title: Synthesis of DIBAC analogues with excellent SPAAC rate constants.
abstract: In search for increased reactivity in strain-promoted azide alkyne cycloadditions (SPAAC), the synthesis of new and more reactive cyclooctynes is of pivotal importance. To identify cyclooctynes with enhanced reactivity, without loss of stability, the synthesis and kinetic analysis of new dibenzoazacyclooctyne (DIBAC) analogues were conducted. Starting from iodobenzyl alcohol analogues and ortho-ethynylaniline various substituted dihydrodibenzo[b,f]azocines were produced. Subsequent bromination and elimination proved to be difficult depending on the aromatic substitution pattern, yielding chloro-, bromo-, and methoxy-substituted DIBACs in moderate yield. In the elimination reaction towards nitro- and Br,Cl-DIBAC, the corresponding cyclooctene was obtained instead of the cyclooctyne. Additionally, a dimethoxy-substituted DIBAC analogue was prepared following an alternative route involving light-induced deprotection of a cyclopropenone derivative. In total, four DIBAC analogues were successfully prepared showing excellent rate constants in the SPAAC reaction ranging from 0.45 to 0.9 M(-1) s(-1), which makes them comparable to the fastest cyclooctynes currently known.
authors.affiliation: Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands. F.Rutjes@science.ru.nl.
authors.forename: Marjoke F
authors.initials: MF
authors.lastname: Debets
authors.forename: Jasper S
authors.initials: JS
authors.lastname: Prins
authors.forename: Donny
authors.initials: D
authors.lastname: Merkx
authors.forename: Sander S
authors.initials: SS
authors.lastname: van Berkel
authors.forename: Floris L
authors.initials: FL
authors.lastname: van Delft
authors.forename: Jan C M
authors.initials: JC
authors.lastname: van Hest
authors.forename: Floris P J T
authors.initials: FP
authors.lastname: Rutjes
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D001372:Aza Compounds / Q000138:chemical synthesis*; D001386:Azides / Q000737:chemistry*; D061565:Cycloaddition Reaction; D003521:Cyclopropanes / Q000737:chemistry
chemical_list: D000480:Alkynes; D001372:Aza Compounds; D001386:Azides; D003521:Cyclopropanes; C120343:cyclopropenone