Utilization of 1,3-Dipolar Compounds

The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

Cesium fluoride induced desilylation of immonium salts provides reactive azomethine yields, which are capable of 1,3-dipolar addition to many a, 8-unsaturated compounds to form heterocycles. Examples utilizing... 

From Diazo Compounds via 1,3-Dipolar Cycloaddition. This method has been utilized widely in heterocychc chemistry. Pyrazohne (57) has been synthesized by reaction of ethyl diazoacetate (58) with a,P-unsaturated ester in the presence of pyridine (eq. 12) (42). 

This class of compounds has been prepared only as the S-oxides or dioxides. The most common approach to the S-oxides involves the cyclization of amidrazones with thionyl chloride but the 1,3-dipolar cycloaddition of a nitrileimine to thionyl aniline has also been utilized <84CHEC-I(6)579>. Examples of the former approach are shown in Equation (4) <89JHC205> and Equation (5) <90JCS(P2)1619>. The structure assignment of the product from Equation (5) is based on x-ray analysis (see Section 4.20.2.1). 

It should be noted, however, that the 1,3-dipolar cycloaddition chemistry of diazo compounds has been used much less frequently for the synthesis of natural products than that of other 1,3-dipoles. On the other hand, several recent syntheses of complex molecules using diazo substrates have utilized asymmetric induction in the cycloaddition step coupled with some known diazo transformation, such as the photochemical ring contraction of A -pyrazolines into cyclopropanes. This latter process often occurs with high retention of stereochemistry. Another useful transformation involves the conversion of A -pyrazolines into 1,3-diamines by reductive ring-opening. These and other results show that the 1,3-dipolar cycloaddition chemistry of diazo compounds can be extremely useful for stereoselective target-oriented syntheses and presumably we will see more applications of this type in the near future. 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

Mesoionic compounds have been known for many years and have been extensively utilized as substrates in 1,3-dipolar cycloadditions.158-160 Of the known mesoionic heterocycles, munchnones and sydnones have generated the most interest in recent years. These heterocyclic dipoles contain a mesoionic aromatic system i.e. 206) which can only be depicted with polar resonance structures.158 Although sydnones were extensively investigated after their initial discoveiy in 1935,160 their 1,3-dipolar character was not recognized until the azomethine imine system was spotted in the middle structure of (206). C-Methyl-N-phenylsydnone (206) combines with ethyl phenylpropiolate to give the tetrasub-... 

Arrieta et al. (1998) illustrated the synthesis of (4,3 )-bipyrazole (3) by utilizing the mixture of dimethylhydrazone and ethyl phenylpropiolate under microwave irradiation. They also described the microwave-assisted 1,3-dipolar cycloadditions with electron-dehcient dipolarophiles to afford the corresponding cycloadducts. The use of pyrazolyl hydrazones led to valuable compounds, such as bipyrazoles (4), in good yields, providing a new approach to the preparation of these heterocyclic derivatives. 

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