Page 179 - Academic Press Encyclopedia of Physical Science and Technology 3rd Organic Chemistry
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Encyclopedia of Physical Science and Technology EN007F-314 July 6, 2001 16:59
Heterocyclic Chemistry 335
Several of the early chemotherapeutic agents used in a Fully unsaturated five-membered heterocyclic rings are
wide variety of cancer treatments depend upon an three- often synthesized by the ring closure of 1,4-dicarbonyl
membered ring undergoing nucleophilic attack by an oxy- compounds to give, with ammonia or primary amines,
gen or nitrogen atom in DNA of the cancer cells. Examples pyrroles (Paal–Knorr synthesis); with dehydrating agents,
include cyclophosphamide (which can eject chloride with furan; and with phosphorus pentasulfide, thiophenes.
the formation of an aziridinium ring, a powerful elec-
trophile) and mitomycin. In contrast, epoxides derived by R 1 R 2 + R NH 2 ∆ R 1 R 2
3
metabolism of many polybenzenoid hydrocarbons are O O N
R 3
highly toxic because the epoxides form covalent linkages
Paal-Knorr synthesis of pyrroles
with normal cell DNA.
Another important synthesis of pyrroles is the Knorr
O
pyrrole synthesis, in which alpha-aminoketones or their
H H
HO HN S equivalent are condensed with carbonyl compounds con-
taining active alphamethylene groups.
N OAc
O H NH 2 O
COOEt
COOH
cephalosporin C O COOEt
KOH
+
+ N COOH
_ NH 3 O COOMe H
B. Five-Membered Heterocycles Cl
Knorr pyrrole synthesis
with One Heteroatom
Indoles (benzo[b]pyrroles) are frequently prepared by
1. Synthesis the Fischer indole synthesis, in which aryl hydrazones
Pyrrole, furan, and thiophene are the most important par- undergo rearrangement on heating, usually in the presence
ent heterocycles of this class, and their annelated deriva- of acid. The important drug indomethacin, used to combat
tives constitute a vast array of both naturally occurring and rheumatoid arthritis, has been synthesized by this method.
synthetic compounds. COOH
The ring closure of a four-carbon chain with the incor- COOH
poration of one heteroatom is very easy. MeO MeO
+
sulfide NH 2 O N
N N
Br Br H H
S
tetrahydrothiophene
COOH COOH
MeO MeO
heat
COOH
H 2 N O
N N N
H H
pyrrolidone O
synthesis of indomethacin
A special case of this is the Hofmann–Loeffler–Freytag Cl
reaction, in which pyrrolidines (or piperidines) are formed
by the decomposition of protonated N-haloamines. 2. Naturally Occurring Five-Membered
Heterocycles
H +
H H O Pyrrole (Gk·pyr = fire) was first isolated from bone py-
N Cl + N N
rolyzate; it imparts a bright red color to pinewood moist-
R R R
ened with concentrated hydrochloric acid.
conversion of N-chloramines into pyrrolidines
Condensation of suitable pyrroles in the presence of
This particular free-radical mechanism confers high se- acid leads to dipyrromethene cations, which are precursors
lectivity in the formation of products owing to a preferred to porphyrins, a group of compounds found in all living
six-membered transition state. Another common route to matter and forming the basis of respiratory pigments.
five-membered heterocycles is via 1,3-dipolar cycload-
H
dition.
O
MeOOC + HBr +
MeOOC AgNO 3 , Et 3 N NH HN NH HN
Ph N COOMe +
MeCN _
Ph N COOMe Br
H
formation of pyrrolidines via cycloaddition a dipyrromethene cation