Ruthenium-catalyzed hydroarylation of anilides with alkynes: An efficient route to ortho -Alkenylated anilines

Article abstract of DOI:10.1021/ol403666s

Acetanilides reacted with symmetrical as well as unsymmetrical alkynes in the presence of [{RuCl₂(p-cymene)}₂], pivalic acid, and AgSbF₆ in iso-PrOH providing ortho-alkenylated acetanilides in a highly regio- and stereoselective manner. Later, ortho-alkenylated acetanilides were converted into ortho-alkenylated anilines in the presence of HCl.

Full text of DOI:10.1021/ol403666s

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Hydroarylation of Anilides with Alkynes:
An Efficient Route to Ortho-Alkenylated Anilines
Rajendran Manikandan and Masilamani Jeganmohan*
Department of Chemistry, Indian Institute of Science Education and Research, Pune 411021, India
S
* Supporting Information
ABSTRACT: Acetanilides reacted with symmetrical as well as
unsymmetrical alkynes in the presence of [{RuCl2(p-cymene)}2],
pivalic acid, and AgSbF6 in iso-PrOH providing ortho-alkenylated
acetanilides in a highly regio- and stereoselective manner. Later,
ortho-alkenylated acetanilides were converted into ortho-alkenylated
anilines in the presence of HCl.
he transition-metal-catalyzed hydroarylation of aromatic
electrophiles or organometallic reagents with alkynes is a
In fact, both reactions proceed entirely in a different
T
mechanistic pathway and also provide the hydroarylation
product in a reverse regiochemistry (eqs 1 and 2). Chelating
groups such as amide, carbamate, and phosphine oxide (PO)
substituted aromatics underwent hydroarylation with alkynes in
the presence of ruthenium(II) or rhodium(III) complexes as
catalysts, yielding trisubstituted alkenes in a highly regio- and
stereoselective manner.6 Recently, Miura’s group reported
ruthenium-catalyzed hydroarylation of biphenyl anilines with
alkynes.6f However, in the reaction of biphenyl anilines with
unsymmetrical alkynes, a mixture of regio- and stereoisomeric
products were observed.
convenient route for the synthesis of trisubstituted alkenes in a
highly regio- and stereoselective manner.1 Substituted alkenes
are versatile synthetic precursors which are widely used for
several organic transformations. The alkene unit is also present
in various drug molecules and materials.1 Although this type of
reaction is very effective for synthesizing alkenes, a preactivated
coupling partner such as C−X or C−M on the aromatic moiety
is required. Instead of using a preactivated partner, a similar
type of reaction is carried out utilizing C−H bond activation; it
would be even more useful in organic synthesis.2
Herein, we report a highly regio- and stereoselective
ruthenium-catalyzed hydroarylation of acetanilides with sym-
metrical and unsymmetrical alkynes. The catalytic reaction
provides ortho-alkenylated anilides in good to excellent yields.
The alkyne substituents determine the regiochemistry of the
product. Coordinating groups such as Ph or ester from the
alkynes are trans to the anilides. Later, ortho-alkenylated anilides
were converted into ortho-alkenylated anilines in the presence
of HCl. It is important to note that ortho-alkenylated anilines
are versatile synthetic precursors in a number of organic
transformations and are also efficiently used to synthesize
biologically active molecules.7 It is known that acetanilides
reacted with alkynes in the presence of rhodium or ruthenium
catalysts and an acetate base to give indole derivatives (eq 3).8
In 1995, Murai’s group reported the ruthenium-catalyzed
hydroarylation of aromatic ketones with alkynes through a C−
H bond activation.3a Subsequently, this type of hydroarylation
reaction has been extended with various heteroatom substituted
aromatics by several groups in the presence of catalysts such as
Ru, Rh, Ir, and Pd.3,4 Meanwhile, first row transition metals
such as Mn, Ni, and Co can also be used as catalysts for the
hydroarylation reaction.5 This hydroarylation reaction mecha-
nistically proceeds via an oxidative addition pathway (eq 1).
However, this reaction is not completely regio- and stereo-
selective with unsymmetrical alkynes and mostly provides a
mixture of alkene derivatives.
Interestingly, if the same reaction is carried out in the presence
of an organic acid instead of a base, a different type of ortho-
alkenylated anilide is observed (eq 3). It is interesting to note
This type of regio- and stereoselective problem can be solved
by performing the hydroarylation reaction via a chelation-
assisted concerted deprotonation−metalation pathway (eq 2).6
Received: December 18, 2013
Published: January 17, 2014
© 2014 American Chemical Society
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Letter
that organic acids or an acetate base completely changes the
reaction pattern.
Table 1. Hydroarylation of Substituted Anilides 1b−o with
a
1-Phenyl-1-propyne (2a)
Initially, the hydroarylation of 3,4-dimethoxy aniline with 1-
phenyl-1-propyne (2a) in the presence of [{RuCl2(p-
cymene)}2] (5.0 mol %), AgSbF6 (20 mol %), and pivalic
acid (5.0 equiv) in 1,4-dioxane at 100 °C for 12 h was carried
out. However, in the reaction, no expected ortho-alkenylated
aniline was observed. Next, the hydroarylation reaction was
tested with anilines having a removable directing group at the
nitrogen atom such as acetanilide 1a (NH−COMe),
sulfonamide (NH−SO2Me), and aryl urea (NHCONMe2). In
the reaction of acetanilide 1a with 2a, hydroarylation product
3aa was observed in 41% yield (Scheme 1). In other substrates,
Scheme 1. Hydroarylation of 1a with 2a
no hydroarylation products were observed. The hydroarylation
reaction of 1a and 2a is highly regio- and stereoselective, as a
less hindered C−H bond of 1a coupled with the methyl
substituted carbon of alkyne 2a. To increase the yield of
hydroarylation product 3aa, reactions of 1a with 2a in the
presence of [{RuCl2(p-cymene)}2] (5.0 mol %) and AgSbF6
(20 mol %) with various organic acids and solvents were
examined. We found that the pivalic acid (5.0 equiv) was an
effective organic acid and iso-PrOH was an effective solvent for
the reaction. In the reaction, product 3aa was observed in 89%
isolated yield (for detailed optimization studies, see the
Supporting Information).
The scope of the catalytic reaction was tested with various
substituted anilides 1b−o (Table 1). The reaction was
compatible with various functional groups such as OMe, F,
Cl, Br, I, ester, CN, and OH substituted anilides. Thus,
electron-donating groups such as OH, OMe, and Me
substituted anilides 1b−d reacted efficiently with 2a, yielding
hydroarylation products 3ba−da in 78%, 85%, and 81% yields,
respectively, in a highly regio- and stereoselective manner
(entries 1−3). It is very interesting to note that a free hydroxyl
group substituted acetanilide 1b was also effective for the
reaction. Acetanilide (1e) reacted nicely with 2a, giving product
3ea in 80% yield (entry 4). Halogen groups such as Br, Cl, and
F substituted anilides 1f−h also efficiently participated in the
reaction, providing products 3fa−ha in 79%, 76%, and 69%
yields, respectively, in a highly regio- and stereoselective
manner (entries 5−7). A less reactive electron-withdrawing
group such as CN or ester substituted anilides 1i and 1j also
reacted efficiently with 2a, giving trisubstituted alkenes 3ia and
3ja in 68% and 71% yields, respectively (entries 8 and 9). The
regiochemistry of 3ja was assigned based on the NOESY
experiment. It is also important to note that CN and ester
groups are known as directing groups for the C−H bond
activation reaction.2 The present result shows that NHCOMe is
a better directing group for the reaction compared with ester
and CN. Sterically hindered ortho-methoxy acetanilide 1k was
effectively involved in the reaction, giving product 3ka in 84%
yield (entry 10). Next, the reaction was tested with unsym-
metrical acetanilides 1l−n. A sterically less hindered C−H bond
of meta-methoxy acetanilide 1l and 2-naphthyl acetamide 1m
underwent hydroarylation with 2a, providing alkene derivatives
a
All reactions were carried out using 1b−o (100 mg), 1-phenyl-1-
propyne (2a) (1.2 equiv), [{RuCl2(p-cymene)}2] (0.05 equiv),
AgSbF6 (0.20 equiv), and pivalic acid (5.0 equiv) in iso-PrOH (2.5
mL) at 100 °C for 12 h. Isolated yield. The reaction was carried out
b
c
d
for 4 h. The reaction was carried out for 3 h.
3la and 3ma in excellent 83% and 82% yields, respectively
(entries 11 and 12). The structure of 3la was confirmed by
single crystal X-ray diffraction. In contrast, in the reaction of
3,4-(methylenedioxy)anilide (1n) with 2a, hydroarylation takes
place at a sterically hindered C−H bond of 1n, yielding product
3na in 81% yield (entry 13). The hydroarylation reaction was
tested with 4-methoxyphenyl pivalamide (1o). In the reaction,
product 3oa was observed in 20% yield (entry 14).
The scope of the catalytic reaction was further examined with
substituted alkynes 2b−k (Table 2). Thus, diphenylacetylene
(2b), 1-phenyl-1-butyne (2c), 1-phenyl-1-hexyne (2d), and 1-
phenyl-2-(trimethylsilyl) acetylene (2e) reacted very selectively
at the sterically less hindered C−H bond of 1a, providing
alkene derivatives 3ab−ae in 87%, 83%, 81%, and 61% yields,
respectively (entries 1−4). In alkynes 2c−d, the aromatic C−H
bond of 1a was selectively inserted at the alkyl substituted
carbon of alkynes. In the product 3ae, sensitive SiMe3 was
cleaved under the reaction conditions. Interestingly, ethyl 2-
butynoate (2f), methyl hex-2-ynoate (2g), and methyl oct-2-
ynoate (2h) also nicely participated in the reaction, yielding
products 3af−ah in 88%, 80%, and 78% yields, respectively
(entries 5−7). In these reactions also, the alkyl substituted
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Letter
coupling product 3af in a lesser yield of 32%, respectively. This
result clearly reveals that Ph coordinates better with Ru metal
than ester.
Table 2. Hydroarylation of 3,4-Dimethoxy Acetanilide (1a)
with Substituted Alkynes 2b−h
a
Later, ortho-alkenylated acetanilides 3ca and 3fa were
converted into ortho-alkenylated anilines 4a and 4b in 93%
and 91% yields, respectively, in the presence of a 1:1 mixture of
17% HCl and THF at 100 °C for 17 h (eq 5). The catalytic
reaction was successfully extended with a weak ester directing
group substituted aromatic moiety. Methyl piperonate (5a)
reacted with diphenylacetylene (2b) under similar reaction
conditions, yielding hydroarylation product 6ab in 71% yield in
a highly regioselective manner (eq 6).
A possible reaction mechanism for the hydroarylation
reaction is proposed in Scheme 2. AgSbF6 likely removes the
a
All reactions were carried out using 1a (100 mg), 2b−h (1.2 equiv),
[{RuCl2(p-cymene)}2] (0.05 equiv), AgSbF6 (0.20 equiv), and pivalic
acid (5.0 equiv) in iso-PrOH (2.5 mL) at 100 °C for 12 h. Isolated
yield.
b
carbon of alkynes 2f−h was regioselectively connected at the
ortho carbon of 1a. The regiochemistry of 3af was assigned
based on the NOESY experiment.
Scheme 2. Proposed Mechanism
But, an alkyne, ethyl phenyl propiolate (2i), having two
coordinating groups such as Ph and ester, gave a mixture of
hydroarylation products 3ai and 3ai′ in 81% combined yields in
a 60:40 ratio (Table 3, entry 1). Interestingly, 2-thienyl
a
Table 3. Hydroarylation of 1a with Alkynes 2i−k
b
entry
alkyne
yield
ratio
1
2
3
2i
2j
2k
81%
75%
62%
3ai:3ai′ = 1.5:1
3aj:3aj′ = 3:1
3ak only
Cl− ligand from the [{RuCl2(p-cymene)}2] complex, giving a
cationic ruthenium species 7. Coordination of the carbonyl
group of 1 to a cationic species 7 followed by ortho-metalation
provides a six-membered ruthenacycle intermediate 8. Coor-
dinative regioselective insertion of alkyne 2 into the Ru−carbon
bond of intermediate 8 gives intermediate 9. Protonation at the
Ru−C bond of intermediate 9 in the presence of RCOOH
affords hydroarylation product 3 and regenerates the active
ruthenium species 7 for the next catalytic cycle. In the reaction,
organic acid acts as a proton source. To support the role of an
organic acid, the following deuterium labeling experiment was
carried out. Treatment of 1a with 2a under similar reaction
conditions in the presence of CD3COOD instead of pivalic acid
gave product d-3aa in 40% yield with 76% of deuterium
incorporation at the alkene carbon. In the meantime, 67%
deuterium incorporation was observed at the ortho carbon of
anilide in product d-3aa. It clearly indicates that the ortho C−H
bond cleavage of anilide 1 along with intermediate 8 formation
is a reversible process.
a
All reactions were carried out using 1a (100 mg), alkyne 2i−k (1.2
equiv), [{RuCl2(p-cymene)}2] (0.05 equiv), AgSbF6 (0.20 equiv), and
pivalic acid (5.0 equiv) in iso-PrOH (2.5 mL) at 100 °C for 12 h.
b
Isolated yield (combined yield).
substituted alkyne 2j provided hydroarylation products 3aj and
3aj′ in 75% combined yields in a 3:1 ratio (entry 2). In the
major product 3aj, the 2-thienyl attached carbon of alkyne 2j
was connected with a less hindered carbon of 1a. Surprisingly,
in the reaction of alkyne 2k having Ph and CH2Ph with 1a, a
single coupling product 3ak in 62% yield was obtained (entry
3). In the reaction, 1a was connected selectively at the CH2Ph
attached carbon of alkyne 2k. To know the coordinating effect
of Ph and ester groups, the following crossover reaction was
examined (eq 4). Treatment of 1a with 2a (1.0 equiv) and 2f
In conclusion, we have described a highly regio- and
stereoselective ruthenium-catalyzed hydroarylation of acetani-
lides with alkynes. The catalytic reaction was compatible with
(1.0 equiv) under similar reaction conditions gave alkyne 2a
coupling product 3aa in a major 59% yield and alkyne 2f
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Letter
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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.K. thanks the CSIR for a fellowship.
■
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