Resolution of 1-Aryl-1,2,3,4-Tetrahydroisoquinolines via Crystallization of O-Acetylmandelic Amides

Abstract

(R)-O-Acetylmandelic acid is an efficient chiral auxiliary for the resolution of racemic 1-aryl-1,2,3,4-tetrahydroisoquinolines 2 and 3 via crystallization of the corresponding diastereomeric amides 5 and 7. Acidic hydrolysis of (R,S)-O-acetylmandelylanilide 7b afforded optically pure (>99% ee) (S)-1-(2-aminophenyl)-1,2,3,4-tetrahydroisoquinoline (3b). Removal of the chiral auxiliary attached to the tetrahydroisoquinoline nitrogen (amide 5a) afforded partially racemized amine 2 both under hydrolytic and reductive cleavage conditions. Brønsted acid catalyzes migration of the chiral auxiliary from the isoquinoline nitrogen to aniline (6a → 7a).

Key words

amides - chiral auxiliaries - chiral resolution - rearrangements - quinolines

References

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• 13a

  Complete rearrangement of the acyl group from the aniline nitrogen to the secondary amine under neutral conditions required high temperatures (120-200 °C) [13b] [c] (Scheme [2] ).

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• 15b

  Vedejs, E.; Suna, E., manuscript in preparation

6

CCDC 193514 contains the supplementary crystallographic data for the amide 5a and CCDC 193515 contains data for the amide 7b. These data can be obtained free of charge via the Internet (www.ccdc.cam.ac.uk/conts/retrieving.html).

10

Decomposition of amide 6a was observed after 14 h at 150 °C in DMSO-d ₆ (NMR assay).

12

Alternatively, protonation of the amide could activate it for intramolecular nucleophilic attack by the aniline nitrogen (see also scheme in footnote [13] ). It should be noted, however, that catalytic amounts of TFA (10 mol%) did not effect the rearrangement after 90 h at 70 °C in MeCN-d ₃ (NMR assay). Similarly, representative Lewis acids [BF₃·OEt₂, MgBr₂ and Ti(i-PrO)₄] also did not catalyze the rearrangement after 120 h at r.t. in CDCl₃.

16

The ratio of diastereomers of the crystallized material was determined to be 98.5:1.5 (97% de, HPLC on CSP assay)