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Ferrocenoyl‐Substituted Pyrimidine Nucleobases: An Experimental and Computational Study of Regioselective Acylation of Uracil, Thymine, and 5‐Fluorouracil
Author(s) -
Lapić Jasmina,
Havaić Valentina,
Šakić Davor,
Sanković Krešimir,
Djaković Senka,
Vrček Valerije
Publication year - 2015
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201500647
Subject(s) - chemistry , nucleobase , uracil , thymine , pyrimidine , regioselectivity , proton nmr , dimethylformamide , acylation , deprotonation , nuclear magnetic resonance spectroscopy , nucleophile , stereochemistry , medicinal chemistry , organic chemistry , catalysis , dna , biochemistry , solvent , ion
Uracil, thymine, and 5‐fluorouracil (5‐FU) have been ferrocenoylated selectively at the N 1 position. Deprotonated pyrimidine nucleobases, prepared with sodium hydride (NaH) in N , N ‐dimethylformamide (DMF), reacted with either ferrocenoyl chloride (FcCOCl) or ferrocenoyl ethyl carbonate (FcCOOCOOEt), in DMF to give a single product. The regioselectivity of these reactions were analyzed in detail by using NMR spectroscopy and quantum chemical calculations. The 1 H and 19 F NMR spectra of reaction mixtures, and 13 C NMR and 2D NOESY spectra of products, confirmed the formation of the N 1 ‐isomer only. The calculated energy barrier for acetylation at the N 3 ‐position is significantly higher (> 40 kJ/mol), which suggests that the analogous reaction at the N 1 ‐position is kinetically controlled. The nucleophilic addition of pyrimidine bases to the carbonyl group of FcCOCl proceeds through a concerted S N 2‐like mechanism with the absence of the generally assumed tetrahedral intermediate.