Manganese-catalysed hydroperoxidation of carbon–carbon double bonds using molecular oxygen present in air and hydroxylamine under ambient conditions

Abstract

A highly efficient manganese-catalysed hydroperoxidation of carbon–carbon double bonds of enynes as well as styrene derivatives using N-hydroxyphthalimide, N-hydroxybenzotriazole or N-hydroxysuccinimide was developed. This reaction proceeded at room temperature through the direct incorporation of molecular oxygen present in air. The required catalytic loading of manganese(III) acetylacetonate is extremely low (generally 0.02–0.5 mol%, and a minimum of 0.001 mol%).

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Introduction

Developing a new methodology for transition metal-catalysed oxidation reactions has been extensively studied in the recent decade, and molecular oxygen is essentially recognised as an ideal oxidant.¹ Despite developing several elegant oxidation processes involving molecular oxygen as a sole oxidant,² methodologies for directly incorporating molecular oxygen into organic substrates remain a major challenge in synthetic chemistry. The incorporation of an oxygen atom into substrates, such as C–H oxidation and epoxidation, has been observed in several biological processes,³ and aerobic epoxidation is used as an elegant strategy in organic chemistry.⁴ Recently, several aerobic difunctionalisations of carbon–carbon double bonds, such as oxyazidation,⁵ oxytrifluoromethylation,⁶ oxysulfonylation,⁷ oxysulfoxidation,⁸ oxysulfurization⁹ and oxyphosphorylation,¹⁰ have been demonstrated. In addition, metal-free or transition metal-catalysed aerobic dioxygenation^11–13 of carbon–carbon double bonds using hydroxylamine derivatives, such as N-hydroxyphthalimide (NHPI), N-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (NHS) and hydroxamic acids, has witnessed significant progress (Scheme 1). The transition metal-catalysed oxidative N-hydroxypthalimidation using molecular oxygen was originally reported by Ozaki et al.^13a in 1989 as a side reaction occurring during the manganese(III) tetraphenylporphyrin chloride-catalysed epoxidation of carbon–carbon double bonds present in styrene, 2-norbornene or indene, which resulted in a mixture of β-keto-N-alkoxyphthalimides and β-hydroxy-N-alkoxyphthalimides in moderate yield. Recently, Punniyamurthy et al.^13b demonstrated that 10 mol% Cu(OAc)₂·H₂O-catalysed direct dioxygenation of carbon–carbon double bonds in styrene derivatives using NHPI and molecular oxygen in air at room temperature yields β-keto-N-alkoxyphthalimides in good yield (Scheme 1). Woerpel et al.^13c suggested that in addition to NHPI, HOBt should be added to a carbon–carbon double bond in styrene derivatives or conjugated enynes in the presence of 5–20 mol% [Cu(MeCN)₄]ClO₄ under a pure O₂ atmosphere. Furthermore, Lei et al.^13d,e reported that using 10 mol% of CuCl or Co(OAc)₂·4H₂O promoted the oxidative addition of hydroxamic acids to styrene derivatives under a pure O₂ atmosphere to selectively yield β-keto or β-hydroxy compounds. Xia's group^13f reported that the combination of 10 mol% CuBr₂ and 4.0 equivalents of di-tert-butyl peroxide worked as a catalyst for the direct dioxygenation of styrene derivatives in air to afford β-keto-N-alkoxyphthalimides in moderate to good yields. On the other hand, Tang et al.^13g have demonstrated that 10 mol% of FeCl₃ is an effective catalyst for the oxidative N-hydroxypthalimidation of styrene derivatives to afford β-keto-N-alkoxyphthalimides under a pure O₂ atmosphere. In the methodologies described above involving the direct incorporation of an oxygen atom into a carbon–carbon double bond using N-hydroxylamine derivatives, the existence of metal hydroperoxide 2 is suggested as an intermediate. However, the corresponding hydroperoxide could not be isolated in acceptable yields due to the instability of the intermediate metal hydroperoxide 2 in metal-catalysed dioxygenation reactions. More recently, Woerpel et al.^13h reported a 20 mol% of [Cu(MeCN)₄]ClO₄-catalysed hydroperoxidation of conjugated enynes using NHPI or HOBt under a pure O₂ atmosphere to obtain propargyl hydroperoxides in good yields by lowering the reaction temperature to 0 °C. Furthermore, Punniyamurthy et al.¹³ⁱ also described the hydroperoxidation of styrene derivatives catalysed by 20 mol% Fe(NO₃)₃·9H₂O. While these pioneering research efforts provided new methods for incorporating oxygen atom(s) derived from gaseous dioxygen into organic substrates, several challenges still remain. In particular, developing highly active and robust catalysts capable of directly incorporating molecular oxygen present in air into organic substrates without cooling or heating conditions is in high demand.

Scheme 1 Aerobic hydroperoxidation of a carbon–carbon double bond with N-hydroxyphthalimide.

Herein, we report a highly efficient manganese-catalysed hydroperoxidation of a carbon–carbon double bond using hydroxylamine and molecular oxygen in air (open flask) under ambient conditions.

Results and discussion

The reaction between 4-tert-butylstyrene 1a (1.0 equiv.) and NHPI (1.0 equiv.) in the presence of a metal complex in air at room temperature was initially investigated (Table 1). Using 1.0 mol% of Mn(acac)₃ in MeCN as a catalyst for 5 h gave a mixture of hydroperoxide 5a and β-keto-N-alkoxyphthalimide 3a in good yield (61%, 5a : 3a = 4 : 1, entry 1). Decreasing the amount of Mn(acac)₃ to 0.02 mol% improved the yield and the product ratio of hydroperoxide 5a and ketone 3a (92%, 5a : 3a = >20 : 1, entry 3). We interpreted this result as being indicative of the fact that further decomposition of hydroperoxide 5a to ketone 3a and other side products by a manganese complex was effectively suppressed due to reduced catalyst loading. To test the scalability of the hydroperoxidation reaction, a gram-scale reaction was performed at 0.02 mol% catalyst loading in air (entry 4). The reaction proceeded in >99% yield at room temperature. Although a further reduction of catalyst loading to 0.001 mol% required a longer reaction time in air at room temperature, the desired hydroperoxide 5a was obtained in high yield with an excellent product ratio (84% yield, 5a : 3a = >20 : 1, entry 6). A series of solvents were screened, and it was observed that MeCN was essential for this reaction, while EtCN, CH₂Cl₂, benzene, THF, DMF, DMSO and MeOH afforded poor yields (entries 7–13).¹⁴

Table 1 Optimisation of manganese-catalysed aerobic hydroperoxidation of 4-tert-butylstyrene^a

Entry	Mn(acac)3 (mol%)	Solvent	Time (h)	Yield^b (%)	(5a : 3a)^c
a Reaction conditions: 1a (0.50 mmol), metal salt (0.001–1.0 mol%), O2 in air at room temperature. b Isolated yield. c The ratio was determined by ^1H NMR analysis of the crude sample. d The reaction was conducted at the 1.04 g (6.50 mmol) scale of 1a.
1	1.0	MeCN	5	61	(4 : 1)
2	0.1	MeCN	16	90	(4 : 1)
3	0.02	MeCN	24	92	(>20 : 1)
4^d	0.02	MeCN	72	>99	(>20 : 1)
5	0.01	MeCN	31	83	(>20 : 1)
6	0.001	MeCN	46	84	(>20 : 1)
7	0.01	EtCN	24	5	(17 : 1)
8	0.01	CH2Cl2	24	7	(>20 : 1)
9	0.01	Benzene	24	Trace	—
10	0.01	THF	24	11	(>20 : 1)
11	0.01	DMF	24	Trace	—
12	0.01	DMSO	24	Trace	—
13	0.01	MeOH	24	Trace	—
14	none	MeCN	24	No reaction

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Using these optimal reaction conditions, potential substrates for this manganese-catalysed aerobic hydroperoxidation reaction were evaluated (Table 2). The reaction with styrene 1b gave hydroperoxide 5b in 64% yield. Styrenes substituted with a methyl group at the 4- or 3-position 1c and 1d were transformed into the corresponding hydroperoxides 5c and 5d, respectively, in excellent yield without the oxidation of the methyl group at the benzylic position. The reaction of the styrene derivatives bearing a 4-fluoro, 4-chloro or 4-bromo moiety on the aromatic ring produced the corresponding hydroperoxide 5e, 5f or 5g, respectively, in high yield (88%–94%). The electron-rich styrene derivative 1h with a methoxy group at the 4-position was effective under these oxidation conditions to provide hydroperoxide 5h in good yield (60%). Sterically hindered α-methylstyrene 1i could be efficiently oxidised in >99% yield. In addition, β-substituted styrenes 1j and 1k were transformed into the corresponding hydroperoxides 5j and 5k, respectively, in good yields with moderate diastereoselectivity.

Table 2 Styrene derivatives as potential substrates for aerobic hydroperoxidation styrene derivatives

a Mn(acac)₃ (0.02 mol%). b Mn(acac)₃ (0.2 mol%). c Mn(acac)₃ (0.5 mol%). d The diastereomeric ratio (dr) was determined by ¹H-NMR analysis of the crude sample.

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Furthermore, we investigated the hydroperoxidation of the conjugated enyne and dienes (Scheme 2).¹⁵ Treatment of enyne 6 with 0.02 mol% of Mn(acac)₃ in air at room temperature for 3 h offered hydroperoxide 7 in 81% yield, while the carbon–carbon triple bond remained intact under these oxidation conditions. The conjugated dienes 8a and 8b were also viable substrates. The dioxygenation of 2,5-dimethyl-2,4-hexadiene 8a in the presence of 0.2 mol% of Mn(acac)₃ provided the 1,4-dioxygenated product 9a in 79% yield as a single E-isomer. On the other hand, when 2,3-dimethyl-1,3-butadiene 8b was used as a substrate, the 1,2-dioxygenated product 9b and the 1,4-dioxygenated product 9c were obtained in 61% and 24% yield (as a geometric mixture of 3 : 1), respectively.

Scheme 2 Aerobic hydroperoxidation of the conjugated enyne and dienes.

Subsequently, we evaluated the incorporation of molecular oxygen into a carbon–carbon double bond using HOBt or NHS instead of NHPI (Tables 3 and 4). The oxidative addition of HOBt to styrene 1b in the presence of 0.2 mol% of Mn(acac)₃ occurred at room temperature in air to give hydroperoxide 10b in excellent yield (90%). On the other hand, the reaction of 4-substituted styrene derivatives, such as 4-tert-butylstyrene 1a, resulted in moderate yield (52%). Both α- and β-alkyl-substituted styrene derivatives 1i and 1j performed well as substrates providing the corresponding hydroperoxides 10i and 10j in 96% and 89% yield (anti : syn = 5 : 1), respectively. In addition, the oxidative addition of NHS to styrene derivatives, such as 1a, 1b, 1i and 1j, led to similar results yielding the corresponding hydroperoxides 11a, 11b, 11i and 11j, respectively.

Table 3 Aerobic hydroperoxidation of styrene derivatives with HOBt^a

a Styrene derivatives 1a, b, i and j (0.50 mmol). b The diastereomeric ratio (dr) was determined by ¹H-NMR analysis of the crude sample.

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Table 4 Aerobic hydroperoxidation of styrene derivatives with NHS^a

a Styrene derivatives 1a, b, i and j (0.50 mmol). b The diastereomeric ratio (dr) was determined by ¹H-NMR analysis of the crude sample.

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Moreover, the manganese-catalysed oxidative addition of HOBt or NHS to the conjugated enyne 6 and diene 8a was also examined (Scheme 3). The dioxygenation of both enyne 6 and diene 8a using HOBt in air proceeded at low catalyst loading to afford hydroperoxides 12 and 14, respectively, in high yields compared to the reaction using NHS.

Scheme 3 Aerobic hydroperoxidation of conjugated enyne 6 and diene 8a.

Conclusions

To summarise our study, we have developed a manganese-catalysed aerobic hydroperoxidation method for conjugated alkenes. Notably, the unprecedentedly low catalyst loading of Mn(acac)₃ promoted the oxidative addition of NHPI, HOBt or NHS to conjugated alkenes through the direct incorporation of molecular oxygen from air (pure oxygen is not required) without any other additives. Considering the desirable features, such as the simplicity of operation, inexpensive catalysts, a wide range of substrates and mild reaction conditions, this novel reaction provides an attractive synthetic approach to produce hydroperoxides. The investigation of the reaction mechanism involved in the manganese-catalysed aerobic hydroperoxidation reactions is currently ongoing in our laboratory.

Experimental

Representative procedure for manganese-catalyzed hydroperoxidation with NHPI

To a stirred solution of 4-tert-butylstyrene (80.1 mg, 0.500 mmol) and N-hydroxyphthalimide (81.6 mg, 0.500 mmol) in MeCN (0.9 mL) at room temperature was added a solution of Mn(acac)₃ in MeCN (100 μL, 0.10 μmol, 1.0 mM in MeCN) in air (open flask). The solution was stirred for 24 h at room temperature and quenched with saturated aqueous NaCl solution (0.5 mL). The resulting mixture was extracted with ethyl acetate (3 × 1.0 mL). The combined organic phases were washed with brine (1.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (silica gel, hexane : EtOAc = 3 : 1) to afford 5a (163 mg, 0.459 mmol, 92%).

Gram-scale synthesis

To a stirred solution of 4-tert-butylstyrene (1.04 g, 6.50 mmol) and N-hydroxyphthalimide (1.06 g, 6.50 mmol) in MeCN (13.0 mL) at room temperature was added a solution of Mn(acac)₃ in MeCN (1.0 mL, 1.3 μmol, 1.3 mM in MeCN) in air (open flask). The solution was stirred for 72 h at room temperature and quenched with saturated aqueous NaCl solution (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 14 mL). The combined organic phases were washed with brine (14 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (silica gel, hexane : EtOAc = 3 : 1) to afford 5a (2.31 g, 6.50 mmol, >99% yield).

2-(2-(4-(tert-Butyl)phenyl)-2-hydroperoxyethoxy)isoindoline-1,3-dione (5a)

Colorless oil; ¹H NMR (400 MHz, CDCl₃) δ: 9.37 (OOH), 7.89–7.84 (m, 2H, Ar–H), 7.80–7.75 (m, 2H, Ar–H), 7.39 (d, J = 8.8 Hz, 2H, Ar–H), 7.33 (d, J = 8.8 Hz, 2H, Ar–H), 5.40 (dd, J = 7.7, 3.8 Hz, 1H, CHOOH), 4.55 (dd, J = 11.6, 3.8 Hz, 1H, CH(OOH)CH₂O), 4.50 (dd, J = 11.6, 7.7 Hz, 1H, CH(OOH)CH₂O), 1.30 (s, 9H, Ar–C₄H₉); ¹³C NMR (100 MHz, CDCl₃) δ: 163.8, 152.0, 134.7, 132.6, 128.7, 126.9, 125.7, 123.8, 85.3, 78.9, 34.6, 31.2; IR (neat) 3402, 3098, 3062, 3032, 2962, 1789, 1730, 1466, 1375, 1186, 1132, 1081, 1018, 997, 877, 701 cm⁻¹; HRMS (FAB, NBA) m/z calcd for C₂₀H₂₁NNaO₅ [M + Na]⁺ 378.1317, found 378.1319.

Acknowledgements

This work was partially supported by a Grant-in-Aid for Young Scientists B (15K18837) from JSPS and a Kitasato University Research Grant for Young Researchers. We thank Dr K. Nagai and Ms M. Sato of Kitasato University for instrumental analyses.

Notes and references

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14. The solvent effects suggest that the ligation of less hindered acetonitrile to a manganese complex plays an important role in the progress of this hydroperoxidation reaction of the carbon–carbon double bond.
15. The oxidation of the conjugated enyne and dienes catalysed by 20 mol% of [Cu(MeCN)₄]ClO₄ under a pure O₂ atmosphere was reported by Woerpel et al., see ref 13c and h.

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Footnotes

† Celebrating the 75^th Birthday of Professor Barry Trost.

‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00318d

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