Solvent- and halide-free synthesis of pyridine-2-yl substituted ureas through facile C-H functionalization of pyridine: N -oxides

Article abstract of DOI:10.1039/c6gc02556k

A novel solvent- and halide-free atom-economical synthesis of practically useful pyridine-2-yl substituted ureas utilizes easily accessible or commercially available pyridine N-oxides (PyO) and dialkylcyanamides. The observed C-H functionalization of PyO is suitable for the good-to-high yielding synthesis of a wide range of pyridine-2-yl substituted ureas featuring electron donating and electron withdrawing, sensitive, or even fugitive functional groups at any position of the pyridine ring (63-92%; 19 examples). In the cases of 3-substituted PyO, the C-H functionalization occurs regioselectively providing a route for facile generation of ureas bearing a 5-substituted pyridine-2-yl moiety.

Full text of DOI:10.1039/c6gc02556k

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Page 1 of 16
Green Chemistry
Solvent- and Halide-free Synthesis of Pyridine-2-yl Substituted Ureas
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through Facile C–H Functionalization of Pyridine N-oxides DOI: 10.1039/C6GC02556K
Valentin A. Rassadin,*a Dmitry P. Zimin,a Gulnara Z. Raskil’dina,a,b Alexander Yu. Ivanov,c
Vadim P. Boyarskiy,a Semen S. Zlotskii,b Vadim Yu. Kukushkin*a
a – Institute of Chemistry, Saint Petersburg State University, Universitetskaya Nab. 7/9, 199034 Saint Petersburg, Russia;
E-mail: v.rassadin@spbu.ru, v.kukushkin@spbu.ru
b – Ufa State Petroleum Technological University, Kosmonavtov 1, Ufa, Bashkortostan, Russia
с – Research Park SPbSU, Center for Magnetic Resonance, Saint Petersburg State University, Universitetskaya Nab. 7/9,
199034 Saint Petersburg, Russia
Abstract
A novel solvent- and halide-free atom-economic synthesis of practically useful pyridine-2-yl
substituted ureas utilizes easily accessible or commercially available pyridine N-oxides (PyO) and
dialkylcyanamides. The observed C–H functionalization of PyO is suitable for the good-to-high
yielding synthesis of a wide range of pyridine-2-yl substituted ureas featuring electron donating and
electron withdrawing, sensitive, or even fugitive functional groups in any position at the pyridine ring
(63–92%; 19 examples). In cases of 3-substituted PyO, the C–H functionalization occurs
regioselectively providing a route for facile generation of ureas bearing 5-substituted pyridine-2-yl
moiety.

Green Chemistry
Page 2 of 16
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DOI: 10.1039/C6GC02556K
Introduction
Ureas, especially those functionalized with a heterocyclic moiety, are widely applied in drug
design1,2 and demonstrate antimicrobial,3,4 antimalarial,5–7 antivirus,8 and anticancer9–14 activities.
Moreover, ureas act as kinase (LIM, VEGFR2, FGFR, FLT3) inhibitors,15–20 they control gastric acid
secretion,21 and are used as plant grow regulators.22,23 All known syntheses of ureas employ either
various organic (in particular, chlorinated) solvents or heavy metals. In many instances, the reported
methods start from toxic and/or halide-containing substrates or require special laboratory set up to
perform the reaction under high pressure. The most straightforward approach to ureas includes
reaction of amines with poisoning phosgene24,25 or hazardous isocyanates26–28 and led – apart from
the target products – to huge amounts of halide-containing waste (Scheme 1).
Scheme 1. Environmentally unfriendly synthesis of pyridine-2-yl substituted ureas.
It is clear that the employment of volatile and highly toxic phosgene is a serious drawback of
that method, especially for large-scale industrial processes. Therefore several “phosgene
surrogates”,29 viz. trichloromethylchloroformate (diphosgene),30 bis(trichloromethy1)carbonate
(triphosgene),31,32
diethyl
carbonate,33
S,S-dimethyl
dithiocarbonate,34,35
bis(4-
nitrophenyl)carbonate,36 carbonyldiimidazole,37,38 methanol,39 1,1’-carbonylbisbenzotriazole,40 have
been applied for preparation of ureas (Scheme 1). Although the listed surrogates are less dangerous
than phosgene itself, these solvent-involving methods could not be considered as atom-economic as
they led to substantial amounts of waste and this contradicts with one of cornerstones of the green
chemistry.41
Another halide-involving synthesis of bisaryl-substituted ureas is based on metal-catalyzed
cross-coupling of aryl halides and unsubstituted urea. Despite good yields of the target ureas, the
2

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cross-coupling requires employment of a toxic heavy metal (i.e. palladium) and occurs either in DME,
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or in dioxane in the presence of toxic xanthene-based bidentate ligands (Scheme 1).42–44
Yet another protocol employs Se-catalyzed oxidative carbonylation of amines with a mixture
of CO and O2 (Scheme 1). It is widely used for the preparation of symmetrically substituted ureas and
for the synthesis of pyridine-2-yl unsymmetrically substituted ureas in toluene in the presence of
selenium.45 In most cases, the carbonylation of amines requires elevated temperatures and moderate
to high pressures of CO. Not only is CO toxic, but a risk of explosion of the mixture of CO and O2
should also be taken into account.46 In another method, unsymmetrically substituted pyridyl ureas
can be selectively obtained by Se- or SeO2-catalyzed reductive carbonylation of nitropyridines with
CO in the presence of various amines (Scheme 1).47–50
In view of the current ecological requirements, on the one hand, and the significance of ureas,
on the other hand, development of solvent- and halide-free sustainable reactions giving these species
is a challenging task. It is not surprisingly that a few efforts have recently been carried out to find out
green chemical processes for the synthesis of ureas and the obtained results were published in this
journal (Scheme 2).51–53 The suggested routes start from amine and CO2 and they were conducted
under extremely high pressure of CO2 (25–55 atm) and, in some instances, performed in highly
reprotoxic solvent such as N-methylpyrrolidinone;54 ureas were isolated in low yields and the scope
of the reaction include only rather simple alkylamines such as butyl- or benzylamine. Although it is
obvious that certain progress in elaboration of green routes to ureas has already been reached, the
developed approaches still need further improvement.
Scheme 2. Attempted green synthesis of ureas.
Upon our studies on gold-catalyzed generation of 2-amino-1,3-oxazoles from terminal
alkynes and cyanamides in the presence of 2-picoline N-oxide,55 we observed that when excess of 2-
picoline N-oxide is used in the reaction, the heterocyclization is complicated with a side reaction
furnishing 1,1-dimethyl-3-(6-methylpyridin-2-yl)urea. Being interested in understanding this unusual
C–H functionalization of 2-picoline N-oxide, in this work, we found a way that turns the side reaction
into high yielding green approach to pyridine-2-yl substituted ureas. We now report on solvent- and
halide-free atom-economic synthesis of N,N-dialkyl-N'-pyridine-2-yl ureas based upon C–H
functionalization between pyridine N-oxides and dialkylcyanamides.
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Results and discussion
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DOI: 10.1039/C6GC02556K
Toward environmentally benign conditions of the C–H functionalization
In our previous work,55 we reported that the formation of 1,1-dimethyl-3-(6-methylpyridin-2-
yl)urea from 2-picoline N-oxide and Me2NCN proceeds under acid catalysis. This result indicates that
the first step of the studied reaction is most likely activation of the cyanamide by protonation. To the
best of our knowledge, acid- or metal-catalyzed addition of pyridine N-oxide to nitriles or cyanamides
is yet unknown reaction and only alkylnitrilium salts react with pyridine N-oxide accomplishing
different amide derivatives.56,57 The optimization of the reaction conditions was performed with
unsubstituted pyridine N-oxide (1a) and Me2NCN (2a). Initially the reaction was performed in neat
dimethylcyanamide (2a) (10 equiv) in the presence of 1.0 equiv of methane sulfonic acid, MeSO3H
(3), at 60 °C for 3 h. Although we achieved full conversion of pyridine N-oxide (1a) (Table 1, entry
1) and isolated yield of urea 4a was 93% (NMR based conversion is 100%), this approach does not
meet requirements of green chemistry as it far from being atom-economic.
Table 1. Optimization of the reaction conditionsa.
Molar ratio of reagents
Acid
Conditions
(Conversion,b %)
Entry
2a
1
10 MeSO3H
1.0 MeSO3H
1.5 MeSO3H
2.0 MeSO3H
1.5 MeSO3H
1.5 MeSO3H
1.0
1.0
1.0
1.0
0.1
0.1
0.1
0.1
1.0
1.0
1.0
60 °C, 3 h (100)
60 °C, 3 h (85)
60 °C, 3 h (98)
60 °C, 3 h (98)
60 °C, 3 h (46)
60 °C, 8 h (74)
60 °C, 3 h (7)
60 °C, 3 h (92)
40 °C, 3 h (56)
60 °C, 1 h (78)
60 °C, 2 h (98)
2
3
4
5
6
7
1.5
H3PO4
8
1.5 CF3SO3H
1.5 MeSO3H
1.5 MeSO3H
1.5 MeSO3H
9
10
11
a – for more information related to optimization of the reaction condition
see Supporting Information; b – conversion of the PyO was estimated by
1H NMR
4

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On the next step amount of dimethylcyanamide (2a) was reduced to 1.0, 1.5, and 2.0 equiv
(Table 1, entries 2–4), and it appears that 1.5 equiv of 2a is optimal for achieving almost full
conversion of the starting pyridine N-oxide (1a) to substituted urea 4a and the reaction takes 3 h.
Further, we attempted the reaction with catalytic amounts of MeSO3H. In the case of 0.1 equiv of
methane sulfonic acid, conversion of 1a was 46% and 74% after 3 h and 8 h, respectively (Table 1,
entries 5 and 6). However, small amount of yet unidentified by-product (10 and 5% for entries 5 and
6, respectively) was detected in the reaction mixture.
We assumed that changing of the acid would effect on the reaction rate and probably would
decreases the amount of the undesirable by-product. For rather weak H3PO4, the conversion of the
pyridine N-oxide was only 7% after 3 h (Table 1, entry 7), although employment of the stronger
CF3SO3H gave better result. Conversion of 1a was 92% after 3 h and amount of the by-product was
less than 6% (Table 1, entry 8). However, we continued our study with an equimolar amount of
MeSO3H, because employment of catalytic amount either methane sulfonic or trifluoromethane
sulfonic acid led to formation of small amount of the by-product and required longer reaction time.
The formed pyridinium salt can be easy transformed to the corresponding free base by treatment with
potassium carbonate and thus formed CF3SO3K can be utilized in preparation of antiperspirants.58
The effect of temperature and reaction time was then studied. The reaction was slow at 40 °C
and the conversion of 1a was only 56% after 3 h (Table 1, entry 9). Higher temperatures were not
tested insofar as our idea was to find out environmentally friendly conditions that do not anticipate
elevated temperatures. With respect of the reaction time, we have found that keeping the mixture at
60 °C for 1 h resulted in poor conversion of 1a, whereas stirring for 2 h is sufficient to achieve almost
quantitative conversion of 1a to urea 4a, like in the case when the reaction was performed for 3 h
(Table 1, entries 3, 10, and 11).
To demonstrate the possibility of the scale up synthesis of target urea 4a, we carried out the
reaction starting from 1.90 g of 1a and the isolated yield of 4a was 3.04 g (92%). We succeeded in
recycling 550 mg (78% of excess Me2NCN) of 2a from the reaction mixture.
To summarize optimization of the reaction conditions, we found that employment 1.5 equiv
of cyanamide and 1.0 equiv of methane sulfonic acid leads to the best synthetic results. Noteworthy
that excess of the cyanamide was recycled by conventional vacuum distillation.
Reaction scope and limitation of the green synthesis of pyridine-2-yl substituted ureas
To verify the scope and limitations of the developed approach several pyridine N-oxides and
dialkylcyanamides were tested (Scheme 3).
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Scheme 3. Reaction scope with various pyridine N-oxides and cyanamides.
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In most cases, pyridine N-oxides 1 were prepared by oxidation of the corresponding pyridine
with a mixture of hydrogen peroxide and acetic acid according to conventional protocol.59
Alternatively, green oxidation of N-heteroaromatic amines based on lipase–glucose oxidase system
can also be applied in these syntheses.60 Firstly, we tested several dialkylcyanamides, whose
intriguing chemistry becomes increasingly popular in recent years.61–68 In all cases, target ureas 4a-s
were obtained in 73–92% yields (Scheme 3). Even for 4-morpholinecarbonitrile, urea 4f was isolated
in 89% yield. To check an effect of substitution in the pyridine rings and to demonstrate stability of
a wide range of functional groups under the reaction conditions, several N-oxides were tested. Firstly,
we checked 2- and 4-substituted pyridine N-oxides and no significant difference between
unsubstituted pyridine N-oxide (1a) and its derivatives bearing strong electron donating (4-MeO 1k),
6

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weak electron donating (4-Me 1h, 2-Me 1g, 2-PhCH2 1j), and strong electron withdrawing (4-NO2
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1l) groups was observed. In the case of 3-substituted pyridine derivatives the situation was slightly
different. Thus, 3-cyanopyridine N-oxide (1n) reacts similarly to the other substituted pyridine N-
oxides and target urea 4n was isolated in 80% yield. At the same time 3-methoxypyridine N-oxide
(1m) reacted slower and full conversion of 1m was achieved only after stirring of the reaction mixture
at 60 °C for 5 h. The isolated yield of urea 4m was 72%.
Surprisingly, in the case of 3-substituted pyridine N-oxides (3-Me 1i, 3-MeO 1m, and 3-CN
1n), only 2,5-disubstituted pyridine ureas were formed in good yields. We were unable to detect by
1H NMR even traces of the isomeric 2,3-disubstituted pyridine urea in the reaction mixture. It means
that the C–H functionalization proceeds regioselectively and could be used for the synthesis of 5-
substituted ureas 4 starting from meta-substituted derivatives of pyridine N-oxides.
The halogen substituted pyridine N-oxides (2-Br 1o, 2-Cl 1p) gave appropriate ureas 4o and
4p in 68 and 63% yields. Pyridine N-oxides featuring cyano (3-NC 1n, 4-NC 1q, 2-NC 1r) and
methoxycarbonyl (4-MeO2C 1s) groups efficiently undergo the reaction and in all cases
corresponding ureas were isolated in 63–83% yields. Important that obtained ureas 4n–s potentially
suitable for further modifications. Thus, halogen atom in the pyridine ring of 4o and 4p could be
substituted with various nucleophiles through SNAr69–74 or metal-catalyzed reactions,75–82 whereas the
methoxycarbonyl group in 4s could be convert to amides, esters, reduced to alcohols or aldehyde as
well as undergo the Barton decarboxylation.83
Based on the above discussion a plausible mechanism for formation of the urea is given on Scheme
4.
Scheme 4. Plausible mechanism of formation of urea 4a.
The first step of the reaction most likely includes the activation of the cyanamide by protonation (A
in Scheme 4) followed by nucleophilic addition of pyridine N-oxide to cation A giving B, which then
undergoes intramolecular cyclization furnishing C. In C, the heterolytic N–O bond cleavage results
7

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in the ring opening giving D, which restores the aromaticity via proton elimination thus
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accomplishing target urea 4a.
Unexpected reaction pathway for 2-methoxypyridine N-oxide
Interesting and unexpected result has been obtained when the C–H functionalization was performed
with 2-methoxypyridine N-oxide (1t). Based on the LC-HRMS data two isomeric compounds were
1
13
1
formed and the brutto-formula corresponds to desired urea 4t. The H and C as well as H–13C
1
HMBC and H–13C HSQC spectra clearly indicate that both isomers featuring the same fragments,
but the position of the substituents in the pyridine ring need to be specified; the 1H–15N HSQC and
1H–15N HMBC NMR experiments allowed the identification of both products (Scheme 5). A mixture
of ureas of 5t and 4t (molar ratio 5:1) was formed in 90% overall yield.
Scheme 5. Formation of ureas 5t and 4t.
Cross-peaks correspond to coupling between the urea nitrogen and the H-4 proton of the pyridine ring
and also between the pyridine nitrogen and the H-5 and H-6 protons was observed in 1H–15N HMBC
experiment for the major isomer. In the case of the minor isomer, we observed cross-peaks
corresponding to coupling of the pyridine nitrogen and the H-3 and H-5 protons of the pyridine ring
(for more details see ESI). Moreover, for the major isomer, the signal of the H-5 proton (6.84 ppm)
appears as a doublet of doublet (J = 5.0, 7.8 Hz), whereas for the minor isomer the signal of the H-4
proton (7.39 ppm) appears as a triplet (J = 7.9 Hz). These data agree with well-known fact that for
3
pyridines value for H-2/H-3 coupling constant is smaller than for H-3/H-4 (for pyridine: JH-2/H-3
=
4.88 Hz and 3JH-3/H-4 = 7.67 Hz).84 Unfortunately column chromatography on silica did not allow the
separation of a mixture of ureas 5t and 4t, because of their similar retention. We isolated pure urea
5t (328 mg, 42%) by the repeated recrystallization of a mixture of 5t and 4t from hexane/Et2O. The
structure of 3-(2-methoxypyridin-3-yl)-1,1-dimethylurea (5t) in the solid state has been additionally
confirmed by single-crystal X-ray diffraction (Fig. 1) The bonds length values in the C(2B)–N(2B)
–
C(7B)–(O(2B))–N(3B) moiety of urea 5t are typical for pyridine-3-yl substituted ureas and are in
agreements with reported data.85–88
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Fig. 1. View of molecular structure of 5t (CCDC: 1473655). Thermal ellipsoids are drawn at the 50%
probability level. Only one of two crystallographically independent molecules is presented. Selected
bond lengths (Å): N(2B)–C(2B) 1.403(2); N(2B)–C(7B) 1.385(2); O(2B)–C(7B) 1.226(2); N(3B)–C(7B)
1.361(2).
Such unusual results obtained for 2-methoxypyridine N-oxide (1t) forced us to pay more
attention to the structures of ureas obtained from pyridine N-oxide bearing either OMe group or,
especially, halogen atom in the second position, which can react similar to N-oxide 1t. In the case of
3-(4-methoxypyridin-2-yl)-1,1-dimethylurea (4k), the structure was confirmed by NOESY NMR. We
observed two cross-peaks due to NOE between the protons of the methoxy group and two protons
(H-3 and H-5) of the pyridine ring. For bromo- and chlorosubstituted ureas (4o and 4p) the structures
were additionally confirmed by single-crystal X-ray diffraction (Fig. 2).
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Fig. 2. View of molecular structure of 4o (CCDC: 1473656) and 4p (CCDC: 1473657). Thermal
ellipsoids are drawn at the 50% probability level. Selected bond lengths (Å): N(2)–C(1) 1.400(4); N(2)–
C(6) 1.401(5); O(1)–C(6) 1.233(4); N(3)–C(6) 1.350(5) for 4o; N(2)–C(1) 1.396(2); N(2)–C(6) 1.396(2); O(1)–
C(6) 1.235(2); N(3)–C(6) 1.349(2) for 4p.
For both ureas 4o and 4p bonds length values in the C(1)–N(2)–C(6)–O(1)–N(3) moiety are usual
for pyridine-2-yl substituted ureas and correspond to reported data.85,89–91 All these results indicate
that 2-methoxypyridine N-oxide (1t) reacts differently to all others studied pyridine N-oxides and, in
our opinion, the detailed investigation of a plausible mechanism goes beyond the scope of this work.
We are going to provide a full account report (including both experimental and theoretical studies)
on the mechanism of the observed transformation and corresponding works are underway in our
group.
Conclusions
We have developed solvent- and halide-free green synthesis of pyridine-2-yl substituted ureas that is
based on facile C–H functionalization of various pyridine N-oxides with a wide range of
dialkylcyanamides. The observed C–H functionalization of PyO is suitable for the good-to-high
yielding synthesis of a broad spectrum of pyridine-2-yl substituted ureas featuring either electron
donating, or electron withdrawing groups in any position at the pyridine ring. Labile functional groups
10

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Green Chemistry
such as halogen atoms, cyano or methoxycarbonyl groups survive the reaction conditions and
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obtained ureas could be used for the synthesis of more complex structures.
Experimental Section
Experimental procedures and analytical data of all compounds (1H and 13C{H} NMR, IR,
1
HRESIMS), copy of the H, 13C{H}, and 2D NMR spectra and also X-ray data are available in the
Supporting Information.
Acknowledgements
V.A.R. gratefully acknowledges the support of the Scientific Council of the President of the Russian
Federation (Grant MK-3228.2015.3) and he also thanks Saint Petersburg State University for
postdoctoral grant (12.50.1190.2014). G.Z.R. expresses her gratitude to the Russian Foundation for
Basic Research for sabbatical grant (15-33-50913 mol_nr). Structural studies of the obtained
compounds were supported by Saint Petersburg State University (research grant 12.37.214.2016). All
physicochemical measurements were performed at the Center for Magnetic Resonance, Сenter for
Chemical Analysis and Material Research, Center for X-ray Diffraction Methods, and Educational
Center of Chemistry (all belong to Saint Petersburg State University).
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Page 16 of 16
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DOI: 10.1039/C6GC02556K
A solvent- and halide-free atom-economic synthesis of practically useful pyridine-2-yl substituted ureas
utilizes pyridine N-oxides and dialkylcyanamides.