N N R O R¢¢ R¢ O N N P R O R¢¢ R¢ O O OEt OEt P(OEt)3 CH2Cl2 N N R O R¢¢ R¢ O P OEt OEt O + 1 3 4 N N Br R O R¢¢ R¢ O 2 NBS, AlBN CCl4 N N R O R¢¢ R¢ O 5 i, NaH, ii, paraformaldehyde R = R¢¢ = Me, R¢ = H R = R¢ = R¢¢ = Me R = Me, R¢ = H, R¢¢ = Ac R = R¢ = Me, R¢¢ = Ac R = R¢¢ = Ac, R¢ = H R = R¢¢ = Ac, R¢ = Me 1a–3a, 5a 1b–3b, 5b 1c–3c, 5c 1d–3d, 5d 1e–4e 1f–2f, 4f 382 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 382 J. Chem. Research (M), 1997, 2347–2357 Regioselective Routes to Functionalised Piperazine- 2,5-diones Christina L.L. Chai*a,b and Alison R. Kingb aDepartment of Chemistry, The Faculties, Australian National University, ACT 0200, Australia bResearch School of Chemistry, Australian National University, ACT 0200, Australia The regioselectivities observed in the reactions of bromopiperazine-2,5-diones with triethyl phosphite depend markedly on the N-substituents a to the brominated carbon atom. The competing reactions of phosphite esters with a-haloketones to give phosphonate esters or vinyl phosphates have long been realised.6,7 The former product results from the direct nucleophilic displacement of the halogen by the phosphorus atom of the phosphite ester onto the a-carbon atom (Michaelis–Arbuzov reaction).2 In contrast, the isomeric vinyl phosphate is most likely formed via nucleophilic substitution onto the carbonyl carbon (Perkow reaction).The regioselective control of the reaction depends on the reaction conditions as well as the nature of the leaving group.6,7 In comparison to the a-haloketones, the reactions of a-halo- a-amino acids and their derivatives with phosphite esters yield the synthetically useful phosphonate ester.3 Surprisingly there are no reports on the formation of the Perkow product from a-halo-a-amino acids under similar conditions.In our quest to develop synthetic routes to functionalised piperazine- 2,5-diones (cyclic dipeptides), we discovered that the choice of mechanisms can be controlled by the subtle change in the nature of the N-substituents a to the halogen atom.This is summarised in the Scheme. In cases where the bromine group is a to an N-methyl substituent (piperazinediones 2a–2d, the usual Michaelis–Arbuzov products (piperazinediones 3a–3d are formed. In contrast, in cases where the bromine atom is a to an N-acetyl substituent (piperazinediones 2e,2f, the Perkow reaction predominates and vinyl phosphates (piperazinediones 4e,4f are obtained.The regiocontrol observed in these cases may be attributed to the differing electronic properties of the adjacent nitrogen atom. The ability to control the outcome of reactions in this manner is of synthetic significance. For example, the phosphonate esters 3a–3d can be converted to the previously unknown 1-methyl-6-methylenepiperazine-2,5-diones 5a–5d under Wittig–Horner olefination conditions. These methylene piperazine-2,5-diones are important synthetic precursors for further chemical elaboration.13 Techniques used: 1H, 13C, 31P NMR References: 14 Schemes: 3 Table 1: Yields of phosphonate esters, vinyl phosphates and methylene compounds are summarised Received, 7th May 1997; Accepted, 23rd July 1997 Paper E/7/03155F References cited in this synopsis 2 A.K. Bhattacharya and G. Thyagarajan, Chem. Rev., 1981, 81, 415. 3 (a) R. Kober and W. Steglich, Liebigs Ann. Chem., 1983, 599; (b) K. Burger, E. Heistracher, R. Simmerl and M. Eggersdorfer, Z. Naturforsch., Teil B, 1992, 47, 424. 6 P. A. Chopard, V. M. Clark, R. F. Hudson and A. J. Kirby, Tetrahedron, 1965, 21, 1961. 7 For examples, see (a) J. F. Allen and O. H. Johnson, J. Am. Chem. Soc., 1955, 77, 2871; (b) H. I. Jacobson, M. J. Griffin, S. Preis and E. V. Jensen, J. Am. Chem. Soc., 1957, 79, 2608. 13 C. L. L. Chai and A. R. King, Tetrahedron Lett., 1995, 36, 4295. *To receive any correspondence (e-mail: christina.chai@anu. edu.au). Scheme