Nickel-Catalyzed C-O Cross-Coupling Reaction at Low Catalytic Loading with Weak Base Participation

Article abstract of DOI:10.1002/ejoc.201901851

Herein, we report a nickel-catalyzed crossing-coupling reaction for the synthesis of diaryl ethers. The desired products are achieved by coupling heterocyclic alcohols with aryl bromides bearing strong electron withdrawing nitro group under the catalyst system of NiCl₂(PPh₃)₂ and weak base KHCO₃. This mild reaction exhibits a broad functional group tolerance. Compound 4 as an important intermediate is suitable for further structural modification of MALT1 inhibitor MI-2.

Full text of DOI:10.1002/ejoc.201901851

A Journal of
Accepted Article
Title: Nickel-Catalyzed C-O Cross-Coupling Reaction at Low Catalytic
Loading and Weak Base Participation
Authors: Fan Wu, Kejie Zhu, Guolin Wu, Yu Gao, and Haijun Chen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901851
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901851
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10.1002/ejoc.201901851
European Journal of Organic Chemistry
COMMUNICATION
Nickel-Catalyzed C-O Cross-Coupling Reaction at Low Catalytic
Loading and Weak Base Participation
Fan Wu,[a]+ Kejie Zhu,[a]+ Guolin Wu,[a] Yu Gao,[a] and Haijun Chen*[a]
[a]
Key Laboratory of Molecule Synthesis and Function Discovery (Fujian Province University), College of Chemistry, Fuzhou University, Fuzhou, Fujian
350116, China E-mail: chenhaij@gmail.com
[
＋]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Herein, we report a nickel-catalyzed crossing-coupling
reaction for the synthesis of diaryl ethers. The desired products are
achieved by coupling heterocyclic alcohols with aryl bromides
bearing strong electron withdrawing nitro group under the catalyst
system of NiCl2(PPh3)2 and weak base KHCO3. This mild reaction
exhibits a broad functional group tolerance. Compound 4 as an
important intermediate is suitable for further structural modification of
MALT1 inhibitor MI-2.
Table 1. Optimization of the reaction conditions.[a]
entry
1
catalyst
CuI
ligand
base
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KHCO3
KHCO3
KHCO3
yield(%)[b]
L-proline
<5
49(45)
58
2[c]
CuI
L-proline
3
CuI
L-proline
Introduction
4
CuSO4
EDTA
63
5
6[d]
NiCl2·6H2O
NiCl2(PPh3)2
NiCl2(PPh3)2
NiCl2(PPh3)2
NiCl2(PPh3)2
-
EDTA
69
Diaryl ethers are an important class of organic compounds
throughout the pharmaceuticals and agricultural chemicals.[1]
The development of useful methods for preparing diaryl ethers
has received continuous attention from the synthetic
community.[2] Among the existing methods, metal-catalyzed
cross-coupling reactions as the most important transformations
have been intensively applied in both academia and industry
fields.[2b,3] For example, Cu-[3d,4] and Pd-catalyzed[5] C-O bond-
forming reactions have become fast and economical methods to
synthesize aryl ethers,[3a,6] and those methods are often used in
the reactions between aryl halides with phenols or alcohols.[7]
EDTA
79
7
-
-
-
-
81
8[e]
9[e,f]
10
91
97(85)
0
[a] Reaction condition: 2 (0.05 mmol), 3 (1.0 equiv), base (1.0 equiv), DMSO
(1 mL), catalyst (10 mol%), ligand (20 mol%), 90 oC for 16 h under argon
atmosphere. [b] Determined by 1H NMR analysis of the crude products. The
isolated yield is given in parentheses. [c] The reaction time was 2.5 h. [d] The
reaction time was 7 h. [e] 2 (0.3 mmol), 3 (1.2 equiv), base (1.5 equiv). [f]
NiCl2(PPh3)2 (1 mol%).
Toledo cells (Figure 1B).[12b] During the synthesis of 1, the key
intermediate 4 was obtained by coupling 2 and 3 with the above
modified reaction condition (Table1, entry 2). However, when we
conducted a large-scale production with same reaction condition,
the desired product 4 was observed with a significant decrease
in efficiency. In this case, we decided to explore the one more
optimal reaction conditions.
Results and Discussion
We began our studies by using 5-(3,4-dichlorophenyl)-1H-
pyrazol-3-ol 2 and 1-bromo-4-nitrobenzene 3 as the model
substrates. After considerable efforts, the optimized reaction
conditions were found to furnish the desired product efficiently.
Initially, we chose K3PO4 as the base in the presence of CuI and
L-proline, but no significant reaction was observed (entry 1).
K2CO3 showed higher reactivity, providing the product in 58%
yield (entry 3). On this basis, we screened different catalysts and
found that the NiCl2(PPh3)2 provided the optimal result (entry 4-
6). The product was afforded in 79% yield when EDTA as ligand.
Interestingly, there was a significant increase in yield without
ligand involvement (entry 7). The capability of KHCO3 was better
Figure 1. Recent work for the synthesis of diaryl ethers and the application of
this work.
At current stage, with the emergence of various catalytic
systems,[5h,8] some significant improvements have been made
for the both reaction conditions. A dramatic increase of reaction
yields have been realized using strong bases,[2f,9] novel
ligands,[10] and high reaction temperature (Figure 1A).[4b,11]
MI-2 is an irreversible MALT1 inhibitor featuring direct binding
to MALT1 and suppression of its protease function.[12] As a new
skeleton, compound 1 is a structural modification of MI-2 and
exhibits a nearly equipotent antiproliferative effect with MI-2 in
1
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COMMUNICATION
Figure 2. Reaction conditions: Heterocyclic alcohols (0.3 mmol), aryl bromides (1.2 equiv), KHCO3 (1.5 equiv), NiCl2(PPh3)2 (1 mol%), 90 oC, 16 h, Ar, isolated
yield. [a] The reaction was carried out at r.t. for 1 h. [b] The reaction was carried out at 95 oC. [c] Please see supporting information for detailed reaction conditions.
than K2CO3, providing 4 in the yield of 91% (entry 8). Weak base
participation is more suitable for this reaction to avoid the
undesired products. Further optimization showed that 1 mol% of
NiCl2(PPh3)2 is optimal (entry 9).
conformation of compounds 1 and MI-2 with MALT1 was
evaluated by using the AutoDock Vina algorithm (Figure 3B).[13]
The molecular docking results suggest that compound 1 and MI-
2 have excellent binding affinity to MALT1.
Having established the optimal reaction conditions, the
substrate scope was then investigated to examine the generality
of this protocol. As shown in Figure 2, the reaction conditions
could be applied to various of substrates, to provide the
corresponding products in moderate to excellent yields. Notably,
the fluoro, chloro, and nitro in heterocyclic alcohols were all
tolerated in our catalytic system, and the corresponding products
(4-9, 14, 18, 19) were obtained in good yields. The chemical
structure of 4 was further established by X-ray crystallographic.
Certainly, different electron-donating groups, such as methyl,
methoxy and ethyl were satisfactory substrates giving the
corresponding arylated products (10-12, 15-17) in high yields.
The optimized reaction conditions could be applied to various
heterocycle or groups affording the desired products 20-25 in
58-84% yields. Finally, when the standard reaction conditions
are changed, the method is also suitable for the synthesis of
complex compounds no containing pyrazole ring, leading to the
formation of 26-31 in 54-86% yields.
Figure 3. (A) Three-step synthesis of compound 1 (gram- scale). (B) Predicted
binding mode of MI-2 (magenta) and 1 (light blue) to MALT1.
According to the previous literature,[8f,14] the possible reaction
pathway is proposed in Figure 4. The active Ni(0) species I
which may be generated in situ in the presence of KHCO3 under
the reaction conditions. Ni(II) species II is formed via the
oxidative addition of active Ni(0) with substrate. Coordination of
the heterocyclic alcohol to key species II, followed by
deprotonation, would form complex IV. Reductive elimination of
IV delivered diaryl ether and regenerate the catalytic species I.
Gram-scale synthesis of compound 1 was started from
compound 4 via three-step reactions (Figure 3A). The predicted
2
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10.1002/ejoc.201901851
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Keywords: Nickel-catalyzed • low catalytic loadings • weak base
• MALT1 inhibitor • MI-2
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Figure 4. Proposed mechanism for C-O cross-coupling reaction.
Conclusions
In conclusion, a low dosage NiCl2(PPh3)2 and weak base
KHCO3 catalytic system has been developed for the aromatic C-
O coupling reaction. This reaction proceeds under mild reaction
conditions and is applicable to a wide variety of substrates with
strong electron-withdrawing nitro group. This new protocol can
complement existing reaction methods.
Experimental Section
General Procedure for the formation of diaryl ethers. To a vial
equipped with a magnetic stirrer bar were added heterocyclic
alcohols (0.3 mmol), aryl bromides (0.36 mmol), DMSO (1 mL),
KHCO3 (0.45 mmol) and NiCl2(PPh3)2 (1 mol%). The reaction
o
mixture was stirred at 90 C under argon atmosphere. After the
reaction was completed (monitored by TLC analysis), the
mixture was poured into 0.5 N HCl solution and the aqueous
phase was extracted with EtOAc. The organic layer was washed
sequentially with H2O and brine, then dried over Na2SO4. The
solvent was removed under vacuo and the crude product was
purified by chromatography on silica gel to give the desired
product.
CCDC 1539289 (for 4) contains the supplementary
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Centre.
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This research was supported by the Natural Science Foundation
of Fujian Province (2019J01202) and the Joint research project
of Health and Education of Fujian Province (No. WKJ2016-2-06).
3
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4
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Entry for the Table of Contents
Key Topic: Cross Coupling
Nickel-Catalyzed C-O Cross-Coupling Reaction at Low Catalytic Loading and Weak Base Participation
A series of diaryl ethers have been synthesized through nickel-catalyzed C-O cross coupling by using a low dosage NiCl2(PPh3)2 and
weak base KHCO3 under mild conditions.
F. Wu, K. Zhu, G. Wu, Y. Gao, H. Chen*
5
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