Pd-catalyzed cross-electrophile Coupling/C-H alkylation reaction enabled by a mediator generatedviaC(sp3)-H activation

Article abstract of DOI:10.1039/d1sc01731d

Transition-metal-catalyzed cross-electrophile C(sp²)-(sp³) coupling and C-H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C-H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediatorsviaprimary or secondary C(sp³)-H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

Full text of DOI:10.1039/d1sc01731d

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Pd-catalyzed cross-electrophile Coupling/C–H
alkylation reaction enabled by a mediator
generated via C(sp3)–H activation†
Cite this: Chem. Sci., 2021, 12, 8531
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
*
Zhuo Wu, Hang Jiang and Yanghui Zhang
Transition-metal-catalyzed cross-electrophile C(sp2)–(sp3) coupling and C–H alkylation reactions
represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we
report a Pd-catalyzed cascade cross-electrophile coupling and C–H alkylation reaction of 2-iodo-
alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional
groups and common protecting groups, were utilized as crucial mediators via primary or secondary
C(sp3)–H activation. The reaction provides an innovative and convenient access for the synthesis of
alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional
materials.
Received 26th March 2021
Accepted 19th May 2021
DOI: 10.1039/d1sc01731d
rsc.li/chemical-science
were reactive agents, whereas alkyl chlorides, which are more
inexpensive and less toxic, were usually unreactive.3f A stoi-
Introduction
chiometric amount of metals, such as Zn or Mn, were frequently
employed as reductants in these reactions, which produced
a large amount of metal waste.5
The introduction of alkyl moieties into aromatic rings is an
essential transformation in organic synthesis. Nowadays,
transition-metal-catalyzed cross-coupling reactions between an
electrophile and a nucleophile, generally an organic (pseudo)
halide and an organometallic reagent, have been a powerful tool
for this transformation.1 However, organometallic reagents
used in these reactions need presynthesis and careful handling,
which limits their applications.
The coupling between two electrophiles avoids the use of
organometallic reagents and thus becomes a promising alter-
native strategy for C(sp2)–C(sp3) bond formation.2 However,
there are several obstacles for developing cross-electrophile
coupling reactions. Firstly, because of electrophilic properties
of both halides, achieving the selective formation of cross-
products over two potential symmetric dimers is challenging.
Secondly, unlike the traditional coupling between an electro-
phile and a nucleophile, the catalyst loses electrons in total aer
coupling two electrophiles, and thus appropriate reductants are
required to regenerate the catalyst. Moreover, the coupling
becomes even more challenging, considering the great tendency
of b-H elimination of alkyl-metal species. Despite these diffi-
culties, in the past few decades, the cross-electrophile C(sp2)–
C(sp3) coupling reactions have been successfully developed with
Ni3 or Co4 catalysts (Fig. 1a). These reactions proceeded through
an alkyl radical mechanism. Typically, alkyl iodides or bromides
The alkylation of arenes via C–H bond activation represents
an even more efficient strategy for the incorporation of an
aliphatic moiety. In recent years, great progress has been made
in transition-metal-catalyzed alkylation reactions of arenes with
alkyl halides, alkenes, or alkylmetal reagents.6 In most cases, an
ortho-directing group was required, and the majority of the
directing groups were derived from carbonyl,7 carboxyl,8
amido,9 or N-heteroaryl10 groups. By contrast, the hydroxyl
School of Chemical Science and Engineering, Shanghai Key Laboratory of Chemical
Assessment and Sustainability, Tongji University, 1239 Siping Road, Shanghai
200092, China. E-mail: zhangyanghui@tongji.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc01731d
Fig. 1 Cross-electrophile C(sp2)–C(sp3) coupling and C–H alkylation
of phenol derivatives.
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Table 1 Survey of reaction conditions for coupling of 1a with 1-
chlorobutane
group of phenols and their derivatives was much less frequently
utilized as a directing group for C–H alkylation. In the current
C–H alkylation reactions of phenol derivatives, transition metal
catalysts are primarily limited to Co, Ru, Re and Y (Fig. 1b).11
Furthermore, for directing groups in transition metal-catalyzed
C–H activation, almost all of them rely on the coordination of
catalysts to heteroatoms they contain to assist C–H cleavage. It
is desirable to develop new directing strategies for C–H
functionalization.
Entry Base (equiv.) Additive (equiv.)
Solvent 3aaa (%) 3ba (%)
Herein, we report an unusual Pd-catalyzed cascade cross-
electrophile coupling and C–H alkylation reaction between
ortho-iodophenol derivatives and alkyl chlorides by utilizing
a methoxy or benzyloxy group as a mediator. Pd catalysts are
much less frequently applied in cross-electrophile C(sp2)–C(sp3)
coupling than Ni catalysts,12 because they tend not to undergo
a radical mechanism,13 which sets the cross-selectivity difficult
to achieve. In this reaction, C(sp3)–H bond activation of the
ortho-methoxy and benzyloxy groups plays a crucial role for the
cross-selectivity.14 For substrates with the positions ortho to the
alkoxyl group unsubstituted, C–H alkylation was initiated. The
methoxy and benzyloxy groups served as directing groups
herein. The methoxy and benzyloxy groups are different from
traditional directing groups relying on the coordination of
heteroatoms and represent a new class of directing groups for
transition-metal-catalyzed C–H activation.
1
2
3
4
K3PO4 (3)
K2CO3 (3)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
—
—
DMF
DMF
9
7
64
73
71
66
10
0
0
0
0
0
0
0
0
nBu4NBr (3), BnOH (1) DMF
nBu4NBr (3), BnOH (1) NMP
nBu4NBr (3), BnOH (1) NMP
5c
6c
7c
8c
9c,d
nBu4NBr (3), A1 (1)
nBu4NBr (3), A2 (1)
nBu4NCl (3), A2 (1)
nBu4NBr (3), A2 (1)
nBu4NBr (3), A2 (1)
NMP
NMP
NMP
NMP
NMP
72 (68b)
27
45
14
10c,e K2CO3 (5)
0
a
The yields were determined by 1H NMR analysis of the crude reaction
b
mixture using CHCl2CHCl2 as the internal standard. Isolated yield.
c
85 ꢀC. d n-BuBr. e n-BuI.
an alcohol, the repeatability of the reaction became low, and an
undesired trialkylated product 3c was formed in 5–10% yield.
Next, we studied the substrate scope of the dialkylation
reaction. The ortho-iodoanisole scope was rst probed. The
functional group compatibility was investigated by examining
the reactions of ortho-iodoanisoles bearing various substituents
para to the methoxy group. The reaction has very high func-
tional group compatibility. A wide range of functionalities,
Results and discussion
We commenced our research by investigating the reaction of 2-
iodoanisole (1a) with 1-chlorobutane (2a). The 2-iodoanisole
substrates can be readily synthesized via iodination of anisoles
or phenols. Cheap and low-toxicity alkyl chlorides are also ideal
alkylating reagents. It should be mentioned that 2-iodoanisoles
could undergo homocoupling using a methoxy group as the
directing group.15 The homocoupling should be overcome to
develop reactions with external reagents. Surprisingly, the ex-
pected monoalkylated product was not formed, whereas dia-
lkylated product 3aa and homocoupling product 3b were
obtained in low yields in the presence of K3PO4 (Table 1, entry
1).16 When K2CO3 was used as a base, the homocoupling
product was suppressed (entry 2). The addition of n-Bu4NBr and
benzyl alcohol improved the yield of 3aa greatly, and the yield
was further increased to 73% when NMP was used as the solvent
(entries 3 and 4). Tetraalkylammonium halides can promote the
coupling reactions of aryl halides by stabilizing nano-sized
palladium colloids.17 The reaction remained almost unaf-
fected when carried out at 85 ꢀC (entry 5). Although benzyl
alcohol was benecial to the reaction, its oxidized and O-alky-
lated products caused difficulty for the isolation of the desired
product. Thus, a range of alcohols with high polarity were
surveyed, and A2 was found to be an effective reductant (entries
6 and 7). When n-Bu4NCl was used instead of n-Bu4NBr, the
yield decreased to 27% (entry 8). 1-Bromo or 1-iodobutane was
also a suitable alkylating agent (entries 9 and 10). However, the
yields were much lower. It should be mentioned that the addi-
Scheme 1 Ortho-Iodoanisole scope. aIsolated yields. bMonoalkylated
tion of an alcohol is necessary for the reaction. In the absence of product. c100 ꢀC.
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including electron-donating and -withdrawing ones, were
compatible (Scheme 1, 3ba–3ia), and halo groups were well-
tolerated (3ja–3la). The performance of meta-substituted ortho-
iodoanisoles was also investigated. Notably, even in the pres-
ence of a meta-substituent, ortho-iodoanisoles were dialkylated
by overcoming the steric hindrance imposed by the meta-
substituents, forming tetrasubstituted arenes (3ma–3ra).
However, for the substrates bearing a meta-ester or -tert-butyl
group, only monoalkylated products were formed due to the
steric hindrance (3sa and 3ta). Heteroaryl groups including
pyridyl and pyrrolyl groups were compatible (3ua and 3va), and
heteroarenes and its derivative could also undergo the dia-
lkylation reaction (3wa–3ya).
The rst step of the dialkylation reaction should be the
alkylation of aryl iodides, which represents a new Pd-catalyzed
cross-electrophile coupling. Therefore, we sought to study the
reactions by using ortho-iodoanisoles without an ortho-
hydrogen. As shown in Scheme 2, a range of ortho-substituted
ortho-iodoanisoles cross-coupled with n-butyl chloride to form
alkylated anisole products (5aa–5ia). Intriguingly, for 2-iodo-1-
methoxynaphthalene, the dehydrogenative coupling reaction
occurred aer the alkylation to form cyclized product 5ja.
The alkyl chloride scope was then probed. A wide array of
alkyl chlorides containing various functionalities and with
different alkyl-chain lengths were effective alkylating reagents,
and a range of dialkylated anisoles were formed (Scheme 3,
3ab–3al). Sterically hindered alkyl chlorides could also couple
with 1a, albeit in lower yields (3am–3ao).
The cross-coupling involving secondary alkyl halides is
usually challenging.18 The reactivity of secondary alkyl halides
in the coupling reaction were examined. Whereas 2-chlor-
opropane failed to alkylate 4b, 2-bromopropane could couple
with 4b in a moderate yield (Scheme 4, 5bp). The substrate
bearing an ortho-ester group (4f) was also compatible.
The methoxy group of ortho-iodoanisoles acts as a mediator
to enable the cross-electrophile coupling and C–H alkylation
reaction. We envisioned that other alkoxy groups could also
facilitate such a cascade reaction. Gratefully, the benzyloxy
group was found to be an effective mediator for the dialkylation
reaction (Scheme 5, 7aa).19 Substituted benzyl groups also
Scheme 3 Alkyl chlorides scope. aIsolated yields. b4 equiv. of alkyl
chloride.
Scheme 4 Coupling of 2-iodoanisoles with 2-bromopropane.
enabled the alkylation (7ba–7da), and functionalized iodo-
benzenes and alkyl chlorides could undergo the cascade reac-
tion smoothly (7ea, 7fa, 7ad, and 7af). It should be noted that
benzyl groups could be cleaved readily, which allows for the
further manipulation of the resulted phenol products.
The dialkylation reaction provides a straightforward method
for the synthesis of ortho-dialkylated phenol derivatives. The
current synthetic methods for ortho-dialkylated phenols
primarily include: (1) Claisen rearrangement of phenoxy allyl
ether;20 (2) Coupling of 2,6-dihalophenol derivatives with alkyl
organometallic reagents.21 The rst method requires multiple-
step synthesis, and the Claisen rearrangement was usually
Scheme 2 Ortho-Substituted 2-iodoanisoles scope. aIsolated yields.
b10 mol% of Pd(OAc)2, 5 equiv. of K2CO3, 3 equiv. of KOAc, 2 equiv. of Scheme 5 Coupling reaction utilizing a benzyloxy group as a medi-
n-Bu4NBr, and 4 equiv. of n-BuCl were used. A2 was not added.
ator. a Isolated yields. b 2.5 equiv. of alkyl chloride.
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carried out under harsh conditions. The second method agent.24 It should be noted that all the 2-iodoanisole substrates
employs alkylmetallic reagents, and the use of dihalogenated in our alkylation reactions were prepared in one or two steps by
substrates is not atom-economic. Our dialkylation reaction using low-cost reagents.
features readily available reagents, comparatively mild condi-
tions, and high atom-economy.
The dialkylation reaction is also applicable to the dia-
lkylation of complex molecules. For example, the estradiol- and
It should be noted that dialkylated phenol derivatives are tyrosine-derived iodides could be dialkylated under the stan-
essential structural motifs widely found in bioactive molecules.22 dard conditions (Fig. 2b). It should be mentioned that the
Furthermore, they are also key intermediates in the synthesis of product 9aa was slightly racemized, which could be caused by
biologically active compounds and organic functional materials. the base and the high temperature. Furthermore, the dia-
For example, compound 3aq, which was synthesized by the lkylation reaction was scalable, and the methyl group of dia-
dialkylation of 1a with 2q under the standard conditions, could lkylated anisoles could be removed (Fig. 2c). The resulting
be hydrolyzed to 3aq-A (Fig. 2a). 3aq-A was the synthetic inter- hydroxy group allows for further functionalization.
mediate for a novel H-shaped chromophore.20a And 7er-A, which
Preliminary mechanistic studies were conducted (Fig. 3).
could be readily obtained from compound 7er, was the inter- When 3-iodoanisole 10a (or 4-iodoanisole 10b) and 1-chlor-
mediate in the synthesis of a liver X receptor b-selective ago- obutane were subjected to the standard conditions, the alky-
nist.20b For the original method, 7er-A was synthesized in eight lated products were not detected, and only the homocoupling
steps under harsh conditions. The monoalkylated anisoles were product 11a (or 11b) was obtained (Fig. 3a). The outcomes
also intermediates in the synthesis of bioactive compounds. For indicated that the presence of the ortho-methoxy group is
instance, compound 5ea was the synthetic intermediate for an crucial for the alkylation reaction. Deuterium-labeling experi-
antibacterial agent.23 Furthermore, monoalkylated product 5di ments were also carried out (Fig. 3b). When the deuterated
could afford 5di-A, which was used to synthesize an anti-cancer analogue 1a-D3 was subjected to the standard conditions, 3aa-
D2 was obtained as the major product. The proportion of 3aa-D2
was further enhanced to 95% when 20 equivalents of water was
added. Moreover, when the alkylation reaction of 1a was carried
out using CD3OD as the reductant, deuteration occurred at the
methoxy group in 40% yield. These experiments implied that
the activation of the methoxyl C(sp3)–H bond occurred and the
alcohol was one of the major reductants.25 Intermolecular
competition experiments between 1a and 1a-D3 were conduct-
ed, and the KIE value was 1.4 : 1 (Fig. 3c). The kinetic isotope
effect supported the involvement of the methoxy group in the
reaction via C–H bond activation, which might be involved in
the rate-determining step.
Fig.
2 Practical applications. Standard condition A: 10 mol% of
Pd(OAc)2, 5 equiv. of K2CO3, 3 equiv. of n-Bu4NBr, 1 equiv. of A2, NMP,
85 ꢀC, 12 h; standard condition B: 10 mol% of Pd(OAc)2, 4 equiv. of
K2CO3, 2 equiv. of n-Bu4NBr, 1 equiv. of A2, NMP, 85 ꢀC, 12 h. Other
conditions: (1) NaOH, MeOH/H2O, 60 ꢀC; (2) BnCl, K2CO3, DMF, rt; (3)
a. NaI, NaOH, NaClO aq., MeOH, 0 ꢀC; b. MeI, K2CO3, DMF, rt; (4)
CF3CO2H, NIS, MeCN, rt.
Fig. 3 Preliminary mechanistic studies.
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Fig. 4 Plausible mechanism.
On the basis of the mechanistic studies and the previous
reports,14,15,26 a possible mechanism was proposed in Fig. 4 for
the dialkylation reaction. The substrate undergoes oxidative
addition and C(sp3)–H activation to afford palladacycle B. Pal-
ladacycle B has high reactivity towards alkyl halides, and
undergoes the oxidative addition to generate Pd(IV) species C.27
The reductive elimination of C gives D. Then, the aryl C–H is
cleaved, affording a second palladacycle E. E undergoes the
same process as that for the formation of D to introduce
a second alkyl group. Eventually, alkylpalladium G is reduced,
yielding the product and releasing Pd0.
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Conclusions
In conclusion, we have developed cascade Pd-catalyzed cross-
electrophile coupling and C–H alkylation reaction of 2-iodo-
alkoxylarenes with alkyl chlorides. The ortho-methoxy or ben-
zyloxy group acted as a mediator via primary or secondary
C(sp3)–H activation. It is very rare and intriguing that the cross-
electrophile coupling is achieved by the assistance of an alkoxyl
group, which can be readily removed. The methoxy and ben-
zyloxy groups also served as non-heteroatom-chelating directing
groups for C–H alkylation reaction. The reaction provides an
efficient and innovative method for the synthesis of alkylated,
especially 2,6-dialkylated, phenol derivatives, which are ubiq-
uitous in bioactive compounds and organic functional
materials.
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Z. Wu and H. Jiang performed the experiments and analysed the
data. Y. Zhang conceived the project and analysed experimental
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´
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