Indium-catalyzed heteroaryl-heteroaryl bond formation through nucleophilic aromatic substitution

Article abstract of DOI:10.1002/anie.201005750

Unique performance: Bi-, ter-, and quater-heteroaryls have been prepared under indium catalysis by nucleophilic aromatic substitution (S_NAr). This is the first example of catalytic heteroaryl-heteroaryl bond formation based on S_NAr b

Full text of DOI:10.1002/anie.201005750

DOI: 10.1002/anie.201005750
Indium Catalysis
Indium-Catalyzed Heteroaryl–Heteroaryl Bond Formation through
Nucleophilic Aromatic Substitution**
Teruhisa Tsuchimoto,* Mami Iwabuchi, Yuta Nagase, Kenji Oki, and Hiroshi Takahashi
Table 1: Effect of changing X.[a]
Heteroaromatic molecules bearing heteroaryl–heteroaryl
bonds are an important class of building blocks found in a
variety of areas; for example, optoelectronic materials,[1]
liquid crystals,[2] biological compounds,[3] and ligands for
asymmetric catalysis.[4] Over the past 35 years, transition-
metal-catalyzed cross-coupling reactions have been chiefly
responsible for making (hetero)aryl–(hetero)aryl bonds.[5] On
X
Conv. of 2 [%][b]
Yield of 3a [%][c]
the other hand, nucleophilic aromatic substitution (SNAr) has
actually been studied to construct such biaryl linkages since
the 1940s.[6] However, aromatic compounds, which are
intrinsically electron-rich, are in general unreactive toward
nucleophilic substitution.[7] Therefore, two aryl substrates
with entirely opposite electronic demands must be arranged
to realize biaryl synthesis by the SNAr reaction. Thus,
electron-rich aryl nucleophiles with highly electropositive
metals (e.g. Li+, Mg2+, Zn2+) and/or electron-poor aryl
electrophiles with one or more strong electron-withdrawing
groups (EWGs; e.g. CF3, NO2, CN, CO2R) have each been the
aryl substrate of choice.[8] More than a stoichiometric amount
of promoter is also often necessary.[8c,p,q] These requisites may
have limited the widespread applicability of biaryl synthesis
based on SNAr. We envisioned that catalytic biaryl synthesis
by SNAr independent of such activated aryl substrates would
be an attractive alternative to the transition-metal-catalyzed
cross-coupling strategy. Herein, we report the first example of
I
Br
Cl
NO2
CN
OMe (2a)
OAc
OTf
3
2
5
9
5
<1
<1
<1
<1
<1
35
99
24
>99
<1
<1
[a] Reaction conditions: 1a (0.325 mmol), 2 (0.250 mmol), In(OTf)3
(5.00 mmol), 1,4-dioxane (1.0 mL), 858C, 5 h. [b] Determined by GC
analysis. [c] Determined by 1H NMR spectroscopy. Tf=SO2CF3.
sharp contrast, 2a, having a methoxy group, reacted with 1a
to give thienylindole 3a in 35% yield, while the related
oxygen-based leaving groups such as OAc and OTf gave
disappointing results, despite their better leaving ability
compared with OMe.[9] Next, we tested other solvents in the
reaction of 1a with 2a (Table 2). The ethereal solvent DME,
which is similar to 1,4-dioxane, was efficient while other
solvents made the reaction sluggish. After thorough inves-
tigations on a co-solvent for 1,4-dioxane and DME, we found
that the yield of 3a was markedly increased to 80% in a mixed
solvent system, consisting of 1,4-dioxane and toluene (25:1).
Other indium salts as well as metal triflates were less effective
(Table 3). No reaction occurred without a catalyst. With
In(OTf)3 as a catalyst, the fine-tuning of the solvent volume
finally raised the yield up to 86%. The results in Table 3 might
a
catalytic heteroaryl–heteroaryl bond-forming reaction
based on SNAr without using both the heteroarylmetal
nucleophile and heteroaryl electrophile substituted with
EWGs.
Initially, we studied the effect of changing the leaving
group X in thiophene derivatives 2 (acting as electrophiles) in
the indium-catalyzed reaction of 2-methylindole (1a; acting
as a nucleophile; Table 1). On treatment of 1a and 2 bearing
various halides (X = I, Br, Cl) with 2 mol% of In(OTf)3 (Tf =
SO2CF3) in 1,4-dioxane at 858C for 5 h, no desired reaction
occurred. Neither the nitro nor cyano groups, which often
behave as leaving groups in SNAr reactions, worked at all. In
Table 2: Effect of solvents.[a]
Solvent
Conv. of 2a [%][b]
Yield of 3a [%][c]
[*] Prof. Dr. T. Tsuchimoto, M. Iwabuchi, Y. Nagase, K. Oki,
H. Takahashi
1,4-dioxane
DME
CH3CH2CN
ClCH2CH2Cl
PhCl
99
71
44
36
10
12
99
95
35
53
25
21
2
8
80
73
Department of Applied Chemistry
School of Science and Technology
Meiji University, Higashimita, Tama-ku, Kawasaki, 214-8571 (Japan)
Fax: (+81)44-934-7228
E-mail: tsuchimo@isc.meiji.ac.jp
PhCH3
1,4-dioxane/PhCH3[d]
Homepage: http://www.isc.meiji.ac.jp/~tsuchi/
[d]
DME/PhCH3
[**] Financial support by a Grant-in-Aid for Scientific Research
(no. 19750083) from the Ministry of Education, Culture, Sports,
Science and Technology is gratefully acknowledged.
[a] Reaction conditions: 1a (0.325 mmol), 2a (0.250 mmol), In(OTf)3
(5.00 mmol), solvent (1.0 mL), 858C, 5 h. [b] Determined by GC analysis.
[c] Determined by 1H NMR spectroscopy. [d] The solvent ratio is 25:1
(1.0 mL:40 mL). DME=dimethoxyethane.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005750.
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Communications
Table 3: Effect of Lewis acids.[a]
Lewis acid
Conv. of 2a [%][b]
Yield of 3a [%][c]
In(OTf)3
In(ONf)3
In(NTf2)3
InCl3
Cu(OTf)2
AgOTf
99
>99
38
<1
81
99
98
45
13
80
74
18
<1
59
73
73
18
4
Bi(OTf)3
Sc(OTf)3
Y(OTf)3
Yb(OTf)3
none
24
<1
>99
8
<1
86
[d]
In(OTf)3
[a] Reaction conditions: 1a (0.325 mmol), 2a (0.250 mmol), Lewis acid
(5.00 mmol), 1,4-dioxane/PhCH3 (1.0 mL:40 mL), 858C, 5 h. [b] Deter-
mined by GC analysis. [c] Determined by 1H NMR spectroscopy. [d] Used
1,4-dioxane/PhCH3 [0.5 mL:40 mL (12.5:1)]. Nf=SO2C4F9.
indicate that Lewis acids consisting of a rather soft metal and
strong electron-withdrawing ligands tend to be favorable as
catalysts, owing to the lower catalytic activity of the hard
Lewis acids with strong electron-withdrawing ligands such as
Sc-, Y-, and Yb(OTf)3 and of the soft Lewis acid with weaker
electron-withdrawing ones like InCl3.[10] Notably, 3a is
accessible in one step from commercially available 1a and
2a; this is important because presynthesis of heteroarylmetal
nucleophiles and heteroaryl electrophiles substituted with
EWGs is not desired.
We next examined the substrate scope. As shown in
Scheme 1, indoles 1 with Me, nBu, OMe, Br, Ph, and/or p-
MeOC6H4 groups displaced the OMe group from 2a to afford
3b–3j, where 1,2,3-triarylindole 3j, having a fully extended p-
conjugation system, is included. The OMe groups on indole
substrates remained intact, thus showing remarkable chemo-
selectivities (see 3b, 3c, 3i, 3j, and 3l). 3-Methoxythiophene
(2b) also reacted with 1 to give 3k and 3l. Even more
electron-rich 2,5-dimethoxythiophene (2c; as compared with
2a) also participated in this reaction (Scheme 2). The
interesting aspect is that the appropriate choice of reaction
conditions enables exclusive access to either the single or
double substitution of 2c, thus leading to 3m or 3n,
respectively.[11] The single substitution even proceeded at
room temperature in a higher yield. Potentially useful quater-
heteroaryl 3o was obtained directly by the double substitu-
tion of 2d with 1b [Eq. (1)].
Scheme 1. Indium-catalyzed SNAr reaction of various indoles 1 with 2a
or 2b. Yields of isolated 3a–3l are shown here. Further details on
reaction conditions for each reaction are provided in the Supporting
Information. [a] In(ONf)3 (10 mol%) instead of In(OTf)3 was used.
Scheme 2. Indium-catalyzed SNAr reaction of 1a with 2c.
The strategy is also applicable to the synthesis of other bi-
and ter-heteroaryls. While the In(OTf)3-catalyzed reaction of
1a with 2e bearing the OMe group delivered no desired
product, replacing 2e with 2 f having the OTf group and
replacing In(OTf)3 with Bi(OTf)3 altered the result drasti-
cally, giving pyridylindole 3p in 67% yield [Eq. (2)]. 3-
Acetoxyindole (2g) is an excellent electrophile in terms of the
reaction efficiency, but unfortunately not with respect to the
regiochemistry [Eq. (3)].[12] We then found that pyrroles 1c
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Angew. Chem. Int. Ed. 2011, 50, 1375 –1379

appears to be the most plausible, as well demonstrated in the
SNAr reaction via p complexes between transition metals and
arenes.[14] Heteroaryl rings with higher p-electron density are
thought to be more favorable for complexation with an
electrophilic InIII atom,[15] thereby they are activated more
efficiently. Accordingly, the findings that 2c with two
methoxy groups is much more reactive than 2a and that
thiophenes 2 with electron-withdrawing groups (halides, NO2,
CN, OTf) are inactive also support the validity of the reaction
proceeding via complex A (Scheme 1, Scheme 2, and
Table 1).
Taking the above observations into consideration, possi-
ble mechanisms are depicted in Scheme 4, which shows the
reaction of HetAr–D 1 and 2a.[16] Although it is still unclear at
and 1d also work well as nucleophiles [Eqs. (4) and (5)]. As
Equation (5) shows, the substitution of the OMe group in 3m,
which was prepared as shown in Scheme 2, with 1,2-dime-
thylpyrrole (1d) provided ter-heteroaryl 3s that is connected
regularly in the order of pyrrole, thiophene, and indole rings.
In this case, In(ONf)3 was a superior catalyst to its triflate
salt.[13]
A possible route for this reaction is depicted in Scheme 3,
which exemplifies the reaction of 2a with HetAr–H 1. At least
three coordination modes of 2a to InX3 (In; complexes A, B,
and C) appear to be possible as triggers of this reaction. To
gain insight into the details, we performed the reaction of
deuterium-labeled indole [D]-1e (95%[D]) with 2a under
the standard conditions [Eq. (6)]. The reaction gave [D]-3g
and [D]-3g’ incorporating a deuterium atom on the C3’- or
C5’-poition of the thiophene ring with 72% total deuterium
Scheme 4. Possible reaction mechanisms.
present which one of either path a or path b is in operation,
allylindium-type intermediates 4 and/or 4’ would be formed
first by the nucleophilic attack of 1 to complex A,[17] in which
the In moiety can be regarded as a tentative EWG to make 2a
electrophilic enough to react. Subsequent transfer of the
deuterium atom from the HetAr+–D to the a site and/or g site
in the allylindium unit would give 5 and/or 5’.[18] The
elimination of MeOH(D) for the re-aromatization would
lead to [D]-3 and [D]-3’. The 23% loss of the D atom (95%
deuteration of [D]-1e to total 72% deuteration of [D]-3g and
[D]-3g’) should be ascribed to the final step in which both
MeOH and MeOD would be eliminated.
À
content, thus suggesting that a carbon indium bond trapped
by D+ is formed during the reaction. Therefore, complex A in
which the carbon atoms of 2a coordinate directly to the In
In summary, for the first time, we have achieved catalytic
heteroaryl–heteroaryl bond formation based on the SNAr
reaction using two easily available heteroaryl substrates that
require no activating groups. We also considered the reason
why heteroaryl electrophiles 2 without EWGs work well,
based on the mechanistic studies on which complex A is the
Scheme 3. A possible reaction route through complexes A, B, or C.
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Communications
cross-coupling reaction: e) K. Tamao, T. Hiyama, E.-i. Negishi, J.
Organomet. Chem. 2002, 653, 1 – 4.
[6] Biaryl synthesis via the SNAr process has already been achieved
in 1942: R. C. Fuson, S. B. Speck, J. Am. Chem. Soc. 1942, 64,
2446 – 2448.
[7] M. B. Smith, J. March, Marchꢀs Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, Wiley, Hoboken, 2007,
pp. 481 – 482 and 853 – 857.
plausible coordination mode. In general, transition-metal-
catalyzed cross-coupling using indolyl- and pyrrolylmetal
compounds is impractical since their presynthesis requires
multiple steps.[19] Our strategy will thus be highly useful in
such cases.
Experimental Section
[8] a) R. C. Fuson, F. W. Wassmundt, J. Am. Chem. Soc. 1956, 78,
5409 – 5413; b) J. M. Wilson, D. J. Cram, J. Org. Chem. 1984, 49,
4930 – 4943; c) G. P. Stahly, J. Org. Chem. 1985, 50, 3091 – 3094;
d) D. J. Cram, J. A. Bryant, K. M. Doxsee, Chem. Lett. 1987, 19 –
22; e) M. Shindo, K. Koga, K. Tomioka, J. Am. Chem. Soc. 1992,
114, 8732 – 8733; f) D. C. Reuter, L. A. Flippin, J. McIntosh, J. M.
Caroon, J. Hammaker, Tetrahedron Lett. 1994, 35, 4899 – 4902;
g) K. Kamikawa, M. Uemura, Tetrahedron Lett. 1996, 37, 6359 –
6362; h) T. Hattori, M. Suzuki, N. Tomita, A. Takeda, S. Miyano,
J. Chem. Soc. Perkin Trans. 1 1997, 1117 – 1123; i) D. P. G.
Norman, A. E. Bunnell, S. R. Stabler, L. A. Flippin, J. Org.
Chem. 1999, 64, 9301 – 9306; j) S. Boisnard, L. Neuville, M. Bois-
Choussy, J. Zhu, Org. Lett. 2000, 2, 2459 – 2462; k) B. A. Moosa,
K. A. A. Safieh, M. M. El-Abadelah, Heterocycles 2002, 57,
1831 – 1840; l) T. Hattori, A. Takeda, O. Yamabe, S. Miyano,
Tetrahedron 2002, 58, 233 – 238; m) T. Hattori, Y. Shimazumi, H.
Goto, O. Yamabe, N. Morohashi, W. Kawai, S. Miyano, J. Org.
Chem. 2003, 68, 2099 – 2108; n) T. Hattori, H. Iwato, K. Natori, S.
Miyano, Tetrahedron: Asymmetry 2004, 15, 881 – 887; o) Y. M.
Al-Hiari, A. M. Qaisi, M. M. El-Abadelah, W. Voelter, Monatsh.
Chem. 2006, 137, 243 – 248; p) M. Cecchi, A. Micoli, D. Giomi,
Tetrahedron 2006, 62, 12281 – 12287; q) M. De Rosa, D. Arnold,
M. Medved’, Tetrahedron Lett. 2007, 48, 3991 – 3994; see also the
following reviews: r) G. Bringmann, R. Walter, R. Weirich,
Angew. Chem. 1990, 102, 1006 – 1019; Angew. Chem. Int. Ed.
Engl. 1990, 29, 977 – 991; s) T. G. Gant, A. I. Meyers, Tetrahe-
dron 1994, 50, 2297 – 2360; t) T. Hattori, S. Miyano, J. Synth. Org.
Chem. Jpn. 1997, 55, 121 – 131.
Synthesis of 3a (Scheme 1): In(OTf)3 (2.8 mg, 5.0 mmol) was added to
a 20 mL Schlenk tube, which was heated at 1508C in vacuo for 2 h and
then filled with argon. To this were added 1,4-dioxane (0.5 mL) and
toluene (40 mL), and the resulting solution was stirred at RT for
10 min before 2-methylindole (42.6 mg, 0.325 mmol) and 2-methox-
ythiophene (28.5 mg, 0.250 mmol) were added successively. After
stirring at 858C for 5 h, a saturated NaHCO3 aqueous solution
(0.5 mL) was added and the aqueous phase was extracted with EtOAc
(5 mL ꢀ 3). The combined organic layer was washed with brine and
then dried over anhydrous Na2SO4. Filtration and evaporation of the
solvent and subsequent column chromatography on silica gel (n-
hexane/EtOAc = 6:1) gave 2-methyl-3-(thiophen-2-yl)-1H-indole
(3a; 45.6 mg, 82%).
Received: September 14, 2010
Published online: December 30, 2010
Keywords: aromatic substitution · heteroarenes · heterocycles ·
.
indium · Lewis acids
[1] For selected recent examples, see: a) Y. Matano, T. Miyajima, T.
Fukushima, H. Kaji, Y. Kimura, H. Imahori, Chem. Eur. J. 2008,
14, 8102 – 8115; b) N. Blouin, A. Michaud, D. Gendron, S.
Wakim, E. Blair, R. Neagu-Plesu, M. BelletÞte, G. Durocher, Y.
Tao, M. Leclerc, J. Am. Chem. Soc. 2008, 130, 732 – 742; c) J. Liu,
R. Zhang, G. Sauvꢁ, T. Kowalewski, R. D. McCullough, J. Am.
Chem. Soc. 2008, 130, 13167 – 13176; d) H.-L. Wong, C.-C. Ko,
W. H. Lam, N. Zhu, V. W.-W. Yam, Chem. Eur. J. 2009, 15,
10005 – 10009.
[9] M. B. Smith, J. March, Marchꢀs Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, Wiley, Hoboken, 2007,
pp. 496 – 502.
[10] For a review on the hard and soft acids and bases principle: S.
Woodward, Tetrahedron 2002, 58, 1017 – 1050, and references
therein.
[2] For selected recent studies, see: a) A. S. Matharu, S. J. Cowling,
G. Wright, Liq. Cryst. 2007, 34, 489 – 506; b) S. Ellinger, U.
Ziener, U. Thewalt, K. Landfester, M. Mꢂller, Chem. Mater.
[11] A 2,5-bis(3’-indolyl)thiophene structure derived from the double
substitution is interesting because of its antitumor properties,
see: P. Diana, A. Carbone, P. Barraja, A. Montalbano, A.
Martorana, G. Dattolo, O. Gia, L. D. Via, G. Cirrincione, Bioorg.
Med. Chem. Lett. 2007, 17, 2342 – 2346.
[12] Separate treatment of 3q or 3q’ with In(OTf)3 (10 mol%) in 1,4-
dioxane/toluene (25:1) at 1008C for 18 h resulted in quantitative
recovery of each starting material 3q or 3q’, respectively, thus
indicating that no isomerization occurs between 3q and 3q’
under the conditions. As previously demonstrated, formation of
3q’ may possibly be attributed that a cationic intermediate
leading to 3q’ is formed via migration of the 2-methylindol-3-yl
group from C3’ to C2’ in a cationic intermediate for 3q: N. P.
Grimster, C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew.
Chem. 2005, 117, 3185 – 3189; Angew. Chem. Int. Ed. 2005, 44,
3125 – 3129, and references therein.
´
2007, 19, 1070 – 1075; c) M. Ste˛pien, B. Donnio, J. L. Sessler,
Angew. Chem. 2007, 119, 1453 – 1457; Angew. Chem. Int. Ed.
2007, 46, 1431 – 1435; d) Y. A. Getmanenko, R. J. Twieg, J. Org.
Chem. 2008, 73, 830 – 839; e) J. Luo, B. Zhao, J. Shao, K. A. Lim,
H. S. O. Chan, C. Chi, J. Mater. Chem. 2009, 19, 8327 – 8334.
[3] For selected recent reports, see: a) W. Jiang, J. J. Fiordeliso, X.
Chen, Z. Sui, J. Heterocycl. Chem. 2006, 43, 1391 – 1396; b) Y.
Sugimoto, A. Shimizu, T. Kato, A. Satoh, S. Ozaki, H. Ohta, O.
Okamoto, Bioorg. Med. Chem. Lett. 2006, 16, 3569 – 3573;
c) W. T. McElroy, P. DeShong, Tetrahedron 2006, 62, 6945 – 6954;
d) U. Jacquemard, N. Dias, A. Lansiaux, C. Bailly, C. Logꢁ, J.-M.
Robert, O. Lozach, L. Meijer, J.-Y. Mꢁrour, S. Routier, Bioorg.
Med. Chem. 2008, 16, 4932 – 4953.
[4] For selected recent reviews, see: a) T. T.-L. Au-Yeung, A. S. C.
Chan, Coord. Chem. Rev. 2004, 248, 2151 – 2164; b) H. Shimizu,
I. Nagasaki, T. Saito, Tetrahedron 2005, 61, 5405 – 5432.
[13] Under the same reaction conditions, use of In(OTf)3 instead of
In(ONf)3 as a catalyst gave 3s in 26% yield.
[14] Coordination of p systems of arene rings to various transition
metals is known to activate the rings toward SNAr reaction; for
stoichiometric reactions: a) M. F. Semmelhack, A. Chlenov in
Transition Metal Arene p-Complexes in Organic Synthesis and
Catalysis (Ed.: E. P. Kꢃndig), Springer, Berlin, 2004, pp. 43 – 69;
for catalytic reactions: b) M. Otsuka, K. Endo, T. Shibata, Chem.
Commun. 2010, 46, 336 – 338.
[5] For representative recent reviews, see: a) J. Hassan, M. Sꢁv-
ignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102,
1359 – 1469; b) A. de Meijere, F. Diederich, Metal-Catalyzed
Cross-Coupling Reactions, Wiley-VCH, Weinheim, 2004; c) T.
Satoh, M. Miura, Chem. Lett. 2007, 36, 200 – 205; for a recent
special issue on the cross-coupling reaction, see: d) Acc. Chem.
Res. 2008, 41, 1439 – 1564, see also a brief historical note on the
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[15] For example, see: E. P. Kꢃndig in Transition Metal Arene p-
Complexes in Organic Synthesis and Catalysis (Ed: E. P.
Kꢃndig), Springer, Berlin, 2004, pp. 3 – 20.
[18] Allylindium species are reportedly deuterated by D+ sources:
T. D. Haddad, L. C. Hirayama, B. Singaram, J. Org. Chem. 2010,
75, 642 – 649.
[16] In the cases of 2 f and 2g, we cannot presently exclude other
routes via coordination modes other than the type such as
complex A.
[17] As one reviewer suggested, there is also a possibility of a
stepwise route at the first stage, consisting of indium-activated
formation of a carbocation on the C2 atom of 2a, stabilized by
the adjacent oxygen and sulfur atoms, and then nucleophilic
attack of HetAr–D 1 to the cation.
[19] a) I. Kawasaki, M. Yamashita, S. Ohta, Chem. Pharm. Bull. 1996,
44, 1831 – 1839; b) M. Amat, S. Hadida, G. Pshenichnyi, J. Bosch,
J. Org. Chem. 1997, 62, 3158 – 3175; c) A. Nishida, N. Miyashita,
M. Fuwa, M. Nakagawa, Heterocycles 2003, 59, 473 – 476; d) K.
Billingsley, S. L. Buchwald, J. Am. Chem. Soc. 2007, 129, 3358 –
3366.
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