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.

Synthesis of substituted tetrahydroisoquinolines by lithiation then electrophilic quench

“…This result indicates that the rotation of the Boc group is slow at -78 °C, but fast at -50 °C, in line with previous work. 4,7 The n-BuLi coordinates to the carbonyl oxygen atom of the Boc group (sometimes referred to as a 'complex induced proximity effect'), 6 so for benzylic lithiation to occur in high yield the Boc group must rotate under the conditions of the reaction. Please do not adjust margins Please do not adjust margins …”

“…1). 4 Here we demonstrate that the chemistry is amenable to other substituted tetrahydroisoquinolines and to a variety of different electrophiles, leading to its application to the syntheses of the alkaloids (±)-crispine A and (±)-dysoxyline.In our earlier work we showed that the Boc group in N-Boctetrahydroisoquinoline rotates slowly at -78 °C. 4 As the lithiation at the 1-position is directed by complexation of the base (n-butyllithium) with the carbonyl of the Boc group, 6 better yields can be obtained at -50 °C since the Boc rotation is faster.…”

“…3 We have reported that an efficient and relatively mild method is to use the N-Boc derivative with deprotonation by using n-BuLi. 4,5 However we have so far reported only a few examples with the parent compound NBoc-tetrahydroisoquinoline 1 and with the 6,7-dimethoxy derivative 2 ( Fig. 1).…”

Enantioselective amine α-functionalization via palladium-catalysed C–H arylation of thioamides

“…While tetrahydroquinoline gave low yield (20%), tetrahydroisoqinoline is arylated exclusively at the C-3 position in good yield and excellent enantioselectivity ( 2g ). It is worth noting that under lithiation conditions, the functionalization will occur at the more acidic C-1 position 32 . Considering the broad utility of acyclic chiral amines in organic synthesis, we attempted asymmetric C–H arylation of N,N -diethyl- and N,N -ethylbutyl-amines.…”

Intermolecular Nucleophilic Addition of N‐Diaminophosphinoyl‐Protected α‐Carbanions Derived from Secondary Amines to Arynes: Synthesis of 1‐Aryl‐1,2,3,4‐tetrahydroisoquinolines

“…was treated with n BuLi (2.36 mmol, 1.1 equiv.) in THF (10 mL) at –50 °C under nitrogen atmosphere . The dark red colored solution so obtained was stirred at this temperature for 30 min.…”