A direct method for the N-tetraalkylation of azamacrocycles

Abstract

An efficient protocol for the direct synthesis of N-tetraalkylated derivatives of the azamacrocycles cyclam and cyclen has been developed, using a partially miscible aqueous-organic solvent system with propargyl bromide, benzyl bromide, and related halides. The method works most effectively when the reaction mixture is shaken, not stirred. A crystal structure of the N-tetrapropargyl cyclam derivative 1,4,8,11-tetra(prop-2-yn-1-yl)-1,4,8,11-tetraazacyclotetradecane diperchlorate is reported.

Keywords: N-alkylation; azamacrocycles; biphasic system; cyclam; cyclen.

Scheme 1

N-Tetraalkylation of cyclam (1) and cyclen (2) with alkyl halides in partially miscible aqueous–organic biphasic systems. Reagents and conditions: H₂O/CH₃CN (1:1), NaOH (1 M), RCH₂Br (4.1 equivalents), rt, 6 h; R = C≡CH (3 and 8), C₆H₅ (4 and 9), o-bromophenyl (5 and 10), p-nitrophenyl (6 and 11), 2-naphthyl (7 and 12, see Table 1 for yields.).

Figure 1

Ball-and-stick depiction of the crystal structure obtained for [(3)H₂](ClO₄)₂, generated with X-Seed [51] and POV-Ray [52]. Ellipsoids shown at 50% probability. The asymmetric unit consists of one half of the ligand and one perchlorate anion.