Categories: Synthesis of N-Heterocycles, Synthesis of O-Heterocycles >
Synthesis of 2-isoxazolines
tert-Butyl hypoiodite (t-BuOI), generated in situ from t-BuOCl and NaI, is a powerful reagent for the cycloaddition of oximes to alkenes or alkynes, leading to various isoxazolines or isoxazoles under mild conditions.
S. Minakata, S. Okumura, T. Nagamachi, Y. Takeda, Org. Lett., 2011, 13, 2966-2969.
A hypervalent iodine species, which is formed in situ in the presence of oxone as terminal oxidant, catalyzes the oxidation of aldoximes to generate nitrile oxides. A subsequent reaction with alkenes gives the corresponding isoxazolines in good yields, whereas the reaction with alkynes gives the corresponding isoxazoles in moderate yields.
A. Yoshimura, K. R. Middleton, A. D. Todora, B. J. Kastern, S. R. Koski, A. V. Maskaev, V. V. Zhdankin, Org. Lett., 2013, 15, 4010-4013.
In a convenient one-pot, three-step procedure for the synthesis of isoxazolines starting from aldehydes, the aldehydes are first transformed with hydroxylamine sulfate into aldoximes, which are then oxidized to nitrile oxides by an in situ generated hypervalent iodine compound. Finally, a 1,3-dipolar cycloaddition between the nitrile oxides and alkenes provides isoxazolines in good yields.
L. Han, B. Zhang, C. Xiang, J. Yan, Synthesis, 2014, 46, 503-509.
The dehydration of primary nitro compounds can be performed by bases in the presence of dipolarophiles. Among the organic bases examined, DABCO gave the best results. The reaction is applicable to activated nitro compounds and to phenylnitromethane and affords isoxazoline derivatives in higher yields compared with those of other methods. The reaction, however, is not compatible with nitroalkanes.
L. Cecchi, F. De Sarlo, F. Machetti, Eur. J. Org. Chem., 2006, 4852-4860.
Iodobenzene diacetate efficiently oxidizes aldoximes to nitrile oxides in MeOH containing a catalytic amount of TFA. Nitrile oxides may be trapped in situ with olefins in a bimolecular or an intramolecular mode. Tandem oxidative dearomatization of phenols/intramolecular nitrile oxide cycloaddition sequences lead to useful synthetic intermediates.
B. A. Mendelsohn, S. Lee, S. Kim, F. Tayssier, V. S. Aulakh, M. A. Ciufolini, Org. Lett., 2009, 11, 1539-1542.
A method for aliphatic C-H bond oxidation of oximes and hydrazones mediated by 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) enables the concise assembly of substituted isoxazole and pyrazole skeletons.
X. Zu, Y.-F. Wang, W. Ren, F.-L. Zhang, S. Chiba, Org. Lett., 2013, 15, 3214-3214.
Unprotected O-propargylic hydroxylamines undergo cyclisations when exposed briefly to silver nitrate adsorbed onto silica gel to give 4,5-dihydroisoxazoles [2-isoxazolines] in very good yields, while N-acetyl derivatives give the corresponding 2,5-dihydroisoxazoles [3-isoxazolines] in similar yields.
D. W. Knight, A. J. Proctor, J. M. Clough, Synlett, 2010, 628-632.
3-alkylpropargyl or 3-arylpropargyl hydroxylamines hydrochlorides were converted to 2-isoxazolines in good yields in refluxing methanol in the presence of K2CO3. Methods for 3-unsubstituted compounds and the direct transformation of a O-propargyl phthalimide into 2-isoxazolines have been developed.
L. Pennicott, S. Lindell, Synlett, 2006, 463-465.
Efficient Pd-catalyzed intramolecular O-allylations of ketoximes enable the synthesis of 5-vinyl-2-isoxazolines. The reactions either involve Pd(0)-catalyzed π-allyl formation via leaving group ionization or Pd(II)-catalyzed allylic C-H activation followed by intramolecular nucleophilic oxime oxygen attack.
R. A. Fernandes, A. J. Gangani, A. Panja, Org. Lett., 2021, 23, 6277-6231.
The use of TEMPO enables a novel, metal-free, and regioselective approach for the synthesis of isoxazolines or cyclic nitrones substituted with methylene groups via tandem iminoxyl radical-promoted cyclization or TEMPO-mediated Cope-like elimination, respectively.
F. Chen, X.-L. Yang, Z.-W. Wu, B. Han, J. Org. Chem., 2016, 81, 3042-3050.
A 2,2,2-trifluoroacetophenone-catalyzed oxidation of allyloximes enables a green and efficient synthesis of isoxazolines utilizing H2O2 as the oxidant. A variety of substitution patterns, both aromatic and aliphatic moieties, are well tolerated, leading to isoxazolines in good yields.
I. Triandafillidi, C. G. Kokotos, Org. Lett., 2017, 19, 106-109.
A facile oxidative heterocyclization of commercially available amines and tert-butyl nitrite with alkynes or alkenes providies isoxazoles or isoxazolines. This reaction is highly efficient, regiospecific, operationally simple, mild, and tolerates a variety of functional groups.
X.-W. Zhang, X.-L. He, N. Yan, H.-X. Zhang, X.-G. Hu, J. Org. Chem., 2020, 85, 15726-15735.
An unprecedented cross-coupling reaction between copper carbenes and nitroso radicals provides various isoxazolines via construction of C-C, C-O, and C=N bonds in a one-pot process. The convenient method offers mild reaction conditions and wide substrate scope.
R. Chen, Y. Zhao, S. Fang, W. Long, H. Sun, X. Wan, Org. Lett., 2017, 19, 5896-5899.
3-Acylisoxazoles were synthesized by the reaction of alkenes or alkynes with ketones (acetone or acetophenone), as both a reagent and the solvent, by three methods: iron(III) nitrate under reflux, iron(III) salt-nitrogen dioxide (NO2) at room temperature, and iron(III) nitrate under microwave irradiation (MW).
K.-I. Itoh, H. Sakamaki, N. Nakazato, A. Horiuchi, E. Horn, C. A. Horiuchi, Synthesis, 2005, 3541-3548.
A copper salt promotes a [3 + 2] annulation of alkenes with α-nitrobenzyl bromides to produce a diverse array of 2-isoxazoline N-oxides with perfect regioselectivity under mild conditions. The obtained products can readily be converted to related heterocycles such as 2-isoxazolines and isoxazoles. A radical-polar crossover pathway initiated by single-electron transfer is proposed.
M. Iwasaki, Y. Ikemoto, Y. Nishihara, Org. Lett., 2020, 22, 7577-7580.
Enamine-triggered [3+2]-cycloaddition reactions of aldehydes and N-hydroximidoyl chlorides in the presence of triethylamine gives 3,4,5-trisubstituted 5-(pyrrolidinyl)-4,5-dihydroisoxazoles. Subsequent oxidation of the cycloadducts offers a high yielding, regiospecific and metal-free synthetic route for the synthesis of 3,4-disubstituted isoxazoles.
Q.-f. Jia, P. M. S. Benjamin, J. Huang, Z. Du, X. Zheng, K. Zhang, A. H. Conney, J. Wang, Synlett, 2013, 24, 79-84.