Molecular iodine-mediated S-N and C-N cross-coupling and oxidative aromatization of 3,4-dihydropyrimidin-2(1H)-thiones with secondary amines

Article abstract of DOI:10.1016/j.tetlet.2013.01.113

A domino S-N and C-N coupling/oxidative aromatization process to synthesize 2-aminothio-phenylpyrimidines and 2-amino-phenylpyrimidines by S-N and C-N cross-coupling reactions is described. This methodology couples 3,4-dihydropyrimidine-2-thiones and secondary amines catalyzed by molecular iodine. Remarkably the C-N coupled product was obtained via a desulfitative coupling-aromatization reaction in one-pot reaction.

Full text of DOI:10.1016/j.tetlet.2013.01.113

Tetrahedron Letters 54 (2013) 1884–1887
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Tetrahedron Letters
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Molecular iodine-mediated S–N and C–N cross-coupling and oxidative
aromatization of 3,4-dihydropyrimidin-2(1H)-thiones with secondary amines
⇑
Zheng-Jun Quan, Ying Lv, Zhong-Jie Wang, Zhang Zhang, Yu-Xia Da, Xi-Cun Wang
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China, Gansu 730070, PR China
Gansu Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, 967# Anning East Road, Lanzhou, Gansu 730070, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A domino S–N and C–N coupling/oxidative aromatization process to synthesize 2-aminothio-phenylpyr-
imidines and 2-amino-phenylpyrimidines by S–N and C–N cross-coupling reactions is described. This
methodology couples 3,4-dihydropyrimidine-2-thiones and secondary amines catalyzed by molecular
iodine. Remarkably the C–N coupled product was obtained via a desulfitative coupling-aromatization
reaction in one-pot reaction.
Received 8 December 2012
Revised 16 January 2013
Accepted 28 January 2013
Available online 4 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
C2-Functionalized pyrimidines
Oxidative aromatization
3,4-Dihydropyrimidin-2(1H)-ones
S–N coupling
C–N coupling
Introduction
the synthesis of C2-substituted pyrimidines by cross-coupling
reaction of pyrimidin-2-ylsulfonates or 2-hydroxypyrimidine
Biginelli 3,4-dihydropyrimidin-2(1H)-ones (DHPMs)1 are cen-
tral subunits in a broad range of medicinal agents which display
interesting pharmacological and biological properties such as cal-
with nucleophiles at room temperature.8 Kappe and our groups
have developed an efficient desulfitative carbon–carbon coupling
reaction between 3,4-dihydropyrimidin-2-thiones and boronic
acids9 or alkynes10 under modified Liebeskind-Srogl Pd-catalyzed
and Cu(I)-mediated conditions. Dehydrogenation of the DHPMs is
also a well known difficult process leading to low yield, when
oxidizing agents such as SeO2, 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ), or HNO3 were used.11 The dehydrogenation
of DHPMs using tert-butylhydroperoxide (TBHP) has been intro-
duced by Yamamoto et al.,12 which can be applied on a large
scale. (Diacetoxyiodo)benzene, ceric ammonium nitrate (CAN),
Mn(OAc)3, and MnO2 have been employed in the oxidative aro-
matization of 1,4-dihydropyrimidine.13
cium channel modulators,
a1a-adrenergic receptor antagonists,
mitotic kinesin inhibitors, and hepatitis B virus replication inhib-
itors.2 The DHPM core is also found in several marine derived
natural products such as Crambine, Batzelladine B, (potent HIV
gp-120CD4 inhibitors) and Ptilomycalin alkaloids.3 Additionally,
the DHPMs are important building blocks in the synthesis of
multifunctionalized pyrimidines. Although much effort has been
made on the development of methods for the synthesis of the
pyrimidine derivatives,4 few methodologies are available toward
efficient synthesis of C2-substituted pyrimidines from DHPMs.
In general, C2-substituted pyrimidines were obtained from
DHPMs by a four-step strategy involving sequential dehydroge-
nation, tautomerization, activation, and coupling with a nucleo-
phile.5,6 It was not until 2005 that a more efficient approach
was achieved via PyBroP-mediated coupling reaction of 1,4-dihy-
dropyrimidine with nucleophiles.7 Recently, our group realized
To date, a simple S–N or C–N cross-coupling and oxidative-aro-
matization of 3,4-dihydropyrimidine-2(1H)-thione with an amine
have never been used for the direct synthesis of 2-aminothio-phe-
nylpyrimidine and 2-amino-phenylpyrimidine derivatives. Herein
we present the first I2-catalyzed S–N and C–N coupling/oxidative
aromatization process for the synthesis of C2-substituted pyrimi-
dine derivatives from 3,4-dihydropyrimidine-2(1H)-thione and
amines (Scheme 1). This direct method from 3,4-dihydropyrimi-
dine-2(1H)-thione does not need any additives and proceeds with
high selectivity at different temperatures, which selectively forms
2-aminothio-phenylpyrimidines and 2-amino-phenylpyrimidines
at rt and 140 °C, respectively.
⇑
Corresponding author. Fax: +86 931 7972626.
E-mail address: wangxicun@nwnu.edu.cn (X.-C. Wang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.113

Z.-J. Quan et al. / Tetrahedron Letters 54 (2013) 1884–1887
1885
Ar
O
Ar
N
O
Ar
N
O
X
I2, Cs2CO3, air
140 oC, 12h
I2, Cs2CO3, air
rt, 24h
X
EtO
Me
NH
EtO
Me
N
EtO
Me
N
+
N
N
H
N
H
S
N
S
X
X = O; CH2
Scheme 1. Direct coupling/aromatization of 3,4-dihydropyrimidin-2-thiones with amines.
xylene, and DMF, provided worse results (entries 7–11). PEG-400
also exhibited good results yielding 3aA in 73% yield with a small
amount of 4aA (entry 12). Reducing the amount of I2 led to the for-
mation of 3aA in a lower yield (entry 13). Prolonged reaction times
gave a lower yield of 3aA with a slightly higher yield of 4aA (entry
14). Improving the reaction temperature led to the increase of 4aA
yield and the best yield of 4aA in 65% was obtained at 140 °C for
12 h using PEG-400 as the solvent (entries 15 and 16).
Results and discussion
As a starting point in our investigations, we examined the reac-
tion between model substrate 3,4-dihydropyrimidine-2(1H)-thi-
one (1a, 0.5 mmol) and morpholine (2a, 1.0 mmol, 2.0 equiv). To
our delight, when the reaction was performed using molecular io-
dine (0.2 equiv) as the catalyst under air atmosphere in dichloro-
methane (DCM) at room temperature for 24 h, a S–N cross-
coupling and aromatization product 3aA was obtained, albeit with
a low yield (56%) together with the isolation of a C–N coupling-aro-
matization product 4aA (12%) (Table 1, entry 1). Similar reaction
yield and selectivity were also observed when combining 0.2 equiv
of I2 with 1.0 equiv of CAN or DDQ as the catalysts, which provided
product 3aA in yield of 42% and 40%, respectively (entries 2 and 3).
Good reaction yield and selectivity were observed when using
2.0 equiv of I2 as the catalyst, which provided the S–N coupling
product 3aA in good yield of 74% (entry 4). When the reaction
was performed under an oxygen atmosphere at rt, the yield of
4aA was increased to 75% within 12 h (entry 5). These results are
in agreement with the observation that compound 1a can be cou-
pled to give the functionalized bis(2-pyrimidyl) disulfide under air
atmosphere catalyzed by Cu(II),14 which indicated that O2 plays a
role in the oxidative stage. It was confirmed when 1a was treated
with 2a under a nitrogen atmosphere, no coupling reaction was ob-
served to take place as determined by TLC and 1H NMR spectros-
copy (entry 6). Other solvents, such as toluene, THF, MeCN,
Based on these results and reported procedure,14 we proposed
the mechanism of the formation of S–N and C–N coupling products
as shown in Scheme 2. The formation of disulfide D was performed
catalyzed by air and I2, then S–N and C–N coupling of D with mor-
pholine 2a occurred respectively at rt and 140 °C. The formation of
the intermediate D and 3aA with 4aA was detected in the reaction
of 1a with 2a at 100 °C by LC–MS. The alternative mechanism is
also plausible. That is, the C–N coupling reaction may be completed
by the substitution of 3aA with morpholine 2a. This was confirmed
by the reaction of 3aA with morpholine 2a in PEG-400 at 140 °C for
5 h to give the C–N product 4aA. We propose that iodine serves not
only as the catalyst but also as the oxidant. We speculate that io-
dine is probably transformed into some hypervalent iodine species
in the presence of oxygen from the air and of Cs2CO3. This could
thus explain why the reaction needs an excess amount of I2.
With the optimized conditions in hand, we then examined the
scope of 3,4-dihydropyrimidine-2(1H)-thione substrates by vary-
ing the substituents on the aromatic ring to explore the generality
Table 1
Optimization conditions for S–N couplinga
O
O
O
O
Conditions
O
EtO
Me
N
EtO
Me
NH
EtO
N
+
+
air or O2
N
N
H
N
S
N
H
1a
S
Me
N
N
O
2a
3aA
4aA
Entry
Catalyst (equiv)
Solvent
Temp (°C)
3aAb
4aAb
Time (h)
1
2
3
4
I2 (0.2)
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
Xylene
THF
MeCN
DMF
PEG-400
PEG-400
DCM
PEG-400
PEG-400
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
100
140
56
42
40
74
75
—
60
60
54
45
20
73
45
69
25
5
12
10
10
10
12
—
11
12
10
12
5
5
5
17
55
65
24
24
24
24
12
24
24
24
24
24
24
12
12
36
12
12
I2 (0.2)/CAN(1.0)
I2 (0.2)/DDQ(1.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
I2 (1.0)
I2 (2.0)
I2 (2.0)
I2 (2.0)
5c
6d
7
8
9
10
11
12
13
14
15
16
a
b
c
Reaction conditions: 1a (0.5 mmol) and 2a (1.0 mmol, 2.0 equiv), I2 (1.0 mmol, 2.0 equiv), Cs2CO3 (0.5 mmol, 1.0 equiv) in solvent (3 mL) under air atmosphere.
Isolated yield.
The reaction was carried out under an O2 atmosphere.
The reaction was carried out under a N2 atmosphere.
d

1886
Z.-J. Quan et al. / Tetrahedron Letters 54 (2013) 1884–1887
O
Ph
O
Ph
O
Ph
tautomerization
I2 and O2/air
EtO
Me
N
EtO
N
EtO
NH
oxidative
N
H
S
Me
N
C
SH
Me
N
H
S
dehydrogenation
B
1a
oxidative
coupling
O
Ph
Me OEt
O
Ph
N
EtO
Me
N
N
O
and
EtO
O
2a
N
N
N
S
N
Ph
N
Me
S
3aA
O
Ph
N
S
4aA
D
O
N
2a
, I2, Cs2CO3
PEG-400, 140 oC
OEt
Scheme 2. A proposed mechanism for the S–N and C–N coupling reactions.
Table 2
S–N coupling of 3,4-dihydropyrimidine-2(1H)-thiones 1 with amines 2a
O
Ar
N
O
Ar
X
DCM, air
rt, 24h
X
EtO
Me
N
EtO
Me
NH
+
N
N
H
S
N
H
S
2a-2b
3aA-3fB
1a-1h
2a
2b
X = O, ; CH2,
Ar (1)
Amine 2
Product (yieldb, %)
Ar (1)
Amine 2
Product (yieldb, %)
C6H5 (1a)
2a
2a
2a
2a
2a
2a
2a
3aA (74)
3bA (80)
3cA (81)
3dA (72)
3eA (73)
3fA (70)
3gA (72)
4-ClC6H4 (1h)
C6H5 (1a)
2a
2b
2b
2b
2b
2b
2b
3hA (74)
3aB (72)
3bB (78)
3cB (78)
3dB (69)
3eB (70)
3fB (72)
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-BrC6H4 (1d)
4-NO2C6H4 (1e)
3-NO2C6H4 (1f)
4-FC6H4 (1g)
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-BrC6H4 (1d)
4-NO2C6H4 (1e)
3-NO2C6H4 (1f)
a
Reaction conditions: 1 (1.0 mmol) and 2 (2.0 mmol, 2.0 equiv), I2 (2.0 mmol, 2.0 equiv), Cs2CO3 (1.0 mmol, 1.0 equiv) in DCM (3 mL) under air atmosphere at rt for 24 h.
Isolated yield.
b
Table 3
C–N coupling of 3,4-dihydropyrimidine-2(1H)-thiones 1 with amines 2a
O
Ar
N
O
Ar
X
EtO
N
PEG-400, air
140 oC, 12h
EtO
Me
NH
+
Me
N
N
H
N
H
1a-1h
S
X
2a-2b
4aA-4hB
2a;
2b
CH2,
X = O,
Ar (1)
Amine 2
Product (yieldb, %)
Ar (1)
C6H5 (1a)
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-BrC6H4 (1d)
4-FC6H4 (1g)
Amine 2
Product (yieldb, %)
C6H5 (1a)
2a
2a
2a
2a
2a
2a
4aA (65)
4bA (68)
4cA (70)
4dA (58)
4gA (62)
4hA (61)
2b
2b
2b
2b
2b
2b
4aB (61)
4bB (55)
4cB (63)
4dB (58)
4gB (60)
4hB (59)
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-BrC6H4 (1d)
4-FC6H4 (1g)
4-ClC6H4 (1h)
4-ClC6H4 (1h)
a
Reaction conditions: 1 (1.0 mmol) and 2 (2.0 mmol, 2.0 equiv), I2 (2.0 mmol, 2.0 equiv), Cs2CO3 (1.0 mmol, 1.0 equiv) in PEG-400 (3 mL) under air atmosphere at 140 °C for
12 h.
b
Isolated yield.
of these S–N and C–N coupling reactions. The reaction tolerated a
variety of dihydropyrimidin-2-thiones giving a series of pyrimidine
derivatives via S–N (Table 2) and C–N cross-coupling (Table 3). No
matter what substituent groups are on the aromatic rings of 3,4-
ate to good yields. In terms of the effect of structural features,
introducing electron donating groups (Table 3, substrates 1b and
1c) to the aromatic ring is proved favorable to the reaction, with
the desired products being isolated in slightly higher yields than
those with electron withdrawing groups (Table 3, substrates 1d–
h). The structures of the S–N coupling products were confirmed
dihydropyrimidine-2(1H)-thione,
the
reactions
proceeded
smoothly, and the cross-coupling products were isolated in moder-

Z.-J. Quan et al. / Tetrahedron Letters 54 (2013) 1884–1887
1887
Supplementary data
Supplementary data (details of experimental procedures and
characterization data (copies of 1H NMR, 13C NMR for all new com-
pounds)) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.113. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
References and notes
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Figure 1. ORTEP diagram of compound 3dA.
by example of X-ray diffractometry of 3dA (Fig. 1).15 Cyclic second-
ary amines piperidine and morpholine are most successful in this
process; however, acyclic amines did not give promising results.
It is noteworthy that the study reported above, to our best
knowledge, is the first general exploration of cross-coupling reac-
tion of 3,4-dihydropyrimidine-2(1H)-thiones with amines to selec-
tively give S–N and C–N coupled product under mild reaction
conditions. This cross-coupling reaction, in which only one step
is needed for directly using 3,4-dihydropyrimidine-2(1H)-thiones
as starting material, is superior to other reported processes.
Remarkably the C–N coupled product was obtained via a desulfita-
tive coupling-aromatization reaction in one-pot reaction.
Conclusions
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In summary, we have developed a novel and efficient synthetic
method to prepare S–N and C–N functionalized pyrimidines by the
I2-catalyzed S–N and C–N coupling/oxidative aromatization pro-
cess between 3,4-dihydropyrimidine-2(1H)-thiones and amines.
Compared to previously known approaches, the simplicity (only
one-step is needed for using 3,4-dihydropyrimidine-2(1H)-thiones
as starting material) and higher efficiency make this method par-
ticularly attractive.
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this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
We are thankful for the financial support from the National Nat-
ure Science Foundation of China (No. 20902073 and 21062017),
and Scientific and Technological Innovation Engineering program
of Northwest Normal University (nwnu-kjcxgc-03-64).