Efficient Synthesis of Quinolines via a Knoevenagel/Staudinger/aza-Wittig Sequence

Article abstract of DOI:10.1080/00397911.2015.1105982

A simple and efficient method for the construction of quinoline derivatives from 2-azidobenzaldehyde and various carbonyl compounds was developed. The process involves a Knoevenagel condensation of 2-azidobenzaldehyde with carbonyl compound and subsequently an intramolecular normal Staudinger/aza-Wittig reaction to form the quinolone ring in satisfactory yields.

Full text of DOI:10.1080/00397911.2015.1105982

Synthetic Communications
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Efficient Synthesis of Quinolines via a
Knoevenagel/Staudinger/aza-Wittig Sequence
Feng Qu, Ping He, Ruo-Fei Hu, Xiao-Hong Cheng, Song Wang & Jing Wu
To cite this article: Feng Qu, Ping He, Ruo-Fei Hu, Xiao-Hong Cheng, Song Wang & Jing Wu
(2015): Efficient Synthesis of Quinolines via a Knoevenagel/Staudinger/aza-Wittig Sequence,
Synthetic Communications
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Date: 03 November 2015, At: 10:38

EFFICIENT SYNTHESIS OF QUINOLINES VIAA
KNOEVENAGEL/STAUDINGER/AZA-WITTIG SEQUENCE
Feng Qu1, Ping He1,2, Ruo-Fei Hu1, Xiao-Hong Cheng2, Song Wang2, Jing 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
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
Abstract
A simple and efficient method for the construction of quinoline derivatives from
2-azidobenzaldehyde and various carbonyl compounds was developed. The process
involves a Knoevenagel condensation of 2-azidobenzaldehyde with carbonyl compound,
and subsequently an intramolecular normal Staudinger/aza-Wittig reaction to form the
quinolone ring in satisfactory yields.
KEYWORDS: Quinolones, 2-Azidobenzaldehyde, Knoevenagel/aza-Wittig reaction
INTRODUCTION
1

Compounds possessing the quinoline skeletons are of great importance due to their
versatile biological properties, such as antibacterial,1,2 antiplatelet,3 anti-inflammatory4
and anticancer.5 Several classical methods have been developed to synthesis quinoline
derivatives, such as Skraup-Doebner-von Miller quinoline synthesis,6 Friedlander
synthesis,7 Pfitzinger-Borsche reaction,8,9 Conrad-Limpach synthesis10 and Combes
quinoline synthesis.11 However, these methods usually require harsh reaction conditions
or consist of multiple steps, which limited their applications. Transition metal-catalysis
also have been employed in order to modify those processes, such as Friedlander
quinoline synthesis.12,13 Very recently Yu and his coworkers report the synthesis of
quinolines through an unexpected cascade reaction of
Michael/Staudinger/aza-Wittig/aromatization process, which contains the addition and
release of nitromethane.14 Although these methods are effective, most of them suffer
from strong acid or base conditions, high reaction temperatures or dull procedures of
work-up. So, the development of a simple and efficient methodology for the construction
of quinolines is still in need. On the other hand, the method of using aza-Wittig reactions
to synthesis of compounds with carbon-nitrogen double bonds has received increased
attention in recent years.15-27 And the tandem Staudinger/aza-Wittig-mediated annulation
strategy has also received increased attention due the widely application in the synthesis
of heterocyclic compounds.28,29 Meanwhile, multi-component reactions have undoubtedly
become a powerful synthetic tool in the preparation of organic compounds due to their
various advantages such as high atom-economy, high time-saving, high structural
diversity and molecular complexity over classical multistep methods.30-36 The
combination of multicomponent reactions with aza-Wittig reaction have been utilized in
2

the synthesis of various heterocyclic molecules.37-44 Recently we have been interested in
the synthesis of various heterocyclic systems especially starting from
2-azidobenzaldehyde.45,46 Herein, we report a simple and efficient synthesis of quinolines
derivatives via a Knoevenagel/Staudinger/aza-Wittig sequence starting from
2-azidobenzaldehyde and carbonyl compounds in high yields.
RESULTS AND DISCUSSION
A mixture of 2-azidobenzaldehyde 1 (1 mmol) and carbonyl compound (1 mmol) was
stirred in tetrahydrofuran at room temperature in the presence of a catalytic amount of
piperidine. The Knoevenagel reaction was carried out smoothly and completed within 2
hours. And then one equiv of triphenylphosphine was added to the mixture at the reflux
temperature without the isolation of the Knoevenagel reaction product. At end of the
nitrogen evolution of the Staudinger reaction, a reasonable time of heating was given to
complete the intramolecular aza-Wittig reaction to afford quinoline derivatives. The
results are listed in Table 1 (entries 1-10). The quinoline derivatives were obtained all in
moderate to high yields whether the carbonyl compounds that used were alkyl or aryl.
The synthesis of quinolines 2 can be viewed as an initial Knoevenagel condensation
reaction to form the intermediate 3, which undergoes the normal Staudinger reaction to
give the iminophosphorane 4 as the key intermediate, and finally the quinolines were
formed through the intramolecular aza-Wittig reaction under heating conditions (Scheme
1).
In order to expand and evaluate the method for the preparation of quinolines, dicarbonyl
compounds were used to take part in the reactions. As exhibited in Table 1, quinolines
3

were obtained in high yields when 1,3-dicarbonyl compounds were employed (entries
11-14). It is worthy to note that Zhao et al. reported the synthesis of
1H-pyrazolo[1,5-b]indazoles by a domino Staudinger/aza-Wittig cyclization starting from
2-azidobenzaldehyde and active methylene compounds previously, and no quinolines
were obtained in their attempts.47 It’s well known that the azide products 5 could react
with triphenylphosphine with two different ways under different conditions in the
Staudinger reaction. As shown in Scheme 2, 1H-pyrazolo[1,5-b]indazoles 7 were formed
via intermediate indazol-2-yl-iminophosphorane 6 when abnormal Staudinger reaction
happened.48,49 On the other hand, the quinoline derivatives 9 were formed through the
phenyliminophosphorane 8 when the normal Staudinger reaction happened.50,51 And
when 2,3-dicarbonyl compounds was used as the starting material, quinolines were still
the only product and obtained in good yields despite that a selective cyclization may
emerged (entries 15-16). It is presumed that quinoline compound 12 appear to be far
more stable than 13 because 12 are highly conjugated and their lower activity energy for
the formation than 13 (Scheme 3). All the quinoline products are known compounds
expect 2i, 2j and 2p, and the spectra of these known compounds are consistent with the
literature values.
CONCLUSIONS
In conclusion, we have developed a new and efficient synthesis of quinolines via a
Knoevenagel/Staudinger/aza-Wittig sequence. Due to its mild reaction conditions, high
yields and simple work-up, the method may serve as an efficient way for construction of
4

many biologically active quinoline derivatives, and its further application in natural
product synthesis is undergoing in our laboratory.
EXPERIMENTAL SECTION
General Procedures
Melting points were determined using a X-4 model apparatus and were uncorrected. MS
were measured on a Finnigan Trace MS spectrometer. NMR spectra were recorded on a
Bruker Avance III 400 or 600 spectrometer in CDCl3 and chemical shifts ( ) were given
in ppm using (CH3)4Si as an internal reference ( = 0). IR were recorded on a PE-983
infrared spectrometer as KBr pellets with absorption in cm-1. Elementary analyses were
taken on a Vario EL III elementary analysis instrument. The 2-azidobenzaldehyde and
the 1,2,4-triazol carbonyl compound were prepared according to the known methods.52,53
And all the products (2a–2p) were confirmed by their spectrum data.
General Preparation Of Quinolines (2a-2p)
To a solution of 2-azidobenzaldehyde 1 (0.44 g, 3 mmol) and catalytic amount of
piperidine (2 drops) in dry tetrahydrofuran at room temperature (15 mL), carbonyl
compound (3 mmol) in dry tetrahydrofuran (5 mL) was added under nitrogen. The
Knoevenagel reaction was carried out smoothly and the condensation was completed
within 2 hours. And then triphenylphosphine (0.79 g, 3 mmol) was added to the mixture
at the reflux temperature without the isolation of the Knoevenagel product, and with the
end of the nitrogen evolution of the Staudinger reaction, the solution was heated at reflux
5

for a reasonable time to complete the intramolecular aza-Wittig reaction to afford
quinoline derivatives. After the completion of the reaction (monitoring by TLC), the
solvent was evaporated, and the residue was purified by recrystallization from
dichloromethane/ether.
11H-Indeno[1,2-B]Quinoline (2a)
White crystals, mp 168-169 ºC (lit.54 mp: 166 ºC); 1H NMR (CDCl3, 400 MHz) δ (ppm):
8.33-8.20 (m, 3H, Ar-H), 7.84-7.49 (m, 6H, Ar-H), 4.06 (s, 2H, CH2). 13C NMR (100
MHz, CDCl3) δ (ppm): 161.6, 148.0, 145.0, 140.3, 134.5, 131.1, 129.9, 129.0, 128.7,
127.7, 127.4, 127.3, 125.6, 125.4, 122.0, 33.9. MS (m/z, %): 217 (M+, 100), 203 (80),
127 (67). Anal. Calcd for C16H11N: C, 88.45; H, 5.10; N, 6.45; Found: C, 88.38; H, 5.21;
N, 6.41.
FUNDING
We gratefully acknowledge financial support of this work by the National Natural
Science Foundation of China (No. 21302047 and No. 21401053), the Natural Science
Foundation of Hubei Province, China (No. 2013CFC030), the key (cultivation) discipline
construction project achievements of Hubei University of Arts and Science
(2015ChemEng01) and the scientific and technological development project of
Xiangyang, Hubei Province of China.
SUPPLEMENTAL MATERIAL
6

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 quinolines 2 form 2-azidobenzaldehyde 1 and carbonyl compound.
Entry Carbonyl
Product
Heating
condition
120
Yield
(%)a
88
compound
1
min
min
min
min
min
min
min
min
min
2a
2b
2c
2d
2e
2f
66 °C
120
2
3
4
5
6
7
8
9b
90
92
89
92
88
90
90
85
66 °C
100
66 °C
120
66 °C
120
66 °C
120
66 °C
120
2g
2h
2i
66 °C
90
66 °C
90
66 °C
10b
90
min
88
2j
66 °C
12

11
12
13
14
15
16
30
min
min
min
min
min
min
82
88
80
82
80
85
2k
2l
66 °C
60
66 °C
60
2m
2n
2o
2p
66 °C
60
66 °C
30
66 °C
30
66 °C
aIsolated yields based on 2-azidobenzaldehyde 1.
b1,2,4-triazol carbonyl compound were prepared according to the known methods.
13

Scheme 1. Synthesis of quinolines form carbonyl compound and 2-azidobenzaldehyde 1.
14

Scheme 2. Reactions of 2-azidobenzaldehyde 1 with 1,3-dicarbonyl compounds.
15

Scheme 3. Reactions of 2-azidobenzaldehyde 1 with 2,3-dicarbonyl compounds.
16