Direct Hydroxylation and Amination of Arenes via Deprotonative Cupration

Article abstract of DOI:10.1021/jacs.6b03855

Deprotonative directed ortho cupration of aromatic/heteroaromatic C-H bond and subsequent oxidation with t-BuOOH furnished functionalized phenols in high yields with high regio- and chemoselectivity. DFT calculations revealed that this hydroxylation reaction proceeds via a copper (I → III → I) redox mechanism. Application of this reaction to aromatic C-H amination using BnONH₂ efficiently afforded the corresponding primary anilines. These reactions show broad scope and good functional group compatibility. Catalytic versions of these transformations are also demonstrated.

Full text of DOI:10.1021/jacs.6b03855

Subscriber access provided by - Access paid by the | UCSB Libraries
Article
Direct Hydroxylation and Amination of Arenes via Deprotonative Cupration
Noriyuki Tezuka, Kohei Shimojo, Keiichi Hirano, Shinsuke Komagawa, Kengo Yoshida,
Chao Wang, Kazunori Miyamoto, Tatsuo Saito, Ryo Takita, and Masanobu Uchiyama
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03855 • Publication Date (Web): 27 Jun 2016
Downloaded from http://pubs.acs.org on June 27, 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 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Direct Hydroxylation and Amination of Arenes via Deprotonative
Cupration
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
Noriyuki Tezuka,†,§ Kohei Shimojo,†,§ Keiichi Hirano,*,† Shinsuke Komagawa,†,¶ Kengo Yoshida,‡
Chao Wang,† Kazunori Miyamoto,† Tatsuo Saito,† Ryo Takita,‡ and Masanobu Uchiyama*,†,‡
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7ꢀ3ꢀ1 Hongo, Bunkyoꢀku, Tokyo 113ꢀ0033, Japan
‡Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource Science, and Elements Chemistry
Laboratory, RIKEN, 2ꢀ1 Hirosawa, Wakoꢀshi, Saitama 351ꢀ0198, Japan
ABSTRACT: Deprotonative directed ortho cupration of aromatic/heteroaromatic C–H bond and subsequent oxidation with
tBuOOH furnished functionalized phenols in high yields with high regioꢀ and chemoselectivity. DFT calculations revealed this hyꢀ
droxylation reaction proceeds via a copper (I → III → I) redox mechanism. Application of this reaction to aromatic C–H amination
using BnONH2 efficiently afforded the corresponding primary anilines. These reactions show broad scope and good functional
group compatibility. Catalytic versions of these transformations are also demonstrated.
• Phenol- and Aniline-derivative in Biologically Active Agents
INTRODUCTION
OH
O
OH
O
O
OH
O
H
N
OH
O
NH2
Directed ortho Metalation (DoM) reaction was discovered
over 75 years ago by Gilman1 and Wittig,2 and is now a funꢀ
damental synthetic reaction for the regioselective preparation
of aryl metal compounds.3 Since the development of improved
chemoselective bases,4 DoM has become a general tool for
access to a wide range of aromatic and heteroaromatic subꢀ
strates and for regioꢀcontrolled synthesis of multiꢀ
functionalized aromatics by utilizing intermediary aryl metal
species as aryl anion equivalents and as crossꢀcoupling partꢀ
ners. However, only limited attention has been paid to applicaꢀ
tion of DoM for phenol5/aniline6 synthesis, probably due to the
lack of efficient and reliable transformation routes from the
aryl metal intermediates.7,8 This situation is in contrast to reꢀ
cent extensive developments in Pdꢀcatalyzed aromatic C–H
hydroxylation chemistry pioneered by Fujiwara,9 Yu,10 and
others,11 as well as Ruꢀ12 and Cuꢀbased13 methodologies
(though most of those are only for use in phenol synthesis).
Densely functionalized phenol and aniline derivatives are
found in natural products and biologically active compounds
(Figure 1) and thus functional groupꢀcompatible, highꢀ
yielding, and reliable C–H hydroxylation/amination reactions
should of significant value in synthesis and drug discovery.
Therefore, a new, simple, chemoselective method suitable for
lateꢀstage installation of OH and NH2 on arenes would still be
highly desirable to complement currently available reactions.
N
NH2
N
NC
N
OH
NMe2
HO
N
F
Favipiravir
Olprinone
Tetracycline
CO2H
NH2
CO2H
O
N
O
O
O
O
S
NH
OH
H2N
O
N
N
H
S
O
O
N
O
O
N
N
COOH
N
H
H2N
N
H
Aztreonam
Oxybuprocaine
Pemetrexed
• This Work: Oxidative Hydroxylation and Amination of Aryl C–H Bond
OH
Hydroxylation
DMG
FG
H
[Cu]
Cu-ate Base
DMG
DMG
via Redox Action of Cu
FG
FG
Deprotonative
Cupration
NH2
DMG
FG
Amination
Figure 1. Aromatic Hydroxylation and Amination.
the presence of various directed metalation groups (DMGs).14
Functionalized aryl cuprate intermediates act as versatile and
potent aryl anions, reacting with various electrophiles in a
polar fashion. The intermediates also undergo oxidative ligand
coupling reaction in the presence of PhNO2,14a,15 and furtherꢀ
more, can be transformed into the corresponding phenols by
reaction with molecular oxygen.14a However, this method sufꢀ
fers from significant limitations; for example, oxidation by
molecular oxygen usually results in poor yields and incomꢀ
plete conversion of aryl metal intermediates, and is accompaꢀ
nied by formation of ligandꢀcoupling side products. Additionꢀ
We have recently shown that TMPꢀCuꢀate base
(RCu(CN)(TMP)Li2, R = alkyl, phenyl, or TMP; TMP =
2,2,6,6ꢀtetramethylpiperidido) promotes chemoꢀ and regioseꢀ
lective deprotonative cupration of functionalized aromatics in
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
ally, the oxidation requires a stoichiometric amount of CuCN occur at all, and only the starting benzamide 1a was recovered
1
2
3
4
5
6
7
8
and the operationally tedious procedure shows poor reproducꢀ
ibility and chemoselectivity.
(Entry 9). This observation ruled out a nucleophilic oxidation
mechanism, and the combination of Cuꢀate intermediate and
hydroperoxide proved to be crucial for smooth oxidation.
We present here a chemoꢀ and regioselective direct aromatic
C–H hydroxylation via deprotonative cupration followed by
hydroxylation with tertꢀbutyl hydroperoxide (TBHP). DFT
calculations revealed the hydroxylation pathway and the key
role of a copper redox process. We utilized this theoretical
information to design a direct aromatic C–H amination, as
well as catalytic versions of these transformations, and conꢀ
firmed their utility.
With the optimized reaction conditions in hand (Table 1, enꢀ
try 8), we examined the scope of this hydroxylation reaction
(Table 2). 4ꢀHalogenated N,Nꢀdiisopropylbenzamides were
efficiently converted to the corresponding phenols in high
yields (2b, 2c, and 2d). It is worth emphasizing that
Table 2. ortho Hydroxylationa
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
Optimization of Hydroxylation Reaction. We focused on
screening of suitable reagents/processes for smooth introducꢀ
tion of phenolic OH by using N,Nꢀdiisopropylbenzamide (1a)
as a model substrate. All initial attempts to oxidize the interꢀ
mediary aryl cuprates with various metal oxidants such as
CAN, permanganate or chromate salts, or organic oxidants
including percarboxylic acid derivatives, DDQ, or Oxone were
unsuccessful. The employment of ROOLi7d,16 occasionally
gave the desired phenols, but the process suffered from low
substrate generality and irreproducible yields. Surprisingly, the
direct use of TBHP, where the deprotonation of TBHP was
omitted, gave the corresponding phenols in good to excellent
yields with good reproducibility (Table 1).17 TMPꢀCuꢀates are
effective for this transformation (one bulky amide is required,
but the scope of the other ligands is rather wide). However,
Table 1. Optimization of Conditions
Entry
Ate Base
X
Y
Yield (%)a
1
2
3
4
5
6
7
8
(TMP)2Cu(CN)Li2
(iPr2N)2Cu(CN)Li2
nBuCu(CN)(TMP)Li2
tBuCu(CN)(TMP)Li2
(HMDS)2Cu(CN)Li2
(TMP)2Cu(CN)Li2
(TMP)2Cu(CN)Li2
(TMP)2Cu(CN)Li2
tBu2Zn(TMP)Li
2.2
2.2
2.2
2.2
2.2
1.3
1.3
1.3
2.2
2.0
2.0
2.0
2.0
2.0
1.2
1.2b
2.0
2.0
98
79
93
79
0
92c
89c
94c
0
a
b
c
d
g
Isolated yields. 7.0 mmol scale. Cupration at –78°C.
TBHP (1.2 eq.). e (TMP)2Cu(CN)Li2 (1.5 eq.). f TBHP (1.4 eq.).
9
(TMP)2Cu(CN)Li2 (2.2 eq.). h Oxidized by CHP. i Sodium benzoꢀ
a
b
j
NMR yields based on mesitylene as an internal standard.
Oxidized with CHP instead of TBHP. Isolated yields. HMDS =
1,1,1,3,3,3ꢀhexamethyldisilazido.
ate as substrate. NMR Yield based on mesitylene as an internal
standard.
c
4ꢀiodoꢀN,Nꢀdiisopropylbenzamide (1d), in which the C–I bond
is generally susceptible to metal reagents, afforded the correꢀ
sponding phenol 2d in excellent yield without any loss of ioꢀ
dine atom. A strongly electronꢀwithdrawing CF3 group was
well tolerated (2e: 92%). The styreneꢀtype substrate 1f could
be chemoꢀ and regioselectively oxidized at the aromatic C–H
bond without any side polymerization reactions via this deproꢀ
tonative cupration/oxidation sequence (2f: 71%) Naphthyl
derivatives gave the corresponding products in moderate to
high yields (2g: 89%, 2h: 76%). The substrate derived from 3ꢀ
anisic acid 1i was selectively hydroxylated at the 2ꢀposition by
no product formation was observed using the HMDS complex,
probably due to the low basicity (Entries 1–5). Decreasing the
amounts of both (TMP)2Cu(CN)Li2 and TBHP did not lead to
a significant decrease of product yield (Entry 6). Cumene hyꢀ
droperoxide (CHP) gave comparable results to TBHP (Entry
7). The use of excess TBHP (2 eq.) evaded protonation of the
aryl anion and improved the yield of the desired oxidation
reactions (Entry 8). On the other hand, the TMPꢀZnꢀate base
developed by our group4h also efficiently underwent DoM
reaction, but installation of the OH group with TBHP did not
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
virtue of the double directing effect of the amide and methoxy
Scheme 1. DFT Calculation of the Reaction Mechanism
(M06/SVP for Cu and 6-31+G* for Others; Energy in
kcal/mol). Natural Charge of Cu in Blue.
1
2
3
4
5
6
7
8
groups (2i: 79%). The sterically less hindered N,Nꢀ
diethylbenzamide (1j) was also tolerated, affording the desired
product 2j in 90% yield. Next, several other DMGs were exꢀ
amined. CN, OMOM, simple OMe, and PO(Cy)2 groups effecꢀ
tively assisted ortho metalation, and the subsequent oxidation
reaction proceeded smoothly (2k, 2l, 2m, and 2n). It should be
emphasized that this reaction is easily scaledꢀup and 2a was
obtained in 91% yield (1.41 g). Highꢀyielding formation of 2n
demonstrates the potential utility of this methodology in deriꢀ
vatization of phosphine ligand structure. An ester moiety is
generally vulnerable to strong nucleophiles. Alkyl benzoates
1o and 1p were converted to salicylates 2o and 2p by using
less nucleophilic CHP in 87% and 68% yields, respectively.
Benzoic acid itself was also a good substrate in the form of the
sodium salt (2q: 67%). The sp2ꢀhybridized nitrogen atom in
aromatic rings served as an efficient DMG. Isoquinoline and
benzothiazole gave isoquinolinꢀ1(2H)ꢀone (2r) and benꢀ
zo[d]thiazolꢀ2(3H)ꢀone (2s) regioselectively in good yields.
Even thiophene 1t could be converted to the corresponding
hydroxylated product 2t in 81% yield without degradation of
the thiophene ring under the oxidative conditions. The oxygen
atom was also introduced on the benzothiophene ring in 81%
yield (2u).
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
C–H Amination Reactions. Taking this mechanism in acꢀ
count, we applied this oxidation reaction of the Cuꢀate comꢀ
plex to amination reaction of aromatics.20,21 This reaction was
shown to be triggered by deprotonative ligation of the oxidant
to the Cu center,21 and we speculated that RONH2 should enaꢀ
ble amination to occur via formation of ArCu(NHOR)(CN)Li,
followed by redox reaction of Cu. Indeed, this deprotonative
amination worked well and an electronꢀdonating substituent
(R = Bn or Me) on the oxygen atom of RONH2 gave better
results than an electronꢀwithdrawing group (R = nitrobenzoyl
or mesitylsulfonyl), as expected from the DFT findings.
DFT Calculations. In order to shed light on the reaction
mechanism, DFT calculations (M06/631SVP)18 were perꢀ
formed to examine the hydroxylation reaction. The putative
reaction pathway is depicted in Scheme 1. We employed N,Nꢀ
dimethylbenzamide (RT) and methyl hydroperoxide as chemiꢀ
cal models for the substrate and oxidant, respectively. Directed
ortho cupration reaction of RT using (R2N)2Cu(CN)Li2 proꢀ
ceeds to form the intermediary arylꢀCuꢀate, Arꢀ
Cu(NR2)(CN)Li2 (IM1). Deprotonation of methyl hydroperoxꢀ
ide by the amido ligand NR2 of IM1 was shown to be kinetꢀ
ically advantageous over the thermodynamically favored
deprotonation by aryl ligand, and leads to ligand exchange,
forming a new arylꢀCuꢀate, ArCu(CN)(OOMe)Li (IM2). Less
efficient product formation with ROOLi (vide supra) and no
Representative results of the amination of various functionꢀ
alized arenes are summarized in Table 3. The aminations gave
comparable results/chemoselectivities to those of the hydroxꢀ
ylations with ROOH. The standard substrate 1a was smoothly
aminated to give 3a in 93% yield. In this amination reaction,
the C–I bond survived, as was the case in the hydroxylation
reaction (3d). The desired amination products were obtained
using substrates with a CF3 group and naphthalene ring in 70%
and 76% yields, respectively (3e and 3g). Other DMG groups
than N,Nꢀdiisopropylamides worked well and the correspondꢀ
ing anilines were obtained in high yields (3j–3o). The ester
moiety was well tolerated even in the presence of highly nuꢀ
cleophilic alkoxyamine, giving 2ꢀaminobenzoate 3o in 79%
yield. Various kinds of heteroaromatic substrates could be
tolerated under these reaction conditions. Electronꢀpoor isoꢀ
quinoline 1r and heteroaromatics with electronꢀrich πꢀsystems
1t and 1vꢀ1x were well converted to the corresponding amiꢀ
nated products, which are otherwise almost inaccessible synꢀ
thetically, in moderate to high yields (3r, 3t, and 3vꢀ3x). Amiꢀ
nation reaction also proceeded with a ferroceneꢀbased subꢀ
strate in 63% yield (3y). In contrast to research aimed at synꢀ
thesizing primary anilines via transition metalꢀcatalyzed crossꢀ
coupling between aryl halides and ammonia,22ꢀ24 this reaction
is, to our knowledge, the first reliable and versatile method for
direct installation of a free NH2 group in an aromatic ring via
C–H bond cleavage in a regioꢀ and chemoselective manner.25
t
product formation with BuOOtBu indicate that deprotonative
ligand exchange17 on the copper center is the key step for the
following oxidation reaction. The results of several examinaꢀ
tions indicated that the reaction pathway of OH installation
shown in Scheme 1 is the most probable.19 This transformation
takes place as a twoꢀstep reaction involving two electronꢀ
oxidation/reduction of the copper center during the reaction.
Oxidative addition of the peroxide ligand to the copper atom
(CuI
➝
CuIII) occurs with an activation barrier of +25.4
kcal/mol. The subsequent reductive elimination step from IM3
would proceed smoothly (∆E‡ = +12.9 kcal/mol) and the sysꢀ
tem would gain large stabilization energy (–92.7 kcal/mol)
because of the reꢀformation of a typical Lipshutzꢀtype cuprate
with several stable O–Cu and O–Li bonds. Natural bond orꢀ
bital (NBO) analysis of IM2, IM3, and IM4 supported an inꢀ
crease and then decrease of the positive charge of the Cu atom
as it goes from Cu(I) to Cu(III) and then back to Cu(I) along
the reaction pathway. These results strongly suggest that this
hydroxylation reaction is not a simple ionic reaction between
carbanion and peroxide, but occurs via redox reaction of the
copper center, in accordance with the experimental observaꢀ
tions (Tables 1, entry 9).
Table 3. ortho Amination of Aromaticsa
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
9). Under these reaction conditions, functionalized benzamide
1
2
3
4
5
6
7
1e, isoquinoline 1r and benzothiazole 1s were successfully
hydroxylated (2e, 2r, and 2s). Catalytic amination reactions
with the same substrates proceeded smoothly as well (3a, 3e,
3r, and 3s). This Cuꢀcatalyzed approach is expected to be apꢀ
plicable to oxidation of organometallics other than zinc (lithiꢀ
um, magnesium, etc.) and should also broaden the synthetic
scope for phenols and anilines.
8
9
CONCLUSION
We have developed efficient aromatic hydroxylation and
amination reactions via directed ortho cupration. DFT calculaꢀ
tion indicated that oxidative addition of peroxide to aryl copꢀ
per species is the key step for introduction of the hydroxyl
group, and this unique redox characteristic of copper also enaꢀ
bles amination reaction using alkoxyamines. This hydroxylaꢀ
tion/amination methodology shows high chemoꢀ and regioseꢀ
lectivity, and is applicable to a wide range of functionalized
aromatic and heteroaromatic compounds. This reaction is the
first example of an efficient oneꢀpot synthesis of functionalꢀ
ized phenols and anilines from the same substrates via deproꢀ
tonative cupration and successive oxidation by choosing apꢀ
propriate oxidants. We also demonstrated Cuꢀcatalyzed hyꢀ
droxylation/amination of aryl zincates prepared by deprotonaꢀ
tive zincation of (hetero)aromatic compounds. Work to expand
the scope of the reactions (i.e., introduction of other heteroaꢀ
toms, and hydroxylation and amination at sp3ꢀcarbon) and
mechanistic studies on the catalytic reaction are in progress in
our laboratory.
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
a Isolated yields. b Cupration at –78°C. c Inseparable contaminaꢀ
d
e
tion of 4ꢀphenylphenol.
(TMP)2Cu(CN)Li2 (1.5 eq.).
(TMP)2Cu(CN)Li2 (2.2 eq.) and BnONH2 (2.0 eq.).
Catalytic Reactions in Copper. Finally, we examined the
CuCNꢀcatalyzed hydroxylation/amination of metalated aroꢀ
matics. The redox action of Cu in the hydroxylation/amination
process, according to DFT calculation (vide supra), implies
that a catalytic system can potentially be achieved by approꢀ
priate reaction design. We employed the redoxꢀinactive TMPꢀ
Znꢀate for deprotonation of the substrate and TBHP for subseꢀ
quent oxidation in the presence of a catalytic amount of CuCN
ASSOCIATED CONTENT
Supporting Information
Experimental details, and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
Table 4. CuCN-catalyzed ortho Hydroxylation and Amina-
tion of Aromaticsa
*k1hirano@mol.f.uꢀtokyo.ac.jp
*uchiyama@mol.f.uꢀtokyo.ac.jp
Present Addresses
¶Graduate School of Pharmaceutical Sciences, Osaka University
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was partly supported by JSPS KAKENHI (S) (No.
24229011), The Asahi Glass Foundation, Foundation NAGASE
Science Technology Development, and Sumitomo Foundation (to
M. U.), JSPS GrantꢀinꢀAid for Young Scientists (Startꢀup) (No.
24850005) and JSPS GrantꢀinꢀAid for Young Scientists (A) (No.
16H06214) and (B) (No. 26860010) (to K. H.), and JSPS Grantꢀ
inꢀAid for Young Scientists (A) (to R. T.) (No. 25713001). The
calculations were performed on the Riken Integrated Cluster of
Clusters (RICC). We thank the Advanced Center for Computing
and Communication (RIKEN) for providing computational reꢀ
sources.
a Isolated yields.
(Table 4). After extensive optimization, the desired phenol 2a
was gratifyingly obtained in good yield (66%), whereas no
product was formed in the absence of CuCN (Table 1, entry
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
1989, 54, 24ꢀ26. (c) Trécourt, F.; Mallet, M.; Mongin, O.;
REFERENCES
1
2
3
4
5
Quéguiner, G. J. Org. Chem. 1994, 59, 6173ꢀ6178. Si: (d)
Bracegirdle, S.; Anderson, E. A. Chem. Commun. 2010, 46,
3454ꢀ3456. (e) Sunderhaus, J. D.; Lam, H.; Dudley, G. B. Org.
Lett. 2003, 5, 4571ꢀ4573.
(1) (a) Gilman, H.; Bebb, R. L. J. Am. Chem. Soc. 1939, 61,
109ꢀ112. (b) Gilman, H.; Langham, W.; Jacoby, A. L. J. Am.
Chem. Soc. 1939, 61, 106ꢀ109.
(2) (a) Wittig, G.; Fuhrmann, G. Chem. Ber. 1940, 73, 1197ꢀ
1218. (b) Wittig, G.; Pockels, U.; Dröge, H. Ber. Dtsch. Chem.
Ges. 1938, 71, 1903ꢀ1912.
(9) (a) Jintoku, T.; Taniguchi, H.; Fujiwara, Y. Chem. Lett.
1987, 1865ꢀ1868. (b) Jintoku, T.; Nishimura, K.; Takaki, K.;
Fujiwara, Y. Chem. Lett. 1990, 1687ꢀ1688.
(10) Zhang, Y.ꢀH.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2009, 131,
14654ꢀ14655.
6
7
(3) For a comprehensive review on DoM reactions, see: (a)
Snieckus, V. Chem. Rev. 1990, 90, 879ꢀ933. (b) Beak, P.;
Snieckus, V. Acc. Chem. Res. 1982, 15, 306ꢀ312. (c) Snieckus,
V. Heterocycles 1980, 14, 1649ꢀ1676. For stereoꢀ and regioꢀ
controlled deprotonative metalation of various types of C–H
bonds by utilizing complex induced proximity effects, see: (d)
Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356ꢀ363.
(4) Mg amide bases are powerful tools for arene functionalꢀ
ization. (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. An-
gew. Chem. Int. Ed. 2006, 45, 2958ꢀ2961. (b) Kondo, Y.; Yoꢀ
shida, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1996,
2331ꢀ2332. (c) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J.
J. Org. Chem. 1995, 60, 8414ꢀ8416. (d) Eaton, P. E.; Lee, C.ꢀ
H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111, 8016ꢀ8018. Mulꢀ
vey et al. elucidated the structure of the KnochelꢀHauser base
(TMPMgCl•LiCl) based on Xꢀray crystallographic analysis,
see: (e) GarcíaꢀÁlvarez, P.; Graham, D. V.; Hevia, E.; Kennedy,
A. R.; Klett, J.; Mulvey, R. E.; O’Hara, C. T.; Weatherstone, S.
Angew. Chem. Int. Ed. 2008, 47, 8079ꢀ8081. We have been
extensively working on chemoselective deprotonative metaꢀ
lation reactions with Znꢀate bases and Alꢀate base. Zn-ate
bases: (f) Uchiyama, M.; Kobayashi, Y.; Furuyama, T.; Nakaꢀ
mura, S.; Kajihara, Y.; Miyoshi, T.; Sakamoto, T.; Kondo, Y.;
Morokuma, K. J. Am. Chem. Soc. 2008, 130, 472ꢀ480. (g)
Uchiyama, M.; Matsumoto, Y.; Nobuto, D.; Furuyama, T.;
Yamaguchi, K.; Morokuma, K. J. Am. Chem. Soc. 2006, 128,
8748ꢀ8750. (h) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoꢀ
to, T. J. Am. Chem. Soc. 1999, 121, 3539ꢀ3540. Al-ate base:
(i) Naka, H.; Morey, J. V.; Haywood, J.; Eisler, D. J.;
McPartlin, M.; García, F.; Kudo, H.; Kondo, Y.; Uchiyama,
M.; Wheatley, A. E. H. J. Am. Chem. Soc. 2008, 130, 16193ꢀ
16200. (j) Naka, H.; Uchiyama, M.; Matsumoto, Y.; Wheatley,
A. E. H.; McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem.
Soc. 2007, 129, 1921ꢀ1930. For a review on deprotonative
metalation using ate bases, see: (k) Mulvey, R. E.; Mongin, F.;
Uchiyama, M.; Kondo, Y. Angew. Chem. Int. Ed. 2007, 46,
3802ꢀ3824.
(5) (a) Synthetic and Natural Phenols, Tyman, J. H. P., Ed.;
Elsevier: New York, 1996. (b) The Chemistry of Phenols,
Rappoport, Z., Ed.; John Wiley & Sons Ltd.: Chichester, 2003.
(6) The Chemistry of Anilines, Rappoport, Z., Ed.; John
Wiley & Sons Ltd.: Chichester, 2007.
(7) Aryl metals generated via DoM react with molecular oxꢀ
ygen, albeit in low to moderate yields. For examples, see: Li:
(a) Parker, K. A.; Koziski, K. A. J. Org. Chem. 1987, 52, 674ꢀ
676. Mg: (b) Bellamy, E.; Bayh, O.; Hoarau, C.; Trécourt, F.;
Quéguiner, G.; Marsais, F. Chem. Commun. 2010, 46, 7043ꢀ
7045. Al: See ref. 4j. Cu: (c) Lambert, G. J.; Duffley, R. P.;
Dalzell, H. C.; Razdan, R. K. J. Org. Chem. 1982, 47, 3350ꢀ
3353. See also ref. 9a. For an example of oxidation reaction
with tBuOOLi, see: (d) Julia, M.; SaintꢀJalmes, V. P.; Verpeaux,
J.ꢀN. Synlett 1993, 233ꢀ234.
8
9
(11) (a) Yan, Y.; Feng, P.; Zheng, Q.ꢀZ.; Liang, Y.ꢀF.; Lu, J.ꢀ
F.; Cui, Y.; Jiao, N. Angew. Chem. Int. Ed. 2013, 52, 5827ꢀ
5831. (b) Shan, G.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem.
Int. Ed. 2012, 51, 13070ꢀ13074. (c) Mo, F.; Trzepkowski, L.
J.; Dong, G. Angew. Chem. Int. Ed. 2012, 51, 13075ꢀ13079.
(d) Choy, P. Y.; Kwong, F. Y. Org. Lett. 2013, 15, 270ꢀ273. (e)
Zhang, H.ꢀY.; Yi, H.ꢀM.; Wang, G.ꢀW.; Yang, B.; Yang, S.ꢀD.
Org. Lett. 2013, 15, 6186ꢀ6189. Sanford et al. reported the
related Pdꢀcatalyzed acetoxylation, see: (f) Desai, L. V.; Malik,
H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141ꢀ1144. (g) A
review on Pdꢀcatalyzed aromatic C–O bond formation reacꢀ
tions, see: Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40,
4912ꢀ4924.
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
(12) (a) Yang, Y.; Lin, Y.; Rao, Y. Org. Lett. 2012, 14, 2874ꢀ
2877. (b) Thirunavukkarasu, V. S.; Hubrich, J.; Ackermann, L.
Org. Lett. 2012, 14, 4210ꢀ4213.
(13) (a) Li, X.; Liu, Y.ꢀH.; Gu, W.ꢀJ.; Li, B.; Chen, F.ꢀJ.; Shi,
B.ꢀF. Org. Lett. 2014, 16, 3904ꢀ3907. (b) Liu, Q.; Wu, P.; Yang,
Y.; Zeng, Z.; Liu, J.; Yi, H.; Lei, A. Angew. Chem. Int. Ed.
2012, 51, 4666ꢀ4670. (c) Chen, X.; Hao, X.ꢀS.; Goodhue, C.
E.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2006, 128, 6790ꢀ6791.
(14) (9) (a) Usui, S.; Hashimoto, Y.; Morey, J. V.; Wheatley,
A. E. H.; Uchiyama, M. J. Am. Chem. Soc. 2007, 129, 15102ꢀ
15103. For mechanistic studies, see: (b) Komagawa, S.; Usui,
S.; Haywood, J.; Harford, P. J.; Wheatley, A. E. H.; Matsumoꢀ
to, Y.; Hirano, K.; Takita, R.; Uchiyama, M. Angew. Chem. Int.
Ed. 2012, 51, 12081ꢀ12085. (c) Haywood, J.; Morey, J. V.;
Wheatley, A. E. H.; Liu, C.ꢀY.; Yasuike, S.; Kurita, J.;
Uchiyama, M.; Raithby, P. R. Organometallics 2009, 28, 38ꢀ
41.
(15) Nguyen, T. T.; Marquise, N.; Chevallier, F.; Mongin, F.
Chem. Eur. J. 2011, 17, 10405ꢀ10416.
(16) Reaction of ROOMgX with Grignard reagents, see:
Lawesson, S.ꢀO.; Yang, N. C. J. Am. Chem. Soc. 1959, 81,
4230ꢀ4233.
(17) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.;
Marek, I. Nature 2012, 490, 522ꢀ526.
(18) M06/631SVP denotes the basis set of SVP for Cu and
6ꢀ31+G* for other atoms with the M06 functional.
(19) Possible oxygenation pathways via 1,2ꢀmetalate rearꢀ
rangement mechanisms were computed to have rather high
activation barriers (> +40 kcal/mol, calculated at the level of
M06/631SVP).18
(8) Indirect oxidation reactions of aryl metals via arylꢀB and
arylꢀSi species have been reported. B: (a) Beak, P.; Brown, R.
A. J. Org. Chem. 1982, 47, 34ꢀ46. (b) Iwao, M.; Iihama, T.;
Mahalanabis, K. K.; Perrier, H.; Snieckus, V. J. Org. Chem.
For the 1,2ꢀrearrangement, see: Scott, H. K.; Aggarwal, V.
K. Chem. Eur. J. 2011, 17, 13124ꢀ13132. See also ref. 17.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
(20) For a review on electrophilic amination reactions of orꢀ Torborg, C.; Enthaler, S.; Schäffner, B.; Dumrath, A.; Spanꢀ
1
2
3
4
5
6
7
8
ganometallic compounds, see: Erdik, E.; Ay, M. Chem. Rev.
1989, 89, 1947ꢀ1980.
nenberg, A.; Neumann, H.; Börner, A.; Beller, M. Chem. Eur.
J. 2009, 15, 4528ꢀ4533. (e) Lundgren, R. J.; Peters, B. D.;
Alsabeh, P. G.; Stradiotto, M. Angew. Chem. Int. Ed. 2010, 49,
4071ꢀ4074. (f) Dumrath, A.; Lübbe, C.; Neumann, H.; Jackꢀ
stell, R.; Beller, M. Chem. Eur. J. 2011, 17, 9599ꢀ9604. (g)
Alsabeh, P. G.; Lundgren, R. J.; McDonald, R.; Johansson
Seechurn, C. C. C.; Colacot, T. J.; Stradiotto, M. Chem. Eur. J.
2013, 19, 2131ꢀ2141. (h) Crawford, S. M.; Lavery, C. B.;
Stradiotto, M. Chem. Eur. J. 2013, 19, 16760ꢀ16771. (i)
Cheung, C. W.; Surry, D. S.; Buchwald, S. L. Org. Lett. 2013,
15, 3734ꢀ3737. A highlight article of Pdꢀcatalyzed amination
and hydroxylation of aryl halides, see: (j) Willis, M. C. Angew.
Chem. Int. Ed. 2007, 46, 3402ꢀ3404. A review for Pdꢀ
catalyzed amination of aryl halides using ammonia, see: (k)
Kim, J.; Kim, H. J.; Chang, S. Eur. J. Org. Chem. 2013, 3201ꢀ
3213.
(21) Ricci et al. reported electrophilic amination reactions
of homoleptic Lipshutzꢀcuprates (R2Cu(CN)Li2) prepared
from RLi and CuCN. Indirect route to primary anilines with
TMSONHTMS: (a) Casarini, A.; Dembech, P.; Lazzari, D.;
Marini, E.; Reginato, G.; Ricci, A.; Seconi, G. J. Org. Chem.
1993, 58, 5620ꢀ5623. For preparation of Nꢀalkyl anilines: (b)
Bernardi, P.; Dembech, P.; Fabbri, G.; Ricci, A.; Seconi, G. J.
Org. Chem. 1999, 64, 641ꢀ643.
(22) Cu: (a) Xia, N.; Taillefer, M. Angew. Chem. Int. Ed.
2009, 48, 337ꢀ339. (b) Lang, F.; Zewge, D.; Houpis, I. N.;
Volante, R. P. Tetrahedron Lett. 2001, 42, 3251ꢀ3254.
(23) Ni: (a) Borzenko, A.; RottaꢀLoria, N. L.; MacQueen, P.
M.; Lavoie, C. M.; McDonald, R.; Stradiotto, M. Angew.
Chem. Int. Ed. 2015, 54, 3773ꢀ3777. (b) Green, R. A.; Hartꢀ
wig, J. F. Angew. Chem. Int. Ed. 2015, 54, 3768ꢀ3772.
(24) Pd: (a) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 10028ꢀ10029. (b) Surry, D. S.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 10354ꢀ10355. (c) Vo, G. D.; Hartwig, J.
F. J. Am. Chem. Soc. 2009, 131, 11049ꢀ11061. (d) Schulz, T.;
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
(25) For a recent perspective on transition metalꢀcatalyzed
C–H amination of (hetero)aromatics, see: (a) Kim, H.; Chang,
S. ACS Catal. 2016, 6, 2341ꢀ2351 and references therein.
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
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
7
ACS Paragon Plus Environment