A Facile Construction of Bisheterocyclic Methane Scaffolds through Palladium-Catalyzed Domino Cyclization

Article abstract of DOI:10.1002/cjoc.202100242

A convenient palladium-catalyzed domino cyclization reaction for the construction of bis(benzofuranyl)methane scaffolds bearing an all-carbon quaternary center has been described. In the cascade process, one C(sp²)—O bond, two C(sp²)—C(sp³) bonds as well as two benzofuran rings are formed in a single synthetic sequence. The approach shows wide scope of substrates and good functional-group tolerance. Moreover, this methodology is successfully extended to the synthesis of benzofuranyl methyl chromane derivatives.

Full text of DOI:10.1002/cjoc.202100242

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Title: A Facile Construction of Bisheterocyclic Methane Scaffolds through
Palladium-Catalyzed Domino Cyclization
Authors: Hongbo Qi, Kaiming Han, Shufeng Chen*
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Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
A Facile Construction of Bisheterocyclic Methane Scaffolds
through Palladium-Catalyzed Domino Cyclization
Hongbo Qi,a Kaiming Han,a Shufeng Chen*,a
a Inner Mongolia Key Laboratory of Fine Organic Synthesis, Department of Chemistry and Chemical Engineering, Inner Mongolia University,
Hohhot 010021, People’s Republic of China
Keywords
Bisheterocyclic methane| Heterocyclic compound | Palladium | Catalysis | Domino cyclization
Main observation and conclusion
A convenient palladium-catalyzed domino cyclization reaction for the construction of bis(benzofuranyl)methane scaffolds bearing an all-
carbon quaternary center has been described. In the cascade process, one C(sp2)−O bond, two C(sp2)−C(sp3) bonds as well as two benzo-
furan rings are formed in a single synthetic sequence. The approach shows wide scope of substrates and good functional-group tolerance.
Moreover, this methodology is successfully extended to the synthesis of benzofuranyl methyl chromane derivatives.
Comprehensive Graphic Content
I
I
R1
R2
R5
O
R6
O
Pd
R4
R3
OH
R1
R3
R3
R2
R5
R6
Bisheterocyclic scaffolds
O
O
O
O
R4
to
R4
scope
Broad substrate
Scalable
to
94%
83%
Up
yield
Up
yield
Good functional-group tolerance
17 Examples
28 Examples
*E-mail: shufengchen@imu.edu.cn
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CAS,
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&
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First author et al.
Report
We initiated a systematic study on the palladium-catalyzed
domino cyclization using 1-iodo-2-((2-methylallyl)oxy)benzene 1a
and 2-(phenylethynyl)phenol 2a as model substrates (Table 1). To
our delight, the desired product 3a was formed in 26% yield in the
presence of 2.0 equiv. of K2CO3 catalyzed by Pd(OAc)2 (10.0 mol %)
and P(2-furyl)3 (20.0 mol %) at 90 °C after 15 h in 1,4-dioxane (entry
1). Encouraged by these results, the effect of phosphine ligand was
carefully investigated firstly, and P(2-furyl)3 was found to be opti-
mal compared to Xantphos, dppb and PPh3 (entries 1-4). Next, the
effect of base on this domino reaction was also explored. Na2CO3
and Cs2CO3 were found to be inefficient (entries 5 and 6). The reac-
tion with NaOH provided 3a in a high isolated yield (entry 7).
Switching NaOH to KOH or t-BuOLi did not increase the yield of the
product (entries 8 and 9). Subsequently, different palladium cata-
lysts were also examined, and Pd2(dba)3 showed a great perfor-
mance in comparison with Pd(TFA)2, Pd(PhCN)2Cl2, and [Pd(η3-
C3H5)Cl]2, affording the product 3a in 83% yield (entries 10-13). In
order to further improve the efficiency of the
Background and Originality Content
Diphenylmethane derivatives are one type of privileged struc-
tural motifs, which are widely existed in building blocks,[1] func-
tional materials,[2] pharmaceutical molecules,[3] and biologically ac-
tive natural products.[4] Moreover, the attractive properties can be
obtained when replacing the benzene rings with other aromatic
heterocycles, such as indole,[5] pyrazole,[6] and pyrrole.[7] Benzofu-
ran scaffolds,[8] as the bioisosteres of indoles,[9] are also found in an
array of natural products and pharmaceuticals with diverse biolog-
ical and medicinal properties (Fig. 1). Compared with single heter-
ocyclic scaffolds, the compounds with bisheterocyclic scaffolds may
lead to more attractive biological activities.[10] To our knowledge,
the reported studies on the formation of dibenzofuran scaffolds are
scarce,[11] even though several dibenzofuran derivatives possess bi-
ological activities.[12] Among these compounds, bis(benzo-
furanyl)methane framework displayed superior activity against hu-
man African trypanosomiasis (HAT).[12a] Therefore, exploring the ef-
fective and practical strategies for the construction of bis(benzo-
furanyl)methanes is still highly desirable and challenging.
Table 1 Optimization of Reaction Conditionsa
Ph
I
catalyst
ligand (20.0
mol%)
mol%)
(10.0
O
O
O
O
O
O
+
base
solvent
90°C, Ar
O
(2.0 equiv.)
(0.1
O
O
M)
Ph
3a
OH
NH
HN
1a
2a
N
N
H2N
NH2
NH
HN
NH
HN
NH
HN
entry catalyst
ligand
base
solvent
yield b /%
Figure 1 Representative Antileishmanial Activity Bis(benzofuranyl)me-
thane Scaffolds.
1
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(TFA)2
P(2-furyl)3 K2CO3
1,4-dioxane 26
1,4-dioxane 21
2
Xantphos
dppb
K2CO3
K2CO3
K2CO3
On the other hand, transition-metal-catalyzed domino reac-
tions have great advantages for the rapid formation of bishetero-
cyclic scaffolds via in situ generation of organometallic species in
organic synthesis.[13,14] For instance, domino reactions have been
extensively developed for the synthesis of biologically useful ben-
zofuran scaffolds (Scheme 1a).[13b, 15] Inspired by these previous
studies as well as a continuation of our efforts to develop novel re-
action methodologies for the synthesis of heterocyclic derivatives
through cascade reactions,[16] we report herein a facile and conven-
ient palladium-catalyzed domino cyclization reaction between allyl
ether and o-ethynylphenol, providing various bis(benzofuranyl)me-
thane scaffolds. Significantly, one C(sp2)−O bond, two C(sp2)−C(sp3)
bonds as well as two benzofuran rings are formed in a single syn-
thetic sequence (Scheme 1b). Moreover, this methodology is suc-
cessfully extended to the synthesis of benzofuranyl methyl chrom-
ane derivatives.
3
1,4-dioxane
1,4-dioxane trace
1,4-dioxane
0
4
PPh3
5
P(2-furyl)3 Na2CO3
P(2-furyl)3 Cs2CO3
P(2-furyl)3 NaOH
P(2-furyl)3 KOH
0
6
1,4-dioxane trace
1,4-dioxane 78
1,4-dioxane 54
7
8
9
P(2-furyl)3 t-BuOLi 1,4-dioxane 67
10
11
12
13
14
15
16
17
18
P(2-furyl)3 NaOH
P(2-furyl)3 NaOH
P(2-furyl)3 NaOH
1,4-dioxane 78
1,4-dioxane 68
1,4-dioxane 83
1,4-dioxane 73
PdCl2(PhCN)2
Pd2(dba)3
[Pd (η3-C3H5)Cl]2 P(2-furyl)3 NaOH
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
P(2-furyl)3 NaOH
P(2-furyl)3 NaOH
P(2-furyl)3 NaOH
P(2-furyl)3 NaOH
MeCN
DCE
54
58
41
Scheme 1 Pd-Catalyzed Domino Cyclization Reaction
toluene
1,4-dioxane 55c, 47d
an
center
quaternary
The
of benzofuran scaffolds bearing
(a)
synthesis
PdX
R
I
-
NaOH
1,4-dioxane
0
=
R
TMS
[Pd]
I,
Bpin,
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (10.0 mol %),
O
O
O
ligand (20.0 mol %), 1,4-dioxane (2.0 mL, 0.1 M), base (0.4 mmol), 90 °C, 15
c
d
h, under an argon atmosphere. b Isolated yields. Pd2(dba)3 (5.0 mol %).
work
)
Design for the
of bisheterocyclic methane scaffolds This
(b)
synthesis
(
Pd2(dba)3 (2.5 mol %).
I
O
O
Intramolecular
Pd
attack
nucleophilic
XPd
O
P
Ph
Ph
P
O
O
P
P
Ph
Bis(benzofuranyl)methane
OH
Coordination
OH
Xantphos
dppb
reaction, several solvents other than 1,4-dioxane were investigated.
However, the results indicated that CH3CN, DCE, and toluene were
inferior to 1,4-dioxane and generated the desired product in 54%,
Results and Discussion
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
58%, and 41% yields, respectively (entries 14-16). In addition, much
lower yields were obtained when the catalyst loading was reduced
to 5.0 mol % and 2.5 mol % (entry 17). Finally, for comparison, a
control experiment revealed that the reaction did not occur in the
absence of a phosphine ligand (entry 18).
nitro group, performed satisfactorily, giving the corresponding
product 3s in high yield. Moreover, halides (Cl and Br) at ortho- and
meta- positions were also investigated, and the corresponding
products were obtained in 49-76% yields (3t-3w). Significantly, sub-
strate containing a heteroaryl group was also found to be a suitable
reaction partner affording the corresponding product 3x in 65% iso-
lated yield. Furthermore, in addition to aromatic ring groups, the
alkyl substituents could also be introduced to the furan moiety with
moderate yields (3y and 3z). Unfortunately, substrates 1a’ and 1b’
with an aryl and ether group at the α-position of the double bond
failed to complete this transformation, none of the desired prod-
ucts 3a’ and 3b’ were detected. Finally, the exact structure of 3d
was further unambiguously identified by single-crystal X-ray analy-
sis.
Moreover, this domino cyclization reaction was successfully ap-
plied to the synthesis of chroman-containing bisheterocyclic me-
thane derivatives (Scheme 3). Integration of a chromanmoiety into
heterocyclic methanes is synthetically valuable because both of
them are widely utilized in the synthesis of natural products and
biologically active molecules.[17] However, the synthetic methods to
access these complex polyheterocyclic frameworks are very limited.
We found that under the same reaction conditions, the palla-
dium-catalyzed domino cyclization of 1-iodo-2-((3-methylbut-3-en-
1-yl)oxy)benzene 4a with
Under the above optimal conditions established, the scope of
this domino cyclization reaction was investigated by using a series
of allyl ethers 1 and ortho-alkynylphenol derivatives 2 (Scheme 2).
As shown in Scheme 2, various functional groups on the aromatic
ring of 1, such as chloro, bromo, methyl and tert-butyl (3b-e) were
tolerated, readily affording the desired products in moderate to
high yields. With respect to R3 substituents on the phenol ring, the
methyl and tert-butyl substituted substrates worked well and gave
the desired products 3h and 3i in 69% and 54% yields, respectively.
Chloro group at 4-position of the phenol ring also converted to the
corresponding products, albeit with a slightly lower yield (3g). How-
ever, only trace of the desired product 3f was detected when a sub-
strate possessing a chloro group at 3-position was employed. The
electron-withdrawing substituents were also tested, and it was
found that substrate with a trifluoromethyl group could underwent
this reaction, providing the corresponding product 3j in 65% yield.
Unfortunately, substrates bearing a terminal alkyne or a trime-
thylsilyl functionality failed to produce the desired product 3l and
3m under the standard conditions, and a complex mixture was ob-
served. Our next objective was to check the scope of R3 groups of
ortho-alkynylphenol substrates. Different substituents on the phe-
nyl ring at para-positions were tested, and it was found that these
substrates could also undergo the cascade reaction smoothly under
the optimal conditions to afford the desired
Scheme 3 Synthesis of Chroman-Containing Bisheterocyclic Molecules a,b
R3
R4
Pd
2(dba)3 (10.0
P(2-furyl)3 (20.0
mol%)
mol%)
R1
R2
I
+
R1
R3
R2
NaOH
(2.0 equiv.)
O
O
O
R4
OH
1,4-dioxane
(0.1M)
90°C, Ar
4
2
5
Scheme 2 Synthesis of Bis(benzofuranyl)methane Derivatives a,b
Cl
Br
R1
R3
R4
3 (10.0
P(2-furyl)3 (20.0
NaOH
R2
I
Pd2dba
mol%)
mol%)
R1
O
R2
O
O
O
3
R
+
O
Ph
5a
O
O
O
(2.0 equiv.)
dioxane
M)
O
Ph
O
O
Ph
5b
R4
Ph
1,4
(0.1
90°C, Ar
OH
64%
,
5d
5c
78%
41%
,
,62%
,
3
1
2
tBu
CF3
Cl
Br
Cl
O
O
O
O
O
Ph
83%
O
O
O
O
O
O
O
O
O
Ph
Ph
Ph
5f trace
Ph
Ph
Ph
5e
3b
50%
,
3a
,
3c
65%
,
86%
,
5g
5h
73%
,
57%
,
,
tBu
Cl
O
O
O
O
O
Ph
O
O
O
O
O
O
O
O
O
Ph
O
Ph
3d
67%
,
2047715
CCDC:
Ph
3e
,
66%
Cl
68%
3f trace
,
Cl
Br
R
5i
53%
,
5j
5k
,
5l
,
75%
50%
,
=
=
=
=
3n Ar
3o Ar
3p Ar
-FC H
58%
,
6
4
p
,
,
,
,
p-ClC6
H4
66%
66%
,
,
O
O
O
p
p
-BrC H
O
6
4
O
O
Ph
Ar
Ph
3q Ar
3r Ar
-MeC H
36%
,
6
4
3k
,
66%
=
p-OMeC6
H4
51%
,
,
O
Cl
=
=
,
3g
R
O
,
,
Cl,
33%
O
=
3s Ar
3t Ar
-NO
H4
p
o
2C6
H4
80%
O
,
3h
R
CH3,
tBu,
69%
=
64%
,
,
,
-ClC6
,
m
-ClC6
=
=
=
S
=
3u Ar
3v Ar
3w, Ar
H4
,
76%
3i
R
=
R
54%
65%
,
O
O
O
R
o
-BrC6H4 57%
,
3j
,
CF3,
5m 77%
,
3x
,
65%
5n
,
94%
m
-BrC6H4
49%
,
=
=
R
3l
R
S
,
0%.
TMS,
0%
CCDC: 2047716
H,
3m
,
Ph
OMe
Ph
O
O
O
O
O
O
tBu
O
O
nBu
O
O
O
O
Ph
O
O
nBu
3z
tBu
Ph
Ph
3a'
0%
5o
5p
72%
,
,
3y
,
69%
64%
3b'
,
0%
,
5q
0%
,
65%
,
a
Reaction conditions: 4 (0.2 mmol), 2 (0.3 mmol), Pd2(dba)3 (10.0 mol %), P(2-
furyl)3 (20.0 mol %), 1,4-dioxane (2.0 mL), NaOH (0.4 mmol), 90 °C, 15 h,
under an argon atmosphere. b Isolated yields.
a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Pd2(dba)3 (10.0 mol %),
P(2-furyl)3 (20.0 mol %), 1,4-dioxane (2.0 mL), NaOH (0.4 mmol), 90 °C, 15 h,
under an argon atmosphere. b Isolated yields.
products 3n-3s in moderate to good yields, regardless of the elec-
tron-withdrawing groups and the electron-donating groups on the
aromatic rings. It should be noted that a substrate bearing a strong
electron-withdrawing substituent on the aromatic ring, such as a
ortho-alkynylphenol 2a led to the formation of chroman-containing
bisheterocyclic product 5a in 78% yield. Subsequent investigations
indicated that halogen and alkyl groups on the chroman ring at 4-
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

First author et al.
Report
position were well-tolerated, affording the corresponding products
in moderate to good yields (5b-e). Similarly, the generality of ortho-
alkynylphenol partners were also evaluated. It was found that a va-
riety of substituted ortho-alkynylphenols underwent the reactions
successfully to afford the corresponding bisheterocyclic products
5g-m in 50-77% yields except for the substrate with a chloro group
at 3-position, which only afforded the trace of corresponding prod-
uct 5f. Notably, when an ortho-alkynylphenol containing a het-
eroaromatic functionality such as thienyl group was used as a sub-
strate, the domino reaction proceeded well and afforded the de-
sired product 5n in excellent yield. The exact structure of 5n was
further unambiguously identified by single-crystal X-ray analysis.
Moreover, substrates bearing a tert-butyl or an n-butyl group were
also furnished this reaction smoothly, generating the desired prod-
ucts 5o and 5p in 69% and 72% yields. Furthermore, substrate 1q
with an aryl group at the α-position of the double bond was con-
firmed not suitable for this transformation and no desired product
5q was detected.
In order to evaluate the efficiency and practicality of this
method, a gram-scale experiment of 1a with 2a was carried out,
and 75% yield of desired product 3a was isolated on the 4.0 mmol
scale under the standard conditions (Scheme 4, eq 1). Moreover,
a synthetic transformation of 3a was then performed. The bromo-
substituted bis(benzofuranyl)methane 6 was obtained in high yield
when 3a reacted with N-bromosuccinimide (NBS) in the presence
of azodiisobutyronitrile (AIBN) in carbon tetrachloride at 100 oC for
4 h (Scheme 4, eq 2).
Scheme 5 Proposed Mechanism.
I
n
Pd(0)L
O
1a
Ph
O
Pd
Ln
O
O
O
O
Ph
I
PdLn
IV
3aa
I
+
NaI H2O
HO
L+ NaOH
PdILn
Ph
Ph
Pd
Ln-1
O
I
OH
2a
L
II
O
III
Conclusions
In conclusion, we have successfully developed a novel palla-
dium-catalyzed domino cyclization reaction, which constructs
bisheterocyclic methane scaffolds bearing an all-carbon quaternary
center. This protocol is an effective and practical strategy to pre-
paring new bisheterocyclic methane frameworks with potential bi-
ological and medicinal properties. Good functional group tolerance,
broad substrate scope and moderate to good yields make the pre-
sent protocol attractive for academia and industry. Further investi-
gations toward this reaction for the synthesis of other bisheterocy-
clic methane compounds are in progress in our lab.
Scheme 4 Gram-Scale Experiment and Synthetic Transformations
Ph
I
+
standard conditions
1)
2)
(eq
(eq
O
O
O
Ph
g,
OH
2a
3a
75%)
mmol,
1a
1.1
Ph
(1.02
g)
(4.0
Br
NBS
AIBN
(2.2 equiv.)
(2.0 equiv.)
CCl
M)
4 (0.1
C,
O
O
O
O
100 o 4 h
Ph
,
6
92%
3a
Experimental
On the basis of the above results and related literature,[13a, 18]
we proposed a plausible mechanism to account for the palladium-
catalyzed domino cyclization, as shown in Scheme 5. The catalytic
cycle is initiated by oxidative addition of the carbon−halogen bond
to Pd (0). Subsequently, the intermediate Ⅰ preferentially under-
goes an intramolecular Heck cyclization, generating a primary al-
kylpalladium species Ⅱ. Coordination of the alkylpalladium inter-
mediate Ⅱ to the triple bond of 2a is accompanied by the intra-
molecular nucleophilic attack of the oxygen atom and generates
the intermediate Ⅲ. Then, assisted by a base, intermediate Ⅲ
could easily convert to the intermediate Ⅳ. Finally, reductive elim-
ination of intermediate Ⅳ produces the product 3a while regen-
erating the Pd (0) species for the catalytic cycle.
A sealed tube was charged with compounds 1 or 4 (0.2 mmol,
1.0 equiv.), compounds 2 (0.3 mmol, 1.5 equiv.), Pd2(dba)3 (18.31
mg, 10.0 mol %), P(2-furyl)3 (9.28 mg, 20.0 mol %) and NaOH (16.0
mg, 0.4 mmol) in 1,4-dioxane (2.0 mL) under an argon atmosphere.
Then, the reaction mixture was stirred at 90 °C for 15 h. After cool-
ing at room temperature, the mixture was concentrated under re-
duced pressure. The residue was purified by silica gel chromatog-
raphy (petroleum ether/ethyl acetate = 100: 1, v/v)) to afford the
products 3 or 5.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
Acknowledgement
Generous financial support from the National Natural Science
Foundation of China (22061031) and the Natural Science Founda-
tion of Inner Mongolia of China (2020MS02013) is gratefully
acknowledged. We thank Prof. Shuo Guo for helpful discussions.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2021
Manuscript revised: XXXX, 2021
Manuscript accepted: XXXX, 2021
Accepted manuscript online: XXXX, 2021
Version of record online: XXXX, 2021
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
Entry for the Table of Contents
A Facile Construction of Bisheterocyclic Methane Scaffolds through Palladium-Catalyzed Domino Cyclization
Hongbo Qi, Kaiming Han, Shufeng Chen*
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
I
I
R1
R2
R5
R4
R3
R1
R3
O
R5
R6
R6
R2
O
R3
O
O
OH
Pd
R4
O
O
Pd
R4
to
Bisheterocyclic scaffolds
scope
94%
yield
Scalable
Good functional-group tolerance
Up
Broad substrate
45 Examples
A convenient palladium-catalyzed domino cyclization reaction for the construction of bis(benzofuranyl)methane scaffolds bearing an all-carbon quater-
nary center has been described. In the cascade process, one C(sp2)−O bond, two C(sp2)−C(sp3) bonds as well as two benzofuran rings are formed in a
single synthetic sequence. This methodology is also successfully extended to the synthesis of benzofuranyl methyl chromane derivatives.
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de