Stepwise aromatic nucleophilic substitution in continuous flow. Synthesis of an unsymmetrically substituted 3,5-diamino-benzonitrile library

Aromatic or heteroaromatic ring precursors with 2–3 identical functionalities are often used in sequential derivatization depending on the reactivity difference or the selective execution of the reaction such as nucleophilic aromatic substitution. Continuous flow chemistry offers an enhanced paramet...

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Bibliographic Details
Published in:Molecular diversity 2011-08, Vol.15 (3), p.631-638
Main Authors: Lengyel, László, Gyóllai, Viktor, Nagy, Tamás, Dormán, György, Terleczky, Péter, Háda, Viktor, Nógrádi, Katalin, Sebők, Ferenc, Ürge, László, Darvas, Ferenc
Format: Article
Language:English
Subjects:
Biochemistry
Biomedical and Life Sciences
Catalysis
Chemical reactions
Chemical reactors
Chemical synthesis
Chemistry - methods
Combinatorial Chemistry Techniques - methods
Full-Length Paper
Life Sciences
Nitriles - chemistry
Organic Chemistry
Pharmacy
Polymer Sciences
Small Molecule Libraries
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Summary:Aromatic or heteroaromatic ring precursors with 2–3 identical functionalities are often used in sequential derivatization depending on the reactivity difference or the selective execution of the reaction such as nucleophilic aromatic substitution. Continuous flow chemistry offers an enhanced parameter space (pressure and temperature) with rapid parameter optimization that ensures selectivity in many cases. We developed a flow chemistry procedure to carry out a stepwise aromatic nucleophilic substitution of difluoro-benzenes having an activating group in meta position to the fluorines. The mono-aminated products were obtained in high yield and selectivity in an extremely short reaction time, while applying higher temperature, longer reaction zone (or time), and employing higher excess of another amine reactant, the subsequent introduction of the second amino group was also successfully achieved leading to an unsymmetrically substituted 3,5-diamino-benzonitrile library.
ISSN:1381-1991
1573-501X
DOI:10.1007/s11030-010-9300-3