Intramolecular Capture of a Cyclobutylthionium Ion for the Synthesis of New Strained Heterocycles and Carbocycles: A Rapid Assembly of the BCD Ring Sequence of Penitrems

Abstract

The first example of intramolecular interception of a cyclobutyl thionium ion for the synthesis of cyclobutathiochromenes, hexahydrocyclobutaquinolines and hexahydrocyclobutanaphthalenes is reported.

Key words

heterocycles - carbocycles - ring expansion - tandem reaction - rearrangement

References and Notes

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10

Derivatives 6b-e are inseparable mixtures of the two possible regioisomers of cyclization (6b and 6d in the ratio of 90:10, while 6c in a ratio of 82:18 and 6e in a ratio of 66:34).

11

A cis geometry was tentatively assigned to the R group and the phenylthio group of derivatives 6b-e, on the basis of the steric constraints present during the cyclization step. In any case, we were not able to register any NOE effects between the protons of the phenylthio and the methyl group of compound 6b, but we recorded the presence of a NOE effect between the benzylic proton and the methyl group of the compound obtained by desulfuration of 6b with Raney nickel.

12

All new compounds have been fully characterized by ¹H NMR (300 MHz), ¹³C NMR (75.4 MHz), IR, GLC mass spectra (70 eV) and elemental analyses. Selected analytical data for some representative derivatives are reported.
General Procedure for the Synthesis of 1a-d. To a stirred solution of Na (119.8 mg, 5.21 mmol) in MeOH (20 mL) at r.t. under argon, thiophenol (0.57 mg, 5.21 mmol) in MeOH (5 mL) was added dropwise. After 30 min, epoxide 7 (1 g, 5.21 mmol) was added and the reaction mixture was stirred for 16 h. After this time the MeOH was evaporated under vacuum and the residue dissolved in Et₂O. The ethereal solution was washed with 1 N NaOH, brine, dried on anhyd Na₂SO₄ and concentrated under vacuum. The crude product was purified by chromatography on silica gel column using light PE-Et₂O (1:1) as eluent.
2-(Phenylsulfanyl)-1-[1-(phenylsulfanyl)cyclopropyl]eth-anol (1a): yellow oil; yield 75%. IR (neat): 3420 cm^-1. ¹H NMR (CDCl₃): δ = 0.90-1.21 (m, 4 H), 2.60 (br s, 1 H), 2.95 (dd, 1 H, J = 14.0, 9.9 Hz), 3.51-3.58 (m, 2 H), 7.12-7.42 (m, 10 H). ¹³C NMR (CDCl₃): δ = 12.0, 14.4, 29.3, 39.8, 72.0, 126.0, 126.2, 128.7, 128.9, 128.9, 129.3, 135.0, 135.8. MS: m/z (%) = 302 (45) [M⁺], 285 (2), 193 (43), 175 (62), 162 (28), 149 (28), 123 (91), 109 (100), 91 (58), 77 (67), 45 (58). Anal. Calcd for C₁₇H₁₈OS₂: C, 67.51; H, 6.00; S, 21.20. Found: C, 67.48; H, 6.01; S, 21.22.
General Procedure for the Synthesis of 2a-c
A solution of the appropriate amine (2.3 mmol) and of the 2-[1-(phenylsulfanyl)cyclopropyl]epoxide (7, 450 mg, 2.3 mmol) in dry EtOH (10 mL) was refluxed for 16 h. After this time the solvent was evaporated under vacuum and the residue was purified by chromatography on a silica gel column using light PE-Et₂O (1:1) as eluent.
1-[1-(Phenylsulfanyl)cyclopropyl]-2-(4-toluidino)ethanol (2b): yellow oil; yield 45%. IR (neat): 3340 cm^-1. ¹H NMR (CDCl₃): δ = 0.96-1.19 (m, 4 H), 2.22 (s, 3 H), 3.11 (dd, 1 H, J = 9.3, 12.0 Hz), 3.13 (br s, 1 H), 3.48 (dd, 1 H, J = 3.3, 12.0 Hz), 3.59 (dd, 1 H, J = 3.3, 9.3 Hz), 6.49 (d, 2 H, J = 8.4 Hz), 6.57 (d, 2 H, J = 8.4 Hz), 6.94 (d, 2 H, J = 8.4 Hz), 7.14-7.29 (m, 2 H), 7.46 (d, 1 H, J = 6.9 Hz). ¹³C NMR (CDCl₃): δ = 12.7, 13.8, 20.3, 28.8, 48.9, 73.4, 113.5, 115.2, 126.2, 128.8, 129.1, 129.7, 136.1, 145.6. MS: m/z (%) = 299 (16) [M⁺], 190 (3), 172 (2), 120 (100), 109 (2), 91 (12), 77 (9). Anal. Calcd for C₁₈H₂₁NOS: C, 72.20; H, 7.07; N, 4.68; S, 10.71. Found: C, 72.18; H, 7.08; N, 4.69; S, 10.71.
General Procedure for the Synthesis of 3a-d To a solution of cyclopropylphenylsulfide (1.8 g, 12 mmol) in dry THF (40 mL), under Argon n-BuLi (7.5 mL, 12 mmol, 1.6 M solution in hexane) was added dropwise at 0 °C. After stirring for 5 h the resulting mixture was cooled to -40 °C and the ketone or aldehyde (12 mmol) was added. After 16 h, the reaction mixture was quenched with sat. aq NH₄Cl (10 mL) and extracted with Et₂O. The organic layer was dried on anhyd Na₂SO₄ and concentrated under vacuum. The crude oil was purified by chromatography on a silica gel column using light PE-Et₂O (1:1) as eluent.
4-(3-Methoxyphenyl)-2-[1-(phenylsulfanyl)cyclo-propyl]butanol (3b): colorless oil; yield 60%. IR (neat): 3460 cm^-1. ¹H NMR (CDCl₃): δ = 0.92-1.32 (m, 4 H), 1.25 (s, 3 H), 1.78 (s, 1 H), 1.90-2.10 (m, 2 H), 2.65-2.77 (m, 2 H), 3.78 (s, 3 H), 6.71-6.77 (m, 4 H), 7.15-7.48 (m, 5 H). ¹³C NMR (CDCl₃): δ = 13.4, 24.6, 30.3, 35.0, 42.2, 55.1, 74.6, 111.0, 114.0, 120.7, 126.0, 128.6, 129.2, 129.4, 136.9, 144.0, 159.5. MS: m/z (%) = 219 (4) [M⁺ - 109], 189 (13), 179 (14), 150 (24), 135 (39), 121 (100), 109 (22), 91 63), 77 (29), 43 (27). Anal. Calcd for C₂₀H₂₄O₂S: C, 73.13; H, 7.36; S, 9.76. Found: C, 73.10; H, 7.37; S, 9.78.
Procedure for the Synthesis of Methyl 3-Hydroxy-2-(3-methylbenzyl)-3-[1-(phenylthio)cyclopropyl]propanoate ( 3e). To a stirred solution of lithium diisopropylamide (LDA), prepared from diisopropylamine (1.3 mL, 9.2 mmol) and n-BuLi (1.2 M in hexane; 7.66 mL, 9.2 mmol) in dry THF (30 mL) in the customary manner, cooled at -78 °C, a solution of methyl 3-(3-methylphenyl)propanoate (1.64 g, 9.2 mmol) in THF (10 mL) was added dropwise. After stirring for 1 h at the same temperature, the 1-(1-phenylsulfanyl)cyclo-propyl carbaldehyde (1.64 g, 9.2 mmol) in THF (10 mL) was added. After 16 h, the mixture was diluted with Et₂O and washed with 10% NaHCO₃. The organic layer was dried over anhyd Na₂SO₄ and concentrated under vacuum. The residue was purified by chromatography on a silica gel column using light PE-Et₂O (1:1) as eluent. Spectral data refer to a 50:50 mixture of two inseparable diastereoisomers.
Yellow oil; yield 66%. IR (neat): 3470, 1740 cm^-1. ¹H NMR (CDCl₃): δ = 0.85-1.26 (m, 8 H), 2.28 (s, 3 H), 2.31 (s, 3 H), 2.82-2.92 (m, 2 H), 3.13-3.20 (m, 2 H), 3.39-3.68 (m, 4 H), 3.49 (s, 3 H), 3.61 (s, 3 H), 6.92-7.50 (m, 18 H). ¹³C NMR: δ = 11.5, 13.6, 13.9, 14.6, 21.3, 22.6, 29.3, 31.9, 33.8, 36.2, 49.8, 51.4, 51.8, 52.1, 74.3, 75.9, 125.8, 126.3, 126.4, 127.0, 127.2, 128.1, 128.3, 128.7, 128.8, 129.5, 129.9, 135.3, 135.8, 137.8, 138.0, 138.9, 174.8, 176.0.
General Procedure for the Synthesis of Derivatives 4a-d, 5c, 6b-e. A stirred solution of cyclopropylcarbinol 1-3 (1.2 mmol) and PTSA (20 mg, 0.12 mmol for 1a-d, 3a-d; 220 mg, 1.3 mmol for 2c and 3e) in dry benzene (10 mL) was refluxed for 2 h in a Dean-Stark apparatus. The reaction mixture was then washed with 10% NaHCO₃ and brine, dried over anhyd Na₂SO₄ and concentrated under vacuum. The residue was chromatographed on a silica gel column using Et₂O-light PE (1:1) as eluent.
8b-(Phenylsulfanyl)-1,2a,3,8b-tetrahydro-2H-cyclo-buta[c]thiochromene (4a): mixture of cis/trans isomers (75:25).
Major isomer: yellow oil; yield 51%. ¹H NMR (CDCl₃): δ = 1.78-1.86 (m, 1 H), 2.29-2.40 (m, 1 H), 2.47-2.56 (m, 2 H), 2.78 (dd, 1 H, J = 13.2, 9.0 Hz), 3.16 (dd, 1 H, J = 12.9, 5.4 Hz), 2.85-2.91 (m, 1 H), 3.10-3.16 (m, 1 H), 7.04-7.44 (m, 9 H). ¹³C NMR (CDCl₃): δ = 21.8, 32.1, 35.7, 44.2, 55.2, 125.7, 126.4, 128.2, 128.4, 129.5, 132.9, 134.6, 135.0, 140.1. MS: m/z (%) = 284 (35) [M⁺], 256 (3), 175 (100), 160 (10), 147 (90), 134 (30), 109 (45), 89 (10), 65 (30). Anal. Calcd for C₁₇H₁₆S₂: C, 71.79; H, 5.67; S, 22.54. Found: C, 71.68; H, 5.61; S, 22.8.
Minor isomer: yellow oil; yield 21%. ¹H NMR (CDCl₃): δ = 1.94-2.13 (m, 4 H), 2.76-2.90 (m, 1 H), 3.01 (dd, 1 H, J = 13.2, 10.5 Hz), 3.16 (dd, 1 H, J = 13.2, 4.8 Hz), 7.19-7.63 (m, 9 H). ¹³C NMR (CDCl₃): δ = 23.2, 32.1, 34.9, 46.5, 65.8, 126.2, 128.0, 128.7, 128.9, 129.9, 132.4, 134.2, 135.8, 136.4. MS: m/z (%) = 284 (20) [M⁺], 256 (3), 221 (5), 175 (100), 160 (15), 147 (95), 134 (34), 109 (65), 91 (9), 77 (16), 65 (26). Anal. Calcd for C₁₇H₁₆S₂: C, 71.79; H, 5.67; S, 22.54. Found: C, 71.70; H, 5.60; S, 22.7.
7-Methoxy-8b-(phenylsulfanyl)-1,2,2a,3,4,8b-hexahydro-cyclobuta[c]quinoline (5c): colorless oil; yield 42%. ¹H NMR (CDCl₃): δ = 1.83-1.91 (m, 2 H), 2.12-2.19 (m, 1 H), 2.41-2.51 (m, 1 H), 2.84-2.89 (m, 3 H), 3.76-3.80 (m, 1 H), 3.77 (s, 3 H), 6.47 (d, 1 H, J = 8.7 Hz), 6.66 (dd, 1 H J = 8.7, 3.0 Hz), 7.14-7.38 (m, 6 H). ¹³C NMR (CDCl₃): δ = 18.6, 36.9, 41.3, 42.7, 51.0, 55.8, 114.0, 114.9, 116.2, 128.2, 128.5, 133.2, 135.8, 138.8, 152.5. MS: m/z (%) = 297 (11) [M⁺], 268 (10), 253 (5), 188 (100), 173 (10), 160 (11), 145 (6), 117 (7), 96 (5), 71 (5), 57 (6), 43 (4). Anal. Calcd for C₁₈H₁₉NOS: C, 72.69; H, 6.12; N, 4.71; S, 10.78. Found: C, 72.60; H, 6.05; N, 4.73; S, 10.80.
6-Methoxy-2a-methyl-8b-(phenylsulfanyl)-1,2,2a,3,4,8b-hexahydrocyclobuta[a]naphthalene (6b): spectral data refer to a 90:10 mixture of two inseparable regioisomers. Colorless oil; yield 68%. ¹H NMR (CDCl₃): δ = 1.43 (s, 6 H), 1.45-1.89 (m, 8 H), 2.15-2.24 (m, 2 H), 2.43-2.64 (m, 6 H), 3.71 (s, 3 H), 3.77 (s, 3 H), 6.53-7.53 (m, 16 H).
Major isomer: MS: m/z (%) = 228 (2) [M⁺ - 28], 267 (2), 233 (4) 201 (100), 185 (4), 159 (35), 144 (10), 128 (20), 109 (85), 91 (13), 77 (30), 65 (60), 39 (40).
Minor isomer: MS: m/z (%) = 201 (5) [M⁺ - 109], 189 (100), 185 (10), 173 (7), 156 (10), 147 (17), 121 (25), 109 (45), 91 (62), 77 (51), 65 (64), 51 (30), 39 (65).
Methyl-6-methyl-8b-(phenylsulfanyl)-1,2,2a,3,4,8b-hexa-hydrocyclobuta[a]naphthalene-3-carboxylate (6e): yellow oil; yield 65%. Mixture of four inseparable isomers (50:16:10:24). IR (neat): 1740 cm^-1. ¹H NMR (CDCl₃): δ = 1.62-1.86 (m, 8 H), 2.02-2.64 (m, 12 H), 2.30 (s, 3 H), 2.32 (s, 3 H), 2.46 (s, 3 H), 2.47 (s, 3 H), 2.66-3.20 (m, 12 H), 3.64 (s, 3 H), 2.65 (s, 3 H), 2.67 (s, 3 H), 2.71 (s, 3 H), 6.90-7.42 (m, 32 H).
First isomer (50%): MS: m/z (%) = 338 (4) [M⁺], 229 (62), 197 (11), 169 (93), 154 (45), 141 (35), 128 (32), 109 (100), 91 (4), 77 (10), 65 (28).
Second isomer (16%): MS: m/z (%) = 338 (7) [M⁺], 261 (14), 229 (75), 197 (25), 169 (93), 154 (50), 141 (52), 128 (41), 109 (100), 91 (4), 77 (15), 65 (32).
Third isomer (10%): MS: m/z (%) = 338 (100) [M⁺], 295 (50), 250 (64), 235 (50), 221 (27), 202 (31), 197 (25), 189 (11), 147 (20), 128 (17), 115 (24), 91 (10), 77 (8), 59 (21).
Fourth isomer (24%): MS: m/z (%) = 338 (100) [M⁺], 295 (60), 250 (62), 235 (45), 221 (27), 202 (45), 197 (25), 189 (20), 169 (75), 155 (32), 141 (44), 128 (37), 115 (47), 91 (12), 77 (21), 59 (51).
Procedure for the Synthesis of 2-[1-(Phenylsulfanyl)cy-clopropyl]epoxide ( 7). To a solution of dimethyloxosulfonium methylide, prepared under Argon from pentane washed NaH (0.2 g, 4.9 mmol, 60% mineral oil dispersion) trimethyloxosulfonium iodide (1 g, 4.9 mmol) and 10 mL of DMSO, was added at r.t. a solution of 1-(phenylthio)cyclopropane carbaldehyde (0.8 g, 4.5 mmol) in 5 mL of DMSO. After 6 h, 20 mL of brine was added and the mixture was extracted with Et₂O. The ethereal solution was dried on anhyd Na₂SO₄ and concentrated under vacuum. The crude product was purified by chromatography on silica gel column using light PE-Et₂O (1:1) as eluent.
Colorless oil; yield 82%. ¹H NMR (CDCl₃): δ = 0.88-1.26 (m, 4 H), 2.49 (dd, 1 H, J = 2.4, 5.1 Hz), 2.70 (dd, 1 H, J = 3.9, 5.1 Hz), 3.22 (dd, 1 H, J = 2.4, 3.9 Hz), 7.17-7.45 (m, 5 H). ¹³C NMR (CDCl₃): δ = 11.2, 13.9, 25.1, 46.8, 54.1, 126.2, 128.7, 129.1, 135.7. MS: m/z (%) = 192 (4) [M⁺], 147 (6), 123 (82), 110 (33), 91 (35), 77 (33), 65 (58), 45 (89), 39 (100). Anal. Calcd for C₁₀H₁₀OS: C, 67.38; H, 5.65; S, 17.99. Found: C, 67.30; H, 5.68; S, 18.04.