‘Ligand-Free-Like’ CuCl-Catalyzed Atom Transfer Radical Cyclization of N-Substituted N-Allyl Polychloroamides to γ-Lactams

Abstract

Atom transfer radical cyclization (ATRC) of N-alkyl Nallyl dichloroamides to g-lactams, catalyzed by 'naked' CuCl, worked efficiently in DMF, whereas, when the same dichloroamides were N-sulfonylated, DMF needed to be replaced by acetonitrile. The outcome of the cycloisomerization with N-substituted N-allyl trichloroacetamides was less affected by solvent choice, although for an effective reaction to occur, the solvent had to dissolve the cuprous salt. Catalyst loading ranged between 5 and 20 mol%.

Efficient and Green Route to γ‐Lactams by Copper‐Catalysed Reversed Atom Transfer Radical Cyclisation of α‐Polychloro‐N‐allylamides, using a Low Load of Metal (0.5 mol%)

“…When this occurs, less active systems have to be used. Indeed, when 6 was reacted with CuCl under ligand free‐like conditions,19c the cyclisation proceeded smoothly (Scheme ), yielding a result analogous to the one we obtained previously with the less reducing complex CuCl/TMEDA 19t…”

“…Hence the cyclisation becomes relatively slow and the electrophilic N ‐allylcarbamoylmethyl radical B could be reduced by the catalytic system. Amides, like 5 , and their cyclisation products are on the other hand quite reactive,19c and are likely to undergo parasitic reactions that bring about a premature catalyst depletion.…”

“…All the amides were thoroughly purified! Products 1a ,19c 3a ,19t 4a ,19c 5a ,19c 6a ,19t 8a ,19c 10a ,19 11a 19d and 12a 19d are known compounds, which were all obtained through copper‐catalysed ATRC reactions. NMR spectra were recorded on a “Varian 500 MHz” spectrometer.…”

Copper Catalyzed Atom Transfer Radical Cyclization Reactions

“…In general, bulky or electron‐withdrawing substituents favour cyclization (Scheme ) 15. More recently, it has been possible to lower catalyst loadings, decrease reaction temperatures and cyclize less reactive dichloroacetamides by using different solvents (as these will affect the redox potential of the catalyst and substrate) 16…”

“…Replacement of acetonitrile with the more basic solvent DMF increased the efficiency of the cyclization of dichloroacetamide 11a (CH 3 CN, 20 mol‐% CuCl, 120 °C, 24 h, yield 12a = 71 % as 60:40 cis / trans isomers; DMF, 20 mol‐% CuCl, 80 °C, 23 h, yield 12a = 91 % as 63:37 cis / trans isomers). Replacing the N ‐protecting group from benzyl 11a to methanesulfonyl 11b also increased the efficiency of the cyclization due to a lowering of the LUMO energy of the C–Cl bond by the electron‐withdrawing sulfonyl group (CH 3 CN, 10 mol‐% CuCl, 100 °C, 24 h, yield 12b = 97 % as 57:43 cis / trans isomers) 16…”