A novel enzymatic synthesis of quinoline derivatives

Article abstract of DOI:10.1007/s10562-012-0774-8

A new mild enzymatic methodology for synthesizing quinoline derivatives by Friedlaender condensation was developed. A series of quinoline derivatives were synthesized and characterized by ¹H NMR, ¹³C-NMR, IR and MS. The probable enzymatic mechanism was proposed. It provides a novel method to prepare quinoline derivatives.

Full text of DOI:10.1007/s10562-012-0774-8

Catal Lett (2012) 142:573–577
DOI 10.1007/s10562-012-0774-8
A Novel Enzymatic Synthesis of Quinoline Derivatives
Hui Zheng
Qiao Yue Shi
•
Juan Liu
•
•
Yi Jia Mei
•
Peng Fei Zhang
Received: 1 December 2011 / Accepted: 20 January 2012 / Published online: 1 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A new mild enzymatic methodology for syn-
thesizing quinoline derivatives by Friedl a¨ nder condensa-
tion was developed. A series of quinoline derivatives were
nitrogen-containing heterocycles, which display a broad
range of biological activities such as antibacterial, anti-
malaria, anti-asthmatic, antitumor, antiplatelet, etc. [5–8]
Traditional synthetic routes usually have poor yields, long
reaction times, and harsh conditions. Therefore, new
methods for constructing quinoline derivatives are con-
stantly sought [9–17].
1
13
synthesized and characterized by H NMR, C-NMR, IR
and MS. The probable enzymatic mechanism was pro-
posed. It provides a novel method to prepare quinoline
derivatives.
Owing to high efficiency and mild conditions, enzy-
matic synthesis has attracted much attention in organic
chemistry [18–20]. As part of our continued interest in
enzymatic synthesis and exploring new synthetic approa-
ches to quinoline derivatives [21, 22], we herein report a
novel, mild, and efficient preparation of quinoline deriva-
tives using catalytic enzymes as shown in Scheme 1.
Keywords Enzymatic catalysis Á Heterocycles Á
Cyclization Á Condensation
1
Introduction
Nitrogen-containing heterocycles have attracted much
attention in the organic and medicinal chemistry fields for
their diverse biological properties and pharmacophores
2 Experimental
[
1–4]. Quinoline derivatives are a very important class of
Commercial reagents were used without further purifica-
tion. Reactions were performed in an end-over-end rotator.
TLC: Merck precoated TLC (silica gel 60 F 254) plates.
The melting-point was determined using a XT-4 melting-
point apparatus and were uncorrected. IR spectra were
recorded on a Bruker Equinox-55 spectrophotometer using
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-012-0774-8) contains supplementary
material, which is available to authorized users.
H. Zheng (&) Á J. Liu Á Y. J. Mei Á Q. Y. Shi Á P. F. Zhang
College of Material, Chemistry and Chemical Engineering,
Hangzhou Normal University, Hangzhou 310036,
People’s Republic of China
-1
1
13
KBr discs in the 4,000–400 cm region. H- and C-NMR
spectra: Bruker Advance 400 spectrometer in CDCl using
3
e-mail: huizheng@hznu.edu
TMS as internal standard. GC/MS: Agilent 5975C. All
enzymes were purchased from Acros, Alfa, Aldrich and TCI,
and used directly.
J. Liu
e-mail: tomlewissuper@yahoo.com
General procedure for the synthesis of Quinoline
derivatives 3: a mixture of 2-amino-3,5-dibromobenzalde-
hyde (1, 0.1 mmol), cyclopentanone or cyclohexanone (2,
0.2 mmol) and enzyme (15 mg) was introduced to a test
tube (10 mL), then the mixture was subjected to a shaker
under 150 rpm end-over-end rotation at 30 or 40 °C for the
Y. J. Mei
e-mail: 43465674@qq.com
Q. Y. Shi
e-mail: liumin86@tom.com
P. F. Zhang
e-mail: 1304112697@qq.com
123

5
74
H. Zheng et al.
Table 2 Friedl a¨ nder quinoline synthesis catalyzed by lipase from
porcine pancreas in various solvents
a
Time Conversion Product
Entry Solvent
(
h)
(%)
1
Dimethyl sulfoxide
DMSO)
Ethanol
24
100
Br
Scheme 1 Enzyme-catalyzed Friedl a¨ nder reaction of 2-amino-3,5-
dibromo-benzaldehyde and cyclopentanone
(
N
2
3
24
74.36
82.16
Br
Dimethyl formamide 24
DMF)
specified time (see Table 3). After completion of the
reaction as monitored by TLC, the reaction mixture was
treated with water (5 mL) and ethyl acetate (5 mL). Then
the mixture was stirred for 5 min, the residue was then
filtered off, the organic phase was dried over anhydrous
(
4
5
6
Acetone
24
24
24
6.44
3.39
3.03
Acetonitrile
Tetrahydrofuran
(
THF)
MgSO , and evaporation of the solvent was followed by
4
7
8
9
1
1
Ethyl acetate
Dioxane
24
24
24
24
24
2.67
1.59
0.41
8.85
2.25
purification on silica gel to afford compounds 3.
Toluene
0
1
Dichloromethane
Cyclohexane
3
Results and Discussions
Reaction conditions: 15 mg lipase from porcine pancreas, 0.1 mmol
We initially chose 2-amino-3,5-dibromo-benzaldehyde and
cyclopentanone in ethanol as a model reaction. The
2
1
a
-amino-3,5-dibromo-benzaldehyde, 0.2 mmol cyclopentanone,
mL solvent, 30 °C, 150 rpm end-over-end rotation for 24 h
Conversion based on GC/MS
Table 1 Friedl a¨ nder reaction between 2-amino-3,5-dibromo-benzal-
dehyde and cyclopentanone in the presence of different catalysts
reaction was performed at room temperature (Scheme 1).
In order to select the appropriate enzyme, several types of
enzymes were screened (Table 1).
a
Entry Catalyst
Time Conversion
(
h)
(%)
As illustrated in Table 1, the result with the highest
conversion was achieved by using Lipase from porcine
pancreas (PPL) as catalyst in 24 h (Table 1, entry 1).
Pepsin from hog stomach and Albumin from bovine also
showed moderate to low catalytic ability (Table 1, entry 2
and 3), and other tested enzymes exhibited very low
activities for this conversion.
1
2
3
4
5
6
7
8
9
1
1
Lipase from porcine pancreas (PPL)
24
24
24
24
100.0
46.3
14.2
9.0
Pepsin from hog stomach
Albumin from bovine
Trypsin from porcine pancreas
Amino lipase A from aspergilllus niger 24
Amino lipase M from mucor javanicus 24
8.4
8.0
Amylase
24
24
24
24
24
7.5
a-Amylase from Bacillus subtilis
Cellulase
Trace
Trace
Trace
Trace
0
1
b-Amylase from soybean Ao448
Amino lipase from Pseudomonas
fluorescens
1
1
1
2
3
4
Lipase AY30
24
24
24
Trace
Trace
Trace
a-Amylase from Aspergillus oryzae
Lipase a cyrlic resin from Candida
antarctica
1
5
6
Lipase from porcine pancreas
b
24
48
Trace
0
(
inactivated)
1
No enzyme
Reaction conditions: 15 mg enzyme, 0.1 mmol 2-amino-3,5-dibromo-
benzaldehyde 0.2 mmol cyclopentanone, 1 mL ethanol, 30 °C,
1
50 rpm end-over-end rotation for 24 h. Reaction progress was
monitored by TLC (petroleum ether/dichloromethane, 1:1) and GC/
MS
Fig. 1 Effect of PPL loading on the yield of the reaction. Conditions:
1
benzaldehyde, 0.2 mmol cyclopentanone, 1 mL solvent, 30 °C,
150 rpm end-over-end
a
Conversion based on GC/MS
5 mg lipase from porcine pancreas, 0.1 mmol 2-amino-3,5-dibromo-
b
Lipase from porcine pancreas devitalized with urea at 100 °C for
0 h [23]
1
1
23

A Novel Enzymatic Synthesis
575
Table 3 PPL catalyzed synthesis of Friedl a¨ nder quinolines
a
Entry
1
Substrate 2
Quinoline 3
3a
Reaction time (h)
20
Yield (%)
95
Product
Br
O
N
N
Br
2
3
O
O
3b
3c
30
30
70
68
Br
Br
Br
Br
N
4
5
O
3d
3e
30
30
60
73
Br
N
Br
O
OH
N
CH
3
Br
Br
Br
6
7
8
9
O
O
3f
30
14
14
Trace
92
O
N
Br
O
O
3g
3h
O
Br
O
O
N
Br
O
O
90
O
Br
N
Br
b
O
3i
40
40
ND
–
–
Cl
1
0
1
O
Cl
3g
ND
ND
1
3k
40
–
O
Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), 15 mg lipase from porcine pancreas, 1 mL DMSO, reactions conducted at 30 °C unless where
noted, 150 rpm end-over-end rotation for certain time
a
Isolated yield
b
No product is detected
We also performed blank control and inactivated
enzyme experiments to demonstrate that this catalytic
ability comes from the enzyme and not some amino acid
impurities. None or a trace of quinoline product were
detected (Table 1, entry 15 and 16).
conversion. Ethanol and dimethyl formamide also pro-
moted this reaction (Table 2, entry 2 and 3). It seems likely
that polar solvents are beneficial to the reaction. Based on
the solvents screened, we chose dimethyl sulfoxide as the
optimum solvent.
The reaction solvent is one of the most important factors
influencing the reaction process. Consequently, some of the
common solvents were screened (Table 2). The results
demonstrated that dimethyl sulfoxide was best with high
We optimized the amount of PPL on this reaction. As
shown in Fig. 1, the conversion was 48.62 and 100% with
5 and 15 mg enzyme, respectively. However, amounts of
PPL greater than 15 mg, did not increase the conversion to
123

5
76
H. Zheng et al.
Scheme 2 Proposed
mechanism of enzymatic
Friedl a¨ nder condensation
product. Consequently, we selected 15 mg PPL as the
optimum amount for this reaction.
Sci-tech Innovation Team of Zhejiang Province (No. 2010R50017)
for providing financial support.
We further examined the influence of reaction temper-
ature. We carried out experiments under 25, 30, and 40°°C.
Conversion was complete after 30 h at 25 °C and 20 h at
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