Microwave-assisted reactions

The use of microwave chemistry is spreading rapidly wherever polar materials are present and often no solvent is required. When a polar solvent is present, the success 

Microwave irradiation has recently become a possible method to improve reaction yields and dramatically shorten reaction times. Numerous types of reaction with highly enhanced rates have been found, and very high yields and clean reactions have been obtained by applying only small amounts of energy.  

Stille reactions have also shown to be suitable for these flash heating conditions, and rapid and successful Stifle couplings were reported by Hallberg and Larhed in 1996 [Equation (5.3.21)].  

The same authors also reported a solid-phase version of this reaction [Equation (5.3.22)]. 

the conventional heating approach delivered only poor yields with other more fluorous-tagged organotins (F-21), whereas the microwave-accelerated reaction delivered 75% yield after 6 min [Equation (5.3.24)].72 

One of the reasons why there has been phenomenal growth in research in microwave chemistry since the early 1990s is the realization that it can provide a rapid method for screening reactions. With a heating rate of 10 °C per second being achievable it is easy to see how the overall reaction time can be considerably shortened. Although there are examples of 

There are several examples of N-alkylation and acylation being successfully carried out, sometimes using a solid catalyst. Whilst most reactions proceed as expected, where different isomeric products are obtainable significantly different ratios have sometimes been noted compared to when 

In addition to organic reactions, acid catalysed hydrolysis of cellulose has been performed in a rapid and controlled manner using a microwave reactor. Given this reaction, it is likely that aqueous phase microwave assisted reactions will play an important role in the rapid development of biorefinery based materials and chemicals. 

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Fig. 7 Examples of microwave-assisted reactions and functional group transformations that are covered in Sect. 2...

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. 

Fig. 39 Microwave-assisted synthesis of pyridinones from resin-bonnd 2(iH)-pyrazinones. Reagents and conditions a dimethyl acetylenedicarboxylate, chlorobenzene, reflux (132 °C), 1-2 days or 1,2-dichlorobenzene, MW 220 °C, 20-40min b bromobenzene, reflux (156 °C), 2h or 1,2-dichlorobenzene, MW 220 °C, 10min R = OC2H4C2H c TFA, reflux (72 °C), 20-24 h or TFA/Ch2Cl2, MW 120 °C, 10-40min. R=OMe or Ph, R = methoxyphenyl. All microwave-assisted reactions were rim in sealed vessels...

Oxazoles have attracted considerable interest due their presence as subunits of several biologically active compoimds or as rigid mimetics of a peptidic ring. A first synthesis of 2-phenyl-4,5-substituted oxazoles 54 [47] was described by microwave-assisted reaction of enolizable ketones with benzoni-trile in the presence of mercury(II) p-toluenesulfonate (Scheme 17). 

The same reaction, carried out with conventional heating at the same temperature, took more that 6 h to give comparable yields of the products. Dihydropyrazoles were also obtained by microwave-assisted reaction of poly-substituted vinyl ketones 122 with hydrazines, followed by reaction of the unstable pyrazole 123 with electrophiles (Scheme 43) [80]. 

Pyridazines 160 were obtained by microwave-assisted reaction of 1,4-dicarbonyl compounds and hydrazine in AcOH and in the presence of DDQ as oxidant in order to obtain the aromatic compound in a one pot reaction [ 105]. The yields reported were relatively low although the method can be applied to the preparation of arrays of trisubstituted pyridazines with high molecular diversity (Scheme 57). 

Triazines have been prepared by microwave-assisted reaction of substituted benzonitriles 161 and cyanoguanidines 162 using the ionic hquid [bmim][PF6] as the solvent at 130°C for 10-15 min [106]. Nine differently... 

A modified Pechmann microwave-assisted reaction has been reported using an electron-rich phenol 229 and an a,/l-unsaturated acid in order to obtain coumarins without a substituent in position 4 [147]. Even in this case, the use of an acid solid catalyst (the support) was needed. Best results were obtained with Dowex or Amberhte-15 at 120 °C for 15 min (Scheme 84). 

A solvent-free synthesis of flavones was recently reported by microwave-assisted reaction of phloroglucinol 231 and differently substituted /1-ketoesters 232 [148]. The reaction was simply carried out by mixing the phenol and the ester in an open test tube followed by irradiation for 2-3 min. The internal temperature reached 240 °C and yields were in the range from 68 to 96%. Scheme 85 describes the application of this procedure to the synthesis of the natural product chrysin 233. 

A case study on the influence of microwave-assisted reactions carried out in open or closed vessel has been described by Kappe and co-workers [ 158]. One of the examples deals with the cyclocondensation of tetrahydroquinohne and malonic esters. The reaction gave tricyclic hydroxyquinolones with loss of two molecules of ethanol, similar to the reaction described in Scheme 79. The results showed clearly that this reaction carried out in an open vessel gave more reproducible results. 

Another synthesis of diazepines (tricyclic) was carried out by reaction of an amino chloropyridine 258 and anthranilic acid [163]. First, a nucleophilic substitution occurred (Scheme 95) followed by an intramolecular amidation on compound 259 by microwave irradiation to give structure 260. The reaction was carried out at 100 °C for more than 2 h, a remarkably long time for a microwave-assisted reaction. 

Scheme 7.7 Water-based microwave assisted reactions...

From the studies covered in this chapter, it can be concluded that a completely green chemical process in the synthesis of this kind of material is still a challenge. Some protocols, despite using non-toxic precursors, are time- and/or energy-consuming processes or require the use of non-friendly and non-recyclable solvents. Reaction times in microwave-assisted reaction processes have shown to be shorter. On the other hand, the substitution of conventional solvents for chemical and thermally stable I Ls allowed the reutilization of the solvent and also provided control of the size and shape of NPs. 

The highly potent anti-HIV natural product daurichromenic acid (10-100) was synthesized by Jin and coworkers [36] using a microwave-assisted reaction of the phenol derivative 10-97 and the aldehyde 10-98 (Scheme 10.25). Normal heating gave the desired benzo[b]pyran 10-99 by a domino condensation/intramolecular SN2 -type cyclization reaction only in low yield. However, when the reaction mixture was irradiated twenty times in a microwave for 1-min intervals, 10-99 was obtained in 60% yield. This compound was then transformed into 10-100 by cleavage of the ester moiety. 

For a review on microwave-assisted reactions in organic synthesis, see (a) S. Cad-dick, Tetrahedron 1995, 52, 10403-10432 ... 

Pyridazino[l,6- ]quinazolin-6-one of type 105b (with other substitution at positions 2, 3, and 4) was prepared by microwave-assisted reaction from the appropriate 104b <2003MOL910>. 

The process was also applicable to microwave-assisted reactions. Thus, 140a, 140b, and 140 (R1 = z-Pr, R4 = indol-3-ylmethyl) were prepared in a two-step, one-pot synthesis in yields of 55%, 39%, 20%, and with 70%, 73%, 50% ee, respectively. In the first step anthranilic acid was reacted with the appropriate A-BOC-protected amino acid (glycine, L-alanine, and L-valine, respectively) in the presence of P(OPh)3 and dry pyridine under irradiation at 150 °C for 140a or conventional heating at 55 °C for 140b and 140 (R1 = z-Pr, R4 = indol-3-ylmethyl). In the second step the resulting... 

The tetrahydropyrimido[l,2- ]quinazoline 195, a representative of the angularly fused benzologues, has been formed in the microwave-assisted reaction of aminopyrimidine, dimedone, and an aromatic aldehyde (Equation 20) <2002HC0299>. 

As already mentioned, the scale-up of microwave-assisted reactions is of specific interest in many industrial laboratories. For this purpose, Milestone offers two different continuous-flow systems (Fig. 3.11). 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

As already mentioned above, a different strategy to achieve high throughput in microwave-assisted reactions can be realized by performing automated sequential microwave synthesis in monomode microwave reactors. Since it is currently not feasible to have more than one reaction vessel in a monomode microwave cavity, a robotic system has been integrated into a platform that moves individual reaction... 

One major benefit of performing microwave-assisted reactions at atmospheric pressure is the possibility of using standard laboratory glassware (round-bottomed flasks, reflux condensers) in the microwave cavity to carry out syntheses on a larger scale. In contrast, pressurized reactions require special vessels and scale-up to more... 

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

The use of metals or metallic compounds in microwave-assisted reactions can also lead to damage to the reaction vessels. As metals interact intensively with microwaves, the formation of extreme hot spots may occur, which might weaken the vessel surface due to the onset of melting processes. This will destroy the stability of the vessels and may cause explosive demolition of the reaction containers. If catalysts are used which can produce elemental metal precipitates (for example, of palladium or copper), stirring is recommended to avoid the deposition of thin metal layers on the inner surfaces of the reaction vessels. 

Other microwave-assisted reactions involving metal catalysts or metal-based reagents are shown in Scheme 6.79 [164—167]. 

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