Nitrile oxide formation

Cycloreversion with nitrile oxide formation is known not only in furoxans but also in isoxazolines, 1,2,4-oxadiazoles, furazans, and some other live-membered heterocycles (76). Such process, eliminating nitrile oxide fragment 3-R CeHiC N+Cr ", was observed mass spectrometrically in 3a,4,5,6-tetrahydro-[ 1,2,4 oxadiazolo[4,5-a J [ 1,5 benzodiazepine derivatives 11 (83). 

R2=MeC>2C, R3 = d-F CC F ), regioisomeric 4-trifluoromethyl-5-isoxazole-carboxylates, 213 (R1 =Me02C, R2 =CF3, R3 = 4-F3CC6H4) and unexpectedly oximinoyl chloride 214, resulted by 1,4-addition. Product distribution is rationalized in terms of two competing reactions, either 1,4-addition of the oximate anion to the acetylenic ester or formation of the nitrile oxide followed by 1,3-dipolar cycloaddition. Anionic 1,4-addition of the oximinoyl chloride to the acetylenic ester is favoured at low temperatures, while nitrile oxide formation, followed by cycloaddition, occur at temperatures above 0 ° (371). 

One-Pot Operations for Nitrile Oxide Formation From Oximes... 

Nitrile oxide formation. Oxidative derivatives is advantageous. Side reactions c. 

Nitrile oxide formation. The reaction of aldoxitne O-tributylstannyl ethers with t-BuOCl results in chlorination and then 1,3-elimination. In the presence of a dipolarophile, the isoxazoline or isoxazole cycloadduct is formed. 

Oxidation of N-O Compounds. The preparation of disub-stituted oxazolines from aldoximes has been accomplished via in situ nitrile oxide formation using Mn02 (eq 60). Oxidation of hydroxylamines and oximes to nitrones " and aldehydes/ ket- ones, respectively, has been found to occur upon treatment with Mn02 (eqs 61 and 62). 

The INOC reaction also plays a crucial role in the synthesis of the trans-hydrindane derivative 322, a potential intermediate for the synthesis of the C2-symmetric pentacychc alkaloid papuamine 319 (1997CC495). Nitroal-kene 321 was prepared from racemic anhydride 320 in a few steps. Nitrile oxide formation was then carried out in situ by the reaction of 321 with PhNCO which resulted in cyclization to afford the racemic irares-hydrin-dane 322 (Scheme 58). 

A further type of nitro-group rearrangement gives rise to a cyclic hydroxamic ether. Noland e.t aL describe the action of cold, dilute sulfuric acid on the sodium salt of 5-nitronorbornene (98), which results in conversion to the oxazinone (101). This complex rearrangement is rationalized by the sequence 98 101 involving intermediate formation of the nitrile oxide (99) and the hydroxamic acid (100). 

Cycloaddition of 2-nitrosopyridine 48 with nitrile oxides can give either di-A -oxides such as 49 or 3-mono-A -oxides such as 50 (93JHC287). In general, greater electron withdrawing character in the aromatic substituent appears to favor formation of the di-A -oxides. Sulfur ylides such as compound 51 are obtained from aryl isothiocyanates and l-amino-2-methylthiopyridinium iodides (84JCS(P1)1891) nitrogen ylides can be obtained from a similar reaction (86H(24)3363). 

As shown by the Italian school, the formation of isoxazole derivatives by the action of nitric acid or nitrogen oxides on acetylene derivatives and related reactions proceeds through intermediate nitrile oxides and must, therefore, be included with this type of synthesis. 

For the reactions of other 1,3-dipoles, the catalyst-induced control of the enantio-selectivity is achieved by other principles. Both for the metal-catalyzed reactions of azomethine ylides, carbonyl ylides and nitrile oxides the catalyst is crucial for the in situ formation of the 1,3-dipole from a precursor. After formation the 1,3-di-pole is coordinated to the catalyst because of a favored chelation and/or stabiliza-... 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

The mechanism is thought to be analogous to that suggested for the formation of 1,3,5-benzoxadiazepines from nitrile oxides and 2-phenylbenzazete (see Section 4.2.1.4.2.1.). 

Nitrile oxides are usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

The above methodology has been extremely useful for the synthesis of a variety of INOC precursors. For instance, treatment of 0-trimethylsilyl a-bro-moaldoximes 52b, e, f with F ion in presence of unsaturated alcohols 57 produces oximino ethers 58 which can be readily oxidized using NaOCl (Scheme 8) [29]. The transient nitrile oxide intermediates formed undergo spontaneous cyclization to fused isoxazolines 59. The preferred stereoisomer in the formation of the five-membered ring ethers is trans whereas in the six-membered ring ethers the cis isomer predominates (see Table 5). MM2 calculations helped rationalize the experimentally observed stereoselectivites (see Table 5). 

Monoalkylation of Af-tosylallylamine 10 with dibromoalkane 101 proceeded in 60-90% yield (Eq. 10 see also Scheme 3 and Eq. 2) [17]. The bromoalkyl-amines 102 were converted to nitro compounds 103. In situ transformation of 103 into nitrile oxides led to spontaneous cycloaddition with formation of isox-azolines fused to 5-, 6-, and 7-membered ring heterocycles 104 a-c. Under very high dilution conditions, 103 d was converted to 104 d, an isoxazoline fused to an 8-membered azocine, in low (10%) yield. 

The addition of mesityl nitrile oxide to stable derivatives of a germanethi-one21 and a germaneselone22 is closely related to the addition of nitrones. The reaction is regioselective again, with formation of the germanium-oxygen bond. 

Besides the use of porphyrins as azomethinic ylide derivatives, the porphyrin macrocycle can also be used to generate porphyrinic nitrile oxides 55 (Scheme 17) <04RCB(E)2192>. Thus, the treatment of oxime 54 with /V-bromosuccinimide in the presence of triethylamine, led to the formation of nitrile oxide 55, which was trapped in 1,3-DC reactions with dimethyl maleate and 2,5-norbomadiene to afford 56 and 57, respectively. In the reaction with 2,5-norbomadiene, if an excess of 55 was used, then the corresponding bis-adduct was obtained in good yield. 

Isoxazolines 38 and 39 were obtained in different ratios by direct cycloaddition of 4-t-butylbenzonitrile oxide with acids 35 (R = H, path B) and by the intermediate formation of cyclodextrin derivatives 36 and 37 followed by basic hydrolysis and acidification (path A). The reversed regioselectivity as well as an increased rate of the cycloaddition step could be explained through the temporary association of the nitrile oxide with the cyclodextrin to give the inclusion complex 40 <06CEJ8571>. 

The first application of microwave irradiation in conjunction with dry media in the generation of nitrile oxide intermediates was reported by Hamelin [29]. In this example, methyl nitroacetate (170) was mixed with a dipolarophile in the presence of catalytic amounts of toluene-p-sulfonic acid (PTSA) (10% weight). Subsequent microwave irradiation led to the formation of the corresponding heterocyclic adducts (Scheme 9.52). Reactions were performed in an open vessel from which water was continuously removed [103], Likewise, irradiation in a domestic oven of a mixture of ethyl chloro(hydroxyimino)acetate (173) and a dipolarophile over alumina led to the same results in only a few minutes (Scheme 9.52) [103]. 

Aroylnitrile oxides can also be generated from diaroyl furoxans 183 under micro-wave irradiation [33]. Formation of the nitrile oxide intermediate 184 and its cycloaddition with dipolarophiles proceeds at atmospheric pressure within minutes in the absence of solvent and in good yields (Scheme 9.56). The reaction occurs by the rear-... 

The major fragmentation in mass spectra of 1,2,5-oxadiazoles is attributed to the loss of nitrile and nitrile oxide or expulsion of NO. The conversion of 3,4-dicyano-l,2,5-oxadiazole-2-oxide (3,4-dicyanofuroxan) 10 to cyanogen iV-oxide 11 (Equation 5) was investigated under the conditions of collisional activation (CA) and neutralization-reionization (NR) mass spectrometry. Flash vacuum thermolysis mass-spectrometry (FVT-MS) and flash vacuum thermolysis infra-red (FVT-IR) investigations of furoxans 10, 12, and 13 reveal that small amounts of cyano isocyanate accompany the formation of the main thermolysis product 11 <2000J(P2)473>. 

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