C-1 Alkynylation of N-Methyltetrahydroisoquinolines through CDC: A Direct Access to Phenethylisoquinoline Alkaloids

Abstract

Direct cross-coupling between N-methyltetrahydroisoquinolines and alkynes using CuI-DEAD is presented. It affords the regioselective C-1-alkynylated products in good yield. This regio­selectivity is in contrast to the results reported earlier in the reaction of N,N-dimethylbenzyl amine where the N-methyl alkynylated product was formed exclusively or predominantly. The C-1-substituted propargylic isoquinolines were easily reduced to phenethylisoquinolines with Pd/C. This reaction sequence provides a short route to synthesize methopholine, homolaudanosine and other phenethylisoquinoline alkaloids.

Key words

cross-coupling - regioselectivity - alkaloids - alkynes - amines

References and Notes

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14

General Procedure: To a solution of appropriate N-methyltetrahydroisoquinoline (1 mmol) in THF (2 mL), taken in 10-mL two-necked round bottom flask, was added DEAD (1.1 mmol) dropwise in 1-2 min at 0-5 ˚C and the reaction mixture was allowed to reach r.t. and stirred for 1 h. After re-cooling the reaction mixture to 0-5 ˚C, CuI (0.05 mmol) was added followed by dropwise addition of the alkyne (1.5 mmol). The resulting mixture was stirred for 5-6 h at r.t. and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatog-raphy over silica gel using hexane-EtOAc mixture (9:1-6:4) as the eluent to give the pure products 8a-j.
Spectral data of selected compounds:
1-(4-Chlorophenylethynyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (8f): yellow viscous liquid. ^¹H NMR (300 MHz, CDCl₃): δ = 7.23-7.27 (m, 2 H), 7.15-7.18 (m, 2 H), 6.97 (s, 1 H), 6.49 (s, 1 H), 4.53 (s, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H), 2.86-2.96 (m, 2 H), 2.78-2.83 (m, 1 H), 2.70-2.73 (m, 1 H), 2.51 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃-CCl₄): δ = 148.35, 147.54, 134.15, 132.96, 128.54, 126.73, 125.48, 121.62, 111.35, 110.37, 88.59, 85.21, 56.42, 55.96, 55.80, 48.53, 43.58, 28.33. MS (ESI): m/z = 342.1 [M + H]⁺.
6,7-Dimethoxy-1-(3,4-dimethoxyphenylethynyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (8h): yellow viscous liquid. ^¹H NMR (300 MHz, CDCl₃): δ = 6.90 (dd, J = 8.1, 1.8 Hz, 1 H), 6.80 (d, J = 1.8 Hz, 1 H), 6.72 (s, 1 H), 6.65 (d, J = 8.4 Hz, 1 H), 6.49 (s, 1 H), 4.50 (s, 1 H), 3.78 (s, 6 H), 3.77 (s, 6 H), 2.73-2.94 (m, 3 H), 2.58-2.62 (m, 1 H), 2.52 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 149.39, 148.59, 148.21, 147.45, 127.18, 125.43, 125.00, 115.38, 114.61, 111.27, 110.93, 110.48, 86.14, 85.90, 56.57, 56.52, 55.92, 55.89, 55.74, 48.66, 43.66, 28.39. MS (ESI): m/z = 368.1 [M + H]⁺.

16

Spectral data of selected phenethylisoquinolines:
1-(4-Methoxyphenethyl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline (10): light yellow oil. ^¹H NMR (300 MHz, CDCl₃): δ = 7.07-7.14 (m, 6 H), 6.79-6.82 (m, 2 H), 3.77 (s, 3 H), 3.46 (t, J = 5.4 Hz, 1 H), 3.12-3.18 (m, 1 H), 2.64-2.84 (m, 4 H), 2.42-2.47 (m, 1 H), 2.44 (s, 3 H), 2.00-2.09 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 157.60, 138.18, 134.94, 129.29, 128.71, 127.06, 125.80, 125.74, 113.70, 63.03, 55.22, 48.31, 42.82, 36.93, 30.59, 26.14. Anal. Calcd for C₁₉H₂₃NO: C, 81.10; H, 8.24; N, 4.98. Found: C, 81.19; H, 8.33; N, 4.89.
6,7-Dimethoxy-2-methyl-1-phenethyl-1,2,3,4-tetra-hydroisoquinoline (12):^¹7 yellow pasty mass. ^¹H NMR (300 MHz, CDCl₃): δ = 7.16-7.21 (m, 2 H), 7.09-7.12 (m, 3 H), 6.50 (s, 1 H), 6.44 (s, 1 H), 3.77 (s, 3 H), 3.74 (s, 3 H), 3.44 (t, J = 4.8 Hz, 1 H), 3.11-3.19 (m, 1 H), 2.66-2.87 (m, 4 H), 2.50-2.59 (m, 1 H), 2.44 (s, 3 H), 1.94-2.10 (m, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 147.46, 147.33, 142.43, 128.74, 128.39, 128.29, 125.85, 125.65, 111.26, 110.06, 62.59, 55.93, 55.76, 47.41, 42.03, 36.64, 31.76, 24.82. MS (ESI): m/z = 308.1 [M + H]⁺.