Hedefli hetaril karbonillerin sentez ve reaksiyonları
Synthesis of targeted hetaryl carbonyl compounds and reactions
Yazar: KUMSAL EROĞLU
Danışman: PROF. DR. OLCAY ANAÇ
İstanbul Teknik Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Ana Bilim Dalı / Kimya Bilim Dalı
Derece: Yüksek Lisans, 2018
Konu: Kimya = Chemistry

Özet:
Bir veya daha çok sayıda heterohalka içeren yapıların farmasotik özellik gösterme potansiyeli yüksektir. Bu bağlamda farklı sübstitüentler içeren yeni heterohalkalı bileşik sentezleri için son yıllarda giderek artan sayıda metot arayışları söz konusudur. 
Diğer taraftan diazo bileşiklerinin metal katalizörlüğündeki bozunmalarından oluşan metal karbenoidler geniş bir reaksiyon spektrumuna sahiptirler ve son yıllarda organik sentezlerde sıklıkla tercih edilmektedirler. Metal karbenoidin oluşumuna ve sonraki reaksiyon yolunun gerçekleşmesine etkin olan parametrelerden birincisi metalin ve metal ligandının yapısıdır. Örneğin dirodyum tetrakarboksilat tuzları bu anlamda en sık kullanılan katalizörlerdendir. İkinci faktör ise diazo bileşiklerinin sübstitüentlerinin donör veya akseptör özellikleridir. Donör ve akseptör sübstitüentler, diazo bileşiğinin karben veya karbenoid oluşturma hızını, ara yapının kararlılığını ve seçiciliğini etkiler. Son olarak reaktanın sterik ve elektronik yapısı da reaksiyonun oluşumunda etkili olacaktır.
Bu çalışmada kullanılan diazo bileşikleri (dimetil diazomalonat ve 1-diazo-1-fenilpropan-2-on) uygun reaksiyonlarla elde edilmişlerdir. Sentezlenen bu iki  diazokarbonil bileşiği, 2-konumlarında aynı en-mono-metilketon fonksiyonunu içeren üç adet furil/tiyofenil/N-metilpirolil bileşiği bakır/rodyum katalizörleri varlığında reaksiyona sokulmuş ve reaksiyonlar karşılaştırılmıştır. Çalışmada kullanılan hetaril bileşikleri, (E)-4-(1-metil-1H-pirol-2-il)but-3-en-2-on, (E)-4-(furan-2-il)but-3-en-2-on, (E)-4-(tiyofen-2-il)but-3-en-2-on olup uygun çıkış bileşiklerinden aldol kondenzasyonu reaksiyonu ile sentez edilmişlerdir. Yine aynı reaksiyonla iki taraflı kondenzasyon ürünleri olan (1E,4E)-1,5- bis(1-metil- 1H-pirol-2-il)penta-1,4-dien-3-on, (1E,4E)-1,5-di(furan-2-il)penta-1,4-dien-3-on ve (1E,4E)-1,5-di(tiyofen-2-il)penta-1,4-dien-3-on bileşikleri de sentez edilmiştir. 
Metal karbenoid reaksiyonlarında kullanılan katalizör ve koşullar olarak Rh2(OAc)4 /C6H6(CH2Cl2)/80°C (40°C) ve CuCl/AgSbF6/C6H6(CH2Cl2)/80°C (40°C)  seçilmiştir.
Beş-üyeli bu üç farklı heterohalkalı bileşiğin aynı reaksiyon koşullarında gerçekleştirilen bu ilk metal karbenoid reaksiyonlarında genel anlamda iki olası mekanizma söz konusudur. Reaksiyon ya hetaril fonksiyon üzerinden ya da hetaril grubuna bağlı orto-sübstitüentinin üzerinden gerçekleşecektir. Araştırma sonuçlarına göre:

i)	N-metilpirolil grubu içeren çıkışlarda hetaril fonksiyonuna metal karbenoidin "C-H araya girme" (insertion) ürünleri baskındır (kemo seçici reaksiyon).

ii)	Fakat furil/tiyofenil içeren çıkışlarda hiç hetaril C-H araya girme ürünleri gözlenmemiştir. Bunun yerine 2-sübstitüenti olan enon karbonilinden türeyen karbonil-ilidinin halka kapanması ürün/leri (dihidrofuran ve epoksit) oluşmaktadır (kemo seçici reaksiyon).

Furil/tiyofenil grubu içeren çıkışlarda akseptör-akseptör sübstitüentler taşıyan dimetil diazomalonat ve akseptör-donör  sübstitüentler taşıyan 1-diazo-1-fenil-2-propanon bileşiklerinin karbonil-ilid üzerinden yürüyen reaksiyonlarında kemo seçicilik gözlenmiştir. 
 	
iii)	Katalizör farklılığının bir ölçüde değişime neden olduğu görülmüştür. CuCl/AgSbF6 katalizörü ile daha yüksek verimli ve az da olsa dihidrofuran seçici reaksiyonların oluştuğu gözlenmiştir.

Abstract:
To date, studies with heterocyclic derivatives have been gaining increased importance to produce many naturally occurring bioactive compounds and synthetic pharmaceuticals. Developments that facilitate the synthesis of heterocyclic compounds or elucidate their reaction mechanisms are significant for process chemists in the pharmaceutical industry. However, chemoselective formations of multi-functional heterocyclic derivatives is still a formidable challenge.
On the other hand, metal carbenoids are generally obtained via metal-catalyzed decomposition of diazo compounds. The kind of metal and the structure of ligand(s) affect the reactivity and reaction pathway of the initially formed metal carbenoid drastically. For example, dirhodium tetracarboxylates have recently been widely used as such catalyst. Apart from rhodium, several other transition metal/salts have also found applications for selective carbenoid reactions as catalyst. Besides, acceptor/donor properties of diazo compounds have effect on the reaction mechanism, expectedly. Finally, the structure and electronic properties of the substrat will have effect on the total direction of mechanism/s.
In recent years, an increasing number of methods that involved metal carbenoid reactions have also enriched the current syntheses of five-membered heterocycle derivatives. Because heterocycles containing oxygen, sulphur and nitrogen atoms are electron-rich compounds and can easily undergo reactions with electrophilic metal carbenoids. Although metal carbenoid reactions for the modification of pyrrole cores were reported, previously reactions with metal carbenoid and furan/thiophene derivatives have scarcely been investigated.
According to present literature on the carbenoid reactions of 2-substituted hetaryl compounds, variation of substituents may alter the reaction pathway either deriving from heterocyclic core or from substituent. 	
In this study, for the first time, three different five-membered heterocyclics with the ene-monomethylketo substituent were reacted with the two metal carbenoids under the same conditions. 
So, starting hetaryl carbonyls (E)-4-(1-methyl-1H-pyrrol-2-yl)-but-3-ene-2-one, (E)-4-(furan-2-yl)but-3-en-2-one and (E)-4-(thiophen-2-yl)but-3-en-2-one were synthesized by condensation reactions of corresponding aldehyde derivatives (1-methyl-1H-pyrrole-2-carbaldehyde, furan-2-carbaldehyde, thiophene-2-carbaldehyde) and acetone. We also prepared di-condensation products (1E,4E)-1,5- bis(1-methyl-1H-pyrrol-2-yl)penta-1,4-dien-3-one, (1E,4E)-1,5-di(furan-2-yl) penta -1,4-dien-3-one ve (1E,4E)-1,5-di(thiophen-2-yl)penta-1,4-dien-3-one by increasing mol ratio of the staring hetaryl aldehydes.
The used catalysts and also the other reaction conditions were: Rh2(OAc)4/C6H6 (CH2Cl2)/80°C (40°C) and CuCl/AgSbF6/C6H6 (CH2Cl2)/80°C (40℃).
All the reactions were controlled by IR,  thin layer and also gas chromatography. Metal carbenoid reactions were realized under nitrogene atmosphere. Diazo compounds were dropped through a syringe for 9 hours. Purifications were realized by flash colon chromatography and sometimes preparative-thin layer chromatography. The compounds obtained were identified by gas-mass chromatography, proton-NMR, carbon-NMR and sometimes NOESY-NMR techniques.
The literature studies shows that the relative reactivities and regioselectivities of hetaryl derivatives towards electrophiles are mostly variable depending on the positions and nature of the substituents and also types of electrophiles.
In our reactions two general mechanism directions may be discussed: 
i)	Mechanism over hetaryl function: This mechanism starts with the addition of carbenoid (carbene) to the less substituted double bond of hetaryl function and then proceeds with insertion to hetaryl motif. 
ii)	Mechanism over hetaryl's 2-substituents: Metal carbenoid attacks to carbonyl function and forms carbonyl-ylide. Then this carbonyl-ylide undergoes either  a [1,5]- or [1,3]- electrocyclic ring closure reaction producing a dihydrofuran derivative or probably an  oxirane derivative. According to our proposition, in our studied conditions the oxiran derivatives were immediately decomposed.
 As known, the reactivity of pyrrole, furan and thiophene towards electrophilic substitution is in the following order:  pyrrole > furan > thiophene. Also the present studies shows that the relative reactivities and regioselectivities of hetaryl derivatives towards electrophiles are mostly variable depending on the positions and nature of the substituents and also types of electrophiles. 
 In this study,  comparing  the reaction mechanisms of furyl, thiophenyl and N-methyl pyrrolyl derivatives  that contain the same ene-monomethylketo function at their 2-positions with two diazo carbonyl compounds using two different catalytic conditions we could have the chance to observe the possible differences if there were.  In these reactions the results were summerized below: 
i)	In the reaction of N-methyl pyrrole derivative, with both diazo compounds  under two different catalytic conditions, insertion products  to pyrrole core were dominant. Reactivity of pyrrole core had been effective for this chemo-selective reaction. 

Just the contrary, no hetaryl-insertion product was observed in the reactions with furyl and thiophenyl derivatives. The solely observed products from furyl and thiophenyl derivatives with dimethyl diazomalonate were dihydrofurans  formed by [1,5]-ring closure reactions over carbonyl-ylides derived (chemo selective reactions). On the other hand, among several decompositon products, the only detectable compound was 1-phenylpropane-1,2-dione in the reactions of furyl and thiophenyl derivatives with 1-diazo-1-phenyl-2-propanone. There were recent manuscripts related with the synthesis of 1-phenylpropane-1,2-dione starting from entirely different reactants.

Moreover, Yu and co-workers synthesized dimethyl 2-oxomalonate by Cu-catalyzed deoxygenation of epoxides with dimethyl diazomalonate.
We postulated that under our reaction conditions both formation and then the decomposition of an epoxide occurred consecutively.

ii)	While dimethyl diazomalonate with acceptor-acceptor substituents directed the reaction to the [1,5]-electrocyclic ring closure reaction, 1-diazo-1-phenyl-2-propanone with donor-acceptor substituents to the [1,3]-electrocyclic ring closure reaction (chemo specific reaction).

iii)	The type of catalyst did make difference to some extent: The  CuCl/AgSbF6 catalyst yielded selective reactions with respect of dihydrofuran formation in high yields.