Ruthenium-Catalyzed Alkynylation of Benzoic Acids Mediated by a Weakly Coordination-Directing Auxiliary

Article abstract of DOI:10.1002/ejoc.201700788

A method for the ruthenium-catalyzed ortho-alkynylation of benzoic acids was developed. The reaction was found to be directed by a weakly coordinating carboxyl group and offers a facile route for the synthesis of ortho-alkynylated derivatives. A rare exam

Full text of DOI:10.1002/ejoc.201700788

A Journal of
Accepted Article
Title: Ruthenium-Catalyzed Alkynylation of Benzoic Acids Mediated by
a Weakly-Coordination Directing Auxiliary
Authors: Changpeng Chen
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10.1002/ejoc.201700788
European Journal of Organic Chemistry
COMMUNICATION
Ruthenium-Catalyzed Alkynylation of Benzoic Acids Mediated by
a Weakly-Coordination Directing Auxiliary
Changpeng Chen,[a] and Xiaoming Zeng*[a,b]
Abstract: It was reported a ruthenium-catalyzed ortho-alkynylation
of benzoic acids. The reaction was directed by a weakly-coordination
carboxyl group, provides a feacile route to the synthesis of ortho-
base of K2CO3 (entry 4). However, other bases such as Cs2CO3
and CsOAc inhibited the alkynylation (entries 5, 7 and 8). These
results suggest that base plays an important role in the
promotion of the conversion. Further studies suggested that t-
Amyl-OH was suitable solvent for the alkynylation of benzoic
acids (entries 10–13). In the absence of base or ruthenium
complex of [{RuCl2(p-cymene)}2], the reaction of C–H bonds did
not take place (entries 9 and 14).
alkynylated derivatives.
A rarely example of bis(alkynylation)
reaction of C–H bonds was described.
Aromatic alkynes are key building blocks in organic synthesis,
which has been widely utilized in the construction of valuable
molecules such as common chemicals, drugs and materials.[1]
The development of efficient methodology to access to such
motifs is of central importance. In the past decade, transition-
metal-catalyzed functionalization of C–H bonds has emerged as
one of the most powerful tools to form appealing molecules in
the chelation assistance of directing auxiliaries.[2] Since
Gevorgyan’s group reported the example of alkynylation of C–H
bonds with palladium catalysis,[3] various synthetic protocols
have been developed to the formation of aromatic alkynes by
transition metal-catalyzed alkynylation, mainly focusing on the
use of amide-bearing multi-dentated directing groups (Scheme
1a).[4–16] Although the progress, to our knowledge, there has
rarely been reported on the ortho-alkynylation of aromatics that
was assisted by a weakly-coordination directing auxiliary.[17]
Carboxyl is synthetically useful functional group that could be
modified by decarboxylative cross-coupling reactions to form C–
C, C–O and C–N bonds. However, because of the facile addition
of carboxyl across unsaturated C–C triple bond, carboxyl-
directed alkynylation of C–H bonds has not been achieved, even
though the known cases of annulation in the formation of
benzofuran-1-ones mediated by carboxyl directing auxiliaries.
Herein, we report a carboxyl-directed alkynylation of benzoic
acids with ruthenium catalysis. The reaction provides an efficient
strategy for the preparation of ortho-alkynylated benzoic acids
without annulation, even for the formation of bis(alkynylated)
products that are rarely accessed by C–H functionalization
(Scheme 1b).
Scheme 1. Transition Metal-Catalyzed ortho-Alkynylation of Aromatics
Inspired by recent progress in ruthenium-catalyzed C–H
functionalization of aromatic amides and esters,[18] we started
our investigation by the use of commercially available complex
of [{RuCl2(p-cymene)}2] as catalyst to probe the alkynylation of
benzoic acids. As shown in Table 1, it was found that the
reaction between ortho-methyl-substituted benzoic acid and
(bromoethynyl)triisopropylsilane proceeded smoothly in the
presence of base, giving the desired alkynylation compound 2a
in 67% yield (entry 1). The best result was obtained when using
entry
1
base
NaHCO3
KHCO3
Na2CO3
K2CO3
Cs2CO3
NaOAc
KOAc
solvent
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
DCE
yield (2a)
67%
80%
81%
86%
ndb
2
3
4
5
6
62%
50%
ndb
[a]
C. Chen, Prof. Dr. X. Zeng
Center for Organic Chemistry, Frontier Institute of Science and
Technology, Xi’an Jiaotong University, Xi’an 710054, China.
E-mail: zengxiaoming@mail.xjtu.edu.cn
7
8
CsOAc
none
9
ndb
[b] Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University, Chengdu
610064, China
10
11
K2CO3
K2CO3
71%
70%
toluene
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European Journal of Organic Chemistry
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12
13
K2CO3
K2CO3
K2CO3
1,4-dioxane
THF
79%
77%
ndb
trifluoromethyl into the ortho position of benzoic acids largely
decreased the reaction rate, giving the products 2e and 2f at
high temperature. Interestingly, the steric hindrance around C–H
bonds has no obviously effect on the alkynylation. The related
multi-substituted benzoic acid derivatives 2g–2j were formed in
54–88% yields. The reaction with meta-methyl or trifluoromethyl-
substituted benzoic acids favors to install an alkynyl scaffold at a
position of less steric repulsion (2k and 2l). It was noteworthy
that the use of more electron-rich methoxy-containing benzoic
acid led to a bis(alkynylated) product 2m in 71% yield. This also
proves an electron-rich aromatic-favorable ortho-alkynylation of
C–H bonds. Furthermore, bis(alkynylated) benzoic acids 2n–2p
can be prepared by this methodology, even for thiophene-3-
carboxylic acid derivative 2q. In addition, the ortho-C–H bond of
1-methyl-1H-indole-3-carboxylic acid is amenable to the
alkynylation, the formation of the related derivative 2r in 67%
yield. However, the reaction with aromatic ketone and ester
cannot give the alkynylated compounds.
14c
t-Amyl-OH
[a] Conditions: 1a (0.1 mmol), (bromoethynyl)triisopropylsilane (0.15 mmol),
[{RuCl2(p-cymene)}2] (2.5 mol %), base (0.2 mmol), solvent (0.5 mL), 80 oC, 24
h. Yield was determined by HPLC analysis using acetophenone as internal
standard. [b] Not detected. [c] Without [{RuCl2(p-cymene)}2].
Table 1. Studying the Effect of Bases and Solvents on the ortho-Alkynylation
of Benzoic Acid a
[a] Reaction conditions: 2 (0.2 mmol), TBAF (0.4 mmol), THF (4 mL), rt. 2 h.
Isolated yields were given.
Scheme 3. Late-Stage Functionalization of 2a
[a] Conditions: 1 (0.2 mmol), (bromoethynyl)triisopropylsilane (0.3 mmol),
[{RuCl2(p-cymene)}2] (2.5 mol %), K2CO3 (0.4 mmol), t-Amyl-OH (1 mL),
80 °C. 24 h. Isolated yields were given. [b] (Bromoethynyl)triisopropylsilane
(0.5 mmol). [c] The reaction was carried out at 100 °C. [d] [{RuCl2(p-
cymene)}2] (5 mol %).
Scheme 2. Ru-Catalyzed ortho-Alkynylation of Aromatic and (Hetero)aromatic
Carboxylic Acidsa
With the optimal reaction conditions in hand, we next examined
the substrate scope of the carboxyl-directed ortho-alkynylation.
The reaction proceeded effectively with electron-rich benzoic
acids, leading to the corresponding alkynylated compounds 2b–
2d in good yields (Scheme 2). In contrast, the incorporation of
Scheme 4. Mechanistic Studies
We then explored the feasibility of the functionalization of the
resulting alkynylated benzoic acids. As shown in Scheme 3, by
electron-deficient
substituent
such
as
chloride
and
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General Procedure for Ru-Catalyzed Alkynylation of Aromatic Carboxylic
Acids: mixture of
1 (0.2 mmol), [{RuCl2(p-cymene)}2] (2.5 mol %),
(bromoethynyl)triisopropylsilane (0.3 mmol), and K2CO3 (0.4 mmol), t-Amyl-OH
(1 mL) in a 15 mL glass vial was heated at 80 °C for 24 h. The reaction
mixture was cooled to room temperature and concentrated under a reduced
pressure. The resulting residue was purified by column chromatography on
silica gel to give the corresponding product 2.
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Keywords: ruthenium-catalyzed • Alkynylation • Benzoic Acids •
C–H bonds • Weakly-Coordination
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COMMUNICATION
C-H alkynylation
C. P. Chen, X, M. Zeng*
Page 1. – Page 4.
Ruthenium-Catalyzed Alkynylation of
Benzoic Acids Mediated by a Weakly-
Coordination Directing Auxiliary
Ruthenium-catalyzed direct C−H alkynylation of aromatic acids is reported. The
reaction proceeds under exceedingly mild reaction conditions, and tolerance for a
broad range of functional groups. Alkynylated products can smoothly converted by
a 5-exo cyclization into 2-benzofuran-1-one in moderate to good yields.
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