Ruthenium-catalyzed oxidative ortho-benzoxylation of acetanilides with aromatic acids

Article abstract of DOI:10.1039/c3cc45350b

Substituted acetanilides reacted with aromatic acids in the presence of [{RuCl₂(p-cymene)}₂], AgSbF₆ and (NH ₄)₂S₂O₈ in ClCH₂CH ₂Cl at 100 °C for 24 h yielding ortho-benzoxylated acetanilides in good to excellent yields in a highly regioselective manner via C-H bond activation. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45350b

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Ruthenium-catalyzed oxidative ortho-benzoxylation of acetanilides with
aromatic acids
Kishor Padala and Masilamani Jeganmohan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Ruthenium-catalyzed ortho arylation, alkenylation, hydroxylation
50 and amination of aromatics have been reported in the literature.7-8
However, there is no report on ortho-benzoxylation of aromatics
in the presence of ruthenium catalyst. Herein, we report for the
first time an unprecedented oxidative ortho-benzoxylation of
substituted acetanilides with benzoic acids in the presence of
55 [{RuCl2(p-cymene)}2], AgSbF6 and (NH4)2S2O8 in a highly
regioselective manner. The catalytic reaction was also compatible
with acetic acid.
Substituted acetanilides reacted with aromatic acids in the
presence of [{RuCl2(p-cymene)}2], AgSbF6 and (NH4)2S2O8 in
ClCH2CH2Cl at 100 C for 24 h yielding ortho-benzoxylated
acetanilides in good to excellent yields in
a highly
10 regioselective manner via C-H bond activation.
The transition-metal-catalyzed chelation-assisted transformation
of an unreactive ortho C-H bond of aromatics to C-C, C-X, C-N
and C-O bonds via C-H bond activation is one of the efficient and
highly atom-economical methods in organic synthesis.1 Among
15 them, C-O bond construction is quite difficult and less known in
the literature. This is most probably due to high electronegativity
of the element and also due to the metal-ligand bond strength.2
Generally, substituted alcohols and carboxylic acids are widely
used as a coupling partner (oxygen source) for the reaction.3-5 In
20 fact, coupling of carboxylic acids with aromatics is more
challenging due to rapid complex formation of the carboxylic
acids with the metals. To avoid the complex formation,
carboxylate sources such as PhI(OR)2, anhydride, acid halide,
etc., have been used instead of the corresponding carboxylic
The reaction of acetanilide (1a) with 4-chlorobenzoic acid (2a)
60 in the presence of [{RuCl2(p-cymene)}2] (3 mol %), AgSbF6 (15
mol %) and (NH4)2S2O8 (2.0 equiv) in 1,2-dichloroethane (DCE)
at 100 C for 24 h afforded ortho-benzoxylated acetanilide 3a in
72% isolated yield (eq. 1). Initially, the reaction of 1a and 2a was
tested with various oxidants (2.0 mmol) in the presence of
65 [{RuCl2(p-cymene)}2] and AgSbF6 in DCE at 100 C for 24 h.
Various oxidants such as Ag2CO3, AgOAc, Ag2O, Cu(OAc)2,
CsOAc, KOAc, NaOAc, K2S2O8, PhI(OAc)2, Na2S2O8 and oxone
were examined. Among them, only silver salts such Ag2CO3,
AgOAc and Ag2O were active for the reaction, giving 3a in 78%,
70 51% and 49% NMR yields, respectively. The yield of product 3a
was determined by the 1H NMR integration method using
mesitylene as an internal standard. Then, the catalytic reaction
was tested with (NH4)2S2O8 oxidant to avoid the silver salt
oxidant. Gratifyingly, product 3a was observed in 80% NMR
75 yield. Next, the catalytic reaction was tested with various solvents
such as DCE, chlorobenzene, THF, DMSO, DMF, DME, 1,2-
dioxane, toluene, benzene, MeOH, tert-BuOH and AcOH.
Among them, DCE solvent was effective for the reaction,
providing 3a in 80% NMR yield. Chlorobenzene was partially
80 effective for the reaction, affording 3a in moderate 49% yield.
Remaining solvents were totally inactive for the reaction. The
reaction was tried with a catalytic amount of AgBF4, AgOTf and
KPF6 instead of AgSbF6 (15 mol %). AgOTf was slightly
effective for the reaction, yielding 3a in 42% yield. Remaining
85 additives were not effective for the reaction. The control
experiments clearly revealed that a catalytic amount of AgSbF6
and ruthenium complex were crucial for the reaction.
25 acid.4-5 Metal-catalyzed acetoxylation of heteroatom-substituted
h-i
such as 2-pyridyl,4a-c,
oxime,4d carbonyl,4e amide4e and
acetamide (NH-COMe)4g aromatics with various acetate sources
have been well documented in the literature. Palladium- or
ruthenium-catalyzed hydroxylation of heteroatom substituted
30 such as acid,5a ketone,5b ester5c and amide5d-e aromatics in the
presence of a TFA/TFAA combination has been reported recently
in the literature. However, most of these transformations are
limited to acetoxylation and hydroxylation of aromatics and there
is no such report on benzoxylation of aromatics. In 2005, Sanford
35 et al. reported benzoxylation of 2-phenylpyridines with benzoate
iodonium salts in the presence of palladium catalyst.6a In 2009,
Cheng’s group demonstrated benzoxylation of 2-phenylpyridines
with benzoic acids in the presence of rhodium catalyst.6b
Subsequently, benzoxylation of 2-pheny pyridines with benzoyl
40 chlorides and benzaldehydes has been reported in the presence of
copper catalyst.6c-d Very recently, Shi’s group reported ortho-
benzoxylation of aromatic ketoximes with benzoic acids in the
presence of palladium catalyst.6e Until, only benzoxylation of 2-
phenylpyridines and aromatic ketoximes with benzoic acids is
45 known in the literature.
Recently, a less expensive ruthenium complex has gained
tremendous attention in heteroatom directed C-H bond activation
of aromatics due to its remarkable reactivity and selectivity.
The scope of ortho-benzoxylation of various substituted
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acetanilides 1 with 4-chlorobenzoic acid (2a) under the optimized
Methoxy acetanilide (1k) underwent ortho-benzoxylation with 2a
reaction conditions was examined (Table 1). The reaction of 4-
methoxy 1b and 4-n-butoxy 1c acetanilides with 2a provided
selectively at a less hindered C-H bond under similar reaction
conditions, affording 3k in 65% yield.DOLIi:k1e0w.1i0sVe3i,9ew/C3A3-rbCtirCcol4em5O3on5li0nBe
coupling products 3b and 3c in 72% and 75% yields, respectively 35 acetanilide (1l) reacted with 2a at a less hindered C-H bond,
5
(entries 1 and 2). Similarly, other electron-donating group
substituted acetanilides such as 4-methyl 1d and 4-n-butyl 1e
acetanilides yielded the corresponding coupling products 3d and
3e in 66% and 72% yields, respectively (entries 3 and 4). This
providing 3l in 62% yield. Similarly, 3,4-dimethoxy acetanilide
(1m) and 3,4-(methylenedioxy) acetanilide (1n) also underwent
coupling with 2a at a less hindered C-H bond, giving products
3m and 3n in 81% and 72% yields, respectively. However, in the
result clearly revealed that more electron releasing substituents 40 reaction of 1n with 2a, the other regioisomer 3n’ was also
10 such as O-nBu and n-Bu gave slightly better yields than a less
electron releasing substituents such as OMe and Me. Halogen
group substituted acetanilides were also compatible for the
reaction. Thus, the reaction of 4-bromo 1f, 4-chloro 1g and 4-
fluoro 1h acetanilides with 2a gave the corresponding ortho-
15 benzoxylated acetanilides 3f-h in 74%, 73% and 71% yields,
respectively (entries 5-7). The catalytic reaction also worked
effectively with electron-withdrawing group substituted
acetanilide 1i. The reaction of 4-methyl ester acetanilide (1i) with
2a yielded product 3i in 69% yield (entry 8). It is important to
20 note that an ester is also a good directing group for the C-H bond
activation reaction. However, in the reaction, the C-H bond
activation takes place only ortho to the NHCOMe of the aromatic
moiety. ortho-Methoxy acetanilide 1j was also efficiently
involved in the reaction with 2a, providing coupling product 3j in
25 67% yield (entry 9).
observed in addition to 3n. For the reaction of 1m and 1n with
2a, Ag2CO3 (1.0 mmol) oxidant was used instead of (NH4)2S2O8
in CH2Cl2 solvent. Oxidant (NH4)2S2O8 was not effective for
these reactions.
Me
Me
H
Cl
H
N
O
O
N
O
exclusively
[{RuCl2(p-cymene)}2] (3 mol %)
AgSbF6 (15 mol %)
COOH
O
(NH4
DCE, 100 °C, 24 h
)2S2O8 (2.0 mmol)
Cl
MeO
Me
MeO
3k, 65%
2a
1k
Me
O
H
Cl
H
N
O
O
N
exclusively
same conditions
2a
O
3l, 62%
Me
Br
Br
1l
Me
H
Cl
H
N
O
O
N
O
exclusively
same conditions
Ag2CO3, DCM
2a
O
MeO
MeO
Me
OMe
Cl
3m, 81%
OMe
1m
Me
Me
H
H
N
H
N
O
O
O
O
N
O
Table 1 The coupling of 1b-j with 4-chlorobenzoic acid (2a)a
O
same conditions
Ag2CO3
2a
O
Yield (%)b
O
O
O
O
Entry Acetanilides 1b-j
Product 3b-j
O
O
1n
Cl
3n
3n'
72% (9:1)
45
Scheme 1 Regioselective studies
1
1b: R1 = OMe
1c: R1 = O-nBu
1d: R1 = Me
3b: R1 = OMe
72
75
66
72
2
3
4
3c: R1 = O-nBu
3d: R1 = Me
1e: R1 = n-Bu
3e: R1 = n-Bu
5
6
7
1f: R1 = Br
1g: R1 = Cl
1h: R1 = F
3f: R1 = Br
3g: R1 = Cl
3h: R1 = F
74
73
71
8
9
69
67
Me
H
Cl
N
O
Scheme 2 Scope of the substituted benzoic acids 2
MeO
O
O
This ortho-benzoxylation reaction was successfully extended
3j
50 with various aromatic acids 2 (Scheme 2). Benzoic acid (2b)
reacted with 1b or 1m under similar reaction conditions to yield
the corresponding coupling products 3o and 3p in 72% and 78%
yields, respectively. In the reaction of 1m with 2b, Ag2CO3
oxidant was used. 4-Bromobenzoic acid (2c) reacted with 1a,
a All reactions were carried out using 1b-j (1.20 mmol), 2a (1.0 mmol),
[{RuCl2(p-cymene)}2] (3 mol %), AgSbF6 (15 mol %) and (NH4)2S2O8
(2.0 mmol) in 1,2-dichloroethane at 100 C for 24 h. bIsolated yield.
30
Next, the regioselectivity of unsymmetrical acetanilides 1k-n
with 4-chlorobenzoic acid (2a) was studied (Scheme 1). 3-
2
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giving coupling product 3q in 68% yield. Electron deficient 4-
(SR/S1/OC-26/2011), India for the support of this research. K. P.
fluorobenzoic acid (2d) and electron rich 4-methylbenzoic acid 50 thanks the Council of Scientific and Industrial Research (CSIR)
View Article Online
DOI: 10.1039/C3CC45350B
(2e) also efficiently participated in the reaction with 1a or 1b,
providing coupling products 3r-t in 56%, 46% and 51% yields,
respectively. Next, the catalytic reaction was tested with meta
substituted benzoic acid. The reaction of meta-chloro benzoic
acid 2f with 1b gave coupling product 3u in 58% yield. 2-
Naphthoic acid (2g) also nicely participated in the reaction,
yielding product 3v in 42% yield. In fact, the catalytic reaction
for a fellowship.
5
Notes and references
a Department of Chemistry, Indian Institute of Science Education and
Research, Pune 411021, India; E-mail: mjeganmohan@iiserpune.ac.in
55 † Electronic Supplementary Information (ESI) available: Detailed
experimental
procedures
and
spectroscopic
data.
See
DOI: 10.1039/b000000x/
10 was also tested with 4-cyano, 4-nitro, 4-acetyl and 4-
methoxybenzoic acids. However, in these reactions, no expected
coupling products were observed. These results clearly showed
that the catalytic reaction is highly sensitive to the type of the
substituent present on the aromatic ring of the benzoic acids.
15 Moderate electron releasing as well as electron withdrawing
substituents such as Me, H, Br, Cl and F on the aromatic acids
nicely participated in the reaction. But, strong electron donating
as well as electron withdrawing substituents such as OMe, NO2,
CN and COMe on the aromatic acids were not suitable substrates
20 for the reaction.
1
Selected reviews: (a) Selected reviews: V. Ritleng, C. Sirlin and M.
Pfeffer, Chem. Rev. 2002, 102, 1731; (b) D. A. Colby, R. G.
Bergman and J. A. Ellman, Chem. Rev. 2010, 110, 624. (c) T. W.
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Pan, J. Cheng, Synlett 2012, 23, 357; (e) H. M. L. Davies, J. D. Bois
and J.-Q. Yu, Chem. Soc. Rev. 2011, 40, 1855; (f) G. Song, F. Wang
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Dixneuf, Chem. Soc. Rev. 2013, 42, 5744.
60
65
2
3
W. Li and P. Sun, J. Org. Chem. 2012, 77, 8362.
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Malik and M. S. Sanford, Org. Lett. 2006, 8, 1141; (b) G. W. Wang
and T. T. Yuan, J. Org. Chem. 2010, 75, 476.
70 4 Selected acetoxylations: (a) S. R. Neufeldt and M. S. Sanford, Acc.
Chem. Res. 2012, 45, 936; (b) A. R. Dick, K. L. Hull and M. S.
Sanford, J. Am. Chem. Soc. 2004, 126, 2300; (c) B. V. S. L. Reddy,
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A. Kubato and M. S. Sanford, Chem. Sci. 2012, 3, 3192; (e) K. M.
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80
85
90
Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res. 2012, 45,
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Chem. Soc. 2006, 128, 6790; (g) G.-W. Wang, T.-T. Yuan and X.-L.
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Chen, J. Org. Chem. 2009, 74, 7203; (i) W. Wang, F. Luo, S. Zhang
and J. Cheng, J. Org. Chem. 2010, 75, 2415.
Selected hydroxylations: (a) Y.-H. Zhang and J.-Q. Yu, J. Am. Chem.
Soc. 2009, 131, 14654; (b) G. Shan, X. Yang, L. Ma and Y. Rao,
Angew. Chem., Int. Ed. 2012, 51, 13070; (c) Y. Yang, Y. Lin and Y.
Rao, Org. Lett. 2012, 14, 2874; (d) V. S. Thirunavukkarasu, J.
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5
6
The catalytic reaction was also compatible with acetic acid
(2h) (eq. 2). Treatment of acetanilide (1a) with acetic acid (2h)
under the optimized reaction conditions gave ortho-acetoxylation
25 product 3w in 56% yield. Similarly, 4-methoxy acetanilide 1b
afforded ortho-acetoxylation product 3x in 62% yield.
The catalytic reaction likely proceeds via removal of chloride
ligand by Ag+ salt from [{RuCl2(p-cymene)}2] complex followed
30 by reaction with aromatic carboxylic acid 2, giving cationic
ruthenium carboxylate complex 4 (eq. 3). Coordination of the
carbonyl oxygen of acetanilide 1 to the ruthenium cationic
species 4 followed by ortho-metalation provides a six-membered
ruthenacycle 5 and RCOOH.9a Coupling of carboxylic acid 2 into
95 7 Ruthenium reviews: (a) P. B. Arockiam, C. Bruneau and P. H.
Dixneuf, Chem. Rev. 2012, 112, 5879; (b) L. Ackermann, Acc. Chem.
Res. 2013, DOI: 10.1021/ar3002798. Seleceted papers: (c) P. B.
Arockiam, C. Fischmeister, C. Bruneau and P. H. Dixneuf, Angew.
Chem. Int. Ed., 2010, 49, 6629; (d) P. B. Arockiam, C. Fischmeister,
100
C. Bruneau and P. H. Dixneuf, Green Chem. 2011, 13, 3075; (e) B.
Sundararaju, M. Achard, G. V. M. Sharma and C. Bruneau, J. Am.
Chem. Soc., 2011, 133, 10340; (f) Y. Hashimoto, K. Hirano, T.
Satoh, F. Kakiuchi and M. Miura, Org. Lett, 2012, 14, 2058; (g) L.
Ackermann, A. V. Lygin and N. Hofmann, Angew. Chem., Int. Ed.,
2011, 50, 6379; (h) K. Parthasarathy, N. Senthilkumar, J. Jayakumar
and C.-H. Cheng, Org. Lett. 2012, 14, 3478; (i). M. Ramu Yadav, R.
K. Rit and A. K. Sahoo, Org. Lett. 2013, 15, 1638.
(a) CG. Ravi Kiran and M. Jeganmohan, Chem. Commun., 2012, 48,
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35 the ruthenacycle
5 affords an intermediate 6. Reductive
elimination of intermediate 6 gives the final product 3 and a
Ru(0) species.9b Later, (NH4)2S2O8 oxidizes Ru(0) to an active
Ru(II) carboxylate species 4 in the presence of carboxylic acid for
the next catalytic cycle.
105
110
115
40
In conclusion, we have discussed a ruthenium-catalyzed
benzoxylation of acetanilides with benzoic acids to provide
ortho-benzoxylated acetanilides in good to moderate yields. The
catalytic reaction was also compatible with acetic acid. Further
extension of the C-H bond activation of other chelating group
8
9
45 substituted aromatics and functionalization with other hetero
nucleophiles (R-COOH, R-OH and R2NH) and detailed
mechanistic investigations are in progress.
(a) E. F. Flegeau, C. Bruneau, P. H. Dixneuf and A. Jutand, J. Am.
Chem. Soc., 2011, 133, 10161; (b) J. Racowski, A. R. Dick and M. S.
Sanford, J. Am. Chem. Soc. 2009, 131, 10974.
We thank the Department of Science and Technology (DST)
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