Heterocyclic Chemistry: Parts 2 and 3

Year 3, Semester 1 Dr Boa, C301, a.n.boa@hull.ac.uk

Contents Overview Part 2 1. HETEROCYCLES - INTRODUCTION 2. QUINOLINES & QUINOLONES 3. ISOQUINOLINES 4. INDOLES 5. MISC. HETEROCYCLES & MID COURSE REVIEW Part 3 1. 1,3-DIPOLAR CYCLOADDITION REACTIONS - INTRODUCTION 2. ISOXAZOLES AND ISOXAZOLINES 3. ISOXAZOLIDINES 4. DIAZOLES AND TRIAZOLES 5. COURSE REVIEW Suggested reading Organic Chemistry, 1st Ed., J. Clayden, N. Greeves, S. Warren and P. Wothers, OUP. Chapters 42, 43 and 44 (sections thereof). Aromatic Heterocyclic Chemistry, D.T. Davies, OUP, QD 400 D2 Heterocyclic Chemistry, T.L. Gilchrist, QD 400 G5 Heterocyclic Chemistry, J.A. Joule, K. Mills and G.F. Smith, QD 400 J8 Learning outcomes: At the end of the course you should be able to: 1. Identify, draw and be familiar with the names of the classes of heterocyclic molecules covered in the course (not detailed nomenclature) 2. Distinguish between cyclisation and cycloaddition reactions and describe the general features of each class 3. Formulate products arising from cyclisation and cycloaddition reactions. I.e. work out what heterocycle is produced from a given set of reagents (including methods for making 1,3-dipoles) 4. Apply the ring modification reactions covered to given heterocycles 5. Give synthetic sequences for the syntheses covered (identify intermediates) 6. Describe the influence of reaction conditions on product (isomer) distribution 7. Explain isomer distribution in cyclisation reactions in terms of thermodynamic and kinetic effects. 8. Describe the effect of ring substituents on rates of cyclisation reaction and isomer distribution. For a full set of notes and sample past paper questions (some with solutions) see http://www.hull.ac.uk/php/chsanb/teaching.html

HETEROCYCLE PROBLEMS Formulate the products from the following reactions, all of which are the Doebner-von Miller variation of the Skraup quinoline synthesis.
H 1 + NH2 H3 C O ?

Br 2 H2 N + Ph

H O ?

3 NH2

CH3 CH3 + H3C O ?

O 4 Br + NH2
O 5 Et NH2 + Ph CH3 ?

H Ph

Et 6 F
Br 7 H2N + H3C O

NH2

O + H Ph ?

? CH2CH3

Formulate the products from the following reactions, all of which are Fischer indole syntheses.
O 8 NHNH2 + H3 C ?

O 9 NHNH2 + H3 C CH3 ?

10 NHNH2
Br 11 H2NHN +

O + ?
O CH3CH2 CH2CH3 ?

Br 12 NHNH2 + H3C

O CH3
O NHNH2

13 MeO

O 14 NHNH2 CH3
O 15 CH3 NHNH2 + ?

H3C

Ph

16

F NHNH2

O + ?

From what starting materials could you make these two indoles? Will there be any problems with formation of isomeric products? If so what is (are) their structure(s)?
17 ? + ? H3C N H

CH3

18

MeO

N H

Given the information provided formulate the unknown products from the following reactions.
O 19 N H O O + CH3 N H CH3CH2 O + CH3 O Ph KOH EtOH-H2O heat N O Ph KOH EtOH-H2O heat Ph CO2H

H3C 20 ? O Ph 1. 150 oC 2. c. H2SO4 NH2 + O OEt

1. AcOH, 40 oC, with azeotropic removal of H2O 2. Ph2O, 250 oC