Iron-Catalyzed Remote Arylation of Aliphatic C-H Bond via 1,5-Hydrogen Shift

Article abstract of DOI:10.1021/acscatal.7b03458

Catalytic amounts of an iron(III) salt and a N-heterocyclic carbene ligand catalyze the arylation of 2-iodoalkylarenes with diphenylzinc selectively at the C-H bond of the alkyl side chain. Several lines of evidence suggest that the iron catalyst reacts with the aryl iodide moiety of the substrate to generate an aryliron intermediate that behaves in a radical manner and cleaves the aliphatic C-H bond through 1,5-hydrogen transfer; the resulting alkyliron intermediate undergoes reductive elimination to give the arylated product.

Full text of DOI:10.1021/acscatal.7b03458

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Letter
Iron-Catalyzed Remote Arylation of Aliphatic C-H Bond via 1,5-Hydrogen Shift
Bingwei Zhou, Hiroki Sato, Laurean Ilies, and Eiichi Nakamura
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03458 • Publication Date (Web): 17 Nov 2017
Downloaded from http://pubs.acs.org on November 18, 2017
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ACS Catalysis
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Iron-Catalyzed Remote Arylation of Aliphatic C–H Bond via 1,5-
Hydrogen Shift
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Bingwei Zhou,† Hiroki Sato, Laurean Ilies*, and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, To-
kyo 113-0033
KEYWORDS: iron catalysis, aliphatic C–H, hydrogen shift, remote functionalization, arylation
ABSTRACT: Catalytic amounts of an iron(III) salt and a N-heterocyclic carbene ligand catalyze the arylation of 2-iodoalkylarenes
with diphenylzinc selectively at the g C–H bond of the alkyl side chain. Several lines of evidence suggest that the iron catalyst re-
acts with the aryl iodide moiety of the substrate to generate an aryliron intermediate that behaves in a radical manner and cleaves
the aliphatic C–H bond through 1,5-hydrogen transfer; the resulting alkyliron intermediate undergoes reductive elimination to give
the arylated product.
Regioselective functionalization of an alkane1 has attracted
much attention,2 but the control of regioselectivity in the reac-
tion of C(sp3)–H bonds having similar electronic and steric
properties is still a great challenge.3 We envisioned that a hy-
drogen shift strategy4 would enable us to achieve both regiose-
lective cleavage of a remote C(sp3)–H bond5 in an alkylarene
and subsequent C–C bond formation. We report here that an
aromatic halide directs the arylation of a C(sp3)–H bond at the
g-position of an alkylarene6 with high regioselectivity under
iron catalysis 7 (Scheme 1). This reaction design took ad-
vantage of the potential carbon radical reactivity of an organ-
oiron species8 previously exploited for the a-functionalization
of amines; a similar strategy has not been successful to date
for the more challenging regioselective functionalization of
simple alkylarenes, albeit a deuteration experiment suggested
its feasibility.9
Scheme 1. Iron-Catalyzed Remote Arylation of 2-
Iodobutylbenzene and Possible Reaction Intermediates
PhMgBr (4 equiv)
ZnBr2•TMEDA (2 equiv)
Fe(acac)3 (10 mol %)
H
H
Ph
4 (20 mol %)
γ
+
I
fluorobenzene, 50 °C
[Fe]-I
H
H
1
2: 57%
single isomer
3: 21%
Ph[Fe]
Ph
I
[Fe]
i-Pr
i-Pr
N
N
Cl
H
i-Pr i-Pr
H
[Fe]
Ph
I
1,5-hydrogen
transfer
A
4
B
Thus, we envisioned that an organoiron generated from an
iron salt and an organometallic reagent may transfer an elec-
tron to the aryl iodide 110 to generate an iron intermediate A,
which will show a radical reactivity and hence selectively
transfer the g-H though 1,5-permutation to generate B, fol-
lowed by its recombination and reductive elimination to create
The influence of the key parameters on the reaction out-
come is described in Table 1. Aromatic compounds such as
benzene (entry 2) or fluorobenzene (entry 1) were the solvent
of choice because they may stabilize low-valent organoiron;12
we typically used the latter for its lower toxicity. Ether sol-
vents such as tetrahydrofuran (entry 3) were partially arylated
under these conditions,8, and they also generated a large
13
a
new C–C bond. According to this scenario, 2-
iodobutylbenzene (1) was allowed to react with diphenylzinc
in the presence of a catalytic amount of an iron salt and a N-
heterocyclic carbene (NHC) ligand (4) in fluorobenzene at 50
°C, to obtain 1,3-diphenylbutane (2) in 57% isolated yield. No
regioisomers of 2 were detected, and the only byproduct was a
hydrodehalogenated product (3, 21% yield) and biphenyl
(36% based on 1) formed through iron-catalyzed homocou-
pling of an organoiron intermediate.11 The cross-coupling be-
tween 1 and diphenylzinc proceeded only in a trace amount,
presumably because of steric hindrance; a dimeric product
from the coupling of 1 with zinc intermediate C (cf. Scheme
2) was not observed at all.
amount of butylbenzene (3). The reaction did not proceed at
all in the absence of the iron catalyst (entry 4). An Fe(II) salt
also catalyzed this reaction, suggesting that the iron precursor
is reduced by an organometallic reagent to a common reactive
species, as also suggested by the formation of biphenyl11 in the
present reaction. The NHC ligand (4) slightly improved the
catalytic turnover, presumably by stabilizing the organoiron
species,14 but the reaction also proceeded in its absence (entry
6). Mono-, diphosphine, or bipyridine ligands gave inferior
results (SI). ZnCl2 can be used instead of ZnBr2 with similar
efficiency (entry 7). TMEDA has an important yet unknown
role (entry 8). A monoorganozinc reagent (PhZnBr) generated
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in situ from PhMgBr and ZnBr•TMEDA was unreactive (entry kylarene possessing a cyclohexyl group reacted well, but gave
1
2
9).
a mixture of stereoisomers (entry 10), in agreement with the
radical nature of intermediate B.15
3
4
5
6
Table 1. The Influence of the Key Parameters on the Iron-
Catalyzed Reaction of 2-Iodobutylbenzene (1) with Diphe-
nylzinca
Table 2. Iron-Catalyzed Reaction of 2-Haloalkylarenes
with Diarylzinca
7
8
9
entry
ArMgBr
product
Ph
yield (%)b
substrate
PhMgBr (4 equiv)
ZnX2 (2 equiv)
cat. Fe / ligand
H
Ph
H
1
2
57
47c
PhMgBr
10
11
12
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+
solvent, 50 °C
I
I
H
H
H
H
H
H
1
2
3
Ph
Ph
Ph
Ph
3
4
5
PhMgBr
31d
2 (%)b
3 (%)b
entry
reaction conditions
Br
1
2
3
4
5
6
7
8
9
standard
57
59
21
19
n-C6H13
benzene as solvent
THF as solvent
no Fec
n-C6H13
PhMgBr
50
10
83
I
I
ndd
ndd
c
Fe(acac)2
37
23
Ph
no ligandc
46
25
50
Ph
PhMgBr
ZnCl2•TMEDAc
no TMEDAc
“PhZnBr” c,e
52
23
5
14
trace
trace
6
7
8
PhMgBr
PhMgBr
PhMgBr
28
38
54
I
I
I
H
H
aThe standard reaction conditions refer to the one shown in
Scheme 1: substrate (0.1 mmol), Fe(acac)3 (10 mol %), and
NHC ligand (20 mol %) were dissolved in fluorobenzene (2
mL) at 50 °C, and a fluorobenzene solution of diphenylzinc
freshly prepared from PhMgBr (4 equiv) and ZnBr2•TMEDA
(2 equiv) was added dropwise over 10 min, and the resulting
mixture was stirred for 2 h at 50 °C. bYield estimated by GC in
the presence of tridecane as an internal standard. cBenzene was
used as the solvent. dNot detected. ePrepared in situ from
PhMgBr (2 equiv) and ZnBr2•TMEDA (2 equiv).
Ph
Ph
H
H
Ph
35
(E/Z = 3.5:1)e
PhMgBr
PhMgBr
9
I
I
The iron-catalyzed reaction of various 2-haloalkylarenes
with diarylzinc is shown in Table 2. All these reactions afford-
ed the product as a single regioisomer via 1,5-hydrogen shift,
together with the dehalogenated compound (e.g., butylben-
zene) essentially as the only byproduct from the 2-
haloalkylarene substrate. The reaction took place on both pri-
mary and secondary C–H bonds, but the latter gave higher
yields in agreement with the radical mechanism involving the
intermediate B. 2-Iodoalkylarenes reacted better than the cor-
responding bromides (entry 1 vs. 3), possibly because of the
lower reduction potential favoring electron transfer. Long al-
kyl chains (entries 4 and 5) could be arylated with high regi-
oselectivity at the g C–H. Notably, the 1,5-transfer dictates the
regioselectivity, overriding electronic effects: the g position
was selectively arylated over benzylic C–H (entry 5). Despite
the lower reactivity of primary C–H bonds, a primary g C–H
was selectively arylated over a secondary C–H (entry 6). The
primary C–H bond in a t-Bu group reacted well (entry 8), and
an allylic C–H bond did not show any significant preference
over the simple reduction of the aryl iodide moiety (entry 9).
The alkene underwent partial isomerization, suggesting the
involvement of low-valent organoiron species.12c An al-
Ph
55
(dr = 3.6:1)e
10
H
R
Me
11
12
13
14
R =
55
60
31
38
OMe
NMe2
F
R
MgBr
I
I
I
H
MeO
MgBr
15
58
MeO
H
MgBr
16
55
H
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aReaction conditions: substrate (0.2 mmol), Fe(acac)3 (10 mol %),
thesis typically relies on transition-metal-catalyzed cross-
1
2
3
4
5
6
7
8
and NHC ligand (20 mol %), were dissolved in fluorobenzene (2
mL) at 50 °C, and a fluorobenzene solution of diarylzinc freshly
prepared from the corresponding arylmagnesium bromide (4
equiv) and ZnBr2•TMEDA (2 equiv) was added dropwise over 10
min, and the resulting mixture was stirred for 2 h at 50 °C. bYield
coupling using alkyl (pseudo)halides that are difficult to ac-
cess.15, Further studies will focus on improvement of the
17
preference of 1,5-transfer process over transmetalation, and to
extend this strategy to a variety of molecules of synthetic im-
portance.5
c
d
of the isolated product. Reaction using 2 mmol of substrate. Y-
1
ield determined by H NMR in the presence of an internal stand-
ASSOCIATED CONTENT
AUTHOR INFORMATION
ard. eRatio determined by 1H NMR.
9
Both electron-rich (entries 11–13) and electron-deficient
(entry 14) diarylzinc reagents could be utilized, and the former
gave a slightly better yield. Para- (entries 11–14) and meta-
substituted reagents, including naphthyl (entries 15 and 16)
reacted equally well. Alkenylzinc compounds did not react
under these conditions; dimethylzinc cross-coupled with sub-
strate 1, and a benzyl reagent mainly dimerized.
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Corresponding Author
laur@chem.s.u-tokyo.ac.jp, nakamura@chem.s.u-tokyo.ac.jp
Present Address
†State Key Laboratory Breeding Base of Green Chemistry-Synthesis
Technology, Zhejiang University of Technology, Hangzhou 310014,
People’s Republic of China
When we quenched the reaction of 1 with D2O, the phe-
nylated product 2 showed no deuterium incorporation, and the
dehalogenated byproduct 3 showed 97% deuterium incorpora-
tion on the carbon where the iodine atom was located in 1
(Scheme 2). An additional piece of mechanistic information
was obtained for an olefinic iodide 5, which gave a cyclization
product 6 (eq. 1) suggestive of a radical character of the first
intermediate A.16 These results suggest a bifurcation of two
pathways from A, a fast radical pathway resulting in 1,5-
hydrogen transfer to give B,4,8 and the formation of a stable
organozinc reagent C, which is responsible for the formation
of 3(D) upon deuteration.
SUPPORTING INFORMATION
Experimental procedures and physical properties of the com-
pounds. The Supporting Information is available free of charge on
the ACS Publications website.
ACKNOWLEDGMENTS
We thank MEXT for financial support (KAKENHI 15H05754 for
E.N. and 26708011 to L.I.).
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Scheme 2. Deuterium-Labeling Experiment.
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10
H
Ph
Ph2Zn
cat. Fe
fluorobenzene,
50 °C, 2 h
I
H
57%
single isomer
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