Microwave irradiation mixtures

Benzenediamine (185) and benzoin (186) gave a separable mixture of 2,3-diphenyl-1,2-dihydroquinoxaline (187, R = Ph) and 2,3-diphenylquinoxaline (188, R = Ph) (dry mixture, microwave irradiation under reflux, 4 min 21% and 67%, respectively) in contrast, similar treatment with m,m -dichloro-benzoin gave only the aromatized product, 2,3-bis(m-chlorophenyl)quinoxa-line (188, R = C6H4Cl-m) (94%). ... 

The Suzuki reaction has been successfully used to introduce new C - C bonds into 2-pyridones [75,83,84]. The use of microwave irradiation in transition-metal-catalyzed transformations is reported to decrease reaction times [52]. Still, there is, to our knowledge, only one example where a microwave-assisted Suzuki reaction has been performed on a quinolin-2(lH)-one or any other 2-pyridone containing heterocycle. Glasnov et al. described a Suzuki reaction of 4-chloro-quinolin-2(lff)-one with phenylboronic acid in presence of a palladium-catalyst under microwave irradiation (Scheme 13) [53]. After screening different conditions to improve the conversion and isolated yield of the desired aryl substituted quinolin-2( lff)-one 47, they found that a combination of palladium acetate and triphenylphosphine as catalyst (0.5 mol %), a 3 1 mixture of 1,2-dimethoxyethane (DME) and water as solvent, triethyl-amine as base, and irradiation for 30 min at 150 °C gave the best result. Crucial for the reaction was the temperature and the amount of water in the... 

Microwave irradiation has been used to accelerate the Gewald reaction for the one-pot synthesis of N-acyl aminothiophenes on solid support [67]. A suspension of cyanoacetic acid Wang resin 35, elemental sulfur, DBU and an aldehyde or ketone 36 in toluene was irradiated for 20 min at 120 °C in a single-mode microwave synthesizer (Scheme 13). Acyl chloride 37 was added, followed by DIPEA, and the mixture was irradiated for 10 min at 100 °C. After cooling to room temperature, the washed resin was treated with a TEA solution to give M-acylated thiophenes 38 in 81-99% yield and purities ranging from 46-99%. 

The synthesis of functionahzed tetrahydrocarbazoles can be promoted by microwave irradiation [84], The organocatalytic four-component reaction of a solution of 2-substituted indole, aromatic aldehyde (2 equiv) and Mel-drum s acid in benzene in the presence of DL-proline proceeds when heated under Dean-Stark conditions for 5 min in a single-mode microwave reactor to give the tetrahydrocarbazole product as a mixture of diastereoisomers (Scheme 24). 

The description of the association of heterocychc chemistry and microwave irradiation has also shown that performing microwave-assisted reactions should be considered with special attention. A few of these considerations can be applied generally for conducting microwave-assisted reactions and include the following (a) the ratio between the quantity of the material and the support (e.g., graphite) or the solvent is very important (b) for solid starting materials, the use of solid supports can offer operational, economical and environmental benefits over conventional methods. However, association of liquid/solid reactants on solid supports may lead to uncontrolled reactions which may result in worse results than the comparative conventional thermal reactions. In these cases, simple fusion of the products or addition of an appropriate solvent may lead to more convenient mixtures or solutions for microwave-assisted reactions. 

The imidazole ring is a privileged structure in medicinal chemistry since it is found in the core structure of a wide range of pharmaceutically active compounds efficient methods for the preparation of substituted imidazole libraries are therefore of great interest. Recently, a rapid synthetic route to imidazole-4-carboxylic acids using Wang resin was reported by Henkel (Fig. 17) [64]. An excess aliphatic or aromatic amine was added to the commercially available Wang-resin-bound 3-Ar,M-(dimethylamino)isocyano-acrylate, and the mixture was heated in a sealed vial with microwave irradi-... 

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. 

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

Benzoxazine, an heterocycle present as structural subunit in many naturally occurring and synthetic bioactive compounds, was prepared under microwave irradiation from a mixture of 2-aminophenol 218 and an a-bromoester 219 (Scheme 80). The reaction proceeded through an initial base-catalyzed alkylation of the phenoUc OH followed by spontaneous amidation. Yields from 44 to 78% were reported for 17 different benzoxazines 220 [ 141]. 

Quinoxalines have been prepared starting from common 1,2-diketones and 1,2-aryldiamines in MeOH/AcOH at 160 °C for 5 min under microwave irradiation (Scheme 81). Several differently substituted quinoxalines 223 and pyrido[2,3-b]pyrazines were prepared with this method, which Umitation may be the symmetry of the diketone 221 or the diamine 222 employed, in order to avoid the formation of a mixture of regioisomers [142],... 

Microwave irradiation of a mixture of substituted anthranilic acid 224 with formamide (5 equiv) at 150 °C for 5 min gave quinazoUnones 225 in good yields (Scheme 82). This microwave version of the Niementowski reaction [ 143] showed significantly improved yields compared to the conventional reaction conditions [144]. 

An interesting parallel was found while the microwave-enhanced Heck reaction was explored on the C-3 position of the pyrazinone system [29]. The additional problem here was caused by the capability of the alkene to undergo Diels-Alder reaction with the 2-azadiene system of the pyrazinone. An interesting competition between the Heck reaction and the Diels-Alder reaction has been noticed, while the outcome solely depended on the substrates and the catalyst system. Microwave irradiation of a mixture of pyrazinone (Re = H), ethyl acrylate (Y = COOEt) and Pd(dppf)Cl2 resulted in the formation of a mixture of the starting material together with the cycloaddition product in a 3 1 ratio (Scheme 15). On the contrary, when Pd(OAc)2 was used in combination with the bulky phosphine ligand 2-(di-t-butylphosphino)biphenyl [41-44], the Heck reaction product was obtained as the sole product. When a mixture of the pyrazinone (Re = Ar) with ethyl acrylate or styrene and Pd(dppf)Cl2 was irradiated at 150 °C for 15 min, both catalytic systems favored the Heck reaction product with no trace of Diels-Alder adduct. 

For the further decoration of the pyrazinone scaffold via transition metal-catalyzed chemistry, the Sonogashira reaction [45-50] has also been investigated on the C-3 position of the pyrazinone, applying microwave irradiation conditions (Scheme 17) [29]. It was found that microwave irradiation at 120 °C for 15 min of a mixture of the starting material, Pd(OAc)2, Cul and PPha in TEA/DMF were the appropriate reaction conditions. 

All attempts to use milder reaction conditions such as mixtures of TFA in DCM (95 5) at RT or DDQ failed, while microwave irradiation of compounds at 120 °C in a (1 1) or (1 2) TFA/DCM mixtures provided deprotected products in yields comparable to those obtained under conventional heating (69-96%). It should be noted that this microwave-enhanced procedure not only resulted in milder reaction conditions, but also represents a considerable shortening of reaction time (10-20 min compared to 6-12 h). 

Finally, we tried to deprotect the amide nitrogen of the obtained pyridi-nones upon reflirx in neat trifluoroacetic acid (TFA) for 18 h [ 116]. Products were isolated in 73% and 79% yield, respectively. In contrast, upon microwave irradiation at 120 °C for only 20 min, a (1 2) TFA/DCM mixture sufficed to deprotect the pyridinones (isolated yields 75% and 73% respectively). Surprisingly, deprotection with either refluxing neat TFA (18 h) or microwave irradiation in neat TFA with a catalytic amount of methanesulfonic acid (20 min) did not work for dihydrofuropyridinone. 

In the resulting binary solvent mixtures of either OSM or TSM micronising step procedures, one apolar component (n-hexane or n-heptane) serves to give high swelling-melting power to the polymer but does not heat under microwave irradiation. The second polar component (ethyl acetate, acetone, and isopropyl alcohol) has... 

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