Synthesis of isoxazoles
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.
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.
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.
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.
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 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.
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.
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.
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.
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 RfCHN2.
X.-W. Zhang, W.-L. Hu, S. Chen, X.-G. Hu, Org. Lett., 2018, 20, 860-863.