Gold catalysis on immobilized substrates: A heteroannulation approach to the solid-supported synthesis of indoles

Article abstract of DOI:10.1039/c2ob06881h

A gold-catalyzed cyclization of immobilized 2-alkynylanilines was developed as the key step in the synthetic sequence for the preparation of 2-substituted indoles. These results demonstrate the potential of the unexplored combination of gold catalysis and solid-phase organic synthesis. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob06881h

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COMMUNICATION
Gold catalysis on immobilized substrates: a heteroannulation approach to the
solid-supported synthesis of indoles†
Agustina La-Venia, Sebastián A. Testero, Mirta P. Mischne* and Ernesto G. Mata*
Received 8th November 2011, Accepted 18th January 2012
DOI: 10.1039/c2ob06881h
Indoles are arguably one of the most important heterocyclic
systems. A large number of indole-based natural products and
indole-derived synthetic drugs have demonstrated a wide range
of biological activities.8,9 Among the extensive literature on the
synthesis of indoles,10 only a few solution-phase studies involve
gold catalysis.11–13 Even though the annulation of 2-alkynylani-
lines is a logical approach, intermolecular dimerization may
occur under gold catalysis, as depicted by Praveen et al.14 We
envisaged that a solid-supported substrate will avoid the homo-
coupling products.
A gold-catalyzed cyclization of immobilized 2-alkynylanilines
was developed as the key step in the synthetic sequence for
the preparation of 2-substituted indoles. These results
demonstrate the potential of the unexplored combination of
gold catalysis and solid-phase organic synthesis.
Introduction
Over recent years, research in homogeneous gold catalysis has
reached a high level of development, showing its potential in a
series of metal-catalyzed transformations that lead to new
carbon–carbon or carbon–heteroatom bonds.1 The outstanding
feature of gold complexes is their soft carbophilic Lewis acid
character, which allows the activation of unsaturated moieties
toward the attack by a variety of nucleophilic species.2
Application of organometallic chemistry to solid-phase
organic synthesis has increased substantially in the last decade.3
This originated from the emergence of new and more efficient
catalysts and the inherent advantages of solid-supported chem-
istry. Apart from the classical advantage of easy purification, this
chemistry has grown in interest due to the spatial separation of
substrates achieved by immobilization on a polystyrene resin.
Such site–site isolation is particularly useful in cross coupling
reactions to avoid undesired homocoupling products.4,5 Despite
the arrival of homogeneous gold catalysis in mainstream chem-
istry, applications of this metal in solid-supported synthesis have
not, to the best of our knowledge, been disclosed.
Results and discussion
The synthetic sequence15 started with the immobilization of the
4-bromo-3-nitrobenzoic acid (2) to Wang resin (1) by a standard
coupling procedure to obtain the resin-bound ester 3 (Scheme 1).
Resin 3 was then subjected to Sonogashira coupling. In initial
studies, we utilized phenylacetylene (4a) for an exploratory
sequence. High-yielding conditions were found when resin 3
was treated with phenylacetylene (4a) (5 equiv), PdCl2(PPh3)2
(5 mol%) and CuI (10 mol%) for 4 h.16 Formation of the
expected resin-bound 2-alkynylnitrobenzene 5a was corroborated
by FTIR and gel-phase 13C NMR.
Reduction of the nitro group was then carried out in the pres-
ence of tin(II) chloride dihydrate. The best results were obtained
by treating resin 5a with 10 equivalents of SnCl2·2H2O in
DMF17 to give the desired 2-alkynylaniline derivative tethered to
Wang resin (6a). After 10 min at 153 °C, formation of 6a was
As part of our research program concerning the application of
organometallic chemistry to the solid-phase synthesis of biologi-
cally relevant compounds,6 herein we report the first example of
gold catalysis in solid-phase organic chemistry in which the sub-
strate is immobilized.7 This methodology is illustrated by its
application to the synthesis of 2-substituted indoles.
Instituto de Química Rosario (CONICET – UNR), Facultad de Ciencias
Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario,
Suipacha 531, 2000 – Rosario, Argentina. E-mail: mischne@
iquir-conicet.gov.ar, mata@iquir-conicet.gov.ar; Fax: +54-341-
4370477; Tel: +54-341-4370477
†Electronic supplementary information (ESI) available: Detailed exper-
1
imental procedures, spectroscopic data, H NMR and 13C NMR spectra.
Scheme 1 Synthesis of the immobilized 2-alkynylaniline derivative
6a.
See DOI: 10.1039/c2ob06881h
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Table 1 Au-catalyzed heteroannulation of immobilized 2-alkynyl-
aniline 6a
Entry
Catalyst
Time (h)
Solvent
Yield (%)a,b
1
2
3
4
5
6
7
8
9
10
AuCl (5 mol%)
AuCl (5 mol%)
AuCl (5 mol%)
AuCl (10 mol%)
AuCl (10 mol%)
AuCl (5 mol%)
AuCl (5 mol%)
AuCl (10 mol%)
AuCl3 (10 mol%)
AuClPPh3 (10 mol%)
4
20
20
4
18
2
4
4
4
4
DCM
DCM
THF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
—
—
—
—
3 (10)
20 (65)c
34 (94)c
35 (95)c
20 (65)c
Scheme 2 Synthesis of immobilized indole 7a by Au-catalyzed
cyclization.
c
—
a Overall isolated yield of indole 8a, after flash column chromatography
(based on the initial loading level of Wang resin (1), five reaction steps).
b Data in brackets are yields for the gold-catalyzed cyclization step,
calculated from the ratio between the overall yield of indole 8a and the
overall yield of the immobilized 2-alkynylaniline 6a, after releasing
from resin and methylation. c Starting resin 6a was thoroughly washed
with THF before the cyclization step.
evident from the presence of two bands at 3482 cm−1 and
3381 cm−1 in the FTIR spectrum, corresponding to the N–H
unsymmetrical and symmetrical stretching. The yield of the
sequence until this step was determined to be 40% by cleaving
an aliquot of 6a with 10% TFA in DCM and subsequent methyl-
ation with diazomethane.
With the immobilized precursor 6a in hand, the catalytic
activity of gold salts was evaluated (Scheme 2). We initiated our
study by testing gold(I) catalysis, since AuCl3 could be more
oxophilic and lead to premature cleavage from the resin.18
First we carried out the reaction of resin 6a with 5 mol% of
AuCl in dichloromethane for 4 h at room temperature (entry 1,
Table 1). Under these conditions, formation of the desired resin-
bound indole 7a was not spectroscopically detected. After
testing different conditions (entries 2–5), only when 10 mol% of
AuCl in dichloromethane for 18 h was used, did we detect a
peak by gel-phase 13C NMR at 99.9 ppm, corresponding to the
C-3 indole atom, corroborating the presence of product 7a. Final
treatment of resin 7a with 10% TFA in DCM and subsequent
methylation with diazomethane afforded the resin-free indole 8a,
albeit in low overall isolated yield (3%, based on the initial
loading level of Wang resin) (entry 5). This result represents
only 10% yield for the gold-catalyzed step.19 Although we had
proved the feasibility of the gold catalysis on solid-supported
substrates, the modest yield obtained prompted us to analyze all
the aspects related to the synthetic sequence.
Scheme 3 Sequence for a gold(I)-catalyzed generation of 2-substituted
indoles.
AuClPPh3 catalysis was unable to promote the cyclization
(entry 10).
Then, we decided to reconsider the nitro group reduction step.
Although SnCl2·2H2O reduction of nitro groups is one of the
most reliable methods in solid-phase chemistry, we were worried
about some reports showing that a considerable amount of tin
by-products can be retained by the polymer matrix.20 Since these
by-products could interfere with gold(I) catalysis, we thoroughly
washed resin 6a with THF before the cyclization step. To our
delight, this simple experimental adjustment led to a significant
improvement in the efficiency of the sequence (20% overall iso-
lated yield) (entry 6). The highest yield was obtained when resin
5a was treated with either 5 mol% or 10 mol% of AuCl in
dichoromethane for 4 h (entries 7 and 8). After releasing into
solution with 10% TFA–DCM followed by esterification with
diazomethane, the crude product was purified by flash chromato-
graphy to furnish the indole 8a in 34–35% overall isolated yield
for the five steps (based on the manufacturer’s loading of the
Wang resin) and 94–95% yield for the gold(I)-catalyzed hetero-
annulation step.
With the optimal conditions in hand, we further explored the
potential of the gold(I)-catalyzed heteroannulation by testing
different immobilized 2-alkynylanilines. With this purpose in
mind, a series of alkynes were coupled to the resin-bound o-bro-
monitrobenzene derivative 3 (Scheme 3).
After Sonogashira coupling and reduction, the corresponding
resin-bound 2-alkynylanilines (6b–f) were obtained in yields
ranged from 14 to 60%, for the overall synthetic sequence.22 As
before, the reduction was the less efficient step. Gold-catalyzed
cyclization was then performed under the optimized conditions
(5 mol% AuCl in DCM, 4 h). The results are summarized in
Table 2.‡ Examination of the scope of the alkyne substituents
revealed that aromatic moieties give excellent yields for the Au-
catalyzed heteroannulation step (entries 1–3, data in brackets). In
the case of supported 2-alkynylanilines bearing non-aromatic
alkyne substituents (entries 4–6, data in brackets), gold catalysis
was less efficient.
Being a classical gold-catalyzed activation of an alkyne, the
Interestingly, the use of AuCl3 provided the indole 8a,
reaction mechanism23 can be rationalized by the nucleophilic
although in lower overall yield (20%) (entry 9).21 Conversely,
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Table 2 Solid-phase synthesis of 2-substituted indoles based on gold(I)
Promoción Científica y Tecnológica, Fundación Prats, and Uni-
versidad Nacional de Rosario from Argentina, is gratefully
acknowledged. AL thanks CONICET for fellowships.
catalysisa
Entry
1
Product
R
Yield (%)b,c
34 (94)
8a
Notes and references
2
3
8b
8c
14 (93)
13 (93)
‡Representative procedure for the Au-catalyzed hetero-annulation of
immobilized 2-alkynylanilines: Support-bound 2-alkynylaniline (6a)
(210 mg, 0.95 mmol g−1, 0.20 mmol) in a 20 mL polypropylene fil-
tration tube with polyethylene frit was suspended in anhydrous dichloro-
methane (3 mL), AuCl (2.5 mg, 0.01 mmol, ca. 5 mol%) was added
under a nitrogen atmosphere, and the mixture was shaken at room temp-
erature for 4 h. After that, the resin was filtered, washed with THF (3 ×
3 mL), MeOH (3 × 3 mL), CH2Cl2 (4 × 3 mL), and dried under high
vacuum. For releasing the product from the solid phase, the resin was
treated with 5 mL of 10% TFA in CH2Cl2 for 1 h. The mixture was
filtered and the filtrate was evaporated under reduced pressure. This
crude material was dissolved in CH2Cl2 (3 mL) and treated with diazo-
methane at 0 °C until yellowish coloration was achieved. After 30 min,
diazomethane was quenched by AcOH, solvent was evaporated under
reduced pressure, and the residue was purified by column chromato-
graphy to afford the indole 8a (17.5 mg, 35% overall yield from Wang
resin).
4
5
6
8d
8e
8f
–(CH2)2CH3
–(CH2)4CH3
–(CH2)3Cl
5 (14)
22 (45)
15 (25)
a Conditions: 5 mol% of AuCl in dichoromethane for 4 h, at room
temperature. b Overall isolated yield of indole 8, after flash column
chromatography (based on the initial loading level of Wang resin (1),
five reaction steps). c Data in brackets are yields for the gold-catalyzed
cyclization step, calculated from the ratio between the overall yield of
indole 8 and the overall yield of the immobilized 2-alkynylaniline 6,
after releasing from resin and methylation.
1 For recent reviews, see: (a) A. S. K. Hashmi and G. J. Hutchings, Angew.
Chem., Int. Ed., 2006, 45, 7896; (b) A. Fürstner and P. W. Davies, Angew.
Chem., Int. Ed., 2007, 46, 3410; (c) A. S. K. Hashmi, Chem. Rev., 2007,
107, 3180; (d) E. Jiménez-Núñez and A. M. Echavarren, Chem. Rev.,
2008, 108, 3326; (e) Z. Li, C. Brouwer and C. He, Chem. Rev., 2008,
108, 3239; (f) D. J. Gorin, B. D. Sherry and F. D. Toste, Chem. Rev.,
2008, 108, 3351; (g) A. S. K. Hashmi and M. Rudolph, Chem. Soc. Rev.,
2008, 37, 1766; (h) H. C. Shen, Tetrahedron, 2008, 64, 3885; (i) H.
C. Shen, Tetrahedron, 2008, 64, 7847; ( j) A. Fürstner, Chem. Soc. Rev.,
2009, 38, 3208; (k) A. Das, S. M. A. Sohel and R.-S. Liu, Org. Biomol.
Chem., 2010, 8, 960; (l) M. Rudolph and A. S. K. Hashmi, Chem. Soc.
Rev., 2012, DOI: 10.1039/c1cs15279c.
2 N. Bongers and N. Krause, Angew. Chem., Int. Ed., 2008, 47, 2178.
3 S. A. Testero and E. G. Mata, J. Comb. Chem., 2008, 10, 487.
4 D. D. Young and A. Deiters, Angew. Chem., Int. Ed., 2007, 46, 5187.
5 A. A. Poeylaut-Palena and E. G. Mata, Org. Biomol. Chem., 2010, 8,
3947.
6 (a) S. A. Testero and E. G. Mata, Org. Lett., 2006, 8, 4783;
(b) A. A. Poeylaut-Palena and E. G. Mata, J. Comb. Chem., 2009, 11,
791.
Scheme 4 Proposed reaction mechanism
attack of the amino group to the π-coordinated alkyne in a 5-
endo-dig manner, to lead to the vinyl–Au intermediate (10)
(Scheme 4).24 Finally, this intermediate undergoes a proto-deme-
tallation to afford the indole 7.
7 For the application of an immobilized gold catalyst in synthesis, see:
Y. Miyazaki and S. Kobayashi, J. Comb. Chem., 2008, 10, 355.
8 C. Gil and S. Bräse, J. Comb. Chem., 2009, 11, 175.
9 D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103,
893.
Conclusion
10 There are several examples of annulation of supported alkynyl anilines
using palladium catalyst: (a) M. C. Fagnola, I. Candiani, G. Visentin,
W. Cabri, F. Zarini, N. Mongelli and A. Bedeschi, Tetrahedron Lett.,
1997, 38, 2307; (b) H.-C. Zhang, K. K. Brumfield and B. E. Maryanoff,
Tetrahedron Lett., 1997, 38, 2439; (c) M. D. Collini and J. W. Ellingboe,
Tetrahedron Lett., 1997, 38, 7963.
11 A. Arcadi, G. Bianchi and F. Marinelli, Synthesis, 2004, 610.
12 M. Alfonsi, A. Arcadi, M. Aschi, G. Bianchi and F. Marinelli, J. Org.
Chem., 2005, 70, 2265.
In summary, we report the first solid-phase example of a gold-
catalyzed reaction in which the substrate is supported. The reac-
tion conditions developed above were found to be applicable to
the preparation of a small library of 2-substituted indoles. In our
hands, AuCl was more efficient than its Au(III) counterpart for
the heteroannulation step. Under the optimized conditions, AuCl
catalyzed the formation of the indoles in high yield, particularly
for aromatically substituted alkynes. The present work provides
a proof of concept of the combination of gold catalysis and
solid-supported chemistry, expanding the use of this kind of cat-
alyst. Further studies are in progress to extend our knowledge of
this combination and the results will be detailed in due course.
13 I. Nakamura, U. Yamagishi, D. Song, S. Konta and Y. Yamamoto, Angew.
Chem., Int. Ed., 2007, 46, 2284.
14 C. Praveen, S. Jegatheesan and P. T. Perumal, Synlett, 2009, 2795.
15 For reviews on the solid-phase synthesis of indoles, see: (a) J. Tois,
R. Franzén and A. Koskinen, Tetrahedron, 2003, 59, 5395;
(b) S. A. Patil, R. Patil and D. D. Miller, Curr. Med. Chem., 2009, 16,
2531; (c) Ref. 7.
16 86% yield, determined by cleaving an aliquot of the immobilized 2-alky-
nylnitrobenzene with 10% TFA in DCM and subsequent methylation
with diazomethane.
17 J. Portilla, J. Quiroga, R. Abonía, B. Insuasty, M. Nogueras, J. Cobo and
E. G. Mata, Synthesis, 2008, 387.
18 A. W. Sromek, M. Rubina and V. Gevorgyan, J. Am. Chem. Soc., 2005,
127, 10500.
Acknowledgements
Financial support from Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET), Agencia Nacional de
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19 Yield calculated from the ratio between the overall yield of indole 8a and
the overall yield obtained after releasing from resin and methylation of
the 2-alkynylaniline 6a.
20 R. A. Scheuerman and D. Tumelty, Tetrahedron Lett., 2000, 41, 6531.
21 An evaluation of the washing residues after AuCl3-catalyzed reaction
showed no evidence of premature cleavage of any material from the resin.
22 Determined by cleaving an aliquot of the immobilized 2-alkynylaniline
with 10% TFA in DCM and subsequent methylation with diazomethane.
23 For mechanistic studies, see: (a) A. S. K. Hashmi, J. P. Weyrauch,
W. Frey and J. W. Bats, Org. Lett., 2004, 6, 4391;
(b) J. J. Kennedy-Smith, S. T. Staben and F. D. Toste, J. Am. Chem. Soc.,
2004, 126, 4526; (c) A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49,
5232.
24 Isolation of a vinyl NHC-gold(I) complex related to intermediate 10 have
been recently reported, see: A. S. K. Hashmi, T. D. Ramamurthi and
F. Romingera, Adv. Synth. Catal., 2010, 352, 971.
This journal is © The Royal Society of Chemistry 2012
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