Stepwise aromatic nucleophilic substitution in continuous flow. Synthesis of an unsymmetrically substituted 3,5-diamino-benzonitrile library
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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.
KeywordsContinuous flow chemistry Nucleophilic substitution Enhanced parameter space Fluorine–amine exchange
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- 8.Darvas F, Dormán G, Lengyel L, Kovács I, Jones R, Ürge L (2009) High pressure, high temperature reactions in continuous flow. Merging discovery and process chemistry. Chim Oggi 27: 40–43Google Scholar
- 9.Razzaq T, Glasnov TN, Kappe CO (2009) Continuous flow microreactor chemistry under high temperature/pressure conditions. Eur J Org Chem 1321–1325. doi: 10.1002/ejoc.200900077
- 12.Simplex Pro is a product of Compudrug Ltd., Sedona, AZ, USA. http://www.compudrug.com
- 13.Hiroyuki N, Satoru O, Atsumi Minami R, Mochizuki M, Hirotani M, Kumazawa K, Eiji E (2005) Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. III. synthesis and antitumor activity of 3-phenylpiperazinyl-1-trans-propenes. Chem Pharm Bull 53: 153–163. doi: 10.1248/cpb.53.153 CrossRefGoogle Scholar
- 14.Tehrani LR, Smith ND, Huang D, Poon SF, Roppe JR, Seiders TJ, Chapman DF, Chung J, Cramer M, Cosford NDP (2005) 3-[Substituted]-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitriles: identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonists. Bioorg Med Chem Lett 15: 5061–5064. doi: 10.1016/j.bmcl.2005.07.062 PubMedCrossRefGoogle Scholar
- 15.Poon SF, Eastman BW, Chapman DF, Chung J, Cramer M, Holtz G, Cosford NDP, Smith ND (2004) 3-[3-Fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine: a highly potent and orally bioavailable metabotropic glutamate subtype 5 (mGlu5) receptor antagonist. Bioorg Med Chem Lett 14: 5477–5480. doi: 10.1016/j.bmcl.2004.09.011 PubMedCrossRefGoogle Scholar
- 19.X-Cube FlashTM is a product of ThalesNano Inc, Budapest, Hungary, www.thalesnano.com