A simple access to N-(un)substituted isoquinolin-1(2H)-ones: unusual formation of regioisomeric isoquinolin-1(4H)-ones

Abstract

A ligand/additive/Pd-free Cu-mediated coupling/cyclization strategy afforded the first practical, one-pot and general approach towards synthesis of N-(un)substituted isoquinolin-1(2H)-ones. Both the catalyst and the solvent used are recyclable. The use of the Cu reagent in excess led to the unusual formation of regioisomeric and uncommon isoquinolin-1(4H)-ones.

Triaryl-Like MONO-, BIS-, and TRISKITPHOS Phosphines: Synthesis, Solution NMR Studies, and a Comparison in Gold-Catalyzed Carbon–Heteroatom Bond Forming 5-exo-dig and 6-endo-dig Cyclizations

“…Under the same conditions, 2 mol % of 9a /AgOTf catalyzed the 6- endo- dig O-cyclization of 22a – c to give good yields of the corresponding 1 H -isochromen-1-imine in reasonably short reaction times and with no evidence for competing 5- exo- dig or N -6- endo- dig cyclization. As far as we are aware, there have been no reports of the gold­(I)-catalyzed cycloisomerization of 2-(phenylethynyl)­benzamides for a direct comparison; however, 9a /AgOTf competes with AgOTf in dichloroethane and outperforms AgSbF 6 in toluene, which requires a higher reaction temperature, longer reaction time, and 25 mol % of catalyst to achieve acceptable yields of the 6- endo- dig cyclization product. , In a more recent development, a copper-mediated coupling–cyclization sequence between a 2-iodobenzamide and a terminal alkyne occurred via the 6- endo -dig pathway to provide a complementary pathway to isoquinolin-1­(2 H )-ones; however, further studies will be required to assess the relative merits of this system against our KITPHOS-based gold catalysts . As 9a /AgOTf forms an efficient and selective catalyst for the 6- endo- dig cyclization of 2-(phenylethynyl)­benzamides, it will be interesting to apply this combination to the cycloisomerization of 2-(1-alkynyl)­phenylacetamides, as this reaction has recently been catalyzed by PPh 3 AuCl/AgSbF 6 with complete 7- endo -dig selectivity; however, 10 mol % catalyst and a reaction temperature of 120 °C was required to achieve practical yields. ,, On the basis that silver salts have been reported to catalyze this cyclization, a series of control experiments were conducted under identical conditions with 5 mol % AgOTf.…”

“…63a,b In a more recent development, a copper-mediated coupling−cyclization sequence between a 2iodobenzamide and a terminal alkyne occurred via the 6-endodig pathway to provide a complementary pathway to isoquinolin-1(2H)-ones; however, further studies will be required to assess the relative merits of this system against our KITPHOS-based gold catalysts. 64 As 9a/AgOTf forms an efficient and selective catalyst for the 6-endo-dig cyclization of 2-(phenylethynyl)benzamides, it will be interesting to apply this combination to the cycloisomerization of 2-(1-alkynyl)phenylacetamides, as this reaction has recently been catalyzed by PPh 3 AuCl/AgSbF 6 with complete 7-endo-dig selectivity; however, 10 mol % catalyst and a reaction temperature of 120 °C was required to achieve practical yields. 61d,e,g On the basis that silver salts have been reported to catalyze this cyclization, a series of control experiments were conducted under identical conditions with 5 mol % AgOTf.…”

Accessing the Ene–Imine Motif in 1H-Isoindole, Thienopyrrole, and Thienopyridine Building Blocks

“…For our initial target, isoindole 10a , o -alkynylamide 7a was used ( Scheme 1 ). 10 Incorporation of the triflate handle required first a 5- exo - dig cyclization to lactam 8a , followed by deprotonation and then trapping of the oxygen with a triflating reagent. Although there are a number of interesting metal-catalyzed methods to make the isoindolinone moiety, 11 the cyclization can be carried out using our standard literature procedure, 11f with a mild base, to provide methylene-isoindolinone 8a in excellent yield.…”

C-H amination in the synthesis of N-heterocycles

“…The synthesis of isoquinolin-1(2H)-ones via coppermediated amination has been developed by Chary et al 24 ( Figure 8). Reaction of 2-iodobenzamides (20) with alkynes in PEG 400 afforded N-substituted isoquinolin-1(2H)-ones (21) in moderate to good yields.…”

“…Copper-catalyzed synthesis of isoquinolin-1(2H)-ones. In the same year, Xu and Fu 26 reported a sequential copper-catalyzed Ullmann-type N-arylation and aerobic oxidative intramolecular C-H amination by using substituted 2-halo-N-alkylbenzamides, 2-chloro-N-propylpyridine-3carboxamide (24), imidazole, and benzimidazole derivatives (25) as the starting materials ( Figure 10). The reactions applied inexpensive CuI/L-proline as the catalyst system and molecular oxygen as the oxidant.…”