Synthesis of 2H-pyrrolo[3,4-C]quinoline via an Aldol/Van Leusen/Staudinger/aza-Wittig sequence

Article abstract of DOI:10.1080/00397911.2016.1204462

An aldol/van Leusen/Staudinger/aza-Wittig reaction for the preparation of the derivatives of 2H-pyrrolo[3,4-c]quinolines from 2-azidobenzaldehyde, acetyl compounds, and tosylmethyl isocyanide was developed. The process involves an aldol condensation of 2-

Full text of DOI:10.1080/00397911.2016.1204462

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Synthesis of 2H-pyrrolo[3,4-c]quinoline via an
aldol/van Leusen/Staudinger/aza-Wittig Sequence
Yu-Qing Shi, Li-De Liao, Ping He, Yang-Gen Hu, Hua Cheng, Song Wang & Jun-
Jun Wu
To cite this article: Yu-Qing Shi, Li-De Liao, Ping He, Yang-Gen Hu, Hua Cheng, Song Wang &
Jun-Jun Wu (2016): Synthesis of 2H-pyrrolo[3,4-c]quinoline via an aldol/van Leusen/Staudinger/
aza-Wittig Sequence, Synthetic Communications
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Date: 26 June 2016, At: 01:46

SYNTHESIS OF 2H-PYRROLO[3,4-C]QUINOLINE VIAAN ALDOL/VAN
LEUSEN/STAUDINGER/AZA-WITTIG SEQUENCE
Yu-Qing Shi1, Li-De Liao1, Ping He1,2, Yang-Gen Hu3, Hua Cheng1, Song Wang2,
Jun-Jun Wu1
1College of Chemical Engineering and Food Science, Hubei University of Arts and
Science, Xiangyang, China, 2Hubei Key Laboratory of Low Dimensional Optoelectronic
Materials and Device, Hubei University of Arts and Science, Xiangyang, China, 3Hubei
Key Laboratory of Wudang Local Chinese Medicine Research and Department of
Pharmacy of Taihe Hospital, Hubei University of Medicine, Shiyan, China
Address correspondence to Ping He, College of Chemical Engineering and Food Science,
Hubei University of Arts and Science, Xiangyang, China. E-mail: pinghe129@163.com;
Address correspondence to Yang-Gen Hu, Institute of Medicinal Chemistry, Hubei
University of Medicine, Shiyan 442000, China. E-mail: huyg@hbmu.edu.cn
Abstract
An aldol/van Leusen/Staudinger/aza-Wittig reaction for the preparation of the derivatives
of 2H-pyrrolo[3,4-c]quinolines from 2-azidobenzaldehyde, acetyl compounds and
tosylmethyl isocyanide was developed. The process involves an aldol condensation of
2-azidobenzaldehyde with acetyl compound in base, and subsequently a van Leusen
reaction to form the key pyrrole intermediates, then a Staudinger and intramolecular
aza-Wittig reaction occurred with the addition of triphenylphosphine to complete the
formation of pyrrolo[3,4-c]quinoline ring in high yields.
1

GRAPHICAL ABSTRACT
KEYWORDS: pyrrole, 2H-pyrrolo[3,4-c]quinolines, aldol/van
Leusen/Staudinger/aza-Wittig reaction, 2-azidobenzaldehyde
INTRODUCTION
Compounds possessing the pyrroloquinoline skeletons have exhibited widespread
biological activities, such as antimalarial,1,2 anticancer,3,4 antiulcer,5 and also have been
found in many natural products.6-8 Among these pyrroloquinoline derivatives,
pyrrolo[3,4-c] quinolines attracted much attention due to their significant potential
application to be used as analgesic9 and caspase-3 inhibitor.10-12 Particularly, a number of
natural products also contain the core of pyrrolo[3,4-c]quinoline ring,13-15 and some of
them have exhibited excellent antitumor activities and selectivity.16 Some literatures
reported the methods for the synthesis of pyrrolo[3,4-c]quinoline derivatives by using van
Leusen/hydrogenation/ condensation reaction,9,17-19 electrocyclisation reaction20,21 or
Pfitzinger/dehydration reaction,3,10-12,22 However, a simple and efficient way to construct
this skeleton is still in need.
2

Over the past twenty years, the isocyanide based multicomponent reactions
(IMCRs) have become a superior tool in the synthesis of combinational libraries of
compounds.23-25 Van Leusen reaction is an isocyanide based reaction and well-known in
the construct of heterocycles, such as oxazoles,26 pyrroles27 and imidazoles.28 On the
other hand, the strategy of tandem Staudinger/aza-Wittig-mediated annulation has been
widely used in the synthesis of heterocyclic compounds.29 Moreover, the synthesis of
molecules with carbon-nitrogen double bonds by using the aza-Wittig reactions together
with post transformation has received extensive attention.30-31 Therefore it is anticipated
that combining the isocyanide based reaction with a post aza-Wittig reaction would
facilitate access to a series of biologically useful fused heterocycles.32-35 Recently, we
have synthesized a series of benzoxazines,36 dihydroquazolines,37
indolo[1,2-c]quinazolines38 and indoles39 in our laboratory using isocyanide as starting
material. Hence, continuing our interest in the construct of various heterocycles via
aza-Wittig reaction,40-44 we wish to report herein a simple and efficient synthesis of
2H-pyrrolo[3,4-c]quinoline derivatives, which were prepared via sequential aldol/van
Leusen/Staudinger/aza-Wittig reaction in high yields.
RESULTS AND DISCUSSION
The initial investigation for the construction of 3,4-disubstituted pyrrole derivative
focused on the one pot model reaction between 2-azidobenzaldehyde (1),
4-methoxyacetophenone (2a) and tosylmethyl isocyanide (TosMIC 3). When 1.5 equiv of
lithium hydroxide monohydrate was added to the mixture of 2-azidobenzaldehyde, and
3

4-methoxyacetophenone in ethanol, the aldol condensation reaction was carried out
smoothly and completed within 40 min which was monitored by TLC. And then one
equiv of TosMIC was added to the mixture without the isolation of the aldol reaction
product. And the van Leusen reaction was completed with the end of the solid
precipitated from the ethanol (Scheme 1). The substrate scope of the acetyl compounds
was evaluated and the results are listed in Table 1 (Entries 1-10). The pyrrole derivatives
were obtained all in moderate to high yields whether the acetyl compounds that used
were alkyl or aryl.
The followed Staudinger and intramolecular aza-Wittig reaction of azides 4 with
triphenylphosphine was examined. When azides 4 were treated with one equiv of
triphenylphosphine in dichloromethane at ambient temperature, the expected Staudinger
reaction and intramolecular aza-Wittig reaction occurred with a reasonable time at room
temperature and 2H-pyrrolo[3,4-c]quinoline derivatives were isolated in good yields
(85-95%, Scheme 2, Table 2, 6a-6j). The formation of 2H-pyrrolo[3,4-c]quinoline
derivatives can be viewed as an initial Staudinger reaction between the azide 4 and
triphenylphosphine to form the key intermediate iminophosphorane 5. The
2H-pyrrolo[3,4-c]quinolines 6 were finally produced via the further intramolecular
aza-Wittig reaction of 5 directly with the elimination of triphenylphosphine oxide.
The compounds of 2H-pyrrolo[3,4-c]quinoline derivatives 6 were confirmed by their
spectral data. For example, the 1H NMR spectrum of 6a showed singlet at 3.86 ppm due
to the methoxyl group linking to the phenyl ring. And the signals attributable to the
4

protons of the pyrrolo[3,4-c]quinoline and phenyl rings were found at 8.19-7.13 ppm as
mutiplets, while the signal of the pyrrole ring belong to the nitrogen-hydrogen bond was
found at 12.84 ppm as singlet compared to singlet at 11.74 ppm in the intermediate
pyrrole ring 4a. The 13C NMR spectrum data in 6a showed the carbon signal of
carbon-nitrogen double bond at 160.2 ppm and in the intermediate 4a the carbon signal of
carbonyl group at 189.0 ppm.
CONCLUSIONS
In conclusion, we have developed an efficient synthesis of 2H-pyrrolo[3,4-c]quinoline
derivatives via combining aldol/van Leusen/Staudinger/aza-Wittig reactions starting from
2-azidobenzaldehyde, acetyl compounds and TosMIC in high yields. Due to the mild
reaction conditions, easily accessible starting material and straightforward product
isolation, We think that the versatile synthetic approach discussed here in many cases
compares favorably with other existing methods for synthesis of many biologically active
pyrrolo[3,4-c]quinoline derivatives, and further application, optimization and in natural
product synthesis of the method are underway.
EXPERIMENTAL SECTION
General Methods.
Reactions were generally carried out in an appropriate round bottom flask with magnetic
stirring. Thin layer chromatography (TLC) was performed on a silica gel. All melting
points were determined using a X-4 model apparatus and were uncorrected. IR were
recorded on a PE-983 infrared spectrometer as KBr pellets with absorption in cm-1. NMR
5

spectra were recorded on Bruker Avance III 400 spectrometer in CDCl3 or DMSO-d6.
Mass spectra were obtained on a LC-MS-2010A spectrometer with ESI. Elementary
analyses were taken on a Vario EL III elementary analysis instrument.
General Preparation of 3,4-Disubstituted Pyrroles (4a-4j).
Lithium hydroxide monohydrate (0.18 g, 4.5 mmol) was added to the mixture of
2-azidobenzaldehyde 1 (0.44 g, 3 mmol) and acetyl compounds 2 (3 mmol) in ethanol,
the aldol condensation reaction was carried out smoothly and completed within 40 min
which was monitored by TLC. And then TosMIC (0.59 g, 3 mmol) was added to the
mixture without the isolation of the aldol reaction product. And the van Leusen reaction
was completed with the end of the solid precipitated from the ethanol, then filtered and
washed with ethanol. The residual was recrystallized from methylene dichloride/ethanol
to give 4a-4j in good yields.
(4-(2-Azidophenyl)-1H-Pyrrol-3-yl)(4-Methoxyphenyl)Methanone (4a)
Yellow crystals, mp 168-169 ºC; IR: 3176, 2119, 1601, 1508, 1288, 895, 761; 1H NMR
(DMSO-d6, 400 MHz) δ (ppm): 11.74 (s, 1H, NH), 7.36 (d, 2H, J = 8.0 Hz, Ar-H), 7.25
(q, 3H, J = 8.0 Hz, Ar-H), 7.13-7.09 (m, 3H, Ar-H), 6.96 (q, 2H, J = 2.8 Hz, Ar-H), 3.80
(s, 3H, OCH3); 13C NMR (DMSO-d6, 100 MHz) δ (ppm): 189.0, 151.7, 136.8, 131.2,
128.2, 127.6, 124.7, 124.4, 123.1, 122.3, 120.6, 119.9, 118.8, 111.5, 110.4, 55.6; LC-MS
(m/z): 318; Anal. Calcd for C18H14N4O2: C, 67.92; H, 4.43; N, 17.60; Found: C, 67.91; H,
4.49; N, 17.81;
6

General Preparation of 2H-Pyrrolo[3,4-c]Quinolines (6a-6j).
To a stirred solution of 3,4-disubstituted pyrroles 4 (1 mmol) in dichloromethane (5 mL)
was added drop wise of triphenylphosphine (0.26 g, 1 mmol) in dichloromethane (5 mL)
at room temperature. The reaction mixture was stirred for 3-6 hours at room temperature
and monitored by thin-layer chromatography. Once completed, the solvent was removed
off under reduced pressure and the residual was recrystallized from dichloromethane/
petroleum ether to give 2H-pyrrolo[3,4-c]quinolines 6.
4-(4-Methoxyphenyl)-2H-Pyrrolo[3,4-c]Quinoline (6a)
White crystals, mp 177-178 ºC (lit.17 mp: 168-170 ºC); IR: 3431, 2962, 1617, 1498, 1444,
1250, 1031, 946, 831, 761, 740; 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 12.84 (s, 1H,
NH), 8.19-8.17 (m, 3H, Ar-H), 8.10-7.90 (m, 2H, Ar-H), 7.72 (s, 1H, Ar-H), 7.64-7.43
(m, 2H, Ar-H), 7.13 (t, 2H, J = 9.6 Hz, Ar-H), 3.86 (s, 3H, OCH3); 13C NMR (DMSO-d6,
100 MHz) δ (ppm): 160.2, 154.7, 142.3, 132.5, 129.8, 129.0, 128.3, 125.7, 124.5, 122.6,
121.6, 115.9, 114.2, 113.9, 110.1, 55.2; LC-MS (m/z): 274; Anal. Calcd for C18H14N2O: C,
78.81; H, 5.14; N, 10.21; Found: C, 78.87; H, 5.11; N, 10.10;
FUNDING
We gratefully acknowledge financial support of this work by the National Natural
Science Foundation of China (No. 21302047), the Natural Science Foundation of Hubei
7

Province, China (No. 2014CFB635), the key (cultivation) discipline construction project
achievements and the Project for Discipline Groups Construction of Food New–type
Industrialization of Hubei University of Arts and Science, the fund of Hubei 2011
Cooperative Innovation Center (No. 2011JH-2014CXTT07).
SUPPORTING INFORMATION
Full experimental detail, IR, CHN analysis, mass spectra, and 1H NMR and 13C NMR
spectra for this article can be accessed on the publisher’s website.
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Table 1. Synthesis of pyrroles 4 form 2-azidobenzaldehyde 1, acetyl compounds 2 and
TosMIC 3
Entry Acetyl compound
Product
Conditions
Yield
(%)a
88
1
First 40 min at 0°C
Then 120 min at
25°C
4a
4b
4c
4d
4e
2a
2
First 40 min at 0°C
Then 120 min at
25°C
90
82
88
80
2b
3
First 40 min at 0°C
Then 120 min at
25°C
2c
4
First 40 min at 0°C
Then 120 min at
25°C
2d
5
First 40 min at
2e
20°C Then 120 min
13

at 25°C
First 40 min at 0°C
Then 180 min at
25°C
6
88
90
85
95
82
4f
4g
4h
4i
2f
7
2g
First 40 min at 0°C
Then 120 min at
25°C
8
First 40 min at 0°C
Then 120 min at
25°C
2h
9
First 40 min at 0°C
Then 120 min at
25°C
2i
2j
10
4j
First 40 min at
20°C Then 120 min
at 25°C
aIsolated yields based on 2-azidobenzaldehyde 1.
14

Table 2. Preparation of 2H-pyrrolo[3,4-c]quinolines 6 via Staudinger/aza-Wittig reaction
from azides 4
Entry
Product
Conditions
Yield (%)a
1
3 hours 25°C
90
6a
2
3
92
88
6b
6c
3 hours 25°C
3 hours 25°C
4
96
6d
3 hours 25°C
5
6
7
90
88
92
6e
6f
6 hours 25°C
4 hours 25°C
3 hours 25°C
6g
8
95
6h
3 hours 25°C
15

9
92
85
6i
3 hours 25°C
6 hours 25°C
10
6j
aIsolated yields based on azides 4.
16

Scheme 1. Synthesis of 3,4-disubstituted pyrrole 4a.
17

Scheme 2. Preparation of 2H-pyrrolo[3,4-c]quinolines 6 via Staudinger/aza-Wittig
reaction.
18