Figure 1
Caramboxin structure (1) and the tetrahydroisoquinolinic derivative 2 synthesized by Quintiliano and Silva.44 Quintiliano, S. A. P.; Silva Jr., L. F.; Tetrahedron Lett. 2012, 53, 3808.
Scheme 1
Three approaches (A, B, and C) explored in this work to prepare lactam 4.
Scheme 2
(a) LiAlH4, THF, 0 ºC → rt, N2, 1 h (99%); (b) PBr3, dioxane, 40 ºC, N2, 1 h (97%); (c) Boc2O, NaHCO3, DMAP (cat.), dioxane/H2O (2:1), rt, overnight (quantitative); (d) 14, Cs2CO3, CH3CN, rt, N2, 24 h (80%); (e) Tf2O, 2-ClPy or DMAP, DCM, N2, 0 ºC → rt, overnight.
Scheme 3
(a) Diethyl malonate, K2CO3, MeCN, MW, 150 W, 130ºC, N2, 3 × 10 min (77%); (b) KOH, EtOH, 30 ºC, N2, 30 min (67%); (c) (i) DPPA, TEA, toluene, reflux, N2, 1.5 h; (ii) BF3·Et2O, 0 → 50 ºC, N2, 5 h; (iii) 2 M NaOH, rt, 1 h (59%).
Scheme 4
(a) POCl3, DMF, 0 → 75 ºC, N2, 2.5 h (90%).
Scheme 5
(a) HBTU, TEA, DCM, rt, N2, 2.5 h (7% for 8 and 66% for 21); (b) HBTU, TEA, DCM, rt, N2, 2.5 h (68%).
Scheme 6
(a) Cs2CO3, KI (cat.), DMF, rt, 12 h (12% for 24 and 19% for 25); (b) Cs2CO3, MeCN, MW (150 W, 130 ºC, 10 min) (77%).
Scheme 7
(a) HCl 6 mol L-1, MW (200 W, 130 ºC), 10 min.
Scheme 8
(a) CH3I, Cs2CO3, DMF, rt, N2, 30 min (59%); (b) KI (cat.), Cs2CO3, MeCN, rt, overnight (60%); (c) HCl 6 mol L-1, CH3COOH, MW (150 W, 90 ºC, 10 min) (94%).
Scheme 9
(a) NaN3, POCl3, 50 ºC, N2, 1 h (67%); (b) KI, Cs2CO3, MeCN, rt, 48 h (78%); (c) NaOH 2 mol L-1, ultrasonic bath, 80 ºC, 45 min (67%); (d) KOH 35%, EtOH, 80 ºC, N2, 2.5 h (45%); (e) HCl 2 mol L-1, dioxane, reflux, N2, 48 h (12%).
