Synthesis of diethyl 2-thioxo-1,2,3,4-tetrahydroand hexahydropyrimidine-5-phosphonates

Article abstract of DOI:10.1016/j.mencom.2008.01.019

The reaction of sodium enolate of diethyl (2-oxoprop-1-yl)phosphonate with N-(1-tosylprop-1-yl)thiourea results in the stereoselective formation of diethyl (4R*,5R*,6R*)-6-ethyl-4-hydroxy-4-methyl-2-thioxohexahydropyrimidine-5-phosphonate, which is transformed into diethyl 4-ethyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-phosphonate and diethyl (4R*,5S*,6R*)-4-ethyl-6-methyl-2-thioxohexahydropyrimidine-5-phosphonate by acid-catalysed dehydration and stereoselective reduction with NaBH₄-CF₃COOH, respectively.

Full text of DOI:10.1016/j.mencom.2008.01.019

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 51–53
Synthesis of diethyl 2-thioxo-1,2,3,4-tetrahydro-
and hexahydropyrimidine-5-phosphonates
Anastasia A. Fesenko, Dmitrii A. Cheshkov and Anatoly D. Shutalev*
Department of Organic Chemistry, Moscow State Academy of Fine Chemical Technology, 119571 Moscow,
Russian Federation. Fax: +7 495 936 8909; e-mail: shutalev@orc.ru
DOI: 10.1016/j.mencom.2008.01.019
The reaction of sodium enolate of diethyl (2-oxoprop-1-yl)phosphonate with N-(1-tosylprop-1-yl)thiourea results in the stereo-
selective formation of diethyl (4R*,5R*,6R*)-6-ethyl-4-hydroxy-4-methyl-2-thioxohexahydropyrimidine-5-phosphonate, which is
transformed into diethyl 4-ethyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-phosphonate and diethyl (4R*,5S*,6R*)-
4-ethyl-6-methyl-2-thioxohexahydropyrimidine-5-phosphonate by acid-catalysed dehydration and stereoselective reduction with
NaBH4–CF3COOH, respectively.
Hydrogenated pyrimidin-2-ones/thiones bearing functional groups
at the 5-position (e.g., 1 and 2) are of interest because of their
biological activity. For instance, 4-aryl-2-oxo(or 2-thioxo)-
1,2,3,4-tetrahydropyrimidine-5-carboxylic acid esters (1 R' = aryl,
FG = COOR''), Biginelli compounds, are inhibitors of kinesin
Eg5,1 selective antagonists of α1a adrenoceptors;2 they possess
high antihypertensive activity.3,4
P(O)(OEt)2
P(O)(OEt)2
NaH
NaO
O
Me
Me
Br
P(OEt)3
5
4
O
Me
CH2
(EtO)2P(O)O
6
Me
R'
R'
FG
R
FG
R
Scheme 1
HN
HN
3. Therefore, it was necessary to develop a convenient procedure
to purify phosphonate 5. This problem was solved by the treat-
ment of a diethyl ether solution of a mixture of 5 and 6 with a
known ratio of the components by a calculated amount of
NaH.† Precipitated sodium enolate 4 was filtered off, dried and
used in further reactions without additional purification.‡
We found that enolate 4 reacted with readily available
N-(1-tosylprop-1-yl)thiourea 714 in dry THF for 8 h at room
temperature to produce expected hydroxypyrimidine 3 in 81%
yield (Scheme 2).§
X
N
H
X
N
H
1
2
X = O, S
FG = functional group
Pyrimidines 1 bearing carboxamide (1 FG = CONR''R'''),5
carboxyl (1 FG = COOH),6 cyano (1 FG = CN),7 acyl (1 FG =
= COR''),8 nitro (1 FG = NO2),9 sulfonyl (1 FG = SO2R'')10 groups
and halogen atoms11 at C(5) are also compounds with potential
biological activity. However, 1,2,3,4-tetrahydro- and hexahydro-
pyrimidin-2-ones/thiones 1 and 2, respectively, bearing phos-
phorus atoms at the 5-position remain poorly studied. Gong et al.12
described the synthesis of 4-aryl-2-oxo-1,2,3,4-tetrahydropyri-
midine-5-phosphonic acid esters [1 R' = aryl, FG = PO(OEt)2]
by the reaction of urea with diethyl (2-oxoprop-1-yl)phosphonate
and aromatic aldehydes in the presence of ytterbium triflate.
Thus, the development of general synthetic methods for the
preparation of pyrimidines with organophosphorus moieties at
the C(5) atom, particularly dialkoxyphosphoryl groups, is of
considerable interest.
Diethyl 6-ethyl-4-hydroxy-4-methyl-2-thioxohexahydro-
pyrimidine-5-phosphonate 3 served as a key heterocyclic
compound. It was obtained by the reaction of enolates of
α-functionalised aldehydes or ketones with α-tosyl-substituted
ureas/thioureas.13,14 We used sodium enolate 4 of diethyl
(2-oxoprop-1-yl)phosphonate 5 as a nucleophile for the pre-
paration of pyrimidine 3. Compound 5 was obtained as described
elsewhere15,16 by heating bromoacetone with triethylphosphite
at 165–170 °C without solvent (Scheme 1).
Note that both stages of compound 3 formation (nucleophilic
substitution of tosyl group in 7 and subsequent heterocycliza-
tion of intermediate thiourea 8) proceeded with high diastereo-
1
selectivity. The H NMR spectrum of crude 3 showed a single
diastereomer. The vicinal coupling constants of 6-H with 5-H
and N(1)H¶ in this diastereomer (J5-H,6-H 11.7 Hz, JN(1)H,6-H 0 Hz)
reveal a diequatorial orientation of ethyl and diethoxyphosphoryl
groups. The orientation of substituents at the quaternary C(4)
†
Synthesis of 4. A mixture (1.150 g; 5.92 mmol) of phosphonate 5 and
ester 6 in a ratio of 85:15 (according to 1H NMR data) obtained as
described in refs. 15, 16 and distilled in vacuo three times (bp 126–139 °C/
12 Torr, nD20 1.4320) was dissolved in dry diethyl ether (15 ml). The
solution was added dropwise to a NaH suspension (0.105 g, 4.38 mmol)
in dry diethyl ether (15 ml) for 18 min away from air moisture with
stirring. The formed mixture was vigorously stirred for 11 min; the
white solid was then filtered off, promptly washed with dry diethyl ether
and light petroleum and dried in a round-bottom flask under vacuum
up to constant weight to give 4 (0.666 g; 70.4%), which was used
immediately after preparation.‡
‡
Treatment of an aqueous solution of 4 with an equivalent amount of
A considerable amount of ester 6 (up to 20% according to
1H NMR data) forms in this reaction along with phosphonate 5.
The presence of 6 in 5 strongly decreased the yield of pyrimidine
glacial acetic acid, extraction with diethyl ether, drying and removal
of the solvent afforded pure 5 without the impurity of ester 6 (according
to the 1H NMR spectrum).
– 51 –
© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 51–53
p-toluenesulfonic acid in refluxed ethanol for 1.5 h to give
Me
diethyl 1,2,3,4-tetrahydropyrimidine-5-phosphonate 9 in 89%
yield (Scheme 2) (Method A).†† The latter can also be obtained
directly from sulfone 7 in 73% overall yield without isolation of
3. For this purpose, p-toluenesulfonic acid was added to the
reaction mixture formed by the reaction of 7 with 4 (THF,
20 °C, 7 h) followed by heating at reflux for 2 h (Method B).††
Previously, we found that NaBH4–CF3COOH readily reduces
5-unsubstituted 1,2,3,4-tetrahydro- and 4-hydroxy(or 4-alkoxy)-
hexahydropyrimidin-2-ones/thiones.18 This reducing agent
was used for the preparation of diethyl hexahydropyrimidine-
5-phosphonate 10 from 3. Expected hexahydropyrimidine 10
was obtained after adding an excess of CF3COOH to a mixture
of pyrimidine 3 and NaBH4 (molar ratio of 1:8) in THF at 0 °C
followed by stirring the solution for 7 h at room temperature
(Scheme 2). The yield of the recrystallised product was 65%.‡‡
Note that the reduction of 3 involving the chiral C(4)
atom proceeded with high diastereoselectivity. Compound 10
formed as a single stereoisomer with (4R*,5S*,6R*)-configura-
O
S
O
P(O)(OEt)2
HN
Et
NH2
+
– 4-MeC6H4SO2Na
S
NaO
Me
Et
7
4
P(O)(OEt)2
O
HN
Et
S
NH2 Me
P(O)(OEt)2
Me
HN
8
S
N
H
TsOH
– H2O
9
Et
Et
P(O)(OEt)2
P(O)(OEt)2
OH
Me
HN
HN
1
NaBH4
tion according to the H NMR spectrum of crude product. This
S
N
H
Me
10
S
N
CF3COOH
follows from analysis of coupling constants between N(1)H,
N(3)H, 4-H, 5-H and 6-H protons. In contrast to compound 3,
which exists in the conformation of a slightly flat chair, com-
pound 10 in [2H6]DMSO has the conformation of a distorted
chair with the pseudo-axial orientation of the 6-Me group and
the pseudo-equatorial orientation of the 4-Et group. This conclu-
sion is based on the following coupling constants: J4-H,5-H 7.0 Hz,
J5-H,6-H 4.3 Hz, JN(3)H,4-H 2.3 Hz and JN(1)H,6-H 3.0 Hz.
The stereoselectivity of hydroxypyrimidine 3 reduction can
be explained in terms of SN1 mechanism via the formation of a
practically planar acyliminium cation. Subsequent hydride ion
transfer from bulky sodium tris(trifluoroacetoxy)borohydride,19
which is formed by the reaction of NaBH4 with an excess of
CF3COOH, occurs preferably from the side opposite to the
diethoxyphosphoryl group.
H
3
Scheme 2
atom was determined from the 1H–1H NOESY spectrum in
[2H6]DMSO. Cross-peaks between the hydrogen of the OH group
and axial hydrogen 6-H, as well as between the hydrogens
of the 4-Me group and axial hydrogen 5-H, indicate that the
orientation of the hydroxyl group is axial. This was confirmed
by the presence of a distant coupling constant between the OH
proton and the axial 5-H proton (JOH,5-H 1.2 Hz). Thus, the
obtained compound has (4R*,5R*,6R*)-configuration.
Hydroxypyrimidine 3 easily dehydrates in the presence of
§
Synthesis of diethyl (4R*,5R*,6R*)-6-ethyl-4-hydroxy-4-methyl-2-thioxo-
hexahydropyrimidine-5-phosphonate 3. A mixture of enolate 4 (0.795 g,
3.68 mmol), sulfone 7 (0.904 g, 3.32 mmol) and dry THF (15 ml) was
stirred for 8 h at room temperature. The reaction mixture containing a
white precipitate was evaparated to dryness in vacuo. The residue was
kept in vacuo for 20 min and triturated with heptane (5 ml). A saturated
aqueous solution of NaHCO3 (4 ml) was added to the obtained suspen-
sion. The mixture was allowed to stand for 3 h in a water bath (40 °C),
cooled to 0 °C; the precipitate was filtered off, washed with ice water
and heptane and dried to yield 0.837 g (81.3%) of chromatographically
pure 3 (Silufol, chloroform–methanol, 9:1); mp 148.5 °C (ethanol;
decomp.). 1H NMR (Bruker DPX 300, 300.13 MHz, [2H6]DMSO) d:
8.30 (dd, 1H, N(3)H, JN(3)H,P 4.1 Hz, JN(3)H,N(1)H 1.6 Hz), 7.97 (dd, 1H,
N(1)H, JN(1)H,P 3.5 Hz, JN(1)H,N(3)H 1.6 Hz, JN(1)H,6-H 0 Hz), 6.12 (d, 1H,
OH, JOH,5-H 1.2 Hz), 3.94–4.06 (m, 4H, OCH2), 3.69 (m, 1H, 6-H,
J6-H,5-H 11.7 Hz, J6-H,P 7.0 Hz, J6-H,CH(A) 3.6 Hz, J6-H,CH(B) 3.6 Hz,
J6-H,N(1)H 0 Hz), 1.98 (ddd, 1H, 5-H, J5-H,P 17.3 Hz, J5-H,6-H 11.7 Hz,
J5-H,OH 1.2 Hz), 1.85 [m, 1H, CH(A) in 6-CH2, JCH(A),CH(B) 14.6 Hz,
JCH(A),Me 7.3 Hz, JCH(A),6-H 3.6 Hz], 1.68 [m, 1H, CH(B) in 6-CH2,
JCH(B),CH(A) 14.6 Hz, JCH(B),Me 7.3 Hz, JCH(B),6-H 3.6 Hz], 1.69 (s, 3H,
4-Me), 1.21 (t, 3H, Me in OEt, JMe,CH 7.1 Hz), 1.20 (t, 3H, Me in OEt,
JMe,CH 7.1 Hz), 0.79 (t, 3H, Me in 6-Et,2JMe,CH 7.3 Hz). 13C NMR (Bruker
†† Synthesis of diethyl 4-ethyl-6-methyl-2-thioxo-1,2,3,4-tetrahydropyri-
midine-5-phosphonate 9 (Method A). A stirred solution of hydroxy-
pyrimidine 3 (0.381 g, 1.23 mmol) and TsOH·H2O (0.072 g, 0.38 mmol)
in ethanol (6 ml) was refluxed for 1.5 h, the solvent was removed in vacuo,
and the solid residue was treated with a saturated aqueous solution of
NaHCO3 (2 ml). The obtained suspension was cooled to 0 °C, the preci-
pitate was filtered off, washed with ice water and heptane and dried to
yield 0.318 g (88.6%) of chromatographically pure 9 (Silufol, chloroform–
methanol, 9:1); mp 169–169.5 °C (acetonitrile). 1H NMR (Bruker DPX 300,
300.13 MHz, [2H6]DMSO) d: 10.04 [br. d, 1H, N(1)H, JN(1)H,P 3.6 Hz],
9.08 [br. m, 1H, N(3)H], 3.85–4.03 (m, 4H, OCH2), 3.80 (m, 1H, 4-H,
J4-H,P 8.3 Hz, J4-H,CH 5.4 Hz, J4-H,N(3)H 3.6 Hz), 2.05 (d, 3H, 6-Me,
2
JMe,P 2.5 Hz), 1.44 (dq, 2H, CH2 in 4-Et, JCH ,Me 7.4 Hz, JCH ,4-H 5.4 Hz),
2
2
1.22 (t, 6H, Me in OEt, J
7.0 Hz), 0.80 (t, 3H, Me in 4-Et, J
Me,CH2
Me,CH2
7.4 Hz). 13C NMR (Bruker DPX 300, 75.48 MHz, [2H6]DMSO) d: 175.27
(s, C=S), 145.26 [d, C(6), J 20.4 Hz], 95.24 [d, C(5), J 202.4 Hz], 60.87
(d, OCH2, J 5.4 Hz), 60.80 (d, OCH2, J 5.4 Hz), 52.48 [d, C(4), J 14.3 Hz],
29.48 (s, CH2 in 4-Et), 16.83 (d, 6-Me, J 3.4 Hz), 16.07 (d, Me in OEt,
J 6.2 Hz), 7.96 (s, Me in 4-Et). 31P NMR (Bruker DPX 300, 121.49 MHz,
[2H6]DMSO, using 85% H3PO4 as an external standard) d: 20.43.
IR (FT-IR Bruker ‘Equinox 55/S’) (Nujol, n/cm–1): 3176 (s, νN–H), 1644
(s, νC=C), 1578 (s, ‘thioamide-II’), 1227 (s, νP=O), 1210 (s, δN–H), 1038
(sh), 1029 (s, νP–O–C). Found (%): C, 45.03; H, 7.01; N, 9.61. Calc. for
C11H21N2O3PS (%): C, 45.20; H, 7.24; N, 9.58.
2
2
DPX 300, 75.48 MHz, [2H6]DMSO) d: 174.89 (s, C=S), 78.41 [s, C(4)],
61.53 (d, OCH2, J 6.0 Hz), 60.62 (d, OCH2, J 6.2 Hz), 49.45 [s, C(6)],
42.63 [d, C(5), J 143.1 Hz], 27.54 (s, 4-Me), 23.23 (s, CH2 in 6-Et),
16.09 (d, Me in OEt, J 6.0 Hz), 16.01 (d, Me in OEt, J 6.6 Hz), 6.93 (s,
Me in 6-Et). 31P NMR (Bruker DPX 300, 121.49 MHz, [2H6]DMSO,
using 85% H3PO4 as an external standard) d: 26.61. IR (FT-IR Bruker
‘Equinox 55/S’) (Nujol, n/cm–1): 3294 (m), 3261 (s), 3192 (s), 3111 (m)
(νN–H, νO–H), 1577 (s), 1534 (s) (‘thioamide-II’), 1226 (vs, νP=O), 1211
(m, δN–H), 1047 (s), 1020 (s, νP–O–C). Found (%): C, 42.47; H, 7.69;
N, 9.10. Calc. for C11H23N2O4PS (%): C, 42.57; H, 7.47; N, 9.03.
Synthesis of 9 (Method B). A mixture of enolate 4 (0.706 g, 3.27 mmol),
sulfone 7 (0.806 g, 2.96 mmol) and dry THF (14.5 ml) was stirred for
7 h at room temperature. Then, TsOH·H2O (0.314 g, 1.65 mmol) was
added, and the mixture was refluxed with stirring for 2 h. The solvent
was removed in vacuo, the residue was kept in vacuo for 20 min and
triturated with heptane (5 ml). A saturated aqueous solution of NaHCO3
(4 ml) was added to the obtained suspension. The mixture was allowed
to stand at room temperature overnight and then cooled to 0 °C; the
precipitate was filtered off, washed with ice water and heptane and dried
to give 9 (0.633 g, 73.2%).
¶
Previously,17 we proposed a convenient criterion for the determination
of substituents orientation at C(4) and C(6) in hexahydropyrimidin-
2-ones/thiones, which is based on the coupling constants between C(4)H
and N(3)H, C(6)H and N(1)H.
– 52 –

Mendeleev Commun., 2008, 18, 51–53
Thus, we developed a synthetic method for the preparation
References
of previously unknown derivatives of 2-thioxo-1,2,3,4-tetra-
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This method includes the stereoselective formation of diethyl
4-hydroxy-2-thioxohexahydropyrimidine-5-phosphonates and
their subsequent transformations.
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‡‡ Synthesis of diethyl (4R*,5S*,6R*)-4-ethyl-6-methyl-2-thioxohexa-
hydropyrimidine-5-phosphonate 10. CF3COOH (12 ml) was added drop-
wise for 37 min with the protection from air moisture to a stirred, cooled
in an ice bath suspension of finely powdered NaBH4 (0.612 g, 16.18 mmol)
and hydroxypyrimidine 3 (0.634 g, 2.04 mmol) in dry THF (6 ml). The
obtained solution was stirred for 7 h at room temperature, evaporated
in vacuo at 50–60 °C, the viscous oil formed was neutralised with a
saturated aqueous solution of K2CO3. The product was extracted with
CHCl3 (5×10 ml); the combined organic layers were washed with water
and a saturated aqueous solution of NaCl and dried over Na2SO4. The
solvent was removed in vacuo; the solid residue was triturated with dry
diethyl ether and cooled to –10 °C; the white precipitate was filtered off,
washed with cooled dry diethyl ether and dried to give product (0.535 g)
containing 80 mol% 10 and 20 mol% unidentified organophosphorus
compound according to 1H NMR data. After recrystallization of this
mixture from ethyl acetate (24 ml), pure 10 (0.393 g, 65.4%) was
obtained; mp 166–168 °C (ethyl acetate). 1H NMR (Bruker Avance 600,
600.13 MHz, [2H6]DMSO) d: 8.13 [br. d, 1H, N(1)H, JN(1)H,6-H 3.0 Hz],
7.95 [br. d, 1H, N(3)H, JN(3)H,4-H 2.3 Hz], 3.98–4.07 (m, 4H, OCH2),
3.59 (m, 1H, 6-H, J6-H,P 19.3 Hz, J6-H,Me 6.7 Hz, J6-H,5-H 4.3 Hz, J6-H,N(1)H
3.0 Hz), 3.53 (m, 1H, 4-H, J4-H,P 8.9 Hz, J4-H,5-H 7.0 Hz, J4-H,CH(A)
5.3 Hz, J4-H,CH(B) 5.3 Hz, J4-H,N(3)H 2.3 Hz), 2.22 (ddd, 1H, 5-H, J5-H,P
19.9 Hz, J5-H,4-H 7.0 Hz, J5-H,6-H 4.3 Hz), 1.67 [m, 1H, CH(A) in 4-CH2,
JCH(A),CH(B) 14.1 Hz, JCH(A),Me 7.3 Hz, JCH(A),4-H 5.3 Hz], 1.55 [m, 1H,
CH(B) in 4-CH2, JCH(B),CH(A) 14.1 Hz, JCH(B),Me 7.3 Hz, JCH(B),4-H 5.3 Hz],
3
4
5
6
7
8
9
G. Ya. Remennikov, I. V. Boldyrev, S. A. Kravchenko and V. V. Pirozhenko,
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17 A. Ignatova, A. D. Shutalev, M. T. Pagaev and B. V. Unkovskii, Khim.
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Transl.), 1988, 24, 197].
1.24 (t, 6H, Me in OEt, JMe,CH 7.0 Hz), 1.22 (d, 3H, 6-Me, JMe,6-H 6.7 Hz),
2
0.83 (t, 3H, Me in 4-Et, JMe,CH 7.3 Hz). 13C NMR (Bruker DPX 300,
2
75.48 MHz, [2H6]DMSO) d: 175.15 (s, C=S), 61.44 (d, OCH2, J 6.6 Hz),
61.21 (d, OCH2, J 6.7 Hz), 49.95 [s, C(4)], 44.58 [d, C(6), J 1.6 Hz],
35.17 [d, C(5), J 142.9 Hz], 26.34 (d, CH2 in 4-Et, J 6.5 Hz), 18.39
(d, 6-Me, J 1.9 Hz), 16.23 (d, Me in OEt, J 5.9 Hz), 16.19 (d, Me in
OEt, J 5.9 Hz), 8.17 (s, Me in 4-Et). 31P NMR (Bruker DPX 300,
121.49 MHz, [2H6]DMSO, using 85% H3PO4 as an external standard) d:
27.67. IR (FT-IR Perkin-Elmer Spectrum BX) (KBr, n/cm–1): 3434 (br. s),
3183 (s), 3107 (m, νN–H), 1579 (s), 1564 (s), 1544 (s, ‘thioamide-II’),
1246 (s, νP=O), 1210 (s, δN–H), 1046 (s), 1020 (s), 967 (s, νP–O–C). Found
(%): C, 44.81; H, 7.88; N, 9.37. Calc. for C11H23N2O3PS (%): C, 44.89;
H, 7.88; N, 9.52.
18 A. D. Shutalev, E. N. Komarova and L. A. Ignatova, Khim. Geterotsikl.
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Received: 4th June 2007; Com. 07/2953
– 53 –