Synthesis and antimicrobial properties of new derivatives of morpholine and piperidine based on 1-Chloro-3-methoxy-propylbenzene

Article abstract of DOI:10.14233/ajchem.2018.20876

The compounds 1-(3-methoxy-1-phenyl-propyl)morpholine and 1-(3-methoxy-1-phenyl-propyl)piperidine have been synthesized using (3-methoxy-propenyl)benzene and 1-chloro-3-methoxy-propylbenzene. The structures of the synthesized compounds were analyzed by NM

Full text of DOI:10.14233/ajchem.2018.20876

Asian Journal of Chemistry; Vol. 30, No. 2 (2018), 269-272
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2018.20876
Synthesis and Antimicrobial Properties of New Derivatives of Morpholine and
Piperidine Based on 1-Chloro-3-methoxy-propylbenzene
1
,*
1
1
2
G.SH. DURUSKARI , M.N. MAHARRAMOV , U.SH. HASANOVA , KH.G. GANBAROV ,
1
2
1
G.M. EYVAZOVA , A.A. ISRAYILOVA and A.M. MAHARRAMOV
1
2
Department of Organic Chemistry, Baku State University, Z. Khalilov Str. 23, Baku, Azerbaijan
Department of Microbiology, Baku State University, Z. Khalilov Str. 23, Baku, Azerbaijan
*
Corresponding author: Tel: +994 503459245; E-mail: gduruskari@mail.ru
Received: 19 June 2017; Accepted: 14 September 2017;
Published online: 31 December 2017;
AJC-18690
The compounds 1-(3-methoxy-1-phenyl-propyl)morpholine and 1-(3-methoxy-1-phenyl-propyl)piperidine have been synthesized using
3-methoxy-propenyl)benzene and 1-chloro-3-methoxy-propylbenzene. The structures of the synthesized compounds were analyzed by
(
NMR and IR spectroscopic methods. Biological activities of obtained products were investigated against Gram-negative and Gram-
positive microorganisms. It has been showed that all the synthesized compounds possess pronounced antimicrobial activity against
pathogenic bacteria Acinetobacter baumannii BDU32, Escherichia coli BDU12, Klebsiella pneumoniae BDU44, Pseudomonas aeruginosa
BDU49 and Staphylococcus aureus BDU23.
Keywords: Ethylbenzene, Ether, Morpholine, Piperidine, Antibacterial activity, Pathogenic bacteria.
The design of molecules with antimicrobial properties by
INTRODUCTION
means of introduction of amino moiety and methoxy group in
the molecule can lead to the purposeful tuning of their chemical
Arene derivatives containing functionally substituted
amine fragment in side chain shows the high biological activity.
These compounds reveal activity as antiectoparasitic [1], in
inactivation of cytochrome P-450 [2-4], pesticide [5], anti-HIV
properties and hence the biological activity as well. Beside
this, aromatic ring is a constituent part of most naturally occurring
biologically active compounds and artificially synthesized
drugs. The paper reports the synthesis and antimicrobial pro-
perties of functionalized substituted amine compounds viz.,
new derivatives of morpholine and piperidine based on 1-chloro-
[
6], inhibitor of potassium channels [7], having antidepressant
activity [8] ligands of calsium receptors [9,10], antihepatit C
agent [11], anticancer [12], antihypertensive [13] compounds
and at cure of coronary disease [14]. Beside these, this compounds
demonstrate high potency for design of new drugs having anti-
microbial properties [15-18].
3
-methoxy-propylbenzene.
EXPERIMENTAL
H, C NMR spectra have been taken on the spectrometer
The searching of new antimicrobial agents still remains
an important and challenging problem due to rise of mortality
and morbidity that caused by different pathogenic bacteria.
In addition, the increasing number of multi-drug resistant
microbial strain is considered to be one of the major problems
in the world nowadays [19]. It is known that 70 % of bacterial
infections are resistant to one or more of the antibiotics that
generally used to eradicate the infection. Bacteria are able to
reduce or eliminate the effectiveness of drugs by different
mechanisms such as mutation of their genome, destruction or
inactivation and efflux pump system. Therefore, development
and synthesis of new effective antimicrobial agents for the
treatment of resistant bacterial diseases is an urgent task
1
13
Brucker-300 (300 MGz) of system AVANCE, for measure of
refract constant used IRF454BM. FTIR spectra were recorded
on a Varian 3600 FTIR spectrophotometer. The spectrum was
-1
taken in the range of 4000-400 cm at room temperature. The
ethylbenzene, morpholine, piperidine reagents were purchased
from Sigma Aldrich 99 %, ethanol 95 %, ZnCl
PEAXIME.
2
98 % from
Synthesis of 1-(chloro-3-methoxy-propenyl)benzene:
Chlorodimethyl ether (8 g, 0.1 mol) dissolved in 25 g (0.3 mol)
of hexane and then 14 g (0.1 mol) of α-chloro-ethyl-benzene
added drop-wise to solution. 1 g of ZnCl
2
used as catalyst of
[
20,21].
reaction. The reaction mixture was stirred for 4 h at 60 °C. At

270 Duruskari et al.
Asian J. Chem.
the end of reaction the colour of reaction mixture turned black.
The hexane was distilled off and residue was dissolved in
benzene. Obtained mixture washed with water till neutral
reaction several times, then benzene was distilled in vacuo.
Pseudomonas aeruginosa BDU49, Gram-positive bacterium
Staphylococcus aureus BDU23 using agar well diffusion
method [22,23]. The cultures of microorganisms were grown
in autoclaved Muller-Hinton media and 0.5 McFarland
20
20
8
Yield 75 %; m.p.: 72 °C\1 mm n
D
15160 d
, δ, m.d) 2.3 (M, 2H, CH
), 3.42 (M, 2H, CH O), 5.21 (m, 1H, 7.33 (m, 5H,
, δ, m.d) 39.5 (C, CH Cl), 58.5
), 60.9 (C, CH), 69.2 (C, CH O), 127.4 (2C, CHarom
28.7 (C, CHarom.), 129.0 (2C, CHarom). IR (cm ): 3064-2927
C-H Ar), 1600-1454 (C-C Ar), 1120-705 (C-H(d) Ar), 760,
4
10807 DMSO
bacterial culture (1.5 × 10 cfu/mL) were swabbed on the agar
1
H NMR (DMSO-d
H, OCH
6
2
Cl), 3.25 (C,
plate. The 8 mm wells were made in the center of the plate
with a sterile cork borer. Each wells filled with the two different
concentrations (0.1 %, 0.05 %) of compounds, which were
solved in the ethanol and solvent is used as a control during
investigation. The antimicrobial activities were determined by
measuring the diameter of the complete inhibition (mm) zones
of compounds after incubation of plates at 37 °C for 24 h. The
standard error for the experiment was ± 0.001 cm and the
antibacterial investigation was repeated three times under same
condition.
3
3
2
13
arom.). C NMR (DMSO-d
C, OCH
6
2
(
3
2
,
-1
1
(
6
98 (C-Cl), 2828 (OCH ). Anal. Calc. for C10H13ClO, % C 65,
3
0
41, H 7, 096, Cl 19, 198. Found: C 65.01, H 6.998, Cl 19.09.
Synthesis of 1-(3-methoxy-1-phenyl-propyl)morpholines
(
I): 1-(Chloro-3-methoxy-propenyl)benzene (6 g, 0.03 mol)
was added drop-wise to 30 g (0.3 mol) morpholine and reaction
mixture was stirred for 4 h at 100 °C. C OH and KOH was
RESULTS AND DISCUSSION
H
2 5
added to reaction mixture and then extracted with benzene
and washed with water until neutral media. Organic layer was
For the purposeful synthesis of benzene derivative, that
contain methoxy group and amine fragment in side chain we
carried out the reaction of halogen ethers of aromatic compounds
with morpholine and piperidine. Compounds with amine func-
tional group can be obtained by three main ways: alkylation
of amines, hydrogenolysis of amides and reductive amination
of carbonyl compounds. It is known that the presence of methoxy
group in the molecules allow to obtain the biologically active
compounds which being insensitive to esterases are resistant
to the hydrolysis that in turn increase their retention time in
the cell [24].
The synthesis of 1-(3-methoxy-1-phenylpropyl)piperidine
and 1-(3-methoxy-1-phenyl-propyl)morpholine have been
taken from initial 1-(chloro-3-methoxy-propenyl)benzene,
which was obtained by reaction of 1-chloroethylbenzene with
chlorodimethyl ether in the presence of zinc chloride catalyst.
We studied the molar concentration ratio of reagents on the
course of reaction. It was found that carrying out the reaction
at 40-60 ºC and equimolar amount of zinc chloride and chloro-
dimethyl ether leads to obtaining of the product of reaction 1-
separated, washed and distillated. Yield 68.30 %. m.p.: 122
1
°
(
3
7
C DMSO H NMR spectra: (DMSO-d
6
, δ, m.d, ), 1.81-2.22
N), 3.08 (t, 2H, C 3.11 (S,
O), 3, 42 (t, 1H, CHN), 3.53 (t, 4H, 2CH O), 7.19-
.37 (m, 5H, Ar). IR (cm ) 3060-2955 (C-H Ar), 1600-1492
m-m, 2H, CH
2
), 2.28 (d, 4H, 2CH
2
H, CH
3
2
-1
(
(
(
C-C Ar), 1110-705 (C-H(d) Ar), 3500-3450 (NH), 2808
OCH ), 2960-2910 (C-H alif) 1500-1350 (C-H(d) alif), 1452
CH2(d)), 1328, 1186, 567 (morpholine’s ether group). Anal.
(I) % C 71, 455; H 8, 995, N 5, 952. Found:
3
s
Calc. for C14
H21NO
2
C 71.35, H 8.91, N 5.78.
Synthesis of 1-3-methoxy-1-phenylpropyl-piperidine (II)
was carried out by similar protocol. Yield 71.2 %; m.p.: 85
1
°
C, DMSO H NMR spectra (DMSO-d
6
, δ, m.d, ), 1.23 (m,
), 1.85-2.17 (m-m, 2H, CH ),
N), 3.11 (s, 3H, CH O), 3.24 (t, 2H, CH O),
.48 (t, 1H, CHN), 7.15-7.31 (m, 5H, Ar). C NMR spectra
, δ, m.d, ), 24.83, 26.40, 32.00, 50.77, 58.28, 6.38,
2
2
3
H, CH
2
), 1.40 (m, 4H, 2CH
2
2
.26 (t, 4H, 2CH
2
3
2
13
(DMSO-d
6
-1
7
0.07, 127.27, 128.18, 128.83, 139.29. IR (cm ) 3060-2931
(
(
(
C-H Ar), 1451-1600 (C-C Ar), 1118-702 (C-H(d) Ar), 3447
NH), 2852-2803 (OCH ), 1491-1358 (C-H(d) alif), 2752
piperidine band). Anal. Calc. for C15 23NO (II) %: C 7, 205,
(chloro-3-methoxy-propyl)benzene with 90 % yield. The reaction
3
begins by the attack of zinc chloride on chlorodimethyl ether
and then continues as shown in Scheme-I.
H
H 9, 935, N 6, 002 Found: C 7.00, H 9.91, N 5.99.
Synthesis of (3-methoxy-prop-1-en-1-yl)benzene (III):
Synthesis of compound (3-methoxy-prop-1-en-1-yl)benzene,
was carried out by dehydrochlorination of initial compound
H
CH2
CH CH OCH
2
2
3
H C Cl
2
CHCl
CHCl
1
-(chloro-3-methoxy-propyl)benzene. Dehydrochlorination
ZnCl2
HCl
OMe
was carried out at 110 °C for 1.5 h by using potassium diethyl-
-
1
glycolate. H NMR spectra:Yield 78 %; m.p.: 120 °C, DMSO
-ZnCl2
1
H NMR (DMSO-d
6 3
, δ, m.d), 3.27 (S, 3H, CH O), 4.00-4.02(d-
Scheme-I: Attack of zinc chloride on chlorodimethyl ether
d, 2H, CH
2
O), 6.33 (m, 1H, CH), 6.58 (d, 1H, CH), 7.23-7.44
13
(
m, 5H, Ar). C NMR spectra (DMSO-d
6
, δ, m.d), 57.74,
It is known that in benzyl chloride molecule, chlorine atom
7
2.63, 126.74, 126.85, 128.02, 129.04, 131.72, 136.87. IR
undergoes nucleophile replacement, which can be explained
by the stability of formed benzyl carbocation and by small
steric hindrance of chlorine atom. That is why this compound
is most traditional agent in benzylation of organic compound.
Aniline, diethylamine and some other nucleophile reagents
are not able to react with 1-chloroethylbenzene, due to the fact
that reaction centers are shielded in a great extent in opposite
to piperidine, morpholine. So we use piperidine and morpholine
-1
(
(
8
cm ): 3060-2925 (C-HAr), 1450-1600 (C-CAr), 2820-2815
OCH ), 1600-1520 (C C). Anal. Calc. for C10 12O (III) %:C
1, 043, H 8, 161 Found: C 80.98, H 8.06
Determination of antibacterial activity: All the synthe-
3
H
sized compounds were screened for their antibacterial activities
against Acinetobacter baumannii BDU32, Gram-negative
bacteria Eschericha coli BDU12, Klebsiella pneumoniaeBDU44,

Vol. 30, No. 2 (2018)
Synthesis and Antimicrobial Properties of New Derivatives of Morpholine and Piperidine 271
as nucleophiles in the alkylation of preliminarily synthesized
-(chloro-3-methoxy-propenyl)benzene. It was also interesting
to find out the effectiveness of 1-(chloro-3-methoxy-propyl)-
benzene in synthesis of (3-methoxy-prop-1-en-1-yl)benzene
by dehydrochlorination in the presence of sodium ethylate. This
reactions are presented in Scheme-II.
Antibacterial studies of the synthesized compounds:
In vitro antibacterial study was carried out for all new synthe-
sized arene derivatives compounds. It revealed that all chemical
compounds possessed antibacterial activity against tested
Gram-positive and Gram-negative bacteria. All compounds
exhibited potential inhibition activity and the clear zones
around wells inhibited the bacterial growth were determined
as shown in Table-2. The antimicrobial effect of molecules
was different not only depending on the species of bacteria
but also concentration of tested compounds.
1
CH CH OCH
2
2
3
CH CH OCH
2 2 3
CH CH OCH
2
2
3
CH
N
O
CHCl
CH
N
NH
HN
O
Compound 1 [1-(3-methoxy-1-phenyl-propyl)morpholine]
at the concentration of 0.1 % showed better result when tested
with the A. baumannii BDU32 and P. aeruginosa BDU49, while
at the concentration of 0.05 % inhibition zones were similar
for all studied pathogens except K. pneumoniae BDU 44.
The bacterial activity results revealed that compound 2
I
II
RONa
CHCH OCH
2
3
CH
[1-(3-methoxy-1-phenyl-propyl)piperidine] at two concentra-
III
tions, showed potential activity against all tested pathogenic
bacteria except S. aureus BDU23. Compare with other two
chemicals, compound 2 showed high activity against P. aeruginosa
BDU49, while any inhibition was not detected against E. coli
BDU12 when the effect of the compound was tested at concen-
tration of 0.05 %.
The high inhibition zones were detected against E. coli
BDU12 and A. baumannii BDU32 at the concentration of 0.1 %
of compound III (3-methoxy-propenyl)benzene, whereas chemical
exhibited the lowest activity when tested with S. aureus BDU23
and P. aeruginosa BDU49 at the concentration of 0.05 %. From
the results, it is clear that all the new synthesized compounds
have sufficiently activity against all tested Gram-negative bacteria,
only Gram-positive bacterium S. aureusBDU23 are less sensitive.
Scheme-II: Reactions of 1-(chloro-3-methoxy-propenyl)benzene
Physico-chemical data of the synthesized compounds pre-
sented in Table-1. Have been reported about the bioconversion
of tetrahydropyridines with some strains of the mycellar fungi
[
25]. Antimicrobial properties of morpholine and piperidine
derivatives obtained from the substitution reaction of α-chloro-
ethers of propylbenzene are not reported in literature. For
finding out the correlation structure-activity, we introduce the
morpholine and piperidine moieties by substitution of the
chlorine atom in 1-chloro-(3-metoxy-propyl)benzene. The
presence of piperidine and morpholine groups provide effective
antimicrobial properties of synthesized compounds.
TABLE-1
ANTIBACTERIAL RESULTS OF ARENE DERIVATIVES
Antibacterial activity (zone of inhibition in mm)
Conc.
Number
Compound
Acinetobacter
baumannii
Klebsiella
pneumoniae
Pseudomonas
aeruginosa
Staphylococcus
aureus
(
%)
Escherichia coli
CH CH OCH
3
2
2
HC
N
O
0
0
.10
.05
16
10
14
12
10
8
15
11
13
12
I
CH CH OCH
3
2
2
HC
N
0
0
.10
.05
16
14
12
0,0
13
11
20
19
0,0
0,0
II
CHCH OCH
2
3
CH
0
0
.10
.05
16
11
15
13
10
14
12
7
9
8
III
IV
Control ethanol
5
4
4
4
4
(
95 %)

272 Duruskari et al.
Asian J. Chem.
TABLE-2
PHYSICAL-CHEMICAL DATA OF SYNTHESIZED COMPOUNDS
20
20
Compound
m.p. (°C/1 mm)
d4
n4
MRD
Calculated
CH CH OCH
3
2
2
HC
N
O
1
22
1.0369
0.9869
0.9914
1.5180
1.5350
1.5150
68.68
68.30
46.00
71.20
CH CH OCH
3
2
2
HC
N
8
5
46.60
70.84
CHCH OCH3
2
CH
1
20
1
1
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Conclusion
We reported synthesis of morpholine and piperidine
derivatives of aromatic compounds containing β-methoxy
group in side chain with good yield. The structures of the synthe-
sized compounds were identified by NMR and IR spectroscopy
methods. It was found that introduction of morpholine and
piperidine fragments in the structures of molecules influence
on their antimicrobial activities. All compounds exhibited
potential inhibition activity against Gram-positive and Gram-
negative bacteria.
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