Palladium-catalyzed decarbonylative C–N coupling to convert arylcarbamoyl chlorides to urea derivatives

Article abstract of DOI:10.1080/00397911.2020.1793207

This paper describes the development of a palladium-catalyzed decarbonylative C–N coupling reaction that transforms arylcarbamoyl chlorides into tetrasubstituted ureas under a nitrogen atmosphere. A broad range of functional groups are compatible with this reaction, and diverse urea derivatives can be obtained with good to high yields.

Full text of DOI:10.1080/00397911.2020.1793207

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Palladium-catalyzed decarbonylative C–N coupling
to convert arylcarbamoyl chlorides to urea
derivatives
Aihong Fan , Jinsong Peng , Dun Zhou , Xiang Li & Chunxia Chen
To cite this article: Aihong Fan , Jinsong Peng , Dun Zhou , Xiang Li & Chunxia Chen (2020):
Palladium-catalyzed decarbonylative C–N coupling to convert arylcarbamoyl chlorides to urea
derivatives, Synthetic Communications, DOI: 10.1080/00397911.2020.1793207
To link to this article: https://doi.org/10.1080/00397911.2020.1793207
View supplementary material
Published online: 20 Jul 2020.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1793207
Palladium-catalyzed decarbonylative C–N coupling to
convert arylcarbamoyl chlorides to urea derivatives
Aihong Fan, Jinsong Peng, Dun Zhou, Xiang Li, and Chunxia Chen
College of Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University,
Harbin, PR China
ABSTRACT
ARTICLE HISTORY
Received 24 April 2020
This paper describes the development of a palladium-catalyzed
decarbonylative C–N coupling reaction that transforms arylcarbamoyl
chlorides into tetrasubstituted ureas under a nitrogen atmosphere. A
broad range of functional groups are compatible with this reaction,
and diverse urea derivatives can be obtained with good to high
yields.
KEYWORDS
Palladium-catalyzed; decar-
bonylative coupling; C–N
bond formation;
arylcarbamoyl chlorides;
symmetrical ureas
GRAPHICAL ABSTRACT
Introduction
Polysubstituted ureas are frequently found in the subunits of synthetic molecules with a
wide range of applications in agriculture, petrochemicals, pharmaceuticals, organocataly-
sis, and material science.[1] In particular, substituted ureas have been utilized as
“privileged scaffolds” for the discovery and development of drugs and agrochemicals,
numerous compounds display versatile biological activities (A–F, Fig. 1). For instance,
Diuron (A),[2] Cumyluron (B),[3] and Tebuthiuron (D)[4] are commercially available
herbicides widely used to control a wide variety of annual and perennial weeds on hard
surfaces. Sorafenib (C), an oral multiple kinase inhibitor, was found to be successful in
the treatment of HCC patients.[5] The anthelmintic drug Hetrazan (E) is effective
against microfilariae and adults of tropical diseases.[6] Cariprazine (F), an antipsychotic
drug for the treatment of schizophrenia and bipolar mania in adults, is currently also
under clinical investigation for the treatment of bipolar depression and major depressive
disorder.[7] Due to their great interest of pharmaceutical and biological research,
CONTACT Jinsong Peng
Utilization, Northeast Forestry University, Harbin, PR China; Chunxia Chen
jspeng1998@nefu.edu.cn
College of Chemistry, Chemical Engineering and Resource
ccx0109@nefu.edu.cn College of
Chemistry, Chemical Engineering and Resource Utilization, Northeast Forestry University, Harbin, PR China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
A. FAN ET AL.
Figure 1. Selected examples of biologically active substituted ureas.
considerable attention has been devoted to synthetic approaches toward functional-
ized ureas.[1]
Generally, the conventional approaches for urea synthesis are mainly based on phos-
gene,[8] phosgene substitutes,[1c,9] isocyanates,[10] carbonyl derivatives (such as carbo-
nates, carbamates, carbonyldiimidazole, and dicyclohexylcarbodiimide),[1c,11] and C–N
migration rearrangement reactions (Hoffman, Curtius, and Lossen rearrangement).[12]
Recently, much effort has been focused on the design and development of novel and
efficient processes as alternatives to classical pathways. One of alternative methods
employed for the synthesis of symmetrical ureas is transition metal-catalyzed oxidative
carbonylation of amines using a C-1 unit as the carbonyl source (CO2 or CO) and an
oxidant.[13] Although significant progress in the Mn-,[14] Co-,[15] Ni-,[16] Ru-,[17] Rh-
[15c,18]
,
Pd-,[19] W-,[20] Cu-,[21] and Au-catalyzed[22] urea syntheses have been made,
high temperatures, moderate-to-high pressures, and sometimes the use of oxidant
[19d,23]
reagents (I2
or copper salts[24]) in stoichiometric amount, led to a need to explore
new strategies for transition metal-catalyzed urea synthesis in the milder reaction condi-
tions. Over the past decade, studies in urea synthesis have mainly focused on palla-
dium-catalyzed reactions. For example, the Buchwald group developed a Pd-catalyzed
synthesis of unsymmetrical diaryl urea via a one-pot arylation-deprotection protocol,
followed by a second arylation.[25] Shortly afterward, they demonstrated a practical way
to synthesize unsymmetrical ureas through a Pd-catalyzed cross-coupling of aryl chlor-
ides with sodium cyanate.[26] In the presence of near-stoichiometric carbon monoxide, a
novel palladium-catalyzed carbonylation of ureas with aryl halides was successfully
developed for the preparation of N-benzoyl ureas by Skrydstrup.[27] Using organoazides
as the substrates, an elegant Pd-catalyzed protocol to afford unsymmetrical ureas and
carbamates under low CO pressure was described by Zhang[28] and Jiao,[29] respectively.
Recently, a few successful procedures for palladium-catalyzed tandem synthesis of
unsymmetrical ureas through the reaction of aryl halides, sodium azide and C-1 unit
(CO, CHCl3, and chromium hexacarbonyl) have been developed by Peng-Wu,[30]
Wang,[31] and Nowrouzi.[32]
Transition metal-catalyzed decarbonylative coupling reactions have emerged as
attractive and alternative strategies for constructing CꢀC and Cꢀ heteroatom bonds in

R
SYNTHETIC COMMUNICATIONSV
3
organic synthesis. Recent years have witnessed an increasing interest in decarbonylative
coupling reactions using various carbonyl functionalities (acyl chlorides, anhydrides,
esters, amides, aldehydes, and ketones) as counterparts.[33] With our continuous efforts
in Pd-catalyzed C–N bond-forming reactions for the assembly of functional mole-
cules,[34] we were interested in decarbonylative coupling reactions of readily accessible
carbamoyl chlorides for the C–N formation.[35]
Results and discussion
Methyl(phenyl)carbamic chloride 1a was selected as a model substrate for a palladium-
catalyzed decarbonylative C–N coupling reaction to construct the symmetrical tetrasub-
stituted urea 2a. The blank experiment (without the catalyst) of 1a was examined in
1,4-dioxane at 100 ꢁC for 48 h using Na2CO3 or KHCO3 as the base, and no desired
product 2a was obtained (entry 1, Table 1). Fortunately, we found that 1a can be trans-
formed into the desired product 2a in 86% yield in the presence of 5 mol% Pd(PPh3)4
(entry 2, Table 1). Thus, to optimize reaction conditions, different catalysts, bases, sol-
vents, reaction time, and temperature were examined, as shown in Table 1. First, the
effect of bases (such as Na2CO3, Cs2CO3, CsF, K2CO3, NaHCO3, KOAc, K3PO4,
KHCO3, NaOH, KOH, CH3ONa, KOt-Bu, and NEt3) on the reaction was investigated
using 5 mol% Pd(PPh3)4 as the catalyst (entries 2–14, Table 1). It was found that the
nature of base greatly influenced the outcome of the reaction, weak inorganic bases pro-
vided better yields (86–95%, entries 2–9) than strong inorganic bases and organic base
(73–79%, entries 11–15). Among all the weak bases examined, KHCO3 seemed to be
more effective and gave 2a in 95% yield (entry 9). It was also worth noting that the
reaction provided the worse results in the absence of KHCO3 or N2, 2a was obtained in
45% and 10% yields, respectively (entry 9, Table 1). In addition, a higher ratio of base
to substrate is preferable to afford a better result [80% (1:1), and 95% (2:1); entry 9].
When the amount of catalyst was reduced to 2 mol% and 1 mol%, the desired product
2a was obtained in 82% and 73% yield, respectively (entry 10). Second, a survey of reac-
tion media showed that weak polar solvents generally provided better results (95%, 1,4-
dioxane, entry 9; 80%, acetonitrile, entry 21) than strong polar solvents (trace, DMSO;
39%, DMF; 67%, DMA; 72%, NMP; entries 16–19) and non-polar solvent (64%, toluene,
entry 20). The effect of palladium sources on the reaction was next investigated,
Pd(PPh3)4 was found to give the best result (95% yield, entry 9), and 1a can also be
converted into 2a in high yields using a phosphine-free palladium catalyst (entries
22–24). Finally, a series of experiments were conducted to reveal the role of reaction
time and temperature on the reaction (entries 25–29). Generally, higher yields were
obtained with the reaction time increasing; however, when the reaction temperature is
over 100 ꢁC, the yield gradually decreased with the increase of temperature.
Having established the feasibility of symmetrical urea synthesis via palladium-cata-
lyzed decarbonylative C–N coupling reaction, we then explored the scope and limitation
of carbamoyl chlorides under the standard conditions (Table 2). As shown in Table 2, a
variety of diversely substituted groups (such as alkyl, -OMe, -OPh, -F, -Cl, -CN, -CF3,
-COOMe, -SMe, -NMe2, morpholino) on the aromatic moiety of anilines were applic-
able, and the corresponding ureas 2fꢀ2z can be obtained in moderate to high yields

4
A. FAN ET AL.
Table 1. Optimization of reaction conditions for Pd-catalyzed urea synthesisa.
Entry
Catalyst
Base
Solvent
Dioxane
Time/temp.
Yield (%)b
1
2
3
4
5
6
7
8
–
Na2CO3, KHCO3
Na2CO3
Cs2CO3
CsF
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
48 h/100 ꢁC
24 h/100 ꢁC
36 h/100 ꢁC
48 h/90 ꢁC
0
86
88
77
91
89
89
90
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
K2CO3
NaHCO3
CH3COOK
K3PO4
9
KHCO3
KHCO3
NaOH
95/10c/45d/80e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
82f/73g
79
KOH
73
73
74
74
39
67
72
trace
64
CH3ONa
t-BuOK
Et3N
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
DMA
NMP
DMSO
Toluene
CH3CN
80
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
88/89h
85/90h
86
Pd(OAc)2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
73
85
60
74
48 h/110 ꢁC
48 h/120 ꢁC
68
aReaction conditions: 1a (0.2 mmol), palladium catalyst (5 mol%, 0.01 mmol), base (0.4 mmol), solvent (1.0 mL).
bIsolated yield.
cWithout N2.
dWithout KHCO3.
e1 Equiv of KHCO3 was used.
f2 mol% of Pd(PPh3)4 was used.
g1 mol% of Pd(PPh3)4 was used.
h10 mol% of PPh3 was added.
(25–93%). Phenylcarbamoyl chlorides 1a–1e were first investigated to elucidate the
influence of different N-substituted groups (methyl, ethyl, n-butyl, benzyl, cyclohexyl,
and phenyl) on the reaction.
For aliphatic substituted substrates, the reaction yield remarkably decreased from
95% to 30% with the increase of the steric hindrance of substituents on the N atom.
However, the introduction of the aromatic substituent on the N atom (e.g., diphenyl-
carbamoyl chloride substrate) seemed to hamper the reaction, and the corresponding
urea was not obtained. Next, the limitations of N-methyl arylcarbamoyl chloride sub-
strates were assessed. Most of monosubstituted (para-, meta-, and ortho-substituted),
disubstituted, trisubstituted, or fused arylcarbamoyl chlorides underwent the reaction
and afforded the corresponding tetrasubstituted ureas. N-methyl arylcarbamoyl

R
SYNTHETIC COMMUNICATIONSV
5
Table 2. Scope and generality of arylcarbamoyl chloridesa,b
.
aReaction conditions: 1 (0.2 mmol), Pd(PPh3)4 (0.01 mmol), KHCO3 (0.4 mmol), 1,4-dioxane (1.0 mL), 100 ꢁC, 48 h,
under N2.
bIsolated yield.
chlorides containing groups at the para or meta position of benzene ring were
generally more reactive than those bearing substituents at the ortho position and
provided higher yields. para-Substituted arylcarbamoyl chlorides containing electron-
donating groups underwent the reaction smoothly and afforded the corresponding
products in good yields (2f–2l, 44–90%); however, the presence of ester group led to
an inferior result (2q, 25% isolated yield), and substrates having nitro and bromine
groups provided no products under the standard conditions. The incorporation of
the group (such as methyl, chlorine, and dimethyl) in the ortho position of aryl
moiety seemed to hamper the reaction to some extent, and the corresponding ureas
were obtained in low yields. The decarbonylative C–N coupling process was com-
pletely inhibited when methoxyl group was introduced, probably because of the
strong steric repulsion between the ortho substituent and the palladium center. In
addition, a- or b-naphthylcarbamoyl chloride can also be transformed into the
desired products 2w and 2x in 39 and 55% yields, respectively.
To gain insight into the mechanism of the reaction, catalyst-free process of arylcarba-
moyl chloride 1a was conducted in the presence of KHCO3, no desired product 2a was
formed and arylcarbamoyl chloride 1a was completely recovered. In addition, the direct
reaction of N-phenyl-N-methyl carbamoyl chloride 1a with N-methyl aniline in the
presence of 5 mol% of 4-dimethylaminopyridine (DMAP) using Et3N as the base in the

6
A. FAN ET AL.
Scheme 1. Possible reaction mechanism.
1,4-dioxane for 48 h, 2a can be obtained only in 36% yield, and the yield of 2a was
reduced to 22% in the absence of DMAP. Based on the above results, a plausible reac-
tion pathway for symmetrical tetrasubstituted urea formation through palladium-cata-
lyzed decarbonylative coupling reaction was outlined. Scheme 1 shows a simplified
sequence of events beginning with the active Pd(0) species. The initial step involved the
oxidative addition of arylcarbamoyl chloride 1 by Pd(0) to generate 3. Under a nitrogen
atmosphere, intermediate 3 subsequently underwent a CO extrusion step to give an
amino-palladium complex 4.[35] Nucleophilic addition of intermediate 4 across the
C ¼ O bond provided intermediate 5, which was followed by b-chlorine elimination to
afford the urea product 2 and Pd(II)L2Cl2. The latter can be reduced to Pd(0) species
for the next catalytic cycle in the presence of PPh3, CO and inorganic base.[36]
Conclusion
In conclusion, we have developed an approach for the synthesis of diverse symmetrical
tetrasubstituted urea derivatives through Pd-catalyzed decarbonylative C–N coupling
reaction of carbamoyl chlorides under a nitrogen atmosphere. This synthetic method
exhibits a broad substrate scope with moderate to good yields.
Experimental
Chemicals were all purchased from commercial supplies and used without further puri-
fication unless otherwise stated. Solvents were dried and purified according to the
standard procedures before use. Reactions were monitored by analytical thin-layer chro-
matography (TLC). All reactions were conducted in dried glassware. Purification of

R
SYNTHETIC COMMUNICATIONSV
7
reaction products was done by flash chromatography with 230–400 mesh silica gel.
Melting points were determined on a melting point apparatus in open capillaries and
1
are uncorrected. H NMR spectra were recorded on a 500 MHz spectrometer, and 13C
NMR spectra were recorded at 126 MHz. Unless otherwise stated, deuterochloroform
(CDCl3) was used as a solvent. High-resolution mass spectra were recorded on a BIO
TOF Q mass spectrometer equipped with an electrospray ion source (ESI), operated in
the positive mode.
Procedure for the synthesis of urea 2y
A 10 mL Schlenk tube equipped with a magnetic stirring bar was charged with arylcar-
bamoyl chloride 1 h (0.2 mmol, 1.0 equiv), and KHCO3 (40 mg, 0.4 mmol), and then
Pd(PPh3)4 (0.01 mmol, 11.56 mg) were added. Finally, 1,4-dioxane (1.0 mL) was added
to the mixture via syringe at room temperature under N2. The tube was sealed and put
into a preheated oil bath a 100 ꢁC for 48 h. The mixture was cooled to room tempera-
ture, quenched with water (5 mL), and diluted with ethyl acetate (5 mL). The layers
were separated, and the aqueous layer was extracted with 2 ꢂ 5 mL of ethyl acetate. The
combined organic extracts were dried over anhydrous sodium sulfate, filtered, and con-
centrated in vacuo. The crude product was then purified by flash chromatography on
silica gel (H), eluting with 30ꢀ35% ethylacetate/petroleum ether.
1,3-Bis(3,5-dimethylphenyl)-1,3-dimethylurea (2y)
1
Yield, 89% (26.6 mg); light yellow solid, mp 62–65 ꢁC. H NMR (500 MHz, CDCl3) d
6.50 (s, 2H), 6.31 (s, 4H), 3.08 (s, 6H), 2.05 (s, 12H). 13C NMR (126 MHz, CDCl3) d
161.1, 145.3, 138.0, 126.4, 123.9, 39.4, 21.0. HRMS (ESI) m/z calcd for C19H25N2Oþ
(M þ H)þ 297.1961, found 297.1962.
1
Experimental detail, H and 13C NMR spectra of the products and High-resolution
mass spectra of new compounds. This material can be found via the “Supplementary
Content” section of this article’s webpage.
Disclosure statement
The authors declare no conflict of interest.
Funding
The authors are grateful for financial support from the Fundamental Research Funds for the
Central Universities (2572017DB07), and Natural Science Foundation of Heilongjiang Province
(B2017002, LC2018003).
References
[1] (a) Guan, A.; Liu, C.; Yang, X.; Dekeyser, M. Application of the Intermediate
Derivatization Approach in Agrochemical Discovery. Chem. Rev. 2014, 114, 7079–7107.
DOI: 10.1021/cr4005605. (b) Gallou, I. Unsymmetrical Ureas. Synthetic Methodologies
and Application in Drug Design. Org. Prep. Proced. Int. 2007, 39, 355–383. DOI: 10.1080/

8
A. FAN ET AL.
00304940709458592. (c) Bigi, F.; Maggi, R.; Sartori, G. Selected Syntheses of Ureas
through Phosgene Substitutes. Green Chem. 2000, 2, 140–148. DOI: 10.1039/b002127j. (d)
Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Substituted Ureas. Methods of
Synthesis and Applications. Russ. Chem. Rev. 1985, 54, 249–261. DOI: 10.1070/
RC1985v054n03ABEH003022.
[2] Cabrera, A.; Cox, L.; Velarde, P.; Koskinen, W. C.; Cornejo, J. Fate of Diuron and
Terbuthylazine in Soils Amended with Two-Phase Olive Oil Mill Waste. J. Agric. Food
Chem. 2007, 55, 4828–4834. DOI: 10.1021/jf070525b.
[3] Askew, S. D.; McNulty, B. M. S. Methiozolin and Cumyluron for Preemergence Annual
Bluegrass (Poa Annua) Control on Creeping Bentgrass (Agrostis Stolonifera) Putting
Greens. Weed Technol. 2014, 28, 535–542. DOI: 10.1614/WT-D-14-00018.1.
^
[4] Tonieto, T. A. P.; de Pierri, L.; Tornisielo, V. L.; Regitano, J. B. Fate of Tebuthiuron and
Hexazinone in Green-Cane Harvesting System. J. Agric. Food Chem. 2016, 64, 3960–3966.
DOI: 10.1021/acs.jafc.5b04665.
[5] Llovet, J. M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J. F.; de Oliveira,
A. C.; Santoro, A.; Raoul, J. L.; Forner, A.; et al. Sorafenib in Advanced Hepatocellular
Carcinoma. N Engl. J. Med. 2008, 359, 378–390. DOI: 10.1056/NEJMoa0708857.
[6] Awadzi, K.; Gilles, H. M. Diethylcarbamazine in the Treatment of Patients with
Onchocerciasis. Br. J. Clin. Pharmacol. 1992, 34, 281–288. DOI: 10.1111/j.1365-2125.1992.
tb05632.x.
[7] (a) Kehr, J.; Yoshitake, T.; Ichinose, F.; Yoshitake, S.; Kiss, B.; Gyertyan, I.; Adham, N.
Effects of Cariprazine on Extracellular Levels of Glutamate, GABA, Dopamine,
Noradrenaline and Serotonin in the Medial Prefrontal Cortex in the Rat Phencyclidine
Model of Schizophrenia Studied by Microdialysis and Simultaneous Recordings of
Locomotor Activity. Psychopharmacology (Berl). 2018, 235, 1593–1607. DOI: 10.1007/
s00213-018-4874-z. (b) Shen, Y.; McCorvy, J. D.; Martini, M. L.; Rodriguiz, R. M.;
Pogorelov, V. M.; Ward, K. M.; Wetsel, W. C.; Liu, J.; Roth, B. L.; Jin, J. D2 Dopamine
Receptor G Protein-Biased Partial Agonists Based on Cariprazine. J. Med. Chem. 2019, 62,
4755–4771. DOI: 10.1021/acs.jmedchem.9b00508.
[8] Babad, H.; Zeiler, A. G. Chemistry of Phosgene. Chem. Rev. 1973, 73, 75–91. DOI: 10.
1021/cr60281a005.
[9] (a) Majer, P.; Randad, R. S. A Safe and Efficient Method for Preparation of N, N0-
Unsymmetrically Disubstituted Ureas Utilizing Triphosgene. J. Org. Chem. 1994, 59,
1937–1938. DOI: 10.1021/jo00086a061. (b) Scialdone, M. A.; Shuey, S. W.; Soper, P.;
Hamuro, Y.; Burns, D. M. Phosgenated p-Nitrophenyl(Polystyrene)Ketoxime or Phoxime
Resin. A New Resin for the Solid-Phase Synthesis of Ureas via Thermolytic Cleavage of
Oxime-Carbamates. J. Org. Chem. 1998, 63, 4802–4807. DOI: 10.1021/jo9716542.
[10] Ozaki, S. Recent Advances in Isocyanate Chemistry. Chem. Rev. 1972, 72, 457–496. DOI:
10.1021/cr60279a002.
[11] (a) Padiya, K. J.; Gavade, S.; Kardile, B.; Tiwari, M.; Bajare, S.; Mane, M.; Gaware, V.;
Varghese, S.; Harel, D.; Kurhade, S. Unprecedented “in Water” Imidazole Carbonylation:
Paradigm Shift for Preparation of Urea and Carbamate. Org. Lett. 2012, 14, 2814–2817.
DOI: 10.1021/ol301009d. (b) Dube, P.; Nathel, N. F. F.; Vetelino, M.; Couturier, M.;
Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Carbonyldiimidazole-
Mediated Lossen Rearrangement. Org. Lett. 2009, 11, 5622–5625. DOI: 10.1021/ol9023387.
(c) Han, C.; Porco, J. A. Synthesis of Carbamates and Ureas Using Zr (IV)-Catalyzed
Exchange Processes. Org. Lett. 2007, 9, 1517–1520. DOI: 10.1021/ol0702728. (d) Gallou, I.;
Eriksson, M.; Zeng, X.; Senanayake, C.; Farina, V. Practical Synthesis of Unsymmetrical
Ureas from Isopropenyl Carbamates. J. Org. Chem. 2005, 70, 6960–6963. DOI: 10.1021/
jo0507643. (e) Bogolubsky, A. V.; Moroz, Y. S.; Mykhailiuk, P. K.; Granat, D. S.; Pipko,
S. E.; Konovets, A. I.; Doroschuk, R.; Tolmachev, A. Bis(2,2,2-Trifluoroethyl) Carbonate as
a Condensing Agent in One-Pot Parallel Synthesis of Unsymmetrical Aliphatic Ureas.
ACS Comb. Sci. 2014, 16, 303–308. DOI: 10.1021/co500025f.

R
SYNTHETIC COMMUNICATIONSV
9
[12] (a) Aube, J., Fehl, C., Liu, R., McLeod, M. C., Motiwala, H. F. (Eds.). Comprehensive
Organic Synthesis II, 2nd ed.; Elsevier: Amsterdam, 2014. (b) Zhao, Y.-X.; Xie, T.; Yang,
S.-K.; Yang, X.-J. A Novel C–N Migration Rearrangement Based on N–F Compounds for
the Synthesis of N-Alkyl Diaryl Ureas. Eur. J. Org. Chem. 2020, 2020, 437–445. DOI: 10.
1002/ejoc.201901602.
ꢀ
[13] (a) Dıaz, D. J.; Darko, A. K.; McElwee-White, L. Transition Metal-Catalyzed Oxidative
Carbonylation of Amines to Ureas. Eur. J. Org. Chem. 2007, 2007, 4453–4465. DOI: 10.
1002/ejoc.200700148. (b) Ragaini, F. Away from Phosgene: Reductive Carbonylation of
Nitroarenes and Oxidative Carbonylation of Amines, Understanding the Mechanism to
Improve Performance. Dalton Trans. 2009, 32, 6251–6266. DOI: 10.1039/b902425p. (c)
Mancuso, R.; Raut, D. S.; Della Ca’, N.; Fini, F.; Carfagna, C.; Gabriele, B. Catalytic
Oxidative Carbonylation of Amino Moieties to Ureas, Oxamides, 2-Oxazolidinones, and
Benzoxazolones. ChemSusChem 2015, 8, 2204–2211. DOI: 10.1002/cssc.201500343. (d) Ca’,
N. D.; Bottarelli, P.; Dibenedetto, A.; Aresta, M.; Gabriele, B.; Salerno, G.; Costa, M.
Palladium-Catalyzed Synthesis of Symmetrical Urea Derivatives by Oxidative
Carbonylation of Primary Amines in Carbon Dioxide Medium. J. Catal. 2011, 282,
120–127. DOI: 10.1016/j.jcat.2011.06.003. (e) Jiang, T.; Ma, X.; Zhou, Y.; Liang, S.; Zhang,
J.; Han, B. Solvent-Free Synthesis of Substituted Ureas from CO2 and Amines with a
Functional Ionic Liquid as the Catalyst. Green Chem. 2008, 10, 465ꢀ469. DOI: 10.1039/
b717868a. (f) Sun, D.-L.; Ye, J.-H.; Fang, Y.-X.; Chao, Z.-S. Green Synthesis of N,
N00Dialkylureas from CO2 and Amines Using Metal Salts of Oxalates as Catalysts. Ind.
Eng. Chem. Res. 2016, 55, 64–70. DOI: 10.1021/acs.iecr.5b02936.
[14] (a) Srivastava, S. C.; Shrimal, A. K.; Srivastava, A. Reactions of (g-Methylcyclopentadienyl)
Manganese Tricarbonyl with Primary Amines. J. Organomet. Chem. 1991, 414, 65–69.
DOI: 10.1016/0022-328X(91)83242-V. (b) Li, K. T.; Peng, Y. J. Oxidative Carbonylation of
Aniline Using Manganese-Based Catalysts. J. Catal. 1993, 143, 631–634. DOI: 10.1006/jcat.
1993.1306.
[15] (a) Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. Acyclic and Cyclic Urea Formation
via the Cobalt-Catalysed Oxidative Carbonylation of Aromatic Primary Amines. J. Mol.
Catal. 1990, 60, 41–48. DOI: 10.1016/0304-5102(90)85065-P. (b) Enquist, P. A.; Nilsson,
P.; Edin, J.; Larhed, M. Super Fast Cobalt Carbonyl-Mediated Synthesis of Ureas.
Tetrahedron Lett. 2005, 46, 3335–3339. DOI: 10.1016/j.tetlet.2005.03.076. (c) Park, J. H.;
Yoon, J. C.; Chung, Y. K. Cobalt/Rhodium Heterobimetallic Nanoparticle-Catalyzed
Oxidative Carbonylation of Amines in the Presence of Carbon Monoxide and Molecular
Oxygen to Ureas. Adv. Synth. Catal. 2009, 351, 1233–1237. DOI: 10.1002/adsc.200900106.
[16] Giannoccaro, P.; Nobile, C. F.; Mastrorilli, C.; Ravasio, J. Oxidative Carbonylation of
Aliphatic Amines Catalysed by Nickel-Complexes. J. Organomet. Chem. 1991, 419,
251–258. DOI: 10.1016/0022-328X(91)86180-X.
ꢀ
[17] (a) Fournier, J.; Bruneau, C.; Dixneuf, P. H.; Lecolier, S. Ruthenium-Catalyzed Synthesis
of Symmetrical N,N’-Dialkylureas Directly from Carbon Dioxide and Amines. J. Org.
Chem. 1991, 56, 4456–4458. DOI: 10.1021/jo00014a024. (b) Mulla, S. A. R.; Rode, C. V.;
Kelkar, A. A.; Gupte, S. P. Activity of Homogeneous Transition Metal Catalysts for
Oxidative Carbonylation of Aniline to N,N’-Diphenyl Urea. J. Mol. Catal. A: Chem. 1997,
122, 103–109. DOI: 10.1016/S1381-1169(97)00023-X. (c) Kim, S. H.; Hong, S. H.
Ruthenium-Catalyzed Urea Synthesis Using Methanol as the C1 Source. Org. Lett. 2016,
18, 212–215. DOI: 10.1021/acs.orglett.5b03328. (d) Krishnakumar, V.; Chatterjee, B.;
Gunanathan, C. Ruthenium-Catalyzed Urea Synthesis by NꢀH Activation of Amines.
Inorg. Chem. 2017, 56, 7278–7284. DOI: 10.1021/acs.inorgchem.7b00962.
[18] Bu, X.-B.; Wang, Z.; Wang, Y.-H.; Jiang, T.; Zhang, L.; Zhao, Y.-L. Rhodium-Catalyzed
Oxidative Coupling Reaction of Isocyanides with Alcohols or Amines and Molecular
Oxygen as Oxygen Source: Synthesis of Carbamates and Ureas. Eur. J. Org. Chem. 2017,
2017, 1132–1138. DOI: 10.1002/ejoc.201601484.
[19] (a) Gupte, S. P.; Chaudhari, R. V. Oxidative Carbonylation of Aniline over PdC Catalyst:
Effect of Promoters, Solvents, and Reaction Conditions. J. Catal. 1988, 114, 246–258.

10
A. FAN ET AL.
DOI: 10.1016/0021-9517(88)90028-0. (b) Choudary, B. M.; Rao, K. K.; Pirozhkov, S. D.;
Lapidus, A. L. Conversion of Primary Amines to N,N’-Disubstituted Ureas Using
Montmorillonitebipyridinepalladium (II)-Acetate and di-Tert Butyl Peroxide. Synth.
Commun. 1991, 21, 1923–1927. DOI: 10.1080/00397919108021783. (c) Valli, V. L. K.;
Alper, H. Oxidative Carbonylation of Aliphatic Mono-, Di-, and Triamines Catalyzed by
Montmorillonite–Bipyridinylpalladium(II) Acetate. Organometallics 1995, 14, 80–82. DOI:
2ꢀ
10.1021/om00001a016. (d) Shi, F.; Deng, Y.; SiMa, T.; Yang, H. A Novel ZrO2–SO4
Supported Palladium Catalyst for Syntheses of Disubstituted Ureas from Amines by
Oxidative Carbonylation. Tetrahedron Lett. 2001, 42, 2161–2163. DOI: 10.1016/S0040-
4039(01)00124-1. (e) Chiarotto, I.; Feroci, M. Selective and Environmentally Friendly
Methodologies Based on the Use of Electrochemistry for Fine Chemical Preparation: An
Efficient Synthesis of N,N’-Disubstituted Ureas. J. Org. Chem. 2003, 68, 7137–7139. DOI:
10.1021/jo034750d. (f) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. Efficient Synthesis
of Ureas by Direct Palladium-Catalyzed Oxidative Carbonylation of Amines. J. Org. Chem.
2004, 69, 4741–4750. DOI: 10.1021/jo0494634. (g) Orito, K.; Miyazawa, M.; Nakamura, T.;
Horibata, A.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda,
M. Pd(OAc)2-Catalyzed Carbonylation of Amines. J. Org. Chem. 2006, 71, 5951–5958.
DOI: 10.1021/jo060612n. (h) Zheng, S.-Z.; Peng, X.-G.; Liu, J.-M.; Sun, W.; Xia, C.-G. N-
Heterocyclic Carbene-Palladium Complex Catalyzed Oxidative Carbonylation of Amines
to Ureas. Chin. J. Chem. 2007, 25, 1065–1068. DOI: 10.1002/cjoc.200790196. (i) Ragaini,
F.; Gasperini, M.; Cenini, S.; Arnera, L.; Caselli, A.; Macchi, P.; Casati, N. Mechanistic
Study of the Palladium–Phenanthroline Catalyzed Carbonylation of Nitroarenes and
Amines: Palladium–Carbonyl Intermediates and Bifunctional Effects. Chemistry 2009, 15,
8064–8077. DOI: 10.1002/chem.200801882. (j) Giannoccaro, P.; Ferragina, C.; Gargano,
M.; Quaranta, E. Pd-Catalysed Oxidative Carbonylation of Amino Alcohols to N,N’-Bis
(Hydroxyalkyl) Ureas under Mild Conditions Using Molecular Oxygen as the Oxidant.
Appl. Catal. A 2010, 375, 78–84. DOI: 10.1016/j.apcata.2009.12.022. (k) Guan, Z. H.; Lei,
H.; Chen, M.; Ren, Z. H.; Bai, Y.; Wang, Y. Y. Palladium-Catalyzed Carbonylation of
Amines: Switchable Approaches to Carbamates and N,N’-Disubstituted Ureas. Adv. Synth.
Catal. 2012, 354, 489–496. DOI: 10.1002/adsc.201100545. (l) Krogul, A.; Litwinienko, G.
One Pot Synthesis of Ureas and Carbamates via Oxidative Carbonylation of Aniline-Type
Substrates by CO/O2 Mixture Catalyzed by Pd-Complexes. J. Mol. Catal. A: Chem. 2015,
407, 204–211. DOI: 10.1016/j.molcata.2015.06.027. (m) Sara, R.; Peter, B.; Patrik, N.; Mats,
L.; Luke, O.; Jonas, E. Synthesis of 11C-Labelled Ureas by Palladium (II)-Mediated
Oxidative Carbonylation. Molecules 2017, 22, 1688. (n) Francesco, F.; Edoardo, B.;
Claudia, G.; Doaa, R.; Fabio, R. Palladium/Iodide Catalyzed Oxidative Carbonylation of
Aniline to Diphenylurea: Effect of Ppm Amounts of Iron Salts. J. Catal. 2019, 369,
257–266.
[20] (a)McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.; McElwee-White, L.
W(CO)6-Catalyzed Oxidative Carbonylation of Primary Amines to N,N’-disubstituted
ureas in single or biphasic solvent systems. Optimization and functional group compatibil-
ity studies. J. Org. Chem. 2000, 65, 5216–5222. DOI: 10.1021/jo000364þ. (b) Zhang, L.;
Darko, A. K.; Johns, J. I.; McElwee-White, L. Catalytic Oxidative Carbonylation of
Arylamines to Ureas with W(CO)6/I2 as Catalyst. Eur. J. Org. Chem. 2011, 2011,
6261–6268. DOI: 10.1002/ejoc.201100657.
[21] (a) Zheng, S.; Li, F.; Liu, J.; Xia, C. A Novel and Efficient (NHC) CuI (NHC ¼ N-
Heterocyclic Carbene) Catalyst for the Oxidative Carbonylation of Amino Compounds.
Tetrahedron Lett. 2007, 48, 5883–5886. DOI: 10.1016/j.tetlet.2007.06.049. (b) Casiello, M.;
Iannone, F.; Cotugno, P.; Monopoli, A.; Cioffi, N.; Ciminale, F.; Trzeciak, A. M.; Nacci, A.
Copper(II)-Catalysed Oxidative Carbonylation of Aminols and Aminesin Water: A Direct
Access to Oxazolidinones, Ureas and Carbamates. J. Mol. Catal. A: Chem. 2015, 407,
8–14. DOI: 10.1016/j.molcata.2015.06.007.

R
SYNTHETIC COMMUNICATIONSV
11
[22] Shi, F.; Deng, Y. Q. Polymer-Immobilized Gold Catalysts for the Efficient and Clean
Syntheses of Carbamates and Symmetric Ureas by Oxidative Carbonylation of Aniline and
Its Derivatives. J. Catal. 2002, 211, 548–551. DOI: 10.1016/S0021-9517(02)93772-3.
[23] Pri-Bar, I.; Alper, H. Oxidative Coupling of Amines and Carbon Monoxide Catalyzed by
Palladium Complexes. Mono-and Double Carbonylation Reactions Promoted by Iodine
Compounds. Can. J. Chem. 1990, 68, 1544–1547. DOI: 10.1139/v90-238.
[24] Giannoccaro, P. Palladium-Catalysed N,N’-Disubstituted Urea Synthesis by Oxidative
Carbonylation of Amines under CO and O2 at Atmospheric Pressure. J. Organomet.
Chem. 1987, 336, 271–278. DOI: 10.1016/0022-328X(87)87174-7.
[25] Breitler, S.; Oldenhuis, N. J.; Fors, B. P.; Buchwald, S. L. Synthesis of Unsymmetrical
Diarylureas via Pd-Catalyzed C-N Cross-Coupling Reactions. Org. Lett. 2011, 13,
3262–3265. DOI: 10.1021/ol201210t.
[26] Vinogradova, E. V.; Fors, B. P.; Buchwald, S. L. Palladium-Catalyzed Cross-Coupling of
Aryl Chlorides and Triflates with Sodium Cyanate:
A Practical Synthesis of
Unsymmetrical Ureas. J. Am. Chem. Soc. 2012, 134, 11132–11135. DOI: 10.1021/
ja305212v.
[27] Bjerglund, K.; Lindhardt, A. T.; Skrydstrup, T. Palladium-Catalyzed N-Acylation of
Monosubstituted Ureas Using near-Stoichiometric Carbon Monoxide. J. Org. Chem. 2012,
77, 3793–3799. DOI: 10.1021/jo3000767.
[28] Zhao, J.; Li, Z.; Yan, S.; Xu, S.; Wang, M.-A.; Fu, B.; Zhang, Z. Pd/C Catalyzed
Carbonylation of Azides in the Presence of Amines. Org. Lett. 2016, 18, 1736–1739. DOI:
10.1021/acs.orglett.6b00381.
[29] Ren, L.; Jiao, N. PdCl2 Catalyzed Efficient Assembly of Organic Azides, CO, and Alcohols
under Mild Conditions: A Direct Approach to Synthesize Carbamates. Chem. Commun.
(Camb) 2014, 50, 3706–3709. DOI: 10.1039/c4cc00538d.
[30] Chen, B.; Peng, J. B.; Ying, J.; Qi, X.; Wu, X. F. A Palladium-Catalyzed Domino
Procedure for the Synthesis of Unsymmetrical Ureas. Adv. Synth. Catal. 2018, 360,
2820–2824. DOI: 10.1002/adsc.201800496.
[31] Wang, L.; Wang, H.; Li, G.; Min, S.; Xiang, F.; Liu, S.; Zheng, W. Pd/C-Catalyzed Domino
Synthesis of Urea Derivatives Using Chloroform as the Carbon Monoxide Source in
Water. Adv. Synth. Catal. 2018, 360, 4585–4593. DOI: 10.1002/adsc.201800954.
[32] Mozaffari, M.; Nowrouzi, N. Palladium-Catalyzed Synthesis of Symmetrical and
Unsymmetrical Ureas Using Chromium Hexacarbonyl as a Convenient and Safe
Alternative Carbonyl Source. Eur. J. Org. Chem. 2019, 2019, 7541–7544. DOI: 10.1002/
ejoc.201901273.
[33] (a) Zhao, Q.; Szostak, M. Redox-Neutral Decarbonylative Cross-Couplings Coming of
Age. ChemSusChem 2019, 12, 2983–2987. DOI: 10.1002/cssc.201900408. (b) Guo, L.;
Rueping, M. Transition-Metal-Catalyzed Decarbonylative Coupling Reactions: Concepts,
Classifications, and Applications. Chemistry 2018, 24, 7794–7809. DOI: 10.1002/chem.
201704670. (c) Guo, L.; Rueping, M. Decarbonylative Cross-Couplings: Nickel Catalyzed
Functional Group Interconversion Strategies for the Construction of Complex Organic
Molecules. Acc. Chem. Res. 2018, 51, 1185–1195. DOI: 10.1021/acs.accounts.8b00023.
[34] (a) Chen, C.; Shang, G.; Zhou, J.; Yu, Y.; Li, B.; Peng, J. Modular Synthesis of
Benzimidazole-Fused Phenanthridines from 20Arylbenzimidazoles and o-Dibromoarenes
by a Palladium-Catalyzed Cascade Process. Org. Lett. 2014, 16, 1872–1875. DOI: 10.1021/
ol500248h. (b) Zhao, G.; Chen, C.; Yue, Y.; Yu, Y.; Peng, J. Palladium(II)-Catalyzed
Sequential CꢀH Arylation/Aerobic Oxidative C–H Amination: One-Pot Synthesis of
Benzimidazole-Fused Phenanthridines from 2-Arylbenzimidazoles and Aryl Halides. J.
Org. Chem. 2015, 80, 2827–2834. DOI: 10.1021/jo502632b. (c) Yu, Y.; Yue, Y.; Wang, D.;
Li, X.; Chen, C.; Peng, J. Modular Synthesis of Quinazolinone-Fused Phenanthridinones
by a Palladium-Catalyzed Cascade C–H/N–H Arylation Process. Synthesis 2016, 48,
3941–3950. DOI: 10.1055/s-0035-1561481. (d) Li, X.; Chen, X.; Wang, H.; Chen, C.; Sun,
P.; Mo, B.; Peng, J. Palladium-Catalyzed Tandem One-Pot Synthesis of p-Expanded

12
A. FAN ET AL.
Imidazoles through Sequential Heck and Oxidative Amination Reaction. Org. Biomol.
Chem. 2019, 17, 4014–4023. DOI: 10.1039/C9OB00482C.
[35] Tsukano, C.; Okuno, M.; Takemoto, Y. Palladium-Catalyzed Amidation by
Chemoselective C(sp3)H Activation: Concise Route to Oxindoles Using a Carbamoyl
Chloride Precursor. Angew. Chem. Int. Ed. Engl. 2012, 51, 2763–2766. DOI: 10.1002/anie.
201108889.
[36] (a) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A.; Meyer, G. Evidence for the
Ligation of Palladium(0) Complexes by Acetate Ions: Consequences on the Mechanism of
Their Oxidative Addition with Phenyl Iodide and PhPd(OAc)(PPh3)2 as Intermediate in
the Heck Reaction. Organometallics 1995, 14, 5605–5614. DOI: 10.1021/om00012a029. (b)
Amatore, C.; Azzabi, M.; Jutand, A. Role and Effects of Halide Ions on the Rates and
Mechanisms of Oxidative Addition of Iodobenzene to Low-Ligated Zerovalent Palladium
Complexes Pd0(PPh3)2. J. Am. Chem. Soc. 1991, 113, 8375–8384. DOI: 10.1021/
ja00022a026.