Convenient entry to N-pyridinylureas with pharmaceutically privileged oxadiazole substituents via the acid-catalyzed C[sbnd]H activation of N-oxides

Article abstract of DOI:10.1016/j.tetlet.2019.151108

Pyridine-N-oxides bearing a pharmacophoric oxadiazole moiety could be C[sbnd]H functionalized via the acid-catalyzed reaction with dialkylcyanamides, providing access to hitherto undescribed pyridine-2-yl substituted ureas, which have potential as “lead-l

Full text of DOI:10.1016/j.tetlet.2019.151108

Tetrahedron Letters 60 (2019) 151108
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Tetrahedron Letters
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Convenient entry to N-pyridinylureas with pharmaceutically privileged
oxadiazole substituents via the acid-catalyzed CAH activation
of N-oxides
b
a
a,c
Kirill Geyl a, Sergey Baykov a, , Marina Tarasenko , Lev E. Zelenkov , Vladislava Matveevskaya
,
⇑
Vadim P. Boyarskiy a
a Institute of Chemistry, Saint Petersburg State University, Saint Petersburg 199034, Russian Federation
b Yaroslavl State Technical University, Yaroslavl 150023, Russian Federation
c Kizhner Research Center, National Research Tomsk Polytechnic University, Tomsk 634050, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2019
Revised 28 August 2019
Accepted 3 September 2019
Available online 4 September 2019
Pyridine-N-oxides bearing a pharmacophoric oxadiazole moiety could be CAH functionalized via the
acid-catalyzed reaction with dialkylcyanamides, providing access to hitherto undescribed pyridine-2-yl
substituted ureas, which have potential as ‘‘lead-like” scaffolds for medicinal chemistry. Atom-economy,
environmental friendliness (no halide-containing or toxic reagents), simple work-up, as well as scalabil-
ity are the main advantages of the employed procedure.
Ó 2019 Elsevier Ltd. All rights reserved.
Keywords:
Ureas
N-Oxides
Dialkylcyanamides
CAH activation
Introduction
co-workers found that the same process occurs between 2-methyl-
pyridine-N-oxide and dimethylcyanimide [27,28]. However, only
The capability of N-pyridinylureas to participate in hydrogen
bonding or anion binding with target enzymes makes them an
engaging pharmacophoric motif for drug discovery. This moiety is
incorporated into small molecules exhibiting various biological
activities, which are associated with therapeutic areas such as
oncology [1–7], age-related degenerative diseases [8–10], and
metabolic disorders including type II diabetes [11–15]. Moreover
N-pyridinylureas were recognized as antischistosomal [16] and
antibacterial [17,18] agents, as well as inhibitors of fatty acid
amide hydrolase (FAAH) – the validated target for the treatment
of a number of pathologies, including chronic pain, inflammation,
psychoses, depression, nausea, and vomiting [19–23].
N-oxides bearing a simple substituent (Me, MeO, halogen, NO2,
CN, COOMe) on the pyridine ring were investigated, whereas
medicinal chemistry is concerned with more complicated mole-
cules, particularly with a different heterocyclic periphery. The
1,2,4-oxadiazole ring represents one such privileged motif, as
reflected in numerous published medicinal chemistry studies
[29–34] and newly-marketed drugs (TranslarnaÒ [35], EdarbiÒ
[36]). 1,3,4-Oxadiazoles also have broad pharmaceutical applica-
tions [37–39], and in some ADMET parameters, is even more attrac-
tive than the 1,2,4-isomer [40,41]. In light of this, we studied the
acid-catalyzed CAH functionalization of pyridine-N-oxides bearing
1,2,4- and 1,3,4-oxadiazole substituents by dialkylcyanamides.
Disappointingly, the most straightforward route to ureas
involves the reaction of amines with toxic reagents such as
phosgene [24] or isocyanates [25], that leads to large amounts of
harmful halide-containing wastes. As a ‘‘greener” alternative,
Prokhorov and co-workers described the acid-catalyzed reaction
of 4-arylpyrimidine-1-oxides with cyanamide, which resulted in
the formation of the respective ureas [26]. Later Rassadin and
Results and discussion
Because the synthesis of the required oxadiazole-substituted
pyridine-N-oxides was not described, we first had to develop an
appropriate procedure for their preparation. Since strong acylation
(acyl chlorides, anhydrides) or dehydration (phosphorus oxychlo-
ride, thionyl chloride) reagents, which are commonly used for
oxadiazole ring formation [42–44], can react with highly reactive
N-oxides [45–47], we decide to initially assemble the oxadiazole
⇑
Corresponding author.
E-mail address: sergei.v.baikov@yandex.ru (S. Baykov).
https://doi.org/10.1016/j.tetlet.2019.151108
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
K. Geyl et al. / Tetrahedron Letters 60 (2019) 151108
Scheme 2. Synthesis of the 2-substituted pyridine-N-oxides.
core from pyridine containing precursors followed by N-oxidation.
The amidoxime [48,49] and tetrazole [50] routes were chosen for
the preparation of the 1,2,4-oxadiazole and 1,3,4-oxadiazole series,
respectively (Scheme 1).
Most of the 1,2,4-oxadiazole bearing pyridines were success-
fully converted into the corresponding N-oxides using H2O2 in
AcOH according to the literature method [28], while 1,3,4-oxadia-
zoles decomposed under these conditions. Therefore, m-CPBA in
CH2Cl2 was utilised for the N-oxidation of the 1,3,4-oxadiazole ser-
ies. The synthesis of pyridine-N-oxides containing a 1,2,4-oxadia-
zole moiety in the 2-position was the most difficult task. These
Scheme 1. Synthesis of the starting pyridine-N-oxides.
Table 1
Optimization of the reaction conditions.
Entry
2a (equiv.)
Solvent (20 equiv.)
Conversion of 1aa, % (isolated yield of 3a, %)
1
2
3
4
5
6
7
8
1.5
10.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
3.0
2.0
2.0
2.0
–
–
21
98 (68)
66
MeCN
MeCN
acetone
DMF
EtOH
AcOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
56b
53
13
35
24
9
98 (49)c
91 (54)d
80
10
11
12
13
14
15
83
98 (76)e
98 (59)f
85g
a
b
c
d
e
f
Conversion of the N-oxide was estimated by 1H NMR spectroscopy.
10 equiv. of MeCN was used.
Reaction mixture was heated at 80 °C.
Reaction time was 18 h.
1.5 equiv. of MsOH was used.
The reaction was performed with 4.5 mmol of 1a and 6.8 mmol of MsOH.
g
Microwave heating was used.

K. Geyl et al. / Tetrahedron Letters 60 (2019) 151108
3
compounds decomposed in H2O2/AcOH and were also not oxidized
by m-CPBA in CH2Cl2. Therefore, the reaction sequence was altered
and the N-oxidation was performed at the first stage. The subse-
quent oxadiazole core assembly was carried out under mild condi-
tions according to our previous developed procedures (Scheme 2)
[51–53].
3a was obtained in an improved isolated yield (76%) (Table 1, entry
13). The structure of product 3a was established by NMR spec-
troscopy and HRMS. In addition to 3a the N-oxide reduction pro-
duct – 5-methyl-3-(pyridin-4-yl)-1,2,4-oxadiazole – was isolated
(ꢀ10%) from the reaction mixture. We then studied the possibility
of increasing the reaction scale under these conditions. An increase
in the reagent amounts by 4.5 times (Table 1, entry 14) did not lead
to a noticeable decrease in the product yield, which indicates the
scalability of the proposed procedure.
Disappointedly, the acid-catalyzed CAH functionalization with
dialkylcyanamides reported by Rassadin and co-workers [28] was
not suitable in the case of oxadiazoles due to decomposition.
Therefore, we had to develop a new methodology. Initial optimiza-
tion showed that the reaction needed to be carried out in a solvent
(Table 1, entries 1–8). Although complete conversion of the N-
oxide and isolation of the corresponding urea 3a was achieved in
moderate yield (68%) using excess dimethylcyanamide (DMCA,
Table 1, entry 2) as the solvent, this method is too wasteful and
expensive for the practical use. MeCN was recognized as the most
appropriate solvent for this reaction. However, due to moderate N-
oxide conversion (66%), the optimization was continued by study-
ing the effect of the temperature and the reaction time (Table 1,
entries 9 and 10). Unfortunately, these efforts did not provide the
desired result despite a significant increase in the conversion of
the starting N-oxide. Increasing the temperature (up to 80 °C), as
well as prolonging the reaction time, led to an increase in the
impurities formed. According to our observations, the latter are
formed due to 1,2,4-oxadiazole ring decomposition. Then we tried
to vary the DMCA and MsOH amounts (Table 1, entries 11–13). An
increase in the DMCA amount used to 2 equiv. led to an increased
conversion (Table 1, entry 11), while the use of a larger excess had
no effect (Table 1, entry 12). The reaction with 1.5 equiv. of MsOH
resulted in full (98%) conversion of N-oxide 1a and the desired urea
Finally, we examined the possibility of using microwave heat-
ing and found that this does not noticeably affect the speed of
the process (Table 1, entry 15).
Used these optimized conditions, we verified the scope of the
reaction using a number of 1,2,4- and 1,3,4-oxadiazolyl-substi-
tuted N-oxides 1 as well as selected commercially available
dialkylcyanamides 2 (Scheme 3). Firstly, we replaced DMCA 2a
with other dialkylcyanamides (diethylcyanamide 2b, 1-
piperidinecarbonitrile 2c, 4-morpholinecarbonitrile 2d) in the
reaction with 1a. In the case of diethylcyanamide the yield of pro-
duct 3b decreased, whereas ureas (3c,d) were obtained in good
yields. Further, a number of structural variations related to the
1,2,4-oxadiazole ring, including replacement of the substituents
at positions 3 and 5 of the heterocycle, were explored. There were
no observed effects from the replacement of Me with Ph (3e), as
well as the relocation of substituents (3f,g). In contrast, the change
from 4-pyridine to 3-pyridine led to a lower yield (3h). However,
the most intriguing results were obtained in cases of 2-pyridine
substrates. 2-(5-Phenyl-1,2,4-oxadiazol-3-yl)pyridine 1-oxide 1e
reacted with cyanamide 2a providing the desired urea 3i in moder-
ate yield (63%), whereas N-oxides 1f and 1g, bearing a 1,2,4-oxadi-
Scheme 3. Reaction scope with various N-oxides 1 and dialkylcyanamides 2.

4
K. Geyl et al. / Tetrahedron Letters 60 (2019) 151108
4.00
3.50
3.00
2.50
2.00
1.50
1.00
0.50
0.00
-0.50
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151108.
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Funding information
The 1,2,4-oxadiazole derivatives study was funded by the Rus-
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