Aromaticity-Dependent Regioselectivity in Pd(II)-Catalyzed C-H Direct Arylation of Aryl Ureas

Article abstract of DOI:10.1021/acs.orglett.5b03153

Palladium-catalyzed C-H direct arylation generally occurs on the ortho-position of directing groups. By comparing meta-arylated products of 2-naphthyl urea to ortho-arylated products of phenyl urea, the ortho- and meta-regioselectivity of aryl ureas were found to depend on the aromaticity of the corresponding aryl substituents. Thus, aromaticity is a new factor which can affect the regioselectivity in C-H direct arylation. The finding was further confirmed by regioselective direct arylation of indole and pyrrole derivatives.

Full text of DOI:10.1021/acs.orglett.5b03153

Letter
pubs.acs.org/OrgLett
Aromaticity-Dependent Regioselectivity in Pd(II)-Catalyzed C−H
Direct Arylation of Aryl Ureas
Pingping Jiang,† Feng Li,† Yongbao Xu, Qingwen Liu, Jing Wang, Hong Ding, Renfu Yu,
and Qifeng Wang*
International Joint Research Laboratory of Nano-Micro Architecture Chemistry (NMAC), Department of Organic Chemistry,
College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, P. R. China
S
* Supporting Information
ABSTRACT: Palladium-catalyzed C−H direct arylation gen-
erally occurs on the ortho-position of directing groups. By
comparing meta-arylated products of 2-naphthyl urea to ortho-
arylated products of phenyl urea, the ortho- and meta-
regioselectivity of aryl ureas were found to depend on the
aromaticity of the corresponding aryl substituents. Thus,
aromaticity is a new factor which can affect the regioselectivity
in C−H direct arylation. The finding was further confirmed by
regioselective direct arylation of indole and pyrrole derivatives.
irect C−H functionalization is one of the most powerful
unexpected factor that affects the regioselectivity of C−H bond
direct arylation.
D
and atom-economical methods for the construction of
C−C bonds.1 A serious problem in this field is the control of
regioselectivity when multiple C−H bonds exist in one
molecule. Based on the Directed ortho Metalation theory,
transition metal catalyzed ortho C−H bond direct functional-
ization could be realized regioselectively via the C−M bond
formed in situ (M = transition metal). In recent years, chemists
have begun developing efficient methods for achieving remote
C−H bond activation.2 For example, Yu et al. reported a
covalent template strategy for remote C−H activation and
norbornene as a transient mediator for meta-C−H activatio-
n.2a,b Gaunt et al. reported copper(II) catalyzed meta-arylation
of aromatics using diaryliodonium salts as coupling partners.2c
However, only very few studies on direct arylation of C−H
bonds adjacent to in situ generated C−M bonds have been
reported (Scheme 1).3 Such a strategy not only can realize
At the beginning of this work, the reaction of 2-naphthyl urea
1a with o-tolylboronic acid 2a was performed under our
previously reported conditions (entry 1 in Table 1). Under
these conditions, 2-naphthyl urea 1a decomposed completely
and no arylated products were generated. We thus turned our
attention to identifying suitable oxidative conditions for this
coupling reaction. In entry 2, when K2S2O8 was used as the
oxidant in a mixture of toluene and acetic acid,5 the
monoarylated product was generated in 55% crude yield (as
estimated by NMR), despite the presence of byproducts which
were difficult to remove. With benzoquinone as the oxidant, the
corresponding monoarylated product was not detected (entry
3). By changing the shoichiometry of the oxidant to 3.0 equiv
of PhCO3Bu-t, the estimated yield of monoarylated product
was identified as 76%, with complete decomposition of the
remaining starting material 1a (entry 4). Although the use of a
combination of 2.0 equiv of PhCO3Bu-t with 1.0 equiv of
Cu(OAc)2·H2O gave the monoarylated product in a relatively
low yield (63%), starting material 1a was recoverd, thus
providing the possibility for further improvement (entry 5). In
entry 6, the estimated yield from NMR data could be slightly
improved to 69% when the loading of coupling partner 2a was
raised to 3 equiv. The reaction was found to be strongly
affected by the acidity of the solvent. In entry 7, the reaction
proceeded very poorly in toluene, giving the monoarylated
product in only 39% NMR yield. In contrast, we were delighted
to see the reaction proceeding smoothly in HOAc, with a 79%
yield in the arylated product. With an additional 1.0 equiv of
TsOH·H2O, the yield could be further improved to 85%, with
Scheme 1. Direct Arylation of C−H Bond Adjacent to the
C−M Bond
remote C−H bond activation but also can supply possibilities
for new chemical transformations. Very recently, our group
reported the palladium-catalyzed meta-direct arylation of β-
naphthyl carbamate via an ortho-metalation/meta-direct aryla-
tion pathway.4 However, direct arylation of phenyl carbamates
under the same conditions proved unsuccessful, which made
the nature of the regiochemical outcome puzzling. To give a
clear interpretation of this unique regioselectivity, we report
herein the results of the direct arylation of aryl urea derivatives.
The degree of aromaticity of the aryl groups was revealed as an
Received: October 31, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03153
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Table 1. Optimization of the Reaction Conditions for C−H
Bond Direct Arylation
Table 2. Scope Of Aryl Boronic Acids In Direct meta-
Arylation of 1a
a
yield
entry
1
oxidant (equiv)
K2S2O8 (6.0)
additive (equiv)
AgOAc (0.05)
solvent
(%)
b
TFA/HOAc
= 2/1
N.D.
2
3
4
5
K2S2O8 (3.0)
BQ (5.0)
TsOH·H2O
PhMe/HOAc
= 1/1
55
(1.0)
b
TsOH·H2O
(1.0)
PhMe/HOAc
= 1/1
N.D.
76
PhCO3Bu (3.0)
PhCO3Bu (2.0)
TsOH·H2O
(1.0)
PhMe/HOAc
= 1/1
TsOH·H2O
(1.0)
PhMe/HOAc
= 1/1
63
Cu(OAc)2·H2O
(1.0)
c
6
PhCO3Bu (2.0)
TsOH·H2O
PhMe/HOAc
= 1/1
69
39
79
85
(1.0)
Cu(OAc)2·H2O
(1.0)
c
7
PhCO3Bu (2.0)
TsOH·H2O
(1.0)
PhMe
HOAc
HOAc
Cu(OAc)2·H2O
(1.0)
c
8
PhCO3Bu (2.0)
TsOH·H2O
(1.0)
Cu(OAc)2·H2O
(1.0)
c
9
PhCO3Bu (2.0)
TsOH·H2O
(2.0)
Cu(OAc)2·H2O
(1.0)
a
Yields were calculated according to 1H NMR using 4-methoxyphenol
b
c
as internal standard. N.D. = not detected. 3.0 equiv of 2a were used.
complete consumption of 1a. Therefore, the reaction was
optimally performed using 5 mol % Pd(OAc)2 as a catalyst
precursor, 2 equiv of PhCO3Bu-t and 1 equiv of Cu(OAc)2·
H2O as oxidants, and 2 equiv of TsOH·H2O as an additive at
25 °C in HOAc under an air atmosphere.
Under these optimized conditions, we examined the scope of
aryl boronic acids and identified the structure of monoarylated
2-naphthyl urea (Table 2). In entry 1, the isolated yield of 3aa
was 78%. Phenyl boronic acid provided the monoarylated
product 3ab in 64% isolated yield (entry 2). By removing the
N,N-dimethyl carbamic group, the resulting compound could
be confidently assigned as the meta-phenylated 2-naphthyl
amine (see Supporting Information (SI)).6 Phenyl boronic acid
bearing a methyl group on the para- or meta-position of the
phenyl ring could be transformed into the corresponding meta-
arylated products 3ac and 3ad in 66% and 64% yields,
respectively (entry 3 and 4). Electron-rich p-methoxyphenyl
boronic acid could give the meta-arylated product 3ae in 63%
isolated yield (entry 5). Phenyl boronic acids bearing electron-
withdrawing substituents such as p-F, p-Cl, and m-Cl groups
provided the meta-arylated products 3af, 3ag, and 3ah in 60%,
52%, and 53% yields, respectively (entries 6, 7, and 8). We also
tested the reactivity of polyaromatic boronic acids. Both α- and
β-naphthyl boronic acids could react smoothly with 1a to
a
b
Isolated yields. 1.5 equiv of 1a were used.
generate meta-arylated products 3ai and 3aj in moderate to
good yields (entries 9, 10). 4-Biphenylboronic acid 2k could
also be successfully introduced on the meta-position of 1a,
giving 3ak in 78% yield (entry 11). To further confirm the
B
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regioselectivity, X-ray diffraction of compound 3ah was
performed, and its connectivity was verified (see SI).
Scheme 3. Proposed Mechanism
Next, direct arylation of phenyl ureas was investigated. As
shown in Scheme 2, under the same optimized conditions as
Scheme 2. Direct Arylation of Phenyl Urea with Arylboronic
Acids under Optimized Conditions
described above, phenylboronic acid and its electron-rich and
-poor derivatives gave exclusively ortho-arylated products.
Although the electron-rich arylboronic acids gave ortho-arylated
products in lower yields (3bc, 3be, and 3bn), no meta- or para-
arylated products were formed. Changing the solvent to
toluene, the yields were effectively improved. The regioselec-
tivity in this reaction is consistent with that in Lipshutz and co-
workers’ work7 and unambiguously demonstrated that directed
ortho-metalation could occur in this catalytic system.
According to the different regioselectivity of 2-naphthyl urea
and phenyl urea, we conclude that the difference in
nucleophilicity and aromaticity of the aryl groups lead to
different reaction pathways. A proposed mechanism is depicted
in Scheme 3. After coordination of the palladium catalyst to the
directing group, electrophilic attack of the palladium catalyst to
the ortho-position of the urea substituent occurs, generating the
corresponding C−Pd bond. In this step, ortho-C−H bond
cleavage may occur via SEAr, concerted metalation/deprotona-
tion (CMD) or other mechanisms, generating intermediate A
in Cycle 1. Nevertheless, dearomatization of aryl groups can
alternatively proceed, giving a carbocationic species D in Cycle
2. The competition between ortho C−H bond cleavage and
dearomatization leads to different reaction pathways. Since the
aromaticity of a phenyl ring is stronger than a single aromatic
ring of the naphthyl group, C−H bond cleavage occurs and
ortho-arylated product C is formed via successive trans-
metalation and reductive elimination (Cycle 1). On the other
hand, 2-naphthyl urea undergoes dearomatization in one
aromatic ring, generating benzylic carbocationic species D.
Intermediate D undergoes transmetalation with aryl boronic
acids, followed by intramolecular nucleophilic rearrangement
and rearomatization to give the final meta-arylated product H
(Cycle 2 in Scheme 3).4
arylation. As mentioned in Scheme 3, once the ortho C−H
bond is cleaved, ortho-arylation occurs. With a more stable ortho
C−C bond, dearomatization becomes the only possible
pathway. Therefore, β-arylated product 1db could be obtained
via Cycle 2. Under the same conditions, we changed the
substrate to 1e bearing an an α-C−H bond and the α-arylated
product 1eb was formed exclusively in 42% isolated yield,
indicating the formation of α-C−Pd bond and its tendency in
ortho C−H bond arylation versus β-arylation and dearomatiza-
tion. Because it has been reported that Cu2+ could arguably
affect the regioselectivity of indole derivatives,8 we also changed
the oxidant to K2S2O8 to confirm the α- and β-regioselectivity.
Under condition b in Scheme 4, β-arylated product 1db was
obtained in 62% isolated yield and α-arylated product 1eb was
isolated in 72% yield. It should be stressed that N-propyl-2-
methylindole was still inert to phenylboronic acid 2b under
condition b, even though the solvent was diluted with toluene
to avoid its decomposition (condition c). Pyrrole derivatives
were also tested under these two conditions. Although most of
the starting material 1g decomposed under the oxidative
conditions, α-arylated N-pyrrole carbamate 1gb was isolated in
16% and 6% yields under condition a and b, respectively. Using
2,5-dimethyl pyrrole carbamate as the substrate, decomposition
of 1f proceeded very rapidly in the presence of PhCO3Bu-t and
Cu(OAc)2·H2O, but β-arylated product 1fb was obtained in
Because heteroarenes have a low degree of aromaticity, we
used indole and pyrrole derivatives as the substrates to further
study this mechanism. As shown in Scheme 4, using N-propyl-
2-methylindoles to react with phenylboronic acid 2b under our
reaction conditions, we found the starting material gradually
decomposed and no arylated products could be detected. In
contrast, changing the indole N-substituent to N-dimethylcar-
bomic (1d) led to β-arylated product 1db in 33% isolated yield.
This result proved the necessity of the directing group for β-
C
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Letter
Scheme 4. Regioselective Direct Arylation of Indole and
Pyrrole Derivatives under Different Conditions
ACKNOWLEDGMENTS
■
The work was supported by National Natural Science
Foundation of China (No. 21202060) and Creative Program
in Jilin University (No. 336OEP06).
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24% isolated yield when K2S2O8 was used as the oxidant
(Condition b). These results are similar to those obtained in
the indole experiments and are consistent with our proposed
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In conclusion, we have developed a method for the direct
meta-arylation of 1,1-dimethyl-3-(naphthalen-2-yl) urea. The
reaction proceeded in an ortho-metalation/meta-direct arylation
process. By comparing the regiochemical outcome in the direct
arylation of 2-naphthyl urea versus phenyl, the important
relationship between substrate aromaticity and selectivity
became clear. This finding was further confirmed by performing
the direct arylation of indole and pyrrole derivatives with aryl
boronic acid. This finding will be potentially helpful for remote
C−H bond functionalization of diverse polyaromatics.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03153.
Experimental procedures and characterization data for
new compounds (PDF)
Crystallographic data for 3ah (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wangqifeng@jlu.edu.cn.
Author Contributions
†P.J. and F.L. contributed equally.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.5b03153
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