Photochemical substitution of olefins and aromatic compounds with difluoromethyl radicals bearing ester and phosphonate groups

Article abstract of DOI:10.1016/j.tet.2005.12.057

Efficient and selective substitution of cyclic and acyclic vinyl ethers with photo-generated difluoromethyl radicals bearing ester and phosphonate groups, in the presence of 2,4,6-trimethylpyridine and diphenyl diselenide was successfully carried out to provide the corresponding regioselective unsaturated difluoromethylene adducts selectively. The reaction involves phenylselenyl transfer at an early stage followed by elimination of phenylselenol from the adducts once formed to provide the unsaturated difluoromethylene adducts selectively. This novel photochemical method was successfully extended to aromatic and heteroaromatic substitutions to provide the corresponding α-aryl-α,α-difluoroacetates and α-aryl-α,α- difluoromethylphosphonates in good to moderate yields.

Full text of DOI:10.1016/j.tet.2005.12.057

Tetrahedron 62 (2006) 3761–3769
Photochemical substitution of olefins and aromatic
compounds with difluoromethyl radicals bearing
ester and phosphonate groups
*
Satoru Murakami, Hideki Ishii, Toshiki Tajima and Toshio Fuchigami
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
Received 18 November 2005; accepted 26 December 2005
Available online 28 February 2006
Abstract—Efficient and selective substitution of cyclic and acyclic vinyl ethers with photo-generated difluoromethyl radicals bearing ester
and phosphonate groups, in the presence of 2,4,6-trimethylpyridine and diphenyl diselenide was successfully carried out to provide the
corresponding regioselective unsaturated difluoromethylene adducts selectively. The reaction involves phenylselenyl transfer at an early
stage followed by elimination of phenylselenol from the adducts once formed to provide the unsaturated difluoromethylene adducts
selectively. This novel photochemical method was successfully extended to aromatic and heteroaromatic substitutions to provide the
corresponding a-aryl-a,a-difluoroacetates and a-aryl-a,a-difluoromethylphosphonates in good to moderate yields.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
radical additions.8 However, their preparation is still
limited.
It is well known that introduction of a fluorine atom into an
organic molecule causes dramatic changes in its biological
activities, mainly due to the high electoronegativity of
fluorine, the strong carbon–fluorine bond, increased solu-
bility in lipids, and mimic effect.1 Therefore, fluorinated
compounds are of great importance in the pharmaceutical
and agrochemical industries. In particular, difluoromethy-
lene compounds have attracted a great deal of interest due to
their unique biological activities.2 For example, CF2/O
transposition in methylenephosphonate has proven to be one
of the most valuable approaches to the preparation of
hydrolytically stable functional groups as phosphonate
mimetics.3 Therefore, their synthesis has become a major
interest in organic chemistry. In general, difluorometylene
compounds have been prepared using DAST,4 NFBS,5
cross-coupling reactions,6 electrochemical oxidations7 and
Previously, we reported photochemical reaction of ethyl
a,a-difluoro-a-(phenylseleno)acetate (1) with various
olefins as shown in Scheme 1.9
Interestingly, we obtained not only radical adducts
(saturated products) but also difluoromethylene-substituted
products (unsaturated products). The formation of difluoro-
methylene-substituted products prompted us to carry out
aromatic and heteroaromatic substitutions with difluoro-
methyl radicals photo-generated from 1 and diethyl a,a-
difluoromethyl-a-(phenylseleno)phosphonate (5) as shown
in Scheme 2.10
However, the selectivity of the substitution of olefins in
Scheme 1 was low,9 and the yields of aromatic and
hn(l>280 nm)
PhSe CF2COOEt
R
+
R
+
R
CF2COOEt
CF2COOEt
1
Scheme 1.
Keywords: Photoreaction; Difluoromethyl radicals; C–CF2 bond formation; Group transfer; Selenide.
*
Corresponding author. Tel./fax: C81 45 924 5406; e-mail: fuchi@echem.titech.ac.jp
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.057

3762
S. Murakami et al. / Tetrahedron 62 (2006) 3761–3769
X
X
X
-PhSeH
PhSe
CF2EWG
CF2EWG
X=Me,F
hn
PhSe CF2EWG
A
SePh
CF2EWG
1:EWG=COOEt
5:EWG=P(O)(OEt)2
-PhSeH
Y
Y
CF2EWG
Y=NR,O,S
EWG=COOEt, P(O)(OEt)2
Y
Scheme 2.
heteroaromatic substitutions with difluoromethyl radicals
were moderate to low.10
the presence of olefins, and they did not obtain selenium-
free adducts like 3 and 4 at all. Although the adducts 2
is a single stereoisomer, we could not establish its
stereochemistry.
In order to improve the selectivity and yields, we
investigated photochemical substitutions under various
conditions. In this paper, we report the substitution of
various vinyl ethers and aromatic compounds with
difluoromethylene groups photo-generated from 1 and 5.
In order to disclose the mechanism for the formation of 3
and 4, we investigated the photolysis of the phenylselenyl
group transfer adduct 2. We found that compounds 3 and 4
were formed from the adduct 2 (Scheme 4).
This result clearly indicates that the phenylselenyl group
transfer adduct 2 is a precursor to compounds 3 and 4.
2. Results and discussion
2.1. Photoreaction of ethyl a,a-difluoro-a-(phenylseleno)-
acetate (1) with 2,3-dihydrofuran
2.2. Time-conversion of the photoreaction of ethyl
a,a-difluoro-a-(phenylseleno)acetate (1) with
2,3-dihydrofuran
We attempted the photoreaction of 1 with a large excess
amount of 2,3-dihydrofuran as the electron-rich olefin in
CH2Cl2 (Scheme 3). The reaction was conducted using a
100-W high-pressure mercury-vapor lamp with a Pyrex
vessel inside the light source.
In order to obtain more information on the reaction
mechanism, the yields of 2–4 and the recovery of 1 in
the time course of the photochemical reaction of 1 in the
presence of 2,3-dihydrofuran were investigated and the
results are illustrated in Figure 1.
As shown in Scheme 3, the group transfer reaction took
place to provide a phenylselenyl group transfer adduct 2, a
difluoromethyl-substituted product 3 and a radical adduct 4
in good total yields (25, 28, 28%, respectively). Moreover,
the difluoromethyl unit was regioselectively introduced to
the 3-position of 2,3-dihydrofuran in all products. Byers
et al. obtained always phenylselenyl group transfer products
by the photolysis of dialkyl a-(phenylseleno)malonates11,12
and tetraethyl phenylselenomethylenediphosphonate13 in
As shown in Figure 1, the starting material 1 was consumed
linearly with the photo-irradiation time while the yield of
the phenylselenyl group transfer adducts 2 also increased
linearly to ca. 50% with the reaction time, and then the yield
of 2 gradually decreased. Additionally, difluoromethylene-
substituted product 3 also increased gradually with the
time and no maximum yield was observed even after long
SePh
O
O
O
O
hn(l>280 nm)
+
+
+
PhSe CF2COOEt
CH2Cl2
2.5 h.
CF2COOEt
28%
CF2COOEt
28%
4
CF2COOEt
25%
20 equiv
1
2
3
Scheme 3.
SePh
O
O
O
hn(l>280 nm)
+
CH2Cl2
3 h.
CF2COOEt
58%
CF2COOEt
22%
4
CF2COOEt
3
2
Scheme 4.

S. Murakami et al. / Tetrahedron 62 (2006) 3761–3769
3763
Figure 1. The yields of 2–4 and the recovery of 1 in the time-course of the photoreaction of 1 in the presence of 2,3-dihydrofuran.
photo-irradiation. In sharp contrast, the formation of the
radical adduct product 4 started after 80 min and gradually
increased. When the starting compound 1 and the adduct 2
completely vanished after prolonged photo-irradiation time,
the yields of the substituted product 3 and the radical adduct
4 reached maxima. Moreover, a considerable amount of
diphenyl diselenide was detected. From the above result, we
assumed the substituted product 3 is formed probably by the
elimination of phenylselenol from the adduct 2 and
the resulting phenylselenol would be involved in the
formation of 4 since phenylselenol is a good hydrogen
atom donor.
results in the formation of the difluoromethyl-substituted
product 3 eliminating phenylselenol (path A). Since the
formation of 4 required induction time, 4 would be formed
by the photochemically homolytic cleavage of the Se–C
bond followed by abstraction of a hydrogen atom from
phenylselenol (path B).
2.3. Effect of a base
From the above hypothesis, it is expected that when the
formation of phenylselenol as a good hydrogen atom donor
is inhibited by using a base for deprotonation of
phenylselenol, the formation of 4 would be suppressed.
Consequently, the selectivity for the formation of 3 would
be increased.
In consideration to the above results and the UV absorption
bands of 1 at 265, 217 nm, we propose a plausible reaction
mechanism as shown in Scheme 5.
In order to confirm our assumption, photochemical
reaction of 1 with 2,3-dihydrofuran was investigated in
the presence of various bases. The results are summarized
in Table 1.
When the homolytic cleavage of the Se–CF2 bond takes
place by photolysis of 1 in the presence of 2,3-dihydrofuran,
the phenylselenyl group transfer reaction proceeds quickly
to provide 2, and then further photolysis of 2 once formed
O
SePh
O
O
hn
hn
-PhSe
PhSe CF2COOEt
PhSe CF2COOEt
CF2COOEt
CF COOEt
H
2
1
3
2
path A
hn
path B
O
O
SePh
O
H
SePh
SePh
CF2COOEt
CF2COOEt
CF2COOEt
4
A
Scheme 5.

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S. Murakami et al. / Tetrahedron 62 (2006) 3761–3769
Table 1. Photoreaction of 1 in the presence of 2,3-dihydrofuran with various bases
SePh
O
O
O
O
hn(l> 280 nm)
+
+
+
+
Base
PhSe CF2COOEt
CH2Cl2
CF2COOEt
CF2COOEt
CF2COOEt
under Ar
10 equiv 5 equiv
1
2
3
4
Run
Base
Time (h)
Yield (%)a
Ratio 3/4
2
3
4
1
2
3
4
5
6
7
8
None
DBU
Pyridine
DMAP
DMAP
Imidazole
2,6-Lutidine
2,4,6-Trimethylpyridine
3
5
5
—
—
—
65
31
—
—
—
51
7
40
—
22
—
2
18
32
15
1.3
—
1.9
—
10.5
3.4
1.8
4.4
41
20
21
61
58
66
5
10
10
10
10
a Determined by 19F NMR.
As shown in Table 1, when 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) was used, 3 was formed solely although the yield
was extremely low (run 2). When 4-(N,N-dimethylamino)-
pyridine (DMAP) was used, the reaction proceeded
smoothly to provide 2 and 3 in good total yield and
saturated adduct 4 was not formed at all (run 4). However, in
this case, group transfer adduct 2 was mainly formed.
Therefore, the reaction time was doubled (10 h). However,
the yield of 3 did not increase although the yield of the
group transfer adduct 2 decreased (run 5). In sharp contrast,
when pyridine and 2,6-lutidine were used, the product
selectivity (the ratio of 3 to 4) was not so different from the
case in the absence of a base (run 1, vs runs 3 and 7). The
photochemical reaction in the presence of imidazole and
2,4,6-trimethylpyridine provided 3 and 4 in good yields and
high product selectivities (runs 6 and 7). Since the addition
of 2,4,6-trimethylpyridine resulted in higher selectivity
compared with imidazole, 2,4,6-trimethylpyridine was
found to be the most suitable base for the selective
photochemical reaction.
2.4. Effect of diphenyl diselenide
We found 2,4,6-trimethylpyridine as the most suitable base
to suppress the formation of 4, but 4 was still formed. From
path B in Scheme 5, we assumed that radical intermediate A
would also abstract the hydrogen atom from dichloro-
methane as a solvent. It is expected that the addition of
diphenyl diselenide to the reaction system would suppress
the hydrogen abstraction of A to provide 4 as shown in
Scheme 6. In this case, 3 would be formed mainly via 2
derived from A and diphenyl diselenide.
In order to suppress the formation of 4, we investigated the
photochemical reaction in the presence of both diphenyl
SePh
O
O
O
hn
PhSe SePh
CF2COOEt
CF COOEt
-PhSe H
2
CF2COOEt
3
2
A
Scheme 6.
Table 2. Photoreaction of 1 in the presence of diphenyl diselenide and 2,4,6-trimethylpyridine
O
hn(l> 280 nm)
(PhSe)2
O
+
+
PhSe CF2COOEt
+
CH2Cl2
under Ar
N
10 equiv
5 equiv
1
SePh
O
O
+
+
CF2COOEt
CF2COOEt
CF2COOEt
2
3
4
Run
(PhSe)2 (equiv)
Time (h)
Yield (%)a
2
3
4
1
2
3
0.1
0.5
1
12
12
16
—
—
—
68
78
80 (78)
12
16
—
a Determined by 19F NMR. Figure in parenthesis shows isolated yield.

S. Murakami et al. / Tetrahedron 62 (2006) 3761–3769
3765
diselenide and 2,4,6-trimethylpyridine. The results are
summarized in Table 2.
2.5. Photochemical reaction of ethyl a,a-difluoro-a-
(phenylseleno)acetate (1) and diethyl a,a-difluoro-
methyl-a-(phenylseleno)phosphonate (5) with various
As shown in Table 2, the yield of 3 was increased in all cases.
Especially, the photochemical reaction of 1 in the presence of
1 equiv of diphenyl diselenide provided product 3 solely in
good yield (run 3) although the reaction time was longer.
Therefore, 1 equiv of diphenyl diselenide was found to be the
most suitable additive for the selective formation of 3.
unsaturated compounds
Next, we carried out the photo-induced substitution of 1
with various unsaturated substrates in the presence of 2,4,6-
trimethylpyridine and diphenyl diselenide. The results are
shown in Table 3.
Table 3. Photoreaction of 1 in the presence of 2,4,6-trimethylpyridine and diphenyl diselenide
hn(l> 280 nm)
(PhSe)2
1 equiv
+
+
Product
PhSe CF2COOEt
Substrate
10 equiv
+
CH2Cl2
under Ar
N
5 equiv
1
Run
1
Substrate
Time (h)
16
Recovery of 1 (%)a
Yield (%)a
O
O
O
25
CF2COOEt
6 46 (41)
O
2
30
3
25
—
CF2COOEt
6 43
O
O
O
3b
CF2COOEt
CF2COOEt
60 34 (31)
6 44 (40)
tBuO
tBuO
70 22 (18)
CF2COOEt
CF2COOEt
CF2COOEt
4
18
3
—
—
tBuO
7 76 (72) (E/ZZ3.2)
tBuO
tBuO
CF2COOEt
5b
tBuO
70 46 (40)
7 46 (40) (E/ZZ3.2)
6c
25
—
—
CF2COOEt
8 79 (70)
7b,c
9
CF2COOEt
8 60 (53)
CF2COOEt
O
O
8c
25
6
—
—
9 72 (67)
CF2COOEt
O
S
S
O
9b,c
9 29 (26)
CF2COOEt
S
S
10c
25
8
—
—
10 62 (53)
CF2COOEt
11b,c
10 44 (34)
a Determined by 19F NMR. Figures in parentheses show islated yields.
b Without 2,4,6-trimethylpyridine and diphenyl diselenide.
c Neat conditions.

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S. Murakami et al. / Tetrahedron 62 (2006) 3761–3769
hn (l > 280 nm)
PhSe CF2COOEt
+
CF2COOEt
CH2Cl2
Ar
N
N
R
1
11:R=H(4h) 44a(40)b %
12:R=Me(4h) 68a(65)b %
13:=Ph(6h) 49a(46)b %
R
5 equiv
a 19F NMR yield
b Isolated yield
Scheme 7.
Regardless of substrates, the selectivity of products and
yields were improved when 2,4,6-trimethylpyridine and
diphenyl diselenide were used. In contrast to run 3, the
photochemical reaction with 3,4-dihydro-2H-pyran in the
presence of 2,4,6-trimethylpyridine and diphenyl diselenide
gave a difluoromethyl-substituted product 6 solely in
moderate yield and radical adduct 60 was not formed at all
(run 1). In this case, a considerable amount of starting
material 1 still remained. In order to obtain better yield, the
reaction time was extended to almost double, but the yield
of 6 was not increased and the conversion of 1 did not
change (run 2). A similar photochemical reaction with tert-
butyl vinyl ether proceeded to afford difluoromethyl-
substituted product 7 in much higher yield (run 4) compared
with the reaction in the absence of diphenyl diselenide and
a base (run 5). In this case, the product selectivity (7/70)
was also improved. Photochemical reaction with benzene in
the presence of 2,4,6-trimethylpyridine and diphenyl
diselenide also gave a much higher yield of the substituted
product 8 (run 6) compared with the reaction without these
additives (run 7). Moreover, the reaction was applicable to
heteroaromatic compounds: the substitution with the
difluoromethylene group at the a-position of heteroaromatic
compounds proceeded selectivity to provide the correspond-
ing substitution products 9–10 in much better yields (runs 8
and 10) compared with the reactions in the absence of the
additives (runs 9 and 11). Notably, the yield of 9 was
markedly increased.
change and a considerable amount of 1 was recovered. This
seems to be due to the formation of dark colored by-
products adsorbed on the wall of the Pyrex vessel, which
interfered with UV light absorption of 1 to result in the low
conversion of 1.
Finally, we tried similarly the photo-induced substitution of
a,adifluoromethylphosphonate 5 with various unsaturated
substrates in the presence of 2,4,6-trimethylpyridine and
diphenyl diselenide. The results are summarized in Table 4.
Regardless of substrates, the conversion of 5 became much
lower (runs 1 and 3) or lower (run 5 and 7) in the presence of
the additives. However, the yields of substitution products
based on the consumed 5 increased without exception.
Interestingly, substitution product 15 was formed exclu-
sively in the reaction with 1,2-dihydrofuran. Notably, the
absolute yield of 17 markedly increased to 55% in the
presence of the additives (run 5). These results suggest that
the photochemical substitution proceeds selectively in the
presence of the additives although the reaction became
much slower. However, in the case of 1-methylpyrrole, the
yield did not increase even in the presence of additives. In
the reactions, diethyl difluoromethylphosphonate, HCF2-
P(O)(OEt)2 was formed as a by-product except for runs 5
and 6 and a considerable amount of diphenyl diselenide was
also detected. These facts also clearly indicate that
homolytic cleavage of the Se–CF2 bond took place by
photolysis of 5.
Next, photochemical substitution with nitrogen-containing
heterocycles was investigated. As shown in Schemes 7
and 8, the reactions proceeded to provide the corresponding
substitution products in moderate to reasonable yields.
Notably, in the case of 1-phenylpyrrole and indole, the
substitution at the a-position of the pyrrole ring took place
exclusively and the substitution at the benzene ring did not
take place at all. In these cases, the yields were not increased
in the presence of 2,4,6-trimethylpyridine and diphenyl
diselenide, which is in sharp contrast to the cases of furan
and thiophene. Even when the reaction time was extended
longer in the case of indole, the conversion of 1 did not
By the way, the substitution of the difluoromethylene group
at the a-position of furan proceeded exclusively while the
substitution of the difluoromethylene group at the b-position
of 2,3-dihydrofuran exclusively. Since the difluoromethyl
radicals generated from 1 and 5 are electron deficient, they
usually react as electrophiles. Therefore, the regioselectivity
of these radical reactions seems to be controlled by
SOMO–HOMO interaction between radicals and substrates.
The HOMOs of 2,3-dihydrofuran and furan calculated by
CAChe MOPAC AM1 are shown in Figure 2.
hn (l > 280 nm)
PhSe CF2COOEt
+
CH2Cl2
Ar
CF2COOEt
1
N
N
H
14 16a(13)b %
H
5 equiv
a 19F NMR yield
b Isolated yield
Scheme 8.

S. Murakami et al. / Tetrahedron 62 (2006) 3761–3769
3767
Table 4. Photoreaction of 5 in the presence of 2,4,6-trimethylpyridine and diphenyl diselenide
hn(l> 280 nm)
(PhSe)2
1 equiv
+
+
Product
PhSe CF2P(O)(OEt)2
Substrate
10 equiv
+
CH2Cl2
under Ar
N
5 equiv
5
Run
1
Substrate
Time (h)
18
Conversion (%)a
Yield (%)b
O
O
O
35
CF2P(O)(OEt)2
15 71
O
O
2c
3
69
60
CF2P(O)(OEt)2
CF2P(O)(OEt)2
150 20
15 46
3d
60
CF2P(O)(OEt)2
16 62
4c,d
9
100
75
CF2P(O)(OEt)2
16 53
CF2P(O)(OEt)2
O
O
5d
30
17 73
CF2P(O)(OEt)2
O
S
S
O
S
S
6c,d
6
57
8
96
60
72
17 27
CF2P(O)(OEt)2
7d
18 50
CF2P(O)(OEt)2
8c,d
18 35
Me
N
Me
N
CF2P(O)(OEt)2
9c,d
8
68
19 34
a Determined by 19F NMR.
b Isolated yield based on consumed starting material 5.
c Without 2,4,6-trimethylpyridine and diphenyl diselenide.
d Neat conditions.
vinyl ethers together with aromatic and heteroaromatic
compounds. In the presence of 2,4,6-trimethylpyridine and
diphenyl diselenide, the yields and product selectivity were
increased in many cases. This method may be highly useful
for the preparation of various CF2-containing building
blocks towards biological activities.
Figure 2. The HOMOs of 2,3-dihydrofuran and furan calculated by CAChe
MOPAC AM1.
4. Experimental
The b-position of 2,3-dihydrofuran has the largest coeffi-
cient of HOMO while the a-position of furan has the largest
one. Therefore, the different regioselectivity of the radical
reactions with furan and 2,3-dihydrofuran can be reasonably
explained.
4.1. General procedure for photoreaction
A solution of ethyl a,a-difluoro-a-phenyselenolacetate (1)9
or diethyl a,a-difluoromethyl-a-phenyselenolphosphonate
(5)8b (0.17 mmol) and an olefin (1.70 mmol) in CH2Cl2
(40 ml) in the presence of 2,4,6-trimethylpyridine
(0.85 mmol) and diphenyl diselenide (0.17 mmol) was
bubbled with Ar at room temperature for 0.5 h and then
photolyzed with 100-W high-pressure mercury-vapor lamp.
3. Conclusion
We have developed novel and efficient substitution using
photo-generated difluoromethyl radicals with cyclic, acyclic

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S. Murakami et al. / Tetrahedron 62 (2006) 3761–3769
The reaction was conducted using a Pyrex vessel inside the
light source. After the photoreaction, the resulting solution
was evaporated under vacuum and the residue was purified
by silica gel column chromatography (linear gradient of
0–20% EtOAc in hexane) or by HPLC (Develosil ODS-5,
MeCN as an eluent) to provide pure products.
HRMS Calcd for C8H9F2NO2: m/z 189.0601. Found:
189.0591.
4.1.13. Ethyl a,a-difluoro-a-[2-(1-methylpyrrolyl)]-
1
acetate (12). H NMR d 6.7 (dd, 1H, JZ2.8, 2.0 Hz), 6.4
(dd, 1H, JZ3.8, 2.0 Hz), 6.1 (dd, 1H, JZ3.8, 2.8 Hz), 4.38
(q, 2H, JZ7.0 Hz), 3.76 (s, 3H), 1.37 (t, 3H, JZ7.0 Hz);
13C NMR d 163.28 (t, JZ34.1 Hz), 129.06, 126.98 (t, JZ
2.2 Hz), 112.22 (t, JZ5.6 Hz), 111.16 (t, JZ245.9 Hz),
107.29, 63.22, 35.48 (t, JZ3.4 Hz), 14.03. 19F NMR d
K19.62 (s, 2F); MS (m/z) 203 (MC), 130; HRMS Calcd for
C9H11F2NO2: m/z 203.0758. Found: 203.0764.
4.1.1.
3-(Ethoxycarbonyldifluorometyl)-2-(phenyl-
1
selenyl)tetrahydrofuran (2). H NMR (270 MHz, CDCl3)
d 7.62–7.27 (m, 5H), 5.99 (d, 1H, JZ3.5 Hz), 4.06–4.01 (m,
2H), 4.32 (q, 2H, JZ7.0 Hz), 3.16–2.98 (m, 1H), 2.19–1.98
(m, 2H), 1.33 (t, 3H, JZ7.0 Hz); 13C NMR d 162.96 (t, JZ
32.4 Hz), 137.21 (t, JZ253.8 Hz), 133.98, 128.89, 127.67,
114.76 (t, JZ253.20 Hz), 81.89 (t, JZ3.9 Hz), 66.81,
63.20, 51.21 (dd, JZ23.48, 22.92 Hz), 25.15 (dd, JZ3.35,
2.80 Hz), 13.90. 19F NMR (254 MHz, CDCl3) d K34.10
(dd, 1F, JZ257.0, 14.7 Hz), K35.32 (dd, 1F, JZ257.0,
14.7 Hz); MS (m/z) 350 (MC), 305, 277, 77; HRMS m/z
Calcd for C14H16F2O3Se: 350.0233. Found: 350.0203.
4.1.14. Ethyl a,a-difluoro-a-[2-(1phenylpyrrolyl)]-
acetate (13). H NMR d 7.4–7.3 (m, 5H), 6.9 (dd, 1H,
1
JZ2.6, 2.0 Hz), 6.6 (dd, 1H, JZ3.6, 2.0 Hz), 6.3 (dd, 1H,
JZ3.6, 2.6 Hz), 4.13 (q, 2H, JZ7.3 Hz), 1.21 (t, 3H, JZ
7.3 Hz); 13C NMR d 162.95 (t, JZ34.1 Hz), 139.23, 132.42,
128.73, 128.27, 127.16 (t, JZ2.2 Hz), 126.86 (t, JZ
1.6 Hz), 112.90 (t, JZ5.0 Hz), 110.62 (t, JZ245.4 Hz),
108.36, 63.09, 13.87. 19F NMR d K15.65 (s, 2F); MS (m/z)
265 (MC), 192, 77; HRMS Calcd for C14H13F2NO2: m/z
265.0914. Found: 265.0922.
4.1.2. 3-(Ethoxycarbonyldifluorometyl)-2,3-dihydro-
furan (3). See Ref. 9.
4.1.3. 3-(Ethoxycarbonyldifluorometyl)tetrahydrofuran
(4). See Ref. 9.
1
4.1.15. Ethyl a,a-difluoro-a-[2-(indolyl)]acetate (14). H
NMR d 8.68–8.46 (br, 1H), 7.66 (d, 1H, JZ7.7 Hz), 7.43
(dd, 1H, JZ8.1, 0.7 Hz), 7.30 (dt, 1H, JZ7.7, 0.7 Hz), 7.16
(dt, 1H, JZ8.1, 0.6 Hz), 6.89–6.86 (m, 1H), 4.38 (q, 2H, JZ
7.0 Hz), 1.3 (t, 3H, JZ7.0 Hz); 13C NMR d 163.22 (t, JZ
34.7 Hz), 136.36, 127.814 (t, JZ30.7 Hz), 126.18, 124.20,
121.69, 120.72, 111.56, 110.09 (t, JZ248.7 Hz), 104.17 (t,
JZ5.0 Hz), 63.68, 13.99. 19F NMR d K24.12 (s, 2F); MS
(m/z) 239 (MC), 166; HRMS Calcd for C12H11F2NO2: m/z
239.0758. Found: 239.0756.
4.1.4. 2H-3,4-Dihydro-5-(ethoxycarbonyldifluoro-
methyl)pyran (6). See Ref. 9.
4.1.5. 2H-3,4,5,6-Tetrahydro-3-(ethoxycarbonyldifluoro-
methyl)pyran (60). See Ref. 9.
4.1.6. trans-Ethyl 5-t-butoxy-2,2-difluoro-3-butenoate
(7). See Ref. 9.
4.1.16.
3-(Diethoxyphosphonyldifluorometyl)-2,3-
4.1.7. cis-Ethyl 5-t-butoxy-2,2-difluoro-3-butenoate (7).
See Ref. 9.
1
dihydrofuran (15). H NMR (270 MHz, CDCl3) d 6.88–
6.78(m, 1H), 4.51 (t, 2H, JZ9.7 Hz), 4.34–4.23 (m, 4H),
2.87 (ddt, 2H, JZ2.0, 2.0, 9.7 Hz), 1.39 (t, 6H, JZ7.1 Hz).
31P NMR d 6.32 (ttt, 1P, JZ117.3, 7.4, 7.4 Hz). 19F NMR
(254 MHz, CDCl3) d K27.68 (d, 2F, JZ116.7 Hz); MS
((m/z) 256 (MC), 119; HRMS m/z Calcd for C9H15F2O4P:
256.0676. Found: 256.0685.
4.1.8. Ethyl 5-t-butoxy-2,2-difluorobutanoate (70). See
Ref. 9.
4.1.9. Ethyl a,a-difluoro-a-phenylacetate (8). See
Ref. 6d.
4.1.17. 3-(Diethoxyphosphonyldifluorometyl)tetrahydro-
4.1.10. Ethyl a,a-difluoro-a-[2-(furyl)]acetate (9). 1H
NMR d 7.52 (dd, 1H, JZ1.65, 0.82 Hz), 6.76 (dd, 1H,
JZ3.30, 0.82 Hz), 6.46 (dd, 1H, JZ3.30, 1.65 Hz), 4.38 (q,
2H, JZ7.02 Hz), 1.36 (t, 3H, JZ7.02 Hz); 13C NMR d
162.25 (t, JZ33.5 Hz), 144.73 (t, JZ2.2 Hz), 131.86,
111.56 (t, JZ3.4 Hz), 110.68 (t, JZ1.1 Hz), 108.59 (t,
JZ248.2 Hz), 63.55, 14.00. 19F NMR d K25.95 (s, 2F); MS
(m/z) 190 (MC), 117; HRMS Calcd for C8H8F2O3: m/z
190.0442. Found: 190.0424.
1
furan (150). H NMR (270 MHz, CDCl3) d 4.34–4.23 (m,
4H), 4.00–3.74 (m, 4H), 3.09–2.82 (m, 1H), 2.21–2.01 (m,
2H), 1.39 (t, 6H, JZ7.1 Hz). 31P NMR d 7.03 (tttd, 1P, JZ
108.4, 7.4, 7.4, 3.0 Hz). 19F NMR (254 MHz, CDCl3) d
K38.53 (ddd, 1F, JZ301.5, 109.1, 16.6 Hz), K39.90 (ddd,
1F, JZ301.5, 109.1, 16.6 Hz); MS (m/z) 258 (MC); HRMS
m/z Calcd for C9H17F2O4P: 258.0833. Found: 258.0848.
4.1.18. Diethyl a,a-difluoromethyl-a-phenylphospho-
nate (16). See Ref. 6a.
4.1.11. Ethyl a,a-difluoro-a-[2-(thienyl)]acetate (10). See
Ref. 6b.
4.1.19. Diethyl a,a-difluoromethyl-a-[2-(furyl)]phospho-
nate (17). H NMR d 7.55 (dd, 1H, JZ1.3, 1.0 Hz), 6.82
1
4.1.12. Ethyl a,a-difluoro-a-[2-(pyrrolyl)]acetate (11).
1H NMR d 9.03–8.55 (br, 1H), 6.90 (dd, 1H, JZ2.6,
1.8 Hz), 6.55 (dd, 1H, JZ3.3, 1.8 Hz), 6.24 (dd, 1H, JZ3.3,
2.6 Hz), 4.36 (q, 2H, JZ7.3 Hz), 1.37 (t, 3H, JZ7.3 Hz).
19F NMR d K21.32 (s, 2F); MS (m/z) 189 (MC), 116;
(dd, 1H, JZ3.6, 1.0 Hz), 6.48 (dd, 1H, JZ3.6, 1.3 Hz),
4.35–4.27 (m, 4H), 1.36 (t, 6H, JZ6.9 Hz); 31P NMR d 4.93
(ttt, 1P, JZ109.9, 7.4, 7.4 Hz). 19F NMR d K30.81 (d, 2F,
JZ109.0 Hz); MS (m/z) 254 (MC); HRMS Calcd for
C9H13F2O4P: m/z 254.0520. Found: 254.0539.

S. Murakami et al. / Tetrahedron 62 (2006) 3761–3769
3769
4. (a) Hagele, G.; Haas, A. J. Fluorine. Chem. 1996, 76, 15–19.
(b) Solas, D.; Hale, R. L.; Patel, D. V. J. Org. Chem. 1996, 61,
1537–1539.
See Ref. 14.
4.1.20. Diethyl a,a-difluoromethyl-a-[2-(1-methylpyrro-
lyl)]phosphonate (19). H NMR d 6.69 (dd, 1H, JZ2.6,
1
5. Taylor, S. D.; Kotoris, C. C.; Dinaut, A. N.; Chen, M.-J.
Tetrahedron 1998, 54, 1691–1714.
1.8 Hz), 6.56 (dd, 1H, JZ3.4, 1.8 Hz), 6.10 (dd, 1H, JZ3.4,
2.6 Hz), 4.33–4.09 (m, 4H), 3.80 (s, 3H), 1.34 (t, 6H, JZ
6. (a) Yokomatsu, T.; Murano, T.; Suemune, K.; Shibuya, S.
Tetrahedron 1997, 53, 815–822. (b) Eto, H.; Kaneko, Y.;
Sakamoto, T. Chem. Pharm. Bull. 2000, 48, 982–990. (c)
Tellier, F.; Sauvetre, R.; Normant, J.-F. Tetrahedron Lett.
1986, 27, 3147–3148. (d) Sato, K.; Kawata, R.; Ama, F.;
Omote, M.; Ando, A.; Kumadaki, I. Chem. Pharm. Bull. 1999,
47, 1013–1016.
7.0 Hz); 31P NMR d 6.36 (ttt, 1P, JZ117.3, 7.4, 7.4 Hz). 19
F
NMR d K24.48 (d, 2F, JZ116.67 Hz); MS (m/z) 267 (MC),
130; HRMS Calcd for C10H16F2NO3P: m/z 267.0836.
Found: 267.0823.
Acknowledgements
7. (a) Brigaud, T.; Laurent, E. Tetrahedron Lett. 1990, 31,
2287–2290. (b) Yoshiyama, T.; Fuchigami, T. Chem. Lett.
1992, 1995–1998. (c) Konnno, A.; Fuchigami, T. J. Org.
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42, 3009–3011.
We would like to thank Prof. Ikuyoshi Tomita and his
co-workers of Tokyo Institute of Technology for their
measurement of 31P NMR spectra.
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