Nucleophilic substitutions microwave-assisted

Fig. 40 Microwave-assisted substitution of imidazole on C-2 in solid-phase. Reagents and conditions a benzaldehyde, N,N-diisopropylethylamine, CH2CI2, 24 h, rt b Nucleophile, TEA, Bp3Et20, THP, MW 120 °C, 5 min, closed vessel...

Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine could be easily fimc-tionalized at C-3 and C-4 in a one-pot two-step microwave-assisted process (Scheme 34) [55]. Ding and Schultz reported that nucleophilic substitution of the addition-elimination type at the C-4 position with amines and anilines smoothly occurred under acidic conditions in dioxane upon irradiation... 

Another synthesis of diazepines (tricyclic) was carried out by reaction of an amino chloropyridine 258 and anthranilic acid [163]. First, a nucleophilic substitution occurred (Scheme 95) followed by an intramolecular amidation on compound 259 by microwave irradiation to give structure 260. The reaction was carried out at 100 °C for more than 2 h, a remarkably long time for a microwave-assisted reaction. 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

The microwave-assisted nucleophilic substitution of 4-hydroxy-6-methyl-2(lH)-pyridones [101] has also been studied (Scheme 8.72). 

An 8000-member library of trisamino- and aminooxy-l,3,5-triazines has been prepared by use of highly effective, microwave-assisted nucleophilic substitution of polypropylene (PP) or cellulose membrane-bound monochlorotriazines. The key step relied on the microwave-promoted substitution of the chlorine atom in monochlorotriazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively harsh conditions such as 80 °C for 5 h or very long reaction times (4 days), all substitution reactions were found to proceed within 6 min, with both amines and solutions of cesium salts of phenols, and use of microwave irradiation in a domestic oven under atmospheric reaction conditions. The reactions were conducted by applying a SPOT-synthesis technique [36] on 18 x 26 cm cellulose membranes leading to a spatially addressed parallel assembly of the desired triazines after cleavage with TFA vapor. This concept was later also extended to other halogenated heterocycles, such as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37]. 

Compared to the dramatic increase in microwave heating in cross-coupling and metal-mediated nucleophilic substitutions, the number of published microwave-assisted Heck reactions is limited. Thus, only seven additional examples emphasizing different concepts will be presented in this section. 

Solventless, Microwave-Assisted Synthesis of Coumarins via a Tandem Knoevenagel Condensation and an Intramolecular Nucleophilic Acyl Substitution... 

Rebeiro, G. L., Khadilkar, B. M. Microwave assisted aromatic nucleophilic substitution reaction under solventless condition. Synth. 

Aromatic nucleophilic substitution An expeditious microwave-assisted S Ar reaction with cyclic amines has been reported for activated aromatic substrates [141] (Eq. 55) ... 

Microwave-assisted solid-phase synthesis of purines on an acid-sensitive meth-oxybenzaldehyde (AMEBA)-linked polystyrene has been reported [50]. The heterocyclic scaffold was first attached to the polymer support via an aromatic nucleophilic substitution reaction by conventional heating in l-methyl-2-pyrrolidinone (NMP) in the presence of N,N-diisopropylethylamine. The key aromatic nucleophilic substitution of the iodine with primary and secondary amines was conducted by microwave heating for 30 min at 200 °C in l-methyl-2-pyrrolidone (Scheme 16.28). After reaction the products were cleaved from the solid support by use of trifluoroacetic acid-water at 60 °C. 

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