The preparation and intra- and intermolecular addition reactions of acyclic N-acylimines: application to the synthesis of (+/-)-sertraline.
Intramolecular endo-cyclization reactions of N-acyliminium ions have seen wide application for the synthesis of heterocyclic compounds. The corresponding exocyclic variant, which would provide 1-aminotetralin derivatives, for example, has little precedent. We have discovered that acyclic N-acylcarbamates can be readily reduced to the corresponding N-acylhemiaminal derivatives in high yield using DIBAL as the reducing agent. These intermediates are remarkably stable and, if desired, can be purified and stored. The acyclic N-acylhemiaminals undergo both intra- and intermolecular nucleophilic addition reactions mediated by strong Lewis acids, such as TiCl(4). Diastereoselectivity, induced either by a substituent on the newly formed ring, or by utilizing a chiral ester on the carbamic acid, was disappointingly low. This methodology was successfully applied to the synthesis of the racemic form of the marketed antidepressant sertraline.
DeNinno
M P
MP
PGRD Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340, USA. michael_p_deninno@groton.pfizer.com
Eller
C
C
Etienne
J B
JB
D000928:Antidepressive Agents / Q000138:chemical synthesis*; D007097:Imines / Q000737:chemistry; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis*; D020280:Sertraline / Q000138:chemical synthesis*; D013764:Tetrahydronaphthalenes / Q000737:chemistry
D000928:Antidepressive Agents; D007097:Imines; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; D013764:Tetrahydronaphthalenes