Metal-free synthesis of pyridin-2-yl ureas from 2-aminopyridinium salts

Article abstract of DOI:10.1016/j.tetlet.2019.07.030

An unprecedented base promoted domino approach has been developed for the synthesis of pyridin-2-yl urea derivatives via the reaction of 2-aminopyridinium salts and arylamines. The developed strategy tolerated a wide range of functional groups and afforded pyridin-2-yl ureas in moderate to good yields. The reaction was postulated to involve tandem cyclization, intermolecular nucleophilic addition, ring opening, and demethylation.

Full text of DOI:10.1016/j.tetlet.2019.07.030

Accepted Manuscript
Metal-Free Synthesis of Pyridin-2-yl Ureas from 2-Aminopyridinium Salts
Saroj, Om P.S. Patel, Krishnan Rangan, Anil Kumar
PII:
S0040-4039(19)30688-4
https://doi.org/10.1016/j.tetlet.2019.07.030
TETL 50939
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 April 2019
12 July 2019
15 July 2019
Please cite this article as: Saroj, Patel, O.P.S., Rangan, K., Kumar, A., Metal-Free Synthesis of Pyridin-2-yl Ureas
from 2-Aminopyridinium Salts, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.07.030
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Tetrahedron Letters
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Metal-Free Synthesis of Pyridin-2-yl Ureas from 2-Aminopyridinium Salts
Saroj,a Om P. S. Patel,a Krishnan Rangan,b and Anil Kumar*,a
aDepartment of Chemistry, BITS Pilani, Pilani Campus, Pilani 333031, Rajasthan, India.
bDepartment of Chemistry, BITS Pilani, Hyderabad Campus, Secunderabad 500078, Telangana, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An unprecedented base promoted domino approach has been developed for the synthesis of
pyridin-2-yl urea derivatives via the reaction of 2-aminopyridinium salts and arylamines. The
developed strategy tolerated a wide range of functional groups and afforded pyridin-2-yl ureas in
moderate to good yields. The reaction was postulated to involve tandem cyclization,
intermolecular nucleophilic addition, ring opening, and demethylation.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Metal-free
Tandem reaction
Pyridyl urea
2-Aminopyridinium salts
2-Aminopyridine
Urea derivatives have been investigated for an array of
biological activities including antimicrobial,1 antitubercular,2
antimalarial,3 antiviral,4 and anticancer.5 Substituted ureas with
an attached heterocyclic ring system represent an important motif
in medicinal chemistry.6 In particular, ureas bearing a pyridin-2-
yl ring (I and II) are key scaffolds in the development of
glucokinase activators (GKAs) for the treatment of type-2-
diabetes mellitus (T2DM) (Fig. 1).7 Pyridin-2-yl substituted urea
Due to the valuable role of pyridyl ureas in drug discovery,
there has been significant focus toward the development of
efficient, practical and novel synthetic routes for the preparation
of substituted ureas (Scheme 1). Traditionally, pyridyl ureas are
synthesized via the reaction of aminopyridines and amines with
phosgene11 or isocyanates,10 which are usually highly toxic,
moisture sensitive and generate large amounts of halide
containing waste. Later, transition metal-catalyzed cross coupling
approaches were developed for the synthesis of pyridyl ureas via
the reaction of halopyridines and unsubstituted urea.12 Selenium-
catalyzed oxidative carbonylation approaches were also
developed for the synthesis of pyridyl ureas by employing a
mixture of toxic carbon monoxide and oxygen.13 Kukushkin and
co-workers reported the methane sulfonic acid promoted
synthesis of pyridin-2-yl substituted ureas from pyridine N-
oxides (PyO) and dialkylcyanamides.14 Recently, Mahajan and
co-workers reported the synthesis of N-substituted ureas via the
reaction of amines with potassium isocyanate in water without an
organic co-solvent.15 Although there has been marked progress
towards the synthesis of substituted pyridyl ureas, their synthesis
under environmentally benign and mild reaction conditions
remains a topic of interest.
VU0463841 (III) was identified as
a negative allosteric
modulator (NAM) of metabotropic glutamate receptor subtype 5
(mGlu5).8 Omecamtiv mecarbil (IV) is being studied in Phase 3
clinical trials as a selective cardiac myosin activator of cardiac
myosin to determine its effectiveness for the treatment of heart
failure with reduced ejection fraction.9 Pyridin-2-yl urea
derivative V has been reported as a new class of antibacterial
agent targeting bacterial topoisomerase binding targets.10
N
Me
Me
N
H
H
O
N
N
CN
H
H
H
H
N
N
N
N
O
Me
Me
N
O
Cl
N
O
N
II
O
MeO
S
F
III
VU0463841, NAM of mGlu5
Me
HO
I
O
N
AM-2394
Me
H
H
F
N
N
N
H
H
HN
N
N
N
In continuation of our research interests toward developing
synthetic transformations using 2-aminopyridinum salts,16 herein,
we report an unprecedented approach for the synthesis of pyridin-
2-yl urea derivatives from 2-amino-1-ethoxycarbonyl-
methylpyridium bromides (Scheme 1). The method involves
tandem cyclization, intermolecular nucleophilic addition, ring
opening, and demethylation to give pyridin-2-yl ureas in
moderate to good yields under mild and transition metal-free
conditions.
O
O
O
O
N
Me
N
N
S
N
N
OMe
IV
V
Omecamtiv Mecarbil
O
CF3
Figure 1. Representative bioactive pyridyl ureas.
__________________
*Corresponding author
Email: anilkumar@pilani.bits-pilani.ac.in
Fax: +91-1596-244183, Ph: +91-1596-515663

2
Previous work
O
With the optimized reaction conditions in hand (Table 1,
+
ArX
X = NH2 or NO2
NH2
ArHN
X
+
entry 16), we then explored the substrate scope and generality of
this reaction (Table 2). The reaction of 1a with aryl amines (2a-
h) possessing methyl, methoxy, fluoro, chloro, and bromo
substituents afforded the corresponding ureas 4aa-ah in moderate
to good yields (32-68%). The yields were relatively lower for
halogen-substituted aryl amines which can be attributed to their
lower nucleophilicity. Similarly, the reaction of 2-
aminopyridinium salts processing chloro, bromo, methyl, phenyl,
4-methoxyphenyl, and 4-chlorophenyl substituents on the
pyridine ring (1b-i) with aniline (2a) afforded the corresponding
ureas 4ba-ia in 36-62% yield. Higher yields were obtained using
2-aminopyridinium salts possessing electron-donating groups on
the pyridine ring. The reaction of substituted pyridinium salt 1d
with the substituted anilines 4-methoxyaniline (2c) and 4-
bromoaniline (2f) gave ureas 4dc and 4df in 65% and 50%
yields, respectively. Similarly, the reaction of other substituted
pyridinium salt 1e with 2c and 2f gave ureas 4ec and 4ef in 51%
and 29% yield, respectively.
N
+
NH2
ArNCO
N
NH2
N
Cu or Pd
Ligands
e
S
O2
+
O
C
O
Phosgene
MeSO3H
R
CN
+
ArNH2
N
R
+
N
N
NHAr/R
N
NH2
N
O
H
K3PO4 ( 2.5 equiv.)
DMF, 100 °C, 20 h
This work
ArNH2
+
N
NH2
OEt
Br
O
Scheme 1. Reported methods and our approach for the synthesis of
pyridin-2-yl ureas.
Initially, we were interested in developing a novel method for
the synthesis of 3-aminoaryl-imidazopyridines from 2-
aminopyridinium salts. To test our hypothesis, 2-
aminopyridinium salt (1a) and 4-methoxyaniline (2c) were
treated with CuI (10 mol %) and K3PO4 (1.5 equiv.), at 100 C in
DMSO (3 mL). Surprisingly, instead of the expected 3-
Table 1. Optimization of the reaction conditions.a,b
aminoarylimidazopyridine
(3ac),
we
obtained
1-(4-
OCH3
O
Base
N
NH2
OEt
methoxyphenyl)-3-(pyridin-2-yl) urea (4ac) in 20% yield
H2N
OCH3
Br
Solvent, temp., 20 h
N
N
N
(Scheme 2). The structure of 4ac was established using H, 13C
1
H
H
1a
2c
4ac
O
NMR, ESI-HRMS, and IR spectroscopic analysis (see ESI). The
appearance of a strong peak at 1689 cm-1 (C=O stretch) along
with two peaks at 3209 and 3124 cm-1 (N-H stretch) in the IR
spectrum suggested the presence of an amidic/urea functional
group. The presence of two singlets at 10.42 and 9.38 ppm for
Temp.
(C)
Yield
(%)b
4ac
Entry Base
Solvent
1
2
3
4
5
6
7
8
9
K3PO4
KOH
K2CO3
tBuOK
Cs2CO3
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
100
100
100
100
100
100
100
100
100
35
22
20
23
33
15
1
D2O exchangeable protons along with other protons in the H
NMR spectrum and a peak at 155.4 ppm in the 13C NMR
spectrum also suggested the presence of disubstituted urea
functionality. Finally, a peak at m/z 244.1084 in the ESI-HRMS
analysis corresponding to the molecular formula C13H13N3O2
confirmed the structure of 4ac.
NEt3
Trace
Trace
50
Piperidine DMSO
K3PO4
DMF
1,4-
Dioxane
Toluene
DCE
MeCN
H2O
DMF
N
NH2
OH
OCH3
N
CuI (10 mol%)
O
10
K3PO4
100
23
K3PO4 (1.5 equiv.)
N
NH2
OEt
NH
Br
N
N
N
H
X
DMSO, 110 oC, 20 h
H
11
12
13
14
15 c
16 d
17 e
18 d
19 d
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
100
100
100
100
100
100
100
120
80
17
24
29
25
57
63
62
42
46
OMe
O
4ac
, 20%
MeO
1a
3ac
2c
Scheme 2. Synthesis of 1-(4-methoxyphenyl)-3-(pyridin-2-yl) urea
4ac.
DMF
DMF
DMF
Encouraged by the unexpected, but remarkable result for the
reaction of 1a and 2c, we systematically screened other reaction
parameters to improve the yield of 4ac (Table 1). Interestingly, a
slightly improved yield (35%) was obtained in the absence of
CuI, indicating that the reaction is mediated only by the base and
CuI has no role (Table 1, entry 1). Next, we screened different
inorganic and organic bases (Table 1, entries 1-8) and found that
K3PO4 was the most suitable base. We then investigated the
effect of solvents on the reaction using K3PO4 as the base. To our
satisfaction, 4ac was obtained in 50% yield in DMF, whereas
other organic solvents such as 1,4-dioxane, toluene, DCE,
MeCN, and water gave lower yields (Table 1, entries 9-14). Next,
we examined the K3PO4 loading (Table 1, entries 15-17).
Increasing the amount of K3PO4 from 1.5 equivalents to 2.5
equivalents resulted in an increased yield. Further increasing the
K3PO4 amount from 2.5 equivalents to 3.0 equivalents did not
DMF
aReagents and conditions: 1a (1.2 mmol), 2c (1.0 mmol), base
(1.8 mmol), solvent (3 mL), 20 h.
bIsolated yield.
c2.4 mmol K3PO4 was used.
d3.0 mmol K3PO4 was used.
e3.6 mmol K3PO4 was used.
The structures of all the synthesized pyridin-2-yl ureas were
established using IR, 1H NMR, 13C NMR, and ESI-HRMS
analysis. The structure of 4ab was further confirmed by single
crystal X-ray (CCDC No. 1852803) analysis (Fig. 2).
significantly effect the yield.
Finally, the effect of the
temperature was evaluated (Table 1, entries 18-19). Lower yields
were obtained upon increasing or decreasing the reaction
temperature.

3
Figure 2. ORTEP diagram and the atomic numbering of 4ab.
intermediate 10ac (observed by ESI-MS) after ring opening.
Displacement ellipsoids are drawn at the 50% probability level.
Intermediate 10ac undergoes demethylation with the assistance
of base18 to give the desired product 4ac.
Table 2. Substrate scope for the synthesis of pyridin-2-yl ureas.a,b
Radical scavenger
K3PO4 (2.5 equiv.)
NH2
R1
OCH3
+
O
H3CO
N
N
(i)
R1
Br
R2
N
NH2
OEt
+
O
OCH3
K3PO4 (2.5 equiv.)
DMF, 100 °C,
20 h
R2
Br
N
N
N
N
NH2
OEt
H2N
H
H
4ac
5
N
N
N
DMF, 100 °C,
20 h
OCH3
O
H
H
a) TEMPO (5.0 equiv.)
b) BHT (5.0 equiv.)
c) DPE (5.0 equiv.)
60%
45%
55%
8%
trace
trace
1a
2c
1
O
4
2
CH3
OCH3
O
O
O
Optimized conditions
(ii)
N
2c
N
4ac
+
+
N
N
N
N
N
N
N
N
H
HBr
N
N
N
30%
6a
H
H
H
H
H
O
4ac,
63%
4ab,
68%
4aa,
54%
Br
CH3
Optimized conditions
F
(iii)
(iv)
O
4ac
N
2c
O
N
O
O
43%
N
N
N
H
6a
N
N
CH3
N
N
H
N
H
H
H
H
Optimized conditions
4af,
CH3
O
42%
OEt
O
HN
OCH3
4ae,
49%
4ad,
2c
47%
+
Br
+
+
4ac
N
NH2
CH3
Cl
Cl
O
trace
O
EtO
O
7
8
9,
70%
N
N
N
H
N
N
H
N
H
N
N
H
K3PO4 (2.5 equiv.)
DMF, 100 °C, 3 h
H
H
2c
Br
(v)
+
8
N
NH2
OEt
7
4ba,
Br
45%
4ac
42%
CH3
4ah,
32%
O
4ag,
36%
17 h
Br
H3C
1a
O
O
O
N
N
N
H
O
N
N
H
N
N
N
H
N
O
K3PO4 (2.5 equiv.)
DMF, 100 °C, 10 h
H
H
(vi)
H
N
N
H
N
I-
N
N
N
H3CO
4ca,
4da,
4ea,
H
51%
O
62%
40%
H
H
Me
10aa
4aa,
46%
Cl
Ph
O
O
N
N
H
N
H
N
N
H
N
H
Scheme 3. Control experiments
N
N
H
N
H
Cl
4ga,
47%
O
4ha,
38%
4fa,
47%
H3C
OCH3
H3C
OCH3
O
Br
O
N
N
H
N
H
H2N
N
N
H
N
H
N
K3PO4
N
H
2c
N
NH2
OEt
N
N
H
N
H
O
HBr
O
Br
N
N
4ia,
4dc,
OCH3
36%
65%
Br
4df,
Br
50%
Br
Br
6a
O
O
O
1a
6a


Observed in ESI-MS
[M+H]+ = 135.0549
H3CO
N
N
H
N
N
N
N
H
H
H
4ec,
51%
4ef,
29%
aReagents and conditions: 1 (1.2 mmol), 2 (1.0 mmol), K3PO4
(3.0 mmol), DMF (3 mL), 100 C, 20 h.
bIsolated yield.
OCH3
H
N
OCH3
O
NH
O
O
base
demethylation
N
N
N
N
H
N
N
N
H
Br
H
H
Br
CH3
H
10ac
4ac
B
Observed in ESI-MS
[M-Br]+ = 259.1370
Next, a set of control experiments was performed to
investigate the mechanistic pathway (Scheme 3). Initially, we
performed the reaction in the presence of radical scavengers such
as TEMPO, BHT, and DPE under the optimized reaction
conditions. Product 4ac was obtained in 60%, 45% and 55%
yield, respectively (Scheme 3, entry i). The fact that there was
little or no significant change in the product yields indicated
absence of a radical-mediated pathway. The reaction of cyclic
amide 6a′ and 6a′′ with 2c under the optimized reaction
conditions gave 4ac in 30% and 43% yield, respectively (Scheme
3, entry ii and iii). Next, the one-pot, multicomponent reaction of
2-aminopyridine (7), ethyl bromoacetate (8) and 2c under the
Scheme 4. Proposed mechanism.
An unprecedented transition metal-free strategy has been
developed for the synthesis of pyridin-2-yl ureas from simple and
nontoxic 2-aminopyridinium salts under mild reaction conditions.
The developed method tolerated various functional groups and
resulted in the formation of aryl substituted pyridin-2-yl ureas in
moderate to good yields.
Acknowledgments
optimized
reaction
conditions
gave
ethyl
(4-
The authors sincerely acknowledge financial support [Project
EMR/2016/002242] by the Science and Engineering Research
Board (SERB), New Delhi to carry out this work. Saroj is
grateful to CSIR, New Delhi, India for the senior research
fellowship and O.P.S. Patel is thankful to SERB-New Delhi for
methoxyphenyl)glycinate (9) in 70% yield along with trace
amounts of the desired product 4ac observed by TLC (Scheme 3,
entry iv). The one-pot, sequential reaction of 7 with 8, followed
by the addition of 2c gave the desired product 4ac in 42% yield
(Scheme 3, entry v). Finally, we prepared 1-methyl-2-(3-
phenylureido)pyridin-1-ium iodide (10aa) via the reaction of
4aa with methyl iodide following a literature method.17 The
reaction of 10aa under the optimized conditions led to the
formation of 4aa in 46% yield (Scheme 3, entry vi). This
further indicated that 10 may be a possible intermediate in
this transformation.
the
national
post-doctorate
fellowship
(File
No.
PDF/2017/001910). The authors also sincerely acknowledge
DST-FIST [SR/FST/CSI-270/2015] for the use of the HRMS
facility and Central Analytical Lab, BITS Pilani for the use of the
NMR and single crystal XRD facility.
Supplementary Material
Although a detailed mechanism for this reaction remains to be
investigated, on the basis of control experiments and literature
precedence18 a plausible mechanism is depicted in Scheme 4.
First, the 2-aminopyridinium salt undergoes intramolecular
nucleophilic substitution in the presence of a base to form cyclic
amide intermediate 6a′ (observed by ESI-MS). Intermediate 6a′
further undergoes intermolecular nucleophilic attack of aniline to
form hemiaminal intermediate B, which may generate
Supplementary material [materials & methods, experimental
procedures, NMR (1H and 13C), HRMS and X-ray data] for this
article
can
be
found
online
at
https://doi.org/10.1016/j.tetlet……..

4
McVean, M.; Rhodes, S. P. J. Med. Chem. 57 (2014) 8180-
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Metal-Free Synthesis of Pyridin-2-yl Ureas
from 2-Aminopyridinium Salts
Leave this area blank for abstract info.
Saroj, Om P. S. Patel, Krishnan Rangan, and Anil Kumar
Department of Chemistry, BITS Pilani, Pilani Campus, Pilani 333031, Rajasthan, India.
Department of Chemistry, BITS Pilani, Hyderabad Campus, Secunderabad 500078, Telangana, India
R1
R1
O
R2
K3PO4 (2.5 equiv)
R2
N
NH2
OEt
+
N
N
N
H2N
Br
DMF, 100 C
H
H
20 examples
upto 68% yield
Transition metal-free
domino approach
O
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Graphical
Abstract
 Good to moderate (29-66%) yields of
pyridin-2-yl urea derivatives.
Highlights
 Tandem
intramolecular
cyclization,
nucleophilic addition and demethylation.
 Metal-free, base mediated synthesis of
pyridin-2-yl urea derivatives.