Copper-Catalyzed Regioselective C-H Amination of Phenol Derivatives with Assistance of Phenanthroline-Based Bidentate Auxiliary

Article abstract of DOI:10.1021/acscatal.9b01145

A copper-catalyzed regioselective direct amination of phenol derivatives with diarylamines via phenanthroline-based bidentate auxiliary-directed C-H cleavage has been developed. This reaction proceeds smoothly with only a copper salt and air as a terminal oxidant to produce the corresponding o-aminophenols in good yields. Moreover, the directing group can be easily attached, detached, and recycled. Additionally, preliminary computational studies of the reaction with DFT have also been performed.

Full text of DOI:10.1021/acscatal.9b01145

Subscriber access provided by ALBRIGHT COLLEGE
Article
Copper-Catalyzed Regioselective C-H Amination of Phenol Derivatives
with Assistance of Phenanthroline-Based Bidentate Auxiliary
Kazutaka Takamatsu, Yoshihiro Hayashi, Susumu Kawauchi, Koji Hirano, and Masahiro Miura
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01145 • Publication Date (Web): 30 Apr 2019
Downloaded from http://pubs.acs.org on May 1, 2019
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 39
ACS Catalysis
1
2
3
4
5
6
7
8
9
Copper-Catalyzed Regioselective C-H Amination of
Phenol Derivatives with Assistance of Phenanthroline-
Based Bidentate Auxiliary
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
†
‡
‡
,†
Kazutaka Takamatsu, Yoshihiro Hayashi, Susumu Kawauchi, Koji Hirano,*
and
Masahiro Miura*,†
†
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
‡
Department of Chemical Science and Engineering, School of Materials and Chemical
Technology, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8552,
Japan
ABSTRACT: A copper-catalyzed regioselective direct amination of phenol derivatives with
diarylamines via phenanthroline-based bidentate auxiliary directed C-H cleavage has been
developed. This reaction proceeds smoothly with only a copper salt and air as a terminal
ACS Paragon Plus Environment
1

ACS Catalysis
Page 2 of 39
oxidant to produce the corresponding ortho-aminophenols in good yields. Moreover, the
directing group can be easily attached, detached, and recycled. Additionally, preliminary
computational studies of the reaction with DFT have also been performed.
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
Key words: amination, bidentate auxiliary, copper, C–H functionalization, phenols
ACS Paragon Plus Environment
2

Page 3 of 39
ACS Catalysis
INTRODUCTION
1
2
3
4
5
6
7
8
Phenol derivatives are important classes of compounds in the food, material, and pharmaceutical fields.1
Therefore, the efficient strategy to functionalize them are highly desirable. The aromatic electrophilic
substitution is one of the most classical and promising methods for the direct transformation of phenols,
and it is in common use for the synthesis of various useful compounds (Scheme 1a).2 Recently,
homolytic aromatic substitution (HAS) has also been developed along with rapid advances made in radical
chemistry in past thirty years (Scheme 1b).3 However, the low regioselectivity and narrow substrate
scope are often problematic points of these reactions.
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. C-H Functionalization of Phenols
a) Electrophilic Aromatic Substitution
OH
OH
OH
H
H
H
E
H
H
E+
+
+
H
H
ortho
E
para
b) Homolytic Aromatic Substitution (HAS)
OH
OH
OH
H
H
H
R
H
H
R
H
H
ortho
R
para
On the other hand, the transition-metal-catalyzed, directing-group-assisted C-H functionalization has
been attracted much attention as the more atom- and step-economical methods than traditional cross-
coupling reactions with organic halides and/or organometallic reagents.4,5 This strategy overcomes the
aforementioned regioselectivity issues in the direct functionalization of phenols, and a variety of
ACS Paragon Plus Environment
3

ACS Catalysis
Page 4 of 39
monodentate directing groups including pyridyl/pyrimidyl,6 ester,7 carbamate,8 silyl/silanol,9 and
transient phosphite10 are developed for the valuable C-H functionalization reactions.11 However, noble
transition metals such as palladium and rhodium are essential in most cases.
1
2
3
4
5
6
7
8
9
Recently, well-designed bidentate directing groups enable otherwise challenging C-H bond
functionalization. In particular, since the seminal work by Daugulis, various bidentate auxiliaries have
been developed for the regioselective C-H functionalization of carboxylic acids and amines (Figure 1).12
In contrast, such a bidentate chelation approach has not been reported for the direct functionalization of
phenols, to the best of our knowledge. There is only one example of platinum-containing metallacycle
formation in a stoichiometric manner (Scheme 2).13 Herein, we report a new protocol for the base-metal-
catalyzed direct functionalization of phenols by using a phenanthroline-based bidentate auxiliary: a
copper-catalyzed regioselective C-H amination of phenol derivatives with diarylamines is described
(Scheme 3). This reaction proceeds smoothly with only a copper salt and air as a terminal oxidant to
produce the corresponding ortho-aminophenols. The phenols can also be regarded as triarylamines,
which are widely utilized in optoelectronic materials.14 This reaction is one of limited successful
examples of triarylamine synthesis via directed C-H cleavage.15 Moreover, the directing group can be
easily attached, detached, and recycled. Additionally, the original phenol moiety can be readily
manipulated to deliver a variety of functionalized triarylamines.
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
4

Page 5 of 39
ACS Catalysis
a) Examples of Bidentate Directing Groups for Carboxylic Acids
O
1
2
3
4
5
6
7
8
O
O
O
R
N
R
N
R
N
R
N
H
H
H
H
N
N
N
SMe
Dauglis (2005)
O
Chatani (2009)
Dauglis, Baran (2010)
O
Shi (2013)
O
R
N
R
N
R
N
N
O
Bn
9
N
N
H
H
H
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
N
O
Yu, Dai (2014)
Ackermann (2014)
Niu, Song (2014)
b) Examples of Bidentate Directing Groups for Amines
O
Me O
O O
S
O
R
S
R
R
R
H
N
N
N
N
H
H
H
N
N
N
N
OMe
Ma (2013)
Dauglis (2005)
Sahoo (2012)
Carretero (2013)
Figure 1. Examples of bidentate directing groups for C-H functionalization of carboxylic acids and
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
amines
Scheme 2. Bidentate Directing Group Assisted Pt-Containing Metallacycle Formation with Phenol
Derivatives
K2PtCl4
AcOH
O
N
H
O
N
N
Pt
Cl
N
Scheme 3. Copper-Catalyzed C-H Amination of Phenol Derivatives with Diarylamines by Using a
Phenanthroline-type Bidentate Directing Group
ACS Paragon Plus Environment
5

ACS Catalysis
Page 6 of 39
1
2
3
4
O
N
O
N
cat. Cu
Ar2NH
+
H
H
N
Ar2N
NAr2 N
air
5
6
R1
R1
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
RESULTS and DISCUSSION
Our group16 and others17 have focused on inexpensive, less toxic, and abundant copper salts, and
developed copper-mediated unique C-H functionalization reactions.
In particular, nitrogen-based
bidentate directing groups allow such a base metal to be adopted in place of noble transition metals and
sometimes promote otherwise challenging C-H transformations. We envisioned that suitable N,N-
bidentate directing groups should be effective not only for carboxylic acids and amines but also for
phenols. We thus selected the C-H amination of phenols with diarylamines as the model reaction and
tested this hypothesis (Scheme 4). With Cu(OAc)2 (1.0 eq.) under air in DMSO at 90 ºC, the reaction
of simple phenol (1a-H), phenyl acetate (1a-Ac), phenyl dimethylcarbamate 1a-CONMe2, or
phenoxypyridine (1a-Py) with diphenylamine (2a) did not produce any aminated products. In contrast,
a phenol derivative that bears the bipyridyl group (1a-Bpy) reacted with 2a to form mono- and di-
aminated products in 10 and 26% yields, respectively. Moreover, the reaction efficiency was greatly
enhanced with the phenanthrolyl group (1a) to produce the targeted di-aminated product 3aa in 73% yield
with high chemoselectivity.
Scheme 4. Effects of Directing Groups on Oxygen in Copper-Mediated C-H Amination of Phenols
1 with Diphenylamine (2a)
ACS Paragon Plus Environment
6

Page 7 of 39
ACS Catalysis
DG
DG
DG
O
O
O
Cu(OAc)2 (1.0 eq.)
1
2
3
4
Ph2N
NPh2
NPh2
Ph2NH
+
+
DMSO
90 ºC, air
20-24 h
2a (2.0 eq.)
1
3
4
5
6
7
8
R
O
O
N
O
N
O
N
9
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
1a-R
R = H, Ac, CONMe2
(partial) decomposition
or no reaction
1a-Py
no reaction
1a-Bpy
26/10% (3/4)
1a
73% (only 3)
The structure of 3aa was unambiguously confirmed by NMR, HRMS, and X-ray analysis.18 The
starting 1a can be easily synthesized from phenol and 2-chloro-1,10-phenanthroline (5), which is
commercially available but can also be readily prepared on a deca-gram scale from inexpensive
phenanthroline monohydrate in two steps (Scheme 5).19 Thus, we identified 1a to be the promising
substrate and performed additional optimization studies to increase the product yield and turnover of
copper (Table 1). We first examined the amount of copper catalyst (entries 1-3). The yield remained
even with 50 mol % Cu(OAc)2 (entry 2), but the reaction was not completed with 20 mol % catalyst
loading, and mono-aminated 4aa was formed as the major product (entry 3). We also tried the selective
mono-amination by decreasing amounts of diphenylamine (2a), but the di-aminated product 3aa was
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
always competitively formed (entries 4 and 5).
Neither increasing and decreasing the reaction
temperature improved the product yield (entries 6 and 7). The addition of acid or base decreased the
yield (entries 8-11). Attempts to apply other oxidants under N2 also remained unsuccessful (entries 12-
14). We next surveyed various copper catalysts, with Cu(OPiv)2 proving to be optimal (entries 15-18).
Finally, we were pleased to find that the C-H amination reaction proceeded smoothly in the presence of
30 mol % Cu(OPiv)2 in DMSO at 90 ºC for 23 hours to produce 3aa in 83% yield (entry 19): the 30 mol
% catalyst loading was essential for the full consumption of starting 1a under current conditions
Notably, the yield was significantly diminished under N2 even with a stoichiometric amount of Cu(OPiv)2
ACS Paragon Plus Environment
7

ACS Catalysis
Page 8 of 39
(entry 20), thus indicating an important role of molecular oxygen in this reaction.
The control
1
2
3
experiment without Cu(OPiv)2 confirmed the necessity of the copper salt in this reaction (entry 21).
4
5
6
7
8
9
Scheme 5. Synthesis of Directing Group 5 and Substrate 1a
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
POCl3
DMF
H2O2
N
O
N
Cl
N
CH2Cl2
0 ºC to rt
AcOH
75 ºC
N
N
N
·H2O
5
62%
55 mmol, 12 g
100 mmol
OH
89%
K2CO3
O
N
Cl
N
N
DMF
N
5
160 ºC
1a
93%
Table 1. Optimization Studies for Diamination of 1a with 2aa
Phen
Phen
Phen
O
cat. Cu
additives
O
O
Ph2N
NPh2
NPh2
Ph2NH
+
+
DMSO (1.5 mL)
conditions
2a (2.0 eq.)
20-24 h
1a
3aa
4aa
yield (%)[b]
cat. Cu (mol
additives
(mmol)
entry
conditions
90 ºC, air
%)
3aa/4aa
Cu(OAc)2
1
-
73/n.d.
(100)
ACS Paragon Plus Environment
8

Page 9 of 39
ACS Catalysis
2
3
Cu(OAc)2 (50)
Cu(OAc)2 (20)
Cu(OAc)2
-
-
90 ºC, air
90 ºC, air
73 (76)/n.d.
23/40
1
2
3
4
5
6
7
8
9
4
5
-
-
90 ºC, air
20/39
21/36
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
(100)
90 ºC, O2
(1
Cu(OAc)2
atm,
(100)
balloon)
6
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
-
-
110 ˚C, air
70 ºC, air
90 ºC, air
90 ºC, air
90 ºC, air
90 ºC, air
90 ºC, N2
90 ºC, N2
90 ºC, N2
58/n.d.
73/n.d.
46/8
7
8
AcOH (0.25)
PivOH (0.25)
K2CO3 (0.25)
Cy2NMe (0.25)
MnO2 (1.0)
9
45/14
10
11
12
13
14
trace/22
66/n.d.
7/34
NMO (1.0)
n.d./n.d.
n.d./n.d.
K2S2O8 (1.0)
ACS Paragon Plus Environment
9

ACS Catalysis
Page 10 of 39
15
16
17
18
19
Cu(OPiv)2 (20)
Cu(eh)2 (20)
CuCl2 (20)
-
-
-
-
-
90 ºC, air
90 ºC, air
90 ºC, air
90 ºC, air
90 ºC, air
63/16
1
2
3
4
5
6
7
8
47/23
n.d./n.d.
n.d./n.d.
79 (83)/n.d.
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
Cu(OTf)2 (20)
Cu(OPiv)2 (30)
Cu(OPiv)2
20
21
-
-
90 ºC, N2
90 ºC, air
11/20
(400)
-
n.d./n.d.
a Reaction conditions: 1a (0.25 mmol), 2a (0.50 mmol), copper catalyst, additives, DMSO (1.5
mL).
b
1
Determined by H NMR with dibenzyl ether as internal standard.
Isolated yield in
parentheses. Phen = 2-(1,10-phenanthrolyl), Piv = tert-butylcarbonyl, eh = 2-ethylhexanoate,
Tf = trifluoromethanesulfonyl.
With the optimal conditions in hand, we examined the substrate scope (Scheme 6; 0.25 mmol scale).
Phenol derivatives bearing both electron-donating and electron–withdrawing substituents at the para-
position reacted with diphenylamine (2a) to produce di-aminated products in good yield (3aa-3ha; 70-
ACS Paragon Plus Environment
10

Page 11 of 39
ACS Catalysis
92%). Only one exception was CF3-substituted phenol (3ia), in which the reaction efficiency was slightly
decreased and the mono-aminated 4ia was also formed. It is noteworthy that the C-H amination
preferably occurred over the Ullmann-type amination to afford 3fa and 3ga with the Ar-Br and Ar-I
moieties left intact, which can be good synthetic handles for further derivatizations. The reaction of
meta-Me-substituted substrate and 2-naphthol derivative proceeded at less sterically hindered positions to
produce mono-aminated products exclusively (4ja and 4la). The electron-withdrawing and smaller F
substituent at the meta position also showed the mono-amination selectivity and good regioselectivity in
a ratio of 9.2:1, albeit with the moderate reactivity (4ka and 4ka’). The ortho- substituents were also
compatible to form the triarylamines in good yields (4ma and 4na). We next performed the C-H amination
of 1a with various amines 2. Diarylamines with methyl (3ab, 3af, 3ai, and 3ak), methoxy (3ah and
3aj), halogen (3ac, 3ad, and 3ag), and phenyl (3ae and 3ag) groups underwent the reaction to afford the
corresponding di-aminated compounds. As a general trend, the electron-rich amine gave a lower yield,
probably because of competitive oxidative decomposition (3ha). Again, bromo and iodo groups in the
diarylamines were tolerated (3ac, 3ad, and 3ag). The mono- and di-aminated products (3al/4al and
3am/4am) were also obtained from cyclic amine 2l and N-methylaniline (2m) albeit in moderate
combined yields. The N-benzylaniline (2n) also underwent the reaction with efficiency and selectivity
to similar to those of N-methylaniline (2m; 3an + 4an). The benzyl group can be deprotected under
hydrogenolysis, possibly giving the corresponding secondary NH amine. Moreover, electron-rich
carbazoles could be coupled with 1a to form the corresponding mono- and di-aminated products (3ap/4ap
and 3aq/4aq). Additionally, the C-H amination could be easily conducted on a ten- or four-fold larger
scale, thus indicating the good reproducibility and practicality of this process (3aa, 3ba, and 4ja). On
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
the other hand, attempts to apply primary amines and dialkylamines remained unsuccessful.
These amines removed the phenanthroline auxiliary from 1a by attack at the imine moiety to
form the parent phenol (data not shown).
ACS Paragon Plus Environment
11

ACS Catalysis
Page 12 of 39
Scheme 6. Copper-Catalyzed C-H Amination of Various Phenol Derivatives 1 with Amines 2.a
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
12

Page 13 of 39
ACS Catalysis
a Conditions: Cu(OPiv)2 (0.075 mmol), 1 (0.25 mmol), 2 (0.50 mmol), DMSO (5.0 mL), 100 ℃,
1
2
3
4
5
6
7
8
9
20-24 h, air. The combined yield of diaminated product 3 and monoaminated product 4 is
shown. The ratio of 3/4 is in parentheses. Value in brackets indicates NMR yield. b On a
1.0 mmol scale. c For two days. d On a 2.5 mmol scale. e A regioisomeric ratio of 4ka and
4ka’. f With 0.75 mmol of 2. Phen = 2-(1,10-phenanthrolyl).
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
To investigate the reactivity trend, we performed the several competitive experiments (Scheme 7).
The substrate 1m was preferably coupled with the electron-deficient 2c over the relatively electron-rich
1a.
On the other hand, the more electron-rich phenol derivative 1j showed higher reactivity than the
electron-deficient 1k.
Scheme 7. Competitive Experiments
ACS Paragon Plus Environment
13

ACS Catalysis
Page 14 of 39
Phen
O
H
1
2
N
Me
Ph2NH
3
4
5
6
Br
Br
2a (2.0 eq.)
2c (2.0 eq.)
Br
N
1m (0.25 mmol)
7
8
9
Phen
Phen
Me
O
O
30 mol% Cu(OPiv)2
Me
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
DMSO
90 ºC, air, 24 h
Br
4ma
4mc
12% (NMR)
86% (NMR)
Phen
O
Phen
O
Ph2NH
2a (2.0 eq.)
Me
1j (0.25 mmol)
F
1k (0.25 mmol)
Phen
O
Phen
NPh2
Phen
O
O
30 mol% Cu(OPiv)2
NPh2
Ph2N
DMSO
90 ºC, air, 24 h
and
Me
F
F
4ja
4ka/4ka’
26% (NMR)
12% (NMR)
To gain more insight into the mechanism, we first investigated the effect of directing groups in the C-
H activation in the absence of the coupling partner, diphenylamine (2a). In the presence of Cu(OPiv)2
and AcOD-d4, the H/D exchange of phenoxypridine (1a-Py) was not observed at all (Scheme 8, eq 1).
In contrast, deuterium incorporation in the phenol ring with the bipyridyl group (1a-Py) and the
phenanthrolyl group (1a) were detected in 17% and 38%, respectively (eqs 2 and 3). These results
apparently indicate positive effects of the bidentate directing group, especially phenanthrolyl group in the
C-H activation step. We also carried out kinetic studies with the deuterium-labeled substrate 1a-d5.
Even at an early stage of the reaction, the D/H exchange of 1a-d5 was not observed (eq 4), thus suggesting
that the C-H bond cleavage is irreversible in the presence of diphenylamine coupling partner 2a.
Moreover, KIE value from the parallel reactions with 1a and 1a-d5 was determined to be 1.45, which is
relatively small but meaningful (eq 5). On the other hand, Stahl et al. recently reported the homo-
coupling reaction of diarylamines in the presence of a copper salt under O2 to produce
ACS Paragon Plus Environment
14

Page 15 of 39
ACS Catalysis
tetraarylhydrazines.20 The reported conditions are similar to our optimal conditions. Thus, we
independently prepared tetraphenylhydrazine (6a) and investigated its intermediacy in the C-H amination
of 1a. The reaction with one equivalent of 6a instead of diphenylamine (2a) proceeded smoothly to
form the same diaminated product 3aa in a good yield (eq 6). Moreover, the aminated products 3aa and
4aa were obtained even under N2 atmosphere, albeit with decreased efficiency. However, the reaction
of the hydrazine without the copper catalyst produced no product (eq 7). Therefore, the hydrazine
generated in situ from the amine may be a truly reactive component in the copper-catalyzed C-H
amination, and molecular oxygen plays a role in the hydrazine formation. However, significant amount
of tetraphenylhydrazine 6a rapidly decomposed in DMSO at 90 ºC under air or N2 to form the parent
diphenylamine 2a in 46% or 42% yield, respectively (eq 8). Thus, the possibility that in eq 6 the reaction
with the decomposed 2a produced 3aa cannot be excluded. In contrast, the reaction with bicarbazole 6o
did not gave any product in the presence and absence of molecular oxygen, and the hydrazine-type
intermediate is thus unlikely involved in the reaction with carbazoles (eq 9).
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
Scheme 8. Mechanistic Studies
ACS Paragon Plus Environment
15

ACS Catalysis
Page 16 of 39
1
2
30 mol % Cu(OPiv)2
4.0 eq. AcOD-d4
O
N
O
N
(1)
3
4
5
H/D
H/D
DMSO
90 ºC, air, 6 h
0%D
6
1a-Py
1a-Py
7
8
9
30 mol % Cu(OPiv)2
4.0 eq. AcOD-d4
O
N
O
N
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
(2)
N
H/D
H/D N
17%D
DMSO
90 ºC, air, 6 h
1a-BPy
1a-BPy
30 mol % Cu(OPiv)2
4.0 eq. AcOD-d4
O
N
O
N
(3)
N
H/D
H/D N
38%D
DMSO
90 ºC, air, 6 h
1a
1a
Phen
D
Phen
O
O
91%D
91%D
91%D
H/D
91%D
D/H
2.0 eq. 2a
D
30 mol % Cu(OPiv)2
(4)
99%D
DMSO
D
D
99%D
D
D
90 oC, air, 3 h
99%D
99%D
D
D
88%D
88%D
1a-d5
1a-d5
(3% of 3aa-d3, 30% of 4aa-d4)
Phen
Phen
Phen
O
O
O
Ph2N
NPh2
NPh2
2.0 eq. 2a
30 mol % Cu(OPiv)2
1a
or
Phen
D
3aa
4aa
Phen
or
(5)
DMSO
Phen
90 oC, air
O
O
O
91%D
91%D
kH/kD = 1.45
D
Ph2N
D
NPh2
D
D
NPh2
D
D
99%D
D
D
99%D
D
D
D
3aa-d3
4aa-d4
88%D
1a-d5
Phen
Phen
O
O
30 mol % Cu(OPiv)2
Ph2N/H
NPh2
(6)
Ph2N NPh2
+
DMSO
90 ºC, air or N2, 23 h
6a (x eq.)
1a
3aa/4aa
x=1.0, air: 65%/trace
x=2.0, N2: 23%/41%
ACS Paragon Plus Environment
16

Page 17 of 39
ACS Catalysis
Phen
Phen
O
O
1
2
3
without Cu
Ph2N/H
NPh2
(7)
Ph2N NPh2
+
DMSO
90 ºC, air or N2, 19-23 h
6a (1.0 eq.)
4
5
6
1a
3aa/4aa
n.d.
7
8
9
Ph2N NPh2
Ph2NH
(8)
DMSO
90 ºC, air or N2, 19 h
6a
2a
air: 46%
N2: 42%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
tBu
tBu
Phen
O
Phen
O
30 mol % Cu(OPiv)2
Ar2N/H
NAr2
N N
+
(9)
DMSO
90 ºC, air or N2
3ao/4ao
x=1.0, air: n.d.
x=2.0, N2: n.d.
1a
tBu
tBu
6o (x eq.)
On the basis of the above results and literature information, we propose two reaction mechanisms of 1a
with 2a as shown in Schemes 9 and 10 (mechanism A and B, respectively). In the mechanism A,
tetraphenylhydrazine (6a) is formed as the reactive intermediate (Scheme 9). An initial coordination
promoted by the N,N-chelation of the phenanthroline moiety in 1a to copper center generates a chelated
complex 7. Subsequent irreversible C-H bond cleavage forms the six-membered intermediate 8. This
metallacycle is then oxidized to the copper(III) species 921 with the hydrazine 6a, which is produced by
the copper-catalyzed homo-coupling of 2a in the presence of O2. The corresponding mono-aminated
product 4aa is obtained by reductive elimination and the following dissociation of the copper salt from
complex 10. The same C-H amination occurs at another ortho position to form the observed di-aminated
product 3aa. The resulting copper(I) species 11 is finally oxidized into copper(II) with 6a to complete
the catalytic cycle. The hydrazine 6a could be regenerated immediately from the amino radical species by
the copper catalyst and O2.
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
In the mechanism B, diphenylamine (2a) directly participates in the amination (Scheme 10). An initial
coordination of 1a to copper center and subsequent C-H bond cleavage produces the metallacycle 8
ACS Paragon Plus Environment
17

ACS Catalysis
Page 18 of 39
through the same mechanism as in mechanism A. This intermediate is then oxidized to the copper(III)
species 9 with another copper(II) species. The mono-aminated product 4aa is obtained by reductive
elimination and the following dissociation of the copper salt from complex 10. The resulting copper(I)
species 11 is finally oxidized into copper(II) with molecular oxygen to complete the catalytic cycle.
Given the observation in eqs 6 and 7, we cannot provide any conclusive statement on the reaction
mechanism of 1a and 2a, only with experimental studies. Thus, to confirm which mechanism is likely
involved, computational studies with DFT were performed.
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
Scheme 9. Plausible Reaction Mechanism A (X = OPiv or NPh2)
HX
Ph2NH
2a
CuX2
O2
O
N
O
N
Cu
N
Cu
N
Ph2N NPh2
O
N
X
X
X
6a
N
7
8
1a
Ph2N•
CuX2
Ph2N•
O
N
Cu
N
NPh2
X
CuX
11
9
6a
NPh2
O
N
O
N
Cu
X
N
NPh2 N
10
4aa
3aa
ACS Paragon Plus Environment
18

Page 19 of 39
ACS Catalysis
Scheme 10. Plausible Reaction Mechanism B (X = OPiv or NPh2)
1
2
3
4
5
HX
6
7
8
9
O
N
O
N
Cu
N
Cu
N
O
N
X
X
X
CuX2, 2a
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
7
8
1a
CuX, HX
CuX2
H2O
N
O
Cu
N
NPh2
X
CuX
11
9
O2, HX
NPh2
O
N
O
N
Cu
N
NPh2 N
10
X
4aa
3aa
The enthalpy profiles of mechanism A and B are shown in Figure 2 and 3. In mechanism A, a chelate
complex A undergoes the C-H cleavage of ortho-position of phenoxy leading to the six-membered
intermediate B with 17.7 kcal mol–1 of activation enthalpy and 15.6 kcal mol–1 reaction enthalpy. B is
oxidized and aminated by the hydrazine forming the copper(III) species C and NPh2 radical. This step
was 33.6 kcal mol–1 endothermic. If oxidation of B by the hydrazine directly leads to C and half equivalent
of the hydrazine, this step was 14.8 kcal mol–1 endothermic process. The reductive elimination of C
leading to the mono-aminated D was nearly barrierless and 53.8 kcal mol–1 exothermic reaction.
In mechanism B, the six-membered intermediate B was generated by the same C-H cleavage as
mechanism A. B is oxidized by the copper cluster species of [Cu(OAc)2]2 to the copper(III) species E.
This step was 3.4 kcal mol–1 endothermic. The amination of F to the aminated species G was almost
barrierless. Although AcOH was removed from G to lead C for the convenience of calculation, the
ACS Paragon Plus Environment
19

ACS Catalysis
Page 20 of 39
continuous reductive elimination can progress from G. The reductive elimination was barrierless and
highly exothermic reaction. The oxidation and amination steps by [Cu(OAc)2]2 and NHPh2 (mechanism
B) are energetically favored than those by the hydrazine (mechanism A), indicating that mechanism B is
likely involved.
1
2
3
4
5
6
7
8
9
C
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
+ NPh2
O
N
III
N
49.2
(38.5)
Cu
NPh2
OAc
1/2 Ph2NNPh2
C
+ 1/2 Ph2NNPh2
Ph2NNPh2
TS(C-D)
31.4
(28.3)
31.7
(28.2)
C-H cleavage
Oxidation
& Amination
TS(A-B)
B
Reductive
elimination
17.7
(19.4)
15.6
(4.7)
AcOH
O
N
II
N
A
0
Cu
OAc
O
N
NPh2
II
N
Cu
OAc
O
N
OAc
I
N
D
Cu
-22.1
(-25.7)
OAc
Figure 2. Enthalpy (Gibbs energy) profile of Mechanism A.
ACS Paragon Plus Environment
20

Page 21 of 39
ACS Catalysis
1
2
3
4
5
6
7
8
O
N
O
N
III
III
Reductive
elimination
N
N
Cu
Cu
O
N
NPh2
OAc
II
N
OAc
C-H cleavage
Cu
OAc
E
TS(C-D)
C
OAc
TS(A-B)
Amination
21.5
(13.9)
21.7
(13.8)
19.0
(7.6)
B
17.7
(19.4)
TS(F-G)
G
F
15.6
(4.7)
AcOH
13.4
(20.0)
13.8
(19.6)
12.4
(18.0)
1/2 [CuX]2
AcOH
NHPh2
1/2 [CuX2]2
9
Oxidation
A
0
O
N
III
Cu
O
N
III
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
N
Cu
NPh2
O
OAc
OAc
O
O
N
HOAc
II
N
Cu
HNPh2
OAc
OAc
NPh2
O
N
I
N
Cu
D
OAc
-32.1
(-40.1)
Figure 3. Enthalpy (Gibbs energy) profile of Mechanism B.
ACS Paragon Plus Environment
21

ACS Catalysis
Page 22 of 39
Given the results observed in Scheme 7, the more acidic amine is more easily deprotonated, leading to
the aminated intermediate corresponding to G preferably. The C–H cleavage can involve the acetate-
ligand-assisted concerted metalation-deprotonation (CMD)-type pathway, but the electrophilic nature is
also important in the product-determining step.22 However, the role of molecular oxygen still remains
unclear even from DFT calculation, and further studies are required for clarification. On the other hand,
a mechanism of type B can be operative also in the C-H amination with carbazoles because the reaction
of 1a with bicarbazole 6o did not occur at all (eq. 9, vide supra).
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
We finally attempted the derivatization of the aminated products (Scheme 11). The directing group of
3aa could be easily removed with potassium tert-butoxide in toluene at 125 ºC, and both free phenol 12aa
and phenanthrolidone (13) were obtained in nearly quantitative yields after treatment of the crude mixture
with trifluoroacetic acid (TFA) in CH2Cl2. Subsequent dehydrative chlorination of 13 furnished the
chlorophenanthrizine 5 in a good overall yield, which can be recycled as the directing group (Scheme 3).
The phenol 12aa was coupled with Ph2IOTf in the presence of tetrabutylammonium fluoride hydrate
(TBAF·nH2O) and NaHCO3 to form the O-arylated product 14aa in 70% yield.23 Moreover, 12aa
reacted with PhNTf2 in acetonitrile at 60 ºC to furnish the triflate 15aa, and successive thia-Fries
rearrangement of 15aa produced 16aa in 96% yield. The directing group of mono-aminated product 4ja
could also be removed to produce phenol 12ja in 93% yield. The deoxyfluorination reaction of 12ja
with PhenoFluor Mix24 was also possible, and the fluorine-containing triarylamine 17ja was obtained in
an acceptable yield. Finally, the triflate 15ja prepared from 12ja underwent the Suzuki-Miyaura
coupling with phenylboronic acid to produce 18ja in 66% yield.
ACS Paragon Plus Environment
22

Page 23 of 39
ACS Catalysis
Scheme 11. Derivatization of the Aminated Products
1
2
3
4
5
6
Ph
Ph2IOTf
TBAF·nH2O
NaHCO3
O
Ph2N
NPh2
Cl
N
5
N
7
CH2Cl2
40 ºC
91%
8
9
14aa
70%
POCl3
toluene
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
120 ºC, N2
(1)
KOtBu
toluene
Phen
OH
O
125 ºC, N2
Ph2N
NPh2
Ph2N
NPh2
O
N
(2)
TFA
CH2Cl2
rt
H
N
12aa
98%
13
99%
3aa
PhNTf2, Et3N
MeCN
60 ºC, N2
OH
OTf
Ph2N
NPh2
Ph2N
NPh2
o-xylene
140 ºC, N2
Tf
15aa
93%
16aa
96%
(1)
toluene
125 ºC, N2
KOtBu
Phen
OH
F
O
PhenoFluor Mix
NPh2
NPh2
NPh2
(2)
TFA
CH2Cl2
rt
mesitylene
170 ºC, N2
Me
Me
Me
12ja
93%
4ja
17ja
53%
PhNTf2, Et3N
MeCN
Ph-B(OH)2
Pd2(dba)3
CyJohnPhos
K2CO3
60 ºC, N2
OTf
Ph
NPh2
NPh2
toluene
90 ºC, N2
Me
Me
15ja
93%
18ja
66%
CONCLUSIONS
In conclusion, we have developed a copper-catalyzed direct amination of phenol derivatives
with diarylamines via phenanthroline-based, bidentate auxiliary directed C-H cleavage. The
reaction proceeds smoothly with only a copper salt and air as a terminal oxidant to produce the
ACS Paragon Plus Environment
23

ACS Catalysis
Page 24 of 39
corresponding ortho-aminophenols in good yields. Moreover, the directing group can be easily
1
2
3
4
attached, detached, and recycled. Additionally, preliminary computational studies with DFT are also
5
6
7
performed.
The obtained results will find wide applications in other base-metal-catalyzed C-H
8
9
functionalization of phenols and even more challenging aliphatic alcohol derivatives.
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:
The Supporting Information is available free of charge on the ACS Publications website at DOI:
xxx.
Procedures and characterization data (PDF)
X-ray crystallographic data for 3aa (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: k_hirano@chem.eng.osaka-u.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
ORCID
Koji Hirano: 0000-0001-9752-1985
ACS Paragon Plus Environment
24

Page 25 of 39
ACS Catalysis
Masahiro Miura: 0000-0001-8288-6439
1
2
3
4
5
Notes
6
7
8
The authors declare no competing financial interest.
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
ACKOWLEDGEMENTS
This work was supported by JSPS KAKENHI Grant Nos. JP 17J00349 (Grant-in-Aid for JSPS
Research Fellow) to K.T., JP 15H05485 (Grant-in-Aid for Young Scientists (A)) and 18K19078
(Grant-in-Aid for Challenging Research (Exploratory)) to K.H. and JP 17H06092 (Grant-in-Aid
for Specially Promoted Research) to M.M. The numerical calculations were carried out on the
TSUBAME 3.0 supercomputer at the Tokyo Institute of Technology, Tokyo, Japan, and on the
supercomputer at the Research Center for Computational Science, Okazaki, Japan. This
computational work was partly supported by a JST CREST (Grant Number JPMJCR1522 to S.
K.) and Grant-in-Aid for Young Scientists (B) (JSPS KAKENHI Grant Number JP17K17720 to
Y. H.).
REFERENCES
ACS Paragon Plus Environment
25

ACS Catalysis
Page 26 of 39
(1) (a) Tyman, J. H. P. Synthetic and Natural Phenols, Elsevier Science, Amsterdam, 1996. (b)
Rappoport, Z. The Chemistry of Phenols, John Wiley & Sons, Ltd, Chichester, 2003.
(2) A review: (a) Galabov, B.; Nalbantova, D.; Schleyer, P. von R.; Schleyer, III, H. F.
Electrophilic Aromatic Substitution: New Insights into an Old Class of Reactions. Acc. Chem.
Res. 2016, 49, 1191. For an example of amination, see: (b) Brandes, S.; Bella, M.; Kjærsgaard,
A.; Jørgensen, K. A. Chirally Aminated 2-Naphthols-Organocatalytic Synthesis of Non-Biaryl
Atropisomers by Asymmetric Friedel-Crafts Amination. Angew. Chem., Int. Ed. 2006, 45, 1147.
(3) A review: (a) Bowman, W. R.; Storey, J. M. D. Synthesis using aromatic homolytic
substitution—recent advances. Chem. Soc. Rev. 2007, 36, 1803. For examples of amination,
see: (b) Louillat-Habermeyer, M.-L.; Jin, R.; Patureau, F. W. O2-mediated dehydrogenative
amination of phenols. Angew. Chem., Int. Ed. 2015, 54, 4102. (c) Zhao, Y.; Huang, B.; Yang,
C.; Xia, W. Visible-Light-Promoted Direct Amination of Phenols via Oxidative Cross-
Dehydrogenative Coupling Reaction. Org. Lett. 2016, 18, 3326. (d) Goswami, M.; Konkel, A.;
Rahimi, M.; Louillat-Habermeyer, M.-L.; Kelm, H.; de Bruin, R. Jin, B.; Patureau, F. W.
Mechanism of the Dehydrogenative Phenothiazination of Phenols. Chem.—Eur. J. 2018, 24,
11936.
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
26

Page 27 of 39
ACS Catalysis
(4) Recent selected reviews: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Palladium(II)-
Catalyzed C-H Activation/C-C Cross-Coupling Reactions: Versatility and Practicality. Angew.
Chem., Int. Ed. 2009, 48, 5094. (b) Ackermann, L.; Vicente, R.; Kapdi, A. R. Transition-Metal-
Catalyzed Direct Arylation of (Hetero)Arenes by C-H Bond Cleavage. Angew. Chem., Int. Ed.
2009, 48, 9792. (c) Dudnik, A. S.; Gevorgyan, V. Formal Inverse Sonogashira Reaction: Direct
Alkynylation of Arenes and Heterocycles with Alkynyl Halides. Angew. Chem., Int. Ed. 2010, 49,
2096. (d) Satoh, T.; Miura, M. Oxidative Coupling of Aromatic Substrates with Alkynes and
Alkenes under Rhodium Catalysis. Chem.—Eur. J. 2010, 16, 11212. (e) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. C-H Bond Functionalization: Emerging Synthetic Tools for Natural
Products and Pharmaceuticals. Angew. Chem., Int. Ed. 2012, 51, 8960. (f) Drapeau, M. P.;
Gooßen, L. J. Carboxylic Acids as Directing Groups for C-H Bond Functionalization. Chem.—
Eur. J. 2016, 22, 18654. (g) Sambiagio, C.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.;
Wiesinger, T.; M. Zia, F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnürch, M. A
comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation
chemistry. Chem. Soc. Rev. 2018, 47, 6603. (h) Gandeepan, P.; Muller, T.; Zell, D.; Gera, G.;
Warratz, S.; Ackermann, L. 3d Transition Metals for C–H Activation. Chem. Rev. 2019, 119,
2192. See the Supporting Information for a complete list of references.
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
27

ACS Catalysis
Page 28 of 39
(5) For a pioneering work, see: Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Efficient catalytic addition of aromatic carbon-hydrogen bonds to
olefins. Nature 1993, 366, 529.
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
(6) (a) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Palladium-Catalyzed Acylation of sp2
C−H Bond: Direct Access to Ketones from Aldehydes. Org. Lett. 2009, 11, 3120. (b) Gu, S.;
Chen, C.; Chen, W. Ortho-Functionalization of 2-Phenoxypyrimidines via Palladium-Catalyzed
C−H Bond Activation. J. Org. Chem. 2009, 74, 7203. (c) Chu, J.-H.; Lin, P.-S.; Wu, M.-J.
Palladium(II)-Catalyzed
Ortho
Arylation
of
2-Phenoxypyridines
with
Potassium
Aryltrifluoroborates via C−H Functionalization. Organometallics 2010, 29, 4058. (d) Ackermann,
L.; Diers, E.; Manvar, A. Ruthenium-Catalyzed C–H Bond Arylations of Arenes Bearing
Removable Directing Groups via Six-Membered Ruthenacycles. Org. Lett. 2012, 14, 1154. (e)
Yao, J.; Feng, R.; Wu, Z.; Liu, Z.; Zhang, Y. Palladium-Catalyzed Decarboxylative Coupling of
α-Oxocarboxylic Acids with C(sp2)-H of 2-Aryloxypyridines. Adv. Synth. Catal. 2013, 355, 1517.
(f) Ma, W.; Ackermann, L. Ruthenium(II)-Catalyzed C-H Alkenylations of Phenols with
Removable Directing Groups. Chem.—Eur. J. 2013, 19, 13925. (g) Liu, B.; Jiang, H.-Z.; Shi, B.-
F. Palladium-Catalyzed Oxidative Olefination of Phenols Bearing Removable Directing Groups
under Molecular Oxygen. J. Org. Chem. 2014, 79, 1521. (h) Lou, S.-J.; Wang, Y.-F.; Xu, D.-Q.;
ACS Paragon Plus Environment
28

Page 29 of 39
ACS Catalysis
Du, X.-H.; He, J.-Q.; Mao, Y.-J.; Xu, Z.-Y. Palladium-Catalyzed Oxidative Olefination of Phenols
Bearing Removable Directing Groups under Molecular Oxygen. ACS Catal. 2015, 5, 2846.
(7) Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. Pd(II)-Catalyzed C−H
Activation/Aryl−Aryl Coupling of Phenol Esters. J. Am. Chem. Soc. 2010, 132, 468.
(8) (a) Zhao, X.; Yeung, C. S.; Dong, V. M. Palladium-Catalyzed Ortho-Arylation of O-
Phenylcarbamates with Simple Arenes and Sodium Persulfate. J. Am. Chem. Soc. 2010, 132,
5837. (b) K. Yamazaki.; S. Kawamorita.; H. Ohmiya.; M. Sawamura. Directed Ortho Borylation
of Phenol Derivatives Catalyzed by a Silica-Supported Iridium Complex. Org. Lett. 2010, 18,
3978. (c) Gong, T.-J.; Xiao, B.; Liu, Z.-J.; Wan, J.; Xu, J.; Luo, D.-F.; Fu, Y.; Liu, L. Rhodium-
Catalyzed Selective C–H Activation/Olefination of Phenol Carbamates. Org. Lett. 2011, 13,
3235. (d) Feng, C.; Loh, T.-P. Rhodium-catalyzed direct ortho C–H olefination of phenol
derivatives. Chem. Commun. 2011, 47, 10458. (e) John, A.; Nicholas, K. M. Palladium
Catalyzed C–H Functionalization of O-Arylcarbamates: Selective ortho-Bromination Using NBS.
J. Org. Chem. 2012, 77, 5600.
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
(9) (a) Boebel, T. A.; Hartwig, J. F. Silyl-Directed, Iridium-Catalyzed ortho-Borylation of Arenes.
A One-Pot ortho-Borylation of Phenols, Arylamines, and Alkylarenes. J. Am. Chem. Soc. 2008,
130, 7534. (b) Huang, C.; Gevorgyan, V. TBDPS and Br-TBDPS Protecting Groups as Efficient
ACS Paragon Plus Environment
29