Synthesis of 2-isoxazolyl-2,3-dihydrobenzofuransviapalladium-catalyzed cascade cyclization of alkenyl ethers

Article abstract of DOI:10.1039/d1cc00709b

A novel palladium-catalyzed cascade cyclization reaction of alkenyl ethers with alkynyl oxime ethers for the construction of poly-heterocyclic scaffolds has been developed, in which the electron-rich alkene moiety functions as a three-atom unit, simultaneously dealing well with the coordination and regioselectivity of electron-rich olefins under metal catalysis. The strategy features excellent regio- and chemoselectivities as well as good functional group tolerance. Moreover, the newly formed 2-isoxazolyl-2,3-dihydrobenzofuran products can be further transformed to diverse complex heterocycles, demonstrating their potential applications in organic synthesis and medicinal chemistry.

Full text of DOI:10.1039/d1cc00709b

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Synthesis of 2-isoxazolyl-2,3-dihydrobenzofurans
via palladium-catalyzed cascade cyclization of
alkenyl ethers†
Cite this: Chem. Commun., 2021,
57, 4799
Received 6th February 2021,
Accepted 31st March 2021
a
Fei Zhou,a Can Li,a Meng Li,a Yangbin Jin,a Huanfeng Jiang,
Yingjun Zhangb
a
and Wanqing Wu
*
DOI: 10.1039/d1cc00709b
rsc.li/chemcomm
A novel palladium-catalyzed cascade cyclization reaction of alkenyl and efficient methods for the facile construction of diverse poly-
ethers with alkynyl oxime ethers for the construction of poly- heterocycles is highly desirable, especially for those bearing both
heterocyclic scaffolds has been developed, in which the electron-rich benzodihydrofuran and isoxazole cores.9
alkene moiety functions as a three-atom unit, simultaneously dealing
On the other hand, alkenes and their derivatives are some of the
well with the coordination and regioselectivity of electron-rich olefins most frequently used synthetic feedstocks for the building of various
under metal catalysis. The strategy features excellent regio- and che- functionalized molecules.10 Compared with a large amount of
moselectivities as well as good functional group tolerance. Moreover, research on electron-deficient alkenes, electron-rich ones receive
the newly formed 2-isoxazolyl-2,3-dihydrobenzofuran products can be less attention. The possible reason is the massive interactions of the
further transformed to diverse complex heterocycles, demonstrating transition metal with the lone pairs of electron-rich olefins, which
their potential applications in organic synthesis and medicinal chemistry. severely limit their insertion reactivity and selectivity owing to the
profound electronegativity of nitrogen as well as oxygen or sulfur
Polyheterocyclic compounds, possessing different heterocyclic ske- atoms and the repulsion effect from their electron pairs
letons as well as rich reactive sites, usually display more excellent (Scheme 1a).11 Until now, three reaction modes have been estab-
biological or pharmaceutical activities than single heterocyclic lished for the transformations of electron-rich alkenes (Scheme 1b):
compounds.1 Among them, 2-heteroaryl-substituted benzodihydro- (i) mono-functionalization including hydroxylation,12a esterifica-
furans have attracted much attention due to their extraordinary tion,12b alkenylation12c and arylation;12d–g (ii) difunctionalization
pharmaceutical activities compared with simple furans.2 For exam- including hydroarylation,13a hydroamination,13b hydroalkenyla-
ple, Liliflol A, a molecule containing 2-heteroaromatic-2,3-dihydro- tion,11,13c and amine esterification;13d and (iii) cyclization reactions
benzofuran, is a selective COX-2 inhibitor.3 Recent studies also leading to different donor-substituted cyclobutanes, pyrrolidines,
proved that the introduction of the benzofuran moiety can improve
the antitumor activity of novel farnesyltransferase inhibitors, which
exhibit effective enzyme inhibitory activity.4 Additionally, isoxazoles
are found to be one significant class of structural skeletons in drug
molecules with a wide range of biological activities, such as anti-
inflammatory,5 antinociceptive6 and anticancer activities.7 RX-37 is
explored as a new type of potent bromodomain and extra terminal
protein (BET) inhibitor, which selectively inhibits cell growth in
human acute leukemia cell lines.8 Thus, the development of novel
a State Key Laboratory of Pulp and Paper Engineering,
School of Chemistry and Chemical Engineering, South China University of
Technology, Guangzhou 510640, China. E-mail: cewuwq@scut.edu.cn;
Fax: +86-20-87112906
b State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357),
Sunshine Lake Pharma Company, Ltd, Dongguan 523871, China
† Electronic supplementary information (ESI) available. CCDC 2000121 and
2053026. For ESI and crystallographic data in CIF or other electronic format
Scheme 1 Reaction modes of electron-rich olefins under metal catalysis.
Chem. Commun., 2021, 57, 4799–4802 | 4799
see DOI: 10.1039/d1cc00709b
This journal is © The Royal Society of Chemistry 2021

View Article Online
Communication
ChemComm
isoxazolidines, isoxazoles, cyclohexenes and cyclohepta[b] TBAB (1.0 equiv.) and K2CO3 (2.0 equiv.) in THF at 60 1C for 12 h
indoles.14a–f However, the above-mentioned methods typically focus (Table 1, entry 13).
on utilizing electron-rich olefins as two-carbon units, while the
Under the optimized reaction conditions, the generality and
employment of electron-rich olefins as three-atom units (CQC–X) limitations of this palladium-catalyzed cascade cyclization were
is relatively unexplored and challenging due to the regio- and explored. The effects of substituents on the alkynyl oxime
chemoselectivity control. Herein, we disclose an efficient palla- ethers (R1) were first investigated (Table 2). To our delight, aryl
dium-catalyzed cascade cyclization reaction of alkenyl ethers with substituted alkynyl oxime ethers with an electron-donating or
alkynyl oxime ethers for the selective construction of 2-isoxazolyl-2,3- electron-withdrawing group at the para-, meta- or ortho-position
dihydrobenzofurans (Scheme 1c).
of the phenyl ring were well tolerated in this reaction (3a–3j).
O-Methyl oxime (1a) and o-iodophenyl alkenyl ether (2a) were The structure of product 3c was confirmed unambiguously by
employed as model substrates for the optimization of reaction X-ray diffraction (CCDC† 2000121). Particularly, aryl oximes
conditions, and the results are summarized in Table 1. Gratifyingly, with strong electron-withdrawing groups, such as –CF3 and
in the presence of 10 mol% of Pd(OAc)2, 2.0 equiv. of CuCl2, –SCF3 groups, were also compatible with this transformation,
1.0 equiv. of TBAB and 2.0 equiv. of K2CO3 in DMF, the desired and the corresponding products 3f and 3g were obtained in
4-(2,3-dihydrobenzofuran-2-yl)-3,5-diphenylisoxazole product (3a) 74% and 77% yields, respectively. When the substrate with the
was detected in 42% NMR yield (Table 1, entry 1). Solvent investiga- naphthyl substituent was applied, the target product 3k could
tion revealed that THF was the optimal choice, which provided 3a be isolated in 72% yield. In addition, the reaction of 2-furan-
in 64% yield (Table 1, entries 2–4). The influence of different substituted oxime ether proceeded smoothly under the optimal
palladium catalysts was then explored, and 15 mol% of Pd(OAc)2 conditions, leading to 3l in 75% yield. Moreover, the oxime
gave the best result (Table 1, entries 5–8). Next, different oxidants, ether bearing cyclohexyl could be converted to the desired
such as AgOAc, BQ, CuBr2 and CuCl2, were tested (Table 1, entries product 3m in moderate yield. Encouraged by these promising
9–12). When 2.5 equiv. of CuCl2 was used in this reaction system, results, various alkynyl oxime ethers with different substituents
the desired heterocycle 3a was afforded in 74% yield (Table 1, entry
12). Temperature examination showed that 60 1C was the most
suitable for this transformation (Table 1, entries 13 and 14).
Table 2 Scope of alkynyl oxime ethersa
A control experiment further suggested that 3a could not be
obtained without palladium catalyst (Table 1, entry 15). Therefore,
the optimal reaction conditions were determined as follows: 1a
(0.2 mmol), 2a (2.0 equiv.), Pd(OAc)2 (15 mol%), CuCl2 (2.5 equiv.),
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Oxidant
Solvent
T (1C)
Yieldb (%)
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
AgOAc
BQ
CuBr2
CuCl2
CuCl2
CuCl2
CuCl2
DMF
Toluene
MeCN
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
110
110
110
110
110
110
110
110
110
110
110
110
60
42
27
36
64
57
47
25
72
n.d.
Trace
52
74
87 (81)
37
7
8c
9c
10c
11c
12cd
13cde
14cde
15de
r.t.
60
n.d.
a
All reactions were performed with 1a (0.2 mmol), 2a (0.4 mmol),
palladium catalyst (10 mol%), oxidant (2.0 equiv.), TBAB (1.0 equiv.),
and K2CO3 (2.0 equiv.) in the indicated solvent (2.5 mL) for 4.5 h.
b
NMR yields were determined by 1H NMR using CH2Br2 as the internal
c
d
standard. With 15 mol% of catalyst. With 2.5 equiv. of oxidant.
e
a
2 h. Data in parentheses indicate isolated yields. TBAB = tetrabutyl
Conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (15 mol%), CuCl2
ammonium bromide; BQ = p-benzoquinone; n.d. = not detected; (2.5 equiv.), TBAB (1.0 equiv.), K2CO3 (2.0 equiv.), THF (2.5 mL), 60 1C,
r.t. = room temperature.
12 h.
4800 | Chem. Commun., 2021, 57, 4799–4802
This journal is © The Royal Society of Chemistry 2021

View Article Online
ChemComm
Communication
(R2) were then tested. Regardless of the electronic nature of the
para-substituents, 3n–3p could all be obtained in good yields.
Delightfully, both meta- and ortho-substituted aryl oximes were
well adapted in this protocol and transformed to the corres-
ponding products 3q and 3r in 75% and 68% yields, respec-
tively. Notably, the bulky aromatic-substituted alkynyl oxime
ether was found to be a suitable substrate for this transforma-
tion, and the target heterocycle 3s was formed in 81% yield. It
should be noted that the polyheterocyclic product 3t (R2 = 3-thienyl)
was also obtained in 70% yield, suggesting that the heterocyclic
substrates exhibited good compatibility with this system. More
importantly, diverse aliphatic alkynes worked well under the
standard reaction conditions. Both acyclic alkyl chain- (n = 2–6)
and cyclopropyl-substituted alkynyl oxime ethers were tolerable in
this reaction, converting to the desired products 3u–3z in 45%–57%
yields.
Next, the scope of alkenyl ethers 2 was examined under the
optimal conditions. As shown in Table 3, diverse alkenyl ethers
bearing various functional groups, such as electron-donating
groups (CH3, t-Bu) and electron-withdrawing groups (Br, CF3,
Cl) at the para- and meta-positions of the aryl ring, transformed
smoothly to the corresponding isoxazolyl-substituted dihydro-
benzofurans 3aa–3ae in 47–56% yields. Unfortunately, when
2-fluorine substituted alkenyl ether was applied in this cascade
cyclization, only trace product 3af could be detected. It is worth
noting that the internal alkene ether was compatible with this
process, affording the desired product 3ag in 62% yield. The
anti-relationship of the methyl group and the isoxazole moiety
of 3ag was characterized by analyzing the X-ray crystallography
data (CCDC† 2053026, see the ESI† for details). However, the
corresponding products 3ah and 3ai from trisubstituted alkene
ethers could not be obtained, which might be due to the steric
hindrance of internal alkene ethers.
Scheme 2 Gram-scale reaction and synthetic applications (conditions:
see the ESI† for details).
reaction was successfully scaled up to 10 mmol, and the desired
product 3a was obtained in 73% yield (Scheme 2a). The synthetic
value was further demonstrated by various efficient transforma-
tions. For instance, the Pd-catalyzed Suzuki coupling of 3e and
phenylboronic acid gave biphenyl compound 4 in 92% yield
(Scheme 2b) and the Sonogashira coupling of 3e with phenylace-
tylene afforded the desired functionalized alkyne 5 in 87% yield
(Scheme 2c). Furthermore, a conjugated triazole skeleton 6 was
synthesized in 87% yield via click reaction (Scheme 2d). Notably,
the products could be transformed into diverse N-heterocycles,
such as morpholine 7, piperazine 8, and thiomorpholine 9, which
showed their potential applications in materials science and
medicinal chemistry (Scheme 2e–g).
Several control experiments were conducted to clarify the
reaction mechanism (Scheme 3). Firstly, when using oxime as
the substrate, the desired product 3a was detected in only 17%
yield under the standard conditions (Scheme 3a), while the
O-benzyl oxime transformed to 3a in 70% yield, with benzyl
To evaluate the utility of this method, a gram-scale experiment
was performed (Scheme 2). Under the standard conditions, the
Table 3 Scope of alkenyl ethersa
a
Conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (15 mol%), CuCl2
(2.5 equiv.), TBAB (1.0 equiv.), K2CO3 (2.0 equiv.), THF (2.5 mL), 60 1C,
12 h.
Scheme 3 Mechanistic studies.
This journal is © The Royal Society of Chemistry 2021
Chem. Commun., 2021, 57, 4799–4802 | 4801

View Article Online
Communication
ChemComm
in organic synthesis and medicinal chemistry. Further studies
on the substrate scope and biological activities of the polyhe-
terocyclic products are ongoing in our laboratory.
The authors thank the National Nature Science Foundation
of China (21871095), the State Key Laboratory of Pulp and Paper
Engineering (202012) and the Fundamental Research Funds for
the Central Universities (x2hgD2200520) for financial support.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 (a) L. Zhou, S. Y. Yu, Y. Tang and L. Wang, Angew. Chem., Int. Ed.,
2019, 58, 15016; (b) X. Wang, J. Zhang, D. Chen, B. Wang, X. Yang,
Y. Ma and M. Szostak, Org. Lett., 2019, 21, 7038.
2 G. Albano and L. A. Aronica, Eur. J. Org. Chem., 2017, 7204.
3 R. P. Pandit, S. T. Kim and D. H. Ryu, Angew. Chem., Int. Ed., 2019,
58, 13427.
Scheme 4 Proposed mechanism.
4 A. Radadiya and A. Shah, Eur. J. Med. Chem., 2015, 97, 356.
5 G. Daidone, D. Raffa, B. Maggio, F. Plescia, V. M. C. Cutuli,
N. G. Mangano and A. Caruso, Arch. Pharm., 1999, 332, 50.
6 M. P. Giovannoni, C. Vergelli, C. Ghelardini, N. Galeotti, A. Bartolini
and P. V. Dal, J. Med. Chem., 2003, 46, 1055.
7 S. Li, Y. Du and Q. Kang, Org. Chem. Front., 2019, 6, 2775.
8 X. Ran, Y. Zhao, L. Liu, L. Bai, C.-Y. Yang, B. Zhou, J. L. Meagher,
K. Chinnaswamy, J. A. Stuckey and S. Wang, J. Med. Chem., 2015,
58, 4927.
9 (a) J. Chen, X. Hu, L. Lu and W. Xiao, Acc. Chem. Res., 2016, 49, 1911;
(b) J. Feng and J. Zhang, ACS Catal., 2016, 6, 6651.
10 (a) M. Yu, Y. Xie, J. Li and Y. Zhang, Adv. Synth. Catal., 2011,
353, 2933; (b) W. Wu, S. Yi, W. Huang, D. Luo and H. Jiang,
Org. Lett., 2017, 19, 2825; (c) W. Wu, S. Yi, Y. Yu, W. Huang and
H. Jiang, J. Org. Chem., 2017, 82, 1224.
bromide detected by GC analysis (Scheme 3b), which suggested
the initiation process of this cascade cyclization reaction.
Additionally, when the iodo-substituent in 2a was changed to
–bromo, –chloro or –H, the yield of 3a decreased dramatically
or even could not be obtained, indicating that the oxidative
addition might be involved in this process and the C–I bond
exhibited the highest reactivity (Scheme 3c). Moreover, when
the reaction was conducted with 1-(allyloxy)-2-iodobenzene
instead of 2a, the corresponding chroman product could not
be detected, illustrating the key role of the alkenyl ether moiety
in the success of this transformation (Scheme 3d).
11 W. Chen, Y. Li, Y. Chen and C. Ho, Angew. Chem., Int. Ed., 2018,
57, 2677.
Based on the above experimental results and previous
reports,15
a
plausible reaction mechanism is proposed 12 (a) F. Foubelo, A. Gutierrez and M. Yus, Tetrahedron Lett., 1999,
´
40, 8173; (b) Y. Nishimoto, H. Ueda, M. Yasuda and A. Baba,
(Scheme 4). The reaction is initiated by trans-oxypalladation
of alkynyl oxime ethers 1, generating the oxonium intermediate
I, which would transform to the alkenylpalladium intermediate
II via the elimination of methyl bromide. Subsequently, migra-
tory insertion of o-iodophenyl alkenyl ether 2 into the C–Pd
bond affords the key alkylpalladium species III. Next, b-hydrogen
elimination of III gives the key intermediate IV, which undergoes
oxidative addition to afford the arylpalladium intermediate V.
Then an intramolecular Heck coupling occurs and generates the
alkylpalladium intermediate VI. Finally, the protonolysis of VI
yields the desired product 3 and a palladium(II) species, which
continues to the catalytic cycle with the aid of CuCl2.
In summary, we developed a palladium-catalyzed cascade
cyclization reaction of alkenyl ethers with alkynyl oxime ethers,
providing an efficient and convenient strategy for the construc-
tion of various 2-isoxazolyl-2,3-dihydrobenzofurans. Noteworth-
ily, the electron-rich alkene moiety served as a three-atom unit,
realizing the selective synthesis of a structurally novel polyhe-
terocyclic skeleton. With merits such as a facile operation
process, high regio- and chemoselectivities, and good tolerance
of functional groups, the protocol shows potential applications
Angew. Chem., Int. Ed., 2012, 51, 8073; (c) A. Stadler, H. Schenck,
K. S. A. Vallin, M. Larhed and A. Hallberg, Adv. Synth. Catal., 2004,
346, 1773; (d) L. Xu, W. Chen, J. Ross and J. Xiao, Org. Lett., 2001,
3, 295; (e) J. Mo and J. Xiao, Angew. Chem., Int. Ed., 2006, 45, 4152;
( f ) T. Iwasaki, Y. Miyata, R. Akimoto, Y. Fujii, H. Kuniyasu and
N. Kambe, J. Am. Chem. Soc., 2014, 136, 9260; (g) W. Lin, W. Li,
D. Lu, F. Su, T. Wen and H. Zhang, ACS Catal., 2018, 8, 8070.
13 (a) Y. Ebe and T. Nishimura, J. Am. Chem. Soc., 2015, 137, 5899;
(b) L. Ouyang, L. Zhan, J. Li, Q. Zhang, C. Qi, W. Wu and H. Jiang,
Org. Lett., 2018, 20, 550; (c) L. Yang, W. Ji, E. Lin, J. Li, W. Fan, Q. Li
and H. Wang, Org. Lett., 2018, 20, 1924; (d) L. Ouyang, J. Li, J. Zheng,
J. Huang, C. Qi, W. Wu and H. Jiang, Angew. Chem., Int. Ed., 2017,
56, 15926.
14 (a) W. Srisiri and A. B. Padias, J. Org. Chem., 1993, 58, 4185;
(b) K. Hori, J. Ito, T. Ohta and I. Furukawa, Tetrahedron, 1998,
54, 12737; (c) H. Kusama, M. Ebisawa, H. Funami and N. Iwasawa,
J. Am. Chem. Soc., 2009, 131, 16352; (d) C. D. Schmidt, J. Kaschel,
T. F. Schneider, D. Kratzert, D. Stalke and D. B. Werz, Org. Lett.,
2013, 15, 6098; (e) Z. Wang and J. Sun, Org. Lett., 2017, 19, 2334;
( f ) A. N. Parker, M. C. Martin, R. Shenje and S. France, Org. Lett.,
2019, 21, 7268.
15 (a) J. P. Waldo and R. C. Larock, Org. Lett., 2005, 7, 5203; (b) Z. She,
D. Niu, L. Chen, M. A. Gunawan, X. Shanja, W. H. Hersh and
Y. Chen, J. Org. Chem., 2012, 77, 3627; (c) Q. Wang, L. Huang, X. Wu
and H. Jiang, Org. Lett., 2013, 15, 5940; (d) C. Li, J. Li, F. Zhou, C. Li
and W. Wu, J. Org. Chem., 2019, 84, 11958; (e) W. Wu, C. Li, F. Zhou,
J. Li, X. Xu and H. Jiang, Adv. Synth. Catal., 2019, 361, 3813.
4802 | Chem. Commun., 2021, 57, 4799–4802
This journal is © The Royal Society of Chemistry 2021