Iron-Catalyzed Aminative Cyclization/Intermolecular Homolytic Aromatic Substitution Using Oxime Esters and Simple Arenes

Article abstract of DOI:10.1002/asia.201701634

Intermolecular C?H alkylation of simple arenes in the presence of an iron catalyst has been achieved in a cascade manner with an aminative cyclization triggered by N?O bond cleavage of an alkene-tethered oxime ester. Various arenes, including electron-rich and electron-poor arenes, and heteroarenes can be employed in the reaction system. Regioselectivity and radical trapping experiments support the involvement of alkyl radical species, which undergo a homolytic aromatic substitution (HAS) to afford the arylation products.

Full text of DOI:10.1002/asia.201701634

CHEMISTRY
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Accepted Article
Title: Iron-Catalyzed Aminative Cyclization/Intermolecular Homolytic
Aromatic Substitution Using Oxime Esters and Simple Arenes
Authors: Takuya Shimbayashi, Kazuhiro Okamoto, and Kouichi Ohe
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10.1002/asia.201701634
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COMMUNICATION
Iron-Catalyzed Aminative Cyclization/Intermolecular Homolytic
Aromatic Substitution Using Oxime Esters and Simple Arenes
Takuya Shimbayashi, Kazuhiro Okamoto* and Kouichi Ohe*[a]
Abstract: Intermolecular C–H alkylation of simple arenes in the
presence of an iron catalyst has been achieved in a cascade manner
with an aminative cyclization triggered by N–O bond cleavage of an
alkene-tethered oxime ester. Various arenes, including electron-rich
and electron-poor arenes, and heteroarenes can be employed in the
reaction system. Regioselectivity and radical trapping experiments
support the involvement of alkyl radical species, which undergo a
homolytic aromatic substitution (HAS) to afford the arylation products.
heterocycles.8 Reductive cleavage of an N–O bond in oxime
esters or ethers with transition metals or photoredox catalysts
has been applied to the generation of iminyl radicals and radical
cascade with tethered unsaturated bonds9,10 since Narasaka’s
pioneering work (Scheme 2a).11 Most recently, much attention in
this area has focused on iron catalysis.12
a) Narasaka's Iminyl Radical Cyclization
Cu
or
X
R
O
ArONa
N
N
N
O
N
Radical-based aromatic C–H functionalization such as homo-
lytic aromatic substitution (HAS) reactions has emerged as an
atom-efficient and direct route to substituted arenes because
less functionalized starting materials can be employed.1 HAS
reactions often involve intramolecular reactions because the
slow rate of radical addition to simple arenes, in particular with
alkyl radicals,2 means that radical quenching is difficult to avoid.
In contrast to the intramolecular reactions, the number of
intermolecular variants of HAS that take advantage of electron
transfer induced by strong base, transition-metal catalysts, and
photoredox catalysts, has grown significantly,3 and many
successful examples, such as biaryl coupling,4 fluoroalkylation,5
or alkylation5b,6 have been developed (Scheme 1a). However,
these alkylation reactions are typically limited to heteroarenes.
Furthermore, intermolecular HAS reactions involving an alkyl
radical generated through atom transfer radical addition (ATRA)
to alkenes in a cascade manner are scarce (Scheme 1b).7
Ph
Ph
Ph
X = H, Cl, Br, SPh, SePh
Ph
b) This Work
R
O
Ar
cat.[Fe]
Ar
O
N
N
Ph
H
Ph
Me
Me Me
Me
· Aminoarylation of alkene
· C–H alkylation of arene
Scheme 2. Aminative transformation involving iminyl radicals.
Our research interests have focused on N–O bond cleavage
of oxime derivatives with a variety of transition metals for new
transformations involving reactive species, such as nitrene or
ketimido complexes, and catalytic synthesis of N-containing
heterocycles13 and isolation of Rh(III)-imine and Ru(IV)-ketimido
complexes14 have been described. The Ru(IV)-ketimido complex
would be a key intermediate for aminochlorination of tethered
alkenes or alkynes,14b which prompted us to explore their
catalytic aminative transformation. In the course of many trials,
we found that oxime esters undergo N–O bond cleavage with a
cationic Fe(II)-bipyridine complex followed by 5-exo-trig
cyclization with a tethered alkene to give an intermediate12c that
is applicable to the intermolecular HAS reactions (Scheme 2b).
Here, we report catalyst screening, substrate scope, and
mechanistic insight on this transformation.
a) Precedent Intermolecular HAS (Homolytic Aromatic Substitution)
H
R
R
HAS
R = Aryl
Alkyl, Fluoroalkyl
b) Intermolecular HAS via ATRA
H
X
X
X
ATRA
HAS
Substitution with functionalized alkyl groups
During our development of an aminative transformation
reaction of oxime ester 1a-t-Bu in benzene solvent under
Fe(OTf)2 catalysis (Table 1), we were surprised to observe the
formation of phenylated product 3aa together with a small
amount of hydrogen atom adduct 4a and acyloxylated product
5a-t-Bu (entry 1). Intense efforts were then made to optimize the
conditions for the phenylation reaction. Various ligands for the
iron catalyst were examined.15 The use of bipyridyl ligands
slightly improved the yield of 3aa (entries 2–4). Among the
ligands tested, L1 was found to give the best result (entry 2).
Raising the reaction temperature to 120 °C gave 3aa in the
highest yield (entry 5). The reaction was also catalyzed by
Fe(OTf)3, albeit in lower yield (entry 6). The substituent R on the
carboxyl group had a significant effect on the results. When
acetyl ester (1a-Me) was used, the yield of 3aa decreased (entry
7). The use of picolinoyl ester (1a-2-Py) afforded 3aa in an
Scheme 1. C–H Functionalization via HAS.
The iminyl radical, which is a highly reactive N-centered
radical, has been applied to the synthesis of N-containing
[a]
T. Shimbayashi, Dr. K. Okamoto, Prof. Dr. K. Ohe
Department of Energy and Hydrocarbon Chemistry, Graduate
School of Engineering, Kyoto University
Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: kokamoto@scl.kyoto-u.ac.jp
ohe@scl.kyoto-u.ac.jp
Supportinginformation and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.xxxxxxxxx.
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10.1002/asia.201701634
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COMMUNICATION
identical yield to that obtained with a t-butyl group (1a-t-Bu)
without forming acyloxylated product 5a-2-Py (entry 8).
Interestingly, pentafluorobenzoyl ester (1a-C6F5), having an
electron-withdrawing nature, prohibited the formation of 3aa,
affording acyloxylated product 5a-C6F5 in high yield (entry 9).16
addition of trifluoroacetic acid, probably because of protonation
of the nitrogen atom of pyridine. Thiophenes 2s or 2t afforded
3as or 3at, respectively, in good yield with high C-2 selectivity.
R
O
N
Ar
Fe(OTf)2 (10 mol%)
O
Table 1. Optimization of reaction conditions.[a]
L1 (10 mol%)
N
Arene 2 (150 equiv)
120 °C, 12 h
conv 100%
Ph
Ph
Me Me
1a-t-Bu, 1a-2-Py
Me
Me
Fe(OTf)2
(10 mol%)
Ligand
R
O
N
3a
Ph
H
OCOR
Cl
Cl
O
N
N
N
Ph
(10 mol%)
Ph
Ph
Ph
Ph
C6H6 (2a)
(168 equiv)
temp, time
N
N
equiv
of arene
Me
Me
Me
Me
Me
Me
Me Me
1a-x
entry
3ac
N
Ph
Cl
Ph
3aa
4a
5ax
Me
3aa
52%a,b
1a
2b
3a
4a
Me
Me
3ab
62%a
70% 150
31% 150
Me
Ph
Me
3ac
Me
Cl
Entry Ligand
R
Temp (°C) Time (h) 3aa (%) 4a (%) 5ax (%)
55%
44%
50
20
(o:m:p =68:24:8)
1
none
t-Bu (1a-t-Bu) 100
20
38
11
14
2
3
L1
L2
t-Bu
t-Bu
100
100
20
20
51
45
12
9
10
17
Cl
Cl
+
N
N
Cl
Ph
Ph
Me
Me
Me
Me
4
L3
L1
L1
L1
L1
t-Bu
100
120
120
120
20
12
12
12
12
47
11
13
11
10
45
0
3ad
43%a
3ad'
25%a
5
t-Bu
54(52)b 11
X-ray
F
Br
6c
t-Bu
33
30
11
6
Cl
CO2Me
Cl
7
Me (1a-Me)
8
2-Py (1a-2-Py) 120
C6F5 (1a-C6F5) 100
54(52)b 13
Br
F
N
N
N
Cl
N
NC
9
L1
20
9
0
79(68)b
Ph
Ph
Ph
Me
3af
60%a
(50 equiv of arene) (75 equiv of arene)
Me
3ag
46%a
Me
Me
Me
3ae
36%a
Ph
Me
Me
3ah
Me
[a] Reaction conditions: 1a-x (0.20 mmol), Fe(OTf)2 (0.020 mmol), ligand
(0.020 mmol), C6H6 (3.0 mL, 33.7 mmol). Yields were determined by 1H NMR.
[b] Isolated yield. [c] Fe(OTf)3 was used instead of Fe(OTf)2.
58%a(7.3:1)
Cl
Cl
O
OPh
Me
Me
Me
Me
N
N
N
N
N
Me
Me
N
N
N
CN
Ph
L1
L2
L3
3ak
N
Me
3aj
70%a
Cl
Me
Me
Ph
67%a,c
(2.2:1)
(75 equiv of arene)
Me
3ai
49%a (2:1)
Me
With the optimized reaction conditions in hand, the scope of
the reaction with various arenes was explored (Scheme 3). For
substituted arenes, picolinoyl ester (1a-2-Py) provided better
results than pivaloyl ester (1a-t-Bu). Reaction with
chlorobenzene 2b afforded the product 3ab in good yield, albeit
with low regioselectivity (o/m/p = 68:24:8) which is in good
accordance with other HAS-type reactions.4g The reaction with
p-dichlorobenzene 2c also afforded the product 3ac in good
yield. The amount of 2c could be reduced to 50 or 20
equivalents, although the yield of 3ac was decreased. o-
Dichlorobenzene 2d also showed good reactivity, affording 3ad
and 3ad’ in 43% and 25% yield, respectively.16 1,3,5-
Trichlorobenzene 2e was also applicable despite its steric
hindrance. Other haloarenes such as p-dibromobenzene (2f)
and p-difluorobenzene (2g) could also be used. Various
functional groups such as nitrile (3ah and 3ai), ester (3ah), ether
(3aj), and ketone (3ak) were tolerated under the present
reaction system. Major structures are shown for 3ah, 3ai, and
3ak. The reaction with ketone 2k required a higher reaction
temperature because of its high melting point. It is noted that the
reactions were applicable to both electron-rich and electron-poor
arenes. Polycyclic aromatic compounds such as naphthalene 2l
and pyrene 2m showed high reactivity in the reaction system.16
The reaction with 2l could be performed at larger scale (1.5
mmol). Nitrogen- or sulfur-containing heteroarenes 2o–t also
worked well, affording products in good yield. High C-2
selectivity in the reaction with pyridine 2o was observed with
Ph
Me
(o:m:p =51:39:10)
+
N
N
Ph
Ph
Me
3al
61%a
Me
Me
Me
3al'
11%a
13%a,d
X-ray
58%a,d
(50 equiv of arene)
N
N
+
Ph
N
Me
Me
3ao
60%b
N
Ph
Me
Me
3am + 3am'
76%b,c
(3.8:1)
Ph
(C-2:C-3+C-4 = 60:40)
62%b,e
(C-2:C-3+C-4 = 88:12)
Me
Me
(75 equiv of arene)
N
t-Bu
X
N
S
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Me
Me
Me
Me
3ar
49%b
Me
Me
Me
Me
3ap
61%b
(C-4:C-2:C-5 = 59:31:10)
3aq
67%b
3as (X = H): 71%a
3at (X = Cl): 69%a
(C-2:C-4:C-3 = 1:0.09:trace)
Scheme 3. Scope of arenes. Reaction conditions: 1a-t-Bu or 1a-2-Py (0.20
mmol), Fe(OTf)2 (0.020 mmol), L1 (0.020 mmol), arene (30 mmol). Isolated
yields are shown. Major regioisomer were shown. The ratio were shown in
parentheses. a 1a-2-Py was used. b 1a-t-Bu was used. c Reaction at 150 °C.
d
Reaction at 1.5 mmol scale. e Trifluoroacetic acid (1.8 mmol) was added.
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10.1002/asia.201701634
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COMMUNICATION
Based on the scope of the reaction with respect to arenes, the
substituent effect on oxime esters 1 was then examined using
thiophene as a reaction partner because of its high reactivity and
regioselectivity (Scheme 4). Oxime esters bearing sterically
hindered alkene moieties (1b-2-Py, 1c-2-Py) were applicable to
the reaction system, giving 3bs and 3cs in good yields. It is
noteworthy that arylation on the secondary carbon was possible
(3cs). Substituents such as R3 or R4 at the α-position to the
oxime were not necessary for the reaction to occur, with 3ds
being obtained. Spirocyclic product 3es was also successfully
obtained. The substituent R5 was altered to other aromatic
groups such as 2-pyridyl (3fs) and 2-naphthyl group (3gs).
Tricyclic compound 3hs could also be obtained. The reaction
was also applicable to oxime ester 1i-2-Py, having an alkyl
substituent at R5, to afford the product 3is.
have a tertiary alkyl center (R’ = H), the reactive center of C
adds to arenes to give arenyl radical D, which readily under-
goes deprotonation to form arene-radical anion E. Finally, back
electron transfer from radical anion E to iron releases product 3,
thereby regenerating iron catalyst A.
On the other hand, when C has a tertiary center (R’ = R’’ =
Me), addition of C to arenes become slower compared with the
other reaction pathway. Instead, C may undergo one-electron
oxidation to form stable cation intermediate F, which affords
either the pivaloxylated product 5j-t-Bu or deprotonated olefinic
product 6j and 7j (Scheme 5a).
Me
Me
Me
Me
Ph
OPiv
N
N
t-Bu
O
N
Fe(OTf)2
(10 mol%)
L1
Me
Me
Ph
Ph
Me
Me
Me
Me
5j-t-Bu
69%
O
3ja
0%
Me
S
2-Py
O
N
(10 mol%)
R2
R2
Fe(OTf)2 (10 mol%)
(a)
Ph
Me
R1
R1
O
L1 (10 mol%)
C6H6
(168 equiv)
120 °C, 12 h
Me
Me Me
N
Thiophene 2s (150 equiv)
120 °C, 12 h
N
N
R5
1j-t-Bu
R4
S
R3
R2
3xs
R3 R4
conv 100%
Ph
Ph
Me
Me
1x-2-Py
Me
Me
7j
8%
6j
10%
S
S
S
S
Me
2-Py
2-Py
t-Bu
O
Ph
H
Fe(OTf)2 (10 mol%)
Me
Me
N
N
N
N
N
L1 (10 mol%)
n-Bu3Sn-H (1.5 equiv)
O
N
N
N
N
Ph
Ph
Ph
Ph
(b)
Me
Me
3cs
Me
Me
Me
Me
Ph
Ph
Ph
Me
Me
C6H6 (168 equiv)
120 °C, 12 h
Me
3aa
0%
Me
4a
67%
Me Me
3bs
48%
3ds
64%
3es
64%
3fs
57%
1a-2-Py
59% (dr = 1.2:1.0)
S
S
S
Me
Me
O
Ph
N
O
Me
Me
Fe(OTf)2 (10 mol%)
N
L1 (10 mol%)
TEMPO (8) (1.0 equiv)
O
N
N
N
N
N
(c)
Ph
Ph
Ph
Me
Me
C6H6 (168 equiv)
120 °C, 12 h
Me
Me
3gs
Me Me
Ph
Me
Me
3hs
62% (dr = 2.7:1.0)
3is
48%
1a-2-Py
3aa
0%
9a
74%
C6H5(C6D5)
59%
O
Fe(OTf)2 (10 mol%)
O
N
L1 (10 mol%)
Scheme 4. Scope of oxime esters. Reaction conditions: 1x-2-Py (0.20 mmol),
Fe(OTf)2 (0.020 mmol), L1 (0.020 mmol), thiophen (30 mmol). Isolated yields
are shown. dr = diastereomer ratio. Diastereomer ratio was determined by 1H
NMR.
N
(d)
120 °C, 12 h
Ph
Ph
Me
Me
3aa + 3aa-d5
50% kH/kD = 1.0
C6H6 (90 equiv)
C6D6 (90 equiv)
Me Me
1a-t-Bu
Scheme 5. Preliminary mechanistic studies.
Preliminary experiments also provided some mechanistic in-
sights into the reaction. The reaction of terminally disubstituted
alkene 1j-t-Bu with benzene gave no phenylated product 3ja;
alternatively, pivaloxylated product 5j-t-Bu was obtained in good
yield together with small amounts of dehydropivaloxylation
products 6j and 7j (Scheme 5a). The addition of n-Bu3SnH
resulted in complete inhibition of arylation and gave the
hydrogen atom adduct (Scheme 5b). The addition of radical
scavenger (TEMPO) also prevented arylation completely, giving
TEMPO adduct 9a (Scheme 5c). These results imply the
[Fen]
R''
R
O
N
Ph
R'
A
O
R''
N
Generation
of
Ph
Ph
Iminyl Radical
Me
Me
Me Me
3
1
R''
ROCO [Fen+1
N
]
R'
N
[Fen+1
]
R''
Homolytic
Aromatic
Substitution
(HAS)
Ph
Ph
Me
Me
E
Me Me
involvement of
a radical intermediate. Deuterium labeling
Radical
5-exo cyclization
B
–RCO2H
R''
experiments using an equimolar amount of benzene and
benzene-d6 showed no kinetic isotope effect (Scheme 5d). This
result is consistent with the general HAS reaction in which C–H
bond cleavage should proceed through deprotonation.1b,c
Based on these observations, a plausible mechanism is
shown in Scheme 6.17 First, an iminyl radical or iron-ketimido is
generated by N–O bond cleavage of oxime ester 1 induced by
iron catalyst A. Intermediate B then undergoes 5-exo-trig
cyclization to give intermediate C.12c When the latter does not
H
ROCO [Fen]
Me
[Fen+1
]
ROCO [Fen+1
R'
]
Me
N
ROCO
Ph
R''
R' = H
N
Me
Me
N
Ph
Me
R' = R'' = Me
Me
F
D
Ph
Me
Me
C
5j-t-Bu or 6j or 7j
+
[Fen] (A)
Scheme 6. Aminative transformation involving iminyl radicals.
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10.1002/asia.201701634
Chemistry - An Asian Journal
COMMUNICATION
2015, 6, 1454; g) P. Liu, W. Liu, C.-J. Li, J. Am. Chem. Soc. 2017, 139,
14315.
In summary, we have demonstrated the iron-catalyzed direct
alkylation of unactivated arenes, which takes place through HAS
in a cascade manner with aminative cyclization of alkene-
tethered oxime esters. C–H alkylation of both electron-rich and
electron-poor arenes has been achieved, albeit with the
requirement for an excess amount of arene. Mechanistic studies
support the involvement of radical intermediates. The present
transformation involving intermolecular HAS reaction will find
synthetic application in the construction of intricate molecules
when combined with atom transfer radical addition.
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This study has been financially supported by Grant-in-aid for
JSPS Research Fellow (T. Shimbayashi) (Grant No. 17J09627),
Kansai Research Foundation for technology promotion (K.
Okamoto), and JSPS KAKENHI (a Scientific Research (C);
Grant No. 17K05861).
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Conflict of interest
The authors declare no conflict of interest.
Keywords: Iron • Aromatic substitution • Radical reaction •
Amination • Cyclization
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This article is protected by copyright. All rights reserved.

10.1002/asia.201701634
Chemistry - An Asian Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
T. Shimbayashi, K. Okamoto,* K. Ohe*
Fe(OTf)2 (10 mol%)
R
O
N
Me
Me
Page No. – Page No.
Ar
N
L1 (10 mol%)
N
O
Iron-Catalyzed Aminative
N
Ph
Cyclization/Intermolecular Homolytic
Aromatic Substitution Using Oxime
Esters and Simple Arenes
H
Ar
Ph
Me Me
Me
Me
R = t-Bu or 2-Py
Ar = electron-rich & electron-poor arene
Directly come in!: Iron-catalyzed intermolecular homolytic aromatic substitution
(HAS) employing simple arenes was achieved in cascade manner with aminative
cyclization of alkene-tethered oxime esters ignited by N–O bond cleavage. This
system will open a path to application of intermolecular HAS reaction into
construction of intricate molecules.
This article is protected by copyright. All rights reserved.