Diastereoselective C-Arylation of Prochiral Enolates by the S RN 1 Reaction MARI ´ A T. BAUMGARTNER, 1 * GUILLERMO A. LOTZ, 1 and SARA M. PALACIOS 2 * 1 INFIQC, Depto. de Quı´mica Orga ´nica, Fac. de Ciencias Quı´micas, U.N.C. Ciudad Universitaria, Universidad Nacional de Co ´rdoba, Argentina 2 Centro de Excelencia en Productos y Procesos de Co ´rdoba (CEPROCOR), Co ´rdoba, Argentina ABSTRACT Chiral phenyl acetamide enolate ions were diastereoselectively arylated using aromatic substrates by means of the S RN 1 reaction. The substitution took place with a diastereomeric excess that varied from 31 – 98%, depending on the enolate coun- terion, the reaction temperature, the solvent, and the aromatic substrate. The absolute configuration of the new stereogenic center of the products (4R,5S)-1,5-dimethyl-4- phenyl-3-[2V-phenyl-2V-arylacetyl]-imidazolidin-2-one (Aryl = 3-quinolyl, 1-naphthyl, 4- anisyl, 4-benzonitryl, 4-tolyl, 9-phenanthryl) was determined by 1 H NMR spectroscopy and theoretical calculations. Chirality 16:212 – 219, 2004. A 2004 Wiley-Liss, Inc. KEY WORDS: amides; arylation; diastereoselection; configuration; theoretical studies Over the last decades there has been a rapid develop- ment in the use of alkyl and aryl radicals for the formation of aliphatic C-C bonds and in the establishment of new synthetic methods that involve radical substitutions. 1 The radical nucleophilic substitution, or S RN 1, reaction has been shown to be an excellent route for performing nucleophilic substitution of unactivated aromatic com- pounds possessing suitable leaving groups. 2 Among the different functionalizations that could be accomplished, the introduction of an aromatic moiety to an enolate ion seems to be the most attractive because this reaction shows exclusively C-substitution and important synthetic drug intermediates can be prepared. In a previous work, we communicated the first stereo- selective arylation of acetamide derivatives by S RN 1 joined to a chiral auxiliary. 3 In this article we report a more extensive study of the stereoselectivity of the reaction to determine how it is affected by the enolate counterion, the reaction temperature, and the solvent. The effects caused by each of these variables were studied separately, as well as the effect of different aryl substrates. In addition, we determined the absolute configuration of the new stereogenic center of the asymmetric products using an indirect method. 4 The existence of a preferential conformer for each of the compounds studied was confirmed by means of theoretical calculations and the absolute configuration was determined by correlation of these results with the chemical shifts of 1 H NMR. Finally, the validity of this approach was confirmed by X-ray crystallography. MATERIALS AND METHODS General 1 H-NMR and 13 C-NMR spectra were recorded on a Bruker A.C. 200 nuclear magnetic resonance spectrometer with CDCl 3 as solvent. The position of the signals is reported in parts per million relative to Me 4 Si (d). Mass spectra were recorded with a CG/MS Perkin Elmer (Norwalk, CT) Q-Mass 910. Liquid chromatographic analyses were performed with a Konik 500-A high- pressure liquid chromatograph equipped with a UVIS-200 ultraviolet detector and a SP-4600 integrator. A 4.5 Â 250 mm column packed with C-18 ODS-2 reverse phase was used. Quantitative analysis was done by the external standard method. Optical rotations were measured using a Jasco DIP-370 polarimeter at ambient temperature and [a] D values are given in units of 10 À1 deg. cm 2 g À1 . Melting points were measured with a Melt-Temp II. Irradiation was conduced in a reactor equipped with two 400W lamps emitting maximally at 350 nm (Philips, Mahwah, NJ, Model HPT, air and water refrigerated). Materials 1-Iodonaphthalene, 4-iodobenzonitrile, 4-iodoanisole, 4- iodotoluene, 3-bromoquinoline, 9-bromophenantrene, magnesium chloride, calcium chloride, and titanium(IV ) chloride were obtained from Aldrich (Milwaukee, WI) and used as received. (4R,5S)-1,5-dimethyl-4-phenyl-3- (2V-phenylacetyl)-imidazolidin-2-one (1) was obtained quantitatively from the reaction of (4R,5S)-1,5-dimethyl-4- phenyl-imidazolidin-2-one with phenylacetyl chloride in dry CH 2 Cl 2 with Na 2 CO 3 at room temperature under Contract grant sponsors: Consejo Nacional de Investigaciones Cientı ´ficas y Te ´cnicas (CONICET), CONICOR, SECyT (fellowship to G.A.L.), Fundacio ´ n Antorchas, IFS; Contract grant numbers: A-13740/1-18, F- 1378/2. *Correspondence to: Marı ´a T. Baumgartner, Depto. de Quı ´mica Orga ´nica, Fac. de Ciencias Quı ´micas, U.N.C. Ciudad Universitaria, (5000) Co ´ rdoba, Argentina. E-mail: tere@dqo.fcq.unc.edu.ar or Sara M. Palacios, Centro de Excelencia en Productos y Procesos de Co ´ rdoba (CEPROCOR), Alvarez de Arenales, 230, (5000) Co ´ rdoba, Argentina. spalacio@ceprocor. uncor.edu. Received for publication 7 July 2003; Accepted 5 December 2003 A 2004 Wiley-Liss, Inc. CHIRALITY 16:212–219 (2004)