And microwave reactions

Microwave irradiation has been widely used in organic synthesis on a laboratory scale during the last few years. Several categories of reactions, for example, Diels-Alder reactions, ortAo-Claisen condensations, ene-reactions, oxidations, esterification of carboxylic acids with alcohols, and hydrolysis of esters and amides to carboxylic acids, have been successfully carried out in conventional microwave ovens. Table 26.4, adapted from Majetich and Hicks (1994), provides representative examples of some of these reactions. It can be seen that the conditions under which the conventional and microwave reactions are carried out differ significantly for most reactions. Hence, in comparing reactions with micro-waves with conventional syntheses with reflux, it is necassary to make the comparisons based on the total amount of energy input to the reaction volume. 

SCHEME 7.28 Examples of comparisons between flow and microwave reaction conditions. 

Thennal dissociation is not suitable for the generation of beams of oxygen atoms, and RF [18] and microwave [19] discharges have been employed in this case. The first excited electronic state, 0( D), has a different spin multiplicity than the ground 0( P) state and is electronically metastable. The collision dynamics of this very reactive state have also been studied in crossed-beam reactions with a RF discharge source which has been... 

At T < tunneling occurs not only in irreversible chemical reactions, but also in spectroscopic splittings. Tunneling eliminates degeneracy and gives rise to tunneling multiplets, which can be detected with various spectroscopic techniques, from inelastic neutron scattering to optical and microwave spectroscopy. The most illustrative examples of this sort are the inversion of the... 

Gupta et al. reported that the Vilsmeier-Haack cyclisation of acetanilides 20 using supported reagents and microwave-irradiation in solvent-free conditions is rapid and efficient. Reaction yields are good, although only a few activated derivatives have been investigated. 

The investigation on the use of K-10 montmorillonite under free solvent conditions was then extended to inner ring dienes such as furan and its 2,5-dimethyl derivative [9] (Table 4.3). The cycloadditions generally proceed slowly, and Zn(II)-doped clay and microwave irradiation were used to accelerate the reactions. The reaction with maleic anhydride preferentially affords the thermodynamically favored exo adduct. 

Hydrolysis of nitriles normally requires quite harsh conditions and long reaction times [101,102]. Applying microwave irradiation for this type of re-... 

The use of microwave irradiation for decarboxylation reactions is well appreciated [107-110]. Still, only one example of a decarboxylation performed on 2-pyridone starting materials has been reported (Fig. 10) [111]. Notably, this decarboxylation reaction is a selective and reagent-free method performed in N-methyl-2-pyrrohdin one (NMP) and microwave irradiation at 220 °C for 10 min. The products 65 were isolated in excellent yields (92-99%) by a simple aqueous work-up (Fig. 10). 

This chapter has taken the reader through a number of microwave-assisted methodologies to prepare and further functionalize 2-pyridone containing heterocycles. A survey of inter-, intramolecular-, and pericyclic reactions together with electrophilic, nucleophilic and transition metal mediated methodologies has been exemplified. Still, a number of methods remain to be advanced into microwave-assisted organic synthesis and we hope that the smorgasbord of reactions presented in this chapter will inspire to more successful research in this area. 

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

In all cases, besides resulting in good to excellent yields, the microwave-assisted multistep syntheses resulted in much faster reactions compared to earlier published procedures at atmospheric pressure under conventional heating conditions. It is also noteworthy that in some cases the strong thermal effect due to graphite/microwave interaction, can efficiently be used for the synthesis of heterocyclic skeletons, especially benzothiazoles but, in fact, there is no general rule and some reactions performed in the presence of solvent may sometimes be more convenient than the same dry-media conditions. 

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. 

Rapid aminations of 1-bromonaphthalenes with piperidine under microwave irradiation were reported by Hamann using Pd2(dba)3/rac. PPFA (N,N-dimethyl-1-[2-(diphenylphosphanyl)ferrocenyl]ethylamine) precatalyst in combination with NaO-t-Bu in toluene at 120 °C (Scheme 92) [97]. Typically, reactions performed under conventional heating at 120 °C (oil bath) were still progressing after 16 h and were essentially complete by 24 h, whereas the microwave reactions appeared to be finished after 10 min. The same reaction conditions were also useful to functionalize 5- and 8-bromoquinolines with anilines and aliphatic amines (Schemes 93 and 94). Remarkably, no product formation was observed with 5-bromo-8-cyanoquinoline and 5-bromo-8-methoxyquinoline under conventional heating for 24 h at the same temperature, while the desired 5-aminoquinolines were smoothly obtained under microwave irradiation in a reaction time of only 10 min. 

The cyclization of 1,2-dicarbonyl compounds with aldehydes in the presence of NH4OAC to give imidazoles was employed in a combinatorial study that compared conventional and microwave heating in the preparation of a library of sulfanyl-imidazoles (Scheme 15). The study employed an array of expandable reaction vessels that could accommodate a pressure build-up system for heating without loss of volatile solvents or reagents. A 24-membered library of imidazoles (48 and 49) was prepared in 16 min instead of the 12 h required using conventional heating [45]. 

The pyrrolidines were obtained in a two-step, one-pot reaction in good yields and short reaction time (5 min vs. 36 h reported for the conventional heating) [73], using a single-mode microwave apparatus [74]. 

Pr)4, " borohydride-exchange resin,and formic acid. When the last is used, the process is called the Wallach reaction. Conjugated aldehydes are converted to alkenyl-amines with the amine/silica gel followed by reduction with zinc borohydride.In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Esch-weiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid, " or formamides, as a substitute for the Wallach conditions. This method is called the Leuckart reaction,and in this case the products obtained are often the N-formyl derivatives of the amines instead of the free amines. Primary and secondary amines can be iV-ethylated (e.g., ArNHR ArNREt) by treatment with NaBH4 in acetic acid. Aldehydes react with aniline in the presence of Mont-morillonite KIO clay and microwaves to give the amine. Formaldehyde with formic acid converts secondary amines to the N-methyl derivative with microwave irradiation. 

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