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

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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

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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

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Commercial Preparation of Pyrrole

RNH2 / H2O Al2O3 / 400oC

N R

Commercial Preparation of Thiophene

Butane Butenes Butadiene 600oC

+ Sulfur

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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

Heterocyclic Compounds - Page 6

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

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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

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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

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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.

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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.

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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

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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

Heterocyclic Compounds - Page 13

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

Heterocyclic Compounds - Page 14

Diels-Alder Reaction
O O + O O O + N H O O CO2H N H CO2H O O O O

NO REACTION! S

Heterocyclic Compounds - Page 15

Pyridine
N

Pyridine

Pyrrole

Heterocyclic Compounds - Page 16

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

Heterocyclic Compounds - Page 17

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

Heterocyclic Compounds - Page 18

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

Heterocyclic Compounds - Page 19

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

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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

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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

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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

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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

Heterocyclic Compounds - Page 24

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

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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

Heterocyclic Compounds - Page 26

Mechanism:

N N H H NH NH H NH3 NH2

N N H H

NH NH2

N H

N H

Heterocyclic Compounds - Page 27

The Benzopyridines

N
Quinoline

N
Isoquinoline

Electrophilic aromatic substitution occurs at the benzene ring. Nucleophilic aromatic substitution occurs at the pyridine ring.

Heterocyclic Compounds - Page 28

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

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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

Heterocyclic Compounds - Page 30

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