Unusual ipso substitution of diaryliodonium bromides initiated by a single-electron-transfer oxidizing process

Article abstract of DOI:10.1002/anie.200907281

(Chemical Equation Presented) Aromatic substitution: The treatment of diaryliodonium bromides 1 with aromatic nucleophiles 2, afforded a variety of heteroaryl-containing biaryls 3 in good yields. The ipso-substitution process at the heteroaryl ring in 1 occurs through the formation of aromatic cation radicals, which are initiated by the single-electron-transfer (SET) oxidation of 2. (HFIP = hexafluoroisopropanol)

Full text of DOI:10.1002/anie.200907281

Communications
DOI: 10.1002/anie.200907281
Aromatic Substitution
Unusual ipso Substitution of Diaryliodonium Bromides Initiated by a
Single-Electron-Transfer Oxidizing Process**
Toshifumi Dohi, Motoki Ito, Nobutaka Yamaoka, Koji Morimoto, Hiromichi Fujioka, and
Yasuyuki Kita*
The diaryliodonium salts Ar1I+Ar2Xꢀ, which have two aryl
groups bound to an iodine atom as a ligand, represent one of
the most popular classes of hypervalent iodine compounds[1]
and they have application as important arylating agents in
organic synthesis.[2] In general, the aryla-
Herein, we report a unique single-electron-transfer (SET)
oxidizing strategy using diaryliodonium salts as selective
heteroaryl transfer agents during ipso substitution. Recently,
ꢀ
our research group has reported a metal-free C H coupling
method of thiophenes and aromatic compounds using iodo-
nium salts.[8] The method, using TMSBr in hexafluoroisopro-
panol (HFIP), is useful for the coupling reaction of the
thiophene iodonium salts and introduces aromatic nucleo-
philes to the g positions of the iodine(III)–carbon bonds
[Eq. (1)]. However, this reaction is not suitable for coupling
through the ipso substitution of the thiophene iodonium salts
1a-X [X = OTs, Br; Eq. (2)].
tion of nucleophiles with these iodonium
salts is assumed to involve the tricoordi-
nated intermediate A before the final
ligand-coupling (LC) steps.[3] Owing to
the competition of the two LC pathways
of Ar1 and Nu (LCAr1) or Ar2 and Nu
(LCAr2) at the iodine atoms in the inter-
mediates, a mixture of two types of
1
2
ꢀ
ꢀ
arylated products, Ar Nu and Nu Ar , are potentially
obtained in the unsymmetrical salts (Ar1 ¼ Ar2) during the
aromatic substitution. Previous studies have revealed that the
product produced from these pathways should be effected by
both electronic and steric factors exerted by the two differ-
ential aryl rings of the initial salts—where the nucleophiles
would preferentially react with a relatively electron-deficient
aryl ring and/or sterically congested ipso carbon atom (i.e. the
so-called “ortho effect”).[4] Therefore, the introduction of
nucleophiles to an electron-rich heteroaromatic ring is known
to be particularly difficult through typical thermal LC
processes, which involve the collapse of the intermediate
A.[5–7] Despite their rich chemistry, the utility of diaryliodo-
nium salts as a heteroaryl transfer agent in LC processes has
been somewhat limited.
To overcome this drawback, screening was undertaken to
find a suitable acid additive that accelerated the reaction by
activating the thiophene iodonium salt 1a using the modified
reaction conditions shown in Table 1. Among the general
acids and typical silicon- and boron-based Lewis acids we
examined (Table 1, entries 2–5),[9] the yield of 3aa was
significantly enhanced when TMSOTf was added (Table 1,
entry 3). Similarly, a Brønsted acid (TfOH) performed as a
good catalyst for the present ipso-substitution process
(Table 1, entry 6). Other additives, such as trifluoroacetic
acid and other analogous superacids (i.e. HNTf2), did not
improve the yield of 3aa. The aromatic nucleophile 2a did not
react with 1a under the reported conditions. Moreover, other
general methods for activating iodonium salts with transition
metals were unsuccessful.[10] Pleasingly, our method permitted
the formation of the ipso-substitution product of the hetero-
aryl ring. Further optimization using TMSOTf as the acid
additive[11] led to a dramatic improvement in the yield of 3aa
(74%; Table 1, entries 7 and 8). The major by-product was
2,3-dimethylthiophene after formal protonolysis.
[*] Dr. T. Dohi, N. Yamaoka, Dr. K. Morimoto, Prof. Dr. Y. Kita
College of Pharmaceutical Sciences
Ritsumeikan University, 1-1-1 Nojihigashi
Kusatsu, Shiga 525-8577 (Japan)
Fax: (+81)77-561-5829
E-mail: kita@ph.ritsumei.ac.jp
Dr. T. Dohi, M. Ito, Prof. Dr. H. Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1–6
Yamada-oka, Suita, Osaka 565-0871 (Japan)
[**] This work was supported by Grants-in-Aid for Scientific Research (A)
from the Japan Society for the Promotion of Science (JSPS), Grants-
in-Aid for Young Scientists (B) from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), and the Ritsu-
meikan Global Innovation Research Organization (R-GIRO) project.
T.D. acknowledges support from the Industrial Technology Research
Grant Program from the New Energy and Industrial Technology
Development Organization (NEDO) of Japan. M.I. acknowledges a
Research Fellowship for Young Scientists from JSPS.
The unique and selective ipso substitution at the hetero-
aryl ring is a general phenomenon of thienyliodonium
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907281.
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Chemie
Table 1: Screening of reaction accelerators,[a] see [Eq. (2)].
Table 2: Reactions using methoxybenzenes (2a–c) as nucleophiles
Entry
Additive
Yield of 3aa [%][b]
1
2
3
4
5
6
none
TMSCl
0
21
46
32
36
40
57
74
TMSOTf
BF3·Et2O
(c-Hex)2BOTf
TfOH
Entry Iodonium salt 1
Product 3
Yield [%][b]
7
TMSOTf[c]
TMSOTf[c]
8[d]
[a] Reactions were performed using 1a-Br (1 equiv), 2a (1.5 equiv), and
an additive (1 equiv) in HFIP (0.15m of 2a) at room temperature in the
absence of TMSBr. [b] Yield was determined by GC analysis and was
based on the amount of 1a used. [c] Used TMSOTf (2 equiv). [d] Con-
centration of 2a was 0.075m. c-Hex=cyclohexyl, Tf=trifluoromethane-
sulfonyl TMS=trimethylsilyl.
1
2
3
4
5
6
1a-Br, R1 =R2 =Me
3aa, R3 =H
3ba, R3 =H
77
70
71
75
81
50
1b-Br, R1 =Hex, R2 =Me
1c-Br, R1 =Me, R2 =(CH2)5Br 3ca, R3 =H
_
1d-Br, R1R2 =(CH2)4
1e-Br, R1 =p-Tol, R2 =Me
1 f-Br, R1 =p-MeOC6H4,
R2 =Me
3da, R3 =H
3eb, R3 =Br
3 fb, R3 =Br
bromides, however, no product resulting from phenyl group
transfer was observed in all cases shown in Table 2. Under the
optimized reaction conditions, the derivatives of 1a having
other alkyl (Table 2, entries 2 and 3), cyclic (Table 2, entry 4),
and aryl (Table 2, entry 5) groups on the thiophene rings
provided the corresponding heteroaryl-containing biaryl
compounds in good yields. The presence of electron-rich
aromatic moieties in the iodonium salts slightly affected the
yield of the cross-coupling product (Table 2, entry 6). A
similar ipso substitution occurred in the a-free (R2 = H)
thienyliodonium salts 1g and 1h (Table 2, entries 7 and 8),
and no other regioisomer of 3gb and 3hb (such as the 2-
arylated thiophenes) were produced. Comparable results
were obtained using the other salts 1i and 1j based on the
exclusive transfer of the furan and pyrrole rings to the
aromatic nucleophiles 2 (Table 2, entries 9 and 10). To the
best of our knowledge, these results are the first general
examples which enable the carbon–carbon bond formation
between the ipso carbon atom of the heteroaromatic rings in
the iodonium salts with unfunctionalized aromatic nucleo-
philes.[12]
7
8
1g-Br, R1 =Me
3gb, R3 =Br
3hb, R3 =Br
70
64
1h-Br, R1 =c-Hex
9
1i-Br
3ia, R3 =H
66
10
1j-Br, Ar=4-NO2C6H4
3jc, R3 =OMe
66
[a] Reactions were performed using 1 (0.2–0.6 mmol) and 2a–c (3 equiv)
for 3 h. [b] Yield of isolated product. Tol=tolyl.
It seems that one cannot assume that the classical
intermediates A are involved in the observed ipso-substitu-
tion process because this would result in transfer of the phenyl
group. Indeed, we have now succeeded in confirming the SET
oxidizing ability of the iodonium 1a-Br toward electron-rich
aromatic compounds (Figure 1). With the aid of TMSOTf, 1a-
Br could generate a stable radical species of 1,4-dimethoxy-
benzene in HFIP at room temperature; this species was
detected by ESR spectroscopy. Based on UV spectroscopic
measurements of the reaction solution under the optimized
conditions, we concluded that the typically strong absorption
band between 400 and 500 nm (the visible region) corre-
sponds to the dimethoxybenzene cation radical B.[13–15] The
detection of this radical species suggests the involvement of a
unique SET reaction mechanism during the course of the
reaction. Interestingly, no related cationic radical species
were detected by ESR and UV measurements when TMSBr
was added instead of TMSOTf.
Figure 1. Detection of an aromatic cationic radical formed by SET
oxidation with diaryliodonium bromide 1a.
previous studies,[13] we found that the SET oxidation of
aromatic compounds by hypervalent iodine atoms should
include the preformation of the charge-transfer (CT) complex
of the reagents and aromatic rings before inducing the SET.
With regard to the role of TMSOTf, it seems to facilitate the
initial interaction of 1a with the aromatic nucleophile 2a, and
The substrate 1a-Br was itself inactive toward the
aromatic compound 2a, and the added TMSOTf played a
key role for inducing the SET oxidation process. In our
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then forms a CT complex by enhancing the electrophilicity of
that is, 2,2’,4,4’,5,5’-hexamethoxybiphenyl (see the Supporting
Information). The expected heteroaryl-transfer product 3aj
was also obtained.
the iodine atom of 1a through coordination with the bromo
atom, thus assisting in the smooth generation of the cation
radicals of 2a to which the electron-rich heteroaryl ring is
transferred (Scheme 1).[16]
In summary, we have discovered uncovered the SET
oxidizing ability of the diaryliodonium bromides and have
succeeded in carrying out the unusual, although versatile,
heteroaryl transfer toward electron-rich aromatic compounds
based on the SET mechanism. This new strategy includes an
unprecedented formal substitution process at the ipso carbon
atom of the heteroaryl rings in the diaryliodonium salts,
thereby enabling the production of a variety of heteroaryl-
containing biaryl compounds under metal-free conditions.
Received: December 25, 2009
Published online: April 1, 2010
ꢀ
Keywords: C C coupling · chemoselectivity · electron transfer ·
hypervalent compounds · iodine
.
Scheme 1. Unique SET reaction pathway through a CT complex of
diaryliodonium salt 1a and aromatic nucleophile 2a.
[1] For the recently improved preparative methods, see: a) T. Dohi,
M. Ito, K. Morimoto, Y. Minamitsuji, N. Takenaga, Y. Kita,
Chem. Commun. 2007, 4152; b) L. Kraszkiewicz, L. Skulski,
Synthesis 2008, 2373; c) M. Bielawski, D. Aili, B. Olofsson, J.
Org. Chem. 2008, 73, 4602, and references therein.
[2] a) G. F. Koser in The Chemistry of Functional Groups, Supple-
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Angew. Chem. Int. Ed. 2009, 48, 9052.
[3] For discussions, see: a) V. V. Grushin, Acc. Chem. Res. 1992, 25,
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[4] a) A. Shah, V. W. Pike, D. A. Widdowson, J. Chem. Soc. Perkin
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[5] a) Y. Yamada, M. Okawara, Bull. Chem. Soc. Jpn. 1972, 45, 2515;
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Y. T. Lee, T. G. Baik, Tetrahedron Lett. 1998, 39, 2127.
[6] By exploting this principle, a-thienyl groups have been utilized
successfully as nonparticipating aryl groups in ligand coupling
processes of diaryliodonium salts, see: a) T. L. Ross, J. Ermert, C.
Hocke, H. H. Coenen, J. Am. Chem. Soc. 2007, 129, 8018;
b) D. B. Haydock, T. P. C. Mulholland, B. Telford, J. M. Thorp,
J. S. Wain, Eur. J. Med. Chem. 1984, 19, 205.
Based on the new reaction mechanism, the oxidation
potential of the aromatic nucleophiles 2 should be one of the
important factors in the determination of the reaction
progress. Accordingly, we extended the scope of the nucleo-
philes 2 by evaluating other electron-rich aromatic com-
pounds, which have oxidation potentials similar to that of
dimethoxybenzene 2a (Scheme 2). It was apparent to us that
various aromatic and heteroaromatic compounds 2d–h, which
are sensitive to the SET oxidizing processes with hypervalent
iodine reagents,[13] except for mesitylene 2i,[17] exhibit com-
parable performances with acceptable functional group
tolerances in the reactions with 1a (Scheme 2). Interestingly,
the carbon–boron bond was not oxidized in nucleophile 2e.
During this screening, additional strong evidence that
accounts for the generation of the cationic radical species of
aromatic nucleophiles 2 was also found; the reaction of the
1,2,4-trimethoxybenzene (2j) with 1a resulted in the forma-
tion of a radical homocoupling product that incorporated 2j,
[7] Symmetrical heteroaromatic salts were used to avoid this
chemoselectivity issue, see: a) V. K. Aggarwal, B. Olofsson,
Angew. Chem. 2005, 117, 5652; Angew. Chem. Int. Ed. 2005, 44,
5516; b) Z. Xue, D. Y. Yang, C. Y. Wang, J. Organomet. Chem.
2006, 691, 247.
[8] Y. Kita, K. Morimoto, M. Ito, C. Ogawa, A. Goto, T. Dohi, J.
Am. Chem. Soc. 2009, 131, 1668.
[9] We have also tested several metal-based Lewis acids, such as
AlBr3, FeCl3, Cu(OTf)2, AgOTf, Zn(OTf)2, and In(OTf)3, and
they gave poor results (0–28% yield of 3aa).
[10] a) Y. Tamura, M. W. Chun, K. Inoue, J. Minamikawa, Synthesis
1978, 822; b) S. K. Kang, H. W. Lee, S. B. Jang, P. S. Ho, J. Org.
Chem. 1996, 61, 4720.
Scheme 2. Use of various aromatic nucleophiles 2d–i having oxidation
potentials similar to that of 1,3-dimethoxybenzene 2a. pin=pinacol.
[11] The iodonium salts 1a-X having other counterions (X = OTs,
OCOCF3, OTf, F, Cl, BF4, NO3, etc.) did not react under the
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Angewandte
Chemie
optimized conditions using TMSOTf. For unique radical reac-
tivities of IIII–Br bonds, see: a) T. Dohi, N. Takenaga, A. Goto, A.
Maruyama, Y. Kita, Org. Lett. 2007, 9, 3129; b) T. Dohi, N.
Takenaga, A. Goto, H. Fujioka, Y. Kita, J. Org. Chem. 2008, 73,
7365, and references therein.
quez, F. Hahn, B. Beden, P. Crouigneau, A. Rakotondrainibe, C.
Lamy, Synth. Met. 1997, 88, 187.
[15] The cationic radical species of 2a was also detected by ESR and
UV/Vis spectroscopic measurements. See the Supporting Infor-
mation.
[16] A few examples of carbon-based groups involved in ligand
transfer from iodine(III) atoms toward aromatic cation radicals
have been reported, see: a) T. Dohi, K. Morimoto, N. Takenaga,
A. Goto, A. Maruyama, Y. Kiyono, H. Tohma, Y. Kita, J. Org.
Chem. 2007, 72, 109; b) T. Dohi, M. Ito, N. Yamaoka, K.
Morimoto, H. Fujioka, Y. Kita, Tetrahedron 2009, 65, 10797.
[17] Mesitylene (2i) was less reactive in SEToxidations, see: T. Dohi,
M. Ito, K. Morimoto, M. Iwata, Y. Kita, Angew. Chem. 2008, 120,
1321; Angew. Chem. Int. Ed. 2008, 47, 1301.
[12] No general method dealing with selective heteroaryl transfer has
ꢀ
yet appeared in metal-catalyzed C H bond arylation, see
Ref. [2d].
[13] a) Y. Kita, H. Tohma, K. Hatanaka, T. Takada, S. Fujita, S.
Mitoh, H. Sakurai, S. Oka, J. Am. Chem. Soc. 1994, 116, 3684;
b) Y. Kita, T. Takada, H. Tohma, Pure Appl. Chem. 1996, 68, 627.
[14] a) S. Sankararaman, W. A. Haney, J. K. Kochi, J. Am. Chem. Soc.
1987, 109, 5235; b) M. C. de Martinez, O. P. Marquez, J. Mar-
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