Electroorganic reactions in ionic liquids

Electrochimica Acta 49 (2004) 3367–3372

Electroorganic reactions in ionic liquids 5 [1]. Anodic fluorodesulfurization of phthalide, ethylene carbonate, and glucopyranosides having arylthio groups Masaru Hasegawa, Toshio Fuchigami∗ Department of Electronic Chemistry, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8502, Japan Received 6 February 2004; received in revised form 17 March 2004; accepted 17 March 2004 Available online 4 May 2004

Abstract Anodic fluorodesulfurization of 3-phenylthiophthalide, 4-phenylthio-1,3-dioxolan-2-one, and 1-arylthio-2,3,4,6-tetra-O-acetyl-␤-dglucopyranoside in ionic liquids like Et3 N·nHF (n = 4–5) and Et4 NF·nHF (n = 4, 5) without any solvents provided the corresponding monofluorinated products exclusively in moderate to good yields. In sharp contrast, the anodic fluorination in Et3 N·3HF with and without co-solvents resulted in ␣-fluorination without desulfurization exclusively or preferentially. It was also demonstrated that the electrochemical fluorodesulfurization of 3-phenylthiophthalide under solvent-free conditions was achieved repeatedly four times by the reuse of a fluoride salt, Et4 NF·4HF. This is the first example of fluorodesulfurization by the reuse of an ionic fluoride salt. © 2004 Elsevier Ltd. All rights reserved. Keywords: Anodic fluorination; Ionic liquid; Alkylamine polyhydrogen fluoride; Alkylammonium polyhydrogen fluoride; Fluorodesulfurization

1. Introduction Electrochemical partial fluorination of various compounds has been studied mainly in organic solvents containing supporting fluoride salts such as Et3 N·nHF (n = 2–5) and Et4 NF·nHF (n = 3–5) [2–4]. The fluorinated product selectivity and fluorination efficiency are very often greatly affected by the kinds of solvents and supporting fluoride salts [5–7]. Therefore, a choice of combination of a solvent and supporting fluoride salt is of much importance. The use of organic solvents like acetonitrile sometimes causes anodic passivation which results in low efficiency for anodic fluorination. However, interesting recent development in electrochemical fluorination is the use of liquid salts like Et3 N·3HF and Et4 NF·4HF without any solvents as the electrolytic media.

∗ Corresponding author. Tel.: +81-45-924-5406; fax: +81-45-924-5406. E-mail address: [email protected] (T. Fuchigami).

0013-4686/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.electacta.2004.03.015

Momota et al. have reported that fluoride salts, Et4 NF·nHF (n = 3–5) were promising supporting electrolytes for electrochemical fluorination [8,9]. In order to avoid the anode passivation and acetamidation, anodic fluorination in liquid fluoride salts without any solvents is an alternative method. In fact, Meurs and Eilenberg carried out anodic fluorination of benzofuran in liquid Et3 N·3HF [10]. Momota et al. successfully carried out anodic fluorination of various aromatics in liquid Et4 NF·nHF (n = 4, 5) at high current densities and with high current efficiency [8,9]. On the other hand, recently, Yoneda and coworkers found that liquid Et3 N·5HF is a useful supporting electrolyte for anodic fluorination and they showed anodic fluorination of ␣-alkylcyclic ketones in Et3 N·5HF without a solvent resulted in the C–CO bond cleavage leading to ␻-fluoroacyl fluorides in high yields [11]. Suryanarayanan and Noel also reported that electrochemical fluorination of aromatics containing active methylene groups was promoted in Et3 N·3HF [12]. However, there have been still limited examples of anodic fluorination in such ionic liquid fluoride salts. Here, we describe novel approach to the anodic fluorodesulfurization of oxygen-containing

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heterocyclic compounds using liquid Et3 N·nHF (n = 3, 4) and Et4 NF·nHF (n = 4, 5) as reaction media.

2. Experimental 2.1. General Caution: All precautions which are applied to the use of HF should likewise be applied when using Et3 N·nHF and Et4 NF·nHF (n = 4, 5). It is recommended that rubber gloves should be used. The recommended procedure for an HF burn is to wash with water, pack with ice and obtain medical attention as quickly as possible. 1 H, 13 C, 19 F NMR spectra were obtained on a JEOL JNM EX-270 in a deuteriochloroform (CDCl3 ) solution using tetramethylsilane (TMS) as an internal standard, unless otherwise stated. 19 F NMR spectra were given in δ (ppm) with CFCl3 as an external standard (actual internal standard was monofluorobenzene). Mass spectra were obtained by EI method with Shimadzu GCMS-QP5050A. High-resolution mass spectra were obtained on JEOL MStation JMS-700 mass spectrometer operating at the ionization energy of 70 eV. Cyclic voltammetry was performed using ALS CH instruments Electrochemical Analyzer Model 600A. Preparative electrolysis experiments were carried out using a Hokutodenko Potentiostat/Galvanostat HA-501. 2.2. Material The supporting fluoride salts, Et3 N·nHF (n = 3–5) and Et4 NF·nHF (n = 4, 5) are kind gifts of Morita Chemical Industries Co. Ltd. (Japan) and used for the electrolysis without further purification. Starting material 3-phenylthiophthalide (1), 4-phenylthio-1,3-dioxolan-2-one (4) were prepared according to the known procedures [6,13]. 1-Phenylthio- and 1-(p-methoxyphenyl)thio-␤-d-glucopyranoside tetraacetate (7) and (10) were synthesized as a standard procedure: Starting with commercially available ␤-d-galactose pentaacetate; a glycosylation with corresponding arylthiol was carried out in the presence of a Lewis acid. 2.3. General procedure of electrolysis 2.3.1. Electrolysis procedure for anodic fluorodesulfurization and anodic fluorination The electrochemical cell was fabricated using polypropylene. A single compartment polypropylene cell of 2 ml capacity was used. Anodic fluorination of 1 (0.5 mmol) was carried out at a constant current (10 mA/cm2 ) with platinum electrodes (1 cm × 1 cm) in 2 ml of an anhydrous solvent containing a fluoride salt (0.5 M) or an ionic liquid fluoride salt (ca. 5 M) solvent-free conditions at ambient temperature. After electrolysis, the electrolytic solution was extracted repeatedly by ether and the ethereal extracts were

washed with brine to remove the fluoride salt. The organic layer was dried over anhydrous Na2 SO4 , and evaporated to give a crude product, which was purified by column chromatography (EtOAc:hexane = 1:3). 3-Fluorophthalide (2), 3-fluoro-3-phenylthiophthalide (3), 4-fluoro-1,3-dioxolan-2-one (5) and 4-fluoro-4-phenylthio1,3-dioxolan-2-one (6) were identified by 19 F NMR and 1 H NMR spectral data of their authentic samples [6,7]. 2.4. Spectral data 2.4.1. 1-Fluoro-1-phenylthio-α-d-glucopyranoside tetraacetate (9α) 1 H NMR (270 MHz, CDCl ), δ: 7.56–7.53 (m, 2H), 3 7.34–7.36 (m, 3H), 5.50–5.37 (m, 2H), 5.16 (d, J = 9.5 Hz), 4.22–4.08 (m, 2H), 3.74 (d, J = 12 Hz, 1H); 13 C NMR (67.8 MHz, CDCl3 ), δ: 170.3, 169.8, 169.1, 168.7, 135.0 (d, J = 1.70 Hz), 129.3, 129.1, 126.0, 121.4 (d, J = 255 Hz), 73.18 (d, J = 27.4 Hz), 72.25 (d, J = 2.79 Hz), 71.59 (d, J = 7.81 Hz), 67.55, 61.05, 20.71, 20.69, 20.64, 20.63; 19 F NMR (CDCl , 254 MHz), δ: −3.88 (d, J = 9.2 Hz); 3 MS (m/z): 458 (M+ ), 439, 350; HRMS, m/z calcd. for C20 H23 FO4 S: 458.1047. Found: 458.1051. 2.4.2. 1-Fluoro-1-phenylthio-β-d-glucopyranoside tetraacetate (9β) 1 H NMR (270 MHz, CDCl ), δ: 7.60–7.32 (m, 5H), 5.40 3 (t, J = 9.7 Hz, 1H), 5.26 (dd, J = 21, 9.7 Hz, 1H), 5.12 (t, J = 9.5 Hz, 1H), 4.21 (dd, J = 13, 4.6 Hz, 1H), 4.14 (m, 1H), 4.10 (m, 1H), 2.09 (s, 3H), 2.02 (s, 3H), 2.02 (s, 3H), 1.99 (s, 3H); 13 C NMR (67.8 MHz, CDCl3 ), δ: 170.2, 169.7, 169.2, 169.1, 136.5 (d, J = 1.1 Hz), 129.7, 128.7, 126.4, 118.3 (d, J = 266 Hz), 71.64 (d, J = 4.48 Hz), 71.34 (d, J = 26 Hz), 70.86, 67.06, 60.92, 20.73, 20.61, 20.59, 20.58; 19 F NMR (CDCl3 , 254 MHz), δ: −26.84 (d, J = 20 Hz); MS (m/z): 458 (M+ ), 439, 184; HRMS, m/z calcd for C20 H23 FO4 S: 458.1047. Found: 458.1052. 3. Result and discussion 3.1. Anodic fluorination of 3-phenylphthalide (1) At first, cyclic voltammetry of 3-phenylthiophthalide (1) was carried out in ionic liquid Et4 NF·4HF. As shown in Fig. 1, cyclic voltammetry of Et4 NF·4HF in the absence of 1 showed no oxidation peak in the region of +0.6 to +3.0 V. When substrate (0.5 mmol) was added to the electrolytic solution (neat Et4 NF·4HF), one irreversible oxidation peak appeared at around 2.2 V versus Ag/AgCl which seems to be attributable to the oxidation of 1. Almost the same oxidation potential (2.23 V) of 1 was also observed in MeCN. Thus, the anodic stability of Et4 NF·4HF was proved to be high enough to allow the efficient anodic fluorination of 1. Then, anodic fluorination of 1 was carried out in various liquid fluoride salts without a solvent. The results are listed in Table 1.

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F O

O

F SPh

SPh -e,-PhS• F /CH2Cl2

O

O

-2e, -H+

O

O

F /DME

O

O

O

5

4

6

Scheme 1.

Fig. 1. Cyclic voltammogram of 1 in Et4 NF·4HF at Pt disk electrode (Ø1 mm). Potential scan rate: 100 mV s−1 : (a) neat Et4 NF·4HF; (b) 0.25 M of 1 in Et4 NF·4HF.

Fluorodesulfurization of 1 proceeded smoothly regardless of fluoride salts except for Et3 N·3HF to provide 2 exclusively in good to excellent yields. Among the fluoride salts used, Et4 NF·4HF was the best choice and the yield of 2 was almost quantitative (Run 4), and Et3 N·5HF and Et4 NF·5HF were also suitable for the fluorination. In sharp contrast, the use of Et3 N·3HF gave mainly the corresponding ␣-fluorinated product 3 in reasonable yield besides 2, however the total yield of 2 and 3 was low because of simultaneous oxidation of Et3 N·3HF during the electrolysis. Previously, we found a unique marked solvent effect on fluorinated product selectivity [5,6]. For example, anodic fluorodesulfurization of 4-phenylthio-1,3-dioxolan-2-one (4) proceeded predominantly in CH2 Cl2 while the use of 1,2-dimethoxyethane (DME) resulted in selective ␣fluorination without desulfurization as shown in Scheme 1. Therefore, this media effect of Et3 N·nHF (n = 4, 5), Et4 NF·nHF (n = 4, 5) seems to be similar to that of CH2 Cl2 . Namely, those ionic fluoride salts destabilize the radical cation intermediate electrogenerated from 1 to result in desulfurization. Table 1 Media effect on anodic fluorination of 3-phenylthiophthalide (1)

Run

1 2 3 4 5

Reaction media

Et3 N·3HF Et3 N·4HF Et3 N·5HF Et4 NF·4HF Et4 NF·5HF a

Determined by

19 F

NMR.

Charge passed (F/mol)

Yield (%)a 2

3

4.2 4.2 3.2 3.3 4

4 77 96 99 93

21 – – – –

Next, we focused on the anode potential during electrolysis in order to develop more efficient fluorination. The anode potential change was monitored during the electrolysis. The anode potential dependence on the electrical charge passed during the electrochemical fluorination of 1 is shown in Fig. 2. The potential was almost stable up to 2.5 F/mol (140 ◦ C passed). But, after the electricity of 2.5 F/mol was passed, the anode potential increased gradually. After ca. 3 F/mol was passed, the anode potential increased greatly. These facts indicate that electrolysis was completed at ca. 3 F/mol passed. In general, the anode potential increases gradually or greatly after a starting material is almost consumed in the case of constant current electrolysis. The increase of the anode potential is usually attributed to the anodic oxidation of a solvent and/or an electrolyte other than a starting material. With these facts in mind, our attention was focused on the reuse of reaction media. The reuse of a mixture of ionic liquids, 1-ethyl-3-methyl imidazolium trifluoromethanesulfonate and Et3 N·5HF for the anodic fluorodesulfurization of 3-phenylthiophthalide has been demonstrated in our recent work [7]. However, the yield was decreased in the third cycle due to the large consumption of HF in the fluoride salt, Et3 N·5HF. On the other hand, a large amount of HF exists in the liquid fluoride salts under the present solvent-free conditions. Therefore, it was expected that the yield would not be decreased. Thus, we examined the possibility of the reuse of the fluoride salt Et4 NF·4HF for anodic fluorodesulfurization, and results are summarized in Table 2. After electrolysis of 1 in Et4 NF·4HF, the product 2 was readily separated by extraction with hexane/ether (4:1)

Fig. 2. Dependence of anode potential on the electricity during the electrolysis of 1 in Et4 NF·4HF.

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Table 2 Recyclable anodic fluorodesulfurization of 3-phenylthiophthalide (1) in Et4 NF·4HF

Cycle

Yield of 2 (%)a

First Second Third Fourth

99 96 93 94

Table 3 Media effect on anodic fluorination of 4-phenylthio-1,3-dioxolan-2-one (4)

Run

1 2

Et3 N·3HF Et3 N·4HF a

a

Determined by

19 F

Reaction media

Determined by

19 F

Charge passed (F/mol)

Yield (%)a 5

6

3.2 3.6

– 51

12 –

NMR.

NMR.

(2 ml 3×). The residual organic solvent in Et4 NF·4HF was removed by heating 80 ◦ C for 1 h, and then the recovered Et4 NF·4HF was reused for the electrolytic reaction without any pretreatment. This system could be recycled four times without significant decrease of the product yield.

intermediate of 4 to result in desulfurization as observed in the anodic fluorination of 4 in CH2 Cl2 (Scheme 1) [5,6]. 3.3. Anodic fluorination of 1-arylthio-2,3,4,6tetra-O-acetyl-␤-d-glucopyranoside (7) and (10)

3.2. Anodic fluorination of 4-phenylthio-1,3-dioxolan-2one (4)

Finally, anodic fluorination of 7 was comparatively studied in organic solvents and neat liquid fluoride salts such as Et3 N·3HF and Et3 N·4HF. The electrolytic results are summarized in Table 4. When DME or THF were used as a solvent, ␣-monofluorinated products, 9␣ and 9␤ were formed exclusively without desulfurization in reasonable to moderate total yield (Runs 1 and 2). This trend is similar to the anodic fluorination of phenylthioethylene carbonate as shown in Scheme 1 [5,6]. Interestingly, even in MeCN and CH2 Cl2 , ␣-monofluorination proceeded exclusively without desulfurization (Runs 3 and 4) although CH2 Cl2 seemed to

In order to generalize the media effect, we extended this solvent-free condition to 4-phenylthio-1,3-dioxolan-2-one (4). As shown in Table 3, anodic ␣-fluorination of 4 leading to product 6 proceeded in Et3 N·3HF although the yield was low (Run 1). In sharp contrast, fluorodesulfurization of 4 took place exclusively in Et3 N·4HF to give 5 in moderate yield (Run 2). The effect of fluoride salts on the fluorinated product selectivity was quite similar to the case of 3-phenylthiophthalide. Namely, Et3 N·4HF destabilizes the radical cation Table 4 Anodic fluorination of 7 under various conditions

Run

1b

Solvent

DME THF MeCN CH2 Cl2 – – –

2 3 4 5c 6 7d a b c d

Determined by 19 F NMR. Compound 7 (46%) was recovered. Multi-products were formed. 0.1 eq. Et4 NBr was added.

Supporting electrolyte

Et3 N·3HF Et3 N·3HF Et3 N·3HF Et3 N·3HF Et3 N·3HF Et3 N·4HF Et3 N·4HF

Charge passed (F/mol)

4 4 4 4 4 4.2 4

Yield (%)a 8

9␣

9␤

– – – – 12 62 66

10 12 11 17 5.7 – –

22 55 46 41 20 – –

M. Hasegawa, T. Fuchigami / Electrochimica Acta 49 (2004) 3367–3372

3371

OAc O

AcO AcO

SPh AcO -•SPh

-e

7

OAc O

F

O

AcO AcO

O

F AcO

H 3C

OAc O

AcO AcO

OAc O

AcO AcO

8

7a SPh

AcO

H

B

+

-H , -e

NEt3

AcO AcO

OAc O SPh O

F

OAc O

AcO AcO

SPh

O

AcO

H3C

F

9 and 9

7b Scheme 2.

AcO AcO

OAc O

AcO AcO

SPh O

OAc O SPh O

O

H3 C

O

H3C

A

B

Fig. 3. Resonance effect with both oxygen and sulfur atoms.

destabilize the radical cation intermediate B (Scheme 2) similar to the case as shown in Scheme 1. On the contrary, when the same fluoride salt Et3 N·3HF was used without an organic solvent, product selectivity was significantly changed. In liquid Et3 N·3HF, desulfurization product 8 was formed appreciably in addition to 9␣ and 9␤ (Run 5). In sharp contrast, the use of Et3 N·4HF afforded the fluorodesulfurization product, ␤-anomer 8 exclusively in moderate yield (Run 6). These results indicate that neat Et3 N·4HF destabilized radical cation intermediate B much more than Et3 N·3HF. The former fluoride salt does not contain free amine, Et3 N at all while the latter one contains considerable amount of free amine, Et3 N. Since the donor number of Et3 N is very large (61) [14], free Et3 N may strongly coordinate cationic species B to stabilize B and it also abstracts the ␣-proton of B as shown in Scheme 2. For these reasons, exclusive or selective formation of 9␣ and 9␤ can be explained. On the other hand, Et3 N·4HF has no coordi-

AcO AcO

OAc O

nation ability to cationic species, therefore exclusive formation of 8 is reasonable. The stereoselectivity of 9 can be explained as follows. Anodically generated carbocation may be stabilized by the resonance effect with both oxygen and sulfur atoms as shown in Fig. 3. The stereoselectivity of the fluorodesulfurization product 8 can be explained by the presence of the oxonium ion intermediate 7a with anchimeric assistance of the acetyl group at C-2 as shown in Scheme 2. We also attempted electrolysis in the presence of Et4 NBr (0.1 eq.) as the mediator for anodic fluorodesulfurization in order to improve the yield of 8 and the yield was slightly increased (Table 3, Run 7). Motherwell and coworkers reported that glycosyl fluoride was prepared in 65% yield by the fluorodesulfurization reaction of 1-phenylthioglycoside (7) with difluoroiodobenzene [15]. In this case, the formation of ␣-acetoxonium ion presumably shields the stereoelectronically favored axial attack of a fluoride ion and explains the formation of both isomers (␣:␤ = 2:3). We also expected that the use of p-methoxyphenylthio moiety of 10 as a better leaving group in this reaction would increase the yield, however electrolysis did not smoothly proceed and the yield decreased to 33% in spite of its lower oxidation potential compared with that of 7 (Scheme 3).

-e, -p -MeOC6H4 S•

S AcO

Et3N•4HF 4 F/mol

AcO AcO

OAc O F AcO

OMe 10

8

Scheme 3.

33%

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4. Conclusion

References

Anodic fluorodesulfurization of 3-phenylthiophthalide, 4-phenylthio-1,3-dioxolan-2-one, and 1-arylthio-2,3,4,6tetra-O-acetyl-␤-d-glucopyranoside was successfully carried out in ionic liquids, Et3 N·4HF and Et4 NF·4HF without any solvents. When Et3 N·3HF was used as the electrolytic medium, ␣-fluorination without desulfurization took place considerably or exclusively depending on the substrates owing to free Et3 N contaminating in Et3 N·3HF. Thus, it was demonstrated for the first time that liquid fluoride salts like Et3 N·nHF (n = 3, 4) and Et4 NF·4HF greatly affect anodically fluorinated product selectivity. These new findings seem to open a new avenue to successful electrochemical fluorination toward green chemistry.

[1] Electrolytic Partial Fluorination of Organic Compounds, Part 75, Part 4: Ref [7]. [2] T. Fuchigami, in: H. Lund, O. Hammerrich (Eds.), Organic Electrochemistry, 4th ed., Marcel Dekker, New York, 2001, Chapter 25. [3] T. Fuchigami, in: P.S. Mariano (Ed.), Advances in Electron Transfer Chemistry, vol. 6, JAI Press, CN, 1999, p. 41. [4] M. Noel, V. Suryanarayanan, S. Chellammal, J. Fluorine Chem. 83 (1997) 31. [5] H. Ishii, N. Yamada, T. Fuchigami, Chem. Commun. 17 (2000) 1617. [6] H. Ishii, N. Yamada, T. Fuchigami, Tetrahedron 57 (2001) 9067. [7] M. Hasegawa, H. Ishii, T. Fuchigami, Green Chem. 5 (2003) 512. [8] K. Momota, M. Morita, Y. Matsuda, Electrochim. Acta 38 (1993) 619. [9] K. Momota, M. Morita, Y. Matsuda, Electrochim. Acta 38 (1993) 1123. [10] J.H.H. Meurs, W. Eilenberg, Tetrahedron 47 (1991) 705. [11] S. Chen, Q.T. Hatakeyama, T. Fukuhara, S. Hara, N. Yoneda, Electrochim. Acta 42 (1997) 1951. [12] V. Suryanarayanan, M. Noel, J. Fluorine Chem. 92 (1998) 177. [13] T.H. Fife, N.C. De, J. Am. Chem. Soc. 96 (1974) 6158. [14] V. Gutmann, E. Wychera, Inorg. Nucl. Chem. Lett. 2 (1966) 257. [15] S. Caddick, W.B. Motherwell, J.A. Wilkinson, J. Chem. Soc., Chem. Commun. (1991) 674.

Acknowledgements This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (A) “Exploitation of Multi-Element Cyclic Molecules” from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We also would like to express our thanks to Morita Chemical Industrials Co. Ltd. for generous gifts of fluoride salts.