Palladium-Catalyzed Solvent-Controlled Selective Synthesis of Acyl Isoureas and Imides from Amides, Isocyanides, Alcohols and Carboxylates

Article abstract of DOI:10.1002/adsc.201801245

A highly selective synthesis of acyl isoureas and imides from readily accessible amides, isocyanides, alcohols and carboxylates based on reaction solvent selection is described. In the presence of a catalytic amount of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and cupric acetate, treatment of amides and isocyanides in alcohols at 60 °C provided acyl isoureas in high yields. Interestingly, when other solvents such as acetonitrile was used instead of alcohols, imides were exclusively produced in good to excellent yields via direct N-acylation of amides with carboxylates as the acyl sources. This protocol offers an attractive alternative approach toward isoureas and imides. (Figure presented.).

Full text of DOI:10.1002/adsc.201801245

Title: Palladium-Catalyzed Solvent-Controlled Selective Synthesis of
Acyl Isoureas and Imides from Amides, Isocyanides, Alcohols
and Carboxylates
Authors: Ming Cao, Liqiu Liu, shi Tang, Zhiyuan Peng, and Yingchun
Wang
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801245
Link to VoR: http://dx.doi.org/10.1002/adsc.201801245

10.1002/adsc.201801245
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201
Palladium-Catalyzed Solvent-Controlled Selective Synthesis of
Acyl Isoureas and Imides from Amides, Isocyanides, Alcohols
and Carboxylates
Ming Cao,a Liqiu Liu,a Shi Tang,a Zhiyuan Penga,b and Yingchun Wanga,*
a
National Demonstration Center for Experimental Chemistry Education, Hunan Engineering Laboratory for Analyse
and Drugs Development of Ethnomedicine in Wuling Mountains, Jishou University, Jishou 416000, P. R. China
Hunan Provincial Key Laboratory of Controllable Preparation and Functional Application of Fine Polymers, Hunan
b
University of Science and Technology, Xiangtan, 411201, China
Phone: (+86)-743-8563911; fax: (+86)-743-8563911; e-mail: wyingchun@jsu.edu.cn
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Keywords: palladium catalysis; solvent-control;
isocyanides; acyl isoureas; imides
Abstract: A highly selective synthesis of acyl isoureas and
imides from readily accessible amides, isocyanides, alcohols
and carboxylates based on reaction solvent selection is
described. In the presence of a catalytic amount of [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II)
and
cupric acetate, treatment of amides and isocyanides in alcohols
o
at 60 C provided acyl isoureas in high yields. Interestingly,
when other solvents such as acetonitrile was used instead of
alcohols, imides were exclusively produced in good to
excellent yields via direct N-acylation of amides with
carboxylates as the acyl sources. This protocol offers an
attractive alternative approach toward isoureas and imides.
stoichiometric or excess amount of strong Lewis
acids, oxidants or additives, or special preparation of
the substrates is required. Hence, development of
new and efficient strategies for the synthesis of
isoureas is still highly attractive, especially when
their direct access from simple substrates could be
secured under mild conditions. Recently, Ji et al.
developed a Co(II)-catalyzed synthesis of sulfonyl
isoureas by the reactions of sulfonyl azides with
isocyanides in alcohols via nitrene intermediate,
which provided an alternative route to isoureas.[9]
Herein, we would like to report a novel and
efficient methodology for the synthesis of acyl
isoureas from readily available amides, isocyanides
and alcohols. In the presence of a catalytic amount of
Pd(dppf)Cl2 and Cu(OAc)2, acyl isoureas were
synthesized in high yields by treating primary amides
Introduction
Isourea moiety is prevalent functional group widely
existing in not only agrochemicals but also
pharmaceuticals, functional materials, and other
versatile intermediates.[1] Owing to their wide
occurrence and importance, the methods for the
synthesis of isoureas are of high interest. To date, the
reported methods for the synthesis of isoureas are
highly concentrated on intermolecular addition of
alcohols to carbodiimides catalyzed by copper salts,[2]
zinc salts,[3] or actinide complexes[4] (Scheme 1a).
Although these methods have the advantages of being
atom-efficient, there are limitations, such as limited
substrate availability, comparatively complicated
catalyst species and a relatively long reaction time. In
addition, intramolecular amino-oxylation of alkenes
also provided access to bicyclic isoureas by the use of
a catalytic amount of Pt,[5] Ag,[6] or excess amount of
Lewis acids (Scheme 1b).[7] Moreover, Shi and co-
workers reported the Cu-catalyzed intramolecular
amino- versus oxy-acetoxylation of N-allyl ureas for
the efficient synthesis of cyclic isoureas (Scheme
1c).[8] However, in most of these methods, a
o
with isocyanides in alcohols at 60 C for 2 h.
Interestingly, when other solvents such as CH3CN,
was used instead of alcohols, imides were
exclusively produced in good to excellent yields via
N-acylation of primary amides. Despite numerous
methods including acylation of amides with
carboxylic acids derivatives,[10] oxidation of N-
alkylamides or oxazoles,[11] coupling of amides with
1
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10.1002/adsc.201801245
Advanced Synthesis & Catalysis
aldehydes,[12] aminocarbonylation of aryl halides with
amides[13] and Mumm rearrangement of isoimides[14]
being available for the synthesis of imides, to the best
of our knowledge, direct N-acylation of amides to
imides using carboxylates as acyl sources has not
been reported, and this protocol also offers an
attractive alternative method for the synthesis of
structurally diverse imides.
isolated yield, which was characterized as N-
acetylbenzamide 3a on the basis of its spectral and
analytical data (Table 1, entry 15).
Table 1. Optimization of reaction conditions.[a]
tBu
O
O
N
O
O
Catalyst, Additive
Solvent, 60 OC, 2 h
NH2
N
O
N
H
But
N
C
+
+
+
H
OH
2a
3a
1a
Yields
of 2a
(%)b
92
0
0
89
87
84
82
0
<5%
0
0
92
Yields
Entr
y
Additive
(mol%)
Pd Catalyst (mol%)
Solvent
of 3a
Previous routes to isoureas
OR1
cat. [Cu], [Zn] or
(%)b
0
Actinide complexes
R2
R2
N
R2
R2
C
a)
R1 OH +
N
H
N
1
2
3
4
5
6
7
8
9
Pd(dppf)Cl2 (10)
Pd(dppf)Cl2 (10)
none
Pd(OAc)2 (10)
PdCl2 (10)
Pd(CF3COO)2 (10)
Pd(PPh3)2Cl2 (10)
Pd(dppf)Cl2 (10)
Pd(dppf)Cl2 (10)
Pd(dppf)Cl2 (10)
Pd(dppf)Cl2 (10)
Pd(dppf)Cl2 (20)
Cu(OAc)2 (40)
none
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
N
0
0
0
0
0
0
0
0
O
R
(
NTs
O
Cu(OAc)2 (40)
Cu(OAc)2 (40)
Cu(OAc)2 (40)
Cu(OAc)2 (40)
Cu(OAc)2 (40)
CuCl2 (40)
CuSO4 (40)
CuI (40)
CuO (40)
N
cat. [Pd], [Ag] or Lewis acids
HN
NHTs
n= 1, 2
b)
)
n
(
)
n
R
bicyclic isoureas
NTs
O
10 mol % Cu(MeCN)4PF6
PhI(OAc)2 (1.5 equiv)
Bn
N
O
Bn
c)
d)
N
NHTs
R
R
DCM/HOAc
10
11
12
0
0
0
AcO
cyclic isoureas
R2
O
Cu(OAc)2 (100)
5 mol% CoC2O4
R1
N
C
TsN3
R2OH
R1
Ts
+
+
13
Pd(dppf)Cl2 (10)
Cu(OAc)2 (20 )
EtOH
56
0
N
N
via nitrene
H
CH3CN/
EtOH
(1:1)
sulfonyl isoureas
14
Pd(dppf)Cl2 (10)
Pd(dppf)Cl2 (10)
Cu(OAc)2 (40 )
Cu(OAc)2 (40)
87
50
<5
35
This work
15c
[a]
CH3CN
t
Pd(dppf)Cl2
/
Bu
N
C
R3
O
Pd(dppf)Cl2 /Cu(OAc)2
R3
O
Reactions conditions: benzamide 1a (0.5 mmol), tert-
O
N
O
O
O
N
C
)
R2
(
O
C
R4
M
x
R1
N
butyl isocyanide (0.5 mmol), Pd catalyst (0.05 mmol, 10
mol%), additive (0.2 mmol, 40 mol%), solvent (2.0 mL),
R1
N
R4
R1
NH2
H
R2OH
H
CH3CN
o
60 C, 2 h (except for entries 2-3 and 12-13). Entry in
Scheme 1. Comparison of previous study and our work.
bold highlights optimized reaction conditions.
[b] Isolated yield of pure product based on 1a.
Having identified the optimal conditions for the
synthesis of acyl isoureas 2a, a range of reactions of
amides 1 and isocyanides in alcohols were carried out,
aiming to determine the scope of the acyl isoureas
synthesis. As summarized in Table 2, wide ranges of
benzamides with different substituents or substitution
patterns on the phenyl ring worked effectively to
afford the corresponding acyl isoureas (2a-j) in
excellent yields (81-95%), and the structure of 2j was
further confirmed by X-ray crystallography analysis,
as described in Figure 1. The 1-naphthamide and
thiophene-2-carboxamide gave the pruducts 2k and 2l
in 92% and 85% yields, respectively. Besides,
cinnamamide and 2-phenylacetamide also exhibited
good reactivities in this transformation, delivering the
target products 2m and 2n in 75% and 78% yields,
respectively. Unfortunately, only trace amount of
product could be detected when acrylamide was
applied in the reaction (2o). To further explore the
diversity of products, the scope of alcohols and
isocyanides were also investigated. The reactions of
1a with tert-butyl isocyanide in different alcohols,
such as butan-1-ol, 3-methylbutan-1-ol, cyclohexanol
and benzyl alcohol, proceeded readily to produce the
desired acyl isoureas 2p-s in high yields. However,
when tert-butanol was used as the solvent, along with
30% yield of imide 3a, only trace amount of isourea
2t could be detected, other compounds, such as
phenol and trifluoroethanol did not give any products.
In case of isocyanides, the reaction of 1a with
Results and Discussion
We selected benzamide (1a) as the model compound
to examine its behavior under different conditions
(Table 1). After extensive screenings, the optimized
reaction conditions for the formation of acyl isourea
(2a) was obtained when a mixture of 1a and tert-
butyl isocyanide (1:1 mol ratio) was treated with 10
mol % Pd(dppf)Cl2 and 40 mol % Cu(OAc)2 in
ethanol at 60 oC for 2 h (Table 1, entry 1). It was
found that both Pd catalyst and Cu(OAc)2 were
necessary for the successful transformation, since in
the absence of Pd(dppf)Cl2 or Cu(OAc)2, no desired
product 2a was detected (Table 1, entries 2-3). Other
Pd salts also showed good catalytic activity (Table 1,
entries 4−7), whereas other Cu salts, such as CuCl2,
CuSO4, CuI or CuO, were not effective for this
conversion (Table 1, entries 8−11). 10 mol % of the
Pd(dppf)Cl2 and 40 mol % of Cu(OAc)2 were
sufficient to promote the reaction effectively, and the
yield of 2a was not improved when 20 mol % of the
Pd(dppf)Cl2 and 1 equiv of Cu(OAc)2 were used
(Table 1, entry 12). However, decreasing the loading
amount of Cu(OAc)2 reduced the yield to 56% (Table
1, entry 13). It was noted that the reaction could also
lead to 2a in 87% yield when the 1:1 ratio of ethanol
and CH3CN solvent mixtures was used instead of
ethanol (Table 1, entry 14). Interestingly, when 1a,
tert-butyl isocyanide and stoichiometric ethanol were
subjected to CH3CN, along with 50% yield of 2a, a
white solid was unexpectedly generated in 35%
cyclohexyl
isocyanide,
isocyanide, 1,1,3,3-tetramethylbutyl
benzyl
isocyanide
and
2,6-
2
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10.1002/adsc.201801245
Advanced Synthesis & Catalysis
dimethylphenyl isocyanide in ethanol performed well,
affording the corresponding acyl isoureas 2u-x in
excellent yields.
Subsequently, the substrate scope of this N-
acylation of primary amides with carboxylates was
explored and the results are summarized in Table 3.
A variety of benzamides bearing several substituents
(-Me, -Cl, -F, -I, -CF3, -OMe, -OEt, -NH2) at different
positions of the benzene ring fairly tolerated the
reaction conditions, giving the desired imides 3a-m
in good to high yields. In general, primary amides
possessing electron-withdrawing groups on the
phenyl ring provided higher yields than those bearing
electron-donating groups (3c-e vs. 3f-g). Notably,
sensitive functionalities such as -NH2 (3f) and -I (3i)
were unaffected under the present reaction conditions.
In addition, 1-naphthamide and thiophene-2-
carboxamide also proceeded smoothly, leading to
imides 3n and 3o in 87% and 74% yields,
respectively. Cinnamamide also reacted with
Cu(OAc)2, delivering the target product 3p in 68%
yield. Unfortunately, the simple alkyl-substituted
primary amides failed to generate the desired
products under the current conditions. The
carboxylate substrates were further investigated, and
to our delight, various carboxylates, such as sodium
benzoate, copper(II) methacrylate and copper bis(2-
ethylhexanoate), reacted successfully and afforded
the corresponding products (3q-s) in good yields.
Table 2. Substrate scope for the reaction of amides 1 and
isocyanides in alcohols.[a,b]
Pd(dppf)Cl2 (10 mol%)
Cu(OAc)2 (40 mol%)
R3
O
O
N
O
R2
R3
N C
R1
N
+
R1
NH2
R2OH, 60 OC, 2 h
H
2
1
R = H, 2a, 90%
R = F, 2b, 92%
tBu
O
tBu
O
N
O
N
R = F, 2f, 87%
R = CF3, 2g, 85%
R = EtO, 2h, 81%
R = CF3, 2c, 95%
R = NO2, 2d, 88%
R = CH3O, 2e, 85%
N
N
H
O
H
R
R
tBu
tBu
tBu
O
tBu
O
N
O
N
F
O
F
N
O
N
H3CO
N
O
N
O
N
N
O
H
H
H
H
S
OCH3
2j, 86%
2l, 85%
2i, 84%
2k, 92%
tBu
N
tBu
O
tBu
tBu
O
O
N
O
N
O
N
N
O
N
N
H
O
N
O
H
H
H
2p, 94%
2m, 78%
2o, <5%
2n, 75%
tBu
O
tBu
O
tBu
tBu
O
O
N
O
N
O
N
O
N
N
N
N
O
N
H
H
H
H
2t, < 5%
2q, 95%
2r, 91%
2s, 89%
O
N
O
N
O
N
O
N
N
O
N
O
N
O
N
O
H
H
H
H
2u, 87%
2w, 81%
2v, 85%
2x, 84%
Table 3. Substrate scope for the reaction of amides 1 and
[a] Reactions conditions: 0.5 mmol of 1 and 0.5 mmol of
isocyanides in the presence of Pd(dppf)Cl2 (10 mol %)
and Cu(OAc)2 (40 mol %) in 2.0 mL of alcohols at 60 oC
for 2 h.
carboxylates in CH3CN.[a,b]
Pd(dppf)Cl2 (10 mol%)
O
O
O
O
C
t
( 1 epuiv.)
C
N
Bu
O
R4
+
)
x
(
R1
N
H
3
R4
R1
NH2
M
CH3CN, 60 OC, 2 h
[b] Isolated yield of pure product based on 1.
1
R = H, 3a, 82%
R = Me, 3b, 83%
R = Cl, 3c, 86%
R = F, 3d, 88%
O
R
O
O
O
R = F, 3h, 84%
R = I, 3i, 80%
N
N
H
H
R = CF3, 3j, 79%
R = EtO, 3k, 70%
R = CF3, 3e, 90%
R = NH2, 3f, 75%
R = MeO, 3g, 72%
R
O
O
O
O
F
O
F
O
O
O
H3CO
N
N
N
H
N
H
H
H
S
OCH3
3o, 74%
3l, 79%
3m, 72%
3n, 87%
O
O
O
O
O
O
O
O
N
N
H
N
H
N
H
H
3r, 76%d
3p, 68%
3q, 78%c
3s, 75%e
Figure 1. X-ray crystal structure of acyl isourea 2j (CCDC
1868295).
[a]
Reactions conditions: 0.5 mmol of 1 and 0.5 mmol of
Cu(OAc)2 in the presence of Pd(dppf)Cl2 (10 mol %)
and tert-butyl isocyanide (1.0 equiv.) in 2.0 mL of
CH3CN at 60 oC for 2 h.
Imide
bond
is
ubiquitous
in
various
pharmaceuticals, natural products, and polymers,[15]
and the above findings led us to envisage that the
selective synthesis of imides via direct N-acylation of
amides using carboxylates as acyl sources may be
realized. Thus, the optimization of the imides
synthesis was also investigated. After a series of
experiments, the optimized reaction conditions for the
formation of imide 3a was obtained when a mixture
of 1a, Cu(OAc)2 and tert-butyl isocyanide (1:1:1 mol
ratio) was treated with 10 mol % Pd(dppf)Cl2 in
CH3CN at 60 oC for 2 h, whereby N-acetylbenzamide
3a was obtained in 82% isolated yield (see Table S1,
entry 1 in the Supporting Information).
[b] Isolated yield of pure product based on 1.
[c] Sodium benzoate was used as the carboxylate.
[d] Copper(II) methacrylate was used as the carboxylate.
[e]
Copper bis(2-ethylhexanoate) was used as the
carboxylate.
To test the practicality of the method, gram-scale
(10 mmol-scale) synthesis of acyl isourea 2a and
imide 3a were carried out. The reaction of benzamide
(1a) and tert-butyl isocyanide in 20 mL of ethanol on
the 10 mmol scale gave the desired product 2a in
84% yield (Scheme 2a). When 1a, cupric acetate and
3
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10.1002/adsc.201801245
Advanced Synthesis & Catalysis
tBu
tert-butyl isocyanide (1:1:1 mol ratio) in 20 mL of
acetonitrile were used as starting materials, the
reaction proceeded efficiently to obtain 1.63 g of 3a
(77% isolated yield) (Scheme 2b).
Pd(dppf)Cl2 (10 mol%)
Cu(OAc)2 ( 40 mol%)
O
N
O
N
O
NH2
But
N
C
H
a)
b)
+
+
EtOH (ultradry), Ar, 60 oC, 2h
2a, 91%
1a
Pd(dppf)Cl2 (10 mol%)
(1 epuiv.)
O
O
O
But
N
C
But
NH2
N
H
Pd(dppf)Cl2 (10 mol%)
O
N
Cu(OAc)2
O
CH3CN(ultradry), Ar, 60 oC, 2 h
Cu(OAc)2 (40 mol%)
N
O
NH2
1a
But
N C
3a, 83%
tBu
+
a)
H
CH3CH2OH (20 mL), 60 OC, 2 h
O
N
Pd(dppf)Cl2 (10 mol%)
Cu(OAc)2 ( 40 mol%)
O
2a, 84%, 2.48g
1a (10 mmol)
(10 mmol)
N
18 O
NH2
But
N C
c)
d)
H
+
EtOH/H218O (10:1), 60 oC, 2h
Pd(dppf)Cl2 (10 mol%)
O
O
O
[
18O]-2a, 0%
18O
1a
But
N C (1 epuiv.)
NH2
N
+
b)
Cu(OAc)2
(10 mmol)
O
O
H
Pd(dppf)Cl2 (10 mol%)
(1 epuiv.)
CH3CN (20 mL), 60 oC, 2 h
But
N C
N
NH2
+
H
Cu(OAc)2
1a (10 mmol)
3a, 77%, 1.63g
CH3CN/H218O (10:1） , 60 oC, 2 h
1a
Scheme 2. Gram-scale synthesis of acyl isourea 2a and
imide 3a.
[
18O]-3a, 0%
TEMPO or BHT (1mmol)
Pd(dppf)Cl2 (10 mol%)
Cu(OAc)2 (40 mol%)
tBu
O
O
N
NH2
N
O
But
N C
e)
+
H
Some control experiments were carried out in order
to explore the possible reaction pathway. The
reaction of 1a with tert-butyl isocyanide in ultradry
EtOH under Argon atmosphere provided 2a in 91%
yield (Scheme 3a). The reaction of 1a and Cu(OAc)2
in the presence of 10 mol % Pd(dppf)Cl2 and 1.0
equivalent of tert-butyl isocyanide in ultradry CH3CN
under Argon atmosphere generated 3a in 83% yield
(Scheme 3b). In addition, no 18O-labeled product
[18O]-2a or [18O]-3a were detected in the presence of
EtOH, 60 OC, 2 h
1a (0.5 mmol)
0.5 mmol
2a, 90%
TEMPO or BHT (1mmol)
Pd(dppf)Cl2 (10 mol%)
O
O
O
NH2
But
N C
(1 epuiv.)
N
+
Cu(OAc)2
0.5 mmol
f)
H
CH3CN, 60 oC, 2 h
1a (0.5 mmol)
3a, 80%
Scheme 3. Control experiments.
C
N
R3
CuI
L
PdIICl2
18
H2 O under the standard conditions (Scheme 3c and
CuII
2Cl-
3d). The above results indicated that the oxygen
atom of the acyl isourea and imide product was not
originated from H2O or molecular oxygen.
Furthermore, the yields of acyl isourea 2a and imide
3a were nearly unaffected in reactions conducted
in the presence of radical scavengers TEMPO or
BHT (2 equiv), which argues against a radical
pathway (Scheme 3e and 3f).
R3
O
N
R2
O
R3
O
R1
N
Pd0
O
O
L
Cl
O
N
H
Cl
R3
N
C PdII
L
R1
N
R4
OH
HCl
2
R1
N
A
H
N
R3
R4
C
O
O
D
R2
R1
NH2
OH
R3
N
O
1
R3
N
R1
N
PdII Cl
R3
C
O
+ CO2
NH2
H
O
C
L
O
O
HCl
(
O
R4
)
x
M
B
R1
N
H
R4
3
On the basis of the above results, a proposed
mechanism is listed in Scheme 4. The isocyanide-
ligated Pd species A is first formed,[16] then reacts
with amide 1 to give complex B. In alcohols, the
reaction of the complex B with alcohol affords acyl
isourea 2 and the resultant Pd(0) species is reoxidized
to Pd(II) by Cu(II) in the system to complete the
cycle.[17] Whereas in CH3CN, the complex B reacts
with carboxylates to generate the Pd(0) species and
intermediate C, which undergoes rearrangement to
form intermediate D. Immediately, the unstable
intermediate D conducts decomposition to furnish the
final imide product 3.
Scheme 4. Proposed mechanism for the formation of acyl
isoureas and imides.
Conclusion
In summary, we have developed a facile and efficient
synthesis of imides and acyl isoureas from readily
accessible amides, carboxylates and isocyanides in a
highly selective manner by variation of the reaction
solvent. In addition, this transformation also features
good yields, good functional group tolerance and
experimentally convenient catalytic process. Further
study on extension of the scope of the present
protocol to construct the biologically active
molecules is ongoing in our laboratory.
Experimental Section
General Experimental Details
Proton nuclear magnetic resonance spectra (1H NMR) and
carbon nuclear magnetic resonance spectra (13C NMR)
were recorded at 400 MHz and 100 MHz, respectively.
HRMS (ion trap) were recorded using ESI. Melting points
are uncorrected. Precoated silica gel plates F-254 were
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801245
Advanced Synthesis & Catalysis
used for thin-layer analytical chromatography. Column
chromatography was performed on silica gel (300-400
mesh). Unless otherwise noted, all reagents were obtained
commercially and used without further purification.
162.3, 158.0, 131.5, 131.4, 128.8, 119.8, 113.4, 64.4, 63.2,
51.7, 29.5, 14.9, 14.5 ppm; HRMS (m/z) (ESI): calcd for
C16H25O3N2 293.1865 [M+H]+; found 293.1841.
(Z)-1-tert-butyl-3-(2,6-difluorobenzoyl)-2-
ethylisourea (2i): colorless oil; 1H NMR (400 MHz,
CDCl3): δ 10.00 (s, 1H), 7.29–7.21 (m, 1H), 6.97–6.80 (m,
2H), 4.42 (q, J = 7.1 Hz, 2H), 1.42 (s, 9H), 1.34 (t, J = 7.1
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 173.0, 162.5,
General experimental procedure for synthesis of acyl
isoureas 2.
A mixture of amides 1 (1.0 equiv, 0.5 mmol),
isocyanides (1.0 equiv, 0.5 mmol), Pd(dppf)Cl2 (10 mol %,
0.05 mmol), Cu(OAc)2 (40 mol %, 0.2 mmol) and 2 mL of
alcohols was stirred at 60 oC for 2 h. The progress of the
reaction was monitored by thin-layer chromatography. The
mixture was then cooled and evaporated under reduced
pressure, and the residue was purified by flash column
chromatography (petroleum ether/ethyl acetate) to afford
acyl isoureas 2.
1
1
161.5 (d, JCF = 251 Hz), 160.1 (d, JCF = 250 Hz), 130.1,
130.0 (d, 4JCF = 3.0 Hz), 111.7 (d, 2JCF = 19.0 Hz), 111.6 (d,
2JCF = 19.0 Hz), 64.1, 52.2, 29.3, 14.4 ppm; HRMS (m/z)
(ESI): calcd for C14H19O2N2F2 285.1415 [M+H]+; found
285.1394.
(Z)-1-tert-butyl-3-(3,5-dimethoxybenzoyl)-2-
o
ethylisourea (2j): light yellow solid, m.p. 92.5–95.7 C;
1H NMR (400 MHz, CDCl3): δ 10.21 (s, 1H), 7.40 (d, J
= 2.4 Hz, 2H), 6.59 (t, J = 2.4 Hz, 1H), 4.55 (q, J = 7.1
Hz, 2H), 3.83 (s, 6H), 1.46–1.38 (m, 12H) ppm; 13C
NMR (100 MHz, CDCl3): δ 176.8, 162.6, 160.4, 140.2,
106.7, 104.2, 63.5, 55.5, 51.8, 29.4, 14.5 ppm; HRMS
(m/z) (ESI): calcd for C16H25O4N2 309.1814 [M+H]+; found
309.1791.
(Z)-1-benzoyl-3-tert-butyl-2-ethylisourea
(2a):
colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.22 (s, 1H),
8.33–8.12 (m, 2H), 7.50–7.35 (m, 3H), 4.56 (q, J = 7.1 Hz,
2H), 1.44–1.39 (m, 12H) ppm; 13C NMR (100 MHz,
CDCl3): δ 177.3, 162.6, 138.1, 131.4, 129.1, 128.3, 127.9,
63.4, 51.8, 29.5, 14.6 ppm; HRMS (m/z) (ESI): calcd for
C14H21O2N2 249.1598 [M+H]+; found 249.1586.
(Z)-1-(1-naphthoyl)-3-tert-butyl-2-ethylisourea (2k):
colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H),
9.03 (d, J = 8.6 Hz, 1H), 8.25 (dd, J = 7.2, 1.1 Hz, 1H),
7.92 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.57–
7.51 (m, 1H), 7.49 (dd, J = 10.5, 4.8 Hz, 2H), 4.53 (q, J =
(Z)-1-tert-butyl-2-ethyl-3-(4-fluorobenzoyl)isourea
1
(2b): colorless oil; H NMR (400 MHz, DMSO): δ 10.12
(s, 1H), 8.21–8.05 (m, 2H), 7.05 (s, 2H), 4.48 (q, J = 7.1
7.1 Hz, 2H), 1.47 (s, 9H), 1.41 (t, J = 7.1 Hz, 3H) ppm; 13
C
Hz, 2H), 1.39–1.33 (m, 12H) ppm; 13C NMR (100 MHz,
1
NMR (100 MHz, CDCl3): δ 180.1, 162.4, 136.1, 134.0,
131.4, 131.3, 128.9, 128.3, 126.7, 126.6, 125.6, 124.7,
63.5, 51.9, 29.6, 14.6 ppm; HRMS (m/z) (ESI): calcd for
C18H23O2N2 299.1754 [M+H]+; found 299.1738.
DMSO): δ 175.4, 164.8 (d, JCF = 248 Hz), 162.5, 134.5,
3
4
131.5 (d, JCF = 8.0 Hz), 114.90, 114.8 (d, JCF = 2.0 Hz),
63.5, 51.7, 29.5, 14.6 ppm; HRMS (m/z) (ESI): calcd for
C14H20O2N2F 267.1503 [M+H]+; found 267.1487.
(Z)-1-tert-butyl-2-ethyl-3-(4-
(Z)-1-tert-butyl-2-ethyl-3-(thiophene-2-
1
1
carbonyl)isourea (2l): Colorless oil; H NMR (400 MHz,
(trifluoromethyl)benzoyl)isourea (2c): colorless oil; H
CDCl3): δ 9.91 (s, 1H), 7.75 (dd, J = 3.7, 1.1 Hz, 1H), 7.41
(dd, J = 5.0, 1.0 Hz, 1H), 7.04 (dd, J = 4.9, 3.8 Hz, 1H),
4.49 (q, J = 7.1 Hz, 2H), 1.41–1.34 (m, 12H) ppm; 13C
NMR (100 MHz, CDCl3): δ 172.5, 162.1, 144.2, 130.8,
130.6, 127.7, 63.6, 51.9, 29.4, 14.5 ppm; HRMS (m/z)
(ESI): calcd for C12H19O2N2S 255.1167 [M+H]+; found
255.1151.
NMR (400 MHz, CDCl3): δ 10.19 (s, 1H), 8.30 (d, J = 8.1
Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 4.56 (q, J = 7.1 Hz, 2H),
1.45–1.37 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ
175.8, 162.8, 141.3, 132.8 (q), 129.9, 128.2, 124.9 (q),
124.1(q), 63.7, 52.0, 29.4, 14.5 ppm; HRMS (m/z) (ESI):
calcd for C15H20O2N2F3 317.1471 [M+H]+; found
317.1455.
(Z)-1-tert-butyl-3-cinnamoyl-2-ethylisourea
(2m):
(Z)-1-tert-butyl-2-ethyl-3-(4-nitrobenzoyl)isourea (2d):
yellow solid, m.p. 76.7-78.8 oC; 1H NMR (400 MHz,
CDCl3): δ 10.19 (s, 1H), 8.36–8.32 (m, 2H), 8.24–8.21 (m,
2H), 4.58 (q, J = 7.1 Hz, 2H), 1.46–1.43 (m, 12H) ppm;
13C NMR (100 MHz, CDCl3): δ 174.9, 162.9, 149.6, 143.7,
129.9, 123.1, 63.9, 52.1, 29.3, 14.5 ppm; HRMS (m/z)
(ESI): calcd for C14H20O4N3 294.1454 [M+H]+; found
294.1432.
colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.17 (s, 1H),
7.68 (d, J = 15.9 Hz, 1H), 7.54 (d, J = 6.7 Hz, 2H), 7.40–
7.28 (m, 3H), 6.63 (d, J = 15.9 Hz, 1H), 4.47 (q, J = 7.1
Hz, 2H), 1.42–1.35 (m, 12H) ppm; 13C NMR (100 MHz,
CDCl3): δ 178.0, 162.4, 140.8, 135.7, 129.3, 128.7, 128.1,
127.9, 63.2, 51.7, 29.5, 14.5 ppm; HRMS (m/z) (ESI):
calcd for C16H23O2N2 275.1760 [M+H]+; found 275.1737.
(Z)-1-tert-butyl-2-ethyl-3-(2-phenylacetyl)isourea (2n):
(Z)-1-tert-butyl-2-ethyl-3-(4-methoxybenzoyl)isourea
1
o
1
colorless oil; H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H),
(2e): white solid, m.p. 69.8-72.2 C; H NMR (400 MHz,
CDCl3): δ 10.18 (s, 1H), 8.28–8.03 (m, 2H), 6.89 (dd, J =
6.7, 4.8 Hz, 2H), 4.53 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H),
1.44–1.35 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ
176.9, 162.4, 162.3, 131.0, 130.8, 113.1, 63.2, 55.3, 51.6,
29.5, 14.5 ppm; HRMS (m/z) (ESI): calcd for C15H23O3N2
279.1709 [M+H]+; found 279.1688.
7.35–7.18 (m, 5H), 4.35 (q, J = 7.1 Hz, 2H), 3.64 (s, 2H),
1.34–1.27 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ
184.6, 162.1, 137.1, 129.6, 128.2, 126.2, 63.3, 51.6, 48.1,
29.4, 14.4 ppm; HRMS (m/z) (ESI): calcd for C15H23N2O2
263.1760 [M+H]+; found 263.1742.
(Z)-1-benzoyl-3-tert-butyl-2-butylisourea
(2p):
colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.24 (s, 1H),
8.22 (d, J = 7.4 Hz, 2H), 7.48–7.38 (m, 3H), 4.51 (t, J =
6.5 Hz, 2H), 1.83–1.73 (m, 2H), 1.52 (d, J = 7.5 Hz, 2H),
1.41 (s, 9H), 1.00 (t, J = 7.4 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3): δ 177.3, 162.8, 138.0, 131.4, 129.1, 127.9,
67.3, 51.7, 31.0, 29.5, 19.4, 13.8 ppm; HRMS (m/z) (ESI):
calcd for C16H25O2N2 277.1916 [M+H]+; found 277.1897.
(Z)-1-tert-butyl-2-ethyl-3-(2-fluorobenzoyl)isourea
(2f): colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.14 (s,
1H), 8.05 (td, J = 7.8, 1.8 Hz, 1H), 7.42–7.36 (m, 1H),
7.18–7.02 (m, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.43–1.36 (m,
12H); 13C NMR (100 MHz, CDCl3): δ 175.7, 162.5, 162.0
1
3
(d, JCF = 256 Hz), 132.4 (d, JCF = 9.0 Hz), 131.9, 126.7,
4
2
123.4 (d, JCF = 4.0 Hz), 116.7 (d, JCF = 23.0 Hz), 63.6
51.9, 29.4, 14.5 ppm; HRMS (m/z) (ESI): calcd for
C14H20O2N2F 267.1509 [M+H]+; found 267.1490.
(Z)-1-tert-butyl-2-ethyl-3-(2-
(Z)-1-benzoyl-3-tert-butyl-2-isopentylisourea
(2q):
colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H),
8.25–8.15 (m, 2H), 7.48–7.37 (m, 3H), 4.54 (t, J = 6.8 Hz,
2H), 1.84–1.76 (m, 1H), 1.71–1.64 (m, 2H), 1.41 (s, 9H),
0.99 (d, J = 6.6 Hz, 6H) ppm; 13C NMR (100 MHz,
CDCl3): δ 177.3, 162.7, 138.1, 131.4, 129.1, 127.9, 66.0,
51.7, 37.7, 29.6, 29.5, 25.1, 22.5 ppm; HRMS (m/z) (ESI):
calcd for C17H27O2N2 291.2073 [M+H]+; found 291.2049.
(Z)-1-benzoyl-3-tert-butyl-2-cyclohexylisourea (2r):
colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.25 (s, 1H),
8.21–8.14 (m, 2H), 7.49–7.43 (m, 1H), 7.43–7.36 (m, 2H),
5.39–5.29 (m, 1H), 2.05–1.97 (m, 2H), 1.81–1.75 (m, 2H),
1.69–1.64 (m, 2H), 1.61–1.55 (m, 2H), 1.56–1.47(m, 2H),
1.42 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.2,
162.2, 138.2, 131.3, 129.0, 127.9, 75.7, 51.7, 31.7, 29.5,
1
(trifluoromethyl)benzoyl)isourea (2g): colorless oil ; H
NMR (400 MHz, DMSO): δ 9.92 (s, 1H), 7.90–7.33 (m,
4H), 4.59–4.12 (m, 2H), 1.37 (t, J = 7.1 Hz, 9H), 1.30 (t, J
= 7.1 Hz, 3H) ppm; 13C NMR (100 MHz, DMSO): δ 178.4,
162.4, 139.8, 131.8, 129.9, 129.9, 129.8, 126.3, 63.8, 52.0,
29.4, 14.5 ppm; HRMS (m/z) (ESI): calcd for
C15H20O2N2F3 317.1477 [M+H]+; found 317.1453.
(Z)-1-tert-butyl-3-(2-ethoxybenzoyl)-2-ethylisourea
1
(2h): colorless oil; H NMR (400 MHz, CDCl3): δ 10.14
(s, 1H), 7.90 (dd, J = 7.9, 1.8 Hz, 1H), 7.38–7.29 (m, 1H),
6.92 (dd, J = 11.4, 4.3 Hz, 2H), 4.47 (q, J = 7.1 Hz, 2H),
4.14 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H), 1.41–
1.34 (m, 12H) ppm; 13C NMR (100 MHz, CDCl3): δ 178.4,
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201801245
Advanced Synthesis & Catalysis
25.6, 23.6 ppm; HRMS (m/z) (ESI): calcd for C18H27O2N2
25.7 ppm; HRMS (m/z) (ESI): calcd for C9H8O2NFNa
204.0437 [M+Na]+; found 204.0423.
303.2067 [M+H]+; found 303.2051.
(Z)-1-benzoyl-2-benzyl-3-tert-butylisourea
(2s):
N-acetyl-4-(trifluoromethyl)benzamide (3e): white
solid, m.p. 105.7–107.1oC (lit.[22]111−112°C); 1H NMR
(400 MHz, CDCl3): δ 9.89 (d, J = 5.2 Hz, 1H), 8.09 (d, J =
8.2 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 2.63 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 174.4, 165.2, 136.0, 134.6
(q), 128.6, 125.8 (q), 123.5(q), 29.6 ppm; HRMS (m/z)
(ESI): calcd for C10H8O2NF3Na 254.0405 [M+Na]+; found
254.0388.
colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.31 (s, 1H),
8.30–8.21 (m, 2H), 7.52–7.33 (m, 8H), 5.57 (s, 2H), 1.41
(s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.4, 162.5,
137.9, 136.2, 131.6, 129.1, 128.6, 128.3, 128.2, 128.0,
52.0, 30.0 ppm; HRMS (m/z) (ESI): calcd for C19H23O2N2
311.1760 [M+H]+; found 311.1740.
(Z)-1-benzoyl-3-cyclohexyl-2-ethylisourea
(2u):
colorless oil; 1H NMR (400 MHz, CDCl3): δ 10.04 (s, 1H),
8.27–8.16 (m, 2H), 7.48–7.44 (m, 1H), 7.43–7.37 (m, 2H),
4.53 (q, J = 7.1 Hz, 2H), 3.75–3.61 (m, 1H), 2.00–1.94 (m,
2H), 1.77–1.71 (m, 2H), 1.69–1.51 (m, 2H), 1.41–1.32 (m,
7H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.4, 162.2,
138.0, 131.5, 129.1, 127.9, 63.5, 49.9, 32.9, 25.5, 24.5,
14.7 ppm; HRMS (m/z) (ESI): calcd for C16H23O2N2
275.1760 [M+H]+; found 275.1740.
N-acetyl-4-aminobenzamide (3f): yellow solid, m.p.
97.5–101.4oC; 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H),
7.74–7.62 (m, 2H), 6.79–6.58 (m, 2H), 4.17 (s, 2H), 2.59
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 173.5, 164.9,
151.3, 129.9, 121.6, 114.2, 25.4 ppm; HRMS (m/z) (ESI):
calcd for C9H10O2N2Na 201.0640 [M+Na]+; found
201.0626.
N-acetyl-4-methoxybenzamide (3g): light yellow solid,
1
(Z)-1-benzoyl-2-ethyl-3-(2,4,4-trimethylpentan-2-
yl)isourea (2v): colorless oil; 1H NMR (400 MHz, CDCl3):
δ 10.29 (s, 1H), 8.36–8.04 (m, 2H), 7.46 (ddd, J = 6.2, 3.6,
1.3 Hz, 1H), 7.40 (t, J = 7.3 Hz, 2H), 4.56 (q, J = 7.1 Hz,
2H), 1.75 (s, 2H), 1.47–1.40 (m, 9H), 1.00 (s, 9H) ppm;
13C NMR (100 MHz, CDCl3): δ 177.2, 162.4, 138.0, 131.4,
129.1, 127.9, 63.3, 55.4, 52.1, 31.7, 31.5, 30.2, 14.7 ppm;
HRMS (m/z) (ESI): calcd for C18H29O2N2 305.2229
[M+H]+; found 305.2208.
m.p. 108.3–111.5oC (lit.[23]119−119.5°C); H NMR (400
MHz, CDCl3): δ 9.10 (s, 1H), 7.94–7.81 (m, 2H), 6.98 (d, J
= 8.9 Hz, 2H), 3.88 (s, 3H), 2.60 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 174.0, 165.2, 163.6, 129.9, 124.8, 114.2,
55.6, 25.6 ppm; HRMS (m/z) (ESI): calcd for
C10H11O3NNa 216.0637 [M+Na]+; found 216.0623.
N-acetyl-2-fluorobenzamide (3h): light yellow solid,
m.p. 40.5–43.8 oC; 1H NMR (400 MHz, CDCl3): δ 9.01 (s,
1H), 8.00 (td, J = 7.8, 1.7 Hz, 1H), 7.59–7.53 (m, 1H),
7.29 (dd, J = 9.5, 5.7 Hz, 1H), 7.16 (dd, J = 12.0, 8.4 Hz,
1H), 2.56 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
(Z)-1-benzoyl-3-benzyl-2-ethylisourea (2w): white
1
solid, m.p. 58.6–62.3 oC; H NMR (400 MHz, CDCl3): δ
1
3
10.36 (s, 1H), 8.24–8.21 (m, 2H), 7.50–7.44 (m, 1H),
7.42–7.26 (m, 7H), 4.59–4.47 (m, 4H), 1.38 (t, J = 7.1 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 177.7, 162.9,
137.8, 137.5, 131.6, 129.2, 128.7, 127.9, 127.6, 127.5,
63.8, 45.0, 14.6 ppm; HRMS (m/z) (ESI): calcd for
C17H19O2N2 283.1447 [M+H]+; found 283.1426.
172.6, 162.1, 160.5 (d, JCF = 248 Hz), 135.1 (d, JCF
=
=
4
3
10.0 Hz), 132.1, 125.2 (d, JCF = 3.0 Hz), 120.2 (d, JCF
2
11.0 Hz), 116.5 (d, JCF = 24.0 Hz), 25.9 ppm; HRMS
(m/z) (ESI): calcd for C9H8O2NFNa 204.0437 [M+Na]+;
found 204.0423.
N-acetyl-2-iodobenzamide (3i): yellow solid, m.p.
(Z)-1-benzoyl-3-(2,6-dimethylphenyl)-2-ethylisourea
69.8–73.2 oC; 1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H),
(2x): colorless oil; 1H NMR (400 MHz, CDCl3): δ 11.43 (s, 7.92 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 4.9 Hz, 2H), 7.23–
1H), 8.39–8.27 (m, 2H), 7.57–7.42 (m, 3H), 7.18–7.08 (m,
3H), 4.55 (q, J = 7.1 Hz, 2H), 2.27 (s, 6H), 1.33 (t, J = 7.1
7.14 (m, 1H), 2.56 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 172.5, 167.7, 140.4, 140.1, 132.3, 128.4, 128.3,
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 178.2, 162.2, 92.0, 25.4 ppm; HRMS (m/z) (ESI): calcd for C9H8O2NINa
137.6, 135.2, 133.8, 131.9, 129.4, 128.1, 128.1, 127.4, 63.9, 311.9497 [M+Na]+; found 311.9471.
18.5, 14.7 ppm; HRMS (m/z) (ESI): calcd for C18H21O2N2
N-acetyl-2-(trifluoromethyl)benzamide (3j): white
297.1603 [M+H]+; found 297.1591.
solid, m.p. 89.8–92.9oC; H NMR (400 MHz, CDCl3): δ
1
General experimental procedure for synthesis of
imides 3. A mixture of amides 1 (1.0 equiv, 0.5 mmol),
tert-butyl isocyanide (1.0 equiv, 0.5 mmol), carboxylates
(1.0 equiv, 0.5 mmol), Pd(dppf)Cl2 (10 mol %, 0.05
mmol) and 2 mL of CH3CN was stirred at 60 oC for 2 h.
The progress of the reaction was monitored by thin-layer
chromatography. The mixture was then cooled and
evaporated under reduced pressure, and the residue was
purified by flash column chromatography (petroleum
ether/ethyl acetate) to afford imides 3.
8.83 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.65–7.58 (m, 2H),
7.51 (d, J = 6.8 Hz, 1H), 2.49 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3): δ 172.2, 166.9, 134.1, 132.1, 130.9, 127.7,
127.4(q), 126.8 (q), 123.3 (q), 25.2 ppm; HRMS (m/z)
(ESI): calcd for C10H8O2NF3Na 254.0405 [M+Na]+; found
254.0389.
N-acetyl-2-ethoxybenzamide (3k): white solid, m.p.
84.2–86.9oC; 1H NMR (400 MHz, CDCl3): δ 10.45 (s, 1H),
8.25–8.02 (m, 1H), 7.53–7.46 (m, 1H), 7.12–7.03 (m, 1H),
6.98 (d, J = 8.1 Hz, 1H), 4.22 (t, J = 7.0 Hz, 2H), 2.55 (s,
3H), 1.55 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 173.2, 164.0, 157.2, 134.7, 132.8, 121.6, 120.2,
112.7, 65.3, 29.6, 14.6 ppm; HRMS (m/z) (ESI): calcd for
C11H13O3NFNa 230.0793 [M+Na]+; found 230.0779.
N-acetyl-2,6-difluorobenzamide (3l): white needle
crystal, m.p. 138.5–140.3oC (lit.[24] 141.5°C); 1H NMR
(400 MHz, CDCl3): δ 8.82 (s, 1H), 7.48–7.28 (m, 1H),
6.92 (td, J = 8.4, 2.0 Hz, 2H), 2.54–2.33 (m, 3H) ppm;13C
N-acetylbenzamide (3a): white solid, m.p. 107.9−109.8
1
oC (lit.[18] 109−110°C); H NMR (400 MHz, CDCl3): δ
9.20 (s, 1H), 7.94–7.85 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H),
7.49 (t, J = 7.7 Hz, 2H), 2.60 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3): δ 174.0, 165.9, 133.2, 132.7, 128.9, 127.9,
25.7 ppm; HRMS (m/z) (ESI): calcd for C9H9O2NNa
186.0531 [M+Na]+; found 186.0518.
N-acetyl-4-methylbenzamide (3b): white solid, m.p.
1
1
101.9–103.2 oC (lit.[19] 103−104°C); H NMR (400 MHz,
NMR (100 MHz, CDCl3): δ 172.0, 160.5 (d, JCF = 253.0
1
3
CDCl3): δ 8.79 (s, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.30 (d, J
= 8.0 Hz, 2H), 2.61 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 173.6, 165.6, 144.2, 129.8, 129.7,
127.7, 25.6, 21.7 ppm; HRMS (m/z) (ESI): calcd for
C10H11O2NNa 200.0687 [M+Na]+; found 200.0674.
Hz), 159.9 (d, JCF = 253 Hz), 159.8, 133.2 (d, JCF = 10.0
3 2
Hz), 133.1 (d, JCF = 11.0 Hz), 112.2 (d, JCF = 22.0 Hz),
25.5 ppm; HRMS (m/z) (ESI): calcd for C9H7O2NF2Na
222.0343 [M+Na]+; found 222.0329.
N-acetyl-3,5-dimethoxybenzamide (3m): white solid,
m.p. 157.2–159.5oC (lit.[25] 161–163°C); 1H NMR (400
MHz, CDCl3): δ 8.93 (s, 1H), 6.99 (d, J = 2.2 Hz, 2H),
N-acetyl-4-chlorobenzamide (3c): white solid, m.p.
1
136.9–138.4 oC (lit.[20] 140−142°C); H NMR (400 MHz,
CDCl3): δ 9.36 (s, 1H), 7.86 (dd, J = 8.9, 2.0 Hz, 2H),
7.62–7.35 (m, 2H), 2.60 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 174.2, 165.0, 139.8, 131.0, 129.4, 129.3, 25.8
ppm; HRMS (m/z) (ESI): calcd for C9H8O2ClNNa
220.0141 [M+Na]+; found 220.0133.
6.66 (t, J = 2.2 Hz, 1H), 3.84 (s, 6H), 2.60 (s, 3H) ppm; 13
C
NMR (100 MHz, CDCl3): δ 173.6, 165.6, 161.2, 134.7,
105.6, 105.5, 55.7, 25.6 ppm; HRMS (m/z) (ESI): calcd for
C11H13O4NNa 246.0742 [M+Na]+; found 246.0727.
N-acetyl-1-naphthamide (3n): light yellow solid, m.p.
1
N-acetyl-4-fluorobenzamide (3d): white needle crystal,
m.p. 108.2–109.9oC (lit.[21]111−112°C); 1H NMR (400
MHz, CDCl3): δ 9.52 (s, 1H), 8.13–7.84 (m, 2H), 7.23–
7.03 (m, 2H), 2.61 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
174.4, 165.8 (d, 1JCF = 254 Hz), 164.9, 130.5 (d, 3JCF = 9.0
109.2–112.1oC; H NMR (400 MHz, CDCl3): δ 8.94 (s,
1H), 8.29 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H),
7.84 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.0 Hz, 1H), 7.58–
7.48 (m, 2H), 7.41 (dd, J = 10.9, 4.3 Hz, 1H), 2.57 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 173.2, 167.0, 133.8,
132.5, 131.8, 130.2, 128.6, 127.8, 126.8, 126.2, 124.9,
4
2
Hz), 128.8 (d, JCF = 3.0 Hz), 116.1 (d, JCF = 22.0 Hz),
6
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10.1002/adsc.201801245
Advanced Synthesis & Catalysis
124.5, 25.6 ppm; HRMS (m/z) (ESI): calcd for
C13H11O2NNa 236.0687[M+Na]+; found 236.0673.
Moret, R. J. Pieters, N. I. Martin, Org. Biomol.
Chem. 2016, 14, 8670.
N-acetylthiophene-2-carboxamide (3o): light yellow
1
solid, m.p. 108.3–110.5oC (lit.[21] 134–135°C); H NMR
[2]a) S. E. Forman, C. A. Erickson, H. Adelman, J. Org.
Chem. 1963, 28, 2653; b) E. Vowinkel, I. Bgthe,
Chem. Ber. 1974, 107, 1353; c) E. D-britz, Angew.
Chem. Int. Ed. Engl. 1966, 5, 470; d) L. J. Mathias,
Synthesis 1979, 561; e) G. Heinisch, B. Matuszczak,
D. Rakowitz, K. J. Mereiter, Heterocycl. Chem.
2002, 39, 695; f) S. Crosignani, P. D. White, R.
Steinauer, B. Linclau, Org. Lett. 2003, 5, 853.
(400 MHz, CDCl3): δ 8.79 (s, 1H), 7.71 (d, J = 3.8 Hz,
1H), 7.67 (d, J = 5.0 Hz, 1H), 7.16 (t, J = 4.3 Hz, 1H), 2.60
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 173.2, 159.9,
137.5, 133.6, 130.5, 128.3, 25.5 ppm; HRMS (m/z) (ESI):
calcd for C7H7O2NNaS 192.0095 [M+Na]+; found
192.0080.
N-acetylcinnamamide (3p): light yellow needle crystal,
o
1
m.p. 109.2–112.8 C (lit.[23] 131–132°C); H NMR (400
MHz, CDCl3): δ 9.50 (s, 1H), 7.83 (d, J = 15.7 Hz, 1H),
7.58 (dt, J = 7.4, 3.6 Hz, 2H), 7.41 (dd, J = 6.3, 3.9 Hz,
3H), 6.97 (d, J = 15.6 Hz, 1H), 2.49 (s, 3H) ppm; 13C NMR
(101 MHz, CDCl3): δ 173.4, 165.8, 145.9, 134.2, 130.8,
129.0, 128.5, 119.5, 25.4 ppm; HRMS (m/z) (ESI): calcd
for C11H11O2NNa 212.0687 [M+Na]+; found 212.0674.
N-Benzoylbenzamide (3q): white solid, m.p. 143.6–
[3] A. Williams, I. T. Ibrahim, Chem. Rev. 1981, 81,
589.
[4] a) I. S. R. Karmel, M. Tamm, M. S. Eisen, Angew.
Chem. Int. Ed. 2015, 54, 12422; b) R. J. Batrice, C. E.
Kefalidis, L. Maron, M. S. Eisen, J. Am. Chem. Soc.
2016, 138, 2114; c) R. J. Batrice, M. S. Eisen, Chem.
Sci. 2016, 7, 939; d) H. Liu, M. Khononov, N.
Fridman, M. Tamm, M. S. Eisen, Inorg. Chem. 2017,
56, 3153; e) T. Ghatak, N. Fridman, M. S. Eisen,
Organometallics 2017, 36, 1296; f) H. Liu, N.
Fridman, M. Tamm, M. S. Eisen, Organometallics
2017, 36, 3896; g) H. Liu, N. Fridman, M. Tamm, M.
S. Eisen, Organometallics 2017, 36, 4600.
1
145.2oC (lit.[18] 144–145°C); H NMR (400 MHz, CDCl3):
δ 9.06 (s, 1H), 7.87 (d, J = 7.9 Hz, 4H), 7.60 (t, J = 7.4 Hz,
2H), 7.50 (t, J = 7.5 Hz, 4H) ppm; 13C NMR (100 MHz,
CDCl3): δ 166.5, 133.4, 133.1, 128.9, 128.0 ppm; HRMS
(m/z) (ESI): calcd for C14H11O2NNa 248.0687 [M+Na]+;
found 248.0672.
N-methacryloylbenzamide (3r): light yellow solid,
1
m.p. 68.6–72.4oC (lit.[26] 71–72°C); H NMR (400 MHz,
CDCl3): δ 8.92 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.56 (dd,
J = 8.9, 4.5 Hz, 1H), 7.45 (dd, J = 14.3, 7.0 Hz, 2H), 5.82
(d, J = 0.5 Hz, 1H), 5.59 (s, 1H), 2.03 (s, 3H) ppm; 13C
NMR (100MHz, CDCl3): δ 166.4, 165.4, 139.3, 132.3,
132.0, 127.8, 126.9, 121.0, 17.4 ppm; HRMS (m/z) (ESI):
calcd for C11H11O2NNa 212.0687 [M+Na]+; found
212.0672.
[5] K. Muꢂiz, A. Iglesias, Y. Fang, Chem. Commun.
2009, 5591.
[6] H. Li, R. A. Widenhoefer, Tetrahedron 2010, 66,
4827.
N-(2-ethylhexanoyl)benzamide (3s): White solid, m.p.
1
94.1–98.3oC; H NMR (400 MHz, CDCl3): δ 8.94 (s, 1H),
7.95–7.84 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7
Hz, 2H), 3.58–3.42 (m, 1H), 1.83–1.70 (m, 2H), 1.65–1.49
(m, 2H), 1.36–1.26 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H), 0.87
(t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
179.3, 165.6, 133.2, 133.1, 128.9, 127.8, 47.1, 31.2, 29.5,
25.0, 22.9, 14.0, 11.7 ppm; HRMS (m/z) (ESI): calcd for
C15H21O2NNa 270.1470 [M+Na]+; found 270.1454.
[7] a) B. M. Cochran, F. E. Michael, Org. Lett. 2008, 10,
5039; b) U. Farid, T. Wirth, Angew. Chem., Int. Ed.
2012, 51, 3462.
[8] W.-H. Rao, X.-S. Yin, B.-F. Shi, Org. Lett. 2015, 17,
3758.
[9] T. Jiang, Z.-Y. Gu, L. Yin, S.-Y. Wang, S.-J. Ji, J.
Org. Chem. 2017, 82, 7913.
Acknowledgements
[10] a) D. Savoia, V. Concialini, S. Roffia, L. Tarsi, J.
Org. Chem. 1991, 56, 1822; b) P. Y. Reddy, S.
Kondo, T. Toru, Y. Ueno, J. Org. Chem. 1997, 62,
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Tetrahedron Lett. 1998, 39, 5465; d) J. Lee, M. Hong,
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Feng, L. Yuan, Org. Lett. 2011, 13, 4628.
We would like to thank the National Natural Science
Foundation of China (21762017) and the Science Research
Project of Hunan Provincial Department of Education (16B211).
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8
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10.1002/adsc.201801245
Advanced Synthesis & Catalysis
FULL PAPER
Palladium-Catalyzed Solvent-Controlled Selective
Synthesis of Acyl Isoureas and Imides from
Amides, Isocyanides, Alcohols and Carboxylates
R3
Pd(dppf)Cl2 (10 mol%)
Cu(OAc)2 (40 mol%)
O
N
R1 = aryl, heteroaryl, styryl, benzyl
R2
R3
N C
R2 = alkyl, benzyl
R1
N
O
R3 = alkyl, benzyl, phenyl
H
R2OH, 60 OC, 2 h
75-95% yield
22 examples
O
R1
NH2
O
Pd(dppf)Cl2 (10 mol%)
(1 epuiv.)
O
O
Adv. Synth. Catal. Year, Volume, Page – Page
R4
)
C
x
(
O
But
N C
R1 = aryl, heteroaryl, styryl
R4 = alkyl, phenyl, alkenyl
M
R1
N
R4
H
CH3CN, 60 OC, 2 h
68-90% yield
19 examples
Ming Cao,a Liqiu Liu,a Shi Tang,a Zhiyuan Penga,b
and Yingchun Wanga,*
9
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