The document discusses several heterocyclic compounds including quinolines, isoquinolines, and indoles. It summarizes key reactions used to synthesize these compounds, including the Combes, Friedlander, Knorr, and Skraup reactions for quinoline synthesis. It also discusses the Bischler-Napieralski, Pictet-Spengler, and Pomeranz-Fritsch reactions for isoquinoline synthesis and the Fischer, Madelung, and Reissert reactions for indole synthesis, along with mechanisms and examples of each reaction. Reactivity and substitution patterns are also covered for quinolines, isoquinolines and indoles.

1. Heterocyclic
compounds

2. Quinolines and Isoquinolines

3. Reactivity

4. Quinoline and isoquinoline both have
1. Have basic, pyridine-like nitrogen atoms, which undergo
electrophilic substitutions.
2. Are less reactive toward electrophilic substitution than
benzene because of the electronegative nitrogen atom that
withdraws electrons from the ring.
3. Electrophilic substitution occurs on the benzene ring rather
than on the nitrogen-containing pyridine ring, and a mixture of
substitution products is obtained.

6. Important method of synthesis

7. Combes Quinoline Synthesis
The Combes reaction is a sequence of the following reactions:
(a)condensation of an arylamine with a 1,3-diketone, keto-
aldehyde or dialdehyde providing enamine, and
(b)cyclodehydration to provide quinoline.

8. Mechanism

9. Friedlander Quinoline Synthesis
The Friedliinder quinoline synthesis combines an α -amino
aldehyde or ketone with another aldehyde or ketone with at
least one methylene α to the carbonyl to furnish a substituted
quinoline. The reaction can be promoted by acid, base, or
heat.

10. Mechanism

11. Knorr Quinoline Synthesis
The Knorr quinoline synthesis refers to the formation of a-
hydroxyquinolines from p- ketoesters and aryl amines The
intermediate anilide undergoes cyclization by dehydration
with concentrated sulfuric acid

12. Mechanism

13. Skraup Reaction
The Skraup reaction involves the synthesis of quinoline from
the reaction of aniline and glycerol in the presence of a strong
acid and an oxidant.

14. Doebner-Miller synthesis
An primary arylamine with unsubstituted ortho-position is
reacted with α,β-unsaturated compound in presence of an
proton acid and an oxidant to give quinolines.

15. Mechanism

16. Examples

17. Bischler-Napieralski Reaction
The Bischler-Napieralski' reaction involves the cyclization of
phenethyl amides in the presence of dehydrating agents such
as P205 or POC13 to afford 3,4-dihydroisoquinoline products

18. Mechanism

19. Pictet-Spengler Isoquinoline Synthesis
This reaction involves the condensation of a P-arylethyl amine
with an aldehyde, ketone, or 1,2-dicarbonyl compound to give
the corresponding tetrahydroisoquinoline

20. Mechanism

21. Pomeranz-Fritsch Reaction
The Pomeranz-Fritsch reaction involves the preparation of
isoquinolines via the acid- mediated cyclisation of the
appropriate aminoacetal intermediate

22. Mechanism

23. General reactions

26. Indoles

27. Reactivity

28. indoles undergoes electrophillic substitution at C3 or C2 (if C3
is blocked)
indole anion is obtained at deprotonation. The indolyl anion
get substituted at N to give N-substituted derivatives.

29. Important method of synthesis

30. Fischer Indole Synthesis
The Fischer indole synthesis can be regarded as the cyclization
of an arylhydrazone of an aldehyde or ketone by treatment
with acid catalyst or effected thermally to form the indole
nucleus

31. Mechanism

32. Madelung Indole Synthesis
The intramolecular cyclization of N-acylated-o-alkylanilines
in the presence of a strong base at elevated temperatures is
known as the Madelung indole synthesis

33. Mechanism

34. Reissert Indole Synthesis
The Reissert procedure involves base-catalyzed condensation
of an α-nitrotoluene derivative with an ethyl oxalate which is
followed by reductive cyclization to an indole-2carboxylic
acid derivative

35. Mechanism

36. General reactions