Selectfluor-mediated highly selective radical dioxygenation of alkenes

Abstract

A practical and simple selectfluor mediated highly selective radical dioxygenation of alkenes was achieved under mild conditions. Various hydroxylamines, such as N-hydroxyphthalimide (NHPI), N-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (NHSI), could react smoothly with alkenes to give β-oxo alcohols and α-oxy ketones in good to moderate yields. The reaction mechanism was primarily investigated and a radical process was proposed.

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Alkenes are the most ubiquitous prochiral functional groups, and direct difunctionalization of alkenes (whereby two functional groups are added to the same double bond) has attracted considerable attention in organic synthesis.¹ Following the pioneering work of Sharpless and co-workers,² metal-free as well as transition-metal-catalyzed difunctionalization of alkenes, such as dioxygenation,³ aminooxygenation, diamination, aminohalogenation, fluoroamination, azidooxygenation and carboamination have been intensively studied.⁴ Among which, the selective and sustainable dioxygenation of alkenes is a valuable synthetic tool for the preparation of 1,2-diols, α-hydroxyketones, and 1,2-dicarbonyl compounds, which have high utility in organic synthesis.⁵ Although there have been significant developments in this area in recent decades, the development of selective dioxygenation reactions remains challenging. For example, current methods suffer from the use of toxic and/or expensive transition metals or require dialkylperoxides as initiators.

N-Hydroxyphthalimide (NHPI) is not only a cheap, nontoxic catalyst for C–H bond functionalization by using an in situ generated phthalimide N-oxyl (PINO) radical, but also a precursor of oxime ethers.⁶ Recently, Punniyamurthy,^7a Woerpel,^7b Liang,^7c and Tang^7d independently reported transition-metal catalysed oxidation of alkenes using molecular oxygen and NHPI. Similarly hydroxamic acid derivatives are also used as radical precursors for dioxygenation of alkenes in the works of Alexanian⁸ and Lei et al.⁹ As part of our continuing interest in employing efficient O-centered radical precursors, such as NHPI, N-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (NHSI) and hydroxamic acid derivatives, for the construction of a C–O bond directly from a C–H bond,¹⁰ we present herein our recent progress in selectfluor-mediated¹¹ highly selective radical dioxygenation of alkenes, in which versatile β-oxo alcohols and α-oxy ketones can be synthesized in a single process (Scheme 1).

Scheme 1 Direct dioxygenation of alkenes using hydroxylamines.

The initial screening studies were carried out using styrene (1a) and N-hydroxybenzotriazole (2a, HOBt) as model substrates. As shown in Table 1, use of FeCl₂ as a catalyst and selectfluor as oxidant at room temperature for 12 h in MeCN produced the desired product 3a in 47% yield together with the corresponding products 4a (entry 1). The solvent was found to have a significant influence on the reaction efficiency. The results showed that DCE is a highly effective solvent, affording the product 3a with the highest isolated yield (Table 1, entry 2–4). Surprisingly, control experiment in the absence of Fe catalyst significantly improved the yield of 3a to 93% yield with high regioselectivity as well as absolute chemoselectivity (Table 1, entry 5). Notably, an example of a direct transformation from 1a and 2a to 3a has not been reported until this work. Neither 3a nor 4a was observed when selectfluor was absent (Table 1, entry 6). Selectfluor was the most effective oxidant in the process. Other oxidants such as tert-butylhydroperoxide (TBHP), 30% H₂O₂ and Na₂S₂O₈ did not perform well (Table 1, entries 7–9). To maximize the yields of 4a, different catalysts and additives were also tested. Instead of FeCl₂, the use of some other iron catalysts such as FeCl₃ and Fe(NO₃)₃ decreased the yields of 4a dramatically (Table 1, entries 10 and 11). Then several additives were screened, such as Mn(OAc)₃ and pyridinium chlorochromate (PCC), and PCC gave a better result (70%; Table 1, entries 12 and 13).

Table 1 Optimization of the reaction conditions^a

Entry	Oxidant	Catalyst	Additive	Solvent	Yield^b (%)
					3a	4a
a Reaction conditions: 1a (0.36 mmol), 2a (0.3 mmol), oxidant (0.3 mmol), catalyst (0.03 mmol), additive (0.3 mmol), solvent (3.0 mL), at room temperature, in air, 12 h.b Yield of the isolated product.c TBHP (70% in water).d H2O2 30% in water.e 3 h.
1	Selectfluor	FeCl2	—	CH3CN	47	36
2	Selectfluor	FeCl2	—	DCE	85	Trace
3	Selectfluor	FeCl2	—	DMF	26	15
4	Selectfluor	FeCl2	—	CH2Cl2	10	Trace
5	Selectfluor	—	—	DCE	93	0
6	—	FeCl2	—	DCE	0	0
7	TBHP^c	—	—	DCE	Trace	Trace
8	H2O2^d	—	—	DCE	Trace	Trace
9	Na2S2O8	—	—	DCE	Trace	Trace
10	Selectfluor	FeCl3	—	CH3CN	41	20
11	Selectfluor	Fe(NO3)3	—	CH3CN	34	27
12	Selectfluor	—	Mn(OAc)3	CH3CN	21	36
13^e	Selectfluor	—	PCC	CH3CN	Trace	70

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With the optimized reaction conditions in hand, the scope of this highly selective method was investigated. As described in Table 2, styrenes 1 with different substituents on the aromatic ring, including electron-donating and electron-withdrawing groups, can be transformed into the corresponding products 3 in moderate to excellent yields (3a–r). Halo-substituted styrenes (1b–e, 1g–i) were tolerated in the dioxygenation reaction, and could be very useful for further transformations. Notably, trans-anethole was amenable to this protocol as well and afforded the desired product 3n in 90% yield. 1,1-Disubstituted alkenes such as 1o–r were also effective to provide 3o–r in 66–90% yields. With the role of HOBt established in the dioxygenation, we sought to explore other hydroxylamines that would effect similar oxidations. The dioxygenation of styrenes using NHPI also produced β-oxo alcohols in 80–93% yields (3s–y). In all cases, the reactions proceeded smoothly at room temperature under very mild reaction conditions, and the desired β-oxo alcohols (3a–y) were consistently obtained in moderate to excellent yields with high regioselectivity and excellent chemoselectivity (Table 3).

Table 2 Selective synthesis of β-oxo alcohols 3^a,b

a Standard reaction conditions: 1 (0.36 mmol), 2 (0.3 mmol), selectfluor (0.3 mmol), DCE (3.0 mL), at room temperature, in air, 12 h.b Yield of the isolated products.

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Table 3 Selective synthesis of α-oxy ketones 4^a,b

a Standard reaction conditions: 1 (0.36 mmol), 2 (0.3 mmol), selectfluor (0.3 mmol), PCC (0.3 mmol), CH₃CN (3.0 mL), at room temperature, in air, 3 h.b Yield of the isolated products.

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The success of dioxygenation of alkenes encouraged us to further explore the scope of this protocol. When PCC was used as additive, a series of α-oxy ketones were obtained in moderate to good yields (Scheme 3). Halosubstituted styrenes were also tolerated in this transformation, forming the corresponding α-oxy ketones 4b–h, 4l, 4o–r and 4u in 38–75% yields. (E)-1,2-Diphenylethene can produce the desired 4w in 45% yield. In addition, starting from NHSI, the corresponding product 4x could be obtained in 54% yields.

Several control experiments were performed to probe the reaction mechanism. When the radical scavenger 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO, 2.0 equiv.) was added to the reaction of styrene 1a under the optimal condition, after 12 h, a TEMPO-captured product 5 was isolated (69%) and only a trace amount of 3a was detected (Scheme 2a). In addition, adding a radical inhibitor 2,6-ditert-butyl-4-methylphenol (BHT) to the reaction system, the formation of the dioxygenation product was also suppressed. The results indicates that a radical addition mechanism was involved in this transformation. Furthermore, the reaction of 1a, 2a and morpholine did not result in the formation of 6 (Scheme 2b). When aniline was introduced into the model reaction mixture, no oxoamination product 7 was observed (Scheme 2c). The above results indicate that the benzylic carbocation was not involved in this dioxygenation process. It is notable that no reaction occurred under N₂ and the substrates 1a and 2a were completely recovered (Scheme 2d). To gain insight in the reaction pathway, the model reaction between 1a and 2a using H₂¹⁸O was conducted and no ¹⁸O-labeled product 3a′ was generated, indicating the oxygen source may be O₂ and not H₂O (Scheme 2e).

Scheme 2 Mechanistic experiments.

Based on the experimental results and literature precedent,^7–10,12 a possible mechanism was proposed in Scheme 3. Initially, selectfluor reacts with NHPI to generate NIPO radical. Then, radical addition of NIPO radical to styrene affords carbon-centered radical A, which would further react quickly with dioxygen and be transformed into peroxyl radical B.¹³ Subsequently, an intermolecular hydrogen abstraction process occurs between NHPI and B, delivering NIPO radical and intermediate C. Finally, the intermediate C can be further transformed into the desired product 3a under acid conditions.¹⁴ When PCC was used as additive, the β-oxo alcohols 3a can be further oxidized to give the α-oxy ketones 4a (see ESI†).

Scheme 3 Proposed mechanism.

In summary, we have reported a novel selectfluor mediated operationally simple method for selective radical dioxygenation of alkenes. Various styrenes and a diverse range of hydroxylamines such as NHPI, HOBt and NHSI were efficient. The mild reaction conditions, broad substrate scope and high chemoselectivity and regioselectivity would make this process attractive. Further investigations to gain a detailed mechanistic understanding of this reaction and apply this strategy in other difunctionalization reactions of alkenes are currently in progress.

Acknowledgements

We gratefully acknowledge the Science & Technology Foundation of Henan Province, the Foundation of Henan Educational Committee (15A150029), the open project of Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis (130028651) and AYNU-KP-A04 for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra16266e

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