A Multicomponent Reaction of Arynes, Isocyanides, and Terminal Alkynes: Highly Chemo‐ and Regioselective Synthesis of Polysubstituted Pyridines and Isoquinolines

Sha, Feng; Huang, Xian

doi:10.1002/ange.200900212

Cited by 66 publications

(10 citation statements)

References 40 publications

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“…[2] Traditionally, they have been prepared by condensation of amine and carbonyl compounds. [4] Also, direct functionalization of pyridine cores also allows access to elaborate pyridine derivatives. [4] Also, direct functionalization of pyridine cores also allows access to elaborate pyridine derivatives.…”

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Synthesis of Pyridines by Carbenoid‐Mediated Ring Opening of 2H‐Azirines

et al. 2013

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Roaming the range: The title reaction tolerates a wide range of substituents on the resulting pyridine ring using mild reaction conditions (see scheme; esp=α,α,α′,α′‐tetramethyl‐1,3‐benzenedipropionic acid). The formation of the key intermediate is catalyst‐controlled, and subsequent cyclization and oxidation affords pyridines in excellent yields. The method has been used for the efficient synthesis of polyarylpyridines.

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Synthesis of Pyridines by Carbenoid‐Mediated Ring Opening of 2H‐Azirines

et al. 2013

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“…It is also imperative to develop routes to highly-substituted isoquinolines to fully explore this chemical space, for example, for potential pharmaceutical targets. While recent synthetic efforts have greatly expanded the diversity of isoquinoline motifs available (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29), new routes to isoquinolines are still highly desirable, particularly ones with the ability to directly access the isoquinoline moiety in a range of oxidation levels and which do not require highly-specialized starting materials.…”

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Synthesis of substituted isoquinolines utilizing palladium-catalyzed α-arylation of ketones

Donohoe

Pilgrim

Jones

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The utilization of sequential palladium-catalyzed α-arylation and cyclization reactions provides a general approach to an array of isoquinolines and their corresponding N-oxides. This methodology allows the convergent combination of readily available precursors in a regioselective manner and in excellent overall yields. This powerful route to polysubstituted isoquinolines, which is not limited to electron rich moieties, also allows rapid access to analogues of biologically active compounds.T he isoquinoline motif and its derivatives form the cores of numerous natural products (1, 2), are the central components of a number of pharmaceutical agents (3-5), and can provide the scaffold for chiral ligands (6, 7) and valuable organic materials (8). However, traditional isoquinoline syntheses such as the Bischler-Napieralski (9, 10), 12), and Pomeranz-Fritsch reactions (13-15) all centre around the lynchpin of electrophilic aromatic substitution and are thus often limited to electron-rich carbocycles (Scheme 1A). It is also imperative to develop routes to highly-substituted isoquinolines to fully explore this chemical space, for example, for potential pharmaceutical targets. While recent synthetic efforts have greatly expanded the diversity of isoquinoline motifs available (16-29), new routes to isoquinolines are still highly desirable, particularly ones with the ability to directly access the isoquinoline moiety in a range of oxidation levels and which do not require highly-specialized starting materials.Originally reported by Palucki and Buchwald (30), Hamann and Hartwig (31), and Miura and coworkers (32), the palladiumcatalyzed α-arylation of enolates has recently emerged as a powerful new reaction in synthetic organic chemistry (33-35). Key to its success has been the design of appropriate ligands for palladium that have precisely engineered steric and electronic properties to enable the various steps in the catalytic cycle to proceed with maximum efficiency (36-39). The reaction's utility has also been greatly enhanced by the development of robust preformed palladium catalysts. Properties such as air stability and very high reactivity in a range of systems have greatly expanded the potential uses of these catalysts (40-43). However, the α-arylation reaction has seen limited use in the de novo construction of aromatic compounds (44-51) and is still greatly underused in this regard, especially because the bond forming abilities provided by this powerful reaction can greatly simplify the design of routes to heavily-substituted aromatic compounds. Hence, we decided to explore the scope of this new catalytic method in the synthesis of important heteroaromatic ring systems, beginning our investigations with the isoquinoline nucleus. ResultsIn our disconnection approach we envisaged that key pseudo-1,5-dicarbonyl intermediates 3 could be accessed via the palladiumcatalyzed α-arylation of ketones 1 with aryl halides 2 possessing a protected aldehyde or ketone in the ortho-position (52). Subsequent treatment of these inter...

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“…Recently, transition metal-catalyzed reactions involving arynes, which are generated by fluoride-induced elimination of Kobayashi's silylaryl triflate under mild conditions [5], have been well documented [6][7][8][9][10][11][12][13][14][15][16][17]. Since Guitián and co-workers [6] first reported Pd(0)-catalyzed cyclotrimerization of arynes to generate triphenylenes in 1998 (Scheme 1), a variety of important triphenylene derivatives, which demonstrated potent applications in organic materials, have been prepared under similar reaction conditions [18][19][20][21][22][23][24][25].…”

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confidence: 98%