1,3-ditiyolenil ve 1,3-ditiyepenil sübstitüye propargilaminlerin halka genişleme tepkimeleri
Ring expansion reactions of 1,3-dithiolanyl and 1,3-dithiepenyl substituted propargylamines
Yazar: MERT DİNÇ
Danışman: DOÇ. DR. BARIŞ YÜCEL
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Yüksek Lisans, 2024
Konu: Kimya = Chemistry

Özet:
Halka genişleme yöntemi, farklı büyüklükteki karbohalkalı ya da heterohalkalı yapıların üretilmesinde oldukça etkili bir stratejidir. Diğer yöntemlerle, özellikle büyük halkalı yapıların üretimi daha zor ve düşük verimle gerçekleştirilebilir. Halka genişleme tepkimelerinde, halkalı bir yapıdan yola çıkılarak, daha yüksek üyeli bir halkalı yapıya bir katalizatör varlığında veya basit reaktifler eşliğinde tek bir adımda ulaşılmaktadır. Bu da halka genişleme tepkimelerini atom ekonomisi ve tepkime verimi açısından oldukça önemli kılmaktadır.
Bu bağlamda, özellikle ditiyoasetal türevleri büyük ilgi çekmektedir. Ditiyoasetal türevlerini karbonil bileşikleri gibi basit moleküllerden elde etmek kolay ve ekonomiktir. Bunların arasında, özellikle 1,3-ditiyen ve 1,3-ditiyolen türevleri organik sentez çalışmalarında önemli bir rol oynamaktadır. İlk olarak, karbonil gruplarını koruma görevi üstlenirler ve hem altı üyeli 1,3-ditiyen hem de beş üyeli 1,3-ditiyolen yapıları bu amaçla sıkça kullanılır. Ayrıca uygun 1,3-ditiyen türevleri güçlü bazlar aracılığıyla açil anyon eşdeğerlerini oluşturarak çeşitli elektrofiller ile tepkimeye girerler.  
Bu çalışmada 1,3-ditiyolenil ve 1,3-ditiyepenil sübstitüye propargilaminlerin  bazik koşullar altında halka genişleme tepkimeleri incelendi. Kuvvetli bir baz ile bu yapıların öncelikle  propargilik protonunu kaybettiğini ve sonrasında 1,3-ditiyolenil ve 1,3-ditiyepenil halkalarının  genişlemesiyle sırasıyla 8- ve 10-üyeli kükürt içeren heterohalkalara yeniden düzenlendiği saptandı. Tepkime koşulları optimize edilerek farklı amino ve aril gruplarına sahip 8- ve 10-üyeli S,S-heterohalkalı yapılar iyi verimlerle sentezlendiler. Baz içeren düzenlenme tepkimesi için radikalik bir mekanizma önerildi. Önerilen mekanizma döteryum etiketleme ve radikal tuzaklama deneyleriyle desteklendi.

Abstract:
Since sulfur-containing heterocycles are extensively found in medications, agrochemicals, natural goods, and organic electronic materials, they are of special importance in organic synthesis. Medium-sized sulfur rings with extra heteroatoms and amino substituents are essential structural components of several US FDA-approved drugs, pharmaceutically relevant molecules, and natural compounds. Although thiophene and 5- and 6-membered S-heterocycles are the most encountered units in biologically active compounds. However, because of torsional stresses and unfavorable transannular contacts, it is more difficult to build medium-sized rings by intramolecular cyclization events. The synthesis of medium-sized ring structures can be accomplished by a variety of techniques, including radical cyclization, ring-expansion processes, ring-closing metathesis, and metal-catalyzed or -mediated cyclization reactions. 
Derivatives of 1,3-dithiane serve as beneficial tools that have been applied for a while in chemical synthesis as protective groups for carbonyl compounds and as acylanion equivalents. They are also crucial points of reference for the synthesis of heterocycles and acyclic molecules containing sulfur. Because 1,3-dithiolene derivatives fragment rings in different ways with strong bases, they are not appropriate for this task (Figure 1.2b). First pioneered by Corey and Seebach, the polarization reversal (umpolung) technique of the carbonyl group with 1,3-dithiane derivatives continues to garner a lot of interest.
1,3-dithianes can be transformed into S,S-heterocycles. Dithiane derivatives featuring a leaving group on their side chain underwent expansion resulting in bicyclic sulfonium ions and subsequent thionium intermediates. Upon the elimination of a proton within these intermediates, the reaction regularly gives a mixture of stereoisomers and simple S,S-heterocyclic products without functional groups. Depending upon whether or not a nucleophile is present in the media, the thionium ion is trapped in order to form a ring without requiring for a double bond. Also, 2-alkyl or 2-aryl-1,3-dithianes can undergo expansion using various electrophiles, leading to a formation of a thionium intermediate and the resulting 7-membered dithiepine derivatives. According to the number and kind of electrophiles worked with as well as the substituent on the aryl group, functionally substituted dithiepines are feasible. To the best of our knowledge, larger rings produced through this strategy were not reported, nevertheless. Under catalytic settings, expansion of the 1,3-dithiane ring was rarely noticed. Propargylic 1,3-dithianes, depending on what type of substituent at the 2 position of the dithiane ring, were transformed via an Au-catalyzed procedure into 8-membered dithio-substituted cyclic allenes and dithiocine equivalents. The cyclic allene is most likely produced by a 1,2-sulfur shift which takes place after the formation of an Au-carbene intermediate. Recently, we observed that 3-amino-4-iodothiophenes can be formed by electrophilic iodocyclization of 1-(1,3-dithian-2-yl) propargylamines by iodide-induced ring fragmentation of bicyclic sulfonium produced as an intermediate product. 
In this research, ring expansion reactions of 1,3-dithiolenyl and 1,3-dithiepenyl substituted propargylamines under basic conditions have been worked on. It was found that these compounds initially lost the propargylic proton when they reacted with strong bases, and that this was followed by the expansion of the 1,3-dithiolenyl and 1,3-dithiepenyl rings into heterocycles with eight and ten members, respectively, that included sulfur. High yields of variably amino and aryl substitued 8- and 10-membered S,S-heterocyclic compounds were produced when reaction conditions were optimized. 
Strong bases are utilized in DMF, DMSO, and DMAc solvents in a variety of processes that have recently been demonstrated to work via an electron-transfer mechanism. In these reactions, the solvent deprotonates to generate the appropriate anion, which is then transferred to the solvent molecule by a single electron, changing it into the carbamoyl radical (from DMF), dimsyl radical (from DMSO), or dimethylcarbamoyl radical (from DMAc). Furthermore, corresponding radicals were formed as a result of electrons being transferred from the carbamoyl, dimsyl, and dimethylcarbamoyl anion to different species such aryl iodides, aryl methyl sulfones, and benzil derivatives. It is known that introducing modest quantities of strong bases to DMF and DMSO at room temperature can result in the production of long-lived radical species.
We undertook additional control experiments in the presence of radical scavengers since the KOtBu-DMF system was intimately related to the electron-transfer process. Under standard circumstances, the reaction of A with 2.0 equivalent of TEMPO yielded Dt-A in 36% yield, which was lower than the reaction's maximal yield of 75% (Figure 3.2). On the other hand, introducing 2.0 equiv of BHT (2,6-di-tert-butyl-4-methylphenol) and DPPH (2,2-diphenyl-1-picrylhydrazyl radical) completely prevented the production of Dt-A. 
BHT inhibited cyclization because it quickly interacted with KOtBu to produce potassium peroxide. Then, using standard conditions (see Table S8), we examined various amounts of the radical scavengers and p-BQ (p-benzoquinone) in the reaction of 1a with 0.5 and 1.0 equivalent of KOtBu. The full inhibition of the reaction was observed when 0.20 equivalent of DPPH and 0.25 equiv. of p-BQ were included, indicating which a radical pathway was followed while in rearrangement.
The carbamoyl anion is produced in the first stage when KOtBu deprotonates DMF. A carbamoyl radical and a radical anion are then most likely produced by this anion. Intermediate I is formed when the propargylic hydrogen is abstracted by the carbamoyl radical. After intermediate I's dithiane ring dissociates, sulfur-centered radical intermediate II is produced. This radical then goes through a regioselective 9-endo-dig radical cyclization process to produce intermediate III, a 9-membered heterocylic compound. The intermediate III creates the nine-membered ring product by separating hydrogen from H2O or alternative possible proton source, such as t-BuOH. When the R group is methyl,  intermediate II undergoes an 8-exo-dig cyclization, giving intermediate IV, which leads to the formation of an 8-membered ring with an exocyclic double bond (Figure 3.6). It is well known that carbamoyl radicals are produced via the hydroxyl radicals and maybe the tert-butoxy radicals by hydrohen removing from DMF.
In conclusion, a novel technique based on the mildly mediated rearrangement of dithioacetyl-substituted propargylamines by KOtBu-DMF was created. To produce amino-functionalized S,S-heterocycles with varying ring sizes, the rearrangement reaction entails the enlargement of the dithioacetal ring and proceeds by an exclusive endo-dig radical cyclization.