(NHC)Cu-Catalyzed Mild C-H Amidation of (Hetero)arenes with Deprotectable Carbamates: Scope and Mechanistic Studies

Article abstract of DOI:10.1021/jacs.6b07486

Primary arylamines are an important unit broadly found in synthetic, biological, and materials science. Herein we describe the development of a (NHC)Cu system that mediates a direct C-H amidation of (hetero)arenes by using N-chlorocarbamates or their sodio derivatives as the practical amino sources. A facile stoichiometric reaction of reactive copper-aryl intermediates with the amidating reagent led us to isolate key copper arylcarbamate species with the formation of a C-N bond. The use of ^tBuONa base made this transformation catalytic under mild conditions. The present (NHC)Cu-catalyzed C-H amidation works efficiently and selectively on a large scale over a range of arenes including polyfluorobenzenes, azoles, and quinoline N-oxides. Deprotection of the newly installed carbamate groups such as Boc and Cbz was readily performed to afford the corresponding primary arylamines.

Full text of DOI:10.1021/jacs.6b07486

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
(NHC)Cu-Catalyzed Mild C-H Amidation of (Hetero)Arenes with
Deprotectable Carbamates: Scope and Mechanistic Studies
Weilong Xie, Jung Hee Yoon, and Sukbok Chang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Sep 2016
Downloaded from http://pubs.acs.org on September 1, 2016
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 free 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 accessible to all
readers and 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.
Journal of the American Chemical Society 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 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
(NHC)CuꢀCatalyzed Mild C‒H Amidation of (Hetero)Arenes with
Deprotectable Carbamates: Scope and Mechanistic Studies
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
Weilong Xie,†,‡ Jung Hee Yoon,†,‡ and Sukbok Chang*,†,‡
†Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305ꢀ701, South Korea
‡Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 305ꢀ701, South Korea
ABSTRACT: Primary arylamines are an important unit broadly found in synthetic, bio, and materials science. Herein we describe
the development of a (NHC)Cu system that mediates a direct C–H amidation of (hetero)arenes by using Nꢀchlorocarbamates or
their sodio derivatives as the practical amino sources. A facile stoichiometric reaction of reactive copperꢀaryl intermediates with the
t
amidating reagent led us to isolate key copper arylcarbamate species with the formation of a C–N bond. The use of BuONa base
made this transformation catalytic under mild conditions. The present (NHC)Cuꢀcatalyzed C–H amidation works efficiently and
selectively on a large scale over a range of arenes including polyfluorobenzenes, azoles, and quinoline Nꢀoxides. Deprotection of
the newly installed carbamate groups such as Boc and Cbz was readily performed to afford the corresponding primary arylamines.
ꢀ INTRODUCTION
Functionalized arylamines are versatile compounds to show
broad utility in various fields such as organic synthesis, medicꢀ
inal chemistry, and materials science (Figure 1).1 For instance,
cefdinir is a thirdꢀgeneration antibiotic for treating infections
caused by Gram positive and negative bacteria,1c and triꢀ
phenylamines (TPA) draw interests in the field of organic
lightꢀemitting diodes (OLED).1fꢀh As a result, various preparaꢀ
tive methods have been developed for the synthesis of arylaꢀ
mines.2 Among those, whereas a tandem procedure of nitration
followed by reduction is the most conventional route,2,3 it ofꢀ
ten needs to deal with issues of selectivity and functional
tolerance. In this context, transition metalꢀcatalyzed
construction of C–N bonds has attracted a special attention.4 In
particular, Pdꢀcatalyzed Nꢀarylation of aryl (pseudo)halides is
now well established with broad applications by the
pioneering contributions of Buchwald and Hartwig.4,5 On the
other hand, as an alternative approach, direct C–H amination
of arenes has recently been scrutinized with the use of several
late transition metals such as Pd, Ru, Rh, and Ir.6 The direct
C–H amination approach has also been examined by using
firstꢀrow transition metals due to their abundance, cost
efficiency, and environmental compatibility.7 In this line,
copper has been investigated in the C–H amination that occurs
through an oxidative coupling pathway8 as well as in the
conventional nucleophilic amination.9
Figure 1. Selected examples of arylamines in applications.
acyl hydroxylamine derivatives were also shown to be an effiꢀ
cient aminating source in the C–H amination by the action of
several metal catalysts including Pd,12aꢀd Rh,12e Co,12f or Cu.12gꢀ
h Su et al. proved that electronꢀdeficient anilines can be directꢀ
ly reacted with (hetero)arenes by copper catalyst in the presꢀ
ence of TEMPO and alkoxide base under aerobic oxidative
conditions to afford secondary diraylamines (Scheme 1a: botꢀ
tom).13 We previously showed that silver, cobalt, or mangaꢀ
nese species can effectively mediate a nonꢀdirected C–H amiꢀ
nation of azoles.14 Detailed mechanistic studies of these reacꢀ
tions revealed that they involve an oxidative rearomatization
process as a key element, thus giving rise to difficulty in exꢀ
panding the substrate scope beyond azoles.15
Recently, Miura et al. introduced secondary chloroamines
as a highly efficient electrophilic aminating source for the
copperꢀcatalyzed C–H amination of azoles (Scheme 1a: top).10
Those amino precursors were subsequently utilized in the Rhꢀ
or Feꢀcatalyzed orthoꢀamination of arenes.11 In addition, Oꢀ
Continuing our interests in the direct C–H amination
reactions,16 we herein present the development of (NHC)Cuꢀ
catalyzed C–H amidation of (hetero)arenes by using Nꢀ
chlorocarbamates or their sodio derivatives as the practical
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 11
1
2
3
4
5
6
7
amino sources. Stoichiometric studies to fully characterize two
Scheme 2. Synthesis of Reactive CopperꢀAryl Complexes
key copper intermediates led us to optimize mild catalytic
conditions that were successfully applied to various substrates
including fluoroarenes, azoles, and quinoline Nꢀoxides. Facile
deprotection of initially introduced carbamate groups readily
delivered primary arylamines.
Mes
Mes
F
F
N
N
i) tBuONa, RT, 1 h
Cu Cl
Cu
R
ii) Polyfluorobenzene
RT, 1 h
N
N
F
F
Mes
Mes
8
9
(Mes = 2,4,6ꢀC6Me3H2)
2a (R = F, 70%)
2b
Scheme 1. CuꢀCatalyzed C–H Amination of (Hetero)arenes
1a
(R = H, 85%)
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
Figure 2. ORTEP of 2a with thermal ellipsoids set at 50% probaꢀ
bility level (H atoms and benzene solvent are omitted for clarity).
Selected bond lengths (Å) and angles (deg): Cu1−C1, 1.888(6);
Cu1−C12, 1.907(6); C1−Cu1−C12, 180.0.
Scheme 3. Stoichiometric C−N Bond Formation
F
Mes
F
F
THF
Mes
F
F
N
ꢀ78 to 25 o
C
Na
Cl
N
Cu
N
+
Cu
N
F
N
12 h
63%
Boc
N
F
F
Mes
O
O
Mes
3
tBu
(Mes = 2,4,6ꢀC6Me3H2)
ꢀ RESULTS AND DISCUSSIONS
2a
4
Stoichiometric Amidation: Characterization of Key Copꢀ
per Intermediates. Recently, Nꢀheterocyclic carbene (NHC)ꢀ
copper complexes have been fruitfully utilized in various imꢀ
portant catalytic reactions.17 Along with this methodology
development, detailed mechanistic investigations have been
made mainly by the characterization of key intermediates
bearing NHC as a stabilizing ligand.18 Inspired by the Nolan
and Hou’s independent studies,19,20 we recently reported a
(NHC)Cuꢀcatalyzed C–H allylation and homoallylation of
polyfluoroarenes or heteroarenes.21 Subsequently, we were
curious if a similar catalyst system of (NHC)Cu can also be
applied to the direct C–H amination of (hetero)arenes.
We decided to initiate this perspective program first by
figuring out key plausible intermediates in a stoichiometric
transformation to see whether the envisioned C–H amination
would indeed be feasible. We, therefore, attempted the
characterization of a (NHC)Cuꢀaryl species that would serve
as a precursor in a subsequent C–N bond formation.
Figure 3. ORTEP of 4 with thermal ellipsoids set at 50% probaꢀ
bility level (H atoms are omitted for clarity). Selected bond
lengths (Å) and angles (deg): Cu1−C1, 1.8720(13); Cu1−N3,
1.8742(11); C1−N1, 1.3609(19); C1−N2, 1.3594(18); N3−C22,
1.3529(18); C1−Cu1−N3, 173.53(6); N1−C1−Cu1, 128.15(11);
N2−C1−Cu1, 127.55(11).
2
ACS Paragon Plus Environment

Page 3 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
A NHCꢀbound copper complex, [(IMes)CuCl] [1a, IMes =
N,N’ꢀbis(2,4,6ꢀtrimethylphenyl)imidazolꢀ2ꢀylidene] was
the complex 2a, and the Cu–N bond length is slightly longer
than the reported Cu–N distance in copper anilido complex
[1.846(2) Å].23 The angle of C1−Cu1−N3 is 173.53(6)o, only
slightly distorted from the linearity. Interestingly, weak interꢀ
actions of C–H———F–C and C–H———O=C were displayed from
the crystal packing of this complex (see Table S14 in the
Supporting Information for details). To our best knowledge,
this copper complex [(IMes)CuꢀN(Boc)(2,3,5,6ꢀC6F4H)] (4) is
the firstly characterized copper species obtained from a
copper-mediated C–N bond forming-process.
treated with sodium tertꢀbutoxide (1.0 equiv) in benzene and
then 1.0 equiv of pentafluorobenzene was added at room
temperature (Scheme 2). The reaction was completed within 2
h to afford a new copper species that was isolated (70%) and
its structure was determined by NMR to be [(IMes)Cuꢀ(C6F5)]
(2a). Similarly, an analogous copperꢀaryl species, [(IMes)Cuꢀ
(2,3,5,6ꢀC6F4H)] (2b) could be isolated in 85% yield by
employing 1,2,4,5ꢀtetrafluorobenzene in THF solvent.
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
Pleasingly, the molecular structure of 2a was confirmed by
an Xꢀray crystallographic analysis to display that this copper
complex is monomeric (Figure 2). The angle of CNHC–Cu–Caryl
bonds is 180.0o to indicate that the bonding configuration is
completely linear. Bond lengths of Cu–CNHC and Cu–Caryl are
1.888(6) and 1.907(6) Å, respectively. The Cu–Caryl bond in
this complex turns out to be shorter when compared to that of
Cu–Caryl in a previously reported tetrameric pentafluorophenyl
copper species [1.962(2) to 2.007(2) Å],22a but slightly longer
than that of a pentafluorophenyl copperꢀpyridine complex
[1.8913(17) Å].22b The Cu–Caryl bond length in complex 2a is
similar to that in a dimeric complex of (4ꢀmethoxyꢀ2,3,5,6ꢀ
tetraꢀfluorophenyl)copperꢀphenanthroline reported by the
Daugulis group, where the corresponding bond length is
1.932(2) Å.19d It should be noted that the complex 2a represents
the first example of structurally characterized NHC-bound copper
polyfluoroaryl species to our best knowledge. In fact, while
polyfluoroarenes are known to readily react with (NHC)Cu
complexes to afford the corresponding copperꢀaryl species
which were proposed as the key intermediate in a number of
NꢀChoroꢀN-sodioꢀcarbamates as the Practical Amidating
Reagent. The above stoichiometric reactions demonstrated
that copperꢀaryl complexes, generated from copperꢀmediated
C–H activation of (hetero)arenes, readily react with Nꢀchloroꢀ
Nꢀsodioꢀtertꢀbutylcarbamate (3) forming a new C–N bond.
This result led us to anticipate that the development of a direct
C–H amination with the (NHC)Cu system would be highly
feasible. First, we tried to establish a preparative procedure of
the amidating precursor. While we recently reported a Rhꢀ
catalyzed Cꢀ8 amidation of quinoline Nꢀoxides by using Nꢀ
chlorocarbamates,24 these amino presursors are often difficult
to handle because of troublesome physical properties (e.g.,
tertꢀbutyl chlorocarbamates: m.p. 39 oC24).
In this text, we desired to employ a more convenient and
practical type of amino sources for the C–H amination.
Previously, it was reported that NꢀchloroꢀNꢀsodioꢀtertꢀ
butylcarbamate was readily prepared by the reaction of tertꢀ
t
butylcarbamate (BocꢀNH2) with BuOCl followed by treating
with NaOH/MeOH.25 In our case, the same product could be
obtained in high yield by a reaction of BocꢀNH2 with
trichloroisocyanuric acid (TCCA) followed by a treatment
with NaOH/MeOH (Scheme 4). It should be mentioned that
trichloroisocyanuric acid is cheap and the byproduct
(isocyanuric acid) is nonꢀtoxic. This reaction could be
performed on a large scale to produce NꢀchloroꢀNꢀsodioꢀtertꢀ
butylcarbamate (3). The isolation process is also easy: a
conventional workup provides the analytically pure solid
product in high yield (see the Supporting Information for
details). Importantly, NꢀchloroꢀNꢀsodioꢀtertꢀbutylcarbamate (3)
is convenient to handle and stable to store without decomposiꢀ
tion for a few months at ꢀ20 oC.
reactions,19a,20a,b,21
these
species
have
not
been
crystallographically characterized while {(IPr)Cu[C6H4(4ꢀ
OMe)]} complex obtained from a reaction of [(IPr)Cu(OtBu)]
with arylboronic ester was known [IPr = N,N’ꢀbis(2,6ꢀ
diisopropylphenyl)imidazolꢀ2ꢀylidene]. 18b
With these isolated copperꢀaryl complexes [(NHC)CuꢀArF]
in hand, we next examined the feasibility of a copperꢀmediated
C–N bond formation by reacting with amino precursors. As
the plausible amino sources, we first chose Nꢀchlorocarbamate
derivatives since they are easy to prepare and convenient to
handle. Moreover, we envisioned that, upon deprotection of
initially
formed
carbamateꢀbearing
products,
the
corresponding primary arylamines can readily be accessible.
To our delight, when [(IMes)Cuꢀ(2,3,5,6ꢀC6F4H)] (2b) was
allowed to react with NꢀchloroꢀNꢀsodioꢀtertꢀbutylcarbamate
[(Boc)N(Na)(Cl)] (3), easily prepared from BocꢀNH2 (vide
infra), the aryl group was smoothly transferred from the
copper center to the nitrogen atom of the carbamate group to
deliver [(IMes)CuꢀN(Boc)(2,3,5,6ꢀC6F4H)] (4) in THF solvent
(63%), thus generating a new C–N bond (Scheme 3). This
complex was fully characterized by NMR and Xꢀray analysis
to disclose that complex 4 is also monomeric (Figure 3).
The carbamate group is shown to be bound to the copper
center in an ŋ1−N−ŋ1−O fashion forming a threeꢀcoordinate
copper species. Interestingly, an alkoxy group instead of
carbonyl oxygen is weakly coordinated to the copper center
(Cu1−O2: 2.838 Å). Bond lengths of Cu–CNHC and Cu–N are
1.8720(13) Å and 1.8742(11) Å, respectively. The Cu–CNHC
bond length in the complex 4 is slightly shortened compared to
Scheme 4. Preparative Route to NꢀChloroꢀNꢀsodioꢀtertꢀ
butylcarbamate (3)
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 11
1
2
3
4
5
6
7
8
9
Catalytic C–H Amidation with (NHC)Copper System.
Encouraged by the above stoichiometric transformations, we
initiated an optimization study of the (NHC)Cuꢀcatalyzed C–H
amidation of 1,2,4ꢀtrifluorobenzene26 in reaction with 1.1
equiv of NꢀchloroꢀNꢀsodioꢀtertꢀbutylcarbamate (3) (Table 1).
When preꢀgenerated (NHC)Cu catalysts (5 mol %) were
9
10
‒
tBuONa
‒
THF
THF
<1
<1
3
1c
1c
1c
1c
1c
1c
1c
1c
1c
11
tBuOLi
tBuOK
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
THF
12
THF
12
45
<1
<1
58
65
63
t
examined in the presence of 2 equiv of BuONa, the desired
amidation was found to proceed more efficiently at room
temperature with IMes or IiPr [IiPr = 1,3ꢀdiisopropylimidazolꢀ
2ꢀylidene] ligands when compared to IPr (entries 1–3). Other
copper NHC complexes including ICyCuCl (1d) or ItBuCuCl
(1e) displayed slightly lower efficiency comapred to IiPrCuCl
(1c) (entries 4–5). In addition, copper catalysts bearing
saturated NHCs such as SIMes (1f) or SIiPr (1g) were also
effective for the present amidation (entries 6–7). A reaction
with CuCl alone took place only in low efficiency (entry 8)
while no conversion was observed in the absence of copper
species or base (entries 9–10). Counter cations of tert-butoxide
base were influential on the amidation efficiency to reveal that
lithium or potassium was less effective than sodium (compare
entries 3 and 11–12). While the use of 1,4ꢀdioxane solvent led
to slightly decreased yield than THF (compare entries 3 and
13), other nonꢀpolar solvents were totally ineffective (entries
14–15). When the reaction was carried out in dark, no
noticeable change was observed (entry 16) to imply that the
amidation is not affected by visible light as sometimes
observed in the copperꢀcatalyzed reactions.27 The amidation
gave a similar yield when tert-butyl Nꢀchlorocarbamate [Bocꢀ
NH(Cl) in Scheme 4] was employed as an amino source, but
with higher loading of tBuONa (entry 18).
13
1,4ꢀDioxane
Toluene
ClCH2CH2Cl
THF
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
14
15
16c
17d
18d,e
THF
THF
a1,2,4ꢀTrifluorobenzene (0.2 mmol), 3 (1.1 equiv), base (2.0
equiv), catalyst (5.0 mol %) and dibenzyl (0.5 equiv, internal
standard) in THF (0.5 mL). Crude NMR yields. Performed in
dark. For 12 h. tertꢀButyl Nꢀchlorocarbamate was used as the
b
c
d
e
amidation source with 3.0 equiv of base.
Table 2. Scope of Fluoroarenes in the C
–
H Amidationa
cat.
1c
(2 ~ 10 mol %)
NHBoc
Fn
tBuONa (2.0 equiv)
Na
Boc
Fn
N
+
25 oC, THF
Cl
3
F
F
F
F
F
MeO
NHBoc
tBuO
NHBoc
F
F
F
Table 1. Optimization for the Amidation Conditionsa
5a, 2 h, 86%
Xꢀray of 5a
5b, 2 h, 70%
F
F
F
F
F
F
F
F
F
Br
NHBoc
NC
NHBoc
F
NHBoc
F
F
5d, 4 h, 78%b
5c, 2 h, 68%
5e, 2 h, 64%
F
F
F
F
NHBoc
NHBoc
F
F
NHBoc
F
F
F
F
5h, 12 h, 36%c
5g, 12 h, 59%c
5f, 2 h, 68%
12 h, 66%d
Entry
Catalyst
1a
Base
Solvent
THF
Yield(%)b
F
NC
F
NHBoc
F
1
2
3
4
5
6
7
8
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
tBuONa
43
12
57
48
51
42
56
14
NHBoc
NHBoc
THF
1b
F
F
5i, 12 h, 13%d
5j, 12 h, 0%d
5k, 12 h, 62%c
THF
THF
1c
F
NO2
F
F
F
F
F
1d
tBuO
O
NHBoc
NHBoc BocHN
NHBoc
THF
THF
THF
1e
F
F
F
F
F
5l, 12 h, 60%d
5m, 12 h, 59%d
5n, 2 h, 70%e
1f
aFluoroarenes (0.5 mmol), 3 (1.1 equiv), BuONa (2.0 equiv) and
t
1g
1c (2.0 mol %) in THF (0.5 mL); isolated product yields shown.
bLiOtBu used as the base. c1c (5.0 mol %). 1c (10.0 mol %). 2.5
d
e
CuCl
THF
Equiv of 3 and 4.0 equiv of tBuONa.
4
ACS Paragon Plus Environment

Page 5 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Substrate Scope of the (NHC)CuꢀCatalyzed C–H Amiꢀ
found in important biomolecules,30 underwent the desired
dation. With the optimized conditions in hand, a range of
polyfluoroarenes were next examined. Pleasingly, substrates
bearing various substituents were amidated with NꢀchloroꢀNꢀ
sodioꢀtertꢀbutyl carbamate (3, 1.1 equiv) in satisfactory yields
at room temperature (Table 2). Tetrafluoroanisole was reacted
to give the desired product (5a, 86% in 2 h) using 2.0 mol %
of catalyst 1c. Structure of 5a was confirmed by an Xꢀray
crystallographic analysis. Likewise, a substrate bearing a tertꢀ
butoxy group was reacted smoothly (5b). Labile substituents
such as bromo or cyano groups were compatible with the
present conditions (5c–5d). Two isomeric tetrafluorobenzenes
were amidated without difficulty (5e–5f). Not surprisingly,
substrates bearing less acidic C–H reactive sites were found to
exhibit lower reactivity. Trifluorobenzenes were amidated in
moderate yields with higher loading of copper catalyst (5g–
5h). It needs to be mentioned that the position of amidation is
controlled by the relative acidity of the potentially reactive C–
H bonds present (5g).28 On the other hand, challenging
substrates including diꢀ or monofluorobenzene were sluggish
under the present conditions (5i–5j). However, we were
pleased to see that electronꢀwithdrawing groups other than
fluoro can also be effective substituents for the present copperꢀ
catalzyed C–H amidation. Indeed, benzenes substituted with
cyano, ester, and nitro groups were readily amidated under the
present catalyst system to afford the corresponding products in
satisfactory (5k, 5l, and 5m, respectively). It should be noted
that tertꢀbutyl 3,5ꢀdifluorobenzoate was selectively amidated
at the Cꢀ4 position (5l). Interestingly, a biphenyl substrate
bearing octafluoro substituents was smoothly amidated at both
C–H bonds leading to a bisamidated product (5n), a
potentially valuable compound in materials science.1f,g
With the successful results on polyfluoroarenes, we
subsequently turned our attention to the C–H amidation of
heteroarenes (Table 3). Benzothiazole was efficiently
amidated at the Cꢀ2 position (6a) with NꢀchloroꢀNꢀsodioꢀtertꢀ
butyl carbamate (3, 1.1 equiv) by using catalyst 1c (5 mol %),
and structure of 6a was confirmed crystallographically.
Derivatives having bromo or amido substituents also
underwent the desired amidation without difficulty (6b–6c).
Thiazole was reacted selectively at the Cꢀ2 position28 to afford
synthetically valuable 2ꢀamidothiazole (6d).29 Again, the
structure of 6d was confirmed by an Xꢀray crystallographic
analysis. Significantly, the position of C–H bonds in the
amidation of thiazoles was found to be altered by the presence
of the preꢀexisting substituents. For instance, 2ꢀbromothiazole
was selectively amidated at the Cꢀ5 position leaving C4–H
bond intact while the labile bromo group was remained
untouched (6e). Monoamidation of 2,2'ꢀbithiazole was
achieved by using 1.1 equiv of NꢀchloroꢀNꢀsodioꢀtertꢀbutyl
carbamate (3) at slightly higher temperature in good yield (6f).
It needs to be mentioned that Daugulis and coworkers
succeeded in the direct Cꢀ2 arylation of thiazoles with
reaction to afford 8ꢀamidocaffeine (6j). In addition, quinoline
Nꢀoxides were observed to be amidated selectively at the Cꢀ2
position. When quinoline Nꢀoxide was allowed to react with
NꢀchloroꢀNꢀsodioꢀtertꢀbutyl carbamate (3, 1.1 eqiuv) in 1,4ꢀ
dioxane, the corresponding amidated product (6k) was
o
obtained in moderate yield (25 C, 12 h). A derivative bearing
a chloro group at the Cꢀ6 position underwent the C–H
amidation more efficiently to give the desired product (6l), and
its structure was confirmed by an Xꢀray analysis.
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
Table 3. Scope of Heteroarenes in the C
–
H Amidationa
cat. 1c (5 mol %)
tBuONa (2.0 equiv)
Na
Boc
Het
Het
+
NHBoc
N
25 oC, THF
3
Cl
N
N
S
NHBoc
NHBoc
+
S
Br
6b, 2 h, 55%
6a, 2 h, 80%
Xꢀray of 6a
N
N
S
NHBoc
Me
NHBoc
S
N
Boc
b
6d
, 12 h, 67%
6c
, 2 h, 75%
Xꢀray of 6d (Dimer)
N
N
N
S
N
S
S
N
Br
NHBoc
O
NHBoc
NHBoc
b
c
6e, 2 h, 77%
6f
6g
, 12 h, 62%
, 2 h, 54%
Me
N
N
N
N
O
N
N
NHBoc
NHBoc
MeO
NHBoc
O
O
N
N
Me
F3C
O
c
c
6j, 12 h, 41%
6h
6i,
2 h, 69%
, 2 h, 69%
Cl
N
O
NHBoc
N
O
NHBoc
d
Xꢀray of 6l
6k
6l,
, 12 h, 45%
12 h, 73%d
t
aHeteroarenes (0.2 mmol), 3 (1.1 equiv), BuONa (2.0 equiv) and
1c (5.0 mol %) in THF (0.5 mL); isolated product yields shown.
o
c
d
bAt 60 C. LiOtBu was used as the base. 1,4ꢀDioxane was used
as the solvent.
It should be mentioned that the present copper catalyst
system for the Cꢀ2 amidation of quinoline Nꢀoxides turns out
to be complementary to the previously reported C–H
amidation routes in regard to the regioselectivity. We recently
showed that quinoline Nꢀoxides can be amidated selectively at
the C-8 position under the Ir or Rh catalyst systems by
employing sulfonyl azides or Nꢀchlorocarbamates as the
amino sources.16d,24 In this appraoch, the Nꢀoxide moiety of
quinoline Nꢀoxide substrates works as a directing group to
iodobenzene by using
a copper/phenanthroline catalyst
system.19c,d
Oxadiazoles were amidated effectively by employing
tBuOLi base in these substrates (6g–6i). Electronic variation at
the 2ꢀphenyl moiety of 1,3,4ꢀoxadiazoles little influenced the
amidation efficiency. Significantly, caffeine, a structural motif
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 11
1
2
3
4
5
6
7
8
9
guide the remote C8–H bond activation by forming the
Mechanistic Studies. To shed light on the present C–H
amidation pathway, a serious of mechanistic experiments were
performed. No measurable kinetic isotope effect (KIE) was
corresponding metallacyclic intermediates. This aspect is
clearly distinct to the present approach wherein the most
acidic C–H bond is selectively amidated without the need of
directing groups in substrates.
observed
in
competition
reactions
between
(tetrafluoro)alkoxybenzene and its deuterated derivative
(Scheme 5a). The absence of intermolecular kinetic isotope
effect (KIE) suggests that the C–H bond cleavage of arenes
may not be related to the rateꢀdetermining step.
In addition to the scope of (hetero)arenes, we also briefly
investigated the feasibility of synthetically valuable
carbamates as additional types of deprotectable amidating
sources. We were pleased to see that a wide range of Nꢀ
chlorocarbamates were readily employed with the present
(NHC)Cu catalyst system under mild conditions (Table 4). For
instance, Nꢀbenzyloxycarbonyl (Cbz) could be introduced at
the 2ꢀposition of benzothiazole (7a). In addition, alkoxy group
in carbamates was found to be flexible to include methyl, ethyl,
and chiral menthyl groups (7b–7d). Trimethylsilylethyl
carbamate was also installed in satisfactory yield (7e) that has
been widely used as an aminoꢀprotecting group as well as in
the synthesis of glycosides.31 We were pleased to observe that
Nꢀchlorobenzamide could be served as an efficient amidating
precursor in a reaction with benzothiazole (7f). In addition, the
application of benzyl Nꢀchlorocarbamate (Cbz) was successful
with several (hetero)arenes such as 2ꢀbromothiazole (7g),
tetrafluoroanisole (7h), and polyfluorobiphenyl (7i). It is
noteworthy that the C–H amidation of heteroarenes was also
examined with isolated NꢀchloroꢀNꢀsodio benzylcarbamate
[(Cbz)N(Na)(Cl)] as the amidating reagent. Pleasingly, the
reaction efficiency was observed to be similar when compared
to the product yields obtained from amidation with
[(Cbz)NH(Cl)] (7a, 7g, 7h, and 7i).
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 5. Preliminary Mechanistic Studies
a) Intermolecular kinetic isotope effects
F
F
H/D
1c (2 mol %)
tBuO
F
F
F
F
F
F
Na
Cl
tBuONa (2.0 equiv)
+
N
Boc
THFꢀd8, 25 o
C
N(Na)Boc
OtBu
kH/kD = 1.0
b) H/D Exchange
H
N(Na)Boc
F
H
1c (2 mol %)
tBuONa (2.0 equiv)
F
F
F
F
F
F
F
F
Na
+
N
Cl
+
THFꢀd8, 25 oC, 40 min
F
Boc
F
F
X
X
D
38%
62%
(X: H/D = 2:1)
(X: H/D = 1:2.2)
No informative intramolecular KIE
c) Effect of electron transfer inhibitors
H
OMe
F
F
i) 1c (2 mol %)
BocHN
F
F
F
tBuONa (2.0 equiv)
Na
N
F
F
F
F
F
F
+
Boc
+
THFꢀd8, 25 o
ii) H2O
C
Cl
F
F
F
OMe
OMe
F
F
Table 4. Scope of NꢀChlorocarbamatesa
OMe
w/TEMPO (1.5 equiv)
w/o TEMPO
92%
90%
3%
3%
a
t
(Hetero)arenes (0.2 mmol), amidation source (1.1 equiv), BuOꢀ
Na (3.0 equiv), and 1c (5.0 mol %) in THF (0.5 mL); isolated
product yields. bUsing NꢀchloroꢀNꢀsodio benzylcarbamate (1.1
t
equiv) and BuONa (2.0 equiv); the values in parentheses refer to
the NMR yields. c1c (10.0 mol %). dAt 60 oC.
6
ACS Paragon Plus Environment

Page 7 of 11
Journal of the American Chemical Society
1
2
3
t
ro precursor 1b with BuONa, and that 1b’ was subsequently
reacted with 2ꢀbromothiazole affording the same complex 8
also in quantitative yield. Structure of 8 was characterized by
an Xꢀray analysis (Figure 4) to reveal that the Cu–CNHC and
Cu–Caryl bond lengths are 1.897(2) Å and 1.895(2) Å,
respectively, and the angle of C1−Cu1−C28 is 173.15(10)o.
Based on the above mechanistic studies and literature
precedents,17ꢀ21,32,33 a proposed pathway of the (NHC)Cuꢀ
catalyzed C–H amidation of (hetero)arenes is presented in
Scheme 6. First, a catalyst precursor [(NHC)CuꢀCl] (I) exꢀ
changes its chloro ligand with alkoxide base to form an isolaꢀ
ble [(NHC)CuꢀOtBu] complex (II) that will subsequently react
with arene substrates (Ar–H) with the generation of a structurꢀ
ally fully characterized copperꢀaryl intermediate (III). We
propose that an oxidative insertion of an amidating reagent (Nꢀ
chloroꢀNꢀsodioꢀalkyl carbamates or Nꢀchlorocarbamates) at
the Cu(I) center of III will occur, thus forming a Cu(III) comꢀ
plex (IV). In fact, copperꢀaryl species were known to react
with chloroamines or Oꢀacyl hydroxylamines to form Cu(III)
complexes according to the independent studies of Buchwald,
Miura, and others.10,12g,33 Moreover, Stahl provided a solid
evidence for the involvement of the Cu(I)/Cu(III) cycle in the
C–N bond formation with the isolation of a wellꢀdefined
Cu(III) complex.32c
4
5
6
7
8
9
10
11
12
13
Figure 4. ORTEP of 8 with thermal ellipsoids set at 50% probaꢀ
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
bility level (H atoms and diethyl ether solvent are omitted for
clarity). Selected bond lengths (Å) and angles (deg): Cu1−C1,
1.897(2); Cu1−C28, 1.895(2); C28−C29, 1.360(4); C28−S1,
1.717(3); C29−N3, 1.385(3); C1−Cu1−C28, 173.15(10).
When 1,2,4,5ꢀtetrafluorobenzeneꢀd was subjected to the
amidation conditions, a H/D exchange was observed in this
substrate leading us to conclude that no informative
intramolecualr KIE values can be obtained (Scheme 5b).
Notably, a small amount of a byproduct, 1,1'ꢀbiphenyl, was
detected in NMR and GCꢀMS analysis from an amidation of
2,3,5,6ꢀtetrafluoroanisole under the current catalyst system.
Based on the precedent examples, this result can be interpreted
that a higher order of oxidation state of copper species may be
involved.32 Moreover, a radical pathway could be ruled out
since the addition of TEMPO did not affect the reaction
outcome (Scheme 5c).
Again, it is believed that the reactive Cu(III) species IV
will undergo a transfer of an aryl group to the carbamate moieꢀ
ty affording a Cu(I) carbamato intermediate (V) by forming
the desired C–N bond as characterized in the above study.
Finally, this copper species V will exchange a ligand with base,
sodium tertꢀbutoxide, thus delivering the amidation product
with concurrent regeneration of catalytically active copper
specie II.
We were also curious about the final stage in the catalytic
cycle: the regeneration of catalytically active copper species
with product release (Scheme 5d). When an isolated copper
carbamato complex [(IMes)CuꢀN(Boc)(2,3,5,6ꢀC6F4H)] (4)
Scheme 6. Proposed Mechanism
t
was allowed to react with BuOH (2.0 equiv) that is generated
I
NHC
CuCl
in situ from the copperꢀaryl formation, no conversion (<1%)
was observed, thus indicating that protonolysis of [(IMes)Cuꢀ
N(Boc)(ArF)] intermediate is less likely. However, when
tBuOLi (2.0 equiv) was added to this solution,
[(IMes)Cu(OtBu)] started to form slowly at room temperature
and the conversion was reached to 30% after 5 h at the same
temperature. Significantly, the same conversion was
completed within 10 min by the addition of sodium base
(tBuONa, 2.0 equiv) under otherwise identical conditions to
amidated
product
tBuONa
CO2R
Ar
ArꢀH
NHC
CuOtBu
II
Na
N
isolated
√
tBuOH
tBuONa
III
NHC
Cu Ar
X-ray
form
[(IMes)Cu(OtBu)]
quantitatively
along
with
R
isolated
,
√
O
[(Na)N(Boc)(ArF)] (see the Supporting Information for details).
These results suggest that the copper carbamato complex
[(NHC)CuꢀN(Boc)(ArF)] readily exchanges the amido ligand
with tertꢀbutoxide to relase product with the regeneration of
catalytically active copper species [(IMes)Cu(OtBu)], and its
efficiency is dependent on the counter cations although the
exact reason is not clear at the present stage.
In addition, a Cu(I) aryl complex 8 generated from the C–
H activation at the Cꢀ5 position of 2ꢀsubstituted thiazoles was
confirmed crystallographically for the first time (Scheme 5e).
When [IPrCuCl] (1b) was reacted with 2ꢀbromothiazole in the
presence of sodium tertꢀbutoxide, a new copper complex was
isolated in 63% yield (in 2 h at 25 oC). It was also proved that
[(IPr)Cu(OtBu)] (1b’) was formed quantitatively from its chloꢀ
O
V
NHC
Cu
N
Ar
Cl
CO2R
N
isolated
,
X-ray
√
Na
NaCl
Ar
Cu Cl
NHC
RO2C
IV
N
Na
Scheme 7. Synthetic Application
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 11
1
2
3
4
5
6
7
8
9
We have developed the (NHC)Cuꢀcatalyzed C–H amidation
of (hetero)arenes using Nꢀchlorocarbamates or their sodio
derivatives as the amidating sources. In particular, the latter
one (NꢀchloroꢀNꢀsodioꢀcarbamates) was found to be convenꢀ
ient to handle, easy to scale up, stable to store, and environꢀ
mentally friendly giving rise to NaCl as a single byproduct in
the present C–H amidation system. In stoichiometric reactions,
two types of key copper intermediates were isolated and fully
characterized for the first time which subsequently led us to
optimize the catalytic conditions. The developed amidation
protocol works highly efficiently and selectively over a broad
range of substrates to include polyfluorobenzenes, azoles, and
quinoline Nꢀoxides. The installed carbamate groups can readiꢀ
ly be deprotected to deliver primary arylamines, thus anticipatꢀ
ing an immediate application in synthetic, medical, and mateꢀ
rials chemistry.
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
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures and
characterization of new compounds, mechanistic study and Xꢀray
analyses. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*sbchang@kaist.ac.kr
Notes
The authors declare no competing financial interest.
Synthesis of Primary Aromatic Amines. Synthetic utility
of the present (NHC)Cu catalyst system was briefly demonꢀ
strated as shown in Scheme 7. The C–H amidation was highly
convenient even on a gram scale where the catalyst loading
could be lowered without affecting the efficiency (Scheme 7a).
As anticipated, the newly introduced carbamate groups were
readily deprotected under the wellꢀestablished conditions to
afford primary arylamines. For instance, after the initial C–H
amidation of benzothiazole, the NHꢀBoc group was removed
by acid to give 2ꢀaminobenzothiazole (9a) in 80% yield over 2
steps (Scheme 7b).
The present amidation approach is highly flexible in
choosing amidating precursors as proved in the synthesis of an
aniline derivative (Scheme 7c). Two amino sources (Bocꢀ and
Cbzꢀcarbamates) can be efficiently utilized in the C–H amiꢀ
dation, and the corresponding amidated compounds were subꢀ
sequently subjected to the individual deprotection conditions
to afford 2,3,5,6ꢀtetrafluoroꢀ4ꢀmethoxyaniline (9b). Finally,
this catalytic system can be applied as an orthogonal route to
install multiꢀamino moieties with different protecting groups
(Scheme 7d). For instance, a double C–H amidation of
octafluorobiphenyl occurred through a tandem manner to afꢀ
ford a bisamidated compound (9c) bearing two different carꢀ
bamate groups (Bocꢀ and Cbzꢀ). Importantly, each protecting
group could selectively be removed without affecting the other
carbamate moiety (9d and 9e).
ACKNOWLEDGMENT
This article is dedicated to Professor Masahiro Murakami on the
occasion of his 60th birthday. This research was supported by the
Institute for Basic Science (IBSꢀR010ꢀD1) in Korea.
REFERENCES
(1) (a) Lawrence, S. A. Ed. Amines: Synthesis, Properties and Ap-
plications, Cambridge University Press: Cambridge, 2005. (b) Hili, R.;
Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (c) Cabri, W.; Ghetti, P.;
Pozzi, G.; Alpegiani, M. Org. Process Res. Dev. 2007, 11, 64. (d)
Rappoport, Z. Ed. The Chemistry of Anilines, Parts 1 and 2; John
Wiley & Sons: New York, 2007. (e) Ricci, A. Ed. Amino Group
Chemistry: From Synthesis to the Life Sciences, WileyꢀVCH:
Weinheim, 2008. (f) Hirata, S.; Totani, K.; Zhang, J.; Yamashita, T.;
Kaji, H.; Marder, S. R.; Watanabe, T.; Adachi, C. Adv. Funct. Mater.
2013, 23, 3386. (g) Zacharias, P.; Gather, M. C.; Rojahn, M.; Nuyken,
O.; Meerholz, K. Angew. Chem., Int. Ed. 2007, 46, 4388. (h) Yuan, W.
Z.; Gong, Y.; Chen, S.; Shen, X. Y.; Lam, J. W. Y.; Lu, P.; Lu, Y.;
Wang, Z.; Hu, R.; Xie, N.; Kwok, H. S.; Zhang, Y.; Sun, J. Z.; Tang,
B. Z. Chem. Mater. 2012, 24, 1518.
(2) (a) Blaser, H. U.; Siegrist, U.; Steiner, H.; Studer, M. Aromatic
nitro compounds, In Fine Chemicals through Heterogeneous
Catalysis, Sheldon, R. A.; van Bekkum, H., Eds., WileyꢀVCH:
Weinheim, 2001, p 389. (b) Mallat, T.; Baiker, A.; Kleist, W.;
Koehler, K. Amination Reactions. In Handbook of Heterogeneous
Catalysis, 2nd ed., Ertl, G.; Knozinger, H.; Schuth, F.; Weitkamp, J.
Eds., WileyꢀVCH: Weinheim, 2008, p 3548.
(3) (a) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods
and Mechanisms, VCH: Weinheim, Germany, 1989; (b) Tafesh, A.
ꢀ CONCLUSIONS
8
ACS Paragon Plus Environment

Page 9 of 11
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
M.; Weiguny, J. Chem. Rev. 1996, 96, 2035. (c) Ono, N. The Nitro
(16) (a) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.;
Chang, S. J. Am. Chem. Soc., 2012, 134, 9110. (b) Park, S. H.; Kwak,
J.; Shin, K.; Ryu, J.; Park, Y.; Chang, S. J. Am. Chem. Soc. 2014, 136,
2492. (c) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S. J. Am. Chem.
Soc. 2015, 137, 4534. (d) Hwang, H.; Kim, J.; Jeong, J.; Chang, S. J.
Am. Chem. Soc. 2014, 136, 10770.
(17) For recent reviews, see: (a) Gaillard, S.; Cazin, C. S. J.; Nolan,
S. P. Acc. Chem. Res. 2012, 45, 778. (b) Egbert, J. D.; Cazin, C. S. J.;
Nolan, S. P. Catal. Sci. Technol. 2013, 3, 912. (c) Lazreg, F.; Cazin, C.
S. J. in N-Heterocyclic Carbenes-Effective Tools for Organometallic
Synthesis; Nolan, S. P., Ed.; WileyꢀVCH: Mannheim, 2014, 199ꢀ242.
(d) Lazreg, F.; Nahra, F.; Cazin, C. S. J. Coord. Chem. Rev. 2015, 293,
48.
(18) Selected examples for the isolation of Cu(NHC) intermediates,
see: (a) Herron, J. R.; Ball, Z. T. J. Am. Chem. Soc. 2008, 130, 16486.
(b) Ohishi, T.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed., 2008, 47,
5792. (c) Takatsu, K.; Shintani, R.; Hayashi, T. Angew. Chem., Int.
Ed. 2011, 50, 5548. (d) Zhang, L.; Cheng, J.; Carry, B.; Hou, Z. J. Am.
Chem. Soc. 2012, 134, 14314. (e) Suess, A. M.; Uehling, M. R.; Kaꢀ
minsky, W.; Lalic, G. J. Am. Chem. Soc. 2015, 137, 7747.
(19) (a) Boogaerts, I. I. F.; Fortman, G. C.; Furst, M. R. L.; Cazin,
C. S. J.; Nolan, S. P. Angew. Chem., Int. Ed. 2010, 49, 8674. (b)
Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem., Int. Ed. 2010,
49, 8670. (c) Do, H.ꢀQ.; Daugulis, O. J. Am. Chem. Soc. 2007, 129,
12404. (d) Do, H.ꢀQ.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc.
2008, 130, 15185.
(20) (a) Lesieur, M.; Lazreg, F.; Cazin, C. S. J. Chem. Commun.
2014, 50, 8927. (b) Fortman, G. C.; Slawin, A. M. Z.; Nolan, S. P.
Organometallics 2010, 29, 3966. (c) Yao, T.; Hirano, K.; Satoh, T.;
Miura, M. Angew. Chem., Int. Ed. 2011, 50, 2990. (d) Makida, Y.;
Ohmiya, H.; Sawamura, M. Angew. Chem., Int. Ed. 2012, 51, 4122.
(21) Xie, W.; Chang, S. Angew. Chem., Int. Ed. 2016, 55, 1876.
(22) (a) Sundararaman, A.; Lalancette, R. A.; Zakharov, L. N.;
Rheingold, A. L.; Jäkle, F. Organometallics 2003, 22, 3526. (b)
Sundararaman, A.; Zakharov, L. N.; Rheingold, A. L.; Jäkle, F. Chem.
Commun. 2005, 1708.
Group in Organic Synthesis, WileyꢀVCH: New York, 2001.
(4) For selected reviews, see: (a) Muci, A. R.; Buchwald, S. L. Top.
Curr. Chem. 2002, 219, 131. (b) Hartwig, J. F. Acc. Chem. Res. 2008,
41, 1534. (c) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.;
Tada, M. Chem. Rev. 2008, 108, 3795.
(5) (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116,
5969. (b) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
7901.
(6) For selected reviews, see: (a) Collet, F.; Dodd, R. H.; Dauban, P.
Chem. Commun. 2009, 5061. (b) Cho, S. H.; Kim, J. Y.; Kwak, J.;
Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (c) Louillat, M.ꢀL.;
Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901. (d) Shin, K.; Kim, H.;
Chang, S. Acc. Chem. Res. 2015, 48, 1040. (e) Jiao, J.; Murakami, K.;
Itami, K. ACS Catal. 2016, 6, 610. (f) Kim, H.; Chang, S. ACS Catal.
2016, 6, 2341.
(7) For recent reviews, see: (a) Sun, C.ꢀL.; Li, B.ꢀJ.; Shi, Z.ꢀJ. Chem.
Rev. 2011, 111, 1293. (b) Guo, X.ꢀX.; Gu, D.ꢀW.; Wu, Z.; Zhang, W.
Chem. Rev. 2015, 115, 1622. (c) Cahiez, G.; Moyeux, A. Chem. Rev.
2010, 110, 1435. (d) Moselage, M.; Li, J.; Ackermann, L. ACS Catal.
2016, 6, 498. (e) Wan, J.ꢀP.; Jing, Y. Beilstein J. Org. Chem. 2015, 11,
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
2209. (f) Subramanian, P.; Rudolf, G. C.; Kaliappan, K. P. Chem.
Asian J. 2016, 11, 168.
–
(8) For the selected references, see: (a) Monguchi, D.; Fujiwara, T.;
Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607. (b) Wang, Q.;
Schreiber, S. L. Org. Lett. 2009, 11, 5178. (c) Tran, L. D.; Roane, J.;
Daugulis, O. Angew. Chem., Int. Ed. 2013, 52, 6043. (d) Roane, J.;
Daugulis, O. J. Am. Chem. Soc. 2016, 138, 4601. (e) Li, G.; Jia, C.;
Chen, Q.; Sun, K.; Zhao, F.; Wu, H.; Wang, Z.; Lv, Y.; Chen, X. Adv.
Synth. Catal. 2015, 357, 1311. (f) Zhu, C.; Yi, M.; Wei, D.; Chen, X.;
Wu, Y.; Cui, X. Org. Lett. 2014, 16, 1840. (g) Shang, M.; Sun, S.ꢀZ.;
Dai, H.ꢀX.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2014, 136, 3354. (h) Xu, H.;
Qiao, X.; Yang, S.; Shen, Z. J. Org. Chem. 2014, 79, 4414.
(9) For the selected references, see: (a) Ullmann, F. Chem. Ber.
1901, 34, 2174. (b) Ullmann, F. Chem. Ber. 1903, 36, 2382. (c)
Ullmann, F.; Sponagel, P. Chem. Ber. 1905, 38, 2211. (d) Goldberg, I.
Chem. Ber. 1906, 39, 1691. (e) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054. (f) Monnier, F.; Taillefer, M. Angew.
Chem., Int. Ed. 2009, 48, 6954.
(10) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900.
(11) (a) Matsubara, T.; Asako, S.; Ilies, L.; Nakamura, E. J. Am.
Chem. Soc. 2014, 136, 646. (b) Grohmann, C.; Wang, H.; Glorius, F.
Org. Lett. 2012, 14, 656. (c) Ng, K.ꢀH.; Zhou, Z.; Yu, W.ꢀY. Org. Lett.
2012, 14, 272.
(12) (a) Yoo, E. J.; Ma, S.; Mei, T.ꢀS.; Chan, K. S. L.; Yu, J.ꢀQ. J.
Am. Chem. Soc. 2011, 133, 7652. (b) Zhu, D.; Yang, G.; He, J.; Chu,
L.; Chen, G.; Gong, W.; Chen, K.; Eastgate, M. D.; Yu, J.ꢀQ. Angew.
Chem., Int. Ed. 2015, 54, 2497. (c) Dong, Z.; Dong, G. J. Am. Chem.
Soc. 2013, 135, 18350. (d) Gou, Q.; Liu, G.; Liu, Z.ꢀN.; Qin, J. Chem.
(23) Goj, L. A.; Blue, E. D.; Delp, S. A.; Gunnoe, T. B.; Cundari, T.
R.; Pierpont, A. W.; Petersen, J. L.; Boyle, P. D. Inorg. Chem. 2006,
45, 9032.
(24) Gwon, D.; Hwang, H.; Kim, H. K.; Marder, S. R.; Chang, S.
Chem. –Eur. J. 2015, 21, 17200.
(25) Herranz, E.; Sharpless, K. B. J. Org. Chem. 1980, 45, 2710.
(26) In the report of Miura et al., Cu(OAc)2/phenꢀcatalyzed
amination
of
1,2,4ꢀtrifluorobenzene
with
OꢀbenzoylꢀN,Nꢀ
dibenzylhydroxylamine generated 3% of the desired amination
product, see: Ref. [12g].
(27) Photoinduced C–N bond formation via a radical pathway was
reported by Fu et al., see: Creutz, S. E.; Lotito, K. J.; Fu, G. C.; Peters,
J. C. Science 2012, 338, 647.
(28) For pKa values, see: Shen, K.; Fu, Y.; Li, J.ꢀN.; Liu, L.; Guo,
Q.ꢀX. Tetrahedron 2007, 63, 1568.
(29) (a) Khalil, A.; Edwards, J. A.; Rappleye, C. A.; Tjarks, W.
Bioorg. Med. Chem. 2015, 23, 532. (b) Navarre, J.ꢀM.; Guianvarc’h,
D.; Giorgio, A. F.ꢀD.; Condom, R.; Benhida, R. Tetrahedron Lett.
2003, 44, 2199.
(30) (a) Saladino, R.; Mincione, E.; Crestini, C.; Negri, R.; Mauro,
E. D.; Costanzo, G. J. Am. Chem. Soc. 1996, 118, 5615. (b)
Michelson, A. Z.; Chen, M.; Wang, K.; Lee, J. K. J. Am. Chem. Soc.
2012, 134, 9622.
(31) (a) IsidroꢀLlobet, A.; Álvarez, M.; Albericio, F. Chem. Rev.
2009, 109, 2455. (b) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemꢀ
ler, S. R.; Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(c) Meyers, A. I.; Roland, D. M.; Comins, D. L.; Henning, R.; Flemꢀ
ing, M. P.; Shimizu, K. J. Am. Chem. Soc. 1979, 101, 4732.
(32) (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (b) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem.
–
Eur. J. 2015, 21, 15491. (e) Grohmann, C.; Wang, H.; Glorius, F.
Org. Lett. 2013, 15, 3014. (f) Patel, P.; Chang, S. ACS Catal. 2015, 5,
853. (g) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2011, 13, 2860. (h) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M.
Synthesis 2012, 44, 1792.
(13) Zhao, H.; Wang, M.; Su, W.; Hong, M. Adv. Synth. Catal.
2010, 352, 1301.
(14) (a) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem.,
Int. Ed. 2009, 48, 9127. (b) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang,
S. Angew. Chem., Int. Ed. 2010, 49, 9899.
(15) (a) Wertz, S.; Kodama, S.; Studer, A. Angew. Chem., Int. Ed.
2011, 50, 11511. (b) Li, Y.; Liu, J.; Xie, Y.; Zhang, R.; Jin, K.; Wang,
X.; Duan, C. Org. Biomol. Chem. 2012, 10, 3715. (c) Wang, R.; Liu,
H.; Yue, L.; Zhang, X.ꢀK.; Tan, Q.ꢀY.; Pan, R.ꢀL. Tetrahedron Lett.
2014, 55, 2233.
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
1
2
2007, 72, 6190. (c) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc.
S. S. J. Am. Chem. Soc. 2009, 131, 5044. (f) Casitas, A.; Canta, M.;
2008, 130, 9196. (d) Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J.
Am. Chem. Soc. 2009, 131, 78. (e) King, A. E.; Brunold, T. C.; Stahl,
Solà, M.; Costas, M.; Ribas, X. J. Am. Chem. Soc. 2011, 133, 19386.
(33) Shi, S.ꢀL.; Buchwald, S. L. Nat. Chem. 2015, 7, 38.
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
10
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
Table of Contents
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
11
ACS Paragon Plus Environment