Synthesis of Enantiomerically Enriched Oxazolinyl[1,2]Oxazetidines Renzo Luisi, Vito Capriati, Saverio Florio,* and Eliana Piccolo Dipartimento Farmaco-Chimico, Universita ` di Bari, Via E. Orabona 4, I-70126 Bari, C.N.R., Istituto di Chimica dei Composti OrganoMetallici “ICCOM”, Sezione di Bari, Italy florio@farmchim.uniba.it Received September 15, 2003 Abstract: The first stereoselective synthesis of oxazolinyl- [1,2]oxazetidines based on the reaction of lithiated 2-(1- chloroethyl)-2-oxazolines with nitrones is described. Highly enantioenriched oxazolinyl[1,2]oxazetidines have also been prepared starting from a 1:1 diastereomeric mixture of optically active 2-(1-chloroethyl)-2-oxazolines. Highly strained molecules such as small cyclic com- pounds have interested chemists ever since the end of the nineteenth century. Synthesis, reactivity, structural features, and spectroscopic properties have been thor- oughly investigated. Only few theoretical and spectro- scopic studies on four-membered ring heterocycles be- longing to the family of 1,2- and 1,3-oxazetidines have been reported so far. 1 The chemistry as well as synthetic procedures to oxazetidines have been rather recently reviewed. 2 The importance for this kind of heterocycles is ascribed to their strain features, which make them available to synthetic elaboration and of interest for theoretical and spectroscopic studies. We have recently reported that lithiated 2-alkyl-2- oxazolines add to nitrones to furnish highly stereoselec- tive cis- and trans-2-alkenyl-2-oxazolines. 3 A further investigation directed to the elucidation of the reaction mechanism provided us with evidence that under ap- propriate experimental conditions one can prepare 1,6- dioxa-2,9-diazaspiro[4,4]nonanes, isoxazolidin-5-ones, and some oxazolinyl[1,2]oxazetidines. 4 In this paper, we report an unprecedented and efficient stereoselective synthesis of oxazolinyl[1,2]oxazetidines based on the addition of easily available lithiated 2-(1- chloroethyl)-2-oxazolines to nitrones. The choice for lithi- ated 2-(1-chloroethyl)-2-oxazolines was driven by their carbenoidic character, 5 a nucleophile and an electrophile at the same time, that makes them potential precursors to oxazetidines. Lithiation of 2-(1-chloroethyl)-4,4-dimethyl-2-oxazoline 1 with LDA at -98 °C in THF generated lithio derivative 2, which proved to be quite stable as previously reported. 6 The addition of R-phenylnitrone 3a followed by quenching with saturated aqueous NH 4 Cl after 3 h resulted in the formation of the R*,S* oxazolinyl[1,2]oxazetidines 4a in good yield (75%) together with a small amount of the R*,R* isomer 5a. 7 Reaction with aromatic nitrones 3b,c gave quite good yields of oxazolinyl[1,2]oxazetidines 4b,c highly stereoselectively (Table 1). In the case of the reaction with the nitrone 3d, an appreciable amount of the diastereomeric oxazolinyl[1,2]oxazetidine 5d was isolated. No reaction took place when lithiated species 2 was treated with the nitrone 3e (Scheme 1): the alkenylox- azoline 6 was the only product isolated in this case. 8 Therefore, it seems like as the oxazetidines formation is limited to aromatic nitrones. In a previous paper, 4 we reported that oxazolinyl[1,2]- oxazetidines can derive from a sort of ring contraction involving spirocyclic compounds. An investigation on the reaction mechanism, using nitrone 3d, revealed that quenching the reaction mixture at shorter reaction times (10 min) furnished the spirocyclic precursor 7 and oxazolinyl[1,2]oxazetidine 4d (Scheme 2). Spirocyclic compound 7 was isolated and, upon treat- ment with LDA, was converted into the corresponding oxazolinyl[1,2]oxazetidine 5d proving the reaction ste- reospecificity (Scheme 3). 9 The R*,S* and R*,R* relative configuration of the oxazetidines 4 and 5 could be assigned either by NOESY experiments or by 13 C NMR spectroscopy on the basis of the long-range coupling constants 3 J CH between the hydrogen and the methyl group on the oxazetidine ring. 10 Considering the high diastereoselectivity of the addi- tion reaction of nitrones to lithiated 2-(1-chloroethyl)-2- oxazoline 2, it was almost obvious at this stage that the * To whom correspondence should be addressed. Phone: +39805442749. Fax: +39805442251. (1) (a) Readio, J. D. J. Org. Chem. 1970, 35, 1607-1611. (b) Magers, D. H.; Davis, S. R. THEOCHEM 1999, 487, 205-210. (2) Snider, B. B.; Duvall, J. R. Tetrahedron Lett. 2003, 44, 3067- 3070. (3) Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R. Tetrahedron Lett. 2001, 42, 9183-9186. (4) Capriati, V.; Degennaro, L.; Florio, S.; Luisi, R. Eur. J. Org. Chem. 2002, 17, 2961-2969. (5) Rocchetti, M. T.; Fino, V.; Capriati, V.; Florio, S.; Luisi, R. J. Org. Chem. 2003, 68, 1394-1400. (6) Abbotto, A.; Bradamante, S.; Florio, S.; Capriati, V. J. Org. Chem. 1997, 62, 8937-8940. (7) Oxazolinyl[1,2]oxazetidine 5a could not been isolated; it was detected by 1 H NMR spectroscopy in the crude reaction mixture. (8) The alkenyloxazoline 6 was assigned the E configuration by analogy to what was reported in the case of similar alkenyloxazolines (see ref 4). (9) The relative configuration of the spirocyclic compound 7 was simply ascertained by a NOESY experiment. TABLE 1. Stereoselective Synthesis of Oxazolinyl[1,2]oxazetidines R nitrone 3 oxazetidine 4 (% yield) a oxazetidine 5 (% yield) ratio 4/5 (R*,S*)/(R*,R*) c Ph 3a 4a (75) 5a b 90/10 p-CF3C6H4 3b 4b (60) 5b b >98/2 p-MeOC6H4 3c 4c (85) 5c b >98/2 p-ClC6H4 3d 4d (48) 5d (32) a 60/40 a Isolated yields. b Oxazetidines 5a-c were not isolated. c Di- astereomeric ratio calculated on the basis of 1 H NMR spectroscopy of the crude reaction mixture. 10.1021/jo035360u CCC: $25.00 © 2003 American Chemical Society J. Org. Chem. 2003, 68, 10187-10190 10187 Published on Web 12/03/2003