1 Introduction
Carboxylate groups are among the protecting groups most commonly used for blocking amino functions. Several methods to introduce a wide variety of these groups were proposed [1]. The use of different sulfonyloxycarbamates (ArSO3NHCO2R) in the amination reactions gives directly several N-acyloxy protected nitrogen-containing compounds [2].
In the course of our study, we reported an aza-Michael initiated ring closure (MIRC) [3] route to efficiently obtain a large number of different functionalized aziridines [4]. The increasing complexity of the synthesized aziridines due to substituents of the ring carbon atoms seems to play a fundamental role in the transformation reactions of the aziriridine ring, first of all the nitrogen deprotection reaction. Protecting groups must be easily removed in order to obtain corresponding unblocked aziridines, thus obtaining an additional site for further synthetic transformations. Considering the value of aziridines like versatile building blocks [5] for the synthesis of a large number of nitrogen-containing compounds, it is very important the choice of the sulfonyloxycarbamate employed in the direct aziridination of functionalized olefins.
Recently we synthesized and tested several nosyloxycarbamates (NsONHCO2R, Ns = 4-nitrophenylsulfonyl) bearing different R groups as efficient aza-MIRC reactants [6].
In this communication, we report the first results about the role of substituents on the ring carbon atoms in the deprotection reaction of different functionalized aziridines. These latter were obtained by the aziridination of the corresponding olefins with four different carbamates, namely ethyl, tert-butyl, benzyl and 9-fluorenylmethyl nosyloxycarbamates.
2 Results and discussion
The carbamates 1a–d were synthesized according to a procedure reported in Ref. [7]. We considered different olefins bearing electron-withdrawing groups. The aza-MIRC reactions were performed in the presence of CaO in CH2Cl2 at room temperature and gave the expected N-protected aziridines 2–6 in very high yields (Fig. 1).
Synthesis and deprotection of N-acyloxy aziridines.
Compounds 2–6 were treated under the usual deprotection conditions for each considered protecting group [1]. Reaction conditions and results are depicted in the Table 1.
Deprotection of N-acyloxy aziridines
| Entry | Z | Deprotection procedure | 2e | 3e | 4e | 5e | 6e |
| 1 | CO2Et | NaOH/MeOH a | – b | Traces | – | – | – |
| 2 | Boc | BF3·Et2O c | – d | 36%e | 30% e | – | – d |
| 3 | Cbz | Pd/C 10% HCO2NH4 MeOH f | – | Traces | Traces | Quant. conv. | Quant. conv. |
| 4 | Fmoc | 20% Piperidine CH2Cl2 | Quant. 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.
As reported in Table 1, the cleavage of the ethoxycarbonyl group (entry 1) failed for 2 and gave the undesired transesterification reaction of the carbamate function, while in the other considered cases only GC traces of unprotected aziridines were observed. With tert-butoxycarbonyl (Boc) group as the protecting group (entry 2), a partial deprotection was obtained with aziridines 3b and 4b. 5b gave a complex mixture of unidentified decomposition products. Aziridines 2b and 6b cannot be obtained using tert-butyl nosyloxycarbamate.
Carbobenzoxy (Cbz) group (entry 3) was successfully removed from substrates 5c and 6c, but the reductive deprotection procedure was not compatible with the functional groups carried by aziridines 2c–4c.
Free aziridines were efficiently obtained from compounds 3d–6d by using a 20% piperidine solution in dichloromethane to remove 9-fluorenylmethyloxycarbonyl (Fmoc) group (entry 4). A typical procedure to remove the Fmoc group [8] is reported as follows for 5e: N-protected aziridine 5d (0.42 g, 1 mmol) was dissolved in 3 ml of a 20% piperidine solution in dichloromethane and stirred at room temperature for 15 min. After solvent removal, cold MeOH was added and the mixture was filtered. By evaporation, 5e was obtained in quantitative yield. 1H NMR (200 MHz, CDCl3) δ = 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) δ = 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 reasonable compatibility could not be achieved with the considered polyfunctionalized aziridines. EWG groups, like nitro or carbonyl, seem to strongly interfere with the reaction outcome, while the mild basic deprotection conditions are the most versatile, both for the stability of the aziridine ring and for the different functional groups. An easy and generally compatible method for the deprotection of aziridines is a goal of valuable importance [9] for the design and construction of aziridine combinatorial libraries [10] directed towards particular pharmacological targets.
Acknowledgements
We thank the Italian Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) and the Università degli Studi di Roma La Sapienza (National Project ‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’) for financial support.