Preparation of pyrimidine derivatives through three-component reactions of dialkyl (2-oxo-3,3,3-trifluoropropyl)phosphonates

Article abstract of DOI:10.1007/s10593-011-0863-4

Methods are proposed for the preparation of fluorophosphorus-containing pyrimidines through three- component reactions of dialkyl (3,3,3-trifluoro-2- oxopropyl)phosphonates. Cyclocondensation of these phosphonates with urea and aryl aldehydes gave 6-aryl-

Full text of DOI:10.1007/s10593-011-0863-4

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
PREPARATION OF PYRIMIDINE DERIVATIVES
THROUGH THREE-COMPONENT REACTIONS OF DIALKYL
(2-OXO-3,3,3-TRIFLUOROPROPYL)PHOSPHONATES
V. M. Timoshenko1*, Yu. N. Markitanov1, and Yu. G. Shermolovich1
Methods are proposed for the preparation of fluorophosphorus-containing pyrimidines through three-
component reactions of dialkyl (3,3,3-trifluoro-2-oxopropyl)phosphonates. Cyclocondensation of these
phosphonates with urea and aryl aldehydes gave 6-aryl-4-hydroxy-2-oxo-4-trifluoromethylhexa-
hydropyrimidin-5-ylphosphonates and reaction with urea and trialkyl orthoformates led to 4-alkoxy-
2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-5-ylphosphonates.
Keywords: hexahydropyrimidinone, dihydropyrimidinone, orthoformate, oxophosphonate, tetra-
hydropyrimidinone, trifluoromethyl group, Biginelli reaction, multicomponent reaction.
Progress in the chemistry of multicomponent reactions and an increasing interest when compared with
traditional, multistage syntheses is evidence for the high synthetic potential of this route which is both a simple
and rapid method for preparing different classes of compounds [1].
Multicomponent reactions leading to formation of nitrogen-containing heterocyclic systems such as
pyridine and pyrimidine [2, 3] have recently been studied. Derived compounds show a broad spectrum of
biological activity [4, 5] hence preparation of novel representatives of this class of compounds is an urgent
challenge in the chemistry of heterocycles [6]. Amongst a significant number of synthesized, functionally
substituted pyrimidines finding use in pharmaceutical chemistry [7, 8], pyrimidines containing phosphorus
substituents remain little studied due to the limited number of methods of preparing them.
One of the most widely used methods currently in use for preparing pyrimidines is the three- component
Biginelli reaction. The use of traditional methodology in this reaction for the cyclocondensation of dialkyl
2-oxopropylphosphonates, aryl aldehydes, and urea is inefficient, the 4-aryl-5-(O,O-dialkylphosphoryl)-
3,4-dihydropyrimidin-2-ones being obtained only under catalysis with the use of Yb(OTf)3 [9]. A further
reported method for preparing hexahydropyrimidine-5-phosphonates is the reaction of N-(1-tosylprop-
1-yl)thiourea with 2-oxopropylphosphonate enolates [10].
We have found that diethyl (3,3,3-trifluoropropyl-2-oxo)phosphonate (1a) reacts with aryl aldehydes
and urea under Biginelli conditions to give the diethyl (6-aryl-4-hydroxy-2-oxo-4-trifluoromethylhexa-
hydropyrimidin-5-yl)phosphonates 2a-c.
_______
*To whom correspondence should be addressed, e-mail: vadim@ioch.kiev.ua.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska St., Kyiv 02094,
Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1191-1197, August, 2011.
Original article submitted March 25, 2011.
0009-3122/11/4708-0977©2011 Springer Science+Business Media, Inc.
977

In our study of this three-component cyclization, we have employed conditions used for similar
condensations of -dicarbonyl compounds, i.e. stirring in acetonitrile at room temperature with a catalytic
amount of trimethylchlorosilane [11, 12]. As in the examples of the Biginelli reaction of -dicarbonyl
compounds with fluoroalkyl groups [12-16], the cyclization products of the oxophosphonate 1a are the
4-hydroxytetrahydropyrimidin-2-ones (2a-c) but dehydratation and formation of classical 3,4-dihydro-
pyrimidin-2-one Biginelli reaction products are not observed.
Ar
O
Ar
O
O
(EtO)2P
(EtO)2P
6
TMSCl
MeCN
NH
2
5
4
NH2
+
F3C
N
H
O
H2N
O
F3C
O
HO
1a
2a–c
Ar
4
5
AcOH
NH
AcOH
2
6
– (EtO)2P OH
O
–
(EtO)2P OH
O
F3C
N
H
O
3a–c
2, 3 a Ar = Ph, b Ar = p-MeOC6H4, c Ar = p-BrC6H4
The tetrahydropyrimidin-2-ones 2a-c contain three asymmetric carbon atoms which supposes the
1
possible formation of four diastereomers. However, according to the H NMR spectroscopic data for the crude
products, only a single diastereomer is formed in all of the examples we studied. The 13C NMR spectra of
compounds 2a-c showed a highly characteristic signal for the C-4 atom of the pyrimidine ring at around 81 ppm
which appears as a quartet of doublets and confirms the formation of the tetrahydropyrimidinone ring. It is not
possible to make an unambiguous assignment of the stereochemistry of compounds 2a-c on the basis of just the
data obtained.
1
Compounds 2a-c are unstable in DMSO-d6 solutions. Measured after one week the H NMR spectra
show the presence of an aryl aldehyde signal and the 19F and 31P NMR spectra show signals for the
oxophosphonate hydrate 1a and diethyl phosphate (EtO)2P(O)OH. Formation of the latter can be the result of
dephosphonylation and this was confirmed by heating compounds 2a-c in acetic acid. In these conditions the
4-aryl-6-trifluoromethyl-3,4-dihydropyrimidin-2-ones 3a-c were formed in good yields as the dephos-
phonylation products of the 1,2,3,4-tetrahydropyrimidin-2-ones 2a-c.
Carrying out the initial multicomponent reaction in acetic acid was also accompanied by
dephosphonylation of the Biginelli reaction products formed at the initial step to give the corresponding
dihydropyrimidin-2-one dephosphorylation products 3a-c. The course of the reaction was monitored by 19F and
31P NMR spectroscopy of the reaction solutions. The 19F NMR spectra of the initial reaction step show the
presence of a signal at -82 ppm corresponding to the trifluoromethyl group signal of the products 2a-c which
disappears over time and is replaced by a signal at -70 ppm corresponding to formation of compounds 3a-c. In
the 31P NMR spectra the signal for the diethyl phosphonate group at 23 ppm for compounds 2a-c disappears and
a signal for diethyl phosphate appears at 2 ppm.
We have also discovered a simple and efficient method for preparing stable phosphorus-containing
pyrimidinones based on the three-component reaction of dialkyl (2-oxo-3,3,3-trifluoropropyl)phosphonates 1a,b
with urea and trialkyl orthoformates. Refluxing a mixture of oxophosphonate 1 and urea in an excess of the
trialkyl orthoformate gives the dialkyl 4-(alkoxy(hydroxy)-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydro-
978

pyrimidin-5-yl)phosphonates 4a-c which precipitate from the mixture during the reaction process.
O
O
O
(RO)2P
O
NH
2
6
(R1O)3CH
5
4
P(OR)2
+
+
F3C
– 2R1OH
H2N
NH2
F3C
N
H
O
R1O
1a,b
1 a R = Et; b R = Me; 4 a R = Et, R1 = H; b R = R1 = Me; c R = Me, R1 = Et
4a–c
Evidently, the reaction occurs via intermediate A, formation of which has been reported by us in the
reaction of 3-arylsulfonyl-1,1,1-trifluoropropan-2-ones with orthoformates [17]. The intermediate ester A
condenses with urea to form the acyclic intermediate B. Subsequent intramolecular cyclization gives the
pyrimidine heterocyclic system.
O
O
H
(R1O)3CH
–2R1OH
(RO)2P
CO(NH2)2
– R1OH
(RO)2P
OR1
N
1a,b
O
NH2
F3C
O
F3C
O
A
B
O
O
(MeO)2P
(MeO)2P
– H2O
+ H2O
NH
NH
R = Me
F3C
O
O
N
N
H
F3C
HO
D
C
R1OH
R = Et
4a
4b,c
The 4-hydroxy derivative C formed in the condensation process can dehydrate under thermal conditions
to the pyrimidin-2-one D. The double bond of the CF3–C=N fragment in pyrimidine D is quite electrophilic and
adds a molecule of the alcohol liberated in the initial stages of the reaction to form the dimethylphosphonyl-
substituted 4-alkoxypyrimidines 4b,c. The difference in structure for the products of this reaction can evidently
be explained by their different solubility in the reaction medium. The diethylphosphonyl-substituted
4-hydroxypyrimidinone 4a precipitated from the reaction mixture with heating while the dimethylphosphonyl
analog C is soluble in the mixture and dehydrates upon subsequent refluxing to the intermediate D (which then
adds a molecule of the alcohol to give the difficultly soluble 4-alkoxypyrimidinones 4b,c).
It should be noted that, with use of fluorinated -oxophosphonates in the three-component reaction, the
condensation (which consists of three consecutive stages) occurs in a one pot. In analogous reactions of
-dicarbonyl compounds reported in the literature the construction of a pyrimidine ring occurs in two stages
with separation of intermediates of type A [18] or B [19], cyclization of which to pyrimidin-2-ones in the
subsequent step demands more rigorous conditions and the use of base.
Hence we have developed a simple synthetic route to fluoroalkyl-containing phosphonyl-substituted
pyrimidinones through three-component heterocyclization reactions of dialkyl (3,3,3-trifluoro-2-oxopropyl)-
phosphonates with urea and trialkyl orthoformates.
979

EXPERIMENTAL
IR spectra were obtained on a UR-20 spectrometer for KBr tablets. 1H NMR spectra were recorded on a
Varian VXR-300 spectrometer (300 MHz) and 13C NMR, APT, 1H–1H COSY, and 13C–1H HETCOR spectra on
a Bruker Avance 400 (400 and 100 MHz, respectively) for solutions in DMSO-d6 with residual solvent signals
at 2.50 ppm for 1H and 39.52 ppm for 13C used as standard. 19F and 31P NMR spectra were recorded on a Varian
Gemini-200 instrument (188 and 81 MHz respectively) with C6F6 (-162.9 ppm relative to CFCl3) and H3PO4
(0.00 ppm) as internal standards. Mass spectra were taken on an Agilent 1100 series LC/MSD SL instrument
with chemical ionization at atmospheric pressure (APCI) as the ionization method. Melting points were
determined on a Boetius apparatus.
The oxophosphonates 1a,b were prepared by acylation of the lithium salts of dimethyl- or diethyl
methylphosphonate using ethyl trifluoroacetate according to method [20].
Hexahydropyrimidines 2a-c (General Method). A mixture of the oxophosphonate 1a (0.5 g, 2 mmol),
the corresponding aryl aldehyde (2 mmol), urea (0.12 g, 2 mmol), and trimethylchlorosilane (0.06 ml,
0.5 mmol) in acetonitrile (4 ml) was stirred at room temperature for 5-8 h. The precipitate formed was filtered
off and crystallized from acetonitrile.
Diethyl (4-Hydroxy-2-oxo-4-trifluoromethyl-6-phenylhexahydropyrimidin-5-yl)phosphonate (2a).
1
Yield 60%; mp 150-151ºC (MeCN). IR spectrum, , cm-1: 1690 (C=O), 2950, 3000, 3110, 3220. H NMR
3
3
2
spectrum, , ppm (J, Hz): 0.98 (3H, t, J = 7.1, CH3); 1.12 (3H, t, J = 7.1, CH3); 2.81 (1H, dd, JH–P = 20.5,
3J5,6 = 6.8, H-5); 3.60-4.10 (4H, m, 2CH2); 4.79 (1H, dm, J6,5 = 6.8, H-6); 7.09 (1H, s, NH); 7.25-7.36 (6H, m,
3
H Ph + NH); 7.65 (1H, br. s, OH). 13C NMR spectrum, , ppm (J, Hz); 15.7 (d, JC–P = 6.3, CH3); 15.9 (d,
3
3JC-P = 6.0, CH3); 45.3 (d, JC–P = 145.0, C-5); 52.1 (s, C-6); 60.8 (d, JC–P = 6.7, CH2); 61.1 (d, JC–P = 6.5, CH2);
2
2
2
2
3
81.1 (qd, JC–F = 31.5, JC–P = 3.1, C-4); 123.3 (qd, JC–F = 290.0, JC–P = 5.0, CF3); 126.9, 127.3, 127.9 (s, C Ph);
140.7 (d, 3JC–P = 7.1, ipso-C Ph); 154.5 (s, C=O). 19F NMR spectrum, , ppm: -82.18 (s, CF3). 31P NMR spectrum,
, ppm: 23.01 (m). Mass spectrum, m/z (Irel, %): 397 [M+H]+ (5), 379 [M+H-H2O]+ (40), 337 (M+H-urea)+ (100),
106 (20). Found, %: C 45.73; H 5.00; N 7.01. C15H20F3N2O5P. Calculated, %: C 45.46; H 5.09; N 7.07.
Diethyl
[4-Hydroxy-6-(4-methoxyphenyl)-2-oxo-4-trifluoromethylhexahydropyrimidin-5-yl]-
phosphonate (2b). Yield 57%; mp 139-141ºC (MeCN). IR spectrum, , cm-1: 1680 (C=O), 2940, 3000, 3110,
3220. 1H NMR spectrum, , ppm (J, Hz): 0.98 (3H, t, 3J = 6.6, CH3); 1.11 (3H, t, 3J = 6.6, CH3); 2.75 (1H, dd,
3
2JH–P = 20.5, J5,6 = 7.1, H-5); 3.60-4.10 (4H, m, 2CH2); 3.73 (3H, s, OCH3); 4.73 (1H, m, H-6); 6.89 (2H, m,
H Ar); 7.10 (1H, s, NH); 7.15-7.20 (3H, m, H Ar + NH); 7.65 (1H, br. s, OH). 13C NMR spectrum, , ppm
(J, Hz): 15.7 (d, 3JC–P = 5.9, CH3); 16.0 (d, 3JC–P = 6.2, CH3); 46.1 (d, JC–P = 145.3, C-5); 51.8 (s, C-6); 55.1 (s,
OCH3); 60.7 (d, 2JC–P = 6.5, CH2); 62.3 (d, 2JC–P = 6.9, CH2); 81.2 (qd, 2JC–F = 32.2, 2JC–P = 3.1, C-4); 113.4 (s,
m-C Ar); 123.5 (qd, JC–F = 289.3, 3JC–P = 3.9, CF3); 128.6 (s, o-C Ar); 132.3 (d, 3JC–P = 7.3, ipso-C Ar); 154.8 (s,
C=O); 158.8 (s, p-C Ar). 19F NMR spectrum, , ppm: -82.03 (s, CF3). 31P NMR spectrum, , ppm: 22.59 (m).
Mass spectrum, m/z (Irel, %): 427 [M+H]+ (5), 409 [M+H-H2O]+ (50), 367 [M+H-urea]+ (20), 162 (100). Found,
%: C 45.23; H 5.00; N 6.39. C16H22F3N2O6P. Calculated, %: C 45.08; H 5.20; N 6.57.
Diethyl [6-(4-Bromophenyl)-4-hydroxy-2-oxo-4-trifluoromethyl-6-hexahydropyrimidin-5-yl]phos-
phonate (2c). Yield 55%; mp 164-165ºC (MeCN). IR spectrum, , cm-1: 1710 (C=O), 2950, 3000, 3120, 3230. 1H
NMR spectrum, , ppm (J, Hz): 1.06 (3H, t, 3J = 7.0, CH3); 1.13 (3H, t, 3J = 7.0, CH3); 2.82 (1H, dd, 2JH–P = 20.7,
3
3
3
3J5,6 = 7.0, H-5); 3.70-4.10 (4H, m, 2CH2); 4.81 (1H, ddd, JH–P = 9.2, J6,5 = 7.0, J6,1 = 2.0, H-6); 6.88 (1H, t,
3J1,6 = 2.0, JH–P = 1.8, 1-NH); 7.20 (1H, s, 3-NH); 7.26 (2H, AA'XX', JAX = 8.5, H Ar); 7.52 (2H, AA'XX',
3JAX = 8.5, H Ar); 7.55 (1H, br. s, OH). 13C NMR spectrum, , ppm (J, Hz): 15.6 (d, 3JC–P = 6.0, CH3); 15.8 (d,
3JC–P = 6.0, CH3); 45.1 (d, JC–P = 145.0, C-5); 51.7 (s, C-6); 61.1 (d, 2JC–P = 6.8, CH2); 62.2 (d, 2JC–P = 6.8, CH2);
4
3
2
2
3
81.1 (qd, JC–F = 32.2, JC–P = 3.5, C-4); 120.5 (s, p-C Ar); 124.2 (qd, JC–F = 289.0, JC–P = 4.0, CF3); 129.4 (s,
m-C Ar); 130.8 (s, o-C Ar); 139.9 (d, JC–P = 7.2, ipso-C Ar); 154.3 (s, C=O). 19F NMR spectrum, , ppm:
3
-81.89 (s, CF3). 31P NMR spectrum, , ppm (J, Hz): 22.01 (m). Mass spectrum, m/z (Irel, %): 417
980

and 415 [M+H-urea]+ (100 and 95), 185 and 187 (20 and 20). Found, %: C 38.06; H 3.93; N 6.00.
C15H19BrF3N2O5P. Calculated, %: C 37.91; H 4.03; N 5.90.
Dihydropyrimidines 3a-c (General Method). A solution of the oxophosphonate 1a (0.5 g, 2 mmol),
the corresponding aryl aldehyde (2 mmol), and urea (0.12 g, 2 mmol) in acetic acid (4 ml) was heated for 5-7 h
on an oil bath at 80ºC. The end of the reaction was determined by 19F and 31P NMR spectroscopy of the reaction
mixture. The mixture was poured into water (6 ml) and the precipitate formed was filtered off, washed with
water (2 ml), dried, and crystallized.
4-Phenyl-6-trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3a). Yield 70%; mp 124-125ºC (EtOH)
(mp 120-121ºC [21]). 1H NMR spectrum, , ppm (J, Hz): 5.15 (1H, m, H-4); 5.53 (1H, m, H-5); 7.30-7.45 (5H, m,
H Ph); 7.48 (1H, s, NH); 9.34 (1H, s, NH). 13C NMR spectrum, , ppm (J, Hz); 54.1 (s, C-4); 103.3 (q, 3JC–F = 5.1,
C-5); 120.1 (q, JC–F = 272.6, CF3); 125.9 (q, 2JC–F = 34.6, C-6); 126.2, 127.8, 128.8 (s, C Ar); 143.4 (s, ipso-C Ar);
19
152.4 (s, C=O). F NMR spectrum, , ppm: -69.18 (s, CF3). Mass spectrum, m/z (Irel, %): 243 [M+H]+ (40), 77
(100). Found, %: C 54.75; H 3.92; N 11.49. C11H9F3N2O. Calculated, %: C 54.55; H 3.75; N 11.57.
4-Methoxyphenyl-6-trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3b). Yield 69%; mp 168-170ºC
(H2O-EtOH, 1: 1). IR spectrum, , cm-1: 1700 (C=O); 2870, 2970, 3110, 3220, 3300. 1H NMR spectrum, , ppm
3
(J, Hz): 3.74 (3H, s, CH3); 5.08 (1H, m, H-4); 5.48 (1H, m, H-5); 6.94 (2H, AA'XX', JAX = 8.1, H Ar); 7.21
3
13
(2H, AA'XX', JAX = 8.1, H Ar); 7.39 (1H, s, NH); 9.28 (1H, s, NH). C NMR spectrum, , ppm (J, Hz): 53.5
3
(s, C-4); 55.2 (s, CH3); 103.6 (q, JC–F = 4.8, C-5); 114.2 (s, m-C Ar); 120.1 (q, JC–F = 272.0, CF3); 126.0 (q,
2JC-F = 34.5, C-6); 127.4 (s, o-C Ar); 135.5 (s, ipso-C Ar); 152.4 (s, C=O); 158.9 (s, p-C Ar). 19F NMR
spectrum, , ppm: -69.16 (s, CF3). Mass spectrum, m/z (Irel, %): 273 [M+H]+ (100). Found, %: C 53.05; H 4.00;
N 10.40. C12H11F3N2O2. Calculated, %: C 52.94; H 4.07; N 10.29.
4-Bromophenyl-6-trifluoromethyl-3,4-dihydropyrimidin-2(1H)-one (3c). Yield 65%; mp 147-149ºC
(H2O-EtOH). IR spectrum, , cm-1: 1690 (C=O), 2880, 2970, 3110, 3220, 3320. 1H NMR spectrum, , ppm (J,
3
Hz): 5.15 (1H, m, H-4); 5.53 (1H, m, H-5); 7.24 (2H, AA'XX', JAX = 8.1, H Ar); 7.52 (1H, s, NH); 7.58 (2H,
AA'XX', 3JAX = 8.1, H Ar); 9.41 (1H, s, NH). 13C NMR spectrum, , ppm (J, Hz): 53.5 (s, C-4); 102.9 (q, 3JC–F = 5.1,
C-5); 120.9 (s, p-C Ar); 126.5 (q, 2JC–F = 34.9, C-6); 128.5 (s, o-C Ar); 131.8 (s, m-C Ar); 142.8 (s, ipso-C Ar);
152.3 (s, C=O). 19F NMR spectrum, , ppm: -69.28 (s, CF3). Mass spectrum, m/z (Irel, %): 321 and 323 [M+H]+
(100 and 95). Found, %: C 41.40; H 2.56; N 8.91. C11H8BrF3N2O. Calculated, %: C 41.15; H 2.51; N 8.72.
Tetrahydropyrimidines 4a-c (General Method). A mixture of the corresponding oxophosphonate
1a,b (4 mmol), urea (0.24 g, 4 mmol), and the corresponding trialkyl orthoformate (16 mmol) was refluxed for
2-4 h. The precipitate formed on refluxing was cooled to room temperature and filtered. After liquid
chromatography the purity of the products 4a-c was greater than 95%; for analytical purposes the samples were
recrystallized from acetonitrile.
Diethyl (4-hydroxy-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-5-yl)phosphonate (4a)
was prepared from phosphonate 1a, urea, and trimethyl- or triethyl orthoformate. Yield 70%; mp 162-164ºC
1
(MeCN). IR spectrum, , cm-1: 1710 (C=O), 2940, 3000, 3110, 3220. H NMR spectrum, , ppm (J, Hz): 1.20
(6H, t, 3J = 7.0, 2CH3); 3.80-4.00 (4H, m, 3J = 7.2, 2CH2); 7.11 (1H, dd, 3J H–P = 14.3, 3J6,5 = 5.8, H-6); 7.42 (1H,
3
br. s, OH); 8.41 (1H, d, J1,6 = 5.8, 1-NH); 9.88 (1H, s, 3-NH). 13C NMR spectrum, , ppm (J, Hz): 16.0 (d,
3
2
2
3JC-P = 6.8, CH3); 16.1 (d, JC–P = 6.8, CH3); 61.3 (d, JC–P = 5.3, CH2); 61.6 (d, JC–P = 5.6, CH2); 82.3 (qd,
2JC-F = 33.7, 2JC–P = 11.0, C-4); 93.2 (d, JC–P = 203.2, C-5); 123.0 (q, JC–F = 288.3, CF3); 143.0 (d, 3JC–P = 15.4,
C-6); 149.8 (s, C=O). 19F NMR spectrum, , ppm:-82.64 (s, CF3). 31P NMR spectrum, , ppm: 17.54 (m). Mass
spectrum, m/z (Irel, %): 301 [M+H-H2O]+ (25), 157 (20). Found, %: C 33.90; H 4.49; N 8.96. C9H14F3N2O5P.
Calculated, %: C 33.97; H 4.43; N 8.80.
Dimethyl (4-methoxy-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-5-yl)phosphonate (4b)
was prepared from phosphonate 1b, urea, and triethyl orthoformate. Yield 68%; mp 148-150ºC (MeCN). IR
1
spectrum, , cm-1: 1720 (C=O), 2940, 3130, 3230, 3320. H NMR spectrum, , ppm (J, Hz): 3.16 (3H, s, CH3);
3.58 (3H, d, 3JH–P = 11.2, CH3); 3.62 (3H, d, 3JH–P = 11.2, CH3); 7.33 (1H, dd, 3JH–P = 14.2, 2J = 5.8, H-6); 8.57 (1H,
d, 2J = 5.8, 1-NH); 10.16 (1H, s, 3-NH). 13C NMR spectrum, , ppm (J, Hz): 49.1 (s, CH3); 52.0 (d, 2JC–P =5.6,
981

2
CH3); 52.3 (d, 2JC–P = 5.6, CH3); 87.3 (dq, 2JC–F = 33.1, JC–P = 11.1, C-4); 88.3 (d, JC–P = 205.5, C-5); 122.1 (q,
3
JC-F = 288.0, CF3); 145.9 (d, JC–P = 15.1, C-6); 150.0 (s, C=O). 19F NMR spectrum, , ppm: -81.38 (s, CF3).
31P NMR spectrum, , ppm: 19.86 (m). Mass spectrum, m/z (Irel, %): 273 [M+H-MeOH]+ (100), 157 (10).
Found, %: C 31.70; H 3.92; N 9.40. C8H12F3N2O5P. Calculated, %: C 31.59; H 3.98; N 9.21.
Dimethyl (4-ethoxy-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-5-yl)phosphonate (4c)
was prepared from phosphonate 1b, urea, and triethyl orthoformate. Yield 65%; mp 129-131ºC (MeCN). IR
1
spectrum, , cm-1: 1700 (C=O); 2960, 3100, 3230, 3300. H NMR spectrum, , ppm (J, Hz): 1.14 (3H, t,
3J = 6.9, CH3); 3.38 (2H, q, 3J = 6.9, CH2); 3.58 (3H, d, 3JH–P = 10.6, OCH3); 3.62 (3H, d, 3JH–P = 10.6, OCH3);
3
2
2
7.29 (1H, dd, JH–P = 14.3, J = 4.8, H-6); 8.55 (1H, d, J = 4.8, 1-NH); 10.12 (1H, s, 2-NH). 13C NMR
spectrum, , ppm (J, Hz): 14.6 (s, CH3); 52.4 (d, 2JC–P, OCH3); 52.7 (d, 2JC–P = 6.6, OCH3); 57.9 (s, CH2); 87.0
(qd, 2JC–F = 32.9, 2JC–P = 11.0, C-4); 88.7 (d, JC–P = 206.1, C-5); 122.4 (q, JC–F = 287.5, CF3); 146.1 (d, 3JC–P = 15.3,
C-6); 150.5 (s, C=O). 19F NMR spectrum, , ppm: -81.61 (s, CF3). 31P NMR spectrum, , ppm: 19.52 (m). Mass
spectrum, m/z (Irel, %): 273 [M+H-EtOH]+ (5), 157 (100). Found, %: C 34.05; H 4.53; N 8.95. C9H14F3N2O5P.
Calculated, %: C 33.97; H 4.43; N 8.80.
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