Synthesis of novel, highly reactive 1-oxyl-2,2,6,6-tetramethyl-1,2,5,6-tetrahydropyridine derivatives

Abstract

New multipurpose spin labels and synthons can be synthesizcd from I-oxyl-2,2,6,6-tetramethyl-l,2,5,6-tetrahydropyridine-4-carboxylic acid (1). Either 1, its pentafluorophenylester (2). or acylcarbonate (3) (prepared from 1 with ethyl chloroformatc) can be reduced to I-oxyl-2,2,6,6-tetramethyl-4-hydroxymeth I ,2,5,6-tetrahydropyridine (4). The methanesulfonate (6) and the bromo compound (7) are highly reactivc alkylating reagents due, in large part, to the allylic linkage in the nitroxide ring. Thc latter can be reacted with KSS02CH1 to givc methanethiolsulfonate (9). A novel side chain spin-labelled a-amino acid ester (11) is made by a phase-transfer alkylation of a Schiff basc with 7. Compound 11 can be coupled with the protected L-phenylalanine in the presencc of dicyclohcxylcarbodiimide (DCC) to producc the nitroxide dipeptide (12).JOZSEF CSEKO, H. OLGA HANKOVSZKY et KALMAN HIDEG. Can. J . Chem. 63, 940 (1985).On peut synthttiser de nouveaux synthons et de nouveaux marqueurs de spin a usage multiple ii partir de I'acide oxyl-l tCtramCthyl-2,2,6,6 tttrahydro-I ,2,5.6 pyridinecarboxylique-4 (1). On peut rkduire soit le composC 1, soit son ester pentafluorophCnyle (2) ou son acylcarbonate (3) (que I'on peut prkparer ii partir de 1 par reaction avcc Ic chloroformate d'Cthyle) en oxyl-l tdtramCthy1-2,2,6,6 hydroxyrndthyl-4 tCtrahydro-1,2,5.6 pyridinc (4). Le mCthanesulfonate (6) ainsi que le dCrivC bromC (7) sont des reactifs alkylants trks rkactifs ii causc, en grandc partie, de la liaison allylique dans le cycle nitroxyde. On peut faire rCagir le dCrivC bromC avec le KSS02CH3 pour obtenir lc mCthanethiosulfonate 9. On a prCparC le nouvel ester 11 d'un acidc a-aminC portant un marqueur de spin sur la chaine IatCrale cn cffectuant unc alkylation par transfert de phase d'une base de Schiff par le composC 7. Dans Ic but d'obtenir le nitroxyde dipeptide (12), on peut coupler Ic composC 11 avec une L-phinylalanine en prksence dc dicyclohexylcarbodiimide (DCC).[Traduit par le journal] Introduction Reactive functional groups attached to stable nitroxide free radicals have been used as spin labels for studying biomolecules in recent decades (1). The most frequently used types of nitroxides are the pyrroline-the pyrrolidine-, and the piperidine-N-oxyls:

Recent results in chemistry and biology of nitroxides

“…This is a key intermediate in nitroxide chemistry, because this is the parent compound of all piperidine nitroxides via borohydride reduction [22] and all 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine nitroxides via cyanohydrine formation [34] followed by elimination to give compound (5b). This nitrile derivative can be converted further to aldehyde (5c), carboxylic acid (5d) and allylic bromide (5e) [35]. Although piperidine nitroxides are cheaper and they are more widely used in polymer chemistry and in organic chemistry as co-oxidants than pyrroline or pyrrolidine nitroxides, their stability is smaller towards putative reducing agents such as thiols and ascorbates [36].…”

“…The β-bromo-α,β-unsaturated aldehyde 13d was found a very valuable key compound: the treatment with sodium salt of n-butyl glycolate gave 4,4,6,6-tetramethyl-4,6-dihydro-5H-furo[2,3-c]pyrrole compound (35) [55]. The Suzuki cross-coupling of 13d with phenylboronic acid followed by oxidation with Ag 2 O to 36 carboxylic acid allowed us a more simple approach to β-substituted-α,β-unsaturated paramagnetic acids.…”

Synthesis and functional survey of new Tacrine analogs modified with nitroxides or their precursors

“…In order to alkylate the amino-group of Tacrine ( 1b ) [14] it was condensed with aldehydes 2 [15] and 3 [16] in toluene in the presence of piperidine to result in a Schiff-base, which was reduced with lithium aluminum hydride in THF to offer compounds 4b and 5 . Treatment of 9-chloro-1,2,3,4-tetrahydroacridine 6 [17] with five equivalents of piperazine in refluxing pentanol offered compound 7 , a key intermediate, which could be alkylated easily on secondary amine with a paramagnetic allylic bromide 8 [18] to offer compound 9b .…”

“…Qualitative TLC was carried out on commercially available plates (20 × 20 × 0.02 cm) coated with Merck Kieselgel GF 254 . Triacetonamine, 1,2,2,6,6-pentamethylpiperidone, 1-methyl piperidone, compound 14 , Tacrine and all other chemicals were purchased from Aldrich, compound 2 [15], 3 [16], 6 [17], 8 [18], 11 [19], 18 [23] were prepared as described earlier.…”

Synthesis and study of 2-amino-7-bromofluorenes modified with nitroxides and their precursors as dual anti-amyloid and antioxidant active compounds

“…Qualitative TLC was carried out on commercially available plates (20 × 20 × 0.02 cm) coated with Merck Kieselgel GF 254 . TEMPOL and all other chemicals were purchased from Aldrich, compound 2a [20], 2b [21], 2c [22], 2d [23] and KO-162 [4] was prepared as described earlier.…”