Ligand-Free, Copper-Catalyzed Aerobic Benzylic sp 3 C-H Oxygenation

Article abstract of DOI:10.1055/s-0036-1588969

A ligand-free and operationally simple copper-catalyzed aerobic benzylic sp ³ C-H oxygenation was developed. The addition of tert -butyl hydroperoxide, either in a catalytic or stoichiometric amount, was key for activating stable C-H bonds under mild conditions to furnish the corresponding ketones or esters in moderate to excellent yield.

Full text of DOI:10.1055/s-0036-1588969

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Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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H. Tanaka et al.
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Ligand-Free, Copper-Catalyzed Aerobic Benzylic sp C–H Oxygen-
ation
Hirotaka Tanakaa
Kounosuke Oisaki*a
Motomu Kanai*a,b
O
H
H
O2 (open air)
CuCl (10 mol%)
X
X
R
R
TBHP (0.3–3 equiv)
t-BuOH (0.1 M), 50 °C, 12 h
a
Graduate School of Pharmaceutical Sciences, The University of
ligand-free
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
oisaki@mol.f.u-tokyo.ac.jp
kanai@mol.f.u-tokyo.ac.jp
inexpensive CuCl as catalyst
mild conditions
simple operation
b
ERATO, Kanai Life Science Catalysis Project, Japan Science and
Technology Agency (JST), 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-0033, Japan
Received: 16.01.2017
Accepted after revision: 16.02.2017
Published online: 08.03.2017
tiators and found that adding TBHP (3 equiv) promoted the
C–H oxygenation in quantitative yield (entry 2). Reducing
the amount of TBHP revealed that even a substoichiometric
amount of TBHP was sufficient to promote the reaction (en-
DOI: 10.1055/s-0036-1588969; Art ID: st-2017-r0042-c
Abstract A ligand-free and operationally simple copper-catalyzed aer-
tries 3–5), suggesting that O was the actual terminal oxi-
2
3
obic benzylic sp C–H oxygenation was developed. The addition of tert-
dant. We determined that the conditions shown in entry 3
using 0.3 equiv TBHP were optimal for the oxygenation of
isochromans (see Table 2, entries 1 and 14–19). Catalyst
loading could be reduced to 1 mol%, although the yield was
slightly decreased compared with the yield produced when
TBHP was used in the same amounts (Table 1, entries 6 and
butyl hydroperoxide, either in a catalytic or stoichiometric amount, was
key for activating stable C–H bonds under mild conditions to furnish
the corresponding ketones or esters in moderate to excellent yield.
3
Key words sp C–H oxygenation, copper, oxygen, ligand-free, benzyl-
ic oxidation
7
vs. entries 4 and 2, respectively).
3
Direct sp C–H functionalization is an important reac-
The indispensable role of O was also supported when
2
tion for realizing efficient synthetic routes toward complex
the reaction was performed under argon (Ar) atmosphere
with the solvent deoxygenated by freeze–pump–thaw cy-
cling. Product 2a was obtained in only 16% yield and 1-tert-
butylperoxyisochromane (3) was detected in 44% yield (Ta-
ble 1, entry 8). When the reaction was conducted without
the copper catalyst, 3 was again formed as the major prod-
uct (34%) and 2a was produced in 2% yield (entry 9). When
the reaction was carried out with other copper sources, 2a
was generally obtained in almost quantitative yield, except
when a Cu(II) source was used (entries 10–14). Metal salts
containing other elements such as Ni, Fe, Sn, Zn, and In,
1
2
molecules. Among them, base-metal-catalyzed, ligand-
3
3
free aerobic sp C–H oxidations that directly introduce ox-
ygen functionalities to stable organic molecules using diox-
ygen (O ) as a terminal oxidant are especially advantageous
2
in view of atom economy, low cost of earth-abundant ele-
ments, simple operation (especially beneficial to small
scale), environmental friendliness, and minimal generation
of toxic byproducts. Reports of such reactions without the
4
use of directing groups, however, are still rare. Although
there are a few examples of ligand-free, copper-catalyzed
3
aerobic sp C–H oxygenation, the substrate scope of those
gave 2a in low yield (entries 15–20). Pd(OAc) was a good
2
5
reactions is quite limited. Herein, we report a ligand-free
catalyst (entry 21). When 1 mol% IrCl was used as catalyst,
3
3
copper-catalyzed aerobic oxygenation of benzylic sp C–H
the reaction did not proceed (entry 22), but the yield was
dramatically improved in the presence of ligands (entries
23–25). Overall, CuCl was the most favorable choice in view
of reactivity and cost (Sigma–Aldrich, $64.8/500 g).
bonds in the presence of tert-butyl hydroperoxide (TBHP),
with a comparatively broad substrate scope.
We began our studies by surveying catalytic metal
3
6,7
sources for the direct aerobic sp C–H oxygenation of iso-
We investigated the substrate generality under the
chroman (1a) under ligand-free conditions (Table 1). When
the oxygenation was conducted using 10 mol% CuCl in tert-
butanol (t-BuOH, 0.1 M) at 50 °C for 12 h under open air
conditions, the desired isochromanone (2a) was obtained
in low yield (5%, entry 1). We then investigated external ini-
optimized conditions of 10 mol% CuCl and 3 equiv TBHP
(0.3 equiv when isochromans were used as substrates) in t-
BuOH under open air at 50 °C for 12 h (Table 2). Fluorene
(1b) was a good substrate for the oxygenation to give 9-fluo-
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H. Tanaka et al.
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Table 1 Optimization of Reaction Conditions
good substrates, producing the corresponding esters 2h and
2i in 70 and 96% yield, respectively (entries 11 and 13).
O
air
These results demonstrated the applicability of the current
method as a mild, oxidative deprotection method of O-ben-
zyl- or O-p-methoxylbenzyl-protected alcohols after con-
version into the corresponding esters and hydrolysis. Iso-
chroman derivatives possessing various substituents 1j–o
could be oxidized with 0.3 equiv TBHP (entries 14–19). Al-
though the yields were slightly decreased, both electron-
donating and electron-withdrawing groups were compati-
ble. Both benzylic methyl and methine groups are suscepti-
ble to the current oxidation conditions, but difficulties as-
sociated with controlling the oxidation state led to lower
yields (entries 20 and 21). Oxygenation of an allylic position
was also difficult under our reaction conditions (see the
Supporting Information).
metal
O
O
TBHP (X equiv)
t-BuOH (0.1 M)
1a
50 °C, 12 h
2a
Entry
Metal (mol%)
TBHP (X equiv)
Yield (%)a
1
2
3
4
5
6
7
8b
9
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (1)
CuCl (1)
CuCl (1)
none
0
5
100
100
99
61
83
92
16
2
3
1
0.3
0.1
0.3
3
3
3
Table 2 Copper-Catalyzed Aerobic Benzylic sp C–H Oxygenation
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
CuBr (10)
CuI (10)
3
100
96
62
100
100
8
O
H
H
air
3
CuCl (10 mol%)
X
X
R
R
CuCl
CuOAc (10)
Cu O (10)
NiCl
2
·H
2
O (10)
3
TBHP (3 equiv)
t-BuOH (0.1 M)
50 °C, 12 h
1
2
3
2
3
Yield (%)a
100
Entry
1
Substrate
Product
2
(10)
(10)
(10)
3
O
FeCl
2
3
3
33
30
3
O
O
FeCl
3
1
a
SnCl
ZnCl
In(OTf)
Pd(OAc)
IrCl (1)
Ir(cod)(acac) (1)
2
·2H
(10)
(10)
(10)
2
O (10)
3
2
2
a
2
3
30
0
O
3
3
2b
3
22b
83
2
3
87
0
3
1b
3
b
3
79
88
82
O
[Cp*IrCl
2
]
2
(1)
(1)
3
4
5
6
54
70
45
2
[Ir(cod)Cl]
2
3
1
c
a
1
Yield based H NMR spectroscopic analysis with 1,1,2,2-tetrachloroethane
as internal standard.
2c
b
O
The reaction was performed under Ar with deoxygenated solvent.
renone (2b) in 83% isolated yield (entry 3). Diphenylmeth-
ane (1c) was also oxidized in moderate yield (entry 4). In-
dan (1d) and 1,2,3,4-tetrahydronaphthalene (1e), which
each have two reaction sites, were selectively oxidized to
the corresponding mono-ketones 2d and 2e, respectively, in
moderate to high yield (entries 5 and 6). Butylbenzene (1f),
possessing an acyclic aliphatic chain at the benzylic posi-
tion, showed poor reactivity (entry 7). On the other hand,
oxygenation of p-ethylanisole (1g) produced p-methoxyac-
etophonone (2g) in 53% yield due to activation by an elec-
tron-donating methoxy group (entry 9). Dibenzyl ether
1d
2
d
O
O
1
1
e
f
2e
Me
Me
7
16
2
f
(
1h) and (4-methoxybenzyl) methyl ether (1i) were also
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H. Tanaka et al.
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Table 2 (continued)
O
O
Entry
Substrate
Product
Yield (%)a
air
CuCl
(1 mol%)
air
O
TBHP (3 equiv)
2a : 83%
+
Me
O
1a : 64%
2a : 2%
8b
9
14b
53
(1)
Me
t-BuOH
0 °C, 12 h
3
: 34%
t-BuOH
50 °C, 12 h
O
MeO
5
t-Bu
O
MeO
1a
1
g
2
g
O
O
O
0b
1
35b
70
3 : 12%
1
1
O
1
h
Ar, degas
CuCl
2
h
Ar, degas
TBHP (3 equiv)
1a : 71%
2a : 2%
(1 mol%)
1a : 22%
2a : 43%
3 : 30%
O
1a
(2)
3
: 24%
t-BuOH
50 °C, 12 h
OMe
t-BuOH
50 °C, 12 h
1
1
2b
3
OMe
40b
96
MeO
1
Scheme 1 Control experiments
i
MeO
2
i
O
O
To gain insight into the reaction mechanism, several
control experiments were conducted (Scheme 1). Com-
pound 1a reacted with 3 equiv TBHP under open air condi-
tions without CuCl for 12 h to give 64% recovered 1a, 2% 2a,
and 34% 3a (Scheme 1, eq. 1, left arrow, and Table 1, entry
O
4b
1
79
1
j
2
j
O
9
). The result suggests that thermally generated tert-butyl
Br
O
Br
·
8
5b
O
peroxy radical (t-BuOO ) cleaves the benzylic C–H bond of
1
1
1
63
65
78
1
a, and that subsequent trapping of the thus-generated
1
k
2
F
2
k
·
benzylic carbon radical with t-BuOO should produce 3a.
The addition of 1 mol% CuCl to the resulting mixture with
stirring for an additional 12 h resulted in the complete con-
sumption of 1a and the production of 2a in 83% yield
O
F
O
6b
O
1
l
(Scheme 1, eq. 1, right arrow). These findings demonstrated
l
the important role of CuCl for accelerating both the C–H ac-
O
Me
tivation and conversion of 3 into 2a. Although O had little
2
O
Me
7b
O
effect on the reaction under CuCl-free conditions (Scheme
1
1
m
1, eq. 1, left arrow vs. eq. 2, left arrow), O significantly ac-
2
2
2
m
celerated the consumption of 1a as well as the production
of 2a, but not consumption of 3, by the addition of CuCl
(Scheme 1, eq. 1, right arrow vs. eq. 2, right arrow).
O
O
O
1
8b
72
A possible mechanism for the present catalytic cycle ex-
emplified by oxygenation of 1a is proposed in Scheme 2.
First, TBHP is activated through a thermal route (to form t-
Me
n
Me
n
·
·
BuOO ) or Fenton type mechanism (to form t-BuOO or t-
O
O
MeO
·
O
MeO
BuO ). The thus-generated peroxy or alkoxyl radical ab-
O
1
2
2
9b
54
17
stracts a benzylic hydrogen atom from 1a, affording carbon
8
1
o
radical A. Radical A reacts with O to form B, which ab-
2
2
o
stracts a hydrogen atom from 1a to produce hydroperoxide
C and regenerates A (path a). Peroxide C is dehydrated to
Me
Me
·
OH
give 2a. Alternatively, radical A reacts with t-BuOO to form
0
MeO
1
9
3
(path b), which can also be converted into 2a. Both path-
MeO
2
p
p
ways either from C or 3 to 2a are accelerated in the pres-
ence of a copper species,1
0,11
perhaps in a mode similar to a
Me
OH
Me 27 (2g)
4 (2q)
Fenton type mechanism.
In summary, we have developed a facile copper-cata-
lyzed, ligand-free benzylic sp3 C–H oxygenation reaction
Me
1
2g +
2
MeO
1
MeO
2q
q
with TBHP and O under mild reaction conditions. This li-
2
a
Isolated yield.
TBHP (0.3 equiv) was used.
gand-free, earth-abundant copper-catalyst system is bene-
b
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H. Tanaka et al.
Cluster
(
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t-Bu
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O
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O
"Cu"
B
C
6
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(
2
2
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Acknowledgment
(s) Yi, H.; Bian, C.; Hu, X.; Niu, L.; Lei, A. Chem. Commun. 2015,
5
1, 14046.
This work was supported by JSPS KAKENHI Grant Number
JP#16H01007 in Precisely Designed Catalysts with Customized Scaf-
folding (K.O.) and ERATO from JST (M.K.).
(
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588969.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(g) Yu, J.-W.; Mao, S.; Wang, Y.-Q. Tetrahedron Lett. 2015, 56,
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