Fluorophosphonylated monomers for dental applications

Article abstract of DOI:10.1021/op500108m

The synthesis of acrylate derivatives bearing a difluorophosphonic acid function has been realized by ring-opening reaction of oxacycles and alkylation of fluorinated carbanions. Their use in self-etch adhesives is reported. The resulting adhesives based on difluorophosphonic acid monomers provide significantly higher dentin shear bond strength (SBS) than the one based on phosphonic acid, mainly due to the presence of fluorine atoms.

Full text of DOI:10.1021/op500108m

Article
pubs.acs.org/OPRD
Fluorophosphonylated Monomers for Dental Applications
Mathieu Derbanne,† Anais Zulauf,‡ Stephane Le Goff,† Emmanuel Pfund,‡ Michael Sadoun,†
́
̈
Thi-Nhan Pham,*,‡ and Thierry Lequeux*,‡
̀
‡Laboratoire de Chimie Molec
́
ulaire et Thio-Organique UMR CNRS 6507, INC3M, FR 3038, ENSICAEN and Universite
Basse Normandie, 6 boulevard du Marechal Juin, 14050 Caen, France
́
de Caen -
́
†Unite
Descartes, Sorbonne Paris Cite,
́
de Recherche en Biomater
́
iaux Innovants et Interfaces (URB2I) - EA4462 and Faculte
1 rue Maurice Arnoux, 92120 Montrouge, France
de Chirurgie Dentaire, Universite Paris
́ ́
́
S
* Supporting Information
ABSTRACT: The synthesis of acrylate derivatives bearing a difluorophosphonic acid function has been realized by ring-opening
reaction of oxacycles and alkylation of fluorinated carbanions. Their use in self-etch adhesives is reported. The resulting adhesives
based on difluorophosphonic acid monomers provide significantly higher dentin shear bond strength (SBS) than the one based
on phosphonic acid, mainly due to the presence of fluorine atoms.
lysable phosphoric acid function. Introduction of fluorine atoms
next to the phosphoric acid residue should have some effect on
the adhesive properties due to the modification of its ionic
character. To the best of our knowledge, few works have been
realized in this field. Recently, the preparation of an acrylamide
containing a bis-monofluorophosphonic acid function,11 and a
methacrylate containing a bis-difluoromethylphosphonic acid
function have been reported (Figure 2).12 However, the
adhesive properties of dental adhesive systems containing
these phosphonates were unknown or disappointing.
INTRODUCTION
■
Dental adhesive systems mediate the bond between tooth
substrate (dentin or enamel) and restorative materials.
Amongst the currently available adhesive systems, two-step
self-etching adhesive (SEA) systems combine etching and
priming into one step and do not require rinsing.1 These
systems contain a self-etching primer (SEP) that needs to be
able to etch enamel and dentin in order to promote the
infiltration of the adhesive into the etched/demineralized
substratum and to bond with the adhesive. Phosphonylated
monomers represent an important class of reagents,2 and in
dentistry, they are employed as components of dental self-
etching primers.1 The self-etching effect is due to the presence
of one or more acidic functions, which are able to demineralize
the dental tissues.3 As dentin is mainly composed of collagen
and hydroxyapatite (HAp), the interactions between the acidic
function and calcium ions present in HAp contribute to these
adhesive properties.4 The most popular acidic monomer is the
10-methacryloyloxydecyl dihydrogen phosphate 1 (10-MDP,
Figure 1). However, durability of the adhesion might be
Figure 2. Previous fluorinated phosphorus-containing monomers.
RESULTS AND DISCUSSION
■
As difluorophosphonates are the best phosphate mimics in
medicinal chemistry,13 we evaluated the potential of this
function in monomers involved in SEP. It is well established
that difluorophosphonic acids are more acidic (pKa2 = 5.6) than
the corresponding phosphonic (pKa2 = 7.6) or phosphoric acids
(pKa2 = 6.4).14 In the present case, it is expected, at
physiological pH (7.4),15 that difluoromethylphosphonic acids
would be mainly diionic and would form strong bindings with
calcium ions present in HAp (Figure 3).
Figure 1. 10-MDP component of SEP and targeted generic structure
of monomers.
Recently, we reported the synthesis of difluorophosphony-
lated methacrylate 4 and compared its contribution to adhesive
properties to that of the nonfluorinated phosphonic acid
analogue 2 and of the corresponding bis-phosphonate 3 to
evaluate the contribution of the fluorine atoms (Figure 3).16
affected by slow hydrolysis of the linker.5−7 Recently, a
particular attention was focused on the modification of the
phosphoric acid moiety, leading to the introduction of a
phosphonic acid function.8,9
In the case of 10-MDP, it was already demonstrated that
phosphoric acid residues are able to interact with HAp and
collagen,10 and in this context, we focused our study on the
synthesis and the evaluation of new monomers bearing a α,α-
difluoromethylphosphonic acid function instead of a hydro-
Special Issue: Fluorine Chemistry 14
Received: March 28, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
case. This is in agreement with previous observations already
done when the reaction was performed in the presence of
copper catalyst.20 The resulting alcohols were then function-
alized by introduction of a methacrylate head with methacrylic
anhydride in the presence of catalytic amount of DMAP,
affording monomer precursors 10 and 12, in good yields.
To access the other series containing various spacers between
the methacrylate head and the phosphonic acid moiety, the
alkylation reaction of carbanion 6 was explored. It is well-
known that this anion is highly basic, and alkylation reactions
with alkyl halides are quite difficult to perform due to a
competitive elimination reaction, even from primary alkyl
halides.21 Having in hand the sulfide 5, the alkylation of the
anion 6 with functionalized bromoalkanes was performed by
applying our previous experimental procedure (Scheme 3).22
The alkylation reactions were realized from protected
bromoalcohol, containing a nine-carbon atom spacer in order
to prepare the closest analogue of 10-MDP. When the anion
was trapped at −78 °C by addition of protected bromoalcohol
and then warmed up slowly to −10 °C over 1 h, the
corresponding difluorophosphonate 13 was obtained in 89%
yield. The compound 13 was then submitted to acidic
hydrolysis in the presence of H+-supported resin, and the
crude alcohol was converted into the corresponding meth-
acrylate derivative 14. This later was isolated in 66% overall
yield. The preparation of acrylamide derivatives was attempted
by alkylation of anion 6 with dibromoalkanes. In these cases,
the alkylation reaction was more sensitive to the nature of the
dibromoalkanes, and when applying the previous protocol used
for the preparation of 13, the addition products 15a−f were
isolated in moderate to good yields, depending on the length of
the alkyl chain. From short alkyl chains (3−5 carbon atoms)
yields were lower than those observed with longer alkyl chains
(8−10 carbon atoms), and for these latter, products 15d−f
were isolated in 52−60% yields. The preparation of the
acrylamides 16e−f was realized by alkylation of methylamine
with bromides 15e−f, followed by their treatment with acryloyl
chloride, to afford acrylamides 16e−f in 75−78% overall yields.
The last investigated series concerned the preparation of a
short functionalized spacer, and in particular the preparation of
a monomer containing a ketophosphonate function, as a
potential metal binding group, as observed for matrix
metalloproteinase (MMP) inhibitors.23 The synthesis of
difluoromethyl ketophosphonates is well documented in the
literature, and a straightforward route consists of the reaction of
ethyl ester with the anion 6.24 In order to produce rapidly a
ketophosphosphonate containing a terminal hydroxyl function,
the addition of 6 onto caprolactone was explored (Scheme 4).
The addition reaction performed from −78 to −10 °C over 1 h
afforded a mixture of compounds. The NMR analysis (19F
NMR) of the crude mixture revealed the presence of the
expected alcohol 17 and another product 18 in a 2:1 ratio. This
second product, presenting a second-order pattern in 19F NMR
spectra, was attributed to the corresponding cyclic hemiketal
intermediate 18. Treatment of the crude product by NEt3 (1
equiv) overnight in CH2Cl2 induced a slight modification of the
ratio in favor of the corresponding alcohol 17 up to 7:3.
However, the alcohol 17 was never obtained exclusively.
This crude mixture was then involved in the next step
without further purification to introduce the methacrylate
function. Indeed, treatment of the crude mixture of 17 and 18
by methacrylic anhydride in the presence of NEt3 and a
Figure 3. Dentin shear bond strength (SBS in MPa) values of
phosphonic acids.
Formulation of this SEP with N,N-diethyl-1,3-bis(acrylamido)-
propane (DEBAAP) as hydrolytically stable cross-linkers
allowed the determination of the dentin shear bond strength
(SBS) values. In this case, the use of difluorophosphonic acid 4
allowed for better adhesive properties than the nonfluorinated
analogue 2 and similar properties than those observed from the
corresponding bis-phosphonates 3. These particular properties
prompted us to pursue this study to develop a new series of
monomers containing a difluorophosphonic acid function.
Since the chain length as well as the nature of acidic function
appeared important to facilitate the penetration of the SEP and
stabilize the interaction with calcium ions, the present study is
focused on the synthesis of difluoromethylphosphonic acid
derivatives containing various spacers. The preparation of
monomers containing alkyl chain lengths varying from 5 to 10
carbon atoms between the phosphonic acid function and the
methacrylic head (Figure 3) and the evaluation of these
monomers as potential components for SEP as functional
monomer are reported.
The synthesis of difluoromethylphosphonates was realized
from fluorosulfide 5, which has been developed in order to
avoid the utilization of CFCs as starting materials, and in
particular HCF2Cl (Scheme 1).17 The key step synthesis is the
Scheme 1. Preparation of azide derivatives
formation of the phosphonodifluoromethyl carbanion 6, which
was trapped either with alkyl halides or reacted with
tetrahydrofuran in the presence of BF3−Et2O. In the first
approach, to introduce the larger, functionalized alkyl chain, the
ω-hydroxy-difluoromethyl phosphonate 7 obtained by the ring-
opening reaction of THF was used as the main building
block.18 The alcohol was easily converted into the correspond-
ing azide 8,19 which was then involved the in 1,3-dipolar
cycloaddition reaction with alkynes.
Cycloaddition reactions were realized with propargylic
alcohol and functionalized alkynes, under Sharpless conditions
(Scheme 2). Products 9 and 11 were obtained in 90% and 74%
yields, respectively, and one regioisomer was obtained in each
B
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Scheme 2. Synthesis of triazolylacrylates
Scheme 3. Preparation of linear phosphonylacrylates and acrylamides
Scheme 4. Synthesis of ketophosphonates
CH2Cl2 over 48 h, and the corresponding phosphonic acids
20−24 were obtained in 90−95% yields (purity ≥95%)
(Scheme 5).
Shear Bond Strength. One method to correlate the
efficiency of these monomers consists of preparing SEP and
evaluating the resistance to mechanical pressure exerted onto
the composite linked to dentin with these primers. The two-
step self-etching adhesive systems containing the fluorinated
Scheme 5. Preparation of phosphonic acids
catalytic amount of DMAP, afforded the acrylate 19 in 46%
overall yield.
To evaluate the potential of the effect of these new
monomers on the bonding effectiveness of two-step self-
etching adhesive systems, the deprotection of the representative
structure for each series of phosphonate esters (10, 12, 14, 16e,
19) was realized by their treatment with Me3SiBr, followed by
MeOH.25 In all cases, the reaction proceeded at 20 °C in
C
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
Table 1. Formulation of primers 20−24
primer (wt %)
P1
P2
P3
P4
P5
monomer (mg)
20 26.21
36.49
14.62
21.88
0.36
21 24.59
37.35
14.94
22.41
0.31
22 33.08
32.90
13.14
19.67
0.53
23 26.85
36.23
14.47
21.66
0.36
24 26.10
36.17
14.70
22.20
0.35
DEBAAP (10% mol)
water
ethanol
CQ
EDAB
BHT
0.41
0.36
0.66
0.41
0.45
0.03
0.03
0.03
0.03
0.03
Figure 4. Mean SBS (MPa) and standard deviation (MPa) for fluorophosphonate acids SEP.
phosphonic acids were prepared (Table 1). The standard SEP
formulation used for this study includes bis-acrylamides such as
N,N-diethyl-1,3-bis(acrylamido)propane (DEBAAP) as hydro-
lytically stable cross-linkers.26 Each self-etching primer (SEP)
contains an acidic monomer, DEBAAP, water, ethanol as
cosolvent, a photoinitiator [camphorquinone (CQ)], a co-
initiator [ethyl 4-(dimethylamino)benzoate (EDAB)], and a
stabilizer [2,6-di-tert-butyl-4-methylphenol (BHT)]. In each
D
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
primer, components are present in the same molar ratio, each
formulation containing 5% molar of phosphonic acid and 10%
molar of DEBAAP (Table 1). SEPs were formulated in a dark
room, as described in a previous article.7b,27
value, could contribute to this durability as a potential MMP
inhibitor. Study of the effect of the fluorine atoms on the
permeability and the durability of the bonded joint obtained
from the various self-etch adhesives based on these new acidic
monomers are under investigation and will be reported
elsewhere.
Each primer, coupled with the AdheSE bonding resin
(Ivoclar-Vivadent, Schaan, Lichtenstein), has then been used
to generate a bond between a composite (Z100 A3, 3M/ESPE,
Saint-Paul, MN, U.S.A.) and dentin. The samples were stored
in deionized water at 37 °C for 24 h prior to SBS testing. They
were then shear loaded to fracture using a guillotine-type
shearing device and a universal testing machine. Shear bond
strength (SBS) to dentin has been measured 10 times for each
primer. Mean shear bond strength values (mean SBS) as well as
standard deviations (SD) are reported in Figure 4. In order to
assess the adhesive performance of these new SEPs with
available ones, the shear bond strengths of SEP-containing 1,
25−27 were presented with our previous SBS results already
reported.27 These values were obtained with the same testing
machine, and primer formulations contained the same
additional components.
Dentin shear bond strength measurements have shown that
two-step SEA with difluoromethylphosphonic acid containing
SEP are significantly more efficient than the one based on the
corresponding phosphonic acid. The use of the SEP containing
the 10-carbon-atom monomer, 20, presented a value of 24.2
MPa (Figure 4), allowed for the highest SBS value compared to
the use of widespread SEP-containing monomers 1 and 25,
with a value of 17.9 and 15.1 MPa, respectively. This significant
gap is essential to improve durability of the adhesive.
EXPERIMENTAL SECTION
■
General. All commercially available reagents were bought
and used as received. For anhydrous conditions, the glassware
was flamed under a continuous nitrogen flow and cooled to 20
°C before running the experiment. Anhydrous solvents (THF,
CH2Cl2, CH3CN, and toluene) were dried in a solvent
generator, which uses an activated alumina column to remove
water. DMF, Et3N, and pyridine were distilled under CaH2 or 4
Å molecular sieves. Flash column chromatography was realized
on silica gel 60 (40−63 μm) with air pressure, and products
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 400 or 500 MHz
apparatus at 25 °C. All chemical shifts are reported in δ parts
per million (ppm) using TMS or CFCl3 as internal references,
and coupling constants (J) are in hertz (Hz). The following
abbreviations mean: s: singlet; d: doublet; t triplet; q:
quadruplet; quint: quintuplet; sext: sextet; sep: septet; m:
multiplet. High-resolution mass data were recorded on a
Micromass Q-TOF (Quadrupole Time-of-Flight) instrument
with an electrospray source in the EI or ESI mode.
Preparation of Methacrylates Containing a Triazolyl
Difluoromethylphosphonate. General Procedure for 1,3-
Dipolar Cycloaddition Reaction. To a solution of diisopropyl
5-azido-1,1-difluoropentylphosphonate 819 (1 equiv) in tBuOH
(8 mL) and H2O (8 mL), were added propargylalcohol (1.1
equiv) and then CuSO4·5H2O (0.05 equiv) and sodium
ascorbate (0.1 equiv). After 23 h under stirring at 20 °C, the
solvents were removed under reduced pressure. The residue
was taken up with dichloromethane and washed with brine.
The organic layer was dried over MgSO4 and concentrated
under reduced pressure. The crude product was purified by
flash column chromatography on silica gel using CH2Cl2/
CH3OH (9:1) as eluent to afford the corresponding product.
General Procedure for the Preparation of Methacrylates.
To a solution of difluorophosphonylated alcohol (1 equiv) in
dichloromethane (10 mL), were added triethylamine (1.1
equiv) and DMAP (0.05 equiv) at 20 °C under N2. Methacrylic
anhydride (1 equiv) was then added dropwise. The mixture was
stirred 6 h at room temperature. H2O (5 mL) was added, and
the organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel using
EtOAc/MeOH (95:5) to give the expected product.
Diisopropyl 1,1-Difluoro-5-(4-(hydroxymethyl)-1H-
1,2,3-triazol-1-yl)pentylphosphonate (9). Starting from
819 (800 mg, 2.55 mmol) and propargylalcohol (164 μL, 2.81
mmol), the product 9 was isolated as a colorless oil (850 mg,
90%). 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 4.85−4.77
(m, 4H), 4.37 (t, J = 7.0 Hz, 2H), 2.87 (m, 1H), 2.09−1.90 (m,
4H), 1.66−1.62 (m, 2H), 1.31 (d, J = 5.9 Hz, 6H), 1.30 (d, J =
5.9 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ −112.7 (dt, J =
109.0 Hz, J = 18.8 Hz, 2F); 31P NMR (161 MHz, CDCl3) δ
5.07 (t, J = 109.0 Hz, 1P); 13C NMR (101 MHz, CDCl3) δ
148.5, 123.6, 121.6, 120.0 (dt, J = 260.1 Hz, 217.0 Hz), 73.6 (d,
J = 7.1 Hz), 55.9, 49.8, 32.9 (dt, J = 21.1 Hz, 14.7 Hz), 29.6,
This result confirmed our previous observation (monomers 2
and 4) and showed again that the introduction of fluorine
atoms on the functional monomer as part of the SEP has a
significant effect on the adhesive performance mediated by the
resulting SEA. The introduction of a larger spacer between the
phosphonic acid function and the methacrylate function also
has a significant effect since the SEP-containing 20 allowed for
the highest SBS value, contrasting with the results obtained
through the use of the SEP-containing short spacer such as
compound 4. However, the introduction of a heterocycle in the
spacer has a negative influence, and the SEP-containing
monomer 23 allowed for lower SBS value than that of 4,
even if the spacer was larger. In contrast, introduction of bis-
methacrylate function corrected this deviation, and the cross-
linker monomer 22 has an effect similar to that of monomer 4.
The introduction of a ketophosphonic function appeared
efficient, and in the case of monomer 21, the highest SBS value
was obtained.
CONCLUSION AND SUMMARY
■
In conclusion, all these results confirm that the nature of the
acidic group has a great influence on dentin adhesion, and
except for SEP-containing monomers 23 and 24, all fluorinated
monomers allowed for higher SBS values than the commercially
representative well-known monomers used in dentistry (i.e.
compounds 1, 25, 26). In the acrylamide series, surprisingly the
replacement of the phosphonic function by a difluorophos-
phonic function has no significant effect, and primers
containing monomers 24 and 27 give similar SBS values.
Therefore, fluorinated monomers appear to be great candidates
to enter adhesive formulations, and due to their chelating
properties difluorophosphonic acids should also improve dentin
adhesion durability. In addition, ketophosphonate 21, which
appeared to be the best candidate allowing for the highest SBS
E
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
23.9 (d, J = 3.5 Hz), 23.5 (d, J = 4.8 Hz), 17.9 (q, J = 4.6 Hz);
IR: 3407, 2985, 2940, 2901, 1465, 1456, 1388, 1378, 1254, 986.
HRMS (ESI) m/z: calcd for C14H27N3O4F2P [M + H]+
370.1707. Found 370.1711.
mixture was stirred 5 min at −78 °C followed by the addition of
the dibromoalkane (2 equiv). The reaction was stirred 30 min
at −78 °C and for an hour at −10 °C. After completion, the
reaction was quenched with a saturated aqueous solution of
NH4Cl at −10 °C. The product was extracted with dichloro-
methane, and combined organic layers were washed with a
saturated aqueous solution of NaHCO3, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography to afford the
expected product.
(1-(5-(Diisopropoxyphosphoryl)-5,5-difluoropentyl)-
1H-1,2,3-triazol-4-yl)methyl Methacrylate (10). Starting
from 9 (850 mg, 2.30 mmol) and using the general procedure,
the reaction was performed over 15 h. The product 10 (950
1
mg, 85%) was isolated as a colorless oil. H NMR (400 MHz,
CDCl3) δ 7.62 (s, 1H), 6.14 (m, 1H), 5.58 (m, 1H), 4.85
(dsept, J = 6.2 Hz, J = 6.2 Hz, 2H), 4.38 (t, J = 7.2 Hz, 2H),
2.18−1.93 (m, 4H), 1.95 (m, 3H), 1.72−1.61 (m, 2H), 1.48−
1.38 (m, 2H), 1.37 (d, J = 6.0 Hz, 6H), 1.36 (d, J = 6.0 Hz,
6H); 19F NMR (376 MHz, CDCl3) δ −112.8 (dt, J = 109.0 Hz,
J = 18.8 Hz, 2F); 31P NMR (161 MHz, CDCl3) δ 5.17 (t, J =
109.0 Hz, 1P); 13C NMR (101 MHz, CDCl3) δ 166.2, 142.0,
135.5, 125.5, 123.3, 119.5 (dt, J = 259.0 Hz, 217.2 Hz), 72.8 (d,
J = 7.0 Hz), 57.1, 49.1, 32.4 (dt, J = 21.1 Hz, 14.6 Hz), 29.1,
23.2 (d, J = 3.5 Hz), 22.9 (d, J = 4.8 Hz), 17.4, 17.3 (q, J = 4.7
Hz); IR: 2983, 1716, 1455, 1388, 1377, 1264, 1156, 986.
HRMS (ESI) m/z: calcd for C18H31N3O5F2P [M + H]+
438.1969. Found 438.1980.
Diisopropyl 1,1-Difluoro-10-(tetrahydro-2H-pyran-2-
yloxy)decylphosphonate (13). Starting from diisopropyl
1,1-difluoromethylphosphonate 5 (500 mg, 1.90 mmol) and 2-
(9-bromononyloxy)tetrahydro-2H-pyrane (1.17 g, 3.80 mmol),
the product 13 (747 mg, 89%) was isolated as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 4.83 (dsept, J = 6.2 Hz, J = 6.2
Hz, 2H), 4.58−4.56 (m, 1H), 3.89−3.83 (m, 1H), 3.72 (dt, J =
6.8 Hz, 2.8 Hz, 1H), 3.53−3.46 (m, 1H), 3.38 (dt, J = 6.8 Hz,
2.8 Hz, 1H), 2.09−1.93 (m, 2H), 1.88−1.77 (m, 1H), 1.75−
1.64 (m, 1H), 1.62−1.47 (m, 8H), 1.38 (d, J = 6.0 Hz, 6H),
1.37 (d, J = 6.0 Hz, 6H), 1.36−1.28 (m, 10H); 19F NMR (376
MHz, CDCl3) δ −112.7 (dt, J = 110.2 Hz, J = 20.7 Hz, 2F); 31
P
NMR (161 MHz, CDCl3) δ 5.81 (t, J = 110.2 Hz, 1P); 13C
NMR (101 MHz, CDCl3) δ 120.5 (dt, J = 258.6 Hz, 217.2 Hz),
98.7, 73.2 (d, J = 7.0 Hz), 67.5, 62.2, 33.7 (dt, J = 20.8 Hz, 14.2
Hz), 30.7, 29.6, 29.3, 29.2, 29.1, 29.0, 26.1, 25.4, 24.0 (d, J = 3.4
Hz), 23.6 (d, J = 4.9 Hz), 20.4 (q, J = 4.7 Hz), 19.6; IR: 2981,
2931, 2858, 1467, 1377, 1268, 986. HRMS (ESI) m/z: calcd for
C21H41O5F2NaP [M + Na]+ 465.2557. Found 465.2544.
Diisopropyl 1,1-Difluoro-10-(decyl methacrylate)-
phosphonate (14). To a solution of 13 (1.43 g, 3.23
mmol) in methanol (6.5 mL) was added amberlyst H-15 (97
mg). After 1 h at 45 °C, the mixture was filtered. The solvents
were removed under reduced pressure to afford the
corresponding alcohol (1.13 g) which was involved in the
Diisopropyl 1,1-Difluoro-5-(4-(3-hydroxy-2-
(hydroxymethyl)propyl)-1H-1,2,3-triazol-1-yl)-
pentylphosphonate (11). Starting from 819 (975 mg, 3.11
mmol) and 2-(prop-2-ynyl)propane-1,3-diol (391 mg, 3.42
mmol), product 11 (986 mg, 74%) was isolated as a colorless
oil. 1H NMR (400 MHz, CDCl3) δ 7.39 (br s, 1H), 4.81 (dsept,
J = 6.8 Hz, J = 6.8 Hz, 2H), 4.36 (t, J = 6.8 Hz, 2H), 3.81−3.64
(m, 4H), 3.17 (m, 1H), 2.82 (d, J = 6.9 Hz, 2H), 2.11−1.93 (m,
5H), 1.64−1.55 (m, 2H), 1.36 (d, J = 6.2 Hz, 6H), 1.35 (d, J =
6.2 Hz, 6H): 19F NMR (376 MHz, CDCl3) δ −112.1 (dt, J =
109.0 Hz, J = 18.8 Hz, 2F); 31P NMR (161 MHz, CDCl3): δ
4.97 (t, J = 109.0 Hz, 1P); 13C NMR (101 MHz, CDCl3) δ
145.9, 122.0, 120.1 (dt, J = 255.0 Hz, 214.0 Hz), 73.8 (d, J = 7.2
Hz), 63.4, 49.8, 42.6, 33.1 (dt, J = 20.9 Hz, 14.8 Hz), 29.6, 23.9
(d, J = 3.5 Hz), 23.7, 23.5 (d, J = 4.8 Hz), 18.0 (q, J = 4.8 Hz);
IR: 3390, 2984, 2936, 2875, 1465, 1388, 1378, 1253, 1099, 990.
HRMS (ESI) m/z: calcd for C17H33N3O5F2P [M + H]+
428.2126. Found 428.2125.
1
next step without purification. H NMR (400 MHz, CDCl3) δ
4.84 (dsept, J = 6.2 Hz, J = 6.2 Hz, 2H), 3.64 (t, J = 6.6 Hz,
2H), 2.12−1.94 (m, 2H), 1.62−1.52 (m, 6H), 1.38 (d, J = 6.4
Hz, 6H), 1.37 (d, J = 6.4 Hz, 6H), 1.38−1.28 (m, 8H), 1.48 (m,
1H); 19F NMR (376 MHz, CDCl3) δ −112.7 (dt, J = 109.4 Hz,
J = 19.9 Hz, 2F); 31P NMR (161 MHz, CDCl3) δ 5.79 (t, J =
109.4 Hz, 1P); 13C NMR (101 MHz, CDCl3) δ 120.1 (dt, J =
259.7 Hz, 217.6 Hz), 73.1 (d, J = 7.1 Hz), 61.9, 33.2 (dt, J =
20.9 Hz, 14.3 Hz), 32.3, 29.0, 28.9, 28.8, 28.7, 25.4, 23.6 (d, J =
3.4 Hz), 23.2 (d, J = 4.8 Hz), 20.2 (q, J = 4.6 Hz); IR: 3455,
2985, 2928, 2857, 1388, 1378, 1258, 987. HRMS (ESI) m/z:
calcd for C16H34O4F2P [M + H]+ 359.2163. Found 359.2147.
To a solution of alcohol (1.13 g, 3.16 mmol) in
dichloromethane (40 mL) were added NEt3 (1.1 equiv) and
DMAP (0.05 equiv) at 20 °C under N2. Methacrylic anhydride
(1 equiv) was then added dropwise. The mixture was stirred 6
h at 20 °C. H2O was added, and the organic layer was
separated, then washed with brine, dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was
purified by flash column chromatography on silica gel to give
the expected product 14 (889 mg, 66%) isolated as a colorless
2-((1-(5-(Diisopropoxyphosphoryl)-5,5-difluoropen-
tyl)-1H-1,2,3-triazol-4-yl)methyl)propane-1,3-diyl Bis(2-
methyl acrylate) (12). Starting from 11 (986 mg, 2.31
mmol) and using the general procedure, the product 12 (1.01
1
g, 78%) was isolated as a colorless oil. H NMR (400 MHz,
CDCl3) δ 7.35 (s, 1H), 6.10 (m, 2H), 5.57 (m, 2H), 4.83
(dsept, J = 6.2 Hz, J = 6.2 Hz, 2H), 4.34 (t, J = 7.2 Hz, 2H),
4.27−4.15 (m, 4H), 2.86 (d, J = 7.2 Hz, 2H), 2.66−2.58 (m,
1H), 2.16−1.94 (m, 4H), 1.96 (m, 6H), 1.68−1.61 (m, 2H),
1.37 (d, J = 6.2 Hz, 6H), 1.36 (d, J = 6.4 Hz, 6H); 19F NMR
(376 MHz, CDCl3) δ −112.8 (dt, J = 109.0 Hz, J = 18.8 Hz,
2F); 31P NMR (161 MHz, CDCl3) δ 5.19 (t, J = 109.0 Hz, 1P);
13C NMR (101 MHz, CDCl3); δ 170.0, 166.1, 150.8, 143.8,
135.4, 124.9, 121.2, 119.6 (dt, J = 258.7 Hz, 217.2 Hz), 72.7 (d,
J = 7.0 Hz), 63.2, 48.9, 37.1, 32.5 (dt, J = 20.9 Hz, 14.4 Hz),
29.5, 29.2, 23.9, 23.4 (d, J = 3.4 Hz), 22.9 (d, J = 4.8 Hz), 17.5,
17.4 (q, J = 4.8 Hz); IR: 2982, 1717, 1455, 1295, 1158, 999.
HRMS (ESI) m/z: calcd for C25H41N3O7F2P [M + H]+
564.2650. Found 564.2635.
1
oil. H NMR (400 MHz, CDCl3) δ 6.09 (m, 1H), 5.54 (m,
1H), 4.84 (dsept, J = 6.8 Hz, J = 6.8 Hz, 2H), 4.13 (t, J = 6.8
Hz, 2H), 2.12−2.01 (m, 2H), 1.94 (m, 3H), 1.72−1.53 (m,
6H), 1.38 (d, J = 6.4 Hz, 6H), 1.37 (d, J = 6.4 Hz, 6H), 1.36−
1.28 (m, 8H); 19F NMR (376 MHz, CDCl3) δ −112.7 (dt, J =
109.4 Hz, J = 18.3 Hz, 2F); 31P NMR (161 MHz, CDCl3) δ
5.79 (t, J = 109.4 Hz, 1P); 13C NMR (101 MHz, CDCl3) δ
General Procedure for Alkylation of Carbanion 6 with
Bromoalkanes. To a solution of tBuLi (1.3 equiv) in
anhydrous THF (20 mL) at −78 °C, was added diisopropyl
1,1-difluoromethylphosphonate 5 (1 equiv) dropwise. The
F
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
166.9, 136.1, 124.6, 120.2 (dt, J = 258.5 Hz, 217.4 Hz), 72.9 (d,
J = 7.0 Hz), 64.3, 33.5 (dt, J = 20.9 Hz, 14.2 Hz), 29.9, 28.9,
28.8, 28.7, 28.2, 25.5, 23.7 (d, J = 3.4 Hz), 23.3 (d, J = 4.9 Hz),
20.7 (q, J = 4.6 Hz), 17.8; IR: 2982, 2931, 2857, 1717, 1268,
1162, 987. HRMS (ESI) m/z: calcd for C20H38O5F2P [M + H]+
427.2425. Found 427.2416.
Hz); IR: 2982, 2932, 1467, 1387, 1377. HRMS (ESI) m/z:
calcd for C15H31O3F2P79Br [M + H]+ 407.1162. Found
407.1161.
Diisopropyl 1,1-Difluoro-10-bromodecylphosphonate
(15e). Starting from 5 (2 g, 7.60 mmol) and 1,8-
dibromononane (3.09 mL, 15.30 mmol), the product 15e
1
Diisopropyl 1,1-Difluoro-3-bromopropylphosphonate
(15a). Starting from 5 (100 mg, 0.38 mmol) and 1,3-
dibromopropane (77.4 μL, 0.76 mmol), the product 15a
(1.93 g, 60%) was isolated as a colorless oil. H NMR (400
MHz, CDCl3) δ 4.84 (dsept, J = 6.4 Hz, J = 6.4 Hz, 2H), 3.40
(t, J = 6.8 Hz, 2H), 2.10−1.95 (m, 2H), 1.85 (quint, J = 7.2 Hz,
2H), 1.60−1.38 (m, 4H), 1.42 (d, J = 6.2 Hz, 6H), 1.41 (d, J =
6.2 Hz, 6H), 1.32−1.28 (m, 8H); 19F NMR (376 MHz,
CDCl3) δ −112.8 (dt, J = 109.8 Hz, 20.0 Hz, 2F); 31P NMR
(161 MHz, CDCl3) δ 5.79 (t, J = 109.8 Hz, 1P); 13C NMR
(101 MHz, CDCl3) δ 120.6 (dt, J = 259.2 Hz, 217.4 Hz), 73.3
(d, J = 7.1 Hz), 33.9, 33.8 (dt, J = 20.9 Hz, 14.2 Hz), 32.8, 29.3,
29.2, 29.1, 28.7, 28.1, 24.1 (d, J = 3.4 Hz), 23.7 (d, J = 4.9 Hz),
20.6 (q, J = 4.7 Hz); IR: 2982, 2932, 1467, 1387, 1377. HRMS
(ESI) m/z: calcd for C16H33O3F2P79Br [M + H]+ 421.1319.
Found 421.1306.
1
(41.1 mg, 32%) was isolated as a colorless oil. H NMR (400
MHz, CDCl3) δ 4.84 (dsept, J = 6.4 Hz, J = 6.4 Hz, 2H), 3.46
(t, J = 6.2 Hz, 2H), 2.29−2.13 (m, 4H), 1.40 (d, J = 6.0 Hz,
6H), 1.38 (d, J = 6.0 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ
−112.4 (dt, J = 109.0 Hz, 18.8 Hz, 2F); 31P NMR (161 MHz,
CDCl3) δ 5.05 (t, J = 109.0 Hz, 1P); 13C NMR (101 MHz,
CDCl3) δ 120.1 (dt, J = 260.1 Hz, 217.4 Hz), 73.6 (d, J = 7.1
Hz), 32.6, 32.5 (dt, J = 21.1 Hz, 14.9 Hz), 24.3 (q, J = 5.1 Hz),
24.1 (d, J = 3.5 Hz), 23.7 (d, J = 4.9 Hz); IR: 2983, 2935, 1262,
988. HRMS (ESI) m/z: calcd for C10H21O3F2P79Br [M + H]+
337.0380. Found 337.0381.
Diisopropyl 1,1-Difluoro-11-bromoundecylphospho-
nate (15f). Starting from 5 (1 g, 3.80 mmol) and 1,8-
dibromodecane (2.29 g, 7.60 mmol), the product 15f (870 mg,
Diisopropyl 1,1-Difluoro-4-bromobutylphosphonate
(15b). Starting from 5 (100 mg, 0.38 mmol) and 1,4-
dibromobutane (90 μL, 0.76 mmol), the product 15b (38
1
52%) was isolated as a colorless oil. H NMR (400 MHz,
1
mg, 29%) was isolated as a colorless oil. H NMR (400 MHz,
CDCl3) δ 4.83 (dsept, J = 6.2 Hz, J = 6.2 Hz, 2H), 3.39 (t, J =
6.8 Hz, 2H), 2.05−1.95 (m, 2H), 1.85 (quint, J = 7.2 Hz, 2H),
1.59−1.52 (m, 2H), 1.49−1.21 (m, 12H), 1.36 (d, J = 6.2 Hz,
6H), 1.35 (d, J = 6.2 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ
−112.8 (dt, J = 18.8 Hz, 109.0 Hz, 2F); 31P NMR (161 MHz,
CDCl3) δ 5.80 (t, J = 109.0 Hz, 1P); 13C NMR (101 MHz,
CDCl3) δ 120.6 (dt, J = 260.8 Hz, 217.0 Hz), 73.2 (d, J = 5.3
Hz), 33.8 (dt, J = 21.2 Hz, 14.4 Hz), 32.8, 29.3, 29.2, 28.6, 28.1,
24.0, 23.7, 20.5 (q, J = 4.2 Hz); IR: 2977, 2927, 2856, 1467,
1377, 1268, 986. HRMS (ESI) m/z: calcd for C17H35O3F2P79Br
[M + H]+ 435.1475. Found 435.1453.
General Procedure for the Preparation of Acrylamide
Derivatives. The bromoalkanes (1 equiv) were diluted in
absolute EtOH (30 mL), and MeNH2 in CH3OH 33 wt % (20
equiv) was added dropwise. The mixture was stirred under N2
at 40 °C over 18 h. Then the solvents were removed under
reduced pressure, and H2O (20 mL) was added. A solution of
NaOHaq (10%) was introduced until pH ≥ 11. The aqueous
layer was extracted with CH2Cl2 twice. Combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The product was then
involved in the next step without any purification. To a solution
of difluorophosphonylated amine (1 equiv) in CH2Cl2 (20 mL)
was added NEt3 (1.1 equiv) at 0 °C under N2. Acryloyl chloride
(1 equiv) was added dropwise. After 30 min at 0 °C, the
mixture was stirred 4 h at 20 °C. H2O (10 mL) was added. The
organic layer was washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography on silica gel to
give the expected product.
CDCl3) δ 4.84 (dsept, J = 6.4 Hz, J = 6.4 Hz, 2H), 3.41 (t, J =
6.6 Hz, 2H), 2.15−1.99 (m, 2H), 1.96−1.89 (m, 2H), 1.79−
1.67 (m, 2H), 1.38 (d, J = 6.1 Hz, 6H), 1.37 (d, J = 6.1 Hz,
6H); 19F NMR (376 MHz, CDCl3) δ −112.8 (dt, J = 108.5 Hz,
19.6 Hz, 2F); 31P NMR (161 MHz, CDCl3) δ 5.40 (t, J = 108.5
Hz, 1P); 13C NMR (101 MHz, CDCl3) δ 120.2 (dt, J = 258.2
Hz, 217.4 Hz), 73.5 (d, J = 7.2 Hz), 33.0 (dt, J = 21.1 Hz, 14.6
Hz), 32.9, 32.2, 24.1 (d, J = 3.5 Hz), 23.7 (d, J = 4.9 Hz), 19.6
(q, J = 5.0 Hz); IR: 2982, 2933, 1388, 1378, 1264, 995. HRMS
(ESI) m/z: calcd for C11H23O3F2P79Br [M + H]+ 351.0536.
Found 351.0547.
Diisopropyl 1,1-Difluoro-5-bromopentylphosphonate
(15c). Starting from 5 (100 mg, 0.38 mmol) and 1,5-
dibromopentane (104 μL, 0.76 mmol), the product 15c (68
1
mg, 49%) was isolated as a colorless oil. H NMR (400 MHz,
CDCl3) δ 4.84 (dsept, J = 6.4 Hz, J = 6.4 Hz, 2H), 3.40 (t, J =
6.6 Hz, 2H), 2.12−1.98 (m, 2H), 1.96−1.87 (m, 2H), 1.79−
1.66 (m, 2H), 1.65−1.57 (m, 2H), 1.47 (d, J = 6.2 Hz, 6H),
1.46 (d, J = 6.2 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ
−112.8 (dt, J = 109.0 Hz, 18.8 Hz, 2F); 31P NMR (161 MHz,
CDCl3) δ 5.57 (t, J = 109.0 Hz, 1P); 13C NMR (101 MHz,
CDCl3) δ 120.2 (dt, J = 260.2 Hz, 217.4 Hz), 73.3 (d, J = 7.2
Hz), 33.5 (dt, J = 21.0 Hz, 14.4 Hz), 33.3, 32.3, 27.7, 24.0 (d, J
= 3.4 Hz), 23.6 (d, J = 4.8 Hz), 19.8 (q, J = 4.9 Hz); IR: 2982,
2938, 1387, 1377, 1268, 983. HRMS (ESI) m/z: calcd for
C12H25O3F2P79Br [M + H]+ 365.0693. Found 365.0684.
Diisopropyl 1,1-Difluoro-9-bromononylphosphonate
(15d). Starting from 5 (1 g, 3.8 mmol) and 1,8-dibromooctane
(1.42 mL, 7.60 mmol), the product 15d (818 mg, 53%) was
1
isolated as a yellow oil. H NMR (400 MHz, CDCl3) δ 4.84
Diisopropyl 1,1-Difluoro-(10-(N-methylacrylamido))-
decylphosphonate (16e). The reaction was placed at 40
°C, and starting from 15e (1.93 g, 4.58 mmol), the
corresponding methylamine derivative (1.54 g, 91%) was
(dsept, J = 6.8 Hz, J = 6.8 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H),
2.10−1.95 (m, 2H), 1.85 (quint, J = 6.9 Hz, 2H), 1.60−1.38
(m, 4H), 1.37 (d, J = 6.1 Hz, 6H), 1.36 (d, J = 6.1 Hz, 6H),
1.35−1.30 (m, 6H); 19F NMR (376 MHz, CDCl3) δ −112.8
(dt, J = 20.0 Hz, J = 109.7 Hz, 2F); 31P NMR (161 MHz,
CDCl3) δ 5.77 (t, J = 109.7 Hz, 1P); 13C NMR (101 MHz,
CDCl3) δ 120.6 (dt, J = 259.3 Hz, 217.3 Hz), 73.4 (d, J = 7.1
Hz), 33.8 (dt, J = 20.9 Hz, 14.2 Hz), 33.9, 32.7, 29.2, 29.1, 28.5,
28.0, 24.1 (d, J = 3.5 Hz), 23.7 (d, J = 4.9 Hz), 20.5 (q, J = 4.7
1
isolated as a colorless oil. H NMR (400 MHz, CDCl3) δ
4.77 (dsept, J = 6.2 Hz, J = 6.2 Hz, 2H), 2.48 (t, J = 7.2 Hz,
2H), 2.35 (s, 3H), 1.99−1.86 (m, 2H), 1.81 (m, 1H), 1.59−
1.29 (m, 4H), 1.30 (d, J = 6.2 Hz, 6H), 1.29 (d, J = 6.2 Hz,
6H), 1.28−1.21 (m, 10H); 19F NMR (376 MHz, CDCl3) δ
−112.8 (dt, J = 109.0 Hz, 18.8 Hz, 2F); 31P NMR (161 MHz,
G
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
CDCl3) δ 5.79 (t, J = 109.0 Hz, 1P); 13C NMR (101 MHz,
CDCl3) δ 120.4 (dt, J = 260.2 Hz, 218.1 Hz), 73.1 (d, J = 7.1
Hz), 51.9, 36.2, 33.6 (dt, J = 21.0 Hz, 14.2 Hz), 29.6, 29.2, 29.1,
29.0, 28.9, 27.0, 23.9 (d, J = 3.4 Hz), 23.5 (d, J = 4.9 Hz), 20.3
(q, J = 4.7 Hz); IR: 2977, 2926, 2855, 1467, 1377, 1267, 1178,
1103, 987. HRMS (ESI) m/z: calcd for C17H37NO3F2P [M +
H]+ 372.2479. Found 372.2471. The product was then involved
in the next step, and from methylamine derivative (1.54 g, 4.15
mmol), the product 16e (1.33 g, 75%) was isolated as a yellow
reaction mixture was quenched at −78 °C by addition of a
saturated aqueous solution of NH4Cl (20 mL), and the mixture
was slowly warmed up to 20 °C. The aqueous layer was
extracted with CH2Cl2 (20 mL), and the organic layer was
washed twice with an aqueous solution of NaHCO3 and then
with NaCl and dried over MgSO4. Solvents were evaporated
under reduced pressure, and crude product 17 was obtained
(4.5 g) as a colorless oil and was used in the next step without
any purification. 1H NMR (CDCl3, 500 MHz) δ 1.29−1.35 (m,
2H), 1.36 (d, J = 6.3 Hz, 6H), 1.37 (d, J = 6.3 Hz, 6H), 1.47−
1.80 (m, 4H), 2.65−2.82 (m, 2H), 3.69 (t, J = 6.5 Hz, 2H),
4.86 (dsept, J = 6.1 Hz, 6.1 Hz, 2H); 31P NMR (CDCl3, 202
MHz) δ 1.27 (t, J = 98.8 Hz, 1P); 19F NMR (CDCl3, 470
MHz) δ −118.89 (d, J = 98.8 Hz, 2F); 13C NMR (CDCl3, 101
MHz) δ 22.9, 23.8 (d, J = 5.1 Hz), 24.1 (d, J = 3.5 Hz), 24.6,
30.3 (dt, J = 4.6 Hz, 4.6 Hz), 32.1, 62.8, 73.8 (d, J = 6.9 Hz),
113.5 (dt, J = 198.9 Hz, 267.5 Hz), 206.9 (dt, J = 14.3 Hz, 22.1
Hz). HRMS (ESI) m/z: calcd for C13H26F2O5P [M + H]+
331.2359. Found 331.2370. Starting from 17 (2.16 g, 5.72
mmol) and using the general procedure used for compound 10,
the corresponding product 19 (1.05 g, 46%) was isolated as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.09 (m, 1H), 5.55
(m, 1H), 4.87 (dsept, J = 6.4 Hz, J = 6.4 Hz, 2H), 4.14 (t, J =
6.4 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 1.94 (m, 3H), 1.76−1.54
(m, 4H), 1.47−1.26 (m, 2H), 1.39 (d, J = 6.2 Hz, 6H), 1.38 (d,
J = 6.2 Hz, 6H); 19F NMR (376 MHz, CDCl3): δ −118.8 (d, J
= 97.5 Hz, 2F); 31P NMR (161 MHz, CDCl3) δ 5.1 (t, J = 97.5
Hz, 1P); 13C NMR (101 MHz, CDCl3) δ 198.8 (dt, J = 23.5
Hz, 14.4 Hz), 167.4, 136.4, 125.3, 113.2 (dt, J = 273.2 Hz,
198.1 Hz), 74.9 (d, J = 7.1 Hz), 64.3, 37.5, 28.3, 25.2, 24.1 (d, J
= 3.4 Hz), 23.5 (d, J = 5.2 Hz), 22.1, 18.3; IR: 2986, 2942,
2901, 1743, 1717, 1378, 1321, 1275, 1163, 992. HRMS (ESI)
m/z: calcd for C17H30O6F2P [M + H]+ 399, 1748. Found.
399.1758.
1
oil. H NMR (400 MHz, CDCl3) δ 6.56 (m, 1H), 6.31 (m,
1H), 5.66 (m, 1H), 4.84 (dsept, J = 6.2 Hz, J = 6.2 Hz, 2H),
3.41 and 3.33 (t, J = 7.5 Hz, 2H), 3.05 and 2.99 (s, 3H), 2.09−
1.93 (m, 2H), 1.59−1.53 (m, 4H), 1.38 (d, J = 6.2 Hz, 6H),
1.37 (d, J = 6.2 Hz, 6H), 1.36−1.28 (m, 10H); 19F NMR (376
MHz, CDCl3) δ −112.8 and −112.7 (dt, J = 109.0 Hz, 18.8 Hz,
2F); 31P NMR (161 MHz, CDCl3) δ 5.79 and 5.74 (t, J = 109.0
Hz, 1P); 13C NMR (101 MHz, CDCl3) δ 166.0, 165.7, 127.7,
127.4, 127.0, 120.3 (dt, J = 259.4 Hz, 217.6 Hz), 73.0 (d, J = 7.1
Hz), 49.7, 47.6, 35.1, 33.6, 33.5 (dt, J = 21.0 Hz, 14.2 Hz), 29.0,
28.9, 28.8, 28.7, 28.5, 26.8, 26.5, 26.3, 23.8 (d, J = 3.4 Hz), 23.4
(d, J = 4.8 Hz), 20.2 (q, J = 4.9 Hz); IR: 2980, 2929, 2857,
1650, 1613, 1266, 1178, 1103, 985. HRMS (ESI) m/z: calcd for
C20H39NO4F2P [M + H]+ 426.2585. Found 426.2567.
Diisopropyl 1,1-Difluoro-(11-(N-methylacrylamido))-
undecylphosphonate (16f). The reaction was placed at 40
°C, and starting from 15f (870 mg, 2.0 mmol), the
corresponding methylamine derivative (767 mg, 99%) was
1
isolated as a yellow oil. H NMR (400 MHz, CDCl3) δ 4.77
(dsept, J = 6.2 Hz, J = 6.2 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H),
2.36 (s, 3H), 2.02−1.89 (m, 3H), 1.50−1.36 (m, 4H), 1.31 (d, J
= 6.1 Hz, 6H), 1.30 (d, J = 6.1 Hz, 6H), 1.29−1.20 (m, 12H);
19F NMR (376 MHz, CDCl3) δ −112.8 (dt, J = 110.0 Hz, 18.8
Hz, 2F). 31P NMR (161 MHz, CDCl3): δ 5.78 (t, J = 110.0 Hz,
1P); 13C NMR (101 MHz, CDCl3) δ 120.6 (dt, J = 259.4 Hz,
217.7 Hz), 73.2 (d, J = 7.1 Hz), 52.0, 36.3, 33.7 (dt, J = 20.9
Hz, 14.2 Hz), 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 27.2, 24.0 (d, J =
3.4 Hz), 23.6 (d, J = 4.8 Hz), 20.5 (q, J = 4.7 Hz); IR: 2977,
2925, 2855, 1467, 1377, 1268, 1178, 1103 988. HRMS (ESI)
m/z: calcd for C18H39NO3F2P [M + H]+ 386.2636. Found
386.2623. Starting from the methylamine derivative (767 mg,
2.0 mmol), the product 16f (661 mg, 78%) was isolated as a
General Procedure for the Preparation of Phosphonic
Acids (20−24). Phosphonic ester was diluted in dry dichloro-
methane (25 mL), under N2 at 0 °C. Freshly distilled Me3SiBr
(5 equiv) was added dropwise. After 30 min at 0 °C, the
mixture was placed at room temperature for 48 h. The solvents
were evaporated under reduced pressure and MeOH (25 mL)
was added. The mixture was stirred 2 h at room temperature.
The MeOH was then evaporated under reduced pressure. The
product was obtained with a purity >95% and used without any
further purification.
1
yellow oil. H NMR (400 MHz, CDCl3) δ 6.34 (m, 1H), 6.20
(m, 1H), 5.40 (m, 1H), 4.58 (dsept, J = 6.2 Hz, J = 6.2 Hz,
2H), 3.16 and 3.10 (t, J = 7.2 Hz, 2H), 2.81 and 2.73 (s, 3H),
1.81−1.68 (m, 2H), 1.38−1.25 (m, 4H), 1.13 (d, J = 5.9 Hz,
6H), 1.12 (d, J = 5.9 Hz, 6H), 1.11−1.01 (m, 12H); 19F NMR
(376 MHz, CDCl3) δ −112.9 and −113.0 (dt, J = 109.4 Hz,
18.8 Hz, 2F). 31P NMR (161 MHz, CDCl3): δ 5.57 and 5.45 (t,
J = 109.4 Hz, 1P); 13C NMR (101 MHz, CDCl3) δ 165.6,
165.3, 127.5, 127.1, 126.7, 120.0 (dt, J = 259.4 Hz, 217.7 Hz),
72.7 (d, J = 7.0 Hz), 49.4, 47.3, 34.7, 33.3 (dt, J = 21.2 Hz, 14.3
Hz), 33.2, 28.8, 28.7, 28.6, 28.3, 26.5, 26.2, 26.0, 23.5 (d, J = 3.4
Hz), 23.1 (d, J = 4.9 Hz), 20.0 (q, J = 4.9 Hz); IR: 2977, 2927,
2856, 1651, 1614, 1466, 1376, 1268, 1178, 1103, 986. HRMS
(ESI) m/z: calcd for C21H41NO4F2P [M + H]+ 440.2741.
Found 440.2740.
Diisopropyl 1,1-Difluoro-7-(methacryloyloxy)-2-oxo-
heptylphosphonate (19). To a cooled solution of tBuLi
(11.4 mL, 1.3 M in pentane, 14.90 mmol) in dried THF (50
mL) at −78 °C was added dropwise neat 5 (3 g, 11.40 mmol).
After 5 min of stirring, a solution of BF3−Et2O (2.4 mL, 22.8
mmol) was added, and then caprolactone (1.65 mL, 14.90
mmol) in THF (5 mL) was slowly added. After 10 min the
1,1-Difluoro-10-(methacryloyloxy)decylphosphonic Acid
(20). Starting from diisopropyl 1,1-difluoro-10-(decyl
methacrylate)phosphonate 14 (889 mg, 2.09 mmol), the
1
product 20 (717 mg, 99%) was isolated as a colorless oil. H
NMR (400 MHz, MeOD) δ 6.03 (m, 1H), 5.56 (m, 1H), 4.08
(t, J = 6.8 Hz, 2H), 2.03−1.95 (m, 2H), 1.88 (m, 3H), 1.72−
1.51 (m, 4H), 1.31−1.27 (m, 10H); 19F NMR (376 MHz,
MeOD) δ −114.7 (dt, J = 109.4 Hz, 18.8 Hz, 2F); 31P NMR
(161 MHz, MeOD); δ 6.27 (t, J = 109.4 Hz, 1P); 13C NMR
(101 MHz, MeOD) δ 168.9, 137.8, 125.9, 122.2 (dt, J = 257.5
Hz, 209.3 Hz), 65.9, 34.8 (dt, J = 21.2 Hz, 14.6 Hz), 30.5, 30.4,
30.3, 30.2, 29.6, 26.9, 21.9 (q, J = 4.6 Hz), 18.4; IR: 3379, 2929,
2856, 1699, 1457, 1299, 1168, 1011, 931. HRMS (ESI) m/z:
calcd for C14H24O5F2P [M − H]+ 341.1329. Found 341.1337.
1,1-Difluoro-7-(methacryloyloxy)-2-oxoheptylphosphonic
Acid (21). Starting from diisopropyl 1,1-difluoro-7-(methacry-
loyloxy)-2-oxoheptylphosphonate 19 (611 mg, 1.53 mmol), the
1
product 21 (534 mg, 99%) was isolated as a colorless oil. H
NMR (400 MHz, MeOD) δ 6.03 (m, 1H), 5.56 (m, 1H), 4.10
H
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(t, J = 6.5 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 1.88 (m, 3H),
1.70−1.58 (m, 4H), 1.43−1.32 (m, 2H); 19F NMR (376 MHz,
MeOD) δ −121.2 (dt, J = 94.0 Hz, 2F); 31P NMR (161 MHz,
MeOD) δ 1.45 (t, J = 94.0 Hz, 1P); 13C NMR (101 MHz,
MeOD) δ 200.9 (dt, J = 23.3 Hz, 13.9 Hz), 168.8, 137.7, 126.0,
115.5 (dt, J = 270.5 Hz, 190.2 Hz), 65.6, 38.3, 30.9, 29.4, 26.7,
18.3; IR: 2947, 2866, 1740, 1716, 1689, 1632, 1456, 1299,
1168, 942. HRMS (ESI) m/z: calcd for C11H16O6F2P [M −
H]+ 313.0695. Found 313.0688.
1 , 1 - D i fl u o r o - 5 - ( 4 - ( 3 - ( m e t h a c r y l o y l o x y ) - 2 -
(methacryloyloxymethyl)propyl)-1H-1,2,3-triazol-1-yl)-
pentylphosphonic Acid (22). Starting from 2-((1-(5-(diisopro-
poxyphosphoryl)-5,5-difluoropentyl)-1H-1,2,3-triazol-4-yl)-
methyl)propane-1,3-diyl bis(2-methyl acrylate) 12 (1.01 g, 1.80
mmol), the product 22 (880 mg, 99%) was isolated as a
colorless oil. 1H NMR (400 MHz, MeOD) δ 8.47 (s, 1H), 6.03
(m, 2H), 5.61 (m, 2H), 4.58 (t, J = 7.2 Hz, 2H), 4.23−4.19 (m,
4H), 3.01 (d, J = 7.2 Hz, 2H), 2.65−2.51 (m, 1H), 2.18−1.99
(m, 4H), 1.90 (s, 6H), 1.68−1.58 (m, 2H); 19F NMR (376
MHz, MeOD) δ −114.5 (dt, J = 105.3 Hz, 18.8 Hz, 2F); 31P
NMR (161 MHz, MeOD) δ 5.69 (t, J = 105.3 Hz, 1P); 13C
NMR (101 MHz, MeOD) δ 168.3, 152.8, 143.4, 137.4, 128.6,
126.7, 122.0 (dt, J = 258.5 Hz, 210.5 Hz), 64.9, 53.9, 49.8, 38.8,
33.9 (dt, J = 21.4 Hz, 14.8 Hz), 30.0, 24.1, 19.1 (q, J = 4.9 Hz),
18.4; IR: 2956, 1716, 1635, 1455, 1320, 1296, 1155. HRMS
(ESI) m/z: calcd for C19H27O7F2N3P [M − H]+ 478.1555.
Found 478.1549.
approved by the review board of the Dental Faculty of Paris
Descartes University. The teeth were stored in 1% Chloramine
T solution at 4 °C until used. Ten teeth were randomly
assigned to each of the six experimental groups as described in
Figure 4. Preparation of samples for dentin bonding tests. The
occlusal surface of each tooth was ground under water on a
Pedemax polishing device (Struers A/S, Ballerup, Denmark)
with #80 SiC paper to obtain a flat surface and expose middle
dentin. The teeth were then embedded in cylindrical molds
using methacrylic resin (Plexcil 6, Escil, Chassieu, France). The
obtained samples were stored in deionized water at 4 °C until
used. Just before usage, the surface of the sample was ground
with #800 SiC paper under water to expose a clean and flat
dentin surface of suitable roughness.
Bonding. The SEP were actively brushed onto the exposed
surfaces with a regular size microbrush for 15 s. A waiting time
of 15 s was respected before progressively air drying the SEP
until no movement was observed. The bonding agent (AdheSE
#2 bottle, Ivoclar-Vivadent, Schaan, Liechtenstein) was applied
followed by air thinning for less than 5 s. The adhesive was then
polymerized for 20 s using an LED curing unit (LCU-Radii
Plus, Southern Dental Industries Ltd., Bayswater, Victoria,
Australia). A Teflon mold with a 3 mm cylindrical hole, 4 mm
in height, was secured on the samples. The mold was filled with
two increments of composite (Z100 A3, 3M/ESPE, Saint-Paul,
MN, U.S.A.). Each increment was light cured for 20 s. The
irradiance of the LCU was controlled with a radiometer (Cure
Rite, Dentsply Caulk, Milford, DE, U.S.A.) before each batch of
sample and was superior to 1500 mW·cm−2. The samples were
stored in deionized water at 37 °C for 24 h prior to SBS testing.
They were then shear loaded to fracture using a guillotine-type
shearing device and a universal testing machine (Lloyd
Instruments LRX, Ametek S.A.S., Elancourt, France) at a
crosshead speed of 0.5 mm·min−1. The SBS results were
statistically analyzed (SPSSPASW Statistics version 18, IBM
Corporation, Armonk, NY, U.S.A.). Results were analyzed for
dentin and enamel separately. Chain length parameter was
assessed by one way ANOVA. Pairwise comparison was
assessed by an LSD test. The significance level was 0.05 for
each test.
1,1-Difluoro-5-(4-(methacryloyloxymethyl)-1H-1,2,3-tria-
zol-1-yl)pentylphosphonic Acid (23). Starting from (1-(5-
(diisopropoxyphosphoryl)-5,5-difluoropentyl)-1H-1,2,3-triazol-
4-yl)methyl methacrylate 10 (951 g, 2.17 mmol), the product
23 (780 mg, 99%) was isolated as a colorless oil. 1H NMR (400
MHz, MeOD) δ 8.40 (s, 1H), 6.11 (m, 1H), 5.64 (m, 1H), 5.31
(s, 2H), 4.54 (t, J = 7.2 Hz, 2H), 2.10−1.99 (m, 4H), 1.90 (s,
3H), 1.65−1.57 (m, 2H); 19F NMR (376 MHz, MeOD) δ
−114.6 (dt, J = 105.3 Hz, 18.8 Hz, 2F); 31P NMR (161 MHz,
MeOD) δ 5.74 (t, J = 105.3 Hz, 1P); 13C NMR (101 MHz,
MeOD) δ 167.8, 141.2, 137.5, 128.8, 127.6, 121.9 (dt, J = 258.5
Hz, 210.5 Hz), 56.2, 53.5, 34.0 (dt, J = 21.2 Hz, 15.0 Hz), 30.2,
19.0 (q, J = 4.5 Hz), 18.3; IR: 3320, 2949, 1721, 1636, 1456,
1316, 1295, 1149, 994, 928. HRMS (ESI) m/z: calcd for
C12H17O5F2N3P [M − H]+ 352.0874. Found 352.0865.
1,1-Difluoro-(10-acrylamide)decylphosphonic Acid (24).
Starting from 16e (1.33 g, 3.12 mmol), the product 24 (1.27
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for compounds 9−14, 15, 16e,f, 19−
24. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
g, 99%) was isolated as a colorless oil. H NMR (400 MHz,
MeOD) δ 6.70 and 6.69 (dd, J = 16.8 Hz, 10.6 Hz, 1H), 6.18
and 6.17 (dd, J = 16.8 Hz, 1.6 Hz, 1H), 5.73 (m, 1H), 3.45−
3.38 (m, 2H), 3.09 and 2.97 (s, 3H), 2.07−1.92 (m, 2H), 1.62−
1.49 (m, 4H), 1.36−1.24 (m, 10H); 19F NMR (376 MHz,
MeOD) δ −114.7 (dt, J = 108.5 Hz, 18.8 Hz, 2F); 31P NMR
(161 MHz, MeOD) δ 6.23 (t, J = 108.5 Hz, 1P); 13C NMR
(101 MHz, MeOD) δ 169.1, 169.0, 129.5, 128.5, 128.2, 122.2
(dt, J = 258.5 Hz, 210.8 Hz), 51.6, 36.7, 34.9, 34.7 (dt, J = 21.2
Hz, 14.5 Hz), 30.4, 30.3, 30.2, 29.4, 27.8, 27.7, 27.4, 21.8 (q, J =
4.7 Hz); IR: 3389, 2987, 2922, 2849, 2197, 1648, 1515, 1462,
1165, 1148, 1022, 969, 943. HRMS (ESI) m/z: calcd for
C14H25NO4F2P [M − H]+ 340.1489. Found 340.1503.
Shear Bond Strength Measurements. Shear bond strength
(SBS) to dentin was assessed using the method described by
ISO/TS11405 standard. Fifty unrestored, caries-free, third
human molars deemed suitable for testing were used within
three months after extraction. The teeth were gathered
following informed consent according to the protocols
AUTHOR INFORMATION
Corresponding Authors
*E-mail: nhan.pham@ensicaen.fr (T.-N.P).
*E-mail: Thierry.Lequeux@ensicaen.fr (T.L.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the INC3M institute (FR CNRS
3038) for the fellowship to A.Z. CNRS (Centre National de la
́
Recherche Scientifique), GIS-Fluor network, “Region Basse-
Normandie”, and the European Union (FEDER funding) are
acknowledged for financial support, and Mr. V. Besse for his
technical assistance during the preparation of solution of
primers.
I
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(22) Diab, S.; De Schutter, C.; Muzard, M.; Pfund, E.; Plantier-
Royon, R.; Lequeux, T. J. Med. Chem. 2012, 55, 2758−2768.
(23) (a) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, A. J. H.
Chem. Rev. 1999, 99, 2735−2776. (b) Jacobsen, J. A.; Major Jourden, J.
L.; Miller, M. T.; Cohen, S. M. Biochim. Biophys. Acta 2010, 1803, 72−
94.
(24) (a) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Shoemarker, R. K. J.
Org. Chem. 1996, 61, 4666−4675. (b) Lequeux, T.; Percy, J. M. J.
Chem. Soc., Chem. Commun. 1995, 2111−2112.
(25) McKenna, C. E.; Schmidhauser, J. J. Chem. Soc., Chem. Commun.
1979, 739−741.
REFERENCES
■
(1) (a) Moszner, N.; Salz, U. Macromol. Mater. Eng. 2007, 292, 245−
271. (b) Tyas, M. J.; Burrow, M. F. Aust. Dent. J. 2004, 49, 112−121.
(c) Van Meerbeek, B.; Vargas, M.; Inoue, S.; Yoshida, Y.; Peumans,
M.; Lambrechts, P.; Vanherle, G. Oper. Dent. 2001, 6, 119−144.
(2) Monge, S.; David, G. Phosphorus-Base Polymers, from Synthesis to
Applications; RCS Polymer Chemistry Series; Royal Society of
Chemistry: Cambridge, 2014.
(3) (a) Van Landuyt, K. L.; Snauwaert, J.; De Munck, J.; Peumans,
M.; Yoshida, Y.; Poitevin, A.; Coutinho, E.; Suzuki, K.; Lambrechts, P.;
Van Meerbeek, B. Biomaterials 2007, 28, 3757−3785. (b) Moszner,
N.; Salz, U.; Zimmermann, J. Dent. Mater. 2005, 21, 895−910.
(4) (a) Peumans, M.; Kanumilli, P.; De Munck, J.; Van Landuyt, K.;
Lambrechts, P.; Van Meerbeek, B. Dent. Mater. 2005, 21, 864−881.
(b) Fukegawa, D.; Hayakawa, S.; Yoshida, Y.; Suzuki, K.; Osaka, A.;
Van Meerbeek, B. J. Dent. Res. 2006, 85, 941−944.
(26) Salz, U.; Bock, T. J. Adhes. Dent. 2010, 12, 7−10.
(27) (a) See reference 7b. (b) Derbanne, M. A.; Besse, V.; Le Goff,
S.; Sadoun, M.; Pham, T.-N. Polym. Degrad. Stab. 2013, 98, 1688−
1698.
(5) (a) Bresci, L.; Mazzoni, A.; Ruggeri, A.; Cadenaro, M.; Di
Lenarda, R.; De Stefano Dorigo, E. Dent. Mater. 2008, 24, 90−101.
(b) De Munck, J.; Van Landuyt, K.; Peumans, M.; Poitevin, A.;
Lambrechts, P.; Braem, M.; Van Meerbeek, B. J. Dent. Res. 2005, 84,
118−132. (c) Hashimoto, M. J. Biomed. Mater. Res. Part. B 2010, 92B,
268−280.
(6) (a) Inoue, S.; Koshiro, K.; Yoshida, Y.; De Munck, J.; Nagakane,
K.; Suzuki, K.; Sano, H.; Van Meerbeek, B. J. Dent. Res. 2005, 84,
1160−1164. (b) Ikemura, K.; Tay, F. R.; Nishiyama, N.; Pashley, D.
H.; Endo, T. Dent. Mater. 2006, 25, 566−575. (c) Sahin, G.; Albayrak,
A. Z.; Bilgici, Z. S.; Avci, D. J. Polym. Sci. Part. A: Polym. Chem. 2009,
47, 1953−1965.
(7) (a) Moszner, N.; Angermann, J.; Fischer, U.; Bock, T. Macromol.
Mater. Eng. 2013, 298, 454−461. (b) Catel, Y.; Degrange, M.; Le
Pluart, L.; Madec, P.-J.; Pham, T.-N.; Picton, L. J. Polym. Sci. A: Polym.
Chem. 2008, 46, 7074−7090.
(8) Catel, Y.; Fischer, U. K.; Moszner, N. Polym. Int. 2013, 62, 1717−
1728.
(9) Van Meerbeek, B.; Yoshihara, K.; Yoshida, Y.; Mine, A.; De
Munck, J.; Van Landuyt, K. L. Dent. Mater. 2011, 27, 17−28.
(10) (a) Fukegawa, D.; Hayakawa, S.; Yoshida, Y.; Suzuki, K.; Osaka,
A.; Van Meerbeek, B. J. Dent. Res. 2006, 85, 941−944. (b) Hiraishi, N.;
Tochio, N.; Kigawa, T.; Otsuki, M.; Tagami, J. J. Dent. Res. 2013, 92,
284−288.
(11) Bala, J. L. F.; Kashemirov, B. A.; McKenna, C. E. Synth.
Commun. 2010, 40, 3577−3584.
(12) Zeuner, F.; Moszner, N.; Volkel, T.; Vogel, K.; Rheinberger, V.
̈
Phosphorum, Sulfur Silicon Relat. Elem. 1999, 144−146, 133−136.
(13) Romanenko, V. D.; Kukhar, V. P. Chem. Rev. 2006, 106, 3868−
3935.
(14) (a) Blackburn, G. M.; England, D. A.; Kolkmann, F. J. Chem.
Soc., Chem. Commun. 1981, 930−932. (b) Blackburn, G. M.; Kent, D.
E.; Kolkmann, F. J. Chem. Soc., Perkin Trans 1 1984, 1119−1125.
(15) Seifter, J. In Goldman’s Cecil Medicine, Goldman, L., Schafer, A.
I., Eds. Saunders, Elsevier: Philadelphia; 2011.
(16) Catel, Y.; Besse, V.; Zulauf, A.; Marchat, D.; Pfund, E.; Pham, T.
N.; Bernache-Assolant, D.; Degrange, M.; Lequeux, T.; Madec, P.-J.;
Le Pluart, L. Eur. Polym. J. 2012, 48, 318−330.
(17) Henry-dit-Quesnel, A.; Toupet, L.; Pommelet, J. C.; Lequeux, T.
Org. Biomol. Chem. 2003, 1, 2486−2491.
(18) Ozouf, P.; Binot, G.; Pommelet, J. C.; Lequeux, T. Org. Lett.
2004, 6, 3747−3750.
(19) Diab, S.; Hienzch, A.; Lebargy, C.; Guillarme, S.; Pfund, E.;
Lequeux, T. Org. Biomol. Chem. 2009, 4481−4490.
(20) (a) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36,
1249−1262. (b) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today
2003, 8, 1128−1137. (c) Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40, 2004−2021.
(21) (a) Jakeman, D. L.; Ivory, A. J.; Williamson, M. P.; Blackburn, G.
M. J. Med. Chem. 1998, 41, 4439−4452. (b) Bigge, C. F.; Drummond,
J. T.; Johnson, G. Tetrahedron Lett. 1989, 30, 7013−7016. (c) Halazy,
S.; Ehrhard, A.; Danzin, C. J. Am. Chem. Soc. 1991, 113, 315−317.
J
dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX