Synthesis of targeted hetaryl carbonyl compounds and reactions

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.