Intermolecular Heck coupling

Multiple Heck Couplings of Oligohaloarenes with Alkenes 11.09.2.1 Intermolecular Couplings... 

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... 

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]. 

The phosphine-thiazole ligand 149 has been shown to promote asymmetric intermolecular Heck coupling of 2,3-dihydrofuran with aryl triflates <07ASC2595>. Microwave irradiation of a mixture of 2,3-dihydrofuran (6 equiv.), aryl triflates (1 equiv.) and DIPEA (3 equiv.) in THF in the presence of Pd2(dba)3 (3 mol%) and the ligand 149 (6 mol%) at 120 °C provides 2-aryl-2,5-dihydrofurans 150 in high enantioselectivity. Other phosphine-thiazole ligands have also been evaluated, and ligand 149 proves to be the best in terms of enantioselectivity. 

Chromans and isochromans can be obtained by the reductive Pd-catalysed Heck cyclisation of 4-(2-bromophenoxy)-2-methylbut-l-ene and 3-(2-bromobenzyloxy)-2-methylpropene respectively <07TL2307>. Bromopropyl derivatives of 3,5-dihydroxy-iodobenzene and of 3,5-dihydroxymethyliodobenzene undergo sequential intramolecular alkylations and an intermolecular Heck coupling on treatment with an acrylate under microwave irradiation and Pd-catalysis mediated by norbornene. The products are 5-alkenyl derivatives of pyrano[3,2-g]benzo-2/7-1 -pyrans and pyrano[4,3-/]bcnzo-l77-2-pyrans (Scheme 13) <07JOC775>. 

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]. 

The above approach of an intermolecular ortho-alkylation followed by an intermolecular Mizoroki-Heck coupling was later extended to heteroaryl iodides by Lautens [48], Using a Pd(OAc)2/triarylphosphine catalyst system, 3-iodothiophene, -benzothiophene, and -indole were transformed to the o/t/zo-alkylation/Mizoroki-Heck coupling products in good to excellent yields (Scheme 17). Unfortunately, 2-iodoheteroaryls were found to be poor substrates for the reaction. 

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... 

D. INTRA-INTERMOLECULAR TWOFOLD HECK COUPLING OF l>BIS(NONAFLUOROBUTANESULFONYLOXY)CYCLOHEXADIENE... 

The treatment of the dienediol bisnonaflate 309 containing an ( >— 1)-alkenyl substituent with the typical Heck precatalyst cocktail in the presence of an external alkene, such as an acrylate, gives rise to the formation of the bicyclic tetraene 310 by an intramolecular Heck coupling followed by an intermolecular Heck coupHng (Scheme 8.66) [239]. This reaction can be performed using chiral catalysts to achieve asymmetric induction with up to 30% ee (cf. Scheme 8.77). 

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. 

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