title: 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.
abstract: The lithiation of N-tert-butoxycarbonyl (N-Boc)-1,2,3,4-tetrahydroisoquinoline was optimized by in situ IR (ReactIR) spectroscopy. Optimum conditions were found by using n-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 N-Boc-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and led to the efficient synthesis of the racemic alkaloids salsolidine, carnegine, norlaudanosine and laudanosine.
authors.affiliation: Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK.
authors.forename: Xiabing
authors.initials: X
authors.lastname: Li
authors.forename: Daniele
authors.initials: D
authors.lastname: Leonori
authors.forename: Nadeem S
authors.initials: NS
authors.lastname: Sheikh
authors.forename: Iain
authors.initials: I
authors.lastname: Coldham
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008297:Male; D019906:Nuclear Magnetic Resonance, Biomolecular; D012490:Salsoline Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D013034:Sparteine / Q000737:chemistry; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000470:Alkaloids; D007546:Isoquinolines; D008024:Ligands; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C024133:heliamine; D013034:Sparteine; C014843:1,2,3,4-tetrahydroisoquinoline; C001522:laudanosine; C585428:carnegine; C059665:salsolidine