A diversity-oriented approach to the palladium-catalyzed modular assembly of conjugated compounds and heterocycles: high-value compounds from trichloroethylene

Thumbnail Image
Geary, Laina Michelle
Journal Title
Journal ISSN
Volume Title
Trichloroethylene, a simple and very inexpensive material, has been identified as a tri- and tetrafunctionalizable building block. A combination of selective palladium-catalyzed cross-coupling reactions with standard lithiation and electrophilic quenching yields a wide variety of unsaturated linear or cyclic compounds in excellent yields in few synthetic steps. Dichlorovinyl ethers, obtained from a nucleophilic displacement reaction with trichloroethylene, are the basic starting materials. Two sets of conditions have been developed to achieve the reaction of either electron-rich or –deficient phenols with trichloroethylene to give the resultant dichlorovinyl ethers in high yields. Site selective palladium-catalyzed cross-coupling for the specific functionalization of a single C-Cl bond was developed, and could install alkyl, alkenyl, alkynyl and (hetero)aryl moieties. The resulting electrophiles could be reacted with a second organometallic nucleophile forming trisubstituted, electron-rich alkenes, dienes, trienes or enynes in only two or three steps. Alternatively, the product from the first cross-coupling reaction could be isolated, deprotonated and quenched with an electrophile, then cross-coupled with a second organometallic nucleophile to give tetrasubstituted, electron-rich alkenes and dienes. In the course of studying the site selective cross-coupling, it was found that prolonged exposure of the C1-functionalized materials to palladium promoted an intramolecular C-H activation, forming 2-substituted benzofurans. This reaction proved to be very general, and a wide variety of benzofurans were synthesized, containing both electron-withdrawing and electron-donating group groups in the donor arenes, as well as alkyl, alkenyl, alkynyl and aryl functionalities at the 2-position. This method was also extended to the synthesis of 2-substituted indoles from anilines, trichloroethylene and boronic acids.
palladium, heterocycles, direct arylation, cross-coupling, boronic acids, trichloroethylene
Geary, Laina M.; Hultin, Philip G. (2009). Modular Construction of Benzo[b]furans from 1,2-Dichlorovinyl Ethers, Organic Letters, 11(23): 5478-5481.
Geary, Laina M.; Hultin, Philip G. (2010). Palladium-Catalyzed Modular Assembly of Electron–Rich Alkenes, Dienes, Trienes and Enynes from (E)-1,2 Dichlorovinyl Phenyl Ether, Journal of Organic Chemistry 75(19):6354-6371.
Geary, Laina M.; Hultin Philip G. (2010) 2-Substituted Benzo[b]furans from (E)-1,2-Dichlorovinyl Ethers and Organoboron Reagents: Scope and Mechanistic Investigations into the One-Pot Suzuki Coupling/Direct Arylation, European Journal of Organic Chemistry (29):5563-5573.