Divergent synthesis of 5- and 4-(2,1-azaborine) substituted isoxazoles via regioselective [3 + 2] cycloadditions of nitrile oxides and B-ethynyl-1,2-azaborines

Abstract

Herein we report the highly regioselective synthesis of 5- and 4-(2,1-azaborine) substituted isoxazoles via [3 + 2] cycloaddition reactions between nitrile oxides and B-ethynyl-1,2-azaborines. 5-(2,1-Azaborine) substituted isoxazoles are favored in the absence of a catalyst, while 4-(2,1-azaborine) substituted isoxazoles are favored in the presence of a ruthenium catalyst. The reaction exhibits excellent regioselectivity, mild reaction conditions, high functional group tolerance and a broad substrate scope.

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Introduction

Isoxazoles, especially (hetero)aryl-substituted isoxazoles, are highly important structural units found in drugs and bioactive molecules, such as dopamine D4 receptors, anticancer agents, and antirheumatic drugs (Scheme 1A).¹ Therefore, the design and synthesis of structurally diverse isoxazoles^2,3 has stimulated a lot of interest in the synthetic community. On the other hand, 1,2-azaborines have garnered considerable attention as isosteres of benzene rings because their aromatic character is preserved and they possess unique electronic properties. These molecules have found potential use in medicinal chemistry, materials science, and catalysis.⁴ Given that isoxazoles and 1,2-azaborines are two important building blocks in biologically active molecules, we speculate that the merging of isoxazoles with azaborines instead of all-carbon aromatic rings may provide a new opportunity for drug discovery. However, a method to prepare 1,2-azaborine-substituted isoxazoles is extremely rare. To date, the only precedent has been from Molander et al., reporting the synthesis of 4-(2,1-borazaronaphthyl)-isoxazoles via an annulation/aromatization reaction of isoxazolyl trifluoroborate and substituted 2-aminostyrenes under SiCl₄ and Et₃N, but lower yields and a limited substrate scope have hindered the development of this method.⁵ Hence, an efficient approach to synthesize 1,2-azaborine-substituted isoxazoles from readily available substrates would facilitate the intensive investigation of the azaborine-isoxazole building blocks for subsequent utilization.

Scheme 1 Regioselective synthesis of 5- and 4-(2,1-azaborine) substituted isoxazoles.

The [3 + 2] cycloaddition of nitrile oxides with alkynes has been proved to be an efficient method for the construction of isoxazoles.^2,6 In this scenario, we envisioned that the design and synthesis of a class of B-ethynyl-1,2-azaborines (see the ESI† for details) followed by a [3 + 2] cycloaddition with nitrile oxides might achieve the goal of synthesizing structurally diverse 1,2-azaborine-isoxazoles. However, previous [3 + 2] cycloaddition of nitrile oxides with ethynylboronate had exhibited poor regioselectivity;⁷ therefore, how to control the regioselectivity of such [3 + 2] cycloadditions is a big challenge. Herein we report divergent and highly regioselective [3 + 2] cycloadditions of nitrile oxides and B-ethynyl-2,1-azaborine to afford 5- and 4-(2,1-azaborine) substituted isoxazoles, respectively. This method features excellent regioselectivity, mild reaction conditions, high functional group tolerance and a broad substrate scope.

Results and discussion

We first designed and synthesized a series of B-ethynyl-1,2-azaborines (see the ESI† for details).⁸ Then, we began our study by using B-ethynyl-2,1-borazaronaphthalene 1a and oxime chloride 2a as the model substrates (Table 1). To our delight, the 3,5-disubstituted isoxazole product 3a was smoothly obtained exclusively in 74% yield using Et₃N as the base at room temperature (entry 1). The structure of 3a was determined by X-ray crystallographic analysis (CCDC 2202557†). Further base screening indicated that N,N-diisopropylethylamine (DIPEA) was the best one (entries 2–4), providing 5-(2,1-borazaronaphthyl)-isoxazole 3a in 85% isolated yield (entry 2). Inspired by Fokin's Ru-catalyzed [3 + 2] cycloaddition,⁹ we then attempted a regioselective synthesis of 3,4-disubstituted isoxazole product 4a by Ru catalysis. When [Cp*RuCl(cod)] was used, 4-(2,1-borazaronaphthyl)-isoxazole 4a was successfully obtained, albeit with poor regioselectivity (the ratio of 4a to 3a is 3.5). This result encouraged us to further study the optimization of the conditions. Investigation of the solvent showed that dichloromethane (DCM) was optimal compared to tetrahydrofuran (THF) and toluene (entries 6–8), and the ratio of 4a to 3a reached 3.8 (entry 6). The regioselectivity was further improved when the loading of 2a and the base was decreased (entry 9). With the addition of additives, the regioselectivity was significantly improved (entries 10–12). When AgOTf was used as the additive, the best regioselectivity (the ratio of 4a to 3a is 39) was achieved with 72% isolated yield (entry 10). Unfortunately, lower catalyst loadings resulted in poor regioselectivity (entry 13).

Table 1 Reaction optimization^a

Entry	Catalyst	Base	Solvent	Additive	3a/4a ^b	Yield of 3a ^b (%)	Yield of 4a ^b (%)
a Reaction conditions: 1a (1 equiv.), 2a (1.5 equiv.), base (1.5 equiv.) in 1 mL of solvent at rt for 12 h. b Determined by ^1H NMR analysis using CH2Br2 as an internal standard. c Isolated yield. d 1a (1 equiv.), 2a (1.2 equiv.) and base (1.2 equiv.).
1	—	Et3N	DCE	—	—	74	—
2	—	DIPEA	DCE	—	—	88 (85)^c	—
3	—	Na2CO3	DCE	—	—	79	—
4	—	NaHCO3	DCE	—	—	67	—
5	[Cp*RuCl(cod)] (5 mol%)	DIPEA	DCE	—	1 : 3.5	19	67
6	[Cp*RuCl(cod)] (5 mol%)	DIPEA	DCM	—	1 : 3.8	20	76
7	[Cp*RuCl(cod)] (5 mol%)	DIPEA	THF	—	3 : 1	66	22
8	[Cp*RuCl(cod)] (5 mol%)	DIPEA	Toluene	—	1 : 1	40	40
9^d	[Cp*RuCl(cod)] (5 mol%)	DIPEA	DCM	—	1 : 14	5	70
10^d	[Cp*RuCl(cod)] (5 mol%)	DIPEA	DCM	AgOTf (5 mol%)	1 : 39	2	78 (72)^c
11^d	[Cp*RuCl(cod)] (5 mol%)	DIPEA	DCM	AgBF4 (5 mol%)	1 : 35	2	70
12^d	[Cp*RuCl(cod)] (5 mol%)	DIPEA	DCM	AgNTf2 (5 mol%)	1 : 21.3	3	64
13^d	[Cp*RuCl(cod)] (2 mol%)	DIPEA	DCM	AgOTf (2 mol%)	1 : 2	30	60

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With the optimized reaction conditions in hand, we first evaluated the compatibility of this regioselective [3 + 2] cycloaddition for 3,5-disubstituted isoxazoles (Scheme 2). In all the cases studied, only 3,5-disubstituted isomers were obtained under the standard conditions. A variety of both electron-donating (3c–3g) and electron-withdrawing (3o) aryl oxime chlorides could be successfully used in this cycloaddition process, affording the desired 5-(2,1-borazaronaphthyl) isoxazoles in good to excellent yields. And remarkably, the 2,4,6-trimethyl substituent (3g) was compatible, with a moderate yield because of steric hindrance. Substrates bearing boronic ester (3i), halogens (3k–3n), and carboxylic ester (3o) functionalities were tolerated well, affording good to excellent yields, which are of utmost value for further structural modifications. 1-Naphth and 2-naphth oxime chlorides were also amenable to this reaction, providing good yields (3o and 3p). It is noted that alkenyl (3q and 3r) and alkyl (3s) oxime chlorides were good substrates for this transformation as well. To our delight, 1,1-dibromoformaldoxime and ethyl-2-chloro-2-(hydroxyimino)acetate as substrates could also successfully furnish the corresponding products 3t and 3u. Furthermore, various B-ethynyl-2,1-borazaronaphthalenes were investigated for 5-(2,1-borazaronaphthyl) isoxazoles (3v–3af). Substituents at the different (4-, 5-, 6-, 7- and 8-) positions of B-ethynyl-2,1-borazaronaphthalenes had minimal influence on the reactivity (3v–3ad), which also shows that the electronic properties of substituents had little effect on the reaction. Notably, N-substituted B-ethynyl-2,1-borazaronaphthalenes (3ae and 3af) were efficient substrates for this regioselective [3 + 2] cycloaddition. Internal alkynes, such as B-(hex-1-yn-1-yl)-1,2-azaborines, do not react under our standard conditions.

Scheme 2 Substrate scope of regioselective [3 + 2] cycloaddition for 3,5-disubstituted isoxazoles. Reaction conditions: 1 (0.2 mmol, 1 equiv.), 2 (1.5 equiv.), and DIPEA (1.5 equiv.) in 2 mL of DCE at rt for 12 h; isolated yield.

We next examined the substrate scope of this regioselective [3 + 2] cycloaddition for 3,4-disubstituted isoxazoles, and we discovered that the Ru-catalyzed process gave a high level of regioselectivity with trace 3,5-disubstituted regioisomers (Scheme 3). Obviously, the electronic properties and the positions of the substituents on the aromatic ring of the oxime chlorides exerted little effect on the reactivity (4b–4j). The structure of 4i was determined by X-ray crystallographic analysis (CCDC 2202558†). Similarly, alkenyl chlorides were also suitable substrates for this transformation (4k). This Ru-catalyzed reaction worked well with different B-ethynyl-2,1-borazaronaphthalenes, producing the desired 3,4-disubstituted products in good to excellent yields. In addition, subsequent efforts expanded the scope of B-ethynyl-1,2-azaborines to B-ethynyl-9,10-phenanthrene 5, providing the corresponding 3,5-disubstituted product 6 (Scheme 4A) and 3,4-disubstituted product 7 (Scheme 4B) in 50 and 80% yield, respectively.

Scheme 3 Substrate scope of regioselective [3 + 2] cycloaddition for 3,4-disubstituted isoxazoles. Reaction conditions:  1 (0.2 mmol, 1 equiv.), 2 (1.2 equiv.), [Cp*RuCl(cod)] (5 mol%), AgOTf (5 mol%), and DIPEA (1.2 equiv.) in 2 mL of DCM at rt for 12 h; isolated yield.

Scheme 4 Regioselective [3 + 2] cycloaddition with B-ethynyl-9,10-phenanthrene.

This regioselective [3 + 2] cycloaddition could be easily scaled up to 5 mmol under the standard conditions with the desired 5-(2,1-azaborine) substituted isoxazole 3e in 92% yield (Scheme 5A). In addition, product 3e was smoothly iodinated to give 8 with excellent regioselectivity,¹⁰ followed by Sonogashira cross-coupling, Negishi cross-coupling, and reductive coupling¹¹ to obtain structurally diverse products 9, 10, and 11 (Scheme 5B). It was noted that product 3u was easily transformed to the isoxazole amide 12 (Scheme 5C), which is the core structure of many bioactive molecules.¹²

Scheme 5 Scale-up reaction and synthetic transformations. Reaction conditions: (a) (3-MeO)C₆H₄C≡CH (3 equiv.), CuI (5 mol%), PdCl₂(PPh₃) (5 mol%), Et₃N/THF = 2 : 1, rt, 12 h. (b) (3-MeO)C₆H₄ZnBr (1.6 equiv.), Pd₂(dba)₃ (2 mol%), PCy₃ (8 mol%), NMI (1.2 equiv.), THF/NMP = 1 : 1, rt, 16 h. (c) alkyl iodide (1.2 equiv.), NiCl₂·glyme (10 mol%), 4,4′-dimethyl-2,2′-bipyridyl (10 mol%), NaBF₄ (0.5 equiv.), Mn (2 equiv.), 4-ethylpyridine (1 equiv.), cyclohexane/DMA = 3 : 1, 40 °C, 16 h.

Conclusions

In conclusion, we have developed a new class of terminal alkyne reagents, B-ethynyl-1,2-azaborines, and then developed the regioselective [3 + 2] cycloadditions of nitrile oxides with them to access 5- and 4-(2,1-azaborine) substituted isoxazoles. Features such as readily available materials, mild reaction conditions, a broad substrate scope, high functional group tolerance, and excellent regioselectivity illustrate the use of this method.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the National Natural Science Foundation of China (21931013, 22001038), the Natural Science Foundation of Fujian Province (2022J02009, 2022J05016), Fuzhou University (510578), and the Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University is gratefully acknowledged.

References

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2202557 and 2202558. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2qo01421a

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