3-Methoxalylchromone - A novel versatile reagent for the regioselective purine isostere synthesis

Article abstract of DOI:10.1039/c0ob00379d

The first synthesis of 3-methoxalylchromone was described. The reaction of the latter with electron-rich aminoheterocycles afforded a set of heteroannelated pyridines bearing a CO₂Me substituent located at the α-position of the pyridine core.

Full text of DOI:10.1039/c0ob00379d

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3-Methoxalylchromone—a novel versatile reagent for the regioselective purine
isostere synthesis†
Satenik Mkrtchyan,a Viktor O. Iaroshenko,*a,b Sergii Dudkin,a Ashot Gevorgyan,a Marcelo Vilches-Herrera,a
Gagik Ghazaryan,a Dmitriy M. Volochnyuk,b,c Dmytro Ostrovskyi,a Zeeshan Ahmed,a Alexander Villinger,a
Vyacheslav Ya. Sosnovskikhd and Peter Langer*a,e
Received 5th July 2010, Accepted 13th September 2010
DOI: 10.1039/c0ob00379d
The first synthesis of 3-methoxalylchromone was described.
The reaction of the latter with electron-rich aminohetero-
cycles afforded a set of heteroannelated pyridines bearing a
CO2Me substituent located at the a-position of the pyridine
core.
It occurred to us that 3-methoxalylchromone (2), a new
chromone derivative containing a a-ketoester moiety, might be
a versatile synthetic building block containing four electrophilic
centers. To the best of our knowledge, there has been only an
isolated report of a related molecule, namely 6,7-dimethoxy-3-
ethoxalyl-2-methylchromone. The latter was prepared from 2-
hydroxyacetophenone, diethyl oxalate and acetic anhydride.14 The
chemistry of this molecule was not studied.
It is known that 3-acylchromones 1 are available by reaction of
3-(dimethylamino)-1-(2-hydroxyphenyl)-propen-1-one with var-
ious electrophiles.15,16 We have found that hitherto unknown
3-methoxalylchromone (2) can be prepared in 79% yield by
reaction of 3-(dimethylamino)-1-(2-hydroxyphenyl)propen-1-one
with methyl 2-chloro-2-oxoacetate (Scheme 1). The structure of 217
was independently confirmed by X-ray crystal structure analysis
(Fig. 1).
Purine isosteres and purine like scaffolds are of a great interest
as privileged scaffolds1 in medicinal chemistry and drug design.
Functionalized derivatives of purine-like scaffolds are of consid-
erable interest as lead structures and synthetic building blocks in
medicinal and agricultural chemistry.2–8
On the other hand, purine- and pyridine-like scaffolds,9 bearing
a carboxylic or carbonylic function at position 2 of the purine
core, are recognized to be potent inhibitors of inosine 5¢-
monophosphate dehydrogenase (IMPDH). IMPDH constitutes
a group of enzymes which is playing a key role in the purine
de novo biosynthesis.10 In the last two decades, IMPDH became
an important target enzyme for drug design.9
At the same time, derivatives of 4H-1-benzopyran-4-one, also
known as 4H-chromen-4-ones or chromones, are prominent
natural products possessing a wide range of interesting bio-
logical properties.11 In addition, many natural and synthetic
chromones are used as valuable synthetic intermediates in the
preparation of pharmacologically relevant products and new
heterocyclic systems.12 The synthetic utility of 2-unsubstituted 3-
acylchromones 1 primarily derives from the reactivity of their
three electron-deficient centers, i.e. carbon atoms C-2 and C-4 of
the chromone moiety and the acyl group attached to carbon C-
3. The majority of the known reactions of these compounds are
nucleophilic additions with concomitant opening of the pyrone
ring leading to various types of heterocyclic products.13 The
synthesis and chemical properties of a variety of 3-acylchromones
1 have been previously studied.
Fig. 1 Molecular structure of chromone 2.
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059
Rostock, Germany. E-mail: viktor.iaroshenko@uni-rostock.de, iva108@
googlemail.com, peter.langer@uni-rostock.de; Fax: +49 381 49864112;
Tel: +49 381 4986410
bNational Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33,
01033, Ukraine. E-mail: iva108@googlemail.com
Scheme 1 Synthesis of 3-methoxalylchromone (2).
c“Enamine Ltd.” 23 A. Matrosova st., 01103 Kyiv, Ukraine
Based on the retrosynthetic analysis and on our previous exper-
tise in cyclization reactions of electron-rich systems18 we started
a project directed towards the development of a new synthesis
of ester-substituted purine isosteres starting with 2. Continuing
our research program dedicated to the design and synthesis of
novel inhibitors of IMPDH and in view of the unique biological
properties displayed by many fused pyridines and pyrimidine
dDepartment of Chemistry, Ural State University, 620083 Ekaterinburg,
Russian Federation
eLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, 18059 Rostock, Germany
† Electronic supplementary information (ESI) available: Experimental
details and 1H and 13C NMR spectra of products. CCDC reference
numbers 783350–783352. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ob00379d
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heterocycles containing imidazole, pyrazole and thiazole rings,2–8
we have studied the reactions of 3-methoxalylchromone (2)
with electron-rich aminoheterocycles 3–8 (Fig. 2). Besides the
pharmacological relevance of the products, the reactions are also
interesting in their own right from the viewpoint of their chemo-
and regioselectivity.19 Recently, we have reported the synthesis of a
wide range of trifluoromethylated fused pyridines by reaction of 3-
(trifluoroacetyl)chromone 1 (R = CF3) with heterocyclic amines.20
These reactions provided a variety of heteroannelated pyridines
12d–r bearing a CO2Me group located at the a-position of the
pyridine core (Scheme 2, Table 1). It is worth mentioning that the
best results were obtained when the reactions were carried out in
acetic acid. Only 4-aminoimidazoles 5 proved to be unstable in the
presence of acetic acid. Therefore, DMF/TMSCl was used as a
water scavenger.
Fig. 2 Structures of the used 1,3-C,N-dinucleophiles.
Scheme 2 Reagents and conditions: (i): AcOH, reflux, 2–5 h (for 3, 4, 6,
7, 8); (ii): DMF/TMSCl, 80–100 ◦C (for 5).
We have started our investigation in this area by the study of
the reaction of 2 with aminopyrroles 3a–c in order to obtain
the corresponding pyrrolo[2,3-b]pyridine ring system. The latter
represents an important synthetic target, due to its unique pharma-
cological properties.5 It was found that, compared to the analogous
reactions of 1 (R = CF3), the reaction of 3-methoxalylchromone
(2) with amines 3 proceeded under milder conditions (AcOH,
reflux 2–5 h) and with an excellent regioselectivity to give products
12a–c. The structure of the products was confirmed by X-ray
crystal structure analyses (Fig. 3). To study the scope and
limitations of the methodology, we investigated the reactions of
2 with other electron-rich aminoheterocycles and anilines 4–10.
In all cases, ring opening of the pyrone ring takes place
with subsequent annulation of the pyridine core. In fact, the
cyclization of 2 with aminoheterocycles 3–8 turned out to be
highly regioselective and did not result in the formation of isomeric
mixtures. In case of the aromatic amines 9 and 10, we observed (by
HPLC) the formation of a complex mixture of many unidentified
products as well as low quantities of two possible regioisomers
(both in acetic acid or using DMF/TMSCl). Many attempts to
isolate and separate these products failed.
The formation of products 12a-r can be explained by conjugate
addition of the enamine carbon atom of the aminoheterocycle to
the double bond of 2 to give intermediate A. Subsequent pyrone
ring opening delivers intermediate of type B. The intramolecular
attack of the amino group to the carbonyl group affords interme-
diate C which undergoes elimination of water to give pyridines 12
(Scheme 2).
The structures of compounds 12a and 12l were confirmed by
an X-ray crystal structure analysis21 (Fig. 3 and 4), whereas the
structures of the other fused pyridines were assigned on the basis
of their spectroscopic features in comparison with those of 12a
and 12l.
Finally, the hydrolysis of several representatives of 12 was
conducted; these reactions were carried out in a solution of
Fig. 3 Molecular structure of compounds 12a in the form of a solvate
complex with DMF.
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Table 1 Synthesis of fused heterocycles 12d–r
Table 1 (Contd.)
Amine
Product
% (12)a
Amine
Product
% (12)a
3a
12a
78
7b
7c
8a
12m
71
12n
12o
77
64
3b
3c
12b
12c
75
89
8b
8c
8d
12p
12q
12r
55
60
44
4a
4b
5a
12d
12e
12f
57
80
71
a Yields of isolated products.
5b
5c
12g
12h
73
64
Fig. 4 Molecular structure of compound 12l.
5d
5e
12i
12j
70
69
potassium hydroxide in methanol. Subsequent acidification of the
reaction mixture with concentrated hydrochloric acid gave the
corresponding acids 13 in excellent yields (Scheme 3, Table 2).
6
12k
12l
73
68
Scheme 3 Reagents and conditions: (i): a) MeOH, KOH, reflux, 2 h; b)
conc. HCl.
7a
In summary, we have reported the synthesis of 3-
methoxalylchromone and its cyclocondensation with various
electron-rich aminoheterocycles. This simple one-pot procedure
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Table 2 Synthesis of acids 13d, k, l, p
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now opens new avenues to
a
wide range of fused
pyridines. Studies addressing the biological activity and chem-
ical properties of pyridines synthesised are currently under
investigation.
Acknowledgements
Financial support by the State of Mecklenburg-Vorpommern
(scholarship for M. S.) is gratefully acknowledged. Funding for
Dr V. O. I by the German Ministry of Education and Research
(BMBF) is gratefully acknowledged (grant No. 03IS2081A).
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