Metal-free C-H cross-coupling toward oxygenated naphthalene-benzene linked biaryls

Article abstract of DOI:10.1021/ol202632h

The intermolecular C-H cross-coupling between aromatic ethers has been achieved for the first time using perfluorinated hypervalent iodine(III) compounds as extreme single-electron-transfer (SET) oxidants. The demonstrations of this specific coupling coul

Full text of DOI:10.1021/ol202632h

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6208–6211
Metal-Free CꢀH Cross-Coupling toward
Oxygenated Naphthalene-Benzene Linked
Biaryls
Toshifumi Dohi,† Motoki Ito,†,‡ Itsuki Itani,† Nobutaka Yamaoka,† Koji Morimoto,†
Hiromichi Fujioka,‡ and Yasuyuki Kita*,†
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi,
Kusatsu, Shiga 525-8577, Japan, and Graduate School of Pharmaceutical Sciences,
Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
kita@ph.ritsumei.ac.jp
Received September 30, 2011
ABSTRACT
The intermolecular CꢀH cross-coupling between aromatic ethers has been achieved for the first time using perfluorinated hypervalent iodine(III)
compounds as extreme single-electron-transfer (SET) oxidants. The demonstrations of this specific coupling could provide a direct route to
valuable oxygenated mixed naphthalene-benzene biaryls 3 only, without formation of other biaryl-derived byproducts.
The oxidative coupling between arene CꢀH bonds is
recognized as a straightforward and attractive approach
that creates new CꢀC bonds of biaryl molecules without
the use of prefunctionalized substrates, i.e., organometallic
compounds or halides.1 A recent breakthrough in this
synthetic area by participation of transition metal chem-
istry has permitted direct access to a variety of mixed biaryl
compounds containing heteroaromatic rings2 and metal-
coordinating directing groups3 by CꢀH cross-couplings.
On the other hand, oxidative cross-coupling between CꢀH
bonds of aromatic hydrocarbons not containing directing
groups, such as naphthalenes and benzenes, is still difficult
in regard to the product selectivity and yield even after
modern synthetic advances.4 Previously, we reported the
unprecedented success of the cross-coupling between na-
phthalenes and alkylbenzenes using phenyliodine bis-
(trifluoroacetate) (PIFA).5 As a continuation of our
† Ritsumeikan University.
‡ Osaka University.
(1) (a) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38,
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Tohma, H.; Takada, T. Chem. Commun. 1996, 1481. (b) Takada, T.;
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r
10.1021/ol202632h
Published on Web 10/28/2011
2011 American Chemical Society

research involving metal-free biaryl couplings using hy-
pervalent iodine chemistry,5ꢀ8 we now report the extre-
mely specific CꢀH cross-coupling for a new combination
of aromatic rings, that is, between aromatic ethers, to give
the corresponding valuable oxygenated mixed biaryls (see
examples in eq 1).
cross-coupling of the naphthalene and phenyl ethers 1a
and 2a (eq 1) produced the expected naphthalene-benzene
linked biaryl 3aa in 63% yield (Table 1, entry 1). Never-
theless, PIFA caused homocoupling in this case, along
Highly oxygenated biaryl structures, which are frequently
involved in many natural products, have been extensively
utilized as the core components of pharmaceuticals, dyes,
liquid crystals, organic devices, and conductors and for
the design of ligands and catalysts in organic synthesis.9
The intramolecular oxidative couplings of phenyl ether
rings are widely used for the construction of the cyclic
biaryl structures of these natural products and other useful
compounds.10 However, some difficulties emerge when
performing intermolecular cross-coupling by the methods.
The first commonly known problem is the coformation of
an undesired homocoupling dimer together with a mixed
biaryl product.11,12 Another specific concern regarding the
coupling of aromatic ethers is that the formed biaryls, that
is, the oxidation-sensitive electron-rich compounds,13
would be further oxidized and produce oligomers, quinone
derivatives, and other byproducts, thus decreasing the
yield of the coupling product. The intermolecular coupling
for obtaining oxygenated mixed biaryls is believed to be
very troublesome because of the chemoselective issues of
both the substrates and products.
Table 1. Influence of the Structure of Hypervalent Iodine Re-
agents in the Cross-Coupling of 1a and 2a (eq 1)a
oxidant Ar-
I(OCOCF3)2
mixed biaryl
3aab (%)
homocoupling
entry
of 2ac
1
Ar = Ph (PIFA)
Ar = 4-MeC6H4
Ar = 4-MeOC6H4
Ar = 2,4,6-MeC6H2
Ar = 4-CF3C6H4
Ar = C6F5 (FPIFA)
Ar = 4-CF3C6F4
(FPIFA)
63
14
þ (10%)
2
þ
þ
þ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3
24
4
26
5
63
6
82
7
78
8d
9d,e
>99
96
(FPIFA)
a Reactions were examined using 1a (1 equiv) and 2a (2 equiv) with
oxidants (1 equiv) in the presence of BF3 Et2O (2 equiv) at 0 oC.
3
b Isolated yield of the pure product based on the substrate 1a used.
c The formation of the homodimer of 2a, that is, 2,20-dimethyl-4,40,6,60-
tetramethoxybiphenyl, was checked by 1H NMR, GC, and HPLC.
d Reaction was performed at ꢀ40 oC. e 4 equiv of 2a.
with ca. 10% formation of the undesired dimer of methox-
ybenzene 2a. Detailed screenings of the reaction condi-
tions, such as the concentration, temperature, solvent,
amounts of the reagent and activator, order of the reagent
addition and their addition rate, were examined for the
With respect to the excellent single-electron-transfer
(SET) oxidizing ability of hypervalent iodine reagents to
aromatic rings,14 wefirst anticipated their possible use with
the intermolecular cross-coupling between aromatic ethers
employing PIFA. Indeed, the treatment of PIFA in the
PIFA/BF3 Et2O system for the purpose of suppressing the
3
presence of the activator BF3 Et2O5ꢀ7 in an attempt at the
homodimer, the formation of which had not yet been
eliminated. An alternative use of bromotrimethylsilane
as an activator8 was then investigated, which did not yield
the mixed biaryl 3aa. Instead, we found that a subtle
change in the oxidant nature significantly affected the
distribution of the coupling products, the cross-coupling
biaryl 3aa versus the homodimer of 2a, as well as the
reaction yield.
3
(8) Cross-couplings: (a) Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.;
Goto, A.; Dohi, T. J. Am. Chem. Soc. 2009, 131, 1668. (b) Morimoto, K.;
Yamaoka, N.; Ogawa, C.; Nakae, T.; Fujioka, H.; Dohi, T.; Kita, Y.
Org. Lett. 2010, 12, 3804.
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Chem. Rev. 2011, 111, 563. (b) Hertweck, C. Angew. Chem., Int. Ed.
2009, 48, 4688. (c) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.;
Tasler, S. Prog. Chem. Org. Nat. Prod. 2001, 82, 1. (d) van Leeuwen, P.
W. N. M.; Kamer, P. C. J.; Claver, C.; Pamies, O.; Dieguez, M. Chem.
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Lett. 2009, 11, 3474. See also our methods in ref 6.
In comparison to PIFA, the relatively electron-rich aryl
moieties in the oxidants Ar-I(OCOCF3)2, where Ar =
4-Me, 4-MeO, and 2,4,6-Me, were less positive, and the
product 3aa was no longer formed in good yield (entries
2ꢀ4). In addition, formation of the homodimer of 2a was
observed. On the contrary, the oxidant having the CF3
substituent as the electron-deficient group showed a degree
of product formation similar to that of PIFA, while the
homodimer was not detected (entry 5). With this perspec-
tive, we further evaluated the perfluorinated PIFA15aꢀc
(11) (a) Nyberg, K. Acta. Chem. Scand. 1973, 27, 503. (b) Nyberg, K.
Chem. Scr. 1974, 5, 120.
(12) The oxidative cross-couplings of naphthols were reported, which
are not applicable to the naphthyl ether couplings: (a) Hovorka, M.;
Gunterova, J.; Zavada, J. Tetrahedron Lett. 1990, 31, 413. (b) Vyskocil,
S.; Smrcina, M.; Lorenc, M.; Hanus, V.; Polasek, M.; Kocovsky, P.
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Yang, J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 5500.
(13) Oxyganated aryl naphthalenes are sensitive to oxidations. For
examples of quinone formations, see: (a) Lumb, J.-P.; Trauner, D. Org.
Lett. 2005, 7, 5865. (b) Larsen, D. S.; O’Shea, M. D. J. Org. Chem. 1996,
61, 5681. (c) Schafer, H. J. In Organic Electrochemistry; Lund, H., Baizer,
M. M., Eds.; Marcel Dekker: New York, 1991; Chapter 23.
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Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684.
Accounts: (b) Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem. 1996,
68, 627. (c) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.;
Kita, Y. Tetrahedron 2009, 65, 10797.
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(a) Moriarty, R. M.; Prakash, I.; Penmasta, R. J. Chem. Soc., Chem.
Commun. 1987, 202. (b) Moriarty, R. M.; Penmasta, R.; Awasthi, A. K.;
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€
Org. Lett., Vol. 13, No. 23, 2011
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(FPIFA) and its CF3-substituted derivative.15d Gratefully,
both oxidants worked well as more effective promoters for
the cross-coupling (entries 6 and 7). A more pronounced
advantage of the perfluorinated oxidants was no forma-
tion of the homodimer, which is in clear contrast to PIFA.
Further improvement of the product yield was achieved
after optimization of the conditions, and the use of com-
mercial FPIFA gave a perfect result (entry 8). It should be
noted that the perfluorinated oxidant, FPIFA, did not
induce the homodimer formation even in the presence of a
greater excess amount of the methoxybenzene 2a (entry 9).
None of other typical chemical SET oxidants10 [speci-
fically, FeCl3, MoCl5, Mn(OAc)3, Ce(NH4)2(NO3)6
(CAN), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)] or anodic oxidations11a produced the cross-
coupled 3aa as the major product.
of the initially added biaryl 3aa and over 99% of the biaryl
3ab during the control experiments. This is also rationa-
lized by considering the steric factor in the formed C-T
complex (Figure 1, right). Apparently, the existence of the
angular methoxybenzene ring in the products 3aa and 3ab
forces the complexation with FPIFA to be unfavorable.
For these reasons, the extended series of the phenyl
ethers 2bꢀi could also be used as the coupling partners
of the naphthalene ether 1a with the optimized oxidant
(Table 2). All coupling reactions proceeded to satisfacto-
Table 2. Examples of the Cross-Coupling Partners 2bꢀia
It became evident that selection of the oxidant is very
important for successful cross-coupling. The consumup-
tion of all of the naphthalene ether 1a and the nearly
perfect yield of 3aa as the sole coupling product suggested
the increased SET oxidation efficiency of the perfluori-
nated hypervalent iodine compounds over PIFA to quan-
titatively produce the naphthalene cation radical14a of 1a
(Figure 1, left), which was then trapped by the neutral 2a to
Figure 1. Selective C-T complex formation between FPIFA
and 1a.
give the mixed biaryl 3aa. The generation of the cation
radical of 2a that led to the homodimer did not occur.
Hence, the Lewis acidity of the iodine atom in the FPIFA/
a Reactions were perfomed using naphthalene ether 1a (1 equiv) and
2bꢀd,gꢀi (2 equiv) under the optimized conditions in Table 1 unless
otherwise noted. b Isolated yield of the pure products based on the
substrate 1a used. c 4 equiv of 2e and 2f was used. nd = not determined
(less than 3% yield formation). Ts = p-tosyl.
BF3 Et2O adduct should just match the formation of the
3
C-T complex with the naphthalene ether 1a that was
involved before starting the SET oxidation process. Simi-
larly, overoxidation of the formedbiaryl 3 can be ruled out.
The reaction of the substrates 1a (0.200 mmol) and 2a
(0. 40 mmol) or 2b (R0 = OMe, 0.40 mmol) in the presence
of the prepared 3aa (0.200 mmol) or 3ab (0.200 mmol)
under the standard coupling conditions resulted in the
recovery of 0.364 mmol (for 3aa) and >0.399 mmol (for
3ab) of the biaryls after isolation (see Supporting
Information), which revealed the revival of at least 82%
rily give the corresponding oxygenated mixed biaryls 3
without formation of the homodimer in these cases. Several
protecting groups (benzyl, acetyl, etc.) and functionalities
(alkyne, phenol, amine, and others) were acceptable as the
coupling partners 2. The phenyl ethers 2gꢀi produced two
separable cross-coupling products with preference of the
biaryls, 3ag, 30ah, and 30ai, by the para-reactions of the
6210
Org. Lett., Vol. 13, No. 23, 2011

methoxy group or acidic substituents of 2h and 2i (entries
6ꢀ8). To our surprise, the oxidations of the phenol and
aniline rings16 were relatively slower than the cross-coupling
with FPIFA (entries 7 and 8).
Regarding the naphthalene ring, the use of similar
protecting groups and functionalities was also possible
(Scheme 1). In 1c, the couplings preferentially occurred
elaboration of the obtained biaryl in our method toward
the benz[b]phenanthridine structure18 was demonstrated
(Scheme 3). The biaryl 3ad was thus converted into the aryl
naphthoquinone 4 by treatment of CAN13b followed by the
installation of an amino group, and its cyclization could
afford the target tetracyclic compound 6. Considering the
necessity of sacrificial functional groups, such as halogens,
in order to construct the phenanthrizine structures via other
synthetic routes, our metal-free CꢀH coupling method is
capable of providing unique access toward molecules re-
taining such functional groups.
Scheme 1. Reactions of Naphthalene Ethers 1bꢀda
Scheme 3. Elaboration of the Biaryl Structure of 3ad
a Reactions were performed using 2 equiv of 2b.
at the less hindered position of the naphthalene ring.
Curiously, the naphthalene ether 1d selectively reacted at
the ortho position of the methyl group to give only the
biaryl 30db. On the other hand, interesting remote regios-
electivity controls at the naphthalene rings were observed
(Scheme 2). Particulary, the OTBDPS and halogen in 1f
In summary, we have reported for the first time the
intermolecular CꢀH cross-coupling between the aromatic
ethers 1 and 2. The key point of the reaction success is the
utilization of the excellent ability of hypervalent iodine
reagents, especially the perfluorinated PIFAs, in the SET
oxidation process. The remarkable high affinity of the
reagents to the naphthalene ethers 1 over the phenyl ethers
2 as well as the formed mixed biaryl products 3 in the
reactions can definitively exclude the undesired homocou-
pling and overoxidation of the biaryl products 3, thus
realizing the specific cross-coupling.
Scheme 2. Remote Regioselectivity Control in Naphthalenesa
Acknowledgment. This work was partially supported by
Grant-in-Aid for Scientific Research (A) from the Japan
Society for the Promotion of Science (JSPS) and Ritsumeikan
Global Innovation Research Organization (R-GIRO) pro-
ject. T.D. is thankful for support from The Sumitomo
Foundation and the Industrial Technology Research Grant
Program from the New Energy and Industrial Technology
Development Organization (NEDO) of Japan.
a TBDPS = tert-butyldiphenylsilyl
and 1gshowed different regioselectivities tothe OAc group
in 1e, which even overwhelmed the steric influence of the
isobutyl group in substrate 1h.
The oxygenated aryl naphthalenes 3 belong to a class of
valuable synthetic intermediates that are the core structures
of many useful compounds.17 Their further oxidized aryl
naphthoquinones are also versatile for divergent access
to naturally occurring types of compounds. Accordingly,
Supporting Information Available. Representative ex-
perimental procedures and detailed spectroscopic data of
the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
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references therein. (b) Mori, K.; Ohmori, K.; Suzuki, K. Angew. Chem.,
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