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Heterocyclic chemistry:Heterocyclic chemistry: Furan, Thiophene, Pyrrole, Imidazole, Indole

Dr. Taj Khan Dept. of Pharmaceutical Chemistry, Oriental college of pharmacy Sanpada, New Mumbai.

Furan

O

OxoleOxacyclopentandiene

1

2

34

5α

β

α'

β’

Drugs:Furosemide, Nitrofurantoin, Nitrofurazone, Prazocin, Ranitidine

Scheele 1780

Less stable than pyrrole & thiopheneless reactive than pyrrole towards E+

Aromatic as lone pair of e participate in Pi cloud, follow Huckel’s rule of aromaticity 4n + 2πO and 4 C SP2 hybridised & lie in same plane

Synthesis of Furan: 1) From carbohydrate:

COH

C

C

C

OH

H

OH

H

HO

H

Pentose

CH2OH

H+

COH

C

C

C

OH

H

OH

H

HO

H

CH2OH

COH

C

CH

C

OH

OHH

CH2OH

-H2O

COH

C

C

C

O

OHH

CH2OH

H H-H2OC C

CHO

OH2C

O

H

H HH+

O

H

H

OH

CHO

H+

-H2O

O CHO

~100%

200 0C/Pd/C-CO

O

Polysaccharide (Oat)

Acidhydrolysis

Furfuraldehyde

2-furoic acid

Decarboxylation

Furan

2) Synthesis of furan from Oxazole

N

O

Ph

+ HC C COOCH3

DA rxn

Diene DienophileN

OH3COOC

Ph

O

COOCH3

+PhCN

Methyl-3-furoate

3) Synthesis of 3-substituted furan from DA adduct

O+ C C

DA rxn

Diene Dienophile

O

CF3

+

CF3F3C OCF3

CF3

OCF3

CF3

F3C

H2C CH2

3,4 trifluoromethyl furan

400 0C

4) Synthesis of furan by Paal –Knorr method: Ring closure mtd. Subst. open chain compd (1,4 diketone) cyclize by acid to give furan

O

Ph

Ph

OH Ph

O

OHPhH

O

Ph

Ph

H +

-H2O

H +

150 0C

Mechanism via mono enol formation. Sterically hindered diketone do not cyclize to furan

Chemical reactions of furan:1)Reaction with acid: F can be hydrolysed easily by acid to give aldehyde. Mild conditions shd be used otherwise protonated F undergoes polymerization can occur.

O O

H

H

H2OOHC CHO

Succinaldehyde

F with EWD more stabile to acids

Chemical reactions of furan:1)Reaction with Base:

O O Li O R

BuLi RX

Chemical reactions of furan:2) Electrophilic aromatic substitution: more reactive than benzene. 2 position more reactive. Conditions need to be controlled.

A) Halogenation: proceeds quickly to give mix of either mono and poly subs or resin

O

Cl2/ DCM

1.6 moles eq O-40 0C

Cl O ClCl+O ClCl

+Gradual addition:

Cl 2/

DC

ME

xces

s

O ClClCl Cl

Cl Cl

2-chloromajor

2,5 dichloro

Cl

2,3,5 trichloro

% of 2 subst product can be increased by using less amt of Cl2

2- Bromo can be obtd by Br2 in dioxane

Chemical reactions of furan:2)Electrophilic aromatic substitution:

B) Nitration: Mild nitrating agents used acetyl nitrate (acetic anhydride + HNO3

O

furan

CH3CO2NO2

O NO2

Further Nitration

O NO2O2N


C) Sulfonation: Mild sulfonating agents used Pyridine- SO3 complex If H2SO4 used, it gives resin

OFuran

pyridine:SO3

O SO3H

pyridine:SO3Excess5 hr

35-40 0C

O SO3HHO3S

2-Furan sulfonic acid


D) Friedel Crafts reaction: Anhydride and acyl halide need Lewis catalyst. But reactive anhydride like (CF3CO)2O work without catalyst.Alkylation not successful, polymerization. F containing EWD can be alkylated.

OFuran O C

O

CH3

(CH3CO)2O

ZnCl2

Chemical reactions of furan:3) Carbene and nitrene: Cabene add across 2,3 C db.There is not much report of reactions of nitrene with furan

OFuran

O

O

COOCH3

HO

H

COOCH3

Carbene adduct

160 0C

CIs-transmuconaldehydetautomerization

CH2N2

Chemical reactions of furan:4) Reaction with reducing agents: dependent on catalyst, solvent & temp

OFuran

O

Raney Ni125 0C

100atm

Pt/CH3COOH

OH

Pt/Al

Or Cu/Al150 0C

O O

Selective reduction

THF

Chemical reactions of furan:5) Reaction with oxidizing agents: F is O2/air sensitive, 1,4 addition to diene system

OFuran

Air

O

O O

Transannular peroxide

OHC CHOSuccinaldehyde

Further Rxn

CH3OH

OO OH

4-Hydroxy-2-butenolide(Lactone)

Air

Chemical reactions of furan:6) DA Reaction : Furan as a diene reacts with dienophiles to give DA adduct.But due to aromatic character and ring strain in cycloadduct it is thermolabile, revert to SM.

Ether/25 0C

O

H

H

Endo 59%

+O

H H

Exo 60%more stable

O

Furan

+

Extra

O

furan

CH3CO2NO2

O NO2

pyridine:SO3

O SO3H

C6H5N2+

O NN

(CH3CO)2O, BF3

O CO

CH3

2 Position reactiveExtra

O

furan

O CH=O

O Br

O HgCl O I

1. HCN, HCl

2. H2O

Br2

dioxane

HgCl2

CH3CO2Na

I2

CH3COCl

O CO

CH3

Extra

Thipohene

S1

2

34

alfa

Beta

alfa'

Beta'

5

Have two pairs of nonbonding e but only 1 pair is in the unhybridized p orbital and is able to overlap with the C of the ring.

Mayer 1882

Coal tar, pt and animal metabolite

Synthesis of Thiophene:1)Using Na-SuccinateClassical mtd Phos. trisulfide ( Red P +S)

SCOONaNaOOC

P2S3 180 0C

S

S

Industrial mtd use hydrocarbon (butane/butene/1,3-butadiene and elemental S

600 0C

Synthesis of Thiophene:2) Ring closure Mtd A) From unsaturated compds/ Fiesselmann mtd:

S

COOH

COOH S

COOCH3

COOCH3 S

COOCH3

COOCH3

H2N

S

COOCH3

COOCH3

HON

S

COOCH3

COOCH3

OHC

COOCH3

HCCOOCH3

CH2C

S

OH3CO

NaOCH3

CH3OH-OCH3

-

NH2OH

HCl

Reduction

1) NANO2, HCl

2)H3PO2, H2O

1) KOH, H2O, Heat

2) H+

Methyl thioglycolate Dimethyl

fumarate

H

H

H

H

Condensation Rxn

Synthesis of Thiophene:2) Ring closure MtdB) Paal Knor mtd: General mtd

S R1

R

S R1R

HO

H

OS R1ROO R1R

P2S5

95 0C

-H2O

H

Synthesis of Thiophene:2) Ring closure Mtd C) Hinsberg Mtd: 1,2 dicarbonyl compound diethylthiodiacetate in presence of st base involved 2 aldol condensation betn reactant and forms half ester

PhPh

O Ot-BuOK

rt

PhPh

HC

SOEt

O

OEtOOC OEtOOC S COOEt

Base

-OEt

Ph Ph

CS

O

O

EtOOCO

H

C CO

PhPh

CS

EtOOCCHCOOK

Base

Base

S

Ph PhOCOOK

HEtOOC

-H2O

S

PhPh

EtOOC COOK

H+

S

PhPh

EtOOC COOH

Chemical reactions of thiophene:1)Reaction with acid: T stable to acid. V. st acid can cause polymerization. Orthophosphoric acid under mild condition gives trimer.

S

Orthophosphoric acid

SS S

Chemical reactions of Thiophen:1)Reaction with Base:

S S Li S R

BuLi RX

Chemical reactions of Thiophene:2)Electrophilic aromatic substitution: more reactive than benzene.Pyrrole>furan>Thiophene>Benzene 2 position more reactive. A) Halogenation: Rxn with NBS gives 2- bromo T

S Cl S ClCl+

36% 14%

S Br S BrBr+

78% 13%

S I S II+

70% Minor

Br Br

S

0 0C

30 0C

Br2, CH3COOH

SO HNO3

O

SO

O

O2N

S S NO2 SNO2

+O2N

Major

HNO3/AC2O

Chemical reactions of Thiophene:2)Electrophilic aromatic substitution: more reactive than benzene.Pyrrole>furan>Thiophene>Benzene 2 position more reactive. B) Nitration:


C) Sulfonation: 95% H2SO4 used at rt readily occurs

SThiophene

H2SO4 95%

S SO3H

2-thiophene sulfonic acid

Chemical reactions of furan:2)Electrophilic aromatic substitution: D) Friedel Crafts reaction: wide variety of choices available

SThiophene

Actyl chloride

S COCH3

2-Acetyl thiophene

SnCl4

SThiophene

RefluxS

2,2' thienoylbenzoic acid

AlCl3

O COOH

O

O

O

+

Chemical reactions of furan:3) Reaction with carbene & Nitrene: caboethoxy carbene adds to C2-C3 bond to give cyclopropane compd, which can be opened with acid to give thiophene Beta-acetic ester

R=C:

R–N: acts as E+

SThiophene

+ CHCOOEtS

COOEtH

S

COOEt

S

COOEtH

HHCl, EtOH

S

COOEt

S N3COOEt NS COOEt-S

NCOOEt

Ethyxycarbonylnitrene reacts with T to give 1,4-adduct which loses S to form N-carboethoxypyrrole

Chemical reactions of furan:4) Reaction with Nu: Every positional combination of Nitro and Halo T actiavate system towards SN rxn

S

Br CuCl, pyridineDMSO

S

Cl

Seems like normal displacement Rxn

Chemical reactions of furan:5) Reaction with free radicals/ Gomberg Bachmann rxn:1 of the best & simple mtd for synthesis of aryl thiophenes

S+ (PhCOO)2

S

HH

OCOPh

DimerizationS

HH

PhOCO2

-PhCOOH

S S

benzoyl peroxide

2,2'-bithienyl

Chemical reactions of furan:6) Reaction with oxidising agents: Resistant to mild oxidising agents.HNO3 breaks ring to maleic acid and oxalic acid.Peracid (perbenzoic acid attacks S atom)

Initial sulfoxide ca not be isolated due to dimerization & further oxidation to

SS O

O O

Thiophene 1,1’ dioxide/ Thiolane can form it’s also reactive but isolable

SO O

Chemical reactions of furan:7) Reaction with reducing agents:

S

Na, CH3OH

NH3 -40 0C S S+ + Butenethiol

S

Pd/C

SH2

70%

Chemical reactions of furan:8) Diels-Alder reaction: Acetylenic dienophiles. Chelotropic expulsion of S from unstable intermediate, which gives benzene derivative

S +

CNCCCN

SCN

CN

CN

CN-S

Pyrrole

NH1

2

34

5 α

β

α'

β’

Ketorelac, atorvastatinHb, Chlorophyl, Vit B12, bile pigment

Runge 1837

Greek: Red

Synthesis methods:1) From Furan

O NH

NH3

Steam/400 0C

O NR

Al2O3RNH2 +

2)From Primary amine:

The Knorr Synthesis:Imp & widely used mtdCondensation of Alfa amino ketone with another dicarbonyl compound with active methylene grp in presence of acetic acid

NH

H3CCOOEt

EtOOC CH3N

H

CH3COOEt

EtOOC CH3

O

N

CH3COOEt

EtOOC CH3

OH

NH2

CH3 COOEt

EtOOCCH3

O

H

O

CH3COOH

-H2O

-H2O

Alfa amino acetoacetic ester

NH

H3CCOOEt

EtOOC CH3

OH H

Hantzch synthesis of pyrrole:Alfa halo ketone/aldehyde react with beta keto ester (Beta chloro ketone)In presence of N containing base (NH3 or amine) which acts as base as well as solvent.Yield moderate to good.

NH

EtOOC

H3C CH3

H3C

NH3 Ether

-H2OO

EtOOC

H3C NH2

EtOOC CH3O

CH2Cl

NH

EtOOC

H3C CH3

Cl

OH

The Paal Knorr Synthesis of Pyrrole:General mtdCondensation of 1,4 diketone with NH3 or primary amine.

NH

H3C CH3

-2H2O

O OCH3

H3C

NH3

(NH4)2SO4

OCH3

H3C

HO NH2 N

H

HO OH

H H

H3C CH3

H

The Piloty Robinsons Synthesis:Monocyclic version of Fischer indole synthesis.Ketazine with st acid to give pyrrole through [3,3] sigmatropic rearrangement of tautomeric divinyl hydrazine

R1 R1

R2R2

NH

R1 R1

R2R2

N NH H

CCR1 R1

R2R2

N N

H H

CCR1 R1

R2R2

N N

Pyridine

Benzene

H+

Xylene, 140 0C

-NH3

Chemical reactions of Pyrrole:1) Reaction with acid:H attached at N undergoes rapid exchange in acid & alkaliSimilar exchange also possible for H at C under more acidic conditionExchange rate of α proton is double than that of β proton

NH

AcidPolymer(Pyrrole -red)

Isolation of trimer of pyrrole could be achieved by controlled addition of acid

Chemical reactions of Pyrrole:2) Reaction with base:

pKa 17.5 which is larger than imidazole so pyrrole is wk acid than imidazole.Weaker than phenol but equal to EtOH It reacts with K to liberate H2 and form saltAcidity of P can be increased by putting EWG at position 3 which stabilizes anion by resonance

NH

NH

N Netc

Base

Resonance structures of furan Thiphene and Pyrrole

Mono-C-alkylation of pyrroles cannot be achieved by direct reaction with simple alkyl halides, either alone or with a Lewis-acid catalyst, e.g. pyrrole does not react with methyl iodide even above about 150 °C, gives further heating leads to a complex mixture made up mostly of polymeric material together with some poly-methylated pyrroles. The more reactive allyl bromide reacts with pyrrole at room temperature, but mixtures of mono- to tetra-allyl-pyrroles together with oligomers and polymers are obtained.

Chemical reactions of Pyrrole:3) Alkylation:

Chemical reactions of Pyrrole: 3) Electrophilic Aromatic substitution: π e density is more as compared to benzene.ES Rxn occurs similar to benzenoid systemOccurs at 2 position if blocked to other positionMax resonance max stability/probability

NH

NH N

HNH

NH N

H

E

H

E

H

E

H

E

H

E

H

2 positionFollowed by 3

Chemical reactions of Pyrrole:3) Electrophilic Aromatic substitution:A)Halogenation: Extremely reactiveChlorination (SO2Cl2)Bromination (Br2 CH3COOH)Iodination (I2/KI3)All these gives tetra halo derivativesHard to get mono halo derivative

Halo-pyrroles are v. unstable, decompose in air & light

NH

Ether, 0 0C

SO2Cl2

NH

Cl Cl

ClCl

Chemical reactions of Pyrrole:3) Electrophilic Aromatic substitution:B) Nitration: Extremely reactive

HNO3

NH

NH

NO2 NH

+

Major

HNO3/AC2O

NH

H2SO4Tar

-10 0C

NO2

Very Minor

Chemical reactions of Pyrrole:2)Electrophilic aromatic substitution:C) Sulfonation: If H2SO4 used at rt forms polymerSo mild sulfonating agent (Pyridine sulfur trioxide complex) used

NH

Pyrrole

NH

SO3H

2-Pyrrole sulfonic acid

N SO3-

90%

Chemical reactions of Pyrrole:4) Reaction with oxidising agents: EasyAutoxidation by air, light red brown colour.

Ozonolysis at low temp breakdown of ring.If ring does survive it forms maleinimide deri.With H2O2 also it gives similar prodt

O3

NH

50 0CNH

O

H3C Et

CH3Or H2O2

H3C Et

CH3

Chemical reactions of Pyrrole:5) Reaction with reducing agents: P won’t respond to rxn with LAH, Na/Liq NH3

But reduction is possible in acidic mediaSpecies under attack protonated

Zn, CH3COOH

N rt NRR

HH

NR

NR

NR

NR

NR

Pyrrolidine deri

3 Pyrroline

Chemical reactions of Pyrrole:6) Diels Alder reaction:

N

+

NCH3CH3

NH

+

NH

Azanorbornadiene derivative

DA adduct

Chemical reactions of Pyrrole:7) Reaction with carbene & nitrene:

NH

CCl2

CCl2

NH

N

Cl-HCl

CHCl3

NaOH

Cl

Cl

NH

Cl

Cl

H NH

CHCl2

H2O -2HCl

NH

CHO

2-pyrrolecarbaldehyde

NH

Halocyclopropyl int

NH

N N CHCOOEt+Cu

100 0CNH

CH2COOEt

Ethyl pyrrole acetate

Diazoester

Rx with carbene

N

NCH2COOEt

NHH

HN

H

N CH2COOEt-N2

N3COOEt

N NH2

CH2COOEt

Rx with Nitrene:Gives homoazopyrrole which rearranges to give final prdt

5 Membered Heterocyclic ring containing 2 hetero atoms

N

NH

NNH

Imidazole Pyrazole

Imidazole

N

NH

Imidazole1

2

34

5

Aka IminazolineAzopyrrole2 N atom separated by C

Histamine, Histidine,Pilocarpine & allantoinBenzimidazole in Vit B12

Resonance structure of Imidazole:

N

NH

N- like pyridine deactivate its vicinal positions

most strongly activated position1

2

34

5

Attack at 5If blocked then on 4

1) Synthesis from imidazoline: Dehydrogenation of imidazoline in +ce of SAnother variation is use of Barium mangnate

N

NH

R

N

NH

R

BaMnO4-NH3

H2CH2C NH2

NH2+

NC

REthanediamine

Alkylnitrile

2)Synthesis from α Haloketone: 2,4 disubs Imidazole from Benzimidine & α Haloketone

CH2BrC

PhO +

HNC

H2NPh

-Br-

-H2ON

NH Ph

Ph

3)Radiszewski method: Imp mtdCondensation of diketone with aldehyde in +ce of NH3

-3H2O N

NH Ph

PhCC

O

O

Ph

Ph

+

H2NH

H2NH

+ CH

PhO

PhN

N

H

Ph

Ph

Ph

Reaction of imidazole with acid & baseBase and form crystalline salt with acid. More acidic than pyrroles and thus forms salts of the following type with Grignard reagent or metal ions.

Reaction of imidazole with oxidising agents:stable to auto oxidation and to the action of chromic acid Can be oxidised by KmnO4 . H2O2 Readily opens the ring to form oxamide

N

NH

NH

NH

O2 / MeOH

O

MeO

MeO

Oxygen in the presence of a sensitizer (single oxygen) reaction gives an imidazolidine derivative

Reactions of imidazole -Electrophilic substitution Rxn:E + would attack the unshared electron pair on N-3, but not that on the ‘pyrrole’ nitrogen since it is the part of the aromatic sextet.

It is more susceptible to E + attack than thiazole, furan and thiophene. Attack takes place at the 4th and 5th position

Reactions of imidazole -Nitration:

Bromination

Reactions of imidazole - Sulfonation:

NN

CH3

BuLi RXN

N R

N

Nph

N

Nph

Li

ph

R

BuLiN

N

CH3

R

Li

N

NH

N

N

NNH

NN

Ac2O

COCH3

CH2N2

CO2CH3

H3CCH3

H3C

CO2CH3

Acylation

Alkylation

Lithiation

Reactions of imidazole -

Catalysis role of imidazole - Ester Hydrolysis.Inspired by evidence that the imidazole ring of histidine residues present in varioushydrolytic enzymes is responsible for their proteolytic activities, imidazole itself has been shown to be an excellent catalyst of ester hydrolysis In intramolecular transesterifications and hydrolyses of 2-hydroxymethylbenzoic acid derivatives, the accelerating role of imidazole is due to its ability to act as a proton transfer catalyst rather than as a nucleophile.

Indole:

Indole

NH1

2

345

6

7

abundant in naturetryptophan, indole-3-acetic acid,serotonin, natural products, drugs Isolated industrially from coal tarBiosynthesis of tryptophan

Isoelectronic with naphthalene Very weakly basic: pKa of protonated indole: 2.4Protonation occurs at C–3 preferentiallyEasily oxidized (atmospheric oxygen) very e richElectrophilic attack occurs at C–3 (site of most electron density)

N–1 is the most nucleophilic site

C–2 is the second most reactive site

C–3 is more reactive to electrophilic attack than benzene

Resonance structure of indole:

Intramolecular cyclization of N-phenylamides using strong base at high temperature.

The Fischer indole synthesis :best methods for preparing indoles. converts arylhydrazones into indoles in the presence of an acid catalyst.

Reactions of indole:Protonation

Bischler indole synthesis:2-aryl-indole from α-bromo-acetophenone and excess aniline

Reissert indole synthesis:Basic condensation of o-nitrotoluene with oxalic ester to o-nitrophenylpyruvic ester, reduction of the nitro group to an amino group, cyclization to indole-2-carboxylic acid and final decarboxylation

Reactions of indole:


Indoles – Electrophilic Substitution





Oxidative cleavage of 2,3 db
