A high-yielding, expeditious, and multicomponent synthesis of urea and carbamate derivatives by using triphenylphosphine/trichloroisocyanuric acid system

Article abstract of DOI:10.1080/10426507.2015.1085038

An efficient method for the synthesis of urea and carbamate derivatives from amines and alcohols is described by using triphenylphosphine (PPh₃)/trichloroisocyanuric acid system. The protocol allows for the preparation of symmetrical, unsymmetrical di, tri-, and tetra-substituted ureas and carbamates and is tolerant of a wide range of functional groups. To optimize the reaction conditions, experimental variables including temperature, the concentration of amine and alcohol, solvent, and reaction time were studied. Satisfactory yields were obtained at the optimized conditions. The present methodology is experimentally simple, mild, and represents a valuable alternative to the existing methods.

Full text of DOI:10.1080/10426507.2015.1085038

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
A high-yielding, expeditious, and multicomponent
synthesis of urea and carbamate derivatives by
using triphenylphosphine/trichloroisocyanuric
acid system
Sara S. E. Ghodsinia & Batool Akhlaghinia
To cite this article: Sara S. E. Ghodsinia & Batool Akhlaghinia (2016) A high-yielding,
expeditious, and multicomponent synthesis of urea and carbamate derivatives by using
triphenylphosphine/trichloroisocyanuric acid system, Phosphorus, Sulfur, and Silicon and the
Related Elements, 191:1, 1-7, DOI: 10.1080/10426507.2015.1085038
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Date: 18 January 2016, At: 00:09

PHOSPHORUS, SULFUR, AND SILICON
2016, VOL. 191, NO. 1, 104–110
http://dx.doi.org/10.1080/10426507.2015.1085038
A high-yielding, expeditious, and multicomponent synthesis of urea and carbamate
derivatives by using triphenylphosphine/trichloroisocyanuric acid system
Sara S. E. Ghodsinia and Batool Akhlaghinia
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran
ABSTRACT
ARTICLE HISTORY
Received 18 April 2015
Accepted 17 August 2015
An efficient method for the synthesis of urea and carbamate derivatives from amines and alcohols is
described by using triphenylphosphine (PPh3)/trichloroisocyanuric acid system. The protocol allows for
the preparation of symmetrical, unsymmetrical di, tri-, and tetra-substituted ureas and carbamates and is
tolerant of a wide range of functional groups. To optimize the reaction conditions, experimental variables
including temperature, the concentration of amine and alcohol, solvent, and reaction time were studied.
Satisfactory yields were obtained at the optimized conditions. The present methodology is experimentally
simple, mild, and represents a valuable alternative to the existing methods.
KEYWORDS
Triphenylphosphine;
trichloroisocyanuric acid;
urea; carbamate; amine;
alcohol
GRAPHICAL ABSTRACT
Introduction
phosgene and phosgene derivatives,16-28 carbonyl-imida-
zoles,29-31 carbon monoxide,32-34 isocyanate (which are often
generated in situ in the presence of alcohols via the Hofmann,35
Curtius,36 Lossen,37 and Schmidt38 rearrangements or the
reductive carbonylation of nitroaromatic compounds39),40-43
acid anhydrides,44 and chloroformates.45-49 Also, other meth-
ods have been developed involving the reaction of amines with
reagents which originate from CO2 reacting with ammonium,50
ethylene oxide or ethanol,51 and alkyl halides52 such as urea,53
ethylene carbonate,54 or diethyl carbonate.55
However, some of the reported methods suffer from the use
of costly and toxic chemicals directly or indirectly, limited sub-
strate scope, harsh reaction conditions, multiple-step prepara-
tions or the lack of readily available starting materials. (For
instance, using phosgene and phosgene derivatives as highly
toxic reagents which is not environmental friendly opens
many worrying toxicological and environmental problems.17
N-containing compounds such as urea and carbamate deriva-
tives, as an important class of carbonyl compounds, are signifi-
cant subunits present in numerous naturally occurring
compounds. They have interesting applications in organic
chemistry, medicinal chemistry, agriculture, petrochemicals,
biology, and material science.1-5 Several substituted ureas,
which can be used as intermediates for the production of carba-
mates,5-7 possess a marked inhibitory effect on HIV-1 protease,
p38 MAP kinase,8-12 microbial alkaline protease,13 and several
other classes of enzymes.14 It was found that trace amounts of
urea derivatives enhances the photoreduction of nitrobenzene
by catalyzing the proton transfer step.15 Thus, to satisfy their
demand, numerous synthetic methods have been developed for
the formation of the urea and carbamate linkages by convenient
and safe methodologies. Traditional synthesis of urea and car-
bamates derivatives involves the reaction of amines with
CONTACT Batool Akhlaghinia
akhlaghinia@um.ac.ir
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad 9177948974, Iran
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
© 2016 Taylor & Francis

PHOSPHORUS, SULFUR, AND SILICON
105
Preparation of carbamates and ureas by using costly, toxic, and effect of different molar ratios of reactants as well as solvents at
limited number of commercially available isocyanates suffers different temperatures on the reaction rate. The obtained
from limited substrate scope and multiple-step reaction.56 In results are summarized in Table 1. Since the intermediates and
addition, in some cases, various kinds of metal and nonmetal PPh3 are reactive species and extremely sensitive to moisture, it
catalysts,34,57-65 were used which have tremendous toxicological is critical to use an anhydrous solvent. At first, benzyl carbamic
and environmental problems although different alternative acid was prepared by passing gaseous carbon dioxide through a
methods that do not involve the use of toxic reagents have also solution of benzyl amine in 1,4-dioxane at ambient tempera-
been reported (such as phosgene-free synthesis of carbamates ture. By adding 0.3:1 mixture of TCCA:PPh3 in 1,4-Dioxane to
over zeolite-based catalysts,66 one-pot synthesis of substituted the reaction mixture which was followed by addition of aniline,
ureas from the corresponding amines using Mitsunobu’s 1-benzyl-3-phenylurea was prepared. On the basis of our previ-
reagent,67 synthesis of urea derivatives from amines and CO2 in ous studies,90,92 the optimized molar ratios of TCCA: PPh3 was
the absence of catalyst and solvent68). Thus, an alternative selected as 0.3:1. Applying 0.3:1:1:1 molar ratio of TCCA:PPh3:
environmentally benign synthetic method for the preparation benzyl amine:aniline in 1,4-dioxane at 80ꢀC produced the
of ureas and carbamates is demanded. Carbon dioxide as a desired product in 95% isolated yield (Table 1, entry 1). To
nontoxic, noncorrosive, inflammable, abundant, and cheap car- investigate the effect of temperature on model reaction rate, the
bon source is particularly attractive in urea and carbamate syn- aforementioned condition was performed at room temperature,
thesis. Urea and carbamate linkages can be obtained from the 90ꢀC and reflux (Table 1, entries 2–4). According the data from
reaction of carbon dioxide with amines followed by the treat- Table 1, the reaction has not progressed at room temperature
ment of produced carbamic acid with amines and alcohols, whereas higher temperature (90ꢀC and reflux) have no any
respectively. Carbon dioxide easily combines with amines at influence on the reaction rate. We tried many other solvents
ambient temperature and atmospheric pressure to produce car- like, CH3CN, DMF, DMSO, THF, toluene, and CH3NO2 in
bamic acids.69-71 A few reports exist on direct synthesis of ureas preparation of 1-benzyl-3-phenylurea by applying 0.3:1:1:1
and carbamates from CO2 and amines.57,72-79
molar ratio of TCCA:PPh3:benzyl amine:aniline. Performing
Herein, we aimed to successfully prepare urea and carba- the reaction in CH3CN, DMF, and DMSO produced the
mate derivatives from carbamic acids (which was prepared in desired product in low yields after longer reaction times
situ from the reaction between amines and CO2 as the carbonyl (Table 1, entries 5–7) while in THF, toluene and CH3NO2 no
source) by using triphenylphosphine/trichloroisocyanuric acid/ product was obtained even after long period of time (Table 1,
amine (or alcohol) system.
entries 8–10). Additional amount of aniline has not any influ-
ence on the reaction rate (Table 1, entry 11).
Passing gaseous CO2 through amine 1 solution generated
unstable carbamic acid I.68,72 On the other hand, the initial
attack at the halogen in TCCA by triphenylphosphine leads to
the halogen–phosphonium salt II. The reaction of halogen-
phosphonium salt with carbamic acid I yields the activated spe-
cies III and [1,3,5]triazine-2,4,6-triol (IV), which is in equilib-
rium with [1,3,5]triazinane-2,4,6-trione (V). As soon as III is
formed, a nucleophilic attack occurs between III and amine 2/
or alcohol to form triphenylphosphine oxide and correspond-
ing urea/or carbamate. To elucidate the reaction path more
clearly, we attempted to isolate and identify the IV and V
(Scheme 2). FTIR spectrum of two tautomeric forms [1,3,5]
Results and discussion
Our own interest in the synthesis of ureas and carbamates
stems from our recent studies in application of triphenylphos-
phine/N-halo reagents systems,80-93 and the other reports94-99
in organic synthesis. Here, we have utilized triphenylphos-
phine/trichloroisocyanuric acid system in preparation of sym-
metrical, unsymmetrical di, tri-, and tetra-substituted ureas
and carbamates (Scheme 1).
To begin with, we investigated the preparation of 1-benzyl-
3-phenylurea as a model reaction by using triphenylphosphine/
trichloroisocyanuric acid system. In this study, we tested the
Scheme 1. Synthesis of urea and carbamate derivatives.

106
S. S. E. GHODSINIA AND B. AKHLAGHINIA
Scheme 2. Proposed mechanism of urea and carbamate synthesis.
triazine-2,4,6-triol (IV) and [1,3,5] triazinane-2,4,6-trione (V) reaction of amine 2 with carbamic acid. For instance, 2-chloro
showed a broad absorption band at 3350–3100 cm¡1 due to benzylamine and 2-methoxy benzylamine react more slowly
OH and NH stretching vibration of IV and V. Presence of than n-butyl amine with phenyl carbamic acid (compare entries
CHN and CHO was confirmed by the appearance of absorption 6,7 with entry 8). Also, morpholine and pyrrolidine as two sec-
bands at 1613 and 1755–1713 cm¡1, respectively.
ondary amine, show low reactivity than n-butyl amine (com-
With the best conditions in hand, a variety of structurally pare entries 9, 10 with entry 8).
divergent aliphatic and aromatic amines were selected to
Seeking to widen the applicability of the present protocol, we
explore the generality and scope of the present mixed reagent envisioned an alternative approach to add to the existing meth-
in the preparation of symmetrical, unsymmetrical di, tri-, and ods of carbamate synthesis. After establishing the methodology
tetra-substituted ureas. The obtained results are summarized in for ureas, we examined the preparation of benzyl phenyl carba-
Table 2. As can be seen in Table 2, the reaction was highly tol- mate by using triphenylphosphine/ trichloroisocyanuric acid
erant of the amine 1 and amine 2 structure. The optimized system. Benzyl phenylcarbamate was synthesized from the
reaction conditions (0.3:1:1:1 molar ratio of TCCA:PPh3:amine reaction between benzyl carbamic acid (which was prepared by
1:amine 2 in dry 1,4-dioxane at 80ꢀC) were used for all reac- passing gaseous carbon dioxide through a solution of benzyl
tions and the corresponding ureas were prepared within 2.5– amine in 1,4-dioxane at ambient temperature) and benzyl alco-
5.5 h with good to excellent yields.
According the results of Table 2, primary aliphatic amines TCCA:PPh3:benzyl amine:benzyl alcohol in high yields (97%).
have more reactivity than aromatic amines and tertiary amines Under the optimized reaction conditions established, vari-
hol in 1,4-dioxane at 80ꢀC, using a 0.3:1:1:1 molar ratio of
toward benzyl carbamic acids (compare entries 2, 3 with entries ous kinds of carbamates were prepared through the reaction of
1, 4). The difference in reactivity can be attributed to low various kinds of structurally diverse primary and secondary
nucleophilicity of aromatic amine and the steric hindrance of alcohols and phenol with variety of carbamic acids using
tertiary amine. Steric effects play an essential role in the TCCA:PPh3 system, to afford the corresponding carbamates in
Table 1. Synthesis of 1-benzyl-3-phenylurea (1) by using triphenylphosphine/trichloroisocyanuric acid system in various solvents, different molar ratios of reactants, and
different temperatures.
Entry
Molar ratio TCCA/PPh3/benzyl amine/aniline
Solvent
Temp. (ꢀC)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1
0.3/1/1/1.5
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
CH3CN
DMF
DMSO
THF
Toluene
CH3NO2
80
90
Reflux
r.t.
Reflux
90
90
Reflux
100
Reflux
80
4
4
4
10
5
5
95
90
90
0
60
55
60
0
5
10
10
10
4
9
10
11
0
0
95
1,4-Dioxane

PHOSPHORUS, SULFUR, AND SILICON
107
Table 2. Preparation of structurally different symmetrical and unsymmetrical ureas by using triphenylphosphine/trichloroisocyanuric acid system.
Entry
R1
R2
R3
R4
Time (h)
Isolated yield (%)
References
1
2
3
4
5
6
7
8
Benzyl
Benzyl
Benzyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Phenyl
Benzyl
n-Butyl
tert-Butyl
Phenyl
H
H
H
H
H
H
H
H
4
3
2.5
4.5
4
3.5
3
2
5
5
3
4
95
92
98
90
95
90
92
95
95
98
98
95
98
88
98
98
107
108
109
100
110
—
111
109
112
113
114
—
Benzyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
p-Tolyl
p-Tolyl
p-Tolyl
o-Pyridyl
Cyclohexyl
R1 D R2 D
o-Chlorobenzyl
o-Methoxybenzyl
n-Butyl
9
R3 D R4 D
R3 D R4 D
Benzyl
Morpholine
Pyrrolidine
10
11
12
13
14
15
16
H
H
o-Chlorobenzyl
R3 D R4 D
tert-Butyl
n-Butyl
Pyrrolidine
5.5
3
3
115
116
117
118
H
H
Pyrrolidine
R3 D R4 D
Pyrrolidine
5.5
high yields as mentioned in Table 3. Again, steric effects have the formation of corresponding products (see “Supplemental
1
essential effect in the reaction of alcohol with carbamic acid. As Materials” file). In the H NMR and 13C NMR spectra, sig-
can be seen from Table 3, primary alcohols react faster than nals at 8.66–7.18 and 156.8–156.7 ppm due to the NH and
secondary ones (compare entry 2 with entry 3). Similarly, quaternary carbon atom of urea, respectively.
because of low nucleophilicity of phenol, the reaction of phenol
with carbamic acids was completed in longer reaction time case of unsymmetrical urea synthesis and urea in the case of
(compare entries 4, 6 with entry 1). carbamate synthesis) were observed during the course of the
No side reactions/products (e.g., symmetrical urea in the
In our experiments, completion of the reaction was con- reaction; thus, we believe that the present methodology opens
firmed by the disappearance of the amine/or alcohol on new possibilities for the synthetic organic chemistry and could
TLC, followed by the disappearance of NH2/or OH stretch- be an important addition to the existing methodologies.
ing frequencies at 3500 and 3300/or 3400–3300 cm¡1 in the
The efficiency of the present protocol was compared with
Fourier transform infrared (FTIR) spectra. It is worthy to the previously reported methods in the literature. The results
note that all the products listed in Tables 2 and 3 could be are shown in Table 4. It can be seen from Table 4 that, most of
simply purified by flash column chromatography and char- the reported methods suffer from using environmentally haz-
acterized using FTIR, NMR, and mass spectrometry (MS). ardous, high corrosive and high cost chemicals, harsh reaction
Absorption bands at 3383–3302/or 3364–3274 and 1689– conditions, multiple-step procedures, tedious work-up, long
1627/or 1716–1636 cm¡1 corresponding to NH and car- reaction times to achieve reasonable yields and limited sub-
bonyl groups of urea/or carbamate, respectively, confirmed strate scope.
Table 3. Preparation of structurally different carbamate by using triphenylphosphine / trichloroisocyanuric acid system.
Entry
R1
R2
R3
Time (h)
Isolated yield (%)
References
1
2
3
4
5
6
Phenyl
Phenyl
Phenyl
Phenyl
tert-Butyl
tert-Butyl
H
H
H
H
H
H
Benzyl
1-Heptyl
1-Phenylethyl
Phenyl
3
2.5
4
4.5
3.5
4
97
98
95
90
95
92
119
120
121
122
123
124
Benzyl
Phenyl

108
S. S. E. GHODSINIA AND B. AKHLAGHINIA
Table 4. Comparison of various methods and catalysts in 1-benzyl-3-phenylurea synthesis.
Entry
1
Substrates and reagents
Explanations
Catalysts
Time (h)
1
Isolated yield (%)
68
74
RNH2, CO2, DBU, PBu3, DBAD, N2
Low yield, multiple-step reaction, expensive reagent
(DBU, DBAD)
Long reaction time, multiple-step reaction, low yield
Tedious work-up, using of toxic cyanamides, limited
substrate scope
—
2
3
Cyanamides, benzyl alcohol, DCE (solvent)100
Cyanamides, dibenzyl ether, Aceticacid
(Solvent) 101
FeCl3
BF3.Et2O
4.5
2
86
94
4
5
6
N’-Phenyl urea, benzaldehyde, triethylsilane,
trifluoroacetic acid, toluene (solvent)102
RNH2, 2,2,2-trichloroethyl-N-phenyl carbamate,
THF (solvent)103
Long reaction time, highly corrosive reagent (TFA)
—
—
Se
18
30
97
97
Harsh reaction conditions, high-pressure conditions,
long reaction time
R2NH, nitrobenzene, CO, Et3N104
Hightemperature (150–160ꢀC), low yield, mixed
products (nonselective products), harsh reaction
conditions
1.5
14.4
7
8
9
N-benzyl-N’-phenylthiourea, thiophosgene in
Using of toxic thiophosgene which is not
environmental friendly, low yield, harsh reaction
conditions
Long reaction times, using costly and limited number
of commercially available 4-nitrophenyl-N-
benzylcarbamate
Excellent yield, short reaction time, using low-priced
reagents and experimental convenience, mild
reaction conditions, easy work-up, low-pressure
—
—
—
2
6
1
75
83
95
water, acetone (solvent)105
RNH2, 4-nitrophenyl-N-benzylcarbamate, Et3N,
dichloromethane (solvent)106
RNH2 or R2NH, CO2, TCCA, PPh3, dry 1,4-dioxane
(solvent)
Experimental
stirring. After completion of the reaction (4 h) as confirmed by
TLC, the reaction mixture was then poured into 15 mL distilled
water and extracted with ethyl acetate (3 £ 10). The organic
General
The products were purified by column chromatography. The layer was separated and dried over anhydrous sodium sulfate
purity determinations of the products were accomplished by and then passed through a short silica-gel column using n-hex-
TLC on silica gel polygram STL G/UV 254 plates (Merck, Ger- ane-ethyl acetate (1:1) as the eluent. 1-Benzyl-3-phenylurea
many). The melting points of products were determined with was obtained with 95% yield (0.214 g) after removing the sol-
an Electrothermal Type 9100 melting point apparatus (UK). vent under reduced pressure.
The FTIR spectra were recorded on an Avatar 370 FTIR
Therma Nicolet spectrometer (USA). The nuclear magnetic
Typical experimental procedure for preparation of benzyl
resonance (NMR) spectra were provided on Brucker Avance
phenyl carbamate (Table 2, entry 1)
300 and 400 MHz instruments in DMSO-d6. Coupling con-
stants J are given in Hz. Abbreviations used for 1H NMR signals Aniline (0.093 g, 1 mmol) was taken in dry 1,4-dioxane (10 mL)
are: s D singlet, d D doublet, t D triplet, q D quartet, and m D and gaseous CO2 was bubbled through it for 20–30 min at
multiplet. Elemental analyses were performed using a Thermo room temperature. To a cold solution of triphenylphosphine
Finnegan Flash EA 1112 Series instrument. Mass spectra (0.262 g, 1 mmol) in dry 1,4-dioxane (2 mL) trichloroisocyanu-
were recorded with a CH7A Varianmat Bremem instrument ric acid (0.076 g, 0.3 mmol) was added with continuous stirring.
(Germany) at 70 eV; in m/z (rel%). All of the products were The resultant white suspension was added slowly in two to
known compounds and characterized by the IR, MS, and com- three small portions to the produced phenyl carbamic acid,
parison of their melting points with known compounds. The which was followed by addition of benzyl alcohol (0.108 g,
1
structures of the novel products were further confirmed by H 1 mmol). The reaction temperature was raised to 80ꢀC with
NMR, 13C NMR spectroscopy, and elemental analysis data. stirring. After completion of the reaction (3.5 h) as confirmed
The full characterization data and sample IR, mass spectra and by TLC, the reaction mixture was then poured into 15 mL dis-
1H and 13C NMR spectra are presented in the Supplemental tilled water and extracted with ethyl acetate (3 £ 10). The
Materials (Figures S1–S69).
organic layer was separated and dried over anhydrous sodium
sulfate and then passed through a short silica-gel column using
n-hexane-ethyl acetate (1:1) as the eluent. Benzyl phenyl carba-
mate was obtained with 97% yield (0.205 g) after removing the
solvent under reduced pressure. The characterization data of
Typical experimental procedure for preparation of
1-benzyl-3-phenylurea (Table 2, entry 1)
Benzylamine (0.107 g, 1 mmol) was taken in dry 1,4-dioxane known urea derivatives and carbamates is presented in the Sup-
(10 mL) and gaseous CO2 was bubbled through it for 20– plemental Materials.
30 min at room temperature. To a cold solution of triphenyl-
phosphine (0.262 g, 1 mmol) in dry 1,4-dioxane (2 mL) tri-
chloroisocyanuric acid (0.076 g, 0.3 mmol) was added with
Conclusion
continuous stirring. The resultant white suspension was added A new, convenient and efficient protocol for the formation of
slowly in 2–3 small portions to the produced benzyl carbamic CÀÀO, and CÀÀN bonds essential to numerous organic synthe-
acid which was followed by addition of aniline (0.093 g, ses is described. The present method generates urea and carba-
1 mmol). The reaction temperature was raised to 80ꢀC with mate derivatives in good to excellent yields. The elegance of

PHOSPHORUS, SULFUR, AND SILICON
109
this process lies in its mild reaction conditions, substrate versa-
tility, high yields, short reaction times, using low-priced
reagents and experimental convenience.
12. Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A.G.;
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J.H. J. Med. Chem. 2004, 47, 1729-1738.
Funding
The authors gratefully acknowledge the partial support of this study by
Ferdowsi University of Mashhad Research Council.
15. Fu€ldner, S.; Mitkina, T.; Trottmann, T.; Frimberger, A.; Gruber, M.;
€
Konig, B. Urea derivatives enhance the photocatalytic activity of dye-
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