Nucleophilic Cyclization/Electrophilic Substitution of (2,2-Dialkoxyethyl)ureas: Highly Regioselective Access to Novel 4-(Het)arylimidazolidinones and Benzo[d][1,3]diazepinones

Abstract

Imidazolidin-2-one and 1,3-benzodiazepin-2-one scaffolds are structural motifs of many biologically active compounds. Herein, we report a highly regioselective acid-catalyzed intramolecular nucleophilic cyclization/intermolecular electrophilic substitution reaction sequence of (2,2-dialkoxyethyl)ureas. The reaction benefits from readily available starting materials, a simple workup procedure, moderate to high yields of target compounds, and provides a convenient entry to previously unknown 4-(het)arylimidazolidinones and 5-(het)arylbenzodiazepinones. The proposed mechanism of the reaction is also discussed.

The Highly Regioselective Synthesis of Novel Imidazolidin-2-Ones via the Intramolecular Cyclization/Electrophilic Substitution of Urea Derivatives and the Evaluation of Their Anticancer Activity

“…Yield 91%. The spectral characteristics were in agreement with the previously published data [ 19 ].…”

“…In all cases, the reaction provided the desired imidazolidinones 2 in good to high yield. The previously reported conditions were employed, i.e., refluxing toluene and a triflouroacetic acid (TFA) as catalysts [ 19 ]. Notably, the 15-fold excess of catalyst was used in these preliminary experiments.…”

“…The chemical shifts of methyne and methylene protons for 4- and 5-substituted imidazolidin-2-ones differ notably [ 19 ] (see Supplementary Materials, Figure S2 ). Thus, the substitution site of the imidazolidinone ring for the N -methyl substituted compounds 2h – m and 4h – l was determined by the comparison of their NMR spectra with the spectra of previously described 4-substituted imidazolidin-2-ones, 2g and 4g [ 19 ] (for example, see Supplementary Materials, Figures S3 and S4 ). Additionally, the structures of the compounds 2j and 2k were confirmed by X-ray analysis ( Figure 2 ; for details, see Supplementary Materials, pp.…”

“…Earlier, we have described the approach to 2-substituted pyrrolidine derivatives based on the in situ generation of a cyclic iminium ion from 4-aminobutanal acetals (4,4-diethoxybutan-1-amines) and its trapping by various nucleophiles [ 16 , 17 , 18 ]. Our preliminary studies indicate that N -(2,2-dialkoxyethyl) ureas are also capable of the formation of cyclic imidazolinium cations and the reaction results in cyclic urea derivatives—imidazolidinones or benzo [ d ] [1,3] diazepinones [ 19 ]. As the continuation of our efforts, herein, we report the successful application of this methodology to the synthesis of the series of 4-(hetero) arylimidazolidin-2-ones starting from N -(2,2-dialkoxyethyl) ureas and (hetero) aromatic nucleophiles ( Scheme 1 ).…”

Diastereoselective intramolecular cyclization/Povarov reaction cascade for the one-pot synthesis of polycyclic quinolines

“…The deprotonation of the cation C1 furnishes the imidazolinone 3a, which may undergo re-protonation resulting in the cation C2. 6,11 Further stages involve the interaction of the imi- The 4,4′-bi(imidazole-2-one) 4 was initially supposed to be the "dead end" of the reaction due to the impossibility of the intramolecular aromatic electrophilic substitution. In order to check this assumption, we subjected it to the same reaction conditions, i.e., 10% of TfOH in refluxing o-xylene.…”