Ugi-Type Reactions of Spirocyclic Indolenines as a Platform for Compound Library Generation

Abstract

A simple and efficient method for the synthesis of highly substituted spiroindoline derivatives is presented. A Fischer indolization is combined with Ugi-type reactions to explore the chemical space concerning this privileged structure. Moreover, spiropiperidine derivatives could be postmodified for the production of a small-molecule library that will be part of the Joint European Compound Library of the European Lead Factory.

Key words

scaffold - spiroindoline - Ugi-type reaction - compound library

• References and Notes

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• 21 General Procedure for the Ugi-Type Reaction Indolenine 3 (1 equiv) was dissolved in CH₂Cl₂ (1 M) followed by the addition of the corresponding acid (1.05 equiv) and isocyanide (1.05 equiv). The reaction mixture was stirred for 24 h at r.t. Afterwards, CH₂Cl₂ was evaporated under vacuum to achieve the crude residue that was subjected to column chromatography (SiO₂, CH₂Cl₂–EtOAc = 4:1).
• 22 N-(tert-Butyl)-1′-pivaloylspiro[cyclohexane-1,3′-indoline]-2′-carboxamide (4b) Reaction of spiroindolenine 3a (100 mg, 0.54 mmol), pivalic acid (64 μL, 58 mg, 0.57 mmol), and tert-butyl isocyanide (64 μL, 47 mg, 0.57 mmol) afforded 4b (199 mg, 0.43 mmol, 81%) as a yellowish solid. TLC (cyclohexane–EtOAc, 4:1 v/v): R_f  = 0.5; mp 142.4 °C. ¹H NMR (500 MHz, CDCl₃): δ = 8.12 (d, J = 8.0 Hz, 1 H), 7.23 (td, J = 8.1, 1.4 Hz, 1 H), 7.17 (d, J = 6.4 Hz, 1 H), 7.10 (td, J = 7.4, 1.0 Hz, 1 H), 5.23 (s, 1 H), 4.92 (s, 1 H), 2.04–1.48 (m, 10 H), 1.36 (s, 9 H), 1.11 (s, 9 H) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 177.2 (C*), 169.0 (C*), 142.7 (C*), 140.0 (C*), 128.1 (CH), 125.1 (CH), 122.6 (CH), 119.0 (CH), 72.0 (CH), 51.28 (C*), 49.53 (C*), 40.61 (C*), 38.17 (CH₂), 30.28 (CH₂), 28.40 (CH₃), 28.0 (CH₃), 25.7 (CH₂), 23.3 (CH₂), 22.9 (CH₂) ppm. IR (neat): ν_max = 2972.1, 2922.0, 2852.5, 1670.2, 1647.1, 1541.0, 1473.5, 1456.2, 1396.4, 1348.1, 1340.4, 1184.2, 761.8 cm^–1. ESI-HRMS: m/z calcd for C₂₃H₃₄N₂NaO [M + Na]⁺: 393.2512; found: 393.2493.
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