Substituent effects in ring-chain tautomerism of the condensation products of non-racemic 1,2-aminoalcohols with aromatic aldehydes Márta Juhász a , László Lázár a,⇑ , Ferenc Fülöp a,b,⇑ a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary b Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6., Hungary article info Article history: Received 17 October 2011 Accepted 21 November 2011 Available online 4 January 2012 abstract The condensation of (S)-2-amino-2-phenylethanol or (S)-2-amino-3-phenylpropanol with substituted benzaldehydes in methanol or water led to crystalline products, which proved to exist in CDCl 3 at 300 K as three-component (ring cis -open-ring trans ) tautomeric mixtures. The electronic effects of the 2-aryl substituents on the tautomeric equilibria were described by the Hammett equation. Good correlations were found between the equilibrium constants and the Hammett–Brown parameter (r + ) of the substitu- ent X on the 2-phenyl group. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction The synthesis and derivatization of 1,2- and 1,3-aminoalcohols are of both pharmaceutical and chemical interest. These di- functional moieties are frequently occurring structural motifs in biologically active compounds. Non-racemic 1,2- and 1,3-aminoal- cohols are often utilized as resolving agents in the preparation of enantiopure substances or as chiral auxiliaries in various asym- metric transformations. 1 Oxazolidine derivatives, obtained by the condensation of 1,2-aminoalcohols with oxo compounds, are also widely applied as intermediates or catalysts in asymmetric syntheses. 2 Excellent enantioselectivities have been achieved in the alkynylation of alde- hydes, 3 in the Diels–Alder reactions of 1,2-dihydropyridines 4 and in a domino Michael–aldol reaction 5 through the use of chiral oxa- zolidine organocatalysts. Also, high yields and enantiomeric ex- cesses have been attained in the bisoxazolidine-catalyzed nitroaldol reactions of different aliphatic and aromatic aldehydes. 6 The structures of N-unsubstituted oxazolidines can be charac- terized by tautomeric equilibria of the cyclic and the corresponding Schiff base open-chain forms. Although Baldwin’s rules suggest that ring closure of the open form is an unfavored 5-endo-trig pro- cess, a rapid equilibrium reaction has been observed to occur in solution. 7,8 The ring-chain tautomeric character of oxazolidine derivatives provides these compounds with dual reactivity (substitution at the NH and/or addition at the C@N group), which is widely utilized in various synthetic transformations, for example the Reformat- sky 9 and Ugi reactions 10 with the participation of the open tauto- meric forms, or N-acetylation of the cyclic forms via iminium intermediates. 11 The diastereoselective formation of bicyclic lactams in the domino ring-closure reactions of chiral phenylglycinols with c-, d- or e-keto acids was earlier rationalized in terms of the differ- ences in the rates of the acylation steps for the ring-chain tauto- meric oxazolidine intermediates. These lactams are valuable building blocks in the enantioselective synthesis of structurally diverse piperidine-containing natural products and bioactive mol- ecules. 12 Thanks to their ring-chain tautomeric character, oxazoli- dines have been applied as aldehyde sources in carbon-transfer reactions toward fused pyran and pyridine derivatives 13 and in the modified Pictet–Spengler synthesis of tetrahydro-b-carbo- lines. 14 Reductive aminations of oxo compounds with 1,2-aminoal- cohols occur via oxazolidine intermediates, 15 and the ring-chain tautomeric character of oxazolidines also contributes to the devel- opment of prodrugs 16 or the creation of dynamic combinatorial libraries. 17 As concerns the analogous N-unsubstituted 1,3-X,N-heterocy- cles (X = O, S, NR), the substituent dependence of the ring-chain tautomeric equilibria of oxazolidines was thoroughly studied ear- lier. 7,8,18,19 Investigations of a considerable number of 2-aryl- substituted derivatives led to the conclusion that the tautomeric ratios were substantially influenced by the electronic properties of the aryl substituents. For the tautomeric equilibria of 2-(X-phe- nyl)-substituted oxazolidines, a linear Hammett-type correlation was found between the log K (K = [ring]/[chain]) values of the equilibria and the Hammett–Brown electronic parameter (r + ) of substituent X on the 2-phenyl group (Eq. 1): 7,8,18,19 log K ¼ qr þ þ log K X¼H ð1Þ 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.11.011 ⇑ Corresponding authors. Tel.: +36 62 545562; fax: +36 62 545705. E-mail addresses: lazar@pharm.u-szeged.hu (L. Lázár), fulop@pharm.u-szeged. hu (F. Fülöp). Tetrahedron: Asymmetry 22 (2011) 2012–2017 Contents lists available at SciVerse ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy