Base mediated direct C-H amination for pyrimidines synthesis from amidines and cinnamaldehydes using oxygen as green oxidants

Article abstract of DOI:10.1016/j.cclet.2015.09.012

A direct metal-free C-H amination reaction of cinnamaldehydes and amidines to realize the synthesis of polysubstituted pyrimidines was developed in the presence of base. This greener synthetic methodology provides a straightforward approach to the synthes

Full text of DOI:10.1016/j.cclet.2015.09.012

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CCLET-3436; No. of Pages 4
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Chinese Chemical Letters
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Original article
Base mediated direct C–H amination for pyrimidines synthesis from
amidines and cinnamaldehydes using oxygen as green oxidants
Wei Guo a,b,
*
a School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China
b Key Laboratory of Organo-pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou 341000, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A direct metal-free C–H amination reaction of cinnamaldehydes and amidines to realize the synthesis of
polysubstituted pyrimidines was developed in the presence of base. This greener synthetic methodology
provides a straightforward approach to the synthesis of a variety of pyrimidine derivatives under mild
reaction condition using oxygen as sole oxidants.
Received 4 August 2015
Received in revised form 26 August 2015
Accepted 9 September 2015
Available online xxx
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
C–H amination
Pyrimidines
Amidines
Cinnamaldehydes
Oxygen
1. Introduction
Guirado published a chloroform elimination of 2,4-diaryl-6-
trichloromethyl-1,6-dihydropyrimidines to 2,4-diarylpyrimidines
Pyrimidines are very important heterocycles featuring promi-
nently in the synthesis of pharmaceuticals, agrochemicals, and
functional materials as well [1]. Particularly, they represent an
increasing valuable goal because of their large range of applica-
tions as anti-plasmodial agents, antimalarial agents, cytotoxic
inhibitors and photophysical materials [2]. While there exist
various synthetic methods for the useful heterocyles via cycliza-
tion–oxidation processes, amidines are frequently used to prepare
multiple-nitrogen-containing heterocycles because of their innate
structural advantages [3]. Numbers of synthetic routes have also
been developed for the synthesis of pyrimidines through the
cascade condensation cyclization–oxidation of amidines with 1,3-
starting from 2,2,2-trichloroethylidene-acetophenones and ben-
zamidines [7] (Scheme 1, c). The condensation of propargylamine
and benzamidine to give pyrimidine was also developed by Chen
and co-workers [8] (Scheme 1, d). However, most of the mentioned
methods suffered from harsh reaction conditions (special reaction
medium, microwave irradiation, transition-metals) and the use of
relatively unavailable starting materials. Hence, the development
of a simple and efficient procedure for acquisition of pyrimidines
from easily available starting materials under mild conditions
continues to attract the interest of organic chemists due to their
remarkable application value.
Direct C–H diamination represents one of the most powerful
synthetic protocols for the construction of N-heterocycles, avoiding
the pre-installation of transformable functional groups and posses-
sing atom economy and environmental sustainability [9]. Many
elegant methods involving transition-metal catalization and the use
of overstoichiometric amounts of oxidants have been dominated
[10]. For green and sustainable chemistry, molecular oxygen is
considered as an ideal oxidant due to its natural, inexpensive, and
environmentally friendly characteristics, and therefore shows
attractive academic and industrial prospects [11]. In the past few
years, our group developed serials of C–H dioxygen activation
reactions using molecular oxygen as the terminal oxidant [12], we
therefore think about employment of the molecular oxygen as the
dicarbonyl derivatives or a,b-unsaturated ketones [4]. Bagley and
co-workers successfully demonstrated a tandem oxidation/het-
erocyclocondensation of a propargylic alcohol and benzamidine
for the synthesis of pyrimidines using BaMnO4 under microwave
irradiation [5] (Scheme 1, a). Lin developed a Cu(OTf)2-catalyzed
tandem reaction of propargylic alcohols with amidine, providing a
general approach to pyrimindines [6] (Scheme 1, b). Recently,
*
Correspondence to: School of Chemistry and Chemical Engineering, South China
University of Technology, Guangzhou 510640, China.
E-mail address: guoweigw@126.com
http://dx.doi.org/10.1016/j.cclet.2015.09.012
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: W. Guo, Base mediated direct C–H amination for pyrimidines synthesis from amidines and
cinnamaldehydes using oxygen as green oxidants, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.012

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Previous work
R
N
OH
NH
MnO2, Na2CO3
N
R
a)
+
+
R1 NH2 HCl
R2
CH3CN, MW, 150 oC
R1
N
R2
NH
N
O
Cu(OTf)2, air
b)
TMS
R1 NH2 HCl
R1
R2
PhCl, reflux
R2
N
(1) CH3COOOH
t-BuOH, r.t., 5 min
N
NH
N
+
NH2 HCl
(2)t-BuOK, 4 mol/L HCl
c)
d)
dioxane, 85 oC, 0.5 h
O
NH
N
+
Ar1 NH2 HCl
Ar2
CCl3
Ar1
N
Ar2
This work
NH
R4
O
KOH (2 equiv.)
O2 (1 atm)
DMSO, 120 oC
R3
R4
N
R2
e)
+
R1 NH2 HCl
R3
R1
N
R2
12 h
1
2
3
Scheme 1. General approaches for the synthesis of pyrimidine derivatives.
oxidant for the pyrimidine synthesis. Herein, we further report a
base mediated direct C–H amination of amidines and cinnamalde-
hydestoafford polysubstitutedpyrimidinesusingmolecularoxygen
as sole oxidant (Scheme 1, e).
114.54; MS (EI, 70 eV) m/z: 232.13, 129.11, 116.16, 102.08; HRMS
(ESI) Calcd. C16H13N2 [M+H]+: 233.1073, found: 233.1070. The data
of 3ab–3la were available in Supporting information.
3. Results and discussion
2. Experimental
We initiated our study by using benzamidine hydrochloride 1a
and cinnamaldehyde 2a as model substrates under various
conditions and the results are summarized in Table 1. In the
absence of a base, the reaction between 1a and 2a gave a low yield
of 2,4-diphenylpyrimidine 3aa (Table 1, entry 1). When this
reaction was performed in the presence of bases, such as NaHCO3,
Li2CO3, Na2CO3, K2CO3, CH3COONa, CH3COOK, CS2CO3 and KOH,
the yield of 3aa increased (Table 1, entries 2–9). Especially, the
reaction performed with CS2CO3 gave the best result (89% GC yield)
(Table 1, entry 9). Trace of 3aa was detected in N2 atmosphere
(Table 1, entry 10). As a result, both the base and O2 were found to
be indispensable. Organic bases such as Et3N, DBU, and DABCO
exhibited poor results (Table 1, entries 11–13). Considering the
costs of Cs2CO3 and KOH, we used KOH to further optimize this
transformation. Screening of different solvents revealed that
DMSO was the best solvent for this process. Trace or No 3aa were
detected by GC–MS when using toluene or 1,4-dioxane as solvents
(Table 1, entries 14–15). Therefore, the best conditions for this
transformation involved 2 equiv. KOH, in DMSO at 120 8C for 12 h.
Under the established conditions, benzamidine hydrochloride
1a and various cinnamaldehydes were explored as substrates, and
the results are summarized in Fig. 1. A series of para-substituted
cinnamaldehydes, including some with electron-donating groups
and some with electron-withdrawing groups (R0 = F, Cl, CF3, NO2),
proceeded smoothly and afforded the desired pyrimidine products
in high yields (3ab–3af). Other substituted cinnamaldehydes, such
as meta-, and ortho-substituted substrates, could also provide the
desired product (3ag–3ai). These results showed that this
transformation was tolerant towards the electronic and steric
All of the reagents were used directly as obtained commercially.
Column chromatography was performed with silica gel (200–300
mesh) and analytical TLC on silica GF254. Melting points were
measured using a melting point instrument and are uncorrected.
1H NMR and 13C NMR spectra were recorded on a 400 MHz NMR
spectrometer. IR spectra were obtained with an infrared spec-
trometer on either potassium bromide pellets or liquid films
between two potassium bromide pellets. GC–MS data were
obtained using electron ionization. HRMS was carried out on a
high-resolution mass spectrometer (LCMS-IT-TOF).
2.1. General procedure for 3aa
A mixture of benzamidine hydrochloride 1a (0.25 mmol),
cinnamaldehyde 2a (0.30 mol) and KOH (0.50 mmol, 2 equiv.)
was stirred in DMSO (1.0 mL) under 1 atm O2 atmosphere at 120 8C
for 12 h. After completion of the reaction (monitored by TLC),
water (10 mL) was added to the reaction mixture, and the resulting
mixture was extracted with ethyl acetate. The combined organic
layers were then dried over MgSO4, filtered, and then concentrated
in vacuo. The residue was purified by flash chromatography on
silica gel to give the desired product 3aa as a white solid (using the
mixture of petroleum ether and ethyl acetate as eluents). Yield:
0.045 g (78%), mp 63–65 8C; IR (KBr, cmꢀ1):
1383, 1182, 1068, 1030, 747, 691; 1H NMR (400 Hz, CDCl3):
8.78–8.77 (m, 1H), 8.59–8.58 (m, 2H), 8.19–8.18 (m, 2H), 7.52–7.49
(m, 7H); 13C NMR (100 Hz, CDCl3):
164.59, 163.87, 157.86,
137.91, 136.96, 131.01, 130.78, 128.97, 128.59, 128.36, 127.24,
n 3064, 1563, 1422,
d
d
Please cite this article in press as: W. Guo, Base mediated direct C–H amination for pyrimidines synthesis from amidines and
cinnamaldehydes using oxygen as green oxidants, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.012

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W. Guo / Chinese Chemical Letters xxx (2015) xxx–xxx
3
Table 1
effects of the aromatic ring. In addition, polysubstituted cinna-
maldehydes also gave satisfied results (3aj–3ak). (E)-3-(Furan-2-
yl)acrylaldehyde (2l) also produced the desired products in fair
yields. To our delight, (E)-3-(naphthalen-1-yl)acrylaldehyde could
give the corresponding product in 64% yield (3am). Interestingly,
the transformation of (E)-2-methyl-3-phenylacrylaldehyde pro-
ceeded efficiently under the optimized conditions affording the
desired product (3an) in a moderate yield. In particular, (E)-
chalcone delivered the products (3ao) in 83% yield, which might be
Selected optimization studies.a
N
O
NH
O2
N
H
NH2 HCl
+
base, DMSO
3aa
1a
2a
Base
Entry
Solvent
Yield (%)b
1
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
1,4-dioxane
<5
24
2
NaHCO3
Li2CO3
Na2CO3
K2CO3
CH3COONa
CH3COOK
Cs2CO3
KOH
attributed to the formation of macro
promoting the amination process.
p-conjugation bonds,
3
36
4
67
To further expand the substrate scope, the substrates
benzamidines were investigated (Fig. 2). To our satisfaction, both
electron-donating and electron-withdrawing groups attached
benzamidines were all suitable for this protocol, and provided the
corresponding products in 61–77% yields (3ba–3ia). Gratifyingly,
72% yield of 3ja was observed when isonicotinamidine was used
in this amination reaction. Non-aromatic amidines were also
tolerated well, delivering the desired products (3ka–3ma) in
moderate to good yields. It is worth noting that an important
pharmaceutical intermediates (3la) [13] was successful obtained
from guanidine and cinnamaldehyde. The product provides an
opportunity for further selective function at amino group in
pharmaceuticals/agrochemicals design.
5
71
6
61
7
66
8
89
9
84 (78)
Trace
13
10c
11
12
13
14
15
KOH
Et3N
DBU
0
DABCO
KOH
0
Trace
0
KOH
a
Reaction conditions: Unless otherwise noted, all reaction were performed with
1a (0.25 mmol), 2a (0.30 mmol) and base (2 equiv.) in a 1.0 mL DMSO under 1 atm O2
atmosphere at 120 8C for 12 h.
b
GC yield based on 1a with n-dodecane as an internal standard. The data in
parentheses is the yield of the isolated product.
Based on the above-mentioned experimental observations and
previous report [14], we proposed the mechanism for the reaction
c
At N2 atmosphere.
Fig. 1. Scope of cinnamaldehydes substrates. Reaction conditions: 1a (0.25 mmol), 2 (0.30 mmol) and KOH (2 equiv.) in a 1.0 mL DMSO under 1 atm O2 atmosphere at 120 8C
for 12 h. Isolated yield based on 1a.
Fig. 2. Scope of amidines substrates. Reaction conditions: 1 (0.25 mmol), 2a (0.30 mmol) and KOH (2 equiv.) in a 1.0 mL DMSO under 1 atm O2 atmosphere at 120 8C for 12 h.
Isolated yield based on 1.
Please cite this article in press as: W. Guo, Base mediated direct C–H amination for pyrimidines synthesis from amidines and
cinnamaldehydes using oxygen as green oxidants, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.012

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Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2015.09.012.
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´
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4. Conclusion
In conclusion, we have developed the facile synthesis of
pyrimidine derivatives by a simple based mediated direct C–H
amination of amidines and cinnamaldehydes to afford polysub-
stituted pyrimidines using molecular oxygen as green oxidant. This
greener synthetic methodology provides a straightforward ap-
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We are grateful to the China Postdoctoral Science Foundation
Funded Project (No. 2014M562165), Jiangxi Natural Science
Foundation (Nos. 20133BCB24011, 20141BBG70070 and
20151BAB203011) and the Science Foundation of Jiangxi Provin-
cial Department of Education (No. Gjj4669) for support of this
research.
Please cite this article in press as: W. Guo, Base mediated direct C–H amination for pyrimidines synthesis from amidines and
cinnamaldehydes using oxygen as green oxidants, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.09.012