Palladium-catalyzed carbonylative cyclization of 2-(2-bromovinyl)benzimidazoles leading to pyrrolone-fused benzimidazoles

Article abstract of DOI:10.1016/j.jorganchem.2015.12.040

2-(2-Bromovinyl)benzimidazoles are carbonylatively cyclized under carbon monoxide pressure in toluene in the presence of a catalytic amount of PdCl₂ and PPh₃ along with a base to give 1H-benzo[d]pyrrolo[1,2-a]imidazolones in good yields.

Full text of DOI:10.1016/j.jorganchem.2015.12.040

Accepted Manuscript
Palladium-catalyzed carbonylative cyclization of 2-(2-bromovinyl)benzimidazoles
leading to pyrrolone-fused benzimidazoles
Byeong Woo Yang, Son Long Ho, Ho-Jin Lim, Chan Sik Cho
PII:
S0022-328X(15)30254-0
10.1016/j.jorganchem.2015.12.040
JOM 19346
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 15 September 2015
Revised Date: 24 December 2015
Accepted Date: 27 December 2015
Please cite this article as: B.W. Yang, S.L. Ho, H.-J. Lim, C.S. Cho, Palladium-catalyzed carbonylative
cyclization of 2-(2-bromovinyl)benzimidazoles leading to pyrrolone-fused benzimidazoles, Journal of
Organometallic Chemistry (2016), doi: 10.1016/j.jorganchem.2015.12.040.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Byeong Woo Yang, Son Long Ho, Ho-Jin Lim, Chan Sik Cho*
Palladium-catalyzed carbonylative cyclization of 2-(2-bromovinyl)benzimidazoles
leading to pyrrolone-fused benzimidazoles
N
N
benzimidazole
PdCl , PPh , NaOAc
2
3
N
N
CO (10 atm), toluene
H
pyrrolone
O
Br

ACCEPTED MANUSCRIPT
Journal of Organometallic Chemistry (Note)
Palladium-catalyzed carbonylative cyclization of 2-(2-
bromovinyl)benzimidazoles leading to pyrrolone-fused benzimidazoles
a
a
b
a,*
Byeong Woo Yang , Son Long Ho , Ho-Jin Lim , Chan Sik Cho
a
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701,
Republic of Korea
b
Department of Environmental Engineering, Kyungpook National University, Daegu
702-701, Republic of Korea
Abstract
-(2-Bromovinyl)benzimidazoles are carbonylatively cyclized under carbon monoxide
2
2 3
pressure in toluene in the presence of a catalytic amount of PdCl and PPh along with a
base to give 1H-benzo[d]pyrrolo[1,2-a]imidazolones in good yields.
Keywords: Benzimidazoles; Carbon monoxide; Cyclization; Palladium catalyst;
Pyrrolone.

ACCEPTED MANUSCRIPT
*
Corresponding author. Tel.: +82 53 950 5586; fax: +82 53 950 6594.
E-mail address: cscho@knu.ac.kr (C.S. Cho)
1. Introduction
It is known that benzimidazole-containing compounds exhibit a wide spectrum of
biological activities, such as anti-inflammatory [1], antimicrobial [2], anticancer [3],
antihistaminic [4], analgesic [5], antiprotozoal [6], antiulcer [7], antiviral [3a,8],
antifungal [9], antibacterial [10], antiarrhythmic [11], antiasthmatic [12], anticonvulsant
properties [13]. Thus, many benzimidazole-containing compounds have been
synthesized and tested for biological activity. As part of our ongoing studies directed
towards transition metal-catalyzed cyclization reactions of β-bromo-α,β-unsaturated
aldehydes and their derivatives, we have identified several new methods for the
synthesis of various carbonyl group-containing heterocycles via palladium-catalyzed
carbonylative cyclization under carbon monoxide pressure [14,15]. β-Bromo-α,β-
unsaturated aldehydes and their derivatives are readily prepared from α-methylene
group-containing ketones by bromination under Vilsmeier-Haack conditions [16], and
2

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the products can serve as valuable building blocks for the construction of various cyclic
compounds [17]. Under these circumstances, with an effort to develop a new protocol
for the construction of carbonyl group-containing compounds using β-bromo-α,β-
unsaturated aldehydes and their derivatives, this report describes palladium-catalyzed
carbonylative cyclization of 2-(2-bromovinyl)benzimidazoles leading to a new class of
pyrrolone-fused benzimidazoles, 1H-benzo[d]pyrrolo[1,2-a]imidazolones (Scheme 1).
To the best of our knowledge, no reports are found for the synthesis of such a scaffold
via carbonylative cyclization of 2-(2-bromovinyl)benzimidazoles.
2. Results and discussion
Table 1 gives several results for the attempted carbonylative cyclizations of 2-(2-
bromocyclohex-1-en-1-yl)-1H-benzo[d]imidazole (1a) for the optimization of
o
conditions. Treatment of 1a under carbon monoxide (5 atm) in toluene at 110 C for 5 h
3

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2 3 3
in the presence of a catalytic amount of PdCl and PPh along with Et N afforded
1,2,3,4-tetrahydro-11H-benzo[4,5]imidazo[2,1-a]isoindol-11-one (2a) in 40% isolated
yield (entry 1). The carbon monoxide pressure affected the yield of 2a and the yield
increased with the carbon monoxide pressure up to 10 atm (entry 2). Not shown in
Table 1, performing the reaction under lower concentration gave no significant change
to 2a yield. Lower yield of 2a was observed under lower reaction temperature (entry 3).
The reaction also proceeded in the presence of various other inorganic bases such as
2 3 3 4 3
K CO , NaOAc, K PO and NaHCO , but the yields of 2a were generally lower than
3
those obtained in the presence of Et N except for NaOAc, which exhibited similar
3
activity as Et N (entries 4-7). Among solvents examined under the employed conditions,
toluene was shown to be the solvent of choice (entries 8-10). As a result, after further
tuning with reaction time and palladium catalytic systems (entries 11-16), the best
result in terms of both product yield and complete conversion of 1a, which was
monitored until 1a had disappeared on thin-layer chromatography (TLC), is obtained
using the standard set of reaction conditions shown in entry 12 of Table 1.
[Insert Table 1]
4

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After the reaction conditions had been optimized, various known 2-(2-
bromovinyl)benzimidazoles 1 were subjected to the reaction under carbon monoxide
pressure in order to investigate the scope of the reaction, and several representative
results are summarized in Table 2. The carbonylative cyclization of 1b also proceeded
to give the corresponding benzo[d]pyrrolo[1,2-a]imidazolone 2b in similar yield. From
the carbonylative cyclization of six-membered 2-(2-bromovinyl)benzimidazoles 1c and
1d, the corresponding benzo[d]pyrrolo[1,2-a]imidazolones 2c and 2d were also
produced in similar yields irrespective of methyl and phenyl substituents on 1c and 1d.
With 2-(2-bromovinyl)benzimidazoles (1f-h) having various ring sizes, the
carbonylative cyclized products were produced in the range of 66-80% yields. However,
no product was observed with five-membered 2-(2-bromovinyl)benzimidazole 1e,
giving many unidentifiable products. The carbonylative cyclization readily took place
with
benzo[g]benzo[4,5]imidazo[2,1-a]isoindol-7-one
dehydrogenation of the initially
benzo-fused
2-(2-bromovinyl)benzimidazole
1i.
However,
produced
7H-
(2i)
was
by
formed
5,6-dihydro-7H-
benzo[g]benzo[4,5]imidazo[2,1-a]isoindol-7-one under the employed conditions. The
+
high resolution mass spectrum of 2i shows peak at m/z = 270.0795 (M , 100%
intensity). Similar dehydrogenation was observed in our recent reports on copper-
5

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catalyzed coupling and cyclizations of β-bromo-α,β-unsaturated amides with
formamide [17p] and β-bromo-α,β-unsaturated carboxylic acids with terminal alkynes
[
17t]. On the other hand, in contrast to the synthesis of pyrrolone-fused benzimidazoles,
it is reported that isoindolone-fused benzimidazoles, 11H-benzo[4,5]imidazo[2,1-
a]isoindol-11-ones can be synthesized by cyclization of 1,2-phenylenediamines with
phthalic anhydride, phthalic acid and 2-formylbenzoic acid [18]. Similar treatment of 2-
(2-bromoaryl)benzimidazoles 1j and 1k under the employed conditions also afforded
isoindolone-fused benzimidazoles 2j and 2k in good yields via such a carbonylative
cyclization.
[Insert Table 2]
A plausible reaction pathway is presented in Scheme 2. Oxidative addition of the
carbon-bromide bond of 1 to palladium(0) produces a vinylpalladium(II) intermediate 3,
where carbon monoxide coordination to palladium and then vinyl migration from
palladium to the carbon of carbon monoxide occurs to give an acylpalladium(II)
complex 4. Complex 4 reacts with a base to produce a palladacycle 5 which can
reductively eliminate to give 2.
6

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N
N
N
N
Pd
H
O
2
Br
1
N
N
N
H
N
Pd
PdBr
3
O
5
N
O
CO
basehHBr
N
H
PdBr
base
4
Scheme 2.
3. Conclusion
In summary, it has been shown that 2-(2-bromovinyl)benzimidazoles undergo
carbonylation and subsequent cyclization under carbon monoxide pressure in the
2 3
presence of PdCl and PPh along with a base to give a new class of benzimidazoles,
benzo[d]pyrrolo[1,2-a]imidazolones. The present reaction shows first example for the
synthesis of such scaffolds from readily available starting compounds. Further studies
on the syntheses of N-fused heterocycles using transition metal-catalyzed cyclization
7

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reaction are way.
4. Experimental
1
13
H (400 and 500 MHz) and C NMR (125 and 100 MHz) spectra were recorded on
Bruker Avance spectrometers using TMS as an internal standard. Melting points were
determined on a Stanford Research Inc. MPA100 automated melting point apparatus.
High-resolution mass spectrometry (HRMS) was performed with a Jeol JMS-700
spectrometer at the Korea Basic Science Center, Daegu Korea. The isolation of pure
products was carried out via thin layer (silica gel 60 GF254, Merck) chromatography.
The starting 2-(2-bromovinyl)benzimidazoles and 2-(2-bromoaryl)benzoimidazoles
were prepared from the corresponding carboxylic acids and 1,2-phenylenediamines
according to literature procedures [19]. Commercially available organic and inorganic
compounds were used without further purification except for solvents, which was
distilled by known methods before use.
4.1. General procedure for palladium-catalyzed carbonylative cyclization of 2-(2-
bromovinyl)benzimidazoles and 2-(2-bromoaryl)benzimidazoles
8

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2
To a 50 mL stainless steel autoclave were added 1 (0.5 mmol), PdCl (0.004 g, 0.025
3
mmol), PPh (0.013 g, 0.05 mmol), base (3 mmol) and solvent (5 mL). After the system
was flushed and then pressurized with carbon monoxide, the reaction mixture was
o
allowed to react at 80-110 C for an appropriate time. The mixture was then cooled to
room temperature, and filtered through a short column of silica gel (ethyl acetate) to
remove inorganic salts. Removal of the solvent left a crude mixture, which was
separated by thin layer chromatography [silica gel 60 GF254 (Merck), ethyl acetate –
hexane or methanol-dichloromethane] to give desired products 2. Except for known 2j
[
18] and 2k [20], all new products prepared by the above procedure were characterized
spectroscopically as shown below.
4.1.1. 1,2,3,4-Tetrahydro-11H-benzo[4,5]imidazo[2,1-a]isoindol-11-one (2a)
o
1
Solid, m.p. 115-117 C (from CHCl
3 3
-hexane); H NMR (400 MHz, CDCl ): δ 1.69-
1
1
1
.78 (m, 4H), 2.26-2.30 (m, 2H), 2.47-2.52 (m, 2H), 7.07-7.12 (m, 1H), 7.17-7.21 (m,
1
3
3
H), 7.47-7.53 (m, 2H); C NMR (125 MHz, CDCl ): δ 20.9, 21.4, 21.4, 21.6, 111.7,
21.5, 124.1, 126.7, 130.4, 140.5, 143.9, 148.9, 160.0, 163.4. Anal. Calc. for
9

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C H N O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.87; H, 5.35; N, 12.60.
14
12
2
4.1.2. 7,8-Dimethyl-1,2,3,4-tetrahydro-11H-benzo[4,5]imidazo[2,1-a]isoindol-11-one
(2b)
o
1
Solid, m.p. 148-150 C (from CHCl
3 3
-hexane); H NMR (500 MHz, CDCl ): δ
1
7
2
.69-1.77 (m, 4H), 2.22 (s, 3H), 2.24 (s, 3H), 2.25-2.28 (m, 2H), 2.46-2.49 (m, 2H),
1
3
.26 (s, 1H), 7.27 (s, 1H); C NMR (125 MHz, CDCl
3
): δ 20.3, 20.6, 20.9, 21.4, 21.5,
1.6, 112.5, 121.9, 128.8, 132.6, 136.0, 139.9, 143.8, 147.3, 159.5, 163.6. Anal. Calc.
for C H N O: C, 76.16; H, 6.39; N, 11.10. Found: C, 76.05; H, 6.33; N, 11.27.
16
16
2
4.1.3. 3-Methyl-1,2,3,4-tetrahydro-11H-benzo[4,5]imidazo[2,1-a]isoindol-11-one (2c)
o
1
3 3
Solid, m.p. 107-108 C (from CHCl -hexane); H NMR (400 MHz, CDCl ): δ 1.05
(d, J = 6.6 Hz, 3H), 1.27-1.38 (m, 1H), 1.80-1.90 (m, 2H), 2.01-2.10 (m, 1H), 2.19-2.29
(m, 1H), 2.37-2.45 (m, 1H), 2.62-2.69 (m, 1H), 7.08-7.12 (m, 1H), 7.18-7.22 (m, 1H),
13
7
.48-7.54 (m, 2H); C NMR (100 MHz, CDCl
3
): δ 20.7, 21.2, 28.0, 29.4, 29.7, 111.8,
121.5, 124.1, 126.7, 130.5, 140.2, 143.7, 148.9, 159.9, 163.3. Anal. Calc. for
10

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C H N O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.57; H, 5.84; N, 11.80.
15
14
2
4.1.4. 3-Phenyl-1,2,3,4-tetrahydro-11H-benzo[4,5]imidazo[2,1-a]isoindol-11-one (2d)
o
1
2 2 3
Solid, m.p. 130-132 C (from CH Cl -hexane); H NMR (500 MHz, CDCl ): δ 1.74-
1
.82 (m, 1H), 2.04-2.08 (m, 1H), 2.28-2.37 (m, 1H), 2.42-2.48 (m, 1H), 2.52-2.59 (m,
H), 2.82-2.93 (m, 2H), 7.07-7.10 (m, 1H), 7.16-7.20 (m, 4H), 7.24-7.27 (m, 2H), 7.48
1
1
3
(
d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H); C NMR (125 MHz, CDCl
3
): δ 21.3, 28.7,
9.2, 39.2, 111.7, 121.6, 124.1, 126.8, 126.9, 126.9, 128.9, 130.4, 140.2, 143.6, 144.4,
48.9, 159.5, 162.9. Anal. Calc. for C H N O: C, 79.98; H, 5.37; N, 9.33. Found: C,
2
1
7
2
0
16
2
9.82; H, 5.35; N, 9.39.
4.1.5. 7,8,9,10-Tetrahydrobenzo[d]cyclohepta[3,4]pyrrolo[1,2-a]imidazol-11(6H)-one
(2f)
o
1
Solid, m.p. 92-94 C (from CHCl
3 3
-hexane); H NMR (400 MHz, CDCl ): δ 1.60-
1
2
.65 (m, 2H), 1.67-1.73 (m, 2H), 1.76-1.81 (m, 2H), 2.45-2.49 (m, 2H), 2.67-2.70 (m,
1
3
H), 7.09-7.13 (m, 1H), 7.17-7.21 (m, 1H), 7.48-7.50 (m, 1H), 7.53-7.55 (m, 1H); C
11

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NMR (125 MHz, CDCl
3
): δ 25.4, 26.1, 26.8, 26.9, 30.7, 111.8, 121.5, 124.2, 126.6,
1
31.0, 142.6, 145.4, 149.2, 161.1, 164.0. Anal. Calc. for C H N O: C, 75.61; H, 5.92;
15 14 2
N, 11.76. Found: C, 75.52; H, 5.90; N, 11.85.
4.1.6. 6,7,8,9,10,11-Hexahydro-12H-benzo[d]cycloocta[3,4]pyrrolo[1,2-a]imidazol-12-
one (2g)
o
1
Solid, m.p. 88-89 C (from CHCl
3 3
-hexane); H NMR (400 MHz, CDCl ): δ 1.50-
1
2
.59 (m, 4H), 1.66-1.72 (m, 2H), 1.79-1.85 (m, 2H), 2.48-2.51 (m, 2H), 2.68-2.71 (m,
1
3
H), 7.09-7.13 (m, 1H), 7.18-7.22 (m, 1H), 7.49-7.51 (m, 1H), 7.53-7.55 (m, 1H); C
3
NMR (100 MHz, CDCl ): δ 22.6, 23.7, 25.6, 26.1, 27.1, 27.8, 111.8, 121.5, 124.2, 126.7,
1
30.8, 140.8, 144.3, 149.1, 160.9, 164.0. Anal. Calc. for C H N O: C, 76.16; H, 6.39;
16
16
2
N, 11.10. Found: C, 75.90; H, 6.30; N, 11.24.
4.1.7. 6,7,8,9,10,11,12,13,14,15-Decahydro-16H-benzo[d]cyclododeca[3,4]pyrrolo[1,2-
a]imidazol-16-one (2h)
o
1
2 2 3
Solid, m.p. 101-102 C (from CH Cl -hexane); H NMR (500 MHz, CDCl ): δ 1.23-
12

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1.41 (m, 12H), 1.67-1.72 (m, 2H), 1.84-1.89 (m, 2H), 2.35-2.38 (m, 2H), 2.53-2.56 (m,
1
3
2
H), 7.09-7.12 (m, 1H), 7.18-7.21 (m, 1H), 7.49-7.51 (m, 1H), 7.54-7.56 (m, 1H); C
NMR (125 MHz, CDCl
11.8, 121.5, 124.2, 126.6, 130.4, 140.9, 144.4, 149.2, 160.8, 164.1. Anal. Calc. for
C H N O: C, 77.89; H, 7.84; N, 9.08. Found: C, 77.68; H, 7.80; N, 9.12.
3
): δ 21.8, 22.2, 22.6, 22.6, 24.2, 24.8, 25.1, 25.3, 26.1, 26.3,
1
20
24
2
4.1.8. 7H-Benzo[g]benzo[4,5]imidazo[2,1-a]isoindol-7-one (2i)
o
1
Solid, m.p. 191-193 C (from CH
2 2 3
Cl -hexane); H NMR (400 MHz, CDCl ): δ 7.18-
7.22 (m, 1H), 7.25-7.29 (m, 1H), 7.54-7.63 (m, 2H), 7.66-7.69 (m, 2H), 7.73 (d, J = 8.3
13
Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 8.69-8.71 (m, 1H); C
NMR (100 MHz, CDCl
29.2, 129.6, 130.1, 130.7, 132.3, 133.0, 137.0, 149.9, 157.8, 161.7. Anal. Calc. for
C H N O: C, 79.99; H, 3.73; N, 10.36. Found: C, 79.78; H, 3.70; N, 10.42. HRMS
3
): δ 112.6, 120.8, 121.6, 125.0, 126.05, 126.9, 127.3, 128.9,
1
18
10
2
+
(
EI) Anal. Calc. for C H N O (M ): 270.0793. Found: 270.0795.
18 10 2
Acknowledgement
13

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This research was supported by Basic Science Research Program through the
National Research Foundation of Korea (NRF) funded by the Ministry of Education,
Science and Technology (2010-0007563).
References
[1] (a) E.S. Lazer, M.R. Matteo, G.J. Possanza, J. Med. Chem. 30 (1987) 726;
(b) A.A.M. Abdel-Aziz, K.E.H. ElTahir, Y.A. Asiri, Eur. J. Med. Chem. 46 (2011) 1648;
(c) R.T. Hendricks, J.C. Hermann, R.K. Kondru, Y. Lou, S.M. Lynch, T.D. Owens, M.
Soth, C.W. Yee, PCT Int. Appl. 155 (2011) 683789;
(
(
(
d) K.C.S. Achar, K.M. Hosamani, H.R. Seetharamareddy, Eur. J. Med. Chem. 45
2010) 2048;
e) G. Chen, Z. Liu, Y. Zhang, X. Shan, L. Jiang, Y. Zhao, W. He, Z. Feng, S. Yang, G.
Liang, ACS Med. Chem. Lett. 4 (2013) 69.
[
(
2] (a) Z. Ates-Alagöz, S. Yildiz, E. Buyukbingol, Chemother. 53 (2007) 110;
b) M.M.K. Jayasekera, K. Onheiber, J. keith, H. Venkatesan, A.E.M. Stocking, L. Tang,
J. Miller, L. Gomez, B. Rhead, T. Delcamp, S. Huang, R. Wolin, E.V. Bobkova, K.J.
Shaw, Antimicrob. Agents Chemother. 49 (2005) 131;
14

ACCEPTED MANUSCRIPT
(c) Y. Ozkay, Y. Tunai, H. Karaca, I. Isikdag, Eur. J. Med. Chem. 45 (2010) 3293;
(d) A.A. Mir, V.V. Mulwad, G.K. Trivedi, J. Heterocycl. Chem. 47 (2010) 214;
(e) S. Ozden, F. Usta, N. Altanlar, H. Goker, J. Heterocycl. Chem. 48 (2011) 1317.
[3] (a) F. Cachoux, T. Isarno, M. Wartmann, K.H. Altmann, ChemBioChem 7 (2006)
5
4;
b) K. Starčević, M. Kralj, K. Ester, I. Sabol, M. Grce, K. Pavelić, G. Karminski-
Zamola, Bioorg. Med. Chem. 15 (2007) 4419;
(
(
(
(
c) M.M. Ramla, M.A. Omar, H. Tokuda, H.I. El-Diwani, Bioorg. Med. Chem. 15
2007) 6489;
d) H. Hoang, D.V. LaBarbera, K.A. Mohammed, C.M. Ireland, E.B. Skibo, J. Med.
Chem. 50 (2007) 4561;
(e) A. Monem, A. Abdel-Hafez, Arch. Pharm. Res. 30 (2007) 678;
(f) S. Lee, C. Shinji, K. Ogura, M. Shimizu, S. Maeda, M. Sato, M. Yoshida, Y.
Hashimoto, H. Miyachi, Bioorg. Med. Chem. Lett. 17 (2007) 4895;
g) T.D. Penning, V.B. Gandhi, G. Zhu, Y. Tong, K.W. Woods, C. Lai, J. Gong, A.S.
Florjancic, PCT Int. Appl. 154 (2011) 158499;
(
(
h) S. Yadav, D. Sinha, S.K. Singh, V.K. Singh, Chem. Biol. Drug. Des. 80 (2012) 625;
i) M.A. Omar, Y.M. Shaker, S.A. Galal, M.M. Ali, S.M. Kerwin, J. Li, H. Tokuda, R.A.
(
15

ACCEPTED MANUSCRIPT
Ramadan, H.I.E. Diwani, Bioorg. Med. Chem. 20 (2012) 6989.
[
4] J. Velík, V. Baliharová, J. Fink-Gremmels, S. Bull, J. Lamka, L. Skálová, Res. Vet.
Sci. 76 (2004) 95.
5] K.C. Achar, K.M. Hosamani, H.R. Seetharamareddy, Eur. J. Med. Chem. 45 (2010)
048.
6] S.K. Katiyar, V.R. Gordon, G.L. Mclaughlin, T.D. Edlind, Antimicrob. Agents
Chemother. 38 (1994) 2086.
7] S.Y. Cho, S.K. Kanf, S.S. Kim, H.G. Cheon, J.K. Choi, E.K. Yum, Bull. Korean
Chem. Soc. 22 (2001) 1217.
8] (a) M.L. Morningstar, T. Roth, D.W. Farnsworth, M.K. Smith, K. Watson, R.W.,Jr.
[
2
[
[
[
Buckheit, K. Das, W. Zhang, E. Arnold, J.G. Julias, S.H. Hughes, C.J. Michejda, J. Med.
Chem. 50 (2007) 4003;
(
b) Y.F. Li, G.F. Wang, Y. Luo, W.G. Huang, W.T. Chun-Lan Feng, L.P. Shi, Y.D. Ren,
Z.P. Zuo, W. Lu, Eur. J. Med. Chem. 42 (2007) 1358;
c) S.M. Rida, S.A. El-Hawash, H.T. Fahmy, A.A. Hazzaa, M.M. Meligy, Arch. Pharm.
Res. 29 (2006) 823;
d) T.E. Fisher, B. Kim, D.D. Staas, T.A. Lyle, S.D. Young, J.P. Vacca, M.M. Zrada, D.J.
Hazuda, P.J. Felock, W.A. Scheif, L.J. Gabryelski, M.R. Anari, C.J. Kochansky, J.S.
(
(
16

ACCEPTED MANUSCRIPT
Wai, Bioorg. Med. Chem. Lett. 17 (2007) 6511.
[
(
[
(
(
(
9] H. Göker, C. Kus, D.W. Boykin, S. Yildiz, N. Altanlar, Bioorg. Med. Chem. 10
2002) 2589.
10] (a) T. Lubbers, P. Angehrn, H. Gmunder, S. Herzig, Bioorg. Med. Chem. Lett. 17
2007) 4708;
b) M.J. Macielag, B. Zhu, PCT Int. Appl. 151 (2009) 491162;
c) P. Bandyopadhyay, M. Sathe, S. Ponmmariappan, A. Sharma, P. Sharma, A.K.
Srivastava, M.P. Kaushik, Bioorg. Med. Chem. Lett. 21 (2011) 7306.
11] A.M. Likhosherstov, O.V. Filippova, V.P. Peresada, S.A. Kryzhanovskii, M.B.
Vititnova, N.V. Kaverina, K.M. Reznikov, Pharm. Chem. 37 (2003) 6.
12] R.V. Kumar, S.D. Vaidya, B.V.S. Kumar, U.N. Bhise, S.B. Bhirud, U.C. Mashelkar,
Eur. J. Med. Chem. 43 (2008) 986.
[
[
[
13] R.V. Shingalapur, K.M. Hosamani, R.S. Keri, M.H. Hugar, Eur. J. Med. Chem. 45
(2010) 1753.
[
14] (a) H.M. Colquhoun, D.J. Thompson, M.V. Twigg, Carbonylation: Direct
Synthesis of Carbonyl Compounds, Plenum Press, New York, 1991;
(b) J. Tsuji, Palladium Reagents and Catalysis, Wiley, Chichester, 1995;
(c) E. Negishi (Ed.), Handbook of Organopalladium Chemistry for Organic Synthesis,
17

ACCEPTED MANUSCRIPT
vol. II, Wiley, New York, 2002;
(
(
(
[
(
(
(
(
(
(
(
(
[
d) L. Kollár (Ed.), Modern Carbonylation Methods, Wiley-VCH, Weinheim, 2008;
e) A. Brennführer, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 48 (2009) 4114;
f) R. Grigg, S.P. Mutton, Tetrahedron 66 (2010) 5515.
15] (a) C.S. Cho, H.S. Shim, Tetrahedron Lett. 47 (2006) 3835;
b) C.S. Cho, J.U. Kim, H.-J. Choi, J. Organomet. Chem. 693 (2008) 3677;
c) C.S. Cho, H.B. Kim, Catal. Lett. 140 (2010) 116;
d) C.S. Cho, H.B. Kim, S.Y. Lee, J. Organomet. Chem. 695 (2010) 1744;
e) H.K. Lee, C.S. Cho, Appl. Organomet. Chem. 26 (2012) 185;
f) H.K. Lee, C.S. Cho, Appl. Organomet. Chem. 26 (2012) 406;
g) C.S. Cho, J.I. Son, N.S. Yoon, Appl. Organomet. Chem. 26 (2012) 499;
h) Y.K. Bae, C.S. Cho, Synlett 24 (2013) 1848;
i) I.C. Yoon, C.S. Cho, Appl. Organomet. Chem. 29 (2015) 226.
16] (a) Z. Arnols, A. Holly, Collect. Czech. Chem. Commun. 26 (1961) 3059;
(
[
(
(
b) R.M. Coates, P.D. Senter, W.R. Baker, J. Org. Chem. 47 (1982) 3597.
17] (a) S. Brahma, J.K. Ray, Tetrahedron 64 (2008) 2883;
b) R. Jana, I. Chatterjee, S. Samanta, J.K. Ray, Org. Lett. 10 (2008) 4795;
c) P. Karthikeyan, A. Meena Rani, R. Saiganesh, K.K. Balasubramanian, S. Kabilan,
18

ACCEPTED MANUSCRIPT
Tetrahedron 65 (2009) 811;
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
(
d) S. Samanta, R. Jana, J.K. Ray, Tetrahedron Lett. 50 (2009) 6751;
e) S. Nandi, J.K. Ray, Tetrahedron Lett. 50 (2009) 6993;
f) R. Jana, S. Paul, A. Biswas, J.K. Ray, Tetrahedron Lett. 51 (2010) 273;
g) S. Samanta, N. Yasmin, D. Kundu, J.K. Ray, Tetrahedron Lett. 51 (2010) 4132;
h) N. Yasmin, J.K. Ray, Synlett (2010) 924;
i) S. Paul, T. Gorai, A. Koley, J.K. Ray, Tetrahedron Lett. 52 (2011) 4051;
j) C.S. Cho, D.B. Patel, S.C. Shim, Tetrahedron 61 (2005) 9490;
k) C.S. Cho, D.B. Patel, Tetrahedron 62 (2006) 6388;
l) C.S. Cho, H.B. Kim, J. Organomet. Chem. 696 (2011) 3264;
m) H.K. Lee, C.S. Cho, Appl. Organomet. Chem. 26 (2012) 570;
n) S.L. Ho, C.S. Cho, H.-J. Choi, H.-S. Sohn, Appl. Organomet. Chem. 27 (2013) 277;
o) J.I. Son, C.S. Cho, H.-J. Choi, Appl. Organomet. Chem. 27 (2013) 380;
p) S.L. Ho, C.S. Cho, Appl. Organomet. Chem. 27 (2013) 507;
q) S.L. Ho, C.S. Cho, Synlett 24 (2013) 2705;
r) Y. Jiao, S.L. Ho, C.S. Cho, Synlett 26 (2015) 1081;
s) S.L. Ho, C.S. Cho, H.-S. Sohn, Synthesis 47 (2015) 216;
t) S.L. Ho, I.C. Yoon, C.S. Cho, H.-J. Choi, J. Organomet. Chem. 791 (2015) 13.
19

ACCEPTED MANUSCRIPT
[
18] (a) S.K. Meegalla, G.J. Stevens, C.A. McQueen, A.Y. Chen, C. Yu, L.F. Liu, L.R.
Barrows, E.J. LaVoie, J. Med. Chem. 37 (1994) 3434;
(b) S. Kumar, N. Kumar, P. Roy, S.M. Sondhi, Mol. Divers. 17 (2013) 753;
(c) E.V. Gromachevskaya, A.V. Fin’ko, A.V. Butin, K.S. Pushkareva, V.D. Strelkov. L.I.
Isakova, G.D. Krapivin, Chem. Heterocycl. Comp. 49 (2013) 1331.
19] K.H. Chung, C.M. So, S.M. Wong, C.H. Luk, C.P. Lau, Z. Zhou, F.Y. Kwong.
Synlett 23 (2012) 1181.
20] T. Nakano, A. Martin, J. Heterocycl. Chem. 16 (1979) 1235.
[
[
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Table 1
a
Optimization of conditions for the reaction with 1a
N
N
N
PdCl , PPh
2
3
N
CO
H
Br
O
1a
2a
o
Entry Palladium
catalysts
Bases
Solvents
Temp ( C) Time (h) CO (atm) Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
2
2
/2PPh
/2PPh
/2PPh
/2PPh
/2PPh
/2PPh
/2PPh
/2PPh
3
3
3
3
3
3
3
3
3
3
3
3
Et
Et
Et
3
3
3
N
N
N
Toluene
Toluene
Toluene
Toluene
110
110
80
5
5
40
50
15
23
48
4
5
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
K
2
CO
3
110
110
110
110
110
110
5
NaOAc Toluene
5
K
3
PO
NaHCO
Et
Et N
4
Toluene
Toluene
DMF
5
3
5
28
9
3
N
5
PdCl /2PPh
Dioxane
5
19
5
2
3
0
1
2
3
4
5
6
PdCl
2
/2PPh
Et
3
N
Acetonitrile 110
5
PdCl /2PPh
Et N
Toluene
110
110
110
110
110
110
10
10
10
10
10
10
63
71
9
2
3
PdCl
2
/2PPh
NaOAc Toluene
NaOAc Toluene
NaOAc Toluene
PdCl /dppp
2
Pd(OAc)
2
/2PPh
3
39
26
28
Pd(PPh ) /2PPh NaOAc Toluene
3
4
3
Pd
2
3 3
(dba) /2PPh NaOAc Toluene
a
Reaction conditions: 1a (0.5 mmol), palladium catalyst (0.025 mmol), base (3 mmol),
solvent (5 mL).
21

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Table 2
Palladium-catalyzed carbonylative cyclization of 1 leading to
benzo[d]pyrrolo[1,2-a]imidazolones 2.a
R
R
R
N
N
R
PdCl , PPh , NaOAc
2
3
N
N
H
CO (10 atm), toluene
Br
O
1
2
1
2
Yield (%)
R
R
N
N
N
R
R
N
H
O
Br
a R = H
b R = Me
1
1
2
a
71
77
2b
N
N
N
R
R
N
H
Br
O
1
1
c R = Me
d R = Ph
2
c
64
67
2d
N
N
N
N
H
Br
O
1
1
e
f
2e
0
N
N
N
N
H
Br
O
2f
68
N
N
N
N
H
Br
O
1
1
g
2
2
g
66
80
N
N
N
N
H
Br
O
h
h
N
N
N
N
H
Br
O
1
i
2i
91
R
R
R
N
N
N
R
N
H
O
Br
j R = H
1
2
j
73
87
1
k R = Me
2k
a
Reaction condition: 1 (0.5 mmol), PdCl (0.025 mmol), PPh (0.05 mmol),
2
3
o
NaOAc (3 mmol), CO (10 atm), toluene (5 mL), 110 C, for 10 h.
22

ACCEPTED MANUSCRIPT
Palladium-catalyzed carbonylation with carbon monoxide followed by cyclization
Synthesis of a new class of pyrrolone-fused benzimidazoles starting from readily
available ketones
Synthesis of N-fused heterocycles via carbonylative cyclization of 2-(2-
bromovinyl)benzimidazoles