Acrylates cycloaddition reactions with nitrile oxides

This regioselectivity is practically not influenced by the nature of subsituent R. 3,5-Disubstituted isoxazolines are the sole or main products in [3 + 2] cycloaddition reactions of nitrile oxides with various monosubstituted ethylenes such as allylbenzene (99), methyl acrylate (105), acrylonitrile (105, 168), vinyl acetate (168) and diethyl vinylphosphonate (169). This is also the case for phenyl vinyl selenide (170), though subsequent oxidation—elimination leads to 3-substituted isoxazoles in a one-pot, two-step transformation. 1,1-Disubstituted ethylenes such as 2-methylene-1 -phenyl-1,3-butanedione, 2-methylene-1,3-diphenyl- 1,3-propa-nedione, 2-methylene-3-oxo-3-phenylpropanoates (171), 2-methylene-1,3-dichlo-ropropane, 2-methylenepropane-l,3-diol (172) and l,l-bis(diethoxyphosphoryl) ethylene (173) give the corresponding 3-R-5,5-disubstituted 4,5-dihydrooxazoles. 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

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). 

By using a multicomponent cascade reaction. Parsons et al. [88] achieved one-pot sequential [1+4] and [3+2] cycloadditions to synthesize highly substituted iso-xazolines via nitrile oxides (Scheme 11.28). These five-component reactions proceed by initial formation of isonitriles 109 that react with nitroalkenes 110 to form unstable N-(isoxazolylidene)alkylamines, which in turn fragment to generate the nitrile oxides 111. Cycloaddition then occurs with methyl acrylate, chosen for its expected reactivity with nitrile oxide dipoles, to generate the isoxazolines 112. Reactions using standard thermal conditions and microwave irradiation were com-... 

Baker s yeast catalyzed the regioselective cycloaddition of stable aromatic nitrile oxides ArCNO [Ar = 2,6-C12C6H3, 2,4,6-Me3C6H2, 2,4,6-(MeO)3C6H2] to ethyl cinnamate, ethyl 3-(p-tolyl)acrylate, and tert-butyl cinnamates (218). Reactions of dichloro- and trimethoxybenzonitrile oxides with all three esters proceeded regio- and stereoselectively to form exclusively alkyl tran.v -3,5-diary 1 -... 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

Multicomponent reactions (MCRs) were applied to the synthesis of substituted isoxazolines. For example, 64 was obtained by addition of nitro-alkene 60 and acrylate 61 to a solution of isonitrile 59 generated in situ by reaction of trimethylsilyl cyanide and isobutene oxide in the presence of Pd(CN)2 <05OL3179>. This cascade MCR is believed to occur through [1+4] cycloaddition of 59 with 60, subsequent fragmentation of 62 and 1,3-DC of nitrile oxide 63 with 61. Under microwave irradiation, reaction times could be reduced from several hours to 15 min, with comparable yields. 

MBH adducts and their derivatives derived from methyl acrylate and aldehydes undergo stereoselective cycloadditions with diazomethane and benzonitrile oxide to give the corresponding cycloadducts in good yields (Scheme 3.214). The stereochemical outcome can be explained by the so-called inside alkoxy elfect theory.However, in the case of diazomethane cycloadditions, electrostatic factors play a reduced role compared to the corresponding nitrile oxide reactions, while steric elfects are of major importance in governing the stereoselectivity. This dilferent behavior of the two 1,3-dipoles has been rationalized by analysis of the atomic charges, as calculated at the RHF/3-21G level of theory, for the transition structure of these reactions. 

Another [3+2]-cycloaddition process that has proven value in the construction of macrocyclic natural products, but has been underexplored to date for medicinal chemistry purposes, is the intramolecular addition of nitrile oxides (typically generated in situ from the corresponding oxime) with alkenes (Scheme 11.23). For example, this reaction has been employed for the conversion of oxime-acrylate 172 into 173, an intermediate for the synthesis of the macrosphelide skeleton, and for the construction of macrocycles useful in studies directed towards an asymmetric synthesis of brefeldin... 

---