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DOI: 10.1055/s-2007-968472
Synthesis of Furobenzazepinones by an Intramolecular Heck Reaction
Contributor(s):Victor Snieckus, Wei GanPublication History
Publication Date:
24 April 2007 (online)
Key words
Heck reaction - intramolecular - furobenzazepinones - tricyclic lactams
Significance
A synthesis of tricyclic lactams, furobenzazepinones using an intramolecular Heck reaction as a key step is reported. The key intermediate 1 was synthesized in six steps from commercially available 2-hydroxyl-3-methoxybenzaldehyde in 30% overall yield. Interestingly, when R2 = H, direct intramolecular Heck reaction from intermediate 4 to the product could not be achieved. However, treatment of 2, readily prepared from 1 by treatment with β-chloroacetyl chloride under Heck conditions, gave the targeted compound, via the in situ produced acrylamide 3, which could be isolated. The intramolecular Heck reaction is an unusual 7-endo-trig process. In addition, an intermolecular Heck reaction was achieved by reaction of 2-acetyl-4-bromo-7-methoxybenzo[b]furan with 3-chloro-propionamide showing that alkyl chlorides could be used for the Heck process.
Comment
Many 3,4-fused tricyclic benzo[b]furans show PARP-1 inhibitory activity (J. J. Chambers et al. J. Med. Chem. 2003, 46, 3526-3535) which is related to ischemic, inflammatory, and multiple sclerosis diseases. The prepared furobenzazepinones show weak PARP-1 inhibitory and moderate hBLT2 activities. The major finding of this report is the use of β-chloro amides as precursors for the Heck reaction which may have general value for heterocyclic ring construction.