New calcineurin inhibiting 3-dimethylaminopropyl substituted diarylheterocycles by sonogashira reactions and catalytic hydrogenation

Abstract

A series of calcineurin inhibiting compounds 1 consisting of a central aromatic N‐heterocycle, two aryl substituents and a 3‐dimethylaminopropyl chain was synthesized by introduction of the side chain. A corresponding haloheterocycle 3 was transformed into a 3‐dimethylaminopropynylheterocycle 2 by Sonogashira coupling and was in turn hydrogenated in the presence of Pd/C to afford the 3‐dimethylaminopropyl‐sub‐stiuted heterocycles 1. Some of the products showed calcineurin inhibiting activity.

Transition metals in organic synthesis: Highlights for the year 2005

“…Iron catalyzed the formation of 1,5-dihalo-1,4-dienes, ␣,␤-unsaturated ketones, or cyclic ethers from aldehydes and alkynes (Eqs. (175) and (176)) [933]. Copper catalyzed a coupling of imines, acid chlorides and organotin reagents (Eq.…”

“…(14)) [18]. (14) Heterocyclic ring systems were shown to readily participate in Sonogashira-type couplings [175,306]. Some more complex examples include reaction of 5-iodoarabinosyluridine [307], 3-iodofuran [308], 6-chloro-9H-purine [309], 8-bromoadenosine [310], 2,6-bis(4-iodopyrazol-1-yl)pyridine [311], 6-chloro-3H-pyrimidin-4-one [312], bromo-oxabicyclo[3.2.1]octadienes [28], a triazolopyrazinyl bromide [172], 5-trifloxyindoles [29], 5-bromobenzofuran [183], 3-iodo-5-bromoindole and 3-iodo-5-bromo-3-indazole [182], 7-bromo-pyrido [2,3-b]pyrazine [185], 5-iodo-1,2,3-triazoles [186,313], 4,5-diiodoimidazole [314] and 4-iodo-2-bromoquinoline [315] derivatives.…”

“…(10) A large variety of functionalized heterocyclic halides and sulfonates were employed in the palladiumcatalyzed Suzuki reaction. Heterocyclic ring-systems such as, bromo-oxabicyclo[3.2.1]octadienes [28], 6-bromoimidazo[1,2-a]pyridine [174], 3,5-dichloropyrimidine and 3,5-dichloropyridine [175], 4,7-dibromo-2,1,3-benzothiazole with a 3-indolylboronic acid [176], halo-amino-pyridines, pyrazines and pyrimidines [154], chloropyrazines in a synthesis of botryllazines [14], 4-chloroquinoline-2-one [177], 3-trifloxypyrazole [178], 8-bromo-2 -deoxyguanosine [179], 2-chloro-2 -deoxyinosine [180], 6-halopurines [30], 6-fluoro-, 6-(3-methylbutylsulfanyl)-, and 6-(3-methylsulfonyl)purine [181], 5-trifloxyindoles [29], 3-iodo-5-bromoindole [182], 4-bromobenzofuran [183], 5,7-dichloro-1,6-naphthyridin-2-(1H)-one [184], 7-bromo-pyrido [2,3-b]pyrazine [185], 5-iodo-1,2,3-triazoles [186], 3-bromo-2,5-dihydrofuran-2-one [187], 3-halo-indazoles [188,189], 3-chloro-2-pyrazolines and 3-chloro-1-phenyl-1,4,5,6-tetrahydropyridazine [190] and 3-iodo-4H-chromen-4-one [191] were used in Suzuki type cross-couplings. Regioselective coupling in the 4-position of 3-bromo-4-trifloxyquinolin-2(1H)-one [192], the 2-position of di-and tribrominated pyrroles [193] and the 3-position of 3,5-dichloropyrazin-2-ones [194] were reported.…”

Five‐Membered Heterocycles: 1,2‐Azoles. Part 1. Pyrazoles

“…Ultrasound irradiation using N-halosuccinimides [324], N-iodosuccinimide [325] and a mild and efficient method for the regioselective iodination of pyrazoles have been reported [326]. 8.5.1.2.5 Acylation: Vilsmeier-Haack and Friedel-Crafts reactions 1-Substituted pyrazoles are formylated and acetylated at C4.…”

“…This is a field of growing importance related to Suzuki, Miyaura, Sonogashira [325] and other cross-coupling reactions. Examples of C-arylation [52,54,154,336], Calkylation [154,159] and C-alkynylation [325,337,338] have been reported.…”