Direct electrophilic fluorination of naproxen with NF-reagents

Journal Pre-proof Direct electrophilic fluorination of naproxen with NF-reagents Gennady I. Borodkin, Innokenty R. Elanov, Yury V. Gatilov, Vyacheslav G. Shubin

PII:

S0022-1139(19)30339-2

DOI:

https://doi.org/10.1016/j.jfluchem.2019.109412

Reference:

FLUOR 109412

To appear in:

Journal of Fluorine Chemistry

Received Date:

27 September 2019

Revised Date:

31 October 2019

Accepted Date:

4 November 2019

Please cite this article as: Borodkin GI, Elanov IR, Gatilov YV, Shubin VG, Direct electrophilic fluorination of naproxen with NF-reagents, Journal of Fluorine Chemistry (2019), doi: https://doi.org/10.1016/j.jfluchem.2019.109412

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Direct electrophilic fluorination of naproxen with NF-reagents

Gennady I. Borodkina,b,*, Innokenty R. Elanova, Yury V. Gatilova,b, Vyacheslav G. Shubina

a

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentiev Ave., Novosibirsk, 630090, Russia

b

Novosibirsk State University, 2 Pirogov St., Novosibirsk, 630090, Russia

*

Corresponding author at: N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, 9 Acad. Lavrentiev Ave., Novosibirsk,

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630090, Russia. E-mail address: [email protected] (G.I. Borodkin)

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Graphical Abstract



Method for direct fluorination of naproxen with NF-reagents has been developed. The procedure is operationally simple, free from metal ions, and tolerant of sensitive functional group COOH.



The reaction provides a convenient route to fluorinated derivatives of naproxen as method for the late-stage functionalization.

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

The reaction of naproxen with NF-reagents in MeCN and H2O gives 2-(5,5-difluoro-6oxo-5,6-dihydronaphthalen-2-yl)propionic acid and (5-fluoro-6-methoxynaphthalen-2yl)propionic acid.



The reaction of naproxen with an excess of Selectfluor in MeOH gives difluoroketal.

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Abstract A novel effective protocol has been developed for direct fluorination of naproxen using the electrophilic fluorinating reagents 1-chloromethy1-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™, F-TEDA-BF4) and N-fluorobenzenesulfonimide (NFSI) in

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MeCN and H2O solvents with the formation of 2-(5-fluoro-6-methoxynaphthalen-2-yl)propionic

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and 2-(5,5-difluoro-6-oxo-5,6-dihydronaphthalen-2-yl)propionic acids. The reaction of naproxen with an excess of Selectfluor (mol. ratio NF-reagent/naproxen = 2.2) in MeOH gives methyl 2-

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(5,5-difluoro-6,6-dimethoxy-5,6-dihydronaphthalen-2-yl)propionate as the main product. The

Keywords:

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mechanistic aspects of the reactions and X-ray data of products are discussed.

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NF-reagent, naproxen, mechanism of fluorination, X-ray analysis ___________

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1. Introduction

Naproxen, 2-(6-methoxynaphthalen-2-yl)propionic acid, is a widely prescribed nonsteroidal

anti-inflammatory drug that relieves pain, fever, swelling and stiffness. Naproxen is known to exert its protective effects as anti-cancer agent [1]. Recently, naproxen was discovered to also exhibit antiviral activity, reducing viral load in cells infected with influenza А(H1N1, H3N2) [2,

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3]. Industrial production of naproxen is currently about ten thousand tons per year, which creates a good basis for conducting research on its structural modification [4]. Significant efforts have been made on structural modification of naproxen [5, 6], including the introduction of fluorine atom into the side chain of this molecule [7]. In medicinal chemistry, introducing fluorine into a molecule usually increases a metabolic stability of a drug, often improving their transportation properties, increasing binding to target molecules and lipophilicity of the biologically active compound [8, 9]. Therefore, we decided to study the possibility of direct introduction of fluorine atom into the aromatic ring of naproxen using NF-reagents [10, 11]. Among the NF-reagents 1-

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chloromethy1-4-fluoro-l,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™, FTEDA-BF4) and N-fluorobenzenesulfonimide (NFSI) are the most widely utilized chemicals [12, 13]. These reagents are stable, easy to use and show sufficient selectivity in the fluorination of

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many organic compounds. Earlier, 5-fluoronaproxen was synthesized by using a 9-step synthetic

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scheme including Balz-Schiemann fluorination [14]. However, synthesis of the necessary functionalized precursors was complex and time consuming and, therefore, a more convenient

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approach to the synthesis of fluorinated derivatives of naproxen is the direct electrophilic

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fluorination.

2. Results and discussion

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2.1. Synthetic procedures

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The fluorination of naproxen (1) with F-TEDA-BF4 and NFSI has been carried out in MeCN and H2O. The reaction of naproxen with NF-reagents gives 2-(5-fluoro-6-methoxynaphthalen-2yl)propionic acid (2) and 2-(5,5-difluoro-6-oxo-5,6-dihydronaphthalen-2-yl)propionic acid (3) (Scheme 1). The relative quantities of each product were strongly dependent on the reaction conditions and molar ratio 1/NF-reagent (Tables 1, 2).

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Scheme 1. Fluorination of naproxen with NF-reagents.

The reaction of naproxen with an excess of Selectfluor (mol. ratio NF-reagent/naproxen = 2.2) gives difluoride 3 as the main product, and the intermediate in this reaction is monofluoride 2. The difluoride 3 is also formed in fluorination of naproxen 1 when using an approximately

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equimolar amount of Selectfluor or NFSI. We considered that the formation of difluoride 3 on

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treatment of naproxen with NF-reagents proceeded via the monofluoride 2, so that preparation of difluoride 3 by direct fluorination seemed feasible. Indeed, treatment of monofluoride 2 with 1.2

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equiv. of Selectfluor at room temperature in MeCN gave the expected difluoride 3 (Table 1, entry 22). The relative proportion of monofluoride 2 increases with decreasing reaction

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temperature (Table 1, entry 1, 3, 4).

The fluorination of naproxen with Selectfluor when adding base (Et3N, C5H5N, K2CO3,

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Rb2CO3) proceeds in a highly selective manner to furnish the monofluorinated product 2 in 1852% yields (Table 1, entry 14, 15, 19, 20). The yield of products 2 and 3 in the reaction of

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naproxen with Selectfluor in MeCN when adding 5 equivalents of base M2CO3, (M = Li, Na, K, Rb and Cs) decreases with increasing metal atomic number (Z) (Table 1, entry 17-21), while the ratio of 2/3 increases (Figures 1 and 2).

5 2

60

50

2 Yield, %

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3

30

2 2

20

3

2

10

3

3

3

0

Li2CO3

Na2CO3

K2CO3

Rb2CO3

Cs2CO3

Molar ratio of 2/3 Cs

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25

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Figure 1. Effect of metal carbonates on yields of 2 and 3 (MeCN, mol. ratio 1 : Selectfluor : M2CO3 = 1 : 1.1 : 5, R.T., 22 h).

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10

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15

K

5

Li

Na

0 0

10

20

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Rb

30

40

50

60

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Z

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Figure 2. Effect of metal carbonates on the ratio of 2/3 (MeCN, mol. ratio 1 : Selectfluor : M2CO3 = 1 : 1.1 : 5, R.T., 22 h, Z -atomic number of the metal).

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The formation of anionic intermediates 1’ and 2’ may occur when using metal carbonates (Scheme 2).

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Scheme 2. Fluorination of naproxen with Selectfluor in the presence of metal carbonates.

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Conditions that favor the formation of salts 1’ and 2’ should therefore lead to increased rate of the reaction and higher yields of the fluorinated products. However, low solubility of metal carbonates in MeCN does not significantly increase yields. In addition, Selecfluor is a strong oxidizing agent [13] and can be involved in the oxidation of metal carbonates. The solubility of

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Cs2CO3 in MeCN is probably higher than that of Li2CO3 (cf. ref. [15]) which leads to greater

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decomposition of Selectfluor resulting in a decrease in yield of the fluorinated products (see Supplementary data).

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NFSI is a weaker fluorinating reagent compared with Selectfluor [16] and only small amounts of fluorides 2 and 3 are formed at room temperature (Table 2, entry 1 and 2). Temperature

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increase to 80 °C led to an increase in conversion of naproxen to 2 and 3 (Table 2, entry 1, 3). The fluorination of naproxen with NFSI in the presence of Et3N at 80 oC gives 2 only in 2%

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yield whereas the use of NaHCO3 as base gives 2 in 41% yield (Table 2, entry 6, 7). In order to check the possibility of fluorination of naproxen under solvent-free conditions we chose dry

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NFSI. Successful transformation of naproxen to its fluoro derivatives was achieved at 115 °C using an approximately equimolar amount of NFSI (Table 2, entry 9). In this case fluorination was carried out more selectively in comparison with using MeCN as solvent (ratio 2:3 = 7.4).

2.2. Mechanistic studies At present two possible pathways are considered for fluorine atom transfer to the arene: nucleophilic substitution at the fluorine atom (polar SEAr mechanism) and one electron transfer

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involving into the process a cation radical (SET mechanism) [9, 12, 17, 18, 19]. Both mechanisms, SET and SEAr, involve a formation of -complex, as the key intermediate, which

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transforms into fluorinated aromatic derivative through proton elimination (Scheme 3).

Scheme 3. A mechanism for the formation of compound 2 and 3.

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Attempts to probe the possible involvement of cation radicals in the reaction of naproxen with Selectfluor in MeCN using 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) as a trap were

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unsuccessful. Under the standard reaction conditions, when the radical scavenger TEMPO (1.0

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equiv.) was added in MeCN, the fluorination process of naproxen with Selectfluor (mol. ratio NF-reagent/naproxen = 1.1) at room temperature was inhibited and only a trace of product 2 (~5% yield) was obtained. Under the same conditions the reaction between Selectfluor and

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TEMPO leads to conversion of TEMPO to a complex mixture of products (cf. [20]) and the use of TEMPO as a radical trap is therefore unreliable.

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The fluorination rate of naproxen (1) with Selectfluor in CD3CN-D2O (95:5 v/v) is higher than

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that of 5-fluoronaproxen (2) (Figure 3) that may be due to the influence of an electron-acceptor substituent F in 2.

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100

90

1, 2 (%)

80

70

60

50

2 1

40 0

1000

2000

3000

4000

5000

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Time (s)

Figure 3. Plot of the content of 1 and 2 versus time for the fluorination with Selectfluor in

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CD3CN-D2O (95:5 v/v) at 25 oC.

High-quality kinetic data of fluorination of 2 were obtained from

1

H NMR kinetic

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bimolecular mechanism (Scheme 3):

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experiments. The kinetics of the reaction of 2 with F-TEDA-BF4 in CD3CN-D2O conforms to the

v = k[A][F-TEDA-BF4], where [A] is the concentration of 2. The 1/[A] – 1/[A]o values are linearly related to time [k25°C = (2.42 ± 0.04)·10–2 L·mol-1·s-1]

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(Figure 4).

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120

100

1/[A] - 1/[A]o

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80

y = 0.0242x -1.24

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R = 0.9987

40

20

0 0

1000

2000

3000

4000

5000

Time (s)

Figure 4. The kinetics of fluorination of 2 with Selectfluor in CD3CN-D2O (95:5 v/v) at 25 oC.

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The difluoride 3 was apparently formed by trace amounts of water in MeCN and reagents (Scheme 3). This mechanistic hypothesis is supported by our observation that the ratio of 2:3 decreases with the addition of water in MeCN (Table 1, entry 2, 7) and the predominant formation of difluoride 3 when using water as a solvent (Table 1, entry 8, 9). If the reaction 1 is carried out with Selectfluor in MeCN-H2O with an 18O-labelled water, in the end of the reaction, the 18O isotope is exclusively found in difluoride 3 (see Supplementary data). This is indicative of the fact that a nucleophilic attack of -complex B with H218O has occurred (Scheme 3).

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The reaction of naproxen with Selectfluor (mol. ratio NF-reagent/naproxen = 1.1) in MeOH at 65 oC and MeOH-C5H5N (molar ratio base:1 = 5) at room temperature gives methyl 2-(5,5difluoro-6,6-dimethoxy-5,6-dihydronaphthalen-2-yl)propionate (4) as the main product with 59% and 58% yield respectively. A plausible mechanism of the transformation 1→4 is shown in

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Scheme 4.

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Scheme 4. A plausible mechanism for the formation of ketal 4.

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2.3. Spectral and X-ray analysis Compounds 2, 3 and 4 were characterized by IR, NMR (1H,

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C,

data supporting the proposed structures (see Supplementary data). shows a doublet at -148.1 ppm (J = 8.2 Hz), while the

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19

F) spectroscopy with all

F NMR of compound 2

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F NMR of 3 and 4 shows singlet at -

102.1 ppm and -115.0 ppm respectively. The structures of 2 and 3 were additionally confirmed by X-ray analysis (Figures 5 and 6).

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Figure 5. Structure of fluoride 2 with selected bond lengths (thermal ellipsoids of 30%

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probability, only one of two independent molecules is shown).

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Figure 6. Structure of difluoride 3 with bond lengths (thermal ellipsoid of 20% probability, only one of two independent molecules is shown).

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When the molecular structure of fluoride 2 is compared to naproxen [21] the following similarities can be observed: the methoxy group shows a tendency to be coplanar with

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naphthalene fragment (C7-C6-O1-C12 9.5 and -3.1o for two independent molecules) giving rise

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to shortening of C-O bond (C6-O1 1.370 and 1.363 Å). A similar effect has been observed in the case of naproxen as being due to some degree of conjugation between O and naphthalene rings [21]. The naphthalene fragments of fluorides 2 and 3 are nearly planar within ±0.010 and ±0.045 Å respectively. The carboxylic groups of fluorides 2 and 3 are twisted significantly out of naphthalene rings (C1-C2-C9-C10 -101.7, -20.2 and -54.7, 47.0º for two independent molecules) and participate in intermolecular hydrogen bonding with the COOH group of neighboring molecule forming dimers. Hydrogen bonds OH...O parameters are H…O 1.69-1.85, O…O

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2.610-2.695 Å. Naproxen shows similar type of hydrogen bonding between carboxylic groups but forming chains in (S) enantiomer and dimers in racemic crystal [22, 23]. The fluorine atoms of 2 and 3 do not participate in strong hydrogen bonding, but molecule 3 has a weak hydrogen bond (C3-H…F, H…F 2.55 Å).

3. Conclusion

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In conclusion, we have developed a method for direct fluorination of naproxen with NFreagents. The reaction provides a convenient route to fluorinated derivatives of naproxen as method for the late-stage functionalization. The procedure is operationally simple, free from metal ions, and tolerant of sensitive functional group COOH. The reaction of naproxen with an

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excess of NF-reagents in MeCN and H2O gives 2-(5,5-difluoro-6-oxo-5,6-dihydronaphthalen-2-

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yl)propionic acid (3) as the main product, and the intermediate in this reaction is (5-fluoro-6methoxynaphthalen-2-yl)propionic acid (2). The formation of difluoride 3 in MeCN proceeds via

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the monofluoride 2 involving trace amounts of water in the solvent. The reaction of naproxen with an excess of Selectfluor in MeOH gives ketal 4 as the main product. The fluorination of

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naproxen with Selectfluor in the presence of the base proceeds in a highly selective manner to

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furnish the monofluorinated product 2.

4. Experimental

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4.1. Materials and methods SelectfluorTM and NFSI were purchased from Sigma-Aldrich and Acros Organics and used

without further purification. CH3CN and CH3OH were dried by standard methods. The 1H and 19

F NMR spectra were recorded on a Bruker AV-300 spectrometer using the residual proton of

CDCl3 (δH 7.24 ppm) and PhCF3 (δF -63.73 ppm) as internal references. The

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C NMR spectra

were measured on a Bruker DRX-500 spectrometer using CDCl3 (δC 76.9 ppm) as an internal

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reference. The chemical shifts (δ) are given in ppm relative to TMS (1H,

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C) and CFCl3 (19F).

FT-IR spectra were recorded on a Bruker Vector 22 spectrometer. The high resolution mass spectra (HRMS) were recorded on a Thermo Scientific DFS and an Agilent 7200 Q-TOF instruments. Single crystal X-ray diffraction measurements were performed on a Bruker Kappa Apex II diffractometer. Absorption correction was applied using the SADABS program. The structures were solved by the direct method and refined by full-matrix least-squares method in an anisotropic approximation (except H atoms) using the SHELXL-97 program. Crystallographic

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data for the structures 2 and 3 have been deposited with the Cambridge Crystallographic Data Centre (CCDC 1896495 and 1896496, recpectively). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223

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336033 or e-mail: [email protected]).

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4.2. General procedure for study of fluorination of naproxen

A mixture of naproxen, F-TEDA-BF4 (1.1 or 2.2 equivalents) or NFSI (1.1 or 2.2 equivalents),

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and the solvent (3 mL) was stirred for certain hours at various temperatures (Tables 1, 2). The mixture was evaporated at a reduced pressure or with air flow at room temperature and analyzed

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by 1H, 19F NMR as solution in CDCl3. Cl2CHCHCl2 and PhCF3 were used as internal standards

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for peak integration.

4.3. Synthetic procedures

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4.3.1. 2-(5-Fluoro-6-methoxynaphthalen-2-yl)propionic acid (2) A mixture of naproxen (230 mg, 1 mmol), F-TEDA-BF4 (460 mg, 1.3 mmol) and CH3CN (18

mL) was stirred at 80 oC for 6 h under an argon atmosphere. After cooling to room temperature the mixture was evaporated under reduced pressure. The yellow-brown solid was stirred with CHCl3 (10 mL), filtrated, the filtrate was evaporated under reduced pressure. The brown oil obtained was purified by column chromatography (SiO2, CHCl3 as eluent) and then by

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recrystallization (from n-hexane-CHCl3). Off-white plates, yield – 0.061 g (25%), mp 123-125 o

C. FT-IR (CHCl3): 1710 (C=O), 1645, 1614, 1574, 1493, 1462 cm-1. 1H NMR (300 MHz,

CDCl3): 11.64 (br s, 1H, COOH), 7.98 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.53 (d, J = 9 Hz, 1H), 7.46 (dd, J = 8.75, 1.4 Hz, 1H), 7.26 (t, J = 8.5 Hz, 1H), 3.99 (s, OCH3), 3.86 (q, J = 7.2 Hz, 1H), 1.58 (d, J = 7.2 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3): 180.5 (C=O), 146.5 (d, 1JCF = 248 Hz, C-5’), 142.8 (d, J = 9.4 Hz), 135.8, 129.1 (d, J = 3.6 Hz), 126.4, 125.7 (d, J = 1.8 Hz), 123.7, 123.6 (d, J = 4.8 Hz), 120.1 (d, J = 5.3 Hz), 116.1, 57.5 (OCH3), 45.2 (C-2), 17.9 (CH3).

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NMR (282 MHz, CDCl3): -148.08 (d, 1F, J = 8.2 Hz, 5’-CF). HRMS (DFS), m/z: calcd for

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C14H13O3F+ 248.0843; found 248.0845.

4.3.2. 2-(5,5-Difluoro-6-oxo-5,6-dihydronaphthalen-2-yl)propionic acid (3)

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A mixture of naproxen (200 mg, 0.87 mmol), F-TEDA-BF4 (680 mg, 1.92 mmol), CH3CN (26.6 mL) and water (1.4 mL) was stirred at room temperature for 23 h. Then the solvents were

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removed under reduced pressure. The yellow solid obtained was shaken with ether (50 mL), filtrated, the organic solution was evaporated under reduced pressure. The yellow-brown oil

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obtained gradually solidified. Yellow-brownish solid, yield – 0.192 g (87%). The crystals of compound 3 suitable for X-ray analysis were obtained by recrystallization from n-hexane-

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CHCl3. White needles, mp 88-90 oC. FT-IR (CHCl3): 1703 (two overlapping signals of C=O groups), 1603, 1576, 1458 cm-1. 1H NMR (300 MHz, CDCl3): 11.20 (br s, 1H, COOH), 7.77 (d,

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J = 8 Hz, 1H), 7.46 (dd, J = 8, 1.3 Hz, 1H), 7.40 (d, J = 10.1 Hz, 1H), 7.32 (d, J = 0.8 Hz), 6.22 (dt, J = 10.1, 2.7 Hz, 1H), 3.80 (q, J = 7.2 Hz, 1H), 1.55 (d, J = 7.2 Hz, 3H, CH3). 13C NMR (125

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MHz, CDCl3): 187.2 (t, J = 24.8 Hz, C6’=O), 179.3 (C=O), 145.2, 143.9, 132.2 (t, J = 23.7 Hz), 130.6 (t, J = 5.7 Hz), 130.1, 129.1, 128.0 (t, J = 3 Hz), 123.8, 105.3 (t, 1JCF = 245 Hz, C-5’), 44.9 (C-2), 17.8 (CH3).

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F NMR (282 MHz, CDCl3): -102.06 (s, 2F, 5’-CF2). HRMS (DFS), m/z:

calcd for C13H10O3F2+ 252.0593; found 252.0592. 4.3.3. Methyl 2-(5,5-difluoro-6,6-dimethoxy-5,6-dihydronaphthalen-2-yl)propionate (4)

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A mixture of naproxen (100 mg, 0.434 mmol), F-TEDA-BF4 (340 mg, 0.96 mmol) and dry CH3OH (15 mL) was stirred at 65 oC for 5 h. After cooling to room temperature the mixture was evaporated under reduced pressure. The solid obtained was shaken with CH2Cl2 (10 mL), filtered, the solution was concentrated, the yellow-brownish oil obtained was purified by column chromatography (SiO2, CHCl3 as eluent) to afford 4 as a colorless oil, yield – 0.0677 g (50%). FT-IR (neat): 1738, 1610, 1458, 1435, 1334, 1282, 1192, 1172, 1145, 1084, 1054, 1016, 981, 927, 841 cm-1. 1H NMR (300 MHz, CDCl3): 7.60 (d, J = 7.9 Hz, 1H), 7.25 (dd, J = 7.9, 1.7 Hz, 1H), 7.09 (d, J = 1 Hz, 1H), 6.55 (d, J = 10.1 Hz, 1H), 5.89 (dt, J = 10.1, 2.5 Hz, 1H), 3.71 (q, J

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= 7.2 Hz, 1H), 3.65 (s, 3H, OCH3), 3.43 (s, 6H, OCH3), 1.48 (d, J = 7.2 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3): 174.2 (C=O), 143.4 (t, J = 2.1 Hz), 132.1 (t, J = 5.6 Hz), 129.9 (t, J = 24 Hz), 129.4, 128.6 (t, J = 1.3 Hz), 127.7, 126.4, 124.7 (t, J = 5.7 Hz), 117.8 (t, 1JCF = 251 Hz, C-

F NMR (282 MHz, CDCl3): -115.0 (s, 2F, 5’-CF2). HRMS (Q-TOF), m/z: calcd for

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C16H18O4F2+ 312.1168; found 312.1168.

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5’), 95.9 (t, J = 24.2 Hz), 52.0 (COOCH3), 50.5 (t, J = 1.7 Hz, (OCH3)2, 45.1 (C-2), 17.8 (CH3).

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The authors declare no conflict of interest.

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Acknowledgements

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The authors would like to acknowledge the Multi-Access Chemical Research Center of SB RAS for spectral and analytical measurements. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi: https://doi.org/

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References [1] A. Mohammed, N. S. Yarla, V. Madka, C. V. Rao, Clinically relevant anti-inflammatory agents for chemoprevention of colorectal cancer: new perspectives, Int. J. Mol. Sci. 1 (2018) 2332-2350. https://doi.org/10.3390/ijms19082332.

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[2] D.S. Hui, N. Lee, P.K. Chan, J.H. Beigel, The role of adjuvant immunomodulatory agents for treatment of severe influenza, Antivir. Res. 150 (2018) 202-216. https://doi.org/10.1016/j.antiviral.2018.01.002.

-p

[3] N. Lejal, B. Tarus, E. Bouguyon, S. Chenavas, N. Bertho, B. Delmas, R.W.H. Ruigrok, C.D. Primo, A. Slama-Schwok, Structure-based discovery of the novel antiviral properties of

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naproxen against the nucleoprotein of influenza A virus, Antimicrob. Agents Chemother. 57

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(2013) 2231-2242. https://doi.org/10.1128/AAC.02335-12. [4] A.M. Demin, Amides of (S)-naproxen and other chiral acids: synthesis, separation of stereoisomers and biological activity, Ph.D. Thesis, Institute of Organic Chemistry,

na

Ekaterinburg, Russia, 2005.

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[5] S.-W. Tsai, C.-C. Chen, H.-S. Yang, I-S. Ng, T.-L. Chen, Implication of substrate-assisted catalysis on improving lipase activity or enantioselectivity in organic solvents, Biochim.

Jo

Biophys. Acta, 1764 (2006) 1424-1428. https://doi.org/10.1016/j.bbapap.2006.07.001.

[6] A. Adeniji, Md.J. Uddin, T. Zang, D. Tamae, P. Wangtrakuldee, L.J. Marnett, T.M. Penning, Discovery of (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid as a potent and selective aldoketo reductase 1C3 inhibitor, J. Med. Chem. 59 (2016) 7431-7444. https://doi.org/10.1021/acs.jmedchem.6b00160.

16

[7] O. Goj, S. Kotila, G. Haufe, Convenient Routes to 2-Aryl-2- fluoropropionic Acids: Synthesis of Monofluorinated Analogues of (±)-Ibuprofen, (±)-Naproxen and Related Compounds, Tetrahedron 39 (1996) 12761-12774. https://doi.org/10.1016/0040-4020(96)00758-2

[8] V. Gouverneur, K. Müller, Fluorine in Pharmaceutical and Medical Chemistry. From Biophysical Aspects to Clinical Applications, Imperial College Press, London, 2012.

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[9] P.A. Zaikin, G.I. Borodkin, Electrophilic and Oxidative Fluorination of Aromatic

Compounds, in: A. Postigo (Ed.), Late-Stage Fluorination of Bioactive Molecules and Biologically-Relevant Substrates, Elsevier, Amsterdam, 2019, pp. 105-135.

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https://doi.org/10.1016/B978-0-12-812958-6.00003-3.

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[10] P. Kirsch, Modern Fluoroorganic Chemistry. Synthesis, Reactivity, Applications, WileyVCH, Weinheim, 2004.

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[11] K. Uneyama, Organofluorine Chemistry, Blackwell, Oxford, 2006. [12] G.I. Borodkin, V.G. Shubin, The selectivity problem in electrophilic fluorination of

na

aromatic compounds, Russ. Chem. Rev. 79 (2010) 259-283. https://doi.org/10.1070/RC2010v079n04ABEH004091.

ur

[13] R.P. Singh, J.M. Shreeve, Recent highlights in electrophilic fluorination with 1chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), Acc. Chem.

Jo

Res. 37 (2004) 31-44. https://doi.org/10.1021/ar030043v.

[14] F.S. Alvarez, US Patent, 2-(6'-Methoxynaphth-2’-yl)propylene oxide and 5’-halo derivatives. 3,637,767A, Jan. 25,1972.

[15] J.A. Cella, S.W. Bacon, Preparation of dialkyl carbonates via the phase-transfer-catalyzed alkylation of alkali metal carbonate and bicarbonate salts, J. Org. Chem. 49 (1984) 11221125. https://doi.org/10.1021/jo00180a033.

17

[16] D.S. Timofeeva, A.R. Ofial, H. Mayr, Kinetics of electrophilic fluorinations of enamines and carbanions: comparison of the fluorinating power of N−F reagents, J. Am. Chem. Soc. 140 (2018) 11474−11486. https://doi.org/10.1021/jacs.8b07147. [17] C. Geng, L. Du, F. Liu, R. Zhu, C. Liu, Theoretical study on the mechanism of selective fluorination of aromatic compounds with Selectfluor, RSC Adv. 5 (2015) 33385–33391. https://doi.org/10.1039/c4ra15202f. [18] I. Pravst, S. Stavber, Fluorination of 4-alkyl-substituted phenols and aromatic ethers with

ro of

fluoroxy and N-F reagents: cesium fluoroxysulfate and N-fluoro-1,4-diazoniabicyclo[2.2.2]octane dication salts case, J. Fluorine Chem. 156 (2013) 276–282. https://doi.org/10.1016/j.jfluchem.2013.07.002.

-p

[19] P.T. Nyffeler, S.G. Durón, M.D. Burkart, S.P. Vincent, C.-H. Wong, Selectfluor: mechanistic insight and applications, Angew. Chem. Int. Ed. 44 (2005) 192-212.

re

https://doi.org/10.1002/anie.200400648.

lP

[20] S.H. Wood, S. Etridge, A.R. Kennedy, J.M. Percy, D.J. Nelson, The electrophilic fluorination of enol esters using Selectfluor: a polar two-electron process, Chem. Eur. J. 25 (2019) 5574–5585. https://doi.org/10.1002/chem.201900029.

na

[21] K. Ravikumar, S.S. Rajan, V. Pattabhi, E.J. Gabe, Structure of naproxen, C14H14O3, Acta Cryst. C41 (1985) 280-282. https://doi.org/10.1107/S0108270185003626.

ur

[22] B. Hachuła, The nature of hydrogen-bonding interactions in nonsteroidal anti-inflammatory

Jo

drugs revealed by polarized IR spectroscopy, Spectrochim. Acta Part A: Mol. Biomol. Spectrosc.188 (2018) 189–196. https://doi.org/10.1016/j.saa.2017.07.005.

[23] D.E. Braun, M. Ardid-Candel, E. D'Oria, P.G. Karamertzanis, J.-B. Arlin, A.J. Florence; A.G. Jones, S.L. Price, Racemic naproxen: a multidisciplinary structural and thermodynamic comparison with the enantiopure form, Cryst. Growth Des. 11 (2011) 5659-5669. https://doi.org/10.1021/cg201203.

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FLUOR_2019_265

Table 1. Reaction conditions for fluorination of naproxen with Selectfluor. Molar ratio

Solvent

Temperature, o

1/Selectfluor

Time, h

2, %a

3, %a

C

Ratio 2/3

1:1.1

MeCN

R.T.

2

2

1:1.1

MeCN

R.T.

22

3

1:1.1

MeCN

-8÷4

2

4

1:1.1

MeCN

-18

68

5

1:1.1

MeCN

80

4

6

1:1.1

MeCN

80

7

1:1.1

MeCN-H2O

51

34

1.5

34b

1.7

46

10

4.6

44

15

2.9

66

32

2.1

5

48

35

1.4

22

31

43

0.7

R.T.

2

2

29

0.07

80

2

3

50

0.06

MeCN

R.T.

2

28

56

0.5

MeCN

R.T.

2

3

80

0.04

MeCN

26

0.2

68

0.003

MeCN

80

5

6

52

0.1

1:1.1

H2O

9

1:1.1

H2O

10

1:1.5

11

1:2.2

12

1:2.2

13

1:2.2

R.T.

14

1:1.1

MeCN-Et3Nc

R.T.

22

31

1

31

15

1:1.1

MeCN-C5H5Nc

R.T.

22

52

1

52

16

1:1.1

MeCN-NaHCO3c

R.T.

22

59

36

1.6

17

1:1.1

MeCN-Li2CO3c

R.T.

22

58

29

2

18

1:1.1

MeCN-Na2CO3c

R.T.

22

40

10

4

19

1:1.1

MeCN-K2CO3c

R.T.

22

22

2.5

8.8

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ur

na

8

lP

(9:1 v/v)

R.T.

-p

58b

re

1

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Entry

19 20

1:1.1

MeCN-Rb2CO3c

R.T.

22

18

2

9

21

1:1.1

MeCN-Cs2CO3c

R.T.

22

9

0.4

22

22

1:1.2d

MeCN

R.T.

24

0

100

0

a

Determined by 19F NMR spectroscopy. b Mean deviation of three measurements for 2 and 3 is ±3.8 and ±2.7 respectively. c Molar ratio base:1 = 5. d Molar ratio 2/Selectfluor

Table 2. Reaction conditions for fluorination of naproxen with NFSI. Molar ratio

Solvent

Temperature, o

1/NFSI

Time, h

R.T.

2

2

1:1.1

MeCN

R.T.

22

3

1:1.1

MeCN

80

2

4

1:1.1

MeCN

80

5

1:1.1

MeCN

80

6

1:1.1

MeCN-Et3Nb

80

7

1:1.1

MeCN-NaHCO3c

80

8

1:2.2

MeCN

9

1:1.1

Solvent-free

3

1

3

6

6

1

49

11

4.5

-p

MeCN

62

18

3.4

10

62

23

2.7

2

2

0

-

2

41

5

8.2

80

2

67

28

2.4

115

1

53

7.2

7.4

lP

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5

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Determined by 19F NMR spectroscopy. b Molar ratio Et3N:1 = 5. c Molar ratio NaHCO3:1 = 5

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Ratio 2/3

1:1.1

na

3, %a

C

1

a

2, %a

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Entry