Base-mediated insertion reaction of alkynes into carbon-carbon σ-bonds of ethanones: synthesis of hydroxydienone and chromone derivatives

Article abstract of DOI:10.1039/c7ob00476a

Transition-metal free insertions of alkynes into carbon-carbon σ-bonds of ethanones have been reported. These tandem reactions offer an efficient synthesis of hydroxydienones and multi-substituted chromones. This is the first example of base-promoted insertion reactions of isolated carbon-carbon triple bonds into carbon-carbon σ-bonds with active methylene compounds bearing only one electron-withdrawing group.

Full text of DOI:10.1039/c7ob00476a

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Base-mediated insertion reaction of alkynes into
carbon–carbon σ-bonds of ethanones: synthesis
of hydroxydienone and chromone derivatives†
Cite this: DOI: 10.1039/c7ob00476a
Received 25th February 2017,
Accepted 28th February 2017
Fangfang Zhang, Qiyi Yao, Yang Yuan, Murong Xu, Lingkai Kong and Yanzhong Li*
DOI: 10.1039/c7ob00476a
rsc.li/obc
Transition-metal free insertions of alkynes into carbon–carbon whether another molecular scaffold containing a C–H moiety
σ-bonds of ethanones have been reported. These tandem reactions of suitable acidity would result in a new carbon–carbon
offer an efficient synthesis of hydroxydienones and multi-substi- σ-bond insertion reaction. Herein we report a transition-metal
tuted chromones. This is the first example of base-promoted inser- free procedure which involves the insertion of alkynes into
tion reactions of isolated carbon–carbon triple bonds into carbon–carbon σ-bonds of ethanones, resulting in the for-
carbon–carbon σ-bonds with active methylene compounds mation of hydroxydienone or chromone derivatives with high
bearing only one electron-withdrawing group.
stereoselectivity. This is the first example of base-promoted
insertion reactions of isolated carbon–carbon triple bonds into
carbon–carbon σ-bonds with active methylene compounds
bearing only one electron-withdrawing group, to the best of
our knowledge (Scheme 1).
We first investigated the reactions of 3-phenyl-1-p-tolylprop-
2-yn-1-one 1a with 1,2-diphenylethanone 2a (1.0 equiv.) in the
presence of Cs2CO3 (2.0 equiv.) in DMF in air, unfortunately,
only a complex mixture was obtained (Table 1, entry 1). To our
delight, when the reaction was carried out under a nitrogen
The direct insertion of unsaturated bonds into carbon–carbon
σ-bonds is of great value in synthetic organic chemistry
because it provides straightforward routes for constructing
complex carbon frameworks by the simultaneous formation of
two carbon–carbon bonds without any byproducts.1 In this
context, Takai and Kuninobu groups have developed excellent
rhenium-catalyzed insertion reaction of alkynes into
β-ketoesters.2 Other transition-metal-catalyzed insertion reac-
tions of alkynes into C–C σ-bonds have also been disclosed,
such as nickel3 and palladium.4 Stoltz’s,5 Yoshida’s6 and
Rodriguez’s7 groups have reported insertion reactions of
highly reactive arynes into carbon–carbon σ-bonds of
β-dicarbonyl compounds, which offer facile approaches to
highly functionalized arenes. Nevertheless, transition-metal-
free insertion reactions of isolated alkynes into carbon–carbon
σ-bonds are very rare. We have recently disclosed the insertion
of alkynes into carbon–carbon σ-bonds of dicarbonyl com-
pounds under transition-metal-free conditions,8 which offer
efficient routes for the synthesis of xanthones or medium-
sized ring compounds being otherwise difficult to prepare.
However, the applicability of the reaction is totally restricted to
active methylene compounds bearing two electron-withdraw-
ing groups. As part of our continuing efforts to explore novel
carbon–carbon σ-bond cleavage reactions, we wondered
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. E-mail: yzli@chem.ecnu.edu.cn;
Fax: +86 021 54340096
†Electronic supplementary information (ESI) available: CCDC 1521120 and
1521121. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c7ob00476a
Scheme 1 Insertion of triple bonds into carbon–carbon σ-bonds.
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Table 1 Screening of the reaction conditions for the formation of 3a a
Table 2 Substrate scope of hydroxydienone compoundsa,b
Entry
Solvent
Base
Time (h)
Yieldsb (%)
1
2
3
4
5
6
7
8
DMF
DMF
DMAc
DMSO
Tol
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
2
2
2
Complex mixturec
81
74
61
Trace
Complex mixture
Trace
Trace
36
2
22
22
22
24
1
3
24
1
THF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K3PO4
9
tBuOK
NaOH
10
11
12
13
61
DABCO
Cs2CO3
Cs2CO3
No reaction
79d
4
55e
a Unless otherwise noted, the reactions were conducted on a 0.2 mmol
scale with the ratio of 1a : 2a = 1 : 1 in 2.0 mL of solvent at room temp-
erature under N2. b Isolated yield. c In air. d Using 3.0 equiv. of Cs2CO3.
e Using 1.5 equiv. of Cs2CO3.
atmosphere, the C–C σ-bond insertion product 3a was pro-
duced in 81% yield (entry 2). Other solvents such as DMAc and
DMSO also gave the desired 3a in 74 and 61% yields, respect-
ively (Table 1, entries 3 and 4). Toluene and THF are ineffective
for the formation of 3a (Table 1, entries 5 and 6). Then various
bases were screened using DMF as the solvent. K2CO3 and
a Reactions were conducted on a 0.3 mmol scale with the ratio of 1 : 2 =
1 : 1 in 3.0 mL of DMF at room temperature under N2. b Isolated yields.
K3PO4 gave only a trace amount of the desired product groups were used, the corresponding hydroxydienones 3j
t
(Table 1, entries 7 and 8). BuOK resulted in 36% of 3a within and 3k could also be obtained in high yields, in which
1 h. When KOH was employed, 3a was obtained in 61% yield. the halogens (-Br, -Cl) were well tolerated during the
Organic bases such as DABCO gave no desired product at all reaction. The structure of 3j was further confirmed by X-ray
(Table 1, entry 11). When the amount of Cs2CO3 was increased crystallography.9
to 3.0 equiv., 79% yield of 3a was obtained within 1 h (Table 1,
entry 12). Conversely, 1.5 equiv. of Cs2CO3 resulted in a much ortho-halide-substituted arene ring would undergo further
lower yield (Table 1, entry 13). intramolecular nucleophilic aromatic substitution reaction
We envisioned that hydroxydienones such as 3j bearing an
With the optimal reaction conditions in hand (Table 1, (SNAr) to give cyclic compounds when the reaction temperature
entry 2), we explored the substrate scope with respect to is increased. Thus, the reaction of 1-(2-bromophenyl)-3-phenyl-
ynones 1 (Table 2). Firstly, the effect of the substituent R1 on prop-2-yn-1-one 4a with 2a was selected as the prototypical
the aryl ring was explored (Table 2, 3a–3c). Substrates both case to screen the experimental conditions. Fortunately, the
with electron-withdrawing and electron-donating groups on corresponding chromone 5a could be produced at an elevated
the aryl ring were suitable for the reaction, offering the desired reaction temperature. To improve the yield of 5a, different reac-
hydroxydienones in good to high yields. Notably, the substrate tion parameters, such as temperature and solvents were
with a p-Br aryl group was tolerable to the reaction conditions, screened (see ESI, Table S1†). It was found that the best result
affording 3b in 54% yield. Subsequently, the R2 substituents for the synthesis of 5a (94% yield) was to use 2.0 equiv. of
on the triple bond were explored (Table 2, 3d–3f). It was found Cs2CO3 as the base and DMF as the solvent at 80 °C. Structural
that R2 with electron-donating (-4-Me and -4-MeO) aryl groups identification of 5a was carried out by X-ray crystallography.9
afforded the corresponding products 3d and 3e in 74% yields, When chloro or fluoro-substituted ynones were used instead of
respectively. An electron-withdrawing (-4-Cl) aryl group also 4a, the desired 5a could also be produced in 92% and 87%
gave 63% of the desired 3f. Next, R3 substituents on ethanones yields, respectively. It was clear that ynones bearing a bromo
were investigated. Again, R3 substituents both with electron- leaving group gave a higher yield of the desired product. Next,
donating (-4-Me and -4-MeO) and electron-withdrawing (-4-Br) the scope of the reaction was explored using various substrates
aryl groups were compatible in the reaction to produce the 4 bearing a bromo leaving group. The results are depicted in
desired 3g, 3h and 3i in 80%, 66% and 95% yields, respect- Table 3. Good to high yields of chromone 5 were obtained
ively. Interestingly, when R1 substituents with o-Br or o-Cl aryl irrespective of the presence of electron-donating or electron-
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Table 3 Substrate scope of chromone compoundsa,b
Scheme 3 Plausible reaction mechanism.
indicates that the formation of chromones may involve a step-
wise pathway.
On the basis of our experimental results and the reported
work,5 a plausible reaction mechanism has been proposed with
model substrates 4a and 2a (Scheme 3). Firstly, 4a was attacked
by ethanone 2a in the presence of a base to give intermediate A,
which presumably undergoes an intramolecular nucleophilic
addition/fragmentation cascade resulting in an alkyne insertion
into the carbon–carbon σ-bond of the ethanone to give C.
Enolization affords intermediate 3j. Nucleophilic aromatic
substitution (SNAr)10 leads to the desired chromone 5a.
In summary, we have developed an efficient base-promoted
carbon–carbon σ-bond cleavage reaction of ethanones using
ynones as the reaction partner, which provides an effective
access to hydroxydienone and chromone compounds under
mild conditions. This process represents the first example of
transition-metal free insertion reaction of isolated internal
alkynes into carbon–carbon σ-bonds of methylene compounds
bearing only one electron-withdrawing group.
a Reactions were conducted on a 0.3 mmol scale with the ratio of 4 : 2 =
1 : 1 in 3.0 mL of DMF at 80 °C under N2. b Isolated yields of two
isomers.
withdrawing groups of the aryl ring on the triple bond (5b–5e).
However, when R2 was nBu, no desired compound was
obtained. Ynone bearing a pyridine ring also reacted smoothly
with 2a to provide the corresponding 5f in 83% yield.
Concerning the R1 substituent on the carbonyl carbon, the
electron-donating (-4, 5-di-MeO) aryl group gave 5g in77%
yield. Electron-withdrawing groups on the aryl ring, such as,
-5-F (5h) and -4-F (5i) were all applicable in the reaction,
offering the chromone compounds in high yields. Next, R3
substituents on ethanones were investigated. Again, R3 substi-
tuents, such as 4-Me-phenyl (5j), 1-naphthyl (5k) and phenyl
(5l) were all compatible in the reaction to produce the corres-
ponding chromones in high yields.
Acknowledgements
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.
Notes and references
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Scheme 2 Control experiment.
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