Academic thesis for obtaining the master's degree M. Sc))
Chemistry group - organic chemistry trend
Green synthesis of fused 2-phenylimidazoles using ionic liquid
Imidazoles are an important group of heterocyclic compounds that have various biological and medicinal activities such as anti-hypertensive, anti-cancer, anti-HIV, antibacterial and pain reliever. In this thesis, new derivatives of 2-phenylimidazole were synthesized using different derivatives of salicylic acid and naphthalene-3,2-diamine or 2,1-diaminobenzene, using ionic liquid and with good yields (68-87%). Keywords: 2-phenylimidazole, salicylic acid, naphthalene-3, 2-diamine, 2,1-diaminobenzene, ionic liquid
Chapter One
Introduction and theory
1- Introduction
Nitrogen-containing heterocyclic compounds are of great historical importance due to their biological and medicinal effects. Since the synthesis of new derivatives of imidazoles has been carried out in this thesis, we will briefly introduce imidazoles and their synthesis methods.
1-1 imidazole
Among five-membered heterocycles with two heteroatoms, imidazole having two nitrogen atoms, one of which is similar to pyridine nitrogen and the other is similar to nitrogen is pyrrole, in terms of properties, it is considered similar to both of these compounds [1].
This compound is stronger than pyrazole and pyrrole base, and due to the easy transfer of hydrogen on the nitrogen atoms of positions 1 and 3, it has two tautomeric forms that are quickly converted to each other (Figure 1-1) [2]
(images are available in the main file)
The imidazole ring can form a bispheric structure by establishing a hydrogen bond, which leads to a much higher boiling point than its similar heterocyclic compound such as pyrrole (256 oC compared to 187 oC) (Figure 2-1).
Figure 1-2 Hydrogen bond in imidazole
Regarding imidazole reactions, it can be said that nucleophilic substitution reactions mainly take place in the position of two imidazole rings, and nucleophilic substitution in other positions depends on specific reaction conditions, including the presence of activating substituents or high temperatures. Also, the electrophilic substitution reaction is mostly carried out in position 4 or 5 (Figure 3-1) [3]. Small heterocycles have a vital role in the functioning of macromolecules in living systems. For example, imidazoles are very valuable in medical and pharmaceutical research because the structure of many drugs is based on the imidazole skeleton. Among them, we can name anti-allergic compounds [1], anti-parasitic [2], anti-cancer [3], anti-blood pressure [4] and pain relievers [5]. Figure 1-4 shows the structure of some examples of them [4-7].
Figure 1-4 of the structure of a number of imidazoles with medicinal properties
In addition to the synthetic methods of preparing imidazoles, these compounds can also be found in natural compounds. Among them, we can mention the bioactive bromopyrrole alkaloids [6] such as auroidine [7] (4) and stheonsine [8] (5), which are isolated from sea sponges (Figure 5-1) [8]. Substitution
1-2-1-1 synthesis of monosubstituted imidazoles with:
1-2-1-1-1 copper iodide catalyst
In this investigation, the coupling reaction of aryl iodide 6 with imidazole (7) in the presence of copper iodide catalyst with tetrazole acetic acid ligand, disolvent Methylformamide and sodium hydroxide were used to obtain imidazole derivatives 8 in 12 hours with a yield of 35-92% (Scheme 1-1) [9].
Scheme 1-1 of the synthesis of monosubstituted imidazole derivatives with copper iodide catalyst
1-2-1-1-2 pie pyridine
from the one-pot and three-component reaction of imidazole (7), aromatic aldehydes and pie pyridine (9) with molar ratio 1:2:3 in toluene solvent, imidazole monoacetyl derivatives 10 were synthesized with 81-86% yield (Scheme 2-1). In this directional reaction, substitution at the position of two imidazole rings indicates the presence of an imidazolium ylide intermediate, but normally, during Mannich-like substitution [9], the substituted imidazole product is expected at position 4 or 5 [10]. Amine
To obtain the basic structure of a group of drugs with dual antifungal and antibacterial effects, bisimidazoles 14 and 17 were synthesized from a two-step reaction. First, propene products 13 and 16 were produced from the reaction of arylmethyl ketone 11 or thionylmethyl ketone 15 with dimethylamine 12 in the presence of acetic acid, and then by adding imidazole (7) to them in ethanol, the expected bisimidazoles were obtained. This reaction using microwave conditions is of interest from a qualitative point of view (Scheme 1-3) [11].
Scheme 1-3 Synthesis of monosubstituted imidazole derivatives with dimethylamine
1-2-1-1-4 carbon disulfide
Monosubstituted imidazole derivatives 20 were synthesized during a two-step reaction. First, from the reaction of substituted anilines 18 with ammonium thiocyanate in bromine and acetic acid, thiocyanate compound 19 was produced, and then from its reaction with ethylenediamine in carbon disulfide, the desired products were obtained (Scheme 1-4) [12].
Scheme 1-4 Synthesis of monosubstituted imidazole derivatives with carbon disulfide
1-2-1-1-5 thiophene-2-carboxylic acid
In a two-step reaction for the synthesis of imidazole substituted with a thiophene ring, first the reaction of thiophene-2-carboxylic acid (21) with ethylenediamine (22) was used, which obtained the imidazole compound 23 with a yield of 84%, and then by placing compound 23 in the vicinity of palladium carbon In reflux with diphenyl oxide, in a short period of time, 2-(thionyl-2)imidazole 24 was synthesized with good yield (Scheme 1-5) [13].
1-2-1-2-1 glyoxal
From the reaction of glyoxal 25 and ammonium acetate in water solvent and ultrasonic conditions, (4 or 5)-aryl-2-arylyl-(H1)-imidazole derivatives 26 and 27 were synthesized with 72-95% yield (Scheme 6-1). Gibbs free energy calculations about these two products showed a higher thermodynamic stability in isomer 26.
Scheme 1-6 Synthesis of imidazole disubstituted derivatives with glyoxal
The proposed mechanism of this reaction is that the intermediate 28 is formed from the attack of aldimine on another aldimine molecule with the removal of a water molecule, which produces compound 29. According to the path A and B, after hydrogen displacement 1 and 5, compounds 26 and 27 are produced respectively (Scheme 1-7) [14].
Scheme 1-7 Synthesis mechanism of imidazole disubstituted derivatives with glyoxal
1-2-1-2-2 ?-hydroxy ketone
during the reaction According to [10], from the two-component reaction between form.amide (30) and ?-hydroxyketone 31 with a ratio of (2:1), disubstituted imidazoles 32 were synthesized with suitable yield (Scheme 1-8) [15].
Scheme 1-8 Synthesis of disubstituted imidazole derivatives with ?-hydroxyketone
1-2-1-2-3 2-bromo-1-arylethanone
From the two-component reaction of amide 33 and 2-bromo-1-arylethanone 34 under microwave conditions and with the catalyst of triethylbenzylammonium chloride, disubstituted imidazoles 35 were produced in 3-5 minutes (Scheme 1-9) [16].
Scheme 1-9 of the synthesis of imidazole disubstituted derivatives with 2-bromo-1-arylethanone
One of the advantages of this method is the short reaction time due to the use of microwave conditions.