Synthesis of 4-oxoindeno[1,2-b]pyrroles through copper-catalyzed tandem reactions of 1-(2-haloaryl)enones with isocyanides

Article abstract of DOI:10.1055/s-0030-1260171

Copper-catalyzed tandem reactions of 1-(2-haloaryl)-enones with isocyanides for the synthesis of 4-oxoindeno[1,2-b]pyrroles are described. Highly reactive cyclic organocopper intermediates are generated in the copper-catalyzed [3+2]-cycloaddition reaction

Full text of DOI:10.1055/s-0030-1260171

PAPER
3037
Synthesis of 4-Oxoindeno[1,2-b]pyrroles through Copper-Catalyzed Tandem
Reactions of 1-(2-Haloaryl)enones with Isocyanides
Synthesis of
4e
n
[1,2-
b
]pyrro
g
les tao Zhou, Liangbing Fu, Jiajia Wie, Ke Ding, Qian Cai*
Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health,
Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou, 510530, P. R. of China
Fax +86(20)32015266; E-mail: cai_qian@gibh.ac.cn
Received 22 April 2011; revised 13 July 2011
ly useful for the synthesis of 4-oxoindeno[1,2-b]pyrroles
Abstract: Copper-catalyzed tandem reactions of 1-(2-haloaryl)-
because the 1-(2-haloaryl)enone substrates could be easi-
ly prepared through condensation of the corresponding
ketones with aldehydes. Herein, we describe the copper-
enones with isocyanides for the synthesis of 4-oxoindeno[1,2-
b]pyrroles are described. Highly reactive cyclic organocopper inter-
mediates are generated in the copper-catalyzed [3+2]-cycloaddition
reactions of isocyanides to double or triple bonds. Successful in- catalyzed tandem reactions of 1-(2-haloaryl)enones with
tramolecular trapping of the organocopper intermediates led to the
isocyanides.
efficient formation of 4-oxoindeno[1,2-b]pyrroles.
R2
Key words: copper-catalyzed, isocyanide, enones, pyrroles
O
X
O
CuI, Cs2CO3
R1
R1
R3
R2
Cu
X
CNCH2R3
ref. 7
N
The 4-oxoindeno[1,2-b]pyrroles and analogues are bio-
logically important structures that have found extensive
use in medicinal chemistry; such compounds have been
used as 5HT2c receptor agonists1 and antiviral agents.2
However, the synthesis of such compounds often takes
several steps and is not efficient. General methods for pre-
paring these compounds from simple starting materials
are lacking, which has greatly hindered studies on their bi-
ological activities.3
highly active
O
O
X
R2
CuI, Cs2CO3
R2
CNCH2R3, r.t., air
this work
R1
R3
R1
N
H
Scheme 1 Copper-catalyzed tandem reaction of isocyanides with 1-
(2-haloaryl)unsaturated ketones for the synthesis of 4-oxoindeno[1,2-
b]pyrroles
Transition-metal-catalyzed cycloaddition reactions of iso-
cyanides to double or triple bonds have been extensively
explored in recent years, which has led to the development
of a number of general ways to access a diverse range of
heterocycles, such as pyrroles and oxazolines.4–6 The
mechanisms of such reactions were proposed to follow a
formal [3+2] cycloaddition process, which produces a cy-
clic organometal intermediate that undergoes rapid proto-
nation to form the stable products. We realized that the
cyclized organometal intermediates may act as reactive
intermediates for further aryl C–C coupling. Based on this
hypothesis, we designed some novel tandem reactions to
trap the organometal intermediates and thus open the way
to new synthetic methods to access heterocycles.7 In a pre-
vious communication,7a we reported our research on the
intramolecular trapping of an organocopper intermediate
produced in the copper-catalyzed cycloaddition reaction
of isocyanides with 1-(2-iodoaryl)ynones, which led to
the efficient formation of 4-oxoindeno[1,2-b]pyrrole
compounds (Scheme 1). Further exploration revealed that
the protocol was also applicable to the reaction of isocya-
nides with 1-(2-haloaryl)enones, which also furnished 4-
oxoindeno[1,2-b]pyrrole products through an additional
oxidation step. The new protocol could become practical-
Based on the idea of intramolecular trapping of the orga-
nocopper intermediate, we speculated that the copper-cat-
alyzed tandem reactions of 1-(2-haloaryl)enones with
isocyanides would produce the corresponding 4-oxo-
1,2,3,4-tetrahydroindeno[1,2-b]pyrrole products, which
may be easily oxidized into the corresponding 4-oxoinde-
no[1,2-b]pyrroles (Scheme 1).
To test this idea, we first explored the conditions required
for copper-catalyzed reaction of ethyl isocyanoacetate
(1a) with (E)-1-(2-iodophenyl)-3-p-tolylprop-2-en-1-one
(2a). Surprisingly, instead of producing the expected tan-
dem product 3a, or the protonolysis byproduct 4a, this re-
action generated 4-oxoindeno[1,2-b]pyrrole 5a in
approximately 68% yield [reaction performed under an N2
atmosphere (balloon); Scheme 2]. We speculated that the
formation of 5a is likely the result of oxidation of initially
formed 3a by the small amount of air contained in the N2.
Since the reaction was thought to involve an oxidation
process, we then tested it with oxygen as the oxidant.
However, the yield of the reaction was reduced to only
31% (Table 1, entry 2). It was reasonable to assume that
oxygen could oxidize the Cu(I) to Cu(II), which is unfa-
vorable for the copper-catalyzed coupling step. We spec-
ulated that a small amount of O2 may be better for the
reaction, which was confirmed by the slightly improved
SYNTHESIS 2011, No. 18, pp 3037–3044
x
x.
x
x
.
2
0
1
1
Advanced online publication: 16.08.2011
DOI: 10.1055/s-0030-1260171; Art ID: H59411SS
© Georg Thieme Verlag Stuttgart · New York

3038
F. Zhou et al.
PAPER
O
I
O
O
I
CNCH2CO2Et (1a)
CuI, Cs2CO3
+
4 h, r.t.
N2 (balloon)
CO2Et
CO2Et
N
N
2a
H
H
3a not isolated
4a not isolated
O
CO2Et
N
H
5a 68%
Scheme 2 Copper-catalyzed reaction of ethyl isocyanoacetate with 1-(2-iodophenyl)-3-p-tolylprop-2-en-1-one
yields (70%) when the reaction was performed in air
(Table 1, entry 3). The important effect of the small
Table 1 Reaction Conditions for the Copper-Catalyzed Tandem Re-
amount of O2 was further confirmed by conducting the re-
action in Argon (balloon) with high purity; under these
conditions, the product 5a was obtained with only about
20% yield (Table 1, entry 4). Furthermore, we explored
the model reaction with different solvents, bases and cop-
per salts in air. The results revealed that the combination
of CuI, Cs2CO3, and N,N-dimethylformamide (DMF) was
the best choice for our reaction; other solvents, bases, and
copper salts led to lower yields (Table 1, entries 5–14). No
improvement was observed upon increasing the reaction
temperature to 60 or 90 °C (Table 1, entries 15 and 16). In
fact, some side products were produced and the reaction
system became very complex at higher temperatures.
actiona
O
O
conditions
CNCH2CO2Et
+
I
CO2Et
N
H
5a
1a
2a
Entry Catalyst Base
Solvent
DMF
Temp (°C) Yield (%)b
1
2
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOH
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t
68c
31d
70
CuI
DMF
3
CuI
DMF
Under the optimized conditions, the new tandem protocol
was applied to reactions of a series of 1-(2-iodoaryl)-
enones with a range of isocyanides (Table 2). For the 1-
(2-iodoaryl)enone substrates, the results revealed that the
1-(2-iodoaryl)enones bearing aryl groups at the terminal
of a double bond were favored over those bearing alkyl
groups (Table 2, entries 1–11). The low yields of the latter
substrates were at least partially caused by dimerization or
polymerization of the 3-alkyl enones.8 For aryl substitu-
tions at the double bond terminal, the results also showed
that electron-rich aryl groups gave better results than elec-
tron-deficient aryl groups (Table 2, entries 1–6 and 7–9).
The electronic effects of substituents on the 1-(2-idoaryl)
ring were much clearer; compounds bearing electron-
withdrawing groups on the 1-(2-idoaryl) ring provided the
4
CuI
DMF
20e
51
5
CuI
DMSO
MeCN
dioxane
toluene
DMF
6
CuI
50
7
CuI
23
8
CuI
n.d.f
47
9
CuI
10
11
12
CuI
K3PO4
DMF
r.t
32
CuI
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
r.t
34
CuBr
CuOTf
CuSO4
CuI
DMF
r.t
33
corresponding products in good yields (Table 2, entries 13
14–18), whereas compounds bearing electron-donating
groups delivered the corresponding products only in low
yields (Table 2, entries 12 and 13). The situation could be
slightly improved by increasing the reaction temperature
to 50 °C.
DMF
r.t
41
14
DMF
r.t
40
15
16
DMF
60
90
46
CuI
DMF
32
a Reaction conditions: 1a (0.55 mmol), 2a (0.5 mmol), CuI (10 mg,
A second isocyanide, toluenesulfonylmethyl isocyanide
(TOSMIC; 1b) was also explored in the copper-catalyzed
tandem reactions, and it was found that this substrate also
furnished the corresponding products in acceptable yields
10 mol%), Cs2CO3 (1 mmol), r.t., 4 h, in air.
b Isolated yield.
c Under N2 (balloon).
d Under O2.
(Table 2, entries 19 and 20). However, for the less reac- e Under Argon (balloon).
f No desired product was detected.
tive 1-(2-bromoaryl)enones, no desired products were
detected when the reaction was performed at room tem-
Synthesis 2011, No. 18, 3037–3044 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Oxoindeno[1,2-b]pyrroles
3039
perature. When the reaction temperature was increased to
100 °C, lower yields were obtained in some cases
(Table 2, entries 15 and 16). In the case of 1-(2-chloroar-
yl)enone substrates, no desired products were detected
even under such harsh reaction conditions.
The structures of the indeno[1,2-b]pyrroles produced in
these reactions were assigned by analogy to that of 5h, the
structure of which was unambiguously determined by X-
ray crystallographic analysis (Figure 1).9
Based on literature reports6e,f and on our experimental ob-
servations, a plausible reaction mechanism for the copper-
catalyzed tandem reactions of isocyanides with 1-(2-ha-
loaryl)enones was proposed as shown in Scheme 3. In this
pathway, Cu-catalyst species A or A¢ was first formed
through the reaction of the isocyanide with CuI in the
presence of a base, which then generates the cyclic orga-
nocopper intermediate B through a [3+2] cycloaddition
reaction with the 1-(2-haloaryl)enone. Intermediate B is
transformed into intermediate C by intramolecular inser-
tion of Cu into the aryl C–X bond and then the coupling
Figure 1 X-ray crystal structure of 5h
product D is generated to end the catalytic cycle. Finally,
4-oxoindeno[1,2-b]pyrroles are produced by a tautomer-
ization–oxidation process from D.
Table 2 Scope of the Copper-Catalyzed Tandem Reactions of 1-(2-Haloaryl)enones with Isocyanidesa
O
R2
O
CuI, Cs2CO3
DMF, r.t., air
R2
CNCH2R3
R1
+
R3
R1
N
I
H
1
2
5
Entry Aryl iodide
Product
Yield Entry Aryl iodide
(%)b
Product
Yield
(%)b
NEt2
O
O
O
O
CO2Et
CO2Et
1
74
58
61
58
11
12
13
14
32
CO2Et
I
N
NEt2
I
H
CO2Et
N
H
2l
2b
5l
5b
NH2
O
O
I
O
O
2
35c
33c
76
I
MeO
NH2
CO2Et
CO2Et
N
H
N
H
MeO
2m
2c
5m
5c
OMe
O
O
O
O
3
Bn2N
I
I
OMe
OMe
CO2Et
N
H
CO2Et
N
H
Bn2N
2n
2d
5n
5d
5e
O
O
O
I
O
OMe
4
MeO2C
I
CO2Et
N
H
CO2Et
N
MeO2C
H
2e
2o
5o
Synthesis 2011, No. 18, 3037–3044 © Thieme Stuttgart · New York

3040
F. Zhou et al.
PAPER
Table 2 Scope of the Copper-Catalyzed Tandem Reactions of 1-(2-Haloaryl)enones with Isocyanidesa (continued)
O
R2
O
CuI, Cs2CO3
DMF, r.t., air
R2
CNCH2R3
R1
+
R3
R1
N
I
H
1
2
5
Entry Aryl iodide
Product
Yield Entry Aryl iodide
(%)b
Product
Yield
(%)b
MeO
OMe
OMe
O
I
O
O
OMe
OMe
O
O
78
O
5
73
15
(38)d
MeO2C
CO2Et
N
H
I
MeO
CO2Et
N
2f
MeO2C
H
5f
2p
5p
O
I
O
O
O
78
6
60
55
16
17
(40)d
O2N
I
CO2Et
CO2Et
N
N
H
O2N
H
2g
2q
5g
5h
5q
O
O
O
Cl
N
O
N
7
62
58
43
Cl
CO2Et
NC
I
I
N
H
CO2Et
N
NC
H
2h
2r
5r
CN
O
O
I
O
O
8
42c
41c
30
18
I
Cl
CN
CO2Et
CO2Et
N
N
H
H
Cl
2s
2i
5i
5s
NO2
O
O
O
9
19 2a
I
NO2
Ts
CO2Et
N
H
N
H
2j
5j
5t
O
O
O
10
20 2o
45
CO2Et
N
H
I
Ts
N
H
MeO2C
2k
5k
5u
a Reaction conditions: 1 (0.55 mmol), 2 (0.5 mmol), CuI (0.05 mmol), Cs2CO3 (1.0 mmol), r.t., 4–6 h. For entries 1–18, ethyl isocyanoacetate
(1a) was used; for entries 19 and 20, TOSMIC (1b) was used.
b Isolated yield.
c Reaction conducted at 50 °C.
d X = Br, 100 °C.
Although the proposed organocopper intermediate was reaction of aryl ynone with isocyanide failed.7a However,
successfully trapped intramolecularly, our attempts to trap when adding iodomethane to the copper-catalyzed reac-
the intermediate in an intermolecular manner did not give tion of (E)-chalcone and ethyl isocyanoacetate, the fully
satisfactory results. Previous attempts to achieve intermo- substituted pyrrole product 6 was isolated, albeit in low
lecular trapping of the organocopper intermediate in the yield (Scheme 4),10 which partially confirmed our as-
Synthesis 2011, No. 18, 3037–3044 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Oxoindeno[1,2-b]pyrroles
3041
R1
N
O
O
R3
[O]
R3
R1
R2
R2
R1
R1
N
R1
Cu[I]
base
H
N
D
N
Cu-C
N
Cu-C
A'
A
2
R1
O
R3
R3
O
N
path a
R2
R1
R2
R1
N
Cu
Cu
I
N
I
C
B
Scheme 3 Proposed mechanism
O
Na2SO4, and concentrated in vacuum. The residue was loaded on a
silica column and purified by column chromatography (SiO2; PE–
EtOAc, 8:1) to afford the final product 5a–u.
O
MeI, CuI
Ph
CO2Et
Ph
Cs2CO3, DMF
CNCH2CO2Et
air, r.t.
N
(E)-chalcone
Me
6 about 5%
Ethyl 4-Oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-2-car-
boxylate (5a)
1H NMR (400 MHz, DMSO-d6): d = 12.82 (br s, 1 H), 7.55 (d, J =
8.0 Hz, 2 H), 7.42–7.48 (m, 2 H), 7.37 (d, J = 7.2 Hz, 1 H), 7.23–
7.27 (m, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 4.22 (q, J = 7.2 Hz, 2 H),
2.34 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H).
Scheme 4 Attempt at intermolecular trapping
sumption that the intermediate can also be trapped in an
intermolecular fashion.
13C NMR (125 MHz, DMSO-d6): d = 185.2, 160.3, 151.5, 139.7,
137.2, 134.0, 131.3, 133.4, 129.9, 129.3, 129.0, 128.5, 127.8, 123.0,
122.9, 121.6, 119.5, 60.1, 20.9, 14.1.
MS (ESI): m/z = 332.1 [M + H+].
HRMS (ESI): m/z [M + H]+ calcd for C21H18NO3: 332.1281; found:
In summary, this investigation has led to the development
of an efficient and practically useful method for the syn-
thesis of 4-oxoindeno[1,2-b]pyrroles through copper-cat-
alyzed tandem reaction of 1-(haloaryl)enones with
isocyanides. The process takes place efficiently with a va-
riety of 1-(2-iodoaryl)enone substrates and displays wide
ranging functional-group compatibility. The method is a
complementary alternative to our previously reported re-
actions of 1-(2-haloaryl)ynones and isocyanides because
1-(haloaryl)enones are much easier to prepare. Further ap-
plications of these methods are underway in our laborato-
ry.
332.1282.
Ethyl 3-[4-(Diethylamino)]-4-oxo-1,4-dihydroindeno[1,2-b]pyr-
role-2-carboxylate (5b)
1H NMR (400 MHz, CDCl3): d = 9.81 (br s, 1 H), 7.77 (d, J =
8.8 Hz, 2 H), 7.49 (d, J = 7.2 Hz, 1 H), 7.30 (t, J = 7.2 Hz, 1 H),
7.16–7.22 (m, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 4.32 (q, J = 7.2 Hz,
2 H), 3.38 (q, J = 7.2 Hz, 4 H), 1.33 (t, J = 7.2 Hz, 3 H), 1.18 (t, J =
7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 185.8, 161.4, 151.2, 148.0, 140.7,
140.0, 132.6, 132.2, 131.7, 129.0, 123.6, 123.0, 120.0, 118.2, 117.8,
110.4, 60.7, 44.3, 14.3, 12.7.
All products were characterized by their H and 13C NMR on a
1
Bruker AV-400 or -500 MHz spectrometer, respectively. Mass
spectrometric analyses were performed on an Agilent 1956B single
quadrupole mass spectrometer. High resolution mass spectra
(HRMS) were obtained on a Q-STAR Elite ESI-LC-MS/MS spec-
trometer. All reactions were carried out in 5 mL tubes. DMF was
distilled from CaH2 and stored over 4 Å activated molecular sieves.
Cs2CO3 (Alfa Aesar), CuI (Aldrich) and all other solid materials
were stored in the presence of P2O5 in a bench-top desiccator under
vacuum at r.t. and weighed in air. Petroleum ether (PE) used was the
fraction boiling in the temperature range 60–90 °C.
MS (ESI): m/z = 389.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C24H25N2O3: 389.1860; found:
389.1862.
Ethyl 3-(4-Amino)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-
carboxylate (5c)
1H NMR (400 MHz, DMSO-d6): d = 12.64 (br s, 1 H), 7.43–7.47
(m, 4 H), 7.36 (d, J = 7.2 Hz, 1 H), 7.23–7.27 (m, 1 H), 6.56 (d, J =
8.8 Hz, 2 H), 5.45 (br s, 2 H), 4.23 (q, J = 7.2 Hz, 2 H), 1.25 (t, J =
7.2 Hz, 3 H).
4-Oxoindeno[1,2-b]pyrroles; General Procedure
13C NMR (125 MHz, DMSO-d6): d = 185.6, 160.9, 151.8, 149.0,
140.4, 134.4, 133.7, 131.6, 131.5, 129.4, 123.3, 122.2, 121.6, 119.8,
119.0, 112.9, 60.3, 14.6.
MS (ESI): m/z = 333.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2O3: 333.1234; found:
Isocyanide 1 (0.55 mmol) was added to a mixture of Cs2CO3 (325
mg, 1.0 mmol, 2.0 equiv), CuI (10 mg, 0.05 mmol, 10% equiv), and
2 (0.5 mmol, 1.0 equiv) in DMF (1 mL) at the stated temperature.
The mixture was stirred under air for 4–6 h (until TLC showed that
the reaction was complete), then H2O (5 mL) was added and the
aqueous phase was extracted with EtOAc (3 × 5 mL). The com-
bined organic phase was washed with brine (3 × 5 mL), dried over
333.1235.
Synthesis 2011, No. 18, 3037–3044 © Thieme Stuttgart · New York

3042
F. Zhou et al.
PAPER
Ethyl 3-(4-Methoxy)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-
carboxylate (5d)
Ethyl 3-(4-Cyanophenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyr-
role-2-carboxylate (5i)
1H NMR (400 MHz, DMSO-d6): d = 12.80 (br s, 1 H), 7.64 (d, J =
8.0 Hz, 2 H), 7.42–7.47 (m, 2 H), 7.37 (d, J = 6.8 Hz, 1 H), 7.26 (t,
J = 6.8 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 2 H), 4.23 (q, J = 6.8 Hz, 2 H),
3.80 (s, 3 H), 1.23 (t, J = 6.8 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 13.08 (br s, 1 H), 7.82–7.88
(m, 4 H), 7.46 (m, 2 H), 7.39 (m, 1 H), 7.28–7.30 (m, 1 H), 4.23 (q,
J = 7.2 Hz, 2 H), 1.19 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 185.6, 160.5, 152.2, 139.9,
137.0, 134.4, 134.2, 131.7, 131.3, 129.8, 127.2, 124.2, 123.7,
122.1, 120.1, 119.3, 110.7, 60.9, 14.4.
MS (ESI): m/z = 343.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H15ClN2O3: 343.1077;
13C NMR (125 MHz, DMSO-d6): d = 185.7, 160.8, 159.5, 151.9,
140.2, 134.4, 133.9, 131.9, 129.8, 129.6, 124.1, 123.4, 123.0, 121.9,
119.9, 113.11, 60.1, 55.5, 14.6.
MS (ESI): m/z = 348.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H18NO3: 348.1230; found:
found: 343.1078.
348.1230.
Ethyl 3-(4-Nitrophenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyr-
role-2-carboxylate (5j)
Ethyl 3-(3-Methoxyphenyl)-4-oxo-1,4-dihydroindeno[1,2-
b]pyrrole-2-carboxylate (5e)
1H NMR (400 MHz, DMSO-d6): d = 13.11 (br s, 1 H), 8.24 (d, J =
8.8 Hz, 2 H), 7.91 (d, J = 8.8 Hz, 2 H), 7.47–7.48 (m, 2 H), 7.40 (d,
J = 7.2 Hz, 1 H), 7.27–7.30 (m, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 1.21
(t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 12.88 (br s, 1 H), 7.43–7.48
(m, 2 H), 7.38 (d, J = 7.2 Hz, 1 H), 7.23–7.31 (m, 4 H), 6.92 (d, J =
7.2 Hz, 1 H), 4.22 (q, J = 7.2 Hz, 2 H), 3.79 (s, 3 H), 1.21 (t, J =
7.2 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 185.6, 160.4, 152.2, 147.1,
139.8, 139.0, 134.4, 134.2, 131.7, 129.8, 126.6, 124.4, 123.7, 122.9,
122.2, 120.2, 61.0, 14.4.
MS (ESI): m/z = 363.0 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H15N2O5: 363.0975; found:
13C NMR (125 MHz, DMSO-d6): d = 185.2, 160.3, 158.3, 151.6,
139.7, 134.0, 133.5, 132.7, 129.1, 128.2, 123.3, 123.0, 122.4, 121.7,
119.5, 115.2., 113.6, 60.1, 55.0, 14.0.
MS (ESI): m/z = 348.0 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H18NO4: 348.1230; found:
363.0972.
348.1235.
Ethyl 3-tert-Butyl-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-
carboxylate (5k)
Ethyl 3-(Furan-2-yl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrole-2-
carboxylate (5f)
1H NMR (400 MHz, CDCl3): d = 9.62 (br s, 1 H), 7.46 (d, J =
7.2 Hz, 1 H), 7.30 (m, 1 H), 7.19 (m, 1 H), 7.12 (d, J = 7.2 Hz, 1 H),
4.37 (q, J = 7.2 Hz, 2 H), 1.52 (s, 9 H), 1.40 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 12.92 (br s, 1 H), 7.78 (s, 1 H),
7.41–7.50 (m, 3 H), 7.27–7.30 (m, 2 H), 6.62–6.63 (m, 1 H), 4.33
(q, J = 7.2 Hz, 2 H), 1.34 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 185.4, 160.5, 150.3, 143.6, 140.2,
134.4, 133.4, 132.8, 129.1, 123.8, 123.6, 117.5, 60.9, 33.2, 31.1,
14.4.
MS (ESI): m/z = 298.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.1438; found:
13C NMR (125 MHz, DMSO-d6): d = 184.4, 160.3, 152.0, 146.9,
143.5, 140.0, 134.1, 133.9, 129.8, 123.6, 122.4, 120.6, 120.0, 117.9,
112.8, 112.1, 60.9, 14.7.
MS (ESI): m/z = 308.0 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H14NO4: 308.0917; found:
298.1441.
308.0924.
Diethyl 4-Oxo-1,4-dihydroindeno[1,2-b]pyrrole-2,3-dicarboxy-
late (5l)
Ethyl 3-(Naphthalen-1-yl)-4-oxo-1,4-dihydroindeno[1,2-b]pyr-
role-2-carboxylate (5g)
1H NMR (500 MHz, CDCl3): d = 10.12 (br s, 1 H), 7.50 (d, J =
7.2 Hz, 1 H), 7.32–7.36 (m, 1 H), 7.22–7.25 (m, 1 H), 7.19 (m,
1 H), 4.35–7.44 (m, 4 H), 1.13–1.43 (m, 6 H).
1H NMR (400 MH, DMSO-d6): d = 13.08 (br s, 1 H), 7.95 (t, J =
8.4 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.40–7.55 (m, 6 H), 7.25–
7.34 (m, 2 H), 3.92 (q, J = 6.4 Hz, 2 H), 0.71 (t, J = 6.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 184.3, 163.0, 160.3, 150.6, 139.4,
133.7, 133.2, 129.6, 126.3, 124.1, 123.5, 118.6, 118.3, 61.7, 61.7,
14.1, 14.1
MS (ESI): m/z = 314.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C17H16NO5: 314.1023; found:
13C NMR (125 MH, DMSO-d6): d = 185.6, 160.6, 152.0, 140.0,
134.8, 134.0, 133.3, 131.9, 130.9, 129.6, 128.4, 128.3, 127.9, 126.3,
126.1, 126.0, 125.8, 125.4, 123.8, 123.5, 120.0, 60.2, 13.8.
MS (ESI): m/z = 368.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C24H19NO3: 368.1281; found:
314.1028.
368.1282.
Ethyl 7-Methoxy-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyr-
role-2-carboxylate (5m)
Ethyl 3-(2-Chloropyridin-3-yl)-4-oxo-1,4-dihydroindeno[1,2-
b]pyrrole-2-carboxylate (5h)
1H NMR (400 MHz, DMSO-d6): d = 12.72 (br s, 1 H), 7.54 (d, J =
8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 2 H),
7.09 (d, J = 2.0 Hz, 1 H), 6.73 (dd, J = 8.0, 2.0 Hz, 1 H), 4.22 (q, J =
7.2 Hz, 2 H), 3.84 (s, 3 H), 2.34 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 13.16 (br s, 1 H), 8.42 (dd, J =
4.8, 2.0 Hz, 1 H), 7.79 (dd, J = 7.6, 2.0 Hz, 1 H), 7.44–7.48 (m,
3 H), 7.37 (d, J = 7.2 Hz, 1 H), 7.25–7.29 (m, 1 H), 4.11 (q, J =
7.2 Hz, 2 H), 1.03 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 185.1, 164.1, 160.7, 150.3,
137.6, 136.7, 132.5, 130.4, 129.6, 129.0, 128.3, 125.3, 123.2, 123.1,
111.9, 108.0, 60.5, 56.2, 21.3, 14.6.
MS (ESI): m/z = 362.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H20NO4: 362.1387; found:
13C NMR (125 MHz, DMSO-d6): d = 185.4, 160.4, 151.9, 149.9,
149.2, 141.2, 139.8, 134.8, 134.2, 129.8, 125.6, 123.7, 123.1, 122.8,
120.1, 60.7, 14.3.
MS (ESI): m/z = 353.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H14ClN2O3: 353.0687;
362.1388.
found: 353.0691.
Synthesis 2011, No. 18, 3037–3044 © Thieme Stuttgart · New York

PAPER
Synthesis of 4-Oxoindeno[1,2-b]pyrroles
3043
Ethyl 7-(Dibenzylamino)-4-oxo-3-p-tolyl-1,4-dihydroinde-
no[1,2-b]pyrrole-2-carboxylate (5n)
HRMS (ESI): m/z [M + H]+ calcd for C22H17N2O3: 357.1234; found:
357.1236.
1H NMR (400 MHz, DMSO-d6): d = 12.58 (br s, 1 H), 7.52 (d, J =
8.0 Hz, 2 H), 7.37 (m, 4 H), 7.28 (m, 6 H), 7.14 (m, 3 H), 7.07 (m,
1 H), 6.35 (d, J = 8.0 Hz, 1 H), 4.78 (s, 4 H), 4.17 (q, J = 6.8 Hz,
2 H), 2.33 (s, 3 H), 1.18 (t, J = 6.8 Hz, 3 H).
Ethyl 7-Chloro-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyr-
role-2-carboxylate (5s)
1H NMR (400 MHz, DMSO-d6): d = 10.5 (br s, 1 H), 7.62 (d, J =
8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.19–7.24 (m, 4 H), 4.33 (q,
J = 7.2 Hz, 2 H), 2.39 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 185.2, 160.8, 153.1, 138.1,
137.3, 136.8, 130.5, 130.5, 129.3, 129.2, 128.2, 127.5, 127.0, 125.4,
123.6, 122.4, 109.6, 104.9, 60.3, 54.2, 21.3, 14.6.
MS (ESI): m/z = 527.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C35H31N2O3: 527.2329; found:
13C NMR (125 MHz, DMSO-d6): d = 184.3, 160.6, 150.0, 138.6,
138.3, 137.8, 136.4, 130.4, 129.8, 128.9, 128.7, 128.3, 124.9, 123.8,
122.7, 120.0, 60.7, 21.3, 14.5.
MS (ESI): m/z = 366.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H17ClNO3: 366.0891;
527.2329.
2-Ethyl 7-Methyl 4-Oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyr-
role-2,7-diarboxylate (5o)
found: 366.0890.
1H NMR (400 MHz, DMSO-d6): d = 12.85 (br s, 1 H), 8.07 (s, 1 H),
7.86 (d, J = 7.6 Hz, 1 H), 7.56 (d, J = 7.6 Hz, 2 H), 7.48 (d, J =
7.6 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 2 H), 4.22 (q, J = 7.2 Hz, 2 H),
3.89 (s, 3 H), 2.35 (s, 3 H), 1.24 (t, J = 7.2 Hz, 3 H).
3-p-Tolyl-2-tosylindeno[1,2-b]pyrrol-4(1H)-one (5t)
1H NMR (400 MHz, DMSO-d6): d = 13.41 (br s, 1 H), 7.55 (d, J =
8.4 Hz, 2 H), 7.48–7.75 (m, 2 H), 7.42 (d, J = 8.0 Hz, 2 H), 7.38 (d,
J = 7.2 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.27–7.31 (m, 1 H), 7.20
(d, J = 8.0 Hz, 2 H), 2.35 (s, 3 H), 2.33 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 184.4, 165.7, 160.5, 151.0,
143.9, 137.8, 134.7, 134.1, 131.2, 130.4, 129.8, 128.7, 128.3, 123.8,
123.3, 122.6, 120.0, 60.6, 52.9, 21.3, 14.5.
MS (ESI): m/z = 390.0 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C23H20NO5: 390.1336; found:
13C NMR (125 MHz, DMSO-d6): d = 185.4, 151.9, 144.6, 139.5,
139.4, 138.3, 134.1, 134.1, 130.4, 130.0, 129.4, 129.2, 128.8, 128.6,
128.4, 127.5, 126.6, 123.7, 122.2, 120.2, 21.4, 21.3.
MS (ESI): m/z = 414.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C25H20NO3S: 414.1158;
390.1337.
found: 414.1154.
2-Ethyl 7-Methyl 4-Oxo-3-(3,4,5-trimethoxyphenyl)-1,4-dihy-
droindeno[1,2-b]pyrrole-2,7-dicarboxylate (5p)
Ethyl 4-Oxo-3-p-tolyl-2-tosyl-1,4-dihydroindeno[1,2-b]pyrrole-
7-carboxylate (5u)
1H NMR (400 MHz, DMSO-d6): d = 12.89 (br s, 1 H), 8.09 (s, 1 H),
7.88 (dd, J = 7.6, 1.2 Hz, 1 H), 7.52 (d, J = 7.6 Hz, 1 H), 7.15 (s,
2 H), 4.27 (q, J = 7.2 Hz, 2 H), 3.90 (s, 3 H), 3.81 (s, 6 H), 3.72 (s,
3 H), 1.26 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6): d = 13.46 (br s, 1 H), 8.10 (s, 1 H),
7.89 (d, J = 8.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.50 (d, J =
7.6 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H),
7.21 (d, J = 7.6 Hz, 2 H), 3.90 (s, 3 H), 2.36 (s, 3 H), 2.34 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 184.5, 165.8, 160.5, 152.1,
151.0, 143.8, 138.0, 134.6, 134.2, 131.3, 130.0, 126.8, 123.8, 123.5,
122.6, 120.1, 108.4, 60.8, 60.5, 56.3, 52.9, 14.6.
MS (ESI): m/z = 466.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C25H24NO8: 466.1496; found:
13C NMR (125 MHz, DMSO-d6): d = 183.6, 165.1, 150.5, 144.1,
142.7, 138.7, 137.9, 133.9, 133.8, 131.0, 130.0, 129.8, 129.5, 129.4,
128.2, 127.8, 126.8, 126.2, 123.1, 122.3, 119.7, 52.4, 20.8, 20.7.
MS (ESI): m/z = 472.0[M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C27H22NO5S: 472.1213;
466.1500.
found: 472.1209.
Ethyl 7-Nitro-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrole-
2-carboxylate (5q)
Ethyl 4-Benzoyl-1,5-dimethyl-3-phenyl-1H-pyrrole-2-carboxy-
late (6)
1H NMR (500 MHz, DMSO-d6): d = 8.21 (d, J = 1.5 Hz, 1 H), 8.11
(dd, J = 8.0, 1.5 Hz, 1 H), 7.56 (m, 3 H), 7.20 (d, J = 8.0 Hz, 2 H),
4.23 (q, J = 7.0 Hz, 2 H), 2.35 (s, 3 H), 1.24 (t, J = 7.0 Hz, 3 H).
Ethyl isocyanoacetate (1a; 0.55 mmol) was added to a mixture of
CsCO3 (325 mg, 1.0 mmol, 2.0 equiv), CuI (10 mg, 0.05 mmol, 10%
equiv), (E)-chalone (0.5 mmol, 1.0 equiv), and MeI (1.25 mmol, 2.5
equiv) in DMF (1 mL) at r.t. The mixture was stirred under air for
4–6 h, then H2O (5 mL) was added and the aqueous phase was ex-
tracted with EtOAc (3 × 5 mL). The combined organic phase was
washed with brine (3 × 5 mL), dried over Na2SO4, and concentrated
under vacuum. The residue was loaded on a silica column and puri-
fied by column chromatography (SiO2; PE–EtOAc, 8:1) to afford 6.
13C NMR (125 MHz, DMSO-d6): d = 183.1, 160.4, 151.0, 149.6,
144.9, 137.9, 135.6, 130.3, 129.8, 128.4, 125.5, 124.4, 123.9, 123.4,
123.3, 114.2, 60.8, 21.3, 14.4.
MS (ESI): m/z = 377.1 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H17N2O5: 377.1132; found:
377.1134.
Yield: 8.5 mg (5%).
Ethyl 7-Cyano-4-oxo-3-p-tolyl-1,4-dihydroindeno[1,2-b]pyr-
role-2-carboxylate (5r)
1H NMR (400 MHz, CDCl3): d = 7.47 (d, J = 7.2 Hz, 2 H), 7.19–
7.23 (m, 1 H), 7.08 (t, J = 8.0 Hz, 2 H), 7.01–7.03 (m, 2 H), 6.94–
6.99 (m, 3 H), 3.98 (q, J = 7.2 Hz, 2 H), 3.85 (s, 3 H), 2.31 (s, 3 H),
0.87 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 194.1, 161.9, 139.1, 138.6, 134.9,
132.9, 131.8, 129.5, 127.6, 126.9, 126.4, 122.3, 119.6, 60.0, 32.9,
13.5, 11.7.
1H NMR (500 MHz, DMSO-d6): d = 12.97 (br s, 1 H), 7.78 (d,
J = 7.5 Hz, 1 H), 7.70 (s, 1 H), 7.51–7.55 (m, 3 H), 7.19 (d, J =
8.0 Hz, 2 H), 4.23 (q, J = 7.0 Hz, 2 H), 2.35 (s, 3 H), 1.22 (t, J =
7.0 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 183.8, 160.7, 150.4, 143.7,
138.1, 135.2, 134.9, 130.5, 130.0, 129.8, 128.7, 128.5, 124.4, 124.0,
122.9, 122.1, 118.8, 115.8, 61.0, 21.5, 14.7.
MS (ESI): m/z = 347.1 [M + H]+.
MS (ESI): m/z = 357.1 [M + H]+.
Synthesis 2011, No. 18, 3037–3044 © Thieme Stuttgart · New York

3044
F. Zhou et al.
PAPER
(4) For some recent important reviews on transition-metal-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
catalyzed reaction of isocyanides, see: (a) Gulevich, A. V.;
Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G. Chem.
Rev. 2010, 110, 5235. (b) Lygin, A. V.; de Meijere, A.
Angew. Chem. Int. Ed. 2010, 49, 9094.
Primary Data for this article are available online at http://
www.thieme-connect.com/ejournals/toc/synthesis and can be cited
using the following DOI: 10.4125/pd0017th.
(5) For representative examples of transition metal-catalyzed
reaction of isocyanides, see: (a) For Rh, see: Takaya, H.;
Kojima, S.; Murahashi, S. Org. Lett. 2001, 3, 421. (b) For
Pt, Rh, see: Motoyama, Y.; Kawakami, H.; Shimozono, K.;
Aoki, K.; Nishiyama, H. Organometallic 2002, 21, 3408.
(c) For Au, see: Ito, Y.; Sawamura, M.; Hayashi, T. J. Am.
Chem. Soc. 1986, 108, 6405. (d) For Ag, see: Sawamura,
M.; Hamashima, H.; Ito, Y. J. Org. Chem. 1990, 55, 5935.
(6) For representative copper-catalyzed reaction of isocyanides,
see: (a) Lygin, A. V.; Larionov, O. V.; Korotkov, V. S.;
de Meijere, A. Chem. Eur. J. 2009, 15, 227. (b) Bonin,
M.-A.; Giguère, D.; Roy, R. Tetrahedron 2007, 63, 4912.
(c) Kanazawa, C.; Kamijo, S.; Yamamoto, Y. J. Am. Chem.
Soc. 2006, 128, 10662. (d) Benito-Garagorri, D.; Bocokiae,
V.; Kirchner, K. Tetrahedron Lett. 2006, 47, 8641.
(e) Larionov, O. V.; de Meijere, A. Angew. Chem. Int. Ed.
2005, 44, 5664. (f) Kamijo, S.; Kanazawa, C.; Yamamoto,
Y. J. Am. Chem. Soc. 2005, 127, 9260. (g) Ito, Y.;
Matsurra, T.; Saegusa, T. Tetrahedron Lett. 1985, 26, 5781.
(h) Saegusa, T.; Ito, Y.; Kinoshita, H.; Tomita, S. J. Org.
Chem. 1971, 36, 3316.
Acknowledgment
We thank Dr Mei Pan at Sun Yat-Sen University for the conducting
the X-ray studies. The 100-talent program of CAS, National Natural
Science Foundation (Grant 21002102), and Shanghai Institute of
Organic Chemistry (Grant 10184), Chinese Academy of Sciences
are acknowledged for their financial support.
References
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(9) For details, see the Primary Data.
(10) No fully substituted product 6 was detected without adding
CuI as the catalyst.
Synthesis 2011, No. 18, 3037–3044 © Thieme Stuttgart · New York