Cobalt-catalyzed cross-coupling reaction of arylzinc reagents with ethyl bromodifluoroacetate

Article abstract of DOI:10.1016/j.tet.2013.03.041

Transition metal-catalyzed cross-coupling reactions of arylmetal reagents with ethyl bromodifluoroacetate have been explored. After intensive investigations, we have successfully found that a cobalt-catalyzed cross-coupling reaction (catalytic alkoxycarbonyldifluoromethylation) of arylzinc reagents with ethyl bromodifluoroacetate smoothly proceeded to afford the corresponding ethyl aryldifluoroacetates in moderate to good yields.

Full text of DOI:10.1016/j.tet.2013.03.041

Tetrahedron xxx (2013) 1e6
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cobalt-catalyzed cross-coupling reaction of arylzinc reagents with
ethyl bromodifluoroacetate
*
Keisuke Araki, Munenori Inoue
Sagami Chemical Research Institute (SCRI), 2743-1 Hayakawa, Ayase, Kanagawa 252-1193, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Transition metal-catalyzed cross-coupling reactions of arylmetal reagents with ethyl bromodi-
fluoroacetate have been explored. After intensive investigations, we have successfully found that a co-
balt-catalyzed cross-coupling reaction (catalytic alkoxycarbonyldifluoromethylation) of arylzinc
reagents with ethyl bromodifluoroacetate smoothly proceeded to afford the corresponding ethyl
aryldifluoroacetates in moderate to good yields.
Received 27 November 2012
Received in revised form 5 March 2013
Accepted 9 March 2013
Available online xxx
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cobalt-catalyzed
Cross-coupling
Arylzinc reagent
Alkoxycarbonyldifluoromethylation
Ethyl aryldifluoroacetate
1. Introduction
coupling reactions play an important role in the formation of
carbonecarbon bonds in organic synthesis, most of the metal-
Organofluorine compounds have attracted considerable at-
tention from the fields of medicinal chemistry, agricultural
chemistry, and material science because they show unique
chemical, physical, and biological properties.1 Therefore, the se-
lective introduction of a fluorine-containing functional group at
the desired position of organic substrates to synthesize various
kinds of organofluorine compounds is one of the most important
topics in current organic chemistry. Among them, aryldifluoro-
acetic acid derivatives have been known as important biological
active and functionalized compounds2 and, to date, several syn-
thetic methods to prepare aryldifluoroacetic acid derivatives have
been disclosed as follows (Scheme 1): (i) gem-difluorination of
arylglyoxylic acid derivatives with sulfur tetrafluoride (SF4) ana-
logues, such as diethylaminosulfur trifluoride (DAST),3a,b bis(2-
methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor),3c dieth-
ylaminodifluorosulfinium tetrafluoroborate (XtalFluor-E),3d and
4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead),3e (ii)
mediated cross-coupling reactions of difluorohaloacetates with
arylmetal species or halogenated aromatics proceeded in the
presence of stoichiometric amounts of Cu or Cd metals.6 Recently,
(i) gem-difluorination
(ii) electrophilic or
(iii) radical reaction
nucleophilic fluorination
O
F
Br
F
OR'
OR'
OR'
+
R
R
O
R
O
O
SF4
analogues
base, F+
radical initiator
or -e-, F-
F
F
OR'
R
O
Cu or Cd
Co cat.
a
-fluorination of arylacetates with electrophilic or nucleophilic
fluorinating reagents,4 (iii) radical-mediated alkoxycarbonyldi-
fluoromethylation using difluorohaloacetates,5 and (iv) metal-
mediated cross-coupling reaction using difluorohaloacetates or
F
Y
F
F
Br
F
X
ZnCl
TMEDA
OR'
OR'
+
+
R
R
-silyldifluoroacetates.6,7 While transition-metal catalyzed cross-
O
O
a
(X=halogen)
(Y=halogen, TMS)
this work
(iv) metal-mediated
cross-coupling reaction
* Corresponding author. Tel.: þ81 467 77 4208; fax: þ81 467 77 4113.
Scheme 1. Methods for the preparation of aryldifluoroacetic acid derivatives.
e-mail address: inoue@sagami.or.jp (M. Inoue).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.041
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2
K. Araki, M. Inoue / Tetrahedron xxx (2013) 1e6
Table 2
Amii et al. disclosed copper-catalyzed cross-coupling reactions of
aryl iodides with -silyldifluoroacetates and they demonstrated
the conversion of the resulting aryldifluoroacetates to the cor-
responding
-difluorotoluene derivatives.7 While several
methods are available to synthesize aryldifluoroacetic acid de-
rivatives, it is still required to develop a facile method to access to
those compounds. During the course of our development of the
transition-metal catalyzed introduction of a fluorine-containing
functional group to aromatic rings,8 we initiated a project to
develop a novel catalytic alkoxycarbonyldifluoromethylation re-
action.9 Herein, we would like to report a cobalt-catalyzed cross-
coupling reaction of arylzinc reagents 3 with ethyl bromodi-
fluoroacetate (4).
Co-catalyzed cross-coupling reaction of ethyl bromodifluoro-acetate with Grignard
reagents
a
CoCl2
a,a
F
F
F
Br
F
MgBr
(0.05 eq.)
OEt
OEt
+
NMe2
O
X
O
X
NMe2
5a: X=H
5b: X=F
5c: X=OMe
2a: X=H
2b: X=F
2c: X=OMe
4
6 (0.06 eq.)
THF
Entry
AreMgBr
Conditions
Yielda
1
2
3
4
2a (2.4 equiv)
2a (1.3 equiv)
2b (1.3 equiv)
2c (1.3 equiv)
0
0
ꢀC, 5 min; rt, 20 min
ꢀC, dropwise for 30 min; 0 ꢀC, 10 min
rt, dropwise for 2 h; rt, 10 min
rt, dropwise for 2 h; rt, 10 min
34%
70%
71%
42%
2. Results and discussion
a
19F NMR yield (benzotrifluoride was used as an internal standard).
At the beginning, we investigated the cross-coupling reactions
between various phenylmetal species 1ae3a and ethyl bromodi-
fluoroacetate (4) as shown in Table 1. The initial attempts of
alkoxycarbonyldifluoromethylation reactions catalyzed by Pd,10
Fe,11 or Ni12 complexes gave disappointing results, leading to the
formation of trace amounts (<5%) of the expected coupling product
(entries 1e3) even though the corresponding cross-coupling re-
actions with ethyl bromoacetate under the same reaction condi-
tions were reported to proceed in good yield.10e12 Fortunately,
taking advantage of Yorimitsu and Oshima’s procedure,13 the
cobalt-catalyzed cross-coupling reaction14,15 of phenylmagnesium
bromide (2a) with 4 in the presence of cobalt (II) chloride and trans-
1,2-bis(dimethylamino)cyclohexane (6) gave promising results
(entry 4), furnishing the desired ethyl 2,2-difluoro-2-phenylacetate
(5a) in 22% yield (based on 19F NMR).
possessing an electron-withdrawing group produced ethyl 2,2-
difluoro-2-(4-fluorophenyl)acetate (5b) in 71% yield (entry 3),
however, the use of 4-methoxyphenylmagnesium bromide (2c)
having an electron-donating group diminished the yield of ethyl
2,2-difluoro-2-(4-methoxyphenyl)acetate (5c) (42%, entry 4). We
reasoned that the relative high reactivity of 2c may cause side re-
actions such as an addition of the Grignard reagent to the carbonyl
group of ethyl bromodifluoroacetate and the bromineemagnesium
exchange reaction,16 lowering the yield of the desired product.
To avoid these unwanted side reactions, instead of using
Grignard reagents we then explored the Co-catalyzed reaction of
arylzinc reagents14d having low nucleophilicity toward the car-
bonyl group and the bromine atom of 4 (Table 3). The first attempt
using 4-methoxyphenylzinc chloride (3c), prepared from 2c and
zinc chloride, unfortunately did not proceed (entry 1), but any
undesired side reaction was not observed. To enhance the re-
activity of the zinc reagent, N-methyl-2-pyrrolidone (NMP) was
employed as an additive,17 however, the yield was not improved
(entry 2). To our delight, we found that the coupling reaction took
place to produce the desired product 5c in moderate yield when
3ceN,N,N0,N0-tetramethylethylenediamine (TMEDA) complex,
prepared by transmetalation of 2c with ZnCl2eTMEDA complex,
was used as an arylzinc reagent (entry 3).18 After further optimi-
zation (entries 4 and 5), the reaction performed in the presence of
2 equiv of the arylzinc reagent 3ceTMEDA complex at room
temperature afforded the best result, yielding a 79% of 5c.19 Fur-
thermore several amine ligands were explored under the reaction
Table 1
Metal-catalyzed cross-coupling reaction of ethyl bromodifluoro-acetate with phe-
nylmetal species
F
F
F
Br
F
M
Catalyst
OEt
OEt
+
O
Ligand, THF
O
5a
1a: M=B(OH)
2a: M=MgBr
3a: M=ZnCl
4
2
Entry PheM
Catalyst, ligand
Conditions
Yielda
1
1a (1.2 equiv) Pd (OAc)2 (0.03 equiv) rt, 20 h
P (o-Tol)3 (0.09 equiv)
<5%
K2CO3 (5.0 equiv)
2a (1.2 equiv) FeCl3 (0.05 equiv)
TMEDA (1.2 equiv)
3a (2.0 equiv) Ni(acac)2 (0.01 equiv)
PPh3 (0.01 equiv)
2a (1.2 equiv) CoCl2 (0.05 equiv)
6 (0.06 equiv)
2
3
4
0
0
ꢀC, 1 h
<5%
<5%
Table 3
Co-catalyzed cross-coupling reaction of ethyl bromodifluoro-acetate with p-me-
thoxyphenylzinc halides
ꢀC, dropwise
for 30 min; 10 min
0
ꢀC, 5 min; rt, 20 min 22%
CoCl
2
F
F
F
Br
F
ZnX
(0.05 eq.)
OEt
OEt
+
NMe
NMe
2
O
2
MeO
3c (X=Cl)
3c' (X=Br)
O
MeO
6 :
.
NMe
NMe
5c
4
2
2
a
19F NMR yield (benzotrifluoride was used as an internal standard).
6 (0.06 eq.)
Additive, THF
Entry
1
AreZnX
Additive
Conditions
Yielda
Thus, we decided to focus on the cobalt-catalyzed cross-cou-
pling reaction and a further investigation was carried out as
depicted in Table 2. While increasing the amount of the Grignard
reagent to 2.4 equiv raised the yield slightly (entry 1), the yield was
dramatically improved by slow addition of the Grignard reagent to
a mixture of ethyl bromodifluoroacetate (4) and the cobalt catalyst
in THF, leading to produce a 70% yield of 5a (entry 2). Next, we
employed other Grignard reagents under the slow addition con-
dition. The reaction using 4-fluorophenylmagnesium bromide (2b)
3c (1.2 equiv)
3c0 (1.2 equiv)
3c (1.2 equiv)
d
0
ꢀC, dropwise for
30 min; rt, 30 min
ꢀC, dropwise for
30 min; rt, 4 h
ꢀC, dropwise for
5%
2
3
NMP
0
0%
TMEDA
0
33%
30 min; rt, 4 h
rt, 4 h
rt, 4 h
4
5
3c (1.2 equiv)
3c (2.0 equiv)
TMEDA
TMEDA
43% (isolated 50%)
64% (isolated 79%)
a
19F NMR yield (benzotrifluoride was used as an internal standard).
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K. Araki, M. Inoue / Tetrahedron xxx (2013) 1e6
3
condition in entry 5. While 1,10-phenanthroline as a ligand in
i-PrMgCl
THF, -20 ºC;
place of 6 gave a disappointing result (6%), other amine ligands (no
ligand, 1,3-bis(dimethylamino)propane, 1,4-bis(dimethylamino)
butane, or 2,3-bis(dimethylamino)naphthalene) gave moderate
yields (57e70%) of the desired product 5c. We decided that further
investigations would be carried out using the best reaction con-
dition (2 equiv of ArZnCleTMEDA, 1 equiv of 4, 0.05 equiv of CoCl2,
and 0.06 equiv of trans-1,2-bis(dimethylamino)cyclohexane in THF
at rt).
I
ZnCl
TMEDA
MeOOC
MeOOC
ZnCl2-TMEDA
THF, rt
7
3s-TMEDA
complex
F
F
OEt
Br
CF2CO2Et
O
4
With the optimized reaction condition in hand, the substrate
scope was evaluated by using several arylzinc reagent 3eTMEDA
complexes as depicted in Table 4. The developed reaction could
tolerate various functional groups, such as alkyl and phenyl groups,
electron-withdrawing substituents (fluorine, chlorine, and bro-
mine atoms, and trifluoromethyl group), and electron-donating
groups (methoxy, phenoxy, and methylthio groups). The o-
substituted substrate also worked well for this coupling (entry 16).
This method was applicable to prepare ethyl 2,2-difluoro-2-(40-
methoxy-4-biphenylyl)acetate (5k), an important synthetic in-
termediate for the liver X-receptor modulating effector (entry 11).2b
CoCl2 (0.05 eq.), THF
NMe2
MeOOC
5s
(51%)
, rt, 18h
NMe2
6 (0.06 eq.)
Scheme 2. Co-catalyzed cross-coupling reaction of ethyl bromodifluoroacetate with
arylzinc reagent 3s prepared via Knochel direct magnesiation.
3. Conclusion
In summary, we have accomplished the Co-catalyzed cross-
coupling reaction of arylzinc reagents with ethyl bromodi-
fluoroacetate. This method is very mild and applicable to various
arylzinc reagents, having alkyl and phenyl groups, electron-
withdrawing substituents (fluorine, chlorine, and bromine atoms,
trifluoromethyl, and methoxycarbonyl groups), and electron-
donating groups (methoxy, phenoxy, and methylthio groups), to
afford variety of the corresponding ethyl aryldifluoroacetates,
which are important intermediates in the fields of the medicinal,
agricultural, and material sciences.
Table 4
Co-catalyzed cross-coupling reaction of ethyl bromodifluoro-acetate with arylzinc
reagents
R1
R2
R3
R1
R4
CoCl2
ZnCl
TMEDA
+
F
F
F
Br
F
R2
R3
(0.05 eq.)
OEt
OEt
NMe2
O
R4
O
NMe2
6 (0.06 eq.)
THF, r.t.
3-TMEDA
complex
(2.0 eq.)
5
4
4. Experimental
4.1. General methods
Entry
Product
R1
R2
R3
R4
Time
Yield
All reactions involving air- and moisture-sensitive reagents
were carried out using oven-dried glassware and standard
syringe-septum cap techniques. Routine monitoring of reaction
was carried out using glass-supported Merck silica gel 60 F254 TLC
plates. Flash column chromatography was performed on Kanto
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
F
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
22 h
4 h
4 h
74%
70%
79%
70%
73%
59%
54%
48%
72%
57%
68%
50%
69%
58%
79%
61%
69%
MeO
Me
Ph
CF3
Br
Cl
PhO
MeS
16 h
13 h
20 h
16 h
19 h
17 h
19 h
16 h
13 h
16 h
12 h
24 h
14 h
13 h
Chemical Silica Gel 60 N (spherical, neutral 40e50 mm). All sol-
vents and reagents were obtained from commercial suppliers and
were used without further purification. Melting points were
taken on a Mettler Toledo MP70 melting point system and were
uncorrected. 1H, 13C, and 19F NMR spectra were measured with
a Bruker DRX-250 or a Bruker AVANCE III spectrometers. Chem-
ical shifts are expressed in parts per million using tetrame-
9
10
11
12
13
14
15
16
17
p-MeOC6H4
(EtO)2CH
F
F
H
H
H
thylsilane (
d
¼0, 1H NMR) and CFCl3
(
d
¼0, 19F NMR) as standard
MeO
H
MeO
substances. 19F NMR spectra were recorded with 1H decoupling.
Multiplicities are indicated by s (singlet), br s (broad singlet),
d (doublet), br d (broad doublet), t (triplet), br t (broad triplet),
q (quartet), dd (doublet of doublet), br dd (broad doublet of
doublet), dt (doublet of triplet), and m (multiplet). Infrared (IR)
spectral measurements were carried out with a HORIBA FT-720
spectrometer.
MeO
O
O
18
5r
H
H
H
13 h
53%
The cross-coupling reaction of 4-(methoxycarbonyl)phenylzinc
reagent 3seTMEDA complex, prepared via Knochel direct magne-
siation,20 also proceeded in 51% yield (Scheme 2). Unfortunately, all
attempts using alkyl-, alkenyl-, and alkynyl-zinc reagents in place
of arylzinc reagents under the same manner failed. Yorimitsu and
Oshima proposed that cobalt-mediated cross-coupling reactions of
ArMgX with alkyl halides involved an electron transfer (ET) proc-
ess13b and we regarded that our developed reactions also pro-
ceeded via the same reaction mechanism except for the use of
arylzinc reagents.
4.2. General procedure for Co-catalyzed cross-coupling re-
action of ethyl bromodifluoroacetate (4) with arylmagnesium
bromide 2
To a stirred solution of anhydrous cobalt (II) chloride (6.5 mg,
0.050 mmol) in anhydrous THF (3.0 ml) was added trans-1,2-
bis(dimethylamino)cyclohexane (6) (10.2 mg, 0.060 mmol) and
ethyl bromodifluoroacetate (4) (0.13 ml, 1.0 mmol) sequentially at
room temperature under Ar and the resulting mixture was stirred
at room temperature for 5 min. To the resulting mixture was added
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K. Araki, M. Inoue / Tetrahedron xxx (2013) 1e6
dropwise a solution of ArMgBr 2 in anhydrous THF (1.0 M, 1.3 ml,
1.3 mmol) for 2 h at room temperature and the resulting mixture
was stirred at room temperature for 10 min. Benzotrifluoride was
added as an internal standard and the resulting solution was sub-
jected to quantitative analysis by 19F NMR.
d
7.49 (br d, J¼8.3 Hz, 2H), 7.24 (br d, J¼8.3 Hz, 2H), 4.28 (q,
J¼7.3 Hz, 2H), 2.38 (s, 3H), 1.29 (t, J¼7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d
164.3 (t, JCF¼36 Hz), 141.2 (t, JCF¼1.7 Hz), 130.0
(t, JCF¼26 Hz), 124.3 (2C), 125.3 (t, JCF¼5.9 Hz, 2C), 113.5 (t,
JCF¼252 Hz), 63.0, 21.3, 13.8; 19F NMR (376 MHz, CDCl3)
d
ꢂ103.4
(2F); IR (neat) 2987, 2970, 2941, 2929, 1763, 1616, 1516, 1448, 1371,
1300, 1267, 1213, 1188, 1140, 1095, 1028, 1014, 991, 860, 840, 821,
748, 700, 638 cmꢂ1; Anal. Calcd for C11H12F2O2: C, 61.68; H, 5.65.
Found: C, 61.83; H, 5.61.
4.3. General procedure for Co-catalyzed cross-coupling re-
action of ethyl bromodifluoroacetate (4) with arylzinc reagent
3eTMEDA complex
To a stirred suspension of ZnCl2eTMEDA (505 mg, 2.0 mmol) in
anhydrous THF (0.50 ml) was added dropwise a solution of ArMgX
in anhydrous THF or Et2O (2.0 equiv) at 0 ꢀC under Ar and the
resulting mixture was stirred at room temperature for 30 min to
prepare arylzinc reagent 3eTMEDA complex. To a solution of an-
hydrous cobalt (II) chloride (6.5 mg, 0.050 mmol) in anhydrous THF
(3.0 ml) was added trans-1,2-bis(dimethylamino)cyclohexane (6)
(10.2 mg, 0.060 mmol) and ethyl bromodifluoroacetate (4) (0.13 ml,
1.0 mmol) sequentially at room temperature under Ar and the
resulting mixture was stirred at room temperature for 5 min. To this
resulting mixture was added dropwise the above prepared mixture
of arylzinc reagent 3eTMEDA complex in THF at 0 ꢀC and the
resulting mixture was stirred at room temperature for an indicated
reaction time. The reaction mixture was quenched with 13%
aqueous NH4Cl solution (2.0 ml) and extracted with ether
(4.0 mlꢁ3). The extract was washed with water (4.0 ml) and brine
(4.0 ml), then dried over MgSO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by silica gel column
chromatography (hexane/ethyl acetate) to give ethyl 2-aryl-2,2-
difluroacetate 5.
4.3.5. Ethyl 2-(4-biphenylyl)-2,2-difluoroacetate (5e).7a The re-
action was carried out for 13 h according to the general procedure
using 4-biphenylylmagnesium bromide in THF (4.0 ml, 2.0 mmol)
as ArMgX. Colorless oil (201 mg, 73%); 1H NMR (250 MHz, CDCl3)
d
7.72e7.63 (m, 4H), 7.59 (br d, J¼8.0 Hz, 2H), 7.51e7.35 (m, 3H),
4.33 (q, J¼7.5 Hz, 2H), 1.33 (t, J¼7.5 Hz, 3H); 19F NMR (235 MHz,
CDCl3)
d
ꢂ103.9 (2F).
4.3.6. Ethyl 2,2-difluoro-2-[4-(trifluoromethyl)phenyl]acetate (5f).3a
The reaction was carried out for 20 h according to the general
procedure using 4-(trifluoromethyl)phenylmagnesium bromide in
THF (2.3 ml, 2.0 mmol) as ArMgX. Colorless oil (157 mg, 59%);
1H NMR (250 MHz, CDCl3)
d
7.79e7.70 (m, 4H), 4.32 (q, J¼7.3 Hz,
2H), 1.33 (t, J¼7.3 Hz, 3H); 19F NMR (250 MHz, CDCl3)
(3F), ꢂ104.8 (2F).
d
ꢂ63.3
4.3.7. Ethyl 2-(4-bromophenyl)-2,2-difluoroacetate (5g).7a The re-
action was carried out for 16 according to the general
h
procedure using 4-bromophenylmagnesium bromide in THF
(2.0 ml, 2.0 mmol) as ArMgX. Colorless oil (151 mg, 54%); 1H NMR
(250 MHz, CDCl3)
d
7.70e7.40 (m, 4H), 4.30 (q, J¼7.0 Hz, 2H), 1.33 (t,
4.3.1. Ethyl 2,2-difluoro-2-phenylacetate (5a).3b The reaction was
carried out for 22 h according to the general procedure using
phenylmagnesium bromide in THF (2.8 ml, 2.0 mmol) as ArMgX.
J¼7.0 Hz, 3H); 19F NMR (235 MHz, CDCl3)
d
ꢂ104.1 (2F).
4.3.8. Ethyl 2-(4-chlorophenyl)-2,2-difluoroacetate (5h).4b The re-
action was carried out for 19 h according to the general procedure
using 4-chlorophenylmagnesium bromide in Et2O (2.0 ml,
2.0 mmol) as ArMgX. Colorless oil (112 mg, 48%); 1H NMR
Colorless oil (148 mg, 74%); 1H NMR (250 MHz, CDCl3)
d 7.62 (br d,
J¼8.0 Hz, 2H), 7.52e7.44 (m, 3H), 4.31 (q, J¼7.5 Hz, 2H), 1.31
(t, J¼7.5 Hz, 3H); 19F NMR (235 MHz, CDCl3)
d
ꢂ104.2 (2F).
(250 MHz, CDCl3)
d
7.65e7.55 (br d, J¼8.0 Hz, 2H), 7.49e7.44 (br d,
4.3.2. Ethyl 2,2-difluoro-2-(4-fluorophenyl)acetate (5b).3b The re-
action was carried out for 4 h according to the general procedure
using 4-fluorophenylmagnesium bromide in THF (2.0 ml,
2.0 mmol) as ArMgX. Colorless oil (152 mg, 70%); 1H NMR
J¼8.0 Hz, 2H), 4.30 (q, J¼7.0 Hz, 2H), 1.30 (t, J¼7.0 Hz, 3H); 19F NMR
(235 MHz, CDCl3)
d
ꢂ104.1 (2F).
4.3.9. Ethyl 2,2-difluoro-2-(4-phenoxyphenyl)acetate (5i). The re-
action was carried out for 17 h according to the general pro-
cedure using 4-phenoxyphenylmagnesium bromide in THF
(4.0 ml, 2.0 mmol) as ArMgX. Colorless oil (210 mg, 72%);
(250 MHz, CDCl3)
d
7.64 (br dd, J¼8.8 Hz, JHF¼5.3 Hz, 2H), 7.16 (br
dd, J¼8.8 Hz, JHF¼8.8 Hz, 2H), 4.32 (q, J¼7.0 Hz, 2H),1.33 (t, J¼7.0 Hz,
3H); 19F NMR (235 MHz, CDCl3)
d
ꢂ103.6 (d, JFF¼2.8 Hz, 2F), ꢂ109.3
(t, JFF¼2.8 Hz, 1F).
1H NMR (400 MHz, CDCl3)
d
7.56 (br d, J¼8.8 Hz, 2H), 7.38
(br dd, J¼8.5, 7.5 Hz, 2H), 7.17 (br t, J¼7.5 Hz, 1H), 7.06e7.01 (m,
4.3.3. Ethyl 2,2-difluoro-2-(4-methoxyphenyl)acetate (5c). The re-
action was carried out for 4 h according to the general pro-
cedure using 4-methoxyphenylmagnesium bromide in THF
(4.0 ml, 2.0 mmol) as ArMgX. Colorless oil (182 mg, 79%); 1H
4H), 4.31 (q, J¼7.1 Hz, 2H), 1.32 (t, J¼7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d
164.3 (t, JCF¼36 Hz), 160.0 (br s), 155.9, 130.0
(2C), 127.3 (t, JCF¼6.1 Hz, 2C), 127.1 (t, JCF¼26 Hz), 124.3, 119.9
(2C), 118.0 (2C), 113.4 (t, JCF¼252 Hz), 63.1, 13.9; 19F NMR
NMR (400 MHz, CDCl3)
d
7.54 (br d, J¼9.0 Hz, 2H), 6.95 (br d,
(376 MHz, CDCl3)
d
ꢂ102.8 (2F); IR (neat) 2987, 1763, 1589, 1508,
J¼9.0 Hz, 2H), 4.29 (q, J¼7.0 Hz, 2H), 3.84 (s, 3H), 1.31 (t,
1489, 1238, 1199, 1170, 1138, 1095, 1022, 991, 870, 837, 750,
692 cmꢂ1; Anal. Calcd for C16H14F2O3: C, 65.75; H, 4.83. Found:
C, 66.14; H, 5.09.
J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
164.4 (t, JCF¼36 Hz),
161.6 (br s), 127.0 (t, JCF¼5.9 Hz, 2C), 124.9 (t, JCF¼26 Hz), 114.0
(2C), 113.6 (t, JCF¼251 Hz), 63.0, 55.3, 13.8; 19F NMR (376 MHz,
CDCl3)
d
ꢂ102.6 (2F); IR (neat) 2983, 2941, 2910, 2843, 1761,
4.3.10. Ethyl 2,2-difluoro-2-[4-(methylthio)phenyl]acetate (5j). The
reaction was carried out for 19 h according to the general procedure
using 4-(methylthio)phenylmagnesium bromide in THF (2.0 ml,
2.0 mmol) as ArMgX. Colorless oil (141 mg, 57%); 1H NMR
1614, 1587, 1516, 1466, 1444, 1421, 1371, 1290, 1271, 1250, 1178,
1138, 1095, 1032, 1018, 989, 858, 833, 794, 758, 704, 642 cmꢂ1
;
Anal. Calcd for C11H12F2O3: C, 57.39; H, 5.25. Found: C, 57.39; H,
5.25.
(400 MHz, CDCl3)
d
7.50 (d, J¼8.7 Hz, 2H), 7.28 (d, J¼8.7 Hz, 2H),
4.29 (q, J¼7.2 Hz, 2H), 2.50 (s, 3H), 1.30 (t, J¼7.2 Hz, 3H); 13C NMR
4.3.4. Ethyl 2,2-difluoro-2-(4-methylphenyl)acetate (5d). The re-
action was carried out for 16 h according to the general procedure
using p-tolylmagnesium chloride in THF (2.0 ml, 2.0 mmol) as
ArMgX. Colorless oil (150 mg, 70%); 1H NMR (400 MHz, CDCl3)
(100 MHz, CDCl3)
d
164.2 (t, JCF¼36 Hz), 142.8 (br s), 129.1
(t, JCF¼26 Hz), 125.9 (t, JCF¼6.0 Hz, 2C), 125.7 (2C), 113.3 (t,
JCF¼252 Hz), 63.1, 15.1, 13.9; 19F NMR (376 MHz, CDCl3)
d
ꢂ103.6
(2F); IR (neat) 2985, 2924, 1761, 1601, 1495, 1437, 1402, 1371, 1267,
Please cite this article in press as: Araki, K.; Inoue, M., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.041

K. Araki, M. Inoue / Tetrahedron xxx (2013) 1e6
5
1142, 1092, 1011, 989, 822, 762, 739, 690 cmꢂ1; Anal. Calcd for
11H12F2O2S: C, 53.65; H, 4.91. Found: C, 53.59; H, 4.93.
(400 MHz, CDCl3)
d
7.57 (br d, J¼7.5 Hz, 1H), 7.37 (br dd, J¼7.5,
C
7.5 Hz, 1H), 7.27 (br dd, J¼7.5, 7.5 Hz, 1H), 7.23 (br dd, J¼7.5, 7.5 Hz,
1H), 4.32 (q, J¼7.0 Hz, 2H), 2.42 (t, J¼2.2 Hz, 3H), 1.30 (t, J¼7.0 Hz,
4.3.11. Ethyl 2,2-difluoro-2-(40-methoxy-4-biphenylyl)acetate (5k).
The reaction was carried out for 16 h according to the general
procedure using (40-methoxy-4-biphenylyl)magnesium bromide in
THF (10 ml, 2.0 mmol) as ArMgX. White solid (207 mg, 68%); mp
3H); 13C NMR (100 MHz, CDCl3)
d
164.2 (t, JCF¼35 Hz), 136.4 (t,
JCF¼2.9 Hz), 131.9, 131.1 (t, JCF¼24 Hz), 130.8 (br s), 126.1 (t,
JCF¼8.8 Hz), 125.9 (s), 114.3 (t, JCF¼252 Hz), 63.1, 19.7 (t, JCF¼2.6 Hz),
13.9; 19F NMR (376 MHz, CDCl3)
d
ꢂ101.3 (2F); IR (neat) 2985, 2970,
95e98 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.65 (br d, J¼8.9 Hz, 2H), 7.62
2944, 1763, 1608, 1458, 1458, 1448, 1371, 1284, 1252, 1203, 1140,
1080, 1053, 1014, 989, 858, 838, 783, 742, 725, 667 cmꢂ1; Anal.
Calcd for C11H12F2O2: C, 61.68; H, 5.65. Found: C, 61.46; H, 5.59.
(br d, J¼8.9 Hz, 2H), 7.54 (br d, J¼8.8 Hz, 2H), 6.99 (br d, J¼8.8 Hz,
2H), 4.32 (q, J¼7.2 Hz, 2H), 3.86 (s, 3H), 1.32 (t, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
d
164.3 (t, JCF¼35 Hz), 159.8, 143.6 (br s),
132.4,131.0 (t, JCF¼26 Hz),128.3 (2C),126.8 (2C),125.9 (t, JCF¼6.1 Hz,
4.3.17. Ethyl 2-(3,5-dimethoxyphenyl)-2,2-difluoroacetate (5q). The
reaction was carried out for 13 h according to the general procedure
using 3,5-dimethoxyphenylmagnesium bromide in THF (4.8 ml,
2.0 mmol) as ArMgX. Colorless oil (179 mg, 69%); 1H NMR
2C), 114.4 (2C), 113.5 (t, JCF¼252 Hz), 63.1, 55.4, 13.9; 19F NMR
(376 MHz, CDCl3)
d
ꢂ103.5 (2F); IR (neat) 3006, 2842, 1765, 1603,
1581, 1533, 1294, 1265, 1203, 1149, 1120, 1103, 1030, 1012, 989, 825,
809, 766, 719, 694 cmꢂ1; Anal. Calcd for C17H16F2O3: C, 66.66; H,
5.27. Found: C, 66.52; H, 5.19.
(400 MHz, CDCl3)
d
6.73 (d, J¼2.3 Hz, 2H), 6.55 (t, J¼2.3 Hz,1H), 4.30
(q, J¼7.1 Hz, 2H), 3.81 (s, 6H), 1.31 (t, J¼7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d
164.1 (t, JCF¼35 Hz), 161.0 (2C), 134.8 (t,
4.3.12. Ethyl 2-[4-(diethoxymethyl)phenyl]-2,2-difluoroacetate
(5l). The reaction was carried out for 13 h according to the gen-
eral procedure using 4-(diethoxymethyl)phenylmagnesium bro-
mide in THF (4.3 ml, 2.0 mmol) as ArMgX. Colorless oil (151 mg,
JCF¼26 Hz), 113.2 (t, JCF¼252 Hz), 103.5 (t, JCF¼6.4 Hz, 2C), 103.1 (br
s), 63.2, 55.6 (2C), 13.9; 19F NMR (376 MHz, CDCl3)
d
ꢂ103.9 (2F); IR
(neat) 3006, 2943, 2843, 1763, 1599, 1460, 1429, 1354, 1335, 1294,
1205, 1157, 1101, 1059, 1024, 852, 746, 683 cmꢂ1; Anal. Calcd for
50%); 1H NMR (400 MHz, CDCl3)
d
7.63e7.51 (m, 4H), 5.52 (s, 1H),
C12H14F2O4: C, 55.38; H, 5.42. Found: C, 55.25; H, 5.34.
4.29 (q, J¼7.2 Hz, 2H), 3.70e3.50 (m, 4H), 1.30 (t, J¼7.2 Hz, 3H), 1.24
(t, J¼7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
164.2 (t, JCF¼36 Hz),
4.3.18. Ethyl 2-[3-(1,3-dioxolan-2-yl)phenyl]-2,2-difluoroacetate
(5r). The reaction was carried out for 13 h according to the gen-
eral procedure using 3-(1,3-dioxolan-2-yl)phenylmagnesium bro-
mide in THF (2.3 ml, 2.0 mmol) as ArMgX. Colorless oil (144 mg,
142.2 (br s), 132.8 (t, JCF¼26 Hz), 127.1 (2C), 125.4 (t, JCF¼6.1 Hz, 2C),
113.4 (t, JCF¼252 Hz), 101.5, 63.1, 61.3 (2C), 15.2 (2C), 13.9; 19F NMR
(376 MHz, CDCl3)
d
ꢂ103.7 (2F); IR (neat) 2976, 2924, 2879, 1766,
1444, 1392, 1371, 1335, 1267, 1093, 1053, 837, 806 cmꢂ1; Anal. Calcd
for C15H20F2O4: C, 59.59; H, 6.67. Found: C, 59.33; H, 6.50.
53%); 1H NMR (400 MHz, CDCl3)
d 7.74 (br s, 1H), 7.64e7.59 (m, 2H),
7.47 (br dd, J¼7.8, 7.7 Hz, 1H), 5.84 (s, 1H), 4.29 (q, J¼7.2 Hz, 2H),
4.17e4.02 (m, 4H), 1.30 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
4.3.13. Ethyl 2,2-difluoro-2-(4-fluoro-3-methylphenyl)acetate (5m).
The reaction was carried out for 16 h according to the general
procedure using (4-fluoro-3-methylphenyl)magnesium bromide in
THF (2.0 ml, 2.0 mmol) as ArMgX. Colorless oil (160 mg, 69%); 1H
d
164.1 (t, JCF¼35 Hz), 138.9, 133.1 (t, JCF¼26 Hz), 132.2 (br s), 128.8,
126.3 (t, JCF¼6.0 Hz), 123.7 (t, JCF¼6.0 Hz), 113.3 (t, JCF¼252 Hz),
103.0, 65.4 (2C), 63.2,13.9; 19F NMR (376 MHz, CDCl3)
d
ꢂ103.7 (2F);
IR (neat) 2985, 2893, 1763, 1448, 1371, 1284, 1194, 1095, 1076, 1028,
943, 804, 710 cmꢂ1; Anal. Calcd for C13H14F2O4: C, 57.35; H, 5.18.
Found: C, 57.45; H, 5.04.
NMR (400 MHz, CDCl3)
d
7.47e7.38 (m, 2H), 7.07 (dd, J¼8.8, 8.8 Hz,
1H), 4.30 (q, J¼7.1 Hz, 2H), 2.31 (br s, 3H), 1.31 (t, J¼7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3)
d
164.2 (t, J¼26 Hz), 162.8 (dt, JCF¼249,
2.2 Hz),128.9 (dt, JCF¼6.1, 6.1 Hz),128.5 (dt, JCF¼26, 3.5 Hz),125.7 (d,
JCF¼18 Hz), 125.0 (dt, JCF¼8.9, 6.3 Hz), 115.4 (d, JCF¼23 Hz), 113.1 (t,
JCF¼252 Hz), 63.2, 14.6 (d, J¼3.4 Hz), 13.9; 19F NMR (376 MHz,
4.4. Co-catalyzed cross-coupling reaction of ethyl bromodi-
fluoroacetate (4) with (4-methoxycarbonylphenyl)zinc chlo-
ride (3s)eTMEDA complex to synthesize methyl 4-
[(ethoxycarbonyl)difluoromethyl]benzoate (5s)
CDCl3)
d
ꢂ103.0 (d, JFF¼2.6 Hz, 2F), ꢂ113.4 (t, JFF¼2.6 Hz, 1F); IR
(neat) 2987, 2935, 1763, 1601, 1504, 1290, 1263, 1168, 1097, 1032,
991, 823, 754, 651 cmꢂ1; Anal. Calcd for C11H11F3O2: C, 56.90; H,
4.77. Found: C, 56.78; H, 4.69.
To a stirred solution of methyl 4-iodobenzoate (7) (524 mg,
2.0 mmol) in anhydrous THF (4 ml) was added dropwise a solution
of i-propylmagnesium chloride in THF (2.0 M, 1.0 ml, 2.0 mmol) at
ꢂ20 ꢀC under Ar and the resulting mixture was stirred at ꢂ20 ꢀC for
1 h. To the resulting solution of 4-(methoxycarbonyl)phenyl-
magnesium chloride in THF was added ZnCl2eTMEDA (505 mg,
2.0 mmol) and the resulting mixture was stirred at room temper-
ature for 30 min. To a stirred suspension of anhydrous cobalt (II)
chloride (6.5 mg, 0.050 mmol) in anhydrous THF (3.0 ml) was
added trans-1,2-bis(dimethylamino)cyclohexane (6) (10.2 mg,
0.060 mmol) and ethyl bromodifluoroacetate (4) (0.13 ml,
1.0 mmol) sequentially at room temperature under Ar and the
resulting mixture was stirred at room temperature for 5 min. To the
resulting mixture was added dropwise the above prepared solution
of (4-methoxycarbonylphenyl)zinc chloride (3s)eTMEDA complex
in THF at 0 ꢀC and the resulting mixture was stirred at room tem-
perature for 18 h. The reaction mixture was quenched with 13%
aqueous NH4Cl solution (2.0 ml) and extracted with ether
(4.0 mlꢁ3). The extract was washed with water (4.0 ml) and brine
(4.0 ml), then dried over MgSO4. Concentration of the solvent in
vacuo afforded a residue, which was purified by silica gel column
chromatography (hexane/ethyl acetate¼10/1) to give methyl 4-
[(ethoxycarbonyl)difluoromethyl]benzoate (5s) (131 mg, 51%) as
4.3.14. Ethyl 2-(3,4-difluorophenyl)-2,2-difluoroacetate (5n).3a The
reaction was carried out for 12 h according to the general procedure
using 3,4-difluorophenylmagnesium bromide in THF (2.2 ml,
2.0 mmol) as ArMgX. Colorless oil (138 mg, 58%); 1H NMR
(250 MHz, CDCl3)
d
7.53e7.21 (m, 3H), 4.34 (q, J¼7.0 Hz, 2H), 1.34
(t, J¼7.0 Hz, 3H); 19F NMR (235 MHz, CDCl3)
d
ꢂ103.6 (d, J¼2.4 Hz,
2F), ꢂ133.5 (dt, J¼21, 2.4 Hz, 1F), ꢂ135.7 (d, J¼21 Hz, 1F).
4.3.15. Ethyl 2,2-difluoro-2-(3-methoxyphenyl)acetate (5o).2c The
reaction was carried out for 24 h according to the general procedure
using 3-methoxyphenylmagnesium bromide in THF (2.0 ml,
2.0 mmol) as ArMgX. Colorless oil (181 mg, 79%); 1H NMR
(250 MHz, CDCl3)
d
7.35 (dd, J¼8.3, 8.3 Hz, 1H), 7.21e7.10 (m, 2H),
7.01 (br d, J¼8.3 Hz, 1H), 4.30 (q, J¼7.3 Hz, 2H), 3.83 (s, 3H), 1.31
(t, J¼7.3 Hz, 3H); 19F NMR (235 MHz, CDCl3)
d
ꢂ104.0 (2F).
4.3.16. Ethyl 2,2-difluoro-2-(2-methylphenyl)acetate (5p). The re-
action was carried out for 14 h according to the general procedure
using 2-methylphenylmagnesium bromide in THF (2.0 ml,
2.0 mmol) as ArMgX. Colorless oil (131 mg, 61%); 1H NMR
Please cite this article in press as: Araki, K.; Inoue, M., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.041

6
K. Araki, M. Inoue / Tetrahedron xxx (2013) 1e6
5. (a) Murakami, S.; Kim, S.; Ishii, H.; Fuchigami, T. Synlett 2004, 815; (b) Mur-
a colorless oil; 1H NMR (400 MHz, CDCl3)
d
8.12 (d, J¼8.0 Hz, 2H),
akami, S.; Ishii, H.; Tajima, T.; Fuchigami, T. Tetrahedron 2006, 62, 3761; (c)
Ohtsuka, Y.; Yamakawa, T. Tetrahedron 2011, 67, 2323.
7.69 (d, J¼8.0 Hz, 2H), 4.30 (q, J¼7.1 Hz, 2H), 3.95 (s, 3H), 1.30
(t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.1, 163.7
6. (a) Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.; Uehara, H.; Endo, H.;
Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103; (b) Sato, K.; Kawata, R.; Ama, F.;
Omote, M.; Ando, A.; Kumadaki, I. Chem. Pharm. Bull. 1999, 47, 1013; (c)
Ashwood, M. S.; Cottrell, I. F.; Cowden, C. J.; Wallace, D. J.; Davies, A. J.;
Kennedy, D. J.; Dolling, U. H. Tetrahedron Lett. 2002, 43, 9271; (d) Sato, K.;
Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem. 2004, 125, 509; (e) Zhu, J.;
Zhang, W.; Zhang, L.; Liu, J.; Zheng, J.; Hu, J. J. Org. Chem. 2010, 75, 5505.
7. (a) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560; (b)
Fujikawa, K.; Kobayashi, A.; Amii, H. Synthesis 2012, 44, 3015.
(t, JCF¼35 Hz), 137.0 (t, JCF¼26 Hz), 132.6 (br s), 129.9 (2C), 125.7
(t, JCF¼6.0 Hz, 2C), 113.0 (t, JCF¼252 Hz), 63.4, 52.4, 13.8; 19F NMR
(376 MHz, CDCl3)
d
ꢂ104.5 (2F); IR (neat) 2987, 2956, 1765, 1728,
1437, 1410, 1277, 1192, 1099, 1012, 993, 862, 841, 825, 785, 742,
715 cmꢂ1; Anal. Calcd for C12H12F2O4: C, 55.82; H, 4.68. Found: C,
56.00; H, 4.85.
8. Inoue, M.; Araki, K.; Kawada, K. Jpn. Kokai Tokkyo Koho JP 2009234921.
9. (a) Inoue, M.; Araki, K. Jpn. Kokai Tokkyo Koho JP 2010116363. (b) Inoue, M.;
Araki, K. Gekkan Fine Chem. 2011, 40, 40 (in Japanese).
Acknowledgements
10. Gooßen, L. J. Chem. Commun. 2001, 669.
11. Jin, M.; Nakamura, M. Chem. Lett. 2011, 40, 1012.
12. Klingstedt, T.; Frejd, T. Organometallics 1983, 2, 598.
13. (a) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886; (b)
Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62,
2207.
We thank Mrs. A. Sato at A Rabbit Science Co., Ltd. for elemental
analysis.
References and notes
14. For reports on the cobalt-catalyzed cross coupling reactions between
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1. (a) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluo-
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19. One reviewer suggested the possibility of diarylzinc reagents for the coupling
reaction with 4. In the case of using 1.0 equiv of bis(4-methoxyphenyl)zinc,
prepared from 2.0 equiv of (4-methoxyphenyl)magnesium bromide and 1.
0 equiv of ZnCl2eTMEDA, almost the same result as entry 5 in Table 3 was
obtained. This suggestion is helpful to reduce an amount of ZnCl2. Further
experimental results will be disclosed in due course.
€
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€
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Laurent, E.; Marquet, B.; Tardivel, R. J. Fluorine Chem. 1990, 49, 115.
Please cite this article in press as: Araki, K.; Inoue, M., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.03.041