Aryl ether as a Negishi coupling partner: An approach for constructing C-C bonds under mild conditions

Article abstract of DOI:10.1002/chem.201103784

An etheric Negishi coupling: The first cross-coupling reaction between aryl alkyl ethers and dianion-type zincate reagents to afford biaryl compounds through selective cleavage of the etheric C(sp²)-O bond was developed. Dianion-type zincates showed excellent reactivity toward the aromatic ethers under mild conditions, with good functional group compatibility (see scheme). Copyright

Full text of DOI:10.1002/chem.201103784

DOI: 10.1002/chem.201103784
Aryl Ether as a Negishi Coupling Partner: An Approach for Constructing
À
C C Bonds under Mild Conditions
Chao Wang,*[a, b] Takashi Ozaki,[a, b] Ryo Takita,[a, b] and Masanobu Uchiyama*[a, b]
Owing to their high efficiency and broad applicability to
only several reports on transition-metal-catalyzed cross-cou-
À
À
À
form C C/C X bonds, transition-metal-catalyzed cross-cou-
pling reactions have long been regarded as a pillar of organ-
ic synthesis.[1] Various organometallics, catalysts, and activa-
tors have been developed for these transformations, and
have found wide application both academically and industri-
ally. The electrophiles principally exploited in these reac-
tions have been organic iodides and bromides,[1] and in more
recent years, inert halides such as chlorides,[2] fluorides,[3] or
pseudo-halides (nitriles)[4]. In addition, hetero-atom-contain-
ing compounds, particularly oxygen-based substrates, have
been employed.[5] As depicted in Scheme 1, many O-based
pling C C bond formation reactions with aryl alkyl ethers,
involving the Kumada–Tamao–Corriu (KTC)-type[10] and
the Suzuki–Miyaura (SM)-type of reactions (Scheme 2).[11]
Scheme 2. Cross-coupling of aryl ether with different organometallics.
However, as inspiring as these results are, their application
to the elaboration of complex organic structures has still
been limited because of narrow functional group tolerance
(KTC-type) or the need for harsh reaction conditions and
additional efforts for preparation of boronic reagents (SM-
type). Hence, the development of new methodologies com-
plementary to the KTC-type and SM-type reactions for
Scheme 1. O-based substrates applied as electrophiles in cross-coupling
reactions.
À
functionalization of the aryl ether C O bond would be prac-
tically very useful. Organozinc reagents are excellent trans-
metalation reagents with several advantages, such as broad
functional-group compatibility, high reactivity/selectivity and
easy preparation,[1,13] but to our knowledge, cross-coupling
between organozinc and aryl alkyl ether (i.e., Negishi-type)
has never been reported. Here, we describe the first cross-
coupling reaction of aryl alkyl ethers with dianion-type zinc-
leaving groups, such as sulfonate,[5] phosphate,[5] and carbox-
ylate,[5–8] facilitate the coupling process because the adjacent
hetero-atom moiety stabilizes the intermediate/transition
[8]
À
state, or polarizes/activates the targeted C O bond. Very
recently, the cross-coupling of phenolic salts has also been
advanced.[9]
2
À
However, the development of efficient functionalization
ates through selective cleavage of etheric C
affording biaryls under mild conditions.
N
À
of the C O bond in simple aryl ethers has remained an im-
portant challenge.[5,10–12] Ethers are generally unreactive, and
are found widely in natural products, bioactive compounds,
pharmaceuticals, and functional materials. Since the pioneer-
ing work of Wenkert et al. as early as in 1979,[9a] there were
We started by screening suitable organozinc reagents,
using the nickel-tricyclohexylphosphine (Ni-PCy3) system as
a model catalyst, because this catalyst system has the highest
activity toward O-based electrophiles, such as carbox-
ylates,[5–8] phenolic salts,[9] or ethers.[10–12] Initially, several at-
tempts to couple 2-methoxynaphthalene (1a) with PhZnX
(X=Cl, Br, or Ph) under various conditions afforded no
product, but only recovered starting materials. Our next ap-
proach capitalized on the high reactivity and wide chemose-
lectivity of organozincate reagents, which allow flexible
design and fine-tuning by modification of the ligation envi-
ronment. Several attempts to use monoanion-type zinc-
ates[14–15] such as PhZnMe2Li (readily generated through an
exchange reaction between iodobenzene and Me3ZnLi)
proved unsuccessful in terms of yield. Although utilization
of dianion-type zincate[14–15] PhZnMe3Li2 (2a) in N,N-di-
methylacetamide (DMA) also failed to provide any coupling
[a] Dr. C. Wang, T. Ozaki, Prof. Dr. R. Takita, Prof. Dr. M. Uchiyama
Advanced Elements Chemistry Research Team
Advanced Science Institute, RIKEN
2–1 Hirosawa, Wako-shi, Saitama, 351-0198 (Japan)
Fax : (+81)3-5841-0732
E-mail: chaowang@riken.jp
[b] Dr. C. Wang, T. Ozaki, Prof. Dr. R. Takita, Prof. Dr. M. Uchiyama
Graduate School of Pharmaceutical Sciences
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku
Tokyo 113-0033 (Japan)
E-mail: uchiyama@mol.f.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103784.
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Table 1. Optimization of reaction conditions for nickel-catalyzed cross-
coupling of aryl ether 1aa with zincate 2a.
Entry
Solvent
T
[8C]
3aa
[%][b]
1
2
3
4
5
6
7
8
DMA
THF
100
100
100
100
75
50
RT
0
–
31
53
57
66
68
82
12
nBu2O
toluene
toluene
toluene
toluene
toluene
[a] [NiCl2ACHTUNGTRENNUNG(PCy3)] (4 mol%) or [NiACHTUNGTREN(NUNG cod)2] (4 mol%)/PCy3 (8 mol%) was
used as a catalyst with the same activity. Lowering either the catalyst
loading or the amount of zincate reduced the yields. [b] Isolated product
yield. DMA=N,N-dimethylacetamide.
product (Table 1, entry 1), surprisingly, in THF the expected
coupling product 2-phenylnaphthalene (3aa) was obtained,
albeit in low yield (entry 2). We then tested nBu2O and tolu-
ene as typical less polar solvents and they turned out to pro-
mote the cross-coupling reaction and give better yields of
3aa (Table 1, entries 3–4). Interestingly, as the reaction tem-
perature was lowered, the yield of 3aa rose to 82%, and the
reaction in toluene at room temperature gave the best result
(Table 1, entries 4–8).[16] It should be mentioned that the by-
product, 2,2’-binaphthalenyl, presumably formed by homo-
coupling of 1a, was also observed, and its amount decreased
markedly as the temperature was decreased.
Having established effective procedures for cross-coupling
of aryl ether, we proceeded to explore the scope of this re-
action between assorted aryl methyl ethers and zincates; the
results are summarized in Scheme 3. A variety of aryl zinc-
ates, easily generated by means of exchange reactions of
aryl iodides with Me4ZnLi2, were treated with 1aa in the
presence of a Ni catalyst. Zincates bearing electron-donating
groups (2b–g) afforded biaryl compounds in high yields. In-
triguingly, the methoxy group in the anisole moiety of the
zincates 2e–f remained entirely intact. Zincates 2h and 2i
bearing silyloxy groups presented no difficulty. The elec-
tron-withdrawing, base-sensitive amide functionality in 2j
was also compatible with these conditions. Coupling reac-
tions with zincates having expanded aromatic frameworks
(2l–m), such as biphenyl and naphthalenyl, proceeded suc-
cessfully, indicating good potential for the application of
these reactions in building large p-conjugated systems.
Moreover, 2-methoxynaphthalenes bearing diverse function-
alities (1b–f) underwent this reaction in good yields. 1-Me-
thoxynaphthalene (1g) could couple with zincate 2g in an
analogous trend at a slightly elevated temperature. As with
the SM-type reaction developed by Tobisu and Chatani
et al.,[11] the simple anisole derivative 1h showed lower reac-
tivity than 1a in our method. Finally, heterocycles 1i–j also
underwent this reaction, albeit in lower yield. Thus, many
functional groups, including alkoxy, silyloxy, amino, silyl,
Scheme 3. Cross-coupling of aromatic ethers with aryl zincates. [a]
[NiCl2ACHTNUTRGENN(GU PCy3)] (4 mol%) or [NiCAHTUNGTERN(NUGN cod)2] (4 mol%)/PCy3 (8 mol%) was
used as a catalyst. Isolated product yields are given in brackets. [b] The
reaction was performed at 508C.
amide, and heterocylic, were compatible with the conditions
of this reaction.
Aryl ethers are widely used in pharmaceuticals, agro-
chemistry and related areas. For instance, the (+)-naproxen
is a non-steroidal anti-inflammatory drug usually employed
for reduction of pain fever, and inflammation.[17] As an ex-
ample of the utility for this cross-coupling method,
Scheme 4 shows the phenylation of (+)-naproxen amide 1k.
À
This C C bond formation was achieved efficiently, under
very mild conditions, at a methoxy group that is generally
regarded as unreactive, and further, without racemization at
Scheme 4. Introducing the phenyl group into (+)-naproxen amide with-
out racemization.
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C. Wang, M. Uchiyama et al.
the sensitive benzylic and a-ketonic positions. These results
demonstrate the potential applicability of this method for
late-stage derivatization of functional molecules. These ad-
vantageous properties are considered to be due to the
unique properties of the zincate reagents, which possess
good nucleophilicity and poor basicity.[14–15]
To investigate the chemoselectivity of this coupling, the
reactivities of various ethers 1aa–1ac and pivalate 1ad were
next examined (Scheme 5). Substrates with bulkier substitu-
ents showed lower reactivity, probably because the steric re-
Acknowledgements
This research was partly supported by the Mochida Memorial Founda-
tion, the Naito Foundation, the Hoansha Foundation, and the Takeda
Science Foundation. We thank Prof. Motomu Kanai and Mr. Harunobu
Mitsunuma (The University of Tokyo) for the chiral HPLC measure-
ment. C. W. also gratefully acknowledges the receipts of JSPS Fellowship
and RIKEN-FPR Fellowship.
À
Keywords: C O activation · cross-coupling · ethers · nickel ·
zincates
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À
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Aryl Ether as a Negishi Coupling Partner
COMMUNICATION
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À
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À
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Received: December 2, 2011
Published online: February 28, 2012
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