Addition of nitrile oxides

DFT studies of the intramolecular ene-like (or the so-called 1,3-dipolar ene) reaction between nitrile oxides and alkenes show that this reaction is a three-step process involving a stepwise carbenoid addition of nitrile oxide to form a bicyclic nitroso compound, followed by a retro-ene reaction of the nitrosocyclopropane intermediate. The competitive reactions, either the intramolecular [3 + 2] cycloaddition between nitrile oxides and alkenes or the intermolecular dimerization of nitrile oxides to form furoxans, can overwhelm the intramolecular 1,3-dipolar ene reaction if the tether joining the nitrile oxide and alkene is elongated, or if substituents such as trimethylsilyl are absent (425). 

Substituted 1,2,4-oxadiazoles were prepared by addition of nitrile oxides to imines or hydrazones. It has been reported that interaction of hydroximoyl chlorides 262 with chiral hydrazones 263 in the presence of EtsN leads to intermediates 264 with diastereoselectivity up to 97%. A subsequent N-N bond cleavage to remove chiral auxiliary by formic acid leads to 1,2,4-oxadiazolines 265 with ee up to 91% (equation 113). ... 

Most of the approaches outlined in Figure 15.10 have been successfully realized on insoluble supports, either with the alkene or alkyne linked to the support, or with support-bound 1,3-dipoles (Table 15.16). Nitrile oxides are highly reactive 1,3-dipoles and react smoothly with both electron-poor and electron-rich alkenes, including enol ethers [200]. The addition of resin-bound nitrile oxides to alkenes (Entries 5 and 6, Table 15.16) has also been accomplished enantioselectively under catalysis by diisopropyl tartrate and EtMgBr [201], The diastereoselectivity of the addition of nitrile oxides and nitrones to resin-bound chiral acrylates has been investigated [202], Intramolecular 1,3-dipolar cycloadditions of nitrile oxides and nitrones to alkenes have been used to prepare polycyclic isoxazolidines on solid phase (Entries 7 and 9, Table 15.16). 

A second method of preparation of these compounds is by the 1,3-dipolar addition of nitrile oxides to cyclohexanone enamines, followed by elimination of the amine (Section II,D,2,c). 

Akiyama, T, Okada, K, Ozaki, S, The preparation of optically active A -isoxazolines via addition of nitrile oxides to chiral acryloyl esters bearing cyclitols as auxiliaries. Tetrahedron Lett, 33, 5763-5766, 1992. 

Although the dipolar addition of nitrile oxides to cyclopropenes normally gives 2-oxa-3-aza-bicyclo[3.1.0]hex-3-enes (Section 1.A.1.1.6.1.5.3.2.), the dichlorocyclopropene 1 (X = H) reacted at 0-20 C to give oxazines 2. ... 

These examples show how the combinatorial peptoid approach holds enormous potential for the discovery of novel lead structures for drug development. In this context a postmodification on solid-phase of peptoid side chains, bearing alkene and alkyne moieties, via [3 + 2] cyclo-addition of nitrile oxides, enhances further the molecular diversity and the possibility to find new therapeutic agents [11]. Moreover, polymers of N-substituted glycines containing chiral side chains display interesting conformational preferences [12]. NMR and CD data indicate that the major species adopts in methanol a stable right-handed helical structure with o. v-amidc bonds. 

A variety of precursors of biologically relevant products have also been prepared by addition of nitrile oxides to chiral alkenes bearing a nitrogen substituted allylic stereocen-ter 37, i4°. rai. i46, iso. isi.155 obeyed diastereoselection is generally rather low and... 

Dihydrooxazoles of type (7), which are in turn available by addition of nitrile oxides to allyl acetate, are reduced to / ,y-dihydroxyketones (or protected derivatives thereoO- On treatment with acids, furans are obtained (Scheme 2) <82ACS(B)1, 83T2247, 87ACS(B)426,88BCJ2133,90H(31)597,92H(33)73, 93JCR(M)328, 93JCR(S)58, 94H(38)641>. 

The addition of nitrile oxides to a,P-unsaturated carboxylic acid derivatives opens up a route to chiral, substituted isoxazoline derivatives. The nitrile oxides are generated in situ via deprotonation with a base (e.g. triethylamine) starting from the chlorinated aldoxime as the precursor (solvents CHCI3, CH2CI2, ether, benzene, toluene temperature -78°C up to 110°C). In most cases only one of two possible regioisomeric adducts is formed. 

Scheme 2.54 Kanemasa variant of the addition of nitrile oxides to allyUc alcohols...

Sol 1. 1,3-Dipolar cycloaddition of nitrile oxide to ethyne gives isoxazole. However, in the given case, addition of nitrile oxide to alkene also gives isoxazole due to the labihty of the intermediate isoxazoline under the experimental conditions. 

The addition of nitrile oxides to various olefins was studied by several groups. Similarly to ketenes, the dipolar compounds must be generated in the presence of the other partner, and several methods were used for this purpose. The first one consists of the oxidation of oximes (Z) or ( ), in a biphasic system with aqueous sodium hypochlorite (Fig. 4). Sonication provided a large rate increase, and the reaction was completed in hours instead of days. This result is most probably explained by an efficient emulsification (Ch. 4, p. 108). In a few cases, minor changes in stereoselectivity occur in the irradiated reactions. 

Figure 5 - Addition of nitrile oxides to conjugated acetals...

Additions of nitrile oxides (generated in situ) to alkynes can be carried out in the presence of acetal protecting groups. The resulting isoxazoles can then be reduced to mono-protected 1,4-diketones (Scheme 41). Reaction between... 

The addition of nitrile oxides to 1-phenylthiobuta-l,3-diene has been shown to be regiospecific, leading to a series of amino-substituted unsaturated aldehydes (Scheme 25). ° ... 

The addition of nitrile oxides to 1,3-dipolar intermediates is a well established route to isoxazolines. Chloronitrile oxide (295) has been added to the nitronate salts of ttjS-unsaturated a-nitro crotonic esters (296) to yield the 3-chloroisoxazoline adducts (297) which are useful substrates for transformation into biologically interesting amino acids. ... 

Some potentially useful new synthetic methods were reported. The addition of nitrile oxides to A -20-ketones, previously thought to give only l6a-carbon, 17a-oxygen-linked isoxazolines, has now been shown to produce also the isomeric 17ot-carbon linked compounds (13). If the... 

Another [3+2]-cycloaddition process that has proven value in the construction of macrocyclic natural products, but has been underexplored to date for medicinal chemistry purposes, is the intramolecular addition of nitrile oxides (typically generated in situ from the corresponding oxime) with alkenes (Scheme 11.23). For example, this reaction has been employed for the conversion of oxime-acrylate 172 into 173, an intermediate for the synthesis of the macrosphelide skeleton, and for the construction of macrocycles useful in studies directed towards an asymmetric synthesis of brefeldin... 

The applicability of thioketones in the synthesis of heterocyclic compounds has been further demonstrated. The Diels-Alder reaction of thiobenzophenone with l,3>5-cycloheptatriene gave the (2 + 4) cycloadduct (101) in 40% yield. Cycloheptatrienethione (92) yielded the (8 + 2) cycloadduct (102) quantitatively by reaction with maleic anhydride, and the bicyclic compound (103) in 65% yield by reaction with dimethyl acetylenedicarboxylate. Compound (103) was considered to be a rearrangement product of the probably primarily formed (8 + 2) cycloadduct intermediate (104). " The in situ addition of nitrile oxides to aromatic thioketones resulted in formation of 1,4,2-oxathiazoles, " whereas 1,4,2-oxathiazolidines were the products in the reactions of some alicyclic thiones with nitrones. The formation of thio-ozonides (1,2,4-trithiolans) by treatment of thioketones with amines or chloramine T was investigated recently. ... 

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