Capitulo Heterociclos

Heterocyclic Compounds - Page 1
Chapter 26 Heterocyclic Compounds

Nonaromatic Heterocycles
N H
Tetrahydrofuran (THF)
Piperidine
Heterocyclic Aromatic Compounds

N O N H N S O N H
Furan
Pyrrole
Thiophene
Oxazole
N
Imidazole
Pyridine
Pyrimidine
N N H N S N N H
Benzofuran
Indole
Benzothiophene
Purine
Quinoline
Isoquinoline
Furan, Pyrrole, Thiophene

X X
cyclopentadiene
Furan Resonance structures:

.. X H : X H : X
Pyrrole
H X : H : X
Dipole Moments:
N H
1.7 D
0.7 D
1.57 D
N H 1.80 D
0.52 D
1.87 D
Synthesis of Furan
Pentosans
(oat hulls) (corn cobs) 12% HCl CHO O Furfuraldehyde
pass vapor over
Ni / 280oC (CO)
O Furan
Mechanism:
CHO H C OH HO C H H C OH CH 2OH H (H2O) CHO C OH C H H C OH CH 2OH CHO C O H C H H C OH CH 2OH H (H2O)
C O O H CHO
H H O
H CHO (H2O) OH
CHO
Commercial Preparation of Pyrrole

RNH2 / H2O Al2O3 / 400oC
N R
Commercial Preparation of Thiophene

Butane Butenes Butadiene 600oC
+ Sulfur
Synthesis of Substituted Furans, Pyrroles, Thiophenes

The Paal-Knorr Synthesis
P2O5 (H2O) 160oC R O O R' (NH4)2CO3 (H2O) 100oC
R'
N H
R'
P2S5 (H2O) 100oC
R'
Examples:
O Ph Ph
O Ph O
H Ph OH
Ph
O 62% yield
Ph
H CH3 O O CH3 (NH4)2CO3 H CH3 H H CH3 N H OH CH3 N
H CH3 O
CH3
N H 85% yield
CH3
H Ph O O H H CO2Me Ph S OH CO2Me P2S5 Ph S
H CO2Me O
Ph
S 50% yield
CO2Me
Reactions of Furan, Pyrrole, and Thiophene

Electrophilic Aromatic Substitution
More reactive than benzene Substitution occurs predominantly at the 2- or 5position ( to heteroatom) Nitration of Thiophene:
O S Ac2O + CH C ONO 3 2 10oC Acetyl nitrate S 70% yield NO2 + S 5% yield NO2
S + NO2 S H
NO2 H S H NO2 S S
NO2 H S
NO2 H
NO2
Nitration of Pyrrole:
O N H + CH C ONO 3 2 5oC N NO2 + N H 7% yield NO2
H 83% yield
Nitration of Furan:
O O + CH C ONO 3 2 O CH3 H C O O 60% yield NO2 H
pyridine O NO2
Acylation:
O O + CH 3 C O O C CH3 BF3 Et2O O C CH3
O 85% yield O N H + CH 3 C O O C CH3

no catalyst required
CH3
O H 60% yield O O SnCl4 C 6H 6 S
+ CH C O C CH 3 3
CH3
O 80% yield
Note: Friedel-Crafts alkylation is not generally possible---AlCl3 catalyzes polymerization.
Sulfonation:
95% H2SO4 25oC
SO3H S 75% yield
+ O
N SO3 SO3H O 90% yield
N H
N SO3
SO3H
H 90% yield
Note: Halogenation is generally not synthetically useful---too many products.
Electrophilic Aromatic Substitution on Substituted Furans, Pyrroles, and Thiophenes. In general:

D E X W E X E X X E W D
Examples:
O C O H HNO3 / Ac2O O2N O CHO
Br HNO3 / Ac2O S S
Br NO2
In general:
E E X D E X major E E X W X W + E X W MIXTURE
Ratio depends upon relative directing influence of X vs. W
+ D X minor D
Examples:
NO2 S CH3 HNO3 Ac2O O2N CH 3 + S CH3
70:30 O2N HNO3 S NO2 S NO2 O2N 85:15 + NO2
Other Reactions
Ring Opening
H3 O CH 3 O CH 3 CH 3 H H H 2O O CH 3
CH 3 H2O O
CH 3
CH 3 H O O
CH 3
CH 3
C O
CH 2
CH 2
C O
CH 3
N H
NH2OH
CH2
CH2
NOH
NOH
OEt CH OEt
Ra-Ni
CH 2 CH 3
CH 2 CH 2
OEt CH OEt
Diels-Alder Reaction
O O + O O O + N H O O CO2H N H CO2H O O O O
NO REACTION! S
Pyridine
N
Pyridine
Pyrrole
Synthesis of Pyridines
Pyridine itself is available from coal tar.
Hantzsch Pyridine Synthesis

O 2 R -keto ester H R' EtO2C R N H 1) KOH / EtOH 2) CaO / R N R CO2Et R HNO3 H2SO4 R' EtO2C R N CO2Et + R'CHO aldehyde + NH3 ammonia R' CO2Et R
Mechanism:
EtO2C R R' CH 2 C O R' + C O R O H EtO2C H
NH3 + O
CH 2 R
CO2Et H 2N
CO2Et R
R' EtO2C R O H CO2Et + H 2N R R EtO2C
H R' CO2Et O H 2N H R' CO2Et N H H R' EtO2C R N H CO2Et R R R
H R' EtO2C R O H 2N CO2Et R
EtO2C H R HO
H2O
Example:
O CH3 C CH2 CO2Et + NH4OH + aq CH2O
EtO2C CH3 N H 87% yield
CO2Et CH3 HNO3 H2SO4
EtO2C CH3 N 65% yield
CO2Et CH3
1) KOH / EtOH 2) CaO /
CH3
N 65% yield
CH3
Reactions of Pyridine
Basicity / Nucleophilicity
Pyridine is used as an acid scavenger for many reactions that liberate strong acid. Example:
R CH2 OH + Ts Cl + N R CH2 OTs + N H Cl
Pyridine can serve as a Lewis Base:
+ (CH3)3B N
or a Nucleophile:
N B(CH3)3
Br + N Br N
Electrophilic Aromatic Substitution

The nitrogen atom deactivates the ring toward electrophiles---vigorous conditions are required.
Examples:
NO2 N 22% yield
KNO3 / HNO3 H2SO4 / Fe 300oC
H2SO4 230oC 24 h
SO3H N 71% yield
Electron-Donating Substituents Increase Reactivity Direct Attack

Br N NH2
1) Br2 / HOAc / 20oC 2) NaOH N NH2
90% yield O2N N NHCO2Et 46% yield
NHCO2Et
HNO3 / H2SO4 100oC / 1.5 h
NHCO2Et N HNO3 / H2SO4 100oC / 1.5 h N
NHCO2Et NO2
61% yield NH2 fuming H2SO4 275oC / 4 h N NH2 SO3H N 90% yield
Pyridine-N-Oxide
Pyridine can be oxidized by treatment with peracid:
O C + N Cl O O H CH2Cl2 N O
Nitration of pyridine-N-oxide occurs readily to give the 4-nitro derivative:
N O
N O
H NO2
N O
H NO2
N O
H NO2
HNO3 / H2SO4 90oC / 14 h
N O NO2
N O NO2 PCl3 (POCl3)
N O
H N O
Nucleophilic Aromatic Substitution
+ Nu: N N
H H Nu N Nu
The Chichibabin Reaction:

+ Na NH2 N N NH2 75% yield
Note:
N NH2 Na
+ Ph-Li N N Ph 50% yield
Fused-Ring Heterocycles
Benzofuran
N H Indole
Benzothiophene
Ring fusion serves to Stabilize heterocyclic ring Change orientation of electrophilic aromatic substitution from 2 to 3 Indole is found in many natural products, e.g., the amino acid tryptophan
NH2 CH2 CH CO2H
N H
Indole Alkaloids--- Natural products containing the indole heterocyclic moiety:

N N O O
N H CH3O2C OH
N
N
CH3O N CH3 OH
CO2CH 3
Strychnine
Yohimbine
Vindoline
The Fischer Indole Synthesis
N H
BF3.OEt2 65oC
N H 93% yield
C3H7 C N H N CH3 CuCl 250oC N H 31% yield C3H7 CH3
CH3 N H
C N
PPA 100oC N H 73% yield
Mechanism:
N N H H NH NH H NH3 NH2
N N H H
NH NH2
N H
N H
The Benzopyridines
N
Quinoline
N
Isoquinoline
Electrophilic aromatic substitution occurs at the benzene ring. Nucleophilic aromatic substitution occurs at the pyridine ring.
Quinoline Alkaloids:
H
HO
H
O N HO O
Quinine - Primary alkaloid of Cinchona bark; shows antimalarial activity
Camptothecine - from the wood of Camptocheca acuminata; shows antitumor activity
Isoquinoline Alkaloids:
MeO MeO N H
OH
H H HN MeO MeO
HO O O N
Emetine - The principle alkaloid of ipecac (ground roots of Uragoga ipecacuanha)
Lycorine - From the bulbs of Narcissus and Amaryllis
The Skraup Quinoline Synthesis

CHO + NH 2 CH 2CH 3 CH 2CH 3 N 42% yield
NO 2
H2SO4
S O3 Na
Mechanism:
O + NH2 N H HO H N H R [O] (H2) N H N N H R R HO R R O R
H2O
The Bischler-Napieralski Isoquinoline Synthesis

NH Ph O
NH O Ph
POCl3 / P2O5 xylene / / 1 h
Cl Cl P Cl O N
N H Ph O P O [O] (H2) Ph Cl Cl
O Cl2POH
Ph 100% yield

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Heterocyclic Compounds - Page 1

Chapter 26 Heterocyclic Compounds

Heterocyclic Aromatic Compounds

Heterocyclic Compounds - Page 2

Furan, Pyrrole, Thiophene

Furan Resonance structures:

Heterocyclic Compounds - Page 3

pass vapor over

Heterocyclic Compounds - Page 4

Commercial Preparation of Pyrrole

Commercial Preparation of Thiophene

Heterocyclic Compounds - Page 5

Synthesis of Substituted Furans, Pyrroles, Thiophenes

P2O5 (H2O) 160oC R O O R' (NH4)2CO3 (H2O) 100oC

P2S5 (H2O) 100oC

Heterocyclic Compounds - Page 6

H CH3 O O CH3 (NH4)2CO3 H CH3 H H CH3 N H OH CH3 N

H Ph O O H H CO2Me Ph S OH CO2Me P2S5 Ph S

Heterocyclic Compounds - Page 7

Reactions of Furan, Pyrrole, and Thiophene

Heterocyclic Compounds - Page 8

Heterocyclic Compounds - Page 9

O 85% yield O N H + CH 3 C O O C CH3

O H 60% yield O O SnCl4 C 6H 6 S

Note: Friedel-Crafts alkylation is not generally possible---AlCl3 catalyzes polymerization.

Heterocyclic Compounds - Page 10

SO3H S 75% yield

N SO3 SO3H O 90% yield

Note: Halogenation is generally not synthetically useful---too many products.

Heterocyclic Compounds - Page 11

Electrophilic Aromatic Substitution on Substituted Furans, Pyrroles, and Thiophenes. In general:

Heterocyclic Compounds - Page 12

70:30 O2N HNO3 S NO2 S NO2 O2N 85:15 + NO2

Heterocyclic Compounds - Page 13

Heterocyclic Compounds - Page 14

Heterocyclic Compounds - Page 15

Heterocyclic Compounds - Page 16

Hantzsch Pyridine Synthesis

Heterocyclic Compounds - Page 17

R' EtO2C R O H CO2Et + H 2N R R EtO2C

H R' CO2Et O H 2N H R' CO2Et N H H R' EtO2C R N H CO2Et R R R

H R' EtO2C R O H 2N CO2Et R

Heterocyclic Compounds - Page 18

EtO2C CH3 N H 87% yield

CO2Et CH3 HNO3 H2SO4

EtO2C CH3 N 65% yield

1) KOH / EtOH 2) CaO /

Heterocyclic Compounds - Page 19

Pyridine can serve as a Lewis Base:

Heterocyclic Compounds - Page 20

Electrophilic Aromatic Substitution

KNO3 / HNO3 H2SO4 / Fe 300oC

SO3H N 71% yield

Heterocyclic Compounds - Page 21

Electron-Donating Substituents Increase Reactivity Direct Attack

1) Br2 / HOAc / 20oC 2) NaOH N NH2

90% yield O2N N NHCO2Et 46% yield

HNO3 / H2SO4 100oC / 1.5 h

NHCO2Et N HNO3 / H2SO4 100oC / 1.5 h N