Alkynes reaction with nitrile oxides

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. 

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). 

The other important isoxazole synthesis involves the concerted [3+2] cycloaddition reaction of nitrile oxides 4.18 with either alkynes 4.19 or alkyne equivalents 4.20. 

A few nitrile oxides are stable enough to be isolated (those with electron-withdrawing or highly conjugating substituents, for example) but most are prepared in the presence of the alkyne by one of these methods because otherwise they dimerize rapidly. Both methods of forming nitrile oxides are compatible with their rapid reactions with alkynes. Reaction with aryl alkynes is usually clean and regioselective. 

Of the systems showing 1,3-dipolar reactivity, the nitrile oxide is possibly the longest known and is one of the most reactive.81,82 Such reactivity shows itself in the great variety of both acyclic- (via 1,3-addition) and heterocyclic structures (via 1,3-cycloaddition) that can be synthesized from them.59 In the reactions of nitrile oxides with terminal alkynes, both modes of reaction occur, leading to alkynyloximes (25) and isoxazoles (26). The former readily cyclize to the latter but have been detected or isolated in some cases.83,84 In some substituted alkynes 1,3-addition of a substituent may compete with cycloaddition of the triple bond. For example, the reaction between benzonitrile oxide and 3-aminopropyne gives a mixture of the 1,3-adduct (28) (ca. 40%), the 1,3-cycloadduct (29) (ca. 5%), and the product of both modes of reaction (30) (ca. 15%).85 Competition can also occur... 

The potential of the reaction of nitrile oxides with alkynes was already recognized at the time of the earlier review.1 The realization of that potential was apparent 7 years later in the comprehensive account by Grundmann and Griinanger.59 In Table II we list a selection of the syntheses reported in the period 1970-1978, illustrating new applications of the method and some of the generalizations discussed.59,71,84,89,91-100... 

The general characteristics of the reactions of nitrile oxides with alkenes resemble those of the reactions with alkynes.59 The main differences are (i) that there is no evidence for a two-stage mechanism (1,3-addition followed by cyclization) and (ii) that although they are generally regioselective, they are not always markedly so. A further characteristic is that they are stereospecific with respect to the alkene, whose geometry is preserved in the product. 

Copper(I) catalyzes the reaction between nitrile oxides and terminal alkenes providing 3,4-disubstituted isoxazoles 3 with complete regioselectivity and good yields. The proeess is believed to go through a stepwise mechanism analogous to the copper(l)-catalyzed union of terminal alkynes and organic azides <05JA210>. 

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). 

Figure 3.10 Regioselectivity of reactions of nitrile oxides with monosubstituted alkynes and alkenes...

The alternative approach to isoxazoles relies on the reaction of nitrile oxides with alkynes. We shall see in Chapter 34 that there are two good routes to these reactive compounds, the y-elimination of chlorooximes or the dehydration of nitroalkanes. 

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. ... 

Further attempts to increase the kinetics and biocompatibility of 1,3-dipolar cycloadditions led organic chemists to explore altemative dipoles that react with multiple-bond reaction partners. Nitrile oxides are highly reactive dipoles that can react with various alkenes and alkynes to provide isoxazolines and isoxazoles, respectively. In the absence of a suitable reacting partner, nitrile oxides tend to dimerize to form fiiroxane derivatives, or can alternatively act as electrophiles. However, when generated in situ from suitable precursors such as hydroximoyl chlorides or by mild oxidation directly from oximes, nitrile oxides were successfully applied to the labeling of nucleic acids [43], peptides [44] and carbohydrates [45] (Fig. 7). 

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). ... 

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. 

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