Oxidative cyclization of acyclic ureas with bis(trifluoroacetoxy)iodobenzene to generate N-substituted 2-benzimidazolinones

Design, synthesis and inhibitory activity against Mycobacterium tuberculosis thymidine monophosphate kinase of acyclic nucleoside analogues with a distal imidazoquinolinone

“…However, this step afforded the target compound 13 in a very low yield (15%). This low yield could be due to the presence of an additional arylic NH in 12 that is susceptible to be oxidized under the experimental conditions leading to complex mixtures, as reported in other examples [22].…”

“…3, X ¼ CO; R 1 ¼ NH 2 ; R 2 ¼ H), the synthetic pathway began from the 3-acetamido-1,2,3,4-tetrahydroquinoline (4) obtained from 3-aminoquinoline by described procedures [27,28]. Reaction of 3 with triphosgene in the presence of Et 3 N in THF at 0 C followed by addition of methoxyamine hydrochloride afforded the methoxyurea 5 [22] in 66% yield (Scheme 1).…”

“…The application of these reaction conditions to 6, that is oxidation with PIFA in CHCl 3 at 0 C, afforded after 4 h the cyclic derivative 8 in 90% yield. Finally, the methoxy group in 7 and 8 was removed by catalytic hydrogenation in EtOH in the presence of Pd(OH) 2 /C (20%) to provide the NH derivatives 9 [22] and 10 (83 and 65% yield, respectively).…”

“…The most convenient synthesis of the 5,6-dihydro-1H-imidazo [4,5,1-ij]quinolin-2(4H)-one was described by Romero et al [22], applying the methodology reported by Kawase [23]. This strategy implies, as the key reaction, the oxidative cyclization of Nmethoxyureas with the powerful oxidant bis(trifluoroacetoxy) iodobenzene (abbreviated as PIFA or BTI) followed by removal of the methoxy group.…”

“…The advantages of PIFA, as recently reviewed [24], include its low toxicity, commercial availability and ease of handling. Based on the work published by Romero et al [22,25], we hypothesized that this PIFA-mediated reaction could also be applied to the synthesis of the required imidazoquinolinones with an amino group at position 5 or 8, that either had not been described or had been previously obtained by a more lengthy synthetic procedure, as in the case of the amino group at position 5 [26]. Once obtained, the heterocycles were alkylated with (Z)-1,4-dichlorobut-2-ene followed by incorporation of the thymine base to afford the target compounds.…”