Three-component assembly of stabilized fluorescent isoindoles

Abstract

The tandem addition of an amine and a thiol to an aromatic dialdehyde engages a selective three-component assembly of a fluorescent isoindole. While an attractive approach for diversity-based fluorophore discovery, isoindoles are typically unstable and present considerable challenges for their practical utility. We found that introduction of electron-withdrawing substituents into the dialdehyde component affords stable isoindole products in one step with acceptable yields and high purity.

Fig. 1. N-methylisoindole (1) and a selection of the first isoindoles prepared 4–6 along with a depiction of the substituent-based tautomeric preferences.

Fig. 2. The three-component isoindole reaction. (a) Reaction of phthalaldehyde (7) or 2,3-naphthalenedicarboxaldehyde (11) with amines (8) and thiols (9) to afford fluorescent isoindoles 10 and 12, respectively. (b) Proposed mechanism of the reaction with 7 where the initial formation of imine 7a is followed by an attack by a thiol 9 to form acetal-like species 7b. This undergoes cyclization to give hemiaminal 7c with a subsequent elimination of water to result in isoindole 10.

Fig. 3. One-pot synthesis of fluorescent 1-thio-2H-isoindoles and related structures from aromatic dialdehydes, butylamine and N-(tert-butoxycarbonyl)-l-cysteine methyl ester (Boc-Cys-OMe).

Fig. 4. One-pot synthesis of fluorescent 1-thio-2H-isoindoles from n-butyl- and n-octylphthalimidic phthalaldehydes 17 and 19, aliphatic and aromatic amines, and aliphatic and aromatic thiols.

Fig. 5. Stability analyses on isoindole 18b were evaluated using time course NMR studies. Selected spectra are shown with expansion of the aromatic region from 6.50–8.50 ppm. The predominant product of this degradation step found to be 21b. Expansions and spectra from treating 18a, 18c and 18d under the same conditions are provided in the ESI.