C(sp3)-H Monoarylation of Methanol Enabled by a Bidentate Auxiliary

Article abstract of DOI:10.1021/acs.orglett.0c03786

With the assistance of a practical directing group (COAQ), the first catalytic protocol for the palladium-catalyzed C(sp3)-H monoarylation of methanol has been developed, offering an invaluable synthesis means to establish extensive derivatives of crucial arylmethanol functional fragments. Furthermore, the gram-scale reaction, broad substrate scope, excellent functional group compatibility, and even the practical synthesis of medicines further demonstrate the usefulness of this strategy.

Full text of DOI:10.1021/acs.orglett.0c03786

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Letter
C(sp3)−H Monoarylation of Methanol Enabled by a Bidentate
Auxiliary
Quan Gou,* Binfang Yuan,* Man Ran, Jian Ren, Ming-zhong Zhang, Xiaoping Tan, Tengrui Yuan,
and Xing Zhang
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ABSTRACT: With the assistance of a practical directing group
(COAQ), the first catalytic protocol for the palladium-catalyzed
C(sp3)−H monoarylation of methanol has been developed,
offering an invaluable synthesis means to establish extensive
derivatives of crucial arylmethanol functional fragments. Further-
more, the gram-scale reaction, broad substrate scope, excellent
functional group compatibility, and even the practical synthesis of
medicines further demonstrate the usefulness of this strategy.
nert C−H activation is arguably one of the most powerful
methanol as a practical hydroxymethylation agent to obtain
higher alcohols (Scheme 1). The Krische group independently
developed a few indicative strategies on Ir-catalyzed C−C
couplings of methanol with π-unsaturated reactants (dienes, α-
olefins, and allenes) via the process of transfer hydrogenation
and carbonyl addition, thus making higher alcohols bearing
alkene groups (Scheme 1, path a).8 To realize the
uncomplicated hydroxymethylation of aromatics, another
strategy has exclusively focused on the free-radical process
limited to the means of oxidation or photocatalysis (Scheme 1,
path b).9 From a synthetic perspective, the direct C−H
monoarylation of methanol using a transition-metal-catalyzed
system will be a sufficiently attractive innovation (Scheme 1,
path c). However, this challenging catalytic strategy to achieve
the C-functionalization of methanol is scarce. We suspected
that the reported auxiliaries were too close to the α-C−H bond
of methanol to form the relatively less strained five- or six-
membered cyclometalation intermediate.10 Another challenge
is that the more reactive and less hindered primary C−H
bonds easily produce a diarylation product in the process of
monoarylation.11,14a If the C(sp3)−H monoarylation of
methanol could ideally proceed, then there would be an
innovative route to prepare arylmethanols (Scheme 1, II). To
our knowledge, the unique fragment of arylmethanol is
I
arylation synthesis strategies, making various types of
essential molecular structures to advance molecular value.1
Notably, arousing the considerable interest of synthetic
chemists, aliphatic alcohols play a vital role in natural products
and synthetic intermediates suitable for driving drug
discovery.2 A variety of elegant protocols have been developed
by using a transition metal to achieve the successful C(sp3)−H
functionalization of aliphatic alcohols.3 In comparison, the
transition-metal-catalyzed C(sp3)−H arylation of aliphatic
alcohols is drastically limited. Recently, palladium-catalyzed
C(sp3)−H arylation reactions have been dominantly estab-
lished by Xu4a,b and Yu4c,d with the development of a new
bidentate auxiliary to achieve the diversification of aliphatic
alcohols. Despite these significant advances in the selective
functionalization of aliphatic alcohols by diverse bidentate
directing groups,5 these examples based on the C−H activation
of aliphatic alcohols are limited to the β- or γ-C−H positions
of the oxygen atom. However, the unconventional α-C(sp3)−
H arylation of aliphatic alcohols remains unexplored thus far.
Developing such a protocol could offer a potential opportunity
for the C−H activation of the C1 molecule.
As a vastly abundant solvent, inexpensive feedstock, and
cost-effective reagent for the preparation of industrial
chemicals, pharmaceuticals, alternative fuel, and materials, C1
molecule methanol has aroused widespread interest by
researchers in industry and academia.6 Recently, the utilization
of methanol as a C1 source for the formation of C−C bonds
has been one of the ideal synthesis methods to facilitate the
transformation from lower alcohols to higher alcohols.7
Presently, several remarkable works have been reported on
two different reaction mechanisms for C−C couplings with
Received: November 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03786
© XXXX American Chemical Society
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A

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a
Scheme 1. C-Functionalization of Methanol and
Applications
Table 1. Optimization of Arylation Reaction
yield of
b
entry
catalyst
solvent
base
additive
3a (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2(COD)
Pd(acac)2
THF
AgOAc
AgOAc
AgF
−
−
−
−
−
−
−
−
12
32
0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
anisole
bezene
PhCl
Ag2O
0
LiOAc
NaOAc
KOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
18
12
22
45
dec.
trace
62
80
56
46
55
53
9
−
−
−
10
11
12
13
14
BTF
BTF
BTF
BTF
−
Cu(OAc)2
Mn(OAc)2
−
c
d
15
16
BTF
−
a
Reaction conditions: 1a (0.2 mmol), catalyst (10 mol %), and base
b
widespread in natural products, fragrances, biologically active
compounds, drugs, and valuable synthons (Scheme 1, III).12
Herein we first report a useful and powerful strategy of the α-
C(sp3)−H monoarylation of methanol with the assistance of
an appropriate bidentate directing group to synthesize diverse
arylmethanol derivatives.
(2.0 equiv) in 1.0 mL of solvent at 120 °C for 24 h. Isolated yields.
c
d
Addition of 1.0 equiv of Cu(OAc)2. Addition of 1.0 equiv of
Mn(OAc)2. dec., decomposed; THF, tetrahydrofuran; BTF, benzotri-
fluoride.
presented in the C−H arylation process of methanol.
Considering OAc anion as a basic ligand or an internal base
for straightforwardly promoting C−H activation,16 we
individually checked a variety of OAc salts such as LiOAc,
NaOAc, KOAc, and CsOAc (Table 1, entries 5−8).
Encouragingly, we found that CsOAc was an optimal base,
which accelerated the progress of the monoarylation reaction
via Pd(OAc)2 catalysis, affording the corresponding product in
45% yield (entry 8). As expected,14 we did not observe the
diarylation product 4a along with the monoarylation product.
Because the solvent effect plays a critical role in facilitating the
arylation reaction, various aromatic solvents installed by
electron-donating or electron-withdrawing substituents from
commercial vendors like anisole, benzene, chlorobenzene
(PhCl), and benzotrifluoride (BTF) were carefully investigated
(entries 9−12). To our delight, the BTF was the optimal
solvent, furnishing the desired product 3a in 80% yield (entry
Our investigations commenced with the exploration of a
versatile directing group, which is a useful synthesis tool for the
construction of C−C bonds.1b,13 To seek a suitable directing
group, we designed and synthesized multiple types of
representative directing groups, including monodentate and
bidentate directing groups bearing a N, O, or S atom (Table 1;
see the Supporting Information for details). Unfortunately, the
corresponding arylated product was not observed with any
kind of newly designed auxiliary group using a stoichiometric
amount of AgOAc as an iodide scavenger (Table 1, D-1 to D-
6).14a,b However, we were incredibly lucky to find that the
desired arylated product 3a was furnished by the treatment of
1a attached to the COAQ group with Pd(OAc)2 (10 mol %)
and AgOAc (2.0 equiv) at 120 °C, albeit a significantly lower
yield of 12% was provided (entry 1). Then, we found that the
arylated yield was improved to 32% when toluene was used as
a solvent (entry 2), which commonly acts as a useful solvent in
C−H arylation.15 After examining other silver salts (entries 4
and 5), the significance of the OAc anion was obviously
17
12). Adding extra additives such as Cu(OAc)2 or Mn-
(OAc)2,11a the arylated yields were significantly decreased, and
the abundant starting substrate 1a was observed (entries 13
B
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and 14). After a brief screening of catalysts, the yields of the C-
arylation of methanol were reduced to 55 and 53%,
respectively (entries 15 and 16).
After the optimal C−H monoarylation conditions were
obtained, we investigated the scope of aryl iodides in the
reaction with masked methanol 1a to verify the feasibility of
our protocol (Scheme 2). The different classes of para-
iodides, the electron-deficient substrates with ketones, esters,
amides, or other groups were also well-tolerated to give the
expected product in a slightly lower yield (3j−n). Similarly,
meta-substituted aryl iodides bearing different electrical groups
could also obtain a satisfactory result (3o−p). These substrates
without substituents or with multiple substituents performed
well under the conditions to give the corresponding arylation
products in moderate to good yields (3q−z). Aryl iodides,
including various heteroaryl iodides and polycyclic aryl iodides
with outstanding value in drug molecules, were compatible
with the reaction conditions, providing the monoarylation
products in moderate to excellent yield (3aa−ff). It is worth
noting that the strongly coordinating nitrogen atoms of
quinoline, pyridine, and pyrazole did not completely inhibit
the activity of the Pd catalyst, although relatively weak
reactivity was exhibited. Afterward, a wide range of more
complex molecules attached to unique skeletons were explored
under the optimal reaction conditions to provide the related
more arylmethanol derivatives. Various aryl iodides bearing the
delicate motifs such as indole, 1,3-benzodioxole, alkyl sulfide,
OAc-protected β-D-glucose pentaacetate, hydroxyquinoline,
and protected β-amino acid also performed well, leading to
moderate to excellent yields (3gg−mm). It is worth
mentioning that these reactions not only provided further
evidence that this unconventional method to form distinctive
building blocks of arylmethanol is feasible but also helped to
promote the diversification of methanol by C−H activation.
Furthermore, substrates linked to medicinally indispensable
heterocycles like pyrimidine18a and pyrazole18b were well
tolerated to afford moderate yields (3nn−oo). To our delight,
the use of the COAQ auxiliary with our catalytic system
effectively decreased the directed interference from the
strongly coordinating nitrogen atoms, thereby shutting down
the C−H activation of the ortho position of the aromatic ring
adjacent to pyrimidine or pyrazole groups. Overall, we have
provided a highly versatile protocol to synthesize valuable
arylmethanol derivatives.
a b
,
Scheme 2. Scope of Aryl Iodides
To further demonstrate the practical utility of the method,
we implemented a variety of transformations by using
arylmethanol fragments as the starting materials. The directing
group COAQ could be quickly unloaded from the compound
3q by treatment with NaOH to produce benzyl alcohol 4q in
excellent yield (Scheme 3a; see the Supporting Information for
details). Then, the hydroxyl group of compound 4q could be
conveniently converted to a halogen group.19a−d Meanwhile,
the hydroxymethyl group could be easily transferred to other
functional groups like ketone, ester, cyano, and amine via the
reported references (6−10).19e−i The piperonyl alcohol 4hh
obtained by removing the COAQ was smoothly carried out to
synthesize the piribedil for the treatment of Parkinson’s disease
(Scheme 3b).20a Similarly, the benzyl alcohol 4q was
successfully treated with compound 1e to give the medicine
donepezil for Alzheimer’s disease (Scheme 3b).20b
To gain more insight into the reaction mechanism, we
designed a series of control experiments to verify the
significance of the COAQ auxiliary for the arylation of
methanol under the present reaction conditions. (See the
control experiments in the Supporting Information.) The
methanol without the installation of COAQ shut down the
arylation reaction (eq c1 in the Supporting Information).
Meanwhile, we found that any changes to this bidentate
directing group would stop the reaction (eqs c2 and c3 in the
Supporting Information). These results indicated that the
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (10 mol %), and
CsOAc (2.0 equiv) in 1.0 mL of BTF (benzotrifluoride) at 120 °C for
b
c
24 h. Isolated yields. Gram-scale synthesis.
substituted aryl iodides bearing OMe, Me, Ph, allyl, and MeS
groups were compatible with the reaction conditions, affording
the corresponding monoarylation products in moderate to
good yields (3a−f). To our delight, the application of the
reaction conditions was successfully conducted on gram-scale
synthesis to obtain the desired 3a in 74% yield. (See the
Supporting Information for details.) Additionally, starting
materials containing useful motifs of the protected alcohol,
azide, and tertiary alkylamine also worked smoothly to furnish
the functionalized products, which can be further used as the
especially useful synthons to construct more valuable
molecules (3g−i). Compared with the electron-rich para-aryl
C
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reaction.21 (See the Supporting Information for details.) To
further grasp a feasible reaction pathway, we carried out
detailed density functional theory (DFT) calculations using
Gaussian 09. (See the Supporting Information for details of
computational studies.) As shown in Figure 1, compounds 1a
and 2a were chosen as model substrates. According to a
detailed analysis of the C−H activation and the oxidative
addition steps, the reaction by path B is energetically less
feasible for the C(sp3)−H activation due to the excessively
high transition state ts3′ with an activation energy of 68.4 kcal
mol−1 (Figure 1). In contrast, the A pathway is thermodynami-
cally favorable because the C(sp3)−H activation step only
requires the lower energy transition state ts2 of 10.9 kcal
mol−1.
Scheme 3. Diversified Transformations of Arylmethanol
Fragments
On the basis of previous reports on palladium-catalyzed C−
H bond arylation and the above mechanistic studies, a
plausible reaction mechanism is tentatively proposed, as
shown in Scheme 4. Initially, with the assistance of a bidentate
auxiliary COAQ, substrate 1a could easily coordinate the
Pd(OAc)2 to form the bidentate coordinated palladium(II)
intermediate A. Then, intermediate A underwent C−H
palladation to generate the [5,5]-fused bicyclic palladacycle
intermediate B, followed by the oxidative addition of the
compound 2a to afford a hypervalent Pd intermediate C.
Subsequently, the intermediate D was generated by the
reductive elimination of the high-valent Pd(IV) intermediate.
Finally, the CsOAc accelerated the replacement of the iodine
with an acetate ion to furnish the species E. Next, the arylation
product 3a was liberated, and the catalytic cycle resumed.
COAQ as a bidentate directing group is crucial for the
arylation of methanol under the catalytic system. Next, the
kinetic isotope experiments (parallel intermolecular KIE =
3.26) provided persuasive support for the cleavage of the Csp −
H bond to be the rate-determining step of the arylation
3
Figure 1. Free-energy profiles for the arylation of methanol.
D
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Authors
Scheme 4. Proposed Reaction Mechanism
Man Ran − School of Chemistry and Chemical Engineering,
Yangtze Normal University, Chongqing 408100, China
Jian Ren − Key Laboratory of Jiangxi University for Applied
Chemistry and Chemical Biology, Yichun University, Yichun
336000, China
Ming-zhong Zhang − School of Chemistry and Chemical
Engineering, Yangtze Normal University, Chongqing 408100,
China; orcid.org/0000-0001-5427-3168
Xiaoping Tan − School of Chemistry and Chemical
Engineering, Yangtze Normal University, Chongqing 408100,
China; orcid.org/0000-0001-6531-0251
Tengrui Yuan − Department of Organic and Macromolecular
Chemistry, Ghent University, 9000 Gent, Belgium
Xing Zhang − School of Chemistry and Chemical Engineering,
Yangtze Normal University, Chongqing 408100, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03786
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Qing-sheng Zhao (Yunnan University) for
helpful discussions. We are grateful for financial support from
the Project for Basic Research and Frontier Exploration of
Science and Technology Commission of Chongqing (grant
nos. cstc2019jcyj-msxm1275 and cstc2018jcyjAX0419), the
Program of Fuling District Science and Technology (grant no.
FLKJ,2019ABB2038), and the Science and Technology
Research Program of Chongqing Municipal Education
Commission (grant nos. KJQN202001403 and KJ1601202).
In summary, we have established a new catalytic strategy for
new types of C(sp3)−H monoarylation of C1 molecule
methanol. This C−H arylation approach could be used to
effectively produce a diverse range of arylmethanol derivatives
with crucial functional fragments. The use of a bidentate
directing group (COAQ) is indispensable to achieve this
arylation reaction without any additives. The feasibility of this
protocol has been demonstrated by the broad substrate scope,
excellent functional group compatibility, gram-scale synthesis,
detailed reaction mechanism, and even the valuably diversified
transformations of arylation products to synthesize drugs
conveniently.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03786.
Full experimental procedures, spectroscopic data,
mechanistic studies, and detailed DFT calculations
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Quan Gou − School of Chemistry and Chemical Engineering,
Yangtze Normal University, Chongqing 408100, China;
orcid.org/0000-0002-3066-505X; Email: gouquan@
yznu.edu.cn
Binfang Yuan − School of Chemistry and Chemical
Engineering, Yangtze Normal University, Chongqing 408100,
China; Email: 6781022@163.com
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