A Convenient Synthesis of Unsymmetrically Substituted Ureas via Carbamoyl Azides of α‐N‐Protected Amino Acids

Abstract

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)

Simple and Mild One-Pot Synthesis of Dipeptidyl Ureas via Carbamoyl Azides ofα-N-Protected Amino Acids

“…Moreover, the MS 2 spectra of [M þ Na] þ for the N-Boc-derivatives 1abc, 1bbf, 1cba, 1cbd and 1dba evidenced two fragment ions corresponding to the loss of isobutene and CO 2 . [22] In summary, we have developed an efficient, mild, and simple one-pot synthesis of ureidopeptide esters 1 starting from the carbamoyl azides of a-N-protected amino ONE-POT SYNTHESIS OF DIPEPTIDYL UREAS 1031…”

“…1, Table 1); the first step of the process consisted of the preparation of the a-N-protected carbamoyl azide 2, promptly obtained as previously described. [22] In the second step, the free a-amino acid methyl ester 4 (1.4 equiv. with respect to 3) was slowly added into the reaction mixture containing the crude carbamoyl azide 2, and stirring was continued for 3 h at 45 C. After separation of the organic phase and removal of tetrahydrofuran (THF), the obtained residue was thoroughly washed with water and crystallized from water=MeOH (80:20) to afford the pure a-N-protected dipeptidyl urea methyl ester 1 in 75-95% overall yield.…”

“…Yield: 80%; IR n max (cm À1 ): 3368 (br), 3293 (br), 2954,1756,1687,1634,1539,1513,1459,1254,1154,1038,817,614 1 H,NHCOO),9.23 (br s,1 H,OH); 13 C NMR: d 15.5,18.9,19.2,33.3,38.0,52.4,54.9,60.3,63.8,115.9,127.7,130.9,156.1,156.9,157.1,173.8;, 292 (10), 249 (70), 233 (9), 196 (29), 178 (52), 147 (22), 144 (100), 116 (23), 107 (47) H,7.13;N,11.02. Found: C,56.43;H,7.00;N,11.12. Boc-L-Val-w[NHCONH]-L-Tyr-OMe (1abe).…”

“…[22] In the present paper, we report an efficient use of carbamoyl azides in the one-pot, racemisation-free synthesis of a-N-protected ureidopeptides.…”

Study of the Reaction between Carbamoyl Azides of α‐N‐Protected Amino Acids and Hydrazine Monohydrate

“…One approach was carried out in a two-step reaction sequence (Method A): [19] the first step of the process consisted of the preparation of the carbamoyl azide of α-N-(ethoxycarbonyl)phenylalanine (3db), which was readily available through a previously described procedure. [20] In the second step, hydrazine monohydrate (6 equiv.…”