Synthesis of α-aminonitriles with benzimidazolic and theophyllinic backbones using the strecker reaction

Article abstract of DOI:10.1021/jo401890g

An example of the application of the Strecker reaction in the synthesis of a new class of α-aminonitriles with benzimidazole and theophylline backbones has been developed. For the synthesis of these compounds, first 4-hydroxybenzaldehyde was reacted with

Full text of DOI:10.1021/jo401890g

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Article
Synthesis of alpha-Aminonitriles with Benzimidazolic and
Theophyllinic Backbones Using the Strecker Reaction
Ali Khalafi-Nezhad, Masoumeh Divar, and Farhad Panahi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401890g • Publication Date (Web): 03 Oct 2013
Downloaded from http://pubs.acs.org on October 8, 2013
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Synthesis of α-Aminonitriles with Benzimidazolic
and Theophyllinic Backbones Using the Strecker
Reaction
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Ali Khalafi-Nezhad,* Masoumeh Divar and Farhad Panahi*
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
E-mail: khalafi@chem.susc.ac.ir (A.K.-N.). panahi@shirazu.ac.ir (F.P.)
ABSTRACT.
O
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An example of the Strecker reaction application in the synthesis of a new class of α-aminonitriles
with benzimidazole and theophylline backbone has been developed. For the synthesis of these
compounds, first, 4-hydroxybenzaldehyde was reacted with 1,3 and 1,5
dibromides/epibromohydrin to produce the corresponding bromo-substituted aldehydes. Then,
benzimidazole/theophylline was reacted with the latter to generate the related
benzimidazolic/theophyllinic aldehydes. Finally, the Strecker reactions of synthetic
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benzimidazolic and theophyllinic aldehydes with different amines resulted in the production of
target products.
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INTRODUCTION
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A large number of nitrile-containing compounds have been widely used as drugs for treatment
of many diseases.1 There is widespread interest on α-aminonitrile compounds due to their
medical utilizations. Several α-aminonitriles have been developed as reversible inhibitors of
dipeptidyl peptidase-4 (DPP-4) for treatment of diabetes.2 The chemical structures of four
important α-aminonitrile-based drugs are shown in Figure 1.
Figure 1. The chemical structure of some α-aminonitrile-based drugs
As a stimulant drug amphetaminil was used for the treatment of obesity and narcolepsy.3
Saxagliptin, is a new anti-diabetic drug which classified as potent DPP-4 inhibitor drugs.4 Also,
NVP-DPP728 with a slow-binding inhibitory activity related to DPP-4 has been introduced as a
new therapeutic approach for treatment of type 2 diabete.5 Other most important DPP-4 inhibitor
is vildagliptin which has been used as an efficient anti-diabetic drug in recent years.6 Moreover,
several α-aminonitrile products have been isolated from natural sources.7
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Accordingly, α-aminonitriles are important structural motifs in many biologically active
molecules, pharmaceuticals and natural products. Thus, the development of efficient protocols to
construct such moieties and synthesis of new α-aminonitriles are therefore of great importance to
drug discovery.8 One of the most important strategies for the synthesis of α-aminonitriles is the
Strecker reaction, which was discovered in 1850. This reaction is the first multi-component
reaction that involves the one-pot coupling reaction of an amine, an aldehyde, and hydrogen
cyanide to afford α-aminonitriles.9 Since, α-aminonitriles are precursors for the synthesis of α-
amino acids and many of the materials, the Strecker reaction has clinical significance and for this
reason several modifications of this reaction have been reported in the literature.10 An efficient
one-pot method has been developed for the synthesis of α-amino nitriles by combining
aldehydes, amines, and trimethylsilyl cyanide (TMSCN).11
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In the other hand, theophylline (naturally found in cocoa beans) has been used in therapeutic
agents in treatment of diseases such as conic obstructive pulmonary and asthma. Several
important drugs based on theophylline have been developed.12 Also, benzimidazole is a
recognized advantaged structure in medicinal chemistry, showing various biological
activities.13 There is a special interest towards synthesis of new benzimidazole derivatives due to
their widespread biological and photophysical properties.
Along this line and in continuation of our previous studies on the synthesis of benzimidazole-
and theophylline-based analogues,13 herein, we report an efficient protocol for the synthesis of
some novel α-aminonitriles with benzimidazole and theophylline backbones using the Strecker
reaction as the key step.
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RESULTS AND DISCUSSIONS
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Our primary retrosynthetic approach for preparation of α-aminonitriles-based benzimidazole
and theophylline compounds (1) is summarized in Scheme 1.
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Scheme 1. Retrosynthetic analysis of the designed α-aminonitrile-based benzimidazole
theophyllines
According to the retrosynthesis pathway which is shown in Scheme 1, the key intermediate is
2. Thus, our study started with the production of compound 2. This molecule (2), easily obtained
from reaction of benzimidazole or theophylline (5) and aldehyde 6. To prepare aldehyde 6, 4-
hydroxybenzaldehyde (7) was treated with epibromohydrin (8a)/1,3-dibromopropane (8b)/1,5-
dibromopropane (8c), which gave the corresponding aldehydes (6a-6d) in high isolated yields.
According to our synthetic approach, both products 6a and 6b are produced when theophylline
was reacted with epibromohydrin. Thus, under the reaction conditions (K2CO3, TBAB, CH3CN,
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refux, 20 h), a mixture of 6a and 6b was generated. The resulting mixture, without purification
was used for the next reaction with theophylline (5a) to synthesize aldehyde 2a (Scheme 2).14
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Br
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K2CO3, TBAB
+
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(6a)
HO
CH3CN, reflux
20 h
(7)
(8a)
0.03 mol
+
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0.01 mol
Br
O
OH
(6b)
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K2CO3, TBAB
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+
(6a)
N
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+ (6b)
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OH
N
DMF, reflux
20 h
O
(5a)
O
(2a)
Scheme 2. Synthesis of the theophylline-based aldehyde 2a
For synthesis of other theophylline-based aldehyde (2b), the following synthetic route was
used. In the first step, 4-hydroxybenzaldehyde was reacted with 1,3-dibromopropane (8b) to
produce 4-(3-bromopropoxy)benzaldehyde (6c). Then, addition of theophylline to 6c resulted in
the production of aldehyde 2b in good yield (Scheme 3).
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Scheme 3. Synthesis route for the preparation of theophylline-based aldehyde 2b
For synthesis of benzoxazole-based aldehyde (2c), first 4-hydroxybenzaldehyde was reacted
with 1,5-dibromopropane (8c) to produce 4-((5-bromopentyl)oxy)benzaldehyde (6d) and then
benzoxazole was treated with 6d in order to produce aldehyde 2c in good yield (Scheme 4).
Scheme 4. Synthesis route for the preparation of benzoxazole-based aldehyde 2c
After preparation and characterization of the theophylline-based aldehyde 2a-c, the Strecker
reactions of these aldehydes with different amines were accomplished and a set of α-
aminonitriles with benzoxazole/theophylline backbone were synthesized. Although the synthesis
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of α-aminonitriles has been widely developed previously we devised a modified procedure for
the Strecker reaction of amines, aldehydes and TMSCN using tungstophosphoric acid
(H3PW12O40) as catalyst in EtOH solvent. To the best of our knowledge, up to now, there is no
study on the preparation of α-aminonitriles using H3PW12O40 as catalyst. Thus, we report an
efficient method for the preparation of α-aminonitriles using the Strecker reaction in the presence
of a catalytic amount of H3PW12O40 in EtOH at rt (Scheme 5). Our research group has widely
used these optimized conditions in organic synthesis.15 In this study, these conditions were found
to be efficient for synthesis of α-aminonitriles using Strecker reaction under mild conditions.
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CN
H3PW12O40 (2 mol%)
NH2
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TMSCN
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EtOH
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rt, 24 h
(3)
(4a-d)
RO
(2a-c)
(1a-j)
1.2 mmol
1 mmol
1 mmol
Scheme 5. Strecker synthesis of benzoxazole/theophylline-based α-aminonitriles 1a-j
We synthesized α-aminonitriles 1a-j using this procedure (Scheme 5) and results are
summarized in Table 1.
Table 1. The Products of the Three-component Strecker Reactions of Aldehydes 2a-c,
TMSCN, and Aminesa
Entry
Aldehyde & Amine
Product
Yield (%)b
2a
&
1
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1a
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1g
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a Reagents and conditions: aldehyde 2 (1 mmol), TMSCN (1.2 mmol), amine (1 mmol),
H3PW12O40 (0.04 g, 2 mol %), and EtOH (5 mL). b Isolated yields.
As shown in above, this is an efficient approach for the synthesis of divers benzimidazolic and
theophyllinic α-aminonitriles based on three-component Strecker reactions of aldehydes,
TMSCN, and amines. This facile protocol also can be applied to synthesize a wide range of α-
aminonitriles by selecting the appropriate aldehydes and amines. As shown in Table 1, the
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reaction was satisfactory accomplished for electron-withdrawing and electron-donating groups in
amine component.
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CONCLUSIONS
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In summary, we have elaborated a three-step synthesis of new class of α-aminonitriles with
benzimidazolic and theophyllinic backbones. In these syntheses, the formation of the bromo-
substituted aldehydes (6a-d), and the subsequent reaction of 6a-d with benzimidazole and
theophylline yielded the related aldehydes 2a-c. Finally, the acid-catalyzed Strecker reaction of
different amines and pre-synthesized aldehydes 2a-c with TMSCN led to the formation of the
target molecules 1a-j in good to excellent yields.
EXPERIMENTAL
General Experimental Details. All commercial reagents and solvents were used without
further purification. Melting points were determined in open capillary tubes. FT-IR spectroscopy
was employed for characterization of the synthesized compounds using film KBr pellet
techniques. NMR spectra were acquired in DMSO-d6 with tetramethylsilane (TMS) as the
internal standard. The sample was analyzed by GC/MS for mass spectroscopy and micro-
analyzer for elemental analyses. The reaction monitoring was accomplished by TLC on silica gel
plates. Column chromatography was carried out on columns of silica gel 60 (70–230 mesh).
4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-2-
hydroxypropoxy)benzaldehyde (2a)
Synthesis of 6a and 6b: In a double-necked round-bottomed flask (100 mL), equipped with a
condenser, a mixture of the appropriate 4-hydroxylphenol (0.03 mol), K2CO3 (4.14 g, 0.03 mol),
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epibromohydrin (4.92 g, 0.036 mol), and catalytic amounts of tetra butyl ammonium bromide
(TBAB, 0.1 g) were dissolved in MeCN (40 mL). Then, the mixture was heated to reflux for 10 h
(TLC control). The solvent was evaporated at reduced pressure, and the residue was dissolved in
CHCl3 (150 mL) and washed with H2O (2 x 150 mL). The org. layer was dried (Na2SO4, 10 g)
and concentrated to afford the crude product consisting of a mixture of 6a and 6b. The crude
product was then used without any further purification for the synthesis of 2a according to the
procedure described below.
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Synthesis of 2a: In double-necked round bottom flask (100 mL) equipped with a condenser
was added a mixture consisting of theophylline (0.01 mol, 1.8 g) K2CO3 (1.38 g, 0.01 mol),
appropriate bromo alcohols (6b) & (6a) (0.015 mol), and catalytic amount of TBAB (0.1 g) in
DMF (40 mL). The solution was refluxed until TLC monitoring indicated no further
improvement in the reaction (8-10 hours). After cooling and solvent evaporation the resulted
foam was dissolved in CHCl3, (150 mL) and washed with water (2 x 200 mL). The organic layer
was dried over anhydrous (Na2SO4) and evaporated. The crude was purified by column
chromatography on silica gel eluting with proper solvent (mixture of n-hexane-EtOAc) (1:2) Rf =
0.5 the product was obtained in 70 % (2.5 g). IR (KBr): ν = 3207, 2851, 2365, 1682, 1640, 1737,
1590, 1354, 1157, cm–1. 1H NMR (250 MHz, DMSO-d6/TMS) δ (ppm) 3.32(s, 3H), 3.51 (s, 3H),
4.00-4.06 (m, 2H), 4.38-4.44 (m, 2H),4.60-4.65(m, 1H), 693-7.79 (m, 5H), 8.06 (s, 1H), 9.80(s,
1H). 13C NMR (62.5 MHz, DMSO-d6/TMS) δ (ppm):28.12, 31,13, 80.1, 84.3, 107.1, 115.3,
122.0, 131.2, 142.3, 151.3, 154.2, 157.0, 160.2. Anal. Calcd. for C17H18N4O5: C, 56.98; H, 5.06;
N, 15.63; Found: C, 57.07; H, 5.12; N, 15.71.
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4-(3-bromopropoxy)benzaldehyde (6c)
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In double-necked round bottom flask (100 mL) equipped with a condenser, a mixture,
consisting of p-hydroxyl benzaldehyde (0.02 mol, 2.44 g), 1, 3-dibromopropane (0.06 mole),
K2CO3 (2.76 g, 0.02 mole), and catalytic amount of TBAB (0.1 g) in MeCN (50 mL) was
refluxed for 10 hours. After cooling and solvent evaporation the resulted foam was dissolved in
CHCl3 (150 mL) and washed with water (3 x 150 mL). The organic layer was dried over
anhydrous (Na2SO4) and evaporated. The crude product was purified by column chromatography
on silica gel eluting with proper solvent (mixture of n-hexane-EtOAc) (1:2) Rf = 0.6, this
purification gave white solid in 80% (3.9 g). IR (KBr): ν = 3150, 2900, 2790, 1697, 1730, 1450,
1589, 1154, 1260,670, cm–1. 1H NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 2.13 (m, 2H), 3.50
(t, J = 5 Hz, 2H), 4.02 (t, J = 5 Hz, 2H), 7.20-7.80 (m, 4H), 9.87 (s, 1H). 13C NMR (62.5 MHz,
DMSO-d6/TMS) δ (ppm): 29.9, 32.9, 67.0, 106.8, 114.4, 114.9, 122.0, 128.3, 132.0,190.2. Anal.
Calcd. for C10H11BrO2: C, 49.41; H, 4.56; Found: C, 49.48; H, 4.63.
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4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propoxy)benzaldehyde
(2b)
In double-necked round bottom flask (100 mL) equipped with a condenser, a mixture,
consisting of 4-(3-bromopropoxy)benzaldehyde (0.01 mol, 2.43 g), theophylline (0.01 mol, 1.8
g), K2CO3 (1.38 g, 0.01 mol), and catalytic amount of TBAB (0.1 g) in DMF (50 mL) was
refluxed for 10 hours. After cooling the solvent was evaporated under vacuum and then the
resulted foam was dissolved in CHCl3, (150 mL) and washed with water (3 x 150 mL). The
organic layer was dried over anhydrous (Na2SO4) and evaporated. The crude product was
purified by column chromatography on silica gel eluting with proper solvent (mixture of n-
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hexane-EtOAc) (1:2) Rf = 0.6 this purification gave white solid in 70% (2.4 g). IR (KBr): ν =
3217, 2854, 2360, 1672, 1640, 1735, 1590, 1350, 1150, cm–1. 1H NMR (250 MHz, DMSO-
d6/TMS) δ (ppm): 2.34-2.44 (m, 2H), 3.37 (s, 3H), 3.59 (s, 3H), 4.00 (t, J = 5 Hz, 2H), 4.48 (t, J
= 5 Hz, 2H), 6.51-7.80 (m, 4H), 8.08 (s, 1H), 9.82 (s, 1H). 13C NMR (62.5 MHz, DMSO-
d6/TMS) δ (ppm): 29.0, 30.1, 30.7, 43.0, 64.1, 107.0, 114.9, 128.5, 131.9, 141.0, 148.4, 151.3,
154.8, 165.2, 191.0. Anal. Calcd. for C17H18N4O4: C, 59.64; H, 5.30; N, 16.37; Found: C, 59.71;
H, 5.35; N, 16.41.
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4-((5-bromopentyl)oxy)benzaldehyde (6d)
In double-necked round bottom flask (100 mL) equipped with a condenser, a mixture,
consisting of p-hydroxyl benzaldehyde (0.02 mol, 2.44 g), 1, 5-dibromopropane (0.06 mole),
K2CO3 (2.76 g, 0.02 mole), and catalytic amount of tetra butyl ammonium bromide (TBAB, 0.1
g) in MeCN (50 mL) was refluxed for 10 hours. After cooling and solvent evaporation the
resulted foam was dissolved in CHCl3, (150 mL) and washed with water (3 x 150 mL). The
organic layer was dried over anhydrous (Na2SO4) and evaporated. The crude product was
purified by column chromatography on silica gel eluting with proper solvent (mixture of n-
hexane-EtOAc) (1:2) Rf = 0.7 this purification gave white solid in 75%. Yield: 75% (2.03g),
white crystals,. IR (KBr): ν = 3155, 2920, 2795, 1690, 1735, 1450, 1581, 1250, 1150, 665, cm–1.
1H NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 1.55-1.61 (m, 2H), 1.81-1.97 (m, 4H), 3.62 (t, J =
5, 2H), 4.06 (t, J = 5, 2H),), 7.18-7.88(m, 4H), 9.86 (s, 1H). 13C NMR (62.5 MHz, DMSO-
d6/TMS) δ (ppm): 24.0, 28.5, 32.9, 33.8, 68.7, , 114.2, 114.9, 130.2,190.6. Anal. Calcd. for
C12H15BrO2: C, 53.15; H, 5.58; Found: C, 53.19; H, 5.62.
4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propoxy)benzaldehyde (2c)
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In double-necked round bottom flask (100 mL) equipped with a condenser, a mixture,
consisting of benzimidazole (0.01 mole, 1.18 g), performed compound 6d (0.012 mol), K2CO3
(1.38 g, 0.01 mole), and catalytic amount of TBAB (0.1 g) in MeCN (50 mL) was refluxed for 7
hours. After cooling and solvent evaporation the resulted foam was dissolved in CHCl3, (150
mL) and washed with water (3 x 100 mL). The organic layer was dried over anhydrous (Na2SO4)
and evaporated. The crude product was purified by column chromatography on silica gel eluting
with proper solvent (mixture of n-hexane-EtOAc) (1:1) Rf = 0.7 the white solid was obtained.
Yield: 80% (2.15g), white crystals. IR (KBr): ν = 3125, 2910, 2815, 1690, 1737, 1450, 1581,
1256, 1115 cm–1. 1H NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 1.58-1.64 (m, 2H), 1.83-1.97
(m, 4H), 3.99 (t, J = 5 Hz, 2H), 4.26 (t, J = 5 Hz, 2H),), 6.93-7.45(m, 4H), 8.27 (s, 1H) 9.87 (s,
1H). 13C NMR (62.5 MHz, DMSO-d6/TMS) δ (ppm): 23.3, 29.3, 29.6, 52.3, 66.7, 110.0, 114.9,
119.9, 123.0, 128.5, 131.9, 132.5, 143.8, 144.1, 165.2, 192.Anal. Calcd. for C19H20N2O2: C,
74.00; H, 6.54; N, 9.08; Found: C, 74.05; H, 6.58; N, 9.12.
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General Producer for the synthesis of α-aminonitriles-based benzimidazole/theophylline
compounds (1a-j)
A mixture of aldehyde (2a-c) (1mmol), aniline (1 mmol), TMSCN (1.2 mmol) and
tungestophosphoric acid (0.04 g, 2 mol %) in EtOH (5mL) was stirred in room temperature for
24 hours. The completion of the reaction is confirmed by TLC (eluent/ EtOAc/ MeOH). Then,
the precipitated product was filtered and washed with water (2 x 10 mL) and ethanol (10 mL) to
afford the pure product.
2-((4-bromophenyl)amino)-2-(4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-purin-9-yl)-
2-hydroxypropoxy)phenyl)acetonitrile (1a): Yield: 88% (0.47g), white crystals, mp: 186 ºC. IR
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(KBR): ν = 3409, 2923, 2260, 1697, 1550, 1512, 1242, 946 cm–1. 1H NMR (250 MHz, DMSO-
d6/TMS) δ (ppm): 3.32 (s, 3H, CH3), 3.51 (s, 3H, CH3), 4.00-4.06 (m, 4H, CH2), 4.38-4.44 (m,
2H), 4.61 (s, 1H), 6.93-7.79 (m, 9H), 8.76 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS) δ
(ppm): 29.9, 30.0, 44.1, 55.4, 64.0, 70.5, 75.9, 106.8, 114.2, 114.4,114.4, 122.0, 130.2, 132.0,
141.4, 144.9, 145.0, 149.0, 155.0, 157.5, 157.9, 160.6. MS: 538.12 (18, M+). Anal. Calcd. for
C24H23BrN6O4: C, 53.44; H, 4.30; N, 15.58; Found: C, 53.55; H, 4.27; N, 15.65.
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2-(4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-purin-9-yl)-2-hydroxypropoxy)phenyl)-
2-((4-methoxyphenyl)amino)acetonitrile (1b): Yield: 90% (0.44g), white crystals, mp: 190 ºC. IR
(KBr): ν = 3440, 3317, 2954, 2839, 1697, 1651, 1550, 1512, 1473, 1234, 1180, 825 cm–1. 1H
NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 3.32 (s, 3H), 3.51 (s, 3H), 3.82(s, 3H), 4.20-4.32 (m,
4H), 4.38-4.44 (m, 2H), 4.61(s, 1H), 7.20-7.65 (m, 10H), 8.82 (s, 1H). 13C NMR (62.5 MHz,
DMSO-d6/TMS) δ (ppm): 29.9, 30.0, 44.1, 55.4, 64.0, 70.5, 75.9, 106.8, 114.2, 114.4,114.4,
122.0, 130.2, 132.0, 141.4, 144.9, 145.0, 149.0, 155.0, 157.5, 157.9, 160.6. MS: 490.23 (15, M+).
Anal. Calcd. for C25H26N6O5: C, 61.22; H, 5.34; N, 17.13; Found: C, 61.30; H, 5.27; N, 17.20.
2-((4-chlorophenyl)amino)-2-(4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-9H-purin-9-yl)-
2-hydroxypropoxy)phenyl)acetonitrile (1c): Yield: 91% (0.45g), white crystals, mp: 190 ºC. IR
(KBr): ν = 3442, 3317, 2950, 2837, 1692, 1651, 1550, 1514, 1473, 1234, 1180, 830 cm–1. 1H
NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 3.36 (s, 3H), 3.59 (s, 3H), 4.00-4.06 (m, 4H), 4.58-
4.79 (m, 2H), 4.96(s, 1H), 6.93-7.79 (m, 10H), 8.58 (s, 1H). 13C NMR (62.5 MHz, DMSO-
d6/TMS) δ (ppm): 27.9, 29.9, 30.0, 44.1, 55.4, 64.0, 70.5, 75.9, 106.8, 114.2, 114.4,114.4, 122.0,
130.2, 132.0, 141.4, 144.9, 145.0, 149.0, 155.0, 157.5, 157.9, 160.5. MS: 494.17 (19, M+). Anal.
Calcd. for C24H23ClN6O4: C, 58.24; H, 4.68; N, 16.98; Found: C, 58.35; H, 4.57; N, 17.01.
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2-(4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,4,5,6-hexahydro-9H-purin-9-yl)propoxy)phenyl)-2-((4-
methoxyphenyl)amino)acetonitrile (1d): Yield: 94% (0.44),white crystals, mp: 215 ºC. IR (KBr):
ν = 3375, 2881, 2356, 1689, 1649, 1612, 1550, 1342, 1288, 1249, 1184, 1817, 769 cm–1. 1H
NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 2.34-2.44 (m, 2H), 3.34 (s, 3H), 3.53 (s, 3H), 3.74
(s, 3H), 3.97 (t, J = 5.0 Hz, 2H), 4.46 (t, J = 5.0 Hz, 2H), 4.85 (s, 1H), 6.85-7.84 (m, 9H), 8.39 (s,
1H). 13C NMR (62.5 MHz, DMSO-d6/TMS) δ (ppm): 27.9, 29.7, 29.9, 30.0, 44.1, 55.4, 64.0,
106.8, 114.2, 114.4, 122.0, 130.2, 130.2, 132.0, 141.4, 144.9, 145.0, 149.0, 155.0, 157.5, 157.9,
160.6. MS: 474.21 (12, M+). Anal. Calcd. for C25H26N6O4: C, 63.28; H, 5.52; N, 17.71; Found:
C, 63.36; H, 5.57; N, 17.79.
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2-(4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propoxy)phenyl)-2-((3-
hydroxyphenyl)amino)acetonitrile (1e): Yield: 90% (0.41g), white crystals, mp 175 ºC. IR (KBr):
ν = 3379, 2885, 2360, 1697, 1651, 1612, 1550, 1342, 1288, 1249, 1180, 1817, 763 cm–1. 1H
NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 2.31-2.45 (m, 2H), 3.48 (s, 3H), 3.54 (s, 3H), 4.00 (t,
J = 5 Hz, 2H), 4.48 (t, J = 5 Hz, 2H), 4.85 (s, 1H), 5.10 (s, 1H), 6.91-7.84 (m, 10H), 8.14 (s, 1H).
13C NMR (62.5 MHz, DMSO-d6/TMS) δ (ppm): 27.6, 29.5, 29.9, 30.9, 44.1, 53.6, 64.0, 68.2,
106.8, 114.2, 114.4, 122.0, 130.2, 132.0, 141.4, 144.9, 145.0, 149.0, 155.0, 157.5, 157.9, 160.6,
174.8, 179.1. MS: 460.17 (15, M+). Anal. Calcd. for C24H24N6O4: C, 62.60; H, 5.25; N, 18.25;
Found: C, 62.68; H, 5.29; N, 18.31.
2-((4-chlorophenyl)amino)-2-(4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-
yl)propoxy)phenyl)acetonitrile (1f): Yield: 90% (0.43g), white crystals, mp: 250 ºC. IR (KBr): ν
= 3369, 2889, 2364, 1687, 1652, 1618, 1557, 1345, 1289, 1259, 1180, 1827, 768 cm–1. 1H NMR
(250 MHz, DMSO-d6/TMS) δ (ppm): 2.34-2.44 (m, 2H), 3.24 (s, 3H), 3.46 (s, 3H), 3.94 (t, J =
7.5 Hz, 2H), 4.46 (t, J = 7.5, 2H), 4.81 (s, 1H), 6.60-7.83 (m, 10H), 8.05 (s, 1H). 13C NMR (62.5
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MHz, DMSO-d6/TMS) δ (ppm): 27.4, 29.8, 29.9, 30.0, 44.1, 55.4, 64.0, 106.8, 114.2, 114.4,
122.0, 130.2, 130.2, 132.0, 141.4, 144.9, 145.0, 149.0, 155.0, 157.5, 157.9, 160.6, 166.5, 174.8.
MS: 478.18 (11, M+). Anal. Calcd. for C24H23ClN6O3: C, 60.19; H, 4.84; N, 17.55; Found: C,
60.19; H, 4.84; N, 17.55.
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2-((4-bromophenyl)amino)-2-(4-(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-
yl)propoxy)phenyl)acetonitrile (1g): Yield: 92% (0.48g),white crystals, mp: 175 ºC. IR (KBr): ν
= 3317, 2954, 2360, 1697, 1651, 1589, 1542, 1512, 1404, 1242, 1180, 1072, 825 cm–1. 1H NMR
(250 MHz, DMSO-d6/TMS) δ (ppm): 2.28-2.33 (m, 2H), 3.34 (s, 3H), 3.53 (s, 3H), 3.97 (t, J = 5,
2H), 4.46 (t, J = 5, 2H), 4.95 (s, 1H), 5.34 (s, 1H), 673-7.45 (m, 10H), 8.04 (s, 1H). 13C NMR
(62.5 MHz, DMSO-d6/TMS) δ (ppm): 27.0, 29.5, 29.9, 30.9, 36.8, 44.2, 55.4, 64.0, 106.8, 114.2,
114.4, 122.0, 130.2, 132.0, 141.4, 144.9, 145.0, 149.0, 155.0, 157.5, 157.9, 160.6, 174.8, 179.1.
MS: 522.12 (9, M+). Anal. Calcd. for C24H23BrN6O3: C, 55.08; H, 4.43; N, 16.06; Found: C,
55.12; H, 4.48; N, 16.14.
2-(4-((5-(1H-benzo[d]imidazol-1-yl)pentyl)oxy)phenyl)-2-((4-
methoxyphenyl)amino)acetonitrile (1h): Yield: 92%(0.40g), white crystals, mp: 200 ºC. IR
(KBr): ν = 3440, 3139, 2923, 2351, 1604, 1512, 1249, 108, 817 cm–1. 1H NMR (250 MHz,
DMSO-d6/TMS) δ (ppm): 1.69-1.84 (m, 6H), 3.75 (s, 3H), 3.97 (t, J = 5.0 Hz, 2H), 4.46 (t, J =
5.0 Hz, 2H), 4.81 (s, 1H), 4.95 (s, 1H), 6.95-7.78 (m, 12H), 8.81 (s, 1H). 13C NMR (62.5 MHz,
DMSO-d6/TMS) δ (ppm): 22.5, 28.0, 28.7, 44.8, 48.5, 67.41, 111.5, 114.3, 114.4, 114.5, 114.7,
115.3, 117.5, 119.9, 122.5, 123.3, 123.7, 128.5, 130.1, 132.5, 138.2, 139.7, 142.8, 152.2, 158.7,
161.0. MS: 440.20 (19, M+). Anal. Calcd. for C27H28N4O2: C, 73.61; H, 6.41; N, 12.72; Found:
C, 73.68; H, 6.46; N, 12.79.
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2-(4-((5-(1H-benzo[d]imidazol-1-yl)pentyl)oxy)phenyl)-2-((3-
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hydroxyphenyl)amino)acetonitrile (1i): Yield: 94% (0.40g), white crystals, mp 230 ºC. IR (KBr):
ν = 3446, 3134, 2927, 2361, 1608, 1522, 1249, 1108, 820 cm–1. 1H NMR (250 MHz, DMSO-
d6/TMS) δ (ppm): 1.51-2.04 (m, 6H), 3.97 (t, J = 5.0 Hz, 2H), 4.46 (t, J = 5.0 2H), 4.90 (s, 1H),
5.15 (s, 1H), 6.73-7.67 (m, 12H); 8.82 (s, 1H). 13C NMR (62.5 MHz, DMSO-d6/TMS) δ (ppm):
22.5, 28.0, 28.7, 44.8, 48.5, 67.41, 111.5, 114.3, 114.4, 114.5, 114.7, 115.3, 117.5, 122.1, 123.3,
128.5, 130.1,131.7, 132.5, 138.2, 139.7, 142.8, 161.0. MS: 426.22 (17, M+). Anal. Calcd. for
C26H26N4O2: C, 73.22; H, 6.14; N, 13.14; Found: C, 73.31; H, 6.21; N, 13.20.
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2-(4-((5-(1H-benzo[d]imidazol-1-yl)pentyl)oxy)phenyl)-2-((4-bromophenyl)amino)acetonitrile
(1j): Yield: 91% (0.44), white crystals, mp 156 ºC. IR (KBr): ν = 3438, 3136, 2925, 2349, 1614,
1518, 1259, 1108, 827 cm–1. 1H NMR (250 MHz, DMSO-d6/TMS) δ (ppm): 1.69-1.84 (m, 6H),
3.98 (t, J = 5.0, 2H), 4.48 (t, J = 5.0 Hz, 2H), 4.89 (s, 1H), 5.84 (s, 1H), 6.73-7.67 (m, 12H), 8.33
(s, 1H). 13CNMR (62.5 MHz, DMSO-d6/TMS) δ (ppm): 27.9, 29.7, 29.9, 44.1, 55.4, 64.0, 106.8,
114.2, 114.4, 114.5, 122.0, 130.2, 132.0, 141.4, 144.9, 145.0, 149.0, 155.0, 157.5, 157.9, 160.6.
MS: 488.14 (14, M+). Anal. Calcd. for C26H25BrN4O: C, 63.81; H, 5.15; N, 11.45; Found: C,
63.88; H, 5.19; N, 11.50.
ASSOCIATED CONTENT
Supporting Information. Copies of 1H, 13C NMR for all synthesized compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: khalafi@chem.susc.ac.ir (A.K.-N.). panahi@shirazu.ac.ir (F.P.)
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
The financial supports of research councils of Shiraz University are gratefully acknowledged.
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