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