Synthesis of 2,2-difluoro-2H-chromenes through the tandem reaction of ethyl 3-bromo-3,3-difluoropropionate with salicylaldehyde derivatives

Article abstract of DOI:10.1016/j.tet.2013.10.091

A series of 2,2-difluoro-2H-chromenes were synthesized from the tandem reactions of ethyl 3-bromo-3,3-difluoropropionate with salicylaldehyde derivatives in good yields under basic conditions. In acidic environment defluorination took place during the reaction. A plausible mechanism was proposed based on the experimental results.

Full text of DOI:10.1016/j.tet.2013.10.091

Tetrahedron 69 (2013) 10820e10825
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Synthesis of 2,2-difluoro-2H-chromenes through the tandem
reaction of ethyl 3-bromo-3,3-difluoropropionate with
salicylaldehyde derivatives
*
Song Ou, Min Jiang, Jin-Tao Liu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 August 2013
Received in revised form 12 October 2013
Accepted 28 October 2013
Available online 1 November 2013
A series of 2,2-difluoro-2H-chromenes were synthesized from the tandem reactions of ethyl 3-bromo-
3,3-difluoropropionate with salicylaldehyde derivatives in good yields under basic conditions. In acidic
environment defluorination took place during the reaction. A plausible mechanism was proposed based
on the experimental results.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2,2-Difluoro-2H-chromene
Tandem reaction
Salicylaldehyde
Defluorination
Synthesis
1. Introduction
corresponding cyclic ethers.9 Notably, Fuchigami and coworkers
have developed two anodic stereoselective routes for direct fluo-
Oxygen-containing heterocycles, such as chromenes, chro-
mones, and chromanones have been found in many biologically
active compounds.1 These moieties are of great importance in
natural products and many of them have shown pharmacological
activities. Accordingly, the synthesis of various chromenes has
attracted much attention.2 Among them, the tandem reaction of
rination of chroman-4-ones at the position to the ring oxygen atom.
This is the first report on the regioselective electrochemical direct
fluorination of fused-type, oxygen-containing heterocyclic com-
pounds.10 Another report introduced a method to prepare this
structure through an intramolecular addition of hydroxy to the
terminal difluoroalkenes.11 In this paper we report a mild and ef-
ficient method to prepare 2,2-difluoro-2H-chromenes from the
reactions of ethyl 3-bromo-3,3-difluoropropionate with salicyli-
caldehyde derivatives.
Ethyl 3-bromo-3,3-difluoropropionate (1a) is a conveniently
available fluorine-containing synthon,12 and its synthetic applica-
tion has come in for pilot study,13 which could be prepared easily
from the reaction of dibromodifluoromethane with ethyl vinyl
ether and the subsequent oxidation with Caro’s acid.14
salicylaldehyde derivatives with a, b-unsaturated compounds has
proved to be an effective and convenient approach.3
The altered biological and other properties exerted by fluorine
atom introduction lead to chemist’s great interest in fluorinated
organic molecules.4 As a result, a significant number of pharma-
ceuticals currently on the market contain fluorine atom.5 A con-
venient approach toward the synthesis of fluoroorganic
compounds is through modular assembly via fluorinated building
blocks.6 To the best of our knowledge, there is few report on the
synthesis of 2,2-difluorinated chromenes, partially because their
eOCF2e moiety is liable to defluorination.7 A few heterocycles
containing eOCF2e moiety have been prepared either from the
2. Results and discussion
In our preliminary experiments, compound 1a was treated with
1.0 equiv of phenol in the presence of 2.5 equiv of triethylamine
(Et3N) in N,N-dimethylformide (DMF) at low temperature. Full
conversion of 1a was achieved in 10 h to afford ethyl 3,3-difluoro-3-
phenoxypropanoate 2a and ethyl 3-fluoro-3-phenoxyacrylate 2b in
42% and 30% yield, respectively (Scheme 1, Eq. 1). Encouraged by
nucleophilic fluorination of the corresponding d-lactones with SF4
or DAST reagent,8 or from the electrophilic fluorination of the
* Corresponding author. E-mail address: jtliu@sioc.ac.cn (J.-T. Liu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.091

S. Ou et al. / Tetrahedron 69 (2013) 10820e10825
10821
Scheme 1. Eq. 1) Reaction of ethyl 3-bromo-3,3-difluoropropionate 1a with phenol; Eq. 2) proposed reaction of salicylaldehyde with 1a.
the result, we envisioned that if a carbonyl group was introduced
on ortho-position of the phenoxy, a tandem intramolecular Knoe-
venagel condensation15 might take place to give the 2,2-difluoro-
2H-chromene derivatives. Interestingly, these two reactions could
be performed under the same basic conditions (Scheme 1, Eq. 2).
Next, we examined the reaction of 1a and salicylaldehyde
(1.5 equiv) in the presence of NEt3 (2.5 equiv) at room temperature.
However, only trace of lactone 5a was obtained, which indicated
that defluorination occurred (Table 1, entry 1). Heating the reaction
mixture to 70 ꢀC for 3 h, 45% yield of the expected 2,2-difluoro-2H-
chromene 4a was observed by 19F NMR (entry 2). It was found that
difluorinated chromene 4a was unstable and liable to hydrolyze to
the corresponding lactone 5a during the isolation by silica gel
column chromatography. Gratifyingly, it was successful to purify 4a
by adding 1% NEt3 in eluent.
product and 1,4-diazabicyclo[2.2.2]octane (DABCO) was the best one
to give 4a in 61% yield (entries 7e13). In those reactions, 5a was still
observed. Further optimization of the reaction conditions revealed
that decreasing the amount of salicylaldehyde 3a to 1.0 equiv and
increasing the reaction temperature to 110 ꢀC improved the yield up
to 86% with full conversion of starting material in DMF, and the
formation of byproduct 5a was suppressed successfully (entry 14).
The remnant salicylaldehyde as weak acid may cause the hydrolysis
and the higher temperature accelerated the process of condensation.
Therefore, the optimal conditions were set to 1.0 equiv of 3a,
2.5 equiv of DABCO in DMF at 110 ꢀC.
Using the optimized conditions, we further examined the scope
of salicylaldehydes 3. A variety of both electron-deficient and
electron-rich salicylaldehydes were evaluated and the results are
summarized in Table 2. This transformation tolerated a broad range
Table 1
Optimization of the reaction conditions for the synthesis of 2,2-difluoro-2H-chromene 4a
Entrya
Base
1a/3a/base
Solvent
Temp (ꢀC)
Yield, 4a (%)b
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
KF
K2CO3
NMM
Pyridine
Cinchonidine
DABCO
DABCO
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.5/2.5
1/1.0/2.5
DMF
DMF
rt
0
45
41
10
31
9
0
0
0
21
2
70
70
70
70
70
70
70
70
70
70
70
70
110
DMSO
Dioxane
DCE
Toluene
DMF
DMF
DMF
DMF
DMF
9
10
11
12
13
14
DMF
DMF
DMF
18
61
86
a
Reaction conditions: 1a (1.0 mmol), salicylaldehyde (1.5 mmol or 1.0 mmol), base (2.5 mmol) in solvent (5.0 mL) for 3 h.
b
Determined by 19F NMR.
Furthermore, we screened a range of reaction parameters to find
of functional groups. The electronic nature of the salicylaldehydes
had little influence on the yield of the reaction. Whether electron-
rich substituents (methyl-, methoxy-) or electron-deficient sub-
stituents (fluoro-, chloro-, nitro-) were introduced on the benzene
ring, salicylaldehydes 3 reacted smoothly with 1a to give the cor-
responding 2,2-difluoro-2H-chromene derivatives 4be4h in good
a suitable protocol for selective formation of chromene 4a. As shown
in Table 1, DMF and dimethylsulfoxide (DMSO) gave higher yields
and low yields were obtained with dioxane, 1,2-dichloroethane
(DCE) or toluene as solvent (entries 2e6). Examination of base ef-
fects showed that DBU, KF, and K2CO3 failed to promote any expected

10822
S. Ou et al. / Tetrahedron 69 (2013) 10820e10825
Table 2
phenols, carboxylic acids, and all kinds of strong acids), difluori-
nated chromenes 4 converted to the corresponding lactones 5 in
Scope of functionalized salicylaldehydes
a few minutes (Scheme 2).
COOEt
F
COOEt
O
H+
H2O
R
R
O
O
F
Entrya
3, (R1/R2)
3a, (H/H)
Product
4a
Yield (%)b
4
5
Scheme 2. Hydrolysis of 4.
1
80
We further investigated the reaction of other fluoroalkyl
substituted acetate under the standard conditions. Fortunately
ethyl 4-chloro-3,3,4,4-tetrafluorobutanoate (1b) reacted with
2-hydroxy-naphthalene-1-carbaldehyde (3j) readily to give
2-fluoroalkyl-2-fluoro-2H-chromene 4j in 61% yield (Scheme 3).
The structure of 4j was unambiguously confirmed with the help of
X-ray diffraction analysis on suitable crystals of this compound
(Fig. 1) (see the Supplementary data).16
On the basis of the above experimental results, a plausible re-
action pathway was proposed in Scheme 4. An elimination of 1a in
the presence of base generates the difluoroalkene,12 which reacts
with intermediate A formed from salicylaldehyde and a second
base to produce intermediate B and subsequently undergoes
a condensation to generate 2,2-difluoro-2H-chromene derivatives
4. While excess salicylaldehyde exists, defluorination7 of com-
pound 4 occurs and then the byproduct 5 was formed. In this
transformation the condensation could also be accelerated at
higher temperature.
2
3
4
5
3b, (H/OMe)
3c, (H/Me)
76
78
84
91
4b
4c
3d, (H/COOMe)
3e, (H/NO2)
4d
3. Conclusion
4e
In summary, we have disclosed a convenient synthetic method
for the preparation of 2,2-difluoro-2H-chromenes through the
tandem reaction of ethyl 3-bromo-3,3-difluoropropionate with
salicylaldehyde derivatives under basic conditions. These 2,2-
difluoro-2H-chromenes are useful structural motif in the synthe-
sis of many natural products and bioactive compounds. A plausible
mechanism was proposed based on the experimental results.
6
3f, (H/F)
93
4f
4. Experimental
4.1. General
7
8
3g, (H/Cl)
3h, (OMe/H)
3i,
84
82
91
4g
4h
Unless otherwise mentioned, solvents and reagents were pur-
chased from commercial sources and used as received. Melting
points were measured on a melt-Temp apparatus and uncorrected.
1H NMR spectra were recorded on Bruker AM-300 or Mercury 300
(300 MHz) spectrometers with TMS as the internal standard. 19F
NMR spectra were recorded on Bruker AM-300 or Mercury 300
(282 MHz) spectrometers with CFCl3 as external standard. IR
spectra were obtained with a Nicolet AV-360 spectrophotometer.
Mass spectra were taken on a HP5989A spectrometer. High-
resolution mass data were obtained on a high-resolution mass
spectrometer in the EI mode.
9
4i
a
Reaction conditions: 1a (1.0 mmol), salicylaldehyde 3 (1.0 mmol), DABCO
(2.5 mmol), and the reactions were carried out at 110 ꢀC for 3 h in DMF (5.0 mL).
b
Isolated yield.
4.2. Typical procedure
General procedure for the reaction of ethyl 3-bromo-3,3-
difluoropropionate. Under ambient atmosphere, ethyl 3-bromo-
3,3-difluoropropionate (1a, 1.0 mmol), salicylaldehyde (3, 1.0 mmol),
and NEt3 (2.5 mmol) were added into an Schlenk tube. 5.0 mL of DMF
was added rapidly via a syringe. The reaction mixture was stirred at
110 ꢀC for 3 h and then cooled to room temperature. The reaction was
quenched by the addition of water. The resulted mixture was diluted
yields in 3 h (Table 2, entries 1e8). The reaction of 2-hydroxy-1-
naphthaldehyde (3i) also proceeded well to afford the desired
product 4i in 91% yield (entry 9).
All of these 2,2-difluoro-2H-chromenes (4ae4i) were stable and
the liable eOCF2e moiety could be kept at room temperature for
many weeks. If they contacted with acidic environment (such as

S. Ou et al. / Tetrahedron 69 (2013) 10820e10825
10823
Scheme 3. Reaction of 1b with 3j.
ppm; 19F NMR (282 MHz, CDCl3):
d
ꢁ43.49 (s, 2F) ppm; EIMS (m/z, %):
240 (Mþ, 37.82), 212 (21.88), 195 (100), 167 (38.63), 148 (35.47), 119
(18.54),101 (26.65), 75 (20.39); HRMS (EI) calcd for C12H10F2O3 (Mþ):
240.0598. Found 240.0601; Anal. Calcd for C12H10F2O3: C, 60.00; H,
4.20; F, 15.82. Found: C, 59.61; H, 4.31; F, 15.57%.
4.2.2. 2,2-Difluoro-6-methoxy-2H-chromene-3-carboxylic acid ethyl
ester (4b). 205 mg, 76%; A white solid, mp 99e101 ꢀC; IR (KBr,
cmꢁ1):
y
3047, 2992, 2945, 1749, 1697, 1574, 1495, 1379, 1249, 1037,
824, 796; 1H NMR (300 MHz, CDCl3):
d
7.88 (d, J¼2.4 Hz, 1H),
6.92e7.08 (m, 2H), 6.86 (d, J¼2.4 Hz,1H), 4.33 (q, J¼7.2 Hz, 2H), 3.79
(s, 3H), 1.35 (t, J¼7.2 Hz, 3H) ppm; 19F NMR (282 MHz, CDCl3):
d
ꢁ44.26 (s, 2F) ppm; EIMS (m/z, %): 270 (Mþ, 29.60), 248 (92.51),
225 (26.55), 203 (65.53), 176 (100.00), 77 (32.40), 89 (31.35), 50
(4.47); Anal. Calcd for C13H12F2O4: C, 57.78; H, 4.48; F, 14.06. Found:
C, 57.49; H, 4.62; F, 14.09%.
4.2.3. 2,2-Difluoro-6-methyl-2H-chromene-3-carboxylic acid ethyl
ester (4c). 198 mg, 78%; A white solid, mp 88e90 ꢀC; IR (KBr, cmꢁ1):
Fig. 1. ORTEP drawing of 4j.
Scheme 4. The proposed reaction mechanism.
with ether and washed with water, saturated NaHCO3 aqueous so-
lution, and water. The organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
residue was purified by a flash column chromatography (silica gel) to
give the corresponding products 4 in good yields (petroleum ether/
ethyl acetate/NEt3¼100/5/1).
y
1714, 1642, 1587, 1497, 1301, 1252, 1043, 819; 1H NMR (300 MHz,
CDCl3):
7.92 (t, J¼2.7 Hz, 1H), 7.20e7.29 (m, 2H), 7.04e7.07 (m,
1H), 4.37 (q, J¼7.2 Hz, 2H), 2.34 (s, 3H), 1.38 (t, J¼7.2 Hz, 3H) ppm;
d
19F NMR (282 MHz, CDCl3):
d
ꢁ43.66 (t, J¼2.7 Hz) ppm; EIMS (m/z,
%): 254 (Mþ, 68.37), 226 (33.03), 209 (100.00), 181 (49.95), 162
(38.79), 133 (33.52), 115 (21.05), 77 (19.09); Anal. Calcd for
C
13H12F2O3: C, 61.42; H, 4.76; F, 14.95. Found: C, 61.56; H, 4.97; F,
4.2.1. 2,2-Difluoro-2H-chromene-3-carboxylic acid ethyl ester
14.56%.
(4a). 192mg, 80%;Awhitesolid,mp86e88ꢀC;IR(KBr, cmꢁ1):
y
3078,
2986, 2913, 1727, 1642, 1613, 1577, 1461, 1404, 1389, 1223, 1042, 762,
726; 1H NMR (300 MHz, CDCl3):
7.94 (t, J¼2.4 Hz,1H), 7.38e7.48 (m,
2H), 7.12e7.18 (m, 2H), 4.34 (q, J¼7.2 Hz, 2H), 1.36 (t, J¼7.2 Hz, 3H)
4.2.4. 2,2-Difluoro-2H-chromene-3,6-dicarboxylic acid 3-ethyl ester
6-methyl ester (4d). 250 mg, 84%; A white solid, mp 95e97 ꢀC; IR
d
(KBr, cmꢁ1):
y 3072, 2987, 2968, 2912, 1721, 1641, 1438, 1264, 1218,

10824
S. Ou et al. / Tetrahedron 69 (2013) 10820e10825
1056, 1043, 765; 1H NMR (300 MHz, CDCl3):
d
8.16e8.19 (m, 2H),
118e120 ꢀC; IR (KBr, cmꢁ1): 3087, 2982, 2941, 1664, 1571, 1469,
1377, 1292, 1125, 1054, 1033, 970, 872, 863, 749; 1H NMR (300 MHz,
CDCl3):
8.01 (s, 1H), 7.22e7.26 (m, 1H), 4.39 (q, J¼7.1 Hz, 2H), 3.94 (s, 3H),
1.40 (t, J¼7.1 Hz, 3H) ppm; 19F NMR (282 MHz, CDCl3):
d
ꢁ43.49 (s,
d
8.42 (s, 1H), 7.97 (d, J¼7.7 Hz, 1H), 7.80 (d, J¼8.7 Hz, 1H),
2F) ppm; EIMS (m/z, %): 298 (Mþ, 34.38), 270 (26.60), 267 (38.79),
253 (75.03), 239 (47.27), 206 (28.75), 55 (27.93), 44 (100.00); Anal.
Calcd for C14H12F2O5: C, 56.38; H, 4.06. Found: C, 56.37; H, 4.25%.
7.71 (d, J¼7.8 Hz, 1H), 7.52 (t, J¼7.7 Hz, 1H), 7.36 (t, J¼7.7 Hz, 1H),
7.16 (d, J¼8.7 Hz, 1H), 4.34 (q, J¼7.2 Hz, 2H), 1.36 (t, J¼7.2 Hz, 3H)
ppm; ESI-MS (m/z): 337 (MþꢁF, 100); EIMS (m/z, %): 356 (Mþ, 0.48),
269 (19.19), 223 (100.00), 139 (30.16). HRMS (EI) calcd for
4.2.5. 2,2-Difluoro-6-nitro-2H-chromene-3-carboxylic acid ethyl es-
ter (4e). 259 mg, 91%; A white solid, mp 100e102 ꢀC; IR (KBr,
C
17H12ClF3O3 (Mþ): 356.0427. Found: 356.0436.
cmꢁ1):
y
3074, 3006, 1708, 1648, 1623, 1579, 1529, 1485, 1475, 1345,
4.2.11. A mixture of 2a and 2b, colorless oil. 2a: 1H NMR (300 MHz,
1287, 1235, 1099, 1032, 841, 749; 1H NMR (300 MHz, CDCl3):
CDCl3):
d
6.14e6.82 (m, 5H), 3.95 (q, J¼7.2 Hz, 2H), 2.92
d
8.33e8.37 (m, 2H), 8.01 (t, J¼2.1 Hz, 1H), 7.31 (d, J¼8.7 Hz, 1H),
(t, J¼10.2 Hz, 2H), 1.01 (t, J¼7.2 Hz, 3H) ppm; 19F NMR (282 MHz,
4.38 (q, J¼7.1 Hz, 2H),1.38 (t, J¼7.1 Hz, 3H) ppm; 19F NMR (282 MHz,
CDCl3):
d
ꢁ67.3 (t, J¼9.6 Hz, 2F) ppm.
CDCl3):
d
ꢁ43.76 (s, 2F) ppm; EIMS (m/z, %): 285 (Mþ, 26.96), 257
Z-2b: 1H NMR (300 MHz, CDCl3):
(d, J¼25.8 Hz, 2H), 3.86 (t, J¼7.2 Hz, 2H), 0.95 (t, J¼7.2 Hz, 3H) ppm;
19F NMR (282 MHz, CDCl3):
ꢁ67.0 (d, J¼25.4 Hz, 1F) ppm.
d 6.14e6.82 (m, 5H), 4.16
(75.15), 240 (100.00), 221 (24.20), 194 (93.20), 193 (76.45), 182
(9.46), 166 (22.48), 138 (35.62), 44 (60.02); Anal. Calcd for
d
C
12H9F2NO5: C, 50.54; H, 3.18; N, 4.91; F, 13.32. Found: C, 50.46; H,
E-2b: 1H NMR (300 MHz, CDCl3):
d 6.14e6.82 (m, 5H), 4.86 (d,
3.36; N, 4.74; F, 12.99%.
J¼5.1 Hz, 2H), 3.86 (t, J¼7.2 Hz, 2H), 0.95 (t, J¼7.2 Hz, 3H) ppm; 19
F
NMR (282 MHz, CDCl3):
d
ꢁ65.7 (d, J¼5.1 Hz, 1F) ppm.
4.2.6. 2,2,6-Trifluoro-2H-chromene-3-carboxylic acid ethyl ester
(4f). 240 mg, 93%; A white solid, mp 92e94 ꢀC; IR (KBr, cmꢁ1):
y
4.2.12. Ethyl 2-oxo-2H-chromene-3-carboxylate (5a). This is
3073, 3058, 2987, 1714, 1645, 1585, 1490, 1376, 1293, 1251, 1046,
886, 827, 703; 1H NMR (300 MHz, CDCl3):
7.85 (t, J¼2.7 Hz, 1H),
7.07e7.21 (m, 3H), 4.33 (q, J¼7.2 Hz, 2H), 1.34 (t, J¼7.2 Hz, 3H) ppm;
a known compound.17 A white solid; 1H NMR (300 MHz, CDCl3):
d
d 8.54 (s, 1H), 7.62e7.68 (m, 2H), 7.32e7.37 (m, 2H), 4.43
(q, J¼7.2 Hz, 2H), 1.41 (t, J¼7.2 Hz, 3H) ppm.
19F NMR (282 MHz, CDCl3):
d
ꢁ44.30 (s, 2F), ꢁ119.18 (s, 1F) ppm;
EIMS (m/z, %): 258 (Mþ, 36.68), 230 (26.80), 213 (100.00), 185
(36.90), 166 (35.52), 119 (16.78), 107 (17.06), 99 (14.28), 87 (9.84);
Anal. Calcd for C12H9F3O3: C, 55.82; H, 3.51; F, 22.07. Found: C,
56.14; H, 3.59; F, 21.69%.
Acknowledgements
We thank the National Natural Science Foundation of China for
financial support (No. 21172243).
4.2.7. 6-Chloro-2,2-difluoro-2H-chromene-3-carboxylic acid ethyl
ester (4g). 230 mg, 84%; A white solid, mp 87e89 ꢀC; IR (KBr,
Supplementary data
cmꢁ1):
y
3078, 2994, 2905, 1714, 1645, 1573, 1484, 1374, 1291, 1230,
Copies of 1H NMR and 13C NMR spectra of compounds 4. X-ray
crystallography data for compound 4j. Supplementary data asso-
ciated with this article can be found in the online version at http://
dx.doi.org/10.1016/j.tet.2013.10.091.
819, 673; 1H NMR (300 MHz, CDCl3):
d
7.87 (t, J¼2.4 Hz, 1H),
7.39e7.43 (m, 2H), 7.10 (d, J¼8.4 Hz, 1H), 4.35 (q, J¼7.2 Hz, 2H), 1.36
(t, J¼7.2 Hz, 3H) ppm; 19F NMR (282 MHz, CDCl3):
d
ꢁ44.10 (s, 2F)
ppm; EIMS (m/z, %): 274 (Mþ, 48.73), 255 (2.72), 246 (36.48), 229
(100.00), 201 (26.85), 182 (28.72), 138 (20.05), 99 (24.42); Anal.
Calcd for C12H9ClF2O3: C, 52.48; H, 3.30. Found: C, 52.78; H, 3.33%.
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2. (a) Gembus, V.; Sala-Jung, N.; Uguen, D. Bull. Chem. Soc. Jpn. 2009, 82, 843; (b)
Ye, L. W.; Sun, X. L.; Zhu, C. Y.; Tang, Y. Org. Lett. 2006, 8, 3853; (c) Labrosse, J. R.;
Lhoste, P.; Sinou, D. Synth. Commun. 2002, 32, 3667; (d) Parker, K. A.; Mindt, T. L.
Org. Lett. 2001, 3, 3875; (e) Chauder, B. A.; Lopes, C. C.; Lopes, R. S. C.; Da, S.;
Alcides, J. M.; Snieckus, V. Synthesis 1998, 279; (f) Harrity, J. P. A.; La, D. S.;
Cefalo, D. R.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343; (g)
Majumdar, K. C.; Biswas, P. Heterocycles 1999, 50, 1227.
4.2.8. 2,2-Difluoro-8-methoxy-2H-chromene-3-carboxylic acid ethyl
ester (4h). 221 mg, 82%; A white solid, mp 103e105 ꢀC; IR (KBr,
cmꢁ1):
y
3089, 2947, 2850, 1721, 1641, 1613, 1583, 1487, 1392, 1281,
ꢀ
ꢀ
1252, 1201, 1149, 1102, 1046, 786, 752, 730, 700; 1H NMR (300 MHz,
CDCl3):
d
7.92 (t, J¼2.4 Hz, 1H), 6.98e7.10 (m, 3H), 4.34 (q, J¼7.5 Hz,
2H), 3.92 (s, 3H), 1.36 (t, J¼7.5 Hz, 3H) ppm; 19F NMR (282 MHz,
CDCl3):
d
ꢁ43.35 (s, 2F) ppm; EIMS (m/z, %): 270 (Mþ, 100.0), 242
(17.32), 226 (22.48), 225 (83.94), 222 (17.86), 197 (27.31), 178
(23.55); Anal. Calcd for C13H12F2O4: C, 57.78; H, 4.48; F, 14.06.
Found: C, 57.93; H, 4.35; F, 13.97%.
4.2.9. 3,3-Difluoro-3H-benzo[f]chromene-2-carboxylic acid ethyl es-
ter (4i). 264 mg, 91%; A white solid, mp 99e101 ꢀC; IR (KBr, cmꢁ1):
3. For review see: (a) Shi, Y. L.; Shi, M. Org. Biomol. Chem. 2007, 5, 1499.
4. (a) Selective Fluorination in Organic and Bioorganic Chemistry; Welch, J. T., Ed.;
American Chemical Society: Washington, DC, 1991; (b) Biomedical Frontiers of
Fluorine Chemistry; Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; American
Chemical Society: Washington, DC, 1996.
5. Begue, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992.
6. (a) Special issue on fluorinated synthons: J. Fluorine Chem. 2004, 125, 477; (b)
Fluorine-containing Synthons; Soloshonok, V. A., Ed.; American Chemical Soci-
ety: Washington, DC, 2005; (c) Soloshonok, V. A.; Mikami, K.; Yamazaki, T.;
Welch, J. T.; Hoenk, J. F. Current Fluoroorganic Chemistry: New Synthetic Di-
rections, Technologies, Materials, and Biological Applications; American Chemical
Society: Washington, DC, 2007.
7. Park, J. D.; Cummings, H. L.; Lacher, J. R. J. Org. Chem. 1958, 23, 1785.
8. (a) Zajc, B.; Zupan, M. J. Org. Chem. 1990, 55, 1099; (b) Hasek, W. R.; Smith, W. C.;
Engelhardt, V. A. J. Am. Chem. Soc. 1960, 82, 543; (c) Rozen, S.; Rechavi, D.;
Hagooly, A. J. Fluorine Chem. 2001, 111, 161; (d) Stavber, S.; Sket, B.; Zajc, B.;
Zupan, M. Tetrahedron 1989, 45, 6003.
y
2903, 1718, 1638, 1619, 1578, 1475, 1466, 1378, 1258, 1242, 1139,
1046, 809, 762, 745; 1H NMR (300 MHz, CDCl3):
d
8.72 (t, J¼2.4 Hz,
1H), 8.19 (d, J¼8.4 Hz, 1H), 7.77e7.93 (m, 1H), 7.85 (d, J¼8.4 Hz, 1H),
7.65 (t, J¼8.4 Hz, 1H), 7.48e7.53 (m, 1H), 7.21e7.32 (m, 1H),
4.35e4.44 (m, 2H), 1.36e1.43 (m, 3H) ppm; 19F NMR (282 MHz,
ꢀ
ꢀ
CDCl3):
d
ꢁ41.50 (d, J¼2.2 Hz, 2F) ppm; EIMS (m/z, %): 290 (Mþ,
100.00), 268 (9.32), 262 (27.51), 245 (88.27), 217 (83.06), 198
(29.45), 188 (28.25), 169 (24.42), 151 (13.03), 75 (10.58); Anal. Calcd
for C16H12F2O3: C, 66.21; H, 4.17; F, 13.09. Found: C, 66.19; H, 4.30; F,
12.95%.
4.2.10. 3-(Chlorodifluoromethyl)-3-fluoro-3H-benzo[f]chromene-2-
carboxylic acid ethyl ester (4j). 217 mg, 61%; A white solid, mp

S. Ou et al. / Tetrahedron 69 (2013) 10820e10825
10825
9. (a) Abe, T.; Tamura, M.; Sekiya, A. J. Fluorine Chem. 2005, 126, 325; (b) Abe, T.;
Baba, H.; Okuhara, K.; Fukaya, H. J. Fluorine Chem. 2001, 111, 115; (c) Huang, H.
N.; Persico, D. F.; Lagow, R. J. J. Org. Chem. 1988, 53, 78; (d) Chambers, R. D.;
Grievson, B.; Drakesmith, F. G.; Powell, R. L. J. Fluorine Chem. 1985, 29, 323; (e)
Ono, T.; Inoue, Y.; Fukaya, C.; Arakawa, Y.; Naito, Y.; Yokoyama, K.; Yamanouchi,
K. I.; Kobayashi, Y. J. Fluorine Chem. 1985, 27, 333; (f) Praly, J. P.; Brard, L.; De-
scotes, G.; Toupet, L. Tetrahedron 1989, 45, 4141; (g) Praly, J. P.; Descotes, G.
Tetrahedron Lett. 1987, 28, 1405.
10. (a) Dawooda, K. M.; Fuchigami, T. Tetrahedron Lett. 2001, 42, 2513; (b) Dawooda,
K. M.; Fuchigami, T. J. Org. Chem. 2001, 66, 7691.
11. Kendrick, D. A.; Kolb, M. J. Fluorine Chem. 1989, 45, 273.
12. (a) Leroy, J.; Molines, H.; Wakselman, C. J. Org. Chem. 1987, 52, 290; (b) Molines,
H.; Wakselman, C. J. Fluorine Chem. 1987, 35, 183.
13. Peng, S.; Qing, F. L.; Li, Y. Q.; Hu, C. M. J. Org. Chem. 2000, 65, 694.
14. (a) Fernandez, J. E.; Schwartz, M. L. J. Chem. Eng. Data 1970, 15, 462; (b) Powell,
J. R.; Tucker, S. A.; Acree, W. E.; Sees, J. A.; Hall, L. H. J. Chem. Educ. 1996, 73, 984.
15. (a) Jones, G. Organic Reactions; Wiley: New York, NY, 1967, Vol. 15, pp 204e599;
(b) House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park, CA,
1972; pp 646e653; (c) Tietze, L. F.; Beifuss, U. Comprehensive Organic Synthesis;
Pergamon: Oxford, UK, 1991, Vol. 2, pp 341e394.
16. The crystal data of 4j have been deposited at the Cambridge Crystallographic
Data Center. CCDC: 947194. Empirical formula: C17H12ClF3O3; formula weight:
356.72; crystal color, habit: colorless, prismatic; crystal dimensions: 0.502ꢂ0.
457ꢂ0.415 mm; crystal system: monoclinic; lattice type: primitive; lattice
ꢁ
ꢁ
ꢁ
parameters: a¼12.546(3) A, b¼10.675(3) A, c¼13.224(4) A,
a
¼90ꢀ,
b
¼116.
3
ꢁ
ꢀ
060(4)ꢀ,
g
¼90 , V¼1591.2(7) A ; space group: P2(1)/n; Z¼4; Dcalcd¼1.489 g/
cm3; F000¼728; diffractometer: Rigaku AFC7R; residuals: R; Rw: 0.0725, 0.2183.
17. Yuan, H.J.;Wang,M.;Liu, Y. J.;Wang,L.L.;Liu, J.;Liu, Q.Chem.dEur. J.2010,16,13450.