Ir-Catalyzed C-H Amidation Using Carbamoyl Azides for the Syntheses of Unsymmetrical Ureas

Article abstract of DOI:10.1021/acs.joc.0c00659

An iridium-catalyzed C-H amidation for the syntheses of unsymmetrical urea was developed using carbamoyl azides (R(R′)N-C(O)-N₃) as the nitrogen source. A combination of iridium and silver gave an active catalyst for C-N bond formation. A variety of urea derivatives were synthesized using carbamoyl azides with only dinitrogen byproducts. Finally, the use of the transient directing group strategy with carbamoyl azides extended the substrate scope of the catalytic C-H amidation to yield aldehyde-containing unsymmetrical ureas.

Full text of DOI:10.1021/acs.joc.0c00659

Subscriber access provided by University of Birmingham
Note
Ir-Catalyzed C-H Amidation using Carbamoyl
Azides for the Syntheses of Unsymmetrical Ureas
Kwangho Yoo, Jooyeon Lee, Myung Hwan Park, Youngjo Kim, Hyun Jin Kim, and Min Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00659 • Publication Date (Web): 09 Apr 2020
Downloaded from pubs.acs.org on April 9, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ir-Catalyzed C-H Amidation using Carbamoyl Azides for the Syntheses
of Unsymmetrical Ureas
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Kwangho Yoo,†,⊥ Jooyeon Lee,†,⊥ Myung Hwan Park,‡ Youngjo Kim,*,† Hyun Jin Kim,*,§,¶ and Min
Kim*,†
†Department of Chemistry, Chungbuk National University, Cheongju, Korea 28644
‡Department of Chemistry Education, Chungbuk National University, Cheongju, Korea 28644
§Innovative Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical
Technology (KRICT), Daejeon, Korea 34114
¶Department of New Drug Discovery and Development, Chungnam National University, Daejeon, Korea 34134
*E-mail: ykim@chungbuk.ac.kr (Y.K.), hyunjin@krict.re.kr (H.J.K.), and minkim@chungbuk.ac.kr (M.K)
Supporting Information Placeholder
O
R2
N3
N
R1
O
R2
carbamoyl azide
R1 R2
H
N
N
R1
or
H
"Ir(III) catalyst"
DG
DG
= aryl and alkyl
DG
= amide and imine
highly functionalized unsymmetrical ureas
22 examples up to 96% yields
ABSTRACT: An iridium-catalyzed C-H amidation for the syntheses of unsymmetrical ureas was developed using carbamoyl
azides (R(Rʹ)N-C(O)-N3) as the nitrogen source. A combination of iridium and silver gave an active catalyst for C-N bond
formation. A variety of urea derivatives were synthesized using carbamoyl azides with only dinitrogen byproduct. Finally, use of
the transient directing group strategy with carbamoyl azides extended the substrate scope of the catalytic C-H amidation to yield
aldehyde-containing unsymmetrical ureas.
The industrial synthetic process of urea with ammonium
O
N
NHMe
O
Et
N
H
cyanate developed by German chemist Wöhler in 1828,
provided the opportunity to apply urea to various applications.
The two nitrogens in urea functionality have provided a new
form of medicine through its ability to interact with various
proteins. In particular, recently developed anticancer agents,
anti-virus reagent, and antibiotics showed improved activity
and physical properties by introducing urea (Figure 1).1–3
Additionally, urea developed in agrochemicals are widely used
as herbicides.4,5
N
Cl
Et
NH
O
O
N
N
N
CF3
H
H
H
Me
Lisuride
Sorafenib
OMe
OMe
N
Cl
Cl
MeO
O
O
MeO
O
O
O
O
O O
N
N
N
O
Me
S
S
N
N
N
N
N
N
N
Me
N
Me
H
H
H
H
OMe
Me
Metsulfuron-methyl
Linuron
Tribenuron-methyl
Figure 1. Urea functionalities in recently developed molecules.
Recently, many groups have reported a synthetic method for
urea using transition metals (Scheme 1a).6–12 Specifically, Cu-
catalyst has been employed for formamide-type reactions with
radical initiators, while the Pd employs isocyanate
intermediates, and the iron- or ruthenium-catalyzed
preparation of unsymmetrical urea requires methanol as a
carbonyl source for double C-N bond formation. However,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 10
these methodologies require harsh conditions for efficient temperature or the iridium catalyst loading failed to produce
1
2
3
4
5
6
7
8
transformations and purification. It should also be noted that
the competing reaction, i.e., formation of the symmetrical urea,
must be suppressed to achieve selective unsymmetrical urea
derivatives. Thus, we herein describe our study into the
efficient syntheses of unsymmetrical urea derivatives from
carbamoyl azides using iridium catalysis (Scheme 1b).
greater quantities of the desired unsymmetrical urea derivative.
Two strategies were then employed to control the reactivity
of carbamoyl azides and the coordination ability of the urea
derivatives to the iridium species (Scheme 2). Both the alkyl-
substituted (2b) and the di-substituted carbamoyl azide (2c)
were prepared using the standard carbamoyl azide synthetic
route to investigate the electronic effect of the substituent (2a
and 2b) and to control the chelating ability of the nitrogen
atom (2a and 2c). Surprisingly, the desired product (3ab), was
obtained from the alkyl-substituted 2b, with an isolated yield
of ~10% being achieved. However, increasing the iridium
catalyst loading to 1 equivalent gave no improvement in the
product yield. We therefore assumed that the desired product
(3ab) and/or remaining azide (2b) could deactivate the iridium
catalyst through coordination, since the urea functionality is a
strongly coordinating bidentate ligand for metals. From the
control experiments carried out between the isolated
unsymmetrical urea (3ab) and [IrCp*Cl2]2 in a 1:1 ratio, we
note that the consumption of 3ab was confirmed by thin-layer
chromatography (TLC); however, no single adduct (e.g., an Ir-
urea complex) was obtained from the reaction mixture.
Organic azides are key nitrogen sources for a range of
transformations and heterocyclic compounds. They have
recently been utilized as an amino group source for transition
metal-catalyzed C-N bond formation. Although traditional C-
H amidation with pre-functionalization requires external
oxidants and produces equivalent byproducts such as halide
salts, the C-H amidation using azides proceeds in the absence
of oxidants and releases only dinitrogen gas as a side product
(Scheme 1b).13–16
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Catalytic strategies for urea derivative synthesis
(a) Previous metal-catalyzed unsymmetric urea synthesis
Cu-catalyzed
oxidative coupling
O
O
R1
R1
R3
R3
NH
R2
+
N
N
H
N
R4
R2 R4
Pd-catalyzed
domino reactions
O
Scheme 2. Attempted C-H amidation reactions using
carbamoyl azides
H2N R2
R1
N
C
O
R1
R2
+
N
H
N
H
(R1-I + CO + NaN3)
Fe or Ru-catalyzed
reaction with methanol
[IrCp*Cl2
AgSbF6 (10 mol%)
]
2 (5 mol%)
O
O
O
O
R2
+
H
R1
R2
N3
N
H
+
+
+
N
N
R1 NH2
HN
+
CH3OH
N
N
H
+
H
H
N
H
N
1,2-DCE, 90 oC, 24 h
H
R3
t-BuHN
t-BuHN
t-BuHN
O
t-BuHN
1a
O
R3
2a
3aa
3aa'
, 0%
, 35%
(b) The present study: Ir-catalyzed C-H amidation for unsymmterical urea synthesis
[IrCp*Cl2]2 (5 mol%)
AgNTf2 (40 mol%)
NaOAc (110 mol%)
O
O
O
O
n-Pen
Unsymmetrical Urea
O
+
n-Pen
H
H
n-Pen
n-Pen
N
N
N3
N
H
through C-H amidation
O
N
H
N
H
H
H
t-
BuHN
O
O
1,2-DCE, 90 oC, 24 h
R
O
R
+
H
N
N
R
N3
N
R
H
1a
2b
DG
DG
3ab, 21%
3ab', 26%
carbamoyl azide
[IrCp*Cl2]2 (5 mol%)
AgNTf2 (40 mol%)
NaOAc (110 mol%)
O
O
+
To date, C-H amidation based on azides have been
developed using various transition metals. Specifically, several
pioneering groups reported that Ir-,17–26 Rh-,15,27–32 and Ru-
based27,33–35 catalysts were particularly efficient in the C-H
amidation with various azides. Alkyl- and aryl azides were
converted into amine compounds,28–30 while acyl-24,33 and
sulfonyl azides18,19,21,23,36–39 were successful utilized in the
syntheses of amides and sulfonamides. Moreover,
phosphoramidates have been prepared from phosphoryl azides,
N
H
N
N3
N
N
N
t-
BuHN
1,2-DCE, 35 oC, 12 h
Ph Ph
O
1a
2c
3ac
3ac'
, 54%
, 0%
It was also found that changing the silver salt from AgSbF6
to AgNTf2 increased the conversion for the unsymmetrical
urea to 21% with 2b. However, the Curtius rearrangement
again appeared to dominate to give the symmetrical urea (3abʹ,
26%), and this undesirable reaction was promoted by
increasing either the reaction temperature or the catalyst
loading. Finally, preparation of the desired urea was achieved
using the di-substituted carbamoyl azide (2c) in a reasonable
yield (3ac, 54%), with the Curtius rearrangement being
avoided since transformation of the di-substituted carbamoyl
azide (2c) to the corresponding isocyanate was suppressed
(Scheme 2).
and
carbamate
derivatives
were
obtained
from
azidoformates.17,20,22,40
Although the transition metal-catalyzed C-H amidation is a
versatile method to construct C-N bonds in organic molecules,
preparation of the urea moiety has yet to be achieved using
organic azide chemistry. The key substrate for this
methodology, carbamoyl azide, can be prepared via a radical
pathway from the corresponding aldehyde or carboxylic
acid.41,42 Previously, carbamoyl azides have been employed for
the syntheses of amide-substituted triazoles via Cu-click
chemistry.43 Thus, using N-tert-butyl benzamide (1a) and the
phenyl-substituted carbamoyl azide (2a, Ph-NH-C(O)-N3) as
test substrates, the target C-H amidation was initially
attempted under the general conditions employed for the Ir-
catalyzed C-H amidation with acyl azides (Scheme 2).
However, no conversion to the desired urea derivatives was
observed, and the formation of a symmetrical urea (3aaʹ) via a
Curtius rearrangement between two carbamoyl azides was
confirmed. It was also found that upon increasing the reaction
Table 1. Optimization of the reaction conditionsa
Catalyst (5 mol%)
Silver salt (10 mol%)
Additive
O
O
H
N
NPh2
+
N3
NPh2
H
1,2-DCE, 35 oC, 12 h
t-BuHN
O
t-BuHN
O
1a
2c
3ac
entry catalyst
silver salt
additive
(mol%)
yield
(%)b
1
2
[IrCp*Cl2]2
[IrCp*Cl2]2
AgSbF6
AgNTf2
NaOAc (110)
NaOAc (110)
7
54
ACS Paragon Plus Environment

Page 3 of 10
The Journal of Organic Chemistry
[IrCp*Cl2]2 (5 mol%)
AgNTf2 (10 mol%)
AgOAc (20 mol%)
3
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
AgPF6
NaOAc (110)
9
O
O
H
1
N
NR2
+
N3
NR2
4
5
6
7
AgOTf
AgTFA
AgNTf2
AgNTf2
NaOAc (110)
NaOAc (110)
AgOAc (110)
AgOAc (20)
17
n.r.
94
H
1,2-DCE, 35 oC, 12 h
t-BuHN
O
2
t-BuHN
O
1a
2
3
3
4
5
6
Me
O
O
O
N
N
N
N
99
H
n-Hex
H
N
N
t-BuHN
O
(93)c
H
H
t-BuHN
O
t-BuHN
O
7
8
9
Me
8
[IrCp*Cl2]2
[IrCp*Cl2]2
-
AgNTf2
-
-
31
18% 3ab
3ac
93 3ad
,
93%,
%,
9
AgOAc (20)
AgOAc (20)
AgOAc (20)
AgOAc (20)
AgOAc (20)
AgOAc (20)
AgOAc (20)
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
t-Bu
Cl
F
O
O
O
10
11
12
13
14
15
a
AgNTf2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
H
N
N
H
N
N
N
H
Me
t-BuHN
O
t-BuHN
O
t-BuHN
O
[Ir(OMe)(cod)]2 AgNTf2
[RhCp*Cl2]2
CoCp*2PF6
CoCp2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
Me
F
F
3ae
3af
3ag
88%,
88%,
84%,
O
O
O
N
H
N
N
N
N
H
N
Pd(OAc)2
H
t-BuHN
O
Me
t-BuHN
O
t-BuHN
O
Reaction conditions: 1a (0.15 mmol, 27 mg), 2c (0.1 mmol,
24 mg), catalyst (5 mol%), silver salt (10 mol%), and additives in
1,2-DCE (0.35 mL) for 12 h at 35 °C. Yield based on H NMR
analysis of the crude reaction mixture using CH2Br2 as the
internal standard, n.r. = no reaction. Isolated yield shown in
parentheses.
3ah
3ai
3aj
83%,
86%,
87%,
b
1
O
N
H
N
c
t-BuHN
O
3ak
82%,
Subsequently, optimization of the C-H amidation was
carried out using 1a and 2c, and the results are presented in
Table 1. As outlined in the table, yields of <54% were
achieved from the combination of [IrCp*Cl2]2 with various
silver oxidants and sodium acetate, which represents the
standard conditions for Ir-catalyzed C-H amidation with other
azide sources (entries 1–5). In addition, changing the silver
salt-external additive combination to AgNTf2 and AgOAc
resulted in almost full conversion at 35 °C in 1,2-
dichloroethane (1,2-DCE) (entry 6, see also Table S1). In the
recent C-H amidation studies with tosyl azides and
azidoformates, AgNTf2 produced cationic iridium species and
catalytic amounts of silver acetate provided a dramatic
increasement of reactivity.19,22 Furthermore, decreasing the
AgOAc loading from 110 to 20 mol% gave full conversion
(>99% in NMR), whereby the product was obtained in 93%
yield following isolation by column chromatography (entry 7).
A 1.5 equivalent usage of amide substrate toward azide
displayed the best result among the ratio control (Table S2),
and the equivalent molar ratio between 1a and 2c gave a
slightly decreased isolation yield (82%). Moreover, a poor
reactivity was observed in the absence of AgOAc, and almost
no conversions to 3ac were obtained from the catalytic
condition with acetic acid or PhI(OAc)2 instead of AgOAc
(Table S1). It was found that the choice of external base and
its corresponding amount had a significant influence on the
catalytic transformation (entries 1–9). In the absence of
[IrCp*Cl2]2, the reaction failed to take place (entries 10–15).
a
Reaction conditions: 1a (0.15 mmol, 27 mg), 2 (0.1 mmol),
[IrCp*Cl2]2 (5 mol%, 4 mg), AgNTf2 (10 mol%, 4 mg), and
AgOAc (20 mol%, 3 mg) in 1,2-DCE (0.35 mL) for 12 h at 35 °C.
Isolated yields from an average of three independent experiments.
With the optimized conditions, the substrate scope was
investigated (Table 2). Again, it was found that preparation of
the unsymmetrical urea 3ab was inefficient using the mono-
substituted carbamoyl azide, while both aromatic and aliphatic
di-substituted carbamoyl azides gave good yields of the
corresponding unsymmetrical ureas, and electronic variations
on the aryl rings exhibited a negligible effect on the
conversion (3ac–3ag). Interestingly, the presence of three
different substituents on the urea derivative (3ae and 3af) gave
the desired products using the present methodology where
unsymmetrical di-substituted carbamoyl azides were
employed as the nitrogen source (2e and 2f). Furthermore,
ortho-substitution on the aryl ring of the carbamoyl azide was
tolerated (3ag, 88%), as were di-substituted carbamoyl azides,
aryl-alkyl-substituted and hetero-substituted carbamoyl azides
(2h and 2i), with the corresponding tri-substituted
unsymmetrical urea derivatives being obtained in good yields
(3ah, 83%, and 3ai, 86%). Moreover, cyclic carbamoyl azides
(2j and 2k) were also smoothly converted to afford the desired
products (i.e., 3aj, 87%, and 3ak, 82%, respectively).
Table 3. Ir-catalyzed C-H amidation using a range of
directing groups including substituted benazmidesa
Table 2. Ir-catalyzed C-H amidation using a range of
carbamoyl azidesa
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 10
[IrCp*Cl2]2 (5 mol%)
AgNTf2 (10 mol%)
AgOAc (20 mol%)
We also note that the mechanisms of the Ir-catalyzed
amination and amidation using azides have been studied and
O
R
O
R
1
2
H
N
NPh2
+
N3
NPh2
H
1,2-DCE, 35 oC, 12 h
R2
N
O
R2
N
O
3c
proposed in the literature based on computational approaches
and experimental observations.24,40 Thus, the proposed
mechanism of the present C-H amidation generally follows
those reported for Ir-catalyzed reactions (Scheme S1), where a
cyclometalated intermediate is formed from benzamide, and
subsequently, the carbamoyl azide reacts with the vacant site
on the cationic iridium species. Finally, formation of the
iridium nitrenoid species and the release of dinitrogen gas take
place via an oxidative transformation.
1
2c
3
4
5
6
7
O
O
O
O
N
NPh2
N
NPh2
N
NPh2
N
NPh2
H
H
H
H
Me
i-Pr
N
Ad
H2N
O
N
H
O
O
N
O
H
H
trace
trace
90%, 3bc
96%, 3cc
8
9
Br
F
CF3
O
O
O
O
F
N
NPh2
N
H
NPh2
N
NPh2
H
N
H
NPh2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
t-BuHN
O
The described carbamoyl azide chemistry was then applied
to the transient directing group (TDG) strategy. The TDG
strategy is an emerging research field in the area of transition
metal catalysis, and is widely utilized to solve issues related to
traditional DG, such as the pyridyl and amide groups. TDGs
are generated through reversible reactions such as imine
condensation from aldehydes and amines. Although aldehydes
coordinate poorly to transition metals, the imine could allow
for a significantly stronger and efficient chelation to allow
metal catalysis to take place. In this context, iridium catalysis
has recently been combined with sulfonyl azides using aniline-
based TDG strategies.44–46 We employed such an aniline-based
TDG using an aldehyde starting material to extend the
substrate scope and generality of the Ir-catalyzed syntheses of
unsymmetrical ureas. Starting from ortho-tolualdehyde (4a)
and 2c, the desired unsymmetrical urea bearing an aldehyde
(6ac) was successfully obtained. The aldehyde in the desired
urea derivatives was difficult to be achieved from traditional
methods and other synthetic approaches in Scheme 1a since
they utilized carbonyl reactivities. Among the various
substituted anilines examined herein, 3,5-bis(trifluoromethyl)
aniline (5a) gave the best conversion, with the desired
unsymmetrical urea being obtained in a 51% yield (Scheme 3).
The reaction was totally inefficient without TDG ligand.
t-BuHN
O
t-BuHN
O
t-BuHN
O
3dc
87%, 3ec
3fc
3gc
33%,
88%,
87%,
I
Me
Br
O
O
O
O
N
H
NPh2
N
H
NPh2
N
H
NPh2
Me
N
H
NPh2
t-BuHN
O
t-BuHN
O
t-BuHN
O
t-BuHN
O
3hc
3ic
3jc
3kc
75%,
87%,
36%,
86%,
Me
OMe
O
Ac
O
O
O
N
H
NPh2
N
H
NPh2
N
H
NPh2
t-BuHN
O
t-BuHN
t-BuHN
O
3lc
3mc
90%,
91%,
3nc
93%,
a
Reaction conditions: 1 (0.15 mmol), 2a (0.1 mmol, 24 mg),
[IrCp*Cl2]2 (5 mol%, 4 mg), AgNTf2 (10 mol%, 4 mg), and
AgOAc (20 mol%, 3 mg) in 1,2-DCE (0.35 mL) for 12 h at 35 °C.
Isolated yields obtained from an average of three independent
experiments.
The scope of the directing group (DG) was then examined
using 2c under the optimized conditions (Table 3). While a
variety of N or O-based directing groups such as pyridyl,
oxazole, ketone, ester, and oximes, had poor reactivities in the
Ir-catalyzed C-H amidation (Table S3), amide-based DG were
found to be active. Interestingly, the reactivity varied upon
altering the benzamide substituent, where simple benzamide
and N-methyl benzamide were non-reactive directing groups,
and relatively bulky N-isopropyl, N-tert-butyl, and N-
adamantyl benzamides displayed good reactivities under the
optimized conditions (3ac, 93%; 3bc, 90%; and 3cc, 96%).
The similar phenomena were observed in the rhodium-
catalyzed C-H amidation,30 and should be related with
cyclometallation and ortho-deprotonation.14 In addition,
benzamides substituted with both electron-withdrawing and
electron-donating groups gave good yields of the
corresponding products (Table 3). The para-position
functionalized benzamides generally allowed good conversion
for C-H amidation (with -F, 3ec, 87%; -CF3, 3fc, 88%; -Br,
3gc, 87%; -I, 3ic, 87%; -Me, 3lc, 91%; -OMe, 3mc, 90%; -Ac,
3nc, 93%). In case of m-substituted benzamide, perfect site-
selectivity for C-H activation were achieved, therefore a single
isomer was obtained for 3hc and 3kc. Furthermore, the ortho-
substituted carbamoyl azide afforded the desired product in a
good yield (3ag, Table 2, 88%), likely due to the steric
hindrance imparting an influence on the benzamide reagent.
Poor yields of 3dc and 3jc were obtained under the optimized
conditions using both ortho-fluoro-substituted and ortho-
methyl-substituted benzamides (33% and 36%), respectively.
Based on the good functional group tolerance of the present Ir-
catalyzed amidation, a range of tri-substituted, unsymmetrical
urea derivatives was successfully prepared following simple
purification (Tables 2 and 3).
Scheme 3. TDG strategy for the syntheses of
unsymmetrical ureas using carbamoyl azide
[IrCp*Cl2]2 (10 mol%)
AgNTf2 (40 mol%)
O
O
NH2
NH2
N
N
N3
N
+
1,2-DCE, 85 oC, 24 h
+
+
H
H
H
O
F3
C
CF3
F3
C
CF3
H
O
H
4a
2c
5a
6ac
5a
(10 mol%)
, 51%
H
C
N
F3
CF3
In conclusion, we herein presented the efficient synthetic
route to unsymmetrical urea derivatives based on Ir-catalyzed
C-H activation and C-N bond formation through the use of
unique carbamoyl azides as the nitrogen source. It was found
that the combination of iridium catalysts and silver salts was
essential to achieve high catalytic activities under mild
reaction conditions, and a wide substrate scope was observed
along with a good functional group tolerance. Finally, the
application of this methodology in the transient directing
group strategy was demonstrated using the aldehyde moiety,
and so a wider substrate scope was achieved for the more
general preparation of unsymmetrical ureas. Detail studies on
the mechanistic aspects and synthetic applications for urea
derivatives are now in progress.
EXPERIMENTAL SECTION
ACS Paragon Plus Environment

Page 5 of 10
The Journal of Organic Chemistry
General Information. All commercial reagents and
J = 8.4 Hz, 2H), 7.23 – 7.18 (m, 4H), 7.07 (t, J = 8.3 Hz, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 156.2, 140.1, 137.3, 129.4,
116.4, 116.2; IR (cm-1) 2151, 1684, 1592, 1505, 1488, 1408,
1318, 1289, 1216, 1154, 1092, 1014, 982, 897, 822, 799, 726,
702, 601, 577, 546, 518, 470, 414; HRMS (ESI) m/z [M+Na]+
Calculated for C13H8ClFN4NaO 313.0263; Found: 313.0263.
1
2
3
4
5
6
7
8
solvents were used without additional purifications. Flash
column chromatography was performed on SiO2 (400-630
mesh) and organic eluents. Proton nuclear magnetic resonance
spectra (1H NMR) were recorded on FT AM 500 (500 MHz).
In addition, 13C NMR was recorded on FT AM 500 (125 MHz)
and was fully decoupled by broad band decoupling. Known
amides (1a-1m) were prepared according to the literature
procedures.24,30,47-50 Known carbamoyl azides (2a-2c, 2h, 2j,
and 2k) were prepared according to the literature
procedures.41,43,51-53
(4-Fluoro-2-methylphenyl)(4-fluorophenyl)carbamoyl azide
(Table 2, 2g). Pale yellow liquid (528 mg, 61%); Rf = 0.2
(ethyl acetate/n-hexane, 1:20); H NMR (500 MHz, CDCl3) δ
1
7.29 – 7.27 (m, 2H), 7.21 – 7.14 (m, 3H), 7.01 – 6.95 (m, 2H)
2.20 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 156.1, 139.5,
138.6, 135.4, 130.7, 129.0, 118.2, 118.0, 114.3, 114.1, 18.0;
IR (cm-1) 2145, 1688, 1589, 1489, 1410, 1316, 1266, 1219,
1150, 1093, 1012, 982, 941, 864, 803, 726, 701, 601, 580, 522,
488; HRMS (ESI) m/z [M+Na]+ Calculated for C18H20N4NaO
331.1529; Found : 331.1528.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of Di-Substituted Carbamoyl Azide
Derivatives.43,48 For the first step (N-arylation), to a solution
of primary amine (10 mmol) in o-xylene (100 mL), aryl
bromide (1.25 equiv.), Pd(PPh3)4 (5 mol%), PPh3 (10 mol%)
o
and Cs2CO3 (3 equiv.) were added and stirred at 160 C in
heating mantle for 12 h under N2 atmosphere. After
completion (monitored by TLC), reaction solvent was
evaporated in vacuo, and the residue was purified by
chromatography in silica gel (ethyl acetate/n-hexane) to give
secondary amine product. For the second step, the obtained
secondary amine (3 mmol) and pyridine (2 equiv.) were
dissolved in DCM and triphosgene (0.5 equiv.) was slowly
Methyl(phenyl)carbamoyl azide (Table 2, 2i). Pale yellow
liquid (370 mg, 70%); Rf = 0.2 (ethyl acetate/n-hexane, 1:15);
1H NMR (500 MHz, CDCl3) δ 7.41 – 7.38 (m, 2H), 7.32 (br,
1H), 7.19 (br, 1H) 3.33 (s, 3H), 1.46 (s, 9H); 13C{1H} NMR
(125 MHz, CDCl3) δ156.4, 142.3, 129.3, 127.8, 126.7, 38.4;
IR (cm-1) 3063, 2943, 2436, 2155, 2132, 1682, 1595, 1495,
1454, 1433, 1416, 1359, 1290, 1274, 1222, 1123, 1098, 1074,
1048, 1023, 1001, 930, 809, 766, 726, 695, 674, 663, 592, 570,
527, 466; HRMS (ESI) m/z [M+Na]+ Calculated for
C8H8N4NaO 199.0590; Found: 199.0590.
o
added at 0 C. The reaction mixture was stirred at the same
temperature for 1-2 h, and allowed to warm at room
temperature. After stirring for 2 h at room temperature, the
reaction mixture was quenched 1M HCl, extracted with DCM
three times, dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was used immediately for
the next step without further purification. For the third step, to
a solution of NaN3 (0.20 g, 3 mmol) in acetone (20 mL),
carbamoyl chloride (3 mmol) was slowly added at room
temperature. After stirring for 12 h at room temperature, the
solvent was removed under reduced pressure and the residue
was partitioned between DCM and water. The organic layer
was collected, and the aqueous layer was extracted by DCM
for two times. The combined organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by chromatography in silica gel
(ethyl acetate/n-hexane) to give the desired product.
Synthesis of Unsymmetrical Urea through Ir-Catalyzed
C-H Amidation with Carbamoyl Azides. Amide reagent
(0.15 mmol), carbamoyl azide (0.1 mmol), [IrCp*Cl2]2 (4 mg,
0.005 mmol), AgNTf2 (4 mg, 0.01 mmol) and AgOAc (3 mg,
0.02 mmol) were dissolved in 1,2-dichloroethane (0.35 mL) ay
a screw capped vial with spinvane type triangular-shaped stir
bar. The reaction mixture was stirred at 35 oC in oil bath for 12
h. After completion, the reaction mixture was filtered through
a silica gel and then washed with EtOAc (3 mL x 3). Organic
solvents were removed under reduced pressure and the residue
was purified by chromatography on silica gel (n-
hexane/EtOAc or n-hexane/acetone) to give the desired
product.
N-(tert-Butyl)-2-(3-pentylureido)benzamide (Table 2, 3ab).
Di-p-tolylcarbamoyl azide (Table 2, 2d). Colorless solid
o
Colorless solid (6 mg, 18%); m.p. 172 – 174 C; Rf = 0.2
o
(440 mg, 55%); m.p. 73 – 75 C; Rf = 0.2 (ethyl acetate/n-
1
(ethyl acetate/n-hexane, 1:7); H NMR (500 MHz, CDCl3) δ
1
hexane, 1:10); H NMR (500 MHz, CDCl3) δ 7.17 (s, 8H),
10.16 (br, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.39 – 7.32 (m, 2H),
6.93 – 6.90 (td, J = 7.9, 1.1 Hz, 1H) 6.16 (br, 1H), 3.23 (t, J =
7.2 Hz , 2H), 1.58 – 1.50 (m, 2H), 1.46 (s, 9H), 1.35 – 1.31 (m,
4H), 0.93 – 0.87 (m, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
169.3, 155.5, 140.6, 132.0, 126.5, 120.9, 52.0, 40.6, 29.6, 29.0,
28.7, 22.3, 14.0; IR (cm-1) 3261, 3076, 2958, 2928, 2856, 1677,
1626, 1587, 1552, 1515, 1441, 1392, 1361, 1331, 1284, 1222,
1162, 883, 869, 746, 697, 512, 429; HRMS (ESI) m/z
[M+Na]+ Calculated for C17H27N3NaO2 328.1995; Found:
328.1995.
2.36 (s, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 156.2, 139.2,
129.7, 127.8(br), 125.5(br), 21.0; IR (cm-1) 2922, 2136, 1688,
1607, 1505, 1449, 1325, 1301, 1265, 1215, 1158, 1109, 1041,
1019, 975, 946, 890, 816, 788, 774, 754, 723, 692, 644, 609,
573, 532, 513, 498, 467; HRMS (ESI) m/z [M+Na]+
Calculated for C15H14N4NaO 289.1060; Found: 289.1059.
(4-(tert-Butyl)phenyl)(p-tolyl)carbamoyl azide (Table 2, 2e).
Yellow liquid (398 mg, 43%); Rf = 0.2 (ethyl acetate/n-hexane,
1:15); 1H NMR (500 MHz, CDCl3) δ 7.36 (t, J = 7.6 Hz, 2H),
7.28 (d, J = 9.3 Hz, 2H), 7.19 – 7.16 (m, 4H) 2.35 (s, 3H),
1.31, 1.30 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 156.2,
139.1, 129.8, 1291, 126.1(br), 126.0, 34.5, 31.3, 21.0; IR (cm-1)
2961, 2147, 1689, 1508, 1326, 1299, 1222, 1107, 1020, 979,
895, 807, 780, 757, 722, 639, 591, 558, 522; HRMS (ESI) m/z
[M+Na]+ Calculated for C18H20N4NaO 331.1529; Found:
331.1528.
1,3-Dipentylurea (side product in Scheme 2, 3ab').12
Colorless solid (5 mg, 26%); Rf = 0.2 (ethyl acetate/n-hexane,
1
1:5); H NMR (500 MHz, CDCl3) δ 3.14 (t, J = 7.2 Hz , 4H),
1.52 – 1.46 (m, 4H), 1.35 – 1.25 (m, 8H), 0.88 (t, J = 6.9 Hz,
6H); 13C{1H} NMR (125 MHz, CDCl3) δ 158.7, 40.6, 29.8,
29.0, 22.4, 14.0; IR (cm-1) 3329, 2952, 2929, 2860, 1619, 1572,
1457, 1261, 1227, 1072, 622.
(4-Chlorophenyl)(4-fluorophenyl)carbamoyl azide (Table 2,
2f). Pale yellow liquid (515 mg, 59%); Rf = 0.2 (ethyl
acetate/n-hexane, 1:15); 1H NMR (500 MHz, CDCl3) δ 7.32 (d,
N-(tert-Butyl)-2-(3,3-diphenylureido)benzamide (Table 2,
o
3ac). Colorless solid (36 mg, 93%); m.p. 167 – 169 C; Rf =
0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
Acetone-d6) δ 10.33 (br, 1H), 8.52 – 8.50 (dd, J = 8.5, 1.1 Hz,
1.34(s, 9H); 13C{1H} NMR (125 MHz Acetone-d6) δ 169.5,
1
2
3
4
5
6
7
8
1H), 7.50 – 7.48 (dd, J = 7.8, 1.6 Hz, 1H), 7.44 – 7.35 (m, 9H)
7.29 – 7.26 (m, 2H), 7.13 (br, 1H), 6.93 – 6.90 (td, J = 7.5, 1.2
Hz, 1H), 1.32 (s, 9H); 13C{1H} NMR (125 MHz, Acetone-d6)
δ 169.4, 154.3, 143.7, 141.3, 131.9, 130.2, 128.8, 128.3, 127.1,
123.0, 121.7, 120.6, 52.3, 28.9; IR (cm-1) 3306, 3064, 2965,
2927, 1877, 1663, 1647, 1598, 1585, 1544, 1513, 1491, 1444,
1389, 1359, 1324, 1287, 1222, 1164, 1072, 1048, 1024, 1003,
947, 899, 878, 836, 795, 748, 689, 656, 637, 575, 549, 518,
455, 409; HRMS (ESI) m/z [M+Li]+ Calculated for
C24H25LiN3O2 394. 2101; Found: 394.2096.
164.2, 162.2, 153.9, 142.3, 141.2, 141.1, 141.0, 136.7, 136.6,
133.0, 132.9, 132.1, 129.9, 129.3, 128.4, 127.1, 122.5, 121.9,
120.4, 119.2, 119.1, 115.6, 115.4, 52.3, 28.8, 18.1; IR (cm-1)
3290, 2967, 1663, 1642, 1602, 1586, 1547, 1487, 1443, 1363,
1307, 1220, 1148, 1093, 1011, 959, 865, 820, 800, 749, 698,
665, 595, 577, 549, 510, 480, 458, 437; HRMS (ESI) m/z
[M+Na]+ Calculated for C25H25F2N3NaO2 460.1807; Found:
460.1802.
2-(3-Benzyl-3-phenylureido)-N-(tert-butyl)benzamide
(Table 2, 3ah). Colorless solid (33 mg, 83%); m.p. 166 – 168
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
Acetone-d6) δ 10.04 (br, 1H), 8.54 – 8.52 (dd, J = 8.5, 1.1 Hz,
1H), 7.45 – 7.32 (m, 9H), 7.24 – 7.19 (m, 3H), 7.08 (br, 1H),
6.90 – 6.87 (td, J = 7.5, 1.2 Hz, 1H), 4.95 (s, 2H), 1.29(s, 9H);
13C{1H} NMR (125 MHz Acetone-d6) δ 169.5, 155.4, 142.1,
141.5, 139.9, 131.8, 130.7, 129.7, 129.1, 129.1, 128.5, 128.2,
127.9, 123.0, 121.4, 120.7, 53.6, 53.2, 28.8; IR (cm-1) 3294,
3060, 2971, 2105, 1943, 1738, 1641, 1585, 1545, 1515, 1493,
1445, 1389, 1358, 1322, 1291, 1276, 1210, 1154, 1086, 1071,
1047, 1031, 1016, 944, 910, 880, 868, 854, 820, 793, 777, 752,
734, 695, 664, 634, 586, 550, 510, 487, 458, 424; HRMS (ESI)
m/z [M+Na]+ Calculated for C25H27N3NaO2 424.1995; Found:
424.1993.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(tert-Butyl)-2-(3,3-di-p-tolylureido)benzamide (Table 2,
o
3ad). Colorless solid (39 mg, 93%); m.p. 154 – 156 C; Rf =
0.2 (ethyl acetate/n-hexane, 1:10); 1H NMR (500 MHz,
Acetone-d6) δ 10.26 (br, 1H), 8.55 – 8.53 (dd, J = 8.5, 1.1 Hz,
1H), 7.49 – 7.47 (dd, J = 7.8, 1.6 Hz, 1H), 7.38 – 7.35 (m, 2H),
7.26 – 7.20 (m, 7H), 7.11 (br, 1H), 6.91 – 6.88 (td, J = 7.7, 1.2
Hz, 1H), 2.33 (s, 6H), 1.32 (s, 9H); 13C{1H} NMR (125 MHz
Acetone-d6) δ 168.6, 153.6, 140.6, 140.4, 135.8, 131.1, 130.1,
129.8, 129.0, 128.1, 127.6, 127.4, 127.3, 125.7, 121.9, 120.6,
119.4, 51.4, 27.9, 20.1; IR (cm-1) 3304, 2963, 1650, 1586,
1504, 1442, 1363, 1317, 1292, 1221, 1104, 1019, 881, 810,
747, 691, 667, 597, 559, 509, 453, 415; HRMS (ESI) m/z
[M+Na]+ Calculated for C26H29N3NaO2 438.2152; Found:
438.2151.
N-(tert-Butyl)-2-(3-methyl-3-phenylureido)benzamide
(Table 2, 3ai). Colorless solid (28 mg, 86%); m.p. 196 – 198
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:5); 1H NMR (500 MHz,
Acetone-d6) δ 10.06 (br, 1H), 8.47 – 8.45 (dd, J = 8.5, 1.1 Hz,
1H), 7.50 – 7.44 (m, 3H), 7.38 – 7.32 (m, 4H), 7.11 (br, 1H),
6.89 – 6.85 (td, J = 7.4, 1.2 Hz, 1H), 3.29 (s, 3H), 1.32(s, 9H);
13C{1H} NMR (125 MHz Acetone-d6) δ 169.6, 155.2, 144.1,
141.6, 131.8, 130.7, 128.5, 128.2, 128.1, 122.9, 121.2, 120.6,
52.2, 37.6, 28.8; IR (cm-1) 3272, 3079, 2962, 2931, 2872, 1737,
1659, 1638, 1597, 1584, 1555, 1513, 1494, 1470, 1444, 1391,
1343, 1326, 1299, 1223, 1145, 1102, 1084, 1044, 1025, 983,
949, 881, 872, 853, 793, 778, 750, 697, 676, 665, 617, 552,
507, 461, 427, 406; HRMS (ESI) m/z [M+Na]+ Calculated for
C19H23N3NaO2 348.1682; Found: 348. 1679.
N-(tert-Butyl)-2-(3-(4-(tert-butyl)phenyl)-3-(p-
tolyl)ureido)benzamide (Table 2, 3ae). Colorless solid (41 mg,
o
88%); m.p. 169 – 171 C; Rf = 0.2 (ethyl acetate/n-hexane,
1:7); 1H NMR (500 MHz, Acetone-d6) δ 10.32 (br, 1H), 8.56 –
8.53 (m, 1H), 7.50 – 7.43 (m, 3H), 7.39 – 7.21 (m, 7H), 7.11
(br, 1H), 6.92 – 6.88 (m, 1H), 2.34 (s, 3H), 1.35 (s, 3H), 1.34
(s, 6H), 1.32 (s, 9H); 13C{1H} NMR (125 MHz Acetone-d6) δ
169.4, 154.5, 149.8, 141.5, 141.3, 141.1, 136.8, 131.9, 130.7,
129.9, 128.7, 128.7, 128.4, 128.3, 128.1, 127.3, 127.0, 126.7,
122.7, 121.5, 121.4, 120.5, 120.3, 52.2, 35.0, 31.6, 28.8, 28.8,
21.0; IR (cm-1) 3304, 2960, 1649, 1586, 1504, 1443, 1361,
1293, 1224, 1110, 1017, 881, 842, 812, 755, 690, 644, 586,
513, 456; HRMS (ESI) m/z [M+Na]+ Calculated for
C29H35N3NaO2 480.2621; Found: 480.2622.
N-(2-(tert-Butylcarbamoyl)phenyl)pyrrolidine-1-
N-(tert-Butyl)-2-(3-(4-chlorophenyl)-3-(4-
carboxamide (Table 2, 3aj). Colorless solid (26 mg, 87%);
o
1
fluorophenyl)ureido)benzamide (Table 2, 3af). Colorless solid
m.p. 206 – 208 C; Rf = 0.2 (ethyl acetate/n-hexane, 1:5); H
NMR (500 MHz, CDCl3) δ 10.18 (br, 1H), 8.40 – 8.39 (d, J =
8.5 Hz, 1H), 7.37 – 7.31 (m, 2H), 6.89 – 6.86 (td, J = 7.7, 1.0
Hz, 1H), 3.47 (t, J = 6.7 Hz, 4H), 1.95(t, J = 6.7 Hz, 4H), 1.46
(s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 169.5, 154.1,
140.9, 131.8, 126.4, 121.1, 120.5, 51.8, 45.6, 28.7, 25.5; IR
(cm-1) 3276, 3050, 2970, 2870, 2337, 1630, 1598, 1585, 1555,
1522, 1485, 1469, 1444, 1376, 1339, 1328, 1296, 1283, 1253,
1221, 1178, 1161, 1122, 1079, 1046, 977, 954, 916, 888, 872,
852, 795, 754, 721, 695, 667, 607, 575, 552, 512, 458, 425;
HRMS (ESI) m/z [M+Na]+ Calculated for C16H23N3NaO2
312.1682; Found: 312.1683.
o
(37 mg, 84%); m.p. 177 – 179 C; Rf = 0.2 (ethyl acetate/n-
1
hexane, 1:4); H NMR (500 MHz, Acetone-d6) δ 10.53 (br,
1H), 8.53 – 8.51 (dd, J = 8.5, 1.0Hz, 1H), 7.54 – 7.52 (dd, J =
7.9 1.6 Hz, 1H), 7.49 – 7.45 (m, 2H), 7.44 – 7.36 (m, 5H),
7.25 – 7.20 (m, 2H), 7.19 (br, 1H), 6.95 – 6.91 (td, J = 7.7, 1.2
Hz, 1H), 1.34(s, 9H); 13C{1H} NMR (125 MHz Acetone-d6) δ
169.5, 163.2, 154.1, 142.6, 141.3, 139.2, 132.2, 131.8, 131.3,
131.3, 130.0, 129.7, 128.4, 122.3, 121.8, 120.2, 117.3, 117.1,
52.3, 28.8; IR (cm-1) 3308, 2958, 1651, 1586, 1506, 1488,
1436, 1360, 1303, 1218, 1151, 1091, 1042, 1012, 882, 842,
823, 797, 749, 733, 698, 652, 597, 562, 542, 507, 444, 417;
HRMS (ESI) m/z [M+Na]+ Calculated for C24H23ClFN3NaO2
462.1355; Found: 462.1355.
N-(2-(tert-Butylcarbamoyl)phenyl)piperidine-1-
carboxamide (Table 2, 3ak). Colorless solid (25 mg, 82%);
o
1
N-(tert-Butyl)-2-(3-(4-fluoro-2-methylphenyl)-3-(4-
m.p. 179 – 181 C; Rf = 0.2 (ethyl acetate/n-hexane, 1:7); H
NMR (500 MHz, CDCl3) δ 10.39 (br, 1H), 8.30 – 8.29 (dd, J =
8.5, 1.0 Hz, 1H), 7.38 – 7.31 (m, 2H), 6.92 – 6.89 (td, J = 7.8,
1.2 Hz, 1H), 6.08 (br, 1H), 3.49 (t, J = 5.8 Hz, 4H), 1.65 –
1.58 (m, 6H), 1.45 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3)
δ 169.5, 154.8, 141.0, 131.8, 126.2, 121.5, 121.1, 120.7, 51.9,
44.9, 28.7, 25.7, 24.5; IR (cm-1) 3268, 2941, 2857, 1631, 1587,
1527, 1484, 1444, 1357, 1328, 1277, 1260, 1219, 1165, 1125,
fluorophenyl)ureido)benzamide (Table 2, 3ag). Colorless solid
o
(39 mg, 88%); m.p. 188 – 190 C; Rf = 0.2 (ethyl acetate/n-
1
hexane, 1:5); H NMR (500 MHz, Acetone-d6) δ 10.47 (br,
1H), 8.53 – 8.51 (dd, J = 8.5, 1.0Hz, 1H), 7.54 – 7.52 (dd, J =
7.9, 1.5 Hz, 1H), 7.45 – 7.37 (m, 2H), 7.34 (s, 4H), 7.23 – 7.21
(dd, J = 9.5, 1.0Hz, 1H), 7.19 (br, 1H), 7.16 – 7.12 (td, J = 8.5,
1.0Hz, 1H), 6.95 – 6.92 (td, J = 7.7, 1.1 Hz, 1H), 2.25 (s, 3H),
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
8H), 7.33 – 7.29 (m, 2H), 7.25 -7.23 (dd, J = 8.1, 1.2 Hz, 1H),
1023, 985, 953, 883, 747, 682, 639, 603, 541, 516; HRMS
(ESI) m/z [M+Li]+ Calculated for C17H25LiN3O2 310.2101;
Found: 310.2103.
1.33 (s, 9H); 13C{1H} NMR (125 MHz, Acetone-d6) δ 168.3,
154.3, 143.3, 141.8, 133.3, 133.1 132.8, 132.5, 130.3, 129.4,
128.8, 128.2, 127.5, 126.1, 125.9, 123.9, 117.9, 117.9, 117.9,
117.8, 117.0, 117.0, 117.0, 116.9; IR (cm-1) 3302, 2970, 1674,
1648, 1615, 1583, 1548, 1519, 1490, 1452, 1428, 1319, 1263,
1222, 1200, 1166, 1115, 1071, 956, 917, 892, 878, 834, 786,
758, 742, 694, 674, 645, 578, 537, 501, 448; HRMS (ESI) m/z
[M+H]+ Calculated for C25H25F3N3O2 456.1893; Found:
456.1892.
1
2
3
2-(3,3-Diphenylureido)-N-isopropylbenzamide (Table 3,
o
4
5
6
7
8
9
3bc). Colorless solid (33 mg, 90%); m.p. 143 – 145 C; Rf =
0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
Acetone-d6) δ 10.52 (br, 1H), 8.50 – 8.48 (d, J = 8.5 Hz, 1H),
7.55 – 7.53 (dd, J = 7.9, 1.4 Hz 1H), 7.49 (br, 1H), 7.43 – 7.35
(m, 9H), 7.29 – 7.26 (m, 2H), 6.96 – 6.92 (td, J = 7.8, 1.1 Hz,
1H), 3.99 – 3.90 (m, 1H), 1.15 (s, 3H), 1.14 (s, 3H); 13C{1H}
NMR (125 MHz Acetone-d6) δ 168.9, 154.4, 143.9, 141.6,
132.2, 130.1, 128.7, 128.1, 127.1, 121.9, 121.8, 120.8, 42.2,
22.5; IR (cm-1) 3295, 1659, 1636, 1586, 1517, 1489, 1444,
1319, 1280, 1230, 1127, 1071, 1022, 875, 754, 701, 667, 639,
575, 506, 431; HRMS (ESI) m/z [M+Na]+ Calculated for
C23H23N3NaO2 396. 1682; Found: 396. 1684.
4-Bromo-N-(tert-butyl)-2-(3,3-diphenylureido)benzamide
(Table 3, 3gc). Colorless solid (41 mg, 87%); m.p. 165 – 167
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
Acetone-d6) δ 10.51 (br, 1H), 8.83 (d, J = 2.0 Hz, 1H), 7.47 –
7.39 (m, 8H), 7.31 – 7.28 (tt, J = 6.9, 1.6 Hz, 2H) 7.25 (br,
1H), 7.10 -7.07 (dd, J = 8.4, 2.1 Hz, 1H), 1.30 (s, 9H); 13C{1H}
NMR (125 MHz, Acetone-d6) δ 168.7, 154.2, 143.4, 142.7,
130.2, 130.1, 128.8, 127.4, 125.8, 124.3, 122.9, 121.4, 52.5,
28.8; IR (cm-1) 3304, 2922, 1670, 1649, 1573, 1546, 1485,
1451, 1407, 1363, 1299, 1222, 1112, 1071, 1023, 878, 867,
820, 774, 756, 692, 673, 622, 576, 529, 507, 486, 432; HRMS
(ESI) m/z [M+H]+ Calculated for C24H25BrN3O2 466.1125;
Found: 466.1125.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-((1S,2R,5R)-Adamantan-2-yl)-2-(3,3-
diphenylureido)benzamide (Table 3, 3cc). Colorless solid (45
mg, 96%); m.p. 184 – 186 oC; Rf = 0.2 (ethyl acetate/n-hexane,
1:7); 1H NMR (500 MHz, Acetone-d6) δ 10.32 (br, 1H), 8.53 –
8.51 (dd, J = 8.5, 1.1 Hz, 1H), 7.48 – 7.34 (m, 10H), 7.30 –
7.27 (m, 2H), 6.98 (br, 1H), 6.92 – 6.89 (td, J = 7.5, 1.2 Hz,
1H), 2.09 – 2.07 (br, 3H), 2.01 – 2.00 (d, 3.0 Hz, 6H), 1.74 –
1.68 (m, 6H); 13C{1H} NMR (125 MHz Acetone-d6) δ 169.2,
154.3, 143.7, 141.2, 131.9, 130.2, 128.8, 128.2, 127.1, 123.1,
121.6, 120.4, 53.1, 41.8, 37.2, 30.4; IR (cm-1) 3309, 2902,
1649, 1585, 1515, 1488, 1442, 1358, 1299, 1227, 873, 748,
693, 638, 601, 576, 536, 498, 481, 442; HRMS (ESI) m/z
[M+Na]+ Calculated for C30H31N3NaO2 488.2308; Found:
488.2308.
5-Bromo-N-(tert-butyl)-2-(3,3-diphenylureido)benzamide
(Table 3, 3hc). Colorless solid (35 mg, 75%); m.p. 210 – 212
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
Acetone-d6) δ 10.25 (br, 1H), 8.48 (d, J = 9.0 Hz, 1H), 7.63 (d,
J = 2.4 Hz, 1H), 7.53 – 7.50 (dd, J = 9.1, 2.4 Hz, 2H) 7.44 –
7.38 (m, 8H), 7.31 -7.27 (m, 2H), 1.32 (s, 9H); 13C{1H} NMR
(125 MHz, Acetone-d6) δ 168.0, 154.2, 143.5, 140.5, 134.6,
131.0, 130.2, 128.8, 127.3, 124.8, 122.5, 113.5, 52.6, 28.8; IR
(cm-1) 3297, 2960, 1652, 1578, 1542, 1483, 1450, 1392, 1364,
1291, 1220, 1104, 892, 825, 747, 695, 687, 642, 557, 522, 455,
425, 411; HRMS (ESI) m/z [M+Na]+ Calculated for
C24H24BrN3NaO2 488.0944; Found: 488.0944.
N-(tert-Butyl)-2-(3,3-diphenylureido)-6-fluorobenzamide
(Table 3, 3dc). Colorless solid (14 mg, 33%); m.p. 166 – 168
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:5); 1H NMR (500 MHz,
Acetone-d6) δ 9.44 (br, 1H), 8.23 (d, J = 8.5, 1H), 7.44 – 7.38
(m, 8H), 7.36 – 7.28 (m, 3H), 7.17 (br, 1H), 6.77 – 6.73 (td, J
= 8.4, 0.7 Hz, 1H), 1.31 (s, 9H); 13C{1H} NMR (125 MHz,
Acetone-d6) δ 164.3, 161.5, 159.6, 154.0, 143.5, 141.9, 141.9,
132.1, 132.0, 130.3, 128.8, 127.4, 116.8, 116.8, 113.7, 113.5,
109.5, 109.4, 52.5, 28.9; IR (cm-1) 3337, 2921, 2851, 1673,
1648, 1611, 1586, 1559, 1512, 1488, 1464, 1420, 1365, 1316,
1290, 1259, 1220, 1068, 1025, 982, 877, 798, 759, 748, 694,
652, 629, 588, 560, 510, 464, 407; HRMS (ESI) m/z [M+Na]+
Calculated for C24H24FN3NaO2 428.1745; Found: 428. 1742.
N-(tert-Butyl)-2-(3,3-diphenylureido)-4-iodobenzamide
(Table 3, 3ic). Colorless solid (44 mg, 87%); m.p. 190 – 192
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
Acetone-d6) δ 10.42 (br, 1H), 9.02 (t, J = 9.0 Hz, 1H), 7.44-
7.38 (m, 8H), 7.31 – 7.27 (m, 4H) 7.23 (br, 1H), 1.30 (s, 9H);
13C{1H} NMR (125 MHz, Acetone-d6) δ 168.9, 154.2, 143.4,
142.3, 130.5, 130.2, 129.9, 129.1, 128.8, 127.4, 122.0 98.2,
52.5, 28.8; IR (cm-1) 3302, 2969, 1666, 1649, 1584, 1548,
1491, 1445, 1401, 1317, 1262, 1220, 1171, 1118, 1073, 1022,
876, 834, 778, 750, 691, 672, 641, 574, 530, 477, 429; HRMS
(ESI) m/z [M+H]+ Calculated for C24H25IN3O2 514.0986;
Found: 514.0988.
N-(tert-Butyl)-2-(3,3-diphenylureido)-4-fluorobenzamide
(Table 3, 3ec). Colorless solid (36 mg, 87%); m.p. 186 – 188
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:5); 1H NMR (500 MHz,
Acetone-d6) δ 10.72 (br, 1H), 8.41 – 8.38 (dd, J = 13.0, 2.7 Hz,
1H), 7.61 – 7.58 (dd, J = 8.8, 6.6 Hz, 1H), 7.44 – 7.38 (m, 8H),
7.31 -7.28 (m, 2H) 7.18 (br, 1H), 6.69 – 6.65 (td, J = 8.3, 2.7
Hz, 1H), 1.30 (s, 9H); 13C{1H} NMR (125 MHz, Acetone-d6)
δ 168.7, 166.0, 164.0, 154.3, 143.9, 143.8, 143.4, 130.6, 130.2,
128.8, 127.4, 118.7, 118.6, 108.1, 107.9, 107.0, 106.8, 52.4,
28.8; IR (cm-1) 3318, 2974, 1655, 1597, 1517, 1489, 1427,
1363, 1328, 1279, 1206, 1157, 1138, 1097, 1073, 1022, 991,
940, 867, 821, 776, 744, 696, 673, 641, 602, 570, 539, 478,
455; HRMS (ESI) m/z [M+H]+ Calculated for C24H25FN3O2
406.1925; Found: 406.1922.
N-(tert-Butyl)-2-(3,3-diphenylureido)-6-methylbenzamide
(Table 3, 3jc). Colorless solid (14 mg, 36%); m.p. 168 – 170
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:5); 1H NMR (500 MHz,
Acetone-d6) δ 7.92 – 7.89 (m, 1H), 7.7 (br, 1H), 7.43- 7.39 (m,
4H), 7.37- 7.34 (m, 4H), 7.30 – 7.26 (m, 2H) 6.82 (d, J = 7.6
Hz, 1H) 2.28 (s, 1H), 1.33 (s, 9H); 13C{1H} NMR (125 MHz,
Acetone-d6) δ 168.3, 154.1, 143.7, 137.4, 135.2, 130.3, 129.9,
129.3, 128.7, 127.3, 125.5, 119.7, 52.2, 29.0, 20.1; IR (cm-1)
3316, 2961, 1673, 1640, 1598, 1551, 1511, 1490, 1465, 1417,
1387, 1294, 1261, 1224, 1073, 877, 774, 757, 698, 654, 592,
563, 540, 461; HRMS (ESI) m/z [M+Na]+ Calculated for
C25H27N3NaO2 424.1955; Found: 424.1996.
N-(tert-Butyl)-2-(3,3-diphenylureido)-4-
(trifluoromethyl)benzamide (Table 3, 3fc). Colorless solid (41
mg, 88%); m.p. 175 – 177 oC; Rf = 0.2 (ethyl acetate/n-hexane,
N-(tert-Butyl)-2-(3,3-diphenylureido)-5-methylbenzamide
(Table 3, 3kc). Colorless solid (34 mg, 86%); m.p. 186 – 188
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
1
1:5); H NMR (500 MHz, Acetone-d6) δ 10.36 (br, 1H), 8.96
(d, J = 1.0 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H) 7.45 – 7.41 (m,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 10
Acetone-d6) δ 10.20 (br, 1H), 8.37 (d, J = 1.9 Hz, 1H), 7.42- (4a, 36 mg, 0.3 mmol), diphenylcarbamoylazide (2c, 36 mg,
1
2
3
4
5
6
7
8
7.35 (m, 7H), 7.32 (d, J = 9.0 Hz, 1H) 7.28-7.25 (m, 2H), 7.19
– 7.17 (dd, J = 8.6, 2.1 Hz, 1H), 7.13 (br, 1H), 2.22 (s, 3H),
1.32 (s, 9H); 13C{1H} NMR (125 MHz, Acetone-d6) δ 169.5,
154.4, 143.8, 138.8, 132.5, 131.0, 128.7, 127.0, 123.0, 120.7,
52.2, 28.9, 20.5; IR (cm-1) 3297, 2958, 1667, 1649, 1589, 1521,
1485, 1448, 1362, 1295, 1241, 1227, 1041, 816, 797, 780, 751,
690, 563, 538, 509, 457, 427; HRMS (ESI) m/z [M+H]+
Calculated for C25H28N3O2 402.2176; Found: 402.2174.
0.15 mmol), 3,5-bis(trifluoromethyl)aniline (5a, 14 mg, 0.06
mmol), [IrCp*Cl2]2 (12 mg, 0.015 mmol), AgNTf2 (23 mg,
0.06 mmol) were dissolved in 1,2-dichloroethane (0.50 mL) at
a screw capped vial with spinvane type triangular-shaped stir
bar. The reaction mixture was stirred at 85 oC in oil bath for 24
h. After completion, the reaction mixture was filtered through
a silica gel and then washed with EtOAc (3 mL x 3). Organic
solvents were removed under reduced pressure and the residue
was purified by chromatography on silica gel(n-hexane/EtOAc)
to give the desired product.
N-(tert-Butyl)-2-(3,3-diphenylureido)-4-methylbenzamide
(Table 3, 3lc). Colorless solid (36 mg, 91%); m.p. 188 – 190
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
Acetone-d6) δ 10.48 (br, 1H), 8.38 (d, J = 1.2 Hz, 1H), 7.43-
7.36 (m, 9H), 7.29 – 7.25 (m, 2H), 7.04 (br, 1H) 6.75-6.73 (m,
1H), 2.30 (s, 3H), 1.30 (s, 9H); 13C{1H} NMR (125 MHz,
Acetone-d6) δ 169.5, 154.4, 143.8, 142.3, 141.5, 130.1, 128.7,
127.1, 122.3, 121.0, 120.0, 52.2, 28.9, 21.8; IR (cm-1) 3308,
2964, 1681, 1634, 1609, 1574, 1517, 1448, 1363, 1314, 1279,
1204, 880, 822, 782, 757, 697, 646, 573, 532, 512, 448;
HRMS (ESI) m/z [M+Na]+ Calculated for C25H27N3NaO2
424.1995; Found: 424.1993.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-(2-Formyl-3-methylphenyl)-1,1-diphenylurea (Scheme 3,
o
6ac). Colorless solid (26 mg, 51%); m.p. 128 – 130 C; Rf =
0.2 (ethyl acetate/n-hexane, 1:20); 1H NMR (500 MHz,
Acetone-d6) δ 11.06 (br, 1H), 10.19 (s, 1H) 8.55 (d, J = 8.7 Hz,
1H), 7.46 – 7.39 (m, 9H), 7.33 – 7.30 (m, 2H), 6.88 (d, J = 7.4
Hz, 1H), 2.60 (s, 3H); 13C{1H} NMR (125 MHz, Acetone-d6)
δ 194.6, 154.4, 144.1, 143.8, 143.4, 136.4, 130.3, 128.8, 127.5,
124.9, 119.9, 117.9, 19.2; IR (cm-1) 1677, 1656, 1578, 1525,
1487, 1452, 1391, 1297, 1256, 1237, 1194, 1171, 1155, 1071,
1026, 824, 790, 759, 732, 702, 690, 670, 590, 545, 510, 474,
416.; HRMS (ESI) m/z [M+Na]+ Calculated for
C21H18N2NaO2 353.1260; Found: 353.1261.
N-(tert-Butyl)-2-(3,3-diphenylureido)-4-methylbenzamide
(Table 3, 3mc). Colorless solid (38 mg, 90%); m.p. 168 – 170
oC; Rf = 0.2 (ethyl acetate/n-hexane, 1:7); 1H NMR (500 MHz,
Acetone-d6) δ 10.91 (br, 1H), 8.38 (d, J = 2.6 Hz, 1H), 7.47 (d,
J = 8.8 Hz, 1H), 7.43 – 7.37 (m, 8H), 7.28 (t, J = 7.1 Hz, 2H),
6.96 (br, 1H), 6.47-6.45 (dd, J = 8.8, 2.5 Hz, 1H), 3.79 (s, 3H),
1.29 (s, 9H); 13C{1H} NMR (125 MHz, Acetone-d6) δ 169.3,
163.0, 154.5, 143.7, 130.1, 129.8, 128.8, 127.1, 114.7, 107.5,
105.1, 55.6, 52.1, 28.9; IR (cm-1) 3304, 2967, 1667, 1645,
1609, 1580, 1546, 1516, 1489, 1450, 1362, 1297, 1214, 1160,
1112, 1031, 978, 879, 832, 782, 744, 694, 667, 642, 611, 575,
539, 492, 454; HRMS (ESI) m/z [M+Na]+ Calculated for
C25H27N3NaO3 440.1945; Found: 440.1945.
ASSOCIATED CONTENT
Supporting Information
Experimental details of catalytic reactions, and characterizations
1
of the obtained materials; H and 13C NMR, FT-IR, and HR-MS.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: ykim@chungbuk.ac.kr (Y.K.)
* E-mail: hyunjin@krict.re.kr (H.J.K.)
* E-mail: minkim@chungbuk.ac.kr (M.K)
4-Acetyl-N-(tert-butyl)-2-(3,3-diphenylureido)benzamide
(Table 3, 3nc). Colorless solid (40 mg, 93%); Rf = 0.1 (ethyl
1
acetate/n-hexane, 1:4); H NMR (500 MHz, Acetone-d6) δ
10.25 (br, 1H), 9.15 (d, J = 1.7 Hz, 1H), 7.63 – 7.61 (d, J = 8.1
Hz, 1H), 7.50 – 7.48 (dd, J = 8.1, 1.7 Hz, 1H), 7.45 – 7.40 (m,
8H), 7.33 (br, 1H), 7.32 – 7.28 (m, 2H), 2.55 (s, 3H), 1.33 (s,
9H); 13C{1H} NMR (125 MHz Acetone-d6) δ 197.7, 168.6,
154.3, 143.5, 141.4, 139.9, 130.2, 128.8, 128.7, 127.3, 126.3,
120.9, 120.6, 52.5, 28.7, 26.9; IR (cm-1) 3285, 2967, 1683,
1667, 1649, 1571, 1546, 1514, 1490, 1450, 1418, 1358, 1319,
1282, 1240, 1221, 1194, 1020, 952, 899, 881, 850, 830, 757,
699, 643, 609, 578, 531, 493, 425; HRMS (ESI) m/z [M+H]+
Calculated for C26H27N3NaO3 430.2125; Found: 430.2124.
Author Contributions
The manuscript was written through contributions of all authors.
⊥These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the Basic Science Research Program
(2019R1A2C4070584) and the Science Research Center
(2016R1A5A1009405) through the National Research Foundation
of Korea (NRF) funded by the Ministry of Science and ICT. K.
Yoo and J. Lee were supported by NRF Global Ph.D. Fellowship
program (K. Yoo for 2017H1A2A1045495; J. Lee for
2019H1A2A1076014) funded by the Ministry of Education.
Procedure for the Large-Scale Ir-Catalyzed C-H
Amidation with Carbamoyl Azide. N-(tert-Butyl)benzamide
(1a, 266 mg, 1.5 mmol), diphenylcarbamoyl azide (2c, 238 mg,
1 mmol), [IrCp*Cl2]2 (40 mg, 0.05 mmol), AgNTf2 (39 mg,
0.1 mmol) and AgOAc (33 mg, 0.2 mmol) were dissolved in
1,2-dichloroethane (3.5 mL) at a screw capped vial with
spinvane type triangular-shaped stir bar. The reaction mixture
was stirred at 35 oC in oil bath for 12 h. After completion, the
reaction mixture was filtered through a silica gel and then
washed with EtOAc (15 mL x 3). Organic solvents were
removed under reduced pressure and the residue was purified
by chromatography on silica gel (ethyl acetate/n-hexane, 1:7)
to give the desired product (3ac, 352 mg, 91%).
REFERENCES
(1)
Tsopmo, A.; Ngnokam, D.; Ngamga, D.; Ayafor, J. F.;
Sterner, O. Urea Derivatives from Pentadiplandra Brazzeana. J. Nat.
Prod. 1999, 62, 1435–1436.
(2)
Kozikowski, A. P.; Zhang, J.; Nan, F.; Petukhov, P. A.;
Grajkowska, E.; Wroblewski, J. T.; Yamamoto, T.; Bzdega, T.;
Wroblewska, B.; Neale, J. H. Synthesis of Urea-Based Inhibitors as
Procedure for the Ir-Catalyzed C-H Amidation with
Carbamoyl Azide using TDG Ligand.46 ortho-Tolualdehyde
ACS Paragon Plus Environment

Page 9 of 10
The Journal of Organic Chemistry
Active Site Probes of Glutamate Carboxypeptidase II: Efficacy as
Analgesic Agents. J. Med. Chem. 2004, 47, 1729–1738.
(3) Bankston, D.; Dumas, J.; Natero, R.; Riedl, B.; Monahan,
M. K.; Sibley, R. A Scaleable Synthesis of BAY 43-9006: A Potent
Raf Kinase Inhibitor for the Treatment of Cancer. Org. Proc. Res.
Dev. 2002, 6, 777–781.
(23) Kim, J.; Chang, S. Iridium-Catalyzed Direct C-H
Amidation with Weakly Coordinating Carbonyl Directing Groups
under Mild Conditions. Angew. Chem., Int. Ed. 2014, 53, 2203–2207.
(24) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang, S. Ir(III)-
Catalyzed Mild C-H Amidation of Arenes and Alkenes: An Efficient
Usage of Acyl Azides as the Nitrogen Source. J. Am. Chem. Soc.
2013, 135, 12861–12868.
(25) Patel, P.; Chang, S. N-Substituted Hydroxylamines as
Synthetically Versatile Amino Sources in the Iridium-Catalyzed Mild
C-H Amidation Reaction. Org. Lett. 2014, 16, 3328–3331.
(26) Sun, K.; Sachwani, R.; Richert, K. J.; Driver, T. G.
Intramolecular Ir(I)-Catalyzed Benzylic C-H Bond Amination of
ortho-Substituted Aryl Azides. Org. Lett. 2009, 11, 3598–3601.
(27) Shin, K.; Ryu, J.; Chang, S. Orthogonal Reactivity of Acyl
Azides in C-H Activation: Dichotomy between C-C and C-N
Amidations Based on Catalyst Systems. Org. Lett. 2014, 16, 2022–
2025.
(28) Shin, K.; Baek, Y.; Chang, S. Direct C-H Amination of
Arenes with Alkyl Azides under Rhodium Catalysis. Angew. Chem.,
Int. Ed. 2013, 52, 8031–8036.
(29) Kim, H. J.; Ajitha, M. J.; Lee, Y.; Ryu, J.; Kim, J.; Lee, Y.;
Jung, Y.; Chang, S. Hydrogen-Bond-Assisted Controlled C-H
Functionalization via Adaptive Recognition of a Purine Directing
Group. J. Am. Chem. Soc. 2014, 136, 1132–1140.
1
2
3
4
5
6
7
8
(4)
Gallou, I. Unsymmetrical Ureas. Synthetic Methodologies
and Application in Drug Design. Org. Prep. Proced. Int. 2007, 39,
355–383.
(5)
Guan, A.; Liu, C.; Yang, X.; Dekeyser, M. Application of
the Intermediate Derivatization Approach in Agrochemical
Discovery. Chem. Rev. 2014, 114, 7079–7107.
9
(6)
Kumar, G. S.; Kumar, R. A.; Kumar, P. S.; Reddy, N. V.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Kumar, K. V.; Kantam, M. L.; Prabhakar, S.; Reddy, K. R. Copper
Catalyzed Oxidative Coupling of Amines with Formamides: A New
Approach for the Synthesis of Unsymmetrical Urea Derivatives.
Chem. Commun. 2013, 49, 6686–6688.
(7)
Chen, W. T.; Bao, W. H.; Ying, W. W.; Zhu, W. M.; Liang,
H.; Wei, W. T. Copper-Promoted Tandem Radical Reaction of 2-
Oxindoles with Formamides: Facile Synthesis of Unsymmetrical Urea
Derivatives. Asian J. Org. Chem. 2018, 7, 1057–1060.
(8)
Chen, B.; Peng, J. B.; Ying, J.; Qi, X.; Wu, X. F. A
Palladium-Catalyzed Domino Procedure for the Synthesis of
Unsymmetrical Ureas. Adv. Synth. Catal. 2018, 360, 2820–2824.
(9)
Vinogradova, E. V.; Fors, B. P.; Buchwald, S. L.
(30) Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S.
Rhodium-Catalyzed Direct C-H Amination of Benzamides with Aryl
Azides: A Synthetic Route to Diarylamines. Angew. Chem., Int. Ed.
2012, 51, 9904–9908.
Palladium-Catalyzed Cross-Coupling of Aryl Chlorides and Triflates
with Sodium Cyanate: A Practical Synthesis of Unsymmetrical Ureas.
J. Am. Chem. Soc. 2012, 134, 11132–11135.
(10) Lane, E. M.; Hazari, N.; Bernskoetter, W. H. Iron-
Catalyzed Urea Synthesis: Dehydrogenative Coupling of Methanol
and Amines. Chem. Sci. 2018, 9, 4003–4008.
(11) Kim, S. H.; Hong, S. H. Ruthenium-Catalyzed Urea
Synthesis Using Methanol as the C1 Source. Org. Lett. 2016, 18,
212–215.
(12) Krishnakumar, V.; Chatterjee, B.; Gunanathan, C.
Ruthenium-Catalyzed Urea Synthesis by N-H Activation of Amines.
Inorg. Chem. 2017, 56, 7278–7284.
(13) Shin, K.; Kim, H.; Chang, S. Transition-Metal-Catalyzed
C-N Bond Forming Reactions Using Organic Azides as the Nitrogen
Source: A Journey for the Mild and Versatile C-H Amination. Acc.
Chem. Res. 2015, 48, 1040–1052.
(14) Figg, T. M.; Park, S.; Park, J.; Chang, S.; Musaev, D. G.
Comparative Investigations of Cp*-Based Group 9 Metal-Catalyzed
Direct C-H Amination of Benzamides. Organometallics 2014, 33,
4076–4085.
(15) Park, S. H.; Kwak, J.; Shin, K.; Ryu, J.; Park, Y.; Chang, S.
Mechanistic Studies of the Rhodium-Catalyzed Direct C-H Amination
Reaction Using Azides as the Nitrogen Source. J. Am. Chem. Soc.
2014, 136, 2492–2502.
(16) Intrieri, D.; Zardi, P.; Caselli, A.; Gallo, E. Organic Azides:
“Energetic Reagents” for the Intermolecular Amination of C-H
Bonds. Chem. Commun. 2014, 50, 11440–11453.
(31) Nguyen, Q.; Sun, K.; Driver, T. G. Rh2(II)-Catalyzed
Intramolecular Aliphatic C-H Bond Amination Reactions Using Aryl
Azides as the N-Atom Source. J. Am. Chem. Soc. 2012, 134, 7262–
7265.
(32) Yu, D. G.; Suri, M.; Glorius, F. RhIII/CuII-Cocatalyzed
Synthesis of 1H-Indazoles through C-H Amidation and N-N Bond
Formation. J. Am. Chem. Soc. 2013, 135, 8802–8805.
(33) Kim, J.; Kim, J.; Chang, S. Ruthenium-Catalyzed Direct C-
H Amidation of Arenes Including Weakly Coordinating Aromatic
Ketones. Chem. Eur. J. 2013, 19, 7328–7333.
(34) Thirunavukkarasu, V. S.; Raghuvanshi, K.; Ackermann, L.
Expedient C-H Amidations of Heteroaryl Arenes Catalyzed by
Versatile Ruthenium(II) Catalysts. Org. Lett. 2013, 15, 3286–3289.
(35) Pan, C.; Abdukader, A.; Han, J.; Cheng, Y.; Zhu, C.
Ruthenium-Catalyzed C7 Amidation of Indoline C-H Bonds with
Sulfonyl Azides. Chem. Eur. J. 2014, 20, 3606–3609.
(36) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.;
Chang, S. Rhodium-Catalyzed Intermolecular Amidation of Arenes
with Sulfonyl Azides via Chelation-Assisted C-H Bond Activation. J.
Am. Chem. Soc. 2012, 134, 9110–9113.
(37) Bhanuchandra, M.; Ramu Yadav, M.; Rit, R. K.; Rao
Kuram, M.; Sahoo, A. K. Ru(II)-Catalyzed Intermolecular ortho-C-H
Amidation of Aromatic Ketones with Sulfonyl Azides. Chem.
Commun. 2013, 49, 5225–5227.
(38) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Sulfoximine
Directed Intermolecular o-C-H Amidation of Arenes with Sulfonyl
Azides. Org. Lett. 2013, 15, 1638–1641.
(39) Shi, J.; Zhou, B.; Yang, Y.; Li, Y. Rhodium-Catalyzed
Regioselective Amidation of Indoles with Sulfonyl Azides via C-H
Bond Activation. Org. Biomol. Chem. 2012, 10, 8953–8955.
(40) Kim, H.; Park, J.; Kim, J. G.; Chang, S. Synthesis of
Phosphoramidates: A Facile Approach Based on the C-N Bond
Formation via Ir-Catalyzed Direct C-H Amidation. Org. Lett. 2014,
16, 5466–5469.
(41) Marinescu, L.; Thinggaard, J.; Thomsen, I. B.; Bols, M.
Radical Azidonation of Aldehydes. J. Org. Chem. 2003, 68, 9453–
9455.
(42) Fr⊘Syen, P. One-Flask Conversion of Carboxylic Acids
into Carbamoyl Azides. Synth. Commun. 1996, 26, 4549–4561.
(43) Haldón, E.; Álvarez, E.; Carmen Nicasio, M.; Pérez, P. J.
1,2,3-Triazoles from Carbonyl Azides and Alkynes: Filling the Gap.
Chem. Commun. 2014, 50, 8978–8981.
(17) Gwon, D.; Lee, D.; Kim, J.; Park, S.; Chang, S.
Iridium(III)-Catalyzed C-H Amidation of Arylphosphoryls Leading to
a P-Stereogenic Center. Chem. Eur. J. 2014, 20, 12421–12425.
(18) Lee, D.; Kim, Y.; Chang, S. Iridium-Catalyzed Direct
Arene C-H Bond Amidation with Sulfonyl- and Aryl Azides. J. Org.
Chem. 2013, 78, 11102–11109.
(19) Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. Iridium-
Catalyzed Intermolecular Amidation of Sp3 C-H Bonds: Late-Stage
Functionalization of an Unactivated Methyl Group. J. Am. Chem. Soc.
2014, 136, 4141–4144.
(20) Zhang, T.; Hu, X.; Dong, X.; Li, G.; Lu, H. Iridium-
Catalyzed
Unreactive
C(sp3)-H
Amination
with
2,2,2-
Trichloroethoxycarbonyl Azide. Org. Lett. 2018, 20, 6260–6264.
(21) Kim, Y.; Park, J.; Chang, S. A Direct Access to 7-
Aminoindoles via Iridium-Catalyzed Mild C-H Amidation of N-
Pivaloylindoles with Organic Azides. Org. Lett. 2016, 18, 1892–1895.
(22) Kim, H.; Park, G.; Park, J.; Chang, S. A Facile Access to
Primary Alkylamines and Anilines via Ir(III)-Catalyzed C-H
Amidation Using Azidoformates. ACS Catal. 2016, 6, 5922–5929.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 10
(44) Liu, X. H.; Park, H.; Hu, J. H.; Hu, Y.; Zhang, Q. L.;
(49) Xia, Y.; Liu, Z.; Feng, S.; Zhang, Y.; Wang, J. Ir(III)-
Wang, B. L.; Sun, B.; Yeung, K. S.; Zhang, F. L.; Yu, J. Q. Diverse
ortho-C(sp2)-H Functionalization of Benzaldehydes Using Transient
Directing Groups. J. Am. Chem. Soc. 2017, 139, 888–896.
(45) Zhang, Y. F.; Wu, B.; Shi, Z. J. Ir-Catalyzed C−H
Amidation of Aldehydes with Stoichiometric/Catalytic Directing
Group. Chem. Eur. J. 2016, 22, 17808–17812.
(46) Mu, D.; Wang, X.; Chen, G.; He, G. Iridium-Catalyzed
Ortho-C(sp2)−H Amidation of Benzaldehydes with Organic Azides.
J. Org. Chem. 2017, 82, 4497–4503.
(47) Bellamy, E.; Bayh, O.; Hoarau, C.; Trecourt, F.; Queguiner,
G.; Marsais, F. Ortho-directed functionalization of arenes using
magnesate bases. Chem. Commun. 2010, 46, 7043–7045.
(48) Jiang, H.; Liu, B.; Li, Y.; Wang, A.; Huang, H. Synthesis
of Amides via Palladium-Catalyzed Amidation of Aryl Halides. Org.
Lett. 2011, 13, 1028–1031.
Catalyzed Aromatic C–H Bond Functionalization via Metal Carbene
Migratory Insertion. J. Org. Chem. 2015, 80, 223–236.
(50) Liu, Z.; Zhang, X.; Li, J.; Li, F.; Li, C.; Jia, X.; Li, J.
Exploiting the Reactivity of Isocyanide: Coupling Reaction between
Isocyanide and Toluene Derivatives Using the Isocyano Group as an
N1 Synthon. Org. Lett. 2016, 18, 4052–4055.
(51) Cai, L.; Qian, X.; Song, W.; Liu, T.; Tao, X.; Li, W.; Xie,
X. Effects of Solvent and Base on the Palladium-Catalyzed
Amination: PdCl2(Ph3P)2/Ph3P-Catalyzed Selective Arylation of
Primary Anilines with Aryl Bromides. Tetrahedron 2014, 70, 4754–
4759.
(52) Fr⊘Syen, P. One-Flask Conversion of Carboxylic Acids into
Carbamoyl Azides. Synth. Commun. 1996, 26, 4549–4561.
(53) Kametani, T.; Shio, M. Studies on the syntheses of azole
derivatives. J. Hetero. Cyclic Chem. 1971, 8, 541–544.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment