Copper-mediated hydroxylation of arenes and heteroarenes directed by a removable bidentate auxiliary

Article abstract of DOI:10.1021/ol5016064

A copper-mediated C-H hydroxylation of arenes and heteroarenes using our newly developed PIP directing group has been developed. This procedure is scalable and compatible with a wide range of functional groups and heteroarenes, providing an operationally simple protocol for the synthesis of o-hydroxybenzamides. The hydroxylation of nicotinamides gave 4-oxo-1,4-dihydropyridine-3-carboxamides selectively. Preliminary mechanistic studies implicate that a basic ligand-enabled, irreversible, rate-determining CMD step is most likely involved in this process.

Full text of DOI:10.1021/ol5016064

Letter
pubs.acs.org/OrgLett
Copper-Mediated Hydroxylation of Arenes and Heteroarenes
Directed by a Removable Bidentate Auxiliary
Xin Li,† Yan-Hua Liu,† Wen-Jia Gu,† Bo Li,† Fa-Jie Chen,† and Bing-Feng Shi*,†,‡
†Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A copper-mediated C−H hydroxylation of
arenes and heteroarenes using our newly developed PIP
directing group has been developed. This procedure is scalable
and compatible with a wide range of functional groups and
heteroarenes, providing an operationally simple protocol for
the synthesis of o-hydroxybenzamides. The hydroxylation of
nicotinamides gave 4-oxo-1,4-dihydropyridine-3-carboxamides
selectively. Preliminary mechanistic studies implicate that a basic ligand-enabled, irreversible, rate-determining CMD step is most
likely involved in this process.
unctionalized phenols are an important structural motif in
nature and have extensive application in pharmaceuticals,
report a copper-mediated C−H hydroxylation of arenes and
heteroarenes directed by a removable bidenate directing group.
The reaction possesses several favorable attributes, including a
broad substrate scope, high efficiency, and compatibility with
heteroarenes (Scheme 1B).
F
agrochemicals, and material science.1 Besides, they are also
versatile synthetic intermediates and asymmetric catalysis in
organic synthesis. Therefore, the direct hydroxylation of arenes
to phenols has been the topic of extensive research interests, and
tremendous progress has been made on the direct C−H
hydroxylation reactions catalyzed by the expensive, second-row
transition metals, such as palladium and ruthenium.2−6 In 1990,
the seminal work by Fujiwara reported a Pd(OAc)2-catalyzed
hydroxylation of arenes with molecular oxygen; however, this
protocol suffered from low efficiency, poor selectivity, and harsh
reaction conditions.3 In 2009, Yu described a novel Pd-catalyzed
hydroxylation of arenes directed by a carboxyl group.4 Jiao
reported a novel PdCl2 and NHPI cocatalyzed C−H
hydroxylation of 2-phenylpyridines.5 More recently, the syn-
thesis of hydroxylated arenes via in situ hydrolysis of the
acetoxylated products generated from Pd- or Ru-catalyzed C−H
acetoxylation were disclosed by several groups (Scheme 1A).6
Despite this success, the direct hydroxylation of arenes catalyzed
by less expensive copper catalysts is still very rare.7 Herein, we
Over the past decade, copper-catalyzed oxidative C−H
functionalization has gained significant attention owing to the
abundance, inexpensiveness, and versatile reactivity of copper
catalysts.8,9,11−13 In 2006, Yu and Chatani independently
reported the Cu-mediated C−H functionalization of 2-
arylpyridines.7a,9 Recently, the 8-aminoquinoline-derived biden-
tate auxiliary, which was first developed by Daugulis,10 has been
used in copper-catalyzed direct C−H amination, arylation, and
phenoxylation.12 We also developed a removable bidentate
directing group derived from 2-(pyridine-2-yl)isopropylamine
(PIP-amine).14 This directing group has shown superior
reactivity in the functionalization of C−H bonds. Meanwhile,
Stahl and co-workers have shown both macrocyclic amine and 8-
aminoquinoline benzamide ligands facilitate the oxidative
functionalization of arene C−H bonds.15 Inspired by these
precedents, we reasoned that a copper-catalyzed hydroxylation of
arene C−H bonds assisted by the PIP directing group might be
achieved for the following reasons: (1) the bidentate PIP
auxiliary can facilitate the C−H bond activation and cyclo-
metalation process; (2) the C,N,N-pincer type ligand can
stabilize the high valent Cu(III) intermediate; and (3) the
C,N,N-pincer type Cu(III) intermediate may also facilitate C−O
reductive elimination.
Scheme 1. Transition-Metal-Catalyzed C−H Hydroxylation
To examine this hypothesis, we commenced our studies by the
reaction of benzamide 1a in the presence of Cu(OAc)2 and
Ag2CO3 as the catalyst system in DMF at 100 °C, and to our
Received: June 4, 2014
Published: July 16, 2014
© 2014 American Chemical Society
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Letter
delight, the desired hydroxylated product 2a was obtained in 51%
yield (Table 1, entry 1). Various silver salts, such as AgOAc and
a
Table 1. Optimization of the Reaction Conditions
Figure 1. Substrate scope of arenes. Reaction conditions: 1 (0.2 mmol),
Cu(OAc)2 (0.2 mmol), Ag2CO3 (0.4 mmol) and TBAI (0.4 mmol) in
DMF (2 mL) at 100 °C for 1 h. Isolated yields. Notes: a12 h. b2 mmol.
inantly (2ca, 19% and 2cb, 57%). The strongly electron-deficient
functional groups, such as cyano and nitro, were also tolerated
(2m and 2n). Notably, bromo-substituted benzamide 1o was
also effective, which could be used as versatile handles for further
transformations.
Due to the importance of heteroarenes in pharmaceuticals and
material science, we are particularly interested in the synthesis of
divergent heteroarenes via the direct C−H functionalization
strategy.16 To our delight, a wide range of biologically important
heterocycles were suitable for this conversion (Figure 2). The
hydroxylation of nicotinamides bearing various substitutents
reacted regioselectively at the C-4 position, even when the
sterically bulky 5-methylnicotinamide 4d was employed as
substrate. These results indicated that C(4)−H bond is more
a
Reaction conditions: 1a (0.2 mmol), Cu(OAc)2 (0.2 mmol), [Ag]
b
(0.4 mmol) and additive in DMF (2 mL) at 100 °C. Isolated yield.
c
d
1H NMR yield using CH2Br2 as the internal standard. 90 °C.
AgOTf, were tested, and Ag2CO3 proved to be particularly
effective (entries 2 and 3). We then investigated different
inorganic salts as additives and observed that PhCO2Li was the
most efficient, affording 2a in 63% yield (entries 4−7). Through
extensive optimization of the additives, we were pleased to find
that the reaction can proceed to completion within 1 h at 100 °C
in the presence of 2 equiv of tetrabutylammonium iodide (TBAI)
with high yield (entry 11, 90% yield). The hydroxylation
structure was confirmed by X-ray analysis of compound 2a
(Supplementary Figure S1).
We then investigated the effect of the directing group on the
efficiency of the hydroxylation reaction. No reaction occurred
when the amide 3a was used as the substrate, indicating the
presence of the gem-dimethyl substitution is crucial for the
reaction to proceed. The weakly coordinating N-arylamide 3d
and N-methoxyamide 3b, which have been widely applied in Pd-
catalyzed C−H functionalization reactions of carboxylic acids,
also failed under the optimized conditions. The 8-aminoquiloline
and 2-thiomethylaniline directing group was less effective in this
case (3e, 8% yield and 3f, 28% yield, respectively).
With these optimal reaction conditions in hand, we then
explored the scope of this C−H hydroxylation process. As shown
in Figure 1, this protocol was compatible with a wide range of
functional groups, such as alkyl, trifluoromethyl, methoxy,
chloro, fluoro, cyano, nitro, bromo, and acetylamino. o-
Methylbenzamide 1d gave reduced yield due to the steric effect
of the ortho-substituent, which obstructs the formation of the
putative palladacycle intermediate (2d, 37%). Curiously, when
m-methylbenzamide 1c was subjected to the hydroxylation
reaction, a mixture of 2ca and 2cb was obtained with
hydroxylation of less hindered C−H bond happening predom-
Figure 2. Substrate scope of heteroarenes. Reaction conditions: 1a (0.2
mmol), Cu(OAc)2 (0.2 mmol), Ag2CO3 (0.4 mmol) and TBAI (0.4
mmol) in DMF (2 mL) at 100 °C for 1 h. Isolated yields. Notes: a12 h.
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Letter
reactive than the C(2)−H ones in this reaction system.
Interestingly, NMR spectra of 5a−5e showed that these
Scheme 3. Plausible Reaction Mechanism
1
compounds had carbonyl signals around 178 ppm, and H
NMR signals of the active hydrogen were extremely downfield,
indicating that the exact structure of 5a−5e should be their 4-
oxo-1,4-dihydropyridine isomers. This was undoubtedly con-
firmed by X-ray analysis of compounds 5a and 5c (Supple-
mentary Figure S2). Isonicotinamides 4f−4k were also tolerated
and proceeded smoothly to give the desired products in good
yields. A mixture of isomers was obtained when 2-chloro and 2-
fluoroisonicotinamide 4h and 4i were used as substrates. Besides,
heterocycles such as pyridazine and thiophene also survived
under the reaction conditions (5l−5n). However, no desired
hydroxylation product was observed when picolinamide 4o was
subjected to the standard conditions, since piconamide 4o could
coordinate with copper as a N,N,N-pincer-type ligand.
To highlight the synthetic utility of this procedure, a 5 mmol
scale reaction was conducted using benzamide 1a as substrate,
and the reaction proceeded smoothly to give the corresponding
hydroxylation product 2a in excellent yield (91%, 1.17 g).
Furthermore, removal of the PIP directing group from the o-
hydroxylcarboxamide 2a was achieved under acidic conditions,
and salicylic acid 6 was obtained in 61% yield (Scheme 2).
the C,N,N-pincer type Cu(III)-aryl intermediate C in one
elementary step is also possible as established by Ribas and
Stahl.15 Although the exact role of silver is unclear at this point,
on the basis of our own preliminary studies and earlier
precedent,12d,e we rationalize that Ag2CO3 might not only act
as oxidant but also could react with Cu(OAc)2 to generate the
[LCuII(κ2-CO3)]− (CuII-complex A in Scheme 3, where X = κ2-
CO3, L = deprotonated 1a) as indicated by Stahl.12d,17
In conclusion, we have developed an effective copper-
mediated hydroxylation of arenes and heteroarenes directed by
a removable bidentate auxiliary. Advantages of our protocol
include a broad substrate scope, high functional group tolerance,
compatibility with heteroarenes, simplicity of operation, and the
use of inexpensive copper catalyst. Preliminary mechanistic
studies suggest that a basic ligand-enabled, irreversible, rate-
determining CMD step is most likely involved in this process.
Scheme 2. Large Scale Synthesis and Removal of the Directing
Group
To gain more insights into the mechanism of the C−H
hydroxylation reactions, a series of experiments were conducted.
First, the addition of radical scavengers, such as 1,4-
dinitrobenzene, TEMPO, or 1,1-diphenylethylene, had no
significant influence on the reaction, which rules out the
possibility of a radical mechanism (Supplementary Scheme
S1a). Next, the intermolecular kinetic isotope effect (KIE) was
determined to be 5.3, indicating that C−H bond cleavage of 1a is
the rate-determining step of the catalytic cycle (Supplementary
Scheme S1b). When the reaction was performed in D2O or
AcOD, no deuterium incorporation in both starting material and
product 2a was observed, suggesting that C−H activation step is
irreversible (Supplementary Scheme S1c). Finally, o-acetoxyl
benzamide 7 could be converted to 2a under the reaction
conditions (Supplementary Scheme S1d). This result suggested
that the reaction might go through a Cu(OAc)2-mediated
acetoxylation followed by a rapid hydrolysis.
On the basis of these observations and earlier precedents, a
putative reaction pathway as proposed in Scheme 3 is possible.
First, the complexation of benzamide 1a with copper using the
N,N-bidentate directing group yields a Cu(II)-complex A. A
basic ligand (acetate or carbonate)-enabled, rate-determining
concerted-metalation-deprotonation (CMD) C−H activation
then affords the Cu(II)-aryl species B. The C,N,N-pincer type
Cu(III)-aryl intermediate C was produced by disproportionation
or oxidation. Subsequent reductive elimination leads to the
acetoxylation product 7 together with the formation of a Cu(I)
species. The catalytic cycle is closed by the reoxidation of Cu(I)
to Cu(II) by silver salt. The acetoxylation product 7 is
transformed to 2a via a rapid hydrolysis.7a Alternatively, a
disproportionative C−H activation from Cu(II)-complex A to
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectral data for all new compounds, and X-
ray for 2a, 5a, and 5d. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bfshi@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation of
China (21272206, J1210042), the Fundamental Research Funds
for the Central Universities (2014QNA3008), Zhejiang
Provincial NSFC (Z12B02000), Qianjiang Project
(2013R10033), and Specialized Research Fund for the Doctoral
Program of Higher Education (20110101110005) is gratefully
acknowledged.
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