A gold-catalyzed cascade reaction involving an unusual intramolecular redox process

Article abstract of DOI:10.1002/chem.200901557

A study was conducted to demonstrate a new gold-catalyzed cascade reaction involving a a redox process. The reactivity of secondary 5-hexyn-1-ol derivatives and indoles were investigated under gold-catalyzed conditions to demonstrate the cascade reaction.

Full text of DOI:10.1002/chem.200901557

COMMUNICATION
DOI: 10.1002/chem.200901557
A Gold-Catalyzed Cascade Reaction Involving an Unusual Intramolecular
Redox Process
Josꢀ Barluenga,* Amadeo Fernꢁndez, Fꢀlix Rodrꢂguez, and Francisco J. FaÇanꢁs[a]
Those reactions where a single catalyst promotes two or
more mechanistically distinct processes are a particular case
of concurrent tandem catalysis.[1] These reactions circumvent
the often time-intensive, waste- and costs-increasing and
yield-reducing isolation and purification of intermediates in
stepwise processes.[2] On the other hand, the application of
gold complexes as catalysts for organic transformations has
become very common over the past decade.[3] The increasing
interest in this research field is probably due to the ability
of gold complexes to promote unusual processes. For exam-
ple, some elegant new gold-catalyzed reactions involving
atypical intramolecular redox processes have been recently
Herein we report a new gold-catalyzed cascade reaction
involving a redox process conceptually different from those
mentioned above. Thus, in our case the global reaction sup-
À
poses the oxidation of the X O moiety and the reduction of
the triple bond (Scheme 1, Equation (b)).
We and others became interested in gold-catalyzed reac-
tions involving indoles.[5] In this context, we decided to in-
vestigate the reactivity of secondary 5-hexyn-1-ol derivatives
and indoles under gold-catalyzed conditions. Accordingly,
we initiated our study with the reaction of secondary alky-
nol derivative 1a and N-methylindole 2a in the presence of
a cationic gold(I) complex, generated in situ by the reaction
of 5 mol% of [(Ph3P)AuCl] and 5 mol% of AgSbF6, in di-
chloromethane as solvent at room temperature. Surprisingly,
this reaction led to the formation of the ketone derivative
3a in 84% yield (Table 1, entry 1). Notably, the formation
of ketone 3a is an atypical transformation that formally sup-
published.[4] Interestingly, in all these reactions the X O
À
À
moiety is reduced and the carbon carbon triple bond is oxi-
dized (Scheme 1, Equation (a)).
À
poses the addition of the indole to the carbon carbon triple
bond followed by an unusual intramolecular redox process
in which the alcohol is oxidized to a ketone and the initially
À
formed carbon carbon double bond is reduced to its satu-
Table 1. Ketones 3 from alkynols 1 and indoles 2.
Scheme 1. Gold-catalyzed reactions involving intramolecular redox pro-
cesses.
Entry
1
R1
R2
2
R3
3
Yield
[%][a]
1
2
3
4
5
6
7
8
1a
1b
1b
1b
1c
1d
1e
1f
Me
Et
Et
Et
nBu
iPr
3-butenyl
Et
nPr
Et
H
H
H
H
H
H
H
D
2a
2a
2b
2c
2a
2a
2a
2a
2a
2a
H
H
OMe
I
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
84
91
95
92
87
89
89
79
93
84
[a] Prof. Dr. J. Barluenga, A. Fernꢀndez, Dr. F. Rodrꢁguez,
Dr. F. J. FaÇanꢀs
Instituto Universitario de Quꢁmica Organometꢀlica “Enrique Moles”
Unidad Asociada al CSIC, Universidad de Oviedo
Juliꢀn Claverꢁa 8, 33006 Oviedo (Spain)
Fax : (+34)985103450
9
10
1g
1h
Me
4-MeOC6H4
E-mail: barluenga@uniovi.es
H
3j
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901557.
[a] Yield of isolated product based on starting alkynol 1.
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rated form. To establish whether this reaction was generally
applicable for secondary alkynol derivatives, we extended
the scope of the reaction by using a range of alkynol deriva-
tives 1 and indoles 2 (Table 1). As shown, in all cases we ob-
tained the corresponding ketones 3 in high yield.[6]
To gain some insight about the mechanism of the reaction
we performed labeling studies with deuterated starting ma-
terials (Scheme 2). Thus, the reaction of the deuterated
Scheme 2. Labeling experiments.
alkyne [D]-1b and indole 2a with 5 mol% of [(Ph3P)AuCl]
and 5 mol% of AgSbF6, in dichloromethane as solvent at
room temperature for 4 h cleanly afforded the deuterated
compound [D]-3b in 82% yield (>90% deuterium incorpo-
rated). Interestingly, when we performed the same reaction
with 5 mol% of PtCl2 in THF under the conditions reported
by Cheng and co-workers,[7] we obtained the deuterated
pyran derivative [D]-4b in 79% yield. Compound [D]-4b
was isolated and characterized and then allowed to react
with 5 mol% of [(Ph3P)AuCl] and 5 mol% of AgSbF6, in di-
chloromethane as solvent at room temperature to afford
[D]-3b in 91% yield (>90% deuterium incorporated).
These experiments demonstrate that tetrahydropyranylin-
dole derivatives analogous to [D]-4b are intermediates of
the reaction.
Scheme 3. Proposed mechanism for the formation of ketones 3 from al-
kynols 1 and inloles 2.
uer-type oxidation mechanism to give the final products 3,
regenerating the gold catalytic species. The global process
involves the cooperative action of three catalytic cycles with
the same catalyst facilitating each cycle.
Finally, to further expand the synthetic utility of the reac-
tion, we performed a set of experiments with other heteroar-
omatic compounds. Thus, as shown in Scheme 4, the reac-
All studies support the mechanism outlined in Scheme 3
for the formation of compounds 3.
As a first step, we suppose the formation of a reactive cat-
ionic gold complex from [(Ph3P)AuCl] by reaction with
AgSbF6. Coordination of this gold complex to the triple
bond of the starting alkynol 1 forms the intermediate 5. In-
tramolecular addition of the hydroxyl group to the internal
carbon of the triple bond generates 6. Protodemetallation of
the latter affords the exo-cyclic enol ether 7 and regenerates
the catalytic species.[8] Further coordination of the catalyst
to the double bond of the enol ether 7 leads to the oxonium
intermediate 8 and favors the nucleophilic attack of the
indole 2 to afford the intermediate 9 that evolves through
aromatization and protodemetallation to give the tetrahy-
dropyranylindole derivative 4 and the gold catalytic species.
Coordination of the gold complex to the oxygen of 4 favors
the opening of the pyran ring to form the intermediate 10.
We propose that this intermediate 10 evolves by a formal
1,5-hydride migration through an intramolecular Oppena-
Scheme 4. Reaction of alkynol 1b with heteroaromatic compounds 11 to
give ketones 12.
tion of alkynol 1b with compounds 11 in the presence of
5 mol% of [(Ph3P)AuCl] and 5 mol% of AgSbF6 in di-
chloromethane at room temperature cleanly afforded the
expected ketone 12 in high yield.
In conclusion, a new gold-catalyzed cascade reaction of
secondary 5-hexyn-1-ol derivatives and heteroaromatic com-
pounds has been developed. The process affords 5-heteroar-
yl-substituted ketone derivatives in an efficient and very
simple way. This new catalytic reaction involves and initial
intramolecular hydroalkoxylation reaction followed by an
intermolecular hydroarylation process and finally an unusual
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Gold-Catalyzed Cascade Reaction
COMMUNICATION
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Acknowledgements
We gratefully acknowledge financial support from the MICINN
(CTQ2007-61048/BQU) and PRINCAST (IB08-088).
Keywords: cascade reactions · coupling reaction · gold ·
homogeneous catalysis · redox chemistry
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Received: June 8, 2009
Published online: July 14, 2009
Chem. Eur. J. 2009, 15, 8121 – 8123
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8123