NH(CHR)CO 2 – K + O NAc R Ac 2 O ∆, 2 h R = H, Me NMe 2 O O NHCH(R 2 )CO 2 H O O N OAc Ac R 2 O N (CH 2 ) 2 SMe Ac 1a R 1 = Me b R 1 = OEt 2a R 1 = Me, R 2 = Ph (73%) b R 1 = OEt, R 2 = H (69%) 3a R 1 = Me, R 2 = Ph (48%) b R 1 = OAc, R 2 = H (57%) O OAc 4a R 3 = H b R 3 = Me O N Bu i Ac 7 (45%) 9 (64%) 8 (50%) O O or Me Me EtO 2 C NMe 2 O R 1 EtO 2 C O R 1 NHCH(R 2 )CO 2 H N Ac EtO 2 C R 2 R 1 R 3 R 3 R 3 R 3 R 3 R 3 N Ac (CH 2 ) 2 CO 2 Me i ii 5a R 3 = H, R 2 = Ph (83%) b R 3 = H, R 2 = (CH 2 ) 2 SMe (85%) c R 3 = Me, R 2 = Ph (81%) d R 3 = Me, R 2 = Bu i (94%) 6a R 3 = H, R 2 = Ph (69%) b R 3 = Me, R 2 = Ph (72%) ii i ii An unusual ring expansion from the Zav’yalov pyrrole synthesis: formation of oxacino[2,3-c]pyrroles Christopher D. Gabbutt, a John D. Hepworth, a B. Mark Heron,* a Mark R. J. Elsegood b and William Clegg b a Department of Chemistry, University of Hull, Hull, UK HU6 7RX. E-mail: b.m.heron@chem.hull.ac.uk b Department of Chemistry, University of Newcastle, Newcastle upon Tyne, UK NE1 7RU. E-mail: w.clegg@ncl.ac.uk Received (in Liverpool, UK) 18th November 1998, Accepted 22nd December 1998 Enamino acids 2 and 5 undergo a facile cyclisation to afford the pyrrole 3 and isoindole 6 ring systems; a novel two atom ring expansion ensues when derivatives 5b,d are subjected to the cyclisation conditions, resulting in the formation of the new oxacino[2,3-c]pyrrole system, the structure of which is confirmed by X-ray crystallography. The pyrrole unit 1 occurs in a diversity of natural products, pharmaceutical agents and polymers. 2 The synthesis of this ring system has been the subject of intense activity and has featured in a number of review articles. 3,4 Despite such activity, routes to 2,5-unsubstituted pyrroles and routes which involve the forma- tion of the C-2–C-3 bond are particularly rare. 4 There are several routes to pyrroles that utilise 1,3-dicarbonyl compounds and a-amino acids as the starting components, but in all of these examples the resulting pyrrole retains a carboxylate function at C-2. 5 In 1973, Zav’yalov reported an efficient route to the pyrrole system (Scheme 1), 6 which has been scarcely utilised in the last 25 years. 7 We now report the application of this methodology to the synthesis of some novel substituted pyrroles and fused analogues and describe a unique ring expansion reaction to afford the new oxacino[2,3-c]pyrrole system. Dimethylaminomethylene ketones 1 and 4 were obtained by standard protocols. 8 Their addition–elimination reaction with a range of a-amino acids in aq. EtOH containing NaOAc gave the crystalline enamino acids 2 and 5 in high yields (Scheme 2).† Heating a solution of enamino acids 2a,b and 5a,c in Ac 2 O containing Et 3 N proceeded with the instantaneous formation of a deep red colour which was accompanied by the vigorous evolution of CO 2 (lime water bubbler) as the internal reaction temperature reached reflux. In the case of 5b,d, however, evolution of CO 2 was only slight. After ca. 30 min the reaction mixture was allowed to cool and was subjected to an aqueous work-up. TLC examination of the crude reaction mixtures typically revealed the presence of a fast running major component contaminated with dark base line material rendering initial purification by flash chromatography easy. The cyclisation of enamino acid 2a proceeded with the expected regioselectivity of cyclisation on to the more electro- philic ketonic carbonyl group rather than the ester function to afford a single pyrrole, 3a, confirmed by the presence of signals in its 1 H NMR spectrum associated with the ethyl ester moiety. Of particular note is the efficient preparation of 3b. Existing routes to compounds of this type are often laborious and low yielding. 3c,f,h,4 Formation of the pyrroles 3 and isoindoles 6 and 9 is chemoselective, and in no instances did we observe the presence of any a-amino ketones resulting from a Dakin–West reaction. 9 The 13 C NMR spectra of 7 (from 5b) and 8 (from 5d) contained an additional low field signal at d 168.9 (OAc) and 192.8 (CNO), respectively, when compared to the isoindoles 6a and b. Elemental analysis and HRMS for 7 and 8 confirmed that both contained an additional CO 2 unit. The structure of 8‡ was established as the oxacino[2,3-c]pyrrole by X-ray crystallog- raphy (Fig. 1). The 1 H NMR spectrum of 8§ displayed marked broadening of the signals associated with the aliphatic functions indicating that the molecule is undergoing conformational interconversion. The resolution of the spectrum was improved when it was recorded at low temperature (253 K). It is evident from the 1 H NMR data that the eight-membered ring of 8 is in equilibrium between a number of conformers. 10 However, 7 does not display this behaviour, probably as a Scheme 1 Scheme 2 Reagents and conditions: i, a-amino acid (1.05 equiv.) NaOAc.3H 2 O (1.05 equiv.) eq. EtOH, D; ii, Ac 2 O, Et 3 N (1.1 equiv.), D. Chem. Commun., 1999, 289–290 289