Synthesis of N-1-alkylated 6-benzyluracil-5-carboxylic esters as potential non-nucleoside reverse transcriptase inhibitors

Article abstract of DOI:10.1055/s-2004-829137

A series of N-1-alkylated 6-benzyluracil-5-carboxylic esters 4a-h were synthesized by reacting imines of 3-oxo-4-phenylbutyrates with N-(chlorocarbonyl) isocyanate. An N-1-(4-methoxybenzyl) group could be removed in a dealkylation reaction to give the ethyl and allyl esters 5a and 5b, respectively. They were N-1-alkylated with chloromethyl ethyl ether or dialloxymethane. Unfortunately no biological activity against HIV-1 and HSV was observed for any of the synthesized compounds.

Full text of DOI:10.1055/s-2004-829137

1874
PAPER
Synthesis of N-1-Alkylated 6-Benzyluracil-5-carboxylic Esters as Potential
Non-Nucleoside Reverse Transcriptase Inhibitors
Synthesis
a
of
N
-
1-Alky
n
late
d
6-Benz
u
yluracil-5-ca
s
rboxylic
E
ster S. Larsen,a Erik B. Pedersen,*a Claus Nielsenb
a
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
Fax +4566158780; E-mail: ebp@chem.sdu.dk
b
Retrovirus Laboratory, Department of Virology, State Serum Institute, Artillerivej 5, 2300 Copenhagen, Denmark
Received 2 April 2004
Abstract: A series of N-1-alkylated 6-benzyluracil-5-carboxylic
esters 4a–h were synthesized by reacting imines of 3-oxo-4-phenyl-
butyrates with N-(chlorocarbonyl) isocyanate. An N-1-(4-methoxy-
benzyl) group could be removed in a dealkylation reaction to give
the ethyl and allyl esters 5a and 5b, respectively. They were N-1-
alkylated with chloromethyl ethyl ether or dialloxymethane. Unfor-
tunately no biological activity against HIV-1 and HSV was ob-
served for any of the synthesized compounds.
Key words: HIV-1, HSV, non-nucleoside reverse transcriptase in-
hibitors, uracil-5-carboxylic esters, Emivirine
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
of HIV are a very broad class of structurally diverse mol-
ecules but they show similarity in their 3-D structures. To
date, three compounds from this class have been approved
by the FDA and they include Nevirapine,1–4 Delavirdine5–7
and Efavirenz.8,9 Furthermore Emivirine (formerly known
as MKC-442, Figure 1) was in Phase III clinical trials and
this compound serves as a lead in our NNRTI research
program. Recently, a rather new class of NNRTIs, the py-
ridinones, were synthesized by Dollè et al.10–12 (Figure 1).
Especially 3-carbethoxy-5-ethyl-6-methyl-4-[(3,5-dimethyl-
phenyl)thio]pyridine-2(1H)-one has shown high activity
against HIV-1 (EC50 = 3 nM). Until now, the crystal struc-
tures of these inhibitors complexed with reverse tran-
scriptase (RT) remain to be published and therefore no
current information is available on the exact binding of
these molecules to the enzyme. One can imagine that the
orientation of pyridinones when complexed to the RT can
be in either of the two orientations shown in Figure 1. The
ester group occupies either the C-5 or N-1 position of
Emivirine. It was therefore decided to synthesize N-1-
alkylated 5-ethoxycarbonyl-6-benzyl-uracils because
they can be looked at as hybrids of pyridinones and
Emivirine with two possible orientations in RT, like the
pyridinones as shown in Figure 1.
Figure 1
the corresponding 6-benzyl-5-carbethoxy-1,3-oxazine-
2,4(3H)-dione (1) in 50% yield (Scheme 1).
However, it was not possible to obtain the desired pyrim-
idine by reaction with ammonia in analogy with the
above-mentioned method.
Therefore it was decided to introduce the N-substituent or
a suitable nitrogen protecting group into the molecule be-
fore making the ring closure with N-(chlorocarbonyl) iso-
Analogues of Emivirine have previously been synthesized
using 1,3-oxazine-2,4-diones as intermediates.13,14 The
use of this oxazine-strategy gave easy access to pyrim-
idines by the use of ketones as starting materials15 and
when we tested this strategy on a b-keto ester we obtained
SYNTHESIS 2004, No. 11, pp 1874–1878
x
x.
x
x
.
2
0
0
4
Advanced online publication: 01.07.2004
DOI: 10.1055/s-2004-829137; Art ID: Z07204SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

PAPER
Synthesis of N-1-Alkylated 6-Benzyluracil-5-carboxylic Esters
1875
cyanate. The reactions of imines with N-(chlorocarbonyl) method of Gribble et al.21 using sodium for reduction of
isocyanate have been reported to give uracils in excellent the corresponding nitrile in 94% yield.
yields.16–18 The inspiration came from Grohe and Heitzer
For 4f,g the deprotection of the 4-methoxybenzyl group
who made an analogous reaction with ethyl acetoacetate
(PMB) was unsuccessful with usual reagents like
isolating 5-ethoxycarbonyluracils in 50–76% yield.19 The
26
CAN,22–24 DDQ,25 TiCl4 and HCO2NH4/10% Pd-C27,28
advantage of this method is the easily prepared imines
which gave no or multiple products. However, deprotec-
from the reaction of primary amines with the b-keto ester
to give only one product originating from the major enam-
ine tautomer.
tion using trifluoroacetic acid29 afforded the pyrimidines
5a and 5b in 59% and 67% yields, respectively. The alkyl-
ation to give the target compounds 6a–c in 45–55% yield
was done using standard conditions (Scheme 3).
Scheme 2
Table 1 Preparation of Uracils from Imines
Scheme 3
4
R1
Et
R2
Yield (%)
56
Table 2 Preparation of Uracils 6 from Uracils 4
a
6
a
b
c
R1
R2
Yield (%)
b
c
Et
Et
42
65
Et
Et
55
49
45
Allyl
Et
Et
Allyl
d
e
f
Et
39
71
59
57
62
All the synthesized compounds were tested for antiviral
activity against HIV-1 and HSV, but unfortunately with-
out showing any activity. It was believed that the 5-ester
group in 4a–h and 6a–c would be able to induce the
181Tyr switch and thereby have the potential to gain extra
hydrogen bonding by forming a hydrogen bond to Glu
138. However, this hypothesis had to be abandoned since
no activity was observed. Therefore we have to conclude
that pyrimidines having an ester group in the 5-position
are not able to bind to the hydrophobic pocket of RT.
Et
Et
g
h
Allyl
Allyl
Ethyl 3-oxo-4-phenylbutyrate or its corresponding allyl 3-
oxo-4-phenylbutyrate prepared by transesterification as
reported by Mottet et al.20 were used for the synthesis of
the imines 3a–h (Scheme 2). The synthesis was per-
formed by heating a neat 1:1 mixture of the b-keto ester
and the amine at 50 °C until TLC showed no more reac-
tion. The corresponding crude enamine/imine was reacted
at 0–5 °C in dioxane with N-(chlorocarbonyl) isocyanate
with subsequent refluxing of the mixture. In this way the
uracils 4a–h were synthesized in 39–71% yields. All the
amines were commercially available, except for cyclo-
pentylmethyl amine which was synthesized by a modified
NMR spectra were recorded on a Varian Gemini 2000 NMR spec-
trometer at 300 MHz for 1H NMR and 75 MHz for 13C NMR with
TMS as the internal standard. EIMS were recorded on a Finnigan
Mat SSQ 701 spectrometer whereas MALDI spectra were recorded
on a Fourier Transform Ion Cyclotron Resonance Mass Spectrome-
ter. Melting points were determined on a Büchi melting point appa-
ratus. Elemental analyses were performed at H.C. Ørsted Institute,
University of Copenhagen. Silica gel (0.040–0.063 mm) used for
column chromatography and analytical silica gel TLC plates 60 F254
were purchased from Merck. Solvents for column chromatography
were distilled prior to use. Et2O, toluene and THF were dried over
sodium threads. MeCN was distilled over 1% (w/w) P2O5 and then
over 5% (w/w) K2CO3 and kept over 3 Å molecular sieves. Dioxane
was pre-dried over KOH and kept over 3 Å molecular sieves. The
Synthesis 2004, No. 11, 1874–1878 © Thieme Stuttgart · New York

1876
J. S. Larsen et al.
PAPER
rest of the solvents were used as purchased. The petroleum ether
used had a boiling point range of 60–80 °C.
13C NMR (CDCl3): d = 13.91 (CH3), 36.24 (CH2Ph), 46.00 (NCH2),
62.20 (OCH2), 112.01 (C-5), 120.61 (C-pyridine), 127.73, 129.44,
133.38 (Carom), 144.93 (C-pyridine), 150.03 (C-pyridine), 151.02
(C-2), 154.11 (C-6), 160.03 (C-4), 164.22 (COO).
6-Benzyl-5-carbethoxy-1,3-oxazine-2,4(3H)-dione (1); Typical
Procedure
EIMS: m/z = 365 [M+].
Ethyl 3-oxo-4-phenylbutyrate (5 g, 24.5 mmol) was mixed with N-
(chlorocarbonyl) isocyanate (1.97 ml, 24.5 mmol) in a 100 mL 3-
necked flask fitted with a septum, a condenser and the mixture was
heated at 58 °C for 2 h under a N2 atmosphere. After further heating
at 130 °C for 1 h and then cooling to r.t., the mixture was taken up
in EtOAc (100 mL) and the organic phase was washed with sat.
NaHCO3 (2 × 50 mL, to remove traces of HCl) followed by washing
with H2O (2 × 50 mL). The organic phase was dried (Na2SO4) and
evaporated in vacuo to an oily product which was purified by silica
gel column chromatography with EtOAc–petroleum ether (1:1) to
give compound 1 as a white solid; yield: 3.3 g (50%); mp 120–123
°C.
Anal. Calcd for C20H19N3O4 365.39: C, 65.74; H, 5.24; N, 11.50.
Found: C, 65.81; H, 5.31; N, 11.39.
6-Benzyl-5-ethoxycarbonyl-1-(N,N-dimethylaminoethyl)uracil
(4c)
Yield: 0.65 g (39%); light yellow solid; mp 229–233 °C.
1H NMR (CDCl3): d = 1.20 (t, J = 7.0 Hz, 3 H, CH3), 2.21 (s, 6 H,
2 × NCH3), 2.36 (t, J = 7.0 Hz, 2 H, NCH2), 3.78 (t, J = 7.0 Hz, 2 H,
NCH2), 4.12 (s, 2 H, CH2Ph), 4.26 (q, J = 7.0 Hz, 2 H, OCH2), 7.23–
7.34 (m, 5 H, Harom).
13C NMR (CDCl3): d = 13.95 (OCH2CH3), 36.24 (CH2Ph), 42.91
(NCH2), 45.46 (2 × NCH3), 57.26 (NCH2), 61.98 (OCH2), 111.15
(C-5), 127.52, 128.07, 129.34, 134.27 (Carom), 150.76 (C-2), 154.96
(C-6), 160.20 (C-4), 164.66 (COO).
1H NMR (CDCl3): d = 1.40 (t, J = 7.0 Hz, 3 H, CH3), 3.95 (s, 2 H,
CH2Ph), 4.35 (q, J = 7.0 Hz, 2 H, CH2), 7.25–7.35 (m, 5 H, Harom),
9.30 (s, 1 H, NH).
13C NMR (CDCl3): d = 13.88 (CH3), 37.58 (CH2Ph), 62.56 (CH2),
109.19 (C-5), 128.41, 129.67, 129.92, 133.28 (Carom), 146.02 (C-2),
159.33 (C-6), 162.36 (C-4), 169.87 (COO).
EIMS: m/z = 345 [M+].
Anal. Calcd for C18H23N3O4 345.40: C, 62.59; H, 6.71; N, 12.17.
Found: C, 62.62; H, 6.78; N, 12.30.
EIMS: m/z = 275 [M+].
6-Benzyl-5-ethoxycarbonyl-1-(cyclopentylmethyl)uracil (4d)
Yield: 1.13 g (65%); light brown solid; mp 190–192 °C.
Anal. Calcd for C14H13NO5: 275.26: C, 61.09; H, 4.76; N, 5.09.
Found: C, 61.20; H, 4.81; N, 4.99.
1H NMR (CDCl3): d = 1.43 (t, J = 7.0 Hz, 3 H, CH3), 1.52–2.30 (m,
9 H, 4 × CH2, CH, cyclopentyl), 3.83 (d, J = 7.0 Hz, 2 H, CH2N),
4.12 (s, 2 H, CH2Ph), 4.25 (q, J = 7.0 Hz, 2 H, OCH2), 7.24–7.56
(m, 5 H, Harom), 9.72 (br s, 1 H, NH).
13C NMR (CDCl3): d = 13.92 (CH3), 24.56 (2 × CH2, cyclopentyl),
30.32 (2 × CH2, cyclopentyl), 36.10 (CH2Ph), 40.63 (CH, cyclopen-
tyl), 48.35 (NCH2), 62.05 (OCH2), 111.24 (C-5), 127.43, 127.55,
129.23, 134.08 (Carom), 150.97 (C-2), 155.11 (C-6), 160.08 (C-4),
164.65 (COO).
Preparation of N-1 Substituted Uracil-5-carboxylic Esters 4a-h;
General Procedure
To the b-keto ester 2 (4.9 mmol) was added the appropriate primary
amine (4.9 mmol) and the mixture was heated to 70–80 °C until
TLC showed that no more product was formed. Then the reaction
mixture was left on the oil-pump overnight. The resulting solid or
oily product was then dissolved in anhyd dioxane (25 mL) and the
mixture was cooled in an ice bath under N2 atmosphere. N-(Chloro-
carbonyl) isocyanate (5.39 mmol) was added slowly by syringe and
a precipitate was formed. In the case where the primary amine con-
tained a basic side chain, Et3N (4.9 mmol) was added. Then the re-
action mixture was refluxed for 2 h and after cooling water (100
mL) was carefully added. The mixture was extracted with EtOAc (2
× 100 mL), dried (Na2SO4) and evaporated in vacuo. The product
was purified by silica gel column chromatography with EtOAc–pe-
troleum ether (1:1) to give compounds 4a–h.
EIMS: m/z = 356 [M+].
Anal. Calcd for C20H24N2O4 356.43: C, 67.40; H, 6.79; N, 7.86.
Found: C, 67.30; H, 6.88; N, 7.69.
6-Benzyl-5-ethoxycarbonyl-1-isopropyluracil (4e)
Yield: 1.17 g (71%); light yellow solid; mp 185–186 °C.
1H NMR (CDCl3): d = 1.21 (m, 9 H, 3 × CH3), 3.98 (s, 2 H, CH2Ph),
4.26 (m, 3 H, OCH2, NCH), 7.24–7.44 (m, 5 H, Harom), 9.34 (s, 1 H,
NH).
6-Benzyl-5-ethoxycarbonyl-1-morpholinouracil (4a)
Yield: 0.98 g (56%); white solid; mp 201–202 °C.
13C NMR (CDCl3): d = 13.67 (CH3), 19.01 (2 × CH3), 36.84
(CH2Ph), 52.41 (NCH), 61.98 (OCH2), 111.00 (C-5), 127.32,
128.57, 129.74, 134.87 (Carom), 150.79 (C-2), 154.67 (C-6), 160.03
(C-4), 165.06 (COO).
HRMS–MALDI: m/z [MH+] calcd for C17H20NaN2O4: 339.1315;
found: 339.1310.
1H NMR (CDCl3): d = 1.25 (t, J = 7.0 Hz, 3 H, CH3), 2.10 (m, 1 H,
CH2, morpholino), 3.20 (m, 1 H, CH2, morpholino), 3.50–3.95 (m,
6 H, 3 × CH2, morpholino), 4.01 (s, 2 H, CH2Ph), 4.33 (q, J = 7.0
Hz, 2 H, OCH2), 7.23–7.50 (m, 5 H, Harom), 9.56 (br s, 1 H, NH).
13C NMR (CDCl3): d = 13.97 (CH3), 36.57 (CH2Ph), 51.16 (2 ×
NCH2), 62.15 (OCH2), 66.50 (2 × OCH2), 110.01 (C-5), 127.11,
127.54, 128.40, 135.63 (Carom), 149.30 (C-2), 157.92 (C-6), 159.72
(C-4), 164.23 (COO).
6-Benzyl-5-ethoxycarbonyl-1-(4-methoxyphenylmethyl)uracil
(4f)
Yield: 1.20 g (59%); light yellow solid; mp 143–144 °C.
EIMS: m/z = 359 [M+].
Anal. Calcd for C18H21N3O5: 359.39: C, 60.16; H, 5.89; N, 11.69.
Found: C, 60.14; H, 6.12; N, 11.57.
1H NMR (DMSO-d6): d = 1.25 (t, J = 7.2 Hz, 3 H, CH3), 3.76 (s, 3
H, OCH3), 4.03 (s, 2 H, CH2Ph), 4.19 (t, J = 7.2 Hz, 2 H, OCH2),
5.00 (s, 2 H, NCH2), 7.09–7.68 (m, 9 H, Harom).
13C NMR (DMSO-d6): d = 13.64 (OCH2CH3), 35.31 (CH2Ph),
45.08 (NCH2), 55.04 (OCH3), 61.20 (OCH2), 110.94 (C-5), 114.19,
127.62, 127.97, 129.54, 134.48, 158.49 (Carom), 150.94 (C-2),
153.51 (C-4), 159.85 (C-6), 164.39 (COO).
6-Benzyl-5-ethoxycarbonyl-1-(4-pyridylmethyl)uracil (4b)
Yield: 0.75 g (42%); red solid; mp 242–245 °C.
1H NMR (CDCl3): d = 1.27 (t, J = 7.0 Hz, 3 H, CH3), 3.31 (s, 2 H,
CH2Ph), 4.34 (q, J = 7.0 Hz, 2 H, OCH2), 4.95 (s, 2 H, NCH2), 7.01
(m, 2 H, pyridine-H), 7.20–7.49 (m, 5 H, Harom), 8.30 (m, 2 H, pyri-
dine-H).
Synthesis 2004, No. 11, 1874–1878 © Thieme Stuttgart · New York

PAPER
Synthesis of N-1-Alkylated 6-Benzyluracil-5-carboxylic Esters
1877
HRMS–MALDI: m/z [MH+] calcd for C22H22NaN2O5: 417.1421;
mmol) and the stirring was continued until all the starting material
found: 417.1417.
had dissolved. Then (chloromethyl) ethyl ether (2 mmol) or diallyl-
oxymethane (2 mmol) was added and the reaction mixture was
stirred until TLC showed no further change in amount of starting
material. After evaporation of the solvent in vacuo the product was
chromatographed on a silica gel column with EtOAc–petroleum
ether (1:1) as solvent to obtain the pure N-1 alkylated products 6a–c.
6-Benzyl-5-allyloxycarbonyl-1-(4-methoxyphenylmeth-
yl)uracil (4g)
Yield: 1.13 g (57%); yellow solid; mp 169–173 °C.
1H NMR (CDCl3): d = 3.81 (s, 3 H, OCH3), 3.97 (s, 2 H, CH2Ph),
4.69 (d, J = 2.70 Hz, 2 H, OCH2), 4.90 (s, 2 H, NCH2), 5.15 (d, J =
7.20 Hz, 1 H, CH-allyl), 5.35 (d, J = 10.2 Hz, 1 H, CH-allyl), 5.88
(m, 1 H, CH-allyl), 6.89–7.48 (m, 9 H, Harom), 9.62 (s, 1 H, NH).
13C NMR (CDCl3): d = 35.87 (CH2Ph), 46.47 (NCH2), 55.31
(OCH3), 66.53 (OCH2), 111.17 (C-5), 119.13 (C-allyl), 114.55,
127.82, 128.17, 129.37, 133.93, 159.79 (Carom), 131.16 (C-allyl),
151.12 (C-2), 155.64 (C-4), 159.56 (C-6), 164.10 (COO).
6-Benzyl-5-ethoxycarbonyl-1-ethoxymethyluracil (6a)
Yield: 0.35 g (55%); white solid; mp 120–121 °C.
1H NMR (CDCl3): d = 1.26 (m, 6 H, 2 × CH3), 3.62 (q, J = 7.4 Hz,
2 H, OCH2), 4.21 (s, 2 H, CH2Ph), 4.34 (q, J = 7.1 Hz, 2 H, OCH2),
5.18 (s, 2 H, NCH2), 7.22–7.49 (m, 5 H, Harom), 9.67 (s, 1 H, NH).
13C NMR (CDCl3): d = 13.93 (CH3), 14.94 (CH3) 35.04 (CH2Ph),
62.11 (OCH2), 65.33 (OCH2), 72.63 (NCH2), 112.06 (C-5), 127.53,
127.95, 129.16, 134.28 (Carom), 151.22 (C-2), 154.82 (C-4), 159.90
(C-6), 164.21 (COO).
5-Allyloxycarbonyl-6-benzyl-1-isopropyluracil (4h)
Yield: 1.06 g (62%); orange solid; mp 170–171 °C.
1H NMR (CDCl3): d = 1.16 (m, 6 H, 2 × CH3), 4.00 (s, 2 H, CH2Ph),
4.25 (m, 1 H, NCH), 4.78 (d, J = 2.7 Hz, 2 H, CH2-allyl), 5.35 (m,
2 H, CH-allyl), 5.86 (m, 1 H, CH-allyl), 7.21–7.54 (m, 5 H, Harom),
8.62 (s, 1 H, NH).
HRMS–MALDI: m/z [MH+] calcd for C17H20Na1N2O5: 355.1264;
found: 355.1253.
5-Allyloxycarbonyl-6-benzyl-1-ethoxymethyluracil (6b)
Yield: 0.33 g (49%); white solid; mp 208–209 °C.
13C NMR (CDCl3): d = 19.99 (2 × CH3), 37.84 (CH2Ph), 53.47
(NCH), 67.98 (OCH2), 109.55 (C-5), 117.54 (C-allyl), 127.72,
127.97, 129.68 134.56 (Carom), 131.45 (C-allyl), 150.72 (C-2),
153.97 (C-6), 160.13 (C-4), 164.87 (COO).
HRMS–MALDI: m/z [MH+] calcd for C18H20NaN2O4: 351.1315;
found: 351.1298.
1H NMR (CDCl3): d = 1.21 (t, J = 7.2 Hz, 3 H, CH3), 3.61 (q, J =
7.2 Hz, 2 H, CH2O), 4.27 (s, 2 H, CH2Ph), 4.75 (d, J = 2.70 Hz, 2
H, OCH2-allyl), 5.19 (s, 2 H, NCH2), 5.21 (d, J =1 0.2 Hz, 1 H, CH-
allyl), 5.38 (d, J = 16.2 Hz, 1 H, CH-allyl), 5.95 (m, 1 H, CH-allyl),
7.27–7.48 (m, 5 H, Harom), 9.69 (s, 1 H, NH).
13C NMR (CDCl3): d = 14.93 (CH3), 35.02 (CH2Ph), 65.35 (OCH2),
66.56 (OCH2-allyl), 72.48 (NCH2), 111.70 (C-5), 119.17 (C-allyl),
127.53, 127.94, 129.18, 134.24, (Carom), 131.14 (C-allyl), 151.18
(C-2), 155.26 (C-4), 159.86 (C-6), 163.95 (COO).
Deprotection of 4-Methoxybenzyl Uracils; General Procedure
The 4-methoxybenzyl protected uracils 4f,g were dissolved in tri-
fluoroacetic acid and stirred at r.t. for 48 h after which the solvent
was evaporated in vacuo to give an oily product. The residual mate-
rial was purified by chromatography on a silica gel column with
EtOAc to afford the compounds 5a,b.
HRMS–MALDI: m/z [MH+] calcd for C18H20NaN2O5: 367.1264;
found: 367.1259.
1-(Allyloxymethyl)-6-benzyl-5-ethoxycarbonyluracil (6c)
Yield: 0.31 g (45%); white solid; mp 189–193 °C.
6-Benzyl-5-ethoxycarbonyluracil (5a)
Yield: 0.59 g (59%); light yellow solid; mp 196–198 °C.
1H NMR (CDCl3): d = 1.29 (t, J = 7.1 Hz, 3 H, CH3), 4.14 (d, J =
2.56 Hz, 2 H, CH2-allyl), 4.21 (s, 2 H, CH2Ph), 4.34 (q, J = 7.1 Hz,
2 H, OCH2), 5.16 (s, 2 H, NCH2), 5.28 (m, 2 H, 2 × CH-allyl), 5.90
(m, 1 H, CH-allyl), 7.21–7.42 (m, 5 H, Harom).
13C NMR (CDCl3): d = 13.94 (CH3), 35.14 (CH2Ph), 62.15 (OCH2),
70.77 (OCH2-allyl), 72.38 (NCH2) 112.13 (C-5), 118.08 (C-allyl),
127.91, 128.37, 129.73, 134.20 (Carom), 131.19 (C-allyl), 151.14 (C-
2), 154.73 (C-4), 159.81 (C-6), 164.16 (COO).
1H NMR (DMSO-d6): d = 1.09 (t, J = 7.2 Hz, 3 H, CH3), 3.81 (s, 2
H, CH2Ph), 4.21 (q, J = 7.2 Hz, 2 H, OCH2), 7.24–7.46 (m, 5 H,
Harom), 11.42 (s, 1 H, NH), 11.49 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 13.80 (CH3), 35.75 (CH2Ph), 60.72
(OCH2), 106.09 (C-5), 126.91, 128.47, 135.79 (Carom), 150.27 (C-
2), 155.64 (C-4), 161.14 (C-6), 164.21 (COO).
HRMS–MALDI: m/z [MH+] calcd for C14H14NaN2O4: 275.1026;
found: 275.1027.
HRMS–MALDI: m/z [MH+] calcd for C18H20NaN2O5: 367.1264;
found: 367.1252.
6-Benzyl-5-allyloxycarbonyluracil (5b)
Yield: 0.67g (67%); white solid; mp 157–158 °C.
Cyclopentylmethyl Amine;21 Typical Procedure
1H NMR (DMSO-d6): d = 3.87 (s, 2 H, CH2Ph), 4.73 (d, J = 2.70
Hz, 2 H, OCH2), 5.23 (d, J = 7.20 Hz, 1 H, CH-allyl), 5.38 (d, J =
10.2 Hz, 1 H, CH-allyl), 5.91 (m, 1 H, CH-allyl), 7.27–7.48 (m, 5
H, Harom), 11.45 (s, 1 H, NH), 11.61 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 35.77 (CH2Ph), 65.12 (OCH2), 105.66
(C-5), 118.00 (C-allyl), 126.94, 128.57, 135.79, (Carom), 132.09 (C-
allyl), 150.27 (C-2), 156.33 (C-4), 161.13 (C-6), 163.99 (COO).
To a cold solution (–68 °C) of cyclopentanecarbonitrile (10g, 0.105
mol) in anhyd MeOH (150 mL), Na (23 g, 1.00 mol) was added in
one portion and after the initial vigorous reaction the mixture was
allowed to reach r.t. within 2 h. The mixture was then refluxed for
3 h and then cooled. The mixture was diluted with sat. NaCl (300
mL) and water (300 mL) and extracted with CH2Cl2 (3 × 150 mL).
The organic fractions were dried over Na2SO4 and evaporated in
vacuo to give a clear oil which was not purified any further; yield
9.83 g (94%).
1H NMR (CDCl3): d = 1.45 (m, 4 H, H-3, H-6), 1.86 (m, 4 H, H-4,
H-5), 1.97 (m, 1 H, H-2), 2.75 (m, 2 H, CH2NH2).
13C NMR (CDCl3): d = 25.23 (C-4, C-5), 30.15 (C-3, C-6), 43.36
(C-2), 47.66 (C-1).
HRMS–MALDI: m/z [MH+] calcd for C15H14NaN2O4: 309.0846;
found: 309.0839.
N-1 Alkylation of 5,6-Disubstituted Uracil Derivatives; General
Procedure
To a suspension of the appropriate uracil (5a,b, 2 mmol) in anhyd
CHCl3 was added N,O-bis(trimethylsilyl) acetamide (BSA) (5
Synthesis 2004, No. 11, 1874–1878 © Thieme Stuttgart · New York

1878
J. S. Larsen et al.
PAPER
(12) Dolle, V.; Fan, E.; Nguyen, C. H.; Aubertin, A. M.; Kirn, A.;
Andreola, M. L.; Jamieson, G.; Tarrago-Litvak, L.; Bisagni,
E. J. Med. Chem. 1995, 38, 4679.
(13) Larsen, J. S.; Abdel Aal, M. T.; Pedersen, E. B. J.
Heterocycl. Chem. 2001, 38, 1.
Acknowledgment
The Danish National Research Foundation are acknowledged for
funding the Nucleic Acid Center.
(14) Larsen, J. S.; Christensen, L.; Ludvig, G.; Jørgensen, P. T.;
Pedersen, E. B.; Nielsen, C. J. Chem. Soc., Perkin Trans. 1
2000, 1, 3035.
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