Direct ethoxycarbonyldifluoromethylation of aromatic compounds using Fenton reagent

Article abstract of DOI:10.1016/j.tet.2011.01.049

Direct ethoxycarbonyldifluoromethylation of aromatic compounds by BrCF ₂CO₂Et was investigated using Fenton reagent in dimethylsulfoxide. Various five-membered hetero-aromatic compounds, benzene derivatives and uracil having ethoxyca

Full text of DOI:10.1016/j.tet.2011.01.049

Tetrahedron 67 (2011) 2323e2331
Contents lists available at ScienceDirect
Tetrahedron
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Direct ethoxycarbonyldifluoromethylation of aromatic compounds using Fenton
reagent
*
Yuhki Ohtsuka, Tetsu Yamakawa
Sagami Chemical Research Institute, Catalysis Group, Hayakawa 2743-1, 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:
Direct ethoxycarbonyldifluoromethylation of aromatic compounds by BrCF2CO2Et was investigated using
Fenton reagent in dimethylsulfoxide. Various five-membered hetero-aromatic compounds, benzene de-
rivatives and uracil having ethoxycarbonyldifluoromethyl group were obtained catalytically with the
combination of ferrocene and H2O2 at room temperature. The ethoxycarbonyldifluoromethylation
occurred at the position predicted by the trend of the electrophilic substitution of aromatic compounds.
When para-substituted aniline derivatives were used as a substrate, the one-pot synthesis of 3,3-difluoro-
2,3-dihydroindole-2-one derivatives was achieved through the ethoxycarbonyldifluoromethylation at the
ortho-position to the amino group and the consecutive intramolecular amidation of the amino group and
the adjacent ethoxycarbonyldifluoromethyl group.
Received 6 December 2010
Received in revised form 17 January 2011
Accepted 18 January 2011
Available online 1 February 2011
Keywords:
Ethoxycarbonyldifluoromethylation
Fenton reagent
Ferrocene
Electrophilic radical reaction
3,3-Difluoro-2,3-dihydroindole-2-one
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
1.0 equiv to a substrate.6 Direct ethoxycarbonyldifluoromethylation
of aromatic compounds by an ethoxycarbonyldifluoromethyl radical
Organic compounds possessing fluorine atoms have attracted
much attention in the fields of medicines, agricultural chemicals,
and functional materials.1 Aromatic compounds having alkoxy-
carbonyldifluoromethyl group are important compounds because
they frequently show biologically activity.2 In addition, they can be
used as synthetic intermediates by utilizing the chemical convert-
ibility of the difluoromethylene and alkoxycarbonyl parts to the
other functional groups.3 These compounds are generally and
conveniently synthesized from oxoarylacetate esters by difluori-
was also reported. The reaction of BrCF2CO2Et and PhSeeSePh pro-
vides PhSeeCF2CO2Et from which an ethoxycarbonyldifluoromethyl
radical is generated under photoirradiation.7 The drawback of this
reaction is the high toxicity of selenium. An ethoxycarbonyldi-
fluoromethyl radical is also generated from ClCF2CO2Et in the pres-
ence of Na2S2O4 and NaHCO3. This reaction has the advantage
of proceeding with ClCF2CO2Et, which is less expensive than
BrCF2CO2Et.8
Recently, we found that the radical trifluoromethylation of
various nucleobases, benzene derivatives and five- and six-mem-
bered hetero-aromatic compounds by CF3I was successfully ach-
ieved using the Fenton reagent comprising of FeSO4 or ferrocene
(Cp2Fe) and H2O2 as a catalyst in dimethylsulfoxide (DMSO).9 This
trifluoromethylation can be used in an industrial process, because it
is a simple reaction with the inexpensive materials. Indeed, 5-tri-
fluoromethyluracil (5-TFU) is currently manufactured by this tri-
fluoromethylation of uracil in a one-step process.
We began our investigation at the point that the Fenton reagent
should generate an ethoxycarbonyldifluoromethyl radical from
BrCF2CO2Et. Herein, we report that the Fenton reagent in DMSO
efficiently catalyzed the direct ethoxycarbonyldifluoromethylation
of various aromatic compounds by BrCF2CO2Et. Furthermore,
this report describes the one-pot synthesis of 3,3-difluoro-2,3-
dihydroindole-2-one derivatives from para-substituted aniline
derivatives through ethoxycarbonyldifluoromethylation and con-
secutive intramolecular amidation.
nation of the a-carbonyl carbon of the alkoxal group with (dieth-
ylamino)sulfur trifluoride (DAST).4 However, this difluorination
process is unsuitable for practical use due to the toxic and explosive
nature of DAST. Moreover, the ability of DAST to fluorinate
hydroxyalkyl, acyl, and carboxyl groups restricts usable substrates.5
Direct alkoxycarbonyldifluoromethylation is considered to be an
industrially promising reaction, and it has been explored by some
researchers. In all previously reported reactions, difluorohaloacetate
esters (XCF2CO2R, X¼Br or Cl, and R¼alkyl) or their derivatives were
used as a starting material. The coupling of an aryl iodide and
BrCF2CO2Et proceeds smoothly in the presence of a Cu reagent. Al-
though thiscoupling isverysimple, itrequires a Cureagent more than
* Corresponding author. Tel.: þ81 467769268; fax: þ81 467774113; e-mail
address: t_yamakawa@sagami.or.jp (T. Yamakawa).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.049

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Y. Ohtsuka, T. Yamakawa / Tetrahedron 67 (2011) 2323e2331
2. Results and discussion
an acid was frequently profitable for the reaction.9 In the present
reaction, the addition of an acid retarded the reaction as shown in
Table 2.
2.1. Ethoxycarbonyldifluoromethylation of aromatic
compounds
Table 2
The effect of an acid on ethoxycarbonyldifluoromethylation of 2-acetyl-1-
First, we examined the ethoxycarbonyldifluoromethylation of
2-acetyl-1-methylpyrrole using FeSO4$7H2O; FeSO4 is generally
used in the Fenton reaction because of its cost and availability.10
When a 30% aqueous solution of H2O2 was added dropwise to the
solution of 2-acetyl-1-methylpyrrole, FeSO4$7H2O, and BrCF2CO2Et
in DMSO, followed by stirring at room temperature for 12 h,
only ethyl (5-acetyl-1-methylpyrrol-2-yl)difluoroacetate (1a) was
detected by 19F NMR with 48% yield (Scheme 1).
methylpyrrolea
Entry
Acid
19F NMR yield/%
1
2
3
4
5
6
None
H2SO4
HCl
HBF4
CH3CO2H
CF3CO2H
60
20
11
29
53
30
a
The used amount of an acid is 1.0 mmol. The other reaction conditions were the
same as those in Table 1.
1.0 mmol BrCF2CO2Et
0.15 mmol FeSO4
Further survey of the amount of Cp2Fe, H2O2 and BrCF2CO2Et
used resulted in the 88% yield of 1a. Since the turnover number of
Cp2Fe is 8.8, it is confirmed that Cp2Fe acts as a catalyst. On the
other hand, 1a was not obtained at all from 2-acetyl-1-methyl-
pyrrole using ClCF2CO2Et under the same condition. Chen and co-
workers reported that several benzene derivatives were ethoxy-
carbonyldifluoromethylated by ClCF2CO2Et in the presence of
Na2S2O4 and NaHCO3 despite the low yields.8 It is the disadvantage
of the present ethoxycarbonyldifluoromethylation that less ex-
pensive ClCF2CO2Et cannot be used for the reaction instead of
BrCF2CO2Et.
The results of the ethoxycarbonyldifluoromethylation of various
aromatic compounds examined under the same conditions were
listed in Table 3.
We examined the reactions in Table 3 using FeSO4 and Cp2Fe,
respectively. Interestingly, Cp2Fe gave a higher yield than FeSO4
with all the substrates. This is contrast to the results of tri-
fluoromethylation of aromatic compounds with the Fenton reagent.
Thus, certain substrates preferred FeSO4 to Cp2Fe in the
trifluoromethylation.9
CF2CO2Et
N
N
1.0 mmol H2O2
DMSO (2.5 mL), rt, 12 h
O
O
Me
Me
1a
0.5 mmol
19F NMR yield 48%
Scheme 1.
The selective formation of 1a suggests that the reaction in
Scheme 1 is one of the electrophilic substitution, which generally
occurs on the adjacent carbon of the nitrogen in N-substituted
pyrroles.11 An ethoxycarbonyldifluoromethyl radical should pos-
sess an electrophilic character owing to the electron-withdrawing
nature of fluorine and ethoxycarbonyl group. Taking into account
this character of an ethoxycarbonyldifluoromethyl radical, it is
reasonable to assume that an orientation similar to the electrophilic
substitution of aromatic compounds was observed in Scheme 1. The
trifluoromethylation in which an electrophilic trifluoromethyl
radical participates occurred along with the same orientation as in
Scheme 1; 2-acetyl-1-methyl-5-trifluoromethylpyrrole was selec-
tively obtained from the same substrate.9b
Generally, five-membered hetero-aromatic compounds are
highly reactive in the electrophilic substitution owing to the high
In the trifluoromethylation of 2-acetyl-1-methylpyrrole, Cp2Fe
provided a higher yield than FeSO4.9b When we examined the
ethoxycarbonyldifluoromethylation of 2-acetyl-1-methylpyrrole
with various Fe(II) compounds, Cp2Fe gave a higher yield than the
other inorganic and organic Fe(II) compounds as shown in Table 1.
Although the reason for the availability of Cp2Fe in the reaction
with 2-acetyl-1-methylpyrrole cannot be explained at present, we
believe that the present reaction is one of the rare examples of the
Fenton reaction with Cp2Fe or its derivatives as well as the tri-
fluoromethylation reported previously.9,12
p
-electron density. 5-Acetyl-1-methylpyrrole (entry 1) and 1-phe-
nylpyrrole (entry 2) provided satisfactory yields; these two com-
pounds are particularly reactive in the electrophilic substitution.
Moderate yields were obtained with the other substrates except
entries 6 and 7. 4-Methylpyrazole (entry 6) and 4-phenylimidazole
(entry 7) afforded rather lowyields, suggesting that the 5-position of
these compounds is sterically hindered by the adjacent methyl and
phenyl group, respectively.13 In contrast, 2,4-diphenyloxazole gave
a moderate yield despite the presence of the phenyl group at the 4-
position (entry 8). In the trifluoromethylation using the Fenton
reagent, the yield of 2,4-diphenyl-5-trifluoromethyloxazole from
2,4-diphenyloxazole was also much higher than that of 4-methyl-5-
trifluoromethylpyrazole from 4-methylpyrazole (80% vs 49%).9b We
now consider that certain interactions between Fe(II) and the sub-
strate may be favourable for the reaction though no experimental
evidence supports this claim. With regard to entries 1e7 and 9, the
ethoxycarbonyldifluoromethyl group was selectively introduced to
the 2- or 5-position. Thus, the orientation is certainly explained
based on the trend of the electrophilic substitution of aromatic
compounds.11
Next we optimized the reaction conditions. In the tri-
fluoromethylation by CF3I using the Fenton reagent, the addition of
Table 1
Ethoxycarbonyldifluoromethylation of 2-acetyl-1-methylpyrrole with various Fe(II)
compoundsa
Entry
Fe(II)compound
19F NMR yield/%
1
2
3
4
5
6
7
8
FeSO4$7H2O
Cp2Fe
FeBr2
Fe(BF4)2
Fe(NH4)2(SO4)2$6H2O
Fe(OAc)2
48
60
27
7
6
0
It is noteworthy that the phenyl parts in 2a, 7a, and 8a were not
ethoxycarbonyldifluoromethylated at all.14 This is also consistent
with the trend of the electrophilic substitution because the electron
density of phenyl rings is generally lower than five-membered
hetero-aromatic rings. Similarly, some benzene and pyridine
derivatives afforded very small yields; the latter substrates are
Fe(acac)2
FeCl2$4H2O
25
45
a
The used amounts of Fe(II) compound, 2-acetyl-1-methylpyrrole, BrCF2CO2Et,
and H2O2 were 0.15 mmol, 0.50 mmol, 1.0 mmol, and 1.0 mmol, respectively. All the
reactions were carried out in 2.5 mL of DMSO for 12 h at room temperature.
p-electron deficient as well as benzene derivatives. On the other
hand, the benzene derivatives with an electron-donating group,

Y. Ohtsuka, T. Yamakawa / Tetrahedron 67 (2011) 2323e2331
2325
Table 3
Ethoxycarbonyldifluoromethylation of various aromatic and pseudo-aromatic compoundsa
Entry
1
Product
Isolated
yield/%
Entry
8
Product
Isolated
yield/%
88
55
Ph
N
CF2CO2Et
1a
N
Me
O
Ph
CF2CO2Et
8a
O
2
83
9
61
O
N
CF2CO2Et
2a
N
Ph
N
H
CF2CO2Et
9a
S
3
4
60
63
10
11
34
71
N N
S
CF2CO2Et
3a
S
H2N
Br
CF2CO2Et
10a
NMe2
Br
CF2CO2Et
4a
S
CF2CO2Et
11a
5
6
45
27
12
13
35
61
NHAc
CF2CO2Et
5a
O
Br
CF2CO2Et
12a
Me
OMe
N
N
MeO
CF2CO2Et
13a
CF2CO2Et
6a
N
H
7
14
14
58
Ph
O
H
O
CF2CO2Et
N
CF2CO2Et
7a
N
H
N
H
14a
a
The used amounts of Cp2Fe, a substrate, BrCF2CO2Et, and H2O2 were 0.05 mmol, 0.50 mmol, 1.5 mmol, and 1.0 mmol, respectively. All the reactions were carried out in
2.5 mL of DMSO for 12 h at room temperature.
such as dimethylamino (entry 11), acetoamide (entry 12), and
methoxy (entry 13) group provided moderate yields. Based on the
orientation of the electrophilic substitution, it is reasonable to
assume that the products of 11a and 12a in entries 11 and 12 are
ortho-orientated to the electron-donating groups. The ethoxy-
carbonyldifluoromethylation of uracil, a pseudo-aromatic com-
pound, also occurred selectively at more electronegative 5-position
than 6-position (entry 14) in the same manner as 5-TFU synthesis by
the trifluoromethylation of uracil.9a
substrate. Nevertheless, the choice of Cp2Fe or FeSO4 depended non-
regularly on the substrate in the trifluoromethylation of various
nucleobases and aromatic compounds.9 In contrast, Cp2Fe gave
ahigher yield thanFeSO4 in theethoxydifluoromethylcarbonylation.
Therefore, the role of Cp2Fe seems somewhat complex. Specific in-
teraction between Cp2Fe and BrCF2CO2Et may accelerate the hy-
droxyl radical formation. The detailed investigation is now in
progress.
With regard to the present catalytic ethoxycarbonyldi-
2.2. One-pot synthesis of 3,3-difluoro-2,3-dihydroindole-2-
fluoromethylation,
a
reaction mechanism similar to the tri-
one derivatives
fluoromethylation can be proposed.9a Fig. 1 depicts the speculated
mechanism of the reaction using 2-acetyl-1-methylpyrrole as a sub-
strate. Thus, (i) Fe(II) reduces H2O2 to a hydroxyl radical, (ii) the hy-
droxyl radical is rapidly trapped by the DMSO solvent to form a radical
adduct A, (iii) a methyl radical is generated from A, (iv) the reaction of
BrCF2CO2Et and the methyl radical releases a CF2CO2Et radical, (v) the
CF2CO2Et radical adds to the 2-position of 2-acetyl-1-methylpyrrole to
form a radical species B and (vi) Fe(III) oxidizes B to 1a and is reduced
to Fe(II).
Table 4 shows the results of the ethoxycarbonyldifluoromethy-
lation of the para-substituted aniline derivatives. As predicted from
the orientation of the electrophilic substitution, the ortho-position
to the amino group was ethoxycarbonyldifluoromethylated. In
entries 3e5, it is considered possible that a compound ethox-
ycarbonyldifluoromethylated at two ortho-positions is concomi-
tantly formed. Actually, little such product was detected. The
electron-withdrawing ethoxycarbonyldifluoromethyl group pre-
In step (i), known as the Fenton reaction, the role of a Fe(II)
compound is to generate a hydroxyl radical from H2O2.10 The dif-
ference in the activity of Cp2Fe and FeSO4 would practically depend
on the difference in the ability of hydroxyl radical formation. If so,
either Cp2Fe or FeSO4 should be favourable independent of the
sumably decreases the p-electron density, resulting in the sup-
pression of the second attack of the ethoxycarbonyldifluoromethyl
radical on another ortho-position.
The reactions in Table 4 were carried out for 3 h. In the reactions
for a longer time, another product was detected by 19F NMR. For

2326
Y. Ohtsuka, T. Yamakawa / Tetrahedron 67 (2011) 2323e2331
H2O2
CF2CO2Et
N
Me
Fe(II)
O
+
O
S
H
Fe(III)
Me
Me
CF2CO2Et
OH
-
N
Me
OH
O
B
CF2CO2Et
N
Me
1a
O
OH
O
S
A
Me
Me
Me
Me
MeBr BrCF2CO2Et
CF2CO2Et
O
S
OH
N
Me
O
Fig. 1. Speculated mechanism of ethoxycarbonyldifluoromethylation.
Table 4
Ethoxycarbonyldifluoromethylation of various para-substituted aniline derivativesa
Entry
1
Substrate
Product
Isolated yield/%
44
Cl
Cl
Br
NH2
NH2
Cl
Cl
CF2CO2Et
15a
2
40
Br
NH2
NH2
Me
Me
CF2CO2Et
NH2
16a
3
4
38
31
27
NH2
EtO
EtO
CF2CO2Et
17a
O
O
NH2
NH2
NH2
CF2CO2Et
18a
O
O
5
NH2
NC
NC
CF2CO2Et
19a
a
The used amounts of Cp2Fe, a substrate, BrCF2CO2Et, and H2O2 were 0.1 mmol, 1.0 mmol, 3.0 mmol, and 0.2 mmol, respectively. All the reactions were carried out in 5.0 mL
of DMSO for 3 h at room temperature.
example, a new peak at ꢀ110.6 ppm was found in the 19F NMR
spectrum after the reaction using 2,4-dichloroaniline for 6 h; the
peak of 15a appeared at ꢀ103.1 ppm. This product was isolated and
characterized as 5,7-dichloro-3,3-difluoro-2,3-dihydroindol-2-one
(15b).
occurs through the nucleophilic attack of the lone pair on the
nitrogen of the amino group on the carbonyl carbon in the alkoxy-
carbonylmethyl group.15,16 Considering this reaction, 15b should be
formed from 15a through the intramolecular amidation of the amino
group and the ethoxycarbonyldifluoromethyl group as shown in
Scheme 2.
The intramolecular amidation of (2-aminophenyl)acetate esters
to 2,3-dihydroindole-2-one derivatives is performed in the presence
of an acid15 or a base16 under somewhat severe conditions, for ex-
ample, the reaction in Ref.15 was carried out in 1.0 M HCl at refluxing
temperature. In contrast, the present reaction proceeds under mild
conditions. Moreover, H2O2, which is considered to act as an acid for
the intramolecular amidation, is not so strong acid and is consumed
during the reaction. In the reaction in Scheme 2, the electron-
withdrawing fluorine atoms in the ethoxycarbonyldifluoromethyl
The time course of the formation of 15a and 15b traced by 19F
NMR is illustrated in Fig. 2. The yield of 15a gradually increased
from the start of the reaction and reached 60% at 6 h. At this time,
15b was detected for the first time. After that, the yield of 15a and
15b monotonously decreased and increased, respectively. At 60 h
from the start of the reaction, only 15b was observed with 72%
yield. The behavior of both products clearly indicates the consec-
utive formation of 15b from 15a.
It is known that the intramolecular amidation of (2-amino-
phenyl)acetate esters to 2,3-dihydroindole-2-one derivatives

Y. Ohtsuka, T. Yamakawa / Tetrahedron 67 (2011) 2323e2331
2327
group probably enhance the electrophilicity of the carbonyl carbon,
resulting in the acceleration of the nucleophilic attack of the nitro-
gen in the amino group.
Table 5 lists the yields of the intramolecular amidation of iso-
lated 15ae19a in the presence of various acids or bases. The desired
products were obtained with satisfactory yields in all entries even
at room temperature.
The results in Table 5 suggest that the extra addition of an acid
can accelerate the formation of 15b from 2,4-dichloroaniline via
15a in the reaction shown in Fig. 2; a base that should neutralize
H2O2 is unfit for the extra addition. However, Table 2 reveals that
the addition of an acid is unsuitable for the first ethox-
ycarbonyldifluoromethylation step in Scheme 2. Indeed, when the
reaction was carried out in the presence of 1.0 mmol of H2SO4 at the
start of the reaction, the yield of 15b was only 17% even after 24 h.
Then we focused on the behavior of the formation of 15a and 15b in
Fig. 2. The sum of the yields of 15a and 15b was ca. 70% at 12 h and it
remained at this value thereafter. This behavior implies the
ethoxycarbonyldifluoromethylation in Scheme 2 was completed
after around 12 h. Therefore, the addition of an acid at 12 h from the
start of the reaction should not retard the first step and should
accelerate the second intramolecular amidation step. Then, we
added H2SO4 at 12 h from the start of the reaction and continued
the reaction for another 12 h. As a result, only 15b was successfully
obtained with 73% yield, which is virtually the same as the yield
(72%) obtained at 60 h in Fig. 2. This result prompted us to examine
the one-pot synthesis of 3,3-difluoro-2,3-dihydroindole-2-one de-
rivatives from para-substituted aniline derivatives through the
ethoxycarbonyldifluoromethylation and the addition of H2SO4 in
the middle of the reaction. Table 6 shows the results of the
Fig. 2. Time-course of the yield of 15a (B) and 15b (C). The reaction conditions
except the reaction time are the same as those in Table 4.
Cl
Cl
Cl
H
N
NH2
NH2
O
CF2CO2Et
Cl
Cl
Cl
F
F
15b
15a
Scheme 2.
Table 5
Intramolecular amidation of the ethoxycarbonyldifluoromethylated para-substituted aniline derivatives to 2,3-dihydroindole-2-one derivativesa
Entry
1
Substrate
Product
Acid or base
Isolated yield/%
H2SO4
NEt3
K2CO3
99
98
98
Cl
Cl
H
NH2
N
O
O
Cl
CF2CO2Et
Cl
F
F
15a
15b
2
3
HCl
NEt3
70
81
Br
Br
H
NH2
N
Me
Me
CF2CO2Et
F
F
16a
16b
H2SO4
95
NH2
H
N
EtO
O
CF2CO2Et
EtO
O
F
F
17a
O
17b
18b
19b
4
5
CF3CO2H
98
91
NH2
H
N
O
O
CF2CO2Et
O
F
F
18a
O
CF3CO2H
NH2
H
N
NC
CF2CO2Et
NC
F
F
19a
a
The used amounts of a solvent (DMSO, CH2Cl2 or DMF) and a substrate were 1.0e3.0 mL and 0.2e0.75 mmol, respectively. The ratios of [acid or base]/[substrate] were
2.0e14.4. The reactions were carried out for 6e24 h at room temperature.

2328
Y. Ohtsuka, T. Yamakawa / Tetrahedron 67 (2011) 2323e2331
Table 6
One-pot synthesis of 3,3-difluoro-2,3-dihydroindole-2-one derivativesa
Entry
1
Substrate
Product
Isolated yield/%
72
Cl
Cl
H
N
NH2
O
Cl
Cl
15b
F
F
2
3
4
75
58
43
Br
Br
H
NH2
N
O
Me
Me
F
16b
F
NH2
H
N
EtO
O
EtO
O
17b
F
F
O
NH2
H
N
O
O
18b
F
F
O
5
6
7
8
9
45
50
13
38
21
NH2
NH2
H
N
O
NC
NC
F
19b
F
H
N
O
Cl
O2N
Me
Cl
Cl
20b
F
F
NH2
H
N
O
O2N
Me
Cl
F
21b
F
NHMe
NH2
Me
N
O
F
22b
F
H
N
N
N
O
23b
F
F
a
The used amounts of Cp2Fe, a substrate, BrCF2CO2Et, and H2O2 were 0.1 mmol, 1.0 mmol, 3.0 mmol, and 0.2 mmol, respectively. All the reactions were carried out in 5.0 mL
of DMSO for 24 h at room temperature.
reactions using various para-substituted aniline derivatives as
a substrate. We obtained the products 15be23b despite the
somewhat low yield. The substrates having a protected amino
group (entry 8) or pyridine ring (entry 9) also provided 3,3-
difluoro-2,3-dihydroindole-2-one derivatives despite the low yield,
suggesting that the present one-pot reaction can be applied to
a wide variety of substrates.
3,3-Difluoro-2,3-dihydroindole-2-one derivatives are known to
be biologically active17 and are generally synthesized from 1H-in-
dole-2,3-dione derivatives by fluorination with DAST.4,18 Since the
syntheses of 1H-indole-2,3-dione derivatives require the several
steps from aniline derivatives,19 our synthetic method is superior to
this method not only because of the safety and versatility consid-
erations, as described in Introduction, but also because of its rela-
tive simplicity.
3. Conclusion
Here we presented the direct ethoxycarbonyldifluoromethylation
of various aromatic compounds by BrCF2CO2Et using the Fenton re-
agent as a catalyst in DMSO. Of the Fe(II) compounds tested, Cp2Fe
showed the highest catalytic activity. The selectivity of a product was
predicted by the general trend of the electrophilic substitution of
aromatic compounds, indicating that an electrophilic ethoxy-
carbonyldifluoromethyl radical participates in the reaction. More-
over, 3,3-difluoro-2,3-dihydroindole-2-one derivatives were
successfully synthesized from the corresponding para-substituted
aniline derivatives in the one-pot reaction. The present catalytic re-
action isa simple procedure, thatis, carried out under mild conditions
with inexpensive materials; therefore, it should serve as a promising
process for the synthesis of fluorinated organic compounds.

Y. Ohtsuka, T. Yamakawa / Tetrahedron 67 (2011) 2323e2331
2329
4. Experimental
1666, 1383, 1300, 1240, 1184, 1101, 1016, 904, 779, 746 cmꢀ1. HRMS:
calcd for C11H13F2NO3 (MþHþ): 246.0936; found: m/z 246.0945.
4.1. General techniques
4.3.2. Ethyl (1-phenylpyrrole-2-yl)difluoroacetate (2a). Pale yellow
1H,13C, and 19F NMR spectra were recorded in CDCl3, DMSO-d6 or
CD3CO2D using Bruker DRX-500 (1H 500 MHz, 13C 125 MHz) and
DRX-250 (19F 235 MHz) spectrometers using tetramethylsilane as an
internal reference for 1H and 13C NMR and fluorotrichloromethane
as an external reference for 19F NMR. Chemical shifts were expressed
oil. 1H NMR (CDCl3)
d
1.21 (3H, t, J¼7.1 Hz), 4.14 (2H, q, J¼7.1 Hz),
6.26e6.29 (1H, m), 6.61e6.64 (1H, m), 6.85e6.88 (1H, m),
7.34e7.45 (5H, m). 13C NMR (CDCl3)
13.7, 63.0, 108.4, 110.7 (t,
d
JCF¼246.0 Hz), 112.9 (t, JCF¼5.2 Hz), 124.3 (t, JCF¼30.0 Hz), 126.9,
127.2, 128.3, 128.8, 139.3, 163.1 (t, JCF¼34.0 Hz). 19F NMR (DMSO-d6)
in parts per million (
d
). Multiplicties were indicated by s (singlet), br
d
ꢀ90.9. IR 1763, 1500, 1302, 1257, 1092, 1070, 1036, 939, 768, 731,
s (broad singlet), d (doublet), t (triplet), q (quartet), and m (multi-
plet). 19F NMR yields were calculated with 2,2,2-trifluoroethanol as
an internal standard. The IR, high-resolution mass spectroscopy
(HRMS), and melting point (mp) measurements were carried out
using HORIBA FT-720, Waters LCT Premier XE, and Stanford Research
Systems MPA100, respectively. IR spectra were obtained in the re-
flective mode. All the commercially available reagents were used
without further purification.
696 cmꢀ1. EI-MS: calcd for C14H13F2NO2 (M): 265.091; found: m/z
265. Full characterization is shown in Ref. 7b.
4.3.3. Ethyl (thiophene-2-yl)difluoroacetate (3a). Colorless oil. 1H
NMR (CDCl3)
d
1.36 (3H, t, J¼7.1 Hz), 4.37 (2H, q, J¼7.1 Hz), 7.04e7.10
(1H, m), 7.37e7.42 (1H, m), 7.46e7.51 (1H, m). 13C NMR (CDCl3)
d
13.8, 63.4, 110.7 (t, JCF¼250.4 Hz), 127.1, 128.4 (t, JCF¼5.6 Hz), 129.0
(t, JCF¼1.5 Hz), 134.0 (t, JCF¼30.1 Hz), 163.3 (t, JCF¼35.1 Hz). 19F NMR
(DMSO-d6)
d
ꢀ90.8. EI-MS: calcd for C8H8F2O2S (M): 206.021;
4.2. General procedure
found: m/z 206. Full characterization is shown in Ref. 3b.
4.2.1. Ethoxycarbonyldifluoromethylation of aromatic compounds. A
4.3.4. Ethyl (5-bromothiophene-2-yl)difluoroacetate (4a). Colorless
substrate (0.5 mmol), Cp2Fe (9.3 mg, 0.05 mmol), BrCF2CO2Et (194
mL,
oil. 1H NMR (DMSO-d6)
d
1.27 (3H, t, J¼7.1 Hz), 4.37 (2H, q, J¼7.1 Hz),
1.5 mmol), and DMSO (2.5 mL) were charged in a two-neck flask in Ar
atmosphere. Then, a 30% aqueous solution of H2O2 (0.10 mL, H2O2
1.0mmol)wasadded continuouslyover 2.5min. Thereactionmixture
was stirred at room temperature for 12 h. The reaction mixture was
poured into H2O and the product was extracted to ethyl acetate. The
ethyl acetate layer was washed with a saturated aqueous solution of
NaCl, dried with Na2SO4, and then concentrated under vacuo. The
product was isolated using silica gel chromatography.
7.32e7.35 (1H, m), 7.36e7.39 (1H, m). 13C NMR (DMSO-d6)
d
13.7,
64.2, 110.9 (t, JCF¼249.6 Hz), 116.8, 130.5 (t, JCF¼5.9 Hz), 131.3, 134.0
(t, JCF¼30.2 Hz), 162.0 (t, JCF¼34.2 Hz). 19F NMR (DMSO-d6)
ꢀ91.6.
d
IR 1765, 1431, 1290, 1232, 1093, 1011, 978, 802, 750 cmꢀ1. EI-MS:
calcd for C8H7BrF2O2S (M): 283.932; found: m/z 284. HRMS and
elementary analysis showed little reliability probably due to high
volatility and/or low thermal and chemical stability.
4.3.5. Ethyl (benzo[b]furane-2-yl)acetate (5a). Pale yellow oil. 1H
4.2.2. Intramolecular amidation of ethyl (2-aminophenyl)difluoro-
acetate. The synthetic procedure of 5,7-dicholoro-3,3-difluoro-2,3-
dihydroindole-2-one is used as an example hereinafter. Ethyl
(2-amino-3,5-dicholorophenyl)difluoroacetate (0.75 mmol) and
DMSO solution of H2SO4 (1.0 M, 1.5 mL) were charged in a two-neck
flask in Ar atmosphere. The mixture was stirred at room temperature
for 12 h. The reaction mixture was poured into H2O and the product
was extracted to ethyl acetate. The ethyl acetate layer was washed
with a saturated aqueous solution of NaCl, dried with Na2SO4, and
then concentrated under vacuo. The product was isolated using silica
gel chromatography.
NMR (DMSO-d6)
7.35e7.40 (1H, m), 7.46e7.51 (1H, m), 7.54 (1H, s), 7.70e7.74 (1H,
m), 7.76e7.80 (1H, m). 13C NMR (DMSO-d6)
13.8, 64.3, 109.0 (t,
d
1.28 (3H, t, J¼7.1 Hz), 4.41 (2H, q, J¼7.1 Hz),
d
JCF¼247.5 Hz), 109.3 (t, JCF¼4.1 Hz), 112.1, 122.9, 124.3, 126.2, 127.2,
145.4 (t, JCF¼32.1 Hz), 154.9, 161.4 (t, JCF¼32.6 Hz). 19F NMR (DMSO-
d6)
d
ꢀ102.4. IR 1766, 1290, 1254, 1169, 1101, 1026, 827, 746 cmꢀ1. EI-
MS: calcd for C12H10F2O3 (M): 240.060; found: m/z 240. HRMS and
elementary analysis showed little reliability probably due to high
volatility and/or low thermal and chemical stability.
4.3.6. Ethyl difluoro(4-methylpyrazole-5-yl)acetate (6a). Pale yellow
oil.1H NMR (DMSO-d6)
d
1.25 (3H, t, J¼7.1 Hz), 2.10 (3H, s), 4.33 (2H, q,
4.2.3. One-pot synthesis of 3,3-difluoro-2,3-dihydroindole-2-one
derivatives. A substrate (1.0 mmol), Cp2Fe (19 mg, 0.1 mmol),
J¼7.1 Hz), 7.67 (1H, s), 13.06 (1H, br s). 13C NMR (DMSO-d6)
d 8.1, 13.9,
63.2,112.9 (t, JCF¼243.3 Hz),114.0,130.0,141.9(t, JCF¼26.4Hz),163.3(t,
BrCF2CO2Et (388
mL, 3.0 mmol), and DMSO (5.0 mL) were charged in
JCF¼32.6 Hz). 19F NMR (DMSO-d6)
ꢀ98.7. IR 3172, 2939, 1763, 1296,
d
a two-neck flask in Ar atmosphere. Then, a 30% aqueous solution of
H2O2 (0.20 mL, H2O2 2.0 mmol) was added continuously over 5 min.
The reaction solution was stirred at room temperature for 12 h.
After adding 2.0 mL of DMSO solution of H2SO4 (1.0 M) to the re-
action mixture, the mixture was stirred for another 24 h at room
temperature. The reaction mixture was poured into H2O and the
product was extracted to ethyl acetate. The ethyl acetate layer was
washed with a saturated aqueous solution of NaCl, dried with
Na2SO4, and then concentrated under vacuo. The product was
isolated using silica gel chromatography.
1250, 1080, 1014, 835, 818, 773, 739 cmꢀ1. HRMS: calcd for
C8H10F2N2O2 (MþHþ): 205.0783; found: m/z 205.0791.
4.3.7. Ethyl difluoro(4-phenylimidazole-5-yl)acetate (7a). White
solid. Mp 149 ꢁC (dec). 1H NMR (DMSO-d6)
d
1.18 (3H, t, J¼7.1 Hz),
4.23 (2H, q, J¼7.1 Hz), 7.38e7.43 (1H, m), 7.44e7.50 (2H, m),
7.51e7.56 (2H, m), 7.81 (1H, s), 13.00 (1H, br s). 13C NMR (CD3CO2D)
d
13.9, 64.3, 112.4 (t, JCF¼246.6 Hz), 127.2 (t, JCF¼30.5 Hz), 129.5,
129.6, 129.8, 130.1, 133.8, 137.6, 164.1 (t, JCF¼33.8 Hz). 19F NMR
(DMSO-d6)
d
ꢀ94.9. IR 1751, 1493, 1469, 1298, 1130, 1088, 1059, 953,
777, 700, 658 cmꢀ1. HRMS: calcd for C13H12F2N2O2 (MþHþ):
267.0945; found: m/z 267.0943.
4.3. Characterization of products
4.3.1. Ethyl (5-acetyl-1-methylpyrrole-2-yl)difluoroacetate (1a).
4.3.8. Ethyl difluoro(2,4-diphenyloxazole-5-yl)acetate (8a). White
Colorless oil. 1H NMR (DMSO-d6)
d
1.26 (3H, t, J¼7.1 Hz), 2.43 (3H, s),
solid. Mp 47.3e48.8 ꢁC. 1H NMR (DMSO-d6)
d
1.16 (3H, t, J¼7.1 Hz),
4.29 (2H, q, J¼7.1 Hz), 7.50e7.56 (3H, m), 7.58e7.64 (3H, m),
7.68e7.72 (2H, m), 8.03e8.07 (2H, m). 13C NMR (DMSO-d6)
13.6,
3.89 (3H, s), 4.39 (2H, q, J¼7.1 Hz), 6.51 (1H, d, J¼4.3 Hz), 7.12 (1H, d,
J¼4.3 Hz). 13C NMR (DMSO-d6)
d
13.8, 28.0, 34.4, 64.2, 110.7 (t,
d
JCF¼247.4 Hz), 111.0 (t, JCF¼5.5 Hz),118.4,129.3 (t, JCF¼28.8 Hz), 133.9,
64.4, 109.1 (t, JCF¼247.9 Hz), 125.5, 126.8, 128.4, 128.8, 129.3, 129.5,
162.1 (t, JCF¼33.5 Hz), 189.8. 19F NMR (DMSO-d6)
d
ꢀ97.7. IR 1765,
129.8, 132.1, 135.6 (t, JCF¼34.2 Hz), 142.3 (t, JCF¼2.4 Hz), 161.1 (t,

2330
Y. Ohtsuka, T. Yamakawa / Tetrahedron 67 (2011) 2323e2331
JCF¼34.0 Hz),161.4. 19F NMR (DMSO-d6)
d
ꢀ99.1. IR 1770,1450,1365,
HRMS: calcd for C10H9Cl2F2NO2 (MþHþ): 284.0057; found: m/z
1286, 1084, 953, 781, 715, 688 cmꢀ1. HRMS: calcd for C19H15F2NO3
284.0063.
(MþHþ): 344.1098; found: m/z 344.1094.
4.3.16. Ethyl 2-(2-amino-3-bromo-5-methylphenyl)-2,2-difluoroace-
4.3.9. Ethyl (2-acetoamidethiazole-5-yl)difluoroacetate (9a). White
tate (16a). Pale yellow oil. 1H NMR (DMSO-d6)
d
1.21 (3H, t,
J¼7.1 Hz), 2.20 (3H, s), 4.31 (2H, q, J¼7.1 Hz), 4.96 (2H, br s),
7.13e7.16 (1H, m), 7.46e7.49 (1H, m). 13C NMR (DMSO-d6)
13.8,
solid. Mp 142.7e144.2 ꢁC. 1H NMR (DMSO-d6)
d
1.27 (3H, t,
J¼7.1 Hz), 2.17 (3H, s), 4.37 (2H, q, J¼7.1 Hz), 7.83 (1H, s), 12.54 (1H,
br s). 13C NMR (DMSO-d6)
13.8, 22.5, 64.1, 111.8 (t, JCF¼248.1 Hz),
d
d
19.5, 63.7, 110.6, 113.8 (t, JCF¼250.6 Hz), 116.4 (t, JCF¼23.5 Hz), 126.1
120.7 (t, JCF¼29.1 Hz), 139.9 (t, JCF¼6.6 Hz), 161.1, 162.4 (t,
(t, JCF¼8.1 Hz), 127.1, 136.0, 143.0 (t, JCF¼2.9 Hz), 163.2 (t,
JCF¼34.4 Hz), 169.5. 19F NMR (DMSO-d6)
d
ꢀ90.6. IR 2922, 1766,
JCF¼34.8 Hz). 19F NMR (DMSO-d6)
d
ꢀ102.6. IR 3491, 3394, 1759,
1693, 1562, 1535, 1248, 1173, 1119, 1086, 999, 957, 746 cmꢀ1. HRMS:
1628, 1479, 1298, 1257, 1092, 1038, 866, 748, 700 cmꢀ1. HRMS: calcd
calcd for C9H10F2N2O3S (MþHþ): 265.0458; found: m/z 265.0465.
for C11H12BrF2NO2 (MþHþ): 308.0098; found: m/z 308.0104.
4.3.10. Ethyl (5-amino-1,3,4-thiadiazole-2-yl)difluoroacetate (10a).
4.3.17. Ethyl 2-(2-amino-4-ethoxycarbonylphenyl)-2,2-difluoroace-
tate (17a). Pale yellow solid. Mp 80.5e82.3 ꢁC. 1H NMR (DMSO-d6)
Yellow solid. Mp 172 ꢁC (dec). 1H NMR (DMSO-d6)
d 1.27 (3H, t,
J¼7.1 Hz), 4.38 (2H, q, J¼7.1 Hz), 7.91 (2H, br s). 13C NMR (DMSO-d6)
d
1.23 (3H, t, J¼7.1 Hz),1.27 (3H, t, J¼7.1 Hz), 4.23 (2H, q, J¼7.1 Hz), 4.33
(2H, q, J¼7.1 Hz), 6.08 (2H, br s), 6.81e6.85 (1H, m), 7.74e7.81 (2H, m).
13C NMR (DMSO-d6)
13.8, 14.4, 60.3, 63.7, 112.9 (t, JCF¼24.1 Hz), 114.3
d
13.8, 64.2, 110.2 (t, JCF¼248.2 Hz), 148.2 (t, JCF¼31.0 Hz), 161.2 (t,
JCF¼31.7 Hz),171.6. 19F NMR (DMSO-d6)
d
ꢀ94.9. IR 3271, 3087,1635,
d
1398, 1267, 1119, 1093, 1066, 995, 812, 760 cmꢀ1. HRMS: calcd for
(t, JCF¼250.3 Hz),116.5,116.7,128.4 (t, JCF¼8.2 Hz),133.2,150.4,163.2 (t,
C6H7F2N3O2S (MþHþ): 224.0305; found: m/z 224.0309.
JCF¼35.0 Hz), 165.2. 19F NMR (DMSO-d6)
ꢀ103.0. IR 3469, 3367, 1751,
d
1697,1649,1614,1510,1369,1288,1271,1227,1093,1016, 758, 675 cmꢀ1
.
4.3.11. Ethyl 2-(4-bromo-2-dimethylaminophenyl)-2,2-difluoroacetate
HRMS: calcd for C13H15F2NO4 (MþHþ): 288.1047; found: m/z288.1059.
(11a). Colorless oil. 1H NMR (DMSO-d6)
d
1.21 (3H, t, J¼7.1 Hz), 2.47
(6H, s), 4.25 (2H, q, J¼7.1 Hz), 7.49e7.53 (1H, m), 7.76e7.80 (2H, m).
13C NMR (DMSO-d6)
14.0, 45.0, 62.5, 111.8 (t, JCF¼246.7 Hz), 117.9,
4.3.18. Ethyl 2-(4-acetyl-2-aminophenyl)-2,2-difluoroacetate (18a).
d
Pale yellow solid. Mp 93.5e95.0 ꢁC. 1H NMR (DMSO-d6)
d
1.23 (3H, t,
J¼7.1 Hz), 2.43 (3H, s), 4.32 (2H, q, J¼7.1 Hz), 6.11 (2H, br s),
6.80e6.85 (1H, m), 7.77e7.84 (2H, m). 13C NMR (DMSO-d6)
13.8,
126.1, 128.5 (t, JCF¼6.9 Hz), 132.3 (t, JCF¼23.9 Hz), 135.6, 151.8 (t,
JCF¼4.9 Hz), 162.7 (t, JCF¼32.4 Hz). 19F NMR (DMSO-d6)
d
ꢀ97.7. IR
d
1770, 1487, 1255, 1232, 1088, 1065, 1024, 941, 741, 675 cmꢀ1. HRMS:
26.0, 63.7, 112.9 (t, JCF¼24.1 Hz), 114.3 (t, JCF¼250.3 Hz), 116.2, 125.0,
calcd for C12H14BrF2NO2 (MþHþ): 322.0254; found: m/z 322.0239.
127.6 (t, JCF¼8.0 Hz), 132.8, 150.5, 163.3 (t, JCF¼35.1 Hz), 195.0. 19
F
NMR (DMSO-d6)
d
ꢀ102.8. IR 3475, 3357, 1749, 1649, 1593, 1510,
4.3.12. Ethyl 2-(2-acetylamino-4-bromophenyl)-2,2-difluoroacetate
1360, 1290, 1219, 1072, 1018, 823, 613 cmꢀ1. HRMS: calcd for
(12a). Pale yellow solid. Mp 97.5e98.7 ꢁC 1H NMR (DMSO-d6)
d
1.16
(3H, t, J¼7.1 Hz), 1.96 (3H, s), 4.21 (2H, q, J¼7.1 Hz), 7.28e7.33 (1H,
m), 7.76e7.81 (2H, m), 9.49 (1H, br s). 13C NMR (DMSO-d6)
13.7,
C12H13F2NO3 (MþHþ): 258.0942; found: m/z 258.0939.
d
4.3.19. Ethyl 2-(2-amino-4-cyanophenyl)-2,2-difluoroacetate (19a).
22.9, 63.6, 112.0 (t, JCF¼250.1 Hz), 119.0, 128.7 (t, JCF¼8.4 Hz), 130.6
Pale yellow oil. 1H NMR (DMSO-d6)
d
1.22 (3H, t, J¼7.1 Hz), 4.32 (2H,
q, J¼7.1 Hz), 6.24 (2H, br s), 6.84e6.89 (1H, m), 7.55e7.62 (2H, m).
13C NMR (DMSO-d6)
13.8, 63.9, 96.8, 113.6 (t, JCF¼250.9 Hz), 113.7
(t, JCF¼23.5 Hz), 131.7, 134.9, 135.1, 162.5 (t, JCF¼33.8 Hz), 169.4. 19
F
NMR (DMSO-d6)
d
ꢀ99.5. IR 3311,1770,1660,1522,1302,1221,1095,
d
1016, 829, 654 cmꢀ1. HRMS: calcd for C12H12BrF2NO3 (MþHþ):
336.0047; found: m/z 336.0052.
(t, JCF¼24.4 Hz), 117.2, 119.5, 131.3 (t, JCF¼8.4 Hz), 135.5, 150.1, 162.8
(t, JCF¼34.8 Hz). 19F NMR (DMSO-d6)
d
ꢀ103.1. IR 3492, 3384, 2222,
1755, 1635, 1614, 1506, 1304, 1257, 1095, 1022, 829 cmꢀ1. HRMS:
4.3.13. Ethyl 2-(2,5-dimethoxyphenyl)-2,2-difluoroacetate (13a).
calcd for C11H10F2N2O2 (MþHþ): 241.0789; found: m/z 241.0786.
Colorless oil. 1H NMR (CDCl3)
d
1.31 (3H, t, J¼7.1 Hz), 3.76 (3H, s),
3.81 (3H, s), 4.33 (2H, q, J¼7.1 Hz), 6.86e6.90 (1H, m), 6.96e7.00
(1H, m), 7.19e7.21 (1H, m). 13C NMR (CDCl3)
13.8, 55.7, 56.3, 62.6,
4.3.20. 5,7-Dichloro-3,3-difluoro-2,3-dihydroindole-2-one
(15b). Pale yellow solid. Mp 145 ꢁC (dec). 1H NMR (DMSO-d6)
d
111.8 (t, JCF¼7.7 Hz), 112.0 (t, JCF¼248.6 Hz), 112.9, 117.3, 122.7(t,
d
7.80e7.83 (1H, m), 7.86e7.89 (1H, m), 11.83 (1H, br s). 13C NMR
JCF¼23.9 Hz), 150.7(t, JCF¼5.1 Hz), 153.5, 163.8(t, JCF¼33.8 Hz). 19F
(DMSO-d6)
d
110.5 (t, JCF¼250.9 Hz), 117.1, 122.1 (t, JCF¼23.5 Hz),
NMR (DMSO-d6)
d
ꢀ101.0. IR 1774,1502,1281,1211, 1101, 1082, 1041,
124.2, 128.1, 133.5, 139.8 (t, JCF¼7.5 Hz), 165.7 (t, JCF¼29.1 Hz). 19F
1018, 812, 715 cmꢀ1
.
HRMS: calcd for C12H14F2O4 (MþHþ):
NMR (DMSO-d6)
d
ꢀ110.6. IR 3197, 1761, 1624, 1464, 1271, 1188,
261.0938; found: m/z 261.0919.
1092, 874, 837, 737, 700 cmꢀ1. HRMS: calcd for C8H3Cl2F2NO
(MꢀHþ): 235.9481; found: m/z 235.9506.
4.3.14. Ethyl (2,4-dioxo-1,2,3,4-tetrahydropyrinidine-5-yl)difluoroace-
tate (14a). White solid. Mp 211 ꢁC(dec).1HNMR(DMSO-d6)
d
1.20 (3H,
t, J¼7.1 Hz), 4.25(2H, q, J¼7.1 Hz), 7.29 (1H, s),11.52 (1H, br s),11.57 (1H,
br s). 13C NMR (DMSO-d6)
13.8, 63.1, 105.6 (t, JCF¼25.0 Hz), 111.7 (t,
4.3.21. 7-Bromo-3,3-difluoro-2,3-dihydro-5-methylindole-2-one
(16b). Pale yellow solid. Mp 139 ꢁC (dec). 1H NMR (DMSO-d6)
d
2.29
d
(3H, s), 7.51 (1H, s), 7.57 (1H, s), 11.42 (1H, br s). 13C NMR (DMSO-d6)
JCF¼246.3 Hz),142.6 (t, JCF¼7.4 Hz),150.9,161.7 (t, JCF¼4.3 Hz),162.4 (t,
d
20.1, 103.8, 111.4 (t, JCF¼249.5 Hz), 121.0 (t, JCF¼23.1 Hz), 124.7, 135.1,
JCF¼33.7 Hz). 19F NMR (DMSO-d6)
d
ꢀ102.9. IR 3109, 2999, 2933, 1751,
136.9, 139.6 (t, JCF¼7.6 Hz), 166.0 (t, JCF¼29.3 Hz). 19F NMR (DMSO-d6)
1645,1516,1448,1315,1284,1074,1020, 777, 677cmꢀ1. HRMS:calcdfor
d
ꢀ110.1. IR 3192, 1761, 1626, 1481, 1298, 1192, 1080, 1036, 791, 762, 737,
C8H8F2N2O4 (MþHþ): 235.0530; found: m/z 235.0513.
696 cmꢀ1.HRMS:C9H7F2NOBr(MþHþ):261.9679;found:m/z261.9702.
4.3.15. Ethyl
(15a). Pale yellow oil. 1H NMR (DMSO-d6)
4.33 (2H, q, J¼7.1 Hz), 5.43 (2H, br s), 7.28e7.31 (1H, m), 7.63e7.66
(1H, m). 13C NMR (DMSO-d6)
13.7, 64.0, 113.0 (t, JCF¼251.8 Hz),
2-(2-amino-3,5-dichlorophenyl)-2,2-difluoroacetate
4.3.22. Ethyl 3,3-difluoro-2-oxo-2,3-dihydro-1H-indole-5-carboxyl-
1
d
1.22 (3H, t, J¼7.1 Hz),
ate (17b). Pale yellow solid. Mp 176 ꢁC (dec). H NMR (DMSO-d6)
d
1.31 (3H, t, J¼7.1 Hz), 4.30 (2H, q, J¼7.1 Hz), 7.09e7.13 (1H, m),
d
8.10e8.14 (2H, m), 11.59 (1H, br s). 13C NMR (DMSO-d6)
d
14.2, 61.1,
117.0 (t, JCF¼24.3 Hz),119.7,120.7,124.8 (t, JCF¼8.8 Hz),131.8,141.1 (t,
110.7 (t, JCF¼249.5 Hz), 112.1, 119.6 (t, JCF¼23.1 Hz), 125.1, 125.6,
JCF¼2.9 Hz), 162.6 (t, JCF¼34.5 Hz). 19F NMR (DMSO-d6)
d
ꢀ103.1. IR
135.9, 147.0 (t, JCF¼7.3 Hz), 164.7, 166.1 (t, JCF¼29.4 Hz). 19F NMR
3496, 3404, 1759, 1626, 1466, 1230, 1093, 1026, 868, 762, 694 cmꢀ1
.
(DMSO-d6)
d
ꢀ111.6. IR 3296, 1768, 1739, 1705, 1631, 1240, 1203,

Y. Ohtsuka, T. Yamakawa / Tetrahedron 67 (2011) 2323e2331
2331
1080, 760, 739, 660, 611 cmꢀ1. HRMS: calcd for C11H9F2NO3
d
8.38e8.41 (1H, m), 8.44e8.47 (1H, m), 12.07 (1H, br s). 13C NMR
(DMSO-d6)
110.4 (t, JCF¼252.2 Hz), 115.3 (t, JCF¼23.5 Hz), 126.0,
134.0, 151.1, 155.9 (t, JCF¼7.8 Hz), 165.8 (t, JCF¼28.8 Hz). IR 3051,
(MþHþ): 242.0629; found: m/z 242.0627.
d
4.3.23. 5-Acetyl-3,3-difluoro-2,3-dihydroindole-2-one
yellow solid. Mp 208 ꢁC (dec). 1H NMR (DMSO-d6)
(18b). Pale
2.55 (3H, s),
1772, 1622, 1456, 1284, 1188, 1086, 951, 918, 750, 667, 615 cm .
ꢀ1 19F
NMR (DMSO-d6)
202.9824; found: 202.9810.
d
d
ꢀ112.0. HRMS: calcd for C7H3ClF2N2O (MꢀHþ):
7.08 (1H, d, J¼8.3 Hz), 8.11 (1H, d, J¼8.3 Hz), 8.19 (1H, s), 11.57 (1H,
br s). 13C NMR (DMSO-d6)
d
26.7, 110.9 (t, JCF¼249.5 Hz), 112.0, 119.6
(t, JCF¼23.0 Hz), 125.2, 132.5, 135.1, 146.9 (t, JCF¼7.3 Hz), 166.3 (t,
JCF¼29.4 Hz), 196.1. 19F NMR (DMSO-d6)
d
ꢀ111.5. IR 3159, 1766,
References and notes
1670, 1620, 1362, 1240, 1203, 1109, 1082, 928, 837, 660 cmꢀ1. HRMS:
calcd for C10H7F2NO2 (MþHþ): 212.0523; found: m/z 212.0502.
ꢀ
ꢀ
1. Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine;
Wiley: Hoboken, 2008.
2. Boechat, N.; Kover, W. B.; Bastos, M. M.; Pinto, A. C.; Maciel, L. C.; Mayer, L. M.
U.; da Silva, F. S. Q.; Sa, P. M.; Mendonc¸ a, J. S.; Wardella, S. M. S. V.; Arruda, M. S.
L. J. Braz. Chem. Soc. 2008, 19, 445.
4.3.24. 3,3-Difluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile
ꢀ
(19b). White solid. Mp 241 ꢁC (dec). 1H NMR (DMSO-d6)
d 7.13 (1H,
d, J¼8.3 Hz), 7.97 (1H, d, J¼8.3 Hz), 8.25 (1H, s), 11.68 (1H, br s). 13C
3. (a) Young, R. N.; Billot, X.; Han, Y.; Slipetz, D. A.; Chauret, N.; Belley, M.; Metters,
K.; Mathieu, M.-C.; Greig, G. M.; Denis, D.; Girard, M. Heterocycles 2004, 64, 437;
(b) Eto, H.; Kaneko, Y.; Sakamoto, T. Chem. Pharm. Bull. 2000, 48, 982.
4. Middleton, W. J.; Bingham, E. M. J. Org. Chem. 1980, 45, 2883.
5. Fauq, A. H. In N,N-Deiethylaminosulfur Trifluoride; Paquette, L., Ed.; John Wiley &
Sons: New York, NY, 2004.
6. (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.
NMR (DMSO-d6)
d
105.9,110.2 (t, JCF¼250.3 Hz),113.1,118.4,120.3 (t,
JCF¼23.3 Hz),129.3,139.3,147.0 (t, JCF¼7.3 Hz),165.8 (t, JCF¼29.2 Hz).
19F NMR (DMSO-d6)
d
ꢀ111.8. IR 3211, 2229, 1778, 1745, 1626, 1487,
1296, 1223, 1178, 1095, 843, 768, 665 cmꢀ1. HRMS: calcd for
C9H4F2N2O (MþHþ): 195.0370; found: m/z 195.0379.
7. (a) Murakami, S.; Kim, S.; Ichii, H.; Fuchigami, T. Synlett 2004, 815; (b) Mur-
akami, S.; Ishi, H.; Tajima, T.; Fuchigami, T. Tetrahedron 2006, 62, 3761.
8. Huang, X.-T.; Long, Z.-Y.; Chen, Q.-Y. J. Fluorine Chem. 2001, 11, 107.
9. (a) Uraguchi, D.; Yamamoto, K.; Otsuka, Y.; Tokuhisa, K.; Yamakawa, T. Appl.
Catal., A 2008, 342, 137; (b) Kino, T.; Nagase, Y.; Uraguchi, D.; Yamamoto, K.;
Otsuka, Y.; Tokuhisa, T.; Yamakawa, T. J. Fluorine Chem. 2010, 131, 98.
10. Goldstein, S.; Meyerstein, D.; Czapkj, G. Free Radical Biol. Med. 1993, 15, 435.
11. (a) Eicher, T.; Hauptmann, S. Chemistry of Heterocycles; Wiley: Weinheim, 2003;
(b) Katrizsky, A.-R.; Fan, W.-Q. Heterocycles 1992, 34, 2179.
4.3.25. 5-Chloro-3,3-difluoro-2,3-dihydroindole-2-one (20b). Pale
yellow solid. Mp 188 ꢁC (dec). 1H NMR (DMSO-d6)
d
6.98e7.02 (1H,
m), 7.55e7.59 (1H, m), 7.81e7.84 (1H, m), 11.31 (1H, br s). 13C NMR
(DMSO-d6)
d
110.8 (t, JCF¼250.0 Hz), 113.7, 121.0 (t, JCF¼23.0 Hz),
125.3, 127.5, 134.2, 141.6 (t, JCF¼7.6 Hz), 165.6 (t, JCF¼29.2 Hz). 19F
NMR (DMSO-d6)
d
ꢀ111.4. IR 3207, 1774, 1730, 1622, 1481, 1456,
1271, 1221, 1205, 1090, 833, 762, 710, 660, 617 cmꢀ1. HRMS: calcd
12. (a) Logan, S. R. Can. J. Chem. 1991, 69, 540; (b) Li, L.; Shi, J.; Yao, Y.-J.; Zhao, X.;
Chen, H. Appl. Catal., A 2004, 263, 213; (c) Ishio, M.; Terashima, T.; Ouchi, M.;
Sawamoto, M. Polym. J. 2010, 42, 17; (d) Reger, D. L.; Mintz, E.; Lebioda, L. J. Am.
for C8H4F2NOCl (MꢀHþ): 201.9871; found: m/z 201.9903.
}
Chem. Soc. 1986, 108, 1940; (e) Furstner, A.; Majima, K.; Martin, R.; Krause, H.;
4.3.26. 3,3-Difluoro-2,3-dihydroindole-5-nitro-2-one
yellow solid. 1H NMR (DMSO-d6)
7.16e7.21 (1H, m), 8.39e8.44
(1H, m), 8.54e8.58 (1H, m), 11.86 (1H, br s). 13C NMR (DMSO-d6)
(21b). Pale
Kattnig, G.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 1992; (f)
d
}
Furstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J.
Am. Chem. Soc. 2008, 130, 8773.
13. With regard to entries 6 and 7, the tautmeric isomers should be taken into
account. On the basis of the electron density, the ethoxycarbonyldi-
fluoromethylated positions will be the 3- and 4-position of the isomers of 4-
methylpyrazole and 4-phenylimidazole, respectively. These positions corre-
spond to the 2-position of 4-methylpyrazole and 4-phenylimidazole. Thus, it
can be concluded that the same discussion on the electrophilic substitution is
applied to the tautmeric isomers.
d
108.1 (t, JCF¼250.7 Hz), 112.7, 119.9 (t, JCF¼23.4 Hz), 121.2, 130.8,
143.4, 148.8 (t, JCF¼7.3 Hz), 166.1 (t, JCF¼29.2 Hz). 19F NMR (DMSO-
d6)
d
ꢀ111.9. EI-MS: calcd for C8H4F2N2O3 (M): 214.019; found: m/z
214. Full characterization is shown in Ref. 17.
4.3.27. 3,3-Difluoro-2,3-dihydro-1,5-dimethylindole-2-one
14. In the reaction solution of benzo[b]furane, some very small peaks other than 5a
were detected by 19F NMR. These peaks may be assigned to the products, which
the each phenyl ring was ethoxycarbonyldifluoromethylated. Since the formed
amounts of these products were very small, they were not characterized.
15. Roth, G. J.; Heckel, A.; Colbatzky, F.; Handschuh, S.; Kely, J.; Lehmann-Lintz, T.;
Lotz, R.; Tontsch-Grunt, U.; Ealter, R.; Hilberg, F. J. Med. Chem. 2009, 52, 4466.
(22b). White solid. Mp 85.8e88.0 ꢁC. 1H NMR (DMSO-d6)
d
2.32
(3H, s), 3.14 (3H, s), 7.10 (1H, d, J¼8.0 Hz), 7.41 (1H, d, J¼8.0 Hz), 7.51
(1H, s). 13C NMR (DMSO-d6)
20.4, 26.4, 110.6, 111.5 (t, JCF¼248.0,
d
118.9 (t, JCF¼22.6, 124.9, 133.6, 134.4, 141.7 (t, JCF¼7.4), 164.4 (t,
€
JCF¼30.0). 19F NMR (DMSO-d6)
d
ꢀ111.2. IR 1741, 1626, 1504, 1493,
16. Ozcan, S.; Malci, M. Tetrahedron 2008, 64, 5531.
17. Poel, T.-J. WO2004/074282.Starck, J.-P. WO2006/008067.
18. Torres, J. C.; Garden, S. J.; Pinto, A. C.; de Silva, F. S. Q.; Boechat, N. Tetrahedron
1999, 55, 1881.
19. (a) Marvel, C. S.; Hiers, G. S. In Organic Syntheses Collective, Second Edition;
Gilman, H., Ed.; John Wiley & Sons: New York, NY, 1964; Vol. I, p 327; (b) Lackey,
K.; Sternbach, D. D. Synthesis 1993, 993; (c) Smith, K.; El-Hiti, G. A.; Hawes, A. C.
Synlett 1999, 945.
1298, 1250, 1115, 1068, 1012, 825, 737, 714 cmꢀ1. HRMS: calcd for
C10H9F2NO (MþHþ): 198.0725; found: m/z 198.0705.
4.3.28. 5-Chloro-3,3-difluoro-1,3-dihydropyrrolo[2,3-b]pyridine-2-
one (23b). White solid. Mp 189 ꢁC (dec). 1H NMR (DMSO-d6)