An efficient transformation of ethers to N,N′-disubstituted ureas in a Ritter type reaction

Article abstract of DOI:10.1016/j.tetlet.2012.12.027

A simple, mild, and an alternative protocol for the preparation of N,N′-disubstituted ureas from readily available ethers and cyanamides as starting materials is described. The protocol explores the reactivity of ether in a Ritter type reaction with cyanamide in the presence of BF ₃·Et₂O and resulting in the formation of N,N′-disubstituted urea. Divinyl ether as well as MTBE (methyl tert-butyl ether) can be employed as ether components to afford allyl and tert-butyl ureas respectively.

Full text of DOI:10.1016/j.tetlet.2012.12.027

Tetrahedron Letters 54 (2013) 975–979
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Tetrahedron Letters
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An efficient transformation of ethers to N,N0-disubstituted ureas in a Ritter
type reaction
⇑
Veladi Panduranga, Basavaprabhu, Vommina V. Sureshbabu
#Room 109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B.R. Ambedkar Veedhi, Bangalore 560001, India
a r t i c l e i n f o
a b s t r a c t
A simple, mild, and an alternative protocol for the preparation of N,N0-disubstituted ureas from readily
available ethers and cyanamides as starting materials is described. The protocol explores the reactivity
of ether in a Ritter type reaction with cyanamide in the presence of BF3ꢀEt2O and resulting in the forma-
tion of N,N0-disubstituted urea. Divinyl ether as well as MTBE (methyl tert-butyl ether) can be employed
as ether components to afford allyl and tert-butyl ureas respectively.
Article history:
Received 12 November 2012
Revised 8 December 2012
Accepted 9 December 2012
Available online 19 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyanamides
Ethers
Lewis acid
N,N0-disubstituted ureas
Ureas are the important class of carbonyl compounds which
play a significant role in organic, medicinal, supramolecular, and
materials chemistry.1 Urea is the decisive functionality in nature,
widespread in biological systems, and monitoring various activities
of living beings. Urea derivatives display a wide spectrum of bio-
logical activities, in particular several substituted ureas have been
shown to possess a marked inhibiting effect on HIV protease
enzyme.2
There are ample numbers of reports on the synthesis of disub-
stituted ureas starting from amines. The standard protocol for
the preparation of urea generally involves the use of toxic and
highly reactive phosgene and its derivatives.3 However, widely ac-
cepted ones include the reaction of two amine components in the
presence of carbonylating reagents.4
Usually the synthesis of urea is achieved through the condensa-
tion of amines with isocyanates,5 formamides,6 carbamates,7 or
oxidative carbonylation of amine with carbon monoxide in the
presence of transition metal catalysts.8 Another alternative is the
direct carbonylation of amines by CO2.9 Because of the cost, toxic-
ity, commercial availability of limited number of isocyanates, hur-
dles in preparing and handling of the reagents, an alternative and
high throughput synthetic protocol is desirable for the synthesis
of disubstituted ureas.
lations and in the pharmaceutical field.10,11 In addition, diaryl
ethers constitute an important class of compounds in agricultural
and medicinal chemistry.12 The activation of etheric C–O bonds
through transition-metal catalyzed coupling reactions to construct
C–C bonds is of significant importance in synthetic organic
chemistry.13
Ritter reaction is the classical C–N bond forming reaction.14
Variations of the Ritter reaction for variety of organic transforma-
tions are well documented.15 Anatol16 reported the reaction of tert-
butyl alcohol with cyanamide under elevated temperature to form
urea in less yields (about 30–35%). Recently, the synthesis of di and
trisubstituted ureas catalyzed by Fe (III), starting from cyanamides
and alcohols through a variation of Ritter reaction has been re-
ported by our group.17 Currently we are involved in exploring
the functionalities like ethers in this case as precursor for the prep-
aration of N,N0-disubstituted ureas. Herein, by combining the reac-
tivity of ether in the presence of an acid and utility of cyanamide as
nitrile source in Ritter type reaction, we wish to report a simple,
mild, and an efficient alternative protocol for the synthesis of
disubstituted ureas.
In our previous report17 we have demonstrated the formation
of dibenzyl ether as an intermediate in the preparation of benzyl
urea from benzyl alcohol. Similar kind of intermediacy was not
observed with other alcohols that is, tert-butyl alcohol and allyl
alcohol, wherein they react directly through the formation of sta-
ble carbocation. However, the formation of dibenzyl ether and its
participation in the reaction as masked carbocation source made
us to investigate the conversion of ethers to ureas. During the
study, it was realized that in the presence of acid, cleavage of
C–O bond of ether occurs leading to the formation of a stable
Ethers are the most valuable compounds in our day to day life.
For example, several applications of GMEs (glycerol methyl ethers)
were patented in personal care, cosmetic, laundry, cleaning formu-
⇑
Corresponding author. Tel.: +91 08 2296 1339/99 8631 2937.
E-mail addresses: hariccb@gmail.com, sureshbabuvommina@rediffmail.com
(V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.027

976
V. Panduranga et al. / Tetrahedron Letters 54 (2013) 975–979
Table 1
Optimization of reaction
ether and phenylcyanamide were chosen as model substrates
and various Lewis acids were screened, among which BF3ꢀEt2O
and FeCl3 gave satisfactory results. Before opting acetic acid
(AcOH), various solvents such as dichloromethane (DCM),
dichloroethane (DCE) and acetonitrile (ACN) were employed
for the reaction, except DCE (for FeCl3), remaining solvents
did not afford the desired product quantitatively. At room tem-
perature the reaction was very slow and on further increasing
the temperature, enhancement in the reaction rate was
observed.
In a typical reaction, dibenzyl ether (1a) was treated with phe-
nylcyanamide (4a) in the presence of BF3ꢀEt2O in AcOH and the
reaction mixture was heated at 40–50 °C. The equivalence of
BF3ꢀEt2O being employed was optimized in order to obtain the urea
(5a) in good yield (Scheme 1). The progress of the reaction was
monitored by IR, where the appearance of strong absorption peaks
at mmax 1654 and 1562 cmꢁ1 confirms the formation of urea. The
resulting mixture was then washed with water and purified
through column chromatography to afford the pure product in
good yield. The structure of the product was then confirmed by
mass and NMR analyses.
Generally, Lewis acid catalyzed Ritter type reaction involves
the formation of an oxidative complex which later decomposes
to yield a stable carbocation required for the reaction. As de-
scribed by Anxionnat,21 the carbocation will be formed through
the ether–Lewis acid (FeCl3) complex. In addition, AcOH drives
the reaction toward the product formation by reducing the reac-
tion time. AcOH being a strongly ionizable solvent, at an elevated
temperature it assists in breaking the oxidative complex of ether
and BF3ꢀEt2O and thus helps in the formation of carbocation with
ease (Fig. 1).
H
N
H
N
NHCN
+
O
Catalyst
Solvent, Temp.
O
Entry
Catalysta
Solvent
Yieldb (%)
Time (h)
1
2
3
4
5
6
7
8
AlCl3
FeCl3
FeCl3
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
BF3ꢀEt2O
AcOH
AcOH
DCE
AcOH
AcOH
ACN
25
48
91
52
94
37
56
42
6c
6c
2.5d
4.5c
2d
4d
DCE
DCM
4.5d
5d
a
b
c
30 mol % of catalyst was used.
Isolated yield.
At room temp.
d
At temp. 40–50 °C.
R1
R2
R3
NHCN
R
R1
H
N
H
N
R2
R3
BF3.Et2O (30 mol%)
4
AcOH, 40-50 o
C
+
O
O
5
R
R
1
Scheme 1. Synthesis of benzyl ureas from dibenzyl ether.
Generality of the protocol was further explored, where dibenzyl
ethers substituted by methyl (1b) and nitro (1c) groups at para-
position were also employed as ether components and afforded
corresponding ureas in good to excellent yields.22 The nitro substi-
tuted dibenzyl ether afforded corresponding urea in comparatively
lesser yield than its methyl counterpart. Aromatic cyanamides irre-
spective of their nature of substitution (electron donating or elec-
tron withdrawing) furnished corresponding ureas in respectable
yields (Table 2). Further, the protocol was extended for the prepa-
ration of allyl ureas employing divinyl ether (2) as ether
component.
We first attempted the reaction of divinyl ether with cyanamide
in the presence of FeCl3 in DCE, the product formation was rather
slow and furnished the urea in very low yields. When the same
reaction was repeated with BF3ꢀEt2O, it served as a better catalyst
system in yielding good results with divinyl ether and furnished
the allyl ureas (6) in good yields (Table 3).23
carbocation as reported by Kochetkov et al.18Various reagent sys-
tems including mineral acids and Lewis acids have been reported
for the cleavage of C–O bond of ether.19 In the present context the
choice of the reagent would be such that it has to assist both the
cleavage of ethereal C–O bond as well as the catalysis of the Ritter
reaction.
Thus the synthesis of N,N0-disubstituted urea was undertaken
employing ether and cyanamide in the presence of Lewis acid
catalyst which can assist C–O bond cleavage and catalyze the
subsequent Ritter type reaction. The cyanamide required for
the present protocol was prepared through the reported meth-
odology20 wherein the amine was reacted with cyanogen bro-
mide in dry THF/diethyl ether at 0 °C. The product obtained
was then purified and used for next step. In order to establish
suitable reaction conditions for the above transformation, selec-
tion of Lewis acid, solvent, and temperature are critical and
need to be optimized (Table 1). In an initial study, dibenzyl
In addition, the synthesis of tert-butyl urea was achieved using
MTBE (methyl tert-butyl ether) as ether component. MTBE (3) is
O
BF3.Et2O
O
H
R N
R
N
CH2
N
OH/H
R
N
H
N
H
C
O
BF3
N
H
CH3COOH
H2O (OH/H+)
Figure 1. Possible reaction pathway for BF3ꢀEt2O catalyzed synthesis of N,N0-disubstituted urea.

V. Panduranga et al. / Tetrahedron Letters 54 (2013) 975–979
977
Table 2
List of benzyl ureas prepared
Entry
Ether
Urea
Yielda (%)
94
Time (h)
O
O
N
H
N
H
1
2
(1a)
5a
NO2
O
N
H
N
H
2
3
68
85
3.5
5b
O
N
H
N
H
3
4
5c
NO2
O
O
O
(1b)
4
71
N
H
N
H
5d
N
H
N
H
Cl
5
6
76
66
3.5
5e
O
O
N
N
H
O2N
NO2
H
4
(1c)
O2N
O2N
5f
O
N
H
N
H
7
72
6
5g
a
Isolated yield.
the safe ether available commercially and is cheaper and easy to
handle. Kochetkov et al.,18reported that MTBE serves as a better
source for tert-butyl carbocation in the presence of acid catalyst.
Thus, we started to investigate it for the present protocol. Under
the optimized reaction conditions in presence of BF3ꢀEt2O, MTBE
decomposes to tert-butyl cation and methoxide ion. Thus formed
tert-butyl cation took part in the reaction in Ritter like fashion to
yield the ureas (7). Interesting point noticed with the reaction of
MTBE is the selective formation of tert-butyl carbocation in the
presence of BF3ꢀEt2O and its participation in the urea formation.
With divinyl ether and MTBE, cyanamides possessing electron
donating or electron withdrawing groups afforded corresponding
ureas in good to excellent yields (Scheme 2), as furnished in
Table 4.24
Herein we describe a simple, mild, and an alternative method-
ology which demonstrates the BF3ꢀEt2O catalyzed cleavage of ethe-
real C–O bond and the subsequent Ritter type reaction with
cyanamides under BF3ꢀEt2O catalysis resulting in N,N0-disubsti-
tuted ureas in one pot. The protocol would provide an excellent
alternative to the existing protocols due to its operational
simplicity.
Table 3
Comparison of FeCl3 and BF3ꢀEt2O for allyl urea preparation
H
N
H
N
NHCN
catalyst (30 mol%)
Solvent, Temp.
+
O
O
R1
H
N
H
N
R2
R3
Entry
Catalyst
Solvent
Temp (°C)
Yieldc (%)
O
2
a
R1
O
1
2
3
4
5
FeCl3
FeCl3
AcOH
AcOH
DCE
AcOH
AcOH
rt
13
23
47
38
87
BF3.Et2O (30 mol%)
AcOH, 40-50 o
b
6
R2
R3
NHCN
40–50
40–50
rt
or
or
C
FeCl3
+
R1
BF3ꢀEt2Oa
H
N
H
BF3ꢀEt2Ob
40–50
O
R2
R3
Scheme 2. Synthesis of allyl and tert-butyl ureas.
N
4
O
a
b
c
20 mol % of catalyst was used.
30 mol % of catalyst was used.
Isolated yield.
3
7

978
V. Panduranga et al. / Tetrahedron Letters 54 (2013) 975–979
Table 4
List of allyl and tert-butyl ureas prepared
Entry
Ether
Urea
Yielda (%) (reacn time in h)
O
H
N
H
N
(2)
O
1
76 (3)
Cl
6a
H
N
H
N
2
3
79 (3.5)
74 (2.5)
O
6b
H
H
N
N
O
6c
H
N
H
N
O
O
4
5
86 (2.5)
84 (3)
(3)
7a
H
H
N
N
O
7b
H
N
H
N
O
6
67 (6)
NO2
7c
a
Isolated yield.
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Acknowledgements
We thank the Department of Science and Technology, Govt. of
India (Grant No. SR/S1/OC-52/2011) for the financial assistance
and V.P. thanks CSIR for fellowship.
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(KBr): 3298, 3037, 1663, 1585 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6) d (ppm)
2.28 (s, 3H), 4.21 (d, J = 5.82 Hz, 2H), 6.46 (s, 1H), 6.90–7.35 (m, 9H), 7.47 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d (ppm) 24.4, 44.5, 120.1, 124.5, 126.2,
128.3, 129.4, 136.5, 137.6, 139.4, 141.2, 158.1; HRMS calcd for C15H16N2O, m/z
261.1161 (M+Na); found 261.1160.
1-(4-Methylbenzyl)-3-(3-nitrophenyl)urea (5d): White solid; yield = 71%;
Mp = 223–224 °C; IR (KBr): 3311, 3042, 1658, 1582 cmꢁ1 1H NMR (400 MHz,
;
DMSO-d6) d (ppm) 2.31 (s, 3H), 4.28 (d, J = 5.88 Hz, 2H), 6.53 (s, 1H), 6.97–7.07
(m, 4H), 7.85–8.16 (m, 4H), 8.32 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d (ppm)
22.4, 48.3, 118.5, 120.2, 126.2, 127.8, 128.4, 129.5, 133.6, 136.6, 141.2, 147.8,
158.2; HRMS calcd for C15H15N3O3 m/z 308.1011 (M+Na) found 308.1009.
1-(4-Nitrobenzyl)-3-benzyl urea (5f): White solid; yield = 66%; Mp = 205–
22. General procedure for the preparation of cyanamides (4)
To a solution of amine (1.0 mmol) in dry THF/diethyl ether (10 mL) at 0 °C was
added a solution of CNBr (1.5 mmol) in THF/diethyl ether (4 mL). The mixture
was stirred till the completion of the reaction as judged by TLC and then the
reaction mixture was filtered to remove the residual salt and concentrated to
yield corresponding cyanamide. The crude was then diluted with EtOAc and
washed twice with 10% HCl (10 mL), water, and brine. Organic extract was
dried over anhydrous Na2SO4 and evaporation of the solvent in vacuo results in
cyanamide which was further purified by silica gel column chromatography
(10% EtOAc/hexane system).
206 °C; IR (KBr): 3331, 3059, 1658, 1590 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
d (ppm) 4.26 (d, J = 5.95 Hz, 2H), 4.28 (d, J = 5.86 Hz, 2H), 6.87 (s,1H), 6.92–7.16
(m,5H), 7.80 (d, J = 7.82 Hz, 2H), 8.10 (d, J = 8.1 Hz,2H), 8.51 (s,1H); 13C NMR
(75 MHz, DMSO-d6) d (ppm) 44.8, 119.4, 123.2, 125.4, 127.6, 129.8, 132.4,
139.7, 140.3, 146.8, 157.1; HRMS calcd for C15H15N3O3 m/z 308.0930 (M+Na);
found 308.0933.
1-Allyl-3-p-tolylurea (6b): White solid; yield = 79%; Mp = 188–190 °C; IR (KBr):
23. General procedure for the synthesis of N,N0-disubstituted ureas (5–7)
To a stirred solution of ether (1.0 mmol) in AcOH (6 mL), was added 30 mol % of
BF3ꢀEt2O followed by the addition of cyanamide (1.0 mmol). The reaction
mixture was refluxed at an elevated temperature (40–50 °C) till the completion
of the reaction as monitored by TLC. Upon complete consumption of the
cyanamide, the reaction medium was diluted with EtOAc (15 mL). The organic
layer was washed with water followed by 5% NaHCO3 (2 ꢂ 5 mL), water
(2 ꢂ 5 mL), and brine (5 mL). The organic layer was then dried over anhydrous
Na2SO4 and the solvent was evaporated in vacuo to afford the crude which was
then purified through silica gel column chromatography (30–40% EtOAc/
hexane).
3334, 3078, 1656, 1562 cmꢁ1 1H NMR (400 MHz, DMSO-d6) d (ppm) 2.36
;
(s,3H), 3.92 (d, J = 6.8 Hz, 2H), 4.64–4.70 (m, 2H), 5.57–5.62 (m, 1H), 6.49 (s,
1H), 6.88 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 8.12 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d (ppm) 23.9, 43.6, 116.2, 118.5, 122.5, 124.8, 129.6.5,
130.3, 134.2, 141.8, 157.1; HRMS calcd for C11H14N2O m/z 213.1004 (M+Na);
found 213.1003.
1-tert-Butyl-3-(3-nitrophenyl)urea (7c): White solid; yield = 67%; Mp = 147–
149 °C; IR (KBr): 3381, 3054, 1651, 1572 cmꢁ1 1H NMR (400 MHz, DMSO-d6) d
;
(ppm) 1.31 (s, 9H), 6.52 (s, 1H), 7.12–7.81 (m, 4H), 8.03 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d (ppm) 25.2, 51.2, 121.2, 128.3, 129.6, 130.9, 138.4, 146.5,
158.0; HRMS calcd for C11H15N3O3 m/z 260.1011 (M+Na); found 260.1009.
24. Characterization data for selected compounds:
1-Benzyl-3-m-tolylurea (5c): White solid; yield = 85%; Mp = 175–177 °C; IR