Synthesis of 1‐Substituted Tetrahydroisoquinolines by Lithiation and Electrophilic Quenching Guided by In Situ IR and NMR Spectroscopy and Application to the Synthesis of Salsolidine, Carnegine and Laudanosine. Issue 24 (15th May 2013)

• Record Type: Journal Article
• Authors: Li, Xiabing; Leonori, Daniele; Sheikh, Nadeem S.; Coldham, Iain
• Is Part Of: Chemistry. Volume 19:Issue 24(2013)
• Page Start: 7724
• Page End: 7730
• Publication Date: 2013-05-15
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201301096
• Languages: English
• ISSNs: 0947-6539

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>The lithiation of <italic>N</italic>‐<italic>tert</italic>‐butoxycarbonyl (<italic>N</italic>‐Boc)‐1, 2, 3, 4‐tetrahydroisoquinoline was optimized by in situ IR (ReactIR) spectroscopy. Optimum conditions were found by using <italic>n</italic>‐butyllithium in THF at −50 °C for less than 5 min. The intermediate organolithium was quenched with electrophiles to give 1‐substituted 1, 2, 3, 4‐tetrahydroisoquinolines. Monitoring the lithiation by IR or NMR spectroscopy showed that one rotamer reacts quickly and the barrier to rotation of the Boc group was determined by variable‐temperature NMR spectroscopy and found to be about 60.8 kJ mol⁻¹, equating to a half‐life for rotation of approximately 30 s at −50 °C. The use of (−)‐sparteine as a ligand led to low levels of enantioselectivity after electrophilic quenching and the "poor man's Hoffmann test" indicated that the organolithium was configurationally unstable. The chemistry was applied to <italic>N</italic>‐Boc‐6, 7‐dimethoxy‐1, 2, 3, 4‐tetrahydroisoquinoline and led to the efficient synthesis of the racemic alkaloids salsolidine, carnegine, norlaudanosine and laudanosine.</p> </abstract>