Five-Membered Heterocyclic Compounds (Isoxazole & Isothiazole) - PDF

Organic Chemistry Heterocyclic Compounds Five membered with 2 heteroatoms | Isoxazole & Isothiazole Lec.19 Isoxazole and Isothiazole Contents : Isoxazole 3 Synthesis of isoxazole 7 Isothiazole 12 Isothiazole Synthesis 15 Reaction of 1,2 azole 18 1,2-Azoles in natural products and pharmaceutical drug...

Organic Chemistry Heterocyclic Compounds Five membered with 2 heteroatoms | Isoxazole & Isothiazole Lec.19 Isoxazole and Isothiazole Contents : Isoxazole 3 Synthesis of isoxazole 7 Isothiazole 12 Isothiazole Synthesis 15 Reaction of 1,2 azole 18 1,2-Azoles in natural products and pharmaceutical drugs 31 Isoxazole Isoxazole and Isothiazole Isoxazole: Isoxazole is an azole with an oxygen atom next to the nitrogen. Isoxazole rings are found in some natural products, such as ibotenic acid. Isoxazole and Isothiazole Isoxazoles also form the basis for a number of drugs, including the COX-2 inhibitor valdecoxib (Bextra). Furoxan is a nitric oxide donor. Isoxazole and Isothiazole IUPAC name: isoxazole Properties Molecular formula: C3H3NO Boiling point: 95 °C Synthesis of isoxazole Isoxazole and Isothiazole Synthesis of isoxazole: Reaction of 1,3-dicarbonyl compounds with hydroxylamine under mild acidic conditions. Isoxazole and Isothiazole Synthesis of isoxazole: 1,2-azoles preparation depending on reagent used For 1,2-azoles preparation, we can obtain pyrazole or isoxazole depending on the reagent we use with the same substrate or the starting material, see the reaction below: Isoxazole and Isothiazole Synthesis of isoxazole: Cyclization of ꞵ-keto esters with hydroxylamine to provide 3hydroxy- isoxazoles Isoxazole and Isothiazole Synthesis of isoxazole: 1,3-Dipolar Cycloaddition Formation of a Simple Isoxazole The nitrile oxide is unstable so it is made in situ by reaction of hydroxylamine with an aldehyde see reaction below. The nitrile oxide then reacts with the alkyne to produce the isoxazole. Isothiazole Isoxazole and Isothiazole Isothiazole: IUPAC name: Isothiazole Other names: 1,2-thiazole Properties Molecular formula: C3H3NS Molar mass: 85.13 g/mol Boiling point: 114 °C Isoxazole and Isothiazole Isothiazole: An isothiazole is a type of organic compound containing a fivemembered aromatic ring that consists of three carbon atoms, one nitrogen atom, and one sulfur atom. Isothiazole is a member of a class of compounds known as azoles. In contrast to the isomeric thiazole, the two heteroatoms are in adjacent positions. The ring structure of isothiazole is incorporated into larger compounds with biological activity such as the pharmaceutical drugs ziprasidone and perospirone. Isothiazole Synthesis Isoxazole and Isothiazole Isothiazole Synthesis: Isothiazole can be prepared from thioamides in the following way: By reaction propiolaldehyde with sod. thiosulfate in the presence of ammonia solution Isoxazole and Isothiazole Isothiazole Synthesis: By cyclo-condesation of β-chloro-α,β-unsaturated aldehydes with ammonium thiocyanate will give 4,5- disubstituted isothiazoles: Reaction of 1,2 azole Isoxazole and Isothiazole Reaction of 1,2 azole: Like 1,3 azole, due to the presence of =N- group in the ring, the 1,2 azole are much less reactive towards ES reactions than furan, pyrrole and thiophene. 1,2 azole undergo ES reactions under an appropriate reaction condition. The main substitution takes place at the C-4 position. Pyrazole reactivity like phenol, but isoxazole & isothiazole reactivity like benzene. Isoxazole and Isothiazole Reaction of 1,2 azole: Isoxazole and Isothiazole Reaction of 1,2 azole: Isoxazole and Isothiazole Halogenation/ Bromination or Iodination: Halogenation of Isoxazoles, Pyrazoles and Isothiazoles Halogenation (iodination, bromination) of pyrazole leads to the 4halopyrazole. Poor yields are obtained when attempting to halogenate isoxazole or isothiazole, but bromination can be accomplished when an activating group is present as a substituent. Isoxazole and Isothiazole Nitration important points: Nitration of Isoxazoles, Pyrazoles and Isothiazoles Isoxazole and Isothiazole Nitration important points: Pyrazoles and isothiazoles undergo straightforward nitration: 1. Nitropyrazole is formed in good yield by treatment of pyrazole with the mild nitrating reagent, acetyl nitrate. 2. Nitropyrazole can be rearranged to give 4-nitropyrazole by treatment with acid at low temperature. Isoxazole nitrates in very low yield, but 3-methylisoxazole is sufficiently reactive to undergo nitration at the 4-position. Isoxazole and Isothiazole Reaction of 1,2 azole: Isoxazole and Isothiazole Reaction of 1,2 azole: Isoxazole and Isothiazole Acylation of pyrazole: Acylation of pyrazole Only N-substituted pyrazoles can be C-acylated directly. Vilsmeier formylation produces the 4-formylpyrazole in modest yield. Isoxazole and Isothiazole Reaction of 1,2 azole: Isoxazole and Isothiazole Metallation: Direct Metallation of 4-Bromopyrazoles. Isoxazole and Isothiazole Metallation: At low temperature, N-sulfonyl 4-bromopyrazoles can be lithiated at 5-position without undergoing metal-halogen exchange. Metallation of 4-Bromopyrazoles by Metal-Halogen Exchange. Isoxazole and Isothiazole 1,2-Azoles in natural products and pharmaceutical drugs: