One-pot gold-catalyzed synthesis of 3-silylethynyl indoles from unprotected o-alkynylanilines

Article abstract of DOI:10.3762/bjoc.7.65

The Au(III)-catalyzed cyclization of 2-alkynylanilines was combined in a one-pot procedure with the Au(I)-catalyzed C3-selective direct alkynylation of indoles using the benziodoxolone reagent TIPS-EBX to give a mild, easy and straightforward entry to 2-substituted-3-alkynylindoles. The reaction can be applied to unprotected anilines, was tolerant to functional groups and easy to carry out (RT, and requires neither an inert atmosphere nor special solvents).

Full text of DOI:10.3762/bjoc.7.65

One-pot gold-catalyzed synthesis of 3-silylethynyl
indoles from unprotected o-alkynylanilines
Jonathan P. Brand, Clara Chevalley and Jérôme Waser*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 565–569.
Laboratory of Catalysis and Organic Synthesis, Ecole Polytechnique
Fédérale de Lausanne, EPFL SB ISIC LCSO, BCH4306, 1015
Lausanne, Switzerland
doi:10.3762/bjoc.7.65
Received: 17 February 2011
Accepted: 09 March 2011
Published: 04 May 2011
Email:
Jonathan P. Brand - jonathan.brand@epfl.ch; Jérôme Waser* -
jerome.waser@epfl.ch
This article is part of the Thematic Series "Gold catalysis for organic
synthesis".
* Corresponding author
Guest Editor: F. D. Toste
Keywords:
alkynylation; direct functionalization; gold; hypervalent iodine; indoles
© 2011 Brand et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The Au(III)-catalyzed cyclization of 2-alkynylanilines was combined in a one-pot procedure with the Au(I)-catalyzed C3-selective
direct alkynylation of indoles using the benziodoxolone reagent TIPS-EBX to give a mild, easy and straightforward entry to
2-substituted-3-alkynylindoles. The reaction can be applied to unprotected anilines, was tolerant to functional groups and easy to
carry out (RT, and requires neither an inert atmosphere nor special solvents).
Introduction
Indoles are widespread in both natural products and synthetic the importance of multi-functionalized indoles, it is therefore
drugs [1,2] and as a result, their synthesis and functionalization not surprising that the aniline cyclization–electrophilic substitu-
have been extensively studied [3,4]. Among the numerous tion sequence has been achieved by means of several metal-
syntheses of indoles, the cyclization of 2-alkynylanilines has the catalyzed domino processes (Scheme 1) [8-10].
advantage that the resulting products, 2-substituted indoles, are
easily functionalized by electrophilic aromatic substitution at
position 3. Traditionally, this transformation has been achieved
in two separate steps, with isolation and purification of the
3-unsubstituted indole intermediate. Domino or one-pot
processes constitute a more efficient access to organic mole-
Scheme 1: Domino cyclization–substitution reactions of 2-alkynyl-
anilines.
cules, as they avoid the use of time and resource consuming
work-up, and purification procedures [5-7]. When considering
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Beilstein J. Org. Chem. 2011, 7, 565–569.
Among the different π-activating metals capable of promoting Recently, the direct alkynylation of preformed heterocycles has
nucleophilic attack on acetylenes, gold has recently attracted been intensively investigated [30-34]. Most of the developed
interest from the synthetic chemistry community [11-14]. Gold methods involve the use of haloacetylenes. In contrast, our
catalysts have also been used in domino sequences starting from group has focused on the use of more reactive alkynyl hyperva-
o-alkynylanilines. Arcadi and Marinelli reported that gold- lent iodine reagents in order to expand the scope of direct
catalyzed cyclization of 2-alkynylanilines can be followed by alkynylation methods under milder conditions. We recently
1,4-addition to enones [15,16], iodination [17] or reaction with reported a mild procedure for the C3-selective alkynylation of
1,3-dicarbonyl compounds [18]. Perumal recently demon- indoles using AuCl and the commercially available benziodox-
strated that aldehydes and nitroalkenes can be used as electro- olone TIPS-EBX (1-[(triisopropylsilyl)ethynyl]-1,2-benzio-
philic partners [19,20]. Triple bonds can also serve as a second doxol-3(1H)-one (1)) (Scheme 2) [35-40]. This methodology
electrophile for the construction of tetrahydrofurans [21] and allowed the ethynylation of a wide range of indoles, including
aryl-annulated[a]carbazoles [22]. Nakamura examined the 2-substituted indoles.
cyclization of N-tosyl-o-alkynylanilines and observed an
internal transfer of the sulfonyl group to the 3-position of the In this letter we would like to report the one-pot combination of
formed indoles [23,24]. Similar transformations were also the cyclization of 2-alkynylanilines using NaAuCl4 as catalyst
achieved for the transfer of carbonyl groups, but using platinum [15] followed by C3-alkynylation with AuCl and TIPS-EBX (1)
catalysts [25-28].
(Scheme 3). This method offers an operationally simple access
to 3-silylalkynyl indoles. To the best of our knowledge, this is
To date, there are no gold- or platinum-catalyzed methods for the first example of a one-pot process combining a Au(III) and
the introduction of acetylenes as electrophiles. However, Cacchi a Au(I) catalyst.
developed a palladium-catalyzed domino sequence including
cyclization of o-alkynyltrifluoroacetanilides and alkynylation Findings
with bromoacetylenes [29]. New methods are needed to expand 2-Alkynylanilines 2 can be efficiently prepared from 2-iodoani-
the scope of this transformation and Au catalysis appears espe- lines 4 and terminal alkynes via Sonogashira reaction with Et3N
cially promising, due to its broad functional groups tolerance, as solvent (Scheme 4) [41,42]. The reaction was complete in
which could allow the direct use of unprotected anilines.
less than 2 h and did not require aniline protection, solvent
degassing or drying.
Scheme 4: Synthesis of 2-alkynylanilines 2.
Our first investigations were focused on the cyclization of
2-(phenylethynyl)aniline (2a) into 2-phenylindole (5) with
AuCl as the catalyst at room temperature (Scheme 5, step 1).
Since AuCl has been shown to be the best catalyst for the
alkynylation reaction [35], its use would allow a domino
process with a single catalyst.
Scheme 2: Gold-catalyzed direct alkynylation of indoles with TIPS-
EBX (1).
Despite the fact that the use of AuCl has been reported for step
1 [19,20], in our hands the reaction was not reproducible at
room temperature in a variety of solvents (EtOH, CH3CN,
Et2O). A black precipitate was observed after catalyst addition,
which we postulate was due to the stochastically degradation of
AuCl under these conditions. NaAuCl4 has also been reported
to be successful for the cyclization of 2-(phenylethynyl)aniline
Scheme 3: One-pot alkynylaniline cyclization/direct alkynylation.
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Beilstein J. Org. Chem. 2011, 7, 565–569.
Scheme 5: Domino cyclization–alkynylation of aniline 2a.
(2a) [15]. This catalyst was next examined in different solvents the 2-trimethylsilylacetylene substituted compound 3i was
in order to maximize the chance of finding conditions suitable attempted. Unfortunately, only traces of the indole intermediate
for both steps of the process. Aniline 2a was fully converted were observed in this case. The reaction with 2-ethynylaniline
into 2-phenylindole (5) in EtOH, iPrOH and Et2O after 3 h at to give (3j) was also unsuccessful as previously reported [16].
room temperature using 2 mol % of NaAuCl4 and there was no
problem of reproducibility. Unfortunately, NaAuCl4 was not an These first results on the direct alkynylation reaction combined
efficient catalyst for the direct alkynylation of indole, as no in a one-pot procedure with gold-catalyzed indole ring forma-
reaction was observed when TIPS-EBX (1) was added to the tion are promising, and analogous strategies combining palla-
reaction mixture.
dium-catalyzed synthesis of indoles [3] and gold-catalyzed
alkynylation could also be envisaged. The next step will be to
We then investigated the successive addition of NaAuCl4 and attempt a one-pot 3-steps synthesis of alkynyl indoles starting
AuCl in the same pot. Interestingly, one-pot sequential directly from iodoaniline.
processes using both Au(I) and Au(III) have not yet been
reported. AuCl and TIPS-EBX (1) were added when full In conclusion, an efficient access to 2-substituted 3-silylalkynyl
conversion of the NaAuCl4-catalyzed cyclization was observed. indoles is reported. 2-Alkynylanilines underwent a sequential
When 2 mol % of NaAuCl4 and 2 mol % AuCl were added, the one-pot Au(III)-catalyzed annulation and Au(I)-mediated direct
second step was unsuccessful. However, with 2 mol % of alkynylation. Importantly, this transformation did not require
NaAuCl4 and 4 mol % of AuCl, full conversion was observed prior aniline protection and proceeded under mild conditions.
after 30 h at room temperature in iPrOH (compared with 60% in This methodology represents the first example of the sequential
EtOH and 40% in Et2O). A basic work-up allowed the removal addition of Au(III) and Au(I) catalysts for a one-pot process.
of the 2-iodobenzoic acid and column chromatography afforded
Experimental
the product in 96% yield (average of two reactions). Unfortu-
General procedure for the synthesis of
nately, no reaction was observed when AuCl and TIPS-EBX (1)
were added at the beginning of the reaction.
2-alkynylanilines 2
A solution of 2-iodoaniline (4) (1 equiv), terminal alkyne
(1.2–1.3 equiv), PdCl2(PPh3)2 (10 mol %) and CuI (10 mol %)
was heated under reflux in Et3N (15 mL) for 1.5–2 h under a
nitrogen atmosphere. The resulting mixture was filtered through
Celite®, washed with DCM and concentrated under vacuum.
The resulting solid was purified by column chromatography.
The scope of the reaction was then investigated (Scheme 6).
Methyl- and fluoro groups were tolerated on the 2-aryl
substituent to give products 3b and 3c in good yields. The low
solubility of the indole intermediate in the synthesis of 3d led to
a low yield for the direct alkynylation step. The addition of
CH2Cl2 overcame this problem. Chloro substitution in para-
position of the aniline was also tolerated (3e, 3f). Nevertheless,
General procedure for the synthesis of
when the strongly electron-withdrawing cyano group was 2-substituted 3-alkynyl indoles 3
present, the cyclization step was too slow at room temperature. NaAuCl4 (2–4 mol %) was added to a stirred solution of
However, the use of 4 mol % of NaAuCl4 and a reaction 2-alkynylaniline 2 (0.40 mmol, 1 equiv) in iPrOH (3 mL) under
temperature of 80 °C led to the formation of the desired indole, an ambient atmosphere. The reaction was stirred at RT (80 °C
which could then be alkynylated at room temperature to give for 3g) until full conversion (3 h). TIPS-EBX (1) (1.2–2.4
3g. o-Hexynyl aniline (2h) was efficiently transformed into 3h equiv) and then AuCl (4–8 mol %) were added. The reaction
in 85% yield. In order to access 2-silyl indoles, the synthesis of was stirred until full conversion (4–30 h) and then concentrated
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Beilstein J. Org. Chem. 2011, 7, 565–569.
Scheme 6: Scope of the reaction.
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