Page 183 - 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 339

In the Pfitzinger reaction, isatic acids are condensed RO MeO
with alpha-methylene carbonyl compounds.
N
β α MeO
O
O COONa COOH OMe
N
H Me
NaOH O RCOMe
O HO papaverine OMe
N NH 2 ∆ N R
H R = H morphine
isatin isatic acid R = Me codeine
(sodium salt)
In the Doebner–Miller reaction, quinolines are prepared The Emde and Hofmann degradations have been used
by condensing anilines with unsaturated aldehydes or their in the structural elucidation of numerous naturally oc-
equivalent. curring substances, including many alkaloids. In the
Emde degradation, quaternary ammonium salts are reduc-
OHC tively cleaved by sodium amalgam, N-allyl and N-benzyl
1. H 3 O +
+ groups being preferentially cleaved.
2. PhN=CHMe
NH 2 N
Doebner-Miller synthesis of 2-methylquinoline Na/Hg
N NMe 2
+
Isoquinolines, abundant in nature, can be prepared by Cl _
the cyclodehydration of beta-phenethylamides, a proce- Emde degradation of a quaternary ammonium salt
dure known as the Bischler–Napieralski reaction.

In the Hofmann degradation, pyrolysis of a quaternary
P 2 O 5
ammonium hydroxide induces beta-elimination. Often, an
NH N
O unknown base is alkylated with methyl iodide, then treated
R R
with base, and the procedure is repeated exhaustively. The
Bischler-Napieralski synthesis of dihydroisoquinolines fragments so obtained often help to elucidate the structure
of the nitrogen base.
Isoquinolines are also formed in the Pictet–Spengler
condensation of beta-arylethylamines with carbonyl com- + ∆
pounds. N _ CH 2 =CH 2 + Me 2 NCH 2 CH 2 CH 3
OH
An example of the Hofmann degradation
MeO MeO
HCl
+ R'CHO
NH 2 NH
MeO MeO When the Hofmann degradation is applied to codeine,
R' by quaternization with dimethyl sulfate and subsequent
Pictet-Spengler synthesis of tetrahydroisoquinolines elimination of the quaternary salt with base, methylmor-
phenol is formed.
Quinoline and isoquinoline alkaloids constitute a vast
and important array of nitrogenous bases. The antimalarial MeO
quinine, a major alkaloid found in cinchona bark, contains
a methoxy-substituted quinoline ring.
O

HO
N
methylmorphenol
MeO
N The power of this degradative method is shown by
quinine the formation of the relatively simple and identifiable
four-ring skeleton from the complex structure of codeine.
Morphine, codeine, and papaverine (L. papaver = In early work, the structures of many alkaloids were
poppy) are all found in opium; they are all isoquinoline elucidated by a combination of degradative and synthetic
alkaloids. Morphine and codeine are well-known anal- methods.
gesics, while papaverine is a potent coronary and cerebal Berberineisanantimalarialisoquinoliniumsaltthatwas
vasodilator. first isolated from Berberis vulgaris in 1837.