Oxidation of Biginelli reaction products: Synthesis of 2-unsubstituted 1,4-dihydropyrimidines, pyrimidines, and 2-hydroxypyrimidines

Article abstract of DOI:10.1055/s-0028-1087920

We have devised a new route toward 2-unsubstituted pyrimidine derivatives from the Biginelli product, dihydropyrimidin-2(1H)-thiones in two steps: Oxidation of dihydropyrimidin-2(1H)-thiones using oxone on wet alumina or hydrogen peroxide in the presence

Full text of DOI:10.1055/s-0028-1087920

LETTER
599
Oxidation of Biginelli Reaction Products: Synthesis of 2-Unsubstituted
1,4-Dihydropyrimidines, Pyrimidines, and 2-Hydroxypyrimidines
Oxidation of
B
a
iginelli
R
e
m
action
P
roducts Sik Kim,a Bo Seung Choi,a Jae Hoon Lee,a Ki Kon Lee,a Tae Hee Lee,a Young Ho Kim,b Hyunik Shin*a
a
Chemical Development Division, LG Life Sciences, Ltd./R&D, 104-1, Moonji-dong, Yusong-gu, Daejon 305-380, Korea
Fax +82(42)8665754; E-mail: hisin@lgls.com
b
Department of Fine Chemical Engineering & Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764, Korea
Received 28 October 2008
with either copper(II) catalyst18 or stoichiometric (diacet-
oxyiodo)benzene.19 In contrast to the established oxida-
tion of the Biginelli product, dihydropyrimidin-2(1H)-one
to 2-hydroxypyrimidine, there is no report on the oxida-
Abstract: We have devised a new route toward 2-unsubstituted py-
rimidine derivatives from the Biginelli product, dihydropyrimidin-
2(1H)-thiones in two steps: Oxidation of dihydropyrimidin-2(1H)-
thiones using oxone on wet alumina or hydrogen peroxide in the
presence of catalytic amount of vanadyl sulfate provided 1,4-di- tion of dihydropyrimidin-2(1H)-thiones, which might
hydropyrimidine, which was further oxidized to 2-unsubstituted
provide a new route towards the valuable pharmacophore
pyrimidines by the treatment of KMnO4. Oxidation of dihydropyri-
of 2-unsubstituted pyrimidines via desulfurative oxida-
midin-2(1H)-ones by KMnO4 formed 2-hydroxypyrimidine in ex-
tion. This class of compounds has only been accessible
cellent yield, whereas attempted direct desulfurative aromatization
from the condensation of b-alkoxy-a-acylacrylates with
of dihydropyrimidin-2(1H)-thiones by KMnO4 resulted in the for-
amidines in poor yield of 10–60%.20 Herein, we report the
mation of 2-hydroxypyrimidines, the same products obtained in the
development of a new route towards 2-unsubstituted pyri-
midine from the oxidation of dihydropyrimidin-2(1H)-
thione and facile oxidation of dihydropyrimidin-2(1H)-
one and -thione to 2-hydroxypyrimidine.
oxidation of dihydropyrimidin-2(1H)-one.
Key words: Biginelli reaction, desulfurative oxidation, 2-unsubsti-
tuted pyrimidine, 1,4-dihydropyrimidine, 2-hydroxypyrimidine
We were intrigued by the feasibility of the desulfurative
oxidation of the Biginelli product, pyrimidin-2(1H)-
thione as a route to 2-unsubstituted pyrimidine deri-
vatives21 on the basis of our early protocol used for the
desulfurization of 2-mercaptoimidazole.22 Thus, when di-
hydropyrimidin-2-thione 1a was treated with hydrogen
peroxide in the presence of catalytic amount of vanadyl
sulfate, dihydropyrimidine 2a was obtained in moderate
yield of 48% (entry 1, Table 1). The structure of 2a was
assigned as 1,4-dihydropyrimidine instead of tautomeric
3,4-dihydropyrimidine on the basis of the singlet proton (d
= 5.40 ppm) at the C-4 position in the 1H NMR spectrum
– this proton should appear as a doublet through coupling
with the N–H proton in 3,4-dihydropyrimidine. These
conditions are generally applicable to various substrates
to provide dihydropyrimidines in moderate yield, and the
results are gathered in Table 1. To improve the yield we
tested various oxidizing reagents. m-Chloroperoxybenzo-
ic acid led to complex mixture without any sign of the for-
mation of the desired product, whereas Oxone on wet
alumina23 converted 2-thiones into their 1,4-dihydropyri-
midine derivatives in slightly better yields (entries 1 and
3) than that using hydrogen peroxide.24 Major side prod-
uct of this reaction was found to be dihydropyrimidin-
2(1H)-one, which is formed presumably from the cyclic
sulfite intermediate 9 as illustrated in Scheme 1. Further
Multicomponent reactions have received wide attention
due to the high efficiency of making multiple bonds in a
one-pot manner and the facile generation of diversity. As
one such reaction, the Biginelli reaction which forms di-
hydropyrimidinone derivatives from the reaction of alde-
hyde, keto ester, and urea or thiourea has attracted
renewed interest due to the prominent pharmacological
activity of these products.1 Accordingly, the original
harsh reaction conditions using strong acid were modified
by employing mild Lewis or Brønsted acids to enhance
the yield and to broaden functional-group tolerance sig-
nificantly: use of InCl3,2 InBr3,3 CeCl3·7H2O,4 BiCl3,5 het-
eropoly acid,6 LiClO4,7 TMSCl,8 TMSI,9 FeCl3·6H2O,10
phenylpyruvic acid,11 LaCl3 with catalytic HCl,12 and
BF3·OEt2/CuCl13 are representative examples to date.
Although there have been intensive investigations on the
reaction itself, postmodification of the Biginelli product to
a useful intermediate such as a pyrimidine derivative is
limited. Earlier examples of the oxidation of 3,4-dihydro-
pyrimidin-2(1H)-one to 2-hydroxylpyrimidine using
HNO3,14 DDQ,15 and Pd/C16 as well as electrochemical
oxidation17 could not be used in general due to low func-
tional-group tolerance caused by harsh reaction condi-
tions, discharge of environmentally toxic effluent, and
requirement of special equipment. These shortcomings
were improved significantly by the recent discovery of
oxidation using a combination of tert-butylhydroperoxide
25
oxidation by KMnO4 aromatized 2a–e to pyrimidine
3a–e in good yields26 as shown in Table 1.
From the successful aromatization of 2 to 3 by KMnO4,
we anticipated that dihydropyrimidin-2(1H)-one could be
oxidized by KMnO4 to 2-hydroxypyrimidine as well. De-
lightedly, treatment of dihydropyrimidin-2(1H)-one with
SYNLETT 2009, No. 4, pp 0599–0602
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087920; Art ID: U11708ST
x
x.
x
x.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

600
S. S. Kim et al.
LETTER
peroxide/vanadyl sulfate or Oxone on wet alumina, the
thione group of 1 was oxidized to the cyclic sulfinate 7
which loses sulfur dioxide to form transient N-hetero-
cyclic carbene species 8, and its spontaneous rearrange-
ment provides the dihydropyrimidine 2 as a major
product. On the other hand, when strong oxidant such as
KMnO4 was used, the cyclic sulfinate intermediate 7 is
rapidly oxidized to its sulfite 9, which loses sulfur dioxide
to form dihydropyrimidin-2-one and its further oxidation
resulted in the exclusive formation of 2-hydroxypyrimi-
dine 5.
Table 1 Synthesis of 1,4-Dihydropyrimidines and 2-Unsubstituted
Pyrimidines
CO2Et
CO2Et
CO2Et
N
KMnO4
acetone
r.t., 2 h
method A
or
method B
R
R
R
N
NH
HN
NH
S
N
H
1a–e
2a–e
3a–e
Entry
R
Prod- Yield (%) Prod- Yield (%)
uct
2a
2b
2c
uct
3a
3b
3c
3d
3e
1
2
3
4
5
1a Ph
48a (60b)
43a
73
73
81
87
76
CO2Et
CO2Et
CO2Et
1b 4-EtC6H4
1c n-C5H11
R
R
R
35a (50b)
73a
HN
NH
HN
NH
O
HN
NH
1d PhCH2CH2
1e 4-FC6H4
2d
2e
S
S
S
O
O
50a
7
1
6
a Yield using Method A: 30% H2O2 (3.7 equiv), VOSO4·xH2O (0.002
equiv), H2O–EtOH, 50 °C, 8–12 h.
– SO2
CO2Et
CO2Et
b Yield using Method B: Oxone (3.2–3.7 equiv), wet Al2O3, CHCl3,
r.t., 5–8 h.
R
CO2Et
R
R
HN
NH
O
HN
NH
O
S
HN
NH
O
KMnO4 (2.5 equiv) provided 2-hydroxypyrimidine in
good yield (Table 2).27 With facile oxidation of 1,4-di-
hydropyrimidine and dihydropyrimidin-2(1H)-one by
KMnO4 in hands, we were intrigued by the possibility of
direct desulfurative oxidation of dihydropyrimidin-
2(1H)-thione to 2-unsubstituted pyrimidine. However,
contrary to our expectation, oxidation of thiones by
KMnO4 (4.5 equiv) resulted in the exclusive formation of
2-hydroxypyrimidine, the same product formed from the
oxidation of dihydropyrimidin-2-one (Table 2).
– SO2
4
••
8
O
9
KMnO4
CO2Et
CO2Et
CO2Et
R
R
R
KMnO4
N
N
N
NH
N
N
OH
5
2
3
Scheme 1 Proposed mechanism
Table 2 Oxidation of Dihydropyrimidin-2(1H)-ones and -thiones
by KMnO4
In conclusion, we have devised a new route toward 2-un-
substituted pyrimidine derivatives from the Biginelli
product, dihydropyrimidin-2(1H)-thiones, in two steps.
Oxidation of dihydropyrimidin-2(1H)-thiones using ox-
one on wet alumina or hydrogen peroxide in the presence
of catalytic amount of vanadyl sulfate provided 1,4-di-
hydropyrimidine, which was further oxidized to 2-unsub-
stituted pyrimidines by the treatment of KMnO4.
Oxidation of dihydropyrimidin-2(1H)-ones by KMnO4
formed 2-hydroxypyrimidine products in excellent yield,
whereas attempted direct desulfurative aromatization of
dihydropyrimidin-2(1H)-thiones by KMnO4 resulted in
the formation of 2-hydroxypyrimidines, the same prod-
ucts obtained in the oxidation of dihydropyrimidin-2(1H)-
one.
CO2Et
CO2Et
R
R
KMnO4
acetone
N
N
HN
NH
X
4a–e X = O
1a–e X = S
OH
5a–e
Entry
R
Product
Yield (%)
Yield (%)
from 1a–e
from 4a–e
1
2
3
4
5
Ph
5a
5b
5c
5d
5e
81
62
79
63
79
68
44
73
35
65
4-EtC6H4
n-C5H11
PhCH2CH2
4-FC6H4
References and Notes
(1) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
(2) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270.
On the basis of these observations, we tentatively postu-
lated the mechanism of the oxidation reaction as in
Scheme 1. When using mild oxidant such as hydrogen
Synlett 2009, No. 4, 599–602 © Thieme Stuttgart · New York

LETTER
Oxidation of Biginelli Reaction Products
601
(3) Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J. T.;
Peppe, C. Tetrahedron 2002, 58, 4801.
(4) Bose, D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003,
68, 587.
(5) Ramalinga, K.; Vijayalakshmi, P.; Kaimala, T. N. B. Synlett
2001, 863.
(6) Rafiee, E.; Jafari, H. Bioorg. Med. Chem. Lett. 2006, 16,
2463.
2 H), 2.22 (s, 3 H), 1.12 (t, J = 2.7 Hz, 3 H). 13C NMR (100
MHz, CDCl3): d = 167.4, 145.6, 143.3, 128.9, 127.7, 127.6,
100.7, 60.2, 58.0, 19.3, 14.6. ESI-MS: m/z = 245.3 [M + 1].
Compound 2b: 1H NMR (400 MHz, CDCl3): d = 8.27 (br s,
1 H), 7.26–6.92 (m, 4 H), 5.48 (s, 1 H), 4.08 (q, J = 4.0 Hz,
2 H), 2.62 (q, J = 4.0 Hz, 2 H), 2.22 (s, 3 H), 1.26–1.15 (m,
6 H). 13C NMR (100 MHz, CDCl3): d = 167.3, 145.6, 144.4,
143.9, 142.8, 128.4, 127.5, 101.0, 60.2, 57.2, 28.9, 18.8,
15.8, 14.6. ESI-MS: m/z = 273.4 [M + 1].
(7) Yadav, J. S.; Reddy, B. V. S.; Srinivas, R.; Venugopal, C.;
Ramalingam, T. Synthesis 2001, 1341.
(8) Zhu, Y. L.; Huang, S. L.; Pan, Y. J. Eur. J. Org. Chem. 2005,
Compound 2c: 1H NMR (400 MHz, CDCl3): d = 10.13 (s,
1 H), 9.91 (s, 1 H), 4.83 (t, J = 4.0 Hz, 1 H), 4.26 (m, 2 H),
2.48 (s, 3 H), 1.79–1.14 (m, 11 H), 0.87 (t, J = 2.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 164.3, 161.1, 142.7,
107.4, 61.7, 52.5, 51.7, 47.0, 36.9, 31.6, 23.3, 22.7, 17.9,
14.6, 14.3. ESI-MS: m/z = 239.3 [M + 1].
2354.
(9) Sabitha, G.; Reddy, G. K. K.; Reddy, C. S.; Yadav, J. S.
Synlett 2003, 858.
(10) Lu, J.; Ma, H. Synlett 2000, 63.
(11) Abelman, M. M.; Smith, S. C.; James, D. R. Tetrahedron
Compound 2d: 1H NMR (400 MHz, CDCl3): d = 7.43 (s,
1 H), 7.28–7.14 (m, 5 H), 4.63 (t, J = 4.0 Hz, 1 H), 4.18 (m,
2 H), 2.80–2.67 (m, 2 H), 2.28 (s, 3 H), 1.91–1.82 (m, 2 H),
1.26 (t, J = 3.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
d = 175.9, 165.8, 165.7, 144.5, 141.1, 128.9, 128.7, 126.5,
103.2, 103.1, 60.8, 60.4, 52.3, 38.3, 30.9, 18.6, 14.7. ESI-
MS: m/z = 271.4 [M + 1].
Lett. 2003, 44, 4559.
(12) Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron
Lett. 2000, 41, 9075.
(13) Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem. 1998,
63, 3454.
(14) Mitsushita, A.; Oda, M.; Kawachi, Y.; Chika, J.-i. WO
03006437, 2003.
(15) Watanabe, M.; Koike, H.; Ishiba, T.; Okada, T.; Seo, S.;
Hirai, K. Bioorg. Med. Chem. 1997, 5, 437.
(16) Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26,
1555; this Pd/C dehydrogenation without the use of oxidant
requires rigorous conditions (210 °C) in Ph2O.
(17) Kadis, V.; Strandins, J.; Khanina, E. L.; Duburs, G.
Electrochim. Acta 1989, 34, 899.
Compound 2e: 1H NMR (400 MHz, CDCl3): d = 7.34–6.99
(m, 4 H), 5.57 (s, 1 H), 5.40 (d, J = 4.0 Hz, 1 H), 4.09 (m,
2 H), 2.31 (s, 3 H), 1.20 (t, J = 2.7 Hz, 3 H). 13C NMR (100
MHz, CDCl3): d = 167.1, 162.5 (d, J = 250.0 Hz), 145.1,
142.6, 141.4, 129.2 (d, J = 10.0 Hz), 115.6 (d, J = 20.0 Hz),
115.5, 101.2, 60.3, 57.4, 19.5, 14.6. ESI-MS: m/z = 263.3
[M + 1].
(25) (a) Girke, W. P. K. Chem. Ber. 1979, 112, 1. (b) de Bie,
D. A.; Nagel, A.; van der Plas, H. C.; Koudijs, A.
Tetrahedron Lett. 1979, 649.
(18) Yamamoto, K.; Chen, Y. G.; Buono, F. G. Org. Lett. 2005,
7, 4673.
(19) Karade, N. N.; Gampawar, S. V.; Kondre, J. M.; Tiwari,
(26) General Procedure for the Preparation of 2-Unsubsti-
tuted Pyrimidines 3a–e
G. B. Tetrahedron Lett. 2008, 49, 6698.
(20) (a) Kress, T. J. Heterocycles 1994, 38, 1380. (b) Draper,
R. W. WO 2005007608, 2005. (c) Palani, A.; Shapiro, S.;
Clader, J. W.; Greenlee, W. J.; Vice, S. F.; McCombie, S.;
Cox, K.; Stizki, J.; Baroudy, B. M. Bioorg. Med. Chem. Lett.
2003, 13, 709. (d) McCombie, S. W.; Tagat, J. R.; Vice,
S. F.; Lin, S.-I.; Steensma, R.; Palani, A.; Neustadt, B. R.;
Baroudy, B. M.; Strizki, J. M.; Enders, M.; Cox, K.; Dan, N.;
Chou, C.-C. Bioorg. Med. Chem. Lett. 2003, 13, 567.
(21) (a) Khanina, E. L.; Zolotoyabko, R. M.; Muceniece, D.;
Duburs, G. Khim. Geterotsikl. Soedin. 1989, 1076.
(b) Kanina, E. L.; Mucenice, D.; Kadysh, V. P.; Duburs, G.
Khim. Geterotsikl. Soedin. 1986, 1223; in these references,
pyrimidin-2-thione or its thioether derivative was reduced
by Raney nickel to provide 1,4-dihydropyrimidine.
(22) Chang, J. H.; Lee, K. W.; Nam, D. H.; Kim, W. S.; Shin, H.
Org. Process Res. Dev. 2002, 6, 674.
To a stirred solution of 2a (100 mg, 0.41 mmol) in acetone
(2 mL) was added KMnO4 (87 mg, 0.55 mmol). After the
complete consumption of 2a, excess of KMnO4 was
decomposed by the addition of 2-PrOH. The reaction
mixture was filtered through Celite and washed thoroughly
with acetone (10 mL). Removal of solvent afforded product
3a (72mg, 73%) as a white solid.
Spectroscopic Data
Compound 3a: 1H NMR (400 MHz, CDCl3): d = 9.16 (s, 1
H), 7.68–7.43 (m, 5 H), 4.24 (q, J = 4.0 Hz, 2 H), 2.57 (s, 3
H), 1.10 (t, J = 2.7 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
d = 167.4, 164.7, 162.9, 157.8, 137.2, 131.8, 131.5, 129.9,
128.3, 128.0, 125.7, 61.7, 22.3, 13.4. ESI-MS: m/z = 243.4
[M + 1].
Compound 3b: 1H NMR(400 MHz, CDCl3): d = 9.13 (s, 1
H), 7.60 (d, J = 4.0 Hz, 2 H), 7.37 (d, J = 4.0 Hz, 2 H), 4.26
(q, J = 4.0 Hz, 2 H), 2.73 (q, J = 4.0 Hz, 2 H), 2.62 (s, 3 H),
1.28 (t, J = 2.7 Hz, 3 H), 1.13 (t, J = 2.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d = 168.3, 165.2, 163.6, 158.4, 147.2,
135.8, 128.8, 128.6, 126.2, 62.3, 29.1, 22.9, 15.8, 14.1. ESI-
MS: m/z = 271.3 [M + 1].
(23) Greenhalgh, R. P. Synlett 1992, 235.
(24) General Procedure for the Preparation of 1,4-Dihydro-
pyrimidines 2a–e
To a stirred mixture of 1a (1 g, 3.62 mmol) and a catalytic
amount of vanadium sulfate (0.0072 g, 10 mol%) in EtOH
(2.5 mL) and H2O (2.5 mL) was added dropwise 30% H2O2
(1.52 g, 13.38 mmol) over 1 h maintaining the reaction
temperature at about 50 °C. After 8–12 h, the mixture was
cooled and volatiles were evaporated under vacuum. The
mixture was diluted with CH2Cl2 (10 mL) and washed with
H2O (30 mL). The separated organic layer was dried with
MgSO4, filtered, and concentrated to afford crude 2a.
Column chromatography with EtOAc–n-hexane gave 2a as
a white solid (397 mg, 48%).
Compound 3c: 1H NMR (400 MHz, CDCl3): d = 9.01 (s, 1
H), 4.48 (q, J = 4.0 Hz, 2 H), 2.79 (t, J = 4.0 Hz, 2 H), 2.54
(s, 3 H), 1.77–1.22 (m, 9 H), 0.92 (t, J = 2.7 Hz, 3 H). 13
C
NMR (100 MHz, CDCl3): d = 167.8, 167.7, 164.2, 158.3,
62.2, 36.1, 31.9, 28.9, 22.9, 22.7, 14.4, 14.2. ESI-MS:
m/z = 237.3 [M + 1].
Compound 3d: 1H NMR (400 MHz, CDCl3): d = 9.02 (s, 1
H), 7.40–7.00 (m, 5 H), 4.44 (q, J = 4.0 Hz, 2 H), 3.11–3.02
(m, 4 H), 2.54 (s, 3 H), 1.40 (t, J = 3.3 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 167.6, 166.8, 164.6, 158.5, 128.9,
128.8, 127.2, 126.7, 62.4, 38.2, 35.3, 23.2, 14.6. ESI-MS:
m/z = 271.4 [M + 1].
Spectroscopic Data
Compound 2a: 1H NMR (400 MHz, DMSO-d6): d = 9.30 (s,
1 H), 7.30–7.16 (m, 5 H), 5.40 (s, 1 H), 3.97 (q, J = 4.0 Hz,
Synlett 2009, No. 4, 599–602 © Thieme Stuttgart · New York

602
S. S. Kim et al.
LETTER
Compound 3e: 1H NMR (400 MHz, CDCl3): d = 9.14 (s, 1
H), 7.70–7.65 (m, 2 H), 7.21–7.11 (m, 2 H), 4.27 (q, J = 4.0
Hz, 2 H), 2.63 (s, 3 H), 1.18 (t, J = 2.7 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 168.1, 164.4 (d, d, J = 230.0 Hz),
164.0, 162.4, 158.5, 134.0, 131.0 (d, J = 10.0 Hz), 126.2,
116.2 (d, J = 20.0 Hz), 62.5, 23.0, 14.1. ESI-MS: m/z = 261.3
[M + 1].
Compound 5b: 1H NMR (400 MHz, CDCl3): d = 7.52–7.13
(m, 4 H), 4.80–4.26 (m, 2 H), 3.01 (q, J = 4.0 Hz, 2 H), 2.84
(s, 1 H), 2.69–2.45 (m, 2 H), 2.30 (s, 3 H), 1.26 (t, J = 2.7 Hz,
3 H). 13C NMR (100 MHz, CDCl3): d = 165.8, 141.0, 140.4,
129.0, 128.8, 128.7, 126.9, 126.8, 62.2, 38.8, 31.8, 31.0,
30.7, 30.1, 25.5, 14.6. ESI-MS: m/z = 287.3 [M + 1].
Compound 5c: 1H NMR (400 MHz, CDCl3): d = 4.42 (q,
J = 2.0 Hz, 2 H), 2.80 (t, J = 2.0 Hz, 2 H), 2.53 (s, 3 H),
1.73–1.26 (m, 9 H), 0.90 (t, J = 2.7 Hz, 3 H). 13C NMR (100
MHz, CDCl3): d = 166.0, 158.7, 111.8, 62.1, 32.0, 31.8,
31.5, 22.8, 14.6, 14.29, 14.26. ESI-MS: m/z = 253.3 [M + 1].
Compound 5d: 1H NMR (400 MHz, CDCl3): d = 7.52–7.13
(m, 5 H), 4.80–4.26 (m, 2 H), 3.01 (q, J = 4.0 Hz, 2 H), 2.84
(s, 1 H), 2.69–2.45 (m, 2 H), 2.30 (s, 3 H), 1.26 (t, J = 2.7 Hz,
3 H). 13C NMR (100 MHz, CDCl3): d = 175.9, 165.8, 165.7,
144.5, 141.1, 128.9, 128.7, 126.5, 103.2, 103.1, 60.8, 52.3,
38.3, 30.9, 18.6, 14.7. ESI-MS: m/z = 287.3 [M + 1].
Compound 5e: 1H NMR (400 MHz, CDCl3): d = 7.65–6.97
(m, 4 H), 4.11 (q, J = 4.0 Hz, 2 H), 2.62 (s, 3 H), 1.02 (t,
J = 2.7 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 165.5,
162.4 (d, J = 250.0 Hz), 146.4, 139.7, 139.6, 128.4 (d,
J = 10.0 Hz), 115.5 (d, J = 20.0 Hz), 101.4, 60.1, 55.0, 18.5,
14.2. ESI-MS: m/z = 277.3 [M + 1].
(27) General Procedure for the Preparation of 2-Hydroxy-
pyrimidines 5a–e
To a stirred solution of 4a (1.0 g, 3.84 mmol) in acetone (20
mL) was added KMnO4 (1.52 g, 9.60 mmol). After the
complete consumption of 4a, the excess KMnO4 was
decomposed by the addition of 2-PrOH. The reaction
mixture was filtered through Celite and washed thoroughly
with acetone (30 mL). Removal of solvent afforded product
5a (670mg, 81%) as a white solid.
Spectroscopic Data
Compound 5a: 1H NMR (400 MHz, CDCl3): d = 7.61–7.41
(m, 5 H), 4.05 (q, J = 4.0 Hz, 2 H), 2.62 (s, 3 H), 0.94 (t,
J = 2.7 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 167.4,
164.7, 162.9, 157.8, 137.2, 131.8, 131.7, 131.5, 129.9,
128.3, 128.0, 125.7, 61.7, 22.3, 13.4. ESI-MS: m/z = 259.3
[M + 1].
Synlett 2009, No. 4, 599–602 © Thieme Stuttgart · New York

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