Synthesis and heterocyclizations of 3-alkynyl-6,8-dimethylpyrimido-[4,5-c] pyridazine-5,7(6H,8H)-diones and their lumazine analogues

Article abstract of DOI:10.1002/jhet.5570420308

Synthesis of some condensed pyrrolo-, thieno-, furo-, pyrido- and pyranopteridines as well as isomeric pyrrolo- and thienopyrimido[4,5-c] pyridazines from alkynyl derivatives of 6,8-dimethylpyrimido[4,5-c]pyridazine-5, 7(6H,8H)-dione and 1,3-dimethyllumaz

Full text of DOI:10.1002/jhet.5570420308

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Synthesis and Heterocyclizations of 3-Alkynyl-6,8-dimethylpyrimido-
[4,5-c]pyridazine-5,7(6H,8H)-diones and Their Lumazine Analogues
Anna V. Gulevskaya*, Shee Van Dang, and Alexander F. Pozharskii
Faculty of Chemistry, Rostov-on-Don State University, Zorge str., 7, Rostov-on-Don,
344090 Russian Federation
Synthesis of some condensed pyrrolo-, thieno-, furo-, pyrido- and pyranopteridines as well as isomeric
pyrrolo- and thienopyrimido[4,5-c]pyridazines from alkynyl derivatives of 6,8-dimethylpyrimido[4,5-
c]pyridazine-5,7(6H,8H)-dione and 1,3-dimethyllumazine is represented.
J. Heterocyclic Chem., 42, 413 (2005).
The cyclization of alkynes possessing a nucleophile
in proximity to the triple bond has been shown to be
extremely effective for synthesis of a wide variety of
carbo- and heterocycles [1-4]. In general, such trans-
formations proceed according to Scheme 1 and require
a catalyst (a base, transition metal complex or
electrophile).
its metabolite urothione and pigment russupteridine yellow
(Scheme 2).
Thus, our initial goal consisted in introducing of alkynyl
and nucleophilic groups into diazine nucleus of com-
pounds 1 and 2 (Scheme 3).
One of the best synthetic methods for arylacetylenes is
palladium-catalyzed Sonogashira cross-coupling of aryl-
For some time we were interested in extending this
methodology to pyrimidopyridazine 1 and lumazine 2 in
hope to obtain analogues of some naturally occurring
pteridines, such as molybdenum cofactor molibdopterine,

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Vol. 42
halides with terminal alkynes [5]. We have applied similar
procedure for pyrimidopyridazine and lumazine chlorides
3 and 5 (Scheme 4). As a result alkynyl derivatives 4 and
6 were obtained in good yields. In 6,7-dichlorolumazine 7
the chlorine atoms exhibit strongly different lability mak-
ing it possible to replace them successively: thus at room
Based on these data we have assumed that oxidative
amination of alkynes 4 and 6 could also provide
aminoacetylenes 14 and 16 capable to cyclization into
pyrroles 15 and 17 (Scheme 6). Indeed, we were pleased
to find that the interaction of compounds 4 and 6 with pri-
o
mary alkylamines in the presence of an oxidant at 0-20 C
temperature monoacetylenes 8 are formed, whereas at a
higher temperature diacetylenes 9 can be obtained.
Compounds 8 are converted into 9 by the same way [6-8].
It is well known that common strategy for inserting of
amino and other nucleophilic functions into an azine ring
is replacement of good-leaving groups. However, in last
years nucleophilic substitution of hydrogen finds ever-
increasing use for this aim [9,10]. Recently [11,12], we
have shown that pyrimidopyridazine 1 and its 3-chloride 3
undergo oxidative amination with ammonia and alky-
lamines at position 4 (Scheme 5). Under the same condi-
tions the lumazines 2 and 5 affords 7-amino derivatives 12
and 13 [7,13,14].

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415
produced right away pyrroles 15 and 17 [6,7]. Apparently,
these transformations proceed through intermediate ortho-
aminoacetylenes 14,16 and their cyclizations are likely
promoted by coordination of silver ion with the carbon-
carbon triple bond.
to a procedure recently reported by English chemists
[15]. It involves the addition of bromine to the ary-
lalkyne’s triple bond and subsequent cyclization of the
resulted dibromide at treatment with sodium trithiocar-
bonate. Using acetylenes 4,6 as starting material and
Both pyrroles 15 and 17 were also obtained by
Sonogashira cross-coupling of ortho-aminohalides 11,13
with terminal alkynes (Scheme 7) [7,12].
the pointed out conditions we have prepared desired
thiophenes 19 and 21 in moderate to good yields
(Scheme 8) [7,16].
Next, we attempted to annulate the thiophene ring to
pyrimidopyridazine and lumazine systems according
To obtain pyrroles 23 and 24 isomeric to 17 (Scheme 9)
we have studied the interaction of alkynyllumazines 8 and

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Vol. 42
9 with alkylamines. However, we have found that treat-
ment of alkynylchoride 8a with propylamine at room tem-
perature or under reflux afforded almost quantitative yield
of enamine 25 instead of expected compound 22 or its
cyclization product (Scheme 10) [8]. Perhaps the simplest
explanation for this behaviour of molecule 8a is activation
of the triple bond to nucleophilic attack due to its conjuga-
tion with carbonyl group. On the contrary, the 6-chlorine
atom is deactivated by electron donating influence of the
uracil nitrogen atom.

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Dialkynyllumazines react with primary amines by the
same way to yield adducts 26 (Scheme 11) [8]. As it fol-
lows from spectral data compounds both compounds 25
and 26 are stabilizing by intramolecular hydrogen bonding
shown on Schemes 10,11. But it seems to be not sole rea-
son for their stability, because of enamines 27 derived
from secondary amines are also stable. Evidently, the con-
jugation of amino group with azine π-system should be
also taken into account.
Enamines 25 and 26a are hydrolyzed under reflux in
aqueous trifluoroacetic acid to furnish compounds 28
existing as a mixture of enol and the corresponding
ketone (Scheme 12) [8].
Enamines 25 and 27d as well as enols 28a were suc-
cessfully employed in annulation reactions [8]. Thus,
heating of enamine 25 with potash in DMF solution
leads to formation of pyrrole 29a (Scheme 13).
Prolonged reflux of alkynylchloride 8a with butylamine

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Vol. 42
is also resulted in pyrrole-ring annulation, undoubtedtly
proceeding via enamine intermediate of a type 29. Using
potash as a catalyst we performed cyclizations of com-
pounds 28a and 27d into furopteridine 30 and pyra-
nopteridine 31 respectively.
Interestingly, that enamines and enols derived from
dialkynyllumazines are also able to cyclization. Thus,
when compounds 26c,d were heated with potassium car-
bonate cyclomerization products 32 were isolated (Scheme
14) [8]. Under similar conditions enol 28b produced
pyrane 33. It should be noted, that the above transforma-
tions represent new routes for [c]-condensed pyridines and
pyranes.
In summary, we have elaborated the synthesis of the fol-
lowing nine types of heterocyclic systems, closely related
to naturally occurring pteridines (Scheme 15).
Acknowledgement.
The authors express their thanks to Russian Foundation
for Basic Research for financial support (grants No 04-03-
96800).

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419
REFERENCES AND NOTES
Corresponding authors. E-mail: agulevskaya@chim-
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*
fak.rsu.ru
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