Generation of 3-(1H-pyrrol-3-yl)-1H-inden-1-ones via a tandem reaction of 1-(2-alkynylphenyl)-2-enone, 2-isocyanoacetate, and water

Article abstract of DOI:10.1039/c2cc34509a

A silver triflate-catalyzed tandem reaction of 1-(2-alkynylphenyl)-2-enone, 2-isocyanoacetate, and water provides a novel and efficient route for the delivery of 3-(1H-pyrrol-3-yl)-1H-inden-1-ones. Four bonds are formed during the tandem process.

Full text of DOI:10.1039/c2cc34509a

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COMMUNICATION
Generation of 3-(1H-pyrrol-3-yl)-1H-inden-1-ones via a tandem reaction
of 1-(2-alkynylphenyl)-2-enone, 2-isocyanoacetate, and waterw
Danqing Zheng,a Shaoyu Lia and Jie Wu*ab
Received 4th May 2012, Accepted 4th July 2012
DOI: 10.1039/c2cc34509a
A silver triflate-catalyzed tandem reaction of 1-(2-alkynylphenyl)-
2-enone, 2-isocyanoacetate, and water provides a novel and efficient
route for the delivery of 3-(1H-pyrrol-3-yl)-1H-inden-1-ones. Four
bonds are formed during the tandem process.
Currently, tandem reaction1,2 is used as a powerful strategy for
the generation of small molecules with privileged scaffolds
using diversity-oriented synthesis.3 Usually, several bonds can
be formed in a one-pot procedure with the generation of
molecular complexity and diversity. Recently, we have been
interested in the method development for the assembly of
natural product-like compounds with structural diversity.4
For instance, quinazolino[3,2-a]quinazolines and related
compounds could be produced via a palladium-catalyzed
three-component reaction of bis-(2-iodoaryl)carbodiimide, iso-
cyanide, and amine.4e Tetrahydroindeno[2,1-b]pyrroles could be
Scheme 1 A proposed route for the synthesis of 1H-benzo[f]indol-
generated via a base-promoted tandem reaction of (E)-2-alkynyl-
4(9H)-ones via a reaction of 1-(2-alkynylphenyl)-2-enone 1 with
phenylchalcone with 2-isocyanoacetate.4a During our studies and
2-isocyanoacetate 2.
according to the previous reports,5–7 we noticed that 2-iso-
cyanoacetate was a useful building block for the formation of
Undoubtedly, water was involved in the transformation for
N-heterocycles. Since the reaction of 2-isocyanoacetate with
(E)-2-alkynylphenylchalcone worked well,4a we conceived
the hydrolysis of alkyne. With this unexpected result in hand,
we further explored the optimal conditions for this transforma-
that 1-(2-alkynylphenyl)-2-enone 1 might be a good partner
tion. The preliminary results are shown in Table 1. Since the
as well in the reaction of 2-isocyanoacetate 2 (Scheme 1).
triple bond could be activated by metal salts, various additives
1H-Benzo[f]indol-4(9H)-ones would be obtained if the reaction of
were screened. The yield was increased to 52% when a
1-(2-alkynylphenyl)-2-enone 1 with 2-isocyanoacetate 2 proceeded
catalytic amount of silver triflate (10 mol%) was added in
smoothly as expected. Therefore, we started to explore this
the reaction (Table 1, entry 2). A similar result was obtained
proposed synthetic route.
when the reaction occurred in O2 (Table 1, entry 3). Only a
A model reaction of 1-(2-alkynylphenyl)-2-enone 1a with
trace amount of the product was detected when the amount of
2-isocyanoacetate 2a was selected initially. The reaction occurred in
DBU was reduced to 0.2 equiv. (Table 1, entry 4). The product
the presence of 1.0 equiv. of DBU in MeCN at 80 1C under an air
atmosphere. To our surprise, we did not observe the formation of
could be afforded in 57% yield when 0.5 equiv. of DBU was
employed (Table 1, entry 5). These results encouraged us to
the desired 1H-benzo[f]indol-4(9H)-one. Instead, 3-(1H-pyrrol-3-
evaluate other bases, such as NaOH, Et3N, t-BuOK, Cs2CO3,
yl)-1H-inden-1-one 3a was produced in 26% yield (Scheme 1).
K3PO4, NaOMe and pyridine (Table 1, entries 7–13). However,
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
no better results were obtained. Other metals were examined
subsequently (Table 1, entries 14–21), and silver triflate was
demonstrated to be the best choice. The results were inferior
when the reaction took place in other solvents (Table 1,
entries 22–26). No reaction occurred when the reaction was
performed at 20 1C (Table 1, entry 27). The reaction was
retarded at 50 1C (Table 1, entry 28). Gratifyingly, the yield
could be improved (78%) when the reaction occurred at 110 1C
in a sealed tube (Table 1, entry 29).
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, China
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of
compounds 3, and a CIF file of compound 3a. CCDC 880815. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c2cc34509a
c
8568 Chem. Commun., 2012, 48, 8568–8570
This journal is The Royal Society of Chemistry 2012

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Table 1 Initial studies for the reaction of 1-(2-alkynylphenyl)-2-
enone 1a with 2-isocyanoacetate 2a
Entry [M]
Base
Solvent
Yielda (%)
1
—
DBU (1.0 equiv.)
DBU (1.0 equiv.)
DBU (1.0 equiv.)
DBU (0.2 equiv.)
DBU (0.5 equiv.)
DBU (2.0 equiv.)
NaOH (0.5 equiv.)
Et3N (0.5 equiv.)
Cs2CO3 (0.5 equiv.) MeCN
K3PO4 (0.5 equiv.) MeCN
NaOMe (0.5 equiv.) MeCN
t-BuOK (0.5 equiv.) MeCN
Pyridine (0.5 equiv.) MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
26
52
51
Trace
57
53
Trace
Trace
42
52
42
Trace
nr
Trace
Trace
23
Trace
51
48
2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
FeCl3
3b
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27c
28d
29e
DBU (0.5 equiv.)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
Bi(OTf)3 DBU (0.5 equiv.)
AuCl
PdCl2
AgOAc
AgSbF6
Sc(OTf)3 DBU (0.5 equiv.)
Cu(OTf)2 DBU (0.5 equiv.)
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
DBU (0.5 equiv.)
DBU (0.5 equiv.)
DBU (0.5 equiv.)
DBU (0.5 equiv.)
20
26
Complex
36
Complex
DBU (0.5 equiv.)
DBU (0.5 equiv.)
DBU (0.5 equiv.)
DBU (0.5 equiv.)
DBU (0.5 equiv.)
DBU (0.5 equiv.)
DBU (0.5 equiv.)
DBU (0.5 equiv.)
Toluene
THF
1,4-Dioxane 45
DMF
53
nr
20
78
MeCN
MeCN
MeCN
a
b
Isolated yield based on 1-(2-alkynylphenyl)-2-enone 1a. The reac-
c
tion occurred in O2 (balloon). The reaction was performed at 20 1C.
Scheme 2 Investigation of the scope of the reaction of 1-(2-alkynyl-
phenyl)-2-enone 1 with 2-isocyanoacetate 2.a
d
e
The reaction was performed at 50 1C. The reaction occurred at
110 1C in a sealed tube.
group at the R2 position were all workable in the reactions.
For instance, trifluoromethyl-substituted compound 3i was
obtained in 57% yield. Additionally, reactions of 1-(2-alkynyl-
phenyl)-2-enones 1 with substitutions on the aromatic ring (R1)
were studied. As expected, all reactions proceeded smoothly
to produce the desired products 3 in good yields. Different
substitutions including fluoro, chloro, methyl, and methoxy
groups were all compatible under the optimized conditions.
Although ethyl 2-isocyanoacetate and tert-butyl 2-isocyanoacetate
were good partners with 1-(2-alkynylphenyl)-2-enones 1 in this
tandem reaction, the reaction of 1-(isocyanomethylsulfonyl)-4-
methylbenzene failed to afford the expected product.
We next explored the scope of this silver triflate-catalyzed
tandem reaction of 1-(2-alkynylphenyl)-2-enone, 2-isocyano-
acetate, and water under the optimized conditions (10 mol%
of silver triflate, 0.5 equiv. of DBU, MeCN, 110 1C in a sealed
tube). The results are summarized in Scheme 2. In most cases,
1-(2-alkynylphenyl)-2-enone 1 reacted with 2-isocyanoacetate 2,
giving rise to the corresponding 3-(1H-pyrrol-3-yl)-1H-inden-1-
ones 3 in good yields. Reactions of 1-(2-alkynylphenyl)-2-enone 1
with an aryl group attached at the R3 position worked well with
2-isocyanoacetate 2 under the standard conditions. The reaction
was complex when 1-(2-alkynylphenyl)-2-enone 1 with an alkyl
group attached at the R3 position was employed. For instance,
different aryl substitutions on the R3 position of 1-(2-alkynyl-
phenyl)-2-enone 1 were all tolerated, including 4-methoxyphenyl
and 4-chlorophenyl groups. When the R3 position was changed
to a tert-butyl group, the reaction was complex. It might be due
to the stability issue of the intermediate during the reaction
process. Next, reactions of 1-(2-alkynylphenyl)-2-enones 1 with
substitutions on the R2 position were investigated. It was
found that substrates 1 with aryl groups (including electron-
withdrawing and electron-donating groups) and the thioenyl
With the above results in hand, we proposed a possible
route for the formation of 3-(1H-pyrrol-3-yl)-1H-inden-1-ones
3 via a silver triflate-catalyzed reaction of 1-(2-alkynylphenyl)-
2-enone 1 with 2-isocyanoacetate 2 (Scheme 3). In the presence
of a base, a Michael addition of 2-isocyanoacetate to 1-(2-
alkynylphenyl)-2-enone would occur to generate the inter-
mediate A. Further intramolecular nucleophilic addition
would furnish compound B. In the meantime, the alkyne
would be hydrolyzed to ketone C,8 which would then undergo
an intramolecular condensation and oxidation to provide the
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8568–8570 8569

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Scheme 3 A possible mechanism for the formation of 3-(1H-pyrrol-
3-yl)-1H-inden-1-ones 3.
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Scheme 4 Isolation and reaction of intermediate B1.
3-(1H-pyrrol-3-yl)-1H-inden-1-one 3. To confirm the mechanism,
the reaction of 1-(2-alkynylphenyl)-2-enone 1a with 2-isocyano-
acetate 2a in the absence of a silver(I) catalyst in dry MeCN was
performed. As expected, the intermediate B1 was isolated and
obtained in 60% yield (Scheme 4). After addition of the silver
triflate and water, the corresponding product 3a was generated.
In conclusion, we have described a novel and efficient synthesis
of 3-(1H-pyrrol-3-yl)-1H-inden-1-ones via a silver triflate-catalyzed
tandem reaction of 1-(2-alkynylphenyl)-2-enone, 2-isocyano-
acetate, and water. Four bonds are formed during the transforma-
tion with high efficiency. Efforts using 2-isocyanoacetates for the
generation of other N-heterocycles are currently ongoing.
Financial support from the National Natural Science Founda-
tion of China (No. 21032007, 21172038) is gratefully acknowledged.
Notes and references
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c
8570 Chem. Commun., 2012, 48, 8568–8570
This journal is The Royal Society of Chemistry 2012