Insertion reactions benzofurans synthesis

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

Finally, the a,/ -unsaturated carbene complex may be generated in situ by alkyne insertion into a chromium-carbene bond of a saturated chromium carbene leading to a chromium vinyl carbene (equivalent to intermediate (f )-D in the mechanism of the benzannulation reaction, see Section 8.2.1, Scheme 3), which may undergo subsequent benzannulation with a second equivalent of the alkyne [43a]. This strategy was subsequently applied to the synthesis of (Z)-enediynes and related compounds [43b], and to that of substituted benzofurans (see also Section 8.5) [43c, 43d]. 

An interesting application of the Fujiwara-Moritani/oxidative Heck reaction for the synthesis of benzo furans was recently reported by the Stoltz lab [31]. A variety of allyl phenyl ethers (all containing electron-rich aryl components) react with 10 mol% palladium acetate, 20 mol% ethyl nicotinate, 20 mol% sodium acetate, and one equivalent of benzoquinone at 100°C to provide benzofurans in 52-79% yield (e.g. 16—>17). The mechanism of this transformation begins with arene palladation of Pd(II) followed by olefin insertion, p-hydrogen elimination, and olefin isomerization to the thermodynamically favored benzofuran product. The resulting Pd(0) species is then oxidized to Pd(ll) thus regenerating the active catalyst. 

The mechanism of the Heck reaction with Pd(OAc)2 probably involves the initial in situ reduction of the Pd " ion to Pd(0), which then inserts in the C-X bond (recall the formation of the Grignard reagent from Mg and halides). The species R-PdX that is formed adds to the double bond in the sense of R and PdX, which in an intramolecular reaction will lead to a cyclic product. The adduct eliminates H-PdX to regenerate a double bond. This proposed mechanism is illustrated with the synthesis of the benzofuran 4.36 in Scheme 4.39. 

In 2005, Ohno et al. reported a cascade intramolecular carbopalladation/aromatic C-H bond activation for the synthesis of tri- or tetracyclic heterocycles 174 in the presence of palladium species [70] (Scheme 6.48). The authors proposed that this domino reaction might proceed through the oxidative addition of bromoenyne 173 to Pd(0), insertion of the alkyne into the C-Pd bond of intermediate 175, followed by C-H bond functionalization of the aromatic ring. Not only benzene-substituted substrates but also heteroaromatic rings such as benzofuran and indole, could be introduced efficiently to this reaction. Similar work was reported by Chernyak and Gevorgyan [71]. 

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