Heteroaromatics alkenylation

As noted for the Heck reaction, aryl, alkenyl, and alkynyl bromides, iodides, and triflates are best for the oxidative addition. However, aromatic, heteroaromatic, alkenyl, and even alkyl boronic acids and esters can be coupled effectively. The reaction appears almost oblivious to other functional groups present ... 

Nickel-bpy and nickel-pyridine catalytic systems have been applied to numerous electroreductive reactions,202 such as synthesis of ketones by heterocoupling of acyl and benzyl halides,210,213 addition of aryl bromides to activated alkenes,212,214 synthesis of conjugated dienes, unsaturated esters, ketones, and nitriles by homo- and cross-coupling involving alkenyl halides,215 reductive polymerization of aromatic and heteroaromatic dibromides,216-221 or cleavage of the C-0 bond in allyl ethers.222... 

The reactions of heteroaromatic compounds such as furans, pyrroles, and indoles with alkynoates proceed under very mild conditions (in acetic acid or even in neutral solvents such as CH2C12 at room temperature). For example, the reaction of pyrrole with ethyl phenylpropiolate gives the 2-alkenylated pyrrole (Equation (44)).47c This reaction is applied to the direct synthesis of a /3-alkenylpyrrole, the pyrrole fragment of haemin (Equation (45)).47d The present reaction provides a very convenient method for functionalization of arenes and heteroarenes. 

Recently, with a view to overcome the difficulty on the preparation of aryl or alkenyl halides or sulfonates, thioamides and their S-alkyl derivatives have been proposed as a new class of electrophilic partners. This palladium cross-coupling methodology was developed by Liebeskind and mostly applied to heteroaromatic templates.118 121... 

Alkenyl-, alkynyl-, aryl- and heteroaromatic-stablllzed llthlooxiranes... 

C—H bond alkenylations, 10, 222—223 in cross-coupling polymerization, 11, 687 N-Heteroaromatic compounds, hydrogenation, 1, 792 Heteroaromatic stannanes, preparation, 3, 828 Heteroaryl halides, aminocarbonylatioon, 11, 527 Heteroarylstannanes, preparation, 3, 826 Heteroatoms... 

A number of related distonic superelectrophiles have been generated from A-heteroaromatic compounds (Table 2). Vinyl-dications (111-112) have been produced from the ethynyl pyridines,40 while /V-alkenyl A-heterocycles provide dications (113-115).42a Vinyl-substituted A-heterocycles provide access to distonic superelectrophiles such as dication 116.39 Dications 117 and 118 are generated from their precursors, and both intermediates lead to efficient cyclization reactions with the adjacent... 

Various aryl, alkenyl and even alkylborane reagents of different reactivity can be used for coupling with aryl, alkenyl, alkynyl and some alkyl halides, offering very useful synthetic methods. The cross-coupling of aryl and heteroarylboronic acids with aryl and heterocyclic halides and triflates provide useful synthetic routes to various aromatic and heteroaromatic derivatives. Sometimes, the reaction proceeds in the... 

RC=CKWG) yields 2,4-di-EWG-substituted pyrroles in the presence of copper catalyst but 2,3-di-EWG-substituted pyrroles in the presence of a phosphine catalyst.74 The 3 + 2-cycloaddition of diazoalkanes to (6 )-3-p-tolylsulfinylfuran-2(5//)-one produces diastereoisomeric pyrazolines in almost quantitative yield and with des >98%. (g) The sulfinyl group is responsible for the complete control of the n-facial selectivity in all these reactions.75 The Rh(II)-catalysed intramolecular 1,3-dipolar cycloaddition reaction of diazoamides (57) with alkenyl and heteroaromatic n -bonds yields pen-tacyclic compounds (59), via the ylide (58), in good to excellent yields and in a (g) stereocontrolled manner (Scheme 15).76... 

The reaction worked well when run to ca. 50% conversion, but has yet to be scoped as a general method for the alkenylation of heteroaromatic bases. One further example was examined involving the union of 1-methylcyclohexene and lepidine 31. In that case, elimination of benzoic acid was less favourable and the only product identified was adduct 63, formed in an unspecified yield (Scheme 14). A related metal-catalysed procedure has been described and its effectiveness is also influenced by the nature of the substrates to be coupled <83JCS(P2)531>. 

Figure 2 The structures of ceramide 1, a schematic structure of ceramide that illustrates the sites at which structural modifications may be introduced by chemical synthesis, and the structure of a representative ceramide found in human skin (2). Structural changes in the ceramide molecule have been introduced at many sites. Alterations include the configuration at C-2 and C-3 the lengths of the fatty amide chain and of the aliphatic chain attached to C-5 the positions of the unsaturation and the secondary hydroxy group the replacement of the hydroxyl groups with other atoms (hydrogen or fluorine) or functionalities (methoxy, methylthio, and keto) the incorporation of aromatic, heteroaromatic, and other rings in place of the alkenyl side chain of the sphingoid base and the replacement of the carbonyl group of the carboxamide group. In addition, the 2-amino-1,3-diol functionalities have been incorporated into cyclic structures.

Xanthate 446 undergoes cyclization in the presence of camphorsulfonic acid via a radical chain reaction initiated by a small amount of lauroyl peroxide to give pyrroloimidazoles 449 in 56% yield. The use of an acid and anhydrous medium inhibits nucleophilic attack of the basic heterocycles at the xanthate moiety and allows radical reactions to occur. Fused heteroaromatic compounds can also be prepared directly from benzimidazole carrying an N-alkenyl substituent and xanthates by a tandem radical addition/cyclization to provide, for example, pyrrolobenzimidazole 453 in 57% yield (Scheme 106) <2002OL4345>. 

Asymmetric hydrogenation of either a carbonyl or an imino group to a hydroxyl group or an amino group has frequently been employed for the introduction of chirality in amino acid syntheses. Corey s catecolborane-oxazaborolidine protocol enables transformation of difluoromethyl ketone 1 into alcohol 2 with excellent enantioselectivity. The reaction of diastereoselective amination of a-hydroxyaldehyde 3 with A,A-diallylamine and 2-furyl-boronic acid provides furyl amino alcohol 4 in good chemical yield along with excellent diastereoselectivity. This protocol is applicable for the preparation of amino acids and amino alcohols with a trifluoromethyl group by the combination of /V,/V-diallyl or N,N-dibenzyl amine and aromatic, heteroaromatic and alkenyl boronic acids [7]. The usual chemical transformations as shown in steps 5 to 8 in Scheme 9.1 lead to (2S,3R) difluorothreonine 5 [8]. 

They found that combination of the Ir(T) catalyzed C-H borylation and Suzuki coupling sequence led to a two-step, one-pot C-H Suzuki arylation that enabled direct transformation of the N-Boc pyrrole to the C3 arylated intermediate in 78% yield. Following installation of the required acyl group, an application of their oxidative Pd-catalyzed C-H alkenylation reaction enabled formation of the key structural architecture of the natural deliver the natural product. The orthogonal selectivity characteristics displayed by these C-H functionalization processes makes possible iterative functionalization of the heteroaromatic pyrrole core. Utilization of the highly versatile C-H borylation - Suzuki coupling to install the aromatic functionality opens up possibilities of facile analogue synthesis via this route. 

Coupling reactions. Scopes of many well-established reactions continue to be explored. The Heck reaction of alkenyl(2-pyridyl)dimethylsilanes is benefited by the direction of the heteroaromatic group during carbopalladation and the expediency in product purification and catalyst recovery. ... 

This simple protocol for the preparation of carboxylic acids was also successfully applied to carbonylation of alkenyl and aryl bromides under the same reaction conditions [88]. The reaction of aryl halides (including heteroaromatics, e.g., halothiophenes) with methyl acrylate, phenyl vinyl sulfone, cy-clopentene, and dihydrofuran, proceeded smoothly in water using the same PS-PEG-supported catalyst to give the corresponding alkenylated aromatics in high yields [88,89]. 

III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING 443 C.i.b. Alkenylation... 

Application of Pd-catalyzed cross-coupling to a-aIkynylation,F30 a-alkenylation, and a-arylationF3 of heteroaromatic a,/3-unsaturated carbonyl derivatives, such as 5-iodouracil derivatives, has been known since the early 1980s (Scheme 50). Although these reactions are formally related to the Pd-catalyzed a-substitution discussed herein, the robust aromatic nature of the heteroaromatic substrates makes the requirements for their a-substitution less demanding. These reactions should therefore be viewed as a class of cross-coupling reactions involving aryl halides rather than a-halo-a,jS-unsaturated carbonyl compounds. In most... 

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