Microwave conditions

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. 

Over the last several years research groups have also explored the use of microwaves to increase the reaction rate and efficiency of the Biginelli reaction. In one example, polyphosphate ester (PPE) was used as the promoter under microwave conditions to deliver a variety of DHPMs 38 in yields ranging from 65-95% yield with reaction times typically below 2 minutes. ... 

A completely different kind of macro cycle, a calix-salen type macrocycle, was obtained in good yield by microwave irradiation of various dialdehydes and diamines [165]. This was the first example of a calix-type synthesis under microwave conditions and without the presence of a metal template. An example of a [3 -1- 3] cyclocondensed macrocycle 265, obtained from a bis aldehyde and a chiral diamine is reported in Scheme 97. 

The combination of KF with 2-acetoxypropene under microwave conditions was... 

Fig. 6. Schematic representation of synthesis of starch capped copper nanoparticies under microwave conditions...

Pyrimido[2,l- ][l,3]thiazinones 363 formed in low yield - instead of the targeted lactams 362 - on photoirradiation of the cyclic amidines 361 and the diazoketone 360 (Scheme 59). Under microwave conditions only 362 formed, which on photoirradiation decomposed <2005JOC334>. 

Treatment of 3-(2-pyrrolidino)pyridine with 2 molar equiv of diethyl acetylenedicarboxylate under microwave conditions gives the tetrahydropyrrolonaphthyridine 283 and (presumably) diethyl maleate or fumarate. Under conventional heating conditions, decarboxylated products are also observed (Scheme 71) <2005TL3953>. 

Wang et al. reported two different reaction conditions for a solvent free Friedlander quinoline synthesis. Initially, they reported the reaction of 2-acetyl anilines 73 with a variety of P-diketoesters 74 using / -Ts()H as the catalyst under microwave conditions to form substituted quinolines 75 <060BC104>. They also reported the same reaction using BiCl3 as the catalyst under thermal conditions <06LOC289>. Both sets of conditions afford high yields and simpler experimental procedures. 

Microwave-promoted reactions continue to extend their reach in heterocyclic synthesis. Regioselective N4-aminoethylation of the l,4-benzodiazepin-2-one 94 was observed under microwave conditions in DMF/K2C03 to afford, for example, 96a and 96b in 64% and 67% yield respectively (Table 4). In contrast, the thermal reaction at 80 °C in DMF with K.2CC)3 as base gave the Nl-aminoethylation products (95a, 65%) and (95b, 76%). These results were... 

Most recently, Bentz and co-workers established that the Pd-catalyzed a-arylation of esters and amides, using Reformatsky reagents and the corresponding aryl bromides, can be successfully performed under microwave conditions.417 The reported yields are somewhat lower than those reported by Hartwig 414 however, this approach does not require the use of Q-phos and can be considered as valuable alternative for a-arylation. 

There are many other examples in the literature where sealed-vessel microwave conditions have been employed to heat water as a reaction solvent well above its boiling point. Examples include transition metal catalyzed transformations such as Suzuki [43], Heck [44], Sonogashira [45], and Stille [46] cross-coupling reactions, in addition to cyanation reactions [47], phenylations [48], heterocycle formation [49], and even solid-phase organic syntheses [50] (see Chapters 6 and 7 for details). In many of these studies, reaction temperatures lower than those normally considered near-critical (Table 4.2) have been employed (100-150 °C). This is due in part to the fact that with single-mode microwave reactors (see Section 3.5) 200-220 °C is the current limit to which water can be safely heated under pressure since these instruments generally have a 20 bar pressure limit. For generating truly near-critical conditions around 280 °C, special microwave reactors able to withstand pressures of up to 80 bar have to be utilized (see Section 3.4.4). 

Scheme 4.20 Preparation of ionic liquids under microwave conditions.

Scheme 4.24 Solvent-free parallel synthesis under microwave conditions (domestic oven).

Current single-mode continuous-flow microwave reactors allow the processing of comparatively small volumes. Much larger volumes can be processed in continuous-flow reactors that are housed inside a multimode microwave system. In a 2001 publication, Shieh and coworkers described the methylation of phenols, indoles, and benzimidazoles with dimethyl carbonate under continuous-flow microwave conditions using a Milestone ETHOS-CFR reactor (see Fig. 3.11) [104]. In a typical procedure, a solution containing the substrate, dimethyl carbonate, 1,8-diazabicy-clo[5.4.0]undec-7-ene (DBU) base, tetrabutylammonium iodide (TBAI), and a solvent was circulated by a pump through the microwave reactor, which was preheated to 160 °C and 20 bar by microwave irradiation (Scheme 4.31). Under these condi-... 

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],... 

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