Betti reaction

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The Betti reaction (also Betti condensation ) is a name reaction in organic chemistry that was first described in 1900 and named after the Italian chemist Mario Betti (1875–1942). It is a special case of the Mannich reaction , a multicomponent reaction in which an aldehyde , an amine and a 2-naphthol react with elimination of water . The reaction product, the so-called Betti base, can e.g. B. can be used as a ligand and auxiliary in asymmetric syntheses .

Overview reaction

One of the original descriptions of the Betti reaction was a condensation reaction of at least one equivalent of benzaldehyde with ammonia and 2-naphthol. The reaction has now been successfully expanded so that other aldehydes, primary and secondary amines, and aromatic compounds with a hydroxyl group can also be used. The overview reaction shown here and the reaction mechanism below show the condensation of an aldehyde 1 (R 1 = alkyl or aryl group ) with a primary amine 2 (R 2 = alkyl or aryl group) and 2-naphthol 3 to form the Betti base 4 .

Betti reaction overview reaction V1.svg

Reaction mechanism

It is assumed that initially a reaction between the aldehyde 1 and the amine 2 takes place with elimination of water and formation of the imine 3 . A nucleophilic attack by the amine on the aldehyde takes place. After splitting off water, the imine is formed. The next reaction step is the reaction of the imine with 2-naphthol 4 , with the end product 6 , a β-naphtholalkylamine, being formed after the tautomerization of 5 .

Betti reaction mechanism V1.svg

application

In general, the Betti reaction offers a wide range of applications, since this reaction can be used to provide chiral ligands and auxiliaries in a cost-effective and economical manner . The Betti bases are versatile chemical building blocks that often have several stereocenters and are used in asymmetric synthesis. In addition, the Betti reaction is used in medical research. Specific applications are, for example, in the synthesis of isoniazid - derivatives that using the Betti reaction under mild, environmentally friendly conditions and high yields can be generated. In cancer research , the Betti reaction is also taken advantage of because, for over them. B. selective KDM4 inhibitors can be synthesized, which is of great importance for the therapy of breast tumors .

Individual evidence

  1. ↑ a b The Betti base: the awakening of a sleeping beauty . In: Tetrahedron: Asymmetry . tape 21 , no. 5 , March 30, 2010, p. 507-517 , doi : 10.1016 / j.tetasy.2010.03.020 .
  2. ↑ a b c d Zerong Wang: Betti Reaction . In: Comprehensive Organic Name Reactions and Reagents . John Wiley & Sons, Inc., Hoboken, NJ, USA 2010, ISBN 978-0-470-63885-9 , pp. 374-378 , doi : 10.1002 / 9780470638859.conrr082 .
  3. ↑ Cosimo Cardellicchio, Giuseppe Ciccarella, Francesco Naso, Emanuela Schingaro, Fernando Scordari: The Betti base: absolute configuration and routes to a family of related chiral nonracemic bases . In: Tetrahedron: Asymmetry . tape 9 , no. 20 , October 23, 1998, pp. 3667-3675 , doi : 10.1016 / S0957-4166 (98) 00379-6 .
  4. ↑ Jyotsna Meshram, Ipsita Mohanram: Design, synthesis, and evaluation of isoniazid derivatives acting as potent anti-inflammatory and anthelmintic agents via Betti reaction . In: Medicinal Chemistry Research . tape 23 , no. 2 , February 1, 2014, p. 939-947 , doi : 10.1007 / s00044-013-0693-2 .
  5. ↑ Stephanie Heyl: KDM4 as a point in triple negative breast cancer - Health Markets BW. Health Industry BW, December 11, 2017, accessed December 13, 2018 .
  6. ↑ Roland Schüle, Jochen Maurer, Toufike Kanouni, Jeffrey A. Stafford, Michael B. Wallace: KDM4 Inhibition Targets Breast Cancer Stem-like Cells . In: Cancer Research . tape 77 , no. 21 , November 1, 2017, p. 5900-5912 , doi : 10.1158 / 0008-5472.CAN-17-1754 , PMID 28883001 .
  7. ↑ CJ Schofield, A. Kawamura, PE Brennan, PJ Ratcliffe, CW Pugh: Betti reaction enables efficient synthesis of 8-hydroxyquinoline inhibitors of 2-oxoglutarate oxygenases . In: Chemical Communications . tape 51 , no. 84 , October 8, 2015, p. 15458-15461 , doi : 10.1039 / C5CC06095H .