Azomethine ylides derivations

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... 

Besides the use of porphyrins as azomethinic ylide derivatives, the porphyrin macrocycle can also be used to generate porphyrinic nitrile oxides 55 (Scheme 17) <04RCB(E)2192>. Thus, the treatment of oxime 54 with /V-bromosuccinimide in the presence of triethylamine, led to the formation of nitrile oxide 55, which was trapped in 1,3-DC reactions with dimethyl maleate and 2,5-norbomadiene to afford 56 and 57, respectively. In the reaction with 2,5-norbomadiene, if an excess of 55 was used, then the corresponding bis-adduct was obtained in good yield. 

A final class of dipole shown to be effective in iminium ion catalysed [3+2] cycloadditions are azomethine ylides derived from 35 [71] (Scheme 12). Vicario showed that 20 mol% of diarylprolinol 33 catalysed the cycloaddition between a,P-unsaturated aldehydes 34 and imines 35 (THE, 4 °C, 72 h) to give the densely... 

Dipolar cycloaddition is another route to benzopyrrolo[l,2-a]azepines by pyrrole ring formation. The azomethine ylide derived from imine 88 and difluorocarbene adds to DMAD to produce dimethyl 3-fluoro-9H-dibenzo[c,/]-pyrrolo[l,2-fl]azepine-l,2-dicarboxylate 89 in 20% yield (Equation (12)... 

Harwood and Lilley (87) reported the tandem generation and intramolecular trapping of a stabilized azomethine ylide, derived from the enantiopure template examined in detail in Section 3.2.3. Condensation of 5-hexenal with template 205 under standard conditions led to in situ ylide generation and subsequent cycloaddition of the tethered alkene to furnish 296 as a single enantiomer in 95% yield after purification and this despite the fact that the dipolarophile is unactivated. Hydro-genolytic destruction of the template revealed the bicyclic amino acid 297 in 75% yield (Scheme 3.97). 

In a similar study to that outlined by Grigg, Kanemasa et al. (68) has demonstrated the intramolecular cycloaddition of azomethine ylides derived from either amino acids or esters. Treatment of the amino methyl ester 302 with... 

Padwa et al. (75) found that the unsymmetrical miinchnone 137, which was generated from A-acetyl-7/-benzylglycine (136) and refluxing acetic anhydride, reacts with methyl propiolate to give an 8 1 mixture of pyrroles 138 and 139. The same product ratio is obtained from the reaction of methyl propiolate and the azomethine ylide derived from 7/-benzyl-A(-(a-cyanoethyl)-A(-[(trimethylsilyl)-methyl] amine. 

A new dipolarophile bearing a chirality-controlling heterocyclic auxiliary at the p-position is readily accessible from (5)-A -benzylvalinol and methyl ( )-4-oxo-2-propenoate. However, the dipolarophile is available only as an 86 14 equilibrium mixture of trans and cis stereoisomers (Scheme 11.20) (84). When this is used without separation in the reaction with the Al-hthiated azomethine ylide derived from methyl (benzylideneamino)acetate in THE at 78 °C for 3.5 h, a mixture of two diastereomeric cycloadducts (75 25) was obtained in 82% yield. These two cycloadducts are derived from the trans and cis isomers of acceptor, indicating that both cycloadditions were highly diastereoselective. 

Husson and co-workers (84) investigated the 1,3-dipolar cycloaddition of acyclic chiral azomethine ylides derived from (—)-Af-cyanomethyl-4-phenyl-l,3-oxazoli-dine with electron-deficient alkenes, and in some cases de >95% were obtained. 

Azomethine ylides derived from (55,6/ )-2,3,5,6-tetrahydro-5,6-diphenyl-1,4-oxazin-2-one (53) and various aldehydes have been prepared by Williams and co-workers (87,88) (Scheme 12.19). In a recent communication they reported the application of the azomethine ylide 54 in the asymmetric total synthesis of spirotryprostatin B 56 (88). The azomethine ylide 54 is preferentially formed with ( )-geometry due to the buLkiness of the aldehyde substituent. The in situ formed azomethine ylide 54 reacted with ethyl oxindolylidene acetate to give the 1,3-dipolar cycloaddition adduct 55 in 82% yield as the sole isomer. This reaction, which sets four contiguous stereogenic centers, constmcts the entire prenylated tryprophyl moiety of spirotryprostatin B (56), in a single step. 

Other 1,3-dipolar cycloadditions of chiral azomethine ylides with Cgo (98) and reactions of chiral azomethine ylides derived from l-benzyl-4-phenyl-2-imidazoline with different electron-deficient alkenes have been performed (99). 

Grigg and co-workers (383) found that chiral cobalt and manganese complexes are capable of inducing enantioselectivity in 1,3-dipolar cycloadditions of azomethine ylides derived from arylidene imines of glycine (Scheme 12.91). This work was published in 1991 and is the first example of a metal-catalyzed asymmetric 1,3-dipolar cycloaddition. The reaction of the azomethine yhde 284a with methyl acrylate 285 required a stoichiometric amount of cobalt and 2 equiv of the chiral ephedrine ligand. Up to 96% ee was obtained for the 1,3-dipolar cycloaddition product 286a. 

The above azomethine ylide cycloadditions have been extended to an enantio-selective version involving amino alcohols both as chiral ligands and amine bases. Thus, reactions of the N-metalated azomethine ylides derived from achiral methyl 2-(arylmethyleneamino)acetates, cobalt(II) chloride [or manganese(II) bromide], and chiral amino alcohols, 1 and 2 equiv each, with methyl acrylate as solvent have been performed to provide the enantiomer-enriched pyrrolidine-2,4-dicarboxylates with the enantioselectivities of up to 96% enantiomeric excess (ee) (128,129). However, a large excess of the metal ions and the chiral source (ligand and base) have to be employed. 

The azomethine ylide derived from 79 has also been used in reactions with chiral ( )-y-alkoxy-cc,p-unsaturated esters 80 (Scheme 12.27). The corresponding tetra-substituted pyrrolidines 81 were obtained with complete regiocontrol in fair to excellent de (125). 

Unactivated dipolarophiles readily participate in intramolecular azomethine ylide cycloadditions with a more reactive azomethine ylide. Thus, flash vacuum pyrolysis of aziridine (113) afforded a 67% yield of the 5,5-fused bicyclic pyrrolidine (Scheme 34).59 A singly stabilized azomethine ylide was the apparent intermediate. Similarly, cyclization of the azomethine ylides derived from (114a-c) gave the corresponding cw-fused 6,6-bicyclic pyrrolidines in 69%, 26% and 16% yield, respectively the original double bond stereochemistry was retained in the latter two cases. 

The reactivity of 2/7-azirines 91 and 93 as 1,3-dipolarophiles towards (3-lactam based azomethine ylides derived from oxazolidinones 90 has been investigated [77]. The reaction of 3-(4-methoxyphenyl)-2//-azirine 91 with oxazolidinone 90 did not afford the expected cycloadduct. However, compound 92 was isolated as the... 

A. Formation of Azomethine Ylides Derived from Imines. .. 138... 

Computational studies yielded the models shown in Figure 2.2. These models illustrate how the existence or absence of hydrogen bonding between the silver/ligand complex and the dipolarphile may lead to selection of opposite faces in the reaction with the silver-bound azomethine ylide derived from 111. 

The reactivity of 2H-azirines as 1,3-dipolarophiles towards (5-lactam-based azomethine ylides derived from oxazolidinones has been evaluated <02JCS(P1)2014>, providing cycloadducts 37, which incorporate the novel 2,6-diazatricyclo[4.2.0.02 4]octan-7-one ring system. 

The same chiral auxiliary has been used in the cycloaddition of an optically active azomethine ylide to benzaldehyde and to l-nitro-2-(3,4-methylenedioxyphenyl)ethylene Ae ylide was generated in situ by treating (R)-(+)-/V-(l-phenylethyl)-A -cyanomethyl-A -trimethylsilylmethylamine (33) with silver fluoride. Unfortunately, no selectivity was observed in the first case and only a 3 2 preference was expressed in the second. Use of the azomethine ylide derived in the same manner from (/ )-(-)-N-(l-phenyl-2-methoxyethyl)-/V-cyanomethyl-N-trimethylsilylmethylamine (34) displayed a modest, but potentially useful, 4 1 diastereofacial selectivity in its reaction with l-nitro-2-(3,4-methylenedioxyphenyl)ethylene. The precise structure of the major and minor product was not determined (Scheme 25). 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

The N-unsubstituted azomethine ylides derived from the imines of a-amino nitriles are intramolecularly trapped by acetylenes to give pyrroles... 

TrifluoromethylimidtKoUnes. CFjCN is a 1,3-dipolarophile that forms 4-trifluoromethyl-A -imidazolines with azomethine ylides. Derived from simultaneous... 

A conceptually different approach was taken by Novikov and coworkers using difluorocarbene as a building block. 1,3-Dipolar addition of dipolarophiles to azomethine ylides derived by addition of difluorocarbene to imines produces substituted 2-fluoropyrroles. The process is illustrated below with the imine derived from benzaldehyde and aniline. Using dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile produces the 2-fluoropyrrole derivative 73 (Fig. 3.32). Several substrates were studied and such issues as regiochemistry were addressed. 

Novikov, M.S. Khlebnikov, A.F. Sidorina, E.S. Kostikov, R.R. 1,3-Dipolar cycloaddition of azomethine ylides derived from imines and difluorocarbene to alkynes a new active Pb-mediated approach to 2-fluoropyrrole derivatives. J. Chem. Soc., Perkin Trans. 1 2000, 231-237. 

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