Radical conjugate addition of ambiphilic fluorinated free radicals

Article abstract of DOI:10.1016/j.tet.2013.05.006

The ambiphilic character of fluorinated radicals was noticed during their radical conjugate addition onto electron-deficient alkenes. Free radicals were trapped with enones when the reaction was conducted from iododifluoro-acetate and -phosphonate derivat

Full text of DOI:10.1016/j.tet.2013.05.006

Tetrahedron 69 (2013) 5920e5926
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Radical conjugate addition of ambiphilic fluorinated free radicals
*
Coralie De Schutter, Emmanuel Pfund, Thierry Lequeux
ꢀ
ꢀ
Laboratoire de Chimie Moleculaire et Thioorganique, CNRS UMR 6507 & FR3038, Normandie Universite,
ꢀ
UNICAEN, ENSICAEN 6 Boulevard du Marechal Juin, 14050 Caen Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The ambiphilic character of fluorinated radicals was noticed during their radical conjugate addition onto
electron-deficient alkenes. Free radicals were trapped with enones when the reaction was conducted
from iododifluoro-acetate and -phosphonate derivatives in the presence of Et3B. Competitive addition
reaction onto electron-rich or -deficient alkenes was observed depending on the free radical initiator.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 February 2013
Received in revised form 30 April 2013
Accepted 3 May 2013
Available online 10 May 2013
Keywords:
Fluorine
Radical
Difluoromethyl
Phosphorus
Acetate
1. Introduction
F
F
Bu3SnH,
AIBN
CO2Me
CF2Br
MeO2C
MeO2C
MeO2C
MeO2C
ref 33
CO2Me
The introduction of a fluoroalkyl chain onto organic compounds
is an attractive strategy for the preparation of biomolecules or
materials.1e5 The main strategies to synthesize these compounds
involved the addition of fluorinated carbanion onto a large variety
of electrophiles and the reaction of electrophilic fluoroalkylating
reagents with carbon nucleophiles.6,7 The radical addition reaction
of fluoroalkyl radicals has been mainly studied with electron-rich
alkenes or alkynes as radical traps.8 For example, trifluoromethyl
radical was added onto enolates,9e11 aromatic derivatives,12,13 and
alkoxycarbonyl-, phosphonyl- or phenylsulfonyl-difluoromethyl
radicals onto electron-rich alkenes and alkynes.14e23 Indeed, it
has already been demonstrated that the electrophilic character of
perfluoroalkyl radical Rꢀf predominates and its addition onto
electron-rich alkenes is efficient due to a favorable SOMOeHOMO
interaction.24e28 The addition of fluorinated radicals onto electron-
deficient alkenes is rare, but would be an attractive alternative to
the limited conjugate addition reaction of fluorinated
carbanion.29e32 Few works have been done in this field, and it has
been shown that only the addition of CFꢀ3; RCF2ꢀ ; RCOCF2ꢀ radicals
onto electron-deficient alkenes was possible (Scheme 1).33e39 With
these radicals, additional SOMOeLUMO interaction is expected,
which confers them an ambiphilic character.40
65%
CF3I, Et3B
THF, H2O
F3C
OH
ref 34
ref 36
Ph
CO2Et
Ph
75%
CO2Et
CO2nBu
I
F
F
h
Ph
PhCOCF2I
CO2nBu
51%
O
Scheme 1. Addition of CFꢀ3; RCF2ꢀ ; RCOCF2ꢀ .
We presume that the ambiphilic character of CFꢀ3 and RCF2ꢀ car-
bon centered radicals is due to the attracting effect of one fluorine
atom and the donating effect of the second fluorine atom (Fig. 1).
s
p
F
+M
F
-I
R
R = alkyl, F, COR
Fig. 1. Ambiphilic radical.
For RCOCFꢀ2 carbon centered radical, already substituted by one
electron-withdrawing group and considered as ambiphilic,41e44 the
additional effect of the two fluorine atoms reinforces this character.
* Corresponding author. Tel.: þ33 (0)231452854; fax: þ33 (0)231452865; e-mail
address: thierry.lequeux@ensicaen.fr (T. Lequeux).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.006

C. De Schutter et al. / Tetrahedron 69 (2013) 5920e5926
5921
Previously, we reported our preliminary results focused on the
radical conjugate addition (RCA) of the ði ꢁ PrOÞ2ðOÞPCFꢀ2 radical
onto enones 2, which also confirmed an ambiphilic character
(Scheme 2).45
difluoroester derivatives 5be7b32,46 were obtained in 46e70%
yield. In contrast to the result observed from 1a and enone 8,
a mixture of diastereoisomers 8b was obtained in 76% yield. HOESY
experiment confirmed the trans isomer was the major product.
However, product 8b epimerized slowly in the reaction mixture.
O
RF
I
R
1a, b
2a (77%)
2b (81%)
3a (49%)
3b (64%)
2: R = H
O
RF
Et3B (0.6 to 1.2
equiv), CH2Cl2,
C
3: R = CH3
O
O
R
Et3B (1.2 equiv),
CH2Cl2
R
R
C
O
RF
I
46-76%
n
5 8
n
1a, b
4a (48%)
4b (79%)
RF
5a,b 8a,b
(a): RF = CF2P(O)(iPrO)2
(b): RF = CF2CO2Et
n = 1, 2, 3
R = H or CH3
O
RF
cis:trans = 9/1
a: RF = CF2P(O)(OiPr)2
b: RF = CF2CO2Et
Scheme 3. Radical addition onto cyclic ketones and lactones.
4
Table 1
Radical conjugate addition
Scheme 2. RCA with unsaturated ketones.
Radical acceptor
R
n
Product (yield, %)a
5
H
1
5a (62)
5b (46)
2. Results and discussion
6
7
8
H
H
CH3
2
3
1
6a (69)
6b (70)
7a (58)
7b (67)
We report the scope and limitations of this RCA with the
8a (69) transb
8b (76) cis/trans¼4:6b
ði ꢁ PrOÞ2ðOÞPCFꢀ2 radical and our preliminary results obtained
with the EtO2CCFꢀ radical. The liberation of the phosphonodi-
a
Isolated yields.
2
b
Determined by 19F and HOESY.
fluoromethyl radical was conducted with iodophosphonate 1a
(1 equiv) and triethylborane (0.6e1.2 equiv, 1 M solution in n-
hexane) in the presence of enones (1.2 equiv). This reaction did not
proceed in the presence of sodium hydrosulfite (Na2S2O4), or
dilauroyl peroxide as initiators, but good results were obtained in
the presence of triethylborane. Encouraged by the result obtained
In agreement with literature precedents, the formal conjugate
addition products, obtained in this reaction, were produced
through the formation of the corresponding boron enolate formed
via radical-polar crossover process (Scheme 4).48,49 In order to trap
this boron enolate, a three-component reaction was carried out by
addition of Et3B (1.2 equiv) to a solution of 1a, p-bromobenzalde-
hyde (1.3 equiv), and enone 2 (1.3 equiv) in CH2Cl2.50 After 4 h of
stirring at 20 ꢂC, the 19F NMR analysis of the crude showed the
formation of product 2a, in combination with additional products,
appearing as a second order pattern. Due to the complexity of the
pattern, the ratio 9a/9a02a was estimated to 2:2:1. After purification
one isomer was obtained in the presence of compound 2a, and the
other was isolated as a pure compound in 69% yield.
with 2 the reaction was extended to
(Scheme 2). The introduction of a methyl group onto the
atom was tolerated, and the radical trapped with -substituted
linear enone 3 afforded ketone 3a in 49% yield (Scheme 2). The
addition onto -disubstituted enone 4 was also possible and
b- and
a,
b
-substituted enones
b
carbon
b
a,b
product 4a was isolated in similar yield as a mixture of di-
astereomers (Scheme 2).
The alkoxycarbonyldifluoromethyl radical EtO2CCFꢀ described
2
as rather electrophilic radical than nucleophilic,22,23,28 was then
involved in the RCA. When the experimental procedure used for 1a
was applied to ethyl iododifluoroacetate 1b and enone 2 (Scheme
2), the expected RCA product 2b was produced and isolated in
81% yield after 6 h at 20 ꢂC (Scheme 2). As expected, this result
supports that the carboxydifluoromethyl radical presents also an
ambiphilic character. Indeed, it has been shown recently that
photochemical activation promoted the formation and the addition
of this radical onto acrylate derivatives.38 Addition onto acyclic
enones such as ketones 3, 4 afforded the corresponding ketoesters
3b32,46 and 4b in 64 and 79% yields, respectively (Scheme 2). The
epimerization of 4b was observed in the medium, leading to
a mixture of both cis/trans isomers.
O
O
RF
BEt3
OBEt2
O
OH
PhpBr
pBrPhCHO
RF
Et
EtI
RF
RF
9a-9a'
H2O
RFI
RF = CF2P(O)(OiPr)2
O
This reaction was then extended to cyclic enones 5e8 (Scheme
3). The radical generated from 1a can be added onto five- and
six-membered cyclic enones 5, 6 and also onto larger cyclic enone,
such as cycloheptenone 7 to afford the formal conjugate addition
products 5ae7a in 58e69% yield (Table 1, Scheme 3). The scope and
limitations of the RCA were explored using substituted cyclic
enones (Table 1, Scheme 3). The enone 8 reacted smoothly to pro-
duce the cycloalkanone 8a in 69% yield (Table 1, Scheme 3). The
product 8a was not stable in the medium and fast epimerization
occurred over the reaction or during the work-up affording a single
RF
Scheme 4. Mechanism for the addition to enones.
2a
To extend this reaction to lactones, the intermediate radical was
trapped with Barton carbonate instead of Et3B. Indeed, it is known
that the use of Et3B as free radical initiator allowed the formation of
boron enolates only from ketones and aldehydes.51,52 Of note, the
reaction did not reach completion when the experiment was con-
ducted from lactone 10 and 1a only in the presence of Et3B (Scheme
isomer.47 However, the reaction failed when
b-substituted cyclic
enone was involved. The carboxydifluoromethyl radical formed
from 1b was trapped with cyclic enones 5e7, and corresponding

5922
C. De Schutter et al. / Tetrahedron 69 (2013) 5920e5926
5). To drive the formation of carbon centered radicals from lactones,
the Barton carbonate (pyridine-2-thione-N-oxycarbonyl,
PTOCeOMe) was used as radical trap. The radical addition reaction
was conducted by adding slowly solution of PTOCeOMe
(1.5 equiv), and simultaneously a Et3B solution (1.2 equiv, 1 M in n-
hexane) to a mixture of lactone 10 and 1a (Scheme 5). After 5 h of
stirring at room temperature, compound 10a was formed in the
presence of additional two pyridine-sulfanyl derivatives 11 and 12
in a 1:1:3 ratio.
in the present case, that Et3B may also play the role of Lewis acid.53
These results confirmed that the group transfer reaction is possible
rather with electron-rich alkenes in the presence of sodium
hydrosulfite than with electron-deficient alkenes (Scheme 6).
When electron-deficient alkenes, such as enones, were involved,
the radical addition is possible only in the presence of Et3B, which
drives the reaction by forming the boron enolate as depicted in
Scheme 4. This reaction was conducted with iodoester 1b and
similar product distribution was observed. In this case the main
products were obtained in the presence of many unidentified
fluorinated adducts, making impossible their purification.
a
3. Conclusion
N
S
OCOMe
O
In conclusion, triethyl borane promoted the addition of car-
bonyl- and phosphono-difluoromethyl radicals onto electron-
deficient alkenes, such as enones. These gem-difluorinated radi-
cals present an ambiphilic character, allowing their addition onto
electron-rich and electron-poor alkenes. Depending on the free
radical initiator, it was possible to control the addition reaction.
While sodium hydrosulfite promoted their addition onto electron-
rich alkenes to afford the expected iodoalkanes, triethyl borane
promoted their addition onto electron-poor alkenes, leading to the
corresponding fluorinated ketones. This approach is competitive
with the rare formal anionic conjugate addition reaction of fluo-
roalkyl group onto enones, and opens new routes for the synthesis
of fluorinated biological active compounds. Current works are un-
der investigation to understand the mechanism involved in the
selective free radical addition and to access to highly functionalized
fluoroorganic compounds by cascade reactions.
1a, Et3B, DCM,
O
O
O
O
C
O
+
SPy
CF2P(O)(OiPr)2
11
CF2P(O)(OiPr)2
10a
10
+
(iPrO)2(O)PCF2SPy
12
Scheme 5. Reaction with PTOCeOMe.
The major compound 12 was formed by the free radical addition
of the fluorinated radical onto PTOCeOMe and was isolated in 40%
yield. The minor product 11 was formed by the addition of the
intermediate radical onto PTOCeOMe. The two products 10a and 11
were obtained as an inseparable mixture by flash chromatography.
However, compound 12 was still the main product of the reaction
even when slow additions of the PTOCeOMe reagent or the Et3B
solution were carried out.
Finally, selective radical addition from 1a was attempted by
mixing electron-rich and electron-poor alkenes, such as enone 2
and 1-octene 13 (Scheme 6). The two radical initiators tested were
Et3B (method A: Et3B, CH2Cl2, 20 ꢂC) and sodium hydrosulfite
(method B: Na2S2O4, NaHCO3, CH3CN/H2O, 20 ꢂC). To our surprise,
depending on the initiator it was possible to control the addition
reaction. In the presence of Et3B, the RCA of the phosphonylated
radical onto 2 was the main reaction observed. Products 2a and 14
were formed in 4:1 ratio, and ketophosphonate 2a was isolated in
63% yield. In contrast, in the presence of sodium hydrosulfite the
opposite selectivity was observed (2a/14¼1:9), and compound 14
resulting from the group transfer reaction of 1a onto 13 was iso-
lated in 52% yield. The polarity-matched and -mismatched re-
actions of perfluoroalkyl radicals were recently studied, suggesting
4. Experimental section
4.1. General information
All commercially available reagents were bought from Aldrich
and used as received. For anhydrous conditions, the glassware was
dried in the oven at 120 ꢂC and cooled to room temperature under
a continuous nitrogen flow. THF, CH2Cl2, Et2O, and CH3CN were
dried at a solvent generator from ‘Innovative Technologies Inc.’,
which uses an activated alumina column to remove water. DMF and
ꢁ
NEt3 were distilled under CaH2 or 4 A molecular sieves. Flash col-
umn chromatography was realized on silica gel 60 (40e63
mm)
with air pressure and were detected by thin layer chromatography,
on which the spots were visualized by UV-irradiation and/or
KMnO4 solution. NMR spectra were recorded on a 250 MHz or
400 MHz apparatus in deuterated solvent at 25 ꢂC. 31P and 19F NMR
spectral lines are with respect to the internal references H3PO4
O
(capillary) and CFCl3. All chemical shifts are reported in
d parts per
1a
CF2P(O)(OiPr)2
Method A
million (ppm) and coupling constants are in hertz (Hz). High-
resolution mass data were recorded on a high-resolution mass
spectrometer in the EI or ESI mode. High-resolution mass data were
recorded on a Micromass Q-TOF (Quadrupole Time-of-Flight) in-
strument with an electrospray source in the EI or ESI mode.
or B
2a
+
2
+
I
5
see text
13
(iPrO)2(O)PCF2
5
14
Method A (BEt3):
Method B (Na2S2O4):
2a 63%
2a 5%
14 10%
14 52%
4.2. Diisopropyl 1,1-difluoro-4-oxohexylphosphonate (2a)45
General procedure for the radical conjugated addition. To a stirred
solution of iododifluoromethylphosphonate 1a (100.0 mg,
0.29 mmol) and ethylvinylketone (0.04 mL, 0.40 mmol) in CH2Cl2
(2 mL) was added Et3B (0.36 mL, 1 M in hexane, 1.2 equiv) over 4 h
by portion of 0.1 equiv every 20 min at 20 ꢂC. The mixture was then
concentrated under reduced pressure. Compound 2a was isolated
after flash chromatography (EtOAc/pentane 4:6) as a colourless oil
5
RFI
RF
I
5
5
RF
RF
13
14
(69.8 mg, 79%). 1H NMR (CDCl3, 400 MHz)
2H), 2.69 (t, J 7.3 Hz, 2H), 2.44 (q, J 7.3 Hz, 2H), 2.41e2.35 (m, 2H),
d 4.80 (dsept, J 6.4, 6.4 Hz,
Scheme 6. Selective addition reaction, and mechanism for the group transfer reaction.

C. De Schutter et al. / Tetrahedron 69 (2013) 5920e5926
5923
1.34 (d, J 6.4 Hz, 6H), 1.33 (d, J 6.4 Hz, 6H), 1.04 (t, J 7.3 Hz, 3H); 19
F
261.3, 216.7 Hz), 74.1 (d, J 7.0 Hz), 74.0 (d, J 7.0 Hz), 40.7 (td, J 21.3,
15.1 Hz), 38.3, 37.7, 24.2, 23.9, 22.3 (td, J 5.5, 5.5 Hz). MS-ESI (m/z)
[MþNa]þ 321 (18), 279 (40), 237 (100). HRMS-ESI (m/z) [MþNa]þ
calcd for C12H21O4F2PNa 321.1043, found 321.1039.
NMR (CDCl3, 376 MHz)
NMR (CDCl3, 161 MHz)
d
ꢁ112.84 (dt, J 108.2 Hz, 19.6 Hz, 2F); 31P
d
4.9 (t, J 108.2 Hz, 1P); 13C NMR (CDCl3,
101 MHz) d 208.9, 120.3 (td, J 259.1, 217.9 Hz), 73.7 (d, J 7.1 Hz), 36.1,
33.7 (td, J 9.0, 4.6 Hz), 28.1 (td, J 21.5, 15.7 Hz), 24.2 (d, J 3.3 Hz), 23.8
(d, J 4.8 Hz), 7.9. MS-ESI (m/z) [MþNa]þ 323 (54), 281 (50), 239
(100), 221 (8). HRMS-ESI (m/z) [MþNa]þ calcd for C12H23O4PF2Na
323.1194, found 323.1200.
4.6. Diisopropyl difluoro(3-oxocyclohexyl)methyl-
phosphonate (6a)45
Following the general procedure used for 2a from iododi-
fluorophosphonate 1a (50.0 mg, 0.15 mmol), 2-cyclohexenone
(0.017 mL, 0.18 mmol), and Et3B (0.18 mL) in CH2Cl2 (1 mL), com-
pound 6a was isolated after flash chromatography (EtOAc/pentane
5:5) as a colourless oil (28.4 mg, 62%). 1H NMR (CDCl3, 400 MHz)
4.3. Diisopropyl 1,1-difluoro-2-methyl-4-
oxohexylphosphonate (3a)
Following the general procedure used for 2a from iododi-
fluorophosphonate 1a (100 mg, 0.29 mmol), trans-4-hexen-3-one
(0.037 mL, 0.32 mmol), and Et3B (0.36 mL) in CH2Cl2 (2 mL),
compound 3a was isolated after flash chromatography (EtOAc/
pentane 2:8 to 3:7) as a colourless oil (45.2 mg, 49%). 1H NMR
d
4.84 (dsept, J 6.2, 6.2 Hz, 1H), 4.83 (dsept, J 6.2, 6.2 Hz, 1H),
2.58e2.44 (m, 1H), 2.68e1.61 (m, 8H), 1.37 (d, J 6.2 Hz, 6H), 1.36 (d, J
6.2 Hz, 6H); 19F NMR (CDCl3, 376 MHz)
d
ꢁ115.81 (ddd, J 299.1,108.1,
13.5 Hz, 1F), ꢁ118.02 (ddd, J 299.1, 108.1, 15.9 Hz, 1F); 31P NMR
(CDCl3, 400 MHz)
d
4.78 (dsept, J 6.9, 6.9 Hz, 2H), 3.03e2.36 (m, 2H),
(CDCl3, 161 MHz) d
4.6 (t, J 108.1 Hz, 1P); 13C NMR (CDCl3, 101 MHz)
2.95e2.79 (m, 1H), 2.53e2.36 (m, 2H), 1.38e1.36 (m, 12H), 1.09 (d, J
d 209.0, 120.0 (td, J 263.0, 214.2 Hz), 73.9 (d, J 5.5 Hz), 73.8 (d, J
6.9 Hz, 3H), 1.06 (t, J 7.3 Hz, 3H); 19F NMR (CDCl3, 376 MHz)
5.7 Hz), 42.8 (td, J 20.6, 15.3 Hz), 41.1, 39.9 (td, J 7.9, 4.7 Hz), 24.3,
24.2, 23.8. MS-ESI (m/z) [MþH]þ 313 (40), 271 (100), 229 (75).
HRMS-ESI (m/z) [MþH]þ calcd for C13H24O4F2P 313.1380, found
313.1391.
d
ꢁ114.88 (ddd, J 297.4, 110.5, 17.1 Hz, 1F), ꢁ116.47 (ddd, J 297.4,
110.5, 17.1 Hz, 1F); 31P NMR (CDCl3, 161 MHz)
5.1 (t, J 110.5 Hz, 1P);
13C NMR (CDCl3, 101 MHz)
208.8, 121.5 (td, J 262.8, 213.9 Hz), 73.8
d
d
(d, J 7.2 Hz), 73.7 (d, J 7.2 Hz), 42.2 (td, J 7.3, 4.0 Hz), 36.6, 33.8 (td, J
20.4, 15.5 Hz), 24.3, 23.9, 13.4, 7.8. MS-ESI (m/z) [MþNa]þ 337 (19),
295 (43), 253 (100), 235 (19). HRMS-ESI (m/z) [MþNa]þ calcd for
C13H25O4PF2Na 337.1356, found 337.1355.
4.7. Diisopropyl difluoro(3-oxocycloheptyl)methyl-
phosphonate (7a)
Following the general procedure used for 2a from iododi-
fluorophosphonate 1a (200.0 mg, 0.58 mmol), 2-cyclohepten-1-
one (0.080 mL, 0.72 mmol), and Et3B (0.72 mL) in CH2Cl2 (4 mL),
compound 7a was isolated after flash chromatography (EtOAc/
pentane 4:6) as a colourless oil (83.0 mg, 57%). 1H NMR (CDCl3,
4.4. Diisopropyl (2-acetylcyclohexyl)di-
fluoromethylphosphonate (4a)
General procedure for the radical conjugate addition. To a stirred
solution of iododifluoromethylphosphonate 1a (50 mg, 0.15 mmol),
and 1-acetylcyclohexene (0.023 mL, 0.18 mmol) in CH2Cl2 (1 mL)
was added Et3B (0.18 mL, 1 M in hexane, 1.2 equiv). After 1 h of
stirring, Et3B was added (0.18 mL, 1 M in hexane, 1.2 equiv) and the
mixture was stirred additional 1 h. The mixture was then concen-
trated under reduced pressure. Compound 4a was isolated after
flash chromatography (EtOAc/pentane 2:8) as a colourless oil
(23.9 mg, 48%) in a cis/trans mixture (92:8). 1H NMR (CDCl3,
400 MHz) d 4.87e4.81 (m, 2H), 2.82 (dd, J 15.1, 2.4 Hz, 1H), 2.61 (dd,
J 15.1, 11.6 Hz, 1H), 2.52e2.48 (m, 2H), 2.47e2.37 (m, 1H), 2.36e1.40
(m, 6H), 1.38 (d, J 6.0 Hz, 6H), 1.37 (d, J 6.0 Hz, 6H); 19F NMR (CDCl3,
376 MHz)
298.6, 109.4, 17.3 Hz, 1F); 31P NMR (CDCl3, 161 MHz)
109.4 Hz, 1P); 13C NMR (CDCl3, 101 MHz)
211.8, 120.9 (td, J 264.6,
d
ꢁ113.33 (ddd, J 298.6, 109.4, 15.6 Hz, 1F), ꢁ116.02 (ddd, J
d
5.0 (t, J
d
213.9 Hz), 73.9 (d, J 7.3 Hz), 73.8 (d, J 7.3 Hz), 43.5, 42.5, 41.3 (td, J
19.9,15.6 Hz), 29.0, 28.4, 24.4, 24.2, 23.7. MS-ESI (m/z) [MþNa]þ 349
(5), 307 (19), 265 (100). HRMS-ESI (m/z) [MþNa]þ calcd for
C14H25O4F2PNa 349.1356, found 349.1356.
400 MHz)
1H), 2.43e2.23 (m, 1H), 2.19 (s, 3H), 1.90e1.24 (m, 8H), 1.36 (m,
12H); 19F NMR (CDCl3, 376 MHz)
d 4.82 (dsept, J 6.3, 6.3 Hz, 2H), 3.16 (ddd, J 4.1, 4.1, 4.1 Hz,
d
ꢁ103.08 (dd, J 298.5,106.3 Hz,1F,
trans), ꢁ110.00 (dd, J 298.5, 107.9 Hz, 1F, cis), ꢁ112.77 (ddd, J 298.5,
107.9, 24.1 Hz, 1F, cis), ꢁ118.80 (ddd, J 298.5, 106.3, 23.9 Hz, 1F,
4.8. Diisopropyl difluoro(2-methyl-3-oxocyclopentyl)methyl-
phosphonate (8a)
trans); 31P NMR (CDCl3, 161 MHz)
d 5.2 (t, J 107.9 Hz, 1P, cis), 4.6 (dd,
J 110.5, 106.3 Hz, 1P, trans); 13C NMR (CDCl3, 101 MHz)
d
210.2, 120.0
General procedure for the radical conjugate addition. To a stirred
solution of iododifluoromethylphosphonate 1a (100 mg,
0.29 mmol) and 3-methyl-2-cyclopentenone (0.035 mL,
0.35 mmol) in CH2Cl2 (2 mL) was added Et3B (0.35 mL, 1 M in
hexane, 1.2 equiv). After 1 h of stirring, Et3B was added (0.35 mL,
1 M in hexane,1.2 equiv) and the mixture was stirred additional 1 h.
The mixture was then concentrated under reduced pressure.
Compound 8a was isolated after flash chromatography (EtOAc/
pentane 4:6 to 5:5) as a colourless oil (62.7 mg, 69%). 1H NMR
(td, J 263.0, 214.0 Hz), 73.9 (d, J 6.9 Hz), 73.7 (d, J 7.0 Hz), 44.3, 30.8,
27.5, 25.0, 24.3 (d, J 3.3 Hz), 24.1 (d, J 3.5 Hz), 23.9 (d, J 5.2 Hz), 23.7
(d, J 4.5 Hz), 21.2, 21.1. MS-ESI (m/z) [MþH]þ 341 (8), 299 (32), 257
(100), 239 (15). HRMS-ESI (m/z) [MþH]þ calcd for C15H28O4F2P
341.1693, found 341.1690.
4.5. Diisopropyl difluoro(3-oxocyclopentyl)methyl-
phosphonate (5a)45
(CDCl3, 400 MHz)
6.3 Hz, 1H), 2.59e1.92 (m, 6H), 1.38 (d, J 6.1 Hz, 6H), 1.36 (d, J 6.1 Hz,
6H), 1.23 (d, J 6.8 Hz, 3H); 19F NMR (CDCl3, 376 MHz)
ꢁ110.79
(ddd, J 300.0, 108.5, 9.3 Hz, 1F), ꢁ119.91 (ddd, J 300.0, 108.5, 21.8 Hz,
1F); 31P NMR (CDCl3, 161 MHz) 4.6 (t, J 108.5 Hz, 1P); 13C NMR
(CDCl3, 101 MHz) 218.1, 120.9 (td, J 259.8, 215.1 Hz), 74.0 (d, J
d 4.86 (dsept, J 6.3, 6.3 Hz, 1H), 4.85 (dsept, J 6.3,
Following the general procedure used for 2a from iododi-
fluorophosphonate 1a (100.0 mg, 0.29 mmol), 2-cyclopentenone
(0.049 mL, 0.58 mmol), and Et3B (0.36 mL) in CH2Cl2 (2 mL),
compound 5a was isolated after flash chromatography (EtOAc/
pentane 5:5) as a colourless oil (49.3 mg, 56%). 1H NMR (CDCl3,
d
d
d
400 MHz)
d
4.85 (dsept, J 6.5, 6.5 Hz, 1H), 4.84 (dsept, J 6.5, 6.5 Hz,
7.2 Hz), 73.8 (d, J 7.2 Hz), 48.2 (td, J 20.0, 15.2 Hz), 43.5, 36.8, 24.2 (d,
J 3.3 Hz), 24.1 (d, J 3.7 Hz), 23.8 (d, J 4.8 Hz), 23.7 (d, J 4.9 Hz), 21.1
(td, J 3.7, 3.7 Hz), 15.1 (d, J 2.3 Hz). MS-ESI (m/z) [MþNa]þ 335 (22),
293 (44), 251 (100). HRMS-ESI (m/z) [MþNa]þ calcd for
C13H23O4F2PNa 335.1200, found 335.1216.
1H), 3.02e2.85 (m, 1H), 2.49e2.06 (m, 6H), 1.39e1.37 (m, 12H); 19F
NMR (CDCl3, 376 MHz)
d
ꢁ117.13 (ddd, J 298.0, 108.5, 17.1 Hz, 1F),
ꢁ118.83 (ddd, J 298.0, 108.5, 15.7 Hz, 1F); 31P NMR (CDCl3, 161 MHz)
d
4.8 (t, J 108.5 Hz, 1P); 13C NMR (CDCl3, 101 MHz)
d 216.1, 120.1 (td, J

5924
C. De Schutter et al. / Tetrahedron 69 (2013) 5920e5926
4.9. Three-component reaction: diisopropyl 1,1-difluoro-3-
(hydroxy-parabromobenzyl)-4-oxohexylphosphonate (9a)
(ddd, J 8.1, 4.9, 1.0 Hz, 1H), 4.91e4.80 (m, 2H), 4.75 (ddd, J 11.0, 11.0,
2.4 Hz, 1H), 4.53e4.47 (m, 1H), 4.37 (d, J 7.2 Hz, 1H), 3.25e3.11 (m,
1H), 2.42e2.32 (m, 1H), 2.23e2.13 (m, 1H), 1.36e1.31 (m, 12H); 19
F
To a solution of iodophosphonate 2a (100 mg, 0.29 mmol), para-
NMR (CDCl3, 376 MHz)
d
ꢁ111.83 (ddd, J 302.8, 104.2, 8.7 Hz, 1F),
bromobenzaldehyde (70 mg, 0.37 mmol), and enone 2 (40
mL,
ꢁ118.08 (ddd, J 302.8, 104.2, 21.5 Hz, 1F); 31P NMR (CDCl3, 161 MHz)
0.40 mmol) in CH2Cl2 (2 mL) was added Et3B (360 L,1 M in hexane,
m
d
3.5 (t, J 104.2 Hz, 1P). MS-ESI (m/z) [MþH]þ 424 (7), 382 (27), 340
1.2 equiv) over 4 h by portion of 0.1 equiv every 20 min at 20 ꢂC. The
mixture was quenched by addition of saturated solution NH4Cl
(1 mL), extracted with CH2Cl2 (2ꢃ2 mL), then concentrated under
reduced pressure. The isomer 9a was isolated by flash chroma-
tography (EtOAc/pentane 4:6) as a colourless oil (98 mg, 69%). 1H
(100), 322 (22). HRMS-ESI (m/z) [MþH]þ calcd for C17H25NO5F2PS
424.1159, found 424.1138. Compound (12): 1H NMR (CDCl3,
400 MHz)
d 8.55e8.52 (m, 1H), 7.64e7.61 (m, 2H), 7.24e7.18 (m,
1H), 4.85 (dsept, J 6.2, 6.2 Hz, 2H), 1.33 (dd, J 6.2, 2.4 Hz, 12H); 19F
NMR (CDCl3, 376 MHz)
161 MHz) d d 150.6,
d
ꢁ84.33 (d, J 98.0 Hz, 2F); 31P NMR (CDCl3,
NMR (CDCl3, 400 MHz)
d
7.43 (d, J 8.9, 2H), 7.18 (d, J 8.9, 2H),
1.3 (t, J 98.0 Hz, 1P); 13C NMR (CDCl3, 101 MHz)
4.85e4.57 (m, 3H), 3.58 (d, J 2.5, 1H), 3.31e3.23 (m, 1H), 2.9e1.95
150.4, 137.3, 129.8, 126.8 (td, J 300.7, 219.6 Hz), 123.6, 75.1 (d, J
6.9 Hz), 24.3 (d, J 3.2 Hz), 23.8 (d, J 5.2 Hz). MS-ESI (m/z) [MþH]þ
326 (10), 284 (33), 242 (100). HRMS-ESI (m/z) [MþH]þ calcd for
C12H19NO3F2PS 326.0791, found 326.0801.
(m, 4H), 1.40e1.20 (m, 12H), 0.84 (t, J 6.9, 3H); 19F NMR (CDCl3,
376 MHz)
294.1, 109.3, 29.4, 14.8, 1F); 31P NMR (CDCl3, 161 MHz)
109.4, 104.2 Hz); 13C NMR (CDCl3, 101 MHz)
213.1, 140.4, 131.5,
d
ꢁ107.8 (dddd, J 294.1, 104.3, 29.4, 8.3, 1F), ꢁ113.0 (dddd,
d
4.2 (dd, J
d
127.9, 121.6, 120.1 (td, J 259.8, 217.3 Hz), 73.9 (d, J 7.5 Hz), 73.8 (d, J
7.8 Hz), 72.9, 51.4 (td, J 5.2, 2.5), 37.5, 32.0 (td, J 20.7,16.0 Hz), 24.1 (d,
J 3.3 Hz), 24.0 (d, J 3.4 Hz), 23.6 (d, J 5.2 Hz), 23.5 (d, J 5.1 Hz), 7.1.
HRMS-ESI (m/z) [MþNa]þ calcd for C12H28O5PBrF2Na 507.0718,
found 507.0724.
4.12. Selective radical addition with enone and octene: dii-
sopropyl 1,1-difluoro-3-iodononylphosphonate (14)
General procedure for the selective radical addition with trie-
thylborane. To a stirred solution of iododifluoromethylphosphonate
1a (50 mg, 0.15 mmol), ethylvinylketone (0.017 mL, 0.18 mmol), and
1-octene (0.028 mL, 0.18 mmol) in CH2Cl2 (2 mL) was added Et3B
(0.18 mL, 1 M in hexane, 1.2 equiv) over 4 h by portion of 0.1 equiv
every 20 min at 20 ꢂC. The mixture was then concentrated under
reduced pressure. The residue was purified by flash chromatogra-
phy using EtOAc/pentane 3:7 as eluent to give compound 14
(6.7 mg, 10%) and compound 2a (27.7 mg, 63%) as colourless oils.
4.10.
b-(Diisopropyl 1,1-difluoromethylphosphonate)-d-valer-
olactone (10a)
Following the general procedure used for 2a from iododi-
fluorophosphonate 1a (150 mg, 0.44 mmol), 5,6-dihydro-2H-py-
ran-2-one (0.096 mL, 1.11 mmol), and Et3B (0.54 mL) in CH2Cl2
(2 mL), compound 10a was isolated after flash chromatography
(CH2Cl2 then EtOAc/pentane 5:5) as a colourless oil (43.9 mg, 32%).
4.13. General procedure for selective radical addition with
sodium dithionite
1H NMR (CDCl3, 400 MHz)
d 4.86 (dsept, J 6.3, 6.3 Hz, 1H), 4.84
(dsept, J 6.3, 6.3 Hz, 1H), 4.40 (dt, J 11.5, 5.0 Hz, 1H), 4.25 (ddd, J 11.5,
9.3, 3.8 Hz, 1H), 2.83e2.66 (m, 3H), 2.15e2.10 (m, 1H), 2.08e2.04
To a solution of sodium dithionite (102 mg, 0.59 mmol), sodium
carbonate (25 mg, 0.24 mmol), ethylvinylketone (0.017 mL,
0.18 mmol), and 1-octene (0.028 mL, 0.18 mmol) in a 5:3 mixture of
CH3CN/H2O (0.5 mL), iododifluoromethylphosphonate 1a (50 mg,
0.15 mmol) in CH3CN/H2O 5:3 was introduced. The mixture was
stirred at room temperature for 15 h and then poured into Et2O
(5 mL) and H2O (1 mL). The organic layer was washed with brine,
dried over MgSO4, filtered and concentrated under vacuum. The
residue was purified by flash chromatography using EtOAc/pentane
3:7 as eluent to give compound 14 (34.5 mg, 52%) and compound
2a (2.1 mg, 5%) as colourless oils. Diisopropyl 1,1-difluoro-3-
(m, 1H), 1.39e1.36 (m, 12H); 19F NMR (CDCl3, 376 MHz)
d
ꢁ118.20
(ddd, J 300.4, 105.6, 14.3 Hz, 1F), ꢁ119.31 (ddd, J 300.4, 105.6,
14.3 Hz, 1F); 31P NMR (CDCl3, 161 MHz) 4.0 (t, J 105.6 Hz, 1P); 13
NMR (CDCl3, 101 MHz) 169.7, 119.6 (td, J 263.4, 214.1 Hz), 74.4 (d, J
d
C
d
7.5 Hz), 74.3 (d, J 7.5 Hz), 67.4, 36.2 (td, J 21.4, 15.7 Hz), 28.8 (td, J 5.5,
5.5 Hz), 24.3 (d, J 3.6 Hz), 24.2 (d, J 3.9 Hz), 23.9 (d, J 4.8 Hz), 23.8 (d, J
4.8 Hz), 22.2 (td, J 5.5, 5.5 Hz). MS-ESI (m/z) [MþNa]þ 337 (20), 295
(44), 253 (100). HRMS-ESI (m/z) [MþNa]þ calcd for C12H21O5F2PNa
337.0992, found 337.0982.
4.11. Diisopropyl difluoro-(3S,4S)-2-oxo-3-(pyridin-2-
iodononylphosphonate (14): 1H NMR (CDCl3, 400 MHz)
d 4.84
ylthio)(tetrahydro-2H-pyran-4-yl)-methylphosphonate (11)
(dsept, J 6.4, 6.4 Hz,1H), 4.83 (dsept, J 6.4, 6.4 Hz,1H), 4.46e4.38 (m,
1H), 3.00e2.70 (m, 2H), 1.80e1.71 (m, 2H), 1.55e1.23 (m, 8H), 1.37
(d, J 6.2 Hz, 6H), 1.36 (d, J 6.2 Hz, 6H), 0.87 (t, J 6.7 Hz, 3H); 19F NMR
General procedure for the Barton carbonate preparation. The so-
dium salt of N-hydroxypyridine-2-thione (55 mg, 0.36 mmol) and
methyl chloroformate (33 mg, 0.35 mmol) in CH2Cl2 (1 mL) were
(CDCl3, 376 MHz)
d
ꢁ110.50 (dddd, J 296.7, 105.6, 30.5, 10.4 Hz, 1F),
ꢁ113.91 (dddd, J 296.7, 105.6, 26.8, 10.7 Hz, 1F); 31P NMR (CDCl3,
stirred for
1
h
in the dark. To
a
solution of iododi-
161 MHz) d d 120.0
4.2 (t, J 105.6 Hz, 1P); 13C NMR (CDCl3, 101 MHz)
fluoromethylphosphonate 1a (50 mg, 0.15 mmol) and 5,6-dihydro-
2H-pyran-2-one (0.045 mL, 0.53 mmol) in CH2Cl2 (1.5 mL),
PTOCeOMe (1.5 equiv), freshly prepared, was introduced dropwise
over 4 h. Following general procedure used for 2a, Et3B (0.18 mL,
1 M in hexane) was added, at the same time, to the mixture and the
reaction mixture was stirred at room temperature for 4 h. The
mixture was quenched with H2O, and extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under vacuum. The residue was
purified by flash chromatography using CH2Cl2 then EtOAc/pentane
5:5 as eluent to give 11 in a mixture with the reduced product 10a
(1:1) as a colourless oil (11.7 mg, 10% 11, 13% 10a) and mostly
pyridine-sulfanyl derivative 12 as a colourless oil (19.5 mg, 40%).
(td, J 263.0, 214.6 Hz), 74.0 (d, J 6.2 Hz), 73.9 (d, J 6.2 Hz), 44.7 (td, J
19.8,14.6 Hz), 40.6 (d, J 1.6 Hz), 31.6, 29.7, 28.3, 24.2 (d, J 3.3 Hz), 24.1
(d, J 3.3 Hz), 23.9, 23.8 (d, J 4.8 Hz), 22.6, 14.1. MS-ESI (m/z) [MþNa]þ
477 (20), 435 (45), 393 (100), 349 (55), 307 (51), 287 (24), 265 (73),
243 (24). HRMS-ESI (m/z) [MþNa]þ calcd for C15H30O3F2PINa
477.0843, found 477.0864.
4.14. Ethyl 2,2-difluoro-5-oxoheptanoate (2b)
General procedure used for 2a was followed with ethyl iododi-
fluoroacetate (53 mg, 0.22 mmol), ethyl vinyl ketone (0.027 mL,
0.27 mmol), Et3B (0.264 mL), and CH2Cl2 (1 mL). Purification by
flash chromatography (EtOAc/pentane 5:5) afforded 2b as a col-
Compound (11): 1H NMR (CDCl3, 400 MHz)
1H), 7.52 (ddd, J 8.1, 8.1, 1.0 Hz, 1H), 7.23 (dd, J 8.1, 1.0 Hz, 1H), 7.02
d
8.36 (dd, J 4.9, 1.8 Hz,
ourless oil (37.8 mg, 81%). 1H NMR (CDCl3, 400 MHz)
d
4.27 (q, J
7.1 Hz, 2H), 2.62 (t, J 7.2 Hz, 2H), 2.42 (q, J 7.3 Hz, 2H), 2.40e2.35 (m,

C. De Schutter et al. / Tetrahedron 69 (2013) 5920e5926
5925
2H), 1.32 (t, J 7.1 Hz, 3H), 1.00 (t, J 7.3 Hz, 3H); 19F NMR (CDCl3,
15.6 Hz, 1F, trans); 13C NMR (CDCl3, 101 MHz)
d
217.4 (cis), 217.2
376 MHz)
d
ꢁ106.50 (t, J 17.1 Hz, 2F); 13C NMR (CDCl3, 101 MHz)
(trans), 163.9 (t, J 32.7 Hz, cis), 163.7 (t, J 32.7 Hz, trans), 117.0 (t, J
252.4 Hz, cis), 116.4 (t, J 252.4 Hz, trans), 63.2 (cis), 63.2 (trans), 47.9
(t, J 22.9 Hz, trans), 44.7 (d, J 5.0 Hz, cis), 43.7 (d, J 2.9 Hz, trans), 43.4
(t, J 22.2 Hz, cis), 36.3 (cis), 35.2 (trans), 20.3 (trans and cis), 14.3
(trans), 14.0 (trans), 13.9 (cis), 10.6 (cis). HRMS compound unstable.
d
208.3, 164.0 (t, J 32.7 Hz), 115.7 (t, J 250.0 Hz), 63.0, 35.9, 34.0 (t, J
3.7 Hz), 28.5 (t, J 23.9 Hz), 13.9, 7.7. HRMS-ESI (m/z) [MþNa]þ calcd
for C9H14O3F2Na 231.0809, found 231.0804.
4.15. Ethyl 2-(2-acetylcyclohexyl)-2,2-difluoroacetate (4b)
Acknowledgements
General procedure used for 4a was followed with ethyl iododi-
fluoroacetate 1b (132 mg, 0.56 mmol), 1-acetylcyclohexene
(0.065 mL, 0.51 mmol), Et3B (1.340 mL), and CH2Cl2 (2 mL). Puri-
fication by flash chromatography (CH2Cl2/pentane 6:4) afforded
10b as a colourless oil (99.1 mg, 79%) in a cis/trans mixture (97:3).
ꢂ
This work was supported by the CNRS, the ‘Ministere de l’en-
ꢀ
signement superieur et de la recherche’ and the Crunch Network
(interregional organic chemistry network Region Basse-
Normandie).
1H NMR (CDCl3, 400 MHz)
d
4.35e4.20 (m, 2H), 3.00 (ddd, J 4.0, 4.0,
4.0 Hz,1H), 2.35e2.18 (m,1H), 2.18e1.17 (m, 8H), 2.13 (s, 3H),1.32 (t,
J 7.1 Hz, 3H); 19F NMR (CDCl3, 376 MHz)
Supplementary data
d
ꢁ106.60 (dd, J 268.0,
17.2 Hz, 1F, cis), ꢁ107.89 (dd, J 268.0, J 18.4 Hz, 1F, cis), ꢁ109.69 (dd, J
NMR spectra for all new compounds and HOESY experiment for
compounds 8b. Supplementary data associated with this article can
be found in the online version, at http://dx.doi.org/10.1016/
j.tet.2013.05.006.
257.5, 11.5 Hz, 1F, trans), ꢁ113.82 (dd, J 257.5, 16.1 Hz, 1F, trans); 13C
NMR (CDCl3, 101 MHz) cis isomer: d 209.7, 164.0 (t, J 33.0 Hz), 117.0
(t, J 251.0 Hz), 62.8, 45.0 (t, J 22.2 Hz), 44.4, 30.5, 27.6, 24.8, 21.1, 21.4
(t, J 3.5 Hz), 13.9. MS-ESI (m/z) [MþNa]þ 271 (100), 251 (27), 231
(32). HRMS-ESI (m/z) [MþNa]þ calcd for C12H18O3F2Na 271.1122,
found 271.1113.
References and notes
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(CDCl3, 400 MHz)
2.44e1.95 (m, 6H), 1.35 (t, J 7.1 Hz, 3H); 19F NMR (CDCl3, 376 MHz)
ꢁ111.35 (dd, J 260.7, 14.9 Hz, 1F), ꢁ113.75 (dd, J 260.7, 14.9 Hz, 1F);
13C NMR (CDCl3, 101 MHz)
215.3, 163.6 (t, J 32.8 Hz), 115.9 (t, J
d 4.34 (q, J 7.1 Hz, 2H), 3.06e2.90 (m, 1H),
d
d
252.3 Hz), 63.2, 40.5 (t, J 23.6 Hz), 37.7 (dd, J 4.5, 2.1 Hz), 37.4, 22.0
(dd, J 4.9, 3.4 Hz), 14.0. HRMS compound unstable.
4.17. Ethyl 2,2-difluoro-2-(3-oxocycloheptyl)acetate (7b)
17. Yang, Z.-Y.; Burton, D. J. J. Org. Chem. 1991, 56, 5125e5132.
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(0.112 mL, 1.0 mmol), Et3B (1.0 mL), and CH2Cl2 (4 mL). Purifica-
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ꢀ ꢂ
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a colourless oil (131 mg, 67%). 1H NMR (CDCl3, 400 MHz)
d
4.32 (q, J
22. Leung, L.; Linclau, B. J. Fluorine Chem. 2008, 129, 986e990.
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7.5 Hz, 2H), 2.61e2.41 (m, 5H), 2.07e1.35 (m, 6H), 1.33 (t, J 7.5 Hz,
3H); 19F NMR (CDCl3, 376 MHz)
d
ꢁ110.57 (dd, J 257.0, 13.9 Hz, 1F),
ꢁ113.39 (dd, J 257.0, 13.9 Hz, 1F); 13C NMR (CDCl3, 101 MHz)
d 211.0,
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163.6 (t, J 32.5 Hz), 116.7 (t, J 254.6 Hz), 63.1, 43.5, 42.1, 40.5 (t, J
22.4 Hz), 29.0 (t, J 3.4 Hz), 28.2, 24.2, 14.0. HRMS-ESI (m/z) [MþNa]þ
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(8b)
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a colourless oil (70.2 mg, 76%) in a trans/cis mixture (57:43). 1H
NMR (CDCl3, 400 MHz)
d 4.35e4.28 (m, 2H, trans and cis),
3.13e2.99 (m, 1H, cis), 2.60e2.47 (m, 1H, trans), 2.47e1.77 (m, 5H,
trans and cis), 1.36e1.31 (m, 3H, trans and cis), 1.14 (d, J 7.0 Hz, 3H,
trans), 1.11 (dt, J 7.5, 1.8 Hz, 3H, cis); 19F NMR (CDCl3, 376 MHz)
d
ꢁ106.58 (dd, J 268.3, 17.1 Hz, 1F, cis), ꢁ107.87 (dd, J 268.3, 17.1 Hz,
1F, cis), ꢁ109.71 (dd, J 257.9, 15.6 Hz, 1F, trans), ꢁ113.78 (dd, J 257.9,
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ꢂ
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not stable in the medium, its slow isomerisation afforded the trans isomer as
major product (see Supplementary data).
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