Synthesis of arylthiopyrimidines by copper-catalyzed aerobic oxidative C-S cross-coupling

Full text of DOI:10.1002/bkcs.10641

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DOI: 10.1002/bkcs.10641
BULLETIN OF THE
O. S. Lee et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Arylthiopyrimidines by Copper-catalyzed Aerobic Oxidative
C–S Cross-coupling
†,
Ok Suk Lee,† Hyeji Kim,† Hee-Seung Lee,‡ Hyunik Shin,§, and Jeong-Hun Sohn
*
*
†Department of Chemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764,
Korea. *E-mail: sohnjh@cnu.ac.kr
‡Department of Chemistry, Molecular-Level Interface Research Center, KAIST, Daejeon 305-701, Korea
§Yonsung Fine Chemicals R&D Center, Suwon 443-380, Korea. *E-mail: shin_7@daum.net
Received June 29, 2015, Accepted October 8, 2015, Published online January 14, 2016
Keywords: Arylthiopyrimidine, Aerobic copper catalysis, C–S cross-coupling, Oxidative dehydrogenation
Copper-catalyzed C–S cross-coupling reactions have been
considered as powerful tools in synthetic chemistry and uti-
lized for diverse heterocycle syntheses (Equation 1, Scheme
1).1 In the reactions, the aspects of no need of ligands has been
particular advantage over other metal catalysis.2 Recently, an
interesting feature of copper catalysis has been revealed, in
which sp3 carbons are oxidized to carbonyl carbons using oxy-
gen as an only oxidant.3 As its further extension, we previ-
ously reported the copper-catalyzed aerobic oxidative
dehydrogenation reaction of dihydropyrimidyl thioether 1 to
(alkylthio)pyrimidine 2 with no additives, such as an oxidant,
acid, or base (Equation 2).4 Hinted by relative insensitivity of
the C–S cross-coupling to O2 or air we envisioned a copper-
catalyzed cascade reaction, which combines the C–S cross-
coupling (Equation 1) with concomitant oxidative dehydro-
genation (Equation 2) as shown in Scheme 1. Herein, we
report the synthesis of fully substituted arylthiopyrimidines
4 from 3,4-dihydropyrimidine-2(1H)-thiones (DHPMs) and
aryl iodides under air, presumably via tautomerization, C–S
cross-coupling, and oxidative dehydrogenation (oxidation
followed by elimination) (Equation 3).5
DHPM substrates 3 can be easily synthesized by Biginelli
three component reaction with aryl aldehyde, β-ketoester
and thiourea.6 They could be transformed to 2-
arylthiopyrimidines 4 with providing various C4–C6 substitu-
ents by the proposed cascade reaction. The expected product
4 could be utilized in the production of diversely C-2 aryl-
substituted compounds by cross-coupling reactions such as
the Liebeskind–Srogl reaction.7 Thus, implementation of this
cascade reaction could allow facile access and diversification
of novel pyrimidine compounds, which are embedded as an
important substructures of many valuable drug candidates
or intermediate of drugs, as evidenced by the well-known
rosuvastatin and imatinib (Gleevec).8
Initially, we examined the cascade reaction of DHPM
8 (0.2 mmol) with iodobenzene (2.0 equiv) in the presence
of CuI (20 mol %), K2CO3 (1.0 equivꢀ) and solvent
(0.2 mL) for 8 h under air (Table 1). At ≤ 70 C, the reaction
in PhCH3, THF, or dioxane did not proceed (entries 1–3).
However, the detection of a trace amount of the desired prod-
uct 95 in the case of DMF or NMP solvent (entries 4 and 5) led
us to optimize the reaction conditions. Since higher tempera-
ꢀ
ture (100 C) increased the reaction yield, we carried out the
reaction with further elevation of temperature. We observed
ꢀ
that the reaction yield increased accordingly up to 130 C
and that NMP was better solvent than DMF (entries 6–11).
The reaction under O2 resulted in lower reaction yield with
decomposition than that under air (entry 12). Less amount
of CuI (entries 13 and 14), or other bases such as Cs2CO3, t-
BuOK, i-Pr2NEt, and NEt3 did not enhance the reaction yield
(entries 15–18). Other Cu(I) or Cu(II) catalysts such as CuBr,
CuCl, or Cu(OAc)2 showed lower efficacy than CuI (entries
18–21). In the case that biphenyliodonium triflate was used
as an arylating agent, the reaction exhibited lower yield than
that with PhI (entry 22).
Under optimal conditions, the reaction scope was
subsequently studied with diverse aryl iodide and DHPM
Scheme 1. Copper-catalyzed aerobic cascade reaction for the synthe-
sis of arylthiopyrimidines.
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Table 1. Optimization of the cascade reaction of 8 with iodobenzene.a,b
Entry
[Cu]
Base
Solvent
T (ꢀC)
Yield
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Et3N
i-Pr2NEt
t-BuOK
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PhCH3
THF
70
70
70
70
70
0
0
0
Dioxane
DMF
NMP
DMF
NMP
NMP
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Trace
Trace
21
100
100
110
130
130
150
130
130
130
130
130
130
130
130
130
130
130
28
45
48
85
9
10
11
12
13
14
15
16
17
18
19
20
21
22
a
79
61c
45d
59e
38
23
62
47
23
62
59
59f
CuI
CuI
CuCl
CuBr
Cu(OAc)2
CuI
Reaction conditions: substrate 8 (0.2 mmol), PhI (0.4 mmol), base (0.2 mmol), catalyst (20 mol%), and solvent (0.2 mL) for 8 h under air.
b
c
d
e
f
Isolated yields.
Reaction was accomplished under O2.
5 mol%.
10 mol% CuI were used.
Ph2I+OTf− instead of PhI was used.
substrates. With respect to aryl iodide substrate, the reaction
position of the heteroatom, 2-iodopyridine resulted in a higher
yield than 3-iodopyridine, while similar yields were shown for
2- and 3-iodothiophene (entries 22–25). Bicyclic 1-
iodonaphthalene was also shown to be suitable substrate for
the cascade reaction (entry 26).
method was suitable for a wide range of functional groups
and heterocyclic aryl iodides (Table 2). When the electronic
effect or thepositionof substituent atthearyl iodidewasinves-
tigated the reaction did not exhibit distinct variations depend-
ing on either of them. For electron-donating substituent, the
order of the reaction yield was ortho- (74%) > meta-
(59%) > para-position (53%) in the case of OMe, while
meta- (62%) > ortho- (60%) > para-position (52%) in the
case of Me (entries 1–6). For electron-withdrawing substitu-
ent, NO2 or CF3 group, best result was obtained with para-
position followed by ortho- and then meta-position (entries
7–12). For halide substituted aryl iodides the reaction exhib-
itedcompletely different substrate preference. For eachhalide,
maximum yield was obtained with the substrate, meta-F
(90%), para-Br (81%), and ortho-Cl (72%) (entries 13–21).
Heterocyclic aryl iodides, iodopyrdine and iodothiophene
were also compatible with the reaction. With respect to the
Next, we explored the scope of the reaction with respect to
the DHPMsubstrate. At first, the steric effect of thealkoxy car-
bonyl group at C5 and alkyl group at C6 was investigated
(Scheme 2). For the alkoxy carbonyl group, reaction yields
decreased as its steric bulk increased- an order of t-Bu
(9) > i-Pr (38) > Et (379) > Me (3610). Regarding the substit-
uent at C6, Et and i-Pr group afforded 39 and 40, respectively,
in same yield (76%), which are lower than that in the Me group
case (9, 85%). To examine the substituent effect of C4 aryl
group, the reactions of DHPM substrates possessing
electron-withdrawing and donating substituents, para-F and
para-OMe group were carried out. We observed that both sub-
stituents were suitable for the reaction with aryl iodides. In the
Bull. Korean Chem. Soc. 2016, Vol. 37, 242–245
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Table 2. Reaction scope with respect to aryl iodide.a,b
Entry
Ar
Product
Yield (%)
1
2
3
4
5
6
7
8
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-FC6H4
3-FC6H4
4-FC6H4
2-BrC6H4
3-BrC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
84
69
63
74
72
80
70
95
77
58
66
81
72
59
58
70
72
62
70
53
77
55
46
66
64
88
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
a
4-BrC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-CF3C6H4
3-CF3C6H4
4-CF3C6H4
2-pyridinyl
3-pyridinyl
2-thiophenyl
3-thiophenyl
1-naphthyl
Reaction conditions; DHPM substrate (0.2–0.3 mmol), ArI (2.0 equiv),
K2CO3 (1.0 equiv), CuI (20 mol%) and NMP (0.2–0.3 mL, 1.0 M) for
8–12 h under air.
b
Scheme 2. Reaction scope with respect DHPM and aryl
iodide. aReaction conditions; DHPM substrate (0.2–0.3 mmol),
ArI (2.0 equiv), K2CO3 (1.0 equiv), CuI (20 mol%), and NMP
(0.2–0.3 mL, 1.0 M) for 8–12 h under air. bIsolated yields.
Isolated yields.
case of para-F substituent, the reaction with meta-MeO-PhI, 2-
iodothiophene, 1-iodonaphthalene, PhI, or meta-F-PhI pro-
duced the corresponding product in similar yield (41–45).
For para-OMe substituent, the reaction with PhI or ortho-
MeO-PhI showed slightly lower reaction yield (46 and 48)
compared with meta-F-PhI, 2-iodothiophene or 1-
iodonaphthalene (47, 49, and 50).
by Biginelli three component coupling reaction of aryl alde-
hyde, β-ketoester, and thiourea, the present method provides
a direct access toward diverse 2-arylthiopyrimidines which
have been used as a prominent substructure of drug molecules.
In summary, we have developed a Cu-catalyzed cascade
reaction for the synthesis of fully substituted 2-
arylthiopyrimidines from 3,4-dihydropyrimidine-2(1H)-
thiones (DHPMs) under aerobic conditions. This cascade
reaction of DHPM with aryl iodide proceeds presumably
via sequential tautomerization, C–S cross-coupling, and oxi-
dative dehydrogenation (oxidation followed by elimination).
Considering that DHPM substrates were easily synthesized
Experimental
General. Common solvents were purified before use. Tolu-
ene (PhCH3) and tetrahydrofuran (THF) were purified by dis-
tillation from calcium hydride and sodium-benzophenone,
respectively. N-methyl-2-pyrrolidone (NMP, Aldrich Sure/
Seal), N,N-dimethylformamide (AcroSeal), and 1,4-dioxane
(Aldrich Sure/Seal) were used as received. All reagents were
Bull. Korean Chem. Soc. 2016, Vol. 37, 242–245
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
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General Procedure for Cu-catalyzed Aerobic Cascade
Reaction. To a solution of DHPM (0.2–0.3 mmol) in NMP
(1.0 M) were added ArI (2.0 equiv), CuI (20 mol %), and
K2CO3 (1.0 equiv), and the resulting mixture was allowed
ꢀ
to stir at 130 C for 5–12 h under air. After cooling to room
temperature, saturated NH4Cl was added. The mixture was
extracted with EtOAc, washed with brine, dried over MgSO4,
filtered through silica gel pad, and concentrated under reduced
pressure. The crude product was purified by column chroma-
tography to give the desired pyrimidine compound.
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Acknowledgments.
by the NRF
2013R1A2A1A01008358).
This work was supported
grants (2014R1A1A4A01007933,
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Bull. Korean Chem. Soc. 2016, Vol. 37, 242–245
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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