Ni-Catalyzed Cycloisomerization between 3-Phenoxy Acrylic Acid Derivatives and Alkynes via Intramolecular Cleavage and Formation of the C-O Bond to Give 2,3-Disubstituted Benzofurans

Article abstract of DOI:10.1021/acs.orglett.9b03170

Reactions based on transition-metal-catalyzed C-O bond cleavage have attracted much attention as a new synthetic method. Until now, several intermolecular reactions via C-O bond cleavage of aryl ethers, alkenyl ethers, esters, and others have been reported. Here we report an unprecedented C-O bond cleavage of 3-phenoxy acrylic acid derivatives, followed by intramolecular C-O bond formation with alkynes. This reaction gave 2,3-disubstituted benzofurans having useful functional groups-silyl substituents and acrylic acid derivatives- A t the 2- A nd 3-positions, respectively. This report also described theoretical (DFT) insights into the mechanism.

Full text of DOI:10.1021/acs.orglett.9b03170

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ni-Catalyzed Cycloisomerization between 3‑Phenoxy Acrylic Acid
Derivatives and Alkynes via Intramolecular Cleavage and Formation
of the C−O Bond To Give 2,3-Disubstituted Benzofurans
Shohei Ohno,† Jiawei Qiu,† Ray Miyazaki,‡ Hiroshi Aoyama,† Kenichi Murai,† Jun-ya Hasegawa,‡
and Mitsuhiro Arisawa*,†
†Graduate School of Pharmaceutical Sciences, Osaka University, Yamada-oka 1-6, Suita, Osaka 565-0871, Japan
‡Institute for Catalysis, Hokkaido University, Kita 21 Nishi 10, Kita-ku, Sapporo, Hokkaido 001-0021, Japan
S
* Supporting Information
ABSTRACT: Reactions based on transition-metal-catalyzed C−O bond
cleavage have attracted much attention as a new synthetic method. Until
now, several intermolecular reactions via C−O bond cleavage of aryl ethers,
alkenyl ethers, esters, and others have been reported. Here we report an
unprecedented C−O bond cleavage of 3-phenoxy acrylic acid derivatives,
followed by intramolecular C−O bond formation with alkynes. This reaction
gave 2,3-disubstituted benzofurans having useful functional groupssilyl
substituents and acrylic acid derivativesat the 2- and 3-positions, respectively.
This report also described theoretical (DFT) insights into the mechanism.
been reported, and the C−O bond at the c-position is selectively
cleaved.5 Also, aryl carbamate (R4 = NMe2, R5 = aryl) or aryl
pivalate (R4 = tBu, R5 = aryl) are known to cleave the d-position
of the C−O bond.6 In 2012, Tanaka reported the Rh-catalyzed
intramolecular cyclization of naphthol-linked 1,6-enynes
(Scheme 1B).10a This reaction proceeded via cleavage of the
C(vinyl)−O bond followed by C(vinyl)−O bond formation
with alkyne to give benzofuran derivatives, and there is no doubt
ovel reactions based on transition-metal-catalyzed C−O
Nbond cleavage have attracted much attention as a new
synthetic method.1 Until now, several intermolecular reactions
via C−O bond cleavage of aryl ethers,2,3 alkenyl ethers,4
esters,5,6 and others7−9 have been reported (Scheme 1A). For
Scheme 1. C−O Bond Cleavage Reactions
Table 1. Optimization of Reaction Conditions
a
entry
catalyst
ligand
L1
PCy3
dppe
dcype
SIPr·HCl
L2
L3
L4
L1
L1
solvent
yield (%)
b
c
1
2
3
4
5
6
7
8
9
10
11
12
13
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
NiBr2·glyme
Ni(acac)2
Ni(cod)2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
PhMe
THF
DMF
DMF
DMF
92 (84)
6
0
7
d
6
17
52
38
<1
92
<1
<1
L1
L1
L1
e
example, many reactions of anisole derivatives (R1 = Me) have
been reported, and the C−O bond at the a-position is selectively
cleaved by a transition metal catalyst.2 In addition, many
reactions using aryl aromatic esters (R4 = aryl, R5 = aryl) have
87
Received: September 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. continued
group at the 2-position or vinyl at the 3-position, respectively,
and further chemical transformations of products are rather
difficult. Against this research background, here we report an
unprecedented C−O bond cleavage of 3-phenoxy acrylic acid
derivatives, followed by intramolecular C−O bond formation
with silyl-alkynes (Scheme 1C).
a
entry
catalyst
PtCl2
Rh(cod)BF4
ligand
none
(rac)-binap
solvent
yield (%)
14
15
DMF
DMF
0
0
In this reaction, 2,3-disubstituted benzofurans, which are
present in numerous bioactive natural products and pharma-
ceuticals,11 were obtained, and all atoms contained in the starting
material were retained in the final product. Moreover, these
products have a useful substituent (ex. silyl) and an acrylic acid
derivative at the 2- and 3-positions, respectively. The mechanism
of this reaction was proposed by DFT calculations (Scheme 3).
We prepared substrate 1aa and subjected it to several reaction
conditions (Table 1). As a result, when using Ni(cod)2 and
terpyridine (L1) as a ligand in DMF, the desired benzofuran
(2aa) was obtained in 92% yield (entry 1). Instead of L1,
phosphine ligands (PCy3, dppe, dcype) or N-heterocyclic
carbene ligands (SIPr·HCl) were used; however, the reaction
a
Yields were determined by NMR using 1,3,5-trimethoxy-benzene as
b
c
the internal standard. Isolated yields. [Ni(cod)2] (5 mol %), 6 h.
d
e
With NaOtBu (20 mol %). With 9,10-dihydroanthracene.
that this reaction is useful in organic synthesis. However,
applicable substrates for this reaction are limited to 1,6-enyne
compounds with unsubstituted vinyl ether and simple alkynes
having H, alkyl, or aryl. Therefore, the substituents of benzofuran
derivatives are automatically limited to H or the alkyl or aryl
Table 2. Substrate Scope and Limitations
a
b
Reactions were run in THF. Reactions were run at 120 °C.
B
DOI: 10.1021/acs.orglett.9b03170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hardly progressed (entries 2−5). When other nitrogen-
containing ligands (L2, L3, L4) were used, 2aa was obtained
in 17%, 52%, and 38% yields, respectively (entries 6−8). When
PhMe was used as solvent instead of DMF, or when NiBr2·glyme
or Ni(acac)2 was used as a Ni source instead of Ni(cod)2, the
reaction did not proceed (entries 9, 11, and 12). In the control
experiment with 9,10-dihydroanthracene (entry 13), we knew
that this reaction did not proceed via radical species. Also, when
transition metal catalysts with the property of a π-Lewis acid were
used, the formation of 2aa was not observed (entries 14 and 15).
The substrate scope and limitations of this reaction are
summarized in Table 2.
Scheme 2. Chemical Transformations
Using the best reaction conditions (Table 1, entry 1), we next
examined the effect of alkyne substituents (Table 2A). Having a
silyl group on the alkyne, SiMe3, SiEt3, Si(iPr)3, SiMe2Bn, and
SiMe2Ph, derivatives 1ab−1af gave the corresponding cyclized
products 2ab−2af in 67%, 84%, 34%, 65%, and 71% yields,
respectively. When using substrate 1ab, not only 2ab12 but also
the desilylated products were obtained in 67% and 17% yields,
respectively, together with lower yields of TIPS product 2ad,
probably due to steric hindrance. Derivatives with aryl or alkyl
groups on the alkyne, i.e., phenyl derivative 1ag, tert-butyl
derivative 1ah, n-butyl derivative 1ai, and methyl derivative 1aj,
were converted well to 2ag, 2ah, 2ai, and 2aj in yields of 91%,
95%, 75%, and 73%, respectively. However, the substrate with a
terminal alkyne could not take part in this reaction, resulting in a
complex mixture.
Scheme 3. Possible Reaction Pathway
The effects of substituents on the alkene are summarized in
Table 2B. Ethyl ester derivative 1ak, tert-butyl ester derivative
1al, benzyl ester derivative 1am, phenyl ester derivative 1an, and
dimethyl amide derivative 1ao gave the corresponding cyclized
products 2ak−2ao in 88%, 67%, 91%, 64%, and 59% yields, respec-
tively. However, the substrates having ketone on the alkene (1ba,
1bb) did not take part in this reaction very well,13 and substrates
having sulfone, hydrogen, or methyl on the alkene (1bc−1be) were
not changed at all. These results suggest that the carbonyl group on
the alkene is important for the progress of this cyclization.
Table 2C summarizes the substituent effects on the aromatic
ring. Compounds 1aq−1at and 1av−1ax, which have a substituent
at the 4-, 5-, or 6-position, were converted to the corresponding
cyclized products 2aq−2at and 2av−2ax, respectively, in good
yields. However, substrates 1ap and 1au, with a substituent at the
3-position, were almost unchanged, probably due to their steric
hindrance toward cyclization.
Chemical transformations of 2aa were possible (Scheme 2).
For example, the SiMe2tBu at the 2-position of benzofuran 2aa
was converted to the corresponding 2-aryl derivative 3 in 41%
yield by Hiyama cross coupling14 with 4-bromoanisole. Also, the
acrylic acid methyl ester at the 3-position of 2aa was converted
to the corresponding allyl alcohol derivatives 4 or 5 via reaction
with MeMgBr or LiAlH4/AlCl3 in high yields. These results have
shown that 2aa, efficiently prepared by our cycloisomerization
between silylalkynes and 3-phenoxy acrylic acid derivatives, may
serve as a good synthon.
intermediates A and B, intermediateBis expected to be more stable
by 8.5 kcal/mol. Moreover, comparing the stabilities of
intermediate C (shown in Scheme S1 in SI) formed by O−Ni
insertion to the alkyne of intermediate A and intermediate D
formed by C−Ni insertion to the alkyne of intermediate A or
β-oxygen elimination of intermediate B, intermediate D is expected
to be more stable by 9.8 kcal/mol. These results suggest that the
mechanism via intermediate B and intermediate D is thermody-
namically favored. The observations of the reaction mechanism by
experiments are shown in the Supporting Information.
Although the substrates for this reaction have four possible
C−O bonds that could be cleaved (see Scheme 1c, bonds e, f, g,
and h), the rapid formation of stable nickelacycle B apparently
outcompetes these other processes.
In conclusion, we developed the C−O bond cleavage of
3-phenoxy acrylic acid derivatives, followed by intramolecular
C−O bond formation with alkyne. In this reaction, 2,3-disubstituted
benzofurans 2a, having a silyl substituent and an acrylic acid
derivative at the 2- and 3-positions, respectively, are reported for
the first time to our knowledge. Substituents at the 2- and 3-positions
of compound 2aa were able to convert to other substituents. The
reaction mechanism was proposed by DFT calculations.
Finally, we performed DFT calculations of the stability of each
intermediate expected to form in this reaction (Scheme S1).15
Based on these calculations, the following mechanism is
proposed (see Scheme 3).
First, the substrate is proposed to react with the Ni complex to
form intermediate A (shown in Scheme S1 in SI) via oxidative
addition of the C(vinyl)−O bond to the nickel complex or
intermediate B via oxidative cyclization between the alkyne and
the alkene. As a result of comparing the relative stabilities of
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03170.
Experimental procedures, computational details, and
preparation of compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b03170
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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NMR spectra of compounds (PDF)
Characterization data and X-ray structure analysis (PDF)
Accession Codes
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CCDC 1948857 contains the supplementary crystallographic
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request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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(12) The structure of 2ab was determined by X-ray structure analysis.
(13) The reaction proceeded in 81% yield with the substrate 1ay
having a tBu group on the alkyne and a ketone on the alkene. Products
2ba and 2bb are probably unstable.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: arisaw@phs.osaka-u.ac.jp.
ORCID
Kenichi Murai: 0000-0002-1689-6492
Jun-ya Hasegawa: 0000-0002-9700-3309
Mitsuhiro Arisawa: 0000-0002-7937-670X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid from JSPS
KAKENHI for Precisely Designed Catalysts with Customized
Scaffolding (Grant No. JP 18H04260 and JP 15H05805),
T15K149760, and T15KT00630, by Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research (BINDS)) from AMED under Grant Numbers
JP18am0101084 and JP19am0101084. DFT calculations were
performed with supercomputer at RCCS, Okazaki, Japan.
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D
DOI: 10.1021/acs.orglett.9b03170
Org. Lett. XXXX, XXX, XXX−XXX