Synthesis and biological evaluation of 5-(alkyn-1-yl)-1-(p-toluenesulfonyl) uracil derivatives

Article abstract of DOI:10.1139/V06-041

Sonogashira coupling of 5-iodouracil (2) and trimethylsilylacetylene gave 5-(trimethylsilylethynyl)uracil (3), which was deprotected to give 5-ethynyluracil (4). Copper(I)-catalyzed cyclization of 4 gave furo[2,3-d]pyrimidin-2(3H)-one (5). Tosylation of 2 and 4 gave the 1-(p-toluenesulfonyl) derivatives 6 and 7, respectively. The tosylated compound 6 and trimethylsilylacetylene did not undergo Sonogashira coupling, and copper(I)-catalyzed cyclization of 7 did not occur. Coupling of 2 with several terminal alkynes gave 5-(alkyn-1-yl)uracil derivatives (9), which underwent tosylation to produce the targeted 5-(alkyn-1-yl)-1-(p-toluenesulfonyl)uracil compounds (11). Copper(I)-catalyzed cyclization of 9 gave the respective furopyrimidines (10) in low yields. Again, cyclization did not occur with the tosyl derivatives (11). Activity against varicella-zoster virus (VZV) was observed with longer-chain analogues of 9 and 11, and compound 7 showed activity against human cytomegalovirus (HCMV) at near cytotoxic levels.

Full text of DOI:10.1139/V06-041

580
Synthesis and biological evaluation of 5-(alkyn-
1-yl)-1-(p-toluenesulfonyl)uracil derivatives1,2
Zlatko Janeba, Jan Balzarini, Graciela Andrei, Robert Snoeck, Erik De Clercq,
and Morris J. Robins
Abstract: Sonogashira coupling of 5-iodouracil (2) and trimethylsilylacetylene gave 5-(trimethylsilylethynyl)uracil (3),
which was deprotected to give 5-ethynyluracil (4). Copper(I)-catalyzed cyclization of 4 gave furo[2,3-d]pyrimidin-
2(3H)-one (5). Tosylation of 2 and 4 gave the 1-(p-toluenesulfonyl) derivatives 6 and 7, respectively. The tosylated
compound 6 and trimethylsilylacetylene did not undergo Sonogashira coupling, and copper(I)-catalyzed cyclization of 7
did not occur. Coupling of 2 with several terminal alkynes gave 5-(alkyn-1-yl)uracil derivatives (9), which underwent
tosylation to produce the targeted 5-(alkyn-1-yl)-1-(p-toluenesulfonyl)uracil compounds (11). Copper(I)-catalyzed
cyclization of 9 gave the respective furopyrimidines (10) in low yields. Again, cyclization did not occur with the tosyl
derivatives (11). Activity against varicella-zoster virus (VZV) was observed with longer-chain analogues of 9 and 11,
and compound 7 showed activity against human cytomegalovirus (HCMV) at near cytotoxic levels.
Key words: antiviral screening, furo[2,3-d]pyrimidin-2(3H)-one derivatives, Sonogashira coupling, 1-(p-
toluenesulfonyl)pyrimidine derivatives.
Résumé : Un couplage selon la méthode de Sonogashira du 5-iodouracile (2) avec le triméthylsilylacétylène conduit à
la formation de (triméthylsilyléthynyl)uracile (3) qui, par déprotection, conduit au 5-éthynyluracile (4). La cyclisation
catalysée par le cuivre(I) du composé 4 fournit la furo[2,3-d]pyrimidin-2(3H)-one (5). La tosylation des composés 2 et
4 fournit respectivement les dérivés 1-(p-toluènesulfonyle) 6 et 7. Le composé tosylé 6 et le triméthylsilyacétylène ne
réagissent pas dans les conditions de couplage de Sonogashira alors que la cyclisation catalysée par le cuivre(I) du
composé 7 ne se réalise pas. Le couplage du composé 2 avec plusieurs alcynes terminaux conduit aux 5-(alcyn-1-
yl)uraciles (9) qui peut subir une tosylation pour conduire à la formation des composés cibles 5-(alcyn-1-yl)-1-(p-toluè-
nesulfony)uraciles (11). La cyclisation catalysée par le cuivre(I) des composés 9 fournit les furopyrimidines (10) corres-
pondantes avec de faibles rendements. Encore une fois, la cyclisation des dérivés tosylés 11 ne se produit pas. On a
observé une activité contre le virus varicelle-zoster avec les analogues des composés 9 et 11 à longues chaînes alors
que le composé 7 présente une activité contre le cytomégalovirus humain près des niveaux cytotoxiques.
Mots clés : évaluation antivirale, dérivés de la furo[2,3-d]pyrimidin-2(3H)-one, couplage de Sonogashira, dérivés
1-(p-toluènesulfonyl)pyrimidine.
[Traduit par la Rédaction] Janeba et al. 586
Introduction
incorporation of thymidine and 2′-deoxyuridine into primary
rabbit kidney DNA was observed, but no antiviral activity
was found5 with the 6-butylfuro[2,3-d]pyrimidin-2(3H)-one
2′-deoxynucleoside (prepared in 82% yield by cyclization of
2′-deoxy-5-(hexyn-1-yl)uridine with CuI–Et3N–MeOH (2)).
Two decades later, the remarkable anti-varicella-zoster virus
(VZV) selectivity and potency of such bicyclic pyrimidine
nucleoside analogues (BCNAs) with longer alkyl chains at
Furo[2,3-d]pyrimidin-2(3H)-ones (derivatives of com-
pound 5, Fig. 1) with methyl or sugar substituents at N3 and
alkyl groups at C6 were reported in 1981 by Robins and
Barr (1) as fluorescent by-products (~10%) of coupling reac-
tions of 5-iodo-1-methyluracil and 5-iodo-3′,5′-di-O-acetyl-
2′-deoxyuridine with terminal alkynes (1, 2). Inhibition of
Received 5 August 2005. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 5 May 2006.
With congratulations and best wishes to Professor Walter Szarek.
Z. Janeba3 and M.J. Robins.4 Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700,
USA.
J. Balzarini, G. Andrei, R. Snoeck, and E. De Clercq. Rega Institute for Medical Research, Katholieke Universiteit Leuven,
Leuven B-3000, Belgium.
1This article is part of a Special Issue dedicated to Professor Walter A. Szarek.
2Nucleic acid related compounds Paper 132. Paper 131 is ref. 7b.
3Present address: Moravek Biochemicals, Brea, CA.
4Corresponding author (e-mail: morris_robins@byu.edu).
5M.J. Robins and E. De Clercq. Unpublished results.
Can. J. Chem. 84: 580–586 (2006)
doi:10.1139/V06-041
© 2006 NRC Canada

Janeba et al.
581
Fig. 1. Furo[2,3-d]pyrimidin-2(3H)-one.
Scheme 1. Synthesis of the test compounds. Reagents and condi-
tions: (a) I2–CAN–MeCN; (b) TMSA–Pd(PPh3)4–CuI–Et3N–EtOAc;
(c) NaOH–H2O; (d) CuI–Et3N–DMF, ∆; (e) TsCl–pyridine;
( f ) 1-alkyne–Pd(PPh3)4–CuI–Et3N–DMF; (g) (i) HMDS, ∆,
(ii) TsCl–MeCN, ∆.
7
6
O
7a
5
1
2
O
N
4a
4
O
O
Y
O
N
3
X
H
HN
HN
N
b
d
5
O
N
H
O
N
H
O
N
H
1 X = H
2 X =
3 Y = SiMe3
4 Y = H
5
C6 were discovered (3). Extensive SAR studies have been
pursued by McGuigan, Balzarini, De Clercq, and their co-
workers (4–6).
a
c
I
In 2001, we observed that certain alkyl/alkynyl derivatives
of 5 possess anti-human cytomegalovirus (HCMV) activity
(7). It was recently reported that 2′,3′-dideoxynucleoside
derivatives of 5 substituted at C6 with alkyl chains also in-
hibit HCMV by a “non-nucleoside” mechanism (i.e., activa-
tion by a nucleoside kinase is not required) (8). We have
targeted the furo[2,3-d]pyrimidin-2(3H)-one ring system for
other modifications at N3 and (or) C6 (9).
A prior synthetic approach to 5 employed cyclization of
(E)-5-(2-bromovinyl)uracil (BVU) with potassium tert-
butoxide (10, 11). However, the overall yield of 5 was very
low for this five-stage route from uracil. The Cu(I)-promoted
5-endo-dig cyclization of 5-ethynyluracil (4) (Scheme 1)
represented a plausible route to 5 because this type of
cyclization had been shown to proceed in high yields with 1-
methyl and 1-(2-deoxy-β-D-erythro-pentofuranosyl) deriva-
tives of 5-(alkyn-1-yl)uracil (1, 2). However, such treatment
of 4 produced 5 slowly and in limited yields (~15%). Intro-
duction of a protecting group at N1 of 4 followed by
cyclization and deprotection might provide an improved
route to 5.
Protection with a p-toluenesulfonyl group permits depro-
tection by transamidation (12). Tosylation of 4 gave 5-ethynyl-
1-tosyluracil (7). However, 7 did not undergo cyclization
with CuI–Et3N–DMF under the usual conditions. Because 7
showed weak anti-HCMV activity, a new SAR study (13)
with 5-(alkyn-1-yl)-1-tosyluracils was examined. We now
describe the synthesis of such analogues with alkynyl chains
of 6–10 and 12 carbon atoms and the results of evaluations
against a number of viruses and tumor cell systems.
e
e
O
O
O
I
HN
O
HN
N
N
O
N
O
N
O S O
O S O
O S O
CH3
CH3
CH3
8
6
7
R
O
O
R
O
N
I
HN
O
HN
f
+
N
H
O
N
H
O
N
H
d
2
9
10
g
O
R
HN
9–11: a, R = C4H9; b, R = C5H11; c, R =
C6H13; d, R = C7H15; e, R = C8H17; f, R =
O
N
C
10H21.
O S O
Results and discussion
Chemistry
The 5-iodouracil (2) starting material (Scheme 1) was
conveniently prepared in >60 g scale by a modified ce-
rium(IV)-mediated halogenation (14) of uracil (1). The use
of acetonitrile rather than methanol as the solvent resulted in
direct precipitation of the product 2. Filtration of the reac-
tion mixture and immediate recrystallization of the precipi-
tated material from aqueous ethanol gave 2 (83%) of high
purity.
Sonogashira coupling of 2 and trimethylsilylacetylene
(TMSA) followed by removal of the TMS group from inter-
mediate 3 with NaOH–H2O (15) gave 5-ethynyluracil (4).
Various reaction conditions (solvents, temperature, equiva-
lents of CuI) were then examined. Treatment of 4 with CuI
(1.1 equiv.) in DMF–Et3N at 120 °C gave the best, although
CH3
11
limited, conversion to the cyclized ring system 5 (~15%).
Tosylation of 4 under standard conditions (TsCl–pyridine)
gave 5-ethynyl-1-tosyluracil (7) (25%). Treatment of 7 with
Cu(I) did not give detected quantities of 8. Thus, the N1-
tosyl derivative 7 was more resistant to cyclization than 4
(which gave 5 slowly in ~15% yield). The strongly electron-
withdrawing effect of the p-toluenesulfonyl group could
significantly reduce electron donation from N1 into the 5,6-
double bond. Such a diminished enamine contribution to-
ward the triple bond of the alkyne substituent at C5 and (or)
© 2006 NRC Canada

582
Can. J. Chem. Vol. 84, 2006
the oxo group at C4 (enyne-amine and enamine-one conju-
gated systems, respectively) might result in sufficient retar-
dation of complex formation with copper(I) to cause failure
of the endo-dig cyclization process. Tosylation of 2 gave 5-
iodo-1-tosyluracil (12) (6, 40%), but 6 failed to undergo
Sonogashira coupling effectively with 1-hexyne or 1-octyne.
Attempted coupling at ambient temperature with ethyl ace-
tate as the solvent resulted in formation of more polar mate-
rials and recovery of starting 6 (TLC). Heating at 50 °C
resulted in formation of both less and more polar materials
and generation of dark coloration. Thus, withdrawal of elec-
tron density from N1 by the tosyl group apparently has sig-
nificantly adverse effects on oxidative insertion of palladium
into the C5–iodine bond and (or) subsequent steps in the
Sonogishira cycle.
Because the Cu(I)-promoted cyclization of 5-ethynyluracil
(4) was sluggish, we anticipated that Sonogashira couplings
with 5-iodouracil (2) would give the desired 5-(alkyn-1-
yl)uracil analogues (9) without significant formation of the
cyclized furo[2,3-d]pyrimidin-2-one products (10). As
expected, coupling of 2 with terminal alkynes–Pd(PPh3)4–
CuI–Et3N in DMF at ambient temperature gave the products
9 in moderate to good isolated yields (50%–80%), except for
the highly lipophilic 1-dodecynyl derivative 9f (~20%). Very
minor amounts of the furanopyrimidine by-products (10)
were detected as slower-migrating fluorescent spots (TLC)
during these Sonogashira couplings. In several cases, we iso-
lated the by-products in trace yields (~1%), and they were
fully (10a, 10d, and 10e) or partially (10b) characterized.
This corroborated our finding that cyclization of 5-ethynyl-
uracil (4) without an N1 substituent was difficult, and is in
harmony with another report of Sonogashira coupling of 2
with a terminal alkyne and cyclization to give the furano-
pyrimidine in low yield (16). Our treatment of purified 9d
and 9e with CuI–Et3N–DMF at 70 °C for 4 h resulted in
complete disappearance of the starting materials, but the
furanopyrimidines 10d (34%) and 10e (28%) were isolated
in comparably low yields.
Treatment of pyrimidine bases with TsCl–pyridine and
tosylation of trimethylsilylated pyrimidines have been re-
cently employed for preparation of 1-tosylpyrimidine deriva-
tives (12). Our treatment of 5-(decyn-1-yl)uracil (9e) with
TsCl–pyridine at ambient temperature gave a poor yield
(22%) of the 1-tosyl product 11e, and no 11c was detected
(TLC) upon stirring 5-(octyn-1-yl)uracil (9c) with TsCl and
K2CO3 in DMF for 2 days at ambient temperature. Fortu-
nately, tosylation of the trimethylsilylated derivatives was
successful. Hexamethyldisilazane (HMDS) and the 5-alkynyl
compounds (9) were heated at reflux for 1 h, followed by
evaporation of volatiles and in situ tosylation of the TMS de-
rivatives (TsCl–MeCN, ∆). The 1-tosyl-5-(alkyn-1-yl)uracil
products (11) (47%–75%) were isolated after ~24 h. Longer
reaction times resulted in more complex reaction mixtures
(TLC) with little improvement in the yields of 11. The start-
ing materials 9 were recovered after the 24 h treatment in
18%–28% yields by column chromatography.
HCMV or other DNA viruses such as herpes simplex viruses
type 1 and type 2 and vaccinia virus (VV) (Table 1). No ac-
tivity against RNA viruses such as vesicular stomatitis virus
(VSV), Coxsackie B4 virus, respiratory syncytial virus
(RSV), parainfluenza virus-3, reovirus-1, Sindbis virus, and
Punta Toro virus, or HIV-1 and HIV-2 in cell cultures was
observed (data not shown). The 5-alkynyl-substituted uracil
derivatives (9 series) and their corresponding 1-(p-toluene-
sulfonyl) derivatives (11 series), as well as the bicyclic de-
rivatives (10 series), were devoid of antiviral activity at
subtoxic concentrations, except for 9d, 9e, 11e, and 11f (for
which weak anti-VZV activity (EC50: 10–37 µmol/L) was
found). The absence of significant biological activity with
the 9 and 10 series compounds suggests that they do not
function as substrates of thymidine phosphorylase or other
cellular enzymes that convert pyrimidines to their corre-
sponding nucleoside analogues. Attachment of the bulky
tosyl group at N1 of the uracil base (for the 11 series) did
not produce derivatives with significant intrinsic activity and
precluded glycosyl transfer. No visible cytotoxic effects
were found upon microscopic inspection of cells at com-
pound concentrations as high as 80–400 µmol/L. These
compounds were not markedly inhibitory (cytostatic) to hu-
man embryonic lung (HEL) cell proliferation (Table 1). Sig-
nificant cytostatic effects were not observed with murine
leukemia L1210, murine mammary carcinoma FM3A, hu-
man lymphocyte CEM, and human cervix carcinoma HeLa
cells with these compounds (IC50: 60 to >500 µmol/L, data
not shown).
Conclusions
Sonogashira coupling of 5-iodouracil (2) with terminal
alkynes afforded the 5-(alkyn-1-yl)uracil derivatives (9) in
moderate to good yields. Certain 6-alkylfuro[2,3-d]pyrimidin-
2-ones (10) were isolated as trace by-products. The Cu(I)-
promoted cyclization of 5-ethynyluracil (4) gave the parent
furo[2,3-d]pyrimidin-2(3H)-one (5) in ~15% yield, and the
6-alkyl derivatives (10) were obtained from the correspond-
ing 5-(alkyn-1-yl)uracils (9) in yields of ~30%. In situ
tosylation of trimethylsilylated derivatives of 9 gave the 5-
(alkyn-1-yl)-1-tosyluracils (11) in moderate to good yields.
Biological evaluations were performed with the 5-(alkyn-1-
yl)uracils (9), their 1-tosyl analogues (11), and the 6-
alkylfuro[2,3-d]pyrimidin-2-one derivatives (10a, 10d, and
10e). Weak anti-VZV activity was observed with 9d, 9e,
11e, and 11f, and anti-HCMV activity at near cytotoxic con-
centrations with 7. No significant antiviral activity with
other DNA and RNA viruses and no cytostatic activity of
significance were found with other compounds in this study.
Experimental
Uncorrected melting points were determined with a hot-
stage apparatus. UV spectra were measured with solutions in
1
MeOH. H (500 MHz) and 13C (125 MHz) NMR spectra
were determined with solutions in DMSO-d6. “Apparent”
peak shapes are in quotation marks when the first-order
splitting should be more complex or when the peaks were
poorly resolved. High-resolution mass spectra (HRMS) were
determined by EI or FAB (thioglycerol, NaOAc). Chemicals
and solvents were of reagent quality. Column chromatogra-
Biological evaluations
Compound 6 showed weak activity against VZV (TK+
(strain OKA) and TK– (strain 07/1)), but no activity against
© 2006 NRC Canada

Janeba et al.
583
Table 1. Anti-DNA virus activity and cytotoxic activity of the test compounds in cell cultures.
a
EC50 (µmol/L)
c
HSV-1
(KOS)
(HEL)
HSV-2
(G)
VV
VZV
VZV
HCMV
AD-169
(HEL)
MCCb
CC50
(OKA)
(HEL)
(07/1)
(HEL)
Davis
(µmol/L)
(HEL)
(µmol/L)
Compd.
(HEL)
(HEL)
(HEL)
(HEL)
45
>16
331
>80
>80
37
>16
>80
213
>80
>80
>16
>16
>16
>16
16
80
>16
>400
>80
>80
34
>80
36
>400
>400
>400
>80
>400
>80
>400
>400
>400
>16
>80
>16
>80
>80
>80
>600
9.4
>80
39
400
80
>400
400
>400
>80
>400
240
>400
400
400
80
240
80
>80
48
240
>600
>1000
131
29
200
114
132
67
6
7
9a
9b
9c
9d
9e
9f
10a
10d
10e
11a
11b
11c
11d
11e
11f
BVDU
GCV
>200
>200
>200
>200
>200
>40
>40
>40
>200
>200
>200
>40
>200
>200
>200
>200
>200
>40
>40
>40
>200
>200
>200
>40
>200
>200
>200
>200
>200
>40
>40
>40
>200
>200
>200
>40
>400
>80
>80
>80
>400
>80
>400
>400
>400
>16
51
>16
>16
>16
>80
>600
12
16
63
>16
171
>80
>80
>16
>16
>16
>16
10
>200
>200
>200
>200
61
134
63
98
31
85
>600
115
>40
>40
>40
>200
>200
>200
>200
>200
>200
>200
>200
300
>200
>200
>200
>200
60
>16
0.012
—
27
198
—
0.032
0.032
0.096
>100
a50% Effective concentration (compound concentration required to inhibit virus-induced cytopathogenicity or plaque formation (VZV) by 50%).
bMinimum cytotoxic concentration (compound concentration required to cause a microscopically visible alteration of cell morphology).
c50% cytostatic concentration (compound concentration required to inhibit cell proliferation by 50%).
phy (silica gel, 230–400 mesh) was performed with solu-
tions of CH2Cl2–MeOH.
H2O (500 mL) and filtered, and the filtrate was concentrated
in vacuo to half the volume (~500 mL). The pH of this solu-
tion was adjusted with AcOH (to pH ~ 5), and the suspen-
sion was cooled (~0 °C). The solid was filtered, washed
(H2O, acetone, Et2O), and dried to give 4 (9.59 g, 83%) as a
TLC-homogeneous orange powder with clean 1H NMR
spectra. An analytical sample was recrystallized (EtOH,
84% recovery) to give 4 as a slightly yellow powder; mp >
Method 1: 5-substituted-uracil–TsCl–pyridine is described
in detail for 2 → 6. Method 2: 5-iodouracil–1-alkyne–
Pd(PPh3)4–CuI–Et3N–DMF for 2 → 9a. Method 3: 5-(alkyn-
1-yl)uracil–CuI–Et3N–DMF for 9d → 10d. Method 4: (a) 5-
(alkyn-1-yl)uracil–HMDS; (b) TsCl–MeCN, ∆ for 9a → 11a.
1
220 °C dec. UV max: 284, 224 nm (ε 10 000, 11 300). H
5-Iodouracil (2) (ref. 14)
NMR δ: 4.04 (s, 1H), 7.81 (s, 1H), 11.32 (bs, 2H). 13C NMR
δ: 162.7, 150.5, 146.5, 96.3, 83.2, 76.6. HRMS m/z:
136.0270 (M+ [C6H4N2O2] = 136.0273). Anal. calcd. for
C6H4N2O2: C 52.95, H 2.96, N 20.58; found: C 53.09, H
3.06, N 20.75.
A mixture of uracil (1) (35.0 g, 0.31 mol), iodine (47.0 g,
0.19 mol), and CAN (85.5 g, 0.16 mol) in MeCN (750 mL)
was stirred at reflux for 5 h, and precipitation of a white
solid occurred. The reaction mixture was cooled to ~0 °C in
a refrigerator, and the solid was filtered and washed with a
small amount of cold MeCN. This material was recry-
stallized immediately (EtOH–H2O, 1:1) to give 2 (61.6 g,
83%) as colorless needles; mp > 250 °C dec. (lit. value (14)
mp 198 °C, 245 °C dec; lit. value (17) mp 272 °C). UV
max: 280 nm (ε 7100). 1H NMR δ: 7.88 (s, 1H), 11.15 (br s,
1H), 11.39 (br s, 1H). 13C NMR δ: 161.5, 151.2, 146.9, 67.6.
HRMS m/z: 237.9238 (M+ [C4H3IN2O2] = 237.9239).
Furo[2,3-d]pyrimidin-2(3H)-one (5) (refs. 10 and 11)
A suspension of 4 (680 mg, 5.0 mmol) and CuI (1 g,
5.25 mmol) in a deoxygenated mixture of Et3N (3.5 mL) and
DMF (30 mL) was heated at 120 °C for 23 h. Volatiles were
evaporated in vacuo, and toluene was added to the residue
and then evaporated (3 × 5 mL). The residue was
chromatographed (5% MeOH – CH2Cl2 → 20% MeOH –
CH2Cl2) and recrystallized (EtOH) to give slightly yellow
crystals of 5 (102 mg, 14.7%); mp > 280 °C (lit. value (10)
mp 260 °C; lit. value (11) mp 260–262 °C). UV max: 324,
5-Ethynyluracil (4) (ref. 15)
TMSA (14.5 mL, 10.1 g, 0.103 mol) and then Et3N
(60 mL) were added to a suspension of 2 (20.0 g,
84.0 mmol), Pd(PPh3)4 (4.9 g, 4.24 mmol), and CuI (1.3 g,
6.83 mmol) in deoxygenated EtOAc (220 mL). The reaction
mixture was stirred at ambient temperature under N2 for 3 h,
and then cooled to ~0 °C. The solid TMS derivative 3 was
filtered and then stirred in NaOH–H2O (1 mol/L, 500 mL) at
ambient temperature for 2 h. This mixture was diluted with
1
242 nm (ε 4 800, 10 900). H NMR δ: 6.74 (d, J = 2.8 Hz,
1H), 7.70 (d, J = 2.8 Hz, 1H), 8.34 (s, 1H), 12.15 (br s, 1H).
13C NMR δ: 172.2, 156.0, 144.4, 141.3, 105.1, 104.5.
HRMS m/z: 136.0279 (M+ [C6H4N2O2] = 136.0273). Anal.
calcd. for C6H4N2O2: C 52.95, H 2.96, N 20.58; found: C
52.72, H 3.12, N 20.36.
© 2006 NRC Canada

584
Can. J. Chem. Vol. 84, 2006
[C10H12N2O2] = 192.0899). Anal. calcd. for C10H12N2O2: C
62.49, H 6.29, N 14.57; found: C 62.55, H 6.12, N 14.70.
5-Iodo-1-tosyluracil (6) (ref. 12)
Method 1
A mixture of 2 (1.0 g, 4.2 mmol) and TsCl (881 mg,
4.62 mmol) in pyridine (25 mL) was stirred at ambient tem-
perature for 28 h. MeOH (3 mL) was added, the solution
was stirred for 10 min, and volatiles were evaporated. The
residue was dissolved in CH2Cl2 (60 mL), and the solution
was washed (0.1 mol/L HCl–H2O, satd. NaHCO3–H2O, and
H2O) and dried (MgSO4). Volatiles were evaporated, and the
residue was chromatographed and recrystallized (EtOAc) to
give 6 (662 mg, 40%); mp 250–252 °C. UV max: 276,
5-(Heptyn-1-yl)uracil (9b)
Treatment of 2 (2.0 g, 8.4 mmol) by Method 2 gave 9b
(890 mg, 51%); mp 241–243 °C. UV max: 289, 230 nm
1
(ε 11 400, 13 500). H NMR δ: 0.86 (t, J = 7.3 Hz, 3H),
1.24–1.37 (m, 4H), 1.44–1.49 (m, 2H), 2.32 (t, J = 7.3 Hz,
2H), 7.62 (s, 1H), 11.11 (s, 1H), 11.26 (s, 1H). 13C NMR δ:
162.9, 150.5, 144.6, 97.7, 92.8, 73.0, 30.5, 28.0, 21.7, 18.8,
13.9. HRMS m/z: 206.1052 (M+ [C11H14N2O2] = 206.1055).
Elemental analyses were not obtained for this compound,
but NMR spectra were equally clean.
1
231 nm (ε 9 500, 14 800). H NMR δ: 2.43 (s, 3H), 7.49 (d,
J = 8.3 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H), 8.39 (s, 1H),
12.03 (bs, 1H). 13C NMR δ: 160.3, 147.0, 146.5, 141.0,
132.8, 129.8, 129.2, 73.3, 21.2. HRMS m/z: 391.9333 (M+
[C11H9N2IO4S] = 391.9328). Anal. calcd. for C11H9N2IO4S:
C 33.69, H 2.31, N 7.14; found: C 33.91, H 2.02, N 7.30.
The fluorescent by-product was recrystallized to give 10b
1
(8 mg, 0.5%) as a white solid. H NMR δ: 0.87 (t, J =
6.8 Hz, 3H), 0.88–1.32 (m, 4H), 1.59–1.62 (m, 2H), 2.62 (t,
J = 7.3 Hz, 2H), 6.37 (s, 1H), 8.14 (s, 1H), 11.95 (bs, 1H).
HRMS m/z: 206.1045 (M+ [C11H14N2O2] = 206.1055).
5-Ethynyl-1-tosyluracil (7)
Treatment of 4 (500 mg, 3.67 mmol) by Method 1 gave 7
5-(Octyn-1-yl)uracil (9c)
Treatment of 2 (1.0 g, 4.2 mmol) by Method 2 gave 9c
(263 mg, 25%); mp 206 °C. UV max: 277, 228 nm
(490 mg, 53%); mp 231–235 °C. UV max: 289, 230 nm
1
(ε 14 500, 17 100). H NMR δ: 2.43 (s, 3H), 4.29 (s, 1H),
1
(ε 11 400, 13 500). H NMR δ: 0.87 (t, J = 6.8 Hz, 3H),
7.50 (d, J = 8.3 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H), 8.32 (s,
1H), 12.01 (bs, 1H). 13C NMR δ: 161.2, 146.6, 146.4, 141.3,
132.7, 129.9, 129.3, 100.1, 85.2, 75.1, 21.2. HRMS m/z:
290.0364 (M+ [C13H10N2O4S] = 290.0361). Anal. calcd. for
C13H10N2O4S: C 53.79, H 3.47, N 9.65; found: C 53.83, H
3.60, N 9.66.
1.25–1.31 (m, 4H), 1.32–1.41 (m, 2H), 1.48 (“quint”, J =
~7.2 Hz, 2H), 2.34 (t, J = 6.8 Hz, 2H), 7.64 (s, 1H), 11.13
(s, 1H), 11.28 (s, 1H). 13C NMR δ: 162.9, 150.5, 144.5,
97.7, 92.8, 73.0, 30.8, 28.2, 28.0, 22.1, 18.8, 13.9. HRMS
m/z: 220.1205 (M+ [C12H16N2O2] = 220.1212). Anal. calcd.
for C12H16N2O2: C 65.43, H 7.32, N 12.72; found: C 65.27,
H 7.18, N 12.58.
5-(Hexyn-1-yl)uracil (9a)
5-(Nonyn-1-yl)uracil (9d)
Treatment of 2 (2.0 g, 8.4 mmol) by Method 2 gave 9d
Method 2
A stirred suspension of 2 (2.0 g, 8.4 mmol), (Ph3P)4Pd
(490 mg, 0.42 mmol), and CuI (130 mg, 0.68 mmol) in
DMF (25 mL) was purged with N2 at room temperature. 1-
Hexyne (1.26 mL, 898 mg, 10.9 mmol) was added, followed
by dried Et3N (8 mL). The reaction mixture was stirred un-
der N2 at ambient temperature for 40 h. Volatiles were evap-
orated, and toluene was added to the residue and then
evaporated (2 × 8 mL). The residue was extracted with hot
MeOH (100 mL), and the remaining solid was filtered and
washed (MeOH). Volatiles were evaporated in vacuo from
the combined MeOH extract and wash. Chromatography
(5% MeOH – CH2Cl2) and recrystallization (MeOH) of the
residue gave 9a (980 mg, 61%); mp 248–251 °C. UV max:
(1.19 g, 60%); mp 233–236 °C. UV max: 289, 230 nm
1
(ε 12 500, 14 600). H NMR δ: 0.86 (t, J = 6.6 Hz, 3H),
1.22–1.29 (m, 6H), 1.33–1.38 (m, 2H), 1.47 (“quint”, J =
7.2 Hz, 2H), 2.33 (t, J = 7.1 Hz, 2H), 7.62 (s, 1H), 11.10 (s,
1H), 11.26 (s, 1H). 13C NMR δ: 162.9, 150.5, 144.6, 97.7,
92.7, 72.9, 31.2, 28.2, 22.1, 18.8, 13.9. HRMS m/z:
234.1371 (M+ [C13H18N2O2] = 234.1368). Anal. calcd. for
C13H18N2O2: C 66.64, H 7.74, N 11.96; found: C 66.84, H
7.90, N 12.08.
The fluorescent by-product was recrystallized (EtOAc–
EtOH) to give 10d (19 mg, 1%), mp 265–266 °C; and iden-
tical spectral data with 10d prepared by Method 3.
1
289, 229 nm (ε 11 100, 13 100). H NMR δ: 0.88 (t, J =
5-(Decyn-1-yl)uracil (9e)
Treatment of 2 (2.0 g, 8.4 mmol) by Method 2 gave 9e
7.3 Hz, 3H), 1.37–1.44 (m, 2H), 1.46–1.48 (m, 2H), 2.34 (t,
J = 6.8 Hz, 2H), 7.63 (s, 1H), 11.13 (s, 1H), 11.28 (s, 1H).
13C NMR δ: 162.9, 150.5, 144.6, 97.7, 92.7, 73.0, 30.3, 21.4,
18.5, 13.5. HRMS m/z: 192.0892 (M+ [C10H12N2O2] =
192.0899). Anal. calcd. for C10H12N2O2: C 62.49, H 6.29, N
14.57; found: C 62.56, H 6.23, N 14.72.
(1.73 g, 81%); mp 210–215 °C. UV max: 289, 228 nm
1
(ε 10 300, 12 700). H NMR δ: 0.84 (t, J = 6.8 Hz, 3H),
1.22–1.26 (m, 8H), 1.35–1.37 (m, 2H), 1.46 (“quint”, J =
7.2 Hz, 2H), 2.32 (t, J = 7.0 Hz, 2H), 7.61 (s, 1H), 11.11 (s,
1H), 11.27 (s, 1H). 13C NMR δ: 162.9, 150.5, 144.5, 97.7,
92.8, 73.0, 31.3, 28.7, 28.6, 28.31, 28.26, 22.1, 18.8, 14.0.
HRMS m/z: 248.1517 (M+ [C14H20N2O2] = 248.1525). Anal.
calcd. for C14H20N2O2: C 67.71, H 8.12, N 11.28; found: C
67.90, H 7.96, N 11.19.
The fluorescent by-product was isolated from later frac-
tions and recrystallized (EtOAc–EtOH) to give 10a (25 mg,
1.5%); mp > 220 °C dec. UV max: 327, 244 nm (ε 4 900,
1
14 800). H NMR δ: 0.90 (t, J = 7.6 Hz, 3H), 1.34 (dt, J =
7.3, 7.3 Hz, 2H), 1.59 (“quint”, J = ~7.4 Hz, 2H), 2.63 (t,
J = 7.3 Hz, 2H), 6.37 (s, 1H), 8.14 (s, 1H), 11.96 (bs, 1H).
13C NMR (50 °C) δ: 171.9, 157.6, 155.7, 138.6, 105.9, 99.4,
28.3, 26.8, 21.3, 13.3. HRMS m/z: 192.0898 (M+
The fluorescent by-product was recrystallized (EtOAc–
EtOH) to give 10e (15 mg, 0.7%), mp 255–256 °C; and
identical spectral data with 10e prepared by Method 3.
© 2006 NRC Canada

Janeba et al.
585
101.3, 94.9, 71.7, 30.0, 21.3, 21.2, 18.4, 13.4. HRMS m/z:
346.0980 (M+ [C17H18N2O4S] = 346.0987). Anal. calcd. for
C17H18N2O4S: C 58.94, H 5.24, N 8.09; found: C 58.94, H
5.13, N 7.72.
Starting material 9a (140 mg, 28%) was recovered from
later chromatographic fractions.
5-(Dodecyn-1-yl)uracil (9f)
Treatment of 2 (2.0 g, 8.4 mmol) by Method 2 gave 9f
(380 mg, 19%); mp 224–227 °C. UV max: 289, 229 nm
1
(ε 12 500, 15 000). H NMR δ: 0.85 (t, J = 6.8 Hz, 3H),
1.22–1.27 (m, 12H), 1.37–1.38 (m, 2H), 1.44–1.50 (m, 2H),
2.33 (t, J = 6.8 Hz, 2H), 7.61 (s, 1H), 11.10 (s, 1H), 11.25
(s, 1H). 13C NMR δ: 162.8, 150.4, 144.4, 97.6, 92.7, 72.9,
31.3, 28.9, 28.7, 28.5, 28.22, 28.19, 22.1, 18.8, 13.9. HRMS
m/z: 276.1838 (M+ [C16H24N2O2] = 276.1838). Anal. calcd.
for C16H24N2O2: C 69.53, H 8.75, N 10.14; found: C 69.60,
H 8.59, N 10.00.
5-(Heptyn-1-yl)-1-tosyluracil (11b)
Treatment of 9b (250 mg, 1.21 mmol) by Method 4 gave
11b (205 mg, 47%); mp 180 °C. UV max: 285, 230 nm
1
(ε 13 500, 19 900). H NMR δ: 0.88 (t, J = 7.3 Hz, 3H),
1.29–1.35 (m, 2H), 1.37–1.41 (m, 2H), 1.52 (“quint”, J =
7.2 Hz, 2H), 2.40 (t, J = 7.1 Hz, 2H), 2.43 (s, 3H), 7.49 (d,
J = 8.3 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H), 8.16 (s, 1H),
11.94 (s, 1H). 13C NMR δ: 161.3, 146.5, 146.4, 139.3, 132.8,
129.8, 129.2, 101.3, 95.0, 71.7, 30.5, 27.7, 21.6, 21.2, 18.7,
13.9. HRMS (FAB) m/z: 383.1042 (M+ [C18H20N2O4SNa] =
383.1041). Anal. calcd. for C18H20N2O4S: C 59.98, H 5.59,
N 7.77; found: C 59.79, H 5.56, N 7.73.
6-Heptylfuro[2,3-d]pyrimidin-2(3H)-one (10d)
Method 3
A mixture of 9d (300 mg, 1.28 mmol), CuI (268 mg,
1.41 mmol), and Et3N (5 mL) in deoxygenated DMF
(25 mL) was stirred at 70 °C for 4 h. Volatiles were evapo-
rated, and toluene was added and evaporated (2 × 5 mL).
The residue was extracted with hot MeOH (50 mL), and the
remaining solid was filtered. The filtrate was evaporated,
and the residue was chromatographed (CH2Cl2 → 8%
MeOH – CH2Cl2) and recrystallized (EtOAc–EtOH, 1:4) to
give 10d (103 mg, 34%); mp 267 °C. UV max: 327, 244 nm
(ε 5 800, 17 000). 1H NMR δ: 0.86 (t, J = 6.8 Hz, 3H), 1.26–
1.31 (m, 8H), 1.59–1.62 (m, 2H), 2.62 (t, J = 7.3 Hz, 2H),
6.36 (s, 1H), 8.13 (s, 1H), 11.94 (bs, 1H). 13C NMR (50 °C)
δ: 171.9, 157.6, 155.7, 138.8, 105.9, 99.3, 30.9, 28.1, 28.0,
27.2, 26.2, 21.8, 13.6. HRMS (FAB) m/z: 257.1277 (MNa+
[C13H18N2O2Na] = 257.1266). Anal. calcd. for C13H18N2O2:
C 66.64, H 7.74, N 11.96; found: C 66.59, H 7.76, N 11.96.
Starting material 9b (60 mg, 24%) was recovered from
later chromatographic fractions.
5-(Octyn-1-yl)-1-tosyluracil (11c)
Treatment of 9c (250 mg, 1.13 mmol) by Method 4 gave
11c (320 mg, 75%); mp 168–169 °C. UV max: 284, 230 nm
1
(ε 14 100, 21 300). H NMR δ: 0.87 (t, J = 6.8 Hz, 3H),
1.27–1.28 (m, 4H), 1.39–1.40 (m, 2H), 1.51 (“quint”, J =
7.2 Hz, 2H), 2.39 (t, J = 6.8 Hz, 2H), 2.42 (s, 3H), 7.48 (d, J
= 8.3 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 8.16 (s, 1 H), 11.92
(s, 1H). 13C NMR δ: 161.2, 146.5, 146.4, 139.2, 132.8, 129.8,
129.2, 101.3, 95.0, 71.7, 30.7, 27.9, 22.0, 21.2, 18.7, 13.9.
HRMS (FAB) m/z: 397.1198 (MNa+ [C19H22N2O4SNa] =
397.1198). Anal. calcd. for C19H22N2O4S: C 60.94, H 5.92,
N 7.48; found: C 60.78, H 6.02, N 7.31.
6-Octylfuro[2,3-d]pyrimidin-2(3H)-one (10e)
Treatment of 9e (249 mg, 1.0 mmol) by Method 3 gave
10e (70 mg, 28%); mp 259 °C. UV max: 327, 244 nm
(ε 5 500, 16 000). 1H NMR δ: 0.85 (t, J = 6.8 Hz, 3H), 1.25–
1.30 (m, 10H), 1.59–1.61 (m, 2H), 2.62 (t, J = 7.3 Hz, 2H),
6.36 (s, 1H), 8.13 (s, 1H), 11.92 (bs, 1H). 13C NMR (50 °C)
δ: 171.9, 157.6, 155.7, 138.5, 105.9, 99.3, 31.0, 28.3, 27.2,
26.2, 21.8, 13.6. HRMS m/z: 248.1535 (M+ [C14H20N2O2] =
248.1525). Anal. calcd. for C14H20N2O2: C 67.71, H 8.12,
N 11.28; found: C 67.88, H 8.15, N 11.24.
Starting material 9c (48 mg, 19%) was recovered from
later chromatographic fractions.
5-(Nonyn-1-yl)-1-tosyluracil (11d)
Treatment of 9d (250 mg, 1.07 mmol) by Method 4 gave
11d (218 mg, 52%); mp 159 °C. UV max: 285, 230 nm
1
(ε 13 800, 20 700). H NMR δ: 0.86 (t, J = 6.8 Hz, 3H),
1.26–1.29 (m, 6H), 1.38–1.40 (m, 2H), 1.51 (“quint”, J =
7.1 Hz, 2H), 2.39 (t, J = 7.0 Hz, 2H), 2.42 (s, 3H), 7.49 (d,
J = 8.3 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 8.16 (s, 1H),
11.93 (s, 1H). 13C NMR δ: 161.2, 146.5, 146.4, 139.2, 132.8,
129.8, 129.2, 101.3, 95.0, 71.7, 31.2, 28.2, 22.0, 21.2, 18.7,
13.9. HRMS (FAB) m/z: 411.1363 (MNa+ [C20H24N2O4SNa] =
411.1354). Anal. calcd. for C20H24N2O4S: C 61.83, H 6.23,
N 7.21; found: C 61.68, H 6.37, N 6.95.
5-(Hexyn-1-yl)-1-tosyluracil (11a)
Method 4
A mixture of 9a (500 mg, 2.60 mmol) and HMDS
(15 mL) was refluxed under N2 for 1 h. Volatiles were evap-
orated in vacuo with protection from moisture. The residual
oil was dissolved in dried MeCN (20 mL) and TsCl
(595 mg, 3.12 mmol) was added. The reaction mixture was
refluxed under N2 for 24 h. MeOH (1 mL) was added, and
the mixture was stirred at ambient temperature for 10 min.
Volatiles were evaporated, and the residue was chromato-
graphed (3% MeOH in CH2Cl2) and recrystallized (EtOAc)
to give 11a (518 mg, 57%) as white needles; mp 196–
Starting material 9d (60 mg, 24%) was recovered from
later chromatographic fractions.
5-(Decyn-1-yl)-1-tosyluracil (11e)
Treatment of 9e (200 mg, 0.81 mmol) by Method 3 gave
11e (70 mg, 22%) (as white crystals from MeOH); mp 153–
1
154 °C. UV max: 285, 230 nm (ε 13 300, 20 000). H NMR
1
197 °C. UV max: 284, 230 nm (ε 14 600, 22 300). H NMR
δ: 0.86 (t, J = 6.6 Hz, 3H), 1.26–1.29 (m, 8H), 1.38–1.40
(m, 2H), 1.51 (“quint”, J = 7.1 Hz, 2H), 2.40 (t, J = 6.8 Hz,
2H), 2.43 (s, 3H), 7.49 (d, J = 8.3 Hz, 2H), 7.97 (d, J =
8.3 Hz, 2H), 8.16 (s, 1H), 11.93 (s, 1H). 13C NMR δ: 161.2,
146.5, 146.4, 139.2, 132.8, 129.8, 129.2, 101.3, 95.0, 71.7,
δ: 0.90 (t, J = 7.3 Hz, 3H), 1.40–1.44 (m, 2H), 1.50 (“quint”,
J = 7.0 Hz, 2H), 2.39–2.43 (m, 5H), 7.49 (d, J = 8.3 Hz,
2H), 7.98 (d, J = 8.3 Hz, 2H), 8.16 (s, 1H), 11.92 (s, 1H).
13C NMR δ: 161.2, 146.5, 146.4, 139.2, 132.8, 129.8, 129.2,
© 2006 NRC Canada

586
Can. J. Chem. Vol. 84, 2006
31.2, 28.6, 28.5, 28.2, 27.9, 22.1, 21.2, 18.7, 13.9. HRMS
Acknowledgements
(FAB) m/z: 425.1508 (MNa+ [C21H26N2O4SNa]
=
We gratefully acknowledge pharmaceutical company gift
funds (MJR), Brigham Young University, and the
Geconcerteerde Onderzoeksacties (GOA) – Vlaanderen for
financial support. We thank Ann Absillis, Anita Camps, Ste-
ven Carmans, Frieda De Meyer, Lies Van den Heurck, and
Anita Van Lierde for excellent technical assistance with the
antiviral assays.
425.1511). Anal. calcd. for C21H26N2O4S: C 62.66, H 6.51,
N 6.96; found: C 62.80, H 6.70, N 7.04.
5-(Dodecyn-1-yl)-1-tosyluracil (11f)
Treatment of 9f (177 mg, 0.64 mmol) by Method 4 gave
11f (160 mg, 58%); mp 158–159 °C. UV max: 285, 229 nm
1
(ε 12 900, 19 800). H NMR δ: 0.85 (t, J = 6.6 Hz, 3H),
1.22–1.28 (m, 12H), 1.37–1.40 (m, 2H), 11.51 (“quint”, J =
7.3 Hz, 2H), 2.39 (t, J = 7.1 Hz, 2H), 2.43 (s, 3H), 7.49 (d,
J = 8.3 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 8.16 (s, 1H),
11.95 (s, 1H). 13C NMR δ: 161.3, 146.5, 146.4, 139.2,
132.8, 129.8, 129.2, 101.3, 95.0, 71.7, 31.3, 28.9, 28.7, 28.5,
28.2, 27.9, 22.1, 21.2, 18.7, 14.0. HRMS (FAB) m/z:
453.1834 (MNa+ [C23H30N2O4SNa] = 453.1824). Anal.
calcd. for C23H30N2O4S: C 64.16, H 7.02, N 6.51; found: C
63.96, H 7.02, N 6.36.
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© 2006 NRC Canada