Acetylacetone–metal catalyst modified by pyridinium salt group applied to the NHPI-catalyzed oxidation of cholesteryl acetate

Abstract

Acetylacetone–metal catalysts modified by ionic compounds were used as co-catalysts in the NHPI-catalyzed oxidation of cholesteryl acetate by molecular oxygen under mild conditions. When cholesteryl acetate was oxidized at 30 °C for 10 h, a 79% isolated yield for 7-ketocholesteryl acetate was achieved. The dual role of pyridinium salt group onto the acetylacetone ligand, serving as an electron-withdrawing group and at the same time as a co-catalyst for the decomposition of alkyl hydroperoxide, was responsible for the high isolated yield.

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1. Introduction

The selective oxidation of hydrocarbons using molecular oxygen as the ultimate oxidant is still a primary challenge both in organic synthesis and industrial chemistry.^1–4 The allylic oxidation of cholesteryl acetate to 7-ketocholesteryl acetate (Scheme 1) is a key step in the synthesis of vitamin D₃, which plays a significant role in general life.⁵ The oxidation of cholesteryl acetate is usually carried out in the presence of chromium(VI)-based reagents,^6–9 though manganese dioxide and potassium permanganate¹⁰ are also available for this transformation. The oxidation is achieved by the use of a great excess of oxidant along with abundant noxious chromium residues which should be avoided if possible. The system using catalytic amounts of metal catalysts in combination with t-butyl hydroperoxide (TBHP) was also developed in previous work.^11–13 Nonetheless, from the standpoint of the so-called green and sustainable chemistry, t-butyl hydroperoxide (TBHP) is inappropriate for large scale use in the chemical industry due to its relatively high cost. Molecular oxygen has been becoming increasingly attractive as an oxidant in recent years.^14–17 Methodology for the oxidation of cholesteryl acetate under mild conditions is still keenly sought to produce 7-ketocholesteryl acetate.

Scheme 1 The oxidation of cholesteryl acetate.

Recently an interesting oxidation of a broad range of organic substrates, like alcohols,^18,19alkanes,²⁰ and alkylaromatics,²¹ catalyzed by N-hydroxyphthalimide (NHPI) and transition metal salts, was developed particularly by Ishii and co-workers.²² In the NHPI-catalyzed oxidation, the phthalimide-N-oxyl (PINO) radical is considered to be the active oxidant, which is able to abstract a hydrogen atom from the organic substrates. The formation of the PINO radical from its precursor NHPI can be achieved by using transition metal salts, like Pb(OAc)₄,^23,24acetylacetone–Co(II) (Co(acac)₂).²⁵ The NHPI-catalyzed reactions provide convenient methodologies for oxygenation,²⁶nitration,²⁷ and sulfonation of alkanes.²⁸ However, as far as we know, there have been few reports on the catalytic oxidation of cholesteryl acetate by NHPI.²⁹ Previously, our group reported the oxidation of cholesteryl acetate using NHPI combined with Co(OAc)₂ and Mn(OAc)₂ as catalysts to produce 7-ketocholesteryl acetate with a good yield.³⁰ However, those metal salts cannot be recovered and recycled. One way to circumvent this problem is to modify the metal catalysts by ionic compounds,^31–33 which can be recovered from the organic solution by a water wash method.

Herein we report the novel combination of NHPI and acetylacetone–metal catalysts modified by ionic compounds which demonstrates a more powerful catalytic effect than the NHPI/acetylacetone–metal system in the oxidation of cholesteryl acetate by molecular oxygen.

2. Experimental

2.1 Materials and instruments

All the chemicals were of AR grade. They were commercially purchased and used without further treatment.

The NMR spectra were detected by a Bruker ARX 500 NMR spectrometer with TMS as the internal standard. FT-IR spectra were recorded on a Bruker APEX-III spectrometer using KBr pellets in 400–4000 cm⁻¹ region. ESI–MS analysis was performed on a Bruker Esquire 3000 (Bruker–Franzen Analytik, Bermen, Germany) equipped with an ion trap analyzer system.

2.2 Catalyst preparation

The preparation of the [M(acac–py)₂][Cl₂] was outlined in Scheme 2, which was similar to our previous work.³⁴

Scheme 2 Preparation of [M(acac–py)₂][Cl₂].

2.2.1. Characterization of the [acac–py][Cl]. The [acac–py][Cl] was obtained as a deep brown liquid. ¹H NMR (d₆-DMSO): Acetylacetones are known to exist as both the enol and keto form under normal conditions. The peak area ratio of the enol form [acac–py][Cl] and keto form [acac–py][Cl] is 7 : 1 in d₆-DMSO. Keto-form of [acac–py][Cl]: 1.88(6H, s), 5.87(H, s), 7.93–7.94(1H, d), 8.44–8.34(2H, q), 8.85–8.83 (2H, d). Enol-form of [acac–py][Cl]: 2.23(3H, s), 2.29(3H, s), 8.18–8.20(2H, d), 8.63–8.67(H, d), 8.90–8.93(2H, q). FT–IR (v/cm⁻¹): 3435, 3057, 1735, 1633, 1489, 1380, 1176, 767, 683. ESI–MS: m/z [acac–py]⁺ 177.9, [[acac–py][Cl] + H]⁺ 215.9.

2.2.2. Characterization of the [M(acac–py)₂][Cl₂]. [Cu(acac–py)₂][Cl₂] was obtained as a green power. FT–IR (v/cm⁻¹): 3441, 3057, 1603, 1489, 1447, 1380, 1140, 761, 689, 620. ESI–MS: [[Cu(acac–py)₂][Cl₂] + H]⁺ 490.4.

[Co(acac–py)₂][Cl₂] was obtained as a black liquid. FT–IR (v/cm⁻¹): 3435, 3057, 1735, 1633, 1489, 1380, 1176, 767, 683. ESI–MS: m/z [[Co(acac–py)₂][Cl₂] + H]⁺ 483.6, [[Co(acac–py)₂] − H⁺]⁺ 412.3, [([Co(acac − py)₂] + H)/3]⁺ 136.1.

2.3 Catalytic reaction

In a typical reaction, 4.28 g (10 mmol) cholesteryl acetate, 0.163 g (1 mmol) NHPI, 70 ml acetone, 10 ml 1,4-dioxane, and co-catalyst used as described in the manuscript were added into a three-necked glass-reactor (100 ml). Then the reaction was performed in a water bath with vigorous stirring and dioxygen flowing at a constant flow rate (20 ml min⁻¹). After completion of the reaction (TLC control), the solvent was removed under reduced pressure at 50 °C. Then, the oil residue was treated with a mixture of pyridine (5 ml) and acetic anhydride (20 ml) at room temperature overnight and then the solvent was removed under vacuum. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate–petroleum ether (1 : 11), giving 7-ketocholesteryl acetate as the final product.

3. Results and discussion

3.1. The catalytic behavior of cholesteryl acetate oxidation with NHPI/[M(acac–py)₂][Cl₂] system

A series of acetylacetone–metal salts were synthesized and applied in the oxidation of cholesteryl acetate. Table 1 lists the reaction conditions, along with the corresponding product yields. A blank experiment revealed that NHPI (10 mol%) as the sole catalyst led to only a 3% isolated yield after 12 h (Entry 1). Previous study has shown that the oxidation of hydrocarbons by O₂, catalyzed by NHPI and BPO (benzoyl peroxide), led to the corresponding product with satisfactory results.³⁵ When the same combination was used in the oxidation of cholesteryl acetate, however, only 11% isolated yield was obtained within 14 h (Entry 2). The combined catalytic systems of NHPI with Cu(acac)₂ or Co(acac)₂ were also introduced into the oxidation of cholesteryl acetate, which was more efficient than the NHPI/BPO system (Entries 3–4). Then, the effect of [M(acac–py)₂][Cl₂] on the NHPI-catalyzed oxidation of cholesteryl acetate under a dioxygen atmosphere was examined. To our delight, the isolated yield of 7-ketocholesteryl acetate was sharply increased with [M(acac–py)₂][Cl₂] as a co-catalyst. Under the same reaction conditions as entry 4, the oxidation of cholesteryl acetate using the NHPI/[Cu(acac–py)₂][Cl₂] system afforded the corresponding product with 53% isolated yield (Entry 5). This oxidation process was further improved by replacing [Cu(acac–py)₂][Cl₂] with [Co(acac–py)₂][Cl₂], in which a relatively good yield (60%) was obtained (Entry 6). Because NHPI/[Co(acac–py)₂][Cl₂] presented the best catalytic activity in the oxidation of cholesteryl acetate, this system was selected for further studies.

Table 1 The results of the oxidation of cholesteryl acetate with NHPI and different co-catalysts^a

Entry	Co-catalyst (mol%)^b	Time (h)	Isolated yield (%)
a The oxidation of cholesteryl acetate was performed with cholesteryl acetate (10 mmol), NHPI (1 mmol), co-catalyst (0.05 mmol) in acetone (70 ml) with 1,4-dioxane (10 ml) at 30 °C. b BPO: benzoyl peroxide, Cu(acac)2: copper(II) acetylacetonate, Co(acac)2: cobalt(II) acetylacetonate.
1	—	12	3
2	BPO (0.5%)	14	11
3	Cu(acac)2 (0.5%)	8	33
4	Co(acac)2 (0.5%)	8	35
5	[Cu(acac–py)2][Cl2] (0.5%)	8	53
6	[Co(acac–py)2][Cl2] (0.5%)	8	60

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3.2. The effect of temperature, catalyst concentration, time, and the recycling experiment

It should be noted that the temperature had a strong effect on this oxidation, which is shown in Fig. 1. The isolated yield increased as the temperature increased from 20 °C to 30 °C. However, when the temperature was higher than 30 °C, the over-oxidation product increased remarkably. Those results showed that temperature is a key factor in this reaction, where a suitable temperature is 30 °C for the NHPI/[Co(acac–py)₂][Cl₂] catalyst system.

Fig. 1 The effect of temperature on the oxidation of cholesteryl acetate. Reaction conditions: cholesteryl acetate (10 mmol), NHPI (1 mmol), [Co(acac–py)₂][Cl₂] (0.05 mmol), acetone (70 mL), 1,4-dioxane (10 mL), O₂ (1 atm), 8 h.

The effect of changing the amount of [Co(acac–py)₂][Cl₂] from 0.5% to 3% on the oxidation is shown in Table 2. It was observed that the yield of cholesteryl acetate increased with the increasing of the amount of [Co(acac–py)₂][Cl₂] until its amount reached 2 mol% (Entry 1–3). When 3 mol% [Co(acac–py)₂][Cl₂] was used in the oxidation, the isolated yield (68%) slightly decreased (Entry 4). It should be mentioned that due to the high polarity of [Co(acac–py)₂][Cl₂], cholesteryl acetate could not be completely dissolved in entry 4. These results reveal that 2 mol% [Co(acac–py)₂][Cl₂] is adequate.

Table 2 The results of the oxidation of cholesteryl acetate with NHPI and different amounts of [Co(acac–py)₂][Cl₂]^a

Entry	Co-catalyst (mol%)	Isolated yield (%)
a The oxidation of cholesteryl acetate was performed with cholesteryl acetate (10 mmol), NHPI (1 mmol), [Co(acac–py)2][Cl2] (as described in the table) in acetone (70 mL) with 1,4-dioxane (10 mL) for 8 h at 30 °C.
1	[Co(acac–py)2][Cl2] (0.5%)	60
2	[Co(acac–py)2][Cl2] (1%)	72
3	[Co(acac–py)2][Cl2] (2%)	75
4	[Co(acac–py)2][Cl2] (3%)	68

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To further study the process, the influence of time on the catalytic performance of NHPI/[Co(acac–py)₂][Cl₂] was investigated, which is illustrated in Fig. 2. Cholesteryl acetate was almost linearly oxidized in 8 h under these conditions to give 7-ketocholesteryl acetate. The yield of 7-ketocholesteryl acetate reached a maximum (79%) around 10 h. To the best of our knowledge, it is the best yield achieved by only catalytic amounts of NHPI combined with a sole metal salt using O₂. After 10 h the reaction was almost stopped, suggesting 10 h is a preferable reaction time.

Fig. 2 The isolated yield vs. time plot for the oxidation of cholesterylacetate catalyzed by NHPI combined with [Co(acac–py)₂][Cl₂]. Reaction conditions: cholesteryl acetate (10 mmol), NHPI (1 mmol), [Co(acac–py)₂][Cl₂] (0.2 mmol), acetone (70 mL), 1,4-dioxane (10 mL), 30 °C, O₂ 1 atm.

The catalyst [Co(acac–py)₂][Cl₂] could be easily recovered by a water wash method and then the catalyst was reused for a subsequent reaction. As shown in Table 3, the [Co(acac–py)₂][Cl₂] could be reused at least four times with only a slight loss of catalytic activity.

Table 3 The recycling studies of [Co(acac–py)₂][Cl₂] in the oxidation of cholesteryl acetate^a

Entry	Run times	Time (h)	Isolated yield (%)
a The oxidation of cholesteryl acetate was performed with cholesteryl acetate (10 mmol), NHPI (1 mmol), [Co(acac–py)2][Cl2] (0.2 mmol) in acetone (70 mL) and 1,4-dioxane (10 mL) at 30 °C for 8 h.
1	Fresh	10	79%
2	2nd	10	79%
3	3rd	10	77%
4	4th	11	75%
5	5th	13	72%

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3.3. Reaction mechanism

Scheme 3 illustrates a plausible reaction pathway for the oxidation of cholesteryl acetate by NHPI combined with [Co(acac–py)₂][Cl₂].

Scheme 3 A plausible reaction pathway for the aerobic oxidation of cholesteryl acetate by NHPI combined with [Co(acac–py)₂][Cl₂].

In the previous investigation, the Co species was believed to have two functions: (1) acting as an initiator in generating PINO radicals; (2) catalyzing the decomposition of intermediate hydroperoxides into products.^15,36,37 Here in the NHPI/[Co(acac–py)₂][Cl₂] system, [Co(acac–py)₂][Cl₂] served similar purposes. However, why does [Co(acac–py)₂][Cl₂] exhibits a more powerful co-catalytic effect than the traditional Co(acac)₂ in this system? This fact becomes apparent after further investigation of the role of the pyridinium salt group and then two other experiments were carried out (Table 4). Quaternary ammonium salts has been found to accelerate the oxidation of various hydrocarbons with NHPI as catalyst.^38,39 The oxidation of cholesteryl acetate with O₂ by the NHPI/Co(acac)₂ system was enhanced by adding a catalytic amount of 1-butylpyridinium chloride (1 mol%), giving 7-ketocholesteryl acetate in relatively good yield (46%), while in the absence of 1-butylpyridinium chloride only 35% isolated yield was attained and the promotion effect was remarkable (Entry 1). It revealed that the pyridinium salt group showed a similar promotion effect to quaternary ammonium salts. Our previous work has indicated that ionic substituents alter the charge density carried by the center metal atom on the acetylacetone–metal catalyst. For example, the charge carried by the center metal atom (Fe) in the acetylacetone–Fe catalyst is higher than that of acetylacetone–Fe modified by a pyridine catalyst (0.7 vs. 0.69, respectively).³² In this system, it was believed that the introduction of the pyridinium salt group can significantly change the electron distribution of the center metal.⁴⁰ To test this hypothesis, an experiment using Co(acac–Cl)₂ as co-catalyst was carried out. It was found that Co(acac–Cl)₂ was more active than Co(acac)₂ but less than [Co(acac–py)₂][Cl₂] (Entry 2). It seems that the pyridinium salt group could decrease the charge density of the center metal to some extent, thereby enhancing the O₂ uptake rate. Thus, we suggested here that the pyridinium salt group played a dual role in this oxidation.

Table 4 The results of the oxidation of cholesteryl acetate with NHPI and other co-catalysts

Entry	Co-catalyst (mol%)	Additive	Time (h)	Isolated yield (%)
a The oxidation of cholesteryl acetate was performed with cholesteryl acetate (10 mmol), NHPI (1 mmol), Co(acac)2 (0.05 mmol), 1-butylpyridinium chloride (0.1 mmol) in acetone (70 ml) and 1,4-dioxane(10 ml) for 8 h at 30 °C. b The oxidation of cholesteryl acetate was performed with cholesteryl acetate (10 mmol), NHPI (1 mmol), Co(acac–Cl)2 (0.05 mmol), in acetone (70 ml) and 1,4-dioxane(10 ml) for 8 h at 30 °C. Co(acac–Cl)2: 3-chlorine–acetylacetonate cobalt(II).
1^a	Co(acac)2 (0.5%)	1-Butylpyridinium chloride	8	46
2^b	Co(acac-Cl)2 (0.5%)	None	8	42

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4. Conclusions

In conclusion, the acetylacetone–metal catalyst modified by an ionic compound [M(acac–py)₂][Cl₂] were synthesized and the novel combination of NHPI and [Co(acac–py)₂][Cl₂] was more effective than the NHPI/Co(acac)₂ system in the cholesteryl acetate oxidation. It is interesting to note that pyridinium salt group showed dual function in this oxidation: (1) having some electron-withdrawing power, (2) accelerating the decomposition of alkyl hydroperoxide. The effect of catalyst concentration, temperature, and time were investigated and the results showed that 30 °C, 2 mol% [Co(acac–py)₂][Cl₂], and 10 h might be the best conditions for cholesteryl acetate oxidation catalyzed by NHPI. The NHPI/[Co(acac–py)₂][Cl₂] system provides an effective, mild, easy to recycle method for the cholesteryl acetate oxidation with molecular oxygen as the final oxidant, making it much more feasible for application in industrial processes. Moreover, we believe that the ionic compound modification strategy can be extended to design many more powerful catalysts.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 20990221, No. 20803062. The authors are grateful to Zhejiang NHU Company Ltd, China, for financial support.

References

1. P. R. Schreiner and A. A. Fokin, Chem. Rec., 2004, 3, 247.
2. E. N. Jacobsen, Adv. Synth. Catal., 2004, 346, 109.
3. M. Beller, Adv. Synth. Catal., 2004, 346, 107.
4. C. Galli and P. Gentili, J. Phys. Org. Chem., 2004, 17, 973.
5. R. P. Heaney, Clin. J. Am. Soc. Nephrol., 2008, 3, 1535.
6. W. G. Salmond, M. A. Barta and J. L. Havens, J. Org. Chem., 1978, 43, 2057.
7. C. W. Marshall, R. E. Ray, I. Laos and B. Riegel, J. Am. Chem. Soc., 1957, 79, 6308.
8. D. S. Fullerton and C. M. Chen, Synth. Commun., 1976, 6, 217.
9. M. A. Fousteris, A. I. Koutsourea, S. S. Nikolaropoulos, A. Riahi and J. Muzart, J. Mol. Catal. A: Chem., 2006, 250, 70.
10. M. Hudlicky, Oxidation in Organic Chemistry, American Chemical Society, Washington DC, 1990.
11. S. I. Murahashi, N. Komiya, Y. Oda, T. Kuwabara and T. Naota, J. Org. Chem., 2000, 65, 9186.
12. A. J. Catino, J. M. Nichols, H. Choi, S. Gottipamula and M. P. Doyle, Org. Lett., 2005, 7, 5167.
13. A. J. Catino, R. E. Forslund and M. P. Doyle, J. Am. Chem. Soc., 2004, 126, 13622.
14. C. M. Wang, W. H. Guan, P. H. Xie, X. Yun, H. R. Li, X. B. Hu and Y. Wang, Catal. Commun., 2009, 10, 725.
15. F. Recupero and C. Punta, Chem. Rev., 2007, 107, 3800.
16. W. H. Guan, C. M. Wang, X. Yun, X. B. Hu, Y. Wang and H. R. Li, Catal. Commun., 2008, 9, 1979.
17. J. Y. Mao, N. Li, H. R. Li and X. B. Hu, J. Mol. Catal. A: Chem., 2006, 258, 178.
18. T. Iwahama, Y. Yoshino, T. Keitoku, S. Sakaguchi and Y. Ishii, J. Org. Chem., 2000, 65, 6502.
19. F. Minisci, C. Punta, F. Recupero, F. Fontana and G. F. Pedulli, Chem. Commun., 2002, 688.
20. Y. Ishii, S. Kato, T. Iwahama and S. Sakaguchi, Tetrahedron Lett., 1996, 37, 4993.
21. Y. Yoshino, Y. Hayashi, T. Iwahama, S. Sakaguchi and Y. Ishii, J. Org. Chem., 1997, 62, 6810.
22. R. A. Sheldon and I. Arends, Adv. Synth. Catal., 2004, 346, 1051.
23. S. Coseri, J. Phys. Org. Chem., 2009, 22, 397.
24. S. Coseri, Mini-Rev. Org. Chem., 2008, 5, 222.
25. S. Coseri, Catal. Rev. Sci. Eng., 2009, 51, 218.
26. J. Shen and C. H. Tan, Org. Biomol. Chem., 2008, 6, 4096.
27. S. Sakaguchi, Y. Nishiwaki, T. Kitamura and Y. Ishii, Angew. Chem., Int. Ed., 2001, 40, 222.
28. Y. Ishii, K. Matsunaka and S. Sakaguchi, J. Am. Chem. Soc., 2000, 122, 7390.
29. S. M. Silvestre and J. A. R. Salvador, Tetrahedron, 2007, 63, 2439.
30. Z. Yao, X. B. Hu, J. Y. Mao and H. R. Li, Green Chem., 2009, 11, 2013.
31. X. Yun, X. B. Hu, Z. Y. Jin, J. H. Hu, C. Yan, J. Yao and H. R. Li, J. Mol. Catal. A: Chem., 2010, 327, 25.
32. X. B. Hu, Y. Sun, J. Y. Mao and H. R. Li, J. Catal., 2010, 272, 320.
33. Y. Sun, W. S. Zhang, X. B. Hu and H. R. Li, J. Phys. Chem. B, 2010, 114, 4862.
34. X. B. Hu, J. Y. Mao, Y. Sun, H. Chen and H. R. Li, Catal. Commun., 2009, 10, 1908.
35. F. C. F. Joseph and P. Karlheinzdr, EP Pat, 0 198 351, 1986.
36. R. A. Sheldon and I. Arends, J. Mol. Catal. A: Chem., 2006, 251, 200.
37. C. Galli, P. Gentili and O. Lanzalunga, Angew. Chem., Int. Ed., 2008, 47, 4790.
38. K. Matsunaka, T. Iwahama, S. Sakaguchi and Y. Ishii, Tetrahedron Lett., 1999, 40, 2165.
39. P. J. Figiel, J. M. Sobczak and J. J. Ziolkowski, Chem. Commun., 2004, 244.
40. A. C. Pinto, A. A. M. Lapis, B. V. da Silva, R. S. Bastos, J. Dupont and B. A. D. Neto, Tetrahedron Lett., 2008, 49, 5639.

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