Microwave-assisted Heck reaction

In 1996, the first examples of intermolecular microwave-assisted Heck reactions were published [85]. Among these, the successful coupling of iodoben-zene with 2,3-dihydrofuran in only 6 min was reported (Scheme 75). Interestingly, thermal heating procedures (125-150 °C) resulted in the formation of complex product mixtures affording less than 20% of the expected 2-phenyl-2,3-dihydrofuran. The authors hypothesize that this difference is the result of well-known advantages of microwave irradiation, e.g., elimination of wall effects and low thermal gradients in the reaction mixture. 

Larhed et al. investigated enantioselective Heck reactions with 2,3-dihydrofuran as alkene [86]. In the coupling with phenyl triflate, conditions previously reported by Pfaltz [87] were attempted under microwave irradiation. Interestingly, the catalytic system Pd2(dba)3/(4S)-4-t-butyl-2-[2-(diphenylphosphanyl)phenyl]-4,5-dihydro-l,3-oxazole, identified by the Swiss team, was found suitable for high-temperature microwave-assisted enantioselective Heck reactions (Scheme 76). Using a proton sponge as a base and benzene as a solvent gave the best conversions (Scheme 76). At tempera-... 

Microwave-assisted Heck reaction of (hetero)aryl bromides with N,N-dimethyl-2-[(2-phenylvinyl)oxy]ethanamine, using Herrmann s palladacycle as a precatalyst, yielded the corresponding /3-(hetero)arylated Heck products in a good EjZ selectivity (Scheme 79) [90]. The a/yd-regioselectivity can be explained by the chelation control in the insertion step. This selectivity is better than 10/90 when no severe steric hindrance is introduced in the (hetero)aryl bromides. The process does not require an inert atmosphere. There is evidence that a Pd(0)/Pd(II)- and not Pd(II)/Pd(IV)-based catalytic cycle is involved. Similarly, other j6-amino-substituted vinyl ethers such as... 

This protocol could be extended to a range of different ,/i-unsaturated carbonyl compounds and either activated or deactivated aryl iodides [22], An application of related Heck chemistry to the synthesis of methylated resveratrol (3,4, 5-trihydroxy-( )-stilbene) is shown in Scheme 6.4 [23]. The phytoalexin resveratrol exhibits a variety of interesting biological and therapeutic properties, among them activity against several human cancer cell lines. Botella and Najera have shown that the trimethyl ether of resveratrol (Scheme 6.4) can be rapidly prepared by microwave-assisted Heck reaction of the appropriate aryl iodide and styrene derivatives, using the same oxime-derived palladacycle as indicated in Scheme 6.3. 

Microwave-assisted Heck reactions have also been carried out with triflates as coupling partners, involving some very complex molecules. Winterfeld and coworkers have reported a multigram synthesis of a complex non-symmetrical bis-steroidal diene by microwave-promoted coupling of the corresponding alkene and triflate steroidal moieties (Scheme 6.8) [27]. 

A synthetically useful application of an intramolecular microwave-assisted Heck reaction has been described by Gracias and coworkers (Scheme 6.9) [28], In their approach toward the synthesis of N-containing seven-membered heterocycles, the... 

Shore and coworkers [64] used a capillary reactor with a Pd thin film and microwave-assisted continuous-flow conditions for Suzttki-Miyara and Heck coupling reactions. The Pd film was prepared by passing Pd(OAc)2 solution into the 1150 pm eapillary at 150°C resulting in a highly porous catalyst composed of nanometer-size grains. 

A microwave-assisted synthesis of several isomeric pyrrolopyridines ([2,3-3], [2,3-c], [3,2-3], and [3,2-r ]) has been reported starting from aminohalopyridines <2005S2571>. Intramolecular palladium-catalyzed Heck reactions leading to substituted pyrrolo[3,2-3]pyridines from ketones and aminopyridines have been described <2003JME4702>. 

Lately, a number of papers have dealt with microwave-assisted reactions on palladium-doped A1203. Villemin reported on Stifle, Suzuki, Heck and Trost—Tsuji reactions where potassium fluoride on alumina was used as the base26. The reactions were carried out without solvent or stabilising phosphine ligands in single-mode reactors. The Stifle reactions were noteworthy as the toxic organotin residue remained adsorbed on the solid support, thus allowing a simplified work-up procedure for the otherwise unpleasant, and toxic, stannous by-products. Both the Stifle and the Suzuki reactions could be performed under air. Furthermore, it was noted that with experiments where the... 

Nilsson, P., Gold, H., Larhed, M. and Hallberg, A., Microwave-assisted enantioselective Heck reactions expediting high reaction speed and preparative convenience, Synthesis, 2002, 1611-1614. 

Further application of the powerful intramolecular reductive Heck reaction has been realized in the efficient microwave-assisted synthesis (Pd(PPh3)4, 3 mol%, HCOONa, 1.5 equiv, DMF HzO 3 1, 110 °G) of the important 3-benzazepine system. The precursors were A-ethynoyl derivatives of N-substituted n-bromophenethylamines, which afforded, via a type c ring construction, 3-benzazepin-2-ones with a substituted exocyclic methylene group at the Cl position <20070L3017>. 

A two-step, one-pot process has been developed for the synthesis of aza-indoles under dielectric heating conditions [31]. In the first step, aminopy-ridines and ketones were condensed either at room temperature (in the case of aza-indoles 19-20) or under dielectric heating at 160-220 °C to yield intermediate enamines 18. Subsequent microwave-assisted intramolecular Heck reactions furnished the corresponding 4-, 5-, 6- or 7-azaindoles in moderate to good yields (Scheme 9). 

Compared to the dramatic increase in microwave heating in cross-coupling and metal-mediated nucleophilic substitutions, the number of published microwave-assisted Heck reactions is limited. Thus, only seven additional examples emphasizing different concepts will be presented in this section. 

Scheme 13 A microwave-assisted oxidative Heck reaction...

A range of imines and enamines, formed from tir/Zw-haloaminopyridines and ketones, may be converted to a variety of substituted 4-, 5-, 6-, and 7-azaindoles by microwave-assisted intramolecular Heck reaction <2005S2571>. As an example, 4-amino-3-iodopyridine is converted to azaindole 85 in 46% yield by condensation with ketone 86 followed by Heck reaction of the resulting enamine (Equation 59). 

Imines and enamines, formed from o-haloaminopyridines and ketones, can be converted into substituted 4-, S-, 6-, and 7-azaindoles by microwave-assisted intramolecular Heck reactions <2005S2571>. 

Microwave-assisted Heck coupling reactions have been reported in several instances.[75,81 88] Using microwave dielectric heating, reaction times as short as only a few minutes can be realised and some data from such experiments are listed in Table 6.3. A wide selection of arylhalides were reacted with olefins with Pd/C immobilised in [C8Ciim][BF4] under microwave irradiation.[88]... 

Eberlin also studied the Heck reaction of aryltellurides [45] and Svennebring [19] reported the identification of three types of cationic, catalytic intermediates (Fig. 4A-C) in the microwave-assisted, phosphine-containing Heck arylation of electron rich olefins. In the latter case the authors support a Pd(0)/Pd(II) cycle as opposed to a Pd(II)/Pd(IV) cycle based on ESI-MS evidence for reduction of the palladium(II) precatalyst to Pd(0) by the ligand, and oxidative addition of the aryl substrate to a Pd(0) species. None of the expected Pd-bound olefin intermediates were observed however, this is often the case either because the olefin-bound species is neutral or because OA (oxidative addition) is the turnover-limiting step and the subsequent steps occur too quickly to be observed by the sampling method (in this case sampling included quenching and dilution of samples from a reaction vessel). 

Fig. 4. (A-C) Palladium-containing species observed by ESI-MS and implicated in the microwave-assisted Heck arylation of electron rich olehns. 19] (D) A boron-containing ion implicated in the transmetallation step of the palladium-catalyzed Suzuki cross-coupling reaction 46].

Dawood KM (2007) Microwave-assisted Suzuki-Miyaura and Heck-Mizoroki crosscoupling reactions of aryl chlorides and bromides in water using stable benzothiazole-based palladium(ll) precatalysts. Tetrahedron 63 9642-9651... 

Some synthetic approaches to pyrazines relied on metal-assisted reactions. A synthesis of 6-substituted 5H-pyrrolol2,3-bJpyrazines via Pd-catalyzed heteroannulation from W-(3-chloropyrazin-2-yl)methanesulfonamide and alkynes was developed <04TL8087>, and 3- and 5-substituted 2(l//)-pyrazinones were prepared by Suzuki and Heck reactions using 3,5-dichloro-2(l//)-pyrazinones <04TL1885>. An improved synthesis of 6-substituted-5//-pyrrolo 2,3-iiJ-pyrazines via microwave-assisted Pd-catalyzed heteroannulation was developed <04TL8631>, and the reaction of a-diazo-P-keto esters with Boc amino acid amides in the presence of a Rh catalyst gave, after air oxidation, pyrazin-6-ones 111, which were then converted into tetrasubstituted pyrazines 112 <04OL4627>. 

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