Categories: Synthesis of N-Heterocycles, Synthesis of O-Heterocycles >

Synthesis of isoxazoles

Recent Literature

AuCl₃-catalyzed cycloisomerization of α,β-acetylenic oximes leads to substituted isoxazoles in very good yields under moderate reaction conditions. The methodology is amenable for the selective synthesis of 3-substituted, 5-substituted or 3,5-disubstituted isoxazoles.
C. Praveen, A. Kalyanasundaram, P. T. Perumal, Synlett, 2010, 777-781.

An oxidation of propargylamines to the corresponding oximes followed by CuCl-mediated intramolecular cyclization provides a series of isoxazoles with a wide range of functional group compatibility.
M. Duan, G. Hou, Y. Zhao, C. Zhu, C. Song, J. Org. Chem., 2022, 87, 11222-11225.

Cycloadditions of copper(I) acetylides to azides and nitrile oxides provide ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, respectively. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a nonconcerted mechanism involving unprecedented metallacycle intermediates.
F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210-216.

The use of either tert-butyl nitrite or isoamyl nitrite enables an efficient, one-pot approach for the synthesis of 3,5-disubstituted isoxazoles from substituted aldoximes and alkynes under conventional heating conditions.
K. S. Kadam, T. Gandhi, A. Gupte, A. K. Gangopadhyay, R. Sharma, Synthesis, 2016, 48, 3996-4008.

Various 3-substituted and 3,5-disubstituted isoxazoles have been efficiently synthesized in good yields by the reaction of N-hydroxyl-4-toluenesulfonamide with α,β-unsaturated carbonyl compounds. This strategy is associated with readily available starting materials, mild conditions, high regioselectivity, and wide scope.
S. Tang, J. He, Y. Sun, L. He, X. She, Org. Lett., 2009, 11, 3982-3985.

An efficient reaction of 1,3-bis(het)arylmonothio-1,3-diketones with sodium azide provides 3,5-bis(het)arylisoxazoles in high yields at room temperature in the presence of IBX as catalyst. The reaction is applicable to a broad range of substrates. The reaction of β-ketodithioesters with sodium azide furnishes β-ketonitriles in good yields.
M. A. P, G. L. Balaji, P. Iniyavan, H. Ila, J. Org. Chem., 2020, 85, 15422-15436.

The ketone, enol, and enolate forms of 3-sulfonyloxyimino-2-methyl-1-phenyl-1-butanones can afford different intramolecular cyclization products, depending on the conditions. Reactions under basic conditions afford 2H-azirines via a neutral enol (DABCO) or isoxazoles and oxazoles via an anionic enolate (t-BuOK), while acidic conditions afford oxazoles (AcOH) and isoxales (TFA) via neutral ketones.
Y. Ning, Y. Otani, T. Ohwada, J. Org. Chem., 2018, 83, 203-219.

α-Halohydrazones/ketoximes are transformed into trisubstituted pyrazoles/disubstituted isoxazoles by treatment with phosphine, acyl chloride, and a base. Proper functionalization of α-haloketoximes and a change of conditions also allowed the chemoselective synthesis of chromenone-oximes as well as rearranged isoxazoles.
P. V. Khairnar, T.-H. Lung, Y.-J. Lin, C.-Y. Wu, S. R. Koppolu, A. Edukondalu, P. Karanam, W. Lin, Org. Lett., 2019, 21, 4219-4223.

The reaction of terminal alkynes with n-BuLi, and then with aldehydes, followed by the treatment with molecular iodine, and subsequently hydrazines or hydroxylamine provided the corresponding 3,5-disubstituted pyrazoles or isoxazoles in good yields and with high regioselectivity.
R. Harigae, K. Moriyama, H. Togo, J. Org. Chem., 2014, 79, 2049-2058.

A tandem synthesis of 3-halo-5-substituted isoxazoles from 1-copper(I) alkynes and dihaloformaldoximes under base-free conditions circumvents 1,3-dipolar cycloaddition and all its drawbacks.
W. Chen, B. Wang, N. Liu, D. Huang, X. Wang, Y. Hu, Org. Lett., 2014, 16, 6140-6143.

An oxyboration reaction with activated substrates provides borylated isoxazoles, which are potential building blocks for drug discovery, via B-O σ bond additions to C-C π bonds. Although this reaction can be effectively catalyzed by gold, an uncatalyzed oxyboration is possible too. This oxyboration reaction tolerates groups incompatible with alternative lithiation/borylation and palladium-catalyzed C-H activation/borylation technologies.
K. N. Tu, J. J. Hirner, S. A. Blum, Org. Lett., 2016, 18, 480-483.

A catalytic intramolecular cyclization of 2-alkynone O-methyl oximes and subsequent fluorination proceeds smoothly at room temperature in the presence of 5 mol % of (IPr)AuCl, 5 mol % of AgOTs, 2.5 equiv of Selectfluor, and 2 equiv of NaHCO₃. This process features an efficient one-pot cascade route to fluoroisoxazoles with high yields and high selectivity under mild reaction conditions.
Y. Jeong, B.-I Kim, J. K. Lee, J.-S. Ryu, J. Org. Chem., 2014, 79, 6444-6455.

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.

The sequential use of iron and palladium catalysts in an uninterrupted four-step sequence allows the synthesis of trisubstituted isoxazoles from readily available propargylic alcohols. The advantages of such a strategy are illustrated by the high overall yields and the time-saving procedure.
E. Gayon, O. Quinonero, S. Lemouzy, E. Vrancken, J.-M. Campagne, Org. Lett., 2011, 13, 6418-6421.

A mild, palladium-catalyzed cascade annulation/allylation of alkynyl oxime ethers with allyl halides provides functionalized isoxazoles with good functional group compatibility and convenient operation.
C. Li, J. Li, F. Zhou, C. Li, W. Wu, J. Org. Chem., 2019, 84, 11958-11970.

A metal-free Csp³-H bond functionalization of ketones with tert-butyl nitrite followed by a 1,3-dipolar cycloaddition to alkynes or alkenes provides oxazole and isoxazoline derivatives with diverse functionalities.
P. Dai, X. Tan, Q. Luo, X. Yu, S. Zhang, F. Liu, W.-H. Zhang, Org. Lett., 2019, 21, 5096-5100.

Silica gel-supported sodium hydrogen sulfate (NaHSO₄/SiO₂) or Amberlyst 15 catalyze the formation of nitrile oxides from α-nitro ketones. A subsequent in situ 1,3-dipolar cycloaddition to alkynes provides 3-acylisoxaszoles in very good yields. The heterogeneous catalysts can easily be recovered and reused.
K.-i. Itoh, M. Hayakawa, R. Abe, S. Takahashi, K. Hasegawa, T. Aoyama, Synthesis, 2021, 53, 4636-4643.

The use of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) as catalyst enables a Machetti-De Sarlo reaction of nitroalkenes with alkynes/alkenes under sustainable conditions to afford a library of isoxazole/isoxaline products.
M. Vadivelu, S. Sampath, K. Muthu, K. Karthikeyan, C. Praveen, J. Org. Chem., 2019, 84, 13636-13645.

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.

A copper-catalyzed [3 + 2] cycloaddition reaction of alkynes with nitrile oxides generated in situ from the coupling reaction of a copper carbene and nitroso radical provides isoxazoles in a highly regioselective manner in a single step.
X.-D. Wang, L.-H. Zhu, P. Liu, X.-Y. Wang, H.-Y. Yuan, Y.-L. Zhao, J. Org. Chem., 2019, 84, 16214-16221.

The direct regioselective synthesis of 3,5-disubstituted isoxazoles was achieved through a sequence involving a net bromination of an electron-deficient alkene, in situ generation of a nitrile oxide, 1,3-dipolar cycloaddition, and loss of HBr from an intermediate bromoisoxazoline. This one-pot process enables the direct synthesis of 3,5-disubstituted isoxazoles from electron-deficient alkenes.
J. Xu, A. T. Hamme II, Synlett, 2008, 919-923.

A one-pot, cascade reaction sequence of α-azido acrylates and aromatic oximes provides an efficient, straightforward and metal-free synthesis of 3,4,5-trisubstituted isoxazoles under mild reaction conditions via a 1,3-dipolar cycloaddition.
M. Hu, X. He, Z. Niu, Z. Yan, F. Zhou, Y. Shang, Synthesis, 2014, 46, 510-514.

The consecutive Sonogashira coupling of acid chlorides with terminal alkynes, followed by 1,3-dipolar cycloaddition under dielectric heating of in situ generated nitrile oxides from hydroximinoyl chlorides furnishes isoxazoles in moderate to good yields in the sense of a one-pot three-component reaction.
B. Willy, F. Rominger, T. J. J. Müller, Synthesis, 2008, 293-303.

Alumino-heteroles are obtained from simple precursors in a fully chemo- and regioselective manner by a metalative cyclization. The carbon-aluminum bond is still able to react further with several electrophiles, without the need of transmetalation providing a straightforward access to 3,4,5-trisubstituted isoxazoles and 1,3,4,5-tetrasubstituted pyrazoles.
O. Jackowski, T. Lecourt, L. Micouin, Org. Lett., 2011, 13, 5664-5667.

A large number of functionally substituted 2-alkyn-1-one O-methyl oximes have been cyclized under mild reaction conditions in the presence of ICl to give the corresponding 4-iodoisoxazoles in moderate to excellent yields. The resulting 4-iodoisoxazoles undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles.
J. P. Waldo, R. C. Larock, J. Org. Chem., 2007, 72, 9643-9647.

A thermally promoted cycloaddition between alkynyliodides and nitrile oxides offers excellent regioselectivity and a broad scope with respect to both starting materials. Further functionalization of the highly decorated iodoisoxazole motifs can be achieved via Suzuki cross-coupling.
J. A. Crossley, D. L. Browne, J. Org. Chem., 2010, 75, 5351-5354.

A 1,3-dipolar cycloaddition of phenyl vinylic selenide to nitrile oxides and subsequent oxidation-elimination furnished 3-substituted isoxazoles with good yields in a one-pot, two-step transformation.
S.-R. Sheng, X.-L. Liu, Q. Xu, C.-S. Song, Synthesis, 2003, 2763-2764.

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.

3,5-Disubstituted isoxazoles are regioselectively obtained in good yields by a mild and convenient one-pot, three-step procedure utilizing a copper(I)-catalyzed cycloaddition reaction between in situ generated nitrile oxides and terminal acetylenes.
T. V. Hansen, P. Wu, V. V. Fokin, J. Org. Chem., 2005, 70, 7761-7764.

Pyrazole or isoxazole derivatives are prepared by a palladium-catalyzed four-component coupling of a terminal alkyne, hydrazine (hydroxylamine), carbon monoxide under ambient pressure, and an aryl iodide.
M. S. M. Ahmed, K. Kobayashi, A. Mori, Org. Lett., 2005, 7, 4487-4489.

The reaction of various 2-alkyn-1-one O-methyl oximes with ICl, I₂, Br₂, or PhSeBr provided 3,5-disubstituted 4-halo(seleno)isoxazoles in good to excellent yields under mild reaction conditions.
J. P. Waldo, R. C. Larock, Org. Lett., 2005, 7, 5203-5205.

1,2,3-Triazine 1-oxides are formed by addition of tert-butyl nitrite to the vinylogous position of vinyl diazo compounds. This formal [5 + 1] cycloaddition occurs under mild conditions with high functional group tolerance and regioselectivity, and can be employed for late-stage functionalization. Upon heating in refluxing chlorobenzene, an extrusion of N₂ provides isoxazoles in very high yields.
L. De Angelis, H. Zheng, M. T. Perz, H. Arman, M. P. Doyle, Org. Lett., 2021, 23, 6542-6546.

Using cheap and eco-friendly iron(III) nitrate as the nitration and cyclization reagent and KI as an additive for the synthesis of isoxazoles from alkynes, both self-coupling and cross-coupling products could be successfully prepared. In the cross-coupling and cyclizing of two different alkynes, the iron-mediated system shows a good chemoselectivity.
Z. Lai, Z. Li, Y. Liu, P. Yang, X. Fang, W. Zhang, B. Liu, H. Chang, H. Xu, Y. Xu, J. Org. Chem., 2018, 83, 145-153.

Various primary alcohols were smoothly transformed into 3-substitued isoxazoles in good yields in one pot by successive treatment with PhI(OAc)₂ in the presence of TEMPO, NH₂OH, and then NCS, followed by reaction with alkynes in the presence of Et₃N. The use of PhNHNH₂ instead of NH₂OH and decyl methyl sulfide as additive in a later step enabled the synthesis of pyrazoles.
E. Kobayashi, H. Togo, Synthesis, 2019, 51, 3723-3735.

A one-pot protocol for the construction of fluoroalkylated isoxazoles directly from commercially available amines and alkynes is regioselective, scalable, operationally simple, mild, and tolerant of a broad range of functional groups. Preliminary mechanistic investigations reveal that the transformation involves an unprecedented Cu-catalyzed cascade sequence involving R_fCHN₂.
X.-W. Zhang, W.-L. Hu, S. Chen, X.-G. Hu, Org. Lett., 2018, 20, 860-863.

A metal-free, cascade regio- and stereoselective trifluormethyloximation, cyclization, and elimination strategy of readily available α,β-unsaturated carbonyl compounds with CF₃SO₂Na and tBuONO provides a wide variety of 4-(trifluoromethyl)isoxazoles. Mechanistic studies revealed a radical pathway for the reaction.
P. Pattanayak, T. Chatterjee, J. Org. Chem., 2023, 88, 5420-5430.

Hydrochloric acid mediates a cyclisation of N,O-diBoc-protected β-keto hydroxamic acids to 5-substituted 3-isoxazolols without formation of any 5-isoxazolone byproduct. The N,O-diBoc-protected β-keto hydroxamic acids are obained by a versatile three-step procedure from carboxylic acid derivatives.
U. S. Sørensen, E. Falch, P. Krogsgaard-Larsen, J. Org. Chem., 2000, 65, 1003-1007.

A series of 4-alkyl-5-aminoisoxazoles have been synthesized in high yield by nucleophilic addition of lithiated alkyl nitriles to (α)-chlorooximes.
M. P. Bourbeau, J. T. Rider, Org. Lett., 2006, 8, 3679-3680.

In a reliable procedure that can be used to access a wide range of 3-amino-5-alkyl and 5-amino-3-alkyl isoxazoles, the reaction temperature and pH were key factors that determined the regioselectivity.
L. Johnson, J. Powers, F. Ma, K. Jendza, B. Wang, E. Meredith, N. Mainolfi, Synthesis, 2013, 45, 171-173.

In a reliable procedure that can be used to access a wide range of 3-amino-5-alkyl and 5-amino-3-alkyl isoxazoles, the reaction temperature and pH were key factors that determined the regioselectivity.
L. Johnson, J. Powers, F. Ma, K. Jendza, B. Wang, E. Meredith, N. Mainolfi, Synthesis, 2013, 45, 171-173.

A Cu(I)-free cyclization of nitrile oxides with terminal ynamides provides isoxazoles, which could engage in another cyclization with internal ynamides in the presence of Au(I) catalyst to deliver pyrroles. Both reactions can be carried out in a two-step, one-pot procedure.
. Chen, S. Cui, J. Org. Chem., 2019, 84, 12157-12164.