A Palladium-Catalyzed Domino Procedure for the Synthesis of Unsymmetrical Ureas

Article abstract of DOI:10.1002/adsc.201800496

A palladium-catalyzed carbonylative procedure for the synthesis of unsymmetrical ureas has been developed. This one-pot one-step cascade procedure is consisted by three individual processes: carbonylation, Curtius rearrangement, and nucleophilic addition. A series of unsymmetrical ureas were prepared from easily available aryl iodides and amines in moderate to excellent yields. This procedure provides a convenient and practical approach for unsymmetrical urea synthesis. (Figure presented.).

Full text of DOI:10.1002/adsc.201800496

Title: A Versatile Palladium-Catalyzed Domino Procedure for the
Synthesis of Unsymmetrical Ureas
Authors: Xiao-Feng Wu, bo chen, jin-bao peng, jun Ying, and xinxin qi
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10.1002/adsc.201800496
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.2018
A Palladium-Catalyzed Domino Procedure for the Synthesis of
Unsymmetrical Ureas
Bo Chen,[a] Jin-Bao Peng,*[a] Jun Ying,[a] Xinxin Qi,[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, Institution Universität Rostock, Albert-Einstein-Straße 29a, 18059 Rostock,
b
Germany
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.2018
efficient approaches have been developed for the
for the synthesis of unsymmetrical ureas has been synthesis of functionalized ureas.[4] Traditionally,
Abstract. A palladium-catalyzed carbonylative procedure
developed. This one-pot one-step cascade procedure is
consisted by three individual processes: carbonylation,
Curtius rearrangement, and nucleophilic addition. A series
of unsymmetrical ureas were prepared from easily available
aryl iodides and amines in moderate to excellent yields.
This procedure provides a convenient and practical
approach for unsymmetrical urea synthesis.
ureas were prepared by the nucleophilic addition of
isocyanates with amines[5] or stepwise addition of
amines to phosgene derivatives[6] (Scheme 1, a). Both
reactions involve the use of hazardous reagent such
as phosgene or isocyanates. Alternatively, transition
metal-catalyzed cross-coupling reaction provides an
attractive option. Buchwald and co-workers
developed an efficient protocol for the synthesis of
unsymmetrical ureas by palladium-catalyzed cross-
coupling of aryl chlorides and triflates with sodium
cyanate (Scheme 1, b).[7] The aryl isocyanate can be
generated in-situ by reduction of nitro compounds in
the presence of CO as well. Additionally, transition
metal-catalyzed carbonylation reactions,[8] as one of
the most powerful methods for the synthesis of
carbonyl-containing compounds, have also been
applied in the synthesis of ureas. For example,
transition metal catalyzed oxidative carbonylation of
amines provides a direct route for the synthesis of
ureas (Scheme 1, c).[9] Zhang’s group reported a
carbonylation of azides in the presence of amines for
unsymmetrical ureas synthesis (Scheme 1, d).[10]
However, besides the usage of CO gas, the needs of
already prepared organo azides as the starting
material creates new challenges. Hence, developing
direct and one pot process for urea synthesis from
readily available materials is still highly desirable.
With our continuous interests in developing
carbonylation based cascade reactions for the
Keywords: Cascade reaction ; Unsymmetrical urea ;
Carbonylation ; Curtius rearrangement ; Palladium catalyst
Urea is an important structural unit that presents in a
wide range of natural products, pharmaceuticals and
agrochemicals (Figure 1).[1] For example, Sorafenib is
a multi-targeted inhibitor of several tyrosine and Raf
family kinases. Cumyluron is a urea herbicide mainly
used for the control of creeping grasses. Additionally,
due to the high hydrogen-bonding ability of ureas,
they are also widely used in molecular recognition[2]
and also as organocatalysis.[3]
synthesis
of
various
carbonyl-containing
compounds,[11] we were recently interested in
developing a general procedure for synthesis of
unsymmetrical ureas from commercially abundant
aryl halides. We assume that the carbonylation
reaction of aryl halides with suitable azide would
generate the corresponding aroyl azides, which might
undergo a Curtius rearrangement to give the
corresponding isocyanates, subsequently nucleophilic
addition of amines to the in-situ generated
isocyanates would provide the desired unsymmetrical
Figure 1. Selected examples of urea derivatives in
pharmaceuticals and agrochemicals.
Due to their important applications in
pharmaceuticals and also synthetic chemistry, several
1
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10.1002/adsc.201800496
Advanced Synthesis & Catalysis
ureas (Scheme 1, e). One of the main challenges of
this cascade reaction is the high tendency of
palladium-catalyzed aminocarbonylation reaction of
aryl halides which will lead to amides production.
Here it’s important to mention that Grushin and co-
desired urea product 3ag was detected when
DPEphos was used as the ligand (Table 1, entry 5).
Amide 4ag was obtained in high yield. Other
phosphine ligands including PCy3, PPh3 and DPPF
were all failed to promote this reaction and no urea
product 3ag could be obtained (Table 1, entry 6, see
details in SI). The screening of solvents revealed the
important role of solvents on the outcome of this
reaction. When the reaction was conducted in MeCN
or DCE, the desire product 3ag was isolated in 70%
and 57% yields, respectively (Table 1, entries 8 and
9). However, when the reaction was carried out in
toluene, the yield decreased to 19% (Table 1, entry 7).
The reaction yield can be increased to 89% when 1,4-
dioxane was used as the solvent (Table 1, entry 10).
On the other hand, if we increase the reaction
temperature to 90 ℃ or 120 ℃, the yields decreased
to 82% and 66%, respectively (Table 1, entries 11
and 12). However, no reaction occurred at 30 ℃.
Here, the decreased yield at higher temperature can
be explained by the increased yield of the amide 4ag
and also the diarylurea product exchange the ArNH-
moiety with external amines. Then, a series of
additives were examined. Comparable yields were
workers
developed
a
palladium
catalyzed
azidocarbonylation reaction of aryl iodides with
sodium azide.[12] From the previous achievements, we
realized the importance of proper combination of
catalysts and ligands on the final success.[13] Herein,
we present our recent result on the palladium
catalyzed
carbonylation/Curtius
rearrangement/nucleophilic addition cascade reaction
for the synthesis of unsymmetrical ureas with formic
acid as the CO source via an in-situ formed formic
acetic anhydride in In-Ex tube.
obtained
in
the
presence
of
TBAB
(tetrabutylammonium bromide)
and TBAHS
(tetrabutylammonium hydrogen sulfate) (88% and
83% yields, respectively. See SI). Finally, an
excellent yield of 97% was obtained when the
reaction was performed in the absence of any
additives (Table 1, entry 14). In order to see the
efficiency of palladium precursors in the absence of
additive, the palladium catalysts were tested again
and good yields can be obtained in general (Table 1,
entries 15-17). Notably, 89% yield can be obtained as
well with Mo(CO)6 (2 equiv.) as the CO source under
the same conditions (Table 1, entry 18). However, we
decided continual with formic acid for the substrate
scope due to the produce of metallic waster
Table 1. Unsymmetrical ureas synthesis: Screening
of the reaction conditions.[a]
Scheme 1. Representative procedures for ureas
synthesis.
Initially, iodobenzene 1a and 4-chloroaniline 2g
were selected as the model substrates for this cascade
reaction. It’s worth to mention explain that as
inorganic salt NaN3 was used as one of the reagents,
phase transfer catalyst (PTC) was added to improve
its solubility. To our delight, by using
Pd2dba3/Xantphos as the catalytic system, the desired
urea 3ag was obtained in 61% yield in the presence
of 1.2 equivalents of NaN3 and 0.2 equivalent of
TBAI in THF at 60 ℃ (Table 1, entry 1). Amide 4ag
was detected as the main by-product. A series of
palladium catalysts such as Pd(OAc)2, PdCl2 and
Pd(acac)2 were explored in this reaction. The reaction
yield can be increased to 78% with PdCl2 as the
catalyst (Table 1, entry 3). Then, we investigated the
ligands effect and found out that ligands influenced
the reaction significantly. Only trace amount of the
Yield
Entry
[Pd]
Ligand
Solvent PTC
(%)
TBAI 61
TBAI 67
1
Pd2dba3
xantphos
THF
THF
THF
THF
2
Pd(OAc)2 xantphos
3
PdCl2
Pd(acac)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
xantphos
xantphos
TBAI 78
TBAI 41
TBAI trace
4
5
DPEphos THF
6
PPh3
THF
TBAI
0
7
xantphos
xantphos
xantphos
xantphos
toluene TBAI 19
8
MeCN
DCE
TBAI 70
TBAI 57
9
10
dioxane TBAI 89
2
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10.1002/adsc.201800496
Advanced Synthesis & Catalysis
11[b]
12[c]
PdCl2
PdCl2
xantphos
xantphos
dioxane TBAI 82
dioxane TBAI 66
TBA
53
73
67
76
5
6
7
8
13
PdCl2
xantphos
dioxane
88
B
dioxan
e
14
PdCl2
xantphos
/
97
15
16
17
18
Pd2dba3
xantphos
dioxane
/
/
/
/
81
Pd(OAc)2 xantphos
dioxane
dioxane
dioxane
85
Pd(acac)2
PdCl2
xantphos
xantphos
73
89[d]
[a] Reaction conditions: aryl iodide (0.75 mmol), 4-
chloroaniline (0.5 mmol), PdCl2 (5 mol%), Xantphos (5
mol%), NaN3 (1.2 eq.), [CO] (2 mmol; HCO2H (2 mmol),
Ac2O (2 mmol)), 1,4-dioxane (2 mL), 60 ℃, 12 h, isolated
yields. [CO]: HCO2H : Ac2O = 1 : 1.
[a] Reaction conditions: Iodobenzene (0.75 mmol), 4-
chloroaniline (0.5 mmol), palladium (5 mol%), ligand (10
mol% for monodentate ligands and 5 mol% for bidentate
ligands), NaN3 (1.2 eq.), [CO] (2 mmol), additives (0.2
eq.), solvent (2 mL), 60 ℃, 12 h, isolated yields. [b] 90 ℃.
[c] 120 ℃. [d] Mo(CO)6 (2 equiv.) instead of [CO]. [CO]:
HCO2H : Ac2O = 1 : 1. TBAI: tetrabutylammonium iodide.
TBAB: tetrabutylammonium bromide.
Subsequently, we examined the generality of the
amine coupling partner for this cascade reaction. As
illustrated in Table 3, various substituted anilines
were subjected to the optimized conditions. The
cascade reaction proceeded smoothly and the
corresponding ureas were prepared in moderate to
good yields. With amine as the nucleophile, sterically
bulky and electron-donating group substituted
substrates gave lower yields (Table 3, entry 2 vs entry
3, entry 4 vs entry 6). Heteroaryl amines such as
pyridin-2-amine and naphthalen-1-amine were also
tolerated in this transformation and delivered the
corresponding products in 71% and 45% yields,
respectively (Table 3, entries 8 and 9). In addition,
secondary amine can be tolerated as well. For
example, when N-methylaniline was used in this
reaction, the corresponding product was isolated in
58% yield (Table 3, entry 12).
With the optimized reaction conditions in hand
(Table 1 entry 14), we turned our attention to
investigate the substrates scope of this cascade
reaction. Firstly, we tested the generality of aryl
iodides for this reaction. As summarized in Table 2, a
series of substituted iodobenzenes were successfully
applied to this reaction and produced the
corresponding products in moderate to excellent
yields. Both electron-donating groups (Table 2,
entries 2-5) and electron-withdrawing groups (Table
2, entries 6-8) were well tolerated. Generally,
substrates with electron-donating groups gave higher
yields than those with electron-withdrawing groups.
The steric effect of substituent didn’t affect the
reaction yields (Table 2, entries 2-4). Additionally,
halogen such as fluoro-, chloro- and trifluoromethyl-
substituted iodobenzenes were also well tolerated in
this transformation and delivered the corresponding
ureas in 73%, 67% and 76% yields, respectively
(Table 2, entries 6, 7 and 8).
Table 3. Unsymmetrical ureas synthesis: Substrates
scope of the amines.[a]
Table 2. Unsymmetrical ureas synthesis: Substrates
Yield
(%)
scope of the aryl iodides.[a]
Entry Anilines
Product
90
1
2
3
4
61
81
67
Yield
(%)
Entry Aryl iodide
Product
97
1
2
3
4
81
79
73
58
94
5
6
3
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10.1002/adsc.201800496
Advanced Synthesis & Catalysis
cascade procedure is consisted by three individual
processes: carbonylation, Curtius rearrangement, and
nucleophilic addition. A series of unsymmetrical
ureas were prepared from easily available aryl iodides
and amines in moderate to excellent yields.
59
7
71
45
60
8
9
Experimental Section
General procedure: PdCl2 (4.5 mg, 5 mol%), Xantphos
(14.5 mg, 5 mol%), iodobenzene (0.75 mmol), aniline (0.5
mmol) and sodium azide (0.6 mmol) were transferred into
an oven-dried tube and a small test tube was placed in the
reaction tube. HCOOH (2 mmol) and Ac2O (2 mmol) were
added to the small test tube (In-ex Tube).[14] 1,4-Dioxane
(2 mL) was added to the reaction tube. Then the mixture
was stirred at 60 °C for 12 h. After the reaction finished,
the crude product was filtered and concentrated under
vacuum and was purified by column chromatography on
silica gel column EtOAc/petroleum ether (1:5, v/v) to give
the desired product.
10
63
11
58
12
[a] Reaction conditions: aryl iodide (0.75 mmol), amine
(0.5 mmol), PdCl2 (5 mol%), xantphos (5 mol%), NaN3
(1.2 eq.), [CO] (2 mmol; HCO2H (2 mmol), Ac2O (2
mmol)), dioxane (2 mL), 60 ℃, 12 h, isolated yields. [CO]:
HCO2H : Ac2O = 1 : 1.
Acknowledgements
The authors thank the financial supports from NSFC (21472174,
21772177, 21602201, 21602204), education department of
Zhejiang Province (Y201636555), Zhejiang Sci-Tech University
(16062095-Y) and Zhejiang Natural Science Fund for
Distinguished Young Scholars (LR16B020002).
Based on our results and also previous
literatures,[10,12] a possible reaction mechanism is
proposed in Scheme 2. The catalytic cycle starts with
the oxidative addition of Pd0 with iodobenzene 1 to
give the corresponding phenyl-palladium complex 5.
Then, carbon monoxide coordinates and insert to
intermediate 5 to give an acyl-palladium complex 6.
Then, nucleophilic attack of NaN3 to the 6 generated
the aroyl azide intermediate 8 after reductive
elimination. Catalytic active Pd0 was regenerated and
ready for the next catalyst cycle at the same time.
Subsequently, catalyzed by palladium, aroyl azide 8
underwent Curtius rearrangement to give the
corresponding isocyanate 9. Finally, nucleophilic
addition of amine 2 to isocyanate provides the final
urea product 3.
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4
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800496
Advanced Synthesis & Catalysis
COMMUNICATION
A Versatile Palladium-Catalyzed Carbonylative
Procedure for the Synthesis of Unsymmetrical
Ureas
Adv. Synth. Catal. Year, Volume, Page – Page
Bo Chen, Jin-Bao Peng,* Jun Ying, Xinxin Qi, and
Xiao-Feng Wu*
6
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