Ruthenium-Catalyzed C-H Alkynylation of Aromatic Amides with Hypervalent Iodine-Alkyne Reagents

Article abstract of DOI:10.1021/acs.orglett.6b01281

An efficient C-H activation method for the ortho alkynylation of aromatic N-methoxyamides with hypervalent iodine-alkyne reagent using a ruthenium catalyst is described. The reaction proceeds under mild reaction conditions with broad substrate scope. A possible catalytic cycle involving a ruthenium carboxylate assisted C-H bond cleavage is proposed from the preliminary mechanistic evidence.

Full text of DOI:10.1021/acs.orglett.6b01281

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed C−H Alkynylation of Aromatic Amides with
Hypervalent Iodine−Alkyne Reagents
Ramadoss Boobalan, Parthasarathy Gandeepan, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
S
* Supporting Information
ABSTRACT: An efficient C−H activation method for the ortho alkyny-
lation of aromatic N-methoxyamides with hypervalent iodine−alkyne
reagent using a ruthenium catalyst is described. The reaction proceeds
under mild reaction conditions with broad substrate scope. A possible
catalytic cycle involving a ruthenium carboxylate assisted C−H bond
cleavage is proposed from the preliminary mechanistic evidence.
rganic synthesis relies on the construction of carbon−
carbon (C−C) and C−heteroatom (C−X) bonds. The tra-
Controlled experiments revealed that no product was formed in the
absence of [RuCl2(p-cymene)]2 or NaOAc (entries 15 and 16).
O
ditional cross-coupling reactions to construct these bonds are
environmentally and economically less attractive owing to their
requirement of prefunctionalized starting compounds.1 Recently,
the functionalization of carbon−hydrogen (C−H) bonds has
become a powerful tool for the straightforward, atom-, and step-
economical synthesis of complex molecules.2,3 In the past two
decades, there has been significant progress in the arylation and
alkenation of unactivated C−H bonds.4,5 However, an equally
important C−H alkynylation reaction is less explored. Very
recently, a few reports appeared on the C−H alkynylation
reactions.6 The known methods mostly involve expensive Rh, Pd,
Ir, and Au catalysts and are limited to a few substrates. Our con-
tinuous interest in the C−H functionalization reactions leads us to
think that the development of a C−H alkynylation reaction using
less expensive Ru catalyst should be a significant improvement in
this research area.7,8 In 2012, Tobisu and Chatani reported a
nitrogen heterocycle directed C−H alkynylation by alkynyl bro-
mides using a Ru catalyst6r at 100−130 °C. Very recently, Hong
has demonstrated a Ru(II)-catalyzed C2-selective alkynylation of
N-pyrimidyl-4-quinolone with hypervalent iodine−alkyne reagents.6s
The known reactions worked with substrates containing non-
removable directing groups (DGs) or specific substrates. Direct
Ru-catalyzed C−H alkynylation of substrates bearing a simple,
highly useful, and easily transformable functional group is highly
sought after. In this report, we disclose the ortho C−H alkynylation
of aromatic amides using a [RuCl2(p-cymene)]2 catalyst system.
We began our investigations using N-methoxy-4-methylbenzamide
(1a) and 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-
one (2a) as the substrates. After screening a large number of
reaction conditions, we found that the reaction of 1a (0.20 mmol)
and 2a (0.22 mmol) in the presence of [RuCl2(p-cymene)]2
(2.5 mol %) and NaOAc (1 equiv) in 2,2,2-trifluoroethanol
(TFE) at 60 °C for 20 h gave product 3aa in 75% isolated yield
along with dialkynylation product 4aa in 10% yield (Table 1,
entry 7). Our efforts to further reduce 4aa formation failed.
Among the solvents tested, TFE is most effective to give 3aa
in the highest yield. Similarly, NaOAc was found to be a
more suitable additive tested to promote the present reaction.
a
Table 1. Reaction Optimization Studies
b
yield (%)
additive
(equiv)
temp (°C)/time
entry solvent
(h)
3aa
4aa
1
TFE
MeOH
DCE
ACN
EtOH
TAA
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1.5)
NaOAc (0.5)
NaOAc (0.2)
NaOAc (1)
Na2CO3 (1.5)
NaHCO3 (1)
K2CO3
80/24
80/24
80/24
80/24
80/24
80/24
60/20
60/20
60/20
60/20
50/20
60/20
60/20
60/20
60/20
60/20
60/20
50
44
8
12
5
2
3
27
4
trace
27
5
5
6
trace
75
c
c
7
10
8
8
67
8
46
trace
trace
8
9
41
10
11
12
13
14
15
16
55
72
10
60
5
20
trace
10
Na2CO3 (1.0)
64
NaOAc (1)
d
a
Reactions were performed using 1a (33 mg, 0.20 mmol), 2a (94 mg,
0.22 mmol), and [Ru(p-cymene)Cl2]2 (3.0 mg, 2.5 mol %) under the
b
above-mentioned conditions. The yields were determined by 1H NMR
c
integration method using mesitylene as the internal standard. Isolated
d
yield. No [Ru(p-cymene)Cl2]2 was used.
Received: May 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01281
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
CF3, NO2, and CO2Me on the aromatic ring were also
alkynylated smoothly to give the expected products, 3ia−ka, in
high yields. Substrate 1l contains a vinyl group at the para
position of the ring also proceeded to give product 3la in 67%
yield. The meta-substituted amides, 1m−p, regioselectively
underwent C−H activation at the less hindered site to give the
respective alkynylated products 3ma−pa in 60−75% yields.
Interestingly, the methylenedioxy group substituted amide 1q
underwent C−H activation at the sterically hindered ortho
position to give 3qa as the sole product in 88% yield owing to
the strong directing effect of the methylenedioxy substituent.9
The catalytic ortho C−H alkynylation was not affected by the
steric hindrance of another ortho substitution. Amides 1r and 1s
having chloro and iodo substituents at the ortho position of the
aromatic rings gave alkynylated products 3ra and 3sa in 75%
and 80% yields, respectively. 2-Naphthylamide also underwent
C−H activation selectively at the C3 position instead of C1 to
give product 3ta because of the steric hindrance by the fused
aromatic ring. Heterocycle amides such as furan and thio-
phene substrates were also compatible under the reaction con-
ditions to give C−H alkynylation products 3ua and 3va in
good yields. We also examined the tolerance of different
N-substituted amides under the reaction conditions. Un-
luckily, N-OPiv-, N-OH-, and N-OAc-substituted benzamides
failed to give the corresponding alkynylated products. In
addition to the amide substrates, we also examined different
silyl substitutions in place of the Si(iPr)3 group. The reaction
also worked well with SiMe2(tBu) and SiEt3 groups on the
alkyne moiety. Fortunately, tert-butylethyne (2d) without a
silyl group also proceeded to give 3ad in moderate yield.
However, the phenyl-substituted alkyne did not lead to the
desired alkynylation product. The structures of products 3oa
and 3ra were further confirmed by single-crystal X-ray struc-
ture analysis.10
Scheme 1. Scope of the Ru-Catalyzed C−H Alkynylation of
a
Aromatic Amides
To further explore the scope of the Ru-catalyzed C−H alkyny-
lation reaction, we tested 2-phenylpyridine 4 with 2a under the
standard reaction conditions to give expected products 5a and 5b
in moderate yields (Scheme 2).
Scheme 2. Ru-Catalyzed C−H Alkynylation of
2-Phenylpyridine
a
Reaction conditions: 1 (0.35 mmol), 2 (0.38 mmol), [RuCl2
(p-cymene)]2 (2.5 mol %), and NaOAc (0.35 mmol) in TFE (2.5 mL)
at 60 °C for 20 h. Isolated yields were given. In all cases, 0−7%
dialkynylation products were seen on the crude NMR and could not
be isolated in a pure form.
To understand the mode of action of the present C−H
alkynylation reaction, we performed a series of competition experi-
ments (Scheme 3). The intermolecular competition reactions of
1a and 1b and 1a and 1i with 2a revealed that the amide sub-
strates with neutral or electron-withdrawing substitution showed
higher reactivity than the electron-donating group substituted
amides. In addition, treatment of D5-1b in the presence and
absence of 2a under the standard conditions showed a con-
siderable D/H exchange at the ortho positions of the amide directing
group, suggesting that the initial cycloruthenation via C−H bond
cleavage is reversible. Finally, the observed intermolecular kinetic
isotope effects (KIE) kH/kD = 1.8 for the reaction of 1b and
D5-1b with 2a and intramolecular KIE kH/kD = 3.7 for the
reaction of D1-1b with 2a suggest that the C−H cleavage step is
possibly the rate-limiting step.11
Next, we tested the scope of the C−H alkynylation under the
optimized reaction conditions, and the results are presented
in Scheme 1. The reaction proceeded well with a variety of
aromatic N-methoxyamides having both electron-donating and
electron-withdrawing groups on the aromatic rings. Thus, treat-
ment of p-OMe- and p-tBu-substituted amides gave products
3ca and 3da in 60% yield in both cases. Under the reaction
conditions, halogen-substituted amides were also compatible to
afford the expected alkynylated products, 3ea−ga, in good
yields. Amides with strong electron-withdrawing groups such as
B
DOI: 10.1021/acs.orglett.6b01281
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
affords ruthenium III intermediate. Dissociation of 2-iodobenzoate
followed by reductive elimination affords Ru(II) complex IV.
Protonation and alkyne dissociation from IV through ligand
exchange delivers the final product 3ba. An alternative mech-
anism that involves insertion of the C−C triple bond of 2a into
the Ru−C bond of intermediate I as a key step cannot be ruled
out at this moment.
Scheme 3. Mechanistic Studies
In summary, we have developed a ruthenium-catalyzed mild
C−H activation method for the alkynylation of aromatic amides.
A wide range of substituents on the amide moiety was tolerated and
gave good yields. The preliminary mechanistic studies suggested
that the initial C−H ruthenacycle formation is reversible.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.6b01281.
General experimental procedures, characterization details,
1
and H and 13C NMR spectra of new compounds (PDF)
Crystallographic data for 3oa (CIF)
Crystallographic data for 3ra (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chcheng@mx.nthu.edu.tw. Website: http://mx.nthu.
edu.tw/~chcheng/.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China (MOST-104-2633-M-007-001) for support
of this research.
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Org. Lett. XXXX, XXX, XXX−XXX