Nitrile oxides functional derivatives

Another route involving intramolecular cycloaddition of nitrone and nitrile oxide functionalities of the indole derivative (166) gave a novel class of mitomycin analogues which are dihydro- and tetrahydroisooxazolo[3, 4 3,4]pyrrolo[l,2-a]indole (167) and (168) (Equation (8)) <89TL1421>. 

Nitro compounds are versatile precursors for diverse functionalities. Their conversion into carbonyl compounds by the Nef reaction and into amines by reduction are the most widely used processes in organic synthesis using nitro compounds. In addition, dehydration of primary nitro compounds leads to nitrile oxides, a class of reactive 1,3-dipolar reagents. Nitro compounds are also good precursors for various nitrogen derivatives such as nitriles, oximes, hydroxylamines, and imines. These transformations of nitro compounds are well established and are used routinely in organic synthesis. 

A wide range of aliphatic nitrile oxides 370a-k and 372a-e, variously functionalized on the side chain, were added to MCP and its derivatives, on the route for the synthesis of functionalized dihydropyridones (Tables 29 and 30) [92]. 

Dipolar addition of ethyl propiolate to the nitrile oxide 285, prepared by chlorination of the corresponding oxime, gave, after removal of protecting groups, the C-glycosyl-isoxazole205 (286). These reactions further demonstrate the utility of anomerically functionalized C-/3-D-ribofuranosyl derivatives that can be prepared from the versatile aldehyde 100. 

Cycloaddition with nitrile oxides occur with compounds of practically any type with a C=C bond alkenes and cycloalkenes, their functional derivatives, dienes and trienes with isolated, conjugated or cumulated double bonds, some aromatic compounds, unsaturated and aromatic heterocycles, and fullerenes. The content of this subsection is classified according to the mentioned types of dipolarophiles. Problems of relative reactivities of dienophiles and dipoles, regio- and stereoselectivity of nitrile oxide cycloadditions were considered in detail by Jaeger and... 

The cycloaddition of Weinreb amide functionalized nitrile oxide with a range of dipolarophiles has been studied. N-Methoxy-N-methylcarbonocyanidic amide, nitrile oxide 207 (i.e., a nitrile oxide of Weinreb amide type derivative) was generated from 2-chloro-2-(hydroxyimino)-N-methoxy-N-methylacetamide as intermediate and used in situ. Thus, addition of 3-bromo-l-propyne as dipolarophile to this precursor of 207, followed by quenching with triethylamine, gave 5-(bromo-methyl)-N-(methoxy)-N-methyl-3-isoxazolecarboxamide 208 in 55% to 60% yield (367). 

A total synthesis of functionalized 8,14-seco steroids with five- and six-membered D rings has been developed (467). The synthesis is based on the transformation of (S)-carvone into a steroidal AB ring moiety with a side chain at C(9), which allows the creation of a nitrile oxide at this position. The nitrile oxides are coupled with cyclic enones or enol derivatives of 1,3-diketones, and reductive cleavage of the obtained cycloadducts give the desired products. The formation of a twelve-membered ring compound has been reported in the cycloaddition of one of the nitrile oxides with cyclopentenone and as the result of an intramolecular ene reaction, followed by retro-aldol reaction. 

Actually, nitronates are the closest related derivatives of nitronic acids, that is, aci forms of AN, which exist in labile equilibrium with true AN. Some derivatives of nitronic acids, —CH=N(0)0X, where OX is the good leaving group, are evident intermediates in the most well-developed procedures for the synthesis of nitrile oxides from primary AN. In this chapter, special emphasis is given to particular nitronates, which are generated from a-functionalized AN and can also be considered as precursors of a-functionalized nitrile oxides. 

As can be seen from Scheme 3.88, nitrile oxides can be generated in the reactions of acids or bases with other alkyl nitronates derived from a-functionalized nitro compounds (300, 301). 

Isoxazolines can be transformed into a,p-enones by several methods from the initial aldol product. This strategy was applied by Barco et al. (285) toward the synthesis of ( )-pyrenophorin (98), a macrocychc fow(enone-lactone) with antifungal properties. The hydroxy group was introduced from the nitrile oxide component (95), while the carboxy function was derived from the acrylate dipo-larophile. Thus, cycloaddition of the optically active nitropentyl acetate 94 to methyl acrylate 95 afforded isoxazoline 96 as a mixture of optically active diastereomers. Reductive hydrolysis using Raney nickel/acetic acid gave p-hydro-xyketone (97), which was subsequently utilized for the synthesis of (—)-pyreno-phorin (98) (Scheme 6.63) (285). 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Compounds containing the C=N functional group derivatives undergo anodic oxidation when the nitrogen atom bears an electron-rich heteroatom. Perhaps the simplest such species are aldoximes, which are anodically oxidized to nitrile oxides (34)38. The reaction was carried out in an undivided cell3 , hence the species 34 underwent immediate reduction to a nitrile (equation 19). However, since nitrile oxides are 1,3-dipolar species, one could in principle carry out the oxidation in a divided cell in the presence of a good 1,3-dipolarophile40 to effect the synthesis of substituted heterocycles. 

The 1,3-dipolar cycloaddition of nitrile oxide to an unsaturated ester is a useful synthetic strategy for the synthesis of heterocycles such as A -isooxazolines and a-hydroxy-y-keto or y-imino carboxylic acids. Thus, the 1,3-dipolar cyclo-addition of the 4-0-acryloyl derivative 115 (R = f-butyldimethylsilyl) with two nitrile oxides (R = Ph or t-Bu) was explored by the Tadano group [95] (O Scheme 33). In the case of benzonitrile oxide (R =Ph), a functionalized A -isooxazoline 124 was obtained as a single isomer in excellent yield. Thus, the cycloaddition proceeded smoothly at room temperature with extreme stereoselectivity. 

Asymmetric 1,3-dipolar cycloadditions employing diphenylnitrone and mesito-nitrile oxide were carried out by applying a tyrosine derived Evans auxiliary on solid support [13, 31]. Preparation of the chiral linker 56 started with esterification, protection of the amino functionality and subsequent reduction of commercially available L-tyrosine 54. The obtained alcohol 55 was then cyclized under thermal conditions and has been attached to Wang or Merrifield resin (Scheme 12.21). 

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