Abstract
A method to prepare 1-substituted N-Boc-tetrahydro-β-carbolines was developed by lithiation followed by electrophilic substitution. The deprotonation to give the organolithium was optimized by in situ IR spectroscopy and showed that the Boc group rotates slowly at low temperature. The chemistry was applied to the synthesis of 9-methyleleagnine (N-methyltetrahydroharman) and 11-methylharmicine.
Highlights
Tetrahydro-β-carboline can be lithiated at the 1-position when the indole nitrogen is protected as an alkyl group and the nitrogen atom in the 6-membered ring is part of a formamidine or amide.[10]
We studied tetrahydro-β-carboline 2a, and in situ IR spectroscopic monitoring indicated that lithiation was complete after ∼4 min in Et2O/TMEDA at −50 °C (see the Supporting Information (SI))
The Journal of Organic Chemistry tetrahydro-β-carboline 2b, the reaction with n-BuLi under the same conditions followed by the addition of iodomethane gave an approximately equal mixture of recovered tetrahydro-βcarboline 2b, tetrahydro-β-carboline 1, and its N-methylated analogue (2e); we did not observe any product from Boc migration.[12]
Summary
Tetrahydro-β-carboline can be lithiated at the 1-position when the indole nitrogen is protected as an alkyl group and the nitrogen atom in the 6-membered ring is part of a formamidine or amide.[10].
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