Concerning the nucleophilic displacement of a methylsulfanyl group on substituted pyrimidinones

Article abstract of DOI:10.1055/s-0029-1218839

The nucleophilic displacement of a methylsulfanyl group (SMe) at the C2-position on a pyrimidin-4-one scaffold was achieved after oxidation into a methylsulfonyl group (SO₂Me) using dimethyldioxirane (DMDO), a powerful electrophilic oxygen atom transfer agent. The introduction of amino groups as well as formation of carbon-carbon bonds was thus demonstrated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218839

PAPER
2811
Concerning the Nucleophilic Displacement of a Methylsulfanyl Group on
Substituted Pyrimidinones
Displacement of
a
i
Methy
n
G
ro
c
up fromSu
e
bstituted
P
y
rimidinonest Kikelj, Sylvain Grosjean, Jean-Claude Meslin, Karine Julienne, David Deniaud*
Université de Nantes, CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230,
UFR des Sciences et des Techniques, 2, rue de la Houssinière, BP 92208, 44322 NANTES Cedex 3, France
Fax +33(2)51125402; E-mail: david.deniaud@univ-nantes.fr
Received 13 April 2010; revised 20 April 2010
The methylsulfanyl substituent is located at the C2-posi-
tion of the pyrimidin-4-one 1. It is worth noting the high
difference in reactivity compared to the case of a C4-po-
sitioned substituent on a pyrimidin-2-one scaffold. In-
Abstract: The nucleophilic displacement of a methylsulfanyl
group (SMe) at the C2-position on a pyrimidin-4-one scaffold was
achieved after oxidation into a methylsulfonyl group (SO2Me) us-
ing dimethyldioxirane (DMDO), a powerful electrophilic oxygen
atom transfer agent. The introduction of amino groups as well as deed, we have previously published the direct and easy
formation of carbon–carbon bonds was thus demonstrated.
modification
of
4-methylsulfanylpyrimidin-2-ones
(Scheme 2).5 Nucleophilic displacements of the sulfanyl
group were achieved in good yields with hydrogen sul-
phide in basic medium or potassium hydroxide in alcohol-
ic medium. Other nucleophiles such as sodium alkoxides
or amines were also used with success on pyrimidine-2-
thiones. However, these substitution reactions were limit-
ed to heteroatomic nucleophiles. Indeed, attempts at the
introduction of a carbon–carbon bond failed.
Key words: dimethyldioxirane, oxidation, nucleophilic substitu-
tions, heterocycles, DMDO
During the course of our investigations on heterocyclic
chemistry,1,2 we became interested in the nucleophilic dis-
placement of a methylsulfanyl group on a pyrimidinone
skeleton. We recently published the synthesis of pyrimid-
ic nucleoside analogues from a glucosyldiazadiene and
acylchlorides in a regioselective hetero-cyclocondensa-
tion reaction.3 We are now targeting access to new nucle-
oside analogues bearing more complex and original
heterocyclic bases. Such novel compounds could be gen-
erated by further elaboration of the available pyrimidic
analogues through the introduction of various substituents
on the pyrimidinone ring. It appeared clear that the pres-
ence of the methylsulfanyl group on the heterocycle could
help achieve this goal.
X
X
R
R
nucleophile
X = O or S
N
N
N
N
SMe
Nu
nucleophile = H2S, KOH, R1ONa, R1(R2)NH, NH3
Scheme 2 Modulation of 4-methylsulfanylpyrimidin(e)-2-(thi)ones
by direct substitution of the sulfanyl group
Additionally, we hoped to effect substitution of the C2-
sulfanyl of pyrimidin-4-one 1. We were therefore disap-
pointed to observe the very weak reactivity of this sub-
strate, particularly towards nitrogenous nucleophiles.
Only the hydroxide anion could, under severe conditions
(high temperatures and extended reaction times), generate
the corresponding carbonyl derivative 2 through substitu-
tion and prototropic equilibrium. This difficulty is hardly
mentioned in the literature, even for reactions at the C2-
position on pyrimidine rings. In fact, it has previously
been reported that 2-methylsulfanyl- or 2-chloro-pyrimid-
inones readily react with soft nucleophiles such as
amines,6 and amination of 2-chloropyrido[3,2-d]pyrimi-
dine was also recently reported.7 Nevertheless, very se-
vere conditions were required; reactions were performed
in refluxing 1,4-dioxane for 3–4 hours. In addition, activa-
tion of a sulfide function as the sulfone has been reported
for nucleophilic displacements with a variety of amines on
a polysubstituted 2-methylsulfanylpyrimidine.8 We de-
cided to investigate the latter strategy of oxidation to en-
hance the leaving group ability of the sulfanyl substituent.
Here, we report on studies undertaken with the model sub-
strate 1 into the generation of a nonglycosidic series. Py-
rimidinone 1 was prepared according to our hetero-
cyclocondensation methodology by employing an activat-
ed 1,3-diazabutadienic building block (Scheme 1).4 The
heterodiene, which was obtained in three steps from phe-
nylthiourea in quantitative yield, was condensed with phe-
nylacetyl chloride in the presence of triethylamine to
afford compound 1 in 90% yield.
SMe
N
SMe
N
Cl
Ph
Ph
O
Et3N
N
N
+
O
CH2Cl2
Me2N
Ph
Ph
1
Scheme 1 Preparation of model substrate 1 for methylsulfanyl
group displacement studies
SYNTHESIS 2010, No. 16, pp 2811–2815
x
x.
x
x
.
2
0
1
0
Oxidation of 1 was initially attempted by using m-chlo-
roperoxybenzoic acid (MCPBA), since this reagent is a
Advanced online publication: 25.06.2010
DOI: 10.1055/s-0029-1218839; Art ID: Z09310SS
© Georg Thieme Verlag Stuttgart · New York

2812
V. Kikelj et al.
PAPER
commonly used oxidant for sulfur-containing com- Oxidation of methyl sulfide 1 was carried out with 2.5
pounds. Unfortunately, pyrimidinedione 2 was the only equivalents of DMDO and the corresponding methyl sul-
reaction product. We believe that an oxidation took place, fone 3 was isolated in quantitative yield (Scheme 4). This
but that the intermediate sulfoxide or sulfone underwent procedure turned out to be practical since no purification
hydrolysis (Scheme 3). The same outcome was observed was required; DMDO and acetone were simply removed
when Oxone® (a low-cost potassium monoperoxysulfate under reduced pressure. The only disadvantage was the
triple salt 2 KHSO5–KHSO4–K2SO4) was used as the ox- restricted access to large quantities of reagent (on the lab-
idant. Both MCPBA and Oxone were used under nonan- oratory scale, an experiment can provide a maximum of
hydrous conditions, so it is likely that the oxidized only 5 mmol of DMDO). Therefore, we tried to reduce the
intermediate is very sensitive to humidity, which pre- amount of dioxirane used in each reaction. However, sto-
cludes its isolation. However, these experiments clearly ichiometric oxidation (sulfide 1–DMDO, 1:1) did not af-
show the vast enhancement of reactivity towards nucleo- ford the corresponding sulfoxide as expected (as in the
philes after oxidation of the methylsulfanyl group.
case of methyl phenyl sulfide) but, rather, provided a mix-
ture of sulfide, sulfoxide and sulfone. A test for the nu-
cleophilic displacement of this mixture (SMe, SOMe,
SO2Me) showed no reactivity of the sulfoxide.
SMe
N
SOnMe
Ph
O
Ph
O
Ph
O
A or B
H2O
N
N
N
HN
N
SO2Me
Ph
SMe
N
O
Ph
O
DMDO (2.5 equiv)
acetone
N
N
N
Ph
Ph
Ph
1
2
O
A: m-CPBA, CH2Cl2
B: Oxone®, Al2O3, CH2Cl2
n = 1 or 2
Ph
Ph
1
3
Scheme 3 Unexpected hydrolysis of the oxidation product of the
methylsulfide
Scheme 4 Quantitative oxidation of methylsulfide 1 into methylsul-
fone 3
Dimethyldioxirane (DMDO) was thus finally consid-
ered.9,10 This reagent is widely used to carry out a variety
of oxygen atom transfer reactions, and is easily prepared
from acetone and Oxone, under buffered conditions (pH
7–7.5).11,12 When the substrate and oxidized product toler-
ate hydrolytic conditions, the oxidation can be performed
in situ. Otherwise, distillation of the reaction mixture af-
fords the reagent in the form of a 0.06–0.09 mol·L–1 ace-
tone solution. For quantitative determination of the
dioxirane concentration in this acetone solution, several
methods have been described, among them, iodometric ti-
tration.10 Reactions performed with dioxirane in isolated
form (as a solution in the parent ketone) are best suited to
oxidations under neutral and anhydrous conditions of
acid- or base-sensitive substrates or hydrolytically labile
oxy-functionalized products. DMDO therefore appeared
to be a suitable choice of oxidant in our case.
Nucleophilic displacements of the methylsulfonyl group
on pyrimidinone 3 were then achieved in good yields by
use of various nucleophiles (Scheme 5, Figure 1,
Table 1). Soft nucleophilic amines, and even ammonia,
gave pyrimidinones 4a–c (Table 1, entries 1–3). 2-Ami-
no-pyrimidin-4-ones are of major interest for our ongoing
project, which will be published in due course. Sodium
ethanolate afforded pyrimidinone 5 (Table 1, entry 4). 2-
Cyano-pyrimidinone 6 (Table 1, entry 5) was also easily
isolated after reaction with trimethylsilyl cyanide with tet-
rabutylammonium fluoride activation. The introduction
of a new carbon–carbon bond at the C2-position could be
envisaged to take place through displacement of the cyano
group of 6 with various Grignard reagents.6 However, we
were delighted to notice that it was possible to effect this
conversion from sulfone 3 directly. Indeed, organolithium
reagents led cleanly to pyrimidinones 7a and 7b (Table 1,
entries 6 and 7) through displacement of the methylsulfo-
nyl group of 3. This route avoids the need to implement
cross-coupling methodologies such as palladium-cata-
lyzed Stille, Suzuki–Miyaura or Heck reactions of aro-
matic halides. Although efficient methods for the cross-
coupling of heteroaromatic thioethers with either boronic
acids or organostannanes have been published in recent
years,13,14 these reactions are limited to aryl or vinyl trans-
fers. Our approach is complimentary to these methods,
since we demonstrate the possibility of introducing an
alkyl group. Finally, pyrimidinone 7c (Table 1, entry 8),
which has no substituent at C2, was obtained by using so-
dium borohydride.
Sulfur compounds are typically good substrates for diox-
irane reagents.10–12 Notably, solutions of DMDO are often
assayed for dioxirane content by reacting them with an ex-
cess of methyl phenyl sulfide. Under these conditions, the
sulfide is converted into the sulfoxide – uncontaminated
with sulfone – and the sulfoxide content can be quantified
by 1H NMR analysis. DMDO is referred to as an electro-
philic oxidant, and the reaction with nucleophilic sulfides
is facile and rapid. However, sulfoxides may also be fur-
ther oxidized into sulfones, in which case DMDO also
acts as an electrophile. It may be that the sulfoxide–sul-
fone conversion is initiated by an attack of the negative
oxygen end of the sulfoxide dipole on the dioxirane.
Synthesis 2010, No. 16, 2811–2815 © Thieme Stuttgart · New York

PAPER
Displacement of a Methylsulfanyl Group from Substituted Pyrimidinones
2813
mL). The suspension was subjected to vigourous magnetic stirring
and cooled to 0 °C. On the other side, a 100 mL receiving flask was
cooled to –78 °C and an exit to subsequently apply vacuum to the
whole system was installed. Oxone (triple salt 2 KHSO5–KHSO4–
K2SO4, 50 g) was then added to the reaction mixture in five portions
(5 × 10 g) at 3 min intervals. A 125 mbar vacuum was applied 3 min
after the last addition. The cooling bath was then removed from the
reaction flask to let the temperature return to r.t. (20 °C) and vigor-
ous magnetic stirring was maintained during 70–80 min. The distill-
ing DMDO solution was collected in the cooled (–78 °C) receiving
flask to afford, on average, 30–35 mL of distillate, which was then
dried over K2CO3, filtered, and stored under argon at –20 °C.
SO2Me
Nu
Ph
Ph
O
nucleophile
N
N
N
N
O
Ph
Ph
3
4–7
Scheme 5 Nucleophilic displacements of the methylsulfonyl group
on pyrimidinone 3 with various nucleophiles
NHR1
N
OEt
CN
R2
Ph
O
Ph
O
Ph
O
Ph
O
N
N
N
N
N
N
N
Iodometric Titration of DMDO Solutions
To the above prepared solution of DMDO in acetone (0.50 mL),
was added H2O (5 mL), KI (20 mg) and a few drops of AcOH. The
formed iodide was then titrated with aq Na2S2O3 (0.10 mol·L–1),
giving final DMDO concentrations ranging on average from 0.07 to
0.08 mol·L–1.
Ph
Ph
Ph
Ph
4a–c
5
6
7a–c
Figure 1 Products isolated from pyrimidinone 3 after methylsulfo-
nyl group displacement
Model Substrate Methylsulfide 1
Phenylacetyl chloride (185 mg, 1.2 mmol) and Et3N (243 mg,
2.4 mmol) were added to a solution of 4-(dimethylamino)-2-meth-
ylsulfanyl-1-phenyl-1,3-diazabuta-1,3-diene8 (221 mg, 1.0 mmol)
in CH2Cl2 (5 mL). The reaction mixture was stirred for 18 h at r.t.,
then diluted with CH2Cl2 (20 mL), washed with H2O (2 × 20 mL),
dried over MgSO4, filtered, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography
(CH2Cl2) to afford 1.
Table 1 Nucleophilic Displacement of the Methylsulfonyl Group
on 3 with Nucleophiles
Entry
Nucleophile
BnNH2
Product
4a R1 = Bn
4b R1 = Et
4c R1 = H
5
Yield (%)
1
2
3
4
5
6
7
8
81
92
97
98
96
81
77
79
EtNH2
Yield: 265 mg (90%); white solid; mp 128–130 °C.
NH3 (g)
EtONa
IR: 3092 (w), 2924 (w), 1685 (s), 1581 (w), 1500 (s), 1454 (w),
1368 (m) cm–1.
1H NMR (CDCl3): d = 2.50 (s, 3 H), 7.30–7.45 (m, 5 H), 7.51–7.61
(m, 3 H), 7.69–7.74 (m, 2 H), 8.10 (s, 1 H).
13C NMR (CDCl3): d = 15.4, 122.6, 128.0, 128.3, 128.5, 129.8,
130.0, 133.3, 136.0, 149.9, 161.3, 162.9.
MS: m/z (%) = 294 (71) [M]+, 261 (32), 247 (16), 116 (100).
Me3SiCN, TBAF
MeLi
6
7a R2 = Me
7b R2 = n-Bu
7c R2 = H
n-BuLi
NaBH4
Oxidation Product Methylsulfone 3
DMDO in acetone (0.075 mol·L–1, 43.0 mL, 3.2 mmol) was added
at 0 °C to methylsulfide 1 (383 mg, 1.3 mmol). The reaction mix-
ture was stirred for 30 min, while letting the temperature rise to r.t.,
In conclusion, we have shown that the nucleophilic dis-
placement of a methylsulfanyl group at the C2-position of
a pyrimidine ring becomes practicable after oxidation into then evaporated under reduced pressure to afford 3 in a pure form.
Methylsulfone 3 was stored under argon at –20 °C.
the methylsulfonyl group using dimethyldioxirane. We
went beyond our initial objective, which was the introduc-
tion of an amino group, since we showed the possible es-
tablishment of a carbon–carbon bond.
Yield: 424 mg (quantitative); white solid.
IR: 3057 (w), 1730 (s), 1640 (s), 1582 (w), 1497 (m), 1452 (m)
cm–1.
1H NMR (CDCl3): d = 3.37 (s, 3 H), 7.40–7.48 (m, 5 H), 7.54–7.58
(m, 3 H), 7.72–7.75 (m, 2 H), 8.12 (s, 1 H).
13C NMR (CDCl3): d = 41.0, 128.5, 129.1, 129.4, 130.4, 131.8,
132.6, 147.0, 154.5, 160.3.
All reagents were purchased either from Acros Organics or Aldrich
and were used without further purification. THF was freshly dis-
tilled from Na/benzophenone and CH2Cl2 was distilled over CaH2.
Flash chromatographic purifications were performed on silica gel
Kieselgel SI60 (40–63 mm) from Merck. NMR spectra were record-
ed with a Bruker AC 300 at 300 MHz (1H) and 75 MHz (13C). IR
spectra were recorded with a Bruker Vector 22 (KBr pellets). Mass
spectra were recorded with a Hewlett–Packard 5989 A (electronic
impact at 70 eV or positive chemical ionization at 500 eV with am-
monia).
MS: m/z (%) = 326 (21) [M]+, 247 (77), 116 (100).
Pyrimidinones 4a and 4b
Benzylamine (120 mL, 1.1 mmol) or ethylamine (72 mL, 1.1 mmol)
was added at 0 °C to a solution of methylsulfone 3 (163 mg,
0.5 mmol) in THF (10 mL). The reaction mixture was stirred for 24
h, while letting the temperature rise to r.t., then evaporated under re-
duced pressure, diluted with CH2Cl2 (20 mL), washed with H2O
(2 × 20 mL), dried over MgSO4, filtered, and again evaporated un-
der reduced pressure. The residue was purified by silica gel column
chromatography (PE–EtOAc, 6:4 or CH2Cl2–EtOAc, 9:1, respec-
tively) to afford 4a or 4b, respectively, as white solids.
Preparation of DMDO Solutions
A 2 L two-necked, round-bottomed flask was equipped with a sim-
ple distillation system (steam distillation; Adam and co-workers11,12
used a specific U-tube). The reaction flask was charged with pow-
dered NaHCO3 (24 g) and a mixture of H2O–acetone (10:8, 180
Synthesis 2010, No. 16, 2811–2815 © Thieme Stuttgart · New York

2814
4a
V. Kikelj et al.
PAPER
Pyrimidinone 6
Yield: 143 mg (81%); mp 72–74 °C.
1H NMR (CDCl3): d = 4.47–4.51 (m, 3 H), 7.10–7.34 (m, 10 H),
7.40–7.64 (m, 5 H), 7.95 (s, 1 H).
13C NMR (CDCl3): d = 45.4, 116.7, 126.9, 127.1, 127.6, 127.9,
128.2, 128.5, 128.8, 130.0, 130.7, 134.4, 134.5, 137.7, 152.3, 153.1,
161.5.
TMSCN (119 mg, 1.2 mmol) and TBAF (1.0 mol·L–1 in THF, 1.2
mL, 1.2 mmol) were added at 0 °C to a solution of methylsulfone 3
(326 mg, 1.0 mmol) in THF (20 mL). The reaction mixture was
stirred for 2 h, while letting the temperature rise to r.t., then evapo-
rated under reduced pressure and the residue was purified by silica
gel column chromatography (PE–EtOAc, 8:2) to afford 6.
Yield: 262 mg (96%); white solid; mp 103–104 °C.
IR: 3326 (m), 3059 (w), 3028 (w), 1671 (s), 1585 (m), 1539 (s),
1453 (m) cm–1.
MS: m/z (%) = 353 (68) [M]+, 182 (37), 167 (100), 106 (32), 91 (99).
IR: 3050 (w), 2249 (w), 1690 (s), 1606 (w), 1580 (w), 1507 (m),
1453 (w) cm–1.
1H NMR (CDCl3): d = 7.38–7.52 (m, 5 H), 7.57–7.68 (m, 3 H),
7.71–7.79 (m, 2 H), 8.18 (s, 1 H).
4b
Yield: 134 mg (92%); mp 120–121 °C.
IR: 3419 (s), 2977 (w), 1683 (s), 1550 (s) cm–1.
1H NMR (CDCl3): d = 1.14 (t, J = 6.9 Hz, 3 H), 3.43 (quint,
J = 6.9 Hz, 2 H), 4.19 (br s, 1 H), 7.21–7.40 (m, 5 H), 7.49–7.70 (m,
5 H), 8.01 (s, 1 H).
13C NMR (CDCl3): d = 14.7, 36.7, 116.2, 126.8, 127.9, 128.1, 128.5,
129.9, 130.7, 134.5, 152.4, 153.2, 161.5.
MS: m/z (%) = 291 (100) [M]+, 276 (12), 262 (27), 187 (34), 77 (51).
13C NMR (CDCl3): d = 110.6, 127.7, 128.6, 129.8, 130.2, 131.0,
131.5, 132.0, 134.5, 135.0, 149.0, 159.2.
MS: m/z (%) = 273 (39) [M]+, 245 (12), 218 (8), 129 (17), 77 (100).
Pyrimidinones 7a and 7b
MeLi (3.0 mol·L–1 in Et2O, 120 mL, 0.36 mmol) or n-BuLi
(2.0 mol·L–1 in cyclohexane, 180 mL, 0.36 mmol) was added at 0 °C
to a solution of methylsulfone 3 (98 mg, 0.3 mmol) in THF (10
mL). The mixture was hydrolyzed with H2O (20 mL), extracted
with CH2Cl2 (2 ×20 mL) and the combined organic phases were
dried over MgSO4, filtered, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (PE–
EtOAc, 6:4) to afford 7a or 7b, respectively, as white solids.
Pyrimidinone 4c
A suspension of methylsulfone 3 (326 mg, 1.0 mmol) in toluene (20
mL) was submitted at 0 °C to a gaseous flux of ammonia during 30
min. The reaction mixture was then stirred for 24 h at r.t. After de-
gassing, the mixture was evaporated under reduced pressure, dilut-
ed with CH2Cl2 (20 mL), washed with H2O (2 × 20 mL), dried over
MgSO4, filtered, and again evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (PE–
EtOAc, 4:6) to afford 4c.
7a
Yield: 64 mg (81%); mp 161–162 °C.
IR: 3064 (w), 1690 (s), 1588 (w), 1570 (w), 1535 (s), 1490 (w),
1454 (w) cm–1.
1H NMR (CDCl3): d = 2.23 (s, 3 H), 7.20–7.25 (m, 5 H), 7.47–7.62
Yield: 255 mg (97%); white solid; mp 222–223 °C.
(m, 3 H), 7.65–7.76 (m, 2 H), 8.09 (s, 1 H).
13C NMR (CDCl3): d = 24.2, 125.3, 127.5, 128.3, 128.4, 128.5,
IR: 3457 (s), 3071 (w), 1687 (s), 1631 (s), 1592 (s), 1513 (s), 1473
(w), 1448 (m) cm–1.
1H NMR (CDCl3): d = 5.21 (br s, 2 H), 7.24–7.38 (m, 5 H), 7.51–
7.66 (m, 5 H), 7.89 (s, 1 H).
129.4, 130.1, 133.2, 137.5, 150.0, 158.7, 161.5.
MS: m/z (%) = 262 (40) [M]+, 247 (4), 234 (10), 118 (100), 77 (83).
13C NMR (CDCl3): d = 117.1, 127.1, 127.9, 128.1, 128.2, 130.0,
130.6, 134.2, 134.8, 152.0, 154.5, 161.2.
7b
Yield: 70 mg (77%); mp 140–141 °C.
MS: m/z (%) = 263 (100) [M]+, 235 (19), 192 (7), 144 (9), 119 (27),
77 (50).
IR: 3079 (w), 2960 (w), 1688 (s), 1597 (w), 1574 (w), 1537 (s),
1490 (w), 1420 (w) cm–1.
1H NMR (CDCl3): d = 0.84 (t, J = 7.1 Hz, 3 H), 1.24 (sext,
J = 7.1 Hz, 2 H), 1.59 (quint, J = 7.1 Hz, 2 H), 4.35 (t, J = 7.1 Hz,
2 H), 7.23–7.53 (m, 8 H), 7.65–7.68 (m, 2 H), 7.94 (s, 1 H).
13C NMR (CDCl3): d = 13.5, 18.8, 30.3, 68.8, 121.1, 127.6, 127.8,
128.3, 128.8, 129.2, 133.7, 134.9, 150.1, 155.7, 161.9.
Pyrimidinone 5
NaOEt (0.10 mol·L–1 in EtOH, 3.0 mL, 0.3 mmol) was added at
0 °C to a suspension of methylsulfone 3 (65 mg, 0.2 mmol) in EtOH
(5 mL). The reaction mixture was stirred for 2 h while letting the
temperature rise to r.t., then evaporated under reduced pressure, di-
luted with CH2Cl2 (10 mL), washed with H2O (2 × 10 mL), dried
over MgSO4, filtered, and again evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (PE–
EtOAc, 7:3) to afford 5.
MS (CI+): m/z = 305 [M + H]+.
Pyrimidinone 7c
NaBH4 (14 mg, 0.36 mmol) was added at 0 °C to a solution of
methylsulfone 3 (98 mg, 0.3 mmol) in MeOH (10 mL). The reac-
tion mixture was stirred for 3 h, while letting the temperature rise to
r.t. After addition of sat. aq NaHCO3 (15 mL), the aqueous phase
was extracted with Et2O (2 × 15 mL) and the combined organic
phase was then washed with sat. aq NaCl (15 mL), dried over
MgSO4, filtered, and evaporated under reduced pressure. The resi-
due was purified by silica gel column chromatography (PE–EtOAc,
8:2) to afford 7c.
Yield: 57 mg (98%); white solid; mp 103–105 °C.
IR: 3068 (w), 2926 (w), 1689 (s), 1597 (w), 1536 (s), 1478 (w),
1455 (w) cm–1.
1H NMR (CDCl3): d = 1.26 (t, J = 7.1 Hz, 3 H), 4.42 (quint,
J = 7.1 Hz, 2 H), 7.23–7.53 (m, 8 H), 7.65–7.68 (m, 2 H), 7.94 (s,
1 H).
13C NMR (CDCl3): d = 14.1, 65.0, 121.1, 127.6, 127.8, 128.3, 128.8,
129.2, 133.7, 134.8, 150.1, 155.6, 161.9.
Yield: 59 mg (79%); white solid; mp 98–99 °C.
MS: m/z (%) = 292 (100) [M]+, 264 (23), 144 (66), 116 (31).
IR: 3026 (w), 1679 (s), 1600 (w), 1584 (m), 1493 (m), 1449 (w),
793 (s) cm–1.
Synthesis 2010, No. 16, 2811–2815 © Thieme Stuttgart · New York

PAPER
Displacement of a Methylsulfanyl Group from Substituted Pyrimidinones
2815
1H NMR (CDCl3): d = 7.35–7.63 (m, 8 H), 7.68–7.80 (m, 2 H), 8.15
(br s, 1 H), 8.20 (br s, 1 H).
(5) Robin, A.; Julienne, K.; Meslin, J. C.; Deniaud, D. Eur. J.
Org. Chem. 2006, 634.
(6) Zhang, D.; Sham, K.; Cao, G. Q.; Hungate, R.; Dominguez,
C. Tetrahedron Lett. 2002, 43, 8901.
(7) Tikad, A.; Routier, S.; Akssira, M.; Léger, J. M.; Jarry, C.;
Guillaumet, G. Synthesis 2009, 2379.
13C NMR (CDCl3): d = 126.8, 128.4, 128.6, 129.4, 129.6, 132.9,
137.1, 149.7, 150.5, 160.0.
MS: m/z (%) = 248 (73) [M]+, 220 (8), 144 (30), 104 (38), 77 (100).
(8) Peters, J. U.; Hunziker, D.; Fischer, H.; Kansy, M.; Weber,
S.; Kritter, S.; Müller, A.; Wallier, A.; Ricklin, F.;
Boehringer, M.; Poli, S. M.; Csato, M.; Loeffler, B. M.
Bioorg. Med. Chem. Lett. 2004, 14, 3575.
(9) Adam, W.; Chan, Y. Y.; Cremer, D.; Gauss, J.; Scheutzow,
D.; Schindler, M. J. Org. Chem. 1987, 52, 2800.
(10) Murray, R. W. Chem. Rev. 1989, 89, 1187.
(11) Adam, W.; Hadjiarapoglou, L. Top. Curr. Chem. 1993, 164,
45.
Acknowledgment
The French Ministry of Education and CNRS are gratefully
acknowledged for financial support.
References
(1) (a) Pearson, M. S. M.; Robin, A.; Bourgougnon, N.; Meslin,
J. C.; Deniaud, D. J. Org. Chem. 2003, 68, 8583. (b)Robin,
A.; Meslin, J. C.; Deniaud, D. Tetrahedron Lett. 2004, 45,
9557. (c) Robin, A.; Julienne, K.; Meslin, J. C.; Deniaud, D.
Synthesis 2004, 1633. (d) Robin, A.; Julienne, K.;
Raimbault, S.; Meslin, J. C.; Deniaud, D. Synlett 2005, 2805.
(2) Kikelj, V.; Julienne, K.; Janvier, P.; Meslin, J. C.; Deniaud,
D. Synthesis 2008, 3453.
(12) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991,
124, 2377.
(13) (a) Alphonse, F. A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Synlett 2002, 447. (b) Alphonse, F. A.;
Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org.
Lett. 2003, 5, 803.
(14) (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
(b) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801.
(c) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.;
Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003,
5, 4349.
(3) Kikelj, V.; Setzer, P.; Julienne, K.; Meslin, J. C.; Deniaud,
D. Tetrahedron Lett. 2008, 49, 3273.
(4) Friot, C.; Reliquet, A.; Reliquet, F.; Meslin, J. C. Synthesis
2000, 695.
Synthesis 2010, No. 16, 2811–2815 © Thieme Stuttgart · New York