Palladium-Catalyzed Synthesis of Aryl and Heteroaryl Difluoromethylated Phosphonates

Article abstract of DOI:10.1055/s-0036-1589140

We report the palladium-catalyzed introduction of the difluoromethylposphonate unit onto aryl and heteroaryl iodides under mild conditions. Using the CuCF ₂ PO(OEt) ₂ species generated in situ, the method allows the functionalization

Full text of DOI:10.1055/s-0036-1589140

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
en
M. V. Ivanova et al.
Paper
Synthesis
Palladium-Catalyzed Synthesis of Aryl and Heteroaryl
Difluoromethylated Phosphonates
Maria V. Ivanovaa
Tatiana Besseta
Xavier Pannecouckea
Thomas Poisson*a,b
I
CF2PO(OEt)2
R
R
R
[Pd]
CuCF2PO(OEt)2
or
or
0
0
0
0
0-
0
0
2
0-
5
0
3
9-
6
2
0
I
CF2PO(OEt)2
Het
Het
R
19 examples, 38–80% yield
a Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA
(UMR 6014), 76000 Rouen, France
b Institut Universitaire de France, 103 boulevard Saint-Michel,
75005 Paris, France
thomas.poisson@insa-rouen.fr
Published as part of the Bürgenstock Special Section 2017
Future Stars in Organic Chemistry
Received: 28.09.2017
Accepted after revision: 26.10.2017
Published online: 29.11.2017
HO2C
O
DOI: 10.1055/s-0036-1589140; Art ID: ss-2017-z0628-op
NH2
N
N
CF2PO(OR)2
H
O
Protein tyrosine phosphatase inhibitor
Abstract We report the palladium-catalyzed introduction of the di-
fluoromethylposphonate unit onto aryl and heteroaryl iodides under
mild conditions. Using the CuCF2PO(OEt)2 species generated in situ, the
method allows the functionalization of various otherwise reluctant sub-
strates. In addition, this reaction permits the formation of CF2PO(OEt)2-
containing heterocycles, an important class of compounds. This pro-
cess broadens the current toolbox of methods available to construct
CF2PO(OEt)2-containing molecules.
CF2PO(OR)2
STAT3 Phosphorylation inhibitor
O
CF2PO(OR)2
N
O
H
N
N
Key words fluorine, phosphate mimic, synthetic method, palladium,
I
copper
O
STAT6 Phosphorylation inhibitor
Over the last years, organofluorine chemistry became a
very popular research area.1 This tremendous expansion is
due to the particular properties of the fluorine atom.2 For
instance, its electronegativity (the highest of the periodic
table) and its size strongly impact the physicochemical
properties of the molecules. Hence, fluorinated molecules
play an important role in the discovery of bioactive com-
pounds and currently about 25% of pharmaceuticals and
40% of agrochemicals bear at least one fluorine atom.3
Therefore, the quest for new methods to synthesize
fluorinated compounds is a blossoming research area. As
part of it, the design of new tools to introduce fluorinated
bioisosteres4 is of matter of importance. In that context, the
development of new methodologies to introduce the di-
fluoromethylphosphonate residue (CF2PO(OR)2) is appeal-
ing, since this motif is widely recognized as a phosphate
mimic.5 Indeed, phosphates are involved in a plethora of bi-
ological events and the development of bioisosteres that are
stable in vivo could afford metabolically stable analogues
with interesting biological activities. This paradigm, devel-
oped by Blackburn in the early 1980s,6 already afforded
promising bioactive compounds (Figure 1).7
Figure 1 Biologically active molecules bearing a CF2PO(OR)2 motif
In contrast to the importance of this motif, only a few
methods have been developed to introduce this fluorinated
residue onto arenes prior to 2010. In 1996, Burton reported
the coupling reaction of toxic CdCF2PO(OEt)2 with aryl
iodides in the presence of a stoichiometric amount of CuCl.8
The next year, Shibuya described a similar transformation
using the ZnCF2PO(OEt)2 reagent under ultrasonic condi-
tions.9 Both of these methods suffered from the use of
either a toxic reagent (Cd-derived reagent) or the use of
specialized reaction conditions (ultrasound).
Recently, several alternative methods appeared that
could be used to introduce this motif onto aromatic deriva-
tives (Scheme 1). One should mention the significant con-
tributions from the groups of Zhang10 and Qing,11 who de-
veloped the Suzuki and oxidative cross-coupling reactions
with boronic acid derivatives to introduce the CF2PO(OR)2
motif onto arenes. Additionally, the Ullmann type coupling
reaction on iodobenzoates12 and o-iodo- or o-bromotria-
zenes13 was achieved by Zhang. Recently, our group devel-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
M. V. Ivanova et al.
Paper
Synthesis
oped new approaches for the introduction of the CF2-
PO(OEt)2 group onto aryl diazonium salts14 and aryl iodoni-
um salts15 by using a copper-mediated transformation.
Quite surprisingly, no practical method was reported for
the functionalization of simple halogenated aryl derivatives
and the functionalization of heteroaryl compounds re-
mained scarce, despite their high relevance in medicinal
and agrochemistry.
tion yield (entries 8 and 9). Finally, a control experiment
showed that no reaction occurred in the absence of the pal-
ladium catalyst, even at a higher temperature (entries 10
and 11).
Table 1 Optimization of the Reaction Conditions with 1a
I
[Pd] (5 mol%), Ligand (10 mol%)
CF2PO(OEt)2
Methods after 2010:
CuCF2PO(OEt)2 (1 equiv)
MeCN, 40 °C, 16 h
MeO
MeO
[Pd]cat or [Cu]
B(OH)2
CF2PO(OEt)2
1a
2a
R
R
R
BrCF2PO(OEt)2
or TMSCF2PO(OEt)2
Entry
[Pd]
Pd(OAc)2
Ligand
Yield (%)a
[Cu]cat
CG
CG
1
2
–
trace
65
R
Zn, BrCF2PO(OEt)2
Pd2dba3
Pd(PPh3)4
PdCl2
–
X
X
CF2PO(OEt)2
CG = CO2R or N=N-NR2
X = Br, I
3
–
19
I
4
–
40
Ar
R
CF2PO(OEt)2
5
PdCl2(PPh3)2
PdCl2
–
67 (54)b
11
CuCF2PO(OEt)2
R
or
6
dppf
N2+, X–
7
PdCl2
Xantphos
20
R
8c
9d
10
11e
PdCl2(PPh3)2
PdCl2(PPh3)2
–
–
–
–
–
29
This work:
45
I
I
CF2PO(OEt)2
NR
R
R
R
[Pd]cat
–
NR
or
or
a Yields were determined by 19F NMR spectroscopic analysis using α,α,α-tri-
fluorotoluene as internal standard. NR: no reaction.
b Isolated yield.
CuCF2PO(OEt)2
CF2PO(OEt)2
Het
Het
R
c Reaction was performed at 25 °C.
d [Pd] (2 mol%) was used.
Scheme 1 State of the art and present work
e Reaction was performed at 80 °C.
To tackle this synthetic issue and to afford a straightfor-
ward access to difluoromethylphosphonate-containing
molecules, we envisioned the functionalization of simple
aryl and heteroaryl iodides in the presence of a palladium
catalyst.
Having these optimized conditions in hand, we sought
to extend the scope of this transformation (Scheme 2).
First, 4-iodo-1,1′-biphenyl 1b and 1-iodonaphthalene
1c were tested under the optimized conditions. Pleasingly,
the corresponding difluromethylphosphonates 2b and 2c
were isolated in good yields, 52% and 80% respectively. Elec-
tron-withdrawing groups were well tolerated as substitu-
ents on the aromatic ring. Indeed, p-iodobenzoate and p-
iodo-trifluorotoluene furnished the desired products 2d
and 2e in 58% and 48% isolated yields, respectively. Notably,
o-iodobenzonitrile 1f was readily converted into the fluori-
nated compound 2f in 62% yield. Note that this compound
was reluctant under our previously reported conditions.18
Keto-substituted iodoarenes were suitable substrates, as
demonstrated with 2g and 2h. Iodoarenes 1i and 1j, bearing
an acetamide group, were also readily converted into the
corresponding difluoromethylphosphonates 2i and 2j. Note
that the acetamide coordinating group was not suitable in
the previously reported Ullmann type process.18 Benzyl cy-
anide as well as unprotected phenol derivatives 1k and 1l
were also functionalized in moderate yields. Interestingly,
the iodo-boronate 1m is a suitable substrate, although 2m
was isolated in a moderate 38% yield because of a difficult
At the outset of our investigations, we studied the reac-
tion between p-iodoanisole 1a and the CuCF2PO(OEt)2 spe-
cies, easily generated from TMSCF2PO(OEt)2, a copper salt
and a suitable activator (Table 1).16 First, the reaction of 1a
and the in situ generated CuCF2PO(OEt)2 species was car-
ried out in the presence of Pd(OAc)2 as a catalyst in MeCN at
40 °C and, pleasingly, traces of 2a were detected (entry 1).
Several palladium catalysts were then screened. The use of
Pd2dba3 gave a decent 65% NMR yield (entry 2), whereas
Pd(PPh3)4 and PdCl2 allowed the formation of 2a in 19% and
40% yield, respectively (entries 3 and 4). Pleasingly, the use
of PdCl2(PPh3)2 gave 2a in 67% NMR yield and 54% isolated
yield (entry 5). To improve the reaction yield, various li-
gands were then screened with PdCl2 as catalyst. However,
no improvement of the reaction yield was observed with
1,1′-bis(diphenylphosphino)ferrocene (dppf) or Xantphos
(entries 6 and 7).17 Attempts to decrease the reaction tem-
perature or the catalyst loading did not enhance the reac-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
M. V. Ivanova et al.
Paper
Synthesis
I
I
CF2PO(OEt)2
CF2PO(OEt)2
PdCl2(PPh3)2 (5 mol%)
or
Het
Het
R
R
R
or
R
CuCF2PO(OEt)2 (1 equiv)
MeCN, 40 °C, 16 h
1a–s
2a–s
CF2PO(OEt)2
F3C
CF2PO(OEt)2
CF2PO(OEt)2
Ph
CF2PO(OEt)2
CF2PO(OEt)2
MeO2C
MeO
2a, 64%,a (67%)b
2b, 52%,a (70%)b
2c, 80%,a (93%)b
2d, 58%,a (64%)b
2e, 48%,a (51%)b
O
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
O
CN
NHAc
AcHN
2f, 62%,a (71%)b
2g, 56%,a (62%)b
2h, 43%,a (50%)b
2i, 48%,a (50%)b
2j, 75%,a (99%)b
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
CN
O
B
CF2PO(OEt)2
F
N
Cl
N
O
OH
2k, 51%,a (53%)b
2l, 54%,a (60%)b
2n, 40%,a (50%)b
2o, 70%,a (72%)b
2m, 38%,a (52%)b
Br
N
N
CF2PO(OEt)2
CF2PO(OEt)2
N
CF2PO(OEt)2
CF2PO(OEt)2
Br
N
N
OMe
2s, 46%,a (49%)b
2p, 49%,a (55%)b
2q, 69%,a (80%)b
2r, 65%,a (76%)b
Scheme 2 Scope of the transformation. a Isolated yields. b Yields determined by 19F NMR using α,α,α-trifluorotoluene as an internal standard.
purification. This last example demonstrates the excellent
functional group tolerance of this transformation. The pres-
ence of the boron substituent offers possibilities for a panel
of post-functionalization reactions. Finally, we turned our
attention to the functionalization of heterocyclic deriva-
tives to facilitate access to CF2PO(OEt)2-containing hetero-
cycles, which is an underexplored class of compounds.19
First, iodopyridine derivatives 1n–q, bearing a halogen
atom at the 6- and 5-position, were tested. To our delight,
the corresponding products 2n–q were isolated in moder-
ate to good yields. Notably, that the reaction was highly se-
lective toward the functionalization of the iodo substituent,
since chlorine and even bromine atoms were tolerated as
substituents, offering room for further postfunctionaliza-
tion reactions. 2-Methoxy-3-iodopyridine 1r was also func-
tionalized in a decent 65% yield. Finally, pyrazine 2s was ob-
tained in a moderate 46% yield, demonstrating the applica-
bility of the method to diazine derivatives.
In summary, we reported herein a practical method for
the functionalization of aryl and heteroaryl iodides with
CuCF2PO(OEt)2 in the presence of a palladium catalyst un-
der mild conditions. The reaction proceeded well and al-
lowed the functionalization of various substrates that were
previously reluctant, and demonstrated good functional
group tolerance (phenol, boronate, ketones, nitriles, esters,
etc.). In addition, the reaction proved to be an efficient way
to access heteroaryl CF2PO(OEt)2-containing scaffolds. By
broadening the current toolbox to build up CF2PO(OEt)2-
containing molecules, we believe that this synthetic meth-
od will be useful to access new bioactive molecules.
All reactions were carried out using oven-dried glassware and mag-
netic stirring under an atmosphere of argon unless otherwise stated.
Flash chromatography was performed with silica gel (0.040–
0.060 nm). Reverse-phase chromatography was performed with a
puriFlash®215 using a puriFlash® C18HP 15μm 55G Flash column.
Analytical thin-layer chromatography was performed on silica gel
aluminum plates with F-254 indicator and visualized with UV light
(254 nm) and/or chemical staining with a KMnO4 solution. 1H NMR
spectra were recorded with a Bruker DXP 300 at 300 MHz, 13C NMR
spectra at 75 MHz, 19F NMR spectra at 282 MHz, and 31P NMR at
121 MHz. Chemical shifts (δ) are quoted in parts per million (ppm)
relative to the residual solvent peak for CDCl3 (δH = 7.26 ppm;
δC = 77.16 ppm); or relative to external CFCl3 (δ = 0 ppm). The follow-
ing abbreviations are used: δ (chemical shift), J (coupling constant),
app. (apparent), br. (broad), s (singlet), d (doublet), dd (doublet of
doublets), t (triplet), td (triplet of doublets), dt (doublet of triplets), q
(quartet), m (multiplet). High-resolution mass spectra (HRMS) were
recorded with a Waters LCT Premier, IR spectra were recorded with a
PerkinElmer Spectrum 100.
General Procedure
A tube was loaded with CuCl (50 mg, 0.50 mmol) and CsF (228 mg,
1.50 mmol) and sealed with a rubber septum. Anhydrous acetonitrile
(1 mL) was added and the mixture was cooled to 0 °C. Diethyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
M. V. Ivanova et al.
Paper
Synthesis
[(trimethylsilyl)difluoromethyl]phosphonate (neat, 325 mg, 1.25
mmol) was added and the mixture was heated at 40 °C for 1 h, cooled
to 0 °C and stirred at this temperature for 1 h. Pd(PPh3)Cl2 (18 mg,
0.025 mmol) was added followed by a solution of the corresponding
iodoarene 1 (0.50 mmol) in MeCN (1 mL). The suspension was stirred
for 16 h at 40 °C. The reaction mixture was diluted with diethyl ether
(15 mL), the organic layer was washed with water (15 mL), Na2CO3
(concentrated solution, 15 mL), dried over Na2SO4, and solvents were
carefully removed under vacuum. Reverse-phase chromatography
(H2O/MeCN or MeOH, gradient: 9:1 to 0:1, rate: 1% MeCN or MeOH
per minute) gave the product 2.
13C NMR (75 MHz, CDCl3): δ = 134.1 (d, J = 0.9 Hz), 132.1 (dd, J = 3.4,
1.7 Hz), 129.9 (dd, J = 3.7, 1.8 Hz), 128.6 (d, J = 2.5 Hz), 128.4 (td, J =
20.1, 13.5 Hz), 126.9, 126.4 (td, J = 10.4, 3.6 Hz), 126.3, 126.1 (td, J =
5.2, 0.7 Hz), 124.4 (d, J = 1.7 Hz), 120.0 (td, J = 264.1, 216.8 Hz), 64.8
(d, J = 6.8 Hz), 16.3 (d, J = 5.6 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –102.4 (d, J = 114.6 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 6.7 (t, J = 114.7 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C15H21NF2O3P: 332.1227; found:
332.1233 (1.8 ppm).
Methyl 4-[(Diethoxyphosphoryl)difluoromethyl]benzoate (2d)
Diethyl [(4-Methoxyphenyl)difluoromethyl]phosphonate (2a)
Prepared by following the general procedure from methyl 4-iodoben-
zoate (1d). Reverse-phase chromatography (H2O/MeCN).
Prepared by following the general procedure from 1-iodo-4-
methoxybenzene (1a). Reverse-phase chromatography (H2O/MeCN).
Yield: 58% (94 mg, 0.5 mmol scale); colorless oil.
Yield: 64% (89 mg, 0.5 mmol scale): colorless oil.
IR (neat): 2987, 2917, 2849, 1727, 1437, 1408, 1274, 1164, 1111,
1011, 941 cm−1
.
IR (neat): 2985, 1614, 1515, 1250, 1011 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.11 (d, J = 8.2 Hz, 2 H), 7.70–7.67 (m,
2 H), 4.28–4.08 (m, 4 H), 3.93 (s, 3 H), 1.32–1.28 (m, 6 H).
1H NMR (300 MHz, CDCl3): δ = 7.56 (d, J = 8.3 Hz, 2 H), 6.94 (d, J =
8.6 Hz, 2 H), 4.49–3.97 (m, 4 H), 3.81 (s, 3 H), 1.29 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 166.3, 137.0 (dt, J = 21.9, 13.7 Hz),
132.4–132.3 (m), 129.7 (d, J = 1.3 Hz), 126.5 (dt, J = 6.7, 2.2 Hz), 117.7
(td, J = 263.3, 216.9 Hz), 65.0 (d, J = 6.8 Hz), 52.5, 16.4 (d, J = 5.4 Hz).
13C NMR (75 MHz, CDCl3): δ = 161.5 (dd, J = 3.6, 1.7 Hz), 127.9 (td, J =
6.8, 2.4 Hz), 124.6 (td, J = 22.7, 14.0 Hz), 118.3 (td, J = 263.0, 220.9 Hz),
113.9 (d, J = 1.2 Hz), 64.8 (d, J = 6.7 Hz), 55.4, 16.4 (d, J = 5.6 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –109.8 (d, J = 113.3 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 5.8 (t, J = 112.5 Hz, 1 P).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –107.6 (d, J = 119.7 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 6.6 (t, J = 119.8 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C13H21F2O5PN: 340.1125; found:
HRMS (EI): m/z [M + H]+ calcd for C12H18F2O4P: 295.0911; found:
340.1126 (0.3 ppm).
295.0906 (–1.7 ppm).
Diethyl [(4-{Trifluoromethyl}phenyl)difluoromethyl]phospho-
nate (2e)
Diethyl [(1,1′-Biphenyl)-4-yldifluoromethyl]phosphonate (2b)
Prepared by following the general procedure from 4-iodo-1,1′-biphe-
nyl (1b). Reverse-phase chromatography (H2O/MeCN).
Prepared by following the general procedure from p-iodotrifluoro-
toluene (1e). Reverse-phase chromatography (H2O/MeCN).
Yield: 52% (89 mg, 0.5 mmol scale); brown oil.
Yield: 48% (80 mg, 0.5 mmol scale); orange oil.
IR (neat): 2992, 1414, 1266, 1127, 1066, 1013 cm−1
1H NMR (300 MHz, CDCl3): δ = 7.75–7.65 (m, 4 H), 4.32–4.10 (m, 4 H),
1.31 (t, J = 7.1 Hz, 6 H).
IR (neat): 2984, 1611, 1394, 1267, 1166, 1114, 1013, 978 cm−1
.
.
1H NMR (300 MHz, CDCl3): δ = 7.72–7.66 (m, 4 H), 7.61 (d, J = 7.7 Hz,
2 H), 7.46 (t, J = 7.0 Hz, 2 H), 7.41–7.36 (m, 1 H), 4.32–4.12 (m, 4 H),
1.34 (t, J = 6.9 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 136.9–136.0 (m), 133.6–132.2 (m),
127.0 (td, J = 6.8, 2.3 Hz), 125.6 (qd, J = 3.7, 1.3 Hz), 120.1 (q, J =
272.7 Hz), 117.5 (td, J = 263.6, 217.3 Hz), 65.1 (d, J = 6.8 Hz), 16.4 (d,
J = 5.5 Hz).
13C NMR (75 MHz, CDCl3): δ = 143.7 (dt, J = 2.1, 1.9 Hz), 140.1, 131.5
(dt, J = 22.4, 13.4 Hz), 131.4, 129.0, 128.1, 127.4–127.3 (m), 126.8 (td,
J = 6.8, 2.1 Hz), 118.2 (td, J = 263.9, 216.6 Hz), 64.9 (d, J = 6.8 Hz), 16.4
(d, J = 5.7 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –63.5 (s, 3 F), –109.9 (d, J =
112.8 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 5.6 (t, J = 112.8 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C12H18NF5O3P: 350.0944; found:
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –108.8 (d, J = 116.6 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 6.4 (t, J = 116.4 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C17H23NF2O3P: 358.1384; found:
358.1383 (–0.3 ppm).
found: 350.0938 (–1.7 ppm).
Diethyl [(Naphthen-1-yl)difluoromethyl]phosphonate (2c)
Diethyl [(2-Cyanophenyl)difluoromethyl]phosphonate (2f)
Prepared by following the general procedure from 1-iodonaphthalene
Prepared by following the general procedure from 2-iodobenzonitrile
(1c). Reverse-phase chromatography (H2O/MeCN).
(1f). Reverse phase chromatography (H2O/MeCN).
Yield: 80% (126 mg, 0.5 mmol scale); dark orange oil.
Yield: 62% (89 mg, 0.5 mmol scale); yellow oil.
IR (neat): 2987, 2234, 1445, 1271, 1240, 1129, 1070, 1010, 940 cm−1
1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 7.6 Hz, 1 H), 7.74–7.65 (m,
2 H), 7.61–7.56 (m, 1 H), 4.38–4.20 (m, 4 H), 1.35 (t, J = 7.1 Hz, 6 H).
IR (neat): 2985, 1514, 1269, 1010 cm−1
.
.
1H NMR (300 MHz, CDCl3): δ = 8.45 (d, J = 8.5 Hz, 1 H), 7.95 (d, J =
8.2 Hz, 1 H), 7.86 (d, J = 7.8 Hz, 1 H), 7.81 (d, J = 7.4 Hz, 1 H), 7.59–7.48
(m, 3 H), 4.29–4.01 (m, 4 H), 1.25 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 135.3 (dt, J = 21.5, 13.4 Hz), 134.9,
132.6 (d, J = 1.1 Hz), 131.1 (d, J = 1.6 Hz), 128.8–128.5 (m), 117.3 (td,
J = 265.9, 218.7 Hz), 116.8, 110.7–110.6 (m), 65.5 (d, J = 7.1 Hz), 16.4
(d, J = 5.5 Hz).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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M. V. Ivanova et al.
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Synthesis
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –107.4 (d, J = 111.9 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 4.6 (t, J = 112.1 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C12H18F2N2O3P: 307.1023; found:
Diethyl [(2-Aacetamidophenyl)difluoromethyl]phosphonate (2j)
Prepared by following the general procedure from methyl N-(2-
iodophenyl)acetamide
(H2O/MeCN).
(1j).
Reverse-phase
chromatography
307.1028 (1.6 ppm).
Yield: 75% (121 mg, 0.5 mmol scale); yellow oil.
IR (neat): 3287, 2986, 2922, 1698, 1587, 1530, 1448, 1370, 1299,
1270, 1138, 1105, 1011 cm−1
Diethyl [(2-Acetylphenyl)difluoromethyl]phosphonate (2g)
.
Prepared by following the general procedure from 1-(2-iodophe-
1H NMR (300 MHz, CDCl3): δ = 9.38 (s, 1 H), 7.98 (d, J = 8.1 Hz, 1 H),
7.48–7.42 (m, 2 H), 7.17 (t, J = 7.6 Hz, 1 H), 4.26–4.03 (m, 4 H), 2.14 (s,
3 H), 1.26 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 168.9, 136.3–136.2 (m), 131.9 (d,
J =1.7 Hz), 126.6 (dt, J = 9.9, 2.9 Hz), 126.0, 124.6, 123.2 (dt, J = 20.9,
13.5 Hz), 117.7 (td, J = 264.1, 215.5 Hz), 65.8 (d, J = 7.0 Hz), 24.3, 16.3
(d, J = 5.5 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –108.9 (d, J = 113.7 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 8.1 (t, J = 113.4 Hz, 1 P).
HRMS (EI): m/z [M + H]+ calcd for C13H19F2NO4P: 322.1020; found:
nyl)ethan-1-one (1g). Reverse-phase chromatography (H2O/MeCN).
Yield: 56% (85 mg, 0.5 mmol scale); colorless oil.
IR (neat): 2963, 1706, 1394, 1359, 1257, 1010, 792 cm−1
.
1H NMR (300 MHz, CDCl3): δ = 7.72–7.69 (m, 1 H), 7.53–7.45 (m, 2 H),
7.25–7.22 (m, 1 H), 4.28–4.14 (m, 4 H), 2.56–2.55 (m, 3 H), 1.35–1.30
(m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 204.1, 141.6 (q, J = 3.4 Hz), 131.0 (d, J =
1.6 Hz), 129.2 (d, J = 1.6 Hz), 128.7 (dt, J = 7.2, 1.2 Hz), 128.4 (dt, J =
21.8, 15.4 Hz), 126.0, 118.6 (td, J = 264.7, 217.2 Hz), 65.2 (d, J =
6.8 Hz), 31.8 (d, J = 3.3 Hz), 16.4 (d, J = 5.5 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –101.2 (d, J = 112.7 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 5.5 (t, J = 112.2 Hz, 1 P).
301.1021 (0.3 ppm).
Diethyl [(2-(Cyanomethyl)phenyl)difluoromethyl]phosphonate
(2k)
HRMS (EI): m/z [M + H]+ calcd for C13H18F2O4P: 307.0911; found:
307.0909 (–0.7 ppm).
Prepared by following the general procedure from 2-(2-iodophe-
nyl)acetonitrile (1k). Reverse-phase chromatography (H2O/MeCN).
Diethyl [(4-Acetylphenyl)difluoromethyl]phosphonate (2h)
Yield: 51% (78 mg, 0.5 mmol scale); colorless oil.
Prepared by following the general procedure from 1-(4-iodophe-
nyl)ethan-1-one (1h). Reverse-phase chromatography (H2O/MeCN).
IR (neat): 2985, 2918, 2251, 1584, 1447, 1394, 1264, 1243, 1163,
1129, 1011, 941 cm−1
.
Yield: 43% (66 mg, 0.5 mmol scale); colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.67–7.64 (app d, 1 H), 7.59–7.51 (m,
2 H), 7.46–7.41 (m, 1 H), 4.26–4.09 (m, 6 H), 1.34–1.29 (m, 6 H).
IR (neat): 3670, 2988, 1689, 1613, 1407, 1264, 1011 cm−1
.
1H NMR (300 MHz, CDCl3): δ = 8.01 (d, J = 8.1 Hz, 2 H), 7.70 (d, J =
7.9 Hz, 2 H), 4.28–4.09 (m, 4 H), 2.61 (s, 3 H), 1.30 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 197.4, 138.9 (dd, J = 3.6, 1.9 Hz), 137.1
(td, J = 21.9, 13.6 Hz), 128.4 (d, J = 1.2 Hz), 126.7 (td, J = 6.7, 2.2 Hz),
117.7 (td, J = 263.6, 216.8 Hz), 65.0 (d, J = 6.8 Hz), 26.8, 16.4 (d, J =
5.5 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –105.3 (d, J = 115.3 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 5.9 (t, J = 115.0 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C13H21F2NO4P: 324.1176; found:
13C NMR (75 MHz, CDCl3): δ = 131.8–131.7 (m), 130.6 (d, J = 1.3 Hz),
129.7–129.6 (m), 128.2 (d, J = 1.2 Hz), 128.2–127.9 (m), 128.1 (d, J =
2.5 Hz), 119.0 (td, J = 266.3, 215.5 Hz), 118.1, 65.3 (d, J = 6.9 Hz), 22.2
(d, J = 5.3 Hz), 16.4 (d, J = 5.6 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –105.5 (d, J = 112.9 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 6.3 (t, J = 112.8 Hz, 1 P).
HRMS (EI): m/z [M + H]+ calcd for C13H17F2NO3P: 304.0914; found:
304.0914 (0.0 ppm).
324.1182 (1.9 ppm).
Diethyl [(3-Hydroxyphenyl)difluoromethyl]phosphonate (2l)
Prepared by following the general procedure from 3-iodophenol (1l).
Reverse-phase chromatography (H2O/MeCN).
Diethyl [(4-Acetamidophenyl)difluoromethyl]phosphonate (2i)
Prepared by following the general procedure from methyl N-(4-
Yield: 54% (75 mg, 0.5 mmol scale); yellow oil.
iodophenyl)acetamide
(H2O/MeCN).
(1i).
Reverse-phase
chromatography
IR (neat): 3259, 2986, 1772, 1607, 1593, 1481, 1455, 1296, 1240,
1163, 1122, 1013, 952 cm−1
.
Yield: 48% (77 mg, 0.5 mmol scale); yellow oil.
IR (neat): 3283, 2984, 1694, 1601, 1534, 1408, 1369, 1317, 1258,
1118, 1018 cm−1
1H NMR (300 MHz, CDCl3): δ = 8.05 (s, 1 H), 7.23–7.19 (m, 2 H), 7.02
(d, J = 7.7 Hz, 1 H), 6.89 (t, J = 8.2 Hz, 1 H), 4.24–4.01 (m, 4 H), 1.26 (t,
J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 157.2 (d, J = 1.5 Hz), 133.3 (dt, J = 21.8,
13.8 Hz), 129.8 (d, J = 1.1 Hz), 118.5 (d, J = 1.8 Hz), 117.8 (td, J = 263.9,
220.2 Hz), 117.0 (dt, J = 7.1, 2.8 Hz), 113.6 (dt, J = 6.8, 1.7 Hz), 65.5 (d,
J = 6.8 Hz), 16.4 (d, J = 5.6 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –109.0 (d, J = 118.2 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 6.2 (t, J = 118.3 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C11H19NF2O4P: 298.1020; found:
.
1H NMR (300 MHz, CDCl3): δ = 8.50 (s, 1 H), 7.57–7.54 (m, 2 H), 7.47–
7.45 (m, 2 H), 4.29–4.11 (m, 4 H), 2.14 (s, 3 H), 1.33 (t, J = 6.9 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 169.5, 141.2, 127.0–126.8 (m), 127.3–
126.5 (m), 119.4, 118.1 (td, J = 264.2, 219.7 Hz), 65.1 (d, J = 7.0 Hz),
24.4, 16.4 (d, J = 5.4 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –108.6 (d, J = 119.9 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 6.0 (t, J = 119.2 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C13H22F2N2O4P: 339.1285; found:
298.1022 (0.7 ppm).
339.1284 (–0.3 ppm).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
M. V. Ivanova et al.
Paper
Synthesis
Diethyl [(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nyl)difluoromethyl]phosphonate (2m)
Yield: 49% (84 mg, 0.5 mmol scale); white oil.
IR (neat): 2986, 2928, 1584, 1456, 1369, 1262, 1164, 1091, 1011 cm−1
.
Prepared by following the general procedure from 2-(4-iodophenyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1m). Reverse-phase chro-
matography (H2O/MeCN).
1H NMR (300 MHz, CDCl3): δ = 8.56 (s, 1 H), 7.78–7.75 (m, 1 H), 7.58
(d, J = 8.3 Hz, 1 H), 4.29–4.16 (m, 4 H), 1.35–1.31 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 148.0 (td, J = 7.3, 2.4 Hz), 145.0 (d, J =
2.0 Hz), 136.7 (td, J = 6.2, 1.8 Hz), 128.7–128.0 (m), 128.1, 116.9 (td,
J = 264.9, 219.2 Hz), 65.3 (d, J = 6.9 Hz), 16.5 (d, J = 5.5 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –111.1 (d, J = 112.0 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 4.9 (t, J = 111.3 Hz, 1 P).
HRMS (EI): m/z [M + H]+ calcd for C10H14BrF2NO3P: 343.9863; found:
Yield: 38% (75 mg, 0.5 mmol scale); colorless oil.
IR (neat): 2981, 2915, 2845, 1715, 1612, 1516, 1399, 1360, 1327,
1269, 1144, 1090, 1015, 857 cm−1
.
1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 7.8 Hz, 2 H), 7.60 (d, J =
7.7 Hz, 2 H), 4.24–4.08 (m, 4 H), 1.35 (s, 12 H), 1.30 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 135.1 (dt, J = 21.9, 13.5 Hz), 134.8,
134.8, 125.5 (td, J = 6.8, 2.3 Hz), 118.0 (td, J = 260.0, 219.0 Hz), 84.3,
64.9 (d, J = 6.7 Hz), 24.9, 16.4 (d, J = 5.7 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –109.5 (d, J = 115.6 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 6.3 (t, J = 115.7 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C17H30BF2NO5P: 408.1923; found:
343.9866 (0.9 ppm).
Diethyl [(5-Bromopyridin-2-yl)difluoromethyl]phosphonate (2q)
Prepared by following the general procedure from 5-bromo-2-
iodopyridine (1q). Reverse-phase chromatography (H2O/MeOH).
Yield: 69% (119 mg, 0.5 mmol scale); yellow oil.
408.1920 (–0.7 ppm).
IR (neat): 2986, 2917, 1561, 1464, 1366, 1269, 1228, 1125, 1007, 944,
838 cm−1
.
Diethyl [(6-Fluoropyridin-3-yl)difluoromethyl]phosphonate (2n)
1H NMR (300 MHz, CDCl3): δ = 8.72–8.71 (m, 1 H), 7.95–7.91 (m, 1 H),
7.55 (d, J = 8.3 Hz, 1 H), 4.31–4.19 (m, 4 H), 1.31 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 150.7, 150.0 (dt, J = 24.3, 14.4 Hz),
139.8, 123.0–122.9 (m), 123.0, 116.0 (td, J = 264.6, 214.1 Hz), 65.1 (d,
J = 6.7 Hz), 16.3 (d, J = 5.7 Hz).
Prepared by following the general procedure from 2-fluoro-5-iodo-
pyridine (1n). Reverse-phase chromatography (H2O/MeOH).
Yield: 40% (57 mg, 0.5 mmol scale); yellow oil.
IR (neat): 2990, 1599, 1486, 1386, 1256, 1163, 1126, 1011, 753 cm−1
.
1H NMR (300 MHz, CDCl3): δ = 8.44 (s, 1 H), 8.05–8.00 (m, 1 H), 7.01
(dd, J = 8.5, 2.7 Hz, 1 H), 4.29–4.16 (m, 4 H), 1.32 (t, J = 7.0 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 165.0 (dd, J = 243.7, 1.8 Hz), 146.4 (ddt,
J = 16.3, 7.5, 2.6 Hz), 139.9 (ddt, J = 9.0, 6.0, 1.7 Hz), 127.4–126.5 (m),
117.0 (tdd, J = 264.1, 219.1, 1.4 Hz), 109.7 (dd, J = 37.7, 0.9 Hz), 65.3
(d, J = 6.8 Hz), 16.4 (d, J = 5.4 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –64.7 (s, 1 F), –109.5 (d, J =
112.5 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 5.2 (t, J = 112.4 Hz, 1 P).
HRMS (EI): m/z [M + NH4]+ calcd for C10H17F3N2O3P: 301.0929; found:
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –111.0 (d, J = 106.9 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 4.9 (t, J = 107.1 Hz, 1 P).
HRMS (EI): m/z [M + H]+ calcd for C10H14BrF2NO3P: 343.9863; found:
343.9861 (–0.6 ppm).
Diethyl [(2-Methoxypyridin-3-yl)difluoromethyl]phosphonate
(2r)
Prepared by following the general procedure from 3-iodo-2-
methoxypyridine (1r). Reverse-phase chromatography (H2O/MeOH).
Yield: 65% (66 mg, 0.5 mmol scale); white oil.
301.0922 (–2.3 ppm).
IR (neat): 2986, 2916, 1592, 1583, 1470, 1409, 1304, 1268, 1220,
1164, 1127, 1010, 936 cm−1
.
Diethyl [(2-chloropyridin-3-yl)difluoromethyl]phosphonate (2o)
1H NMR (300 MHz, CDCl3): δ = 8.24–8.22 (m, 1 H), 7.79 (d, J = 7.8 Hz,
1 H), 6.95–6.91 (m, 1 H), 4.29–4.16 (m, 4 H), 3.98 (s, 3 H), 1.33–1.29
(m, 6 H).
Prepared by following the general procedure from 2-chloro-5-
iodopyridine (1o). Reverse-phase chromatography (H2O/MeOH).
Yield: 70% (105 mg, 0.5 mmol scale; note that the product was con-
taminated with 10% of an unknown product); yellow oil.
13C NMR (75 MHz, CDCl3): δ = 161.1–160.9 (m), 149.5 (d, J = 1.8 Hz),
137.7 (dt, J = 8.4, 2.6 Hz), 117.6 (td, J = 263.9, 220.8 Hz), 116.4, 115.5
(dt, J = 22.7, 14.2 Hz), 64.8 (d, J = 6.8 Hz), 53.8, 16.4 (d, J = 5.7 Hz).
IR (neat): 2986, 2917, 1591, 1461, 1372, 1263, 1107, 1012, 575 cm−1
.
1H NMR (300 MHz, CDCl3): δ = 8.56 (s, 1 H), 7.87–7.84 (m, 1 H), 7.40
(d, J = 8.4 Hz, 2 H), 4.28–4.14 (m, 4 H), 1.33–1.28 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 154.2 (dd, J = 4.3, 2.2 Hz), 147.7 (td, J =
7.4, 2.6 Hz), 137.1 (td, J = 6.1, 1.8 Hz), 128.0 (td, J = 22.9, 13.9 Hz),
124.2 (d, J = 1.1 Hz), 117.0 (td, J = 263.8, 219.1 Hz), 65.3 (d, J = 6.9 Hz),
16.4 (d, J = 5.4 Hz).
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –110.4 (d, J = 111.8 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 5.0 (t, J = 111.7 Hz, 1 P).
HRMS (EI): m/z [M]+ calcd for C10H13ClF2NO3P: 299.0290; found:
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –107.3 (d, J = 114.6 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 5.8 (t, J = 114.3 Hz, 1 P).
HRMS (EI): m/z [M + H]+ calcd for C11H17F2NO4P: 296.0863; found:
296.0862 (–0.3 ppm).
Diethyl [(Pyrazin-2-yl)difluoromethyl]phosphonate (2s)
Prepared by following the general procedure from 2-iodopyrazine
(1s). Reverse-phase chromatography (H2O/MeOH).
Yield: 46% (61 mg, 0.5 mmol scale); colorless oil.
299.0277 (–4.2 ppm).
IR (neat): 2987, 2918, 1474, 1446, 1406, 1271, 1163, 1130, 1011, 854
cm−1
.
Diethyl [(6-Bromopyridin-3-yl)difluoromethyl]phosphonate (2p)
1H NMR (300 MHz, CDCl3): δ = 8.94 (s, 1 H), 8.71–7.61 (app d, 2 H),
4.36–4.25 (m, 4 H), 1.35 (t, J = 7.1 Hz, 6 H).
Prepared by following the general procedure from 2-bromo-5-
iodopyridine (1p). Reverse-phase chromatography (H2O/MeOH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

G
M. V. Ivanova et al.
Paper
Synthesis
13C NMR (75 MHz, CDCl3): δ = 147.5 (dt, J = 23.9, 13.8 Hz), 146.5 (d, J =
1.7 Hz), 143.9, 143.2 (dt, J = 5.4, 2.9 Hz), 115.9 (td, J = 264.3, 215.3 Hz),
65.3 (d, J = 6.6 Hz), 16.4 (d, J = 5.5 Hz).
Soc. Rev. 2016, 45, 5441. (n) Besset, T.; Poisson, T.; Pannecoucke,
X. Eur. J. Org. Chem. 2015, 2765. (o) For a special issue on fluo-
rine chemistry, see: Chem. Rev. 2015, 115, 563.
(2) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
19F{1H} NMR (CDCl3, CFCl3, 282 MHz): δ = –112.4 (d, J = 105.4 Hz, 2 F).
31P{1H} NMR (CDCl3, 121 MHz): δ = 4.5 (t, J = 105.2 Hz, 1 P).
HRMS (EI): m/z [M + H]+ calcd for C9H14F2N2O3P: 267.0710; found:
(3) (a) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5,
637. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (c) Gillis, E. P.; Eastman, K. J.; Hill,
M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58,
8315. (d) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432. (e) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T.
J. Med. Chem. 2014, 57, 2832.
267.0709 (–0.4 ppm).
Funding Information
This work was partially supported by INSA Rouen, Rouen University,
CNRS, EFRD, Labex SynOrg (ANR-11-LABX-0029), Région Normandie
(Crunch Network) and the IUF (Institut Universitaire de France). M.V.I.
(4) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
(5) Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T.
Chem. Eur. J. 2016, 22, 10284; and references cited therein.
(6) Blackburn, G. M.; Kent, D. E.; Kolkmann, F. J. Chem. Soc., Chem.
Commun. 1981, 1188.
thanks the MESR for a doctoral fellowship.
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Acknowledgment
(7) (a) Bialy, L.; Waldmann, H. Angew. Chem. Int. Ed. 2005, 44, 3814.
(b) Combs, A. P. J. Med. Chem. 2010, 53, 2333. (c) Morlacchi, P.;
Mandal, P. K.; McMurray, J. S. ACS Med. Chem. Lett. 2014, 5, 69.
(d) Bahta, M.; Lountos, G. T.; Dyas, B.; Kim, S.-E.; Ulrich, R. G.;
Waugh, D. S.; Burke, T. R. Jr. J. Med. Chem. 2011, 54, 2933.
(e) Lau, C. K.; Bayly, C. I.; Gauthier, J. Y.; Li, C. S.; Therien, M.;
Asante-Appiah, E.; Cromlish, W.; Boie, Y.; Forghani, F.;
Desmarais, S.; Wang, Q.; Skorey, K.; Waddleton, D.; Payette, P.;
Ramachandran, C.; Kennedy, B. P.; Scapin, G. Bioorg. Med. Chem.
Lett. 2004, 14, 1043. (f) Johnson, T. O.; Ermolieff, J.; Jirousek, M.
R. Nat. Rev. Drug Discovery 2002, 1, 696.
T.P. would like to thank the organizing committee of the 52nd
Bürgenstock Conference for the invitation and the award of a JSP
Fellowship.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589140.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(8) Qiu, W.; Burton, D. J. Tetrahedron Lett. 1996, 37, 2745.
(9) Yokomatsu, T.; Murano, T.; Suemune, K.; Shibuya, S. Tetrahedron
1997, 53, 815.
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(17) All other tested ligands gave lower or no conversion into 2a.
(18) Ivanova, M. V.; Bayle, A.; Besset, T.; Pannecoucke, X.; Poisson, T.
Chem. Eur. J. 2017, in press; doi: 10.1002/chem.201703542.
(19) Only a few heterocyclic compounds bearing a CF2PO(OEt)2 motif
were synthesized, see refs. 12 and 15.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G