Microwave irradiation development

A one-pot synthesis of thiohydantoins has been developed using microwave heating [72]. A small subset of p-substituted benzaldehydes, prepared in situ from p-bromobenzaldehyde by microwave-assisted Suzuki or Negishi reactions, was reacted in one pot by reductive amination followed by cyclization with a thioisocyanate catalyzed by polystyrene-bound dimethyl-aminopyridine (PS-DMAP) or triethylamine, all carried out under microwave irradiation, to give the thiohydantoin products in up to 68% isolated yield (Scheme 16). 

In recent years, parallel to the emergence of SPOS, microwave-mediated organic synthesis has come to hght and has developed into a popular field [24-31]. The main advantage of microwave dielectric heating compared to other conventional methods, such as hot plate, oil bath or isomantle, is the tremendous rate enhancement generally observed under microwave irradiation conditions. Various theories have been proposed to explain the source of the rapidity of microwave chemistry [32,33]. However, the gener-... 

Hlasta and Deng have developed a two-step solid-phase method for the decoration of azoles at C-2 [188]. First, imidazole was loaded onto a polystyrene-bound carbamyl chloride via a benzaldehyde bridge (Fig. 40). The 2-substi-tuted imidazole was efficiently cleaved in good yields in the presence of various nucleophiles (i.e., water, alcohols, and amines), trifluoroacetic acid, and boron trifluoride under microwave irradiation in a closed vessel at 120 °C for 5 min. 

Another interesting scavenger is polymer-supported anthracene, developed by Porco for the scavenging of dienophiles [109]. An example of its application to the synthesis of a complex 5,8-dihydro-(l,2,4)triazolo[l,2-a]pyridazine-l,3-diones via hetero-Diels-Alder reaction followed by removal of the excess of triazole-3,5-dione under microwave irradiation is depicted in Scheme 24. For this particular example, moving from thermal heating (toluene, 100 °C) to a microwave-assisted protocol (DCE, 150 °C) reduced scavenging time from 3 h to just 15 min. 

Oxa-tetrahydropyridines are interesting intermediates for the preparation of pharmaceuticals and natural product based alkaloid systems. A modified Hantzsch reaction was developed under microwave irradiation for the preparation of 2-oxa-tetrahydropyridines 173 by reaction of Meldrum s acid, a /3-ketoester and an aldehyde, using NH4OAC as the source of ammonia (Scheme 62). Yields ranged from 81 to 91% at temperatures of 100-130 °C depending on the substrate (the aldehyde) employed. All the products obtained have the same structure except for the aromatic substituent in position 4 [109]. 

For the synthesis of coumarins, the Pechmann reaction [145] is one of the most popular synthetic routes. As the reaction is conventionally carried out at high temperature, two microwave-assisted versions have been recently described. Besson and co-workers described the cyclocondensation of different m-amino phenols 226 with /1-ketoesters 227 on graphite/montmorillonite KIO support (Scheme 83). The use of graphite was crucial in the development of the reaction conditions. In fact, microwave irradiation of the reagents using different conditions gave poor results in terms of yields and purity. The optimized conditions, using a monomode microwave system, employed... 

Pt-catalyzed hydration of various aliphatic and aromatic alkynes under phase transfer conditions in (CH2C1)2/H20 in the presence of Aliquat 336 led to either a Markovnikov product, mixtures of two ketones, or ketones with the carbonyl group positioned away from the bulky side.72 In the absence of the phase transfer reagent, Aliquat 336, hardly any reaction took place. Recently, a hydrophobic, low-loading and alkylated polystyrene-supported sulfonic acid (LL-ALPS-SO3H) has also been developed for the hydration of terminal alkynes in pure water, leading to ketones as the product.73 Under microwave irradiation, the hydration of terminal arylalkynes was reported to proceed in superheated water (200°C) without any catalysts.74... 

The final example demonstrates that microwave irradiation allows a perfect fine-tuning of reaction conditions to obtain different products from the same starting materials. In the procedure developed by Garcfa-Tellado and coworkers [41], two domino processes were coupled. The first process consists of a high-yielding synthesis of enol-protected propargylic alcohols 10-111 starting from alkyne 10-109 and aldehyde 10-110 (Scheme 10.28). In the second process, transformation into... 

An efficient single-step procedure for the synthesis of 4,6-diarylpyrimidin-2(l//)-ones 35 promoted by cyanuric chloride and Zn(OTf)2 or Bi(OTf)3 under solvent-free microwave irradiation conditions has been developed <06H1551>. 

Whereas in the last decade microwave irradiation was mainly applied to accelerate and optimize well-known and established reactions, current trends are indicative of the future use of microwave technology for the development of completely new reaction pathways in organic synthesis. Limited by vessel and cavity size, microwave-assisted synthesis has hitherto been focused predominantly on reaction optimiza-... 

Most examples of microwave-assisted chemistry published to date and presented in this book (see Chapters 6 and 7) were performed on a scale of less than 1 g (typically 1-5 mL reaction volume). This is in part a consequence of the recent availability of single-mode microwave reactors that allow the safe processing of small reaction volumes under sealed-vessel conditions by microwave irradiation (see Chapter 3). While these instruments have been very successful for small-scale organic synthesis, it is clear that for microwave-assisted synthesis to become a fully accepted technology in the future there is a need to develop larger scale MAOS techniques that can ultimately routinely provide products on a multi kg (or even higher) scale. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

Sodium cyanoborohydride [123], sodium triacetoxyborohydride [124] or NaBH4 coupled with sulfuric acid [125] are common agents used for the reductive amination of carbonyl compounds. These reagents either generate waste or involve the use of corrosive acids. The environmentally friendlier procedures developed by Varma and coworkers have been extended to a solvent-free reductive amination protocol for carbonyl compounds using moist montmorillonite K 10 day supported sodium borohydride that is facilitated by microwave irradiation (Scheme 6.39) [126]. 

---