Microwave irradiation nucleophilic substitution reactions

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]. 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

Ju and Varma envisioned that the nucleophilic substitution reaction of alkyl halides with amines may be accelerated by microwave energy because of their polar nature [88]. An environmentally friendly synthesis of tertiary amines via direct JV-alkylation of primary and secondary amines by alkyl halides under microwave irradiation was developed (Scheme 21), that pro-... 

Taking into account that nucleophilic substitution reactions of azines 55,56 typically do not occur in untreated DMSO and KF 2H2O under traditional heating, it is safe to assume that microwave irradiation promotes dissociation of KF and desolvation of the fluorine anion, which subsequently takes part in the nucleophilic substitution reaction, similarly to spray-dried KF in anhydrous DMSO (Fig. 2). 

Angrish et al. (2005) reported a rapid and efficient method for aromatic nucleophilic substitution reaction of chloronitrobenzene with number of substituted amines in presence of l-butyl-3-methylimidazolium tetrafluoroborate ionic liquid (green reaction media) to give N-substituted nitrobenzene under microwave irradiation. 

The N-aiylindole subunit is an important species in many biologically active and pharmaceutically important compounds, which display antiestrogen, analgesic, antiallergic, antinticrobial and neuroleptic activity. Xu and Fan (2008) carried out nticrowave-assisted nucleophilic aromatic substitution reaction of indoles with fluo-ro- and chloro-substituted aryl halides to synthesize N-arylindoles via C(sp )-N(sp ) bond formation in the presence of K2CO3 or Cs COj under microwave irradiation (420 W). Reaction was completed within 25-40 min with good yields (46-94%). 

Bromo-N-alkylnaphthalimides undergo aromatic nucleophilic substitution reaction with amines, alkoxides and thiols under microwave irradiation in the presence of KF/AI2O3 under solvent-free conditions to afford a number of fluorescent 4-sub-stituted-l,8-naphthalimide dyes. This is an efficient method for C-N, C-0 and C-S bond formation by applying suitable nucleophiles. Adducts were produced in good to excellent yields (70-95%) and relatively in short times (Bardajee, 2013). 

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. 

Alternatively, esterification of carboxylic acid can be carried out in aqueous media by reacting carboxylic acid salts with alkyl halides through nucleophilic substitutions (Eq. 9.10).20 The reaction rate of alkyl halides with alkali metal salts of carboxylic acids to give esters increases with the increasing concentration of catalyst, halide, and solvent polarity and is reduced by water. Various thymyl ethers and esters can be synthesized by the reactions of thymol with alkyl halides and acid chlorides, respectively, in aqueous medium under microwave irradiation (Eq. 9.11).21 Such an esterification reaction of poly(methacrylic acid) can be performed readily with alkyl halides using DBU in aqueous solutions, although the rate of the reaction decreases with increasing water content.22... 

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 group of Grieco has presented a method for efficiently performing macrocy-clizations on a solid phase (Scheme 7.31) [48]. The preparation of the macrocyclic peptides required several standard transformations, which are not described in detail herein. The final intramolecular nucleophilic aromatic substitution step was carried out under microwave irradiation at 50 °C in a dedicated CombiCHEM system (see Fig. 3.9) utilizing microtiter plates in a multimode batch reactor. The cycli-zation product was obtained in good yield after a reaction time of 10 min and sub-... 

Reaction of 1,2-disubstituted hydrazines with l,2-bis(halomethyl)benzenes 291 under microwave irradiation has shown to yield 2,3-disubstitued 1,2,3,4-tetrahydrophthalazines 292 via double nucleophilic substitution. When a mono-substituted hydrazine is used 2-substituted 1,2-dihydrophthalazine was obtained (Equation 71) <2005TL6011, 2006JOC135>. 

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