Novel phosphono-substituted pyrimidines: Synthesis and characterization

Article abstract of DOI:10.1080/10426500701519435

Fourteen novel organothiophosphonates incorporating pyrimidine heterocycles have been synthesized through an economical synthetic strategy. The products were well characterized through different spectral techniques. The 1H NMR spectra have shown interesti

Full text of DOI:10.1080/10426500701519435

Phosphorus, Sulfur, and Silicon, 182:2779–2789, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701519435
Novel Phosphono-Substituted Pyrimidines: Synthesis
and Characterization
Vijaya Kabra
Arpana Meel
Suneeta Ojha
Department of Chemistry, University of Rajasthan, Jaipur, India
Fourteen novel organothiophosphonates incorporating pyrimidine heterocycles
have been synthesized through an economical synthetic strategy. The products were
1
well characterized through different spectral techniques. The H NMR spectra have
shown interesting diastereotopic properties thus, showing chirality in the molecule.
The chlorothiophosphonates were the first step products which were further sub-
stituted to several other products through nucleophilic substitution reaction. This
study has shown unique prospects for synthesis of chiral molecules.
Keywords Chlorothiophosphonates; diastereotopic properties; nucleophilic substitu-
tion; organothiophosphonates
INTRODUCTION
Phosphorus, a nonmetallic element (Group XV, period III), plays very
crucial and important roles in the living system and also in synthetic
chemistry, hence, in our day-to-day life. Its role in the biochemistry of
cells and tissues is worth mentioning here. Among the synthetic phos-
phorus compounds, the organophosphorus derivatives are undeniably
the most versatile and useful ones.1−10
In our research group, we have developed a novel synthetic route
for the synthesis of organophosphorus derivatives in which phospho-
rus has existed in different coordination states,11−16 where we used the
N-cycloiminium salts as the starting material. In the present work,
we have used another phosphorylating agent, the dichlorophenylphos-
phine, in place of phosphorus trichloride, which has been still utilized
Received May 5, 2007; accepted May 24, 2007.
We are grateful to Head, Department of Chemistry, University of Rajasthan, Jaipur,
for providing necessary facilities.
Address correspondence to Vijaya Kabra, Department of Chemistry, University of
Rajasthan, Jaipur 302004, India. E-mail: sgkabra@sancharnet.in
2779

2780
V. Kabra et al.
in our projects. Through the dichlorophenylphosphine, a variety of new
organothiophosphonates with interesting diastereotopicity have been
synthesized. In connection with our work of thiophosphonates of pyri-
dine heterocycles, we are reporting herein a new series of compounds
involving pyrimidine heterocycles.
Owing to the vital importance of pyrimidine nucleus, we have se-
lected this heterocycle for our proposed research work. The importance
of such type of compounds can be judged from their abounding litera-
ture that provides several synthetic strategies along with their chemical
properties. The reason behind opting for the pyrimidine nucleus is its
remarkably important nature.
RESULTS AND DISCUSSION
2-Aminopyrimidine, on stirring with equimolar amount of substituted
methylhalides, in tetrahydrofuran at room temperature, afforded
N-alkyl-2-aminopyrimidinium halides (1) in quantitative yields. These
salts (1) were treated with equimolar amount of dichlorophenylphos-
phine and two equivalents of triethylamine in a mixture of toluene and
methylene chloride, at 0–5◦C. After 4–5 h of stirring at ambient temper-
ature, the N-alkyl-2-pyrimidinylidenamido(chloro)(phenyl)phosphines
(2) were in situ oxidized with elemental sulfur to access the N-alkyl-
2-pyrimidinylidenamido(chloro)(phenyl)thiophosphonates (3) (Scheme
1).
SCHEME 1
For the substituted thiophosphonates, the N-alkyl-2-pyrimi dinyli-
denamido(chloro)(phenyl)thiophosphonates (3) were subsequently sub-
jected to nucleophilic substitution with different secondary amines viz.
diethylamine, and N-methylcyclohexylamine to achieve the substituted
thiophosphonates (4, 5) (Scheme 2).

Phosphono Substituted Pyrimidines
2781
SCHEME 2
All the newly synthesized products were cream to yellow colored,
sharp melting solids, which are soluble in slightly polar solvents. The
physical parameters of these products have been summarized in Table I.
Characterization
These compounds were characterized through elemental analysis and
1H, 31P and 13C NMR techniques. The results have been represented
in Table II. Taking into consideration the different chemical shift val-
ues for different protons, as a result of shielding, deshielding and
anisotropic effects, assignments for different protons of these com-
pounds have been made.
31P NMR Spectra
The 31P NMR chemical shift values for these were found to be be-
tween δ 55.0-73.4 ppm and displayed a sharp signal. This observation
is suggestive of tetra-coordination around the phosphorous atom in the
above derivatives.
1H NMR Spectra
In the most upfield region, a triplet was observed at δ 1.00–1.08
ppm for methyl protons of 1PNCH2CH3 moiety of 4, with coupling con-
3
stant JHH = 6.9–7.0 Hz. The methylene protons of the same moiety
resonated as a set of doublet of doublet of quartet at δ 3.06–3.26 and

2782
V. Kabra et al.
TABLE I Analytical Data of Synthesized Compounds
Elemental analysis (%)
Mol. formula
(M W)
Yield
(%)
M. P.
(◦C)
Compound
5a
Color
C
H
N
C11H11N3PSCl
(283.721)
58
48
62
57
53
70
68
73
63
78
62
60
65
70
115–17
White
46.56
3.90
14.81
(46.51) (3.87) (14.90)
48.41 4.40 14.11
(48.40) (4.37) (14.15)
56.75 4.20 11.68
(56.71) (4.23) (11.69)
45.69 3.84 12.29
(45.63) (3.83) (12.25)
47.26 4.25 11.81
(47.23) (4.23) (11.84)
56.23 6.60 17.48
(56.25) (6.61) (17.43)
57.75 6.93 16.75
(57.72) (6.95) (16.77)
63.61 6.36 14.13
(63.60) (6.33) (14.10)
58.94 6.92 16.17
(58.92) (6.90) (16.19)
55.08 6.42 14.27
(55.03) (6.40) (14.24)
59.98 6.99 15.54
(59.95) (6.97) (15.52)
60.94 7.27 14.96
(60.92) (7.25) (14.94)
66.03 6.69 12.83
(66.01) (6.65) (12.82)
58.32 6.77 12.95
(58.31) (6.75) (12.92)
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
C
12H13N3PSCl
(297.748)
120–122 White
110–112 White
110–112 White
114–116 White
102–105 Yellow
106–107 Yellow
C17H15N3PSCl
(359.819)
C
12H13N3O2SCl
(341.758)
C
14H15N3O2PSCl
(355.785)
C
15H21N4PS
(320.4)
C
16H23N4PS
(334.4)
C21H25N4PS
(396.4)
96–99
Yellow
C
17H23N4PS
(346.4)
110–112 Yellow
118–120 Yellow
110–112 Yellow
115–117 Yellow
107–110 Yellow
120–122 Yellow
C
18H25N4O2PS
(392.4)
C18H25N4PS
(360.5)
C
19H27N4PS
(374.5)
C24H29N4PS
(436.6)
C
21H29N4O2PS
(432.5)
δ 3.29–3.47 ppm, respectively, due to geminal and vicinal couplings
along with three-bond coupling with phosphorus atom. The coupling
2
3
constants observed for these peaks were J = 11.4–15.0 Hz, J
=
HH
PH
3.0–4.2 Hz, 3 J = 6.0–7.2 Hz, respectively.
HH
All the eleven protons of the cyclohexyl moiety of 5 resonated as a
complex multiplet at δ 0.78–1.51 ppm. Since these protons experience
slightly different magnetic fields, they absorbed at different positions.
The equatorial protons, however, resonated slightly downfield in com-
parison to the axial protons with a difference of about δ 0.12–0.70 ppm.
The CH3 protons of the same moiety resonated as a doublet in the range
δ 1.41–2.56 ppm, due to three-bond coupling with the phosphorus nu-
cleus (3 J = 8.0–12.0 Hz). Among the pyrimidine ring protons, the H-5
PH

2783

2784

2785

2786
V. Kabra et al.
proton was shifted to the higher field and was observed in the region δ
6.26–6.33 ppm, since it experienced shielding. The doublet of doublet,
which was observed for H-5 proton, was due to three-bond coupling
with both H-4 and H-6 protons, with coupling constants, 3 J = 6.0 Hz
HH
and 3 J = 6.0 Hz, respectively. The H-4 and H-6 protons also showed
HH
doublet of doublets at δ 7.94 ppm and δ 7.91 ppm, respectively, due to
three- and four-bond couplings. Since these protons have nearly the
same chemical environment, they resonated as a merged signal, in few
cases. The NCH2 of 5c-e showed a set of doublet in the range δ 4.54–5.23
ppm and δ 4.73–5.36 ppm, respectively due to diastereotopic nature of
these protons which has caused geminal coupling (2 J = 14.0–18.2
HH
Hz). It was interesting to note that the NCH2 protons of 5b showed an
unresolved quartet at δ 3.47 ppm (3 J = 6.0 Hz).
HH
The phenyl protons of PC6H5 moiety appeared as a multiplet or split
singlets at δ 7.36–7.44 ppm. The splitting of the signal is most probably
due to slightly different magnetic environments of the ring protons.
13C NMR Spectra
The 13C NMR data were also found helpful in the characterization
of the compounds.
The methyl and methylene carbons of PNCH2CH3 moiety resonated
at δ 14.1 and 39.9 ppm, respectively. The CH2 and CH3 carbon reso-
nances of the OCH2CH3 moiety were observed at δ 52.7 ppm and δ 54.4
ppm, respectively. The presence of a signal at δ 62.2 ppm was due to
NCH2 carbon.
The pyrimidine ring carbons, C-2, C-4, C-5, and C-6, resonated at δ
153.8, 163.9, 104.7, and δ 148.2 ppm, respectively.
The carbons of the phenyl ring have shown different shifts in 13C
spectrum: Co at δ 130.7 and δ 130.8 ppm (2 J = 9.8 Hz), CP at δ 129.8
CP
ppm and Cm at δ127.6 and 127.7 ppm (3 J = 12.8 Hz). The ipso carbon
CP
signal of the phenyl ring appeared as a doublet at δ 138.3 and 140.1
ppm (1 J = 135.8 Hz).
CP
The CO carbon resonated at δ 166.8 ppm, due to its being the most
deshielded one. The peaks for Ci, C-2 and CO were of minimum intensity
due to their quaternary nature (no NOE available).
EXPERIMENTAL
All the solvents and commercial reagents were purified prior to use.
The glasswares, syringes and needles used in these moisture sensitive
reactions were oven dried at 140◦C. Upon work, solvents were evapo-
rated under reduced pressure, using high vacuum. Melting points were
measured by capillary method on an electric tempo m.p. apparatus and

Phosphono Substituted Pyrimidines
2787
are uncorrected. 31P spectra were recorded on Jeol AL 300 at 121.50
1
MHz (Obset 156 KHz) using 85% H3PO4 as external standard and H
spectra were recorded on Jeol AL 300 at 300.4 MHz (Obset 130 KHz)
using TMS as internal standard. Elemental analyses were carried out
on Heraeus Carlo Erba 1108 analyzer.
Synthesis of N-Alkyl-2-pyrimidinylidenamido(chloro)
(phenyl)thiophosphonates (3)
To a well-stirred suspension of 2-aminopyrimidinium halide (2.37 g,
0.01 mol) in toluene (10 ml), was added a mixture of dichlorophenylphos-
phine (1.37 ml, 0.01 mol) in toluene (20 ml), through a dropping funnel,
along with the addition of two equivalents of triethylamine (2.78 ml;
0.02 mol), at 0–5◦C. The addition was completed in one- half h, after
which the mixture was slowly brought to ambient temperature. After
4-5 h stirring at ambient temperature, an equimolar amount of sulfur
powder (0.32 g, 0.01 mol) was added, followed by the addition of methy-
lene chloride (30 ml). The reaction mixture was then filtered off, after 2
days, and the solvent was removed in vacuo. The crude product so ob-
tained was properly dried and then extracted with diethylether (3 × 50
ml). The combined ethereal extract was concentrated to one-fourth of
its initial volume and kept in a refrigerator, whereupon a white colored
solid was obtained. It was separated and dried under reduced pressure.
Synthesis of N-Alkyl-2-pyrimidinylidenamido
(diethylamido)(phenyl)thiophosphonates (4)
N-Alkyl-2-aminopyrimidinium halide (3.0 g, 0.01 mol) was suspended
in toluene (10 ml) under nitrogen atmosphere. To this suspension was
then added triethylamine (2.78 ml, 0.02 mol), along with the dropwise
addition of dichlorophenylphosphine (1.34 ml, 0.01 mol) also mixed in
toluene (20 ml), while maintaining the temperature of the reaction mix-
ture at 0–5◦C. The addition was completed in 1 h, after which the reac-
tion mixture was slowly brought to ambient temperature. After 3–4 hr.
of stirring, sulfur powder (0.32 g, 0.01 mol) was added to it, along with
methylene chloride (30 ml). Two equivalents of diethylamine (2.09 ml,
0.01 mol) mixed in methylene chloride were also added dropwise to the
reaction mixture. Afterwards it was stirred for 24 h, while maintaining
the temperature at 0–5◦C. The reaction mixture was then filtered off
after stirring for next 2–3 days at ambient temperature, and the sol-
vent of the filtrate was trapped out under reduced pressure. The crude
product so obtained was extracted with diethylether (3 × 50 ml), and the

2788
V. Kabra et al.
combined ethereal extract was concentrated to one-fourth of its original
volume and kept in a refrigerator. After 4–8 h, a yellow colored solid
compound was deposited, which was separated, washed with hexane,
and dried under reduced pressure.
Synthesis N-Alkyl-2-pyrimidinylidenamido
(N-methylcyclohexylamido)(phenyl)thiophosphonates (5)
To a well-stirred suspension of N-alkyl-2-aminopyrimidinium halides
(3.0 g, 0.01 mol) in toluene (10 ml), was added triethylamine (2.78 ml,
0.02 mol), along with dropwise addition of dichlorophenylphosphine
(1.34 ml, 0.01 mol) in toluene (20 ml), while maintaining the tempera-
ture of the reaction mixture at 0-5◦C, with continuous stirring. In 1 h,
the addition was completed and the reaction mixture was then slowly
brought to room temperature. Afterwards, sulfur powder (0.32 g, 0.01
mol) was added to this mixture over 3-4 h, along with the addition
of methylene chloride (20 ml). A mixture of N-methylcyclohexylamine
(1.32 ml, 0.01 mol) in methylene chloride (20 ml) was also added drop-
wise, along with triethylamine (1.39 ml, 0.01 mol). During the addition,
the temperature of the reaction was maintained at 0-5◦C. The stirring
was continued for another 24-30 h at room temperature. The reaction
mixture was filtered off and the solvent of the filtrate was trapped out
in vacuo. The crude obtained thereon was extracted with diethylether
(3 × 50 ml), and the combined ethereal extract was concentrated to one-
fourth of its original volume and then kept in a refrigerator, whereupon
a while-yellow solid product was obtained. It was separated, washed
with hexane ,and dried under reduced pressure.
CONCLUSION
An economical synthetic route has been developed for the synthe-
sis of organothiophosphonates including a pyrimidine nucleus. These
molecules are expected to be highly bioactive, hence we will perform
further research work on bioscreening of these molecules.
REFERENCES
[1] P. Kafarskiand and B. Lejczak, Phosphorus, Sulfur, Silicon and Relat. Elem., 63,
193–215 (1991).
[2] F. R. Atherton, C. H. Hassal, and R. W. Lambert, J. Med. Chem., 29, 29 (1986).
[3] V. Pham, W. Zhang, V. Chen, T. Whitney, J. Yao, D. Froese, A. D. Friesen, J. M.
Diakur, and W. Haque, J. of Med. Chem., 46, 3680–3687 (2003).
[4] A. Amberg, A. Tamke, W. H.Carelmann, and J. W. Engels, Nucleosides, Nucleotides
and Nucleic Acids, 22, 631–1634 (5–8) (2003).

Phosphono Substituted Pyrimidines
2789
[5] L. Mou, G. Singh, and J. W. Nicholson, J. Chem. Comm., 5, 345–346, (2000).
[6] A. G. Pokrovsky, T. R. Pronayeva, N. V. Fedyuk, E. A. Shirokova, A. L. Khamdazhin-
skaya, N. B. Tarusova, I. L. Karpenko, and A. A. Krayevsky, Nucleosides, Nucleotides
and Nucleic Acids, 20(4–7), 767–769 (2001).
[7] B. E. Maryanoff, and A. B. Reitz, Chem. Rev., 89, 863 (1989).
[8] N. Bricklebank, Organophosphorus Chem., 33, 289 (2003).
[9] N. Kann and T. Rein, Synthesis, 13, 579 (2003).
[10] T. Du, J. Chem, and D. Cao, J. of Material Science, 36, 3903–3907 (2001).
[11] R. K. Bansal, V. Kabra, R. Munjal, and N. Gupta, Indian J. Chem., 33B, 992–994
(1994).
[12] R. K. Bansal, V. Kabra, and N. Gupta, Indian J. Chem., 31B, 254–256 (1992).
[13] R. K. Bansal, N. Gupta, V. Kabra, C. Spindler, K. Karaghioroff, and A. Schmidpeter,
Heteroatom Chem., 3, 359 (1992).
[14] R. K. Bansal, V. Kabra, R. Munjal, and N. Gupta, Phosphorus, Sulfur, and Silicon,
97, 141–147 (1994).
[15] V. Kabra, N. Gupta, S. Jain, and V. Saxena, Heteroatom Chem., 14(6), 498–502
(2003).
[16] N. Gupta, V. Kabra, V. Saxena, S. Jain, and K. Bhatnagar, Phosphorus, Sulfur, and
Silicon, 178, 851–861 (2003).
[17] V. Kabra, N. Gupta, and R. Mathur, J. Indian Chem. Soc., 81, 338–341 (2004).