Palladium-catalyzed cross-coupling of ethyl α-bromo-α- fluoroacetate with arylboronic acids: Facile synthesis of α-aryl-α- fluoroacetate

Article abstract of DOI:10.1055/s-0029-1218740

Palladium-catalyzed Suzuki-Miyaura coupling reactions of ethyl α-bromo-α-fluoroacetate with various structurally diverse arylboronic acids using a phosphine ligand proceeded smoothly to afford α-aryl-α-fluoroacetate in moderate to good yields. This method provides a practical and efficient route to diverse α-monofluorinated α-arylcarbonyl compounds. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218740

SPECIAL TOPIC
1837
Palladium-Catalyzed Cross-Coupling of Ethyl a-Bromo-a-fluoroacetate with
Arylboronic Acids: Facile Synthesis of a-Aryl-a-fluoroacetates
F
a
acile Synthesis
h
a
-Aryl-
a
-f
e
luoroacetat
n
es Guo,a Xuyi Yue,a Feng-Ling Qing*a,b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
b
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road,
Shanghai 201620, P. R. of China
Fax +86(21)64166128; E-mail: flq@mail.sioc.ac.cn
Received 22 February 2010
pounds.7
A
versatile transition-metal-catalyzed8 or
Abstract: Palladium-catalyzed Suzuki–Miyaura coupling reactions
of ethyl a-bromo-a-fluoroacetate with various structurally diverse
arylboronic acids using a phosphine ligand proceeded smoothly to
afford a-aryl-a-fluoroacetates in moderate to good yields. This
organocatalytic9 approach has also been developed using
N-fluorobenzenesulfonimide as an electrophilic fluorina-
tion agent for the asymmetric a-fluorination of benzyl es-
method provides a practical and efficient route to diverse a-mono- ter equivalents.
fluorinated a-arylcarbonyl compounds.
Recently, transition-metal-catalyzed arylation has be-
Key words: cross coupling, fluorinated compounds, boronic acids
come a useful and general synthetic method for the prep-
aration of a-arylacetic acid derivatives.10 Buchwald and
Hartwig have successfully developed the palladium-cata-
lyzed a-arylation of enolates of esters or amide using aryl
halides as electrophiles (Scheme 1, path I).11 An alterna-
tive arylation strategy employed a-haloacetic acid deriva-
tives as electrophiles and ArM as nucleophiles (Scheme 1,
path II). Utilizing path II, Goossen and Deng investigated
the reactions of unsubstituted a-bromoacetic acid deriva-
tives with arylboronic acid derivatives [ArB(OH)2] under
palladium catalysis,12 and it was found that the bulky,
The a-arylacetic acid moiety is found in various important
medicines, such as nonsteroidal anti-inflammatory drugs
(NSAIDs) Naproxen and Flurbiprofen.1 As a C–F bond is
presented in numerous bioactive compounds due to its re-
sistance to metabolism with minimal steric interference
and other unique effects on the biological activity of com-
pounds,2 a-aryl-a-fluorocarbonyl compounds are expect-
ed to be useful in drug discovery and, thus, many different
methods for their synthesis have been developed. Earlier,
Chapman et al. described the synthesis of ethyl a-fluoro-
a-phenylacetate in 53% yield from the reaction of ethyl a-
bromo-a-phenylacetate with anhydrous potassium fluo-
ride.3 The anodic oxidation of benzylic ketones, esters,
and nitriles using triethylamine trihydrofluoride as a fluo-
rinating reagent allowed the regioselective introduction of
a fluorine atom at the a-position of the electron-withdraw-
ing group.4 Direct conversion of a benzylic alcohol with
N,N-diethylaminosulfur trifluoride (DAST)5 into the cor-
responding fluoride has been one of the most effective ap-
proaches. Recently, Fasan and co-workers reported a
strategy that combined cytochrome P450-catalyzed oxy-
genation with a deoxofluorination reaction in which the
newly generated hydroxy group was substituted by fluo-
rine using DAST. In this way, a-aryl-a-fluoroacetates
could be prepared from the corresponding a-arylacetic es-
ters with high enantioselectivity and in moderate yields.6
Alternative strategies involve the introduction of fluorine
into benzylcarbonyl compounds by electrophilic fluorina-
tion. Middleton et al. reported that initial conversion of
carbonyl compounds into their enol silyl ethers and fol-
lowed by treatment with trifluoromethyl hypofluorite
gave the corresponding a-aryl-a-fluorocarbonyl com-
moderately
electron-donating
phosphine
ligand
[P(Nap)3]12a and co-catalyst (Cu2O)12b played key roles in
the successful cross-coupling reaction. Lei et al. found
that Ni(PPh3)4 served as a highly effective catalyst for the
promotion of the direct arylation of a-halocarbonyl com-
pounds with various arylboronic acids under mild condi-
tions.13 Fu et al. reported that a nickel(II) chloride/
norephedrine-based catalyst accomplished the cross cou-
pling of secondary a-bromo esters with aryltrifluorosi-
lanes (ArSiF3).14 As fluorine is the most electronegative
element, it is natural that a-fluorinated a-haloacetic acid
derivatives will be more active in the cross-coupling reac-
tion as shown in path II (Scheme 1). Actually, Kumadaki
and co-workers found that in the presence of copper pow-
der, ethyl a-bromo-a,a-difluoroacetate reacted with iodo-
benzene to give cross-coupling product (Scheme 1,
equation 1) and this was a fairly facile process.15 Inspired
by these results, we anticipated that the cross-coupling re-
action of a-bromo-a-fluoroacetates with ArM or ArI
would be a practical and efficient route to a-aryl-a-fluoro-
acetates (Scheme 1, equation 2).
Our initial efforts focused on the reaction of ethyl a-bro-
mo-a-fluoroacetate (1) with iodobenzene in the presence
of copper powder;15 to our disappointment, the starting
material 1 remained intact. This failure led us to turn our
attention to the palladium-catalyzed Suzuki–Miyaura
cross-coupling of ethyl a-bromo-a-fluoroacetate (1) with
arylboronic acids. Recently, it has been found that im-
SYNTHESIS 2010, No. 11, pp 1837–1844
x
x.
x
x
.
2
0
1
0
Advanced online publication: 15.04.2010
DOI: 10.1055/s-0029-1218740; Art ID: C00110SS
© Georg Thieme Verlag Stuttgart · New York

1838
C. Guo et al.
SPECIAL TOPIC
Ar
tripotassium triphosphate trihydrate (K3PO4·3 H2O) was
an effective base for the coupling reaction (entry 14). As
the handling of anhydrous tripotassium phosphate powder
is troublesome due to its hygroscopic nature, tripotassium
triphosphate trihydrate was used as the base instead of an-
hydrous tripotassium phosphate for the cross-coupling re-
action. Toluene was by far the most effective solvent, the
use of ether solvents resulted in simultaneous formation of
byproduct 3 (entries 15, 16).
OR2
OM
OR2
path I
R1
ArX
X
+
R1
O
Ar
path II
OR2
OR2
R1
ArM
R1
+
O
O
CF2CO2Et
I
With these optimized conditions established, the scope of
the cross-coupling reaction in terms of substrates was in-
vestigated. As illustrated in Table 2, The catalytic system
was broadly applicable to a wide variety of para- and
meta-substituted arylboronic acids (entries 2–15) to af-
ford the corresponding a-aryl-a-fluoroacetates 2b–o in
moderate to good yields. Electron-withdrawing and elec-
tron-donating substituents on the aryl rings exhibited little
effect on the yields (50–82%), except in the case of halo-
genated 2d,e or extremely electron-deficient substrates
2o. Arylboronic acids bearing ortho-substituents were
also suitable coupling partners, however, the reaction
yields were remarkably affected by the electronic and
steric properties of their substituents (entries 16–21).
When 2-methylphenylboronic acid was employed, small
decrease in the yield of 2p was noted compared to that for
2h from 4-methylboronic acid (entry 16 vs 8, 69% cf.
82%). However, when an ortho-methoxy-, ortho-trifluoro-
methyl-, or ortho-fluoro group was present in the phenyl-
boronic acid the yields of the corresponding products 2q–s
were dramatically reduced (entries 17–19). Surprisingly,
sterically encumbered biphenyl-2-ylboronic acid took
part in the coupling process smoothly with little difference
in its reactivity compared to biphenyl-4-ylboronic acid
(entry 20 vs 10), while reaction with 2,6-dimethylboronic
acid did not proceed as efficiently as the reaction with 2-
methylboronic acid (entry 21 vs 16). 6-Methoxynaphtha-
len-2-ylboronic acid reacted to afford the coupling prod-
uct 2v in reasonable yield (entry 22); 2v has a similar
scaffold to Naproxen. In addition, 2-heterocyclic boronic
acids were suitable coupling partners, furnishing the prod-
ucts 2w,x in lower yields and this was probably due to
their inherent instability (entries 23 and 24).17 It is note-
worthy that an alternative catalytic system of Pd(OAc)2/
RuPhos (Table 1, entry 2), which was more active in the
preparation of electron-deficient and hindered biaryls,16
was found to be suitable for substrates where the
Pd(OAc)2/PPh3 combination showed limited success,
leading to the coupling products in higher yields (Table 2,
entries 15, 17–19, 23, 24).
Cu
DMSO, 55 °C
BrCF2CO2Et
+
(1)
(2)
Ar
Br
?
OR
OR
F
ArM (or ArI)
+
F
O
O
Scheme 1 a-Arylation of esters
provements in Suzuki–Miyaura coupling reactions have
relied a great deal on the increased reactivity and stability
of the metal catalysts by use of increasing efficacious sup-
porting ligands. Among these ligands, dialkylbiarylphos-
phines such as SPhos and RuPhos developed by
Buchwald et al. presented unprecedented activities for
various types of cross-coupling reactions.16 Accordingly,
we started by examining the reaction between 1 and phe-
nylboronic acid under palladium(II) acetate catalysis us-
ing a series of Buchwald’s ligands to see whether a-
arylation would be achieved practically. As shown in
Table 1, the reaction of 1 with phenylboronic acid (2.0
equiv) in the presence of palladium acetate and tripotassi-
um phosphate with use of Buchwald’s ligands L1–L4 in
toluene at 100 °C for 12 hours afforded the desired cross-
coupling product 2a, but byproduct 3 was also formed
(entries 1–3) and the starting material 1 was not totally
converted in the case of JohnPhos (L4) (entry 4). It was
found that SPhos (L1) and RuPhos (L2) showed high cat-
alytic effectiveness compared to XPhos (L3) and that 2a
and 3 were formed in a comparable ratio (entry 3). To
achieve both total conversion of 1 and formation of 2a as
the sole product, we next turned our attention to diphos-
phine bidentate and monodentate phosphine ligands.
When a,w-diphosphine bidentate ligands L5–L7 were
employed, although compound 1 underwent complete
conversion, a large amount of byproduct 3 was observed
(entries 5–7). To our delight, when either triphenylphos-
phine (L8) or tri-2-methylphenylphosphine (L9) was used
as the ligand, the coupling product 2a was formed exclu-
sively with full conversion of 1 (entries 8, 9). As triphe-
nylphosphine (L8) is simple, stable, and inexpensive
ligand, it was chosen as the ligand for this cross-coupling
reaction. Furthermore, examination of the 19F NMR of the
reaction mixture every hour showed that compound 1 un-
derwent total conversion in three hours (entry 10). Further
investigation examining suitable bases showed that the
use of sodium acetate, cesium carbonate, and cesium
fluoride resulted in either no reaction or unavoidable
formation of byproduct 3 (entries 11–13). Gratifyingly,
In conclusion, we report that by using a catalytic system
of palladium(II) acetate and triphenylphosphine or
RuPhos, the Suzuki–Miyaura cross-coupling reactions of
various arylboronic acids with ethyl a-bromo-a-fluoro-
acetate proceed smoothly to afford a-aryl-a-fluoroacetates
in moderate to good yields. To the best of our knowledge,
this represents the first preparation of a-aryl-a-fluorocar-
bonyl scaffolds in a single step. All reagents used are
readily available and easy to handle and the reaction con-
Synthesis 2010, No. 11, 1837–1844 © Thieme Stuttgart · New York

SPECIAL TOPIC
Facile Synthesis of a-Aryl-a-fluoroacetates
1839
Table 1 Optimization of the Suzuki–Miyaura Cross-Couplings of 1 with Phenylboronic Acid under Palladium Catalysisa
O
O
O
Ph
H
Pd(OAc)2 (5 mol%), ligand (L1–L9)
+
Br
O
O
PhB(OH)2
(2 equiv)
+
O
base (3 equiv), solvent (0.10 M)
F
F
F
1
2a
3
X = Cy, R1 = R2 = OMe, R3 = H
PX2
R2
SPhos (L1)
RuPhos (L2)
XPhos (L3)
X = Cy, R1 = R2 = Oi-Pr, R3 = H
X = Cy, R1 = R2 = R3 = i-Pr
X = t-Bu, R1 = R2 = R3 = H
R1
JohnPhos (L4)
R3
Ph2P-(CH2)n-PPh2
n = 2 dppe (L5)
n = 3 dppp (L6)
n = 4 dppb (L7)
R = Ph (L8)
R = o-tolyl (L9)
PR3
Entry
1
Ligand
Base
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
Temp (°C), time (h)
100, 12
100, 12
100, 12
100, 12
100, 12
100, 12
100, 12
100, 12
100, 12
100, 3
Molar ratiob 1/2a/3
–:1:0.17
–:1:0.13
–:1:0.98
0.47:1:0
–:1:4.9
SPhos (L1)
RuPhos (L2)
XPhos (L3)
JohnPhos (L4)
dppe (L5)
K3PO4
2
K3PO4
3
K3PO4
4
K3PO4
5
K3PO4
6
dppp (L6)
dppb (L7)
PPh3 (L8)
K3PO4
–:1:1.9
7
K3PO4
–:1:2.1
8
K3PO4
only 2ac
only 2ac
only 2a
9
P(o-tolyl)3 (L9)
PPh3 (L8)
K3PO4
10
11
12
13
14
15
16
K3PO4
PPh3 (L8)
NaOAc
Cs2CO3
CsF
100, 3
n.r.d
PPh3 (L8)
100, 3
–:1:0.07
–:1:0.19
only 2ae
–:1:0.58
–:1:0.31
PPh3 (L8)
100, 3
PPh3 (L8)
K3PO4·3 H2O
K3PO4·3 H2O
K3PO4·3 H2O
100, 3
PPh3 (L8)
60, 3
PPh3 (L8)
diglyme
100, 3
a Reaction conditions: Pd(OAc)2 (5 mol%), ligand (L1–L7, 10 mol%) or ligand (L8, L9, 20 mol%), 1 (1.0 equiv), PhB(OH)2 (2.0 equiv), base
(3.0 equiv), solvent (0.10 mol L–1 of 1).
b Determined by 19F NMR of the reaction mixture.
c Isolated yield: 73%.
d No reaction, 1 remained intact.
e Isolated yield: 79%.
All reactions were carried out under an argon atmosphere. All re-
agents were used as received from commercial sources, unless spec-
ified otherwise. 1H and 13C NMR spectra were recorded on a Bruker
AM-300 spectrometer and Varian MR-400, respectively. 19F NMR
spectra were recorded on a Bruker AM-300 spectrometer (CFCl3 as
outside standard and low field is positive). IR spectra were recorded
on a Bio-Rad FTS-185 system. LRMS and HRMS analyses were
performed on Agilent 5973N (EI, 70 eV) and Waters Micromass
GCT Premier respectively.
ditions are mild, hence, we believe that this method pro-
vides a practical and efficient route for the preparation of
potentially bioactive a-monofluorinated a-arylcarbonyl
compounds. The asymmetric version of the coupling reac-
tion is ongoing in our laboratory.
Synthesis 2010, No. 11, 1837–1844 © Thieme Stuttgart · New York

1840
C. Guo et al.
SPECIAL TOPIC
Table 2 Suzuki–Miyaura Cross-Couplings of 1 with Structurally Diverse Aryl- and Heterocyclic Boronic Acidsa
O
O
Pd(OAc)2 (5 mol%), Ph3P (20 mol%)
Br
Ar
ArB(OH)2
(2 equiv)
Entry
+
O
O
K3PO4⋅3H2O (3 equiv), toluene (0.10 M)
F
100 °C, 3 h
F
1
2a–x
Product
Yieldb (%)
Entry
Product
Yieldb (%)
F
F
CO2Et
1
2
3
CO2Et
79
13
14
15
64
F
2a
2m
F
F
CO2Et
CO2Et
81
66
50
MeO
2b
2n
F
F
F3C
CO2Et
26 (47c)
CO2Et
F
CF3
F
2c
2o
2p
F
CO2Et
CO2Et
4
5
6
7
37
38
61
77
16
17
18
19
CO2Et
69
Cl
2d
F
F
19 (45c)
35 (46c)
–d (45c)
CO2Et
Br
OMe
F
2e
2q
F
CO2Et
CO2Et
F3C
CF3
F
2f
2r
2s
F
O
CO2Et
CO2Et
O
F
F
2g
F
CO2Et
CO2Et
8
9
82
65
20
21
68
32
2h
2t
F
F
CO2Et
CO2Et
2u
2i
Synthesis 2010, No. 11, 1837–1844 © Thieme Stuttgart · New York

SPECIAL TOPIC
Facile Synthesis of a-Aryl-a-fluoroacetates
1841
Table 2 Suzuki–Miyaura Cross-Couplings of 1 with Structurally Diverse Aryl- and Heterocyclic Boronic Acidsa (continued)
O
O
Pd(OAc)2 (5 mol%), Ph3P (20 mol%)
Br
Ar
ArB(OH)2
(2 equiv)
Entry
+
O
O
K3PO4⋅3H2O (3 equiv), toluene (0.10 M)
F
100 °C, 3 h
F
1
2a–x
Product
Yieldb (%)
Entry
Product
Yieldb (%)
F
F
CO2Et
CO2Et
10
67
22
52
MeO
2v
2j
F
F
F
CO2Et
11
12
66
78
23
24
23 (38c)
O
O
CO2Et
2w
2k
CO2Et
32 (45c)
CO2Et
F
OMe
2x
2l
a Reaction conditions: Pd(OAc)2 (5 mol% ), PPh3 (20 mol%), 1 (1.0 equiv), ArB(OH)2 (2.0 equiv), K3PO4·3 H2O (3.0 equiv), toluene (0.10 mol
L–1 of 1), 100 °C, 3 h.
b Isolated yield.
c Isolated yield by the use of RuPhos (10 mol%) instead of PPh3.
d No reaction when PPh3 was used as ligand.
Ethyl a-Aryl-a-fluoroacetates 2a–x; General Procedure
An oven-dried Schlenk tube containing a magnetic stirrer bar was
charged with Pd(OAc)2 (5.6 mg, 0.025 mmol, 5 mol%), PPh3 (26.2
mg, 0.10 mmol, 20 mol%), ArB(OH)2 (1.0 mmol, 2.0 equiv), and
K3PO4·3 H2O (400 mg, 1.5 mmol, 3.0 equiv). The Schlenk tube was
capped with a rubber septum and then evacuated and backfilled
with argon (this sequence was repeated 3 ×). Toluene (5.0 mL) was
added through the septum via syringe and the resulting mixture was
stirred at r.t. for 5 min. Ethyl a-bromo-a-fluoroacetate (1, 92.5 mg,
0.50 mmol, 1.0 equiv) was added dropwise via syringe. The
Schlenk tube was sealed and the mixture was heated at 100 °C with
vigorous stirring for 3 h. The mixture was then allowed to cool to
r.t. and quenched with H2O (10 mL). The layers were separated and
the aqueous phase was extracted with Et2O (3 × 5 mL). The com-
bined organic phases were washed with brine (20 mL), dried (anhyd
Na2SO4), filtered, and concentrated. The crude product was purified
by flash chromatography (silica gel (petroleum ether–EtOAc, 50:1)
to give the coupling compound.
Ethyl 2-Fluoro-2-(4-methoxyphenyl)acetate (2b)4a,b,18b,19
IR (thin film): 1758 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.39 (d, J = 8.4 Hz, 2 H), 6.93 (d,
J = 8.4 Hz, 2 H), 5.71 (d, J = 48.0 Hz, 1 H), 4.21–4.27 (m, 2 H),
3.82 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 169.0 (d, J = 28.3 Hz), 160.8 (d,
J = 2.2 Hz), 128.7 (d, J = 5.2 Hz), 126.5 (d, J = 20.9 Hz), 114.3,
89.3 (d, J = 183.1 Hz), 61.8, 55.4, 14.2.
19F NMR (282 MHz, CDCl3): d = –175.0 (d, J = 45.4 Hz).
MS (EI): m/z (%) = 212 (12) [M]+, 139 (100) [M – CO2Et]+.
Ethyl 2-Fluoro-2-(4-fluorophenyl)acetate (2c)4c,18d
IR (thin film): 1761 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44–7.48 (m, 2 H), 7.07–7.13 (m,
2 H), 5.75 (d, J = 47.4 Hz, 1 H), 4.22–4.27 (m, 2 H), 1.26 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.0 (d, J = 27.8 Hz), 163.1 (dd,
J = 247.2, 2.3 Hz), 129.8 (dd, J = 20.8, 3.2 Hz), 129.0, 128.3 (dd,
J = 8.5, 5.8 Hz), 126.8, 115.5 (d, J = 21.7 Hz), 88.3 (d, J = 184.7
Hz), 61.6, 13.6.
19F NMR (282 MHz, CDCl3): d = –111.9 (s, 1 F), –178.9 (d,
J = 47.9 Hz, 1 F).
Ethyl 2-Fluoro-2-phenylacetate (2a)3,7,18
IR (thin film): 1759 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.47 (m, 5 H), 5.78 (d,
J = 48.0 Hz, 1 H), 4.22–4.28 (m, 2 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.5 (d, J = 27.3 Hz), 134.3 (d,
J = 20.3 Hz), 129.6 (d, J = 2.4 Hz), 128.8, 126.6 (d, J = 6.0 Hz),
89.3 (d, J = 184.3 Hz), 61.8, 14.0.
MS (EI): m/z (%) = 200 (9) [M]+, 127 (100) [M – CO2Et]+.
Ethyl 2-(4-Chlorophenyl)-2-fluoroacetate (2d)4c,18d,19
19F NMR (282 MHz, CDCl3): d = –180.3 (d, J = 51.3 Hz).
MS (EI): m/z (%) = 182 (12) [M]+, 109 (100) [M – CO2Et]+.
IR (thin film): 1761 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36–7.44 (m, 4 H), 5.75 (d,
J = 47.4 Hz, 1 H), 4.22–4.27 (m, 2 H), 1.26 (t, J = 7.2 Hz, 3 H).
Synthesis 2010, No. 11, 1837–1844 © Thieme Stuttgart · New York

1842
C. Guo et al.
SPECIAL TOPIC
13C NMR (100 MHz, CDCl3): d = 168.3 (d, J = 26.8 Hz), 135.8 (d,
J = 2.2 Hz), 132.9 (d, J = 20.9 Hz), 129.2, 128.1 (d, J = 6.0 Hz),
88.8 (d, J = 186.1 Hz), 62.2, 14.2.
13C NMR (100 MHz, CDCl3): d = 168.7 (d, J = 27.8 Hz), 152.7 (d,
J = 2.3 Hz), 131.2 (d, J = 20.8 Hz), 126.5 (d, J = 5.6 Hz), 125.7,
89.2 (d, J = 183.8 Hz), 61.7, 34.7, 31.2, 14.0.
19F NMR (282 MHz, CDCl3): d = –181.2 (d, J = 49.4 Hz).
MS (EI): m/z (%) = 216 (12) [M]+, 143 (100) [M – CO2Et]+.
19F NMR (282 MHz, CDCl3): d = –178.3 (d, J = 47.1 Hz, 1 F).
MS (EI): m/z (%) = 238 (23) [M]+, 223 (85) [M – CH3]+, 165 (100)
[M – CO2Et]+.
Ethyl 2-(4-Bromophenyl)-2-fluoroacetate (2e)19
HRMS (EI): m/z [M]+ calcd for C14H19FO2: 238.1369; found:
238.1375.
IR (thin film): 1758 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55 (d, J = 8.1 Hz, 2 H), 7.35 (d,
J = 8.1 Hz, 2 H), 5.73 (d, J = 47.7 Hz, 1 H), 4.22–4.27 (m, 2 H),
1.26 (t, J = 7.2 Hz, 3 H).
Ethyl 2-(Biphenyl-4-yl)-2-fluoroacetate (2j)
IR (thin film): 1760 cm–1.
13C NMR (100 MHz, CDCl3): d = 168.0 (d, J = 27.3 Hz), 133.2 (d,
J = 20.8 Hz), 131.9, 128.1 (d, J = 6.5 Hz), 123.8 (d, J = 2.8 Hz),
88.7 (d, J = 185.6 Hz), 62.0, 14.0.
19F NMR (282 MHz, CDCl3): d = –181.7 (d, J = 47.4 Hz, 1 F).
1H NMR (300 MHz, CDCl3): d = 7.38–7.66 (m, 9 H), 5.83 (d,
J = 48.0 Hz, 1 H), 4.25–4.31 (m, 2 H), 1.30 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.6 (d, J = 27.5 Hz), 142.6 (d,
J = 2.2 Hz), 140.3, 133.2 (d, J = 20.1 Hz), 128.9, 127.7, 127.5,
127.2, 127.1, 89.2 (d, J = 183.8 Hz), 61.9, 14.1.
19F NMR (282 MHz, CDCl3): d = –179.9 (d, J = 49.4 Hz).
MS (EI): m/z (%) = 258 (21) [M]+, 185 (100) [M – CO2Et]+.
HRMS (EI): m/z [M]+ calcd for C16H15FO2: 258.1056; found:
MS (EI): m/z (%) = 260, 262 (16) [M]+, 187, 189 (100) [M –
CO2Et]+.
Ethyl 2-Fluoro-2-[4-(trifluoromethyl)phenyl]acetate (2f)
IR (thin film): 1764, 1328 cm–1.
258.1057.
1H NMR (300 MHz, CDCl3): d = 7.69 (d, J = 8.4 Hz, 2 H), 7.62 (d,
J = 8.4 Hz, 2 H), 5.85 (d, J = 47.7 Hz, 1 H), 4.24–4.29 (m, 2 H),
1.27 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.7 (d, J = 26.8 Hz), 138.0 (d,
J = 19.5 Hz), 129.4, 128.9, 128.5, 127.2, 126.6 (d, J = 6.7 Hz),
125.7 (q, J = 7.5 Hz), 88.5 (d, J = 186.9 Hz), 62.2, 14.0.
19F NMR (282 MHz, CDCl3): d = –63.3 (s, 3 F), –184.6 (d, J = 45.4
Hz, 1 F).
MS (EI): m/z (%) = 250 (2) [M]+, 177 (100) [M – CO2Et]+.
HRMS (EI): m/z [M]+ calcd for C11H10F4O2: 250.0617; found:
Ethyl 2-Fluoro-2-(3-methylphenyl)acetate (2k)19
IR (thin film): 1759 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.19–7.32 (m, 4 H), 5.73 (d,
J = 47.7 Hz, 1 H), 4.21–4.28 (m, 2 H), 2.37 (s, 3 H), 1.26 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.6 (d, J = 27.3 Hz), 138.5,
134.1 (d, J = 19.9 Hz), 130.3 (d, J = 2.4 Hz), 128.6, 127.2 (d,
J = 6.0 Hz), 123.7 (d, J = 6.0 Hz), 89.4 (d, J = 184.2 Hz), 61.7, 21.3,
14.0.
250.0614.
19F NMR (282 MHz, CDCl3): d = –179.2 (d, J = 49.6 Hz, 1 F).
MS (EI): m/z (%) = 196 (20) [M]+, 123 (100) [M – CO2Et]+.
Ethyl 2-(1,3-Benzodioxol-5-yl)-2-fluoroacetate (2g)20
IR (thin film): 1758, 1250 cm–1.
Ethyl 2-Fluoro-2-(3-methoxyphenyl)acetate (2l)4c
1H NMR (300 MHz, CDCl3): d = 6.92–6.94 (m, 2 H), 6.80–6.83 (m,
1 H), 5.98 (s, 2 H), 5.65 (d, J = 47.7 Hz, 1 H), 4.21–4.27 (m, 2 H),
1.27 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.7 (d, J = 29.0 Hz), 148.9 (d,
J = 3.0 Hz), 148.2, 128.0 (d, J = 20.8 Hz), 121.5 (d, J = 6.7 Hz),
108.5 (d, J = 1.5 Hz), 107.3 (d, J = 5.2 Hz), 101.6, 89.3 (d,
J = 184.6 Hz), 62.0, 14.2.
IR (thin film): 1754 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.29–7.34 (m, 1 H), 7.01–7.05 (m,
2 H), 6.91–6.95 (m, 1 H), 5.74 (d, J = 47.4 Hz, 1 H), 4.21–4.27 (m,
2 H), 3.81 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.4 (d, J = 27.3 Hz), 159.8,
135.6 (d, J = 20.3 Hz), 129.8, 118.8 (d, J = 6.4 Hz), 115.3 (d,
J = 2.3 Hz), 111.7 (d, J = 6.5 Hz), 89.2 (d, J = 184.8 Hz), 61.8, 55.2,
14.0.
19F NMR (282 MHz, CDCl3): d = –175.3 (d, J = 49.4 Hz).
MS (EI): m/z (%) = 226 (17) [M]+, 153 (100) [M – CO2Et]+.
19F NMR (282 MHz, CDCl3): d = –180.3 (d, J = 49.4 Hz, 1 F).
MS (EI): m/z (%) = 212 (35) [M]+, 139 (100) [M – CO2Et]+.
Ethyl 2-Fluoro-2-(4-methylphenyl)acetate (2h)19,21
IR (thin film): 1760 cm–1.
Ethyl 2-Fluoro-2-(3-fluorophenyl)acetate (2m)
1H NMR (300 MHz, CDCl3): d = 7.35 (d, J = 7.2 Hz, 2 H), 7.21 (d,
J = 8.1 Hz, 2 H), 5.73 (d, J = 48.0 Hz, 1 H), 4.20–4.26 (m, 2 H),
2.36 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.6 (d, J = 27.7 Hz), 139.5 (d,
J = 2.3 Hz), 131.2 (d, J = 20.8 Hz), 129.3 (d, J = 0.9 Hz), 126.6 (d,
J = 5.5 Hz), 89.2 (d, J = 183.8 Hz), 61.6, 21.1, 13.9.
19F NMR (282 MHz, CDCl3): d = –177.8 (d, J = 45.1 Hz, 1 F).
MS (EI): m/z (%) = 196 (18) [M]+, 123 (100) [M – CO2Et]+.
IR (thin film): 1765 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.42 (m, 1 H), 7.18–7.24 (m,
2 H), 7.07–7.12 (m, 1 H), 5.77 (d, J = 47.4 Hz, 1 H), 4.20–4.32 (m,
2 H), 1.27 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.0 (d, J = 26.8 Hz), 162.8 (d,
J = 246.3 Hz), 136.5 (q, J = 20.8, 7.4 Hz), 130.4 (d, J = 7.9 Hz),
122.1 (q, J = 6.5, 3.2 Hz), 116.5 (q, J = 21.3, 1.9 Hz), 113.5 (q,
J = 23.2, 7.0 Hz), 88.5 (dd, J = 186.1, 2.3 Hz), 62.0, 14.0.
19F NMR (282 MHz, CDCl3): d = –112.0 (q, J = 16.4, 8.2 Hz, 1 F),
–182.2 (d, J = 49.6 Hz, 1 F).
MS (EI): m/z (%) = 200 (10) [M]+, 127 (100) [M – CO2Et]+.
Ethyl 2-(4-tert-Butylphenyl)-2-fluoroacetate (2i)
IR (thin film): 1762 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38–7.45 (m, 4 H), 5.75 (d,
J = 47.7 Hz, 1 H), 4.21–4.29 (m, 2 H), 1.32 (s, 9 H), 1.28 (t, J = 7.2
Hz, 3 H).
HRMS (EI): m/z [M]+ calcd for C10H10F2O2: 200.0649; found:
200.0648.
Synthesis 2010, No. 11, 1837–1844 © Thieme Stuttgart · New York

SPECIAL TOPIC
Facile Synthesis of a-Aryl-a-fluoroacetates
1843
Ethyl 2-(3,5-Dimethylphenyl)-2-fluoroacetate (2n)
126.1 (q, J = 10.2, 5.6 Hz), 85.0 (dq, J = 182.4, 5.1, 2.8 Hz), 62.0,
13.8.
IR (thin film): 1760 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.03–7.08 (m, 3 H), 5.69 (d,
J = 48.0 Hz, 1 H), 4.21–4.29 (m, 2 H), 2.33 (s, 6 H), 1.27 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.7 (d, J = 27.5 Hz), 138.4,
134.0 (d, J = 20.1 Hz), 131.2 (d, J = 2.9 Hz), 124.4 (d, J = 5.2 Hz),
89.4 (d, J = 183.9 Hz), 61.7, 21.2, 14.0.
19F NMR (282 MHz, CDCl3): d = –58.0 (s, 3 F), –174.9 (d, J = 49.6
Hz).
MS (EI): m/z (%) = 250 (1) [M]+, 177 (100) [M – CO2Et]+.
HRMS (EI): m/z [M]+ calcd for C11H10F4O2: 250.0617; found:
250.0621.
19F NMR (282 MHz, CDCl3): d = –178.7 (d, J = 49.6 Hz).
MS (EI): m/z (%) = 210 (16) [M]+, 137 (100) [M – CO2Et]+.
HRMS (EI): m/z [M]+ calcd for C12H15FO2: 210.1056; found:
Ethyl 2-Fluoro-2-(2-fluorophenyl)acetate (2s)
IR (thin film): 1761, 1021 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.49 (m, 2 H), 7.13–7.23 (m,
2 H), 6.06 (d, J = 47.1 Hz, 1 H), 4.24–4.30 (m, 2 H), 1.27 (t, J = 7.2
Hz, 3 H).
210.1058.
Ethyl 2-[3,5-Bis(trifluoromethyl)phenyl]-2-fluoroacetate (2o)
13C NMR (100 MHz, CDCl3): d = 168.0 (d, J = 27.5 Hz), 160.3 (d,
J = 244.9 Hz), 131.7 (dd, J = 8.2, 3.0 Hz), 128.8 (dd, J = 5.2, 3.0
Hz), 124.5 (dd, J = 3.7, 1.5 Hz), 115.9 (d, J = 22.3 Hz), 83.4 (dd,
J = 183.1, 3.7 Hz), 62.0, 14.0.
19F NMR (282 MHz, CDCl3): d = –118.0 (d, J = 15.8 Hz, 1 F),
–181.3 (d, J = 51.6 Hz, 1 F).
IR (thin film): 1767, 1281 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.92–7.96 (m, 3 H), 5.92 (d,
J = 46.8 Hz, 1 H), 4.28–4.31 (m, 2 H), 1.30 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.0 (d, J = 26.1 Hz), 136.8 (d,
J = 21.5 Hz), 132.2 (d, J = 33.5 Hz), 128.6, 126.3 (q, J = 7.4 Hz),
124.3, 123.3, 121.5, 87.7 (d, J = 189.1 Hz), 62.6, 14.0.
MS (EI): m/z (%) = 200 (7) [M]+, 127 (100) [M – CO2Et]+.
19F NMR (282 MHz, CDCl3): d = –63.4 (s, 6 F), –186.6 (d, J = 45.1
Hz, 1 F).
HRMS (EI): m/z [M]+ calcd for C10H10F2O2: 200.0649; found:
200.0650.
MS (EI): m/z (%) = 299 (10) [M – F]+, 245 (100) [M – CO2Et]+.
HRMS (EI): m/z [M]+ calcd for C12H9F7O2: 318.0491; found:
Ethyl 2-(Biphenyl-2-yl)-2-fluoroacetate (2t)
IR (thin film): 1760 cm–1.
318.0493.
1H NMR (300 MHz, CDCl3): d = 7.35–7.60 (m, 9 H), 5.85 (d,
J = 47.1 Hz, 1 H), 4.19–4.24 (m, 2 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 169.1 (d, J = 29.1 Hz), 142.8 (d,
J = 4.5 Hz), 139.5, 131.9 (d, J = 19.4 Hz), 130.5 (d, J = 1.5 Hz),
129.73 (d, J = 3.7 Hz), 129.67 (d, J = 1.5 Hz), 128.3, 128.0 (d,
J = 2.2 Hz), 127.74, 127.69, 86.4 (d, J = 181.7 Hz), 61.7, 14.0.
Ethyl 2-Fluoro-2-(2-methylphenyl)acetate (2p)19
IR (thin film): 1761 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.20–7.41 (m, 4 H), 5.97 (d,
J = 47.7 Hz, 1 H), 4.22–4.29 (m, 2 H), 2.44 (s, 3 H), 1.27 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.5 (d, J = 27.8 Hz), 136.2 (d,
J = 3.7 Hz), 132.4 (d, J = 19.0 Hz), 130.5, 129.2 (d, J = 2.7 Hz),
127.0 (d, J = 6.5 Hz), 125.9 (d, J = 0.9 Hz), 86.9 (d, J = 183.3 Hz),
61.4, 18.8, 13.7.
19F NMR (282 MHz, CDCl3): d = –169.5 (d, J = 45.4 Hz).
MS (EI): m/z (%) = 258 (24) [M]+, 185 (34) [M – CO2Et]+, 165
(100) [M – CO2Et – HF]+.
HRMS (EI): m/z [M]+ calcd for C16H15FO2: 258.1056; found:
258.1054.
19F NMR (282 MHz, CDCl3): d = –179.8 (d, J = 48.2 Hz).
MS (EI): m/z (%) = 196 (12) [M]+, 123 (100) [M – CO2Et]+.
Ethyl 2-(2,6-Dimethylphenyl)-2-fluoroacetate (2u)
IR (thin film): 1754 cm–1.
Ethyl 2-Fluoro-2-(2-methoxyphenyl)acetate (2q)
IR (thin film): 1759 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.03–7.19 (m, 3 H), 6.19 (d,
J = 46.2 Hz, 1 H), 4.20–4.29 (m, 2 H), 2.41 (s, 6 H), 1.25 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 169.1 (d, J = 26.8 Hz), 137.5 (d,
J = 3.3 Hz), 131.1 (d, J = 17.2 Hz), 129.3 (d, J = 0.9 Hz), 129.2 (d,
J = 2.3 Hz), 128.9 (d, J = 1.9 Hz), 128.4, 127.1, 86.0 (d, J = 183.3
Hz), 61.6, 19.8 (d, J = 1.8 Hz), 13.9.
1H NMR (300 MHz, CDCl3): d = 7.36–7.39 (m, 2 H), 6.92–7.02 (m,
2 H), 6.09 (d, J = 47.7 Hz, 1 H), 4.24–4.28 (m, 2 H), 3.86 (s, 3 H),
1.27 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 169.1 (d, J = 27.5 Hz), 157.3 (d,
J = 3.7 Hz), 131.3 (d, J = 3.7 Hz), 129.2 (d, J = 5.2 Hz), 122.9,
120.8 (d, J = 2.2 Hz), 111.2 (d, J = 1.5 Hz), 85.0 (d, J = 181.6 Hz),
61.6, 55.7, 14.1.
19F NMR (282 MHz, CDCl3): d = –183.7 (d, J = 45.4 Hz).
MS (EI): m/z (%) = 210 (20) [M]+, 137 (100) [M – CO2Et]+.
19F NMR (282 MHz, CDCl3): d = –178.6 (d, J = 49.6 Hz).
MS (EI): m/z (%) = 212 (29) [M]+, 139 (87) [M – CO2Et]+, 91 (100).
HRMS (EI): m/z [M]+ calcd for C12H15FO2: 210.1056; found:
210.1053.
HRMS (EI): m/z [M]+ calcd for C11H13FO3: 212.0849; found:
212.0848.
Ethyl 2-Fluoro-2-(6-methoxynaphthalen-2-yl)acetate (2v)22
IR (thin film): 1758 cm–1.
Ethyl 2-Fluoro-2-[2-(trifluoromethyl)phenyl]acetate (2r)
IR (thin film): 1763 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.73–7.86 (m, 3 H), 7.50–7.53 (m,
1 H), 7.13–7.19 (m, 2 H), 5.89 (d, J = 47.4 Hz, 1 H), 4.21–4.28 (m,
2 H), 3.90 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.6 (d, J = 28.2 Hz), 158.3 (d,
J = 1.0 Hz), 134.9 (d, J = 1.4 Hz), 129.6 (d, J = 1.0 Hz), 129.1 (d,
J = 20.8 Hz), 128.2, 127.4, 126.5 (d, J = 7.0 Hz), 124.0 (d, J = 4.6
1H NMR (300 MHz, CDCl3): d = 7.38–7.74 (m, 4 H), 6.16 (d,
J = 47.1 Hz, 1 H), 4.19–4.31 (m, 2 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.8 (d, J = 27.8 Hz), 132.5,
132.4 (t, J = 1.0 Hz), 129.8 (d, J = 2.8 Hz), 128.9, 128.8, 127.3,
Synthesis 2010, No. 11, 1837–1844 © Thieme Stuttgart · New York

1844
C. Guo et al.
SPECIAL TOPIC
Hz), 119.4, 105.5 (d, J = 1.0 Hz), 89.5 (d, J = 183.8 Hz), 61.7, 55.2,
13.9.
19F NMR (282 MHz, CDCl3): d = –177.4 (d, J = 45.1 Hz).
MS (ESI): m/z = 285 [M + Na]+, 301 [M + K]+.
(4) (a) Laurent, E.; Marquet, B.; Tardivel, R.; Thiebault, H.
Tetrahedron Lett. 1987, 28, 2359. (b) Laurent, E.; Marquet,
B.; Tardivel, R. Tetrahedron 1989, 45, 4431. (c) Laurent,
E.; Marquet, B.; Tardivel, R. J. Fluorine Chem. 1990, 49,
115.
(5) (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574. For
reviews, see: (b) Hudlicky, M. Org. React. 1988, 35, 513.
(c) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561.
(6) Rentmeister, A.; Arnold, F. H.; Fasan, R. Nat. Chem. Biol.
2009, 5, 26.
Ethyl 2-(Benzofuran-2-yl)-2-fluoroacetate (2w)
IR (thin film): 1766 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.51–7.63 (m, 2 H), 7.25–7.39 (m,
2 H), 6.95–6.96 (m, 1 H), 5.94 (d, J = 48.0 Hz, 1 H), 4.33–4.38 (m,
2 H), 1.33 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.1 (d, J = 27.6 Hz), 155.3 (d,
J = 1.4 Hz), 148.9 (d, J = 20.9 Hz), 127.2 (d, J = 2.3 Hz), 125.8 (d,
J = 1.5 Hz), 123.3, 121.8 (d, J = 2.2 Hz), 111.8 (d, J = 1.5 Hz),
108.7 (d, J = 5.9 Hz), 82.6 (d, J = 184.7 Hz), 62.4, 14.0.
19F NMR (282 MHz, CDCl3): d = –177.5 (d, J = 49.4 Hz).
MS (EI): m/z (%) = 222 (19) [M]+, 149 (100) [M – CO2Et]+.
HRMS (EI): m/z [M]+ calcd for C12H11FO3: 222.0692; found:
(7) Middleton, W. J.; Bingham, E. M. J. Am. Chem. Soc. 1980,
102, 4845.
(8) (a) Suzuki, T.; Hamashima, Y.; Sodeoka, M. Angew. Chem.
Int. Ed. 2007, 46, 5435. (b) Paull, D. H.; Scerba, M. T.;
Alden-Danforth, E.; Widger, L. R.; Lectka, T. J. Am. Chem.
Soc. 2008, 130, 17260.
(9) (a) Steiner, D. D.; Mase, N.; Barbas, C. F. III Angew. Chem.
Int. Ed. 2005, 44, 3706. (b) Beeson, T. D.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2005, 127, 8826.
(10) For reviews, see: (a) Culkin, D. A.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234. (b) Schlummer, B.; Scholz, U. In
Modern Arylation Methods; Ackermann, L., Ed.; Wiley-
VCH: Weinheim, 2009, Chap. 3.
(11) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 11108. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem.
Soc. 1997, 119, 12382.
(12) (a) Goossen, L. J. Chem. Commun. 2001, 669. (b) Liu,
X.-X.; Deng, M.-Z. Chem. Commun. 2002, 622.
(13) Liu, C.; He, C.; Shi, W.; Chen, M.; Lei, A. Org. Lett. 2007,
9, 5601.
(14) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew. Chem. Int.
Ed. 2007, 46, 3556.
(15) (a) Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A.;
Kumadaki, I. Chem. Pharm. Bull. 1999, 47, 1013. (b) Sato,
K.; Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem.
2004, 125, 509.
(16) For a review, see: (a) Martin, R.; Buchwald, S. L. Acc.
Chem. Res. 2008, 41, 1461. For selected examples, see:
(b) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem. Int. Ed. 2004, 43, 1871. (c) Barder, T.
E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685. (d) Milne, J. E.; Buchwald, S.
L. J. Am. Chem. Soc. 2004, 126, 13028. (e) Han, C.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532.
(f) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L.
Angew. Chem. Int. Ed. 2006, 45, 3484.
222.0696.
Ethyl 2-(Dibenzo[b,d]furan-4-yl)-2-fluoroacetate (2x)
IR (thin film): 1759 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.92–7.99 (m, 2 H), 7.32–7.61 (m,
5 H), 6.40 (d, J = 47.1 Hz, 1 H), 4.25–4.32 (m, 2 H), 1.24 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.2 (d, J = 27.8 Hz), 156.2,
153.7 (d, J = 3.7 Hz), 127.7, 125.9 (d, J = 4.7 Hz), 125.0 (d, J = 0.9
Hz), 123.8, 123.1, 123.0 (d, J = 1.4 Hz), 122.3 (d, J = 2.8 Hz),
120.8, 118.4 (d, J = 20.8 Hz), 111.9, 84.6 (d, J = 183.8 Hz), 62.0,
14.1.
19F NMR (282 MHz, CDCl3): d = –178.5 (d, J = 45.4 Hz).
MS (EI): m/z (%) = 272 (25) [M]+, 199 (100) [M – CO2Et]+.
HRMS (EI): m/z [M]+ calcd for C16H13FO3: 272.0849; found:
272.0846.
Acknowledgment
National Natural Science Foundation of China, and Shanghai Mu-
nicipal Scientific Committee are greatly acknowledged for funding
this work.
References
(17) (a) Billingsley, K. L.; Buchwald, S. L. J. Am. Chem. Soc.
2007, 129, 3358. (b) Knapp, D. M.; Gillis, E. P.; Burke, M.
D. J. Am. Chem. Soc. 2009, 131, 6961.
(1) (a) Lloyd-Jones, G. C. Angew. Chem. Int. Ed. 2002, 41, 953.
(b) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 8410. (c) Moradi, W. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7996.
(2) (a) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. Rev. 2004,
104, 1. (b) Boehm, H.-J.; Banner, D.; Bendels, S.; Kansy,
M.; Kuhn, B.; Mueller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637. (c) Shimizu, M.; Hiyama, T.
Angew. Chem. Int. Ed. 2005, 44, 214. (d) Purser, S.; Moore,
P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008,
37, 320. (e) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(3) Chapman, N. B.; Scrowston, R. M.; Westwood, R. J. Chem.
Soc. C 1967, 528.
(18) (a) Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.;
Huffman, M. A. Org. Lett. 2004, 6, 1465. (b) Dinoiu, V.;
Fukuhara, T.; Miura, K.; Yoneda, N. J. Fluorine Chem.
2003, 121, 227. (c) Fujisawa, H.; Takeuchi, Y. J. Fluorine
Chem. 2002, 117, 173. (d) Lee, S. M.; Roseman, J. M.;
Zartman, C. B.; Morrison, E. P.; Harrison, S. J.; Stankiewicz,
C. A.; Middleton, W. J. J. Fluorine Chem. 1996, 77, 65.
(e) Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1991, 56,
4925.
(19) Watanabe, S.; Fujita, T.; Sakamoto, M.; Endo, H.;
Kitazume, T. J. Fluorine Chem. 1990, 47, 187.
(20) Cavalleri, B.; Cometti, A. Farmaco 1970, 25, 565.
(21) Laurent, E.; Marquet, B.; Tardivel, R. Tetrahedron 1991, 47,
3969.
(22) Fried, J. H.; Harrison, I. T. US 4,001,301, 1977.
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