Scavenging microwave-assisted

Scheme 23 Preparation of a library of 3-oxopiperazinium salts using microwave-assisted scavenging of excess amines...

The microwave-induced N3-acylation of the dihydropyrimidine (DHPM) Bigi-nelli scaffold using different anhydrides has been discussed in a comprehensive report [130] (Scheme 16.85). The process included purification of the reaction mixture by means of a microwave-assisted scavenging technique. Several scavenging reagents with different loadings of amino functionalities have been used to sequester excess benzoic anhydride (BZ2O) from the reaction mixture [130, 139, 140]. 

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. 

In a detailed investigation, Turner and coworkers have described the preparation and application of solid-supported cyclohexane-1,3-dione as a so-called capture and release reagent for amide synthesis, as well as its use as a novel scavenger resin [125]. Their report included a three-step synthesis of polymer-bound cyclohexane-1,3-dione (CHD resin, Scheme 7.104) from inexpensive and readily available starting materials. The key step in this reaction was microwave-assisted complete hydrolysis of 3-methoxy-cyclohexen-l-one resin to the desired CHD resin. 

Dallinger, D., Gorobets, N.Y. and Kappe, C.O., High-throughput synthesis of N3-acylated dihydropyrimidines combining microwave-assisted synthesis and scavenging techniques, Org. Lett., 2003, 5, 1205. 

It should be highlighted that in some cases the distinction between a traditional solid-phase synthesis and a process involving solid-supported reagents is often difficult. The reader is advised to refer also to the chapter on the integration of microwave-assisted synthesis with solid supported reagents and scavengers (Chapter 6). 

In the synthesis of a compound library of allosteric Akt kinase inhibitors 39, Lindsley and coworkers employed different HTS techniques (Scheme 24) [54]. A polymer-supported base and a fluorous thiol scavenger were used in the alkylation reaction of 40. F-SPE purified intermediate was then used for microwave-assisted cycloaddition of 41. Similar intermediates have been used for generation of an unnatural canthine alkaloid library 42 by performing cycloaddition reactions with an indo-tethered acyl hy-drazide [55]. 

Combined with expedient purification techniques (e.g., scavengers, reagents on solid support, and solid phase extraction techniques) [ 14], microwave-assisted synthesis is leading the way towards genuine high-throughput chemistry that will hopefully ease the chemistry-related bottleneck in the drug development process. 

Microwave-assisted fluorous Ugi reactions were presented where the reaction times and convenient separation techniques appeared more attractive than the corresponding room temperature methods with traditional scavenging techniques. ... 

Another interesting development is the use of fluorous-based scavengers in conjunction with microwave synthesis and fluorous solid-phase extraction (F-SPE) for purification. This was recently illustrated by Werner and Curran [74] in their investigation of the Diels-Alder cycloaddition of maleic anhydride to diphenylbutadiene (Scheme 11.23). After performing microwave-assisted cycloaddition (160 °C, 10 min) with a 50% excess of the diene, the excess diene reagent was scavenged by a structurally related maleimide fluorous dienophile under the same reaction conditions. Elution of the product mixture from an F-SPE column with Me0H-H20 provided the desired cycloadduct 89 in 79% yield and 90% purity. Subsequent elution with diethyl ether furnished the fluorous Diels-Alder cycloadduct. 

As in other areas of organic synthesis, microwave irradiation has been adapted in Fischer indolizations (Table 3) [70-77], Whereas montmorillonite KSF worked well as reported for entries 1 to 3 [70], it utterly failed as reported for entries 4 to 5 [71], Entry 9 represents a novel decarboxylation of indole-2-carboxylic acids during microwave heating [73], For entries 10 and 11, yields are invariably higher under microwave conditions than with conventional heating, and the former represents an excellent synthesis of y-carbolines [74], Entries 12 to 15 feature propyl phospho-nic acid cyclic anhydride (T3P) as a mild water scavenger [75], Kremsner and Kappe have studied microwave-assisted organic synthesis in near-critical water at 300 °C,... 

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. 

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