Author: Rita Mažeikaitė
Dissertation title: Search for synthetic methods of compounds containing thiophene, indole and pyrazole framework
Fields of science: Physical sciences, Chemistry (03P)
Scientific supervisor: dr. Linas Labanauskas
Defence of the dissertation: 2015-06-26
Compounds containing thiophene, indole and pyrazole framework often possess important properties that are widely applied in practice. Substituted thiophene derivatives containing electron-withdrawing substituents and pyrazole complexes with metals represent classes of active optical materials, such as organic light emitting diodes. Moreover, thiophene, indole and pyrazole frameworks can be often found in various biologically active compounds. For example, some time ago, a non-selective histone deacetylase inhibitor (HDAC) Panobinostat (LBH-589) bearing indole moiety and hydroxamic acid functionality was developed. Synthesis of functionally substituted thiophene, indole and pyrazole derivatives is a highlighting task, since this modification opens possibility for construction of new heterocyclic systems.
In these investigations we put our attention on the development of efficient synthetic methods for preparation of 2,3-disubstituted thiophenes, substituted 3-[4-(piperazin-1-yl)butyl]-IH-indoles and 3-substituted pyrazoles. First, we envisioned three main problems associated with the synthesis of these classes' compounds and their plausible solutions:
I. 2,3-Disubstituted thiophenes are usually synthesized from 3-halogeno-2-substituted thiophene derivatives obtained by modification of the 2m! thiophene ring position of corresponding 3-substituted thiophenes. But it should be noted that this methodology is not very selective and sometimes modification at the 5th position takes place. Having an ortho orienting group at 3rd position of thiophene ring, a selective modification of the second position becomes possible by direct lithiation. Synthesis of 2,3-disubstituted thiophenes from 2-halogenothiophene derivatives by protecting the 5th position and then selective introduction of nitro functional group at 3n.t position, looks much more acceptable and allows further modification of both 2nd and 3th positions of thiophene ring.
2. 3-[(Piperazin-l-yl)alkyl]-IH-indole derivatives are often synthesized by modification of mono-substituted piperazine with IH-indol-3-yl-alkyl halides, mesylates or tosylates. But availability of mono-substituted piperazine derivatives is limited and their synthesis is rather complicated. Our main focus was in 3-[4-(piperazin-1-yl)butyl]-lH-indole derivatives, because of not only for their structural similarity to Panobinostat (LBH- 589), but also the synthesis of 3-[(piperazin-l-yl)alkyl]-IH-indoles with longer than propyl chain is not fully investigated. Thus, we chased commercially available 4-(lH
indol-3-yl)butanoic acid as starting material for the synthesis of 3-[4-(piperazin-1- yl)butyl]-lH-indole. And by further modification of free NH group of piperazine ring, higher variety of substituted 3-[4-(piperazin-1-yl)butyl]-lH-indole derivatives can be synthesized.
3. Electrophilic substitution ofpyrazole ring usually occurs at the 4th position. Thus, one of the most common approaches for the synthesis of 3-substituted pyrazoles is based on formation of the pyrazole ring via condensation reaction of substituted 1,3-dicarbonyl derivatives with hydrazine. Unfortunately, this method usually generates mixture of regioisomers and cause problems with isolation of products. Moreover, only limited number of dicarbonyl compounds are readily available. Another approach for the synthesis of 3-substituted pyrazoles is by transition metal catalyzed cross-coupling reactions of 3-halogcno or 3-organometalic pyrazole derivatives. 3-Br(Cl or I)-IH pyrazole derivatives are commercial available but very expensive and availability of 3-halogen-lH-pyrazole derivatives with substituents at the 4th or 5th positions is very limited due to their complicated synthesis. Pyrazoles readily fonn complexes with transition metals so before performing cross-coupling reactions of 3-halogeno-lH pyrazoles, it is necessary to protect free NH group. Thus, transition metal-catalyzed cross coupling reactions are usually carried out using N-alkyl-, N-ary! or N-benzylpyrazoles. We decided to find simple and effective method for the synthesis of 4- or 5-substituted 3-halo IH-pyrazoles protected by easy removable lert-butyloxycarbonyl (Boc), 2-ethoxyethyl (EtOEt) or 2-tetrahydro-2H-pyranyl (THP) groups, because it can open possibilities for the synthesis of substituted pyrazoles with free NH group.