A new environmentally friendly method for the Baeyer–Villiger oxidation of cyclobutanones catalyzed by thioureas using H₂O₂ as an oxidant

Abstract

A new environmentally friendly method for the Baeyer–Villiger oxidation of cyclobutanones has been developed. The reaction can be performed at room temperature by using thioureas as catalysts and H₂O₂ as the oxidant in toluene, and the desired γ-butyrolactone compounds are obtained in high yields.

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Introduction

Since its discovery more than a century ago,¹ Baeyer–Villiger oxidation has been used as a valuable tool in organic synthesis to transform cyclic or acyclic carbonyl compounds to the corresponding lactones or esters.^2,3 A reaction of this type is usually performed with peracids or hydrogen peroxide as an oxidant. However, the former gives carboxylic acids as wasteful co-products. On the other hand, while the latter offers several advantages, i.e., cheap, clean, safe, and green (water is the sole by-product), it mostly requires the use of strong acids or metal-directed promoters due to its low activity.⁴

Recently, considerable attention has been focused on the use of organocatalytic methods, mainly due to their environmentally friendly characteristics.⁵ Indeed, organocatalytic Baeyer–Villiger oxidation with hydrogen peroxide is considered to be one of the most challenging issues in this field.^6,7

In our laboratory, we have been working to develop new methods for carbonyl group functionalization using hydrogen-bonding activation through thiourea-based organocatalysis.^8,9 As an extension of these works, we expected that the Baeyer–Villiger oxidation of cyclic ketones with hydrogen peroxide might also be promoted by thioureas (Scheme 1).¹⁰ Herein we describe the realization of this expectation.

Scheme 1 Thiourea-catalyzed Baeyer–Villiger oxidation.

Results and discussion

First, we examined the reaction of 3-phenylcyclobutanone (1a) with aqueous or non-aqueous hydrogen peroxide in the presence of thiourea and related organocatalysts 2 (Chart 1) in toluene at room temperature as a model system. The results are summarized in Table 1.

Chart 1 Thiourea-related organocatalysts.¹¹

Table 1 Baeyer–Villiger oxidation of 3-phenylcyclobutanone (1a) with H₂O₂ in the presence of catalyst 2: optimization

Entry	Catalyst(2)	Method^a	Time (h)	Yield(%)^b
a Method A: 1a (0.2 mmol), 30% aq H2O2 (1.1 equiv) in toluene (1.0 mL) at r.t.; Method B: 1a (0.2 mmol), H2O2 in Et2O (1.1 equiv) in toluene (1.0 mL) at r.t.; Method C: 1a (0.2 mmol), H2O2 in Et2O (1.1 equiv) in CH2Cl2 (1.0 mL) at r.t. b Isolated yield. c 5 mol% of 2a was used. d 30 mol% of 2a was used.
1	—	A	30	trace
2	2a	A	30	59
3	2a	B	5	94
4^c	2a	B	7	88
5^d	2a	B	4	89
6	2b	B	78	56
7	2c	B	24	78
8	2d	B	42	70
9	2a	C	3	91

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While no reaction was observed in the absence of a catalyst, we found that 2a could catalyze the desired reaction using 30% aqueous H₂O₂ as the oxidant, albeit in rather low yield after 30 h (Table 1, entries 1 and 2). After several experiments to optimize the conditions, we were delighted to find that the use of H₂O₂ in Et₂O as the oxidant¹² was most favorable for the present purpose.¹³ Thus, the treatment of 1a with 1.1 equiv of an ethereal solution of H₂O₂ (0.5∼0.6 M) in the presence of 10 mol% of 2a in toluene produced γ-butyrolactone 3a in 94% yield after 5 h at r.t. (Table 1, entry 3). With respect to the catalyst loading, we found that at least 10 mol% of the catalyst were necessary to achieve high yield, and a reduction to 5 mol% compromised the reactivity (Table 1, entries 3–5).¹⁴

Next, it became clear that there was a significant catalyst effect: urea homologue 2b and half-alkylated 2c were both less effective than 2a (Table 1, entries 6 and 7). Very similar observations were recognized in our previous study on Diels–Alder reactions.⁹ The fact that sulfamide 2d shows less catalytic activity means that the acidity of N–H is not proportional to the catalyst activity in this transformation (Table 1, entry 8).¹⁵ Finally, the use of CH₂Cl₂ as the solvent gave comparable results, and 3a was obtained in 91% yield after 3 h (Table 1, entry 9). Thus, the best conditions were as follows: H₂O₂ in Et₂O (1.1 equiv) and catalyst 2a (10 mol%) in toluene at r.t.

We initially thought that the catalyst 2 can coordinate with cyclobutanones through hydrogen-bond formation. To confirm this speculation, ¹³C NMR experiments were performed (Fig. 1). A downfield shift of 0.2 ppm for C=O and an up-field shift of 0.019 and 0.01 ppm for CH₂ and CHPh was observed when complexed with 2a, while 2b showed a rather weak interaction: a downfield shift of 0.076 ppm for C=O and ±0.0 ppm for both CH₂ and CHPh.

Fig. 1 Chemical shift changes (Δδ) observed for the ¹³C NMR signals (125.8 MHz, CDCl₃) of 1a complexed with 2a (30 mol%).

With the optimized reaction conditions in hand, we then investigated the general scope of this chemistry by using various substituted cyclobutanones as substrates (Table 2).

Table 2 2a-catalyzed Baeyer–Villiger oxidation of cyclobutanones 1 with H₂O₂ in Et₂O^a

Entry	Substrate (1)	Time (h)	Product (3)	Yield^b (%)
a Reaction conditions: 1 (0.2 mmol), cat 2a (10 mol%), H2O2 in Et2O (1.1 equiv), in toluene (1.0 mL) at r.t. b Isolated yield. c 3i : 3j = 87 : 13.
1		5		85
2		5		86
3		5		90
4		4		97
5		8		80
6		4		97
7		2		80
8		5		91^c

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As expected, a variety of aryl and alkyl group-substituted cyclobutanones smoothly underwent Baeyer–Villiger oxidation to give the corresponding γ-butyrolactones 3 in high yields (Table 2, entries 1–8). In all cases, the reaction follows the normal mode of migratory aptitude, but the norbornane-fused cyclobutanone 1i gave a regioisomeric mixture of 3i and 3j in a ratio of 87 : 13 (Table 2, entry 8). Unfortunately, we found that the present method was only successful for cyclobutanone substrates, and other cyclic ketones such as cyclopentanones and cyclohexanones gave only the corresponding H₂O₂ adducts (>95% conversion).¹⁶

Finally, to demonstrate the synthetic value of this methodology, we briefly examined the possibility of extending it to asymmetric versions using chiral thiourea catalysts 2e–2h (Table 3).¹⁷ However, no remarkable results were obtained, probably due to the less efficient diastereoselective discrimination at the initial stage of the Criegee intermediate formation or the difficulty of controlling subsequent alkyl-group migration.

Table 3 Extension to asymmetric Baeyer–Villiger oxidation of 3-phenylcyclobutanone (1a) with H₂O₂^a

Entry	Catalyst (2)	Time (h)	Yield (%)^b	ee (%)^c
a 1a (0.2 mmol), H2O2 in Et2O (1.1 equiv), chiral cat 2 (10 mol%) in toluene (1.0 mL) at r.t. b Isolated yield. c Determined by chiral HPLC using Chiralpak AD. Based on our previous data, the absolute configuration of 3a was determined. See Ref. 18.
1	2e	24	83	0
2	2f	36	80	0
3	2g	36	75	0
4	2h	24	73	3 (R)

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Conclusions

In summary, we have developed a new efficient and significantly mild procedure for the Bayer-Villiger oxidation of cyclobutanones using H₂O₂ in Et₂O as the oxidant and 2a as a catalyst. This method is of great value as a metal- and acid-free environment-friendly system.¹⁹ Although the extension of this reaction to asymmetric versions is still at an introductory stage, further studies to realize high levels of chiral induction are now in progress in our laboratory.

Experimental section

General procedure

To a solution of cyclobutanones (0.2 mmol) and catalyst 2a (10 mg, 0.02 mmol) in toluene (1.0 mL) was added H₂O₂ in Et₂O (0.5 M, 0.44 mL, 0.22 mmol) at r.t., and the mixture was stirred until the reaction was complete. The mixture was then diluted by the addition of Et₂O and the excess of H₂O₂ was quenched by addition of aq Na₂S₂O₃. The mixture was extracted with Et₂O, and the extracts were washed with H₂O and brine, dried (MgSO₄), and concentrated. The crude product was purified by silica gel column chromatography (elution with hexane-AcOEt = 4 : 1) to afford the pure γ-lactones 3.

3-Phenyl-γ-butyrolactone (3a)²⁰

Colorless solid, mp 45–46 °C (lit.²⁰ 40–41 °C); R_f 0.25 (hexane-AcOEt = 4 : 1); FTIR (KBr) ν 1765, 1496, 1456, 1422, 1355, 1164, 1011 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 2.66–2.75 (1H, m), 2.91–2.99 (1H, m), 3.76–3.84 (1H, m), 4.26–4.32 (1H, m), 4.66–4.72 (1H, m), 7.23–7.40 (5H, m); ¹³C NMR (125.8 MHz, CDCl₃) δ 35.7, 41.1, 74.0, 126.7 (×2), 127.7, 129.1 (×2), 139.3, 176.4.

3-(4-Methoxyphenyl)-γ-butyrolactone (3b)^7b

Colorless solid, mp 68–70 °C (lit.^7b 92–94 °C); R_f 0.18 (hexane-AcOEt = 4 : 1); FTIR (KBr) ν 1767, 1610, 1584, 1514, 1455, 1257, 1178, 1168, 1032, 1017 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 2.64 (1H, dd, J = 17.5, 9.0 Hz), 2.90 (1H, dd, J = 17.5, 8.5 Hz), 3.74 (1H, quintet, J = 8.5 Hz), 3.81 (3H, s), 4.22 (1H, t, J = 8.5 Hz), 4.64 (1H, t, J = 8.5 Hz), 6.88–6.91 (2H, m), 7.14–7.16 (2H, m); ¹³C NMR (125.8 MHz, CDCl₃) δ 35.9, 40.4, 55.3, 74.3, 114.4 (×2), 127.7 (×2), 131.1, 159.0, 176.5.

3-(4-Chlorophenyl)-γ-butyrolactone (3c)^7b

Colorless solid, mp 51–52 °C (lit.^7b 72–74 °C); R_f 0.20 (hexane-AcOEt = 4 : 1); FTIR (KBr) ν 1775, 1498, 1169, 1092, 1017 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 2.63 (1H, dd, J = 17.5, 8.5 Hz), 2.94, (1H, dd, J = 17.5, 8.5 Hz), 3.77 (1H, quintet, J = 8.0 Hz), 4.24 (1H, dd, J = 9.5, 7.5 Hz), 4.66 (1H, dd, J = 9.0, 7.5 Hz), 7.17 (2H, d, J = 8.5 Hz), 7.33–7.35 (1H, m); ¹³C NMR (125.8 MHz, CDCl₃) δ 35.6, 40.5, 73.8, 128.0 (×2), 129.3 (×2), 133.5, 137.9, 176.0.

3-(4-Fluorophenyl)-γ-butyrolactone (3d)^7b

Colorless solid, mp 63–65 °C (lit.^7b 58–60 °C); R_f 0.15 (hexane-AcOEt = 4 : 1); FTIR (KBr) ν 1770, 1516, 1220, 1166, 1012 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 2.64 (1H, dd, J = 17.5, 9.0 Hz), 2.93 (1H, dd, J = 17.5, 9.0 Hz), 3.79 (1H, quintet, J = 9.0 Hz), 4.24 (1H, dd, J = 9.0, 8.0 Hz), 4.66 (1H, dd, J = 9.0, 8.0 Hz), 7.04–7.08 (2H, m), 7.19–7.22 (2H, m); ¹³C NMR (125.8 MHz, CDCl₃) δ 35.8, 40.4, 74.0, 115.9, 116.1, 128.2, 135.1, 161.1, 163.0, 176.1.

3-(2-Naphthyl)-γ-butyrolactone (3e)^7b

Colorless solid, mp 118–119 °C (lit.^7b 116–117 °C); R_f 0.21 (hexane-AcOEt = 4 : 1); FTIR (KBr) ν 1762, 1160, 1050, 1010 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 2.79 (1H, dd, J = 17.5, 9.0 Hz), 3.00 (1H, dd, J = 17.5, 9.0 Hz), 3.95 (1H, quintet, J = 8.0 Hz), 4.37 (1H, dd, J = 9.5, 8.0 Hz), 4.74 (1H, dd, J = 9.5, 8.0 Hz), 7.33 (1H, dd, J = 8.5, 2.0 Hz), 7.47–7.52 (2H, m), 7.67 (1H, s), 7.80–7.84 (2H, m), 7.86 (1H, d, J = 9.0 Hz); ¹³C NMR (125.8 MHz, CDCl₃) δ 35.7, 41.2, 73.9, 124.4, 125.5, 126.2, 126.6, 127.6(2), 127.6(6), 129.1, 132.6, 133.3, 136.6, 176.4.

4-Methyl-4-phenyl-γ-butyrolactone (3f)^7b

Colorless solid, mp 45–48 °C; R_f 0.31 (hexane-AcOEt = 4 : 1); FTIR (KBr) ν 1776, 1497, 1381, 1281, 1174, 1021 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.53 (3H, s), 2.69 (1H, d, J_AB = 17.0 Hz), 2.93 (1H, d, J_AB = 17.0 Hz), 4.42 (2H, AB q, J_AB = 9.0 Hz), 7.17–7.19 (2H, m), 7.26–7.30 (1H, m), 7.36–7.39 (2H, m); ¹³C NMR (125.8 MHz, CDCl₃) δ 28.1, 42.0, 44.1, 78.4, 125.1 (×2), 127.2, 129.0 (×2), 144.1, 176.3.

4-Dodecyl-γ-butyrolactone (3g)²¹

Colorless solid, mp 36–37 °C (lit.²¹ 38–39 °C); R_f 0.31 (hexane–AcOEt = 4 : 1); FTIR (KBr) ν 1764, 1472, 1464, 1380, 1280, 1187, 1134 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 0.88 (3H, t, J = 7.5 Hz), 1.26–1.39 (22H, m), 1.41–1.49 (1H, m), 1.56–1.63 (1H, m), 1.71–1.78 (1H, m), 1.82–1.90 (1H, m), 2.33 (1H, ddd, J = 12.8, 7.0, 6.5 Hz), 2.54 (2H, dd, J = 9.0, 7.5 Hz), 4.50 (1H, dq, J = 7.0, 6.5 Hz); ¹³C NMR (125.8 MHz, CDCl₃) δ 14.1, 22.7, 25.2, 28.0, 28.9, 29.3(3), 29.3(5), 29.4(5), 29.5(2), 29.6 (×3), 31.9, 35.6, 81.2, 177.5.

Hexahydrobenzofuran-2-one (3h)²²

Colorless oil; R_f 0.22 (hexane-AcOEt = 4 : 1); FTIR (neat) ν 1777, 1174 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 1.22–1.31 (2H, m), 1.42–1.54 (2H, m), 1.61–1.75 (3H, m), 2.06–2.10 (1H, m), 2.25 (1H, dd, J = 17.0, 3.0 Hz), 2.36–2.42 (1H, m), 2.62 (1H, dd, J = 17.0, 7.0 Hz), 4.51 (1H, dt, J = 4.5, 4.0 Hz); ¹³C NMR (125.8 MHz, CDCl₃) δ 19.8, 22.8, 27.1, 27.7, 34.8, 37.5, 79.1, 177.6.

Mixture of hexahydro-4,7-methanobenzofuran-2-one (3i) and hexahydro-4,7-methanoisobenzofuran-1-one (3j)²³

Colorless oil; R_f 0.25 (hexane-AcOEt = 4 : 1); inseparable mixture of 3i : 3j = 87 : 13; FTIR (neat) ν 1772, 1360, 1174, 1026 cm⁻¹.

Major 3i. ¹H NMR (500 MHz, CDCl₃) δ 1.10–1.36 (3H, m), 1.47–1.67 (3H, m), 2.10 (1H, d, J = 3.5 Hz), 2.18 (1H, dd, J = 19.0, 3.5 Hz), 2.35–2.39 (1H, m), 2.48 (1H, d, J = 4.5 Hz), 2.75 (1H, dd, J = 19.0, 11.0 Hz), 4.48 (1H, d, J = 6.5 Hz); ¹³C NMR (125.8 MHz, CDCl₃) δ 23.2, 27.9, 31.4, 33.4, 40.9, 41.7, 41.9, 86.5, 178.2.

Minor 3j. ¹H NMR (500 MHz, CDCl₃) δ 1.10–1.36 (3H, m), 1.47–1.67 (3H, m), 2.27 (1H, d, J = 4.0 Hz), 2.44 (1H, dt, J = 9.5, 4.0 Hz), 2.52 (1H, d, J = 9.0 Hz), 2.67 (1H, d, J = 4.0 Hz), 3.90 (1H, dd, J = 9.0, 4.0 Hz), 4.44 (1H, t, J = 9.0 Hz); ¹³C NMR (125.8 MHz, CDCl₃) δ 27.2, 27.9, 33.4, 40.5, 41.8, 42.6, 48.1, 72.9, 179.6.

Acknowledgements

This work was supported in part by the Yamada Science Foundation, and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan. One of the authors (N. S.) is grateful for a Sasakawa Scientific Research Grant from the Japan Science Society.

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