Synthetic Studies on Psychotrimine: Palladium-Catalysed Arylation of 2-(N-Indolyl) Amides

Dedicated to Professor Steve Ley FRS on the occasion of his 70^th birthday

Abstract

Through careful choice of conditions, 2-(N-indolyl) amides can be directed to undergo selectively either enolate arylation to give oxindoles or direct arylation to give indolo-fused benzodiazepines. The former chemistry facilitates the synthesis of the hexahydropyrrolindole core of psychotrimine.

Key words

alkaloids - arylation - cyclisation - polycycles - total synthesis

• References and Notes

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• 17 General Procedure for the Synthesis of Oxindoles 14 To a mixture of Pd₂(dba)₃ (0.05 equiv), 1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride (0.01 equiv), and NaOt-Bu (3.0 equiv) was added toluene (ca. 0.10 M). A solution of the substrate (1.0 equiv) in the minimum volume of toluene was added, and the mixture was stirred and heated to 80 °C for 8 h. After cooling to r.t., the reaction mixture was concentrated under reduced pressure to leave a dark brown powdery residue. This was dry-loaded onto a silica gel column and purified by chromatography. By this procedure, amide 13a (0.10 g, 0.14 mmol) gave, after chromatography (eluent EtOAc–PE, 1:5), oxindole 14a (66.8 mg, 73%) as a yellow oil; R_f = 0.31 (solvent Et₂O–PE, 1:1). IR (film): ν_max = 2928, 1730, 1693, 1612, 1459, 1364, 1171, 1098 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.58–7.24 (9 H, m, ArH), 7.10 (1 H, d, J = 7.2 Hz, ArH), 7.00 (1 H, t, J = 7.5 Hz, ArH), 6.91 (1 H, d, J = 7.8 Hz, ArH), 6.77 (1 H, t, J = 7.7 Hz, ArH), 6.29 (1 H, d, J = 8.4 Hz, ArH), 5.04 (1 H, d, J = 15.4 Hz, NCH _AH_BPh), 4.87 (1 H, d, J = 15.4 Hz, NCH_A H _BPH), 3.74–3.46 (4 H, m, OCH₂, NCH₂), 3.18–2.66 (7 H, m, NCH₃, CqCH₂, ArCH₂), 1.43 [9 H, br s, OC(CH₃)₃], 0.82 [9 H, s, SiC(CH₃)₃], –0.01 (3 H, s, SiCH₃), –0.06 (3 H, s, SiCH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 174.9 (oxindole C=O), 155.8 (Boc C=O), 142.4 (ArCq), 135.6 (ArCq), 129.8 (ArCH), 129.5 (ArCq), 128.9 (2 × ArCH), 128.7 (ArCq), 128.4 (ArCq), 128.3 (ArCH), 128.0 (ArCH), 127.5 (ArCH), 124.4 (ArCH), 123.4 (ArCH), 121.8 (ArCH), 119.5 (ArCH), 118.9 (ArCH), 113.1 (ArCq), 111.5 (ArCH), 109.7 (ArCH), 79.3 [OC(CH₃)₃], 64.9 (Cq), 58.2 (OCH₂), 49.8 (NCH₂), 44.4 (NCH₂Ph), 40.1 (CqCH₂), 34.4 (NCH₃), 28.5 [OC(CH₃)₃], 25.9 [SiC(CH₃)₃], 23.8 (ArCH₂), 18.2 [SiC(CH₃)₃], –5.4 [Si(CH₃)₂]. HRMS: m/z calcd for C₃₉H₅₂N₃O₄Si [MH⁺]: 654.3722; found: 654.3720.
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