Rhodium-catalyzed oxidative coupling of benzoic acids with terminal alkynes: An efficient access to 3-ylidenephthalides

Article abstract of DOI:10.1021/acs.organomet.6b00107

Herein we disclose the first example of transition-metal-catalyzed oxidative coupling/annulation of simple benzoic acids with terminal alkynes via C-H activation. A range of aromatic carboxylic acids and terminal alkynes have been found to be viable subst

Full text of DOI:10.1021/acs.organomet.6b00107

Communication
pubs.acs.org/Organometallics
Rhodium-Catalyzed Oxidative Coupling of Benzoic Acids with
Terminal Alkynes: An Efficient Access to 3‑Ylidenephthalides
Yang Liu, Yudong Yang,* Yang Shi, Xiaojie Wang, Luoqiang Zhang, Yangyang Cheng, and Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Medical School, Sichuan University, 29 Wangjiang Road, Chengdu 610064, People’s Republic of China
S
* Supporting Information
ABSTRACT: Herein we disclose the first example of
transition-metal-catalyzed oxidative coupling/annulation of
simple benzoic acids with terminal alkynes via C−H activation.
A range of aromatic carboxylic acids and terminal alkynes have
been found to be viable substrates in this reaction, providing a
simple and efficient method for the synthesis of diverse 3-
ylidenephthalides with complete Z selectivity.
he phthalide structural motif is prevalent in many
pharmaceuticals, natural products, and organic synthetic
Scheme 2. Synthesis of 3-Ylidenephthalides via Catalytic C−
H Activation
T
intermediates (Scheme 1).1,2 In particular, 3-ylidenephthalides
Scheme 1. Examples of Biologically Active 3-
Ylidenephthalides
exhibit a broad spectrum of biological activities, such as anti-
HIV, antidiabetic, antispasmodic, and antiallergic proper-
ties.2a−e,3 Therefore, a number of methods have been
developed to construct 3-ylidenephthalides,4,5 including con-
densation of phthalic anhydrides with carboxylic acids,5a,b
olefination of phthalic anhydrides,5c Baylis−Hillman reactions
of 2-carboxybenzaldehyde,5d condensation of aromatic alde-
hydes with phthalides,5e,f transition-metal-catalyzed or -medi-
ated carbonylation of ortho-substituted aryl ketones,5g−i and
intramolecular cyclization of 2-(1-alkynyl)benzoic acids5j,k and
alkenoic acids.5l From the viewpoint of atom and step
economy, operational simplicity, and availability of substrates,
transition-metal-catalyzed direct C−H functionalization is
regarded as a more appealing strategy to streamline access to
diverse complex molecules from simple substrates.6 Miura and
Lee realized the palladium-catalyzed oxidative annulation of
ortho-substituted aromatic carboxylic acids with vinylarenes to
synthesize (Z)-benzylidenephthalides (Scheme 2a).7 Gooßen
disclosed the rhodium-catalyzed sequential acylation/cycliza-
tion of benzoic acids with aliphatic anhydrides (Scheme 2b).8
Wen reported the rhodium-catalyzed oxidative coupling of
benzoic acids with 2-alkylvinyl acetates to give a mixture of
isocoumarin and 3-alkylidenephthalide (Scheme 2c).9 How-
ever, these protocols suffer from limitations such as narrow
substrate scope, high reaction temperature, moderate regiose-
lectivity, and/or incomplete Z/E selectivity. Herein we disclose
a rhodium-catalyzed oxidative annulation of benzoic acids with
terminal alkynes to afford 3-ylidenephthalides in a completely Z
selective manner (Scheme 2d). It is noteworthy that this is also
the first example of transition-metal-catalyzed oxidative
coupling/annulation of simple benzoic acids with terminal
alkynes via C−H activation.
2-Methylbenzoic acid (1a) and ethynyltriisopropylsilane (2)
were selected as the model substrates to optimize the reaction
Special Issue: Organometallics in Asia
Received: February 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.6b00107
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
ab
,
conditions (Table 1). In the presence of 2.5 mol % of
Table 2. Scope of Benzoic Acids
[Cp*RhCl2]2, 10 mol % of AgSbF6, 2.0 equiv of Ag2O, and 1.0
a
Table 1. Optimization of Reaction Conditions
b
entry
oxidant
Ag2O
additive
PivOH
solvent
DCE
yield (%)
1
55
2
Ag2O
DCE
n.d.
n.d.
49
3
Ag2O
PivOCs
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
DCE
4
Ag2CO3
AgOAc
Cu(OAc)2
K2S2O8
BQ
DCE
5
DCE
n.d.
n.d.
n.d.
n.d.
trace
n.d.
76
6
DCE
7
DCE
8
DCE
9
Ag2O
t-amylOH
DMF
10
11
12
13
Ag2O
a
Reaction conditions: 1 (0.25 mmol), 2 (0.375 mmol), [Cp*RhCl2]2
Ag2O
1,4-dioxane
toluene
o-xylene
o-xylene
o-xylene
o-xylene
(2.5 mol %), AgSbF6 (10 mol %), PivOH (0.25 mmol), Ag2O (0.50
Ag2O
69
b
mmol), and o-xylene (3.0 mL) at 100 °C for 24 h. Isolated yields.
Ag2O
91
c
DCE (3.0 mL) and Ag2CO3 (0.50 mmol) were used instead.
c
14
Ag2O
41
15
n.d.
n.d.
d
16
Ag2O
the ortho-unprotected benzoic acids typically exhibited less
conversion efficiency, resulting in a great deal of unreacted
substrates. Both electron-rich and -deficient benzoic acids were
converted smoothly to the corresponding 3-ylidenephthalides
(3c−i). However, a diminished yield was obtained when 2-
methoxylbenzoic acid was used (3i). The configuration of 3i
was confirmed by single-crystal X-ray analysis. In addition,
treatment of 1-naphthalenecarboxylic acid (1j) with ethynyl-
triisopropylsilane (2) under the standard conditions gave the
corresponding product in 54% yield. It is notable that only Z
isomers were observed in all cases.
The generality of alkynes was next investigated. As illustrated
in Table 3, various aromatic alkynes 4 cyclized with 2-
methylbenzoic acid (1a) to afford the corresponding 3-
ylidenephthalides 5 in moderate to good yields (5a−g). Both
electron-rich and -deficient phenylacetylenes were compatible
with the reaction conditions. Some reactive functional groups,
including acetyl, ester, and halogen, were tolerated under our
a
Reaction conditions: 1 (0.25 mmol), 2 (0.375 mmol, 1.5 equiv),
[Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %), PivOH (1.0 equiv),
oxidant (2.0 equiv), and solvent (3.0 mL) at 100 °C for 24 h.
Abbreviations: TIPS = triisopropylsilyl, DMF = dimethylformamide, t-
b
amylOH = tert-amyl alcohol, n.d. = not detected. Isolated yield.
c
d
Ag2O (1.5 equiv) was used. Without [Cp*RhCl2]2.
equiv of PivOH, a 55% yield of 3-ylidenephthalide 3a was
obtained in DCE, along with the generation of the alkyne dimer
as a byproduct (entry 1). No desired product was detected in
the absence of PivOH (entry 2). PivOCs was ineffective for this
reaction (entry 3). The oxidant was next optimized. It was
found that Ag2CO3 gave a slightly lower yield and AgOAc did
not deliver any product (entries 4 and 5). Other oxidants,
including Cu(OAc)2, K2S2O8, and BQ, were all unsuccessful in
our tests (entries 6−8). The solvents were also examined. Very
poor results were obtained in DMF and t-amylOH (entries 9
and 10). 1,4-Dioxane and toluene proved to be efficient, giving
3a in 76% and 69% yields, respectively (entries 11 and 12). To
our delight, the desired product was obtained in a 91% yield by
employing a catalytic system comprising [Cp*RhCl2]2 (2.5 mol
%), Ag2O (2.0 equiv), AgSbF6 (10 mol %), and PivOH (1.0
equiv) in o-xylene at 100 °C for 24 h (entry 13). It is notable
that only a trace amount of isocoumarin product was detected,
indicating a high regioselectivity of this transformation. In
addition, 2 equiv of Ag2O was essential for a high reaction
efficiency, presumably because the formation of silver(I)
acetylide with excess alkyne consumed Ag2O (entry 14). No
reaction was detected in the absence of either [Cp*RhCl2]2 or
an oxidant (entries 15 and 16).
a b
,
Table 3. Scope of Terminal Alkynes
With the optimized conditions in hand, we then examined
the substrate scope of aromatic carboxylic acids (Table 2). Not
only ortho-substituted but also benzoic acids that were
unsubstituted and substituted at other positions were suitable
substrates to deliver the desired products (3a−d). This result is
distinctly different from that of previous reports,7b in which
only ortho-substituted benzoic acids were effective. However,
a
Reaction conditions: 1a (0.25 mmol), 4 (0.50 mmol), [Cp*RhCl2]2
(2.5 mol %), AgSbF6 (10 mol %), PivOH (0.25 mmol), Ag2O (0.50
mmol), and o-xylene (3.0 mL) at 100 °C for 30 h. Isolated yields.
b
B
DOI: 10.1021/acs.organomet.6b00107
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
conditions. In addition to aryl alkynes, aliphatic alkynes could
also be compatible in this transformation, delivering 5h in a
66% yield. In contrast, only either 3-alkylidenephthalides or 3-
arylidenephthalides could be accessed through the previously
reported transition-metal-catalyzed C−H coupling of benzoic
acids with unsaturated components.6−8
To probe the reaction mechanism, 2,2,6,6-tetramethylpiper-
idine-N-oxyl (TEMPO) was added. Only a trace amount of the
desired product was detected in the presence of 0.5 equiv of
TEMPO, thus implying that this reaction might involve a
radical process.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.6b00107.
■
S
Experimental procedures, characterization data, and
NMR spectra (PDF)
X-ray crystallographic data for 3i (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail for Y.Y.: yangyudong@scu.edu.cn.
*E-mail for J.Y.: jsyou@scu.edu.cn.
■
While the mechanism of this reaction is still under
investigation, a tentative mechanism is proposed on the basis
of the above results and previous reports (Scheme 3).5j,k,10
Notes
Scheme 3. Proposed Mechanism
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National NSF of
China (Nos. 21432005 and 21321061), and Comprehensive
Training Platform of Specialized Laboratory, College of
Chemistry, Sichuan University.
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DOI: 10.1021/acs.organomet.6b00107
Organometallics XXXX, XXX, XXX−XXX