Saturated heterocycles Reac0ons of saturated heterocycles Saturated nitrogen heterocycles: amines, but more nucleophilic Reac0ons of saturated heterocycles Saturated nitrogen heterocycles: amines, but more nucleophilic Reac0ons of saturated heterocycles Aziridine: ring strain promotes ring opening Reac0ons of saturated heterocycles Oxygen heterocycles Reac0ons 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 reac0ons Making heterocycles: ring-closing reac0ons Making heterocycles: ring-closing reac0ons Thermodynamic control over ring size The Thorpe–Ingold effect Baldwin’s rules Aroma0c Heterocycles Aroma0city 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 Ac0vated pyridines will do electrophilic aroma0c subs0tu0on Pyridine N-oxides are reacve towards both electrophilic and nucleophilic subs0tu0on Pyridine as a catalyst and reagent Five-membered aroma0c heterocycles are good at electrophilic subs0tu0on Five-membered aroma0c heterocycles are good at electrophilic subs0tu0on 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 reac0ons of five-membered heterocycles Nucleophilic subs0tu0on requires an ac0va0ng group Five-membered heterocycles act as dienes in Diels–Alder reacons More reac0ons 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 Aroma0city survives when parts of benzene’s ring are replaced by nitrogen atoms HOBt is an important reagent in pepde synthesis PuRng more nitrogen atoms in a six-membered ring Fusing rings to pyridines: quinolines and isoquinolines A nitrogen atom can be at a ring junc0on Fused rings with more than one nitrogen Aroma0c 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? Aroma0c 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 reacHons are preferreD to intermolecular reacHons. • 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 selec0vity 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 cycliza0on to an ortho posi0on More heteroatoms in fused rings mean more choice in synthesis Summary: the three major approaches to the synthesis of aroma0c heterocycles Ring construc0on by ionic cycliza0on Summary: the three major approaches to the synthesis of aroma0c heterocycles Ring construc0on by ionic cycliza0on Summary: the three major approaches to the synthesis of aroma0c heterocycles Ring construc0on by ionic cycliza0on Summary: the three major approaches to the synthesis of aroma0c heterocycles Ring construc0on by cycloaddi0ons Summary: the three major approaches to the synthesis of aroma0c heterocycles Ring modifica0on.