Ruthenium-catalyzed dimerization of propiolates: A simple route to α-pyrones

Article abstract of DOI:10.1021/ol4035929

A ruthenium-catalyzed regioselective intermolecular multistep homo- and heterodimerization of substituted propiolates providing α-pyrone-5- carboxylates and α-pyrone-6-carboxylates is described. The synthetic utilities of α-pyrone derivatives are shown. The proposed mechanism is strongly supported by experimental evidence.

Full text of DOI:10.1021/ol4035929

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Dimerization of Propiolates: A Simple Route to
α‑Pyrones
Rajendran Manikandan and Masilamani Jeganmohan*
Department of Chemistry, Indian Institute of Science Education and Research, Pune 411021, India
S
* Supporting Information
ABSTRACT: A ruthenium-catalyzed regioselective intermo-
lecular multistep homo- and heterodimerization of substituted
propiolates providing α-pyrone-5-carboxylates and α-pyrone-6-
carboxylates is described. The synthetic utilities of α-pyrone
derivatives are shown. The proposed mechanism is strongly
supported by experimental evidence.
α-Pyrones are naturally occurring six-membered unsaturated
lactones. This core is found in various natural products, and it
shows a wide range of biological activities.1 In addition, α-
pyrone is a highly useful building block for synthesizing more
complex organic molecules.2 Particularly, 5- or 6-carboxylate-
substituted α-pyrones show various biological activities and
tremendous applications in organic synthesis.3 Substituted α-
pyrones are traditionally prepared by lactonization of
substituted α,β-unsaturated enones or intramolecular cycliza-
tion of 3,5-diketo carboxylic acids.4 However, the preparation of
the corresponding α,β-unsaturated enones or 3,5-diketo
carboxylic acids needs a number of steps, and the overall
observed yields are much less. Alternatively, α-pyrones are
efficiently prepared by metal-catalyzed organic transforma-
tions.5 Metal-catalyzed cyclization of halogen-substituted α,β-
unsaturated esters with alkynes5a or allenylstannanes,5b
cyclization of β-ketoesters with alkynes,5c cyclization of α,β-
unsaturated acids with alkynes,5d,e intramolecular cyclo-
isomerization of carbon−carbon π-components,5f−i and cyclo-
addition of π-components5j are widely used to synthesize α-
pyrones. However, the control of regioselectivity and
observation of competitive side products are practical problems
in the reaction.
Transition-metal-catalyzed cyclization of π-components via a
five-membered metallacycle intermediate is a unique method to
synthesize heterocyclic compounds from easily available
starting materials in a highly regioselective manner.6 Various
π-component combinations such as alkyne/alkyne, alkyne/
alkene, allene/alkene, alkene/alkene, and C−C π-components/
heteroatom presented π-components are known in the reaction.
Among these combinations, oxidative cyclization of unsym-
metrical alkyne/alkyne is quite difficult and very challenging
due to the possibility of formation of several side products.7
Thus, dimerization of alkynes/alkynes has not been well-
explored in the literature.
and alkyl-substituted 5- or 6-carboxylate α-pyrone derivatives
are prepared in a highly regioselective manner. In the present
method, four different types of reactions are involved in one
pot. Later, various synthetic utilities of α-pyrone derivatives in
organic synthesis are shown. A possible reaction mechanism is
proposed, and the mechanism is supported by experimental
evidence.
The intermolecular dimerization of ethyl phenylpropiolate
(1a) proceeded smoothly in the presence of [{RuCl2(p-
cymene)}2] (5 mol %), AgSbF6 (20 mol %), and pivalic acid
(10.0 equiv) in 1,4-dioxane at 110 °C for 12 h, yielding 5-ester-
substituted α-pyrone derivative 2a in 85% yield (eq 1) (for
detailed optimization studies, see Tables S1−S3 in the
Supporting Information). The catalytic reaction is highly
regioselective; only compound 2a is observed, and the other
competitive side products are not observed. The structure and
regioselectivity of product 2a was confirmed by a single-crystal
X-ray diffraction (see Supporting Information). The present
catalytic reaction proceeds via a five-membered metallacycle
intermediate. In substrate 1a, two coordinating groups such as
Ph and CO2Me are there. Thus, three different types of
metallacycle intermediates A, B, and C are expected (eq 2). It is
expected that the Ph group might coordinate with ruthenium
better than the ester group. Thus, intermediate A is expected
Herein, we report an unprecedented, highly regioselective
synthesis of α-pyrone derivatives via alkyne/alkyne intermo-
lecular homocyclization of substituted propiolates and hetero-
cross-cyclization of substituted propiolates in the presence of a
ruthenium catalyst. By employing this method, various aromatic
Received: October 15, 2013
Published: January 15, 2014
© 2014 American Chemical Society
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Letter
for the reaction. Surprisingly, intermediate C was observed in
the reaction.
Under the optimized reaction conditions, the homo-
cyclization of substituted propiolates 1b−h was examined
(Table 1). Thus, methyl phenylpropiolate (1b) and the
The scope of the cyclization reaction was tested with two
different propiolates 1. Initially, the hetero-cross-oxidative
cyclization of 1a with 1e was examined. In the reaction, three
different types of α-pyrone derivatives such as homocyclization
of 1a, homocyclization of 1e, and heterocyclization of 1a and
1e are observed (eq 3). Next, the hetero-cross-cyclization of 1e
a
Table 1. Scope of the Homocyclization of Propiolates
was tested with a less reactive methyl oct-2-ynoate (1g). In the
reaction, the heterocyclization product 4b was observed in 45%
yield (eq 4). Still, the homocyclization of 1e and 1g is formed.
On the basis of these results, we have concluded that internal
alkynes favor homocyclization, and the cyclization of internal
alkyne and terminal alkyne combination could be the better
choice for the reaction.
Hence, the cyclization of terminal alkyne, ethyl propiolate
(1h), and internal alkyne, ethyl but-2-ynoate (1e) was
examined (Table 2). As we expected, the corresponding
Table 2. Scope of the Hetero-Cross-Cyclization of Two
a
Different Substituted Propiolates
a
All reactions were carried out using 1b−h (1.0 mmol), [{RuCl2(p-
cymene)}2] (5 mol %), AgSbF6 (20 mol %), and pivalic acid (10.0
equiv) in 1,4-dioxane (3.0 mL) at 110 °C for 12 h. Isolated yield.
b
electron-deficient phenylpropiolate 1c underwent cyclization
efficiently to yield 5-ester-substituted α-pyrone derivatives 2b
and 2c in 85 and 81% yields, respectively (entries 1 and 2).
Interestingly, sterically hindered ethyl naphthylpropiolate 1d
also underwent oxidative cyclization, smoothly affording α-
pyrone derivative 2d in 71% yield (entry 3). In products 2b−d,
aromatic and ester groups are adjacent to each other as in 2a. In
contrast, alkyl-substituted propiolates 1e−g such as ethyl but-2-
ynoate (1e), methyl hex-2-ynoate (1f), and methyl oct-2-
ynoate (1g) underwent cyclization effectively, yielding 6-ester-
substituted α-pyrone derivatives 3a−d in 75, 72, and 70%
yields, respectively (entries 4−7). In products 3a−d, two alkyl
groups are adjacent to each other, which is the reverse
regiochemistry of that of products 2a−d. In these reactions,
products consistent with the involvement of intermediate B
were observed exclusively in which both alkyne ester moieties
coordinate with ruthenium (eq 2). The catalytic reaction was
also compatible with terminal alkyne 1h. Thus, ethyl propiolate
(1h) underwent intermolecular cyclization to provide 6-ester α-
pyrone 3d in 45% yield as with 3a regiochemistry (entry 7).
a
All reactions were carried out using 1h (1.0−1.5 mmol), 1b−j (1.0
mmol), [{RuCl2(p-cymene)}2] (5 mol %), and AgSbF6 (20 mol %) in
acetic acid (3.0 mL) at 110 °C for 12 h. Isolated yield.
b
heterocyclization product 5a was observed in 55% yield (entry
1). However, the homocyclization of 1e and 1h products 3a
and 3d was also observed in 10 and 5% yields, respectively. To
avoid the homocyclization products, the reaction was examined
with various solvents. Very interestingly, in acetic acid solvent,
no homocyclization products were observed, and the hetero-
cyclization product 5a was observed in 68% yield (entry 1). It is
very interesting to note that only the ester group of methyl
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Letter
propiolate (1h) underwent selective C−O bond formation with
1e, and the ester moiety of 1e was intact in the reaction. The
catalytic reaction is highly regioselective; the ester moiety of 5a
was placed in the C-6 position, and the alkyl group was placed
in the C-5 position of the α-pyrone. Encouraged by this result,
we examined the cyclization reaction of 1h with other alkyl-
group-substituted propiolates 1f and 1g in acetic acid solvent.
In the reaction, 5,6-substituted α-pyrone derivatives 5b and 5c
were observed in 65 and 63% yields, respectively (entries 2 and
3). However, in the reaction, only homocyclization of 1h was
observed in only 2−3% yield. Next, the cyclization reactions of
1h with aromatic-group-substituted propiolates 1a and 1b and
methoxy-substituted 1i were examined. In the reaction,
cyclization products 6a−c were observed in 79, 76, and 77%
yields, respectively (entries 4−6). In the reaction, only
homocyclization of 1a, 1b, and 1i was observed in 2−3%
yield. The structure and regioselectivity of product 6c was
confirmed by a single-crystal X-ray diffraction (see Supporting
Information). Heteroaromatic-group-substituted ethyl 2-thienyl
propiolate 1j also efficiently participated in the reaction with 1h
to yield cyclization product 6d in 71% yield (entry 7).
Interestingly, no homocyclization products were observed in
the reaction. These reactions are highly regioselective; the ester
moiety of 6a−d was attached at the C-5 position and the aryl or
2-thienyl group was attached at the C-6 position of the α-
pyrone. The cyclization reaction was also tested with
diphenylacetylene, 1-phenyl-1-propyne, and 3-phenylprop-2-
yn-1-ol with propiolate 1e or 1h. However, in the reaction, no
expected α-pyrone derivatives were observed.
Scheme 1. Proposed Mechanism
ruthenium of intermediate 9 by the organic acid via a Ru-
carbene intermediate 10 or O-bound enolate formation gives
intermediate 11.6,7 Nucleophilic attack of the carbonyl oxygen
of the ester moiety to the ruthenium in intermediate 11 yields
intermediate 12.5a Reductive elimination of intermediate 12
yields cyclic product 2 and regenerates the ruthenium species 8.
In the selective protonation in intermediate 9, it seems likely
that an O-bound enolate could be involved, which would favor
protonation on the carbon of the ester. In the cross-cyclization
reaction, only the ester moiety of terminal alkyne 1h was
involved in the C−O bond formation. The internal alkyne ester
moiety was not involved. It could be possible that steric
hindrance at the ester group of terminal alkyne is less compared
with internal alkyne in intermediates 9a,b.
The substituent present on the propiolates decides the
regioselectivity of the reaction. In the aryl- or 2-thienyl-
substituted propiolates 1a−d and 1j, 5-carboxylate pyrones 2a−
d and 6a−d, alkyl-substituted propiolates 1e−h, and 6-
carboxylate α-pyrones 3a−d and 5a−c were observed. We
strongly believe that aryl or 2-thienyl or ester groups in
intermediate 9 coordinate with Ru better than alkyls. In the
alkynes 1a−d, two coordinating groups such as Ph and ester are
there. Thus, intermediates C and 9a are favorable. In the
alkynes 1e−h, only an ester coordinating group is there. Thus,
intermediates type B and 9b are favorable (eq 2, Scheme 1).
The proposed mechanism in Scheme 1 was strongly
supported by the following experimental evidence. Initially,
we have tried to isolate the key intermediate 9 in the reaction of
1a with a stoichiometric amount of ruthenium and silver salt. In
the reaction, a Ru species was obtained in impure form, which
was tentatively identified as structure 9 (eq 8). Further, the
By employing the present method, 5-carboxylate pyrones
2a−d and 6a−d and 6-carboxylate α-pyrones 3a−d and 5a−c
were prepared (Tables 1 and 2). Pyrone-5-carboxylates are
called coumalates, which have been widely used as a key
synthetic precursor for various organic transformations.3 To
show the utility of coumalates, the cycloaddition of 2a with
ethyl propiolate (1h) in xylene at 180 °C for 12 h was carried
out.3b In the reaction, a synthetically useful polymer precursor,
phenyl-substituted isopthalate 7a, was observed in 40% yield
(eq 5). It is also known that pyrone-6-carboxylic acid 7b shows
tumor growth inhibition activity (eq 6).3a It can be prepared by
base-mediated de-esterification at the ester group of 3d (eq 6).8
Further, decarboxylation of the α-pyrone derivative of 2a in the
presence of a 1:1 mixture of AcOH and H2SO4 at 120 °C
yielded decarboxylated α-pyrone derivative 7c in 90% yield (eq
7).8
A possible reaction mechanism for the present dimerization
of propiolates is proposed in Scheme 1. Silver salt AgSbF6 likely
removes the chlorine ligand from the [{RuCl2(p-cymene)}2]
complex, forming a cationic ruthenium complex 8. Highly
regioselective coordination of propiolates 1 to the complex 8
followed by oxidative cyclometalation leads to intermediate 9.7
Selective protonation at the ester attached to the carbon next to
intermediate was treated with acetic acid at 110 °C for 12 h. In
the reaction, the expected product 2a was observed. Further,
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the cyclization of 1a was examined in CD3COOD solvent (eq
9). In the reaction, deuterated α-pyrone derivative D-2a was
observed in 45% yield in 75% deuterium incorporation at the
C-3 carbon of α-pyrone. These results clearly revealed that the
catalytic reaction proceeds via a five-membered metallacycle
intermediate and only organic acid protonates the metallacycle
intermediate. Further, the treatment of 1a with propiolic acid
(1l) gave α-pyrone derivative 6a in 43% yield (eq 10). This
result clearly reveals that the acid group of propiolic acid was
involved in the C−O bond formation of product 5 or 6.
In conclusion, we have shown a ruthenium-catalyzed
dimerization of substituted propiolates. In these reactions,
substituted α-pyrone-5-carboxylates and α-pyrone-6-carboxy-
lates were prepared. Further extension of cyclization of other π-
components is in progress.
(7) Jeganmohan, M.; Cheng, C. H. Chem.Eur. J. 2008, 14, 10876.
(8) Bickel, C. L. J. Am. Chem. Soc. 1950, 72, 1022.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedure and characterization details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mjeganmohan@iiserpune.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the DST (SR/S1/OC-26/2011), India, for the
support of this research. R.M. thanks the CSIR for a fellowship.
■
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