Heck reaction microwave-heated reactions

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. 

Another example of a one-pot indole synthesis, which proceeds through a Heck carbonylation and a Suzuki coupling, is shown below. The reaction conditions are similar to the previous example however microwave heating is employed [174] (Scheme 6.54). 

In a recent article by Botella and Najera, controlled mono- and double-Heck arylations in water catalyzed by an oxime-derived palladacycle were described [22], When the reaction was carried out under microwave irradiation at 120 °C in the presence of dicyclohexylmethylamine with only 0.01 mol% of palladium catalyst (palladium acetate or palladacycle), monoarylation took place in only 10 min with a very high turnover frequency (TOF) of > 40000 (Scheme 6.3). As regards diarylation, 1 mol% of the palladacycle catalyst and 2 equivalents of iodobenzene had to be utilized to obtain moderate to good yields of diarylated product. Whereas microwave heating at 120 °C provided a 31% yield after 10 min, a 66% isolated yield of product was obtained by heating the reaction mixture under reflux for 13 h at 100 °C. Here, the... 

Other enantioselective reactions performed by microwave heating include asymmetric Heck reactions (Scheme 6.53 a) [109] and ruthenium-catalyzed asymmetric hydrogen-transfer processes (Scheme 6.53 b) [110]. 

The first reports of the use of microwave heating to accelerate Heck, Suzuki and Stille reactions on the solid phase [54] and in solution did not appear until 1996 [55], Since then, many metal-catalyzed reactions have been performed within minutes by microwave heating in pressurized systems, sometimes with high regio- and enan-tioselectivity [56, 57]. 

A perhaps more exotic substrate for the Heck reaction is 1,2-cyclohexanedione [25], The reactivity of this molecule under Heck coupling conditions can probably be attributed to its resonance enol form. This reaction is attractive, because the literature contains relatively few examples of the preparation of 3-aryl-l,2-cyclohexane-diones. Yields varied from good to modest when classic heating and electron-rich aryl bromides were used, and reaction times typically ranged from 16 to 48 h. Similar yields were obtained under continuous microwave irradiation with a single-mode microwave reactor for 10 min at 40-50 W (Eq. 11.10) [25],... 

Traditional Heck arylation of the corresponding ethyl vinyl ether afforded high yields with most of the aryl bromides investigated (Eq. 11.11). Under continuous singlemode microwave treatment the transformations were complete within 10-12 min [25], Heck reactions without solvent in a domestic microwave oven have been examined by Diaz-Ortiz [26]. The reactions were conducted in closed vessels with reported temperatures of 150 °C. A study was performed in which reactions performed with microwave irradiation were compared with oil-bath-heated reactions with identical reaction times and temperatures. The isolated yields tended to substantially favor the microwave-heated reactions (Eq. 11.12). 

Microwave-heated Heck reactions in water have also been performed using phase-transfer catalysis. A number of phase-transfer systems were investigated with TBAB, once more giving the best results51 (Scheme 2.18). 

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. 

Microwave-heated Heck reactions in water using ultralow palladium catalyst concentrations have been performed by Arvela and Leadbeater [46]. Different catalyst concentrations were investigated using a commercially available 1000 ppm palladium solution as the catalyst source. Impressively, useful Heck arylations were performed with palladium concentrations as low as 500 ppb (Scheme 8). 

A nonclassical substrate for the Heck reaction is 2,3-epoxycyclohexanone. The reactivity of this molecule under Heck coupling conditions is most likely attributed to its in situ isomerization to 1,2-cyclohexanedione. The 1,2-diketone subsequently reacts with aryl bromides as an olefin via the enol tautomer. Thus, within 5 to 30 min of directed microwave heating of the aqueous PEG mixture, up to 13 different C3-arylations were conducted using less than 0.05 mol % palladium acetate and no phosphine ligand (Scheme 12) [51]. 

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]... 

As with all solvent alternatives discussed in this book, palladium catalysed C-C bond-forming reactions in RTILs have been studied at length. Because of the low volatility of ionic liquids and their rapid dielectric heating upon microwave irradiation, reaction times for Heck couplings have been significantly reduced by combining the two technologies. ... 

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