Phase Transfer Catalyzed Dialkylation of Sterically Hindered Arylacetonitriles

Michał Fedoryński ,  Tomasz Wojciechowski 

Warsaw University of Technology, Faculty of Chemistry, Koszykowa 75, Warszawa 00-662, Poland

Abstract

Phase transfer catalysis (PTC) seems to be the most general, efficient and environment friendly methodology of performing reactions in which organic anions (particularly carbanions) react with organic substrates[1]. PT catalyzed reactions are carried out in two phase systems containing two mutually immiscible phases. One phase (inorganic) is a source of base for generation of carbanions. The second (organic phase) contains organic reactants, usually neat or sometimes in appropriate solvent. Upon the introduction of a catalyst - tetraalkylammonium (TAA) salt - continuous transfer of reacting anions produced in the interfacial region, into the organic phase in the form of lipophilic ion pairs with the catalyst cation takes place. All the further reactions occur in the organic phase.

It is well established that the monoalkylation of arylacetonitrile carbanions with primary alkyl bromides carried out in the presence of 50% aqueous sodium hydroxide and TAA catalyst results in high yields. However under these conditions the yields of reactions with sec-alkyl bromides seldom exceed 50%, introduction of the second alkyl group to the 2-arylalkanenitriles proceeds with difficulty, yields of 1-aryl-1-cyanocyclobutanes in reactions with 1,3-dibromopropane are low and finally cyclopropanation of phenylacetonitrile with 1,2-dichloro- or 1,2-dibromoethanes does not proceed - dehydrohalogenation of the dihaloalkane is the only observed process. Such alkylations are often important steps in the syntheses of biologically active compounds (Verapamil, Sibutramine, Anastrozole etc.).

In all the cases mentioned, a simple replacement of 50% sodium hydroxide solution for 60-75% potassium hydroxide results in a significant increase of the yields and purity of products or allows the reaction to proceed[2,3].

Now we found that sterically hindered arylacetonitriles, for instance 2-bromophenylacetonitrile, can be efficiently dialkylated using alkyl bromide in the presence of TAA salt and concentrated aq. KOH solution. An example is given below.

Such reactions occur very slowly or not at all when carried out in the presence of concentrated NaOH solution. A possible explanation of the facts presented above involves a kinetic effect, since for more concentrated solutions of hydroxides alkylation proceeds much faster and dominates over side reactions.

2-(2-Bromophenyl)-2-propylpentanenitrile (1) is an important intermediate in the synthesis of benzocyclobutenones, which in turn are powerful synthetic intermediates in organic synthesis, leading to lactones, lactams, cyclopentanones, benzodiazepines etc. [4].

References:

1. M. Mąkosza, M. Fedoryński, Current Catal., 1, 79 (2012); M. Fedoryński, Przem. Chem., 89, 1428 (2010); M. Mąkosza, M. Fedoryński, Catal. Rev., 45, 321 (2003); M. Fedoryński, Chem. Rev., 103, 1099 (2003).

2. M. Barbasiewicz, K. Marciniak, M. Fedoryński, Tetrahedron Lett., 47, 3871 (2006).

3. M. Fedoryński, M. Jezierska-Zięba, B. Kąkol, Przem. Chem.88, 872 (2009).

4. R. Martin, A. Flores-Gaspar, Org. Synth., 89, 159 (2012).

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Presentation: Oral at IX Multidyscyplinarna Konferencja Nauki o Leku, by Michał Fedoryński
See On-line Journal of IX Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2014-03-25 21:22
Revised:   2014-05-02 19:06
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