Palladium-catalyzed direct arylation for the synthesis of indeno[2,1-b]-pyrrol-8-ones

Article abstract of DOI:10.1055/s-0032-1317347

Treatment of 2-bromophenyl (N-tosylpyrrol-2-yl)-ketones with Pd(OAc) ₂, Ph₃P, and K₂CO₃ resulted in the formation of indeno[2,1-b]pyrrol-8-ones in moderate to good yields.

Full text of DOI:10.1055/s-0032-1317347

2704▌
LETTER
letter
Palladium-Catalyzed Direct Arylation for the Synthesis of Indeno[2,1-b]-
pyrrol-8-ones
Indeno[2,1-b]pyrrol-8-ones
Junbiao Chang,* Li Sun, Jingjing Dong, Zhenhua Shen, Yueteng Zhang, Jie Wu, Ruiyong Wang, Jinqian Wang,
Chuanjun Song*
College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, P. R. of China
E-mail: changjunbiao@zzu.edu.cn; E-mail: chjsong@zzu.edu.cn
Received: 07.08.2012; Accepted after revision: 11.09.2012
2a was obtained in 30% isolated yield. However, the regi-
Abstract: Treatment of 2-bromophenyl (N-tosylpyrrol-2′-yl)-
oselectivity was poor. A substantial amount (12%) of the
ketones with Pd(OAc)2, Ph3P, and K2CO3 resulted in the formation
3-acylation product was also isolated. Other Lewis acids
(AlCl3, TiCl4, BBr3, CuBr, SnCl2, FeCl3) were then eval-
uated. Among these, FeCl3 was found to be the most suit-
able both in terms of productivity and regioselectivity.
of indeno[2,1-b]pyrrol-8-ones in moderate to good yields.
Key words: direct arylation, palladium catalyst, acylation,
indeno[2,1-b]pyrrol-8-one, pyrroles
The desired product 2a could be isolated in 78% yield, to-
gether with a small amount (3%) of the 3-acylation prod-
Transition-metal-catalyzed direct arylation (C–H activa-
uct.
tion)1 is an attractive alternative to the classical cross-cou-
pling reactions (e.g., Suzuki–Miyaura,2 Negishi,3 Stille,4
Kumada,5 Hiyama6).
With 2a in hand, we then carried out the direct arylation
reaction. The reaction proceeded slowly in acetonitrile
when Pd(OAc)2 was used as catalyst and gave a variety of
products upon completion. Addition of Ag2CO3 to the re-
action system, or using other palladium catalysts such as
Pd(PPh3)2Cl2 or Pd2(dba)3, under a variety of conditions
all failed to deliver the desired product in acceptable yield.
After some optimization, we were delighted to find out
that with our initially applied Pd(OAc)2 as catalyst, Ph3P
as ligand, and K2CO3 as base, the reaction proceeded
smoothly in DMF and gave the detosylated direct aryla-
tion product 1a10 in 78% isolated yield.
The intramolecular direct arylation reactions have been
utilized to construct a series of fluorenone analogues,7 a
class of compounds with important biological activities
and also useful synthetic intermediates.8 Surprisingly,
such reactions involving a pyrrole moiety remain unex-
plored, probably because an efficient strategy to prepare
the required precursors is not available yet. Previously,
one of us had developed a TFAA-mediated regioselective
acylation of N-tosylpyrroles using carboxylic acids as ac-
ylating agents.9 Adapting this methodology to 2-halo-
benzoic acids, we would then be able to develop a simple
sequence to indeno[2,1-b]pyrrol-8-ones 1 following intra-
molecular direct arylation reactions of 2-halophenyl pyr-
rolylketones 2 (Scheme 1).
After establishing the reaction conditions, palladium-cat-
alyzed direct arylation of other 2-bromophenyl (N-tosyl-
pyrrol-2′-yl)ketones were examined, and the results are
collected in Table 1. The desired indeno[2,1-b]pyrrol-8-
ones could be obtained in moderate to good isolated yields
for substrates with sterically hindered (Table 1, entry 2),
electron-donating (Table 1, entry 3), or electron-with-
drawing substituents (Table 1, entry 4) on the phenyl ring.
Under these conditions, direct arylation of substrates with
a 5′-arylpyrrolyl moiety (Table 1, entries 5–7) also
worked well.
Initial studies started with acylation of N-tosylpyrrole
with 2-bromobenzoic acid. Unfortunately, the desired
acylation product 2a (Table 1) was not obtained after re-
fluxing a mixture of N-tosylpyrrole, 2-bromobenzoic ac-
id, and TFAA in DCE for 24 hours. Since it was believed
that the mechanism for the acylation reaction involved the
formation of mixed anhydride,9 we reasoned that it should
be facilitated by the addition of Lewis acids. Indeed, addi-
tion of Sc(OTf)3 to the reaction system showed promising
results. The reaction was complete within 0.5 hours, and
Finally, we tested the palladium-catalyzed direct arylation
of 2-bromophenyl pyrrol-2′-ylketone (3) (Scheme 2).
However, indeno[2,1-b]pyrrol-8-one 1a was not evident
R2
X
X
R2
direct arylation
Pd
acylation
TFAA
R2
R1N
+
HO
N
R1
N
R1
O
O
O
2
1
Scheme 1 Retrosynthetic analysis of indeno[2,1-b]pyrrol-8-ones
SYNLETT 2012, 23, 2704–2706
Advanced online publication: 12.10.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317347; Art ID: ST-2012-W0665-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Indeno[2,1-b]pyrrol-8-ones
2705
on TLC. After completion of reaction (8.5 h), a major formation. This indicated that protection of the pyrrolyl
product was isolated, the structure of which was proved to nitrogen was necessary for an efficient direct arylation re-
be 9H-pyrrolo[1,2-a]indol-9-one (4),11 obviously result- action.
ing from palladium-catalyzed intramolecular C–N bond
Table 1 Synthesis of Indeno[2,1-b]pyrrol-8-ones
R2
R2
R1
Br
Pd(OAc)2
Br
TFAA, FeCl3
DCE, reflux
Ph3P, K2CO3
R2
HN
R1
+
R1
HO
DMF, 120 °C
N
N
Ts
Ts
O
O
O
Entry
1
Substrate
Product
Isolated yield (%)
Br
HN
78
N
Ts
O
O
2a
1a
Br
HN
2
77
N
Ts
O
O
1b
2b
2c
Br
OMe
OMe
HN
3
4
55
54
N
Ts
O
O
1c
Br
NO2
NO2
HN
N
Ts
O
O
1d
2d
Br
HN
Ph
5
47
N
Ts
O
O
2e
1e
F
Br
HN
6
63
N
Ts
F
O
O
2f
1f
MeO
Br
HN
7
47
N
Ts
MeO
O
O
2g
1g
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2704–2706

2706
J. Chang et al.
LETTER
Org. Lett. 2000, 2, 3675. (e) Campo, M. A.; Larock, R. C.
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Br
Br
N
a
b
N
N
Ts
H
O
O
O
2a
3
4
Scheme 2 Reagents and conditions: a) KOH, THF–H2O, reflux,
12 h, 95%; b) Pd(OAc)2, Ph3P, K2CO3, DMF, 120 °C, 8.5 h, 70%.
(8) (a) Li, V.-S.; Choi, D.; Wang, Z.; Jimenez, L. S.; Tang, M.-
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Compound 4 is the key precursor to the cytostatic mito-
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spectrum of biological activities.8f,12 Although a number
of methodologies for the synthesis of analogues of 4 have
been developed,11,13 those involving a direct arylation re-
action are rare.7d,e Therefore, our findings may provide a
new entry to these polycyclic systems.
In summary, we have developed a novel approach to
indeno[2,1-b]pyrrol-8-ones through palladium-catalyzed
direct arylation reactions of 2-bromophenyl (N-tosylpyr-
rol-2′-yl)ketones. We assumed that the mechanism fol-
lowed a direct arylation–in situ detosylation, rather than a
detosylation–direct arylation reaction sequence. If deto-
sylation was first carried out on the substrates, palladium-
catalyzed C–N bond formation of the resulting 2-bromo-
phenyl pyrrol-2′-ylketones would then lead to the forma-
tion of the isomeric 9H-pyrrolo[1,2-a]indol-9-ones. These
investigations are currently under way.
(9) Song, C.; Knight, D. W.; Whatton, M. A. Tetrahedron Lett.
2004, 45, 9573.
(10) A mixture of 2a (210 mg, 0.52 mmol), Pd(OAc)2 (11 mg,
0.05 mmol), Ph3P (26 mg 0.10 mmol), and K2CO3 (216 mg,
1.56 mmol) in anhyd DMF (11 mL) under N2 was heated to
120 °C for 9 h and cooled. The mixture was partitioned
between EtOAc (60 mL) and H2O (100 mL). The separated
aqueous phase was extracted with EtOAc (3 × 50 mL). The
combined organic extracts were washed with brine (150
mL), then dried (Na2SO4), filtered, and evaporated. The
residue was purified by column chromatography on silica
gel (35% EtOAc in PE) to give 1a (68 mg, 78%) as a red
solid; mp 205–206 °C. IR: νmax = 3222, 1690, 1632, 1607,
1509, 1450, 1357, 1319, 1272, 1098 cm–1. 1H NMR (300
MHz, DMSO-d6): δ = 6.19 (1 H, m), 6.99–7.27 (5 H m),
12.00 (1 H, s). 13C NMR (75 MHz, DMSO-d6): δ = 103.8,
119.0, 122.6, 126.9, 131.2, 131.7, 133.2, 138.0, 139.1,
142.9, 180.0. ESI-MS: m/z (%) = 192 (100) [M + Na]+, 170
(53) [M + H]+. HRMS: m/z calcd for C11H7NNaO: 192.0425;
found: 192.0416 [M + Na]+.
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (#30825043; #20902085) for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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Synlett 2012, 23, 2704–2706
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