Alberto Morreale

Lucio Pellacani

Paolo Antonio Tardella

Stefania Fioravanti

Comptes Rendus Chimie

Preliminary communication / CommunicationCan functionalized N-acyloxy aziridines be easily deprotected?Stefania Fioravanti *, Alberto Morreale, Lucio Pellacani *, Paolo Antonio Tardella *Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le Aldo Moro 2, I-00185 Roma, ItalyReceived 2 November 2004; accepted after revision 17 December 2004Available online 13 March 2005AbstractNitrogen deprotection of polyfunctionalized N-acyloxy aziridines was studied considering the compatibility of reaction con-ditions with the different functional groups on the aziridine ring. To cite this article: S. Fioravanti et al., C. R. Chimie 8(2005).© 2005 Académie des sciences. Published by Elsevier SAS. All rights reserved.RésuméLa déprotection de l’azote de N-acyloxy aziridines fonctionnalisées a été étudiée en considérant la compatibilité des condi-tions de réaction avec les différents groupes fonctionnels sur l’anneau des aziridines. Pour citer cet article : S. Fioravanti et al.,C. R. Chimie 8 (2005).© 2005 Académie des sciences. Published by Elsevier SAS. All rights reserved.Keywords: Carbamates; Aziridines; Protecting groupsMots clés : Carbamates ; Aziridines ; Groupes protecteurs1. IntroductionCarboxylate groups are among the protecting groupsmost commonly used for blocking amino functions.Several methods to introduce a wide variety of thesegroups were proposed [1]. The use of different sulfo-nyloxycarbamates (ArSO3NHCO2R) in the aminationreactions gives directly several N-acyloxy protectednitrogen-containing compounds [2].In the course of our study, we reported an aza-Michael initiated ring closure (MIRC) [3] route to effi-ciently obtain a large number of different functional-ized aziridines [4]. The increasing complexity of thesynthesized aziridines due to substituents of the ringcarbon atoms seems to play a fundamental role in thetransformation reactions of the aziriridine ring, first ofall the nitrogen deprotection reaction. Protecting groupsmust be easily removed in order to obtain correspond-ing unblocked aziridines, thus obtaining an additionalsite for further synthetic transformations. Consideringthe value of aziridines like versatile building blocks [5]for the synthesis of a large number of nitrogen-* Corresponding authors. Tel.: +39 06 49 913673; fax: +39 06 490631.E-mail address: lucio.pellacani@uniroma1.it (L. Pellacani).C. R. Chimie 8 (2005) 845–847http://france.elsevier.com/direct/CRAS2C/1631-0748/$ - see front matter © 2005 Académie des sciences. Published by Elsevier SAS. All rights reserved.doi:10.1016/j.crci.2005.02.010containing compounds, it is very important the choiceof the sulfonyloxycarbamate employed in the directaziridination of functionalized olefins.Recently we synthesized and tested several nosy-loxycarbamates (NsONHCO2R, Ns = 4-nitrophenylsul-fonyl) bearing different R groups as efficient aza-MIRC reactants [6].In this communication, we report the first resultsabout the role of substituents on the ring carbon atomsin the deprotection reaction of different functionalizedaziridines. These latter were obtained by the aziridina-tion of the corresponding olefins with four different car-bamates, namely ethyl, tert-butyl, benzyl and9-fluorenylmethyl nosyloxycarbamates.2. Results and discussionThe carbamates 1a–d were synthesized accordingto a procedure reported in Ref. [7]. We considered dif-ferent olefins bearing electron-withdrawing groups. Theaza-MIRC reactions were performed in the presence ofCaO in CH2Cl2 at room temperature and gave theexpected N-protected aziridines 2–6 in very high yields(Fig. 1).Compounds 2–6 were treated under the usual depro-tection conditions for each considered protecting group[1]. Reaction conditions and results are depicted in theTable 1.As reported in Table 1, the cleavage of the ethoxy-carbonyl group (entry 1) failed for 2 and gave the unde-sired transesterification reaction of the carbamate func-tion, while in the other considered cases only GC tracesof unprotected aziridines were observed. With tert-butoxycarbonyl (Boc) group as the protecting group(entry 2), a partial deprotection was obtained with aziri-dines 3b and 4b. 5b gave a complex mixture of uniden-tified decomposition products. Aziridines 2b and 6bcannot be obtained using tert-butyl nosyloxycarba-mate.Carbobenzoxy (Cbz) group (entry 3) was success-fully removed from substrates 5c and 6c, but the reduc-tive deprotection procedure was not compatible withthe functional groups carried by aziridines 2c–4c.Fig. 1. Synthesis and deprotection of N-acyloxy aziridines.Table 1Deprotection of N-acyloxy aziridinesEntry Z Deprotectionprocedure2e3e 4e5e 6e1 CO2Et NaOH/MeOHa – b Traces – – –2 Boc BF3·Et2Oc – d 36%e 30% e – – d3 Cbz Pd/C 10%HCO2NH4 MeOHf– Traces Traces Quant. conv. Quant. conv.4 Fmoc 20% PiperidineCH2Cl2Quant. conv. Quant. conv. Quant. conv. Quant. conv.a 1 mmol of aziridine and 0.15 mmol of NaOH in 5 ml of MeOH at room temperature for 24 h.b 56% of methyl 1-nitro-7-azabicyclo[4.1.0]heptane-7-carboxylate was obtained.c 1 mmol of both aziridine and BF3 in 2 ml of anhydrous Et2O at room temperature for 24 h.d tert-butyl nosyloxycarbamate did not react with the considered olefin.e N-protected aziridine was partially recovered (up to 20%).f 1 mmol of aziridine and 8 mmol of HCO2NH4 in the presence of 0.3% of catalyst in 20 ml of MeOH at 40 °C for 4.846 S. Fioravanti et al. / C. R. Chimie 8 (2005) 845–847Free aziridines were efficiently obtained from com-pounds 3d–6d by using a 20% piperidine solution indichloromethane to remove 9-fluorenylmethyloxy-carbonyl (Fmoc) group (entry 4). A typical procedureto remove the Fmoc group [8] is reported as followsfor 5e: N-protected aziridine 5d (0.42 g, 1 mmol) wasdissolved in 3 ml of a 20% piperidine solution in dichlo-romethane and stirred at room temperature for 15 min.After solvent removal, cold MeOH was added and themixture was filtered. By evaporation, 5e was obtainedin quantitative yield. 1H NMR (200 MHz, CDCl3)d = 1.18–1.31 (m, 9H), 2.53 (s, broad, 1H), 2.63 (q, 1H,J = 5.5 Hz), 4.15–4.30 (m, 4H) ppm; 13C NMR(50 MHz, CDCl3) d = 14.0, 14.1, 15.2, 39.7, 45.6, 61.7,62.5, 166.1, 168.6 ppm; GC–MS: m/z (%): 201 (M+,<1), 156 (11), 155 (28), 128 (14), 127 (81), 110 (25),100 (17), 82 (24), 56 (19), 55 (100), 54 (30), 45 (37);ES-MS Q-TOF m/z Calc. for C9H16NO4 (MH+)202.1079. Found 202.1073.Drastic deprotection conditions showed that a rea-sonable compatibility could not be achieved with theconsidered polyfunctionalized aziridines. EWG groups,like nitro or carbonyl, seem to strongly interfere withthe reaction outcome, while the mild basic deprotec-tion conditions are the most versatile, both for the sta-bility of the aziridine ring and for the different func-tional groups.An easy and generally compatible methodfor the deprotection of aziridines is a goal of valuableimportance [9] for the design and construction of aziri-dine combinatorial libraries [10] directed towards par-ticular pharmacological targets.AcknowledgementsWe thank the Italian Ministero dell’Istruzione,dell’Università e della Ricerca (MIUR) and the Univer-sità degli Studi di Roma La Sapienza (National Project‘Stereoselezione in Sintesi Organica. Metodologie edApplicazioni’) for financial support.References[1] T.W. Greene, P.G.M. Wuts, Protective Groups in OrganicSynthesis, third ed, Wiley, New York, 1999 (Chapter 7).[2] D. Colantoni, S. Fioravanti, L. Pellacani, P.A. Tardella, Org.Lett. 6 (2004) 197.[3] R.D. Little, J.R. Dawson, Tetrahedron Lett. 21 (1980) 2609.[4] S. Fioravanti, A. Morreale, L. Pellacani, P.A. Tardella, Eur. J.Org. Chem. (2003) 4549 (and refs. therein reported).[5] J.B. Sweeney, Chem. Soc. Rev. 31 (2002) 247.[6] S. Fioravanti, A. Morreale, L. Pellacani, P.A. Tardella, Synlett(2004) 1083.[7] W. Lwowski, T.J. Maricich, J. Am. Chem. Soc. 87 (1965)3630.[8] L.A. Carpino, D. Sadat-Aalaee, M. Beyermann, J. Org. Chem.55 (1990) 1673.[9] T. Schirmeister, M. Peric, Bioorg. Med. Chem. 8 (2000) 1281.[10] B.S. Iyengar, R.T. Dorr, D.S. Alberts, E.M. Hersh,S.E. Salmon, W.A. Remers, J. Med. Chem. 42 (1999) 510.847S. Fioravanti et al. / C. R. Chimie 8 (2005) 845–847

Can functionalized <i>N</i>-acyloxy aziridines be easily deprotected?

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Can functionalized <i>N</i>-acyloxy aziridines be easily deprotected?

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