Preparation and Synthetic Application of Naproxen-Containing Diaryliodonium Salts

The synthesis of naproxen-containing diaryliodonium salts has been realized from naproxen methyl ester and ArI(OH)OTs activated by trimethylsilyl trifluoromethanesulfonate (TMSOTf) in a solvent mixture comprising dichloromethane and 2,2,2-trifluoroethanol (TFE). Those iodonium salts have been successfully used in the functionalization of an aromatic ring of naproxen methyl ester, including fluorination, iodination, alkynylation, arylation, thiophenolation, and amination and esterification reactions. Moreover, further hydrolysis of the obtained 5-iodo-naproxen methyl ester afforded 5-iodo-naproxen.


Introduction
Naproxen I, 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 an anticancer agent [1]. Recently, naproxen has also been discovered to exhibit antiviral activity, reducing viral load in cells infected with influenza A (H1N1, H3N2) [2,3]. Industrial production of naproxen is currently about ten thousand tons per year, which creates a good basis for conducting research on its structural modification. Significant efforts have been made in the structural modification of naproxen [4,5], including the introduction of fluorine atom into the side chain of this molecule or an esterification process of the carboxylic acid with alcohols ( Figure 1A, Ia) [6,7]. There have also been a few scattered methods for the functionalization of the aromatic ring of naproxen, including the introduction of the halogen atom into the aromatic ring ( Figure 1B, Ib-Id) [8][9][10]. Some special functionalization has also been applied to the aromatic ring, including hydroxylation and the incorporation of the SCF 3 group ( Figure 1B, Ie, If) [11,12]. However, these separated methods and monotonous modifications are not conducive to the systematic expansion of naproxen. Therefore, there is an urgent and long-term need for more efficient and systematic methods to modify the aromatic ring of naproxen, particularly in the process of screening and discovering new drugs in medicinal chemistry. In this communication, we envision that the incorporation of the naproxen moiety with iodonium salts will open a new door to the generation of naproxen-based active molecules. Those naproxen-containing iodonium salts could serve as a versatile intermediate for library construction in medicinal chemistry.
In the past several decades, hypervalent iodine chemistry has witnessed prosperous development in organic synthesis [13][14][15]. Diaryliodonium salts, as one kind of the bestknown iodine (III) compounds, are widely used as arylating agents and offer an alternative approach to realizing aryl group transformations under mild conditions. Stable iodonium salts have been found to have numerous practical applications, and a summary of the biological properties of iodonium salts is provided in review [14]. In a specific example, a study of the in vitro activities of several iodonium salts against oral and dental anaerobes has demonstrated that their activities are comparable to that of chlorhexidine and these compounds may be suitable for incorporation into an oral mouthwash [16]. Since the pioneering contributions of Kita et al., λ 3 -iodanes have been known to substitute electron-rich arenes with certain nucleophiles (e.g., N 3 , CN, OAc) [17][18][19][20][21][22][23]. As part of our long-term interest in the synthesis and application of hypervalent iodine compounds [24][25][26][27][28][29], we envision that diaryliodonium salts may serve the purpose of the modification of naproxen backbone. In this communication, we would like to report an effective approach to the synthesis of naproxen-containing diaryliodonium salts, i.e., naproxen methyl ester diaryliodonium salts, and the modification of the aromatic ring by substitution from formed naproxen methyl ester diaryliodonium salts (Scheme 1). In the past several decades, hypervalent iodine chemistry has witnessed prosperous development in organic synthesis [13][14][15]. Diaryliodonium salts, as one kind of the bestknown iodine (Ⅲ) compounds, are widely used as arylating agents and offer an alternative approach to realizing aryl group transformations under mild conditions. Stable iodonium salts have been found to have numerous practical applications, and a summary of the biological properties of iodonium salts is provided in review [14]. In a specific example, a study of the in vitro activities of several iodonium salts against oral and dental anaerobes has demonstrated that their activities are comparable to that of chlorhexidine and these compounds may be suitable for incorporation into an oral mouthwash [16]. Since the pioneering contributions of Kita et al., λ 3 -iodanes have been known to substitute electron-rich arenes with certain nucleophiles (e.g., N3, CN, OAc) [17][18][19][20][21][22][23]. As part of our long-term interest in the synthesis and application of hypervalent iodine compounds [24][25][26][27][28][29], we envision that diaryliodonium salts may serve the purpose of the modification of naproxen backbone. In this communication, we would like to report an effective approach to the synthesis of naproxen-containing diaryliodonium salts, i.e., naproxen methyl ester diaryliodonium salts, and the modification of the aromatic ring by substitution from formed naproxen methyl ester diaryliodonium salts (Scheme 1). In the past several decades, hypervalent iodine chemistry has witnessed prosperous development in organic synthesis [13][14][15]. Diaryliodonium salts, as one kind of the bestknown iodine (Ⅲ) compounds, are widely used as arylating agents and offer an alternative approach to realizing aryl group transformations under mild conditions. Stable iodonium salts have been found to have numerous practical applications, and a summary of the biological properties of iodonium salts is provided in review [14]. In a specific example, a study of the in vitro activities of several iodonium salts against oral and dental anaerobes has demonstrated that their activities are comparable to that of chlorhexidine and these compounds may be suitable for incorporation into an oral mouthwash [16]. Since the pioneering contributions of Kita et al., λ 3 -iodanes have been known to substitute electron-rich arenes with certain nucleophiles (e.g., N3, CN, OAc) [17][18][19][20][21][22][23]. As part of our long-term interest in the synthesis and application of hypervalent iodine compounds [24][25][26][27][28][29], we envision that diaryliodonium salts may serve the purpose of the modification of naproxen backbone. In this communication, we would like to report an effective approach to the synthesis of naproxen-containing diaryliodonium salts, i.e., naproxen methyl ester diaryliodonium salts, and the modification of the aromatic ring by substitution from formed naproxen methyl ester diaryliodonium salts (Scheme 1). Scheme 1. Preparation and synthetic application of naproxen methyl ester diaryliodonium salts. Scheme 1. Preparation and synthetic application of naproxen methyl ester diaryliodonium salts.

Selective Synthesis of Naproxen Methyl Ester Diaryliodonium Salts
At the outset of the study, we attempted to synthesize naproxen-containing iodonium salts according to the literature as shown in Scheme 2A [30,31]. Unfortunately, we did not get the desired iodonium salts by these methods. We speculated that the carboxylic acid on the side chain may interfere with the formation of diaryliodonium salts. Therefore, we decided to complete methylation of the carboxylic acid group. The methylation of naproxen with methanol and sulfuric acid was carried out at 70 • C. Koser's reagent and its derivatives were prepared according to the reported literature [32]. The initial reactivity assay employed a simple Koser's reagent 2a as the model substrate to optimize the reaction parameters. Initially, the reaction conditions were optimized for naproxen methyl ester diaryliodonium salts with Koser's reagent in dichloromethane [33]. However, the low solubility of Koser's reagent in dichloromethane might prevent the formation of the diaryliodonium salt. As known, Koser's reagent could be dissolved with TFE as a co-solvent. In this case, diaryliodonium salts were observed by TLC when one equivalent of TMSOTf was added, but it could not be crystalized from ether. To our surprise, when 0.9 equivalent of TMSOTf was added, naproxen methyl ester diaryliodonium salt was formed as a white solid from ether (Scheme 2B). Herein, TMSOTf was employed to activate the Koser's reagent and simultaneously deliver the triflate anion to the salts. Furthermore, the structure of 3a was undoubtedly confirmed by X-ray analysis ( Figure 2; for details see Table S1 in the Supporting Information).
At the outset of the study, we attempted to synthesize naproxen-contai donium salts according to the literature as shown in Scheme 2A [30,31]. Unfort we did not get the desired iodonium salts by these methods. We speculated that boxylic acid on the side chain may interfere with the formation of diaryliodoniu Therefore, we decided to complete methylation of the carboxylic acid group. The ation of naproxen with methanol and sulfuric acid was carried out at 70 °C. Kos gent and its derivatives were prepared according to the reported literature [32]. Th reactivity assay employed a simple Koser's reagent 2a as the model substrate to o the reaction parameters. Initially, the reaction conditions were optimized for n methyl ester diaryliodonium salts with Koser's reagent in dichloromethane [33 ever, the low solubility of Koser's reagent in dichloromethane might prevent mation of the diaryliodonium salt. As known, Koser's reagent could be dissolv TFE as a co-solvent. In this case, diaryliodonium salts were observed by TLC w equivalent of TMSOTf was added, but it could not be crystalized from ether. To prise, when 0.9 equivalent of TMSOTf was added, naproxen methyl ester diarylio salt was formed as a white solid from ether (Scheme 2B). Herein, TMSOTf was em to activate the Koser's reagent and simultaneously deliver the triflate anion to t Furthermore, the structure of 3a was undoubtedly confirmed by X-ray analysis (F for details see Table S1 in the Supporting Information).   donium salts according to the literature as shown in Scheme 2A [30,31]. Unfortuna we did not get the desired iodonium salts by these methods. We speculated that the boxylic acid on the side chain may interfere with the formation of diaryliodonium Therefore, we decided to complete methylation of the carboxylic acid group. The me ation of naproxen with methanol and sulfuric acid was carried out at 70 °C. Koser's gent and its derivatives were prepared according to the reported literature [32]. The i reactivity assay employed a simple Koser's reagent 2a as the model substrate to opti the reaction parameters. Initially, the reaction conditions were optimized for napr methyl ester diaryliodonium salts with Koser's reagent in dichloromethane [33]. H ever, the low solubility of Koser's reagent in dichloromethane might prevent the mation of the diaryliodonium salt. As known, Koser's reagent could be dissolved TFE as a co-solvent. In this case, diaryliodonium salts were observed by TLC when equivalent of TMSOTf was added, but it could not be crystalized from ether. To our prise, when 0.9 equivalent of TMSOTf was added, naproxen methyl ester diaryliodo salt was formed as a white solid from ether (Scheme 2B). Herein, TMSOTf was empl to activate the Koser's reagent and simultaneously deliver the triflate anion to the Furthermore, the structure of 3a was undoubtedly confirmed by X-ray analysis (Figu for details see Table S1 in the Supporting Information).    Analogously, 4-methylphenyl and mesityl Koser's reagents were successful in giving corresponding diaryliodonium salts by this approach (Scheme 3). However, in sharp contrast to the above method, the newly prepared 4-methoxy Koser's reagent was quite unstable and decomposed violently during the isolation process [34]. After an extensive screening and optimization of reaction conditions, the corresponding 4-methoxyphenyl naproxen methyl ester diaryliodonium salt 3d was prepared with 1-(diacetoxyiodo)-4methoxybenzene activated by TMSOTf in a solvent of hexafluoroisopropanol at room temperature for 1 h in only 3% yield [35]. When TMSCl was used instead of TMSOTf, iodonium salt 3d was obtained in 6% yield. The corresponding naproxen methyl ester diaryliodonium salt with 3-methoxyphenyl was prepared by the same method in 26% yield. Interestingly, TMSOTf was successfully used to prepare the corresponding naproxen methyl ester diaryliodonium salt with 2-methoxyphenyl in 39% yield (Scheme 4). Analogously, 4-methylphenyl and mesityl Koser's reagents were successful in giving corresponding diaryliodonium salts by this approach (Scheme 3). However, in sharp contrast to the above method, the newly prepared 4-methoxy Koser's reagent was quite unstable and decomposed violently during the isolation process [34]. After an extensive screening and optimization of reaction conditions, the corresponding 4-methoxyphenyl naproxen methyl ester diaryliodonium salt 3d was prepared with 1-(diacetoxyiodo)-4methoxybenzene activated by TMSOTf in a solvent of hexafluoroisopropanol at room temperature for 1 h in only 3% yield [35]. When TMSCl was used instead of TMSOTf, iodonium salt 3d was obtained in 6% yield. The corresponding naproxen methyl ester diaryliodonium salt with 3-methoxyphenyl was prepared by the same method in 26% yield. Interestingly, TMSOTf was successfully used to prepare the corresponding naproxen methyl ester diaryliodonium salt with 2-methoxyphenyl in 39% yield (Scheme 4).

The Application of Naproxen Methyl Ester Diaryliodonium Salts
Next, we attempted to investigate the synthetic application of these new naproxen methyl ester diaryliodonium salts. The mesityl naproxen methyl ester diaryliodonium salts 3c reacted smoothly with CsF, 4-ethynyltoluene, 4-methylbenzeneboronic acid, sodium thiophenolate, and aniline to give substituted naproxen methyl ester in moderate to good yields (Figure 3, 4a, 4c-4f) [36][37][38]. However, when 3c was treated with 4-methylbenzoic acid, the desired product was obtained in a low yield of 7% because of the preference to transfer the mesityl moiety. According to the general regular pattern and encouraged by Olofsson's method, the methoxyphenyl group was then chosen as the dummy aromatic group of naproxen methyl ester diaryliodonium salts to improve selectivity [39,40]. As expected, the 4-methoxyphenyl naproxen methyl ester diaryliodonium salt 3d reacted with 4-methylbenzoic acid to give aryl ester 4g with good selectivity and yield (Figure 3, 4g) and 2-methoxypheny iodonium salt 3f showed the same good selectivity and yield as 3d. In addition, iodonium salt 3a reacted smoothly with KI to realize the iodination of naproxen methyl ester and further hydrolysis of the obtained 5-iodo naproxen methyl ester 4b afforded 5-iodo-naproxen 6 in 97% yield (Figure 3, 4b and 6). Analogously, 4-methylphenyl and mesityl Koser's reagents were successful in giving corresponding diaryliodonium salts by this approach (Scheme 3). However, in sharp contrast to the above method, the newly prepared 4-methoxy Koser's reagent was quite unstable and decomposed violently during the isolation process [34]. After an extensive screening and optimization of reaction conditions, the corresponding 4-methoxyphenyl naproxen methyl ester diaryliodonium salt 3d was prepared with 1-(diacetoxyiodo)-4methoxybenzene activated by TMSOTf in a solvent of hexafluoroisopropanol at room temperature for 1 h in only 3% yield [35]. When TMSCl was used instead of TMSOTf, iodonium salt 3d was obtained in 6% yield. The corresponding naproxen methyl ester diaryliodonium salt with 3-methoxyphenyl was prepared by the same method in 26% yield. Interestingly, TMSOTf was successfully used to prepare the corresponding naproxen methyl ester diaryliodonium salt with 2-methoxyphenyl in 39% yield (Scheme 4).

The Application of Naproxen Methyl Ester Diaryliodonium Salts
Next, we attempted to investigate the synthetic application of these new naproxen methyl ester diaryliodonium salts. The mesityl naproxen methyl ester diaryliodonium salts 3c reacted smoothly with CsF, 4-ethynyltoluene, 4-methylbenzeneboronic acid, sodium thiophenolate, and aniline to give substituted naproxen methyl ester in moderate to good yields (Figure 3, 4a, 4c-4f) [36][37][38]. However, when 3c was treated with 4-methylbenzoic acid, the desired product was obtained in a low yield of 7% because of the preference to transfer the mesityl moiety. According to the general regular pattern and encouraged by Olofsson's method, the methoxyphenyl group was then chosen as the dummy aromatic group of naproxen methyl ester diaryliodonium salts to improve selectivity [39,40]. As expected, the 4-methoxyphenyl naproxen methyl ester diaryliodonium salt 3d reacted with 4-methylbenzoic acid to give aryl ester 4g with good selectivity and yield (Figure 3, 4g) and 2-methoxypheny iodonium salt 3f showed the same good selectivity and yield as 3d. In addition, iodonium salt 3a reacted smoothly with KI to realize the iodination of naproxen methyl ester and further hydrolysis of the obtained 5-iodo naproxen methyl ester 4b afforded 5-iodo-naproxen 6 in 97% yield (Figure 3, 4b and 6).

The Application of Naproxen Methyl Ester Diaryliodonium Salts
Next, we attempted to investigate the synthetic application of these new naproxen methyl ester diaryliodonium salts. The mesityl naproxen methyl ester diaryliodonium salts 3c reacted smoothly with CsF, 4-ethynyltoluene, 4-methylbenzeneboronic acid, sodium thiophenolate, and aniline to give substituted naproxen methyl ester in moderate to good yields (Figure 3, 4a, 4c-4f) [36][37][38]. However, when 3c was treated with 4-methylbenzoic acid, the desired product was obtained in a low yield of 7% because of the preference to transfer the mesityl moiety. According to the general regular pattern and encouraged by Olofsson's method, the methoxyphenyl group was then chosen as the dummy aromatic group of naproxen methyl ester diaryliodonium salts to improve selectivity [39,40]. As expected, the 4-methoxyphenyl naproxen methyl ester diaryliodonium salt 3d reacted with 4-methylbenzoic acid to give aryl ester 4g with good selectivity and yield (Figure 3, 4g) and 2-methoxypheny iodonium salt 3f showed the same good selectivity and yield as 3d. In addition, iodonium salt 3a reacted smoothly with KI to realize the iodination of naproxen methyl ester and further hydrolysis of the obtained 5-iodo naproxen methyl ester 4b afforded 5-iodo-naproxen 6 in 97% yield (Figure 3, 4b and 6). Molecules 2021, 26, x FOR PEER REVIEW 5 of 11 Figure 3. The modification of the aromatic ring of naproxen methyl ester from iodonium salts 3.

General Information
All reactions were carried out using a pre-dried screw capped tube with a Teflonlined septum under nitrogen, unless otherwise noted. None of the solvents were dried before use, unless otherwise noted. The methylation of naproxen with methanol catalyzed by 10 mol% sulfuric acid was carried out at 70 °C. Koser's reagent and its derivatives were prepared according to the reported literature [32], 1-(diacetoxyiodo)-4-methoxybenzene was prepared according to the reported literature [35], and other starting materials were commercially available and used without further purification. Column chromatography was performed using silica gel (particle size 10-40 μm, Ocean Chemical Factory of Qingdao, China). 1 H-NMR, 13 C-NMR, and 19 F-NMR spectra were recorded on a JNM-ECA600, JNM-ECS400, or JNM-ECZ400S spectrometer (supplied by JEOL, Tokyo, Japan) at ambient temperature with CDCl3 or DMSO-d6 as the solvent. Chemical shifts (δ) were given in ppm, referenced to the residual proton resonance of CDCl3 (7.26) or DMSO-d6 (2.54), to the carbon resonance of CDCl3 (77.16) or DMSO-d6 (40.45). Coupling constants (J) were given in Hertz (Hz). The terms m, q, t, d, and s refer to multiplet, quartet, triplet, doublet, and singlet, respectively. High-resolution mass spectra were acquired on LCMS-IT/TOF (Shimadzu, Kyoto, Japan) in an 80% acetonitrile−20% water mixture.

General Information
All reactions were carried out using a pre-dried screw capped tube with a Teflon-lined septum under nitrogen, unless otherwise noted. None of the solvents were dried before use, unless otherwise noted. The methylation of naproxen with methanol catalyzed by 10 mol% sulfuric acid was carried out at 70 • C. Koser's reagent and its derivatives were prepared according to the reported literature [32], 1-(diacetoxyiodo)-4-methoxybenzene was prepared according to the reported literature [35], and other starting materials were commercially available and used without further purification. Column chromatography was performed using silica gel (particle size 10-40 µm, Ocean Chemical Factory of Qingdao, China). 1 H-NMR, 13 C-NMR, and 19 F-NMR spectra were recorded on a JNM-ECA600, JNM-ECS400, or JNM-ECZ400S spectrometer (supplied by JEOL, Tokyo, Japan) at ambient temperature with CDCl 3 or DMSO-d 6 as the solvent. Chemical shifts (δ) were given in ppm, referenced to the residual proton resonance of CDCl 3 (7.26) or DMSO-d 6 (2.54), to the carbon resonance of CDCl 3 (77.16) or DMSO-d 6 (40.45). Coupling constants (J) were given in Hertz (Hz). The terms m, q, t, d, and s refer to multiplet, quartet, triplet, doublet, and singlet, respectively. High-resolution mass spectra were acquired on LCMS-IT/TOF (Shimadzu, Kyoto, Japan) in an 80% acetonitrile−20% water mixture.

The Synthesis of Naproxen Methyl Ester Diaryliodonium Salts
Method A for 3a-3c: Naproxen methyl ester (1.22 g, 5.0 mmol) was added to a solution of ArI(OH)OTs (5.0 mmol) in DCM (15 mL) and 2,2,2-trifluoroethanol(TFE) (3.5 mL) in a 100 mL round-bottomed flask equipped with a stirring bar. The stirring solution was cooled to 0 • C and trimethylsilyl trifluoromethanesulfonate (TMSOTf) (815 µL, 4.5 mmol) was added dropwisely. The solution was warmed to room temperature and stirred for 2 h. The solvent was evaporated under reduced pressure, then ether (30 mL) was added. A white precipitate was separated, filtered with suction, and washed with ether (20 mL) to obtain the product as a white solid. If the diaryliodonium salt was not precipitated, ether was evaporated under reduced pressure and dried under vacuum for 1 h. Then, ether (30 mL) was added again and stirred vigorously. The white precipitate was separated, filtered with suction, and washed with ether (20 mL) to obtain the product as a white solid.
Method B for 3d-3f: Naproxen methyl ester (1.22 g, 5.0 mmol) was added to a solution of MeO-PhI(OAc) 2 (5.0 mmol) in hexafluoroisopropanol (HFIP) (15 mL) in a 50 mL sealed tube. The stirring solution was cooled to 0 • C and trimethyl chlorosilane (TMSCl) (634 µL, 5.0 mmol) was added dropwisely. The solution was warmed to room temperature and stirred for 1 h. The solvent was evaporated under reduced pressure, then ether (30 mL) was added. A white precipitate was separated, filtered with suction, and washed with ether (5 mL) to obtain the product as a white solid.
Molecules 2021, 26, x FOR PEER REVIEW mL) was added again and stirred vigorously. The white precipitate w with suction, and washed with ether (20 mL) to obtain the product a Method B for 3d-3f: Naproxen methyl ester (1.22 g, 5.0 mmol) w tion of MeO-PhI(OAc)2 (5.0 mmol) in hexafluoroisopropanol (HFIP) sealed tube. The stirring solution was cooled to 0 °C and trimethyl c (634 μL, 5.0 mmol) was added dropwisely. The solution was warmed and stirred for 1 h. The solvent was evaporated under reduced pre mL) was added. A white precipitate was separated, filtered with s with ether (5 mL) to obtain the product as a white solid.

Data Availability Statement:
The data presented in this study are available in the communication.