Intramolecular heterocyclization of o -propargylated aromatic hydroxyaldehydes as an expedient route to substituted chromenopyridines under metal-free conditions

Article abstract of DOI:10.1021/acs.orglett.5b00067

A concise and regioselective approach to the synthesis of chromenopyridine and chromenopyridinone derivatives was developed. The synthetic strategy relies on the O-propargylation of aromatic hydroxyaldehydes followed by reaction with propargylamine. The i

Full text of DOI:10.1021/acs.orglett.5b00067

Letter
pubs.acs.org/OrgLett
Intramolecular Heterocyclization of O‑Propargylated Aromatic
Hydroxyaldehydes as an Expedient Route to Substituted
Chromenopyridines under Metal-Free Conditions
Selbi Keskin and Metin Balci*
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
S
* Supporting Information
ABSTRACT: A concise and regioselective approach to the
synthesis of chromenopyridine and chromenopyridinone derivatives
was developed. The synthetic strategy relies on the O-
propargylation of aromatic hydroxyaldehydes followed by reaction
with propargylamine. The intramolecular cycloaddition reaction
between the alkyne and azadiene, which is formed as an
intermediate, furnished the desired skeletons.
itrogen-containing heterocyclic compounds are extremely
important because of their abundance in various natural
icity against some cancer cell lines.13 Compounds that contain 2-
(2-oxo-2H-chromen-3-yl)-5H-chromeno[4,3-b]pyridin-5-one
(4) skeletons have antibacterial and antimicrobial activity
(Figure 2).14
N
products as well as in synthetic organic compounds. Accordingly,
the construction of the C−N bond is of significant importance as
it opens up avenues for the introduction of nitrogen into organic
molecules.
Coumarins1 are an important group of heterocyclic compound
due to their significant functions in nature and their
pharmacological applications.2 In this regard, they are ubiquitous
in numerous natural products, dyes, pharmaceuticals, and
agrochemicals and in materials science.
Chromenopyridine 1 and chromenopyridinone 2, with a 2H-
chromene ring and a 2H-chromen-2-one ring fused to a pyridine
ring (Figure 1), are well-known for their pharmacological
Figure 2. Structures of 5H-chromeno[4,3-b]pyridine (3) and 5H-
chromeno[4,3-b]pyridin-5-one (4).
The intramolecular [4 + 2] Diels−Alder cycloaddition
reactions play a very important role in the design of heterocyclic
scaffolds. It requires efficient linking of the two reacting moieties
prior to the reaction. Upon heating, the compounds 6, which
were synthesized starting from o-hydroxybenzamidine 5 in a few
steps, undergo an intramolecular Diels−Alder reaction and a
subsequent retro-Diels−Alder reaction to yield the chromeno-
pyridines 8 (Scheme 1).15
Figure 1. Structures of 5H-chromeno[4,3-b]pyridine (1) and 5H-
chromeno[4,3-b]pyridin-5-one (2).
properties, such as antimicrobial,3,4 antiinflammotory,3 anti-
bacterial,5,6 antifungal,6 and anticancer7 activities including as an
estrogen receptor βselective ligand8 in TNFα inhibition,9 and in
anti-inflammatory processes.10 Furthermore, chromeno[4,3-
b]quinoline and chromene derivatives have been found to have
other activities, such as fluorescent pH sensors.11
An efficient and straightforward method for the synthesis of
chromenopyridines via the catalyst-free, three-component
condensation of 3-formylchromones, amines, and dialkyl
acetylenedicarboxylate was reported by Bazgir and co-workers.12
Lee and co-workers synthesized chromenopyridine derivative 3a
and determined that this compound shows moderate cytotox-
Palacios et al.16 reported the synthesis of a variety of tricyclic
and tetracyclic condensed chromenopyridines using an aza-
Wittig reaction of N-vinylic phosphazenes with functionalized
aldehydes. More recently, a new [3 + 2 + 1] cycloaddition
strategy was demonstrated using an aldehyde, an aldimine of a
glycine ester, and a terminal triple bond with AuCl3 catalyst to
generate novel fused-tricyclic heterocycles such as 5H-
chromeno[4,3-c]pyridines.17 Recently, Singh et al.18 attempted
Received: January 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00067
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Organic Letters
Letter
For the synthesis of 5H-chromeno[4,3-b]pyridin-5-one deriva-
tive 16, the product 15 was oxidized with CrO3 in pyridine/
methylene chloride to yield the desired product 16 in almost
quantitative yield.
Scheme 1. Synthesis of Chromenopyridine Derivatives 8 via
an Intramolecular [4 + 2] Cycloaddition Reaction
A tentative mechanism for the formation of 15 is outlined in
Scheme 4. It is proposed that the first step is formation of the
Scheme 4. Mechanism for the Formation of
Chromenopyridine Derivative 15
to prepare 5H-chromeno[3,4-c]pyridine derivatives 12 by
adopting an established strategy related to the domino
Knoevenagel/Diels−Alder reaction, involving O-propargyl
salicylaldehyde (9) and malononitrile or ethyl cyanoacetate or
cyanoacetamide (Scheme 2). Unfortunately, instead of for-
mation of the expected product 12, the product 13 was formed.
Scheme 2. Attempted Synthesis of Chromenopyridine 12
condensation product, imine 17. With this step, two alkyne
functionalities were now incorporated into the starter molecule.
The terminal alkyne connected to the imine group can undergo
base-catalyzed isomerization to form an allene structure 18,
which is conjugated with the imine double bond. Recently, we
demonstrated that alkynes having similar structures can easily
undergo isomerization into the corresponding allenes upon
treatment with bases.21 Then, the intramolecular [2 + 4]
heterocycloaddition reaction between the alkyne and the diene
system (formed with the imine and allene double bond) afforded,
after a 1,5-H shift, the tricyclic product 15.
With these encouraging results in hand, we embarked on the
evaluation of the substrate scope for this useful transformation.
First, two aromatic alkynes with substituents at the meta-position
(referred to the aldehyde functionality), 21 and 25, were tested.
We were able to show that these compounds were also suitable
substrates for the synthesis of chromenopyridine derivatives 23
and 27 (Scheme 5). Next, we tested alkynes 28, 31, and 34
substituted with methyl groups. Generally, disubstituted alkynes
are usually less reactive than terminal alkynes. For the synthesis
of the starting materials, we used 1-bromobut-2-yne as a reagent
instead of propargyl bromide. The desired heterocyclization
products 29, 32, and 35 were also formed in high yields (Scheme
5).
Therefore, an efficient synthetic methodology for the
preparation of chromenopyridine derivatives substituted at the
pyridine ring as well as at the benzene ring would be of interest.19
Herein, we report a new, concise methodology for the synthesis
of the chromenopyridine scaffold in just two steps, where alkyne
cyclization is used as the major reaction without metals to
promote the process.
For the construction of the chromenopyridine skeleton, first
we synthesized 2-(prop-2-yn-1-yloxy)benzaldehyde (9) starting
from salicylaldehyde (14). Treatment of salicylaldehyde (14)
with propargyl bromide in the presence of potassium carbonate
afforded compound 9 in 84% yield (Scheme 3).20 For the
incorporation of the second propargyl group, the appropriate
compounds were reacted with the propargylamine in the
presence of DBU to form the corresponding condensation
product 17. To our delight, the cyclization proceeded, and 15
was isolated in 94% yield. The structure was determined by 1D
and 2D (DEPT, COSY, HSQC, and HMBC) NMR spectral data.
Next, the effect of substituents conjugated with alkyne
functionality was tested. The Sonogashira cross-coupling
reaction22 was used for the synthesis of the desired starting
materials 37 and 38. For the Sonogashira coupling reaction, we
used a palladium catalyst and a copper(I) cocatalyst. To our
delight, N-alkynes substituted with aromatic groups 37 and 38
underwent a facile cyclization reaction upon treatment with
propargylamine at elevated temperature followed by cyclization
to give access to substituted chromenopyridine derivatives 39
and 40 (Scheme 6). Oxidation of the methylene groups with
CrO3 furnished the chromenopyridinone derivatives 41 and 42
in high yields.
Scheme 3. Synthesis of Chromenopyridine 15 and
Chromenopyridinone 16
Finally, to explore the scope of this reaction, three isomeric
hydroxynapthaldehydes 43−45 were also evaluated. First, the O-
propargylated naphthaldehydes 46−48 were prepared from the
corresponding hydroxynaphthaldehydes with good to excellent
B
DOI: 10.1021/acs.orglett.5b00067
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Structures of Chromenone Derivatives 23, 27, 30,
33, and 36 and Their Precursors
Scheme 7. Structures of Benzochromenopyridinone
Derivatives 52−54 and Their Precursors
a
a
a
Yields are given in parentheses.
Scheme 6. Synthesis of Chromenopyridine Derivatives
Substituted with Aromatic Groups
a
Yields are given in parentheses.
alkyne functionality by Sonogashira cross-coupling; (iii) alkyne
cyclization via heterocycloaddition to form the chromenopyr-
idine scaffold; and (iv) CrO3 pyran oxidation reaction. This
synthetic strategy also represents a reasonable methodology, that
will allow us to introduce various substituents into all positions of
the target compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental conditions and spectroscopic data (1D and 2D
NMR spectra) of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mbalci@metu.edu.tr.
Notes
yields as described above (Scheme 7). Using the optimized
conditions, naphthaldehydes 46−48 were treated with prop-
argylamine and DBU under the reflux temperature of ethanol.
The isomeric benzochromenopyridine derivatives 49−51 were
formed in high yields. Oxidation of those compounds with CrO3
in methylene dichloride resulted in the formation of the
corresponding benzochromenopyridinone derivatives 52−54
(Scheme 7).
In conclusion, we describe a concise synthetic methodology
for obtaining (benzo)chromenopyridine and (benzo)-
chromenopyridinone derivatives. The key features of our
method include (i) the synthesis of O-propargylated benz- and
naphthaldehydes; (ii) the introduction of substituents into the
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Scientific and Technological
Research Council of Turkey (TUBITAK, Grant No. TBAG-
112 T360 and TBAG 113Z901), the Turkish Academy of
Sciences (TUBA), and Middle East Technical University
(METU) is gratefully acknowledged.
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