Altın katalizli A3-kenetlenme tepkimesi aracılığıyla 1-(1,3-ditiyen-2-il)propargilamin türevlerinin sentezi
Synthesis of 1-(1,3-dithian-2-yl)propargylamine derivatives via gold-catalyzed A3-coupling reaction
Yazar: EDA İSMAİLOĞLU
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: Katalizörler = Catalysts ; Kenetlenme tepkimesi = Coupling reaction ; Oksidatif fosforilasyon = Oxidative phosphorylation

Özet:
Propargilaminler organik kimyanın birçok alanında geniş uygulamaları bulunan çok yönlü yapı taşlarıdır. Bulundurdukları yapısal birim, propargilaminleri çeşitli doğal ürünler, terapötik ilaç molekülleri ve biyolojik aktiviteye sahip pek çok molekül için değerli kılar. Bunun yanı sıra propargilaminlerde birkaç tepkime merkezi bulunması onları kademeli tepkimelerde ara basamak olarak kullanılarak N, S, O içeren heterohalkalı yapılar sentezlenmesi için elverişli kılar. Propargilaminlerin sentezi için çalışılan çeşitli metotlar arasında aldehit, amin ve alkinin üç bileşenli kenetlenme tepkimeleri; atom ekonomik yaklaşımı, elverişli  tepkime koşulları ve yüksek ürün verimliliği gibi sebeplerle araştırmacılar için tercih sebebi olmuş ve yaygın olarak kullanılmıştır. Günümüze kadar yapılan pek çok çalışma incelendiğinde A3-kenetlenme tepkimesi yaklaşımı, hem doğrudan hedeflenen propargilaminlerin sentezini hem de anahtar ara ürün değeri taşıyan çok yönlü moleküllerin sentezini mümkün kılmıştır.
Bu çalışmada Au katalizli A3 (Aldehit, Alkin, Amin) üç bileşenli kenetlenme tepkimesi aracılığıyla 1,3 ditiyen sübstitüye amin türevlerinin sentezi hedeflenmiştir. Çalışma için anahtar çıkış bileşeni 1,3 ditiyen-2-karbaldehit türevleri olmakla birlikte ditiyen içeren bir kenetlenme bileşeniyle A3-tepkimesi literatürde yer almamaktadır.
A3-kenetlenme tepkimesinin aldehit fonksiyonu olan 1,3-ditiyen-2-karbaldehit'ler karşılık gelen 1,3-ditiyen türevlerinden başarılı bir şekilde sentezlenmiştir. A3-kenetlenme ürünü elde etmeye yönelik çalışmalara öncelikle 2-p-tolil-1,3-ditiyen-2-karbaldehit, morfolin ve fenilasetilenin reaktant olarak kullanıldığı çözücü ve katalizörün eşliğinde gerçekleşen bir model tepkime ile başlanmıştır. Model tepkime üzerinden yapılan optimizasyon çalışmaları esnasında katalizör çeşitleri ve miktarı, çözücü çeşitleri ve miktarı, tepkime süresi ve tepkime sıcaklığı üzerinde çeşitli değişiklikler yapılarak pek çok tepkime denenmiştir. Tepkimenin optimizasyonu 2-p-tolil-1,3-ditiyen-2-karbaldehit (1.0 eşdeğer), morfolin (2.0 eşdeğer) ve fenilasetilen'in (3.0 eşdeğer) AuBr3 (%10 mol) katalizatörü eşliğinde MeOH (0.25 mL) içerisinde 70 oC sıcaklıkta 24 saat süreyle gerçekleşen tepkime koşulları altında sağlanmıştır. Tepkime eldivenli kabin içinde azot atmosferi altında kapaklı tepkime şişesi içinde yapılmıştır. Tepkime sonucu oluşan ürünler kolon kromatografisiyle saflaştırılmıştır. Verimi yükseltmek için yapılan bir dizi optimizasyon çalışmasının ardından hedeflenen kenetlenme ürününe belirtilen optimize koşullarda %81 izole verimle ulaşılmıştır. A3-kenetlenme tepkimesi için uygun tepkime koşulları bulunduktan sonra belirlenen optimize koşullarda aldehit, amin ve alkin fonksiyonları türevlendirilerek farklı 1,3 ditiyen sübstitüye propargilaminler sentezlenmiştir. Bazı tepkimelerde verimi yükseltmek için sıcaklık ve süre açısından optimize koşullarda küçük değişiklikler yapılmıştır. 
Bu çalışma kapsamında altın katalizli A3-kenetlenme tepkimesi aracılığıyla 34 adet 1-(1,3-ditiyen-2-il)propargilamin türevi sentezlenmiştir. Aril sübstitüye, heteroaril sübstitüye ve alkil sübstitüye 1,3-ditiyen türevi propargilaminler ile aldehit fonksiyonunda sübstitüent içermeyen doğrudan 1,3-ditiyen türevi olan propargilaminler çok iyi, iyi ve orta verimlerde elde edilmiştir. Elde edilen tüm moleküllerin yapısı 1H-NMR, 13C-APT NMR ve kütle spektroskopisi ile karakterize edilmiştir.

Abstract:
Propargylamines are versatile building blocks with wide applications in many areas of organic chemistry. Their structural unit makes propargylamines valuable for various natural products, therapeutic drug molecules and many molecules having biological activity. In addition, the presence of several reaction centers in propargylamines makes them suitable for synthesis of N, S, O containing heterocyclic structures. In these synthetic protocols, they generally appear as an intermediate funtional compounds in cascade/domino reactions. Among various methods  for the synthesis of propargylamines, three component coupling reactions of aldehyde, amine, and alkyne so called A3-coupling reaction plays important role since this reaction provides an atom economic approach, favorable reaction conditions and high product efficiency. In addition, the A3-coupling reaction is highly successful for both the direct synthesis of targeted propargylamines and the synthesis of versatile heterocycles in a one-pot reactions.
In this study, the synthesis of 1,3-dithiane substituted propargylamine derivatives via Au-catalyzed A3 (Aldehyde, Alkyne, Amine) three-component coupling reaction was aimed. The key output component for the study is 1,3-dithiane-2-carbaldehyde derivatives. The A3-coupling reaction with a dithiane containing coupling compound was not known in the literature.
Studies to obtain desired A3-coupling products were started with a model reaction in the presence of solvent and catalyst, in which 2-p-tolyl-1,3-dithiane-2-carbaldehyde, morpholine and phenylacetylene were used as reactants. During the optimization studies on the model reaction, different reaction conditions were tried by using various catalysts, solvents and additives for different reaction times and at various reaction temperature. Moreover, the effect of catalsyt loading and the concentration of the reaction were tested to reach the maximum yields. 
The reaction of 2-p-tolyl-1,3-dithiane-2-carbaldehyde (1.0 eqv.), morpholine (2.0 eq) and phenylacetylene (2.0 eq) in the presence of AuBr3 (10% mol) catalyst in MeOH at 60 oC for 24 hours gave the corresponding A3-coupling product in 61% yield in one of our initial attempts. The reaction was carried out in a screw-cap reaction vial equipped with a stirring bar under nitrogen atmosphere in a glove box. After the reaction was completed, it was followed by thin layer column chromatography (TLC). Except for the product spot, three additional spots were determined on the plate. All the products yielded by the reaction under these conditions were purified by a column chromatography. One of the these products belonged to the starting aldehyde component 2-p-tolyl-1,3-dithiane-2-carbaldehyde which is not completely consumed during the reaction. The targeted coupling product was achieved with an isolated yield of 61% and it was characterized by NMR spectroscopy. The other products isolated were acetophenone and  a dialkyne derivative namely, 1,4-diphenylbuta-1,3-diene. Therefore, it was necessary that more attempts had to be carried out to eliminate byproducts and to increase the yield of  the  coupling product by using the same model reaction. To increase the reaction temperature (65-75 oC)  and to prolong the reaction time (48 hours) did not lead to the complete conversion of the starting 1,3-dithiane-2-carbaldehyde. 
It is well-know that alkynes produce ketone and dialkyne derivatives as a result of hydration and oxidative homocoupling in the presence of oxygen and water in Au-catalyzed reactions. In addition, it is known that water is produced as a by-product in A3-coupling reactions. Although dry methanol was used as a solvent in the coupling reaction, it was understood that moisture was absorbed from the reactants or the environment in which the reaction prepared. Based on these knowledge, to reduce the formation of by-products, it was required that water in the reaction medium had to be removed, and also the amount of phenylacetylene component had to be increased. Thus, freshly activated molecular sieves and  one more equivalent of phenylacetylene were added into the reaction. After these changes were made, it was observed that the starting 1,3-dithiane-2-carbaldehyde was completely consumed and it was converted to A3-coupling product in 75% yield. When concentration of the reaction was increased fourfold,  it was observed that the yield of coupling product reached 81%. The same reaction was also performed in 4.0 mmol scale and the coupling product was isolated in 76% yield.
While performing optimization studies with the model reaction, many metal catalysts were tried, but it was seen that the best result was obtained with a gold catalyst. The model reaction was repeated with various copper catalysts such as CuBr2, CuBr, CuCl and CuI, but low product yields were observed. Moreover, model reaction was also tested with many different solvents such as dioxane, toluene, CPME and H2O by using AuBr3 as catalyst. The highest product yield was achieved in MeOH, so it was  used as a standart solvent for the coupling reaction. Since the gold catalyst gave good result, different gold catalysts such as  AuCl3, AuCl, KAuCl4 and Na(AuCl)4.2H2O were also tested in methanol. Among them, the best result (81%) was achieved with Na(AuCl)4.2H2O. Based on all these findings, studies were carried out to obtain different dithiane substituted propargylamines in order to expand the limits of the A3-coupling reaction.
Firstly, A3-coupling reactions of different 2-aryl-1,3-dithiane-2-carbaldehydes bearing electron donating and withdrawing groups with acetylenes were studied under the optimized reaction conditions. It was chosen morpholine as the secondary amine group of these experiments. In the optimum conditions determined, targeted coupling products were generally obtained in moderate to good yields. The only exception was the coupling reaction of 2-p-tolyl-1,3-dithiane-2-carbaldehyde, morfoline and 1-ethynyl-4-methoxybenzene having a strong electron donating methoxy substituent, which produced the corresponding A3 product  in 30% yield.
The coupling reactions with N,N-dimethyaminophenyl substituted dithiane were rather sluggish, mixtures had to be heated at 80 °C, for 24 hours to reach the maximum yields. At this conditions corresponding A3-coupling products were synthesized in yields of 77% and 47%. On the other hand, to obtain higher yields from heteroaryl substituted 1,3-dithiane-2-carbaldehydes, the reaction temperature had to be decreased to 60°C, and prolonged reaction times (30 h) were necessary. 
The reactions of 2-methyl-1,3-dithiane-2-carbaldehyde with aryl acetylenes bearing an electron withdrawing (Cl) or donating group (OMe) and morpholine furnished the desired products in good yields (77% and 67%, respectively) under the optimized conditions (70 °C, 24 h).
However, the coupling of 2-methyl-1,3-dithiane-2-carbaldehyde with 4-(trifluoromethyl)-phenylacetylene required heating at 80 °C for 48 h, for total consumption of aldehyde and to achieve the targeted propargylamine in 57% yield. The coupling reaction with benzyl substituted dithiane carbaldehyde, morpholine and phenylacetylene produced the corresponding A3-coupling product in good yield (73%) under optimum reaction conditions. 
Moreover, the A3-coupling reactions of 1,3-dithiane-2-carbaldehyde with phenylacetylene and 4-chlorophenyl acetylene produced the coupling products  in very good yields (87% and 79%, respectively). In addition, the reaction of 1,3-dithiane-2-carbaldehyde with 1-ethynyl-4-methoxybenzene and morfoline gave the desired propargylamine in very good yield (94%) under the optimized reaction conditions. 
In the second stage of this study, coupling reactions were performed with different amine groups other than morpholine to expand the scope of A3-coupling products. The coupling reaction with piperidine gave the corresponding propargylamine derivative in only 29% yield together with 2-p-tolyl-1,3-dithiane-2-carbaldehyde and N-formyl piperidine by-products under the optimized reaction conditions (70 oC, 24 h). To obtain the coupling product in a higher yield and to eliminate by-products, reaction temperature was decreased to 50 oC and reaction time was prolonged to 72 hours. Under this conditions, the piperidine substituted coupling product was isolated in 50% yield. On the other hand, under the optimized conditions, the reaction of 2-methyl-1,3-dithiane-2-carbaldehyde with piperidine and phenylacetylene produced the corresponding coupling product in a very good yield (89%) without byproducts similar to those observed in the coupling of 2-p-tolyl-1,3-dithiane-2-carbaldehyde and N-formyl piperidine.
Apart from morpholine and piperidine, reactions with various amines were also studied. The reactions of 2-methyl-1,3-dithiane-2-carbaldehyde and phenylacetylene in the presence of N-benzylpiperazine, N-ethylpiperazine and thiomorfoline afforded the corresponding propargylamine derivatives under previously determined optimum reaction conditions in 81%, 58% and 62% yields, respectively. Conversely, three component reactions with diallylamine and diethylamine at 50 °C for 72 hours provided the desired propargyl amines in low yields 44% and 28%, respectively.
It was observed that the reaction of 2-methyl-1,3-dithiane-2-carbaldehyde in the presence of piperidine and pyrrolidine provided high yields like 89% and 98%. However, the A3-coupling reaction of the same dithiane substituted starting material with diethyl amine resulted in lower 44% yield. Lastly, the reaction of 1,3-dithiane-2-carbaldehyde with pyrrolidine under the optimized reaction conditions produced the corresponding propargylamine derivative in 53% yield which is surprisingly lower than expected.
As a result, within the scope of this study,  34 variously substituted 1-(1,3-dithiane-2-yl)propargylamine derivatives were synthesized generally in good yields via gold-catalyzed A3-coupling reaction. All obtained compounds were purified by column chromatography. The structure of all isolated molecules was characterized by 1H-NMR, 13C-APT NMR and high resolution mass spectroscopy.