A simple and efficient two‐step synthesis of unsymmetrically substituted ureas containing an amino acid derivative is reported. The procedure involves the reaction between the carbamoyl azides of α‐N‐protected amino acids and ammonium hydroxide or a primary or a secondary amine. The reaction proved to be very fast (0.5 h) with small, highly reactive ammonium hydroxide and slower (4 h) with sterically hindered tert‐butylamine. The 1H NMR spectra of the synthesized, new, unsymmetrical ureas carried out in [D6]DMSO suggest that the protons in the –αCH–NHCONH–CH– moiety assume a trans conformation. Moreover, analysis of the mass spectra (EI and ESI) revealed some interesting common features. The reported synthesis represents the first example of the potential value of carbamoyl azides as versatile chiral starting materials for many synthetic purposes.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

S y n t h e s i s o f C a r b a m o y l A z i d e s o f a -N -P r o t e c t e d A m i n o A c i d sAbstract: A fast and simple one-pot synthesis of carbamoyl azides of a-N-protected amino acids is reported. The procedure involves the reaction between sodium azide and the mixed anhydride obtained from an a-N-protected amino acid and isobutyl chloroformate, in the presence of KH 2 PO 4 . The reaction rate was influenced by the nature of both the a-N-protection and the amino acid side chain. Surprisingly, tert-butyloxycarbonyl (a-N-Boc) and benzyloxycarbonyl (a-N-Cbz) protected proline afforded the corresponding isocyanates instead of the expected carbamoyl azides.Carbamoyl azides are an important class of compounds having a wide range of applications in organic synthesis. 1 Some are used as intermediates in the synthesis of heterocyclic, 2 pharmaceutical 3 and non-crosslinked foam 4 compounds. Carbamoyl azides are generally prepared by reacting the corresponding carbonyl halides with inorganic azides, 2d,5 by nitrosation of semicarbazides, 2b,3b,6 and by the addition of hydrazoic acid 3c,4,7 or organometallic polyazides 8 to isocyanates. All these procedures suffer limitations associated with the availability of precursors and hazards in handling reagents (triphosgene in the synthesis of carbamoyl halides from amines and hydrazoic acid). Carbamoyl azides have also been obtained starting from carboxaldehydes 9 and carboxylic acids 10 but, to our knowledge, the use of a-N-protected amino acids as precursors does not appear to have any precedent in the literature. In this paper we report an efficient extension of the mixed anhydride method to the one-pot synthesis of a-Nprotected carbamoyl azides.The simple and convenient synthesis of a-N-protected carbamoyl azides 3, reported here, was accomplished in a two-step, one-pot reaction sequence (Scheme 1; Table 1). The first step of the process consisted of the preparation of the mixed anhydride 2, which was obtained by reacting the N-methylmorpholinium salt of an a-N-protected amino acid 1 with isobutyl chloroformate (IBCF), in tetrahydrofuran at -10°C. After a few minutes (second step), solid potassium dihydrogenphosphate (6 equiv) was added in one portion at 0°C to the resulting well-stirred mixture, followed by slow addition of an aqueous solution of sodium azide (3 equiv). The resulting mixture was then stirred at room temperature for 1.5-3 hours to afford, after work-up, the carbamoyl azide 3 in a spectroscopically pure form without any further purification in 80-90% overall yield.From a mechanistic point of view, the reaction of the mixed anhydride 2 with sodium azide, gives rise to the azide 4 (Scheme 2) which, in contrast to the isolable Fmoc-amino acid azides reported by Babu et al., 11 proved to be unstable and led to the corresponding isocyanate 5 by the Curtius rearrangement. Compound 5, in the presence of excess sodium azide, yields the corresponding carbamoyl azide 3.It was essential for the success of our synthetic method to carry out the second step of the...

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Synthesis. -The synthesis of the target compounds (II) is achieved in a two-step one-pot procedure via intermediate mixed anhydrides. Surprisingly, N-protected prolines afford isocyanates. -(VERARDO*, G.; BOMBARDELLA, E.; GEATTI, P.; STRAZZOLINI, P.; Synthesis 2008, 3, 438-444; Dip. Chim. Sci. Tecnol., Univ. Udine, I-33100 Udine, Italy; Eng.) -Mais 23-187