Synthesis of Piperidinone and Azepanone Fused Indoles via a Wagner–Meerwein Type 1,2-Amide Migration of 2-Spiropseudoindoxyls

Abstract

Spiropseudoindoxyls were synthesized by using a gold(III)-catalyzed intramolecular nitroalkyne redox–dipolar cycloaddition cascade. These compounds were then transformed into novel piperidinone and azepanone fused indoles via a straightforward hydrogenation. The reaction mechanism of this ring expansion is believed to proceed through a rare Wagner–Meerwein type 1,2-amide migration.

Key words

dihydro-γ-carbolinone - Wagner–Meerwein - indoles - 1,2-acyl shift - spirocycles

• References and Notes

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• 18 Synthesis of carboxylic acids 4; Typical procedure for 4a. A flame-dried, three-necked, flat-bottom flask was charged with DMSO (35 mL). CO₂ was dried by sublimating dry ice and bubbled through two wash bottles containing concentrated sulfuric acid, similar to Vogel’s procedure. The dried CO₂ was bubbled through the DMSO solution for 5 min before adding the reagents. Caesium fluoride (3.12 g, 20.5 mmol) was dissolved in the stirring mixture and 1-(2-nitrophenyl)-2-trimethylsilylacetylene (3.00 g, 13.7 mmol) was added subsequently by using a syringe. After reaction for 2 h at room temperature, the mixture was acidified with 2 M aq HCl and extracted with ethyl acetate (5 × 75 mL). The combined organic phases were concentrated to a total volume of ca. 150 mL, washed with brine (5 × 150 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired carboxylic acid 4a (90%, 2.36 g, 12.3 mmol) as a pale-pink solid. ¹H NMR (250 MHz, DMSO-d ₆): δ = 14.22 (br s, 1 H), 8.23 (dd, J = 7.5, 1.5 Hz), 7.75–7.95 (m, 3 H). ¹³C NMR (63 MHz, DMSO-d ₆): δ = 153.9, 149.5, 135.5, 134.1, 131.8, 125.2, 124.8, 87.3, 79.1.
• 19 Synthesis of amides 5; Typical procedure for 5a. A round-bottom flask was charged with carboxylic acid 4a (250 mg, 1.3 mmol) dissolved in methanol (0.1 M). Subsequently, formaldehyde (37% in water; 97 μL, 1.3 mmol) and allylamine (98 μL, 1.3 mmol) were added and the resulting mixture was stirred for 15 min at room temperature. tert-Butyl isocyanide (148 μL, 1.3 mmol) was added and the reaction was heated to 50 °C and stirred overnight. Upon completion, the reaction mixture was concentrated in vacuo, dissolved in EtOAc (25 mL), and washed with aqueous saturated NaHCO₃ (25 mL), 1 M aq HCl (25 mL) and brine (25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude mixture was purified by silica gel column chromatography (EtOAc/hexanes, 50%) to afford the desired amide 5a (75%, 0.34 g, 0.98 mmol) as a red oil. R_f 0.27 (EtOAc/hexanes, 50%). IR (neat): 3325, 3088, 3064, 2974, 2224, 1684, 1648, 1567, 1341 cm^–1. ¹H NMR (250 MHz, CDCl₃): δ = 8.08 (m, 1 H), 7.73 (m, 1 H), 7.60 (m, 2 H), 6.09 and 5.84* (br s, 1 H), 5.88–5.63 (m, 1 H), 5.20 (m, 2 H), 4.36 and 4.11* (d, J = 6.0 Hz, 2 H), 4.17 and 3.90* (s, 2 H), 1.27 and 1.25* (s, 9 H). ¹³C NMR (63 MHz, CDCl₃): δ = 167.0 and 168.8*, 154.7 and 154.3*, 149.4, 136.3 and 136.1*, 133.7 and 133.6*, 132.0 and 131.6, 131.0, 125.2, 119.1, 115.9, 87.5 and 87.2*, 85.3 and 84.5*, 52.9 and 51.63*, 51.8 and 51.56*, 49.7 and 48.6*, 28.7. HRMS: m/z [M + H]⁺ calcd: 344.1605; found: 344.1612. * Double signals due to rotamers across the C–N bond of the amide as well as the carbamate.
• 20 Gold-catalyzed cycloisomerization towards spiropseudoindoxyls 1; Typical procedure for 1a. A round-bottom flask was charged with amide 5a (200 mg, 0.58 mmol) and dissolved in toluene (6 mL; 0.1 M relative to 1a). To this solution was added dichloro(2-pyridinecarboxylato)gold (11.4 mg, 0.029 mmol) in one portion. The resulting mixture was stirred at room temperature for 4 h. Subsequently, the reaction was concentrated in vacuo, followed by the addition of ethyl acetate (6 mL, 0.1 M relative to 1a). This resulted in the formation of a gray precipitate, which was separated by decantation. The decanted organic phase was filtered through a silica plug, washed with additional EtOAc and concentrated in vacuo. Both the precipitate and the solid obtained from the EtOAc fraction were deemed pure based on HPLC and NMR analysis and combined to afford the desired spiropseudoindoxyl 1a (84%, 0.17 g, 0.5 mmol) as a gray solid. Mp 206–207 °C (decomp.). IR (neat): 3332, 2970, 2933, 1682 (br), 1606, 909, 727 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.71 (m, 2 H), 7.49 (d, J = 8.1 Hz, 1 H), 7.33 (t, J = 7.5 Hz; 1 H), 5.94 (br s, 1 H), 4.03–3.86 (m, 4 H), 3.83 (dd, J = 9.5, 5.2 Hz, 1 H), 3.50 (dd, J = 10.0, 4.9 Hz), 3.41 (m, 1 H), 1.38 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 195.1, 168.6, 166.2, 162.9, 137.8, 126.9, 126.1, 124.3, 119.0, 83.0, 73.3, 51.9, 51.2, 48.7, 44.6, 28.9. HRMS: m/z [M + H]⁺ calcd: 344.1605; found: 344.1606.
• 21 Hydrogenation towards indoles 3; Typical procedure for 3a. A Teflon insert for a Parr hydrogenation vessel was flushed with argon and charged with spiropseudoindoxyl 1a (240 mg, 0.70 mmol). After dissolving this solid in methanol (10 mL; ca. 0.05 M), the resulting solution was flushed again with argon. Palladium on carbon (74 mg, 10wt%, 0.07 mmol.) was added in one portion, followed by rinsing of the insert walls with methanol if necessary. The reaction mixture was then subjected to 5 bar of hydrogen in a Parr series 4793 high-pressure vessel and stirred for 16 h at room temperature. Subsequently, the reaction mixture was transferred to a vial of appropriate size and centrifuged to afford a semiclear solution, which was filtered through a plug of Celite. The precipitated solid was washed with MeOH (2 × 5 mL) and DMSO (1 mL) in MeOH (5 mL) and the centrifugation/filtration steps were repeated. The resulting solution was concentrated in vacuo until only the DMSO (ca. 1 mL) remained. This crude mixture was purified by reverse-phase column chromatography with liquid loading and using Milli-Q water+0.1% TFA / acetonitrile+0.1% TFA as eluents (see the Supporting Information for gradient details). Acetonitrile and trifluoroacetic acid were evaporated and the remaining water was removed by freeze-drying to afford the desired fused indole 3a (55%, 126 mg, 0.38 mmol) as a white solid. Mp 241–242 °C. IR (neat): δ = 1660, 1623, 1489, 1454, 1218, 1177, 785, 741 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 11.60 (br s, 1 H), 7.91 (d, J = 7.5 Hz, 1 H), 7.53 (br s, 1 H), 7.41 (d, J = 7.5 Hz, 1 H), 7.11 (m, 2 H), 5.00 (br s, 1 H), 4.08 (d, J = 15.4 Hz, 1 H), 3.94 (d, J = 15.4 Hz, 1 H), 3.77 (m, 2 H), 3.66 (dd, J = 9.2, 8.5 Hz, 1 H), 3.57 (dd, J = 12.2, 6.4 Hz, 1 H), 3.24 (qt, J = 5.7 Hz, 1 H), 1.28 (s, 9 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 168.4, 164.1, 144.6, 136.2, 125.2, 121.6, 120.6, 119.6, 111.7, 105.2, 61.6, 50.2, 49.8, 48.8, 36.3, 28.6. HRMS: m/z [M + H]⁺ calcd: 330.1812; found: 330.1810.