Synthesis of Benzofuran Derivatives through Cascade Radical Cyclization/Intermolecular Coupling of 2-Azaallyls

Article abstract of DOI:10.1002/anie.201812369

Benzofurans are among the most popular structural units in bioactive natural products, however, the synthesis of such structures by radical cyclization cascade reactions is rare. Herein, we report a mild and broadly applicable method for the construction

Full text of DOI:10.1002/anie.201812369

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Accepted Article
Title: Synthesis of Benzofuran Derivatives via Cascade Radical
Cyclization/Intermolecular Coupling of 2-Azaallyls
Authors: Patrick Joseph Walsh, Guogang Deng, Minyan Li, Kaili Yu,
Chunxiang Liu, Shengzu Duan, Wen Chen, Xiaodong Yang,
Hongbin Zhang, and Zhengfen Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812369
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10.1002/anie.201812369
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COMMUNICATION
Synthesis of Benzofuran Derivatives via Cascade Radical
Cyclization/Intermolecular Coupling of 2-Azaallyls
Guogang Deng,+ Minyan Li,+ Kaili Yu, Chunxiang Liu, Zhengfen Liu, Shengzu Duan, Wen Chen,
Xiaodong Yang,* Hongbin Zhang,* and Patrick J. Walsh*
Abstract: Benzofurans are among the most popular structural units
in bioactive natural products, however, the synthesis of such
structures by radical cyclization cascade reactions is rare. Herein we
report a mild and broadly applicable method for the construction of
complex benzofurylethylamine derivatives through a unique radical
cyclization cascade mechanism. Single-electron-transfer (SET) from
2-azaallyl anions to 2-iodo aryl allenyl ethers initiates a radical
cyclization that is followed by intermolecular radical–radical coupling.
This expedient approach enables the synthesis of a range of
polycyclic benzofurans that would otherwise be difficult to prepare.
couplings, the chemoselective radical hetero-coupling (vs.
homo-coupling) must be controlled and side-reactions, such as
hydrogen atom transfer (HAT) must be suppressed.
Scheme 1. a. Bioactive benzofurylethylamine derivative (prepared in 5 steps,
20% yield). b. Intramolecular radical cyclization to form benzofurans.
Benzofurans are common structural units in bioactive
compounds,[1] and are bioisosteres of indoles.[1a] They have
attracted tremendous attention due to their profound
physiological and chemotherapeutic properties.[2] In 2015, 34
clinically approved drugs were benzofuran derivatives, including
Darifenacin, Vilazodone, and Ramelteon.[3] A subclass of these,
benzofurylethylamines, have gained interest because they are
precursors in the synthesis of α2-adrenoceptor antagonists[4] and
are known to exhibit high affinities for the serotonin 5-HT2 and 5-
HT1A receptors. Their reported synthesis, however, is lengthy,
low yielding and employed dangerous reagents (diazomethane,
lithium aluminum hydride, and hydrazine, Scheme 1a).[5]
One potentially powerful pathway to benzofurans enabled by
Murphy’s “super electron donors” (SEDs) is through radical
cyclization reactions, as exemplified in Scheme 1b.[6] Building on
this strategy, a more sophisticated approach would involve
capture of the cyclized radical intermediate to form an additional
C–C bond, ideally with a functionalized coupling partner. The
high functional group tolerance and gentle conditions of radical
cyclization cascade reactions make them very attractive.[7]
However, the interception of radical intermediates via
intermolecular radical-radical coupling is challenging and,
therefore, rare.[7b] This is largely attributed to the highly reactive
and fleeting nature of radical species.[7b] To succeed in such
Recently, we introduced a unique radical generation strategy[8]
for the transition metal-free C(sp3)–C(sp3) and C(sp3)–C(sp2)
coupling reactions between 2-azaallyl radicals[9] and alkyl or aryl
radicals (Scheme 2a).[10] Specifically, the single-electron-transfer
(SET) process between 2-azaallyl anions[8] and aryl iodides or
alkyl iodides or bromides led to the generation of the 2-azaallyl
radical and aryl or alkyl radicals. The radical generation relies on
the “super-electron-donor” (SED) feature of 2-azaallyl anions,
which initiates the reaction. We hypothesized that the high
chemoselectivity in the radical-radical coupling is due to the
relative stability of the 2-azaallyl radical, which behaves as a
persistent radical.[11]
We desired to explore the potential of this coupling strategy to
build complexity through scalable and practical tandem reactions.
Thus, in the present work we envisioned the use of 2-iodo aryl-
allenyl ethers (Scheme 2b) as radical precursors. We
hypothesized that SET from the 2-azaallyl anion to the aryl
iodide would lead to an aryl radical that would undergo addition
to the allene to generate a benzofuran methyl radical. This
radical might then couple with the 2-azaallyl radical to form a
second
C–C
bond
and
provide
the
desired
benzofurylethylamines. Herein, we report the first radical
cascade cyclization/intermolecular coupling between 2-azaallyl
anions and aryl allenyl ethers.
benzofurylethylamine derivatives were prepared in good to
excellent yields in three steps from 2-iodophenols.
A
diverse series of
[*] G. Deng, K. Yu, C. Liu, Z. Liu, S. Duan, Dr. W. Chen, Prof. Dr. X. Yang,
Prof. Dr. H. Zhang
Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of
Education and Yunnan Province, State Key Laboratory for Conservation
and Utilization of Bio-Resources in Yunnan, School of Chemical Science
and Technology, Yunnan University
We selected 2-iodophenyl propadienyl ether 2a as the model
substrate,[10a] which was easily synthesized using the method of
Grigg[12] by reaction of 2-iodo phenol with propargyl bromide
(82% yield, see Supporting Information). We initiated our studies
with the allenyl ether 2a and ketimine 1a with NaN(SiMe3)2 in
DME (dimethoxyethane) at room temperature for 12 h. To our
delight, the tandem radical cyclization/coupling product 3aa was
obtained in 63% assay yield (AY, as determined by 1H NMR
integration against an internal standard, Table 1, entry 1).
Replacing NaN(SiMe3)2 with LiN(SiMe3)2 gave increased AY
[76%, Table 1, entry 2. Switching to other bases, such as
KN(SiMe3)2, LiOtBu, NaOtBu and KOtBu, however, led to lower
Kunming, 650091 (P. R. China)
E-mail: xdyang@ynu.edu.cn, zhanghb@ynu.edu.cn
Dr. M. Li, Prof. Dr. P. J. Walsh
Roy and Diana Vagelos Laboratories
Department of Chemistry, University of Pennsylvania
231 South 34th Street, Philadelphia, PA (USA)
E-mail: pwalsh@sas.upenn.edu
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/anie.20180xxxx.
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10.1002/anie.201812369
Angewandte Chemie International Edition
COMMUNICATION
spectroscopy of the crude reaction mixtures using CH2Br2 as an internal
AY or no reaction (entries 3–6). We next studied the effect of
solvent [CPME (cyclopentyl methyl ether), MTBE (methyl tert-
butyl ether), toluene, THF, and dioxane].
standard. [c] Isolated yield after chromatographic purification. [d] 60 oC. [e] 80
oC.
Encouraged by the potential synthetic utility of this tandem
SET/radical–radical coupling, and with an interest in determining
its dependence on the SED properties of the 2-azaallyl anion,
we initiated investigation of the scope of ketimines. As shown in
Table 2, in general, N-benzyl groups bearing neutral, electron-
rich and electron-deficient Ar groups provided good to excellent
yields under the optimized conditions (Table 1, entry 12). Like
the parent ketimine (1a) N-benzyl groups containing electron-
rich arenes (1b, 4-OMe and 1c, dioxol) afforded products 3ba
and 3ca in 60% and 70% yield, respectively. N-Benzyl groups
possessing electron-withdrawing substituents, such as 3-CF3, 4-
F, 4-Cl, 2-Br and 3,5-di-F, were also suitable coupling partners,
leading to the corresponding products 3da, 3ea, 3fa, 3ga and
3ha in 84, 68, 82, 74 and 82% yields, respectively. The sterically
hindered 1-naphthyl derivative (1i) reacted with 2a to generate
the product 3ia in 58% yield. Interestingly, heterocyclic ketimines
possessing 4-pyridyl (1j), 3-pyridyl (1k) and 2-thiophenyl (1l)
were also competent coupling partners, affording benzofurans
3ja, 3ka and 3la in 75–77% yields.
a. Past work
Ar’
Ar’–I
Alkyl–I, Br
Alkyl
Ph
Ar’
Ar
Ph
N
Ar
N
+
Radical-radical
coupling
SET
Ph
Ph
R = Ar’, alkyl
R
Ph
Ph
Ar
Ar
N
N
–
Ph
Ph
H
H
b. This work
NH2
Ar
Ph
Ar
N
Ph
Ar
N
–
Radical-radical
coupling
Ph
H
O
Ph
I
H
SET
work-up
O
R
O
O
R
R
R
Scheme 2. a. Transition-metal-free arylation and alkylation of 2-azaallyl
radicals. b. Radical cyclization cascade of aryl-allenyl ethers enabled by 2-
azaallyl anions as SED and sequential radical-radical coupling.
The reaction performed best in DME (entries 7–11).[13]
Concentration can also play an important role in radical-radical
coupling reactions. Reducing the concentration from 0.2 M to 0.1
M resulted in a slight increase to 78% AY, with 75% isolated
yield (entry 12). In contrast, conducting the reaction at 0.05 M
afforded only 50% AY (entry 13). The reaction proved to be
relatively insensitive to temperature, as judged by heating to 60
Table 2: Scope of using ketimines as SED precursors and radical coupling
partners[a,b]
NCPh2
Ar
I
Ar
N
Ph
LiN(SiMe3)2 (3 equiv)
DME, rt, 12 h, 0.1 M
+
Ph
1a-1l
O
O
2a
3aa-3la
o
(2 equiv )
(1 equiv)
(76% AY, entry 14) or 80 C (73% AY, entry 15). Based on this
optimization, the standard conditions for the tandem
cyclization/coupling reaction that will be used for the remainder
of the study are those in entry 12 of Table 1.
Yield
(%)[b]
Yield
(%)[b]
74
Ar
Product
Ar
Product
Ph
3aa
3ba
75
2--C6H4-Br
3ga
3ha
4-C6H4-OMe
Ph[d]1,3-
dioxol
60
3,5--C6H3-F2
82
Table 1: Optimization of radical cyclization/coupling of ketimine 1a and allenyl
ether 2a[a,b]
3ca
70
1-naphthyl
3ia
58
NCPh2
3--C6H4-CF3
4--C6H4-F
4--C6H4-Cl
3da
3ea
3fa
84
68
82
4-pyridyl
3ja
3ka
3la
77
75
75
3-pyridyl
Ph
I
base (3 equiv)
solvent, conc.
rt, 12 h
Ph
N
Ph
2-thiophenyl
+
[a] Reactions were conducted on a 0.4 mmol scale using 2 equiv ketimine, 1
equiv allenyl ether 2a and 3 equiv LiN(SiMe3)2 at 0.1 M. [b] Isolated yields after
chromatographic purification.
O
Ph
O
1a
2a
3aa
(2 equiv)
(1 equiv)
We next evaluated the ability of the tandem reaction to
accommodate various substituents on the aryl ring of the aryl
allenyl ether. As noted, allenyl ethers were easily synthesized
from the corresponding aryl propargylic ethers (76–87%).[12, 14]
Coupling of the parent ketimine 1a with 4-tBu substituted aryl
allenyl ether 2b furnished product 3ab bearing 5-(tert-
butyl)benzofuran in 81% yield (Table 3). Electron-donating 5-
methoxy substituents will make SET more difficult. Nonetheless,
2c underwent the radical cyclization/coupling reaction to provide
6-methoxybenzofuran derivative (3ac) in 76% yield. Aryl allenyl
ether 2c bearing acetal and methoxy groups furnished the 5-
(dimethoxymethyl)-7-methoxybenzofuran) 3ad in 76% yield.
Coupling 1a with allenyl ethers bearing electron-withdrawing
functional groups were also compatible under the standard
Entry
1
2
3
4
5
6
7
8
Base
Solvent
Conc.
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.2 M
0.1 M
0.05 M
0.1 M
0.1 M
Assay yield (%)
NaN(SiMe3)2
LiN(SiMe3)2
KN(SiMe3)2
LiOtBu
DME
DME
DME
DME
DME
63
76
23
0
0
0
44
42
16
67
0
NaOtBu
KOtBu
DME
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
CPME
MTBE
Toluene
THF
Dioxane
DME
9
10
11
12
13
14[d]
15[e]
78(75)[c]
50
76
73
DME
DME
DME
reaction
conditions,
affording
products
3ae
(5-
[a] Reactions conditions: 1a (0.2 mmol, 2.0 equiv), 2a (0.1 mmol, 1.0 equiv),
base (3.0 equiv), rt, 12 h. [b] Assay yields determined by 1H NMR
(trifluoromethyl)benzofuran), 3af (5-fluorobenzofuran), 3ag (5-
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10.1002/anie.201812369
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COMMUNICATION
chlorobenzofuran) and 3ah (6-bromobenzofuran) in 62, 69, 67
and 50% yields, respectively. The reaction with 2h, where in the
iodide undergoes selective reduction over the bromide, suggests
that good chemoselectivity in the SET is achieved. Reaction with
biphenyl derived allenyl ether 2i led to 3ai in 77%, offering a
unique disconnection for benzofuro bi-aryl compounds.
2k. Reaction of 2k with 1a under the standard conditions
afforded product 3ak in 61% yield (Scheme 4a).
a. Synthesis of π-expanded products.
NCPh2
Ph
I
Ph
N
Ph
LiN(SiMe3)2 (3 equiv)
DME, rt, 12 h, 0.1 M
+
Ph
O
O
3aj, 64%
1a
2j
Table 3: Scope of benzofuran from aryl allenyl ethers precursors and the
parent ketimine 1a[a]
NCPh2
Ph
(2 equiv)
Cl
I
Cl
NCPh2
Ph
Ph
N
Ph
As above
+
O
O
I
Ph
Ph
N
Ph
LiN(SiMe3)2 (3 equiv)
DME, rt, 12 h, 0.1 M
N
N
+
R
R
Ph
O
1a
(2 equiv)
2k
3ak, 61%
O
1a
(2 equiv )
3ab-3ai
2b-2i
(1 equiv)
NCPh2
b. Synthesis of difuran products
Ph
O
O
I
Yield
(%)[b]
Yield
(%)[b]
69
Ph
N
Ph
As above
R of 2b-2i
Product
R of 2b-2i
Product
+
O
Ph
Ph
Ph2CN
I
O
4-tBu (2b)
3ab
3ac
81
4-F (2f)
3af
1a
(4 equiv)
2l
3al, 60%
5-OMe (2c)
76
4-Cl (2g)
3ag
67
Ph2CN
NCPh2
Ph
I
I
4-CH(OMe)2-6-
OMe (2d)
Ph
N
Ph
Ph
As above
3ad
3ae
76
5-Br (2h)
4-Ph (2i)
3ah
3ai
50
+
Ph
O
O
O
O
4-CF3 (2e)
62
77
2m
1a
3am, 45%
[a] Reactions were conducted on a 0.4 mmol scale using 2 equiv ketimine, 1
equiv allenyl ether and 3 equiv base at 0.1 M. [b] Isolated yields after
chromatographic purification. NaN(SiMe3)2 was used as base for 3ae, 3af and
3ag. R groups refers to substituents on the arenes of 2b-2i.
(4 equiv)
NCPh2
c. Substitution of the allenyl ether
I
Ph
Ph
N
Ph
As above, but with:
+
The lack of sensitivity of the reaction to the substrate
structures outlined in Tables 2 and 3 inspired us to set our sights
on the synthesis of more elaborate aryl allenyl ethers with the
aim of preparing novel fused heterocyclic ring systems. As
outlined in Scheme 3, several potential avenues for elaboration
of the benzofuran moiety could be realized by (a)
functionalization of the aryl group; (b) extending the aryl system;
(c) installation of functional groups at C1 of the allene motif and
(d) adding carbon linkers between the aryl group and ether
oxygen.
Ph
O
O
NaN(SiMe3)2 (3 equiv)
1a
(2 equiv)
2n
3an, 68%
NCPh2
Ph
d. Insertion of methylene linkers
I
LiN(SiMe3)2 (3 equiv)
DME, rt, 12 h, 0.1 M
Ph
N
Ph
+
O
O
(
)
(
)
n
n
Ph
1a
2o, n=1
2p, n=2
3ao, 62% (n=1)
3ap, 38% (n=2)
(2 equiv)
Scheme 4. Synthesis of novel poly-heterocyclic amine derivatives by
modification of allenyl ethers.
Sites for Elaboration.
a) Add functionality
b) Extend ring system
We next examined the possibility of fused heterocyclic ring[15]
synthesis from double-intramolecular radical cyclization followed
by coupling with two 2-azaallyl radicals (Scheme 4b). The 1,4-di-
allenyl diether 2l was prepared and coupled with 4 equiv of
ketimine 1a leading to product 3al in 60% yield. When isomeric
1,3-di-allenyl diether 2m was employed, product 3am was
obtained in 45% yield. Both products are ~1:1 mixtures of
diastereomers (see Supporting Information).
Ar
N=CPh2
c) Install substituents
on allene C1
Ph
Ar
N
R
I
R
A1
Ph
H
R
R
O
0–2
O
SET
radical cyclization
d) Insert methylenes
Scheme 3. Potential of modifications of the aryl allenyl ether coupling partner
to more elaborate heterocyciic structures
We explored the suitability of the cyclization/coupling reaction
to functionalize the 2-position of the benzofuran ring
(modification c, Scheme 3). Under the standard conditions,
coupling of ketimine 1a with methyl allenyl ether 2n furnished
the 2-methyl benzofuran product 3an in 68% yield (Scheme 4c).
Many radical cyclization reactions perform well in the formation
of 5-membered rings, but are not suitable for the synthesis of
larger analogues.[7b] To put our cyclization to the test, we
examined modification d (Scheme 3). As shown in Scheme 4d,
substrates 2o and 2p were tested. In the case of the one carbon
homologated substrate 2o, the 6-member-ring isochromene 3ao
was obtained with a yield similar to those in Tables 2–3 (62%).
To explore the versatility of the tandem cyclization/coupling
reaction, we examined the modifications in Scheme 3.
Modification b (Scheme 4) involved extension of the aryl allenyl
ether system to naphthyl allenyl ether (2j). Subjecting 2j to the
standard coupling conditions enabled the assembly of the
naphthol[2,1-b]furan framework found in 3aj in 64% yield
(Scheme 4a). Combining modifications a and b (Scheme 3) by
replacing the naphthyl backbone with a chloro substituted
quinoline led us to synthesize the 5-chloro quinoline allenyl ether
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10.1002/anie.201812369
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COMMUNICATION
The 7-member-ring benzooxepine 3ap was isolated in 38% yield. and separation of trace transition metal-containing impurities,
Taken together, the results in Scheme 4 indicate that the
tandem cyclization/radical-radical coupling reaction proceeds
with diverse substrates and enables the synthesis of an array of
heterocyclic products.
which is crucial and often very expensive in the pharmaceutical
industry.[17]
For a method to be practical, it must be straightforward and
scalable. The scalability of our method was evaluated through
the telescoped gram-scale synthesis starting with 2-
bromobenzylamine. Thus, treatment of 2-bromobenzylamine
with the benzophenone imine in dichloromethane at rt for 12 h
was followed by solvent removal under reduced pressure
(Scheme 5a). The unpurified imine 1g was combined with the
parent allenyl ether 2a and 3 equiv LiN(SiMe3)2 in DME following
the standard procedure. After 12 h at rt, workup and purification
on silica gel 1.35 g of 3ga was isolated (70% yield, Scheme 5a).
Hydrolysis of benzofurylethylamine 3ga afforded the
corresponding benzofurylethylamine 4ga in 94% yield (Scheme
5b). Compound 4ga was characterized by X-ray crystallography,
confirming its structure. The synthetic value was further
demonstrated by an intramolecular Heck-type cyclization
reaction. Thus, using Pd(OAc)2 (10 mol %), PPh3 (40 mol %) at
150 oC under microwave heating successfully converted
benzofurylethylamine 4ga to tetracyclic product 5ga in 82% yield
(Scheme 5c).[16]
Acknowledgements
Support provided by the NSFC (21662043, 21332007,
21572197 and U1702286), the Program for Changjiang Scholars
and Innovative Research Teams in Universities (IRT17R94), the
Donglu Scholar & excellent young talents of YNU and the
YunLing Scholar of Yunnan Province. P. J. W. thanks the US
NSF (CHE-1464744).
Keywords: radical cyclization • cascade reactions • radical
coupling • benzofurylethylamine • azaallyl anions
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[5]
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Ph2CN
Br
Br
1) DCM, rt
12 h
O
H2N
4 mmol
NH
4 mmol
Ph
N
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2) Remove
solvent
LiN(SiMe3)2 (3 equiv)
DME, rt, 0.1 M, 12 h
Ph
O
1g
Ph
Ph
3ga
1.35 g, 70%
4 mmol
c.
b.
NH2
Ph2CN
Ph2CN
Br
Br
10 mol % Pd(OAc)2
40 mol % PPh3
K2CO3 (2 equiv)
1) 1 M HCl
MeOH
THF, 0.1 M
2) NaOH
O
O
O
3ga
MW, 150 oC, 2 h
4ga, 94%
5ga, 82%
[7]
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a) C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91,
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Scheme 5. a. Gram-scale sequential one-pot synthesis. b. Product hydrolysis.
c. Synthesis of tetracyclic product 5ga via intramolecular Heck-type cyclization.
In summary, we have developed
constructing polycyclic architectures in
a
unique strategy of
single synthetic
a
operation that provides functionalized benzofuran derivatives of
biologically active compounds. In this reaction, simple, readily
synthesized 2-iodo aryl allenyl ethers and ketimines were
coupled to afford a wide variety of benzofurylethylamines. This
transformation was accomplished via a tandem SET/radical
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coupling partner. In particular, the 2-iodo aryl allenyl ethers can
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This article is protected by copyright. All rights reserved.

10.1002/anie.201812369
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Guogang Deng, Minyan Li, Kaili Yu,
Chunxiang Liu, Zhengfen Liu, Shengzu
Duan, Wen Chen, Xiaodong Yang,*
Hongbin Zhang,* Patrick J. Walsh*
Page No. – Page No.
Synthesis of Benzofuran Derivatives
via Cascade Radical
Cyclization/Intermolecular Coupling
of 2-Azaallyls
Well behaved radicals: a mild and broadly applicable method for the construction of complex benzofurylethylamine derivatives
through a unique radical cyclization cascade mechanism is presented. SET from 2-azaallyl anions to 2-iodo aryl allenyl ethers
initiates a radical cyclization that is followed by intermolecular radical–radical coupling.
This article is protected by copyright. All rights reserved.