O₂-mediated C(sp²)–X bond oxygenation: autoxidative carbon–heteroatom bond formation using activated alkenes as a linkage

Abstract

Autoxidative carbon–heteroatom bond formation using activated alkenes as a linkage is described. Heteroatom (O, S) nucleophiles could be transformed into different kinds of valuable β-keto compounds via an O₂-mediated C(sp²)–X bond oxygenation process, without using any external organic oxidants or metal catalysts.

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As a classic reaction in organic chemistry, transition metal catalyzed C(sp²)–X bond functionalization has made great advances during the past century.¹ Meanwhile, it is also widely recognized that such transformations present a great challenge when it comes to designing simple and safe industrial processes, especially for the pharmaceutical industry, owing to the problem of catalyst residues.² As a result, functionalization of C–X bonds based on metal-free conditions is of enormous importance for chemical synthesis, and has yielded significant progress in the construction of biaryls, with pioneering works reported by Itami,³ Lei,⁴ Kwong,⁴ Shi⁵ and Hayashi⁶ et al., but has rarely seen application in other areas of fine chemical production. Herein, we would like to present our discoveries in this field, illustrating a novel C(sp²)–X bond functionalization process without need for any organic oxidants or catalysts (Scheme 1).

Scheme 1 O₂-mediated oxidative C(sp²)–X bond oxygenation.

On the other hand, seeking operationally simple and environmentally friendly methods to prepare chemicals is commonly acknowledged to contribute significantly to achieving ideal chemical manufacture with low cost and waste levels.⁷ In this vein, chemical conversions mediated solely by dioxygen are emerging as one of the most fascinating synthetic strategies, with extremely attractive advantages in both sustainability and economy.⁸ Despite great efforts, only a few satisfactory results have been reported.^9,10 Recently, the groups of Klussmann and Kürti have made breakthroughs in this area by reporting O₂-mediated autoxidative C(sp³)–C(sp³) and C(sp²)–C(sp³) bond formations, respectively.¹¹ However, multiple autoxidative carbon–heteroatom bond formations based on multicomponent reactions still remain less studied. In particular, methods for the selective construction of C–S bonds are relatively limited, even among transition-metal-catalyzed transformations.¹²

The major challenge for realizing autoxidative coupling may be the strong antioxidation capacity of the substrates or the intermediates generated in situ under metal-free conditions.^9–11 On this basis, the choice of suitable reactants and improving the reduction capacity of intermediates would be the key to achieving autoxidative coupling. According to this view, we chose α-bromostyrene (1a) and benzenesulfinic acid (2a) as substrates to construct multiple carbon–heteroatom bonds for several reasons,¹³ namely: (a) sulfinic acid is a good electron donor, which could be readily transformed to sulfonyl radical via an autoxidation process; (b) the Highest Occupied Molecular Orbital (HOMO) of α-bromostyrene has a high potential energy, which could interact smoothly with the Singly Occupied Molecular Orbital (SOMO) of an electrophilic radical; (c) the bromine atom could stabilize the carbon-centred radical generated by the addition of sulfonyl radical to 1a, thus offering greater opportunity to achieve radical autoxidative coupling.

Based on our hypothesis, the pivotal part of this strategy relies on the selectivity after the initial radical addition step; the oxidation process under metal-free conditions has been less reported, while the atom transfer radical addition process has been well studied.¹⁴ Not surprisingly, undesired products were dominant when we treated 1a directly with 2a in chloroform at 45 °C under air (for details, see Table S1, ESI†). Subsequently, pyridine was added to deactivate benzenesulfinic acid, and the expected β-keto sulfone (3aa) could be isolated in 85% yield. Very recently, aerobic oxysulfonylation of styrenes and alkynes has offered an elegant route to β-keto sulfones, in which transition metals and/or additional oxidants such as K₂S₂O₈ were often used.^10,15 This protocol requires no external organic oxidants or catalysts, which increases its potential practicality for the synthetic community, especially the pharmaceutical industry.² Further screening revealed that 3aa could be isolated in 95% yield with high selectivity by using THF as the optimal solvent in the presence of pyridine and 3 equivalents of 1a under air. Notably, the desired product 3aa was obtained in 61% yield under O₂, while no product was obtained under N₂, indicating that the concentration of O₂ plays a vital role in this process.

The generality of the reaction was next evaluated. As shown in Table 1, sulfinic acids with electronically different para-substituents on the aryl ring reacted smoothly with α-bromostyrene at room temperature, affording the corresponding β-keto sulfones 3aa–3af in good to excellent yields. Br, Cl and F substituents were well tolerated in this reaction (3ad–3af), offering opportunities for further modification. Moreover, the use of a bulky sulfinic acid, 2-naphthylsulfinic acid, did not lower the efficiency of the reaction, giving product 3ag in 77% yield. For α-bromostyrene derivatives, those featuring either electron-rich or electron-poor substituents on the aromatic ring were suitable for this protocol, giving the expected products in good to excellent yields (3ba–3ha). While heteroaryls are usually sensitive to oxidative conditions, 2-(1-bromovinyl)thiophene was also applicable in this transformation, giving the desired product 3ia in 73% yield. Nevertheless, no desired product was detected when aliphatic alkenes, such as 1-bromo-1-butene, were utilized. Encouraged by the promising results, we further applied this protocol to less reactive α-chlorostyrene derivatives. Pleasingly, the reactions between different α-chlorostyrenes and 2a took place smoothly at 60 °C, furnishing the desired β-keto sulfones in good yields. Not only that, but other α-substituted styrene derivatives with good leaving groups were also suitable for this protocol. For example, a substrate with a C–O bond (X = OP(O)(OEt)₂) was found to be suitable for this protocol, affording the expected product 3aa in 87% yield; a substrate with a C–N bond (X = NHAc) was applicable as well, and the product 3aa could be obtained in 89% yield.

Table 1 Aerobic oxysulfonylation of alkenes^a

Product	Yield	Product	Yield
a Unless otherwise specified, all reactions were carried out using 1 (0.20 mmol), 2 (0.60 mmol), and pyridine (0.24 mmol) in THF (4.0 mL) under 1 atm of air (balloon) for 1 h. Isolated yields are reported. Yields are for X = Br unless noted otherwise; yields for X = Cl are shown in parentheses.b 1 (0.20 mmol), 2 (0.80 mmol), and pyridine (0.32 mmol) in MeCN (4.0 mL) at 60 °C for 6 h.c X = OP(O)(OEt)2.d X = NHAc.e MeCN (4.0 mL) at 60 °C for 6 h.f Determined by ^1H NMR analysis using dibromomethane as internal standard.g 5 h.h 2g (0.80 mmol) and pyridine (0.32 mmol) were used, 8 h.i 3 h.j 10 h.k 7 h.
	95% (67^b%) 87^b^,^c% 89^d^,^e%		92^f%
	95%		83%
	77^g%		40%
	77^h%		81^g%
	68%		83%
	91^i%		79^j% (66^b%)
	79%		78^k%
	73^g%		(70^b%)

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Initially, this reaction was presumed to proceed through a radical process, thus radical trapping experiments were firstly carried out, and the results supported this assumption. The model reaction was completely inhibited by using traditional radical scavengers 2,6-di-tert-butyl-4-methylphenol (BHT) or 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (for details, see ESI†).

Subsequently, isotope labeling experiments were performed. To avoid the influence of water in the substrate,¹⁶ α-chlorostyrene (1a′) was used for the reaction with 2a under ¹⁸O₂, giving the product 3aa in 38% yield with 34.4% isotopic purity (Scheme 2, eqn (1)). The moderate labeling ratio was likely due to oxygen-exchange between ¹⁸O-3aa and water in the reagent under these conditions, and an H₂¹⁸O labeling experiment further supported this point (eqn (2)). These results demonstrated that O₂ takes part in this reaction and is transformed into the β-keto sulfone.

Scheme 2 O¹⁸ isotope labeling experiments.

For a reaction involving a gas, a change in the gas pressure often influences the reaction rate remarkably. We next attempted to use operando IR to investigate the influence of O₂ pressure on this reaction. As shown in Fig. 1, the initial rates of the reaction between 1a and 2a increased accordingly with the increasing oxygen pressure, suggesting that the diffusion of dioxygen might play an important role in the reaction rate during this transformation.

Fig. 1 The kinetic profiles of the reaction of 1a (0.2 mmol), 2a (0.6 mmol) and pyridine (0.24 mmol) in CH₂Cl₂ (4.0 mL) at room temperature under different oxygen pressures (balloon), at 1000 rpm (stirring speed).

On the basis of the results described above and previous studies,^9–11 a tentative mechanism for this reaction is depicted in Scheme 3. Initially, benzenesulfinic acid 2a reacts with pyridine to release free sulfinyl anion I, which is further oxidized by dioxygen via single electron transfer (SET), affording an oxygen-centered radical II resonating with sulfonyl radical III. Subsequent addition of sulfonyl radical III to α-bromostyrene (1a) generates a carbon-centered radical IV, which could be easily oxidized by dioxygen and then translated into peroxyl radical V. Then, the generated radical V affords peroxide VI through successive SET and PT (proton transfer) processes with I and pyridinium, respectively. Thereafter, VII is formed through reduction of VI by I,¹⁷ and undergoes rapid intramolecular nucleophilic substitution to furnish the target molecule 3aa.

Scheme 3 Possible mechanism for the formation of 3aa.

According to the mechanism proposed in Scheme 3, other hydrocarbons which could realize single electron transfer (SET) processes with dioxygen through autoxidation would also be suitable for this protocol. To further probe the feasibility of the pathway and broaden the practical application of this method, a representative O-centered radical precursor, N-hydroxy-N-phenylcarbamate (NHPI, 4), was examined (Scheme 4). Delightfully, the desired product 5 was obtained in moderate yield via an autoxidative ketooxygenation process.¹⁸ This is the first report to synthesize 5 through a direct oxidative process.

Scheme 4 Autoxidative ketooxygenation of 1a.

Conclusions

We have developed a novel dehalogenative oxygenation reaction under mild and simple conditions towards a series of valuable β-keto compounds, in which dioxygen serves as the sole promoter without the assistance of external organic oxidants or metal catalysts, making this protocol sustainable and environmentally friendly. These advantages may open the opportunity for its further use in the green synthesis community. Further studies to clearly understand the reaction mechanism and synthetic applications are currently underway.

Acknowledgements

This work was supported by the 973 Program (2012CB725302, 2011CB808600), the National Natural Science Foundation of China (21390400, 21272180, and 21302148), and the Research Fund for the Doctoral Program of Higher Education of China (20120141130002) and the Program for Changjiang. Scholars and Innovative Research Team in University (IRT1030) and the Ministry of Science and Technology of China (2012YQ120060). The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental details, analytical data. See DOI: 10.1039/c4ra17106c

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