Aromatic Ring Strain in Arylselenenyl Bromides: Role in Facile Synthesis of Selenenate Esters via Intramolecular Cyclization

Abstract

The synthesis and reactivity of 2,6-disubstituted arylselenium compounds derived from 2-bromo-5-tert-butylisophthalic acid (43) are described. The syntheses of bis(5-tert-butylisophthalic acid dimethyl ester)diselenide (46) and bis(5-tert-butylisophthalic acid diisopropyl ester)diselenide (47) have been achieved by the reaction of the corresponding ester precursors with disodium diselenide. Reduction of diselenide 46 with lithium aluminum hydride affords 2,2'-bis(5-tert-butylbenzene-1,3-dimethanol)diselenide (53). Diselenides 46 and 47 exhibit intramolecular Se...O interaction. Compound 53 does not show any intramolecular Se...O interaction. The anomalous Se...O nonbonded coordination observed in the single-crystal X-ray structures of compounds 46, 47 and 53 is compared and contrasted. The corresponding selenenyl bromides 54 and 55, derived from the reaction of diselenides 46 and 47 with bromine, are quite stable in the solid state. However, they undergo hydrolysis and subsequent intramolecular cyclization upon heating or after having been kept in solution over a period of time to give the corresponding selenenate esters 56 and 57. The X-ray crystallographic study and density functional theory calculations on 54 at the B3LYP/6-31G(d) level of theory indicate a significant distortion in planarity of the aromatic ring. Glutathione peroxidase-like activities of diselenides 46 and 47 and their selenenate esters 56 and 57 have been studied both by thiophenol and bioassay methods. The very low glutathione peroxidase-like activity of the diselenides (46 and 47) and their selenenate esters (56 and 57) in the thiophenol assay is attributed to the presence of the relatively strong Se...O intramolecular interaction in the selenenyl sulfide intermediates. The interaction retards the catalytic activity through both thiol exchange and an intramolecular cyclization reaction.

Synthesis, Structure, and Glutathione Peroxidase‐Like Activity of Amino Acid Containing Ebselen Analogues and Diaryl Diselenides

“…Also, it has been known that the resultant arylselenenyl halides undergo facile intramolecular cyclization reaction with a reactive functionality present at the ortho position 37. 38 Hence, we thought, it could be a better approach to get the desired ebselen analogue 34 (method II, Scheme ). The reaction of n BuSeLi with the aryl halides 31 and 32 resulted in the formation of the unsymmetrical monoselenides 35 and 36 , respectively, in 27 % yield.…”

“…The required precursor diselenide 38 was obtained from 37 40. Compound 37 was prepared by using a reported procedure 38. The reaction of diselenide 38 with glycine methyl ester hydrochloride by using the DCC coupling procedure afforded the desired glycine derivative 34 in moderate yield (61 %).…”

“…This contrasting reactivity is essentially due to the presence of a aromatic ring strain in 2,6‐disubstituted aryl selenium systems 25b. 38 The strain is resulting from the intramolecular coordination and steric crowding around the selenium center 38…”

Synthesis of alpha‐methyl selenocysteine and its utilization as a glutathione peroxidase mimic

“…However, ebselen is not water soluble, making rapid intravenous administration impossible, and has shown cellular toxicity in some studies . Other selenium‐containing GPX mimics have been synthesized, and some have potent GPX‐like activity including cyclic seleninate and selenenate esters, spirodioxyselenuranes, pincer selenuranes, and spirodiazaselenuranes . However, many of these compounds are expected to be toxic, are not water soluble, are unstable, or quickly lose catalytic activity in the presence of thiols …”

Organoselenium(ii) halides containing the pincer 2,6-(Me2NCH2)2C6H3ligand – an experimental and theoretical investigation

“…1,6 Examples include mainly organic groups with oxygen as a potential donor atom in the pendant arm, e.g. the diselenides such as [2,6- 20 or [2,6-{MeOCH(Me)} 2 C 6 H 3 ]SeOTf. 21 Compounds based on the asymmetric ligand 2-NO 2 -6-(PhNvCH)C 6 H 3 were also reported recently.…”