Ru(II)-catalyzed ortho-amidation and decarboxylation of aromatic acids: A versatile route to meta-substituted N-aryl benzamides

Article abstract of DOI:10.1007/s11426-015-5364-3

Carboxylate as a promising and valuable directing group has attracted a great deal of attention. However, employing it as a traceless direction group has rarely been reported. We developed the ruthenium-catalyzed amidation of substituted benzoic acids wit

Full text of DOI:10.1007/s11426-015-5364-3

SCIENCE CHINA
Chemistry
• ARTICLES •
doi: 10.1007/s11426-015-5364-3
· SPECIAL ISSUE · CH bond activation
Ru(II)-catalyzed ortho-amidation and decarboxylation of aromatic
acids: a versatile route to meta-substituted N-aryl benzamides
Xian-Ying Shi1*, Xue-Fen Dong1, Juan Fan1, Ke-Yan Liu1, Jun-Fa Wei1 & Chao-Jun Li2*
1Key Laboratory of Applied Surface and Colloid Chemistry (Ministry of Education); Key Laboratory for Macromolecular Science of
Shaanxi Province; School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710062, China
2Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada
Received November 17, 2014; accepted December 12, 2014
Carboxylate as a promising and valuable directing group has attracted a great deal of attention. However, employing it as a
traceless direction group has rarely been reported. We developed the ruthenium-catalyzed amidation of substituted benzoic ac-
ids with isocyanates via directed C–H functionalization followed by decarboxylation to afford the corresponding meta-
substituted N-aryl benzamides, in which the carboxylate serves as a unique, removable directing group. Notably, this protocol
can provide an efficient alternative to access meta-substituted N-aryl benzamides, which are much more difficult to prepare
than ortho-substituted analogues.
amides, decarboxylation, amidation, C–H functionalization, homogeneous catalysis
substantial interest attributable to the potential shortening of
1 Introduction
synthetic steps [6]. Employing functional group-directed
C–H functionalization reactions, several methods were also
developed to construct amide motifs. For example, Chang et
al. [7] described the selective C–C amidation under thermal
rhodium catalysis. Cheng et al. [8a] and Ellman et al. [8b]
successively demonstrated the amidation of 2-arylpyridines
with isocyanates via C–H bond activation catalyzed by rho-
dium or ruthenium. However, in all of these reports, the
amide group was introduced into the ortho position of the
directing group (Scheme 1, Route (a)) and the directing
group stayed in the original place.
Transition-metal-catalyzed decarboxylative coupling re-
actions are receiving increasing attention for their use in
C–C bond formation reactions [9]. In this context, Larrosa
et al. [10] displayed carboxylic acids as traceless directing
group for a formal meta-selective direct arylation: namely,
carboxyl group-directed ortho C–H activation followed by
decarboxylation. However, the application of this concept to
the synthesis of meta-substituted compounds has not been
as closely investigated [11]. In our study on the insertion of
Amide represents an important structural motif that is pre-
sent in many natural products, polymers, pharmaceuticals,
and biological systems [1]. They are also important inter-
mediates for the preparation of various useful compounds
[2]. Amide bonds are typically formed from amines and
preactivated carboxylic acid derivatives such as acid chlo-
rides and anhydrides, or via in situ activation of carboxylic
acid with coupling reagents such as carbodiimides [3]. Alt-
hough all of these methods are very effective, they possess
considerable drawbacks in terms of the poor overall atom
economy and the use of hazardous reactive reagents, both of
which can also complicate product purification [4]. There-
fore, great efforts have been made recently to develop more
efficient processes for amide synthesis [5].
In recent years, the selective functionalization of C–H
bonds of directing group-containing arenes has attracted a
*Corresponding authors (email: shixy@snnu.edu.cn; cj.li@mcgill.ca)
© Science China Press and Springer-Verlag Berlin Heidelberg 2015
chem.scichina.com link.springer.com

2
Shi et al. Sci China Chem June (2015) Vol.58 No.6
C–H to polarized C–N double bonds, we observed unex-
pectedly that 3-methyl-N-phenylbenzamide was generated
under a ruthenium catalyst (Scheme 1, Route (b)). This re-
sult demonstrates that carboxylic acids act as a unique, re-
movable directing group. Motivated by this finding, we en-
visioned that meta-substituted N-aryl benzamides, which are
much more difficult to prepare than ortho-substituted ana-
logues, could be readily synthetized using this strategy.
Moreover, although ruthenium complexes have been con-
sidered to be versatile [12], less-expensive alternative cata-
lysts to commonly used transition metals in C–H activation
chemistry, few studies have employed them in carboxylate-
directed C–H activation and decarboxylation cross-coupling
reactions. Herein, we present a convenient synthesis of
meta-substituted N-aryl benzamides via a ruthenium-
catalyzed ortho-amidation and decarboxylation of benzoic
acids.
mmol), and KH2PO4 (13.6 mg, 0.1 mmol). After the vessel
was evacuated and purged with argon three times, 1,4-
dioxane (0.5 mL) was added to the system by syringe. The
mixture was stirred at 130 °C for 24 h. When the reaction
was complete, the resulting mixture was cooled to room
temperature and filtered through a short silica-gel pad. The
mixture was then concentrated in vacuo to give a residue,
which was purified by preparative thin layer chromatog-
raphy (TLC) to afford the corresponding product.
3 Results and discussion
In the preliminary experiments, o-toluic acid was treated
with [RuCl2(p-cymene)]2 (5 mol%), phenyl isocyanate (2.5
equiv.), and K2HPO4 (2.0 equiv.) in 1,4-dioxane (0.5 mL) at
130 °C for 24 h. To our delight, the desired product 3a was
obtained in 62% yield. In view of the importance of solvent
effect in catalytic reactions, different solvents were tested
first to optimize the reaction conditions; of these, 1,4-
dioxane appeared to be the best choice. Other solvents such
as THF, toluene, xylene, C6H5Cl, and DCE can also be used
in this reaction to furnish a lower yield of 3a (Table 1,
Entries 3–7). DMF, however, failed to give 3a (Entry 8).
No desired product was observed without K2HPO4 (Entry
1), which suggested that the choice of salt is crucial for the
success of the present catalytic reaction. Therefore, a series
of salts was examined. Replacing K2HPO4 with other alkali
metal salts such as Na2HPO4, KOAc, LiOAc, Li2CO3, and
Na2CO3 led to decrease in reaction yield (Entries 9–13).
Only trace amounts of the desired product were detected
with CsOAc, AgOAc, and Ag2CO3 (Entries 14–16). The
presence of Cu(OAc)2, Cu(OAc)2·H2O, K2CO3, and Cs2CO3
failed to produce any desired product (Entries 17–20).
2 Experimental
2.1 General information
All commercial chemicals were used as received, without
1
further purification. H NMR spectra were measured on a
300, 400, or 500 MHz spectrometer; 13C NMR spectra were
measured on a 300 or 600 MHz spectrometer (13C NMR 75
or 150 MHz), with tetramethylsilane (TMS) as the internal
standard at room temperature. Chemical shifts are given in 
relative to TMS; the coupling constants J are given in Hz.
High-resolution mass spectra (HRMS) were obtained from a
Bruker Compass-Maxis instrument (ESI, Germany).
2.2 General experimental procedure for the synthesis
Subsequently, various conditions related to the amount of
K2HPO4, phenyl isocyanate, reaction time, and other addi-
tives were examined to optimize the formation of 3a. A
slightly higher yield was obtained when 0.5 equiv. of
K2HPO4 was employed (Entry 21). Eventually, the combi-
nation of 0.5 equiv. K2HPO4 and 0.5 equiv. KH2PO4 in-
creased the product yield to 76% (Entry 22).
of N-aryl benzamides
An oven-dried reaction vessel was charged with [RuCl2(p-
cymene)]2 (Ru*, 6.1 mg, 0.01 mmol, 5 mol%), acids (0.2
mmol), isocyanates (0.5 mmol), K2HPO4 (17.4 mg, 0.1
Having determined these optimized reaction conditions,
we next sought to investigate the substrate scope with re-
spect to benzoic acid derivatives and phenyl isocyanate
(Table 2). Significant electronic effects of the substituents
on the reactivity were observed. A strong electron-
withdrawing group such as NO2, obviously inhibited the
reaction and could not give the desired product under the
optimized reaction conditions. On the contrary, benzoic
acids-bearing electron-donating substituents, in general,
afforded better yields. For example, 2-methyl, 4-methyl,
2-methoxyl, and 4-methoxyl benzoic acids generated the
desired products in moderate to good yields (3a, 3b, 3d, 3e).
This reaction is also compatible with chloro-substituted
benzoic acids, which furnished the respective products in
Scheme 1 Synthesis of N-aryl benzamides via C–H functionalization.

Shi et al. Sci China Chem June (2015) Vol.58 No.6
Table 1 Selected results for optimizing reaction conditions a) Table 2 Substrate scope for substituted benzoic acids a)
3
Entry
1
Additive (equiv.)
–
Solvent
1,4-dioxane
1,4-dioxane
THF
Yield (%) b)
0
Entry
1
Substrate
Product
Yield (%) b)
CH3
2
K2HPO4 (2.0)
K2HPO4 (2.0)
K2HPO4 (2.0)
K2HPO4 (2.0)
K2HPO4 (2.0)
K2HPO4 (2.0)
K2HPO4 (2.0)
Na2HPO4 (2.0)
KOAc (2.0)
62
COOH
3
42
70
49
37
4
Toluene
46
H
5
Xylene
54
6
C6H5Cl
55
OCH3
7
DCE
36
ND c)
H
O
8
DMF
2
3
NHPh
9
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
49
10
11
12
13
14
15
16
17
18
19
20
21
22
32
3b
LiOAc (2.0)
Li2CO3 (2.0)
Na2CO3 (2.0)
CsOAc (2.0)
AgOAc (2.0)
Ag2CO3 (2.0)
Cu(OAc)2 (2.0)
Cu(OAc)2·H2O (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
K2HPO4 (0.5)
34
22
34
trace
trace
trace
ND
ND
ND
ND
67
4
5
6
35
64
31
K2HPO4 (0.5), KH2PO4 (0.5) 1,4-dioxane
76
a) Reaction conditions: 1a (0.1 mmol), 2a (0.25 mmol), [RuCl2(p-
cymene)]2 (5 mol%), additive, solvent (0.5 mL), 130 °C for 24 h, under
argon in pressure tubes; b) determined by H NMR analysis of the crude
reaction mixture using mesitylene as internal standard; c) ND=not detected.
1
CH3
H3C
moderate yields (3c, 3f). Several disubstituted benzoic acids
could proceed smoothly and generate the corresponding
products in moderate to good yields (3g–3j). The 2,4-
dimethylbenzoic acid gave the highest yield of the desired
product (3h).
7
8
59
80
NHPh
3g
O
O
CH3
CH3
COOH
H
A variety of isocyanates were reacted with 2,4-dimethyl-
benzoic acid under the optimized reaction conditions to
further explore the substrate scope and limitations of this
transformation (Table 3). A screening of isocyanates indi-
cated that apart from phenyl isocyanate, phenyl isocyanates
with methyl, methoxyl, and chloro are also effective in the
reaction. Compared with meta-substituted phenyl isocyanate,
the ones bearing substituents at the para position were read-
ily converted into the corresponding products in higher
yields (3k vs. 3l, 3o vs. 3p). Particularly noteworthy is that
chloro on the aromatic ring of the isocyanate remained in-
tact in the product, which provides the possibility for further
useful transformations through common cross-coupling
strategies. This transformation also tolerated disubstituents;
for example, 3,5-dimethylphenyl isocyanate and 3,4-dichlo-
rophenyl isocyanate proceeded smoothly to afford products
in 62% and 49% respective yields (3n, 3q).
NHPh
H3C
H3CO
Cl
H3C
3h
OCH3
OCH3
COOH
H
9
56
68
NHPh
H3CO
3i
O
CH3
10
NHPh
3j
O
a) Reactions were carried out with acids (0.2 mmol), isocyanates (0.5
mmol), [RuCl2(p-cymene)]2 (5 mol%), 0.5 mL dioxane, K2HPO4 (0.5
equiv.), KH2PO4 (0.5 equiv.), 130 °C, 24 h; b) yield of isolated product was
reported.

4
Shi et al. Sci China Chem June (2015) Vol.58 No.6
Table 3 Substrate scope for isocyanates a)
Entry
1
Substrate
Product
Yield (%) b)
74
2
3
4
90
69
Scheme 2 Proposed catalytic cycle for the ortho-selective decarboxyla-
tive C–H amidation of aromatic acids with isocyanates.
62
75
C–H activation affords a five-membered ruthenium-cyclic
intermediate B and releases a proton at the same time. Sub-
sequently, Complex B was proposed to undergo coordina-
tion and migratory insertion with isocyanate to furnish the
key intermediate D. It is noteworthy that such additions to
C-heteroatom multiple bonds are scarce in ruthenium
(II)-catalyzed C–H activation. Protonation of D gives in-
termediate E. Then, decarboxylation of E followed by pro-
tonation affords the final product and regenerates the active
Ru(II) species.
NCO
5
6
Cl
92
49
4 Conclusions
NCO
We have succeeded in developing a ruthenium-catalyzed
regiospecific ortho amidation of aromatic acid with con-
comitant decarboxylation. This protocol, which provides a
convenient access to the synthesis of meta-substituted N-aryl
benzamides derivatives, allows to use a less-expensive pre-
cious metal Ru(II) as catalyst and readily available acids
and isocyanates as starting materials. In these reactions, the
carboxyl functions effectively serve as a unique, removable
directing group. More important is that this protocol can
provide an efficient alternative to access meta-substituted
N-aryl benzamides, which are much more difficult to pre-
pare than ortho-substituted analogues.
7
Cl
Cl
a) Reactions were carried out with acids (0.2 mmol), isocyanates (0.5
mmol), [RuCl2(p-cymene)]2 (5 mol%), 0.5 mL dioxane, K2HPO4 (0.5
equiv.), KH2PO4 (0.5 equiv.), 130 °C, 24 h; b) yield of isolated product was
reported.
Based on the known chemistry of Ru-catalyzed directing-
group-assisted C–H bond activation reaction and metal-
mediated decarboxylation reactions [13,14], a possible
mechanism to account for the present catalytic reaction was
proposed (Scheme 2). The catalytic cycle is likely initiated
by the dissociation of the dimer precatalyst [RuCl2(p-
cymene)]2 into the coordinatively unsaturated monomer.
With the help of K2HPO4, the coordination of a carboxylic
oxygen atom to the ruthenium center and subsequent ortho
Supporting information
The supporting information is available online at chem.scichina.com and
link.springer.com/journal/11426. The supporting materials are published as
submitted, without typesetting or editing. The responsibility for scientific
accuracy and content remains entirely with the authors.

Shi et al. Sci China Chem June (2015) Vol.58 No.6
5
This work was supported by the National Natural Science Foundation of
China (20906059, 21272145), the Shaanxi Innovative Team of Key Science
and Technology (2013KCT-17), the Fundamental Research Funds for the
Central Universities (GK201503030, GK261001095), the 111 Project, and
Canada Research Chair (to CJL) for providing financial support for this
research.
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