Nitrile oxides, cycloadditions, furan

Among heteroaromatic compounds able to react with nitrile oxides as dipo-larophiles, furan, probably, is the best known. Recently, a novel nitrile oxide was generated from a sulfoximine and converted in situ to a cycloadduct with furan (Scheme 1.25) (287). The starting racemic N-methyl-S-nitromethyl-S-phenylsul-foximine 124 was prepared in 87% yield via nitration of N,S-dimethyl-S-phenyl-sulfoximine. Reaction of 124 with p-chlorophenyl isocyanate and a catalytic quantity of triethylamine, in the presence of furan, afforded dihydrofuroisoxazole 125, the product of nitrile oxide cycloaddition, in 42% yield (65 35 diastereomer ratio). The reaction of 125 with phenyllithium and methyllithium afforded compounds 126, which are products formed by replacement of the sulfoximine group by Ph and Me, respectively. 

Eully hydroxylated 1,4-iminopolyols have been obtained using cis-4-oxyisoxa-zolines. This synthesis involves nitrile oxide cycloaddition to furan followed by various oxidative transformations of the C2 enol ether portion of the resulting furoisoxazoline cycloadducts (21,82,293,294) (see Section 6.4.3). 

The sesquiterpene skeleton has also been assembled by the intramolecular nitrile oxide cycloaddition sequence. Oxime 238 (obtained from epoxy silyl ether 237), on treatment with sodium hypochlorite gave isoxazoline 239, which was sequentially hydrolyzed and then subjected to the reductive hydrolysis conditions-cyclization sequence to give the furan derivative 240 (330) (Scheme 6.93). In three additional steps, compound 240 was converted to 241. This structure contains the C11-C21 segment of the furanoterpene ent-242, that could be obtained after several more steps (330). 

Dihydrofuran (376) and 2,5-dihydrofuran (377) react with nitrile oxides to give furo[2,3-6 ]isoxazoles (378) and furo[3,4-rf]isoxazoles (379), respectively, as cycloadducts. The double bonds of furan, pyrrole and thiophene also react when the nitrile oxide is generated in situ. Thus furan and benzonitrile oxide gave (380), and with 2-methyl-2-oxazoline the cycloadduct (381) was obtained (71AG(E)810). These and related cycloadditions are discussed in Chapter 4.36. 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

The intramolecular cycloaddition reactions of the nitrile oxides 357 (n = 1, 2, 3, 9), obtained in situ from the 2,5-difunctional furan hydroximoyl chlorides or nitro compounds (415) has specific features because of the 2,5-arrangement of two open chains bearing acetylenic and fulminic moieties. Only with 357 (n = 3) is the expected furanoisoxazolophane 358 formed, in acceptable yield. Compound 357 ( =9) gives a complex product mixture whereas 357 ( = 1, 2) gives rise to the exclusive reaction of the dipole with a double bond of the furan system. 

The cycloaddition of some nitrile oxides to trani-l,2-disubstituted alkenebor-onates afforded the respective isoxazoline-4-boronates with high regioselectivity. These products were then used to prepare the 4-hydroxy derivatives (139) complementing earlier approaches that took advantage of 4-modification (140,141) of furan cycloaddition products (20,21) (see Section 6.4.4). 

The intramolecular cycloaddition of nitrile oxides to substituted furans was reported to occur with low stereoselectivity (274). Inserting a stereogenic unit within the chain connecting the dipole and dipolarophile did not increase the stereoselectivity (274). 

The same salt from acetylene afforded similarly adducts with furan and 1,3-diphenyl i sobenzofuran. A number of alkynyl iodonium salts underwent also [2 + 3] cycloaddition with dipolarophiles such as a-diazocarbonyl compounds, nitrile oxides, etc., allowing the preparation of iodonium salts with an alkenyl or a heterocyclic moiety [7],... 

Intermolecular [3+2] 1,3-dipolar cycloaddition of a D-glyceraldehyde-derived nitrile oxide to the 4,5-double bond of 2-methylfuran gave a 60 40 diastereomeric ratio of the two furoisozaxoline isomers. This chemistry was employed in the synthesis of L-furanomycin <2005EJ03450>. As depicted in Scheme 43, an intramolecular cycloaddition of a furan with a carbonyl ylide dipole proceeded under rhodium-catalyzed microwave-promoted conditions to provide the cycloadduct in a modest yield <20040L3241>. 

More promising, in terms of green efficiency, was the procedure [18] for obtaining 1 depicted in Scheme 16.1. The key step of this procedure is an extremely atom efficient and regiospecific dipolar cycloaddition between an in situ generated nitrile oxide and isobutene diacetate (2). The cycloadduct is then converted into 1 by a simple saponification/hydrogenolysis/furan ring formation three-step sequence. 

Benzyne can be trapped in 1,3-dipolar cycloaddition reactions provided that the 1,3-dipolar species is sufficiently stable under the conditions necessary for benzyne generation. As an illustration of this, benzyne reacts with the nitrile oxide group in preference to the furan ring of compound 19, whereby adduct 20 is obtained.27 Benzyne and the nitrone 21 give adduct 22,28 and... 

Jurij Svete was born in Ljubljana, Slovenia, in 1962. He received his diploma in chemistry in 1986 and his Ph.D. in 1990 under supervision of Professor Stanovnik. He continued to work as a researcher with the group of Professor Stanovnik. In 1997, he spent one year as a Humboldt Fellow at the University of Stuttgart, Germany, working with Professor Jager on the synthesis of imonopolyols fom furan-nitrile oxide cycloadducts. In 1996, he became an assistant professor at the University of Ljubljana and a full professor in 2006. His research interests include synthesis of heterocyclic compounds with emphasis on chiral functionalized heterocycles, stereoselective synthesis, chemistry of enaminones, 1,3-dipolar cycloadditions, and combinatorial synthesis. 

Additional examples of synthetic applications of hypervalent iodine-induced heterocyclizations include the following the metal-free one-pot synthesis of 2-acylbenzothiazoles by oxidative cyclization of multiform substrates [434], iodine(III)-mediated tandem oxidative cyclization for construction of 2-nitrobenzo[ ]furans [435], hypervalent iodine mediated oxidative cyclization of o-hydroxystilbenes into benzo- and naphthofu-rans [436], PhI(OCOCF3)2-mediated synthesis of 3-hydroxy-2-oxindoles and spirooxindoles from anilides [437], synthesis of isoxazoles by hypervalent iodine-induced cycloaddition of nitrile oxides to alkynes [438],... 

Six-membered Rings.— The versatility of 1,3-dipolar cycloadditions and of hetero-Diels-Alder reactions is, once again, used to great effect for the synthesis of 1,2-oxazine derivatives. Useful, multifunctionalized heterocycles are obtained by reaction of nitrile oxides with sulphoxonium allylides, followed by conversion of the initially formed furans (257) to oxazines (258) by treatment with tosic acid. Treatment with NEts causes migration of the alkoxycarbonyl group forming the pyrrolone (259). 

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