further by developing an intermolecular carbon-carbon
bond-forming process, which, to the best of our knowledge,
is unprecedented. Consequently, we report herein the first
direct and regioselective synthesis of ꢀ-heteroarylated ketones
from propargyl alcohols through a ruthenium/indium-
catalyzed tandem redox isomerization/conjugate addition
(RICA) sequence.
Scheme 1. Proposed Working Model for the Tandem Redox
Isomerization/Conjugate Addition (RICA) Reactiona
In initial experiments hex-3-yne-2-ol (2a) was exposed to
ruthenium complex 1 (2.5 mol %),11 indium triflate, and
R-camphorsulfonic acid (CSA) (each 5 mol %) for 2 h at
64 °C in THF followed by the addition of 2-methylfuran
(3a, 2.0 equiv) at room temperature (Table 1). After 16 h,
adduct 4a was isolated in a reasonable yield of 43% (entry
1). The amount of furan 3a could be lowered from 2.0 to
1.3 equiv, if the reaction was conducted at 64 °C, which
furnished the corresponding ketone 4a in a significantly
improved yield of 86% (entry 2).12 These results merit
additional comment, since reports on the Lewis or Brønsted
acid catalyzed Friedel-Crafts alkylation of furans employing
unactivated enones as electrophiles are rather scarce.13 In a
number of cases the employment of comparatively large
excesses (4-5 equiv) of nucleophiles were reported to be
operational.13a,b In that regard our method proved superior,
as only 1.3 equiv of the furan derivatives were necessary to
obtain conjugate addition products in high yields.
a MLn ) In(OTf)3 or [IndRu(PPh3)2]+, Ind ) indenide, het-Ar )
heteroarene.
provides considerable advantages over traditional multistep
approaches, in particular with respect to the principles of
atom economy and minimal generation of hazardous waste.7
The inherent atom-economic nature manifests itself in the
fact that formation of propargyl alcohols of type 2, which
become the electrophiles for the Friedel-Crafts reaction, just
involves the simple addition of terminal alkynes into alde-
hydes. Consequently, ꢀ-heteroaryl ketones 4 are rapidly
derived from an addition sequence of three components:
terminal alkynes, aldehydes, and heteroarenes. Simulta-
neously, this feature provides a profound advantage over
common procedures for the synthesis of R,ꢀ-unsaturated
carbonyl compounds, which generally rely on rather wasteful
olefination chemistry involving phosphorus ylides.8
With a basic set of conditions in hand, investigations
continued with exploring the scope of this method. Thus,
various electron-rich, -neutral, and -deficient heteroarenes
were tested (Table 1). While the electron-rich 2,3-dimeth-
ylfuran (3b) gave access to ketone 4b in an excellent yield
of 97%,11 the use of its electron-deficient analog, methyl
2-methylfurancarboxylate (3c), resulted merely in the forma-
tion of hex-3-en-2-one and unreacted furan 3c (entry 4).
Thus, under these operating conditions, simple enones are
not activated sufficiently by the catalyst system to promote
Friedel-Crafts/conjugate addition reactions with electron-
poor furans.
In the course of the reaction sequence, propargyl alcohols
of type 2 are first chemoselectively isomerized to the desired
electrophiles (Scheme 1, Cycle I). Subsequently, the latter
undergo conjugate additions facilitated presumably by the
same catalysts involved in the preceding step to give adducts
4 (Cycle II).9 In previous work we demonstrated that oxygen-
and nitrogen-based nucleophiles can undergo intramolecular
conjugate addition reactions into R,ꢀ-unsaturated carbonyl
compounds derived from propargyl alcohols through redox
isomerization. The transiently formed Michael acceptors were
shown to provide the corresponding oxa- and azacycles in
good to excellent yields.10 Driven by the high potential of
these tandem reactions, we wanted to advance this method
We next focused on the employment of nitrogen-contain-
ing heteroarenes, such as indole derivatives. In general, the
addition products were isolated in good to excellent yields
ranging from 73% to 91% even with only 1.1 equiv of the
indole nucleophiles (entries 5, 6, 9-11). The substrate
2-phenylindole (3f) furnished ketone 4f in only 53% yield,
presumably due to steric and electronic factors (entry 7). This
hypothesis was supported by the observation that replacement
of the phenyl ring for the smaller methyl group (entry 6, 3e)
(10) (a) Trost, B. M.; Maulide, N.; Livingston, R. C. J. Am. Chem. Soc.
2008, 130, 16502–16503. (b) Trost, B. M.; Gutierrez, A. C.; Livingston,
R. C. Org. Lett. 2009, 11, 2539–2542.
(11) In the course of experiments 5 mol % of ruthenium catalyst 1 were
found to provide the most reliable results for the RICA reactions.
(12) Due to the high volatility of adducts 4a and 4b the yields were
determined by 1H NMR using 4-methoxyacetophenone as an internal
standard.
(7) Trost, B. M. Science 1991, 254, 1471–1477. (b) Anastas, P. T.;
Warner, J. C. Green Chemistry: Theory and Practice; Oxford University
Press: New York, 1998.
(8) (a) Gosney, I.; Rowley, A. G. Org. Synth. 1979, 1, 5–153. Maryanoff,
B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863.
(13) (a) For an example of an asymmetric addition, see: Adachi, S.;
Tanaka, F.; Watanabe, K.; Harada, T. Org. Lett. 2009, 11, 5206–5209. For
nonasymmetric examples, see: (b) Soriente, A.; Arienzo, R.; De Rosa,
M.; Palombi, L.; Spinella, A.; Scettri, A. Green Chem. 1999, 1, 157–162.
(c) Poirier, J.-M.; Dujardin, G. Heterocycles 1987, 25, 399–407. In these
reported experiments 2-methylfuran was used in large excess (4-5
equiv).
(9) When hex-3-en-2-one, derived from alcohol 2a, was separately
reacted with indole 3h in the presence of either Ru-catalyst 1, In(OTf)3, or
CSA, both the In- and the CSA-catalyst provided adduct 4h in similar yields
and reaction time when compared to the mixture of catalysts. Ru-complex
1, however, did not provide any of adduct 4h.
Org. Lett., Vol. 13, No. 3, 2011
399
Trost, Barry M.
