2,3-Unsubstituted chromones and their enaminone precursors as versatile reagents for the synthesis of fused pyridines

Article abstract of DOI:10.1039/c1ob06494k

A divergent and regioselective approach to fused pyridines was developed through formal [3 + 3] cyclocondensations from simple 2,3-unsubstituted chromones or their enaminone precursors.

Full text of DOI:10.1039/c1ob06494k

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PAPER
2,3-Unsubstituted chromones and their enaminone precursors as versatile
reagents for the synthesis of fused pyridines†
Viktor O. Iaroshenko,*a,b Satenik Mkrtchyan,a Ashot Gevorgyan,a,c Mariia Miliutina,a Alexander Villinger,a
Dmytro Volochnyuk,d Vyacheslav Ya. Sosnovskikhe and Peter Langer*a, f
Received 31st August 2011, Accepted 27th October 2011
DOI: 10.1039/c1ob06494k
A divergent and regioselective approach to fused pyridines was developed through formal [3 + 3]
cyclocondensations from simple 2,3-unsubstituted chromones or their enaminone precursors.
In the recent decades, heteroannulated pyridines, which can be
classified as purine isosteres, purinomimetics and psuedopurines,
have attracted considerable attention of medicinal and synthetic
organic chemists because of a wide range of biological activities,1–4
like, antitumor, anti-inflammatory, antiallergic, and inhibitors of
DNA-dependent protein kinase. Moreover, purines and purine
isosteres as well as their nucleosides bearing aryl or heteroaryl
group at the 2- and 6- positions are scaffolds widely known for
their biological activity.5,6
Recently, laboratories of Iaroshenko,7 Sosnovskikh,7,8 and
Volochnyuk9 have published a number of methods related to
the synthesis of various fused pyridine/pyrimidine derivatives.
The syntheses were succeeded via the [3 + 3] heteroannulation
reaction of pyridine/pyrimidine moiety on the core of electron-
rich aminoheterocycles and anilines involving a set of 1,3-CCC-
and 1,3-CNC-dielectrophiles. These elaborated strategies afford
the possibility to generate a large number of pharmacologically
important compounds.
This domino-transformation usually involves initial nucleophilic
addition on the 2-position of the chromone skeleton with the
subsequent g-pyrone ring opening. The transformations of this
type are facilitated by the electron-withdrawing group at the 3-
position.8c,8d,9,10
However, to the best of our knowledge, very scarce infor-
mation is available about the reactions of 2,3-unsubstituted
chromones with dinucleophiles leading to the pyrone ring opening
with the subsequent formation of the new heterocyclic system.
There have been only a handful of papers describing some
reactions of chromone with dimethyl acetonedicarboxylate11 and
N-iminopyridinium ylide.12 Recently, our laboratory have com-
municated a TMS-triflate mediated reaction of 2,3-unsubstituted
chromones with 1,3-bis-silyl ethers, which resulted in the prepa-
ration of functionalized 6H-benzo[c]chromen-6-one derivatives.13
All these reactions proceed by nucleophilic 1,4-addition followed
by pyrone ring opening. A small number of such transformations
can be explained taking into account the low electrophilicity of the
2-position of the chromone ring comparing with the derivatives
having an EWG group in the 3-position.
Continuing our research program dedicated to the design and
synthesis of novel fused pyridines7 and in a view of the unique
biological properties displayed by these compounds,1–4 we have
started our investigation in this area by the study of the reactions of
2,3-unsubstituted chromones 1 with a set of commercially available
electron-rich heterocyclic amines 3–10 and aromatic amines 11–14
(Fig. 1).
It is known that 2,3-unsubstituted chromones 1 can be obtained
in two steps from o-hydroxyacetophenones.14 The first step is
a synthesis of (E)-3-(dimethylamino)-1-(2-hydroxyaryl)prop-2-en-
1-ones 2 by reaction of o-hydroxyacetophenones with DMFDMA
(N,N-dimethylformamide dimethyl acetal). Subsequent treatment
of the product with perchloric acid leads to the chromone
formation. In this work, the best reaction conditions for the
synthesis of chromones 1 were found (DMF/TMSCl, under
argon, 100 ◦C, 1–3 h) and of special interest is the forma-
tion of these compounds in nearly quantitative yield (90–97%)
(Scheme 1). By this method we have prepared a set of chromones
Among the 1,3-CCC-dielectrophiles used are 3-substituted
chromones10 -moieties containing hidden 1,3-dielectrophilic frag-
ments as a part of g-pyrone framework. We and others have
demonstrated that chromones bearing electron-withdrawing sub-
stituents in the 3-position react with 1,2- and 1,3-dinucleophiles
delivering the corresponding five- and six-membered heterocycles.
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str., 3a, 18059,
Rostock, Germany. E-mail: viktor.iaroshenko@uni-rostock.de, iva108@
googlemail.com; Fax: 00 49 381 49864112; Tel: 0049 381 4986410
bNational Taras Shevchenko University, 62 Volodymyrska St., Kyiv-33,
01033, Ukraine. E-mail: iva108@googlemail.com
cFaculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025,
Yerevan, Armenia
d“Enamine Ltd.” 23 A. Matrosova St., 01103, Kyiv, Ukraine
eDepartment of Chemistry, Ural State University, 620083, Ekaterinburg,
Russian Federation
f
Leibniz-Institut fu¨r Katalyse, Van der Universita¨t Rostock, Albert-Einstein-
Str. 29a, 18059, Rostock, Germany
† Electronic supplementary information (ESI) available: CCDC reference
numbers 835825–835830. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1ob06494k
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Table 1 Synthesis of chromones 1
1
R
Yield (%)a
a
b
c
d
e
f
g
h
H
93
97
94
97
90
95
95
94
6-Methyl
6-Bromo
6-Chloro
7,8-Benzo
6-Methoxy
6-Chloro-7-methyl
7-Methoxy
a Yields of isolated products.
unsuccessful, leading mainly to the decomposition of the amine
component. Next, it was decided to melt both reagents under
inert atmosphere. Indeed, this delivered the desired products,
however the reaction proceeded with low overall yields laying in
the range of less then 20%. Recently,9 water scavenging system
DMF/TMSCl has gained the wide application as a media for the
cyclocondensation reactions. Logically, this reaction media was
taken as a reaction condition of choice.
Chromones 1a–d and benzo[h]chromone 1e were reacted with
aminoheterocycles 3–10 in DMF solution at 90–120 ◦C in
the presence of Me3SiCl. Under these conditions formation
of the expected fused pyridines 15–24 as a result of pyri-
dine ring annulation by 2,3-unsubstituted chromones onto the
amine moiety was observed. Majority of the tested electron-
excessive aminoheterocycles reacted with chromones 1 deliver-
ing the corresponding pyridines in 55–97% yields (Scheme 1,
Table 2).
Giving insight into the reaction mechanism, it was necessary to
admit that the pyridine ring annulation most probably proceeds as
a consecutive domino-transformation involving formation of the
intermediates A–D (Scheme 2). We suppose that the reaction starts
with the formation of the benzopyrylium salt A by initial silylation
which facilitates the nucleophilic attack. Subsequent electrophilic
attack of A by the most electrophilic C-2 atom occurs on the
enamine position of electron-excessive amine giving the first in
this cascade intermediate B. Subsequently, g-pyrone ring opens
Fig. 1 Structures of the chromones and aminoheterocycles used in this
study.
Scheme 1 Reagents and conditions: (i) DMF/TMSCl, under argon,
90–120 ◦C, 1–4 h.
1a–h (Table 1), however for the current study only chromones 1a–e
were used.
First, we have concentrated our efforts mainly on the setting
optimal conditions for the reaction of 1 with heterocyclic amines
3–10. We were aware that this transformation demands harsh
reaction conditions. As a starting point acetic acid under reflux as
well as DMF at 150 ◦C were tried, however, all these attempts were
Scheme 2 Putative reaction mechanism.
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Table 2 Synthesis of fused pyridines 15–24 from chromones 1 (yields in
brackets are from aminoenones 2)
Fig. 2 Molecular structure of compound 15b.
Fig. 3 Molecular structure of compound 21b.
Table 3 Synthesis of fused pyridines 26–30 from aminoenones 25
by cleavage of the C–O bond to form an intermediate C. Note
that in our previous study we have described some similar struc-
tures, for instance (E)-3-(4-amino-2-(pyrrolidin-1-yl)thiazol-5-yl)-
1-arylprop-2-en-1-ones, that were stable and have been isolated
and characterized; in strong acidic media these compounds were
converted to the thiazolo[4,5-d]pyridines.15 Then, intermediate C
undergoes the intramolecular attack of the free amine group onto
carbonyl moiety forming the silylated pyridine hydrate D, which
loses Me3SiOH molecule giving rise to the fused pyridines 15–24.
Encouraged by this finding, next optimization of the method
discovered was conducted. We have considered the corresponding
precursors 2 to be suitable for the pyridine ring annulation
reaction. In this context, we have scanned the amines depicted
in Fig. 1 and have compared the yields of the reaction with
the one conducted by the recruiting of the chromones 1. In
fact, cyclocondensations proceeded smoothly giving rise to the
corresponding pyridines. As shown in Table 2, the reaction
with 2 appeared to be a versatile synthetic method for the
preparation of the fused pyridines 15–24, their yields are in
brackets.
As a part of an ongoing research, we desired the expedient
access to a-aryl substituted fused pyridines by employing easily
accessible enaminones 25 without o-hydroxyl group. The inves-
tigated reaction proceeded regioselectively to give pyridines 26–
30 in good to excellent yields (50–93%) as a single product.
The method illustrated here is also suitable for the introduction
of heteroaryl substituent, namely b- and g-pyridyl rests in a-
position of annulated pyridine ring (Scheme 3, Table 3). Note that
compounds 9–13 appeared to be inactive towards the pyridine ring
annulation. The NMR spectral properties of pyridines 26–30 are
in a good correspondence with the scaffolds 15–24 and previously
The constitution of the synthesized fused pyridines 15–24 was
mainly established by 1D and 2D NMR methods. Moreover, the
structures of compounds 15a–c, 17a, and 21b were independently
established by X-ray single crystal analysis (Fig. 2, 3 and Fig.
1–3 in the ESI†).16 In all structures the intramolecular hydrogen
bonding is present.
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chromones 1 as well as enaminones 2 giving rise to the correspond-
ing naphtho[2,3-f ]quinolones. Unfortunately, due to extremely
low solubility of these products, NMR methods could not be
used to confirm the structure. However, the mass-spectrometry
as well as HRMS and element analysis have proven the formation
of the naphtho[2,3-f ]quinolone framework, but there are doubts
with regards to the regioselectivity, since the formation of two re-
gioisomers, namely 1- or 3-substituted naphtho[2,3-f ]quinolones,
is possible. In the case of 5-aminopyrimidine-2,4(1H,3H)-dione
(10), in reactions with 1 and 2 the formation of the mixture of
unidentified by-products was observed.
Finally, the synthesis of the fused pyridines was developed
by the two-component heteroannulation reaction starting from
non-activated 2,3-unsubstituted chromones, aminoenones, and
electron-rich heterocyclic amines. The scope and limitations of
this new methodology have been studied with a wide range of
substrates. The majority of the products obtained are not readily
available by other methods.
Scheme 3 Reagents and conditions: (i) DMF/TMSCl, under argon,
90–120 ◦C, 1–2 h.
synthesized purine isosters. The X-ray single crystal analysis has
confirmed the structure of compound 29b (Fig. 4).16
Experimental
General procedure for the synthesis of compounds 1, 15–24, 26–30
Corresponding chromone 1 or enaminone 2 or 25 (2 mmol)
and heterocyclic amine (2.2 mmol) were placed in pressure tube
under the flow of dry argon and dissolved in dry DMF (10 mL)
containing 1 mL of TMSCl. The mixture was heated at 90–
120 ◦C during 1–4 h (controlled by TLC, Table 1 and 2 in the ESI†).
Then this solution was evaporated under reduced pressure, treated
with water, filtrated, dried on the air, and recrystallized from an
appropriate solvent, or was subjected to a column chromatography
over silica gel.
Fig. 4 Molecular structure of compound 29b.
Acknowledgements
The putative reaction mechanism can be summarized in the
four steps represented in the Scheme 3, namely, the first step
which initiates this reaction is formation of the salt E by reaction
of enaminones 25 with TMSCl. Electrophilic attack of the
iminium fragment onto the enamine-position of electron-excessive
aminoheterocycles gives rise to second intermediate F. The latter,
through the intermolecular reaction of the free amino group with
silyl-enol ether moiety forms dehydropyridines G. Elimination
of the dimethyl amine molecule delivers final fused pyridines
26–30.
It is important that very recently synthesis of substituted
pyrido[2,3-d]pyrimidinediones by the reaction of 6-aminouracils
with enaminones of type 25 has been described. The reac-
tion was conducted in acetic acid, however, it was accom-
plished by formation of the 1,3,5-triaroylbenzene derivatives
as products of enaminone trimerization; this significantly de-
creased the overall yields.17 Under our reaction conditions
the formation of the self-condensation products were not
observed.
Financial support by the DAAD (scholarship for S M.) is
gratefully acknowledged.
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