Ruthenium(II)-Catalyzed Alkene C-H Bond Functionalization on Cinnamic Acids: A Facile Synthesis of Versatile α-Pyrones

Article abstract of DOI:10.1021/acs.orglett.5b02631

An inexpensive ruthenium(II) complex enabled oxidative annulation of alkynes by using cinnamic acid derivatives to provide diversely decorated multisubstituted α-pyrones.

Full text of DOI:10.1021/acs.orglett.5b02631

Letter
pubs.acs.org/OrgLett
Ruthenium(II)-Catalyzed Alkene C−H Bond Functionalization on
Cinnamic Acids: A Facile Synthesis of Versatile α‑Pyrones
Rashmi Prakash,†,‡ Kommuri Shekarrao,†,‡ and Sanjib Gogoi*,†,‡
†Medicinal Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India
‡Academy of Scientific and Innovative Research, New Delhi, India
S
* Supporting Information
ABSTRACT: An inexpensive ruthenium(II) complex enabled
oxidative annulation of alkynes by using cinnamic acid
derivatives to provide diversely decorated multisubstituted α-
pyrones.
a
Table 1. Optimization Study for α-Pyrone Synthesis
α-Pyrones with various substitution patterns are among the
most abundant heterocycles found in bioactive natural products
or pharmacologically active compounds.1 Because of the
importance of α-pyrones, there is a continued strong demand
for new methods of construction of these heterocycles.2
In recent years, transition metal catalyzed annulation
reactions which proceed via activation of a C−H bond have
revolutionized the construction of cyclic compounds.3 Miura
and co-workers have used the rhodium-catalyzed C−H
activation and functionalization of acrylic acids with alkynes
for the synthesis of functionalized α-pyrones.2e Recently, the
same group also disclosed a rhodium-catalyzed annulation of
maleic acids with alkynes for the construction of α-pyrones.2f
The high cost of the rhodium(III) catalysts used in these
methods is the main limitation of these approaches. Recently,
ruthenium(II) complexes, which are considerably less expensive
than those of rhodium(III), were identified as viable catalysts
for C−H activation and annulation reactions.3b,4 In continu-
ation of our work on the development of novel methods for the
syntheses of important heterocycles,5 herein, we report an
unprecedented Ru(II) catalyzed C−H activation and annula-
tion reaction of commercially available cinnamic acids with
alkynes for the easy construction of a wide range of
multisubstituted α-pyrones. Notably, the oxidative annulation
reactions of cinnamic acid with some unsymmetrical alkynes are
very regioselective in this Ru catalyzed reaction.
At the outset, the performance of the ruthenium(II) catalyst
for the oxidative annulation reaction of cinnamic acid 1a with
diphenylacetylene 2a for the synthesis of α-pyrone 3aa2g was
studied (Table 1). In the absence of either the oxidant or the
ruthenium catalyst, the desired product 3aa was not formed
(entries 1 and 2). Among a set of representative solvents
screened to perform this reaction (entries 3−7), t-AmOH
provided the highest yield (88%) of 3aa. The use of cocatalytic
additives KPF6 and AgSbF6 that form cationic ruthenium(II)
catalysts could not further improve the catalytic activity (entries
8−9). Moreover, the use of oxidants CuBr2 and AgOAc instead
of Cu(OAc)2·H2O delivered an inferior yield of 3aa (entries
10−11).
b
entry
oxidant
additive
solvent
yield (%)
1
−
−
−
−
−
−
−
−
t-AmOH
t-AmOH
t-AmOH
PhMe
−
−
88
c
2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuBr2
3
4
61
d
5
MeOH
80
6
H2O
67
52
76
70
15
43
7
MeCN
8
KPF6
AgSbF6
−
t-AmOH
t-AmOH
t-AmOH
t-AmOH
9
10
11
AgOAc
−
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), catalyst (2.5 mol
%), oxidant (1.0 mmol), solvent (5.0 mL), 90 °C, 20 h; unless
otherwise mentioned. Isolated yields. No catalyst. Temperature 64
b
c
d
°C.
With the optimized reaction conditions in hand, we first
tested its scope in the oxidative annulation of cinnamic acid 1a,
utilizing representative disubstituted alkynes 2a−o (Scheme 1).
The diaryl-substituted alkynes bearing electron-donating and
-withdrawing groups in the phenyl rings were well tolerated,
providing 76−92% yields of α-pyrones 3aa−3ad. Moreover, the
annulation reaction of an alkyne substituted with a pair of
heteroaromatic moieties proceeded well to afford correspond-
ing α-pyrone 3ae in 67% yield. Similarly, the dialkyl-substituted
alkynes were also found to be suitable substrates in this
annulation reaction, delivering the desired α-pyrones 3af and
3ag in 76−80% yields. The unsymmetrically substituted alkynes
substituted with aryl, heteroaryl, and alkyl groups were also
Received: September 11, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b02631
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Scheme 1. Scope with Substituted Alkynes (2a−o)
Scheme 2. Synthesis of Various Substituted α-Pyrones
Scheme 3. Intermolecular Competition Reactions
found to be good substrates for this annulation reaction. The
reaction of 1a with alkynes 2h−i provided a mixture of α-
pyrones 3ah−3ai in 71−76% yields. The α-pyrones 3ah and
3ah′ (1.5:1) were easily separated by silica gel column
chromatography. We were pleased to observe that sensitive
functional groups such as hydroxyl and bromo were well
tolerated (3an and 3ao). Remarkably, reactions of 1a with
unsymmetrical alkynes 2j−n were highly regioselective to afford
products 3aj−3an in good yields (66−83%). The regioselec-
tivity of the α-pyrones was proven by their NOE spectra. The
selectivity pattern of the annulation products 3aj−3an was
similar to the case of the reported transition metal catalyzed
annulation reactions, where insertion of alkyne into carbon−
metal bonds occurred with the metal atom normally attacking
the more negative carbon of the alkyne.6
Next, the annulation reaction was tested with alkyne 2a using
various functionalized cinnamic acids 1b−j (Scheme 2). We
were delighted to observe that numerous useful electron-
donating and -withdrawing groups at different positions on the
phenyl ring of the cinnamic acids were well tolerated to provide
70−89% yields of α-pyrones 3ba−ja under the standard
conditions. To observe the wide scope of the oxidative
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DOI: 10.1021/acs.orglett.5b02631
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Letter
annulation reaction, reactions of 2a with various 3-heteroaryl/
3-alkyl/2-alkyl-3-aryl substituted propenoic acids 1k−n were
also studied. The 3-heteroaryl substituted propenoic acids 1k−
1l reacted smoothly with 2a to provide α-pyrones 3ka−3la in
84−85% yields. Moreover, 1l was converted easily to the 4,5,6-
triheteroaryl α-pyrone 3lm with alkyne 2e in 82% yield. The 3-
alkyl propenoic acid 1m and 2,3-disubstituted propenoic acid
1n also turned out to be very good substrates for this
annulation reaction to provide 71−86% yields of 3ma−3na2a
with 2a. Notably, 5-aryl substituted penta-2,4-dienoic acid 1o
also reacted with 2a to selectively afford α-pyrone 3oa in 89%
yield.
Scheme 4. Isotopically Labelled Experiments
The intermolecular competition experiments performed with
differently substituted alkynes revealed an aryl substituted
alkyne (2a) as well as an electron-poor alkyne (2d) to be
preferentially converted to their corresponding α-pyrones
(Scheme 3). In addition, the reaction between 1a and 2a
performed under standard conditions in CD3OD (20 h) and
D2O (48 h) employing an excess of 1a resulted in a significant
D/H exchange in the olefinic C−H of the recovered starting
material [D]-1a (eqs 1−2, Scheme 4). This result provided
evidence for a reversible C−H bond ruthenation step. The
intermolecular kinetic isotope effect experiment performed
between 1a + D-1a (1:1) and 2a provided a 1:1 mixture of
unreacted 1a + D-1a in 2 h (eq 3, Scheme 4). However, the β-
hydrogen atom of cinnamic acid showed 2% exchange with the
deuterium of the solvent CD3OD, when the reaction between
1a and 2a mentioned in eq 1, Scheme 4 was performed under
standard conditions for 2 h. Therefore, 1a reacted with 2a
slightly faster than [D]-1a and the ratio of the recovered
cinnamic acids (1a:[D]-1a) reached up to 1:1 after the
hydrogen exchange with t-AmOH; as a result, kH/kD > 1.0.7
Based on our mechanistic studies and previous results on
ruthenium metal catalyzed C−H activation and functionaliza-
tion reactions,4,8 we propose the mechanism for the formation
of 3, which is shown in Scheme 5. The catalytically active
species 4a on reversible cycloruthenation forms the complex 4c.
Subsequently, migratory insertion of alkyne 2, followed by
reductive elimination, furnishes desired compound 3. The
active catalyst is regenerated by the oxidation reaction with
Cu(OAc)2.
Scheme 5. Proposed Mechanism
In summary, we have described the first use of rather
inexpensive ruthenium catalysts for the oxidative annulation of
cinnamic acids with disubstituted alkynes via a C−H/O−H
functionalization strategy. The broad substrate scope, high
regioselectivity with some unsymmetrical alkynes, and high
yield of products α-pyrones are the noteworthy features of this
reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02631.
1
Experimental procedures; characterization data; H and
13C NMR spectra for 3aa−3oa, 3ba−3oa; NOESY for
3aj, 3am (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: skgogoi1@gmail.com.
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DOI: 10.1021/acs.orglett.5b02631
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Organic Letters
Letter
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors thank CSIR, New Delhi, for financially supporting us
with the CSIR-ORIGIN (CSC-0108) project. We are grateful
to the Director, CSIR-NEIST for his keen interests.
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