A new rapid multicomponent domino heteroannulation of heterocyclic ketene aminals: Solvent-free regioselective synthesis of functionalized benzo[g]imidazo[1,2-a]quinolinediones

Article abstract of DOI:10.1039/c2ob27137k

A highly efficient and straightforward three-component cascade reaction was developed to synthesize benzo[g]imidazo[1,2-a]quinolinedione derivatives from heterocyclic ketene aminals (HKAs), aldehydes, and 2-hydroxy-1,4-naphthoquinone (HNQ) via Et₃N-catalyzed tandem [3 + 2 + 1] annulation under solvent-free conditions. The reactions were very mild, convenient and highly regioselective to form new fused tetracyclic target molecules. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ob27137k

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A new rapid multicomponent domino
heteroannulation of heterocyclic ketene aminals:
solvent-free regioselective synthesis of functionalized
benzo[g]imidazo[1,2-a]quinolinediones†
Cite this: Org. Biomol. Chem., 2013, 11,
781
Li-Rong Wen, Qi-Chang Sun, Hai-Liang Zhang and Ming Li*
A highly efficient and straightforward three-component cascade reaction was developed to synthesize
benzo[g]imidazo[1,2-a]quinolinedione derivatives from heterocyclic ketene aminals (HKAs), aldehydes,
and 2-hydroxy-1,4-naphthoquinone (HNQ) via Et3N-catalyzed tandem [3 + 2 + 1] annulation under
solvent-free conditions. The reactions were very mild, convenient and highly regioselective to form new
fused tetracyclic target molecules.
Received 2nd August 2012,
Accepted 8th November 2012
DOI: 10.1039/c2ob27137k
www.rsc.org/obc
and Annona cherimolia,4 exhibits antimicrobial and anticancer
Introduction
activities against several cell lines.5 Phomazarin, isolated from
Naturally occurring tricyclic quinone alkaloids possess exten- cultures of Phoma terrestris Hansen (Pyrenochaeta terrestris
sive biological properties ranging from antimicrobial capacity Hansen), shows in vitro cytotoxic activity.6 Jadomycins, isolated
to cytotoxicity.1 Among them, the benzo[g]quinoline-5,10- from Streptomyces venezuelae ISP5230, belong to the angucy-
dione skeleton is ubiquitous in a wide variety of naturally cline group of polyketides, angular tetracyclines that are
occurring and synthetic compounds that exhibit important known to display a range of important biological activities,
biological activities (Fig. 1). For example, cleistopholine, iso- including antibacterial, anti-tumor, antiviral, cytotoxic, and
lated from Porcelia macrocarpa,2 Oncodostigma monosperma,3 Aurora-B kinase inhibitory activities.7 Hence, the synthesis of
the benzo[g]imidazo[1,2-a]quinolinediones could be a valuable
strategy to discover new bioactive compounds.
Multicomponent reactions (MCR)8 are an important strat-
egy in drug discovery,9 especially in the synthesis of hetero-
cyclic scaffolds,10 as well as in the total synthesis of natural
products,11 which allows the generation of high levels of diver-
sity giving rise to complex structures by the simultaneous for-
mation of two or more bonds from simple substrates and
provide unmatched opportunities for the expeditious increase
in complexity of synthetic outcomes.12 The solvent-free reac-
tion (SFR)13 is an important synthetic procedure from the view-
point of green and sustainable chemistry. This approach can
help to reduce the amounts of undesired hazardous chemicals
used, increase the selectivity towards the given products, and
also enhance the rate of many organic reactions. So, develop-
ing a new, environmentally benign MCR has been recognized
Fig. 1 Structures of naturally occurring benzo[g]quinoline-5,10-dione
as one of the most important topics of green chemistry.
skeletons.
Heterocyclic ketene aminals (HKAs),14 have proven to be
fascinating and versatile synthons in the construction of
heterocyclic systems. Reactions of cyclic ketene aminals with a
variety of biselectrophilic groups have so far been applied to
make five- and six-membered, and fused heterocycles during
the past years.15 In continuation of our research interests
regarding the development of MCRs,16 we wish to report
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and
Molecular Engineering, Qingdao University of Science and Technology, Qingdao
266042, P. R. China. E-mail: liming928@qust.edu.cn
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all new compounds. CCDC 857572. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2ob27137k
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herein an simple and convenient protocol for the regioselective
synthesis of benzo[g]imidazo[1,2-a]quinolinedione derivatives
via a three-component reaction, involving the assembling of
the scaffold from [3 + 2 + 1] atom fragments (Scheme 1). So far,
to the best of our knowledge, there have been no reports on the
synthetic application of HKAs with arylaldehyde, 2-hydroxy-1,4-
naphthoquinone (HNQ) under solvent-free conditions.
Results and discussion
The Knoevenagel condensation and aza-ene reaction17 are two
fundamental reactions in organic chemistry. Our approach
towards the design and development of a new three-com-
ponent aza-ene reaction involves the use of HNQ 3, HKAs 1,
and aldehydes 2 to construct benzo[g]imidazo [1,2-a]quinoline-
dione derivatives.
Fig. 2 X-Ray crystal structure of 4a.
Encouraged by this interesting result, we continued to
focus on the optimization of the reaction conditions, and the
results are listed in Table 1. In the initial experiment, the
aza-ene type reaction of 2-(imidazolidin-2-ylidene)-1-phenyl-
ethanone (1a) (0.5 mmol) with 4-chlorobenzaldehyde (2a)
(0.5 mmol) and HNQ (3) (0.5 mmol) in EtOH (2 mL) was inves-
tigated. No reaction occurred without the addition of a catalyst
at room temperature for 24 h (Table 1, entry 1), but at reflux
temperature the product 4a was obtained in 23% yield
(Table 1, entry 2). However, when Et3N (1.0 equiv.) was added
in refluxing EtOH, the yield of 4a could reach 81% (Table 1,
entry 3). Then, several other bases such as DBU, DABCO, pyri-
dine, K2CO3, KOH, and an acid, such as AcOH, were also
employed to improve the yield, but the results showed that
these catalysts could not promote this reaction efficiently
except for DABCO (Table 1, entries 4–9). Next, the model reac-
tion was performed in other solvents, such as MeCN, THF,
CH3OH, CF3CH2OH and DMF, but the yield of 4a could not be
increased (Table 1, entries 10–14). Then the amount of Et3N
was tested (Table 1, entries 15 and 16), the results show that
1.0 equiv. of Et3N was the best amount. Finally, inspired by
Two directions of the reaction are outlined in Scheme 2.
The intermediate [C] undergoes a regioselective intramolecular
N-cyclization by the amino group attacking the two different
carbonyl groups in 3 leading to the formation of 4 or 4′
1
respectively. Common characterization involving IR, H NMR,
13C NMR, and HRMS could not identify the structure of
the product as 4 or 4′. Fortunately, we obtained the single
crystal of product 4a, and the X-ray diffraction analysis of 4a
(Fig. 2)18 revealed that only 4 not 4′ was obtained exclusively,
demonstrating that the three-component reactions described
show high regioselectivity.
Scheme 1 Retrosynthesis of benzo[g]imidazo[1,2-a]quinolinediones.
Scheme 2 Two directions of the reaction.
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Table 1 Optimization of reaction conditions for the synthesis of 4aa
Table 2 Solvent-free synthesis of compounds 4/5a
Product Time
4/5
Yieldb
(min) (%)
Entry R1/1
R2/2
Catalyst
Entry (equiv.)
Temp
(°C)
Time
(h)
Yieldb
(%)
1
2
3
4
5
6
7
8
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
C6H5/1a
4-ClC6H4/1b
4-BrC6H4/1c
4-CH3C6H4/1d
4-ClC6H4/2a
4-BrC6H4/2b
4-FC6H4/2c
4-NO2C6H4/2d
C6H5/2e
4a
4b
4c
4d
4e
15
20
15
15
20
25
25
20
20
30
30
30
15
15
20
20
30
15
25
30
20
85
82
88
60
78
66
72
80
83
68
66
65
86
83
81
80
80
87
68
65
60
Solvent
1
2
3
4
5
6
7
8
—
—
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
THF
rt
24
24
10
7
12
6
5
5
7
8
8
6
6
7
10
7
Trace
23
81
80
53
39
35
38
70
78
54
40
39
43
58
82
68
83
85
80
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Et3N (1.0)
DABCO (1.0)
Pyridine (1.0)
DBU (1.0)
K2CO3 (1.0)
KOH (1.0)
AcOH (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (1.0)
Et3N (0.5)
Et3N (1.5)
Et3N (1.0)
Et3N (1.0)
Et3N (0.5)
Et3N (0.2)
4-CH3OC6H4/2f 4f
4-CH3C6H4/2g
3-ClC6H4/2h
2-ClC6H4/2i
Furan/2j
CH3CH2/2k
CH3CH2CH2/2l 4l
4-ClC6H4/2a
4-ClC6H4/2a
4-ClC6H4/2a
4g
4h
4i
4j
4k
9
10
11
12
13
14
15
16
17
18
19
20
21
9
10
11
12
13
14
15
16
17
18
19
20
4m
4n
4o
4p
4q
4r
4s
4t
CH3OH
CF3CH2OH Reflux
4-CH3OC6H4/1e 4-ClC6H4/2a
DMF
EtOH
EtOH
100
3-ClC6H4/1f
2,4-Cl2C6H3/1g
CH3/1h
4-ClC6H4/2a
4-ClC6H4/2a
4-ClC6H4/2a
4-CH3C6H4/2g
4-ClC6H4/2a
Reflux
Reflux
100
120
120
c
—
1
CH3/1h
c
—
30 min
15 min
20 min
4u
c
—
c
—
120
1i
a The mixture of 1a (0.5 mmol), 2a (0.5 mmol), and 3 (0.5 mmol) was
22
23
24
2,4-Cl2C6H3/1j
2-ClC6H4/1k
C6H5/1l
4-ClC6H4/2a
4-ClC6H4/2a
4-ClC6H4/2a
5a
5b
5c
30
30
30
70
73
0
stirred in a 25 mL flask. b Isolated yield. c In an oil bath.
a The mixture of 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol) and Et3N
(0.25 mmol) was stirred at 120 °C in oil bath. b Isolated yield.
our published synthetic method,16b solvent-free conditions
were attempted. To our surprise, the reaction time was greatly
reduced from 10 h to 1 h at 100 °C under solvent-free
conditions using 1.0 equiv. of Et3N as the catalyst (Table 1, entries 11 and 12). It is observed that the substituents on
entry 17). Then, the reaction was performed at different tempera- the aromatic rings had some influence on the yields. The
tures such as 80 °C, 120 °C, and 140 °C, and the results aromatic aldehydes with electron-withdrawing groups such
suggested that at 120 °C the yield of 4a was highest and the reac- as fluoro, chloro, and bromo groups, but not a nitro group,
tion time was also decreased to 30 min (Table 1, entry 18). The (Table 2, entries 1–4) reacted faster and gave higher yields than
high efficiency of the solvent-free conditions for the synthesis of those with electron-donating groups such as methyl and meth-
4a encouraged us to test the amount of Et3N once more. oxyl groups (Table 2, entries 6 and 7). What is more, the sub-
We found that when the amount of Et3N was decreased to 0.5 strates
2 with substituents at para- and ortho-positions
equiv., the reaction still performed well and the reaction time afforded higher yields than those counterparts with substitu-
was shortened to 15 min (Table 1, entry 19). Thus, it ents at the meta-position (Table 2, entries 1, 8, and 9), which
was concluded that the optimum reaction conditions were could be related to the electronic effect. Heteroaromatic alde-
Et3N (0.5 equiv.) as the catalyst under solvent-free conditions hydes such as furan-2-carbaldehyde, and aliphatic aldehydes
at 120 °C.
Having established the optimal reaction conditions, we gave lower yields and needed a longer reaction time.
tested the scope of two substrates (Table 2).
Next, the substrates 1 were also extended by using other
such as propaldehyde or butylaldehyde (Table 2, entries 10–12)
First, we tested the scope of the substrates 2 (Table 2, five-membered HKAs 1b–i to react with 2a and 3, the similar
entries 1–12). The reactions of various aldehydes 2a–l with 1a reactivities were observed (Table 2, entries 13–21). As can be
and HNQ 3 showed that the present process could tolerate seen, substituted aromatic HKAs 1b–g with both electron-with-
both aromatic aldehydes with electronically different substitu- drawing and electron-donating groups gave excellent yields
ents (Table 2, entries 1–9) and heteroaromatic aldehydes such with a similar efficiency (Table 2, entries 13–18), while the
as furan-2-carbaldehyde (Table 2, entry 10), and even aliphatic other two HKAs, 1-(imidazolidin-2-ylidene)-propan-2-one (1h)
aldehydes such as propaldehyde or butylaldehyde (Table 2, and 2-(nitromethylene)imidazolidine (1i), provided low yields
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participated in the chemical transformation that led to the
concomitant creation of three new bonds (two C–C bonds, one
C–N bond) and one tetraheterocycle. There are several advan-
tages associated with the use of SFR over the use of an organic
solvent. These include: (1) rapid assembly of imidazo(pyri-
mido)[1,2-a] quinolinediones by simply mixing the three com-
ponents; (2) a high atom economy and ecologically benign
process since two molecules of water were lost; (3) the reaction
completed within only 15–30 min lowering energy usage.
Undoubtedly, this domino synthetic strategy provides a con-
venient and green way to construct the benzo[g]imidazo[1,2-a]-
quinolinediones in an atom-economic manner. We hope this
approach may be of value to others seeking novel synthetic
fragments with unique properties for medicinal chemistry.
Scheme 3 Plausable mechanism for the formation of compounds 4.
and the reaction time was also longer, which was due to elec-
tronic effects (Table 2, entries 19–21).
In order to further investigate the scope of HKAs, three six-
membered HKAs 1j–l were also employed in this process
(Table 2, entries 22–24). Surprisingly, the non-substituted six-
membered HKA 1l did not give the corresponding product,
unlike the five-membered HKA 1a. What’s more, the six-mem-
bered HKAs 1j and 1k with substituents at the ortho-position
also afforded lower yields than those five-membered counter-
parts (Table 2, entries 22 and 18). It could be concluded that
the ring size of HKAs can influence the yields of the reaction.
The structures of benzo[g]imidazo[1,2-a]quinolinediones 4
and benzo[g]pyrimido[1,2-a] quinolinediones 5 were identified
by their IR, 1H NMR, 13C NMR, HRMS spectra, and were as-
certained by the single-crystal X-ray diffraction analysis of 4a,
which revealed that all reactions afforded the corresponding
products in racemic form.
It is worth mentioning that the products from substrates 1
with a Cl atom at the ortho-position, such as the products 4r,
5a and 5b, could give rise to rotamers due to the large tor-
sional barrier with the adjacent 1,3-indanedione group.16c
On the basis of the above results, a plausible mechanism
for this reaction is proposed and shown in Scheme 3. First,
Et3N is an effective catalyst for the formation of the Knoevena-
gel adducts [A], which are readily prepared from aldehydes 2
and HNQ 3. Then, [A] reacts with HKAs 1 proceeding through
an aza-ene reaction to form the intermediates [B],17 which
undergo a rapid imine–enamine tautomerization to give [C].
Finally, intramolecular cyclization of [D] with the loss of a mo-
lecule of H2O leads to the formation of dihydrobenzo[g]-
imidazo[1,2-a]quinoline-6,11(1H,5H)-dione 4.
Experimental section
General information
All reagents and solvents were obtained from commercial sup-
pliers and used without further purification. All reagents were
weighed and handled in air at room temperature. Melting
points were recorded on a RY-1 microscopic melting apparatus
1
and uncorrected. H NMR spectra were recorded on 500 MHz
and 13C NMR spectra were recorded on 125 MHz by using a
Bruker Avance 500 spectrometer. Chemical shifts were
reported in parts per million (δ) relative to tetramethylsilane
(TMS). IR spectra were recorded on a Nicolet iS10 FT-IR spec-
trometer and only major peaks are reported in cm−1. Mass
spectra were performed on an Ultima Global spectrometer
with an ESI source. The X-ray single-crystal diffraction was per-
formed on a Saturn 724+ instrument.
General procedure for the synthesis of products 4/5. HKAs 1
(0.5 mmol), aldehydes 2 (0.5 mmol) and HNQ 3 (0.5 mmol)
and Et3N (0.25 mmol) were added into a 25 mL flask and the
mixture was stirred for the appropriate reaction time at 120 °C
in an oil bath until the HKAs 1 were completely consumed.
The solid mixture was washed with EtOH (2 × 5 mL). The
crude residue was recrystallized from EtOH or separated by
column chromatography (silica gel, petroleum ether–EtOAc,
2 : 1, v/v) to afford the pure products 4/5.
4-Benzoyl-5-(4-chlorophenyl)-2,3-dihydrobenzo[g]imidazo-
[1,2-a]quinoline-6,11(1H, 5H)-dione (4a). Black Solid, mp. 247–
248 °C; IR (KBr, ν, cm−1): 3294 (NH), 1663 (CvO),
1
1636 (CvO). H NMR (500 MHz, DMSO-d6) (δ, ppm): 9.54 (s,
1H, NH), 6.80–7.98 (m, 13H, ArH), 5.22 (s, 1H), 4.53–4.58 (m,
1H, CH2), 4.33–4.39 (m, 1H, CH2), 3.77–3.87 (m, 2H, CH2);
Conclusion
13
C NMR (125 MHz, DMSO-d6) (δ, ppm): 191.6, 181.7, 180.6,
In summary, we have successfully developed a novel and eco- 156.4, 146.0, 142.2, 139.9, 134.9, 133.9, 131.6, 131.5, 131.2,
nomical, environmentally friendly one-pot three-component 129.5, 128.6, 126.7, 125.7, 122.2, 86.4, 47.7, 44.1, 36.7; HRMS
reaction to synthesize novel functionalized benzo[g]imidazo (ESI-TOF, [M + H]+): calcd for C28H20N2O3Cl, 467.1162; found,
[1,2-a]quinolinediones via Et3N-assisted annulations under 467.1158.
solvent-free conditions, which is the first reported prepara-
5-(4-Chlorophenyl)-4-nitro-2,3-dihydrobenzo[g]imidazo[1,2-
tion of the title compounds by use of HKAs, aldehydes, and a]quinoline-6,11(1H,5H)-dione (4u). Red solid, mp. 282–283 °C;
2-hydroxy naphthalene-1,4-dione. In this three-component IR (KBr, ν, cm−1): 3353 (NH), 1672 (CvO), 1647 (CvO);
1
domino process, at least six chemically distinct reactive sites
H NMR (500 MHz, DMSO-d6) (δ, ppm): 9.68 (s, 1H, NH),
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7.27–8.02 (m, 8H, ArH), 5.45 (s, 1H, CH), 4.64–4.69 (m, 1H,
CH2), 4.47–4.53 (m, 1H, CH2), 3.87–3.90 (m, 2H, CH2);
(g) A. J. Birch and T. J. Simpson, J. Chem. Soc., Perkin Trans.
1, 1979, 816.
13
C NMR (125 MHz, DMSO-d6) (δ, ppm): 190.3, 189.1, 161.6,
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21072110 and 20872074)
and the Natural Science Foundation of Shandong Province
(Nos. ZR2010BM007 and ZR2012BM003).
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