Organometallic alkylation of 2-chloro-4,6-dimethoxy-1,3,5-triazine: a study Simona Samaritani, Giovanni Signore, Corrado Malanga and Rita Menicagli * Dipartimento di Chimica e Chimica Industriale, Universita ` di Pisa, Via Risorgimento 35, 56126 Pisa, Italy Received 30 August 2004; revised 4 February 2005; accepted 18 February 2005 Available online 23 March 2005 Abstract—The reactivity of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1) has been investigated in Pd- or Ni-catalyzed cross-coupling processes with organostannanes, Grignard reagents, organoalanes and organozinc halides. All organometallic reagents considered form new C–C bonds on the heteroaromatic ring and afford the corresponding 2-alkyl-4,6-dimethoxy-1,3,5-triazines in moderate to very good yields. The collected data allows the choice of the alkylating agent as well as the experimental conditions depending on the residue to transfer. q 2005 Elsevier Ltd. All rights reserved. 1. Introduction During the last few years the potential of 1,3,5-triazine derivatives in molecular recognition, agrochemical and medicinal properties has been subject to investigation. 1 Our studies pointed out that 2-alkyl-4,6-dihetero(N,O)alkyl- 1,3,5-triazines (Fig. 1) show interesting antitumor proper- ties. 1c–e Among the structures studied, 2-(alk-1 0 -ynyl)-4,6- dimethoxy-1,3,5-triazines were the most promising com- pounds. In order to gain an insight into the structure–activity relationship, the synthesis of 2-aryl (alkyl or alk-1 0 -enyl or benzyl or allyl)-4,6-dimethoxy-1,3,5-triazines was necessary. The use of transition metal-catalyzed cross-coupling reac- tions, between 2-chloro-4,6-dimethoxy-1,3,5-triazine (1) and different organometallic reagents, is hereby reported and critically discussed in order to provide the most convenient procedures for the synthesis of the desired compounds. 2. Results and discussion Since the 1990s, transition metal catalyzed cross-coupling reactions have been described for the preparation of symmetrical and non-symmetrical 1,3,5-triazine systems, starting from 2,4,6-trichloro-1,3,5-triazine or its deriva- tives. 2 Recently we used Sonogashira cross-coupling to prepare 2-(alk-1 0 -ynyl)-4,6-dialkoxy-1,3,5-triazines. 3 The good results obtained in the Sonogashira 3 and in the Stille 1e cross-couplings prompted us to extend this last approach to the transfer of other unsaturated residues onto the hetero- aromatic ring (Scheme 1). The use of tributylalk-1- enylstannanes in Pd-catalyzed cross-coupling procedures is well known, 4 and in our case the introduction of prop-1- enyl residue was successfully achieved, affording (E,Z)-2a (Scheme 1). The diastereomeric composition (glc) of the product was the same as the starting organotin derivative. In turn, when Stille cross-couplings are carried out with allyl stannanes, a process of isomerization of the double bond is often observed, 4,5 which can sometimes be prevented by using tri(2-furyl)phosphine as the palladium ligand. 5d Nevertheless, the description of Stille non-isomerized allyl products under more usual conditions is frequent. 4,5b,6 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.02.085 Tetrahedron 61 (2005) 4475–4483 Figure 1. Scheme 1. Keywords: 2-Chloro-4,6-dimethoxy-1,3,5-triazine; Organometallics; Coupling reactions; Palladium and nickel catalysts. * Corresponding author. Tel.: C39 50 2219281; fax: C39 50 2219260; e-mail: rime@dcci.unipi.it