Design and synthesis of ruthenium bipyridine catalyst: An approach towards low-cost hydroxylation of arenes and heteroarenes

Article abstract of DOI:10.1016/j.tetlet.2017.08.037

Two new ruthenium bipyridine complexes were designed and synthesized for intermolecular Csp²-H hydroxylation. An environmentally begin and inexpensive oxidant was employed as an oxygen source thereby enhancing its applicability and resulting in the remarkable increase of yield. In the catalytic process a ruthenium (IV) cationic complex is formed which enables the regioselective C–O bonds formation and also proves to be tolerant to a broad substrate scope. Activation of C–H bonds adjacent to removable and non-removable directing groups have been explored efficiently.

Full text of DOI:10.1016/j.tetlet.2017.08.037

Accepted Manuscript
Design and Synthesis of Ruthenium Bipyridine Catalyst: An Approach towards
Low-cost Hydroxylation of Arenes and Heteroarenes
Sanchari Shome, Surya Prakash Singh
PII:
S0040-4039(17)31035-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.08.037
TETL 49227
Reference:
Tetrahedron Letters
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7 August 2017
14 August 2017
Please cite this article as: Shome, S., Singh, S.P., Design and Synthesis of Ruthenium Bipyridine Catalyst: An
Approach towards Low-cost Hydroxylation of Arenes and Heteroarenes, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.08.037
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Design and Synthesis of Ruthenium Bipyridine Catalyst:Leave this area blank for abstract info.
An Approach towards Low-cost Hydroxylation of
Arenes and Heteroarenes
Sanchari Shome, Surya Prakash Singh

1
Tetrahedron Letters
journal homepage: www.els evier.com
Design and Synthesis of Ruthenium Bipyridine Catalyst: An Approach towards Low-
cost Hydroxylation of Arenes and Heteroarenes
Sanchari Shome†‡, Surya Prakash Singh∗†‡
† Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007.
‡ Academy of Scientific and Innovative Research (AcSIR New Delhi).
E-mail: spsingh@iict.res.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Two new ruthenium bipyridine complexes were designed and synthesized for intermolecular
Csp2-H hydroxylation. An environmentally begin and inexpensive oxidant was employed as an
oxygen source thereby enhancing its applicability and resulting in the remarkable increase of
yield. In the catalytic process a ruthenium (IV) cationic complex is formed which enables the
regioselective C-O bonds formation and also proves to be tolerant to a broad substrate scope.
Activation of C-H bonds adjacent to removable and non-removable directing groups have been
explored efficiently.
Received in revised form
Accepted
Available online
Keywords:
Hydroxylation
Ruthenium bipyridine
Oxone
2009 Elsevier Ltd. All rights reserved.
Regioselective
C-H Activation
Introduction
context, several catalysts like ruthenium p-cymene, ruthenium
mesitoate etc. have been extensively used.27-29
Design and development of different homogeneous catalysts
and utilising them for direct C-C/C-O/C-N/C-X bond formation
has always been a challenge to the chemists worldwide. The
direct hydroxylation of C(sp2)-H bonds1-3 is of immense
importance as the phenol derivatives are omnipresent in the
synthesis of a number of drugs and natural products.4-6 In 1990,
Fujiwara and co-workers reported a pioneering work on
Pd(OAc)2 catalyzed hydroxylation of benzene using molecular
oxygen as the sole oxidant.7 Later on Sun and co-workers
reported Pd(OAc)2 catalyzed hydroxylation using TBHP
(tertiarybutyl hydrogen peroxide) as oxidant.8 Recently, Sanford9
and co-workers as well as Yu10 and co-workers have reported
two efficient protocols towards ortho-acetoxylation and
hydroxylation. C-O functionalization reactions have achieved
considerable success using versatile ruthenium(II) catalysts
(Scheme 1).11,12-14 Reports have shown that ruthenium(II)-
catalyzed hydroxylation of substrates bearing directing groups
shows excellent site selectivity.15
O
H
O
[RuCl2(p-cymene)]2
OR
OR
Ref 11
TFA/TFAA, 800C, 7-10h
K2S2O8 or HIO3
OH
Previous Work
N
N
Pd(OAc)2
Ref 8
H
OH
DCE, TBHP
Br
N
O
Ru
N
N
O
N
Our Work
Br
H
OH
TFA/TFAA, 1400C
Oxone, DCE
Scheme 1: Schematic representation for the ortho-
hydroxylation of heteroarenes.
The ortho-hydroxylation reactions with weakly coordinating
groups, including amides,16,17 carbamates,18,19 esters,20 amines,21
anilides,22 ketones,23,24 and aldehydes,25 are well studied in the
literature compared strongly coordinating groups. The presence
of Lewis basic heterocyclic directing groups, in bioactive organic
compounds26 has enabled the study of C-H activation of these
components such as pyridines or pyrimidine’s.
An excellent catalytic protocol was well established using
ruthenium mesitoate as an efficient catalyst for hydroxylation.20
The presence of mesitoate group enhances the activity of the
catalyst as it helps to form a thermodynamically stable cyclic
intermediate directing the coupling partner site selectively.
However, we noticed that there are limited reports on the
synthesis of new ruthenium (II) catalysts for oxidative coupling
reactions.30,31 Milstein et.al have developed several PNP and NNP
type ruthenium pincer catalysts31,32 using substituted bipyridine
ligands for highly effective oxidative addition reactions. The use
Challenges have been accepted by researchers for the
development of highly stable ruthenium catalysts that performs
site selective activation even in less mole percent. In this
———
∗ Corresponding author. Tel.: +91-40-2719-1384; fax: +91-40-2716-0921; e-mail: spsingh@iict.res.in

2
Tetrahedron
of tridentate ligands drew our attention to replace ruthenium (II)
found to be highly regioselective and exclusively resulted in
mono-hydroxylated products with good efficiency.
p-cymene dimer in a more effective manner by synthesizing new
Ru-catalyst and utilizing them in the C-H activation chemistry.
We have already accomplished the effective catalytic activity for
C-H activation on conversion of ruthenium (II) p-cymene dimer
to ruthenium (II) mesitoate.33 Herein, we derivatized our catalyst
replacing one COOH- group by bipyridine and substituted
bipyridine ligands in ruthenium (II) mesitoate (Fig.1.)
These catalysts were highly stable and showed promising
results for C-O bond formation reactions with both removable24
and non-removable coordinating groups. Although there is not
much difference in the yields with SPS-Bpy and SPS-DB-Bpy
we observed better results with SPS-DB-BPy. This may be due to
the presence of electron withdrawing bromine moiety that helps
to stabilize the HOMO level [34] of the catalyst for the easy
electron flow during the oxidative addition process. After
rigorous screening, (7:3/v: v) ratio of TFA/TFAA (trifluoroacetic
acid/ trifluoroacetic anhydride) co-solvent was found to be best
reaction condition leading to the improved yield up to 77%.20 C-
H bond cleavage via ortho-metallation process through chelation
of the Ru-metal center with nitrogen of pyridine (Scheme 3a) or
oxygen of carbonyl (Scheme 3b) is expected to take place under
proper acidic conditions. This is followed by the reductive
elimination leading to the formation of the desired C-O bonds.
Figure 1. Chemical structure of SPS-Bpy and SPS-DB-Bpy catalyst.
Results and Discussion
The hydroxylation reactions were screened with a variety of
solvents [table 1] and major yield was obtained with chlorinated
solvent compared to non-chlorinated ones even alcoholic
solvents disappointed to show good results which prove that H-
bonding do not facilitate the reaction.35 The solvent screening
was performed keeping the other parameters same. The reaction
was also screened with a variety of oxidants like TBHP,
PhI(OAc)2 etc.
To study the effect of substitution of one of the mesitoate
groups with bipyridine we have synthesized two catalysts SPS-
Bpy and SPS-DB-Bpy using bipyridine and dibromobipyridine as
the respective substituent (Scheme 2). In order to understand the
efficiency and test its versatility we studied the catalytic behavior
of the synthesized catalysts for one of the most challenging C-O
coupling reactions. These catalysts were successfully
characterized using 1H NMR, ESI-MS, and HRMS (See ESI).
Table 1. Solvent screening for hydroxylation of
phenylpyridinea
Br
O
dibromobipyridine
DCM, 18hrs
2,2-bipyridine
DCM, 18hrs
N
Ru
O
N
O
O
Ru
O
Sl.No]
Solvent
Ru
Yield(%)
SPS-Bpy[b]
Yield(%)
SPS-DB-Bpy[b]
O
N
O
N
O
Br
SPS-DB-Bpy
SPS-Bpy
1
Acetonitrile
Acetone
DCM
32
38
56
24
16
33
1
40
42
65
32
28
38
3
Scheme 2. Synthetic scheme of SPS-Bpy and SPS-DB-Bpy.
2
It was found that on substituting one of the mesitoate with
bipyridine ligands the catalysts proved to be efficient in the C-O
coupling reactions. Both SPS-Bpy and SPS-DB-Bpy (Fig. 1)
showed moderate to high reactivity in various solvents. The
mesitoate anion is expected to assist the deprotonation of the
hydrogen from aryl derivatives thereby increasing the feasibility
of the reaction.
3
4
DMF
5
THF
6
Toluene
MeOH
7
8
EtOH
-
-
N
N
Catalyst, DCE, Oxone
OH
a
9
1,4-dioxane
1,2-DCE
Chloroform
DMSO
22
68
63
32
36
75
71
28
sealed tube, 1400C
TFA/TFAA
10
11
12
O
O
Catalyst, DCE, Oxone
R
R
O
O
b
sealed tube, 1400C
TFA/TFAA
OH
[a] Reagents and conditions: phenylpyridine (0.3 mmol),catalyst
(5 mol%),oxone (0.5mmol), 8 h at 140 ᵒC, TFA: TFAA=0.6
ml:0.4 ml. [b] Isolated yields.
Scheme 3. (a) Hydroxylation of phenylpyridines. (b) Hydroxylation
of aryl ester.
However, it is still unknown whether the mesitoate anion in
the counterpart of the cationic complex or the mesitoate anion
directly attached to the catalyst, which gets dissociated in the
course of the reaction is exactly responsible for the abstraction of
proton. The C-O coupling reactions showed promising results in
presence of chlorinated solvents. Here the reaction was
These oxidants were much stronger and yielded in a large
number of byproducts. PhI(OAc)2 resulted in the formation of the
acetyl derivative of the hydroxylated product and also some
unwanted homocoupling products. TBHP was comparatively
better but resulted in low yields under our catalytic conditions.
We further tried the reaction with another mild oxidant Oxone
and were surprised to observe much improved yields. Oxone is
performed both with strongly coordinating [Scheme 3a] as well
as weakly coordinating [Scheme 3b] directing groups and was

3
cheap, commercially available and non-toxic 9 thereby making it
a preferred oxidant in our catalytic system [table 2].
reaction time up to 36h under reflux condition and isolated only
30-40% yield.
Having an optimized catalytic system ready to use, we tested
its versatility with a series of representative arenes. We have tried
out a range of phenylpyridines starting from strong electron
releasing group (ERG) substituted phenylpyridines followed by
weak ERG and further by both strong and weak electron
withdrawing group (EWG) substituents as shown in Fig 2.
N
N
N
N
OH
OH
OH
OH
H3C
F
CH3
2c
F
Table 2. Variation of a range of oxidant for the
hydroxylation of phenylpyridinea
2d
Yield: 48/63
2a
2b
Yield: 72/78
Yield: 68/71
Yield: 32/45
Yield(%)
SPS-Bpy[b]
Yield(%)
SPS-DB-Bpy[b]
Sl.No
Oxidant
N
N
N
1
2
3
4
5
6
7
8
PhI(OAc)2
Cu(OAc)2
TBHP
46
48
63
70
42
-
50
55
66
75
48
-
OH
OH
N
OH
OH
O
O
O
CH3
2g
2h
Yield: 70/72
2e
2f
Oxone
Yield: 50/55
Yield: 47/49
Yield: 66/70
N
H2O2
N
N
O2
N
OH
OH
OH
OH
K2S2O8
Benzoquinone
2
6
F
F
F
F
-
-
N
F
F
O
O
[a] Reagents and conditions: phenylpyridine (0.3mmol),catalyst
(5mol%),oxidant (0.5mmol), 8 h at 140 ᵒC, TFA: TFAA=0.6
ml:0.4 ml. [b] Isolated yields.
2i
2j
Yield: 72/77
2k
Yield: 67/70
2l
Yield: 70/75
Yield: 63/66
Figure 2. Substrate scope and their corresponding yields. The yields
are represented as SPS-Bpy/ SPS-DB-Bpy.
The catalytic activity of SPS-BPY and SPS-DB-BPY was also
compared with other ruthenium catalysts under the above
optimized conditions as depicted below [table 3].
The strong ERGs are less effective (Fig 2, 2e, 2f) in
facilitating the oxidative addition step thereby reducing the yields
to a considerable extent. Moderate electron withdrawing groups
at para position (Fig 2, 2a, 2j) shows considerable high yields as
these groups enhances the C-H bond polarity hence; ortho-
metallation process in the first catalytic step is therefore
enhanced. However, strong EWG fails to be as effective as their
weaker counterpart (Fig 2, 2g, 2i) Fig 2. In all the cases SPS-DB-
Bpy shows better results in comparison to SPS-Bpy.
Table 3. Variation of ruthenium catalyst for the
hydroxylation of phenylpyridinea
Yield(%)b
Sl.No Catalyst
[RuCl2(p-cymene)]2
62
65
75
70
68
1
2
3
4
5
Ru(MesCO2)2 (p-cymene)
Ru(pcymene)(diBrbpy)(MesCO2)
Ru(p-cymene)(bpy)(MesCO2)
Ru(p-cymene)(TFA)2
CO2Et
OH
CO2Me
OH
CO2Me
OH
O
3a
Yield: 70/74
CO2Me
OH
3c
Yield: 63/65
CO2Me
OH
3b
Yield: 66/73
CO2Me
OH
[a] Reagents and conditions: phenylpyridine
(0.3mmol),catalyst (5mol%),oxidant (0.5mmol), 8 h at
140 ᵒC, TFA: TFAA=0.6 ml:0.4 ml. [b] Isolated yields.
F
H3C
F
The reaction with ERG at the meta-position (Fig 2, 2d) was
very slow and subsequent amount of product (63%) was formed
after heating the reaction for more than 12h. This result is
anticipated for the fact that effect of electron density is generally
less at the meta-position and also there is a chance of severe
steric hindrance on one side and hence the reaction takes place on
the other ortho position.
3d
Yield: 61/68
3e
Yield: 71/78
3f
Yield: 66/73
CO2Me
OH
CH3
3g
However, the reaction with electron donating groups at the
para-position (Fig 2, 2c) is seen to be most difficult as the
increased electron density in the para-position retards the
polarization of the C-H bond and decreases the probability of
efficient ortho-metallation step.35 To verify, we prolonged the
Yield: 69/70
Figure 3. Substrate scope and corresponding yields. The yields
are represented as SPS-Bpy/ SPS-DB-Bpy.

4
Tetrahedron
In order to further extend the substrate scope we investigated
derivatives. It is presumed that C-O bond formation goes via
cationic ruthenium (IV) complex, formed in situ, and enables the
effective intermolecular oxygenations which proceeded with
excellent positional selectivity. The optimized catalyst SPS-Bpy
and SPS-DB-Bpy were found to be highly chemo-selective and
showed broad applicability in converting aromatic carboxylate
esters efficiently. These catalytic processes have additional
advantage in tolerating Lewis basic heterocyclic directing groups
and can be utilized in a broader way. Further extensions on the
detailed catalytic pathway are under investigation.
the feasibility of the reaction in presence of weakly coordinating
groups. Hydroxylation of benzoates tolerated a broad range of
substrates that neatly yielded their corresponding products with
moderate to high yields. It is surprising to note that the reaction
takes place at the more hindered site unlike that of the phenyl
pyridines (Fig 3, 3f, and 3g). The range of substrates extends
from moderate to strong electron donating as well as electron
accepting groups. However, there is a little difference in the yield
of substituted ethyl and methyl benzoates. We have emphasized
on the methyl benzoate derivatives as shown in the Fig 3.
Acknowledgments
The strong EWGs e.g fluorine (F) yielded higher in
comparison to EDGs e.g methoxy (OMe), methyl (Me) etc. With
increase in the strength of withdrawing group there is an increase
in the acidity of the proton ortho or para to it. The dual effect of
two withdrawing groups meta to each other in 3f, increases the
central C-H bonds acidity making it easier for the mesitoate
anion to abstract that proton. Although for 3e the electron pulling
effect is nullified due to the presence of F in the para position of
the ester, we still observe an increased yield for 3e compared to
3f. This can be accounted for the fact that hydroxylation of
methyl-3-fluorobenzoate is sterically hindered than methyl-
4fluorobenzoate. The steric factor overcomes the acidity factor in
this case.
SPS and SS thank DST Fast Track Young Scientist Project
(CS-83/2012) for funding. SS also thanks AcSIR for PhD
registration.
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6
Tetrahedron
Research highlights
• First report on the hydroxylation of
aryl pyridines and aryl esters with Ru-
bipyridine catalyst.
• An environmentally benign and cheap
oxidant was employed as an oxygen
source.
• Activation of C-H bonds adjacent to
removal/non-removable directing
groups have been explored.
• Regioselective C-O bond formation
and also proves to be tolerant to a
broad substrate scope.