Synthesis of 1-[cis-3-(hydroxymethyl)cyclobutyl]-uracil, -thymine and -cytosine

Article abstract of DOI:10.1039/a803878c

4-(Benzylsulfanyl)pyrimidin-2(1H)-one 6a is prepared from 1-benzoyluracil 10a in three steps and in satisfactory overall yield. Reproducible conditions are found for the cycloaddition reaction between allyl benzyl ether and dichloroketene, leading to the

Full text of DOI:10.1039/a803878c

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Synthesis of 1-[cis-3-(hydroxymethyl)cyclobutyl]-uracil, -thymine
and -cytosine
Miriam Frieden, Matthieu Giraud, Colin B. Reese* and Quanlai Song
Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS
4-(Benzylsulfanyl)pyrimidin-2(1H)-one 6a is prepared from 1-benzoyluracil 10a in three steps and in
satisfactory overall yield. Reproducible conditions are found for the cycloaddition reaction between
allyl benzyl ether and dichloroketene, leading to the cyclobutanone derivative 17 in good yield.
trans-3-(Benzyloxymethyl)cyclobutan-1-ol 15 reacts under standard Mitsunobu conditions with the
pyrimidine derivative 6a on O-2 to give compound 20, which is converted into 2-[cis-3-(hydroxymethyl)-
cyclobutoxy]pyrimidin-4(3H)-one 24 in good overall yield. Under the same Mitsunobu conditions,
3-benzoyluracil 11a and 3-benzoylthymine 11b react with the trans-alcohol 15 on N-1 to give their
1-[cis-3-(benzyloxymethyl)cyclobutyl] derivatives 27a and 27b, respectively. The latter compounds 27a
and 27b are converted into 1-[cis-3-(hydroxymethyl)cyclobutyl]uracil 13a and 1-[cis-3-(hydroxymethyl)-
cyclobutyl]thymine 13b in satisfactory overall yields. The uracil derivative 13a is converted into 1-[cis-3-
(hydroxymethyl)cyclobutyl]cytosine 14 in good yield.
Cl
Introduction
O
N
We have previously reported1,2 that 2-amino-6-[(4-chloro-
S
N
N
phenyl)sulfanyl]-9H-purine 1a, its 2-N-phenylacetyl derivative
NH
1b and 6-[(4-chlorophenyl)sulfanyl]-9H-purine 1c are useful
and potentially versatile building blocks in the synthesis of
9-alkylpurine derivatives. The bulky (4-chlorophenyl)sulfanyl
group promotes alkylation on N-9 (rather than on N-7) with
a high degree of regioselectivity and, following oxidation with
3-chloroperoxybenzoic acid, the products readily undergo
nucleophilic substitution at C-6. We first demonstrated1 that
the 2-aminopurine derivative 1a could readily be converted into
acyclovir 2 and its 6-deoxy derivative 3. We have recently
shown2 that the other two purine building blocks 1b and 1c can
be converted into 9-[cis-3-(hydroxymethyl)cyclobutyl]-guanine
and -adenine (4 and 5, respectively), which are potential anti-
viral agents. In the present study, we first set out to examine
N
N
NH2
O
N
H
HO
N
R
1 a; R = NH2
2
b; R = NHCOCH2Ph
c; R = H
O
N
NH
N
N
N
N
NH2
N
N
NH2
O
HO
HO
4
3
whether
a 4-(arylsulfanyl)- or 4-(alkylsulfanyl)-pyrimidin-
NH2
2(1H)-one 6 would be a useful building block for the prepar-
ation of the corresponding 1-alkyl derivatives of uracil and
cytosine.
SR
S
N
N
N
N
HN
We selected 4-(benzylsulfanyl)pyrimidin-2(1H)-one 6a as
a suitable building block of this type. 4-(Benzylsulfanyl)-
pyrimidin-2(1H)-one 6a had previously been prepared3 in 46%
yield by allowing 4-thiouracil4 7 to react with benzyl chloride in
aqueous sodium hydroxide. There are a number of literature
reports4–7 relating to the conversion of uracil 8a into 4-thio-
uracil 7 by treatment with phosphorus pentasulfide4–6 or with
2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-
disulfide (Lawesson’s reagent)7 9. However, in our hands, due
most probably to the physical properties of 4-thiouracil 7,
work-up of the reaction products proved to be laborious.
Furthermore, reaction between uracil 8a and Lawesson’s
reagent 9 is reported7 not to occur regiospecifically on C-4.
N
O
N
H
O
N
H
HO
5
6 a; R = PhCH2
7
O
S
S
S
S
R
HN
P
P
O
N
H
MeO
OMe
8 a; R = H
b; R = Me
9
excess of benzoyl chloride in pyridine–acetonitrile to give their
1-benzoyl derivatives (10a and 10b, respectively) in good yields.
We had further reported8 that when uracil 8a and thymine
8b were treated with more than 2 mol equiv. of benzoyl
chloride, and the products were then subjected to basic
hydrolysis under mild conditions [Scheme 1(a), step ii], their
3-benzoyl derivatives (11a and 11b, respectively) were obtained,
also in good yields (see Experimental section).
Results and discussion
It occurred to us that, if the 1,2-lactam function of uracil
8a was protected, thiation would be completely regiospecific,
and the physical properties of the intermediate would be
such that the thiation and benzylation steps would both be
facilitated. We had previously reported8 [Scheme 1(a), step i]
that uracil 8a and thymine 8b both react with a very slight
We now report that when 1-benzoyluracil 10a was heated,
under reflux, with Lawesson’s reagent 9, it was converted
J. Chem. Soc., Perkin Trans. 1, 1998
2827

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(a)
O
N
NH2
O
O
O
R
NH
N
R
R
R
H
HN
HN
BzN
ii
i
a; R = H
iii
O
N
O
O
N
H
O
N
O
N
H
Ph
OH
O
Bz
HO
HO
Ph
H
10
11
8
b; R = Me
13 a; R = H
b; R = Me
14
15
(b)
Cl
O
S
S
Ph
O
Cl
O
O
Ph
ii
i
HN
HN
N
iv,v
O
Ph
O
H
17
O
N
O
N
O
N
H
16
18
Bz
Bz
10a
12
6a
iii
H
OH
v
iv,v
Ph
OH
S
O
Ph
H
O
H
HN
15
19
Scheme 2 Reagents and conditions: i, Cl3CCOCl, Zn–Cu couple,
MeOCH2CH2OMe, Et2O, reflux, 100 h; ii, Zn dust, AcOH, reflux; iii,
O
N
H
L-Selectride, THF, Ϫ78 ЊC; iv, 4-(O2N)C6H4CO2H, Ph3P, EtO2CN᎐
NCO2Et (DEAD), THF, room temp.; v, NaOH, aq. dioxane, room
temp.
᎐
7
Scheme 1 Reagents and conditions: i, BzCl (ca. 1.1 mol equiv.), MeCN,
C5H5N, room temp.; ii, (a) BzCl (ca. 2.2 mol equiv.), MeCN, C5H5N,
room temp., 24 h, (b) K2CO3, H2O–dioxane (1:2 v/v), room temp.,
30 min; iii, Lawesson’s reagent 9, PhMe, reflux, 3–4 h; iv, PhCH2Cl,
Pri2NEt, CH2Cl2, room temp., 7 h; v, MeNH2, EtOH, room temp., 1.5 h
added to the reactants (see Experimental section), a good yield
(75%) of cycloadduct 17 can reproducibly be obtained. It
should be noted that the cycloaddition reaction is surprisingly
slow, and that a reaction time of ca. 4 days is required if a good
yield is to be obtained.
The cyclobutanol derivative 15 and the pyrimidine building
block 6a were coupled together in the presence of triphenyl-
phosphine and DEAD in THF solution (Scheme 3), under
standard Mitsunobu conditions,9 to give a single product which
[Scheme 1(b), step iii] into its 4-thio derivative 12, which was
readily isolated as a crystalline solid in 79.5% yield. 1-Benzoyl-
4-thiouracil 12 was then allowed to react with benzyl chloride in
the presence of N,N-diisopropylethylamine in dichloromethane
solution. As previously reported,8 debenzoylation of 1-benzoyl-
uracil 10a occurs under very mild basic conditions. Therefore
the intermediate 1-benzoyl-4-benzylsulfanyl derivative obtained
was not isolated, but the crude products were treated directly
with alcoholic methylamine to give the desired building block
6a as a crystalline solid in 69% overall yield. 4-Thiouracil 7 was
also very conveniently prepared and isolated as a crystalline
solid in good yield by treating its 1-benzoyl derivative 12 with
alcoholic methylamine. The above approach has the advantage
of complete regiocontrol, and the intermediates involved
both in the thiation and benzylation steps have very favourable
solubility properties. We believe that these factors more than
compensate for the two extra steps (i.e. benzoylation and
debenzoylation) required.
S
Ph
O
N
N
H
S
Ph
4
5
3
N
i
6a
+
6
2
H
O
N
1
1′
Ph
O
OH
Ph
O
In order to complement our previous work2 on the synthesis
of 9-[cis-3-(hydroxymethyl)cyclobutyl]-guanine and -adenine
(4 and 5, respectively), we decided to investigate whether the
pyrimidine building block 6a could be used in the preparation
of the 1-[cis-3-(hydroxymethyl)cyclobutyl]-pyrimidine deriva-
tives 13a and 14 which, to the best of our knowledge, had not
previously been described in the literature. In the preparation
of the purine derivatives, the cyclobutyl side-chain was intro-
duced by means of a Mitsunobu reaction9 involving trans-
(3-benzyloxymethyl)cyclobutan-1-ol2 15, the purine building
block 1b or 1c, diethyl azodicarboxylate (DEAD) and
triphenylphosphine.
As can be seen from Scheme 2, the key intermediate 15,
required for the introduction of the 3-(hydroxymethyl)-
cyclobutyl side-chain is prepared2 in five steps from allyl benzyl
ether 16. Of these five steps, we regard the first (Scheme 2, step
i), involving the in situ generation of dichloroketene and its
cycloaddition to the olefin 16, as being the most crucial. We
were previously2 unable to optimize the yield of the cyclo-
addition product 17, and indeed attempts to increase the scale
of the reaction led2 to diminished yields. We now find that if the
modification to the original reaction conditions suggested by
Johnston et al.10 is implemented, and 1,2-dimethoxyethane is
H
20
ii
15
O
N
O
N
HN
HN
iii
2
O
O
1′
1′
HO
Ph
O
24
23
S
Ph
O
O
N
O
N
H
NO2
Ph
O
Ph
O
H
22
21
Scheme 3 Reagents and conditions: i, DEAD, Ph3P, THF, 0 ЊC to room
temp., 15 h; ii, (a) [2-(HO3C)C6H4CO2]2Mg, EtOH, room temp., 1 h;
(b) MeC(᎐O)C(᎐NOH)Me, (Me2N)2C᎐NH, MeCN, room temp., 20 h;
᎐
᎐
᎐
iii, 10% Pd/C, HCO2H, MeOH, room temp., 3 h
2828
J. Chem. Soc., Perkin Trans. 1, 1998

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was isolated as a colourless oil in 90% yield. On the basis of
its 13C NMR spectrum [δC(CDCl3) 68.3, assigned to C-1Ј],
this product was believed to be 2-[cis-3-(benzyloxymethyl)-
cyclobutoxy]-4-(benzylsulfanyl)pyrimidine 20 rather than the
desired 1-[cis-3-(benzyloxymethyl)cyclobutyl]-4-(benzylsulfan-
yl)pyrimidin-2(1H)-one 21. It is noteworthy that the chemical
shift of the C-1 resonance signal in the 13C NMR spectrum
(in CDCl3) of the 4-nitrobenzoate ester2 22 is 67.4 ppm, and the
chemical shift of the C-1Ј resonance signal in the 13C NMR
spectrum [in (CD3)2SO] of 9-[cis-3-(hydroxymethyl)cyclo-
butyl]adenine2 5 is 44.3 ppm. Oxidation of compound 20 with
magnesium monoperoxyphthalate11 followed by treatment
with the N1,N1,N3,N3-tetramethylguanidinium salt of butane-
2,3-dione monooxime2,12 (Scheme 3) gave the benzyl ether 23.
The latter compound 23 was converted into 2-[cis-3-(hydroxy-
methyl)cyclobutoxy]pyrimidin-4(3H)-one 24 under transfer
hydrogenation conditions.13 The constitution of compound 24
{δC[(CD3)2SO] 68.2, assigned to C-1Ј} was confirmed by ultra-
violet (UV) absorption spectroscopy. The UV spectrum of
compound 24 [λmax(H2O) 254 nm (ε 6200)] is closely similar to
that of 2-methoxypyrimidin-4(3H)-one 25 [λmax(H2O) 256 nm
(ε 5800)],14 but it is quite distinct from that of 1-methyluracil
26 [λmax(H2O) 267 nm (ε 9700)].14
cyclobutyl]thymine 28b [δC(CDCl3) 46.0, assigned to C-1Ј] in
70% isolated yield. Removal of the benzyl protecting group
from the uracil derivative 28a by transfer hydrogenolysis gave
1-[cis-3-(hydroxymethyl)cyclobutyl]uracil 13a as a colourless
crystalline solid in 94% isolated yield. The structure assigned
to compound 13a {δC[(CD3)2SO] 46.4, C-1Ј} was supported
by its UV spectrum [λmax(H2O) 268 nm (ε 10 000)], which
is very similar to that of 1-methyluracil14 26 (see above). In
the same way, the thymine derivative 28b was converted into 1-
[cis-3-(hydroxymethyl)cyclobutyl]thymine 13b in 93% isolated
yield.
It is not at all obvious why 4-(benzylsulfanyl)pyrimidin-
2(1H)-one 6a and 3-benzoyluracil 11a should undergo alkyl-
ation, under Mitsunobu conditions, virtually regiospecifically
on O-2 and N-1, respectively. It is perhaps worth noting that
O-2 is more hindered in 3-benzoyluracil 11a than it is in the
4-benzylsulfanyl derivative 6a. However, this does not explain
why the latter compound 6a undergoes virtually regiospecific
alkylation on O-2. It is particularly noteworthy that 13C NMR
has proved to be a much more useful analytical tool than
1H NMR spectroscopy in distinguishing between N-1- and
O-2-alkyl derivatives of uracil and thymine. Thus, while the
C-1Ј resonance signals [in (CD3)2SO] of 2-[cis-3-(hydroxy-
methyl)cyclobutoxy]pyrimidin-4(3H)-one 24, 1-[cis-3-(hydroxy-
methyl)cyclobutyl]uracil 13a and 1-[cis-3-(hydroxymethyl)-
cyclobutyl]thymine 13b are observed at δ 68.2, 46.4 and 46.1,
respectively, their H-1Ј multiplets resonate at δ 5.01, 4.59 and
4.60, respectively. The C-1Ј and the H-1Ј resonance signals [in
It was thus clearly evident that 4-(benzylsulfanyl)pyrimidin-
2(1H)-one 6a was not a suitable building block for the
preparation of 1-[cis-3-(hydroxymethyl)cyclobutyl]-uracil and
-cytosine (13a and 14, respectively). The coupling reaction
between 3-benzoyluracil8 11a and the trans-alcohol2 15 was
then carried out, also under standard Mitsunobu conditions
(Scheme 4). A single pyrimidine derivative, which on the basis
(CD3)2SO] of 9-[cis-3-(hydroxymethyl)cyclobutyl]adenine2
are observed at δ 44.3 and 4.86, respectively.
5
Finally, 1-[cis-3-(hydroxymethyl)cyclobutyl]uracil 13a was
converted into the corresponding cytosine derivative 14 by the
procedure indicated in Scheme 5. Following trimethylsilyl-
O
O
HN
HN
O
NH2
O
N
MeO
N
Me
NH
N
26
25
O
i,ii
N
O
N
O
R
O
N
NBz
HO
HO
R
13a
14
NBz
N
H
O
i
Scheme
5
Reagents and conditions: i, (a) Me3SiCl, 1-methyl-
11
O
pyrrolidine, MeCN, room temp., 1 h, (b) (CF3CO)2O, 0 ЊC, 35 min, (c)
4-nitrophenol, 0 ЊC, 3 h; ii, conc. aq. NH3 (d 0.88)–dioxane (1:4 v/v),
50 ЊC, 24 h
+
H
1′
Ph
O
Ph
O
OH
27
ation of compound 13a and activation with trifluoroacetic
anhydride,15 4-nitrophenol was added.16 The products of this
one pot reaction were then treated with ammonia in aqueous
dioxane at 50Њ to give 1-[cis-3-(hydroxymethyl)cyclobutyl]-
cytosine 14, which was isolated as a colourless crystalline
solid in 84% overall yield. Unfortunately, although they were
not found to be toxic, none of the unprotected nucleoside
analogues 13a, 13b, 14 and 24 showed any significant anti-
human immunodeficiency virus (anti-HIV) activity.
H
ii
15
a; R = H b; R = Me
O
O
R
R
NH
NH
iii
N
O
N
O
1′
1′
Ph
O
HO
13
28
Experimental
Mps were measured with a Büchi melting point apparatus
and are uncorrected. H NMR spectra were measured at 360
Scheme 4 Reagents and conditions: i, DEAD, Ph3P, THF, 0 ЊC to room
temp., 24 h; ii, MeNH2, EtOH, room temp., 1 h; iii, 10% Pd/C,
HCO2H, MeOH, room temp., 3 h
1
MHz with a Bruker AM 360 spectrometer; 13C NMR spectra
were measured at 90.6 MHz with the same spectrometer.
Tetramethylsilane was used as an internal standard, and
J values are given in Hz. UV spectra were measured with a
Perkin-Elmer Lambda-3 spectrophotometer; IR spectra were
measured with a Perkin-Elmer model 983G spectrometer.
Merck silica gel 60 F254 TLC plates were developed in solvent
systems A [light petroleum (distillation range 40–60 ЊC)–ethyl
acetate (3:7 v/v)], B [light petroleum (distillation range 40–
of its 13C NMR spectrum [δC(CDCl3) 46.6, assigned to C-1Ј]
was identified as 3-benzoyl-1-[cis-3-(benzyloxymethyl)cyclo-
butyl]uracil 27a, was obtained in 73% isolated yield. The latter
compound 27a reacted with methylamine in ethanol solution
to give 1-[cis-3-(benzyloxymethyl)cyclobutyl]uracil 28a, which
was isolated as a colourless crystalline solid in virtually
quantitative yield. In the same way, 3-benzoylthymine8 11b
was converted in two steps into 1-[cis-3-(benzyloxymethyl)-
J. Chem. Soc., Perkin Trans. 1, 1998
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60 ЊC)–ethyl acetate (1:1 v/v)], C [chloroform–methanol (19:1
v/v)] and D [chloroform–methanol (9:1 v/v)]. Merck silica
gel H was used for short column chromatography. Aceto-
nitrile, THF, dioxane, 1,2-dimethoxyethane, pyridine, 1-methyl-
pyrrolidine and N,N-diisopropylethylamine were dried by
heating, under reflux, over calcium hydride, and were then
distilled; N1,N1,N3,N3-tetramethylguanidine was dried by distil-
lation over calcium hydride under reduced pressure. Toluene
was dried by distillation at atmospheric pressure with the first
20% of distillate being discarded; diethyl ether and dichloro-
methane were dried over sodium wire and phosphorus pentaox-
ide, respectively, and were then distilled.
1-Benzoyl-4-thiouracil 12
A mixture of 1-benzoyluracil 10a (2.132 g, 9.9 mmol) and
2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-
disulfide (Lawesson’s reagent) 9 (2.395 g, 5.9 mmol) in dry
toluene (18 cm3) was heated, under reflux, in an atmosphere of
argon. After 3 h, the cooled products were concentrated under
reduced pressure and recrystallized from acetonitrile to give
the title compound 12 (1.821 g, 79.5%) (Found: C, 56.76; H,
3.36; N, 12.11. C11H8N2O2S requires C, 56.89; H, 3.47; N,
12.06%) as yellow needles, mp 181 ЊC (decomp.); Rf 0.28
(system C); δH[(CD3)2SO] 6.43 (1 H, d, J 7.6), 7.52 (2 H, m),
7.68 (1 H, m), 7.78 (1 H, d, J 7.7), 7.86 (2 H, m), 12.92 (1 H,
br s); δC[(CD3)2SO] 113.8, 128.4, 129.7, 132.3, 133.9, 135.0,
146.6, 169.3, 192.0.
1-Benzoyluracil 10a†
Benzoyl chloride (1.28 cm3, 11.0 mmol) was added in one
portion to a stirred suspension of uracil 8a (1.121 g, 10.0 mmol)
in dry acetonitrile (10 cm3) and pyridine (2 cm3) at room
temperature. After 2.5 h, the suspended product (0.671 g) was
collected by filtration. A second crop of product precipitated
from the filtrate; it was collected by refiltration, and a third crop
was obtained by adding water to the resulting filtrate. Total
4-Thiouracil 7
A solution of 1-benzoyl-4-thiouracil 12 (0.334 g, 1.44 mmol) in
ca. 8 mol dmϪ3 ethanolic methylamine (14 cm3, ca. 0.11 mol)
was stirred at room temperature. After 1.5 h, the products were
concentrated under reduced pressure and were then triturated
with dichloromethane. The residue was recrystallized from
aqueous methanol to give 4-thiouracil 7 (0.143 g, 77.5%)
(Found: C, 37.60; H, 2.96; N, 21.77. Calc. for C4H4N2OS:
C, 37.49; H, 3.15; N, 21.86%) as yellow needles, mp 289 ЊC
(decomp.) (lit.,7 292–296 ЊC decomp.); Rf 0.39 (system D);
δH[(CD3)2SO] 6.18 (1 H, d, J 7.0), 7.31 (1 H, d, J 7.1), 11.53
(1 H, br), 12.43 (1 H, br); δC[(CD3)2SO] 111.6, 138.2, 148.6,
191.3.
yield of the title compound 10a, 1.817 g (84%) (Found: Mϩ,
12
216.0533.
C
1H814N216O3 requires M, 216.0535), mp 167–
11
168.5 ЊC; Rf 0.32 (system D); δH[(CD3)2SO] 5.85 (1 H, dd, J 2.0
and 8.1), 7.25 (2 H, m), 7.67 (1 H, m), 7.82 (2 H, m), 7.92 (1 H,
d, J 8.1), 11.58 (1 H, br s); δC[(CD3)2SO] 103.7, 128.4, 129.6,
132.9, 133.7, 140.5, 149.4, 163.3, 169.7.
3-Benzoyluracil 11a†
Uracil 8a (2.24 g, 20.0 mmol), benzoyl chloride (5.2 cm3, 44.8
mmol), dry acetonitrile (20 cm3) and dry pyridine (8 cm3) were
stirred together at room temperature. After 24 h, the products
were concentrated under reduced pressure and the residue
was partitioned between dichloromethane (100 cm3) and water
(100 cm3). The organic layer was separated and then evaporated
under reduced pressure. The residue was dissolved in a mixture
of aqueous potassium carbonate (0.5 mol dmϪ3, 20 cm3) and
dioxane (40 cm3) at room temperature. After 30 min, the pH
was lowered to ca. 5 by the careful addition of glacial acetic
acid. The products were concentrated under reduced pressure,
and the residue was stirred with saturated aqueous sodium
hydrogen carbonate (100 cm3) at room temperature. After 1 h,
the products were filtered and the residue was washed with
cold water (3 × 10 cm3). Crystallization of this material from
aqueous acetone gave the title compound 11a as an off-white
solid (3.65 g, 84%) (Found, in material recrystallized from
absolute ethanol: C, 61.32; H, 3.66; N, 12.90. Calc. for
C11H8N2O3: C, 61.11; H, 3.73; N, 12.96%) mp 173.5–175 ЊC;
Rf 0.40 (system D); δH[(CD3)2SO] 5.75 (1 H, d, J 7.7), 7.60 (2 H,
t, J 7.8), 7.67 (1 H, d, J 7.7), 7.77 (1 H, t, J 7.4), 7.96 (2 H, m),
11.62 (1 H, br); δC[(CD3)2SO] 100.4, 129.8, 130.6, 131.7, 135.8,
143.7, 150.4, 163.3, 170.4.
4-(Benzylsulfanyl)pyrimidin-2(1H)-one 6a
N,N-Diisopropylethylamine (2.24 cm3, 12.9 mmol) and benzyl
chloride (1.49 cm3, 12.9 mmol) were added to a stirred solution
of 1-benzoyl-4-thiouracil 12 (1.50 g, 6.5 mmol) in dry dichloro-
methane (65 cm3) at room temperature. After 7 h, the products
were concentrated under reduced pressure and ca. 8 mol dmϪ3
ethanolic methylamine (16 cm3, ca. 0.13 mol) was added. The
resulting solution was stirred at room temperature for 1.5 h,
and was then evaporated under reduced pressure. The residue
was dissolved in chloroform (75 cm3) and the solution was
washed with saturated aqueous sodium hydrogen carbonate
(2 × 50 cm3). The dried (MgSO4) organic layer was concen-
trated under reduced pressure and the residue was crystallized
from aqueous methanol to give 4-(benzylsulfanyl)pyrimidin-
2(1H)-one 6a (0.973 g, 69%) (Found: C, 60.51; H, 4.56; N,
12.81. Calc. for C11H10N2OS: C, 60.50; H, 4.62; N, 12.83%) as
colourless crystals, mp 201–203 ЊC (lit.,3 202–204 ЊC); Rf 0.40
(system C); δH[(CD3)2SO] 4.38 (2 H, s), 6.27 (1 H, d, J 6.7), 7.28
(3 H, m), 7.40 (2 H, m), 7.64 (1 H, d, J 6.7), 11.54 (1 H, br);
δC[(CD3)2SO] 32.3, 101.6, 127.1, 128.4, 128.9, 137.3, 143.5,
154.2, 176.3.
2,2-Dichloro-3-(benzyloxymethyl)cyclobutan-1-one 17
Redistilled trichloroacetyl chloride (20 cm3, 0.18 mol) was
added to a magnetically-stirred suspension of freshly prepared
zinc–copper couple (13.3 g), allyl benzyl ether2 (10.0 g, 67.5
mmol), dry 1,2-dimethoxyethane (33 cm3) and dry diethyl
ether (250 cm3) in a flame-dried flask in an atmosphere of
argon. The reactants were heated, under gentle reflux, for 100 h.
The products were then filtered, and the residue was washed
with ether. The residue was discarded. The combined filtrate
and washings were concentrated under reduced pressure to ca.
80 cm3. Light petroleum (bp 30–40 ЊC, 100 cm3) was added, and
the mixture was stirred vigorously. After 5 min, the supernatant
was decanted and more light petroleum (ca. 40 cm3) was added.
After vigorous stirring the supernatant was again decanted
and mixed with the original supernatant. The resulting solution
was washed in turn with saturated aqueous sodium hydrogen
carbonate (2 × 200 cm3) and brine (100 cm3). The dried
(MgSO4) organic layer was concentrated under reduced
pressure and the residue was distilled to give 2,2-dichloro-3-
3-Benzoylthymine 11b†
Thymine 8b (1.261 g, 10.0 mmol), benzoyl chloride (2.55 cm3,
22.1 mmol), dry acetonitrile (10 cm3) and dry pyridine (4 cm3)
were stirred together at room temperature. After 16 h, the
products were worked up and treated with potassium carbonate
as above in the preparation of 3-N-benzoyluracil 11a. The
product obtained was crystallized from aqueous acetonitrile to
give the title compound 11b as colourless needles (1.847 g, 80%)
(Found: C, 62.57; H, 4.36; N, 12.32. Calc. for C12H10N2O3:
C, 62.61; H, 4.38; N, 12.17%), mp 178–180 ЊC (followed by
resolidification at ca. 190 ЊC and remelting at 210–215 ЊC);
Rf 0.45 (system D); δH[(CD3)2SO] 1.82 (3 H, s), 7.58 (3 H, m),
7.77 (1 H, t, J 7.3), 7.94 (2 H, m), 11.40 (1 H, br); δC[(CD3)2SO]
11.7, 107.9, 129.5, 130.2, 131.4, 135.4, 138.8, 150.0, 163.6,
170.2.
† Experiment first carried out by Dr K. A. Cruickshank.8,12
2830
J. Chem. Soc., Perkin Trans. 1, 1998

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(benzyloxymethyl)cyclobutan-1-one2 17 (13.1 g, 75%) as a pale
yellow viscous liquid, bp 158 ЊC/3.0 mmHg; νmax(film)/cmϪ1
1811; δH(CDCl3) 3.08–3.22 (2 H, m), 3.41 (1 H, m), 3.68 (1 H,
m), 3.83 (1 H, m), 4.56 (2 H, s), 7.35 (5 H, m); δC(CDCl3) 45.0,
45.3, 68.9, 73.3, 87.5, 127.7, 127.9, 128.4, 137.4, 192.3.
3-Benzoyl-1-[cis-3-(benzyloxymethyl)cyclobutyl]uracil 27a
Diethyl azodicarboxylate (1.95 cm3, 12.4 mmol) was added to a
stirred solution of trans-3-(benzyloxymethyl)cyclobutan-1-ol3
15 (0.96 g, 5.0 mmol), 3-benzoyluracil 11a (1.62 g, 7.5 mmol)
and triphenylphosphine (3.28 g, 12.5 mmol) in dry THF
(50 cm3) at 0 ЊC (ice–water bath), and the reactants were
allowed to warm to room temperature. After 24 h, the products
were concentrated under reduced pressure and the residue was
fractionated by short column chromatography on silica gel. The
appropriate fractions, which were eluted with toluene–ethyl
acetate (95:5 to 80:20 v/v), were combined and evaporated
under reduced pressure to give a colourless solid. Crystalliz-
ation of this material from aqueous methanol gave the title
compound 27a (1.43 g, 73%) (Found: C, 70.67; H, 5.56; N,
7.10. C23H22N2O4 requires C, 70.75; H, 5.68; N, 7.17%), mp
107–108 ЊC; Rf 0.57 (system A); δH(CDCl3) 2.23 (2 H, m), 2.38
(1 H, m), 2.51 (2 H, m), 3.49 (2 H, d, J 3.9), 4.55 (2 H, s), 4.86
(1 H, m), 5.67 (1 H, d, J 8.1), 7.35 (5 H, m), 7.47 (2 H, m), 7.63
(2 H, m), 7.92 (2 H, m); δC(CDCl3) 28.0, 31.2, 46.6, 72.1, 73.5,
102.1, 127.9, 128.0, 128.7, 129.3, 130.6, 131.6, 135.2, 138.3,
141.4, 149.8, 162.4, 169.2.
2-[cis-3-(Benzyloxymethyl)cyclobutoxy]-4-(benzylsulfanyl)pyr-
imidine 20
Diethyl azodicarboxylate (1.4 cm3, 8.9 mmol) was added to a
stirred solution of trans-3-(benzyloxymethyl)cyclobutan-1-ol2
15 (0.70 g, 3.6 mmol), 4-(benzylsulfanyl)pyrimidin-2(1H)-one
6a (0.96 g, 4.4 mmol) and triphenylphosphine (2.31 g, 8.8
mmol) in dry THF (40 cm3) at 0 ЊC (ice–water bath), and the
reactants were allowed to warm up to room temperature. After
15 h, the products were concentrated under reduced pressure
and the residue was fractionated by short column chroma-
tography on silica gel. The appropriate fractions, which were
eluted with light petroleum (bp 40–60 ЊC)–ethyl acetate (95:5
to 85:15 v/v), were combined and evaporated under reduced
pressure to give 2-[cis-3-(benzyloxymethyl)cyclobutoxy]-4-
(benzylsulfanyl)pyrimidine 20 as a colourless oil (1.30 g, ca.
90%); Rf 0.76 (system B); δH(CDCl3) 2.01 (2 H, m), 2.27 (1 H,
m), 2.60 (2 H, m), 3.49 (2 H, d, J 6.4), 4.44 (2 H, s), 4.52 (2 H, s),
5.09 (1 H, m), 6.76 (1 H, d, J 5.5), 7.24–7.39 (10 H, m), 8.11 (1
H, d, J 5.3); δC(CDCl3) 26.9, 33.6, 33.9, 68.3, 73.0, 74.7, 112.4,
127.5, 127.6, 127.7, 128.4, 128.7, 128.9, 136.7, 138.5, 156.7,
163.9, 171.7.
1-[cis-3-(Benzyloxymethyl)cyclobutyl]uracil 28a
A
solution of 3-benzoyl-1-[cis-3-(benzyloxymethyl)cyclo-
butyl]uracil 27a (1.17 g, 3.0 mmol) in ethanolic methylamine
(8 mol dmϪ3, 30 cm3) was stirred at room temperature. After
1 h, the products were evaporated under reduced pressure, and
the residue was fractionated by short column chromatography
on silica gel. The appropriate fractions, which were eluted with
dichloromethane–methanol (100:0 to 99:1 v/v) were com-
bined and evaporated under reduced pressure to give the title
compound 28a as a colourless solid (0.84 g, 97%) [Found,
in material recrystallized from ethyl acetate–light petroleum
(distillation range 40–60 ЊC): C, 67.11; H, 6.29; N, 9.79.
C16H18N2O3 requires C, 67.12; H, 6.34; N, 9.78%], mp 92–
93 ЊC; Rf 0.26 (system A), 0.68 (system D); δH(CDCl3) 2.19
(2 H, m), 2.38 (1 H, m), 2.50 (2 H, m), 3.49 (2 H, d, J 4.1), 4.55
(2 H, s), 4.90 (1 H, m), 5.60 (1 H, dd, J 2.2 and 8.0), 7.35 (5 H,
m), 7.52 (1 H, d, J 8.1), 9.15 (1 H, br); δC(CDCl3) 27.9, 31.3,
46.2, 72.1, 73.4, 102.3, 127.9, 128.0, 128.6, 138.3, 141.4, 150.9,
163.5.
2-[cis-3-(Benzyloxymethyl)cyclobutoxy]pyrimidin-4(3H)-one 23
Magnesium monoperoxyphthalate hexahydrate (ca. 80%,
0.928 g, ca. 1.5 mmol) was added to a stirred solution of 1-[cis-
3-(benzyloxymethyl)cyclobutoxy]-4-(benzylsulfanyl)pyrimidine
20 (0.396 g, 1.0 mmol) in absolute ethanol (10 cm3) at room
temperature. After 1 h, the products were evaporated under
reduced pressure. The residue was dissolved in dichloromethane
(40 cm3) and the solution was washed with water (2 × 20 cm3).
The dried (MgSO4) organic layer was redissolved in aceto-
nitrile (5 cm3). Butane-2,3-dione monooxime (0.303 g, 3.0
mmol) and N1,N1,N3,N3-tetramethylguanidine (TMG, 0.38
cm3, 3.0 mmol) were added to the stirred solution at room
temperature. After 20 h, the products were concentrated
under reduced pressure, and the residue was fractionated by
short column chromatography on silica gel. The appropriate
fractions, eluted with light petroleum (bp 40–60 ЊC)—ethyl
acetate (60:40 v/v), were combined and evaporated under
reduced pressure. Crystallization of the residue from ethyl
acetate–light petroleum (bp 40–60 ЊC) gave the title compound
23 (0.264 g, ca. 91%) (Found: C, 67.09; H, 6.24; N, 9.78.
C16H18N2O3 requires C, 67.12; H, 6.34; N, 9.78%), mp 134–
135 ЊC; Rf 0.71 (system D); δH(CDCl3) 1.94 (2 H, m), 2.17 (1 H,
m), 2.51 (2 H, m), 3.40 (2 H, d, J 6.0), 4.45 (2 H, s), 5.05
(1 H, m), 6.03 (1 H, d, J 6.6), 7.25 (5 H, m), 7.65 (1 H, d, J 6.6),
11.31 (1 H, br); δC(CDCl3) 25.7, 32.5, 68.5, 72.0, 72.9, 107.9,
126.6, 127.4, 137.2, 154.3, 155.5, 164.1.
1-[cis-3-(Benzyloxymethyl)cyclobutyl]thymine 28b
Diethyl azodicarboxylate (1.95 cm3, 12.4 mmol) was added to
a stirred solution of trans-3-(benzyloxymethyl)cyclobutan-
1-ol3 15 (0.96 g, 5.0 mmol), 3-benzoylthymine 11b (1.73 g,
7.5 mmol) and triphenylphosphine (3.28 g, 12.5 mmol) in
dry THF (50 cm3) at 0 ЊC (ice–water bath). The reaction was
allowed to proceed and the products were worked up and
chromatographed as in the above preparation of 3-benzoyl-1-
[cis-3-(benzyloxymethyl)cyclobutyl]uracil 27a to give a colour-
less oil (ca. 1.5 g). A solution of the latter material in ethanolic
methylamine (8 mol dmϪ3, 30 cm3) was stirred at room tem-
perature. After 1 h, the products were evaporated under
reduced pressure, and the residue was fractionated by short
column chromatography on silica gel. The appropriate frac-
tions, which were eluted with dichloromethane–methanol
(100:0 to 99:1 v/v) were combined and evaporated under
reduced pressure to give the title compound 28b as a colourless
solid (1.05 g, 70%) (Found: C, 68.02; H, 6.70; N, 9.27.
C17H20N2O3 requires C, 67.98; H, 6.71; N, 9.33%), mp 153–
154 ЊC; Rf 0.36 (system A); δH(CDCl3) 1.79 (3 H, d, J 1.0),
2.19 (2 H, m), 2.38 (1 H, m), 2.47 (2 H, m), 3.50 (2 H, d, J 4.1),
4.55 (2 H, s), 4.91 (1 H, m), 7.34 (6 H, m), 9.37 (1 H, br);
δC(CDCl3) 12.5, 28.0, 31.3, 46.0, 72.3, 73.4, 110.8, 127.8, 127.9,
128.6, 137.0, 138.5, 151.1, 164.1.
2-[cis-3-(Hydroxymethyl)cyclobutoxy]pyrimidin-4(3H)-one 24
2-[cis-3-(Benzyloxymethyl)cyclobutoxy]pyrimidin-4(3H)-one
23 (0.23 g, 0.8 mmol), 10% palladium on activated carbon (0.23
g), formic acid (1.2 cm3) and methanol (10.8 cm3) were stirred
together at room temperature. After 3 h, the products were
filtered and the filtrate was evaporated under reduced pressure.
The residual solid was recrystallized from dichloromethane–
cyclohexane to give the title compound 24 (0.15 g, 95%) (Found:
C, 54.82; H, 6.20; N, 14.00. C9H12N2O3 requires C, 55.09;
H, 6.16; N, 14.28%), mp 179–181 ЊC; Rf 0.41 (system D);
λmax(H2O)/nm 254 (ε 6200); λmin/nm 232 (ε 4400); δH[(CD3)2SO]
1.85 (2 H, m), 2.01 (1 H, m), 2.35 (2 H, m), 3.37 (2 H, d, J 5.2),
4.60 (1 H, br), 5.01 (1 H, m), 5.91 (1 H, d, J 6.6), 7.67 (1 H,
d, J 6.6), 12.22 (1 H, br); δC[(CD3)2SO] 28.5, 32.1, 63.8, 68.2,
108.4, 153.9, 157.2, 163.8.
1-[cis-3-(Hydroxymethyl)cyclobutyl]uracil 13a
1-[cis-3-(Benzyloxymethyl)cyclobutyl]uracil 28a (0.80 g, 2.8
mmol), 10% palladium on activated carbon (0.40 g), formic
J. Chem. Soc., Perkin Trans. 1, 1998
2831

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acid (3 cm3) and methanol (27 cm3) were stirred together
at room temperature. After 3 h, the products were filtered
and the filtrate was evaporated under reduced pressure. The
residue was fractionated by short column chromatography
on silica gel. The appropriate fractions, which were eluted
with dichloromethane–methanol (97:3 to 95:5 v/v) were
combined and evaporated under reduced pressure to give the
title compound 13a as a colourless solid (0.52 g, 94%) [Found,
in material recrystallized from ethyl acetate–light petroleum
(distillation range 40–60 ЊC): C, 54.75; H, 5.96; N, 14.12.
C9H12N2O3ؒ0.1H2O requires C, 54.59; H, 6.21; N, 14.15%], mp
171–172 ЊC; Rf 0.37 (system D); λmax(H2O)/nm 268 (ε 10 000);
λmin/nm 233 (ε 1460); δH[(CD3)2SO] 1.97 (2 H, m), 2.15 (1 H, m),
2.26 (2 H, m), 3.40 (2 H, t, J 5.2), 4.62 (2 H, m), 5.59 (1 H, d,
J 8.0), 7.74 (1 H, d, J 8.0), 11.20 (1 H, br); δC[(CD3)2SO] 29.7,
30.9, 46.4, 63.7, 100.9, 142.0, 150.7, 163.2.
yellow solution was concentrated under reduced pressure
and the residue was co-evaporated with absolute ethanol
(3 × 10 cm3). The residue was fractionated by short column
chromatography on silica gel. The appropriate fractions, which
were eluted with dichloromethane–methanol–triethylamine
(96.5:3:0.5 to 91.5:8:0.5 v/v) were combined and concen-
trated under reduced pressure to give the title compound 14
as a colourless solid (0.164 g, 84%) (Found, in material
recrystallized from ethanol–ethyl acetate: C, 54.96; H, 6.73;
N, 21.22. C9H13N3O2ؒ0.1H2O requires C, 54.87; H, 6.75;
N, 21.33%), mp 202–205 ЊC; Rf 0.05 (system D); δH[(CD3)2SO]
1.87 (2 H, m), 2.13 (1 H, m), 2.25 (2 H, m), 3.39 (2 H, t, J 5.2),
4.57 (1 H, m), 4.63 (1 H, m), 5.70 (1 H, d, J 7.3), 6.99 (2 H, br),
7.66 (1 H, d, J 7.3); δC[(CD3)2SO] 29.7, 31.2, 46.9, 63.9, 93.2,
142.2, 155.6, 165.3.
Acknowledgements
1-[cis-3-(Hydroxymethyl)cyclobutyl]thymine 13b
We thank Professor Jan Balzarini of the Rega Institute, Leuven,
Belgium and Dr Naheed Mahmood of the MRC Collaborative
Centre, Mill Hill for carrying out the biological tests.
1-[cis-3-(Benzyloxymethyl)cyclobutyl]thymine 28b (0.60 g, 2.0
mmol), 10% palladium on activated carbon (0.30 g), formic
acid (2 cm3) and methanol (18 cm3) were stirred together
at room temperature. After 3 h, the products were worked up
and fractionated as in the above preparation of 1-[cis-3-
(hydroxymethyl)cyclobutyl]uracil 13a to give the title compound
13b as a colourless solid (0.39 g, 93%) [Found, in material
recrystallized from ethyl acetate–light petroleum (distillation
range 40–60 ЊC): C, 56.38; H, 6.61; N, 13.06. C10H14N2O3ؒ0.15
H2O requires C, 56.41; H, 6.77; N, 13.16%], mp 149–151 ЊC;
Rf 0.48 (system D); λmax(H2O)/nm 274 (ε 9600); λmin/nm 238
(ε 1780); δH[(CD3)2SO] 1.80 (3 H, d, J 1.0), 1.98 (2 H, m), 2.14 (1
H, m), 2.25 (2 H, m), 3.42 (2 H, d, J 5.1), 4.63 (2 H, m), 7.61 (1
H, m), 11.17 (1 H, br s); δC[(CD3)2SO] 12.0, 29.7, 31.0, 46.1,
63.9, 108.6, 137.5, 150.6, 163.8.
References
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methane (3 × 20 cm3). The combined organic extracts were
dried (MgSO4) and evaporated under reduced pressure. The
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Paper 8/03878C
Received 22nd May 1998
Accepted 26th June 1998
2832
J. Chem. Soc., Perkin Trans. 1, 1998