1.3- dipolar cycloaddition reactions regioselective addition

Analogously, the 1,3-dipolar cycloaddition reaction of 2-diazopropane with propargyl alcohol 62b, performed at 0 °C in dichloromethane, was completed in less then 10 h and led to a monoadduct 63b with the same regioselective addition mode of 59 to the triple bond. The HMBC spectrum showed correlations between the ethylenic proton and the carbons C3 and C5 and between the methyl protons and the carbons C3 and C4. 

In addition to the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity. Norbomene, for example, is consistently more reactive than cyclohexene in 1,3-dipolar cycloadditions. Conjugated functional groups also usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enamines, enol ethers, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with a few 1,3-dipoles are given in Table 6.3. Scheme 6.5 gives some examples of 1,3-dipolar cycloaddition reactions. 

The relative reaction rates of the 1,3-dipolar cycloaddition reaction of phenyl azide to dipolarophiles containing the C=C bond can be predicted by using the Jaguar V. 3.0 ab initio electronic package. Thermodynamic analysis of the 1,3-dipolar cycloaddition of organic azides with conjugated nitroalkenes at 273-398 K shows that temperature does not affect the course of these reactions in the vapour phase. Density-functional procedures have been used to explain the regioselectivity displayed by the 1,3-dipolar cycloaddition of azides with substituted ethylenes. A density-functional theory study of the 1,3-dipolar cycloaddition of thionitroso compounds with fulminic acid and simple azides indicates that the additions are not stereospeciflc. ... 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

Whereas the Rh2(OAc)4-catalyzed addition of diazoalkanes to propargyl alcohols readily gives the insertion of the carbene into the 0-H bond, with only a small amoimt of cyclopropenation of the resulting propargylic ether [54] the 2-diazopropane 59 reacts at 0 °C with l,l-diphenyl-2-propyn-l-ol 62a in dichloromethane and exclusively gives, after 10 h of reaction, only the adduct 63a isolated in 75% yield and corresponding to the regioselective 1,3-dipolar cycloaddition of the 2-diazopropane to the alkyne C - C bond (Scheme 15). 

Dipolar addition to nitroalkenes provides a useful strategy for synthesis of various heterocycles. The [3+2] reaction of azomethine ylides and alkenes is one of the most useful methods for the preparation of pyrolines. Stereocontrolled synthesis of highly substituted proline esters via [3+2] cycloaddition between IV-methylated azomethine ylides and nitroalkenes has been reported.147 The stereochemistry of 1,3-dipolar cycloaddition of azomethine ylides derived from aromatic aldehydes and L-proline alkyl esters with various nitroalkenes has been reported. Cyclic and acyclic nitroalkenes add to the anti form of the ylide in a highly regioselective manner to give pyrrolizidine derivatives.148... 

Dipolar cycloadditions to electron-deficient allenes are not regioselective, taking place at the electron-poor C=C bond, in all cases. For example, the reaction of 372 with nitrile oxide 378 furnishes a mixture of products 379-383 [356], Obviously, 379, 380 and 381 result from different [2 + 3]-cycloadditions followed by tautomer-ism, whereas 382 and 383 are formed from the primary products of the 1,3-dipolar cydoaddition via addition of a second equivalent of 378 to the remaining exocyclic C—C bond. 

Coppola et al. (81) extensively studied the dipolar cycloaddition of methyl propiolate with unsymmetrical miinchnones. In addition to their own results (Table 10.3), these investigators summarized much previous data on these cycloadditions. In the authors words No single criterion can successfully be used to correlate the experimental observations regarding the regioselectivity in milnch-none cycloaddition reactions. Steric and electronic effects must be considered in... 

Besides the 1,3-dipolar cycloaddition of azomethine ylides to C60, the Bingel cycloprop anation reaction is widely used for regioselective functionalization of fullerenes. In principle, this versatile modification involves the generation of carbon nucleophiles from a-halo esters and their subsequent addition to C60 [19]. The addition takes place exclusively on double bonds between two six-membered rings of the fullerene skeleton, yielding methanofullerenes. As shown in Scheme 2, addition of diethylbromomalonate to C60, in the presence of an auxiliary base... 

These results indicate that the sulfinyl group seems to be much more efficient in the control of the stereoselectivity of 1,3-dipolar cycloadditions (endo or exo adducts are exclusively obtained in de> 80%) than in Diels-Alder processes (mixtures of all four possible adducts were formed). Additionally, complete control of the regioselectivity of the reaction was observed. Despite these clearly excellent results, the following paper concerning asymmetric cycloaddition of cyclic nitrones and optically pure vinyl sulfoxides was reported nine years later [154]. (Meanwhile, only one paper [155], related to the synthesis of /1-nicotyri-nes, described the use of reaction of nitrones with racemic vinyl sulfoxides, but these substrates were merely used as a masked equivalent of acetylene dipolaro-phile). In 1991, Koizumi et al. described the reaction of one of the best dipolarophiles, the sulfinyl maleimide 109, with 3,4,5,6-tetrahydropyridine 1-oxide 194 [154]. It proceeded in CH2C12 at -78 °C to afford a 60 20 10 6 mixture of four products in ca. 90 % yield (Scheme 92). 

The addition of ZnBr2 to the tandem 1,3-azaprotio cyclotransfer-cycloaddition of a ketoxime with divinyl ketone results in rate enhancement and the exclusive formation of l-aza-7-oxabicyclo[3.2.1]octan-3-ones7 The 1,3-dipolar cycloaddition of 1-aza-l-cyclooctene 1-oxide with alkenes produces the corresponding isoxazolidines in high yields with a minimum of polymeric material. The cycloaddition of thiophene-2-carhaldehyde oxime with acetonitrile and methyl acrylate produces the 1,3-dipolar adduct, suhstituted isoxazolidines, and not the previously reported 4 - - 2-adducts. Density functional theory and semi-empirical methods have been used to investigate the 3 + 2-cycloaddition of azoxides with alkenes to produce 1,2,3-oxadiazolidines. The 3 -h 2-cycloaddition of a-nitrosostyrenes (62) with 1,3-diazabuta-1,3-dienes (63) and imines produces functionalized cyclic nitrones (64) regioselectively (Scheme 22). The first imequivocal 1,3-dipolar cycloaddition of sulfines involves the reaction of 2,2,4,4-tetramethyl-3-thioxocyclobutanone S-oxide with diaryl thioketones to produce... 

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