Synthesis and spectroscopic and structural characterization of spiro[indoline-3,3′-indolizine]s formed by 1,3-dipolar cycloadditions between isatins, pipecolic acid and an electron-deficient alkene

Abstract

Five new spiro[indoline-3,3′-indolizine]s have been synthesized with high regio- and stereospecificity in one-pot three-component reactions between a substituted indole-2,3-dione, (S)-pipecolic acid and trans-3-benzoylacrylic acid, and subsequently characterized using a combination of elemental analysis, IR and 1H and 13C NMR spectroscopy, mass spectrometry and crystal structure analysis. (1′SR,2′SR,3RS,8a′RS)-2′-Benzoyl-5-fluoro-2-oxo-1′,5′,6′,7′,8′,8a′-hexahydro-2′H-spiro[indoline-3,3′-indolizine]-1′-carboxylic acid, C23H21FN2O4, (I), and (1′SR,2′SR,3RS,8a′RS)-2′-benzoyl-5-methyl-2-oxo-1′,5′,6′,7′,8′,8a′-hexahydro-2′H-spiro[indoline-3,3′-indolizine]-1′-carboxylic acid, C24H24N2O4, (II), are isomorphous, as are (1′SR,2′SR,3RS,8a′RS)-2′-benzoyl-1-methyl-2-oxo-1′,5′,6′,7′,8′,8a′-hexahydro-2′H-spiro[indoline-3,3′-indolizine]-1′-carboxylic acid, C24H24N2O4, (III), and (1′SR,2′SR,3RS,8a′RS)-2′-benzoyl-5-chloro-1-methyl-2-oxo-1′,5′,6′,7′,8′,8a′-hexahydro-2′H-spiro[indoline-3,3′-indolizine]-1′-carboxylic acid, C24H23ClN2O4, (IV). Within each isomorphous pair, the spiro ring systems show some conformational differences. In each of (I) and (II), the molecules are linked into complex sheets by a combination of four types of hydrogen bond, and in each of (III) and (IV), a combination of O—H...O and C—H...π(arene) hydrogen bonds links the molecules to form a chain of centrosymmetric rings. In (1′SR,2′SR,3RS,8a′RS)-2′-benzoyl-1-hexyl-2-oxo-1′,5′,6′,7′,8′,8a′-hexahydro-2′H-spiro[indoline-3,3′-indolizine]-1′-carboxylic acid, C29H34N2O4, (V), a combination of five hydrogen bonds links the molecules into sheets of alternating R 2 2(16) and R 6 6(46) rings. A mechanism is proposed for the formation of compounds (I)–(V) and some comparisons with related structures are made.

Synthesis, characterization, antibacterial activity and cytotoxicity of (1′R,2′S,7a′S)‐2′‐(2,5‐dichlorothiophene‐3‐carbonyl)‐1′‐(aryl)‐1′,2′,5′,6′,7′,7a′‐hexahydrospiro[indoline‐3,3′‐pyrrolizin]‐2‐one derivatives

“…Therefore, for each compound, the reference molecule was selected as one having the R configuration at atom C18 ( 4e ) and C22 ( 4g , 4h ); on this basis, the configurations at atoms C6, C7, and C14 ( 4g and 4h ) are S, R and S, respectively. Bond distances and angles for the determined derivatives fall within the range reported for derivatives containing spiro[indoline‐3,3 ′ ‐pyrrolizin]‐2‐one [9, 10] and 2,5‐dichlorothiophene [19, 21, 22]. Selected geometrical parameters are listed in Table 2.…”

“…Compounds 4(a–j) were synthesized by one pot 1,3‐dipolar cycloaddition reaction of chalcones 3(a–u) , with an azomethinylide formed from l ‐proline and 2,3‐indolinedione in MeOH (Scheme 1). The proposed mechanism for the formation of all derivatives has been reported [9, 10, 25, 26] for related compounds.…”

“…The aryl substituents (tert-butyl)phenyl in 4e, fluorophenyl in 4g and chlorophenyl in 4h) and the 2,5-dichlorothiophene-3-carbonyl are connected to spiro [indoline-3,3 0 -pyrrolizin]-2-one through carbons C1 0 and C2 0 (crystallographic numbering C7 and C6), respectively. Compounds 4e, 4g, and 4h contain chiral centers at atoms C6, C7, C14 or C18 (4e), (Figure 1), and the crystallization in centrosymmetric space groups (Table 1) indorse the crystallization as a racemic mixture [9,10]. Therefore, for each compound, the reference molecule was selected as one having the R configuration at atom C18 (4e) and C22 (4g, 4h); on this basis, the configurations at atoms C6, C7, and C14 (4g and 4h) are S, R and S, respectively.…”

“…For example, the combination of an electron deficient alkene, isatin and an amino acid [6][7][8]. Some other spiro[indoline-3,3 0 -indolizine]s synthesized by the reaction between isatins, pipecolic acid and an electron-deficient alkene [9]. The mixture of the corresponding isatin, a cyclic amino compound and an electron-deficient alkene furnished dispiro [indoline-3,3 0 -pyrrolizine-1 0 ,5 0 -thiazolidine] derivatives [10].…”