The efficient synthesis of 2-arylpyrimidine acyclic nucleoside phosphonates using Liebeskind-Srogl cross-coupling reaction

Article abstract of DOI:10.1016/j.tet.2011.07.040

A series of novel acyclic nucleoside phosphonates with various aryls attached to the C-2 position of the pyrimidine moiety has been prepared using the Liebeskind-Srogl cross-coupling protocol. The reactions of highly functionalised 2-(methylsulfanyl)pyrim

Full text of DOI:10.1016/j.tet.2011.07.040

Tetrahedron 67 (2011) 7379e7385
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The efficient synthesis of 2-arylpyrimidine acyclic nucleoside phosphonates using
LiebeskindeSrogl cross-coupling reaction
ꢀ
*
ꢀ
ꢁ
ꢀ
ꢁ
ꢁ
Petra Brehova, Michal Cesnek, Martin Dracínsky, Antonín Holy, Zlatko Janeba
ꢁ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, CZ-166 10 Prague 6, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel acyclic nucleoside phosphonates with various aryls attached to the C-2 position of the
pyrimidine moiety has been prepared using the LiebeskindeSrogl cross-coupling protocol. The reactions
of highly functionalised 2-(methylsulfanyl)pyrimidines with various arylboronic acids were studied and
optimised.
Received 18 March 2011
Received in revised form 21 June 2011
Accepted 12 July 2011
Available online 21 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
LiebeskindeSrogl cross-coupling
Acyclic nucleoside phosphonates
Pyrimidines
Arylboronic acids
Microwave
1. Introduction
R
N
NH2
N
N
Acyclic nucleoside phosphonates (ANPs) are nucleotide ana-
logues containing a stable phosphonomethyl moiety. ANPs possess
a broad spectrum of biological activities, e.g., antiviral, cytostatic
and antiprotozoal.1 The most pronounced is their antiviral activity
against retroviruses and DNA viruses and they are currently used as
successful drugs against HIV, HBV and herpes viral infections. The
choice of a heterocyclic base of antivirally active ANPs is limited,
with the exception of cytosine, to purine derivatives (adenine, 2,6-
diaminopurine and guanine).2 A second generation of ANPs is de-
rived from 2,4-diamino-6-hydroxy- (e.g., compounds 1a and 2,
Fig. 1) and 2-amino-4,6-dihydroxypyrimidine (e.g., compound 1b,
Fig. 1), bearing the (phosphonomethoxy)alkyl side chain attached
to the oxygen atom at the C-6 position of the pyrimidine ring.3
These compounds mimic purine acyclic nucleoside phospho-
nates4 and are recognised by HIV-1 reverse transcriptase as purine
nucleotides.5 The antiviral activities of pyrimidine ANPs closely
resemble the activities of the parent purine derivatives.
N
H2N
O
H2N
O
OH
O
O
P(O)(OH)2
P(O)(OH)2
1a,
R = NH2
1b, R = OH
2
Fig. 1. Examples of the second generation of ANPs.
broad availability of reaction partners offer a powerful tool for or-
ganic synthesis. The LiebeskindeSrogl8 cross-coupling of thio-
organics with arylboronic acids extends the versatility of the
SuzukieMiyaura9 and Stille10 cross-coupling reactions. The Lie-
beskindeSrogl cross-coupling methodology comprises
a Pd-
catalysed and copper(I)-mediated reactions of thioethers with
arylboronic acids under the base-free conditions. This methodology
has also been successfully applied to various hetarylthioether re-
actions11 and selective reactions of functionalized 2-(methyl-
sulfanyl)pyrimidinones.12
Herein, we report on the efficient synthesis of 2-arylpyrimidine
acyclic nucleoside phosphonates using the LiebeskindeSrogl
cross-coupling protocol. The reactions of highly functionalised 2-
(methylsulfanyl)pyrimidines with various arylboronic acids were
optimized and two series of novel acyclic nucleoside phosphonates
were prepared.
Cross-coupling reactions of heteroaromatics with various or-
ganometallic reagents are widely used in drug design for modifi-
cations of purine6 and pyrimidine7 bases of biologically active
compounds. Mild reaction conditions, high selectivity, and the
* Corresponding author. Tel.: þ420 220183143; fax: þ420 220183560; e-mail
address: janeba@uochb.cas.cz (Z. Janeba).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.040

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7380
2. Results and discussion
results it can clearly be seen that the crucial role is played by the
organocopper(I) salt used in the cross-coupling reactions.
As expected, the reaction of the more functionalized compound
4b with phenylboronic acid using Pd(PPh3)4 in the presence of
CuTC (1.5 equiv) gave lower yield (23%) of the product 5b (entry 6,
Table 1), compared to the analogous reaction of derivative 4a (53%
of 5a, entry 1, Table 1).
To improve the yields, the influence of microwave heating
on the LiebeskindeSrogl reaction14 of compound 4b using
a Pd(PPh3)4/CuTC catalytic system was studied next (Table 1). The
results show that the microwave-assisted reactions afforded only
2.1. Chemistry
Starting 2-(methylsulfanyl)pyrimidine derivatives 4a and 4b
bearing the 2-(phosphonomethoxy)ethoxy (PMEO) and (R)-3-
hydroxy-2-(phosphonomethoxy)propoxy (HPMPO) side chain, re-
spectively, were readily prepared by an alkylation of commercially
available 4,6-dihydroxy-2-(methylsulfanyl)pyrimidine (A) with the
phosphonate-bearing building blocks 3a and 3b according to the
previously described procedure (Scheme 1).13
OH
OH
R1
X
NaH, DMSO, 120 °C
N
N
+
O
R1
N
O
S
CH3
N
OH
S
P(O)(Oi-Pr)2
O
CH3
, R1 = H; X = Cl
, R = (R)-CH2OH, X = OTs
3a
3b
A
P(O)(Oi-Pr)2
, R1 = H
1
4a
4b
1
, R = (R)-CH2OH
Scheme 1. Synthesis of the starting ANPs bearing 2-(methylsulfanyl) group.
Phenylboronic acid and protected phosphonate 4a were chosen
as model compounds for the optimisation study of the Lie-
beskindeSrogl cross-coupling reaction (Scheme 2) and the in-
fluence of various catalytic systems was studied (entries 1e5,
Table 1). Reactions of the compound 4a with phenylboronic acid
using various Pd catalysts in the presence of copper(I) thiophene-2-
carboxylate (CuTC, 1.5 equiv) afforded the product 5a in 52e60%
yields in 48 h (entries 1,4 and 5, Table 1). An increased loading of the
CuTC (2.2 equiv) under otherwise identical reaction conditions did
not improve the yield of 5a (entry 2, Table 1). On the other hand, the
conversion of 4a to 5a under catalysis with Pd(PPh3)4 in the pres-
ence of copper(I) 3-methylsalicylate (CuMeSal, 2.2 equiv) was nearly
quantitative (98%) in only 24 h (entry 3, Table 1), whilst a lower ratio
of CuMeSal is not sufficient to afford satisfactory yields.12 From the
slightly higher yields of the product 5b (entries 7 and 8, Table 1)
compared to the conventional heating (entry 1, Table 1), however,
the reaction times were significantly decreased (30 and 60 min
compared to 48 h). Not even prolonged reaction times (3 h) of the
MW-assisted reactions improved the yields dramatically.
Finally, we studied the influence of Zn(OAc)2, which has been
reported as an essential additive in some cases of the Lie-
beskindeSrogl cross-coupling.11a In our case, the addition of
Zn(OAc)2 (1.2 equiv) significantly lowered the yields of the product
5b under both conventional heating (entry 9, Table 1) and MW ir-
radiation (entry 10, Table 1). Complex mixtures of products were
formed in both cases apparently owing to the instability of the
starting material and/or the product under the reaction conditions.
In analogy to compounds 5a, the best yield of the coupled
product 5b (86%) was obtained by the conventional reaction of the
starting compound 4b under the catalysis with the Pd(PPh3)4/
CuMeSal system (entry 11, Table 1).
To summarize the optimisation, the best results of the cross-
coupling of 2-(methylsulfanyl)pyrimidines 4a and 4b with phe-
nylboronic acid were achieved with a Pd(PPh3)4 (5%) in the pres-
ence of CuMeSal (2.2 equiv) as metal co-factor.
Subsequently, we have decided to exploit our optimised re-
action conditions of the LiebeskindeSrogl cross-coupling protocol
for the synthesis of the acyclic nucleoside phosphonates with
OH
OH
PhB(OH)2
Pd cat.
CuTC or CuMeSal
THF
N
N
R1
R1
N
N
O
S
O
O
CH3
O
P(O)(Oi-Pr)2
P(O)(Oi-Pr)2
, R1 = H
1
, R1 = H
6a,
4a
5a
4b
, R = (R)-CH2OH
R
1 = (R)-CH2OH
Scheme 2. Optimisation of the reaction of 4a and 4b with phenylboronic acid.
Table 1
Optimisation of the LiebeskindeSrogl cross-coupling reaction of compounds 4a and 4b with phenylboronic acid (Scheme 2)
Entry
Compd
R2
Pd catalyst
Cu (I) salt
Reaction conditions
Time
Yielda (%) of 5a/6a
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Pd(PPh3)4, 5%
Pd(PPh3)4, 5%
Pd(PPh3)4, 5%
Pd(PPh3)2Cl2, 5%
Pd2(dba)3, 4%, Ph3P 20%
Pd(PPh3)4, 5%
Pd(PPh3)4, 5%
Pd(PPh3)4, 5%
Pd(PPh3)4, 5%
Pd(PPh3)4, 5%
Pd(PPh3)4, 5%
CuTCb (1.5 equiv)
CuTC (2.2 equiv)
CuMeSalc (2.2 equiv)
CuTC (1.5 equiv)
CuTC (1.5 equiv)
CuTC (1.5 equiv)
CuTC (1.5 equiv)
CuTC (1.5 equiv)
CuTC (1.5 equiv)
CuTC (1.5 equiv)
CuMeSal (2.2 equiv)
60 ꢀCd
60 ꢀCd
60 ꢀCd
60 ꢀCd
60 ꢀCd
65 ꢀCd
100 ꢀCe
100 ꢀCe
65 ꢀCd,f
100 ꢀCe,f
60 ꢀCd
48 h
48 h
24 h
48 h
48 h
48 h
30 min
60 min
8 h
30 min
24 h
53
54
98
52
60
23
54
62
27
34
86
9
10
11
a
Yield were determined by HPLC.
b
c
d
e
f
CuTC (copper(I) thiophene-2-carboxylate).
CuMeSal (copper(I) 3-methylsalicylate).
Conventional heating.
Microwave irradiation.
Addition of Zn(OAc)2 (1.2 equiv).

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P. Brehova et al. / Tetrahedron 67 (2011) 7379e7385
7381
Table 3
substituted aryls attached to the pyrimidine moiety at the C-2
Formation of the free phosphonic acids 7 and 8 (Scheme 3)
position. We have attempted to elucidate the influence of either
electron withdrawing or electron donating substituents at the C-4
position of the phenylboronic acid on the reactivity and the
yields of 2-arylpyrimidine ANPs. Thus, compounds 4a and 4b
reacted under the optimised conditions (Pd(PPh3)4 (5%), CuMeSal
(2.2 equiv)) with a number of 4-substituted phenylboronic acids
giving the desired pyrimidine ANPs with PMEO and HPMPO side
chains, compounds 5aef and 6aef, respectively (Scheme 3,
Table 2). The best isolated yields (89% for 5a and 75% for 6a) were
obtained with the unsubstituted phenylboronic acid (entries 1
and 7, Table 2). All other coupled products 5bef and 6bef were
obtained in moderate to good yields (41e65%) and no significant
effect of the C-4 substituent of the phenylboronic acid on the
reaction yields of the cross-coupling reaction was observed.
Entry
R1
R2
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
Phenyl
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
16
16
16
16
16
16
16
16
16
16
16
16
79
67
61
77
82
79
66
76
81
71
90
76
40-Fephenyl
40-CH3Oephenyl
40-NO2ephenyl
40-CF3ephenyl
40-OHephenyl
Phenyl
(R)-CH2OH
(R)-CH2OH
(R)-CH2OH
(R)-CH2OH
(R)-CH2OH
(R)-CH2OH
40-Fephenyl
40-CH3Oephenyl
40-NO2ephenyl
40-CF3ephenyl
40-OHephenyl
9
10
11
12
a
Isolated yield.
leukaemia HL-60 cells and human cervix carcinoma HeLa S3 cells
(Dr. I. Votruba, IOCB, Prague) but none of the compounds exhibited
considerable cytostatic activity or cytotoxicity. None of the pre-
pared derivatives displayed any significant inhibitory activity
against the viruses so far tested (HCMV, VZV, HCV).
OH
OH
R2B(OH)2
N
N
R1
R1
R2
N
Pd(PPh3)4 (5 mol %)
CuMeSal (2.2 eq.)
THF, 60 °C
N
O
S
O
O
CH3
O
P(O)(OR3)2
P(O)(Oi-Pr)2
, R1 = H
1
-
, R1 = H; R3 = i-Pr
4a
5a 5f
3. Conclusions
, R1 = (R)-CH2OH; R3 = i-Pr
4b
6a 6f
-
, R = (R)-CH2OH
Me3SiBr
CH3CN
A series of 12 new 2-(4-substituted-aryl)pyrimidine acyclic
nucleoside phosphonates with PMEO and HPMPO side chains was
prepared using the LiebeskindeSrogl cross-coupling protocol as the
key synthetic step. The reaction conditions of the cross-coupling
were optimised and Pd(PPh3)4 (5%)/CuMeSal (2.2 equiv) catalytic
system was found to give the best yields. As for the arylboronic
acids, the best yields of the 2-arylpyrimidines were obtained by the
coupling with unsubstituted phenylboronic acid. No significant
influence of the substituent at the C-4 position of the phenyl-
boronic acid on the reaction course was observed. The presence of
the functional groups of ANPs is well tolerated under the reaction
conditions. Analogous reactions with hetarylboronic acids or het-
eroaryl stannanes failed. None of the final free phosphonic acids
7aef and 8aef displayed any cytostatic or antiviral activity.
, R1 = H;R3 = H
7a 7f
-
8a 8f
-
, R1 = (R)-CH2OH; R3 = H
Scheme 3. LiebeskindeSrogl cross-coupling of 4a and 4b with arylboronic acids and
formation of the free phosphonic acids 7 and 8.
Table 2
Synthesis of 2-arylpyrimidine ANPs
(Scheme 3)
5 and 6 via LiebeskindeSrogl reaction
Entry
R1
R2
Product
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
Phenyl
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
24
24
24
24
24
24
24
24
24
24
24
24
89
64
57
56
50
41
75
54
60
41
65
63
40-Fephenyl
40-CH3Oephenyl
40-NO2ephenyl
40-CF3ephenyl
40-OHephenyl
Phenyl
(R)-CH2OH
(R)-CH2OH
(R)-CH2OH
(R)-CH2OH
(R)-CH2OH
(R)-CH2OH
4. Experimental section
4.1. General methods
40-Fephenyl
9
40-CH3Oephenyl
40-NO2ephenyl
40-CF3ephenyl
40-OHephenyl
10
11
12
Solvents were dried by standard procedures. Tetrahydrofuran
(THF) was freshly distilled from sodium/benzophenone under ar-
a
Isolated yield.
€
gon. Melting points were determined on a Buchi Melting Point
B-545 apparatus and are uncorrected. TLC was performed on plates
of Kieselgel 60 F254 (Merck) in 5% MeOH in CHCl3 (solvent system A)
or in 10% MeOH in CHCl3 (solvent system B). 1H and 13C NMR
spectra were recorded on Bruker Avance 500 (500 MHz for 1H and
125.8 MHz for 13C) and Bruker Avance 400 (1H at 400, 13C at
100.6 MHz) spectrometers in CDCl3, DMSO-d6, or D2O. Chemical
The above synthetic protocol has also been applied to the
synthesis of 2-heteroaryl pyrimidines. Unfortunately, the
reactions of compounds 4a and 4b with 2-furyl-, 3-pyridyl- and
4-pyridylboronic acids were unsuccessful and an analogous treat-
ment of 2-(sulfanylmethyl)pyrimidines with heteroaryl stannanes
failed as well. Attempts with elevated temperature, or with the
described11a addition of Zn(OAc)2 only led to the complex reaction
mixtures.
Eventually, the compounds 5aef and 6aef were converted to
the desired final products 7aef and 8aef, respectively, by the
standard transesterification reaction with bromotrimethylsilane
(TMSBr) and subsequent hydrolytic cleavage of the corresponding
silylester phosphonates (Scheme 3, Table 3).
shifts (in ppm, d
scale) were referenced to TMS (for 1H NMR spectra
in CDCl3) and/or to the solvent signal (CDCl3
d
¼7.26 ppm for 1H
NMR and
d
¼77.0 ppm for 13C NMR; DMSO-d6 for 1H NMR
d
¼2.5 ppm and for 13C
¼39.7). Chemical shifts in D2O were ref-
d
erenced to 1,4-dioxane for 1H NMR
d
¼3.75 and for 13C NMR
d¼67.19. Mass spectra were measured on a ZAB-EQ (VG Analytical)
spectrometer using FAB (ionization by Xe, accelerating voltage 8 kV,
glycerol matrix) or on a LCQ classic spectrometer using electrospray
ionization (ESI). Elemental microanalysis was performed using a PE
2400 Series II CHNS/O Analyzer (Perkin Elmer, USA). IR spectra
were recorded on an FTIR spectrometer Bruker IFS 55 (Equinox) in
CHCl3. Preparative HPLC purification was performed on a column
2.2. Biological evaluation
The compounds 7aef and 8aef were tested for their in vitro
inhibition of cell growth in mouse leukaemia L1210 cells, human
T-lymphoblastoid CCRF-CEM cell line, human promyelocytic
packed with 10
m
m C18 reversed phase (Luna), 250 mmꢁ21 mm
using linear gradient of MeOH (0e100%) in H2O. Flash

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P. Brehova et al. / Tetrahedron 67 (2011) 7379e7385
7382
chromatography was performed on ISCO combi flash Companion
(prepacked silicagel columns).
finally with brine (20 mL). The organic layer was dried over MgSO4,
evaporated in vacuo and the residue was purified by flash chro-
matography (0e7% MeOH in CHCl3).
It is important to note that 13C NMR signals of the pyrimidine
carbons of 4-hydroxypyrimidine derivatives were usually not ob-
served most probably because of the tautomer exchange reaction
(amideeiminol) of intermediate rate on the NMR time scale. In
some cases, the carbon atom C-6 could be detected in the 2D-H,
C-HMBC spectra, where the three-bond correlations from the side
chain were observed. The structure of the compounds is confirmed
by HRMS analysis.
4.2.1. 6-{2-[(Diisopropoxyphosphoryl)methoxy]ethoxy}-4-hydroxy-
2-phenylpyrimidine (5a). White solid (320 mg, 89%), Rf 0.46 (A), mp
69 ꢀC (recryst from EtOAc/light petroleum). 1H NMR (DMSO-d6):
12.43 (br s,1H, OH), 8.18 (m, 2H) and 7.55 (m, 3H, arom.), 5.63 (s,1H,
H-5), 4.59 (m, 2H, CHipr.), 4.44 (m, 2H, H-10), 3.86 (m, 2H, H-20),
3.82 (d, JH,P¼8.3, 2H, PCH2),1.23 (d, J¼6.2, 6H) and 1.22 (d, J¼6.2, 6H,
CH3ipr.). 13C NMR (DMSO-d6): 169.5 (C-4), 131.6 (C-400),128.5 (C-300),
127.7 (C-200), 88.7 (C-5), 70.4 (d, J¼11.8, C-20), 70.0 (d, J¼6.4, CHipr.),
65.4 (C-10), 64.7 (d, J¼164.4, PCH2), 23.7 (d, J¼3.8) and 23.5 (d,
J¼4.5, CH3ipr.). MS (ESI): m/z (%)¼411.2 (100) [MþH]þ; 433.2 (80)
[MþNa]þ. HRMS (ESI) for C19H27O6N2NaP calcd: 433.1499; found
433.1499.
4.1.1. 6-{2-[(Diisopropoxyphosphoryl)methoxy]ethoxy}-4-
hydroxy-2-methylsulfanylpyrimidine (4a). 4,6-Dihydroxy-2-(meth-
ylsulfanyl)pyrimidine (6.00 g, 38.2 mmol) in DMSO (200 mL) was
treated with NaH (60% dispersion in mineral oil, 1.42 g, 35.5 mmol)
and the reaction mixture was heated at 60 ꢀC under argon atmo-
sphere for 30 min. 2-[(Diisopropoxyphosphoryl)methoxy]ethyl
chloride (9.6 g, 36.2 mmol) in DMSO (20 mL) was added dropwise
(30 min) and the resulting mixture was heated at 120 ꢀC for 8 h. The
mixture was cooled to room temperature, poured into ice cold
water (250 mL) and the product was extracted with CHCl3
(3ꢁ100 mL) and dried over MgSO4. Flash chromatography afforded
4a as a colourless oil (5.00 g, 34%), Rf 0.35 (A). 1H NMR (DMSO-d6):
12.32 (br s, 1H, OH), 5.39 (br s, 1H, H-5), 4.59 (d, JCH,CH3¼6.2,
JCH,P¼7.8, 2H, CHipr.), 4.33 (m, 2H, H-10), 3.80 (m, 2H, H-20), 3.79 (d,
JCH2,P¼8.3, 2H, CH2P), 2.47 (s, 3H, SCH3), 1.24 (d, JCH3,CH¼6.0, 6H)
and 1.22 (d, JCH3,CH¼6.0, 6H, CH3ipr.). 13C NMR (DMSO-d6): 169.2
(C-4), 86.1 (C-5), 70.7 (d, J2,P¼11.9, C-20), 70.4 (d, JC,O,P¼6.3, CHipr.),
65.8 (C-10), 65.0 (d, JC,P¼164.5, CH2P), 24.0 (d, JCH3,P¼3.6) and 23.9
(d, JCH3,P¼4.4, CH3ipr.), 13.1 (SCH3). MS (ESI): m/z (%)¼403 (100)
[MþNa]þ. HRMS (FAB) for C14H26N2O6PS [MH]þ calcd: 381.1249,
found 381.1265.
4.2.2. 6-{2-[(Diisopropoxyphosphoryl)methoxy]ethoxy}-4-hydroxy-
2-(4-fluorophenyl)pyrimidine (5b). White solid (360 mg, 64%), Rf
0.48 (A). 1H NMR (500 MHz, DMSO-d6): 8.25 (m, 2H, H-200), 7.36 (m,
2H, H-300), 5.66 (br s, 1H, H-5), 4.58 (d, JHeCeOeP¼7.8, JCH,CH3¼6.2,
2H, CHipr.), 4.44 (m, 2H, H-10), 3.86 (m, 2H, H-20), 3.81 (d, JH,P¼8.3,
2H, PCH2),1.22 and 1.21 (2ꢁ d, JCH3,CH¼6.2, 2ꢁ 6H, CH3ipr.). 13C NMR
(125.8 MHz, DMSO-d6): 164.5 (d, J4 ,F¼249.8, C-400), 130.6
00
(d, J2 ,F¼9.1, C-200), 129.8 (C-100), 115.9 (d, J3 ,F¼21.8, C-300), 88.8 (C-5),
00
00
70.7 (d, J2 ,P¼11.9, C-20), 70.4 (d, JCeOeP¼6.4, CHipr.), 65.7 (C-10), 65.0
0
(d, JC,P¼164.5, PCH2), 24.0 (d, JC,P¼3.7) and 23.9 (d, JC,P¼4.5, CH3ipr.).
MS (ESI): m/z (%)¼429.1 (100) [MþH]þ, 451 (17) [MþNa]þ. HRMS
(ESI) calcd for C19H27O6N2FP [MþH]þ 429.1585; found 429.1585.
4.2.3. 6-{2-[(Diisopropoxyphosphoryl)methoxy]ethoxy}-4-hydroxy-
2-(4-methoxyphenyl)pyrimidine (5c). White solid (332 mg, 57%), Rf
0.54 (A). 1H NMR (500 MHz, DMSO-d6): 12.42 (br s, 1H, OH), 8.16
(m, 2H, H-200), 7.06 (m, 2H, H-300), 5.52 (br s, 1H, H-5), 4.59 (dh,
JH,C,O,P¼7.8, JCH,CH3¼6.2, 2H, CHipr.), 4.40 (m, 2H, H-10), 3.85 (m, 2H,
H-20), 3.84 (s, 3H, OCH3), 3.81 (d, JH,C,P¼8.3, 2H, PCH2), 1.23 and 1.22
(2ꢁ d, JCH3,CH¼6.2, 2ꢁ 6H, CH3ipr.). 13C NMR (125.8 MHz, DMSO-d6):
169.7 (C-4), 162.4 (C-400), 160.3 (C-2), 132.5 (C-100), 129.9 (C-200),
114.2 (C-300), 88.5 (C-5), 70.8 (d, JC,O,P¼6.3, CHipr.), 65.7 (C-10), 65.0
(d, JC,P¼164.5, PCH2), 55.7 (OCH3), 24.0 (d, JC,P¼3.4) and 23.9 (d,
JC,P¼4.4, CH3ipr.). MS (ESI): m/z (%)¼441 (100) [MþH]þ, 463.2 (35)
[MþNa]þ. HRMS (ESI) calcd for C20H30O7N2P [MþH]þ 441.1785,
found 441.1785.
4.1.2. 6-(2R)-{2-[(Diisopropoxyphosphoryl)methoxy]-3-hydrox-
ypropoxy}-4-hydroxy-2-methylsulfanylpyrimidine
(4b). 4,6-Dihy-
droxy-2-(methylsulfanyl)pyrimidine (3.55 g, 22.6 mmol) in DMSO
(50 mL) was treated with NaH (60% dispersion in mineral oil, 544 mg,
13.6 mmol) and the reaction mixture was heated at 60 ꢀC under
argon atmosphere for 30 min (R)-2-[(Diisopropoxyphosphoryl)
methoxy]-3-hydroxypropyl-1-p-toluenesulfonate (4.8 g, 11.3 mmol)
in DMSO (10 mL) was added dropwise (30 min) and the resulting
mixture was heated at 120 ꢀC for 48 h. The mixture was cooled to
room temperature, poured into ice cold water (100 mL) and the
product was extracted with CHCl3 (3ꢁ100 mL) and dried over
MgSO4. Flash chromatography afforded 4b as a colourless oil (2 g,
43%), Rf 0.36 (B). 1H NMR (CDCl3): 13.37 (br s, 1H, NH), 5.50 (s, 1H, H-
5), 4.71e4.84 (m, 2H, CHipr.), 4.33e4.39 (m, 2H, H-10), 4.06 (dd,
Jgem¼14.0, JH,C,P¼7.6,1H, PCHa), 3.80e3.88 (m, 3H, PCHb, H-20, H-30a),
4.2.4. 6-{2-[(Diisopropoxyphosphoryl)methoxy]ethoxy}-4-hydroxy-
2-(4-nitrophenyl)pyrimidine (5d). Yellowish solid (334 mg, 56%), Rf
0.45 (A). 1H NMR (500 MHz, DMSO-d6): 12.30 (br s, 1H, OH), 8.47
(m, 2H, H-200), 8.35 (m, 2H, H-300), 5.90 (br s, 1H, H-5), 4.58 (dh,
JH,C,O,P¼7.8, JCH,CH3¼6.2, 2H, CHipr.), 4.52 (m, 2H, H-10), 3.88 (m, 2H,
H-20), 3.82 (d, JH,C,P¼8.3, 2H, PCH2), 1.22 and 1.21 (2ꢁ d, JCH3,CH¼6.2,
6H, CH3ipr.). 13C NMR (125.8 MHz, DMSO-d6): 170.5 (C-4), 159.6 (C-
2), 149.2 (C-400), 141.5 (C-100), 129.3 (C-200), 123.9 (C-300), 89.3 (C-5),
0
0
0
3.68 (dd, Jgem¼12.3, J3 be2 ¼5.7, 1H, H-3 b), 2.56 (s, 3H, SCH3), 1.35 (d,
JCH3,CH¼6.1, 6H) and 1.33 (d, JCH3eCH¼6.0, 6H, CH3ipr.). 13C NMR
0
(CDCl3): 169.2 (C-6), 167.1 (C-4), 163.1 (C-2), 88.0 (C-5), 81.8 (d, J2 -
¼8.3, C-20), 71.9 (d, JCeOeP¼6.7) and 71.4 (d, JCeOeP¼6.9, CHipr.), 66.5
P
(C-10), 65.4 (d, JCeP¼169.0, PCH2), 61.7 (C-30), 23.8e24.1 (m, CH3ipr.),
13.2 (SCH3). MS (ESI): m/z (%)¼433.1 (100) [MþNa]þ. HRMS (ESI) for
C15H28O7N2PS calcd: 411.1349; found: 411.1350.
70.7 (d, J2 ,P¼11.9, C-20), 70.4 (d, JC,O,P¼6.3, CHipr.), 65.7 (C-10), 65.0
0
(d, JC,P¼164.3, PCH2), 24.0 (d, JC,P¼3.6) and 23.9 (d, JC,P¼4.4, CH3ipr.).
MS (ESI): m/z (%)¼456 (100) [MþH]þ, 478 (44) [MþNa]þ. HRMS
(ESI) calcd for C19H27O8N3P [MþH]þ 456.1530; found 456.1529.
4.2. LiebeskindeSrogl cross-coupling reaction. General
procedure
4.2.5. 6-{2-[(Diisopropoxyphosphoryl)methoxy]ethoxy}-4-hydroxy-
2-(4-trifluorophenyl)pyrimidine (5e). White solid (312 mg, 50%), Rf
0.56 (A). 1H NMR (500 MHz, DMSO-d6): 12.34 (br s, 1H, OH), 8.42
(m, 2H, H-200), 7.89 (m, 2H, H-300), 5.82 (br s, 1H, H-5), 4.58 (dh,
JH,C,O,P¼7.7, JCH,CH3¼6.2, 2H, CHipr.), 4.49 (m, 2H, H-10), 3.87 (m, 2H,
H-20), 3.82 (d, JH,C,P¼8.3, 2H, PCH2), 1.22 and 1.21 (2ꢁ d, JCH3,CH¼6.2,
2ꢁ 6H, CH3ipr.). 13C NMR (125.8 MHz, DMSO-d6): 170.3 (C-4), 159.0
A mixture of compound 4a or 4b (0.3 mmol), arylboronic acid
(1.75 equiv, 0.525 mmol), CuMeSal (2.2 equiv, 6.66 mmol, 141 mg)
and Pd(PPh3)4 (5%, 0.015 mmol, 17 mg) in dry THF under argon
atmosphere was heated at 60 ꢀC until complete absorption of the
starting material (TLC). The solvent was removed in vacuo and the
residue was dissolved in ethylacetate (50 mL) and washed with
saturated NaHCO3 (25 mL), saturated aqueous EDTA (25 mL) and
(C-2), 138.7 (C-100), 131.2 (q, J4 ,F¼31.7, C-400), 128.8 (C-200), 125.7
00
(q, J3 ,F¼3.8, C-300), 124.2 (q, JC,F¼272.3, CF3), 89.3 (C-5), 70.7 (d,
00

ꢀ
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P. Brehova et al. / Tetrahedron 67 (2011) 7379e7385
7383
J2 ,P¼11.9, C-20), 70.3 (d, JC,O,P¼6.4, CHipr.), 65.7 (C-10), 65.0 (d,
DMSO-d6): 12.33 (br s, 1H, OH), 8.48 (m, 2H, H-200), 8.36 (m, 2H,
H-300), 5.90 (br s, 1H, H-5), 4.88 (br s, 1H, OH-30), 4.54e4.61 (m,
0
JC,P¼164.4, PCH2), 24.0 (d, JC,P¼3.8) and 23.9 (d, JC,P¼4.5, CH3ipr.).
MS (ESI): m/z (%)¼479 (100) [MþH]þ, 501 (34) [MþNa]þ. HRMS
(ESI) calcd for C20H27O6N2F3P [MþH]þ 479.1553; found 479.1553.
3H, CHipr., H-10a), 4.38 (dd, Jgem¼11.4, J1 b,2 ¼5.9, 1H, H-1 b),
3.86e3.96 (m, 2H, PCH2), 3.80 (m, 1H, H-20), 3.55e3.62 (m, 2H, H-
30), 1.19e1.22 (m, 12H, CH3ipr.). 13C NMR (125.8 MHz, DMSO-d6):
170.6 (C-4), 149.2 (C-400), 141.2 (C-100), 129.3 (C-200), 123.9 (C-300),
0
0
0
4.2.6. 6-{2-[(Diisopropoxyphosphoryl)methoxy]ethoxy}-4-hydroxy-
2-(4-hydroxyphenyl)pyrimidine (5f). White solid (231 mg, 41%), Rf
0.24 (A). 1H NMR (500 MHz, DMSO-d6): 10.29 (br s, 1H, OH), 8.04
(m, 2H, H-200), 6.86 (m, 2H, H-300), 5.46 (br s, 1H, H-5), 4.58 (dh,
JH,C,O,P¼7.7, JCH,CH3¼6.2, 2H, CHipr.), 4.39 (m, 2H, H-10), 3.84 (m, 2H,
H-20), 3.80 (d, JH,C,P¼8.3, 2H, PCH2), 1.22 and 1.21 (2ꢁ d, JCH3,CH¼6.2,
2ꢁ 6H, CH3ipr.). 13C NMR (125.8 MHz, DMSO-d6): 169.7 (C-4), 161.3
(C-400),157.7 (C-2),130.1 (C-200),123.2 (C-100),115.7 (C-300), 88.3 (C-5),
89.4 (C-5), 80.3 (d, J2 ,P¼11.3, C-20), 70.3e70.4 (m, CHipr.), 66.0 (C-
0
10), 64.0 (d, JC,P¼164.7, PCH2), 59.9 (C-30), 23.83e24.01 (m,
CH3ipr.). MS (ESI): m/z (%)¼486.01 (100) [MþH]þ, 508.08 (89)
[MþNa]þ. HRMS (ESI) calcd for C20H29O9N3P [MþH]þ 486.16359;
found 486.16380.
4.2.11. 6-(2R)-{2-[(Diisopropoxyphosphoryl)methoxy]-3-
hydroxypropoxy}-4-hydroxy-2-(4-trifluorophenyl)pyrimidine
(6e). White solid (424 mg, 65%), Rf 0.47 (B). 1H NMR (600 MHz,
DMSO-d6): 12.36 (br s, 1H, OH), 8.42 (m, 2H, H-200), 7.89 (m, 2H, H-
300), 5.82 (br s, 1H, H-5), 4.88 (br s, 1H, OH-30), 4.54e4.60 (m, 3H,
70.3 (d, J2 ,P¼12.0, C-20), 70.6 (d, JC,O,P¼6.4, CHipr.), 65.8 (C-10), 65.1
0
(d, J¼164.4, PCH2), 24.1 (d, JC,P¼3.8) and 23.9 (d, JC,P¼4.5, CH3ipr.).
MS (ESI): m/z (%)¼427 (40) [MþH]þ, 449.1 (100) [MþNa]þ. HRMS
(ESI) calcd for C19H27N2O7P [MþH]þ 427.1629; found 427.1630.
0
CHipr, H-10a), 4.36 (dd, Jgem¼11.4, J1 b,2 ¼5.9, 1H, H-1 b), 3.86e3.95
(m, 2H, PCH2), 3.79 (m, 1H, H-20), 3.55e3.60 (m, 2H, H-30), 1.19e1.22
(m, 12H, CH3ipr.). 13C NMR (151 MHz, DMSO-d6): 170.5 (C-4), 159.2
0
0
4.2.7. 6-(2R)-{2-[(Diisopropoxyphosphoryl)methoxy]-3-
hydroxypropoxy}-4-hydroxy-2-phenylpyrimidine
(6a). Colourless
oil (75%), Rf 0.40 (B). 1H NMR (CDCl3): 13.23 (br s, 1H, OH), 8.23 (m,
2H, H-200), 7.52e7.61 (m, 3H, H-300, H-400), 5.74 (s, 1H, H-5),
4.70e4.83 (m, 2H, CHipr.), 4.43e4.49 (m, 2H, H-10), 4.09 (dd,
Jgem¼14.1, JH,P¼7.5,1H, PCHa), 3.91 (m, 1H, H-20), 3.86 (dd, Jgem¼14.1,
JH,P¼8.3, 1H, PCHb), 3.86 (m, 1H, H-30a), 3.73 (dd, Jgem¼12.3,
(C-2), 138.8 (C-100), 131.3 (q, J4 ,F¼31.8, H-400), 128.9 (C-200), 125.7 (q,
00
J3 ,F¼3.7, C-300), 124.3 (q, JC,F¼272.1, CF3), 89.3 (C-5), 80.3 (d,
00
J2 ,P¼11.5, C-20), 70.3e70.4 (m, CHipr.), 66.0 (C-10), 64.0 (d,
0
JC,P¼164.8, PCH2), 59.9 (C-30), 23.8e24.1 (m, CH3ipr.). MS (ESI): m/z
(%)¼507.2 (100) [MꢂH]ꢂ. HRMS (ESI) calcd for C21H27O7N2F3P
[MꢂH]ꢂ 507.15135; found 507.15079.
0
0
0
J3 b,2 ¼6.0, 1H, H-3 b), 1.34 (d, 6H) and 1.33 (d, JCH3,CH¼6.2, 6H,
CH3ipr.). 13C NMR (CDCl3): 170.0 (C-6), 167.0 (C-4), 157.2 (C-2), 132.5
(C-400), 131.3 (C-100), 128.9 (C-300), 127.9 (C-200), 90.8 (C-5), 81.9 (d,
4.2.12. 6-(2R)-{2-[(Diisopropoxyphosphoryl)methoxy]-3-
hydroxypropoxy}-4-hydroxy-2-(4-hydroxyphenyl)pyrimidine
(6f). White solid (369 mg, 63%), Rf 0.28 (B). 1H NMR (500 MHz,
DMSO-d6): 12.26 and 10.29 (2ꢁ br s, 2ꢁ OH), 8.05 (m, 2H, H-200),
6.86 (m, 2H, H-300), 5.46 (br s, 1H, H-5), 4.85 (br s, 1H, OH-30),
J2 ,P¼8.2, C-20), 71.9 (d, JC,P¼6.6) and 71.4 (d, JC,P¼6.8, CHipr.), 65.5
0
(C-10), 65.4 (d, JC,P¼168.9, PCH2), 61.8 (C-30), 23.9e24.1 (m, CH3ipr.).
MS (ESI): m/z (%)¼441.1 (15) [MþH]þ; 463.2 (100) [MþNa]þ. HRMS
(ESI) for C20H29O7N2NaP calcd: 463.1605; found 463.1603.
0
0
0
4.55e4.62 (m, 2H, CHipr.), 44.4 (dd, Jgem¼11.4, J1 a,2 ¼3.7, 1H, H-1 a),
0
0
0
4.2.8. 6-(2R)-{2-[(Diisopropoxyphosphoryl)methoxy]-3-
hydroxypropoxy}-4-hydroxy-2-(4-fluorophenyl)pyrimidine
(6b). White solid (319 mg, 54%), Rf 0.40 (B). 1H NMR (500 MHz,
DMSO-d6): 12.33 (br s, 1H, OH), 8.26 (m, 2H, H-200), 7.36 (m, 2H, H-
300), 5.66 (br s, 1H, H-5), 4.85 (br s, 1H, OH-30), 4.55e4.62 (m, 2H,
4.26 (dd, Jgem¼11.4, J1 b,2 ¼5.8, 1H, H-1 b), 3.87e3.95 (m, 2H, PCH2),
3.76 (m, 1H, H-20), 3.54e3.58 (m, 2H, H-30), 1.20e1.24 (m, 12H,
CH3ipr.). 13C NMR (125.8 MHz, DMSO-d6): 169.7 (C-4), 161.3 (C-400),
158.5 (C-2), 130.1 (C-200), 123.0 (C-100), 115.6 (C-300), 88.2 (C-5), 80.4
(d, J2 ,P¼11.4, C-20), 70.4e70.5 (m, CHipr.), 66.0 (C-10), 64.0 (d,
0
CHipr.), 4.50 (dd, Jgem¼11.4, J1 a,2 ¼3.4, 1H, H-10a), 4.31 (dd,
JC,P¼164.6, PCH2), 60.0 (C-30), 23.8e24.0 (m, CH3ipr.). MS (ESI): m/z
(%)¼455.2 (100) [MꢂH]ꢂ. HRMS (ESI) calcd for C20H29N2O8P
[MꢂH]ꢂ 455.1589; found 455.1587.
0
0
0
0
0
Jgem¼11.4, J1 b, 2 ¼5.9, 1H, H-1 b), 3.86e3.95 (m, 2H, PCH2), 3.78 (m,
1H, H-20), 3.54e3.60 (m, 2H, H-30), 1.20e1.23 (m, 12H, CH3ipr.). 13C
00
NMR (125.8 MHz, DMSO-d6): 170.0 (C-4), 164.4 (d, J4 ,F¼249.7, C-
400), 130.7 (d, J2 ,F¼9.1, C-200), 130.3 (C-100), 115.9 (d, J3 ,F¼21.9, C-300),
4.3. Deprotection of diisopropyl esters 5 and 6 to free
phosphonic acids 7 and 8. General procedure
00
00
88.8 (C-5), 80.3 (d, J2 ,P¼11.5, C-20), 70.3e70.4 (m, CHipr.), 66.1 (C-
0
10), 64.0 (d, JC,P¼165.0, PCH2), 59.9 (C-30), 23.8e24.0 (CH3ipr.). MS
(ESI): m/z (%)¼459 (98) [MþH]þ, 481 (100) [MþNa]þ. HRMS (ESI)
calcd for C20H29O7N2FP [MþH]þ 459.16909; found 459.16920.
Diisopropyl ester 5 or 6 (0.5 mmol) in CH3CN (20 mL) was
treated with Me3SiBr (2 mL) at room temperature overnight. Vol-
atiles were evaporated under reduced pressure and the residue was
codistilled with water. The crude product was purified by pre-
parative HPLC (linear gradient 20e100% of aqueous MeOH) or on
Dowex 1ꢁ 2 (acetate form): after application of the aqueous solu-
tion of the crude product, alkalized by several drops of aqueous
ammonia onto the column, it was washed with water until the UV
absorption dropped. The column was then eluted with a 0.5 M of
dilute acetic and subsequently with formic acid (1 M). The UV ab-
sorbing eluate was evaporated and the residue was evaporated
several times codistilled with water to remove the formic acid and
crystallized.
4.2.9. 6-(2R)-{2-[(Diisopropoxyphosphoryl)methoxy]-3-
hydroxypropoxy}-4-hydroxy-2-(4-methoxy)pyrimidine (6c). White
solid (363 mg, 60%), Rf 0.45 (B). 1H NMR (600 MHz, DMSO-d6): 12.35
(br s, 1H, OH), 8.16 (m, 2H, H-200), 7.06 (m, 2H, H-300), 5.52 (br s, 1H,
H-5), 4.86 (br s, 1H, OH-30),0 4.55e4.63 (m, 2H, CHipr.), 4.46 (dd,
0
0
0
0
Jgem¼11.4, J1 a,2 ¼3.6, 1H, H-1 a), 4.27 (dd, Jgem¼11.4, J1 b,2 ¼6.0, 1H,
H-10b), 3.88e3.95 (m, 2H, PCH2), 3.83 (s, 3H, OCH3), 3.77 (m, 1H, H-
20), 3.54e3.59 (m, 2H, H-30), 1.20e1.23 (m, 12H, CH3ipr.). 13C NMR
(151 MHz, DMSO-d6): 169.8 (C-4),162.5 (C-400),157.8 (C-2),129.9 (C-
200), 125.1 (C-100), 114.3 (C-300), 88.5 (C-5), 80.4 (d, J2 ,P¼11.4, C-20),
0
70.4e70.45 (m, CHipr.), 66.1 (C-10), 64.0 (d, JC,P¼164.6, PCH2), 60.0
(C-30), 55.7 (OCH3), 23.9e24.1 (m, CH3ipr.). MS (ESI): m/z (%)¼471.1
(100) [MþH]þ, 493.1 (96) [MþNa]þ. HRMS (ESI) calcd for
C21H32O8N2P [MþH]þ 471.1891; found 471.1893.
4.3.1. 4-Hydroxy-2-phenyl-6-[2-(phosphonomethoxy)ethoxy]pyrimi-
dine (7a). White solid (125 mg, 79%), mp 236e238 ꢀC (recryst from
H2O/EtOH); IR (KBr): 3300 (NH), 2700, 2300 (PeOH), 3080, 3038
(]CH), 1677, 1660 (C]O), 1611, 1595, 1502, 1444 (ring). 1H NMR
(DMSO-d6): 8.17 (m, 2H) and 7.50e7.58 (m, 3H, Ph), 5.66 (s, 1H, H-
5), 4.39 (m, 2H, H-10), 3.85 (m, 2H, H-20), 3.63 (d, J¼8.7, 2H, PCH2).
13C NMR (DMSO-d6): 169.9 (C-4), 166.6 (C-6), 158.7 (C-2), 133.2
4.2.10. 6-(2R)-{2-[(Diisopropoxyphosphoryl)methoxy]-3-
hydroxypropoxy}-4-hydroxy-2-(4-nitrophenyl)pyrimidine
(6d). White solid (255 mg, 41%), Rf 0.40 (B). 1H NMR (500 MHz,

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P. Brehova et al. / Tetrahedron 67 (2011) 7379e7385
7384
(C-100), 132.0 (C-400), 128.9 (C-300), 128.1 (C-200), 89.0 (C-5), 70.6 (d,
0
(%)¼325 (48) [MꢂH]ꢂ, 347 [Mꢂ2HþNa]ꢂ. HRMS (ESI) for
C13H14O6N2P calcd: 325.0595; found 325.0595. For C13H15N2O6P
(326.07) calcd: C 47.86, H 4.63, N 8.59, P 9.49; found: C 47.72, H
4.63, N 8.51, P 9.44.
(ESI): m/z (%)¼341.1 (100) [MꢂH]ꢂ. HRMS (ESIꢂ) for C13H14N2O7P
J2 ,P¼11.1, C-20), 66.9 (d, JC,P¼160.0, PCH2), 66.2 (C-10). MS (ESI): m/z
calcd: 341.0544; found 341.0545.
4.3.7. 4-Hydroxy-2-phenyl-6-(2R)-[2-(phosphonomethoxy)-3-
hydroxypropoxy]pyrimidine (8a). Freeze dried, white solid (139 mg,
66%), mp 105e109 ꢀC (recryst from H2O); IR (KBr): 3421, 3287 (NH,
OH), 2800e2000 (PeOH), 3071 (]CH), 1654 (C]O), 1605, 1595,
1502, 1446 (ring). 1H NMR (D2O): 7.76 (m, 2H) and 7.59 (m, 1H) and
4.3.2. 4-Hydroxy-2-(4-fluorophenyl)-6-[2-(phosphonomethoxy)eth-
oxy]pyrimidine (7b). White solid (434 mg, 77%), mp 225e227 ꢀC
(recryst from H2O/EtOH); IR (KBr): 3285 (NH), 2800e2000 (PeOH),
3083, 3050 (]CH), 1653, 1578 (C]O), 1616, 1513, 1406, 1327 (ring).
1H NMR (DMSO-d6): 8.25 (m, 2H) and 7.35 (m, 2H, Ph), 5.69 (s, 1H,
H-5), 4.40 (m, 2H, H-10), 3.85 (m, 2H, H-20), 3.63 (d, J¼8.7, 2H, PCH2).
0
0
7.48 (m, 2H, Ph), 5.64 (s, 1H, H-5), 4.28 (dd, J1 a,2 ¼4.1, Jgem¼11.0, 1H,
H-10a), 4.21 (dd, J1 be2 ¼5.5, Jgem¼11.0, 1H, H-10b), 3.77e4.00 (m, 5H,
H-20, H-30, PCH2). 13C NMR (D2O): 171.3 (C-4), 168.1 (C-6), 158.9 (C-
2), 133.9 (C-400), 131.3 (C-100), 130.1 (C-300), 128.7 (C-200), 90.3 (C-5),
0
0
81.1 (d, J2 ,P¼11.58, C-20), 67.9 (C-10), 66.3 (d, JC,P¼139.9, PCH2), 61.4
0
13C NMR (DMSO-d6): 170.0 (C-4), 167.1 (C-6), 164.5 (d, J4 ,F¼249.8,
(C-30). MS (ESI): m/z (%)¼355.1 (100) [MꢂH]ꢂ. HRMS (ESIꢂ) for
00
C-400), 158.2 (C-2), 130.7 (d, J2 ,F¼9.1, C-200), 130.2 (C-100), 115.9 (d,
C14H16N2O7P calcd: 355.0701; found 355.0700. ½a D25
ꢂ5.0 (c 0.141,
ꢃ
00
J3 ,F¼22.0, C-300), 88.8 (C-5), 70.6 (d, J2 ,P¼11.3, C-20), 66.9 (d,
JC,P¼160.8, PCH2), 66.2 (C-10). MS (ESI): m/z (%)¼343.1 (100)
[MꢂH]ꢂ. HRMS (ESIꢂ) for C13H13N2O6FP calcd: 343.0501; found
343.0502.
DMSO).
00
0
4.3.8. 4-Hydroxy-2-(4-fluorophenyl)-6-(2R)-[2-(phosphonome-
thoxy)-3-hydroxypropoxy]pyrimidine (8b). White solid (186 mg,
76%), mp 196e197 ꢀC (recryst from H2O); IR (KBr): 3557 (OH), 3459,
3417, 3150, (NH, OH), 2800e2000 (PeOH), 1651, 1566 (C]O), 1608,
1511, 1403, 1324 (ring). 1H NMR (DMSO-d6): 8.26 (m, 2H, H-200), 7.35
4.3.3. 4-Hydroxy-2-(4-methoxyphenyl)-6-[2-(phosphonomethoxy)
ethoxy]pyrimidine (7c). White solid (145 mg, 61%), mp 142e144 ꢀC
(recryst from H2O/EtOH); IR (KBr): 3436, 3279 (NH), 2848 (CH3),
1655, 1627 (C]O), 1605, 1593, 1518, 1411 (ring). 1H NMR (DMSO-
d6): 8.15 (m, 2H, H-200), 7.06 (m, 2H, H-300), 5.55 (s, 1H, H-5), 4.64 (m,
2H, H-10), 3.84 (m, 2H, H-20), 3.84 (s, 3H, CH3), 3.62 (d, JP,C¼8.7, 2H,
PCH2). 13C NMR (DMSO-d6): 169.7 (C-4), 166.0 (C-6), 162.5 (C-400),
157.8 (C-2), 129.9 (C-200), 124.9 (C-100), 114.3 (C-300), 88.4 (C-5), 70.6
(m, 2H, H-300), 5.68 (s, 1H, H-5), 4.41 (dd, 1H, Jgem¼11.3, J1 a,2 ¼4.1,
0
0
1H, H-10a), 4.30 (dd, 1H, Jgem¼11.2, J1 be2 ¼5.6, 2H, H-10b),
0
0
3.68e3.78 (m, 3H, CH2P, H-20), 3.54e3.59 (m, 2H, H-30). 13C NMR
(DMSO-d6): 170.0 (C-4), 167.1 (C-6), 164.4 (d, J4 ,F¼249.6, C-400),
00
158.3 (C-2), 130.7 (d, J2 ,F¼9.0, C-200), 130.3 (C-100), 115.9 (d,
00
J3 ,F¼21.9, C-300), 88.8 (C-5), 80.3 (d, J2 ,P¼9.6, C-20), 66.3 (C-10), 66.0
(d, JC,P¼160.4, PCH2), 60.2 (C-30). MS (ESI): m/z (%)¼373.2 (100)
[MꢂH]ꢂ. HRMS (ESIꢂ) for C14H15N2O7FP calcd: 373.0606; found
00
0
(d, J2 ,P¼11.2, C-20), 66.9 (d, JC,P¼160.5, PCH2), 66.1 (C-10), 55.7 (CH3).
0
MS (ESI): m/z (%)¼355.1 (100) [MꢂH]ꢂ. HRMS (ESIꢂ) for
C14H16N2O7P calcd: 355.0701; found 355.0702.
373.0607. ½a 2D5
ꢂ1.1 (c 0.234, DMSO).
ꢃ
4.3.4. 4-Hydroxy-2-(4-nitrophenyl)-6-[2-(phosphonomethoxy)eth-
oxy]pyrimidine (7d). Pale orange solid (185 mg, 77%), mp
224e226 ꢀC (recryst from H2O/EtOH); IR (KBr): 3240, 3100, 3000
(NH), 2800e2000, (PeOH), 1668, (C]O), 1522, 1354, 1345 (eNO2),
1582, 1554, 1433, 1392 (ring). 1H NMR (DMSO-d6): 8.43 (m, 2H, H-
200), 8.31 (m, 2H, H-300), 5.92 (s, 1H, H-5), 4.44 (m, 2H, H-10), 3.86 (m,
2H, H-20), 3.59 (d, J¼9.0, 2H, PCH2). 13C NMR (DMSO-d6): 170.5 (C-
4), 169.5 (C-6), 159.1 (C-2), 149.1 (C-400), 141.2 (C-100), 129.3 (C-200),
4.3.9. 4-Hydroxy-2-(4-methoxyphenyl)-6-(2R)-[2-(phosphonome-
thoxy)-3-hydroxypropoxy]pyrimidine (8c). White solid (220 mg,
81%), mp 197e199 ꢀC (recryst from H2O/EtOH); IR (KBr): 3516 (OH),
3419, 3220 (NH, OH), 2843 (CH3), 1640, 1561 (C]O), 1609, 1592,
1517, 1411 (ring). 1H NMR (DMSO-d6): 8.16 (m, 2H, H-200), 7.06 (m,
2H, H-300), 5.54 (s, 1H, H-5), 4.39 (dd,1H, Jgem¼11.2, J1 a,2 ¼4.2,1H, H-
0
0
0
10a), 4.27 (dd, 1H, Jgem¼11.2, J1 b,2 ¼5.6, 1H, H-1 b), 3.83 (s, 3H,
0
0
OCH3), 3.69e3.78 (m, 3H, CH2P, H-20), 3.56 (d, 2H, J3 ,2 ¼5.3 H-3 ).
13C NMR (DMSO-d6): 169.8 (C-4), 166.1 (C-6), 162.5 (C-400), 157.8 (C-
2), 129.9 (C-200), 125.0 (C-100), 114.3 (C-300), 88.5 (C-5), 80.4 (d,
0
0
0
123.9 (C-300), 89.3 (C-5), 70.3 (d, J2 ,P¼10.0, C-20), 67.5 (d, JC,P¼162.5,
0
PCH2), 66.2 (C-10). MS (ESI): m/z (%)¼370.1 (100) [MꢂH]ꢂ. HRMS
(ESIꢂ) for C13H13N3O8P calcd: 370.0446; found 370.0445.
J2 ,P¼9.8, C-20), 66.3 (C-10), 65.9 (d, JC,P¼160.9, PCH2), 60.2 (C-30),
0
55.7 (OCH3). MS (ESI): m/z (%)¼385.2 (100) [MꢂH]ꢂ. HRMS (ESIꢂ)
4.3.5. 4-Hydroxy-2-(4-trifluorophenyl)-6-[2-(phosphonomethoxy)
ethoxy]pyrimidine (7e). White solid (191 mg, 82%), mp 236e238 ꢀC
(recryst from H2O); IR (KBr): 3427, 3240, 3063 (NH, OH),
2800e2000, (PeOH),1683,1662 (C]O),1602,1520,1403,1268, 852
(ring). 1H NMR (DMSO-d6): 8.40 (m, 2H, H-200), 7.87 (m, 2H, H-300),
5.84 (s, 1H, H-5), 4.44 (m, 2H, H-10), 3.86 (m, 2H, H-20), 3.63 (m, 2H,
PCH2). 13C NMR (DMSO-d6): 170.3 (C-4), 168.4 (C-6), 159.0 (C-2),
for C15H18N2O8P calcd: 385.0806; found 385.0806. ½a D25
ꢂ3.3 (c
ꢃ
0.275, DMSO).
4.3.10. 4-Hydroxy-2-(4-nitrophenyl)-6-(2R)-[2-(phosphonome-
thoxy)-3-hydroxypropoxy]pyrimidine (8d). White solid (130 mg,
71%), dec 237 ꢀC (recryst from H2O/EtOH); IR (KBr): 3433, 3252 (NH,
OH), 1670, 1650 (C]O), 1524, 1350 (eNO2), 1615, 1501, 1400, 1110
(ring). 1H NMR (DMSO-d6): 8.48 (m, 2H, H-200), 7.35 (m, 2H, H-300),
138.5 (C-100), 131.3 (q, J4 ,F¼31.9, C-400), 128.9 (C-200), 125.7 (q,
00
J3 ,F¼3.8, C-300), 124.2 (q, JC,F¼272.4, CF3), 89.3 (C-5), 70.5 (d,
5.93 (s, 1H, H-5), 4.49 (dd, 1H, Jgem¼11.2, J1 a,2 ¼4.2, 1H, H-1 a), 4.38
0
00
0
0
J2 ,P¼10.1, C-20), 67.0 (d, JC,P¼165.4, PCH2), 66.2 (C-10). MS (ESI): m/z
(dd, 1H, Jgem¼11.2, J1 b,2 ¼5.6, 1H, H-1 b), 3.70e3.81 (m, 3H, CH2P, H-
20), 3.55e3.61 (m, 2H, H-30). 13C NMR (DMSO-d6): 170.6 (C-4), 169.4
(C-6), 159.2 (C-2), 149.2 (C-400), 141.2 (C-100), 129.4 (C-200), 123.9
0
0
0
0
(%)¼393.1 (100) [MꢂH]ꢂ. HRMS (ESIꢂ) for C14H13N2O6F3P calcd:
393.0469; found 393.0468.
(C-300), 89.4 (C-5), 80.3 (d, J2 ,P¼9.7, C-20), 66.3 (C-10), 65.9 (d,
0
4.3.6. 4-Hydroxy-2-(4-hydroxyphenyl)-6-[2-(phosphonomethoxy)
ethoxy]pyrimidine (7f). White solid (135 mg, 79%), mp 156e158 ꢀC
(recryst from H2O); IR (KBr): 3492, 3432, 3102 (NH, OH),
2800e2000, (PeOH), 1565, 1439 (C]O), 1611, 1595, 1518, 1419
(ring). 1H NMR (DMSO-d6): 8.05 (m, 2H, H-200), 6.86 (m, 2H, H-300),
5.49 (s, 1H, H-5), 4.35 (m, 2H, H-10), 3.83 (m, 2H, H-20), 3.62 (d,
J¼8.7, 2H, PCH2). 13C NMR (DMSO-d6): 169.7 (C-4), 165.7 (C-6), 161.3
(C-400), 157.7 (C-2), 130.1 (C-200), 123.1 (C-100), 115.6 (C-300), 88.1 (C-5),
JC,P¼160.6, PCH2), 60.1 (C-30). MS (ESI): m/z (%)¼400.1 (100)
[MꢂH]ꢂ. HRMS (ESIꢂ) for C14H15N3O9P calcd: 400.0551; found
400.0551. ½a 2D5
ꢂ1.5 (c 0.374, DMSO).
ꢃ
4.3.11. 4-Hydroxy-2-(4-trifluorophenyl)-6-(2R)-[2-(phosphonome-
thoxy)-3-hydroxypropoxy]pyrimidine (8e). White solid (297 mg,
90%), mp 158e159 ꢀC (recryst from H2O/EtOH); IR (KBr): 3386,
3230, 3080 (NH, OH, H2O), 2800e2000, (PeOH), 1672 (C]O), 1601,
1572, 1595, 1520, 1404 (ring). 1H NMR (DMSO-d6): 8.41 (m, 2H,
70.7 (d, J2 ,P¼11.3, C-20), 66.9 (d, JC,P¼160.5, PCH2), 66.1 (C-10). MS
0

ꢀ
ꢁ
P. Brehova et al. / Tetrahedron 67 (2011) 7379e7385
7385
H-200), 7.88 (m, 2H, H-300), 5.84 (s, 1H, H-5), 4.46 (dd, 1H, Jgem¼11.1,
spectra, the staff of the mass spectroscopy (Dr. J. Cvacka, Head) and
ꢀ
0
0
0
0
0
0
ꢀ
ꢁ
J1 a,2 ¼4.1, 2H, H-1 a), 4.35 (dd, 1H, Jgem¼11.2, J1 b,2 ¼5.6, 2H, H-1 b),
analytical departments (Dr. S. Matejkova, Head) of the Institute.
13
3.70e3.79 (m, 3H, CH2P, H-20), 3.55e3.60 (m, 2H, H-30). C NMR
(DMSO-d6): 170.4 (C-4), 168.5 (C-6), 159.0 (C-2), 138.6 (C-100), 131.3
Supplementary data
(q, J4 ,F¼31.8, C-400), 128.9 (C-200), 125.8 (q, J3 ,F¼3.7, C-300), 124.3 (q,
00
00
JC,F¼272.3, CF3), 89.4 (C-5), 80.3 (d, J2 ,P¼9.7, C-20), 66.3 (C-10), 66.0
0
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.07.040. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
(d, JC,P¼161.2, PCH2), 60.1 (C-30). MS (ESI): m/z (%)¼423.1 (100)
[MꢂH]ꢂ. HRMS (ESIꢂ) for C15H15N2O7F3P calcd: 423.0575; found
423.0573. ½a 2D5
ꢂ1.1 (c 0.242, DMSO).
ꢃ
4.3.12. 4-Hydroxy-2-(4-hydroxyphenyl)-6-(2R)-[2-(phosphonome-
thoxy)-3-hydroxypropoxy]pyrimidine (8f). Pale orange solid
(216 mg, 76%), mp 121e122 ꢀC (recryst from H2O/EtOH); IR (KBr):
3386, 3104 (NH, OH), 2800e2000, (PeOH), 1695, 1648 (C]O), 1610,
1596, 1518, 1420, 1320 (ring). 1H NMR (DMSO-d6): 8.05 (m, 2H, H-
200), 6.88 (m, 2H, H-300), 5.49 (s, 1H, H-5), 4.37 (dd, 1H, Jgem¼11.2,
References and notes
ꢁ
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ꢁ
2. Holy, A. Curr. Pharm. Des. 2003, 9, 2567.
ꢁ
ꢁ
3. (a) Holy, A.; Votruba, I.; Masojídkova, M.; Andrei, G.; Snoeck, R.; Naesens, L.; De
ꢁ
ꢁ
Clercq, E.; Balzarini, J. J. Med. Chem. 2002, 45, 1918; (b) Hockova, D.; Holy, A.;
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Masojídkova, M.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem.
0
0
0
0
0
0
J1 ae2 ¼4.2, 2H, H-1 a), 4.25 (dd, 1H, Jgem¼11.2, J1 b,2 ¼5.6, 02H, H-1 b),
2003, 46, 5064.
3.69e3.78 (m, 2H, CH2P, H-20), 3.56 (d, 2H, J3 ,2 ¼5.3, H-3 ). 13C NMR
ꢁ
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Agents Chemother. 2005, 49, 1177.
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(DMSO-d6): 169.8 (C-4), 165.8 (C-6), 161.4 (C-400), 157.8 (C-2), 130.1
ꢁ
(C-200), 123.0 (C-100), 115.7 (C-300), 88.2 (C-5), 80.3 (d, J2 ,P¼10.0, C-20),
0
66.3 (C-10), 65.8 (d, JC,P¼160.6, PCH2), 60.2 (C-30). MS (ESI): m/z (%)¼
ꢀꢁ
ꢁ
6. (a) Hocek, M. Eur. J. Org. Chem. 2003, 2, 245; (b) Hocek, M.; Dvorakova, H. J. Org.
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371.2 (100) [MꢂH]ꢂ. HRMS (ESIꢂ) for C14H16N2O8P calcd: 371.0650;
ꢁ
ꢁ
ꢁ
7. Hockova, D.; Masojídkova, M.; Holy, A. Collect. Czech. Chem. Commun. 2005, 70,
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ꢂ1.3 (c 0.285, DMSO).
ꢃ
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Acknowledgements
This study was performed as
OZ40550506 of the Institute of Organic Chemistry and Bio-
chemistry. It was supported by Centre for new antivirals and anti-
neoplastics 1M0508 by the Ministry of Education, Youth and Sports
of the Czech Republic, and by Gilead Sciences and IOCB Research
Centre. The authors’ thanks are due to Dr. P. Fiedler for the IR
a
part of research project
12. Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweitzer, B.; Srogl, J.;
Neumann, W. L. Org. Lett. 2003, 5, 4349.
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