Efficient Synthesis of Polyfunctionalized Pyrimidine Derivatives

Article abstract of DOI:10.1055/s-0035-1561381

A simple and direct procedure was developed for the synthesis of a novel series of polyfunctionalized pyrimidines. They were prepared via reaction of N-(substituted carbamothioyl)benzimidamides (prepared from the reaction of benzimidamide hydrochloride an

Full text of DOI:10.1055/s-0035-1561381

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
M. Mahdavi et al.
Letter
Synlett
Efficient Synthesis of Polyfunctionalized Pyrimidine Derivatives
Mohammad Mahdavia
NH2
Hossein Kianfardb
Mina Saeedic,d
Parviz Rashidi Ranjbarb
Abbas Shafiee*e
S
CN
NH
NC
CN
N
R
DMF, 80 °C
CuBr, NEt3
2 h
N
N
Ph
H
H
Ph
N
NH
R
10 examples
60–85%
R = Ph, 2-MeC6H4, 4-MeC6H4, 4-MeOC6H4,
2-FC6H4, 4-FC6H4, 2-ClC6H4, 3-BrC6H4,
4-Me2NC6H4, Me
a Drug Design and Development Research Center, Tehran Uni-
versity of Medical Sciences, Theran, Iran
b School of Chemistry, College of Science, University of Tehran,
PO Box 14155-6455, Tehran, Iran
c Medicinal Plants Research Center, Faculty of Pharmacy, Tehran
University of Medical Sciences, Tehran, Iran
d Persian Medicine and Pharmacy Research Center, Tehran
University of Medical Sciences, Tehran, Iran
e Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
ashafiee@ams.ac.ir
Received: 16.10.2015
Accepted after revision: 20.01.2016
Published online: 17.03.2016
dines have been established. In this regard, microwave-as-
sisted condensation of cyanic acid derivatives with N-
vinyl/aryl amides in the presence of SmCl3,9 the coupling of
acid chlorides with terminal alkynes in the presence of Et3N
followed by the reaction of amines or amidinium salts,10
and reaction of N-vinyl tertiary enamide and isocyanides
using Tf2O11 have been successfully developed.
In recent years, using isothiocyanates as a versatile
starting material has been developed for the synthesis of
various heterocyclic compounds.12–14 At this juncture, syn-
thesis of nonsulfur heterocycles needs efficient desulfuriz-
ing agents such as HgCl2,15,16 molecular iodine,17–23 DCC,24
CuCl,25 and CuI26 were found to be effective in various or-
ganic transformations including a desulfurization step. In
this work, focusing on the efficiency of isothiocyanates and
in continuation of our research program on the synthesis of
novel heterocycles,27 we describe an efficient procedure for
the preparation of novel polyfunctionalized pyrimidines 5
through the reaction of N-(substituted carbamothioyl)ben-
zimidamides 3 and malononitrile (4) in the presence of
CuBr/Et3N in DMF at 80 °C (Scheme 1).
For the preparation of desirable pyrimidine derivatives
5, the required starting materials, N-(substituted carba-
mothioyl)benzimidamides 3 were prepared from the reac-
tion of benzimidamide hydrochloride (1) and isothiocya-
nates 2 (Scheme 1). For this purpose, reaction of equivalent
amounts of benzimidamide hydrochloride (1) and isothio-
cyanates 2 in the presence of a twofold amount of Et3N in
acetonitrile at room temperature gave the corresponding
compounds in good yield (75%).28 Next, reaction of com-
pound 3 and malononitrile (4) was investigated under vari-
ous conditions.
DOI: 10.1055/s-0035-1561381; Art ID: st-2015-b0821-l
Abstract A simple and direct procedure was developed for the synthe-
sis of a novel series of polyfunctionalized pyrimidines. They were pre-
pared via reaction of N-(substituted carbamothioyl)benzimidamides
(prepared from the reaction of benzimidamide hydrochloride and iso-
thiocyanates) and malononitrile in the presence of CuBr/Et3N in DMF at
80 °C.
Key words pyrimidines, heterocycles, isothiocyanates, malononitrile
Pyrimidine and its derivatives1 are of great importance
in nature since they are ubiquitous in many natural prod-
ucts such as vitamin B1.2 Also, they are present in a broad
spectrum of synthetic biologically active derivatives such as
uramustine, floxuridine, and fluorouracil (antineoplastic
agents), piromidic acid, tetroxoprim, and metioprim (anti-
bacterial agents), flucytosine (antifungal agent), idoxuri-
dine and broxuridine (antiviral agents), piribedil (antipar-
kinsonian agent), and tisopurine (antihyperuricaemia
agent).3 Pyrimidines are considered as an integral part of
the nucleic acid structure which plays an important role in
various biological processes.4 Also, metal complexes of py-
rimidine moiety have shown antimicrobial and antibacteri-
al activities.5 Therefore, pyrimidines would be a major can-
didate for the challenge of modern drug-discovery research,
and efficient methods for the synthesis of versatile deriva-
tives are still in demand.
Pyrimidines are usually synthesized through cyclization
reaction of β-dicarbonyl derivatives with N–C–N com-
pounds including amidines, ureas, and guanidines.6 In this
regard, i) reaction of aromatic aldehydes, ketones, and
guanidine carbonate,7 as well as ii) Biginelli-type multicom-
ponent reactions8 have been largely considered in the liter-
ature. Recently, novel methods for the synthesis of pyrimi-
Firstly, N-(phenylcarbamothioyl)benzimidamide (3a)
was selected as a model substrate, and its reaction with
malononitrile (4) was screened in a range of solvents and
desulfurizing agents at different temperature levels (Table
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
M. Mahdavi et al.
Letter
Synlett
NH2
NC
CN
NH
S
CN
NH
MeCN, r.t., 3 h
Et3N
4
N
+
R
NCS
R
Ph
NH2
N
N
Ph
DMF, 80 °C
CuBr, Et3N
2 h
2
H
H
Ph
N
NH
R
HCl
5
1
3
Scheme 1 Synthesis of novel pyrimidine derivatives 5
1). As reported in Table 1, the model reaction was conduct-
ed in the presence of different copper salts such as CuBr,
CuBr2, CuI, as well as HgCl2, EDCI, and AgNO3. Our results re-
vealed that HgCl2 and CuBr were more effective than the
other reagents and promoted the cyclization reaction effi-
ciently. Clearly, CuBr was the best choice due to the mercu-
ry toxicity, in spite the fact that HgCl2 gave better yield (Ta-
ble 1, entries 1 and 2).
To obtain the best yield, the model reaction was investi-
gated in the presence of various amounts of CuBr. It was
found that an equivalent amount of CuBr was sufficient and
higher amounts did not lead to better conditions. The im-
portant thing is related to the necessity of using base in the
reaction.
product. Also, various organic solvents such as DMF, di-
chloromethane, toluene, and THF were examined, and DMF
was found to be the more effective medium. Temperature
screening revealed that the model reaction proceeded slow-
ly at room temperature and when it was heated at 80 °C,
the corresponding product 5a was obtained in 85% yield.
With these results in hand, various N-(substituted car-
bamothioyl)benzimidamides 3a–j were reacted with malo-
nonitrile (4) under the optimized conditions to obtain dif-
ferent polyfunctionalized pyrimidines 5 (Table 2). All sub-
strates possessing electron-rich as well as electron-poor
substituents underwent the cyclization reaction leading to
the formation of the related products 5 within two hours in
good yields. All products were characterized using IR and
NMR spectroscopy as well as elemental analysis.
It was revealed that a fourfold amount of Et3N was nec-
essary to give the corresponding product 5a in good yield,
and using lower amounts of base led to the lower yield of
Table 1 Effect of Various Conditions on the Reaction of N-(Phenylcarbamothioyl)benzimidamide (3a) and Malononitrile (4) for Obtaining Product 5a
NH2
NC
CN
CN
S
NH
NH
4
MeCN, r.t., 3 h
Et3N
N
Ph NCS
Ph
+
N
N
Ph
various conditions
Ph
NH2
Ph
N
NH
Ph
H
H
2a
HCl
5a
3a
1
Entry
Solvent
Reagenta
Temp
80 °C
Time (h)
Yield (%)b
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
HgCl2
CuBr
CuI
2
2
2
2
2
2
3
3
3
2
3
3
3
95
85
60
n.r.c
50
n.r.c
10
40
85
85
50
40
25
80 °C
80 °C
80 °C
80 °C
80 °C
r.t.
3
4
CuBr2
EDCI
AgNO3
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
5
6
7
8
40 °C
80 °C
100 °C
reflux
reflux
reflux
9
10
11
12
13
toluene
CH2Cl2
a All reactions were performed in the presence of an equivalent amount of desulfurizing agent.
b Isolated yields.
c No reaction.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
M. Mahdavi et al.
Letter
Synlett
Table 2 Synthesis of Polyfunctionalized Pyrimidines 5
NH2
NC
CN
NH
S
4
CN
NH
MeCN, r.t., 3 h
Et3N
N
R
NCS
+
R
DMF, 80 °C
CuBr, Et3N
Ph
NH2
N
N
Ph
2
H
H
Ph
N
NH
R
HCl
5
1
3
2 h
Entry
R
Product 5
Yield (%)a
1
2
Ph
5a
5b
5c
5d
5e
5f
85
72
74
76
63
64
67
70
78
60
2-MeC6H4
4-MeC6H4
4-MeOC6H4
2-FC6H4
3
4
5
6
4-FC6H4
7
2-ClC6H4
3-BrC6H4
4-Me2NC6H4
Me
5g
5h
5i
8
9
10
5j
a Isolated yields.
The proposed mechanism is shown in Scheme 2. Loss of
CuS from the activated intermediate 6 gives carbodiimide
intermediate 7. It is attacked by malononitrile (4) in the
presence of Et3N to obtain 8 which is in equilibrium with
intermediate 9. Next, intramolecular cyclization of the in-
termediate 9 following tautomerization of the intermediate
10 leads to the formation of title compounds 5.
During our investigations, focusing on the efficiency of
molecular iodine as a desulfurizing agent, the model reac-
tion was achieved in the presence of I2 (Scheme 3). Interest-
ingly, the desired product 5a was not obtained. Our results
revealed that a different synthetic route as reported in the
literature17 proceeded and N-{benzo[d]thiazol-2-yl}ben-
zimidamide (11) was the main product.
Analysis of spectroscopic data revealed that malononi-
trile (4) did not participate in the reaction. It seems that the
deprotonation of 3a gave intermediate 12, in equilibrium
with intermediate 13, which underwent an intramolecular
substitution to form thiazole ring 14 followed by proton
transfer to afford compound 11 (Scheme 3).
In conclusion, we have developed an efficient strategy
for the preparation of a novel series of polyfunctionalized
pyrimidines through the reaction of N-(substituted carba-
mothioyl)benzimidamides (prepared from the reaction of
benzimidamide hydrochloride and isothiocyanates) and
malononitrile in the presence of CuBr/Et3N in DMF at 80 °C.
A practical and easy approach for the preparation of novel
polyfunctionalized pyrimidines makes this work beneficial
N
Cu Br
NC
NH
S
Cu
N
NH
CN
CN
NH
S
NH
NH2
R
N
N
C
Ph
R
R
R
N
H
N
H
Ph
R
N
N
N
Ph
N
H
N
Ph
Ph
7
H
H
–
6
9
NEt3
3
CuS
8
NC
CN
NEt3
4
NH2
NH
CN
N
CN
HN
Ph
N
NH
R
Ph
N
NH
R
5
10
Scheme 2 Proposed mechanism for the formation of product 5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
M. Mahdavi et al.
Letter
Synlett
NC
CN
I–
I
I
4
I
I
NH
HN
NH
+S
S
S
NH
NH
DMF, 80 °C
I2, Et3N
2 h
Ph
S+
Ph
N
H
N
N
N
N
H
Ph
Ph
N
Ph
H
H
H
N
H
12
13
NEt3
3a
14
NH
HN
Ph
S
N
11
Scheme 3 Investigation of the model reaction in the presence of I2
for both organic and medicinal chemists to develop novel
pyrimidine-based drugs. Also, it was found that if the reac-
tion was conducted in the presence of molecular iodine, a
different synthetic route proceeded and N-benzo[d]thiazole
was obtained.
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Acknowledgment
This research was supported by grants from the research council of
Tehran University of Medical Sciences and Iran National Science
Foundation (INSF).
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http://dx.doi.org/10.1055/s-0035-1561381.
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