Synthesis of unsymmetrical biaryl ureas from N-carbamoylimidazoles: Kinetics and application

Article abstract of DOI:10.1016/j.tet.2012.05.002

N-Carbamoylimidazoles dissociate in solution to yield imidazole and an isocyanate that may be reacted with another aryl amine to form an unsymmetrical biaryl urea. This paper investigates the reaction kinetics and the influence of electron withdrawing/donating substituents on the reaction of N-carbamoylimidazoles with aniline. The overall reaction mechanism involves two zwitterionic intermediates, formed during dissociation and upon reaction of the liberated isocyanate with aniline. The rate limiting step for the reaction is a base catalysed proton transfer from the second zwitterionic intermediate. Although electron withdrawing substituents on the aryl group hinder dissociation, they significantly increase reaction rates compared to compounds bearing electron donating substituents. The imidazole liberated upon dissociation catalyses the rate determining step so that reactions of dissociated N-carbamoylimidazoles proceed more rapidly than those involving only isocyanates. In addition, the imidazole eliminates the need for anhydrous reaction conditions. The N-carbamoylimidazole methodology was demonstrated by preparing sorafenib, a biaryl urea kinase inhibitor, in good yield and excellent purity.

Full text of DOI:10.1016/j.tet.2012.05.002

Tetrahedron 68 (2012) 6065e6070
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of unsymmetrical biaryl ureas from N-carbamoylimidazoles:
kinetics and application
,
b
c
a
Tristan Rawling a , Andrew M. McDonagh , Bruce Tattam , Michael Murray
*
a Pharmacogenomics and Drug Development Group, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia
b Institute for Nanoscale Technology, University of Technology Sydney, NSW 2007, Australia
c Thomas R. Watson Mass Spectroscopy Facility, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Carbamoylimidazoles dissociate in solution to yield imidazole and an isocyanate that may be reacted
with another aryl amine to form an unsymmetrical biaryl urea. This paper investigates the reaction ki-
netics and the influence of electron withdrawing/donating substituents on the reaction of N-carbamoy-
limidazoles with aniline. The overall reaction mechanism involves two zwitterionic intermediates, formed
during dissociation and upon reaction of the liberated isocyanate with aniline. The rate limiting step for
the reaction is a base catalysed proton transfer from the second zwitterionic intermediate. Although
electron withdrawing substituents on the aryl group hinder dissociation, they significantly increase re-
action rates compared to compounds bearing electron donating substituents. The imidazole liberated
upon dissociation catalyses the rate determining step so that reactions of dissociated N-carbamoylimi-
dazoles proceed more rapidly than those involving only isocyanates. In addition, the imidazole eliminates
the need for anhydrous reaction conditions. The N-carbamoylimidazole methodology was demonstrated
by preparing sorafenib, a biaryl urea kinase inhibitor, in good yield and excellent purity.
Received 14 February 2012
Received in revised form 12 April 2012
Accepted 1 May 2012
Available online 8 May 2012
Keywords:
Carbamoylimidazole
Urea
Isocyanate
Imidazole
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1) and examine the influence of electron withdrawing/
donating groups on the rates of the reactions. This facile procedure
The biaryl urea motif is an important pharmacophore with nu-
merous applications in pharmaceutical drugs and agrochemicals.1,2
Unsymmetrical aryl urea compounds are generally prepared by the
coupling of an aryl amine and aryl isocyanate. The limited avail-
ability of many isocyanates often necessitates their synthesis in the
laboratory, commonly using phosgene or its equivalents. This
methodology can be undesirable due to the toxicities of the iso-
cyanates and phosgene, low yields resulting from the instabilities of
the isocyanates, and the unwanted formation of symmetrical urea
by-products. Due to the increasing importance of unsymmetrical
biaryl urea compounds, considerable efforts have been directed
towards the development of new, efficient and safe synthetic pro-
tocols. Numerous alternative methods have been reported.1,3e5
However, their application is restricted by the use of expensive
reagents and laborious reaction procedures, as well as formation of
symmetrical urea by-products.
utilises N,N-carbonyldiimidazole (CDI), a common, inexpensive and
easily handled crystalline solid.
NH2
O
NH2
N
N
H
N
H
N
H
N
N
N
N
N
O
O
R
R
R
1a-e
2a-e
Scheme 1. Synthesis of unsymmetrical biaryl ureas via N-carbamoylimidazoles.
Carbamoylimidazole compounds are readily prepared by treat-
ment of an amine with CDI.6,7 The carbamoylimidazole may then be
used to prepare unsymmetrical ureas. The reaction of N,N-di-
substituted carbamoylimidazoles with primary and secondary
amines to prepare tri- and tetra-substituted ureas is well-known,
and proceeds via a direct nucleophilic attack to the carbonyl
group following activation with iodomethane.6,8 The preparation of
unsymmetrical ureas from N-carbamoylimidazole compounds has
received significantly less attention. Rather than react via direct
nucleophilic attack, it has been established that these compounds
dissociate to an isocyanate and imidazole in solution, which may
then react with amines to form unsymmetrical urea products.9e11
We examine here a straightforward synthetic procedure to pre-
pare aryl urea compounds via N-carbamoylimidazole compounds
* Corresponding author. Tel.: þ61
2
9351 2704; fax: þ61
2 9351 4391;
e-mail addresses: tristan.rawling@sydney.edu.au, trawling@pharm.usyd.edu.au
(T. Rawling).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.002

6066
T. Rawling et al. / Tetrahedron 68 (2012) 6065e6070
Since this discovery almost 60 years ago, its synthetic application
has been limited,12e17 and no work has explored the kinetics of the
reaction. However, as we show here, this reaction provides a useful
pathway to prepare unsymmetrical aryl urea compounds.
from the 1H NMR spectra and are shown in Table 1. Dissociation of
the N-carbamoylimidazole compounds in solution proceeds via
a two-step mechanism: diffusion-controlled transfer of the NeH
proton to the imidazole group is followed by dissociation of the
resulting zwitterionic intermediate to an isocyanate and imidazole
(Fig.1).18 The 1H NMR spectroscopic data of 1aec show that electron
withdrawing substituents decrease the electron densities at the
NeH protons (Table 1), and may therefore be expected to decrease
the NeH pKa values and increase the rate of proton transfer when
forming the zwitterionic intermediate. However, consistent with
previous findings,11 electron withdrawing substituents decreased
the amount of dissociation, while electron donating substituents
increased the degree of dissociation. In contrast to 1aee, the benzyl
substituted compound 1f did not dissociate in solution. This was
attributed to an absence of resonance stabilisation of the zwitter-
ionic intermediate formed after the initial proton transfer step.
2. Results and discussion
The N-carbamoylimidazole compounds, 1aee (Table 1), were
prepared by the reaction of 4-substituted anilines with CDI at 50 ꢀC
for 18 h. 1aee precipitated from the reaction mixtures and were
isolated as white solids, which showed no signs of degradation
after three months at room temperature. For comparison, benzyl-
carbamoylimidazole, 1f, was also prepared by a similar method.
The 1H NMR spectra of 1aee show variations attributed to the
different electron withdrawing or donating strengths of the sub-
stituents. The electron withdrawing groups in 1aec cause a down-
field shift in the aromatic proton resonances compared to those of
the electron donating groups in 1dee. The chemical shifts of the
NeH protons, which appear as broad low-field signals, are affected
in a similar manner (Table 1). The influence of the substituents
extends as far as the imidazole ring, with small shifts observed in
the imidazole proton resonances across the series.
H
N
NH
H
N
N
N
N-
N
NCO
O
O
+
R
R
N
R
Fig. 1. Dissociation of an N-carbamoylimidazole via a zwitterionic intermediate.
The 1H NMR spectra of 1aee also contain additional sets of ar-
omatic proton resonances. These are attributed to the aryl iso-
cyanates that form upon dissociation of 1aee and are upfield from
those of the un-dissociated compounds. Accompanying these sig-
nals are resonances at d 7.51 and 6.95 from free imidazole. The dis-
sociation constants (Kd) for the equilibria between 1aee and the
Unsymmetrical ureas 2aee were prepared by reactions of 1aee
with aniline. The reactions proceeded rapidly (<30 min) and in
good yields (Table 1). 1f, which does not dissociate in solution,
failed to react with aniline and demonstrates that alkyl carba-
moylimidazoles are not suitable starting materials for the prepa-
ration of ureas by this method. Interestingly, it was found that
reactions of 1aee yielded pure products under non-anhydrous re-
action conditions. The initial rates of the reactions of 1aee with
aniline in THF at 20 ꢀC were determined (Table 1). The substituents
on the aryl group have a dramatic effect. Faster rates were observed
for compounds 1aec, which bear electron withdrawing groups,
compared to 1dee, which bear electron donating groups.
corresponding aryl isocyanates and imidazole were determined
Table 1
1H NMR spectroscopic data, dissociation constants (Kd) and rate constants for re-
actions of 1aef with aniline
H
Kd
N
N
N
H N
A linear relationship was observed between log rate and the
Hammett substituent constants for the aromatic substituents
NCO
R
R
+
N
O
1a-f
(Fig. 2). From the slope of the line of best fit a reaction constant,
r, of
2.69 was determined. A positive value is characteristic of reactions
r
that proceed more rapidly as the electron withdrawing character of
the aryl substituent increases, and has been reported for the re-
action of aromatic isocyanates with alcohols.19 In contrast, the
dissociation step, which is hindered by electron withdrawing
H
N
H
N
H
k
NH2
N
N
N
R
R
+
O
O
1a-e
2a-e
groups, has a negative reaction constant (
hypothesised from this data that the rate determining step for this
reaction occurs after liberation of the isocyanate.
r
¼ꢁ1.51, Fig. 2). We
Initial ratec
(10ꢁ7 M sꢁ1
Yield of
a,b
R
NH chemical Kd
shift (ppm)a
)
2aee (%)d
That the dissociation of the N-carbamoylimidazoles is not rate
determining was supported by the reaction orders determined for
1a
1b
9.74
9.65
7.66ꢂ10ꢁ6 3.46
3.89ꢂ10ꢁ5 0.963
84
63
NC
O
O
-2
-3
-4
1c
9.48
5.29ꢂ10ꢁ5 0.507
77
Cl
-5
-6
1d
1e
9.30
9.24
7.98
1.67ꢂ10ꢁ4 0.0448
3.01ꢂ10ꢁ4 0.00205
77
-7
-8
63
O
-9
-10
1f
N/A
N/A
N/A
-0.5
0
0.5
1
a
1H NMR spectra recorded in THF-d8. Concentrations of 1aef were 2 mM.
Dissociations constants (Kd) for 1aee.
Initial reaction rates for reactions of 1aee (10 mM) with aniline (10 mM) in THF
b
c
Hammett Substituent Constant,
at 20 ꢀC.
Fig. 2. Graph showing log rate (A) and log Kd (:) versus Hammett substituent
d
Isolated yields based on aniline for reactions in chloroform.
constant.

T. Rawling et al. / Tetrahedron 68 (2012) 6065e6070
6067
1aee and aniline using the method of initial rates. In all cases the
reactions were found to be first order with respect to both 1aee
and aniline; the appearance of aniline in the rate law excludes the
possibility that dissociation of 1aee is rate limiting.
targeted mechanism of action, sorafenib is the subject of ongoing
optimization studies.17,23e27 A key step in the synthesis of sorafenib
is construction of the unsymmetical urea moiety, which is generally
achieved by reaction of amine 4 (shown in Scheme 2) with 4-chloro-
3-(trifluoromethyl)-phenyl isocyanate.22,28 The procedure suffers
the problems associated with use of isocyanates, and the product
may require HPLC purification.28 Furthermore, due to the limited
range of commercially available aryl isocyanates, preparation of
structurally diverse analogues requires isocyanate synthesis using
phosgene or equivalents. Recently, the use of phenyl carbamates was
reported as a safe isocyanate alternative, however reaction yields
were moderate (48e62%).29 We found that the N-carbamoylimid-
azole methodology offered a facile, non-hazardous and high yielding
route to sorafenib. Carbamoylimidazole 3, readily prepared from CDI
and 4-chloro-3-(trifluoromethyl)-aniline, reacted rapidly with 4,
affording sorafenib in high yield (77%). Pure product was obtained
without the need for anhydrous conditions or chromatographic
purification. The procedure is amenable to the synthesis of sorafenib
analogues, which is likely to be of great future utility as the need for
novel analogues for the treatment of drug-resistant clonal tumour
populations increases.
The role of the imidazole formed upon dissociation was in-
vestigated by comparing the initial reaction rate of 1d with that of
p-tolyl isocyanate (which is a dissociation product of 1d. We mea-
sured the initial rates of reactions of these species with aniline in
the solvents THF and acetonitrile (ACN) (Table 2). In both solvents,
reactions of 1d were faster than those of p-tolyl isocyanate despite
the maximum concentration of p-tolyl isocyanate liberated from 1d
being w0.5 mM (calculated from Kd). The enhanced rates of 1d
arise from base catalysed proton transfer from the zwitterion
formed upon reaction of the isocyanate and aniline (Fig. 3).20 That
is, upon dissociation of 1d, the free imidazole catalyses the proton
transfer step (step 2 in Fig. 3). This was confirmed experimentally
by including imidazole (0.58 mM for the dissociation of 1d) in the
reaction of aniline with p-tolyl isocyanate (Table 2, entry 5). The
addition of imidazole accelerated the reaction, yielding a similar
rate to that for 1d under the same conditions (Table 2, entry 3).
Even though aniline can act as both a reagent and proton transfer
catalyst,21 the increase in reaction rate upon addition of imidazole
is a function of its greater basicity compared to aniline.
An important aspect of the reactions of 1aee with aniline is that
undesired symmetrical biaryl ureas were not detected at any stage.
Reactions involving isocyanates under non-anhydrous conditions
can give rise to symmetrical ureas when amines, formed by iso-
cyanate hydrolysis, react with another isocyanate. We therefore
propose that the imidazole-catalyzed reactions are sufficiently
rapid such that any water commonly found in AR grade solvents
under ambient conditions does not hydrolyse the isocyanate in-
termediates, and obviates the need for strictly anhydrous condi-
tions. This highlights the utility of the method to form exclusively
unsymmetrical aryl urea compounds.
O
N
N
H
N
Cl
N
N
N
N
Cl
F3C
NH2
65%
O
F3C
3
O
O
N
77%
H
H2N
4
O
Table 2
Initial rates of reactions of 1d and p-tolyl isocyanate with aniline at 20 ꢀC
Cl
F3C
O
O
N
H
Entry
Reactanta
Conditions
Initial rate (10ꢁ9 M sꢁ1
)
N
H
N
1
2
3
4
5
1d
THF
THF
ACN
ACN
2.04ꢃ0.01
1.92ꢃ0.05
1.90ꢃ0.02
1.48ꢃ0.08
2.01ꢃ0.03
H
p-Tolyl isocyanate
1d
p-Tolyl isocyanate
p-Tolyl isocyanate
Sorafenib
Scheme 2. Synthesis of sorafenib via N-carbamoylimidazole 3.
ACNþimidazoleb
a
[Compound 1d]t¼0¼[p-tolyl isocyanate]¼2.00 mM. [Aniline]¼5.00 mM.
b
The imidazole concentration was 0.58 mM, which was calculated using the Kd
value determined for 1d.
3. Conclusions
In conclusion, we have prepared several examples of un-
symmetrical aryl urea compounds starting from N,N-carbon-
yldiimidazole and substituted aromatic amines. The reaction
proceeds via the formation of two zwitterionic intermediates. The
overall reaction rate is independent of the degree of dissociation
and is enhanced by electron withdrawing substituents. Imidazole
released during the dissociation of the N-carbamoylimidazoles
catalyses the reaction of the liberated isocyanate and obviates the
need for anhydrous reaction conditions. Overall, N-carbamoylimi-
dazole compounds are useful synthetic reagents that permit rapid,
safe and straightforward access to unsymmetrical ureas in good
yield and purity.
R1
H
R1
2 N+
H
O
C
N
O
N
R2
N
R
BH+
B
R1
O
R1
N
O
N
B
BH+
N
R2
R2
N
H
Fig. 3. Reaction mechanism for the base catalysed reaction of isocyanates with weakly
basic amines.20
4. Experimental
4.1. General
We applied the N-carbamoylimidazole methodology to the syn-
thesis of sorafenib (Scheme 2), in a two-step adaptation of a litera-
ture22 procedure. Sorafenib is a novel biaryl urea multi-targeted
kinase inhibitor marketed as NexavarÒ by Bayer for the treatment
of advanced renal cell and hepatocellular carcinomas. By virtue of its
low toxicity, broad spectrum anticancer activity and novel multi-
All chemicals and anhydrous solvents were purchased from
Sigma Aldrich (Castle Hill, Australia). Biaryl ether 4 was synthesised
according to a literature procedure.22 1H NMR and 13C NMR spectra

6068
T. Rawling et al. / Tetrahedron 68 (2012) 6065e6070
were recorded using a Varian 400-MR instrument operating at
400 MHz. Spectra were referenced internally to NMR solvent (THF-
4.2.1.5. N-(4-Methoxyphenyl)-1H-imidazole-1-carboxamide
(1e). Yield 0.514 g (50%); mp (decomp.)¼116e152 ꢀC. 1H NMR
d8; 1H
d
1.73. DMSO-d6; 1H
d
2.48, 13C
d
40.45). Because N-carba-
(400 MHz, THF-d8):
d
9.24 (s, 1H), 8.18 (d, J¼0.8 Hz, 1H), 7.60 (d,
moylimidazoles 1aee and 3 dissociate in solution their NMR
spectra contain resonances arising from the parent compounds and
their dissociation products. Resonances attributed to dissociated
imidazole and isocyanate species are labelled with ‘im’ and ‘iso’,
respectively. Melting points were measured on a Stuart SMP10
melting point apparatus. We note that N-carbamoylimidazoles
1aee displayed broad melting points, which were attributed to
thermal decomposition of these compounds.30 Elemental analyses
were carried out by the Microanalytical Unit at the Research School
of Chemistry, Australian National University.
J¼0.8 Hz, 1H), 7.56 (s, 0.36H), 7.55e7.45 (m, 2H, AA0BB0), 7.40e7.53
(m, 0.72H, AA0BB0, iso), 6.99 (d, J¼0.8 Hz, 1H), 6.94 (s, 0.72H, im),
6.90e6.80 (m, 2H, AA0BB0), 6.80e6.75 (m, 0.72H, AA0BB0, iso), 3.77
(s, 3H), 3.72 (s, 1.08H). 13C NMR (100.5 MHz, DMSO-d6):
d 156.7,
154.7, 153.4, 136.7, 135.6 (im), 130.1, 133.4, 130.6, 130.1 (iso), 123.4
(iso), 120.3 (im), 117.4, 114.5, 114.4, 55.7, 55.6. ESI-MS: m/z (%): 218
([MþH]þ). Anal. Calcd for C11H11N3O2: C, 60.82; H, 5.10; N, 19.34.
Found: C, 60.90; H, 5.36; N 19.63.
4.2.1.6. N-(Benzyl)-1H-imidazole-1-carboxamide
(1f). Yield
8.08
0.807 g (85%); mp¼124e125 ꢀC. 1H NMR (400 MHz, THF-d8):
d
(s, 1H), 7.98 (s, 1H), 7.49 (d, J¼1.2 Hz, 1H), 7.40e7.20 (m, 5H), 6.94 (d,
4.2. Syntheses
J¼1.2 Hz, 1H), 4.53 (d, J¼1.6 Hz, 2H). 13C NMR (100.5 MHz, DMSO-
d6): d 149.4, 138.9, 136.5, 130.1, 128.9, 128.6, 127.7, 127.6, 127.4, 117.1,
4.2.1. General procedure for the synthesis of 1aef. CDI (1.055 g,
6.5 mmol) was suspended in anhydrous 1,2-dichloroethane (10 mL)
under nitrogen. The substituted aniline (4.7 mmol) was added, and
the mixture was heated to 50 ꢀC, during which time a clear solution
was obtained. After stirring for 18 h, the resulting suspension was
cooled in an ice bath for 1 h. The solid was collected by filtration
and washed with 1,2-dichloroethane, yielding 1aef as white solids.
43.9. ESI-MS: m/z (%): 202 ([MþH]þ). Anal. Calcd for C11H11N3O: C,
65.66; H, 5.51; N, 20.88. Found: C, 65.46; H, 5.23; N 20.93.
4.2.2. General procedure for the synthesis of 2aee. Compound 1aee
(1.28 mmol) were dissolved in the minimum volume of chloroform
at 50 ꢀC, and aniline (0.060 g, 0.65 mmol) was added. The solution
was stirred for 30 min at 50 ꢀC and then cooled in an ice bath for
10 min. The resulting solids were collected by filtration and washed
with cool chloroform, yielding the biaryl ureas 2aee as white
solids.
4.2.1.1. N-(4-Cyanophenyl)-1H-imidazole-1-carboxamide
(1a). Yield 0.751 g (75%); mp (decomp.)¼165e187 ꢀC. 1H NMR
(400 MHz, THF-d8):
d 9.74 (s, 1H), 8.23 (s, 1H), 7.89e7.78 (m, 2H,
AA0BB0), 7.77e7.70 (m, 2H, AA0BB0), 7.64 (d, J¼0.8 Hz, 1H), 7.35e7.30
4.2.2.1. 1-(4-Cyanophenyl)-3-phenylurea (2a). Yield 0.129 g
(m, 0.12H, AA0BB0, iso), 7.29e7.25 (m, 0.12H, AA0BB0, iso), 7.03 (d,
(84%); mp¼205e206 ꢀC. 1H and 13C NMR data are in good agree-
J¼0.8 Hz, 1H). 13C NMR (100.5 MHz, DMSO-d6):
d
152.2, 137.1, 135.6
ment with previously reported data.3
(im), 133.9, 133.8 (iso), 130.2, 124.7 (iso), 121.2 (im), 119.6, 118.7,
113.9. ESI-MS: m/z (%): 213 ([MþH]þ). Anal. Calcd for C11H8N4O: C,
62.26; H, 3.80; N, 26.40. Found: C, 61.95; H, 3.71; N 26.43.
4.2.2.2. Methyl 4-[(phenylcarbamoyl)amino]benzoate (2b). Yield
0.110 g (63%); mp¼176e178 ꢀC (lit. mp¼178 ꢀC).31 1H NMR
(400 MHz, DMSO-d6):
d
9.13 (s, 1H), 8.84 (s, 1H), 7.87 (AA0BB0, 2H),
4.2.1.2. Methyl
4-[(1H-imidazol-1-ylcarbonyl)amino]benzoate
7.57 (AA0BB0, 2H), 7.44 (dd, J¼8.4, 1.2 Hz, 2H), 7.29 (t, J¼7.6 Hz, 2H),
(1b). Yield 0.961 g (83%); mp (decomp.)¼166e180 ꢀC. 1H NMR
6.99 (tt, J¼7.6, 1.2 Hz, 1H), 3.79 (s, 3H). 13C NMR (100.5 MHz, DMSO-
(400 MHz, THF-d8):
d
9.65 (s, 1H), 8.23 (s, 1H), 8.08e7.90 (m, 2H,
d6): d 166.6, 152.7, 144.8, 139.7, 130.9 (2C), 129.3 (2C), 122.9, 122.8,
AA0BB0), 7.80e7.70 (m, 2H, AA0BB0), 7.65 (d, J¼1.6 Hz, 1H), 7.51 (s,
0.13H, im), 7.28e7.22 (m, 0.26H, AA0BB0, iso), 7.03 (d, J¼1.6 Hz, 1H),
6.95 (s, 0.26H, im), 3.85 (s, 3H). 13C NMR (100.5 MHz, DMSO-d6):
118.9 (2C), 117.8 (2C), 52.3.
4.2.2.3. 1-(4-Chlorophenyl)-3-phenylurea (2c). Yield 0.122
g
d
166.2, 152.3, 137.0, 135.6 (im), 131.5 (iso), 130.8, 130.7, 130.2, 125.5
(77%); mp¼247e250 ꢀC (lit. mp¼250e253 ꢀC).32 1H NMR
(iso), 120.5 (im), 120.6, 118.0, 117.6. ESI-MS: m/z (%): 246 ([MþH]þ).
Anal. Calcd for C12H11N3O3: C, 58.77; H, 4.52; N, 17.14. Found: C,
58.66; H, 4.52; N 17.03.
(400 MHz, DMSO-d6): d 8.79 (s, 1H), 8.68 (s, 1H), 7.47e7.41 (m, 4H),
7.31e7.24 (m, 4H), 6.95 (t, J¼7.6 Hz, 1H). 13C NMR (100.5 MHz,
DMSO-d6):
d 152.9, 139.9, 139.1, 129.3 (2C), 129.1 (2C), 125.8, 122.5,
120.2 (2C), 118.8 (2C).
4.2.1.3. N-(4-Chlorophenyl)-1H-imidazole-1-carboxamide
(1c). Yield 0.721 g (69%); mp (decomp.)¼151e188 ꢀC. 1H NMR
4.2.2.4. 1-(4-Methylphenyl)-3-phenylurea (2d). Yield 0.112 g
(400 MHz, THF-d8):
d
9.48 (s, 1H), 8.20 (s, 1H), 7.66e7.56 (m, 3H),
(77%); mp¼212e213 ꢀC (lit. mp¼212e213 ꢀC).33 1H and 13C NMR
7.52e7.46 (m, 0.45H), 7.38e7.30 (m, 2H, AA0BB0), 7.24e7.20 (m,
0.30H, AA0BB0, iso), 7.01 (d, J¼1.6 Hz, 1H), 6.95 (s, 0.30H, im). 13C
data are in good agreement with previously reported data.3
NMR (100.5 MHz, DMSO-d6):
d
152.8, 138.9, 135.6 (im), 130.1 (iso),
4.2.2.5. 1-(4-Methoxyphenyl)-3-phenylurea (2e). Yield 0.097 g
(63%); mp¼193e194 ꢀC (lit. mp¼198 ꢀC).4 1H and 13C NMR data are
in good agreement with previously reported data.3
129.2, 129.1,128.9, 128.7,125.9 (iso), 122.9, 120.3 (im), 117.5. ESI-MS:
m/z (%): 224 ([MþH]þ). Anal. Calcd for C10H8ClN3O: C, 54.19; H,
3.64; N, 18.96. Found: C, 54.44; H, 3.74; N 19.12.
4.2.3. N-[4-Chloro-3-(trifluoromethyl)phenyl]-1H-imidazole-1-
carboxamide (3). To a solution of 4-chloro-3-(trifluoromethyl)ani-
line (2.000 g, 10.23 mmol) in anhydrous 1,2-dichloroethane (15 mL)
under nitrogen, was added CDI (2.321 g, 14.32 mmol). The solution
was stirred at 45 ꢀC for 16 h, and then at room temperature for 3 h.
The solid was collected by filtration and washed with 1,2-
dichloroethane, affording 1.925 g (65%) of 3 as a white solid.
4.2.1.4. N-(4-Methylphenyl)-1H-imidazole-1-carboxamide
(1d). Yield 0.693 g (73%); mp (decomp.)¼136e148 ꢀC. 1H NMR
(400 MHz, THF-d8):
d
9.30 (s, 1H), 8.19 (d, J¼0.8 Hz, 1H), 7.65 (s,
0.25H), 7.61 (d, J¼0.8 Hz, 1H), 7.55e7.45 (m, 2H, AA0BB0), 7.38e7.32
(m, 0.50H, AA0BB0, iso), 7.20e7.10 (m, 2H, AA0BB0), 7.05e6.95 (m,
1.50H), 6.94 (s, 0.50H, im), 2.31 (s, 3H), 2.29 (s, 0.75H). 13C NMR
(100.5 MHz, DMSO-d6):
d
153.1, 137.7, 135.6 (im), 130.9, 130.6, 129.7
Mp¼115e118 ꢀC. 1H NMR (400 MHz, DMSO-d6):
¼8.39 (t, J¼1.2 Hz,
d
(iso), 129.6, 125.6 (iso), 121.6 (im), 118.6, 117.5. ESI-MS: m/z (%): 202
([MþH]þ). Anal. Calcd for C11H11N3O: C, 65.66; H, 5.51; N, 20.88.
Found: C, 65.52; H, 5.52; N 20.82.
1H), 8.13 (d, J¼2.8 Hz, 1H), 7.94 (dd, J¼8.8, 2.8 Hz, 1H), 7.80 (t,
J¼1.2 Hz, 1H), 7.74 (d, J¼8.8 Hz,1H), 7.62 (d, J¼0.8 Hz, 0.7H, im), 7.23
(d, J¼8.8 Hz, 0.7H, iso), 7.09 (m, 1H), 6.99 (m, 1.4H, im), 6.96 (d,

T. Rawling et al. / Tetrahedron 68 (2012) 6065e6070
6069
J¼2.8 Hz, 0.7H, iso), 6.75 (dd, J¼8.8, 2.8 Hz, 0.7H, iso). 13C NMR
was performed as described above. Samples were taken at 0, 15, 30
and 45 min. Plots of reaction progress versus time were linear
(R2<0.99).
(100.5 MHz, DMSO-d6): d 152.8, 147.4, 139.4, 137.7, 136.9, 135.6 (im),
132.7 (iso), 130.3, 127.4, 127.3, 127.1, 127.0, 125.9, 125.8 (iso), 123.9,
123.3, 122.1, 121.9 (im), 120.0, 119.9, 119.8, 119.7, 117.5. MS (ESI):
m/z¼290 [MþH]þ.
4.6. LC/MS analyses
4.2.4. 4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-
phenoxy]-N-methylpyridine-2-carboxamide (sorafenib). To a solution
of 3 (1.873 g, 6.47 mmol) in ethyl acetate (20 mL) at 50 ꢀC, was added
4 (0.983 g, 4.04 mmol). The solution was stirred for 45 min, and then
at room temperature for 2 h. The precipitate was collected by fil-
tration, washed with cold ethyl acetate, and dried in vacuo, affording
1.443 g (77%) of sorafenib as a white solid. 13C NMR (100.5 MHz,
Reaction aliquot analyses were performed on a Thermo Scien-
tific TSQ Quantum Access Max LC/MS/MS system (San Jose CA, USA)
fitted with a Thermo Hypersil GOLD column (2.1 mmꢂ150 mm,
5 mm particle size, San Jose CA, USA). The mobile phase was 55%
acetonitrile in water containing 0.1% formic acid, and the flow rate
was 0.30 mL/min. Automated injections (20 L) were used, and
m
samples were stored at 5 ꢀC in the autosampler. The LC/MS in-
terface used electrospray ionization operating in the positive ioni-
zation mode with high purity nitrogen (BOC, Sydney, NSW,
Australia) as the sheath gas at 35 psi. Selected ion monitoring was
used. In all cases baseline separation between the diaryl reaction
product 2aee and other reaction species was achieved. Xcalibur 2.1
Software and Microsoft Excel 2007 were used in data acquisition
and analysis.
DMSO-d6):
d
¼166.4, 164.3, 152.9, 152.8, 150.8, 148.3, 139.8, 137.5,
132.5, 127.0 (q, JCeF¼122 Hz, 1C), 124.6, 123.6, 122.8, 121.9, 121.0,
117.3, 117.2, 117.2, 114.5, 109.1, 26.5. The 1H NMR spectrum of the
product is in good agreement with previously reported data.22 MS
(ESI): m/z¼466 [MþH]þ. C21H16N4O3ClF3 (464.82): calcd. C 54.26, H
3.47, N 12.05; found C 54.18, H 3.38, N 11.99.
4.3. Determination of dissociation constants (kd)
Calibration curves were constructed from 2aee to quantify the
formation of the biaryl reaction products. Stock solutions of 2aee
were prepared from accurately weighed samples, and calibration
solutions were prepared by serial dilution.
Solutions of 1aef in THF-d8 were accurately prepared
(2.00 mM). 1H NMR spectra of the solutions were recorded at 5 min
intervals with the temperature set to 20 ꢀC, until equilibrium was
established. The low-field aromatic resonances assigned to the un-
dissociated compounds, and the upfield aromatic resonances
assigned to the isocyanates were selected as diagnostic. The aver-
aged integration areas of these resonances were used to reflect the
concentrations of 1aef and the dissociated isocyanate. Dissociation
constants were calculated from the concentrations of these species
at equilibrium.
Acknowledgements
The present work was supported by a grant from the Australian
National Health and Medical Research Council.
References and notes
4.4. Initial rate experiments
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Stock solutions of 5.00 mM 1aee and 50.00 mM aniline in
anhydrous THF were combined in sealed reaction vessels with
additional anhydrous THF to give three solutions with the fol-
lowing concentrations: (1) [1aee]¼1.00 mM, [aniline]¼5.00 mM;
(2) [1aee]¼1.00 mM, [aniline]¼10.00 mM; (3) [1aee]¼2.00 mM,
[aniline]¼10.00 mM. The solutions were magnetically stirred at
20 ꢀC with the temperature maintained by means of a thermo-
stated water bath. 0.5 mL samples of the reactions were taken at
set time points (typically every 5 min for rapid reactions, and
every 40 min for slower reactions), and quenched with tert-butyl
amine (100 mL, >100 fold excess relative to aniline) in acetonitrile
(9.5 mL). The reaction aliquots were then analyzed for the for-
mation of the urea product by LC/MS. Four time points were
collected for each reaction. In all cases plots of urea formation
versus time were linear (R2>0.98), and the slopes of the lines
were used to determine the initial rate of the reactions. Plots of
log rate versus log [1aee] for experiments (1) and (2), and (2)
and (3) were used to determine the reaction orders for 1aee and
aniline.
4.5. Initial rate comparison experiments
Stock solutions of 5.00 mM 1d, 5.00 mM p-tolyl isocyanate,
5.00 mM imidazole and 50.00 mM aniline were prepared in an-
hydrous THF and acetonitrile, and combined in sealed reaction
vessels to give solutions of the following concentrations: (1)
[1aee]¼2.00 mM, [aniline]¼5.00 mM in THF and acetonitrile; (2)
[p-tolyl isocyanate]¼2.00 mM, [aniline]¼5.00 mM in THF and
acetonitrile; (3) [p-tolyl isocyanate]¼2.00 mM, [aniline]¼5.00 mM,
[imidazole]¼0.58 mM in acetonitrile. Reactions were maintained at
20 ꢀC by means of a thermostated water bath. Reaction sampling

6070
T. Rawling et al. / Tetrahedron 68 (2012) 6065e6070
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