2-Imidazoline

Synthesis

A variety of routes exist for the synthesis of imidazolines, with the most common methods involving the condensation of 1,2-diamines (e.g. ethylenediamine) with nitriles or esters. The nitrile based route is essentially a cyclic Pinner reaction; it requires high temperatures and acid catalysis and is effective for both alkyl and aryl nitriles.

As natural products

Imidazoline has been found in various natural products. Natural molecules topsentin D and spongotine B were discovered in several marine sponges. These metabolites have received considerable attention because of their potent properties such as antitumor, antiviral, and anti-inflammatory activities.

Biological role

Many imidazolines are biologically active. Most bio-active derivatives bear a substituent (aryl or alkyl group) on the carbon between the nitrogen centers. Some generic names include oxymetazoline, xylometazoline, tetrahydrozoline, and naphazoline.

Applications

Pharmaceutical

2-imidazolines have been investigated as antihyperglycemic, anti-inflammatory, antihypertensive, antihypercholesterolemic, and antidepressant reagents. The imidazoline-containing drug clonidine is used alone or in combination with other medications to treat high blood pressure. It is also used in the treatment of dysmenorrhea, hypertensive crisis, Tourette's syndrome and attention deficit hyperactivity disorder (ADHD).

File:Clonidine.png|Clonidine File:Example_of_imidazoline_as_catalyst.png|Biimidazoline ligands and a complex. File:Grubbs_catalyst_Gen2.svg|Second generation Grubbs' catalyst File:Spongotine B.png|Spongotine B

As p53 activators

Cis-imidazolines act as small-molecule antagonists of MDM2. These compounds bind MDM2/X in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice. The most active compounds are nutlin-3a and rg-7112, but some other analogs also activate p53.

Surfactants

Surfactants based around 2-imidazoline, such as sodium lauroamphoacetate, are used in personal care products where mildness and non-irritancy are particularly important (e.g. baby products, "no more tears" shampoos etc.).

As precursors of imidazoles

Imidazoles can be prepared from dehydrogenation of imidazolines.

Homogeneous catalysis

As a structural analogue of 2-oxazolines, 2-imidazolines have been developed as ligands in coordination chemistry. The substitutions on the nitrogen atom in the imidazoline ring provide opportunities for fine-tuning the electronic and steric properties. Some of the complexes function as catalysts for Suzuki–Miyaura couplings, Mizoroki–Heck reactions, Diels–Alder reactions, asymmetric allylic substitution, [3,3] sigmatropic rearrangement, Henry reactions.

References

References

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6. (October 2008). "Clonidine". Pubmed Health.
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8. (May 2013). "Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development". ACS Medicinal Chemistry Letters.
9. (December 2021). "Sulfonamide derivatives of cis-imidazolines as potent p53-MDM2/MDMX protein-protein interaction inhibitors". Medicinal Chemistry Research.
10. (August 2019). "2,4,5-Tris(alkoxyaryl)imidazoline derivatives as potent scaffold for novel p53-MDM2 interaction inhibitors: Design, synthesis, and biological evaluation". Bioorganic & Medicinal Chemistry Letters.
11. (April 2022). "Synthetic Design and Biological Evaluation of New p53-MDM2 Interaction Inhibitors Based on Imidazoline Core". Pharmaceuticals.
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13. (2006). "An Efficient Preparation of 2-Imidazolines and Imidazoles from Aldehydes with Molecular Iodine and (Diacetoxyiodo)benzene". Synlett.