Ruthenium(II)-catalyzed synthesis of hydroxylated arenes with ester as an effective directing group

Article abstract of DOI:10.1021/ol301104n

An unprecedented Ru(II) catalyzed ortho-hydroxylation has been developed for the facile synthesis of a variety of multifunctionalized arenes from easily accessible ethyl benzoates with ester as an efficient directing group. Both the TFA/TFAA cosolvent system and oxidants serve as the critical success factors in this transformation. The reaction demonstrates excellent reactivity, good functional group tolerance, and high yields.

Full text of DOI:10.1021/ol301104n

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2874–2877
Ruthenium(II)-Catalyzed Synthesis
of Hydroxylated Arenes with Ester
as an Effective Directing Group
Yiqing Yang, Yun Lin, and Yu Rao*
Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and
School of Life Sciences, Tsinghua University, Beijing 100084, China
yrao@mail.tsinghua.edu.cn
Received April 27, 2012
ABSTRACT
An unprecedented Ru(II) catalyzed ortho-hydroxylation has been developed for the facile synthesis of a variety of multifunctionalized arenes from
easily accessible ethyl benzoates with ester as an efficient directing group. Both the TFA/TFAA cosolvent system and oxidants serve as the critical
success factors in this transformation. The reaction demonstrates excellent reactivity, good functional group tolerance, and high yields.
Hydroxylated arenes are common structural scaffolds
found in important pharmaceuticals, agrochemicals, poly-
mers, and biologically active natural compounds,1 which
have also served as versatile intermediates in organic syn-
thesis due to their rich reactivity.2 Direct functionalization
of CÀH3 bonds by transition metals emerged asa powerful
method for generating new CÀO4 bonds in the past decade.
More recently, two elegant methods toward ortho-acetox-
ylation and hydroxylation have been reported individually
by the Sanford5 and Yu6 groups (Scheme 1). In both
studies, Pd(OAc)2 was employed as effective catalyst with
either N-oxime ether or potassium carboxylate as the
coordinating functional groups respectively.
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r
10.1021/ol301104n
Published on Web 05/14/2012
2012 American Chemical Society

research have been focused on metals such as Pd,7 Cu8
or Fe,9 etc. In contrast, other metals, like Ru10 and Rh,11
are rarely reported in this transformation. Furthermore,
developing other appliable directing groups is still highly
desired. The majority of studies so far reported had
relied on using nitrogen-containing coordinating groups
like pyridine,12 amide,13 oxime ether,14 carbamate15 or
oxazoline,16 etc. Lately, carboxylic acids17 have also been
successfully employed as efficient coordinating groups
in many useful chemical transformations (Scheme 1).
In contrast, the application of an ester functionality as the
feasible directing group in the transtion-metal-catalyzed
ortho-aromatic CÀH bond activation has been rarely
reported,18 especially considering that ester functional
groups are not only readily available but also easily con-
verted to alcohols, amides, and other carbonyl com-
pounds. To the best of our knowledge, direct ortho-
hydroxylation of arenes catalyzed by Ru(II) with ester as
efficient directing group has not yet been achieved. Here,
we report the first example of ruthenium(II) catalyzed
ortho-hydroxylation of arenes assisted by ester functional
groups (Scheme 1).
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Scheme 1. Approaches for Hydroxylation of Arenes
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In our continuous studies of preparing multifunctiona-
lized arenes, we proposed that the ruthenium catalyst,
under proper acidic conditions, allows CÀH bond clea-
vage via an orthometalation process through chelation
with carbonyl oxygen from aromatic esters. Consequently,
a CÀO bond formation is possible via the reductive
elimination to afford corresponding hydroxylation or
acetoxylation products. Herein, a model study was in-
itiated with benzoate 1 in the presence of [RuCl2(p-
cymene)]2 in AcOH/Ac2O solvent system with K2S2O8 as
the terminal oxidant to test our hypothesis (Table 1).
However, neither preferred hydroxylation nor acetoxyla-
tion reactions happened. After many fruitless attempts, we
turned our attention to TFA. The hydroxylated product 2
was observed in less than 5% yield after the mixture was
stirred for 6 h at 80 °C in TFA (Entry 4). Encouraged by
this preliminary result, we started to optimize the reaction
conditions. After a comprehensive screening, we found
that TFA/TFAA cosolvent was superior over TFA with a
notably higher level of efficiency. Further investigations
revealed that the ratio of TFA/TFAA is critical for the
reaction as well. For example, the conversion ratio of 2
from 1 was about 61% with TFA/TFAA (9:1/v:v), which
could be further improved to 75% when using TFA/
TFAA (7:3/v:v). A variety of other oxidants were also
examined in the reaction, such as PhI(OAc)2, KIO4,
NaIO4,19 HIO3, Selectfluor, Na2S2O8, and H2O2, etc.
Among them, Selectfluor was noted to have a similar
capability as K2S2O8. It was observed that higher tem-
peratures could speed up the reactions and improve the
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L. J. Am. Chem. Soc. 2010, 132, 468.
(19) Ethyl 3-iodobenzoate was major product when KIO4 or NaIO4
were used as oxidant.
Org. Lett., Vol. 14, No. 11, 2012
2875

yields. There is only slight differences with higher catalyst
loadings in terms of reaction rates and conversion ratios.
Generally, 0.025 equiv of [RuCl2(p-cymene)]2 was enough
to effectively promote the reaction. Attempts to use other
ruthenium catalysts, such as RuCl2(PPh)3, RuHCl(PPh)3,
and Ru3(CO)12, were not very successful. Typically, the
reaction will proceed to completion in TFA/TFAA within
11 h, in a clean manner, with 1.1 equiv of oxidant at 90 °C.
isopropyl, propyl, butyl, and benzyl. Among them, methyl
benzoates were found to have the similar practicality to its
ethyl counterparts to furnish hydroxylated products in
good yields (30, 31).
Table 1. Optimization of the Reaction Conditions
oxidant
entry
(1.1 equiv)
conditions
yielda (%)
1
2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
KIO4
AcOH/Ac2O/9:l, 80 °C, 7 h
AcOH/Ac2O/6:4, 80 °C, 7 h
AcOH/Ac2O/3:7, 80 °C, 7 h
TFA, 80 °C, 7 h
0
0
3
0
4
<5
50
44
31
61
75
7
5
TFA/TFAA/8:2, 80 °C,7 h
TFA/TFAA/7:3, 80 °C,7 h
TFA/TFAA/6:4, 80 °C,7 h
TFA/TFAA/9:1, 80 °C,7 h
TFA/TFAA/7:3, 80 °C, 11 h
TFA/TFAA/7:3, 80 °C,11 h
TFA/TFAA/7:3, 80 °C, 11 h
TFA/TFAA/7:3, 80 °C,11 h
TFA/TFAA/7:3, B0 °C, 11 h
TFA/TFAA/7:3, 80 °C, 11 h
TFA/TFAA/7:3, 80 °C, 11 h
TFA/TFAA/7:3, 80 °C,11 h
TFA/TFAA/6:4, 90 °C,4 h
TFA/TFAA/6:4, 90 °C,6 h
AcOH/Ac2O/6:4, 90 °C, 8 h
AcOH/Ac2O/9:l, 90 °C, 8 h
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
NaIO4
trace
20
44
0
HIO3
PhI(OAc)2
Cu(OAc)2
H2O2
0
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
73b
41
53
0
Figure 1. Substrate scope. (a) Isolated yield. (b) K2S2O8 as
oxidant. (c) Iodic acid as oxidant.
0
The applicability of this reaction was further demon-
strated in an iterative ortho-hydroxylation of substrate 32.
The optimum reaction conditions proved to be successful
to provide dihydroxylated compound 34 with a satisfac-
tory yield. This new method also provides new opportu-
nities for the construction of some biologically important
molecules, which was exemplified in Scheme 2. Ethyl
3-nitrobenzoate was readily converted to hydroxylated
compound 36, which could be further transformed into
Mesalazine, an anti-inflammatory drug, via a facile, se-
quential hydrolysis and reduction.20
a Conversion ratio. b Isolated yield.
Having identified these optimal conditions, we set out to
explore the scope for this new reaction. As displayed in
Figure 1, a variety of mono- and disubstituted ethyl
benzoates were surveyed. The scope of the benzoate sub-
stituents was found to be very broad. Various benzoates
was smoothly transformed into the corresponding ortho-
hydroxylated products in moderate to excellent yields. The
ortho-, meta-, and para-substituted aryl groups, as well as
the electron-rich and electron-deficient aryl groups, were
well tolerated. For instance, with iodic acid as the oxidant,
satisfactory yields were also observed with substrates
which contain strong electron-withdrawing groups, such
as CF3 and NO2, etc. (9, 10, 18). Most meta-substituted
substrates gave only one regioisomer, but in some cases,
another regioisomeric product (compounds 19, 22, and 23)
was obtained albeit in minor amounts. Notably, hetero-
aromatic ethyl thiophene-2-carboxylate was also success-
fully employed to provide compound 21. Besides ethyl
benzoates, the feasibility of other alkyl benzoates in this
transformation were tested as well, such as methyl,
Scheme 2. Iterative Hydroxylation and Application
2876
Org. Lett., Vol. 14, No. 11, 2012

As shown in Scheme 3, parallel competition experiments
clearly show that the electron-rich aromatic ring reacts
faster than its eletron-poor counterpart to furnish the ethyl
2-hydroxyl-5-methyl benzoate 2. In addition, to probe the
reaction mechanism, an intra- and an intermolecular iso-
tope effect studies were conducted in parallel and a KIE
value of 2.3 and 1.821 was obtained respectively (Scheme 4).
While these results indicate that CÀH activation might be
involved in the rate-limiting step of this transformation,
other possibilities could not be totally excluded at the
current stage.22
Scheme 4. Kinetic Isotope Effect
Scheme 3. Separate Rate Constants Study
transformation. This method has been found to be generally
useful for the preparation of ortho-hydroxylated ethyl benzo-
ates, some of which are difficult to make via conventional
approaches. The reaction demonstrates excellent reactivity,
good functional group tolerance, and high yields, behavior
that has been further exemplified in the synthetic applica-
tions. By employing a combination of [RuCl2(p-cymene)]2,
terminal oxidants, and a TFA/TFAA solvent system, we
have discovered a highly efficient catalyst system for this
unique CÀO bond formation reaction. Further investiga-
tions into the mechanism and synthetic applications of this
method are currently underway in our laboratory.
Although details about the mechanism still remain un-
clear, on the basis of these observations, it is possible that
the catalytic pathway may go through a Ru(IV) intermedi-
ate CÀRuÀO thatreductively eliminates toafford the final
product. The terminal oxidants could be involved in the
reoxidation step of Ru(II). It should also be noted that a
mechanism involving the common Ru(0)ÀRu(II) catalytic
cycle could not be completely ruled out.
In summary, an unprecedented Ru(II) catalyzed ortho-
hydroxylation has been developed for the facile synthesis
of multifunctionalized arenes from easily accessible start-
ing materials. The TFA/TFAA cosolvent system serves as
a critical success factor, and potassium persulfate, Select-
fluor, or iodic acid is employed as a key oxidant in this
Acknowledgment. This work was supported by the na-
tional ‘973’ grant from the Ministry of Science and Tech-
nology (grant no. 2011CB965300), National Natural
Science Foundation of China (grant no. 21142008), Tsinghua
University 985 Phase II funds,and Tsinghua University
Initiative Scientific Research Program. We thank Prof. Lei
Liu (Tsinghua University) for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and characterization data of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
€
(20) Schmidt, B.; Holter, F.; Berger, R.; Jesse, S. Adv. Synth. Catal.
2010, 352, 2463.
(21) When the reaction was run in one flask, the corresponding KIE
value was 4.0.
(22) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2877