Page 174 - 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

330 Heterocyclic Chemistry

to the products. In terms of valence bond theory, the first and isoquinolines can be alkylated in the 2-, 2-, and 1-
drawn canonical form, formed by ortho attack on pyridine positions, respectively. Acylation of protonated pyridines,
by nitronium ion, is of high energy because it carries a pos-
itive charge on the electronegative nitrogen atom. Hence acid
this form contributes little to the overall stability of the + ROOH
N N R
cation formed by attack at the ortho position. The same
arguments apply to attack at the para position. However, in alkylation of pyridine
the meta orientation all three forms contribute to lowering quinolines, pyrazines, and quinoxalines via free radicals
the energy of the cation; in practice the nitrated product all proceed in fair yield. Thus, treatment of pyridine with
is found to be almost exclusively m-nitropyridine. Much free radicals generated from formamide gives isonico-
of the electrophilic and nucleophilic chemistry of het- tinamide and the 2-isomer.
erocycles has been successfully rationalized along these
CONH 2
lines.
Fe 2+
+ HCONH 2 + Bu OOH +
t
+
NO 2 + + N N N CONH 2
H H H
o-attack +
N N N N isonicotinamide
NO 2 NO 2 NO 2
In marked contrast, homolytic arylation of heterocy-
+ H H
+ H
NO 2 NO 2 cles often gives low yields and is unselective. Phenyl
NO 2 NO 2
m-attack + + radicals attack pyridine to give a mixture of 2-, 3-, and
N N N N
4-phenylpyridines.
attack of nitronium ion on pyridine
E. Electrocyclic Reactions
The canonical forms of pyridine N-oxide predict that
the ring should be attacked by both nucleophiles and elec- Electrocyclic reactions are very important both for the
trophiles. Both are indeed observed, such as the forma- synthesis of heterocycles and in their transformation to
tion of 2- and 4-chloro- and 4-nitropyridine N-oxides, new cyclic structures. Occasionally, intramolecular Diels–
respectively. Alder reactions are used to form large heterocyclic rings.
+
O
∆
O
+ +
N N N
_ O _ O _ O
More often, two fragments undergo [4 + 2]cycloaddition
+ to give a heterocyclic ring, as exemplified for the synthesis
N
_ of pyridines and furans from oxazoles. Similar transfor-
_ O
mations include the conversion of pyrroles into azabicyclo
+ _ + _ +
N N N
COOMe COOMe
O O O EtO O COOMe ∆ EtO COOMe HCl HO COOMe
+ O
N EtOH
canonical forms of pyridine N-oxide COOMe N N
D. Radical Reactions O COOH ∆ COOH - PhCN COOH
+ O
N
Halogenation of heterocycles at high temperature gives Ph Ph N O
products in which the substitution pattern suggests that
free radicals (rather than ionic halogen) are involved in synthesis of pyridines and furans via cycloaddition reactions
their production. compounds and pyridazines into pyridines.
COOMe COOEt
450 °C N
+ Br 2 ∆ COOMe
+
N N Br N
COOEt COOMe COOMe
bromination of quinoline
COOMe
Me
Although neutral heteroaromatics often undergo alky- ∆ - HCN MeOOC Me
+
lation by radical species in poor yield, if protonated N N N
N NEt 2
heterocycles are used, good yields are frequently ob- COOEt NEt 2 NEt 2
tained. Under suitable conditions, pyridines, quinolines, synthesis of azaheterocycles via cycloaddition reactions