Intermolecular Heck coupling reactions

TABLE 1. Fast Intermolecular Heck Coupling Reactions Under Microwave Irradiation s... 

IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION 1163 TABLE 2. Intermolecular Heck Coupling Reactions... 

Whereas inter- and intramolecular Diels-Alder reactions normally require electron-deficient dienophiles, the 67r-electrocyclization proceeds with a large vaiiety of substituents on a hexatriene. In one such approach, the intramolecular Heck-type reaction of a 2-bromo-1 -en-(ft> — l)-yne 66 is used as a trigger to initiate an intermolecular Heck coupling with an alkene to form the conjugated 1,3,5-hexatriene 67 which eventually cyclizes in a 67T-electrocyclic process (Scheme 3-21) [173]. In many cases, aromatization of the cyclohexadiene 68 formed primarily occurs to yield carbo- and heterobicyclic compounds of type 70 [173a,b]. But with alkyl ethenyl ethers the cyclohexadienes 69 can be obtained in moderate yields [173b]. 

Zembower and co-workers explored the double Heek reaetion in one-pot and completed the synthesis of DG-041 1, EPj receptor antagonist [18]. A practically reliable catalytic system Pd(OAc)2/(o-tolyl)3 afifeeted both the transformations, intramolecular Heck reaction of bromo intermediate 38 to form indole ring, as well as intermolecular Heck coupling of resulting indole intermediate with acrylic acid 39 to give 40, en route to 41 (Seheme 9.10). 

Alkynes may undergo a threefold coupling if suitably substituted. For example, 3-phenylallyl propargyl ether yields an E/Z mixture of 3-diarylmethylene-4-benzylidenetetrahydrofuran, when treated with an aryl halide under Jeffery conditions (Scheme 5-35). This domino reaction (see also 1, Scheme 5-201) starts with an intermolecular coupling (alkyne relay), followed by intramolecular coupling of the intermediate a-ethenylpalladium complex and finally a second intermolecular Heck coupling. 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

In one case, the intermolecular Heck reaction of 3-pyridyltriflate with ethyl acrylate was accelerated by LiCl to give 159 [127,128], Here, both electronic and steric effects all favored p-substitution. In another case, however, electronic effects prevailed and complete a-substitution was observed. In the presence of an electron-donating substituent (i.e., a protected amine), 3-bromopyridine 160 was coupled with f-butoxyethylene to give 3-pyridyl methyl ketone 162 [126]. The regiochemistry of the Heck reaction was governed by inductive effects, leading to intermediate 161. 

The participation of halopyrroles in Heck coupling is mostly limited to intramolecular transformations. In a recent example of intermolecular Heck reaction different A-protcctcd 3-iodo-4-trimethylsilyl-pyrroles were coupled... 

The intermolecular Heck reactions of oxazoles and thiazoles with olefins are not too common. They are rarely high yielding since in several cases they are biased by dehalogenation. Due to this reason the olefination of these systems is usually achieved through Stille coupling with vinylstannanes. 

Intramolecular versions of the Heck reaction are very useful for the construction of ring systems. The entropic advantage of having both coupling partners present in the same molecule increases the efficiency of the insertion reaction and leads to efficient reactions. Moreover the intramolecular version can be carried out on hindered substituted alkenes, whereas the intermolecular Heck reaction is largely restricted to monosubstituted alkenes. These reactions illustrate the syn stereochemistry of both the insertion reaction and the elimination. A number of multicyclic natural products have been synthesized using intramolecular Heck reactions to assemble the skeletons, and this has become a powerful synthetic tool for such compounds. 

The same group developed an interesting intermolecular palladium-catalyzed alienation of aryliodide with N-tosyl o-iodoanilines with nucleophiles in combination with two palladium-coupling reactions [69]. In this reaction, the N-allyl(2-iodopalladium)aniline intermediate 52 underwent an intramolecular Heck reaction followed by a cross-coupling reaction with phenyl boronic acid to give the 3,3-disubstituted indoline 53 in 78% yield (Scheme 8.27). 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

Although intermolecular Heck reactions are common, intramolecular Heck reactions can also be used for carbon-carbon coupling reactions. 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

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