One-pot/four-step/palladium-catalyzed synthesis of indole derivatives: The combination of heterogeneous and homogeneous systems

Article abstract of DOI:10.1002/adsc.200800405

One-pot, four-step syntheses of indoles using both solid-supported heterogeneous and homogeneous palladium catalysts and reagents were carried out. Such a combination of these two-phase catalysts and reagents causes a dramatic increase in yield, and it is a simple process. The presented methodology is effective for four-step reactions to provide various functionalized indoles.

Full text of DOI:10.1002/adsc.200800405

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DOI: 10.1002/adsc.200800405
One-Pot/Four-Step/Palladium-Catalyzed Synthesis of Indole
Derivatives: The Combination of Heterogeneous and
Homogeneous Systems
Hayato Sakai,a Ken Tsutsumi,a,* Tsumoru Morimoto,a and Kiyomi Kakiuchia
a
Graduate School of Materials Science, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma,
Nara 630-0192, Japan
Fax : (+81)-743-72-6089; e-mail: tsutsumi@ms.naist.jp
Received: June 30, 2008; Revised: August 23, 2008; Published online: October 16, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800405.
Abstract: One-pot, four-step syntheses of indoles
using both solid-supported heterogeneous and ho-
mogeneous palladium catalysts and reagents were
carried out. Such a combination of these two-phase
catalysts and reagents causes a dramatic increase in
yield, and it is a simple process. The presented
methodology is effective for four-step reactions to
provide various functionalized indoles.
doles were mostly limited to two-step reactions or ex-
quisite combinations of catalysts and reagents with
fine-tuning of the reaction conditions.[2]
In order to develop a widely applicable and versa-
tile one-pot multi-step synthetic methodology, we pro-
pose the combination of solid-supported heterogene-
ous[3] and homogeneous catalysts (catalysts A–C) or
reagents (reagents A–C) (Scheme 1).
In such a system, co-existing catalysts or reagents
should scramble slowly compared with a homogene-
ous only system because they are treated in separate
heterogeneous and homogeneous phases. Thus the
avoidance of scrambling by the catalysts and reagents
allows the multi-step reaction (S!P1!P2!···!PN)
to proceed smoothly in one-pot.
Keywords: homogeneous catalysis; indoles; one-pot
multi-step synthesis; palladium; supported catalysts
The synthetic methods for indole derivatives, includ-
To test the combined heterogeneous and homoge-
ing metal-catalytic reactions, have been given wide at- neous reaction system, we focused on a palladium-cat-
tention because of their unique biological activities alyzed, multi-step synthesis of indole derivatives[1b,4]
and utility as the building blocks of various natural because palladium is one of the most widely applica-
products.[1] In many cases, multi-step reactions are re- ble catalysts in organic syntheses.[5] We took particular
quired with regard to the construction of the indoles. note of Cacchiꢀs report on a four-step synthesis of in-
Recently, one-pot multi-step syntheses have gained a doles which used the following sequence (Table 1).[4c]
position of increasing significance because of their en- At first, Sonogashira coupling of 2-iodoaniline 1 with
vironmental and economical advantages, which are trimethylsilylacetylene 2-TMS provides 2-[(trimethyl-
derived from the avoidance of the typical separation
ACHTUNGTRENsNUGN ilyl)ethynyl]aniline 3-TMS. In the second step, desily-
and isolation of products required in each conversion lation gives ethynylaniline 3-H. Then, Sonogashira
step. However, the reported one-pot syntheses of in- coupling of 3-H with an aromatic iodide, such as 4a, is
Scheme 1. One-pot, multi-step reaction in heterogeneous and homogeneous systems.
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Table 1. Effect of the combination of the polymer-supported heterogeneous and homogeneous catalysts and reagents.
Entry
Pd catalyst
PdCl2A(PPh3)2
TBAF
t 1 [h]
t 2 [h]
5a[a] [%]
1
2
3
4
5
6
7
G
TBAF in THF
2
0.5
0.5
2
2
2
39
27
60
9
0
0
[b]
[b]
[d]
[e]
PdCl DPP-ꢀ
TBAF in THF
12
12
12
12
12
12
Si
2
PdCl DPP-ꢀ
TBAF on silica[c]
TBAF on silica[c]
TBAF on silica[c]
TBAF on silica[c]
TBAF on silica[c]
Si
2
PdCl TPP-ꢀ
JJ
2
PdCl TPP-ꢀ
PS
2
Pd EnCat TPP30[f]
2
2
[g]
PdCl DPP-ꢀ
41
Si
2
[a]
Isolated yield.
[b]
PdCl DPP-ꢀ is a silica-supported catalyst. Prepared from SilicaBond Diphenylphosphine (SILICYCLE Inc.) and
Si
2
PdCl2ACHTUNGTRENNUNG
(PPh3)2; 0.224–0.245 mmol Pd/g.[6]
[c]
[d]
Commercially available (Aldrich Chemical Co.); 1.0–1.5 mmol F/g.[7]
PdCl TPP-ꢀ is JandaJelTM-supported catalyst. Prepared from JandaJelTM, triphenylphosphine (Aldrich Chemical Co.) and
JJ
2
PdCl2ACHTUNGTRENNUNG
(PPh3)2; 1.14 mmol Pd/g.[8]
[e]
[f]
PdCl TPP-ꢀ is polystylene resin-supported catalyst. Commercially available (Aldrich Chemical Co.); 1.0 mmol Pd/g.[8]
PS
2
Commercially available (Aldrich Chemical Co.); 0.4 mmol Pd/g.[9]
[g]
Prepared from SilicaBond Diphenylphosphine (SILICYCLE Inc.) and small amounts of PdCl2ACHTNUGTRENUNG(PPh3)2; 0.127 mmol
Pd/g.[6]
performed as the third step to introduce a new func- the commercially available silica-supported phosphine
tional group at the terminal position of the alkynyl (SILICYCLE Inc.) in dry benzene was stirred at
moiety. In the last step, cyclization of the coupling reflux temperature for 24 h. Then, the suspension was
product, such as 3a, affords indole 5a.
filtered and the solid residue was washed with ben-
This sequential four-step reaction was carried out in zene, hexane, acetonitrile and diethyl ether to give
a single vessel using homogeneous catalysts and re- the corresponding silica-supported palladium catalyst.
agents as follows: PdCl
solution of TBAF (tetrabutylammonium fluoride) in stead of PdCl CTHUGNTRENNNUG
(PPh3)2 in the first step, THF
Although the silica-supported palladium catalyst in-
2A(PPh3)2 in the four-step reaction result-
the second step, and PdCl2 in the fourth step. In the ed in a low yield (Table 1, entry 2), the employment
third step, the remaining palladium catalyst could be of both silica-supported palladium catalyst and TBAF
reused. However, in that case, the corresponding immobilized on silica[7] improved the yield dramatical-
indole 5a was obtained in low yield (Table 1, entry 1). ly (Table 1, entry 3). The average yield of each step in
Hence performing the multi-step reaction in a one- the one-pot sequence is estimated to be 88%. In the
pot system, especially when using transition metal cat- four-step synthesis of indoles, triphenylphosphine acti-
alysts, is an extremely severe challenge because the vates a Pd(0 catalyst for Sonogashira coupling but
metal catalysts are very sensitive to coordinating li- poisons Pd(II)Cl2 preventing cyclization. The oxida-
gands and the oxidation state.
tion states of the two catalysts are different [Sonoga-
In order to improve the efficiency, the effects of shira coupling: Pd(0), cyclization: Pd(II)]. This sug-
various combinations of heterogeneous and homoge- gests that the two homogeneous palladium catalysts
neous catalysts and reagents were examined. For that may scramble rapidly for coordinating phosphine li-
purpose, a silica-supported (ꢀ) palladium catalyst gands and/or electrons to result in moderate yields.
Si
was prepared according to the modified procedure re-
Moreover, free TBAF may affect the palladium cat-
ported by Huang.[6] A suspension of PdCl
2ACHTNUGTRNEG(UN PPh3)2 and alysts, which retards the reactions. A combination of
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Hayato Sakai et al.
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solid-supported heterogeneous and homogeneous cat- oaromatic substituted indoles 5b and 5c were pre-
alysts and reagents may prevent the scrambling in situ pared with good average yields (Table 2, entries 1 and
because each catalyst and reagent is treated separate- 2). Interestingly, 5c and 5d were obtained in better
ly in heterogeneous and homogeneous phases.
isolated yields compared with the previous results re-
Other heterogeneous catalysts were tested in the ported by Cacchi (Table 2, entries 2 and 3, reported
four-step reactions. A JandaJel-supported (ꢀ) catalyst results: 53% and 33%).[4c] In the case of 4e, the iodo
JJ
instead of silica-supported palladium catalyst pre- group reacted selectively to give a bromophenyl-sub-
pared from the commercially JandaJelTM triphenyl- stituted indole 5e (Table 2, entry 4). When the reac-
[8]
phosphine (Aldrich Chemical Co.) and PdCl
G
tion was carried out with trifluoromethanesulfonate
gave 5a in 9% yield (Table 1, entry 4). A commercial- compound 4f, the corresponding indole 5f was ob-
ly available polystylene resin-supported (ꢀ) catalyst[8] tained (Table 2, entry 5). Even in the case of the
PS
and a nanoparticle-type catalyst, PdEnCat TPP 30 highly functionalized steroid 4g, the one-pot reaction
consisting of Pd(II) and PPh3 ligated by the urea en- provided a steroid-substituted indole 5g (Table 2,
capsulation matrix,[9] were not effective in this reac- entry 6). Furthermore, the one-pot reaction afforded
tion (Table 1, entries 5 and 6). It is well known that various functionalized indoles at the C5 position 5h–k
silica swells very little in most solvents and that the effectively (Table 2, entries 7–10). In particular, 5j is
active sites are well dispersed on its surface and, known as a NorA MDR pump inhibitor.[12] Thus, this
therefore, these sites are easily accessible to reactants. methodology is superior with the following notewor-
However, all the other organic solid-supported cata- thy features: many of functionalized indoles can be
lysts are affected by solvents. Thus, the silica catalyst created in a one-pot reaction. It is not necessary to
may be the most suitable and widely applicable for prepare the corresponding substituted 1-alkynes.
use in the one-pot reaction system. We also found Therefore, the one-pot reaction could be exploited
that the yield crucially depends on the loading level widely to develop various research areas as a conven-
of the catalyst (Table 1, entry 7). In the case of using ient and efficient synthetic methodology.
the catalyst at a low loading level, PdCl2 for the last
In summary, we have presented a practical and
step may be captured by the free phosphine moiety useful one-pot, multi-step synthetic methodology
on the silica gel to decrease the amount of PdCl2 in using silica-supported heterogeneous and homogene-
the solution phase.
ous catalysts and reagents. In this system, one-pot
These one-pot, four-step reactions provided small multiple reactions proceed effectively to give various
amounts of indoles when only using the silica-support- functionalized indoles. Such a combination of hetero-
ed palladium catalyst or the homogeneous PdCl2. In- geneous- and homogeneous-phase reactions may
dependently each reaction was performed to give the reduce the limitations of other one-pot, multi-step
following yields; 3-TMS: 93% (the first), 3-H: 91% syntheses. Currently, we are applying this protocol to
(the second), 3a: 92% (the third), 5a: 82% (the other metal-catalyzed multiple syntheses.
fourth). These results show that the total yield of the
four-step reactions from 1a was 64%. As for the reac-
tion yield, the presented one-pot system is compara- Experimental Section
ble to the multi-pot one. In addition, the silica-sup-
ported palladium catalyst was reused effectively in Synthesis of PdCl2DPP-ꢀSi
the third step. Thus, each four-step reaction takes
PdCl2ACTHNUGTRNE(UNG PPh3)2 (0.851 g, 1.21 mmol) and commercially avail-
place in heterogeneous and homogeneous phases,
which serve as pseudo micro-vessels in a large single
vessel. Therefore, the presented reaction system may
resemble biosynthesis using enzymes.[10] We prelimi-
nary elucidated the one-pot, two-step synthesis of
indole: Sonogashira coupling between a 2-aminoaryl
halide and an alkyne followed by intramolecular cycli-
zation of the resulting 2-alkynylanilines. In this reac-
tion the combination of silica-supported palladium
catalyst and PdCl2 showed the best result in compari-
able SilicaBond Diphenylphosphine (1.01 mmol P/g; SILI-
CYCLE Inc.) (1.00 g, 1.01 mmol P) were put into a flask.
Then, dry benzene (32.3 mL) was added to the flask, and
the suspension was stirred at reflux temperature for 24 h.
Then, the suspension was filtered and the solid residue was
washed with benzene, hexane, MeCN and Et2O. The result-
ing solid was dried under vacuum at room temperature,
giving a yellow powder. Pd loading was confirmed to be
0.232–0.260 mmol Pd/g by MIP-MS analysis. Similar reac-
tions of smaller amounts of PdCl2ACHTUNRGTNEUNG(PPh3)2 (0.426 g,
0.61 mmol) and silica-bound diphenylphosphine (1.00 g,
1.01 mmol P) provided the silica-supported catalyst with a
lower loading level (0.127 mmol Pd/g).
son with PdCl2ACHTUNGTRENNUNG(PPh3)2 and other heterogeneous cata-
lysts instead of silica-supported palladium.[11] These
results indicate the efficiency of the combination of
heterogeneous and homogeneous palladium catalysts.
The one-pot, four-step syntheses of various func-
tionalized iodides were carried out to explore the
scope of the presented methodology (Table 2). Heter-
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Table 2. One-pot four-step synthesis of 2-substituted indoles.[a]
Entry
1
1
4
t 3 [h] t 4 [h]
5
Yield[b] [%]
40 (80)
1a
4b
4
2
45
5
5b
2
3
4c
5c
57 (87)
59 (88)
4d
2
7
5d
4
5
4e
4f
3
3
5
6
5e
5f
28 (73)
38 (79)
6[c]
4g
4a
20
24
5g
21 (68)
7
8
9
1b
1c
1d
2
2
2
7
5h
5i
52 (85)
47 (83)
11 (58)
24
7
5j
10
1e
2
7
5k
20 (67)
[a]
PdCl DPP-ꢀ was prepared from SilicaBond Diphenylphosphine (SILICYCLE Inc.) and PdCl
2ACHTUGNTRENN(GNU PPh3)2; 0.224–0.245 mmol
Si
2
Pd/g.[6] The reaction procedure is described in the Experimental Section.
Isolated yield. Average yield of each step in parentheses.
DMF/MeCN (1/1 was used as solvent).
[b]
[c]
the mixture was stirred at 608C for 12 h. After cooling,
TBAF on silica (0.420 g, 0.420 mmol) was added, and the
mixture was stirred at room temperature for 2 h. Subse-
quently, aryl iodide (0.300 mmol) was added, and the mix-
ture was stirred at 608C for 2–20 h. After the completion of
the Sonogashira coupling, 1 N HCl aqueous (0.690 mL,
0.690 mmol) and PdCl2 (2.66 mg, 0.0150 mmol) were added,
and the reaction mixture was stirred at reflux temperature
General Procedure for the One-Pot Four-Step
Synthesis of Indoles
Aromatic iodoaniline (0.30 mmol), silica-supported palladi-
um catalyst (PdCl DPP-ꢀ) (0.015 mmol) and CuI (1.15 mg,
Si
2
6.0 mmol) were suspended in dry MeCN (3.00 mL). (i-
Pr)2NH (0.12 mL, 0.81 mmol) and trimethylsilylacetylene
(60.0 mL, 0.420 mmol) were added to the suspension, and
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Hayato Sakai et al.
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ˇ
for 5–45 h. The resulting mixture was filtered, and the fil-
trate was diluted with ethyl acetate. The obtained solution
was washed with a saturated aqueous NaHCO3. Then the or-
ganic layer was dried (MgSO4) and concentrated under
vacuum. Purification by column chromatography (silica gel)
gave the corresponding indoles.
Kobaslija, D. T. McQuade, Org. Biomol. Chem. 2005, 3,
2899; c) R. I. Storer, T. Takemoto, P. S. Jackson, S. V.
Ley, Angew. Chem. Int. Ed. 2003, 42, 2521; d) S. V. Ley,
I. R. Baxendale, G. Brusotti, M. Caldarelli, A. Massi,
M. Nesi, Il Farmaco 2002, 57, 321.
[4] a) L. Djakovitch, V. Dufaud, R. Zaidi, Adv. Synth.
Catal. 2006, 348, 715; b) P. Rollet, W. Kleist, V. Dufaud,
L. Djakovitch; J. Mol. Catal. A: Chem. 2005, 241, 39;
c) A. Arcadi, S. Cacchi, F. Marinelli, Tetrahedron Lett.
1989, 30, 2581.
Acknowledgements
[5] Palladium Reagents and Catalysts, (Ed.: J. Tsuji), John
This work was supported in part by a Grant-in-Aid for Scien-
tific Research on Priority Areas (No. 16033243, “Reaction
Control of Dynamic Complexes”) from the Ministry of Edu-
cation, Culture, Sports, Science, and Technology, Japan, and
the Iketani Science and Technology Foundation. We also
thank Mr. Masahiro Fujiwara and Ms. Yoshiko Nishikawa
for assistance in obtaining MIP-mass and HR-mass spectra,
respectively.
Wiley & Sons, Chichester, 1995.
[6] M.-Z. Cai, C.-S. Song, X. Huang, Synthetic Commun.
1998, 28, 693.
[7] TBAF on silica (tetrabutylammonium fluoride on silica
gel, loading level: 1.0–1.5 mmolgꢁ1) is commercially
available from Aldrich Chemical Co.
[8] JandaJel (JJ)-supported catalyst was prepared accord-
ing to a similar method for silica-supported catalyst
(see Supporting Information). Polystyrene resin-sup-
ported catalyst (dichorobistriphenylphosphine)palla-
dium polymer-bound, loading level: 1.0 mmol Pd/g) is
commercially available from Aldrich Chemical Co., see
also: N. E. Leadbeater, M. Marco, Chem. Rev. 2002,
102, 3217.
[9] PdEnCat TPP 30 (loading level: 0.4 mmol Pd/g) is com-
mercially available from Aldrich Chemical Co., see
also: S. J. Broadwater, D. T. McQuade, J. Org. Chem.
2006, 71, 2131, and references cited therein.
[10] a) Y. Wang, X.-S. Ye, L.-H. Zhang, Org. Biomol. Chem.
2007, 5, 2189; b) A. Bruggink, R. Schoevaart, T. Kie-
boom, Org. Process Res. Dev. 2003, 7, 622; c) S. F.
Mayer, W. Kroutil, K. Faber, Chem. Soc. Rev. 2001, 30,
332.
References
[1] For recent reviews on synthesis of indole delivatives,
see: a) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006,
106, 2875; b) S. Cacchi, G. Fabrizi, Chem. Rev. 2005,
105, 2873; c) G. W. Gribble, in: Comprehensive Hetero-
cyclic Chemistry II, Vol. 2 (Eds.: A. R. Katrizky, C. W.
Rees, E. F. V. Scriven), Pergamon, Oxford, 1996, p 20.
[2] For examples of the one-pot two-step synthesis of in-
doles, see: a) S. Fukuoka, T. Naito, H. Sekiguchi, T.
Somete, A. Mori, Heterocycles 2008, 78, 819; b) O. Leo-
gane, H. Lebel, Angew.Chem. Int. Ed. 2008, 47, 350;
c) M. McLaughlin, M. Palucki, I. W. Davies, Org. Lett.
2006, 8, 3307; d) S. S. Palimkar, P. H. Kumar, R. J.
Lahoti, K. V. Srinivasan, Tetrahedron 2006, 62, 5109;
e) M. Pal, V. Subramanian, V. R. Batchu, I. Dager, Syn-
lett 2004, 11, 1965; f) M. Gruber, S. Chouzier, K. Koeh-
ler, L. Djakovitch, Appl. Catal. A: General 2004, 265,
161; g) N. Olivi, P. Spruyt, J.-F. Peyrat, M. Alami, J.-D.
Brion, Tetrahedron Lett. 2004, 45, 2607; h) S. Chouzier,
M. Gruber, L. Djakovitch, J. Mol. Catal. A: Chem.
2004, 212, 43; i) K. B. Hong, C. W. Lee, E. K. Yum, Tet-
rahedron Lett. 2004, 45, 693; j) N. Suzuki, S. Yasaki, A.
Yasuhara, T. Sakamoto, Chem. Pharm. Bull. 2003, 51,
1170; k) T. Y. H. Wu, S. Ding, N. S. Gray, P. G. Schultz,
Org. Lett. 2001, 3, 3827; l) G. W. Kabalka, L. Wang,
R. M. Pagni, Tetrahedron 2001, 57, 8017; m) H.-C.
Zhang, H. Ye, A. F. Moretto, K. K. Brumfield, B. E.
Maryanoff, Org. Lett. 2000, 2, 89; n) M. C. Fagnola, I.
Candiani, G. Visentin, W. Cabri, F. Zarini, N. Mongelli,
A. Bedeschi, Tetrahedron Lett. 1997, 38, 2307; o) M.
Botta, V. Summa, F. Corelli, G. D. Pietro, P. Lombardi,
Tetrahedron: Asymmetry 1996, 7, 1263.
[11] One-pot, two-step reactions indicated the best combi-
nation of silica-supported palladium and PdCl2 {yields
of the indole: 38% [PdCl2ACHTNUTRGNE(UNG PPh3)2], 77% (silica-support-
ed Pd), 0–50% (other solid-supported catalysts)}; See
Supporting Information.
[12] a) S. Samosorn, J. B. Bremner, A. Ball, K. Lewis,
Bioorg. Med. Chem. 2006, 14, 857; b) R. H. Bahekar,
M. R. Jain, A. Goel, D. N. Patel, V. M. Prajapati, A. A.
Gupta, P. A. Jadav, P. R. Patel, Bioorg. Med. Chem.
2007, 15, 3248.
[3] For recent reports and a review on multi-step reactions
using solid-supported reagents, catalysts and/or scav-
engers, see: a) B. Voit, Angew. Chem. Int. Ed. 2006, 45,
4238; b) S. J. Broadwater, S. L. Roth, K. E. Price, M.
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