Indoline Ring System Research Articles

Divergent Synthesis of Indolenine and Indoline Ring Systems by Palladium‐Catalyzed Asymmetric Dearomatization of Indoles**

AbstractDearomatized indole derivatives bearing a C3‐ or C2‐stereocenter exist ubiquitously in natural products and biologically active molecules. Despite remarkable advances in their synthesis, stereoselective and regio‐divergent methods are still in a high demand. Herein, a Pd‐catalyzed intermolecular asymmetric spiroannulation of 2,3‐disubstituted indoles with internal alkynes has been developed for the efficient construction of indoline structures with a C2‐quaternary stereocenter. Stereospecific aza‐semipinacol rearrangement of these indoline derivatives under acidic conditions afforded indolenine products bearing a C3‐quaternary stereocenter, where the migrating group could be controlled by the reaction sequence. The asymmetric spiroannulation together with the subsequent aza‐semipinacol rearrangement enabled a divergent access to dearomatized indole derivatives with either a C3‐ or a C2‐quaternary stereocenter.

Divergent Synthesis of Indolenine and Indoline Ring Systems by Palladium‐Catalyzed Asymmetric Dearomatization of Indoles**

Dearomatized indole derivatives bearing a C3- or C2-stereocenter exist ubiquitously in natural products and biologically active molecules. Despite remarkable advances in their synthesis, stereoselective and regio-divergent methods are still in a high demand. Herein, a Pd-catalyzed intermolecular asymmetric spiroannulation of 2,3-disubstituted indoles with internal alkynes has been developed for the efficient construction of indoline structures with a C2-quaternary stereocenter. Stereospecific aza-semipinacol rearrangement of these indoline derivatives under acidic conditions afforded indolenine products bearing a C3-quaternary stereocenter, where the migrating group could be controlled by the reaction sequence. The asymmetric spiroannulation together with the subsequent aza-semipinacol rearrangement enabled a divergent access to dearomatized indole derivatives with either a C3- or a C2-quaternary stereocenter.

Diversity-Oriented Synthetic Approaches for Furoindoline: A Review.

The furo [2,3-b] indoline ring system is one of the most important structural units in various natural products. It has been known to have inherent biological activities and is utilized as a synthetic target for a number of natural compounds; therefore, this has contributed to a great demand for the growth of synthetic methods for this ring system. Most important compounds with furoindoline ring system are physovenine, madindoline A and B and makomotindoline etc. These compounds are well known to exhibit biological activity against different diseases such as glaucoma, cancer, cachexia, Castleman's disease, rheumatoid arthritis, etc. The current article focuses on various synthetic approaches for furoindoline containing compounds and essential furoindoline moiety, such as oxindole-5-O-tetrahydropyranyl ether route etc., and various other diastereoand enantio- controlled approach in a very concise way.

Synthesis of fused indolines by interrupted Fischer indolization in a microfluidic reactor

This study describes our development of a microfluidic reaction scheme for the synthesis of fused indoline ring systems found in several bioactive compounds. We have utilized a continuous-flow microfluidic reactor for the reaction of hydrazines with latent aldehydes through the interrupted Fischer indolization reaction to form fused indoline and azaindoline products. We have identified optimal conditions and evaluated the scope of this microfluidic reaction using various hydrazine and latent aldehyde surrogates. This green chemistry approach can be of general utility to rapidly produce indoline scaffolds and intermediates in a continuous manner.

5′-Nitro-1,4-dihydrospiro[3,1-benzoxazine-2,3′-indolin]-2′-one

In the title compound, C15H11N3O4, the six-membered oxazine ring adopts a half-chair conformation and is oriented at an angle of 78.63 (9)° with respect to the pyrrolidine ring of the indoline ring system, which adopts an envelope conformation. The spiro centre C atom is tetrahedral and lies 0.147 (1) Å out of the plane of other four pyrrolidone ring atoms. The nitrobenzene and benzene rings exhibit near planar conformations with C—C—C—N and C—C—C—C torsion angles of 178.1 (2) and 178.8 (2)°, respectively. In the crystal, N—H...O and C—H...O hydrogen bonds connect the molecules, generating a sheet-like structure parallel to thebcplane. Within the sheets, pairs of intermolecular N—H...O hydrogen bonds form inversion dimers enclosingR22(8) ring motifs. In addition, the N—H...O and C—H...O hydrogen bonds generateR32(11) andR22(10) graph-set ring motifs extending the two-dimensional structure. A supramolecularR66(28) loop for each set of six molecules is formed by N—H...O hydrogen bonds within the extended sheet structure and stabilizes the packing. π–π stacking interactions between the nitrobenzene and benzene rings [intercentroid distance = 3.711 (1) Å] and N—O...π interactions further consolidate the crystal packing.

(R*)-1-Benzyl-3-(2-hydroxyphenyl)indoline-2-one

The title compound, C21H17NO2, crystallizes with two independent molecules (AandB) in the asymmetric unit. The indoline ring system is almost planar in both molecules (r.m.s. deviations = 0.020 and 0.024 Å for moleculesAandB, respectively). The benzyl and phenol rings are inclined to the indole ring system by 80.39 (12) and 68.39 (12)° in moleculeA, and by 79.90 (13) and 74.88 (10)° in moleculeB. The aryl rings are inclined to one another by 33.30 (14) and 30.62 (14)° in moleculesAandB, respectively. In the crystal,Amolecules are linked by pairs of O—H...O hydrogen bonds, forming inversion dimers. The same situation is observed for theBmolecules and both sets of inversion dimers encloseR22(14) ring motifs. These dimers stack along thea-axis direction and are linked by offset π–π interactions [intercentroid distance = 3.6802 (13) Å] involvingAandBindole ring systems, forming layers parallel to theabplane.

1-Allyl-3′-phenyl-6′H-spiro[indoline-3,4′-isoxazolo[4′,5′:5,6]pyrido[2,3-d]pyrimidine]-2,5′,7′(8′H,9′H)-trione dimethyl sulfoxide monosolvate

In the title solvated compound, C24H17N5O4·C2H6OS, the solvent molecule, dimethyl sulfoxide, is linked to the title molecule by an N—H...O hydrogen bond. The pyridine ring adopts a twist-boat conformation. The isoxazole ring is inclined to the indoline ring system, the pyrimidine ring, and the phenyl ring by 82.31 (7), 10.41 (8) and 53.77 (10)°, respectively. There is an intramolecular C—H...π interaction present involving the phenyl ring and the indoline ring system. In the crystal, molecules are connected by two pairs of N—H...O hydrogen bonds, forming chains along the b-axis direction, and enclosing R 2 2(8) and R 2 2(14) ring motifs. The chains are linked by C—H...O and C—H...N hydrogen bonds and offset π–π interactions, between the pyrimidine and isoxazole rings of inversion-related molecules [centroid–centroid distance = 3.7140 (9) Å], forming a three-dimensional structure.

1-Benzyl-3′-[(1H-indol-3-yl)carbonyl]-1′-methyl-2-oxo-4′-(pyridin-3-yl)spiro[indoline-3,2′-pyrrolidine]-3′-carbonitrile

In the title compound, C34H27N5O2, the central pyrrolidine ring adopts an envelope conformation, with the N atom as the flap. The mean planes of the two indoline ring systems are inclined to the mean plane of the central pyrrolidine ring by 86.26 (9) and 69.30 (9)°, respectively. The dihedral angle between the benzene and pyridine rings is 75.09 (11)°. In the crystal, molecules are linked by N—H...N and C—H...N hydrogen bonds, forming sheets parallel to theabplane.

5-Bromo-1-methylindoline-2,3-dione

In the title compound, C9H6BrNO2, the indoline ring system, the two ketone O atoms and the Br atom are nearly coplanar, with the largest deviation from the mean plane being −0.1025 (4) Å. In the crystal, molecules are linked by two weak C—H...O hydrogen bonds and π–π interactions [inter-centroid distance = 3.510 (2) Å], forming a three-dimensional structure.

5-Bromo-1-nonylindoline-2,3-dione

In the title compound, C17H22BrNO2, the indoline ring system, the two ketone O atoms and the Br atom are nearly coplanar, with an r.m.s. deviation of 0.029 Å. The indoline ring system makes a dihedral angle of 70.64 (7)° with the mean plane through the nonyl chain, which has an extended conformation. In the crystal, molecules pack in a herringbone arrangement. They are linked by two strong and two weak C—H...O hydrogen bonds, forming slabs parallel to (010).

1-(3-Bromopropyl)indoline-2,3-dione

In the title compound, C11H10BrNO2, the indoline ring system has an r.m.s. deviation of 0.026 Å. The side chain (including the Br atom) has atrans–gaucheconformation, as indicated by the N—C—C—C and C—C—C—Br torsion angles of −177.5 (3) and 68.1 (3)°, respectively. In the crystal, molecules are linked by weak C—H...O hydrogen bonds, forming a three-dimensional network.

1-Benzyl-5-bromoindoline-2,3-dione

In the title compound, C15H10BrNO2, the indoline ring system, the two ketone O atoms and the Br atom lie in a common plane, with the largest deviation from the mean plane being 0.073 (1) Å for the Br atom. The fused-ring system is nearly perpendicular to the benzyl ring, as indicated by the dihedral angle between them of 74.58 (10)°. In the crystal, molecules are linked by weak C—H...O hydrogen bonds and by π–π interactions [inter-centroid distance = 3.625 (2) Å], forming a two-dimensional structure.

5-Chloro-1-(prop-2-ynyl)indoline-2,3-dione

In the title isatin derivative, C11H6ClNO2, the indoline ring is planar (r.m.s. deviation = 0.009 Å), with the two ketone O atoms lying in the plane and the chlorine atom displaced by 0.036 (1) Å. The dihedral angle between the mean plane of the indoline ring system with that of the propynyl chain is 73 (8)°. In the crystal, molecules are linked by C—H...O hydrogen bonds, forming zigzag chains propagating along theb-axis direction. The chains are linkedviaweak π–π interactions [inter-centroid distance = 3.728 (1) Å], forming slabs parallel to thebcplane.

5-Bromo-1-octylindoline-2,3-dione

The title compound, C16H20BrNO2, crystallizes with two molecules in the asymmetric unit. The indoline ring system and the two ketone O atoms are nearly coplanar, with the largest deviations from the mean plane being 0.077 (2) and 0.055 (2) Å in the two molecules. In each molecule, the mean plane through the octyl chain is nearly perpendicular to the mean plane of the indoline ring system, as indicated by the dihedral angles between them of 86.6 (1) and 76.1 (1)°. In the crystal, molecules are linked by week C—H...O hydrogen bonds, forming a three-dimensional network.

Crystal structure of 5-bromo-1-ethylindoline-2,3-dione

The title compound, C10H8BrNO2, crystallizes with two independent molcules (A and B) in the asymmetric unit. In each mol­ecule, the indoline ring system is almost planar, with the largest deviation from the mean plane being 0.016 (2) Å in mol­ecule A and 0.040 (13) Å in mol­ecule B. In each mol­ecule, the ethyl group is nearly perpendicular to the indoline ring system with C—C—N—C torsion angles of −94.8 (3) and 93.0 (3)° in mol­ecules A and B, respectively. In the crystal, the two mol­ecules are inclined to each other, making a dihedral angle of 6.28 (8)°. In the molecular packing, the A and B mol­ecules are linked by C—H⋯O hydrogen bonds, forming –A–B–A–B– chains along [01-1]. Parallel chains are linked via a weak slipped parallel π–π inter­action [inter-centroid distance = 3.6107 (14) Å] and a short Br⋯O contact [3.183 (2) Å], forming a three-dimensional structure.

ChemInform Abstract: Recent Advance of the Application of Interrupted Fischer Indolization Toward Bioactive Indoline Alkaloids

AbstractReview: 42 refs.

Crystal structure of 1'-(prop-2-yn-1-yl)-1,4-di-hydro-spiro-[benzo[d][1,3]oxazine-2,3'-indolin]-2'-one.

In the title compound, C18H14N2O2, the six-membered oxazine ring adopts a half-chair conformation and its mean plane makes a dihedral angle of 83.23 (7)° with the pyrrolidine ring of the indoline ring system. In the crystal, mol­ecules are linked via N—H⋯O hydrogen bonds, forming chains along [100]. The chains are linked by C—H⋯π inter­actions, forming slabs parallel to (001).

Crystal structure of ethyl 2'',3-dioxo-7',7a'-di-hydro-1'H,3H,3'H-di-spiro[benzo[b]thio-phene-2,6'-pyrrolo-[1,2-c]thia-zole-5',3''-indoline]-7'-carboxyl-ate.

In the title compound, C23H20N2O4S2, the central pyrrolidine ring adopts an envelope conformation with the spiro C atom, shared with the benzo­thio­phene ring system, as the flap. The thia­zole ring has a twisted conformation on the S—C bond, where the C atom is that closest to methine C atom. The mean planes of the benzo­thio­phene and indoline ring systems are inclined to the mean plane of the central pyrrolidine ring by 82.75 (8) and 80.03 (8)°, respectively, and to each other by 61.49 (6)°. In the crystal, mol­ecules are linked via pairs of N—H⋯O hydrogen bonds, forming inversion dimers with an R 2 2(8) ring motif. The dimers are linked via C—H⋯O and C—H⋯N hydrogen bonds, forming a three-dimensional structure. The eth­oxy­carbonyl group is disordered over two orientations, with an occupancy ratio of 0.717 (12):0.283 (12).

Crystal structure of ethyl 5''-fluoro-2'',3-dioxo-6',7',8',8a'-tetra-hydro-2'H,3H,5'H-di-spiro-[benzo[b]thio-phene-2,1'-indol-izine-3',3''-indoline]-2'-carboxyl-ate.

In the title compound, C25H23FN2O4S, the fused piperidine ring of the octa­hydro­indolizine ring system adopts a chair conformation and the five-membered ring has a twisted conformation on the N—C(spiro) bond. The mean planes of the benzo­thio­phene and indoline ring systems are inclined to the mean plane of the pyrrolidine ring by 83.1 (1) and 84.9 (1)°, respectively, and to each other by 29.37 (17)°. In the crystal, mol­ecules are linked via pairs of N—H⋯O hydrogen bonds, forming inversion dimers with an R 2 2(8) ring motif. The dimers are linked via C—H⋯O hydrogen bonds, forming slabs lying parallel to (100). The packing between the slabs features a short [2.734 (2) Å] F⋯F contact.

Crystal structure of ethyl 1',5-dimethyl-2'',3-dioxo-3H-di-spiro-[benzo[b]thiophene-2,3'-pyrrolidine-2',3''-indoline]-4'-carboxyl-ate.

The title compound, C23H22N2O4S, crystallized with two independent mol­ecules (A and B) in the asymmetric unit. They have very similar conformations with the pyrrolidine ring having a twisted conformation, on the Cspiro—Cspiro bond, in both mol­ecules. In mol­ecule A, the mean planes of the benzo­thio­phene and indoline ring systems are inclined to the mean plane of the pyrrolidine ring by 87.59 (10) and 84.51 (11)°, respectively, and to one another by 72.69 (7)°. The corresponding angles in mol­ecule B are 87.15 (10), 84.58 (10) and 72.07 (7)°, respectively. In the crystal, the A and B mol­ecules are linked to one another by two N—H⋯O hydrogen bonds, forming a dimer. These dimers are linked via C—H⋯O hydrogen bonds, forming a three-dimensional structure.