Ring-closing metathesis: Novel routes to aromatic heterocycles

Olefin metathesis has been established as an important and general reaction in synthetic organic chemistry. Recently, it has attracted interest as a powerful tool for the construction of aromatic heterocycles. The importance of heteroaromatic motifs in medicinal chemistry and biology, as well as the efficiency and wealth of metathesis transformations, have resulted in significant success in this rapidly developing area. © 2008 Wiley-VCH Verlag GmbH and Co. KGaA

Ring-closing metathesis as a key step in the synthesis of 2-pyridones and pyridine triflates

The ring-closing metathesis transformation has been employed to construct a library of functionalized 2-pyridones and pyridine triflates. Using this mild approach, a range of substituent patterns can be built into the aromatic core, including groups which can be demanding to incorporate using alternative protocols. © Georg Thieme Verlag Stuttgart

A metathesis-based approach to the synthesis of 2-pyridones and pyridines.

The ring-closing metathesis reaction has been successfully employed to form a range of dihydropyridone intermediates, which are in the correct oxidation state to undergo a base-induced elimination to reveal the aromatic 2-pyridone. This mild and novel approach to six-membered heteroaromatic compounds then provides access to a wide variety of substituted pyridines in excellent overall yield

A metathesis-based approach to the synthesis of furans.

The enol ether-olefin ring-closing metathesis reaction has been employed to generate 2,3-dihydrofurans that are equipped with a leaving group. These substrates are at the correct oxidation state to undergo an acid-catalyzed aromatization, and this strategy has been utilized to provide a mild and rapid route (four steps) to a range of novel 2,5-disubstituted furans. [reaction: see text

Short and Efficient Syntheses of Protoberberine Alkaloids using Palladium-Catalyzed Enolate Arylation.

A concise synthesis of the biologically active alkaloid berberine is reported, and a versatile palladium-catalyzed enolate arylation is used to form the isoquinoline core. The overall yield of 50 % is a large improvement over the single, previous synthesis. By design, this modular route allows the rapid synthesis of other members of the protoberberine family (e.g., pseudocoptisine and palmatine) by substitution of the readily available aryl bromide and ketone coupling partners. Moreover, by combining enolate arylation with in situ functionalization, substituents can be rapidly and regioselectively introduced at the alkaloid C13 position, as demonstrated by the total synthesis of dehydrocorydaline. The avoidance of electrophilic aromatic substitution reactions to make the isoquinoline allows direct access to analogues possessing more varied electronic properties, such as the fluorine-containing derivative synthesized here

Modular isoquinoline synthesis using catalytic enolate arylation and in situ functionalization.

A methyl ketone, an aryl bromide, an electrophile, and ammonium chloride were combined in a four-component, three-step, and one-pot coupling procedure to furnish substituted isoquinolines in overall yields of up to 80%. This protocol utilizes the palladium catalyzed α-arylation reaction of an enolate, followed by in situ trapping with an electrophile, and aromatization with ammonium chloride. tert-Butyl cyanoacetate participated in a similar protocol; after functionalization and decarboxylation, 3-amino-4-alkyl isoquinolines were prepared in high yield

Ring-closing metathesis for the synthesis of heteroaromatics: evaluating routes to pyridines and pyridazines

Ring-closing olefin metathesis (RCM) has been applied to the efficient synthesis of densely and diversely substituted pyridine and pyridazine frameworks. Routes to suitable metathesis precursors have been investigated and the scope of the metathesis step has been probed. The metathesis products function as precursors to the target heteroaromatic structures via elimination of a suitable leaving group, which also facilitates earlier steps by serving as a protecting group at nitrogen. Further functionalisation of the metathesis products is possible both prior to and after aromatisation. The net result is a powerful strategy for the de novo synthesis of highly substituted heteroaromatic scaffolds. © 2009 Elsevier Ltd. All rights reserved

Synthesis of substituted pyridines and pyridazines via ring closing metathesis.

RCM can be used to make aromatic heterocycles, namely pyridines and, for the first time, pyridazines; the key step after RCM involves elimination of sulfinate to provide the aromatic system

Palladium-catalyzed enolate arylation as a key C-C bond-forming reaction for the synthesis of isoquinolines.

The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an α-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after α-arylation with carbon or heteroatom-based electrophiles, or by performing an α,α-heterodiarylation to install aryl groups at this position. The α-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the α-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C-H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route

Flexible metathesis-based approaches to highly functionalised furans and pyrroles

A range of differentially functionalised furans and pyrroles have been synthesised in short order by the judicious use of a ring-closing metathesis/aromatisation strategy. Two contrasting approaches are described exploiting a palladium-catalysed union of allylic alcohols and sulfonamides in one case, and a titanium mediated methylenation of homoallylic esters in another. A number of groups that are difficult to install via traditional methods were incorporated successfully. © 2007 Elsevier Ltd. All rights reserved