Nitroalkanes nitrile oxide generation

Nitrile oxide generation. Dehydration of nitroalkanes with a diisocyanate-triethylamine combination simplifies the product (of 1,3-dipolar cycloaddition) purification, because the urea byproduct is polymeric which can be filtered off. 

In this volume we present five selected contributions by well-known authors, each an authority in his field. The first chapter deals with construction of isoxazolines (dihydroisoxazoles) via 1,3-dipolar cycloadditions of nitronates or of nitrile oxides generated from nitroalkanes. This includes inter- as well as intramolecular processes. Many of these heterocycles possess important synthetic and biological properties and are shown to lead to stereo- and re-gioselective introduction of multifunctional molecules such as amino alcohols, )6-amino acids, aldols, nitriles, and others. 

Isoxazole-isoxazoline polyheterocyclic systems have been synthesized for applications as ionophores using resin boimd alkenes/alkynes as dipo-larophiles. For instance, the isoxazole possessing an alkene moiety 41 was reacted with a nitrile oxide, generated from nitroalkane 13d imder Mukaiyama conditions, to afford isoxazoline 42 in high yield (Scheme 12) [ 104]. 

Zhao and co-workers reported a regioselective cycloaddition of nitrile oxide generated from nitroalkane 13f with N-vinyl bases 43 to generate nude-... 

Both the chiron and the auxiliary approaches have been adopted for developing the asymmetric versions of intermolecular 13DC of nitrile oxides generated from nitroalkanes as described below. To our knowledge, the corresponding catalytic approach remains obscure. 

Nitroalkanes bearing a chiral unit 88 were employed for generation of enantiopure nitrile oxides 89 (Scheme 26) [120]. These nitrile oxides reacted with ( )-hexene 90 to afford 2-isoxazolines 91 in moderate yields and low stereoselectivities (de for trans 10-15%). Similar results were obtained when oximes were used as substrates for nitrile oxide generation. 

Bhattacharjya and co-workers reported the synthesis of chiral cyclic ether fused isoxazolines via INOC of allyl glucose derivatives [136]. The pentaallyl nitroalkane 131 when subjected to nitrile oxide generation under Mukaiyama... 

Solid-supported isoxazoles were obtained from resin-bound alkynes and nitrile oxides generated in situ from nitroalkanes and isocyanate (Scheme 11.50). The isoxazoles were cleaved from the resin via hydantoin formation upon heating and 18 diverse products were obtained in high purities. 

The photochemical cyclisation of p.y-unsaturated ketoximes to 2-isoxazolines, e.g., 16—>17, has been reported <95RTC514>. 2-Isoxazolines are obtained from alkenes and primary nitroalkanes in the presence of ammonium cerium nitrate and formic acid <95MI399>. Treatment of certain 1,3-diketones with a nitrating mixture generates acyl nitrile oxides, which can be trapped in situ as dipolar cycloadducts (see Scheme 3) <96SC3401>. 

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 Mukaiyama-Hoshino reaction between a nitroalkane and phenyl isocyanate generates a nitrile oxide, and this method has been used in the synthesis of 1,2,4-oxadiazoles as discussed in CHEC-II(1996) <1996CHEC-II(4)179>. In a more recent advance, nitroethane undergoes ultrasound-mediated cycloaddition with trichloroacetonitrile to give the extremely useful (see Equation 11) 5-trichloromethyl-l,2,4-oxadiazole 228 (Equation 45) <1995TL4471>. 

Generation of nitrile oxides by the Mukaiyama procedure, viz., dehydration of primary nitroalkanes with an aryl isocyanate, usually in the presence of Et3N as a base, is of high importance in nitrile oxide chemistry. Besides comprehensive monographs (4, 5), some data concerning the procedure and its use in organic synthesis can be found in References 61 and 62. 

Nitrile oxides, which are formed by dehydration of nitroalkanes or by oxidation of oximes with hypochlorite,87 88 are also useful 1,3-dipoles. They are highly reactive and must be generated in situ.ss They react with both alkenes and alkynes. Entry 5 in Scheme 6.5 is an example in which the cycloaddition product (an isoxazole) was eventually converted to a prostaglandin derivative. 

Isoxazoline derivatives of Cgo such as 250 (Scheme 4.40) are accessible by 1,3-dipolar cycloadditions of nitrile oxides to [6,6] double bonds of the fullerene [2, 278, 291-305]. The nitrile oxides 249 with R = methyl, ethyl, ethoxycarbonyl and anthryl are generated in situ from the corresponding nitroalkane, phenyl isocyanate and triethylamine. The isoxazoline derivative of Cgo 250 (with R = anthryl) crystallizes in black prisms out of a solvent mixture of CS2 and acetone (3 2) [292]. X-ray crystal structure analysis shows that addition of the nitrile oxide occurs on a [6,6] double bond of the fullerene framework. 

Examples of optically active aldehydes or nitroalkanes that have been used for the generation of nitrile oxides (mostly via hydroximoyl chlorides) and subsequent cycloadditions to olefins are collected in Table 6.9. 

Isoxazoles and their partially or fully saturated analogs have mainly been prepared, both in solution and on insoluble supports, by 1,3-dipolar cycloadditions of nitrile oxides or nitrones to alkenes or alkynes (Figure 15.10). Nitrile oxides can be generated in situ on insoluble supports by dehydration of nitroalkanes with isocyanates, or by conversion of aldehyde-derived oximes into a-chlorooximes and dehydrohalogenation of the latter. Nitrile oxides react smoothly with a wide variety of alkenes and alkynes to yield the corresponding isoxazoles. A less convergent approach to isoxazoles is the cyclocondensation of hydroxylamine with 1,3-dicarbonyl compounds or a,[3-unsatu-rated ketones. 

Dipolar cycloaddition of nitrile oxides to olefins and acetylenes is among the most widely exploited synthetic routes towards isoxazoles and isoxazolines. It is well-known that microwave irradiation in cycloaddition reactions considerably reduces reaction times. Indeed, the use of dielectric heating (microwave-heated reactions were performed in a flask with a reflux condenser mounted outside the apparatus) allowed for a remarkable reduction of the cycloaddition reaction time from 6-12 hours to merely 3 minutes [69]. Simple aqueous workup provided the target isoxazoles and isoxazolines. The requisite nitrile oxides for the cycloaddition reaction were generated in situ from the corresponding nitroalkanes, 4-(4,6-dimethoxy [1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 4-dimethylaminopyridine (DMAP) (Scheme 22). 

The principal sources (Scheme 20) of nitrile oxides comprise hydroximoyl halides and oximes nitrolic acids and their precursors and primary nitroalkanes. In addition there is a range of miscellaneous methods of generation which can be applied in particular instances. 

In related procedures acetyl chloride and acetic anhydride have been used to prepare nitrile oxides from lithium nitronates (86T3825), whereas the nitronic ester (18), prepared by 0-alkylation of the nitroalkane (17), underwent thermal elimination of methanol to generate benzenesulfonylni-trile oxide (19) (Scheme 6) (84H2187). The latter procedure is potentially HAZARDOUS, as the nitronic ester (18) has been reported to be EXPLOSIVE (85JMC1109), and base-induced elimination of methanol from the... 

Apart from a few stable species, nitrile oxides exhibit a high tendency toward dimerization to furoxans for this reason, several methods have been developed for the in situ generation of such dipoles in the presence of the desired acceptor. The most common procedures involve thermal or base-mediated deydrohalogenation of hydroxymoyl halides, oxidation of aldoximes, and dehydration of primary nitroalkanes <1984CHEC(6)1>. 

Maugein, N., Wagner, A., Mioskowski, C. New conditions for the generation of nitrile oxides from primary nitroalkanes. Tetrahedron Lett. 1997,38, 1547-1550. 

Nitrile oxides could also be prepared from nitroalkanes by reaction with (Boc)20 in the presence of catalytic amounts of DMAP at room temperature under N2 [276]. Alternatively they could also be prepared via base-induced dehydrohalogenation from hydroximinoyl chlorides, which can be either purchased or generated hy chlorination of the corresponding aldoximes with N-chlorosucdnimide. 

Isothiocyanates. Both a-chloro aldoximes and nitroalkanes give isothiocyanates on reaction with thiourea. The former needs a base (e.g., E N) to generate nitrile oxides in situ, and the latter requires both a base and a dehydrating agent, such as 4-chlorophenyl isocyanate. 

Nitrile oxides are conveniently generated from primary nitroalkanes RCH2NO2 (R = Me, Et, Ph, etc.) by the action of di-t-butyl dicarboiiate or ethyl chloroformate, catalysed by 4-dimethylaminopyridine. In the presence of olefins, isoxazolines are obtained in good yields <97S309>. 

The reagent DMTMM has been used also for the generation of nitrile oxides in situ from nitroalkanes under very mild conditions using microwave irradiation. The reaction requires the presence of 4-dimethylaminopyridine (DMAP) as catalyst (Scheme 66). 

Owing to their tendency to dimerize to furoxans (1,2,5-oxadiazole 2-oxides), nitrile oxides 5 are usually generated in situ, i.e., in the presence of suitable dipolarophiles such as alkenes, alkynes, etc., from stable precursors such as aldoximes 12 (X = H) or from primary nitroalkanes 13 (Scheme 2) [5,57-67]. Generation of nitrile oxides 5 from aldoximes 12 (X = H) involves either direct oxidation or halogenation of aldoximes 12 (X = H) to hydroximoyl halides 12 (X = Cl or Br) followed by dehydrohalogenation [5,57-67,79,80]. Alternatively, nitrile oxides 5 are conveniently generated via dehydration of primary nitroalkanes 13 [ 17,38,39,65,66,81-95]. This review covers the literature in the last 10-15 years pertaining to the chemistry of isoxazoHnes synthesized from primary nitroalkanes 13. 

Mioskowski and co-workers reported the use of Burgess salt, DAST, ox-alyl chloride and phosphorus oxychloride for dehydration of nitroaUcanes 13 among which they found DAST to be the best reagent [87]. Recently, a microwave-assisted generation of nitrile oxide 5 under the catalytic influence of 4-(4,6-dimethoxy[l,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM)/DMAP [88] has been described. However, di-f-butyl dicarbonate (Boc20)/DMAP, a method reported by Basel and Hassner, allows the dehydration of nitroalkanes 13 under much milder conditions (Scheme 4) [89]. In fact, this has become an efficient method because of the innocuous nature of the side products (f-BuOH and CO2), which simplifies the purification of the ultimately desired isoxazoHne product. 

Among the dipoles used for the construction of the isoxazoline ring, nitrile oxides have a prominent place in the Uterature owing to the convenient generation of this intermediate from diverse precursors such as oximes, a-halooximes and nitroalkanes (see Section 2.1). Cycloaddition of nitrile oxides with multiple bonds, especially alkenes, has been extensively investigated in recent years both from the theoretical and synthetic perspectives. 

When nitrile oxide 5g, generated in situ from nitroalkane 13g, was reacted with diethyl fumarate and diethyl maleate 46, stereospecific cycloaddition took place to afford the adducts 47 in 35% and 60% yield, respectively (Scheme 14) [108]. However, when presynthesized nitrile oxide 5g was used, the yields improved to 98% and 93%, respectively. 

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