Nickel-catalyzed ring-opening cross-coupling of cyclic alkenyl ethers with arylboronic esters via carbon-oxygen bond cleavage

Article abstract of DOI:10.1246/cl.160712

We have developed a nickel-catalyzed cross-coupling reaction of cyclic alkenyl ethers with arylboronic esters that leads to the formation of unsaturated alcohols via ring-opening by the cleavage of a C(sp²)-O bond. The use of 1,3-dicyclohexylimidazol-2-ylidene as the ligand is essential to promote this cross-coupling process.

Full text of DOI:10.1246/cl.160712

Advance Publication Cover Page
Nickel-catalyzed Ring-opening Cross-coupling of Cyclic Alkenyl Ethers with Arylboronic
Esters via Carbon‒Oxygen Bond Cleavage
Akimichi Ohtsuki, Shun Sakurai, Mamoru Tobisu,* and Naoto Chatani*
Advance Publication on the web August 25, 2016
doi:10.1246/cl.160712
© 2016 The Chemical Society of Japan
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1
Nickel-catalyzed Ring-opening Cross-coupling of Cyclic Alkenyl Ethers with Arylboronic
Esters via Carbon‒Oxygen Bond Cleavage
Akimichi Ohtsuki,1 Shun Sakurai,2 Mamoru Tobisu,*1,2 and Naoto Chatani*,2
1Center for Atomic and Molecular Technologies, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
2Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
(E-mail: tobisu@chem.eng.osaka-u.ac.jp; chatani@chem.eng.osaka-u.ac.jp)
We have developed a nickel-catalyzed cross-coupling
these conditions (Entry 1). Our success in catalytic activation
of inert C-O bonds using an NHC ligand2g,2h,7b,8 immediately
led us to examine a series of NHC ligands in this ring-opening
cross-coupling reaction. Although NHC ligands bearing
aromatic (Entries 2 and 3) and adamantyl groups (Entries 4
and 5) at their nitrogen atoms failed to give 1a, the use of
cyclohexyl-substituted NHC (ICy) led to the formation of 1a
in 10% yield (Entry 6). The yield of 1a was markedly
increased to 80% by raising the reaction temperature to
140 °C (Entry 7). Interestingly, comparable reactivity was
observed even when the reaction was conducted in the
absence of a stoichiometric amount of an external base (i.e.,
CsF) (Entry 8).8f The stereochemistry of the alkene moiety in
reaction of cyclic alkenyl ethers with arylboronic esters that
leads to the formation of unsaturated alcohols via ring-
opening by the cleavage of a C(sp2)-O bond. The use of 1,3-
dicyclohexylimidazol-2-ylidene as the ligand is essential to
promote this cross-coupling process.
In the field of cross-coupling chemistry, development of
methods that use phenol or its non-activated derivatives (e.g.,
anisole or phenyl pivalate) as one of the coupling partners has
gained considerable attention because phenols are abundant in
nature.1 Alkenyl ethers2,3 and esters4,5 have also been used as
readily available, waste-less alternatives to alkenyl halides in
cross-coupling reactions to form substituted alkenes. If these
methods can be extended to cyclic alkenyl ethers, such as 2,3-
dihydrofuran and 3,4-dihydro-2H-pyran (1), unsaturated
alcohols would be formed through ring-opening cross-
coupling (Scheme 1). In 1979, Wenkert and coworkers first
realized this type of ring-opening cross-coupling using
ArMgX as a nucleophile in the presence of a nickel catalyst.2a
Since then, considerable progress has been made in ring-
opening Kumada-Tamao-Corriu type cross-coupling of cyclic
alkenyl ethers, allowing its application in natural product
synthesis,6 and low temperature chemoselective cross-
coupling,2f and extension to alkylation2h,2j and alkynylation.2g
Rueping reported that an organolithium reagent can also serve
1
1a was determined to be exclusively E based on H NMR
analysis. This stereochemical outcome is in sharp contrast to
the reactions using Grignard2a,2f,2g,2h,2j and organolithium2i
reagents, in which the Z isomer is selectively formed.
Table 1. Optimization of reaction conditionsa
as
a suitable nucleophile for this ring-opening cross-
coupling.2i Herein, we report the use of an organoboron
nucleophile for the cross-coupling of cyclic alkenyl ethers.
Scheme 1. Nickel-catalyzed ring-opening cross-coupling of cyclic
alkenyl ethers.
aReaction conditions: 1 (0.50 mmol), 2a (0.60 mmol), Ni(cod)2 (0.050
mmol), ligand (0.10 mmol), and NaOtBu (0.10 mmol) in toluene (1.5mL)
for 12 h. bRun in the absence of NaOtBu. cRun in the absence of CsF.
During the course of our investigation on the cross-coupling
reaction of aryl ethers with organoboron reagents,7 we found
that alkenyl ethers are also similarly cross-coupled using
Ni(cod)2/PCy3 as a catalyst.2c Therefore, we initiated our
investigation by simply applying the Ni(cod)2/PCy3 system to
Examination of the time dependence of the E/Z ratio of 1a
revealed that the Z isomer was formed predominantly at the
beginning of the reaction and the selectivity for the E isomer
increased as the reaction time extended (Table 2). These
the reaction of
1 with boronic ester 2a (Table 1).
Unfortunately, the desired product 1a was not formed under

2
results indicate that the cross-coupling reaction proceeds in a
Z-selective manner as in the reactions using Grignard or
organolithium reagents, but the product can isomerize under
the catalytic conditions. To obtain some insight into the
factor(s) controlling this isomerization process, we conducted
several control experiments using independently synthesized
Z-1a (Table 3). Although Z-1a was geometrically stable when
heated at 140 °C for 12 h, isomerization occurred when a
catalytic amount of either Ni(cod)2 or ICy·HCl and NaOtBu
were present. Complete isomerization to E-1a took place
under the catalytic conditions used for the ring-opening cross-
coupling of 1a (Entry 4).9
coupling. Alkenyl alcohols bearing naphthyl and indolyl
groups can also be synthesized by the reaction using 2k and 2l,
respectively.
Table 4. Scope of boron reagentsa
Table 2. Time dependence of the E/Z ratio
Table 3. Isomerization of 1a under various conditions
aReaction conditions: 1 (0.50 mmol), 2b-l (0.60 mmol), Ni(cod)2 (0.050
mmol), ICy·HCl (0.10 mmol), and NaOtBu (0.10 mmol) in toluene (1.5
mL) at 140 °C for 12 h. Ratios in parentheses refer to the E/Z ratio of the
product determined by 1H NMR spectroscopy. bRun in the presence of
CsF (1.0 mmol) using 1.0 mmol of boronic ester.
Additive
toluene, 140 °C, 12 h
Ar OH
Ar
OH
1a
(Ar = p-Tolyl)
Z-1a
(E/Z = 6/94)
This ring-opening cross-coupling was successfully
applied to 2,3-dihydrofuran (3), leading to the formation of
-unsaturated alcohol 3a (Table 5). The arylation occurred
smoothly even when more sterically demanding trisubstituted
alkenes, such as 5 and 6, were used. Unsaturated diol
derivatives can also be synthesized by the ring-opening
arylation of 7. Benzofuran was unreactive under these
conditions. This protocol was also applicable to acyclic
alkenyl ether 8.
In summary, we developed a nickel-catalyzed ring-
opening arylation of cyclic alkenyl ethers using organoboron
reagents. The ICy ligand is uniquely effective among the
ligands examined, demonstrating outstanding activity of ICy
for the activation of ether C-O bonds. The current method
allows 1 and 3 to serve as readily available, waste-less C4 and
C5 sources that can be introduced onto aromatic rings. Further
investigation of nickel-catalyzed cross-coupling reactions of
ethers is ongoing in our laboratories.
E/Z
Additive
Entry
1
None
Ni(cod)2 (10 mol%)
ICy·HCl (20 mol%) + NaOtBu (20 mol%)
7/93
45/55
76/24
100/0
2
3
4
Ni(cod)2 (10 mol%)
+ ICy·HCl (20 mol%) + NaOtBu (20 mol%)
The scope of the Ni/ICy-catalyzed reaction of 1 with
different organoboron reagents was investigated (Table 4).
Although we used neopentylglycol-protected boronic ester 2a
in our initial optimization studies, pinacolate ester 2b also
reacted with comparable efficiency. The reaction did not
proceed when arylboronic acid 2c was used. Bulky aryl
groups such as the ortho-tolyl moiety in 2d can be introduced
successfully. This ring-opening cross-coupling is sensitive to
the electronic nature of the boronic esters, with electron-rich
boron reagents being generally more reactive. Although the
Ni/ICy system is known to promote the cleavage of C-O
bonds in methoxyarenes, no byproducts arising from C-OMe
cleavage were observed in the reaction using 2g. Carbonyl
functionalities including ester 2j and carbamate 2i were
compatible with this nickel-catalyzed ring-opening cross-
Table 5. Scope of alkenyl ethersa

3
2013, 42, 5270. h) J. Cornella, C. Zarate, R. Martin, Chem.
Soc. Rev. 2014, 43, 8081. i) M. Tobisu, N. Chatani, Acc.
Chem. Res. 2015, 48, 1717.
2
Selected examples by nickel catalysts: a) E. Wenkert, E. L.
Michelotti, C. S. Swindell, J. Am. Chem. Soc. 1979, 101,
2246. b) T. Hayashi, Y. Katsuro, M. Kumada, Tetrahedron
Lett. 1980, 21, 3915. c) T. Shimasaki, Y. Konno, M. Tobisu,
N. Chatani, Org. Lett. 2009, 11, 4890. d) L. G. Xie, Z. X.
Wang, Chem.-Eur. J. 2011, 17, 4972. e) F. Zhao, D.-G. Yu,
R.-Y. Zhu, Z. Xi, Z.-J. Shi, Chem. Lett. 2011, 40, 1001. f) J.
Cornella, R. Martin, Org. Lett. 2013, 15, 6298. g) M. Tobisu,
T. Takahira, A. Ohtsuki, N. Chatani, Org. Lett. 2015, 17, 680.
h) M. Tobisu, T. Takahira, N. Chatani, Org. Lett. 2015, 17,
4352. i) L. Guo, M. Leiendecker, C.-C. Hsiao, C. Baumann,
M. Rueping, Chem. Commun. 2015, 51, 1937. j) M. Tobisu,
T. Takahira, T. Morioka, N. Chatani, J. Am. Chem. Soc. 2016,
138, 6711.
3
4
5
Selected examples by other metal catalysts: [Rh] a) T.
Iwasaki, Y. Miyata, R. Akimoto, Y. Fujii, H. Kuniyasu, N.
Kambe, J. Am. Chem. Soc. 2014, 136, 9260. b) T. Matsuda, S.
Shiose, Y. Suda, Adv. Synth. Catal. 2011, 353, 1923. [In] c)
Y. Nishimoto, T. Nishimura, M. Yasuda, Chem.–Eur. J. 2015,
18301. [Ga] d) Y. Nishimoto, H. Ueda, M. Yasuda, A. Baba,
Angew. Chem. Int. Ed. 2012, 51, 8073.
Selected examples by nickel catalysts: [Ni] a) B.-J. Li, Y.-Z.
Li, X.-Y. Lu, J. Liu, B.-T. Guan, Z.-J. Shi, Angew. Chem. Int.
Ed. 2008, 47, 10124. b) C. L. Sun, W. Yang, Z. Xiao, Z. H.
Wu, B. J. Li, B. T. Guan, Z. J. Shi, Chem.–Eur. J. 2010, 16,
5844. c) J. Yang, T. Chen, L.-B. Han, J. Am. Chem. Soc.
2015, 137, 1782. d) L. Guo, C.-C. Hsiao, H. Yue, X. Liu, M.
Rueping, ACS Catal. 2016, 6, 4438.
Selected examples by other metal catalysts: [Ru] e) Y.
Matsuura, M. Tamura, T. Kochi, M. Sato, N. Chatani, F.
Kakiuchi, J. Am. Chem. Soc. 2007, 129, 9858. f) Y. Ogiwara,
M. Tamura, T. Kochi, Y. Matsuura, N. Chatani, F. Kakiuchi,
Organometallics 2014, 33, 402. g) Y. Ogiwara, T. Kochi, F.
Kakiuchi, Chem. Lett. 2014, 43, 667. [Rh] h) J.-Y. Yu, R.
Kuwano, Angew. Chem. Int. Ed. 2009, 48, 7217. i) H. W. Lee,
F. Y. Kwong, Synlett 2009, 3151. j) J.-Y. Yu, R. Shimizu, R.
Kuwano, Angew. Chem. Int. Ed. 2010, 49, 6396. k) H. Kinuta,
J. Hasegawa, M. Tobisu, N. Chatani, Chem. Lett. 2015, 44,
366. [Fe] l) B.-J. Li, L. Xu, Z.-H. Wu, B.-T. Guan, C.-L. Sun,
B.-Q. Wang, Z.-J. Shi, J. Am. Chem. Soc. 2009, 131, 14656.
m) C.-L. Sun, A. Fürstner, Angew. Chem. Int. Ed. 2013, 52,
13071. n) D. Gärtner, A. L. Stein, S. Grupe, J. Arp, A. Jacobi
von Wangelin, Angew. Chem. Int. Ed. 2015, 54, 10545. o) A.
C. P. Rivera, R. Still, D. E. Frantz, Angew. Chem. Int. Ed.
2016, 55, 6689.
aReaction conditions: alkenyl ether (0.50 mmol), 2a (0.60 mmol),
Ni(cod)2 (0.050 mmol), ICy·HCl (0.10 mmol) and NaOtBu (0.10 mmol)
in toluene (1.5 mL) at 140 °C for 12 h. Ratios in parentheses refer to the
E/Z ratio of the product determined by 1H NMR spectroscopy. bRun using
2a (1.0 mmol), Ni(cod)2 (0.10 mmol), ICy·HCl (0.20 mmol) and NaOtBu
c
(0.20 mmol). This ratio is that of the E and Z isomers of 5a to an exo
alkene isomer [i.e., 5-(p-tolyl)hex-5-en-1-ol]. dPhenylboronic ester was
used instead of 2a to avoid the complexity associated with the formation
of the E/Z isomers.
6
a) P. Kocieński, C. Love, R. Whitby, D. A. Roberts,
Tetrahedron Lett. 1988, 29, 2867. b) P. J. Kocieński, C. J.
Love, W. Richard J, G. Costello, D. A. Roberts, Tetrahedron
1989, 45, 3839. c) J. P. Ducoux, P. Le Menez, N. Kunesch, E.
Wenkert, J. Org. Chem. 1993, 58, 1290.
a) M. Tobisu, T. Shimasaki, N. Chatani, Angew. Chem. Int.
Ed. 2008, 47, 4866. b) M. Tobisu, A. Yasutome, H. Kinuta, K.
Nakamura, N. Chatani, Org. Lett. 2014, 16, 5572.
a) M. Tobisu, T. Shimasaki, N. Chatani, Chem. Lett. 2009, 38,
710. b) T. Shimasaki, M. Tobisu, N. Chatani, Angew. Chem.
Int. Ed. 2010, 49, 2929. c) M. Tobisu, A. Yasutome, K.
Yamakawa, T. Shimasaki, N. Chatani, Tetrahedron 2012, 68,
5157. d) T. Morioka, A. Nishizawa, K. Nakamura, M. Tobisu,
N. Chatani, Chem. Lett. 2015, 44, 1729. e) K. Nakamura, M.
Tobisu, N. Chatani, Org. Lett. 2015, 17, 6142. f) K.
Nakamura, K. Yasui, M. Tobisu, N. Chatani, Tetrahedron
2015, 71, 4484. g) H. Kinuta, M. Tobisu, N. Chatani, J. Am.
Chem. Soc. 2015, 137, 1593. h) M. Tobisu, J. Zhao, H.
Kinuta, T. Furukawa, T. Igarashi, N. Chatani, Adv. Synth.
Catal. 2016, 358, 2417.
Although the mechanism for E/Z isomerization remains
elusive, this process is possibly mediated by Ni-H species,
which can be generated in situ via C-H activation. T.
Furukawa, M. Tobisu, N. Chatani, Chem. Commun. 2015, 51,
6508–6511.
This work was supported by ACT-C (J1210B2576) from
JST, Japan and Scientific Research on Innovative Area
"Precisely Designed Catalysts with Customized Scaffolding"
(16H01022 ） from MEXT, Japan. We also thank the
Instrumental Analysis Center, Faculty of Engineering, Osaka
University, for assistance with HRMS.
7
8
Supporting Information is also available electronically on J-
Stage.
References and Notes
1
General reviews on C(aryl)−O activation: a) D.-G. Yu, B.-J.
Li, Z.-J. Shi, Acc. Chem. Res. 2010, 43, 1486. b) B.-J. Li, D.-
G. Yu, C.-L. Sun, Z.-J. Shi, Chem. -Eur. J. 2011, 17, 1728. c)
B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N, Zhang, A.-M.
Resmerita, N. K. Garg, V. Percec, Chem. Rev. 2011, 111,
1346. d) T. Mesganaw, N. K. Garg, Org. Process Res. Dev.
2013, 17, 29. e) M. Tobisu, N. Chatani, Top. Organomet.
Chem. 2013, 44, 35. f) J. Yamaguchi, K. Muto, K. Itami, Eur.
J. Org. Chem. 2013, 2013, 19. g) F.-S. Han, Chem. Soc. Rev.
9