Synlett 2018; 29(14): 1842-1846
DOI: 10.1055/s-0037-1610189
letter
© Georg Thieme Verlag Stuttgart · New York

Metal-free Deamidative Ugi Access to Isoindolinones

Samira Baaziz
a  Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech - UMR 7652, Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau, France   Email: laurent.elkaim@ensta-paristech.fr
c  Laboratoire de Chimie Organique Appliquée, Université des Sciences et de la Technologie Houari Boumediene (USTHB), 16111 Alger, Algeria   Email: lhammal@usthb.dz
,
Mansour Dolè Kerim
a  Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech - UMR 7652, Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau, France   Email: laurent.elkaim@ensta-paristech.fr
,
Marie Cordier
b  Laboratoire de Chimie Moléculaire, CNRS, Ecole Polytechnique - UMR 9168, Université Paris-Saclay, Route de Saclay, 91128 Palaiseau, France
,
Lamouri Hammal*
c  Laboratoire de Chimie Organique Appliquée, Université des Sciences et de la Technologie Houari Boumediene (USTHB), 16111 Alger, Algeria   Email: lhammal@usthb.dz
,
a  Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech - UMR 7652, Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau, France   Email: laurent.elkaim@ensta-paristech.fr
› Author Affiliations
We thank the Ministry of Higher Education and Scientific Research (Algeria) and ENSTA ParisTech for financial support.
Further Information

Publication History

Received: 16 April 2018

Accepted after revision: 24 May 2018

Publication Date:
10 July 2018 (online)

Abstract

A two-step isoindolone synthesis has been achieved by using an Ugi/oxidative vicarious nucleophilic substitution sequence starting from 3-nitrobenzoic acid and aromatic aldehydes. Loss of the amido group was observed as well as a further oxidative process towards hydroxyisoindolone derivatives after prolonged stirring open to the atmosphere.

Supporting Information

 
  • References and Notes


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  • 15 Typical Procedure for the Ugi/Oxidative VNS for 1a/2a To a solution of 4-chlorobenzaldehyde (281 mg, 2.0 mmol) in MeOH (2 mL) were added successively n-butylamine (0.19 mL, 2.0 mmol), 3-nitrobenzoic acid (334 mg, 2.0 mmol), and tert-butyl isocyanide (0.22 mL, 2.0 mmol). The resulting mixture was stirred at rt for 1 d. The solvent was removed under reduced pressure and the crude was purified by flash column chromatography on silica gel (EtOAc/n-pentane 30:70) to afford the Ugi adduct 1a as a white solid in 92 % yield (816 mg, 1.8 mmol). Mp 113–114 °C. Rf 0.4 (AcOEt/n-pentane 30:70). IR (thin film): 3424, 3315, 309, 2968, 2248, 1654, 1577, 1354, 1301. 1H NMR (400 MHz, CDCl3): δ = 8.32–8.26 (m, 2 H), 7.80 (dt, J = 7.6, 1.2 Hz, 1 H), 7.63 (td, J = 7.6, 0.9 Hz, 1 H), 7.48–7.37 (m, 4 H), 5.84 (br, 1 H), 5.66 (br, 1H), 3.31–3.19 (m, 2 H), 1.36 (s, 9 H), 1.35–1.22 (m, 2 H), 1.00–0.88 (m, 2 H), 0.58 (br, 3 H). 13C NMR (100.6 MHz, CDCl3): δ = 170.1, 168.0, 147.9, 138.1, 134.7, 133.8, 132.8, 130.7, 129.9, 129.2, 124.4, 121.7, 62.9, 51.8, 48.5, 31.7, 28.6, 19.8, 13.3. HRMS: m/z [M – CONHt-Bu] calcd for C18H18ClN2O3: 345.1006; found: 345.0999. To a solution of 1a (178 mg, 0.4 mmol) in DMSO (1 mL) was added potassium tert-butoxide (112 mg, 1 mmol, 2.5 equiv). The resulting mixture was stirred at rt for 1 h under an inert atmosphere. After completion of the reaction, HCl (1 mL, 18% solution in water) was added and the mixture diluted with ethyl acetate and washed with water. The organic layer was dried with MgSO4 and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Et2O/n-pentane 60:40) to afford isoindolone 2a as a yellow oil in 60% yield (82 mg, 0.24 mmol). Rf 0.22 (Et2O/n-pentane 60:40). IR (thin film): 2964, 2933, 275, 2249, 1694, 1536, 1349. 1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 2.1 Hz, 1 H), 8.34 (dd, J = 8.3, 2.1 Hz, 1 H), 7.37 (d, J = 8.6 Hz, 2 H), 7.32 (d, J = 8.3 Hz, 1 H), 7.08 (d, J = 8.6 Hz, 2 H), 5.53 (s, 1 H), 3.95 (dt, J = 14.1, 8.0 Hz, 1 H), 2.89–2.82 (m, 1 H), 1.57–1.48 (m, 2 H), 1.34–1.27 (m, 2 H), 0.89 (t, J = 7.3 Hz, 3 H). 13C NMR (100.6 MHz, CDCl3): δ = 166.3, 151.3, 148.8, 135.5, 134.0, 133.5, 129.90, 128.9, 126.9, 124.3, 119.5, 63.8, 40.4, 30.3, 20.2, 13.8. HRMS: m/z calcd for C18H17ClN2O3: 344.0928; found: 344.0926.