Nickel-catalyzed hydroheteroarylation of vinylarenes

Article abstract of DOI:10.1002/anie.201001470

(Figure Presented) In the nickel of time: A nickel/carbene catalyst effects the hydroheteroarylation of vinylarenes to give 1,1-diarylethanes that contain various heteroaryl moieties with excellent regioselectivity. EWC = electron-withdrawing group.

Full text of DOI:10.1002/anie.201001470

Angewandte
Chemie
DOI: 10.1002/anie.201001470
À
C H Activation
Nickel-Catalyzed Hydroheteroarylation of Vinylarenes**
Yoshiaki Nakao,* Natsuko Kashihara, Kyalo Stephen Kanyiva, and Tamejiro Hiyama*
In memory of Keith Fagnou
The metal-catalyzed hydroarylation of vinylarenes is a
versatile and highly atom-economical way to obtain 1,1-
diarylmethyl structural motifs that are found in many
pharmaceuticals and biologically active molecules.[1] This
catalytic reaction can be classified into two major types
depending on the possible mechanism (Scheme 1). The
ent and a few furan and thiophene derivatives.[4] On the other
hand, we recently reported that a nickel/tricyclopentylphos-
phine (PCyp3) catalyst effects the hydroarylation of 2-vinyl-
naphthalene with a highly electron-poor arene, pentafluoro-
benzene.[5] Subsequent studies on the mechanism of the
alkyne hydrofluoroarylation by the same nickel catalyst
revealed that the catalysis was initiated by oxidative addition
[6]
À
of the C H bonds of fluoroarenes to nickel(0). These
studies prompted us to examine the hydroarylation of vinyl-
arenes that contain relatively electron-poor heteroarenes.
These compounds also undergo addition across alkynes,
À
possibly through oxidative addition of C H bonds to
nickel(0).[7] Herein, we report the hydroheteroarylation of
vinylarenes to give 1,1-diarylalkanes that contain a variety of
heteroaryl groups.[8]
First, we examined the reaction of methyl 1-methylindole-
3-carboxylate (1a) with styrene (2a) in the presence of a
nickel catalyst that was derived from [Ni(cod)2] (5–10 mol%)
and a ligand (Table 1). We found that the use of 1,3-
Table 1: Hydroheteroarylation of styrene (2a) with 1a.
Scheme 1. Possible mechanisms for the metal-catalyzed hydroarylation
of vinylarenes. M=(transition) metal.
reaction can be initiated by oxidative addition of aromatic
À
C H bonds to a metal catalyst, before hydrometalation and
reductive elimination. However, to the best of our knowledge,
there is only a single report of this mechanism affording 1,1-
diarylethane compounds,[2] with 1,2-diarylethanes being gen-
erally obtained as the major products from this mechanistic
pathway.[3] Another type of hydroarylation reaction of vinyl-
arenes involves the Friedel–Crafts-type alkylation of arenes,
wherein a metal catalyst acts as a Lewis acid to activate the
double bond of vinylarenes.[4] Although 1,1-diarylethanes are
generally obtained from this reaction with good to excellent
regioselectivity, the scope of arenes that can participate in this
mechanism is severely limited to highly electron-rich arenes,
including indoles that contain an electron-donating substitu-
Entry
Ligand
Solvent
Yield of 3aa [%][a]
1[b]
2
3
4
5
IMes
IMes
IMes
IMes
IPr
hexane
toluene
THF
83
82
35
35
2
NMP
toluene
toluene
toluene
6
7
PCyp3
P(nBu)3
<5
<5
[a] Estimated by GC based on 1a. [b] Run with 5 mol% of nickel and
IMes. IMes=1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene, IPr=1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene, Cyp3 =tricyclopentylphos-
phine, NMP=1-methyl-2-pyrrolidinone.
[*] Dr. Y. Nakao, N. Kashihara, K. S. Kanyiva, Prof. Dr. T. Hiyama
Department of Material Chemistry, Graduate School of Engineering
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2445
dimesitylimidazol-2-ylidene (IMes) in nonpolar solvents,
such as hexane and toluene, was crucial to obtaining methyl
1-methyl-2-(1-phenylethyl)indole-3-carboxylate (3aa) in over
80% yield (Table 1, entries 1 and 2 vs 3 and 4); the use of a
different ligand, 1,3-(2,6-diisopropylphenyl)imidazol-2-yl-
idene (IPr), in toluene also gave inferior results (Table 1,
entry 5). The carbene ligand, IMes, is known to be effective in
the C6-selective alkylation of 2-pyridone derivatives with 2-
E-mail: yoshiakinakao@npc05.mbox.media.kyoto-u.ac.jp
thiyama@z06.mbox.media.kyoto-u.ac.jp
[**] This work has been supported financially by a Grant-in-Aid for
Scientific Research (S) from MEXT. K.S.K. acknowledges Honjo
International Scholarship Foundation for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001470.
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Communications
vinylnaphthalene.[9] No trace amount of the regioisomeric 1,2-
alized indole 3ak (Table 2, entry 11). The same regioselec-
tivity was also observed in the reaction of pentafluorobenzene
with 2k, and is presumably derived from a p-allylnickel
intermediate.[5] On the other hand, 1-tridecene (2l) gave
linear adduct 3al exclusively (Table 2, entry 12). Lack of
functionalities that contain a p system could retard the
formation of a secondary alkylnickel intermediate in the
absence of any stabilization available with p-benzyl- or p-
allylnickel species to favor the migration of a hydride to the
C2-position of the aliphatic 1-alkene.
diarylethane product was detected. PCyp3, the ligand of
choice for hydrofluoroarylation of vinylarenes,[5] and P(nBu)3
were completely ineffective (Table 1, entries 6 and 7). In the
presence of the nickel/IMes catalyst, a variety of vinylarenes
that contain phenyl groups bearing both electron-rich and
electron-poor substituents reacted successfully with 1a
À
(Table 2). In particular, an Ar F bond was tolerated under
Table 2: Hydroheteroarylation of vinylarenes with 1a.
The nickel/IMes catalysis also showed a wide scope of
tolerance for heteroarenes (Table 3). Indoles that have an
acetyl or a cyano group at the C3-position were alkylated to
Table 3: Hydroheteroarylation of 2a.
Entry
2 (R)
t
[h]
Product
Yield of 3
[%][a]
1
2
2a
2b
H
31
32
10
10
22
22
3aa
3ab
3ac
3ad
3ae
3af
90
85
100
86
94
98
Entry
1
Heteroarene
t [h]
Product
Yield of 3 [%][a]
2-MeO
3-MeO
4-MeO
4-Me
3[b] 2c
4
5
2d
2e
1b 23
3ba
89
6[b,c] 2 f
4-F
7[b] 2g 4-MeO2C 12
3ag
80
2[b,c]
1c
7
9
3ca
3da
85
86
8[b] 2h
8
3ah
80
3
1d
4
5
6
7
1e
1 f
2
7
4
6
3ea
3 fa
3ga
3ha
97
41
81
77
9[b] 2i
2
3ai
3aj
89
17
1g
1h
10[b,d] 2j
22
[a] Yield of isolated product based on 1. [b] Run with 10 mol% of nickel
and IMes. [c] Run with 3.0 mmol of 2a. hetAr=heteroaryl.
11[e] 2k
9
4
3ak
3al
62
80
12[f]
2l
give their corresponding 1,1-diarylethanes in good yields
(Table 3, entries 1 and 2). Azoles, including benzimidazole
(1d), benzoxazole (1e), oxazole (1 f), and benzothiazole (1g)
underwent hydroheteroarylation to give modest to good
yields (Table 3, entries 3–6). The addition of benzofuran (1h)
across styrene (2a) proceeded exclusively at the C2-position
(Table 3, entry 7).
[a] Yield of isolated product based on 1. [b] Run with 10 mol% of nickel
and IMes. [c] Run in toluene. [d] Conversion of 1a was estimated to be
36%. [e] Run with [Ni(cod)2] (10 mol%) and P(nBu)3 (10 mol%) as a
ligand. [f] Run with 1-tridecene (5.0 mmol), [Ni(cod)2] (10 mol%), and
IPr (10 mol%). Np=naphthyl.
To gain insight into the reaction mechanism we prepared
methyl 2-deutero-1-methylindole-3-carboxylate ([D1]-1a)
and examined its reaction with 2h under the optimized
conditions [Eq. (1)]. The reaction was stopped after 3 hours
to obtain [D1]-3ah in 36% yield with 15% total deuteration
[Eq. (1)]. Interestingly, deuteration occurred not only at the
terminal methyl group (Cb-D) but also at the benzylic position
(Ca-D). In addition, recovered [D1]-1a and 2h showed partial
deuteration: both the a and b positions of the vinyl group in
2h were deuterated. These data suggest a plausible catalytic
the reaction conditions, even though a related nickel/N-
À
heterocyclic carbene catalyst was reported to effect Ar F
bond activation.[10] In addition to vinylarenes, 1-phenylpro-
pene (2i) and indene (2j) also participated in the hydro-
heteroarylation reaction to give 1,1-diarylethane 3ai and 1-
heteroarylindane 3aj, respectively (Table 2, entries 9 and 10).
The vinylogous styrene, 1-phenyl-1,3-butadiene (2k), reacted
exclusively at its terminal double bond to give C2-function-
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Chemie
HCl (aq) at 1008C for 21 hours to give 2-phenylpropanoic
acid in 81% yield [Eq. (2)]. This two-step reaction could be
an alternative way to access 2-arylpropanonic acid deriva-
tives, which are also found in many biologically active
compounds.
In summary, we have demonstrated the nickel-catalyzed
hydroheteroarylation of vinylarenes to exclusively give a
variety of 1,1-diarylethanes that contain a heteroaryl motif. A
catalytic cycle, initiated by the oxidative addition of the
cycle that is initiated by reversible oxidative addition of an
À
Ar H bond to the nickel(0)/IMes catalyst to give nickel
hydride B through h2-arenenickel A (Scheme 2). The coordi-
heteroarene C2 H bonds, is suggested on the basis of some
À
mechanistic studies. The use of relatively electron-poor
heteroarenes in this study is complementary to the well-
documented Friedel–Crafts-type hydroarylation of vinylar-
enes with electron-rich arenes to give a wide variety of 1,1-
diarylethanes. Current efforts are directed toward further
expansion of the scope of the reaction, especially with the aid
of a Lewis acid co-catalyst to activate the otherwise unreac-
[13]
tive C H bonds of heteroarene and amide[14] substrates as
À
well as development of an enantioselective protocol using a
chiral N-heterocyclic carbene ligand.
Experimental Section
A general procedure for nickel-catalyzed hydroheteroarylation of
vinylarenes: A solution of [Ni(cod)2] (14 mg, 50 mmol) and IMes
(15 mg, 50 mmol) in hexane (1.0 mL) was added to a heteroarene
(1.0 mmol) in a 3 mL-vial in a dry box before addition of the
vinylarene (1.5 mmol). After undecane (internal standard, 78 mg,
0.50 mmol) was added, the vial was screw-capped, taken outside the
dry box, and heated at the required temperature for the time specified
in Tables 1–3. The resultant mixture was filtered through a pad of
silica gel and then concentrated in vacuo. The residue was purified by
flash chromatography on silica gel to give the corresponding products
in the yields listed in Tables 1–3.
Scheme 2. A plausible mechanism for the hydroheteroarylation of
À
vinylarenes. L=IMes; X=NMe, O, S; Y=C(H) EWG, N; EWG=elec-
tron-withdrawing group.
Received: March 11, 2010
Published online: April 30, 2010
nation of vinylarenes C and subsequent hydronickelation are
both reversible and give 1-arylethylnickel D, that reductively
eliminates 1,1-diarylethanes irreversibly to regenerate A. The
final step could be the rate-determining step, as has been
discussed previously for the nickel-catalyzed hydrocyana-
tion[11] and hydroalkynylation[12] of vinylarenes. The primary
reaction pathway could compete with the coordination and
migratory insertion of alkenes to give 1,2-diarylethanes via C’
and D’. Whilst this minor pathway is not product-forming for
vinylarenes, it becomes an exclusive reaction pathway with
aliphatic 1-alkenes, presumably because of the lack of
stabilization of the alkylnickel species and steric repulsion
(Table 2, entry 12). Deuteration at both the a and b positions
of 3ah, the recovery of 2h, as well as the loss of deuteration
and scrambling in [D1]-1a can be understood in terms of these
major and minor reversible reaction pathways.
À
Keywords: carbene ligands · C H activation · heterocycles ·
.
nickel · vinylarenes
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