Iridium-catalyzed selective synthesis of 4-substituted benzofurans and indoles via directed cyclodehydration

Article abstract of DOI:10.1002/adsc.200900570

A directed cyclization-dehydration cascade of α-aryloxy ketones and α-arylamino ketones was efficiently catalyzed by a cationic iridiumBINAP complex, which afforded various types of 4-substituted benzofurans and indoles in high yields with complete regios

Full text of DOI:10.1002/adsc.200900570

COMMUNICATIONS
DOI: 10.1002/adsc.200900570
Iridium-Catalyzed Selective Synthesis of 4-Substituted
Benzofurans and Indoles via Directed Cyclodehydration
Kyoji Tsuchikama,a Yu-ki Hashimoto,a Kohei Endo,a and Takanori Shibataa,*
a
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Okubo,
Shinjuku, Tokyo 169-8555, Japan
Fax : (+81) 3-5286-8098; e-mail: tshibata@waseda.jp
Received: August 17, 2009; Published online: November 13, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900570.
Abstract: A directed cyclization-dehydration cas-
cade of a-aryloxy ketones and a-arylamino ketones
was efficiently catalyzed by a cationic iridium-
BINAP complex, which afforded various types of 4-
substituted benzofurans and indoles in high yields
with complete regioselectivity. The newly developed
protocol also enabled the enantioselective prepara-
tion of chiral 4-acetyloxindole using a chiral iridium
catalyst.
of strong Brønsted acids or Lewis acids are required
in most cases.[7] Consequently, the development of
versatile alternatives using a mild catalyst for the se-
lective synthesis of 4-substituted benzoheteroles is
highly desired. We herein report the successful reali-
zation of this challenging transformation by cationic
iridium-catalyzed cyclodehydration using a directing
group. From the results obtained in this report, we as-
sumed that the installation of a directing group at the
meta position enabled carbon-iridium bond formation
À
À
À
Keywords: C C bond formation; C H functionali-
zation; heterocycles; homogeneous catalysis; iridi-
um
at the congested ortho position through C H bond
cleavage or an electrophilic metallation mecha-
nism.[8,9] Subsequently, intramolecular 1,2-addition to
a carbonyl moiety[10] and dehydration yielded 4-substi-
tuted benzoheteroles as the sole regioisomer
(Scheme 1).[11]
Our group has disclosed that cationic rhodium- and
Heterocycles are a ubiquitous class of compounds in iridium-biaryl diphosphine complexes can operate as
2
À
nature. Benzofuran and indole scaffolds are particu- effective catalysts in the directed sp C H bond acti-
larly of great interest and are widespread in a myriad vation of aryl ketones.[12] Very recently, we also realiz-
3
of bioactive compounds and pharmaceutical agents.[1] ed sp C H bond activation of amides by cationic iri-
À
Therefore, many organic chemists have been prompt- dium catalysis.[13] Therefore, these cationic metal spe-
ed to develop various efficient synthetic protocols for cies were tested in the cyclization of 1-(3-acetylphe-
the preparation of these target compounds.[2,3] Among
these protocols, cyclodehydration, namely the cycliza-
tion-dehydration cascade of a-aryloxy ketones and a-
arylamino ketones is an attractive and reliable strat-
egy because (i) the starting materials can be readily
À
prepared, (ii) the C H bond can be directly function-
alized in the cyclization process, and (iii) the waste
by-product is water.[4] However, substitution on the
arene moiety often invokes the issue of regioselectivi-
ty. The application to the synthesis of 4-substituted
benzoheteroles is especially challenging, because the
meta-substituted precursors tend to cyclize at the less
hindered ortho position, leading to the predominant
formation of 6-substituted benzoheteroles or a mix-
ture of 6-substituted and 4-substituted benzoheter-
Scheme 1. A proposed mechanism for the iridium-catalyzed
directed cyclization-dehydration cascade of a-aryloxy ke-
oles.[5,6] Moreover, excess or stoichiometric amounts tones and a-arylamino ketones.
2850
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2850 – 2854

Iridium-Catalyzed Selective Synthesis of 4-Substituted Benzofurans and Indoles
COMMUNICATIONS
Table 1. Optimization of the reaction conditions.[a]
philic metallation, as depicted in Scheme 1, rather
than a Friedel–Crafts-type reaction.[14]
The directed cyclodehydration of several types of
a-aryloxy ketones was then examined under the es-
tablished iridium-based catalytic system (Table 2 and
Scheme 2). In all runs, efficient syntheses of 4-substi-
tuted benzofurans were achieved, along with com-
plete regioselectivity. Cyclization of a-aryloxy tert-
butyl ketone 3 and a-aryloxy phenyl ketone 5 success-
fully proceeded to afford the 4-acetylbenzofurans,
possessing a bulky substituent at the C-3 position, in
excellent yield (Table 2, entries 1 and 2). Substitution
at the a-position of the carbonyl moiety was tolerat-
ed: 2,3-dimethylbenzofuran 8, tricyclic benzofuran 10,
and 2-anisylbenzofuran 12 were obtained in high
yields (Table 2, entries 3–5).
Subsequently, the effect of the substituent at the
arene moiety was investigated. It was found that a
methoxy group could be installed on any position,
and the corresponding 4-acetylbenzofurans were effi-
ciently obtained as sole regioisomers (Table 2, en-
tries 6–8). Notably, in addition to the acetyl group,
ester and amide moieties also operated as effective di-
recting groups, leading to the selective formation of 4-
methoxycarbonylbenzofuran 20 and 4-acetylamino-
benzofuran 22 (Table 2, entries 9 and 10).[15] More-
over, the iridium catalyst promoted the double cyclo-
Entry
X[b]
Yield of 2 [%][c]
Yield of 2’ [%][c,d]
1[e]
2
3
OTf
OTf
BF4
SbF6
BARF
BARF
6
6
n.d.
4
n.d.
n.d.
n.d.
71
48
85
94
94
4
5
6[f]
[a]
Unless otherwise noted, reaction conditions were as fol-
lows: substrate 1 (0.1 mmol), [Ir(cod)2]X (5 mmol), rac-
BINAP (5 mmol), PhCl (0.2 mL), 1358C, 24 h.
OTf=trifluoromethanesulfonate,
bis(trifluoromethyl)phenyl]borate.
Isolated yield.
n.d.=not detected.
Performed in 1,2-dichloroethane at 958C.
Substrate 1 (0.25 mmol), [IrACHTNUTRGNENG(U cod)2]BARF (2.5 mmol), rac-
AHCTUNGTRENNUNG
[b]
BARF=tetrakisACHTGUNTERNNU[G 3,5-
[c]
[d]
[e]
[f]
BINAP (2.5 mmol), PhCl (0.1 mL), 1608C under micro-
wave irradiation (200 W), 20 min.
noxy)propan-2-one (1). Initial screening revealed that dehydration of 5-acetylresorcinol ether 23 to provide
the cationic iridium-BINAP complex afforded 4-ace- 4-acetylbenzodifuran 24 (Scheme 2).[16]
tylbenzofuran 2 and benzofuranol 2’ in low yield at
The current iridium catalysis was also applicable to
958C (Table 1, entry 1), whereas the corresponding the directed cyclodehydration of a-arylaminoketones
rhodium catalyst did not afford any cyclized products. (Scheme 3). As was the case for benzofuran synthesis,
A higher temperature (1358C) improved the conver- several types of 4-acetylindoles were selectively ob-
sion of aryloxy ketone 1 along with the complete de- tained in satisfactory yield. It is noteworthy that the
hydration of benzofuranol 2’ (Table 1, entry 2). Fur- substrates possessing an amine moiety could be di-
ther optimization of the reaction conditions also re- rectly subjected to the reaction to yield protection-
vealed that the counteranion of the iridium complex
significantly affected the product yield (Table 1, en-
tries 3–5): the tetrakisACTHNUGRTENUNG[3,5-bis(trifluoromethyl)phenyl]-
borate anion (BARF) was found to be optimal and
benzofuran 2 was obtained in excellent yield without
the formation of undesired 6-substituted benzofuran
(Table 1, entry 5). Moreover, short-time synthesis was
achieved under microwave irradiation, using only
Scheme 2. Synthesis of benzodifuran 24 via the iridium-cata-
1 mol% of the catalyst (Table 1, entry 6). Although lyzed double cyclodehydration.
the Ir+/PPh3 system afforded the product in accepta-
ble yield (77% NMR yield), ligands other than
BINAP and PPh3 were ineffective (see Table S1 in
the Supporting Information).
To shed light on the reaction mechanism, 1-phen-
ACHTUNGTRENNUNGoxypropan-2-one, an electron-rich and directing
group-free variant, was subjected to cyclization under
the same reaction conditions as entry 5 in Table 1;
howACHTUNGTRENNUNGever, in this reaction, the corresponding benzofur-
an was not obtained at all. This result suggests that
the present iridium-catalyzed cyclodehydration should
À
proceed via directed C H bond cleavage or electro- Scheme 3. Synthesis of unprotected 4-acetylindoles.
Adv. Synth. Catal. 2009, 351, 2850 – 2854
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2851

Kyoji Tsuchikama et al.
COMMUNICATIONS
Table 2. Synthesis of 4-substituted benzofurans.[a]
Entry
1
Substrate
Product
Yield [%][b]
95
2
3
4
5
94
88
84
87
6
87
7
8
15
17
16 (R1 =6-MeO)
18 (R1 =7-MeO)
quant.
95
9
82
84
10
[a]
Reaction conditions: substrate (0.1 mmol), [IrACTHNUTRGNE(NUG cod)2]BARF (5 mmol), rac-BINAP (5 mmol), PhCl (0.2 mL), 1358C, 24 h.
Isolated yield.
[b]
free 4-acetylindoles, which is an apparently difficult found that the use of (S)-H8-BINAP was effective and
transformation in the case of strong acid catalysts. the product was afforded with acceptable enantiose-
Finally, the iridium-catalyzed cyclization of pyruv- lectivity.
ACHTUNGTRENNUNG In conclusion, we have discovered the high catalytic
guingly, dehydration did not proceed and the tert-al- activity of a cationic iridium-BINAP complex in the
cohol moiety remained intact, resulting in the selec- directed cyclodehydration of a-aryloxy ketones. Vari-
tive formation of chiral 4-acetyloxindole 34. To ous types of substrates efficiently participated in the
extend this reaction to an enantioselective variant, transformation, affording the corresponding 4-substi-
several chiral ligands were then examined. It was tuted benzofurans with complete regioselectivity.
2852
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2850 – 2854

Iridium-Catalyzed Selective Synthesis of 4-Substituted Benzofurans and Indoles
COMMUNICATIONS
[3] Selected recent examples of benzofuran synthesis:
a) H. Zhang, E. M. Ferreira, B. M. Stoltz, Angew.
Chem. 2004, 116, 6270–6274; Angew. Chem. Int. Ed.
2004, 43, 6144–6148; b) D. Yue, T. Yao, R. C. Larock,
J. Org. Chem. 2005, 70, 10292–10296; c) N. Isono, M.
Lautens, Org. Lett. 2009, 11, 1329–1331; d) F. Manarin,
J. A. Roehrs, R. M. Gay, R. Brand¼o, P. H. Menezes,
C. W. Nogueira, G. Zeni, J. Org. Chem. 2009, 74, 2153–
2162. Indole synthesis: e) C. Koradin, W. Dohle, A. L.
Rodriguez, B. Schmid, P. Knochel, Tetrahedron 2003,
59, 1571–1587; f) L. T. Kaspar, L. Ackermann, Tetrahe-
dron 2005, 61, 11311–11316; g) K. Alex, A. Tillack, N.
Schwarz, M. Beller, Angew. Chem. 2008, 120, 2337–
2340; Angew. Chem. Int. Ed. 2008, 47, 2304–2307; h) J.
Takaya, S. Udagawa, H. Kusama, N. Iwasawa, Angew.
Chem. 2008, 120, 4984–4987; Angew. Chem. Int. Ed.
2008, 47, 4906–4909; i) D. R. Stuart, M. Bertrand-La-
perle, K. M. N. Burgess, K. Fagnou, J. Am. Chem. Soc.
2008, 130, 16474–16475; j) Z. Shi, C. Z. S. Li, D. Pan, S.
Ding, Y. Cui, N. Jiao, Angew. Chem. Int. Ed. 2009, 48,
4572–4576, and references cited therein.
[4] Classical examples of benzoheterole synthesis via cyclo-
dehydration: a) R. Mçhlau, Ber. dtsch. chem. Ges. 1881,
14, 171–175; b) A. Bischler, H. Brion, Ber. dtsch. chem.
Ges. 1892, 25, 2860–2879; c) W. R. Boehme, Org.
Synth. 1963, 590–593. For recent examples, see: d) Z.
Chen, X. Wang, W. Lu, J. Yu, Synlett 1991, 121–122;
e) D. St. C. Black, D. C. Craig, N. Kumar, R. Rezie, Tet-
rahedron 1999, 55, 4803–4814; f) M. P. Kumar, R.-S.
Liu, J. Org. Chem. 2006, 71, 4951–4955; g) Jumina,
P. A. Keller, N. Kumar, D. St. Black, Tetrahedron 2008,
64, 11603–11610; h) M. Kuramoto, Y. Sakata, K. Terai,
I. Kawasaki, J.-i. Kunitomo, T. Ohishi, T. Yokomizo, S.
Takeda, S. Tanaka, Y. Ohishi, Org. Biomol. Chem.
2008, 6, 2772–2781.
Scheme 4. Enantioselective synthesis of 4-acetyloxindole 34.
Along with the acetyl group, ester and amide moieties
also functioned as directing groups. Moreover, the es-
tablished protocol was successfully applied to the syn-
thesis of protection-free 4-acetylindoles and the enan-
tioselective synthesis of chiral 4-acetyloxindole. Fur-
ther modification of the catalytic system, elucidation
of the detailed reaction mechanism, and application
to natural product synthesis are in progress.
Experimental Section
Typical Experimental Procedure (Table 1, entry 5)
[IrACHTUNGTRENNUNG(cod)2]BARF (6.7 mg, 5 mmol) and rac-BINAP (3.2 mg, 5
mmol) were placed in an oven-dried Schlenk tube, which
was then evacuated and backfilled with argon (ꢁ3). 1-(3-
Acetylphenoxy)propan-2-one (1, 19.3 mg, 0.1 mmol) and
PhCl (0.2 mL, pre-treated by argon bubbling) were added to
the reaction vessel. The solution was then stirred at 1358C
for 24 h. The resultant mixture was cooled to room tempera-
ture and the solvent was evaporated. The crude products
were purified by thin-layer chromatography (hexane/ethyl
acetate=3:1) to yield analytically pure benzofuran 2; yield:
16.6 mg (94%).
[5] a) A. G. Schultz, W. K. Hagmann, J. Org. Chem. 1978,
43, 3391–3393; b) R. W. Guthrie, G. L. Kaplan, F. A.
Mennona, J. W. Tilley, R. W. Kierstead, M. OꢂDonnell,
H. Crowley, B. Yaremko, A. F. Welton, J. Med. Chem.
1990, 33, 2856–2864; c) P. Magnus, I. S. Mitchell, Tetra-
hedron Lett. 1998, 39, 4595–4598; d) K. E. Bashford,
A. L. Cooper, P. D. Kane, C. J. Moody, S. Muthusamy,
E. Swann, J. Chem. Soc. Perkin Trans. 1 2002, 1672–
1687; e) H. Dehmlow, J. D. Aebi, S. Jolidon, Y.-H. Ji,
E. M. von der Mark, J. Himber, O. H. Morand, J. Med.
Chem. 2003, 46, 3354–3370; f) C. Santini, G. D. Berger,
W. Han, R. Mosley, K. MacNaul, J. Berger, T. Doebber,
M. Wu, D. E. Moller, R. L. Tolman, S. P. Sahoo, Bioorg.
Med. Chem. Lett. 2003, 13, 1277–1280.
Acknowledgements
This work was supported by a Waseda University Grant for
Special Research Projects. K.T. thanks the Japan Society for
the Promotion of Science (JSPS) for a fellowship. We appre-
ciate Umicore ([IrACHTUNGTRENNUNG(cod)2]BARF) and Takasago International
Corporation (H8-BINAP) for their generous donations.
[6] Only a few examples of the selective synthesis of 4-sub-
stituted benzofurans by cyclodehydration were report-
ed a) Y. Kawase, M. Takashima, Bull. Chem. Soc. Jpn.
1967, 40, 1224–1231; b) Y. Kawase, S. Takata, E. Hi-
kishima, Bull. Chem. Soc. Jpn. 1971, 44, 749–753; c) I.
Kim, S.-H. Lee, S. Lee, Tetrahedron Lett. 2008, 49,
6579–6584.
[7] Strong acids often promote the migration of C-3 aryl
group to C-2 position in benzoheteroles. For examples,
see refs.[4d,4g]
References
[1] Comprehensive Heterocyclic Chemistry II, Vol. 2 (Eds.:
A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Perga-
mon Press, New York, 1996, pp 210–257 (indoles) and
pp 413–436 (benzofurans).
[2] For selected reviews of heterocycle synthesis including
benzofuran and indole derivatives, see: a) I. Nakamura,
Y. Yamamoto, Chem. Rev. 2004, 104, 2127–2198; b) G.
Zeni, R. C. Larock, Chem. Rev. 2004, 104, 2285–2310;
c) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–
2920; d) G. R. Humphrey, J. T. Kuethe, Chem. Rev.
2006, 106, 2875–2911.
[8] For selected reviews on direct functionalization of aro-
À
matic compounds via C H bond activation and electro-
À
philic metallation: a) G. Dyker, Handbook of C H
Adv. Synth. Catal. 2009, 351, 2850 – 2854
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2853

Kyoji Tsuchikama et al.
COMMUNICATIONS
transformations: applications in organic synthesis,
Wiley-VCH Weinheim, 2005; b) D. Alberico, M. E.
Scott, M. Lautens, Chem. Rev. 2007, 107, 174–238; c) F.
Kakiuchi, T. Kochi, Synthesis 2008, 3013–3039.
6781; b) H. Harada, R. K. Thalji, R. G. Bergman, J. A.
Ellman, J. Org. Chem. 2008, 73, 6772–6779. Isobenzo-
À
furan synthesis by rhenium-catalyzed directed C H ac-
tivation/aldehyde insertion: c) Y. Kuninobu, Y. Nishina,
C. Nakagawa, K. Takai, J. Am. Chem. Soc. 2006, 128,
12376–12377. Benzoxazole synthesis by copper-cata-
À
[9] For selected examples of iridium-catalyzed C H bond
functionalization of aromatic compounds, see: a) R.
Aufdenblatten, S. Diezi, A. Togni, Monatsh. Chem.
2000, 131, 1345–1350; b) T. Matsumoto, D. J. Taube,
R. A. Periana, H. Taube, H. Yoshida, J. Am. Chem.
Soc. 2000, 122, 7414–7415; c) Y. Nishinaka, T. Satoh,
M. Miura, H. Morisaka, M. Nomura, H. Matsui, C. Ya-
maguchi, Bull. Chem. Soc. Jpn. 2001, 74, 1727–1735;
d) Y. Fukumoto, K. Sawada, M. Hagihara, N. Chatani,
S. Murai, Angew. Chem. 2002, 114, 2903–2905; Angew.
Chem. Int. Ed. 2002, 41, 2779–2781; e) R. Dorta, A.
Togni, Chem. Commun. 2003, 760–761; f) W. J. Tenn,
K. J. H. Young, G. Bhalla, J. Oxgaard, W. A. Goddard,
R. A. Periana, J. Am. Chem. Soc. 2005, 127, 14172–
14173; g) T. Ishiyama, N. Miyaura, Pure Appl. Chem.
2006, 78, 1369–1375; h) B. Lu, J. R. Falck, Angew.
Chem. 2008, 120, 7618–7620; Angew. Chem. Int. Ed.
À
lyzed electrophilic metallation/C O bond formation:
d) S. Ueda, H. Nagasawa, J. Org. Chem. 2009, 74,
4272–4277.
[12] Cationic rhodium catalysis: a) K. Tsuchikama, Y.
Kuwata, Y.-k. Tahara, Y. Yoshinami, T. Shibata, Org.
Lett. 2007, 9, 3097–3099. Tanaka and co-workers inde-
pendently reported a similar reaction: b) K. Tanaka, Y.
Otake, A. Wada, K. Noguchi, M. Hirano, Org. Lett.
2007, 9, 2203–2206. Cationic iridium catalysis: c) K.
Tsuchikama, M. Kasagawa, Y.-k. Hashimoto, K. Endo,
T. Shibata, J. Organomet. Chem. 2008, 693, 3939–3942.
[13] K. Tsuchikama, M. Kasagawa, K. Endo, T. Shibata,
Org. Lett. 2009, 11, 1821–1823.
[14] We also ascertained that reversible carbon-iridium
bond formation should be involved in the mechanism
by an H/D exchange experiment using D2O (see
Scheme S1 in the Supporting Information). However,
À
2008, 47, 7508–7510. Recently, iridium-catalyzed C H
arylation of heteroarenes via electrophilic metallation
was reported: i) B. Join, T. Yamamoto, K. Itami,
Angew. Chem. 2009, 121, 3698–3701; Angew. Chem.
Int. Ed. 2009, 48, 3644–3647.
À
at present, we cannot determine either C H bond
cleavage or electrophilic metallation as a feasible
mechanism.
[10] Selected examples of 1,2-addition of carbon-transition
metal bond to simple ketones: a) A. Takezawa, K. Ya-
maguchi, T. Ohmura, Y. Yamamoto, N. Miyaura, Syn-
lett 2002, 1733–1735; b) S. Oi, M. Moro, H. Fukuhara,
T. Kawanishi, Y. Inoue, Tetrahedron 2003, 59, 4351–
4361; c) K. Ueura, S. Miyamura, T. Satoh, M. Miura, J.
Organomet. Chem. 2006, 691, 2821–2826; d) G. Liu, X.
Lu, Tetrahedron 2008, 64, 7324–7330.
[15] The synthesis of bioactive compounds using 4-acylami-
no-3-methylbenzofuran as a synthetic intermediate:
A. P. Kozikowski, D. Ma, L. Du, N. E. Lewin, P. M.
Blumberg, Bioorg. Med. Chem. Lett. 1994, 4, 637–640.
[16] Recently, some reports on high electron and hole trans-
portation ability of benzodifuran derivatives were dis-
closed: a) H. Tsuji, C. Mitsui, L. Ilies, Y. Sato, E. Naka-
mura, J. Am. Chem. Soc. 2007, 129, 11902–11903; b) R.
Shukla, S. H. Wadumethrige, S. V. Lindeman, R. Ra-
thore, Org. Lett. 2008, 10, 3587–3590; c) N. Hayashi, Y.
Saito, H. Higuchi, K. Suzuki, J. Phys. Chem. A 2009,
113, 5342–5347.
[11] There have been several reports of heterocycle synthe-
sis by directed cyclization. Dihydrobenzofuran and in-
À
doline synthesis by rhodium-catalyzed C H activation/
olefin insertion: a) R. K. Thalji, K. Ahrendt, R. G.
Bergman, J. A. Ellman, J. Org. Chem. 2005, 70, 6775–
2854
asc.wiley-vch.de
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2850 – 2854