Heterocyclic Chemistry

Professor J. Stephen Clark

Room C4-04 Email: stephenc@chem.gla.ac.uk

20112012
http://www.chem.gla.ac.uk/staff/stephenc/UndergraduateTeaching.html
1

Recommended Reading
Heterocyclic Chemistry J. A. Joule, K. Mills and G. F. Smith Heterocyclic Chemistry (Oxford Primer Series) T. Gilchrist Aromatic Heterocyclic Chemistry D. T. Davies

Introduction

Course Summary

Definition of terms and classification of heterocycles Functional group chemistry: imines, enamines, acetals, enols, and sulfur-containing groups Intermediates used for the construction of aromatic heterocycles

Synthesis of aromatic heterocycles Carbonheteroatom bond formation and choice of oxidation state Examples of commonly used strategies for heterocycle synthesis
Pyridines General properties, electronic structure Synthesis of pyridines Electrophilic substitution of pyridines Nucleophilic substitution of pyridines Metallation of pyridines Pyridine derivatives Structure and reactivity of oxy-pyridines, alkyl pyridines, pyridinium salts, and pyridine N-oxides Quinolines and isoquinolines General properties and reactivity compared to pyridine Electrophilic and nucleophilic substitution quinolines and isoquinolines General methods used for the synthesis of quinolines and isoquinolines
3

Course Summary (cont)

Five-membered aromatic heterocycles General properties, structure and reactivity of pyrroles, furans and thiophenes Methods and strategies for the synthesis of five-membered heteroaromatics

Electrophilic substitution reactions of pyrroles, furans and thiophenes Strategies for accomplishing regiocontrol during electrophilic substitution Metallation of five-membered heteroaromatics and use the of directing groups
Indoles Comparison of electronic structure and reactivity of indoles to that of pyrroles Fisher and Bischler indole syntheses Reactions of indoles with electrophiles Mannich reaction of indoles to give 3-substituted indoles (gramines) Modification of Mannich products to give various 3-substituted indoles 1,2 and 1,3-Azoles Structure and reactivity of 1,2- and 1,3-azoles Synthesis and reactions of imidazoles, oxazoles and thiazoles Synthesis and reactions of pyrazoles, isoxazoles and isothiazoles
4

Introduction
Heterocycles contain one or more heteroatoms in a ring
X Y X Z Y X

carbocycle

heterocycles X, Y, Z are usually O, N or S

Aromatic, or partially or fully saturated this course will focus on aromatic systems Heterocycles are important and a large proportion of natural products contain them Many pharmaceuticals and agrochemicals contain at least one heterocyclic unit Heterocyclic systems are important building-blocks for new materials possessing interesting electronic, mechanical or biological properties

Classification Aromatic Six-Membered

Isoelectronic carbocycle
4 3 2
N

Heterocycles
4 5 6 1 pyridine 4 3 2 N
N

3 2 1
O
X

5 6

pyrylium 4 4
N

5 6

3 N 2
N

5 6

3 2
N

5 6 1 pyrazine

1 pyridazine

1 pyrimidine

4 3 2
N

5 6 7 3 2N

5 6 7

8 1 quinoline

1 8 isoquinoline

Isoelectronic carbocycle

Classification Aromatic Five-Membered

Heterocycles
3 5 2
O

3 2 1
N H

4 5 1 furan 2

4 5
S

pyrrole 3 2
N

1 thiophene 3 5 2
S N

4 1
N H

3 5 2

N O

4 5

imidazole 3 2N 1
N H

1 oxazole 3 4 5
O

1 thiazole 3 2N
S

4 5

4 5

2 N

pyrazole 4 3 2 1
N H

1 isoxazole

1 isothiazole

5 6 7

indole

Classification Unsaturated / Saturated

Unsaturated
O O

aromatic dipolar resonance form

O O

4()-pyrone

N H

N H

OH

2-pyridone

Saturated
O O O O N H O

ethylene oxide

THF

1,4-dioxan

pyrrolidine

dihydropyran

Functional Group Chemistry

Imine Formation
R3 O R1 H H R R2
3

R3 N

R3NH2 H R2 H3O R1

N R2 H R1

R2

H O R1

N R1

H OH R2

H R
3

R3 OH2 R2 R1 N

N R1

R2

Removal of water is usually required to drive the reaction to completion If a dialkylamine is used, the iminium ion that is formed cant lose a proton and an enamine is formed

Functional Group Chemistry

Enols and Enolates
O R
1

OH R R
2 1

B H H R
2

O R
1

O R1 R
2

E R
2

R1

keto form

enol form

enolate

The enol form is favoured by a conjugating group R2 e.g. CO2R, COR, CN, NO2 etc. Avoid confusing enols (generated under neutral/acidic conditions) with enolates (generated under basic conditions) Enolates are nucleophilic through C or O but react with C electrophiles through C Enol Ethers
3

R O R
1

OR

OR R
1

R O H R
1

R OH

acetal

R2

enol ether

H2O R1

10
R
2

Functional Group Chemistry

Enamines
R3 O R1 R2 N H R3 H R1 R2 R3 N H H R1 R2 R3 R
3

R N

iminium ion (Schiff base)

R3 N R
1

enamine

R3

R3 N E R1

R3 H2O E R2 R1 R2 O E

R2

Analogues of enols but are more nucleophilic and can function as enolate equivalents Removal of water (e.g. by distillation or trapping) drives reaction to completion Enamines react readily with carbon nucleophiles at carbon Reaction at N is possible but usually reverses

11

Functional Group Chemistry

Common Building-Blocks
O R OH R O R NH2 NH NH2

carboxylic acids
O H2N NH2 H2N NH NH2

amides

amidines
O O R2

O R1

O OR2

R1

urea

guanidine

-diketones

-keto esters

Building-Blocks for Sulfur-Containing Heterocycles

O R
1

P2S5 R
2

S R R
1

SH

R1 S

R2

thioketones

thiols

thioethers

Heterocycle synthesis requires: CO or CN bond formation using imines, enamines, acetals, enols, enol ethers CC bond formation using enols, enolates, enamines During heterocycle synthesis, equilibrium is driven to the product side because of removal of water, crystallisation of product and product stability (aromaticity) 12

General Strategies for Heterocycle Synthesis

Ring Construction Cyclisation 5- and 6-membered rings are the easiest to form CX bond formation requires a heteroatom nucleophile to react with a C electrophile
Y Y

+
X

+ +
X X, Y = O, S, NR

conjugate addition

Manipulation of Oxidation State

[O] H2 X X [ O] H2 X

or
X

[ O] H2 X

hexahydro

tetrahydro

dihydro

aromatic

Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation

13

General Strategies for Heterocycle Synthesis

Common Strategies 4+1 Strategy
X X H N NH3 2H2O O O N H O O NH3 2H2O N H N

Strategy can be adapted to incorporate more than one heteroatom 5+1 Strategy
X
H NH3 2H2O O O N H [O ] H2 N

1,5-Dicarbonyl compounds can be prepared by Michael addition of enones

14

General Strategies for Heterocycle Synthesis

3+2 Strategy
or
X X X
X X

3+3 Strategy
or
X

Examples
X H2N

H2N O H2N OH

+ +
O

OH

H2N

+
O

+ Hal +
O Hal = Cl, Br, I

+
O E E

NH2

NH2

OH

OH

15

Bioactive Pyridines
H
N H N H

N N O O S NH2

nicotine

sulphapyridine

Nicotine is pharmacologically active constituent of tobacco toxic and addictive Sulphapyridine is a sulfonamide anti-bacterial agent one of the oldest antibiotics
NH2 O NH

Me

Me
N

paraquat

isoniazide

Paraquat is one of the oldest herbicides toxic and non-selective Isoniazide has been an important agent to treat tuberculosis still used, but resistance 16 is a significant and growing problem

Drugs Containing a Pyridine

MeO N S N H N N H N O OMe N S O O OMe

Name: Nexium 2008 Sales: $4.79 billion 2008 Ranking: 2 branded Company: AstraZeneca Disease: Acid reflux

Name: Aciphex 2008 Sales: $1.05 billion 2008 Ranking: 34 branded Company: Eisai Disease: Duodenal ulcers and acid reflux

S O O O NH

N N

H N

N HN N O N

Name: Actos 2008 Sales: $2.45 billion 2008 Ranking: 10 branded Company: Eli Lilly Disease: Type 2 diabetes

Name: Gleevec 2008 Sales: $0.45 billion 2008 Ranking: 87 branded Company: Novartis 17 Disease: Chronic myeloid leukemia

Pyridines Structure
1.40 1.39
N 1.34

2.2 D
N

1.17 D

<

..

Isoelectronic with and analogous to benzene Stable, not easily oxidised at C, undergoes substitution rather than addition I Effect (inductive electron withdrawal) M Effect
+ + +

Weakly basic pKa ~5.2 in H2O (lone pair is not in aromatic sextet) Pyridinium salts are also aromatic ring carbons are more + than in parent pyridine
etc.
N H N H N H

<

<

N H

<

18

Pyridines Synthesis
The Hantzsch synthesis (5+1)
O Me Me O Ph O H O Me NH3 pH 8.5 Me O Me aldol condensation Me O O Me O Ph O Me Me OO Me O H Ph O Me

Michael addition Me

and dehydration

O Me Me

Ph

O Me HNO3 Me

Ph

O Me Me

Ph

O Me

Me

oxidation

Me

N H

Me

Me H2N

Me

The reaction is useful for the synthesis of symmetrical pyridines The 1,5-diketone intermediate can be isolated in certain circumstances A separate oxidation reaction is required to aromatise the dihydropyridine
19

Pyridines Synthesis
From Enamines or Enamine Equivalents the Guareschi synthesis (3+3)
CO2Et CN H2N Me N H O O Me O O HN 2 Me K2CO3 EtO2C N 73% Me K2CO3 CN CO2Et CN Me CN

The -cyano amide can exist in the enol form Using Cycloaddition Reactions (4+2)
CO2H Me O N Me O Me CO2H H+ N Me O Me N

CO2H H H H

Diels-Alder Me cycloaddition

CO2H Me H2O Me N 70% HO Me Me

CO2H

Oxazoles are sufficiently low in aromatic character to react in the Diels-Alder reaction
20

Pyridines Electrophilic Reactions

Pathways for the Electrophilic Aromatic Substitution of Pyridines

N E N E

E N E N E

The position of the equilibrium between the pyridine and pyridinium salt depends on the substitution pattern and nature of the substituents, but usually favours the salt

21

Pyridines Electrophilic Reactions

Regiochemical Outcome of Electrophilic Substitution of Pyridines
E E H N N H N E H

E N E H H E N H H E E N H H E

N N N

Resonance forms with a positive charge on N (i.e. 6 electrons) are very unfavourable The -substituted intermediate, and the transition state leading to this product, have more stable resonance forms than the intermediates/transition states leading to the 22 / products

Pyridines Electrophilic Reactions

Regiochemical Outcome of Electrophilic Substitution of Pyridinium Ions
E E H N E N E H N E E H

+
E N E E H E H N E H E H E N E H H E

N E N E N E

Regiochemical control is even more pronounced in the case of pyridinium ions In both pyridine and pyridinium systems, substitution is favoured but the reaction is slower than that of benzene Reaction will usually proceed through the small amount of the free pyridine available
23

Pyridines Electrophilic Reactions

N Substitution
NO2 BF4 N BF4 NO2 R Cl SO3, CH2Cl2 O N MeI N Me

N O

Cl R

N SO3

C Substitution Reaction at C is usually difficult and slow, requiring forcing conditions Friedel-Crafts reactions are not usually possible on free pyridines

24

Pyridines Electrophilic Reactions

Nitration of Pyridine
NO2 c-H2SO4, c-HNO3 300 C, 24 h N N 6% !

Use of Activating Groups

Me Me Me NO2 c-HNO3, oleum 100 C Me N Me Me Me N H Me MeI Me N Me Me I N Me Me c-HNO3, oleum 100 C Me I N Me Me 70% Me Me N 90% Me NO2 Me

Multiple electron-donating groups accelerate the reaction Both reactions proceed at similar rates which indicates that the protonation at N occurs 25 prior to nitration in the first case

Pyridines Electrophilic Reactions

Sulfonation of Pyridine
H2SO4, SO3 (low yield) N HgSO4, H2SO4, 220 C 70% N SO3H

N HgSO3

Low yield from direct nitration but good yield via a mercury intermediate

Halogenation of Pyridine
Cl Cl2, AlCl3, 100 C N 33% N Br2, oleum 130 C N 86% Br

Forcing reaction conditions are required for direct halogenation

26

Pyridines Reduction
Full or Partial Reduction of Pyridines
R H2, Pt, AcOH, rt N H N R Na-NH3, EtOH N H R

Na, EtOH

N H

Pyridines generally resist oxidation at ring carbon atoms and will often undergo side-chain oxidation in preference to oxidation of the ring Full or partial reduction of the ring is usually easier than in the case of benzene

27

Pyridines Nucleophilic Reactions

Regiochemical Outcome of Nucleophilic Addition to Pyridines

H N Nu Nu Nu N

H Nu N

H Nu N

H Nu N Nu N H Nu

H Nu N Nu H

N Nu H

Nu

N N N N

Nitrogen acts as an electron sink Substitution is less favoured because there are no stable resonance forms with the negative charge on N Aromaticity will is regained by loss of hydride or a leaving group, or by oxidation
28

Pyridines Nucleophilic Reactions

Nucleophilic Substitution
X Nu N X = Cl, Br, I, (NO2) Nu = MeO , NH3, PhSH etc. N X Nu

Favoured by electron-withdrawing substituents that are also good leaving groups The position of the leaving group influences reaction rate ( > >> )
Cl NaOEt N N OEt

Cl

Cl Cl

N NO2

Cl

Relative rate

80

40

3 104

29

Pyridinium Ions Nucleophilic Reactions

Nucleophilic Substitution
X Nu N R X = Cl, Br, I, (NO2) N R X Nu

Nu = MeO , NH3, PhSH etc.

Conversion of a pyridine into the pyridinium salt greatly accelerates substitution Substituent effects remain the same (, >> ) but now >
Cl O2N O O NO2

N Me

N Me

Cl Cl Cl

N Me

Cl

N Me

N Me

Relative rate

5 107

1.5 104

104

30

Pyridines Pyridyne Formation

Substitution via an Intermediate Pyridyne
Cl H NH2 NH2 N NaNH2 N N 27% H NH2 H2N

H2N benzyne Cl H NH2 NaNH2 N

H NH2 NH2

N 44%

When very basic nucleophiles are used, a pyridyne intermediate intervenes Pyridynes are similar to benzynes and are very reactive (not isolable)

31

Pyridines Nucleophilic Reactions

Nucleophilic Attack with Transfer of Hydride
PhLi, Et2O, 0 C Ph N H N Li Ph N O2 (air)

LiNH2

H2 H2N H H N Li NHX H2N N

H2O LiNH2 HN Li N

X = H (NH3) / 2-aminopyridine

A hydride acceptor or oxidising agent is required to regenerate aromaticity The reaction with LiNH2 is referred to as the Chichibabin reaction

32

Pyridines Metal-Halogen Exchange

Direct Exchange of Metal and a Halogen
X n-BuLi N N Li n-Bu X

X = Cl, Br, I

Halogenated pyridines do not tend to undergo nucleophilic displacement with alkyl lithium or alkyl magnesium reagents Metallated pyridines behave like conventional Grignard reagents
N Li Br n-BuLi, Et2O, 78 C N N N Li PhC N Ph

O Ph H2O N N

NH Ph

33

Pyridines Directed Metallation

Use of Directing Groups
Me OMe Li O t-BuLi, Et2O, 78 C N O Ni-Pr2 LiTMP, 78 C N N Ph NMe2 N O Li O Ni-Pr2 O N N 90% Ph O Me Ni-Pr2 Me N Li LiTMP Me Me O I(CH2)2Cl O I O OMe

Directing groups allow direct lithiation at an adjacent position A Lewis basic group is required to complex the Lewis acidic metal of the base

34

Oxy-Pyridines Structure
Oxy-Pyridines/Pyridones

N OH OH N H O O N H zwitterion O O

1,3-dipole O

N N H N H zwitterion O O N H

OH

N N H zwitterion N H N H N H

Subject to tautomerism The , systems differ from the systems in terms of reactivity and structure In the case, the equilibrium is highly solvent dependent, but the keto form is favoured 35 in polar solvents

Amino Pyridines Structure

Amino Pyridine Systems

etc. N H NH N NH2 N NH2

Contrast with oxy-pyridines Amino pyridines are polarised in the opposite direction to oxy-pyridines

36

Oxy-Pyridines Reactions
Electrophilic Substitution
Br OH Br2, H2O, rt N O c-H2SO4, c-HNO3 100 C, 2 days N H N H 38% Br N O NO2 OH

Br

Reactions such as halogenation, nitration, sulfonation etc. are possible N is much less basic than that in a simple pyridine Substitution occurs ortho or para to the oxygen substituent (cf. phenols)

37

Oxy-Pyridines Reactions
Nucleophilic Substitution
PCl5 Cl N H Cl O PCl4 N H Cl O PCl3 N Cl H O Cl PCl3

Cl N H Cl O PCl3 Cl N Cl H O PCl3

Replacement of the oxygen substituent is possible In this case, the reaction is driven by the formation of the very strong P=O bond

38

Oxy-Pyridines Reactions
Cycloaddition
O Me N Me Me CO2Me CO2Me O CO2Me Me Me N CO2Me

Oxy-pyridines have sufficiently low aromatic character that they are able to participate as dienes in Diels-Alder reactions with highly reactive dienophiles

39

Alkyl Pyridines Deprotonation

Deprotonation with a Strong Base
CH3 PhLi N O R1 R2 OH R1 R2 N N CH2 CH

etc.

Deprotonation of and alkyl groups proceeds at a similar rate, but alkyl groups are much more difficult to deprotonate Bases are also potential nucleophiles for attack of the ring
40

Pyridinium Salts Reactions

Nucleophilic Attack with Reducing Agents
H BH3 N NaBH4, EtOH N Me H BH3 N Me H3B N H Me N Me Me N Me H BH3 N Me

Nucleophilic attack is much easier (already seen this) Deprotonation of alkyl substituents is easier (weak bases are suitable) Ring opening is possible by attack of hydroxide

H N O2N OH O2N N O OH O2N

etc.

41
NO2 NO2 NO2

Pyridine N-Oxides
N-Oxide Formation
RCO3H N N O O Cl O O H N O N O

meta-chloroperoxybenzoic acid (m-CPBA)

The reactivity N-oxides differs considerably from that of pyridines or pyridinium salts A variety of peracids can be used to oxidise N but m-CPBA is used most commonly N-Oxide formation can be used to temporarily activate the pyridine ring to both nucleophilic and electrophilic attack

42

Pyridine N-Oxides
Electrophilic Substitution
H c-H2SO4, N O c-HNO3, 100 C N O N O N O NO2 H NO2 NO2

The N-oxide is activated to attack by electrophiles at both the and positions Nitration of an N-oxide is easier than nitration of the parent pyridine Reactivity is similar to that of a pyridinium salt in many cases e.g. nucleophilic attack, deprotonation of alkyl groups etc. Removal of O
NO2 PPh3 N O PPh3 N O PPh3 O N PPh3 NO2 NO2

Deoxgenation is driven by the formation of the very strong P=O bond

43

Pyridines Synthesis of a Natural Product

Synthesis of Pyridoxine (Vitamin B6) Using the Guareschi Synthesis
EtO CN EtO O2N CN c-HNO3, Ac2O, 0 C Me N H 90% O Me N H 32% EtO CN

O Me O

H2N

piperidine, EtOH, heat

C PCl5, POCl3, 150

HO OH HO H2N 1. NaNO2, HCl, 90 C N 2. 48% HBr (neat) 3. AgCl, H2O, heat Me

EtO NH2 O2N H2, Pd/Pt, AcOH N 40% Me

EtO CN

Me

N 40%

Cl

The final sequence of steps involves formation of a bis-diazonium salt from a diamine Pyridoxine performs a key role as the coenzyme in transaminases
44

Bioactive Quinolines/Isoquinolines
H Me HO N H MeO MeO HN NEt2

quinine

chloroquine

Quinine is an anti-malarial natural product isolated from the bark of the Cinchona tree Chloroquine is a completely synthetic anti-malarial drug that has the quinoline system found in quinine parasite resistance is now a problem
MeO N MeO OMe

OMe

papaverine

Papaverine is an alkaloid isolated from the opium poppy and is a smooth muscle45 relaxant and a coronary vasodilator

Drugs Containing a Quinoline/Isoquinoline

S Cl N CO2H Ph CO2Et N H O HO2C N

Name: Singulair 2008 Sales: $2.90 billion 2008 Ranking: 7 branded Company: Merck Disease: Asthma and allergies

HO

Name: Quinapril 2008 Sales: $133 million 2008 Ranking: 84 generic Company: N/A Disease: Hypertension and heart failure

N HN OH

Cl

Name: Hydroxychloroquine 2008 Sales: $74 million 2008 Ranking: 146 generic Company: N/A Disease: Malaria, lupus erythematosus, rheumatoid arthritis

46

Malaria
Approximately 500 million cases of malaria each year and 13 million deaths Disease is caused by protazoan parasites of the genus Plasmodium (falciparum, vivax, ovale and malariae) Disease spread by the Anopheles mosquito (female)

Cinchona pubescens

47

Anopheles mosquito

Plasmodium monocyte

Quinolines Synthesis
Structure
N N

pKa values (4.9 and 5.4) are similar to that of pyridine Possess aspects of pyridine and naphthalene reactivity e.g. form N-oxides and ammonium salts Combes Synthesis (3+3)
MeO Me H2O NH2 MeO MeO N Me MeO c-H2SO4, MeO Me MeO Me OH MeO H O H2O N MeO 23% Me MeO N H Me MeO N H Me Me N H Me O O Me MeO O Me MeO O Me

48

Quinolines Synthesis
Conrad-Limpach-Knorr Synthesis (3+3)
O Me rt, H2O NH2 N H Me 70% N Me N H Me O O OEt 270 C OEt OH O

Very similar to the Combes synthesis by a -keto ester is used instead of a -diketone Altering the reaction conditions can completely alter the regiochemical outcome

O Me

O O OEt N H

Me 250 C, H2O O

Me

Me

140 C, H2O NH2

N 50% H

OH

49

Quinolines Synthesis
Skraup Synthesis (3+3)
OH H H 130 C, H2SO4 NH2 N H N H H O O H

H [O] (e.g. I2) N 85% N H H2O N H

OH

Acrolein can be generated in situ by treatment of glycerol with conc. sulfuric acid A mild oxidant is required to form the fully aromatic system from the dihydroquinoline
1. Me Me ZnCl2 or FeCl3, NH2 EtOH, reflux 2. [O] N O Me Me

65%

50

Quinolines Synthesis
Friedlander Synthesis (4+2)
Ph O NH2 Me Me c-H2SO4, AcOH heat N H Me O Ph H O Me H2O N Ph Me

88%

Me

Ph Me O NH2

O Me KOH aq., EtOH 0 C OH

Ph O H2O

Ph

N H Me

71%

N Me

The starting acyl aniline can be difficult to prepare Acidic and basic conditions deliver regioisomeric products in good yields
51

Isoquinolines Synthesis
Pomeranz-Fritsch Synthesis (3+3)
EtO OEt OEt OEt H , EtOH N N

H2N O H H2O

Bischler-Napieralski Synthesis (5+1)

MeCOCl NH2 NH O Me Me 93% Me P4O10, heat N Pd-C, 190 C N

Cyclisation can be accomplished using POCl3 or PCl5 Oxidation of the dihydroisoquinoline can be performed using a mild oxidant
52

Isoquinolines Synthesis
Pictet Spengler Synthesis (5+1)
MeO MeO HCHO 20% aq. NH2 heat N MeO 20% HCl aq. 100 C N H

MeO [O] N

MeO NH 80%

MeO NH H

An electron-donating substituent on the carboaromatic ring is required A tetrahydroisoquinoline is produced and subsequent oxidation is required to give the fully aromatic isoquinoline

53

Quinolines/Isoquinolines Electrophilic Reactions

Regiochemistry
*

N N H H

Under strongly acidic conditions, reaction occurs via the ammonium salt Attack occurs at the benzo- rather than hetero-ring Reactions are faster than those of pyridine but slower than those of naphthalene
NO2 fuming HNO3, N C cH2SO4, 0 72% N 8% NO2 N

Nitration

In the case of quinoline, equal amounts of the 5- and 8-isomer are produced

54

Quinolines/Isoquinolines Electrophilic Reactions

Sulfonation
HO3S 30% oleum3, 90 C N N SO3H 54% N >250 C

thermodynamic product

Halogenation is also possible but product distribution is highly dependent on conditions It is possible to introduce halogens into the hetero-ring under the correct conditions Friedel-Crafts alkylation/acylation is not usually possible

55

Quinolines/Isoquinolines Nucleophilic Reactions

Regiochemistry
N N

Attack occurs at hetero- rather than benzo-ring They are enerally more reactive than pyridines to nucleophilic attack Carbon Nucleophiles
2-MeOC6H4Li Et2O, rt N N Li [O] H H2O OMe N H H OMe

N MeO

56

Quinolines/Isoquinolines Nucleophilic Reactions

n-BuLi N benzene, rt N Li H n-Bu H n-Bu n-Bu H2O NH [O] N

Oxidation is required to regenerate aromaticity Amination

KNH2, NH3 (l) 65 C N KMnO4, 65 C N K H NH2 N K KMnO4, 40 C NH2 >45 C H NH2

50%

NH2

60%

thermodynamic product

57

Quinolines/Isoquinolines Nucleophilic Substitution

Displacement of Halogen

NaOEt, EtOH reflux N Cl N Cl OEt OMe Cl N 87% N N OEt

Cl NaOMe, MeOH N DMSO 100 C

OMe

58

Quinolines/Isoquinolines The Reissert Reaction

PhCOCl N O N CN Ph O KCN H N CN Ph

base, MeI

NaOH aq. Me N Me HO O N CN Ph O N Me CN Ph

The proton adjacent to the cyano group is extremely acidic The reaction works best with highly reactive alkyl halides
59

Isoquinolines Synthesis of a Natural Product

Synthesis of Papaverine
O MeO MeO Me Me2CH(CH2)2ONO, NaOEt, EtOH, rt MeO MeO 75% N OH MeO O O MeO ZnCl2, HCl, rt NH2 Cl O

KOH aq., rt

H MeO P4H10, N MeO 30% OMe MeO xylene, heat MeO O MeO

OH MeO Na-Hg, H2O, 50 C NH MeO O

O OMe NH

OMe

60% OMe MeO MeO OMe

Cyclisation is achieved by the Pictet-Grams reaction cf. the Bischler-Napieralski reaction

60

Bioactive Furans, Pyrroles and Thiophenes

NO2 Me2N O N S NHMe

ranitidine

Ranitidine (Zantac, GSK) is one of the biggest selling drugs in history. It is an H2-receptor antagonist and lowers stomach acid levels used to treat stomach ulcers
O N Ph CO2H

ketorolac

Ketorolac (Toradol, Roche) is an analgesic and anti-inflammatory drug

Me N S

banminth

Pyrantel (Banminth, Phibro) is an anthelminthic agent and is used to treat worms in 61 livestock

Drugs Containing a Furan/Thiophene/Pyrrole

MeO2C N S O2N O Cl O N NH N

Name: Plavix 2008 Sales: $3.80 billion 2008 Ranking: 3 branded Company: Bristol-Myers Squibb Disease: Stroke and heart attack risk

O Name: Nitrofurantoin 2008 Sales: $92 + 72 million 2008 Ranking: 119 and 149 generic Company: N/A Disease: Antibiotic for urinary tract infections F

N H O S

HO2C Ph HO N NHPh

HO

Name: Cymbalta 2008 Sales: $2.17 billion 2008 Ranking: 14 branded Company: Eli Lilly Disease: Depression

Name: Lipitor 2008 Sales: $5.88 billion 2008 Ranking: 1 branded Company: Pfizer Disease: Lowers LDL levels

62

Furans, Pyrroles and Thiophenes Structure

Structure

X
O

N H S

..

6 electrons, planar, aromatic, isoelectronic with cyclopentadienyl anion Resonance Structures

etc.
X X X

..

Electron donation into the ring by resonance but inductive electron withdrawal
1.44 1.35 0.71 D 1.37 O 1.38 N
H

1.43 1.37 1.55 D 1.37

1.42 0.52 D 1.71 S

1.68 D
O N H

1.57 D
S

1.87 D

O and S are more electronegative than N and so inductive effects dominate

63

Furans Synthesis
Paal Knorr Synthesis
R1 O O H H heat H H R1 R2 R1 R2 R1 R2 R2 R1 O O H R2 R1 OH R2

O H

OH2

The reaction is usually reversible and can be used to convert furans into 1,4-diketones A trace of acid is required usually TsOH (p-MeC6H4SO3H)

64

Furans Synthesis
Feist-Benary Synthesis (3+2)
Me EtO2C O O

+ Me +

EtO2C

Me

EtO2C Cl

Me

Cl

Me

Cl

Me

NaOH aq., rt OH Me H EtO2C

EtO2C

Me H2O

EtO2C

Me OH

OH Cl

Me

Me

Me

isolable

The product prior to dehydration can be isolated under certain circumstances Reaction can be tuned by changing the reaction conditions

65

Furans Synthesis
Modified Feist-Benary
I EtO2C O

+ Me +

EtO2C O

Me

EtO2C O Me O

Me

Me

Cl I

Me

NaI, NaOEt, EtOH

EtO EtO2C H 2 O Me Me O Me Me O OH Me O EtO2C EtO2C H Me O

Iodide is a better leaving group than Cl and the carbon becomes more electrophilic The Paal Knorr sequence is followed from the 1,4-diketone onwards The regiochemical outcome of the reaction is completely altered by addition of iodide

66

Thiophenes Synthesis
Synthesis of Thiophenes by Paal Knorr type reaction (4+1)
Me Me Me Me O O Me O S Ph Ph P4S10 Me S O Me S Ph Ph Me

Reaction might occur via the 1,4-bis-thioketone

67

Pyrroles Synthesis
Paal Knorr Synthesis (4+1)
Me O NH3, C6H6, heat H R1 R2 R1 R2 O Me Me O HN Me Me O H2N Me

Me

N H

Me

N H

N OH H

Ammonia or a primary amine can be used to give the pyrrole or N-alkyl pyrrole

68

Pyrroles Synthesis
Knorr Pyrrole Synthesis (3+2)
EtO2C O Me KOH aq. MeO2C O NH2 HO2C N H 53%
N

EtO2C

Me

H2N

Me

Me

Me

NH2

Me

Use of a free amino ketone is problematic dimerisation gives a dihydropyrazine

EtO2C O Me NaOH aq. EtO2C O NH3 Cl EtO2C N H EtO2C Me HO EtO2C Me EtO2C O Me

via
EtO2C NH2 O

or
EtO2C N H

Problem can be overcome by storing amino carbonyl compound in a protected form Reactive methylene partner required so that pyrrole formation occurs more rapidly than dimer formation 69

Pyrroles Synthesis
Liberation of an Amino Ketone in situ by Oxime Reduction
EtO2C O Me Zn, AcOH Me O or Na2S2O4 aq. (sodium dithionite) N OH Me N H EtO2C Me

Preparation of -Keto Oximes from -Dicarbonyl Compounds

H O O OEt NaNO2, H (HNO2) H2O N O O O OEt

O OEt N OH

O H

O OEt N O

70

Pyrroles Synthesis
One-Pot Oxime Reduction and Pyrrole Formation
O O O EtO2C CO2Et OEt Zn, AcOH EtO2C N OH CO2Et

N H

CO2Et

Hantzsch Synthesis of Pyrroles (3+2)

EtO2C O

Cl H Me O EtO2C O Me NH Me

+ Me +

EtO2C

Me

Cl

Me

NH2

NH3 aq. rt to 60 C EtO2C H2O Me Me N H 41% Me Me N H OH Me EtO2C EtO2C O NH2 Me

A modified version of the Feist-Benary synthesis and using the same starting materials: an -halo carbonyl compound and a -keto ester 71

Furans, Pyrroles Thiophenes Electrophilic Substitution

Electrophilic Substitution Regioselectivity
H

X E X E E H

E H X E H

E H X E H X

E H X E

X X X

Pyrrole > furan > thiophene > benzene Thiophene is the most aromatic in character and undergoes the slowest reaction Pyrrole and furan react under very mild conditions -Substitution favoured over -substitution more resonance forms for intermediate and so the charge is less localised (also applies to the transition state) Some -substitution usually observed depends on X and substituents
NO2 AcONO2 X X NO2 X

72

X = NH 4:1 6:1 X=O

Furans Electrophilic Substitution

Nitration of Furans
AcONO2, O <0 C (Ac2O, HNO3) NO2 AcO NO2 O H AcO H O NO2 H N

isolable

pyridine, heat AcOH

NO2 O H O NO2

Nitration can occur by an addition-elimination process When NO2BF4 is used as a nitrating agent, the reaction follows usual mechanism Bromination of Furans
Br2, dioxan, 0 C O Br Br Br O Br H Br H O Br H O 80% Br HBr

Furan reacts vigorously with Br2 or Cl2 at room temp. to give polyhalogenated products It is possible to obtain 2-bromofuran by careful control of temperature
73

Furans Electrophilic Substitution

Friedel-Crafts Acylation of Furan
O Me Ac2O, SnCl 4, H3PO4 cat., 20 C O O : 6800:1 Me O Me O Ac2O, SnCl 4, Me 150 C Me O 77% Me

Blocking groups at the positions and high temperatures required to give acylation Vilsmeier Formylation of Furan
Me Me2NCO, POCl3, 0 to 100 C O O 76% H Me O

Mannich Reaction of Furans

CH2O, Me2NH.HCl O O CH2 NMe2 O H NMe2 O 66% NMe2

74

Thiophenes Electrophilic Substitution

Nitration of Thiophenes
NO2 AcONO2 S S NO2 S

Reagent AcONO2 generated in situ from c-HNO3 and Ac2O

Halogenation of Thiophenes
Br2, Et2O, Br S 48% HBr, Br 10 10 C S Br2, Et2O, 48% HBr, 25 5 C S Br

Occurs readily at room temperature and even at 30 C Careful control or reaction conditions is required to ensure mono-bromination

75

Pyrroles Electrophilic Substitution

Nitration of Pyrroles
AcONO2 AcOH, 10 C N H N H 51% NO2 N H 13% NO2

Mild conditions are required (c-HNO3 and c-H2SO4 gives decomposition) Vilsmeier Formylation of Pyrroles
Me N Me H O POCl3 Me Me N H Me OPCl2 Me N H K2CO3 aq. N H 83% Cl

H Cl N H Cl N H Me Me N H NMe2 N H

NMe2

76

Pyrroles Porphyrin Formation

OH OH N H R
1

OH2 N H R
1

N H

H N H
1 2

R N H N H R1

N H

N H

N H

R ,R =H

NH

HN

NH

HN

NH

NH

HN

NH

HN

HN

no extended aromaticity

18 -electron system

The extended aromatic 18 -electron system is more stable than that having four isolated aromatic pyrroles 77

Porphyrin Natural Products

CO2H N Fe N N H2N N H N N HO2C N Mg N N

porphobilinogen
MeO2C HO2C CO2H O O C20H39 O

haem

chlorophyll-a

The pigment haem is found in the oxygen carrier haemoglobin Chlorophyll-a is responsible for photosynthesis in plants Both haem and chlorophyll-a are synthesised in cells from porphobilinogen

78

Furans, Pyrroles Thiophenes Deprotonation

Metallation
n-BuLi X Bu H X >> X = O pKa (THF) X = NR pKa (THF) X=S pKa (THF) 35.6 39.5 33.0 Li

Deprotonation of Pyrroles
R M N H pKa (THF) 39.5 N M M N N M

H pKa (THF) 17.5

Free pyrroles can undergo N or C deprotonation Large cations and polar solvents favour N substitution A temporary blocking group on N can be used to obtain the C-substituted compound
79

Furans, Pyrroles Thiophenes Directed Metallation

Control of Regioselectivity in Deprotonation
Y n-BuLi X X H Y Li Bu Li X Y

Common directing groups: CO2H(Li), CH2OMe, CONR2, CH(OR)2

Synthesis of ,-Disubstituted Systems

Y Y Y

n-BuLi
E X
1

n-BuLi
X E
1

E2

E2

Use of a Trialkylsilyl Blocking Group

Y n-BuLi Me3SiCl X X Y n-BuLi SiMe3 E E X SiMe3 Y F E X Y

80

Furans Synthesis of a Drug

Preparation of Ranitidine (Zantac) Using a Mannich Reaction
Me2NH.HCl, O O O OH CH2O, rt Me2N O OH HS(CH2)2NH2, c-HCl, heat

furfural

NO2

NO2 Me2N O N S NHMe

MeS

NHMe Me2N O NH2 S

ranitidine

Furfural is produced very cheaply from waste vegetable matter and can be reduced to give the commercially available compound furfuryl alcohol The second chain is introduced using a Mannich reaction which allows selective substitution at the 5-position The final step involves conjugate addition of the amine to the ,-unsaturated nitro compound and then elimination of methane thiol 81

Indoles Bioactive Indoles

O H Me X CO2H H NH2 MeNH N H N H N X = OH lysergic acid H X = NEt2 lysergic acid diethyamide (LSD) O S O NMe2 N H

tryptophan

sumatriptan

Tryptophan is one of the essential amino acids and a constituent of most proteins Sumatriptan (Imigran, GSK) is a drug used to treat migraine and works as an agonist for 5-HT receptors for in the CNS LSD is a potent psychoactive compound which is prepared from lysergic acid, an alkaloid natural product of the ergot fungus
HO NH2

N H

5-hydroxytryptamine (serotonin)

82

Indoles Lysergic Acid

The Beggars (The Cripples) by Pieter Breugel the Elder (1568) Louvre Museum, Paris

83

Drugs Containing an Indole

H NMe2 H N S O O N H N H N

O N

Name: Imitrex 2008 Sales: $0.97 billion 2008 Ranking: 35 branded Company: GlaxoSmithKline Disease: Migraine
NMe2 O S N N N N H Ph O

Name: Cialis O 2008 Sales: $0.56 billion 2008 Ranking: 66 branded Company: Eli Lilly Disease: Erectile disfunction

N H

Name: Maxalt 2008 Sales: $0.22 billion 2008 Ranking: 148 branded Company: Merck Disease: Migraine

Name: Relpax 2008 Sales: $0.21 billion 2008 Ranking: 151 branded Company: Pfizer Disease: Migraine

84

Indoles Synthesis
Fischer Synthesis
R NH2
1

O R H2O N H
2

R1 R N
2

H or Lewis acid NH3 N H

N H

Ph ZnCl2, 170 C N N H 76% H Ph Ph NH N H N H H Ph [3,3] N H NH2 H NH NH2 NH2 NH2 Ph Ph NH3 N H H Ph

A protic acid or a Lewis acid can be used to promote the reaction

85

Indoles Synthesis
Bischler Synthesis
H O Me polyphosphoric acid (PPA), 120 C N O CF3 N O CF3 O Me H2O KOH aq. N 64% H Me

An -arylaminoketone is cyclised under acidic conditions

The reaction also works with acetals of aldehydes

Me EtO OEt (CF3CO)2O, CF3CO2H, heat N O CF3 93% O N CF3 Me

86

Indoles Electrophilic Substitution

Nitration of Indoles
O2N Me N 84% H c-H2SO4, c-HNO3 0 C N H Me PhCO2NO2, 0 C N 35% H NO2 Me

Polymerisation occurs when there is no substituent at the 2-position Halogenation is possible, but the products tend to be unstable Acylation of Indoles
Ac2O, AcOH, heat N H Ac2O, AcONa N -product! Me Ac2O, AcOH, heat O O Me NaOH aq., rt N 60% H O Me

N O Me

Acylation occurs at C before N because the N-acylated product does not react

87

Indoles Electrophilic Substitution

Mannich Reaction
NMe2 CH2O, Me2NH, N H H2O, 0 C N H2O, heat 93% or AcOH, rt 68% NMe2 H2C NMe2 (preformed) 95% N H

A very useful reaction for the synthesis of 3-substituted indoles The product (gramine) can be used to access a variety of other 3-substituted indoles Synthesis of Tryptophan from Gramine
EtO2C NMe2 EtO2C Na N H CO2Et NHAc NHAc N 90% H NaOH aq. then H2SO4, heat N 80% H NH2 CO2Et CO2H

PhMe, heat

88

Indoles Electrophilic Substitution

Synthesis of Other 3-Substituted Indoles from Gramine
MeSO4 NMe3 NaCN aq., 70 C N H2O H H2O H N N 100% H CN CN

The nitrile group can be modified to give other useful functionality

CN NH2 LiAlH4 N H N H acid/base hydrolysis N H CO2H

89

Indoles Synthesis of a Drug

Synthesis of Ondansetron (Zofran, GSK) using the Fischer Indole Synthesis
O O O O

ZnCl2, heat
H2O

NH N H

NHNH2 N N O N H N Me N Me

N H MeI, K2CO3

Me Me3N I O

Me2NH.HCl, CH2O N Me then MeI N Me

Ondansetron is a selective 5-HT antagonist used as an antiemetic in cancer chemotherapy and radiotherapy Introduction of the imidazole occurs via the ,-unsaturated ketone resulting from 90 elimination of the ammonium salt

1,3-Azoles Bioactive 1,3-Azoles

H2N N Me N O MeO N S HO N N Me N H Me MeHN H N S CN N

O-methylhalfordinol

vitamin B1 (thiamin)

cimetidine

O-Methylhalfordinol is a plant-derived alkaloid Vitamin B1 (thiamin) is essential for carbohydrate metabolism. Deficiency leads to beriberi, a disease which is characterised by nerve, heart and brain abnormalities Cimetidine (Tagamet, GSK) is an H2-receptor antagonist which reduces acid secretion in the stomach and is used to treat peptic ulcers and heartburn

91

Drugs Containing a 1,3-Azole

NO2 H N N S NH2 N N N N N S H N

Name: Mirapex 2008 Sales: $0.34 billion 2008 Ranking: 108 branded Company: Boehringer Ingelheim Disease: Parkinson's disease

Name: Azathioprine 2008 Sales: $53 million 2008 Ranking: 178 generic Company: N/A Disease: Kidney transplant rejection
Cl N

S N O H N N N H O Ph OH N H O Ph O

N S N

OH N N NH N

Name: Norvir 2008 Sales: $0.31billion 2008 Ranking: 112 branded Company: Abbott Disease: HIV/AIDS

Name: Cozaar 2008 Sales: $0.69 billion 2008 Ranking: 54 branded Company: Merck Disease: Hypertension

92

1,3-Azoles Synthesis
The Hantzsch Synthesis (3+2)
O NH2 Me S

+ Me +
Cl

Me C6H6, heat S O NH2 Me HO

Me N S

Me

Me N S 43% Me H2O HO

Me N S Me

The reaction is particularly important for the synthesis of thiazoles A thiourea can be used in place of a thioamide leading to a 2-aminothiazole

93

1,3-Azoles Synthesis
Cyclodehydration of -acylaminocarbonyl compounds
H N Ph O O H Ph c-H2SO4, rt Ph O O N Ph Ph H2O O Ph Ph O 72% Ph H H H N H2O N

A particularly important strategy for the synthesis of oxazoles which is known as the Robinson-Gabriel Synthesis The starting -acylaminocarbonyl compounds are easily prepared From Isocyanides
Ts H Me N H N C Ts K2CO3, MeOH H Me H Me N N C H Me H N Me N Ts N N

t-Bu

Ts = O2S

t-Bu

t-Bu

t-Bu
94%

Tosylmethylisocyanide (TOSMIC) is a readily available isocyanide Route can be adapted to give oxazoles and thiazoles using an acid chloride or a 94 thiocarbonyl compound

1,3-Azoles Electrophilic Substitution

Nitration
N N H c-HNO3, 1% oleum, rt N H 90% S O2N N N Me N2O4/BF3 rt 70 C O2N S 59% N O2N N

+
Me S 27% Me

Imidazoles are much more reactive to nitration than thiazoles (activation helps) Imidazoles usually nitrate at the 4-position and thiazoles tend to react at the 5-position Oxazoles do not generally undergo nitration Halogenation
N N H Br2, AcOH, NaOAc, rt Br N H 78% Br

Br N Na2SO3 aq., heat

Br N N H 58%

Imidazoles are brominated easily and bromination at multiple positions can occur Thiazole does not brominate easily but 2-alkylthiazoles brominate at the 5-position
95

1,3-Azoles Electrophilic Substitution

Acylation
O Ph N PhCOCl, Et3N, MeCN, rt N Me N Me N Me N Me O N N O Ph N Ph N Me 71% O O Ph H2O N Ph

1,3-Azoles do not undergo Friedel-Crafts acylation because complexation between the Lewis acidic catalyst and N deactivates the ring Acylation can be accomplished under mild conditions via the N-acylimidazolium ylide

96

1,3-Azoles Nucleophilic Substitution

Displacement of Halogen
N S Cl PhSNa, MeOH, rt S 75% N SPh

There are many examples of displacement of halogen at the 2-position 2-Halothiazoles react rapidly with sulfur nucleophiles, and are even more reactive than 2-halopyridines

n-Pr N n-Pr O Cl PhNHMe, xylene, 155 C

n-Pr N Ph n-Pr O 96% N Me

2-Halo-1-alkylimidazoles and 2-halooxazoles will react with nitrogen nucleophiles

97

1,3-Azoles Metallation
Direct Deprotonation
N N SO2NMe2 n-BuLi, THF, 78 C then ZnCl2 N N 1. N Pd(PPh3)4 ZnCl 2. acid aq. Br N H 90% N N

SO2NMe2

Direct deprotonation oxazoles, thiazoles and N-alkylimidazoles occurs preferentially at either the 2- or 5-position Transmetallation of the lithiated intermediate is possible Metal-Halogen Exchange
Br N N H Ph Ph 1. t-BuLi (2 equiv.) 2. Ph2CO N H 64% N OH

Metallation at the 4-position can be accomplished by metal-halogen exchange In the case of imidazoles without substitution at the 1-position, two equivalents of base 98 are required

1,2-Azoles Bioactive 1,2-Azoles

O NH N Me N O CF3 Me CF3 N

leflunomide

celecoxib SO2NH2

Leflunomide (Arava, Sanofi-Aventis) inhibits pyrimidine synthesis in the body and is used for the treatment of rheumatoid arthritis and psoriatic arthritis Celecoxib (Celebrex, Pfizer) is a non-steroidal anti-inflamatory (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms Celecoxib is a COX-2 inhibitor, blocking the cyclooxygenase-2 enzyme responsible for the production of prostaglandins. It is supposed to avoid gastrointestinal problems associated with other NSAIDs, but side effects (heart attack, stroke) have emerged
99

1,2-Azoles Synthesis
Synthesis of Pyrazoles/Isoxazoles from 1,3-Dicarbonyl Compounds and Hydrazines or Hydroxylamines (3+2)

Me H2NNH2, NaOH aq., rt Me

Me

OEt H2NOH.HCl H2O, heat N O 84%

Me O H2N

O NH2

N N H 75%

EtO OEt HO

OEt NH2

This is the most widely used route to pyrazoles and isoxazoles The dicarbonyl component can be a -keto ester or a -keto aldehyde (masked) When a -keto ester is used a pyrazolone/isoxazalone is formed

100

1,2-Azoles Synthesis
Synthesis of Isoxazoles by Cycloaddition of Nitrile Oxides to Alkynes or Enamines (3+2)
Et EtO2C EtCNO Me N O C N Me N EtO2C H EtO2C Me N O N Et EtO2C Et

Me

N O 70%

Nitrile oxides react readily with alkenes and alkynes Addition to an alkene generates an isoxazoline unless a leaving group is present
Ph Cl N HO Ph Et3N, Et2O, rt N O Ph PhCCH Ph N O 76% Ph

Mono-alkyl/-aryl alkynes react to give 3,5-disubstituted isoxazoles but when the alkyne possesses two substituents mixtures of 3,4- and 3,5-disubstituted isoxazoles are usually produced
101

1,2-Azoles Electrophilic Substitution

Nitration of Isoxazoles, Pyrazoles and Isothiazoles
O2N c-HNO3, Ac2O, N N H AcOH, rt N 70% N c-H2SO4, 0 C NO2 N N H 80%

Pyrazoles and isothiazoles undergo straightforward nitration 1-Nitropyrazole is formed in good yield by treatment of pyrazole with the mild nitrating reagent, acetyl nitrate 1-Nitropyrazole can be rearranged to give 4-nitropyrazole by treatment with acid at low temperature
Me f-H2SO4, N O c-HNO3, 0 70 C N O 40% O2N Me

Isoxazole nitrates in very low yield, but 3-methylisoxazole is sufficiently reactive to undergo nitration at the 4-position
102

1,2-Azoles Electrophilic Substitution

Halogenation of Isoxazoles, Pyrazoles and Isothiazoles
H Br Br Br2, NaOAc N N H N H Br N N H N Br Br

Halogenation (iodination, bromination) of pyrazole leads to the 4-halopyrazole Poor yields are obtained when attempting to halogenate isoxazole or isothiazole, but bromination can be accomplished when an activating group is present as a substituent Acylation
Me Ph N N PhCOCl, AlCl3, 95 C N Me Me Me O Me O N N N H Me2NCHO, POCl3, 95 C then H 2O N Me 33% N

Cl

Cl

Only N-substituted pyrazoles can be C-acylated directly Vilsmeier formylation produces the 4-formylpyrazole in modest yield
103

1,2-Azoles Metallation
Direct Metallation of Isoxazoles, Pyrazoles and Isothiazoles
Ph n-BuLi, MeI N N Ph Me N N Ph S N n-BuLi, THF, 78 C then CO 2 HO2C N S 88% Ph

1-Substituted pyrazoles and isothiazoles can be lithiated and alkylated at the 5-position

N H N N H CH2O, EtOH, heat N N N

1. n-BuLi, THF, 78 C 2. PhNCO 3. HCl aq.

N N H 79%

PhNH

It is possible to temporarily protect the 1-position of pyrazole and then perform sequential deprotonation and alkylation/acylation at the 5-position
104

1,2-Azoles Metallation
Direct Metallation of 4-Bromopyrazoles
Br n-BuLi, Et2O, N N SO2Ph 78 C Li N N SO2Ph Br CO2 HO2C N N SO2Ph 65% Br

At low temperature, N-sulfonyl 4-bromopyrazoles can be lithiated at 5-position without undergoing metal-halogen exchange Metallation of 4-Bromopyrazoles by Metal-Halogen Exchange
H Br n-BuLi, THF, N N H 78 C N Li N 39% N H Li O S S N OH

Treatment of 4-bromopyrazole with two equivalents on n-butyllithium results in N-deprotonation and exchange of lithium for bromine 2,5-Dilithiopyrazole reacts with carbon electrophiles to give the 4-substituted product
105

1,2-Azoles Side Chain Deprotonation

Deprotonation of 5-methylisothiazole and 5-methylisoxazole
3-O2NC6H4CHO, Me N S Ac2O, piperidine 150 C 42% O2N N S

A weak base can be used to deprotonate 5-methylisothiazole and 5-methylisoxazole In this case above, dehydration of the initial product occurs in situ Surprisingly, 3-methylisothiazole does not deprotonate as easily as 5-methylisothiazole and the same effect is found in isoxazoles
Me n-BuLi, THF, Me N O Li 78 C O N O 80% Me CH2CHCH2Br N Me

Metal-halogen exchange can be used to avoid deprotonation of alkyl groups

Me Br2 Me N O Me N O Br Me 1. n-BuLi, THF, 78 C 2. CO2 3. HCl aq. HO2C Me

Me

N O

106

1,2-Azoles Synthesis of a Drug

Synthesis of Celecoxib (Celebrex, Pfizer)
CF3 N Me O O Me NH2NH2 N CF3

Me

F3C

N N

celecoxib SO2NH2
SO2NH2 SO2NH2

A regioisomeric mixture is formed requiring separation and disposal of the side product
Me CF3 F3C N HN Et3N, THF, EtOAc 5 10 C SO2NH2 SO2NH2 72% SO2NH2 N Me O OSO2Ph N N N CF3

1,3-Dipolar cycloaddition of a nitrile imine offers a regioselective alternative route

107