1-(1,3-ditiyen-2-il)propargilaminlerin iyodosiklizasyonuyla 3-amino-4-iyodotiyofenlerin sentezi
Synthesis of 3-amino-4-iodothiophenes through iodocyclization of 1-(1,3-dithian-2-yl)propargylamines
Yazar: ZEYNEP MERT
Danışman: DOÇ. DR. BARIŞ YÜCEL
İstanbul Teknik Üniversitesi / Lisansüstü Eğitim Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Yüksek Lisans, 2022
Konu: Kimya = Chemistry
Dizin: Kenetlenme tepkimesi = Coupling reaction ; Sentezleme = Synthesizing ; Sülfonlar = Sulfones

Özet:
Tiyofen türevleri biyolojik aktiviteye sahip doğal ve sentetik ürünlerin yapısında sıklıkla görülmektedir. Özellikle multi- sübstitüe olmuş ve üzerinde bir amino grubu ihtiva eden tiyofen türevleri sitotoksik, anti-enflamatuar, antiviral ve antibakteriyel aktiviteler göstermektedirler. Aynı zamanda güçlü biyolojik aktivitelere sahip multi-sübstitüe iyodotiyofenler metal katalizli çapraz bağlama reaksiyonları ile tiyofen halkasını daha da işlevselleştirmek için kullanılan değerli ara maddelerdir. Öte yandan tiyofen türevleri materyal kimyasında iletken oligomerik ya da polimerik yapılarda da yer almaktadır.
Bu çalışmanın amacı 1,3-ditiyenil sübstitüe propargilamin türevlerinden yola çıkarak iyodosiklizasyon reaksiyonu ile 3-amino-4-iyodotiyofen türevlerinin sentezi için yeni ve verimli bir yöntem geliştirmektir. 
Başlangıç maddeleri olan 1-(1,3-ditiyen-2-il)propargilaminlerin sentezi bu tez kapsamında olmamakla birlikte, literatürde A3- kenetlenme reaksiyonu olarak bilinen bir yöntem ile sentezlenmişlerdir. Literatür araştırmalarından yola çıkılarak A3-kenetlenme ürünlerinin ditiyen bölgesinin bir dizi reaksiyonu tetikleyebileceği öngörülmüş ve A3- kenetlenme ürününün iyot ile aktive edilen üçlü bağa kükürt atomu saldırısı yoluyla molekül içi bir siklizasyona uğradığı anlaşılarak iyodotiyofen türevlerinin sentezi gerçekleştirilmiştir. 
İyodosiklizasyon reaksiyonu için gerçekleştirilen optimizasyon çalışmaları bir model reaksiyon üzerinden denendi ve 3-amino-4-iyodotiyofen türevi olan 4-(4-iyodo-5-fenil-(2-p-tolil)tiyofen-3-il)morfolinin başarıyla sentezlendiği görülerek yapısı tek kristal X- ray spektroskopisi ile aydınlatıldı. Optimizasyon çalışmaları sonunda aril ve heteroaril sübstitüe kenetlenme ürünleri için en iyi sonuç CH2Cl2 içinde 3 eşdeğer oranında I2 ile gerçekleştirilen reaksiyon koşulu ile sağlandı. Yapısında alkil sübstitüe ditiyenil grubu bulunan A3- kenetlenme ürünlerinin iyodosiklizasyon reaksiyonları için optimize edilen reaksiyon koşulu ise 1.5 eşdeğer CaCO3 ve 3.0 eşdeğer I2 varlığında diokzan-su karışımı içinde 70 oC sıcaklık olarak bulundu. Sonuç olarak aril, heteroaril ve alkil sübstitüe iyodotiyofen türevleri iyi- orta verimlerle sentezlendi ve flaş kolon kromotografisi ile izole edildi. 
1,3-Ditiyenil sübstitüe A3- kenetlenme ürünleri, iyodosiklizasyon reaksiyonu için optimize edilen koşullarda beklenen iyodotiyofen türevlerini üretmediler. Bu başlangıç maddeleri baz içeren optimize koşullarda morfolin sübstitüe dihidroiyodotiyofen türevlerini verirken, baz içermeyen optimize koşullarda ise tiyoalkil sübstitüe iyodotiyofen türevlerini ürettiler. 
Bu tez kapsamında yapılan son çalışma ise A3- kenetlenme ürünü 4-(3-fenil-1-(2-(p-tolil)-1,3-ditiyen-2-il)prop-2-in-1-il)morfolinin bromosiklizasyon reaksiyonu ile 3-amino-4-bromotiyofen türevine dönüşümünün incelenmesidir. Optimizasyon çalışmalarının sonunda en iyi verimin 3.0 eşdeğer Br2 kullanıldığı ve 40 oC sıcaklıkta 66 saat süreyle gerçekleştirilen reaksiyon ile istenilen 3-amino-4-bromotiyofen türevini verdiği saptandı.
Sonuç olarak bu çalışmada 1-(1,3-ditiyen-2-il)propargilamin türevlerinin iyodosiklizasyon reaksiyonu ile 3-amino-4-iyodotiyofen türevlerinin sentezi gerçekleştirilmiştir. Bu çalışma bildiğimiz kadarıyla üzerinde bir amino grubu ihtiva eden iyodotiyofenlerin, propargilamin türevlerinden tek adımlı sentezi için ilk yaklaşımdır. Çalışma sahip olduğu bu yönler bağlamında organik sentez için bir önem ve yenilik oluşturmaktadır. Çalışmada toplamda literatürde tanımlanmamış 26 farklı tiyofen ve dihidrotiyofen türevi sentezlendi ve yapıları 1H-NMR, 13C-APT NMR ve HRMS ile karakterize edildi.

Abstract:
Thiophene derivatives are encountered frequently in biologically active natural and synthetic products. Many multi- substituted thiophene derivatives, particularly those with an amino group, have been developed as chemotherapeutic agents and have a wide range of activities including cytotoxicity, anti-inflammatory, antiviral, and antibacterial. In addition to aminothiophenes, multi- substituted iodothiophenes have also a diverse range of biological activities and are useful intermediates for further functionalizing the ring such as via metal-catalyzed cross-coupling reactions. Besides the biological properties, thiophene derivatives are also involved in conductive oligomeric or polymeric structures in material chemistry. 
In this study, a new and efficient methodology has been developed for the synthesis of 3-amino-4-iodothiophene derivatives by iodocyclization reaction, starting from 1-(1,3-dithian-2-yl)propargylamines. In synthetic organic chemistry, 1,3-dithiane derivatives are mostly used as acyl anion equivalents and protective groups. Their applicability in catalytic or stoichiometric reactions for a variety of purposes is highly restricted. Despite the fact that cyclic and acyclic ketene dithioacetals have been reported to be converted to differently substituted thiophene rings, this study offers a completely novel route to iodothiophenes from 1,3-dithiane derivatives. This important and innovative conversion of 1-(1,3-dithian-2-yl)propargylamines to multi- substituted iodothiophenes will increase the synthetic interest in 1,3-dithiane derivatives as a powerful tool for the direct and regioselective synthesis of heterocyclic systems.
Although the synthesis of 1-(1,3-dithian-2-yl)propargylamines is not within the scope of this study, they were prepared by gold-catalyzed one-pot, the three-component reaction of 1,3-dithiane-2-carbaldehydes, amines, and alkynes so-called A3- coupling reaction. A3- coupling reactions have recently been employed in the synthesis of heterocyclic structures. Based on these reports, it was hypothesized that a tandem reaction might be triggered by dithiane functionality in 1-(1,3-dithian-2-yl)propargylamines. Therefore, the synthesis of iodothiophene derivatives was realized by A3- coupling products which undergo an intramolecular cyclization via attack of a sulfur atom to the iodine-activated triple bond.
In recent years, cyclization reactions with molecular iodine have been widely used in the synthesis of various heterocyclic structures. Molecular iodine has been attracting attentions as a non-toxic, powerful, economical, and environmentally friendly alternative to transition-metal catalysts. Molecular iodine is apolar, but it is easily polarized and gains electrophilic character through to the π electrons of the C=C double bond. Because of its electrophilic nature, molecular iodine is commonly utilized for the cyclization of compounds with alkynyl or alkenyl regions in their structure. Iodocyclization is an intramolecular mechanism in which unsaturated bonds activated by molecular iodine are attacked by a nucleophilic group in the structure, resulting in cyclic compounds.

The successful conditions performed for iodocyclization reactions in the literature were used to initiate the synthesis and optimization of 3-amino-4-iodothiophenes. For the optimization studies, the A3- coupling product, 4-(3-phenyl-1-(2-(p-tolyl)-1,3-dithian-2-yl)prop-2-yn-1-yl)morpholine, was used as the starting material. It was observed that 4-(4-iodo-5-phenyl-2-(p-tolyl)thiophene-3-yl)morpholine, a 3-amino-4-iodothiophene derivative, was successfully synthesized and its structure was elucidated by the single-crystal X-ray spectroscopy method. 
The iodocyclization of 4-(3-phenyl-1-(2-(p-tolyl)-1,3-dithian-2-yl)prop-2-yn-1-yl)morpholine was tested in CH2Cl2, CH3CN, C2H4Cl2, THF, CH3OH, DMSO, and dioxane by using I2 or NIS as iodinating agents at different temperatures such as 25, 40 and 70°C for different reaction times (between 10 min. and 24 h). Inorganic bases such as K2CO3, Na2CO3, and CaCO3 were also investigated. The best result was obtained by reacting the A3- coupling product (1.0 eq) with I2 (3.0 eq) in CH2Cl2 for 24 hours at room temperature, yielding the corresponding 3-amino-4-iodothiophene.
Under these reaction conditions, derivatization studies were carried out. 2-Aryl-1,3-dithianyl substituted A3- coupling products were subjected to iodocyclization under optimized conditions and the corresponding 3-amino-4-iodothiophenes were successfully obtained generally in high yields. On the other hand, the iodocyclization with N,N-dimethyl-4-(2-(1-morpholino-3-phenylprop-2-yn-1-yl)-1,3-dithian-2-yl)-aniline which contains a strong electron-donating group, did not generate the expected 3-amino-4-iodothiophene derivative. Among the furyl and thienyl substituted A3-coupling products, it was reported that only the thienyl-containing coupling product successfully undergoes iodocyclization to give the 2,2'-bithiophene derivative. In addition to morpholine, different secondary amines like N-benzylpiperazine, N-ethyl piperazine, piperidine, thiomorpholine, and methyl benzylamine containing aryl-substituted A3- coupling products were tested. The yields of the corresponding 3-amino-4-iodothiophenes were found to be lower than those with morpholine substituted A3- products. Furthermore, iodocyclization of propargylamine derivatives comprising diallylamine and diethylamine resulted unsuccessfully. As a result, fourteen aryl and heteroaryl substituted 3-amino-4-iodothiophene derivatives were synthesized with good to moderate yields.
2-Alkyl-1,3-dithianyl substituted A3- coupling products were subjected to iodocylization under conditions similar to those already employed for aryl-substituted A3- products involving the use of 3.0 equivalent molecular iodine in CH2Cl2 at 25 °C for 24 hours. The desired 3-amino-4-iodothiophenes, however, could not be synthesized with high yields. Therefore, a new optimization study was carried out. The best reaction condition for the synthesis of the alkyl-substituted 3-amino-4-iodothiophene derivatives was found as 70 oC in a dioxane-water mixture with 1.5 equivalents of CaCO3 and 3.0 equivalents of I2. In this manner, four alkyl-substituted 3-amino-4-iodothiophenes were generated in good to moderate yields. Furthermore, the coupling product containing the strongly electron-withdrawing 4-(trifluoromethyl)phenyl moiety was successfully iodocyclized, and analysis of the reaction mixture confirmed the corresponding iodothiophene, but it could not be isolated by a column chromatography. The conversion of the A3- product, which has a benzyl group in its structure, was completed, although its yield was found to be lower than those of other alkyl-substituted iodothiophenes. Replacing the morpholino groups with secondary amines in alkyl-substituted A3- products could not fabricate the corresponding 3-amino-4-iodothiophene derivatives. Interestingly, they produced an unexpected iodothiophene derivative that does not contain an amino group in its structure.
According to the proposed mechanism, the iodocyclization begins with the activation of the triple bond on the A3- coupling product by iodine yielding a cyclic iodonium ion. The cyclic iodonium ion is then attacked by a regioselective (5-endo-dig) nucleophilic attack of one of the sulfur atoms in the dithiane ring, resulting in a bicyclic sulfonium intermediate. The bicyclic sulfonium ion is then cleaved with the iodide ion to form dihydrothiophene. Following the removal of a thietanium ion, dihydrothiophene undergoes aromatization to give the corresponding 3-amino-4-iodothiophene derivatives. 
The reactivity of 1,3-dithianyl substituted A3- coupling products in iodocylization reaction was also investigated. However, at both optimized conditions, they displayed varied reactivity and did not produce the expected 3-amino-4-iodothiophenes. These starting materials generated morpholine and thioalkyl substituted dihydroiodothiophene derivatives in the presence of 1.5 equivalents of CaCO3 and 3.0 equivalents of I2 at 70 °C for 20 minutes in a dioxane-water mixture, while in the presence of 3.0 equivalents of I2 in C2H4Cl2 at 70 °C for 20 minutes, they produced thioalkyl substituted iodothiophene derivatives. It was found that the A3- coupling products containing groups with different electronic effects such as Cl and OMe in the alkyne region gave the same products in both conditions. Therefore, in the reaction mechanism, the nucleophilic attack of sulfur is favored by  when an aryl or methyl group together with the thioalkyl moiety on the same carbon. As a result of the formation of thietanium ion, an elimination-aromatization pathway leads to the desired 3-amino-4-iodothiophenes. On the other hand, the presence of a hydrogen atom instead of an aryl or an alkyl group is not substantial enough to activate the intramolecular cyclization of the thioalkyl arm, hence the generation of thietanium cation is not possible. The Ingold-Thorpe effect is at work in our regioselective iodocyclization reaction, as evidenced by this result. As a result, six different thioalkyl substituted iodothiophene and dihydroiodothiophene were obtained.
The last study within the scope of this thesis is the bromocyclization of A3- coupling product, 4-(3-phenyl-1-(2-(p-tolyl)-1,3-dithian-2-yl)prop-2-in-1-yl)morpholine. After a brief optimization study, the best conditions for the synthesis of corresponding bromothiophene was found when A3- coupling product (1.0 equiv.) was subjected to react with 3.0 equivalent molecular bromine in CH2Cl2 for 66 hours at 40°C in poor yield.
As a result, the synthesis of tetra-substituted 3-amino-4-iodothiophenes was carried out by the regioselective iodocyclization reaction. Due to the best of our knowledge, this study involves the first approach to the construction of iodothiophenes bearing an amino substituent in a single operation from 1-(1,3-dithian-2-yl)propargylamine derivatives. As a conclusion, a total of twenty-six different thiophene and dihydrothiophene derivatives were synthesized and characterized by 1H NMR, 13C-APT NMR, and HRMS.