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Home , Acylation, Azole, Cycloaddition, Furan, Heteroatom, Iminium

HeterocyclicHeterocyclic ChemistryChemistry

Professor J. Stephen Clark Room C4-04 Email: [email protected]

2011 –2012

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

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

2 Course Summary Introduction • Definition of terms and classification of heterocycles • chemistry: , , , , and -containing groups Intermediates used for the construction of aromatic heterocycles • Synthesis of aromatic heterocycles • –heteroatom bond formation and choice of • Examples of commonly used strategies for heterocycle synthesis • General properties, electronic structure • Synthesis of pyridines • Electrophilic substitution of pyridines • Nucleophilic substitution of pyridines • Metallation of pyridines derivatives • Structure and reactivity of oxy-pyridines, pyridines, salts, and pyridine N- and • General properties and reactivity compared to pyridine • Electrophilic and nucleophilic substitution quinolines and isoquinolines 3 • General methods used for the synthesis of quinolines and isoquinolines Course Summary (cont) Five-membered aromatic heterocycles • General properties, structure and reactivity of , and • 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 • Comparison of electronic structure and reactivity of indoles to that of pyrroles • Fisher and Bischler syntheses • Reactions of indoles with • of indoles to give 3-substituted indoles (gramines) • Modification of Mannich products to give various 3-substituted indoles 1,2 and 1,3- • Structure and reactivity of 1,2- and 1,3-azoles • Synthesis and reactions of , and • Synthesis and reactions of , and isothiazoles 4 Introduction

• Heterocycles contain one or more heteroatoms in a ring

Z X X X

Y Y 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

5 Classification – Aromatic Six-Membered Isoelectronic carbocycle Heterocycles

4 4 3 5 3 5 2 6 2 1 6 N O 1 X pyridine pyrylium

4 4 4 N 3 5 3 N 5 3 5

2 N 6 2 6 2 6 N N N 1 1 1

4 5 4 5 3 6 3 6

2 7 2 N 7 N 1 8 1 8 6 Classification – Aromatic Five-Membered Isoelectronic carbocycle Heterocycles 3 4 3 4 3 4

2 1 5 2 5 2 5 N O S H 1 1

3 4 3 4 3 4 N N N 2 1 5 2 5 2 5 N O S H 1 1

3 4 3 4 3 4

2 N 1 5 2 N 5 2 N 5 N O S 1 1 H isothiazole

4 3 5 6 2 1 N 7 7 H indole Classification – Unsaturated / Saturated Unsaturated O O

aromatic dipolar form

O O

4(γγγ)-pyrone

N O N O N OH H H 2-pyridone

Saturated

O

O

OO N O H ethylene oxideTHF 1,4-dioxan dihydropyran 8 Functional Group Chemistry

Imine Formation

R3 R3 O 3 N N R NH2 H

1 2 1 2 1 2 R R H3O R R R R

H −−−H

H H 3 H H R H O 3 3 N R N OH R N OH2

R1 R2 R1 R2 R1 R2 R1 R2

• Removal of is usually required to drive the reaction to completion • If a dialkylamine is used, the that is formed can’t lose a proton and an is formed

9 Functional Group Chemistry Enols and

O OH O B O O H 1 1 R R E R1 H R1 R1 2 2 R R R2 R2 R2 keto form form 2 • The enol form is favoured by a conjugating group R e.g. CO 2R, COR, CN, NO 2 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 R3O OR3

R1 R3OH R3 2 3 R OR O

R1 H R1

R2 R2 O enol H2O

R1 10

R2 Functional Group Chemistry

Enamines R3 R3 R3 R3 R3 R3 O N N N H H H R1 R1 H R1

R2 R2 R2 iminium ion enamine (Schiff )

R3 R3 R3 R3 N N O H2O E E R1 E R1 R1

R2 R2 R2 • Analogues of enols but are more nucleophilic and can function as enolate equivalents • Removal of water (e.g. by or trapping) drives reaction to completion • Enamines react readily with carbon at carbon • Reaction at N is possible but usually reverses

11 Functional Group Chemistry Common Building-Blocks O O NH R R R

OH NH2 NH2 carboxylic amidines

O NH OO OO

1 2 1 2 H2N NH2 H2N NH2 R R R OR urea β-diketones β-keto

Building-Blocks for Sulfur-Containing Heterocycles

O S 1 2 P2S5 R R R SH S R1 R2 R1 R2 thioethers

• Heterocycle synthesis requires: C−O or C −N bond formation using imines, enamines, acetals, enols, enol ethers C−C 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 () 12 General Strategies for Heterocycle Synthesis Ring Construction • Cyclisation – 5- and 6-membered rings are the easiest to form •C−X bond formation requires a heteroatom to react with a C

Y δ−Y δ−

δ+ δ+ conjugate addition

δ X +

X

X, Y = O, S, NR

Manipulation of Oxidation State

[O] [O] [O] or − − − H2 H2 H2 X X X X 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

XX

H N N NH3 NH3 −2H O −2H O 2 N 2 N OO OO H H • Strategy can be adapted to incorporate more than one heteroatom

“5+1” Strategy

XX

H

NH3 [O] − − 2H2O H2 OO N N H 14 • 1,5- compounds can be prepared by Michael addition of enones General Strategies for Heterocycle Synthesis “3+2” Strategy “3+3” Strategy

or or XX X XX X

Examples δ− δ−

δ− δ− X H2N H2N O H2N OH

O δ+ δ− δ δ− + X H2N O OH

δ+ δ+ Hal O δ+ Hal = Cl, Br, I δ+ O O

E E

15 NH2 NH2 OH OH Bioactive Pyridines

H

N N

H N S NH2 H O N O sulphapyridine • Nicotine is pharmacologically active constituent of tobacco – toxic and addictive • Sulphapyridine is a anti-bacterial agent – one of the oldest

NH2 O NH

Me N N Me N isoniazide

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

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

Name: Nexium Name: Aciphex 2008 Sales: $4.79 billion 2008 Sales: $1.05 billion 2008 Ranking: 2 branded 2008 Ranking: 34 branded Company: AstraZeneca Company: Eisai Disease: reflux Disease: Duodenal ulcers and acid reflux

H S N N O NH N O O N HN N

N O N Name: Actos Name: Gleevec 2008 Sales: $2.45 billion 2008 Sales: $0.45 billion 2008 Ranking: 10 branded 2008 Ranking: 87 branded Company: Eli Lilly Company: Novartis 17 Disease: Type 2 Disease: Chronic myeloid leukemia Pyridines – Structure 1.40 Å

1.39 Å 2.2 D 1.17 D < < N 1.34 Å N < N < .. H • Isoelectronic with and analogous to • Stable, not easily oxidised at C, undergoes substitution rather than addition • −I Effect (inductive withdrawal) • −M Effect δ+

δ+ δ+ N NNNN δ−

• Weakly basic – pK a ~5.2 in H 2O ( is not in aromatic sextet) • Pyridinium salts are also aromatic – ring are more δ+ than in parent pyridine

etc.

N NN

HH 18 H Pyridines – Synthesis

The Hantzsch synthesis (“5+1”)

Ph H O O O Ph O OOH Ph

O Me Me NH3 pH 8.5 Me Me Me Me

Me O O Me aldol condensation Me O O Me Michael addition MeOO Me and dehydration

O Ph O OOH Ph OOH Ph

Me Me Me Me Me Me HNO3

Me MeN Me MeN Me O Me oxidation H2N H

• 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”) CN CN CO2Et CO2Et Me CN CN O H2N O H2N Me

K2CO3 K2CO3 Me N O Me O EtO2CN Me H • The β-cyano can exist in the ‘enol’ form 73%

Using Reactions (“4+2”) CO2H CO2H CO2H H Me Me Me H O H+ H O O

N Diels-Alder Me N Me N Me cycloaddition

CO H 2 H CO2H HO Me − Me H2O

Me N Me N 70% • 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 γγγ βββ E E ααα N N

E −E

E E

N N

E E

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

21 Pyridines – Electrophilic Reactions Regiochemical Outcome of Electrophilic Substitution of Pyridines

E E E H H H βββ

N N N

ααα E E E N N N H H H

E H E H E H

γγγ

N N N

• Resonance forms with a positive charge on N (i.e. 6 ) are very unfavourable • The β-substituted intermediate, and the transition state leading to this product, have more stable resonance forms than the intermediates/transition states leading to the α/γ products 22 Pyridines – Electrophilic Reactions Regiochemical Outcome of Electrophilic Substitution of Pyridinium

E E E H H H βββ

N N N

EE E

δ+

ααα E E E δ+ δ+ N N N N H H H E E E E H E H E H

γγγ

N N N

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

NO2 BF4 MeI

N O N N

BF4 NO2 Me

R Cl SO3, CH2Cl2

N Cl N

SO3 O R

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 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 N Me Me N Me

H 90% Me Me Me

NO2 MeI c-HNO3, oleum 100 °C Me N Me Me N Me Me N Me

I Me I Me 70% • Multiple electron-donating groups accelerate the reaction • Both reactions proceed at similar rates which indicates that the at N occurs prior to nitration in the first case 25 Pyridines – Electrophilic Reactions Sulfonation of Pyridine SO3H H2SO4, SO3 (low yield) N N

HgSO , H SO , 4 2 4 70% 220 °C

N

HgSO3 • Low yield from direct nitration but good yield via a mercury intermediate

Halogenation of Pyridine Cl Br

Cl2, AlCl3, Br2, oleum 100 °C 130 °C N N N 33% 86% • Forcing reaction conditions are required for direct 26 Pyridines – Reduction Full or Partial Reduction of Pyridines

R R R

H2, Pt, Na-NH3, AcOH, rt EtOH N N N H H

Na, EtOH

R

N H

• Pyridines generally resist oxidation at ring carbon 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 to Pyridines

ααα H H H N N N N Nu Nu Nu Nu

Nu H H H Nu Nu Nu βββ

N N N N

Nu H Nu H Nu H Nu γγγ

N N N N

• acts as an electron sink • β Substitution is less favoured because there are no stable resonance forms with the negative charge on N • Aromaticity will is regained by loss of or a , or by oxidation 28 Pyridines – Nucleophilic Reactions Nucleophilic Substitution X Nu Nu

N N X

X = Cl, Br, I, (NO2)

Nu = MeO , NH3, PhSH etc. • Favoured by electron-withdrawing substituents that are also good leaving groups • The position of the leaving group influences reaction rate ( γ > α >> β)

Cl OEt NaOEt

N N Cl Cl

Cl

N N Cl N

NO2 Relative rate 80 40 1 3 × 10 −4 29 Pyridinium Ions – Nucleophilic Reactions Nucleophilic Substitution X Nu Nu

N N X

RRX = Cl, Br, I, (NO2)

Nu = MeO , NH3, PhSH etc. • Conversion of a pyridine into the pyridinium salt greatly accelerates substitution • effects remain the same ( α, γ >> β) but now α > γ

Cl O2N O O NO2

N N

Me Me Cl

Cl Cl

N Cl N N N

Me Me Me 30 Relative rate 5 × 10 7 1.5 × 10 4 1 10 −4 Pyridines – Pyridyne Formation Substitution via an Intermediate Pyridyne

Cl H NH2

H H2N

NH2

NaNH2 NH2 N N N 27%

H2N H H NH N NH benzyne 2 2 Cl NH2 NaNH2

N N 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 O2 (air) Ph N N Ph N H Li

LiNH2

H O − 2 −−H2 H N 2 LiNH2 N H N N HN N H 2 Li Li

H NHX

X = H (NH3) / 2-aminopyridine

• A hydride acceptor or oxidising agent is required to regenerate aromaticity

• The reaction with LiNH 2 is referred to as the Chichibabin reaction

32 Pyridines – Metal- Exchange Direct Exchange of Metal and a Halogen

X Li n-BuLi n-Bu X

N N X = Cl, Br, I • Halogenated pyridines do not tend to undergo nucleophilic displacement with alkyl or alkyl reagents • Metallated pyridines behave like conventional Grignard reagents

N Li

Br Li n-BuLi, PhC N Ph

Et2O, −−−78 °C N N N

O NH

Ph Ph H2O

N N 33 Pyridines – Directed Metallation Use of Directing Groups Me

OMe O OMe Li I

O O O t-BuLi, I(CH2)2Cl − Et2O, −−78 °C N N N 90% O Ph O Li O O

Me Me Ni-Pr2 Ni-Pr2 Ni-Pr2 N Me Me −−− LiTMP, 78 °C O Li N N N LiTMP Ph NMe2

• 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

ααα

N OH N OON H H zwitterion OH OO 1,3- O γγγ

N N N N H H H zwitterion

OH O O O O βββ

N N N N N H H H H zwitterion

• Subject to tautomerism • The α, γ systems differ from the β systems in terms of reactivity and structure • In the α case, the equilibrium is highly dependent, but the keto form is favoured in polar 35 Amino Pyridines – Structure Amino Pyridine Systems

etc.

N NH NNH2 NNH2 H

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

36 Oxy-Pyridines – Reactions Electrophilic Substitution

Br

OH OH Br2, H2O, rt

N BrN Br

O O

NO2 c-H2SO4, c-HNO3 100 °C, 2 days N N H H 38%

• 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 substituent (cf. )

37 Oxy-Pyridines – Reactions Nucleophilic Substitution

PCl5 Cl Cl PCl3 N O N O N O Cl H H PCl3 H Cl PCl4 Cl

Cl

PCl3 N Cl N O Cl H 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

CO2Me Me Me O N Me N CO2Me Me CO2Me Me CO2Me

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

39 Alkyl Pyridines – Deprotonation Deprotonation with a Strong Base

CH3 CH2 CH

PhLi etc.

N N N

O

R1 R2 OH

R1 R2

N

• Deprotonation of α and γ alkyl groups proceeds at a similar rate, but β 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 N N NaBH , 4 Me Me H BH3 Me EtOH N

Me H BH3 N N N

Me H3B H Me 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 N O N O

O2N OH O2N OH O2N etc.

41

NO2 NO2 NO2 Pyridine N-Oxides N- Formation

RCO3H

N N N N

O O O O

Cl O O H

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 NO H NO2 H NO2 2

c-H2SO4,

c-HNO3, N 100 °C N N N

O O O O • The N-oxide is activated to attack by electrophiles at both the α and γ 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 NO2 NO2

PPh3

N N N

O O O PPh3 PPh3 PPh3 • Deoxgenation is driven by the formation of the very strong P=O bond 43 Pyridines – Synthesis of a

Synthesis of ( B 6) Using the Guareschi Synthesis

EtO CN EtO EtO

CN O2N CN O H2N O c-HNO3, Ac2O, 0 °C , Me O EtOH, heat Me N O Me N O H H 90% 32%

PCl5, POCl3, 150 °C

HO EtO EtO OH NH2

HO H2N O2N CN 1. NaNO2, HCl, 90 °C H2, Pd/Pt, AcOH 2. 48% HBr (neat) Me N 3. AgCl, H2O, heat Me N Me N Cl 40% 40% • 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 NEt2 Me

HO N HN H MeO MeO

N N • 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 is an isolated from the opium poppy and is a 45 relaxant and a coronary vasodilator Drugs Containing a Quinoline/Isoquinoline

HO2C S CO2H CO2Et N Cl N Ph N H O Name: Singulair Name: 2008 Sales: $2.90 billion HO 2008 Sales: $133 million 2008 Ranking: 7 branded 2008 Ranking: 84 generic Company: Merck Company: N/A Disease: Asthma and allergies Disease: and heart failure

N HN OH

Cl N

Name: 2008 Sales: $74 million 2008 Ranking: 146 generic Company: N/A 46 Disease: , lupus erythematosus, rheumatoid arthritis Malaria

• Approximately 500 million cases of malaria each year and 1–3 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

• pK a values (4.9 and 5.4) are similar to that of pyridine • Possess aspects of pyridine and reactivity e.g. form N-oxides and salts Combes Synthesis (“3+3”) Me Me MeO OO MeO MeO

O O Me Me − H2O NH2 N Me N Me H MeO MeO MeO

c-H2SO4,

Me MeO Me MeO Me OH MeO H O

− H2O N Me N Me N Me H H MeO MeO MeO 48 23% Quinolines – Synthesis Conrad-Limpach-Knorr Synthesis (“3+3”)

OEt OO OH O

O Me OEt 270 °C − rt, −−H2O NH2 N Me N Me N Me H 70% H

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

Me OO Me Me

O Me OEt 250 °C, −−−H2O

140 °C, −−−H2O NH2 N O N O N OH H 50% H

49 Quinolines – Synthesis Skraup Synthesis (“3+3”) OH H H H H O O

130 °C, H2SO4 NH2 N N H H

H OH

− [O] (e.g. I2) −−H2O

N N N 85% H H • can be generated in situ by treatment of with conc. • A mild oxidant is required to form the fully aromatic system from the dihydroquinoline

1. O Me Me Me Me

ZnCl2 or FeCl3, NH2 EtOH, reflux N 50 2. [O] 65% Quinolines – Synthesis

Friedlander Synthesis (“4+2”)

Ph Ph O Ph H Me O Me Me −−− O Me H2O

c-H2SO4, AcOH NH2 heat N Me N Me H 88%

Ph Ph O Ph Me O −−− O Me H2O KOH aq., EtOH 0 °C N N NH2 71% OH H Me Me

• The starting acyl 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

H2N OEt H , EtOH −−− O H2O N N

H

Bischler-Napieralski Synthesis (“5+1”)

MeCOCl P4O10, heat Pd-C, 190 °C

NH2 NH N N O

Me Me Me 93%

• Cyclisation can be accomplished using POCl 3 or PCl 5 • Oxidation of the dihydroisoquinoline can be performed using a mild oxidant

52 Isoquinolines – Synthesis

Pictet Spengler Synthesis (“5+1”)

MeO MeO MeO HCHO 20% aq. 20% HCl aq. heat 100 °C NH2 N N H

MeO MeO MeO [O] N NH NH

80% H

• An electron-donating substituent on the carboaromatic ring is required • A 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

Nitration NO2

fuming HNO3,

N cH2SO4, 0 °C N N 72% 8% NO2

• In the case of quinoline, equal amounts of the 5- and 8- are produced 54 Quinolines/Isoquinolines – Electrophilic Reactions

Sulfonation

HO3S 30% oleum3, >250 °C 90 °C N N N

SO3H 54% thermodynamic product

• Halogenation is also possible but product distribution is highly dependent on conditions • It is possible to introduce into the hetero-ring under the correct conditions • Friedel-Crafts / 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 H2O

Et2O, rt H OMe H OMe N N N H Li

[O]

N 56

MeO Quinolines/Isoquinolines – Nucleophilic Reactions

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

H n-Bu H n-Bu n-Bu • Oxidation is required to regenerate aromaticity

Amination H NH2

KNH2, NH3 (l) >−45 °C −65 °C H N N N NH K 2 K − − KMnO4, 65 °C KMnO4, 40 °C

NH2

NNH N 50% 2 60% thermodynamic product 57 Quinolines/Isoquinolines – Nucleophilic Substitution

Displacement of Halogen

NaOEt, EtOH reflux Cl N Cl N N OEt OEt

OMe Cl OMe NaOMe, MeOH Cl N DMSO 100 °C N N 87%

58 Quinolines/Isoquinolines – The Reissert Reaction

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

base, MeI

NaOH aq. Me Me N Me N N CN CN

HO Ph O Ph O

• 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 O O

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

KOH aq., rt

H OH O OMe MeO MeO MeO OMe P4H10, Na-Hg, H2O, 50 °C , heat N O NH O NH MeO MeO MeO

30% 60%

OMe OMe OMe

MeO MeO MeO • Cyclisation is achieved by the Pictet-Grams reaction cf. the Bischler-Napieralski reaction 60 Bioactive Furans, Pyrroles and Thiophenes

NO2

Me2N S O NHMe N

H • 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 CO H N 2 Ph • Ketorolac (Toradol®, Roche) is an analgesic and anti-inflammatory drug Me

N

S N

banminth • (Banminth®, Phibro) is an anthelminthic agent and is used to treat worms in livestock 61 Drugs Containing a Furan/Thiophene/Pyrrole MeO C Cl 2 O

N N N NH O N S 2 O

Name: Plavix Name: Nitrofurantoin O 2008 Sales: $3.80 billion 2008 Sales: $92 + 72 million 2008 Ranking: 3 branded 2008 Ranking: 119 and 149 generic Company: Bristol-Myers Squibb Company: N/A Disease: Stroke and heart attack risk Disease: for urinary tract infections

F

N H HO2C O Ph S HO HO N NHPh

Name: Cymbalta Name: Lipitor O 2008 Sales: $2.17 billion 2008 Sales: $5.88 billion 2008 Ranking: 14 branded 2008 Ranking: 1 branded Company: Pfizer Company: Eli Lilly 62 Disease: Depression Disease: Lowers LDL levels Furans, Pyrroles and Thiophenes – Structure Structure βββ ααα X O N S .. H • 6 π electrons, planar, aromatic, isoelectronic with cyclopentadienyl anion

Resonance Structures δ− δ−

etc. δ− δ− X XX X .. δ+ • Electron donation into the ring by resonance but inductive electron withdrawal

1.44 Å 1.43 Å 1.42 Å 1.35 Å 1.37 Å 1.37 Å 0.71 D 1.55 D 0.52 D 1.37 Å O 1.38 Å N 1.71 Å S H

1.68 D 1.57 D 1.87 D O N S H 63 • O and S are more electronegative than N and so inductive effects dominate Furans – Synthesis

Paal Knorr Synthesis

R1 R2 R1 R2 R1 R2 O OO OO OH HH H

H heat H H

R1 R2 R1 R2 R1 R2 O O O 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-MeC 6H4SO 3H)

64 Furans – Synthesis

Feist-Benary Synthesis (“3+2”) Me O

EtO2C O δ+ Me EtO2C O Me EtO2C δ + Cl Me O Cl Me O Cl Me O

NaOH aq., rt

OH Me OH Me EtO2C Me EtO2C H OH EtO2C Cl − H2O

Me Me O O Me O 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 δ+ Me EtO2C Me EtO2C Me δ + O O Me O Cl Me O Me O I NaI, NaOEt, EtOH

EtO EtO2C EtO2C H EtO2C Me −H2O Me O Me Me Me O O OH 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 Ph

P4S10 S O Me Ph Me Me Ph OO S

Me Ph O S

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

67 Pyrroles – Synthesis

Paal Knorr Synthesis (“4+1”)

Me Me Me Me Me Me

OO O HN O H2N

NH3, C6H6, heat H H

Me Me R1 R2 R1 R2 N N N H H OH H

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

68 Pyrroles – Synthesis (“3+2”)

EtO2C Me EtO2C O Me KOH aq.

HO2C MeO2C O NH2 N H 53%

H2N O Me Me N

Me O NH2 N Me • Use of a free amino is problematic – dimerisation gives a dihydropyrazine

HO Me EtO2C Me EtO2C O Me EtO2C EtO2C O Me NaOH aq. via or NH2 EtO2C EtO2C O NH3 Cl N EtO2C O EtO2C N H 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 formation 69 Pyrroles – Synthesis Liberation of an Amino Ketone in situ by Reduction

EtO2C Me EtO2C O Me Zn, AcOH or Na S O aq. 2 2 4 Me Me O N ( dithionite) N H OH

Preparation of α-Keto from β-Dicarbonyl Compounds H OO OO NaNO2, H

(HNO2) OEt OEt

H2O N O

OO OO H

OEt OEt

N N OH O 70 Pyrroles – Synthesis One-Pot Oxime Reduction and Pyrrole Formation O

OO CO2Et

EtO2CCO2Et OEt Zn, AcOH EtO C 2 N N H OH CO2Et

Hantzsch Synthesis of Pyrroles (“3+2”) Cl H EtO2C O δ+ Me EtO2C Me EtO2C Me δ + O O Me O Cl Me NH2 Me NH

NH3 aq. rt to 60 °C

EtO2C EtO2C EtO2C Me −H2O Me O Me Me Me N N OH Me NH2 H H 41% • A modified version of the Feist-Benary synthesis and using the same starting materials: an α-halo carbonyl compound and a β-keto ester 71 Furans, Pyrroles Thiophenes – Electrophilic Substitution Electrophilic Substitution – Regioselectivity −H ααα E E E E X X X X X E H H H

E E E E H H −H βββ X 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 • α-Substitution favoured over β-substitution more resonance forms for intermediate and so the charge is less localised (also applies to the transition state) • Some β-substitution usually observed – depends on X and substituents NO2

AcONO2

NO2 X X X 72 X = NH 4:1 X = O 6:1 Furans – Electrophilic Substitution Nitration of Furans

AcONO2, <0 °C NO2 AcO NO2 O (Ac2O, HNO3) O H H O H N NO2 AcO isolable pyridine, heat −AcOH

NO2 NO O H O 2 • Nitration can occur by an addition-elimination process

• When NO 2BF 4 is used as a nitrating agent, the reaction follows usual mechanism

Bromination of Furans

− Br2, dioxan, HBr 0 °C Br Br Br Br O Br O H H O H O Br 80% Br

• Furan reacts vigorously with Br 2 or Cl 2 at room temp. to give polyhalogenated products 73 • It is possible to obtain 2-bromofuran by careful control of temperature Furans – Electrophilic Substitution Friedel-Crafts Acylation of Furan O

Me

Ac2O, SnCl4, Ac2O, SnCl4, O H PO cat., 20 °C 150 °C 3 4 Me Me Me Me O O O O Me ααα:βββ 6800:1 77% • Blocking groups at the α positions and high temperatures required to give β acylation

Vilsmeier Formylation of Furan Me Me

Me2NCO, POCl3, O 0 to 100 °C O O H 76% Mannich Reaction of Furans

CH2O,

Me2NH.HCl NMe O O CH2 NMe2 O H 2 O 66% NMe2 74 Thiophenes – Electrophilic Substitution

Nitration of Thiophenes

NO2

AcONO2

NO S S 2 S

• Reagent AcONO 2 generated in situ from c-HNO 3 and Ac 2O

Halogenation of Thiophenes

Br2, Et2O, Br2, Et2O, 48% HBr, 48% HBr, Br Br Br S −10 →→→ 10 °C S −25 →→→ −5 °C S

• 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 NO2

AcONO2 AcOH, −10 °C NO N N 2 N H H H 51% 13%

• Mild conditions are required (c-HNO 3 and c-H2SO 4 gives decomposition)

Vilsmeier Formylation of Pyrroles

Me O Me OPCl2 Me Cl POCl3 N N N Me H Me H Me H

H K2CO3 aq. H H Cl N Cl Me N N N H H NMe H NMe H O N 2 2 83% H Me

76 Pyrroles – Formation

OH OH OH2 N R1 R2 N N 2 2 H H R1 R H R1 R

H R2 N N N N N 1 N H 1 2 H H 1 2 H H R R R R R H

R1, R2 = H

NH HN NH HN NH N

NH HN NH HN N HN

no extended aromaticity 18 π-electron system

• The extended aromatic 18 π-electron system is more stable than that having four isolated aromatic pyrroles 77 Porphyrin Natural Products

CO2H

N N HO2C N N

Fe Mg

NN N NN H H2N

MeO2C O HO CCO H O 2 2 O haem C20H39 -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

H X X Li ααα>>βββ Bu X = O pKa (THF) 35.6

X = NR pKa (THF) 39.5

X = S pKa (THF) 33.0

Deprotonation of Pyrroles

R M M

H N N N N M pKa (THF) 39.5 H pKa (THF) 17.5 M • 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 Y Li Y

n-BuLi Bu Li H X X X

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

Synthesis of α,α’-Disubstituted Systems

Y Y Y n-BuLi n-BuLi 1 2 E E1 E E2 E1 X X X

Use of a Trialkylsilyl Blocking Group

Y Y Y Y n-BuLi n-BuLi F

Me3SiCl SiMe E E SiMe E X X 3 X 3 X 80 Furans – Synthesis of a Drug Preparation of Ranitidine (Zantac®) Using a Mannich Reaction

Me2NH.HCl, Me2N CH2O, rt O O O O OH OH HS(CH2)2NH2, c-HCl, heat NO2

NO 2 MeS NHMe Me2N S Me2N S O O NHMe N NH2 ranitidine H

• Furfural is produced very cheaply from waste vegetable matter and can be reduced to give the commercially available compound furfuryl • 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 α,β-unsaturated and then elimination of methane 81 Indoles – Bioactive Indoles O H Me X N CO2H NMe2 H

H O O

NH2 S MeNH

N N N H H X = OH lysergic acid H

sumatriptan X = NEt2 lysergic acid diethyamide (LSD) • Tryptophan is one of the essential amino acids and a constituent of most • Sumatriptan (Imigran®, GSK) is a drug used to treat 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

NH HO 2

N

H 5-hydroxytryptamine () 82 Indoles – Lysergic Acid

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

83 Drugs Containing an Indole O H

N

NMe2 N N H H O N S OO N O H Name: Imitrex Name: Cialis O 2008 Sales: $0.97 billion 2008 Sales: $0.56 billion 2008 Ranking: 35 branded 2008 Ranking: 66 branded Company: GlaxoSmithKline Company: Eli Lilly Disease: Migraine Disease: Erectile disfunction

NMe2

O O N S N Ph N N N N H H Name: Maxalt Name: Relpax 2008 Sales: $0.22 billion 2008 Sales: $0.21 billion 2008 Ranking: 148 branded 2008 Ranking: 151 branded Company: Merck Company: Pfizer 84 Disease: Migraine Disease: Migraine Indoles – Synthesis

Fischer Synthesis 1 O R R1 2 R1 R H or R2 Lewis acid R2 −−− −−− NH2 H2O N NH3 N N N H H H Ph ZnCl2, 170 °C Ph N N N H 76% H

H H Ph

Ph NH N N NH3 H H

H Ph Ph Ph [3,3]

NH2 NH2 NH2 N NH NH2 H H 85 • A protic acid or a Lewis acid can be used to promote the reaction Indoles – Synthesis

Bischler Synthesis

H Me O Me O Me − polyphosphoric −−H2O acid (PPA), 120 °C KOH aq. N N N 64% H O CF 3 O CF3 • An α-arylaminoketone is cyclised under acidic conditions

• The reaction also works with acetals of

Me EtO OEt Me (CF3CO)2O,

CF3CO2H, heat N N

CF3 O CF3 93% O

86 Indoles – Electrophilic Substitution Nitration of Indoles NO2

O2N c-H2SO4, c-HNO3 PhCO2NO2, 0 °C Me Me Me 0 °C N N N

84% H H 35% H • Polymerisation occurs when there is no substituent at the 2-position • Halogenation is possible, but the products tend to be unstable

Acylation of Indoles O O Me Me

Ac2O, AcOH, heat NaOH aq., rt

N N N

H βββ-product! 60% H O Me

Ac2O, AcONa Ac2O, AcOH, heat

N

O Me 87 • Acylation occurs at C before N because the N-acylated product does not react Indoles – Electrophilic Substitution Mannich Reaction

NMe2

CH2O, Me2NH, H2O, heat 93% H O, 0 °C or AcOH, rt 68% N 2 N N

H H NMe2

H2C NMe2 (preformed) 95%

• A very useful reaction for the synthesis of 3-substituted indoles • The product () can be used to access a variety of other 3-substituted indoles

Synthesis of Tryptophan from Gramine

EtO2C CO2H CO2Et

NMe2 EtO2CCO2Et NHAc NH2 Na NHAc NaOH aq. then PhMe, heat H SO , heat N N 2 4 N

H 90% H 80% H 88 Indoles – Electrophilic Substitution

Synthesis of Other 3-Substituted Indoles from Gramine

MeSO4 NMe3 CN CN

NaCN aq., 70 °C

N N N

H2O H H2O H 100% H

• The group can be modified to give other useful functionality

CN CO2H

NH2

LiAlH4 acid/base hydrolysis

N N N

H H H

89 Indoles – Synthesis of a Drug Synthesis of Ondansetron (Zofran®, GSK) using the

O O O O

ZnCl2, heat −−−H O NH 2 N NHNH2 N H H N Me MeI, K2CO3

N Me3N I

O N O O

Me N H Me2NH.HCl, CH2O then MeI N N N

Me Me Me

• Ondansetron is a selective 5-HT antagonist used as an antiemetic in and radiotherapy • Introduction of the imidazole occurs via the α,β-unsaturated ketone resulting from elimination of the ammonium salt 90 1,3-Azoles – Bioactive 1,3-Azoles

MeHN H N H 2 N N N Me S N N Me CN N N Me O S N H MeO N HO O-methylhalfordinol vitamin B1 (thiamin) cimetidine

• O-Methylhalfordinol is a plant-derived alkaloid • Vitamin B1 (thiamin) is essential for carbohydrate . Deficiency leads to beriberi, a disease which is characterised by nerve, heart and brain abnormalities

• Cimetidine (Tagamet®, GSK) is an H 2-receptor antagonist which reduces acid secretion in the stomach and is used to treat peptic ulcers and heartburn

91 Drugs Containing a 1,3- NO2

H N N H S S N

NH2 N N N N N Name: Mirapex Name: 2008 Sales: $0.34 billion 2008 Sales: $53 million 2008 Ranking: 108 branded 2008 Ranking: 178 generic Company: Boehringer Ingelheim Company: N/A Disease: Parkinson's disease Disease: transplant rejection Cl N S N OH N Ph S N N NH O O N N H N NN N O H H O OH Ph Name: Norvir Name: Cozaar 2008 Sales: $0.31billion 2008 Sales: $0.69 billion 2008 Ranking: 112 branded 2008 Ranking: 54 branded Company: Abbott Company: Merck 92 Disease: HIV/AIDS Disease: Hypertension 1,3-Azoles – Synthesis

The Hantzsch Synthesis (“3+2”)

Me Me H O δ+ Me HO NH2 C6H6, heat ONH2 N δ+ Me Me S Cl S Me S

Me Me − HO N H2O N

Me Me S S 43%

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

93 1,3-Azoles – Synthesis Cyclodehydration of α-acylaminocarbonyl compounds H H H H N c-H2SO4, rt N N −H2O N Ph Ph Ph Ph Ph Ph Ph Ph OO OO H O O O 2 72% H • A particularly important strategy for the synthesis of oxazoles which is known as the Robinson-Gabriel Synthesis • The starting α-acylaminocarbonyl compounds are easily prepared

From Ts Ts H Ts H H Me K2CO3, MeOH N C N N Me Me N Me H N H N H N N C t-Bu t-Bu t-Bu t-Bu Ts = O S Me 2 94%

• Tos yl methyl iso (TOSMIC) is a readily available • Route can be adapted to give oxazoles and thiazoles using an acid chloride or a thiocarbonyl compound 94 1,3-Azoles – Electrophilic Substitution Nitration O2N O2N N c-HNO , N N N O /BF N N 3 2 4 3 + 1% oleum, rt rt →→→ 70 °C Me O N Me Me N N S 2 S S H H 90% 59% 27% • Imidazoles are much more reactive to nitration than thiazoles (activation helps) • Imidazoles usually at the 4-position and thiazoles tend to react at the 5-position • Oxazoles do not generally undergo nitration

Halogenation Br Br

N Br2, AcOH, N Na2SO3 aq., N NaOAc, rt heat N Br N Br N H H H 78% 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 O O

Ph Ph Ph

N PhCOCl, Et3N, N N N H2O N MeCN, rt Ph Ph N N N N N

Me Me Me Me O Me O 71%

• 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

96 1,3-Azoles – Nucleophilic Substitution

Displacement of Halogen

N PhSNa, MeOH, rt N

S Cl S SPh 75% • 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-Pr N PhNHMe, N xylene, 155 °C Ph n-Pr O Cl n-Pr O N 96% Me • 2-Halo-1-alkylimidazoles and 2-halooxazoles will react with nitrogen nucleophiles

97 1,3-Azoles – Metallation

Direct Deprotonation 1.

N n-BuLi, THF, −−−78 °C N N Br N N then ZnCl2 Pd(PPh3)4 N N ZnCl 2. acid aq. N H SO NMe SO NMe 2 2 2 2 90% • 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 OH Ph Br Ph N 1. t-BuLi (2 equiv.) N

2. Ph2CO N N H H 64% • 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 are required 98 1,2-Azoles – Bioactive 1,2-Azoles

CF O 3

NH N N N Me Me O

CF3

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 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 or Hydroxylamines (“3+2”)

Me Me OEt

H2NNH2, H2NOH.HCl Me O N EtO OEt N NaOH aq., rt Me H O, heat N 2 O O NH2 H OEt NH2 H N HO 2 75% 84%

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

100 1,2-Azoles – Synthesis Synthesis of Isoxazoles by Cycloaddition of Nitrile Oxides to or Enamines (“3+2”)

Et H EtO C Et EtO2C Et EtO2C 2 EtO C EtCNO C 2 Me N N N Me N Me N Me N O O O 70%

• Nitrile oxides react readily with and alkynes • Addition to an generates an unless a leaving group is present

Ph Ph Cl Ph Et3N, Et2O, rt PhCCH

N N N Ph HO O O Ph 76% • Mono-alkyl/-aryl alkynes react to give 3,5-disubstituted isoxazoles but when the 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, c-H2SO4, 0 °C N AcOH, rt N N NO N N 2 N H H 70% 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 O2N Me

f-H2SO4,

N c-HNO3, N O 0 →→→ 70 °C O 40% • Isoxazole 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 Br Br Br Br2, NaOAc N N N N N N H H H • 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 O Me Ph Me O

N N H Cl Cl N N PhCOCl, AlCl3, Me2NCHO, POCl3,

95 °C N 95 °C then H 2O N N N

Me Me 33% Me Me • 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 Ph n-BuLi, MeI n-BuLi, THF, N N N −−−78 °C then CO N Me 2 HO C N N S 2 S 88% Ph Ph • 1-Substituted pyrazoles and isothiazoles can be lithiated and alkylated at the 5-position

N 1. n-BuLi, THF, H −−−78 °C O N CH2O, EtOH, heat N 2. PhNCO N N N 3. HCl aq. N H H PhNH 79% N

• 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 Br Br

n-BuLi, Et2O, CO2 N −−−78 °C N N Li HO C N N 2 N

SO2Ph SO2Ph SO2Ph 65% • 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 OH

Br Li S n-BuLi, THF, O S N −−−78 °C N N N N N H 39% H Li • Treatment of 4-bromopyrazole with two equivalents on n-butyllithium results in N-deprotonation and exchange of lithium for • 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 O N 3-O2NC6H4CHO, 2 N Ac O, piperidine N Me 2 S 150 °C S 42% • 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 Me Me

n-BuLi, THF, CH2CHCH2Br N −−−78 °C N N Me O O O Li 80%

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

Me Br Me HO C Me 1. n-BuLi, THF, 2 − Br2 −−78 °C N N 2. CO N Me Me 2 Me O O O 3. HCl aq. 106 1,2-Azoles – Synthesis of a Drug Me

Synthesis of Celecoxib (Celebrex®, Pfizer) CF3

CF3 N N N Me O + F C Me 3 N O NH2NH2

celecoxib SO2NH2 SO2NH2

SO2NH2 • A regioisomeric mixture is formed requiring separation and disposal of the side product Me CF3

CF3 F3C OSO2Ph N N N N HN N N Me

Et3N, THF, EtOAc O 5 →→→ 10 °C

SO2NH2 SO2NH2 72% SO2NH2 107 • 1,3-Dipolar cycloaddition of a nitrile offers a regioselective alternative route