Synthesis of 2-substituted pyrimidines via cross-coupling reaction of pyrimidin-2-yl sulfonates with nucleophiles in polyethylene glycol 400

Article abstract of DOI:10.1055/s-0030-1258080

A mild and rapid procedure to the synthesis of 2-substituted pyrimidines was developed via sequential functionalization of easily available Biginelli 3,4-dihydropyrimidine-2(1H)-ones via oxidation, esterification, followed by cross-coupling reaction of pyrimidin-2-yl sulfonates with N, S, and O nucleophiles in PEG-400 as a green reaction medium at room temperature. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258080

LETTER
1657
Synthesis of 2-Substituted Pyrimidines via Cross-Coupling Reaction of
Pyrimidin-2-yl Sulfonates with Nucleophiles in Polyethylene Glycol 400
S
ynthesis of 2-Sub
i
stituted
-
Pyrimid
C
ines un Wang,*a,b Guo-Jun Yang,a,b Zheng-Jun Quan,a,b Peng-Yan Ji,a,b Jun-Ling Liang,a,b Rong-Guo Rena,b
a
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, P. R. of China
Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University,
Anning East Road 967#, Lanzhou, Gansu 730070, P. R. of China
b
Fax +86(931)7971971; E-mail: wangxicun@nwnu.edu.cn
Received 28 April 2010
on a large scale. Chlorination using POCl3 at high temper-
atures could be problematic for substrates with sensitive
functionalities,7a and S-alkylation was absolutely neces-
sarily for sulfide oxidation.8b,e Organic solvents were
Abstract: A mild and rapid procedure to the synthesis of 2-substi-
tuted pyrimidines was developed via sequential functionalization of
easily available Biginelli 3,4-dihydropyrimidine-2(1H)-ones via
oxidation, esterification, followed by cross-coupling reaction of
pyrimidin-2-yl sulfonates with N, S, and O nucleophiles in PEG- widely used in the process. In 2005, Kang et al.11 have de-
400 as a green reaction medium at room temperature.
scribed a two-step procedure to convert Biginelli DHPM
to the C2-functionalized pyrimidines via Kappe dehydro-
genation and PyBroP-mediated coupling with nucleo-
philes at room temperature for 24 hours. However, the
synthesis of C2-functionalized pyrimidines has been pre-
dominantly carried out in organic solvents. Some limita-
tions such as elevating temperatures, catalyst, and
hazardous organic solvents were involved. Thus, the de-
velopment of a simple and efficient method under green
reaction conditions for constructing these compounds has
been advocated.
Keywords: 2-substituted pyrimidines, oxidation, esterification,
cross-coupling reaction, PEG-400
Reducing or eliminating the use of volatile organic sol-
vents can minimize waste formation, which is one of the
key objectives in green chemistry. Recently, polyethylene
glycol (PEG) and its monomethyl ethers have emerged as
alternative green reaction medium with unique properties
such as thermal stability, commercial availability, nonvol-
atility, immiscibility with a number of organic solvents,
and recyclability. On the other hand, PEG is inexpensive,
nonhalogenated, easily degradable, and possess low tox-
icity.1 The use of PEG as a reaction solvent has received
considerable attention in synthetic organic chemistry.2
Herein, we report a mild and rapid procedure for the syn-
thesis of C2-substituted pyrimidines by sequential func-
tionalization of easily available Biginelli 3,4-
dihydropyrimidine-2(1H)-ones via oxidation, esterifica-
tion, followed by cross-coupling reaction of pyrimidin-2-
yl sulfonates with N, S, and O nucleophiles in PEG-400 at
room temperature (Scheme 1).
Over the years, research interest in Biginelli 3,4-dihydro-
pyrimidin-2(1H)-ones (DHPM)3 has surged rapidly ow-
ing to the pharmacological properties associated with
many derivatives of this privileged heterocyclic core, such
as calcium channel modulators, a1a-adrenergic receptor
antagonists, mitotic kinesin inhibitors, and hepatitis B vi-
rus replication inhibitors.4 Several marine-derived natural
products such as Crambine, Batzelladine B (potent HIV
gp-120CD4 inhibitors), and Ptilomycalin alkaloids also
contain the DHPM core.5 Although pyrimidine deriva-
tives are found in a wide range of biologically active mol-
ecules,6 there has been a lack of a methodology to
efficiently synthesize 2-substituted pyrimidines. In gener-
al, 2-substituted pyrimidines were obtained from Biginelli
DHPM by a C-2 O/S substitution strategy involving aro-
matization, chlorination,7 or sulfide oxidation8 and cou-
pling with a nucleophile. Aromatization of the Biginelli
DHPM is known to be exceedingly difficult.9 To our de-
light, Yamamoto et al.10 developed a mild and practical
procedure for dehydrogenation of DHPM using tert-
butylhydroperoxide (TBHP) in 2005, and demonstrated
O
Ar
O
Ar
R2
N
R2
NH
K2CO3
TBHP
CuCl2
PEG-400
R1
N
OH
R1
O
N
H
1
O
2
Ar
O
Ar
R2
N
R2
N
NuH
base, PEG-400
R1
N
Nu
R1
N
OTs
3
4–6
Scheme 1
The Biginelli DHPM 1 and their dehydrogenated com-
pounds 2 were readily prepared according to the proce-
dures by Matsushima et al.12 and Yamamoto et al.10 We
noticed that sulfonic esters are important intermediates in
organic synthesis.13 The esterification reactions were car-
ried out most frequently in dry dichloromethane or chlo-
roform in the presence of triethylamine, pyridine, or
aqueous sodium hydroxides as bases.14 In this study, the
pyrimidin-2-yl sulfonates 3 were prepared by employing
SYNLETT 2010, No. 11, pp 1657–1660
x
x
.x
x
.2
0
1
0
Advanced online publication: 10.06.2010
DOI: 10.1055/s-0030-1258080; Art ID: W06810ST
© Georg Thieme Verlag Stuttgart · New York

1658
X.-C. Wang et al.
LETTER
Table 1 Preparations of Pyrimidin-2-yl Sulfonatesa
O
Ar
O
Ar
O
S
R2
N
R2
N
K2CO3
+
Cl
PEG-400
0 °C to r.t.
R1
N
OH
R1
N
OTs
O
2
3
Entry
Ar
Ph
R1
R2
Product 3
Yield (%)b
1
2
3
4
5
6
7
8c
Me
Me
Me
Me
Me
Me
i-Pr
Me
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
3a
3b
3c
3d
3e
3f
80
81
79
80
82
85
86
83
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-FC6H4
Ph
3g
3h
a Reaction conditions: 2 (1.0 mmol), p-toluenesulfonyl chloride (1.5 mmol), K2CO3 (1.5 mmol), PEG-400 (2.0 g), 0 °C to r.t., ca. 40 min.
b Isolated yield.
c Benzenesulfonyl chloride (1.5 mmol).
PEG-400/K2CO3 system. To a suspension of compounds 21). In addition, alcohols gave corresponding 2-alkyloxy-
2 (1 equiv) and p-toluenesulfonyl chloride (1.5 equiv) in pyrimidines in 90 minutes (entries 22–24), while phenols
PEG-400, K2CO3 (1.5 equiv) was added at 0 °C. The re- provided O–S cleavage products under strongly basic
action mixture was stirred for 40 minutes at room temper- NaOt-Bu (Table 3).17 Hence after the reaction, phenolic
ature. After completion of the reaction, the mixture was toluenesulfonates 7 and compounds 2 were isolated.
poured into water and filtered, then recrystallized from
It is noteworthy that the study reported above is the first
exploration of cross-coupling reaction of pyrimidin-2-yl
sulfonates with N, S, and O nucleophiles to give C2-sub-
ethanol to give the pure pyrimidin-2-yl sulfonates 3 in
good to excellent yields (Table 1).15
We began our coupling investigation with amines stituted pyrimidines using PEG-400 as a green reaction
(Table 2).16 Sulfonates 3a–g were dissolved in PEG-400 medium at room temperature. This cross-coupling reac-
and added to a mixture of amines (1.5 equiv) and K2CO3 tion was fast as compared to the other reported metal-
(1.5 equiv) at room temperature. After stirring for 30–60 catalyzed processes. In this study, we have also observed
minutes, the reaction mixture was poured into water to in- two competing pathways (i.e., C–O bond cleavage path
duce precipitation. The solid was filtered and washed with vs. the S–O bond-cleavage path). Generally, the C–O
copious amounts of water, then recrystallized from ethan- bond-cleavage reaction is favored with stronger nucleo-
ol and petroleum ether to give the desired 2-aminopyri- philes with a higher polarizability (amines, thiophenox-
midines 4a–p. Over the course of this study, it was found ide). However, the S–O bond cleavage reaction is favored
that cyclic secondary amines were the most effective sub- with those nucleophiles with a lower polarizability
strates for this process (entries 1–14). The nature of sub- (C6H5O–). Reaction of 3a with CH3CH2O–, (CH3)2CHO–,
stituents on the heterocyclic fragment of sulfonate esters PhCH2O– produced C2-substituted pyrimidines via cleav-
did not play a significant role in this reaction. Acyclic age of C–O bond in high yields.
amines also gave promising results (completed within 60
In conclusion, a simple, rapid, and environmentally be-
min), but took a longer reaction time than that with sec-
nign methodology towards the synthesis of C2-substituted
ondary acyclic amines (entries 15 and 16). However, aro-
pyrimidines has been reported. A series of pyrimidin-2-yl
matic amines failed to react even under high temperature
sulfonates are excellent precursors for the generation of
and long time (entry 17). Control experiments suggested
C2-substituted pyrimidines via cross-coupling of the reac-
that prolonged reaction times did not improve the product
tive sulfonate group with different nitrogen, sulfur, and
oxygen nucleophiles. Compared to other processes for the
yields.
We next turned our attention to sulfur and oxygen nucleo- synthesis of C2-substituted pyrimidines and the cross-
philes (entries 18–24) by treating sulfonates 3 with 1.5 coupling of aryl sulfonates with nucleophiles, our proto-
equivalents of S, O nucleophiles in PEG-400/K2CO3 or col has the advantages of milder reaction conditions, fast-
NaOt-Bu at room temperature. p-Thiocresol gave the cor- er reaction rate, and the use of nonmetal catalyst.
responding 2-arylthiopyrimidines in 30 minutes (entries Additionally, our protocol is a practical approach that uses
18–20). However, HOOCCH2SH failed to react (entry
Synlett 2010, No. 11, 1657–1660 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Substituted Pyrimidines
1659
Acknowledgment
Table 2 Coupling of Pyrimidin-2-yl Sulfonates 3 with NuH
Ar
O
Ar
O
We are thankful for the financial support from the National Nature
Science Foundation of China (No. 20902073), the Natural Science
Foundation of Gansu Province (No. 096RJZA116), and Scientific
and Technological Innovation Engineering program of Northwest
Normal University (nwnu-kjcxgc-03-64).
R2
N
R2
N
K2CO3 or NaOt-Bu
+ NuH
PEG-400
r.t.
R1
N
OTs
R1
N
Nu
4–6
3
Entry Sulfonate 315 NuH
Product16,17 Yield (%)a
References and Notes
1
2
3a
3b
3c
3d
3e
3f
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
EtNH2
4a
4b
4c
4d
4e
4f
84b
81
83
81
85
86
80
82
80
80
83
80
82
84
82
80
n.r.d
80
78
81
n.r.d
82e
86
80
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4
5
6
7
3g
3a
3b
3c
3d
3e
3f
4g
4h
4i
8
9
10
11
12
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14
15c
16c
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4j
4k
4l
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Pleiss, U.; Stoltefuss, J.; Graef, E.; Koletzki, D.;
4m
4n
4o
4p
Masantschek, R. N. A.; Reimann, A.; Jaeger, R.; Groß, R.;
Beckermann, B.; Schlemmer, K.-H.; Haebich, D.;
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3g
3a
3a
3a
3a
3b
3d
3a
3a
3a
3a
HOCH2CH2NH2
4-MeC6H4NH2
4-MeC6H4SH
4-MeC6H4SH
4-MeC6H4SH
HOOCCH2SH
EtOH
5a
5b
5c
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Deshpande, M. V.; Srinivasan, K. V. Tetrahedron 2008, 64,
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Hirai, K. Bioorg. Med. Chem. 1997, 5, 437. (b) Kim, D. C.;
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B. Y.; Yoo, K. H. Eur. J. Med. Chem. 2003, 38, 525.
(c) Kasparec, J.; Adams, J. L.; Sisko, J.; Silva, D. J.
Tetrahedron Lett. 2003, 44, 4567. (d) Gayo, L. M.; Suto,
M. J. Tetrahedron Lett. 1997, 38, 211. (e) Matloobi, M.;
Kappe, C. O. J. Comb. Chem. 2007, 9, 275. (f) Obrecht, D.;
Abrecht, C.; Grieder, A.; Villalgordo, J. M. Helv. Chim. Acta
1997, 80, 65. (g) Vanden Eynde, J. J.; Labuche, N.;
Van Haverbeke, Y.; Tietze, L. ARKIVOC 2003, (xv), 22.
(9) Vanden Eynde, J. J.; Audiart, N.; Canonne, V.; Michel, S.;
Van Haverbeke, Y.; Kappe, C. O. Heterocycles 1997, 45,
1967.
6a
6b
6c
i-PrOH
BnOH
a Isolated yield.
b Reaction conditions for compounds 4 and 5: 3 (1.0 mmol), amine
(1.5 mmol), K2CO3 (1.5 mmol), PEG-400 (2.0 g), r.t., 30 min.
c Completed within 60 min.
d No reaction.
e Reaction conditions for compounds 6a–c: 3 (1.0 mmol), NuH (1.5
mmol), NaOt-Bu (1.5 mmol), PEG-400 (2.0 g), r.t., 90 min.
PEG-400 as a readily commercially available green sol-
vent with low cost and recyclable property.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 11, 1657–1660 © Thieme Stuttgart · New York

1660
X.-C. Wang et al.
LETTER
Table 3 Coupling of Pyrimidin-2-yl Sulfonates 3 with Phenol
OH
R
O
Ph
O
Ph
base
EtO
N
EtO
N
+
+
R
OTs
PEG-400, r.t.
N
3
OTs
N
2
OH
7
Entry
1a
Sulfonate 3
R
Product 7
Yield (%)c
3a
3a
3a
H
7a
7a
7b
88
90
80
2b
H
3a
Cl
a Reaction conditions A: 3 (1.0 mmol), phenol (1.5 mmol), K2CO3 (1.5 mmol), PEG-400 (2.0 g), r.t., 60 min.
b Reaction conditions B: 3 (1.0 mmol), phenol (1.5 mmol), NaOt-Bu (1.5 mmol), PEG-400 (2 g), r.t., 90 min.
c Isolated yield.
(10) Yamamoto, K.; Chen, Y. G.; Buono, F. G. Org. Lett. 2005,
7, 4673.
(11) Kang, F. A.; Kodah, J.; Guan, Q. Y.; Li, X. B.; Murray,
W. V. J. Org. Chem. 2005, 70, 1957.
(12) Matsushima, A.; Oda, M.; Kawachi, Y.; Chika, J. WO 03/
006439 A1, 2003.
mmol). After the mixture was stirred at r.t. for 0.5–1 h (TLC
monitoring), it was poured into H2O to induce precipitation.
The solid was filtered and washed with copious amounts
water, then recrystallized from EtOH and PE to give pure
products 4 and 5 as white solid.
Selected Data for Compounds 4a
(13) (a) Rueter, J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.;
Reitz, A. B. Tetrahedron Lett. 1998, 39, 975. (b) Zhang, M.
J.; Moore, J. D.; Flynn, D. L.; Hanson, P. R. Org. Lett. 2004,
6, 2657. (c) Cho, C.-L.; Yun, H.-S.; Park, K. J. Org. Chem.
2003, 68, 3017. (d) Choi, J. H.; Lee, B. C.; Lee, H. W.; Lee,
I. J. Org. Chem. 2002, 67, 1277. (e) Gao, C.-Y.; Yang,
L.-M. J. Org. Chem. 2008, 73, 1624.
Mp 118–119 °C. 1H NMR (400 MHz, CDCl3): d = 0.95 (t, 3
H, J = 7.2 Hz), 2.50 (s, 3 H), 3.76 (t, 4, J = 4.8 Hz), 3.93 (m,
3 H), 4.04 (q, 2 H, J = 7.2 Hz), 7.40–7.58 (m, 5 H). 13C NMR
(100 MHz, CDCl3): d = 13.5, 23.1, 44.1, 60.9, 66.9, 114.5,
128.1, 128.2, 129.5, 139.3, 160.2, 165.7, 167.0, 168.9. ESI-
MS: m/z 328 ([M+H+]).
Selected Data for Compounds 5a
(14) Bříza, T.; Král, V.; Martásek, P.; Kaplánek, R. J. Fluorine
Mp 65–66 °C. 1H NMR (400 MHz, CDCl3): d = 1.04 (t, 3 H,
J = 7.2 Hz), 2.39 (s, 3 H), 2.50 (s, 3 H), 4.14 (q, 2 H, J = 7.2
Hz), 7.21–7.53 (m, 9 H). 13C NMR (100 MHz, CDCl3):
d = 13.6, 21.3, 22.6, 61.7, 121.4, 125.9, 128.3, 128.4, 129.7,
130.1, 135.1, 137.4, 139.2, 163.5, 165.8, 168.1, 172.4. ESI-
MS: m/z = 365 [M + H+].
Chem. 2008, 129, 235.
(15) General Procedure for the Preparation of 3
To a stirred mixture of compound 2 (1 mmol) and
p-toluenesulfonyl chloride (1.5 mmol) in PEG-400 (2 g),
K2CO3 (1.5 mmol) was added at 0 °C. The reaction mixture
was taken slowly to r.t. and stirred for ca. 40 min. After
complete conversion (TLC monitoring), the crude reaction
mixture was poured into H2O to induce precipitation. The
solid was filtered and washed with copious amounts H2O,
then recrystallized from EtOH to give pure pyrimidin-2-yl
sulfonates 3 as white solid.
(17) General Procedure for the Preparation of 6
To a stirred mixture of compound 3 (1 mmol) in PEG-400 (2
g) at r.t. were added nucleophiles (1.5 mmol) and NaOt-Bu
(1.5 mmol). After the mixture was stirred at r.t. for 1.5 h
(TLC monitoring), the reaction mixture was treated with
H2O, and extracted with EtOAc, the organiclayers were
dried over Na2SO4. The crude product was purified by flash
chromatography (PE–EtOAc, 10:1) to give pure products 6
as colorless oil.
Selected Data for Compound 3a
Mp 106–108 °C. 1H NMR (400 MHz, CDCl3): d = 1.06 (t,
3 H, J = 7.2 Hz), 2.45 (s, 3 H), 2.57 (s, 3 H) 4.20 (q, 2 H,
J = 7.2 Hz), 7.32–8.03 (m, 9 H). 13C NMR (100 MHz,
CDCl3): d = 13.6, 21.7, 22.5, 62.2, 123.8, 128.5, 128.5,
129.3, 129.4, 130.8, 133.8, 136.3, 145.5, 158.7, 166.7,
167.2, 169.6. ESI-MS: m/z = 413 [M + H+].
Selected Data for Compound 6a
1H NMR (400 MHz, CDCl3): d = 0.92 (t, 3 H, J = 7.2 Hz),
1.34 (t, 3 H, J = 6.8 Hz), 2.47 (s, 3 H), 4.05 (m, 2 H), 4.40 (q,
2 H, J = 7.2 Hz), 7.30–7.56 (m, 5 H). 13C NMR (100 MHz,
CDCl3): d = 13.4, 14.2, 22.5, 61.3, 63.5, 119.5, 128.0, 128.1,
129.8, 137.7, 163.9, 166.2, 168.1, 168.4. ESI-MS: m/z = 287
[M + H+].
(16) General Procedure for the Preparation of 4 and 5
To a stirred mixture of compound 3 (1 mmol) in PEG-400 (2
g) at r.t. were added nucleophiles (1.5 mmol) and K2CO3 (1.5
Synlett 2010, No. 11, 1657–1660 © Thieme Stuttgart · New York