ZUSCHRIFTEN 3328  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 0044-8249/01/11317-3328 $ 17.50+.50/0 Angew. Chem. 2001, 113, Nr. 17 The Use of Carbon Monoxide and Imines as Peptide Derivative Synthons: A Facile Palladium-Catalyzed Synthesis of a-Amino Acid Derived Imidazolines** Rania D. Dghaym, Rajiv Dhawan, and Bruce A. Arndtsen* Of the many basic building blocks used in pharmaceutical development, the peptide unit is perhaps the most ubiquitous. In addition to linear polypeptides, this unit is found in a range of biologically relevant heterocyclic compounds. [1] Traditional routes to prepare peptide-containing compounds have fo- cused on the use of presynthesized or isolated a-amino acid derivatives as synthons. [2] However, examination of the peptide structure suggests that it might also be conceived to arise from the coupling of an imine and carbon monoxide, and its synthesis approached by metal-mediated alternating in- sertion (Scheme 1). [3] Considering the ready availability and CO (bipy)Pd CH 3 NCMe (bipy)Pd O N R' H Tol R N R Tol H CO (bipy)Pd N O H Tol R O R' Cl – N Bn O Ph H Tol + 1 + X – + 3 + [Pd 2 (dba) 3 ] bipy 2 (R' = CH 3 ; X = OTf) 4 (R' = Ph; X = Cl) Scheme 1. Palladium-mediated synthesis of peptides. dba  dibenzylidene acetone. flexibility of imines as substrates, CO and imine coupling would provide an attractive general route to both natural and nonnatural amino acid containing products. We have recently reported that the sequential insertion of CO and an imine can be achieved with [(bipy)Pd(CH 3 )(NCCH 3 )]  OTf  (1) (bipy  2,2'-bipyridine), which demonstrates the feasibility of this process. [3±5] Here we report the development of a novel catalytic method to construct a-amino acid containing hetero- cycles, by using an imine, CO, and an acid chloride as the sole building blocks. The addition of Tol(H)CNR (Tol  p-C 6 H 4 CH 3 ) and 1 atm CO to complex 1 has been found to lead to the formation of the Pd-chelated amide complex 2. [3] In order to generate an amino acid derivative from 2, the further insertion of CO into the Pd  C bond is necessary. However, the attempted reaction of 2 with CO has been unsuccessful, even at elevated temperature and pressure. A plausible rationale for this behavior is that strong chelation of the amide ligand in 2 effectively blocks the coordination site required for CO insertion. [3] To address this issue, we examined the use of the more coordinating halide counteranion, which might weaken amide chelation through coordination, or stabilize the product of CO insertion. [6] Anion exchange of 2 with NaCl allows the in situ incorporation of the chloride anion into the metallacycle; however, a more facile route to this class of compounds is described in Scheme 1. This involves the oxidative addition of acyliminium salt 3 to [Pd 2 (dba) 3 ] ´ CHCl 3 in the presence of 2,2'-bipyridine to form 4 in 92 % yield. [7, 8] In contrast to the behavior of 2, the reaction of 4 with 1 atm CO in CD 3 CN leads to the slow disappearance of starting materials over the course of 5 days at 55 8C. Surprisingly, however, product isolation yields the carboxylate-substituted imidazoline 5 in 35 % yield (Scheme 2). (bipy)Pd Cl O Ph N Tol H Bn O Ph Cl N O (bipy)Pd Ph Bn Tol H Cl – 13 CO CD 3 CN N N Ph Bn Bn CO 2 – Tol Tol H (bipy)Pd N Ph O H Tol O Bn Cl 7 + 3 55 o C 5 * - {(bipy)Pd} 4 6 * + bipy * CO Pd 0 Scheme 2. Formation of the carboxylate-substituted imidazoline 5. Carboxylate-substituted imidazolines such as 5 are bio- logically relevant heterocycles, formally incorporating an a- amino acid residue into the heterocyclic core. [10±12] Thus, the generation of 5 from palladium complex 4 suggests that the imine and CO have been coupled into a peptide unit, followed by subsequent reactions. To determine the origin of 5, and to optimize its synthesis, the mechanism of the transformation was examined. Performing the reaction of 4 with 13 CO leads to the incorporation of 13 C label in the carboxylate group (d  166.4). This presumably arises from insertion of 13 CO into 4 to form the palladium-bound amino acid derivative 6 (Scheme 2). Examination of the structure of 5 suggests that it is formed by the coupling of the amino acid ligand in 6 with the imine. However, no imine was added to the reaction. The source of additional imine was determined by monitoring the reaction by 1 H NMR, which revealed the concurrent forma- tion of [(bipy)Pd(COPh)Cl] (7) (40 % yield) along with imidazoline 5. In the light of the synthesis of 4 by the oxidative addition of acyliminium salt 3, a plausible explanation for the formation of 7 involves the reductive fragmentation of 4 to regenerate 3 and Pd 0 . [9] The 1 H NMR of 3 in CD 3 CN at 55 8C reveals that it is in rapid equilibrium with PhCOCl and Tol(H)C  NBn. This would both provide a source of free imine, and allow for the formation of 7 by oxidative addition of PhCOCl to Pd 0 . The mechanism described in Scheme 2 shows that palla- dium complex 4 is in rapid equilibrium with imine and acid chloride under the reaction conditions. This suggests that the synthesis of the imidazoline core might be more easily achieved by starting directly from imine, CO, and acid chloride. Indeed, the one-pot reaction of Tol(H)C NBn, [*] Prof. B. A. Arndtsen, R. D. Dghaym, R. Dhawan Department of Chemistry, McGill University 801 Sherbrooke St. W., Montreal, Quebec H3A 2K6 (Canada) Fax: ( 1) 514-398-3797 E-mail: bruce.arndtsen@mcgill.ca [**] This work was supported by NSERC (Canada) and FCAR (Quebec). R.D. and R.D.D. thank McGill University for McGill Major Fellow- ships. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author.