A Convergent Synthesis of Tetracyclic Indole Compounds by a ­Palladium-Catalyzed Cross-Coupling and Tandem Cyclization ­Reaction

Abstract

A new strategy for the convergent synthesis of the ABCD ring system of indole terpene alkaloids has been developed based on a Sonogashira coupling of an o-iodoaniline (the A ring) with an alkyne bearing the D ring. After a tandem palladium-catalyzed cyclization, the tetracyclic ABCD ring structure found in the terpene indole alkaloids was obtained in good yield.

Key words

indole terpene alkaloids - alkaloids - convergent synthesis - tandem reaction - palladium catalysis - cyclization

Publication History

Received: 20 October 2022

Accepted after revision: 21 November 2022

Article published online:
19 December 2022

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• 22 This substrate was synthesized in a similar manner to that of 11. For the details, see the Supporting Information.
• 23 The structure was determined by MS and 2D NMR spectral analyses. The key correlations and coupling constants of the NMR spectra are shown in Figure 2.
• 24 Because Pd(Ph₃P)₄ catalyzed the cascade reaction, a mechanism involving a Pd(0) catalyst cannot be excluded (Scheme 6). In this, the bromide undergoes oxidative addition to Pd(0), and the resulting Pd(II) species 27 intramolecularly coordinates to the alkyne moiety; this is followed by aminopalladation. Reductive elimination of the resulting palladacycle 28 provides the product 2. A similar mechanism was proposed in ref. 17(c).
• 25 The same reaction with PdCl₂(PhCN)₂ as a catalyst gave a comparable yield of 13. However, as the removal of PhCN was laborious, PdCl₂(MeCN)₂ was selected as the optimal catalyst.
• 26 In the absence of a Pd catalyst, the reaction did not proceed under the same conditions.
• 27 N-Tosylate 14 PdCl₂(MeCN)₂ (155 mg, 0.597 mol) was added to a suspension of anilide 11 (1.43 g, 3.12 mmol) and dry K₂CO₃ (3.12 g, 22.6 mmol) in anhyd DMF (150 mL) under argon. The mixture was stirred at 50 °C for 1.5 h, then poured into sat. aq NH₄Cl (200 mL). The aqueous layer was separated and extracted with Et₂O (3 × 200 mL). The combined organic layer was washed with H₂O (3 × 500 mL), dried (Na₂SO₄), and concentrated to dryness in vacuo. The residue was purified by column chromatography [silica gel (20 g), Et₂O–hexane (1:10)] to give a white amorphous solid; yield: 918 mg (78%). IR (film): 2965, 2923, 2845, 1445, 1372, 1363, 1237, 1187, 1174, 1119, 1092 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.11 (s, 3 H, CH₃ ), 2.15–2.42 (m, 4 H, CHCH₂ CH=CH, CCH_a H_bCH=CH, and CH₂CHCH₂), 2.34 (s, 3 H, CH₃ of Ts), 2.51 (m, 1 H, HC=CCH_a H_bCH), 2.71 (dd, J = 14.5, 6.5 Hz, 1 H, HC=CCH_a H_b CH), 2.95 (br dd, J = 16.5, 5.0 Hz, 1 H, CH₃CCH_a H_b CH=CH), 5.70 (m, 1 H, CH₂CH=CH), 5.77 (m, 1 H, CH₂CH=CH), 7.19 (d, J = 8.5 Hz, 2 H, aromatic of Ts), 7.21–7.29 (m, 2 H, aromatic), 7.38 (br d, J = 7.0 Hz, 1 H, aromatic), 7.69 (d, J = 8.5 Hz, 2 H, aromatic of Ts), 8.12 (br d, J = 7.5 Hz, 1 H, aromatic). ¹³C NMR (100 MHz, CDCl₃): δ = 16.0, 21.5, 27.0, 27.2, 38.0, 44.1, 49.9, 114.8, 119.2, 123.2, 123.7, 126.4, 126.4, 126.4, 126.7, 126.9, 129.7, 136.6, 140.3, 144.5, 150.7. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₂₃NNaO₂S: 400.1342; found: 400.1322.
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