Scheme 3. Sonogashira/Cyclization Reaction Sequence for the Synthesis of 4-Substituted N-Amino-imidazolin-2-ones Table 2. Sonogashira/Cyclization Reaction Sequence Yields a Starting material was recovered. through-space interaction between the vinyl proton and the methylene of imidazolidinone 15c in a 2D NOESY experiment revealed an exclusive exocyclic Z double bond geometry. Acid cleavage of the tert-butyl ester promoted double bond migration inside the five-membered ring to furnish 17a (Scheme 3).25 In the NaH-promoted 5-exo-dig cyclization, the fluorine p-substituent was well tolerated and gave 15c in 64% yield (Table 2). Substrates 14 with electron-withdrawing substituents (i.e., trifluoromethyl) reacted rapidly giving complete consumption of the starting material, albeit with (25) Partial epimerization (er 74:26) was observed for 15a, likely due to the alkaline cyclization conditions (see SI). The extent of racemization is consistent with that (er 88:12 85:15) observed during the NaH- promoted cyclization of phenylalanine-containing methionine-sulfo- nium dipeptides, to provide R-amino-γ-lactams in ref 1b. lower yields due to decomposition. In contrast, electron- rich aza-p-methoxyphenylpropargylglycinamide 14b afforded N-amino-imidazolin-2-one 15b in only 10% yield with recovered starting material. Imidazolyl alkyne 14g failed to react and was exclusively recouped. In contrast, N-Boc-3-indolyl alkyne 14f underwent base-promoted cyclization to afford constrained tryptophan mimic imi- dazolin-2-one 15f in 40% yield with recovered starting material. 4-Substituted N-amino-imidazolin-2-ones have been prepared as hybrids of the covalent and electronic con- straints of R-amino-γ-lactams and aza-amino acids. Opportunity for adding side-chain functionality was demonstrated by using a Sonogashira arylation prior to NaH-promoted 5-exo-dig cyclization of aza-propargylgly- cinamide to afford 4-substituted N-amino-imidazolin-2- one mimics. The propensity of the N-amino-imidazolin-2- one subunit to induce turn conformations was confirmed using X-ray crystallography and NMR spectroscopy of model peptide 10. Considering their conformational pre- ferences and potential for their diversification, N-amino- imidazolinones represent a promising class of geometri- cally restrained mimics for studying peptide structure. Incorporation of N-amino-imidazolinones into a biologi- cally active peptide sequence is currently under investiga- tion and will be reported in due time Acknowledgment. This research was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canadian Institutes of Health Research (CIHR) Grant No. TGC-114046. C.P. is grateful to NSERC and Boehringer Ingelheim for graduate student fellowships. The authors thank Dr. A. Fu€rto€s, K. Venne, and M.-C. Tang (Universite de Montreal) for assistance with mass spectrometry. We also thank F. Belanger- Gariepy (Universite de Montreal) and CYLview for X-ray analysis, G. Beaudry-Dubois and S. Bilodeau for NMR analysis (Universite de Montreal), and C. Camy and V. N. G. Lindsay for SFC analysis (Universite de Montreal). Note Added after ASAP Publication. The Table 1 graphic contained an error in the version published ASAP August 14, 2012. The correct version reposted August 22, 2012. Supporting Information Available. Experimental pro- cedures, compound characterization data, and NMR spectra for new compounds. Crystallographic informa- tion files (CIF). This material is available free of charge via the Internet at http://pubs.acs.org. The authors declare no competing financial interest. Org. Lett., Vol. 14, No. 17, 2012 4555