Palladium-catalyzed hydrobenzylation of ortho-tolyl alkynyl ethers by benzylic C-H activation: Remarkable alkynoxy-directing effect

Article abstract of DOI:10.1002/anie.201304893

It's selective: The title reaction involves palladium(0)-catalyzed insertion of Ci￡C bonds into benzylic C(sp³)-H bonds, thus providing efficient access to 2-methylene-2,3-dihydrobenzofurans, which transform into benzofurans upon treatment with a weak acid (e.g., AcOH) and electrophiles. The alkynoxy group serves as a directing group in promoting C-H bond functionalization. Copyright

Full text of DOI:10.1002/anie.201304893

Angewandte
Chemie
DOI: 10.1002/anie.201304893
Heterocycles
Palladium-Catalyzed Hydrobenzylation of ortho-Tolyl Alkynyl Ethers
À
by Benzylic C H Activation: Remarkable Alkynoxy-Directing
Effect**
Yasunori Minami,* Kotomi Yamada, and Tamejiro Hiyama*
3
À
Straightforward C(sp ) H bond functionalization by transi-
tion-metal complexes allows novel synthetic manipulations of
substrates without the requirement for prefunctionalization
and thus contributes to environmentally benign transforma-
provide 97% of the Z-exocyclic alkylidene product 2a along
with 3% of the benzofuran 3a as determined by NMR
spectroscopy [Eq. (1); TIPS = triisopropylsilyl]. The stereo-
chemistry of 2a was unambiguously determined by NOE and
tions through efficient use of natural resources and energy.[1]
Notably, a process that involves C(sp ) H bond activation by
oxidative insertion and subsequent carbometalation of unsa-
turated substrates represents an ideal new carbon–carbon
bond formation with 100% atom economy.[2]
3
À
As we have reported recently, alkynyl aryl ethers react
with internal alkynes through selective palladium(0)-cata-
À
lyzed ortho C H activation, thus providing efficient access to
2-methylidene-2H-chromene derivatives.[3] The facile and
straightforward transformation can be attributed to the
coordination of the alkynoxy directing group with palladium
NOESY experiments. Attempted isolation of 2a by silica gel
or alumina column chromatography resulted in its isomer-
ization into 3a, to some extent. Thus, treatment of the crude
reaction mixture with acetic acid prior to work-up gave 3a in
98% yield upon isolation.[12] Since Pd(OAc)2, PdCl2, and
PtCl2 failed to effect the desired reaction, it is apparent that
the cyclization is not promoted by either the Lewis acid, PCy3.
or Zn(OAc)2 alone.[13] Of note, the reaction took place in the
absence of zinc, albeit at a slower rate, thus indicating that the
combination of Pd(OAc)2, PCy3, and zinc promotes the
cyclization. As the carbon analogue, 4-MeOC6H4CH-
(OMe)C ꢀ CTIPS, was inert to the standard reaction con-
ditions, the alkynoxy moiety is definitely essential for the
intramolecular hydrobenzylation reaction.
[4]
À
to effect the ortho C H activation. On the basis of this
preliminary observation, we were intrigued by the possibility
À
of benzylic C H activation. Although cross-coupling reac-
À
tions involving benzylic C H bond cleavage have been briefly
explored to some extent,[5–7] insertion of unsaturated partners
is less studied. In this respect, the work by Yamamoto and co-
workers[8] and Chatani and co-workers[9] are remarkable
II
À
examples of M -catalyzed (M = Pt, Ru) benzylic C H
cleavage of 1-alkyl-2-ethynylbenzenes by vinylidene com-
plexes. Herein, we report that a hydrobenzylation of ortho-
tolyl alkynyl ethers takes place through palladium-catalyzed
3
À
benzylic C(sp ) H bond insertion and subsequent syn-1,2-
addition across the alkyne. The adducts, 2-methylidene-2,3-
dihydrobenzofurans, easily react with acetic acid, azo and
carbonyl compounds, and molecular oxygen to give variously
functionalized benzofurans.[10,11]
Other silyl groups instead of TIPS were used in the
cyclization as depicted in Equation (2). Substrates containing
The reaction of triisopropylsilylethynyl-2,6-xylyl ether
(1a) was conducted in the presence of Pd(OAc)2 (1 mol%),
tricyclohexylphosphine (2 mol%), and Zn metal (1 mol%, in
situ PdII reduction) in toluene at 908C for 30 minutes to
[*] Y. Minami, T. Hiyama
Research and Development Initiative, Chuo University, JST, ACT-C
Kasuga, Bunkyo-ku, Tokyo 112-8551 (Japan)
E-mail: yminami@kc.chuo-u.ac.jp
thiyama@kc.chuo-u.ac.jp
tert-butyldiphenylsilyl
(TBDPS),
tert-butyldimethylsilyl
K. Yamada
(TBDMS), and triethylsilyl (TES) groups on the terminal
ethynyl carbon atom underwent the hydrobenzylation to
produce 2b, 2c, and 2d, respectively, in quantitative yields as
estimated by NMR assays. Isomerization by acetic acid led to
the isolation of the corresponding 3b, 3c, and 3d in essentially
quantitative yields. In contrast, the dimethylphenylsilyl-sub-
stituted ethynyl ether 1e was gave 2e in 60% yield only by
Graduate School of Science and Engineering, Chuo University
Kasuga, Bunkyo-ku, Tokyo 112-8551 (Japan)
[**] This work has been supported financially by a Grant-in-Aid for
Scientific Research (S) (21225005 to T.H.) and Young Scientists (B)
(25870747 to Y.M.) from JSPS.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304893.
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using a higher catalyst loading and a higher reaction temper-
ature.
A variety of aryl triisopropylsilylethynyl ethers (1) were
applied to the hydrobenzylation (Table 1). All the products
were isolated after treatment of 2 with acetic acid before
workup. The ortho-tolyl ethers (R2 = H) containing ethyl,
bearing a methyl group at the meta position (1j) smoothly
reacted to give the 6-methylbenzofuran 3j in 92% yield
(Table 1, entry 5). The fluorinated 1k was efficiently con-
verted into 3k in 86% yield (Table 1, entry 6), and selective
3
À
benzylic C(sp ) H activation of the 2,6-diethylphenyl ether 1l
provided 3l in 92% yield in the presence of 5 mol% catalyst
(Table 1, entry 7) with the terminal methyl group remaining
unaffected. However, 2,6-diisopropylphenyl triisopropylsilyl
ethynyl ether was inert under the present reaction conditions
and most likely because of the increased steric bulk of the
isopropyl moiety, thus indicating that the mechanism of this
reaction contrasts sharply to those of precedented work.[8,9] 1-
Methyl 2-alkynoxynapthalene (1m) was transformed into the
naphthofuran 3m in 67% yield (Table 1, entry 8).
Table 1: Palladium-catalyzed intramolecular hydrobenzylation and sub-
sequent migration in one pot.[a]
Entry
1
t [h] Product
Yield [%][b]
The initial hydrobenzylation product 2 probably has
a zwitterionic resonance structure (2’) showing a nucleophilic
carbanionic character stabilized by silyl groups. From this
viewpoint, the ene reaction of the in situ generated 2 was
examined (Scheme 1). The compound 2d was reacted with
1
2
3
4
5
6
1 f (R1 =6-Et)
1g (R1 =6-MeO)
1h (R1 =6-CF3)
1i (R1 =H)
2
5
1
3 f (R1 =7-Et)
98
89
88
85
92
86
3g (R1 =7-MeO)
3h (R1 =7-CF3)
18 3i (R1 =H)
38 3j (R1 =6-Me)
38 3k (R1 =5-F)
1j (R1 =5-Me)
1k (R1 =4-F)
7
1l
19 3l
92
67
8
1m
13 3m
[a] Unless otherwise noted, a mixture of 1, Pd(OAc)2 (1 mol% for
entries 1–3 and 7, 5 mol% for entries 4–6, 10 mol% for entry 8), PCy3
(2 mol% for 1–3 and 7, 10 mol% for entries 4–6, 20 mol% for entry 8),
Zn (1 mol% for entries 1–3 and 7, 5 mol% for entries 4–6, 10 mol% for
entry 8) and toluene (1.0m for entries 1–3 and, 0.1m for entries 4–6 and
8) was heated at 908C. Then, AcOH (3.0–10 equiv) was added, and the
whole mixture was heated at 908C for 1–10 h. [b] Yield of isolated 3 (two
steps) is given.
Scheme 1. One-pot hydrobenzylation/ene reaction. TES=triethylsilyl,
TIPS=triisopropylsilyl.
diethyl azodicarboxylate (DEAD) and HC(O)CO2Et to give
the ene products 4 and 5 (1.6:1 d.r.), respectively. The major
isomer of 5 was transformed into the ethyl (E)-2-benzofur-
ylacrylate 5’ in 62% yield by a Peterson olefination upon
treatment with BuLi, thus showing that the major adduct is
(aS,bR)-5, as described in Scheme 1. Paraformaldehyde could
be used in the ene reaction at 1008C, thus giving the
silylalcohol 6 in 36% yield. In stark contrast, the bulky
TIPS-substituted 2a reacted with ethyl trifluoropyruvate at
the 3-position, thus forming the C3-substituted benzofuran 7
in 66% yield, possibly as a result of steric repulsion. On the
contrary, 2d gave a complex mixture of C2- and C3-bound
products. The TIPS group in 2a was oxidized by H2O2 and air
to give 2-benzofurylaldehyde (8) in 61% and 42% yields,
respectively. Of note, the reactions of 3d with DEAD and
ethyl trifluoropyruvate were futile, thus clearly demonstrating
that the hydrobenzylation products 2 are ene-active olefins.
The silyl groups in 3 work as an additional reactive
methoxy, and trifluoromethyl groups at the other ortho posi-
tion to the ethereal oxygen atom reacted selectively at the
À
ortho-methyl C H in excellent yields to give adducts (Table 1,
entries 1–3). It is noteworthy that the terminal methyl and
À
methylene C H bonds in the ethyl group at the other
ortho position did not participate in the reaction (Table 1,
entry 1). The methoxy group also remained intact (Table 1,
entry 2). The highly electron-withdrawing trifluoromethyl
group in 1h did not interfere with the reaction (Table 1,
entry 3). When the ortho-tolyl ether 1i was subjected to the
reaction conditions in a low concentration (0.1m), the
corresponding benzofuran 3i was obtained in a high yield
3
(Table 1, entry 4).[14] Notably, selective benzylic C(sp ) H
À
2
À
activation was observed in preference to the aryl C(sp ) H
activation. This observation stimulated us to apply the
methodology to other ortho-tolyl alkynyl ethers. The one
2
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functionality. Protodesilylation of 3a with TBAF gave 2,7-
dimethyl benzofuran in a quantitative yield, and thus the silyl
moiety behaves as a latent nucleophile as is shown by the
TBAF-mediated 1,2-addition of 3e to benzaldehyde, thereby
leading to the corresponding alcohol 9 being isolated in 62%
yield [Eq. (3); TBAF = tetra-n-butylammonium fluoride].
Scheme 2. Kinetic isotope effect experiments.
The Pd/Zn-catalyzed intramolecular hydrobenzylation
reaction is applicable to the aryl ethynyl ethers 10 bearing
a carbonaceous substituent instead of a silyl group [Eq. (4)].
The cyclization smoothly took place to give the corresponding
1a versus [D6]-1a was observed under the catalysis with
5 mol% of Pd(OAc)2/2PCy3/Zn in C6D6 for 2 hours at 508C,
and the ratio was determined to be 12.7 (Scheme 2a), thus
À
indicating that the C H bond is probably cleaved by
a concerted metalation/deprotonation (CMD) transition
state (TS).[16] The substrate [D3]-1a, containing both CH3
and CD3 groups, was exposed to the hydrobenzylation
conditions (508C, 14 h in C6D6) and the resultant KIE value
was found to be 6.9, although an H/D exchange occurred to
some extent at the vinyl carbon atom a to the silyl group
(Scheme 2b). Accordingly, the most probable rate-determin-
À
ing step may be attributed to the C H bond cleavage.
The effect of Zn(OAc)2, generated in situ from the
reaction of Pd(OAc)2 with Zn, is obvious. The [Pd(dba)2]/
PCy3-catalyzed reaction of 1a in the presence or absence of
Zn(OAc)2 was monitored at 608C. The hydrobenzylation
took place in the presence of Zn(OAc)2; without Zn(OAc)2
1a was recovered almost unchanged. To clarify the role of
Zn(OAc)2, we examined other additives such as ZnCl2
(20 mol%), Zn(OTf)2 (20 mol%), NBu4OAc (2 mol%), or
AcOH (2 mol%) for the cyclization of 1a in the presence of
[Pd(dba)2] (1 mol%) and PCy3 (2 mol%), and found that
only AcOH only promoted the reaction and gave 2a
quantitatively. In contrast, the less bulky TES-substituted
1d cyclized to form the isomerized product 3d in 45% in the
presence of NBu4OAc (2 mol%), thus indicating that the
generated Zn(OAc)2 is not merely for the acetate ion
donor.[17] These observations combined with the previous
results indicate that in situ generated Zn(OAc)2 acts as
a Lewis acid and acetate ion donor to promote the cleavage of
products 11, which upon treatment with acetic acid gave the 2-
alkenyl-substituted benzofurans 12 by elimination of meth-
anol.[15] For example, cyclization of the 2,6-xylyl 2-(1-methox-
À
ycyclohexyl)ethynyl ethers 10a (R = R’ = (CH2)5), 10b (R =
R’ = Ph), and 10c (R = Ph, R’ = H) took place in the presence
of 5 mol% of palladium catalyst to form the corresponding
products (11), which readily converted into the 2-alkenyl
benzofurans 12 in moderate yields over two steps. In the case
of 10c, the b-styryl-substituted benzofuran 12c was obtained
as a single isomer. However, the reaction of a less bulky
substrate, the 3-methoxypropynyl ether 10d, turned out futile.
These results clearly demonstrate that the presence of a bulky
substituent on the propargylic position is essential for the
success of the hydrobenzylation reaction.
To gain insight into the mechanism of the present
hydrobenzylation, we conducted deuterium-labeling experi-
ments. The reaction of [D6]-1a in toluene resulted in the
formation of [D6]-2a with 97% deuterium incorporation at
À
benzylic C H bond.
1
the vinyl carbon atom as was evaluated by H NMR analysis
Although more information is necessary to discuss the
reaction mechanism in detail, we propose a mechanism for
the Pd(OAc)2/PCy3/Zn-catalyzed hydrobenzylation as sum-
marized in Scheme 3 with 1i as a representative substrate.
First, the alkyne-coordinated palladium(0) complex 13 is
formed, wherein the intramolecular nucleophilic attack of
electron-rich palladium(0) on the a-carbon atom of the
alkynoxy group presumably occurs to give the complex 14.
The alkynoxy group is reasonably assumed to have a ketene-
like polarized resonance structure, thus indicating that the a-
carbon atom bound to the oxygen center is electrophilic and
the b-carbon atom nucleophilic.[18] Thus, the b-carbanionic
center in 14 is neutralized by Zn(OAc)2 to give the vinyl
[Eq. (5)]. This result demonstrates that the deuterium located
originally on the benzylic carbon atom is transposed cleanly
to the 2-methylidene carbon atom.
The kinetic isotope effect (KIE) was subsequently inves-
tigated (Scheme 2). The relative rate, kH/kD, of the reaction of
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Scheme 3. Proposed reaction mechanism.
palladium acetate 15 by the migration of the generated
acetate ion to the palladium center. An alternative pathway
from 13 to 15 may be also possible: ligation of the b-carbon
atom of 13 to Zn(OAc)2 could give 16, whose palladium
ligated by acetoxy group on Zn attacks the a-carbon atom to
À
give 15. The benzylic C H bond is cleaved by CMD to give
the acetic-acid-coordinated palladacycle intermediate 17,[19,20]
with subsequent rapid protonation of the vinyl zinc moiety by
acetic acid and reductive elimination to the cis-adduct 2i and
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h2-palladium(0) complex to the a-carbon atom owing to steric
repulsion. Moreover, the silyl group (e.g., TIPS) stabilizes the
negative charge at the silicon-bearing carbon atom (a effect)
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À
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In conclusion, the present study demonstrates that the
palladium-catalyzed hydrobenzylation of ortho-tolyl alkynyl
ethers provides efficient access to reactive 2-methylidene-2,3-
3
À
dihydrobenzofurans by selective benzylic C(sp ) H activa-
tion. The alkynoxy moiety containing bulky substituents as
a directing group plays a key role in the present trans-
formation. It is worthy of note that Zn(OAc)2 promotes the
cyclization. The proper choice of the substituents bound to
the terminal ethynyl carbon atom allows additional trans-
formations. Efforts are currently directed toward further
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À
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Received: June 7, 2013
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Revised: July 5, 2013
Published online: && &&, &&&&
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Keywords: alkynes · arenes · heterocycles · palladium ·
synthetic methods
.
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Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2004, 126, 11806;
b) A. S. K. Hashmi, M. Rudolph, J. W. Bats, W. Frey, F.
Rominger, T. Oeser, Chem. Eur. J. 2008, 14, 6672; c) A. S. K.
[20] Selective benzylic C H cleavage rather than ortho C H bond by
intramolecular imino-coordinated bromoplatinum(II) complex
was reported. See: M. Crespo, C. M. Anderson, N. Kfoury, M.
Font-Bardia, T. Calvet, Organometallics 2012, 31, 4401.
[21] The cyclization proceeded in the absence of Zn under the
standard reaction conditions. In this case, it is assumed that the
[Pd(PCy3)(OAc)]À complex is the active catalyst which attacks
the a-carbon atom of the alkynoxy group to give a vinyl
palladium acetate. See: a) C. Amatore, A. Jutand, M. A.
M’Barkl, Organometallics 1992, 11, 3009; b) C. Amatore, E.
Carrꢀ, A. Jutand, M. A. M’Barkl, Organometallics 1995, 14,
1818.
´
Hashmi, M. Rudolph, J. Huck, W. Frey, J. W. Bats, M. Hamzic,
Angew. Chem. 2009, 121, 5962; Angew. Chem. Int. Ed. 2009, 48,
5848.
[14] The reaction in 1.0m concentration gave a mixture of 3i and
À
a dimeric product, by ortho C H activation, in 31 and 55% yield,
respectively.
[15] L. Yu Ukhin, L. V. Belousova, Z. I. Orlova, M. S. Korobov, G. S.
Borodkin, Chem. Heterocycl. Compd. 2002, 38, 1174.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Heterocycles
Y. Minami,* K. Yamada,
T. Hiyama*
&&&& — &&&&
Palladium-Catalyzed Hydrobenzylation of
À
ortho-Tolyl Alkynyl Ethers by Benzylic C H
Activation: Remarkable Alkynoxy-
Directing Effect
It’s selective: The title reaction involves
which transform into benzofurans upon
treatment with a weak acid (e.g., AcOH)
and electrophiles. The alkynoxy group
serves as a directing group in promoting
ꢀ
palladium(0)-catalyzed insertion of C C
3
À
bonds into benzylic C(sp ) H bonds,
thus providing efficient access to 2-
methylene-2,3-dihydrobenzofurans,
À
C H bond functionalization.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!