Copper-mediated direct aryloxylation of benzamides assisted by an N, O -bidentate directing group

Article abstract of DOI:10.1021/ol500166d

Copper-mediated selective mono- or diaryloxylation of benzamides has been achieved by using 2-aminopyridine 1-oxide as a new and removable N,O-bidentate directing group. The reaction system shows a broad substrate scope and provides a straightforward way for the synthesis of mono- and diaryloxylated benzoic acids.

Full text of DOI:10.1021/ol500166d

Letter
pubs.acs.org/OrgLett
Copper-Mediated Direct Aryloxylation of Benzamides Assisted by an
N,O‑Bidentate Directing Group
Xin-Qi Hao,† Li-Juan Chen,† Baozeng Ren,‡ Liu-Yan Li,† Xin-Yan Yang,† Jun-Fang Gong,†
Jun-Long Niu,*,† and Mao-Ping Song*,†
†The College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry and
‡School of Chemical Engineering and Energy, Zhengzhou University, Zhengzhou 450001, People’s Republic of China
S
* Supporting Information
ABSTRACT: Copper-mediated selective mono- or diaryloxylation of benzamides has been achieved by using 2-aminopyridine
1-oxide as a new and removable N,O-bidentate directing group. The reaction system shows a broad substrate scope and provides
a straightforward way for the synthesis of mono- and diaryloxylated benzoic acids.
iaryl ethers represent an important structural motif
because of their broad application in natural products,
Pd or Cu catalysts was achieved by Liu,9a Yoshikai,9b and Zhu9c
(Scheme 1 b). Nevertheless, the intermolecular aryloxylation of
arenes possessing directing groups, which was pioneered by Yu
and co-workers,10 has been less explored (Scheme 1 c).11 Thus,
the search for new variants to accomplish intermolecular C−H
bond aryloxylation is still expected to extend the scope of the
synthetic application.
B
pharmaceuticals, functional materials and other synthetics.1
Consequently, many methods have been developed for the
formation of these molecules.2 Typically, the biaryl ether
linkages are constructed via the metal-assisted Ullmann-type3
couplings of prefunctionalized arene building blocks such as
aryl halides, arylboronic acids or nitrobenzenes with phenols
reported mainly by the Buchwald and the Hartwig groups
(Scheme 1 a).4 From a synthetic perspective, direct C−H
On the other hand, chelating-assisted transformation is now
one of the viable methods for activating specific C−H bond
through a cyclometalation reaction.12 Among them, functional
groups containing neutral or anionic heteroatoms such as
nitrogen, oxygen, and sulfur have been widely used as
monodentate directing groups. Additionally, a double-coordi-
nation strategy employing a bidentate directing group to
promote the activation of C−H bonds via the formation of a
pincer-type metallacycle has been developed. Since the
pioneering work of Daugulis and co-workers13 on the use of
picolinamide or 8-aminoquinoline as an N,N-bidentate
directing group, important advances in palladium-catalyzed
arylation, alkylation, carbonylation, alkoxylation, and intra-
molecular amination of C−H bonds have been made.14,15 Very
recently, notable catalyst improvements based on the relatively
cheaper metal catalysts such as iron, nickel, and ruthenium and
novel synthetic applications were reported by the groups of
Nakamura16 and Chatani.17 Furthermore, Daugulis and Miura
developed copper-catalyzed and copper-mediated direct C−C
and C−X (X = S, F, N) cross-coupling reactions using this
auxiliary strategy.18 Inspired by these successes and the
capability of a terdentate pincer ligand to undergo facile C−
H bond activation and subsequent cyclometalation,19 we
focused our efforts on developing a new bidentate directing
Scheme 1. C−O Bond Formation Routes to Biaryl Ethers
aryloxylation of arenes with phenols would be an attractive and
ideal alternative to the aforementioned couplings. Despite the
boom of C−H bond activation and functionalization,5 such a
reaction involving the coupling of phenol hydroxyls with C−H
bonds has so far remained elusive compared with the C−H
bond alkoxylation and hydroxylation.6,7 The reason is due to
the poor nucleophilicity of the phenoxide resistant to C−O
reductive elimination from the metal center4d and the
sensitivity of phenols to the oxidants such as PhI(OAc).8
Recently, successful intramolecular aryloxylation of arenes with
Received: December 20, 2013
© XXXX American Chemical Society
A
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Letter
group to promote C(sp2)−H activation and functionalization
(Scheme 1, d).
Herein, we report the 2-aminopyridine 1-oxide group, easily
synthesized from 2-aminopyridine, as an N,O-bidentate
directing group for copper-mediated mono- and diaryloxylation
of benzoic acid derivatives. The model reaction of 2-
benzamidopyridine 1-oxide (1a) and phenol (2a) was used to
optimize the reaction conditions (see the Supporting
Information for more extensive screening results). The reaction
was found to proceed more efficiently in nonpolar solvents than
in polar ones, and o-xylene was found to be the best solvent.
The reaction proceeds most efficiently under an air atmosphere.
The screening on different copper salts showed that 3aa could
be isolated in 37% yield by using Cu(OAc)2 in o-xylene after 8
h (Table 1, entry 1). Introduction of 4-dimethylaminopryidine
Figure 1. Directing groups for aryloxylation of C−H bonds.
similar but monodentate directing groups (A−E) highlighted
the key role of the N,O-bidentate coordinating group. In
addition, other N,N- or N,O-bidentate directing groups such as
2-pyridinylmethylamine (G) and 2-methoxyaniline (F) could
not promote this reaction either. Notably, 8-aminoquinoline
(H) was found to be inefficient under the current reaction
conditions.
The scope of the reaction with respect to monoaryloxylation
of benzamide substrates was subsequently examined under the
optimized conditions A (Scheme 2). Evaluation of substituted
a,
b
Table 1. Optimization of Reaction Conditions
Scheme 2. C−H Monoaryloxylation of Benzoic Acid
a b
,
Derivatives
Cu(OAc)2
(equiv)
Cs2CO3
(equiv)
DMAP
(equiv)
3aa
(%)
4aa
(%)
entry
1
2
3
4
5
6
7
1
0
0
37
42
45
71
51
0
0
0
1
0
0.5
0
1
1
0
1
1
0.5
0.5
0.5
0.5
0.75
1.5
27
12
0
0.5
1
1
2
1
63
11
0
9
c
8
c,d
1.5
2
1.5
1.5
55
76
9
a
b
Amide (0.2 mmol), phenol (0.6 mmol), solvent (1 mL). Isolated
c
d
yields. Pyridine solvent. Reaction time is 4 h. DMAP = 4-
dimethylamiopryidine.
(DMAP) or Cs2CO3 resulted in higher yields (entries 2 and 3).
Addition of both Cs2CO3 and DMAP to the reaction system
was found to be crucial for this transformation, producing
monophenoxylated product 3aa and diaryloxylated product 4aa
in a 2.6:1 ratio and 98% combined yield (entry 4). Decreasing
the amount of Cu(OAc)2 to 0.5 equiv led to lower efficiency
(entry 5), and the reaction did not work when Cu(OAc)2 was
removed (entry 6). Next, we aimed at achieving symmetrical
bisfunctionalization of 1a via a double C−H aryloxylation
reaction (entries 7−9). Surprisingly, simply increasing the
amount of Cu(OAc)2 gave reduced efficiency (entries 7 and 8).
To our delight, switching the solvent from o-xylene to pyridine
and increasing the ratio of Cs2CO3/DMAP to 1:1 significantly
improved the selectivity for the diphenoxylated product 4aa,
and a 76% yield was obtained with excellent mono/di selectivity
after a shorter reaction time (entry 9). Structures of 3aa and
4aa were confirmed by X-ray crystallography (Supporting
Information). It is noteworthy that the copper salt is less
expensive and environmentally friendly, and this protocol is
conducted under convenient operating conditions despite the
requirement for stoichiometric or greater quantities of
Cu(OAc)2.
a
b
Conditions A: same reaction conditions as Table 1, entry 4. Yields
correspond to the monoaryloxylated products. The ratio of mono/di is
in parentheses and determined by 1H NMR analysis of the crude
reaction mixture; mono- and diaryloxylated products were readily
separated by silica gel column chromatography. See the Supporting
Information for details. Pyridine solvent.
amides established that the reaction is compatible with
electronically and sterically diverse substituents at the ortho,
meta, and para positions of the phenyl ring including
trifluoromethyl, methoxy, fluoro, and chloro functional groups.
For ortho-substituted substrates 1b,c, single monoaryloxylation
products were isolated in yields of 82% and 61%. When non-
ortho-substituted benzoic acid derivatives 1d−k were used, the
reaction afforded both mono- and diaryloxylated species with
the former as main products; reactions of meta-substituted
amides 1d−g revealed high regioselectivity in favor of activation
of the sterically less hindered C−H bonds. Moreover,
Studies on directing groups (Figure 1) showed that the 2-
aminopyridine 1-oxide motif appeared to be uniquely effective
for the reaction under identical conditions (Table 1, entry 4).
The absence of any reaction in the case of other structurally
B
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Letter
disubstituted substrates 1l−o bearing methyl, methoxy, or
chloro groups provided the corresponding product in moderate
to good yield (3la−oa). The naphthyl substrate could be
successfully employed in 60% yield with single selectivity (3pa).
Different substituted phenols were also investigated, and the
reaction provided the desired product regardless of electronic
and steric properties of substituents (3ab−aj). Notably, the
fluoro, chloro, bromo, and even iodo moieties on amides or
phenols were all well tolerated under these reaction conditions,
providing a complementary platform for further transformation
through cross-coupling reactions.
fluoro, chloro, and bromo but also the more challenging iodide
to afford the highly valuable halo-substituted benamides.
Additionally, multisubstituted products could also be obtained
in moderate yield, and the reaction of sterically hindered
phenols was slightly disfavored (4ah,ak). These reactions are
particularly notable as the preparation of such 2,6-diphenox-
ybenzoic acid derivatives appears to be difficult through the
cross-coupling reaction of benzene halides and phenols.20
Further studies were performed to obtain insight into the
mechanism (Scheme 4). The presence of 2,2,6,6-tetramethylpi-
The diaryloxylation of various amides with phenols was next
tested, and representative results are illustrated in Scheme 3.
Scheme 4. Deuteration and Isotope Effect Experiments
Scheme 3. C−H Diaryloxylation of Benzoic Acid
a b
,
Derivatives
peridine-N-oxyl (TEMPO, 1 equiv) as a radical scavenger had a
negligible effect on the reaction outcome under conditions A
(65% yield of 3aa), which ruled out the possibility of a radical
mechanism proposed by Yu. Next, a deuteration experiment
was conducted for 10 min under otherwise standard reaction
conditions A (Scheme 4). Treatment of a 1:1 mixture of 1a and
1a-d5 provided a kinetic isotopic effect (KIE) of 2.5, thus
indicating that the C−H activation process came into play.
Moreover, a similar KIE was obtained from the comparison of
the initial rates of 1a and the aryl-d5 substrate 1a-d5 (kH/kD =
2.4, Scheme 4, eq 1), suggesting that the C−H bond cleavage
was involved in the rate-determining step (Scheme 4, eq 1). In
addition, the H/D exchange reaction of 1a-d5 was performed in
both the absence and presence of 2a, and a significant loss of
deuterium content was found in the presence of 2a (Scheme 4,
eq 2). These observations suggest that the cleavage of C−H
bond is reversible, and in the absence of 2a, an equilibrium
between substrate + copper and the ortho-metalated species
might be in operation for the initial stage of the reaction. On
the basis of the above results and Stahl’s work on Cu(II)-
mediated oxidation of aryl C−H bonds,21 it seems reasonable
to speculate that the reaction proceeds via a CNO-pincer
Cu(III) intermediate, although the mechanism of the reaction
is unclear at present.
a
b
Conditions B: same reaction conditions as Table 1, entry 9. Yields
correspond to the diaryloxylated products. The ratio of di/mono is in
parentheses and determined by 1H NMR analysis of the crude reaction
mixture; mono- and diaryloxylated products were readily separated by
silica gel column chromatography. Please see Supporting Information
for details. The mono-C6-substituted product.
Finally, we showed that the 2-aminopyridine 1-oxide motif
can be efficiently removed from the monophenoxylated
product 3aa in a one-step procedure (eq 3). In addition, 3aa
Similar to monoaryloxylation, amides with a broad substitution
pattern and of different electronic nature were tolerated. Lower
yields and regioselectivities were observed for meta-substituted
amides 1a and 1c, likely due to steric effects. Nonetheless, the
diaryloxylated products 4da and 4ea could still be isolated in
reasonable yields (45% and 36%, respectively). Not unexpect-
edly, good results were obtained with para-substituted
substrates; in all cases examined, double o-C−H bonds were
activated (4ha−ra), and no monoaryloxylated products were
observed. This reactivity was also observed in various phenols
bearing electron-donating and -withdrawing groups, affording
the single biaryloxylated products with good yield (4ab−aj,al).
Importantly, this protocol was highly compatible with not only
could be obtained on a 2 mmol scale in 68% yield, which
revealed a bench-scale preparation. Coupling of 3aa with 4-
iodophenol provided the bis-diaryl ether 6 in 98% yield. The 2-
aminopyridine 1-oxide auxiliary can also be removed by
ethanolysis affording the corresponding ethyl ester 7 in 78%
yield. This result illustrates an alternative method to prepare
nonsymmetrical diaryloxylated benzoic acids.
C
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Letter
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In conclusion, we have demonstrated that the readily
available 2-aminopyridine 1-oxide can be used as an efficient
N,O-bidentate directing group for the direct copper-mediated
aryloxylation of arenes. The use of this new directing group
enabled selective mono- or diaryloxylation of benzamide
substrates, showing a further beneficial aspect of the bidentate
auxiliary. This protocol presents a series of advantages, such as
a broad substrate scope, cheaply available reagents, and
convenient operating conditions, thus providing a straightfor-
ward way for the synthesis of o-aryloxylated benzoic acids.
Further exploration of the synthetic utilities of this structurally
new bidentate motif and in-depth mechanistic study are
currently in progress.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experiment details and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: niujunlong@zzu.edu.cn.
*E-mail: mpsong@zzu.edu.cn.
Notes
(13) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154.
(14) For a recent review on direct C−H functionalization through
the aid of a bidentate directing group, see: Rouquet, G.; Chatani, N.
Angew. Chem., Int. Ed. 2013, 52, 11726.
The authors declare no competing financial interest.
(15) For representative examples of palladium catalysis, see:
(a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8,
3391. (b) Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J.-Q.
Organometallics 2008, 27, 1667. (c) Gou, F.-R.; Wang, X.-C.; Huo,
P.-F.; Bi, H.-P.; Guan, Z.-H.; Liang, Y.-M. Org. Lett. 2009, 11, 5726.
(d) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965.
(e) Feng, Y.; Wang, Y.; Landgraf, B.; Liu, S.; Chen, G. Org. Lett. 2010,
12, 3414. See the Supporting Information for complete citations.
(16) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am. Chem.
Soc. 2013, 135, 6030.
(17) (a) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135, 5308.
(b) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.; Chatani, N. J. Am.
Chem. Soc. 2011, 133, 14952. (c) Inoue, S.; Shiota, H.; Fukumoto, Y.;
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J. Am. Chem. Soc. 2012, 134, 18237. (d) Nishino, M.; Hirano, K.;
Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2013, 52, 4457.
(19) Our group has recently been working on the new pincer metal
catalysts via the direct metal-induced Caryl−H bond activation. For a
brief review, see: (a) Niu, J.-L.; Hao, X.-Q.; Gong, J.-F.; Song, M.-P.
Dalton Trans. 2011, 40, 5135. For recent publications, see: (b) Hao,
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M.-P. Organometallics 2012, 31, 835. (c) Wang, T.; Hao, X.-Q.; Huang,
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(d) Wang, T.; Niu, J.-L.; Liu, S.-L.; Huang, J.-J.; Gong, J.-F.; Song, M.-
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ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21072177 and 21272217) for financial support of
this work.
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