Palladium(II)-catalyzed tandem annulation reaction of o-alkynylbenzoates with methyl vinyl ketone for the synthesis of isocoumarins
Graphical abstract
Introduction
Conjugate addition of organometallic reagents to α,β-unsaturated carbonyl compounds is one of the basic methods for the construction of C–C bonds. These addition reactions have been used as key steps in the synthesis of numerous biologically active compounds and show a broad scope in synthetic chemistry. The widely employed nucleophiles are Grignard reagents, diorganozinc compounds or organocopper reagents.1 In recent years the transition-metal-catalyzed conjugate addition reaction is attracting more and more attention for the advantage of no need for stoichiometric amounts of organometallic reagents. Among them, palladium is one of the most used transition-metal and many examples have been widely reported.2
Isocoumarins represent one important class of naturally occurring lactones,3 which are structural subunits in numerous natural products that exhibit a wide range of biological activities, such as antimicrobial, androgen-like, phytotoxic, antifungal and pheromonal effects.4 Considerable efforts have been directed toward the synthesis of isocoumarins either by traditional approaches or by transition-metal-catalyzed reactions.5 Recently, a more convenient way for the synthesis of isocoumarins was available from the cyclization of o-alkynylbenzoates.6 On the other hand, our group has explored some palladium(II)-catalyzed conjugate reactions including the addition of arylboron reagents to enals or enones2(e), 2(f), 2(g) and the tandem reaction initiated by nucleopalladation of alkynes.7 Considering the diverse activities of isocoumarins, we wonder whether this kind of compounds could be obtained through Pd(II)-catalyzed cyclization of o-alkynylbenzoates initiated by oxypalladation of alkynes and quenched by conjugate addition to an enone. To the best of our knowledge, there are only few examples for the synthesis of isocoumarins catalyzed by palladium(II) complexes via tandem cyclization of o-alkynylbenzoate and enones.8
Section snippets
Results and discussion
The first attempt for the annulation reaction was carried out by the reaction of 1a and methyl vinyl ketone (2) under the catalysis of Pd(II) salts in the presence of 4 equiv of LiCl.9 To our delight, through initial screening of different catalysts, additives and solvents, it was found that both Pd(OAc)2 and PdCl2 could make the reaction proceed well to form six-membered-ring product (3a)10 regioselectively via 6-endo cyclization in excellent yield. No five-membered-ring product was detected.
Conclusion
In summary, a palladium(II)-catalyzed highly regioselective tandem reaction of o-alkynylbenzoates with methyl vinyl ketone was developed. This methodology provides a convenient way for the synthesis of substituted isocoumarins or 2-pyrones in excellent yields. The biggest advantage of this reaction is that it has good regioselectivity and only six-membered-ring products were given without the formation of the corresponding five-membered-ring lactones.
General methods
All reactions were performed in dried tube and monitored by TLC to ensure the completion of the reaction. All solvents were dried and distilled according to the standard methods before use. Pd(OAc)2 and PdCl2 were purchased from Strem and Aldrich Chemicals Co, respectively. Substrates 1a–s were synthesized by the Sonogashira coupling from o-iodobenzonates or iodoacrylate with arylethynes according to the literature procedures.6(c), 6(f)
Procedure for the synthesis of substrate 1v
Under the N2 atmosphere, the substrate 1u14 (0.4 g,
Acknowledgements
We thank the National Basic Research Program of China (2011CB808706), National Natural Science Foundation of China (21232006, 21272249) and Chinese Academy of Sciences for financial support.
References and notes (14)
- et al.
J. Am. Chem. Soc.
(1994)et al.J. Org. Chem.
(1992) Conjugate Addition Reactions in Organic Synthesis; Tetrahedron Organic Chemistry Series
(1992)et al.Chem. Rev.
(1992)et al.Tetrahedron
(2000)et al.Synthesis
(2001)- Selected examples of Pd-catalyzed conjugate addition... et al.
J. Org. Chem.
(1995)et al.Org. Lett.
(2005)et al.J. Org. Chem.
(2004)et al.J. Org. Chem.
(2005)et al.Org. Lett.
(2010)et al.Tetrahedron Lett.
(2007)et al.Org. Lett.
(2007)et al.Org. Lett.
(2010)et al.J. Am. Chem. Soc.
(2011)et al.Angew. Chem., Int. Ed.
(2003) - et al.
Tetrahedron
(2006) - et al.
Chem. Pharm. Bull.
(1981)et al.Bioorg. Med. Chem.
(1999)et al.Agric. Biol. Chem.
(1981)et al.J. Nat. Prod.
(1996)et al.Anticancer Res.
(1997) Chem. Rev.
(1964)et al.Curr. Org. Chem.
(2011)- et al.
J. Org. Chem.
(1984)et al.Tetrahedron Lett.
(2002)et al.J. Org. Chem.
(2003)et al.Synthesis
(2007)et al.Tetrahedron Lett.
(2008)et al.J. Chin. Chem. Soc.
(2008)et al.J. Org. Chem.
(2011)et al.Adv. Synth. Catal.
(2012)et al.J. Org. Chem.
(2012)
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