Saturated heterocycles Reacons of saturated heterocycles Saturated nitrogen heterocycles: amines, but more nucleophilic Reacons of saturated heterocycles Saturated nitrogen heterocycles: amines, but more nucleophilic Reacons of saturated heterocycles Aziridine: ring strain promotes ring opening Reacons of saturated heterocycles Oxygen heterocycles Reacons of saturated heterocycles Sulfur heterocycles Heteroatoms in rings have axial and equatorial lone pairs Some substuents of saturated heterocycles prefer to be axial: the anomeric effect Making heterocycles: ring-closing reacons Making heterocycles: ring-closing reacons Making heterocycles: ring-closing reacons Thermodynamic control over ring size The Thorpe–Ingold effect Baldwin’s rules Aromac Heterocycles Aromacity survives when parts of benzene’s ring are replaced by nitrogen atoms Pyridine is a very unreacve aromac imine Pyridine is bad at electrophilic aromac substuon Nucleophilic substuon is easy with pyridines Acvated pyridines will do electrophilic aromac substuon

Pyridine N-oxides are reacve towards both electrophilic and nucleophilic substuon Pyridine as a catalyst and reagent Five-membered aromac heterocycles are good at electrophilic substuon Five-membered aromac heterocycles are good at electrophilic substuon Furan and thiophene are oxygen and sulfur analogues of pyrrole

Electrophilic addion may be preferred to substuon with furan Lithiaon of thiophenes and furans More reacons of five-membered heterocycles Nucleophilic substuon requires an acvang group

Five-membered heterocycles act as dienes in Diels–Alder reacons More reacons of five-membered heterocycles Nitrogen anions can be easily made from pyrrole Five-membered rings with two or more nitrogen atoms Five-membered rings with two or more nitrogen atoms Five-membered rings with two or more nitrogen atoms Five-membered rings with two or more nitrogen atoms Benzo-fused heterocycles Indoles are benzo-fused pyrroles Aromacity survives when parts of benzene’s ring are replaced by nitrogen atoms HOBt is an important reagent in pepde synthesis Pung more nitrogen atoms in a six-membered ring Fusing rings to pyridines: quinolines and isoquinolines A nitrogen atom can be at a ring juncon

Fused rings with more than one nitrogen Aromac heterocycles can have many nitrogens but only one sulfur or oxygen in any ring

There are thousands more heterocycles out there Which heterocyclic structures should you learn?

First of all, those every chemist must know: Which heterocyclic structures should you learn? Aromac Heterocycles Synthesis

Making heterocycles is easy—that’s precisely why there are so many of them. Just refl ect. . .

• Making C–O, C–N, and C–S bonds is easy. • Intramolecular reacons are preferred to intermolecular reacons. • Forming fi ve- and six-membered rings is easy. • We are talking about aromac, that is, very stable molecules. Thermodynamics is on our side

Disconnect the carbon–heteroatom bonds first Disconnect the carbon–heteroatom bonds first Heterocycles with two nitrogen atoms come from the same strategy Pyrroles, thiophenes, and furans from 1,4-dicarbonyl compounds Pyrroles, thiophenes, and furans from 1,4-dicarbonyl compounds How to make pyridines: the Hantzsch pyridine synthesis How to make pyridines: the Hantzsch pyridine synthesis Other syntheses of pyridines Other syntheses of pyridines Pyrazoles and pyridazines from hydrazine and dicarbonyl compounds Chemistry hits the headlines—Viagra Chemistry hits the headlines—Viagra Pyrimidines can be made from 1,3-dicarbonyl compounds and amidines Unsymmetrical nucleophiles lead to selecvity quesons Isoxazoles are made from hydroxylamine or by cycloaddion Tetrazoles and triazoles are also made by cycloaddions The Fischer indole synthesis The Fischer indole synthesis The Fischer indole synthesis: sumatriptan The Fischer indole synthesis: ondansetron The Fischer indole synthesis: indomethacin The Reissert indole synthesis Quinolines and isoquinolines Quinolines and isoquinolines Quinolones also come from anilines by cyclizaon to an ortho posion More heteroatoms in fused rings mean more choice in synthesis Summary: the three major approaches to the synthesis of aromac heterocycles Ring construcon by ionic cyclizaon Summary: the three major approaches to the synthesis of aromac heterocycles Ring construcon by ionic cyclizaon Summary: the three major approaches to the synthesis of aromac heterocycles Ring construcon by ionic cyclizaon Summary: the three major approaches to the synthesis of aromac heterocycles Ring construcon by cycloaddions Summary: the three major approaches to the synthesis of aromac heterocycles Ring modificaon