Dipolar Cycloaddition with Nitrile oxides

Diels-Alder reactions of thiete 1,1-dioxides occur readily as exemplified by the syntheses of 151 ° and 152. Adducts of thiete 1,1-dioxide with tetraphenylcyclopentadienone or a-pyrone ° are thermally unstable. Thiete 1,1-dioxides also undergo 1,3-dipolar additions with diazoalkanes, (e.g., the formation of 153 from which the strained bicyclic thietane sulfone 154 is obtained) " nitrile oxides, and cycloadditions with the MA -dimethylenamine of isobutyraldehyde (e.g., the formation of 155). ° ... 

The conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

Glycosyl nitrile oxides 315, generated in situ by reaction of hydroxamoyl chlorides with DBU, participate in 1,3-dipolar cycloaddition with substituted alkenes leading to glycosyl isoxazolines the l,2,5-oxadiazole-2-oxides 316 are isolated as by-products in low yields (Scheme 79) <2004CHC353>. 

A solid-phase synthesis of substituted benzopyranoisoxazoles 356 (I R = H, Me, Et, Pr, Ph, CHMe2 R1 =H, Me, decyl, Ph) has been described (414). The six-step synthesis includes a method of generating nitrile oxides on a polymer support, followed by an intramolecular 1,3-dipolar cycloaddition with a tethered alkyne, for assembly of the benzopyranoisoxazole scaffold. 

Zecchi and co-workers also reported 1,3-dipolar cycloadditions with nitrogen-substituted allenes. As illustrated in Scheme 8.75, the expected isoxazoline derivatives 285 were obtained by [3 + 2] cycloaddition reaction of aminoallenes 246 and nitrile oxide 284 [141, 142], Bis-adducts 286 became the major products when 2equiv. of nitrile oxide 284 were applied with prolonged reaction times. 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

The lactone 88 having an exo-cyclic double bond was applied in a 1,3-dipolar cycloaddition with nitrile oxides in recent work by Gallos et al. (Scheme 12.29) (133). The ip/ro-isoxazoline (89) was obtained as the sole diastereomer from the addition of the stable nitrile oxide 87. The resulting adduct 89 was further subjected to N—O bond cleavage by hydrogenolysis, followed by a spontaneous cyclization to give the carbocyclic product 90 in 64% yield. 

Fluoro-substituted chiral vinyl sulfoxides such as 103 have been used in 1,3-dipolar cycloadditions with various benzonitrile oxides (Scheme 12.34) (158). The reaction proceeded slowly at room temperature, however, after 5-10 days the isoxazoline (104) was obtained with excellent de in good yield. In some cases, the product tends to eliminate the 5-methoxy substituent of the isoxazoline, thus, after loss of two chiral centers, an isoxazole is obtained (158,159). Other chiral suMnyl derivatives have also been used in 1,3-dipolar cycloadditions with nitrile oxides (160,161), and in one case a racemic vinyl phosphine was used in reactions with various nitrile oxides, but with moderate selectivities (151). 

The optically pure tricarbonyl chromium(O) complexes 116 have proven to offer an effective shielding of one of the faces of the alkene. Complex 116 was subjected to a 1,3-dipolar cycloaddition with the sterically crowded nitrile oxide 117 (Scheme 12.39) (172). The reaction proceeds at room temperature to give a 70% yield of 118. After removal of the tricarbonylchromium moiety by a light induced oxidation with air, compound 119 was obtained with an optical purity of 98% enantiomeric excess (ee). 

The auxihary acrylates 161 and 162 have been used in 1,3-dipolar cycloadditions with nitrile oxides. The camphor-derived acrylate 161 underwent a 1,3-dipolar cycloaddition with benzonitrile oxide with up to 56% de (Scheme 12.51) (263). The auxiliary in acrylate 162 is derived from naturally occurring L-quebrachitol, and provided an effective shielding of the re-face of the alkene in the reaction with benzonitrile oxide, as 90% de was obtained (273). Compound 163 was used in a reaction with the nitrone 1-pyrrole-1-oxide, and the reaction proceeded to give a complex mixture of products (274). 

The a,p-unsaturated amides 180-188a have all been used in 1,3-dipolar cycloadditions with nitrile oxides, and some of them represent the most diastereoselective reactions of nitrile oxides. The camphor derivative 180 of Chen and co-workers (294), the sultam 181 of Oppolzer et al. (295), and the two Kemp s acid derived compounds 186 (296) and 187 (297) described by Curran et al. (296) are excellent partners for diastereoselective reactions with nitrile oxides, as very high diastereos-electivities have been observed for all of them. In particular, compound 186 gave, with few exceptions, complete diastereoselection in reactions with a wide range of different nitrile oxides. Good selectivities were also observed when using compounds 183 (298) and 184 (299-301) in nitrile oxide cycloadditions, and they have the advantage that they are more readily available. Curran and co-workers also studied the 1,3-dipolar cycloaddition of 187 with silyl nitronates. However, compared to the reactions of nitrile oxides, lower selectivities of up to 86% de were obtained (302). 

In three separate papers, the use of chiral boronic esters in 1,3-dipolar cycloadditions with nitrile oxides have been described (316-318). The reaction of 203 with nitrile oxides proceeded with low diastereoselectivities (Scheme 12.58). 

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. 

Another example of oligomer preparation by C-C bond formation is outlined in Figure 16.30. In this synthesis, nitroalkyl phenyl selenides are converted into nitrile oxides in the presence of support-bound terminal alkenes, forming isoxazolines. Oxidative elimination of the selenide yields a new alkene, which can then be subjected to further 1,3-dipolar cycloaddition with a new nitrile oxide. Although this synthesis is short and easy to perform, the cycloadditions proceed with low diastereoselectivity... 

Dihydropyridines participate in reactions of 1,3-dipolar cycloaddition with some nitrile oxides [363, 364]. The monoester derivative 330 reacts with several nitrile oxides 331 to produce the corresponding isoxazolo[5,4-Z ]pyridine 332 (Scheme 3.111) in moderate to good yields. The regiochemistry of the cycloaddition was predicted in [363] on the basis of the complementary dipoles of the 331 and enamine double bond and was proven by conversion of 332 (R is Me, Ri is COOH) to the 5-cyano-l,4-dihydropyridine-3-carboxylic acid ester 333. 

Reactions of 3,5-dichloro-2,4,6-trimethyl benzonitrile oxide 241 with fluoro-methyl substituted alkenes 242, bearing a chiral sulfinyl group at -position of the double bond, afford diastereoisomeric 4,5-dihydroisoxazoles 243 and 244 [180] with a stereoselectivity lower than 2 1 (Scheme 110). The authors conclude that the efficiency of allyl sulfoxides to control diastereoselectivity of 1,3-dipolar cycloadditions with nitrile oxides is lower than that of vinyl sulfoxides. 

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