Ru-Catalyzed C(sp2)?H Bond Arylation of Benzamides Bearing a Novel 4-Aminoantipyrine as a Directing Group

Article abstract of DOI:10.1002/ejoc.202100513

A novel design-based removable N,O-bidentate directing group based on cheap and commercially available 4-aminoantipyrine (AAP) is reported. Aromatic AP amides bearing 4-aminoantipyrine underwent efficient Ru-catalyzed C(sp²)?H arylation using [RuCl₂(PPh₃)₃] as a catalyst and aryl bromides as electrophiles. The novel bidentate directing group enabled the C?H functionalization reaction with good scope, good functional group tolerance and in decent yields.

Full text of DOI:10.1002/ejoc.202100513

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Ru-Catalyzed C(sp2)-H bond arylation of benzamides bearing
novel design-based 4-aminoantipyrine as a directing group
Authors: Hamad H Al Mamari, Diana Al Kiumi, Tamadhir Al Rashdi,
Huda Al Quraini, Malak Al Rashdi, and Sumayya Al Sheraiqi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100513
Link to VoR: https://doi.org/10.1002/ejoc.202100513
01/2020

10.1002/ejoc.202100513
European Journal of Organic Chemistry
COMMUNICATION
Ru-Catalyzed C(sp2)-H bond arylation of benzamides bearing
novel design-based 4-aminoantipyrine as a directing group
Hamad H. Al Mamari*, Diana Al Kiumi,Tamadhir Al Rashdi, Huda Al Quraini, Malak Al Rashdi,
Sumayya Al Sheraiqi, Mohammed Al Lamki, Ahmed Al Sheidi, Asma Al Zadjali
Dedication ((optional))
Dr. Hamad H. Al Mamari, Ms. Diana Al Kiumi, Ms. Tamadhir Al Rashdi, Ms. Huda Al Quraini, Ms. Malak Al Rashdi, Ms. Sumayya Al Sheraiqi, Mr Mohammed Al
Malki, Mr Ahmed Al Sheidi, Ms. Asma Al Zadjali
Department of Chemistry, College of Science
Sultan Qaboos University
PO Box 36, Al Khoudh 123, Muscat, Sultanate of Oman
E-mail: halmamari@squ.edu.om
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))



R
R


R
R
Abstract: A novel design-based removable N,O-bidentate directing
group based on cheap and commercially available 4-aminoantipyrine
(AAP) is reported herein. Aromatic AP amides bearing 4-
aminoantipyrine underwent efficient Ru-catalyzed C(sp2)-H arylation
using [RuCl2(PPh3)3] as a catalyst and aryl bromides as electrophiles.
The novel bidentate directing group enabled the C-H functionalization
reaction with good scope, good functional group tolerance and in
decent yields.
R
R


L
L
L
i.
cyclometalation
M
C-H bond

M
H

3
FG
functionalization
1
2
L=N, O, S ...etc
monodentate directing group
five-membered chelate
FG: Functional Group
ii.
two-carbon
distance





R
R



R
R
R
L1
L1
M
cyclometalation
C-H bond
functionalization
L1
L2
L2
L2
H

R
FG
M
4
5
6
L1=N, O, S ...etc
L2=N, O, S ...etc
bidentate directing group
bis-five membered chelate
FG: Functional Group
Scheme 1. Monodentate and bidentate directing groups.
Functionalization of C-H bonds has emerged as a powerful
strategy for formation of chemical bonds. [1] The chemical science
allows transformations of otherwise inert nonreactive C-H bonds
into functional reactive bonds. Functionalization of C-H bonds
could result in rapid access of functionalized molecules from
simple nonreactive readily available starting materials. In turn,
complex target molecules could be achieved in less steps and
shorter reaction times. Thus, C-H bond functionalization is a
manifestation of atom and step economies and is a demonstration
of environmentally benign green approach. Due to the ubiquitous
nature of C-H in organic molecules, functionalization of a specific
Similarly, the two Lewis basic atoms in bidentate directing groups
should be two-carbons away from each other to allow formation
of a second five-membered chelate. Bis-five-membered chelates
are thermodynamically more stable and rigid compared to mono-
chelates. Consequently, bidentate directing groups should be
able to deliver the C-H functionalization product in a better regio-
control (Scheme 1, ii).
Directing groups have allowed a wide range of C-H bond
functionalization reactions catalyzed by various transition metals
typified by second row-transition metals such as Pd, [4] Rh [5] and
Ru. [6] The strategy has extended to the more earth abundant, first
row-transition metals [7] such as Ni, [8] Mn, [9] Fe [10] and Co. [11]
8-Aminoquinoline (7, Figure 1), is now well-established as a
robust N,N-bidentate directing group in directed metal-catalyzed
C-H bond functionalization of its amides (8, Figure 1). [12] Intrigued
by the strategic design of bidentate directing groups, Ackermann
et. al. have recently disclosed a novel-triazole-based (9, Figure 1)
N,N-directing group (triazolyldimethylmethyl, TAM) (10, Figure 1)
that has enabled different C-H bond functionalization reactions
catalyzed by various transition metals. [13] Despite great advances
in the field of directed metal-catalyzed C-H bond functionalization,
the discovery of new efficient approaches and protocols for
controlling the issue of site-selectivity is always sought. As a one
approach, the search for and exploration of novel and efficient
directing groups is a constant target.
C-H selectively has been
a
major issue. Accordingly,
regioselectivity and site-selectivity is a pressing challenge. In one
approach, such issues have been addressed by using
monodentate and bidentate directing groups. Directing groups
contain one Lewis basic atom (monodentate directing group) or
two Lewis basic atoms (bidentate directing groups) appropriately
distanced from the C-H bond to be functionalized. [2] The C(γ)-H
bond, with respect to the Lewis basic atom, gets cleaved, via
chelation-assistance, in C-H functionalization. This carbon
distance is driven by the thermodynamic stability of five-
membered chelates (Scheme 1, i). [3]
TAM
Previous work
O
R1 R2 R3
H2N
Me Me
H
O
R
R



R
R


NH
N
R4
Bn
N
N

N
N
N
H
N
N
N
H
NH2
H
two-carbon
distance
7
8
9
10
8-aminoquinoline
(1.50 Euros/1 mmol
(Aldrich))
modular triazole-based
N,N-directing group
amides containing
8-aminoquinoline
Triazolyldimethylmethyl
(TAM) directing gorup
Figure 1. Modular triazole-based directing groups.
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100513
European Journal of Organic Chemistry
COMMUNICATION
4-Aminoantipyrine (AAP) (11, Figure 2) is known to exhibit
biological activity. It has analgesic, anti-inflammatory and
antipyretic properties. Studies have shown that derivatives (such
as 11DA, 11DB and 11DC (Figure 2)) of 4-aminoantipyrine
possess biological activity as well. [14]
Na2CO3 (3 equiv.) as a base, in toluene at 150 °C for 48 h. To our
delight, the desired C-H arylation product (15a) was obtained in
65% yield. Inspired by this gratifying result, optimization of
reaction conditions was performed (Table 1). Thus keeping all
conditions as the first successful attempt fixed while reducing the
time, resulted in reduction of the yield to 45% (Entry 2).
R
Me
NMe
Me
N
NPh
Me
NMe
NPh
NMe
NPh
OH
NMe
NPh
Table 1. Optimization of reaction conditions
N
N
Me
N
Me
N
NMe
NPh
OH
NMe
NPh
H2N
N
Br
Me
O
H
Me
O
O
O
O
OMe
N
11DB
OH
11
4-aminoantipyrine
(analgesic, antiinflammatory,
antipyretic)
11DA
11DC
N
N
H
[RuCl2(PPh3)3]
H
+
O
O
H
NO2
13a
14a
15a
base (3 equiv.), solvent
T, time
Me
Me
0.5 mmol
1.3 equiv.
Figure 2. 4-Aminoantipyrine and derivatives.
Entry
Catalyst Amount
Base (3 equiv)
Solvent
toluene
Temperature
Time
Yield
65%
45%
98%
-
54%
53%
41%
36%
23%
28%
33%
Structurally, it was envisioned that amides of 4-aminoantipyrine
could serve as bidentate directing groups. It was envisaged that
the two-distance between the nitrogen on the amino group and
the carbonyl oxygen could enable amides bearing 4-
aminoantipyrine (12 & 13, Figure 3), to function as a N,O-
bidentate directing group (Figure 3).
1
2
3
4
5
4
5
6
7
8
9
20 mol %
20 mol %
10 mol %
no catalyst
10 mol %*
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
K2CO3
140 o
140 o
140 o
C
C
C
C
C
48 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24h
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
140 o
140 o
120 o
100 o
140 o
C
140 o
140 o
C
C
C
AP
AP
140 o
Present work
Me
Me
Na2CO3
Na2CO3
C
C
Novel design-based
4-aminoantipyrine
(0.37 Euros/1 mmol
(Aldrich))
NMe
NPh
Me
NMe
NPh
O
O
NMe
NPh
H2O
24 h


R
R


N
H
N
H
H2N
R
Reaction conditions: benzamide (13 a) (0.5 mmol), aryl bromide (14) (1.3 equiv.), catalyst
(10 mol %), base (3 equiv.), solvent (3 mL). *: [(RuCl2(p-cymene)]2 with 40 mol % PPh3 were
used instead of [RuCl2(PPh3)3]

O
O
O

H
H
two-carbon
distance
AAP, 11
12
13
sp2 or sp3
amides containing 4-aminoantipyrine
Figure 3. The design-based 4-aminoantiprine and its amides
Reducing the amount of the catalyst to 10 mol % resulted, after
24 h, in remarkable yield of 98% of the C-H arylation product
(Entry 3). To ascertain the need of the catalyst for the C-H
arylation reaction, the reaction was performed in the absence of
a catalyst. The reaction resulted in no C-H arylation product with
recovery of the starting benzamide and aryl halide (Entry 4). It was
concluded that a catalyst is essential for the reaction. In addition,
and for comparative purposes, the reaction was carried out using
[RuCl2(p-cymene)]2 (10 mol %) as a precatalyst, and PPh3 (40
mol %) as a cocatalyst while keeping other conditions unchanged
(Entry 5). The reaction resulted in 54% yield of the arylation
product (Entry 5). This reaction proved that [RuCl2(PPh3)2] is the
better catalyst. Lowering the reaction temperature to 120 °C and
100 °C reduced the yield significantly (Entries 4 & 5). Changing
the base to NaHCO3 or K2CO3 did not give better results (Entries
6 & 7) than Na2CO3. Other solvents were also tested. Thus DMF
and water resulted in much lower yield of the C-H arylation
product (Entries 8 & 9). As a result, the optimum conditions were
found to be in Entry 3 (Table 1).
Hence, it was hypothesized, that upon treatment with a suitable
metal, amides of 4-aminoantipyrine (12a) could lead to a bis-five-
membered chelate (12abc) Scheme 2). Accordingly, the C-H
bond functionalization was envisaged to take place, after C-H
bond cleavage, at C(γ)-H bond with respect to the amino group N,
giving rise to functionalized product (12af) (Scheme 2).
AP
Me
Me
Me
NMe
NPh
NMe
NPh
NMe
NPh
O
O
O


R
R
R
R
R
R


N
H
[M]
N
H
FG
N
C-H


O
O
O
M
H
functionalization
12a
12abc
12af
bis-five-membered
chelate
Scheme 2. Potential use of 4-aminoantipyrine amides as bidentate directing
groups in C-H bond functionalization.
Inspired by structural features of 4-aminoantipyrine and in
[15]
continuation of our research program
on development and
pursuit of novel directing groups capable of promoting C-H bond
functionalization, we wish to report herein a novel design-based
bidentate directing group based on the cheap commercially
available 4-aminoantipyrine (AAP). Antipyrinyl (AP) benzamides
underwent Ru-catalyzed C(sp2)-H bond arylation with aryl
bromides.
In a control experiment, and in order to determine whether or not
the C-H arylation takes place on the phenyl group of the 4-
aminoantipyrine (11) moiety rather than the arene part, 4-
aminoantipyrine (11), was reacted with 4-bromotoluene (14)
under the optimized reaction reactions (Scheme 3). The test
reaction resulted in recovery of the starting materials. In addition,
N-acetylated 11 (N-antipyrinylacetamide) (11Ac, Scheme 3), was
subjected to the optimized reaction conditions. The acetylated 4-
aminoantipyrine (11Ac) did not react either. The result was
recovery of the starting amide and 4-bromotoluene. As a result,
it was established that the Ru-catalyzed C-H arylation of AP
benzamides, does, in fact, take place on the arene part of 4-
aminoantipyrine amides rather than on the amine itself.
At the outset of the work benzamides containing 4-
aminoantipyrine were synthesized. Thus aromatic benzamides
were prepared using standard protocols, from the corresponding
acid chloride and 4-aminoantipyrene (please refer to the SI). In
order to test the viability of 4-aminoantipyrine in transition metal-
catalyzed C-H bond functionalization, [RuCl2(PPh3)3] was chosen
as a catalyst. This is based on the relatively lower cost of Ru than
Pd or Rh. Toward that end, 2-methylbenzamides containing 4-
aminoantipyrine was chosen as a representative arene substrate
and [RuCl2(PPh3)3] as a Ru catalyst, based on its remarkable
efficacy as we reported recently. In addition, [RuCl2(PPh3)3] is a
cheaper catalyst than [RuCl2(p-cymene)]2 precatalyst, which
would also require a cocatalyst such as the typical PPh3 to be
added with it. Investigations of C-H functionalization viability
mediated by 4-aminoantipyrine began with reacting the
representative substrate, 2-methylbenzamides containing 4-
aminoantipyrine with 4-bromotoluene (14) as an electrophile in
the presence of [RuCl2(PPh3)3] (20 mol %) as a Ru catalyst,
Br
Me
NMe
[RuCl2(PPh3)3] (10 mol %)
NPh
recovery of starting materials
+
H2N
Na2CO3 (3 equiv.), toluene
140 oC, 24 h.
O
Me
14a
1.3 equiv.
11
0.5 mmol
Br
Me
NMe
NPh
[RuCl2(PPh3)3] (10 mol %)
+
recovery of starting materials
AcHN
Na2CO3 (3 equiv.), toluene
140 oC, 24 h.
O
Me
14a
11Ac
0.5 mmol
1.3 equiv.
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100513
European Journal of Organic Chemistry
COMMUNICATION
Scheme 3. Reaction of 4-aminoantipyrine with 4-bromotoluene under optimized
reaction conditions.
The substrate scope results suggest that differently substituted
and
electronically
different
benzamides
bearing
4-
aminoantipyrine as a directing group successfully underwent Ru-
catalyzed C-H arylation, in decent yields and with good functional
group tolerance.
Under the optimum reaction conditions, the new AAP directing
group was compared with the known and commercially available
directing groups typified by benzamides of 8-aminoquinoline
(15aa) and 2-picolylamine (15aaa) (Figure 4). Toward that end,
In addition to the substrate scope above, an electrophilic aryl
bromide scope was also explored (Scheme 5). As indicated in the
optimization table (Table 1), 4-Bromotoluene was established to
be a model aryl bromide electrophile giving rise to the desired
arylated product (15a) in 98% yield. When AP benzamide 13a
was reacted with bromobenzene as the aryl bromide under the
optimized reaction conditions, the arylation product 16a was
obtained in 90% yield (Scheme 5). 4-Bromoanisole, as an
example of an electro-rich aryl bromide gave the desired arylation
product (16b) in 80% yield. Another electron-rich aryl bromide, 4-
bromo-(N,N-dimethylamino)aniline, worked successfully to give
the desired product (16c) in 73% yield. An electron-poor
electrophile, ethyl 4-bromobenzoate, gave the arylation product
(16d) in 96% yield. Reaction of the AP benzamide 13a with
another electron-poor electrophile, 4-bromobenzotrifluoride, gave
the desired arylation product (16e) in 82% yield (Scheme 5).
the
corresponding
2-methylbenzamides
bearing
8-
aminoquinoline and 2-picolylamine were treated with 4-
bromotolunene (14) under the optimized reaction conditions.
While the AAP benzamide delivered the arylation product in a
remarkable 98% yield (Table 1), the analogous 2-methyl 8-
aminoquinolyl amide gave the arylation product in modest 53%
yield and the 2-picolylbenzamide did not react at all (Figure 4).
This result should serve as an evidence for the superiority of the
AAP directing group, reported herein, over the existing directing
groups.
Me
NMe
NPh
Me
O
Me
O
Me
O
N
N
N
H
H
H
O
N
N
Me
15a: 98%
Me
Me
15aa: 53%
15aaa: --
AP
Figure 4. Efficacy of directing groups under optimum reaction conditions.
Me
NMe
NPh
O
H
Br
O
AP
Under the optimized reaction conditions found, the arene
substrate scope of AP benzamides was carried out (Scheme 4).
Thus differently substituted and electronically different AP
aromatic benzamides were subjected to the optimum Ru-
catalyzed C-H arylation conditions (Scheme 4). The Ru-catalyzed
C-H arylation tolerated a wide range of functional groups and
N
[RuCl2(PPh3)3] (10 mol %)
N
R1
R1
H
H
O
+
Na2CO3 (3 equiv.), toluene
140 oC, 24 h.
R2
13
14
16
R2
0.5 mmol
1.3 equiv.
R1
O
O
AP
R1
AP
N
H
N
resulted in the arylation product in very good yields.
H
AP
Me
R2
NMe
NPh
R2
Br
O
O
R1=Me, R2=Me (15a): 98%
R1=Me, R2=H (16a): 90%
AP
[RuCl2(PPh3)3] (10 mol %)
R1=Me, R2=CF3 (16f): 94%
R1=CF3, R2=CF3 (16g): 61%
N
N
R
+
R
H
H
R1=Me, R2=OMe (16b): 80%
R1=Me, R2=NMe2 (16c): 73%
R1=Me, R2=CO2Et (16d): 96%
R1=Me, R2=CF3 (16e): 82 %
O
Na2CO3 (3 equiv.), toluene
140 oC, 24 h.
H
13
0.5 mmol
14a
15
Me
1.3 equiv.
Me
R
O
O
Scheme 5. Electrophile scope of the Ru-catalyzed arylation.
AP
R
AP
R= Me (15c): 94%
R=OMe (15d): 78%
R= F (15e): 95%
N
N
H
H
In addition, meta-substituted AP benzamide with Me and CF3
were reacted with electron-poor electrophile, 4-
R= CF3 (15f): 98%
Me
Me R= Cl (15g): 75%
bromobenzotrifluoride, to give the corresponding arylated
products 16f and 16g in 94% and 61% yields respectively.
Based on the electrophile scope above, the results suggest that
electron-rich and electron-poor aryl bromide electrophiles
participate in the Ru-catalyzed C-H arylation of AP benzamides
bearing 4-aminoantipyrine as a directing group.
R= Me (15a): 98%
R= F (15b): 95%
O
O
AP
AP
N
N
H
H
R
F
Me
Me
R= Me (15h): 63%
R= OMe (15i): 69%
R=F monoarylation product (15j): 69%
diarylation product (15k): 29%
To prove that Ru-catalyzed C-H arylation of AP benzamides
works with 2- and 3-substituted aryl bromides, the standard 2-
methyl AP benzamide (13a) was reacted with N-acetyl 2-
bromoaniline (17a) and N-acetyl 3-bromoaniline (17b) under the
optimum reaction conditions (Scheme 6). The reaction with N-
acetyl 2-bromoaniline (17a) gave the corresponding arylated
product (18a) in modest 19%. The reaction was judged
incomplete after 24 h by TLC. The sterically hindered aryl bromide
was sluggish to effectively react in the given reaction time. Thus
the modest performance of 17a in the reaction was attributed to
the steric hindrance of aryl bromide. On the other hand, the
reaction was N-acetyl 3-bromoaniline (17b) was of a better
outcome. The reaction went to completion after 24 h giving rise to
the corresponding arylated product (18b) in decent 61% yield
(Scheme 6) after multiple purifications by chromatography and
preparative TLC. As a result, it was concluded that steric
hindrance of the aryl bromide plays an important role in the
reaction.
Scheme 4. Substrate scope of the Ru-catalyzed arylation.
Electron-donating groups represented by a methyl group at C2
(15a), C3 (15c) and C4 (15h) delivered the C-H arylation product
un 98%, 94% and 63% yields respectively. Electron-rich AP
benzamides substituted with methoxy (OMe) groups such as 3-
OMe and 4-OMe reacted efficiently giving rise to the
corresponding arylation products 15d and 15i in 78% and 69%
yields respectively. Electron-withdrawing groups as a fluoro (F)
group on C2 (15b), C3 (15e) and C4 (15j) were also tolerated
successfully to give the product in excellent 95%, 95%, and 69%
yields respectively. It was observed, that 4-F AP benzamides not
only gave a monoarylation product (15j, 69%) but also a yielded
a dirylation product (15k) in 29% yield. An AP benzamide
substituted with an electron-withdrawing trifluoromethyl (CF3)
group at C3 participated in the Ru-catalyzed arylation reaction
giving rise to the desired arylation product 15f in excellent 98%
yield. Another halogen (Cl) at C3 was also tolerated under the
optimum reaction conditions to give rise to the desired arylation
product 15g in decent 75% yield.
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202100513
European Journal of Organic Chemistry
COMMUNICATION
Me
Me
experiment suggests that the electron-poor aryl bromides react
NMe
NPh
NMe
NPh
Me
O
Me
O
Br
O
faster than the electron-rich counterparts.
Me
N
H
N
H
[RuCl2(PPh3)3] (10 mol %)
Br
NH
O
O
Me
+
NMe
NPh
H
O
Me
13a
0.3 mmol
17
1.3 equiv.
18
Na2CO3 (3 equiv.), toluene
140 oC, 24 h.
O
N
H
NH
O
NMe2
Me
Me
16c: --%
14c
NMe
NPh
Me
O
H
0.9 mmol (3 equiv.)
[RuCl2(PPh3)3] (10 mol %)
NMe2
+
N
H
+
Me
Me
+
NMe
NPh
NMe
NPh
Me
O
Me
O
O
Na2CO3 (3 equiv.), toluene
140 oC, 24 h.
Br
Me
NMe
NPh
Me
O
N
N
13a (0.3 mmol)
H
H
N
H
O
O
O
16e: 84%
O
CF3
14e
18a: 19%
18b: 61%
NH
CF3
HN
Me
0.9 mmol (3 equiv.)
Me
Scheme 9. Competition experiment between electron-rich aryl bromide 14c and
electron-poor aryl bromide 14e.
O
Scheme 6. Ru-catalyzed C-H arylation of 2-methyl AP benzamide with N-acetyl
2-bromoaniline (17a) and N-acetyl 3-bromoaniline (17b).
It was of strategic importance to investigate the removability of the
4-aminoantiupyrine directing group. Thus 2-methylbenzamide
bearing the directing group 13a was treated with concentrated
HCl to deliver the arylation carboxylic acid 19 in 92% (Scheme 9).
In addition, the arylated product of the 3-Cl benzamide bearing
the AAP directing group 15f was subjected to the same acidic
cleavage conditions to deliver the arylation carboxylic acid 20 in
In order to ascertain that aryl bromides were indeed the most
suitable for the Ru-catalyzed C-H arylation reaction, the
representative AP amide 13a was allowed to react with each of
ethyl 4-bromobenzoate and 4-iodobenzoate under the optimized
reaction conditions (Scheme 7). The former gave the arylation
product in 96% yield while the latter gave the product in 38%
(Scheme 6). Aryl bromides were then confirmed to be more
effective in the reaction.
96% (Scheme 10).
Me
NMe
NPh
Me
O
Me
O
Me
Me
NMe
NPh
NMe
NPh
X
Me
O
Me
O
OH
N
conc. HCl
H
[RuCl2(PPh3)3] (10 mol %)
N
H
N
H
O
O
+
O
13a
Me
19: 92%
140 oC, 48 h
H
Na2CO3 (3 equiv.), toluene
140 oC, 24 h.
13a
0.5 mmol
14d
16d
CO2Et
1.3 equiv.
CO2Et
NMe
NPh
O
O
Me
NMe
NPh
Cl
Me
O
Cl
OH
N
conc. HCl
H
N
X=Br: 96%
X=I: 38%
O
H
O
140 oC, 48 h
Me
Me
CO2Et
15f
20: 96%
Scheme 10. Cleavage of the 4-aminoantipyrine directing group.
Scheme 7. Effect of halogen of the aryl halide in the C-H arylation reaction.
The Ru-catalyzed C-H bond arylation presented is proposed to
proceed via base-assisted cyclometalation of benzamide 13 with
[RuCl2(PPh3)3] to give cyclometalated complex 13mi (Scheme 11).
[16] Base-assisted C-H bond cleavage should result in formation of
double five-membered chelate 13mii. Oxidative addition of the
aryl halide should allow formation of cyclometalated complex
13miii. Subsequent reductive elimination furnishes the arylation
product 15 with regeneration of the Ru catalyst. As noted
previously, electron-deficient AP benzamides competed
effectively with electron-rich AP benzamides for 4-bromotoluene
under the optimum reaction conditions (Scheme 8). In addition, it
was observed that electron-deficient aryl bromides competed
effectively with its electron-rich counterpart for the 2-methyl AP
benzamide (Scheme 9). Electron-deficient amide substrates and
electron-deficient aryl bromide electrophiles facilitate the C-H
arylation reaction. As a result, the Ru-catalyzed C-H arylation
reaction is dominated by the electronic natures of the AP
benzamide substrates and the aryl bromide electrophiles as well.
Since electron-deficient aryl bromides accelerate the oxidative
addition step, it can tentatively be suggested that oxidative
addition could be the rate-determining step in the present Ru-
catalyzed C(sp2)-H arylation reaction.
In order to gain insights into the rate of the reaction of an electron-
rich and an electro-poor benzamide substrates, were allowed to
compete with each other under the optimized reaction conditions.
Thus, electron-rich benzamide substituted with Me group,
benzamide 13c and electron-poor benzamide substituted with a
CF3 group, benzamide 13f were mixed with 4-bromotoluene 14
under the optimized reaction conditions (Scheme 8). Only
arylation product 15f was obtained and isolated and in 92% yield.
This competition experiment suggests that the electron-poor
benzamide 13f reacted faster than the electron-rich counterpart
13c.
Me
Me
NMe
NPh
O
NMe
NPh
O
H3C
H3C
N
N
H
H
O
O
15c: -%
H
Br
13c (0.75 mmol, 3 equiv.)
Me
[RuCl2(PPh3)3] (10 mol %)
+
+
+
Me
Na2CO3 (3 equiv.), toluene
140 oC, 24 h.
NMe
NPh
Me
O
NMe
NPh
Me
14a
0.25 mmol
O
F3C
N
H
F3C
N
H
O
O
H
15f: 92%
13f (0.75 mmol, 3 equiv.)
Me
Scheme 8. Competition experiment between electron-rich benzamide 13c and
electron-poor benzamide 13e.
In another competition experiment designed to determine suitable
electronic nature of the electrophile, the representative AP
benzamide 13a was mixed with electron-rich 14c and electron-
poor 14e under the optimum reaction conditions (Scheme 9). The
reaction took place only between benazamide 13a and electron-
poor 14e to give the corresponding arylation product in 84% yield
(Scheme 8). Electron-rich 14c did not react at all and thus
arylation product 16c was not obtained. This competition
4
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10.1002/ejoc.202100513
European Journal of Organic Chemistry
COMMUNICATION
Me
Me
48, 5094-5115, d) L. Ackermann, A. Althammer. R. Born, Angew. Chem.,
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NMe
NPh
NMe
O
O
H
NPh
N
N
H
13
R
R
H
O
O
Ar
[RuIIX2L3]
15
Na2CO3
NaX, NaHCO3
NaX, NaHCO3
Me
Me
NMe
O
NMe
O
NPh
NPh
N
N
RuII
X
R
R
RuIV
O
O
H
13mi
Me
Ar
X
NMe
NPh
13miii
O
Na2CO3
ArX
14
N
RuII
R
O
NaX, NaHCO3
13mii
Scheme 11. Proposed mechanism for the Ru-catalyzed C-H bond arylation of
benzamides bearing 4-aminoantipyrine.
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In summary, a novel design-based N,O-bidentate directing group
based on the cheap and commercially available material 4-
aminoantipyrine (AAP) is reported herein. Aromatic benzamides
bearing 4-aminoantipyrine (AP benzamides) underwent Ru-
catalyzed C(sp2)-H bond arylation that employed amongst other
optimum reaction conditions; [RuCl2(PPh3)3] (10 mol %) as a
catalyst, an aryl bromide as an electrophile and Na2CO3 as a base.
Differently substituted and electronically different AP benzamides
underwent efficient Ru-catalyzed C(sp2)-H arylation reaction in
decent yields and with good functional group tolerance. This
development of the novel bidentate directing group based on 4-
aminoantiprine presented herein, should contribute to the
advances in the field of directed C-H bond functionalization
catalyzed by transition metals. The present report should set
stage for potentially different C-H bond functionalization reactions
catalyzed by other transition metals, particularly the cheaper and
more earth-abundant second-row transition metals.
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Acknowledgements
The authors would like to thank Sultan Qaboos University for
funding this research through Internal Grant IG/SCI/CHEM/19/02.
Our gratitude is extended for Ms. Maryam Al Jahwary,
Department of Chemistry, College of Science, Sultan Qaboos
University, for running NMR experiments and for Dr. Jamal Al
Sabahi at the Centre Instrumental Laboratory, College of
Agricultural and Marine Sciences, Sultan Qaboos University for
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Keywords: 4-Aminoantipyrine • Directing group • C-H
Functionalization • Ru-Catalysis• Chelation Assistance
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6
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European Journal of Organic Chemistry
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Entry for the Table of Contents
Insert graphic for Table of Contents here. ((Please ensure your graphic is in one of following formats))
AP
Me
[RuCl2{PPh3)3] (10 mol %)
ArBr
NMe
NPh
O
a
O
a
b
g
b
g
AP
N
N
H
R
R
H
O
Na2CO3 (3 equiv.), toluene
150 oC, 24 h.
Ar
H
18 examples, 61-98% yields
Herein, a novel design-based removable N,O-bidentate directing group based on commercially available 4-aminoantipyrine (AAP) is
reported. Aromatic benzamides bearing the AAP directing group underwent efficient Ru-catalyzed C(sp2)-H bond arylation reactions
under mild reaction conditions. The C-H bond arylation employed amongst other reaction conditions; [RuCl2(PPh3)3]. Various
differently substituted and electronically different antipyrinyl (AP) benzamides participated in the Ru-catalyzed C(sp2)-H arylation
reaction and in decent yields and with good functional group tolerance.
7
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