Photoredox-Catalyzed Cascade Difluoroalkylation and Intramolecular Cyclization for Construction of Fluorinated γ-Butyrolactones

Article abstract of DOI:10.1021/acs.joc.7b01279

A cascade visible-light photocatalytic difluoroalkylation and intramolecular cyclization reaction has been developed for the synthesis of difluoroalkylated oxygen heterocycles. The reaction was carried out under very mild conditions, affording fluorinated

Full text of DOI:10.1021/acs.joc.7b01279

Note
pubs.acs.org/joc
Photoredox-Catalyzed Cascade Difluoroalkylation and
Intramolecular Cyclization for Construction of Fluorinated
γ‑Butyrolactones
Wanxing Sha,† Wenzhong Zhang,† Shengyang Ni,† Haibo Mei,†,‡ Jianlin Han,*,†,‡ and Yi Pan†,‡
†School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of
Advanced Organic Materials, Nanjing University, Nanjing 210093, China
‡MaAnShan High-Tech Research Institute of Nanjing University, MaAnShan 238200, China
S
* Supporting Information
ABSTRACT: A cascade visible-light photocatalytic difluoroalkylation and intramolecular cyclization reaction has been developed
for the synthesis of difluoroalkylated oxygen heterocycles. The reaction was carried out under very mild conditions, affording
fluorinated isobenzofuran-1-ones, lactone, and cyclic ethers with up to 97% chemical yields. Furthermore, several types of
bromofluoroalkane precursors bearing ester, keto, amido, and phosphate groups could all work very well in this reaction, which
provides an easy method for the preparation of functionalized difluoroalkylated oxygen heterocycles.
he introduction of fluorine atoms into molecules has
Tattracted much research interest in organic chemistry
because the fluorine atom features unique electronic properties
and fluorine-containing molecules show special bioactivities in
pharmaceutical chemistry.1,2 Thus, introducing fluorine into
molecules continues as a hot topic in organic synthesis.3
Among these research topics, fluorination and trifluoromethy-
lation reactions have gained significant progress and have been
well documented for inducing one or three fluorine atoms into
organic molecules.3b,4 However, difluoroalkylation still does not
receive much attention5 mainly because difluoroalkylation
reagents are usually difficult to prepare, hard to handle, or
incompatible with functional groups. To reverse this situation,
halogenated difluoroacetate (CF2XCOOEt) has been developed
as a difluoroalkylation reagent in organic reactions,6 which is
low cost, convenient to hold, and easy to keep. Furthermore,
the alkoxycarbonyldifluoromethyene (CF2CO2R) group is an
interesting fluorinated motif due to its facile derivatization and
high bioactivity.
carboxylic acids (Scheme 1a). In addition, Rueping11 have
developed fluorolactonization of unsaturated carboxylic acids
by Selecfluor to give fluorinated isobenzofurans (Scheme 1b).
Stuart12 used hypervalent fluoroiodane reagent and unsaturated
Scheme 1. Fluorination of Unsaturated Carboxylic Acids
Unsaturated carboxylic acids are an important type of organic
intermediate and easily undergo the difunctionalization process
to assemble lactone derivatives7 as well as introduce an addi-
tional functional group in one reaction.8 In recent years, several
coupling partners have been developed to trigger intramolecular
cyclization. In particular, fluorination or trifluoromethylation of
CC bond-initiated cyclization have been reported to construct
the lactones and introduce fluoro and trifluoromethyl groups
in the product at the same time. Buchwald9 and Akita10 have
used different methods to synthesize trifluoromethyl lactone
through trifluoromethylation lactonization of unsaturated
Received: May 24, 2017
Published: August 28, 2017
© 2017 American Chemical Society
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DOI: 10.1021/acs.joc.7b01279
J. Org. Chem. 2017, 82, 9824−9831

The Journal of Organic Chemistry
Note
carboxylic acids to deliver novel fluoro lactones in the presence
of AgBF4 (Scheme 1b). To the best of our knowledge, the
difluoroalkylation-triggered cyclization of unsaturated carboxylic
acids in the presence of visible light has not been reported until
now. Notably, the Wu group developed two-step methods on
palladium-catalyzed reactions between polyfluoroalkyl iodides
and 4-pentenoic acid to synthesize fluoroalkylated γ-lactones.13
In our continuous work on the synthesis of fluorine-containing
compounds and functionalized lactones,14,15 we reported herein
an efficient visible light photocatalytic method for the prep-
aration of difluoroalkylated lactones via the reaction between
bromofluoroalkanes and unsaturated acids/alcohols (Scheme 1c).
This reaction was carried out under mild conditions, which
provides a new strategy to difluoroalkylated oxygen heterocycles
from readily available bromofluoroalkanes as starting materials.
Recently, dual catalysis by merging visible-light-induced
photoredox catalysis with other catalytic modes has undergone
signficant development.16 Sanford17 and Liu18 have done elegant
work on combining copper catalysis and photoredox as catalyst.
Thus, we envision that a photocatalyst/copper system could be
efficient for our reaction. We started the reaction conditions
optimization by using unsaturated carboxylic acid 1a as the
model substrate to react with BrCF2COOEt 2a in the presence
of sodium carbonate, photocatalyst fac-[Ir(ppy)3], and CuI at
room temperature. It was pleasing that expected product 3aa was
obtained in 45% yield (Table 1, entry 1) after 12 h of irradiation
with visible light from blue LEDs (5 W, λmax = 455 nm). With a
contrast test, we carried out the reaction without the addition of
CuI and found that dramatically increased yields were obtained
(70%, entry 2). Next, we prolonged the reaction time to 24 h,
and a slightly higher yield was found (entry 3). Photo-
catalyst screening showed that Eosin Y, [Ru(bpy)3]PF6, and
[Ir(ppy)2(dtbbpy)3]PF6 could not promote this reaction, as no
reaction occurred at all (entries 4−6). The use of other regular
solvents, such as DMF and 1,4-dioxane, did not provide any
improvement in the yields (entries 7 and 8), and these results
show that DCM is the best choice. Further reaction condition
optimization found that bases have an obvious effect on this
reaction. Inorganic bases such as NaHCO3 and Na2HPO4 gave
similar results (entries 9 and 10). However, an organic base, such
as Et3N, resulted in a dramatically decreased yield (entry 11).
The highest yield was obtained when HCOONa was used as base
for this reaction (entry 12). Strangely, increasing the amount of
BrCF2COOEt 2a diminished the reaction yields (entries 13 and
14). Finally, control experiments demonstrated that the photo-
catalyst fac-[Ir(ppy)3], visible light, and base were vital to this
reaction (entries 15−17).
With the optimized conditions in hand, we then explored the
scope of different unsaturated carboxylic acids, and the results
are summarized in Scheme 2. This cascade catalytic strategy
is compatible with a variety of alkenoic acids bearing either
electron-donating or -withdrawing groups on the aryl substituent,
affording the corresponding products in moderate to excellent
yields (3aa−3ha). Specifically, the para-substituted methoxy
alkenoic acid could furnish desired product 3ea in 97% yield.
Otherwise, unsaturated carboxylic acids containing a nonterminal
a
Table 1. Optimization of the Reaction Conditions
b
entry
photocatalyst
base
solvent
time (h)
yield (%)
c
1
A
A
A
B
C
D
A
A
A
A
A
A
A
A
A
A
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
Na2HPO4
Et3N
DCM
DCM
DCM
DCM
DCM
DCM
DMF
dioxane
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
12
12
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
45
2
70
73
3
4
NR
NR
NR
47
5
6
7
8
70
9
70
10
11
12
71
26
HCOONa
HCOONa
HCOONa
77
d
13
69
e
14
67
15
trace
NR
NR
f
16
HCOONa
HCOONa
17
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol, 1.0 equiv), base (0.2 mmol, 2.0 equiv), photocatalyst (0.004 mmol, 2 mol %), solvent (2 mL),
b
c
d
e
f
room temperature, 5 W LEDs, 24 h. Isolated yield. Using 0.1 equiv CuI. Using 1.2 equiv of 2a. Using 1.5 equiv of 2a. In the dark.
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Note
a
Scheme 2. Substrate Scope of Unsaturated Acids and Alcohols
a
Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), HCO2Na (0.4 mmol), fac-Ir(ppy)3 (0.004 mmol), DCM (2 mL), at room temperature, 5 W
LEDs, for 24 h. Isolated yield.
a b
,
Scheme 3. Substrate Scope of Bromofluoroalkanes
a
Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), HCOONa (0.4 mmol), fac-Ir(ppy)3 (0.004 mmol), DCM (2 mL), room temperature, 5 W
b
c
d
LEDs, 24 h. Isolated yield. Compound 2b (0.4 mmol, 4 equiv). Compound 2c (0.4 mmol, 4 equiv).
vinyl group could also work well in these reaction conditions with
69% yield (3ia). Because of the importance of the isobenzofuran-
1-ones motif in organic and bioorganic chemistry, we tried to
examine the o-vinyl benzoic acids in the current system. First, we
tested the o-vinyl benzoic acid for this reaction. It was pleasing
that the reaction could take place, affording the expected product
in 43% yield (3ja). Then, we tried the more congested o-vinyl
benzoic acids (1k−1n). Fortunately, these reagents could work
very well, giving the product in good yields regardless of alkenoic
acids bearing either electron-donating or -withdrawing groups
(3ka−3na). Notably, unsaturated alcohol 1o was also a suitable
substrate, and the reaction proceeded smoothly to give expected
α,α-disubstituted tetrahydrofuran 3oa in good yield (82%).
Finally, we extended the substrate to 2-allylphenol 3p;19 unfor-
tunately, no reaction occurred under the standard reaction
conditions. The chemical structure of difluoroalkylated oxygen
heterocycleproducts 3 has been confirmed by X-ray single-crystal
analysis of 3ja (see Supporting Information).
Encouraged by the results from different unsaturated carboxylic
acids with BrCF2COOEt, we further examined other bromofluoro
precursors, such as ester, keto, amide, and phosphate-bearing
bromofluoro compounds, and the results are shown in Scheme 3.
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The Journal of Organic Chemistry
Note
Scheme 4. Control Experiments
Scheme 5. Proposal Mechanism
CF3SO2Cl, BrCF2PO(OEt)2, and BrCHFCOOEt can be applied
to this catalytic system and to obtain the products 3ab−3ad
in moderate yields, respectively. Bromodifluoroareneketones
could also be tolerated in this reaction, however, affording the
corresponding product in low yields (3ae−3ag). Finally, we
tested the amide-containing BrCF2 group. In the case of the
tertiary amide, it could react smoothly with 1a to deliver product
3ah in 74% yield. On the other hand, secondary amide could also
work in the current system but afforded 3ai in obviously lower
yield (40%).
For obtaining mechanistic insight into this reaction, the radical
scavenger 2,2,6,6,-tetramethyl-1-piperidinyloxy (TEMPO) was
introduced into the catalytic system. The formation of 3aa was
suppressed, and only the 2a-TEMPO adduct was detected
by MS, indicating that a radical process is involved (Scheme 4a).
For the radical process to be verified, another radical scavenger
1,1-diphenylalkene was added to the standard reaction con-
ditions. Only a trace amount of product 3aa could be detected by
MS in the reaction mixture, and 1,1-diphenylalkene-2a adduct 4a
could be obtained in 82% yield (Scheme 4b).
On the basis of the experimental results provided above
and previous studies,8 a possible mechanism is illustrated in
Scheme 5. At the first step, the photoredox catalyst fac-[Ir3+(ppy)3]
A is irradiated to the excited state fac-[Ir3+(ppy)3*] B, which
undergoes single-electron transfer to generate fac-[Ir4+(ppy)3] C
and radical ·CF2COOEt D. Subsequently, radical D adds to the
unsaturated carboxylic acids 1a to generate intermediate E.
Then, intermediate E is oxidized to the carbocation inter-
mediate F by the Ir intermediate C as well as regeneration of
the Ir catalyst A. Finally, final product 3aa is produced by
deprotonation of intermediate F in the presence of base.
heterocycles through difunctionalization of unsaturated acids/
alcohols. Several types of bromofluoroalkane precursors bearing
ester, keto, amido, and phosphate groups were developed for this
difluoroalkylation and cyclization reaction, affording the corre-
sponding products in good-to-excellent yields. The reaction
proceeds smoothly under mild conditions, which provides a new
method for the preparation of functionalized difluoroalkylated
oxygen heterocycles.
EXPERIMENTAL SECTION
■
Typical Procedures for the Preparation of Substrates
1a−1h.20a To a suspension of methyltriphenylphosphonium bromide
(4.6 g, 13.0 mmol) in THF (20 mL) was added sodium tert-butoxide
(2.5 g, 26.0 mmol) at 0 °C. The mixture was then stirred for 30 min.
4-Oxo-4-arylbutanoic acid (10.0 mmol) was then added to the reaction
mixture at 0 °C. The mixture was allowed to warm to room temperature
and was then stirred for 16 h. After evaporation of THF, dichloro-
methane and 1 N NaOH were added. The aqueous layer was washed
with dichloromethane. HCl (12 N) was then added until the pH of
the aqueous layer was ∼2. The aqueous layer was then extracted with
dichloromethane twice and dried over magnesium sulfate. Purification
by column chromatography (10% EA−PE) afforded substrates 1a−1h.
4-Phenylpent-4-enoic Acid (1a).20a 1H NMR (400 MHz, CDCl3) δ
7.41−7.23 (m, 5H), 5.32 (s, 1H), 5.10 (d, J = 1.1 Hz, 1H), 2.84 (dd,
J = 8.1, 7.4 Hz, 2H), 2.55−2.51 (m, 2H); 13C NMR (101 MHz, CDCl3)
δ 179.6, 146.6, 140.4, 128.5, 127.7, 126.1, 113.0, 33.0, 30.2.
4-([1,1′-Biphenyl]-4-yl)pent-4-enoic Acid (1b).20b 1H NMR
(400 MHz, DMSO) δ 12.19 (br s, 1H), 7.69−7.36 (m, 9H), 5.43
(s, 1H), 5.14 (s, 1H), 2.78 (t, J = 6.9 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H);
13C NMR (101 MHz, DMSO) δ 174.3, 146.3, 140.1, 139.8, 139.5, 129.4,
128.0, 127.2, 127.0, 126.8, 113.0, 33.2, 30.0.
4-(4-Chlorophenyl)pent-4-enoic Acid (1c).20b 1H NMR (400 MHz,
CDCl3) δ 7.34−7.29 (m, 4H), 5.31 (s, 1H), 5.12 (d, J = 0.9 Hz, 1H),
2.81 (dd, J = 8.0, 7.3 Hz, 2H), 2.52 (dd, J = 8.5, 6.9 Hz, 2H); 13C NMR
(101 MHz, CDCl3) δ 178.8, 145.4, 138.9, 133.5, 128.6, 127.4, 113.5,
32.8, 30.0.
In conclusion, we have developed a novel photoredox-
catalyzed strategy for the synthesis of difluoroalkylated oxygen
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Note
5-Phenylhex-5-enoic Acid (1d).20c 1H NMR (400 MHz, CDCl3) δ
7.39 (dt, J = 3.3, 1.9 Hz, 2H), 7.34−7.24 (m, 3H), 5.31 (d, J = 1.2 Hz,
1H), 5.08 (d, J = 1.3 Hz, 1H), 2.59−2.55 (m, 2H), 2.37 (t, J = 7.4 Hz,
2H), 1.83−1.76 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 179.8, 147.4,
140.8, 128.4, 127.5, 126.1, 113.1, 34.5, 33.3, 23.0.
4-Phenylpent-4-en-1-ol (1o). Compound 1o was synthesized
according to a previously reported method.21b 1H NMR (400 MHz,
CDCl3) δ 7.41 (dt, J = 8.3, 1.9 Hz, 2H), 7.34−7.30 (m, 2H), 7.26
(ddt, J = 5.8, 4.7, 1.4 Hz, 1H), 5.29 (d, J = 1.3 Hz, 1H), 5.10−5.08
(m, 1H), 3.65 (t, J = 6.5 Hz, 2H), 2.62−2.58 (m, 2H), 1.75−1.68
(m, 3H); 13C NMR (101 MHz, CDCl3) δ 148.0, 141.0, 128.4, 127.5,
126.1, 112.6, 62.4, 31.6, 31.2.
4-(4-Methoxyphenyl)pent-4-enoic Acid (1e).20b 1H NMR
(400 MHz, CDCl3) δ 7.36−7.34 (m, 2H), 6.88−6.86 (m, 2H), 5.25
(s, 1H), 5.02 (d, J = 1.1 Hz, 1H), 3.81 (s, 3H), 2.84−2.80 (m, 2H),
2.55−2.51 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 178.6, 159.2, 145.8,
132.8, 127.2, 113.8, 111.4, 55.3, 32.9, 30.2.
Typical Procedures for the Preparation of Substrates
2e−2g.22a To a mixture of ethyl bromodifluoroacetate (10.2 g,
50 mmol) and tetrahydrofuran (50 mL) was added a solution of
arylmagnesium bromide in tetrahydrofuran (3.0 M, 18.3 mL, 55 mmol)
at −78 °C under an argon atmosphere. After the solution was stirred at
that temperature for 3 h, the mixture was quenched with 3 N HCl and
then extracted with diethyl ether. The extract was dried over anhydrous
MgSO4, and the solvent was removed. Flash chromatography (silica gel,
petroleum ether-ethyl acetate) afforded substrates 2e−2g.
4-(4-Fluorophenyl)pent-4-enoic Acid (1f).20a 1H NMR (400 MHz,
CDCl3) δ 7.38−7.34 (m, 2H), 7.04−7.00 (m, 2H), 5.27 (s, 1H), 5.09 (d,
J = 0.8 Hz, 1H), 2.81 (dd, J = 8.0, 7.3 Hz, 2H), 2.52 (dd, J = 8.6, 6.9 Hz,
2H); 19F NMR (376 MHz, CDCl3) δ −114.81 (s, 1F); 13C NMR
(101 MHz, CDCl3) δ 179.1, 162.4 (d, J = 246.6 Hz), 145.6, 136.5
(d, J = 3.4 Hz), 127.7 (d, J = 7.9 Hz), 115.3 (d, J = 21.4 Hz), 113.0
(d, J = 0.8 Hz), 32.9, 30.2.
2-Bromo-2,2-difluoro-1-(furan-2-yl)ethan-1-one (2e).22b 1H NMR
(400 MHz, CDCl3) δ 7.76−7.70 (m, 1H), 7.47 (dd, J = 2.7, 1.1 Hz, 1H),
6.61 (dd, J = 3.7, 1.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −59.84
(s, 2F); 13C NMR (101 MHz, CDCl3) δ 169.4 (t, J = 28.4 Hz), 148.9,
144.4, 123.1 (t, J = 3.9 Hz), 112.1, 111.7 (t, J = 317.0 Hz).
1
4-(4-Bromophenyl)pent-4-enoic Acid (1g). H NMR (400 MHz,
CDCl3) δ 7.47−7.45 (m, 2H), 7.28−7.26 (m, 2H), 5.32 (s, 1H), 5.13
(s, 1H), 2.81 (t, J = 7.6 Hz, 2H), 2.54−2.50 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 178.4, 145.5, 139.4, 131.6, 127.8, 121.7, 113.6, 32.7,
30.0.
2-Bromo-2,2-difluoro-1-(4-methoxyphenyl)ethan-1-one (2f).
1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.1 Hz, 2H), 7.00−6.98
(m, 2H), 3.91 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −57.01 (s, 2F);
13C NMR (101 MHz, CDCl3) δ 180.1 (t, J = 25.4 Hz), 165.1, 133.3
4-(p-Tolyl)pent-4-enoic Acid (1h).20b 1H NMR (400 MHz, CDCl3)
δ 7.30 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 5.29 (s, 1H), 5.06 (d,
J = 1.1 Hz, 1H), 2.85−2.81 (m, 2H), 2.53 (dd, J = 8.7, 6.9 Hz, 2H), 2.34
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 179.3, 146.3, 137.5, 137.5,
129.1, 126.0, 112.2, 33.0, 30.2, 21.1.
(t, J = 2.8 Hz), 121.7, 114.3, 113.8 (t, J = 318.6 Hz), 55.7.
1-(Benzo[d][1,3]dioxol-5-yl)-2-bromo-2,2-difluoroethan-1-one
(2g).22c 1H NMR (400 MHz, CDCl3) δ 7.81 (ddt, J = 8.3, 1.9, 1.0 Hz,
1H), 7.56−7.55 (m, 1H), 6.91 (d, J = 8.3 Hz, 1H), 6.11 (s, 2H);
19F NMR (376 MHz, CDCl3) δ −56.78 (s, 2F); 13C NMR (101 MHz,
CDCl3) δ 179.7 (t, J = 25.5 Hz), 153.6, 148.4, 128.1 (t, J = 3.5 Hz),
123.3, 113.6 (t, J = 318.4 Hz), 110.0 (t, J = 2.6 Hz), 108.4, 102.4.
Typical Procedures for the Preparation of Substrates 2h
and 2i.22d A 20 mL tube equipped with a magnetic stir bar was charged
with lanthanum trifluoromethanesulfonate (0.25 mmol, 5.0 mol %).
The tube was backfilled with argon, and then ethyl bromodifluor-
oacetate (6.0 mmol) and amine (5.0 mmol) were added. The mixture
was stirred at the room temperature and monitored by TLC. After the
amine was exhausted, the mixture was purified by silica gel column
chromatography to give the target amides 2h and 2i.
Typical Procedures for the Preparation of Substrates
1j−1n.21a To a suspension of methyltriphenylphosphonium bromide
(7.14 g, 20.0 mmol) in THF (100 mL) was added potassium tert-
butoxide (3.36 g, 30.0 mmol) at 0 °C. The mixture was then stirred for
30 min. 2-Ketobenzoic acid (10.0 mmol) was added to the reaction
mixture at 0 °C. The mixture was allowed to warm to room temperature
and stirred for 16 h. After evaporation of THF, the mixture was treated
with 10% NaOH (100 mL). The aqueous layer was washed with CH2Cl2
(50 mL) and acidified (pH 1) with 3 N HCl. The aqueous layer was
extracted with ethyl acetate (3× 50 mL). The combined extracts were
washed with a saturated solution of NaCl (100 mL), dried over MgSO4,
and evaporated in vacuo. Purification by column chromatography
(10% EA−PE) afforded substrates 1j−1n.
2-Vinylbenzoic Acid (1j).8h 1H NMR (400 MHz, CDCl3) δ 8.06 (dd,
J = 7.9, 1.2 Hz, 1H), 7.63−7.53 (m, 3H), 7.37 (td, J = 7.8, 1.3 Hz, 1H),
5.68 (dd, J = 17.4, 1.2 Hz, 1H), 5.39 (dd, J = 11.0, 1.2 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ 172.8, 140.7, 136.1, 133.2, 131.3, 127.6, 127.6,
127.2, 116.8.
2-Bromo-2,2-difluoro-1-morpholinoethan-1-one (2h).22d
1H NMR (400 MHz, CDCl3) δ 3.77−3.69 (m, 8H); 19F NMR
(376 MHz, CDCl3) δ −54.53 (s, 2F); 13C NMR (101 MHz, CDCl3) δ
157.9 (t, J = 26.5 Hz), 110.5 (t, J = 314.3 Hz), 66.5, 66.1, 47.3 (t, J =
3.8 Hz), 43.9.
2-(Prop-1-en-2-yl)benzoic Acid (1k).8h 1H NMR (400 MHz,
CDCl3) δ 7.95 (dd, J = 7.8, 1.1 Hz, 1H), 7.50 (td, J = 7.5, 1.4 Hz,
1H), 7.35 (td, J = 7.7, 1.3 Hz, 1H), 7.27 (dd, J = 7.1, 1.4 Hz, 1H),
5.14−5.13 (m, 1H), 4.90 (dd, J = 1.7, 0.9 Hz, 1H), 2.12 (dd, J = 1.3,
0.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.1, 146.6, 146.2, 132.5,
130.7, 129.7, 128.0, 127.0, 114.0, 24.3.
2-Bromo-N-cycloheptyl-2,2-difluoroacetamide (2i). 1H NMR
(400 MHz, CDCl3) δ 6.12 (brs, 1H), 3.97 (dd, J = 8.4, 4.1 Hz, 1H),
2.01−1.95 (m, 2H), 1.68−1.49 (m, 10H); 19F NMR (376 MHz, CDCl3)
δ −60.49 (s, 2F); 13C NMR (101 MHz, CDCl3) δ 158.8 (t, J = 27.9 Hz),
112.0 (t, J = 316.5 Hz), 51.6, 34.5, 27.8, 23.9; HRMS (TOF MS ESI)
calcd for C9H15BrF2NO+ [M + H]+ 270.0300, found 270.0304.
General Procedure for the Photoredox-Catalyzed Cascade
Difluoroalkylation and Intramolecular Cyclization. An oven-dried
reaction vial containing unsaturated carboxylic acids 1 (0.2 mmol), fac-
[Ir(ppy)3] (0.004 mmol), and HCOONa (0.4 mmol) was evacuated
and purged with argon three times. Then, DCM (2 mL) as solution and
2a (0.2 mmol) were added via syringe. The reaction mixture was stirred
for 24 h at room temperature in the presence of 5 W blue LED lamps.
When the reaction was completed, the reaction mixture was purified
by flash chromatography on silica gel (elute: petroleum ether/ethyl
acetate = 5:1) directly to furnish corresponding product 3.
2-(1-(p-Tolyl)vinyl)benzoic Acid (1l).21a 1H NMR (400 MHz,
CDCl3) δ 7.92 (dd, J = 7.8, 1.3 Hz, 1H), 7.55 (td, J = 7.5, 1.4 Hz,
1H), 7.42 (td, J = 7.6, 1.3 Hz, 1H), 7.35 (dd, J = 7.6, 1.1 Hz, 1H),
7.12−7.10 (m, 2H), 7.06−7.04 (m, 2H), 5.63 (d, J = 0.9 Hz, 1H), 5.16
(d, J = 0.9 Hz, 1H), 2.30 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.6,
149.3, 143.8, 138.1, 137.3, 132.4, 131.5, 130.6, 129.5, 128.8, 127.6, 126.7,
113.5, 21.1.
2-(1-Phenylvinyl)benzoic Acid (1m).21a 1H NMR (400 MHz,
CDCl3) δ 7.92 (dd, J = 7.8, 1.1 Hz, 1H), 7.56 (td, J = 7.5, 1.4 Hz,
1H), 7.42 (td, J = 7.6, 1.3 Hz, 1H), 7.37 (dd, J = 7.6, 0.9 Hz, 1H), 7.25−
7.20 (m, 5H), 5.66 (d, J = 1.0 Hz, 1H), 5.22 (d, J = 0.9 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ 171.8, 149.5, 143.6, 140.9, 132.4, 131.6,
130.6, 129.5, 128.1, 127.7, 127.5, 126.8, 114.4.
Ethyl 2,2-Difluoro-3-(5-oxo-2-phenyltetrahydrofuran-2-yl)-
1
propanoate (3aa). Pale yellow oil, 45.6 mg (77% yield). H NMR
(400 MHz, CDCl3) δ 7.40−7.30 (m, 5H), 4.28−4.11 (m, 2H), 2.95−
2.35 (m, 6H), 1.31 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ
−101.10 (d, J = 6.7 Hz, 2F); 13C NMR (101 MHz, CDCl3) δ 175.4,
163.6 (t, J = 31.7 Hz), 141.9, 128.9, 128.5, 124.8, 114.4 (t, J = 251.9 Hz),
84.8 (t, J = 4.4 Hz), 63.5, 45.8 (t, J = 23.1 Hz), 34.7, 28.1, 14.0; IR (cm−1)
1768, 1093, 1073, 923, 701; HRMS (TOF MS ESI) calcd for
C15H17F2O4+ [M + H]+ 299.1089, found 299.1081.
2-(1-(4-Chlorophenyl)vinyl)benzoic Acid (1n).21a 1H NMR
(400 MHz, CDCl3) δ 7.95 (dd, J = 7.8, 1.2 Hz, 1H), 7.57 (td, J = 7.5,
1.4 Hz, 1H), 7.44 (td, J = 7.6, 1.3 Hz, 1H), 7.35 (dd, J = 7.6, 1.0 Hz, 1H),
7.23−7.19 (m, 2H), 7.15−7.12 (m, 2H), 5.65 (d, J = 0.7 Hz, 1H), 5.22
(d, J = 0.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 171.6, 148.6, 143.2,
139.4, 133.3, 132.6, 131.5, 130.9, 129.2, 128.3, 128.0, 127.9, 114.8.
9828
DOI: 10.1021/acs.joc.7b01279
J. Org. Chem. 2017, 82, 9824−9831

The Journal of Organic Chemistry
Note
Ethyl 3-(2-([1,1′-Biphenyl]-4-yl)-5-oxotetrahydrofuran-2-yl)-2,2-
difluoropropanoate (3ba). Pale yellow solid, mp 86−88 °C, 50.6 mg
(68% yield). 1H NMR (400 MHz, CDCl3) δ 7.54−7.48 (m, 4H), 7.36−
7.26 (m, 5H), 4.21−4.05 (m, 2H), 2.92−2.32 (m, 6H), 1.23 (t, J =
7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −101.00 (d, J = 10.1 Hz,
2F); 13C NMR (101 MHz, CDCl3) δ 175.2, 163.4 (t, J = 31.6 Hz), 141.2,
140.6, 140.1, 128.9, 127.7, 127.4, 127.1, 125.2, 114.3 (t, J = 252.0 Hz),
84.6 (t, J = 4.4 Hz), 63.4, 45.6 (t, J = 23.1 Hz), 34.5, 28.0, 13.8; IR (cm−1)
1765, 1222, 1095, 1080, 766, 733, 693; HRMS (TOF MS ESI) calcd for
C21H21F2O4+ [M + H]+ 375.1402, found 375.1396.
(t, J = 251.9 Hz), 84.7 (t, J = 4.0 Hz), 63.3, 45.6 (t, J = 23.0 Hz), 34.4,
28.0, 21.0, 13.8; IR (cm−1): 1770, 1225, 1182, 1092, 922, 822, 777;
+
HRMS (TOF MS ESI) calcd for C16H19F2O4 [M + H]+ 313.1246,
found 313.1250.
Ethyl 2,2-Difluoro-2-(5-oxo-2-phenyltetrahydrofuran-3-yl)-
acetate (3ia). Pale yellow solid, 39.4 mg (69% yield), mp 54−55 °C.
1H NMR (400 MHz, CDCl3) δ 7.44−7.30 (m, 5H), 5.60 (d, J = 5.2 Hz,
1H), 4.29−4.16 (m, 2H), 3.35−3.23 (m, 1H), 2.92−2.79 (m, 2H), 1.27
(t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −111.43 (q, J =
267.8 Hz, 2F); 13C NMR (101 MHz, CDCl3) δ 173.7, 162.5 (t, J =
32.1 Hz), 137.9, 129.2, 129.0, 125.6, 114.4 (t, J = 254.4 Hz), 79.1 (t, J =
4.3 Hz), 63.7, 47.6 (t, J = 23.4 Hz), 28.3 (t, J = 4.0 Hz), 13.8; IR (cm−1)
2929, 1779, 1765, 1144, 1095, 991, 766, 736, 700, 487; HRMS (TOF
MS ESI) calcd for C14H15F2O4+ [M + H]+ 285.0933, found 285.0933.
Ethyl 2,2-Difluoro-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-
propanoate (3ja). Pale yellow solid, 23.2 mg (43% yield), mp 90−
92 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz, 1H), 7.75−
7.71 (m, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 5.70
(dd, J = 9.0, 3.2 Hz, 1H), 4.46−4.35 (m, 2H), 2.85−2.73 (m, 1H), 2.66−
2.52 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ
−104.22 (dd, J = 1762.4, 265.8 Hz, 2F); 13C NMR (101 MHz, CDCl3) δ
169.3, 163.3 (t, J = 32.0 Hz), 148.1, 134.5, 129.8, 126.1, 125.7, 122.0,
114.2 (dd, J = 253.7, 250.8 Hz), 74.7 (dd, J = 7.4, 3.7 Hz), 63.6, 40.3
(t, J = 24.0 Hz), 13.9; IR (cm−1) 1765, 1286, 1186, 1089, 1058, 749, 693,
682; HRMS (TOF MS ESI) calcd for C13H13F2O4+ [M + H]+ 271.0776,
found 271.0778.
Ethyl 3-(2-(4-Chlorophenyl)-5-oxotetrahydrofuran-2-yl)-2,2-di-
1
fluoropropanoate (3ca). Colorless liquid, 48.6 mg (73% yield). H
NMR (400 MHz, CDCl3) δ 7.31−7.28 (m, 2H), 7.24−7.21 (m, 2H),
4.24−4.09 (m, 2H), 2.81−2.30 (m, 6H), 1.26 (t, J = 7.2 Hz, 3H); 19F
NMR (376 MHz, CDCl3) δ −100.37−102.08 (m, 2F); 13C NMR (101
MHz, CDCl3) δ 174.8, 163.3 (t, J = 31.5 Hz), 140.2, 134.3, 128.9, 126.2,
114.1 (t, J = 251.0 Hz), 84.2 (t, J = 4.3 Hz), 63.5, 45.5 (t, J = 23.1 Hz),
34.6, 27.8, 13.8; IR (cm−1) 1768, 1190, 1092, 1012, 922, 832; HRMS
+
(TOF MS ESI) calcd for C15H16ClF2O4 [M + H]+ 333.0700, found
333.0702.
Ethyl 2,2-Difluoro-3-(6-oxo-2-phenyltetrahydro-2H-pyran-2-yl)-
propanoate (3da). Yellow oil, 40.1 mg (64% yield). 1H NMR
(400 MHz, CDCl3) δ 7.34−7.30 (m, 2H), 7.27−7.23 (m, 3H), 4.30−
4.15 (m, 2H), 2.77−2.61 (m, 2H), 2.43−2.26 (m, 4H), 1.72−1.64
(m, 1H), 1.46−1.34 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H); 19F NMR
(376 MHz, CDCl3) δ −99.68 (q, J = 263.8 Hz, 2F); 13C NMR
(101 MHz, CDCl3) δ 168.8, 162.7 (t, J = 31.0 Hz), 141.1, 127.9, 127.0,
123.8, 113.3 (t, J = 251.4 Hz), 83.1 (dd, J = 6.7, 3.0 Hz), 62.3, 46.6
(t, J = 23.3 Hz), 30.2 (d, J = 2.9 Hz), 28.0, 15.9, 12.8; IR (cm−1) 2921,
2852, 1756, 1456, 1376, 813, 763; HRMS (TOF MS ESI) calcd for
C16H19F2O4+ [M + H]+ 313.1246, found 313.1245.
Ethyl 2,2-Difluoro-3-(1-methyl-3-oxo-1,3-dihydroisobenzofuran-
1
1-yl)propanoate (3ka). Colorless oil, 43.8 mg (77% yield). H NMR
(400 MHz, CDCl3) δ 7.82−7.80 (m, 1H), 7.63 (td, J = 7.6, 1.1 Hz, 1H),
7.48 (td, J = 7.6, 0.8 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 4.22 (q, J = 7.2 Hz,
2H), 2.88 (q, J = 15.0 Hz, 1H), 2.66 (q, J = 15.0 Hz, 1H), 1.65 (s, 3H),
1.26 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −101.57 (d, J =
0.8 Hz, 2F); 13C NMR (101 MHz, CDCl3) δ 168.7, 163.4 (t, J =
31.6 Hz), 152.4, 134.4, 129.6, 126.0, 125.2, 121.3, 114.1 (t, J =
252.4 Hz), 82.9 (t, J = 4.3 Hz), 63.5, 43.7 (t, J = 23.4 Hz), 26.9, 13.8;
IR (cm−1) 1758, 1086, 1029, 763, 694; HRMS (TOF MS ESI) calcd for
C14H15F2O4+ [M + H]+ 285.0933, found 285.0934.
Ethyl 2,2-Difluoro-3-(2-(4-methoxyphenyl)-5-oxotetrahydrofur-
1
an-2-yl)propanoate (3ea). White oil, 63.6 mg (97% yield). H NMR
(400 MHz, CDCl3) δ 7.22−7.18 (m, 2H), 6.84−6.80 (m, 2H), 4.20−
4.04 (m, 2H), 3.73 (s, 3H), 2.82−2.69 (m, 2H), 2.66−2.42 (m, 3H),
2.38−2.28 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz,
CDCl3) δ −101.12 (d, J = 4.8 Hz, 2F); 13C NMR (101 MHz, CDCl3) δ
174.3, 162.4 (t, J = 31.6 Hz), 158.4, 132.3, 125.0, 113.2 (t, J = 251.0 Hz),
112.9, 83.6 (t, J = 4.1 Hz), 62.3, 54.3, 44.7 (t, J = 22.9 Hz), 33.3, 27.0,
12.7; IR (cm−1) 1769, 1514, 1252, 1178, 1092, 1030, 922, 833; HRMS
Ethyl 2,2-Difluoro-3-(3-oxo-1-(p-tolyl)-1,3-dihydroisobenzofuran-
1
1-yl)propanoate (3la). Colorless oil, 66.7 mg (93% yield). H NMR
(400 MHz, CDCl3) δ 7.80 (d, J = 7.6 Hz, 1H), 7.60 (td, J = 7.8, 1.1 Hz,
1H), 7.52 (d, J = 7.8 Hz, 1H), 7.44 (td, J = 7.6, 0.9 Hz, 1H), 7.30−
7.28 (m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 4.24−4.11 (m, 2H), 3.35
(ddd, J = 21.8, 15.2, 8.3 Hz, 1H), 3.08 (td, J = 15.7, 9.0 Hz, 1H), 2.23
(s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ
−101.26 (dd, J = 1242.5, 267.6 Hz, 2F); 13C NMR (101 MHz, CDCl3) δ
168.9, 163.4 (t, J = 31.5 Hz), 151.2, 138.6, 136.8, 134.4, 129.6, 129.6,
126.0, 125.0, 124.5, 122.7, 114.0 (dd, J = 254.7, 251.3 Hz), 85.2 (dd, J =
6.1, 2.5 Hz), 63.5, 43.9 (t, J = 23.4 Hz), 21.0, 13.8; IR (cm−1) 1762, 1229,
1113, 1068, 723, 693, 538; HRMS (TOF MS ESI) calcd for
C20H19F2O4+ [M + H]+ 361.1246, found 361.1249.
+
(TOF MS ESI) calcd for C16H19F2O5 [M + H]+ 329.1195, found
329.1197.
Ethyl 2,2-Difluoro-3-(2-(4-fluorophenyl)-5-oxotetrahydrofuran-2-
1
yl)propanoate (3fa). White oil, 46.2 mg (73% yield). H NMR (400
MHz, CDCl3) δ 7.30−7.25 (m, 2H), 7.03−6.98 (m, 2H), 4.23−4.08 (m,
2H), 2.85−2.30 (m, 6H), 1.25 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz,
CDCl3) δ −100.41−102.10 (m, 2F), −113.64 (s, 1F); 13C NMR (101
MHz, CDCl3) δ 174.9, 163.3 (t, J = 31.7 Hz), 162.4 (d, J = 247.9 Hz),
137.5 (d, J = 3.2 Hz), 126.6 (d, J = 8.3 Hz), 115.6 (d, J = 21.7 Hz), 114.1
(t, J = 251.0 Hz), 84.3 (t, J = 4.3 Hz), 63.4, 45.6 (t, J = 23.0 Hz), 34.7,
27.9, 13.8; IR (cm−1) 1769, 1511, 1223, 1090, 1013, 922, 839, 816, 778;
Ethyl 2,2-Difluoro-3-(3-oxo-1-phenyl-1,3-dihydroisobenzofuran-
1
+
HRMS (TOF MS ESI) calcd for C15H16F3O4 [M + H]+ 317.0995,
1-yl)propanoate (3ma). Yellow oil, 61.5 mg (89% yield). H NMR
(400 MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 1H), 7.72−7.68 (m, 1H), 7.62
(d, J = 7.8 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.51−7.48 (m, 2H), 7.40−
7.30 (m, 3H), 4.33−4.20 (m, 2H), 3.44 (ddd, J = 21.8, 15.2, 8.2 Hz, 1H),
3.18 (td, J = 15.6, 9.0 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H); 19F NMR
(376 MHz, CDCl3) δ −101.31 (dd, J = 1300.4, 267.9 Hz, 2F); 13C NMR
(101 MHz, CDCl3) δ 167.7, 162.4 (t, J = 31.5 Hz), 150.0, 138.7, 133.4,
128.6, 127.9, 127.6, 125.0, 123.9, 123.5, 121.7, 112.9 (dd, J = 254.7,
251.3 Hz), 84.1 (dd, J = 6.3, 2.5 Hz), 62.4, 42.9 (t, J = 23.5 Hz), 12.7; IR
(cm−1) 1762, 1286, 1230, 1064, 778, 699, 622; HRMS (TOF MS ESI)
calcd for C19H17F2O4+ [M + H]+ 347.1089, found 347.1089.
Ethyl 3-(1-(4-Chlorophenyl)-3-oxo-1,3-dihydroisobenzofuran-1-
yl)-2,2-difluoropropanoate (3na). White oil, 48.6 mg (64% yield).
1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 1H), 7.73−7.69
(m, 1H), 7.60−7.57 (m, 2H), 7.45−7.43 (m, 2H), 7.36−7.33 (m, 2H),
4.34−4.21 (m, 2H), 3.39 (ddd, J = 20.7, 15.2, 8.5 Hz, 1H), 3.18−3.08
(m, 1H), 1.34 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3)
δ −101.31 (dd, J = 1032.8, 268.5 Hz, 2F); 13C NMR (101 MHz, CDCl3)
δ 168.4, 163.3 (t, J = 31.4 Hz), 150.7, 138.2, 134.8, 134.6, 129.9, 129.1,
found 317.0994.
Ethyl 3-(2-(4-Bromophenyl)-5-oxotetrahydrofuran-2-yl)-2,2-di-
fluoropropanoate (3ga). Yellow oil, 55.7 mg (74% yield). H NMR
1
(400 MHz, CDCl3) δ 7.46−7.43 (m, 2H), 7.20−7.15 (m, 2H), 4.24−
4.08 (m, 2H), 2.85−2.69 (m, 2H), 2.67−2.52 (m, 2H), 2.45−2.30 (m,
2H), 1.25 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −100.36−
102.06 (m, 2F); 13C NMR (101 MHz, CDCl3) δ 174.8, 163.3 (t, J =
31.6 Hz), 140.8, 131.9, 126.4, 122.4, 114.1 (t, J = 252.3 Hz), 84.2
(t, J = 4.3 Hz), 63.5, 45.4 (t, J = 23.1 Hz), 34.6, 27.8, 13.8; IR (cm−1)
1769, 1222, 1190, 1090, 1008, 922, 829, 777; HRMS (TOF MS ESI)
calcd for C15H16BrF2O4+ [M + H]+ 377.0195, found 377.0193.
Ethyl 2,2-Difluoro-3-(5-oxo-2-(p-tolyl)tetrahydrofuran-2-yl)-
propanoate (3ha). White liquid, 53.1 mg (85% yield). 1H NMR
(400 MHz, CDCl3) δ 7.19−7.10 (m, 4H), 4.20−4.04 (m, 2H), 2.86−
2.69 (m, 2H), 2.68−2.59 (m, 1H), 2.55−2.42 (m, 2H), 2.37−2.29
(m, 1H), 2.27 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 19F NMR (376 MHz,
CDCl3) δ −101.06 (d, J = 5.4 Hz, 2F); 13C NMR (101 MHz, CDCl3)
δ 175.3, 163.4 (t, J = 31.7 Hz), 138.6, 138.1, 129.3, 124.6, 114.3
9829
DOI: 10.1021/acs.joc.7b01279
J. Org. Chem. 2017, 82, 9824−9831

The Journal of Organic Chemistry
Note
126.3, 126.1, 124.8, 122.6, 113.8 (dd, J = 254.5, 252.1 Hz), 84.6 (dd, J =
5.8, 3.5 Hz), 63.6, 43.9 (t, J = 23.5 Hz), 13.8; IR (cm−1) 1762, 1286,
1230, 1094, 1067, 1012, 762, 691; HRMS (TOF MS ESI) calcd for
C19H16ClF2O4+ [M + H]+ 381.0700, found 381.0699.
1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 8.3, 1.0 Hz, 1H), 7.35−7.21
(m, 6H), 6.77 (d, J = 8.3 Hz, 1H), 5.98 (s, 2H), 2.94 (t, J = 16.9 Hz, 2H),
2.71−2.48 (m, 3H), 2.41−2.33 (m, 1H); 19F NMR (376 MHz, CDCl3)
δ −96.00 (q, J = 290.7 Hz, 2F); 13C NMR (101 MHz, CDCl3) δ 185.6
(t, J = 29.8 Hz), 174.5, 151.9, 147.1, 141.4, 127.6, 127.1, 126.3 (t, J =
4.5 Hz), 124.9 (t, J = 2.6 Hz), 123.7, 117.3 (t, J = 256.2 Hz), 108.6 (t, J =
2.9 Hz), 107.2, 101.1, 84.3 (t, J = 2.0 Hz), 43.5 (t, J = 21.8 Hz), 33.8,
27.2; IR (cm−1) 1777, 1687, 1445, 1242, 1034, 923, 701; HRMS (TOF
MS ESI) calcd for C20H17F2O5+ [M + H]+ 375.1039, found 375.1040.
5-(2,2-Difluoro-3-morpholino-3-oxopropyl)-5-phenyldihydrofur-
an-2(3H)-one (3ah). Yellow solid, 49.9 mg (74% yield), mp 122−
124 °C. 1H NMR (400 MHz, CDCl3) δ 7.35−7.23 (m, 5H), 3.69−3.45
(m, 8H), 2.97−2.87 (m, 2H), 2.68 (dt, J = 12.3, 8.7 Hz, 1H), 2.56
(ddd, J = 16.7, 8.8, 4.3 Hz, 1H), 2.50−2.43 (m, 1H), 2.35 (dt, J = 17.0,
8.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −95.93 (dd, J = 744.6,
282.7 Hz, 2F); 13C NMR (101 MHz, CDCl3) δ 174.7, 160.6 (t, J =
28.3 Hz), 141.6, 127.6, 127.0, 123.6, 116.7 (t, J = 256.7 Hz), 84.3, 65.5,
65.5, 45.5 (t, J = 6.0 Hz), 44.0 (t, J = 21.7 Hz), 42.6, 33.8, 27.1; IR (cm−1)
1763, 1665, 1110, 712, 600; HRMS (TOF MS ESI) calcd for
C17H20F2NO4+ [M + H]+ 340.1355, found 340.1354.
Ethyl 2,2-Difluoro-3-(2-phenyltetrahydrofuran-2-yl)propanoate
1
(3oa). Pale yellow oil, 46.5 mg (82% yield). H NMR (400 MHz,
CDCl3) δ 7.28−7.23 (m, 4H), 7.19−7.13 (m, 1H), 4.21−4.07 (m, 2H),
3.84−3.74 (m, 2H), 2.72−2.59 (m, 2H), 2.30−2.23 (m, 1H), 2.15−2.10
(m, 1H), 1.91−1.84 (m, 1H), 1.70−1.59 (m, 1H), 1.25 (t, J = 7.2 Hz,
3H); 19F NMR (376 MHz, CDCl3) δ −101.25 (dd, J = 680.5, 264.5 Hz,
2F); 13C NMR (101 MHz, CDCl3) δ 162.9 (dd, J = 32.8, 31.2 Hz),
145.0, 127.2, 125.9, 123.8, 114.3 (t, J = 250.1 Hz), 82.1 (dd, J = 6.7,
3.2 Hz), 67.1, 61.4, 44.7 (t, J = 22.0 Hz), 37.2 (d, J = 3.0 Hz), 24.1, 12.9;
IR (cm−1) 2961, 1795, 1257, 1009, 863, 787; HRMS (TOF MS ESI)
calcd for C15H19F2O3+ [M + H]+ 285.1297, found 285.1292.
5-Phenyl-5-(2,2,2-trifluoroethyl)dihydrofuran-2(3H)-one (3ab).
White solid, 36.1 mg (74% yield), mp 59−61 °C. 1H NMR
(400 MHz, CDCl3) δ 7.43−7.32 (m, 5H), 2.93−2.77 (m, 2H), 2.68−
2.58 (m, 3H), 2.51−2.41 (m, 1H); 19F NMR (376 MHz, CDCl3)
δ −60.54 (s, 3F); 13C NMR (101 MHz, CDCl3) δ 175.2, 141.1, 128.8,
128.5, 124.6, 124.6 (q, J = 277.0 Hz), 84.3 (dd, J = 4.3, 2.2 Hz), 45.2
(q, J = 27.6 Hz), 34.1 (d, J = 1.3 Hz), 28.0; IR (cm−1): 1775, 1382, 1248,
1122, 928, 701; HRMS (TOF MS ESI) calcd for C12H12F3O2+ [M + H]+
245.0784, found 245.0782.
N-Cycloheptyl-2,2-difluoro-3-(5-oxo-2-phenyltetrahydrofuran-2-
yl)propanamide (3ai). White solid, 29.1 mg (40% yield), mp 96−98 °C.
1H NMR (400 MHz, CDCl3) δ 7.33−7.22 (m, 5H), 6.04 (d, J = 6.1 Hz,
1H), 3.75−3.67 (m, 1H), 2.97−2.78 (m, 2H), 2.62−2.30 (m, 4H),
1.91−1.85 (m, 1H), 1.75−1.71 (m, 1H), 1.58−1.48 (m, 4H), 1.45−1.25
(m, 6H); 19F NMR (376 MHz, CDCl3) δ −102.38 (q, J = 262.5 Hz, 2F);
13C NMR (101 MHz, CDCl3) δ 175.5, 162.2 (t, J = 27.4 Hz), 142.0,
Diethyl (1,1-Difluoro-2-(5-oxo-2-phenyltetrahydrofuran-2-yl)-
1
ethyl)phosphonate (3ac). Yellow oil, 54.9 mg (76% yield). H NMR
(400 MHz, CDCl3) δ 7.43−7.31 (m, 5H), 4.30−4.17 (m, 4H), 2.93−
2.59 (m, 5H), 2.49−2.40 (m, 1H), 1.36 (dt, J = 12.5, 7.1 Hz, 6H);
19F NMR (376 MHz, CDCl3) δ −110.58 (ddd, J = 676.8, 300.1, 104.2
Hz, 2F); 31P NMR (162 MHz, CDCl3) δ 5.73 (t, J = 104.2 Hz, 1P);
13C NMR (101 MHz, CDCl3) δ 175.9, 142.9, 128.8, 128.3, 124.8, 119.8
(td, J = 262.7, 216.1 Hz), 85.8 (d, J = 9.4 Hz), 65.0 (t, J = 8.0 Hz), 44.3
(td, J = 19.0, 14.6 Hz), 34.1, 28.4, 16.5 (dd, J = 5.3, 2.4 Hz); IR (cm−1)
1778, 1267, 1178, 1012, 921, 701, 533; HRMS (TOF MS ESI) calcd for
C16H22F2O5P+ [M + H]+ 363.1167, found 363.1171.
Ethyl 2-Fluoro-3-(5-oxo-2-phenyltetrahydrofuran-2-yl)-
propanoate (3ad). White oil, 30.6 mg (55% yield). 1H NMR
(400 MHz, CDCl3) δ 7.35−7.24 (m, 5H), 4.99−4.64 (m, 1H), 4.21−
4.00 (m, 2H), 2.66−2.33 (m, 6H), 1.23−1.16 (m, 3H); 19F NMR
(376 MHz, CDCl3) δ −189.48 (s, 0.43F), −190.14 (s, 0.56F); 13C NMR
(101 MHz, CDCl3) δ 176.3, 175.8, 169.3 (d, J = 10.1 Hz), 169.1 (d, J =
9.9 Hz), 142.6, 141.1, 129.1, 129.0, 128.5, 128.4, 125.2, 124.7, 87.0
(d, J = 33.0 Hz), 86.9 (d, J = 41.0 Hz), 85.4, 85.0, 62.2, 62.1, 44.2 (d, J =
19.5 Hz), 43.9 (d, J = 20.0 Hz), 34.9 (d, J = 3.1 Hz), 34.6 (d, J = 3.3 Hz),
28.6, 28.4, 14.2, 14.2; IR (cm−1) 1777, 1755, 1178, 1089, 1024, 701;
HRMS (TOF MS ESI) calcd for C15H18FO4+ [M + H]+ 281.1184, found
281.1185.
128.6, 128.1, 124.6, 116.3 (t, J = 255.0 Hz), 84.9 (t, J = 3.2 Hz), 50.9, 44.1
(t, J = 22.8 Hz), 35.7, 34.5, 34.4, 27.9, 23.9 (d, J = 1.2 Hz); IR (cm−1)
3322, 2919, 2850, 1779, 1669, 1539, 1194, 1070, 702; HRMS (TOF MS
ESI) calcd for C20H26F2NO3+ [M + H]+ 366.1875, found 366.1883.
Control Experiment with the Addition of 1,1-Diphenyl-
ethylene. An oven-dried reaction vial containing unsaturated
carboxylic acids 1a (0.2 mmol), fac-[Ir(ppy)3] (0.004 mmol), 1,1-
diphenylethylene (0.4 mmol), and HCOONa (0.4 mmol) was
evacuated and purged with argon three times. Then, DCM (2 mL) as
solution and 2a (0.2 mmol) were added via syringe. The reaction
mixture was stirred for 24 h at room temperature in the presence of 5 W
blue LED lamps. When the reaction was completed, the reaction mixture
was purified by flash chromatography on silica gel (elute: petroleum
ether/ethyl acetate = 5:1) directly to furnish corresponding product 4a
with 82% yield.
Ethyl 2,2-Difluoro-4,4-diphenylbut-3-enoate (4a).23 Colorless
1
liquid, 49.6 mg (82% yield). H NMR (400 MHz, CDCl3) δ 7.31−
7.11 (m, 10H), 6.19 (t, J = 11.8 Hz, 1H), 3.83 (q, J = 7.2 Hz, 2H), 1.09
(t, J = 7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −90.95 (s, 2F);
13C NMR (101 MHz, CDCl3) δ 162.4 (t, J = 34.0 Hz), 150.0 (t, J =
9.5 Hz), 139.4, 136.0, 128.8 (t, J = 1.9 Hz), 128.1, 127.6, 127.4, 127.0,
126.9, 118.4 (t, J = 28.4 Hz), 111.5 (t, J = 245.0 Hz), 61.7, 12.6.
5-(2,2-Difluoro-3-(furan-2-yl)-3-oxopropyl)-5-phenyldihydrofur-
1
an-2(3H)-one (3ae). Pale yellow oil, 17.7 mg (28% yield). H NMR
(400 MHz, CDCl3) δ 7.62 (d, J = 1.0 Hz, 1H), 7.30−7.20 (m, 6H), 6.50
(dd, J = 3.7, 1.7 Hz, 1H), 3.05−2.86 (m, 2H), 2.67−2.48 (m, 3H), 2.40−
2.30 (m, 1H); 19F NMR (376 MHz, CDCl3) δ −99.50 (q, J = 280.7 Hz,
2F); 13C NMR (101 MHz, CDCl3) δ 175.8 (t, J = 30.8 Hz), 174.3, 147.9,
146.8, 140.7, 127.6, 127.2, 123.7, 122.2 (t, J = 5.7 Hz), 116.3 (t, J =
254.8 Hz), 111.7, 84.0 (t, J = 2.8 Hz), 43.6 (t, J = 2.2 Hz), 34.0, 27.0;
IR (cm−1) 1773, 1668, 1460, 1191, 1073, 1029, 921, 760, 700; HRMS
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b01279.
■
S
Full spectroscopic data for compounds 3, copies of 1H and
13C NMR spectra, and X-ray single crystal analysis of 3ja
(PDF)
+
(TOF MS ESI) calcd for C17H15F2O4 [M + H]+ 321.0933, found
321.0935.
5-(2,2-Difluoro-3-(4-methoxyphenyl)-3-oxopropyl)-5-phenyldihy-
drofuran-2(3H)-one (3af). Pale yellow oil, 26.8 mg (37% yield).
1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 9.0 Hz, 2H), 7.33−7.20
(m, 5H), 6.86−6.82 (m, 2H), 3.80 (s, 3H), 2.95 (t, J = 16.9 Hz, 2H),
2.74−2.47 (m, 3H), 2.41−2.25 (m, 1H); 19F NMR (376 MHz, CDCl3)
δ −95.46−97.36 (m, 2F); 13C NMR (101 MHz, CDCl3) δ 187.0 (t, J =
298.0 Hz), 175.6, 164.5, 142.5, 132.8, 128.6, 128.1, 124.7, 124.4, 118.5
(t, J = 256.0 Hz), 114.0, 85.5, 55.6, 44.5 (t, J = 21.7 Hz), 34.7, 28.2; IR
(cm−1) 1778, 1688, 1596, 1263, 1169, 700; HRMS (TOF MS ESI) calcd
for C20H19F2O4+ [M + H]+ 361.1246, found 361.1247.
Crystallographic information for 3ja (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: hanjl@nju.edu.cn.
ORCID
Jianlin Han: 0000-0002-3817-0764
Notes
The authors declare no competing financial interest.
■
5-(3-(Benzo[d][1,3]dioxol-5-yl)-2,2-difluoro-3-oxopropyl)-5-phe-
nyldihydrofuran-2(3H)-one (3ag). Yellow oil, 18.5 mg (25% yield).
9830
DOI: 10.1021/acs.joc.7b01279
J. Org. Chem. 2017, 82, 9824−9831

The Journal of Organic Chemistry
Note
2015, 80, 11398−11406. (e) Gao, Y.; Li, X.; Xu, J.; Wu, Y.; Chen, W.;
Tang, G.; Zhao, Y. Chem. Commun. 2015, 51, 1605−1607. (f) Moriyama,
K.; Nishinohara, C.; Sugiue, T.; Togo, H. RSC Adv. 2015, 5, 85872−
85878. (g) Xu, C.; Shen, Q. Org. Lett. 2015, 17, 4561−4563. (h) Hemric,
B. N.; Shen, K.; Wang, Q. J. Am. Chem. Soc. 2016, 138, 5813−5816.
(i) Nakatsuji, H.; Sawamura, Y.; Sakakura, A.; Ishihara, K. Angew. Chem.,
Int. Ed. 2014, 53, 6974−6977. (j) Liu, X.; An, R.; Zhang, X.; Luo, J.;
Zhao, X. Angew. Chem., Int. Ed. 2016, 55, 5846−5850. (k) Paull, D. H.;
Fang, C.; Donald, J. R.; Pansick, A. D.; Martin, S. F. J. Am. Chem. Soc.
2012, 134, 11128−11131. (l) Niu, W.; Yeung, Y.-Y. Org. Lett. 2015, 17,
1660−1663.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (No. 21472082).
Support from the Collaborative Innovation Center of Solid-State
Lighting and Energy-Saving Electronics, the Jiangsu 333 program
(Y.P.), and Changzhou Jin-Feng-Huang program (J.H.) are also
acknowledged.
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