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SYNTHETIC ROUTES FOR SOME COMMON MONOCYCLIC FIVEMEMBERED π-EXCESSIVE HETEROAROMATIC COMPOUNDS


Synthetic Routes to Five membered rings R2

R R1

X

R3

General method (Paal Synthesis) P2O5 / heat - H2O R

3

R

R O

O

R1

O

(NH4)2CO3 / heat

R1

R3 R2

R

R2

1

R2

R

N H

R3

NH3 P2S5 / heat

R2

R R1

S

R3


Mechanisms Formation of Furan

R

R2

R1

P2O5 / heat R3

O

O

R2

R R1

R

R1 O HO

R3 O

HO

R2

R

- H2O R1

O

R3

H

R2 R3


Formation of Pyrrole R2

R R1

(NH4)2CO3 / heat R3

O

R1

NH3

O

R1

R N H

R

3

R1

R2 N

H

R2

R1 N HO

HN

2

R

R R3

O

- H2O R

R2

R

- H2O

R3 -H

Formation of Thiophene R R1

R2

R

P2S5 / heat R1

R3 O

R2

R

R2

R3 O

O

1

R

S

R3

S

R2

R

R1 O

R - H2O

3

R

-H

HS

H

R1 S HO

R2 R3

R3


Synthesis of Furans I- Paal Synthesis ( as before) (II) From α-halocarbonyl compounds (Fiest – Binary Synthesis) This synthesis involves an aldol condensation with the carbonyl group of the halogeno-component, followed by the formation of the oxygen ring by intramolecular displacement of halide, and finally loss of water. O

O R R1 H

O

2

R

+ R3

O

Cl

α-halo carbonyl compounds

base / base R

R2 O

R3

β-diketones - HCl - H2O

OH

H

O R2

R R1 H Cl

OH

O

R3

O R2

R R1 H Cl HO

R3


Example 1: O

O O

Me

Me

+ O

Cl Îą-chloroacetone

base / base

Me

- HCl

Me

acetylacetone

Me O

Me

- H2O

Example 2: O

O Ph

O

OEt

+ Br phenacylbromide

O

Me

Ethyl acetoacetate

base / base - HCl - H2 O

Ph

OEt O

Me


3- From Pentose

CHO H OH HO H H OH CH2OH

HO H H

OH

H OH CHO HO H

dil. HCl / heat - 3 H2O

O

CHO

Furfural


4- Cycloaddition reactions have also been applied to synthesis of furans. O

O H3C

H N

ROCH2-C C-CH2OR

H3 C

∆

O

OR

N RO RO

CH3 OEt

N O

H3CO2C

CO2CH3

CH3O2C-C C-CO2CH3 O

OEt

OR


PYRROLE There are three generally important approaches to pyrrole derivatives. These can be summarized as shown.

1- Paal method (1,4-Dicarbonyl compounds react with ammonia or primary amines to give pyrroles). R2

R2

R3

R3

RNH2 R1

R4 O O

- H2O

R1

N R

R4

NH3 Me

Me OO

acetylacetone

PhH / ∆

Me

N H

Me


2- Knorr Synthesis (From α-Aminoketones and β-diketones) 1

R H

O

R2

NH2

H

+

H

CO2R

R1

- 2H2O

R2

R3

O

CO2R N H

Example 1 CO2Et

O

Me

Me

CO2Et

+ NH2

O

N

Me

H Me

Me

CO2H aq KOH

∆ N H

Me

N H

Me

Me

R3


Synthesis of pyrrole-2,4-dicarboxylic esters

Me O Me

O

EtO2C

Me O Zn / AcOH

NaNO2 ( mole) AcOH

NOH

EtO2C

EtO2C

oxime CO2Et

Me EtO2C

CO2Et N H

Me

Me EtO2C

CO2Et N

Me

O

Me

- 2 H2 O

NH2


iii) Hantzsch Synthesis It

the

reaction

of

α-haloketones,

β-ketoester

and

ammonia.

R1

Cl

CO2R

+ R2

O

O

R3

NH3 -H2O -HCl

R1 R2

CO2R N H

R3


Example CO2Et

CO2Et

Cl

NH3

+ O

Me

Me N H

Me O

Me

Mechanism Cl CO2Et O

Me

NH3 - H2O

H H2 N

CO2Et Me

- HCl

EtO2C H H

CO2Et - H2 O Me

N H

Me

Me O

OH Me N H

Me

EtO2C Me NH2 Me

O


Synthesis Thiophene 1- Paal Synthesis (As before) 2- Hinsberg Synthesis It is the reaction of Îą-diketones and diethyl thioacetate

Ph

Ph

O

O EtO2C

Ph

S

CO2Et

EtO2C

Ph

S

CO2Et


3- Fiesselmann synthesis It is the reaction of methyl thioglycolate with unsaturated compounds

like acetylenic molecules, followed by a base-catalyzed (Dieckmanntype cyclization) to generate substituted thiophenes CO2Me CO2Me +

CO2Me base

Michael addition SH

CO2Me

Me

S

Me O

OH

- MeOH Me

S

CO2Me

Me

S

CO2Me


3- Gewald synthesis Example 1

Me

CN Me

CN

CHO + - H2O

CN

CN

CN S S

NH2

heat TEA


Example 2

Me

Me Me

CN O

CN

Me

+

CN - H2O

CN O acetylacetone

Me

O

CN S / heat

Me S O

NH2 TEA


Synthetic Routes of some common benzofused five-membered π-excessive heteroaromatic compounds


Synthesis of Indole Compounds Fischer Indole synthesis The general procedure by which a phenylhydrazone of an aldehyde or ketone is heated in the presence of a catalyst such as zinc chloride, boron trifluoride, or polphosphoric acid to produce an indole. Me Me N H

N

Me - NH3 N H

Me


Mechanism Me

Me

Me

Me N H

N

N H

hydrazone form

Me H

H

Me

NH NHHN

Me

hydrazide form

Me H NH2

Me

NH

N Me H

N Me H H Me

- NH3

Me N H

NH2HN

Me


B F 3. ( C 2 H 5) 2 O N

N H

C H3C O O H

N H

H3C PPA N

N N

CH3

C H3

C3H7C H2

N H

C H3 N

C3H7

C u Cl N H

C H3


Formally, the Fischer synthesis involves rearrangement with the loss of a molecule of ammonia; the mechanism by which such a molecular manipulation occurs has been the object of much study.

H

N H

N N H

NH NH

NH

H - NH3 NH NH2

N H NH2

N H


In support of this mechanism may be cited the observations that (1) the reaction is acid-catalyzed (2) the nitrogen atom eliminated as ammonia is the farthest removed from the aromatic ring:

H3C

15 N N H

C6H5

15 N H

C6H5


The Reissert Indole Synthesis

The best way for synthesis of indole derivatives with substituents on benzene ring. Thus o-nitrotoluene can be used as starting material via treatment with diethyl oxalate in basic medium. CH3 + COOEt NO2 COOEt

aq. KOH

EtOK 40 oC

OMe

NO2 O

COOEt

OMe

230 oC

OMe

N H

NO2 O

COOH

NH2 O

COOH

OMe

- H2O COOH

- CO2 OMe

N H

OMe


The Bischler Indole Synthesis This reaction involves treatment of an arylamine with α-halo-, α-hydroxyaldehyde or ketones in the presence of an acidic reagent

O

R

O

+ NH2

X

R1

HO

R

N H

1

N H

R

X = Cl, Br, OH

R N H

R1

R R1


BENZO[b]FURANS When arloxyacetone is treated with standard regents (H2SO4, ZnCl2, POCl3, KOH, or PPA), the corresponding 3-alkylbenzofuran is isolated. O CH3 R

R

R

O

Cl

NaOH

O

ONa

OH

CH3 R O

PPA

CH3


O HO

Cl

Cl

CH3

CH3

+ KOH, H3O HO

O

O

CH3

PPA

O

CH3

O

C6H5

O

C 6H 5

PPA

O

CH3

Cl

O

C6H5

CH3

Cl

O

C 6H 5


Hansch reaction Thermal ring closure with subsequent cyclodehydrgenation of orthosubstituted phenols is known as Hansch reaction and can best be demonstrated by the acid-catalyzed cyclization of aldehyde. The key aldehyde is conveniently obtained by ozonlysis of allylphenol. O3 R

CHO

OH

R

OH

PPA - H2O

R

O

allylphenol

R

I R OMe

R

O OMe

- MeOH O

R


BENZO[b]THIOPHENE 1- Via direct pyrolysis of thiophene

S

heat S

S

S

4+ 2 cycloaddn

S

- H2S S


Arylthio dimethoxy propane are readily cyclized in the presence of PPA to

give

substituted

benzo[b]thiophene.

(Arylthio)acetone,

arylphenylsulfides, and S-rylthioglycolic acids react similarly.

MeO

OMe Me

S

Me

S


SYNTHETIC ROUTE TO SUBSTITUTED COMMON SIX-MEMBERED π-DEFICIENT HETEROAROMATIC COMPOUNDS General synthetic routes When the need arises to synthesize any one of the million of possible larger ring organic compounds, a reasonable approach is to “subdivide the target molecule into fragments that will ultimately fit together to generate the desired structure”. The following Scheme shows several of the possible modes of combination to give the simplest π-deficient, six-membered, heteroaromatic molecule, and the pyridine nucleus. A general “rule of thumb” is to choose the largest readily available units for the construction of heteroaromatic nucleus. For example, (4+2) combination could be accomplished by a typical Diels-Alder reaction, and (5+1) could be effected by the condensation of 1,5-diketone with hydroxylamine.


5+1

4+2

Ν

Ν

N

3+3

N

2+2+2

3+2+1

N

N

.

.

Ν

N

N

N

.

. N

Ν

.

. N N

Ν


Hantzsch synthesis Hantzsch synthesis is used to prepare Symmetrical pyridines, which combine two molecule of a β-ketoester like ethyl acetoacetate, an aldehyde, and ammonia source to give the dihydropyridine, which oxidized to pyridines. Ar H

CH EtO2C Me

CO2Et

O O

Me H

N H

O

Me

H

Me

NH O

CO2Et

EtO2C

Me

Me

NH2 O

Ar CO2Et

N

Ar CO2Et

EtO2C

Ar EtO2C

Ar

Me

(O)

EtO2C Me

Ar CO2Et

N H

Me

Me

- H2O

EtO2C Me

CO2Et Me N H OH


3- Pyrylium salts react with ammonia to give excellent yields of substituted pyridines

NH4OAc Ph

O

Ph

AcOH / heat

Ph

N

Ph


4- Diels-Alder reaction Diels-Alder reaction of diverse electron-poor heterocycles with electron-rich dienophiles give rise to bicycyclic intermediate, which undergo reterocycloaddition to generate the heteroaromatic nucleus. Thus, oxazole has been transformed to pyridoxine. O O H3C EtO

N

O EtO

+

O

O

O H3C

O

O

N

OH EtO H3C

CO 2 Et OH

N

HCl EtOH

LiAlH 4

CO 2 Et

EtO H3C

N


The α-pyrone react with benzonitrile to give pyridine, and oxazinones react with ynamines to give the corresponding pyridine

CN

CH3 EtO2C

CH3 O

H O

EtO2C

Me

NEt2

O N

O R

+ Me

EtO2C

H

+ CH3 O

CH3

O

N CH3

- CO2 CH3

NEt2

- CO2 / ∆

N

Me Me

N

R


Synthesis of Quinoline compounds 1. Ring Synthesis There are three important methods for the construction of the quinoline ring system from non-heterocyclic precursors, and all three start with benzene compounds. Anilines react with 1,3-dicarbonyl compounds to give intermediates, which can be cyclized with acid.

H

+ NH2

O

O O

N

H

+ +H - H2O

N


The Skraup Synthesis From arylamines and ι,β-unsaturated carbonyl compounds. The Skraup Synthesis. In this extraordinary reaction, quinoline is produced when aniline, concentrated sulphuric acud, glycerol and a mild oxidizing agent are heated together.

N NH2

+

CH2OH CHOH CH2OH

H2SO4 O2NC6H4SO3Na


O + NH2

OH R

R

R

O

CH N H

CH2

N H R

R (O)

N

- H2O N H

H2SO4


Thus

R O + NH2

R

R (O) CH CH2

N H

R

CHO

+ NH2

N

R

(O)

R C CH2

N H

N


The Friedlander and Pftizinger Syntheses A second generally useful method of preparing substituted quinolines involves the condensation of an o-amino aromatic aldehyde or ketone with a carbonyl compound having the grouping –CH2CO-. Ph

Ph COMe

160 oC

O

- EtOH

COMe N H

heat

Ph

- H2 O

N

O

OH

O NH2 + CO2Et

Ph

OH

KOH

O

Me

EtOH / heat

CO2Et

NH2

Me

O

Ph

Ph

OH

CO2Et

CO2Et N H OH

Me - 2 H O 2

N

Me


CH3

CH3 O

O O NH2 CHO

+ NH2

100oC, 5-10min.

+

O

H2SO4

HO

O N

O

2N HC,reflux 15 min. NaOH

N


Isoquinolines 1- Bischler-Napieralski reaction In the Bischler-Napieralski reaction the β-phenylethylamine is acylated and then cyclodehydrated by reaction with phosphoryl chloride, phosphorus pentaoxide, or other Lewis acids.

P2O5 / heat NH2

N

NH O

R

R Pd / heat N R

(O)


2- Isoquinoline can be obtained by passing the vapours of benzylidene ethylamine through red hot tube

R

R RCH2CH2NH2 CHO

heat N Schiff base

- 2 H2

N


5 synthetic approaches [compatibility mode]