Visible Light-Promoted Phosphine-Catalyzed Difluoroalkylation of Arenes and Heterocycles

Article abstract of DOI:10.1021/acs.joc.9b02882

A visible light-promoted difluoroalkylation reaction of arenes or heterocycles, using triaryl phosphine as the catalyst and difluoroalkyl iodide as the alkylating agent, is presented. The strategy is highlighted by photocatalyst-free, mild reaction conditions and a broad substrate scope. Mechanistic experiments indicate that this reaction involves a radical-chain process that is initiated by an electron donor-acceptor complex formed from difluoroalkyl iodide and phosphine.

Full text of DOI:10.1021/acs.joc.9b02882

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Article
Visible Light-Promoted Phosphine-Catalyzed
Difluoroalkylation of Arenes and Heterocycles
Heng Lu, Dongyu Wang, and Ao Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02882 • Publication Date (Web): 19 Dec 2019
Downloaded from pubs.acs.org on December 19, 2019
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The Journal of Organic Chemistry
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Visible Light-Promoted Phosphine-Catalyzed Difluoroalkylation of
Arenes and Heterocycles
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Heng Lu,†,§ Dong-yu Wang,‡,§ and Ao Zhang*,†,‡,§
†School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
‡CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM),
Chinese Academy of Sciences, Shanghai 201203, China
§University of Chinese Academy of Sciences, Beijing 100049, China
*E-mail: aozhang@simm.ac.cn.
Supporting Information
F
F
H
Rf
I
R
F
F
Ar3P
I
R
R
R
32 examples
up to 97% yield
organic phosphine catalysis
broad substrate scope
transition metal free
mild conditions
ABSTRACT: A visible light-promoted difluoroalkylation reaction of arenes or heterocycles using
triaryl phosphine as the catalyst and difluoroalkyl iodide as the alkylating agent is presented.
The strategy is highlighted by photocatalyst-free, mild reaction conditions, and broad substrate
scope. Mechanistic experiments indicate that this reaction involves a radical-chain process that
is initiated by an EDA complex formed from difluoroalkyl iodide and phosphine.
INTRODUCTION
Fluoroalkanes are highly valuable compounds possessing wide applications in pharmaceuticals
industry, medicinal chemistry, and materials science.1 More specifically, the gem-difluoromethyl
group (CF2) is chemically unique with physicochemical properties distinct from other
monofluoro or trifluoro-containing congeners, and is being more and more commonly used as
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bioisosteres of alcohols, amines or ketones with potentials to improve liver microsome stability
and cellular permeability.2 In the past decade, strategies for direct introduction of difluoroalkyl
groups have received increasing attention.3 Their transition metal-catalyzed difluoroalkylation
of aromatic rings or alkenes has been well-established through a nucleophilic,4 electrophilic,5
radical,6 or metal−difluorocarbene pathway (Scheme 1a).7 Simultaneously, the visible-light-
promoted difluoroalkylation reactions were regarded as a powerful addition for synthesis of
difluoroalkylated skeletons.8 Early in 2011, Stephenson’s group8a reported a radical addition
reaction of ethyl bromodifluoroacetate with olefins using a metal-photoredox catalyst. Later,
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8l
organic photocatalysts such as eosin Y,8f perylene8k and [Mes-Acr]ClO4 were employed in the
difluoroalkylation reactions. Recently, light- or thermo-sensitive electron donor-acceptor (EDA)
complexes have been widely applied in organic synthesis due to the simplicity.9 The formation
of these EDA complexes generally depends on pseudo-electrostatic interactions between
electron donor and acceptor substrates.9a Perfluoroalkyl iodides Rf–I, as a good electron acceptor,
could form intermolecular electrostatic interactions between σ* antibonding orbital of the C–I
bond and lone pairs of electron-rich atoms (carbanion, nitrogen or oxygen atoms).9f
Accordingly, several applications have been reported for the visible light induced generation of
perfluoroalkyl radicals through EDA complexes.10 The Yu’s10e and Chen’s10g groups respectively
reported a halogen bond induced radical addition reaction of iodoperfluoroalkylene with
isocyanide or alkenes, which halogen bonds were caused from nitrogen or phosphorus atoms.
He et al.10l has recently reported substrate-promoted perfluoroalkylation of uracils and cytosines
without catalyst in visible-light irradiation. Further, the Melchiorre’s group developed substrate-
induced perfluoroalkylation reactions, which perfluoroalkyl radical (Rf•) was generated from
EDA complexes formed from perfluoroalkyl iodide and α-cyano arylacetates10a or cyclic β-
ketoester10d under blue light irradiation (Scheme 1b).
Scheme 1. Visible light-promoted fluoroalkylation
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a. TM- and Photocatalyzed Fluoroalkylation
1
2
3
Rf
Rf
Rf
Photocatalysis
TM Catalysis
Rf
Y
Rf
CF2
4
5
6
b. Fluoroalkylation through EDA Complexes
visible-light
SET
X
X:
Y Rf
X:
Y Rf
Rf
7
8
Y
electron
donor
electron
acceptor
donor-acceptor complexes
9
Rf
I
Rf
I
CN
CO2Et
O
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Bn
Bn
Rf
I
N
H
CO2Et
carbanion as
electron donor
nitrogen as
electron donor
oxygen as
electron donor
c. This Work:
H
F
F
R
R
I
F
This work
F
Ar3P
transition metal free
mild conditions
organic phosphine catalysis
broad substrate scope
Meanwhile, organophosphines are widely used as ligands due to their electron-donating ability
in transition metal catalyzed reactions. Recently, several groups reported the use of triaryl
phosphines as single-electronic transfer (SET) medium in visible light-promoted
transformations.11 Sparkled by these pioneering works, we herein report on the application of
triarylphosphine as electron donor of EDA complexes in a photocatalytic system to generate
gem-difluoroalkyl radicals from the commonly used 2,2-difluoro-2-iodoacetate substrates. This
protocol readily facilitated visible light-promoted gem-difluoroalkylation of inactivated arenes
and heterocycles with broad substrate scope (Scheme 1c).
During the completion of our work, The Czekelius group10o reported a similar work for the
photomediated radical addition reaction of alkenes with perfluoroalkyl iodides. Meanwhile, He’s
group10n reported a Heck-type difluoroalkylation or bisfunctionalization of alkenes with
iododifluoroacetate. In their work, they used a phosphine/base (DPPM/DMPU) system through
thermal initiation or phosohine (tri-tert-butylphosphine) system via photo initiation to realize
fluoroalkylation of alkenes, which is similar to ours (P(4-CF3Ph)3/K2CO3) via visible light
irradiation to realize difluoroalkylation of arene or heteroarenes.
RESULTS AND DISCUSSION
Table 1. Optimization of Conditionsa
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OMe
OMe
PAr3. (0.25 eq.)
base. (2.0 eq.)
O
H
1
2
3
4
CF2CO2Et
OMe
I
OEt
solvent, r.t.,
Ar, 24 h.
Blue LEDs
F
F
MeO
1a
OMe
MeO
2a
3
, (2.0 eq.)
, (1.0 eq.)
5
6
7
8
9
entry
1
catalyst
PPh3
base
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
K3PO4
K2CO3
Cs2CO3
DABCO
K2CO3
K2CO3
K2CO3
–
solvent
yield, %b
48
54
63
65
24
–
DCM
DMSO
DMF
2
PPh3
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3
PPh3
4
PPh3
MeCN
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
5
PPh3
6
P(C6F5)3
7
P(4-OMePh)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
–
52
85
76
90
65
71
8
9
10
11
12
13c
14d
15d
16d
17d,e
18d,f
19d,g
88
97
–
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
P(4-CF3Ph)3
–
K2CO3
K2CO3
K2CO3
–
–
63
aReaction condition: 1a (0.2 mmol), 2a (0.1 mmol), base (0.2 mmol),
catalyst (0.025 mmol), solvent (1.0 mL), 24 h, Ar, 16W Blue LED. bYields
c
are determined by GC-MS using dodecane as internal standard. N,N'-
Dimethyl-N,N'-trimethyleneurea (DMPU, 0.01 mmol) as additive.
dsolvent (0.5 mL). edark. dark, 80 oC. gReaction carried out under air.
f
To initiate the reaction, we chose 1,3,5-trimethoxybenzene (1a) and ethyl iododifluoroacetate
(2a) to establish optimal conditions. As shown in Table 1, the reaction was performed using 25
mol% of PPh3 as the catalyst and KOAc (2.0 equiv.) as the base in DCM under irradiation of 16W
blue LED light strips, and the product 3a was obtained in 48% yield (Table 1, entry 1). Then,
several solvents were screened. To our delight, the yield of 3a was increased to 65% by using
acetonitrile as the solvent (Table 1, entry 4). The reaction was also conducted with different
triarylphosphines (Table 1, entries 6-8), and the yield of 3a was improved to 85% when P(4-
CF3Ph)3 was used as the catalyst (entry 8). Subsequently, we screened several inorganic bases
(entries 9-12), and found K2CO3 to be the optimal giving product 3a in 90% yield (entry 10).
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The Journal of Organic Chemistry
Moreover, when N,N'-Dimethyl-N,N'-trimethyleneurea (DMPU) was used as the additive, the
yield of 3a had no changed. Further, we surveyed the concentration of the reaction, and found
that the yield of 3a was increased to 97% when 0.5 mL of MeCN (0.2 M) was used (Table 1, entry
14). Product 3a was not detected in the absence of either phosphine (Table 1, entry 15), base
(Table 1, entry 16) or light irradiation (Table 1, entry 17). In addition, the reaction did not proceed
under traditional heating in oil bath (Table 1, entry 18), thus excluding the possibility of thermal
initiation. Moreover, decreased yield was observed when the reaction was conducted in the air
atmosphere (Table 1, entry 19). Collectively, the condition in entry 14 was selected as the optimal
and standard reaction condition in this protocol.
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Scheme 2. Substrate Scope of gem-Difluoromethylationa
O
P(4-CF3Ph)3 (0.25 eq.)
K2CO3 (2.0 eq.)
H
CF2CO2Et
I
O
MeCN (0.2 M), r.t.
Blue LEDs, Ar, 24 h
(standard condation)
F
F
2a
3
1
OMe
CF2CO2Et
CF2CO2Et
CF2CO2Et
OMe
MeO
3a
, 97%
3b
, 73%
3c
, 42%,
α/β
14/1
=
R
Cl
Cl
CF2CO2Et
3d
3eb
3fb,c
3gb,c
, R= OMe, 65%
, R=Cl, 52%
CF2CO2Et
CF2CO2Et
,
R=l, 43%
OMe
SMe
3h-1b
SMe
3h-2b
, 16%
, R=BPin, 38%
, 48%
O
O
HN
F
N
F
CF2CO2Et
F
F
X
3k
, R= NH, 68%
R=NMe, 76%
3l
,
3m
,R=O, 61%
, R=S, 55%
3n
3j
, 80%
3i
, 71%
O
O
O
N
CF2CO2Et
OMe
CF2CO2Et
N
CF2CO2Et
MeO
N
O
3o
, 74%
3qb
, 81% (72%d)
3p
, 80%
O
CO2Me
CF2CO2Et
CF2CO2Et
HN
N
NHAc
CF2CO2Et
O
O
O
N
O
3sb,e
H
3tb,e
, 47%
, 51%
3rb,e
, 75%
from tryptophan
from xanthotoxin
O
O
N
EtO2CF2C
EtO2CF2C
HO
NH
NH
HO
N
O
O
O
O
OH OH
3vb,e, 59%
OH
3ub,e
, 53%
from 2'-deoxyuridine
from uridine
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aReaction condition: 1 (0.4 mmol), 2a (0.2 mmol), P(4-CF3Ph)3 (0.05 mmol), K2CO3 (0.4 mmol),
in degassed MeCN (1 mL), were irradiated with 16 W blue LED at r. t. for 24 h. Yields of isolated
1
2
3
4
5
6
7
b
c
d
e
product are given. 36 h. 1 (0.2 mmol), 2a (0.4 mmol). Yields in 1.0 mmol scale. DMF instead
of MeCN.
8
9
To explore the scope of the gem-difluoromythylation reaction, various arenes were applied as
the substrate and the results are summarized in Scheme 2. Substrates 1,3,5-trimethoxybenzene
and mesitylene, bearing electron-rich substituents reacted with 2a in a good to excellent yields.
High positional selectivity was observed for naphthalene as the substrate delivering product 3c
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with difluoroalkylation preferentially occurring at the α-position (α/β=14/1, determined by F
NMR). In addition, halogens, such as chloro and iodo, or borate substituted substrates were
compatible as well, affording the corresponding products 3e-h in moderate yields with potential
for further functional transformation. Interestingly, lactamization products 3i and 3j were
obtained in 71% and 80% yields, respectively from aniline substrates, thus providing an easy
access for 3,3-difluoroindolin-2-ones. To expand the utility of this strategy, we turned our
attention to diverse heterocycles as substrates (Scheme 2). Under the standard reaction
conditions, 3-substituted benzoheterocycles such as indole, benzothiophene and benzofuran
were readily transformed to the corresponding products 3k-n in 55-76% yields. Meanwhile,
pyridine, 4H-pyran-4-one, and pyrimidine-dione are also suitable substrates, leading to the
corresponding products 3o-q in 74-81% yields. In addition, 6-phenylpyridazin-3(2H)-one, the
anti-inflammatory xanthotoxin, and the essential amino acid tryptophan all participated in the
reaction as well, providing corresponding products 3r-t in 47-75% yields with difluoroalkylation
preferentially occurring at the electron-rich position. Appealingly, the more reactive 2-
deoxyuridines, derived from antiviral drug trifluridine (TFT)12 also well survived from the
reaction conditions without additional protection, and the corresponding difluoroalkylated
products 3u and 3v were generated in 53% and 59% yields, respectively. To test the synthetic
scalability of our protocol, the reaction of 1,3-dimethyluracil 1q with 2a was conducted at 1 mmol
scale, and the uracil difluoroacetate 3q was obtained in 72% isolated yield. Unfortunately,
simple and monosubstituted benzenes or non-substituted heterocyclic are not suitable for this
method leading to low yields and poor regioselectivity.
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The Journal of Organic Chemistry
Scheme 3. Reactions of Dimethyluracil with Diverse gem-Difluoroalkanes a
1
2
3
H
P(4-CF3Ph)3 (0.25 eq.)
K2CO3 (2.0 eq.)
I
R
R
4
5
F
F
MeCN (0.2M), r.t.
Blue LEDs, Ar, 36 h
F
F
2
1
4
6
7
8
9
O
N
O
O
N
O
N
O
O
N
O
P
O
O
O
O
N
N
N
N
N
N
O
N
F
F
H
F
F
O
O
F
F
F
F
O
O
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11
12
13
14
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4db
4a
4b
4c
, 75%
, 85%
N
, 80%
N
, 54%
O
O
N
N
O
O
O
O
O
O
N
N
S
N
N
S
N
H
F
F
F
F
O
F
F
O
F
F
O
O
4eb
4f
4g
4h,
77%
, 72%
, 52%
, 61%
F
O
F
F
HN
F
F
O
O
F
N
O
N
P
S
O
O
O
OMe
MeO
N
4k
, 64%
4i
4j
, 70%
, 77%
aReaction condition: 1q (0.4 mmol), 2 (0.2 mmol), P(4-CF3Ph)3 (0.05 mmol), K2CO3 (0.4 mmol),
MeCN (1 mL), 24h, Ar, Blue LEDs. Yields of isolated product are given. b0.2 mmol K2CO3.
As shown in Scheme 3, with 1,3-dimethyluracil 1q as the substrate, a class of diverse
iododifluoroalkanes
were
tested
under
the
standard
condition.
Notably,
difluoroiodomethylphosphonate and various difluoro-2-iodoacetamides reacted with 1q
smoothly,
providing
corresponding
products
4a-e
in
54-85%
as
yields.
well as
Iododifluorophenylethanone,
2-(2,2-diofluoro-2-idio
acetyl)thiophenen,
(difluoroiodomethyl)sulfonylbenzene are also suitable difluoromethylation reagents, affording
corresponding products 4f-h in 52-77% yields. In addition, we have also explored several
iododifluoroalkanes reagents with other substrates, to our delight, three different heterocycles
worked smoothly and gave the products 4i-k in 64–77% yields. In a control reaction, the
difluoroalkylation of 1,3-dimethyluracil 1q in Scheme 3 did not occur without phosphine catalyst,
indicating the necessity of P-catalyst in our protocol.
In the meantime, several mechanistic experiments were performed. First, two alkyl-radical
trapping reagent (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and 1,1-diphenylethylene were
used to catch electron-withdrawing gem-difluoroalkyl radical. The adduct TEMPO-CF2CO2Et
was detected by gas chromatography-mass spectrometer (Scheme 4a). Meanwhile,
difluoroacetate-trapped product of 1,1-diphenylethylene was separated and structurally
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confirmed through NMR analysis (see SI Scheme S2). Further, in the UV/Vis absorption study,
treatment of difluoroalkyl iodide 2a with the P(4-CF3Ph)3 induced new absorption bands in the
visible region (Scheme 4b), suggesting the possible formation of an EDA complex. In addition,
the 1:1 molar ratio between 2a and P(4-CF3Ph)3 in the EDA complex was established using Job’s
1
2
3
4
5
6
7
8
19
method13a with F NMR spectroscopy, in which maximal chemical shift difference appeared at
9
50% molar fraction of difluoroalkyl iodide 2a (Scheme 4c). Meanwhile, the equilibrium constant
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13b
KEDA (KEDA = 9.22) was calculated using the Benesi−Hildebrand method (see SI Figure S4).
These results suggest the formation of EDA complex between 2a and P(4-CF3Ph)3. Finally, on
the basis of Glorius’s method,13c we calculated the quantum yield of the reaction (Φ = 2.4),
indicating a chain propagation mechanism. Meanwhile, the reaction was found to continue to
proceed when light was turned off, but with a slower rate, confirming the necessity of constant
irradiation for completion of this reaction (Scheme 4d).14
Scheme 4. Mechanistic Investigation
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(a) Trapping experiment
1
2
3
4
5
6
OMe
O
OMe
standard
condition
CF2CO2Et
OMe
I
N
OEt
N
F
F
O
O
MeO
3a, not
detected
CF2CO2Et
MeO
OMe
5, detected by GC-MS
TEMPO (2.0 eq.)
2a
1a
O
N
O
O
O
N
standard
condition
I
N
OEt
N
CF2CO2Et
CF2CO2Et
F
F
O
7
6, 2.0 eq.
1q, 2.0 eq.
2a, 1.0 eq.
3q, 19%
7, 63%
8
9
(b) Optical absorption spectra of reaction components.
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(c) Job's plot between 2a and P(4-CF3Ph)3.
(d) Light/dark experiments for the model reaction
Light ON Light OFF
Based on the results above, a conceivable mechanism is proposed in Scheme 5. First, an EDA
complex A, is assembled from iododifluoroacetate 2 and phosphine, which then undergoes
visible light irradiation to generate difluoroalkyl radical ( • CF2R) and the intermediate B.
Subsequently, the difluoroalkyl radical is captured by arenes or heteroarenes to afford aryl
radical species C. Aryl cation D is then formed through two possible paths: (a) via a SET
oxidation by intermediate B to recover phosphine catalyst; (b) via a radical exchange with RCF2I
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(2) to generate difluoromethyl radical, which then enters the radical chain process. The final
products 3 or 4 are obtained by deprotonation with a base.
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CONCLUSIONS
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In summary, we describe a mild and efficacious strategy for direct gem-difluoromethylation
of unactivated arenes and heterocycles with iododifluoroalkanes by a radical-chain mechanism
through visible light-promoted phosphine catalysis. A broad range of substrates and diverse
iododifluoroalkanes are well tolerant, facilitating a series of high value gem-difluoroalkanes,
including several pharmaceutical agents.
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Scheme 5. Proposed Reaction Mechanism
RF2C I
2
CF2R
(b)
H
CF2R
H
C
CF2R
(a)
D
Base
Ar
Ar
Ar
I
P
B
CF2R
CF2R
H
Ar
Ar
Ar
3 or 4
P
1
Ar
Ar
Ar
RF2C I
2
P
I
F
R
F
A
EDA complex
Experimental Section
All reactions performed in flame-dried glassware, including sealed tubes or Schlenck tubes.
Liquids and solutions were transferred with syringes. All solvents and chemical reagents were
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obtained from commercial sources and used without further purifications. H, and C NMR
spectra were recorded with tetramethylsilane as an internal reference. Low and high-resolution
mass spectra were recorded on EI-TOF (electrospray ionization-time of flight). Flash column
chromatography on silica gel (200 - 300 mesh) or RP-C18. The column output was monitored by
TLC on silica gel (100 - 200 mesh) precoated on glass plates (15 x 50 mm), and spots were
visualized by UV light at 254 nM. Commercially available chemicals were obtained from Acros
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Organics, Strem Chemicals, Alfa Aesar, Adamas-beta, J&K. UV-Vis spectrum was measured by
Shimadzu UV-2600 with pure MeCN as blank sample. The difluoroalkylation reagents 215-19 were
prepared according to corresponding literature procedures. All reactions were conducted under
blue light bands (Blue sky lighting, 5050 types, 60 LEDs/m, 16W, wavelength range: 420 nm–500
nm). Unless otherwise stated all difluoroalkylation reactions were conducted inside 4 ml screw
neck glass vials with a septa screw cap.
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General procedures for synthesis of compounds 3 and 4. To a dried 4 mL of colorless
glass bottle equipped with magnetic stirring bar, aromatic substrate (0.4 mmol, 2.0 equiv.),
P(4CF3-Ph)3 (0.05 mmol, 22.3 mg, 0.25 equiv.) and K2CO3 (0.4 mmol, 55.2 mg, 2.0 equiv.) were
added. The rubber septum was capped, evacuated briefly under high vacuum and charged with
Ar balloon (5 times). Degassed MeCN (1.0 mL) or DMF (1.0 mL) and iododifluoroacetate
(0.2mmol, 30 μL, 1.0 equiv.) were added by syringe. The bottle was placed at a distance of 1 cm
from the 16W blue LEDs. After 24 h or 36 h, the reaction mixture was filtered and the filtrate was
concentrated. The residue was purified on a preparative TLC with petroleum ether/ethyl acetate
as the eluent to afford products 3 or 4.
For scale-up synthesis of 3q at 1 mmol: To a dried 25 mL of Schlenk tube was charged
with magnetic stirring bar, 1, 3-dimethyluracil (2.0 mmol, 280.0 mg, 2.0 equiv.), P(4CF3-Ph)3
(0.25 mmol, 111.5 mg, 0.25 equiv.) and K2CO3 (2.0 mmol, 276.0 mg, 2.0 equiv.) were added. The
rubber septum was capped, evacuated briefly under high vacuum and charged with Ar balloon
(5 times). Then, degassed MeCN (5.0 mL) and ethyl iododifluoroacetate (1.0 mmol, 150 μL, 1.0
equiv.) were added by syringe. The bottle was placed at a distance of 1 cm from the 16W blue
LEDs. After 36 h, the reaction mixture was filtered and the filtrate was concentrated. The residue
was purified by a flash silica gel column chromatography to give product 3q as a light yellow
solid (189 mg, 72% yield).
Ethyl 2,2-difluoro-2-(2,4,6-trimethoxyphenyl)acetate (3a) The product (57.5 mg, 97% yield)
was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 8:1) as
colorless oil. Known compound.19 1H NMR (400 MHz, CDCl3) δ 6.12 (s, 2H), 4.32 (q, J = 7.2 Hz,
19
2H), 3.82 (s, 3H), 3.79 (s, 6H), 1.33 (t, J = 7.1 Hz, 3H). F NMR (376 MHz, CDCl3) δ -96.3 (s).
13C{1H} NMR (151 MHz, CDCl3) δ 164.8 (t, J = 33.4 Hz), 164.5, 163.2, 160.1 (t, J = 2.6 Hz), 113.3 (t, J =
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248.0 Hz), 102.7 (t, J = 24.2 Hz), 91.3, 62.3, 56.1, 55.3, 14.0. EI-MS (m/z) 290 (M+); HRMS (EI): m/z
[M+] calcd for C13H16F2O5, 290.0960. found, 290.0960.
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Ethyl 2,2-difluoro-2-mesitylacetate (3b) The product (35.3 mg, 73% yield) was obtained
through silica gel chromatography (Petroleum ether/Ethyl acetate = 30:1) as colorless liquid.
Known compound.19 1H NMR (400 MHz, CDCl3) δ 6.87 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 2.43 (t, J =
4.3 Hz, 6H), 2.28 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -98.6 (q, J = 4.4
Hz). 13C{1H} NMR (151 MHz, CDCl3) δ 164.5 (t, J = 35.6 Hz), 139.9, 137.5 (t, J = 3.2 Hz), 131.0, 126.8
(t, J = 22.5 Hz), 116.2 (t, J = 253.3 Hz), 62.9, 21.5 (t, J = 20.9 Hz), 20.7, 13.8. EI-MS (m/z) 242 (M+);
HRMS (EI): m/z [M+] calcd for C13H16F2O2, 242.1112 found, 242.1113.
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Ethyl 2,2-difluoro-2-(naphthalen-1-yl)acetate (3c) The product (21.0 mg, 42% yield) was
obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 30:1) as white
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solid. Known compound.19 mp 74-75 C. H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.3 Hz, 1H),
7.98 (d, J = 8.3 Hz, 1H), 7.93 – 7.86 (m, 2H), 7.60 – 7.51 (m, 3H), 4.29 (q, J = 7.2 Hz, 2H), 1.24 (t, J =
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7.1 Hz, 3H). F NMR (376 MHz, CDCl3) δ -100.0 (s). 13C{1H} NMR (151 MHz, CDCl3) δ 164.4 (t, J =
34.9 Hz), 133.8, 131.9, 129.3 (t, J = 2.3 Hz), 128.8, 128.4 (t, J = 23.1 Hz), 127.3, 126.3, 124.9 (t, J = 9.5
Hz), 124.5, 124.2 (t, J = 2.9 Hz), 114.3 (t, J = 251.2 Hz), 63.2, 13.8. EI-MS (m/z) 250 (M+); HRMS
(EI): m/z [M+] calcd for C14H12F2O2, 250.0800. found, 250.0800.
Ethyl 2-(2,5-dimethoxyphenyl)-2,2-difluoroacetate (3d) The product (33.8 mg, 65% yield) was
obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 15:1) as colorless
liquid. Known compound.19 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J = 3.0 Hz, 1H), 6.98 (dd, J = 9.0
Hz and 3.0 Hz, 1H), 6.87 (d, J = 9.0 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 1.30
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(t, J = 7.1 Hz, 3H). F NMR (376 MHz, CDCl3) δ -102.4 (s). 13C{1H} NMR (151 MHz, CDCl3) δ 163.9
(t, J = 33.8 Hz), 153.5, 150.7 (t, J = 5.0 Hz), 122.7 (t, J = 24.1 Hz), 117.4, 112.8, 112.0 (t, J = 7.7 Hz), 111.8
(t, J = 249.4 Hz), 62.7, 56.3, 55.8, 13.9. EI-MS (m/z) 260 (M+); HRMS (EI): m/z [M+] calcd for
C12H14F2O4, 260.0856. found, 260.0855.
Ethyl 2-(5-chloro-2-methoxyphenyl)-2,2-difluoroacetate (3e) The product (27.5 mg, 52%
yield) was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 15:1) as
colorless oil. Known compound.19 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 2.5 Hz, 1H), 7.41 (dd, J
= 8.8 Hz and 2.5 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.30 (t, J =
7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -103.1 (s). 13C{1H} NMR (151 MHz, CDCl3) δ 163.4 (t, J =
33.7 Hz), 155.3 (t, J = 4.8 Hz), 132.0, 126.6 (t, J = 7.9 Hz), 125.8, 123.4 (t, J = 24.3 Hz), 112.7, 111.4 (t, J
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= 249.7 Hz), 62.8, 56.0, 13.9. EI-MS (m/z) 264 (M+); HRMS (EI): m/z [M+] calcd for C11H11ClF2O3,
264.0363. found, 264.0359.
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Ethyl 2,2-difluoro-2-(5-iodo-2-methoxyphenyl)acetate (3f) The product (30.5 mg, 43% yield)
was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 15:1) as
colorless oily liquid. Known compound.19 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 2.1 Hz, 1H),
7.74 (dd, J = 8.7, 1.8 Hz, 1H), 6.71 (d, J = 8.7 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.30 (t, J =
7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -103.1 (s). 13C{1H} NMR (151 MHz, CDCl3) δ 163.5 (t, J =
33.6 Hz), 156.6 (t, J = 4.8 Hz), 141.0, 135.0 (t, J = 6.5 Hz), 124.1 (t, J = 24.3 Hz), 113.6, 111.2 (t, J = 249.7
Hz), 82.3, 62.8, 55.9, 13.9. EI-MS (m/z) 356 (M+); HRMS (EI): m/z [M+] calcd for C11H11F2IO3,
355.9713. found, 355.9716.
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Ethyl 2,2-difluoro-2-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate
(3g) The product (27.0 mg, 38% yield) was obtained through silica gel chromatography
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(Petroleum ether/Ethyl acetate = 10:1) as colorless oily liquid. H NMR (400 MHz, CDCl3) δ 8.10
(s, 1H), 7.91 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.34 (s,
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12H), 1.28 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -102.7 (s). C{1H} NMR (151 MHz,
CDCl3) δ 164.1 (t, J = 33.9 Hz), 159.1 (t, J = 4.8 Hz), 139.3, 132.9 (t, J = 7.0 Hz), 121.4 (t, J = 24.2 Hz),
112.3 (t, J = 248.4 Hz), 110.5, 83.9, 62.6, 55.6, 24.8, 13.9. EI-MS (m/z) 356 (M+); HRMS (EI): m/z
[M+] calcd for C17H23BF2O5, 356.1602. found, 356.1601.
Ethyl 2-(2-chloro-5-(methylthio)phenyl)-2,2-difluoroacetate (3h-1) The product (28.3 mg, 48%
yield) was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 15:1) as
colorless oily liquid. 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.28 (d, J =
10.0 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz,
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CDCl3) δ -102.6 (s). C{1H} NMR (151 MHz, CDCl3) δ 162.9 (t, J = 33.7 Hz), 138.4, 131.5 (t, J = 24.2
Hz), 130.8, 129.6, 128.1 (t, J = 4.1 Hz), 124.8 (t, J = 8.8 Hz), 112.0 (t, J = 251.5 Hz), 63.4, 15.7, 13.8. EI-
MS (m/z) 280 (M+); HRMS (EI): m/z [M+] calcd for C11H11ClF2O2S, 280.0131. found, 280.0131.
Ethyl 2-(5-chloro-2-(methylthio)phenyl)-2,2-difluoroacetate (3h-2) The product (9.0 mg, 16%
yield) was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 15:1) as
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colorless oily liquid. H NMR (400 MHz, CDCl3) δ 7.69 – 7.65 (m, 1H), 7.46 – 7.37 (m, 2H), 4.35
(q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -102.6 (s).
13C{1H} NMR (151 MHz, CDCl3) δ 163.3 (t, J = 33.7 Hz), 135.2 (t, J = 3.7 Hz), 134.9 (t, J = 23.5 Hz),
132.7, 132.3, 131.3, 126.6 (t, J = 9.3 Hz), 112.2 (t, J =251.5 Hz), 63.2, 18.6, 13.8. EI-MS (m/z) 280 (M+);
HRMS (EI): m/z [M+] calcd for C11H11ClF2O2S, 280.0131. found, 280.0133.
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5-(tert-Butyl)-3,3-difluoroindolin-2-one (3i) The product (32.0 mg, 71% yield) was obtained
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through silica gel chromatography (Petroleum ether/Ethyl acetate = 5:1) as light yellow solid. mp
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87-88 C. H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 7.57 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.98 –
6.89 (m, 1H), 1.32 (s, 9H). 19F NMR (471 MHz, CDCl3) δ -111.6 (s). 13C{1H} NMR (126 MHz, CDCl3)
δ 167.7 (t, J = 30.4 Hz), 147.5, 138.6 (t, J = 7.3 Hz), 130.5, 121.9, 119.9 (t, J = 22.9 Hz), 111.1, 34.6, 31.3.
EI-MS (m/z) 225 (M+); HRMS (EI): m/z [M+] calcd for C12H13F2NO, 225.0965. found, 225.0971.
3,3-Difluoro-1,5-dimethylindolin-2-one (3j) The product (31.5 mg, 80% yield) was obtained
through silica gel chromatography (Petroleum ether/Ethyl acetate = 15:1) as light yellow liquid.
Known compound.20 1H NMR (400 MHz, CDCl3) δ 7.35(s, 1H), 7.31 – 7.27 (d, J = 7.6Hz, 1H), 6.78
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(d, J = 7.6Hz, 1H), 3.19 (s, 3H), 2.36 (s, 3H). 19F NMR (471 MHz, CDCl3) δ -112.2 (s). C{1H} NMR
(126 MHz, CDCl3) δ 165.3 (t, J = 30.4 Hz), 141.5 (t, J = 7.0 Hz), 133.8, 133.7, 125.2, 120.0 (t, J = 22.9
Hz), 111.1 (t, J = 249.8 Hz), 109.2, 26.3, 20.9. EI-MS (m/z) 197 (M+); HRMS (EI): m/z [M+] calcd for
C10H9F2NO, 197.0645. found, 197.0647.
Ethyl 2,2-difluoro-2-(3-methyl-1H-indol-2-yl)acetate (3k) The product (34.4 mg, 68% yield)
was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 30:1) as yellow
oil. Known compound.21 1H NMR (400 MHz, CDCl3) δ 8.50 – 8.32 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.38 (dt, J = 8.3, 1.0 Hz, 1H), 7.30 (m, 1H), 7.18 (m, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.44 (t, J = 2.3 Hz,
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3H), 1.35 (t, J = 7.2 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -101.46 (s). C{1H} NMR (126 MHz,
CDCl3) 163.45 (t, J =35.9 Hz), 135.51, 128.50, 124.21, 123.32 (t, J = 29.7 Hz), 120.03, 119.72, 113.81 (t, J =
3.6 Hz), 111.45, 111.39 (t, J = 251.4 Hz), 63.46, 13.88, 8.44. EI-MS (m/z) 253 (M+); HRMS (EI): m/z
[M+] calcd for C13H13F2NO2, 253.0906. found, 253.0909.
Ethyl 2-(1,3-dimethyl-1H-indol-2-yl)-2,2-difluoroacetate (3l) The product (40.6mg, 76% yield)
was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 5:1) as
colorless oily liquid. Known compound.21 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 1H),
7.37 – 7.32 (m, 2H), 7.18 (dq, J = 7.9 Hz, 4.4 Hz and 3.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.85 (d, J =
1.4 Hz, 3H), 2.46 (t, J = 3.1 Hz, 3H), 1.34 (td, J = 7.2 Hz and 0.9 Hz, 3H). 19F NMR (471 MHz,
CDCl3) δ -98.1 (s). 13C{1H} NMR (126 MHz, CDCl3) δ 163.6 (t, J = 36.0 Hz), 138.0, 127.5, 124.7 (t, J =
28.6 Hz), 124.0, 119.8, 119.6, 114.2 (t, J = 3.8 Hz), 112.3 (t, J = 251.8 Hz), 109.5, 63.4, 31.4 (t, J = 4.3
Hz), 13.9, 8.9 (t, J = 2.7Hz). EI-MS (m/z) 267 (M+); HRMS (EI): m/z [M+] calcd for C14H15F2NO2,
267.1065. found, 267.1065.
Ethyl 2,2-difluoro-2-(3-methylbenzofuran-2-yl)acetate (3m) The product (31.0mg, 61% yield)
was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 10:1) as
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colorless oily liquid. Known compound.21 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, J = 7.5 Hz and 1.1
Hz, 1H), 7.49 (dt, J = 8.3 Hz and 0.9 Hz, 1H), 7.39 (m, 1H), 7.31 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H),
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2.42 (t, J = 2.6 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -103.4 (s). C{1H}
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NMR (126 MHz, CDCl3) δ 162.5 (t, J = 34.1 Hz), 154.2, 141.0 (t, J = 32.6 Hz), 128.9, 126.3, 123.1, 118.0,
112.3 (t, J = 250.1 Hz), 110.3, 108.4, 63.6, 13.9, 7.7. EI-MS (m/z) 254 (M+); HRMS (EI): m/z [M+]
calcd for C13H12F2O3, 254.0746. found, 254.0749.
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Ethyl 2,2-difluoro-2-(3-methylbenzo[b]thiophen-2-yl)acetate (3n) The product (29.7 mg, 55%
yield) was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 10:1) as
colorless oily liquid. Known compound.21 1H NMR (400 MHz, CDCl3) δ 7.88 – 7.82 (m, 1H), 7.80 –
7.74 (m, 1H), 7.47 – 7.41 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 2.53 (t, J = 2.1 Hz, 3H), 1.33 (t, J = 7.1 Hz,
13
3H). 19F NMR (471 MHz, CDCl3) δ -94.4 (s). C{1H} NMR (126 MHz, CDCl3) δ 163.2 (t, J = 35.7
Hz), 140.1, 138.9, 133.9 (t, J = 4.8 Hz), 128.1 (t, J = 28.4 Hz), 126.0, 124.5, 122.7, 122.5, 112.6 (t, J =
252.7 Hz), 63.5, 13.9, 12.0. EI-MS (m/z) 270 (M+); HRMS (EI): m/z [M+] calcd for C13H12F2O2S,
270.0526. found, 270.0522.
Ethyl 2-(2,6-dimethoxypyridin-3-yl)-2,2-difluoroacetate (3o) The product (38.6mg, 74% yield)
was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 5:1) as
colorless oily liquid. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H),
4.33 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz,
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CDCl3) δ -101.6 (s). C{1H} NMR (126 MHz, CDCl3) δ 164.8, 163.8 (t, J = 34.5 Hz), 159.7 (t, J = 5.2
Hz), 138.3 (t, J = 6.2 Hz), 112.2 (t, J = 248.4 Hz), 107.2 (t, J = 26.3 Hz), 101.3, 62.8, 53.8, 53.6, 13.9. EI-
MS (m/z) 261 (M+); HRMS (EI): m/z [M+] calcd for C11H13F2NO4, 261.0812. found, 261.0807.
Ethyl 2-(2,6-dimethyl-4-oxo-4H-pyran-3-yl)-2,2-difluoroacetate (3p) The product (39.4 mg,
80% yield) was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate =
8:1) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.13 – 6.05 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.51
(t, J = 3.4 Hz, 3H), 2.26 (d, J = 0.8 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -
101.3 (q, J = 3.6 Hz). 13C{1H} NMR (126 MHz, CDCl3) δ 176.6 (t, J = 3.5 Hz), 167.3, 165.9, 162.9 (t, J =
31.9 Hz), 119.3 (t, J = 22.4 Hz), 113.6, 112.3 (t, J = 250.2 Hz), 62.9, 19.6, 18.8 (t, J = 4.9 Hz), 13.8. EI-
MS (m/z) 246 (M+); HRMS (EI): m/z [M+] calcd for C11H12F2O4, 246.0693. found, 246.0698.
Ethyl 2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2,2-difluoroacetate (3q) The
product (35.3 mg, 73% yield) was obtained through silica gel chromatography (Petroleum
ether/Ethyl acetate = 4:1) as light yellow solid (42.4 mg, 81% yield). Known compound.22 mp 80-
81 oC. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.47 (s, 3H), 3.29 (s, 3H),
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1.32 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -104.8 (s). C{1H} NMR (151 MHz, CDCl3) δ
162.6 (t, J = 33.1 Hz), 160.3 (t, J = 4.0 Hz), 151.0, 142.7 (t, J = 8.1 Hz), 111.0 (t, J = 249.8 Hz), 106.8 (t, J
= 25.3 Hz), 63.3, 37.6, 27.7, 13.7. EI-MS (m/z) 262 (M+); HRMS (EI): m/z [M+] calcd for
C10H12F2N2O4, 262.0765. found, 262.0760.
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Ethyl 2,2-difluoro-2-(3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)acetate (3r) The product (44.1
mg, 75% yield) was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate
= 2:1) as light yellow solid. mp 191-193 oC. 1H NMR (400 MHz, CDCl3) δ 12.81 – 12.61 (s, 1H), 8.12 (d,
J = 1.2 Hz, 1H), 7.88 – 7.77 (m, 2H), 7.53 – 7.45 (m, 3H), 4.43 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz,
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3H). 19F NMR (376 MHz, CDCl3) δ -108.2 (s). C{1H} NMR (126 MHz, CDCl3) δ 161.9 (t, J = 32.1
Hz), 158.9 (t, J = 4.2 Hz), 145.6, 133.8, 133.7 (t, J = 25.1 Hz), 130.1, 129.1, 128.5 (t, J = 6.6 Hz), 126.0,
110.0 (t, J = 251.7 Hz), 63.7, 13.8. EI-MS (m/z) 294 (M+); HRMS (EI): m/z [M+] calcd for
C14H12F2N2O3, 294.0813. found, 294.0811.
Ethyl 2,2-difluoro-2-(9-methoxy-7-oxo-7H-furo[3,2-g]chromen-4-yl)acetate (3s) The product
(34.5 mg, 51% yield) was obtained through silica gel chromatography (Petroleum ether/Ethyl
acetate = 3:1) as white solid. mp 103-104 oC. 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 10.2 Hz, 1H),
7.77 – 7.72 (m, 1H), 7.14 (q, J = 2.9 Hz, 1H), 6.47 (d, J = 10.1 Hz, 1H), 4.36 (s, 3H), 4.29 (q, J = 7.1 Hz,
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2H), 1.26 (t, J = 7.2 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -95.8(s). C{1H} NMR (126 MHz,
CDCl3) δ 163.5 (t, J = 35.3 Hz), 159.1, 147.4 (t, J = 2.2 Hz), 146.5, 143.5, 140.8 (t, J = 2.5 Hz), 134.8,
125.3 (t, J = 3.9 Hz), 116.0, 114.4 (t, J = 3.1 Hz), 114.2, 113.8 (t, J = 26.7 Hz), 112.2 (t, J = 251.9 Hz), 107.2
(t, J = 7.1 Hz), 63.8, 61.3, 13.8. EI-MS (m/z) 338 (M+); HRMS (EI): m/z [M+] calcd for C16H12F2O6,
338.0590. found, 338.0596.
Methyl (R)-2-acetamido-3-(2-(2-ethoxy-1,1-difluoro-2-oxoethyl)-1H-indol-3-yl)propanoate (3t)
The product (35.9 mg, 47% yield) was obtained through silica gel chromatography (Petroleum
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ether/Ethyl acetate = 1:2) as yellow solid. mp 98-100 C. H NMR (400 MHz, CDCl3) δ 8.80 (s,
1H), 7.70 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H),
6.21 (d, J = 7.5 Hz, 1H), 4.91 (q, J = 7.2 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.68 (s, 3H), 3.38 (qd, J =
14.4, 6.5 Hz, 2H), 1.92 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -99.5 (d, J =
267.1 Hz, 1F), -101.21 (d, J = 267.1 Hz, 1F). 13C{1H} NMR (151 MHz, CDCl3) δ 172.3, 170.0, 163.5 (t, J =
35.6 Hz), 135.7, 127.6, 124.6, 124.4 (t, J = 30.2 Hz), 120.7, 119.8, 112.3, 111.8, 111.2 (t, J = 251.8 Hz), 63.9,
52.8, 52.3, 26.8, 22.9, 13.8. EI-MS (m/z) 382 (M+); HRMS (EI): m/z [M+] calcd for C18H20F2N2O5,
382.1334. found, 382.1335.
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The Journal of Organic Chemistry
Ethyl 2,2-difluoro-2-(1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-2,4-
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dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetate (3u) The product (37.1 mg, 53% yield) was obtained
through silica gel chromatography (Dichloromethane / Methanol = 20:1) as white syrup solid.
Known compound.22 1H NMR (400 MHz, CD3OD) δ 8.69 (s, 1H), 6.27 (t, J = 6.4 Hz, 1H), 4.42 (dt,
J = 6.1 Hz and 3.8 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.97 (q, J = 3.0 Hz, 1H), 3.86 – 3.72 (m, 2H), 2.99
(s, 1H), 2.86 (s, 1H), 2.36 (m, 1H), 2.26 (dt, J = 13.5 Hz and 6.3 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H). 19F
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NMR (471 MHz, CD3OD) δ -104.9 (d, J = 274.4 Hz, 1F), -105.9 (d, J = 274.2 Hz, 1F). C{1H} NMR
(126 MHz, CD3OD) δ 164.2 (t, J = 33.5 Hz), 162.6 (t, J = 4.2 Hz), 151.5, 142.3 (t, J = 8.1 Hz), 112.5 (t, J
= 248.0 Hz), 108.8 (t, J = 25.5 Hz), 89.3, 87.4, 71.9, 64.3, 62.3, 42.0, 14.1. EI-MS (m/z) 351 (M+H);
HRMS (EI): m/z [M+H] calcd for C13H16F2N2O7, 351.0926. found, 351.0923.
Ethyl
2-(1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2,4-dioxo-
1,2,3,4-tetrahydropyrimidin-5-yl)-2,2-difluoroacetate (3v) The product (43.2 mg, 59% yield) was
obtained through silica gel chromatography (Dichloromethane/Methanol = 15:1) as white syrup
solid. Known compound.22 1H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 5.96 (d, J = 3.6 Hz, 1H),
4.33 (q, J = 7.1 Hz, 2H), 4.24 (p, J = 5.0 Hz, 2H), 4.09 (dt, J = 4.3 Hz and 2.1 Hz, 1H), 3.92 (dd, J =
12.1 Hz and 2.4 Hz, 1H), 3.78 (dd, J = 12.1 Hz and 2.1 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H). 19F NMR (471
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MHz, CD3OD) δ -105.0 (d, J = 274.5 Hz, 1F), -105.8 (d, J = 274.5 Hz, 1F). C{1H} NMR (126 MHz,
CD3OD) δ 164.1 (t, J = 33.6 Hz), 162.5 (t, J = 3.5 Hz), 151.7, 142.4 (t, J = 8.0 Hz), 112.5 (t, J = 248.0
Hz), 109.0 (t, J = 25.3 Hz), 91.3, 86.5, 76.3, 70.9, 64.3, 61.5, 49.0, 14.1. EI-MS (m/z) 367 (M+H);
HRMS (EI): m/z [M+H] calcd for C13H17F2N2O8, 367.0954. found, 367.0957.
Diethyl ((1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)difluoromethyl)phosphonate
(4a) The product (48.9mg, 75% yield) was obtained through silica gel chromatography
(Petroleum ether/Ethyl acetate = 4:1) as light yellow solid. Known compound.22 mp 72-73 C. H
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NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 4.39 – 4.25 (m, 4H), 3.44 (s, 3H), 3.33 (s, 3H), 1.38 (t, J = 7.1
Hz, 6H). F NMR (471 MHz, CDCl3) δ -106.6(s, 1F), -106.9 (s, 1F). 13C{1H} NMR (126 MHz, CDCl3)
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δ 159.1, 151.0, 143.9 (td, J = 10.5 Hz and 3.4 Hz), 116.6 (td, J = 265.4 Hz and 223.0 Hz), 106.0 (td, J =
22.8 Hz and 15.2 Hz), 65.4, 65.3, 37.7, 27.9, 16.4, 16.3. EI-MS (m/z) 326 (M+); HRMS (EI): m/z
[M+] calcd for C11H17F2N2O5P, 326.0847. found, 326.0848.
2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-N,N-diethyl-2,2-difluoroacetamide
(4b) The product (49.1 mg, 85% yield) was obtained through silica gel chromatography
(Petroleum ether/Ethyl acetate = 4:1) as white solid. Known compound.22 mp 68-69 oC. 1H NMR
(400 MHz, CDCl3) δ 7.52 (s, 1H), 3.59 (q, J = 7.1 Hz, 2H), 3.45 – 3.36 (m, 5H), 3.31 (s, 3H), 1.26 (t, J
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= 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -100.0 (s). C{1H} NMR (126
MHz, CDCl3) δ 161.5 (t, J = 29.5 Hz), 160.1 (t, J = 3.6 Hz), 151.2, 141.5 (t, J = 9.5 Hz), 115.4 (t, J = 256.8
Hz), 108.6 (t, J = 25.3 Hz), 42.4, 42.2 (t, J = 6.4 Hz), 37.4, 27.7, 14.3, 12.1. EI-MS (m/z) 289 (M+);
HRMS (EI): m/z [M+] calcd for C12H17F2N3O3, 289.1236. found, 289.1232.
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5-(1,1-Difluoro-2-morpholino-2-oxoethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4c) The
product (42.4 mg, 81% yield) was obtained through silica gel chromatography (Petroleum
ether/Ethyl acetate = 3:1) as light yellow solid. mp 100-111 oC. 1H NMR (400 MHz, CDCl3) δ 7.53 (s,
1H), 3.80 (d, J = 4.5 Hz, 2H), 3.72 – 3.68 (m, 4H), 3.63 (s, 2H), 3.41 (s, 3H), 3.28 (s, 3H). 19F NMR
(471 MHz, CDCl3) δ -98.9 (s). 13C{1H} NMR (126 MHz, CDCl3) δ 160.7 (t, J = 29.8 Hz), 160.0 (t, J =
3.6 Hz), 151.0, 141.8 (t, J = 9.5 Hz), 115.3 (t, J = 256.4 Hz), 107.7 (t, J = 24.9 Hz), 66.5, 66.5, 46.5 (t, J
= 6.6 Hz), 43.8, 37.4, 27.7. EI-MS (m/z) 303 (M+); HRMS (EI): m/z [M+] calcd for C12H15F2N3O4,
303.1024. found, 303.1025.
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2-(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2,2-difluoro-N-phenylacetamide
(4d) The product (33.4 mg, 54% yield) was obtained through silica gel chromatography
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(Petroleum ether/Ethyl acetate = 2:1) as light yellow solid. mp 126-127 C. H NMR (400 MHz,
CDCl3) δ 9.00 (s, 1H), 7.75 (s, 1H), 7.59 (d, J = 8.6 Hz, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.14 (t, J = 7.4
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Hz, 1H), 3.43 (s, 3H), 3.29 (s, 3H). F NMR (471 MHz, CDCl3) δ -105.4 (s). 13C{1H} NMR (126 MHz,
CDCl3) δ 160.8 (t, J = 26.1 Hz), 160.6 (t, J = 4.0 Hz), 150.8, 143.7 (t, J = 9.0 Hz), 136.3, 128.9, 125.3,
120.2, 112.6 (t, J = 254.5 Hz), 105.8 (t, J = 26.1 Hz), 37.6, 27.9. EI-MS (m/z) 309 (M+); HRMS (EI):
m/z [M+] calcd for C14H13F2N3O3, 309.0920. found, 309.0919.
N-Butyl-2-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2,2-difluoroacetamide (4e)
The product (35.2 mg, 61% yield) was obtained through silica gel chromatography (Petroleum
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ether/Ethyl acetate = 3:1) as colorless oil. H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 6.95 (s, 1H),
3.43 (s, 3H), 3.34 – 3.26 (m, 5H), 1.54 (p, J = 7.4 Hz, 2H), 1.35 (dq, J = 14.6, 7.3 Hz, 2H), 0.90 (t, J =
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7.3 Hz, 3H). F NMR (471 MHz, CDCl3) δ -106.0 (s). 13C{1H} NMR (126 MHz, CDCl3) δ 162.9 (t, J =
29.5 Hz), 160.2 (t, J = 3.7 Hz), 151.0, 143.3 (t, J = 9.1 Hz), 112.8 (t, J = 253.3 Hz), 106.2 (t, J = 25.9 Hz),
39.5, 37.5, 31.0, 27.8, 19.8, 13.6. EI-MS (m/z) 289 (M+); HRMS (EI): m/z [M+] calcd for
C12H17F2N3O3, 289.1236. found, 289.1236.
5-(1,1-Difluoro-2-oxo-2-phenylethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
(4f)
The
product (42.3 mg, 72% yield) was obtained through silica gel chromatography (Petroleum
ether/Ethyl acetate = 3:1) as light yellow solid. mp 121-122 oC. 1H NMR (400 MHz, CDCl3) δ 8.11 (d,
J = 7.8 Hz, 2H), 7.69 (s, 1H), 7.63 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 2H), 3.51 (s, 3H), 3.31 (s,
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The Journal of Organic Chemistry
3H). 19F NMR (471 MHz, CDCl3) δ -99.9 (s). C{1H} NMR (126 MHz, CDCl3) δ 188.4 (t, J = 31.3
Hz), 160.3 (t, J = 3.9 Hz), 151.2, 142.5 (t, J = 8.6 Hz), 134.1, 132.5, 130.1 (t, J = 2.8 Hz), 128.6, 115.2 (t, J
= 254.9 Hz), 107.9 (t, J = 24.9 Hz), 37.7, 27.9. EI-MS (m/z) 294 (M+); HRMS (EI): m/z [M+] calcd
for C14H12F2N2O3, 294.0816. found, 294.0813.
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5-(1,1-Difluoro-2-oxo-2-(thiophen-2-yl)ethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
(4g)
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The product (31.2 mg, 52% yield) was obtained through silica gel chromatography (Petroleum
ether/Ethyl acetate = 3:1) as light yellow solid. mp 104-105 oC. 1H NMR (400 MHz, CDCl3) δ 8.18 –
8.14 (m, 1H), 7.82 (dd, J = 4.9Hz and 1.0 Hz, 1H), 7.69 (s, 1H), 7.24 – 7.20 (m, 1H), 3.51 (s, 3H), 3.31
(s, 3H). 19F NMR (471 MHz, CDCl3) δ -101.4 (s). 13C{1H} NMR (126 MHz, CDCl3) δ 181.3 (t, J = 32.2
Hz), 160.3 (t, J = 3.9 Hz), 151.2, 142.8 (t, J = 8.6 Hz), 137.9 (t, J = 2.9 Hz), 136.6, 136.3 (t, J = 5.4 Hz),
128.7, 114.8 (t, J = 254.6 Hz), 107.4 (t, J = 25.1 Hz), 37.7, 27.9. EI-MS (m/z) 300 (M+); HRMS (EI):
m/z [M+] calcd for C12H10F2N2O3S, 300.0369. found, 300.0375.
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5-(Difluoro(phenylsulfonyl)methyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione
(4h)
The
product (50.8 mg, 77%) was obtained through silica gel chromatography (Petroleum ether/Ethyl
acetate = 3:1) as light yellow solid. mp 174-175 oC. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.7 Hz,
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2H), 7.78 (t, J = 7.5 Hz, 1H), 7.73 (s, 1H), 7.64 (t, J = 7.8 Hz, 2H), 3.52 (s, 3H), 3.35 (s, 3H). F NMR
(471 MHz, CDCl3) δ -99.5 (s). 13C{1H} NMR (126 MHz, CDCl3) δ 158.2, 150.8, 146.8 (t, J = 8.4 Hz),
135.4, 132.5, 130.9, 129.3, 120.5 (t, J = 289.9 Hz), 100.0 (t, J = 22.5 Hz), 38.0, 28.2. EI-MS (m/z) 330
(M+); HRMS (EI): m/z [M+] calcd for C13H12F2N2O4S, 330.0484. found, 330.0486.
Diethyl ((1,3-dimethyl-1H-indol-2-yl)difluoromethyl)phosphonate (4i) The product (50.8 mg,
77% yield) was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 4:1)
as light yellow oil . 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 6.4 Hz, 2H),
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7.15 (m, 1H), 4.32 – 4.07 (m, 4H), 3.89 (s, 3H), 2.46 (q, J = 3.2 Hz, 3H), 1.33 (t, J = 7.1 Hz, 6H). F
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NMR (471 MHz, CDCl3) δ -106.5 (s, 1F), -106.7 (s, 1F). C{1H} NMR (126 MHz, CDCl3) δ 138.2,
127.6, 124.6 (td, J = 25.8 Hz and 13.5 Hz), 123.7, 119.6, 119.4, 117.3 (td, J = 264.4 Hz and 226.0 Hz),
114.6 (td, J = 7.7 Hz and 4.2 Hz), 109.5, 64.8, 64.7, 31.7, 16.4, 16.3, 9.2. EI-MS (m/z) 331 (M+);
HRMS (EI): m/z [M+] calcd for C15H20F2NO3P, 331.1143. found, 331.1144.
4-(1,1-difluoro-2-oxo-2-phenylethyl)-6-phenylpyridazin-3(2H)-one (4j) The product (45.6 mg,
70%) was obtained through silica gel chromatography (Petroleum ether/Ethyl acetate = 3:1) as
white solid. mp 167-168 oC. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.5 Hz, 2H), 7.81 – 7.72 (m,
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3H), 7.60 (t, J = 7.4 Hz, 1H), 7.51 – 7.43 (m, 5H), 6.99 (d, J = 9.9 Hz, 1H). F NMR (471 MHz,
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CDCl3) δ -89.8 (s). 13C{1H} NMR (126 MHz, CDCl3) δ182.11 (t, J = 29.2 Hz), 158.3, 145.6, 133.9, 133.4,
132.2, 132.12, 131.5, 130.5, 129.3, 129.1, 128.7, 126.3, 112.9 (t, J = 270.3 Hz). EI-MS (m/z) 326 (M+);
HRMS (EI): m/z [M+] calcd for C18H12F2N2O2, 326.0861. found, 326.0865.
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3-(Difluoro(phenylsulfonyl)methyl)-2,6-dimethoxypyridine (4k) The product (42.4 mg, 64%)
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1
solid. mp 161-162 C. H NMR (400 MHz, CDCl3) δ 8.02 – 7.93 (m, 2H), 7.79 – 7.68 (m, 2H), 7.60
19
(t, J = 7.9 Hz, 2H), 6.39 (dt, J = 8.4, 1.0 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 3H). F NMR (471 MHz,
13
CDCl3) δ -98.4 (s). C{1H} NMR (126 MHz, CDCl3) δ 165.7, 161.5, 141.8 (t, J = 6.7 Hz), 134.9, 133.6,
130.8, 129.5, 122.1 (t, J = 298.5 Hz), 101.9, 100.1 (t, J = 23.4 Hz), 53.9, 53.8. EI-MS (m/z) 329 (M+);
HRMS (EI): m/z [M+] calcd for C14H13F2NO4S, 329.0533. found, 329.0540.
Ethyl 2,2-difluoro-4,4-diphenylbut-3-enoate (7) The product (38.2 mg, 63%) was obtained
through silica gel chromatography (Petroleum ether/Ethyl acetate = 15:1) as light yellow liquid.
Known compound.9s 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.20 (m, 10H), 6.28 (t, J = 11.7 Hz, 1H),
19
3.92 (q, J = 7.2 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H). F NMR (471 MHz, CDCl3) δ -90.97 (d, J = 11.8Hz).
13C{1H} NMR (126 MHz, CDCl3) δ 163.4 (t, J = 34.0 Hz), 150.9 (t, J = 11.2 Hz), 140.4, 137.0, 129.8 (t, J
= 1.9 Hz), 129.0, 128.5, 128.3, 127.9, 127.8, 119.4 (t, J =28.4 Hz), 112.5 (t, J = 246.2 Hz), 62.7, 13.6. EI-
MS (m/z) 302 (M+); HRMS (EI): m/z [M+] calcd for C18H16F2O2, 302.1114. found, 302.1113.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Experimental details and NMR data (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: aozhang@simm.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This work was supported by grants from the National Nature Science Foundation of China
(81430080, 81773565) and “Personalized Medicines—Molecular Signature-based Drug Discovery
and Development” of Strategic Priority Research Program of the Chinese Academy of Sciences
(XDA12050411). Supports from the Department of National Science & Technology of China Major
Program on “Key New Drug Creation and Manufacturing Program” (No. 2018ZX09711002-006-
003) and the Key Program of Frontier Science (160621) of the Chinese Academy of Sciences are
also highly appreciated.
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