New spiro[indoline-3,3′-indolizine]s have been synthesized with high regio- and stereospecificity from simple starting materials in a one-step process. Different combinations of hydrogen bonds link the molecules to form either sheets or chains of rings.
Keywords: synthesis; heterocycle; spiro[indoline-3,3′-indolizine]; NMR spectroscopy; reaction mechanism; crystal structure; stereochemistry; molecular conformation; supramolecular assembly
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.
Introduction
Spirooxindoles are a privileged category of heterocycles containing a unique and versatile scaffold for novel drug discovery in fields as diverse as analgesics, anticancer, anti-inflammatory and antimicrobial agents, and antioxidants, whose structure–activity relationships and molecular mechanisms of action have recently been reviewed (Zhou et al., 2020 ▸).
Multicomponent reactions can provide versatile and efficient routes to new heterocyclic systems, permitting the incorporation of a wide variety of functionalities by the combination of three or more simple building blocks (Dömling, 2002 ▸; Hulme & Gore, 2003 ▸; Orru & de Greef, 2003 ▸; Quiroga et al., 2007 ▸, 2014 ▸). The spirooxindole core is readily obtained using 1,3-dipolar cycloadditions between electron-deficient alkenes and an azomethine ylide, generated in situ from an isatin (indole-2,3-dione) and an amino acid (Grigg et al., 1984 ▸; Al-Majid et al., 2020 ▸; Ghosh et al., 2020 ▸). We have recently reported the regio- and stereospecific synthesis, spectroscopic characterization and crystal structures of some spiro[indoline-3,3′-pyrrolizine]s (Quiroga et al., 2017 ▸) and dispiro[indoline-3,3′-pyrrolizine-1′,5′-thiazolidine]s (Romo et al., 2020 ▸), formed in a single step from mixtures of a substituted isatin, a cyclic amino compound and an electron-deficient alkene. As a development of these previous studies, we have now investigated the reactions between isatins, pipecolic acid [(RS)-piperidine-2-carboxylic acid] and trans-3-benzoylacrylic acid [(E)-4-oxo-4-phenylbut-2-enoic acid] to form spiro[indoline-3,3′-indolizine]s. Here we report the synthesis and spectroscopic charaterization, and the molecular and supramolecular structures of five representative examples, namely, (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, (I), (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, (II), (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, (III), (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, (IV), and (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, (V) (Scheme 1).
Compounds (I)–(V) were formed in yields between 48 and 69% in one-pot reactions between an appropriately substituted isatin (see Scheme 2), pipecolic acid acting as the cyclic amine component and trans-3-benzoylacrylic acid acting as the electron-deficient alkene to give the products defined in Scheme 1 and Figs. 1 ▸–5 ▸ ▸ ▸ ▸. Products (I)–(V) were all isolated as single racemic stereoisomers and all have been characterized by a combination of elemental analysis, IR and 1H and 13C NMR spectroscopy, mass spectrometry and X-ray crystal structure analysis, which enables a complete definition of the stereochemistry.
Figure 1.
The molecular structure of the (1′S,2′S,3RS,8a′R) enantiomer of compound (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
Figure 2.
The molecular structure of the (1′S,2′S,3RS,8a′R) enantiomer of compound (II), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
Figure 3.
The molecular structure of the (1′S,2′S,3RS,8a′R) enantiomer of compound (III), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
Figure 4.
The molecular structure of the (1′S,2′S,3RS,8a′R) enantiomer of compound (IV), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
Figure 5.
The molecular structure of the (1′S,2′S,3RS,8a′R) enantiomer of compound (V), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
Experimental
Synthesis and crystallization
All reagents and solvents were obtained commercially and all were used as recieved. For the synthesis of compounds (I)–(V), mixtures of pipecolic acid (64.6 mg, 0.5 mmol), the appropriately substituted isatin (0.5 mmol) [5-fluoroisatin (83.5 mg) for (I), 5-methylisatin (80.6 mg) for (II), 1-methylisatin (80.6 mg) for (III), 5-chloro-1-methylisatin (97.8 mg) for (IV) and 1-hexylisatin (115.6 mg) for (V)] and trans-3-benzoylacrylic acid [(E)-4-oxo-4-phenylbut-2-enoic acid] (88.1 mg, 0.5 mmol) in acetonitrile (10 ml) were heated under reflux until the reactions were complete, as judged by thin-layer chromatography (TLC) monitoring (reactions times were all in the range 8–12 h). The reaction mixtures were allowed to cool to ambient temperature, giving the crystalline products (I)–(V), which were collected by filtration and then dried in air. No further purification was required, as judged by TLC and spectroscopic examination, and crystals suitable for single-crystal X-ray diffraction were, in each case, selected directly from the synthesized samples.
Compound (I): yield 68%; m.p. 508–509 K. Analysis found (%): C 67.6, H 5.2, N 6.8; calculated for C23H21FN2O4 (%): C 67.6, H 5.2, N 6.9. FT–IR (ATR, cm−1): 3478, 3096, 2937, 1715, 1676. NMR (DMSO-d 6): δ(1H) 1.11–1.23 (m, 2H, H8′, H7′), 1.23–1.33 (m, 1H, H6′), 1.42–1.54 (m, 1H, H7′), 1.66–1.79 (m, 1H, H8′), 2.05–2.19 (m, 2H, H5′, H6′), 2.20–2.32 (m, 1H, H5′), 3.25 (t, J = 10.0 Hz, 1H, H8a′), 3.45 (t, J = 9.7 Hz, 1H, H1′), 4.50 (d, J = 9.7 Hz, 1H, H2′), 6.41 (dd, J = 8.6, 4.3 Hz, 1H), 6.54 (dd, J = 8.2, 2.7 Hz, 1H), 6.78 (td, J = 9.0, 2.7 Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.40–7.51 (m, 3H), 10.52 (s, 1H, NH), 12.69 (s, 1H, COOH); δ(13C) 23.7 (C8′), 25.5 (C7′), 31.8 (C6′), 45.6 (C5′), 50.5 (C1′), 55.1 (C2′), 61.5 (C8a′), 71.6 (C3, C-spiro), 110.4 (d, J C–F = 6.9 Hz, CH), 113.5 (d, J C–F = 24.7 Hz, CH), 116.0 (d, J C–F = 23.6 Hz, CH), 127.6 (CH), 129.0 (CH), 129.4 (d, J C–F = 7.4 Hz, C), 133.8 (CH), 136.9 (C), 139.0 (C), 159.5 (C), 173.4 (COOH), 179.3 (C2), 197.4 (C—CO—C). MS (EI, 70 eV) m/z (%): 408 (M +, 10), 368 (17), 336 (37), 313 (12), 275 (36), 259 (16), 231 (39), 141 (22), 105 (49), 77 (34).
Compound (II): yield 48%; m.p. 529–530 K. Analysis found (%): C 71.2, H 5.9, N 7.0; calculated for C24H24N2O4 (%): C 71.3, H 6.0, N 6.9. FT–IR (ATR, cm−1): 3364, 3225, 2957, 1741, 1704, 1668. NMR (DMSO-d 6): δ(1H) 1.10–1.20 (m, 2H, H8′, H7′), 1.21–1.32 (m, 1H, H6′), 1.43–1.50 (m, 1H, H7′), 1.67–1.74 (m, 1H, H8′), 2.05–2.18 (m, 5H, 5-CH3, H5′, H6′), 2.23 (td, J = 10.9, 2.8 Hz, 1H, H5′), 3.22–3.29 (m, 1H, H8a′), 3.44 (t, J = 9.8 Hz, 1H, H1′), 4.47 (d, J = 9.6 Hz, 1H, H2′), 6.30 (d, J = 7.8 Hz, 1H, H7), 6.57 (s, 1H, H4), 6.71 (d, J = 7.8 Hz, 1H, H6), 7.28 (t, J = 7.7 Hz, 2H, Hm), 7.38 (d, J = 7.3 Hz, 2H, Ho), 7.43 (t, J = 7.3 Hz, 1H, Hp), 10.35 (s, 1H, NH), 12.62 (s, 1H, COOH); δ(13C) 21.0 (5-CH3), 23.8 (C8′), 25.5 (C7′), 31.8 (C6′), 45.6 (C5′), 50.5 (C1′), 54.9 (C2′), 61.4 (C8a′), 71.4 (C-spiro), 109.1 (CH, C7), 126.7 (CH, C4), 127.5 (C), 127.6 (CH, Co), 128.8 (CH, Cm), 129.7 (CH, C6), 130.9 (C), 133.4 (CH, Cp), 137.2 (C), 140.3 (C), 173.6 (COOH), 179.3 (C2), 197.6 (C—CO—C). MS (EI, 70 eV) m/z (%): 404 (M +, 9), 368 (5), 332 (39), 315 (15), 271 (30), 255 (17), 227 (69), 141 (33), 105 (100), 77 (69).
Compound (III): yield 49%; m.p. 492–493 K. Analysis found (%): C 71.3, H 5.9, N 6.9; calculated for C24H24N2O4 (%): C 71.3, H 6.0, N 6.9. FT–IR (ATR, cm−1): 2941, 2356, 1709, 1677. NMR (DMSO-d 6): δ(1H) 1.09–1.21 (m, 2H, H8′, H7′), 1.21–1.36 (m, 1H, H6′), 1.38–1.52 (m, 1H, H7′), 1.66–1.81 (m, 1H, H8′), 2.01–2.18 (m, 2H, H5′, H6′), 2.23 (t, J = 10.2 Hz, 1H, H5′), 2.98 (s, 3H, N—CH3), 3.22–3.29 (m, 1H, H8a′), 3.42 (t, J = 10.0 Hz, 1H, H1′), 4.47 (d, J = 9.8 Hz, 1H, H2′), 6.52 (d, J = 7.8 Hz, 1H), 6.79–6.90 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 7.20–7.31 (m, 4H), 7.37–7.47 (m, 1H), 12.66 (s, 1H, COOH); δ(13C) 23.7 (C8′), 25.4 (C7′), 26.2 (CH3), 31.8 (C6′), 45.6 (C5′), 50.4 (C1′), 55.9 (C2′), 61.8 (C8a′), 71.1 (C3, C-spiro), 108.2 (CH), 122.9 (CH), 125.6 (CH), 127.0 (C), 127.4 (CH), 128.7 (CH), 129.6 (CH), 133.5 (CH), 137.0 (C), 144.0 (C), 173.4 (COOH), 177.4 (C2), 197.3 (C—CO—C). MS (EI, 70 eV) m/z (%): 404 (M +, 1), 393 (12), 368 (22), 339 (26), 313 (70), 264 (34), 236 (16), 57 (100).
Compound (IV): yield 69%; m.p. 497–497 K. Analysis found (%): C 65.6, H 5.2, N 6.4; calculated for C24H23ClN2O4 (%): C 65.7, H 5.3, N 6.4. FT–IR (ATR, cm−1): 3378, 3227, 2957, 1744, 1708, 1668. NMR (DMSO-d 6): δ(1H) 1.11–1.22 (m, 2H), 1.22–1.36 (m, 1H), 1.40–1.50 (m, 1H), 1.66–1.79 (m, 1H), 2.05–2.19 (m, 2H), 2.19–2.29 (m, 1H), 2.97 (s, 3H, CH3), 3.24 (td, J = 10.2, 2.5 Hz, 1H, H8a′), 3.43 (t, J = 10.0 Hz, 1H, H1′), 4.48 (d, J = 9.9 Hz, 1H, H2′), 6.56 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.3, 2.2 Hz, 1H), 7.23–7.35 (m, 4H), 7.45 (td, J = 7.0, 1.6 Hz, 1H); δ(13C) 23.6 (C8′), 25.4 (C7′), 26.4 (CH3), 31.7 (C6′), 45.7 (C5′), 50.2 (C1′), 56.1 (C2′), 62.0 (C8a′), 71.1 (C3, C-spiro), 109.9 (CH), 125.5 (CH), 127.0 (C), 127.4 (CH), 128.9 (CH), 129.2 (C), 129.5 (CH), 133.8 (CH), 136.8 (C), 142.9 (C), 173.3 (COOH), 177.0 (C2), 197.3 (C—CO—C). MS (EI, 70 eV) m/z (%): 438 (M +, 1), 336 (17), 313 (18), 275 (17), 231 (30), 141 (41), 105 (91), 77 (55), 57 (87), 43 (100).
Compound (V): yield 48%; m.p. 449–450 K. Analysis found (%): C 73.4, H 7.2, N 5.9; calculated for C29H34N2O4 (%): C 73.4, H 7.2, N 5.9. FT–IR (ATR, cm−1): 2931, 2858, 1723, 1684, 1662. NMR (DMSO-d 6): δ(1H) 0.79–0.91 (m, 3H, CH3), 1.08–1.22 (m, 2H), 1.20–1.33 (m, 7H), 1.35–1.57 (m, 3H), 1.66–1.78 (m, 1H), 2.00–2.10 (m, 1H), 2.11–2.27 (m, 2H), 3.23–3.29 (m, 1H, H8a′), 3.37–3.51 (m, 2H, NCHH, H1′), 3.60 (dt, J = 14.5, 7.4 Hz, 1H, NCHH), 4.48 (d, J = 9.7 Hz, 1H, H2′), 6.60 (d, J = 7.8 Hz, 1H), 6.74–6.91 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 7.19–7.32 (m, 4H), 7.42 (t, J = 7.2 Hz, 1H), 12.68 (s, 1H, COOH); δ(13C) 14.3 (CH3), 22.5 (CH2), 23.7 (C8′), 25.5 (C7′), 26.4 (CH2), 27.4 (CH2), 31.3 (CH2), 31.8 (C6′), 39.7 (CH2), 45.5 (C5′), 50.5 (C1′), 55.4 (C2′), 61.6 (C8a′), 70.9 (C3, C-spiro), 108.4 (CH), 122.7 (CH), 126.0 (CH), 126.9 (C), 127.5 (CH), 128.8 (CH), 129.6 (CH), 133.5 (CH), 143.5 (C), 173.5 (COOH), 177.2 (C2), 197.4 (C—CO—C). MS (EI, 70 eV) m/z (%): 475 (M + + H, 3), 368 (22), 339 (35), 313 (75), 264 (39).
Refinement
Crystal data, data collection and refinement details are summarized in Table 1 ▸. The crystallographic atom labelling followed the convention employed previously (Quiroga et al., 2017 ▸; Romo et al., 2020 ▸). For compound (II), five low-angle reflections which had been attenuated by the beam stop (101, 111, 0
1, 02 and 03) were omitted from the data set. All H atoms were located in difference maps. H atoms bonded to C atoms were then treated as riding atoms in geometrically idealized positions, with C—H = 0.95 (aromatic), 0.98 (CH3), 0.99 (CH2) or 1.00 Å (aliphatic C—H) and U
iso(H) = kU
eq(C), where k = 1.5 for the methyl groups, which were permitted to rotate but not to tilt, and 1.2 for all other H atoms bonded to C atoms. For the H atoms bonded to N or O atoms, the atomic coordinates were refined with U
iso(H) = 1.2U
eq(N) or 1.5U
eq(O), giving the N—H and O—H distances shown in Table 2 ▸.
Table 1. Experimental details.
Experiments were carried out at 100 K with Mo Kα radiation using a Bruker D8 Venture diffractometer. Absorption was corrected for by multi-scan methods (SADABS; Bruker, 2016 ▸). H atoms were treated by a mixture of independent and constrained refinement.
| (I) | (II) | (III) | |
|---|---|---|---|
| Crystal data | |||
| Chemical formula | C23H21FN2O4 | C24H24N2O4 | C24H24N2O4 |
| M r | 408.42 | 404.45 | 404.45 |
| Crystal system, space group | Triclinic, P\overline{1} | Triclinic, P\overline{1} | Triclinic, P\overline{1} |
| a, b, c (Å) | 8.1440 (5), 8.4565 (5), 14.9945 (8) | 8.1874 (6), 8.5015 (6), 15.5775 (12) | 8.6535 (4), 9.2064 (4), 14.4327 (6) |
| α, β, γ (°) | 87.549 (2), 79.926 (2), 68.467 (2) | 85.775 (3), 77.641 (3), 68.022 (2) | 72.660 (1), 74.539 (1), 65.930 (2) |
| V (Å3) | 945.52 (10) | 982.15 (13) | 988.16 (8) |
| Z | 2 | 2 | 2 |
| μ (mm−1) | 0.11 | 0.09 | 0.09 |
| Crystal size (mm) | 0.26 × 0.21 × 0.12 | 0.16 × 0.12 × 0.07 | 0.19 × 0.19 × 0.12 |
| Data collection | |||
| Tmin, Tmax | 0.939, 0.987 | 0.934, 0.993 | 0.944, 0.989 |
| No. of measured, independent and observed [I > 2σ(I)] reflections | 50206, 4727, 3889 | 40953, 4490, 3667 | 47689, 4917, 4145 |
| R int | 0.068 | 0.069 | 0.057 |
| (sin θ/λ)max (Å−1) | 0.668 | 0.650 | 0.667 |
| Refinement | |||
| R[F2 > 2σ(F 2)], wR(F 2), S | 0.037, 0.095, 1.04 | 0.040, 0.098, 1.03 | 0.039, 0.098, 1.04 |
| No. of reflections | 4727 | 4490 | 4917 |
| No. of parameters | 277 | 278 | 275 |
| Δρmax, Δρmin (e Å−3) | 0.32, −0.26 | 0.34, −0.22 | 0.30, −0.33 |
| (IV) | (V) | |
|---|---|---|
| Crystal data | ||
| Chemical formula | C24H23ClN2O4 | C29H34N2O4 |
| M r | 438.89 | 474.58 |
| Crystal system, space group | Triclinic, P\overline{1} | Monoclinic, P21/n |
| a, b, c (Å) | 8.7914 (9), 9.3155 (10), 14.6188 (15) | 11.0442 (4), 17.4707 (6), 13.0081 (4) |
| α, β, γ (°) | 73.437 (4), 76.259 (4), 64.156 (3) | 90, 90.215 (1), 90 |
| V (Å3) | 1023.84 (19) | 2509.89 (15) |
| Z | 2 | 4 |
| μ (mm−1) | 0.22 | 0.08 |
| Crystal size (mm) | 0.41 × 0.32 × 0.14 | 0.23 × 0.13 × 0.12 |
| Data collection | ||
| Tmin, Tmax | 0.934, 0.969 | 0.921, 0.990 |
| No. of measured, independent and observed [I > 2σ(I)] reflections | 41790, 5097, 4493 | 24313, 5765, 4619 |
| R int | 0.055 | 0.059 |
| (sin θ/λ)max (Å−1) | 0.668 | 0.650 |
| Refinement | ||
| R[F2 > 2σ(F 2)], wR(F 2), S | 0.033, 0.081, 1.03 | 0.043, 0.102, 1.03 |
| No. of reflections | 5097 | 5765 |
| No. of parameters | 284 | 320 |
| Δρmax, Δρmin (e Å−3) | 0.33, −0.31 | 0.29, −0.26 |
Table 2. Hydrogen-bond parameters (Å, °).
Cg1 represents the centroid of the C221–C226 ring.
| D—H⋯A | D—H | H⋯A | D⋯A | D—H⋯A | |
|---|---|---|---|---|---|
| (I) | N11—H11⋯O227i | 0.868 (18) | 2.242 (17) | 2.9756 (16) | 142.2 (13) |
| O212—H212⋯O12ii | 0.899 (19) | 1.873 (19) | 2.7723 (14) | 178.4 (15) | |
| C22—H22⋯O211ii | 1.00 | 2.22 | 3.1930 (15) | 164 | |
| C16—H15⋯Cg1iii | 0.95 | 2.63 | 3.4966 (14) | 152 | |
| (II) | N11—H11⋯O227i | 0.880 (18) | 2.181 (18) | 2.9598 (18) | 147.3 (15) |
| O212—H212⋯O12ii | 0.89 (2) | 1.88 (2) | 2.7691 (15) | 179 (2) | |
| C22—H22⋯O211ii | 1.00 | 2.21 | 3.1894 (16) | 165 | |
| C16—H15⋯Cg1iii | 0.95 | 2.75 | 3.6366 (16) | 155 | |
| (III) | O212—H212⋯O211ii | 0.920 (19) | 1.798 (19) | 2.7162 (14) | 175.5 (16) |
| C16—H16⋯Cg1iv | 0.95 | 2.70 | 3.5181 (17) | 144 | |
| (IV) | O212—H212⋯O211ii | 0.863 (19) | 1.854 (19) | 2.7152 (14) | 175.3 (16) |
| C16—H16⋯Cg1iv | 0.95 | 2.52 | 3.3872 (14) | 152 | |
| (V) | O212—H212⋯O12ii | 0.915 (18) | 1.744 (18) | 2.6589 (13) | 178.5 (15) |
| C113—H11F⋯O227v | 0.99 | 2.51 | 3.4738 (17) | 163 | |
| C16—H16⋯O227vi | 0.95 | 2.48 | 3.3947 (17) | 162 | |
| C22—H22⋯O211ii | 1.00 | 2.57 | 3.5693 (16) | 177 | |
| C226—H226⋯O211ii | 0.95 | 2.50 | 3.3854 (17) | 155 |
Symmetry codes: (i) x + 1, y, z; (ii) −x + 1, −y + 1, −z + 1; (iii) −x + 2, −y + 1, −z; (iv) −x, −y + 1, −z; (v) −x + {1\over 2}, y + {1\over 2}, −z + {1\over 2}; (vi) x − {1\over 2}, −y + {1\over 2}, z − {1\over 2}.
Results and discussion
All of the signals for the H and C atoms in compounds (I)–(V) were observed in their NMR spectra, with the sole exception of the carboxyl H-atom signal in compound (IV). All of the signals were assigned using one-dimensional spectra and two-dimensional COSY, HSQC and HMBC spectra. In terms of the formation of the spiro ring system, it is necessary to consider the NMR spectra only for compound (I), as those for (II)–(V) follow very similar lines, apart from the obvious differences arising from the differences in the peripheral substituents. The signals from atoms H1′ and H2′, bonded to atoms C1′ and C2′ (C21 and C22 in the crystallographic numbering scheme; see Fig. 1 ▸) which originated in the electron-deficient alkene, show a mutual coupling of 9.7 Hz, while H1′ is similarly coupled to H8a′, bonded to C8a′ (C28A). These signals confirm the formation of the new ring and the magnitude of the coupling constants show (Karplus, 1959 ▸) that atom H1′ is trans to both H2′ and H8′, so establishing the relative stereochemistry at atoms C1′, C2′ and C8a′ (C21, C22 and C28A). However, the NMR data do not allow definition of the stereochemistry of the spiro C atom relative to these three centres, nor that of the relative location of the benzoyl and carbonyl substituents, both of which were determined from the single-crystal diffraction study.
Compounds (I) and (II) are isomorphous, as are compounds (III) and (IV) (Table 1 ▸). Each compound contains four contiguous stereogenic centres, at atoms C21, C22, C13 and C28A (Figs. 1 ▸–5 ▸ ▸ ▸ ▸), and the centrosymmetric space groups (Table 1 ▸) confirm that each compound has crystallized as a racemic mixture. For each compound, the reference molecule was selected as one having the R configuration at atom C13; on this basis, the configurations at atoms C21, C22 and C28A are S, S and R, respectively, with these atoms corresponding to locants C3, C1′, C2′ and C8a′ in the chemical numbering scheme, so that the overall configuration in each of (I)–(V) is (1′SR,2′SR,3RS,8a′RS). The structure analyses also show that for each compound, the carboxyl group is bonded to atom C21 and the benzoyl group is bonded to atom C22 (Figs. 1 ▸–5 ▸ ▸ ▸ ▸).
A plausible mechanism for the formation of compounds (I)–(V), based on previous work (Pardasani et al., 2003 ▸; Quiroga et al., 2017 ▸; Romo et al., 2020 ▸), involves a condensation reaction between a substituted isatin (A) (Scheme 2) and pipecolic acid (B) to give intermediate (C), followed by dehydration to (D) and decarboxylation to give the ylide (E). The subsequent reaction between ylide (E) and trans-3-benzoylacrylic acid (F), neither of which contains any stereogenic centres, is both regio- and stereospecific. Compounds (I)–(V) were all formed as racemic mixtures of a single stereoisomer, and formation of the alternative regioisomers of type (G) was not detected in any of the reactions. The endo approach of the alkene to the ylide is preferred over the alternative exo approach, as its transition state is better stabilized by π–π interactions between the aryl groups in the two reaction components.
The synthetic pathway defined in Scheme 2 thus significantly amplifies the scope of the ylide/alkene route to novel spiro compounds. The product yields, which are comparable with, say, those of a three-step process with conversions of 80–85% at each stage, are regarded as entirely acceptable in view of the one-step nature of the procedure, the ready availability of starting materials which permit a very wide range of substituent combinations, and the regio- and stereospecificity giving racemic mixtures of single stereoisomers.
The conformations (Evans & Boeyens, 1989 ▸) of the five-membered ring containing atom N24 show some unexpected variations. Thus, in the isomorphous pair (I) and (II), this ring adopts a half-chair conformation in (I), but an envelope conformation in (II). In (I), the ring is twisted about a line between atom C22 and the mid-point of the N24—C28A bond, such that atoms C13 and C21 are displaced to either side of the plane through atoms C22, N24 and C28A by 0.5324 (18) and 0.6374 (15) Å, respectively. In contrast, the corresponding ring in (II) adopts an envelope conformation, with the ring folded across the C21⋯N24 line and with atom C28A displaced by 0.6528 (19) Å from the plane through atoms C21, C22, C13 and N24. Similarly, in the isomorphous pair (III) and (IV), this ring adopts a half-chair conformation, but now twisted across the line between atom C13 and the mid-point of the C21—C28A bond, with atoms C22 and C24 displaced to either side of the plane through C13, C21 and C28A by 0.5410 (18) and 0.5819 (16) Å, respectively, while in (IV), this ring adopts the envelope conformation, folded across the C21⋯C24 line, with atom C28A displaced by 0.6709 (16) Å from the plane of the other four atoms. The same envelope conformation is found in (V), with a displacement of 0.6284 (19) Å for atom C28A. In each of (I)–(V), the six-membered ring containing atom N24 adopts an almost perfect chair conformation, with substituents C13 and C21 both in equatorial sites. The values of the ring-puckering parameters (Cremer & Pople, 1975 ▸; Boeyens, 1978 ▸) are summarized in Table 3 ▸. In view of the conformational differences within the isomorphous pairs (I)/(II) and (III)/(IV), it may not be appropriate to regard these pairs as strictly isostructural (Acosta et al., 2009 ▸; Blanco et al., 2012 ▸).
Table 3. Ring-puckering parameters (Å, °).
Parameters for rings A and B are calculated for the atom sequences N24—C13—C22—C21—C28A and N24—C25—C26—C27—C28—C28A, respectively.
| Ring A | Q 2 | φ2 | |
|---|---|---|---|
| (I) | 0.4391 (11) | 333.05 (17) | |
| (II) | 0.4363 (14) | 332.26 (19) | |
| (III) | 0.4436 (13) | 312.16 (17) | |
| (IV) | 0.4456 (13) | 317.67 (17) | |
| (V) | 0.4125 (13) | 327.81 (18) | |
| Ring B | Q | θ | φ |
| (I) | 0.5673 (14) | 175.99 (14) | 227.3 (19) |
| (II) | 0.5670 (15) | 176.31 (15) | 226 (2) |
| (III) | 0.5846 (14) | 176.53 (14) | 141 (3) |
| (IV) | 0.5913 (14) | 176.98 (14) | 132 (3) |
| (V) | 0.5778 (14) | 179.45 (14) | 219 (22) |
In the structure of compound (I), four hydrogen bonds (Table 2 ▸) link the molecules into complex sheets whose formation can, however, be readily analysed in terms of two one-dimensional substructures (Ferguson et al., 1998a
▸,b
▸; Gregson et al., 2000 ▸). A combination of O—H⋯O and N—H⋯O hydrogen bonds forms a ribbon in the form of a chain of edge-fused centrosymmetric rings running parallel to [100], in which 
(16) (Etter, 1990 ▸; Etter et al., 1990 ▸; Bernstein et al., 1995 ▸) rings centred at (n + 
, , ) alternate with 
(22) rings centred at (n, , ), where n represents an integer in each case (Fig. 6 ▸). The formation of this ribbon is modestly enhanced by a C—H⋯O hydrogen bond involving a C—H bond of rather low acidity. In the second substructure, a combination of O—H⋯O and C—H⋯π(arene) hydrogen bonds forms a second chain of rings, this time running parallel to [10], in which (16) rings centred at (n + , , −n + ) alternate with rings formed by the C—H⋯π(arene) hydrogen bonds, which are centred at (n, , 1 − n), where n represents an integer in each case (Fig. 7 ▸). The combination of these two chain motifs generates a sheet lying parallel to (101), but there are no direction-specific interactions between adjacent sheets. The supramolecular assembly of the isomorphous compound (II) is entirely similar to that in (I).
Figure 6.
Part of the crystal structure of compound (I), showing the formation of a chain of rings along [100] built from O—H⋯O and N—H⋯O hydrogen bonds. For the sake of clarity, H atoms bonded to C atoms have all been omitted.
Figure 7.
Part of the crystal structure of compound (I), showing the formation of a chain of rings along [10] built from O—H⋯O and C—H⋯π(arene) hydrogen bonds. For the sake of clarity, H atoms bonded to those C atoms not involved in the motif shown have been omitted.
In the isomorphous pair of compounds (III) and (IV), there are just two hydrogen bonds (Table 2 ▸), and these link the molecules into a chain of centrosymmetric rings running parallel to [101], in which (8) rings formed by the O—H⋯O hydrogen bonds and centred at (n + , , n + ) alternate with rings formed by C—H⋯π(arene) hydrogen bonds and centred at (n, , n), where n represents an integer in each case (Fig. 8 ▸). There are no direction-specific interactions between adjacent chains.
Figure 8.
Part of the crystal structure of compound (III), showing the formation of a chain of rings along [101] built from O—H⋯O and C—H⋯π(arene) hydrogen bonds. For the sake of clarity, H atoms not involved in the motif shown have been omitted.
Five hydrogen bonds (Table 2 ▸) link the molecules of compound (V) into sheets lying parallel to (10), but the formation of the sheet can, in fact, be analysed in terms of just two of these interactions, those having atoms O212 and C16 as the donors. Inversion-related pairs of molecules are linked by paired O—H⋯O hydrogen bonds to form centrosymmetric (16) dimers, of the type seen also in compounds (I) and (II), although in (V) the dimer formation is weakly augmented by two C—H⋯O interactions. Linkage of these dimers by the C—H⋯O hydrogen bond involving atom C16 then generates a sheet in which centrosymmetric rings of (16) and 
(46) types alternate in a chessboard fashion (Fig. 9 ▸). There are no direction-specific interactions between adjacent sheets.
Figure 9.
Part of the crystal structure of compound (V), showing the formation of a sheet lying parallel to (10) built from O—H⋯O and C—H⋯O hydrogen bonds. For the sake of clarity, H atoms bonded to those C atoms not involved in the motif shown have been omitted.
Overall, therefore, the supramolecular assembly is one-dimensional in each of compounds (III) and (IV), and two-dimensional in (I), (II) and (V); however, a three-dimensional assembly is not observed amongst the examples reported here. This may be contrasted with the behaviour observed in two spiro[indoline-3,3′-pyrrolizine]s (Quiroga et al., 2017 ▸). In (1′RS,2′RS,3SR,7a′RR)-1′,2′-bis(4-chlorobenzoyl)-5,7-dichloro-2-oxo-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indoline-3,3′-pyrrolizine], which crystallizes as a partial dichloromethane solvate, the heterocyclic molecules are linked by N—H⋯O hydrogen bonds to form (8) dimers, while in (1′RS,2′RS,3SR,7a′SR)-2′-benzoyl-1-hexyl-2-oxo-1′,2′,5′,6′,7′,7a′-hexahydrospiro[indoline-3,3′-pyrrolizine]-1′-carboxylic acid, the molecules are linked by O—H⋯O hydrogen bonds to form cyclic (48) hexamers with 
(S
6) symmetry, which are further linked by C—H⋯O hydrogen bonds to form a three-dimensional framework structure.
In summary, therefore, we have developed a new application of the ylide/alkene procedure, which we have now used for the formation of spiro[indoline-3,3′-indolizine]s in a single step, using simple and readily available starting materials. This approach permits the incorporation of a wide variety of substituents and other functional groups for further elaboration. Five representative examples have been fully characterized spectroscopically and structurally, and their patterns of supramolecular assembly have been analysed, described and illustrated.
Supplementary Material
Crystal structure: contains datablock(s) global, I, II, III, IV, V. DOI: 10.1107/S2053229621007142/ky3207sup1.cif
Structure factors: contains datablock(s) I. DOI: 10.1107/S2053229621007142/ky3207Isup2.hkl
Structure factors: contains datablock(s) II. DOI: 10.1107/S2053229621007142/ky3207IIsup3.hkl
Structure factors: contains datablock(s) III. DOI: 10.1107/S2053229621007142/ky3207IIIsup4.hkl
Structure factors: contains datablock(s) IV. DOI: 10.1107/S2053229621007142/ky3207IVsup5.hkl
Structure factors: contains datablock(s) V. DOI: 10.1107/S2053229621007142/ky3207Vsup6.hkl
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207Isup7.cml
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207IIsup8.cml
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207IIIsup9.cml
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207IVsup10.cml
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207Vsup11.cml
Acknowledgments
The authors thank the Centro de Instrumentación Cientifico-Técnica of the Universidad de Jaén (UJA) and its staff for the data collection, and thank COLCIENCIAS, the Universidad del Valle, the Universidad de Jaén and the Consejería de Economía, Innovación, Ciencia y Empleo (Junta de Andalucía, Spain) for financial support.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Crystal structure: contains datablock(s) global, I, II, III, IV, V. DOI: 10.1107/S2053229621007142/ky3207sup1.cif
Structure factors: contains datablock(s) I. DOI: 10.1107/S2053229621007142/ky3207Isup2.hkl
Structure factors: contains datablock(s) II. DOI: 10.1107/S2053229621007142/ky3207IIsup3.hkl
Structure factors: contains datablock(s) III. DOI: 10.1107/S2053229621007142/ky3207IIIsup4.hkl
Structure factors: contains datablock(s) IV. DOI: 10.1107/S2053229621007142/ky3207IVsup5.hkl
Structure factors: contains datablock(s) V. DOI: 10.1107/S2053229621007142/ky3207Vsup6.hkl
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207Isup7.cml
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207IIsup8.cml
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207IIIsup9.cml
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207IVsup10.cml
Supporting information file. DOI: 10.1107/S2053229621007142/ky3207Vsup11.cml