A new entry in catalytic alkynylation of aldehydes and ketones: Dual activation of soft nucleophiles and hard electrophiles by an indium(III) catalyst

Article abstract of DOI:10.1021/ol050069h

(Chemical Equation Presented). A new entry in catalytic alkynylation of carbonyl compounds was developed in which dual activation of both soft nucleophiles (terminal alkynes) and hard electrophiles (aldehydes and ketones) is achieved using an indium(III)

Full text of DOI:10.1021/ol050069h

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1363-1366
A New Entry in Catalytic Alkynylation of
Aldehydes and Ketones: Dual
Activation of Soft Nucleophiles and
Hard Electrophiles by an Indium(III)
Catalyst
Ryo Takita, Yuhei Fukuta, Riichiro Tsuji, Takashi Ohshima,* and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
ohshima@mol.f.u-tokyo.ac.jp; mshibasa@mol.f.u-tokyo.ac.jp
Received January 13, 2005
ABSTRACT
A new entry in catalytic alkynylation of carbonyl compounds was developed in which dual activation of both soft nucleophiles (terminal
alkynes) and hard electrophiles (aldehydes and ketones) is achieved using an indium(III) catalyst. Preliminary mechanistic studies using in
situ IR and NMR spectroscopic analysis are also discussed.
The addition of terminal alkynes to aldehydes and ketones,
especially in an enantioselective manner, is of great interest
because of the versatility of the corresponding propargylic
alcohols.1 Stoichiometric amounts of strong bases such as
organolithium, organomagnesium, or dialkylzinc2 reagents
are widely used for this type of reaction with or without chiral
ligands or chiral Lewis acid complexes. Intrinsic drawbacks,
however, such as the use of stoichiometric amounts of metal
reagents and a separate step for metal acetylide preparation
make it difficult to achieve an atom-economical process with
high total efficiency.
The in situ catalytic generation of metal nucleophiles and
their use in carbon-carbon bond-forming reactions such as
the direct-aldol reaction3,4 is currently a major interest in
organic synthesis. Thus, the development of an alkynylation
of carbonyl compounds using a catalytic amount of metal is
in high demand. Quite recently, Carreira and co-workers
developed an efficient method for in situ generation of zinc
acetylide from terminal alkynes and their addition to carbonyl
compounds using Zn(OTf)2 and an amine base5,6 via π-com-
plex formation.7 They successfully applied this chemistry
to catalytic enantioselective alkynylation of aliphatic alde-
hydes promoted by Zn(OTf)2 (20 mol %), N-methyl ephe-
(1) For a recent review, see: Cozzi, P. G.; Hilgraf, R.; Zimmermann,
N. Eur. J. Org. Chem. 2004, 4095.
(2) (a) For a review, see: Pu, L. Tetrahedron 2003, 59, 9873. See also
ref 1. For recent representative examples, see: (b) Gao, G.; Xie, R.-G.; Pu,
L. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5417. (c) Li, Z.-B.; Pu, L. Org.
Lett. 2004, 6, 1065. (d) Xu, Z.; Chen, C.; Xu, J.; Miao, M.; Yan, W.; Wang,
R. Org. Lett. 2004, 6, 1193. (e) Dahmen, S. Org. Lett. 2004, 6, 2113. (f)
Liu, L.; Pu, L. Tetrahedron 2004, 60, 7427. (g) Kang, Y.-F.; Liu, L.; Wang,
R.; Yan, W.-J.; Zhou, Y.-F. Tetrahedron: Asymmetry 2004, 15, 3155. For
examples of alkynylation of ketones, see: (h) Cozzi, P. G. Angew. Chem.,
Int. Ed. 2003, 42, 2895. (i) Lu, G.; Li, X.; Jia, X.; Chan, W. L.; Chan, A.
S. C. Angew. Chem., Int. Ed. 2003, 42, 5057. (j) Saito, B.; Katsuki, T.
Synlett 2004, 1557. (k) Cozzi, P. G.; Alesi, S. Chem. Commun. 2004, 2448.
(l) Zhou, Y.; Wang, R.; Xu, Z.; Yan, W.; Liu, L.; Kang, Y.; Han, Z. Org.
Lett. 2004, 6, 4147. (m) Liu, L.; Wang, R.; Kang, Y.-F.; Chen, C.; Xu,
Z.-Q.; Zhou, Y.-F.; Ni, M.; Cai, H.-Q.; Gong, M.-Z. J. Org. Chem. 2005,
70, 1084.
(3) For reviews, see: (a) Alcaide, B.; Almendros, P. Eur. J. Org. Chem.
2002, 1595. (b) List, B. Tetrahedron 2002, 58, 5573.
(4) (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187. (b)
Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989. (c)
Ma, J.-A.; Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566. (d)
Multimetallic Catalysts in Organic Synthesis; Shibasaki, M., Yamamoto,
Y., Eds.; Wiley-VCH: Weinheim, 2004.
10.1021/ol050069h CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/09/2005

drine (22 mol %), and Et3N (50 mol %) just by increasing
the temperature to 60 °C.5c Another catalytic alkynylation
of aldehydes and ketones using a catalytic amount of strong
hydroxide, alkoxide, or phosphazene base in polar solvents
has also been reported.8 Although the alkynylation of
carbonyl compounds is realized in these two systems using
only a catalytic amount of metal, the substrate generality is
quite limited. For example, in both systems, aromatic
aldehydes cannot be used due to the side reaction (Carreira
reported that the Cannizzaro reaction is a serious side
reaction5c). Moreover, in each case, broad generality is
lacking, due mainly to high temperature5c or strongly basic
conditions.8 Thus, there remains much room to develop
catalytic alkynylation of various carbonyl compounds under
mild conditions. Herein, we report a new entry in catalytic
alkynylation of aliphatic/aromatic aldehydes and ketones
using indium(III) salt and i-Pr2NEt. Preliminary mechanistic
studies using in situ IR and NMR spectroscopic analysis are
also discussed.
bimetallic catalyst system, however, is difficult. Therefore,
we focused on dual activation by one metal, which should
have both Lewis acidity to carbonyl compounds and π-co-
ordination ability to alkynes. Indium(III) salts are efficient
Lewis acids for carbonyl compounds and, in fact, are utilized
for a wide range of reactions.10 Quite recently, indium(III)
salts have emerged as effective activators of alkynyl groups
in cross-coupling reactions, etc.11 These features prompted
us to examine indium(III) salts for the alkynylation of
carbonyl compounds via dual activation (Scheme 1).
Scheme 1. Alkynylation via Dual Activation of Both Carbonyl
Compounds and Alkynes in Combination with a Catalytic
Amount of Metal Salt and Amine Base
Our group has developed various bifunctional catalysts4
such as heterobimetallic catalysts and Lewis acid-Lewis
base catalysts to achieve efficient enantioselective reactions
under mild conditions with minimal undesired waste. Ap-
plication of this bifunctional strategy seems to be one of the
most promising solutions for developing a catalytic alkynyla-
tion of a broad range of aldehydes and ketones. From this
point of view, dual activation of soft nucleophiles (terminal
alkynes) and hard electrophiles (carbonyl compounds) is very
important. For example, heterobimetallic catalysts, including
soft transition metals and hard Lewis acidic metals, might
be suitable for this purpose.9 The rational design of such a
Using benzaldehyde (1a) or cyclohexanecarboxaldehyde
(1k) with phenylacetylene (2a) as representative substrates,
we screened various indium(III) salts and reaction conditions;
the combination of InBr3 with i-Pr2NEt provided the optimal
reaction efficiency in the alkynylation of aldehydes.12 The
scope and limitations using various aldehydes are sum-
marized in Table 1. Under the optimized reaction conditions
(10 mol % InBr3, 20 mol % i-Pr2NEt, and 2 equiv of terminal
alkynes at 40 °C without solvent), a variety of aromatic
aldehydes were smoothly converted to the corresponding
propargylic alcohols 3. Benzaldehyde derivatives having both
electron-donating substituents (entries 2 and 3) and electron-
withdrawing substituents (entries 4-9) gave the products in
satisfactory yields. The reaction with 1-naphthaldehyde (1i)
(entry 10) and 3-thiophenecarboxaldehyde (1j) (entry 11) also
proceeded well. The reaction with aliphatic aldehyde 1k had
(5) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806. (b) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.; Carreira, E. M.
Acc. Chem. Res. 2000, 33, 373 (c) Anand, N. K.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 9687. (d) Fa¨ssler, R.; Tomooka, C. S.; Frantz, D.
E.; Carreira, E. M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5843. See
also: (e) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
121, 11245.
(6) For the other examples using stoichiometric amounts of metal salts,
see the following. Sn(OTf)2: (a) Yamaguchi, M.; Hayashi, A.; Minami, T.
J. Org. Chem. 1991, 56, 4091. (b) Yamaguchi, M.; Hayashi, A.; Hirama,
M. Chem. Lett. 1992, 2479. GaI3: (c) Han, Y.; Huang, Y.-Z. Tetrahedron
Lett. 1995, 36, 7277. ZnCl2: (d) Jiang, B.; Si, Y.-G. Tetrahedron Lett. 2002,
43, 8323. InBr3: (e) Sakai, N.; Hirasawa, M.; Konakahara, T. Tetrahedron
Lett. 2003, 44, 4171.
(7) Although late transition metals such as Cu(I), Ag(I), and Au(I) are
effective for the formation of metal acetylides in a similar way as Zn(II),
they can be utilized for alkynylation of CdN compounds such as imines,
but not for alkynylation of carbonyl coumpunds. For a review, see: (a)
Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 1472. For representative examples
of Cu, see: (b) Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (c)
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41,
2535. (d) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763. (e) Black, D. A.; Arndtsen, B. A. Org.
Lett. 2004, 6, 1107. Ag: (f) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5,
4473. (g) Ji, J.-X.; Au-Yeung, T. T.-L.; Wu, J.; Yip, C. W.; Chan, A. S. C.
AdV. Synth. Catal. 2004, 346, 42. Au: (h) Wei, C.; Li, C.-J. J. Am. Chem.
Soc. 2003, 125, 9584. Ir: (i) Fischer, C.; Carreira, E. M. Org. Lett. 2001,
3, 4319. (j) Fischer, C.; Carreira, E. M. Synthesis 2004, 1497. Ru-Cu: (k)
Li, C.-J.; Wei, C. Chem. Commun. 2002, 268. For related works, see: (l)
Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (m) Li, Z.; Li, C.-J.
Org. Lett. 2004, 6, 4997.
(9) Li and Wei reported the combination of In(OAc)3 and RuCl3 as a
well-defined catalyst for alkynylation of aldehydes, although the chemical
yields were moderate (27-62%, 12 entries) except for one entry (94%).
They proposed that the C-H bond of alkyne is activated by the ruthenium
catalyst and aldehyde is activated by the indium catalyst: Wei, C.; Li, C.-
J. Green Chem. 2002, 4, 39.
(10) (a) For a review, see: Chauhan, K. K.; Frost, C. G. J. Chem. Soc.,
Perkin Trans. 1 2000, 3015. For recent representative examples, see: (b)
Lin, M.-J.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 13042. (c) Lu, J.; Ji,
S.-J.; Teo, Y.-C.; Loh, T.-P. Org. Lett. 2005, 7, 159. (d) France, S.; Shah,
M. H.; Weatherwax, A.; Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem.
Soc. 2005, 127, 1206 and references therein.
(11) For examples of catalytic activation of alkynes by In(III), see: (a)
Tsuchimoto, T.; Maeda, T.; Shirakawa, E.; Kawakami, Y. Chem. Commun.
2000, 1573. (b) Tsuchimoto, T.; Hatanaka, K.; Shirakawa, E.; Kawakami,
Y. Chem. Commun. 2003, 2454. (c) Nakamura, M.; Endo, K.; Nakamura,
E. J. Am. Chem. Soc. 2003, 125, 13002. (d) Sakai, N.; Annaka, K.;
Konakahara, T. Org. Lett. 2004, 6, 1527. See also ref 6e.
(8) (a) Babler, J. H.; Liptak, V. P.; Phan, N. J. Org. Chem. 1996, 61,
416. (b) Tzalis, D.; Knochel, P. Angew. Chem., Int. Ed. 1999, 38, 1463. (c)
Miyamoto, H.; Yasaka, S.; Tanaka, K. Bull. Chem. Soc. Jpn. 2001, 74,
185. (d) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.;
Saito, S. J. Org. Chem. 2003, 68, 3702. (e) Imahori, T.; Hori, C.; Yamamoto,
Y. AdV. Synth. Catal. 2004, 346, 1090.
(12) See Supporting Information for details.
1364
Org. Lett., Vol. 7, No. 7, 2005

successfully provided the products in moderate yields,
overcoming the retroreaction problem. The fact that even
such a challenging substrate gave greater than 60% chemical
yield without trapping by stoichiometric metals was very
encouraging. Furthermore, less reactive alkylacetylenes
(much less acidic than 2a) were also applicable to the
alkynylation of an aldehyde (Table 1, entry 8) as well as a
ketone (Table 2, entries 3 and 4). In general, under the
Table 1. InBr3-Catalyzed Alkynylation of Aldehydes
Table 2. In(OTf)3-Catalyzed Alkynylation of Ketones
a DME was used as a solvent (5.0 M).
high reactivity and afforded the product 3ka in 84% yield,
although other aliphatic aldehydes gave unsatisfactory results
due to the self-condensation of aldehydes (aldehydes with a
primary alkyl group) and low reactivity (aldehydes with a
tertiary alkyl group). It is worth noting that the reaction was
performed under neat or highly concentrated (5.0 M)
conditions with minimal waste, making this process desirable
in terms of practicality.5c Moreover, to the best of our
knowledge, this is the most effective system for the catalytic
alkynylation of aromatic aldehydes.
a Performed with 10 mol % In(OTf)3. bConcentration was 5.0 M.
c Performed with 5.0 equiv of alkyne. d Major isomer:
e Major isomer:
Next, we examined the alkynylation of ketones using
cyclohexanone (4a) with 2a as model substrates. Under the
optimized conditions for aldehydes, however, the desired
product 5aa was obtained in very low yield (ca. 5% yield).
Changing the indium source from InBr3 to In(OTf)3 (20 mol
%) greatly improved the reactivity to afford 5aa in 90% yield
after 24 h. Even when the catalyst loading was lowered to
10 mol %, the isolated yield was 92% after 63 h. Under the
optimized reaction conditions (20 mol % In(OTf)3 and 50
mol % Et3N at 40 °C in DME), the cyclohexanone deriva-
tives (entries 5-7) as well as bicyclic ketone (entry 8) were
successfully converted to the tertiary propargylic alcohols
5. Despite the high degree of instability of the corresponding
tertiary alcohol of acyclic aliphatic ketones (entries 9 and
10) under basic conditions, the present catalytic reaction
optimized conditions shown in Tables 1 and 2, side reactions
were effectively suppressed; thus, the unreacted carbonyl
compounds were recovered in reasonable yield.
The success of this catalytic reaction can be attributed to
the dual activation of the alkyne and carbonyl compound.
To verify our hypothesis (shown in Scheme 1), we performed
in situ IR5d and NMR spectroscopic studies. First, to gain
precise information about the activation of alkyne, in situ
IR spectra were measured as follows (Figure 1); the
background was measured in the presence of InBr3 and 2
equiv of i-Pr2NEt in DME (similar to the reaction conditions
for aldehydes). When 1 equiv of phenylacetylene (2a) was
added to the above mixture, there was a signal at 3246 cm-1
corresponding to the C-H stretch of the alkyne,13 and this
signal disappeared in less than 1 min. On the other hand,
Org. Lett., Vol. 7, No. 7, 2005
1365

that the indium monoacetylide species was formed.14 Next,
to confirm the activation of the carbonyl compound by Lewis
acidic indium(III) salt,10 NMR spectroscopic analysis was
performed using InBr3. The shift of the peak corresponding
1
to the aldehyde proton (in the H NMR spectrum) and the
carbonyl carbon (in the 13C NMR spectrum) was observed
following the addition of InBr3 to aldehyde in the presence
or absence of i-Pr2NEt and phenylacetylene (2a),12 indicating
the activation of the carbonyl compound by coordination to
the indium(III) species.
In summary, we developed a new catalytic alkynylation
of aldehydes and ketones promoted by the combination of
indium(III) salts and i-Pr2NEt. Dual activation of both soft
nucleophiles and hard electrophiles is the key to this reaction
and was confirmed by in situ IR and NMR spectroscopic
studies. Reactivity and substrate generality might be im-
proved by appropriate ligand choice or further optimization
of the reaction conditions. Application to enantioselective
variants is ongoing.
Acknowledgment. This work was supported by RFTF,
Grant-in-Aid for Encouragements for Young Scientists (A),
and Grant-in-Aid for Specially Promoted Research from the
Japan Society for the Promotion of Science (JSPS) and
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT). R.T. and R.T. thank the JSPS Research
Fellowship for Young Scientists.
Figure 1. In situ IR study of the successive addition of phenyl-
acetylene (2a) to InBr3 and i-Pr2NEt in DME: (a) C-H stretch
signal of 2a and (b) time course of the successive addition (1-4
equiv of phenylacetylene) at 3246 cm-1
.
Supporting Information Available: Experimental pro-
cedures, characterization of the products, and other detailed
results and discussions. This material is available free of
charge via the Internet at http://pubs.acs.org.
when 1-3 equiv of 2a was added (total of 2-4 equiv), the
absorbance at 3246 cm-1 increased with each addition.
Moreover, in the absence of InBr3, the signal corresponding
to the C-H stretch of the alkyne did not disappear. These
results suggested that InBr3 activated the terminal alkyne and
OL050069H
(14) When a similar experiment was performed using In(OTf)3, formation
of indium diacetylide species was implied. For details, see Supporting
Information.
(13) This signal disappeared when phenylacetylene was treated with
EtMgBr in DME. See ref 5d.
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Org. Lett., Vol. 7, No. 7, 2005