Development of an efficient and straightforward methodology toward the synthesis of molecularly diverse 2,6-disubstituted 3,4-dihydropyrimidin-4(3H)-ones

Article abstract of DOI:10.1055/s-2002-33924

A simple and efficient methodology toward the synthesis of highly molecularly diverse 2,6-disubstituted 3,4-dihydropyrimidin-4(3H)-ones of type 3 has been developed. The methodology is based on a selective O-alkylation reaction with i-PrOH under Mitsunobu conditions followed by a nucleophilic heteroaromatic ipso-substitution of sulfones 20 and subsequent acidic hydrolysis of the isopropoxy group.

Full text of DOI:10.1055/s-2002-33924

PAPER
1833
Development of an Efficient and Straightforward Methodology Toward the
Synthesis of Molecularly Diverse 2,6-Disubstituted 3,4-Dihydropyrimidin-
4(3H)-ones
S
ynthesis of 2,6-D
a
isubstituted
v
3,4-Dihydro
i
pyrimi
d
din-4(3
H
)-ones Font, Montserrat Heras, José M. Villalgordo*
Departament de Química, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, 17071 Girona, Spain
Fax +34(972)418150; E-mail: jose.villalgordo@udg.es
Received 6 June 2002
Despite the wide variety of synthetic approaches available
Abstract: A simple and efficient methodology toward the synthesis
of highly molecularly diverse 2,6-disubstituted 3,4-dihydropyrimi-
din-4(3H)-ones of type 3 has been developed. The methodology is
based on a selective O-alkylation reaction with i-PrOH under Mit-
for the construction of the 4-pyrimidinone nucleus, the
most direct and widely used methodology toward these
type of substrates involves the cyclocondensation reaction
sunobu conditions followed by a nucleophilic heteroaromatic ipso- between a bidentate nucleophilic fragment (e.g. urea, thio-
substitution of sulfones 20 and subsequent acidic hydrolysis of the
isopropoxy group.
urea, guanidines or amidines) with 1,3-dicarbonyl deriva-
tives (e.g.
-keto esters and related synthetic
equivalents).13 However, this method has some limita-
tions due to the lack of availability of the corresponding
bidentate fragments. This limitation prevents the intro-
duction of a high degree of molecular diversity over the 2-
position in these derivatives. To circumvent this problem,
the alternative approach based on the nucleophilic dis-
placement of alkylsulfanyl groups with different nucleo-
philes in 2-alkylsulfanylpyrimidones of type 2 has been
used. However, due to the poor attitude of alkylsulfanyl
groups as efficient leaving groups in these type of sys-
tems, this approach needs from harsh reaction conditions
yielding the products 3 in generally low yields.4,14 Activa-
tion of the thioether moiety through oxidation to sulfoxide
4 or sulfone 5 to facilitate nucleophilic displacement does
not also solve the problem since 4 and/or 5 are too labile
and the corresponding pyrimidine-2,4-diones 6 are ob-
tained instead (Scheme 1).15
Key words: 4(3H)-pyrimidinones, 4-isopropoxypyrimidines, se-
lective O-alkylation, Mitsunobu reaction, ipso-substitution, selec-
tive acidic hydrolysis
Pyrimidin-4(3H)-ones of type 1 (Figure 1), are valuable
scaffolds in different areas of research. Thus for instance,
it has been described recently, that members of this class
of compounds display potent and selective activity as non-
nucleoside HIV-1 reverse transcriptase inhibitors.1,2 Other
members of this family of compounds have found utility
as herbicides3 and leishmanicides.4 In addition, these
types of substrates have served as suitable models to con-
duct studies on self-association5 and their application to
supramolecular synthesis.6
O
Within this context, we wished to identify and to develop
a general, simple and efficient methodology that could af-
ford collections of molecularly diverse 4-pyrimidinones
of type 1 that in addition would allow the introduction of
a wide variety of substitution patterns over the heterocy-
clic nucleus.
HN
R1
N
R2
1
Figure 1 The structure of pyrimidin-4(3H)-ones
Recently, we reported on the synthesis of novel 2,6-disub-
stituted 4-alkoxypyrimidines starting from 2-alkylsulfa-
nylpyrimidones of type 2.12 The method is based on a
selective O-alkylation reaction in basic medium with ster-
ically demanding alkylating agents like -haloketones 7
and benefits from the key role played by the thioether
linkage in a double sense. On the one hand the steric effect
exerted by the bulky thioether moiety placed at the 2-po-
sition in pyrimidones of type 2 is likely to be responsible
for the observed high selectivity toward the formation of
the O-alkylation products. On the other hand, this sulfur
linkage, serves as an efficient means for introducing addi-
tional molecular diversity through nucleophilic displace-
ment of the corresponding activated sulfones 9
(Scheme 2).
In connection with our ongoing studies dealing with the
development of efficient methodologies that could readily
be adapted for the combinatorial and/or parallel synthesis,
in solution and/or on solid supports of relevant core struc-
tures with potential therapeutic interest,7–11 we needed to
make use of a number of different molecularly diverse 4-
pyrimidinones of type 1 to incorporate this structural mo-
tif into different types of libraries.12
Synthesis 2002, No. 13, Print: 20 09 2002.
Art Id.1437-210X,E;2002,0,13,1833,1842,ftx,en;P02602SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1834
D. Font et al.
PAPER
O
OR2
Mitsunobu
O
O
N
HN
RS
R2 OH
+
N
∆
HN
RS
HN
Nu
N
R1
RS
N
R1
+
NuH
Low yields
R1
R1
N
2
11
12
3
2
OR2
O
N
OR2
Ox.
Ox.
NuH
NuH
HN
RS(O)n
N
N
R
R1
S
N
R1
Nu
N
R1
O O
4 n = 1
5 n = 2
13
14
O
HN
Hydrolysis
O
Nu
N
R1
HN
3
O
N
H
R1
Scheme 3
6
Scheme 1
sunobu conditions led to the formation of the correspond-
ing 4-alkoxypyrimidine derivatives 18a–c (Scheme 4,
Table 1 and Table 2).
O
R2
O
N
R2
HN
O
X
+
N
O
RS
N
R1
O
O
RS
R1
Et3N
HN
HS
HN
+
Ph
Br
2
7
8
DMF / 0 °C to r.t.
83-87%
R1
N
R1
Ph
S
N
R2
15a R1 = H
17a R1 = H
R2
O
N
16
15b R1 = Ph
17b R1 = Ph
O
N
Ox.
O
NuH
O
N
N
R
S
R1
Nu
R1
O O
R2
O
O
i) R2-OH
R2
N
9
10
+
ii) DIAD / Ph3P
THF /r.t.
N
R1
Scheme 2
Ph
S
N
Ph
S
N
R1
51-92%
19b
18a-c
Based on these results, we reasoned that in complete anal-
ogy with the above-mentioned results, alkylation reaction
with bulky aliphatic alcohols under Mitsunobu conditions
should also lead selectively to O-alkylated pyrimidines
12. Oxidation of the thioether moiety to the corresponding
stable pyrimidine sulfone derivatives 13, followed by nu-
cleophilic ipso-substitution reaction with different nu-
cleophiles and subsequent mild hydrolysis of the 4-alkoxy
group would allow the formation of collections of target
4-pyrimidinones of type 3 (Scheme 3).
R
R
1 = H, Ph
2 = t-Bu, i-Pr
Scheme 4
The use of t-BuOH as alkylating reagent in the Mitsunobu
reaction proceeded as expected with total selectivity af-
fording exclusively the corresponding O-alkylated prod-
uct 18a. However, this reaction proceeded only in
moderated yields (51%), and as much as a 48% of unre-
acted starting material 17a was recovered from the reac-
tion mixture (Table 1, entry 3). Better results were
obtained however by using i-PrOH as alkylating reagent.
The Mitsunobu reaction did proceed in high yields and
with a high degree of selectivity, affording 4-isopropoxy-
pyrimidines 18b,c (Table 1, entries 4 and 6). Only in the
case of 17a, the formation of the corresponding N-alkylat-
Consistent with this goal, t-BuOH and i-PrOH were ini-
tially selected as bulky aliphatic alcohols. Thus, starting
from the readily available 2-sulfanylpyrimidin-4(3H)-
ones 15a,b, alkylation of the sulfanyl group with benzyl
bromide in DMF in the presence of Et3N afforded the cor-
responding pure thioether derivatives 17a,b in 83–87%
yield. Then, reaction with t-BuOH or i-PrOH under Mit-
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,6-Disubstituted 3,4-Dihydropyrimidin-4(3H)-ones
1835
ed product 19b was also detected, but in very small
amounts (<4%) (Table 1, Entry 6).
Table 1 2-Benzylthiopyrimidin-4(3H)-ones 17a,b, 19b and 4-
Alkoxypyrimidines 18a–c
Having established a good and highly selective methodol-
ogy for the synthesis of 4-alkoxypyrimidines of type 18
via a Mitsunobu reaction type, before proceeding with our
initially planned synthetic route toward pyrimidinones of
type 3, we focused our attention in the search for mild and
reliable reaction conditions that could selectively cleave
the 4-alkoxy group. Thus, we found that when 4-tert-bu-
toxypyrimidine 18a was treated with a 1:1 mixture of 5 N
HCl/MeOH at room temperature for 5 hours, pyrimidino-
ne 17a was obtained quantitatively. When these condi-
tions were applied to 4-isopropoxypyrimidine 18b, the
hydrolysis to 17a proved to be unsuccessful. However, by
treating 18b with a 1:1 mixture of H2SO4–AcOH at 90 °C,
the hydrolysis was essentially completed after 15 minutes
(Scheme 5).
Entry
Producta R1
R2
–
Yield (%) Mp (°C)
1
2
3
4
17a
17b
18a
18b
H
83
85
51
88
174–175
243–244
53–54
Ph
H
–
t-Bu
i-Pr
H
colorless
oil
5
6
18c
19b
Ph
H
i-Pr
i-Pr
92
4
81–82
94–95
a Satisfactory microanalyses obtained: C 0.27, H 0.28, N 0.22, S
0.25.
Table 2 MS, IR and NMR Data of 2-Benzylthiopyrimidin-4(3H)-ones 17a,b, 19b and 4-Alkoxypyrimidines 18a–c
Prod-
uct
MS
m/z (%)
IR (KBr)
cm–1
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
17a
17b
18a
220 ([M + 2]+, 14), 219 ([M 3030, 2790, 2698, 2620,
4.50 (s, 2 H, PhCH2S), 6.23 (d, 1 33.7 (t, CH2), 110.1 (d, CHpyrim),
Hpyrim, J = 5.8), 7.40–7.50 (m, 5 127.3, 128.5, 129.0 (3 d, 5
+ 1]+, 100), 218 (17), 185
(4), 167 (5), 165 (5)a
1664, 1557, 1457, 1275,
1227, 1177, 976, 930, 822, Harom), 8.01 (d, 1 Hpyrim, J = 5.6), CHarom), 137.1 (s, Carom), 154.3
707
b
12.19 (br, 1 H, NH)b
(d, CH pyrim), 162.7 (s, Cpyrim)
295 ([M + 1]+, 37), 285
(95), 284 (14), 283 (100),
192 (40), 155 (19), 154
(81), 138 (27), 137 (50),
136 (80)a
2796, 2738, 2675, 1660,
1567, 1461, 1380, 1238,
1207, 1060, 987, 930, 840, 8.05–8.10 (m, 2 Harom), 12.51
4.64 (s, 2 H, PhCH2S) 6.70 (s, 1 33.8 (t, CH2), 103.9 (d, CHpyrim),
Hpyrim), 7.30–7.50 (m, 8 Harom),
126.9, 127.3, 128.5, 128.7,
128.9, 130.6 (6 d, 10 CHarom),
780, 700
(br, 1 H, NH)b
136.0, 137.4 (2 s, 2 Carom), 160.3,
b
162.1, 163.9 (3 s, Cpyrim
)
274 ([M]·+, 12), 219 (40),
217 (99), 186 (44), 184
(100), 158 (32), 140 (51),
123 (25), 121 (49), 96 (49),
91 (89)c
3053, 2975, 2953, 1562,
1427, 1332, 1202, 1154,
973, 850, 687
1.61 (s, 9 H, t-C4H9), 4.45 (s, 2
H, PhCH2S), 6.34 (d, 1 Hpyrim
28.3 (q, 3 CH3), 35.3 (t, CH2),
82.0 (s, C), 105.8 (d, CH pyrim),
,
J = 5.8), 7.30–7.50 (m, 5 Harom), 127.1, 128.5, 128.8 (3 d, 5
8.23 [d, 1 H, J = 5.6, H(6)pyrim
]
CHarom), 137.0 (s, Carom), 156.9
(d, CHpyrim), 168.6, 170.4 (2 s, 2
Cpyrim
)
18b
18c
19b
261 ([M + 1]+, 16), 260
(M+, 75), 219 (18), 218
(81), 217 (32), 186 (34),
185 (100), 158 (33), 141
(20), 140 (32)c
3032, 2981, 2932, 1599,
1439, 1380, 1324, 1106,
979, 825, 707
1.38 [d, 6 H, J = 6.0, CH(CH3)2], 421.7 (q, 2 CH3), 35.2 (t, CH2),
4.44 (s, 2 H, PhCH2S), 5.40 (m, 69.4 (d, CH), 104.4 (d, CHpyrim),
1 H, J = 6, CH), 6.37 (d, 1 Hpyrim
J = 5.6), 7.30–7.50 (m, 5 Harom), CHarom), 137.5 (s, Carom), 157.1
8.24 (d, 1 Hpyrim, J = 5.6) (d, CHpyrim), 168.2, 171.0 (2 s, 2
Cpyrim
,
127.0, 128.4, 128.8 (3 d, 5
)
336 ([M]·+, 90), 294 (97),
293 (40), 261 (100), 172
(64), 171 (42), 103 (28), 91 1265, 1211, 1097, 993, 839, 1 H, J = 6.2, CH), 6.77 (s, 1
(99), 77 (22)c
690 Hpyrim), 7.20–7.70 (m, 8 Harom),
8.0–8.05 (s, 2 Harom
3060, 2971, 2926, 1566,
1533, 1490, 1147, 1400,
1.38 [d, 6 H, J = 6.2, CH(CH3)2], 21.9 (q, 2 CH3), 35.4 (t, CH2),
4.54 (s, 2 H, PhCH2S), 5.46 (m, 69.5 (d, CH), 99.7 (d, CHpyrim),
127.0, 128.4, 128.5, 128.7,
128.8, 130.5 (6 d, 10 CHarom),
136.8, 138.0 (2 s, 2 Carom), 164.6,
)
169.4, 170.8 (3 s, 3 Cpyrim
)
260 ([M]·+, 3), 186 (7), 185 3062, 2971, 2936, 1682,
(39), 171 (6), 170 (11), 169 1576, 1491, 1403, 1305,
1.63 [d, 6 H, J = 6.6, CH(CH3)2], 19.0 (q, 2 CH3), 37.3 (t, CH2),
4.43 (s, 2 H, PhCH2S), 4.67 (m, 58.0 (d, CH), 112.0 (d, CHpyrim),
(100)c
1230, 1183, 1136, 1067,
924, 827, 706
1 H, CH), 6.15 (d, 1 Hpyrim
J = 6.2), 7.30–7.50 (m, 5 Harom), CHarom), 135.6 (s, Carom), 150.8
7.71 (d, 1 Hpyrim, J = 6.2) (d, CHpyrim), 161.9, 162.6 (2 s, 2
Cpyrim
,
127.7, 128.6, 129.3 (3 d, 5
)
a Taken in the FAB+ mode.
b NMR recorded in DMSO-d6.
c Taken in the EI (70 eV) mode.
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York

1836
D. Font et al.
PAPER
Table 3 4-Alkoxypyrimidine Sulfones 20a,b and 4-Alkoxypyrim-
idines 22a–f Prepared
R2
O
N
O
5N HCl/MeOH (1:1)
HN
N
Prod- R1
ucta
R2R3NH
Yield
(%)
Mp
(°C)
18a R1 = H, R2 = t-Bu
R1
Ph
S
Ph
S
N
R1
r.t., 5 h, 97%
18a,b
17a R1 = H
20a
20b
22a
H
–
–
79
88
89
100–101
Ph
H
124–125
colorless oil
H2SO4/AcOH (1:1)
NH2
18b R1 = H, R2 = i-Pr
22b
22c
Ph
H
82
86
colorless oil
colorless oil
90 °C, 15 min, 98%
NH2
NH
Scheme 5
With this good procedure in our hands for selective O- 22d
alkylation of 2-benzylthiopyrimidin-4(3H)-ones of type
17 with i-PrOH under Mitsunobu conditions and subse-
Ph
Ph
85
86
colorless oil
104–105
NH
22e
quent acidic hydrolysis, we then proceeded to complete
NH
our initial plans for the synthesis of collections of molec-
ularly diverse pyrimidinones of type 3. Thus, when 18b,c
were treated with 2.5 equivalents of m-CPBA, the corre-
F3C
N
22f
H
80
57–58
sponding sulfones 20a,b were obtained in good yields
NH
(79–88%). These sulfones of type 20 were allowed to re-
act in dioxane at 60 °C with a variety of N-nucleophiles
(primary and secondary amines, 21a–d) affording the cor-
responding ipso-substitution products 22a–f in good
yields (80–89%). Following acidic hydrolysis under the
previously developed conditions of H2SO4–AcOH (1:1) at
90 °C yielded the corresponding target compounds 23a–f
also in good yields (84–88%) (Scheme 6, Tables 3– 6).
N
F
a Satisfactory microanalyses obtained: C 0.29, H 0.26, N 0.30.
Table 4 MS, IR and NMR Data of Pyrimidines 20a,b and 22a–f
Prod-
uct
MS
m/z (%)
IR (KBr)
cm–1
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
20a
293 ([M + 1]+, 100), 3079, 2986, 2939,
1.38 [d, 6 H, J = 6.2, CH(CH3)2],
21.5 (q, 2 CH3), 57.5 (t, CH2), 71.6 (d,
294 (16), 295 (6),
251 (32), 188 (9),
187 (69), 185 (13),
165 (5)a
2886, 1584, 1530,
1451, 1319, 1246,
1128, 978, 842, 774, 7.30–7.55 (m, 5 Harom), 8.54 (d, 1 Hpyrim
4.75 (s, 2 H, PhCH2S), 5.48 (m, 1 H, CH), 111.7 (d, CHpyrim), 126.8 (s, Carom),
J = 6.2, CH), 6.82 (d, 1 Hpyrim, J = 5.8), 128.6, 128.7, 131.1 (3 d, 5 CHarom),
,
157.5 (d, CHpyrim), 164.4, 169.7 (2 s, 2
Cpyrim
706
J = 5.8)
)
20b
368 ([M]·+, 67), 303 3033, 2980, 2937,
1.43 [d, 6 H, J = 6.2, CH(CH3)2], 4.88
21.7 (q, 2 CH3), 57.3 (t, CH2), 71.6 (d,
(58), 262 (63), 261
(95), 171 (68), 129
(40), 116 (38), 103
(62), 102 (40), 91
(100)a
2904, 1587, 1522,
1453, 1417, 1311,
1251, 1213, 1131,
978, 869, 776
(s, 2 H, PhCH2S), 5.66 (m, 1 H, J = 6.0, CH), 106.0 (d, CHpyrim), 127.1 (s, Carom),
CH), 6.99 (s, 1 Hpyrim), 7.20–7.55 (m, 8 127.2, 128.2, 128.7, 128.8, 131.3, 131.6
Harom), 8.0–8.1 (m, 2 Harom
)
(6 d, 10 CHarom), 135.0 (s, Carom), 164.7,
165.5, 170.9 (3 s, 3 Cpyrim
)
22a
22b
210 ([M + 1]+, 16),
209 (M+, 75), 194
(16), 180 (31), 167
3262, 2967, 2871,
1588, 1531, 1464,
1428, 1366, 1298,
0.97 (t, 3 H, J = 7.2, CH3), 1.35 [d, 6 H, 13.8 (q, CH3), 20.1 (t, CH2), 21.8 (q,
J = 6.4, CH(CH3)2], 1.40–1.70 (m, 4 H, 2 CH3), 31.8, 41.1 (2 t, 2 CH2), 68.2
2 CH2), 3.42 (q, 2 H, J = 6.6, CH2),
(d, CH), 97.5 (d, CHpyrim), 158.0 (d,
(81), 166 (100), 153 1235, 1109, 981,
5.10 (br, 1 H, NH), 5.30–5.35 (m, 1 H, CHpyrim), 162.6, 169.4 (2 s, 2 Cpyrim
J = 6.4, CH), 5.94 (d, 1 Hpyrim, J = 5.6),
)
(61), 152 (43)b
800
8.00 (d, 1 Hpyrim, J = 5.8)
286 ([M + 1]+, 1),
244 (100), 243 (7),
3436, 3269, 2962,
2930, 2868, 1583,
1.00 (t, 3 H, J = 7.2, CH3), 1.40 [d, 6 H, 13.8 (q, CH3), 20.1 (t, CH2), 21.9 (q, 2
J = 6.2, CH(CH3)2], 1.40–1.70 (m, 4 H, CH3), 31.9, 41.2 (2 t, 2 CH2), 68.6 (d,
242 (5), 201 (6), 188 1447, 1387, 1321,
2 CH2), 3.52 (q, 2 H, J = 6.8, CH2),
5.13 (br, 1 H, NH), 5.40–5.45 (m, 1 H, 130.0 (3 d, 5 CHarom), 137.5 (s, Carom)
J = 6.4, CH), 6.40 (s, 1 Hpyrim), 7.30–
CH), 93.3 (d, CHpyrim), 128.8, 128.5,
(6), 187 (7)a
1211, 1106, 770,
696
162.2, 164.9, 170.6 (3 s, 3 Cpyrim)
7.50 (m, 3 Harom), 7.75–8.00 (m, 2 Harom
)
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,6-Disubstituted 3,4-Dihydropyrimidin-4(3H)-ones
1837
Table 4 MS, IR and NMR Data of Pyrimidines 20a,b and 22a–f (continued)
Prod-
uct
MS
m/z (%)
IR (KBr)
cm–1
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
22c
22d
22e
22f
270 ([M]·+, 15), 269 2979, 2927, 2844,
(78), 228 (5), 227 1580, 1497, 1445,
1.38 [d, 6 H, J = 6.2, CH(CH3)2],
2.89 (t, 2 H, J = 5.8, CH2), 4.08 (t, 2 H, CH2), 68.2 (d, CH), 96.9 (d, CHpyrim),
J = 5.8, CH2), 5.00 (s, 2 H, CH2), 5.40– 126.1, 126.2, 126.4, 128.5 (4 d, 4
21.9 (q, 2 CH3), 28.9, 41.4, 46.2 (3 t, 3
(41), 226 (100), 212 1342, 1299, 1238,
(25)b
1088, 939, 799, 745 5.45 (m, 1 H, J = 6.2, CH), 5.99 (d, 1
CHarom), 134.3, 135.2 (2 s, 2 Carom),
Hpyrim, J = 5.8), 7.25–7.40 (m, 4 Harom), 157.8 (d, CHpyrim), 161.4, 169.0 (2 s, 2
8.13 (d, 1 Hpyrim, J = 5.8)
Cpyrim
)
346 ([M + 1]+, 1),
304 (100), 303 (19), 2929, 2841, 1569,
3063, 3023, 2978,
1.44 [d, 6 H, J = 6.2, CH(CH3)2],
3.01 (t, 2 H, J = 6.0, CH2), 4.20 (t, 2 H, CH2), 68.3 (d, CH), 92.6 (d, CHpyrim),
J = 6.0, CH2), 5.07 (s, 2 H, CH2), 5.45– 126.0, 126.1, 126.5, 126.9, 128.4,
5.50 (m, 1 H, J = 6.4, CH), 6.44 (s, 1
Hpyrim), 7.20–7.30 (m, 4 Harom), 7.40–
7.50 (m, 3 Harom), 8.05–8.10 (m, 2 Harom
22.0 (q, 2 CH3), 29.0, 41.5, 46.3 (3 t, 3
200 (17), 172 (9),
1493, 1453, 1321,
1259, 1210, 1100,
979, 769, 695
171 (14)a
128.6, 129.8 (7 d, 9 CHarom), 134.6,
135.4, 138.3 (3 s, 3 Carom), 161.6, 165.2,
)
170.3 (3 s, 3 Cpyrim
)
442 ([M]·+, 12), 255 2983, 2901, 2847,
1.43 [d, 6 H, J = 6.2, CH(CH3)2],
3.37 (t, 4 H, J = 5.0, CH2), 4.12 (t, 4 H, 68.5 (d, CH), 93.2 (d, CHpyrim), 112.5,
J = 5.0, CH2), 5.41 (m 1 H, J = 6.0, CH), 116.1, 119.0 (3 d, 3 CHarom), 124.3 (s,
6.46 (s, 1 Hpyrim), 7.15–7.45 (m, 7
Harom), 7.95–8.05 (m, 2 Harom).
22.0 (q, 2 CH3), 43.7, 48.8 (2 t, 4 CH2),
(13), 243 (21), 242
(89), 212 (19), 201
1536, 1503, 1446,
1381, 1340, 1280,
(26), 200 (100), 172 1223, 1162, 1112,
CF3), 126.9, 128.5, 129.6, 130.0 (4 d,
6 CHarom), 131.5, 138.0, 151.6 (3 s, 3
Carom), 161.7, 165.3, 170.4 (3 s, 3 Cpyrim
(23), 170 (24), 145
962, 778, 698
(13)b
)
316 ([M]·+, 17), 179 2981, 2888, 2851,
1.39 [d, 6 H, J = 6.2, CH(CH3)2],
21.8 (q, 2 CH3), 43.8, 50.4 (2 t, 4 CH2),
(23), 166 (73), 151
(27), 150 (22), 136
2814, 1573, 1504,
1446, 1337, 1229,
3.18 (t, 4 H, J = 5.2, CH2), 3.98 (t, 4 H, 68.3 (d, CH), 97.5 (CHpyrim), 115.6,
J = 5.2, CH2), 5.35 (m, 1 H, J = 6.2,
CH), 5.99 (d, 1 Hpyrim, J = 5.6),
6.90–7.10 (m, 4 Harom), 8.09 (d, 1
Hpyrim, J = 5.6)
118.3 (2 d, 4 CHarom), 148.1, 157.4 (2 s,
2 Carom), 157.9 (d, CHpyrim), 161.7, 169.2
(2 s, 2 Cpyrim).
(24), 124 (100), 122 1150, 1100, 1009,
(32), 95 (27)b
949, 811
a Taken in the FAB+ mode.
b Taken in the EI (70 eV) mode.
Table 5 2-Aminopyrimidin-4(3H)-ones 23a–f Prepared
O
Prod-
ucta
R
R2R3NH
Yield
(%)
Mp
(ºC)
O
m-CPBA (2.5 equiv)
N
N
CH2Cl2 / 0 °C to r.t.
79-88%
Ph
S
N
R1
Ph
S
N
R1
23a
23b
23c
H
87
86
86
116–117
180–181
121–122
O
O
NH2
18b R1 = H
18c R1 = Ph
20a R1 = H
20b R1 = Ph
Ph
H
NH2
NH
R2
R3
23d
23e
Ph
Ph
84
88
183–184
223–224
O
NH
O
N
NH
21a-d
HN
H2SO4/AcOH (1:1)
90 °C, 15 min
84-88%
R2
R1
R2
N
R3
N
N
R3
N
R1
Dioxane/60 °C
80-89%
NH
F3C
N
23a-f
22a-f
Scheme 6
23f
H
84
227–228
NH
N
the 2-position in the heterocyclic nucleus other groups dif-
ferent than amines as in the case of compounds of type 23.
To achieve this goal, we then studied the nucleophilic
ipso-substitution reaction of sulfones 20 with C-nucleo-
philes and O-nucleophiles and the subsequent hydrolysis.
Thus, when compounds 20a,b were prompted to react
F
a Satisfactory microanalyses obtainesd: C 0.18, H 0.21, N 0.26.
With the aim of expanding this simple but efficient meth- with methylmagnesium bromide (24) as C-nucleophile in
odology toward molecularly diverse pyrimidinones of diethyl ether at room temperature, the corresponding sub-
type 3, we next addressed the problem of introducing at stitution products 25a,b were obtained in 65–75% yields.
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York

1838
D. Font et al.
PAPER
Table 6 MS, IR and NMR Data of 2-Aminopyrimidin-4(3H)-ones 23a–f
Prod-
uct
MS
IR (KBr)
cm–1
1H NMR (DMSO-d6/TMS)
, J (Hz)
13C NMR (DMSO-d6/TMS)
m/z (%)a
23a
23b
23c
23d
23e
168 ([M + 1]+, 100),
166 (3), 138 (2), 125
(2)
3157, 2956, 2931,
1665, 1613, 1613,
1577, 1475, 1350,
1294, 976, 801, 702
0.98 (t, 3 H, J = 7.2, CH3), 1.30–1.60
(m, 4 H, 2 CH2), 3.22 (t, 2 H, J = 6.0,
CH2), 5.60 (d, 1 Hpyrim, J = 6.6),
13.7 (q, CH3), 19.5, 31.0, 39.9 (3 t, 3
CH2), 102.6 (d, CHpyrim), 155.3 (d,
CHpyrim), 163.2 (s, Cpyrim
)
6.80 (br, 1 H, NH), 7.65 (d, 1 Hpyrim
,
J = 6.6), 11.0 (br, 1 H, NH)
244 ([M + 1]+, 100),
243 (6), 242 (5), 201
(6), 188 (6), 187 (7)
3296, 3167, 2925,
2868, 1666, 1612,
1459, 1413, 1293,
974, 814, 698
1.03 (t, 3 H, J = 7.2, CH3), 1.05–1.80
(m, 4 H, 2 CH2), 3.60 (q, 2 H, J = 6.4, CH2), 97.3 (d, CHpyrim), 126.6, 128.4,
CH2), 6.15 (br, 1 H, NH), 6.26 (s, 1
Hpyrim), 7.35–7.50 (m, 3 Harom), 8.00–
8.05 (m, 2 Harom), 11.90 (br, 1 H, NH)
13.7 (q, CH3), 19.5, 31.0, 39.9 (3 t, 3
129.9 (3 d, 5 CHarom), 137.4 (s, Carom),
154.5, 161.9, 163.5 (3 s, 3 Cpyrim
)
227 ([M]·+, 100), 226 3102, 3021, 2928,
(41), 132 (52), 104
(38), 96 (49)
2.95 (t, 2 H, J = 5.8, CH2), 3.94 (t, 2 H, 28.7, 41.8, 45.9 (3 t, 3 CH2), 100.6 (d,
J = 5.8, CH2), 4.86 (s, 2 H, CH2), 5.76 CHpyrim), 126.1, 126.2, 126.4, 128.4 (4
(d, 1 Hpyrim, J = 6.2). 7.2 (m, 4 Harom),
7.84 (d, 1 Hpyrim, J = 6.2)
2868, 1658, 1568,
1490, 1445, 1369,
1208, 972, 807, 754
d, 4 CHarom), 133.5, 134.6 (2 s, 2 Carom),
156.4 (d, CHpyrim), 164.3 (s, Cpyrim
)
304 ([M + 1]+, 100),
303 (19), 302 (36),
200 (17), 174 (6), 172 1491, 1448, 1384,
(9), 171 (12) 1232, 973, 748, 696
3057, 3019, 2954,
2927, 1644, 1570,
3.09 (t, 2 H, J = 5.8, CH2), 4.10 (t, 2 H, 27.9, 41.9, 46.0 (3 t, 3 CH2), 95.4 (d,
J = 5.8, CH2), 5.02 (s, 2 H, CH2), 6.34 CHpyrim), 126.1, 126.3, 126.4, 126.7,
(s, 1 Hpyrim). 7.10–7.45 (m, 7 Harom),
8.05–8.10 (m, 2 Harom), 12.1 (br, 1H,
NH)
128.4, 128.5, 130.1 (7 d, 9 CHarom),
133.6, 134.7, 137.3 (3 s, 3 Carom),
156.0, 162.4, 166.2 (3 s, 3 Cpirim
)
401 ([M + 1]+, 2), 339 3096, 2988, 2904,
3.44 (t, 4 H, J = 5.0, CH2), 4.07 (t, 4 H, 43.8, 47.3 (2 t, 4 CH2), 95.7 (d,
(18), 291 (15), 205
(16), 203 (17), 191
(36), 189 (29), 177
(30), 165 (64)
2853, 1649, 1578,
1496, 1448, 1377,
1283, 1230, 1159,
1121, 955, 779, 696
J = 5.0, CH2), 6.38 (s,1 Hpyrim), 7.15–
7.50 (m, 7 Harom), 8.00–8.05 (m, 2
Harom), 12.2 (br, 1H, NH)
CHpyrim), 111.2, 114.9, 119.0 (3d, 3
CHarom), 124.5 (s, CF3), 126.7, 128.5,
130.2, 130.3 (4 d, 6 CHarom), 130.4,
137.3, 151.1 (3 s, 3 Carom), 162.5,
166.5, 172.1 (3 s, 3 Cpyrim
)
23f
275 ([M + 1]+, 100),
274 (32), 273 (24),
154 (18), 150 (32),
138 (35), 137 (38),
136 (29)
3100, 2970, 2921,
2830, 1660, 1567,
1505, 1308, 1225,
1158, 970, 823
3.23 (t, 4 H, J = 5.0, CH2), 3.88 (t, 44.3, 49.2 (2 t, 4 CH2), 101.4 (d,
4 H, J = 5.0, CH2), 5.82 (d, 1 Hpyrim
,
CHpyrim), 115.7, 118.0 (2 d, 4 CHarom),
148.1, 156.7 (2 s, 2 Carom), 156.9 (d,
J = 6.0), 7.15–7.25 (m, 4 Harom), 7.87
(d, 1 Hpyrim, J = 6.0), 11.38 (br, 1H,
NH)
CHpyrim), 165.5 (s, C pyrim
)
a Taken in the FAB+ mode.
Table 7 Pyrimidines 25 and 28 and Pyrimidin-4(3H)-ones 26 and
29 Prepared
Acidic hydrolysis under standard conditions afforded py-
rimidinones 26a,b in good yields. Analogous sequence
using acetylide 27 in THF at –10 °C also afforded 4-iso-
propoxypyrimidines 28a,b in good yields, although the
subsequent hydrolysis gave final products 29a,b in only
moderate yields (Scheme 7, Tables 7 and 8).
In a similar fashion, when sulfones 20a,b were allowed to
react with different phenols 30a,b in the presence of
Cs2CO3 in dioxane at 60 °C, the corresponding 2-aryloxy-
4-isopropoxypyrimidines 31a–d were isolated in good
yields. In addition, when compounds of type 31 were
treated with a 1:1 mixture of H2SO4–AcOH at 90 °C dur-
ing 15 min. the selective cleavage of the 4-isopropoxy
group took place affording to 2-aryloxypyrimidinone der-
ivatives 32a–d in also good yields. (Scheme 8, Tables 9
and 10).
Entry
Producta
25a
R1
H
Yield (%)
Mp (°C)
1
2
3
4
5
6
7
8
61
75
78
82
79
97
30
38
colorless oil
colorless oil
204–205
25b
Ph
H
26a
26b
Ph
H
240–241
28a
colorless oil
colorless oil
168–169
28b
Ph
H
29a
29b
Ph
188–189
a Satisfactory microanalyses obtained: C 0.22, H 0.29, N 0.26.
In summary, we have developed a simple and efficient
methodology that allows the facile synthesis of a collec-
tion of 2,5-disubstituted pyrimidin-4(3H)-ones of type 3
with a high degree of molecular diversity. This methodol-
ogy is based on the key role played by the 2-thioalkyl moi-
ety in 17 in two ways. Due to the steric demand imposed
by the thioether linkage, the O-alkylation reaction with
bulky aliphatic alcohols under Mitsunobu conditions can
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,6-Disubstituted 3,4-Dihydropyrimidin-4(3H)-ones
1839
Table 8 MS, IR and NMR Data of Pyrimidines 25 and 28, and 2-Substituted Pyrimidin-4(3H)-ones 26 and 29
Prod-
uct
MS
IR (KBr)
cm–1
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
m/z (%)a
25a
152 ([M]·+, 6), 111 (21), 2980, 2934, 1576, 1451, 1.37 [d, 6 H, J = 6.4, CH(CH3)2], 21.7, 25.9 (2 q, 3 CH3), 68.7 (d,
110 (83), 95 (35), 94
(100), 93 (27), 82 (71),
69 (32)
1313, 1110, 1035, 986,
968, 829
2.57 (s, 3 H, CH3), 5.40 (m, 1 H, CH), 105.6 (d, CHpyrim), 156.9 (d,
J = 6.4, CH), 6.45 (d, 1 Hpyrim
J = 5.8), 8.29 (d, 1 Hpyrim, J = 5.8)
,
CHpyrim), 167.9, 168.6 (2 s, 2 Cpyrim
)
25b
228 ([M]·+, 31), 213
2980, 2932, 1584, 1549, 1.42 [d, 6 H, J = 6.2, CH(CH3)2],
21.9, 26.2 (2 q, 3 CH3), 68.8 (d,
(94), 187 (36), 186 (92), 1452, 1391, 324, 1210,
185 (100), 170 (94), 158 1111, 1052, 926, 695
(83), 129 (87), 128 (66),
2.70 (s, 3 H, CH3), 5.49 (m, 1 H, CH), 100.9 (d, CHpyrim), 127.0,
J = 6.2, CH), 6.88 (s, 1 Hpyrim),
128.7, 130.1 (3 d, 5 CHarom), 137.5
(s, Carom), 164.9, 168.0, 169.8 (3 s, 3
Cpyrim
7.40–7.50 (m, 3 Harom), 8.00–8.05
104 (72), 102 (94)
(m, 2 Harom
)
)
26a
26b
28a
110 ([M]·+, 100), 95 (5), 3088, 3007, 2926, 2849, 2.36 (s, 3 H, CH3), 6.23 (d, 1 Hpyrim
,
21.3 (q, CH3), 112.8 (d, CHpyrim),
93 (3), 82 (32), 81 (9)
2766, 1681, 1602, 1467, J = 6.0), 7.89 (d, 1 Hpyrim, J = 6.0),
1422, 1307, 1219, 1096, 12.50 (br, NH)b
978, 929, 850
154.4 (d, CHpyrim), 160.0, 162.3 (2 s,
b
2 Cpyrim
)
186 ([M]·+, 100), 185
2990, 2868, 2845, 1655, 2.38 (s, 3 H, CH3), 6.72 (s, 1 Hpyrim), 21.7 (q, CH3), 106.8 (d, CHpyrim),
(64), 158 (25), 117 (19), 1612, 1184, 1120, 858,
7.40–7.50 (m, 3 Harom), 8.00–8.05
126.9, 128.8, 130.5 (3 d, 5 CHarom),
104 (33), 89 (13), 77
(16)
781, 693
(m, 2 Harom), 12.40 (br, NH)b
136.5 (s, Carom), 159.3, 160.7, 163.2
b
(3 s, 3 Cpyrim
)
291 ([M]·+, 2), 191 (56), 3297br, 2980, 2934,
1.39 [d, 6 H, J = 6.2, CH(CH3)2],
21.8, 28.2 (2 q, 5 CH3), 37.1 (t,
190 (27), 176 (21), 149 1714, 1574, 1421, 1375, 1.56 (s, 9 H, t-C4H9) 2.18 (t, 1 H, CH2), 69.6 (d, CH), 70.2, 80.4, 82.1
(94), 148 (100), 133
(21), 121 (94), 120 (53) 1105, 982, 934, 830
1319, 1236, 1157, 1105, J = 2.4, NH), 4.68 (d, 2 H, J = 2.4,
(3 s, 3 C), 104.1 (d, CHpyrim), 152.6
(s, C=O), 157.8 (d, CHpyrim), 159.2,
CH2), 5.38 (m, 1 H, J = 6.2, CH),
6.40 (d, 1 Hpyrim, J = 5.8), 8.37 (d, 1 169.2 (2 s, 2 Cpyrim
Hpyrim, J = 5.8)
)
28b
29a
29b
267 ([M + 1]+, 21), 266 3297br, 2980, 2933,
(70), 252 (17), 225 (37), 1712, 1581, 1554, 1498, 1.61 (s, 9 H, t-C4H9) 2.20 (t, 1 H,
1.44 [d, 6 H, J = 6.2, CH(CH3)2],
22.0, 28.3 (2 q, 5 CH3), 37.2 (t,
CH2), 69.6 (d, CH), 70.2, 80.6, 81.9
(3 s, 3 C), 99.1 (d, CHpyrim), 127.0,
128.7, 130.5 (3 d, 5 CHarom), 136.9
(s, Carom), 153.1 (s, C=O), 159.2,
224 (100), 182 (36)
1454, 1434, 1390, 1368, J = 2.4, NH), 4.80 (d, 2 H, J = 2.4,
1329, 1249, 1215, 1157, CH2), 5.48 (m, 1 H, J = 6.2, CH),
1104, 995, 935, 854
6.84 (s, 1 Hpyrim), 7.45–7.50 (m, 3
Harom), 8.05–8.10 (m, 2 Harom
)
165.1, 170.4 (3 s, 3 Cpyrim
)
150 ([M + 1]+, 20), 149 3117, 2957, 2869, 1649, 1.90–1.95 (m, 1 H, NH), 2.50-2.60 29.3 (t, CH2), 73.9, 81,7 (2 s, C C),
([M]·+, 100), 121 (25)
1589, 1508, 1459, 1382, (m, 2 H, CH2), 6.0 (d, 1 Hpyrim
,
107.4, 157.2 (2 d, 2 CHpyrim), 161.8,
1302, 818
J = 6.0), 6.79 (s, 1 H, NH), 8.19 (d, (s, Cpyrim), 162.1 (s, C=O)b
1 Hpyrim, J = 6.0), 12.0 (br s, 1 H,
NH)b
225 ([M]·+, 100), 224
3354, 3209, 3068, 2971, 3.25–3.30 (m, 1 H, NH), 4.25–4.30 30.0 (t, CH2), 73.1, 81.3 (2 s, C C),
(45), 207 (41), 197 (58), 2932, 2845, 1665, 1618, (m, 2 H, CH2), 6.32 (s, 1 Hpyrim),
196 (22), 129 (30), 102 1452, 1418, 1285, 1254, 6.94 (t, 1 H, J = 6.0, NH), 7.5–7.6
98.2 (d, CHpyrim), 126.7, 128.4,
130.1 (3 d, 5 CHarom), 137.0 (s,
(38), 77 (30)
984, 826, 721
(m, 3 Harom), 8.1–8.15 (m, 2 Harom), Carom), 153.9, 161.6, 163.4 (3 s, 3
b
11.10 (br s, 1 H, NH)b
Cpyrim)
a Taken in the EI (70 eV) mode.
b NMR recorded in DMSO-d6.
be effected with a high degree of selectivity. Furthermore, the cleavage of the 4-isopropoxy group in pyrimidines of
this thioether linkage at the 2-position in 4-isopropoxypy- type 22, 25, 28 and even in those of type 31 is of remark-
rimidines of type 18 can be activated through the forma- able importance for the successful accomplishment of the
tion of the corresponding sulfones 20 toward a subsequent synthesis of pyrimidinones of type 3. The methodology
nucleophilic heteroaromatic ipso-substitution reaction described herein should also be useful for the synthesis of
with a wide variety of nucleophiles (e.g. N-, C-, and O-nu- more elaborated, biologically relevant pyrimidine-4(3H)-
cleophiles). This latter reaction allows the introduction of one derivatives. Synthetic studies along this line are being
additional molecular diversity over the heterocyclic nu- pursued in our laboratory and the results will be published
cleus. Finally the high degree of selectivity observed for in due course.
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York

1840
D. Font et al.
PAPER
O
N
O
N
H2SO4/AcOH 1:1
MeMgBr
24
HN
Me
N
ether/r.t.
65-75%
90 °C, 15 min.
78-82%
R1
Me
R1
26a R1 = H
26b R1 = Ph
25a R1 = H
25b R1 = Ph
O
N
Ph
S
N
R1
O
O
MgCl
O
HN
O
N
20a R1 = H
20b R1 = Ph
BocN
27
MgCl
H2SO4/AcOH 1:1
R1
N
R1
N
THF/-10 °C
79-87%
90 °C, 15 min.
30-38%
NH2
NHBoc
28a R1 = H
28b R1 = Ph
29a R1 = H
29b R1 = Ph
Scheme 7
points (capillary tube) were measured with an electrothermal digital
melting point apparatus IA 9100 and are uncorrected. IR spectra
were recorded on a Mattson-Galaxy Satellite FT-IR spectrometer.
1H and 13C NMR spectra were recorded at 200 and 50 MHz, respec-
tively, on a Bruker DPX200 Advance instrument with TMS as the
internal standard. MS spectra were recorded on a VG Quattro in-
strument in the positive ionisation FAB mode, using 3-NBA or 1-
thioglycerol as the matrix or in a Thermo Quest 2000 series appara-
tus for the EI (70 eV) mode. Elemental analyses were performed on
an apparatus from Thermo instruments, model EA1110-CHNS. An-
alytical TLC was performed on precoated TLC plates, silica gel 60
F254 (Merck). Flash-chromatography purifications were performed
on silica gel 60 (230–400 mesh, Merck).
O
N
O
N
Cs2CO3
Dioxane/60 °C
80-85%
N
+
Ar OH
Ar
R1
O
N
R1
Ph
S
O
O
20a R1 = H
20b R1 = Ph
30a-b
31a-d
O
HN
H2SO4/AcOH 1:1
90 °C, 15 min
80-83%
Ar
O
N
R1
2-Thiobenzylpyrimidin-4(3H)-ones 17a,b; General Procedure
To a suspension of the corresponding 2-mercaptopyrimidin-4(3H)-
one 15a,b (1 equiv) in anhyd DMF (3 mL/mmol) was added Et3N
(1.2 equiv). The mixture was stirred at r.t. for 15–20 min. Benzyl
bromide (1.2 equiv) was added, and the mixture was stirred at r.t.
for an additional 4 h. After this period, the white solid that precipi-
tated was collected by filtration and washed sequentially with small
portions of H2O, MeOH and Et2O and then dried in high vacuum.
Compounds 17a,b were obtained with enough purity to be used in
the next step without further purification (Tables 1 and 2).
32a-d
Scheme 8
Table 9 Pyrimidines 31 and 2-Aryloxypyrimidin-4(3H)-ones 32
Prepared
Producta R1
ArOH
Yield (%) mp (°C)
31a
31b
H
Ph
80
80
colorless oil
68–69
OH
OH
Mitsunobu Reaction of 17a,b; 4-Alkoxypyrimidines 18a–c and
Pyrimidinone 19b; General Procedure (Mitsunobu)
31c
31d
H
Ph
89
85
colorless oil
85–86
A solution of diisopropyl azodicarboxylate (DIAD, 1.2 equiv) in an-
hyd THF (1 mL/mmol) was added dropwise at r.t. to a THF solution
(2 mL/mmol) of Ph3P (1.2 equiv), the appropriate 2-benzylthiopyri-
midine 17a,b (1 equiv) and t-BuOH or i-PrOH (1.2 equiv). The re-
action mixture was stirred at r.t. during 2 h. The solvent was
evaporated under reduced pressure, and the crude mixture separated
by flash chromatography to give the products 18a–c and 19b
(Tables 1 and 2).
O
OH
OH
32a
32b
H
Ph
81
80
203–204
263–264
32c
32d
H
Ph
82
83
240–241
202–203
O
a Satisfactory microanalyses obtained: C 0.24, H 0.30, N 0.19.
Oxidation of 18b,c to Sulfones 20a,b; General Procedure
To a cooled (0 °C) solution of the corresponding pyrimidine deriv-
atives 18b,c (1 equiv) in CH2Cl2 (5 mL/mmol), was added m-CPBA
(2.5 equiv) in small portions. The mixture was stirred at 0 °C for 2
h, diluted with CH2Cl2 (20 mL per mmol) and washed with aq sat.
NaHCO3 solution (2 5 mL/mmol) and brine (5 mL/mmol). The
All commercially available chemicals were used as purchased, ex-
cept DMF that was dried over activated molecular sieves (4 Å) and
THF and Et2O that were dried over Na/benzophenone prior to use.
All reactions were run under a positive pressure of dry N2. Melting
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 2,6-Disubstituted 3,4-Dihydropyrimidin-4(3H)-ones
1841
Table 10 MS, IR and NMR Data of Pyrimidines 31 and 2-Aryloxypyrimidin-4(3H)-ones 32
Prod-
uct
MS
m/z (%)
IR (KBr)
cm–1
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
31a
31b
31c
31d
230 ([M]·+, 6), 189
(12), 188 (74), 187
(23), 173 (10), 172
(73), 146 (34), 145
(100), 144 (26) a
2981, 2930, 1584,
1564, 1491, 1456,
1383, 1275, 1209,
1045, 692
1.34 [d, 6 H, J = 6.4, CH(CH3)2], 5.28
(m, 1 H, J = 6.4, CH), 6.41 (d, 1 Hpyrim
J = 5.6), 7.20–7.50 (m, 5 Harom), 8.20 (d, CHarom), 152.9 (s, Carom), 158.5 (d,
21.6 (q, 2 CH3), 69.9 (d, CH), 103.7 (d,
CHpyrim), 121.7, 125.2, 129.3 (3 d, 5
,
1 Hpyrim, J = 5.6)
CHpyrim, 165.0, 170.9 (3 s, 3 Cpyrim)
306 ([M]·+, 24), 305 2979, 2929, 1588,
1.34 [d, 6 H, J = 6.2, CH(CH3)2], 5.28
(m, 1 H, J = 6.2, CH), 6.84 (s, 1 Hpyrim), CHpyrim), 121.9, 124.8, 127.0, 128.7,
7.30–7.50 (m, 8 Harom), 7.95–8.00 (m, 2 129.1, 130.6 (6 d, 10 CHarom), 136.5,
21.8 (q, 2 CH3), 69.9 (d, CH), 98.6 (d,
(57), 264 (69), 263
(62), 248 (68), 222
(57), 221 (61), 192
(100), 103 (60)a
1551, 1489, 1455,
1358, 1321, 1211,
1065, 936, 767, 689 Harom
)
153.2 (2 s, 2 Carom), 165.0, 166.4, 171.9
(3 s, 3 Cpyrim
)
260 ([M]·+, 55), 218 2983, 2944, 1579,
(49), 202 (56), 176 1507, 1457, 1368,
(42), 175 (100), 160 1330, 1279, 1237,
1.35 [d, 6 H, J = 6.2, CH(CH3)2], 3.84 (s, 21.7, 55.5 (2 q, 3 CH3), 68.9 (d, CH),
3 H, CH3O), 5.34 (m, 1 H, J = 6.2, CH), 103.6 (d, CHpyrim), 114.4, 122.6 (2 d, 4
6.39 (d, 1 Hpyrim, J = 5.8), 6.95 (d, 2
Harom, J = 8.8), 7.14 (d, 2 Harom, J = 8.8), 158.5 (d, CHpyrim), 165.4, 171.0 (2 s, 2
8.19 (d, 1 Hpyrim, J = 5.8) Cpyrim
CHarom), 146.4, 156.8 (2 s, 2 Carom),
(71), 132 (54), 123
1205, 1042, 830
(65), 95 (64)a
)
336 ([M]·+, 76), 335 2975, 2935, 1587,
(65), 294 (53), 251 1505, 1454, 1359,
(100), 236 (57), 223 1317, 1208, 1105,
1.35 [d, 6 H, J = 6.2, CH(CH3)2], 3.87 (s, 21.8, 55.6 (2 q, 3 CH3), 69.6 (d, CH),
3 H, CH3O), 5.30 (m, 1 H, J = 6.2,
98.5 (d, CHpyrim), 114.8, 122.7, 127.0,
128.7, 130.6 (5 d, 9 CHarom), 136.5,
CH), 6.83 (s, 1 Hpyrim), 6.97 (d, 2 Harom
,
(59), 208 (64), 123
1066, 1034, 937,
828, 770
J = 9.0), 7.22 (d, 2 Harom, J = 9.0), 7.95– 146.8, 156.6 (3 s, 3 Carom), 165.3, 166.4,
8.00 (m, 2 Harom 171.9 (3 s, 3 Cpyrim
(74), 103 (61)a
)
)
32a
32b
189 ([M + 1]+, 100), 3080, 1645, 1621,
6.12 (d, 1 Hpyrim, J = 6.4), 7.10–7.60 (m, 108.5 (d, CHpyrim), 121.8, 125.8, 129.6 (3
154 (12), 138 (8),
137 (15), 136 (21),
133 (8), 139 (7)b
1582, 1536, 1495,
1363, 1266, 1198,
828, 785, 742
5 Harom), 7.74 (d, 1 Hpyrim), 12.70 (br,
d, 5 CHarom), 151.5 (s, Carom), 154.0 (d,
c
NH)c
CHpyrim), 158.9, 165.0 (2 s, 2 Cpyrim
)
264 ([M]·+, 54), 263 3060, 2995, 2847,
(21), 221 (26), 194 2750, 1669, 1615,
(26), 193 (100), 180 1580, 1533, 1488,
6.74 (s, 1 Hpyrim), 7.30–7.55 (m, 8 Harom), 102.4 (d, CHpyrim), 121.7, 125.7, 126.6,
7.80–7.85 (m, 2 Harom), 12.75 (br, NH)c
128.8, 129.5, 130.6 (6 d, 10 CHarom),
135.8, 151.8 (2 s, 2 Carom), 158.7, 161.4,
c
(21), 116 (29), 103
(44), 89 (25), 77
(56)a
1323, 1202, 973,
775
166.0 (3 s, 3 Cpyrim)
32c
32d
218 ([M]·+, 18), 185 3081, 3043, 2957,
(23), 175 (37), 167 2711, 2590, 2533,
(36), 149 (100), 124 1649, 1606, 1540,
3.87 (s, 3 H, CH3O), 6.17 (d, 1 Hpyrim
,
55.4 (q, CH3O), 108.5 (d, CHpyrim),
114.5, 122.7 (2 d, 4 CHarom), 144.8 (s,
J = 6.4), 7.06 (d, 2 Harom, J = 9.0), 7.26
(d, 2 Harom, J = 9.0), 7.80 (d, 1 Hpyrim
J = 6.4), 12.80 (br, NH)c
,
Carom), 153.9 (d, CHpyrim), 156.9 (s,
c
(20), 109 (25)a
1496, 1360, 1247,
1196, 1035, 831
Carom), 159.0, 164.7 (2 s, 2 Cpyrim)
294 ([M]·+, 85), 251 2922, 2841, 2750,
(100), 208 (41), 207 1673, 1613, 1500,
3.42 (s, 3 H, CH3O), 6.80 (s, 1 Hpyrim),
55.4 (q, CH3O), 102.5 (d, CHpyrim),
114.4, 119.6, 122.6, 126.6, 128.6, 130.5,
(5 d, 9 CHarom), 135.8, 145.0, 156.7 (3 s,
7.12 (d, 2 Harom, J = 7.8), 7.36 (d, 2 Harom
J = 7.8), 7.40–7.50 (m, 3 Harom), 7.95–
8.00 (m, 2 Harom), 12.80 (br, NH)c
,
(50), 149 (35), 124
(85), 116 (41), 109
(57), 103 (70), 89
(35), 77 (71)a
1451, 1321, 1242,
1198, 1034, 973,
774
3 Carom), 158.5, 161.3, 165.6 (3 s, 3
c
Cpyrim
)
a Taken in the EI (70 eV) mode.
b Taken in the FAB+ mode.
c NMR recorded in DMSO-d6.
separated organic layer was dried (MgSO4), filtered and evaporated.
The resulting crude material was purified by flash chromatography
(n-hexane–EtOAc; Tables 3 and 4).
moved under reduced pressure and the residue was purified by flash
chromatography (n-hexane–EtOAc) to afford pure 22a–f. (Tables 3
and 4).
ipso-Substitution Reaction of Sulfone Derivatives 20a,b with
Primary and Secondary Amines; 4-Alkoxypyrimidines 22a–f;
General Procedure
Removal of the 4-Isopropoxy Group with H2SO4–AcOH; Pyri-
midin-4(3H)-ones 23a–f, 26a,b, 29a,b and 32a–d; General Pro-
cedure
To a solution of the corresponding pyrimidinyl sulfone 20a,b (1
mmol) in dioxane (3 mL) was added the corresponding primary or
secondary amine 21a–d (1.1 mmol). The reaction mixture was
stirred well and heated at 80 °C during 15 h. The solvent was re-
The appropriate 4-isopropoxypyrimidine 22, 25 and 28 (1 equiv)
was added to a mixture of AcOH (2 mL per mmol) and conc. H2SO4
(2 mL per mmol). The reaction mixture was stirred at 90 °C for 15
min. After cooling, the mixture was neutralized with aq 5 N NaOH
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York

1842
D. Font et al.
PAPER
and extracted with CH2Cl2 (3 ). The combined organic layers were
washed with brine and the separated organic layer was dried
(MgSO4), filtered and eliminated under reduced pressure to afford
the corresponding pure pyrimidinones 23, 26 and 32 (Tables 5– 10).
Acknowledgement
Generous financial support from Dirección General de Enseñanza
Superior e Investigación Científica (DGESIC, Spain) through pro-
ject PB98-0451, Universitat de Girona through project UdG98-452
and Roviall Química S.L. (Murcia) is gratefully acknowledged. One
of us (DF) thanks the University of Girona for a predoctoral fel-
lowship. Thanks are also due to Dr. Llüisa Matas (Servei d’Análisi,
Universitat de Girona) for recording the NMR spectra and perfor-
ming the microanalyses.
ipso-Substitution Reaction of Sulfones 20a,b with MeMgBr;
General Procedure
To a cooled (0 °C) solution of the corresponding pyrimidinyl sul-
fone 20a,b (1 mmol) in anhyd Et2O (3 mL) was added dropwise a
solution of MeMgBr (24; 1.1 mmol, 0.37 mL, 3 M in Et2O) at 0 °C
under N2. After stirring for 1 h at 0 °C, the mixture was diluted with
Et2O (20 mL) and washed with H2O (2 10 mL) and brine (10 mL).
The separated organic layer was dried (MgSO4), filtered and evap-
orated to give a residue with was purified by flash chromatography
using n-hexane–EtOAc as eluent (Tables 7 and 8).
References
(1) Mai, A.; Artico, M.; Sbardella, G.; Quartarone, S.; Massa,
S.; Loi, A. G.; Montis, A. D.; Scintu, F.; Putzolu, M.; Colla,
P. L. J. Med. Chem. 1997, 40, 1447.
(2) Mai, A.; Artico, M.; Sbardella, G.; Massa, S.; Novellino, E.;
Greco, G.; Loi, A. G.; Tramontano, E.; Marongiu, M. E.;
Colla, P. L. J. Med. Chem. 1999, 42, 619.
(3) Taylor, E. C.; Zhou, P. Tetrahedron Lett. 1997, 38, 4339.
(4) Ram, V. J.; Singha, U. K.; Guru, P. Y. Eur. J. Med. Chem.
1990, 25, 533.
(5) Vaillancourt, L.; Simard, M.; Wuest, J. D. J. Org. Chem.
1998, 63, 9746.
(6) Liao, R. F.; Lauher, J. W.; Fowler, F. W. Tetrahedron 1996,
52, 3153.
(7) Villalgordo, J. M.; Obrecht, D.; Chucholowski, A. Synlett
1998, 1405.
(8) Chucholowski, A.; Masquelin, T.; Obrecht, D.; Stadlwieser,
J.; Villalgordo, J. M. Chimia 1996, 50, 525.
(9) Obrecht, D.; Abrecht, C.; Grieder, A.; Villalgordo, J. M.
Helv. Chim. Acta 1997, 80, 65.
ipso-Substitution Reaction of Sulfones 20a,b with Acetylide 27;
General Procedure
To a cooled (–10 °C) solution of N-Boc-propargylamine (1.1 mmol)
in anhyd THF (1.5 mL) was added dropwise a solution of i-PrMgCl
(1.1 mL, 2 M in THF, 2.2 mmol). After stirring for 30 min at –15
°C, a solution of the corresponding sulfone 20a,b (1 mmol) in THF
(2 mL) was added. The resulting mixture was stirred from –10 °C to
r.t. for 4 h. The mixture was evaporated to dryness, and the residue
was acidified with aq 2 M HCl and extracted with EtOAc. The or-
ganic phase was separated, washed with brine (10 mL), dried
(MgSO4) and evaporated to give a crude material 28a,b that was pu-
rified by flash chromatography using n-hexane–EtOAc as eluent
(Tables 7 and 8).
ipso-Substitution Reaction of Sulfones 20a,b with Phenols
30a,b; General Procedure
To a solution of the corresponding phenol 30a,b (1.05 mmol) in 1,4-
dioxane (3 mL) was added Cs2CO3 (1.1 mmol). The reaction mix-
ture was stirred at r.t. for 15–20 min. Then, the appropriate sulfone
20a,b (1 mmol) was added. The mixture was stirred at 60 °C for 3
h and then evaporated until dryness. The resulting crude material
was acidified with aq 2 M HCl and extracted with EtOAc. The or-
ganic phase was separated, washed with brine (10 mL), dried
(MgSO4) and evaporated to give a crude material 31a–d that was
purified by flash chromatography using n-hexane–EtOAc as eluent
(Tables 9 and 10).
(10) Heras, M.; Ventura, M.; Linden, A.; Villalgordo, J. M.
Synthesis 1999, 1613.
(11) Fontrodona, X.; Díaz, S.; Linden, A.; Villalgordo, J. M.
Synthesis 2001, 2021.
(12) Font, D.; Heras, M.; Villalgordo, J. M. J. Comb. Chem.,
submitted for publication.
(13) Brown, D. J.; Evans, R. F.; Cowden, W. B.; Fenn, M. D. The
Pyrimidines, Suppl. II; Wiley: New York, 1994.
(14) Bühlmann, P.; Simon, W. Tetrahedron 1993, 49, 7627.
(15) Font, D. Diploma Thesis; Universitat de Girona: Spain,
2001.
Synthesis 2002, No. 13, 1833–1842 ISSN 0039-7881 © Thieme Stuttgart · New York