An efficient one-pot synthesis of N,N′-disubstituted phenylureas and N-aryl carbamates using hydroxylamine-O-sulfonic acid

Article abstract of DOI:10.1016/j.tet.2018.05.072

We have developed an efficient one-pot method for the microwave-assisted synthesis of ureas and carbamates via a proposed Lossen rearrangement. Herein we report the first examples of the direct conversion of benzoyl chlorides into N,N′-disubstituted ureas and N-aryl carbamates using hydroxylamine-O-sulfonic acid as reagent. Using our general method, we have produced 11 examples of N,N′-disubstituted phenylureas in yields up to 95% using various substituted anilines, and primary and secondary amines. Additionally, we were able to generate a series of N-aryl carbamates in moderate yields using primary, secondary and tertiary alcohols.

Full text of DOI:10.1016/j.tet.2018.05.072

Accepted Manuscript
An efficient one-pot synthesis of N,N′-disubstituted phenylureas and N-aryl
carbamates using hydroxylamine-O-sulfonic acid
Jennifer Bao, Dale Kuik, Geoffrey K. Tranmer
PII:
S0040-4020(18)30631-8
10.1016/j.tet.2018.05.072
TET 29579
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 26 February 2018
Revised Date: 23 May 2018
Accepted Date: 24 May 2018
Please cite this article as: Bao J, Kuik D, Tranmer GK, An efficient one-pot synthesis of N,N′-
disubstituted phenylureas and N-aryl carbamates using hydroxylamine-O-sulfonic acid, Tetrahedron
(2018), doi: 10.1016/j.tet.2018.05.072.
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An efficient one-pot synthesis of N,N’-
disubstituted phenylureas and N-aryl
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Jennifer Bao, Dale Kuik and Geoffrey K. Tranmer
College of Pharmacy, University of Manitoba, Winnipeg, MB, Canada

1
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Tetrahedron
journal homepage: www.elsevier.com
An efficient one-pot synthesis of N,N’-disubstituted phenylureas and N-aryl
carbamates using hydroxylamine-O-sulfonic acid
Jennifer Baoa, Dale Kuika and Geoffrey K. Tranmera,b
aCollege of Pharmacy, Faculty of Health Science, University of Manitoba, Winnipeg, MB, R3E 0T5, Canada
bDepartment of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We have developed an efficient one-pot method for the microwave-assisted synthesis
of ureas and carbamates via a proposed Lossen rearrangement. Herein we report the
first examples of the direct conversion of benzoyl chlorides into N,N’-disubstituted
ureas and N-aryl carbamates using hydroxylamine-O-sulfonic acid as reagent. Using
our general method, we have produced 11 examples of N,N’-disubstituted phenylureas
in yields up to 95% using various substituted anilines, and primary and secondary
amines. Additionally, we were able to generate a series of N-aryl carbamates in
moderate yields using primary, secondary and tertiary alcohols.
Available online
Keywords:
N,N’-Disubstituted Ureas
N-Aryl Carbamates
Hydroxylamine-O-sulfonic acid
Microwave-assisted Organic Synthesis
Lossen Rearrangement
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
Several methods currently exist for the synthesis of ureas,
however, these protocols possess limitations as they rely on the
use of potentially explosive reagents or require multiple synthetic
steps and have primarily been synthesized via the in situ
Ureas1 (R-NHCONH-R’) are a general class of heteroatomic
compounds that have been shown to possess biological activity
and serve as templates for numerous medicinal chemistry
programs.2 Historically, barbital (diethylmalonyl urea) was
discovered in the early 1900’s and was first used as the original
commercially available barbiturate (sleep aid/hypnotic).3 In the
following century, urea functional groups have played an integral
part in serving as a backbone motif for many drug discovery
efforts. In fact, entire classes of therapeutic agents exist that
possess ureas as a key functionality of the drug pharmacophore.4
For instance, sulfonylureas are used to treat diabetes5,6 and
nitrosoureas serve as DNA alkylating agents for the treatment of
cancer.7,8 Several other urea-containing therapeutics also exist,
such as the acylampicillins9 (antibiotics), zileuton10 (asthma),
boceprevir11 (HCV protease inhibitor) and sorafenib12,
regorafenib13 (urea kinase inhibitors14), just to name a few.15-18 As
a result, ureas are a privileged motif in the field of medicinal
chemistry and new methods for the synthesis of these
biologically important functional groups are required to give
efficient access to new drug candidates for medicinal chemistry
programs. New methods for the synthesis of structurally similar
carbamates (R-OCONH-R’) are equally important to provide
diversity, and biosimilar functional groups to ureas, in drug
discovery programs.
generation of acyl azides,19 followed by
a
Curtius
rearrangement,20,21 Figure 1 A. Unfortunately, due to the use of
highly toxic, and potentially explosive azidation reagents, these
reactions pose a safety hazard and are difficult to perform on
large scale, however some useful flow chemistry examples
exist.22 The use of transition metal catalyzed reactions for the
synthesis of ureas has also been explored (Pd/C, XPhos, CO),23
however, these reactions also require the use of potentially
explosive aliphatic and aromatic azides.
A
Lossen
rearrangement21,24,25 is a general method for the generation of
ureas and involves the conversion of hydroxamic acids into an
isocyanate, followed by reaction with an amine, Figure 1 B.
Unfortunately, these reactions require several synthetic and
purification steps (generation of hydroxamic acid from
commercially available carboxylic acids), and tend to have long
reaction times.26,27 Similarly, using small modifications of the
above reactions and substituting an alcohol for the amine, many
of these methods have also been used to generate analogous
carbamates. As part of a general research program dedicated to
the development of new synthetic methods, we set out to develop
a method for the synthesis of ureas and carbamates that was safer
(azide-free) and greener (fewer synthetic steps and metal-free
conditions) than existing methods. We envisioned a microwave-
———
Corresponding author. Tel.: +1-204-474-8358; fax: +1-204-789-3744; e-mail: geoffrey.tranmer@umanitoba.ca

2
Tetrahedron
ACCEPTED MANUSCRIPT
assisted method that utilized hydroxylamine-O-sulfonic acid
(HSA) as the key reagent that would enable the conversion of
commercially available active acids into ureas (or carbamates),
following addition of the corresponding amine (or alcohol,
respectively), Figure 1 C. Previously, the McCubbin group had
reported the use of HSA for the conversions of phenylboronic
acids into the corresponding anilines.28 As part of a collaboration,
our group extended this work to include a method for the
sonication and microwave-assisted primary amination of
potassium aryltrifluoroborates and arylboronic acids.29 We
proposed that the use of HSA, following condensation with an
acyl chloride, would generate an O-sulfonylhydroxamic acid
intermediate that would undergo a Lossen rearrangement and
form a reactive isocyanate in situ. Quenching this reactive
intermediate with an amine/alcohol would result in
unsymmetrical N,N’-disubstituted ureas or carbamates as a one-
pot process. Overall, this proposed method would avoid the use
of toxic and potentially explosive reagents, while also allowing
for the development of a rapid and efficient one-pot process via
microwave-assisted organic synthesis (MAOS).30,31 To the best of
our knowledge, a method has not appeared in the literature that
outlines the directly conversion of benzoyl chlorides into N,N’-
disubstituted ureas or carbamates using a hydroxylamine-O-
sulfonic acid reagent, Figure 1 C, and the corresponding
amine/alcohol. Typically, these types of conversions rely on the
use of azidation reagents32-34 or the generation of an activated
leaving group using alternate reagents, such as N-
by column chromatography, Table 1, entry a), via incubating the
reaction using microwave (MW) irradiation for 15 minutes at 100
oC. Following closer inspection, the result of the first step of this
reaction leads to the formation of a reactive isocyanate generated
in situ (Lossen rearrangement), and this result should not be that
surprising. The subsequent reaction of the isocyanate with
aqueous NaOH would simultaneously generate aniline 2 in situ,
following the loss of CO2. The newly generated aniline would
then be free to react with an equivalent of the isocyanate and
generate the desired symmetrical product. Removing the NaOH
from these reaction conditions resulted in no product being
generated, Table 1, entry b, however, adding 1.0 eq. of aniline to
the newly formed isocyanate gave the product in 16% yield
(Table 1, entry c, no water or NaOH). Recombining aqueous
NaOH with an equivalent of aniline and HSA/DIPEA/benzoyl
chloride in acetonitrile, Table 1, entry d, resulted in a moderate
yield of 43%. Under these conditions, both a decrease and
increase in the amount of DIPEA resulted in poorer yields, Table
1, entry e and f, respectively. Interestingly, removing aqueous
NaOH from these last reaction conditions resulted in a doubling
of the isolated yield, 50% versus 25% (entry g vs. f) while an
additional increase of the amount of DIPEA to 6.0 eq. did not
result in an appreciable increase in yield. In the next stage of
surveying reaction conditions, various equivalents of benzoyl
chloride and HSA were explored (entries i and j), along with
various solvents, such as DCM and THF, concentrations and
various temperatures and MW irradiation times, (not shown in
totality in Table 1). Finally, the best reaction conditions were
found to be, for the highest overall general yields, 1.25 eq.
benzoyl chloride 1, 1.0 eq., of aniline 2, 1.5 eq. of HSA, in
anhydrous DCM, at 100 oC for 5 minutes under microwave
irradiation, entry k. These reaction conditions were used in all
subsequent reactions as a general method for the synthesis of
N,N’-disubstituted phenylureas and N-aryl carbamates.
acylbenzotriazoles,35
ethyl
2-cyano-2-(4-nitrophenyl
sulfonyloxyimino)acetate,36 1-propane phosphonic acid cyclic
anhydride37 or Heck reaction conditions38. Herein we are the first
to report on the development of a general method for the
synthesis of N,N’-disubstituted phenylureas and carbamates using
hydroxylamine-O-sulfonic acid from benzoyl chloride (1) and
various amines/alcohols, under microwave conditions.
The overall yields for the synthesis of different ureas via the
condensation of HSA with benzoyl chloride under microwave
conditions, followed by the reaction of the resultant isocyanate
with various amines can be found in Table 2. Applying the
general optimized reaction conditions to the synthesis of 1,3-
diphenylurea using aniline as amine resulted in a 94% isolated
yield following traditional column chromatography. In a practical
sense, the reaction was performed by adding 1.5 eq. of HSA (a
solid) to an oven dried microwave vial, followed by anhydrous
DCM under argon with a rubber stopper. 4.0 eq. of DIPEA was
added dropwise to the vial, and the HSA was stirred until
dissolved (2-3 minutes). The benzoyl chloride was then added to
the reaction via syringe and stirred for 2-3 minutes allowing for
the formation of the O-sulfonyl hydroxamic acid. In the next
stage of the one-pot sequence, 1.0 eq. of aniline was added to the
vial via syringe, and the microwave vessel capped, and irradiated
in the microwave to 100 oC for 5 minutes. Following the reaction,
the crude reaction was placed in a larger round-bottom flask and
pre-absorbed onto silica gel followed by immediate purification
of the desired product by column chromatography, Table 2, entry
a. For this particular reaction, the purified product appeared to
contain an unidentified impurity and the purified product was
triturated using cold chloroform and filtered through a PYREX
36060 fritted glass Buchner funnel (4-5.5 um, fine).
2. Results and discussion
Our initial efforts into the development of a general method
for this type of transformation centered on the use of HSA in the
presence of benzoyl chloride and an amine. Representative
examples of a survey of different reaction conditions for the
development of an optimized method can be found in Table 1.
We started by using the standard conditions developed previously
for the primary amination of phenylboronic acids,29 without the
addition of any aniline 2. Interestingly, we were able to generate
the desired product in 26% isolated yield (following purification

3
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Table 1. Optimization reactions for the synthesis of 1,3-diphenylurea (3) using benzoyl chloride(1), aniline(2) and HSA (Scheme 1)
Entry 1a, 1b, HSA (eq.)
Solvent
MeCN/H2O
MeCN/H2O
MeCN
Base (eq.)
Base
NaOH
--
MW (min.)
Yield %a
a
b
c
d
e
f
1.0, 0, 1.0
1.0, 0, 1.0
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (1.0)
DIPEA (4.0)
DIPEA (4.0)
DIPEA (6.0)
DIPEA (4.0)
DIPEA (4.0)
DIPEA (4.0)
15
15
15
15
15
15
15
15
5
26
--
1.0, 1.0, 1.0
1.0, 1.0, 1.0
1.0, 1.0, 1.0
1.0, 1.0, 1.0
1.0, 1.0, 1.0
1.0, 1.0, 1.0
1.2, 1.0, 1.0
1.2, 1.0, 1.2
1.25, 1.0, 1.5
--
16
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN
NaOH
NaOH
NaOH
--
43
7
25
g
h
i
50
MeCN
--
53
MeCN
--
54
j
MeCN
--
5
46
94a(80)b
k
DCM
--
5
aIsolated yield following column chromatography (cc). bIsolated yield following trituration of cc purified product.
Table 2. Synthesis of N,N’-disubstituted phenylureas using benzoyl chloride (1) and HSA (Scheme 2)
Entry
Amine
Product Name (Compound #)
1,3-Diphenylurea (3)
Product Structure
Yield %a
80b
a
80b
71b
68b
52b
78
b
c
d
e
f
N-(2-Methylphenyl)-N’-phenylurea (4)
N-(4-Methylphenyl)-N’-phenylurea (5)
N-(4-Methoxyphenyl)-N’-phenylurea (6)
N-(4-Chlorophenyl)-N’-phenylurea (7)
N-(2,4-Dimethylphenyl)-N’-phenylurea (8)
N-(2,4,6-Trimethylphenyl)-N’-phenylurea (9)
69
g
66
h
N-Methyl-N,N’-diphenylurea (10)

4
Tetrahedron
ACCEPTED MANUSCRIPT
N-Benzyl-N’-phenylurea (11)
93
i
78
95
j
N-Phenyl-4-morpholinecarboxamide (12)
N-(Phenyl)-N’-butylurea (13)
k
aIsolated yield following column chromatography (cc). bIsolated yield following trituration of cc purified product.
The product was then collected once again and provided for an
80% isolated yield of 1,3-diphenylurea. For subsequent reactions,
some of the products required trituration due the presence of an
impurity following column chromatography (entries a-e) while
others did not, (entries f-k). The yields are reported following
trituration, and/or alone following the initial column
chromatography stage. The NMR of the products can be found in
the supplemental section and the associated purity (as inferred by
the spectra) is representative of the yield following column
chromatography, or trituration if required.
As with many other publications that seek to develop a new
method for the synthesis of ureas, changing the nucleophile to an
alcohol results in the generation of the corresponding carbamate,
generally under similar reaction conditions originally developed
for the generation of the ureas. To examine the synthetic utility of
our general reaction method, we explored the same reaction
conditions using various alcohols to trap the in situ generated
isocyanate. Located in Table 3, are the results of this
interrogation. For entry a, benzyl alcohol was found to give a
moderate isolated yield of 45%, under the same conditions as
previously reported for the ureas, (Table 3, entry a versus Table
2, entry i). Ethanol and propanol were also used under our
general reaction conditions, and gave comparable yields of 48%
and 49%, Table 3, entries b and c. Use of a secondary alcohol
(isopropanol, entry d) also gave a similarly moderate yield of
48%. The very sterically hindered tert-butanol was found to give
a lower yield of 27%, most likely due to the reduced
nucleophilicity of the alcohol (Table 3, entry e). It is proposed
that the reduced yields for the generation of the carbamates, in
comparison to the ureas, is potentially a result of the presence of
water in the alcohol reagents. For the chosen alcohols, an aliquot
was taken from a reagent bottle that had been sitting on the self
for an extend period of time, (rather than new anhydrous
alcohols). There is a potential that these alcohols may contain a
slightly elevated amount of water, in comparison to the anilines,
resulting in reduced yields. In some of the cases, benzoic acid
was observed as a by-product of the reaction, most likely a result
of water quenching any unreacted benzoyl chloride. Alternately,
if these reactions were conducted using anhydrous alcohols, it
would be expected that the product may be generated in higher
overall yields. However, due to the convenience of using easily
obtainable benzoyl chlorides, HSA and readily available alcohols
off-the-shelf, the representative reaction outlined in scheme 3
serves as an example of a useful one-pot synthetic method for the
generation of carbamates, although occurring in moderate yields.
Table 2 summarizes the observed yields for the synthesis of
N,N’-disubstituted phenylureas following addition of various
amines. In comparison to aniline (80%), the substituted anilines
gave similar or slightly diminished final isolated yields for
electron donating substituents ortho-methyl (80%), para-methyl
(71%), para-methoxy (68%), (for entries b,
c and d,
respectively). For the aniline containing an electron-withdrawing
substituent, para-chloro, the yield was found to be the lowest
overall at 52% following trituration. The use of 2,4-dimethyl-
and 2,4,6-trimethylaniline was also explored under the general
reaction conditions and found to give 78% and 69% yield,
respectively (entries f and g). The lower yield of the ortho-
disubstituted aniline (entry g) is most likely a result of the
reduced nucleophilicity of the aniline caused by steric hindrance
and is not unexpected. Similarly, use of the secondary amine, N-
methylaniline, also gave a similar yield of 66%. In the next entry
(i), an amine that would be expected to serve as a stronger
nucleophile (benzylamine) gave an excellent yield of 93%, while
butylamine was found to give the highest overall yield of 95%.
Morpholine, a secondary amine, was found to give a slightly
diminished yield of 78%. Overall, from these 11 examples, it can
be rationalized that the steric and electronic nature of the
nucleophile from the corresponding amine would play a role in
the overall yield of the reactions. The final stage of the reaction is
a result of the nucleophilic addition of the amine, with the
HSA/benzoyl chloride derived isocyanate, which would have an
effect on the final yield. However, this step would normally be
expected to occur relatively quickly.
Table 3. Synthesis of N-aryl carbamates using benzoyl chloride (1) and HSA (Scheme 3)
Entry
Alcohol
Product Name (Compound #)
Product Structure
Yield %a
45
a
Benzyl N-phenylcarbamate (14)

5
ACCEPTED MANUSCRIPT
48
49
48
27
b
c
Ethyl N-phenylcarbamate (15)
Propyl N-phenylcarbamate (16)
Isopropyl N-Phenylcarbamate (17)
tert-Butyl N-Phenylcarbamate (18)
d
e
aIsolated yield following column chromatography (cc).
The proposed mechanism for this reaction is relatively
straight-forward. As eluded to earlier, we envisioned that the
condensation of HSA with benzoyl chloride, under base
catalyzed conditions (DIPEA), would generate an O-sulfonyl
hydroxamic acid derivative that is poised to perform an
intramolecular rearrangement. In the next step, it is possible that
the hydroxamic acid derivative is converted to its conjugate base
by abstraction of a hydrogen atom by base (from nitrogen, not
shown), followed by a spontaneous rearrangement to form an
isocyanate intermediate. However, it is clear that a Lossen
rearrangement is the most likely process that instills a nitrogen
atom in between the aromatic group and the carbonyl carbon,
leading to the generation of an isocyanate. In the next step of the
one-pot reaction, nucleophilic addition of the amine or alcohol
leads to the production of the urea (Table 2) or carbamate (Table
3), respectively.
chlorides) into the corresponding ureas and carbamates using
hydroxylamine-O-sulfonic acid as the key reagent.
4. Experimental section
4.1. General information
All glass microwave vessels were oven dried overnight before
use. Microwave reactions were performed using the CEM
Discover
SP Microwave Synthesizer. All chemicals and
solvents were purchased from commercial sources and used
without further purification. Anhydrous DCM and acetonitrile
were purchased from VWR as DriSolv solvents in septum
sealed bottles and used without further purification. Purification
of products were performed by flash chromatography using the
Combiflash Rf+ system, with RediSep 12g normal phase
disposable columns and crude material pre-absorbed onto silica
gel (40-60µ, 60A RediSep Silica gel) and purified via the solid
load method. Analytical thin layer chromatography was
performed on Merck TLC plates (Silica Gel 60 F254 Aluminum
sheets). 1H-NMR and 13C-NMR spectra were recorded on a
Bruker 400 MHz machine with chemical shifts reported in parts
per million ((CD3)2SO = 2.50 ppm), coupling constants (J) in
Hertz (Hz), and multiplicity as follows: s = singlet, d = doublet,
dd = doublet of doublets, t = triplet, tt = triplet of triplets, q =
quartet, m = multiplet, bs = broad singlet.
O
O
O
OH
HSA
Cl
N
S
H
O
O
Base
Lossen
Rearrangement
H
N
X
N
R
C
HX
+
O
R
O
X = NH, O
Proposed mechanism Lossen rearrangement
4.2. General procedure for the synthesis of N,N’-disubstituted
phenylureas (Table 2)
To an oven dried 10 mL or 35 mL microwave vial capped
with a rubber septum and placed under argon, 0.2545 g
hydroxylamine-O-sulfonic acid (HSA) (1.5 eq., 2.25 mmol) was
added followed by 5 mL of anhydrous DCM with stirring. 1.05
mL diisopropylethyl amine (DIPEA) (4.0 eq., 6 mmol) was
added slowly via syringe to the mixture to allow HSA to
dissolve, and the reaction stirred for approx. 2-3 minutes.
Benzoyl chloride (1.25 eq., 1.88 mmol) was then added dropwise
via syringe to the solution and the reaction stirred for approx. 2-3
minutes, until the reaction appeared to have subsided. Aniline or
amine (1.0 eq., 1.5 mmol) was then added via syringe and the
vial was removed from under argon and capped with a
microwave cap. The reaction vessel was then placed in the
microwave reactor where it was irradiated at 100 oC for 5
minutes. Once complete, the reaction mixture was transferred to a
100 mL RB flask and pre-absorbed onto silica gel where it was
purified via flash chromatography in a gradient of 0 ꢀ 100%
EtOAc/Hexanes to yield the target product.
3. Conclusion
Overall, we have developed a synthetically useful one-pot
method for the generation of ureas and carbamates that uses
readily commercially available reagents, that is performed under
safer (azide-free) and greener conditions (fewer total
synthetic/purification steps and metal-free) than alternate
methods. In total we were able to develop a general method for
the synthesis of N,N’-disubstituted phenylureas, 11 entries, Table
1, with excellent yields up to 95% using microwave irradiation
and very short reaction times (5 minutes). Overall, we used a
number of different amines, from sterically hindered anilines, to
primary and secondary amines to generate products in yields
from 52% to 90+%. When applied to the generation of
carbamates, this method also produced the corresponding N-aryl
carbamates in moderate yields. Correspondingly, we would
expect that the general conditions reported here are well suited to
serve as a general method for the generation of ureas or
carbamates using HSA/acyl chlorides and various nucleophiles
(amines/alcohols). Currently, we are modifying these general
reaction condition to convert carboxylic acids (instead of benzoyl
Some isolated aryl ureas appeared to contain unidentified
1
contaminants as seen in the H-NMR as well as the presence of
colour within the product. Therefore, certain aryl ureas that
required further purification were vacuum filtered through a 15

6
Tetrahedron
mL PYREX 36060 fritted glass Buchner funnel (4-5.5 µm, fine)
trituration with cold chloroform, 193 mg (52% yield) of the title
ACCEPTED MANUSCRIPT
and triturated with small amounts of cold chloroform after flash
chromatography, provided they were insoluble, in order to yield
pure product. The purity of the final triturated products can be
verified by examining the NMR located in the supplemental for
compounds 3 through 7.
compound was obtained as an off-white solid and had similar
spectroscopic data to that reported in the literature.42 Rf: 0.34
(50% EtOAc/Hexanes). H-NMR (400 MHz, DMSO-d6): δ 8.86
1
(s, 1H), 8.75 (s, 1H), 7.51- 7.44 (m, 4H), 7.33- 7.25 (m, 4H), 6.97
(t, J = 7.3, 1H). 13C-NMR (101 MHz, DMSO-d6): δ 152.5, 139.6,
138.8, 128.8, 128.6, 125.3, 122.0, 119.7, 118.3.
4.2.1. 1,3-Diphenylurea (3)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and
aniline (0.14 mL, 1.5 mmol). After flash chromatography, 306
mg (94% yield) of solid was isolated. Following trituration with
cold chloroform, 260 mg (80% yield) of the title compound was
obtained as an off-white solid and had similar spectroscopic data
4.2.6. N-(2,4-Dimethylphenyl)-N’-phenylurea (8)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and 2,4-
dimethylaniline (0.19 mL, 1.5 mmol). After flash
chromatography, 286 mg (78% yield) of the title compound was
obtained as a beige solid and had similar spectroscopic data to
that reported in the literature.43 Rf: 0.42 (50% EtOAc/Hexanes).
1H-NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 7.85 (s, 1H),
7.66 (d, J = 8.2, 1H), 7.45 (d, J = 8.0, 2H), 7.27 (t, J = 7.7, 2H),
6.98- 6.93 (m, 3H), 2.22 (s, 3H), 2.20 (s, 3H). 13C-NMR (101
MHz, DMSO-d6): δ 152.8, 140.0, 134.8, 131.7, 130.7, 128.8,
127.8, 126.6, 121.6, 121.5, 117.9, 20.4, 17.8.
to that reported in the literature.34 Rf
:
0.41 (50%
1
EtOAc/Hexanes). H-NMR (400 MHz, DMSO-d6): δ 8.66 (s,
2H), 7.45 (d, J = 7.9, 4H), 7.27 (t, J = 7.8, 4H), 6.96 (t, J = 7.3,
2H). 13C-NMR (101 MHz, DMSO-d6): δ 152.5, 139.7, 128.8,
121.8, 118.2.
4.2.2. N-(2-Methylphenyl)-N’-phenylurea (4)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and o-
toluidine (0.16 mL, 1.5 mmol). After flash chromatography, 339
mg (98% yield) of solid was isolated. Following trituration with
cold chloroform, 274 mg (80% yield) of the title compound was
obtained as an off-white solid and had similar spectroscopic data
to that reported in the literature.39 Rf: 0.42 (50%
4.2.7. N-(2,4,6-Trimethylphenyl)-N’-phenylurea (9)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and
2,4,6-trimethylaniline (0.14 mL, 1.5 mmol). After flash
chromatography, 263 mg (69% yield) of the title compound was
obtained as an off-white solid and had similar spectroscopic data
to that reported in the literature.34 Rf: 0.37 (50%
1
1
EtOAc/Hexanes). H-NMR (400 MHz, DMSO-d6): δ 9.03 (s,
EtOAc/Hexanes). H-NMR (400 MHz, DMSO-d6): δ 8.68 (bs,
1H), 7.93 (s, 1H), 7.85 (d, J = 7.9, 1H), 7.47 (d, J = 7.6, 2H),
7.28 (t, J = 7.9, 2H), 7.18-7.12 (m, 2H), 6.98-6.92 (m, 2H), 2.24
(s, 3H). 13C-NMR (101 MHz, DMSO-d6): δ 152.7, 139.9, 137.4,
130.2, 128.8, 127.5, 126.2, 122.7, 121.7, 121.0, 118.0, 17.9
1H), 7.61 (s, 1H), 7.44 (d, J = 8.1, 2H), 7.24 (t, J = 7.8, 2H),
6.93-6.87 (m, 3H), 2.22 (s, 3H), 2.16 (s, 6H). 13C-NMR (101
MHz, DMSO-d6): δ 153.3, 140.4, 135.3, 134.9, 132.7, 128.7,
128.3, 121.3, 117.8, 20.5, 18.2.
4.2.3. N-(4-Methylphenyl)-N’-phenylurea (5)
4.2.8. N-Methyl-N,N’-diphenylurea (10)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and p-
toluidine (161 mg, 1.5 mmol). After flash chromatography, 310
mg (91% yield) of solid was isolated. Following trituration with
cold chloroform, 241 mg (71% yield) of the title compound was
obtained as an off-white solid and had similar spectroscopic data
to that reported in the literature.40,41 Rf: 0.42 (50%
EtOAc/Hexanes).1H-NMR (400 MHz, DMSO-d6): δ 8.62 (s,
1H), 8.56 (s, 1H), 7.44 (d, J = 7.9, 2H), 7.33 (d, J = 8.4, 2H),
7.26 (t, J = 7.9, 2H), 7.08 (d, J = 8.3, 2H), 6.95 (t, J = 7.3, 1H),
2.24 (s, 3H). 13C-NMR (101 MHz, DMSO-d6): δ 152.6, 139.8,
137.1, 130.6, 129.2, 128.8, 121.7, 118.3, 118.1, 20.3.
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and N-
methylaniline (0.16 mL, 1.5 mmol). After flash chromatography,
219 mg (66% yield) of the title compound was obtained as a
white solid and had similar spectroscopic data to that reported in
1
the literature.44 Rf: 0.42 (50% EtOAc/Hexanes). H-NMR (400
MHz, CDCl3): δ 7.45 (t, J = 7.6, 2H), 7.36- 7.28 (m, 5H), 7.21 (t,
J = 7.9, 2H), 6.96 (t, J = 7.2, 1H), 6.33 (bs, 1H), 3.32 (s, 3H).
13C-NMR (101 MHz, CDCl3): δ 154.1, 142.6, 138.7, 130.0,
128.5, 127.5, 127.1, 122.5, 118.9, 37.0.
4.2.9. N-Benzyl-N’-phenylurea (11)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and
benzylamine (0.16 mL, 1.5 mmol). After flash chromatography,
308 mg (93% yield) of the title compound was obtained as a
white solid and had similar spectroscopic data to that reported in
4.2.4. N-(4-Methoxyphenyl)-N’-phenylurea (6)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and 4-
methoxyaniline (185 mg, 1.5 mmol). After flash
chromatography, 301 mg (81% yield) of solid was isolated.
Following trituration with cold chloroform, 252 mg (68% yield)
of the title compound was obtained as a pale purple solid and had
similar spectroscopic data to that reported in the literature.40 Rf:
1
the literature.40 Rf: 0.36 (50% EtOAc/Hexanes). H-NMR (400
MHz, DMSO-d6): δ 8.56 (s, 1H), 7.40 (d, J = 8.2, 2H), 7.35-7.29
(m, 4H), 7.25-7.20 (m, 3H), 6.89 (t, J = 7.4, 1H), 6.61 (t, J = 5.8,
1H), 4.30 (d, J = 6.0, 2H). 13C-NMR (101 MHz, DMSO-d6): δ
155.3, 140.5, 140.4, 128.7, 128.3, 127.1, 117.7, 42.7.
1
0.30 (50% EtOAc/Hexanes). H-NMR (400 MHz, DMSO-d6): δ
8.57 (s, 1H), 8.46 (s, 1H), 7.43 (dd, J = 7.5, 1.1, 2H), 7.35 (d, J =
9.0, 2H), 7.26 (t, J = 7.9, 2H), 6.94 (tt, J =7.4, 1.1, 1H), 6.86 (d, J
= 9.0, 2H), 3.71 (s, 3H). 13C-NMR (101 MHz, DMSO-d6): δ
154.4, 152.7, 139.9, 132.7, 128.7, 121.6, 120.0, 118.1, 114.0,
55.2.
4.2.10. N-Phenyl-4-morpholinecarboxamide (12)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and
morpholine (0.13 mL, 1.5 mmol). After flash chromatography,
239 mg (78% yield) of the title compound was obtained as a
white solid and had similar spectroscopic data to that reported in
4.2.5. N-(4-Chlorophenyl)-N’-phenylurea (7)
1
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and 4-
chloroaniline (0.191 g, 1.5 mmol). After flash chromatography,
248 mg (67% yield) of off-white solid was isolated. Following
the literature.45 Rf: 0.33 (100% EtOAc). H-NMR (400 MHz,
CDCl3): δ 7.35-7.32 (m, 2H), 7.30-7.25 (m, 2H), 7.04 (tt, J =
7.3, 1.3, 1H), 6.57 (bs, 1H), 3.69 (t, J = 4.9, 4H), 3.45 (t, J = 4.9,

7
4H). 13C-NMR (101 MHz, CDCl3): δ 155.2, 138.7, 128.9, 123.3,
120.1, 66.4, 44.2.
2H), 7.06 (tt, J = 7.3, 1.1, 1H), 6.83 (bs, 1H), 4.13 (t, J = 6.7,
ACCEPTED MANUSCRIPT
2H), 1.74-1.66 (m, 2H), 0.98 (t, J = 7.4, 3H). 13C-NMR (101
MHz, CDCl3): δ 153.8, 138.0, 128.9, 123.2, 118.6, 66.8, 22.2,
10.3.
4.2.11. N-(Phenyl)-N’-butylurea (13)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and 1-
butylamine (0.15 mL, 1.5 mmol). After flash chromatography,
277 mg (95% yield) of the title compound was obtained as a
white solid and had similar spectroscopic data to that reported in
4.3.4. Isopropyl-N-phenylcarbamate (17)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and 2-
propranol (0.11 mL, 1.5 mmol). After flash chromatography, 123
mg (48% yield) of the title compound was obtained as a colorless
crystalline solid and had similar spectroscopic data to that
1
the literature.40 Rf: 0.37 (50% EtOAc/Hexanes). H-NMR (400
MHz, DMSO-d6): δ 8.37 (s, 1H), 7.37 (d, J = 8.2, 2H), 7.20 (t, J
= 7.8, 2H), 6.86 (t, J = 7.2, 1H), 6.09 (t, J = 5.5, 1H), 3.06 (app.
q, J = 6.4, 2H), 1.44-1.25 (m, 4H), 0.89 (t, J = 7.2, 3H). 13C-
NMR (101 MHz, DMSO-d6): δ 155.2, 140.6, 128.6, 120.9,
117.5, 38.7, 31.9, 19.5, 13.7.
reported in the literature.48 Rf: 0.47 (20% EtOAc/Hexanes). H-
1
NMR (400 MHz, CDCl3): δ 7.39 (d, J = 7.9, 2H), 7.30 (t, J = 7.9,
2H), 7.05 (t, J = 7.3, 1H), 6.66 (bs, 1H), 5.03 (m, 1H), 1.30 (d, J
= 6.2, 6H). 13C-NMR (101 MHz, CDCl3): δ 153.2, 138.1, 129.0,
123.2, 118.5, 68.7, 22.0.
4.3. General procedure for the synthesis of N-aryl carbamates
4.3.5. tert-Butyl-N-phenylcarbamate (18)
(Table 3)
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and tert-
butanol (0.11 mL, 1.5 mmol). After flash chromatography, 83 mg
(27% yield) of the title compound was obtained as a colorless
crystalline solid and had similar spectroscopic data to that
To an oven dried 10 mL or 35 mL microwave vial capped
with a rubber septum and placed under argon, 0.2545 g
hydroxylamine-O-sulfonic acid (1.5 eq., 2.25 mmol) was added
followed by 5 mL of anhydrous DCM with stirring. 1.05 mL
DIPEA (4.0 eq., 6 mmol) was added slowly via syringe to the
mixture to allow HSA to dissolve, and the reaction stirred for
approx. 2-3 minutes. Benzoyl chloride (1.25 eq., 1.88 mmol) was
then added dropwise via syringe to the solution and the reaction
stirred for approx. 2-3 minutes, until the reaction appeared to
have subsided. Alcohol (1.0 eq., 1.5 mmol) was then added via
syringe and the vial was removed from under argon and capped
with a microwave cap. The reaction vessel was then placed in the
microwave reactor where it was irradiated at 100 oC for 15
minutes. Once complete, the reaction mixture was transferred to a
100 mL RB flask and pre-absorbed onto silica gel where it was
purified via flash chromatography in a gradient of 0 ꢀ 20%
EtOAc/ Hexanes to yield the target product.
1
reported in the literature.46 Rf: 0.51 (20% EtOAc/Hexanes). H-
NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.0, 2H), 7.31-7.26 (m,
2H), 7.03 (t, J = 7.3, 1H), 6.49 (bs, 1H), 1.52 (s, 9H). 13C-NMR
(101 MHz, CDCl3): δ 152.7, 138.3, 129.0, 123.0, 118.5, 80.5,
28.3.
Acknowledgments
We thank the Natural Sciences and Engineering Research
Council of Canada (RGPIN-2017-05938) and the University of
Manitoba College of Pharmacy (to GKT and DK) for financial
support.
4.3.1. Benzyl-N-phenylcarbamate (14)
Supplementary data
The title compound was prepared following the general
procedure using benzoyl chloride (0.22 mL, 2.25 mmol) and
benzylalcohol (0.16 mL, 1.5 mmol). After flash chromatography,
157 mg (45% yield) of the title compound was obtained as a
colorless crystalline solid and had similar spectroscopic data to
that reported in the literature.46 Rf: 0.43 (20% EtOAc/Hexanes).
1H-NMR (400 MHz, CDCl3): δ 7.41- 7.29 (m, 9H), 7.08 (t, J =
7.3, 1H), 6.76 (bs, 1H), 5.21 (s, 2H). 13C-NMR (101 MHz,
CDCl3): δ 153.3, 137.7, 136.0, 129.0, 128.6, 128.3, 128.3, 123.5,
118.7, 67.0.
Supplementary material related to this article can be found at
[insert DOI url for website].
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