Studies on the Synthesis of 2-Alkyl-5-aryl-1,3,4-oxadiazolines from N-Acylhydrazones

LETTER 885 Studies on the Synthesis of 2-Alkyl-5-aryl-1,3,4-oxadiazolines from N-Acylhydrazones Synthesis of 2-Alkyl-5-aryl-1,3,4-oxadiazolines Eugenia Marqués-López,a,1, Elena Díez,a Eloísa Martín-Zamora,a Eleuterio Álvarez,b Rosario Fernández,*a José M. Lassaletta*b aDepartamento de Química Orgánica, Universidad de Sevilla, Apdo. de Correos N° 1203, 41071 Seville, Spain E-mail: [email protected]s bInstituto de Investigaciones Químicas (CSIC-US), Américo Vespucio 49, 41092 Seville, Spain Fax +34(95)4460565; E-mail: jmla[email protected]sic.es Received 24 November 2011 SYNLETT 2012, 23, 885–888 xx.xx.2012 Advanced online publication: 15.03.2012 DOI: 10.1055/s-0031-1290609; Art ID: D71011ST © Georg Thieme Verlag Stuttgart · New York Abstract: Reaction of N-acylhydrazones with benzyloxyacetyl chloride in the presence of i-Pr2EtN affords new 1,3,4-oxadiazolines in excellent yields (72–95%), under mild reaction conditions and in short reaction times. The structures of the products were confirmed by single-crystal X-ray diffractometry. A plausible reaction mechanism is proposed. Key words: N-acylhydrazones, oxadiazolines, benzyloxyacetyl chloride, acylation, heterocycles Among five-membered heterocycles, 1,3,4-oxadiazolines and derivatives have been the subject of chemical and biological studies on account of their interesting pharmacological properties, including antimicrobial,2 antiinflammatory,3 antiviral,4 and antitumor activities.5 Selected structures 1–3, are outlined in Figure 1. As a consequence of the significant biological activity, the synthesis of new and easily accessible 1,3,4-oxadiazolines seems an aim of great interest. Previous synthetic methods reported for these compounds involve cyclization of anionic N-acylhydrazones under acylation conditions using acetic anhydride6 or acetyl chloride.7 Other methods include oxidative cyclization of aldazines using Pb(OAc)4.8 On the other hand, the formation of similar structures is described for reactions involving ketenes (generated in situ) and N-acylhydrazones or 2,3-diaza-1,3-dienes (azines) either with moderate to good yields or as by-products.9 The absence of reports for the synthesis of simple 2-alkyl-5-arylderivatives is noteworthy. During the last few years, our research group has been interested in the asymmetric synthesis of b-lactams by a Staudinger-like reaction between aldehyde N,N-dialkylhydrazones and functionalized benzyloxyketene10 (generated in situ from benzyloxyacetyl chloride 4 with a base) or amino ketenes.11 Recently, we decided to explore the behavior of more reactive N-acylhydrazones 5 as the imine component in the [2+2] cycloaddition. Taking advantage of the high relative stability of hydrazones toward enolization, we decided to focus on aliphatic derivatives. Thus, the reaction of isovaleraldehyde benzoyl hydrazone (5a) as a model substrate and benzyloxyacetyl chloride (4) as the reagent, was chosen for preliminary experiments. However, under our previously optimized conditions (2 equiv of 4, 4 equiv of Et3N in anhydrous toluene),10 the reaction afforded no trace of the corresponding b-lactam 6, instead, formation of oxadiazoline 7a in 80% yield was observed after 24 hours at room temperature (Scheme 1). Scheme 1 Formation of oxadiazoline 7a Figure 1 Selected bioactive 1,3,4-oxadiazolines: 1 (antifungal),2 2 (anti-inflammatory),3 and 3a and 3b (antitumor)5a,c N O N MeO MeO O 2 3a: X = NMe2 3b: X = OMe N O N O H 1 MeO F O O2N N O N O HO O X BnO Cl O N O N O BnO Ph NNH H 5a 4 7a N ONH BnO 6 + OPh Et3N Ph O r.t. toluene 80% Downloaded by: Universidad de Sevilla. Copyrighted material. 886 E. Marquéz-López et al. LETTER Synlett 2012,23, 885–888 © Thieme Stuttgart · New York Using the same model reaction, further experiments were performed to investigate the influence of the base and/or the reaction temperature on the product distribution. To this end, reactions performed at room temperature using diisopropylethylamine and tribenzylamine were analyzed after 24 hours and compared with the triethylamine-promoted reaction. The results, collected in Table 1 (entries 1–3), indicate a slight improvement with diisopropylethylamine and a significant drop of yield in the case of the less basic tribenzylamine.12 Finally, performing the reactions at 80 °C not only provided a slightly better yield, but also led to a significant rate acceleration, leading to virtually complete reactions in only five hours (entries 4 and 5). These optimized conditions [hydrazone (2 equiv), iPr2EtN (4 equiv), anhydrous toluene, 80 °C] were then applied to the reaction of different N-acylhydrazones 5a–g with benzyloxyacetyl chloride (4) for the synthesis of adducts 7a–g. The results, collected in Table 2, indicate the efficiency of the reaction for primary (entries 1, 3, 6, and 7), secondary (entries 2 and 5), and even tertiary (entry 4) aliphatic derivatives, although higher reaction temperatures and longer reaction times were required in the latter case. Examples that illustrate the compatibility with electron-withdrawing (entries 4–6) or electron-donating (entry 7) groups are included. In addition to the usual spectroscopic characterization (see the Supporting Information), single-crystal X-ray diffraction analysis of adduct 7e (Figure 2)13 unequivocally confirmed the proposed structure. Two plausible reaction paths can be a priori proposed for this reaction. As is the case in reactions with N,N-dialkylhydrazones, benzyloxyacetyl chloride 4 could possibly react first with the base to form the corresponding benzyloxy ketene 8 after hydrogen chloride b-elimination. Ensuing nucleophilic addition of the sp2 imine nitrogen of 5 to the electron-deficient ketene central carbon and spontaneous cyclization of the resulting zwitterionic intermediate 10 would render the product 7 (Scheme 2, blue path). A second possible path starts with the acylation of the imino nitrogen of the substrate by 4 to form acyl immonium intermediate 9 from which deprotonation by the base renders the final product 7 through the same zwitterionic intermediate 10. Several pieces of evidence suggest that the mechanism involving ketene 8 can be disregarded. First, previous studies11b indicate that the rate of ketene formation decreases in the order Et3N > i-Pr2EtN >> Bn3N, with the latter being much slower than the observed reaction rate. Such a dependence on the base is not consistent with the observed trend. Further evidence for 9 as a reaction intermediate was obtained from the reaction of 5g with 4 in the Table 1 Screening of Reaction Conditionsa Entry Base Temp (°C) Time (h) Yield (%)b 1Et 3Nr.t. 2480 2i-Pr2EtN r.t. 24 84 3Bn 3Nr.t. 24 51 4i-Pr2EtN 80 5 88 5Bn 3N80 5 64 a Reactions performed at 0.5 mmol scale using 4 (2 equiv) and base (4 equiv). b Isolated yield after column chromatography. BnO Cl O N O N O BnO Ph 5a 4 7a H N H NPh OR3N (4 equiv), toluene Table 2 Synthesis of Oxadiazolines 7a–g from N-Acylhydrazones 5a–g Entry 5Ar R Time (h) 7Yield (%)a 15a Ph i-Bu 5 7a 88 25b Ph i-Pr 5 7b 86 35c Ph CH2CH2Ph 5 7c 89 4b5d 4-O2NC6H4t-Bu 16 7d 72 55e 4-O2NC6H4i-Pr 5 7e 93 65f 4-O2NC6H4i-Bu 4 7f 95 75g 4-MeOC6H4i-Bu 4 7g 89 a Isolated yields after column chromatography. b Reaction performed at 100 °C. BnO Cl O toluene i -Pr2EtN N O N O BnO RAr N H N HR Ar O 5a – g 4 7a – g + 80 °C Figure 2 X-ray crystal structure of oxadiazoline 7e. Hydrogen atoms omitted for clarity. Thermal ellipsoids drawn at the 50% probability level. Downloaded by: Universidad de Sevilla. Copyrighted material. LETTER Synthesis of 2-Alkyl-5-aryl-1,3,4-oxadiazolines 887 © Thieme Stuttgart · New York Synlett 2012,23,885–888 presence of a large excess of tribenzylamine (8 equiv) as the base. Under these conditions, a moderate (50% yield) amount of product 7g was obtained, along with a small amount (22%) of enhydrazine by-product 11 (Scheme 3), which is presumed to form by competitive deprotonation of the acidic a-methylene from the same intermediate 9. Scheme 3 In summary, use of diisopropylethylamine as the base enables a mild and efficient synthesis of 5-alkyl-1,3,4-oxadiazolines 7a–g from N-acylhydrazones 5a–g and benzyloxyacetyl chloride 4. Experimental evidence suggests that the reaction proceeds through N-acyliminium intermediates resulting from direct acylation of the hydrazone N(sp2) atom by acyl chloride 4. Supporting Information for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett. Acknowledgment We thank the Spanish Ministerio de Ciencia e Innovación (grant numbers CTQ2010-15297 and CTQ2010-14974), the European FEDER funds, and the Junta de Andalucía (grant numbers 2008/ FQM-3833 and 2009/FQM-4537) for financial support. References and Notes (1) Present address: Laboratorio de Síntesis Asimétrica, Departamento de Química Orgánica, Instituto de Síntesis Química y Catálisis Homogénea, Universidad de ZaragozaCSIC, 50009 Zaragoza, Spain (2) Rollas, S.; Gulerman, N.; Erdeniz, H. Il Farmaco 2002, 57, 171. (3) Rajak, H.; Kharya, M. D.; Mishra, P. Yakugazu Zasshi 2007, 127, 1757. (4) Ali, O. M.; Amer, H. H.; Abdel-Rahman, A. A.-H. Synthesis 2007, 2823. (5) (a) Tahir, S. K.; Han, E. K.-H.; Credo, B.; Jae, H.-S.; Pietenpol, J. A.; Scatena, C. D.; Wu-Wong, J. R.; Frost, D.; Sham, H.; Rosenberg, S. H.; Ng, S.-C. Cancer Res. 2001, 61, 5480. (b) Hans, J.; Wallace, E. M.; Zhao, Q.; Lyssikatos, J. P.; Aicher, T. D.; Robinson, J.; Allen, S. PCT Int. Appl. WO 2006044825, 2006. (c) Lee, L.; Robb, L. M.; Lee, M.; Davis, R.; Mackay, H.; Chavda, S.; Babu, B.; O’Brien, E. L.; Risinger, A. L.; Mooberry, S. L.; Lee, M. J. Med. Chem. 2010, 53, 325. (6) For selected examples, see: (a) Somogyi, L. Liebigs Ann. Chem. 1994, 623. (b) Somogyi, L. Bull. Chem. Soc. Jpn. 2001, 74, 873. (c) El Ashry, E. S. H.; Rashed, N.; Awad, L. F.; Abdel-Rahman, A. A. H.; Rasheed, H. A. J. Chem. Res., Miniprint 2001, 440. (7) (a) Armesto, D.; Gallego, M. G.; Horspool, W. M.; Ramos, A. Tetrahedron Lett. 1988, 29, 3581. (b) Somogyi, L. Tetrahedron 1985, 41, 5187. (8) Gillis, B. T.; Lamontagne, M. P. J. Org. Chem. 1967, 32, 3318. (9) (a) Alcaide, B.; Miranda, M.; Pérez-Castells, J.; Polanco, C.; Sierra, M. A. J. Org. Chem. 1994, 59, 8003. (b) Singh, G. S.; Shang, M.; Ibata, T. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 2000, 39, 554. (c) Singh, G. S. J. Heterocycl. Chem. 2006, 43, 1653. (d) Kaspentakis, G. C.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J. J. Heterocycl. Chem. 2007, 44, 425. (10) (a) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Monge, A. Angew. Chem. Int. Ed. 2000, 39, 2893. (b) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.; Martín-Zamora, E. Angew. Chem. Int. Ed. 2002, 41, 831. (c) Martín-Zamora, E.; Ferrete, A.; Llera, J. M.; Muñoz, J. M.; Pappalardo, R. R.; Fernández, R.; Lassaletta, J. M. Chem. Eur. J. 2004, 10, 6111. (11) (a) Díez, E.; Fernández, R.; Marqués-López, E.; MartínZamora, E.; Lassaletta, J. M. Org. Lett. 2004, 6, 2749. (b) Marqués-López, E.; Martín-Zamora, E.; Díez, E.; Fernández, R.; Lassaletta, J. M. Eur. J. Org. Chem. 2008, 2960. (12) (a) Graton, J.; Besseau, F.; Berthelot, M.; Raczynska, E. D.; Laurence, C. Can. J. Chem. 2002, 80, 1375. (b) Canle, L. M.; Demirtas, I.; Freire, A.; Maskill, H.; Mishima, M. Eur. J. Org. Chem. 2004, 5031. (13) Crystal data for 7e (CCDC 850772): C20H21N3O5; M= 383.40; monoclinic; a= 33.9831 (8) Å, b= 6.14820 Scheme 2 Plausible reaction mechanisms N H N RN ON BnO OCl BnO Ar O Ar O H R + 4 5 8 + Cl– O BnO H H R3N – R3NH+Cl– – R3NH+Cl– 9 R3N N ON BnO Ar O R +- 10 N H N R Ar O 5 + 7 N ON BnO Ar O R + –H Bn3N N O N O BnO Ar N H N H Ar O 5g 4 7g (50%) 11 (22%) Ar = p -anisyl N ON BnO Ar O H H N OH N BnO Ar O + + PhMe r.t. Bn3N 9 Downloaded by: Universidad de Sevilla. Copyrighted material. 888 E. Marquéz-López et al. LETTER Synlett 2012,23, 885–888 © Thieme Stuttgart · New York (10) Å, c= 20.2932 (5) Å, a= 90.00°, b= 118.3420 (10)°, g= 90.00°; V= 3731.71 (14) Å3; T= 100 (2) K; space group C2/c; Z=8; m(MoKa) = 0.100 mm–1; 34754 reflections measured, 5690 independent reflections (Rint = 0.0436). The final R1 values were 0.0474 (I > 2s(I)). The final wR(F2) values were 0.1106 (I > 2s(I)). The final R1 values were 0.0941 (all data). The final wR(F2) values were 0.1314 (all data); goodness-of-fit: 1.030. Downloaded by: Universidad de Sevilla. Copyrighted material.