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Pd‐Catalyzed Ring Assembly by Vinylation and Intramolecular Heck Coupling: A Versatile Strategy Towards Functionalized Azadibenzocyclooctynes
Author(s) -
Jäger Michael,
Görls Helmar,
Günther Wolfgang,
Schubert Ulrich S.
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201202790
Subject(s) - intramolecular force , chemistry , cycloaddition , regioselectivity , ring (chemistry) , azide , alkyne , structural isomer , heck reaction , ring strain , medicinal chemistry , phosphine , combinatorial chemistry , catalysis , stereochemistry , palladium , organic chemistry
A new modular approach based on Pd‐catalyzed CC 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 CX 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 CN 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 ).