Fluorophosphonylated Monomers for Dental Applications - Organic

Jun 18, 2014 - The synthesis of acrylate derivatives bearing a difluorophosphonic acid function has been realized by ring-opening reaction of oxacycle...
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Fluorophosphonylated Monomers for Dental Applications Mathieu Derbanne,† Anais Zulauf,‡ Stéphane Le Goff,† Emmanuel Pfund,‡ Michael̈ Sadoun,† Thi-Nhàn Pham,*,‡ and Thierry Lequeux*,‡ ‡

Laboratoire de Chimie Moléculaire et Thio-Organique UMR CNRS 6507, INC3M, FR 3038, ENSICAEN and Université de Caen Basse Normandie, 6 boulevard du Maréchal Juin, 14050 Caen, France † Unité de Recherche en Biomatériaux Innovants et Interfaces (URB2I) - EA4462 and Faculté de Chirurgie Dentaire, Université Paris Descartes, Sorbonne Paris Cité, 1 rue Maurice Arnoux, 92120 Montrouge, France 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.

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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 selfetching 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.

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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). Recently, we reported the synthesis of difluorophosphonylated 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

Figure 1. 10-MDP component of SEP and targeted generic structure of monomers.

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,αdifluoromethylphosphonic acid function instead of a hydro© XXXX American Chemical Society

Special Issue: Fluorine Chemistry 14 Received: March 28, 2014

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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 functionalized 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 wellknown 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 methacrylate 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 ringopening reaction of THF was used as the main building block.18 The alcohol was easily converted into the corresponding 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

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Scheme 2. Synthesis of triazolylacrylates

Scheme 3. Preparation of linear phosphonylacrylates and acrylamides

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 twostep self-etching adhesive systems containing the fluorinated

Scheme 4. Synthesis of ketophosphonates

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 selfetching 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

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Table 1. Formulation of primers 20−24 primer (wt %)

P1

P2

P3

P4

P5

monomer (mg) DEBAAP (10% mol) water ethanol CQ EDAB BHT

20 26.21 36.49 14.62 21.88 0.36 0.41 0.03

21 24.59 37.35 14.94 22.41 0.31 0.36 0.03

22 33.08 32.90 13.14 19.67 0.53 0.66 0.03

23 26.85 36.23 14.47 21.66 0.36 0.41 0.03

24 26.10 36.17 14.70 22.20 0.35 0.45 0.03

Figure 4. Mean SBS (MPa) and standard deviation (MPa) for fluorophosphonate acids SEP.

contains an acidic monomer, DEBAAP, water, ethanol as cosolvent, a photoinitiator [camphorquinone (CQ)], a coinitiator [ethyl 4-(dimethylamino)benzoate (EDAB)], and a stabilizer [2,6-di-tert-butyl-4-methylphenol (BHT)]. In each

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 hydrolytically stable cross-linkers.26 Each self-etching primer (SEP) D

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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.

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 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. 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 bismethacrylate function corrected this deviation, and the crosslinker 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.

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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 1,3Dipolar 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)-1H1,2,3-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,

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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 difluorophosphonic 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

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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 dichloromethane, 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. Diisopropyl 1,1-Difluoro-10-(tetrahydro-2H-pyran-2yloxy)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. 1 H 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); 31P 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 next step without purification. 1H 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 oil. 1H 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

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. (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 mg, 85%) was isolated as a colorless oil. 1H 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. D i i s op r o p y l 1, 1 -D iflu o r o - 5 - ( 4 - ( 3 - h yd r o x y -2 (hydro xymethyl)propyl) -1H-1,2,3- triazo l-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. 2-((1-(5-(Diisopropoxyphosphoryl)-5,5-difluoropentyl)-1H-1,2,3-triazol-4-yl)methyl)propane-1,3-diyl Bis(2methyl acrylate) (12). Starting from 11 (986 mg, 2.31 mmol) and using the general procedure, the product 12 (1.01 g, 78%) was isolated as a colorless oil. 1H 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); 13 C 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. 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

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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 1,8dibromononane (3.09 mL, 15.30 mmol), the product 15e (1.93 g, 60%) was isolated as a colorless oil. 1H 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. Diisopropyl 1,1-Difluoro-11-bromoundecylphosphonate (15f). Starting from 5 (1 g, 3.80 mmol) and 1,8dibromodecane (2.29 g, 7.60 mmol), the product 15f (870 mg, 52%) was isolated as a colorless oil. 1H 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. 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 isolated as a colorless oil. 1H 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,

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. Diisopropyl 1,1-Difluoro-3-bromopropylphosphonate (15a). Starting from 5 (100 mg, 0.38 mmol) and 1,3dibromopropane (77.4 μL, 0.76 mmol), the product 15a (41.1 mg, 32%) was isolated as a colorless oil. 1H 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-4-bromobutylphosphonate (15b). Starting from 5 (100 mg, 0.38 mmol) and 1,4dibromobutane (90 μL, 0.76 mmol), the product 15b (38 mg, 29%) was isolated as a colorless oil. 1H NMR (400 MHz, 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 1,5dibromopentane (104 μL, 0.76 mmol), the product 15c (68 mg, 49%) was isolated as a colorless oil. 1H 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 isolated as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.84 (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 G

dx.doi.org/10.1021/op500108m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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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. General Procedure for the Preparation of Phosphonic Acids (20−24). Phosphonic ester was diluted in dry dichloromethane (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. 1,1-Difluoro-10-(methacryloyloxy)decylphosphonic Acid (20). Starting from diisopropyl 1,1-difluoro-10-(decyl methacrylate)phosphonate 14 (889 mg, 2.09 mmol), the product 20 (717 mg, 99%) was isolated as a colorless oil. 1H 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-(methacryloyloxy)-2-oxoheptylphosphonate 19 (611 mg, 1.53 mmol), the product 21 (534 mg, 99%) was isolated as a colorless oil. 1H NMR (400 MHz, MeOD) δ 6.03 (m, 1H), 5.56 (m, 1H), 4.10

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 oil. 1H 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 isolated as a yellow oil. 1H 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); 19 F 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 yellow oil. 1H 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-oxoheptylphosphonate (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 H

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(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-Difluoro-5-(4-(3-(methacryloyloxy)-2(methacryloyloxymethyl)propyl)-1H-1,2,3-triazol-1-yl)pentylphosphonic Acid (22). Starting from 2-((1-(5-(diisopropoxyphosphoryl)-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. 1,1-Difluoro-5-(4-(methacryloyloxymethyl)-1H-1,2,3-triazol-1-yl)pentylphosphonic Acid (23). Starting from (1-(5(diisopropoxyphosphoryl)-5,5-difluoropentyl)-1H-1,2,3-triazol4-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 g, 99%) was isolated as a colorless oil. 1H 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

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.

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ASSOCIATED CONTENT

S Supporting Information *

1

H 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.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (T.-N.P). *E-mail: [email protected] (T.L.). Notes

The authors declare no competing financial interest.

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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, “Région BasseNormandie”, 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

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