Pd-Catalyzed Carbonylation of Acyl Azides

Article abstract of DOI:10.1021/acs.joc.9b01048

Pd-catalyzed reactions of azides with CO to access an isocynate intermediate have been developed extensively in recent years. However, the catalytic carbonylation of sensitive acyl azides has not been reported. Herein, we report a simple Pd-catalyzed carbonylation reaction of acyl azides with broad substrate scope, high efficiency, and simple operation under mild conditions, which provides facile access to acyl ureas. In addition, a mechanistic study was carried out by both experiment and DFT calculation. Control experiments and kinetic study revealed that the real active palladium species were Pd(0). The result of kinetic study suggested that palladium catalyst, azide, and CO were all involved in the turnover-limiting step except for amine. Further DFT study suggested that an unprecedented five-membered palladacycle intermediate was the key intermediate in the carbonylation reaction. ?

Full text of DOI:10.1021/acs.joc.9b01048

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Article
Pd-Catalyzed Carbonylation of Acyl Azides
Zongyang Li, Shiyang Xu, Baoliang Huang, Chenhui Yuan,
Wenxu Chang, Bin Fu, Lei Jiao, Peng Wang, and Zhenhua Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01048 • Publication Date (Web): 03 Jul 2019
Downloaded from http://pubs.acs.org on July 3, 2019
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Pd-Catalyzed Carbonylation of Acyl Azides
Zongyang Li,† Shiyang Xu,† Baoliang Huang,† Chenhui Yuan,† Wenxu Chang,† Bin Fu,† Lei Jiao*,‡, Peng
Wang,† Zhenhua Zhang*,†
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† Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural
University, Beijing 100193, China and Department of Applied Chemistry, China Agricultural University,
Beijing 100193, China
‡ Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing
10084, China
via
R2
L
L
O
O
via
R2 XH
Pd
O
O
O
CO
N
R1
N
X
R1
H
R1 N3
N
N
NCO
R
(0)
Pd
X = NH, O
1,10-Phen.
PdII(OAc)2
Compared Experiments
Kinetic Studies
DFT Calculation
real Pd(0) active catalyst
Key words: Acyl azide • Carbonylation • Mechanistic study • Five-membered palladacycle
ABSTRACT: Pd-catalyzed reactions of azides with CO to access isocynate intermediate have been
developed extensively in recent years. However, the catalytic carbonylation of sensitive acyl azides has
not been reported. Herein, we report a simple Pd-catalyzed carbonylation reaction of acyl azides with
broad substrate scope, high efficiency, and simple operation under mild conditions, which provides facile
access to acyl ureas. In addition, mechanistic study was carried out by both experiment and DFT
calculation. Control experiments and kinetic study revealed that the real active palladium species were
Pd(0). The result of kinetic study suggested that palladium catalyst, azide, and CO were all involved in
the turnover-limiting step except amine. Further DFT study suggested that an unprecedented five-
membered palladacycle intermediate was the key intermediate in the carbonylation reaction.
Introduction
Acyl urea derivatives are common motifs in pharmaceuticals and agrochemicals.1 The traditional
method for accessing acyl urea is the transformation of amides with phenyl carbamates, which produces
stoichiometric phenol as a byproduct.2 Other approaches involve the coupling of isocyanates with amides
and acyl isocyanates with amines, both of which usually require the use of unfriendly phosgene.3 Pd-
catalyzed carbonylation has also been well-established as one of the most important ways to introduce
C=O group into organic molecules.4 Recently, simple Pd(II) salts catalyzed reaction of azides with -
donor/-acceptors, such as CO5 and isocyanide6, to form isocyanates and carbodiimides under mild
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conditions received considerable attention from the synthetic community (Scheme 1a). Nevertheless, the
catalytic carbonylation of sensitive acyl azides, which could easily undergo Curtius rearrangement, has
not been achieved (Scheme 1b). Herein, we describe a Pd-catalyzed direct carbonylation of acyl azides
with balloon-pressured CO, followed by one-pot reaction with amines at room temperature to afford acyl
ureas with excellent yields (Scheme 1c). This reaction represents a novel and efficient access to urea
derivatives, and the related mechanistic study revealed a new Pd(0)-initiated pathway, which has not been
established in literature.
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Scheme 1 The approach to synthesize acyl ureas
a). Pd(II) catalyzed carbonylation of azide
Pd(OAc)2
O
or PdCl2
R
R2
R N3
+
CO
R NCO
N
X
R2 XH
- N2
H
X = NH, O
b). The traditional method of acyl urea synthesis
O
R2
Ph
N
O
H
R2NH2
phosgene
O
O
O
O
R2 N C O
NH3
R2
R1
R1
R1
N
N
H
Cl

NH2
H
or cat.
R2 NH2
phosgene
O
O
C
O

R1
N
or cat.
c). This work
O
via
R2
L
L
O
Pd
Pd
+ CO + R2-NH2
O
N
R1
R1
N
N
H
N3
N
N
H
O
Acyl
O
C
R1
N
RESULTS AND DISCUSSION
Optimization of the Reaction Conditions. Initially, Pd-catalyzed carbonylative coupling reaction of
benzoyl azide 1a and 4-methoxyaniline 2a was investigated as the model reaction (Table 1, for more
details, please see Table S1 of the Supporting Information). We first carried out the model reaction with
Pd(OAc)2 as the catalyst without any external ligands, which showed no catalytic activity (entry 1). When
1,10-phen was added as the ligand, the reaction gave an excellent yield of 98% (entry 2). PdCl2 with 1,10-
phen ligand was found to be ineffective (entry 3). Once AcO- was added, the yield varied between 77 to
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98% (entry 4 and 5). Pd(0) catalysts were also proved active. When Pd2(dba)3, Pd(dba)2, and Pd(PtBu3)2
were used, the reaction gave 85%, 80%, and 83% yield respectively. However, Pd2(dba)3 alone showed
no activity (entry 9). In addition, no reaction occurred if CO was replaced by N2 (entry 10).
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Table 1. Conditions of Pd-Catalyzed Reaction of Acyl Azide 1a with CO and Anline 2a.a
5 mol % Catalyst
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OMe
Ligand
O
O
NH2
O
CO balloon
+
Ph
N
N
H
Ph
N3
Solvent, rt
H
MeO
1a
2a
3aa
Entry
Catalyst
Pd(OAc)2
Pd(OAc)2
PdCl2
Ligand (mol %)
--
Yieldb (%)
1
nr
2
1, 10-Phen (5)
1, 10-Phen (5)
98
nr
3
4
PdCl2
1, 10-Phen (5) / NaOAc(20)
98
77
85
80
83
nr
5
PdCl2
1, 10-Phen (5) / NH4OAc(20)
1, 10-Phen (5)
1, 10-Phen (5)
1, 10-Phen (5)
--
6
Pd2(dba)3
Pd(dba)2
Pd(PtBu3)2
Pd2(dba)3
Pd2(dba)3
7
8
9
10c
1, 10-Phen (5)
nr
a. Reaction condition: 1a (0.20 mmol), 2a (0.24 mmol), catalyst (5 mol %), ligand (5 mol %), CO (1 atm),
solvent (3 mL), rt, 8 h. b. Isolated yield. “nr” = no reaction. 1,10-phen = 1,10-phenanthroline. c. N2 instead
of CO.
Substrate Scope. On the basis of the optimized condition, we expanded the scope of substrates to access
a variety of potentially bioactive compounds (Scheme 2). We initially examined different substitutents
including electron-withdrawing groups on the azide component such as -CF3 (3cb) and electron-donating
groups like -OMe (3bb). To our delight, both of them afforded excellent yields. Subsequently, various
substituents on different positions of the acyl azide were investigated in this transformation. The results
showed that para- (3db) and meta- (3eb) substituted products were formed in excellent yields, and ortho-
(3fb) product also afforded good yield. We further expanded the substrate scope to halogen-substituted
acyl azides (3gb, 3hb and 3ib). The corresponding products were obtained with excellent functional group
tolerance except iodide (3ib, 50%). Moreover, 2-phenylacetyl azide and 3-phenylpropanoyl azide were
employed as starting materials, giving 88% (3ob) and 65% (3pb) yields when 2,9-dimethyl-4,7-diphenyl-
1,10-phenanthroline was used as the ligand. Furthermore, we successfully and efficiently formed products
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bearing reactive functionalities, such as 4-CN (3kb), 4-CH=CH2 (3mb), and 4-COOMe (3jb). Finally,
naphthyl-ring (3nb), heterocyclic acyl azides (3qb – 3vb) and aryl / benzyl azides (3wb and 3xb) all
furnished good yields.
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Scheme 2. Substrate Scope of the Carbonylation Reaction of Acyl Azide a
O
O
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5 mol % Pd(OAc)2,
5 mol % 1,10-Phen
O
Ph
+ CO +
Ph NH2
R1
N
N
R1 N3
H
H
THF, rt
2b
3
1
3gb
3hb
3ib
X = 4-Cl, >98%
X = 4-Br, 83%
X = 4-I, 50%
3ab
3bb
3cb
3db
3eb
3fb
X = H, 94%
O
O
X = 4-OMe, >98%
X = 4-CF3, 94%
X = 4-Me, >98%
X = 3-Me, 98%
X = 2-Me, 71%
N
H
N
H
3jb
X = 4-COOMe, 90%
X = 4-CN, >98%
X = 4-Bpin, 65%b
X
3kb
3lb
O
O
O
O
H
H
N
N
N
H
N
H
N
N
H
H
O
O
b
3mb
3nb
92%
O
98%
3ob
88%
O
O
O
O
O
N
N
N
H
N
H
N
H
N
H
H
H
O
O
O
3qb
94%
3pb
65%
O
3rb
84%
O
O
O
O
O
O
N
H
N
H
N
N
H
N
N
H
H
H
N
S
3sb
82%
3tb
3ub
90%
>98%
O
O
O
O
N
N
N
H
N
H
N
H
N
H
N
H
H
3vb
3wb
3xb
36%
94%
94%
a. Reaction conditions: 1 (0.20 mmol), 2b (0.24 mmol), Pd(OAc)2 (5 mol %), 1,10-phen (5 mol %), CO
(1 atm), THF (3 mL), rt, 12h, isolated yield; b. Using 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline as
the ligand. c. 1d (6.21 mmol), 2b (7.45 mmol), Pd(OAc)2 (5 mol %), 1,10-phen (5 mol %), CO (1 atm),
THF (25 mL), rt, 12h, 3db (1.55 g), 98% isolated yield.
On the other hand, various nucleophiles have also been investigated in this reaction (Scheme 3). First,
we surveyed different substituted anilines, including electronic and positional variation of substituents.
Yields of the corresponding desired products were good to quantitative (75-98%). For instance, in 4-CF3
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(3ac), 4-CN (3al), 4-OMe (3aa), and 4-Ph (3am)-substituted cases, both electron-withdrawing and
electron-donating groups gave high yields. Anilines bearing substituents on different positions of the
aromatic ring also gave the corresponding products with high yields. Besides, halogen (3ag-3aj), ester
(3an) and boronic acid ester (3ao)-substituted products were obtained efficiently in good to excellent
yields. Moreover, naphthylamine (3ap) and alkyl amines (3aq-3ar) produced the desired acylureas in
moderate to good yields. In particular, ethanol as the nucleophile also demonstrated good reactivity (3at).
Unfortunately, secondary amines failed to react, which might be attributed to the deactivation of the
palladium catalyst caused by the enhanced coordinative ability of secondary amines.
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Scheme 3 Substrate Scope of the Carbonylation Reaction of Amine a
5 mol % Pd(OAc)2,
5 mol % 1,10-Phen
O
O
R2
R1
O
R2
+ CO +
HN
Ph
N
N
Ph
N3
THF, rt
H
R1
1a
2
3
3ag
3ah
3ai
3aj
3ak
X = 4-F, 88%
X = 4-Cl, 96%
X = 4-Br, 92%
X = 4-I, 93%
X = 2-Cl, 95%
3aa
3ac
3ad
3ae
3af
X = 4-OMe, 98%
X = 4-CF3, 90%
X = 4-Me, 82%
X = 3-Me, 94%
X = 2-Me, >98%
O
O
X
N
N
H
H
O
O
O
O
3al
X = 4-CN, >98%
N
N
Ph
3am
3an
3ao
X = 4-Ph, 75%
X = 4-COOMe, 90%
X = 4-Bpin, 75%
H
H
N
N
H
H
b
3aq
80%
3ap
64%
O
O
O
O
O
O
N
O
N
N
H
N
N
H
H
H
H
b
3as
3at
94%
65%
3ar
50%
a. Reaction conditions: 1 (0.20 mmol), 2 (0.24 mmol), Pd(OAc)2 (5 mol %), 1,10-phen (5 mol %), CO (1
atm), THF (3 mL), rt, 12h, isolated yield; b. Amine was added via syringe.
MECHANISTIC STUDY
Based on the reactions mentioned above, we found that both Pd(0) and Pd(II) could catalyze the
carbonylation reaction of acyl azides. It has been established that in literature that the carbonylation of
aryl azides could be initiated by Pd(II).5b In the study of our own research group, we also discovered that
a sulfonylurea product-derived Pd(II) complex acted as the catalytically active species to interact with the
sulfonylazide.5d In the study of Grushin research group, Pd(0)/Xantphos was found to catalyze the
aromatic azidocarbonylation, and the aroyl azide products did not undergo further Pd-catalyzed
carbonylation.7 Therefore, the observation that Pd(0) species exhibited comparable catalytic activity to
Pd(II) prompted us to investigate the reaction mechanism, in particular to figure out the real catalytic
species and the pathway of azide activation and carbonylation.
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Acyl N3
CO
N2 Acyl
N
Aniline
Isocyanate
6
7
Pd-L
OC Pd-L
Acylurea
8
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Kinetic Study: First we set out to study the kinetic behavior of reactants and catalyst in the catalytic
cycle. The reaction between benzoyl azide (1a) and aniline (2b) employing catalytic Pd(OAc)2/1,10-phen
was selected as the model reaction for kinetic study. Because the reaction under study was rather rapid,
we used relatively low concentrations (around 5 mM) of both 1a and 2b to reach a reasonable reaction
rate. LC-MS method was utilized to perform the quantitative analysis of the reaction mixture.8 The
concentration of product 3ab was followed versus time to detect the initial rate of the reaction, and the
dependence of the initial rate on different reaction components was investigated.
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It was observed that, in all kinetic profiles acquired there were a significant induction period (Figure
1a-d, ca. 2 min). The concentration of aniline (2b) had a minor effect on the initial rate of the reaction
(Figure 1a). The concentration of Pd/Ligand and benzoyl azide (1a) both had positive effects on the
reaction (Figure 1b-1c). The initial rate even exhibited first-order dependence on the concentrations of
both Pd/L and 1a (for more details, please see Part 2.2 and 2.3 of the Supporting Information). The
dependence of initial rate on CO pressure was rather intriguing. Under a low CO pressure (using CO/N2
mixture balloons with CO content varied from 50%, 66.7%, 80%, to 100%)9, a positive dependence was
observed (Figure 1d). However, under a higher CO pressure (2 atm), the reaction was inhibited and the
starting material azide 1a remained intact. These results illustrated that CO had a positive effect on the
reaction under a low pressure, but a negative effect in under a high pressure.
Furthermore, Hammett analyses of different para-substituted anilines and benzoyl azides were
performed by correlating ln(krel) with  For different para-substituted anilines, the slope of the linear
correlation () was +0.021 (Figure 1e), also suggesting that the aniline component was not involved in the
turnover-limiting step of the reaction. For different para-substituted benzoyl azides,  value of -0.305 was
obtained, further implying that azide had a significant impact on the turnover-limiting step.
Pd(OAc)2
1,10-Phen
Pd(OAc)2
1,10-Phen
CO balloon
NH2
NH2
O
O
O
O
O
O
CO balloon
+
+
Ph
N3
Ph
N3
Ph
N
N
Ph
N
N
THF, rt
THF, rt
H
H
H
H
1a
2b
3ab
1a
2b
3ab
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Pd(OAc)2
1,10-Phen
CO balloon
Pd(OAc)2
1,10-Phen
CO
NH2
NH2
O
O
O
O
O
O
+
+
Ph
N3
Ph
N3
Ph
N
N
Ph
N
N
THF, rt
THF, rt
6
H
H
H
H
1a
2b
3ab
1a
2b
3ab
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Pd(OAc)2
1,10-Phen
CO balloon
Pd(OAc)2
1,10-Phen
CO balloon
R
NH2
O
O
1
O
O
O
O
NH2
+
+
Ph
N3
N3
N
N
Ph
N
N
R
THF, rt
H
H
H
H
THF, rt
R
R
1a
2
3
2b
3
Figure 1. The initial rate kinetic data: a). The rate of different concentration of aniline; b). The rate of
different concentration of Pd/1,10-Phen; c). The rate of different concentration of benzoyl azide; d). The
rate of different ratio of CO; e). Hammett plot of amine showing the  value of ca. +0.021 (R2 = 0.97); f).
Hammett plot of benzoyl azide showing the  value of ca. -0.305 (R2 = 0.97).
Investigation into the Induction Period. The induction period existing in the reactions employing the
Pd(II)/ligand catalytic system led us to consider the possibility of precatalyst to catalyst transformation
during this period. To further investigate the actual catalytically active Pd species in the catalytic cycle,
different palladium catalysts, Pd(OAc)2 for Pd(II) and Pd2(dba)3 for Pd(0), were tested in the model
reaction, and the respective kinetic profiles in a 10 min period were acquired (Figure 2). Again, induction
period was observed with 3 mol % Pd(OAc)2/1,10-phen. When 1.5 mol % Pd2(dba)3/1,10-phen was used
instead, the induction period disappeared and higher initial rates were observed (for more details about
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different Pd catalysts, please see Part 2.7 of the Supporting Information). Based on these results, a likely
reason is that during the induction period of the Pd(II)-promoted reaction, a Pd(II) to Pd(0) transformation
occurred and Pd(0) species might act as the actual catalyst for the carbonylation reaction.
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Pd(OAc)2 or Pd2(dba)3
1,10-Phen
NH2
O
O
O
CO balloon
+
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Ph
N3
Ph
N
N
THF, rt
H
H
1a
2b
3ab
Figure 2. Reaction profile of Pd-catalyzed carbonylation.
Probing the Pd(II) to Pd(0) Transformation by XPS Measurements. Since the valence of palladium
has a marked impact on the activity of Pd-catalyzed reactions,4 it is important to verify the valance of Pd
in our catalytic system for acyl azide carbonylation. XPS (X-ray photoelectron spectroscopy)
measurements were performed with both the catalyst alone and the reaction mixtures (Figure 3).
We found that Pd(II) species (Pd(OAc)2 and PdCl2) showed peaks at 338 and 343 eV, Pd(0) species
(Pd2(dba)3) showed peaks at 336 and 341 eV. In the normal reaction catalyzed by Pd(OAc)2/1,10-phen
under CO, both Pd(II) and Pd(0) peaks could be detected (Figure 3a). However, when CO is absent, only
Pd(II) peaks could be detected, and no urea product could be observed (Figure 3b). Moreover, when
employing the PdCl2/1,10-phen/NH4OAc combination as the catalyst, the reaction proceeded well (Table
1, entry 5) and Pd(0) signals were again observed in XPS of the reaction mixture (Figure 3c). In contrast,
without acetate anion, PdCl2/1,10-phen could not catalyze the carbonylation, and only Pd(II) signals were
found (Figure 3d). These results showed that Pd(0) species was closely related to a “successful” reaction,
and thus implied that Pd(0) species, rather than Pd(II) species, acted as the actual catalyst. The Pd(II) to
Pd(0) reduction required the presence of both CO and acetate anion, and it was most possible that this
reduction process took place during the induction period of the reaction promoted by Pd(OAc)2/1,10-
phen.11
Based on the above-mentioned results, we proposed that CO was the key reductant to reduce Pd(II) to
Pd(0). To confirm this hypothesis and to investigate the oxidative product of CO, we detected the gaseous
phase of the reaction mixture employing stoichiometric amount of Pd(OAc)2 by GC-MS. It was found that
CO was the only gaseous component at the beginning, while CO2 was found when the reaction completed
(for more details, please see Part 4 of the Supporting Information). The formation of CO2 from CO
supported the hypothesis.
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Pd(OAc)2
1,10-Phen
without CO
Pd(OAc)2
1,10-Phen
CO
O
O
O
O
O
O
+
PMPNH2
+
PMP
PMPNH2
PMP
Ph
N3
Ph
N
N
Ph
N3
Ph
N
N
THF, rt
THF, rt
H
H
H
H
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PdCl2
1,10-Phen
CO
PdCl2
1,10-Phen
CO
O
O
O
O
O
O
+
PMPNH2
PMP
+
PMPNH2
PMP
Ph
N3
Ph
N
N
without NH4OAc
NH4OAc
THF, rt
Ph
N3
Ph
N
N
H
H
THF, rt
H
H
Figure 3. The XPS results of Pd-catalyzed carbonylation: a) Pd(OAc)2 + 1, 10-Phen. + CO + PhCON3 +
PMPNH2 (343, 341, 338, 336 eV, 93% yield); b) Pd(OAc)2 + 1, 10-Phen. + PhCON3 + PMPNH2 (343,
338 eV); c) PdCl2 + 1, 10-Phen. + CO + PhCON3 + PMPNH2 + NH4OAc (343, 341, 338, 336 eV, 92%
yield); d) PdCl2 + 1, 10-Phen. + CO + PhCON3 + PMPNH2 (343, 338 eV, no reaction).
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To further investigate the role of CO in the reaction, acyl azide (1a) was treated with stoichiometric
amount of Pd2(dba)3/1,10-Phen (Scheme 4). Under identical reaction conditions but in the absence of CO,
more than 95% of 1a was recovered after 24 h, which indicated that CO not only acted as a key reagent
for Pd(II) to Pd(0) reduction, but also played a vital role in the N2 releasing step. In other words, the
activation of acyl azide would not occur without the participation of CO.
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Scheme 4. The Impact of CO.
2.5 mol %. Pd2(dba)3
a)
NH2
O
5 mol % 1,10-Phen
CO balloon
+
1a
disappeared,
85% acyl urea product
Ph
N3
3aa
MeO
was obtained
THF, rt, 24 h
1a
2a
2a
b)
0.5 equiv, Pd2(dba)3
1 equiv, 1,10-Phen
NH2
O
1a
95%
recovered,
+
3aa
no acyl urea product
was detected
Ph
N3
MeO
THF, rt, 24 h
1a
Structure of the Key Pd Species. After confirming the valence of palladium and impact of CO in our
reactions, we further studied the structure of the key palladium species in the reaction. The transition-
metal-catalyzed carbonylation reactions were important transformations of azides, which were usually
catalyzed by Fe, Ni, Co, Cu, Rh, etc. In these transformations, monometallic12 and bimetallic nitrene13
complexes were two common types of key intermediates. Another type of key organometallic species was
the five-membered metallacycle, which was reported in the stoichiometric reactions of Mn(I), Mo(I) and
Os(0) complexes (Figure 4).14 However, the key Pd-containing complex in Pd-catalyzed carbonylation
reaction of azide remains unclear.
The transition metal complexes of azides
L
L
R
N
R
M3
L
X
N
L
N
M2
L
M2
L
M1
N
N
L
L
R
M3 = Mn, Mo etc., X = N, O
five-membered metallacycle
M2 = Cu, Ni, etc.
bimetallic nitrene
M1 = Fe, Ni, Co, etc.
monometallic nitrene
Figure 4. Three intermediates of transition-metal-catalyzed carbonylation of azide
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In previous works, Pd-nitrene was proposed to be an important intermediate in carbonylation reaction
of azides,5b-5d and a bimetallic Pd-nitrene complex ([Pd2Cl2(dppm)2(-NR)]) has also been reported to
generate through the reaction between Pd2Cl2(dppm)2 and azide.15 In order to distinguish whether or not
the bimetallic Pd-nitrene complex was the key species in the catalytic cycle, we performed the following
control experiments (Scheme 5). We found that, the combination of 2.5 mol % Pd2Cl2(dppm)2, 5 mol %
1,10-Phen, and 20 mol % NH4OAc, could successfully catalyze the carbonylation reaction of acyl azide
1a. In contrast, the bimetallic Pd-nitrene complex, Pd2Cl2(dppm)2(-NBz), prepared by the reaction of 1a
with Pd2Cl2(dppm)2, exhibited no catalytic activity. Even when NH4OAc was added. Therefore, we
believe that the bimetallic Pd(II)-nitrene-type complex is not a key intermediate in Pd-catalyzed
carbonylation of acyl azide reactions.
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Scheme 5. Bimetallic Pd-nitrene experiments.
NH2
2a
MeO
Pd2Cl2(dppm)
2 2.5 mol %
OMe
1,10-Phen 5 mol %
NH4OAc 20 mol %
O
O
O
Ph
N
N
Ph
N3
CO
THF, rt
77%
H
H
1a
3aa
O
NH2
Ph
Ph
Ph
N
2a
MeO
Ph
Ph
Ph
P
Pd
Cl
P
equiv)
(1
(dppm)2
Cl2
Pd2
NH4OAc (20 mol %)
CO
Pd
P
P
Ph
THF, rt,
Ph
Cl
Ph
Proposed Catalytic Cycle. Based on the results from the above experimental studies, we could draw a
simplified mechanistic picture of the palladium-catalyzed carbonylation of acyl azides (Scheme 6). First
the precatalyst, Pd(OAc)2, is reduced by CO in the presence of 1,10-phen ligand to produce the
catalytically active Pd(0) species Int-A. Coordination of the acyl azide substrate to Int-A affords
substrate-catalyst complex Int-B. Based on the fact that CO is essential for azide activation, we propose
that Int-B is transformed to a Pd-nitrene complex Int-C1 or a palladacycle complex Int-C2. Subsequent
carbonylation (insertion of CO) leads to the Pd-isocyanate complex Int-D. Ligand exchange by excess
CO releases the isocyanate product and regenerates the catalyst Int-A. Finally, nucleophilic attack of an
amine to the isocyanate affords the acyl urea product.
Scheme 6. Proposed Catalytic Cycle.
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Pd(OAc)2
CO
O
RNH2
1,10-phen
R
Acyl
N
N
H
H
7
8
9
(1,10-phen)Pd(CO)n
O=C=N-Acyl
CO
Acyl-N3
Int-A
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(1,10-phen)Pd(O=C=N-Acyl)
(1,10-phen)Pd(CO)(Acyl-N3)
Int-B
Int-D
O
N
CO
or (1,10-phen)
Pd
N
(1,10-phen)Pd
N
N-Acyl
Acyl
Int-C2
Int-C1
DFT Computational Study. To gain a deeper understanding of the carbonylation mechanism, DFT
calculations were carried out using the Gaussian 09 program package (for more details, see Part 5 of the
Supporting Information).16 The carbonylation of acetyl azide to afford acetyl isocyanate was used as the
model reaction in the calculation. We studied the potential energy surfaces of both Pd(II)- and Pd(0)-
catalyzed scenarios to further confirm the accurate catalytic species.
At the beginning, various Pd(II)-catalyzed carbonylation pathways via either monometallic or
bimetallic nitrene intermediates were calculated. However, the activation barriers, in terms of Gibbs free
energy, of these pathways were too high to be reasonable (see Part 5.1 of the Supporting Information).
These results excluded the possibility of Pd(II)-species acting as active catalysts for acyl azide
carbonylation, which is in agreement with the conclusions drawn from the experimental study.
Therefore, we set out to calculate the Pd(0)-initiated pathway. First, the reduction process of Pd(II) was
calculated (see Part 5.2 of the Supporting Information) to proceed with an activation barrier of 21.4
kcal/mol, which is reasonable for a rapid transformation.11 Subsequently, the Pd(0)/1,10-phen
intermediates with two CO ligands (complex 5), formed through the coordination of 1,10-phen to in situ
generated Pd0(CO)2, was calculated. It was found that complex 5 adopted Pd(0) configuration, in which
the C-Pd-C angle is 120.9o and two Pd-C bonds are 1.85 Å in length. Dissociation of CO from intermediate
5 generates a coordinatively unsaturated complex 6, in which the bond length between the Pd center and
CO is 1.85 Å, and 1,10-phen, Pd, and CO formed an approximate plane to provide an open space for azide
coordination. It is notable that complex 5 is thermodynamically more favorable than complex 6 in terms
of Gibbs free energy under standard conditions.
Coordination of acyl azide to the Pd center produced two different structures: 7a with the coordination
of the terminal nitrogen, and 7b with the coordination of the α-nitrogen, with 7b thermodynamically more
favorable. Following the normal N2 release mechanism of organic azides, we located transition state TS-
1c that corresponds to direct N2 elimination from complex 7b. The activation barrier of this step is 22
kcal/mol (from 7b to TS-1c), and an overall barrier is 31.5 kcal/mol (from 5 to TS-1c). Meanwhile, two
other azide activation transition states leading to five-membered palladacycles via oxidative cyclization,
TS-1a and TS-1b, were also located. TS-1a represents the C-N bond forming process between the CO
and α-nitrogen of the end-on coordinated azide, with an activation barrier of 9.9 kcal/mol; while TS-1b
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relates to the C-N bond forming process between the CO and the terminal nitrogen of the side-on
coordinated azide, with an activation barrier of 13.5 kcal/mol. In terms of overall activation barrier, TS-
1a is more favorable than TS-1b (by 2.1 kcal/mol), and TS-1c is much less favored.
6
7
8
9
The oxidative cyclization transition states lead to exergonic formation of two five-membered
palladacycle species 8a and 8b, with complex 8b being slightly more stable than 8a by 0.9 kcal/mol. In
complex 8a, the length of N(azide)-C(CO) bond is 1.46 Å, suggesting a C-N single bond character. The
Pd-C(CO) bond and Pd-N(azide) bond lengths are 1.98 and 2.00 Å, respectively. Complex 8a
subsequently releases N2 with a very low barrier (1.7 kcal/mol)17 via TS-2a to give a Pd(0) species 10
exergonically (ΔG = −56.2 kcal/mol), in which Pd-N, Pd-C and C-N bonds are 2.09, 1.99 and 1.30 Å in
length, respectively. In the last step, reductive elimination of complex 10 together with ligand exchange
with CO generates the free acetyl isocyanate and complex 6 in a thermodynamically favorable manner
(ΔG = -17.2 kcal/mol). On the other hand, the reaction path of intermediate 8b was also examined. A
transition state TS-2b corresponds to N2 elimination from complex 8b was located, which leads to Pd-
nitrene intermediate 9. Although nitrene complex 9 has the potential to undergo CO insertion to form the
desired product complex 10, this reaction pathway is thermodynamically less favorable due to the high
activation barrier of the N2 releasing step (TS-2b).
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Review the complete potential energy surface (Figure 5), the overall activation barrier for the preferred
reaction pathway (5 → 6 → 7a → TS-1a → 8a → TS-2a → 10) is 20.9 kcal/mol in terms of Gibbs free
energy. The formation of five-membered palladacycle through oxidative cyclization (TS-1a) is the
turnover-limiting step. The computational results are in agreement with our kinetic study, since a rate-
limiting oxidative cyclization step should be first order on both Pd and acyl azide. The fact that dicarbonyl
complex 5 is more stable than monocarbonyl complex 6 suggested possible inhibition of the reaction under
high [CO]. While in a low [CO] regime, positive dependence on [CO] is expected because CO is an
essential substrate for the reaction (for more details about the free energy corrections under different CO
pressures, see Part 5.3 of the Supporting Information). Indeed, both the positive dependence of the initial
rate on CO pressure and the inhibition of the reaction under high CO pressure was observed, which was
in good agreement with the DFT results. The calculation also supported the conclusion drawn from the
experimental study that Pd(0) species, rather than Pd(II) species, initiates the azide activation process.
However, in this reaction system the commonly accepted nitrene mechanism is not operable.
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N
N
N
N
G (kcal/mol)
Pd
N
N
OC
N
Pd
6
7
8
9
Ac
N
O
Ac
TS-1c
27.3
N
TS-2b
N
N
N
Pd
N
21.6
Ac
N
O
18.8
16.7
N
N
N
10
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Pd
TS-1b
OC
N
N
N
N
Pd
7a
O
N
N
Ac
N
N
Ac
6.8
8a
N
N
5.3
N
N
N
Pd
Pd
3.6
N
O
5.3
Ac
N
N
9
O
2.7
0
Ac
-1.7
-1.8
N
N
CO
TS-1a
-4.2
Pd
N
N
N
N
Pd
O
N
OC
Pd
-15.0
N
N
OC
N
-50.9
CO
N
N
Ac
TS-2a
N
N
4
Pd
Ac
7b
O
N
N
Ac
N
6
Pd
Pd
N
N
-68.1
CO
OC
N
N
O
8b
CO
Pd
5
N
N
O
Pd
Ac
N
O
C
N
C O
N
TS-3
Ac
10
Figure 5. Energy profile of the overall catalytic cycle and 3D structure of selected computed transition
states
Conclusions
In summary, we have developed a Pd-catalyzed carbonylation of acyl azides and presented a detailed
mechanistic study. The carbonylation reaction of acyl azides with excellent substrate scope provides facile
access to acyl ureas in mild conditions. Control experiments disclosed that the reaction is initiated by
Pd(0) species rather than Pd(II) species. Kinetic studies and DFT calculations showed that the isocyanate
generation step is the turnover-limiting step, N2 releasing and CO insertion occur at the same time, and a
five-membered palladacycle complex is a key intermediate. Furthermore, this Pd-catalyzed carbonylation
represents a new mechanistic model for Pd-catalyzed reaction of azide with N2 releasing process. We
anticipate more Pd-catalyzed reactions of azides could be realized under this mode.
Experimental section
Caution All these azide compounds mentioned above are potentially explosive substances. Mechanical
actions involving scratching or scraping must be avoided. In addition, all of the compounds must be
synthesized on a small scale. Manipulations must be carried out in a hood behind a safety shield. Eye
protection and latex gloves must be worn at all times.
General Information. All reactions were performed in a Schlenk reaction flask. All solvents were
purchased from Sinopharm Chemical Reagent, and THF was redistilled by sodium. The boiling point of
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petroleum ether is between 60 and 90 oC. For chromatography, 200-300 mesh silica gel (Qingdao, China)
was employed. 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz with Varian Mercury
400 spectrometer at ambient temperature. Chemical shifts are reported in ppm relative to chloroform (1H,
 7.26; 13C,  77.00), DMSO (1H,  2.50; 13C,  39.52). IR spectra were recorded with a Nicolet AVATAR
330 FT-IR spectrometer. Mass spectra were obtained on a Waters Auto Purification LC/MS system.
HMRS were obtained on a Bruker Apex IV FTMS spectrometer. All palladium catalysts were purchased
from Sigma-Aldrich. All ligands were purchased from Energy Chemical. All Acyl chlorides and amines
are commercially available.
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Typical process for synthesis of acyl azide.18 In 50 mL flask, benzoyl chloride (1406 mg, 1.161 mL,
10 mmol) solute into 15 mL of acetone, and sodium azide (780 mg, 12 mmol) was added slowly at 0 oC.
The mixture was stirred until benzoyl chloride cannot observed at TLC. And then filter for removing
sodium azide and sodium chloride, and removing acetone under reduced pressure. Finally, the residue was
purified at flash chromatography with petroleum and ethyl acetate as eluent (PE: EA = 30: 1) and obtained
benzoyl azide 1a (1351 mg, 92%).
N-((4-methoxyphenyl)carbamoyl)benzamide (3aa)19:In a Schlenk reaction flask, benzoyl azide 1a (29 mg,
0.20 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), 1, 10-phenatheroline (2 mg, 0.01 mmol), 4-methoxyaniline 2a
(30 mg, 0.24 mmol), and THF (3 ml) were added, the flask was sealed and evacuated to a vacuum of 15
mmHg and fitted with a CO balloon. The mixture was stirred at room temperature until 1a disappeared as
judged by TLC. The solution was removed under reduced pressure. The residue was then diluted with 20
ml DCM, washed with 20 ml 1M HCl, and the aqueous layer was extracted with DCM (3×20 ml). All
organic extracts were pooled, dried over MgSO4, and concentrated under reduced pressure to leave a
residue which was purified by silica gel chromatography with DCM and ethyl ethoxyethane as eluent
(DCM: Et2O = 15:1) to afford product 3aa (52 mg, 98%). White solid, m. p. = 210-211 oC, 1H NMR (400
MHz, DMSO-d6) δ 10.96 (s, 1H), 10.67 (s, 1H), 8.06 – 7.96 (m, 2H), 7.69 – 7.62 (m, 1H), 7.59 – 7.45
13
(m, 4H), 6.98 – 6.85 (m, 2H), 3.75 (s, 3H) ppm. C{1H} NMR (100 MHz, DMSO-d6) δ 168.6, 155.7,
151.1, 132.9, 132.3, 130.5, 128.5, 128.2, 121.6, 114.1, 55.2 ppm.
o
1
N-(phenylcarbamoyl)benzamide (3ab)20: white solid, 45 mg, 94%, m. p. = 194-195 C, H NMR (400
MHz, DMSO-d6) δ 11.02 (s,1H), 10.83 (s, 1H), 8.08 – 7.94 (m, 2H), 7.66 (ddd, J = 6.8, 4.0, 1.3 Hz, 1H),
7.59 (dt, J = 8.8, 1.7 Hz, 2H), 7.57 – 7.52 (m, 2H), 7.40 – 7.33 (m, 2H), 7.16 – 7.08 (m, 1H) ppm. 13C{1H}
NMR (100 MHz, DMSO-d6) δ 168.6, 151.1, 137.6, 133.0, 132.2, 128.9, 128.5, 128.2, 123.7, 119.8 ppm.
N-((4-(trifluoromethyl)phenyl)carbamoyl)benzamide (3ac): white solid, 56 mg, 90%, m. p. = 220-221 oC,
1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 11.06 (s, 1H), 8.03 (dt, J = 8.5, 1.7 Hz, 2H), 7.83 (d, J
= 8.5 Hz, 2H), 7.72 (d, J = 8.6 Hz, 2H), 7.69 – 7.64 (m, 1H), 7.58 – 7.52 (m, 2H) ppm. 13C{1H} NMR
(100 MHz, DMSO-d6) δ 168.7, 151.2, 141.4, 133.2, 132.1, 128.6, 128.3, 126.2 (q, J = 7.9 Hz), 124.4 (q,
J = 278.4 Hz), 123.6, 119.8 ppm. IR (neat) 1707, 1607, 1563, 1333, 1282, 1112, 1072, 710 cm-1. HRMS
(ESI+) m/z: [M + H] calcd for C15H12F3N2O2: 309.0845, found: 309.0849.
o
1
N-(p-tolylcarbamoyl)benzamide (3ad)19: white solid, 42 mg, 82%, m. p. = 220-221 C, H NMR (400
MHz, DMSO-d6) δ 11.01 (s, 1H), 10.77 (s, 1H), 8.08 – 7.96 (m, 2H), 7.69 – 7.61 (m, 1H), 7.58 – 7.50
(m, 2H), 7.49 – 7.42 (m, 2H), 7.25 – 7.06 (m, 2H), 2.27 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-
d6) δ 168.7, 151.1, 135.1, 133.0, 132.8, 132.3, 129.4, 128.6, 128.3, 119.8, 20.4 ppm.
N-(m-tolylcarbamoyl)benzamide (3ae): white solid, 48 mg, 94%, m. p. = 160-162 oC, 1H NMR (400 MHz,
DMSO-d6) δ 11.03 (s, 1H), 10.81 (s, 1H), 8.07 – 7.99 (m, 2H), 7.71 – 7.64 (m, 1H), 7.54 (dd, J = 10.6,
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4.8 Hz, 2H), 7.39 (d, J = 6.5 Hz, 2H), 7.26 – 7.20 (m, 1H), 6.93 (d, J = 7.7 Hz, 1H), 2.31 (s, 3H) ppm.
13C{1H} NMR (100 MHz, DMSO-d6) δ 168.8, 151.1, 138.4, 137.5, 133.1, 132.3, 128.9, 128.6, 128.3,
124.5, 120.3, 116.9, 21.2 ppm. IR (neat) 1703, 1673, 1598, 1566, 1506, 1275, 1288, 780 cm-1. HRMS
(ESI+) m/z: [M + H] calcd for C15H15N2O2: 255.1128, found: 255.1131.
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N-(o-tolylcarbamoyl)benzamide (3af)19: white solid, 51 mg, >98%, m. p. = 206-218 C, H NMR (400
MHz, DMSO-d6) δ 11.12 (s, 1H), 10.86 (s, 1H), 8.10 – 7.98 (m, 3H), 7.66 (ddd, J = 6.8, 4.0, 1.2 Hz, 1H),
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7.54 (dd, J = 10.6, 4.8 Hz, 2H), 7.28 – 7.20 (m, 2H), 7.09 – 7.02 (m, 1H), 2.32 (s, 3H) ppm. C{1H}
NMR (100 MHz, DMSO-d6) δ 169.1, 151.2, 136.1, 133.1, 132.2, 130.3, 128.6, 128.4, 127.6, 126.5, 123.9,
120.9, 17.7 ppm.
N-((4-fluorophenyl)carbamoyl)benzamide (3ag)20: white solid, 45 mg, 88%, m. p. = 200-202 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.81 (s, 1H), 8.08 – 7.94 (m, 2H), 7.73 – 7.58 (m, 3H), 7.58 –
7.48 (m, 2H), 7.26 – 7.11 (m, 2H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.6, 158.4 (d, J = 240.4
Hz), 151.3, 133.9 (d, J = 2.6 Hz), 133.0, 132.3, 128.5, 128.3, 121.9 (d, J = 6.6 Hz), 115.5 (d, J = 29.6 Hz)
ppm.
N-((4-chlorophenyl)carbamoyl)benzamide (3ah)21: white solid, 53 mg, 96%, m. p. = 232-233 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.87 (s, 1H), 8.07 – 7.96 (m, 2H), 7.70 – 7.60 (m, 3H), 7.59 –
7.49 (m, 2H), 7.41 (d, J = 8.8 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.7, 151.2, 136.7,
133.1, 132.2, 128.9, 128.6, 128.3, 127.4, 121.5 ppm.
N-((4-bromophenyl)carbamoyl)benzamide (3ai)19: white solid, 59 mg, 92%, m. p. = 233-234 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.87 (s, 1H), 8.09 – 7.95 (m, 2H), 7.71 – 7.40 (m, 7H) ppm.
13C{1H} NMR (100 MHz, DMSO-d6) δ 168.7, 151.1, 137.1, 133.1, 132.2, 131.8, 128.6, 128.3, 121.9,
115.4 ppm.
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N-((4-iodophenyl)carbamoyl)benzamide (3aj): white solid, 68 mg, 93%, m. p. = 236-238 C, H NMR
(400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.86 (s, 1H), 8.06 – 7.97 (m, 2H), 7.73 – 7.61 (m, 3H), 7.59 –
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7.49 (m, 2H), 7.49 – 7.40 (m, 2H) ppm. C{1H} NMR (100 MHz, DMSO-d6) δ 169.1, 165.8, 151.5,
138.0, 133.6, 132.7, 129.1, 128.8, 122.6, 87.8 ppm. IR (neat) 1698, 1664, 1589, 1548, 1507, 1482, 1271,
1226 cm-1. HRMS (ESI+) m/z: [M + Na] calcd C14H11IN2O2Na for: 388.9757, found: 388.9764.
N-((2-chlorophenyl)carbamoyl)benzamide (3ak)22: white solid, 52 mg, 95%, m. p. = 220-221 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.45 (s, 1H), 11.27 (s, 1H), 8.33 (dd, J = 8.3, 1.5 Hz, 1H), 8.10 – 7.97 (m, 2H),
7.69 – 7.64 (m, 1H), 7.58 – 7.51 (m, 2H), 7.41 – 7.36 (m, 1H), 7.15 (ddd, J = 8.0, 7.5, 1.6 Hz, 1H) ppm.
13C{1H} NMR (100 MHz, DMSO-d6) δ 169.1, 151.1, 134.7, 133.2, 132.0, 129.4, 128.6, 128.4, 127.9,
124.7, 122.4, 121.5 ppm.
N-((4-cyanophenyl)carbamoyl)benzamide (3al): white solid, 52 mg, >98%, m. p. = 262-263 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.18 (s, 1H), 11.07 (s, 1H), 8.03 (d, J = 7.6 Hz, 2H), 7.82 (s, 4H), 7.66 (d, J =
7.4 Hz, 1H), 7.61 – 7.51 (m, 2H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 169.1, 151.6, 142.6, 133.9,
133.7, 132.6, 129.1, 128.8, 120.4, 119.4, 105.9 ppm. IR (Neat) 1720, 1596, 1549, 1481, 1412, 1281, 1235,
759 cm-1. HRMS (ESI+) m/z: [M + H] calcd C15H12N3O2 for: 266.0923, found: 266.0922.
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N-([1,1'-biphenyl]-4-ylcarbamoyl)benzamide (3am) 20: white solid, 47 mg, 75%, m. p. = 223-235 oC, H
NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.92 (s, 1H), 8.10 – 7.98 (m, 2H), 7.74 – 7.61 (m, 7H),
7.60 – 7.51 (m, 2H), 7.50 – 7.42 (m, 2H), 7.38 – 7.30 (m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-
d6) δ 169.2, 152.1, 151.6, 140.1, 137.6, 136.0, 132.8, 129.5, 129.1, 128.8, 127.7, 126.8, 120.8 ppm.
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methyl 4-(3-benzoylureido)benzoate (3an): white solid, 54 mg, 90%, m. p. = 226-228 oC, 1H NMR (400
MHz, DMSO-d6) δ 11.15 (s, 1H), 11.08 (s, 1H), 8.03 (d, J = 7.3 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 7.74
(d, J = 8.7 Hz, 2H), 7.70 – 7.60 (m, 1H), 7.58 – 7.50 (m, 2H), 3.83 (s, 3H) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6) δ 168.7, 165.7, 151.0, 142.2, 133.2, 132.2, 130.4, 128.6, 128.3, 124.4, 119.1, 104.5, 51.9 ppm.
IR (Neat) 1664, 1606, 1577, 1464, 1448, 1281, 1173, 838 cm-1. HRMS (ESI+) m/z: [M + H] calcd
C16H15N2O4 for: 299.1032, found: 299.1024.
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N-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)benzamide (3ao): white solid, 55
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mg, 75%, m. p. = 222-224 oC, H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.98 (s, 1H), 8.02 (d, J
= 7.5 Hz, 2H), 7.70 – 7.58 (m, 5H), 7.54 (t, J = 7.6 Hz, 2H), 1.29 (s, 12H) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6) δ 169.3, 151.5, 141.0, 136.0, 133.6, 132.7, 129.1, 128.8, 119.2, 84.0, 25.2 ppm. IR (Neat)
1702, 1674, 1592, 1543, 1474, 1360, 1269, 1144 cm-1. HRMS (ESI+) m/z: [M + H] calcd C20H24BN2O4
for: 367.1827, found: 367.1829.(without reference, without spectrum)
N-(naphthalen-1-ylcarbamoyl)benzamide (3ap)19: white solid, 37 mg, 64%, m. p. = 211-213 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.54 (s, 1H), 11.29 (s, 1H), 8.20 – 8.13 (m, 1H), 8.14 – 8.09 (m, 2H), 8.09 –
8.04 (m, 1H), 8.03 – 7.95 (m, 1H), 7.81 – 7.72 (m, 1H), 7.73 – 7.65 (m, 2H), 7.64 – 7.51 (m, 3H) ppm.
13C{1H} NMR (100 MHz, DMSO-d6) δ 169.4, 151.6, 133.6, 133.2, 132.7, 132.3, 132.2, 128.7, 128.6,
128.5, 126.7, 125.9, 125.6, 124.4, 120.4, 118.1 ppm.
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N-(benzylcarbamoyl)benzamide (3aq)23: white solid, 41 mg, 80%, m. p. = 142-143 C, H NMR (400
MHz, DMSO-d6) δ 10.77 (s, 1H), 9.08 (t, J = 5.9 Hz, 1H), 8.00 – 7.87 (m, 2H), 7.66 – 7.58 (m, 1H), 7.55
– 7.47 (m, 2H), 7.37 – 7.23 (m, 5H), 4.46 (d, J = 6.0 Hz, 2H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6)
δ 168.3, 153.6, 139.2, 132.8, 132.5, 128.5, 128.4, 128.1, 127.2, 126.9, 42.7 ppm.
N-(butylcarbamoyl)benzamide (3ar)24: white solid, 22 mg, 50%, m. p. = 69-70 oC, 1H NMR (400 MHz,
DMSO-d6) δ 10.67 (s, 1H), 8.67 (t, J = 5.6 Hz, 1H), 8.00 – 7.93 (m, 2H), 7.67 – 7.57 (m, 1H), 7.56 – 7.43
(m, 2H), 3.23 (dd, J = 12.8, 6.9 Hz, 2H), 1.53 – 1.44 (m, 2H), 1.39 – 1.26 (m, 2H), 0.90 (t, J = 7.3 Hz,
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3H) ppm. C{1H} NMR (100 MHz, DMSO-d6) δ 168.2, 153.5, 132.7, 132.6, 128.5, 128.1, 38.7, 31.3,
19.6, 13.7 ppm.
N-(cyclohexylcarbamoyl)benzamide (3as)25: white solid, 46 mg, 94%, m. p. = 146-147 oC, 1H NMR (400
MHz, DMSO-d6) δ 10.68 (s, 1H), 8.67 (d, J = 7.6 Hz, 1H), 8.12 – 7.85 (m, 2H), 7.61 (dd, J = 10.8, 4.0
Hz, 1H), 7.54 – 7.41 (m, 2H), 3.73 – 3.52 (m, 1H), 1.95 – 1.14 (m, 10H) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6) δ 168.4, 152.6, 132.7, 132.6, 128.5, 128.1, 47.8, 32.3, 25.1, 24.2.
ethyl benzoylcarbamate (3at)19: white solid, 25 mg, 65%, m. p. = 89-90 oC, 1H NMR (400 MHz, DMSO-
d6) δ 10.93 (s, 1H), 8.11 – 7.73 (m, 2H), 7.67 – 7.57 (m, 1H), 7.54 – 7.33 (m, 2H), 4.18 (q, J = 7.1 Hz,
2H), 1.26 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 165.8, 151.6, 133.2, 132.5,
128.3, 128.3, 61.0, 14.2 ppm.
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4-methoxy-N-(phenylcarbamoyl)benzamide (3bb)20: white solid, 53 mg, >98%, m. p. = 216-217 C, H
NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.89 (s, 1H), 8.12 – 7.99 (m, 2H), 7.64 – 7.51 (m, 2H),
7.42 – 7.26 (m, 2H), 7.17 – 6.95 (m, 3H), 3.85 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 167.9,
163.1, 151.3, 137.7, 130.5, 129.0, 124.1, 123.7, 119.8, 113.9, 55.5 ppm.
N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide (3cb)26: white solid, 58 mg, 94%, m. p. = 220-221 oC,
1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 10.69 (s, 1H), 8.37 – 8.07 (m, 2H), 8.09 – 7.82 (m, 2H),
7.71 – 7.53 (m, 2H), 7.47 – 7.22 (m, 2H), 7.25 – 6.79 (m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-
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d6) δ 167.7, 150.8, 137.5, 136.3, 132.4 (q, J = 32.0 Hz), 129.2, 129.0, 125.5 (q, J = 3.8 Hz), 123.9, 123.7
(q, J = 272.8 Hz), 119.9 ppm.
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4-methyl-N-(phenylcarbamoyl)benzamide (3db)26: white solid, 50 mg, >98%, m. p. = 198-199 C, H
NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 9.84 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H),
7.39 – 7.33 (m, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.19 – 7.12 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 168.6,
152.2, 144.3, 137.4, 129.6, 129.4, 129.1, 128.2, 124.5, 120.5, 21.8 ppm.
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3-methyl-N-(phenylcarbamoyl)benzamide (3eb)26: white solid, 50 mg, 98%, m. p. = 167-168 oC, 1H NMR
(400 MHz, DMSO-d6) δ 10.97 (s, 1H), 10.84 (s, 1H), 7.89 – 7.77 (m, 2H), 7.65 – 7.53 (m, 2H), 7.51 –
7.39 (m, 2H), 7.38 – 7.29 (m, 2H), 7.17 – 7.00 (m, 1H), 2.38 (s, 3H) ppm. 13C{1H} NMR (100 MHz,
CDCl3) δ 168.8, 151.1, 138.0, 137.6, 132.2, 129.0, 128.8, 128.8, 128.5, 125.5, 123.7, 119.8, 20.8.
2-methyl-N-(phenylcarbamoyl)benzamide (3fb)26: white solid, 36 mg, 71%, m. p. = 167-168 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.67 (s, 1H), 7.61 – 7.56 (m, 2H), 7.54 – 7.48 (m, 2H), 7.47 –
7.40 (m, 1H), 7.39 – 7.24 (m, 4H), 7.16 – 7.06 (m, 1H), 2.41 (s, 3H) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6) δ 171.4, 150.8, 137.6, 135.9, 134.4, 130.8, 130.7, 129.0, 127.8, 125.6, 123.7, 119.7, 19.5 ppm.
4-chloro-N-(phenylcarbamoyl)benzamide (3gb)27: white solid, 54 mg, 98%, m. p. = 194-196 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.74 (s, 1H), 8.10 – 7.96 (m, 2H), 7.64 – 7.60 (m, 2H), 7.60 –
7.55 (m, 2H), 7.39 – 7.31 (m, 2H), 7.15 – 7.08 (m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ
167.7, 150.9, 137.9, 137.5, 131.2, 130.3, 129.0, 128.7, 123.8, 119.9 ppm.
4-bromo-N-(phenylcarbamoyl)benzamide (3hb): white solid, 53 mg, 83%, m. p. = 234-235 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.74 (s, 1H), 8.00 – 7.88 (m, 2H), 7.82 – 7.70 (m, 2H), 7.63 –
7.53 (m, 2H), 7.42 – 7.29 (m, 2H), 7.19 – 6.97 (m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ
167.8, 150.9, 137.6, 131.6, 130.4, 129.0, 127.0, 123.8, 119.8 ppm. IR (Neat) 1693, 1672, 1600, 1565,
1466, 1270, 1228, 1073 cm-1. HRMS (ESI+) m/z: [M + H] calcd C14H12BrN2O2 for: 319.0082, found:
319.0075.
4-iodo-N-(phenylcarbamoyl)benzamide (3ib): white solid, 37 mg, 50%, m. p. = 247-248 oC, 1H NMR (400
MHz, DMSO-d6) δ 11.10 (s, 1H), 10.74 (s, 1H), 8.05 – 7.86 (m, 2H), 7.83 – 7.75 (m, 2H), 7.67 – 7.52
(m, 2H), 7.44 – 7.27 (m, 2H), 7.24 – 6.99 (m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.2,
150.9, 137.5, 131.8, 130.1, 129.0, 123.8, 119.9, 101.5 ppm. IR (Neat) 1714, 1694, 1644, 1504, 1486, 1470,
1463, 917 cm-1. HRMS (ESI+) m/z: [M + H] calcd C14H12IN2O2 for: 366.9938, found: 366.9944.
methyl 4-((phenylcarbamoyl)carbamoyl)benzoate (3jb): white solid, 54 mg, 90%, m. p. = 208-209 oC, 1H
NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 10.70 (s, 1H), 8.15 – 8.01 (m, 4H), 7.61 – 7.50 (m, 2H),
7.41 – 7.32 (m, 2H), 7.16 – 7.06 (m, 1H), 3.90 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.0,
165.5, 150.8, 137.5, 136.4, 133.1, 129.2, 128.7, 127.8, 119.9, 52.6 ppm. IR (Neat) 1721, 1676, 1690, 1491,
1476, 1271, 1226, 1126 cm-1. HRMS (ESI+) m/z: [M + H] calcd C16H15N2O4 for: 299.1032, found:
299.1021.
4-cyano-N-(phenylcarbamoyl)benzamide (3kb)26: white solid, 52 mg, >98%, m. p. = 208-209 oC, 1H NMR
(400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.64 (s, 1H), 8.20 – 8.09 (m, 2H), 8.08 – 7.96 (m, 2H), 7.67 –
7.51 (m, 2H), 7.36 (t, J = 7.9 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-
d6) δ 168.0, 151.2, 137.9, 137.0, 133.0, 129.5, 128.7, 124.4, 120.4, 118.6, 115.5 ppm.
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N-(phenylcarbamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (3lb): white solid, 48
mg, 65%, m. p. = 218-219 oC, 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 10.76 (s, 1H), 8.01 (d, J
= 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.59 (dd, J = 8.6, 1.0 Hz, 2H), 7.42 – 7.33 (m, 2H), 7.15 – 7.07
(m, 1H), 1.32 (s, 12H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.6, 150.9, 137.6, 134.8, 134.3,
129.0, 127.6, 119.8, 104.6, 84.1, 24.7 ppm. IR (Neat) 1696, 1598, 1556, 1487, 1448, 1361, 1264, 1229
cm-1. HRMS (ESI+) m/z: [M + H] calcd C20H24BN2O4 for: 367.1827, found: 367.1815.
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N-(phenylcarbamoyl)-4-vinylbenzamide (3mb): white solid, 49 mg, 92%, m. p. = 189-190 C, H NMR
(400 MHz, DMSO-d6) δ 11.02 (s, 1H), 10.86 (s, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.61 (dd, J = 16.8, 8.0 Hz,
4H), 7.44 – 7.27 (m, 2H), 7.19 – 7.05 (m, 1H), 6.82 (dd, J = 17.5, 11.0 Hz, 1H), 6.03 (d, J = 17.7 Hz,
1H), 5.43 (d, J = 10.9 Hz, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.2, 151.1, 141.5, 137.6,
135.7, 131.3, 128.8, 126.2, 123.7, 119.8, 117.4, 104.6 ppm. IR (Neat) 1691, 1602, 1562, 1475, 1362, 1273,
1234, 1185 cm-1. HRMS (ESI+) m/z: [M + H] calcd C16H15N2O2 for: 267.1134, found: 267.1126.
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N-(phenylcarbamoyl)-2-naphthamide (3nb)28: white solid, 57 mg, 98%, m. p. = 193-194 C, H NMR
(400 MHz, DMSO-d6) δ 11.18 (s, 1H), 10.89 (s, 1H), 8.73 (s, 1H), 8.26 – 7.95 (m, 4H), 7.83 – 7.53 (m,
4H), 7.49 – 7.27 (m, 2H), 7.23 – 6.96 (m, 1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.8, 151.2,
137.7, 134.9, 131.9, 129.6, 129.5, 129.3, 129.0, 128.6, 128.3, 127.7, 127.1, 124.2, 123.8, 119.8 ppm.
2-phenyl-N-(phenylcarbamoyl)acetamide (3ob)29: white solid, 45 mg, 88%, m. p. = 154-155 oC, 1H NMR
(400 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.46 (s, 1H), 7.57 – 7.40 (m, 2H), 7.40 – 7.23 (m, 7H), 7.13 –
7.03 (m, 1H), 3.72 (s, 2H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 173.7, 150.8, 137.5, 134.4, 129.5,
129.0, 128.9, 128.4, 126.9, 119.7, 42.5 ppm.
3-phenyl-N-(phenylcarbamoyl)propanamide (3pb)30: white solid, 35 mg, 65%, m. p. = 146-147 C, H
NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 10.54 (s, 1H), 7.56 – 7.47 (m, 2H), 7.39 – 7.15 (m, 7H),
7.13 – 7.00 (m, 1H), 2.89 (t, J = 7.7 Hz, 2H), 2.71 (t, J = 7.7 Hz, 2H) ppm. 13C{1H} NMR (100 MHz,
DMSO-d6) δ 174.9, 150.8, 140.5, 137.5, 128.9, 128.4, 128.2, 126.1, 123.7, 119.6, 37.3, 29.9 ppm. IR
(Neat) 1687, 1602, 1562, 1499, 1449, 1235, 753, 697 cm-1. HRMS (ESI+) m/z: [M + H] calcd C16H17N2O2
for: 269.1284, found: 269.1289.
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N-(phenylcarbamoyl)benzo[d][1,3]dioxole-5-carboxamide (3qb)31: white solid, 43 mg, 94%, m. p. = 178-
180 oC, 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.85 (s, 1H), 7.68 (dd, J = 8.2, 1.9 Hz, 1H),
7.60 – 7.58 (m, 2H), 7.58 – 7.56 (m, 1H), 7.35 (dd, J = 8.4, 7.5 Hz, 2H), 7.13 – 7.08 (m, 1H), 7.07 (d, J
= 8.2 Hz, 1H), 6.15 (s, 2H) ppm. C{1H} NMR (100 MHz, DMSO-d6) δ 167.5, 151.4, 151.2, 147.6,
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137.6, 129.0, 125.8, 124.3, 119.8, 108.1, 102.1 ppm.
N-(phenylcarbamoyl)furan-2-carboxamide (3rb)31: white solid, 47 mg, 84%, m. p. = 204-206 oC, 1H NMR
(400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.56 (s, 1H), 8.05 (dd, J = 1.7, 0.7 Hz, 1H), 7.72 (dd, J = 3.6,
0.8 Hz, 1H), 7.62 – 7.44 (m, 2H), 7.50 – 7.19 (m, 2H), 7.24 – 6.97 (m, 1H), 6.75 (dd, J = 3.6, 1.7 Hz, 1H)
ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 158.5, 150.8, 148.0, 145.1, 137.6, 129.0, 123.7, 119.8,
117.7, 112.5 ppm.
N-(phenylcarbamoyl)benzofuran-2-carboxamide (3sb)32: white solid, 48 mg, 82%, m. p. = 234-236 C,
o
1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 10.51 (s, 1H), 8.11 (d, J = 0.9 Hz, 1H), 7.88 – 7.83 (m,
1H), 7.73 (dd, J = 8.4, 0.8 Hz, 1H), 7.61 – 7.52 (m, 3H), 7.42 – 7.33 (m, 3H), 7.16 – 7.09 (m, 1H) ppm.
13C{1H} NMR (100 MHz, DMSO-d6) δ 159.2, 154.9, 151.5, 150.5, 146.4, 137.5, 129.0, 126.7, 123.5,
123.5, 119.9, 113.2, 112.1 ppm.
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N-(phenylcarbamoyl)thiophene-2-carboxamide (3tb)33: white solid, 44 mg, 90%, m. p. = 210-211 oC, 1H
NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 10.67 (s, 1H), 8.28 (dd, J = 3.9, 1.1 Hz, 1H), 8.03 (dd, J =
5.0, 1.1 Hz, 1H), 7.74 – 7.48 (m, 2H), 7.42 – 7.28 (m, 2H), 7.25 (dd, J = 5.0, 3.9 Hz, 1H), 7.21 – 7.03 (m,
1H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 162.8, 150.9, 137.6, 137.2, 134.9, 131.9, 129.0, 128.8,
123.8, 119.9 ppm.
1-methyl-N-(phenylcarbamoyl)-1H-indole-2-carboxamide (3ub): white solid, 57 mg, >98%, m. p. = 228-
229 oC, 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 10.56 (s, 1H), 8.59 (s, 1H), 8.27 – 8.16 (m, 1H),
7.65 – 7.55 (m, 3H), 7.41 – 7.21 (m, 5H), 7.17 – 7.03 (m, 1H), 3.88 (s, 3H) ppm. 13C{1H} NMR (100
MHz, DMSO-d6) δ 165.6, 151.8, 137.9, 137.1, 135.2, 128.9, 126.8, 123.4, 122.8, 121.9, 121.1, 119.7,
110.9, 106.8, 33.5 ppm. IR (Neat) 1719, 1698, 1596, 1561, 1490, 1260, 1232, 1192 cm-1. HRMS (ESI+)
m/z: [M + H] calcd C17H16N3O2 for: 294.1242, found: 294.1233.
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N-(phenylcarbamoyl)quinoline-6-carboxamide (3vb): white solid, 55 mg, 94%, m. p. = 184-185 C, H
NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 10.81 (s, 1H), 9.06 – 9.01 (m, 1H), 8.77 (d, J = 1.6 Hz, 1H),
8.52 (d, J = 8.4 Hz, 1H), 8.27 (dd, J = 8.9, 2.0 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.3, 4.2
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Hz, 1H), 7.61 (d, J = 7.7 Hz, 2H), 7.42 – 7.31 (m, 2H), 7.21 – 7.09 (m, 1H) ppm. C{1H} NMR (100
MHz, DMSO-d6) δ 168.3, 160.4, 152.9, 151.0, 149.2, 137.6, 137.5, 130.1, 130.0, 129.3, 129.0, 127.9,
126.9, 123.8, 122.5, 119.9 ppm. IR (Neat) 1718, 1708, 1675, 1598, 1499, 1281, 1260, 1095 cm-1. HRMS
(ESI+) m/z: [M + H] calcd C17H14N3O2 for: 292.1086, found: 292.1092.
1,3-diphenylurea (3wb)5e: white solid, 40 mg, 94%, m. p. = 238-239 oC, 1H NMR (400 MHz, DMSO-d6)
δ 8.67 (s, 2H), 7.53 – 7.42 (m, 4H), 7.34 – 7.23 (m, 4H), 7.02 – 6.93 (m, 2H) ppm. 13C{1H} NMR (100
MHz, DMSO-d6) δ 152.6, 139.8, 128.9, 121.9, 118.3 ppm.
1-benzyl-3-phenylurea (3xb)5e: white solid, 16 mg, 36%, m. p. = 169-171 oC, 1H NMR (300 MHz, DMSO-
d6) δ 8.57 (s, 1H), 7.54 – 7.14 (m, 9H), 6.89 (t, J = 7.3 Hz, 1H), 6.62 (t, J = 6.0 Hz, 1H), 4.30 (d, J = 5.9
Hz, 2H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6) δ 155.2, 140.5, 140.4, 128.6, 128.3, 127.1, 126.7,
121.1, 117.7, 42.7 ppm.
ASSOCIATED CONTENT
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Supporting Information. Examination details of reaction conditions, H and C NMR spectra for
compounds, DFT calculation data and mechanism study details. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
zhangzhh@cau.edu.cn
leijiao@mail.tsinghua.edu.cn
ACKNOWLEDGMENT
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This project is supported by National Key Research and Development program of China
(2018YFD0200100) and the National Natural Science Foundation of China (No. 21672256). We
appreciate Prof. Zhiyuan Zhang and Ms. Huan Sun of National Institute of Biological Sciences (Beijing)
for LC-MS analysis support of initial rate kinetics experiments. The Tsinghua Xuetang Talents Program
are acknowledged for providing computational resources. We also acknowledge Prof. Haixiang Gao of
China Agriculture University, and Dr. Di Qiu of Tianjin Normal University for helpful discussion.
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