Expedient synthesis of N-fused indoles: A C-F activation and C-H insertion approach

Article abstract of DOI:10.1002/anie.200901986

Easy does it: A wide range of N-fused indole skeletons, which are core structures of many biologically potent molecules, are successfully furnished by a niobiumcatalyzed C(sp³)-H insertion reaction (see picture). The precursors are readily prepared by a palladium-catalyzed amination reaction of bromotrifluorotoluenes with cyclic amines.

Full text of DOI:10.1002/anie.200901986

Communications
DOI: 10.1002/anie.200901986
Synthetic Methods
À
À
Expedient Synthesis of N-Fused Indoles: A C F Activation and C H
Insertion Approach**
Kohei Fuchibe, Tsukasa Kaneko, Keiji Mori, and Takahiko Akiyama*
Indoles are versatile components of many natural and
synthetic biologically active compounds, and a vast number
of pharmaceuticals containing the indole skeleton are being
used for therapeutic purposes.[1] N-fused indoles are indole
derivatives that have great biological and pharmaceutical
importance. For example, mitomycin C[2] and cryptaustoline[3]
possess the N-fused indole structure (Scheme 1). These and
and most importantly, a multistep synthesis of the substrates is
required regardless of the synthetic strategy selected.
Herein we describe an expedient synthesis of N-fused
À
indoles by means of a direct, catalytic C H carbenoid
insertion approach. Our strategy consists of two steps: 1) a
cyclic amine is introduced into o-(trifluoromethyl)bromoben-
zene as a fused ring component by a palladium-catalyzed
3
À
amination reaction, and 2) a niobium-catalyzed C(sp ) H
insertion reaction completes the indole core skeleton
(Scheme 2). The well-established amination reaction, origi-
Scheme 1. Biologically active N-fused indoles.
Scheme 2. Our strategy.
related indole alkaloids exhibit antitumor[4] and tubulin
polymerization inhibitory[5] activities. Pyrazino[1,2-a]indoles
behave as 5-HT2c receptor agonists[6] and are related to the
treatment of hyperglycemia and other diseases by controlling
appetite.
Despite the importance of N-fused indole derivatives, the
synthesis of this class of compounds has not yet been fully
developed: alkyl chain elongation and ring closure on an
existing indole platform have been reported by many research
groups (for example, by intramolecular alkylation,[7a] radical
cyclization,[7b–e] and other methods[7f]). Transannulation reac-
tions[8] also afford N-fused indoles. In recent years, many
transition-metal-catalyzed reactions have been reported.[9]
However, the ring-closure strategy still poses many problems
nally explored by Buchwald and co-workers,[10] will ensure the
flexibility of the fused-ring substructure. Insertion reactions
of a niobium fluorocarbenoid center, which is generated from
2
À
a CF3 group attached to an aromatic nucleus, into a C(sp ) H
bond were developed recently by our group.[11–13]
Scheme 3 shows precursors which were prepared in good
yields mainly by the Buchwald amination reaction (see the
Supporting Information for details).[10] Notably, CF3 groups,
which would generate the key carbenoid centers, were not
À
affected by the C N coupling conditions.
[*] Dr. K. Fuchibe,[+] T. Kaneko, Dr. K. Mori, Prof. Dr. T. Akiyama
Department of Chemistry, Faculty of Science
Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
Fax: (+81)3-3986-0221
E-mail: takahiko.akiyama@gakushuin.ac.jp
Homepage: http://www.cc.gakushuin.ac.jp/~940020/akiyama_
site/index_E.html
[+] Present address: Department of Chemistry
Graduate School of Pure and Applied Sciences
University of Tsukuba, Tsukuba, Ibaraki 305-8571 (Japan)
[**] This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology (Japan). This work was also supported by the
Saneyoshi Scholarship Foundation and the Asahi Glass Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901986.
Scheme 3. List of insertion precursors 1.
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Table 2: Synthesis of N-fused indoles.
À
With the insertion precursors 1 in hand, the key C H
insertion reaction was examined (Table 1). Initially, 1c was
treated with lithium aluminum hydride in the presence of
Table 1: Optimization of the reaction conditions.
Entry
1
Precursor
Product
t [h][a]
Yield [%][b]
1a
6
65, 2a
Entry
NbCl5
Reducing agent[a]
t [h]
Yield [%]
2c
3
1c
1
2
3
4
1.5 equiv
30 mol%
1.0 equiv
1.0 equiv
LiAlH4 (10)
NaAlH4 (4)
49
23
72
24
20
27
–
20
46
–
52
2
3
1b
1c
5
78, 2b
70, 2c
[b]
–
[c]
LiAl(OtBu)H3 (10)
Red-Al (19)[d]
–
–
[c]
[a] The amount of reducing agent (equiv) is indicated in parenthesis.
[b] 4 was obtained in 15% yield. [c] 1c was recovered as the sole product
(yields were not determined). [d] Red-Al=sodium bis(methoxyethoxy)-
aluminum hydride.
23
4
5
6
1d
1e
1 f
13
6.5
19
64, 2d
68, 2e
71, 2 f
1.5 equivalents of niobium(V) chloride.[10a] To our delight,
piperidinoindole 2c and piperidinoindoline 3 were obtained
in 20% yield each, with 1c recovered in 52% yield (Table 1,
entry 1). The conversion rate improved dramatically when
sodium aluminum hydride was used, giving 2c and 3 in yields
of 27% and 46%, respectively (Table 1, entry 2; 30 mol%
niobium(V) chloride).[14,15] In contrast, alkoxy-substituted
aluminum hydride reagents were unreactive, resulting in the
recovery of starting material 1c (Table 1, entries 3 and 4) even
when an equimolar amount of niobium(V) chloride was
used.[16]
7
8
1g
1h
4
6
87, 2g
85, 2h
Dehydrogenation of isolated 3 proceeded smoothly in the
presence of a ruthenium catalyst (Scheme 4). Indoline 3
afforded indole 2c in quantitative yield when treated with
9
1i
1j
15
25
52, 2i
59, 2j
Scheme 4. Ruthenium-catalyzed dehydrogenation of indoline 3.
10
8 mol% ruthenium zirconium phosphate[17] under dioxygen at
atmospheric pressure. 2,6-Dichloro-3,5-dicyano-p-benzoqui-
none (DDQ) was found to be less efficient for this aroma-
tization, giving 75% yield of 2c upon heating for 11 h in
toluene (1 equiv, RT to 508C; not shown).
11
12
1k
1l
13
19
57, 2k
Precursors 1a–l were subjected to niobium-catalyzed
C H insertion conditions and the isolated indolines were
then dehydrogenated with the ruthenium catalyst. Table 2
À
56,[c] 2l
shows the overall yields of indoles 2a–l from the consecutive
À
reactions. The C H insertion step was found to proceed
smoothly with a range of cyclic amino groups: indoles with
five- to nine-membered fused-ring substructures were syn-
À
[a] Reaction time of the C H insertion step. [b] Overall yield of two
contiguous reactions. [c] 1-Benzyl-5-phenylindole was obtained in 11%
yield.
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Communications
thesized in good to high yields (Table 2, entries 1–8). Oxygen,
[1] Reviews on the synthesis of indoles: a) G. R. Humphrey, J. T.
Kuethe, Chem. Rev. 2006, 106, 2875 – 2911; b) G. W. Gribble, J.
Chem. Soc. Perkin Trans. 1 2000, 1045 – 1075; c) S. Cacchi, G.
Fabrizi, Chem. Rev. 2005, 105, 2873 – 2920; see also: d) N. Sakai,
K. Annaka, A. Fujita, A. Sato, T. Konakahara, J. Org. Chem.
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[2] T. Hata, Y. Sano, R. Sugawara, A. Matsumae, K. Kanamori, T.
Shima, T. Hoshi, J. Antibiot. Ser. A 1956, 9, 141 – 146.
[3] J. Ewing, G. K. Hughes, E. Ritchie, W. C. Taylor, Nature 1952,
169, 618 – 619.
sulfur, and nitrogen atoms in the cyclic amino groups did not
interfere with the insertion, and the corresponding hetero-
atom-containing N-fused indoles were obtained in good yields
(Table 2, entries 9–11). Acyclic 1l also underwent insertion,
with the reaction proceeding mainly at an electronically
favored benzylic site (Table 2, entry 12). This result clearly
contrasts with the result of the [Rh2(S-dosp)4]-catalyzed
insertion (dosp = N-(p-dodecylphenylsulfonyl)prolinato),[18]
in which the sterically less hindered methyl site is preferred.
[4] N. Yoda, N. Hirayama, J. Med. Chem. 1993, 36, 1461 – 1464.
[5] M. Goldbrunner, G. Loidl, T. Polossek, A. Mannschreck, E. V.
Angerer, J. Med. Chem. 1997, 40, 3524 – 3533.
À
Mechanistically, the C H insertion reaction can be
2
À
rationalized similarly to our previous C(sp ) H insertion
reactions (Scheme 5):[10c] fluorine-substituted carbenoid inter-
[6] a) M. Bꢀs, F. Jenck, J. R. Martin, J. L. Moreau, V. Mutel, A. J.
Sleight, U. Widmer, Eur. J. Med. Chem. 1997, 32, 253 – 261.
[7] a) R. Peters, P. Waldmeier, A. Joncour, Org. Process Res. Dev.
2005, 9, 508 – 512; b) S. Caddick, K. Aboutayab, K. Jenkins, R. I.
West, J. Chem. Soc. Perkin Trans. 1 1996, 675 – 682; c) M.-L.
Bennasar, T. Roca, F. Ferrando, Org. Lett. 2004, 6, 759 – 762;
d) S.-F. Wang, C.-P. Chuang, Tetrahedron Lett. 1997, 38, 7597 –
7598; e) J.-S. Shiue, J.-M. Fang, J. Chem. Soc. Chem. Commun.
1993, 1277 – 1278; f) M. Ishikura, W. Ida, K. Yanada, Tetrahedron
2006, 62, 1015 – 1024.
mediate 5 is generated in the reaction medium and then the
Scheme 5. Proposed reaction pathway.
[8] K. Tsuboike, D. J. Guerin, S. M. Mennen, S. J. Miller, Tetrahe-
dron 2004, 60, 7367 – 7374.
[9] a) H. Siebeneicher, I. Bytschkov, S. Doye, Angew. Chem. 2003,
115, 3151 – 3153; Angew. Chem. Int. Ed. 2003, 42, 3042 – 3044;
b) J. Liu, M. Shen, Y. Zhang, G. Li, A. Khodabocus, S.
Rodriguez, B. Qu, V. Farina, C. H. Senanayake, B. Z. Lu, Org.
Lett. 2006, 8, 3573 – 3575; c) L. Pꢁrez-Serrano, G. Domꢂnguez, J.
Pꢁrez-Castells, J. Org. Chem. 2004, 69, 5413 – 5418; d) J. Takaya,
S. Udagawa, H. Kusama, N. Iwasawa, Angew. Chem. 2008, 120,
4984 – 4987; Angew. Chem. Int. Ed. 2008, 47, 4906 – 4909; e) A.
Fayol, Y.-Q. Fang, M. Lautens, Org. Lett. 2006, 8, 4203 – 4206;
f) A. K. Verma, T. Kesharwani, J. Singh, V. Tandon, R. C.
Larock, Angew. Chem. 2009, 121, 1158 – 1163; Angew. Chem. Int.
Ed. 2009, 48, 1138 – 1143.
[10] J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 2000, 65, 1144 – 1157.
[11] Our previous studies: a) K. Fuchibe, T. Akiyama, J. Am. Chem.
Soc. 2006, 128, 1434 – 1435; b) K. Fuchibe, K. Mitomi, T.
Akiyama, Chem. Lett. 2007, 36, 24 – 25; c) K. Fuchibe, K.
Mitomi, R. Suzuki, T. Akiyama, Chem. Asian J. 2008, 3, 261 –
271; d) K. Fuchibe, T. Akiyama, J. Synth. Org. Chem. Jpn. 2009,
67, 208 – 218.
À
carbenoid center undergoes insertion into a C H s bond
adjacent to a nitrogen atom. Dehydrofluorination of the
resulting fluoroindoline 6 (not detected) gives indole 2.[19]
Hydrodefluorination of 6, however, gives indolines (for
example, 3).[20] Further studies to gain a full understanding
À
of the niobium-catalyzed C H insertion reaction are ongoing.
In summary, we have developed a new route to biolog-
ically and pharmaceutically important N-fused indole deriv-
atives. Indoles with a nine-membered ring substructure
(maximum ring size) and with a heteroatom-containing ring
substructure could be synthesized in good yields. The
combined use of a palladium-catalyzed amination reaction
3
À
and a newly developed niobium-catalyzed C(sp ) H insertion
reaction has resulted in a facile, short-step synthesis.
[12] Our related papers on niobium reactions: a) K. Fuchibe, T.
Akiyama, Synlett 2004, 1282 – 1284; b) K. Fuchibe, Y. Ohshima,
K. Mitomi, T. Akiyama, Org. Lett. 2007, 9, 1497 – 1499; c) K.
Fuchibe, Y. Ohshima, T. Akiyama, J. Fluorine Chem. 2007, 128,
1158 – 1167.
Experimental Section
Niobium(V) chloride (27 mg, 0.10 mmol, 30 mol%) and sodium
aluminum hydride (65 mg, 1.2 mmol) were added to a solution of 1c
(103 mg, 0.338 mmol) in dioxane (3.3 mL). The reaction mixture was
refluxed for 23 h and then quenched with water at 08C. Purification
by column chromatography (SiO2, hexane/dichloromethane 3:1) gave
indole 2c (23 mg, 0.091 mmol) and indoline 3 (39 mg, 0.16 mmol) in
27 and 46% yield, respectively. Commercially available ruthenium
zirconium phosphate (40 mg, 10 mol% Ru, Kanto Co.) was added to
a solution of isolated 3 in toluene (1.5 mL). Dioxygen (1 atm) was
introduced into the flask and the reaction mixture was heated at
reflux for 24 h. The reaction mixture was filtered through a small pad
of silica gel and purified by column chromatography (SiO2, hexane/
dichloromethane 3:1) to give indole 2c (36 mg, 0.14 mmol, 43%
based on 1c) .
À
[13] A recent review on C F bond activation: a) H. Amii, K.
Uneyama, Chem. Rev. 2009, 109, 2119 – 2183; see also: b) H. L.
Buckley, T. Wang, O. Tran, J. A. Love, Organometallics 2009, 28,
2356 – 2359; c) J. Terao, H. Todo, S. A. Begum, H. Kuniyasu, N.
Kambe, Angew. Chem. 2007, 119, 2132 – 2135; Angew. Chem. Int.
Ed. 2007, 46, 2086 – 2089.
[14] Sodium aluminum hydride is known to be less reactive than
lithium aluminum hydride in the reduction of organic substrates.
Details of this accelerating effect is unclear at present: a) J. S.
Cha, H. C. Brown, J. Org. Chem. 1993, 58, 4727 – 4731; b) H. C.
Brown, J. A. Soderquist, J. Org. Chem. 1980, 45, 849 – 856.
[15] M. Sato, K. Oshima, Chem. Lett. 1982, 157 – 160.
Received: April 14, 2009
Published online: July 3, 2009
3
À
[16] Representative metal-catalyzed C(sp ) H insertion reactions:
a) M. P. Doyle in Comprehensive Organometallic Chemistry II,
Vol. 12 (Eds.: A. W. Abel, F. G. A. Stone, G. Wilkinson),
Pergamon, New York, 1995, pp. 421 – 468; b) H. M. L. Davies,
A. M. Walji in Modern Rhodium-Catalyzed Organic Reactions
Keywords: carbenoids · fused-ring systems · indoles · insertion ·
.
niobium
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(Ed.: P. A. Evans), Wiley-VCH, Weinheim, 2005, pp. 301 – 340;
c) H. Kusama, H. Funami, M. Shido, Y. Hara, J. Takaya, N.
Iwasawa, J. Am. Chem. Soc. 2005, 127, 2709 – 2716; d) S. Z. S.
Ishii, P. Helquist, J. Am. Chem. Soc. 2000, 122, 5897 – 5898; e) T.
Satoh, S. Ogata, D. Wakasugi, Tetrahedron Lett. 2006, 47, 7249 –
7253.
[19] Thin-layer chromatographic analysis of the reaction mixture
suggests that the indole is generated in the reaction medium.
However, partial autooxidation of the indoline to the indole
during work-up was also observed.
[20] When a reaction of 1c was quenched with D2O, 3 with 0.59
deuterium atoms at a benzylic position was obtained. This result
suggests that the benzylic anion is reductively formed from the
presumed intermediate 6 and that protonation of the anionic
intermediate gives 3.
[17] This catalyst is available from Kanto Chemical Co., Inc. (Tokyo,
Japan): ruthenium is supported on zirconium phosphate.
[18] H. M. L. Davies, C. Venkataramani, Angew. Chem. 2002, 114,
2301 – 2303; Angew. Chem. Int. Ed. 2002, 41, 2197 – 2199.
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