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DOI: 10.1039/D2CC02823A (Communication) Chem. Commun., 2022, 58, 9152-9155

tert-Butyl nitrite triggered radical cascade reaction for synthesizing isoxazoles by a one-pot multicomponent strategy†

Leijing Chen a, Zhen Wang a, Hui Liu a, Xinyue Li a and Bin Wang *ab
aKey Laboratory of Xin’an Medicine of the Ministry of Education, Anhui University of Chinese Medicine, Hefei, 230038, P. R. China. E-mail: bw5654@ahtcm.edu.cn; Fax: +86 551-6516-9371
bInstitute of Pharmaceutical Chemistry, Anhui Academy of Chinese Medicine, Hefei, 230038, P. R. China

Received 18th May 2022 , Accepted 14th July 2022

First published on 18th July 2022

Abstract

A metal-free radical cyclization/dehydrogenation cascade of alkenes with aldehydes has been developed for the synthesis of 3,5-disubstituted isoxazoles in a one-pot system. This protocol features excellent functional group tolerance and operational simplicity, and is easily scaled up. The radical process is well supported by TEMPO-adducts and the intermediate β-carbonyl ketoxime.

Creating one-pot, metal-free multistep synthetic routes is an intensive, challenging topic in green chemistry.1 Cascade reactions,2i.e. the combination of multiple successive steps in one-pot, have been described as an efficient approach for the synthesis of complex molecules; advantages such as avoiding tedious and time-consuming preparation of intermediate substrates and high step and/or atom economy meet exactly the green chemistry principles for chemical synthesis.

Isoxazole derivatives are an important class of aromatic five-membered heterocyclic compounds containing an N–O bond;3 isoxazole scaffolds are found in various natural products and synthetic compounds like marketed pharmaceutical drugs, synthetic precursors and functional materials.4 The typical strategies for the synthesis of diverse isoxazoles involve 1,3-dipolar cycloaddition of nitrile oxides5 (Scheme 1a) and alkynes and cycloisomerization of alkynyl ketoxime compounds (Scheme 1b).6 Despite the undisputable progress achieved, these protocols contain certain limitations, such as the presence of pre-functionalized substrates, low yields and regioselectivities, the use of expensive or toxic metals as catalysts, and the low step and/or atom economy. In 1888, Claisen reported that the condensation/cyclization reaction of 1,3-dicarbonyl compounds with hydroxylamine is a preferable alternative route (Scheme 1c); however, the use of the harmful compound hydroxylamine greatly limits its application.7 A simple access to isoxazoles from commercially available reagents in a one-pot cascade approach under metal-free conditions is therefore in high demand. Gasparrini and co-workers reported in 1993 the gold-catalyzed one-pot synthesis of 3,5-disubstituted isoxazoles from terminal alkynes and nitric acid, demonstrating its potential for use in the synthesis of complex molecules.8a The synthesis of 3,5-disubstituted isoxazoles from aldehydes, hydroxylamine and alkyne via [3+2] cycloaddition in one-pot was subsequently reported.8b Recently, several copper-catalyzed multicomponent syntheses of substituted isoxazoles via different intermediates including α-alkynyl ketoxime,8cin situ generated nitrile oxides,8d and nitrostyrolene8e were documented. More recently, Jiang and co-workers developed a palladium-catalyzed cascade in PEG-400 for the synthesis of 4-carboxamide isoxazoles with high atom and step economy.8f One-pot multicomponent reactions can be an attractive and viable alternative to traditional multistep synthesis, as the tandem conversions in multicomponent systems render the synthesis of complex heterocyclic compounds from simple starting materials easy.9


image file: d2cc02823a-s1.tif
Scheme 1 Synthesis methods of isoxazoles.

Alkyl nitrites and more specifically tert-butyl nitrite (TBN) have been reported to present excellent activity in the di-functionalization of alkynes or alkenes, and have been often employed for the introduction of an N–O bond into more complex molecules.8c,8d In recent years, the role of water as an inexpensive reagent and medium in chemical reactions has been widely explored, as highlighted by the key work of Breslow and co-workers and the research team of Sharpless.10 In this line of thought and based on previously successful practice of alkene functionalization in a mixture of TBN and H2O to generate α-sulfonylethanone oximes,11 we presumed that isoxazoles would be obtained by a four-component reaction containing alkene, aldehydes, TBN and H2O. By replacing the sulfonyl radical with a benzoyl radical to attack the C[double bond, length as m-dash]C double bond of the alkene and with the subsequent help of an N[double bond, length as m-dash]O radical, the β-carbonyl ketoxime was formed. Further cyclization/dehydrogenation led to the construction of the targeted isoxazoles (Scheme 1d). We herein describe a novel and efficient multicomponent cascade reaction that involves sequential acylation/oximation/annulation processes in the presence of alkenes, aldehydes, TBN and H2O, providing access to diversely disubstituted isoxazoles in one-pot. This strategy features H2O as a rare oxygen source of the isoxazole ring,12 commercially available substrates and the construction of diverse new bonds in a single pot, which is distinct from already reported studies.

We initiated our studies by using styrene 1a, 4-bromobenzaldehyde 2d, and TBN as model substrates, which reacted in 0.5 mL H2O at 100 °C for 8 hours, and subsequently successfully obtained the envisioned isoxazole 4ad in a surprising 5% yield (Table S1, entry 1, ESI†). Solvent optimization revealed that a solvent mixture of DMF and H2O was the most effective reaction medium (entries 2–4). It is worth noting that the performance was remarkably improved when persulfates were employed, indicating that oxidant Na2S2O8 is of vital importance to provide the compound 4ad (entries 5 and 6). Moreover, temperature adjustment failed to give the desired 4ad in higher yield (entries 7 and 8). Surprisingly, the reaction performance was promoted when a weak acid AcOH was used (entry 9). Prolonging the reaction time to 12 h increased the yield of 4ad to 62%, while when reducing the reaction time to 5 h, the reaction was somewhat sluggish (entries 10 and 11 and see the ESI† for details). Next, the dosages of 1a, 2d, and TBN were carefully optimized. When their molar ratio was 3[thin space (1/6-em)]:[thin space (1/6-em)]1[thin space (1/6-em)]:[thin space (1/6-em)]3, the highest 71% yield of 4ad was obtained (entries 12 and 13). The conditions leading to this result were selected as the optimal ones.

With the optimized experimental conditions in hand, we examined the compatibility of this methodology by employing electronically differentiated aldehydes. As shown in Table 1, the aldehydes bearing electron-withdrawing groups (R = CF3, CN, F, Br, Cl, and NO2) on the phenyl ring favored the reaction more than those bearing electron-donating groups (R = CH3, Et, C(CH3)3, OH, and OCH3), generating the corresponding products in moderate to good yields (Table 1, entries 1–16).

Table 1 Scope of aldehydes and styrenesab

image file: d2cc02823a-u1.tif
Entry R1 R2 Product Yieldb [%]
a Reaction conditions: 1 (0.75 mmol), 2 (0.25 mmol), 3 (0.75 mmol), AcOH (0.625 mmol), Na2S2O8 (0.0625 mmol), Na2SO4 (0.5 mmol), DMF/H2O (v/v = 4[thin space (1/6-em)]:[thin space (1/6-em)]1, 0.5 mL), 100 °C, 12 h, air. b Isolated yields based on 2 after chromatography.
1 Ph Ph 4aa 61
2 Ph 4-FC6H4 4ab 65
3 Ph 4-ClC6H4 4ac 71
4 Ph 4-BrC6H4 4ad 68
5 Ph 3-BrC6H4 4ae 73
6 Ph 2-BrC6H4 4af 64
7 Ph 4-CNC6H4 4ag 85
8 Ph 4-CF3C6H4 4ah 83
9 Ph 3-CF3C6H4 4ai 72
10 Ph 2-CF3C6H4 4aj 60
11 Ph 4-CH3C6H4 4ak 53
12 Ph 4-C2H5C6H4 4al 51
13 Ph 4-OCH3C6H4 4am 45
14 Ph 4-C4H9C6H4 4an 42
15 Ph 2-Naphth 4ao 45
16 Ph 2-OH, 5-NO2C6H4 4ap 46
17 Ph 4-Pyridine 4arq n.d
18 Ph (CH2)4CH3 4ar n.d
19 4-CH3C6H4 Ph 4ba 65
20 4-C4H9C6H4 Ph 4ca 69
21 4-OCH3C6H4 Ph 4da 45
22 4-FC6H4 Ph 4ea 52
23 4-BrC6H4 Ph 4fa 51
24 4-ClC6H4 Ph 4ga 51
25 3-ClC6H4 Ph 4ha 41
26 4-NO2C6H4 Ph 4ia 46
27 4-CH3C6H4 4-BrC6H4 4bd 70
28 4-C4H9C6H4 4-BrC6H4 4cg 73
29 4-OCH3C6H4 4-BrC6H4 4dd 48
30 4-FC6H4 4-BrC6H4 4ed 60
21 4-BrC6H4 4-BrC6H4 4fd 57
32 4-ClC6H4 4-BrC6H4 4gd 56
33 3-ClC6H4 4-BrC6H4 4hd 50
34 4-NO2C6H4 4-CF3C6H4 4ih 52

The sterically more hindered factor had no significant influence on the reaction. For instance, the benzaldehyde with the ortho-substitution of a bromo or trifluoromethyl group afforded 4af or 4aj in slightly lower yield than the para-substitution corresponding species 4ad or 4ah. The aliphatic and heterocyclic substrates 4aq and 4ar resulted in reaction failure (Table 1, entries 17 and 18). As expected, 2-naphthalene substrate 2o was transformed into the desired product 4ao in a moderate yield. Subsequently, we examined the reaction performance by employing styrenes featuring various substituent groups. The electron-withdrawing groups (R = F, Br, Cl, and NO2) on the phenyl ring were minorly unfavourable for the synthesis of the corresponding isoxazoles compared to species with electron-donating groups (R = CH3 and C(CH3)3) (Table 1, entries 19–26, 27–33, and 34). The only exception was the electron-donating OCH3 substituent at position 4 of the phenyl ring that afforded 4da and 4dd in relatively lower yield. The unexpected result can be clarified by the fact that the substrate styrene in our method could convert to both the corresponding major product isoxazole and by-product benzonitrile.13 When 4-methoxystyrene was delivered to the corresponding reaction system, the by-product 4-methoxy benzonitrile 4′ was obtained in an unexpectedly higher percentage (see Fig. 1 and the ESI† for details), hence largely consuming the amount of both 4-methoxystyrene and TBN. As a result, the yield of corresponding major products isoxazole 4da and 4dd was largely decreased. The configuration of product 4ih was confirmed by X-ray crystal diffraction (Scheme 2).14


image file: d2cc02823a-f1.tif
Fig. 1 Synthesis of by-product 4′ and compound 5.

image file: d2cc02823a-s2.tif
Scheme 2 Crystal structure of compound 4ih.

To investigate the potential practicability of the TBN/Na2S2O8-mediated cascade reaction, a scale-up operation (4 mmol scale) was performed (see ESI†). As expected, the targeted product 4ad was obtained in almost the same yield under standard conditions. Additionally, the reaction of product 4ad and styrene under a standard palladium coupling protocol was investigated,15 and successfully provided the product 5 in good yield, highlighting the potential for the pharmaceutical industry (see Fig. 1).

To reveal the possible reaction mechanism, several experiments were carefully designed and performed, and subsequently monitored by 1H NMR, HRMS and GC-MS techniques (see Fig. 2 and the ESI† for details). As shown in Fig. 2a, isoxazole 4ad was obtained in good yield under standard conditions. When adding the radical inhibitor TEMPO into the reaction system starting from 0.25 equivalent, the yield of 4ad decreased markedly and was less than 1% when 2.0 equivalent TEMPO was added. Meanwhile, two adducts containing TEMPO 7a and 7b were successfully captured by the HRMS technique (Fig. 2b and ESI†). These experimental results suggest that our reaction system possibly involves a radical process. Intermolecular competition experiments performed by employing various substituted benzaldehydes under standard conditions showed that the reaction performance was more predominant when using electron-deficient benzaldehydes (Fig. 2c). A positive Hammett value of ρ = 0.69 indicated that a negative charge was formed in the product-determining step (Fig. 2d).16 Next, the experiments of isotope labelling were performed (Fig. 2e and ESI†). We conducted the D/H-exchange by adventitious water or DMF, and the corresponding 1H NMR results indicated that the hydrogen atom at position 4 of the isoxazole skeleton mainly came from the solvent water rather than DMF while 4ah was transformed into deuterated 4ah in 95% yield in D2O at 100 °C for 4 h. To illustrate with certainty whether the oxygen atom in the formed isoxazole skeleton was from the TBN moiety, which readily produced oxygen-containing radical N[double bond, length as m-dash]O, an 18O-labeled experiment was carried out and further studied by GC-MS analysis. To our surprise, the oxygen atom in the 4ah moiety was mainly from water. These results suggest that (i) the formation of the targeted isoxazole skeleton is water-assisted; (ii) H/D exchange may occur between the product isoxazole and D2O; (iii) the acidity of 4ah is responsible for the construction of deuterated 4ah. Based on related literature and previous studies,7b,116a and 6b were carefully selected, and subsequently delivered into the reaction system (Fig. 2f). When we used 6a as a substrate, 4aa was not detected. However, as expected, using 6b as a substrate, the compound 4aa was obtained in 91% yield, indicating that 4aa was formed through the intermediate 6b.


image file: d2cc02823a-f2.tif
Fig. 2 Possible mechanistic analysis. (a) The effect of different amounts of TEMPO on the reaction of 1a and 2d to generate 4ad; (b) investigating the TEMPO adducts in the reaction of 1a and 2d to generate 4ad by HRMS; (c) competition reaction of equal 2h and 2a, and equal 2h and 2k respectively with olefin 1a; (d) competition reaction of equal 2b/2a, 2d/2a, 2k/2a, and 2m/2a with olefin 1a, respectively; (e) isotope experiments: olefin 1a reacted with 2h in different solvents to obtain the product 4ah and isotopically labelled 4ah; the 4ah, 4ah bearing a deuterium atom, and 4ah bearing an oxygen-18 correspond to the m/z ratio of 289, 290, and 291, respectively; (1) using H2O as solvent; (2) replacing H2O with D2O; (3) replacing DMF with DMF-d7; (4) replacing H2O with H2O18; (f) experiments for yielding 4aa by intermediate 6a and 6b.

According to the aforementioned mechanistic understanding and published literature,7b,12,17 we infer a plausible reaction pathway as depicted in Scheme 3. Initially, the homolysis of TBN occurs under high temperature providing two radicals I and II,11 which are captured by TEMPO. The reaction is triggered by the formation of acyl radical A,17b generated in situ via the reaction of aldehyde 2 with the help of Na2S2O8 and radical I. Subsequently, radical A attacks the double bond of alkenes to form a carbon-central radical B. With the help of NO radical II produced from TBN and/or HNO2,8c,8d,12 compound C is obtained, and subsequently a tautomerization process occurs, rapidly forming the essential intermediate β-carbonyl ketoxime.18 When an additive acetic acid is employed,19 the dehydration process of compound D is highly promoted, yielding compound E, followed by dehydrogenation to yield the desired isoxazoles 4.


image file: d2cc02823a-s3.tif
Scheme 3 Possible mechanism.

In conclusion, we developed a new TBN/Na2S2O8-mediated cascade for the construction of disubstituted isoxazoles from commercially available alkenes, aldehydes, TBN and H2O under metal-free and aqueous conditions. The four-component one-pot synthesis features (i) a broad substrate scope (up to 33 examples); (ii) excellent functional group tolerance; (iii) gram-scale synthesis; (iv) operational simplicity; (v) without pre-functionalized substrates and (vi) the construction of diverse new bonds in a single pot. The protocol established provides attractive and viable alternatives to existing approaches for the synthesis of disubstituted isoxazoles.

We are grateful to the Natural Science Foundation of Anhui province (2008085MH271) and the Talent Project (2019rczd002). This work was supported by the Overseas Study Project (gxgwfx2020039).

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2123693. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2cc02823a
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