Oxidative cross-coupling of arenes induced by single-electron transfer leading to biaryls by use of organoiodine(III)oxidants

Article abstract of DOI:10.1002/anie.200704495

(Chemical Equation Presented) Cross-coupling goes green: The direct oxidative cross-coupling reaction of naphthalenes and other electron-rich arenes with mesitylenes has been achieved in high yields using hypervalent iodine(III) reagents. The key for reac

Full text of DOI:10.1002/anie.200704495

Angewandte
Chemie
DOI: 10.1002/anie.200704495
Cross-Coupling
Oxidative Cross-Coupling of Arenes Induced by Single-Electron
Transfer Leading to Biaryls by Use of Organoiodine(III)Oxidants**
Toshifumi Dohi, Motoki Ito, Koji Morimoto, Minako Iwata, and Yasuyuki Kita*
The scientific importance and value of biaryls are easily
recognized from the broad industrial utilization of these
compounds as versatile building blocks for liquid crystals,
organic devices and conductors, dyes, ligands for metal
catalysts, and even in medical fields, since these structures
are ubiquitous in biologically active, naturally occurring
products.[1] Above all, many synthetic efforts have already
been devoted to the practical access of these biaryls and the
resolution of specific problems during their syntheses.[2,3]
Scheme 1. Biaryl products for the oxidative cross-coupling reaction.
Considering current pressure to reduce the number of
synthetic steps and the production of waste, the most ideal
and attractive route to biaryl compounds appears to be the
direct oxidative coupling of two non-activated arenes.[4–9]
Heavy-metal oxidants (i.e. VV, MnIII, MoV, FeIII, TlIII, and
PbIV) in strong acids,[4] nitric acid based oxidants,[5] and anodic
oxidations[6] have typically been employed for direct access to
biaryl compounds. More recently, hypervalent iodine(III)
reagents[7] and combinations of palladium catalysts and
oxidants[8] have been used. However, the majority of these
methods still have limited applications owing to the difficulty
in obtaining cross-coupling products, because the undesired
competitive formation of homocoupling dimers occurs
(Scheme 1). To address this issue, solutions have recently
been provided by Stuart and Fagnou[10] and by Canesi and co-
workers[11] regarding selective indole or aniline cross-cou-
plings by two-electron oxidative activation utilizing the
nitrogen functionalities. Despite a few examples of unprece-
dented direct cross-couplings,[12,13] there remains a strong
demand for the further development of new direct cross-
coupling systems involving alternative mechanistic concep-
tions, which permit other structural types of coupling
combinations. Herein, we report a novel direct oxidative
approach for the cross-coupling of naphthalenes and mesity-
lenes, with the latter representing a selection of the ultimate
nucleophilic partners. This is the first successful example of
selective cross-coupling between unfunctionalized arenes
induced by single-electron transfer (SET) oxidation, taking
advantage of the unusual selectivity for the generation of
aromatic cation radical intermediates using hypervalent
iodine(III) reagents.
Our working hypothesis for the design of a new cross-
coupling method involves the generation of aromatic cation
radicals B as key intermediates (Scheme 2). Thus, using the
Scheme 2. Working hypothesis for oxidative cross-coupling.
[*] Dr. T. Dohi, M. Ito, K. Morimoto, M. Iwata, Prof. Dr. Y. Kita
Graduate School of Pharmaceutical Sciences
Osaka University
appropriate oxidant, generation of radicals B would occur by
the SET oxidation of electron-rich arenes as the first event,
through the charge-transfer complexes A.[14] Subsequent
in situ trapping of the resulting intermediates B by other
existing aromatic molecules and subsequent further one-
electron oxidation and deprotonation would lead to aryl–aryl
bond formation to give the corresponding mixed biaryls. For
the realization of the effective cross-coupling mechanism
without any undesired formation of homodimers, the follow-
ing points should be considered: 1) smooth and selective SET
activation of specific aromatic compounds by a suitable
oxidant in the presence of another aromatic coupling partner,
and, at the same time, 2) the coupling partner must have a
nucleophilicity sufficiently higher than that of the specific
aromatic compound being activated in order to act as an
1-6 Yamada-oka, Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-8229
E-mail: kita@phs.osaka-u.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research
(A) and for Encouragement of Young Scientists, and by a Grant-in-
Aid for Scientific Research on Priority Areas “Advanced Molecular
Transformations of Carbon Resources” from the Ministry of
Education Culture, Sports, Science, and Technology (Japan). T.D.
also thanks the Industrial Technology Research Grant Program from
the New Energy and Industrial Technology Development Organ-
ization (NEDO) of Japan. We are grateful to Dr. S. Obika for his help
with X-ray analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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effective nucleophile. With these aspects in mind, we selected
1.5 equivalents of 2a, but it selectively afforded 3aa (Table 1,
entries 4 and 5). On the other hand, the pentavalent DMP and
DDQ caused the formation of the homodimer 5 instead of the
cross-coupling product (Table 1, entries 6 and 7). Iron(III)
(Table 1, entry 8), thallium(III) (Table 1, entry 9), [Ce(NH4)2-
(NO3)6] (CAN, Table 1, entry 10), Mn(OAc)3, and MoCl5
were then screened as metal-based oxidants[4,5] with generally
negative results (0–25% yields of 3aa). In these cases,
problems with the halogenation,[4b] metalation,[4c] and nitra-
tion of 1a and 2a occurred. Furthermore, anodic oxidations[6]
induced the remarkable formation of the homodimers of 1a
and mesitylenes 2, while the catalyst combination of Pd-
the hypervalent iodine(III)-induced oxidative coupling of
naphthalenes with mesitylenes, assuming the high affinity of
the hypervalent iodine(III) oxidants toward non-nucleophilic
naphthalenes as well as the excellent nucleophilicity of
mesitylenes[15] as suitable coupling partners.
In fact, for the treatment of naphthalene 1a and penta-
methylbenzene 2a with phenyliodine bis(trifluoroacetate)
(PIFA) [Eq. (1)],[16] the cross-coupling reaction afforded the
[10]
(OCOCF3)2 and Cu(OAc)2 resulted in no reaction. These
results clearly indicated that the use of organoiodine(III)
oxidants is essential for the selective activation of naphtha-
lene 1a and efficient reaction progress.
The scope of this cross-coupling reaction was investigated,
and selected examples are summarized in Table 2. For the
PIFA-induced cross-coupling, we found that the halogen
functionality is the best and most versatile directing group,
which allowed control of the regioselectivity and further
elucidation of the mixed biaryl products, such as the results of
À
À
À
C C, C O, and C N bond formations (Table 2, entries 1–4).
Thus, the reaction of 1b–d gave the mixed biaryl 3bb–3db as
the sole products, the regioselectivities of which were
determined by X-ray crystal structure analysis (see below)
or by comparing them to the authentic samples. In contrast,
the presence of an electron-withdrawing group changed the
regioselectivity, and an alternative regioisomer 3eb’ was
produced in preference to 3eb (Table 2, entry 5); this result
suggests that the resonance effect of the halogen atom is
important for the regioselective couplings. As an example of
substitution at the 1-position, we performed the reaction
using 1-phenyl naphthalene (1 f), which exclusively produced
a 1,4-diarylated product 3 fb (Table 2, entry 6). A variety of
desired unsymmetrical biaryl 3aa in high yields, even using a
slight excess of 2a[17] (Table 1, entries 1 and 2). Remarkably,
in spite of the difficulty in the selective activation of
naphthalene 1a in the presence of 2a, which has an oxidation
potential close to that of 1a, the undesired homocoupling
reaction hardly occurred under the stated conditions, and the
homodimers of 1a and 2a were not detected (confirmed by
GC). One plausible reason for the observed high selectivity of
PIFA for naphthalene 1a is the steric hindrance of 2a. We
then compared the present method to a variety of other
organic and representative metal oxidants. Using the PIFA
derivative C6F5I(OCOCF3)2, the undesired homodimer 4 was
formed along with the cross-coupling product 3aa, probably
because the reactivity of the oxidant is too high (Table 1,
entry 3). The Koser reagent PhI(OH)OTs (OTs = p-toluene-
sulfonate)[18] provided an inferior result to PIFA when using
nucleophilic partners
2 were also applicable (Table 2,
entries 7–9). The aryl–aryl bond formations occurred at the
less sterically hindered site of the aromatic nucleophiles 2.
Aryl–aryl bond formation at the sterically hindered
carbon atom of the 1,3-disubstituted benzenes is the most
challenging task now being assessed by modern coupling
strategies.[19] One positive feature of our new biaryl synthetic
method is the high reactivity of the intermediates, which
overcomes the steric influence of
Table 1: Product distribution for representative oxidants.[a]
the starting materials. For sterically
hindered nucleophiles 2, the
Entry
Oxidant
Conditions
3aa [%][b]
Homodimer 4 or 5 [%][b]
method was found to be optimal
for the coupling reaction. Accord-
ingly, the reaction of 1b with 1,3,5-
4: 26
1
2[e]
3
PIFA
PIFA
C6F5I(OCOCF3)2
PhI(OH)OTs
PhI(OH)OTs
DMP
DDQ
FeCl3
Tl(OCOCF3)3
CAN
BF3·Et2O,[c] CH2Cl2, À788C
BF3·Et2O,[c] CH2Cl2, À788C
BF3·Et2O,[c] CH2Cl2, À788C
BF3·Et2O,[c] CH2Cl2, À788C
BF3·Et2O,[c] CH2Cl2, À788C
BF3·Et2O,[c] CH2Cl2, RT
BF3·Et2O,[c] Benzene, RT
Benzene, RT
88(82)[d]
–
–
60
64
85
31
0
4
–
–
tri(isopropyl)benzene (2 f) using
PIFA and BF3·Et2O afforded the
highly congested biaryl 3bf in 70%
yield of isolated product after pu-
5[e]
6
5: 11
5: 34
–
–
–
7
8
9
10
0
12
25
0
rification.[20] Single crystals of 3bf
suitable for a crystallographic anal-
ysis were obtained by recrystalliza-
tion from hexane (Figure 1).[21] It
was revealed that the naphthalene
ring and the other aromatic ring in
BF3·Et2O,[c] CH2Cl2, RT
BF3·Et2O,[c] CH2Cl2, 08C
[f]
[a] Reactions were performed using three equivalents 2a and one equivalent oxidant. [b] Yield was
determined by GC. [c] Two equivalents relative to 1a. [d] Yield of isolated product. [e] 1.5 equivalents of
2a. [f] Nitration products of 2a were obtained. DMP=Dess–Martin periodinane, DDQ=2,3-dichloro-
5,6-dicyano-1,4-benzoquinone, CAN=Ce(NH4)2(NO3)6.
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Chemie
Table 2: Scope of PIFA-induced oxidative cross-coupling.[a]
3bf are exactly perpendicular to each other along the
Entry Arene 1[b]
Nucleophile Mixed biaryl 3
Yield [%][d]
biaryl axis. The conformational rigidity of 3bf derived
from the bulky isopropyl ortho substituents makes a
difference in the environment around the methyl
groups, leading to induction of a remarkable magnetic
shield effect on the neighboring benzyl proton (con-
2[c]
1
firmed by H NMR spectroscopic analysis).
Further investigations using other electron-rich
arenes and heteroarenes, for example thiophenes
[Eq. (2)] and phenylethers, would imply the possibility
1
2
3
4
1a
1b
1c
1d
2b
2b
2b
2b
3ab
3bb
3cb
3 db
63
99
82
57
51
(3eb/
5[e]
1e
2b
of extending of the cross-coupling method (see the
Supporting Information). Research towards enhancing
the practicability of this novel oxidative cross-coupling
method and utilization of the newly obtained biaryl
compounds are now in progress.
3eb’=1:5.5)
Received: September 29, 2007
Published online: December 13, 2007
6
2b[f]
56
À
Keywords: C C coupling · cross-coupling ·
hypervalent compounds · iodine · oxidation
.
[1] a) R. Noyori, Chem. Soc. Rev. 1989, 18, 187; b) K.
Narasaka, Synthesis 1991, 1; c) G. Bringmann, R. Walter,
R. Weirich, Angew. Chem. 1990, 102, 1006; Angew. Chem.
Int. Ed. Engl. 1990, 29, 977; d) G. M. Keserffl, M. Nógrµdi
in Studies in Natural Products Chemistry, Vol. 20 (Ed.:
Atta-ur-Rahman), Elsevier, Amsterdam, 1998, p. 263;
e) I. Cepanec, Synthesis of Biaryls, Elsevier, New York,
2004.
[2] a) D. A. Whiting, in Comprehensive Organic Synthesis,
Vol. 3 (Eds.: B. M. Trost, I. Fleming, G. Pattenden),
Pergamon, Oxford, 1991, p. 659; b) J. Hassan, M. SØv-
ignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002,
102, 1359; c) A. Suzuki in Modern Arene Chemistry (Ed.:
D. Astruc), Wiley-VCH, New York, 2002, chap. 4.
7
8
9
1b
1b
1b
2c
2d
2e
3bc
3bd
3be
87
92
86
[a] All reactions were performed using three equivalents of 2 unless otherwise
noted. [b] 1a R1 =R2 =R3 =H; 1b R1 =Br, R2 =R3 =H; 1c R1 =Br, R2 =Me, R3 =
H; 1d R1 =Br, R2 =H, R3 =Me; 1e R1 =CO2Me, R2 =H, R3 =H; [c] 2c R4 =Et, R5 =
H, R6 =Et; 2d R4 =Me, R5 =H, R6 =tBu; 2e R4 =Me, R5 =Ph, R6 =Me; [d] Yield of
isolated product based on arene 1. [e] Two equivalents PIFA and four equivalents
BF3·Et2O. [f] Ten equivalents 2b.
[3] For recent advances of biaryl synthetic methods using aryl
halides with unfunctionalized arenes, see: a) D. Alberico,
M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174; b) S.
Yanagisawa, T. Sudo, R. Noyori, K. Itami, J. Am. Chem. Soc.
2006, 128, 11748; c) M. Lafrance, K. Fagnou, J. Am. Chem. Soc.
2006, 128, 16496; d) V. Dichiarante, M. Fagnoni, A. Albini,
Angew. Chem. 2007, 119, 6615; Angew. Chem. Int. Ed. 2007, 46,
6495, and references therein.
[4] a) S. M. Kupchan, A. J. Liepa, V. Kameswaran, R. F. Bryan, J.
Am. Chem. Soc. 1973, 95, 6861; b) K. Nyberg, Chem. Scr. 1974, 5,
120; c) A. McKillop, A. G. Turrell, D. W. Young, E. C. Taylor, J.
Am. Chem. Soc. 1980, 102, 6504; d) G. Sartori, F. Maggi, F. Bigi,
M. Grandi, J. Org. Chem. 1993, 58, 7271; e) S. W. Hon, C. H. Li,
J. H. Kuo, N. B. Barhate, Y. H. Liu, Y. Wang, C. T. Chen, Org.
Lett. 2001, 3, 869; f) S. R. Waldvogel, E. Aits, C. Holst, R.
Fröhlich, Chem. Commun. 2002, 1278.
Figure 1. Structural formula and X-ray crystal structure of the highly
congested biaryl 3bf.
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Communications
[5] a) P. Kovacic, F. W. Koch, J. Org. Chem. 1965, 30, 3176; b) M.
[14] a) Y. Kita, H. Tohma, M. Inagaki, K. Hatanaka, T. Yakura,
Tetrahedron Lett. 1991, 32, 4321; b) Y. Kita, H. Tohma, K.
Hatanaka, T. Takada, S. Fujita, S. Mitoh, H. Sakurai, S. Oka, J.
Am. Chem. Soc. 1994, 116, 3684; c) Y. Kita, T. Takada, H.
Tohma, Pure Appl. Chem. 1996, 68, 627.
[15] Polyalkyl-substituted benzenes were estimated to possess higher
nucleophilicities than naphthalene: a) H. Mayr, A. R. Ofial,
Angew. Chem. 1992, 104, 1689; Angew. Chem. Int. Ed. Engl.
1992, 31, 1613; b) H. Mayr, M. Patz, Angew. Chem. 1994, 106,
990; Angew. Chem. Int. Ed. Engl. 1994, 33, 938.
[16] PIFA activation by BF3·Et2O is essential to induce the SET
oxidation. We believe that the trifluoroacetoxy ligand of PIFA
might coordinate to BF3 and generate a reactive cationic
iodine(III) intermediate, see reference [7].
[17] In contrast, the reported coupling methods in references [10–12]
need excess arenes, typically more than ten equivalents relative
to other aromatic substrates.
[18] For cation radical formation of electron-rich aromatic com-
pounds by PhI(OH)OTs, see: a) G. F. Koser, S. Telu, K. K. Laali,
Tetrahedron Lett. 2006, 47, 7011; b) S. Telu, S. Durmus, G. F.
Koser, Tetrahedron Lett. 2007, 48, 1863; c) T. Dohi, M. Ito, K.
Morimoto, Y. Minamitsuji, N. Takenaga, Y. Kita, Chem.
Commun. 2007, 4152.
[19] a) J. Yin, M. P. Rainka, X. X. Zhang, S. L. Buchwald, J. Am.
Chem. Soc. 2002, 124, 1162; b) G. Altenhoff, R. Goddard, C. W.
Lehmann, F. Glorius, Angew. Chem. 2003, 115, 3818; Angew.
Chem. Int. Ed. 2003, 42, 3690; c) O. Nararro, R. A. Kelly, S. P.
Nolan, J. Am. Chem. Soc. 2003, 125, 16194; d) S. D. Walker, T. E.
Barder, J. R. Martinelli, S. L. Buchwald, Angew. Chem. 2004,
116, 1907; Angew. Chem. Int. Ed. 2004, 43, 1871; e) W. Su, S.
Urgaonkar, P. A. McLaughlin, J. G. Verkade, J. Am. Chem. Soc.
2004, 126, 16433.
[20] It should be noted that the synthesis of highly congested biaryl
compounds having secondary and tertiary alkyl groups at the
ortho positions is still problematic by other methods.
[21] CCDC-659614 (3bf) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Tanaka, H. Nakashima, M. Fujiwara, H. Ando, Y. Souma, J. Org.
Chem. 1996, 61, 788.
[6] H. J. Schäfer in Organic Electrochemistry (Ed.: H. Lund, M. M.
Baizer), Marcel Dekker, New York, 1991, chap. 23.
[7] a) H. Tohma, H. Morioka, S. Takizawa, M. Arisawa, Y. Kita,
Tetrahedron 2001, 57, 345; b) H. Tohma, M. Iwata, T. Maegawa,
Y. Kita, Tetrahedron Lett. 2002, 43, 9241; c) T. Dohi, K.
Morimoto, Y. Kiyono, A. Maruyama, H. Tohma, Y. Kita,
Chem. Commun. 2005, 2930; d) T. Dohi, K. Morimoto, A.
Maruyama, Y. Kita, Org. Lett. 2006, 8, 2007.
[8] a) R. VanHelden, G. Verberg, Recl. Trav. Chim. Pays-Bas 1965,
84, 1263; b) S. Mukhopadhyay, G. Rothenberg, G. Lando, K.
Agbaria, M. Kazanci, Y. Sasson, Adv. Synth. Catal. 2001, 343,
455; c) C. A. Mulrooney, X. Li, E. S. DeVirgilio, M. C. Kozlow-
ski, J. Am. Chem. Soc. 2003, 125, 6856; d) K. L. Hull, E. L. Lanni,
M. S. Sanford, J. Am. Chem. Soc. 2006, 128, 14047; e) M.
Takahashi, K. Masui, H. Sekiguchi, N. Kobayashi, A. Mori, M.
Funahashi, N. Tamaoki, J. Am. Chem. Soc. 2006, 128, 10930.
[9] a) T. Saitoh, S. Yoshida, J. Ichikawa, Org. Lett. 2004, 6, 4563;
b) T. Saitoh, S. Yoshida, J. Ichikawa, J. Org. Chem. 2006, 71,
6414.
[10] Palladium-catalyzed direct oxidative cross-coupling using stoi-
chiometric Cu(OAc)2: D. R. Stuart, K. Fagnou, Science 2007,
316, 1172.
[11] Oxidative coupling reaction of anilines with thiophenes: A. Jean,
J. Cantat, D. BØrard, D. Bouchu, S. Canesi, Org. Lett. 2007, 9,
2553.
[12] Other recent reports: a) R. Li, L. Jiang, W. Lu, Organometallics
2006, 25, 5973; b) A. Timothy, N. R. Dwight, D. C. Dagmara, J.
Ryan, D. Brenton, Org. Lett. 2007, 9, 3137; c) K. L. Hull, M. S.
Sanford, J. Am. Chem. Soc. 2007, 129, 11904.
[13] Oxidtive cross-coupling of naphthols by CuII: a) M. Hovorka, J.
Gunterova, J. Zavada, Tetrahedron Lett. 1990, 31, 413; b) S.
Vyskocil, M. Smrcina, M. Lorenc, V. Hanus, M. Polasek, P.
Kocovsky, Chem. Commun. 1998, 585; c) X. L. Li, J. B. Hewgley,
C. A. Mulrooney, J. M. Yang, M. C. Kozlowski, J. Org. Chem.
2003, 68, 5500.
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