Alkynes with nitrile oxide

To produce a 1,2-azole, a 1,3-dicarbonyl compound needs to be condensed with a unit providing the two heteroatoms - a hydrazine or hydroxylamine. The dipolar cycloaddition of alkynes with nitrile oxides or nitrile imines provides a route to isoxazoles and pyrazoles. 

A related method based on an organoselenium resin has been applied to the synthesis of a wide variety of nitrogen-containing heterocycles. Reactions of resin-bound alkenes or alkynes with nitrile oxides and azides gave a variety of isoxazolines, isoxazoles, and 1,2,3-triazoles in high yields and purities (Schemes 11.42 and 11.43). ... 

Alkynic esters react with nitrile oxides in a pH dependent reaction to product isoxazolin-5-ones (Scheme 145) (71JCS(C)86). Alkynic ethers also react with benzonitrile oxide to produce an isoxazole-ether which on treatment with HCl or HBr gave an isoxazolinone (Scheme 145) (63CB1088,58MI41600). The reaction of benzonitrile oxide with dimethoxyketene yielded a dimethyl acetal which was split with acid into the isoxazolinone (Scheme 145) (59G15H). 

Isoxazoles are produced by the dipolar cycloaddition of nitrile oxides to alkynes pyrazoles result from the comparable interaction of alkynes with nitrile imines. 

Cycloadducts of 7-oxabicyclo[2.2.1]heptadienes with nitrile oxides or tetrazines may undergo a cycloreversion giving furans and isoxazoles (pyridazinones) <72CC2i 1,74TL2163). Oxazoles react with alkynes to give 2-aza-7-oxabicyclo[2.2.1] heptadienes (32), which lose a nitrile spontaneously by a cycloreversion reaction yielding furans (Scheme 31). 

The C5 position of dU has been used to attach a variety of labels or reporter groups, in particular fluorophores ° (see section 3.5). The pyrene-modified analogue (39) has been used to detect RNA bulge conformations in the HIV-TAR RNA sequence where the fluorescence is greatly enhanced,and as a donor for the red emitter nile red (40) when the two dyes are adjacent in duplex DNA the result is white light that is emitted upon excitation of (39). A zinc-porphyrin complex has been added to C5 of dU for use in electron transfer. Norbornene has been attached via an alkyne linker for post-synthetic modification with nitrile oxides in a copper-free Click reaction, " and various dienes have been attached for Diels-Alder tagging of DNA. The photoaffinity tag (41) has been incorporated into DNA adjacent to a damaged DNA base (8-oxo-dG or thymine dimer) such that when exposed to repair systems, the repair enzyme is trapped by the diazirine for mass spectroscopic characterisation. ... 

Isoxazoles display a range of biological activities, such as anti-inflammatory, antimicrobial, anticancer, and antinociceptive, that justify a constant effort in the development of new synthetic strategies. New syntheses of isoxazoles 1 and isQxazolines 2 via 1,3-dipolar cycloaddition (1,3-DC) of alkynes and alkenes with nitrile oxides were described (130L4010). The 1,3-dipoles were generated by oxidation of aldoximes catalyzed with hypervalent iodine species formed in situ from catalytic iodoarene and oxone as a terminal oxidant, in the presence of hexafluoroisopropanol (HFIP) in aqueous methanol solution. 

The reactivity of activated C-C double bonds with NHC has been reviewed more specifically. This report details the umpolung reaction involving Michael acceptors, the use of carbenes in Morita-Baylis-Hillman as well as in various cycloadditions. The catalysis of alkyne cycloaddition with nitrile oxide is also covered. 

Soluble PEG resin has been used in the synthesis of isoxazoles from polymer-bound aUtyne (Scheme 11.38). The alkyne was attached to the resin with an ester linkage, and the cycloaddition with nitrile oxides generated in situ gave resin-bound isoxazoles. Treatment with sodium hydroxide released the 5-hydroxymethyl-substituted isoxazoles from the resin in high yields and purities. 

The copper(I)-catalyzed 1,3-dipolar cycloaddition reaction between alkynes and nitrile oxides reported by Sharpless [108] and Hansen et al. [109] has made considerable progress in the synthesis of isoxazoles. This methodology enables the preparation of unsymmetrical 3,5-disubstituted isoxazoles with specific regioselectivity at satisfactory rates and yields. A large number of ort/zo-substituted arylboronic acids were evaluated for their ability to accelerate nitrile oxides [3-1-2] cycloaddition to alkynoic acids [110]. Copper-doped silica cuprous sulfate (CDSCS, 0.05 mol%) as a nanocatalyst and NaHCOj in a solution of z-PrOH/H20 (1 1, V/V) have been used in the reaction of diverse alkynes and in situ generated nitrile oxide [111]. 

On the whole, the cycloaddition of alkynes to nitrile N-oxides is one of the most important routes to isoxazoles, but in spite of its potentially wide application, its synthetic utility is less than that of the corresponding reaction with alkenes for the following reasons. (1)... 

Generalized methods of preparation include the reaction of /3-keto esters (or amides) with hydroxylamine, a-alkynic and a,/3-unsaturated esters (or amides) with hydroxylamine (real or generated in situ), hydroxylamine and nitrile oxides, and /3-keto and a-alkynic nitriles with hydroxylamine (62HC(l7)l, pp. 3,7). 

In a manner analogous to classic nitrile iinines, the additions of trifluoro-methylacetonitrile phenylimine occur regiospecifically with activated terminal alkenes but less selectively with alkynes [39], The nitnle imine reacts with both dimethyl fumarate and dimethyl maleate m moderate yields to give exclusively the trans product, presumably via epimenzation of the labile H at position 4 [40] (equation 42) The nitrile imine exhibits exo selectivities in its reactions with norbornene and norbornadiene, which are similar to those seen for the nitrile oxide [37], and even greater reactivity with enolates than that of the nitnle oxide [38, 41], Reactions of trifluoroacetomtrile phenyl imine with isocyanates, isothiocyanates, and carbodiimides are also reported [42]... 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

One obvious synthetic route to isoxazoles and dihydroisoxazoles is by [3+2] cycloadditions of nitrile oxides with alkynes and alkenes, respectively. In the example elaborated by Giacomelli and coworkers shown in Scheme 6.206, nitroalkanes were converted in situ to nitrile oxides with 1.25 equivalents of the reagent 4-(4,6-di-methoxy[l,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 10 mol% of N,N-dimethylaminopyridine (DMAP) as catalyst [373], In the presence of an alkene or alkyne dipolarophile (5.0 equivalents), the generated nitrile oxide 1,3-dipoles undergo cycloaddition with the double or triple bond, respectively, thereby furnishing 4,5-dihydroisoxazoles or isoxazoles. For these reactions, open-vessel microwave conditions were chosen and full conversion with very high isolated yields of products was achieved within 3 min at 80 °C. The reactions could also be carried out utilizing a resin-bound alkyne [373]. For a related example, see [477]. 

The penam nitrile oxide 36 underwent 1,3-DC reactions with various alkenes and alkynes to give cycloadducts of general formula 37. The corresponding acids (37 R=H) exhibited potent P-lactamase inhibitory activity <00OL3087>. 

Very interesting transformations were reported in terminal alkynes RC=CH (R = alkyl, aryl, alkoxy, carboxylate, etc.). They react readily with nitric acid, in aqueous nitromethane (1 1) and in the presence of catalytic amounts of tetra-butylammonium tetrachloroaurate to give 3,5-disubstituted isoxazoles 15 in 35% to 50% isolable yield (92). The reaction might proceed via a nitrile oxide intermediate by attack of an electrophile (AuCh or H+) and of a nucleophile (N02 ) on the triple bond to form a vinyl nitrite, which is converted to a nitrile oxide by the action of gold(III) or of nitric acid (Scheme 1.8). 

Ammonium cerium(IV) nitrate on reaction with acetone or acetophenone generates acetyl- or benzoylformonitrile oxides, respectively (99). These nitrile oxides dimerize to furoxans and give, in the presence of alkenes and alkynes, 3-acetyl- or 3-benzoyl-4,5-dihydroisoxazoles and 3-acetyl- or 3-benzoylisoxazoles, respectively the yield of the isoxazole derivatives was improved on using ammonium cerium(III) nitrate tetrahydrate-formic acid (99). 

Microwave irradiation promotes the 1,3-dipolar activity of nitrile oxides generated from hydroximoyl chlorides. They interacted in situ over alumina with alkenes and alkynes (150). The effect was demonstrated in reactions of... 

A solid-phase synthesis of substituted benzopyranoisoxazoles 356 (I R = H, Me, Et, Pr, Ph, CHMe2 R1 =H, Me, decyl, Ph) has been described (414). The six-step synthesis includes a method of generating nitrile oxides on a polymer support, followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne, for assembly of the benzopyranoisoxazole scaffold. 

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