Polymer-supported hexaethylene glycolic ionic liquid: efficient heterogeneous catalyst for nucleophilic substitutions including fluorinations

Abstract

Polymer-supported hexaethylene glycol substituted imidazolium salts (PS[hexaEGim][OMs] and PS[dihexaEGim][OMs]) were prepared, and were demonstrated to act as highly efficient heterogeneous catalysts in various nucleophilic substitution reactions using the corresponding alkali metal salts. Furthermore, it was observed that PS[hexaEGim][OMs] could indeed be reused repeatedly without the loss of its catalytic activity in the nucleophilic fluorination using KF, affording the corresponding product in a high yield (approximately 95%) in each cycle.

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Introduction

Much attention has been paid recently to polymer-supported chemistry, mainly due to the inherent properties of the polymer backbone, which allow easy recovery by simple filtration, recycling, and reuse of the catalyst.¹ Immobilization of the catalyst on a polymeric support such as silica gel, metal particle, and polystyrene resins have been widely-used for this purpose.² Functionalized polystyrenes are especially favored due to their stability and chemical inertness.³ Moreover, the solvation property of polystyrenes is crucial for the reaction rate, and provides a microenvironment caused by the reactants within the polymeric support that is unique.³

Nucleophilic substitution reactions employing alkali metal salts as nucleophile sources have occupied a privileged position in organic chemistry, although the low nucleophilicity and solubility of these metal salts in nonpolar organic solvents makes the process difficult.⁴ To overcome this problem, various phase transfer catalysts (PTCs) such as crown ether derivatives⁵ and quaternary ammonium salts⁶ systems have been generally used in polar aprotic solvents such as DMF and DMSO.⁷ In particular, polymer-supported PTCs have been developed for nucleophilic displacement for the easy isolation of products and reuse of these catalysts.⁸ However, these heterogeneous PTCs show low reactivity compared with their homogeneous form.^8,9

Recent studies have revealed that protic solvent systems such as tert-alcohols¹⁰ and n-oligoethylene glycols¹¹ are effective reaction media for nucleophilic substitutions, by virtue of their enhanced reactivity of alkali metal salts as a nucleophile source, in particular metal fluorides, by the formation of hydrogen (H)-bonds between nucleophiles and hydroxyl groups of these protic solvents.

Ionic liquids (ILs), especially imidazolium based ILs, play a crucial role in a variety of chemical reactions due to their unique chemical and physical properties.¹² In particular, ILs and polymer-supported ILs enhance the reactivity of alkali metal salt nucleophiles in nucleophilic substitution reactions.^13,14 More recently, we reported tailor-made oligoethylene glycolic ionic liquids (oligoEGILs) as organic catalysts designed for nucleophilic fluorination.¹⁵ For the recovery and reuse of these oligoEGILs as well as easy separation more in favor of “green chemistry”, we planned to immobilize oligoEGIL on polystyrene resin. Herein, we introduce polystyrene-supported oligoEGIL (PSoligoEGIL) as efficient heterogeneous catalysts for nucleophilic substitution reactions including fluorination with the corresponding alkali metal salts in a tert-alcohol medium.

Results and discussion

1. Synthesis of polystyrene-supported hexaethylene glycol substituted imidazolium salts – (a) PS[hexaEGim][OMs] and (b) PS[dihexaEGim][OMs]

The PSoligoEGILs PS[hexaEGim][OMs] (PS = polymer support; hexaEGim = 3-n-hexaethylene glycolic imidazolium cation; OMs = mesylate anion) and PS[dihexaEGim][OMs] (dihexaEGim = 1,3-n-dihexaethylene glycolic imidazolium cation) were prepared by the procedure shown in Scheme 1. The treatment of Merrifield resin¹⁶1 (1% divinylbenzene, 3.9 mmol Cl/g) with imidazole in dried THF for 4 days afforded an imidazole substituted polystyrene resin 2. This resin 2 was then reacted with the mesylate 3 in CH₃CN at 90 °C for 4 days to obtained PS[hexaEGim][OMs] (1.09 mmol of hexaEGim moiety per gram of polymer-supported product obtained). For preparation of PS[dihexaEGim][OMs], the treatment of the same Merrifield resin 1 with hexaethylene glycol (4) for 4 days yielded resin 5. The mesylation of the resin 5 with mesyl chloride provided a mesylated resin 6. Finally, the mesylated resin 6 was reacted with hexaethylene glycolic imidazole (7) for 4 days to obtain PS[dihexaEGim][OMs] (0.49 mmol of dihexaEGim/g). The PSoligoEGILs were characterized by ¹³C NMR (solid state) spectroscopy and by elemental analysis.

Scheme 1 Preparation of polystyrene-supported hexaethylene glycol substituted imidazolium salts (a) PS[hexaEGim][OMs] and (b) PS[dihexaEGim][OMs].

2. Nucleophilic fluorination using alkali metal fluoride in the presence of PSoligoEGILs

Table 1 summarizes the data of the reactivity of PS[hexaEGim][OMs] and PS[dihexaEGim][OMs] for nucleophilic fluorination of 2-(3-methanesulfonyloxypropyl)naphthalene (8), as a model compound, with various alkali metal fluorides, together with those obtained in other polymer-supported systems reported previously by us.^11b,15,17 Firstly, the nucleophilic fluorination reaction of 8 with KF in the presence of PS[hexaEGim][OMs] (0.5 equiv) in tert-amyl alcohol proceeded for 4 h at 100 °C, which produced the desired fluoro-product 9 in excellent yield (96%, entry 1), whereas the same reaction for 12 h in the absence of catalyst yielded only 10% of the fluorinated product 9 with 90% of unreacted starting material (entry 2). Encouragingly, the results of entries 1, 3 and 8 indicated that both PS[hexaEGim][OMs] and PS[dihexaEGim][OMs] as immobilized catalytic systems have a similar reactivity to a non-immobilized 3-n-hexaethylene glycolic methyl-imidazolium meylate [hexaEGmim][OMs] system. A comparison with entries 1 and 4 established that the hexaethylene glycol chain on PS[hexaEGim][OMs] allows its catalytic activity to increase compared with PS[hmim][BF₄] (hmim = 1-n-hexyl-3-methylimidazolium). Furthermore, entry 5 shows that only 29% of the fluoro-product 9 was converted from the mesylate 8 even after a reaction time of 24 h by the same fluorination in the presence of polystyrene-supported pentaethylene glycol (PSpentaEG). These results indicates that the imidazolium salt core of PS[hexaEGim][OMs] plays a crucial role in its high catalytic reactivity in the reactions as shown in the comparison with entries 1 and 5. The other alkali metals, such as RbF and CsF, also can be efficiently activated by the PS[hexaEGim][OMs] heterogeneous catalyst in this substitution reaction (entries 6 and 7). PS[dihexaEGim][OMs], which have an additional hexaethylene glycol linker, displays better catalytic reactivity that PS[hexaEGim][OMs]; the same fluorination with KF or CsF in the presence of PS[dihexaEGim][OMs] proceeds rapidly and provides an excellent yield of the fluoroalkane 9 (97% in 3.5 h and 30 min for entries 8 and 9, respectively). To investigate how many times PS[hexaEGim][OMs] could be reused, the fluorination was performed repeatedly under the conditions given in entry 1 in Table 1. We observed that PS[hexaEGim][OMs] could indeed be reused repeatedly without the loss of its catalytic activity, and this reaction afforded product 9 in a high yield (approximately 95%) in each cycle.

Table 1 Fluorination of mesylate 8 with MF in the presence of PSoligoEGILs or the stated alternative reagents in tert-alcohol^a

Entry	Catalyst or promoter (0.5 equiv^b)	MF	Time (h)	Yield (%)^c
a All reactions were carried out on a 1.0 mmol reaction scale of mesylate 8 using 3 mmol of MF in 4.0 mL of solvent at 100 °C. b Equivalent amount of the ionic liquid portion, not PS[hexaEGim][OMs] or PS[dihexaEGim][OMs]. c Yields were determined by ^1H NMR spectroscopy. d Isolated yields. e ref. 15. f ref. 17. g ref. 11b.
1	PS[hexaEGim][OMs]	KF	4	96 (93)^d
2	—	KF	12	10
3^e	[hexaEGmim][OMs]	KF	3	98
4^f	PS[hmim][BF4]	KF	7	91^d
5^g	PSpentaEG (1 equiv)	KF	24	29
6	PS[hexaEGim][OMs]	RbF	1.5	93^d
7	PS[hexaEGim][OMs]	CsF	45 min	96 (94)^d
8	PS[dihexaEGim][OMs]	KF	3.5	97 (94)^d
9	PS[dihexaEGim][OMs]	CsF	30 min	97 (93)^d

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3. Various S_N2 reactions in the presence of PS[hexaEGim][OMs]

Diverse nucleophilic transformations were also attempted with various alkali metal salts as nucleophile sources in the presence of 0.5 equiv. of PS[hexaEGim][OMs] in a tert-alcohol medium (Table 2). All transformation reactions – acetoxylation, thioacetoxylation, nitrilation, halogenations and azidation – of the mesylate 8 or bromo-substrate 10 with the corresponding alkali metal salts proceed nearly quantitatively (entries 1–7, 97–99%).

Table 2 S_N2 reactions with various alkali metal salts (MNu) using 0.5 equiv of PS[hexaEGim][OMs]^a

Entry	X	MNu	Time (h)	Yield (%)^b
a All reactions were carried out on a 1.0 mmol reaction scale of mesylate 8 or bromoalkane 10 using 3 mmol of MNu in the presence of 0.5 equiv of PS[hexaEGim][OMs] in 4.0 mL of solvent at 90 °C. b Isolated yields.
1	OMs	KOAc	1	99
2	OMs	KSAc	0.5	98
3	OMs	KCl	8	99
4	OMs	KBr	3	99
5	OMs	KI	1	98
6	Br	NaN3	1.5	99
7	Br	KCN	2	97

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4. Nucleophilic substitutions of various substrates in the presence of PS[hexaEGim][OMs]

In order to demonstrate that this heterogeneous PS[hexaEGim][OMs] catalyst is generally applicable to the other transformation reactions of various substrates, the nucleophilic substitutions of various halide or sulfonate substrates in the presence of 0.5 equiv of PS[hexaEGim][OMs] were characterized (Table 3). Entries 1–5 show the scope of selectivity on nucleophilic substitutions. Initially, in entries 1–4, the fluorination of base sensitive substrates such as a sec-alkyl tosylate and 1-(2-mesylethyl)naphthalene with both KF and CsF in the presence of PS[hexaEGim][OMs] in tert-amyl alcohol proceeded in a highly chemoselective manner with the corresponding fluoro-products produced in excellent yields (90–92%). Moreover, the nucleophilic methoxylation of mesylate 8 even with strong basic KOCH₃ nucleophile under this PS[hexaEGim][OMs]/tert-amyl alcohol condition provided the methoxylated product in a reasonable yield (entry 5, 63%). The fluorination of primary triflate of α-D-galactopyranose proceeded smoothly to afford the desired fluorosugar in 95% yield (entry 6). Entries 7–9 show that the transformation reactions such as fluorination, acetoxylation and azidation transformation reactions of nitroimidazolic mesylate or bromide substrate in the presence of PS[hexaEGim][OMs] were completed within 2 h and provided the corresponding nitroimidazolic derivatives in good yield (89–98%). 3-Chloro-picoline-N-oxide was converted to 3-fluoro-picoline-N-oxide with a yield of 69% (entry 10). In the final examples, biologically important drugs or drug intermediates such as 5,8-dimethoxy-4-fluoropropylquinoline¹⁸ and fluoropropyl ciprofloxacine¹⁹ were produced from their corresponding mesylate precursors in excellent yields (entries 11 and 12, 97 and 95%, respectively).

Table 3 Nucleophilic substitutions including fluorination of various substrates in the presence of PS[hexaEGim][OMs]^a

Entry	Substrate	MNu	Time (h)	T/°C	Yield (%)^b	Comment
a All reactions were carried out on a 1.0 mmol scale of substrate with 3.0 equiv of MNu and 0.5 equiv of PS[hexaEGim][OMs] in 4.0 mL of t-amyl alcohol. b Yields were determined by ^1H NMR spectroscopy. c 4.0 mL of CH3CN was used instead of 4.0 mL t-amyl alcohol.
1		KF	8	100	92	8% alkene
2		CsF	3	100	91	9% alkene
3		KF	5	100	90	10% alkene
4		CsF	1	100	91	9% alkene
5		KOMe	4	90	63	5% alkene 32% alcohol
6		KF	1	90	95	—
7		KF	2	90	89	7% alkene
8^c		KOAc	0.7	90	98	—
9^c		NaN3	1	90	97	—
10		KF	7	90	69	31% alcohol
11		KF	4	100	97	—
12		KF	10	100	95	—

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Conclusion

In summary, we have prepared new polystyrene-supported oligoethylene glycolic imidazolium salts (PSoligoEGIL) as highly efficient heterogeneous catalysts for nucleophilic fluorination and other substitutions using alkali metal nucleophile sources. These PSoligoEGILs are technically attractive in terms of simplicity of purification and the ready recovery and reuse of catalysts, and also significantly enhance the reactivity of alkali metal salts, in particular, a KF with tert-alcohol system. Further studies are currently in progress to develop more efficient heterogeneous ILs using various structural modifications for different organic transformations including ¹⁸F-labeling for PET applications

Experimental

General

Unless otherwise noted all reagents and solvents were commercially available. Reaction progress was followed by TLC on 0.25 mm silica gel glass plates containing F-254 indicator. Visualization on TLC was monitored by UV light. Flash chromatography was performed with 230–400 mesh silica gel. ¹H and ¹³C NMR spectra were recorded on a 400 or 600 MHz spectrometer, and chemical shifts were reported in δ units (ppm) relative to tetramethylsilane. Solid-state ¹³C NMR spectra were recorded on a 600 MHz spectrometer at RT. Low- and high-resolution electron impact (EI, 70 eV) spectra were obtained. Elemental analyses were performed by the Microanalytical Service Laboratory of the University of Illinois.

Resin 2

Imidazole (2.7 g, 39.8 mmol, 10 equiv) was added to a suspension of NaH (60% in mineral oil, 0.955 mg, 39.8 mmol, 10 equiv) in dried THF at 0 °C, and the mixture was stirred for 30 min at 0 °C. Merrifield peptide resin (1.0 g, 3.9 mmol, 1.0 equiv, 1% DVB, 3.9 mmol Cl/g) was then added to the reaction mixture followed by tetra-n-butylammonium iodide (1.5 g, 4.0 mmol, 1.0 equiv), and the reaction mixture was stirred over 4 days at 25 °C. After filtration, the resin was washed repeatedly with THF, water, acetone, water, methanol, and finally with dichloromethane. After drying under high vacuum, 1.2 g of resin 2 was obtained and identified by solid state NMR and elemental analysis: ¹³C NMR (solid state) δ 41 (aliphatic polystyrene skeleton), 120–146 (aromatic polystyrene skeleton and 2 carbon of imidazole), 181 (carbon from imidazole). Anal. N, 9.36 (3.2 mmol imidazole portion/g); Cl, 0.86.

PS[hexaEGim][OMs]

17-Hydroxy-3,6,9,12,15-pentaoxaheptadecyl methanesulfonate (3), (7.49 g, 22.54 mmol) was added dropwise to the mixture of resin 2 (1 g, 3.22 mmol) in CH₃CN (25 mL). The reaction mixture was stirred at 90 °C for 4 days. After filtration, the resin was washed repeatedly with THF, water, acetone, water, methanol, and finally with dichloromethane. After drying under high vacuum, 1.3 g of PS[hexaEGim][OMs] was obtained and identified by solid state NMR and elemental analysis: ¹³C NMR (solid state) δ 50 (-CH₃ from mesylate), 71 (ether carbons), 123–137 (aromatic polystyrene skeleton). Anal. N, 3.92. (1.09 mmol ionic liquid portion/g).

Resin 5

The preparation followed the procedure of resin 2 except using hexaethylene glycol (11.2 g, 39.8 mmol, 10 equiv.) instead of using imidazole and 1.5 g of resin 5 was obtained and identified by solid state NMR and elemental analysis: ¹³C NMR (solid state) δ 41 (aliphatic polystyrene skeleton), 62 (terminal hydroxy methylene carbons), 71–74 (ether carbons) 128–154 (aromatic polystyrene skeleton). Anal. Cl, 0.77.

Resin 6

Methanesulfonyl chloride (1.4 mL, 17.0 mmol) was added to a mixture of the resin 5 (1 g 1.7 mmol hexaEG portion) and triethylamine (2.4 mL, 17.0 mmol) in methylene chloride (50 mL) at 0 °C and allowed to come to room temperature for stirring overnight. After filtration, the resin was washed repeatedly with THF, water, acetone, water, methanol, and finally with dichloromethane. After drying under high vacuum, 1.1 g of resin 6 was obtained and identified by solid state NMR and elemental analysis: ¹³C NMR (solid state) δ 38 (–CH₃ from mesylate), 41 (aliphatic polystyrene skeleton), 71 (ether carbons) 128–146 (aromatic polystyrene skeleton). Anal. Cl, 0.17.

PS[dihexaEGim][OMs]

17-(1H-Imidazol-1-yl)-3,6,9,12,15-pentaoxaheptadecan-1-ol (7) (3.47 g, 10.43 mmol) was added dropwise to a mixture of resin 6 (1 g, 1.49 mmol) in CH₃CN (25 mL). The reaction mixture was stirred at 90 °C for 4 days. After filtration, the resin was washed repeatedly with THF, water, acetone, water, methanol, and finally with dichloromethane. After drying under high vacuum, 1.1 g of PS[dihexaEGim][OMs] was obtained and identified by solid state NMR and elemental analysis: ¹³C NMR (solid state) δ 41 (aliphatic polystyrene skeleton), 50 (–CH₃ from mesylate), 71 (ether carbons) 128–146 (aromatic polystyrene skeleton). Anal. N, 1.76 (0.49 mmol ionic liquid portion/g).

Typical procedure of the fluorination in Table 1

KF (174 mg, 3.0 mmol) was added to the mixture solution of mesylate 8 (281 mg, 1.0 mmol) and PS[hexaEGim][OMs] (500 mg, 0.5 mmol) in tert-amyl alcohol (4 mL). The reaction mixture was stirred for 4 h at 100 °C. We determined the reaction time by checking TLC. The reaction mixture was filtered and washed with diethyl ether. The filtrate was evaporated under reduced pressure. Flash column chromatography (10% EtOAc/hexanes) of the filtrate afforded 191 mg (0.93 mmol, 93%) of 2-(3-fluoropropoxy)naphthalene (9) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.14–2.39 (m, 2H), 4.24 (t, J = 6.2 Hz, 2H), 4.72 (dt, J = 46.8, 5.8 Hz, 2H), 7.16–7.22 (m, 2H), 7.34–7.53 (m, 2H), 7.76–7.83 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 30.4 (d, J = 20.1 Hz), 63.6 (d, J = 25.3 Hz), 80.8 (d, J = 163.9 Hz), 106.8, 118.8, 123.6, 126.4, 126.7, 127.6, 129.1, 129.4, 134.6, 156.7; ¹⁹F NMR (400 MHz, CDCl₃) δ −24.80; MS (EI) m/z 204 (M⁺); HRMS (EI) m/z calcd for C₁₃H₁₃FO(M⁺) 204.0950, Found 204.0932.

Typical procedure for acetoxylation

KOAc (295 mg, 3 mmol) was added to a mixture solution of mesylate 8 (281 mg, 1.0 mmol) and PS[hexaEGim][OMs] (500 mg, 0.5 mmol) in CH₃CN (4 mL) in a reaction vial. The reaction mixture was stirred for 1 h at 90 °C. The reaction mixture was filtered and washed with diethyl ether. The filtrate was evaporated under reduced pressure. Flash column chromatography (10% EtOAc/hexanes) of the filtrate afforded 241 mg (0.99 mmol, 99%) of 2-(3-acetoxypropoxy)naphthalene (11); ¹H NMR (600 MHz, CDCl₃) δ 2.08 (s, 3H), 2.18–2.22 (m, 2H), 4.17 (t, J = 6.18 Hz, 2H), 4.31 (t, J = 6.18 Hz, 2H), 7.10–7.15 (m, 2H), 7.33 (t, J = 7.56 Hz, 1H), 7.43 (t, J = 6.90 Hz, 1H), 7.71–7.77 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 21.1, 28.7, 61.5, 64.4, 106.6, 118.9, 123.7, 126.5, 126.8, 127.7, 129.0, 129.5, 134.6, 156.8, 171.2; MS (EI) m/z 244 (M⁺); HRMS (EI) m/z calcd for C₁₅H₁₆O₃ (M⁺) 244.1099. Found 244.1096.

2-(3-Thioacetoxypropoxy)naphthalene (12)

The preparation followed the typical procedure of the acetoxylation except that KSAc (424 mg, 3.0 mmol) was used and 255 mg (0.98 mmol, 98%) of 2-(3-thioacetoxypropoxy)naphthalene (12) was obtained; ¹H NMR (600 MHz, CDCl₃) δ 2.11–2.16 (m, 2H), 2.34 (s, 3H), 3.10 (t, J = 6.84 Hz, 2H), 4.13 (t, J = 6.18 Hz, 2H), 7.11–7.15 (m, 2H), 7.33 (t, J = 6.84 Hz, 1H), 7.44 (t, J = 6.90 Hz, 1H), 7.71–7.76 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 26.1, 29.3, 30.8, 66.2, 106.7, 118.9, 123.7, 126.5, 126.8, 127.7, 129.0, 129.5, 134.6, 156.8, 195.9; MS (EI) m/z 260 (M⁺); HRMS (EI) m/z calcd for C₁₅H₁₆O₂S (M⁺) 260.0871. Found 260.0874.

Procedure of the halogenation (entries 3–4 in Table 2)

The preparation followed the typical procedure of acetoxylation except that KX (X = Cl, Br, or I) was used and 217 mg (0.99 mmol, 99%) of 2-(3-chloropropoxy)naphthalene (13), 262 mg (0.99 mmol, 99%) of 2-(3-bromopropoxy)naphthalene (10), or 305 mg (0.98 mmol, 98%) of 2-(3-iodopropoxy)naphthalene (14) was obtained, respectively.

2-(3-Chloropropoxy)naphthalene (13)

¹H NMR (600 MHz, CDCl₃) δ 2.28–2.32 (m, 2H), 3.79 (t, J = 6.2 Hz, 2H), 4.23 (t, J = 6.2 Hz, 2H), 7.12–7.15 (m, 2H), 7.34 (t, J = 6.8 Hz, 1H), 7.44 (t, J = 6.8 Hz, 1H), 7.72–7.77(m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 32.17, 41.60, 64.17, 106.56, 118.76, 123.65, 126.38, 126.71, 127.61, 128.94, 129.41, 134.44, 156.57; MS (EI) m/z 220 (M⁺), 144, 115; HRMS (EI) m/z calcd for C₁₃H₁₃OCl (M⁺) 220.0655. Found 220.0667.

2-(3-Bromopropoxy)naphthalene (10)

¹H NMR (400 MHz, CDCl₃) δ 2.36–2.43 (m, 2H), 3.67 (t, J = 6.6 Hz, 2H), 4.23 (t, J = 5.6 Hz, 2H), 7.14–7.17 (m, 2H), 7.34–7.49 (m, 2H), 7.74–7.80 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 30.1, 32.2, 65.2, 106.6, 118.8, 123.7, 126.4, 126.7, 127.6, 128.9, 129.4, 134.4, 156.5; MS (EI) m/z 264 (M⁺), 266 (M⁺), 144 (100), 115; HRMS (EI) m/z calcd for C₁₃H₁₃O⁷⁹Br (M⁺) 264.0150. Found 264.0151.

2-(3-Iodopropoxy)naphthalene (14)

¹H NMR (400 MHz, CDCl₃) 2.32–2.38 (m, 2H), 3.43 (t, J = 6.6 Hz, 2H), 4.16 (t, J = 5.8 Hz, 2H), 7.15–7.17 (m, 2H), 7.35–7.49 (m, 2H), 7.49–7.80 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) 2.7, 32.8, 67.1, 106.6, 118.8, 123.6, 126.4, 126.7, 127.6, 128.1, 129.4, 134.4, 156.5; MS (EI) m/z 312 (M⁺), 185, 144, 115 (100); HRMS (EI) m/z Calcd for C₁₃H₁₃OI (M⁺) 312.0011. Found 312.0006.

2-(3-Azidopropoxy)naphthalene (15)

NaN₃ (195 mg, 3.0 mmol) was added to a mixture solution of 2-(3-bromopropoxy)naphthalene (10) (264 mg, 1.0 mmol) and PS[hexaEGim][OMs] (500 mg, 0.5 mmol) in CH₃CN (4 mL). The reaction mixture was stirred for 1.5 h at 90 °C. The reaction mixture was filtered and washed with diethyl ether. The filtrate was evaporated under reduced pressure. Flash column chromatography (10% EtOAc/hexanes) of the filtrate afforded 224 mg (0.99 mmol, 99%) of 2-(3-azidopropoxy)naphthalene (15); ¹H NMR (600 MHz, CDCl₃) δ 2.10–2.14 (m, 2H), 3.57 (t, J = 6.9 Hz, 2H), 4.17 (t, J = 6.2 Hz, 2H), 7.13–7.16 (m, 2H), 7.32–7.35 (m, 1H), 7.42–7.45 (m, 1H), 7.71–7.77 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 28.9, 48.4, 64.6, 106.7, 118.8, 123.8, 126.5, 126.8, 127.7, 129.1, 129.5, 134.6, 156.7; MS (EI) m/z 227 (M⁺), 169, 143(100), 115; HRMS (EI) m/z calcd for C₁₃H₁₃N₃O (M⁺) 227.1059. Found 227.1060.

2-(3-Cyanopropoxy)naphthalene (16)

The preparation followed the procedure for the preparation of 2-(3-azidopropoxy)naphthalene (15) except using KCN (195 mg, 3.0 mmol) instead of using NaN₃ and 204 mg (0.97 mmol, 97%) of 2-(3-cyanopropoxy)naphthalene (16) was obtained; ¹H NMR (600 MHz, CDCl₃) δ 2.18–2.23 (m, 2H), 2.63 (t, J = 6.90 Hz, 2H), 4.19 (t, J = 6.18 Hz, 2H), 7.12–7.14 (m, 2H), 7.35 (t, J = 6.90 Hz, 1H), 7.45 (t, J = 8.22 Hz, 1H), 7.72–7.78 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 14.4, 25.6, 65.4, 106.9, 118.8, 119.3, 124.0, 126.7, 126.9, 127.7, 129.2, 129.6, 134.5, 156.4; MS (EI) m/z 211 (M⁺); HRMS (EI) m/z calcd for C₁₄H₁₃NO (M⁺) 211.0997. Found 211.0998.

2-(2-Fluoropropoxy)naphthalene

The preparation followed the typical procedure of fluorination and 187 mg (0.92 mmol, 92%) of 2-(2-fluoropropoxy)naphthalene was obtained; ¹H NMR (600 MHz, CDCl₃) δ 1.43 (dd, J = 30.6, 7.2 Hz, 3H), 4.03–4.15 (m, 2H), 4.93–4.99 (m, 0.5H), 5.03–5.07 (m, 0.5H), 7.05 (s, 1H), 7.12 (dd, J = 12, 3 Hz, 1H), 7.27 (t, J = 15 Hz, 1H), 7.37 (t, J = 15 Hz, 1H), 7.64–7.70 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 17.6 (d, J = 86.2 Hz), 70.8 (d, J = 97.62), 88.5 (d, J = 672.1), 106.8, 118.9, 123.9, 126.6, 126.9, 127.8, 129.3, 129.7, 134.5, 156.5; MS (EI) m/z 204 (M⁺); HRMS (EI) m/z calcd for C₁₃H₁₃FO(M⁺) 204.0950, found 204.0952.

1-(2-Fluoroethyl)naphthalene

The preparation followed the typical procedure of fluorination and 156 mg (0.90 mmol, 90%) of 1-(2-fluoroethyl)naphthalene was obtained; ¹H NMR (600 MHz, CDCl₃) δ 3.44 (dt, J = 13.7, 6.9 Hz, 2H), 4.75 (dt, J = 47.5, 6.9 Hz, 2H), 7.30–7.37 (m, 2H), 7.41–7.49 (m, 2H), 7.70 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 33.9 (d, J = 20.1 Hz), 83.6 (d, J = 168.0 Hz), 123.4, 125.6, 125.7, 126.3, 127.3, 127.7, 128.9, 132.0, 132.8 (d, J = 8.5 Hz), 133.9; MS (EI) m/z 174 (M⁺), 141 (100); Anal. calcd: C, 82.73; H, 6.36, found: C, 82.63; H, 6.34.

2-(3-Methoxypropoxy)naphthalene

KOMe (211 mg, 3 mmol) was added to the mixture solution of mesylate 8 (281 mg, 1.0 mmol) and PS[hexaEGim][OMs] (500 mg, 0.5 mmol) in tert-amyl alcohol (4 mL). The reaction mixture was stirred for 4 h at 90 °C. We determined the reaction time by checking TLC. The reaction mixture was filtered and washed with diethyl ether (15 mL). The filtrate was evaporated under reduced pressure. Flash column chromatography (10% EtOAc/hexanes) of the filtrate afforded 136 mg (0.63 mmol, 63%) of 2-(3-methoxypropoxy)naphthalene; ¹H NMR (600 MHz, CDCl₃) δ 2.09–2.16 (s, 2H), 3.37 (S, 3H), 3.60 (t, J = 6.18 Hz, 2H), 4.18 (t, J = 6.18 Hz, 2H), 7.13–7.15 (m, 2H), 7.31 (t, J = 6.84 Hz, 1H), 7.42 (t, J = 6.84 Hz, 1H), 7.71–7.77 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 29.7, 58.9, 64.9, 69.4, 106.7, 119.0, 123.6, 126.4, 126.8, 127.7, 128.9, 129.4, 134.7, 157.0; MS (EI) m/z 216 (M⁺); HRMS (EI) m/z calcd for C₁₄H₁₆O₂ (M⁺) 216.1150, found 216.1149.

1,2:3,4-Di-O-isopropylidene-6-fluoro-6-deoxy-α-D-galactopyranose

The preparation followed the typical procedure of fluorination and 237 mg (0.95 mmol, 95%) of 1,2:3,4-di-O-isopropylidene-6-fluoro-6-deoxy-α-D-galactopyranose was obtained; ¹H NMR (600 MHz, CDCl₃) δ 1.34 (s, 6H), 1.45 (m, 3H), 1.55 (m, 3H), 4.06–4.10 (m, 1H), 4.26–4.28 (m, 1H), 4.34–4.37 (m, 1H), 4.48–4.65 (m, 3H), 5.56 (d, J = 5.5 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 24.48, 24.98, 25.98, 26.10, 66.69 (d, J = 21.5 Hz), 70.47, 70.59 (d, J = 5.8 Hz), 70.64, 82.15 (d, J = 168.00 Hz), 96.25, 108.88, 109.73; HRMS (ESI+) m/z calcd for C₁₂H₂₀FO₅ + H (M⁺ + H) 263.1295, found 263.1298.

1-(3-Fluoropropyl)-4-nitroimidazole

The preparation followed the typical procedure of fluorination and 153 mg (0.89 mmol, 89%) of 1-(3-fluoropropyl)-4-nitroimidazole was obtained; ¹H NMR (600 MHz, CDCl₃) δ 2.20–2.28 (m, 2H), 4.24 (t, J = 6.8 Hz, 2H), 4.50 (dt, J = 46.68 and 5.52 Hz, 2H), 7.49 (s, 1H), 7.81 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 31.46 (d, J = 20.1 Hz), 44.42, (d, J = 4.3 Hz), 79.64 (d, J = 166.6 Hz), 119.20, 136.23, 148.44; MS (EI) m/z 173 (M⁺, 100), 127, 61; HRMS (EI) calcd for C₆H₈FN₃O₂: (M⁺) 173.0601, found 173.0633.

1-(3-Acetoxypropyl)-4-nitroimidazole

The preparation followed the typical procedure of acetoxylation and 208 mg (0.98 mmol, 98%) of 1-(3-acetoxypropyl)-4-nitroimidazole was obtained; ¹H NMR (600 MHz, CDCl₃) δ 2.08 (s, 3H), 2.19–2.23 (m, 2H), 4.13–4.18 (m, 4H), 7.49 (s, 1H), 7.84 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 20.86, 29.99, 45.43, 60.53, 119.25, 136.15, 148.34, 170.80; MS (EI) m/z 213 (M⁺), 153, 140 (100), 68; HRMS (EI) calcd for C₈H₁₁N₃O₄: (M⁺) 213.0750, found 213.0721.

1-(3-Azidopropyl)-4-nitroimidazole

The preparation followed the procedure for the preparation of 2-(3-azidopropoxy)naphthalene (15) and 191 mg (0.97 mmol, 97%) of 1-(3-azidopropyl)-4-nitroimidazole was obtained; ¹H NMR (600 MHz, CDCl₃) δ 2.08–2.13 (m, 2H), 3.41 (t, J = 6.2 Hz, 2H), 4.17 (t, J = 6.8 Hz, 2H), 7.48 (s, 1H), 7.81 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 29.95, 45.24, 47.60, 119.23, 136.22, 148.40; MS (FAB) m/z 197 (M⁺); HRMS (FAB) calcd for C₆H₈N₆O₂: (M⁺) 197.0787, found 197.0785.

3-Fluoropicoline N-oxide

The preparation followed the typical procedure of fluorination and 87 mg (0.69 mmol, 69%) of 3-fluoropicoline N-oxide was obtained; ¹H NMR (600 MHz, CDCl₃) δ 5.38 (d, J = 46.7 Hz, 2H), 7.25–7.28 (m, 1H), 7.32 (t, J = 6.2 Hz, 1H), 8.20 (d, J = 6.2 Hz, 1H), 8.26 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 80.62 (d J = 170.9 Hz), 123.95 (d, J = 5.8 Hz), 126.10, 135.93 (d, J = 18.7 Hz), 137.66 (d, J = 7.2 Hz), 139.16; MS (EI) m/z 127 HRMS (EI) calcd for C₆H₆FNO: (M⁺) 127.0433, found 127.0432.

4-(3-Fluoropropyl)-5,8-dimethoxyquinoline

The preparation followed the typical procedure of fluorination and 241 mg (0.97 mmol, 97%) of 4-(3-fluoropropyl)-5,8-dimethoxyquinoline was obtained; ¹H NMR (600 MHz, CDCl₃) δ 1.95–2.03 (m, 2H), 3.30 (t, J = 7.5 Hz, 2H), 3.84 (s, 3H), 3.96 (s, 3H), 4.43 (dt, J = 47.4, 5.8 Hz, 2H), 6.72 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 4.1 Hz, 1H), 8.70 (d, J = 9.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 32.5 (d, J = 4.3 Hz), 33.0 (d, J = 18.7 Hz), 55.6, 56.2, 83.6 (d, J = 165.2 Hz), 104.9, 106.7, 121.0, 123.8, 141.8, 148.5, 150.0, 150.4; MS (EI) m/z 249 (M⁺), 234 (100); HRMS (EI) m/z calcd for C₁₄H₁₆NO₂F (M⁺) 249.1165, found 249.1162.

N ₄'-3-Fluoropropylciprofloxacin methyl ester

The preparation followed the typical procedure of fluorination and 385 mg (0.95 mmol, 95%) of N₄'-3-fluoropropylciprofloxacin methyl ester was obtained; ¹H NMR (600 MHz, CDCl₃) δ 1.12–1.15 (m, 2H), 1.30–1.33 (m, 2H), 1.89–1.98 (m, 2H), 2.57 (t, J = 14.4 Hz, 2H), 2.67–2.69 (m, 4H), 3.28–3.29 (m, 4H), 3.40–3.44 (m, 1H), 3.91 (s, 3H), 4.55 (dt, J = 46.7, 5.8 Hz, 2H), 7.27 (d, J = 7.5 Hz, 1H), 8.05 (d, J = 13.1 Hz, 1H), 8.55 (s, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 8.20, 27.96 (d, J = 20.1 Hz), 34.57, 50.05 (d, J = 4.3 Hz), 52.12, 53.04, 54.25 (d, J = 5.7 Hz), 84.41 (d, J = 163.7 Hz), 104.80 (d, J = 3.8 Hz), 110.17, 113.37 (d, J = 23.0 Hz), 123.08 (d, J = 7.2 Hz), 138.10, 144.65 (d, J = 11.5 Hz), 148.41, 153.51 (d, J = 248.0 Hz), 166.57, 173.15; MS (EI) m/z 405 (M⁺), 358 (100); HRMS (EI) m/z calcd for C₂₁H₂₅N₃O₃F₂ (M⁺) 405.1864, found 405.1868.

Acknowledgements

This work was supported by the Nuclear Research & Development Program of the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) (grant code: 2011-0006322 and 2011-0030952), the Conversing Research Center Program through the MEST (grant code: 2011K000705).

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra of all compounds and ¹³C solid state NMR spectra of all solid-phase compounds. See DOI: 10.1039/c2ra21142d

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