Regiochemistry of an ambident cyclic ketene-N,O-acetal nucleophile and its anion toward electrophiles Yingquan Song ⇑ , Hondamuni I. De Silva, William P. Henry, Guozhong Ye, Sabornie Chatterjee, Charles U. Pittman Jr. ⇑ Department of Chemistry, Mississippi State University, Mississippi State, MS 39762, USA article info Article history: Received 16 March 2011 Revised 2 June 2011 Accepted 7 June 2011 Available online 21 June 2011 Keywords: Cyclic ketene acetal Ambident nucleophile Regiochemistry abstract The five-membered cyclic ketene-N,O-acetal, 2-oxazolidin-2-ylidene-1-phenylethanone 1, and its anion 2, formed on deprotonation, are ambident nucleophiles. Compound 1 was synthesized by benzoylation of 2-methyl-2-oxazoline to give a ring-opened N,C,O-trisbenzoylation product, 9, followed by N,O-double debenzoylation using methanolic KOH. Compound 1 reacted with benzoyl chloride to give N,C,O-tris- benzoylated 9, and reacted with phenyl chloroformate to give the similar ring-opened carbonic acid 3- [(2-chloro-ethyl)-phenoxycarbonyl-amino]-3-oxo-1-phenyl-propenyl ester phenyl ester, 13. In contrast, ambident anion 2 reacted with benzoyl chloride to give the b,b-bisbenzoylated cyclic ketene-N,O-acetal, 16, and reacted with phenyl chloroformate to give the novel heterocycle 3-(2-hydroxy-ethyl)-6-phenyl- [1,3]oxazine-2,4-dione, 17. Ó 2011 Elsevier Ltd. All rights reserved. 2-Oxazolidin-2-ylidene-1-phenylethanone 1, a five-membered cyclic ketene-N,O-acetal, and its deprotonated form, anion 2, are both ambident nucleophiles (Fig. 1). The ring nitrogen, exocyclic b-carbon and carbonyl oxygen are nucleophilic in both 1 and 2. Compound 1 has been used in the syntheses of fused indole deriv- atives, 1 bicyclic pyridones, 2 1,3-oxazoheterocycle-fused-[1,2-b]iso- quino-lin-1(2H)-imines 3 and 5H-oxazolo[3,2-a]pyridine deriva tives. 4 These reactions used 1 as an ambident nucleophile which re- acted with ambident electrophiles to effect ring closures. The regio- chemistry of 1 reacting with electrophiles having only one nucleophilic site has not been reported. During studies of cyclic ketene-N,O-acetal chemistry with vari- ous electrophiles, 5 interest grew in the regiochemistry of 1 and 2 reacting with acid chlorides and aryl chloroformates. Preliminary results are reported here. Results Benzoylation of 2-methyl-2-oxazoline and 2-methyl-2-oxazine Compound 1 was previously made from ketene dithioacetal 3 and 2-aminoethanol 4 (Eq. 1). Starting material 3, in turn, was pre- pared from acetophenone with NaH and CS 2 , followed by methyl- ation with methyl iodide. In contrast, cyclic ketene-N,O-acetal 4, an analog of 1 with two methyl groups at C-4, was Na O HN O Ph S S O Ph +H 2 N OH 1 3 THF ð1Þ synthesized via benzoylation of 2,4,4-trimethyl-2-oxazoline 5 to give the N,O-bisbenzoylated cyclic ketene-N,O-acetal 6, followed by N-debenzoylation with KOH/methanol (Eq. 2). 6 Thus, an 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.06.023 ⇑ Corresponding authors. Tel.: +1 662 325 7616; fax: +1 662 325 7611. E-mail addresses: yingquan@gmail.com (Y. Song), cpittman@chemistry.mssta- te.edu (C.U. Pittman Jr.). O N H Ph O 1 O N H Ph O 1 O N H Ph O 1 .. .. .. O N Ph O 2 _ _ O N Ph O 2 O N Ph O 2 _ E or or or or + E + E + E + E + E + β β Figure 1. The five-membered cyclic ketene-N,O-acetal 1, and its deprotonated form, anion 2, are ambident nucleophiles. Tetrahedron Letters 52 (2011) 4507–4511 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet