Iron-catalyzed C(sp2)-H bond functionalization with organoboron compounds

Article abstract of DOI:10.1021/ja5070763

We report here that an iron-catalyzed directed C-H functionalization reaction allows the coupling of a variety of aromatic, heteroaromatic, and olefinic substrates with alkenyl and aryl boron compounds under mild oxidative conditions. We rationalize these results by the involvement of an organoiron(III) reactive intermediate that is responsible for the C-H bond-activation process. A zinc salt is crucial to promote the transfer of the organic group from the boron atom to the iron(III) atom.

Full text of DOI:10.1021/ja5070763

Communication
pubs.acs.org/JACS
Iron-Catalyzed C(sp2)−H Bond Functionalization with Organoboron
Compounds
Rui Shang, Laurean Ilies,* Sobi Asako,† and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
As illustrated for the synthesis of a (Z,Z)-diene 3 by coupling
ABSTRACT: We report here that an iron-catalyzed
directed C−H functionalization reaction allows the
coupling of a variety of aromatic, heteroaromatic, and
olefinic substrates with alkenyl and aryl boron compounds
under mild oxidative conditions. We rationalize these
results by the involvement of an organoiron(III) reactive
intermediate that is responsible for the C−H bond-
activation process. A zinc salt is crucial to promote the
transfer of the organic group from the boron atom to the
iron(III) atom.
of the (E)-N-(quinolin-8-yl)tiglamide 1 and Z-alkenylboronic
acid pinacol ester 2 (Scheme 1), the reaction utilizes BuLi for
the conversion of 2 to the corresponding borate at low
temperature, a catalytic amount of Fe(acac)3 and a zinc halide,
a bidentate diphosphine ligand ((Z)-1,2-bis(diphenylphos-
phino)ethene: dppen), and 1,2-dichloroisobutane (DCIB),
which keeps the reaction conditions mildly oxidative.9
Compound 2 is first activated with BuLi,10 followed by in
situ boron-to-iron transmetalation catalyzed by the zinc
halide.11,12 The reaction of BuLi with the Lewis acidic boron
atom is rapid enough to allow the use of a variety of
functionalized boronates for this coupling reaction (e.g., halides
and silyl ether, see below). This procedure allows selective
formation of organoiron(III) intermediates without formation
of a reduced iron species13 that has been an inevitable side
reaction when more electron-rich organomagnesium or zinc
reagents were used as the source of the R group.9
unctionalization of an intrinsically unreactive C−H bond
F
has received wide attention for its synthetic efficiency and
the production of potentially less waste than the classical
substitution reactions.1 C−H functionalization catalyzed by
palladium2 and other precious metals3 has found widespread
use for the coupling of a hydrocarbon bearing a directing group
and a shelf-stable organoboron compound that is readily
available and tolerant of a variety of functional groups.
However, the use of precious metals to catalyze reactions is
not without limitations; for instance, they are expensive, rather
toxic, and unsuitable for alkenyl−alkenyl and alkenyl−arene
couplings (cf. Scheme 1) where the diene and styrene products
We studied the reaction conditions for the reaction of
benzamide 5 and Ph−Bpin (4) (Scheme 2): the borate was
Scheme 2. Iron(III)-Catalyzed Aryl−Aryl Coupling
Scheme 1. Iron(III)-Catalyzed Stereospecific Alkenyl−
Alkenyl Coupling
prepared from 4 (20 mmol) and BuLi (slightly less than 20
mmol) at −78 °C, and then at room temperature a solution of
Fe(acac)3 (0.5 mmol), dppen (0.5 mmol), ZnBr2·TMEDA (1.0
mmol), and 5 (1.31 g, 5.0 mmol) in THF was added. DCIB (10
mmol) was added and the reaction mixture was stirred at 70 °C
for 24 h to obtain an ortho-phenylated amide 6 in 96% yield
(1.62 g) after purification by column chromatography on silica
gel. Careful exclusion of moisture was needed to ensure
reproducibility. We note that 2 equiv of R are consumed for
removal of two hydrogen atoms from the substrate, and 1 equiv
was consumed for delivery of a phenyl group. This procedure is
applicable with little modification to the coupling of alkenyl,
aryl, and heteroaryl compounds bearing the quinolylamide or
are prone to isomerize3a or to undergo further trans-
formations.2c One probable reason for this limitation is the
preferred interaction of the 4d and 5d orbitals in these metals
with the π-bonds in the product. Hence, we conjectured that a
transition metal with a minimum π-back-donation ability
promotes C−H bond activation4,5 over interaction with the
π-bonds in the product. We report here that iron(III)
catalysis6,7 complements or surpasses precious metal catalysis
for substrate scope and for advantages such as abundance in
nature, low cost, and lack of toxicity.8
Received: July 13, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
pyridine group, with alkenyl and aryl boron compounds
(Tables 1 and 2).
Table 2. Products of the Iron-Catalyzed Reaction of Arene
and Heteroarene Carboxamides, Arylpyridine, and
Arylpyrazoles with Alkenyl and Aryl Boronates
a
Table 1. Products of the Iron-Catalyzed Reaction of Alkene
Carboxamides and Alkenylpyridine with Alkenyl and Aryl
a
Boronates
a
The reaction was performed on a 0.4 mmol scale, following the
a
procedure described in the text. The yield is based on a pure isolated
product. 8-Q = 8-quinolyl. See the Supporting Information for details.
The reactions were performed under the same reaction conditions as
those used in Table 1. The yield is based on a pure isolated product.
See the Supporting Information for details. The stereochemical purity
b
b
The stereochemical purity of the starting organoboron was E/Z =
c
d
e
c
7:93. At 50 °C. Using sec-BuLi as a base. At 30 °C.
of the starting organoboron was E/Z = 7:93. Using sec-BuLi as a base.
d
At 30 °C.
As illustrated in Table 1, the use of organoborate reagents
allowed the syn-selective C−H functionalization of olefins
bearing an 8-quinolylamide (NH-8-Q) or pyridine group,
which can be carried out with tolerance of diene, triene, ether,
silylether, and chloride groups. The stereochemistry of E-
boronates was entirely retained, while that of (Z)-1-
propenylboronate 2 (E/Z = 7:93) was retained to an extent
of 80−90%, as illustrated by the synthesis of (Z,Z)-2,3-
dimethylhexa-2,4-dienoic acid amide 3 with 100% selectivity for
the 2Z bond and 82% selectivity for the 3Z bond (88%
retention). (Z,E,E)-Trienes 14 and 15 were similarly prepared
in good yield with 100% retention of the E-geometry in the
dienylboronate. Alkenylamides were also arylated with
arylboronates (e.g., 16, 17, and 48). While tiglamide 1 gave
the product 16 with 100% Z selectivity, an acrylic acid amide
gave cinnamic acid amide 18 with only 27% Z-selectivity
because of the in situ isomerization of the initial Z-product.9c
Methacrylic acid amide gave only a trace amount of the
corresponding alkenylated or arylated product.
Table 2 summarizes the reactions of aryl and heteroaryl
substrates with aryl and alkenyl boronate esters. The top of the
table shows the stereoselective synthesis of styrene derivatives,
including the synthesis of (Z)-1-propenyl product 22 from 2
(84% Z from 93% Z-boronate) as well as a trans-stilbene
product 25 (starting from 100% (E)-styrene boronate) and a 2-
propenylated product 20. We did not observe any ring-opening
side reactions in the synthesis of vinylcyclopropane product 24.
When unsubstituted or para-substituted benzamides were
used as a substrate, mono- and diarylation occurred to give
26a,b and 27a,b, respectively. A meta-substituent in the
benzamide shut off the arylation in the nearby ortho-position,
which resulted in the exclusive formation of monoarylated
products 6, 29−42. Ortho-steric hindrance in the aryl boronate
partner was tolerated as illustrated for ortho-tolyl boronate,
which gave 40 in 51% yield.
Functional group tolerance is an asset of the boron reagents.
For instance, aryl fluoride (29), chloride (30), bromide (31),
sulfide (33), amine (34), nitrile (37), and ester (38) are well
tolerated, demonstrating the synthetic advantage over less
selective organozinc or -magnesium reagents.9 Ester- and nitro-
groups on the boron reagent were not tolerated. Heteroatom-
containing thiophene and indole also served as good substrates
to give amides 43 and 44 in ca. 90% yield.
We can couple Ph−Bpin with arene and alkene substrates
bearing a pyridine- or a pyrazole-directing group in good to
excellent yield (Table 1, compound 19; Table 2, compounds
45−47). However, these substrates are prone to give a larger
amount of the biphenyl side product, which suggests that
anionic chelation by the quinolylamide anion14 provides a
uniquely effective coordination environment for the iron(III)
catalysis. The biphenyl formation was suppressed to a
synthetically viable level by carrying out the reaction at 30 °C
instead of the standard temperature of 70 °C.
We obtained several pieces of information on the mechanism
of the iron catalysis, including the key finding that a
stoichiometric organoiron(III) without added DCIB is effective
for C−H functionalization (eq 1 and Table 3). Thus, the
B
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Journal of the American Chemical Society
Communication
Table 4. Effect of the Ligand on the Catalytic Ortho-
phenylation of 5 with Ph−Bpin/BuLi
reaction of 5 with 4 equiv of Ph−Bpin 4/BuLi using a
stoichiometric or catalytic amount of iron(III) (entries 1, 5, and
6) produces the phenylated product 6 in nearly quantitative
yield and only a small amount of biphenyl (13%). These results
indicate that a phenyliron(III) intermediate effectively partic-
ipates in the C−H cleavage and C−C bond formation through
a metallacycle such as A (eq 1), rather than being consumed by
oxidation of the phenyl ligand. The use of 3 equiv of R−Bpin/
BuLi resulted in a much lower yield, which suggests that the
presence of two R groups on the iron(III) atom is necessary
(entry 2). The dppen ligand is necessary for the reaction
(entries 3 and 10). An iron(II) catalyst is much inferior to
iron(III) under both stoichiometric (38% yield, entry 4) and
catalytic conditions (0% yield, entry 9). The added zinc(II) salt
is absolutely necessary,11,12 but a catalytic amount suffices
(entries 5−7), and so is the iron(III) catalyst (entry 8).
The list of effective ligands (Table 4 top) as opposed to
those that are ineffective (Table 4 bottom) seems rather
unusual in comparison with the ligand preference in a related
precious metal catalyzed C−H functionalization.2,3 Because the
product was obtained in 27% yield in the absence of dppen
(entry 10, Table 3), we see that electron-donating ligands such
as dppe and dppf inhibit the reaction, while electron-accepting
ligands for metal-to-ligand electron transfer (MLCT), of which
1,10-Phen is a typical example, promote the reaction. This
trend apparently contradicts the role of an iron(III)
intermediate in the C−H bond-activation step and, hence,
suggests that the ligand facilitates the process involving an
iron(I) intermediate that is formed by the C−C bond-forming
reductive elimination of the initial iron(III) intermediate. There
is a recent report on the involvement of an iron(I) intermediate
in a related reaction that undergoes oxidative addition to R−X
to form an iron(III) species.15 Given the intrinsic instability of
iron(I) species, we consider that the ligand stabilizes the iron(I)
species through MLCT, for which there are ample examples in
iron chemistry.16 In the catalytic reaction, this iron(I) species is
reoxidized by DCIB9 to the iron(III) species.
In summary, the C−H functionalization of a quinolinyl
amide with an R−BPin organoborate reagent in the presence of
iron and zinc catalysts allows us to synthesize a wide variety of
C−H functionalization products. The key discovery is a zinc-
mediated transmetalation from boron to iron to form an
organoiron(III) intermediate that undergoes C−H cleavage and
C−C bond formation in preference to the oxidation of the R
group. Overall, the reaction illustrates the synthetic significance
of iron catalysis, which has been attracting growing attention in
recent years.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and physical properties of the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
■
Corresponding Authors
laur@chem.s.u-tokyo.ac.jp
nakamura@chem.s.u-tokyo.ac.jp
Present Address
†Division of Chemistry and Biotechnology, Graduate School of
Natural Science and Technology, Okayama University, 3-1-1
Tsushimanaka, Kita-ku, Okayama 700-8530, Japan.
Notes
The authors declare no competing financial interest.
a
Table 3. Effect of Several Key Parameters on the Stoichiometric and Catalytic Ortho-phenylation of 5 with Ph−Bpin/BuLi
b
b
c
entry
Fe source (mol %)
Zn(II) (mol %)
DCIB (mol %)
dppen (mol %)
6
(%)
5
(%)
Ph2 (%)
1
Fe(III), 100
Fe(III), 100
Fe(III), 100
Fe(II), 100
Fe(III), 10
Fe(III), 10
Fe(III), 10
none
ZnBr2·L, 100
ZnBr2·L, 100
ZnBr2, 100
ZnBr2·L, 100
ZnBr2·L, 20
ZnBr2·L, 100
none
0
0
100
100
0
95
0
13
14
44
7
d
c
c
c
2
58
36
e
3
0
0
38
96
99
0
91
d
c
4
0
100
10
10
10
10
10
0
56
0
5
200
200
200
200
200
200
0
<5
0
6
0
7
96
98
64
72
84
0
8
ZnBr2·L, 100
ZnBr2·L, 50
ZnBr2·L, 100
ZnBr2·L, 100
0
0
c
9
Fe(II), 10
Fe(III), 10
Fe(III), 10
0
<5
6
10
11
27
13
10
0
a
b
Fe(II) = Fe(acac)2; Fe(III) = Fe(acac)3; L = TMEDA. Yield determined by NMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal
c
d
standard. Yield determined by GC using tridecane as an internal standard. With 300 mol % Ph−Bpin/BuLi; the reaction produced ca. 300 mol %
Bu−Bpin (GC). Upon quenching with D2O, no D was incorporated into the ortho site of 5 (GC−MS).
e
C
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Journal of the American Chemical Society
Communication
J.; Okopie, R. A.; Sankey, R. F. Angew. Chem., Int. Ed. 2012, 51, 5435−
5438.
ACKNOWLEDGMENTS
■
We thank MEXT for financial support (KAKENHI No.
22000008 to E.N. and Grant-in-Aid for Scientific Research on
Innovative Areas No. 25105711 and Grant-in-Aid for Young
Scientists (A) No. 26708011 to L.I.). R.S. thanks the Chinese
Scholarship Council for a scholarship to visit Tokyo from the
University of Science & Technology of China, and S.A. thanks
the Japan Society for the Promotion of Science for Young
Scientists for a Research Fellowship (No. 23-8207).
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