Synthesis and Antimicrobial Evaluation of Some Novel Pyrido[2,3-d] Pyrimidine Derivatives and Their Ribofuranosides

Article abstract of DOI:10.1002/jhet.3203

2-Amino-3-cyano-4,6-disubstituted pyridines 2a–c on treatment with arylisocyanate and arylisothiocyanate afforded 4-imino-3,5,7-trisubstituted pyrido[2,3-d] pyrimidin-2(1H)-ones 3a–c and 4-imino-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-2(1H)-thiones 4a

Full text of DOI:10.1002/jhet.3203

Month 2018
Synthesis and Antimicrobial Evaluation of Some Novel Pyrido[2,3-d]
Pyrimidine Derivatives and Their Ribofuranosides
*
Sangeeta Bhargava
and Lokesh Kumar Rajwanshi
Department of Chemistry, University of Rajasthan, Jaipur 302004, India
*E-mail: drsbhargava1@gmail.com
Received October 8, 2017
DOI 10.1002/jhet.3203
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
2-Amino-3-cyano-4,6-disubstituted pyridines 2a–c on treatment with arylisocyanate and
arylisothiocyanate afforded 4-imino-3,5,7-trisubstituted pyrido[2,3-d] pyrimidin-2(1H)-ones 3a–c and 4-
imino-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-2(1H)-thiones 4a–c, respectively. The ribofuranosides,
namely, 4-imino-3,5,7-trisubstituted-1-(20,30,50-tri-O-benzoyl-β-D-ribofuranosyl) pyrido[2,3-d]pyrimidin-
2(1H)-ones 7a–c and 4-imino-3,5,7-trisubstituted-1-(20,30,50-tri-O-benzoyl-β-D-ribofuranosyl) pyrido[2,3-
d]pyri-midin-2(1H)-thiones 8a–c, were synthesized by the condensation of trimethylsilyl derivatives of
3a–c and 4a–c with β-D-ribofuranosyl-1-acetate-2,3,5-tribenzoate. The structure of newly synthesized
1
ribofuranosides and their precursors were established by elemental analyses, IR, H NMR and 13C NMR
spectroscopy. All the synthesized compounds were screened for their antibacterial and antifungal activities
against Escherichia coli, Staphylococcus aureus, Aspergillus niger, and Aspergillus flavus.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
pyrimidin-2-(1H)-thiones and their ribofuranosides 7a–c
and 8a–c. Pyrido [2,3-d]pyrimidin-2-(1H)-ones/thiones
and their ribofuranosides have been screened for
antibacterial activities with Escherichia coli and
Staphylococcus aureus and antifungal activity with
Aspergillus niger and Aspergillus flavus.
Pyrido[2,3-d]pyrimidines have attracted tremendous
attention because of their diversified medicinal importance,
for example, antibacterial [1–3], antitumor [4], antiviral
[5], anticancer [6,7], antifungal [8,9], antiulcer [10],
anticonvulsant [11,12], antihypertensive [13], and
antineoplastic [14]. The ribofuranosides of pyrido[2,3-d]
pyrimidines have been reported as antileukemic [15], anti-
AIDS [16,17], antiherpes [18], hypnotic activity [19], and
so forth. Some new pyrido[2,3-d]pyrimidines and their
ribofuranosides have been synthesized in our previous
laboratory work, which showed varying degrees of
antimicrobial activity [20–22]. The manifold applications
of pyrido[2,3-d]pyrimidines and their ribofuranosides
have prompted us to target the synthesis of some novel 4-
imino-3,5,7-trisubstituted pyrido[2,3-d]pyrimidin-2-(1H)-
ones and 4-imino-3,5,7-trisubstituted pyrido[2,3-d]
RESULTS AND DISCUSSION
Chalcones 1a–c and malononitrile on condensation in
the presence of ammonium acetate and ethanol gave 2-
amino-3-cyano-4,6-disubstituted pyridines 2a–c via a
Michael-type reaction. Compound 2a–c on treating with
aryl isocyanate/isothiocyanate afforded 4-imino-3,5,7-
trisubstituted pyrido[2,3-d]pyrimidin-2(1H)-ones 3a–c/
thiones 4a–c. Compound 3a–c/4a–c were treated with
hexamethyldisilazane in toluene, gave the corresponding
© 2018 Wiley Periodicals, Inc.

S. Bhargava and L. K. Rajwanshi
Vol 000
trimethylsilyl derivatives 5a–c/6a–c, which on stirring
with β-D-ribofuranose-1-acetate-2,3,5-tribenzoate in
vacuo, at 155–160°C for 10 h, and gave 4-imino-3,5,7-
trisubstituted-1-(20,30,50-tri-O-benzoyl-β-D-ribofuranosyl)
pyrido[2,3-d]pyrimidin-2(1H)-ones 7a–c/thiones 8a–c,
respectively (Scheme 1).
1500–1355 cmꢀ1 have also been observed in compound
4a–c. Two sharp bands in the region 1545–1530 and
1370–1350 cmꢀ1 were observed because of ꢀNO2
stretching vibrations in compounds 3c, 4c, 7c, and 8c
showed.
The disappearance of the band due to >NH in
compounds 7a–c and 8a–c revealed that N-1 substituted
ribofuranosides are produced. The symmetric and
asymmetric stretching vibrations due to C-O-C linkage of
sugar moiety in compounds 7a–c and 8a–c have
The IR spectra of compound 2a–c showed
a
characteristic sharp band at 2210–2185 cmꢀ1 indicating
the presence of ꢀC≡N group. Band in the region
3440–3305 cmꢀ1 was assigned because of asymmetric
and symmetric stretching vibrations of ꢀNH2 group. The
disappearance of the characteristic absorption band in the
region 2210–2185 cmꢀ1 due to ꢀC ≡ N group indicates
the formation of heterocyclic ring in compounds 3a–c
appeared in the regions 1185 and 1015 cmꢀ1
.
1H NMR spectra of all the synthesized compounds
showed multiplet of aromatic protons at 6.87–
a
8.13 ppm. The >NH protons appeared as a singlet at
7.86–8.02 ppm in compounds 3a–c and 4a–c. The
>C=NH protons in compounds 3a–c, 4a–c, 7a–c, and
8a–c appeared as a singlet at 8.71–8.95 ppm. Peak due to
ꢀOCH3 protons appeared as a singlet at 3.77–3.90 ppm
in compounds 3b, 4b, 7b, and 8b.
The disappearance of the peak due to >NH moiety in
compounds 7a–c and 8a–c indicates the site of
attachment of the sugar. In the sugar, proton at C"1 caused
a doublet at 6.52–6.63 ppm. C"2, C3", and C4" protons
and 4a–c. Compounds 3a–c and 7a–c showed
a
characteristic absorption band in the region 1725–
1685 cmꢀ1 due to >C=O group. Compounds 4a–c
and 8a–c showed an absorption band in the region
1235–1205 cmꢀ1 due to >C=S group. Absorption bands
due to >NH and >C=NH appeared in the regions
3375–3330 and 3180–3135 cmꢀ1
, respectively, are
supportive of the formation of 3a–c and 4a–c.
Three characteristic bands of NHCS moiety in the region
Scheme 1. Synthesis of 4-lmino-3,5,7-trisubstituted pyrido[2,3-d]pyramidines.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Antimicrobial Evaluation of Some Novel Pyrido[2,3-d] Pyrimidine
Derivatives and Their Ribofuranosides
appeared as a multiplet at 4.81–4.96 ppm, and C"5 protons
caused a doublet in the region at 4.31–4.47 ppm. The
characterization data of the synthesized compounds are
given in Table 1.
Antimicrobial studies. All the synthesized compounds
were screened for their antibacterial and antifungal
activities against E. coli (Gram-negative bacteria),
S. aureus (Gram-positive bacteria), A. niger, and A. flavus
(Fungi) at the concentration of 100 μg/disc. Streptomycin
and mycostatin were used as reference compounds,
respectively.
The disc diffusion method developed by Varma et al.
[23] has been followed. The results have been tabulated
(Table 2) in the form of inhibition zones and activity
indices. Although all the compounds show moderate to
fairly good activities, a closer look at the activity indices
reveals that the ribofuranosides are better antimicrobial
agents than their bases.
Table 1
Characterization data of compounds 3a–c, 4a–c, 7a–c, and 8a–c.
Found (%)/(cal.)
H
Compounds
R1
R2
R3
Molecular formula
C23H15N4O2Cl
Yield %
64
M.P. °C
C
N
3a
C4H3Oꢀ
C6H5ꢀ
3-ClC6H4ꢀ
>300
66.58
(66.60)
64.72
(64.80)
63.94
(63.94)
64.50
(64.11)
62.57
(62.55)
63.94
(63.910
68.48
3.61
(3.64)
3.87
(3.85)
3.37
(3.43)
3.48
(3.52)
3.76
(3.72)
3.37
(3.43)
4.07
13.58
(13.51)
12.61
(12.59)
14.88
(14.90)
13.08
(13.00)
12.12
(12.15)
14.88
(14.90)
6.58
3b
3c
4a
4b
4c
7a
7b
7c
8a
8b
8c
C4H3Oꢀ
4-CH3OC6H4ꢀ
C6H5ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
3-ClC6H4ꢀ
C24H17N4O3Cl
C25H16N5O3Cl
C23H15N4OSCl
C24H17N4O2SCl
C25H16N5O2SCl
C49H35N4O9Cl
C50H37N4O10Cl
C51H36N5O10Cl
C49H35N4O8SCl
C50H37N4O9SCl
C51H36N5O9SCl
67
62
78
69
65
75
80
71
68
73
71
274–76
258–60
280–82
244–46
230–32
288–90
220–22
208–10
227–29
213–15
196–98
4-NO2C6H4ꢀ
C4H3Oꢀ
C6H5ꢀ
C4H3Oꢀ
4-CH3OC6H4ꢀ
C6H5ꢀ
4-NO2C6H4ꢀ
C4H3Oꢀ
C6H5ꢀ
(68.50)
67.50
(4.10)
4.27
(6.52)
6.28
(6.30)
7.62
(7.66)
6.35
(6.40)
6.24
C4H3Oꢀ
4-CH3OC6H4ꢀ
C6H5ꢀ
(67.54)
67.04
(4.19)
3.97
4-NO2C6H4ꢀ
C4H3Oꢀ
(67.00)
67.28
(3.97)
4.07
C6H5ꢀ
(67.25)
66.32
(4.03)
4.10
C4H3Oꢀ
4-CH3OC6H4ꢀ
C6H5ꢀ
(66.33)
65.84
(4.12)
3.92
(6.20)
7.52
(7.53)
4-NO2C6H4ꢀ
(65.84)
(3.90)
Table 2
Antimicrobial activity of the synthesized compounds 3a–c, 4a–c, 7a–c, and 8a–c. Zone of inhibition in (mm) (activity index).
Antibacterial activity Antifungal activity
Staphylococcus aureus Aspergillus niger Aspergillus flavus
Compounds
Escherichia coli
3a
3b
3c
4a
4b
4c
7a
7b
7c
8a
8b
8c
7.7 (0.83)
8.1 (0.91)
8.3 (0.88)
8.4 (0.97)
8.7 (1.03)
8.9 (1.04)
9.1 (1.06)
9.2 (1.09)
9.6 (1.12)
9.9 (1.17)
10.2 (1.21)
10.4 (1.24)
7.9 (0.87)
8.2 (0.94)
8.5 (0.96)
8.8 (0.99)
9.2 (0.98)
9.4 (1.06)
9.5 (1.09)
9.7 (1.14)
9.9 (1.17)
10.1 (1.19)
10.4 (1.22)
10.7 (1.25)
8.3 (0.95)
8.8 (1.01)
9.1 (1.06)
9.3 (1.09)
9.5 (1.14)
9.6 (1.18)
9.7 (1.21)
10.0 (1.23)
10.4 (1.25)
10.1 (1.26)
10.8 (1.29)
11.0 (1.31)
9.1 (0.93)
9.7 (1.12)
9.9 (1.15)
9.3 (1.03)
9.6 (1.09)
9.8 (1.13)
10.0 (1.15)
10.1 (1.18)
9.5 (1.08)
10.3 (1.20)
10.4 (1.22)
10.8 (1.24)
Activity index = Inhibition area of the sample/Inhibition area of the standard.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Bhargava and L. K. Rajwanshi
Vol 000
CONCLUSION
139.60, 138.10, 134.10, 130.30, 129.40, 127.20, 124.10,
120.10, 118.20, 111.30, 110.40, 108.60, 105.10 (aromatic
In conclusion, we have described the synthesis of some
novel pyrido[2,3-d]pyrimidine derivatives and their
ribofuranosides; and antimicrobial screening against
E. coli (Gram-negative bacteria), S. aureus (Gram-
positive bacteria), A. niger, and A. flavus (Fungi). A
closer observation reveals that most of the
ribofuranosides exhibited fairly good activities as
compared with their parent nucleus.
carbons); MS: m/z 412.9 [M + H]+ for C23H15N4O2Cl.
4-Imino-3-(30-chlorophenyl)-5-furane-2-yl-7-(40-methoxy-
phenyl)-pyrido[2,3-d] pyrimidin-2(1H)-one (3b).
Yellow
solid, IR (KBr) (νmax/cmꢀ1
) 3335 (>NH), 3145
1
(>C=NH), 1685 (>C=O). H NMR (300 MHz, CDCl3)
3.83 (s, 3H, -OCH3), 6.90–7.84 (m, 12H, ArH), 7.92 (s,
1H, >NH), 8.74 (s, 1H, >C=NH). 13C NMR (75 MHz,
CDCl3) 164.10 (N-C=NH), 160.60 (-C-OCH3) 159.30
(N=C-NH), 158.80(N-C=O), 56.10 (-O-CH3), 156.90,
154.40, 144.40, 142.80, 138.50, 133.90, 130.10, 128.10,
125.10, 120.90, 117.90, 109.80, 110.0, 108.20, 105.40
(aromatic carbons); MS: m/z 443.7 [M + H]+ for
EXPERIMENTAL
C24H17N4O3Cl.
Melting points of all the synthesized compounds were
determined in open capillary tubes and are uncorrected. IR
spectra were determined in KBr disc on SHIMADZU FT-
4-Imino-3-(30-chlorophenyl)-5-(40-nitrophenyl)-7-phenylpyrido
[2,3-d] pyrimidin-2(1H)-one (3c). Brown solid, IR (KBr)
(νmax/cmꢀ1) 3375 (>NH), 3180 (>C=NH), 1710 (>C=O).
1H NMR (300 MHz, CDCl3) 7.03–8.11 (m, 14H, ArH),
8.02 (s, 1H, >NH), 8.90 (s, 1H, >C=NH). 13C NMR
(75 MHz, CDCl3) 164.80 (N-C=NH), 159.10 (N=C-NH),
158.30 (N-C=O), 157.35, 152.20, 149.60, 148.90, 144.50,
139.80, 139.10, 134.40, 130.60, 129.70, 127.50, 124.60,
118.70, 111.80, 108.80 (aromatic carbons); MS: m/z 466.3
[M + H]+ for C25H16N5O3Cl.
1
IR spectrophotometer and H NMR spectra on a JEOL
AL-300 MHz NMR spectrophotometer in CDCl3 using
TMS as an internal standard; and 13C NMR spectra on a
JEOL AL-75 MHz NMR spectrophotometer in CDCl3
using TMS as an internal standard. Mass spectra were
taken on a Thermoscientific TSQ 8000 triple quadrupole
GC–MS/MS with pyroprobe 5000 mass spectrometer. The
purity of compounds was checked by TLC using silica gel
“G” as adsorbent and visualization was accomplished by
UV light or iodine vapors in a chamber. Chalcones were
synthesized by reported method [24].
Synthesis of 4-imino-3,5,7-trisubstituted pyrido[2,3-d]
pyrimidin-2(1H)-thiones (4a–c).
Compounds of 2a–c
(0.01 mol), 3-chlorophenylisothiocyanate (0.01 mol),
dioxane (18.0 mL), and pyridine (2.0 mL) were refluxed
at 150°C for about 14–16 h. After cooling, the contents
of the flask were poured onto crushed ice with constant
stirring. The yellow solid mass, thus obtained, was
washed with water. The dried crude product was
recrystallized form DMF-ethanol (1:10). Spectral data of
Synthesis of 2-amino-3-cyano-4,6-disubstituted pyridine
(2a–c). An appropriate chalcone (0.05 mol), malononitrile
(0.05 mol), and ammonium acetate (0.4 mol) in ethanol
(150 mL) was refluxed on a water bath for 13–15 h, and
then the content of the flask was cooled and was poured
onto crushed ice with constant shaking. The solid, thus
obtained, was washed with water several times and finally
with cold ethanol. The residue was recrystallized from
ethanol.
compound 3a–c are presented in the following.
4-Imino-3-(30-chlorophenyl)-5-furane-2-yl-7-phenylpyrido[2,3-
d]pyrimidin-2(1H)-thione (4a).
Brown solid, IR (KBr)
(νmax/cmꢀ1
)
3340 (>NH), 3160 (>C=NH), 1220
(>C=S). 1H NMR (300 MHz, CDCl3) 6.94–7.82 (m,
13H, ArH), 7.90 (s, 1H, >NH), 8.82 (s, 1H, >C=NH).
13C NMR (75 MHz, CDCl3) 179.40 (N-C=S), 163.20
(N-C=NH), 159.0 (N=C-NH), 158.10, 153.80, 142.10,
140.80, 139.10, 134.0, 130.0, 129.10, 127.0, 125.60,
124.90, 111.25, 110.20, 108.45 (aromatic carbons); MS:
Synthesis of 4-imino-3,5,7-trisubstituted pyrido[2,3-d]
pyrimidin-2(1H)-ones (3a–c).
A mixture of compound
2a–c (0.01 mol), 3-chlorophenylisocyanate (0.01 mol),
dioxane (18.0 mL), and pyridine (2.0 mL) was refluxed at
150°C for about 14–16 h. After cooling, the crushed ice
was added to it with constant stirring. The yellow solid
mass, thus obtained, was washed with water. The dried
crude product, so obtained, was recrystallized from DMF-
ethanol (1:10). The spectral data of compound 3a–c are
m/z 429.65 [M + H]+ for C23H15N4OSCl.
4-Imino-3-(30-chlorophenyl)-5-furane-2-yl-7-(40-methoxyphenyl)-
pyrido[2,3-d] pyrimidin-2(1H)-thione (4b). Yellow solid, IR
(KBr) (νmax/cmꢀ1) 3330 (>NH), 3135 (>C=NH), 1205
(>C=S). 1H NMR (300 MHz, CDCl3) 3.77 (s, 3H,
ꢀOCH3), 6.87–7.79 (m, 12H, ArH), 8.71 (s, 1H,
>C=NH), 7.86 (s, 1H, >NH). 13C NMR (75 MHz,
CDCl3) 179.15 (N-C=S), 163.05 (N-C=NH), 160.20
(ꢀC-OCH3) 159.0 (N=C-NH), 55.80 (ꢀO-CH3),
157.90, 153.60, 142.50, 140.55, 133.75, 132.20,
129.95, 128.0, 125.05, 124.70, 114.80, 111.10, 109.65,
presented in the following.
4-Imino-3-(30-chlorophenyl)-5-furane-2-yl-7-phenylpyrido[2,
3-d]pyrimidin-2(1H)-one (3a). Brown solid, IR (KBr) (νmax
/
1
cmꢀ1) 3355 (>NH), 3170 (>C=NH), 1695 (>C=O). H
NMR (300 MHz, CDCl3) 6.96–7.87 (m, 13H, ArH), 7.96
(s, 1H, >NH), 8.85 (s, 1H, >C=NH). 13C NMR
(75 MHz, CDCl3) 164.40 (N-C=NH), 159.60 (N=C-NH),
157.70 (N-C=O), 156.60, 154.20, 152.40, 142.20,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Synthesis and Antimicrobial Evaluation of Some Novel Pyrido[2,3-d] Pyrimidine
Derivatives and Their Ribofuranosides
108.15, 105.0 (aromatic carbons); MS: m/z 458.9
[M + H]+ for C24H17N4O2SCl.
130.70, 128.20, 129.10, 128.50, 124.30, 120.80,
118.20, 114.70, 111.50, 110.40, 108.60 (aromatic
carbons), 81.10, 74.40, 70.10, 68.80, 65.0 (C"1- C5″
Sugar), 56.30 (ꢀO-CH3); MS: m/z 887.6 [M + H]+ for
4-Imino-3-(30-chlorophenyl)-5-(40-nitrophenyl)-7-phenyl-
pyrido[2,3-d] pyrimidin-2(1H)-thione (4c).
Brown solid,
IR (KBr) (νmax/cmꢀ1) 3365 (>NH), 3175 (>C=NH),
C50H37N4O10Cl.
1
4-Imino-3-(30-chlorophenyl)-5-(40-nitrophenyl)-7-phenyl-1-
(20,30,50-tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin-
2(1H)-ones (7c). Brown solid, IR (KBr) (νmax/cmꢀ1) 3195
1230 (>C=S). H NMR (300 MHz, CDCl3) 7.01–8.05
(m, 14H, ArH), 7.98 (s, 1H, >NH), 8.87 (s, 1H,
>C=NH). 13C NMR (75 MHz, CDCl3) 179.80
(N-C=S), 163.45 (N-C=NH), 159.60 (N=C-NH),
158.15, 149.20, 148.40, 144.0, 140.60, 139.50, 134.30,
130.20, 129.40, 127.90, 127.20, 125.10, 124.30,
123.40, 109.0, 107.80 (aromatic carbons); MS: m/z
483.45 [M + H]+ for C25H16N5O2SCl.
1
(>C=NH), 1725 (>C=O). H NMR (300 MHz, CDCl3)
4.47 (d, 2H, C"5 Sugar), 4.91–4.96 (m, 3H, C2", C"3, and
C"4 Sugar), 6.63 (d, 1H, C"1 Sugar), 7.38–8.19 (m, 15H,
OBz), 7.72–8.13 (m, 12H, ArH), 8.95 (s, 1H, >C=NH).
13C NMR (75 MHz, CDCl3) 168.0 (ꢀOCO-Ph), 164.80
(N-C=NH), 159.40 (N=C-NH), 158.50 (N-C=O), 158.20,
149.40, 148.50, 144.20, 140.70, 139.90, 134.80, 131.0,
129.90, 129.40, 127.50, 125.90, 124.80, 123.60, 118.60,
109.0, 107.80 (aromatic carbons), 81.50, 75.10, 70.2,
69.20, 65.40 (C"1- C5" Sugar); MS: m/z 912.4 [M + H]+
for C51H36N5O10Cl.
Synthesis of 4-imino-3,5,7-trisubstituted-1-(20,30,50-tri-O-
benzoyl-β-D-ribofuranosyl)
pyrido[2,3-d]pyrimidin-2(1H)-
4-Imino-3,5,7-trisubstituted pyrido[2,3-d]
ones (7a–c).
pyrimidin-2(1H)-ones 3a–c (0.002 mol) in toluene
(30 mL) were treated with hexamethyl disilazane
(0.0124 mol) in the presence of few crystals of ammonium
sulfate, and the contents were refluxed for 4 h. The clear-
colored solution, thus obtained, was filtered, and the
solvent was removed in vacuo at 100°C. The sugar β-D-
ribofuranosyl-1-acetate-2,3,5-tribenzoate (0.02 mol) was
added to the previous pasty mixture and then stirred at
140–145°C, under vacuum was regularly applied for
5 min, at the end of each hour. The melt, so obtained, was
boiled in methanol for 10 min, cooled and filtered. The
viscous mass of the ribofuranoside, so obtained, was
recrystallized from diethyl ether. The spectral data of
Synthesis of 4-Imino-3,5,7-trisubstituted-1-(20,30,50-tri-O-
benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin-2(1H)-
thiones (8a–c).
4-Imino-3,5,7-trisubstituted pyrido
[2,3-d]pyrimidin-2(1H)-thiones 4a–c (0.002 mol) in
toluene (30 mL) was reacted with hexamethyldisilazane
(0.0124 mol) in the presence of ammonium sulfate. The
contents were refluxed for 4 h. The clear solution, thus
obtained, was filtered, and the solvent was removed in
vacuo at 100°C. The sugar β-D-ribofuranosyl-1-acetate-
2,3,5-tribenzoate (0.02 mol) was added to the
previous pasty mixture and then stirred at 140–145°C,
under vacuum was regularly applied for 5 min, at the
end of each hour. The melt was boiled in methanol for
10 min, cooled and filtered. The viscous mass of the
ribofuranoside, so obtained, was recrystallized from
diethyl ether. The spectral data of compound 8a–c are
presented in the following.
compound 7a–c are presented in the following.
4-Imino-3-(30-chlorophenyl)-5-furane-2-yl-7-phenyl-1-(20,30,50-
tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin-2(1H)-one
(7a).
Brown solid, IR (KBr) (νmax/cmꢀ1
)
3160
1
(>C=NH), 1705 (>C=O). H NMR (300 MHz, CDCl3)
4.38 (d, 2H, C"5 Sugar), 4.89–4.93 (m, 3H, C2", C"3, and
C"4 Sugar), 6.60 (d, 1H, C"1 Sugar), 7.35–8.15 (m, 15H,
OBz), 7.65–7.90 (m, 13H, ArH), 8.89 (s, 1H, >C=NH).
13C NMR (75 MHz, CDCl3) 167.80 (-OCO-Ph), 164.50
(N-C=NH), 159.20 (N=C-NH), 158.30 (N-C=O), 157.10,
154.10, 153.40, 144.90, 142.20, 139.80, 139.10, 134.60,
130.70, 129.60, 129.0, 128.50, 127.20, 124.40, 120.90,
118.40, 111.90, 110.20, 108.70 (aromatic carbons), 81.30,
74.80, 70.0, 68.90, 65.20 (C"1- C5″ Sugar); MS: m/z 858.1
4-Imino-3-(30-chlorophenyl)-5-furane-2-yl-7-phenyl-1-(20,30,50-
tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin-2(1H)-
thione (8a).
Brown solid, IR (KBr) (νmax/cmꢀ1) 3155
1
(>C=NH), 1225 (>C=S). H NMR (300 MHz, CDCl3)
4.36 (d, 2H, C"5 Sugar), 4.87–4.92 (m, 3H, C2", C"3, and
C"4 Sugar), 6.59 (d, 1H, C"1 Sugar), 7.34–8.13 (m, 15H,
OBz), 7.62–7.85 (m, 13H, ArH), 8.87 (s, 1H, >C=NH).
13C NMR (75 MHz, CDCl3) 177.10 (N-C=S), 167.40
(ꢀOCO-Ph), 164.30 (N-C=NH), 159.10 (N=C-NH),
158.25, 154.0, 153.10, 144.50, 142.40, 139.20, 138.90,
134.30, 130.10, 129.20, 128.40, 128.30, 127.0, 124.20,
120.80, 118.30, 111.20, 110.0, 108.50 (aromatic
carbons), 81.20, 74.70, 70.1, 68.70, 65.10 (C"1- C5"
[M + H]+ for C49H35N4O9Cl.
4-Imino-3-(30-chlorophenyl)-5-furane-2-yl-7-(40-methoxyphenyl)-
1-(20,30,50-tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]pyramidin-
2(1H)-ones (7b).
Brown solid, IR (KBr) (νmax/cmꢀ1
)
3145 (>C=NH), 1700 (>C=O). 1H NMR (300 MHz,
CDCl3) 3.90 (s, 3H, ꢀOCH3), 4.32 (d, 2H, C"5 Sugar),
4.84–4.95 (m, 3H, C2", C3", and C"4 Sugar), 6.54 (d, 1H,
C"1 Sugar), 7.32–8.19 (m, 15H, OBz), 7.55–7.80 (m, 12H,
ArH), 8.80 (s, 1H, >C=NH). 13C NMR (75 MHz,
CDCl3) 167.20 (ꢀOCO-Ph), 164.40 (N-C=NH), 160.60
(ꢀC-OCH3), 159.0 (N=C-NH), 158.50 (N-C=O), 157.80,
154.0, 153.20, 144.80, 142.10, 139.0, 134.40, 132.10,
Sugar); MS: m/z 872.75 [M + H]+ for C49H35N4O8SCl.
4-Imino-3-(30-chlorophenyl)-5-furane-2-yl-7-(40-methoxyphenyl)-
1-(20,30,50-tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]pyramidin-
2(1H)-thiones (8b). Brown solid, IR (KBr) (νmax/cmꢀ1
)
3135(>C=NH), 1215 (>C=S). 1H NMR (300 MHz,
CDCl3) 3.87 (s, 3H, -OCH3), 4.31 (d, 2H, C"5 Sugar),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. Bhargava and L. K. Rajwanshi
Vol 000
4.81–4.90 (m, 3H, C2", C3", and C4" Sugar), 6.52 (d, 1H, C1"
Sugar), 7.30–8.17 (m, 15H, OBz), 7.52–7.92 (m, 12H,
ArH), 8.78 (s, 1H, >C=NH). 13C NMR (75 MHz,
CDCl3) 177.60 (N-C=S), 167.10 (-OCO-Ph), 164.20
(N-C=NH), 160.10 (ꢀC-OCH3), 158.80 (N=C-NH),
158.40, 154.10, 153.0, 144.50, 142.0, 138.80, 134.20,
132.0, 130.40, 128.0, 129.0, 128.20, 124.0, 120.50,
118.10, 114.30, 111.20, 110.20, 108.50 (aromatic
carbons), 81.0, 74.20, 70.0, 68.60, 64.90 (C"1- C5" Sugar);,
56.20 (ꢀO-CH3); MS: m/z 903.8 [M + H]+ for
[3] Agrawal, H.; Swati; Yadav, A. K.; Prakash, L. Phosphosrus,
Sulfur Silicon Relat Elem 1998, 141, 159.
[4] Behaloa, M. S.; Meleb, G. J Heterocyclic Chem 2017, 54, 295.
[5] Pratap, R.; Yarovenkom, V. N. Nucleosides, Nucleotides, and
Nucleic Acid 2000, 19, 845; Chem Abstr 2000, 133, 193394.
[6] Bar, T.; Zimmermann, P.; Boer, R.; Gekeler, V.; Isc, W.; Boss,
H.; Ulrich, W. R. PCT Int. Appl. WO 9,719, 946; Chem Abstr 1997 1997,
127, 81463.
[7] Sharma, A. K.; Swati; Yadav, A. K.; Prakash, L. Phosphosrus,
Sulfur Silicon Relat Elem 1996, 112, 109.
[8] Singh, G.; Swati; Mishra, A. K.; Prakash, L. Indian J Chem
1998, 37B, 517.
[9] Singh, G.; Singh, G.; Yadav, A. K.; Mishra, A. K. Phosphorus,
Sulfur Silicon Relat Elem 2000, 165, 107.
[10] Brown, T. H.; Ife, R. J.; Leach, C. A. Eur. Patent., EP 404, 355
(Cl. C07D 471/04), December 27, 1990; G. B. Appl. 89/12, 336, May 30,
1989, 14 pp; Chem Abstr 1991, 114, 164273.
C50H37N4O9SCl.
4-Imino-3-(30-chlorophenyl)-5-(40-nitrophenyl)-7-phenyl-1-
(20,30,50-tri-O-benzoyl-β-D-ribofuranosyl)pyrido[2,3-d]pyrimidin-
2(1H)-thiones (8c). Brown solid, IR (KBr) (νmax/cmꢀ1
)
[11] Sladowska, H. Farmaco 1993, 48, 77.
3190 (>C=NH), 1235 (>C=S). 1H NMR (300 MHz,
CDCl3) 4.39 (d, 2H, C5" Sugar), 4.90–4.94 (m, 3H, C2", C"3,
and C"4 Sugar), 6.61 (d, 1H, C"1 Sugar), 7.36–8.21 (m, 15H,
OBz), 7.78–8.32 (m, 12H, ArH), 8.93 (s, 1H, >C=NH).
13C NMR (75 MHz, CDCl3) 178.30 (N-C=S), 167.90
(-OCO-Ph), 164.60 (N-C=NH), 159.20 (N=C-NH),
158.30, 149.30, 148.10, 144.0, 140.50, 139.70, 134.60,
131.10, 129.60, 129.0, 127.40, 125.70, 124.50, 123.20,
118.10, 108.80, 107.50, 81.40, 74.80, 70.10, 69.0, 65.30;
MS: m/z 928.5 [M + H]+ for C51H36N5O9SCl.
[12] Shafik, R. M.; Eshba, N. H.; Nabil, H.; El-Semary, M. M.;
Abdelkreem, F. M. Alex J Pharm Sci 1995, 9, 55; Chem Abstr 1995,
123, 1332611.
[13] Monge, A.; Merino, V. M.; Martin, M. C. S. Span. ES 2, 009,
217 (Cl. C07D 471/04), September 16, 1989, Appl. 8, 701, 988, July 7,
1987, 6 pp; Chem Abstr 1991, 114, 164275.
[14] Chae, W. G.; Chan, T. C. K.; Chang, E.-j. Tetrahedron 1998,
54, 8661.
[15] Gossett, L. S.; Shin, C. Eur. Patent Appl. EP, 511, 792 (Cl.
CO7 D 471/04), 04 Nov. 1992, US Patent Appl. 692, 845, 29 Apr.
1991, 16 pp; Chem Abstr 1993, 118, 147572.
[16] Bowlin, T. H. Eur. Pat. Appl., EP 472, 181 (Cl. A61K31/70),
August 26, 1992, U.S. Appl. 517,042, August 22, 1990, 28 pp.; Chem
Abstr 1992, 117, 70267.
[17] Pai, S. B.; Liu, S. H.; Zhu, Y. L.; Chu, C. K.; Cheng, Y. C.
Antimicrob Agents Chemother 1996, 40, 380.
[18] Verheggen, I.; Aerschot, A. V.; Toppet, S.; Snoeck, R.;
Janssen, G.; Balzarini, J.; Clercq, E. D.; Herdewijn, P. J Med Chem
1993, 36, 2033.
[19] Yamamoto, I.; Kimura, T.; Tateoka, Y.; Watanabe, K.; Ho, I. K.
J Med Chem 1987, 30, 2227.
[20] Verma, P.; Kumar, N.; Bhargava, S.; Yadav, A. K. Indian J
Heterocycl Chem 2007, 16, 387.
Acknowledgments. The authors are thankful to the Council of
Scientific and Industrial Research, New Delhi, for providing
financial support as an award of JRF to one of the authors. The
authors are also grateful to the Head, Department of Chemistry,
University of Rajasthan, Jaipur, for providing necessary
facilities during the experimental work.
[21] Tiwari, S.; Yadav, A. K.; Mishra, A. K. E. J Chem 2010, 7(S1),
S85.
REFERENCES AND NOTES
[22] Kumar, N.; Tiwari, S.; Yadav, A. K. Indian J Chem 2007, 46B,
702.
[23] Varma, R. S.; Nobles, W. L. J Pharm Sci 1972, 61, 112.
[24] Furniss, B. S.; Hannaford, A. J.; Rogers, V.; Smith, P. W. G.;
Tatchell, A. R. Vogels Text Book of Practical Organic Chemistry;
Longman Group Ltd.: London, 1980, p. 796.
[1] Gupta, A.; Sharma, A. K.; Prakash, L. Heterocyclic Chem
1993, 3, 117.
[2] Kuyper, L. F.; Garvey, J. M.; Baccanari, D. P.;
Chompness, J. N.; Stammers, D. K.; Beddell, C. R. Bioorg Med Chem
1996, 4, 593.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet