Azomethine imines, pyrazolidine

In situ generation of azomethine imines from furan-3-carbaldehyde and ]V,N -disubstituted hydrazines followed by cycloaddition to N-methylmaleimide results in a 2.8 1 mixture of pyrazolidines 94 and 95 (X = O) separatable by chromatography. Eurther Pd(0) catalyzed cyclization involving the aldehyde and hydrazine moieties leads to the formation of benzoxepines 96 and 97 (X = O) in good yield (Scheme 17 (2003X4451)). 

Azomethine imines were generated by cleavage of certain 1,3,4-oxadia-zolidines (42) and subsequently trapped with dipolarophiles such as styrene and stilbene affording pyrazolidine heterocycles (96TL4323). 

Hydrazones have also been used as azomethine imine precursors to achieve cycloadditions.157 Proto-nated hydrazones act under suitable conditions as quasi-azomethine imines in polar [3+ + 2] cycloadditions. Thus, r.cetaldehyde phenylhydrazone (201) was found to react with styrene in the presence of sulfuric acid in a regiospecific manner to give pyrazolidine (203 Scheme 47) as a diastereomeric mixture.157 The most commonly used azomethine imine has a phenyl group attached to one end of the dipole and hence has a raised HOMO relative to the unsubstituted system. Because the coefficients at the terminal atoms of the dipole are smaller in the LUMO than they are in the HOMO, the phenyl group does not lower the energy of the LUMO as much as it raises the energy of the HOMO. With electron-deficient di-polarophiles like methyl acrylate, the reaction is dipole HOMO-controlled, and mixtures can be expected. In fact, a 1 1 mixture of regioisomers was obtained in the reaction of (201) with acrylonitrile (equation 9).157... 

Azomethine imine cycloadditions provide access to pyrazolidines, pyrazolines and pyrazoles. Intramolecular cyclizations were first reported in 1970.78 The main method for generation of azomethine im-ines involves reaction of a 1,2-disubstituted hydrazine with an aldehyde or an aldehyde precursor. 

The azomethine imine (151), having the alkene attached to the terminal dipole nitrogen, was generated in situ from the corresponding hydrazine by reaction with benzaldehyde (Scheme 47).79 As is typical in these reactions, condensation at the more basic benzyl-substituted nitrogen occurred, rather than at the acyl-substituted nitrogen. Cyclization of (151) afforded the 5,5-fused pyrazolidine and no bridged product. 

Azomethine imines which contain an intervening aromatic ring between the dipole and dipolarophile are accessible from aryl aldehydes and readily undergo cyclization. Thus, imine (154), where the dipolarophile is attached at the carbon of the dipole, afforded cis- and rrans-fused tricyclic pyrazolidines in which the alkene stereochemistry was retained (Scheme 48).78 ... 

The azomethine imine (155), containing a cyclic dipolarophile, cyclized to a tetracyclic pyrazolidine in 48% yield.78 Aldehyde (156), containing a furan ring, reacted with A/-methyl-A/ -(phenylacetyl)hydra-zine to afford an azomethine imine the imine cyclized to one product, probably with the two new rings cis fused.80... 

Aldehyde (166) reacted with excess hydrazine hydrochloride to afford a pyrazoline in 63% yield a mixture of pyrazoline and pyrazolidine was obtained under an inert atmosphere.83 This reaction presumably involves the hydrazone and protonated azomethine imine as intermediates. Using (166) in excess afforded a bisintramolecular adduct in 87% yield. 

Phenylperhydro-l,3,4-oxadiazin-2-ones 151 react with aliphatic or aromatic aldehydes or ethyl 2-oxoacetate to give the intermediates 152. The azomethine imine ylides 152 yield primary oxazolidines 153 <200081170, 2002S1885, 2004TL3127>. These compounds can be synthesized also by treatment of 151 with ethyl oxoacetate or aldehydes in the presence of magnesium bromide etherate. The tandem cycloreversion-cycloaddition of 153 with various electron-poor dipolarophiles then leads to pyrazolidines 154-156 (Scheme 22). 

Asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of C,A-cyclic azomethine imines with c-rich dipolarophiles was accomplished with a high stereo-selectivity by using an axially chiral dicarboxylic catalyst (40)." The metal-free silicon Lewis-acid-catalysed 3-1-2-cycloadditions of A-acylhydrazones with cyclopentadiene provides a mild access to pyrazolidine derivatives in excellent... 

Pyrazolidines and Related Compounds.—Pyrazolidines are obtained by trapping the base-generated azomethine imine derived from a methylhydrazinomaleic acid with suitable dipolarophiles (Scheme 110). ... 

The synthesis of A,A-bicyclic pyrazolidin-3-one derivatives has been accomplished throngh a 1,3-dipolar cycloaddition between A,A -cyclic azomethine imines and hydroxyl styrenes (Scheme 3.42) [40], The chemistry was carried ont nnder mild conditions and afforded moderate yields of the heterocycles with good to excellent selectivity. 

A. A -Bicychc pyrazolidin-3-ones 31, potentially bioactive heterocycles, are also constructed by the [3+2] cycloaddition of Fischer alkynyl carbene complexes 28 with azomethine imines 29 via isolable metal-carbene intermediates 30 (Scheme 5.8) [17]. 

First, the 1,3-dipolar cycloaddition of l-alkylidene-3-oxopyrazolidin-l-ium-2-ide 11 was examined. In this case, a magnesium-mediated system instead of the zinc-mediated system was found to be effective to realize the asymmetric 1,3-dipolar cycloaddition, that is, to a mixture of allyl alcohol (lA) and (R,R)-DIPT were added 3.0 equiv of alkylmagne-sium bromide and azomethine imines 11 successively. The corresponding pyrazolidines 12 were obtained in a good chemical yield with the excellent enantioselectivities as listed in Table 11.1, even in the case of pentyl- and cyclohexyl-substituted ones llg and llh (entries 7 and 8) [14]. 

The 1,3 dipolar cycloaddition between azomethine imines 47 and alkenes 48 delivers pyrazolidines 49 (Scheme 41.11). Highly diasteroselective and enantioselective versions of this cycloaddition have been developed by different research groups... 

Related to azomethine imines, the acylhydrazone 58-olefin 59 cycloaddition also yields pyrazolidines 60 (Scheme 41.13). ... 

Azomethines add with great ease and stereospecificity to carbon-carbon double bonds affording pyrazolidines. They also add to carbon-carbon triple bonds with the formation of pyrazolines. Benzimidazolium iV-imines, e.g. (622), are a special case of azomethines. Its reaction with DMAD yields l-(2-methylaminophenyl)pyrazole (624), which is formed by cleavage of the initial adduct (623) (75JHC225). 

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