[2,2′-bipyridin]-6(1 H)-one, a Truly Cooperating Ligand in the Palladium-Mediated C-H Activation Step: Experimental Evidence in the Direct C-3 Arylation of Pyridine

Article abstract of DOI:10.1021/jacs.8b10680

The ligand [2,2′-bipyridin]-6(1H)-one (bipy-6-OH) has a strong accelerating effect on the Pd-catalyzed direct arylation of pyridine or arenes. The isolation of relevant intermediates and the study of their decomposition unequivocally show that the deprotonated coordinated ligand acts as a base and assists the cleavage of the C-H bond. Mechanistic work indicates that the direct arylation of pyridine with this ligand occurs through a Pd(0)/Pd(II) cycle. Because of this dual ligand-intramolecular base role, there is no need for an available coordination site on the metal for an external base, a difficulty encountered when chelating ligands are used in coupling reactions that involve a C-H cleavage step.

Full text of DOI:10.1021/jacs.8b10680

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Communication
[2, 2’-Bipyridin]-6(1H)-one, a Truly Cooperating Ligand in
the Palladium-Mediated C-H Activation Step: Experimental
Evidence in the Direct C-3 Arylation of Pyridine
VANESA SALAMANCA, Alberto Toledo, and Ana C. Albeniz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10680 • Publication Date (Web): 06 Dec 2018
Downloaded from http://pubs.acs.org on December 7, 2018
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[2, 2’-Bipyridin]-6(1H)-one, a Truly Cooperating Ligand in the Palladi-
um-Mediated C-H Activation Step: Experimental Evidence in the Direct
C-3 Arylation of Pyridine
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Vanesa Salamanca, Alberto Toledo and Ana C. Albéniz*
IU CINQUIMA/Química Inorgánica. Universidad de Valladolid. 47071 Valladolid (Spain).
Supporting Information Placeholder
R
R
ABSTRACT: The ligand [2, 2’-bipyridin]-6(1H)-one (bipy-6-
OH) has a strong accelerating effect in the Pd-catalyzed direct
arylation of pyridine or arenes. The isolation of relevant interme-
diates and the study of their decomposition unequivocally show
that the deprotonated coordinated ligand acts as a base and assists
the cleavage of the C-H bond. Mechanistic work indicates that the
direct arylation of pyridine with this ligand occurs through a
Pd(0)/Pd(II) cycle. Because of this dual ligand-intramolecular
base role, there is no need of an available coordination site on the
metal for an external base, a difficulty encountered when chelat-
ing ligands are used in coupling reactions that involve a C-H
cleavage step.
Ar
Pd
Ar
Pd
b)
a)
L
L
H
H
L
O
E
O
R
Figure 1. Representation of CMD transition states for C-H activa-
tion by a carboxylate (a) or a basic group, E, on the ligand (b).
reasons for their success, and calculations as well as some indirect
gas-phase MS evidence showed that it is feasible.6 However, other
computational reports favor a C-H cleavage by an external base
over an internal assistance of the ligand.7 There is no clear-cut
experimental data that demonstrate the H abstraction by the ligand
in these or any other catalysts. We report here and experimentally
support the cooperating effect in the C-H cleavage of arenes of [2,
2’-bipyridin]-6(1H)-one (bipy-6-OH), whose deprotonated form
effectively brings about the C-H cleavage of an arene. This and
related ligands have been used before in Ir-,8 or Ru-catalyzed
hydrogen transfer reactions,9,10 other applications,11 and by Duan
et al. in oxidative Heck reactions of arenes where they attribute
the improvement in the catalysis to a different reason: the anionic
nature of the deprotonated ligand that favors the dissociation of an
acetate.12 Monodentate pyridone derivatives have also been re-
cently used to accelerate coupling reactions of arenes.13 Again, the
involvement of the ligand in the C-H activation step is plausible
and has just been supported by DFT calculations.13d
Palladium-catalyzed cross coupling reactions that use arenes or
alkanes as coupling partners are extremely interesting since, in
contrast to classic C-C couplings, there is no need to pre-
synthesize the reagents from the parent hydrocarbons, making the
processes more sustainable. Extraordinary progress has been
made to extend the scope of these reactions and the number of
available catalysts is now large.1 The cleavage of the strong and
kinetically sluggish C-H bond is not easy and mechanistic studies
show that, generally, this step is rate determining in the catalysis.
As a consequence, higher temperatures and long reaction times
are often required, so more active catalysts are highly desirable.
The most common pathway for breaking the C-H bond is the so
called concerted metalation-deprotonation (CMD) where a coor-
dinated base, usually carboxylate or carbonate, and the arene form
a 6-membered cyclic transition state leading to a palladium aryl
and the protonated base (Figure 1, a).2,3 We have been exploring
ligands that could favor the CMD transition state by incorporating
the basic moiety into the ligand. This has kinetic advantages since
the coordination of an external base to the metal is not needed, so
it does not compete with the substrate for the metal coordination
sphere and, at the same time, the ligand provides an effective high
local concentration of base playing a bifunctional or cooperating
role (Figure 1, b).
We chose the direct arylation of pyridine as a model reaction to
test the performance of the ligand and study its catalytic behavior.
This useful reaction was reported by J. –Q. Yu using a
Pd(OAc)2/phenanthroline precatalyst mixture and allows to selec-
tively functionalize pyridine at the meta position.14,15 The reaction
is carried out in the coordinating pyridine as reagent and solvent,
so it is also a good test to evaluate the coordination ability of the
ligand. Under these conditions, most monodentate ligands do not
compete favorably with the substrate for coordination to the met-
al. Table 1 shows the results obtained in the reaction depicted in
Eq. 1. Bipy-6-OH has a strong accelerating effect when compared
to 1,10- phenanthroline (phen) used in the original report (entries
1-2, Table 1).14 The presence of an OH group in a position close
to the metal center (6-OH) is crucial. A methoxy group has no
beneficial effect (entry 3, Table 1) and the regioisomeric bipy-4-
OH, with similar electronic features than bipy-6-OH, leads to an
inactive catalyst (entry 4, Table 1).
Ligands with a suitable structure to play this dual role have been
successfully used in Pd-catalyzed couplings involving C-H activa-
tion. Most prominent are the N-monoprotected aminoacids intro-
duced by J. –Q. Yu et al. that are efficient in several transfor-
mations of C(sp2)H and C(sp3)H bonds,4 including enantioselec-
tive couplings.5 The involvement of the protecting groups of the
ligand in the C-H cleavage has been proposed as one of the
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I
[Pd] (5 mol%)
1
2
(1)
+
+ Cs CO
2 3
N
+
L
N
+ CsI + CsHCO3
3
O
4
5
L =
N
HN
N
HN
N
N
O
OMe
6
bipy-6-OMe
bipy-6-OH
bipy-4-OH
7
8
9
Table 1. Direct arylation of pyridine with p-iodotoluene
using different precatalyst.a
10
11
12
13
14
15
16
17
18
19
20
21
22
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Figure 2. Molecular structures of 1 (a) and 10 (b). ORTEP plots
(40% probability) are shown. Hydrogen atoms are omitted for
clarity except that of the OH group in 1, that shows a H-bond with
the Br ligand.
Entry [Pd]
L (mol%) Base:ArI
mol ratio
%Crude
yield (%
%Crude
yield (%
conversion),b conversion),b
6 h
24 h
1
2
3
4
5
6
7
[Pd(OAc)2] phen (15)
3
5 (5)
82 (86)
Scheme 1. Direct arylation of pyridines catalyzed by bipy-
6-OH palladium complexes.
[Pd(OAc)2]
[Pd(OAc)2]
[Pd(OAc)2]
3
3
3
3
1
1
64 (74)
0 (0)
90 (100)
15 (24)
0 (0)
bipy-6-OH
(15)
[Pd(OAc)2] (5 mol%)
bipy-6-
OMe (15)
R
bipy-6-OH (6 mol%)
+
+ CsX
+ CsHCO3
R
X
N
CsCO3,140 ˚C, 6 h
N
0 (0)
bipy-4-OH
(15)
X, Yield (%) crude(o:m:p)/isolated
MeO
[Pd(OAc)2] bipy (15)
1 (2)
6 (7)
N
N
X = I, 74(1:14:1)/72
X = Br, 73(1:14:1)/70b
N
X = I, 85(1:14:2)/78
X = I, 88(1:14:1)/80
X = Br, 88(1:16:3)/82
[Pd(OAc)2]
88 (97)
80 (100)
90 (100)
bipy-6-OH
(6)
CF3
F3C
1
-
F3C
N
N
N
X = I, 96(3:33:1)/93a
X = Br, 81(3:33:1)/80
X = I, 93(1:20:1)/73b
X = I, 98(1:11:1)/81
a) Reaction conditions: ArI (0.5 mmol), pyridine (3.0 mL), [Pd]
(5 mol%), Cs2CO3, 140 ˚C. b) Determined by H NMR (methyl
region). The formation of ArH (toluene) accounts for the differ-
ences between crude yield and conversion. Ar-py is a mixture of
regioisomers: o:m:p = 1:14:1.
F
F
1
NC
F
F
a) 2 h
b) 24 h
N
N
F
N
F
X = I, 93(1:11:1)/89
X = I, 71(8:100:1)/68
X = Br, 70(8:100:1)/67
X = Br, 50(5:100:1)/47b
The amount of ligand and base can be reduced with no erosion of
the yield (cf. entries 2 and 6, Table 1), but the use of a base differ-
ent to Cs2CO3 or a lower temperature strongly decreased the yield
(see SI for control experiments and additional data). The well-
defined precursor [Pd(bipy-6-OH)Br(C6F5)] (1) was also tested. 1
is a plausible model intermediate in the catalytic reaction, after
oxidative addition of ArX, and it also catalyzes the reaction (entry
7, Table 1). The synthetic route used for 1 and other analogous
[PdBr(C6F5)(N-N)] complexes is collected in Eq. 2, and the mo-
lecular structure of 1 is shown in Figure 2 (a).
Scheme 2. Direct arylation of arenes catalyzed by bipy-6-
OH palladium complexes.
I
F3C
1 (5 mol%)
+
+ CsI
R
+ CsHCO3
R
CsCO3,130 ˚C, 6 h
F3C
Yield (%) crude(o:m:p)/isolated
F3C
F3C
F3C
OMe
F
N
N
N
N
bipy-6-OH, 1
bipy-4-OH, 2
bipy-6-OMe, 3
bipy, 4
(2)
1/2 (NBu ) [Pd (µ-Br) Br Pf ] +
2
Pd
N
N
4 2
2
2
2
90(1:11:5)/85a
F3C
77(20:5:1)/74
96(1.5:2:1)/92
F3C
– NBu4Br
Pf
Br
Pf = C6F5
phen, 5
CO2Et
CN
a) 8 h
The synthesis of aryl pyridines catalyzed by
1 or a
83(3:6:1)/80
84(1:28:19)/80
Pd(OAc)2/bipy-6-OH mixture shows the same regioselectivity
(meta-substitution) as those reported for the Pd(OAc)2/phen cata-
lytic system,14 but it is faster (6 h vs 30-48 h, Scheme 1 and SI for
kinetic details). Aryl iodides with electron withdrawing groups
such as p-CF3C6H4I are even faster and the reaction is complete in
2 h. The direct arylation of other arenes catalyzed by 1 can also be
accomplished in short reaction times (Scheme 2). This reaction
does not work with N-chelating ligands such as bipy or phen in
the same reaction conditions.
The direct arylation of pyridine was studied in detail, starting with
the behavior of complex 1 under conditions relevant to the cataly-
sis. When 1 is dissolved in pyridine, the chelating bipy-6-OH is
displaced by the solvent (Scheme 3 and Figure S2). The deproto-
nated bipy-6-O is a better ligand and complex 7 is the only spe-
cies observed in pyridine either when a base is added to the mix-
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Scheme 4. Cleavage of the C(sp2)-H bond by the coordinat-
ed bipy-6-O.
ture formed by 1+pyridine, or when the independently synthe-
1
2
3
4
5
6
7
8
sized 6 is dissolved in pyridine (Scheme 3, Figure S2 and Figure
S17 for the molecular structure of 7). An analogous complex 10
was prepared by oxidative addition of p-CF3C6H4I to Pd(0) in
pyridine in the presence of Cs2CO3 (Eq. 3 and Figure 2b). It is
observed in the catalytic coupling of p-CF3C6H4I and pyridine,
pointing to 10 as the catalyst resting state in the reaction (Figure
S1). Both 7 and 10 are efficient catalysts and their activities are
equal to that of complex 1 (94-96% crude yield in 2 h in the reac-
tion of p-CF3C6H4I and pyridine).
Ar
Toluene
+ ArH
1h, 140˚C
7: 55 %
45%
Ar
+ ArH
py
N
N
+ [PdAr py ]
or Ar-Ar
2
2
O
Pd
30 min, 140˚C
N
Ar
py
7: 61%
10: 53%
39%
Ar = C6F5, 7
p-CF3C6H4,10
44%
13%
3%
5%
9
py, Cs2CO3
10: 82%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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Scheme 3. Behavior of 1 in pyridine.
30 min, 140˚C
NBu4
Scheme 5. Decomposition of complexes 1-5 in pyridine
N
N
py
Pf
py
py
Br
NBu4F
– HF
O
Pd
Pd
Pf
Br
N
N
py
N
N
6
Cs2CO3, py
C6F5
8
+ 8 + 9
Pd
C6F5
Pd
C6F5
N
N
py
25 ˚C
+
py
– NBu4Br
30 min, 140˚C
Br
Br
py
Pf
Br
py
N
OH
Pd
N
N
Pd
Pf
Br
bipy-6-OH, 1
bipy-4-OH, 2
bipy-6-OMe, 3
bipy, 4
1 (0%)
2 (38%)
3 (0%)
4 (9%)
5 (95%)
61%
0%
0%
0%
0%
1
9
Cs2CO3, py
Pf = C6F5
N
N
– CsHCO3, CsBr
+ bipy-6-OH
py = k-N py
O
Pd
Pf
py
7
phen, 5
experiments. The reaction is first order in the palladium complex
and zero order in the aryl halide. Other aryl halides were also
studied and the reaction rate is independent on the ArX concentra-
tion for X = Br, I and Ar = p-CF3C6H4, p-OMeC6H4. The amount
of free halide does not have any influence in the reaction rate. In
contrast, there is a clear kinetic isotope effect when the reactions
were carried using pyridine or pyridine-d5 (Eq. 4).
1/2 [Pd2(dba)3]
+
bipy-6-OH
py, 60 ˚C
N
N
+
+ Cs CO
2
F3C
I
(3)
3
Pd
O
– CsHCO3,
CsI, dba
N
10
F3C
X
When complex 10 was heated up to 140 ˚C in pyridine the for-
mation of the Ar-py coupling product was observed as the major
product (Scheme 4). This indicates that the ligand is capable of
assisting the C-H cleavage. The acid generated in the reaction is
responsible for the formation of the reduction product ArH, either
directly or through the generation of a Pd-H moiety by protona-
tion of Pd(0), and subsequent H transmetalation in a dimer.16 In
the presence of Cs2CO3 the amount of ArH is reduced and Ar-py
was observed in 82% yield. The behavior of 7 upon heating in
pyridine is analogous and it decomposes to give 61% yield of Ar-
py. Interestingly, when 7 was heated in toluene the Ar-Tol cou-
pling product was also observed (Scheme 4). Therefore, bipy-6-O
is a strongly coordinating ligand that efficiently cooperates in the
cleavage of the C(sp2)-H bond.
1 (5 mol%)
+
(4)
+ CsX
F3C
N
Cs2CO3, 140˚C
py/py-d5:
+ CsHCO3
N
F3C
KIE = 4.2 (I), 4.5 (Br) separate flasks
X = I, Br
The coordinated bipy-6-O ligand is capable of bringing about the
C-H cleavage of arenes as shown by the decomposition of com-
plexes 7 or 10 (Scheme 4). DFT calculations at the M06 level on
this step using complex 10 show that the C-H cleavage assisted by
the ligand requires an activation energy of 27.5 kcal mol–1, con-
sistent with the temperature and reaction times required for the
catalysis. The process involves the rearrangement of the coordi-
nated κ–N to η2-pyridine followed by C-H cleavage assisted by
the ligand (Figure 3 and Figure S78). The calculated KIE = 3.58 is
also consistent with the experimental results. Calculations show
that the meta C-H cleavage is favored by 1.6 and 3.1 kcal mol–1
over the para or ortho positions respectively (Figure S76).18 The
alternative pathway corresponding to a C-H cleavage assisted by
Cs2CO3 was explored but the barrier for this process is higher
(30.9 kcal mol–1) than the ligand assisted pathway and it involves
the previous substitution of the coordinated pyridine by the car-
bonate (Figure S75).
As shown in Scheme 5, when complexes 1-5 are dissolved in
pyridine, all the bipyridine neutral ligands are substituted by the
solvent and the amount of complex that remains unaltered gives
the following trend in coordination ability: bipy-6-OH ≈ bipy-6-
OMe < bipy < bipy-4-OH < phen ≈ bipy-6-O ≈ bipy-4-O. As it
has been discussed above the anionic bipy-6-O is coordinated to
palladium in pyridine and the same behavior was observed for the
anionic bipy-4-O (Figure S6). The low activity of bipy-6-OMe in
the catalysis could be attributed to its low coordination ability in
the catalytic conditions. However, none of the ligands in com-
plexes 2-5 assist the C-H cleavage and they do not form the cou-
pling product C6F5-py upon heating in the presence of base, not
even the better coordinating bipy-4-OH or phen (Scheme 5 and
Table S4).17
With these data the plausible catalytic cycle is represented in
Scheme 6. The oxidative addition of ArX to a Pd(0) complex in
the presence of the ligand and the base is possible (Eq. 3) and it is
fast in catalytic conditions. The substitution of the halide by pyri-
dine is also fast (Scheme 3) to give complex 10, observed during
the reaction, as the resting state of the catalyst. The subsequent
ligand-assisted C-H cleavage is the rate-determining step and the
product-forming reductive elimination follows to give a Pd(0) that
re-enters the cycle. The fact that the neutral bipy-6-OH is easily
Kinetic measurements were carried out on the coupling reaction
shown in Eq. 4 using 19F NMR (see SI for details). Complex 1
was used as precatalyst but it is transformed into 7 when dissolved
in pyridine in the presence of Cs2CO3; therefore complex 7 is the
actual catalyst used. No induction time was observed in any of our
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displaced on Pd(II) by free pyridine in excess supports the occur-
rence of anionic coordinated bipy-6-O throughout the cycle.19
(PDF). A combined CIF file for complexes 1, 7 and 10. The
Supporting Information is available free of charge on the ACS
Publications website.
1
2
3
4
5
6
7
8
9
AUTHOR INFORMATION
N
N
Corresponding Author
N
N
Pd
O
H
Pd
O
Ana C. Albéniz: albeniz@qi.uva.es
TS-c1-c2
CF3
N
N
Notes
CF3
c1
TS-c1-c2
27.5
The authors declare no competing financial interests.
TS-c2-c3-Cs2CO3
23.8
TS-10-c1
21.6
Cs2CO3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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c1
17.3
ACKNOWLEDGMENT
c2
8.9
We thank the financial support of the Spanish MINECO (SGPI,
grant CTQ2016-80913-P, BES-2014-067770 fellowship to AT),
the Junta de Castilla y León (grants VA062G18 and VA051P17)
and the UVa (fellowship to VS).
CsHCO3
10
0.0
N
N
N
N
N
N
N
Pd
O
Pd
OH
Pd
O
c3-Cs
-16.5
Cs
REFERENCES
N
N
CF3
CF3
CF3
10
c3-Cs
c2
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Figure 3. Free energy profile for the bipy-6-O assisted cleavage of
the meta C-H bond of pyridine. Energies in kcal mol–1.
Scheme 6. Catalytic cycle for the direct arylation of pyri-
dine.
–
py
O
N
ArX
Cs+
CsX
N Pd
Ar
X
O
–
N
O
N
N Pd
N
Cs+
N
Pd
Ar
L
10
Ar-py
O
–
N
O
N
Cs+
N Pd
Ar
N Pd
Ar
c1
N
N
OH
N
O
H
N Pd
Ar
N
N
CsHCO3
Cs2CO3
N Pd
Ar
O
= bipy-6-O
N
c2
–
N
N
TS-c1-c2
In conclusion, we have experimentally tested that the chelating
anionic ligand 2, 2’-bipyridin-6-onate is an effective cooperating
ligand for the coupling of arenes. The coordination of a base is not
required for C-H activation since this role is played by the ligand.
The direct arylation follows a Pd(0)/Pd(II) catalytic cycle where
only two available coordination sites on the metal are necessary
and therefore this strongly bound chelating ligand can be used
without compromising the coordination of the substrates to the
metal.
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ASSOCIATED CONTENT
Supporting Information
Experimental details, characterization, kinetic and X-ray structure
determination data, selected spectra, and computational details
including cartesian coordinates and calculated potential energies
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behavior is analogous to that of bipy-6-OH. A mixture of bipy-6,6’-(OH)2
and [PdBr(C6F5)(NCMe)2] in pyridine led only to complexes 8 and 9, but
new species formed upon addition of Cs2CO3. When this mixture was
heated at 140 ˚C for 30 min, 63% of the coupling product C6F5-py was
obtained (Figure S7).
(18) These energy differences are small and although the meta activa-
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13.3 vs 14.9 kcal mol–1, Figures 3 and Figure S77). We have depicted one
of these pathways (deprotonation first) in Scheme 6.
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N
N
N
T
O
Pd
F3C
No base
N
7
F3C
8
9
N
N
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Pd
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H
CF3
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