Pd/C-Catalyzed Domino Synthesis of Urea Derivatives Using Chloroform as the Carbon Monoxide Source in Water

Article abstract of DOI:10.1002/adsc.201800954

A Pd/C-catalyzed domino synthesis of symmetrical and unsymmetrical ureas from aryl iodides, sodium azide, amines and CHCl₃ in water has been developed. This reaction proceeds with sequential carbonylation, Curtius rearrangement and nucleophilic addition. CHCl₃ serves as a convenient and safe alternation of CO gas in the presence of KOH. A series of urea derivatives were obtained in moderate to good yields with good functional group tolerance. Furthermore, the Pd/C catalyst could be readily recovered with slight decrease in the catalytic activity after six consecutive runs. (Figure presented.).

Full text of DOI:10.1002/adsc.201800954

Title: Pd/C-catalyzed the domino synthesis of urea derivatives using
chloroform as the carbon monoxide source in water
Authors: Liang Wang, Hao Wang, Guiqing Li, Shuliang Min, Fangyuan
Xiang, Shiqi Liu, and Waigang Zheng
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800954
Link to VoR: http://dx.doi.org/10.1002/adsc.201800954

10.1002/adsc.201800954
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Pd/C-catalyzed domino synthesis of urea derivatives using
chloroform as the carbon monoxide source in water
Liang Wang,a* Hao Wang,a Guiqing Li,a Shuliang Min,a Fangyuan Xiang,a Shiqi Liua
and Waigang Zhenga
a
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology,
Changzhou University, Gehu Raod 1, Wujin, Changzhou, 213164, P. R. China. E-mail: lwcczu@126.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A
Pd/C-catalyzed domino synthesis of
symmetrical and unsymmetrical ureas from aryl iodides,
sodium azide, amines and CHCl3 in water has been
developed. This reaction proceeds with sequential
carbonylation, Curtius rearrangement and nucleophilic
addition. CHCl3 serves as a convenient and safe alternation
of CO gas in the presence of KOH. A series of urea
derivatives were obtained in moderate to good yields with
good functional group tolerance. Furthermore, the Pd/C
catalyst could be readily recovered with slight decrease in
the catalytic activity after six consecutive runs.
Keywords: Green chemistry; Carbonylation; Urea
synthesis; Micellar catalysis; Water
Numerous synthetic approaches have been
developed for the synthesis of urea derivatives due to
their great importance in various research areas.
Traditionally, ureas are synthesized via nucleophilic
addition of amines to isocyanates (or in situ generated
isocyanates) (Scheme 1, a and b).[4] Unfortunately,
these procedures usually suffers from some
drawbacks including environmental unfriendliness,
poor atomic economy, and limited substrate scope.
Recently, much effort has been devoted to the
synthesis of ureas via transition-metal-catalyzed
reactions. For example, Kotecki et al. reported
palladium-catalyzed amidation of aryl halides with N-
monosubstituted ureas (Scheme 1, c).[5] However,
extra steps were required to prepare these starting
materials. Buchwald et al. reported a palladium-
catalyzed procedure toward unsymmetrical aryl ureas
via cross-coupling of aryl chlorides and triflates with
sodium cyanate followed by nucleophilic addition of
amines (Scheme 1, d).[6] Moreover, ureas could also
prepared from amines and alcohols in the presence of
iridium[7] and ruthenium[8] catalysts via “hydrogen-
borrowing” strategy (Scheme 1, e).
Introduction
Urea derivatives are very important compounds that
have found wide applications in pharmaceuticals and
agrochemicals, such as CCR1 antagonist (A),[1a] α7
nAChR agonist (B),[1b] p38 mitogen activated kinase
(MAP) inhibitor (C),[1c] Cumyluron (D)[1d] and
CXCR2 agonist (E).[1e] They also widely utilized in
molecular recognition[2] and organocatalysis[3] (for
example, compound F) owing to their high hydrogen-
bonding ability (Figure 1).
It was also worth noting that transition-metal-
catalyzed carbonylation reaction,[9] being one of the
most powerful way to accessing carbonyl-containing
compounds, was also an alternative strategy for the
synthesis of ureas. For example, aryl amines could
react directly with urea in the presence of CO.
However, such protocol was more suitable for
synthesis of symmetrical ureas (Scheme 1, f).[10-13]
Zhang and co-workers described an elegant protocol
by using azides as the substrates (Scheme 1, g). This
Figure 1. Selected examples of important urea derivatives.
1
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10.1002/adsc.201800954
Advanced Synthesis & Catalysis
Results and Discussion
reaction proceeded smoothly under a balloon of CO
atmosphere to afford the desire unsymmetrical ureas
in good yields. Both the aryl and alkyl azides were
tolerated.[14] Inspired by the contribution from
Grushin group,[15] Wu and co-workers reported a
palladium-catalyzed domino procedure for the
synthesis of unsymmetrical ureas from aryl iodides,
sodium azides and aryl amines in the presence of
HCO2H/Ac2O (Scheme 1, h).[16] However, limited
substrate scope was reported in this protocol. While
acknowledging the pioneering work in this field,
there are still some issues to be addressed from the
green point of view. The reported procedures usually
suffered from the use of homogeneous noble metal
catalysts, toxic solvent (toluene) and CO gas,
inconvenient substrates, and limited substrate scope.
Hence, the development of a facile and green
approach for the synthesis of ureas is still highly
desirable. To improve the methods for urea synthesis
and in continuation of our interest in green
chemistry,[17] we herein report a Pd/C-catalyzed the
domino synthesis of symmetrical and unsymmetrical
ureas using chloroform as the carbon monoxide
source in water.
At the outset of our study, iodobenzene 1a, sodium
azide and aniline 2a were selected as the model
substrates to optimize the reaction conditions (Table
1). To make the reaction more environmentally
benign, Pd/C was employed since it could be safely
handled, removed and reused. For the carbonylation
process, chloroform was selected as the green CO
source since it is inexpensive, readily available and
easy to handle. Recently, there have been some
reports by employing chloroform in carbonylation
reactions.[18-25] Our group also realized a palladium-
catalyzed aminocarbonylation reaction to access
1,3,4-oxadiazoles using chloroform as the CO
source.[17b]
A variety of reaction parameters including ligand,
solvent, amount of chloroform, base and temperature
were then explored. The ligands showed significant
influence on this transformation. No desired product
3a was observed in the absence of any ligands (Table
1, entry 1). Ligands such as PPh3, Cy3P, 1,3-
bis(diphenylphosphino) propane (DPPP) and 1,1'-
bis(diphenylphosphino)ferrocene
(DPPF)
were
inefficient, providing trace amount of 3a (entries 2~5).
Pleasingly, 25% yield of 3a was obtained in toluene
o
at 60 C for 12 h when 2-dicyclohexylphosphino-
2',4',6'-triisopropylbiphenyl (Xphos) was employed
(entry 6). N-containing ligands such as pyridine and
DMAP were also checked, however, the reactions did
not work at all (entry 7 and 8). Notably, both N-
phenylbenzamide and diphenylamine were observed
as the by-products in these cases. Different solvents
were then evaluated. Switching the solvents to
CH3CN, THF and dioxane led to increased yields
(entries 9~11); while reaction in DMF gave a similar
yield (24%, entry 12). Grushin and co-workers
previously found that azidocarbonylation of aryl
iodides resulted in nearly full conversion in H2O-
organic solvent biphasic system.[15] It was assumed
that the iodide released from the ArI might deactivate
the palladium catalyst. By adding water, no excess of
inorganic salts would be accumulated. Encouraged by
their work, we also tried this reaction in pure water,
however, no desired product was detected (entry 13).
This result might be attributed to the poor solubility
of the reactants in water. Pleasingly, attempts by
adding surfactants including tetrabutylammonium
chloride (TBAC, 5%) and tetrabutylammonium
bromide (TBAB, 5%) slightly increased the yields
(entry 14 and 15). Notably, the yields were
significantly increased when performing the reaction
in 2% PTS/H2O or 2% TPGS/H2O (entry 16 and 17,
71% and 85% yields, respectively). The use of non-
ionic amphiphiles PTS[26] and TPGS[27] which were
introduced by Lipshutz’s group has been proved be a
versatile “solubilizer” for organic molecules in water.
Diverse cross-coupling reactions have been
successfully realized under extremely mild reactions
in the nanomicelles formed by PTS or TPGS in water.
It was worth noting that the use of PTS/H2O or
TPGS/H2O as reaction media not only eliminated the
Scheme 1. Different synthetic approaches towards urea
derivatives.
2
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10.1002/adsc.201800954
Advanced Synthesis & Catalysis
use of organic co-solvents, but also could be recycled
and reused. Since base is vital for this reaction, other
bases such as NaOH, LiOH, Et3N and t-BuOK were
tested. However, all of these bases were found to be
inferior to KOH (entries 18~22). Although a slightly
higher yield was obtained by using CsOH•H2O as the
base (entry 20), the lower cost of KOH made it the
best choice. Moreover, decreasing the amount of
CHCl3 to 1 equiv provided product 3a in only 25%
yield, and the same yield was obtained by increasing
the amount of CHCl3 to 5 equiv (entry 23 and 24).
The reaction temperature was also surveyed (entry
giving the corresponding products 3r and 3s in 52%
and 59% yields, respectively.
Table 1. Optimization of reaction conditions.[a]
Entry
Ligand
Solvent
CHCl3
(equiv)
Base
Yield
(%)[b]
0
trace
trace
trace
trace
25
0
0
38
42
57
24
trace
23
20
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
-
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH3CN
THF
dioxane
DMF
H2O
TBAC/H2O
TBAB/H2O
2%PTS/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
2%TPGS-
750-M/H2O
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
PPh3
Cy3P
o
25). Varying the temperature to 50 or 70 C afforded
DPPP
DPPF
XPhos
Pyridine
DMAP
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
3a in 70% and 78% yields, respectively, suggesting
o
that 60 C was the optimal. Survey on the catalyst
loading showed that 5 mol% of Pd/C catalyst was the
best choice (entry 26). Finally, comparison
experiments were performed by using homogeneous
palladium precatalysts such as Pd(OAc)2, PdCl2,
Pd(acac)2 and Pd2dba3 (entry 27). The results showed
that relatively lower yields were obtained, indicating
the usefulness of Pd/C catalyst.
71
85
With the optimized reaction conditions in hand
(Table 1 entry 17), we set out to explore the substrate
scope towards the synthesis of aryl ureas (Table 2).
It was found that reactions for the synthesis of
symmetrical ureas proceeded smoothly to afford the
corresponding products 3a~3f in good yields. Aryl
iodides and anilines bearing both electron-donating
and electron-withdrawing groups were well tolerated.
Substrates with electron-donating groups afforded the
corresponding products in relatively higher yields
than those with electron-withdrawing groups.
Notably, the C–X (X = F, Cl, Br) bonds in 3c~3e
were not affected, enabling further manipulation of
the initial products. Moreover, 1-iodonaphthalene (1f)
and 1-naphthylamine (2f) underwent this cascade
reaction smoothly to give product 3f in 70% yield.
We also extend this catalytic system to aryl bromides.
Unfortunately, the corresponding products 3a and 3b
were obtained in lower yields (42% and 45%,
respectively). Then, synthesis of unsymmetrical ureas
were tried. Initially, the generality of the aryl iodides
was examined (3g~3m). Also, aryl iodides bearing
substituents including methoxyl, methyl, halogen and
nitro group survived well under the reaction
18
19
20
21
22
23
24
25
26
27
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
3
3
3
3
3
1
5
3
3
3
NaOH
LiOH
43
20
CsOH•H2
O
Et3N
87
0
0
t-BuOK
KOH
KOH
KOH
KOH
KOH
25
85
70[c],78[d]
65[e],88[f]
77[g],72[h]
30[i],61[j]
[a]Reaction conditions: 1a (0.3 mmol, 1 equiv.), sodium
azide (1.2 equiv.), 2a (1.5 equiv.), Pd/C (5 mol%), ligand
(10 mol% for monodentate ligands and 5 mol% for
bidentate ligands), CHCl3 (3 equiv.), base (6 equiv.),
solvent (3 mL), 60 oC for 12 h. [b]Isolated yields.
o
o
[c]Reaction at 50 C. [d]Reaction at 70 C. [e]With 2.5 mol%
of Pd/C. [f]With 10 mol% of Pd/C. [g]5 mol% of Pd(OAc)2
was used. [h]5 mol% of PdCl2 was used. [i]5 mol% of
Pd(acac)2 was used. [j]5 mol% of Pd2dba3 was used.
conditions, albeit 4-iodonitrobenzene gave
moderate yield (3k, 62%). The steric effect had some
influence on the reaction. Substrate with
a
a
substitution group at the ortho position showed less
activity, providing the corresponding product in
lower yield (3l, 75%). To explore the generality of
this protocol further, a series of anilines were
evaluated (3g’~3l’). All these reactions also
proceeded well. Similarly, anilines with nitro group
or ortho-substituted group showed less efficiency
(3k’ and 3l’). Cross reactions from aryl iodides,
anilines and sodium azide were also achieved, giving
products 3n~3q in moderate to good yields.
Moreover, heterocyclic amines such as pyridin-2-
amine and quinolin-8-amine were also tolerated,
3
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10.1002/adsc.201800954
Advanced Synthesis & Catalysis
Table 2. Synthesis of aryl ureas.[a]
Table 3. Synthesis of aryl/alkyl ureas.[a]
[a]
Reaction conditions: 1 (0.3 mmol, 1 equiv.), sodium
azide (1.2 equiv.), 4 (1.5 equiv.), Pd/C (5 mol%), XPhos
(10 mol%), CHCl3 (3 equiv.), KOH (6 equiv.), 2%TPGS-
750-M/H2O (3 mL), 60 oC for 12 h, isolated yields.
As shown from the table, a series of alkyl amines
including
benzylamine,
cyclohexylamine,
n-
hexylamine, furan-2-ylmethanamine and thiophen-2-
ylmethanamine reacted well with iodobenzene under
the standard reaction conditions to provide the
desired products 5a~5e in good yields. Reactions
from substituted aryl iodides and amines also
afforded satisfactory yields (5f~5l). Notably, halogen
substituent and heterocycles were well-tolerated.
The use of recoverable Pd/C catalyst is an
important feature in this protocol. Recycling
experiment was then surveyed (Table 4). After each
reaction, the catalyst was recovered by filtration and
washed with acetone. The recovered catalyst was
dried under vacuum and used for the next run. It was
pleased to observed that the same batch of Pd/C
catalyst was capable of catalyzing the reaction at least
six consecutive runs with slightly decrease in the
yield. Since it is still highly contentious that the Pd
leached into the solution can catalyze the reaction,[28]
a palladium leaching test was further carried out to
investigate whether this reaction proceeded in a
heterogeneous or homogeneous way. Initially, the
mixture of Pd/C and XPhos was stirred in 2%
[a]Reaction conditions: 1 (0.3 mmol, 1 equiv.), sodium
azide (1.2 equiv.), 2 (1.5 equiv.), Pd/C (5 mol%), XPhos
(10 mol%), CHCl3 (3 equiv.), KOH (6 equiv.), 2%TPGS-
o
750-M/H2O (3 mL), 60 C for 12 h, isolated yields. [b]Aryl
bromides were used as the substrates.
Encouraged by the above results, we then turned
our attention to the synthesis of unsymmetrical
alkyl/aryl ureas by employing a series of aryl iodides
and alkyl amines. The results are summarized in
Table 3.
o
TPGS/H2O at 60 C for 6 h at room temperature.
Then the mixture was filtrated following by addition
of all the starting materials and base. After reaction
for another 12 h, only 9% yield was obtained by
4
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10.1002/adsc.201800954
Advanced Synthesis & Catalysis
Conclusion
HPLC analysis. This result may suggested that this
reaction proceed through a heterogeneous way, while
the only a small fraction of active catalyst that
released into the solution might also promote the
reaction. Furthermore, the recovered Pd/C catalyst
after six runs was also examined by TEM analysis.
Slight agglomeration of the catalyst was observed
(Figure 2), which might be account for the decreased
catalytic activity of the catalyst.
In summary, we have described a Pd/C-catalyzed the
domino synthesis of symmetrical and unsymmetrical
ureas in water. This reaction occurs in tandem
through one-pot carbonylation, Curtius rearrangement
and nucleophilic addition. It provides an efficient
approach by using simple and cheap starting
materials and safe CO source. A series of urea
derivatives were obtained in moderate to good yields
with good functional group tolerance. Furthermore,
the Pd/C catalyst could be readily recovered and
slight decrease in the catalytic activity was observed
after six consecutive runs.
Table 4. Recycling experiment.[a]
Run
1
3
Yield (%)
Run
2
4
Yield (%)
90
87
84
88
87
81
Experimental Section
5
6
General procedure for synthesis of ureas
A 10-mL reaction vial equipped with a stir bar was
charged with Pd/C (15.8 mg, 5 mol%), XPhos (14.3 mg,
0.03 mmol, 10 mol%), iodobenzene (0.30 mmol, 1.0
equiv), sodium azide (23.4 mg, 0.36 mmol, 1.2 equiv),
amine (0.45 mmol, 1.5 equiv) and chloroform (0.90 mmol,
3.0 equiv), KOH (101.0 mg, 1.80 mmol, 6.0 equiv) and 2
wt% TPGS-750-M/H2O (3.0 mL). The reaction mixture
o
was heated at 60 C for 12 h. After completion of the
reaction, the mixture was cooled to room temperature and
dichloromethane (5.0 mL) was added. The mixture was
further stirred for 5 minutes, followed by filtration to
remove the Pd/C catalyst. The recovered catalyst was
washed with acetone, dried under vacuum and used for the
next run. The organic layer was then dried over anhydrous
sodium sulfate, and concentrated under vacuum to give the
crude product, which was further purified by flash
chromatography over silica gel using EtOAc/petroleum
ether as the eluent.
Figure 2. TEM images: Fresh catalyst (left) and catalyst
after six runs (right).
A plausible mechanism was proposed on the basis
of our results and previous literatures[14-16] (Scheme
2). Initially, oxidative addition of Pd(0) with aryl
halide 1 provides intermediate I. Then an acyl-
palladium complex II is generated through
coordination and insertion of CO which is in situ
formed from chloroform and KOH. After anion
exchange with sodium azide, intermediate III is
formed followed by reductive elimination to give
Pd(0) and aroyl azide IV. The intermediate IV then
undergoes Curtius rearrangement to provide
isocyanate V, which is nucleophilic attacked by an
amine to afford the final product urea.
1,3-Diphenylurea (3a). White solid (54 mg, 85%), mp
o
243-244 C; 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s,
2H), 7.44 (dd, J = 8.6, 1.0 Hz, 4H), 7.28 (dd, J = 10.7, 5.2
Hz, 4H), 7.00 – 6.92 (m, 2H); 13C NMR (75 MHz, DMSO-
d6) δ 152.61, 139.75, 128.86, 121.89, 118.25. HRMS
(ESI): Calcd for C13H13N2O (M + H)+ 213.1022, found
213.1029.
1,3-Bis(4-methoxyphenyl)urea (3b). White solid (71 mg,
87%), mp 240-241 oC; 1H NMR (300 MHz, DMSO-d6) δ
8.36 (s, 2H), 7.36 – 7.30 (m, 4H), 6.88 – 6.82 (m, 4H),
3.71 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ 154.36,
152.99, 132.96, 119.95, 113.99, 55.19. HRMS (ESI): Calcd
for C15H17N2O3 (M + H)+ 273.1234, found 273.1240.
1,3-Bis(4-fluorophenyl)urea (3c). Purple solid (53 mg,
71%), mp 260-262 oC; 1H NMR (300 MHz, DMSO-d6) δ
8.68 (s, 2H), 7.48 – 7.42 (m, 4H), 7.15 – 7.07 (m, 4H); 13
C
NMR (75 MHz, DMSO-d6) δ 157.38 (d, J = 238.1 Hz),
152.76, 136.04 (d, J = 2.3 Hz), 120.04 (d, J = 7.7 Hz),
115.29 (d, J = 22.2 Hz). HRMS (ESI): Calcd for
C13H11F2N2O (M + H)+ 249.0834, found 249.0846.
1,3-Bis(4-chlorophenyl)urea (3d). White solid (62 mg,
o
74%), mp >300 C; 1H NMR (300 MHz, DMSO-d6) δ
8.84 (s, 2H), 7.50 – 7.45 (m, 4H), 7.36 – 7.29 (m, 4H); 13
C
NMR (75 MHz, DMSO-d6) δ 152.36, 138.57, 128.66,
125.51, 119.85. HRMS (ESI): Calcd for C13H11Cl2N2O (M
+ H)+ 281.0243, found 281.0255.
1,3-Bis(4-bromophenyl)urea (3e). White solid (87 mg,
79%), mp 292-294 oC; 1H NMR (300 MHz, DMSO-d6) δ
8.86 (s, 2H), 7.46 – 7.41 (m, 8H); 13C NMR (75 MHz,
DMSO-d6) δ 152.30, 138.99, 131.56, 120.26, 113.42.
Scheme 2 Proposed mechanism.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800954
Advanced Synthesis & Catalysis
HRMS (ESI): Calcd for C13H11Br2N2O (M + H)+ 368.9233,
found 368.9242.
8.3 Hz, 1H), 8.02 (d, J = 6.8 Hz, 1H), 7.96 – 7.91 (m, 1H),
7.66 – 7.45 (m, 6H), 7.31 (t, J = 7.9 Hz, 2H), 6.99 (t, J =
7.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 152.96,
139.83, 134.34, 133.76, 128.94, 128.50, 125.96, 125.95,
125.93, 125.78, 122.96, 121.91, 121.35, 118.14, 117.38.
HRMS (ESI): Calcd for C17H15N2O (M + H)+ 263.1179,
found 263.1189.
1,3-Di(naphthalen-1-yl)urea (3f). Purple solid (65 mg,
70%), mp 272-274 oC; 1H NMR (300 MHz, DMSO-d6) δ
9.18 (s, 2H), 8.25 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 7.5 Hz,
2H), 7.96 (d, J = 7.9 Hz, 2H), 7.68 – 7.47 (m, 8H); 13C
NMR (75 MHz, DMSO-d6) δ 153.34, 134.40, 133.80,
128.53, 126.00, 125.97, 125.93, 125.80, 122.95, 121.42,
117.47. HRMS (ESI): Calcd for C21H17N2O (M + H)+
313.1335, found 313.1350.
1-(4-Methoxyphenyl)-3-(p-tolyl)urea (3o). White solid
o
(68 mg, 88%), mp 234-235 C; 1H NMR (300 MHz,
DMSO-d6) δ 8.43 (d, J = 13.7 Hz, 2H), 7.33 (dt, J = 8.4,
5.0 Hz, 4H), 7.06 (d, J = 8.3 Hz, 2H), 6.89 – 6.82 (m, 2H),
3.71 (s, 3H), 2.23 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
δ 154.41, 152.82, 137.36, 132.86, 130.42, 129.18, 119.97,
118.20, 113.99, 55.17, 20.36. HRMS (ESI): Calcd for
C15H17N2O2 (M + H)+ 257.1285, found 257.1292.
1-(4-Methoxyphenyl)-3-phenylurea (3g). White solid
o
(62 mg, 86%), mp 186-188 C; 1H NMR (300 MHz,
DMSO-d6) δ 8.56 (s, 1H), 8.45 (s, 1H), 7.43 (dd, J = 8.5,
1.0 Hz, 2H), 7.38 – 7.32 (m, 2H), 7.26 (t, J = 7.9 Hz, 2H),
6.94 (t, J = 7.3 Hz, 1H), 6.89 – 6.83 (m, 2H), 3.71 (s, 3H);
13C NMR (75 MHz, DMSO-d6) δ 154.46, 152.74, 139.92,
132.73, 128.77, 121.61, 120.02, 118.08, 114.00 55.18.
HRMS (ESI): Calcd for C14H15N2O2 (M + H)+ 243.1128,
found 243.1139.
1-(4-Bromophenyl)-3-(4-chlorophenyl)urea (3p). White
o
solid (70 mg, 72%), mp >300 C; 1H NMR (300 MHz,
DMSO-d6) δ 8.86 (s, 2H), 7.51 – 7.43 (m, 6H), 7.35 – 7.30
(m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 152.34, 139.02,
138.57, 131.57, 128.68, 125.55, 120.26, 119.86, 113.42.
HRMS (ESI): Calcd for C13H11BrClN2O (M + H)+
324.9738, found 324.9744.
1-(4-Fluorophenyl)-3-phenylurea (3h). White solid (51
mg, 74%), mp 236-237 oC; 1H NMR (300 MHz, DMSO-
d6) δ 8.67 (d, J = 11.7 Hz, 2H), 7.51 – 7.40 (m, 4H), 7.27 (t,
J = 7.9 Hz, 2H), 7.16 – 7.07 (m, 2H), 6.96 (t, J = 7.3 Hz,
1H); 13C NMR (75 MHz, DMSO-d6) δ 157.38 (d, J = 238.0
Hz), 152.69, 139.74, 136.10 (d, J = 2.4 Hz), 128.84,
121.88, 119.99 (d, J = 7.7 Hz), 118.28, 115.33 (d, J = 22.2
Hz). HRMS (ESI): Calcd for C13H12FN2O (M + H)+
231.0928, found 231.0936.
1-(4-Methoxyphenyl)-3-(4-nitrophenyl)urea
(3q).
o
Yellow solid (55 mg, 64%), mp 206-208 C; 1H NMR
(300 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.73 (s, 1H), 8.18 (d,
J = 9.2 Hz, 2H), 7.67 (d, J = 9.3 Hz, 2H), 7.38 (d, J = 9.0
Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 3.72 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) δ 154.97, 152.13, 146.66, 140.84,
131.99, 125.20, 120.55, 117.34, 114.07, 55.20. HRMS
(ESI): Calcd for C14H14N3O4 (M + H)+ 288.0979, found
288.0988.
1-(4-Chlorophenyl)-3-phenylurea (3i). White solid (59
mg, 80%), mp 239-241 oC; 1H NMR (300 MHz, DMSO-
d6) δ 8.81 (s, 1H), 8.70 (s, 1H), 7.51 – 7.42 (m, 4H), 7.35 –
7.24 (m, 4H), 6.97 (t, J = 7.3 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 152.49, 139.59, 138.79, 128.87, 128.69,
125.37, 122.03, 119.74, 118.35. HRMS (ESI): Calcd for
C13H12ClN2O (M + H)+ 247.0633, found 247.0640.
1-Phenyl-3-(pyridin-2-yl)urea (3r). Yellow solid (33
mg, 52%), mp 190-192 oC; 1H NMR (300 MHz, DMSO-
d6) δ 10.46 (s, 1H), 9.41 (s, 1H), 8.27 (d, J = 3.6 Hz,
1H),7.77 – 7.07 (m, 1H), 7.58 – 7.44 (m, 3H), 7.34 – 7.25
(m, 2H), 7.04 – 6.99 (m, 2H); 13C NMR (75 MHz, DMSO-
d6) δ 152.58, 151.74, 146.90, 139.75, 138.66, 128.91,
122.00, 118.19, 117.01, 111.50. HRMS (ESI): Calcd for
C12H12N3O (M + H)+ 214.0975, found 214.0988.
1-(4-Bromophenyl)-3-phenylurea (3j). White solid (71
mg, 82%), mp 243-245 oC; 1H NMR (300 MHz, DMSO-
d6) δ 8.81 (s, 1H), 8.70 (s, 1H), 7.45 (d, J = 5.3 Hz, 6H),
7.28 (t, J = 7.9 Hz, 2H), 6.97 (t, J = 7.3 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 152.42, 139.53, 139.19, 131.55,
128.84, 122.03, 120.13, 118.33, 113.21. HRMS (ESI):
Calcd for C13H12BrN2O (M + H)+ 291.0128, found
291.0140.
1-Phenyl-3-(quinolin-8-yl)urea (3s). Yellow solid (46
mg, 59%), mp 154-157 oC; 1H NMR (300 MHz, DMSO-
d6) δ 9.87 (s, 1H), 9.72 (s, 1H), 8.91 (dd, J = 4.2, 1.6 Hz,
1H), 8.59 (dd, J = 6.1, 3.0 Hz, 1H), 8.37 (dd, J = 8.3, 1.6
Hz, 1H), 7.68 – 7.49 (m, 5H), 7.31 (t, J = 7.9 Hz, 2H), 6.99
(t, J = 7.3 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ
152.45, 148.26, 139.89, 137.75, 136.62, 135.94, 128.86,
127.93, 127.24, 122.01, 121.91, 119.76, 118.13, 114.41.
HRMS (ESI): Calcd for C16H14N3O (M + H)+ 264.1131,
found 264.1147.
1-(4-Nitrophenyl)-3-phenylurea (3k). Yellow solid (48
mg, 62%), mp 255-257 oC; 1H NMR (300 MHz, DMSO-
d6) δ 9.43 (s, 1H), 8.92 (s, 1H), 8.19 (d, J = 9.2 Hz, 2H),
7.69 (d, J = 9.3 Hz, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.31 (t, J
= 7.9 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 151.95, 146.40, 140.99, 139.01, 128.87,
125.16, 122.52, 118.63, 117.45. HRMS (ESI): Calcd for
C13H12N3O3 (M + H)+ 258.0873, found 258.0877.
1-Benzyl-3-phenylurea (5a). Yellow solid (61 mg,
90%), mp 168-171 oC; 1H NMR (300 MHz, DMSO-d6) δ
8.55 (s, 1H), 7.39 (dd, J = 8.6, 1.1 Hz, 2H), 7.36 – 7.28 (m,
4H), 7.27 – 7.18 (m, 3H), 6.92 – 6.86 (m, 1H), 6.60 (t, J =
6.0 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 155.24, 140.47, 140.38, 128.68, 128.33,
127.13, 126.74, 121.10, 117.68, 42.73. HRMS (ESI):
Calcd for C14H15N2O (M + H)+ 227.1179, found 227.1185.
1-Phenyl-3-(o-tolyl)urea (3l). White solid (51 mg, 75%),
mp 197-199 oC; 1H NMR (300 MHz, DMSO-d6) δ 9.02 (s,
1H), 7.92 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.47 (dd, J =
8.5, 1.0 Hz, 2H), 7.32 – 7.24 (m, 2H), 7.16 (ddd, J = 11.4,
7.0, 4.1 Hz, 2H), 7.02 – 6.89 (m, 2H), 2.25 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 152.68, 139.90, 137.42,
130.20, 128.85, 127.49, 126.18, 122.67, 121.72, 121.04,
118.01, 17.91. HRMS (ESI): Calcd for C14H15N2O (M +
H)+ 227.1179, found 227.1184.
1-Cyclohexyl-3-phenylurea (5b). White solid (56 mg,
86%), mp 180-182 oC; 1H NMR (300 MHz, DMSO-d6) δ
8.28 (s, 1H), 7.35 (dd, J = 8.6, 1.1 Hz, 2H), 7.20 (dd, J =
10.7, 5.2 Hz, 2H), 6.91 – 6.83 (m, 1H), 6.05 (d, J = 7.8 Hz,
1H), 3.52 – 3.41 (m, 1H), 1.85 – 1.50 (m, 5H), 1.36 – 1.09
(m, 5H); 13C NMR (75 MHz, DMSO-d6) δ 154.45, 140.60,
128.67, 120.89, 117.48, 47.57, 33.02, 25.28, 24.39. HRMS
(ESI): Calcd for C13H19N2O (M + H)+ 219.1492, found
219.1498.
1-Phenyl-3-(m-tolyl)urea (3m). White solid (54 mg,
80%), mp 174-176 oC; 1H NMR (300 MHz, DMSO-d6) δ
8.68 (s, 1H), 8.62 (s, 1H), 7.49 (dd, J = 8.6, 1.0 Hz, 2H),
7.35 – 7.24 (m, 4H), 7.17 (t, J = 7.7 Hz, 1H), 7.03 – 6.94
(m, 1H), 6.80 (d, J = 7.3 Hz, 1H), 2.30 (s, 3H); 13C NMR
(75 MHz, DMSO-d6) δ 152.54, 139.76, 139.64, 137.96,
128.78, 128.62, 122.57, 121.77, 118.72, 118.16, 115.38,
21.23. HRMS (ESI): Calcd for C14H15N2O (M + H)+
227.1179, found 227.1184.
1-Hexyl-3-phenylurea (5c). White solid (55 mg, 84%),
o
mp 72-74 C; 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s,
1H), 7.37 (dd, J = 8.6, 1.1 Hz, 2H), 7.24 – 7.16 (m, 2H),
6.91 – 6.82 (m, 1H), 6.10 (t, J = 5.6 Hz, 1H), 3.06 (dd, J =
12.6, 6.7 Hz, 2H), 1.45 – 1.23 (m, 8H), 0.87 (t, J = 6.7 Hz,
3H); 13C NMR (75 MHz, DMSO-d6) δ 155.22, 140.65,
128.65, 120.88, 117.54, 39.04, 31.09, 29.79, 26.12, 22.17,
1-(Naphthalen-1-yl)-3-phenylurea (3n). Pale purple
o
solid (57 mg, 72%), mp 242-246 C; 1H NMR (300
MHz, DMSO-d6) δ 9.07 (s, 1H), 8.78 (s, 1H), 8.12 (d, J =
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800954
Advanced Synthesis & Catalysis
13.99. HRMS (ESI): Calcd for C13H21N2O (M + H)+
221.1648, found 221.1659.
DMSO-d6) δ 153.58, 147.24, 140.30, 125.17, 116.68,
47.85, 32.70, 25.20, 24.33. HRMS (ESI): Calcd for
C13H18N3O3 (M + H)+ 264.1343, found 264.1350.
1-(Furan-2-ylmethyl)-3-phenylurea (5d). White solid
1-(Furan-2-ylmethyl)-3-(4-nitrophenyl)urea (5l). White
o
(53 mg, 82%), mp 118-120 C; 1H NMR (300 MHz,
o
1
solid (49 mg, 63%), mp 201-203 C; H NMR (300 MHz,
DMSO-d6) δ 9.33 (s, 1H), 8.17 – 8.12 (m, 2H), 7.66 – 7.60
(m, 2H), 7.59 (dd, J = 1.8, 0.8 Hz, 1H), 6.88 (t, J = 5.7 Hz,
1H), 6.40 (dd, J = 3.2, 1.9 Hz, 1H), 6.28 (dd, J = 3.2, 0.7
Hz, 1H), 4.31 (d, J = 5.7 Hz, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 154.25, 152.65, 147.03, 142.21, 140.58,
125.20, 116.99, 110.54, 106.80, 36.20. HRMS (ESI): Calcd
for C12H12N3O4 (M + H)+ 262.0822, found 262.0829.
DMSO-d6) δ 8.51 (s, 1H), 7.59 (dd, J = 1.8, 0.8 Hz, 1H),
7.38 (dd, J = 8.6, 1.1 Hz, 2H), 7.22 (dd, J = 10.6, 5.2 Hz,
2H), 6.92 – 6.86 (m, 1H), 6.53 (t, J = 5.6 Hz, 1H), 6.39 (dd,
J = 3.2, 1.9 Hz, 1H), 6.25 (dd, J =- 3.2, 0.8 Hz, 1H), 4.28
(d, J = 5.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ
154.94, 153.16, 142.10, 140.34, 128.73, 121.24, 117.71,
110.51, 106.53, 36.12. HRMS (ESI): Calcd for C12H13N2O2
(M + H)+ 217.0972, found 217.0985.
1-Phenyl-3-(thiophen-2-ylmethyl)urea (5e). White solid
Acknowledgements
o
(56 mg, 80%), mp 164-166 C; 1H NMR (300 MHz,
DMSO-d6) δ 8.55 (s, 1H), 7.43 – 7.35 (m, 3H), 7.22 (t, J =
7.9 Hz, 2H), 6.96 (dd, J = 8.5, 3.6 Hz, 2H), 6.90 (t, J = 7.3
Hz, 1H), 6.65 (t, J = 5.9 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H);
13C NMR (75 MHz, DMSO-d6) δ 154.98, 143.64, 140.35,
128.71, 126.74, 125.10, 124.91, 121.24, 117.77, 37.89.
HRMS (ESI): Calcd for C12H13N2OS (M + H)+ 233.0743,
found 233.0756.
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (21302014 and 21676030),
the China Postdoctoral Science Foundation (2018M632289), the
Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology (BM2012110), the Priority Academic Program
Development (PAPD) of Jiangsu Higher Education Institutions,
and the Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center of Changzhou University.
1-Benzyl-3-(4-chlorophenyl)urea (5f). White solid (66
mg, 85%), mp 188-190 oC; 1H NMR (300 MHz, DMSO-
d6) δ 8.72 (s, 1H), 7.43 (d, J = 8.7 Hz, 2H), 7.37 – 7.19 (m,
References
7H), 6.67 (t, J = 5.9 Hz, 1H), 4.29 (d, J = 5.9 Hz, 2H); 13
C
NMR (75 MHz, DMSO-d6) δ 155.13, 140.26, 139.52,
128.51, 128.34, 127.16, 126.77, 124.60, 119.21, 42.79.
HRMS (ESI): Calcd for C14H14ClN2O (M + H)+ 261.0789,
found 261.0796.
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M. Dhar, C. Cavallaro, A. J. Tebben, P. H. Carter, J.
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1-Benzyl-3-(4-nitrophenyl)urea (5g). Yellow solid (55
mg, 68%), mp 218-220 oC; 1H NMR (300 MHz, DMSO-
d6) δ 9.39 (s, 1H), 8.14 (d, J = 9.2 Hz, 2H), 7.64 (d, J = 9.3
Hz, 2H), 7.37 – 7.22 (m, 5H), 6.94 (t, J = 5.8 Hz, 1H), 4.32
(d, J = 5.9 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ
154.51, 147.18, 140.47, 139.85, 128.38, 127.20, 126.88,
125.18, 116.94, 42.84. HRMS (ESI): Calcd for C14H14N3O3
(M + H)+ 272.1030, found 272.1044.
1-benzyl-3-(o-tolyl)urea (5h). White solid (58 mg,
81%), mp 186-188 oC; 1H NMR (300 MHz, DMSO-d6) δ
8.50 (s, 1H), 7.37 – 7.29 (m, 4H), 7.29 – 7.19 (m, 3H),
7.11 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.62 (t, J
= 5.9 Hz, 1H), 4.31 (d, J = 5.9 Hz, 2H), 2.25 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 155.27, 140.40, 137.77,
128.50, 128.30, 127.14, 126.72, 121.87, 118.27, 114.92,
42.76, 21.24. , 139.85, 128.38, 127.20, 126.88, 125.18,
116.94, 42.84. HRMS (ESI): Calcd for C15H17N2O (M +
H)+ 241.1335, found 241.1347.
1-benzyl-3-(m-tolyl)urea (5i). White solid (62 mg, 86%),
mp 189-191 oC; 1H NMR (300 MHz, DMSO-d6) δ 7.88 (d,
J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.40 – 7.31 (m, 4H), 7.30 –
7.22 (m, 1H), 7.11 (dd, J = 9.5, 7.7 Hz, 2H), 7.02 (t, J = 5.8
Hz, 1H), 6.88 (td, J = 7.4, 1.1 Hz, 1H), 4.33 (d, J = 5.8 Hz,
2H), 2.19 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 155.42,
140.24, 138.18, 130.08, 128.36, 127.25, 126.79, 126.71, ,
126.09, 121.93, 120.46, 42.90, 17.91. HRMS (ESI): Calcd
for C15H17N2O (M + H)+ 241.1335, found 241.1347.
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1-Benzyl-3-(naphthalen-1-yl)urea (5j). Pale purple solid
o
(65 mg, 79%), mp 198-200 C; 1H NMR (300 MHz,
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DMSO-d6) δ 8.62 (s, 1H), 8.13 – 8.06 (m, 1H), 8.02 (dd, J
= 7.6, 0.9 Hz, 1H), 7.90 (dd, J = 6.9, 2.5 Hz, 1H), 7.58 –
7.48 (m, 3H), 7.42 (t, J = 7.9 Hz, 1H), 7.39 – 7.31 (m, 4H),
7.27 (td, J = 4.6, 2.6 Hz, 1H), 7.05 (t, J = 5.8 Hz, 1H), 4.37
(d, J = 5.8 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ
155.65, 140.23, 135.12, 133.74, 128.40, 127.26, 126.84,
125.96, 125.78, 125.51, 125.47, 122.13, 121.36, 116.46,
42.98. HRMS (ESI): Calcd for C18H17N2O (M + H)+
277.1335, found 277.1343.
1-Cyclohexyl-3-(4-nitrophenyl)urea (5k). White solid
o
(52 mg, 66%), mp 205-207 C; 1H NMR (300 MHz,
DMSO-d6) δ 9.09 (s, 1H), 8.17 – 8.09 (m, 2H), 7.63 – 7.55
(m, 2H), 6.39 (d, J = 7.8 Hz, 1H), 3.54 – 3.43 (m, 1H),
1.85 – 1.76 (m, 2H), 1.65 (dd, J = 8.8, 3.9 Hz, 2H), 1.58 –
1.49 (m, 1H), 1.36 – 1.11 (m, 5H); 13C NMR (75 MHz,
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This article is protected by copyright. All rights reserved.

10.1002/adsc.201800954
Advanced Synthesis & Catalysis
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10.1002/adsc.201800954
Advanced Synthesis & Catalysis
FULL PAPER
Pd/C-catalyzed the domino synthesis of urea
derivatives using chloroform as the carbon
monoxide source in water
Adv. Synth. Catal. Year, Volume, Page – Page
Liang Wang,* Hao Wang, Guiqing Li, Shuliang
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Zheng
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