Karbazol substıtüye 3,4-dihydropyrimidin-2(1h)-tion türevi bileşiklerin sentezi
Synthesis of carbazol substituted 3,4-dihydropyrimidine-2(1h)-thione deri̇vati̇ves
Yazar: FATİH KIRBAYIR
Danışman: PROF. DR. MUSTAFA ARSLAN
Sakarya Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı / Organik Kimya Bilim Dalı
Derece: Yüksek Lisans, 2024
Konu: Kimya = Chemistry
Dizin: Etil karbazol = Ethyl carbazole

Özet:
Karbazol aromatik bir bileşiktir. Benzofuran grubuna ait halka yapısına sahip bir kimyasal bileşik olması nedeniyle büyük ilgi görmüştür.  Karbazol, özellikle karbon ve hidrojen atomlarını içeren heterosiklik bir bileşik olarak tanımlanır.  Bu bileşik, endüstriyel uygulamalardan ilaç endüstrisine kadar çeşitli alanlarda kullanılan önemli bir organik bileşiktir.
Karbazol türevleri, farmakolojik aktiviteleri nedeniyle büyük ilgi çekici ve önemlidir. Eliptisin, Ochrosia elliptica ağacının yapraklarından izole edilen prido[3,4,-b]karbazol alkaloitidir ve önemli antitümör aktivite sergiler. Bu nedenle, prido[3,4,-b]karbazol bileşikleri bulunduran alkaloitlerin sentetik olan bileşiklerinin türevleri biyolojik açıdan oldukça önemli hale gelmiştir. İndolo[2,3-a]karbazol bulunduran alkaloit bileşikleri antibiyotik, antitümör, antifungal özelliklerinin yanında antimikrobiyel, hipotansif protein kinaz C, topoisomeraz I inhibitörü açısından oldukça geniş biyolojik aktivite potansiyeli gösterir. Piridopirimidin bileşikleri, heterosiklik bileşikler arasında önemli bir sınıftır. Birçok ilaçta bulunabilir ve antialerjik, antibakteriyel, antitümör, antiinflamatuar, antileişmanyak etkenleri, karbonik anhidraz (CA) enzim inhibisyonu ve polifenol oksidaz enzim inhibitörü gibi biyolojik aktiviteler sergilemiştir.
Karbazol bileşiğinden başlayarak dört aşamada hazırlanan karbazol substitüye 3,4-dihidropirimidin-2(1H)-tion türevi bileşiklerin sentezi gerçekleştirilmiştir. Sentez karbazoll bileşiğinin etillenmesi ve asetilasyonu ile başlar. Etilkarbazol bileşiğinin bazik ortamda etanol içinde şalkon eldesi ve elde edilen şalkon bileşiğine tiyoüre katılması ile hedeflenen bileşiklerin sentezi gerçekleşir. Yapısal analizler, 1H NMR, 13C NMR, MASS ve FT yöntemleriyle gerçekleştirilmiştir.
Karbazol bileşiği THF'de çözüldükten sonra KOT-Bu ve Bromo etan ilave edilerek oda sıcaklığında 5 saat karıştırıldı ve reaksiyon TLC ile izlendi ve gerekli saflaştırma işleminden sonra sentezlenen bileşik 1'in yapı analizi yapıldı. 13C NMR, 1H NMR spektrumları ile karakterize edildi.
9-Etilkarbazol (2) bileşiği alındı ve 30 ml DCM ile reaksiyon şişesinde çözüldü. Bizmit klorür eklendi. Reaksiyon karışımı bir buz banyosu içerisinde 0 oC dereceye kadar soğutuldu. Üzerine DCM solüsyonunda çözünmüş asetil klorür damlatıldı.
15 dakika daha buz banyosunda karıştırıldıktan sonra oda sıcaklığında 4 saat karıştırılmasına izin verildi. Reaksiyon tamamlandıktan sonra DCM çözeltisi ile çalışma yapıldı. Organik kısım ayrıldı ve DCM, buharlaştırıcıda çıkarıldı. 1H - NMR ve 13C - NMR spektrumlarına bakılarak bileşiğin saf olduğu belirlendi.
Bileşik (E)-3-(9-etil-9H-karbazol-3-il)-1-fenilprop-2-en-1-on (3) ve tiyoüre, reaksiyon şişesinde etanol içerisinde çözüldü. Karışıma potasyum karbonat ilave edildi ve 24 saat boyunca 80 oC geri akış altında karışmaya bırakıldı.
Reaksiyon tamamlandıktan sonra karışımın oda sıcaklığına soğumasına izin verildi. Reaksiyon ortamındaki etanol, düşük basınç altında buharlaştırıcıda çıkarıldı.
Geriye kalan katı kısım suda çözüldü ve 250 ml'lik bir behere yerleştirildi. İçine buz parçaları atıldı. Nötralizasyon normal HCl ile yapıldı. Ortaya çıkan katılar filtrelendi ve birleştirildi.

Abstract:
Carbazole derivaties are very important and they have attracted great attention due to their Carbazole is an aromatic compound, a chemical compound with a ring structure belonging to the benzofuran group.  Carbazole is defined as a heterocyclic compound containing specifically carbon and hydrogen atoms.  This compound is an important organic compound used in various fields, from industrial applications to the pharmaceutical industry.
Carbazole can be obtained by various synthetic methods.  It is usually produced by the reduction of anthraquinone derivatives and this process often involves the use of metal catalysts.  Carbazole is a colorless crystalline solid with a distinctive benzoin-like odor.  Its chemical formula is C12H9N.
In industrial applications, the use of carbazole is quite varied. Carbazole is considered an important intermediate in many biological and chemical processes. It plays a significant role, particularly in organic synthesis, the pharmaceutical industry, and polymer chemistry. Additionally, it serves as a key component in the synthesis of certain fluorescent compounds and dye pigments.  
In the pharmaceutical industry, carbazole is used in the synthesis of various drugs and biologically active compounds. It is also a building block in the structure of a polymer called polycarbazole, which supports its use in electronic applications due to its electrical conductivity properties.
Compounds containing carbazole group attract attention by showing very important results in the treatment processes of diseases such as specially brain tumors, as well as leukemia, which is very important and then breast cancer and kidney cancer, which are very important. 
The anti-HIV and antitumor activities of these compounds, as well as the fact that they do not cause blood poisoning and do not pose a potential risk to gene mutations, indicate that they have potential as anti-cancer agents. The electron source derivatives of carbazole, which exhibit photoconductivity and nonlinear optical properties, are used in photonics research applications due to their inherent electron providing chemistry. In addition, carbazoles with fluorescence properties are aimed to be used as sensors. Because of the structure of these molecules, their strong push-pull functional groups provide high values in terms of absorption as well as a stokes shift. 
Pyridopyrimidine compounds are an important class among heterocyclic compounds. They can be found in many drugs and have exhibited biological activities such as antiallergic, antibacterial, antitumor, anti-inflammatory, antileishmanial agents, carbonic anhydrase (CA) enzyme inhibition and polyphenol oxidase enzyme inhibitor. In this study, 3,4-Dihydropyrimidine-2-(1H)-tion derivatives were prepared in four steps, starting with carbazole, starting with the ethylating and acetylation of the carbazole. The procedure ends with chalcone formation, thiourea addition and completion of the reaction with cyclic anhydrides.
Thioureas are of great interest because of their biological importance and versatile use in organic chemistry. In addition, the fact that thioureas are easy to synthesise and have high biological activity has enabled a large number of researches and derivatives to be prepared in this field. It has been proposed as a new class of anticancer agents in recent studies. The reason for this is that many thiourea and thiazole derivatives have been proven to have antitumor activities by some studies. Indolyl and acridine conjugated thiourea analogues have been found to be effective on monoamine oxidase and cholinesterase inhibition and therefore have been proposed as a potential option for the treatment of Alzheimer's disease.
Carbazole derivatives are very important and attract great attention due to their pharmacological activities.  Ellipticine, a prido[3,4,-b]carbazole alkaloid, is isolated from the leaves of the Ochrosia elliptica tree and shows significant antitumor activity.  Indolo[2,3-a]carbazole alkaloids show a wide range of potential biological activities, such as antifungal, antimicrobial, hypotensive, antitumor, protein kinase C and topoisomerase I inhibitor. Pyridopyrimidine compounds are an important class among heterocyclic compounds.  They can be found in many medications.  They have shown various biological activities such as antiallergic, antibacterial, antitumor, anti-inflammatory, antileishmanial agents, carbonic anhydrase (CA) enzyme inhibition and polyphenol oxidase enzyme inhibitor.  The synthesis of carbazole substituted 3,4-dihydropyrimidine-2(1H)-thione derivative compounds prepared in three steps starting from ethyl carbazole compound starts with acetylation of carbazole. The procedure ends with the synthesis of the targeted compounds by the chalcone of ethylcarbazole compound in ethanol in basic medium and the addition of thiourea to the obtained chalcone compound.  Structural analysis was performed by 1H - NMR, 13C - NMR, MASS and FT-IR.
After the carbazole compound was dissolved in THF, POT-Bu and Bromo ethane were added and allowed to mix for 5 hours at room temperature and the reaction was monitored by TLC and the structure analysis of compound 1, which was synthesized after the necessary purification process, was characterized by 13C NMR, 1H NMR and FT-IR spectra.
Compound 9-Ethylcarbazole (2) was taken and dissolved with 30 ml DCM in a reaction flask.  Bismuth chloride was added.  The reaction mixture was cooled to 0 oC in an ice bath.  Acetyl chloride dissolved in DCM solution was added.  After stirring for 15 minutes in the ice bath, the mixture was allowed to stir for 4 hours at room temperature.  After the reaction was completed, the DCM solution was run.  The organic moiety was separated and the DCM was removed in an evaporator.  1H - NMR and 13C - NMR spectra showed that the compound was pure.
No problems were encountered during the synthesis of chalcone derivative compounds and when the NMR spectra of the synthesised substances are examined, we say that we can synthesise the desired substances in pure form since their proton and carbon numbers match the proton and carbon numbers. The carbon numbers of the expected structures also prove that we have synthesised the desired substance.
9-Ethylcarbazole (2) compound was taken and dissolved in the reaction flask with 30 ml DCM.  Bismite chloride was added to it.  The reaction mixture was cooled to 0 degrees Celsius in an ice bath.  Acetyl chloride dissolved in DCM solution was dropped onto it.  After mixing in an ice bath for another 15 minutes, it was allowed to mix at room temperature for 4 hours.  After the reaction was completed, work-up was performed with DCM solution.  The organic part was separated and DCM was removed in the evaporator.  By looking at the 1H - NMR and 13C - NMR spectra, it was determined that the compound was pure.
The compound (E)-3-(9-ethyl-9H-carbazol-3-yl)-1-phenylprop-2-en-1-one (4) and thiourea were dissolved in ethanol in the reaction flask.  Potassium carbonate was added to the mixture and allowed to mix under reflux at 80 0C for 24 hours.  After the reaction was completed, the mixture was allowed to cool to room temperature.  The ethanol in the reaction medium was removed in the evaporator under low pressure.  The remaining solid part was dissolved in water and placed in a 250 ml beaker.  Pieces of ice were thrown into it.  Neutralization was done with normal HCl.  The resulting solids were filtered and afied.
When the synthesised substances were examined at the final stage, it was seen that the reaction yield varied according to the position and type of substituents connected to the benzene ring in the structure. It was determined that the yield of substituents such as chlorine and bromine connected to the 4 position in the structure of the synthesised substance was higher, while the yield of compounds with substituents such as nitro and methyl group was lower.
As a result, within the scope of our master's thesis, a new series of thiourea derivative compounds that are not included in the literature have been synthesised and the structures of these synthesised compounds have been elucidated by 1H NMR, 13C NMR and IR spectrometers. The compounds were added to the organic chemistry literature.