Copper-catalyzed meta-selective arylation of phenol derivatives: An easy access to m-aryl phenols

Article abstract of DOI:10.1021/acscatal.0c05481

Achieving selective meta-functionalization of phenols is a significant challenge. Accessing such compounds generally needs elevated temperature or incorporation of complex templates. Here, we report a general approach to achieve meta-arylated phenols with a simple and common directing group. This coppercatalyzed protocol proceeds with complete meta-selectivity and tolerates a variety of functional groups in both coupling partners. Computational studies have revealed that the reaction proceeded via a Heck-like pathway.

Full text of DOI:10.1021/acscatal.0c05481

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Research Article
Copper-Catalyzed Meta-Selective Arylation of Phenol Derivatives:
An Easy Access to m‑Aryl Phenols
Manikantha Maraswami, Hajime Hirao,* and Teck-Peng Loh*
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ABSTRACT: Achieving selective meta-functionalization of phenols is a significant
challenge. Accessing such compounds generally needs elevated temperature or
incorporation of complex templates. Here, we report a general approach to achieve
meta-arylated phenols with a simple and common directing group. This copper-
catalyzed protocol proceeds with complete meta-selectivity and tolerates a variety of
functional groups in both coupling partners. Computational studies have revealed that
the reaction proceeded via a Heck-like pathway.
KEYWORDS: carbamates, phenols, aryliodonium salts, copper, C−H functionalization
n the past 3 decades, enormous growth has been achieved in
the reactivity of anilides in copper-catalyzed reaction5a of
diaryliodonium salts, we hypothesized that phenyl carbamates
may also react with diaryliodonium salts in a similar manner to
provide a meta-arylated product (Scheme 1).9,10
I
the area of C−H bond functionalization.1 Over the past 20
years, directed aryl sp2 C−H bond functionalization has
captured notable attention; however, this approach has
generally been confined to functionalization of the positions
ortho to the directing groups on arenes.2 In contrast to ortho-
functionalization, scope of both transformations and substrates
for selective meta-functionalization of an arene C−H bond is
still in its infancy.3−5 Phenol and its derivatives being
important arene motifs in pharmaceuticals and natural
products are versatile synthetic building blocks for many
organic transformation reactions.6 Hence, selective functional-
ization of phenol derivatives has attracted much interest from
the synthetic community. Many methods have been reported
for the modifications at the ortho/para position of phenols,7
utilizing the electron donating nature of the hydroxyl group.
However, such an electronic property restricts the functional-
ization at the meta positions of the phenol. In recent years,
Yu4a,f,l−n and Larrosa5f independently achieved palladium
catalyzed meta-selective arylation and alkenylation of phenol
derivatives through the “end-on template” directing group
strategy and traceless directing group relay strategy. Recently,
Yu’s group presented an excellent work of sequential
functionalization of a meta C−H bond followed by the
catalytic cleavage of an ipso C−O bond in phenols.4n Although
significant breakthroughs have been made,4o there is an
ongoing search for new approaches for meta C−H function-
alization of phenols. Given our continued interest in the direct
C−H functionalization and copper catalysis,8 our lab has
focused on developing new reactions that work with broad
substrate scope. Copper, being an earth abundant metal, makes
its use more viable and more cost-efficient than precious
transition metal catalysts. The first breakthrough in meta-
activation of arenes5a was reported by Gaunt, which
subsequently led to the development of new concepts for
meta-functionalization in synthetic chemistry. Influenced by
To test this hypothesis, we treated phenyl carbamate 1a with
Ph2I+OTf− in the presence of 10 mol % Cu(OTf)2 in the DCE
solvent at 70 °C. Arylation took place at the meta position to
give 2a and 3a7b in a combined yield of 75% (Table 1, entry
1), and in agreement with our hypothesis, products arylated at
either para or ortho position were not observed (analyzed by
GC). Inspired by this result, we continued with the
optimization of the protocol by retaining the o-cresol core as
our model substrate. It was revealed that changing the acyl
group had a significant effect on the selectivity and yield of the
reaction (Table 1, entries 1−5). The reaction proceeds with
acetate and pivalate groups, although the selectivity and
conversions were moderate and meta-/ortho-arylated products
were obtained with a ratio of 2:1 (Table 1, entries 2 and 3).
However, when carbonates and esters were screened, the
starting materials were retained without affording the desired
arylated products (Table 1, entries 4 and 5). Having identified
the suitable phenol derivative for arylation, we established a
condition for the hydrolysis of carbamates in order to afford
meta-arylated phenols in one pot. Initially, we found that
treating the reaction crude obtained after reaction with
Cu(OTf)2 with 10 equivalents of NaOH in EtOH at 80 °C
for 12 h provided selective meta-arylated phenol 2a in 74%
isolated yield after column chromatography (Table 2, entry 1).
Received: December 14, 2020
Revised: January 27, 2021
Published: February 5, 2021
https://dx.doi.org/10.1021/acscatal.0c05481
© 2021 American Chemical Society
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Scheme 1. Design of Meta-Selective Copper-Catalyzed C−H Bond Arylation
a
a
Table 1. Screening of the Acyl Group
Table 3. Optimization of Arylation of Phenol Carbamates
a
entry
R
Product
yield (%)
b
Entry
catalyst (10 mol %)
salt
temp [°C]
yield [%]
b
1
NMe2
Me2
CMe2
OMe
Ph
2a + 3a
2a + 3b
2a + 3c
2a + 3d
2a + 3e
20 + 55
13 + 40
12 + 52
NIL
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OAc)2
CuBr2
Ph2I+OTf−
70
70
70
60
80
70
70
70
70
70
80
100
66
74
0
c
2
Ph2I+BF4
−
c
3
Ph2I+PF6
−
4
5
Ph2I+BF4
48
56
42
63
64
60
31
26
24
−
NIL
Ph2I+BF4
−
a
b
c
Yields were determined by GC. Isolated yield. Observed meta-/
Ph2I+BF4
−
ortho-arylated products in 2:1 ratio.
Ph2I+BF4
−
Ph2I+BF4
−
CuI
Cu powder
a
Table 2. Effect of Substituents on the Nitrogen Atom
Ph2I+BF4
−
9
Ph2I+BF4
−
10
11
12
Ph2I+BF4
−
Ph2I+BF4
−
a
Reactions were carried out with 1a (1 equiv), salt (1.2 equiv), and
b
catalyst (10 mol %) in DCE (2.0 mL) for 24 h. Isolated yields after
column chromatography.
b
entry
1
2
3
4
5
R
yield (%)
In our next attempt, using (C5H5)2ZrHCl to hydrolyze the
carbamate, we managed to isolate 65% of the arylated phenol
product. Subsequently, a survey of different alkyl groups on the
nitrogen atom of the carbamate was conducted. Among the
alkyl groups screened, N,N-dimethyl-derived carbamate
afforded the desired product in satisfactory yield. We observed
that the optimized condition is applicable even for morpholine-
(Table 2, entry 4) and pyrrolidine (Table 2, entry 5)-derived
carbamates with desired products being formed in 70 and 71%
yields, respectively. Further fine tuning of reaction conditions
with respect to temperature and catalyst loading was also
conducted (Table 3). Among the diaryliodonium salts
screened, the tetrafluoroborate salt gave the product 2a in
CH3
CH3
74
65
68
70
71
c
CH2CH3
(CH2CH2)2O
(CH2)4
a
Reaction conditions: (1) 1a (1 equiv), salt (1.2 equiv), catalyst (10
mol %) in DCE (2.0 mL) for 24 h. (2) NaOH (10 equiv) in EtOH (5
mL) at 80 °C for 12 h. Isolated yields after column chromatography.
(C5H5)2ZrHCl (3 equiv) in THF (5 mL) at room temperature for
b
c
15 h.
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a
Scheme 2. Scope of Meta-Arylation with Phenol
Carbamates
Scheme 3. Scope of Diaryliodonium Salts
a
a
Reaction conditions (1) 1a (1 equiv), salt (1.2 equiv), catalyst (10
mol %), DCE (2.0 mL) 70 °C, 24 h. (2) NaOH (10 equiv), EtOH (5
mL), 80 °C, 12 h.
a
Scheme 4. Access to Meta-Arylated Carbamates
a
Reactions were carried out with 1 (1.0 equiv), salt (1.2 equiv),
b
catalyst (10 mol %) in DCE (2.0 mL) for 24 h. Diphenyliodonium
salt (0.5 equiv). Diphenyliodonium salt (3 equiv).
c
good yield. The source of the Cu catalyst proved crucial for
this transformation.
Both Cu(I) and Cu(II) species gave a phenol product in
moderate to good yield, with Cu(OTf)2 leading to the best
yields among the catalysts examined. Even simple copper
powder can provide a meta-arylated product in moderate yield
(Table 3, entry 9). The meta-arylated product was isolated in
31% yield, when the reaction was performed without the
catalyst at 70 °C (Table 3, entry 10). Subsequent screening of
the reaction in the absence of the copper catalyst at elevated
temperatures showed decrease in the yield without compro-
mising the meta-selectivity (Table 3, entries 11−12). To rule
out the possible contamination from trace impurities of
copper, a catalyst-free reaction at 70 °C was performed in
brand new glassware with a new stirrer bar and the meta-
arylated product was isolated in 28% yield.
a
Reaction conditions (1) 1a (1 equiv), salt (1.2 equiv), catalyst (10
mol %), DCE (2.0 mL) 70 °C, 24 h. (2) Me2NCOCl (1.2 equiv),
b
K2CO3 (1.5 equiv), MeCN (10 mL), 85 °C, 2 h. Diphenyliodonium
salt (0.5 equiv).
Scheme 5. Gram-Scale Synthesis
With the optimized conditions in hand, the scope of this
copper-catalyzed meta-arylation of phenol derivatives was
investigated and the results are summarized in Scheme 2. In
general, with respect to phenol carbamates, both electron-
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a
to good yields. Halogen-substituted products offer the
opportunity for further synthetic elaborations. Arylation of 2-
aryl-substituted (1k and 1m) and 2-cyclohexyl (1l)-substituted
phenol carbamates exclusively occurred at the meta position,
yielding products (2k, 2l and 2m) in good yields.
Scheme 6. Diversification of m-Aryl Carbamate 3a
Substrates bearing electron-withdrawing and electron-
releasing meta-substituents were also reactive in this protocol
(2n−2q). Carbamates bearing the 3-OMe group gave the
meta-arylated phenol (2p) in 67% yield along with an ortho-
arylated product (para to the OMe group),5b which was
obtained in 19% yield. This may be due to the strong influence
exerted by the carbamates over the −OMe group in directing
the incoming aryl moiety. The simple phenol carbamate
system forms the meta-monoarylated and diarylated products
(2r and 2s), which can be selectively accessed by controlling
the stoichiometry of the diaryliodonium salt (refer Supporting
Information). Gratifyingly, the substituent at C-4 position was
also well tolerated, giving the diarylated phenol (2t) in good
yield. Pleasingly, this protocol also accommodates 2,4-
disubstituted phenol carbamate. When 1u was employed as a
substrate, the product 2u was obtained in 64% yield. In
addition, under the optimized conditions, carbamates derived
a
Reaction conditions: aNiCl2(PCy3)2 (5 mol %), TMDSO (2.5
b
equiv), K3PO4 (4.5 equiv), toluene (1.0 mL), 115 °C. NiCl2(PCy3)2
(10 mol %), K3PO4 (7.5 equiv), PhB(OH)2 (4 equiv), toluene (1.5
mL), 130 °C.
donating and electron-withdrawing functional groups, regard-
less of their substitution patterns on the arene moiety, were all
well tolerated, affording the desired products in good to
excellent yield. A series of ortho-substituted phenol carbamates
including electron-releasing and electron-withdrawing sub-
stituents provided arylated products (2a, 2f−2j) in moderate
Figure 1. Proposed mechanisms for Cu-catalyzed meta-arylation of anilides.5a,12
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Figure 2. (a) DFT-calculated free energy profile (kcal/mol) for the Cu-catalyzed meta-arylation. (b) Transition state (TS1) for the meta attack.
Key distances are shown in Å.
Figure 3. Proposed mechanism for uncatalyzed meta-arylation of aryl carbamates.
from naturally occurring estrone (1v) yielded the correspond-
ing arylation product in 61% with exclusive meta-selectivity.
Next, we extended the scope of our copper-catalyzed meta-
arylation of carbamates with an array of diaryliodonium salts
(Scheme 3). The arylating coupling partners possessing both
electron-releasing and electron-withdrawing groups at the para
position produced selective meta-arylated products in good to
moderate yields (2w, 2aa, and 2af were obtained in 80, 57, and
69% isolated yields, respectively). Furthermore, salts bearing
halides (F, Cl, and Br) were compatible under the optimized
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reaction conditions, giving monoarylated products (2x, 2y, and
2z) in good yield. These results provide a platform for further
utilization of meta-arylated products via transition metal-
catalyzed cross-coupling reactions. Diaryliodonium salts
bearing electron-releasing or electron withdrawing meta-
substituents were also effective in this protocol, giving the
corresponding products (2ab−2ad). Also, o-methoxy iodo-
nium salt reacted smoothly to give meta-arylated carbamate
(2ae) in 42% yield.
This arylation method can also be applied to get meta-
arylated carbamates in quantitative yields. After the first step,
treating the crude reaction mixture with Me2NCOCl and
K2CO3 in acetonitrile at 80 °C for 2 h, we can access the
corresponding carbamates in quantitative yields (Scheme 4).
To explore the utility of this process on a preparative scale,
we performed the reaction in gram scale with substrate 1a and
diphenyliodonium tetrafluoroborate salt. Gratifyingly, our
copper-catalyzed meta-arylation of carbamates worked well in
gram scale to give the desired product 2a in 72% isolated yield
(Scheme 5).
reaction is even more favored than the anti attack in
mechanism A, as the TS for the syn attack can have some
degree of stabilization because of the interaction between the
acetoxy oxygen and the CuIII site (Figure S1).
Based on previous literature,15 it is known that diary-
liodonium salts react with electron-rich arenes under metal-free
conditions to form arylated products. It is also known that
iodine and compounds of iodine behave in a similar manner to
the copper-catalyzed transformations.16 Hence, we speculate
that the meta-selective arylation in the absence of copper
catalysts proceeds, as shown in Figure 3. As there is no
possibility to form a very reactive Cu(III)−aryl intermediate in
the absence of the copper catalyst, we support our observation
of less yield at 70 °C for the uncatalyzed reaction. At this
moment, we are not clear about the exact mechanism for the
uncatalyzed reaction, and further investigations are needed to
support the proposed mechanism.17
In summary, we have demonstrated the first example, in the
literature, of a meta-selective arylation protocol of phenol
derivatives catalyzed by copper. The current method provides
room for further functionalization of the obtained products
and thus would find applications in pharmaceuticals and
complex molecule synthesis. Computational studies showed
that the reactions most probably proceeded via Heck-like four-
membered ring TSs.
To demonstrate the synthetic utility of this meta-arylation,
we attempted diversification of 3r using the carbamate as a
synthetic handle (Scheme 6). Carbamate 3r was converted
into possible other products in good yields by using the
reported methods such as reductive cleavage11a and cross-
coupling11b reactions.
In the literature,5a,12 there are two proposed mechanisms for
a similar meta-arylation process, as shown in Figure 1. The
mechanism (A) shown in Figure 1a proceeds via anti-
oxycupration, whereas mechanism (B) shown in Figure 1b
proceeds via a Heck-like four-membered transition state (TS).
Li, Wu, and co-workers have performed density functional
theory (DFT) calculations for the reaction between acetanilide
and PhCu(OTf)2and demonstrated that mechanism B is much
more stable and feasible.12 To probe the mechanism of the
reaction of acyl-type substrates examined in this work, we
performed DFT computational studies of the reaction between
the acetoxy-substituted substrate (2) and PhCu(OTf)2 using
the M06-2X functional.13,14 As in the case of anilides,13 our
DFT results show that the Heck-like mechanism B is much
more favored than mechanism A in the reaction of acyl
substrates, with the reaction in mechanism B proceeding with a
much lower activation barrier. Importantly, the TS for the
meta attack (TS1) is lower (11.0 kcal/mol) in energy than the
TSs for the ortho and para attacks by >6 kcal/mol. The
preference for the meta attack can be attributed to the
coordination bond existing between acetoxy oxygen and the
CuIII site (Figures 1b and 2), which the other TSs cannot form
(Figure S1).
TS1 is followed by a very stable intermediate (Int1), and the
subsequent barrier for proton abstraction from the meta
carbon via TS2 is rather small (6.8 kcal/mol). Therefore, the
selectivity of the reaction is determined by the first C−C bond
formation step, and the DFT results explain well why only the
meta product is obtained in our experiments. As shown by Li,
Wu, and co-workers for anilides, mechanism A has a
prohibitively high barrier (Figure S2). For this mechanism,
especially for the reaction of 2 and at the level of theory
employed here, a CuIII−aryl intermediate could not be
obtained, but C−C bond formation occurred directly after
the TS in mechanism A. These results suggest that mechanism
A is unlikely to operate under actual experimental conditions.
It is also interesting to note that the syn analogue of the
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c05481.
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR, and HRMS) (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Hajime Hirao − School of Life and Health Sciences and
Warshel Institute for Computational Biology, The Chinese
University of Hong Kong, Shenzhen, Guangdong Province
518172, China; orcid.org/0000-0002-8239-3471;
Email: hirao@cuhk.edu.cn
Teck-Peng Loh − Institute of Advanced Synthesis (IAS),
School of Chemistry and Chemical Engineering, Northwestern
Polytechnical University (NPU), Xi’an 710072, China;
Yangtze River Delta Research Institute of NPU, Taicang,
Jiangsu 215400, China; Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, 637371, Singapore;
orcid.org/0000-0002-2936-337X; Email: teckpeng@
ntu.edu.sg
Author
Manikantha Maraswami − Division of Chemistry and
Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, 637371,
Singapore
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c05481
Notes
The authors declare no competing financial interest.
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Warratz, S.; Zell, D.; De Sarkar, S.; Ishikawa, E. E.; Ackermann, L. N-
Acyl Amino Acid Ligands for Ruthenium(II)-Catalyzed meta-C-H
tert-Alkylation with Removable Auxiliaries. J. Am. Chem. Soc. 2015,
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M. F.; Press, N. J.; Frost, C. G. Catalytic meta-Selective C-H
Functionalization to Construct Quaternary Carbon Centres. Chem.
Commun. 2015, 51, 12807−12810. (h) Ruan, Z.; Zhang, S.-K.; Zhu,
C.; Ruth, P. N.; Stalke, D.; Ackermann, L. Ruthenium(II)-Catalyzed
meta C-H Mono- and Difluoromethylations by Phosphine/Carbox-
ylate Cooperation. Angew. Chem., Int. Ed. 2017, 56, 2045−2049.
(i) Leitch, J. A.; McMullin, C. L.; Mahon, M. F.; Bhonoah, Y.; Frost,
C. G. Remote C6-Selective Ruthenium-Catalyzed C-H Alkylation of
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from North-
western Polytechnical University (NPU), China, Tier 1 grant
M4012045.110 (RG12/18-S) from the Ministry of Education
of Singapore and Distinguished University Professor grant,
Nanyang Technological University, Singapore.
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(17) The mechanism was revised during the revision. We thank the
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