Alkylations solvent-free

The synthesis of 4-unsubstituted DHPs in a focused microwave reactor has been reported using alkyl acetoacetates and hexamethylenetetramine 19 as the source of both formaldehyde and ammonia, with additional ammonium acetate to maintain the stoichiometry [57], Irradiation for 100 s under solvent-free conditions gave, for example, 1,4-DHP 20 in 63% isolated yield (Scheme 5). 

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-... 

To pursue the development of environmentally benign synthesis routes for ionic liquids, the alkylation step (Menschutkin reaction) was investigated by the authors in detail. The preparation of the ionic liquid 1-hexyl-3-methyhmidazohum chloride ([CeMlMJCl) was taken as a representative experiment (Scheme 7.2). The process parameters temperature (T = 70-100°C), solvent (ethanol, xylene, cyclohexane, n-heptane, solvent free), concentration of the N-base (c = 1.6-6.7 M), molar ratio n n = 1 0.5-1 4) and reaction time (f = 10-144 h) were investigated. In addition, the N-base was altered in order to proof the transferability of the reaction parameters. 

Scheme 1. The solvent-free controlled thermolysis of gold(I) thiolate complex producing gold nanoparticles stabilized by alkyl groups derived from the precursor.

The groups of Loupy and Jun have presented a chelation-assisted rhodium(I)-cata-lyzed ortho-alkylation of aromatic imines with alkenes (Scheme 6.57) [119]. The use of 2 mol% of Wilkinson s catalyst, RhCl(PPh3)3, and 5 equivalents of the corresponding alkene under solvent-free conditions proved to be optimal, providing the desired ortho-alkylated ketones in high yields after acidic hydrolysis. Somewhat lower yields were obtained when the imine preparation and the ortho-alkylation were realized in a one-pot procedure. 

A very interesting approach toward solid-supported synthesis under microwave heating was introduced by Chandrasekhar and coworkers [64], The authors developed a synthesis of N-alkyl imides on a solid phase under solvent-free conditions employing tantalum(V) chloride-doped silica gel as a Lewis acid catalyst (Scheme 7.53). 

Scheme 7.53 Solvent-free preparation of N-alkyl imides.

Alkylation of several substituted benzoic acid salts with n-octyl bromide was performed under solvent-free PTC with excellent yields (95 %) within a very short reaction time [93] (2-7 min). Oil bath heating (A) led to yields equivalent to those produced under the action of microwave irradiation, which thus revealed only thermal effects in the range of temperature used (145-202 °C) (Eq. 39). 

A new family of furan diethers has been obtained by alkylation of 2,5-furandimetha-nol (Eq. 8) under the action of microwaves under PTC solvent-free conditions. 

A similar reaction is the methylenation of 3,4-dihydroxybenzaldehyde in the presence of a phase-transfer catalyst on a benign calcium carbonate surface [26]. Presumably, bonding of the vicinal hydroxyl groups is low thereby enhancing the reaction with the alkylating agent under the action of solvent-free microwave irradiation (Eq. 15). 

With the purpose of improvement and simplification of the synthesis of potential cosmetic compounds, alkylation of mono- and dihydroxybenzaldehydes with long-chain halides was efficiently realized under solvent-free MW + PTC conditions (Eqs. 16 and 17 and Tab. 5.9) [27, 28],... 

Desyl ethers are key intermediates in the synthesis of biologically active furanopy-rones. MW-assisted synthesis of these has been performed in an open vessel under PTC solvent-free conditions (Eq. 19) by alkylation of 7-hydroxy-4-methyl coumarin with desyl chloride [30],... 

Several solvent-free N-alkylation reactions have been reported which involve the use of phase transfer agent, tetrabutylammonium bromide (TBAB), under microwave irradiation conditions, an approach that is described in Chapt. 5 [34],... 

According to the solvent-free GS/MW process, which enables reaction at high temperatures, the cleavage of these alkyl ethers became possible (Scheme 7.13) [15,16]. 

The reaction of benzo-2-furancarboxylic acid with thiosemicarbazide under microwave conditions enables the use of an equivalent amount of phosphorus oxychloride and a short reaction time <2003SC2891 >. Moreover, solvent-free conditions are achieved when acidic alumina is used as dehydrating agent under microwave heating in the reaction of alkyl carboxylic acids with thiosemicarbazide <2000SC3031>. 

Tetraalkyl- or tetrasilyltetragallium(I) compounds were also obtained by the reactions of the dioxane adducts of Ga2X4 (X = Cl, Br) with bulky alkyl- or silyllithium compounds [Eq. (5)], which were accompanied by disproportionation of Ga(+2) to Ga(+1) and Ga(+3) [44, 45], In particular the yield of the alkyl derivative 21 was very poor and several unknown byproducts were detected by NMR spectroscopy. Furthermore, the reaction requires the employment of a solvent-free lithium compound, which is not readily available. The reaction of tris(trimethylsilyl)silyl lithium yielded the expected product of the disproportionation [(Me3Si)3Si]2GaCl2Li-(THF)2 besides compound 11. 

To demonstrate the catalytic efficiency of thiourea 9 and urea 16 (each 10mol% loading), Friedel-Crafts alkylation of various aromatic and heteroaromatic substrates was performed at room temperature in toluene as well as under solvent-free conditions. The results for the products 1-7 shown in Scheme 6.6 revealed that in all cases the 9-catalyzed reactions gave higher yields. In toluene N-methylpyrroIe reacted smoothly to give the 2-substituted Friedel-Crafts adduct 1, while the adducts 3-5 and 7 formed slowly and required longer reaction times (72 h). The... 

A similar rapid microwave one-pot synthesis of substituted quinazolin-4-ones was also reported, which involved cyclocondensation af anthranilic acid, formic acid (or an orthoester) and an amine under solvent-free conditions (Scheme 3.37)61. A complimentary approach was adopted to synthesise 4-aminoquinazolines in very good yields, involving the reaction of aromatic nitrile compounds with 2-aminobenzonitrile in the presence of a catalytic amount ofbase (Scheme 3.38)62. The reactions were performed in a domestic microwave oven and required only a very short heating time. A microwave-assisted synthesis of a variety of new 3-substituted-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters has also been described (Scheme 3.38)63. 

The Leuckart reductive animation of carbonyl compounds with ammonium formate or formamide was found to benefit strongly, when the reaction was carried out under solvent free conditions with microwave irradiation. Yields of N-alkylated formamides of up to 97% were produced in reaction times of about 30 min, as compared to thermal... 

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