Microwave-assisted silylation-amination of uracil acyclonucleosides to 4-alkylamino-2(1H)-pyrimidinone analogues

Article abstract of DOI:10.1055/s-2008-1067094

The synthesis of acyclic N⁴-substituted cytosine nucleoside phosphonates using a microwave-assisted N⁴-silylation-amina-tion and olefin cross-metathesis as key assembly steps is described. The microwave-assisted silylation-amination is compared to a conventional heating protocol. While yields and purities of the coupling products were comparable under both conditions, microwave.heat-ing allows a significant acceleration of the reaction (from 48 h to 5 h). Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1067094

PAPER
2127
Microwave-Assisted Silylation-Amination of Uracil Acyclonucleosides to
4-Alkylamino-2(1H)-Pyrimidinone Analogues
M
icrowave-Assist
i
e
d
Silyl
n
ation-Amina
c
tion of
U
ra
e
cils nt Roy,a Adam Mieczkowski,a Dimitri Topalis,b Sabine Berteina-Raboin,b Dominique Deville-Bonne,b
Steven P. Nolan,c Luigi A. Agrofoglio*a
a
Institut de Chimie Organique et Analytique, UMR 6005, Université d’Orléans, 45067 Orléans, France
Fax +33(2)38417281; E-mail: luigi.agrofoglio@univ-orleans.fr
Laboratoire d’Enzymologie Moléculaire et Fonctionnelle, FRE CNRS 2852, Université Pierre & Marie Curie,
b
4 place Jussieu, 75005 Paris, France
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
c
Received 10 March 2008; revised 28 March 2008
methods needed an activation of the 4-carbonyl moiety in
1 [mainly by heating with P2S5,7 by tris-(1,2,4-triaz-
olyl)phosphate,8 as o-nitrophenol derivative,9 with
SOCl2,10 or 2,4,6-triisopropylbenzensulfonic chloride11]
Abstract: The synthesis of acyclic N4-substituted cytosine nucleo-
side phosphonates using a microwave-assisted N4-silylation-amina-
tion and olefin cross-metathesis as key assembly steps is described.
The microwave-assisted silylation-amination is compared to a con-
ventional heating protocol. While yields and purities of the coupling and then subsequent treatment with ammonia, primary, or
secondary amine to give the desired N4-modified cytosine
products were comparable under both conditions, microwave heat-
ing allows a significant acceleration of the reaction (from 48 h to 5
h).
analogues 2.
To circumvent these number of steps, we decided to ex-
Key words: microwaves, silylation-amination, olefin cross-
plore the one-pot silylation-amination12 under microwave
metathesis, acyclic nucleoside phosphonates
activation.13 Thus, when N1-crotyluracil (1) was reacted
with various amines in hexamethyldisilazane (HMDS) in
the presence of 2-picoline and a catalytic amount of
chlorotrimethylsilane under microwave heating, the
desired 4-alkylamino-2(1H)-pyrimidinone derivatives
2a–g (Scheme 1) were obtained after 5 hours.
Pyrimidine modified nucleosides and nucleotides are of
importance because several of them have been found to
exhibit anticancer and antiviral activities.1 Considerable
attention has been paid not only to the synthesis of 5-sub-
stituted uracil and cytosine analogues, which are known
H
R
N
O
N
N
N
as antiviral tools against herpes simplex virus (HSV), va-
ricella-zoster-virus (VZV), and human immunodeficiency
virus (HIV),2 but also on N4-substituted derivatives of cy-
tosine.3 It has been shown previously that alkylation of the
exocyclic amino function of cytosine nucleosides has a
marked decrease of the susceptibility of such compounds
to deamination by bacterial deaminases.4
NH
R-NH2
O
microwave
or
classical heating
O
2a–g
1
More recently, and because of their high therapeutic po-
tential, the acyclic nucleoside phosphonates (ANP),5 in-
cluding N4-substituted cytosine analogues6 have proven to
be a cornerstone of antiviral therapy and have triggered
numerous developments in the modification of both the
heterocyclic base and the sugar moiety. These findings
prompted us to prepare, as part of our drug discovery pro-
gram, the hitherto unknown N4-substituted derivatives of
cytosine ANP as potential therapeutic agents and/or
deaminase inhibitors.
We decided to perform the syntheses of N4-substituted cy-
tosine nucleosides starting from the N1-crotyluracil (1).
Several methods have been reported for the conversion of
uracil into cytosine analogues, but they suffer for some
limitations including the number of steps and the protec-
tion of some functional groups. In fact, at first all these
Scheme 1 Reagents and conditions: 1, RNH2 (2 equiv), 2-picoline
(2.7 equiv), HMDS (3 equiv), TMSCl (0.1 equiv), 140 °C, reflux, 48
h (conventional) or 140 °C, 5 h (microwave heating).
While yields and purities of the coupling products were
comparable under heating or microwave conditions,
microwave heating allows a significant reduction of the
reaction time from 48 hours to 5 hours (Table 1).
Finally, the introduction of the phosphonate moiety on
2a–g was performed using cross-coupling olefin
metathesis14 according to the general model for selectivity
reported by Grubbs et al.15 A first attempt to run a cross-
coupling metathesis on unprotected 2a failed; this is main-
ly due to the unprotected secondary amine at C-4.16 Thus,
2a–g were protected with di-tert-butyl dicarbonate as the
Boc derivatives 3a–g in 86–97% yields (Scheme 2). Com-
pounds 3a–g were then converted into the corresponding
phosphonate derivatives 4a–g by cross-coupling metathe-
sis with 4 equivalents of dimethyl allylphosphonate in an-
hydrous dichloromethane and 5 mol% of the second-
SYNTHESIS 2008, No. 13, pp 2127–2133
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1067094; Art ID: Z06208SS
© Georg Thieme Verlag Stuttgart · New York

2128
V. Roy et al.
PAPER
Table 1 Comparison of Microwave and Standard Heating
H2O/CH2Cl2 (Scheme 2). The coupling constants of the
olefinic protons and phosphine oxide are in agreement
with the E-isomer.
Product Amine
Conventional Microwave
(48 h, reflux) (5 h, 140 °C)
In summary, we have demonstrated that controlled micro-
wave heating is an efficient tool in accelerating the silyla-
tion-amination for the synthesis of various N4-alkyl-
amino-2(1H)-pyrimidinones. Microwave heating reduces
the reaction time from 48 hours to a few hours, making
this method suitable for the production of compound li-
braries. Using microwave heating methodology and olefin
cross-metathesis, we have prepared several N4-alkylated
cytosine ANPs.
Yield (%)
Conv (%)
Yield (%)
75
2a
72
>90
NH2
Cl
2b
65
100
74
NH2
NH2
F
2c
44
46
100
>90
75
69
Commercially available chemicals were reagent grade and used as
received. THF was distilled from Na/benzophenone ketyl; CH2Cl2
from CaH2 immediately prior use and benzene over Na. The micro-
wave generator was a Biotage AB Initiator EXP EU with a maxi-
mum power of 300 W. The vials used in the microwave experiments
were EmrysTM process vials 0.5–2 mL. The reactions were moni-
tored by TLC analysis using silica gel plates (Kieselgel 60 F254, E.
Merck). Column chromatography was performed on silica gel 60 M
(0.040–0.063 mm, E. Merck). Melting points are uncorrected and
were measured on a Kofler apparatus. The 1H and 13C NMR spectra
were recorded on a Bruker Avance DPX 250 and Varian Inova Uni-
ty 400 spectrometer (1H: 250 MHz, 13C: 100 MHz) in CD3OD and
CDCl3 and the chemical shifts were reported in ppm relative to
SiMe4 as internal reference. The 31P spectra were recorded using
aqueous phosphoric acid as external reference (31P: 161.97 MHz) in
CD3OD, unless otherwise stated. All J values are in Hz. Evidence
of purity was done from a proton-decoupled 13C NMR spectrum
with a signal-to-noise ratio sufficient to permit seeing peak with 5%
of the intensity of the strongest peak.
2d
2e
NH2
NH2
62
65
>90
100
67
50
( )3
( )4
( )8
2f
NH2
NH2
2g
38
100
56
generation [Ru] catalyst 7.17 The desired cross-metathesis
products were obtained as a mixture of E/Z isomers
(95:5), separable by column chromatography on silica gel.
The E-isomers 4a–g were obtained in moderate yields
(46–67%).
The removal of the Boc protecting group from 4a–g (E-
isomers) was achieved using trifluoroacetic acid in
CH2Cl2. After 90 minutes, the solvent was removed and
the crude residue purified to give compounds 5a–g, re-
1-But-2-enyluracil (1)
A DMF (30 mL) solution of N3-benzoyluracil (2.19 g, 10.1 mmol)
spectively, in excellent yields. Finally, treatment of 5a–g was stirred at r.t. K2CO3 (2.1 g, 15.1 mmol) and crotyl bromide
(1.55 mL, 15.15 mmol) was added to the above solution. The sus-
with a solution of TMSBr in MeCN led to the free phos-
pension was stirred for 1 h at r.t. under positive pressure of dry ar-
gon. After extraction with EtOAc (3 × 40 mL), aq sat. NH4Cl (30
phonates 6a–g in quantitative yield after extraction in
Boc
R
H
R
H
R
Boc
R
N
H
R
N
N
N
N
N
N
N
N
N
N
N
N
N
N
d
b
c
a
O
O
O
O
O
HO
HO
MeO
MeO
MeO
MeO
P
P
P
O
O
O
2a–g
3a–g
4a–g
(+ Z-isomers)
6a–g
5a–g
a
b
c
d
e
f
R = Bn
R = 3-ClC6H4CH2
R = 3-FC6H4CH2
R = c-C6H11
R = C4H9
R = C5H11
R = C9H19
Mes
N
N
Mes
Ph
N
Cl
Cl
Ru
PCy3
g
7
cross-metathesis catalyst
Scheme 2 Reagent and conditions: a) (Boc)2O, DMAP, pyridine; b) dimethyl allylphosphonate (6 equiv), [Ru] catalyst 7 (5 mol%), CH2Cl2,
60 °C, 12 h; c) CF3CO2H, CH2Cl2; d) TMSBr, MeCN.
Synthesis 2008, No. 13, 2127–2133 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Silylation-Amination of Uracils
2129
mL) was added, and the organic phase was dried (MgSO4). After
evaporation, the residue was purified by liquid chromatography on
silica gel (hexanes–EtOAc, 1:2) to an oil (2.5 g, 92%).
N1-Crotyl-N4-(3-fluorobenzyl)cytosine (2c)
Colorless solid; mp 148 °C.
1H NMR (250 MHz, CDCl3): d = 1.67 (dd, 3 H, J = 0.6, 6.0 Hz,
CH3), 4.18 (d, J = 5.3 Hz, 2 H, NCH2trans), 4.30 (d, J = 6.5 Hz, 2 H,
NCH2cis), 4.54 (d, J = 5.7 Hz, 2 H, CH2Ph), 5.45 (dt, J = 5.6, 15.5
Hz, 1 H, CH=), 5.62 (dq, J = 6.0, 15.5 Hz, 1 H, CH=), 5.92 (d,
J = 7.2 Hz, 1 H, H-5), 6.84–7.47 (m, 5 Harom and H-6), 8.90 (s, 1 H,
NH).
N3-Benzoylated 1
1H NMR (CDCl3): d = 1.75 (dd, J = 1.3, 6.6 Hz, 3 H, CH3), 4.26–
4.30 (m, 2 H, U-CH2), 4.39–4.42 (m, 2 H, U-CH2), 5.46–5.58 (m, 1
H, CH=), 5.74–5.92 (m, 1 H, CH=), 5.75 (d, J = 7.9 Hz, 1 H, H-5),
7.27 (d, J = 7.9 Hz, 1 H, H-6), 7.40–7.52 (m, 2 Harom), 7.61–7.68
(m, 1 Harom), 7.91–7.94 (m, 2 Harom).
13C NMR (100 MHz, CDCl3): d = 17.8, 45.1, 50.8, 94.7, 114.2,
114.5, 123.6, 125.5, 130.3, 130.8, 140.8, 140.9, 143.7, 156.9, 161.3.
13C NMR (CDCl3): d = 11.3, 16.0, 42.6, 48.3, 100.3, 100.4, 121.0,
122.1, 127.3, 127.4, 128.7, 128.9, 129.7, 131.0, 133.3, 141.7, 148.0,
148.1, 160.7, 167.2.
HRMS: m/z calcd for C15H16FN3O: 273.3093; found: 273.3089.
N1-Crotyl-N4-cyclohexylcytosine (2d)
Colorless solid; mp 144 °C.
HRMS: m/z calcd for C15H14N2O3: 270.2872; found: 270.2881.
The benzoylated intermediate was reacted with a solution of
MeOH/NH3. After evaporation, the residue was purified by column
chromatography on silica gel (hexanes–EtOAc, 1:1 to 2:8) to yield
1 as a white solid (510 mg, 69%); mp 88 °C (EtOH).
1H NMR (250 MHz, CDCl3): d = 1.15–1.95 (m, 10 Hc-Hex), 1.68 (dd,
J = 1.0, 5.3 Hz, 3 H, CH3), 4.30 (d, J = 6.0 Hz, 2 H, NCH2trans), 4.44
(d, J = 7.2 Hz, 2 H, NCH2cis), 5.06 (br s, 1 Hc-Hex), 5.51–5.80 (m, 2
H, CH=CH), 5.64 (d, J = 5.6 Hz, 1 H, H-5), 7.10 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 17.8, 24.8, 25.6, 33.2, 45.1, 50.7,
1
1H NMR (250 MHz, CDCl3): d = 1.73 (m, 3 H, CH3), 4.29 (d,
J = 6.6 Hz, 2 H, NCH2trans), 4.40 (d, J = 7.2 Hz, 2 H, NCH2cis),
5.43–5.56 (m, 1 H, CH=), 5.72 (d, J = 7.9 Hz, 1 H, H-5), 5.70–5.87
(m, 1 H, CH=), 7.19 (d, J = 7.9 Hz, 1 H, H-6), 10.21 (s, 1 H, NH).
86.2, 95.2, 125.9, 143.3, 157.2, 163.1.
HRMS: m/z calcd for C14H21N3O: 247.3394; found: 247.3401.
N4-Butyl-N1-crotylcytosine (2e)
Colorless solid; mp 122 °C.
1H NMR (250 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 3 H, CH3),
1.38 (sext, J = 7.2 Hz, 2 H, CH2), 1.50–1.63 (m, 2 H, CH2), 1.71 (d,
J = 6.3 Hz, 3 H, CH3), 3.48 (m, 2 H, NCH2alkane), 4.33 (d, J = 6.0
Hz, 2 H, NCH2trans), 4.46 (d, J = 6.9 Hz, 2 H, NCH2cis), 5.50–5.68
(m, 3 H, CH=CH and H-5), 7.14 (d, J = 5.3 Hz, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 18.8, 49.5, 102.3, 124.4, 131.9,
143.8, 151.2, 164.4.
Amination of the Uracil Moiety at C-4 in 1; General Procedure
A solution of 1 (500 mg, 3.01 mmol) in the presence of an amine
(6.02 mmol) in HMDS (1.5 g, 9.28 mmol) containing a-picoline
(848 mg, 9.1 mmol) and chlorotrimethylsilane (0.3 mmol) was
heated either at 140 °C for 2 d (under conventional heating) or un-
der microwaves in a sealed tube for 5 h at 140 °C. The reaction was
monitored by TLC (CH2Cl2–MeOH; 94:6) and the mixture was
treated with 10% aq MeOH (3 mL) at 60 °C. The resulting mixture
was evaporated to dryness and the crude product was purified by
liquid chromatography on silica gel column (CH2Cl2–EtOH, 1:0 to
93:7). The expected N4-substituted cytosine derivatives 2a–g were
isolated, respectively.
13C NMR (100 MHz, CDCl3): d = 13.8, 17.8, 20.1, 31.4, 40.7, 50.7,
90.2, 94.8, 125.8, 130.4, 143.3, 163.8.
HRMS: m/z calcd for C12H19N3O: 221.3016; found: 221.3021.
N1-Crotyl-N4-pentylcytosine (2f)
Colorless solid; mp 103 °C.
1H NMR (250 MHz, CDCl3): d = 0.88 (br s, 3 H, CH3), 1.31 (br s, 4
H, CH2), 1.57 (m, 2 H, CH2), 1.70 (d, J = 6.0 Hz, 3 H, CH3), 3.45
(m, 2 H, NCH2alkane), 4.32 (br d, J = 5.9 Hz, 2 H, NCH2trans), 4.44 (d,
J = 6.9 Hz, 2 H, NCH2cis), 5.57–5.73 (m, 2 H, CH=CH), 5.65 (d,
J = 5.4 Hz, 1 H, H-5), 7.12 (d, 1 H, H-6).
N4-Benzyl-N1-crotylcytosine (2a)
Colorless solid; mp 150 °C.
1H NMR (250 MHz, CDCl3): d = 1.72 (m, 3 H, CH3), 4.34 (d,
J = 5.7 Hz, 2 H, NCH2trans), 4.47 (d, J = 6.9 Hz, 2 H, NCH2cis), 4.68
(m, 2 H, CH2Ph), 5.54–5.69 (m, 3 H, CH=CH and H-5), 7.21 (d,
J = 5.7 Hz, 1 H, H-6), 7.32 (m, 5 Harom).
13C NMR (100 MHz, CDCl3): d = 14.1, 17.8, 22.4, 29.1, 40.9, 50.6,
90.4, 95.1, 125.8, 130.3, 143.1, 157.1, 163.8.
HRMS: m/z calcd for C13H21N3O: 235.3284; found: 235.3288.
13C NMR (100 MHz, CDCl3): d = 17.8, 45.2, 50.8, 94.7, 125.6,
125.9, 127.6, 128.2, 128.8, 130.7, 143.8, 157.1, 163.6.
N1-Crotyl-N4-nonylcytosine (2g)
Colorless solid; mp 92 °C.
HRMS: m/z calcd for C15H17N3O: 255,3188; found: 255.3192.
1H NMR (250 MHz, CDCl3): d = 0.82 (t, J = 6.0 Hz, 3 H, CH3),
1.20–1.52 (m, 14 H, CH2alkane), 1.65 (d, J = 5.3 Hz, 3 H, CH3), 3.39
(d, J = 6.0 Hz, 2 H, NCH2alkane), 4.26 (d, J = 5.7 Hz, 2 H, NCH2trans),
4.40 (d, J = 6.6 Hz, 2 H, NCH2cis), 5.44–5.77 (m, 3 H, CH=CH and
H-5), 7.05 (d, J = 6.9 Hz, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 14.1, 17.7, 22.6, 27.0, 29.3, 29.4,
29.5, 31.9, 40.9, 50.5, 91.4, 95.5, 125.8, 130.1, 142.8, 157.2, 163.9.
N4-(3-Chlorobenzyl)-N1-crotylcytosine (2b)
Colorless solid; mp 128 °C.
1H NMR (250 MHz, CDCl3): d = 1.67 (dd, J = 1.0, 6.0 Hz, 3 H,
CH3), 4.20 (d, J = 6.0 Hz, 2 H, NCH2trans), 4.32 (d, J = 6.9 Hz, 2 H,
NCH2cis), 4.55 (d, J = 5.7 Hz, 2 H, CH2Ph), 5.47 (dt, J = 6.0,
J = 15.4 Hz, 1 H, CH=), 5.63 (dq, J = 6.5, 15.4 Hz, 1 H, CH=), 5.85
(d, J = 6.8 Hz, 1 H, H-5), 6.99 (d, 1 H, H-6), 7.28–7.13 (m, 4 Harom),
8.95 (s, 1 H, NH).
HRMS: m/z calcd for C17H29N3O: 291.4356; found: 291.4359.
Boc Protection of N4-Amine in 2; General Procedure
13C NMR (100 MHz, CDCl3): d = 17.7, 43.5, 50.5, 95.9, 125.5,
125.9, 127.0, 127.4, 129.5, 130.2, 134.0, 140.9, 142.9, 157.3, 164.1.
To a solution of cytosine analogues 2a–g, respectively, (1.31 mmol)
in pyridine (12 mL) under argon was added of 4-dimethylaminopy-
ridine (1.31 mmol) and di-tert-butyl dicarbonate (2.62 mmol). The
resulting mixture was stirred at r.t. for 2 d and the progress of the
reaction was monitored by TLC (eluent: CH2Cl2–EtOH; 95:5). The
solution was concentrated under reduced pressure (azeotroped with
HRMS: m/z calcd for C15H16ClN3O: 289.7636; found: 289.7642.
Synthesis 2008, No. 13, 2127–2133 © Thieme Stuttgart · New York

2130
V. Roy et al.
PAPER
toluene). The crude was dissolved in CH2Cl2 (40 mL), the organic
layer was washed with H2O (2 × 20 mL), and then dried (Na2SO4).
Chromatographic purification was achieved on silica gel using
CH2Cl2–EtOH (1:0 to 95:5) as eluent and led to the expected pro-
tected cytosine analogues 3a–g.
1.72 (m, 3 H, CH3), 4.00 (t, J = 5.7 Hz, 2 H, NCH2alkane), 4.43 (br s,
2 H, NCH2trans), 4.54 (br s, 2 H, NCH2cis), 5.55–5.79 (m, 2 H,
CH=CH), 7.18 (d, J = 7.4 Hz, 1 H, H-5), 7.50 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 13.7, 17.4, 22.1, 27.7, 27.8, 28.7,
45.2, 50.7, 82.3, 98.4, 124.5, 130.9, 145.2, 153.1, 155.7, 163.9.
N4-Benzyl-N4-Boc-N1-crotylcytosine (3a)
Yield: 95%; colorless solid; mp 103 °C.
N4-Boc-N1-crotyl-N4-nonylcytosine (3g)
Yield: 97%; colorless foam.
1H NMR (250 MHz, CDCl3): d = 1.37 (s, 9 H, CH3), 1.73 (dd,
J = 1.0, 6.3 Hz, 3 H, CH3), 4.42 (d, J = 6.3 Hz, 2 H, NCH2trans), 4.53
(d, J = 6.9 Hz, 2 H, NCH2cis), 5.29 (s, 2 H, CH2Ph), 5.53–5.81 (m,
2 H, CH=CH), 7.19–7.30 (m, 6 H, 5 Harom and H-5), 7.46 (d, J = 7.5
Hz, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 17.9, 28.0, 48.4, 51.3, 83.4, 98.7,
124.8, 126.1, 127.1, 127.5, 128.3, 131.0, 131.9, 138.6, 145.6, 153.5,
156.1, 164.4.
1H NMR (250 MHz, CDCl3): d = 0.87 (t, J = 6.3 Hz, 3 H, CH3),
1.26 (m, 12 H, CH2alkane), 1.54 (s, 9 H, CH3), 1.62 (m, 2 H, CH2),
1.72 (d, J = 6.3 Hz, 3 H, CH3), 4.01 (t, J = 7.2 Hz, 2 H, NCH2alkane),
4.41 (d, J = 5.3 Hz, 2 H, NCH2trans), 4.54 (d, J = 6.9 Hz, 2 H,
NCH2cis), 5.53–5.82 (m, 2 H, CH=CH), 7.17 (d, J = 7.5 Hz, 1 H, H-
5), 7.46 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 14.2, 17.9, 22.8, 27.1, 28.3, 28.7,
29.4, 29.6, 29.7, 32.0, 45.8, 51.3, 82.8, 98.9, 124.8, 131.7, 145.2,
153.7, 156.3, 164.4.
N4-(3-Chlorobenzyl)-N4-Boc-N1-crotylcytosine (3b)
Yield: 88%; colorless solid; mp 128 °C.
Olefin Cross-Metathesis Reaction; General Procedure
To a solution of N1-crotylcytosine analogues 3a–g (0.31 mmol), re-
spectively, dissolved in anhyd CH2Cl2 (5 mL) were introduced un-
der argon dimethyl allylphosphonate (1.24 mmol) and the second-
generation [Ru] catalyst 7 (5% mmol) (Nolan’s catalyst17). Under
stirring, the purple mixture was refluxed for 16 h and the progress
of the reaction was monitored by TLC (EtOAc–EtOH: 95:5). The
solvent of the resulting dark solution was removed under reduced
pressure. The residue was purified by liquid chromatography on sil-
ica gel (CH2Cl2–EtOH, from 1:0 to 95:5) and the expected major E-
isomers 4a–g were isolated.
1H NMR (250 MHz, CDCl3): d = 1.39 (s, 9 H, CH3), 1.74 (dd,
J = 1.3, 6.3 Hz, 3 H, CH3), 4.43 (d, J = 6.3 Hz, 2 H, NCH2trans), 4.54
(d, J = 7.2 Hz, 2 H, NCH2cis), 5.27 (m, 2 H, CH2Ph), 5.54–5.82 (m,
2 H, CH=CH), 7.19–7.26 (m, 4 Harom), 7.25 (d, J = 7.4 Hz, 1 H, H-
5), 7.47 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 17.9, 28.0, 47.9, 51.3, 83.7, 98.5,
124.6, 125.7, 127.2, 127.5, 129.6, 132.0, 134.1, 140.7, 145.8, 153.2,
155.9, 164.2.
N4-Boc-N1-crotyl-N4-(3-fluorobenzyl)cytosine (3c)
Yield: 87%; colorless solid; mp 130 °C.
N4-Benzyl-N4-Boc-N1-(4-dimethoxyphosphinylbut-2-enyl)cy-
tosine (4a)
Yield: 52%; colorless viscous oil.
1H NMR (250 MHz, CDCl3): d = 1.38 (s, 9 H, CH3), 1.74 (dd,
J = 1.3, 6.3 Hz, 3 H, CH3), 4.42 (d, J = 6.0 Hz, 2 H, NCH2trans), 4.54
(d, J = 7.5 Hz, 2 H, NCH2cis), 5.28 (d, J = 5.7 Hz, 2 H, CH2Ph),
5.54–5.84 (m, 2 H, CH=CH), 7.05 (d, J = 7.5 Hz, 1 H, H-5), 7.21
(m, 4 Harom), 7.48 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 17.8, 28.0, 48.0, 51.3, 83.6, 98.5,
113.7, 114.0, 114.4, 123.1, 124.7, 129.8, 132.1, 141.2, 145.8, 153.3,
156.0, 164.3.
1H NMR (250 MHz, CDCl3): d = 1.38 (s, 9 H, CH3), 2.61 (dd,
J = 6.1, 22.0 Hz, 2 H, CH2P), 3.72 (s, 3 H, POCH3), 3.76 (s, 3 H,
POCH3), 4.47 (m, 2 H, NCH2), 5.29 (m, 2 H, CH2Ph), 5.66–5.83 (m,
2 H, CH=CH), 7.14–7.27 (m, 6 H, 5 Harom and H-5), 7.44 (d, J = 7.5
Hz, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 27.7, 28.1 (d, J = 140.4 Hz,
CH2PO), 48.2, 50.9, 52.6, 52.7, 83.2, 98.7, 124.9 (d, J = 11.0 Hz,
CH=CHCH2PO), 126.8, 127.2, 128.1, 128.9 (d, J = 14.4 Hz,
CH=CHCH2PO), 138.2, 145.2, 153.2, 155.6, 164.2.
N4-Boc-N1-crotyl-N4-cyclohexylcytosine (3d)
Yield: 86%; colorless solid; mp 108 °C.
1H NMR (250 MHz, CDCl3): d = 1.05–1.79 (m, 10 Hc-Hex), 1.52 (s,
9 H, CH3), 1.93–2.09 (m, 3 H, CH3), 4.38 (dd, J = 1.3, 6.3 Hz, 2 H,
NCH2trans), 4.49 (d, J = 7.3 Hz, 2 H, NCH2cis), 4.71–4.83 (m,
1 Hc-Hex), 5.48–5.82 (m, 2 H, CH=CH), 6.62 (d, J = 7.5 Hz, 1 H, H-
5), 7.35 (d, 1 H, H-6).
N4-(3-Chlorobenzyl)-N4-Boc-N1-(4-dimethoxyphosphinylbut-2-
enyl)cytosine (4b)
Yield: 67%; colorless viscous oil.
1H NMR (250 MHz, CDCl3): d = 1.39 (s, 9 H, CH3), 2.64 (dd,
J = 5.9, 22.0 Hz, 2 H, CH2P), 3.72 (s, 3 H, POCH3), 3.77 (s, 3 H,
POCH3), 4.48 (m, 2 H, NCH2), 5.25 (br s, 2 H, CH2Ph), 5.68–5.88
(m, 2 H, CH=CH), 7.19–7.28 (m, 4 Harom), 7.28 (d, J = 7.5 Hz, 1 H,
H-5), 7.48 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 28.0, 28.3 (d, J = 140.4 Hz,
CH2PO), 47.9, 51.1, 52.8, 52.9, 83.8, 98.7, 125.3 (d, J = 10.9 Hz,
CH=CHCH2PO), 125.7, 127.2, 127.5, 129.2 (d, J = 14.5 Hz,
CH=CHCH2PO), 129.6, 134.1, 140.5, 145.8, 153.1, 155.7, 164.3.
13C NMR (100 MHz, CDCl3): d = 17.8, 25.6, 26.4, 28.2, 30.4, 51.3,
56.9, 82.9, 100.8, 124.8, 131.6, 144.5, 153.8, 156.3, 165.6.
N4-Boc-N4-butyl-N1-crotylcytosine (3e)
Yield: 86%; colorless foam.
1H NMR (250 MHz, CDCl3): d = 0.83 (t, J = 6.9 Hz, 3 H, CH3),
1.23–1.26 (m, 4 H, CH2 alkane), 1.48 (s, 9 H, CH3), 1.65–1.68 (m, 3
H, CH3), 3.92 (t, J = 7.5 Hz, 2 H, NCH2alkane), 4.39 (dd, J = 1.0, 6.3
Hz, 2 H, NCH2trans), 4.52 (d, J = 7.2 Hz, 2 H, NCH2cis), 5.47–5.77
(m, 2 H, CH=CH), 7.13 (d, J = 7.5 Hz, 1 H, H-5), 7.37 (d, 1 H, H-6).
N4-Boc-N4-(3-Fluorobenzyl)-N1-(4-dimethoxyphosphinylbut-2-
enyl)cytosine (4c)
Yield: 67%; colorless viscous oil.
13C NMR (100 MHz, CDCl3): d = 14.0, 17.7, 22.4, 28.0, 29.0, 45.6,
51.1, 82.7, 98.8, 124.7, 131.5, 145.2, 153.5, 156.1, 164.2.
1H NMR (250 MHz, CDCl3): d = 1.39 (s, 9 H, CH3), 2.65 (dd,
J = 6.3, 22.3 Hz, 2 H, CH2P), 3.72 (s, 3 H, POCH3), 3.76 (s, 3 H,
POCH3), 4.48 (m, 2 H, NCH2), 5.27 (br s, 2 H, CH2Ph), 5.73–5.82
(m, 2 H, CH=CH), 6.87–7.28 (m, 4 Harom), 7.27 (d, J = 7.5 Hz, 1 H,
H-5), 7.47 (d, 1 H, H-6).
N4-Boc-N1-crotyl-N4-pentylcytosine (3f)
Yield: 96%; colorless solid; mp 48 °C.
1H NMR (250 MHz, CDCl3): d = 0.89 (t, J = 3.5 Hz, 3 H, CH3),
1.31 (m, 4 H, CH2), 1.55 (s, 9 H, CH3), 1.62 (m, 2 H, CH2), 1.70–
Synthesis 2008, No. 13, 2127–2133 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Silylation-Amination of Uracils
2131
13C NMR (100 MHz, CDCl3): d = 27.9, 28.3 (d, J = 139.7 Hz,
CH2PO), 48.0, 51.1, 52.8, 52.9, 83.7, 98.7, 113.7, 114.0, 114.3,
123.0, 125.2 (d, J = 10.9 Hz, CH=CHCH2PO), 129.2 (d, J = 14.5
Hz, CH=CHCH2PO), 129.8, 141.0, 145.7, 153.1, 155.7, 164.3.
progress of the reaction was monitored by TLC (CH2Cl2–MeOH,
92:8). The solvent was then removed (co-evaporation with toluene)
and the crude residue purified by flash chromatography on silica gel
(elution with a gradient of CH2Cl2–EtOH; 1:0 to CH2Cl2 –MeOH;
94:6) to yield compound 5a–g, respectively.
N4-Boc-N4-Cyclohexyl-N1-(4-dimethoxyphosphinylbut-2-
enyl)cytosine (4d)
N4-Benzyl-N1-(4-dimethoxyphosphinylbut-2-enyl)cytosine (5a)
Yield: 66%; colorless viscous oil.
Yield: 81%; foam.
1H NMR (250 MHz, CDCl3): d = 1.18–2.10 (m, 10 Hc-Hex), 1.54 (s,
9 H, CH3), 2.63 (dd, J = 6.6, 22.6 Hz, 2 H, CH2P), 3.72 (s, 3 H,
POCH3), 3.76 (s, 3 H, POCH3), 4.46 (m, 2 H, NCH2), 4.79 (m,
1 Hc-Hex), 5.68–5.77 (m, 2 H, CH=CH), 6.67 (d, J = 7.5 Hz, 1 H, H-
5), 7.35 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 25.4, 26.1, 28.1, 28.3 (d,
J = 139.7 Hz, CH2-PO), 50.9, 50.9, 52.7, 56.7, 82.8, 100.7, 124.6
(d, J = 10.8 Hz, CH=CHCH2PO), 129.2 (d, J = 14.5 Hz,
CH=CHCH2PO), 144.4, 153.5, 156.0, 165.5.
1H NMR (250 MHz, CD3OD): d = 2.68 (dd, J = 7.1, 22.0 Hz, 2 H,
CH2P), 3.71 (s, 3 H, POCH3), 3.75 (s, 3 H, POCH3), 4.38 (m, 2 H,
NCH2), 4.58 (br s, 2 H, CH2Ph), 5.58–5.88 (m, 2 H, CH=CH), 5.93
(d, J = 7.3 Hz, 1 H, H-5), 7.24–7.31 (m, 5 Harom), 7.50 (d, 1 H, H-6).
13C NMR (100 MHz, CD3OD): d = 28.0 (d, J = 139.9 Hz, CH2PO),
45.3, 51.6, 53.6, 53.7, 97.3, 124.2 (d, J = 11.5 Hz, CH=CHCH2PO),
128.4, 128.7, 129.6, 131.3 (d, J = 14.5 Hz, CH=CHCH2PO), 139.3,
145.8, 159.2, 165.4.
N4-(3-Chlorobenzyl)-N1-(4-dimethoxyphosphinylbut-2-enyl)cy-
tosine (5b)
Boc-N4-butyl-N1-(4-dimethoxyphosphinylbut-2-enyl)cytosine
(4e)
Yield: 88%; foam.
Yield: 59%; colorless viscous oil.
1H NMR (250 MHz, CD3OD): d = 2.72 (dd, J = 7.1, 22.0 Hz, 2 H,
CH2P), 3.70 (s, 3 H, POCH3), 3.75 (s, 3 H, POCH3), 4.37 (m, 2 H,
NCH2), 4.47 (br s, 2 H, CH2Ph), 5.57–5.86 (m, 2 H, CH=CH), 5.92
(d, J = 7.3 Hz, 1 H, H-5), 7.21–7.29 (m, 4 Harom), 7.49 (d, 1 H, H-6).
13C NMR (100 MHz, CD3OD): d = 28.1 (d, J = 139.3 Hz, CH2PO),
44.4, 51.6, 53.6, 53.7, 97.1, 124.1 (d, J = 10.9 Hz, CH=CHCH2PO),
127.0, 128.3, 128.6, 131.1, 131.4 (d, J = 14.5 Hz, CH=CHCH2PO),
135.3, 142.2, 145.8, 159.2, 165.7.
1H NMR (250 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 3 H, CH3),
1.33 (sext, J = 7.2 Hz, 2 H, CH2), 1.54 (s, 9 H, CH3), 1.57–1.63 (m,
2 H, CH2), 2.63 (dd, J = 6.6, 22.0 Hz, 2 H, CH2P), 3.72 (s, 3 H,
POCH3), 3.76 (s, 3 H, POCH3), 4.01 (t, J = 7.5 Hz, 2 H, NCH2alkane),
4.47 (m, 2 H, NCH2), 5.74–5.79 (m, 2 H, CH=CH), 7.20 (d, J = 7.5
Hz, 1 H, H-5), 7.41 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 13.9, 20.1, 28.1, 28.2 (d,
J = 139.9 Hz, CH2PO), 30.6, 45.5, 50.9, 52.8, 52.9, 82.8, 99.0,
124.6 (d, J = 10.9 Hz, CH=CHCH2PO), 129.1 (d, J = 14.5 Hz,
CH=CHCH2PO), 145.1, 153.5, 156.0, 164.4.
N4-(3-Fluorobenzyl)-N1-(4-dimethoxyphosphinylbut-2-enyl)cy-
tosine (5c)
Yield: 90%; foam.
N4-Boc-N1-(4-dimethoxyphosphinylbut-2-enyl)-N4-pentyl-
cytosine (4f)
Yield: 53%; colorless viscous oil.
1H NMR (250 MHz, CDCl3): d = 0.81 (t, J = 5.0 Hz, 3 H, CH3),
1.22 (m, 4 H, CH2), 1.47 (s, 9 H, CH3), 1.48–1.57 (m, 2 H, CH2),
2.55 (dd, J = 5.6, 22.6 Hz, 2 H, CH2P), 3.64 (s, 3 H, POCH3), 3.69
(s, 3 H, POCH3), 3.92 (t, J = 7.8 Hz, 2 H, NCH2alkane), 4.39 (m, 2 H,
NCH2), 5.60–5.78 (m, 2 H, CH=CH), 7.11 (d, J = 7.5 Hz, 1 H, H-
5), 7.35 (d, 1 H, H-6).
1H NMR (250 MHz, CD3OD): d = 2.67 (dd, J = 6.9, 22.0 Hz, 2 H,
CH2P), 3.71 (s, 3 H, POCH3), 3.75 (s, 3 H, POCH3), 4.37 (m, 2 H,
NCH2), 4.58 (br s, 2 H, CH2Ph), 5.60–5.86 (m, 2 H, CH=CH), 5.95
(d, J = 7.2 Hz, 1 H, H-5), 6.93–7.36 (m, 4 Harom), 7.50 (d, 1 H, H-6).
13C NMR (100 MHz, CD3OD): d = 28.1 (d, J = 139.3 Hz, CH2PO),
44.5, 51.7, 53.7, 53.8, 97.3, 114.8, 115.1, 115.7, 124.1 (d, J = 13.1
Hz, CH=CHCH2PO), 127.3, 131.3, 131.4, (d, J = 14.5 Hz,
CH=CHCH2PO), 142.5, 145.8, 159.8, 165.2.
13C NMR (100 MHz, CDCl3): d = 14.0, 22.4, 28.0, 28.1 (d,
J = 138.0 Hz, CH2PO), 28.9, 45.6, 50.9, 52.7, 52.8, 82.8, 98.9,
124.5 (d, J = 10.9 Hz, CH=CHCH2PO), 129.3 (d, J = 14.5 Hz,
CH=CHCH2PO), 145.1, 153.5, 155.9, 164.4.
N4-Cyclohexyl-N1-(4-dimethoxyphosphinylbut-2-enyl)cytosine
(5d)
Yield: 95%; foam.
1H NMR (250 MHz, CD3OD): d = 1.48–1.97 (m, 10 Hc-Hex), 2.73
(dd, J = 6.6, 22.0 Hz, 2 H, CH2P), 3.72 (s, 3 H, POCH3), 3.76 (s, 3
H, POCH3), 3.79 (m, 1 Hc-Hex), 4.37 (m, 2 H, NCH2), 5.60–5.84 (m,
2 H, CH=CH), 5.88 (d, J = 7.5 Hz, 1 H, H-5), 7.51 (d, 1 H, H-6).
13C NMR (100 MHz, CD3OD): d = 25.8, 26.5, 28. (d, J = 139.2 Hz,
CH2PO), 33.4, 51.1, 51.4, 53.6, 53.7, 96.8, 124.5 (d, J = 11.5 Hz,
CH=CHCH2PO), 131.0 (d, J = 15.1 Hz, CH=CHCH2PO), 145.9,
156.4, 162.7.
N4-Boc-N1-(4-dimethoxyphosphinylbut-2-enyl)-N4-nonyl-
cytosine (4g)
Yield: 46%; colorless viscous oil.
1H NMR (250 MHz, CDCl3): d = 0.87 (t, J = 6.3 Hz, 3 H, CH3),
1.26 (br s, 12 H, CH2), 1.54 (s, 9 H, CH3), 1.56–1.62 (m, 2 H, CH2),
2.59 (dd, J = 6.2, 22.0 Hz, 2 H, CH2P), 3.72 (s, 3 H, POCH3), 3.76
(s, 3 H, POCH3), 4.00 (t, J = 7.5 Hz, 2 H, NCH2alkane), 4.47 (m, 2 H,
NCH2), 5.65–5.85 (m, 2 H, CH=CH), 7.19 (d, J = 7.5 Hz, 1 H, H-
5), 7.41 (d, 1 H, H-6).
13C NMR (100 MHz, CDCl3): d = 14.1, 22.6, 26.9, 28.1, 28.1 (d,
J = 140.4 Hz, CH2PO), 28.5, 29.2, 29.4, 29.5, 31.8, 45.7, 51.0, 52.7,
52.8, 82.8, 99.0, 124.6 (d, J = 11.5 Hz, CH=CHCH2PO), 129.3 (d,
J = 14.5 Hz, CH=CHCH2PO), 145.1, 153.5, 155.9, 164.1.
N4-Butyl-N1-(4-dimethoxyphosphinylbut-2-enyl)cytosine (5e)
Yield: 96%; foam.
1H NMR (250 MHz, CD3OD): d = 0.95 (t, J = 7.2 Hz, 3 H, CH3),
1.39 (m, J = 7.2 Hz, 2 H, CH2), 1.52–1.63 (m, 2 H, CH2), 2.72 (dd,
J = 6.6, 22.0 Hz, 2 H, CH2P), 3.34 (m, 2 H, NCH2alkane), 3.71 (s, 3
H, POCH3), 3.76 (s, 3 H, POCH3), 4.36 (m, 2 H, NCH2), 5.57–5.82
(m, 2 H, CH=CH), 5.85 (d, J = 7.5 Hz, 1 H, H-5), 7.45 (d, 1 H, H-6).
Deprotection of Boc Group in 4a–g; General Procedure
1H NMR (100 MHz, CD3OD): d = 14.1, 21.1, 28.0 (d, J = 139.3
Hz, CH2PO), 31.9, 41.6, 51.6, 53.6, 53.7, 58.3, 97.3, 124.2 (d,
The deprotection of acyclonucleosides 4a–g (0.25 mmol) was real-
ized in anhyd CH2Cl2 (2 mL) with a large excess of TFA (650 mg,
5.7 mmol). The mixture was stirred at r.t. during 1.5 h, and the
Synthesis 2008, No. 13, 2127–2133 © Thieme Stuttgart · New York

2132
V. Roy et al.
PAPER
J = 11.5 Hz, CH=CHCH2PO), 131.3 (d, J = 14.5 Hz,
CH=CHCH2PO), 145.3, 158.7, 165.3.
13C NMR (100 MHz, CD3OD): d = 31.4 (d, J = 136.2 Hz, CH2PO),
46.8, 51.5, 95.4, 126.9, 127.7, 129.3, 129.6, 131.6, 135.7, 137.7,
138.9, 148.7, 152.2, 159.2.
31P NMR (161.97 MHz, CD3OD): d = 23.07.
N1-(4-Dimethoxyphosphinylbut-2-enyl)-N4-pentylcytosine (5f)
Yield: 96%; foam.
HRMS (EI): m/z calcd for C15H17ClN3O4P: 369.7434; found:
369.7437.
1H NMR (250 MHz, CD3OD): d = 0.88 (br s, 3 H, CH3), 1.17 (br s,
4 H, CH2), 1.56 (m, 2 H, CH2), 2.69 (dd, J = 7.1, 22.0 Hz, 2 H,
CH2P), 3.30 (t, J = 6.9 Hz, 2 H, NCH2alkane), 3.69 (s, 3 H, POCH3),
3.73 (s, 3 H, POCH3), 4.34 (m, 2 H, NCH2), 5.57–5.77 (m, 2 H,
CH=CH), 5.86 (d, J = 7.4 Hz, 1 H, H-5), 7.42 (d, J = 7.4 Hz, 1 H,
H-6).
13C NMR (100 MHz, CD3OD): d = 14.3, 23.4, 27.9 (d, J = 141.0
Hz, CH2PO), 29.5, 30.2, 41.7, 51.5, 53.6, 53.7, 97.5, 124.2 (d,
J = 10.9 Hz, CH=CHCH2PO), 131.4 (d, J = 14.5 Hz,
CH=CHCH2PO), 145.2, 159.2, 165.5.
N4-(3-Fluorobenzyl)-N1-(4-dihydroxyphosphinylbut-2-enyl)cy-
tosine (6c)
Yield: 98%; white foam.
1H NMR (250 MHz, CD3OD): d = 2.61 (dd, J = 6.2, 21.3 Hz, 2 H,
CH2P), 4.46 (m, 2 H, NCH2), 4.67 (br s, 2 H, CH2Ph), 5.73–5.95 (m,
2 H, CH=CH), 6.14 (d, J = 7.9 Hz, 1 H, H-5), 7.07–7.49 (m, 4
Harom), 7.86 (d, 1 H, H-6).
13C NMR (100 MHz, CD3OD): d = 31.5 (d, J = 135.6 Hz, CH2PO),
46.8, 51.6, 95.4, 115.9, 116.1, 116.4, 125.0, 128.3, 128.4, 131.9,
138.2, 148.6, 152.1, 159.5.
N1-(4-Dimethoxyphosphinylbut-2-enyl)-N4-nonylcytosine (5g)
Yield: 93%; foam.
1H NMR (250 MHz, CD3OD): d = 0.88 (t, J = 6.5 Hz, 3 H, CH3),
1.28 (br s, 12 H, CH2), 1.56 (m, 2 H, CH2), 2.71 (dd, J = 6.7, 22.0
Hz, 2 H, CH2P), 3.33 (t, J = 7.8 Hz, 2 H, NCH2alkane), 3.70 (s, 3 H,
POCH3), 3.75 (s, 3 H, POCH3), 4.35 (m, 2 H, NCH2), 5.59–5.81 (m,
2 H, CH=CH), 5.85 (d, J = 7.5 Hz, 1 H, H-5), 7.43 (d, 1 H, H-6).
31P NMR (161.97 MHz, CD3OD): d = 23.21.
HRMS (EI): m/z calcd for C15H17FN3O4P: 353.2891; found:
353.2899.
N4-Cyclohexyl-N1-(4-dihydroxyphosphinylbut-2-enyl)cytosine
13C NMR (100 MHz, CD3OD): d = 14.4, 23.7, 28.0, 29.9, 30.2,
30.3, 30.4, 30.6, 33.0, 41.8, 51.5, 53.6, 53.7, 97.4, 124.0 (d, J = 11.5
Hz, CH=CHCH2PO), 131.4 (d, J = 14.5 Hz, CH=CHCH2PO),
145.2, 159.5, 165.5.
(6d)
Yield: 79%; white foam.
1H NMR (250 MHz, CD3OD): d = 1.22–2.00 (m, 10 Hc-Hex), 2.59
(dd, J = 6.3, 21.3 Hz, 2 H, CH2P), 3.75 (m, 1 Hc-Hex), 4.44 (m, 2 H,
NCH2), 5.71–5.92 (m, 2 H, CH=CH), 6.09 (d, J = 7.9 Hz, 1 H, H-
5), 7.79 (d, 1 H, H-6).
13C NMR (100 MHz, CD3OD): d = 25.4, 25.9, 32.9, 33.1, 51.4,
52.9, 95.4, 128.3, 128.4, 148.0, 149.4, 157.8.
Deprotection of Diester Phosphonates 5 to Acyclic Nucleoside
Phosphonates 6; General Procedure
To solution of 5a–g (0.165 mmol), respectively, in MeCN (5 mL)
was added TMSBr (220 mL, 1.65 mmol) and the resulting mixture
was stirred at r.t. for 60 h and the progress of the reaction was mon-
itored by TLC (CH2Cl2–MeOH, 9:1). Anhyd MeOH (10 mL) was
then added and the solution was stirred for 1 h at 25 °C. The mixture
was evaporated under reduce pressure with heating (60 °C). MeOH
(10 mL) was added again, and this procedure was repeated three
more times. The residue was extracted with deionized H2O (Elga
system) (10 mL) and CH2Cl2 (3 × 10 mL). The inorganic phase was
evaporated to dryness to give acyclic nucleoside phosphonates 6a–
g in good yield without further purification.
31P NMR (161.97 MHz, CD3OD): d = 23.08.
HRMS (EI): m/z calcd for C14H22N3O4P: 327.3192; found:
327.3194.
N4-Butyl-N1-(4-dihydroxyphosphinylbut-2-enyl)cytosine (6e)
Yield: 96%; colorless viscous oil.
1H NMR (250 MHz CD3OD): d = 0.84 (t, J = 7.2 Hz, 3 H, CH3),
1.26–1.57 (m, 4 H, CH2), 2.48 (m, 2 H, CH2P), 3.17–3.28 (m, 2 H,
NCH2alkane), 4.32 (m, 2 H, NCH2), 5.65–5.71 (m, 2 H, CH=CH),
5.99 (d, J = 7.9 Hz, 1 H, H-5), 7.69 (d, 1 H, H-6).
13C NMR (100 MHz CD3OD): d = 13.9, 20.8, 30.9, 31.8, 43.6, 51.4,
95.4, 128.1, 128.9, 148.0, 149.5, 159.1.
31P NMR (161.97 MHz, CD3OD): d = 21.94.
N4-Benzyl-N1-(4-dihydroxyphosphinylbut-2-enyl)cytosine (6a)
Yield: 90%; colorless viscous oil.
1H NMR (250 MHz, CD3OD): d = 2.60 (dd, J = 6.3, 21.7 Hz, 2 H,
CH2P), 4.46 (br s, 2 H, NCH2), 4.64 (br s, 2 H, CH2Ph), 5.72–5.94
(m, 2 H, CH=CH), 6.14 (d, J = 7.5 Hz, 1 H, H-5), 7.41 (m, 5 Harom),
7.85 (d, 1 H, H-6).
13C NMR (100 MHz, CD3OD): d = 31.8 (d, J = 136.8 Hz, CH2PO),
47.4, 51.6, 95.5, 128.3, 128.5, 129.3, 129.5, 130.7, 135.7, 148.3,
151.8, 159.5.
HRMS (EI): m/z calcd for C12H20N3O4P: 301.2814; found:
301.2817.
N1-(4-Dihydroxyphosphinylbut-2-enyl)-N4-pentylcytosine (6f)
Yield: 95%; colorless viscous oil.
31P NMR (161.97 MHz, CD3OD): d = 21.75
1H NMR (250 MHz, CD3OD): d = 0.94 (t, J = 4.7 Hz, 3 H,CH3),
1.41 (m, 4 H, CH2), 1.70 (quint, J = 6.9 Hz, 2 H,CH2), 2.62 (dd,
J = 6.0, 21.4 Hz, 2 H, CH2P), 3.45 (m, 2 H, NCH2alkane), 4.44 (m, 2
H, NCH2), 5.72–5.89 (m, 2 H, CH=CH), 6.12 (d, J = 7.9 Hz, 1 H,
H-5), 7.81 (d, 1 H, H-6).
HRMS (EI): m/z calcd for C15H18N3O4P: 335.2986; found:
335.2992.
N4-(3-Chlorobenzyl)-N1-(4-dihydroxyphosphinylbut-2-enyl)cy-
13C NMR (100 MHz, CD3OD): d = 14.2, 23.2, 28.6, 29.8, 31.4 (d,
J = 136.0 Hz, CH2PO), 43.9, 51.3, 95.3, 128.3 (d, J = 10.9 Hz,
CH=CHCH2PO), 128.5 (d, J = 14.5 Hz, CH=CHCH2PO), 148.5,
149.3, 159.0.
tosine (6b)
Yield: 94%; foam.
1H NMR (250 MHz, CD3OD): d = 2.63 (dd, J = 6.0, 21.3 Hz, 2 H,
CH2P), 4.44 (m, 2 H, NCH2), 4.68 (br s, 2 H, CH2Ph), 5.75–5.95 (m,
2 H, CH=CH), 6.20 (d, J = 7.8 Hz, 1 H, H-5), 7.35–7.47 (m, 4
Harom), 7.90 (d, 1 H, H-6).
31P NMR (161.97 MHz, CD3OD): d = 22.89
HRMS (EI): m/z calcd for C13H22N3O4P: 315.3082; found:
315.3087.
Synthesis 2008, No. 13, 2127–2133 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Silylation-Amination of Uracils
Van Beers, D.; Holy, A.; Balzarini, J.; De Clercq, E.
2133
N1-(4-Dihydroxyphosphinylbut-2-enyl)-N4-nonylcytosine (6g)
Yield: 88%; white foam.
Antimicrob. Agents Chemother. 2005, 49, 1010. (d) Painter,
G. R.; Almond, M. R.; Trost, L. C.; Lampert, B. M.; Neyts,
J.; De Clercq, E.; Korba, B. E.; Aldern, K. A.; Beadle, J. R.;
Hostetler, K. Y. Antimicrob. Agents Chemother. 2007, 51.
3505.
1H NMR (250 MHz, CD3OD): d = 0.88 (m, 3 H, CH3), 1.29 (br s,
12 H, CH2), 1.67 (m, 2 H, CH2), 2.64 (dd, J = 6.0, 21.7 Hz, 2 H,
CH2P), 3.41 (t, J = 7.2 Hz, 2 H, NCH2alkane), 4.55 (m, 2 H, NCH2),
5.73–5.93 (m, 2 H, CH=CH), 6.14 (d, J = 7.8 Hz, 1 H, H-5), 7.83
(d, 1 H, H-6).
13C NMR (100 MHz, CD3OD): d = 14.4, 21.5, 23.6, 27.6, 28.9,
30.2, 30.2, 30.4, 32.9, 51.3, 43.9, 95.3, 128.0, 128.5, 148.0, 149.3,
158.9.
(6) (a) Chalupová, S.; Hol, A.; Masojídková, M. Collect. Czech.
Chem. Commun. 2005, 12, 2066. (b) Chalupová, S.; Hol,
A.; Masojídková, M. Collect. Czech. Chem. Commun. 2005,
12, 2053.
(7) Fox, J. J.; van Praag, D.; Wempen, I.; Doerc, I. L.; Cheong,
L.; Knoll, J. E.; Edidinoff, M. L.; Bendick, A.; Brown, G. B.
J. Am. Chem. Soc. 1959, 81, 178.
(8) (a) Sung, W. L. Nucleic Acids Res. 1981, 6, 6139.
(b) Matsuda, A. O. K.; Miyasaka, T. Chem. Pharm. Bull.
1985, 33, 2575. (c) Reese, C. B.; Ubasawa, A. Tetrahedron
Lett. 1980, 21, 2265. (d) Perbost, M.; Sanghvi, Y. S.
J. Chem. Soc., Perkin Trans. 1 1994, 2051.
31P NMR (161.97 MHz, CD3OD): d = 19.77
HRMS (EI): m/z calcd for C17H30N3O4P: 371.4154; found:
371.4158.
Acknowledgment
These studies were supported in part by a grant from Sanofi-Aventis
France and Bayer Pharma as part of a multi-organism call for pro-
posals, and in part by an ‘ANR-05-BLAN-0368-03’grant.
(9) Nyilas, A.; Chattopadhyaya, J. Acta Chem. Scand. B 1986,
40, 826.
(10) Lin, T.-S.; Mancini, W. R. J. Med. Chem. 1983, 26, 544.
(11) (a) Dechaux, E.; Monneret, C. Nucleosides Nucleotides
1999, 17, 1. (b) Matsuda, A. Y.; Sasaki, T.; Ueda, T. J. Med.
Chem. 1991, 34, 999.
References
(12) (a) Vorbrüggen, H. Acc. Chem. Res. 1995, 28, 509.
(b) Vorbrüggen, H.; Krolikiewicz, K.; Niedballa, U. Liebigs
Ann. Chem. 1975, 988. (c) Sako, M.; Kihara, T.; Kawada,
H.; Hirota, K. J. Org. Chem. 1999, 64, 9722.
(13) Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH:
Weinheim, 2002, and references cited therein.
(1) (a) Simons, C. Nucleoside Mimetics: Their Chemistry and
Biological Properties, Advanced Chemistry Text Series,
Vol. 3; Gordon and Breach Science: Amsterdam, 2001, 192.
(b) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic
and L-Nucleosides; Kluwer Academic Publishers:
Dordrecht, 1998.
(14) (a) Agrofoglio, L. A.; Nolan, S. P. Curr. Top. Med. Chem.
2005, 5, 1541. (b) Amblard, F.; Nolan, S. P.; Agrofoglio, L.
A. Tetrahedron 2005, 61, 7067. (c) Agrofoglio, L. A.;
Kumamoto, H.; Roy, V. Chem. Today 2006, 24, 16.
(d) Kumamoto, H.; Topalis, D.; Broggi, J.; Pradère, U.; Roy,
V.; Berteina-Raboin, S.; Nolan, S. P.; Deville-Bonne, D.;
Andrei, G.; Snoeck, R.; Garin, D.; Crance, J.-M.;
Agrofoglio, L. A. Tetrahedron 2008, 64, 3517.
(15) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360.
(16) (a) Roy, R.; Das, S. K. J. Chem. Soc., Chem. Commun. 2000,
519. (b) Phillips, A. J.; Abell, A. D. Aldrichimica Acta 1999,
32, 75.
(17) Hang, J.; Stevens, E. D.; Nolan, S. P.; Peterson, J. L. J. Am.
Chem. Soc. 1999, 121, 8168.
(2) (a) Kinchington, D.; Balzarini, J.; De Clercq, E.; Daluge, S.;
Field, H. J. Int. Antivir. News 2000, 65, 2959.
(b) Agrofoglio, L. A.; Amblard, F.; Broggi, J.; Garnier, E.
Modern Approaches to the Synthesis of O- and N-
Heterocyles, Vol. 2; Kaufman, T. S.; Larghi, E. L., Eds.;
Research Signpost: Trivandrum India, 2007, 195–246.
(3) (a) Kanai, T.; Ichino, M.; Hoshi, A.; Kanzawa, F.; Kuretani,
K. J. Med. Chem. 1974, 17, 1076. (b) Wempen, I.; Miller,
N.; Falco, E. A.; Fox, J. J. J. Med. Chem. 1967, 10, 144.
(4) (a) Wempen, I.; Duschinsky, R.; Kaplan, L.; Fox, J. J. J. Am.
Chem. Soc. 1961, 83, 4755. (b) Pizer, L. I.; Cohen, S. S.
J. Biol. Chem. 1960, 235, 2387.
(5) (a) De Clercq, E. Biochem. Pharmacol. 2007, 73, 911.
(b) Ying, C.; Holy, A.; Hocková, D.; Havlas, Z.; De Clercq,
E.; Neyts, J. Antimicrob. Agents Chemother. 2005, 49,
1177. (c) Naesens, L.; Lenaerts, L.; Andrei, G.; Snoeck, R.;
Synthesis 2008, No. 13, 2127–2133 © Thieme Stuttgart · New York