Ultrasound-promoted one-pot five-components synthesis of biologically active novel bis((6-alkyl or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives

Article abstract of DOI:10.1016/j.ultsonch.2014.09.001

We have described a synthesis of novel five-component reaction (5-CR) of bis((6-alkyl or phenyl-2-phe-nylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives under ultrasound irradiation. A useful ultrasound effect was observed and title products we

Full text of DOI:10.1016/j.ultsonch.2014.09.001

Ultrasonics Sonochemistry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Short Communication
Ultrasound-promoted one-pot five-components synthesis of biologically
active novel bis((6-alkyl or phenyl-2-phenylpyrimidine-4-yl) oxy)
alkane or methyl benzene derivatives
⇑
Nosrat Ollah Mahmoodi , Sajede Shoja, Khalil Tabatabaeian, Bahman Sharifzadeh
Department of Organic Chemistry, Faculty of Sciences, University of Guilan, PO Box 41335-1914, Rasht, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2014
Received in revised form 31 August 2014
Accepted 1 September 2014
Available online xxxx
We have described a synthesis of novel five-component reaction (5-CR) of bis((6-alkyl or phenyl-2-phe-
nylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives under ultrasound irradiation. A useful
ultrasound effect was observed and title products were obtained with high yields after 25–40 min son-
ication. Structural confirmation and characterization of the products based on the analytical, chemical,
and spectral analysis. The results show obviously, that to reach a high efficiency of ultrasonic systems
in synthetic chemical processes. Our procedure compared to the conventional heating method has the
benefit of higher reaction yields and shorter reaction times. The in vitro antibacterial tests show that
some of the target compounds have promising activities. Structure–activity relationships (SAR) were
established for the substitutions on the pyrimidine rings and related length of linear chain linker.
Ó 2014 Elsevier B.V. All rights reserved.
Keywords:
Ultrasound
Five-component reaction (5-CR)
Pyrimidine
Antibacterial activity
Structure–activity relationship
1. Introduction
vapor suffers fragmentation to produce reactive particles, such as
carbenes or free radicals. These high-energy particles are concen-
Green chemistry has become a major inspiration for organic
chemists to develop environmentally benign routes for synthesis
of organic compounds of biological values. For instance, perform-
ing reactions under ultrasonic irradiation due to the formation of
high energy intermediates to enhance the reaction efficiency from
both economical and ecological points has significant synthetic
value and received great attention. The waves of ultrasound can
be transmitted through any substance containing elastic property.
The motion of these sounds is transferred to the particles of the
environment, which vibrate in the route of the ultrasound wave.
As the molecules oscillate, the molecular distance decreases in
the compaction cycle and increases during rarefaction. When the
molecular distance exceeds the critical amount necessary to hold
the liquid perfect, the liquid collapse; bubbles and cavities are gen-
erated. This procedure (cavitation), refers to the generation and the
energetic life of bubbles in liquids. The bubbles absorb energy from
the waves of ultrasound and grow. Then bubble collapse conse-
quences in pressure changes and high temperature. The solvent
trated and lead to intermolecular reactions. In general, the yield
of product increases, reactions occur faster, with lower tempera-
tures and minor percentage of by-products achieved [1–6].
Pyrimidine has great biological and medicinal application [7]
including antibacterial [8], antiviral [9], antitumour [10], antihy-
pertensive [11] and several other properties [12–17].
Highly functionalized pyrimidines have been synthesized using
different procedures on the foundation of cross-coupling reactions
between NACAN and CACAC [18], or conventional condensation
reactions [19]. The syntheses of pyrimidine derivatives from ami-
dine group have been previously reported [20–21]. Recently, Hu
et al. developed the base-catalyzed reactions of
a-azidovinyl
ketones with amidines to form functionalized 5-aminopyrimidines
[22]. Laroshenko and co-workers have described the regioselective
cyclizations of benzamidine with CF2Cl-substituted 1,3-dicarbonyl
compounds to give the 4-(chlorodifluoromethyl)-2-phenylpyrimi-
dines [23]. Jiang et al. have reported the synthesis of polysubstitut-
ed thiopyrano or pyranopyrimidine compounds through
multi-component reactions (MCRs) of aromatic aldehydes, tetrahy-
drothiopyran-4-one(tetrahydropyran-4-one), and aryl amidines
using t-BuOK as a base under microwave heating [24].
⇑
Corresponding author. Tel.: +98 1313233262.
E-mail addresses: mahmoodi@guilan.ac.ir (N.O. Mahmoodi), sajede.shojae@
yahoo.com (S. Shoja), taba@guilan.ac.ir (K. Tabatabaeian), shimibahman@yahoo.
com (B. Sharifzadeh).
The main disadvantages of most of these procedures are multi-
step reactions and long reaction times, boring workups, harsh
http://dx.doi.org/10.1016/j.ultsonch.2014.09.001
1350-4177/Ó 2014 Elsevier B.V. All rights reserved.
Please cite this article in press as: N.O. Mahmoodi et al., Ultrasound-promoted one-pot five-components synthesis of biologically active novel bis((6-alkyl
or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives, Ultrason. Sonochem. (2014), http://dx.doi.org/10.1016/
j.ultsonch.2014.09.001

2
N.O. Mahmoodi et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
reaction conditions, low reaction yields, and poor regioselectivity.
Therefore, development of a reliable and efficient method is still
required.
phases were dried out over Na2SO4, filtered, and concentrated in
vacuum to afford the title compound as near colorless oil that
maybe slowly solidified upon standing. The products were estab-
lished by their 1H NMR, 13C NMR, FT-IR and elemental analysis
data.
In assembling valuable chemical products, MCRs have several
advantages over traditional approaches, e.g. linear, iterative or
divergent synthesis. MCRs proceed easily to provide synthetic
products in good to excellent yields. Assuming the same yields
per step, the total yield of the convergent synthesis is considerable
higher than the corresponding linear synthesis. Reports about the
five-component coupling reaction in synthesis of functionalized
organic products are very rare [25]. Here, in contribution to our
previous work [26], a simple and efficient ultrasound-promoted
five-component synthesis of 1a-l with alkyl and benzyl linkages
at r. t. are describe.
Typical characteristic data for compound 1j, 1k and 1l are given
below:
2.2.1. 1,4-bis(((6-methyl-2-phenylpyrimidine-4-yl)oxy)methyl)
benzene (1j)
Pale yellow oil. yield 78%. IR (m
max/cmꢀ1): 1651 (C@N), 1252
(C-O). 1H NMR (400 MHz, CDCl3) (d/ppm): 8.15 (4H, d, J = 8.4 Hz,
ArAH), 7.60–7.70 (6H, m, ArAH), 7.17 (4H, s, benzylic-H), 6.19
(2H, s, H5 of pyrimidine), 4.86 (4H, s, AOCH2A), 2.46 (6H, s,
ACH3). 13C NMR (100 MHz, CDCl3) (d/ppm): 170.6 (C4 of pyrimi-
dine), 166.4 (C6 of pyrimidine), 162.1 (C2 of pyrimidine), 130.3–
136.0 (ArAC), 100.2 (C5 of pyrimidine), 47.5 (AOCH2A), 29.6
(ACH3). Molecular Weight: 474.56. Anal. Calcd. for C30H26N4O2:
C, 75.93; H, 5.52; N, 11.81%. Found C, 75.91; H, 5.50; N, 11.77%.
2. Experimental
2.1. Material and methods
Chemical materials were purchased from Merck, Aldrich, and
Fluka. FT-IR spectra were determined on a Shimadzu IR-470 spec-
trometer. Ultrasound device Astra 3D (9.5 L, 45 kHz frequency,
input power with heating, 305 W, number of transducers, 2) from
TECNO-GAZ was used. All 1H NMR and 13C NMR data were
recorded in CDCl3 using a Bruker Avance 400 and 100-MHz spec-
trometer. Chemical shifts are reported in ppm (d) using deuterated
solvents as internal references. Elemental analysis were made by a
Carlo – Erba EA1110 CNNO-S analyzer and agreed with the calcu-
lated values.
2.2.2. 1,4-bis(((2-phenyl-6-propylpyrimidine-4-yl)oxy)methyl)
benzene (1k)
Pale cream oil. yield 76%. IR (m
max/cmꢀ1). 1657 (C@N), 1252
(C-O). 1H NMR (400 MHz, CDCl3) (d/ppm): 8.14 (4H, d, J = 10.0 Hz,
ArAH), 7.73–7.87 (6H, m, ArAH), 7.00 (4H, s, benzylic-H), 6.09
(2H, s, H5 of pyrimidine), 5.24 (4H, s, AOCH2A), 2.73 (4H, t,
J = 15.8 Hz, ACH2A), 1.63–1.82 (4H, m, ACH2A), 0.95 (6H, t,
J = 15.2 Hz, ACH3). 13C NMR (100 MHz, CDCl3) (d/ppm): 172.47
(C4 of pyrimidine), 172.3 (C6 of pyrimidine), 164.5 (C2 of pyrimi-
dine), 127.4–136.3 (ArAC), 107.4 (C5 of pyrimidine), 57.8 (AOCH2-
A), 43.7 (ACH2A), 26.0 (ACH2A), 22.6 (ACH3). Molecular Weight:
530.67. Anal. Calcd. for C34H34N4O2: C, 76.95; H, 6.46; N, 10.56%.
Found C, 76.93; H, 6.51; N, 10.53%.
2.2. General procedure for the synthesis of 1,n-bis((6-alkyl or phenyl-
2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives
(1a-l)
Benzamidine hydrochloride (1, 31.7 mg, 0.203 mmol), b-ketoes-
ter derivatives (2, 0.184 mmol) and powdered K2CO3 (63.7 mg,
0.461 mmol), were dissolved in DMF (1.5 mL), followed by
dihaloalkane (3, 0.23 mmol) in a 25 mL conical flask. Then the mix-
ture was irradiated in the water bath of an ultrasonic cleaner at r. t.
for the duration as shown in Table 2; and reaction progress was
monitored by TLC. Upon end of the reaction, the reaction mixture
was diluted with EtOAc (10 mL), and washed with sat. aq NaHCO3
(10 mL) and brine (10 mL). The combined aqueous phases were
back-extracted with EtOAc (5 mL), and the combined organic
2.2.3. 1,4-bis(((2,6-diphenylpyrimidine-4-yl)oxy)methyl)benzene (1l)
Pale cream oil. yield 74%. IR (m
max/cmꢀ1): 1621 (C@N), 1253
(CAO). 1H NMR (400 MHz, CDCl3) (d/ppm): 8.27 (4H, d, J = 8.8 Hz,
ArAH), 7.84 (4H, d, J = 7.2 Hz, ArAH), 7.54–7.65 (8H, m, ArAH),
7.39–7.45 (6H, m, ArAH and H5 of pyrimidine), 7.12 (4H, s, ben-
zylic-H), 5.49 (4H, s, AOCH2A). 13C NMR (100 MHz, CDCl3)
(d/ppm): 173.9 (C4 of pyrimidine), 172.1 (C6 of pyrimidine),
164.1 (C2 of pyrimidine), 127.1–138.4 (ArAC), 104.6 (C5 of pyrim-
idine), 45.9 (AOCH2A). Molecular Weight: 598.71. Anal. Calcd. for
Table 1
Effect of solvent on the reaction of benzamidine hydrochloride 2 with ethyl acetoacetate 3a and 1,5-dibromopentane 4b.a
NH
Ph
N
O
O
N
O
O
Ph
. HCl
NH2
4b
Br
Br
(CH2)5
2
2
Ph
N
+
OEt
N
K2CO3, Solvent
Ultrasound, rt.
2
3a
1d
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
Water
EtOH
MeOH
THF
Toluene
DMF
2
1
1
1.5
1.5
0.5
<5
67c
59c
<20
<15
95
a
All reactions were carried out by using 2 (0.203 mmol), 3a (0.184 mmol), 4b (0.230 mmol), and powdered K2CO3 (0.461 mmol) under ultrasound
condition at 25 °C.
b
Isolated yield.
c
Trace conversion to bis-pyrimidine product; reaction stalls at the pyrimidinone intermediate and the reported yields refer to pyrimidinones.
Please cite this article in press as: N.O. Mahmoodi et al., Ultrasound-promoted one-pot five-components synthesis of biologically active novel bis((6-alkyl
or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives, Ultrason. Sonochem. (2014), http://dx.doi.org/10.1016/
j.ultsonch.2014.09.001

N.O. Mahmoodi et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
3
Table 2
Scope of the synthesis of bis-pyrimidine derivatives.a
R2
O
N
O
N
OEt
R1
O
NH
Ph
N
Ultrasound
N
R2
2
2
+
+
X
. HCl
X
NH2
O
R1
R1
K2CO3, DMF, rt.
Ph
Ph
1 a-l
2
3
4
Entry
1
Product
Time (min)
Ultrasoundc
30
Yieldb (%)
Conventionald
210
Ultrasoundc
Conventionald
88
94
Ph
N
O
O
O
N
Ph
(CH2)4
N
N
N
1a
2
30
210
88
89
Ph
N
N
O
N
N
Ph
(CH2)4
N
1b
3
4
5
35
25
25
240
180
210
83
92
85
71
85
76
Ph
Ph
Ph
O
O
O
O
Ph
Ph
(CH2)4
N
N
N
N
Ph
N
Ph
N
1c
O
(CH2)5
N
1d
N
N
O
N
Ph
(CH2)5
N
1e
6
7
8
30
30
30
240
180
180
80
93
89
69
89
81
Ph
Ph
Ph
O
O
O
O
N
Ph
(CH2)5
N
N
N
N
N
Ph
N
Ph
N
1f
O
Ph
Ph
(CH2)6
1g
N
O
N
(CH2)6
N
1h
9
35
240
79
74
Ph
N
O
O
N
Ph
(CH2)6
N
N
Ph
Ph
1i
(continued on next page)
Please cite this article in press as: N.O. Mahmoodi et al., Ultrasound-promoted one-pot five-components synthesis of biologically active novel bis((6-alkyl
or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives, Ultrason. Sonochem. (2014), http://dx.doi.org/10.1016/
j.ultsonch.2014.09.001

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N.O. Mahmoodi et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
Table 2 (continued)
Entry
Product
Time (min)
Yieldb (%)
Ultrasoundc
78
Ultrasoundc
Conventionald
Not reported
Conventionald
Not reported
10
40
Ph
Ph
N
N
N
N
N
O
O
O
O
1j
11
35
40
Not reported
76
74
Not reported
Ph
N
Ph
N
N
N
1k
12
Not reported
Not reported
Ph
N
Ph
N
N
O
O
Ph
Ph
1l
a
All the reactions were carried out with 1 (0.203 mmol), 2 (0.184 mmol), 3 (0.230 mmol), and powdered K2CO3 (0.461 mmol) in DMF (1.5 mL).
Isolated yield.
Ultrasonication at 25 °C.
Reflux at 70 °C [25].
b
c
d
OEt
R1
EtO
R1
O
O
O
O
H2N
HCl.
Ph
NH
Ph
R2
+
+
+
+
. HCl
X
X
NH
NH2
4
Ultrasound
2
3
5-CR
K2CO3, DMF, rt.
R2
X = Br and Cl
4
3
R1
R2
a
b
c
O
N
O
N
Me
Pr
a
b
c
N
R1
R1
Ph
N
Ph
Ph
d
1 a-l
i
j
k
l
1
e
f
g
h
a
b
c
d
3a, 4a 3b, 4a 3c, 4a 3a, 4b 3b, 4b 3c, 4b 3a, 4c 3b, 4c 3c, 4c 3a, 4d 3b, 4d 3c, 4d
3 and 4
Scheme 1. Synthesis of bis-pyrimidine derivatives via 5-CR.
C40H30N4O2: C, 80.25; H, 5.05; N, 9.36%. Found C, 80.24; H, 5.04; N,
9.34%.
Despite of the good solubility of material in H2O, no obvious
progress in this solvent was observed. The pyrimidinone interme-
diate simply were prepared in EtOH and MeOH. Conversely, using
toluene and THF as a solvent almost trace of product was obtained.
The polar aprotic solvents, particularly N,N-dimethylformamide
(DMF) are good solvent for salts and because of selective cation sol-
vation, anions usually show increased nucleophilicity in these sol-
vents [36], the ultrasound waves generally increased the rate of
reaction. The results of this effort are summarized in Table 1.
Pleasantly, DMF enhancing reactivity of nucleophilic anions of 7
prepared in situ from 6 in the presence of K2CO3 as base, and affor-
ded high conversion of these anions to 5-CR targets 1a-l, following
a schematic representation as shown in Scheme 2.
3. Results and discussion
3.1. Chemistry
Based on the our previous works about synthesis of bis-com-
pounds [27–35], five-component synthesis of novel bis-pyrimi-
dines 1a-l, containing alkyl and benzyl linkages here is reported,
following a procedure as shown in Scheme 1.
Initially, we choose to examine the coupling reaction of ben-
zamidine hydrochloride 2 with ethyl acetoacetate (EAA) 3a in the
presence of 1,5-dibromopentane 4b, and K2CO3 as base in various
solvents under ultrasound condition.
Intermolecular condensation of b-ketoesters 3 with benzami-
dine hydrochloride 2 gave intermediates 5 and 6, in the presence
Please cite this article in press as: N.O. Mahmoodi et al., Ultrasound-promoted one-pot five-components synthesis of biologically active novel bis((6-alkyl
or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives, Ultrason. Sonochem. (2014), http://dx.doi.org/10.1016/
j.ultsonch.2014.09.001

N.O. Mahmoodi et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
5
2-CR
2-CR salt
2-CR salt
2-CR
2
3
2
3
7
4
7
5 & 6
5 & 6
5-CR
1
Scheme 2. Schematic representation of a highly convergent 5-CR to target 1.
X-R2-X
K2CO3
DMF
1 a-l
N
NH
N
N
N
N
R1
R1
O
OH
R1
OK
5
6
7
Scheme 3. Proposed intermediates for salt 7.
Table 3
Antimicrobial activity of the selected compounds.
Entry
Compound
Conc. of compound in
Antimicrobial activity (zone of inhibition in mm)
DMSO lg/0.1 mL
Gram-negative
Gram-positive
E. coli
S. enterica
B. subtilis
M. luteus
1
2
3
4
5
6
7
8
1d
1h
1j
1k
12
12
12
12
12
15
30
–
–
16
–
12
14
9
9
22
–
17
9
12
14
–
15
16
16
14
–
10
16
–
8
10
–
1l
7
Erythromycin
Tetracycline
DMSO
16
12
–
8
7
–
of base further reaction between salts 7 via appropriate dihalides 4
in one-pot affords target 5-CR of 1 (Scheme 3). However, it seems
that the rate-limiting step of this reaction is the transfer of
electrons from the potassium to the intermediates 5 and 6 in
solution. Various types of electron transfer under ultrasound con-
ditions are investigated previously [37–38], some of them demon-
strated the addition of electron-transfer agent to sonochemical
reactions lead to increasing in the rate and other aspects of the
reactions [39].
ring and/or influence of the variation of the length of the alkyl
chain. Talk about role of benzyl linkages in new compounds 1j-l
is a bit complicated; so that 1j and 1k exhibited strong activities
against S. enterica and 1k showed strong activity against B. subtilis.
Overall, Gram positive bacteria are more sensitive to Gram neg-
ative ones, mainly due to the two factors: presence of two mem-
branes and a lipopolysaccharide layer in Gram negatives; both of
which are lacking in Gram positives. As can be seen, B. subtilis
and M. luteus were generally more sensitive than the two Gram
negative isolates. Although S. aureus is a Gram positive bacterium,
it was also the most resistant isolate. This is due to the fact that this
bacterium carries many resistance genes, conferring such proper-
ties as enzymatic degradation or expulsion of toxic chemicals or
the capability to utilize metabolic pathways insensitive to antibac-
terial agents. In general, it can be said that the alkyl linkage with
higher ‘‘n’’, which leads to longer distances between the phenyl
groups, yield better results, probably due to less steric hindrance.
However, the effect of the other substituents on pyrimidine ring
should not be ignored.
All of the compounds described in Table 2 were characterized
by FT-IR, 1H NMR, 13C NMR and elemental analysis.
3.2. Structure–activity Relationships
The in vitro antibacterial activities of compounds were evalu-
ated against Gram-positive and Gram-negative bacteria. The
results of selected compounds are reported in Table 3.
As is shown, most of the compounds exhibited strong activities
towards Micrococcus luteus, Bacillus subtilis (Gram-positive bacte-
ria) and Salmonella enterica (a Gram-negative bacterium). The var-
iation in activity, so far as the compounds are concerned, are due to
the influence of the modification of the substituents on pyrimidine
On other hand, compounds of smaller size, being more soluble
in the phospholipid layer, can lead to greater penetration, and thus
a more favorable effect is observed.
Please cite this article in press as: N.O. Mahmoodi et al., Ultrasound-promoted one-pot five-components synthesis of biologically active novel bis((6-alkyl
or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives, Ultrason. Sonochem. (2014), http://dx.doi.org/10.1016/
j.ultsonch.2014.09.001

6
N.O. Mahmoodi et al. / Ultrasonics Sonochemistry xxx (2014) xxx–xxx
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Acknowledgements
The authors are grateful to the Research Council of University of
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Appendix A. Supplementary data
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a
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Please cite this article in press as: N.O. Mahmoodi et al., Ultrasound-promoted one-pot five-components synthesis of biologically active novel bis((6-alkyl
or phenyl-2-phenylpyrimidine-4-yl) oxy) alkane or methyl benzene derivatives, Ultrason. Sonochem. (2014), http://dx.doi.org/10.1016/
j.ultsonch.2014.09.001