Solids microwave synthesis

Other PK variations include microwave conditions, solid-phase synthesis, and the fixation of atmospheric nitrogen as the nitrogen source (27—>28). Hexamethyldisilazane (HMDS) is also an excellent ammonia equivalent in the PK synthesis. For example, 2,5-hexanedione and HMDS on alumina gives 2,5-dimethylpyrrole in 81% yield at room temperature. Ammonium formate can be used as a nitrogen source in the PK synthesis of pyrroles from l,4-diaryl-2-butene-l,4-diones under Pd-catalyzed transfer hydrogenation conditions. 

The microwave-assisted solid-supported synthesis of 1,3,4-thiadiazoles was described applying from acid and thiosemicarbazide on acidic aliunina... 

Fig. 10 Liberty (CEM Corporation), the first automated microwave solid-phase peptide synthesizer, is shown on the left-, the available reaction vessel setup for solid-phase synthesis is depicted on the right...

Representative examples of the recent applications of controlled microwave heating in solid-phase synthesis of heterocychc compounds are summarized. The preparation of monocyclic compoimds is presented hrst, followed by a description of the synthesis of polycyclic structures. 

Fig. 26 Solid-phase synthesis of indol-2-ones by microwave-assisted radical cyclization. Reagents and conditions a NaH, DMF b BusSnH, AIBN, DMF, MW 170 °C, 45 min, sealed vessel c 10% TFA in CH2CI2. R = H, F, Me, OCF3 R = Phe, 3-OMe - Phe, 4-Me - Phe, 3,4-0CH20-Ph, (CH2)4, diMe R" = H, Me R " = H, Me...

A general and efficient solid-phase synthesis of A-9-substituted 2,8-diamino purines 62 has been described. The key synthetic transformation uses a carbodiimide-mediated cyclization of a thiourea 60. The reaction was performed using microwave reaction conditions on solid phase <06TL8897>. 

An example of solid-phase microwave synthesis where the use of open-vessel technology is essential is shown in Scheme 4.10. The transesterification of /3-keto esters with a supported alcohol (Wang resin) is carried out in 1,2-dichlorobenzene (DCB) as a solvent under controlled microwave heating conditions [22], The temperature is kept constant at 170 °C, ca. 10 degrees below the boiling point of the solvent, thereby allowing safe processing in the microwave cavity. In order to achieve full conversion to the desired resin-bound /3-keto ester, it is essential that the methanol formed can be removed from the equilibrium [22]. 

Table 7.1 Swelling behavior, loss tangents (tan <5), and boiling points for solvents used in microwave-assisted solid-phase synthesis.

In another application, the group of Berteina-Raboin demonstrated the solid-supported synthesis of the indole core of melatonin analogues under microwave irradiation (Scheme 7.6) [26]. A benzoic acid derivative was coupled to Rink amide resin by... 

Combs and coworkers have presented a study on the solid-phase synthesis of oxa-zolidinone antimicrobials by microwave-mediated Suzuki coupling [38], A valuable oxazolidinone scaffold was coupled to Bal resin (PS-PEG resin with a 4-formyl-3,5-dimethoxyphenoxy linker) to afford the corresponding resin-bound secondary amine (Scheme 7.18). After subsequent acylation, the resulting intermediate was transformed to the corresponding biaryl compound by microwave-assisted Suzuki coupling. Cleavage with trifluoroacetic acid/dichloromethane yielded the desired target structures. 

As discussed in Section 7.1.4, polymer-bound acetoacetates can be used as precursors for the solid-phase synthesis of enones [33], For these Knoevenagel condensations, the crucial step is to initiate enolization of the CH acidic component. In general, enolization can be initiated with a variety of catalysts (for example, piperidine, piperidinium acetate, ethylenediamine diacetate), but for the microwave-assisted procedure piperidinium acetate was found to be the catalyst of choice, provided that the temperature was kept below 130 °C. At higher reaction temperatures, there is significant cleavage of material from the resin. 

A very interesting approach toward solid-supported synthesis under microwave heating was introduced by Chandrasekhar and coworkers [64], The authors developed a synthesis of N-alkyl imides on a solid phase under solvent-free conditions employing tantalum(V) chloride-doped silica gel as a Lewis acid catalyst (Scheme 7.53). 

Ester aminolysis, in general, occurs under harsh conditions that require high temperatures and extended reaction periods or the use of strong alkali metal catalysts. An efficient solid state synthesis of amides from nonenolizable esters and amines using KO Bu under the action of microwave irradiation [97] has been described. The reaction of esters with octylamine was extensively studied to identify possible micro-wave effects [98] (Eq. (45) and Tab. 3.20). 

Bis(indolyl)nitroethanes are obtained readily in 7-10 min in high yields (70-86%) on fine TLC-grade silica gel (5-40 pm) by Michael reaction of 3-(2 -nitrovinyl) indole with indoles. The same reaction reported requires 8-14 h for completion at room temperature [77]. Several functionalized resins have been prepared from Merrifield resin via a MW-assisted procedure that utilized mixed solvent system to facilitate the swelling of resins and coupling with microwaves [78], These resins can function as solid supports or polymeric scavengers in solid phase synthesis. 

The most successful application of microwave energy in the preparation of heterogeneous solid catalysts has been the microwave synthesis and modification of zeolites [21, 22], For example, cracking catalysts in the form of uniformly sized Y zeolite crystallites were prepared by microwave irradiation in 10 min, whereas 10-50 h were required by conventional heating techniques. Similarly, ZSM-5 was synthesized in 30 min by use of this technique. The rapid internal heating induced by microwaves not only led to a shorter synthesis time, and high crystallinity, but also enhanced substitution and ion exchange [22]. 

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

Recent advances in the use of Lawesson s reagent include its application in microwave assisted solvent-free syntheses, solid-phase synthesis and combinatorial chemistry.165 Despite the ubiquity of Lawesson s reagent for organic thionation reactions, there are still some classes of compounds that it does not... 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

To use microwave heating in solid state synthesis, at least one component of the reaction mixture must absorb microwave radiation. The speed of the reaction process is then increased by both increasing the rate of the solid state reaction and by increasing the rate of diffusion, which, as we mentioned earlier, is often the rate-limiting step. 

An efficient microwave-assisted multi-step synthesis of8//-quinazolino [4,3-b] quina-zolin-8-one has been investigated by Besson and co-workers77. The synthesis involved two Niementowski condensations starting from substituted anthranilic acids (Scheme 3.49). Both homogeneous and heterogeneous conditions were studied in an effort to develop a convenient synthesis of the desired compounds. The solventless procedure allowed easier access to the quinazolino[4,3-fi]quinazolin-8-ones and gave better yields than the method performed in the presence of solvents. However, the procedure with solvents would offer the possibility of investigating the microwave-assisted solid-phase synthesis of these quinazolinones, which would faciltate purification of the final products. 

Varma, R.S., Kumar, D. and Liesen, P.J., Solid state synthesis of 2 arnvlbcnzn [ b ] fui.tns, thiazoles and 3-aryl-5,6-dihydroimidazo [2,1 fo] [ 1,3] thiazoles from a-tosyloxy ketones using microwave irradiation, /. Chem. Soc., Perkin Trans. 1, 1998,4093-4096. 

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