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Issue 27, 2014
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Synthesis of DIBAC analogues with excellent SPAAC rate constants

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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.

Graphical abstract: Synthesis of DIBAC analogues with excellent SPAAC rate constants

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Publication details

The article was received on 01 Apr 2014, accepted on 23 May 2014 and first published on 23 May 2014


Article type: Paper
DOI: 10.1039/C4OB00694A
Citation: Org. Biomol. Chem., 2014,12, 5031-5037
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    Synthesis of DIBAC analogues with excellent SPAAC rate constants

    M. F. Debets, J. S. Prins, D. Merkx, S. S. van Berkel, F. L. van Delft, J. C. M. van Hest and F. P. J. T. Rutjes, Org. Biomol. Chem., 2014, 12, 5031
    DOI: 10.1039/C4OB00694A

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