Selective reductive cleavage of 2-(phenylthio)pyrimidines for efficient synthesis of 2-(H)pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2019.07.002

A reaction method is described for selective reductive cleavage of 2-(phenylthio)pyrimidines using Pd(OAc)₂ and Et₃SiH to produce 2-(H)pyrimidines. The reaction proceeds efficiently with a wide range of 2-(phenylthio)pyrimidines. Con

Full text of DOI:10.1016/j.tetlet.2019.07.002

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Selective reductive cleavage of 2-(phenylthio)pyrimidines for efficient synthe-
sis of 2-(H)pyrimidines
Yujin Oh, Jihong Lee, Hyunik Shin, Jeong-Hun Sohn
PII:
S0040-4039(19)30641-0
https://doi.org/10.1016/j.tetlet.2019.07.002
TETL 50911
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 April 2019
30 June 2019
2 July 2019
Please cite this article as: Oh, Y., Lee, J., Shin, H., Sohn, J-H., Selective reductive cleavage of 2-
(phenylthio)pyrimidines for efficient synthesis of 2-(H)pyrimidines, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.07.002
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Selective reductive cleavage of 2-
(phenylthio)pyrimidines for efficient
synthesis of 2-(H)pyrimidines
Leave this area blank for abstract info.
Yujin Oha, Jihong Leea, Hyunik Shinb and Jeong-Hun Sohna,*
R1
R1
N
Pd(OAc)2
Et3SiH
R2O2C
R3
R2O2C
R1
N
N
PhMe
rt
N
H
S
31 examples
up to 98%
Selective cleavage of thioether

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Tetrahedron Letters
journal homepage: www.elsevier.com
Selective reductive cleavage of 2-(phenylthio)pyrimidines for efficient synthesis of 2-
(H)pyrimidines
Yujin Oha, Jihong Leea, Hyunik Shinb and Jeong-Hun Sohna,*
a Department of Chemistry, College of Natural Sciences, Chungnam National University, Dajeon 305-706, Korea
b Yonsung Fine Chemicals R&D Center, 602 Innoplex 2, 306 Sinwon-ro, Yeongtong-gu, Suwon 443-380 Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
A reaction method is described for selective reductive cleavage of 2-(phenylthio)pyrimidines
using Pd(OAc)2 and Et3SiH to produce 2-(H)pyrimidines. The reaction proceeds efficiently with
Received in revised form
Accepted
Available online
a wide range of 2-(phenylthio)pyrimidines. Considering the ready availability of 2-
(arylthio)pyrimidines derived from oxidative C–S cross coupling of 3,4-dihydropyrimidin-1H-
2-thiones (DHPMs), this method unambiguously provides a shortcut to the preparation of 2-
(H)pyrimidines with unprecedented diversity.
Keywords:
2-(H)pyrimidine
2009 Elsevier Ltd. All rights reserved.
reductive cleavage
2-(arylthio)pyrimidine
selective reduction
decarboxylative coupling
Compounds containing the pyrimidine structure have attracted
much attention from organic and medicinal chemists due to their
biological profile.1 They exhibit antimicrobial, antiviral,
(DHPMs) and aryl iodides, which likely proceeded via C–S
cross-coupling with concomitant oxidation.4 Since DHPM
compounds can be easily prepared by the Biginelli three-
component reaction with aldehyde, β-ketoester, and thiourea to
provide various substituents at the C4–C6 positions,5 we
expected that selective reductive cleavage of a thioether could
provide 2-(H)pyrimidines bearing various substituents at these
positions (Scheme 1).
anticancer,
antimycobacterial,
anti-inflammatory,
antihypertensive, and antidiabetic activities, and inhibitory
activity in the case of xanthin oxidase for treating gout.2 Notably,
the 2-(H)pyrimidine motif has been incorporated into several
commercial tyrosine kinase inhibitor drugs, such as Ruxolitinib,
Tofacitinib, and Baricitinib, and antifungal drugs such as
Voriconazole (Figure 1)3.
1) Previous work: Reductive cleavage of 2-(alkylthio)pyrimidines
N
X
alkyl
F
N
O
CN
N
SOn
oxidation
X
reduction
N
CN
N
n = 1, 2
N
N
N
F
direct reduction
X
HO
N
alkyl
H
N
N
N
S
N
N
F
N
N
2) This work: Reductive cleavage of 2-(arylthio)pyrimidines
N
N
H
N
H
N
H
R1
N
H
R1
N
H
N
R2
R1
R2
R3
Ruxolitinib
Tofacitinib
Voriconazole
Pd
N
N
silane
Figure 1. Examples of pharmacologically important 2-(H)pyrimidines
H
S
ref. 4 oxidative C-S coupling
Notwithstanding their pharmacological importance, where
they act as a binding fragments of biological targets, synthetic
strategies toward 2-(H)pyrimidines bearing diverse substituents
at the C4–C6 positions are limited in scope and generality. We
report herein the synthesis of 2-(H)pyrimidines by selective
reductive cleavage of 2-(arylthio)pyrimidines using a Pd catalyst
and a silane. Previously, we reported one-step synthesis of 2-
(arylthio)pyrimidines from 3,4-dihydropyrimidin-1H-2-thiones
R1
R1
Biginelli
reaction
R2
R3
R2
R3
NH2
NH
O
ref. 5
O
H2N
S
N
S
H
Scheme 1. Strategy for general synthesis of 2-(H)pyrimidines

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2
Tetrahedron Letters
There are several methods for reductive cleavage of
oxidative addition of Pd into the pyrimidine C–S bond (Scheme
(hetero)aryl sulfides, most of which follow two general routes.
First, direct reduction of the C–S bond of a (hetero)aryl sulfide
using Raney nickel as the most common reagent is well known.6
This reaction also uses other reducing agents including Raney
copper,7 NiCl2-NaBH4,8 NiCRA-NiCRAL,9 Zn-HCl,10 Zn-AcOH-
3).22
Table 1. Optimization of the reductive cleavagea,b
O
Ph
O
Ph
conditions
Ar
tBuO
N
tBuO
N
Ac2O,11 Red-Al,12 Al-HgCl2, and Pd/C-hydrazine.14 However,
13
Ph
H
N
S
N
many of these reductants suffer from low functional group
tolerance and use stoichiometric quantities of metal reagents. A
two-step sequence serves as a second approach: oxidation of the
sulfide to the corresponding sulfoxide or sulfone, followed by
reduction.15 This route obviously cannot be used in the presence
of oxidation-labile functional groups and needs an additional
step.
1a
2a
Entry
[Pd]
Silane
Solvent
T (°C)
Yield(%)
1
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
EtMe2SiH
EtMe2SiH
EtMe2SiH
Et3SiH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
rt
87
11
36
96
90
89
92
82
88
93
96
95
92
97
95
88
96
97
2
rt
3
rt
For the single-step route, the catalytic hydrogenation using
Pd/C or Pd(OH)2/C with H2 was utilized but is limited to the
substrates free of functional groups that can be reduced under the
conditions.16 Recently, Graham et al. reported a catalytic
reducing system using Pd/C-silane, which exhibited high
substrate scope and functional group tolerance.17 Martin et al.18
and Nakada et al.19 also reported the catalytic reductive cleavage
of (hetero)aryl sulfides using Ni(COD)2-silane and PdCl2-silane,
respectively. To our best knowledge, reductive cleavage of the
thioether was only accomplished with alkylthiopyrimidines
which requires two-step reaction sequence from DHPMs
including alkylation of sulfur followed by oxidation.20 Thus, we
decided to investigate unreported reductive cleavage of 2-
(arylthio)pyrimidines prepared in a single-step from DHPMs,
which could afford a fast access to the 2-(H)pyrimidines with
enhanced diversity at C4-C6 positions.21
4
rt
5
MePh2SiH
Ph3SiH
Et3SiH
rt
6
rt
7
rt
8
Et3SiH
THF
rt
9
Et3SiH
CH3CN
xylene
PhMe
DMF
rt
10
11
12
13
14
15
16
17
18
Et3SiH
rt
Et3SiH
40
40
40
70
70
70
100
140
Et3SiH
Et3SiH
xylene
PhMe
DMF
Et3SiH
Et3SiH
We initiated our study with the reaction of phenyl (1a), p-
methoxyphenyl (1b) and p-nitrophenylthioethers (1c) to
investigate the electronic effect of the leaving group on C–S
bond cleavage. When the reactions of 1a–c in the presence of
PdCl2 (10 mol%) and EtMe2SiH (3 equiv.) were carried out in
toluene (0.15 M) at room temperature for 8 h under Ar, we
obtained the desired product, 2a, in 60–67% yields (Scheme 2).
The similar yields led us to further optimization with 1a because
iodobenzene is less expensive than 1-iodo-4-methoxybenzene
and 1-iodo-4-nitrobenzene, which are used in the synthesis of
1a–c via oxidative C–S cross-coupling with the corresponding
DHPM.
Et3SiH
xylene
PhMe
PhMe
Et3SiH
Et3SiH
aReaction conditions: substrate 1 (0.15 mmol), silane (0.45
mmol), Pd catalyst (10 mol%), and solvent (1 mL) for 8 h under Ar.
bIsolated yields.
O
O
OtBu
N
OtBu
N
Pd
S
N
R2
H
N
O
Ph
O
Ph
PdCl2
EtMe2SiH
X
tBuO
N
tBuO
N
PhMe
rt, 8 h
H
N
S
N
2a
1a
1b
1c
X = H ( ), OMe ( ), NO2 (
)
1a
1b
O
O
65% for , 60% for
1c
67% for
N
OtBu
N
OtBu
Scheme 2. Initial studies
H
Ph-S
N
R2
N
R2
Pd
Pd
We investigated alternative Pd sources for further
optimization studies: Pd(OAc)2, which provided 2a in 87% yield,
was superior to PdCl2 and other Pd(0) catalysts such as Pd(PPh3)4
and Pd2(dba)3 (entries 1–3, Table 1). With respect to silanes,
Et3SiH gave the desired product in 96% yield and was better than
other silanes, such as EtMe2SiH, MePh2SiH, and Ph3SiH (entries
4–6). Among the solvents examined in our studies, the highest
efficacy was found for toluene (entries 4 and 7–10). Higher
temperature, i.e., 40, 70, 100, and 140 °C, did not significantly
improve the reaction yield (entries 11–18). Thus, we decided to
examine the scope of the substrate at room temperature. A
tentative mechanism for the selectivity of the reaction is likely
R3Si-S-Ph
R3Si-H
Scheme 3. Plausible reaction mechanism
Optimal reaction conditions were used with diverse 2-
(phenylthio)pyrimidines 1 to explore the substrate scope. First,
we tested the reaction with substrates by varying the R1 group of
the alkoxycarbonyl to give the desired products 2b–d in good
yields (86–98%) for methyl-, ethyl-, and i-propyl esters. With