An Efficient Procedure for the Deprotection of N-Pivaloylindoles, Carbazoles and β-Carbolines with LDA

Abstract

Treatment of variously substituted indoles with 2 equivalents of LDA at 40-45 °C led to their fast and efficient deprotection. This method was also extended to N-pivaloylcarbazoles and β-carbolines.

protecting groups - pivalamides - lithium bases - indoles - carbazoles

References

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9

Representative Procedure for the N -Pivaloylation:
To a stirred suspension of NaH (409 mg, 17.08 mmol) in dry THF (20 mL) was added a solution of indole-3-carbaldehyde (1.230 g, 8.54 mmol) in dry THF (20 mL), under an argon atmosphere. After stirring at r.t. for 5 min, hydrogen evolution ceased and the solution became reddish yellow in color. Pivaloyl chloride (1.05 mL, 1.03 g, 8.54 mmol) was added and the reaction mixture was stirred at r.t. for 1 h. After confirming by TLC the disappearance of the starting indole, the reaction mixture was poured onto a sat. aq NH₄Cl solution (30 mL), which was then extracted with CH₂Cl₂ (5 × 30 mL). The combined organic layers were dried over Na₂SO₄ and evaporated to yield 1-pivaloylindole-3-carbaldehyde as a pale orange solid (1.79 g, 92%). Mp 93-95 °C. IR: 1711, 1678, 1551, 1400 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 10.32 (s, 1 H, CHO), 8.46 (d, 1 H, J = 7.8 Hz, H-7), 8.34 (s, 1 H, H-2), 8.28 (d, 1 H, J = 8.1 Hz, H-4), 7.47-7.40 (m, 2 H, H-5 and H-6), 1.58 [(s, 9 H, C(CH₃)₃] ppm. ¹³C NMR (63 MHz, CDCl₃): δ = 185.8 (CHO), 177.2 (CO-t-Bu), 135.5 (C-7), 126.8 (C-4), 126.4 (C-7a), 125.3 (C-2), 123.0 (C-3a), 122.0 (C-3), 121.6 (C-6), 117.6 (C-5), 38.6 [C(CH₃)₃], 28.43 [C(CH₃)₃] ppm. Anal. Calcd for C₁₄H₁₅NO₂: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.04; H, 6.86; N, 6.03.

10

Representative Procedure for the Deprotection:
A 1.6 M solution of butyllithium in hexanes (5.45 mL, 8.72 mmol) was added dropwise to a stirred solution of diisopropylamine (880 mg, 8.72 mmol) in dry THF (20 mL), at 0 °C, under an argon atmosphere. Stirring was continued for 10 min at 0 °C, and the solution of LDA thus prepared was added via cannula to a stirred solution of 1-pivaloyl-indole-3-carbaldehyde (1 g, 4.36 mmol) in dry THF (20 mL), under an argon atmosphere at -78 °C. When the addition was complete, the reaction mixture was heated in an oil bath at 40-45 °C for 2 h, cooled and poured onto a sat. aq NH₄Cl solution (30 mL), which was then extracted with CH₂Cl₂ (5 × 30 mL). The combined organic layers were dried over Na₂SO₄ and evaporated, and the residue was chromatographed on silica gel, eluting with 9:1 EtOAc-petroleum ether, yielding indole-3-carbaldehyde (627 mg, 99%), which was identical in all respects to the commercially available sample employed as starting material for the protection reaction.

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