Selective Insertion of Alkynes into C-C σ Bonds of Indolin-2-ones: Transition-Metal-Free Ring Expansion Reactions to Seven-Membered-Ring Benzolactams or Chromone Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b04081

An unprecedented ring expansion reaction of indolin-2-ones with alkynyl ketones under transition-metal-free conditions has been developed. Base-promoted selective cleavage of a C-C σ bond of the amide is the key in this process, which provides a straightf

Full text of DOI:10.1021/acs.orglett.9b04081

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective Insertion of Alkynes into C−C σ Bonds of Indolin-2-ones:
Transition-Metal-Free Ring Expansion Reactions to Seven-
Membered-Ring Benzolactams or Chromone Derivatives
Mengdan Wang, Yajie Yang, Bo Song, Liqiang Yin, Shuhui Yan, and Yanzhong Li*
Shanghai Key Laboratory of Green Chemistry and Chemical Progresses, School of Chemistry and Molecular Engineering, East
China Normal University, 500 Dongchuan Road, Shanghai 200241, China
S
* Supporting Information
ABSTRACT: An unprecedented ring expansion reaction of indolin-2-ones with alkynyl ketones under transition-metal-free
conditions has been developed. Base-promoted selective cleavage of a C−C σ bond of the amide is the key in this process,
which provides a straightforward and efficient way to synthesize seven-membered-ring benzolactams or chromone derivatives.
The significant advantages of this method include readily accessible starting materials, wide scope and functional group
tolerance, and high atom economy.
the basis of that research, we envisaged that cyclic amides such
arbon−carbon and carbon−nitrogen bonds are widely
Cpresent in organic molecules and biomacromolecules. as indolin-2-ones could be expanded into seven-membered-
ring compounds by an amide C−N bond insertion reaction
(Scheme 1d), which may serve as a platform for producing
various seven-membered N-heterocyclic compounds. Seven-
membered-ring benzolactams are core structures found in
many alkaloids and pharmaceutically related molecules, such as
diazepam (I) and oxazepam (II), with enhancement of
antianxiety activity, and darenzepine (III), an antiulcer agent
(Figure 1).8 The syntheses of seven-membered-ring benzo-
lactams usually require metal catalysis or a multistep strategy.9
Therefore, the development of efficient, transition-metal-free
synthetic procedures starting from easily accessible starting
materials is very appealing. Herein, we report a base-promoted,
atom-economic approach which involves the selective insertion
of ynones into C−C σ-bonds of cyclic amides (Scheme 1e), for
the synthesis of seven-membered-ring benzolactams. More-
over, alkynones containing an ortho-halogenated aryl ring could
also be used, resulting in seven-membered ring-fused
chromone derivatives in good yields. Chromones are also
commonly found in naturally occurring compounds.10
Transformations via cleavage reactions of C−C or C−N bonds
are highly atom-economical methods with skeleton rearrange-
ment. However, it is difficult to achieve C−C or C−N bond
cleavage reactions, which usually require transition metal
catalysts1,2 or activated substrates, such as in situ-generated
arynes3 or cyclohexynes.4 Therefore, it is of great significance
to develop transition-metal-free cleavage reactions of C−C or
C−N bonds under mild conditions. Amides are readily
available compounds containing both C−C and C−N bonds.
The cleavage reactions of amide C−N bonds are well-
known.2,5 Most of these reactions were developed by
employing various transition metals, such as Ni,2a−e Pd,2f−k
or others.2l−p Base-promoted C−N bond cleavage reactions of
amides with highly reactive substrates have also been disclosed.
For example, Liu and Larock reported a transition-metal-free
amide C−N bond cleavage reaction with in situ-generated
arynes (Scheme 1a).3g More recently, an amide C−N bond
cleavage process in the presence of LiHMDS was developed by
the Szostak group (Scheme 1b).6 Generally, the C−N bond of
amides is believed to be more reactive than the C−C bond. In
this context, the development of selective transition-metal-free
C−C bond cleavage reaction of amides remains a great
challenge. Recently, our group disclosed a transition-metal-free
cleavage reaction of the amide C−N bond (Scheme 1c).7 On
We initially tried the reaction of 3-phenyl-1-(p-tolyl)prop-2-
yn-1-one (1a) with indolin-2-one (2a′). However, only 3a′
Received: November 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04081
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. C−N or C−C Bond Activation of Amides
Table 1. Optimization Studies for the Synthesis of 3a
b
entry
base (equiv)
solvent
yield (%)
c
1
Cs2CO3 (2.0)
Cs2CO3 (2.0)
K2CO3 (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (1.0)
t-BuOK (3.0)
t-BuOK (4.0)
DMF
DMF
DMF
DMF
DMAc
DMSO
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
13
42
trace
44
46
2
3
4
5
6
7
56
NP
f
d
8
74
68
52
80
41
e
9
d
10
d
11
d
12
a
All reactions were performed on a 0.2 mmol scale with 1a:2a = 1:1 in
b
2 mL of solvent under N2 for 2 h, unless otherwise noted. Isolated
yields. In air. 1a:2a = 1:1.5. 1a:2a = 1:2. No product.
c
d
e
f
found that a high yield of 80% was observed using 3 equiv of t-
BuOK (entry 11).
After the best conditions were determined (Table 1, entry
11), the substrate scope of this selective C−C insertion
reaction was explored (Scheme 2). The results showed that
Figure 1. Representative bioactive molecules with seven-membered-
ring benzolactams.
a
Scheme 2. Substrate Scope of Alkynones 1
was obtained after screening of various reaction parameters (eq
1; for details, see SI). This product was formed via the Michael
addition of 2a′ to 1a in the presence of a base followed by
isomerization. We reasoned that the isomerization could be
inhibited by employing 3-methyl-substituted indolin-2-one,
and the desired ring-expansion product might be formed. Then
we attempted the reaction of 1a with 3-methylindolin-2-one
(2a) (1.0 equiv) under air in the presence of 2.0 equiv of
Cs2CO3 at room temperature in DMF. The results are shown
in Table 1. To our delight, the ring expansion product 3a was
formed within 2 h, although in a low yield (Table 1, entry 1).
Surprisingly, characterization of 3a by NMR spectroscopy
revealed that the C−C bond instead of the C−N bond of 2a
was selectively cleaved during the reaction process. This may
because that the α-H of 2a is more acidic than N-H. The yield
of 3a was increased to 42% under a nitrogen atmosphere
(entry 2). K2CO3 was almost ineffective for this reaction (entry
3). The yield was slightly increased to 44% when a stronger
base such as t-BuOK was used (entry 4). The reaction was
better in other dipolar aprotic solvents, such as DMAc or
DMSO, with the best outcome occurring in DMSO (entries 5
and 6). Toluene as the solvent gave no desired product at all
(entry 7). Increasing the amount of 2a led to a significantly
higher yield (entries 8 and 9). 3a was obtained in up to 74%
yield with 1.5 equiv of 2a (entry 8). Finally, the effect of the
amount of alkali was investigated (entries 10−12). It was
a
Reaction conditions: 3.0 equiv of t-BuOK, 3 mL of DMSO, 0.3
mmol scale, 1:2a = 1:1.5.
electron-donating R1 groups (4-Me, 4-MeO, 3,4-(MeO)2,
3,4,5-(MeO)3) worked well, affording the desired ring-
expansion products 3a, 3b, 3c, and 3d in 80, 67, 66, and
62% yield, respectively. Electron-withdrawing R1 groups (4-Cl,
4-Br, 2-Br) also gave the corresponding seven-membered-ring
benzolactams 3e, 3f, and 3g in good yields. The 1-naphthyl-
substituted alkynone readily delivered the corresponding
product 3h in 56% yield. The 2-furyl-containing alkyne
B
DOI: 10.1021/acs.orglett.9b04081
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
afforded the desired product 3i in 73% yield. Alkynones with
different R2 substituents also worked well (3j−l). Notably, a p-
CN functional group was tolerable as well, affording 3m in
51% yield.
Scheme 3. Substrate Scope of 4 and 2
Having prepared a series of seven-membered-ring benzo-
lactams, we envisioned that if alkynones bearing an o-bromide-
substituted phenyl ring on the carbonyl carbon were used,
further intramolecular cyclization would occur through
nucleophilic aromatic substitution (SNAr) to give fused-ring
compounds. As we expected, the reaction of 1-(2-bromo-
phenyl)-3-(p-tolyl)prop-2-yn-1-one (4b) with 2a took place
smoothly at 140 °C, affording the desired chromone 5b in 22%
yield (Table 2, entry 1). In order to increase the yield of 5b,
a
Table 2. Optimization Studies for the Synthesis of 5b
b
yield (%)
entry
base (equiv)
solvent
T (°C)
5b
22
57
41
65
36
trace
73
5b′
c
f
1
Cs2CO3 (2.0)
Cs2CO3 (2.0)
t-BuOK (2.0)
Cs2CO3 (2.0)
K2CO3 (2.0)
DABCO (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (3.0)
Cs2CO3 (1.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
DMSO
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
140
140
140
140
140
140
140
140
140
140
140
140
140
120
100
80
−
−
−
−
−
−
−
−
f
2
3
4
5
6
7
8
9
f
f
f
a
f
Reaction conditions: LG = Br, 2.0 equiv of Cs2CO3, 3 mL of DMF,
f
4:2 = 1:1.5, 0.3 mmol scale.
f
66
f
−
44
as -Me, -OMe, and 3,4,5-(OMe)3 afforded 5b−d in >80%
yield. An electron-withdrawing -Cl group resulted in a 68%
yield of 5e. An electron-poor aryl group gave a lower yield than
electron-rich aryl groups (5e vs 5b−d). Interestingly, alkyl-
substituted substrates could also react with 2a to give 5f or 5g
in moderate yields. When a 1-naphthyl-substituted substrate
was subjected to the reaction, the desired product 5h was
formed in 84% yield. Substituents on the aryl group attached to
the carbonyl carbon could be electron-donating groups, such as
3,4-(OMe)2, which gave 5i in 59% yield. Electron-withdrawing
functionalities such as 3-Cl, 3-F, 4-CN, and 4-NO2 were also
compatible with the reaction, producing the desired fused-ring
compounds (5j−m) in 51−78% yield. The heteroaryl
substituent 2-pyridine offered the desired product 5n in 78%
yield. When C3 of the indolin-2-one was substituted with other
functional groups (-Ph, -OEt), the corresponding products
were obtained in 62% and 70% yield, respectively.
In order to make clear the reaction mechanism, the reaction
of 4b with 2a was performed at room temperature, and the
intermediate 5b′ was isolated in 88% yield (Scheme 4a). The
structure of 5b′ was confirmed by X-ray crystallography.
Treatment of 5b′ with Cs2CO3 at 140 °C led to the formation
of the desired product 5b in 80% yield within 2 h (Scheme
4b). This indicates that the fused-ring compound 5b was
formed through a tandem sequence via 5b′.
f
10
11
12
13
14
68
71
82
78
70
−
−
−
−
f
d
f
e
f
d
f
−
d
f
15
16
−
−
26
51
d
f
a
Reaction conditions: 4b:2a = 1:1, 2 mL of solvent, under N2, 2 h, 0.2
b
c
d
e
f
mmol scale. Isolated yields. In air. 4b:2a = 1:1.5. 4b:2a = 1:2. No
product.
optimization of the reaction conditions was conducted by
adjusting reaction parameters, including the base, solvent, and
ratio of the reactants (Table 2). Uncyclized product (5b′) was
mainly produced at lower reaction temperatures (Table 2,
entries 15 and 16). The results show that the reaction
temperature has a great influence on the reaction process. The
structure of 5b′ was fully confirmed by X-ray crystallography.
It was found that the optimal conditions for the preparation of
5b were 2.0 equiv of Cs2CO3 in DMF at 140 °C (Table 2,
entry 12).
Next, a variety of ο-bromo-substituted arenes on the
carbonyl carbon were used to examine the scope of the
reaction (Scheme 3). Not only bromo-substituted alkynones
but also fluoro-, chloro-, or iodo-substituted ones could be
used, delivering the desired product 5a in 87, 78, 83, and 80%
yield, respectively. o-Bromo-substituted arenes were selected to
explore the substrate range since the highest yield of 5a was
achieved when it was used. For the substituents R3 on the aryl
ring attached to the triple bond, electron-donating groups such
On the basis of the results of the control experiments and
our previous reports, a possible reaction mechanism is
proposed (Scheme 5). In the presence of a base, nucleophilic
attack of 3-methylindoline-2-one (2a) on 4b affords allene
intermediate A. Then an intramolecular nucleophilic addition/
ring opening occurs to give the formal alkyne insertion product
C
DOI: 10.1021/acs.orglett.9b04081
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ORCID
Scheme 4. Control Experiments
Yajie Yang: 0000-0002-3782-1131
Yanzhong Li: 0000-0002-2898-3075
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(Grants 21272074 and 21871087) for financial support.
■
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C.10c−e Tautomerization of C offers D. Hydrolysis of D leads
to product 5b′. There are two possible routes from tautomer E
to 5b. One involves nucleophilic aromatic substitution (SNAr)
reaction, and the other is through conjugate addition followed
by elimination of Br−.
In summary, we have reported a transition-metal-free and
atom-economical approach for the synthesis of seven-
membered-ring benzolactams or chromone derivatives. The
key step of this process is the selective insertion of ynones into
C−C σ bonds rather than C−N bonds of cyclic amides.
Advantages such as good functional group tolerance, easily
accessible starting materials, and high atom economy make this
protocol appealing for the synthesis of N-containing seven-
membered rings or fused-ring compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04081.
Experimental procedures, characterization data, and
spectra of new compounds (PDF)
Accession Codes
CCDC 1951341 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
*yzli@chem.ecnu.edu.cn
D
DOI: 10.1021/acs.orglett.9b04081
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Letter
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DOI: 10.1021/acs.orglett.9b04081
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