Chapter 3 Synthesis of aromatic heterocycles SYNTHESIS OF AROMATIC HETEROCYCLES CONSTRUCTION OF THE RING SKELETON I. Carbonyl condensation type reactions II. Cycloadditions a) with 1,3-dipoles b) with ortho-quinodimethanes (DA type react.) III. Nitrene insertion Carbonyl condensations a a X X b b X X X X Strategy a) - 5-membered rings 1,4 dicarbonyl X X X=N: NH , RNH 3 2 H H H H H H Pyrrole R-NH 2 O O O HN OH HO N OH - 2 H2O N ±H ±H R R R (Paal-Knorr Synthesis s 255) Furan H H H H H - H O O O O OH O ±H O OH 2 c.f. furan Thiophene H H LR H H LH: Lawesons reagent S O O S S S S P OMe MeO P S S Strategy a) - 6-membered rings 1,5-dicarbonyl X=N: NH 3 X X H NH H 3 O O HO N OH - 2 H2O N H Strategy b 5-membered rings X X O H H OH H OH EWG H EWG H EWG EWG EWG - 2 H O HX 2 X O O O HO X ±H H ±H X H H EWG: CN, COR etc. X: NR; O, S Enol O (or phenol) HX X HO 6-membered rings X X Enamine (or aniline) OH H OH OH H - 2 H O H H H H 2 O H N ±H ±H HO N N O H O NH O NH H 2 I. Carbonyl condensation type reactions II. Cycloadditions a) with 1,3-dipoles b) with ortho-quinodimethanes (DA type react.) III. Nitrene insertion 1,3-Dipolar Cycloaddition 1,3-dipol Only 5-membered rings b b a c a c d e d e Alkene / alkyne Ex. ozonolysis POCl R 3 R R N O 3 O N N N O O O O O O - H2O R O R O nitriloxide isoxazole Cycloaddition with ortho-Quinodimethanes O X S O - SO 2 X Electrocyclic X X X ring opening - 2 HX X Diels-Alder X Ring formed carbocyclic O O Br O O NaI O O Δ N Br N Me Me N Me I. Carbonyl condensation type reactions II. Cycloadditions a) with 1,3-dipoles b) with ortho-quinodimethanes (DA type react.) III. Nitrene insertion Generation of nitrenes Δ or hν R N N N R N N N R N (c.f. carbene) - N 2 azide Nitrene R C (1,3-dipol) R P(OEt) 3 O Ar R O N S R N O O H O B React. of nitrenes R'-N + R C-H R C N H Insertion 3 3 R' R' N Add. to double bonds R'-N + R C=CR R R 2 2 R R R' R' Dominating react alkyl Rearrangement R C N C N nitrenes H R H Abstraction R'-N + R C-H R'-N-H + R C 3 3 Dimerisation 2 R'-N R'-N=N-R' Nitrene insertion - Heterocyclic synthesis H H + N N R R NO N N H 2 H H

Synthesis of aromatic heterocycles SYNTHESIS OF AROMATIC HETEROCYCLES PDF

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2009

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Preview Synthesis of aromatic heterocycles SYNTHESIS OF AROMATIC HETEROCYCLES

Chapter 3 Synthesis of aromatic heterocycles SYNTHESIS OF AROMATIC HETEROCYCLES CONSTRUCTION OF THE RING SKELETON I. Carbonyl condensation type reactions II. Cycloadditions a) with 1,3-dipoles b) with ortho-quinodimethanes (DA type react.) III. Nitrene insertion Carbonyl condensations a a X X b b X X X X Strategy a) - 5-membered rings 1,4 dicarbonyl X X X=N: NH , RNH 3 2 H H H H H H Pyrrole R-NH 2 O O O HN OH HO N OH - 2 H2O N ±H ±H R R R (Paal-Knorr Synthesis s 255) Furan H H H H H - H O O O O OH O ±H O OH 2 c.f. furan Thiophene H H LR H H LH: Lawesons reagent S O O S S S S P OMe MeO P S S Strategy a) - 6-membered rings 1,5-dicarbonyl X=N: NH 3 X X H NH H 3 O O HO N OH - 2 H2O N H Strategy b 5-membered rings X X O H H OH H OH EWG H EWG H EWG EWG EWG - 2 H O HX 2 X O O O HO X ±H H ±H X H H EWG: CN, COR etc. X: NR; O, S Enol O (or phenol) HX X HO 6-membered rings X X Enamine (or aniline) OH H OH OH H - 2 H O H H H H 2 O H N ±H ±H HO N N O H O NH O NH H 2 I. Carbonyl condensation type reactions II. Cycloadditions a) with 1,3-dipoles b) with ortho-quinodimethanes (DA type react.) III. Nitrene insertion 1,3-Dipolar Cycloaddition 1,3-dipol Only 5-membered rings b b a c a c d e d e Alkene / alkyne Ex. ozonolysis POCl R 3 R R N O 3 O N N N O O O O O O - H2O R O R O nitriloxide isoxazole Cycloaddition with ortho-Quinodimethanes O X S O - SO 2 X Electrocyclic X X X ring opening - 2 HX X Diels-Alder X Ring formed carbocyclic O O Br O O NaI O O Δ N Br N Me Me N Me I. Carbonyl condensation type reactions II. Cycloadditions a) with 1,3-dipoles b) with ortho-quinodimethanes (DA type react.) III. Nitrene insertion Generation of nitrenes Δ or hν R N N N R N N N R N (c.f. carbene) - N 2 azide Nitrene R C (1,3-dipol) R P(OEt) 3 O Ar R O N S R N O O H O B React. of nitrenes R'-N + R C-H R C N H Insertion 3 3 R' R' N Add. to double bonds R'-N + R C=CR R R 2 2 R R R' R' Dominating react alkyl Rearrangement R C N C N nitrenes H R H Abstraction R'-N + R C-H R'-N-H + R C 3 3 Dimerisation 2 R'-N R'-N=N-R' Nitrene insertion - Heterocyclic synthesis H H + N N R R NO N N H 2 H H

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