Aqueous N-Heterocyclization of Primary Amines and Hydrazines with Dihalides:  Microwave-Assisted Syntheses of N-Azacycloalkanes, Isoindole, Pyrazole, Pyrazolidine, and Phthalazine Derivatives

Abstract

[reactions: see text] The synthesis of nitrogen-containing heterocycles from alkyl dihalides (ditosylates) and primary amines and hydrazines via a simple and efficient cyclocondensation in an alkaline aqueous medium that occurs under microwave irradiation is described. This improved greener synthetic methodology provides a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles, such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted 2,3-dihydro-1H-isoindoles, 4,5-dihydropyrazoles, pyrazolidines, and 1,2-dihydrophthalazines.

Variation of the Backbone Conjugation in NLO Model Compounds: Torsion‐Angle‐Restricted, Biphenyl‐Based Push‐Pull‐Systems

“…While piperidine subunits are usually introduced as nucleophiles substituting a halide in an Ullmann-type coupling reaction, [47][48][49] double alkylation of arylamines and hydrazines with alkyl dihalides based on a microwave-assisted approach was reported recently. [50,51] Thus, the amino biphenyl 6a was treated with 1,5-dibromopentane and potassium carbonate as a base in a toluene/ ethanol (1:1) mixture at 150°C for 40 min in the microwave set-up. The desired 4-nitro-4Ј-piperidinyl-biphenyl (1a) was isolated in 40 % yield as an orange solid by CC.…”

“…To transform one of the two terminal amino groups of the model compound 3a into a piperidinyl substituent, a microwave-assisted double alkylation with 1,5-dibromopentane [50] was considered, [51] mainly due to its reported superior yields compared with thermally activated heterocyclization reactions of aniline derivatives. Following a reported protocol, [51] commercially available 4,4Ј-diaminobiphenyl (3a) was treated in the microwave reactor with 1,5-dibromopentane in water with potassium carbonate (K 2 CO 3 ) as a base. The desired monopiperidinyl derivative 7a was isolated in a poor yield of only 10 % and the formation of a black tar at the bottom of the reaction vessel, probably arising from the large amount of undissolved starting material was observed.…”

Solvent Free N-Heterocyclization of Primary Amines to N-Substituted Azacyclopentanes Using Hydrotalcite as Solid Base Catalyst

“…8,9 However, this method is not industrially viable due to use of equimolar quantity of homogeneous base catalyst (K 2 CO 3 ) in aqueous medium generating huge amount of alkaline waste and difficult handling of microwave reaction system for large scale production. Therefore, it is of great interest to develop economically viable and environmentally more benign synthetic route for Nheterocyclization/di N-alkylation to synthesize N-substituted azacycloalkanes.…”

5-Membered N-heterocyclic compounds by dimethyl carbonate chemistry

“…5 In recent years, more sustainable approaches for the synthesis of N-based heterocycles have been reported, 6 such as photocatalytic cyclisation of a,w-diamine carboxylic acids by aqueous semiconductor suspensions 7 and microwave-assisted synthesis from alkyl dihalides and primary amines. 8 However, most of the above-mentioned reactions still require high temperature and long reaction time, utilize chlorine-based chemistry or eventually organic chlorinated solvents.Short chain dialkyl carbonates such as dimethyl carbonate (DMC), produced nowadays by clean processes, 10 are renowned for possessing properties of low toxicity and high biodegradability, which make them true green solvents and reagents. 11 DMC has been used as efficient eco-sustainable substitute of the most common methylating and carboxymethylating agents such as phosgene, methyl halides or methylsulfate that are toxic and highly corrosive.…”

“…5 In recent years, more sustainable approaches for the synthesis of N-based heterocycles have been reported, 6 such as photocatalytic cyclisation of a,w-diamine carboxylic acids by aqueous semiconductor suspensions 7 and microwave-assisted synthesis from alkyl dihalides and primary amines. 8 However, most of the above-mentioned reactions still require high temperature and long reaction time, utilize chlorine-based chemistry or eventually organic chlorinated solvents.…”