Copper-catalyzed synthesis of 2,3-disubstituted indoles

Article abstract of DOI:10.1002/ejoc.200700428

The copper-catalyzed one-step synthesis of 2,3-disubstituted indoles from readily available starting materials, 2-iodoaniline and various β-keto esters was described. The advantage of this method is the use of cheap catalysts and simple experimental procedures under mild reaction conditions. As the substituted indole derivatives are important starting materials for the synthesis of biologically active indole alkaloids and drug candidates, this method would have potential usage for above purpose. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700428

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700428
Copper-Catalyzed Synthesis of 2,3-Disubstituted Indoles
Shinji Tanimori,*[a] Haruna Ura,[a] and Mitsunori Kirihata[a]
Keywords: Indoles / Copper catalyst / BINOL / Domino reactions / One-pot synthesis
The copper-catalyzed one-step synthesis of 2,3-disubstituted
indoles from readily available starting materials, 2-iodoani-
als for the synthesis of biologically active indole alkaloids
and drug candidates, this method would have potential us-
line and various β-keto esters was described. The advantage age for above purpose.
of this method is the use of cheap catalysts and simple exper-
imental procedures under mild reaction conditions. As the
substituted indole derivatives are important starting materi-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Indole derivatives are widely distributed in nature[1] and bon nucleophiles such as malonic acid esters[9] and β-keto
are known to be an important structural unit for the devel- esters[10] have been reported and the conditions were helpful
opment of pharmaceuticals,[2] agrochemicals,[3] material sci- for our present investigations. It was found that the choice
ences[4] and perfumes.[5] For over a hundred years, the syn- of additives (Table 1, Entries 1, 2, 5, 6, 8 and 9), base
thesis of indoles has been an important area of focus for (Table 1, Entries 9, 10 and 11), and solvent (Table 1, En-
organic chemists, and a huge amount of methods for the tries 6 and 7) was crucial in this reaction. When the reaction
synthesis of indoles have been demonstrated.[6] However, it was carried out at 50 °C with the use of 10 mol-% CuI and
was noted that in some cases, specific substitution patterns K2CO3 (1 equiv.), indole 3 was produced in 35% yield
remain difficult to obtain by standard indole-forming reac- (Table 1, Entry 1). The yield decreased in the presence of
tions so the search for new methodologies for the synthesis proline as an additive[11a] (Table 1, Entry 2), although it in-
of indole derivatives is still an important task in synthetic creased when the catalyst loading was increased to 20 mol-
organic chemistry.[6] In this paper, we would like to describe % with a longer reaction time (Table 1, Entry 3). Good con-
the one-step synthesis of 2,3-disubstituted indoles by a cop- version was achieved with the use of strong base (NaH) and
per-catalyzed[7] domino reaction of 2-iodoaniline and β- 50 mol-% CuI (Table 1, Entry 4) even at room temperature.
keto esters (Scheme 1).[8] 2,3-Disubstituted indole substruc- When other additives such as ethylenediamine,[11h] N-meth-
tures are widely distributed in nature as indole alkaloids ylglycin[11a] and 2-thenoic acid[11b] were used, moderate-to-
and drugs, for example, vinblastine, reserpine, okaramines good yields (26 to 66%) were observed (Table 1, Entries 5
and indomethacin, so that it seems necessary to develop a to 8). As a result, the reaction proceeded smoothly at 50 °C
mild and flexible method for the synthesis of such com- with the use of 10 mol-% CuI and 20 mol-% of BINOL[11d]
pounds.[6]
(racemate) with cesium carbonate (1 equiv.) as the base in
DMSO to produce indole 3 in 79% isolated yield (Table 1,
Entry 11).[12]
Next, we investigated the reaction using a variety of β-
keto esters[13] under the optimized conditions. It was found
that β-keto esters including branched and bulky substitu-
ents (Table 2, Entries 2 and 3), terminal alkenes (Table 2,
Entry 4), long chains (Table 2, Entries 5 and 6), aromatic
rings (Table 3, Entries 1 and 2) and heteroaromatic rings
(Table 3, Entries 3–5) were feasible for the present reaction
to give the corresponding indoles in moderate-to-excellent
yields.[14]
Scheme 1. Copper-catalyzed one-step indole-forming reaction.
Table 1 shows the reaction conditions investigated in the
reaction of 2-iodoaniline with methyl acetoacetate as a
model case. The reactions of aromatic halides with soft car-
In summary, we have developed a cheap and simple way
to synthesize 2,3-disubstituted indoles under mild reaction
conditions based on a copper-catalyzed Ullmann-type
coupling reaction. The mechanistic investigation of this
process is now underway.
[a] Department of Bioscience and Informatics, Graduate School of
Life and Environmental Science, Osaka Prefecture University,
1-1 Gakuen-cho, Nakaku, Sakai, Osaka 599-8531, Japan
Fax: +81-72-254-9918
E-mail: tanimori@bioinfo.osakafu-u.ac.jp
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Table 1. Reaction of 2-iodoaniline with methyl acetoacetate.
[a] Isolated yield. [b] Isolated yield based on 2-iodoaniline (1) consumed.
Table 2. Synthesis of 2-alkyl-3-methoxycarbonylindole derivatives.
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Copper-Catalyzed Synthesis of 2,3-Disubstituted Indoles
SHORT COMMUNICATION
Table 2. (continued)
[a] Isolated yield based on 2-iodoaniline (1) consumed. [b] 2 equiv. of β-keto ester 4 was used.
Table 3. Synthesis of 2-aryl/heteroaryl-3-methoxycarbonylindole derivatives.
[a] Isolated yield based on 2-iodoaniline (1) consumed. [b] Yield not optimized. [c] 2 equiv. of β-keto ester 4 was used.
Larsen, T. R. Verhoeven, P. J. Reider, J. Org. Chem. 1997, 62,
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[3] A. Dandia, R. Singh, S. Khaturia, C. Merienne, G. Morgant,
A. Loupy, Bioorg. Med. Chem. 2006, 14, 2409–2417 and refer-
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[4] a) M. Mezlova, J. J. Aaron, J. Svoboda, A. Adenier, F. Maurel,
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[5] G. S. Clark, Perfum. Flavor. 1995, 20, 21–24.
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[7] For a review on the recent advances in copper-mediated reac-
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[9]
[10]
[11]
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Examples for the use of additives in copper-mediated reactions,
see: a) amino acids: D. Ma, H. Z. Quin, J. Org. Chem. 2005,
70, 5164–5173; b) 2-thenoic acid: L. S. Liebeskind, S. Zhang,
D. Zhang, J. Org. Chem. 1997, 62, 2312–2313; c) ethylene
glycol: F. Y. Kwong, A. Klapars, S. L. Buchwald, Org. Lett.
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[12]
Experimental procedure for the synthesis of 3: A mixture of 2-
iodoaniline (0.1 g, 0.46 mmol), ethyl acetoacetate (66 mg,
0.51 mmol), CuI (8.4 mg, 0.046 mmol), BINOL (17.5 mmol,
[8] The Heck route to 2,3-disubstituted indoles from closely re-
lated starting materials: C. Chen, D. R. Lieberman, R. D.
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S. Tanimori, H. Ura, M. Kirihata
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0.092 mmol) and Cs2CO3 (0.15 g, 0.46 mmol) in DMSO (1 mL)
was stirred at room temp. for 4 h under an atmosphere of nitro-
gen. The mixture was partitioned between ethyl acetate and
saturated NH4Cl, the organic layer was washed with brine,
dried with MgSO4 and concentrated in vacuo. The residue was
purified by preparative TLC (hexane/EtOAc, 3:1) to provide
indole 3 (74 mg, 79%) as a solid. Rf = 0.30 (hexane/EtOAc,
2-furyl, 2-thienyl, and 2-pyridyl, see M. J. Alves, A. G. Fortes,
A. Lemos, C. Martins, Synthesis 2005, 555–558).
[14] Selected data for new indole derivatives. 5c: 1H NMR
(400 MHz, CDCl3): δ = 1.35 (s, 9 H), 3.72 (s, 3 H), 7.09 (dt, J
= 1.2, 7.6 Hz, 1 H), 7.20 (dd, J = 1.2, 7.6 Hz, 1 H), 7.30 (dt, J
= 1.5, 8.0 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1 H), 8.84 (br. s, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 27.5 (3ϫCH3), 38.5,
52.5, 115.0, 125.0, 125.1, 125.7, 128.2, 129.1, 130.6, 136.8,
3:1). M.p. 153.9 °C (decomp.). IR (NaCl): ν = 3016, 1687,
˜
1
1453, 1208, 1091 cm–1. H NMR (400 MHz, CDCl3): δ = 2.72
173.0 ppm. 5e: IR: ν = 3305, 2925, 1669, 1457, 1201, 1084,
˜
(s, 3 H), 3.93 (s, 3 H), 7.16–7.30 (m, 3 H), 8.08 (d, J = 7.6 Hz,
1 H), 8.67 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
14.2, 50.8, 104.3, 110.5, 121.2, 121.7, 122.3, 127.1, 134.5, 144.2,
166.6 ppm. HRMS (FAB): calcd. for C11H11NO2 [M]+
189.0790; found 189.0726.
749 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.55 (s, 3 H), 1.61
(s, 3 H), 2.42 (q, J = 7.3 Hz, 2 H), 3.18 (t, J = 7.3 Hz, 2 H),
3.93 (s, 3 H), 5.16–5.22 (m, 1 H), 7.16–7.25 (m, 2 H), 7.28–7.32
(m, 1 H), 8.10–8.14 (m, 1 H), 8.69 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.6, 25.7, 27.5, 28.0, 50.7, 103.8,
110.6, 121.3, 121.6, 122.3, 122.9, 127.1, 133.5, 134.5, 148.2,
166.4 ppm. FAB-MS: m/z (%) = 258 (72) [M + H]+, 227 (30)
[M – OMe]+, 188 (100) [M – C5H9]+. HRMS (FAB): calcd. for
C16H20NO2 [M + H]+ 258.1494; found 258.1438.
[13] The β-keto esters used in the reaction were purchased from
commercial sources (R = Et, iPr, tBu, Ph), or prepared from
methyl acetoacetate by the alkylation of the dianion (R = allyl,
prenyl, and geranyl, see: M. P. Moyer, P. L. Feldman, H. Rapo-
port, J. Org. Chem. 1985, 50, 5223–5230) and from the corre-
sponding methyl ketone by carboethoxylation (R = 2-naphthyl,
Received: May 14, 2007
Published Online: July 10, 2007
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Eur. J. Org. Chem. 2007, 3977–3980