Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki–Heck Coupling of Aryl Iodides

Abstract

A method for highly regio- and stereoselective intramolecular Mizoroki–Heck 5-exo cyclization of aryl iodides to the corresponding spirooxindoles has been developed. Electron-rich and electron-deficient aryl iodide precursors were selectively ring-closed with high stereoselectivity and good yields. The double-bond position in the cyclopentene ring was controlled by careful choice of reaction conditions. These rare spiro compounds were further functionalized to rigidified unnatural amino acid derivatives by a subsequent gas-free Pd(0)-catalyzed alkoxycarbonylation, followed by selective O- and N-deprotections.

Key words

spirooxindoles - Mizoroki–Heck - cyclization - carbonylation

• References and Notes

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• 23 (1S,4R)-2-Azabicyclo[2.2.1]hept-5-en-3-one (3.28 g, 0.03 mol) was dissolved in dry methanol (20.0 mL), and the mixture was cooled to 0 °C. Thionyl chloride (4.0 g, 2.4 mL, 0.033 mol) was added dropwise (rigorous reaction) to the cooled reaction mixture. After addition, the reaction mixture was stirred at room temperature and kept at that temperature for another 2 h. The solvent was evaporated under reduced pressure to give the product (1R,4S)-Methyl 4-aminocyclopent-2-enecarboxylate hydrochloride salt (2a) as a white solid (5.36 g, 0.03 mol, 100%) that was sufficiently pure without further purification. ¹H NMR (500 MHz, DMSO-d ₆): δ = 8.46 (br s, 3 H), 6.06 (m, 1 H), 5.88 (m, 1 H), 4.15 (m, 1 H), 3.69 (m, 1 H), 3.64 (s, 3 H), 2.56 (m, 1 H), 1.94 (m, 1 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 172.7, 134.2, 130.5, 55.2, 51.9, 48.9, 31.2.
• 24 Methyl (R)-4-(2,5-Dimethyl-1H-pyrrol-1-yl)cyclopent-1-ene-1-carboxylate (2b) (1R,4S)-Methyl 4-aminocyclopent-2-enecarboxylate hydrochloride salt (2a, 4.0 g, 22.6 mmol) was dissolved in MeOH (10.0 mL). Hexane-2,5-dione (2.64 g, 23.2 mmol) and DIPEA (2.92 g, 22.6 mmol) were added, and the mixture was stirred for 16 h at room temperature. EtOAc (30.0 mL) and sat. aqueous NH₄Cl (20.0 mL) were added to the reaction mixture and the two phases partitioned. The aqueous phase was washed with another portion EtOAc, and the combined organic phases were washed with brine and dried over MgSO₄. After filtration, the organic phase was concentrated in vacuo to afford a dark yellow oil. The air sensitive intermediate was immediately subjected to double-bond isomerization conditions. For isomerization to 2b, the intermediate (1.0 equiv) was dissolved in dry THF (5.0 mL) under a nitrogen atmosphere and cooled to 0 °C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 3.0 equiv) in dry THF (3.0 mL) was added dropwise, and the mixture was stirred at 0 °C for 15 min. The reaction was allowed to warm to room temperature and stirred overnight, quenched with water (30.0 mL), and extracted with EtOAc (2 × 30.0 mL). The combined organic phases were washed with brine and dried over MgSO₄. After filtration, the solvent was removed under reduced pressure. The crude product was purified by column chromatography ( ⁱ Hex/EtOAc = 80:20) to give a colorless oil (4.0 g, 18.2 mol, 81%). ¹H NMR (400 MHz, CDCl₃): δ = 6.89–6.81 (m, 1 H), 5.82 (s, 2 H), 5.11 (tt, J = 10.3, 6.5 Hz, 1 H), 3.82 (s, 3 H), 3.24–3.03 (m, 2 H), 3.03–2.81 (m, 2 H), 2.27 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 164.97, 141.07, 134.64, 127.81, 106.50, 52.35, 51.70, 40.38, 38.33, 21.10, 13.96. *The product turns yellow when exposed to air over time.
• 25 General Procedure for the Synthesis of Amides 3a–j In a flame-dried flask, AlMe₃ (2 M in toluene, 1.11 mL, 2.18 mmol, 1.2 equiv) was added to dry toluene (3.0 mL) under a nitrogen atmosphere. The mixture was cooled to 0 °C, and the 2-iodoaniline (2.0 mmol, 1.1 equiv) in dry toluene (4.0 mL) was added. The mixture was stirred for a further 5 min at 0 °C. The ice bath was removed, and the mixture was stirred for 20 min at room temperature. The mixture was cooled to 0 °C again, and cyclopentene carboxylate 2b (1.82 mmol, 1.0 equiv) in dry toluene (3.0 mL) was added dropwise over 2 min to the mixture. After stirring for 10 min at 0 °C, the mixture was heated to 60 °C, and stirring was continued for 16 h. After cooling to room temperature, HCl (1 M, 8.0 mL) was added. (Caution: gas evolution, exotherm.) The mixture was stirred for 15 min, then water (20 mL) and EtOAc (30 mL) were added. The mixture was extracted, the organic phase was separated, and the aqueous phase was re-extracted one more time with EtOAc (30 mL). The combined organic phases were washed with brine and dried (MgSO₄). After filtration, the solvent was removed under reduced pressure, and the crude mixture was purified by column chromatography.
• 26 General Procedure for the Synthesis of Spirooxindoles 4a–j To a dried reaction flask, Pd(OAc)₂ (3.60 mg, 0.016 mmol), triphenylphosphine (8.39 mg, 0.032 mmol), and Et₃N (67.8 mg (0.09 mL), 0.67 mmol) were added. The flask was flushed with nitrogen, and dry DMF (3.0 mL) was added. The mixture was allowed to stir at room temperature for 10 min. Precursor 3 (0.32 mmol) in dry DMF (2 mL) was added and the reaction heated to 80 °C. The reaction was allowed to stir at this temperature overnight (assumed as 16 h for convenience). The reaction was later quenched by adding water (10 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous MgSO₄. After filtration, the organic extracts were concentrated under reduced pressure and then passed through a plug of silica, washing with 1:3 EtOAc/i-hexane to remove the palladium catalyst and the ligand. The resulting filtrate was concentrated under reduced pressure and then analyzed by ¹H NMR spectroscopy. Where the regioselectivity was less than 95%, column chromatography was performed on silica (eluted with 7:3 i-hexane/EtOAc).
• 27 Benzyl (1R,4S)-4-(2,5-Dimethyl-1H-pyrrol-1-yl)-2′-oxospiro(cyclopentane-1,3′-indolin)-2-ene-5'-carboxylate (7) A microwave vial was charged with trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) (Hermann’s palladacycle, 24 mg, 0.025 mmol), tri-tert-butylphosphonium tetrafluoroborate, [(t-Bu)₃PH]BF₄ (15 mg, 0.05 mmol), (4S)-5′-bromo-4-(2,5-dimethyl-1H-pyrrol-1-yl)spiro(cyclopentane-1,3′-indolin)-2-en-2′-one (4e, 357 mg, 1.0 mmol), benzyl alcohol (0.31 mL, 3 mmol), molybdenum hexacarbonyl (264 mg, 1.0 mmol), dry THF (2 mL), and DBU (0.45 mL, 3.0 mmol). The vial was sealed under nitrogen and subjected to MW heating at 150 °C for 60 min. After cooling, built-up pressure was slowly released, and water (10 mL) was added. The mixture was extracted twice with EtOAc (2 × 20 mL) washed with more water (3 × 20 mL), and the combined organic phases were dried with MgSO₄. After filtration and evaporation of the solvent under reduced pressure, the resulting crude residue was purified by column chromatography (eluting with 7:3 i-hexane/EtOAc), to afford a white solid (271 mg, 0.66 mmol, 66%). ¹H NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 7.95 (dd, J = 8.2, 1.7 Hz, 1 H), 7.74 (d, J = 1.7 Hz, 1 H), 7.41–7.26 (m, 5 H), 6.87 (d, J = 8.2 Hz, 1 H), 6.28 (dd, J = 5.5, 2.0 Hz, 1 H), 5.78–5.65 (m, 3 H), 5.61 (dd, J = 5.4, 2.6 Hz, 1 H), 5.30 (s, 2 H), 2.62 (dd, J = 13.4, 8.5 Hz, 1 H), 2.51 (dd, J = 13.4, 8.1 Hz, 1 H), 2.30 (s, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 180.72, 166.12, 144.55, 137.09, 136.09, 133.35, 131.78, 131.18, 128.65, 128.55, 128.35, 128.20, 124.98, 124.88, 109.66, 106.57, 66.78, 61.22, 60.19, 42.46, 14.29. HRMS: m/z calcd for C₂₆H₂₅N₂O₃ [M + H]⁺: 413.1865; found: 413.1863.
• 28 (1R,4S)-4-(2,5-Dimethyl-1H-pyrrol-1-yl)-2′-oxospiro[cyclopentane-1,3′-indolin]-2-ene-5′-carboxylic Acid (8) A reaction vial was loaded with nickel(II) chloride hexahydrate (187 mg, 1.44 mmol, 3 equiv) and benzyl ester 7 (200 mg, 0.48 mmol) in MeOH (3 mL). The green solution was stirred and NaBH₄ (164 mg, 4.32 mmol, 9 equiv) was slowly added. The reaction turned black and was left for 2 h. The reaction mixture was passed through a plug of Celite^® (5 mm) and the plug washed with methanol. The resulting solution was concentrated under reduced pressure and purified by preparative HPLC (gradient of 5–100%) in 0.05% HCOOH in H₂O and 0.05% HCOOH in MeCN. A white solid was obtained after lyophilization (114 mg, 74%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.73 (s, 1 H), 10.90 (s, 1 H), 7.86 (dd, J = 8.1, 1.7 Hz, 1 H), 7.74 (d, J = 1.7 Hz, 1 H), 6.95 (d, J = 8.1 Hz, 1 H), 6.33 (dd, J = 5.4, 1.9 Hz, 1 H), 5.83 (tt, J = 8.3, 2.4 Hz, 1 H), 5.74 (dd, J = 5.4, 2.6 Hz, 1 H), 5.61 (s, 2 H), 2.63 (dd, J = 13.2, 8.2 Hz, 1 H), 2.33 (d, J = 12.6 Hz, 1 H), 2.29 (s, 6 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 180.48, 167.69, 146.24, 136.88, 133.86, 132.69, 131.14, 127.97, 124.89, 124.87, 109.76, 106.59, 61.43, 60.32, 42.29, 14.50.
• 29 Benzyl (1R,4S)-4-Amino-2′-oxospiro[cyclopentane-1,3′-indolin]-2-ene-5′-carboxylate (9) A reaction vial was loaded with N-hydroxylamine hydrochloride (100 mg, 1.44 mmol), potassium hydroxide (54 mg, 0.96 mmol), and protected amine 7 (100 mg, 0.24 mmol). Next, aqueous MeOH/H₂O (3 mL, 3:1) was added, the reaction heated to 90 °C and stirred at that temperature for 24 h. The reaction mixture was concentrated, and the resulting solution was purified by preparative HPLC to yield a brown solid (41 mg, 0.12 mmol, 51%). ¹H NMR (400 MHz, MeOH-d ₄): δ = 7.93 (dd, J = 8.2, 1.7 Hz, 1 H), 7.72 (d, J = 1.7 Hz, 1 H), 7.35–7.30 (m, 2 H), 7.30–7.20 (m, 3 H), 6.96 (d, J = 8.2 Hz, 1 H), 6.24 (dd, J = 5.5, 2.4 Hz, 1 H), 5.87 (dd, J = 5.5, 0.7 Hz, 1 H), 5.22 (s, 2 H), 4.52 (dt, J = 7.2, 2.6 Hz, 1 H), 2.56 (dd, J = 14.5, 7.3 Hz, 1 H), 2.23 (dd, J = 14.6, 2.0 Hz, 1 H). ¹³C NMR (101 MHz, MeOH-d₄ ): δ = 181.27, 165.99, 146.55, 139.72, 136.23, 132.70, 131.46, 131.41, 128.25, 127.95, 124.81, 124.48, 109.95, 66.41, 61.09, 56.60, 39.38.