Oxiranyllithium based synthesis of α-keto-2-oxazolines

TETRAHEDRON LETTERS Pergamon Tetrahedron Letters 41 (2000) 8835–8838 Oxiranyllithium based synthesis of a-keto-2-oxazolines Vito Capriati, Saverio Florio,* Renzo Luisi, Vincenzo Russo and Antonio Salomone CNR, Centro di Studio sulle Metodologie Innovative di Sintesi Organiche, Dipartimento Farmaco-Chimico, Università di Bari, Via E. Orabona 4, I-70125 Bari, Italy Received 13 September 2000; accepted 14 September 2000 Abstract a-Keto-2-oxazolines 5a–j have been efficiently prepared by lithiation [sec-(or n-)BuLi/TMEDA, Et2O, −100°C] and rearrangement of oxiranyl oxazolines 2a–j. © 2000 Published by Elsevier Science Ltd. Keywords: oxazolinyl oxiranes; oxiranyllithiums; a-keto-2-oxazolines; oxirane–ketone rearrangement. a-Ketoheterocycles are very interesting and useful substances. Some of them, the peptidyl a-ketoheterocycles, have been reported to possess important biological activity such as the inhibition of human neutrophil elastase (HNE), a serine protease, which is believed to be involved in some pathological effects in pulmonary emphysema, rheumatoid arthritis, atherosclerosis and other inflammatory disorders.1 Peptidyl a-ketoheterocycles have also been reported to act as potent inhibitors against prolyl endopeptidase2 and thrombin.3 Among the a-ketoheterocycles, a-keto-2-oxazolines are important members as peptidyl derivatives have been described as potent inhibitors of HNE.4 a-Keto-2-oxazolines have been reported to be the putative intermediates in the oxidative rearrangement of 2-alkyloxazolines to dihydrooxazinones and morpholinones5 and useful precursors to enantiomerically pure a-hydroxy carboxylic acids.6 There are few reports dealing with the synthesis of a-keto-2-oxazolines. Hansen7 and Meyers8 had reported that certain a-keto-2oxazolines can be prepared by oxidation (O2) of lithiated 2-alkyloxazolines. Quite recently a synthetic route to peptidyl a-keto-2-oxazolines has been published4 which was based on the cyclodehydration oxidation of dipeptide derivatives by an extension of Wipf’s protocol of 2-oxazolines.9 As part of our continuing interest in oxazoline chemistry, in the present paper we * Corresponding author. Fax: +39.080.5442231; e-mail: florio@farmchim.uniba.it 0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. PII: S 0 0 4 0 - 4 0 3 9 ( 0 0 ) 0 1 5 5 8 - 6 8836 report a synthetic procedure to a-keto-2-oxazolines based substantially on the deprotonation– rearrangement of oxazolinyl oxiranes. The oxazolinyl oxiranes 2a–j, needed for the rearrangement, were prepared by the Darzenstype reaction of lithiated 4,4-dimethyl-2-chloromethyl-2-oxazoline 1 with carbonyl compounds.10 When treated with sec-BuLi/TMEDA in Et2O at −100°C trans-oxiranyl oxazoline 2a (Scheme 1) underwent rapid lithiation to give oxiranyllithium 3a which was stable at that temperature and could be easily trapped with a number of electrophiles to give more substituted oxiranes.11 The same oxiranyllithium 3a, in the absence of an external electrophile and upon warming to room temperature and acid quenching, underwent a clean conversion to the oxazolinyl benzyl ketone 5a, likely through the enolate 4a (Scheme 1). Such a hypothesis was supported by the fact that there are precedents that, under basic conditions, oxiranes isomerize to carbonyl compounds via the relevant enolates.12 The same ketone 5a was obtained when oxiranyl oxazoline 2b was isomerized under the experimental conditions above. Scheme 1. Similarly, oxazolinyl oxiranes 2c–h could be converted into oxazolinyl ketones 5c–h upon lithiation at low temperature followed by warming to room temperature and quenching with sat. aq. NH4Cl (Scheme 1, Table 1).† † Typical procedure: A solution of 2e (117 mg, 0.35 mmol) and TMEDA (0.08 mL, 0.53 mmol) in 6 mL of Et2O at −100°C and under N2 was treated with sec-BuLi (0.45 mL, 0.53 mmol, 1.18 M in cyclohexane), and the resulting orange mixture was stirred for 15 min at −100°C. The mixture was then allowed to warm to room temperature and after 3 h (generally, when the putative enolate was formed, the reaction mixture became green from yellow) was quenched with sat. aq. NH4Cl, extracted with EtOAc (3×10 mL) and concentrated in vacuo. Flash chromatography on silica gel (7:3 petroleum ether–EtOAc) afforded the keto oxazoline 5e (70.2 mg, 60 %); mp 123–125°C (hexane). 1 H NMR (300 MHz, CDCl3): d 1.25 (s, 6H), 4.02 (s, 2H), 6.11 (s, 1H), 6.95–7.02 (m, 4H), 7.21–7.26 (m, 4H). GC–MS (70 eV) m/z (%): 329 (55.3) [M+], 328 (14), 203 (100), 183 (40.7), 55 (10.5), 41 (2.17). FT-IR (KBr, cm−1): 1717 (s, CO), 1633 (s, CN). Anal. calcd for C19H17F2NO2: C, 69.29; H, 5.20; N, 4.25. Found: C, 69.69; H, 5.45; N, 4.20. 8837 Table 1 Synthesis of a-keto-2-oxazolines 5a–j from oxazolinyl epoxides 2a–j Epoxides Base used a-Keto-2-oxazolines Yield (%)a,b 2a 2b 2c 2d 2e 2f 2g 2h 2i 2j sec-BuLi sec-BuLi sec-BuLi sec-BuLi sec-BuLi sec-BuLi sec-BuLi sec-BuLi n-BuLid n-BuLid 5a 5a 5c 5d 5e 5f 5g 5h 5i 5j 67 67 62 60 60 30c 80 75 80 63e a Isolated yields. All new compounds showed satisfactory microanalytical data (90.4%) and consistent 1H NMR, IR and MS data. c In this case the anion 3f was highly reactive giving rise to many by-products. d Generally n-BuLi can also be used instead of sec-BuLi as in these examples. e In this case the reaction was stopped at −10°C for the best yield. b Lithiation of 1-(4,4-dimethyl-2-oxazolin-2-yl)-2-methyl-1,2-epoxypropane 2i (n-BuLi/ TMEDA, Et2O, −100°C) (Scheme 2) followed by quenching at −100°C (after 30 min) with MeI provided tetrasubstituted epoxide 6 in high yield (87%). Instead, lithiation of 2i, under the same conditions, warming at room temperature for 2 h and quenching with excess MeI afforded the isopropyl ketone 5i (80% yield) and not 5k (Scheme 2). Attempted trapping of the putative enolate 4i with MeOD to give deuterated ketone 5l (Scheme 2) also failed, the undeuterated ketone 5i being obtained (80% yield). Scheme 2. Equally unsuccessful was the attempt to capture the enolate 4j derived from 3j. Indeed, when epoxide 2j was deprotonated under the above conditions, warmed to room temperature and then D2O or allyl bromide added, the only product that could be obtained was 5j (63% yield). In conclusion, in this paper we report a new synthesis of a-keto-2-oxazolines, which are potentially useful synthetic intermediates, based on the deprotonation–rearrangement of oxazolinyl oxiranes. More work is under way in order to rationalize the observed results. 8838 Acknowledgements Work carried out in the framework of the National Project ‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’ was supported by the Ministero dell’Università e della Ricerca Scientifica e Tecnologica, Rome, and by the University of Bari. The authors would also like to thank the Italian CNR for financial support. References 1. (a) Edwards, P. D.; Wolanin, D. J.; Andisik, D. W.; Davis, M. W. J. Med. 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