ChemInform Abstract: Synthesis of 3,4‐Dihydro‐1(2H)‐isoquinolinones.

Abstract

Approaches toward the preparative-scale synthesis of target 3,4-dihydro-1(2H)-isoquinolinones 1-3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large-scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high-temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)-isoquinolinone (9). Catalytic hydrogenation of 9 provided the desired 3,4-dihydro-5-methyl-1(2H)-isoquinolinone (2) in 65 % overall yield. Similar reduction of a commercially available 5-hydroxy-1(2H)-isoquinolinone precursor 10 followed by an O-alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4-dihydro-1(2H)-isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.

5-Aminoisoquinolin-1-one (5-AIQ), a Water-Soluble Inhibitor of the Poly(ADP-Ribose)Polymerases (PARPs)

“…Reagents & conditions: i, H2O2, AcOH, reflux [60,61,65,66]; ii, (a) Ac2O, reflux, (b) aq. Na2CO3 [60,61,65]; iii, H2, Pd/C, EtOH [60,61,65] or Zn, NH4Cl, water, THF, EtOH [67] ; iv, Ph2O, 230C [68,69] or Bu3N, Ph2O, 230C [70,71] or tetraglyme, 280C [69]; v, Br2, (PhCO2)2, CCl4, h, reflux [72]; vi, Et4N + -CN, MeCN [72]; vii, DiBAL-H, CH2Cl2, -78C [72]; viii, (MeO)2CHNMe2, reflux [65,67,[73][74][75]; ix, (a) HCl, MeOH reflux, (b) aq. Na2CO3 [75]; x, SiO2, hexane, EtOAc [67,73,74]; xi, NH3, EtOH, autoclave [67] or NH3, EtOH, ambient temperature [74] or NH3, MeOCH2CH2OH, reflux [73]; xii, HNO3, H2SO4, 0C-20C [76][77][78] or KNO3, H2SO4 [79,80]; xiv, AcOH, 100C [78] or aq.…”