Transition-Metal-Free Ring Expansion Reactions of Indene-1,3-dione: Synthesis of Functionalized Benzoannulated Seven-Membered Ring Compounds

Article abstract of DOI:10.1021/acs.orglett.8b00206

A novel ring expansion reaction of indene-1,3-dione with alkynyl ketones under transition-metal-free conditions has been developed. This process offers an efficient and direct way to synthesize benzoannulated seven-membered rings or fused-ring compounds t

Full text of DOI:10.1021/acs.orglett.8b00206

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Ring Expansion Reactions of Indene-1,3-dione:
Synthesis of Functionalized Benzoannulated Seven-Membered Ring
Compounds
Qiyi Yao, Lingkai Kong, Mengdan Wang, Yang Yuan, Ruizhuo Sun, and Yanzhong Li*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China
Normal University, 500 Dongchuan Road, Shanghai 200241, China
S
* Supporting Information
ABSTRACT: A novel ring expansion reaction of indene-1,3-
dione with alkynyl ketones under transition-metal-free
conditions has been developed. This process offers an efficient
and direct way to synthesize benzoannulated seven-membered
rings or fused-ring compounds through C−C σ-bond
activation. Notable features of the procedure include easily
accessible starting materials, good functional group tolerance,
and high atom economy.
hemical transformations initiated by the cleavage of C−C
C
bonds are important and highly efficient methods to
synthesize organic compounds because they can reorganize the
skeletons and afford versatile scaffolds that are otherwise difficult
to prepare. However, activation of C−C bonds is highly
challenging because of the inert and stable properties of these
bonds. Thus, such transformations have been restricted to highly
strained molecules, such as three- or four-membered rings.1 For
unstrained systems, the C−C activation reactions are limited to
transition-metal catalysis, using rhenium,2 nickel,3 or others.4
Nevertheless, transition-metal-free C−C cleavage reactions, in
particular, the insertion of alkynes into C−C σ-bonds, are rare,5
with the exception of in situ generated arynes6 or cyclohexynes.7
Recently, we developed a general and efficient base-promoted
protocol for the insertion of alkynyl ketones into the C−C σ-
bonds of 1,3-diketone compounds, which represents the first
example of insertion of a normal alkyne triple bond into a C−C
σ-bond under transition-metal-free conditions.5 We envisioned
that indene-1,3-dione would serve as a platform for the
production of a variety of benzoannulated seven-membered
ring compounds. It is known that benzoannulated seven-
membered ring skeletons widely occur in natural products8
and exhibit interesting biological activities,9 for example,
purpurogallin, theaflavic acid, and hamigeran G (Figure 1).
Cyclization strategies to seven-membered rings are often
inhibited due to entropic factors and transannular interactions.
Accordingly, development of new and efficient synthetic
approaches using easily accessible starting materials is of
considerable interest. We report herein a transition-metal-free
procedure which involves the insertion of ynones into carbon−
carbon σ-bonds of indene-1,3-dione, resulting in ring expansion
by two atoms, for the synthesis of benzoannulated seven-
membered rings. In addition, when alkynes bearing an ortho-
halogenated aryl ring are used, the reaction affords seven-
Figure 1. Selected examples of naturally occurring compounds
containing a benzoannulated seven-membered ring skeleton.
membered, ring-fused cyclic compounds in good to high yields,
which are otherwise difficult to prepare (Scheme 1c,d).
We initially attempted the reactions of 1-phenyl-3-(p-tolyl)-
prop-2-yn-1-one (1a) bearing a tolyl substituent at the alkyne
terminus with indene-1,3-dione (2a) (1.2 equiv) in the presence
of 2.0 equiv of Cs2CO3 at 60 °C in DMSO (3.0 mL). The results
are shown in Table 1. The expected C−C σ-bond insertion/ring
expansion product 3a could be formed in 60% yield within 3 h
(Table 1, entry 1). Formation of 3a suggested that the C−C
bond α to a carbonyl group in 2a was activated during the
reaction process. When 1.4 equiv of 2a was used, the yield of 3a
was increased to 79% (entry 2). However, 2.0 equiv of 2a
resulted in lower yield (Table 1, entry 3). Increasing the reaction
temperature to 110 °C afforded 3a in a higher yield of 81% within
1 h in the presence of 3.0 equiv of Cs2CO3 (entry 5).
Interestingly, the yield of 3a was further increased to 84%
when the reaction was carried out in 5.0 mL of solvent at 110 °C
(entry 6), indicating that both the concentration of the substrates
and reaction temperature have a large influence on the reaction
Received: January 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00206
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
With the optimal reaction conditions in hand (Table 1, entry
6), we next explored the substrate scope of this C−C activation
reaction (Figure 2). The reaction worked well with alkynyl
Scheme 1. Insertion of Triple Bonds into a Carbon−Carbon
σ-Bond
a
Figure 2. Synthesis of 3. Unless otherwise noted, the reactions were
carried out using 3.0 equiv of Cs2CO3 in 5.0 mL of DMSO at 110 °C
under N2 on a 0.2 mmol scale with the ratio of 1/2a = 1:1.4.
Table 1. Screening of Reaction Conditions
ketones bearing various substituents (R2) on the terminal aryl
rings (3a−3e). Substrates with both electron-withdrawing and
electron-donating groups on the aryl ring were suitable for the
reaction, offering the desired ring expansion products in good to
high yields. Notably, a substrate with p-Cl aryl groups was
tolerable to the reactions conditions, affording 3d in 78% yield.
Interestingly, a methyl-substituted substrate could also react with
2a smoothly to give 3e in 47% yield, in which a 1,5-H shift isomer
was formed as the major product. Subsequently, the R1
substituent on the carbonyl carbon was explored (Table 2, 3f−
3l). It was found that R1 with electron-donating (3,4,5-(MeO)3,
4-MeO, 4-Me) aryl groups afforded the corresponding products
3f, 3g, and 3h in 80, 73, and 85% yields, respectively. Electron-
withdrawing (4-F, 4-Cl, 4-Br) aryl groups also provided the
desired benzoannulated seven-membered rings 3i, 3j, and 3k in
good yields. Ring-fused substituents such as 1-naphthyl could be
successfully employed as well to give the corresponding 3l in very
high yield. Other aryl substituents, such as 2-fural or 2-pyrrolyl,
offered the desired products 3m and 3n in 54 and 76% yields,
respectively. When both R1 and R2 were 4-Cl phenyl groups, the
corresponding 3o was formed in 77% yield. Other five-
membered cyclic 1,3-dicarbonyl compounds were also tested.
When 1,3-cyclopentanedione was reacted with 3-phenyl-1-(p-
tolyl)prop-2-yn-1-one at the optimal reaction conditions, the
desired product 3p was formed in 68% yield. However, when
tetronic acid was used, no desired product was obtained.
entry
base (equiv)
solvent
temp (°C) time (h) yield (%)
b
1
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
DABCO (3.0)
KOtBu (3.0)
K2CO3 (3.0)
KOH (3.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
DMF
60
60
3
3
3
2
1
1
1
1
1
1
1
1
1
1
60
79
75
80
81
84
NR
78
68
51
NR
c
2
d
3
60
e
4
60
e
5
110
110
110
110
110
110
110
110
110
110
6
f
7
8
9
DMA
10
11
12
13
14
NMP
DMSO
DMSO
DMSO
DMSO
trace
74
32
a
Unless otherwise noted, the reactions were conducted on a 0.2 mmol
scale with the ratio of 1a/2a = 1:1.4 in 5.0 mL of solvent under N2.
b
c
1a/2a = 1:1.2 in 3.0 mL of DMSO. 1a/2a = 1:1.4 in 3.0 mL of
d
e
f
DMSO. 1a/2a = 1:2.0 in 3.0 mL of DMSO. 3.0 mL of DMSO. No
reaction.
process. Toluene as the solvent gave no desired product at all.
The reactions could also proceed in dipolar aprotic solvents such
as DMF, DMA, or NMP, albeit with lower product yields (entries
8−10). An organic base such as DABCO was ineffective for this
reaction (entry 11). Other bases, such as K2CO3 and KOH,
afforded 3a in 32−74% yields (entries 13 and 14). However, a
stronger base such as KOtBu gave only a trace amount of 3a
(entry 12).
It is worth noting that when substrate 1 bearing an ortho-
bromo-substituted aryl ring on the carbonyl carbon, namely, 1-
(2-bromophenyl)-3-(p-tolyl)prop-2-yn-1-one (4a), was used, a
subsequent intramolecular cyclization reaction occurred to give a
seven-membered, fused-ring compound 5a. Structural identi-
fication of 5a was carried out by X-ray crystallography. To
improve the yield of 5a, different reaction parameters, such as
B
DOI: 10.1021/acs.orglett.8b00206
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Table 2. Screening of Reaction Conditions for the Synthesis of
a
5a
entry
base (equiv)
solvent
DMSO
time (h)
yield (%)
b
1
Cs2CO3 (3.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
Cs2CO3 (2.0)
NaOH (2.0)
KOtBu (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (3.0)
K2CO3 (4.0)
2
2
2
2
2
2
2
2
2
2
5
2
2
2
2
30
b
2
DMSO
DMSO
DMSO
DMA
37
3
61
c
4
31
5
55
6
THF
−d
61
7
DMF
8
CH3OH
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
−d
−d
47
9
10
11
12
trace
69
e
13
77
e
14
84
84
e
15
Figure 3. Synthesis of 5. Unless otherwise noted, the reactions were
carried out using 3.0 equiv of K2CO3 in 5.0 mL of DMSO at 110 °C
under N2 on a 0.3 mmol scale with the ratio of 4/2a = 1.2:1.
a
Unless otherwise noted, the reactions were conducted on a 0.3 mmol
scale with the ratio of 4a/2a = 1.2:1.0 in 3.0 mL of solvent under N2.
4a/2a = 1:1.4. Under air. No product. 5.0 mL of DMSO was used.
b
c
d
e
(Scheme 2a). Treatment of 6a with the general reaction
conditions of our system led to the formation of desired 5a in
bases, solvents, and ratio of the reactants, were screened (Table
2). It was found that the best result for the synthesis of 5a was to
use 3.0 equiv of K2CO3 as the base and DMSO as the solvent at
110 °C (Table 2, entry 14). Thus, the scope of the reaction was
explored using various ortho-bromo-substituted arenes on the
carbonyl carbon with different electronic properties (Figure 3).
For the substituents R3 on the triple bond, substrates with both
electron-withdrawing and electron-donating groups on the aryl
ring were suitable for the reaction, offering the desired products
(5a−5f) in yields of 58−94%. Electron-rich aryl groups gave
yields (5a, 84% yield; 5b, 94% yield; 5c, 93% yield) much higher
than those with electron-poor or electron-neutral aryl groups
(5e, 69%; 5d, 77%). When chloro- or fluoro-substituted ynone
was used instead of bromo-substituted ones, the desired 5d could
also be produced in 58 and 67% yields, respectively. A 1-naphthyl
group was compatible during the reaction to produce the desired
product 5f in 59% yield. With regard to substituents on the
carbonyl carbon, an electron-donating group, 3,4-(OMe)2,
resulted in the formation of 5g in 82% yield. The functionality
of -F and -Cl on the various positions of the aryl ring could also be
accommodated well during the reaction, and the corresponding
products of 5h−5k were formed in 41−92% yields. However,
when other electron-withdrawing functionalities, such as 4-CN
or 4-NO2, were employed, only complex mixtures were observed.
Ynone bearing a pyridine ring also reacted with 2a to provide the
corresponding 5l in 31% yield. To demonstrate the practical
utility of this methodology, the gram scale reactions were
conducted for the preparation of both 3a and 5a, and the
corresponding 3a and 5d were obtained in 77% (2.82 g) and 71%
(0.995 g) yields, respectively (see the Supporting Information).
To clarify the reaction mechanism, the reaction of 4a with 2a
was performed under the optimized reaction conditions at room
temperature. An intermediate 6a, the structures of which were
characterized by X-ray crystallography, was obtained in 52% yield
Scheme 2. Control Experiments
92% isolated yield within 2 h (Scheme 2b). This indicates that
the desired seven-membered, fused-ring compound 5a was
produced through a stepwise path.
Based on the above observation and our previous reports, a
plausible reaction mechanism was proposed with model
substrates 4a and 2a, as depicted in Scheme 3. In the presence
of a base, 4a was attacked by indene-1,3-dione (2a) to give an
intermediate A, which undergoes an intramolecular nucleophilic
addition/ring opening to offer a formal alkyne insertion product
C. Tautermerization of C followed by hydrolysis leads to product
6a, which undergoes nucleophilic aromatic substitution (SNAr)
or conjugate addition followed by elimination of Br− to afford the
final product 5a.
In summary, we have developed a novel base-promoted ring-
expansion reaction of indene-1,3-diones with ynones. This
method provides rapid and efficient access to functionalized
C
DOI: 10.1021/acs.orglett.8b00206
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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benzoannulated seven-membered rings or fused-ring com-
pounds, which are usually difficult to prepare. The C−C σ-
bond cleavage of common indene-1,3-dione occurred during the
reaction process, and the reaction likely proceeds via the
formation of a highly reactive cyclobutenol intermediate. This
method offers several advantages such as easily accessible starting
materials, good functional group tolerance, and mild reaction
conditions. Further studies to extend this transition-metal-free
alkynyl ketone insertion chemistry are in progress in our group.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00206.
Experimental details and spectroscopic characterization of
all new compounds (PDF)
Accession Codes
(7) Gampe, C. M.; Boulos, S.; Carreira, E. M. Angew. Chem., Int. Ed.
2010, 49, 4092.
(8) (a) Gill, M.; Steglich, W. Prog. Chem. Org. Nat. Prod. 1987, 51, 1.
(b) Barltrop, J. A.; Nicholson, J. S. J. Chem. Soc. 1948, 116.
(9) (a) Mehta, G.; Singh, V. Chem. Rev. 1999, 99, 881. (b) Illuminati,
G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
CCDC 1815272−1815273 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yzli@chem.ecnu.edu.cn.
ORCID
Yanzhong Li: 0000-0002-2898-3075
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Grant No. 21272074) and the Program for Changjiang Scholars
and Innovative Research Team in University (PCSIRT) for
financial support.
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D
DOI: 10.1021/acs.orglett.8b00206
Org. Lett. XXXX, XXX, XXX−XXX