Rajah Serfoji Govt. College (Autonomous),Thanjavur – 613 005
Organic Chemistry - III Code: R3PCH6
UNIT - V Heterocyclics
AZEPINE
§
An unsaturated seven-membered heterocycle having six carbon atoms, one nitrogen atom and three double bonds.
Silver forges the ring:
A new and practical silver-catalyzed [5+2] cycloaddition method has been
developed for the synthesis of azepines through the formation of four new
chemical bonds between a γ-amino ketone and an alkyne in one step. This method
provides a new hetero-[5+2] cycloaddition strategy for the construction of
seven.
Oxazine
§
Many isomers exist depending on the relative position of the heteroatoms and
relative position of the double bonds
§
By extension, the
derivatives are also referred to as oxazines; examples include ifosfamide and morpholine(tetrahydro-1,4-oxazine).
A commercially available dihydro-1,3-oxazine is a reagent in the Meyers synthesis for
aldehydes. Fluorescent dyes such as Nile red and Nile blue are
based on the aromatic benzophenoxazine.
Synthesis
·
The Meyers synthesis is an organic synthesis for the preparation of unsymmetrical aldehydes via hydrolysis of an oxazine. The reaction
is named after the American chemist Albert I. Meyers.
·
The
starting compound is a dihydro-1,3-oxazine with an alkyl group in the 2 position. The alpha proton
is acidic and can be abstracted by a strong base such as butyl lithium and subsequently alkylated by an alkyl halide (haloalkane). In the next step the nitrogen to carbon double bond (imine) is reduced with sodium borohydride and the resulting oxazine (ahemiaminal) hydrolyzed with water and oxalic acid to the aldehyde.
Thiazine
v Thiazines are organic compounds containing a ring of four carbon, one nitrogen and one sulfur atom. Chemicals that include thiazine are used for dyes, tranquilizers and insecticides.
Reactions
§ An efficient iodine-catalyzed approach to synthesise
1,3-thiazine has been developed, and this synthetic methodology is economical
and uses cheap and readily available starting materials. This is the first
example of constructing 1,3-thiazine via a sequential thia-Michael addition and
cyclodehydration.
Synthesis
v The
direction of the cyclization of N,N'-disubstituted
malondithioamides 1 into isomeric
5-amino-1,2,3-thiadiazoles 2 and 3. It has been shown
that the ratio of isomeric heterocycles 2 and 3 depends on their
relative stability. The ratio of thiadiazoles 2 and 3 in the mixture is also
influenced by the solvent.
v In
order to prepare new heterocyclic sulfur compounds a systematic study of the
reactions of thioamides 4-6 with
acetylenedicarboxylates and propiolates has been carried out. These reactions
were found to take place in three directions to form thiazine derivatives of
types 7 and 9, thiazoles 8 and allylmercapto
imidazoles 10.
Pyridazine
v Pyridazine is a heterocyclic organic
compound with
the molecular formula (CH)4N2.
It contains a six-membered ring with two adjacent nitrogen atoms, and is
aromatic. It is a colorless liquid with a
boiling point of 208 °C. It is isomeric with two other (CH)4N2 rings,pyrimidine and pyrazine.
Syntheses
v In
the course of his classic investigation on the Fischer indole synthesis,
Emil Fischer prepared the first pyridazine via the condensation of phenylhydrazine and levulinic acid. The parent heterocycle was first
prepared by oxidation of benzocinnoline to the pyridazinetetracarboxylic
acid followed by decarboxylation.
A better route to this otherwise esoteric compound starts with the maleic
hydrazide. These heterocycles are often prepared via condensation of 1,4-diketones or 4-ketoacids with hydrazines.
An
unexpected C-C bond cleavage in the absence of metal enables an efficient
approach toward 3,6-diarylpyridazines and 6-arylpyridazin-3-ones from simple
and commercially available 1,3-dicarbonyl compounds and methyl ketones.
Pyrimidine
v
Pyrimidine is
an aromatic heterocyclic organic compound similar to pyridine. One of the three diazines (six-membered
heterocyclics with two nitrogen atoms in the ring), it has the nitrogens at positions 1 and 3
in the ring. The other diazines
are pyrazine (nitrogens
1 and 4) and pyridazine (nitrogens
1 and 2). In nucleic acids, three types of nucleobases are
pyrimidine derivatives: cytosine (C),thymine (T),
and uracil (U).
Synthesis
v
As is often the
case with parent heterocyclic ring systems, the synthesis of pyrimidine is not
that common and is usually performed by removing functional groups from derivatives.
Primary syntheses in quantity involving formamide have
been reported.
v
As a class,
pyrimidines are typically synthesized by the “Principal Synthesis” involving
cyclization of beta-dicarbonyl compounds with N-C-N compounds. Reaction of the
former with amidines to give 2-substituted pyrimidines, with urea to give
2-pyrimidiones, and guanidines to give 2-aminopyrimidines are typical.
v
Pyrimidines can
be prepared via the Biginelli reaction. Many other methods rely on condensation of carbonyls with
diamines for instance the synthesis of 2-Thio-6-methyluracil from thiourea and ethyl acetoacetate [21] or
the synthesis of 4-methylpyrimidine with 4,4-dimethoxy-2-butanone and formamide.
v
A novel method is
by reaction of certain amides with carbonitriles under electrophilic activation of the
amide with 2-chloro-pyridine and trifluoromethanesulfonic anhydride:
Reactions
Because of the
decreased basicity compared to pyridine, electrophilic substitution of
pyrimidine is less facile. Protonation or alkylation typically
takes place at only one of the ring nitrogen atoms. Mono N-oxidation occurs by
reaction with peracids.
Electrophilic
C-substitution of pyrimidine occurs at the 5-position, the least electron
deficient. Nitration, nitrosation, azo coupling,
halogenation, sulfonation,
formylation, hydroxymethylation, and aminomethylation have been observed with
substituted pyrimidines.
Nucleophilic
C-substitution should be facilitated at the 2-, 4-, and 6-positions but there
are only a few examples. Amination and hydroxylation has been observed for
substituted pyrimidines. Reactions with Grignard or alkyllithium reagents yield
4-alkyl- or 4-aryl pyrimidine after aromatization.
Free radical
attack has been observed for pyrimidine and photochemical reactions have been
observed for substituted pyrimidines. Pyrimidine
can be hydrogenated to give tetrahydropyrimidine.
Pyrazine
Pyrazine
is a symmetrical molecule with point group D2h.
Derivatives such as phenazine are well known for their antitumor,
antibiotic and diuretic activities. Pyrazine is less basic in nature than pyridine, pyridazine and pyrimidine. Tetramethylpyrazine (also known as ligustrazine) is reported to scavenge
superoxide anion and decrease nitric oxide production in human polymorphonuclear leukocytes,[2] and
is a component of some herbs in traditional Chinese medicine.
Synthesis
v
Many methods
exist for the organic synthesis of
pyrazine and its derivatives. Some of these are among the oldest synthesis
reactions still in use.
v
In the Staedel–Rugheimer pyrazine
synthesis (1876) 2-chloroacetophenone is reacted with ammonia to
the amino ketone, then condensed and then oxidized to a pyrazine [4] A
variation is the Gutknecht
pyrazine synthesis (1879)
also based on thisselfcondensation, but differing in the way the alpha-ketoamine is
synthesised.
v
The Gastaldi
synthesis (1921) is another variation
Azoles
v
An azole is a class of five-membered nitrogen heterocyclic ring compounds containing
at least one other non-carbon atom of eithernitrogen, sulfur, or oxygen.[1] The
parent compounds are aromatic and
have two double bonds; there are
successively reduced analogs (azolines and azolidines)
with fewer. One, and only one, lone pair of electrons from each heteroatom in
the ring is part of the aromatic bonding in an azole. Names of azoles maintain
the prefix upon reduction (e.g., pyrazoline, pyrazolidine).
The numbering of ring atoms in azoles starts with the heteroatom that is not
part of a double bond, and then proceeds towards the other heteroatom.
v
Six-membered
aromatic heterocyclic systems with two nitrogens include pyrimidine and purine, which are important biomolecules.
Reaction
Ø 1-Benzoylmorpholine (2.38 g, 12.5 mmol) and
freshly distilled POCl3 (2.5 mL, 26.8 mmol)
were mixed under an atmosphere of dinitrogen. The suspension was heated to 35
ºC until the solids were dissolved. The reaction was stirred at ambient
temperature for another 5 h before pyrrole (0.55
g, 8.2 mmol) in dry 1,2- dichloroethene (ca. 50 mL) was added quickly. This
was stirred overnight. Saturated Na2CO3 was slowly added to the reaction solution until the aqueous
layer reached pH ca. 8. The separated organic layer
was collected and the aqueous solution further extracted to chloroform (4 x 25
mL). Organic solvents were combined and washed with brine (2 x 20 mL) and dried
over Na2SO4. The solvents were removed under reduced pressure to leave an
off-white product. (1.25 g, 89 %).
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