Michael Jäger1, Helmar Görls, Wolfgang Günther, Ulrich S Schubert. 1. Laboratory of Organic and Macromolecular Chemistry (IOMC), Jena Center for Soft Matter (JCSM), Friedrich-Schiller-University Jena, Humboldtstraße 10, 07743 Jena, Germany.
Abstract
A new modular approach based on Pd-catalyzed C-C bond formation is presented for the assembly of a benzannulated azocine scaffold, the key intermediate in the synthesis of functionalized azadibenzocyclooctynes (aza-DIBOs). The intramolecular ring-closing Heck coupling was investigated by variation of the C-X bond. The reaction rate is limited by the initial oxidative addition step and the regiochemistry strongly depends on the auxiliary phosphine. Under optimized conditions, the 8-endo regioisomer was obtained in 71% yield over two steps (with no protecting group chemistry) or in one pot, inclusive of C-N bond formation. The practical generation of the octyne triple bond of a prototypical N-benzoyl aza-DIBO, without the need for chromatographic purification, is also described. The structural features, including those of the ring-strained cyclic octyne, were elucidated by NMR spectroscopy and X-ray crystallographic analysis. The high reactivity of the N-benzoyl aza-DIBO synthesized is demonstrated in a strain-promoted azide-alkyne cycloaddition reaction with an alkyl azide (k=0.38 M(-1) s(-1)).
A new modular approach based on Pd-catalyzed C-C bond formation is presented for the assembly of a benzannulated n class="Chemical">azocine scaffold, the key intermediate in the synthesis of functionalized azadibenzocyclooctynes (aza-DIBOs). The intramolecular ring-closing Heck coupling was investigated by variation of the C-X bond. The reaction rate is limited by the initial oxidative addition step and the regiochemistry strongly depends on the auxiliary phosphine. Under optimized conditions, the 8-endo regioisomer was obtained in 71% yield over two steps (with no protecting group chemistry) or in one pot, inclusive of C-N bond formation. The practical generation of the octyne triple bond of a prototypical N-benzoyl aza-DIBO, without the need for chromatographic purification, is also described. The structural features, including those of the ring-strained cyclic octyne, were elucidated by NMR spectroscopy and X-ray crystallographic analysis. The high reactivity of the N-benzoyl aza-DIBO synthesized is demonstrated in a strain-promoted azide-alkyne cycloaddition reaction with an alkyl azide (k=0.38 M(-1) s(-1)).