A New Facile, High Yielding and Efficient Protocol for the Synthesis of Novel 4-Phenylsulfonamido-6-Aryl-2-Phenylpyrimidine-5-Carbonitrile Derivatives

Article abstract of DOI:10.1080/10426507.2015.1050017

A series of novel 4-phenylsulfonamido-6-aryl-2-phenylpyrimidine-5-carbonitrile derivatives have been synthesized through a two-step process. This protocol includes a facile surfactant-mediated methodology for the synthesis of 4-amino-6-aryl-2-phenylpyrimi

Full text of DOI:10.1080/10426507.2015.1050017

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
A New Facile, High Yielding and Efficient Protocol
for the Synthesis of Novel 4-Phenylsulfonamido-6-
aryl-2-phenylpyrimidine-5-carbonitrile Derivatives
Reza Aryan, Masoomeh Nojavan & Fatemeh Sadeghi
To cite this article: Reza Aryan, Masoomeh Nojavan & Fatemeh Sadeghi (2015): A New Facile,
High Yielding and Efficient Protocol for the Synthesis of Novel 4-Phenylsulfonamido-6-aryl-2-
phenylpyrimidine-5-carbonitrile Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2015.1050017
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1050017
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Synthesis of Novel 4-Phenyl sulfonamido-pyrimidine Derivatives
A New Facile, High Yielding and Efficient Protocol for the Synthesis of Novel 4-
Phenylsulfonamido-6-aryl-2-phenylpyrimidine-5-carbonitrile Derivatives
Reza Aryan1,*, Masoomeh Nojavan1 and Fatemeh Sadeghi1
1Department of Chemistry, Faculty of Science, University of Zabol, P. O. Box: 9861335856,
Zabol, Iran
*Corresponding author E-mail: rezaaryan@uoz.ac.ir, rezaaryanchemist@yahoo.com
Abstract
A series of novel 4-phenylsulfonamido-6-aryl-2-phenylpyrimidine-5-carbonitrile derivatives
have been synthesized through a two-step process. This protocol includes a facile surfactant-
mediated methodology for the synthesis of 4-amino-6-aryl-2-phenylpyrimidine-5-carbonitrile
derivatives through a one-pot, three-component reaction in the presence of a catalytic amount of
cetyltrimethylammonium bromide in water. No additional organic solvents and oxidants were
used. The pyrimidine-5-carbonitrile products were then subjected to a direct sulfonylation of 4-
amino group to 4-phenylsulfonamide-6-aryl-2-phenylpyrimidine-5-carbonitrile derivatives in the
presence of sodium hydride in tetrahydrofuran solution. These new structures were confirmed by
1H- and 13CNMR spectroscopy as well as mass spectrometry and elemental analyses.
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N
O
N
H
1) Surfactant, Water
Reflux
R
H
R
N
+
N
S
O
O
S
2)
O
N
N
- H2N
Cl
NH2
Base
RT
Ph
Cl
O
Keywords
Heterocycles, sulfonylation, green chemistry, surfactants, 4-sulfonamidopyrimidine-5-
carbonitrile.
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INTRODUCTION
The pyrimidine moiety is a structural isostere of naturally occurring nucleotides; hence, it has
been extensively utilized as a drug scaffold in medicinal chemistry. Our previous studies on the
synthesis and biological activity of the pyrimidine ring1 have demonstrated that this building
block reveals extremely potent biological activities. Particularly, its sulfonamide derivatives have
emerged as important building blocks in chemotherapeutic agents such as, sulfadiazine,
2-4
5-7
sulfadimethoxine and sulfisomidine
and as antimicrobial agent such as sulfacytine
in
advanced clinical trials (Figure 1). A great number of methodologies for the synthesis of
8-13
common pyrimidine derivatives have been reported in the literature recently.
Because of
medicinal importance of sulfonamido pyrimidine derivatives, these compounds have been
14-16
synthesized through different methods and evaluated for their biological activities.
Harsh
reaction conditions, using harmful organic solvents and reagents and moderate yields of products
werefound as the main drawbacks of these reports for the synthesis of pyrimidine derivatives.
Recently, much effort has been directed towards using water as an alternative solvent for reasons
17,18
of cost effectiveness, safety, and environmental concerns for organic reactions.
The organic
syntheses in aqueous media are mostly restricted to reactions with water soluble substrates using
special additives. Several research groups have discerned that the addition of surfactants to water
may extend this concept to substrates that have poor water solubility.19,20 It has been emphasized
that most of the substrates and the catalyst are aggregated in the spherical spaces called micelles,
which act as hydrophobic reaction environments inside water and enable the organic reactions to
be accomplished faster.
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Hexadecyltrimethylammonium bromide (CTAB) with its C16 hydrocarbon chain provides a
21
strong hydrophobic force that can solubilize the organic molecules in water. However, from
the viewpoints of practicability and applicability, the surfactant-aided organic synthesis is still at
its infancy. To the best of our knowledge, there are only few reports using the strategy of amino
group sulfonylation for the synthesis of 4-sulfonamidopyrimidine derivatives. 22-24 Inspired by
the significance of 4-sulfonamidopyrimidine derivatives and rare number of synthetic
methodologies, we came up with a novel two-step process for the synthesis of this group of
compounds. In this protocol, a facile surfactant mediated three-component reaction for the
synthesis of 4-amino-6-aryl-2-phenylpyrimidine-5-carbonitrile derivatives in water catalyzed by
hexadecyltrimethylammonium bromide was introduced. Then, the products of the first step were
subjected to sulfonylation of the 4-amino group using benzensulfonyl chloride catalyzed by
NaH.
RESULTS AND DISCUSSION
To achieve the task of preparing novel 4-sulfonamidopyrimidines, we first explored a novel
green methodology toward 4-aminopyrimidine related derivatives. Various conditions were
investigated in the model reaction using 4-chlorobenzaldehyde with malononitrile and
benzamidine hydrochloride under reflux conditions (Scheme 1). Results are summarized in Table
1.
In the absence of any surfactant, only 4-chlorobenzylidiene malononitrile was obtained as
intermediate after 90 minutes (Table 1, Entry 1). Addition of 10% mol of
cetyltrimethylammonium bromide (CTAB) to the reaction mixture led to the formation of
product 4b in moderate yields. When the amount of CTAB was increased, a gradual increase of
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yield reaching a maximum of 98% was obtained (Table 1, Entries 3-5). On the other hand, the
use of SDS, Me4NBr or Bu4NBr (50 mol% each) gave only marginal increases in the yields in
comparison with the case of using CTAB as promoter (Table 1, Entries 6-8).
CTAB provides a strong micellar effect while under the above mentioned conditions Bu4NBr
and other surfactants cannot provide the same effect to the extent CTAB is capable of, thus
explaining the decisive advantage of using CTAB over other surfactants in aqueous medium.
Using the optimized reaction conditions, further investigations were carried out to expand the
scope and limitations of the present methodology (Scheme 2) and the results were summarized in
Table 2.
As shown in Table 2, a series of aromatic aldehydes bearing either electron-donating or electron-
withdrawing groups on aromatic ring were investigated. The substituents on the aromatic ring
did not obviously affect the yields and reaction times under the above mentioned optimal
conditions.
Subsequently, the 4-amino-6-aryl-2-phenylpyrimidine-5-carbonitrile derivatives were subjected
to direct sulfonylation at amino group with benzenesulfonyl chloride. In the model reaction,
various conditions for sulfonylation of 4-amino-6-(4-bromophenyl)-2-phenylpyrimidine-5-
carbonitrile 4c with benzenesulfonyl chloride were investigated (Scheme 3, Table 3).
The best result was obtained using THF as solvent and NaH as the base at room temperature
within short reaction time (5 minutes as monitored by TLC analysis, EtOAc:Petrolium ether, 4:1)
(Table 3, Entry 9). Extra amounts of NaH and higher temperatures did not lead to improving the
process in terms of time and yield of the reaction. So, equimolar amount of NaH and pyrimidine
as reactants were used at room temperature in THF as solvent as the optimized reaction
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conditions. In order to examine the scope and generality of the present protocol, the other
synthesized pyrimidine derivatives were subjected to the sulfonylation process under the
optimized conditions. The reactions were accomplished smoothly and cleanly for the other
pyrimidine derivatives. The products were obtained in moderate to good yields within a very
short reaction time and separated easily from the reaction medium. No further purification was
needed for the products as confirmed by spectral analysis (Scheme 4, Table 4).
As indicated in Table 4, aryl substituents at C-6 with various electron demands were able to
carry out the reaction simply. In only two cases (Entries 2 and 6, Table 4) the pyrimidine
substrates did not undergo the sulfonylation process and no product was formed. Further
attempts to activate these two substrates in sulfonylation by increasing the temperature and
amount of NaH were failed. Nevertheless, these results show very good level of generality for
the synthesis 4-sulfonamidopyrimidine derivatives.
CONCLUSION
In summary, we reported the synthesis of novel 4-phenylsulfonamide-6-aryl-2-
phenylpyrimidine-5-carbonitrile derivatives from the reaction of 4-amino-6-aryl-2-
phenylpyrimidine-5-carbonitrile with benzensulfonyl chloride for the first time. In this protocol,
we have developed an operationally simple and environmentally benign method for the synthesis
of pyrimidine derivatives by the multicomponent reaction of aromatic aldehydes, malononitrile
and benzamidine hydrochloride in the presence of CTAB in water followed by sulfonylation of
the amino substituents using NaH as the base. High yields of the products, short reaction times,
using water and CTAB instead of organic solvents and harmful catalysts and the synthesis of
novel sulfonamido substituted pyrimidine derivatives for the first time are the advantages of the
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present protocol. These compounds are currently under study for revealing their possible
bioactivity effects.
EXPERIMENTAL
Melting points were recorded on a Buchi B-540 apparatus. Infrared (IR) spectra were recorded
1
13
on an ABB Bomem model FTLA200-100 instrument. H and C NMR spectra were measured
with a Bruker DRX-400 Avance spectrometer at 400 and 100 MHz using tetramethylsilane
(TMS) as an internal standard. Chemical shifts (δ) are reported relative to TMS, and coupling
constants (J) are reported in hertz (Hz). Mass spectra were recorded on a Shimadzu QP 1100 EX
mass spectrometer with 70eV ionization potential. Elemental analyses of new compounds were
performed with a Vario EL III 0 serial no. 11024054 instrument.
Typical Procedure for the surfactant mediated synthesis of pyrimidine-5-carbonitrile
derivatives
Benzamidine hydrochloride (2.0 mmol), benzaldehyde derivative (2.0 mmol) and malononitrile
(2.0 mmol) were mixed and poured into a solution of 5 ml water possessing
hexadecyltrimethylammonium bromide (0.5 mmol). The reaction mixture was heated under
reflux for the specified time (Table 2). The reaction progress was monitored by TLC analysis
(various mixtures of ethyl acetate and n-hexane). When the reaction completed, the reaction
mixture was allowed to be cooled down; the precipitates were filtered off and washed several
times with water. The desired pyrimidine products were obtained with good to excellent yields
and characterized by physical and spectral data.
Selected analytical and spectroscopic data for pyrimidine-5-carbonitrile derivatives
4-Amino-2,6-diphenylpyrimidine-5-carbonitrile (4a)
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°
°
1
White powder, Mp 217 C; [lit. Mp 210-212 C] 25-28; HNMR (400 MHz, DMSO-d6): δ 8.45-
13
8.49 (m, 2H), 7.91-7.93 (m, 2H), 7.52-7.70 (m, 7H); CNMR (100 MHz, DMSO-d6): δ 169.6,
166.7, 165.2, 136.0, 133.5, 131.8, 129.6, 129.4, 128.9, 117.9, 86.5; IR (KBr, cm-1):ν 3443, 3395,
2230.
4-Amino-6-(4-chlorophenyl)-2-phenylpyrimidine-5-carbonitrile (4b)
°
°
1
Yellow powder, Mp 215 C; [lit. Mp 222 C] 25-28; HNMR (400 MHz, DMSO-d6): δ 8.31 (m,
13
2H), 7.91 (d, 2H, J= 8.5 Hz), 7.69-7.76 (d, 2H, J= 8.5 Hz), 7.45-7.51 (m, 5H); CNMR (100
MHz, DMSO-d6):δ 165.3, 164.1, 163.2, 137.4, 136.4, 136.0, 133.6, 131.1, 128.9, 128.3, 128.0,
114.5, 83.9; IR (KBr, cm-1): ν 3382, 3091, 2229.
4-Amino-6-(4-bromophenyl)-2-phenylpyrimidine-5-carbonitrile (4c)
°
°
1
Yellow powder, Mp 230-233 C; [lit. Mp 234-236 C] 25-28; HNMR (400 MHz, DMSO-d6): δ
8.44 (br. s, 2H) 8.30-8.35 (m, 2H), 8.12 (d, 2H, J= 8.4 Hz), 7.91 (d, 2H, J= 8.4 Hz), 7.58-7.64
(m, 3H); 13CNMR (100 MHz, DMSO- d6):δ 177.3, 170.2, 169.0, 142.1, 137.0, 134.8, 133.9,
132.5, 131.2, 129.8, 121.8, 116.5, 85.1; IR (KBr, cm-1): ν 3486, 3345, 2221.
4-Amino-6-(4-cyanophenyl)-2-phenylpyrimidine-5-carbonitrile (4d)
White powder, Mp 292-295 °C [lit. Mp 299-300 °C] 29 ; 1HNMR (400 MHz, DMSO-d6): δ 8.43-
8.48 (m, 2H), 8.18-8.23 (m, 2H), 8.09 (d, 2H, J= 8.4 Hz), 8.01 (br. s, 2H), 7.55-7.64 (m, 3H);
13CNMR (100 MHz, DMSO-d6): δ 169.2, 165.6, 164.9, 141.9, 135.2, 133.5, 132.6, 129.8, 129.1,
129.0, 119.4, 117.2, 114.4, 86.7; IR (KBr, cm-1): ν 3477, 3347, 2229, 2201.
4-Amino-6-(4-methoxyphenyl)-2-phenylpyrimidine-5-carbonitrile (4e)
°
°
1
Pale yellow powder, Mp 208 C; [lit. Mp 213 C] 25-28; HNMR (400 MHz, DMSO-d6): δ 8.56-
8.60 (m, 2H), 8.11-8.14 (d, 2H, J= 9.1 Hz), 7.96 (br. s, 2H), 7.61-7.65 (m, 3H), 7.15 (d, 2H, J=
8
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9.1 Hz), 3.77 (s, 3H); 13CNMR (100 MHz, DMSO-d6): δ 166.2, 163.9, 162.7, 160.1, 138.7,
133.7, 131.6, 129.2, 128.9, 128.1, 115.2, 114.9, 84.6, 54.1; IR (KBr, cm-1): ν 3469, 3341, 3209,
2227.
4-Amino-6-(4-nitrophenyl)-2-phenylpyrimidine-5-carbonitrile (4f)
Yellow powder, Mp 215-217 °C; [lit. Mp 215 °C] 25-28; 1HNMR (400 MHz, DMSO-d6): δ 8.71 (d,
2H, J= 6.1Hz), 8.59 (d, 2H, J= 6.1 Hz), 8.48-8.52 (m, 2H), 8.12 (br. s, 2H), 7.62-7.66 (m, 3H);
13CNMR (100 MHz, DMSO- d6): δ 172.3, 169.9, 162.7, 143.4, 138.1, 135.8, 132.3, 129.1, 128.3,
122.0, 118.7, 81.6; IR (KBr, cm-1): ν 3436, 3311, 3222, 2221.
4-Amino-6-(3-nitrophenyl)-2-phenylpyrimidine-5-carbonitrile (4g)
°
1
Yellow powder, Mp 196-197 C [lit. Mp 201-202 °C] 29; HNMR (400 MHz, DMSO-d6): δ 8.68
(s, 1H), 8.58-8.61 (m, 1H), 8.41-8.45 (m, 3H), 8.22 (br, 2H), 7.76-7.83 (m, 1H), 7.53-7.58 (m,
13
1H), 7.42-7.44 (m, 2H); CNMR (100 MHz, DMSO-d6): δ 167.1, 165.0, 164.3, 146.6, 138.2,
136.2, 135.0, 131.7, 130.3, 128.5, 128.4, 125.4, 123.3, 116.0, 86.1; IR (KBr, cm-1): ν 3492, 3385,
2211.
4-Amino-6-(2-bromophenyl)-2-phenylpyrimidine-5-carbonitrile (4h)
°
1
Yellow powder, Mp 247-251 C; HNMR (400 MHz, DMSO-d6): δ 8.57 (d, J= 9Hz), 8.29 (d,
1H, J= 8Hz), 8.10 (d, 1H, J= 8Hz), 7.79-7.84 (m, 1H), 7.57-7.62 (m, 3H), 7.48 (t, 1H, J= 8Hz);
13CNMR (100 MHz, DMSO-d6): δ 173.2, 165.7, 163.6, 142.9, 140.9, 137.1, 131.5, 130.0, 129.1,
128.3, 127.4, 126.9, 126.0, 118.7, 82.3; IR (KBr, cm-1): ν 3484, 3372, 2224; MS: m/z 317 (84),
271 (59), 214 (56), 168 (67), 156 (100), 141 (91), 104 (71), 103 (72), 76 (72), 57 (45), 43 (44);
Elemental analysis: calcd. for C17H11N5O2: C 64.35, H 3.49, N 22.07; O 10.08; found: C 64.35;
H 3.33; N 22.28.
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4-Amino-6-(2-chlorophenyl)-2-phenylpyrimidine-5-carbonitrile (4i)
1
Yellow powder, Mp 200-202 ºC; [lit. Mp196ºC] 25-28; HNMR (400 MHz, DMSO-d6): δ 8.24-
8.28 (m, 2H), 8.01 (br. s, 2H), 7.51-7.59 (m, 3H), 7.43-7.47 (m, 4H); 13CNMR (100 MHz,
DMSO-d6): δ 166.9, 162.0, 160.7, 134.4, 134.3, 132.1, 131.9, 130.0, 129.4, 128.8, 128.1, 127.9,
126.7, 114.0, 86.5; IR (KBr, cm-1): ν 3492, 3342, 2219.
4-Amino-6-(4-methylphenyl)-2-phenylpyrimidine-5-carbonitrile (4j)
White powder, Mp 211 ºC; [lit. Mp 210ºC] 25-28; 1HNMR (400 MHz, DMSO-d6): δ 8.59-8.66 (m,
2H), 8.37-8.44 (m, 2H), 7.87-7.90 (d, 2H, J= 9.0Hz), 7.69 (br. s, 2H), 7.57-7.61 (m, 3H), 3.26 (s,
13
3H); CNMR (100 MHz, DMSO-d6): δ 171.1, 166.8, 163.1, 145.3, 137.9, 136.3, 134.0, 132.1,
129.4, 128.6, 128.0, 117.1, 85.5, 21.9; IR (KBr, cm-1): ν 3455, 3367, 2229.
Typical Procedure for the direct sulfonylation of 4-amino-5-pyrimidinecarbonitrile
derivatives
A mixture containing 4-aminopyrimidine derivative (2.0 mmol), and NaH (2.0 mmol) in 10 ml
THF was stirred for a short period of time at room temperature. Then, benzensulfonyl chloride
(2.0 mmol) was added dropwise to the stirring mixture while maintaining the reaction
temperature. The formation of product precipitates was started quickly while the benzensulfonyl
chloride being added to the reaction mixture. The reaction mixture was stirred for 1 hour at room
temperature in order to make sure that the reaction was completed. Then, the solvent was
removed in vacuo and the solid residues were poured into a 10 ml hydrochloric acid (10% v/v)
solution in order to remove the unreacted NaH. The remaining precipitates were then filtered off
with a Buchi funnel and washed with ethyl acetate and n-hexane and dried at room temperature.
The 4-sulfonamidopyrimidine derivatives were then characterized by physical and spectroscopic
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data. The Supplemental Materials contains selected spectroscopic characterization for 5d and 5e
(Figures S 1 – S 8)
Selected analytical and spectroscopic data for 4-suilfonamidopyrimidine-5-carbonitrile
derivatives
4-Phenylsulfonamide-2,6-diphenylpyrimidine-5-carbonitrile (5a)
1
White powder, Mp 320 ºC; HNMR (400 MHz, DMSO-d6): δ 8.05-8.08 (m, 2H), 7.86-7.91 (m,
3H), 7.51-7.53 (m, 4H), 7.29-7.43 (m, 6H),; 13CNMR (100 MHz, DMSO-d6): δ 175.2, 167.2,
162.4, 148.2, 146.0, 137.3, 130.7, 130.2, 129.9, 128.5, 128.4, 128.3, 128.0, 127.9, 127.6, 126.5,
125.4, 118.2, 91.2; MS: m/z 412(9, M+), 270(19), 259(21), 139(32), 89(82), 63(100), 51(79). IR
(KBr, cm-1): ν 3422, 3059, 2214, 1580, 1532. Elemental analysis: calcd. For C23H16N4O2S C
66.97, H 3.91, N 13.58; found: C 66.53, H 3.77, N 13.51.
4-Phenylsulfonamide-6-(4-bromophenyl)-2-phenylpyrimidine-5-carbonitrile (5c)
1
White powder, Mp 354 ºC; H NMR (400 MHz, DMSO-d6): δ 8.54 (m, 2H), 8.44 (d, 2H, J=
9Hz), 7.85 (d, 2H, J= 9Hz), 7.79 (d, 2H, J= 8Hz), 7.55 (m, 3H), 7.49 (t, J = 8Hz, 1H), 7.45 (m,
13
2H); CNMR (100 MHz, DMSO-d6): δ 173.2, 167.8, 159.8, 143.6, 141.5, 137.7, 134.2, 132.9,
132.1, 130.7, 130.0, 129.8, 129.3, 126.0, 123.5, 118.6, 83.4; MS: m/z 492(12, (M+2)+), 490(9,
M+), 286(16), 231(67), 183(36), 88(100), 73(75), 75(71), 61(83). IR (KBr, cm-1): ν 3440, 2212,
1591, 1576, 1487. Elemental analysis: calcd. for C23H15BrN4O2S: C, 56.22; H, 3.08; Br, 16.26;
N, 11.40; found: C 55.89; H 3.34; N 11.07.
4-Phenylsulfonamide-6-(4-cyanophenyl)-2-phenylpyrimidine-5-carbonitrile (5d)
White powder, Mp 374-376 ºC; 1HNMR (400 MHz, DMSO-d6): δ 8.06-8.10 (m, 4H); 8.01-8.03
(m, 2H), 7.92-7.94 (m, 2H), 7.39-7.49 (m, 6H); 13CNMR (100 MHz, DMSO-d6): δ 166.2, 166.1,
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163.1, 146.2, 142.0, 137.8, 132.8, 131.4, 130.5, 129.9, 128.9, 128.5, 128.4, 127.0, 118.9, 118.2,
113.1, 92.2, 79.4; MS: m/z 437(8, M+), 297(76), 194(100), 104(69), 77(36), 51(17). IR (KBr,
cm-1): ν 3471, 2243, 2207, 1627, 1534, 1493. Elemental analysis: calcd. for C24H15N5O2S: C
65.89, H 3.46, N 16.01; found: C 66.23, H 3.21, N 15.62.
4-Phenylsulfonamido-6-(4-methoxyphenyl)-2-phenylpyrimidine-5-carbonitrile (5e)
1
White powder, Mp 298 ºC; HNMR (400 MHz, DMSO-d6): δ 8.06-8.08 (m, 2H), 7.88-7.93 (m,
13
4H), 7.41 (m, 6H), 7.06-7.09 (m, 2H), 3.82 (s, 3H); CNMR (100 MHz, DMSO-d6): δ 166.3,
166.1, 162.2, 160.9, 146.1, 137.7, 130.6, 130.1, 129.8, 129.5, 128.4, 128.0, 127.9, 126.5, 118.6,
113.6, 90.3, 55.3; MS: m/z 442(19, M+), 83(25), 69(35), 55(100). IR (KBr, cm-1): ν 3483, 3060,
2214, 1603, 1582, 1510, 1450. Elemental analysis: calcd. for C24H18N4O3S: C 65.14, H 4.10, N
12.66; found: C 65.41, H 3.79, N 12.42.
4-phenylsulfonamido-6-(3-nitrophenyl)-2-phenylpyrimidine-5-carbonitrile (5g)
1
White powder, Mp 362 ºC; HNMR (400 MHz, DMSO-d6): δ 8.06-8.08(m, 2H), 7.88-7.90 (m,
13
2H), 7.79-7.81 (d, 2H, J=7.7Hz), 7.38-7.41 (m, 6H), 7.32-7.34 (d, 2H, J=7.7Hz); CNMR (100
MHz, DMSO-d6): δ 176.4, 167.0, 162.3, 146.1, 140.1, 137.7, 134.5, 130.6, 129.8, 128.8, 128.4,
128.0, 127.9, 126.5, 118.3, 90.9; MS: m/z 457(12, M+), 392(85), 344(53), 317(77), 77(100). IR
(KBr, cm-1): ν 3262, 2217, 1562, 1518, 1458. Elemental analysis: calcd. for C23H15N5O4S: C
60.39; H 3.31; N 15.31; found: C 60.73, H 3.03, N 15.69.
4-phenylsulfonamido-6-(2-bromophenyl)-2-phenylpyrimidine-5-carbonitrile (5h)
1
White powder, Mp 286 ºC; HNMR (400 MHz, DMSO-d6): δ 8.00-8.03(m, 2H), 7.90-7.93 (m,
2H), 7.73-7.76 (m, 2H), 7.35-7.53 (m, 8H); 13CNMR (100 MHz, DMSO-d6): δ 168.5, 164.8,
162.5, 145.9, 138.8, 137.5, 132.6, 130.9, 130.8, 130.3, 130.1, 128.5, 128.1, 128.0, 127.7, 127.6,
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126.6, 120.8, 117.0, 93.8,; MS: m/z 492(13, (M+2)+), 490(10, M+), 308(66), 187(84), 61(100).
IR (KBr, cm-1): ν 3452, 2224, 1536, 1479. Elemental analysis: calcd. for C23H15BrN4O2S: C
56.22; H 3.08; N 11.40; found: C 56.49; H 2.62; N 11.79.
4-phenylsulfonamide-6-(2-chlorophenyl)-2-phenylpyrimidine-5-carbonitrile (5i)
1
White powder, Mp 388 ºC; HNMR (400 MHz, DMSO-d6): δ 8.03-8.05(m, 2H), 7.93-7.95 (m,
2H), 7.61-7.63 (m, 2H), 7.39-7.56 (m, 8H); 13CNMR (100 MHz, DMSO-d6): δ 167.7, 165.3,
163.2, 146.4, 138.0, 137.4, 131.7, 131.4, 130.9, 130.6, 130.0, 129.0, 128.6, 128.5, 127.7, 127.1,
117.5, 94.5; MS: m/z 446(14, M+), 129(57), 69(100). IR (KBr, cm-1): ν 3430, 3057, 2223, 1543,
1474. Elemental analysis: calcd. for C23H15ClN4O2S: C 61.81; H 3.38; N 12.54; found: C, 61.52;
H, 3.73; N, 12.11.
4-phenylsulfonamide-6-(4-methylphenyl)-2-phenylpyrimidine-5-carbonitrile (5j)
White powder, Mp 305 ºC; 1HNMR (400 MHz, DMSO- d6): δ 8.07-8.10 (m, 2H), 7.90-7.92 (m,
2H), 7.81-7.83 (d, 2H, J=8.0Hz), 7.38-7.47 (m, 6H), 7.34-7.36 (d, 2H, J=8.0Hz), 2.40 (s, 3H);
13CNMR (100 MHz, DMSO-d6): δ 167.5, 166.4, 162.8, 146.5, 140.5, 138.1, 135.0, 131.1, 130.3,
129.3, 128.9, 128.5, 128.4, 126.9, 118.8, 91.3, 79.4, 21.4; MS: m/z 426(9, M+), 91(100), 57(82).
IR (KBr, cm-1): ν 3426, 2199, 1731, 1537, 1510, 1435. Elemental analysis: calcd. for
C24H18N4O2S: C 67.59; H 4.25; N 13.14; found: C 67.11; H 4.71; N 13.46.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge Dr. Khosrow Jadidi from Shahid Beheshti University, G. C.,
Tehran, Iran for his helpful consultations and sincere guidance.
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Table 1 Evaluation of various surfactants toward synthesis of 4-amino-6-(4-chlorophenyl)-
pyrimidine-5-carbonitrile as model reaction.
Entry
Catalyst (% mol)
-
Time (h)
24
Yield b (%)
1
2
3
4
5
6
7
8
0
CTAB (10)
CTAB (25)
CTAB (50)
CTAB (60)
SDS (50)
12
65
94
98
90
17
40
52
1.5
1.5
1.5
12
TMAB (50)
TBAB (50)
12
12
a All reactions were done with 4-chlorobenzaldehyde under reflux
b
Hexadecyltrimethylammonium bromide (CTAB), Dodecyl sodium sulfate (SDS),
Tetramethylammonium bromide(TMAB), Tetrabutylammonium bromide (TBAB)
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Table 2 Synthesis of 4(a-j) catalyzed with CTAB in water under reflux
Entry
Product
4a
R
Time (min.)
Yielda (%)
1
Ph
60
90
90
50
50
80
90
90
80
60
92
94
90
95
89
81
80
92
95
98
2
4-Cl
4b
4c
3
4-Br
4
4-CN
4-MeO
4-NO2
3-NO2
2-Br
4d
4e
5
6
4f
7
4g
8
4h
4i
9
2-Cl
10
4-Me
4j
a Isolated yield.
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Table 3 Evaluation of various reaction conditions for the sulfonylation of 4-amino-6-(4-
bromophenyl)-2-phenylpyrimidine-5-carbonitrile (4c).
Entry
Basea
Solvent
Temperature
Product
(°C)
r.t
1
2
-
-
-
-
acetonitrile
acetonitrile
acetonitrile
acetonitrile
acetonitrile
DMF
50
reflux
r.t
-
3
-
-
4
NEt3
NaH
DBU
NEt3
NaH
NaH
NEt3
DBU
-
5
r.t
-
6
r.t
-
7
r.t
-
8
DMF
r.t
-
9
THF
r.t
5c (70%)
5c (25%)
-
10
11
THF
r.t
THF
r.t
a Equimolar amount of catalysts and reactant was used.
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Table 4 The synthesis of novel 4-sulfonamidopyrimidine derivatives through amino group
sulfonylation catalyzed with NaH in THF at r.t.
Entry
Product
5a
R
Yield (%)a
M. P. (°C)
320
1
H
88
-
2
5b
4-Cl
-
3
5c
4-Br
92
82
95
-
354
4
5d
4-CN
4-MeO
4-NO2
3-NO2
2-Br
374-376
298
5
5e
6
5f
-
7
5g
91
77
83
87
362
8
5h
286
9
5i
2-Cl
388
10
5j
4-Me
305
a Isolated yield
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Figure 1 The structures of some common sulfonamide drugs
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N
O
NH2
N
H
N
Surfactant, Water
Reflux
N
+
N
Cl
Cl- H2N
NH2
Cl
4b
Scheme 1 The study of surfactant mediated synthesis of 4-amino-2,6-diaryl-pyrimidine-5-
carbonitrile derivatives
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Scheme 2 Synthesis of 4-amino-6-arylpyrimidine-5-carbonitrile derivatives under optimized
surfactant mediated conditions
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Scheme 3 Evaluation of various reaction conditions for the sulfonylation of amino group toward
the synthesis of sulfonamidopyrimidine derivatives
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N
N
H
N
NH2
1) NaH (1eq.),
THF (5ml)
S
R
R
O
O
N
N
N
N
O
, R.T.
Ph S Cl
O
2)
5a-j
4a-j
Scheme 4 Synthesis of novel 4-sulfonamidopyrimidine-5-carbonitrile derivatives through amino
group sulfonylation
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