Pd/C-catalyzed reductive carbonylation of nitroaromatics for the synthesis of unsymmetrical ureas: One-step synthesis of neburon

Article abstract of DOI:10.1039/c8nj02413h

A Pd/C catalyzed reductive carbonylation of nitroarenes for the synthesis of unsymmetrical ureas has been developed. Using inexpensive and stable nitroarenes as the substrates, a series of unsymmetrical ureas were produced in moderate to good yields. A range of functional groups including thioethers, halides and vinyl were compatible with this reaction. As a heterogeneous catalyst, Pd/C was recycled and reused four times without losing activity. Notably, urea-based herbicide neburon was prepared in 64% yield under our standard conditions.

Full text of DOI:10.1039/c8nj02413h

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Pd/C-Catalyzed Reductive Carbonylation of Nitroaromatics for
the Synthesis of Unsymmetrical Ureas: One-Step Synthesis of
Neburon
Chong-Liang Li,[a] Jin-Bao Peng,*[a] Xinxin Qi,[a] Jun Ying,[a] and Xiao-Feng Wu*[a,b]
a
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of
China
E-mail: pengjb_05@zstu.edu.cn; xiao-feng.wu@catalysis.de
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, 18059 Rostock, Germany
b
also been reported as well (Scheme 1, b). However,
nitroarenes for the synthesis of unsymmetrical ureas have the high pressure of CO and excess promotor are not
Abstract. A Pd/C catalyzed reductive carbonylation of
been developed. Using inexpensive and stable nitroarenes
as the substrates, a series of unsymmetrical ureas were
produced in moderate to good yields. A range of functional
groups including thioether, halides and vinyl were
compatible in this reaction. As a heterogeneous catalyst,
Pd/C was recycled and reused for four times without losing
activity. Notably, urea-based herbicide Neburon was
prepared in 64% yield under our standard conditions.
match with the “green chemistry” principles. Besides,
in most cases, these reports usually get symmetrical
diarylureas. Recently, our group have developed a
series of carbonylation reaction based on formic acid
as a CO surrogate.[14] Mo(CO)6 was also widely used
as a solid CO source.[15] Herein, we describe a Pd/C-
catalyzed carbonylation of nitroarenes for the
synthesis of unsymmetrical ureas with stoichiometric
Mo(CO)6 as a solid CO source (Scheme 1, c). The
catalyst can be recycled and reused easily.
Ureas are important structure motifs in organic
chemistry and have attracted considerable attention
due to their wide applications in various areas such as
biological,[1]
pharmaceutical,[2]
agrochemical,[3]
material[4] and also used organocatalyst[5] (Figure 1).
Owing to their importance, various methods have
been developed for the synthesis of urea derivatives.
Conventional procedures for the preparation of ureas
were essentially based on use of highly toxic
phosgene (or its analogs),[6] moisture sensitive
isocyanates,[7] carbonates and carbamates,[8] which
may cause serious environmental and health
problems. Alternative synthetic protocols that exploit
CO or CO2 as a source of the carbonyl fragment have
also been reported.[9] However, the reports usually
require harsh reaction conditions (high pressures and
temperatures) or toxic CO gas manipulation.
Figure 1. Selected structures of important
unsymmetrical ureas.
Among the related carbonylative procedures,
typically aryl halides and aryl azides were used as the
starting materials in the carbonylative synthesis of
ureas. The availability and stability of these reagents
restricted the substrate scope of these reactions. In
comparison, nitroarenes are versatile, readily
available and stable aromatic building blocks in
organic chemistry.[10] The in-situ generation of
isocyanates via reductive carbonylation of
nitroarometics have been reported. Homogeneous
catalysts such as palladium and ruthenium were
usually needed for these transformations (Scheme 1,
a).[11] One of the main drawbacks for homogeneous
catalysis is that the catalysts were usually difficult to
separate. In this aspect, heterogeneous catalysts such
as Pd/C turned out to be an alternative which can be
separated simply by filtration. In addition,
selenium[12] or sulfur[13] promoted carbonylation
process for the ureas synthesis from nitroarenes have
Previous work:
H
NO2
NO2
N
NHAr
Ru3(CO)12
CO, ArNH2
a.
b.
+
CO2
R
R
O
H
H
N
N
cat. S or Se
H2O, CO
+
R
CO2
R
R
O
This work
c.
H
NO2
N
NR'2
Pd/C, HNR'2
Mo(CO)6
R
R
O
heterogeneous catalysis
cheap and abundant substrates
unsymmetrical urea synthesis
CO-gas-free carbonylation
Scheme 1. Carbonylative synthesis of ureas from
nitroarenes.
We began our investigations by exploring the
carbonylative reaction of 4-nitrotoluene 1d with
diethylamine 2a as the substrates. The desired urea
1

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product 1,1-diethyl-3-(p-tolyl)urea 3da was produced
in 79% yield with Pd/C catalyst system using
Mo(CO)6 as a carbonyl source and NaI as additive
(Table 1, entry 1). Notably, NaI additive played a
crucial role in this reaction; no urea product 3da was
obtained without the addition of NaI (Table 1, entry
2). Here, the exact role of NaI in this system is not
clear for the moment. One explanation is that NaI
acting as a phase transfer catalyst in this system and
also assistant the releasing of CO from Mo(CO)6. The
use of Pd(OAc)2 instead of Pd/C can achieve a
relatively milder yield of the product. Moreover, the
monodentate ligand delivered a better yield than
significantly. For example, meta- and para-
nitrotoluene gave higher yields than ortho-
nitrotoluene (Table 1, entries 3, 4 vs entry 2). A range
of functional groups including thioether, halides and
vinyl were compatible in this reaction. 3-fluoro-, 4-
chloro- and 4-bromo- substituted nitroarenes reacted
with diethylamine and produced the corresponding
ureas in 70%, 73% and 83% yields, respectively
(Table 2, entries 6-8). Besides, the vinyl substituted
substrate gave a corresponding product in moderate
yield (Table 2, entry 9). However, when 4-
nitroacetophenone was subjected to the optimized
conditions, only trace amount of the desired product
bidentate ligand (Table 1, entries 3-4). Other solvents, was detected (Table 2, entry 10). In addition to
such as toluene, CH3CN, DMF and cyclohexane,
were less effective and decreased yields (Table 1,
entries 5-8). It should be mentioned that reduction of
nitroarene by Mo(CO)6 in the presence of water was
reported previously. However, no urea product was
obtained when 1 equivalent of H2O was added to the
reaction system (Table 1, entry 9). Finally, reactions
with other bases (DABCO, K3PO4 and DBU) gave
either lower yields, or even no desired product (Table
1, entries 10–12).
diethylamine, heterocyclic pyrrolidine and tert-
butylamine were suitable substrates as well and
provided the corresponding ureas in 58% and 69%
yields, respectively (Table 2, entries 11-12). It should
be noted that Neburon, a widely used herbicide in
agriculture, can be prepared in 64% yield under our
standard conditions (Table 2, entry 13).
Table 2. Scope of nitroarenes and alkyl amines for
the synthesis of ureas.[a]
Table 1. Reaction conditions studies for urea
synthesis.[a]
Yield
(%)
Entry Nitroarenes
1
Amines
HNEt2
Ureas
56
Entry
Variation from the standard
conditions
none
Yield
(%)
79
2
3
4
HNEt2
HNEt2
HNEt2
64
71
79
1
H
2
without NaI
Pd(OAc)2, PCy3 instead of
Pd/C
Pd(OAc)2, Xantphos instead of
Pd/C
trace
70
N
NEt2
3[b]
O
4[c]
58
5
6
7
8
toluene instead of 1,4-dioxane
CH3CN instead of 1,4-dioxane
DMF instead of 1,4-dioxane
Cyclohexane instead of 1,4-
dioxane
1 equiv. H2O was added
1.5 equiv. DABCO was added
1.5 equiv. K3PO4 was added
1.5 equiv. DBU was added
67
38
15
56
5
6
HNEt2
HNEt2
65
70
9
0
10
11
12
16
trace
6
7
8
HNEt2
HNEt2
73
83
[a] Reaction conditions: 1d (1.5 mmol), 2a (1.0 mmol),
Pd/C (10 mg), Mo(CO)6 (1.0 mmol), NaI (0.2 mmol), 1,4-
dioxane (2 mL), 120 °C, 12 h, isolated yield. [b] Pd(OAc)2
(3 mol%), PCy3 (6 mol%); [c] Pd(OAc)2 (3 mol%),
Xantphos (3 mol%).
9
HNEt2
HNEt2
46
After establishing the optimum reaction conditions,
we turned our attention toward exploring various
nitroarenes and amines to examine the scope of the
method (Table 2). Nitrobenzene and alkyl substituted
nitroarenes were successfully gave the corresponding
ureas in good yields (Table 2, entries 1-4). Steric
effect of the substituents affected the reaction yields
10[b]
trace
2

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An oven-dried tube, which was equipped with a magnetic
stir bar, was charged with Pd/C (10 mg; 0.94 mol%; 10
wt.%), Mo(CO)6 (1.0 equiv.), NaI (0.2 equiv.) and
nitroarenes (1.5 equiv.) at room temperature. The tube was
evacuated and backfilled with N2 (this process was
repeated 3 times). Then, a solution of diethylamine (1.0
mmol, 1.0 equiv.) in 1,4-dioxane (2 mL) was added to the
reaction tube via syringe. The tube was sealed and the
mixture was stirred at 120 °C for 12 h. After the reaction
was completed, the reaction mixture was cooled to room
temperature and filtered through a pad of Celite using
excess EtOAc. The crude product was purified via flash
chromatography (petroleum ether/ethyl acetate 5:1) to
provide the pure product.
11
12
58
69
13
64
[a] Reaction conditions: Nitroarenes (1.5 mmol), amine
(1.0 mmol), Pd/C (10 mg; 0.94 mol%; 10 wt.%), Mo(CO)6
(1.0 mmol), NaI (0.2 mmol), 1,4-dioxane (2 mL), 120 °C,
12 h, isolated yield. [b] 16 h.
Acknowledgements
The authors acknowledge financial support from NSFC
(21472174, 21772177, 21602201, 21602204), the education
department of Zhejiang Province (Y201636555), Zhejiang Sci-
Tech University (16062095-Y), and Zhejiang Natural Science
Fund for Distinguished Young Scholars (LR16B020002).
Subsequently, we examined the catalyst recycle.
Pd/C can be separated simply from the reaction
system by filtration and used directly for the next
reaction. The catalyst can be recycled for four times
without decreasing the catalytic activity (Table 3).
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