Alkylation microwave irradiation

Keywords 4-bromophenacyl bromide, azole derivative, /V-alkylation, microwave irradiation, azalieterocycle... 

Keywords sodium carboxylate, halide, layered double hydroxide, carboxylate alkylation, microwave irradiation... 

Keywords azaheterocycle, alkyl halide, A(-alkylation, microwave irradiation, A(-alkyl azaheterocyclic compound... 

Keywords carbazole, alkyl halide, iV-alkylation, microwave irradiation, iV-allg l-carbazole... 

Keywords aryl halide, secondary amine, A-alkylation, microwave irradiation, A-arylamine... 

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

When cyanogen bromide was used instead of CS2, the corresponding guanidines 169 were obtained under analogous conditions [108]. Moreover, differently substituted guanidines 171 could be obtained in very good yields when the isothiourea 168 was alkylated with Mel under microwave irradiation and the product treated with a primary amine. An intramolecular version of this reaction was also described for the preparation of structure 172 present in several important natural products (Scheme 61). 

For the synthesis of quinolines and isoquinolines the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid medium has been reported to be accelerated under microwave irradiation to give differently substituted quinolines and dihydro quinolines [137]. Although the yields are much better and the conditions are milder than under conventional heating, the acidity of the medium may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

Benzoxazine, an heterocycle present as structural subunit in many naturally occurring and synthetic bioactive compounds, was prepared under microwave irradiation from a mixture of 2-aminophenol 218 and an a-bromoester 219 (Scheme 80). The reaction proceeded through an initial base-catalyzed alkylation of the phenoUc OH followed by spontaneous amidation. Yields from 44 to 78% were reported for 17 different benzoxazines 220 [ 141]. 

The reactive compound chlorosulfonyl isocyanate (ClSOaNCO, forms P-lactams even with unactivated alkenes, as well as with imines, allenes, conjugated dienes, and cyclopropenes. With microwave irradiation, alkyl isocyanates also... 

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... 

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... 

Benzannulated NHPs are straightforwardly accessible from AUV-disubsti luted o-phenylenediamines either via base-induced condensation with substituted dichlorophosphines [25] or PC13 [26], or via transamination with tris(dialkylamino) phosphines [13, 14, 27], respectively. An analogous NH-substituted derivative was obtained in low yield via transamination of o-phcnylcncdiaminc with ethoxy-bis(diethylamino)phosphine [28], and condensation of o-phenylenediamine with excess tris(diethylamino)phosphine furnished a l,3-bis(phosphino)-substituted heterocycle [29], Intermediates with one or two NH functions were detectable by spectroscopy but could not be isolated in pure form under these conditions. However, 2-chloro-benzo-l,3,2-diazaphospholene and the corresponding 1-phenyl derivative were prepared in acceptable yield via condensation of PC13 with o-phenylenediamine under microwave irradiation [30], or with A-phenyl-o-phenylenediamine under reflux [27], respectively, in the absence of additional base. The formation of tetrameric benzo-NHPs during transamination of A-alkyl-o-phenylenediamines with P(NMe2)3 has already been mentioned (cf. the section entitled 1,3,2-Diazaphospholes and 1,3,2-Diazaphospholides ). 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

A series of 2-arylbenzothiazoles 41 has been synthesized via microwave irradiation of 1 1 mixture of ortho-nm i noth iophenol s 39 and alkyl or aryl acylacetonitriles <06JHC1609>. This reaction appears to be more efficient than that of ort/20-aminothiophenols with (3-ketoesters to form substituted benzothiazoles reported previously <05H(65)2119>. 

An effort to improve the efficiency of the nucleophilic displacement of halogens in a cyclocondensation reaction of primary amines with alkyl dihalides for the synthesis of N-phenylpiperidine through the use of microwave irradiation (80100 W, 120 °C, 20 min, 96% yield) was reported this year <06JOC135>. 

Potassium acetate, for example, can be readily alkylated by the use of an equivalent amount of an alkylating reagent (for example, an alkyl halide) in the presence of the phase-transfer catalyst Aliquat 336 (10 mol%) (Scheme 4.7) [16]. Yields are always near quantitative within a few minutes of microwave irradiation, irrespective of the chain length and the nature of the leaving group. This procedure has been scaled-up from 50 mmol to 2 mol scale in a large batch reactor [17]. 

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. 

A simple and atom-economical synthesis of hydrogen halide salts of primary amines directly from the corresponding halides, which avoids the production of significant amounts of secondary amine side products, has been described by researchers from Bristol-Myers Squibb [227]. Microwave irradiation of a variety of alkyl halides or tosylates in a commercially available 7 m solution of ammonia in methanol at 100-130 °C for 15 min to 2.5 h followed by evaporation of the solvent provided the corre-... 

The selective N-monoalkylation of anilines with alkyl halides and alkyl tosylates under microwave irradiation has been described by Romera and coworkers (Scheme... 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

A simple two-step synthesis of 5H-alkyl-2-phenyloxazol-4-ones has been reported by Trost and coworkers (Scheme 6.209) [377]. a-Bromo acid halides were condensed with benzamide in the presence of pyridine base at 60 °C to form the corresponding imides. Microwave irradiation of the imide intermediates in N,N-dimethylacetamide (DMA) containing sodium fluoride at 180 °C for 10 min provided the desired 5H-alkyl-2-phenyloxazol-4-ones (oxalactims) in yields of 44—82%. This class of heterocycles served as excellent precursors for the asymmetric synthesis of a-hydroxycar-boxylic acid derivatives [377]. 

In a related study, the same group investigated molybdenum-catalyzed alkylations in solution and on a solid phase [35], demonstrating that microwave irradiation could also be applied to highly enantioselective reactions (Scheme 7.15). For these examples, commercially available and stable molybdenum hexacarbonyl [Mo(CO)6] was used to generate the catalytic system in situ. The reactions in solution provided good yields (see Scheme 6.50). In contrast, the conversion rates for the solid-phase examples were rather poor. However, the enantioselectivity was excellent (>99% ee) for both the solution and solid-phase reactions. 

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