A new rapid multicomponent domino reaction for the formation of functionalized benzo[h]pyrazolo[3,4-b]quinolines

Article abstract of DOI:10.1039/c1ob05034f

A new multicomponent domino reaction for rapid and regioselective synthesis of highly functionalized benzo[h]pyrazolo[3,4-b]quinolines has been established. The reaction can be conducted by using readily available and inexpensive substrates under microwav

Full text of DOI:10.1039/c1ob05034f

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A new rapid multicomponent domino reaction for the formation of
functionalized benzo[h]pyrazolo[3,4-b]quinolines†
Bo Jiang,a Ge Zhang,a Ning Ma,a Feng Shi,a Shu-Jiang Tu,*a Parminder Kaurb and Guigen Li*b
Received 6th January 2011, Accepted 2nd March 2011
DOI: 10.1039/c1ob05034f
A new multicomponent domino reaction for rapid and regioselective synthesis of highly functionalized
benzo[h]pyrazolo[3,4-b]quinolines has been established. The reaction can be conducted by using readily
available and inexpensive substrates under microwave irradiation within short periods of 10–26 min.
Good to excellent chemical yields (61–91%) and complete regioselectivity have been achieved for 22
examples. Tedious work-up procedure can be avoided due to the direct precipitation of products from
the reaction solution. The resulting benzoquinolines have been readily converted into quinoxaline-fused
benzo[h]isoxazolo[5,4-b]quinoline analogues by treating with benzene-1,2-diamine under microwave
irradiation. The structural assignment has been ambiguously confirmed by X-ray analysis. A new
mechanism has been proposed for this new multicomponent domino process.
proceeded along another pathway leading to the formation of
multi-functionalized tricyclo[6.2.2.01,6]dodecanes.7b
Introduction
Assembly of molecular complexity and diversity from readily
available starting materials in regard to economic and environ-
mental aspects constitutes a great challenge in modern organic
chemistry.1–4 For this purpose, multicomponent domino reactions
(MDRs) has become increasingly useful tools for the synthesis of
chemically and biologically important compounds because of their
atom-, structure-, bond-forming economy and green chemistry
characteristic.4–5 These reactions can avoid time-consuming and
costly processes for purification of various precursors and tedious
steps of protection and deprotection of functional groups.6 There-
fore, the development of new regio- and stereoselective domino
reactions is a continuing challenge at the forefront of modern
organic chemistry.
During our continuous efforts on searching for useful multicom-
ponent domino reactions,7–9 we now found a new regioselective
multicomponent domino annulation which provides an easy
access to benzo[h]pyrazolo[3,4-b]quinolines and their derivatives.
This reaction was achieved by reacting aldehydes, pyrazol- or
isoxazolo-amines and 2-hydroxy-1,4-naphthoquinone under mi-
crowave irradiation (MW) in the absence of strong acids or
metal catalysts/promoters (Scheme 1). The resulting benzoquino-
lines has been reacted with benzene-1,2-diamine to give poly-
cyclic heteroaromatics, quinoxaline-fused benzo[h]isoxazolo[5,4-
b]quinolines.
In the past several years, our group and others have developed
various multicomponent domino reactions that can provide easy
access to functionalized multiple heterocycles.7–10 Among these re-
actions is a four-component domino process for concise synthesis
of multi-functionalized quinazoline derivatives.7a The reaction can
be easily performed by simply mixing readily available starting ma-
terials, aromatic aldehydes, cyclopentanone and cyanoacetamide
with K2CO3 in ethylene glycol under microwave (MW) irradiation.
Furthermore, we have also found that when aliphatic aldehydes
were employed to replace their aromatic counterparts, the reaction
Scheme 1
It is well-known that the quinoline subunit plays a prominent
role in organic and medicinal chemistry; and they exist in a wide
variety of naturally occurring compounds and rationally designed
pharmaceutical agents (e.g., quinine, camptothecin).11 Quinolines
are integral to a large number of drug substances with activities
including antimalarial, antiinflammatory, antineoplastic, antifun-
gal, antiseptic/antiinfective, and analgesic properties.12 Therefore,
aSchool of Chemistry and Chemical Engineering, Xuzhou Normal University,
Jiangsu, P.R. China. E-mail: laotu@xznu.edu.cn; Fax: +86(516) 83500065;
Tel: +86(516) 83500065
bDepartment of Chemistry and Biochemistry, Texas Tech University, Lub-
bock, TX, 79409-1061, USA. E-mail: guigen.li@ttu.edu
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05034f
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Table 1 Optimization for the Synthesis of 4a under microwave irradiation
Table 2 Regioselective domino synthesis of products 4 and 5 under MW
Irradiation
Entry
Solvent
T/◦C
Time (min)
Yield (%)
1
2
3
4
5
6
—
100
100
100
100
100
100
10
10
10
10
10
10
13
40
56
84
65
57
EtOH
Glycol
AcOH
DMF
1,4-Dioxane
Entry 4 or 5
R
Time (min) Yield (%)
the development of new methods for their syntheses has been an
area of ongoing interest.13 Surprisingly, to the best of our knowl-
edge, an efficient domino approach to fused benzo[h]pyrazolo[3,4-
b]quinoline and benzo[h]isoxazolo[5,4-b]quinoline derivatives,
containing a naphthoquinone unit, has not been well documented.
In this paper, we would like to report the new reaction for their
syntheses.
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4-Fluorophenyl (1a)
2-Chlorophenyl (1b)
3-Bromophenyl (1c)
3-Nitrophenyl (1d)
10
18
18
10
84
82
89
91
87
83
84
83
86
79
61
87
89
84
88
86
78
82
74
79
67
71
4-Hydroxy-3-nitrophenyl (1e) 12
Phenyl (1f)
20
22
20
18
15
26
12
14
15
10
10
18
20
24
20
4g
4h
4i
4-Methylphenyl (1g)
4-Methoxyphenyl (1h)
Benzo[d][1,3]dioxol-5-yl (1i)
2-Thienyl (1j)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4j
4k
5a
5b
5c
5d
5e
5f
n-Butyl (1k)
Results and discussion
4-Fluorophenyl (1a)
4-Chlorophenyl (1l)
4-Bromophenyl (1m)
4-Nitrophenyl (1n)
3-Nitrophenyl (1d)
Phenyl (1f)
Initially, we conducted this synthesis by reacting 4- fluoroben-
zaldehyde 1a with 2-hydroxy-1,4-naphthoquinone 2 and 3-methyl-
1-phenyl-1H-pyrazol-5-amine 3a to serve as the model case for
condition optimization.
5g
5h
5i
5j
5k
4-Methylphenyl (1g)
3,4-Dimethoxyphenyl (1o)
Benzo[d][1,3]dioxol-5-yl (1p)
4-Dimethylaminophenyl (1q) 24
Thien-2-yl (1j) 22
◦
As shown in Table 1, the use of acetic acid at 100 C allowed
the direct conversion of 2-hydroxy-1,4-naphthoquinone 2 into
the corresponding benzo[h]pyrazolo[3,4-b]quinoline 4a in a yield
of 84% under microwave irradiation condition (Table 1, entry
4). Other polar solvents, such as ethanol, ethylene glycol, N,N-
dimethylformamide, 1,4-dioxane or solvent-free condition re-
sulted in moderate to poor to modest yields of 13%–65% (Table 1,
entries 1–3). The reaction proceeded rapidly to completion within
a few minutes at 100 ◦C. Increasing reaction temperature to 120 ◦C
did not improve chemical yields.
of single crystals that were obtained by slowly evaporating solvent
from the solution containing benzo[h]pyrazolo[3,4-b]quinolines 4h
(Fig. 1).
Next, we studied the substrate scope of this reaction by
subjecting a series of aromatic aldehydes 1b–k to the reactions with
2-hydroxy-1,4-naphthoquinone 2 under the optimal condition.
As shown in Table 2, the reaction of thiophene-2-carbaldehyde
with 2-hydroxy-1,4-naphthoquinone 2 and 3-methyl-1-phenyl-
1H-pyrazol-5-amine can be finished within 15 min to give
thienyl-substituted benzo[h]pyrazolo[3,4-b]quinoline 4j in 79%
yield. In addition, an aliphatic aldehyde also showed high re-
activity under this standard condition providing corresponding
benzo[h]pyrazolo[3,4-b]quinolines in a good yield of 61% (Ta-
ble 2, entry 11). Similarly, benzoquinoline products, 4b–k, were
produced within 10–26 min in good to excellent yields of 67–
91% (Table 2, entries 2–11). Bedsides 3-methyl-1-phenylpyrazol-
5-amine (3a) substrate, 3-methyl-isoxazol-5-amine (3b) was also
proven to be suitable for the reaction with 2-hydroxy-1,4-
naphthoquinone (1) and eleven arylaldehydes bearing electron-
withdrawing or electron-donating groups to give the correspond-
ing benzo[h]isoxazolo[5,4-b]quinoline-5,6-diones (5a–5k) in good
yields (67–89%) and excellent selectivities (Table 1, entries 12–22).
For all these cases, the reaction proceeded rapidly to completion
within 10–24 min.
Fig. 1 The ORTEP drawing of product 4h.
A heteroaromatic substrate (1j) was also employed for
this reaction to give 2-thienyl-substituted benzo[h]isoxazolo[5,4-
b]quinolines (5k) in a yield of 71%. The structural elucidation was
unequivocally determined by NMR analysis and X-ray diffraction
To study the applicational scope of this reaction, benzo-
quinolines 5 were further employed to react with benzene-1,2-
diamine under microwave irradiation. After several solvents were
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Table 3 Synthesis of compounds 6 under MW Irradiation
Entry
6
R
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
4-Fluorophenyl (5a)
4-Chlorophenyl (5b)
4-Bromophenyl (5c)
4-Nitrophenyl (5d)
8
10
8
10
10
10
12
12
94
96
91
97
96
92
91
89
3-Nitrophenyl (5e)
4-Methylphenyl (5g)
Benzo[d][1,3]dioxol-5-yl (5i)
4-Me2N-phenyl (5j)
6g
6h
screened, DMF was found to be the most suitable solvent for this
condensation to afford quinoxaline-fused benzo[h]isoxazolo[5,4-
b]quinolines 6 in excellent yields (89–97%) (Scheme 2, Table 3).
This conversion can be finished within 8–12 min in this solvent
at 120 ◦C. It should be mentioned that the resulting isoxazole-
containing multiheterocycles would be endowed with many
significant pharmacological properties, such as hypoglycemic,
analgesic, anti-inflammatory, antibacterial, anti-HIV, and anti-
cancer activity.14 In addition, they showed agrochemical properties
including herbicidal and soil fungicidal activity for the use of
pesticides and insecticides.15
Scheme 3
Conclusion
In summary, a new multicomponent domino reaction have
been established to afford benzo[h]pyrazolo[3,4-b]quinolines and
benzo[h]isoxazolo[5,4-b]quinolines that serve as versatile building.
The reactions showed high regioselectivity and a broad scopes of
substrates which can employ a wide range of common commercial
starting materials. A new mechanism has been proposed to
explain the reaction process and regioselectivity. The resulting
benzoquinoline products have been successfully converted into
quinoxaline-fused benzo[h]isoxazolo[5,4-b]quinolines by reacting
with benzene-1,2-diamine under microwave irradiation.
Experimental
General
Scheme 2
Microwave irradiation was carried out with microwave oven Emrys
Creator from Personal Chemistry, Uppsala, Sweden. Melting
points were determined in open capillaries and were uncorrected.
1H NMR (13C NMR) spectra were measured on a Bruker DPX 400
(100) MHz spectrometer in DMSO-d6 (or CDCl3)with chemical
shift (d) given in ppm relative to TMS as internal standard.
The exact mass measurements were obtained by high resolution
mass instrument (GCT-TOF instrument). X-Ray crystallographic
analysis was performed with a Siemens SMART CCD and a
Semens P4 diffractometer.
Similar to our previous multicomponent domino processes,7
the present reaction also showed the following attractive charac-
teristics: (1) fast reaction rates which enable the reaction to be
completed within 10–24 min, which can save energy and manpower
for future industrial production; (2) the environmentally friendly
process in which water is nearly a sole byproduct; (3) the conve-
nient work-up which only needs simple filtration since the products
directly precipitate out after the reaction is finished;16–17 (4) high
regioselectivity in which the reactions generated benzoquinolines
with ortho-diketone unit that serve as important building blocks.
General procedure for the synthesis of compounds 4a, 5a, and 6a
Preparation of compounds 4a or 5a, Microwave heating: 4-
fluorobenzaldehyde 1a (1.0 mmol) was introduced in a 10-mL
Emrys reaction vial, and 2-hydroxy-1,4-naphthoquinone 2 (1.0
mmol), 3-methyl-1-phenyl-1H-pyrazol-5-amine 3a or (3-methyl-
isoxazol-5-amine 3b) (1.1 mmol) and HOAc (1.5 mL) were then
successively added. Subsequently, the reaction vial was capped and
then stirred for 20 s. The mixture was irradiated (initial power 100
W and maximum power 200 W) at 120 ◦C until TLC (petroleum
ether/acetone, 4 : 1 v/v) revealed that conversion of the starting
material 1a was complete (10 min or 12 min). The reaction mixture
was then cooled to room temperature and diluted with cold water
(40 mL). The solid product was collected by Bu¨chner filtration and
was purified by flash column chromatography (silica gel, mixtures
of petroleum ether/ethyl acetate, 5 : 1 v/v) to afford the desired
pure products 4a (or 5a) as a red solid.
Proposed reaction mechanism
On the basis of all the above results, a possible mechanism has
been proposed for the formations of benzoquinolines derivatives as
shown in Scheme 3. The formation of 4 involves a ring closure cas-
cade process that consists of initial condensation, intermolecular
Michael addition (A to B), intramolecular nucleophilic cyclization
(B to C) and dehydration (C to D) (Scheme 3). The intermediate
B favors formation of intramolecular hydrogen bond between
carbonyl group (position a) and ortho-hydroxyl group (position
b), in which enolization of hydroxyl group was further enhanced.
During this process, the carbonyl group (position c) would be
easily attracted by the amino group (-NH2) to give intermediate C
which is then converted into the final product via dehydration and
dehydrogenation steps.
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Preparation of compounds 6a: In a 10-mL EmrysTM reaction
vial, quinoxaline-fused benzo[h]isoxazolo[5,4-b]quinolines 5a and
benzene-1,2-diamine (7, 1.1 mmol) and DMF (2.5 mL) were mixed
and capped, and then stirred for 20 s. The mixture was irradiated
for a given time at 120 ◦C under microwave irradiation (initial
power 100 W and maximum power 250 W). When the reaction
was completed (monitored by TLC). The reaction mixture was
then cooled to room temperature and diluted with cold water (40
mL). The solid product was collected by Bu¨chner filtration and
was purified by recrystallization from 95% EtOH to afford the
desired pure products 6a as a pale yellow solid.
Acknowledgements
We are grateful for financial support from the NSFC (Nos.
20928001, 21072163 and 21002083), and Sci. Foundation in
Interdisciplinary Major Res. Project of XZNU (No. 09XKXK01),
Doctoral Research Foundation of Xuzhou Normal Univ. (XZNU,
No. 10XLR20), Robert A. Welch Foundation (D-1361) and NIH
(R03DA026960).
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Red solid, mp: >300 ◦C
1H NMR (400 MHz, DMSO-d6) (d, ppm): 8.76 (d, J = 8.0 Hz,
1H, ArH), 8.30 (d, J = 7.6 Hz, 2H, ArH), 8.05 (d, J = 7.2 Hz, 1H,
ArH), 7.95 (t, J = 7.6 Hz, 1H, ArH), 7.72 (d, J = 7.6 Hz, 1H, ArH),
7.67 (t, J = 8.0 Hz, 2H, ArH), 7.46–7.36 (m, 5H, ArH), 1.89 (s,
3H, CH3).
13C NMR (100 MHz, DMSO-d6, 25 ◦C) (d, ppm): 179.19,
153.28, 145.50, 138.23, 136.57, 135.62, 132.50, 131.94, 131.42,
129.64, 129.57, 129.45, 128.15, 128.13, 127.12, 126.56, 126.48,
120.79, 116.25, 115.12, 114.90, 14.23.
IR (KBr, n, cm-1): 3073, 1680, 1559, 1509, 1419, 1382, 1286,
1217, 1159, 1087, 947, 840, 773, 693, 647.
HRMS (ESI) m/z: calc. for C27H16FN3O2Na: 456.1119, found:
456.1119.
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Red solid, mp: 262–264 ◦C
1H NMR (400 MHz, DMSO-d6) (d, ppm): 8.72 (d, J = 8.0 Hz,
1H, ArH), 8.06 (d, J = 7.6 Hz, 1H, ArH), 7.93 (t, J = 7.2 Hz, 1H,
ArH), 7.74 (t, J = 7.6 Hz, 1H, ArH), 7.48–7.44 (m, 2H, ArH), 7.18
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IR (KBr, n, cm-1): 3069, 1692, 1672, 1573, 1510, 1442, 1341,
1219, 1162, 1076, 936, 842, 774, 611.
13C NMR (100 MHz, DMSO-d6, 25 ◦C) (d, ppm): 178.44,
178.11, 169.04, 163.45, 161.01, 157.21, 155.32, 151.12, 135.56,
132.18, 131.99, 129.78, 129.70, 128.27, 126.83, 123.32, 115.17,
114.96, 113.33, 11.98.
HRMS (ESI) m/z: calc. for C21H11FN2O3Na: 381.0646, found:
381.0640.
Hexacyclic quinoxaline-fused benzo[h]pyrazolo[3,4-b] quinolines
(6a)
Pale yellow solid, mp: > 300 ◦C
1H NMR (400 MHz, CDCl3, 25 ◦C): d = 9.30–9.25 (m, 2H,
ArH), 8.22 (d, J = 7.6 Hz, 1H, ArH), 7.85–7.77 (m, 3H, ArH),
7.71–7.67 (m, 1H, ArH), 7.39–7.28 (m, 5H, ArH), 2.04 (s, 3H,
CH3);
IR (KBr, n, cm-1): 1590, 1569, 1509, 1419, 1383, 1322, 1221,
1126, 998, 810.
HRMS (ESI): m/z calcd for C27H16FN4O: 431.1303, found:
431.1301.
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