Mild synthesis of isoxazoline derivatives via an efficient [4 + 1] annulation reaction of transient nitrosoalkenes and sulfur ylides

An efficient [4 + 1] annulation between α-bromooximes and sulfur ylides via in situ generation of nitrosoalkenes under mild basic reaction conditions has been developed, providing an expeditious and scalable approach to synthesize biologically interesting isoxazoline derivatives with good to excellent yields.


Results and discussion
We test our hypothesis with the easily prepared α-bromooxime 1a and the phenylacyl-substituted sulfur ylide 2a as model substrates. The initial experiment was carried out with potassium carbonate (1.2 equiv.) as base in CH 2 Cl 2 at room temperature. Gratifyingly, the model reaction successfully took place and the desired product 3aa was obtained in a good yield of 71% (Table 1, entry 1). Intrigued by this preliminary result, we examined a variety of reaction parameters to improve product yield and the related key results are illustrated in Table 1. Firstly, the effect of the solvent for this transformation was investigated, and it was shown that CHCl 3 was identified as an ideal medium for the generation of 3aa (Table 1, entries 1-5). Once an efficient solvent was found, crucial for the success of this reaction is the choice of a suitable base, which could promote the in situ generation of the nitrosoalkene intermediates. Therefore, a brief screening of the base was conducted ( With the optimal reaction conditions established (Table 1, entry 11), we started to examine the generality of this [4 + 1] annulation reaction (Fig. 2). Firstly, we explored the tolerance of the functional substitution of substrates 1. A broad range of α-bromooximes 1 underwent the annulation reaction to furnish products 3 in  www.nature.com/scientificreports/ 72-99% yields. For instance, α-bromooximes substituted by either an electron-donating or -withdrawing group at the 4-position of benzene ring were well tolerated in this transformation, affording products with 72-94% yields (3aa-3fa). Substituents at the ortho or meta position on the benzene ring also react well (3ga, 90% yield and 3ha, 99% yield). Significantly, α-bromooximes with two CF 3 substituents on the benzene ring also gave a good yield of 3ia. It is also worth noting that heteroaromatic. α-bromooxime, such as furyl-substituted, was successfully applicable to the desired product 3ja. Furthermore, the scope of α-bromooximes could be smoothly extended to alkyl-and ester-substituted α-bromooximes to provide the corresponding products 3ka and 3la in 99% and 89% yield, respectively. Additionally, introduction of tetrahydronaphthalene in the α-bromooximes could proceed efficiently in the reaction to afford the tricyclic product 3ma in high yield and excellent diastereoselectivity.
Of equal significance is the observation that structural modification of the sulfur ylide substrate is possible. As depicted in Fig. 3, substrates with electron-donating groups (4-Me, 4-OMe) and inductive electron-deficient groups (4-Cl, 4-Br, 3-Br) on the benzene ring were proven to react smoothly with 1a, delivering the corresponding products 3ab-3af in generally high to excellent yields. Moreover, naphthol-derived and heteroaromatic acyl sulfur ylides were also applicable as appropriate substrates for this transformation as products 3ag and 3ah were provided in 94% yield and 76% yield, respectively. In addition, the reaction with alkylacyl-substituted sulfur ylide 2j proceeded successfully to afford the desired product in 51% yield.
Based on previous works about enantioselective [4 + 1] annulation reactions of (R)-BINOL derived chiral sulfur ylide 13,16,21 , we applied this strategy to examine the asymmetric version in our process. To our delight, the enantioselective reaction indeed worked and product 3ac was isolated with 47% ee, which could not be achieved with the corresponding precursor: (R)-BINOL derived chiral sulfonium salts due to the harsh reaction condition for the transformation from the related (R)-BINOL derived chiral sulfonium salts to sulfur ylide 15,21 . In an attempt to show the value of 2-isoxazolines as building blocks in synthesis, we tested a follow-up reduction reaction with Sodium borohydride in MeOH at room temperature. The desired product was obtained in 90% yield with 3:2 dr value after 20 min (Fig. 4a). A plausible mechanism for this [4 + 1] annulation reaction based on our experimental results and previous reports 5, [19][20][21] is illustrated in Fig. 4b. First, the nitrosoalkenes are generated in situ via a 1,4-elimination reaction under basic conditions. Then, a Michael addition occurs between the sulfur ylides 2 and the nitroalkenes, followed by an intramolecular O alkylation with loss of dimethylsulfide, delivering the final product 3.

Conclusion
In conclusion, we have reported an facile [4 + 1] annulation reaction between in situ formed nitrosoalkene intermediates and sulfur ylides via a Michael/intramolecular O alkylation sequence. The protocol provides a direct and efficient entry into valuable 2-isoxazoline derivatives in good to excellent yields. The reaction takes place under relatively mild and simple experimental conditions.

Methods
General procedure for the synthesis of isoxazoline derivatives 3: To a solution of sulfur ylide 2 (0.52 mmol) in trichloromethane (4.0 mL), Na 2 CO 3 (0.52 mmol) was added and stirred at room temperature for 15 min. Then α-bromooxime 1 (0.40 mmol) was added at room temperature. The reaction was monitored via TLC (petroleum ether/ether = 10:3). Upon consumption of the starting materials, the reaction mixture was purified by flash chromatography on silica gel (petroleum ether/ether = 10:1) to give the desired product 3.