.3, 30.1 ppm; F NMR (376 MHz, CDCl3) δ -98.24 (dd, J = 271.1, 15.9 Hz, 1F), -102.56
(dd, J = 271.1, 19.9 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C33H33ClF2NaO2 557.2029; found
+
557.2028.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-3-(4-fluorophenyl)-1-(naphthalen-2-yl)propan-1-one (3i)
colorless oil, 98 mg, 95% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.36 (s,
1H), 7.91 – 7.78 (m, 4H), 7.61 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.43 (dd, J = 8.4, 5.5 Hz, 2H), 7.09
(s, 2H), 7.01 (t, J = 8.7 Hz, 2H), 5.11 (s, 1H), 4.93 (dd, J = 19.8, 16.2 Hz, 1H), 1.30 (s, 18H) ppm; C{1H}
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NMR (100 MHz, CDCl3) δ 190.8 (t, J = 28.7 Hz), 163.3, 160.9, 153.3, 135.9, 135.7, 132.7 (t, J = 3.5 Hz),
132.2, 132.0, 131.3 (d, J = 8.0 Hz), 130.7, 129.9, 129.1, 128.3, 127.7, 126.9, 126.5, 126.1 (d, J = 5.0 Hz), 124.7,
1
2
3
4
5
6
19
119.4 (t, J = 259.6 Hz), 115.5, 115.3, 54.6 (t, J = 21.8 Hz), 34.3, 30.1 ppm; F NMR (376 MHz, CDCl3) δ -
7
8
98.54 (dd, J = 269.6, 16.1 Hz, 1F), -102.69 (dd, J = 269.6, 19.9 Hz, 1F), -115.24 – -115.32 (m, 1F) ppm;
9
+
HRMS (ESI) m/z: [M+Na]+ calcd for C33H33F3NaO2 541.2325; found 541.2325.
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3-(4-bromophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)propan-1-one (3j)
colorless oil, 105 mg, 91% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.37 (s,
1H), 7.89 – 7.79 (m, 4H), 7.61 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.34 (d, J =
8.4 Hz, 2H), 7.08 (s, 2H), 5.12 (s, 1H), 4.90 (dd, J = 19.7, 16.1 Hz, 1H), 1.30 (s, 18H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 190.6 (t, J = 29.7 Hz), 153.3, 136.1 (d, J = 3.6 Hz), 136.0, 135.7, 132.2, 132.0, 131.6, 131.4,
130.6, 130.0, 129.2, 128.3, 127.7, 126.9, 126.5, 125.7 (d, J = 5.0 Hz), 124.7, 121.5, 119.3 (t, J = 259.7 Hz), 54.8
19
(t, J = 21.7 Hz), 34.3, 30.1 ppm; F NMR (376 MHz, CDCl3) δ -98.18 (dd, J = 271.5, 15.9 Hz, 1F), -102.53
+
(dd, J = 271.5, 19.9 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C33H33BrF2NaO2 601.1524; found
601.1523.
3-(2-bromophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)propan-1-one (3k)
colorless oil, 99 mg, 86% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.47 (s,
1H), 7.92 – 7.80 (m, 5H), 7.61 (t, J = 7.3 Hz, 1H), 7.58 – 7.52 (m, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.14 (s, 2H),
13
7.13 – 7.08 (m, 1H), 5.60 (dd, J = 21.0, 15.3 Hz, 1H), 5.11 (s, 1H), 1.32 (s, 18H) ppm; C{1H} NMR (100
MHz, CDCl3) δ 189.9 (t, J = 29.3 Hz), 153.3, 136.8, 135.7 (d, J = 1.6 Hz), 133.3 (d, J = 9.3 Hz), 132.3, 130.3,
130.0, 129.1, 128.8, 128.3, 127.63 (d, J = 16.9 Hz), 126.9, 126.0, 124.9, 119.4 (t, J = 259.4 Hz), 53.6 (t, J =
21.7 Hz), 34.3, 30.2 ppm; 19F NMR (376 MHz, CDCl3) δ -98.12 (dd, J = 270.9, 15.1 Hz, 1F), -100.93 (dd, J =
+
270.8, 21.1 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C33H33BrF2NaO2 603.1503; found 603.1507.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)-3-(thiophen-2-yl)propan-1-one
(3l)
brown oil, 72 mg, 71% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H),
7.91 – 7.77 (m, 4H), 7.60 (t, J = 7.4 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.25 (s, 1H), 7.18 (s, 2H), 7.12 (d, J = 3.1
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Hz, 1H), 7.01 – 6.93 (m, 1H), 5.24 – 5.16 (m, 1H), 5.12 (s, 1H), 1.32 (s, 18H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 190.8 (t, J = 29.0 Hz), 153.6, 138.6, 135.9, 135.6, 132.2, 132.0, 130.8, 130.0, 129.1, 128.2, 127.7,
126.9, 126.6, 125.5, 124.7, 118.7 (t, J = 260.3 Hz), 51.2 (t, J = 22.6 Hz), 34.3, 30.1 ppm; 19F NMR (376 MHz,
CDCl3) δ -99.69 (dd, J = 264.5, 16.0 Hz, 1F), -104.28 (dd, J = 264.5, 18.4 Hz, 1F) ppm; HRMS (ESI) m/z:
[M+Na]+ calcd for C31H32F2NaO2S + 529.1983; found 529.1986.
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3-(4-bromothiophen-2-yl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)propan-1-
one (3m) yellow oil, 76 mg, 65% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ
8.38 (s, 1H), 7.91 – 7.80 (m, 4H), 7.62 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 1.3 Hz, 1H),
7.13 (s, 2H), 7.05 (s, 1H), 5.18 – 5.09 (m, 2H), 1.31 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 190.2 (t,
J = 29.1 Hz), 153.8, 140.4 (d, J = 4.0 Hz), 136.1, 135.7, 132.2, 132.0, 130.5, 130.2, 130.0, 129.2, 128.3, 127.7,
126.9, 126.5, 124.6, 122.9, 118.5 (t, J = 261.2 Hz), 109.3, 51.0 (t, J = 22.5 Hz), 34.3, 30.1 ppm; 19F NMR (376
MHz, CDCl3) δ -98.29 (dd, J = 268.1, 15.0 Hz, 1F), -104.89 (dd, J = 268.2, 19.0 Hz, 1F) ppm; HRMS (ESI)
m/z: [M+Na+ calcd for C31H31BrF2NaO2S + 607.1088; found 607.1089.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)-3-(pyridin-3-yl)propan-1-one
(3n)
yellow oil, 85 mg, 85% yield, Rf = 0.2 (ethyl acetate/hexane = 20%); 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J
= 1.5 Hz, 1H), 8.52 (dd, J = 4.7, 1.3 Hz, 1H), 8.39 (s, 1H), 7.90 – 7.83 (m, 5H), 7.61 (t, J = 7.1 Hz, 1H), 7.54 (t,
J = 7.1 Hz, 1H), 7.28 (dd, J = 7.9, 4.9 Hz, 1H), 7.09 (s, 2H), 5.16 (s, 1H), 4.97 (dd, J = 20.7, 15.1 Hz, 1H), 1.30
13
(s, 18H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 190.3 (t, J = 28.5 Hz), 153.5, 150.8, 148.5, 136.9, 136.2,
135.7, 133.0 (d, J = 3.0 Hz), 132.2 – 132.1 (m), 130.4, 130.0, 129.2, 128.4, 127.7, 127.0, 126.5, 125.2 (d, J =
19
5.3 Hz), 124.6, 123.4, 119.3 (t, J = 257.3 Hz), 53.1 (t, J = 22.0 Hz), 34.3, 30.1 ppm; F NMR (376 MHz,
CDCl3) δ -96.97 (dd, J = 273.2, 15.0 Hz, 1F), -103.12 (dd, J = 273.2, 20.7 Hz, 1F) ppm; HRMS (ESI) m/z:
[M+H]+ calcd for C32H34F2NO2 502.2552; found 502.2552.
+
3-(3,5-diethyl-4-hydroxyphenyl)-2,2-difluoro-1-(naphthalen-2-yl)-3-phenylpropan-1-one (3o) yellow oil, 67
mg, 76% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.00 – 7.77
(m, 4H), 7.56 (dt, J = 14.9, 7.1 Hz, 2H), 7.44 (d, J = 7.3 Hz, 2H), 7.36 – 7.19 (m, 3H), 7.01 (s, 2H), 4.96 (t, J =
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18.2 Hz, 1H), 4.66 (s, 1H), 2.53 (q, J = 7.4 Hz, 4H), 1.13 (t, J = 7.5 Hz, 6H) ppm; C{1H} NMR (100 MHz,
CDCl3) δ 190.5 (t, J = 29.7 Hz), 150.8, 136.9 (d, J = 3.7 Hz), 135.7, 132.2 (d, J = 5.9 Hz), 130.5, 130.0, 129.7,
129.3, 129.1, 128.5, 128.3, 128.2, 127.9 (d, J = 4.4 Hz), 127.7, 127.4, 126.9, 119.4 (t, J = 259.3 Hz), 54.83 (t, J
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= 21.6 Hz), 23.1, 23.0, 13.9, 13.8 ppm; F NMR (376 MHz, CDCl3) δ -96.85 (dd, J = 274.5, 17.7 Hz, 1F), -
9
+
+
100.90 (dd, J = 274.5, 18.4 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na] calcd for C29H26F2NaO2 467.1793;
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found 467.1797.
2,2-difluoro-3-(4-hydroxy-3,5-diisopropylphenyl)-1-(naphthalen-2-yl)-3-phenylpropan-1-one (3p) yellow oil,
81 mg, 86% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.91 –
7.77 (m, 4H), 7.56 (dt, J = 14.9, 7.2 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 7.27 (dt, J = 22.5, 5.7 Hz, 3H), 7.03 (s,
2H), 5.07 – 4.92 (m, 1H), 4.77 (s, 1H), 3.05 (dt, J = 13.7, 6.8 Hz, 2H), 1.14 (dd, J = 13.6, 6.8 Hz, 12H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 190.8 (t, J = 29.5 Hz), 149.5, 136.9 (d, J = 3.7 Hz), 135.7, 135.6, 133.7,
132.2, 132.08 (t, J = 4.4 Hz), 130.7, 129.9, 129.7, 129.1, 128.5, 128.5, 128.3, 127.8, 127.4, 125.2, 124.8, 119.5
(t, J = 259.1 Hz), 55.2 (t, J = 21.5 Hz), 27.2, 22.6, 22.6, 22.5 ppm; 19F NMR (376 MHz, CDCl3) δ -98.43 (dd, J
+
= 271.8, 16.3 Hz, 1F), -101.91 (dd, J = 271.1, 19.8 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na] calcd for
+
C31H30F2NaO2 495.2106; found 495.2106.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-phenyl-3-(p-tolyl)propan-1-one (4a) slight yellow oil, 75
mg, 81% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.8 Hz, 2H),
7.53 (t, J = 7.4 Hz, 1H), 7.41 – 7.29 (m, 4H), 7.16 – 7.06 (m, 4H), 5.10 (s, 1H), 4.81 (dd, J = 20.3, 16.3 Hz,
1H), 2.30 (s, 3H), 1.33 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 191.2 (t, J = 29.6 Hz), 153.2, 137.0,
135.8, 133.8, 133.5, 129.5, 129.2, 128.4, 126.6, 126.3 (d, J = 5.2 Hz), 119.4 (t, J = 259.2 Hz), 55.1 (t, J = 21.6
19
Hz), 34.3, 30.2, 21.0 ppm; F NMR (376 MHz, CDCl3) δ -98.91 (dd, J = 267.6, 16.1 Hz, 1F), -103.49 (dd,
J=267.6, 20.4 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C30H34F2NaO2 487.2419; found 487.2415.
+
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1,3-di-p-tolylpropan-1-one (4b) slight yellow oil, 75 mg,
78% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.32
(d, J = 7.9 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 10.4 Hz, 4H), 5.09 (s, 1H), 4.80 (dd, J = 19.8, 16.7 Hz,
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1H), 2.38 (s, 3H), 2.30 (s, 3H), 1.34 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 190.6 (t, J = 29.3 Hz),
153.1, 144.6, 136.9, 135.7, 133.9 (d, J = 3.7 Hz), 131.0, 129.8 (t, J = 3.4 Hz), 129.5, 129.2, 129.1, 126.5 (d, J =
6.3 Hz), 119.5 (t, J = 259.2 Hz), 55.1 (t, J = 21.6 Hz), 34.3, 30.2, 21.7, 21.0 ppm; 19F NMR (376 MHz, CDCl3)
δ -99.23 (dd, J = 267.8, 17.6 Hz, 1F), -102.98 (dd, J = 267.9, 21.0 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+
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+
calcd for C31H36F2NaO2 501.2576; found 501.2577.
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3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(4-methoxyphenyl)-3-(p-tolyl)propan-1-one (4c) slight
yellow oil, 72 mg, 73% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J =
8.7 Hz, 2H), 7.25 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 4.7 Hz, 4H), 6.78 (d, J = 8.9 Hz, 2H), 5.01 (s, 1H), 4.74 (t, J
= 17.2 Hz, 1H), 3.77 (s, 3H), 2.23 (s, 3H), 1.27 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 188.2 (t, J =
28.8 Hz), 162.9, 152.1, 135.8, 134.7, 133.0 (d, J = 3.7 Hz), 131.3 (t, J = 3.6 Hz), 128.5, 128.1, 125.7 (d, J = 4.8
19
Hz), 125.5, 125.3, 118.7 (t, J = 259.1 Hz), 112.7, 54.5, 54.1 (t, J = 21.7 Hz), 33.3, 29.2, 20.0 ppm; F NMR
(376 MHz, CDCl3) δ -99.21 (dd, J = 267.9, 17.9 Hz, 1F), -102.21 (dd, J = 268.0, 20.7 Hz, 1F) ppm; HRMS
+
(ESI) m/z: [M+H]+ calcd for C31H37F2O3 495.2705; found 495.2705.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(4-fluorophenyl)-3-(p-tolyl)propan-1-one (4d) slight
yellow oil, 84 mg, 87% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J
= 8.3, 5.6 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 9.1 Hz, 4H), 7.04 (t, J = 8.6 Hz, 2H), 5.11 (s, 1H), 4.79
(dd, J = 20.1, 16.6 Hz, 1H), 2.30 (s, 3H), 1.34 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 189.7 (t, J =
29.1 Hz), 167.2, 164.7, 153.2, 137.0, 135.9, 133.7 (d, J = 3.6 Hz), 132.9 – 132.3 (m), 130.0, 129.5, 129.2,
126.5, 126.3 (d, J = 5.0 Hz), 119.5 (t, J = 259.2 Hz), 115.7, 115.5, 55.1 (t, J = 21.6 Hz), 34.3, 30.2, 21.0 ppm;
19F NMR (376 MHz, CDCl3) δ -99.02 (dd, J = 268.3, 16.2 Hz, 1F), -102.96 (dd, J = 268.9, 20.8 Hz, 1F), -
+
103.36 – -103.41 (m, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C30H33F3NaO2 505.2325; found
505.2328.
1-(4-chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-3-(p-tolyl)propan-1-one (4e) slight
yellow oil, 84 mg, 84% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J =
8.3 Hz, 2H), 7.33 (t, J = 8.8 Hz, 4H), 7.16 – 7.06 (m, 4H), 5.12 (s, 1H), 4.77 (dd, J = 20.1, 16.6 Hz, 1H), 2.30
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(s, 3H), 1.34 (s, 18H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 190.2 (t, J = 30.0 Hz), 153.2, 140.2, 137.1,
135.9, 133.6 (d, J = 3.6 Hz), 131.9, 131.0 (t, J = 3.5 Hz), 129.5, 129.3, 128.7, 126.5, 126.2 (d, J = 5.1 Hz),
119.4 (t, J = 259.3 Hz), 55.1 (t, J = 21.5 Hz), 34.3, 30.2, 21.0 ppm; 19F NMR (376 MHz, CDCl3) δ -99.13 (dd, J
= 268.2, 17.3 Hz, 1F), -103.27 (dd, J = 268.3, 21.8 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for
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C30H33ClF2NaO2 521.2029; found 521.2029.
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1-(4-bromophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-3-(p-tolyl)propan-1-one (4f) yellow oil,
89mg, 82% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.5 Hz, 2H),
7.51 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.13 – 7.09 (m, 4H), 5.12 (s, 1H), 4.76 (dd, J = 20.2, 16.5 Hz,
1H), 2.31 (s, 3H), 1.34 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 190.5 (t, J = 30.0 Hz), 153.3, 137.1,
135.9, 133.5 (d, J = 3.2 Hz), 132.4, 131.7, 131.0 (t, J = 3.2 Hz), 129.5, 129.3, 129.0, 126.5, 126.1 (d, J = 4.9
Hz), 119.4 (t, J = 259.2 Hz), 55.1 (t, J = 21.6 Hz), 34.3, 30.2, 21.0 ppm; 19F NMR (376 MHz, CDCl3) δ -99.16
(dd, J = 268.1, 16.3 Hz, 1F), -103.33 (dd, J = 268.0, 19.8 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for
+
C30H33BrF2NaO2 565.1524; found 565.1527.
1-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-4-methyl-1-(p-tolyl)pentan-3-one (4g) colorless oil, 15 mg,
18% yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 7.3 Hz, 2H), 7.17
(s, 2H), 7.13 (d, J = 7.2 Hz, 2H), 5.14 (s, 1H), 4.62 (t, J = 18.6 Hz, 1H), 2.87 – 2.82 (m, 1H), 2.31 (s, 3H), 1.40
(s, 18H), 0.90 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.4 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 206.3 (t, J
= 27.9 Hz), 153.2, 137.1, 135.8, 133.5 (d, J = 4.0 Hz), 129.5, 129.2, 126.4, 126.3 (d, J = 5.2 Hz), 118.8 (t, J =
259.8 Hz), 53.8 (t, J = 21.6 Hz), 36.0, 34.3, 30.3, 21.0, 17.8, 17.5 ppm; 19F NMR (376 MHz, CDCl3) δ -104.85
(dd, J = 259.6, 16.7 Hz, 1F), -109.24 (dd, J = 259.6, 20.3 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for
+
C27H36F2NaO2 453.2576; found 453.2569.
(E)-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-4,4-difluoro-1-phenyl-5-(p-tolyl)pent-1-en-3-one (4h) colorless oil,
74 mg, 75% yield, Rf = 0.4 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 15.8 Hz,
1H), 7.45 (d, J = 7.4 Hz, 2H), 7.40 – 7.33 (m, 5H), 7.20 (s, 2H), 7.12 (d, J = 7.7 Hz, 2H), 6.88 (d, J = 15.9 Hz,
1H), 5.11 (s, 1H), 4.66 (t, J = 18.4 Hz, 1H), 2.29 (s, 3H), 1.36 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
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δ 190.3 (t, J = 29.5 Hz), 153.2, 146.4, 137.1, 135.8, 134.1, 133.7 (d, J = 3.6 Hz), 131.3, 129.5, 129.3, 129.0,
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128.8, 126.5, 118.7, 118.6 (t, J = 258.3 Hz), 54.5 (t, J = 22.0 Hz), 34.4, 30.3, 21.1 ppm; F NMR (376 MHz,
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CDCl3) δ -107.09 (dd, J = 255.6, 17.1 Hz, 1F), -109.08 (dd, J = 255.6, 19.4 Hz, 1F) ppm; HRMS (ESI) m/z:
+
[M+Na]+ calcd for C32H36F2NaO2 513.2576; found 513.2579.
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3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(thiophen-2-yl)-3-(p-tolyl) propan-1-one (4i) slight
yellow oil, 81 mg, 86% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J =
2.7 Hz, 1H), 7.66 (d, J = 4.9 Hz, 1H), 7.36 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 7.8 Hz, 4H), 7.07 – 7.01 (m, 1H),
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5.08 (s, 1H), 4.79 (dd, J = 21.3, 15.4 Hz, 1H), 2.30 (s, 3H), 1.34 (s, 18H) ppm; C{1H} NMR (100 MHz,
CDCl3) δ 183.9 (t, J = 29.6 Hz ), 153.2, 139.3, 137.0, 135.8 (d, J = 8.0 Hz), 135.5 – 135.2 (m), 133.6 (d, J = 3.2
Hz), 129.5, 129.2, 128.4, 126.5, 119.4 (t, J = 259.2 Hz), 55.1 (t, J = 21.7 Hz), 34.3, 30.2, 21.0 ppm; 19F NMR
(376 MHz, CDCl3) δ -100.50 (dd, J = 260.5, 18.3 Hz, 1F), -105.12 (dd, J = 260.5, 23.2 Hz, 1F) ppm; HRMS
(ESI) m/z: [M+Na]+ calcd for C28H32F2NaO2S+ 493.1983; found 493.1980.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(furan-2-yl)-3-(p-tolyl)propan-1-one (4j) slight yellow
oil, 64 mg, 71% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.34
(d, J = 7.9 Hz, 2H), 7.29 – 7.25 (m, 1H), 7.15 (s, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.49 (dd, J = 3.6, 1.4 Hz, 1H),
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5.10 (s, 1H), 4.83 (dd, J = 20.6, 16.7 Hz, 1H), 2.30 (s, 3H), 1.36 (s, 18H) ppm; C{1H} NMR (100 MHz,
CDCl3) δ 178.7 (t, J = 30.7 Hz), 153.2, 149.0, 148.3, 137.1, 135.8, 133.5 (d, J = 3.7 Hz), 129.5, 129.2, 126.4,
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122.9 – 122.4 (m), 118.9 (t, J = 258.1 Hz), 112.5, 54.7 (t, J = 21.7 Hz), 34.3, 30.2, 21.0 ppm; F NMR (376
MHz, CDCl3) δ -102.41 (dd, J = 262.3, 16.5 Hz, 1F), -106.20 (dd, J = 262.3, 20.7 Hz, 1F) ppm; HRMS (ESI)
+
m/z: [M+Na]+ calcd for C28H32F2NaO3 477.2212; found 477.2210.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(furan-2-yl)-3-(thiophen-2-yl)propan-1-one (4k) yellow
oil, 63 mg, 70% yield, Rf = 0.4 (ethyl acetate/hexane = 20%); 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.27
– 7.21 (m, 4H), 7.10 (d, J = 3.3 Hz, 1H), 6.95 (dd, J = 4.8, 3.8 Hz, 1H), 6.48 (dd, J = 3.5, 1.3 Hz, 1H), 5.20 –
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5.08 (m, 2H), 1.37 (s, 18H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 178.4 (t, J = 30.7 Hz), 153.6, 148.8,
148.5, 138.1 (d, J = 4.3 Hz), 135.9, 127.9, 126.7, 126.5, 125.6, 125.3 (d, J = 4.7 Hz), 122.9 (dd, J = 7.4, 5.4
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Hz), 117.9 (t, J = 259.2 Hz), 112.6, 50.8 (t, J = 22.7 Hz), 34.3, 30.2 ppm; F NMR (376 MHz, CDCl3) δ -
103.69 (d, J = 258.9 Hz, 1F), -108.28 (d, J = 258.9 Hz, 1F) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for
C25H28F2NaO3S+ 469.1619; found 469.1615.
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3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-(furan-2-yl)-3-(pyridin-3-yl)propan-1-one (4l) colorless
oil, 70 mg, 79% yield, Rf = 0.2 (ethyl acetate/hexane = 20%); 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.51
(d, J = 4.3 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.66 (s, 1H), 7.32 – 7.26 (m, 2H), 7.11 (s, 2H), 6.52 (d, J = 1.8 Hz,
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1H), 5.21 (s, 1H), 4.92 (dd, J = 21.7, 14.7 Hz, 1H), 1.35 (s, 18H) ppm; C{1H} NMR (100 MHz, CDCl3) δ
177.9 (t, J = 29.7 Hz), 153.5, 150.7, 148.8, 148.6, 137.0, 136.3, 132.6, 126.3, 124.9 (d, J = 5.6 Hz), 123.4, 123.1
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(dd, J = 8.2, 4.2 Hz), 118.4 (t, J = 258.1 Hz), 112.7, 34.3, 30.2 ppm; F NMR (376 MHz, CDCl3) δ -100.27
(dd, J = 266.1, 14.4 Hz, 1F), -107.55 (dd, J = 266.2, 21.5 Hz, 1F) ppm; HRMS (ESI) m/z: [M+H]+ calcd for
+
C26H30F2NO3 442.2188; found 442.2188.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-(dimethylamino)phenyl)-2,2-difluoro-1-(furan-2-yl)propan-1-one
(4m) brown oil, 70 mg, 72% yield, Rf = 0.2 (ethyl acetate/hexane = 10%); 1H NMR (400 MHz, CDCl3) δ 7.62
(s, 1H), 7.30 (d, J = 8.7 Hz, 3H), 7.17 (s, 2H), 6.66 (d, J = 8.7 Hz, 2H), 6.52 – 6.48 (m, 1H), 5.08 (s, 1H), 4.76
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(t, J = 18.8 Hz, 1H), 2.90 (s, 6H), 1.36 (s, 18H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 179.0 (t, J = 31.1
Hz), 153.0, 149.8, 149.1, 148.2, 135.7, 130.4, 126.9 (d, J = 4.7 Hz), 126.3, 123.9 (d, J = 4.0 Hz), 122.6 – 122.4
(m), 119.1 (t, J = 257.8 Hz), 112.5, 54.3 (t, J = 21.8 Hz), 40.5, 34.3, 30.3 ppm; 19F NMR (376 MHz, CDCl3) δ -
103.05 (dd, J = 260.3, 17.4 Hz, 1F), -105.82 (dd, J = 260.4, 20.0 Hz, 1F) ppm; HRMS (ESI) m/z: [M+H]+
+
calcd for C29H36F2NO3 484.2658; found 484.2658.
3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1,3-diphenylpropan-1-one (4n) colorless oil, 75 mg, 83%
yield, Rf = 0.5 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.55 (t, J =
7.4 Hz, 1H), 7.46 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.32 (t, J = 7.3 Hz, 2H), 7.28 – 7.25 (m, 1H),
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7.11 (s, 2H), 5.13 (s, 1H), 4.87 (dd, J = 20.4, 16.0 Hz, 1H), 1.35 (s, 18H) ppm; C{1H} NMR (100 MHz,
CDCl3) δ 191.2 (t, J = 29.1 Hz), 153.2, 136.8 (d, J = 3.6 Hz), 135.8, 133.6, 129.7, 129.6 (t, J = 3.4 Hz), 128.4
(d, J = 9.4 Hz), 127.4, 126.6, 126.1 (d, J = 5.2 Hz), 119.4 (t, J = 259.4 Hz), 77.2, 55.4 (t, J = 21.6 Hz), 34.3,
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30.2 ppm; F NMR (376 MHz, CDCl3) δ -98.82 (dd, J = 268.3, 15.9 Hz), -103.40 (dd, J = 268.3, 20.5 Hz)
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+
ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C29H32F2NaO2 473.2263; found 473.2260.
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3-(4-bromophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-phenylpropan-1-one (4o) colorless
oil, 86 mg, 81% yield, Rf = 0.4 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.7 Hz,
2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.05 (s,
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2H), 5.14 (s, 1H), 4.83 (dd, J = 20.3, 15.7 Hz, 1H), 1.34 (s, 18H) ppm; C{1H} NMR (100 MHz, CDCl3) δ
190.8 (t, J = 28.9 Hz), 153.4, 136.0, 133.8, 133.4, 131.6, 131.3, 129.6 (t, J = 3.1 Hz), 128.5, 126.5, 125.6 (d, J =
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5.3 Hz), 121.5, 119.1 (t, J = 259.6 Hz), 77.2, 54.7 (t, J = 21.7 Hz), 34.3, 30.2 ppm; F NMR (376 MHz,
CDCl3) δ -98.44 (dd, J = 271.1, 15.6 Hz), -103.63 (dd, J = 271.2, 20.3 Hz) ppm; HRMS (ESI) m/z: [M+Na]+
+
calcd for C29H31BrF2NaO2 551.1368; found 551.1369.
3-(4-chlorophenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-phenylpropan-1-one (4p) colorless
oil, 83 mg, 86% yield, Rf = 0.4 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ .78 (d, J = 7.3 Hz,
2H), 7.59–7.48 (m, 1H), 7.45–7.34 (m, 4H), 7.28 (d, J = 8.4 Hz, 2H), 7.06 (s, 2H), 5.14 (s, 1H), 4.86 (dd, J =
20.2, 15.8 Hz, 1H), 1.33 (s, 18H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 188.5 (t, J = 31.0 Hz), 186.2, 150.3,
149.9, 140.2 (t, J = 23.3 Hz), 134.8, 134.7, 132.5, 131.9, 131.3, 130.2 (t, J = 2.9 Hz), 129.91, 128.8, 127.5,
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123.6, 116.4 (t, J = 256.9 Hz), 35.8, 35.4, 29.4, 29.3 (s) ppm; F NMR (376 MHz, CDCl3) δ -98.41 (dd, J =
+
270.8, 16.7 Hz), -103.66 (dd, J = 270.8, 21.5 Hz) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C29H31ClF2NaO2
507.1873; found 507.1877.
3-(4-(tert-butyl)phenyl)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-difluoro-1-phenylpropan-1-one
(4q)
colorless oil, 73 mg, 72% yield, Rf = 0.3 (ethyl acetate/hexane = 5%); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J
= 7.7 Hz, 2H), 7.56 – 7.50 (m, 1H), 7.40 – 7.31 (m, 6H), 7.11 (s, 2H), 5.11 (s, 1H), 4.81 (dd, J = 20.8, 15.8 Hz,
1H), 1.34 (s, 18H), 1.29 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 191.4 (t, J = 29.4 Hz), 153.2, 150.2,
135.8, 133.8, 133.7–133.4 (m), 129.5, 129.3, 128.3, 126.6, 126.2 (d, J = 5.3 Hz), 125.4, 119.5 (t, J = 259.3 Hz),
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77.2, 55.2 (t, J = 21.7 Hz), 34.3, 31.3, 30.2 ppm; F NMR (376 MHz, CDCl3) δ -98.70 (dd, J = 265.7, 15.7
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Hz), -104.07 (dd, J = 265.8, 20.7 Hz) ppm; HRMS (ESI) m/z: [M+Na]+ calcd for C33H40F2NaO2 529.2889;
+
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found 529.2885.
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Synthesis of 2,6-di-tert-butyl-4-(1-(4-chlorophenyl)-2,2-difluoro-3-hydroxy-3-phenylpropyl) phenol (5)
An oven-dried glass tube (10 mL) was equipped with a magnetic stir bar, 4p (0.2 mmol, 97 mg), NaBH4 (3.0
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eq., 0.6 mmol, 23 mg). 1.0 ml THF was added with syringe. The resulting solution was stirred at room
temperature overnight and monitored by TLC. After the reaction was finished, the mixture was concentrated
under vacuum to remove THF, and the residue was purified by chromatography on silica gel (EA/PE = 1/4) to
afford the 5 (colorless oil, 92 mg, 95% yield, dr = 1.87/1, Rf = 0.2 (ethyl acetate/hexane = 20%); 1H NMR (400
MHz, CDCl3) 7.38 (d, J = 8.3 Hz, 2H), 7.35–7.20 (m, 7H), 7.11 (s, 2H), 5.16 (s, 1H), 4.68 (dd, J = 15.3, 7.9 Hz,
1H), 4.29 (t, J = 17.9 Hz, 1H), 2.47 (d, J = 4.2 Hz, 1H), 1.40 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) 153.3,
153.2, 136.7-136.5 (m), 136.2, 136.0, 133.2, 133.0, 131.1, 131.0, 129.0, 128.8, 128.7, 128.5, 128.3, 128.0,
127.7 (d, J = 5.1 Hz), 127.1 (d, J = 4.4 Hz), 126.4, 126.1, 123.0 (t, J = 249.6 Hz), 74.7-73.6 (m), 54.4-53.7 (m),
34.5, 34.4, 30.4, 30.4; 19F NMR (376 MHz, CDCl3) -110.47-113.22 (m); HRMS (ESI) m/z: [M+Na]+ calcd for
+
C29H33ClF2NaO2 509.2029; found 509.2030.
General procedure for the preparation of compound 6a and 7a.
An oven-dried glass tube (10 mL) was equipped with a magnetic stir bar, 4p (0.3 mmol, 146 mg), MnO2 (20
eq., 6 mmol, 522 mg). 2.0 ml DCM was added with syringe. The resulting solution was stirred at room
temperature overnight and monitored by TLC. After the reaction was finished, the mixture was concentrated
under vacuum to remove DCM, and the residue was purified by chromatography on silica gel (ethyl
acetate/hexane = 5% ~ 20%) to afford the 6a and 7a.
3,5-di-tert-butyl-2'-(4-chlorophenyl)-3',3'-difluoro-2'H-spiro[cyclohexa[2,5]diene-1,1'-naphthalene]-
4,4'(3'H) -dione (6a), colorless oil, 55 mg, 38% yield, Rf = 0.2 (ethyl acetate/hexane = 20%); 1H NMR (400
MHz, CDCl3) δ 8.26 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 8.3 Hz,
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2H), 7.16 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 3.2 Hz, 1H), 6.47 (d, J = 2.7 Hz, 1H), 3.88
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(dd, J = 35.6, 3.2 Hz, 1H), 1.16 (s, 9H), 1.10 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 184.8, 184.2 (t, J =
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26.0 Hz), 149.1, 148.1, 143.5, 141.5, 139.7 (d, J = 6.6 Hz), 135.9, 134.8, 131.9, 129.7, 129.7, 129.0, 128.7 (d, J
= 3.2 Hz), 128.6, 128.0, 113.0 (dd, J = 255.8, 249.6 Hz), 55.6 (t, J = 20.0 Hz), 48.7 (d, J = 7.0 Hz), 35.3, 34.9,
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29.1; F NMR (376 MHz, CDCl3) -106.20 (ddd, J = 40.9, 35.8, 4.4 Hz), -110.57 (dd, J = 279.0, 3.7 Hz);
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HRMS (ESI) m/z: [M+H]+ calcd for C29H30ClF2O2 483.1897; found 483.1900.
2,6-di-tert-butyl-4-(1-(4-chlorophenyl)-2,2-difluoro-3-oxo-3-phenylpropylidene)cyclohexa-2,5-dienone (7a),
colorless oil, 39 mg, 27% yield, Rf = 0.2 (ethyl acetate/hexane = 10%); 1H NMR (400 MHz, CDCl3) δ 7.94 (d,
J = 7.5 Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.45 (dd, J = 18.4, 7.9 Hz, 4H), 7.33 (s, 1H), 7.21 (d, J = 7.9 Hz, 2H),
6.68 (s, 1H), 1.22 (s, 9H), 1.11 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 188.5 (t, J = 31.0 Hz), 186.2,
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150.3, 149.9, 140.2 (t, J = 23.3 Hz), 135.3, 134.9 (t, J = 4.8 Hz), 134.7 , 132.3, 132.0, 130.2, 129.9, 128.8,
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128.3, 127.5, 116.5 (t, J = 256.8 Hz), 35.8, 35.4, 29.4, 29.3; F NMR (376 MHz, CDCl3) δ -87.78; HRMS
+
(ESI) m/z: [M+H]+ calcd for C29H30ClF2O2 483.1897; found 483.1896.
General procedure for the preparation of compound 6b and 7b.
An oven-dried glass tube (10 mL) was equipped with a magnetic stir bar, 4o (0.3 mmol, 159 mg), MnO2 (20 eq.,
6 mmol, 522 mg). 2.0 ml DCM was added with syringe. The resulting solution was stirred at room temperature
overnight and monitored by TLC. After the reaction was finished, the mixture was concentrated under vacuum
to remove DCM, and the residue was purified by chromatography on silica gel (ethyl acetate/hexane = 5% ~
20%) to afford the 6b and 7b.
2'-(4-bromophenyl)-3,5-di-tert-butyl-3',3'-difluoro-2'H-spiro[cyclohexa[2,5]diene-1,1'-naphthalene]-
4,4'(3'H) -dione (6b), colorless oil, 55 mg, 35% yield (dr = 1.87/1), Rf = 0.2 (ethyl acetate/hexane = 20%); 1H
NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.8 Hz, 1H), 7.60–7.52 (m, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.32 (d, J =
8.4 Hz, 2H), 7.03 (dd, J = 8.2, 2.7 Hz, 3H), 6.82–6.70 (m, 1H), 6.39 (d, J = 3.1 Hz, 1H), 3.79 (dd, J = 35.5, 3.5
Hz, 1H), 1.09 (s, 9H), 1.02 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.7, 184.1 (t, J = 255.0 Hz), 149.1,
148.1, 143.5, 141.4, 139.6 (d, J = 6.6 Hz), 135.9, 132.2 (d, J = 2.6 Hz), 131.0, 130.2, 129.7, 129.0, 128.7 (d, J =
2.9 Hz), 128.5, 122.9, 113.0 (dd, J = 255.6, 249.8 Hz), 55.7 (t, J = 20.0 Hz), 48.6 (d, J = 6.6 Hz), 35.3, 34.9,
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29.1; F NMR (376 MHz, CDCl3) δ -106.19 (ddd, J = 279.3, 35.4, 4.1 Hz), -110.49 (dd, J = 278.9, 3.1 Hz);
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HRMS (ESI) m/z: [M+Na]+ calcd for C29H29BrF2NaO2 549.1211; found 549.1214.
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4-(1-(4-bromophenyl)-2,2-difluoro-3-oxo-3-phenylpropylidene)-2,6-di-tert-butylcyclohexa-2,5-dienone (7b),
colorless oil, 43 mg, 24% yield, Rf = 0.2 (ethyl acetate/hexane = 10%); 1H NMR (400 MHz, CDCl3) δ 7.86 (d,
J = 7.8 Hz, 2H), 7.61–7.54 (m, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.25 (s, 1H), 7.07 (d, J =
8.1 Hz, 2H), 6.61 (s, 1H), 1.15 (s, 9H), 1.04 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.5 (t, J = 31.0 Hz),
186.2, 150.3, 149.9, 140.2 (t, J = 23.3 Hz), 134.9–134.7 (m), 134.7, 132.5, 131.9, 131.3, 130.2 (t, J = 2.9 Hz),
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129.9, 128.8, 127.5, 123.6, 116.4 (t, J = 256.8 Hz), 35.8, 35.4, 29.4, 29.3; F NMR (376 MHz, CDCl3) δ -
+
87.75; HRMS (ESI) m/z: [M+H]+ calcd for C29H30BrF2O2 527.1392; found 527.1392.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Copies of the 1H NMR, 13C {1H} NMR, 19F NMR and HRMS spectra of all compounds (PDF).
AUTHOR INFORMATION
Corresponding Author
*HLi2@uams.edu
*xzg@cqwu.edu.cn
*18883138277@163.com
ORCID
Hong-yu Li: 0000-0001-9212-2010
Zhi-Gang Xu: 0000-0003-0190-1313
Zhong-Zhu Chen: 0000-0001-9555-6738
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We gratefully acknowledge the National Natural Science Foundation of China (No. 21901027), the Science
and Technology Research Program of Chongqing Municipal Education Commission (KJQN201901345 and
KJQN201901346), Chongqing Natural Science Foundation Postdoctoral Science Foundation Project
(cstc2019jcyj-bshX0053), and the Scientific Research Foundation of the Chongqing University of Arts and
Sciences (R2019FXY11). We would also like to thank Ms H.Z. Liu and J. Xu for obtaining the LC/MS, HRMS
and NMR data.
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