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1,3-Dipolar cycloaddition of methyl 4-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl]phenylcarbamate to non-stabilized azomethine ylides generated by decarboxylation of α-amino acid (sarcosine and proline) adducts with ketones (isatin and ninhydrin) occurred regioselectively with formation of the corresponding spiro compounds having a carbamate moiety.In continuation of our studies on the synthesis of biologically active compounds having a carbamate functionality we examined three-component reactions with participation of methyl 4-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetyl]phenylcarbamate (I) which was prepared in turn by condensation of isatin with methyl (4-acetylphenyl)carbamate [1].3-[(E)-2-Oxo-2-arylethylidene]-2,3-dihydro-1H-indol-2-ones are dipolarophiles in which electronic and steric factors act in opposite directions; therefore, it is difficult to predict regioselectivity of 1,3-dipolar cycloadditions with participation of these compounds [2]. Analysis of electronic effects shows that electron density in their molecules is displaced toward the benzoyl fragment, whereas steric factor favors reaction at the opposite position of the exocyclic double bond.It is known that the structure of 1,3-dipolar cycloaddition products derived from heteroatom N-ylides and 3-[(E)-2-aryl(hetaryl)-2-oxoethylidene]-2,3-dihydro-1H-indol-2-ones [3] and from non-stabilized azomethine ylides and (E)-2-arylmethylidene(furfurylidene)-1,2,3,4-tetrahydronaphthalen-1-ones [4,5] is determined by both dipolarophile nature and reaction conditions. It was shown previously that 1,3-dipolar cycloaddition of azomethine ylides to (Z)-or (E)-oxoindolylideneacetophenones is stereospecific and that its regioselectivity depends on the reaction conditions [6]. According to the 1 H NMR and X-ray diffraction data [2], the regioselectivity in the cycloaddition of 3-[(E)-2-oxo-2-aryl(hetaryl)ethylidene]-2,3-dihydro-1H-indol-2-ones to azomethine ylides generated from L-proline and substituted isatins by heating in boiling aqueous propan-2-ol depends on the electronic nature of substituent in position 7 of isatin which acts as 1,3-dipole. Isatin having no substituent on C 7 gives rise to syn,endo-adducts, whereas syn,exo-addition products are obtained from 7-substituted derivatives (Cl, Me, Et).Synthesis of new functionalized pyrrolidine derivatives is important from the viewpoint of preparation of peptidomimetic library [7]. Spiro-fused pyrrolidines exhibit a broad spectrum of biological activity, in particular antimicrobial, antitumor, and antibacterial; they also inhibit human NK-1 receptors [8].In view of the above stated, it seemed important to involve new 3-[(E)-2-oxo-2-arylethylidene]-2,3-dihydro-1H-indol-2-ones, in particular those possessing a carbamate moiety, in 1,3-dipolar cycloaddition. It was also important to examine the regioselectivity of cycloaddition in three-component reactions with other N-substituted α-amino acids and carbonyl compounds.We found that 1,3-dipolar cycloaddition to carbamate I of azomethine ylides generated by...

Condensation of methyl 4-acetylphenylcarbamate with isatin in the presence of diethylamine afforded methyl 4-[(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]phenylcarbamate which was converted into the corresponding chalcone on heating in glacial acetic acid in the presence of hydrochloric acid.

SHORT COMMUNICATIONS[3 + 2]-Cycloaddition is an efficient method of synthesis of five-membered nitrogen-containing heterocycles, including proline derivatives which exhibit a broad spectrum of biological activity [1,2]. Synthetic precursors of proline derivatives may be Schiff bases that are readily available from aldehydes and α-amino acid esters. The use of Brønsted acids as catalysts in 1,3-dipolar cycloaddition of azomethine ylides to unsymmetrical electron-deficient alkenes was studied to a lesser extent [3] than catalysis by Lewis acids. In these transformations, N-methylmaleimide [4], N-phenylmaleimide, dimethyl maleate, and dimethyl fumarate [3] were used as dipolarophiles.The present communication reports on 1,3-dipolar cycloaddition of Schiff bases derived from ethyl (benzylideneamino)acetate (IIa) and methyl 2-(benzylideneamino)propanoate (IIb) to methyl 4-[1-oxo-2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)ethyl]phenylcarbamate (I) in the presence of L-proline (20 mol %). It is well known that L-proline (a cyclic α-amino acid) effectively catalyzes reactions involving iminium and enamine intermediates and that it is an efficient organocatalyst in various processes [5]. In our case, the acidity of amino acid and its association with 1,3-dipole are important factors. Reaction of α-amino acid with Schiff base generates azomethine ylide as a result of protonation of the imino nitrogen atom and deprotonation of the α-carbon atom. Electrostatic and other interactions of the conjugate base of enantiomerically pure Brønsted acid with azomethine ylide could give rise to asymmetric induction in the subsequent 1,3-dipolar cycloaddition.We found that azomethine ylides generated from Schiff bases IIa and IIb did not react with methyl 4-[1-oxo-2-(2-oxo-2,3-dihydro-1H-indol-3-ylidene)-ethyl]phenylcarbamate (I) in methylene chloride at room temperature over a period of 5 days. On the other hand, heating of the reactants in boiling toluene (reaction time 8 h) gave the corresponding racemic spiro compounds IIIa and IIIb possessing a pyrrolidine ring. The products structure was confirmed by their IR, 1 H and 13 C NMR, and mass spectra. The formation of only one possible regioisomer followed from the 1 H and 13 C NMR data, as well as from comparison of the spectral data with those reported in [6,7]. Ethyl 4′-[4-(methoxycarbonylamino)benzoyl]-2′phenyl-2-oxo-1,2-dihydrospiro[indole-3,3′-pyrroli-R = H, R′ = Et (a); R = R′ = Me (b).

Three-component heterocyclization of 2-aryl-1,1-dicyanoethenes with L-proline and aldehydes leads to the formation of 1-aryltetrahydro-1H-pyrrolysines that under acid (alkaline) hydrolysis conditions are converted into derivatives of 6-carboxy-7-phenyl-2,3,5,7a-or 1,3-diaryl-2-carboxy-5,6,7,7a-tetrahydro-1H-pyrrolysine.