Experimental and theoretical study on the regioselective bis- and polyalkylation of 2-mercaptonicotinonitrile and 2-mercaptopyrimidine-5-carbonitrile derivatives

Article abstract of DOI:10.1016/j.tet.2017.01.047

The synthetic utility of 2-mercaptonicotinonitriles 3 and 4, as well as 2-mercapto-4-oxo-6-phenyl-1,4-dihydropyrimidine-5-carbonitrile 20 as building blocks for novel bis- and poly(pyridines), along with poly(pyrimidines) via alkylation with the corresponding bis- and poy(halo) compounds was investigated. Spectroscopic and theoretical studies confirmed the S-alkylation rather than the N-alkylation.

Full text of DOI:10.1016/j.tet.2017.01.047

Accepted Manuscript
Experimental and theoretical study on the regioselective bis- and polyalkylation of 2-
mercaptonicotinonitrile and 2-mercaptopyrimidine-5-carbonitrile derivatives
Nesma A. Abd El-Fatah, Ahmed F. Darweesh, Adel A. Mohamed, Ismail A.
Abdelhamid, Ahmed H.M. Elwahy
PII:
S0040-4020(17)30070-4
10.1016/j.tet.2017.01.047
TET 28417
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 October 2016
Revised Date: 12 January 2017
Accepted Date: 19 January 2017
Please cite this article as: Abd El-Fatah NA, Darweesh AF, Mohamed AA, Abdelhamid IA, Elwahy
AHM, Experimental and theoretical study on the regioselective bis- and polyalkylation of 2-
mercaptonicotinonitrile and 2-mercaptopyrimidine-5-carbonitrile derivatives, Tetrahedron (2017), doi:
10.1016/j.tet.2017.01.047.
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Tetrahedron
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Experimental and theoretical study on the
regioselective bis- and polyalkylation of 2-
mercaptonicotinonitrile and 2-mercaptopyrimidine-5-
carbonitrile derivatives
Leave this area blank for abstract info.
Nesma A. Abd El-Fataha, Ahmed F. Darweesha, Adel A. Mohamedb, Ismail A. Abdelhamida and Ahmed H. M.
Elwahya*
aChemistry Department, Faculty of Science, Cairo University, Giza, Egypt
bChemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
aelwahy@hotmail.com
1

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Tetrahedron
journal homepage: www.elsevier.com
Experimental and theoretical study on the regioselective bis- and polyalkylation
of 2-mercaptonicotinonitrile and 2-mercaptopyrimidine-5-carbonitrile
derivatives
Nesma A. Abd El-Fataha, Ahmed F. Darweesha, Adel A. Mohamedb, Ismail A. Abdelhamida and Ahmed
H. M. Elwahya*
aChemistry Department, Faculty of Science, Cairo University, Giza, Egypt
bChemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
aelwahy@hotmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The synthetic utility of 2-mercaptonicotinonitriles 3 and 4, as well as 2-mercapto-4-oxo-6-
phenyl-1,4-dihydropyrimidine-5-carbonitrile 20 as building blocks for novel bis- and
poly(pyridines), along with poly(pyrimidines) via alkylation with the corresponding bis- and
poy(halo) compounds was investigated. Spectroscopic and theoretical studies confirmed the S-
alkylation rather than the N-alkylation.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
2-pyridinethione
alkylation
bis- and poy(halo) compounds
bis-and poly(pyridines)
bis- and poly(pyrimidines)
multi-armed heterocycles
DFT calculations
1. Introduction
Compounds incorporating
bis-heterocyclic moieties
occur in numerous bioactive products.36 Recent reports have
demonstrated that among libraries of derivatized heterocycles,
the most active compounds have a bis-heterocyclic structure.37–40
Bis-heterocycles in which two bioactive heterocycles are
fastened by means of an flexible linker have been shown to be
anticancer 41–44and antimicrobial agents.45 Along with these
activities, some bis-heterocyclic derivatives additionally show
intense antialzheimer and antiprion activity.46
Pyridine derivatives occupy a central position in the field
of medicinal chemistry.1 Many naturally occurring compounds
having the pyridine moiety show fascinating biological and
pharmacological activities. Pyridine derivatives have been shown
to have antibacterial,2 antimicrobial,3,4 antifungal,5 cardiotonic6,
analgesic,7 antiinflammatory8 and anti-lung cancer activities.9
Some pyridine derivatives have been identified to possess
herbicide activity,10 and been used for enrichment of cereals,11
for regulation of arterial pressure12 and cholesterol levels in
blood.13 Others constitute an important class of antitumor
compounds.14–16 They have additionally been observed to be
selective IKK – β serine - threonine protein kinase inhibitors.17
In recent years, an expanding number of reports have
identified ‘multi-armed’ molecules for their extensive variety of
applications.47–52 This class of compound is viewed as a
significant host for developing microporous systems, and their
applications in supramolecular host–guest science have been
recently reported.53,54 Some related compounds have likewise
been utilized for the formation of discotic mesogens,55–57 organic
electronic and optoelectronic materials.58–60 They have
additionally been utilized as building units for dendrimers.61–63
Grillaud and Bianco recently gave an account of the biological
activity of some multivalent scaffolds.64
Pyrimidines are also one of the most important
heterocycles exhibiting remarkable pharmacological activities.18
A literature survey indicated that compounds encompassing a
pyrimidine nucleus exhibit a wide range of pharmacological
activities
including
antifungal,19,20
anti-inflammatory,21
antihypertensive,22,23 antiviral,24 antidiabetic,25 antioxidant,26
anticancer activities.27,28 During the last two decades several
pyrimidine derivatives have been reported as antibacterial
drugs.29–35
2

2. Results and Discussion:
2.1. Synthesis:
Microwave irradiation has recently seen widespread
ACCEPTED MANUSCRIPT
application in research laboratories.65,66 It can lead to
dramatically reduced reaction times, higher yields, and cleaner
reaction profiles.67,68Motivated by these findings, we report
herein the synthesis of some novel bis- and poly(pyridines) as
well as bis- and poly(pyrimidines) by alkylation of the
The present study investigates the reaction of 2-
mercaptonicotinonitriles and with the appropriate
3
4
dibromoalkanes 5a-c in basic medium. For this purpose,
compounds 3 and 4 were prepared as previously reported by
heating 2-cyanoethanethioamide (2) with pentane-2,4-dione (1a)
or 1,3-diphenylpropane-1,3-dione (1b) in refluxing ethanol
containing triethylamine as a basic catalyst (Scheme 1).69,70
appropriate
2-pyridinethione
and
2-pyrimidinethione,
respectively, with the corresponding bis- and poy(halo)
compounds under microwave irradiation as well as under
conventional heating methods. The regioselectivity of alkylation
products was confirmed by spectroscopic data as well as
theoretical calculations.
Scheme 1
Our investigation began with an evaluation of KOH as a presence of only one product, which, after classical workup, was
basic catalyst in the reaction of 2-thioxo-1,2-dihydropyridine-3- identified as the corresponding bis-S-alkylated products 2,2'-
carbonitrile (3) with 1,3-dibromopropane (5b) as a model (alkane-1,ω-diylbis(sulfanediyl))bis(4,6-dimethylnicotinonitrile))
reaction (Scheme 2). The reaction was carried out in different 6b(I), the bis-N-alkylated products 1,1'-(alkane-1,2-diyl)bis(4,6-
solvents, including ethanol, methanol, isopropyl alcohol and dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile) 6b(II) or
DMF (Table 1). Among the tested solvents, ethanol proved to be as S-N-alkylated products 2-(2-(3-cyano-4,6-dimethyl-2-
the best and gave the highest yield of the product (Table 1, entry thioxopyridin-1(2H)-yl)alkylthio)-4,6-dimethylnicotinonitrile
2). Examination of the TLC of the reaction mixtures, after 6b(III).
complete consumption of starting material, indicated the
Scheme 2
The regioselectivity was determined by NMR Furthermore the absence of a thiocarbonyl (C=S) signal71 (~ 180
spectroscopy and supported by theoretical calculations at DFT ppm) in the 13C NMR spectrum of 6b strongly supports the
level. The 1H NMR spectra of 6b showed a triplet signal at δ 3.36 alkylation of sulfur. Theoretical calculations give also strong
that integrates for four protons characteristic for the S-CH2 evidence for the preferential formation of the regioisomer 6b (I)
protons of the propyl spacer. These NMR signals indicated that (c.f. Sec. 2.2).
the regioisomers 6b(I) or 6b(II) with symmetric structures can
We next examined a variety of basic conditions, including
exist while the nonsymmetrical regioisomer 6b(III) was sodium ethoxide in ethanol, K2CO3 in ethanol or pyridine (Table
1
discarded. Although the H NMR spectra is still not enough to 1, entries 5-7) which played the dual role as a catalyst as well as
distinguish between the two expected regioisomers, the 13C NMR a solvent. In all cases, the reactions gave regioselectively the
spectrum displayed the methylene carbons at δ 29.3 which same alkylated product, although the reaction proceeded most
indicates that the methylene carbons are attached to sulfur atoms. efficiently using KOH in ethanol under reflux conditions for 1 h.
3

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Table 1: Base and solvent effects on the reaction of 2-thioxo-1,2-dihydropyridine-3-carbonitrile 3 with 1,3-dibromopropane
Yield%a,b
6b (I)
Run
Base
Solvent
1
2
3
4
5
6
7
KOH
KOH
KOH
MeOH
EtOH
Isopropyl alcohol
DMF
66
79
69
61
71
70
50
KOH
NaOEt
K2CO3
Pyridine
EtOH
EtOH
Pyridine
aReaction conditions: 2-mercaptonicotinonitriles / 1,3-dibromopropane / base / solvent (10 mL): 2 / 1 / 2 mmole, at reflux temp.
bisolated yields.
The reaction of 3 with 5b was also investigated under the reaction proceeded with no change in the regioselectivity in a
microwave conditions (Scheme 3). To find the best conditions, short period of time (2 min.) and gave a better yield than that
the reaction mixture was irradiated for varying times and obtained under conventional heating. DMF is an excellent
microwave powers. By irradiation of the reaction mixture using a energy-transfer solvent with a high dielectric constant and was
microwave reactor of power 250 W in the presence of a small used to increase the energy input in a shorter time and provide a
amount of N,N-dimethylformamide (DMF), it was observed that uniform heating. 72–74
MW
3
5b
6b(I)
+
KOH, DMF, 2 min., 160 oC, 250 W
Scheme 3
With optimal conditions in place, we studied the synthesis appropriate 2-thioxo-1,2-dihydropyridine-3-carbonitriles 3 and 4
of some bis 2,2'-(alkane-1,ω-diylbis(sulfanediyl))bis(4,6- with the corresponding dibromoalkane 5a-c under similar
disubstituted nicotinonitrile)) 6a-c and 7a-c by the reaction of the conditions (Table 2, Figure 1).
Figure 1
Table 2: Synthesis of some bis(4,6-disubstituted nicotinonitrile) under thermal and MW irradiation conditions
thermala
yield%
79
Mwb
yield%
86
Product
6a
6b
6c
7a
7b
7c
75
82
73
66
80
85
78
75
76
83
aConditions: Pyridine derivative 3: 2 mmol; dibromoalkane 5: 1 mmol; KOH: 2 mmol; ethanol: 10 mL; reflux 1 h.
b Conditions: Pyridine derivative 3: 2 mmol; dibromoalkane 5: 1 mmol; KOH: 2 mmol; DMF: 1 mL; (250 Watt) at 160 ºC for 2 min.
4

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Using
a
similar
approach,
the
2,2'-(1,4- prepared in 70 and 88% yields, respectively, by the reaction of
phenylenebis(methylene))-bis(sulfanediyl)-bis(nicotinonitriles) 9 the appropriate 2-mercaptonicotinonitriles 3 and 4 with 1,4-
and 10 in which the two pyridine moieties are linked to a bis(bromomethyl)benzene (8a) in ethanol containing potassium
benzene core via a sulfanylmethyl linkage were successfully hydroxide (Scheme 4).
Scheme 4
The synthetic utility of 3 and 4 as building blocks for hexakis(bromomethyl)benzene (17) with four and six equivalents
novel 1,3,5-tris(1,2-dihydropyridine-3-carbonitriles) was also of 3 or 4 under similar conditions afforded 15, 16, 18 and 19 in
investigated (Scheme 5). Thus, threefold substitution of 65, 72, 73, and 50% yields, respectively (Scheme 5). The
tris(bromomethyl)benzene (11) with three equivalents of 3 and 4 synthesis of compounds 12, 13, 15, 16, 18 and 19 under
in refluxing EtOH/DMF mixture containing KOH afforded 12 microwave irradiation conditions was also investigated. The
and 13 in 74 and 82% yields, respectively. The same structures of the synthesized compounds were confirmed by IR
methodology can be extended to the preparation of 1,2,4,5- and NMR spectroscopy, mass spectra and elemental analysis.
tetrakis(1,2-dihydropyridine-3-carbonitriles)benzenes 15 and 16 The symmetry of compounds 12, 13, 15, 16, 18 and 19 is
as
well
as
1,2,3,4,5,6-hexakis(1,2-dihydropyridine-3- manifested by a single set of signals characteristic of the
carbonitriles)benzenes 18 and 19. Thus, four- and sixfold equivalent SCH2 groups in the 1H NMR spectra.
substitution of tetrakis-(bromomethyl)benzene (14) and
Br
R
N
R
N
CN
S
NC
S
Br
Br
R
R
11
KOH, EtOH, reflux, 1 h.
S
MW: KOH, DMF, 1 min.,
160 oC, 250 W
CN
N
R
R
12; R = Me; thermal: 74%; MW: 75%
13; R = Ph; thermal: 82%; MW: 89%
R
R
Br
Br
Br
Br
CN
NC
R
N
CN
SH
14
R
N
N
S
S
S
S
N
N
R
R
R
KOH, EtOH, reflux, 1 h.
MW: KOH, DMF, 1 min.,
160 oC, 250 W
R
CN
NC
3; R = Me
4; R = Ph
R
R
15; R = Me; thermal: 65%; MW: 69%
16; R = Ph; thermal: 72%; MW: 78%
Br
R
R
Br
Br
Br
Br
N
R
NC
R
CN
S
S
NC
Br
17
R
N
N
S
S
S
S
N
N
R
R
R
KOH, EtOH, reflux, 1 h.
MW: KOH, DMF, 1 min.,
160 oC, 250 W
CN
NC
R
CN
R
N
R
R
18; R = Me; thermal: 73%; MW: 77%
19; R = Ph; thermal: 50%; MW: 64%
Scheme 5
5a-d was also investigated. Compound 20 was synthesized via a
multi-components reaction (MCR) of benzaldehyde, ethyl
The
reaction
of
2-mercapto-4-oxo-6-phenyl-1,4-
dihydropyrimidine-5-carbonitrile (20)75 towards dibromoalkanes
5

Tetrahedron
ACCEPTED MANUSCRIPT
cyanoacetate and thiourea in refluxing ethanol in the presence of potassium carbonate (Scheme 6).
Scheme 6
We first studied the reaction of 20 with 1,2- symmetrical bis-derivatives, (S-, S-), (1N-, 1N-), or (3N-, 3-N-) or
dibromoethane (5a, n = 1) in ethanol containing KOH under the asymmetrical derivatives (S-, 1-N-), (S-, 3-N-) or (1N-, 3N-).
conventional heating as well as under microwave irradiation. In Reaction at the sulfur followed by cyclization at nitrogen (1-N-)
all cases, TLC analysis of the reaction mixture indicated the or at nitrogen (3-N-) was also included as possible reaction
presence of only one product which was proposed to be the products (Scheme 7).
O
O
CN
Ph
HN
CN
Ph
N
Ph
N
O
S
H
N
S
N
n
Ph
S
S
N
H
NH
n
NC
N
NC
O
21(I)
21(II)
H
O
N
S
Ph
1
N
CN
O
NC
N
n 1
Ph
S
N
H
22
H
N
Ph
S
O
3
3
N
N
CN
Ph
NC
n
O
S
N
H
23
Br
Ph
O
Br
H
n
NC
O
O
N
S
CN
N
NH
SH
5a-d
1
N
KOH, EtOH, reflux, 1 h
NC
S
N
Ph
N
n
H
Ph
MW: KOH, DMF, 2 min.,
160 oC, 250 W
20
24
O
H
N
Ph
S
CN
Ph
a, n = 1
b, n = 2
c, n = 3
d, n = 4
N
3
N
NC
S
N
H
n
O
25
H
O
N
S
O
1
3
N
N
CN
Ph
NC
n
Ph
S
N
H
26
Ph
Ph
NC
O
1
N
NC
N
n
N
S
S
3
O
N
n
27
28
6

Scheme 7
ACCEPTED MANUSCRIPT
1
The H-NMR spectrum of the reaction product indicates data give evidence for the existence of the fused compounds 27a
the presence of two triplet signals at δ 3.64 and at δ 4.47, both or 28a and exclude all other expected bis-derivatives. Further
integrating for two protons characteristic for the two CH2 groups confirmation of the proposed structure was derived from mass
of the ethylene spacer, together with multiplets in the region of δ spectrometry, which showed the molecular ion peak at 255 (8.6,
7.56-7.58 and δ 7.85-7.87 integrating for five protons. Moreover, M+) corresponding to the mass of compounds 27a or 28a (Figure
the 13C NMR spectrum displayed two methylene carbons at δ 2). DFT calculations strongly support the formation of the
26.91 and at δ 49.46, respectively, characteristic for the regioisomer 28a (c.f. Sec. 2.2).
methylene carbons attached to sulfur and nitrogen atoms. These
Figure 2
Similar results were obtained when 20 was reacted with reaction product (Figure 3). Again, DFT calculations support the
1,3-dibromopropane (5b, n = 2) under the same reaction formation of regioisomer 28b (c.f. Sec. 2.2).
conditions. The structure of 27b or 28b was proposed for the
Figure 3
We also carried out the reaction of 5-cyano-4-oxo-6- replaced. This strongly supports the formation of the symmetrical
phenyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidine (20) with 1,4- regioisomers 21, 22 or 23. The 13C NMR spectrum of the
dibromobutane (5c, n = 3). The regioselectivity of the product reaction product displayed the methylene carbons at 29.71 ppm
was then studied by NMR spectroscopy as well as by theoretical which gives further support to the attachment of the methylene
calculations at DFT level. The 1H NMR spectra showed only one carbons to sulfur atoms. Theoretical calculations give strong
broad singlet signal around δ 3.26 that integrates for four evidence for the formation of the regioisomer 21c (Figure 4) (c.f.
protons, characteristic for the two terminal CH2 protons of the Sec. 2.2). Similar results were obtained when 20 reacted with
butyl spacer together with multiplet signals in the region of δ 1,5-dibromopentane (5d, n = 4) under the same reaction
7.48-7.59 and 7.77-7.91 integrating for ten protons. The presence conditions and the structure 21d was proposed for the reaction
1
of a D2O exchangeable signal around 13.73 ppm in the H NMR product (Figure 4).
spectrum confirms that only one exchangeable proton has been
Figure 4
The 2,2'-(phenylenebis(methylene)bis(sulfanediyl)bis(4- 75 and 80% yields, by the reaction of 20 with 1,3- and 1,4-
oxo-6-phenyl-1,4-dihydro-pyrimidine-5-carbonitriles) 29 and 30 bis(bromomethyl)benzenes 8a and 8b, respectively, under
in which the two pyrimidine moieties are linked to a benzene conventional heating as well as under MW irradiation.
core via a sulfanylmethyl linkage were successfully prepared in
7

Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 8
Our study included also the synthesis of novel 1,3,5- tetrakis(bromomethyl)benzene (14) with three and four
tris(1,4-dihydropyrimidine-5-carbonitrile) 31 and 1,2,4,5- equivalents of 20, respectively, under similar conditions (Scheme
tetrakis(1,4-dihydropyrimidine-5-carbonitrile) 32 in 71 and 78% 9). Compounds 29, 30, 31 and 32 were also prepared, but in
yields,
by
three-
and
fourfold
(11)
substitution
of better yields and shorter reaction times under microwave
and irradiation.
tris(bromomethyl)benzene
Scheme 9
Unfortunately, repeated trials to isolate a pure sample of unsuccessful. The reaction gave instead a mixture of products
1,2,3,4,5,6-hexakis((1,4-dihydro-pyrimidine-5-carbonitrile) 33 that can not be handled, separated or characterized so far
by sixfold substitution of hexakis(bromomethyl)-benzene (17) (Scheme 10).
with six equivalents of 20 under similar conditions was
Scheme 10
The structures of the newly synthesized compounds were confirmed by IR and NMR spectroscopy, mass spectra and elemental
analysis. The symmetry of compounds 31 and 32 are manifested by a single set of signals characteristic of the equivalent SCH2
groups in the 1H NMR spectra.
8

Tetrahedron
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2.2. Molecular orbital calculations:
the transition structure. The thermodynamic functions, the
relative energy, ꢀEr, or reaction energy, ꢀEf, the reaction
enthalpy, ꢀH and the reaction free energy change, ꢀG were
calculated with the conventional equations. Local reactivity
descriptors, Fukui function f(r) and local softiness S(r), at
different centers were calculated using DFT.80,81 Molecular
structures of the reactants 3 and 20 as well as the expected
products 6, 21-23, 27 and 28 were optimized using the B3LYP/6-
31G* method in order to find out the relative stabilities of the
expected products and which one is actually obtained.
Molecular orbital treatment was performed using the
DFT method with the hybrid three-parameter functional
B3LYP.76,77 Various basis sets were used; the standard split-
valence polarization basis set 6-31G(d)78 was chosen for
geometry optimization. The basis sets 6-31G(d,p) 6-31+G(d,p)
and 6-31++G(d,p) were also used for energy refinement. All
calculations were pursued with the GAUSSIAN- 03 program.79
The absence of an imaginary frequency of the vibrational
calculations confirmed that the obtained structures are the true
energy minima on the potential energy surface, while the
presence of one imaginary frequency is used as an indication for
1.1.1.
Structural study of pyridine 3 and its alkylated products:
Pyridine 3 can exist either in thiol 3(I) or thione 3(II) tautomeric forms (Figure 5).
Figure 5
The product of the reaction of pyridine
3 with 1,3- the two structures is positive and thus increasing the temperature
dibromopropane 5b may be one of the structures 6b(I-III), as leads to a predominance of 3(I). The transition state of the
outlined in Scheme 2, depending on the nucleophile existing in thione-thiol tautomerization (Figure 6) was also calculated using
the medium; I or II. So it is valuable to examine thione-thiol the B3LYP/6-31+G* level to prove if it is only thermodynamic
tautomerization of pyridine 3. DFT methods were used to assess control or also kinetic control. The conversion barrier, ꢀE*, of
the relative stability of both tautomers. The basis sets 6-31G*, 6- thiol-thione tautomerism was found to be 28.75 kcal/mol while
31+G* and 6-31++G** were also tested in order to determine the calculated activation energy ꢀEa is 25.47 kcal/mol. These
their effect on the tautomerization. The computed results high values of energies indicate that this conversion is somewhat
collected in Table 3 show that the thione form 3(II) form is difficult and only the thiol form may exist. The high calculated
lower in energy than the thiol form 3(I) using the different basis dipole moment values of the three species indicates that the
sets. The difference is 2.033, 1.562 and 1.738 kcal/mol with the process is dependent on both solvent polarity and temp. This
basis sets 6-31G*, 6-31+G* and 6-31++G**, respectively. means that the tautomerization is a thermodynamically and
Addition of zero point energy, ZPE, and thermal correction, TC, kinetically controlled process. It is worthy to mention that the
terms reverses this stability, i.e. the thiol I becomes more stable tautomeric equilibrium of the parent 2-thio/thiolpyridine was
by 0.458 kcal/mol at the B3LYP/6-31G*level. The previously reported.82–86 The experimental studies showed that
thermodynamic functions corresponding to the studied thione- the tautomeric equilibrium is dependent on environment. The 2-
thiol tautomerization were also calculated using the same levels. thione form was found to be more stable in polar solvents while
This process was found to be exothermic as shown by its ꢀH the thiol is more stable in both the gas phase and nonpolar
value, -0.220, -0.690 and -0.478 kcal/mol using the three levels solvents. X-ray showed that the thione form dimer is the solid
of calculations, Table 3. Moreover, the corresponding Gibbs free state form (Figure 7).87 Binding of the nucleophile 3(I) or 3(II)
energy, ꢀG, of this tautomerization has a low negative value, - with the bis halo compounds 5 can take place via N or S atoms.
0.791, -1.161 and -1.0 kcal/mole, respectively. Accordingly, the The electrophilic and nucleophilic characters of these centers are
thione-thiol conversion is spontaneous and the thiol form 3(I) is studied using both Fukui f(r) and Softeness S(r) functions. Table
thermodynamically more favorable. But since ꢀG is low, it is 4 collects the calculated values of f+ , f-r, S+ and S-r functions of
r
r
valuable to calculate the equilibrium constant K. The K value is nitrogen and sulfur atoms in both tautomers using B3LYP/6-
found to be 1.001 at the B3LYP/6-31G* level, and increases as 31+G* . As shown, in both tautomers the nitrogen atom has
the basis set increases. The latter finding indicates that in the gas lower f+ and S+ values than those of S atom, implying that the
N
N
phase, both forms can exist in equilibrium with a predominance sulphur atom is the preferable site for nucleophilic attack. The
of 3(I). Finally, it can be noted that the entropy value of 3(I) is values calculated in case of 3(II) are higher than that of 3(I).
higher than that of 3(II), so the difference in entropy ꢀS between
9

Tetrahedron
ACCEPTED MANUSCRIPT
The reaction of pyridine 3 with 1,3-dibromopropane 5b is thermodynamically more predominant than thione form 3(II)
was taken as a representative example. Table 5 collects the total and so dibromo compound 5b will attach to the thiol nucleophile
energies and other thermochemical parameters calculated for the tautomer 3(I). Finally, the thermochemical parameters of the
proposed compounds 6a(I-III) using the B3LYP/6-31G* three expected pathways calculated using the B3LYP/6-31G*
method. This data shows that S-S 6b(I) has the lowest total level, table 4, show that the corresponding Gibbs free energy of
energy value, while N-S 6b(III) and N-N 6b(II) are 6.67 and formation, ꢀGf, of both N-N 6b(II) and N-S 6b(III) are positive,
16.32 kcal/mole higher than S-S 6b(I). Therefore, one expects 20.049 and 9.538 kcal/mol, respectively. So these two routes are
6b(I) to be the product, the optimized geometrical structure is nonspontaneous. On the other hand, ꢀGf of the third route,
given in figure 9. This can be explained according to the formation of S-S 6b(I), is negative and equals -0.301 kcal/mol,
following reasons. Firstly, it has the lowest total energy. i.e. it is a spontaneous process.
Secondly, the thiol form 3(I), leading to the formation of 6b(I),
TS 3I-3II
TS 20(I) -20(II)
TS 20(I) -20(III)
Figure 6: Transition states of the thione-thiol tautomerization for both of pyridine and pyrimidine
Figure 7: Pyridine-thione dimer I and pyrimidine thione dimers (II and III)
2.2.1
Structural study of pyrimidine 20 and its alkylated products:
Pyrimidine 20 can adopt many tautomers 20(I-III) as a result of proton transfer between different centers, N and S atoms (Figure 8).
Figure 8
Lapinski et al.88 studied experimentally the thione-thiol one will be the nucleophile that interacts with the appropriate
tautomerism of unsubstituted 2-pyrimidinthiol and found that 2- dibromo compound 5 as outlined in Scheme 7. The computed
pyrimidinthiol is more stable than 2-pyrimidinthione in the gas different energies of the most stable structures of the isomers
phase, while in solution an equilibrium exists between the dimer 20(I-III) are given in table 6 and the optimized geometry of
and the monomer (Figure 7).88 In this part, the levels B3LYP/6- these tautomers are shown in figure 10. Careful inspection of this
31G* and B3LYP/6-31G** were used to show the relative data proves that the thione 20(I) has the lowest total energy at
stability of the above three tautomers in order to find out which both levels; -1061.06833 a.u and -1061.08300 a.u, respectively,
10

i.e. energetically most stable, followed by the thiol 20(III) while equal 18.98 and 12.59 kcal/mol, respectively. The free energy
ACCEPTED MANUSCRIPT
the other thiol isomer 20(II) has the highest total energy, - change ꢀGr corresponding to the reactions producing the other
1061.03016 a.u and -1061.04942 a.u. linear compounds 21a(I), 21a(II), 23a(I), 23a(II), n = 1, have
Using the B3LYP/6-31G** method, it was found that in negative values, table 7, indicating the possibility of their
the gas phase the transfer of the hydrogen atom attached to N5 in formation. The other expected products 24-26 were excluded
thione 20(I) isomer to the S atom to produce the thiol 20(III) is a based on spectroscopic data.
nonspontaneous process; its free energy change ꢀGr equals 9.47
kcal/mol. The same trend was found in the conversion of thione
20(I) to the other thiol isomer 20(II), the ꢀGr change calculated
is 17.86 kcal/mol. This indicates that 20(I) is the predominant
isomer in the gas phase while the thiol forms exist at a lower
percent. The results presented in Table 6 show that the transfer
of the hydrogen atom attached to N5 in thione 20(I) to the S
atom to produce the thiol 20(III) passes a barrier of 36.34
kcal/mol, and the activation energy of the process is 32.13
kcal/mol. On the other hand, the transition state of the conversion
of thione 20(I) to the other thiol 20(II) (Figure 6) has a higher
barrier and activation energy, 43.81 and 39.51 kcal/mol,
respectively. Therefore, the two tautomerization processes, 20(I)-
20(II) or 20(I) -20(III), are thermodynamically and kinetically
nonspontaneous and 20(I) is the major tautomer that may exist.
Freeman and Po used DFT methods to investigate the above
tautomerism and found that the unsubstituted 2-pyrimidinthiol is
more stable than its thione in the gas phase while the thione is
more predominant in solution.89 The f(r) and S(r) functions
calculated using B3LYP/6-311G** for the three structures of
20(I-III) are given in Table 4. The highly negatively charged
atoms in these automers; are N3, S and N5 atoms which may be
attacked by the electropile. The preferable site for nucleophilic
attack is that with maximum f+(r) and S+(r) values. As depicted
from Table 4, the S atom has the highest f+(r) and S+(r) values
followed by the N3 atom, while the N5 has the lowest values.
Therefore, the S atom is the most susceptible site to be attacked
by the electrophile. According to this results 19(I) is most
reactive tautomer towards the electrophile.
The ꢀGr values computed for the two routes yielding the
fused cyclic compounds; 27a, 28a, n = 1, reveal that they are the
most favourable reactions. Therefore, the results of the
calculations at the B3LYP/6-31G* level confirms that the
reaction of 1,2-dibromoethane and pyrimidine 20 yields
thermodynamically
5-oxo-7-phenyl-3,5-dihydro-2H-
thiazolo[3,2-a]pyrimidine-6-carbonitrile 28a as the main product
because the ꢀGr value of this route equals -19.19 kcal/mol
higher than all other routes values, table 7. Figure 10 presents the
geometry of the most stable structure 28a. Similarly, the reaction
of 1,3-dibromopropane 5b and pyrimidine 20 can also afford one
of the corresponding products 21b-23b, 27b and 28b (n = 2). To
verify which one is the main product, the Gibbs free energy
change ꢀGr of each route was also computed at the same level;
B3LYP/6-31G* level, and the results are given in table 7 with
the other parameters. These results show that only one product is
obtained as a result of this reaction, which is the fused cyclic
product
6-oxo-8-phenyl-2,3,4,6-tetrahydropyrimido[2,1-
b][1,3]thiazine-7-carbonitrile 28b, figure 11. This route is
accompanied by high negative ꢀGr value, -16.08 kcal/mol. All
other routes are nonspontaneous due to the corresponding
positive ꢀGr values, table 7. The driving force for these reactions
is the formation of less strained 5- and 6-memberd rings. On the
other hand, the reaction of 1,4-dibromobutane 5c with
pyrimidine 20 was also studied using the same above procedure.
The calculated free energy change ꢀGr of the reactions leading to
formation of fused cyclic products; 27c and 28c, n = 3, are
positive values, 4.26 and 1.07 kcal/mol, respectively.
Consequently, these two pathways are nonspontaneous since
they lead to the formation of 7-membered rings which is less
likely to form due to entropic considerations involved in large
ring formation.90–92
Scheme 7 shows the suggested different products
produced from the reaction of pyrimidine 20 and the suitable
dibromoalkanes. The proposed mechanisms lead either to linear
products or cyclic ones. Experimentally, only one product was
isolated in each case. The knowledge of the thermodynamic
parameters; reaction energy ꢀEr, reaction enthalpy ꢀHr and the
free energy change ꢀGr, for each route is very important so as to
realize the most favorable route and thus the product in each
case. The DFT computed thermodynamic data related to these
routes are collected in table 7. Using dibromoethane as an
alkylating agent, the reactions forming the two linear products,
22a(I) and 22a(II), n = 1, are nonspontaneous because their ꢀGr
The same trend was also found in the case of the routes leading
to the production of 21-24, where ꢀGr and ꢀHr values are higher
i.e. endothermic and nonspontaneous processes. Finally, the free
energy change ꢀGr of the reactions corresponding to the
formation of the structures 21c(I) and 21c(II) are -0.06 and 0.63
kcal/mol, respectively. This result reveals that in this case the
linear structure 21c(I) is the main product. Figure 12 illustrates
the geometrical structure of both tautomers 21c(I) and 21c(II).
11

Tetrahedron
ACCEPTED MANUSCRIPT
Table 3: Total energy Et, au, Zero point energy, ZPE, Thermal correction, TC, entropy S, cal. mol-1 K-1, relative energy ꢀE, Enthalpy
ꢀH, Gibbs free energy change ꢀG and energy barrier (ꢀE*) and activation energy ꢀEa, of thiol 3(I)
thione 3(II) tautomerization
calculated using DFT method and the basis sets 6-31++G**a, 6-31+G*b and 6-31G*c
3(I)
3(II)
-817.38891
TS 3(I)
3(II)
Et , aua
-817.38614
Et+ZPE (Et+TC), au
S, cal. mol-1 K-1
ꢀE , kcal /mol
ꢀH (ꢀG), kcal /mol
Et , aub
Et+ZPE (Et+TC), au
S, cal. mol-1 K-1
ꢀE, kcal /mol
ꢀH (ꢀG), kcal /mol
NBO Atomic charge
N
-817.24527 (-817.23393)
105.2
1.738
-0.478(-1.000)
-817.37322
-817.23183(-817.22055)
104.7
-817.24425 (-817.23308)
103.7
0.0
0.0(0.0)
-817.37571
-817.23036 (-817.21944)
103.2
0.0
0.0(0.0)
-817.32741
-817. 18878(-817.17795)
103.59
(ꢀE*=28.75)
(ꢀEa=25.47)
1.562
-0.690(-1.161)
-0.4975
-0.5534
S
0.0906
-0.5134
H
0.1213
0.3261
EHOMO
-0.2485
-0.2213
ELUMO
-0.0720
-0.0896
ꢀEg
0.1765
0.1317
Et , auc
-817.35781
-817.21608(-817.20476)
105.6
2.033
-0.220(-0.791)
-817.36105
-817.21535(-817.20440)
103.7
0.0
0.0(0.0)
Et+ZPE (Et+TC), au
S, cal. mol-1 K-1
ꢀE, kcal /mol
ꢀH (ꢀG), kcal /mol
Table 4: Fukui functions f and local softness S of some centers of the nucleophiles 3 and 20 calculated using DFT.
N3
S
N5
f+ (S+)
f- (S-)
f+ (S+)
f- (S-)
f+ (S+)
f- (S-)
3(I)
3(II)
0.064 (0.363) 0.027 (0.150) 0.081(0.458) 0.360 (2.038)
0.065 (0.495) 0.041 (0.312) 0.182 (1.380) 0.661 (5.015)
20(I)
20(II)
20(III)
0.031(0.208) 0.030 (0.200) 0.185 (1.249) 0.353 (2.379) -0.011 (-0.072) 0.059 (0.377)
0.075 (0.443) 0.038 (0.225) 0.076(0.447) 0.102 (0.600) -0.001 (-0.007) 0.061(0.359)
0.044(0.283) 0.010(0.064) 0.107 (0.690) 0.126 (0.811) -0.005 (-0.036) 0.041 (0.267)
Table 5: Total energy Et, au, Zero point energy, ZPE, Thermal correction, TC, entropy S, cal. mol-1 K-1, relative energy ꢀE, reaction
energy ꢀEr, Enthalpy ꢀHr and Gibbs free energy change ꢀG, for the formation of 6(I-III) from the reaction of pyridine 3 and 1,3-
dibromopropane 5b, calculated using DFT method and the basis sets 6-31G*
6(I)
-1751.46252 -1751.43652 -1751.45186
Et+ZPE -1751.10929 -1751.07818 -1751.09598
-1751.08225 -1751.05279 -1751.07067
6(II)
6(III)
Et
Et+TC
S
ꢀE
ꢀEr
ꢀHr
ꢀGr
191.10
0.0
-2.868
-3.702
-0.301
179.60
16.320
17.514
14.351
20.049
179.80
6.670
5.855
3.338
9.538
12

Table 6: Total energy E , au, Zero point energy, ZPE, Thermal correction, TC, entropy S, cal. mol-1 K-1, relative energy ꢀE, Enthalpy
ACCEPTED MANUSCRIPT
method and the basis sets 6-31G*a and 6-31G**b
t
ꢀH and Gibbs free energy change ꢀG, energy barrier (ꢀE*) and activation energy ꢀEa of tautomerization calculated using DFT
20(I)
20((II)
20(III)
TS I-III
TS I-II
Eta
Et+ZPE
Et+TC
S
-1061.06833
-1060.90366
-1060.89069
114.79
-1061.03016
-1060.87480
-1060.86126
114.38
-1061.04894
-1060..88845
-1060.87507
116.50
ꢀE
0.0
23.95
12.16
ꢀGr
0.0
17.69
9.27
Etb
Et+ZPE
Et+TC
S
-1061.08300
-1060.91848
-1060.90552
114.78
-1061.04942
-1060.88939
-1060.87584
117.35
-1061.06310
-1060.90298
-1060.88960
116.54
-1061.01318
-1060.85543
-1060.84255
114.27
-1061.02494
-1060.86711
-1060.85431
114.49
ꢀE
ꢀGr
0.0
0.0
21.07
17.86
12.37
9.47
(ꢀE*=43.81)
(ꢀEa=39.51)
(ꢀE*=36.43)
(ꢀEa=32.13)
ꢀE*( ꢀEa)
Atomic charge b
hN3
S
N4
-0.650
-0.217
-0.676
-0.466
0.371
0.378
6.26
-0.866
-0.277
-0.862
-0.778
0.423
0.083
9.26
-0.676
-0.258
-1.029
-0.795
0.239
0.072
6.84
O
H
H
Dipole moment b, D
Table 7: Total energy Et, Zero point energy, ZPE, Thermal correction, TC, entropy S, relative energy ꢀE, reaction energy ꢀEr,
Enthalpy ꢀHr and Gibbs free energy change ꢀG, for the eactions of pyrimidines 20 and dibromo compounds 5a-c. Reactions
calculated using DFT method and the basis sets 6-31G*
Linear
Cyclic
5a
Et. au
Et+ZPE,
au
21a(I)
21a(II)
22a(I)
22a(II)
23a(I)
23a(II)
27a
-
28a
-
-
-
-
-
-
-
2199.50468 2199.52793 2199.53165 2199.45321 2199.52060 2199.55535 1138.45352 1138.47640
-
-
-
-
-
-
-
-
Et+TC,au 2199.14271 2199.16551 2199.16539 2199.09593 2199.16142 2199.18825 1138.25543 1138.27766
S, cal.
mol-1 K-1 2199.11293 2199.13599 2199.13646 2199.06584 2199.13223 2199.15962 1138.24076 1138.26325
-
-
-
-
-
-
-
-
ꢀEr, k
cal. mol-1
ꢀHr, k
cal. mol-1
ꢀGrm k
cal. mol-1
5b
201.26
-19.51
-13.32
-9.69
199.90
-10.53
-10.72
-6.91
195.64
11.49
8.58
204.24
12.79
22.50
18.98
196.89
-5.90
-13.38
-3.66
194.30
-3.376
-10.96
-1.52
123.95
-633
-6.02
121.66
-8.90
-11.59
-19.19
12.59
-14.18
21b(I)
21b(II)
22b(I)
22b(II)
23b(I)
23b(II)
27b
28b
Et
-
-
-
-
-
-
-
-
Et+ZPE
Et+TC
S
2238.81235 2238.84180 2238.84593 2238.78272 2238.86918 2238.83325 1177.76151 1177.78897
-
-
-
-
-
-
-
-
2238.42219 2238.45081 2238.45119 2238.38596 2238.47353 2238.44565 1177.53446 1177.56124
ꢀEr
-
-
-
-
-
-
-
-
ꢀHr
2238.39075 2238.41976 2238.42072 2238.36472 2238.44330 2238.41481 1177.51856 1177.54568
ꢀGr
216.94
-6.09
-0.48
1.83
21c(I)
-
212.08
-1.01
-1.74
1.79
21c(II)
-
208.54
19.23
17.26
20.91
22c(I)
-
210.21
12.51
15.46
20.17
22c(II)
-
206.59
0.99
3.09
7.32
23c(I)
-
208.69
4.36
1.37
6.04
23c(II)
-
131.12
6.89
-3.99
-0.11
27c
127.6
1.44
-1.78
-16.08
28c
5c
Et
-
-
Et+ZPE
Et+TC
S
2278.13334 2278.16057 2278.16327 2278.10058 2278.15017 2278.18552 1217.07154 1217.09020
-
-
-
-
-
-
-
-
2277.71405 2277.74064 2277.73988 2277.68528 2277.73356 2277.76108 1216.81538 1216.83357
ꢀEr
-
-
-
-
-
-
-
-
13

Tetrahedron
ACCEPTED MANUSCRIPT
ꢀHr
ꢀGr
2277.68141 2277.70834 2277.70805 2277.65264 2277.70145 2277.72952 1216.79859 1216.81686
217.23
-10.30
-4.84
214.72
-3.80
-4.41
0.63
214.75
18.82
15.38
19.34
219.59
10.25
13.47
17.29
214.53
2.73
-0.08
5.01
213.31
4.86
1.91
132.79
9.55
9.41
133.27
9.64
6.93
-0.06
6.29
4.26
1.07
Figure 9: The optimized geometry of compounds 6b(II) using B3LYP/6-31G*level
20(I)
20(II)
20(III)
Figure 10: The optimized geometry of 20(I-III) using B3LYP/6-31G*level
28a
28b
Figure 11: The optimized geometry of compounds 28a and 28b using B3LYP/6-31G*level
14

ACCEPTED MANUSCRIPT
21c(I)
21c(II)
Figure 12: The optimized geometry of compounds 21c(I) and 21c(II) using B3LYP/6-31G*level
15

Tetrahedron
ACCEPTED MANUSCRIPT
δ 2.05 (p, 2H, CH2, J = 6.9 Hz), 2.38 (s, 6H, CH3), 2.43 (s, 6H,
3. Conclusion:
CH3), 3.36 (t, 4H, CH2, J = 6.9 Hz), 7.07 (s, 2H, H-5 pyridine);
13C NMR (DMSO-d6) δ 19.72, 23.90, 27.63, 29.35, 103.86,
115.01, 119.95, 152.26, 160.33, 161.34; MS m/z (%) 368 (14.3,
M+), 321 (20.7), 237 (18.7), 204 (100.0), 191 (40.3), 178 (46.7),
164 (82.2), 131 (72.1), 104 (49.0), 77 (47.9). Anal. Calcd for
C19H20N4S2: C, 61.92; H, 5.47; N, 15.20; S, 17.40. Found: C,
61.76; H, 5.44; N, 15.33; S, 17.26%.
We have developed a simple method for the preparation
of novel bis- and poly(pyridines) as well as bis- and
poly(pyrimidines) via alkylation of the appropriate 2-
pyridinethione 3 and 4 or 2-pyrimidinethione 20, respectively,
with the corresponding bis- and poy(halo) compounds. Although
a number of regioisomers are possible from the alkylation
reaction, spectroscopic analyses as well as theoretical
calculations confirmed the formation of one regioisomer formed
by preferential S-alkylation. Full characterization of these
compounds is reported. The new synthesized compounds are
interesting both in their own right as unusual molecules, and for
their promising pharmacological and biological activities. We
hope that the present study will open new perspectives for the
development of novel multi-armed heterocycles.
2,2'-(Butane-1,4-diylbis(sulfanediyl))bis(4,6-
dimethylnicotinonitrile) (6c).
Colorless powder (A, 82 %; B, 85 %); (Ethanol), mp 122-126 ºC;
1
IR (KBr) υ 2213 (C≡N) cm-1; H NMR (DMSO-d6) δ 1.75-1.80
(m, 4H, CH2), 2.38 (s, 6H, CH3), 2.45 (s, 6H, CH3), 3.24-3.28 (m,
4H, CH2), 7.06 (s, 2H, H-5 pyridine); 13C NMR (DMSO-d6) δ
19.55, 24.30, 27.71, 28.75, 104.03, 115.00, 120.07, 152.24,
160.81, 161.30; MS m/z (%) 382 (3.3, M+), 365 (2.9), 349 (3.5),
321 (3.8), 295 (7.5), 219 (100.0), 191 (26.0), 177 (20.7), 165
(70.3), 131 (32.5), 104 (22.9), 77 (16.7). Anal. Calcd for
C20H22N4S2: C, 62.79; H, 5.80; N, 14.65; S, 16.76. Found: C,
62.71; H, 5.86; N, 14.58; S, 16.72%.
4. Experimental
4.1. General:
2,2'-(Ethane-1,2-diylbis(sulfanediyl))bis(4,6-
diphenylnicotinonitrile) (7a).
Melting points were determined in open glass
capillaries with a Gallenkamp apparatus and were not corrected.
Infrared spectra were recorded in potassium bromide disks on a
PyeUnicam SP3-300 and Shimadzu FTIR 8101 PC infrared
spectrophotometer. 1H and 13C NMR spectra were determined on
a Varian Mercury VX 300 NMR spectrometer using TMS as an
internal standard and DMSO-d6 as a solvent. 13C NMR was not
always possible due to poor solubility. Mass spectra were
measured on a GCMS-QP1000 EX spectrometer at 70 eV.
Elemental analyses were carried out at the Microanalytical
Center of Cairo University, Giza, Egypt. Microwave experiments
were carried out using a CEM Discover LabmateTM microwave
apparatus (300 W with ChemDriverTM Software).
Colorless powder (A, 73 %; B, 78 %); (DMF), mp > 300 ºC; IR
1
(KBr) υ 2211 (C≡N) cm-1; H NMR (DMSO-d6) δ 3.97 (s, 4H,
CH2), 7.40-7.66 (m, 16H, ArH), 7.81 (s, 2H, H-5 pyridine), 8.12-
8.14 (m, 4H, ArH); MS m/z (%) 602 (0.5, M+), 573 (0.5), 509
(0.4), 473 (0.4), 406 (0.6), 315 (100.0), 288 (84.4), 255 (12.2),
227 (12.2), 140 (7.2), 64 (18.7). Anal. Calcd for C38H26N4S2: C,
75.72; H, 4.35; N, 9.29; S, 10.64. Found: C, 75.88; H, 4.46; N,
9.10; S, 10.55%.
2,2'-(Propane-1,3-diylbis(sulfanediyl))bis(4,6-
diphenylnicotinonitrile) (7b).
Pale yellow powder (A, 66 %; B, 75 %); (Acetic acid), mp 170-
1
172 ºC; IR (KBr) υ 2212 (C≡N) cm-1; H NMR (DMSO-d6) δ
2.35 (p, 2H, CH2, J = 6.3 Hz), 3.67 (t, 4H, CH2, J = 6.6 Hz), 7.47-
7.66 (m, 16H, ArH), 7.84 (s, 2H, H-5 pyridine), 8.23-8.25 (m,
4H, ArH); MS m/z (%) 616 (3.6, M+), 329 (88.8), 296 (51.3), 288
(80.7), 255 (30.1), 227 (23.6), 80 (42.5), 64 (100.0). Anal. Calcd
for C39H28N4S2: C, 75.94; H, 4.58; N, 9.08; S, 10.40. Found: C,
76.13; H, 4.62; N, 9.23; S, 10.32%.
4.2. Synthesis of bis-nicotinonitrile 6a-c, 7a-c, 9 and 10.
Method A: To a solution of 2-thioxo-1,2-dihydropyridine-3-
carbonitriles 3 or 4 (2 mmol) and KOH (2 mmol) in absolute
ethanol (10 ml), the dibromoalkanes 5a-c or 1,4-
bis(bromomethyl)benzene 8a (1 mmol) were added. The mixture
was refluxed for 1 h and was then allowed to cool to rt.
Thereupon it was poured over crushed ice and the formed
precipitate was filtered off, dried, and purified by
recrystallization.
2,2'-(Butane-1,4-diylbis(sulfanediyl))bis(4,6-
diphenylnicotinonitrile) (7c).
Pale yellow powder (A, 76 %; B, 83 %); (DMF), mp 224-226 ºC;
IR (KBr) υ 2213 (C≡N) cm-1; 1H NMR (DMSO-d6) δ 2.03 (br. s,
4H, CH2), 3.50 (br. s, 4H, CH2), 7.41-7.73 (m, 16H, ArH), 7.86
(s, 2H, H-5 pyridine), 8.20-8.23 (m, 4H, ArH); MS m/z (%) 630
(8.4, M+), 597 (4.4), 543 (5.0), 343 (100.0), 289 (60.3), 255
(28.3), 227 (19.8), 87 (16.7), 64 (26.4). Anal. Calcd for
C40H30N4S2: C, 76.16; H, 4.79; N, 8.88; S, 10.17. Found: C,
76.25; H, 4.88; N, 8.67; S, 10.30%.
Method B:
A mixture of 2-thioxo-1,2-dihydropyridine-3-
carbonitriles 3 or 4 (2 mmol), KOH (2 mmol) and the
dibromoalkanes 5a-c or 1,4-bis(bromomethyl)benzene 8a (1
mmol) in N,N-dimethylformamide (1 ml), in a closed vessel was
irradiated in a focused microwave reactor for the proper time at
o
160 C (250 W). The crude solid was isolated and recrystallized
from the proper solvent.
2,2'-((1,4-Phenylenebis(methylene))bis(sulfanediyl))bis(4,6-
dimethylnicotinonitrile)(9).
2,2'-(Ethane-1,2-diylbis(sulfanediyl))bis(4,6-
dimethylnicotinonitrile) (6a).
Colorless powder (A, 70 %; B, 77 %); (DMF), mp 210-212 ºC;
Brown needles crystals (A, 79 %; B, 86 %); (DMF/EtOH), mp
228-230 ºC; IR (KBr) υ 2203 (C≡N) cm-1; 1H NMR (DMSO-d6)
δ 2.39 (s, 6H, CH3), 2.41 (s, 6H, CH3), 3.60 (s, 4H, CH2), 7.11 (s,
2H, H-5 pyridine); MS m/z (%) 354 (0.6, M+), 343 (0.6), 321
(0.7), 288 (1.3), 191 (100.0), 164 (89.7). Anal. Calcd for
C18H18N4S2: C, 60.99; H, 5.12; N, 15.80; S, 18.09. Found: C,
60.80; H, 4.97; N, 15.71; S, 18.16%.
1
IR (KBr) υ 2212 (C≡N) cm-1; H NMR (DMSO-d6) δ 2.36 (s,
6H, CH3), 2.51 (s, 6H, CH3), 4.46 (s, 4H, CH2), 7.06 (s, 2H, H-5
pyridine), 7.35 (s, 4H, aromatic); MS m/z (%) 430 (31.5, M+),
396 (17.3), 307 (14.3), 266 (100.0), 232 (59.4), 104 (95.3), 78
(33.8). Anal. Calcd for C24H22N4S2: C, 66.94; H, 5.15; N, 13.01;
S, 14.89. Found: C, 66.76; H, 5.29; N, 13.14; S, 14.96%.
2,2'-Propane-1,3-diylbis(sulfanediyl))bis(4,6-
dimethylnicotinonitrile) (6b).
2,2'-((1,4-Phenylenebis(methylene))bis(sulfanediyl))bis(4,6-
diphenylnicotinonitrile) (10).
Yellow needles crystals (A, 75 %; B, 80 %); (Acetic acid), mp
182-184 ºC; IR (KBr) υ 2214 (C≡N) cm-1; 1H NMR (DMSO-d6)
16

Pale yellow powder (A, 88 %; B, 90 %); (DMF/ EtOH), mp 248-
Colourless powder (A, 72 %; B, 78 %); (DMF), mp > 300 ºC; IR
ACCEPTED MANUSCRIPT
1
1
250 ºC; IR (KBr) υ 2212 (C≡N) cm-1; H NMR (DMSO-d6) δ
(KBr) υ 2214 (C≡N) cm-1; H NMR (DMSO-d6) δ 4.86 (s, 8H,
4.69 (s, 4H, CH2), 7.46 (s, 4H, ArH), 7.50-7.59 (m, 12H, ArH),
7.72-7.78 (m, 4H, ArH), 7.89 (s, 2H, H-5 pyridine), 8.23-8.29
(m, 4H, ArH); 13C NMR (DMSO-d6) δ 33.41, 102.72, 115.55,
116.34, 120.79, 127.55, 128.79, 128.87, 128.94, 130.05, 130.72,
135.63, 136.48, 136.58, 154.28, 157.99, 162.15; MS m/z (%) 678
(54.4, M+), 391 (95.3), 357 (77.6), 288 (85.3), 255 (28.9), 227
(27.7), 140 (31.7), 104 (100.0), 91 (52.1), 77 (36.6), 64 (95.2).
Anal. Calcd for C44H30N4S2: C, 77.85; H, 4.45; N, 8.25; S, 9.45.
Found: C, 77.70; H, 4.37; N, 8.17; S, 9.34%.
CH2), 7.30-831 (m, 46H, aromatic and pyridine H); MS m/z (%)
1279. Anal. Calcd for C82H54N8S4: C, 76.97; H, 4.25; N, 8.76; S,
10.02. Found: C, 77.12; H, 4.37; N, 8.63; S, 10.11%.
2,2',2'',2''',2'''',2'''''-((Benzene-1,2,3,4,5,6-
hexaylhexakis(methylene))hexakis(sulfanediyl))-hexakis(4,6-
dimethylnicotinonitrile) (18).
Colorless powder (A, 73 %; B, 77 %); (DMF), mp 310-312 ºC;
1
IR (KBr) υ 2214 (C≡N) cm-1; H NMR (DMSO-d6) δ 2.14 (s,
18H, CH3), 2.38 (s, 18H, CH3), 4.75 (s, 12H, CH2), 6.98 (s, 6H,
H-5 pyridine); MS m/z (%) 1135. Anal. Calcd for C60H54N12S6: C,
63.46; H, 4.79; N, 14.80; S, 16.94. Found: C, 63.35; H, 4.92; N,
14.63; S, 16.84%.
2,2',2'',2''',2'''',2'''''-((Benzene-1,2,3,4,5,6-
hexaylhexakis(methylene))hexakis(sulfanediyl))-hexakis(4,6-
4.3. Synthesis of tris, tetrakis and hexakis-nicotinonitrile 12,
13, 15, 16, 18 and 19.
Method A: To a solution of 2-thioxo-1,2-dihydropyridine-3-
carbonitriles 3 or 4 (3 or 4 or 6 mmol) and KOH (3 or 4 or 6
mmol) in absolute ethanol (10 ml), the appropriate
(bromomethyl)benzene 11, 14 or 17 (1 mmol) was added. The
reaction mixture was heated under reflux for 1 h and was then
allowed to cool to rt. The mixture was poured over crushed ice
and the formed precipitate was filtered off, dried, and purified by
recrystallization.
diphenylnicotinonitrile) (19).
Pale yellow powder (A, 50 %; B, 64 %); (DMF/ EtOH), mp 228-
1
230 ºC; IR (KBr) υ 2214 (C≡N) cm-1; H NMR (DMSO-d6) δ
5.17 (s, 12H, CH2), 7.22-7.24 (m, 18H, ArH), 7.32-7.38 (m, 12H,
ArH), 7.46 (s, 6H, H-5 pyridine), 7.49-7.53 (m, 18H, ArH), 7.95-
8.01 (m, 12H, ArH); 13C NMR (DMSO-d6) δ 29.91, 102.23,
115.30, 120.75, 126.75, 128.42, 128.53, 128.57, 129.92, 130.49,
135.14, 135.43, 136.80, 153.75, 156.99, 161.14; MS m/z (%)
1880. Anal. Calcd for C120H78N12S6: C, 76.65; H, 4.18; N, 8.94;
S, 10.23. Found: C, 76.49; H, 4.00; N, 8.73; S, 10.17%.
4.4. Synthesis of thiazolo[3,2-a]pyrimidine 28a, pyrimido[2,1-
b][1,3]thiazine 28b, and the bis-1,4-dihydropyrimidine-5-
carbonitrile 21c, 21d, 29 and 30.
Method A: To a mixture of 5-cyano-4-oxo-6-phenyl-2-thioxo-
1,2,3,4-tetrahydro-pyrimidine (20) (2 mmol) and KOH (2 mmol)
in absolute ethanol (10 ml), dibromoalkanes 5a-d or
bis(bromomethyl)benzenes 8a or 8b (1 mmol) was added. The
mixture was heated at reflux temperature for 1 h and was then
allowed to cool to rt. Thereupon it was poured over crushed ice
and the formed precipitate was filtered off, dried, and purified by
recrystallization.
Method B: A solution of 5-cyano-4-oxo-6-phenyl-2-thioxo-
1,2,3,4-tetrahydro-pyrimidine (20) (2 mmol) and KOH (2 mmol)
and dibromoalkanes 5a-d or bis(bromomethyl)benzenes 8a or 8b
(1 mmol) in N,N-dimethylformamide (1 ml), in a closed vessel
was irradiated in a focused microwave reactor at 160 oC (250 W).
The crude solid was isolated and recrystallized.
Method B:
A mixture of 2-thioxo-1,2-dihydropyridine-3-
carbonitriles 3 or 4 (3 or 4 or 6 mmol) and KOH (3 or 4 or 6
mmol) and the appropriate (bromomethyl)benzene 11, 14 or 17
(1 mmol) in N,N-dimethylformamide (1 ml), in a closed vessel
was irradiated in a focused microwave reactor at 160 oC (250 W).
The crude solid was isolated and recrystallized.
2,2',2''-((Benzene-1,3,5-
triyltris(methylene))tris(sulfanediyl))tris(4,6-dimethylnicotino-
nitrile) (12).
Colorless powder (A, 74 %; B, 75 %); (DMF), mp 197-200 ºC;
1
IR (KBr) υ 2213 (C≡N) cm-1; H NMR (DMSO-d6) δ 2.36 (s,
9H, CH3), 2.46 (s, 9H, CH3), 4.43 (s, 6H, CH2), 7.05 (s, 3H, H-5
pyridine), 7.36 (s, 3H, aromatic); 13C NMR (DMSO-d6) δ 19.55,
24.18, 32.81, 103.61, 114.83, 120.34, 128.54, 137.94, 152.43,
160.06, 161.27; MS m/z (%) 606 (52.4, M+), 442 (55.6), 409
(32.5), 311 (33.0), 279 (62.3), 246 (32.6), 164 (25.2), 115 (51.2),
64(100.0). Anal. Calcd for C33H30N6S3: C, 65.32; H, 4.98; N,
13.85; S, 15.85. Found: C, 65.11; H, 4.77; N, 13.76; S, 15.73%.
2,2',2''-((Benzene-1,3,5-
triyltris(methylene))tris(sulfanediyl))tris(4,6-diphenyl-nicotino-
nitrile) (13).
Colorless powder (A, 82 %; B, 89 %); (DMF), mp 288-290 ºC;
1
IR (KBr) υ 2213 (C≡N) cm-1; H NMR (DMSO-d6) δ 4.60 (s,
7-Oxo-5-phenyl-3,7-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-
carbonitrile (28a).
6H, CH2), 7.38 (s, 3H, ArH), 7.39-7.41 (m, 6H, ArH), 7.55-7.65
(m, 18H, ArH), 7.74 (s, 3H, H-5 pyridine), 8.09-8.12 (m, 6H,
ArH); MS m/z (%) 979 (38.2, M+), 930 (35.9), 852 (29.7), 788
(26.9), 752 (31.4), 625 (27.7), 518 (35.1), 477 (36.5), 396 (35.1),
348 (34.5), 273 (34.5), 227 (40.2), 166 (39.0), 64 (100.0). Anal.
Calcd for C63H42N6S3: C, 77.27; H, 4.32; N, 8.58; S, 9.82. Found:
C, 77.35; H, 4.21; N, 8.43; S, 9.69%.
Colorless needles crystals (A, 61 %; B, 72 %); (Ethanol), mp
182-184 ºC; IR (KBr) υ 2222 (C≡N), 1670 (C=O) cm-1; 1H NMR
(DMSO-d6) δ 3.64 (t, 2H, CH2, J = 7.8 Hz), 4.47 (t, 2H, CH2, J =
7.5 Hz), 7.56-7.58 (m, 3H, ArH), 7.85-7.87 (m, 2H, ArH); 13C
NMR (DMSO-d6) δ 26.91, 49.46, 85.14, 118.82, 128.16, 128.64,
130.14, 137.59, 162.77, 167.48, 182.89; MS m/z (%) 255 (8.6,
M+), 223 (43.4), 169 (34.8), 141 (35.7), 108 (28.5), 79 (31.7), 44
(100.0). Anal. Calcd for C13H9N3OS: C, 61.16; H, 3.55; N, 16.46;
S, 12.56. Found: C, 61.28; H, 3.46; N, 16.65; S, 12.43%.
8-Oxo-6-phenyl-2,3,4,8-tetrahydropyrimido[2,1-b][1,3]thiazine-
7-carbonitrile (28b).
2,2',2'',2'''-((Benzene-1,2,4,5-
tetrayltetrakis(methylene))tetrakis(sulfanediyl))tetrakis(4,6-
dimethylnicotinonitrile) (15).
Colorless powder (A, 65 %; B, 69 %); (DMF), mp 296-300 ºC;
1
IR (KBr) υ 2215 (C≡N) cm-1; H NMR (DMSO-d6) δ 2.37 (s,
12H, CH3), 2.44 (s, 12H, CH3), 4.62 (s, 8H, CH2), 7.06 (s, 4H, H-
5 pyridine), 7.57 (s, 2H, aromatic); MS m/z (%) 783 (4.8, M+),
715 (4.3), 685 (4.5), 584 (4.8), 404 (5.0), 340 (4.2), 80 (100.0).
Anal. Calcd for C42H38N8S4: C, 64.42; H, 4.89; N, 14.31; S,
16.38. Found: C, 64.65; H, 4.69; N, 14.44; S, 16.51%.
2,2',2'',2'''-((Benzene-1,2,4,5-
Yellow needles crystals (A, 84 %; B, 87 %); (Acetic acid), mp
218-220 ºC; IR (KBr) υ 2214 (C≡N), 1681 (C=O) cm-1; 1H NMR
(DMSO-d6) δ 2.21-2.27 (m, 2H, CH2), 3.28 (t, 2H, CH2, J = 5.7
Hz), 4.02 (t, 2H, CH2, J = 5.4 Hz), 7.52-7.60 (m, 3H, ArH), 7.85-
7.88 (m, 2H, ArH); 13C NMR (DMSO-d6) δ 20.91, 27.68, 42.19,
91.64, 115.93, 120.73, 128.40, 128.55, 131.58, 134.82, 159.78,
165.43; MS m/z (%) 269 (15.3, M+), 241 (55.4), 181 (34.4), 149
(14.8), 91 (34.6), 75 (46.0), 46 (39.5), 30 (100.0). Anal. Calcd for
tetrayltetrakis(methylene))tetrakis(sulfanediyl))tetrakis(4,6-
diphenylnicotinonitrile) (16).
17

Tetrahedron
ACCEPTED MANUSCRIPT
C14H11N3OS: C, 62.43; H, 4.12; N, 15.60; S, 11.91. Found: C,
2,2',2''-((Benzene-1,3,5-
62.38; H, 4.19; N, 15.65; S, 11.83%.
2,2'-(Butane-1,4-diylbis(sulfanediyl))bis(4-oxo-6-phenyl-1,4-
dihydropyrimidine-5-carbonitrile) (21c).
triyltris(methylene))tris(sulfanediyl))tris(4-oxo-6-phenyl-1,4-
dihydropyrimidine-5-carbonitrile) (31).
Colorless plates crystals (A, 71 %; B, 75 %); (Acetic acid), mp
Colorless needles crystals (A, 90 %; B, 91 %); (Acetic acid), mp
300-302 ºC; IR (KBr) υ 3420 (NH), 2214 (C≡N), 1681 (C=O)
1
cm-1; H NMR (DMSO-d6) δ 4.35 (s, 6H, CH2), 7.37 (s, 3H,
290-292 ºC; IR (KBr) υ 3421 (NH), 2213 (C≡N), 1671 (C=O)
1
cm-1; H NMR (DMSO-d6) δ 1.82 (br. s, 4H, CH2), 3.26 (br. s,
ArH), 7.49-7.51 (m, 12H, ArH+NH), 7.85-7.88 (m, 6H, ArH);
13C NMR (DMSO-d6) δ 33.85, 93.15, 115.71, 128.43, 128.61,
128.93, 131.57, 135.10, 136.90, 161.10, 165.44, 167.18; MS m/z
(%) 801 (4.4, M+), 642 (6.3), 337 (15.9), 262 (26.1), 95 (61.0), 67
(100.0). Anal. Calcd for C42H27N9O3S3: C, 62.91; H, 3.39; N,
15.72; S, 12.00. Found: C, 62.78; H, 3.29; N, 15.67; S, 11.91%.
2,2',2'',2'''-((Benzene-1,2,4,5-
tetrayltetrakis(methylene))tetrakis(sulfanediyl)) tetrakis(4-oxo-
6-phenyl-1,4-dihydropyrimidine-5-carbonitrile) (32).
Colorless plates crystals (A, 78 %; B, 88 %); (Acetic acid), mp >
300 ºC; IR (KBr) υ 3417 (NH), 2222 (C≡N), 1651 (C=O) cm-1;
1H NMR (DMSO-d6) δ 4.49 (s, 8H, CH2), 7.41-7.49 (m, 16H,
ArH+NH), 7.58 (s, 2H, ArH), 7.73-7.75 (m, 8H, ArH); MS m/z
(%) 1042 (7.3, M+), 992 (100.0), 815 (67.1), 611 (10.5), 481
(21.9), 249 (12.2). Anal. Calcd for C54H34N12O4S4: C, 62.17; H,
3.29; N, 16.11; S, 12.30. Found: C, 62.28; H, 3.36; N, 15.98; S,
12.13%.
4H, CH2), 7.48-7.59 (m, 6H, ArH), 7.77-7.91 (m, 4H, ArH),
13.73 (br. s, 2H, NH); 13C NMR (DMSO-d6) δ 27.76, 29.71,
92.86, 115.78, 120.75, 128.46, 128.55, 131.65, 135.15, 160.88,
165.94; MS m/z (%) 512 (19.5, M+), 445 (16.1), 421 (41.4), 375
(100.0), 227 (11.0). Anal. Calcd for C26H20N6O2S2: C, 60.92; H,
3.93; N, 16.39; S, 12.51. Found: C, 60.79; H, 3.81; N, 16.52; S,
12.35%.
2,2'-(Pentane-1,5-diylbis(sulfanediyl))bis(4-oxo-6-phenyl-1,4-
dihydropyrimidine-5-carbonitrile) (21d).
Colorless needles crystals (A, 70 %; B, 77 %); (Ethanol), mp
114-116 ºC; IR (KBr) υ 3421 (NH), 2218 (C≡N), 1658 (C=O)
1
cm-1; H NMR (DMSO-d6) δ 1.49-1.52 (m, 2H, CH2), 1.69-1.73
(m, 4H, CH2), 3.11-3.15 (m, 4H, CH2), 7.48-7.51 (m, 6H, ArH),
7.84-7.86 (m, 4H, ArH), 13.34 (br. s, 2H, NH); MS m/z (%) 526
(18.5, M+), 368 (100.0), 255 (20.8), 165 (98.9), 105 (39.8). Anal.
Calcd for C27H22N6O2S2: C, 61.58; H, 4.21; N, 15.96; S, 12.18.
Found: C, 61.69; H, 4.41; N, 15.88; S, 12.33%.
Acknowledgment:
The authors gratefully acknowledge the Alexander von
Humboldt Foundation for a research fellowship.
2,2'-((1,4-Phenylenebis(methylene))bis(sulfanediyl))bis(4-oxo-
6-phenyl-1,4-dihydro-pyrimidine-5-carbonitrile) (29).
Colorless powder (A, 75 %; B, 82 %); (DMF), mp 292-294 ºC;
IR (KBr) υ 3417 (NH), 2218 (C≡N), 1681 (C=O) cm-1; 1H NMR
(DMSO-d6) δ 4.50 (s, 4H, CH2), 7.35 (s, 4H, ArH), 7.53-7.60
(m, 6H, ArH), 7.87-7.95 (m, 6H, ArH+NH); MS m/z (%) 560
(1.7, M+), 495 (75.2), 339 (45.7), 285 (41.0), 211 (100.0), 98
(30.6), 57 (50.2). Anal. Calcd for C30H20N6O2S2: C, 64.27; H,
3.60; N, 14.99; S, 11.44. Found: C, 64.44; H, 3.48; N, 14.86; S,
11.35%.
References:
1.
2.
3.
4.
Baumann, M.; Baxendale, I. R. Beilstein J. Org.
Chem. 2013, 9, 2265–2319.
Konda, S. G.; Khedkar, V. T.; Dawane, B. J. Chem.
Pharm. Res. 2010, 2, 187–191.
Mungra, D. C.; Patel, M. P.; Patel, R. G. 2009, 2009,
64–74.
Vyas, D. H.; Tala, S. D.; Akbari, J. D.; Dhaduk, M.
F.; Joshi, K. A.; Joshi, H. S. Indian J. Chem. Sect. B-
Organic Chem. Incl. Med. Chem. 2009, 48, 833–839.
Gholap, A. R.; Toti, K. S.; Shirazi, F.; Kumari, R.;
Bhat, M. K.; Deshpande, M. V; Srinivasan, K. V
Bioorg. Med. Chem. 2007, 15, 6705–15.
Bekhit, A. A.; Baraka, A. M. Eur. J. Med. Chem.
2005, 40, 1405–1413.
Murata, T.; Shimada, M.; Sakakibara, S.; Yoshino, T.;
Kadono, H.; Masuda, T.; Shimazaki, M.; Shintani, T.;
Fuchikami, K.; Sakai, K.; Inbe, H.; Takeshita, K.;
Niki, T.; Umeda, M.; Bacon, K. B.; Ziegelbauer, K.
B.; Lowinger, T. B. Bioorg. Med. Chem. Lett. 2003,
13, 913–918.
2,2'-((1,3-Phenylenebis(methylene))bis(sulfanediyl))bis(4-oxo-
6-phenyl-1,4-dihydropyrimidine-5-carbonitrile) (30).
Colorless powder (A, 80 %; B, 87 %); (EtOH/ H2O), mp 282-284
1
ºC; IR (KBr) υ 3414 (NH), 2218 (C≡N), 1693 (C=O) cm-1; H
5.
NMR (DMSO-d6) δ 4.43 (s, 4H, CH2), 7.26-7.32 (m, 4H, ArH),
7.48-7.57 (m, 8H, ArH+NH), 7.88-7.91 (m, 4H, ArH); MS m/z
(%) 560 (5.4, M+), 495 (66.5), 395 (19.5), 339 (39.7), 285 (38.3),
211 (100.0), 98 (25.2), 71 (32.7). Anal. Calcd for C30H20N6O2S2:
C, 64.27; H, 3.60; N, 14.99; S, 11.44. Found: C, 64.13; H, 3.52;
N, 14.85; S, 11.33%.
6.
7.
4.5.
Synthesis
of
1,3,5-Tris(1,4-dihydropyrimidine-5-
carbonitriles) 31 and 1,2,4,5-tetrakis(1,4-dihydropyrimidine-
5-carbonitriles) 32
Method A: To a mixture of 5-cyano-4-oxo-6-phenyl-2-thioxo-
1,2,3,4-tetrahydro-pyrimidine (20) (3 or 4 mmol) and KOH (3 or
8.
Hammam, A. E.; El-Salam, O. I. A.; Mohamed, A.
M.; Abdel Hafez, N. Indian J. Chem. Sect. B 2005,
44B, 1887–1893.
Shi, F. Arkivoc 2005, 2005, 137–142.
Temple, C.; Rener, G. a; Waud, W. R.; Noker, P. E. J.
Med. Chem. 1992, 35, 3686–3690.
Badgett, C. O.; Woodward, C. F. J. Am. Chem. Soc.
1947, 69, 2907–2907.
Mercier, J.; Gavend, M.; Vanluv, V.; Dessaigne, S.
Congr Union ther Int 1963, 361.
4
mmol)
in
absolute
ethanol
(10
ml),
1,3,5-
tris(bromomethyl)benzene (11) (1 mmol) or 1,2,4,5-
tetrakis(bromomethyl)benzene (14) (1 mmol) was added. The
reaction mixture was refluxed for 1 h and was then allowed to
cool to rt. The reaction mixture was then poured over crushed ice
and the formed crude products were filtered off, dried, and
purified by recrystallization from acetic acid.
Method B: A solution of 5-cyano-4-oxo-6-phenyl-2-thioxo-
1,2,3,4-tetrahydro-pyrimidine (20) (3 or 4 mmol), KOH (3 or 4
mmol) and 1,3,5-tris(bromomethyl)benzene (11) (1 mmol) or
1,2,4,5-tetrakis(bromomethyl)benzene (14) (1 mmol) in N,N-
dimethylformamide (1 ml), in a closed vessel was irradiated in a
9.
10.
11.
12.
13.
14.
15.
Dorner, V.; Fischer, F. W. Arzneim-Frosch 1961, 11,
110–113.
Boger, D. L.; Nakahara, S. J. Org. Chem. 1991, 56,
880–884.
o
focused microwave reactor for 1 min. at 160 C (250 W). The
crude solid was isolated and recrystallized.
Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989,
18

111, 1517–1519.
42.
ACCEPTED MANUSACnRtoInPinTi, I.; Polucci, P.; Magnano, A.; Gatto, B.;
16.
Zhang, T. Y.; Stout, J. R.; Keay, J. G.; Scriven, E. F.
V.; Toomey, J. E.; Goe, G. L. Tetrahedron 1995, 51,
13177–13184.
Altundas, A.; Ayvaz, S.; Logoglu, E. Med. Chem.
Res. 2011, 20, 1–8.
Sasada, T.; Kobayashi, F.; Sakai, N.; Konakahara, T.
Org. Lett. 2009, 11, 2161–2164.
Agarwal, N.; Raghuwanshi, S. K.; Upadhyay, D. N.;
Shukla, P. K.; Ram, V. J. Bioorg. Med. Chem. Lett.
2000, 10, 703–706.
H. S. Basavaraj; G. M. Sreenivasa; E. Jayachandran;
L. V. G. Nargund; D. S. Rao. Indian J. Heterocycl.
Chem. 2005, 15, 69–70.
Sondhi, S. M.; Jain, S.; Dwivedi, A. D.; Shukla, R.;
Raghubir, R. Indian J. Chem. - Sect. B Org. Med.
Chem. 2008, 47, 136–143.
Hannah, D. R.; Stevens, M. F. G. J. Chem. Res. 2003,
398–401.
Rana, K.; Kaur, B.; Kumar, B. Indian J. Chem. Sect.
B Org. Chem. Incl. Med. Chem. 2004, 43, 1553–1557.
Balzarini, J.; McGuigan, C. J. Antimicrob.
Chemother. 2002, 50, 5–9.
Palumbo, M.; Menta, E.; Pescalli, N.; Martelli, S. J.
Med. Chem. 2003, 46, 3109–15.
43.
44.
45.
46.
Antonini, I.; Polucci, P.; Magnano, A.; Sparapani, S.;
Martelli, S. J. Med. Chem. 2004, 47, 5244–5250.
Wakelin, L. P. G.; Creasy, T. S.; Waring, M. J. FEBS
Lett. 1979, 104, 261–265.
Shaker, R. M. Phosphorus. Sulfur. Silicon Relat.
Elem. 1999, 149, 7–14.
Csuk, R.; Barthel, A.; Raschke, C.; Kluge, R.; Ströhl,
D.; Trieschmann, L.; Böhm, G. Arch. Pharm.
(Weinheim). 2009, 342, 699–709.
Menger, F. M.; Azov, V. A. J. Am. Chem. Soc. 2002,
124, 11159–11166.
Gingras, M.; Pinchart, A.; Dallaire, C. Angew. Chem.
Int. Ed. 1998, 37, 3149–3151.
AL-Smadi, M.; Mohammad, S. J. Heterocycl. Chem.
2009, 46, 201–206.
Achelle, S.; Plé, N.; Kreher, D.; Attias, A.-J.; Arfaoui,
I.; Charra, F. Tetrahedron Lett. 2009, 50, 7055–7058.
Elwahy, A. H. M. Tetrahedron Lett. 2001, 42, 5123–
5126.
van Manen, H.-J.; Fokkens, R. H.; van Veggel, F. C.
J. M.; Reinhoudt, D. N. Eur. J. Org. Chem. 2002,
2002, 3189–3197.
17.
18.
19.
20.
21.
47.
48.
49.
50.
51.
52.
22.
23.
24.
25.
Lee, H. W.; Bok, Y. K.; Joong, B. A.; Sung, K. K.;
Lee, J. H.; Jae, S. S.; Soon, K. A.; Lee, S. J.; Seung,
S. Y. Eur. J. Med. Chem. 2005, 40, 862–874.
Abu-Hashem, A. A.; El-Shehry, M. F.; Badria, F. A.-
E. Acta Pharm. 2010, 60, 311–23.
53.
Steed, J. W.; Turner, D. R.; Wallace, K. J. Core
concepts in supramolecular chemistry and
nanochemistry; John Wiley, 2007.
26.
27.
28.
Xie, F.; Zhao, H.; Zhao, L.; Lou, L.; Hu, Y. Bioorg.
Med. Chem. Lett. 2009, 19, 275–278.
54.
55.
Steed, J. W.; Atwood, J. L. Supramolecular
Chemistry; John Wiley & Sons, 2013.
García-Frutos, E. M.; Omenat, A.; Barberá, J.;
Serrano, J. L.; Gómez-Lor, B. J. Mater. Chem. 2011,
21, 6831.
Gómez-Lor, B.; Alonso, B.; Omenat, A.; Serrano, J.
L. Chem. Commun. 2006, 5012–5014.
Talarico, M.; Termine, R.; García-Frutos, E. M.;
Omenat, A.; Serrano, J. L.; Gómez-Lor, B.;
Golemme, A. Chem. Mater. 2008, 20, 6589–6591.
Traber, B.; Wolff, J. J.; Rominger, F.; Oeser, T.;
Gleiter, R.; Goebel, M.; Wortmann, R. Chemistry
2004, 10, 1227–38.
Kaur, R.; Kaur, P.; Sharma, S.; Singh, G.;
Mehndiratta, S.; M.S. Bedi, P.; Nepali, K. Recent Pat.
Anticancer. Drug Discov. 2014, 10, 23–71.
Wick, von I. K. und A. Helv. Chim. Acta 1977, 60,
3025–3034.
Hawser, S.; Lociuro, S.; Islam, K. Biochem.
Pharmacol. 2006, 71, 941–948.
Schneider, P.; Hawser, S.; Islam, K. Bioorg. Med.
Chem. Lett. 2003, 13, 4217–4221.
Roth, B.; Cheng, C. C. Prog Med Chem 1982, 19,
269–331.
Sharma, P.; Rane, N.; Gurram, V. . K. Bioorg. Med.
Chem. Lett. 2004, 14, 4185–4190.
Prakash, O.; Bhardwaj, V.; Kumar, R.; Tyagi, P.;
Aneja, K. R. Eur. J. Med. Chem. 2004, 39, 1073–
1077.
29.
30.
31.
32.
33.
34.
56.
57.
58.
59.
60.
Shoji, T.; Higashi, J.; Ito, S.; Okujima, T.; Yasunami,
M.; Morita, N. Chemistry 2011, 17, 5116–29.
Bruder, F. K.; Hagen, R.; Roelle, T.; Weiser, M. S.;
Faecke, T. Angew. Chem. Int. Ed. 2011, 50, 4552–
4573.
35.
Agarwal, N.; Srivastava, P.; Raghuwanshi, S. K.;
Upadhyay, D. N.; Sinha, S.; Shukla, P. K.; Ji Ram, V.
Bioorg. Med. Chem. Lett. 2002, 10, 869–874.
Murru, S.; Nefzi, A. ACS Comb. Sci. 2014, 16, 39–45.
Dolle, R. E. J. Comb. Chem. 2005, 7, 739–98.
Dolle, R. E. J. Comb. Chem. 2004, 6, 623–79.
Helal, C. J.; Sanner, M. A.; Cooper, C. B.; Gant, T.;
Adam, M.; Lucas, J. C.; Kang, Z.; Kupchinsky, S.;
Ahlijanian, M. K.; Tate, B.; Menniti, F. S.; Kelly, K.;
Peterson, M. Bioorg. Med. Chem. Lett. 2004, 14,
5521–5525.
Soural, M.; Bouillon, I.; Krchňák, V. J. Comb. Chem.
2008, 10, 923–933.
Thurston, D. E.; Bose, D. S.; Thompson, A. S.;
Howard, P. W.; Leoni, A.; Croker, S. J.; Jenkins, T.
C.; Neidle, S.; Hartley, J. A.; Hurley, L. H. J. Org.
Chem. 1996, 61, 8141–8147.
61.
62.
Astruc, D.; Boisselier, E.; Ornelas, C. Chem. Rev.
2010, 110, 1857–959.
Nanjwade, B. K.; Bechra, H. M.; Derkar, G. K.;
Manvi, F. V; Nanjwade, V. K. Eur. J. Pharm. Sci.
2009, 38, 185–96.
Rajakumar, P.; Raja, S. Tetrahedron Lett. 2008, 49,
6539–6542.
Grillaud, M.; Bianco, A. J. Pept. Sci. 2015, 21, 330–
45.
Perreux, L.; Loupy, A. In Microwaves in Organic
Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA:
Weinheim, FRG, 2004; pp. 61–114.
Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250–
6284.
Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107,
2563–91.
Oliver Kappe, C. Chem. Soc. Rev. 2008, 37, 1127–39.
36.
37.
38.
39.
63.
64.
65.
40.
41.
66.
67.
68.
19

Tetrahedron
ACCEPTED MANUSCRIPT
Krauze, A. A.; Bomika, Z. A.; Shestopalov, A. M.;
69.
Rodinovskaya, L. A.; Pelcher, Y. É.; Dubur, G. Y.;
Sharanin, Y. A.; Promonenkov, V. K. Chem.
Heterocycl. Compd. 1981, 17, 279–284.
Tamboli, R. S.; Amrutkar, R. D.; Jain, K. S.;
Kathiravan, M. K. Lett. Drug Des. Discov. 2013, 10,
906–915.
El Ashry, E. S. H.; El Tamany, E. S. H.; El Fattah, M.
E. D. A.; Boraei, A. T. A.; Abd El-Nabi, H. M. Eur. J.
Med. Chem. 2013, 66, 106–113.
Ellis Harwood Solid Supports and Catalysts in
Organic Synthesis (Ellis Horwood and Prentice Hall
Organic Chemistry Series); London, 1992.
Cornelis, A.; Laszlo, P. Synthesis 1985, 1985, 909–
918.
70.
71.
72.
73.
74.
75.
76.
Varma, R. S. Green Chem. 1999, 1, 43–55.
Kambe, S.; Saito, K. Synthesis 1979, 1979, 287–289.
Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785–789.
77.
78.
Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
Petersson, G. A.; Bennett, A.; Tensfeldt, T. G.; Al-
Laham, M. A.; Shirley, W. A.; Mantzaris, J. J. Chem.
Phys. 1988, 89, 2193.
79.
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Jr, J.
A. M. Gaussian 03, revision Revision A.1, Gaussian,
Inc., Pittsburgh PA; 2003.
80.
81.
82.
83.
Yang, W.; Mortier, W. J. J. Am. Chem. Soc. 1986,
108, 5708–5711.
Yang, W.; Parr, R. G. Proc. Natl. Acad. Sci. 1985, 82,
6723–6726.
Katritzky, A. R.; Jug, K.; Oniciu, D. C. Chem. Rev.
2001, 101, 1421–1450.
Stoyanov, S.; Stoyanova, T.; Akrivos, P. D.;
Karagiannidis, P.; Nikolov, P. J. Heterocycl. Chem.
1996, 33, 927–931.
84.
85.
Ohms, U.; Guth, H.; Kutoglu, A.; Scheringer, C.;
IUCr Acta Crystallogr. Sect. B Struct. Crystallogr.
Cryst. Chem. 1982, 38, 831–834.
Moran, D.; Sukcharoenphon, K.; Puchta, R.; Schaefer,
H. F.; Schleyer, P. v. R.; Hoff, C. D. J. Org. Chem.
2002, 67, 9061–9069.
86.
87.
Abdulla, H. I.; El-Bermani, M. F. Spectrochim. Acta
Part A Mol. Biomol. Spectrosc. 2001, 57, 2659–2671.
Eyduran, F.; Oezyuerek, C.; Dilek, N.; Ocak Iskeleli,
N.; Şendil, K. Acta Crystallogr. Sect. E Struct.
Reports Online 2007, 63, o2415–o2417.
Lapinski, L.; Nowak, M. J.; Fulara, J.; Les, A.;
Adamowicz, L. J. Phys. Chem. 1992, 96, 6250–6254.
Freeman, F.; Po, H. N. J. Phys. Chem. A 2006, 110,
7904–7912.
Yang, X.; Guo, Y.; Strongin, R. M. Org. Biomol.
Chem. 2012, 10, 2739.
Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981,
14, 95–102.
88.
89.
90.
91.
92.
Li, H.; Jin, L.; Kan, Y.; Yin, B. Sensors Actuators B
Chem. 2014, 196, 546–554.
20