Indium-Catalyzed Addition of Active Methylene Compounds to 1-Alkynes

Article abstract of DOI:10.1021/ja038006m

An active methylene compound adds to a 1-alkyne in high to quantitative yield upon heating in the presence of 0.05-5 mol % of In(OTf)₃ to give an α-alkenylated carbonyl compound. Copyright

Full text of DOI:10.1021/ja038006m

Published on Web 10/02/2003
Indium-Catalyzed Addition of Active Methylene Compounds to 1-Alkynes
Masaharu Nakamura,*,† Kohei Endo, and Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received August 19, 2003; E-mail: masaharu@chem.s.u-tokyo.ac.jp; nakamura@chem.s.u-tokyo.ac.jp
Chart 1. Active Methylene Compounds Examined
It is generally accepted that an enolate anion does not undergo
intermolecular addition to a nonactivated C-C multiple bond,1
except for certain limited cases.2 We recently challenged this
conventional wisdom and reported that zinc enolate species derived
from ester, amide, hydrazone, and imine undergo addition to
ethylene and other olefins in high yield.3 The reaction is useful
also for enantioselective synthesis of R-substituted ketones.3a We
report herein the result of our second challengesthe addition of
enolate species to unactivated alkynes (eq 1).
Comparison among phenyl acetylene derivatives for the reaction
with 3-oxo-2-methylbutanoate (entries 1-4) indicated that pheny-
lacetylene 2a is less reactive than 2b (R3 ) 4-CH3OC6H4), and
more reactive than 2c (R3 ) 4-CH3OCOC6H4) and 2d (R3
)
We found that heating of a neat mixture of nearly stoichiometric
amounts of an active methylene compound and a terminal alkyne
at 100-140 °C in the presence of a catalytic amount of In(OTf)3
gives the desired R-alkenylated carbonyl compound in a high to
excellent yield. The reaction possesses several synthetically attrac-
tive features: (1) simple procedure allowing large-scale preparation,
(2) high catalytic efficiency (turnover number up to 2000), (3) high
yield, (4) perfect regioselectivity, (5) no requirement of solvent,
and (6) the ability to create densely functionalized molecules in a
single step without loss of any atoms in the starting materials. These
features make the new reaction particularly attractive among a few
other related reactions of similar nature reported in the literature.4
The following example illustrates the effectiveness of the process.
A mixture of ethyl 3-oxo-2-methylbutanoate 1a (14.5 g, 0.10 mol),
phenylacetylene 2a (R3 ) C6H5) (12.3 g, 0.12 mol), and In(OTf)3
(28.1 mg, 0.05 mol %) was heated under nitrogen at 140 °C for 10
h. Distillation at 120 °C (6.7 Pa) gave the desired product, ethyl
2-acetyl-2-methyl-3-phenyl-3-butenoate 3 (R1, R2 ) CH3, R3 )
C6H5) as a single product (21.7 g, 92% yield; 99% yield on a
4-mmol scale with a chromatographic purification, Table 1, entry
1). In(OTf)3 was found to be the best catalyst after screening of a
number of metal triflates.5 While the reaction is best carried out in
the absence of solvent, the mixture may be diluted with a solvent
such as toluene at the expense of the reaction rate.
The generality of the reaction is illustrated with the results in
Table 1. The yield is essentially quantitative both for the active
methylene compound and for the alkyne, and the regioselectivity
was always 100% favoring the introduction of the carbonyl
compound to the internal alkynic carbon atom. The use of excess
alkyne is beneficial when it is volatile, unreactive, or unstable under
the reaction conditions. Internal alkynes are inert for the coupling
reactions under the present reaction conditions. Despite the high
reaction temperature, no side products were formed due to
decarbonylation or self-condensation of the active methylene
compounds.
4-CF3C6H4): The reaction becomes faster, but the yield becomes
lower (entries 2-4) as the alkyne becomes more electron-rich. The
lower yield with the more reactive alkyne is due to the formation
of high-molecular weight side product. The reaction is, however,
entirely free of such side products for the less reactive substrates.
The reaction with aliphatic alkynes also proceeded in high yield
(entries 5-7). As shown in entries 6 and 7, 1-alkynes bearing a
nearby oxygen functionality (i.e., 2e and 2f) also take part in the
reaction, while the propargyl ether substrate in entry 7 was rather
unstable under the reaction conditions. The addition to a conjugated
enyne compound 2h took place exclusively at the triple bond in
1,2-fashion to give the corresponding diene product in 94% yield
(entry 8).
The reaction tolerates a wide range of structural variations of
the active methylene compound. The â-ketoester can bear a benzoyl
group or can be a part of a ring structure (entries 9-13). We can
also use â-diketones, while they are slightly less reactive than
â-ketoester and need a small modification of the reaction conditions.
Thus, acetylacetone and 3-methyl-2,4-pentandione react with an
excess alkyne to give the desired compounds in high yield in the
presence of an equimolar mixture of 2.5 mol % In(OTf)3, Et3N,
and n-BuLi.6 In contrast, acetylacetone reacts with an alkyne to
give cleanly the R-alkenylation product and give the product 100%
in its enol form (entry 13).7
All reactions shown above proceeded with perfect regioselectivity
to form the new C-C bond at the C2 position of the 1-alkyne. On
the other hand, a silyl acetylene 2i [R3 ) Si(CH3)2C6H5] undergoes
the coupling reaction with completely reversed regioselectivity (eq
2). The adduct 8 has a trans olefinic double bond, indicating that
the cis addition took place.
† PRESTO, Japan Science and Technology Corporation (JST).
9
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J. AM. CHEM. SOC. 2003, 125, 13002-13003
10.1021/ja038006m CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. In(OTf)3-Catalyzed Alkenylation of Active Methylene
Compounds with 1-Alkynesa,b
Figure 1. A mechanistic rationale for the catalytic alkenylation.
of which we elucidated some time ago.9 We expect that the new
reaction described above will further expand the utilities of active
methylene compounds that have already been amply demonstrated
by numerous previous reports.
Acknowledgment. We thank the Ministry of Education, Culture,
Sports, Science, and Technology of Japan for financial supports, a
Grant-in-Aid for Specially Promoted Research, a Grant-in-Aid for
Young Scientists (A) (KAKENHI 14703011) and for the 21st
Century COE Program for Frontiers in Fundamental Chemistry.
Supporting Information Available: Details of the experimental
procedure, characterization, and physical data of products (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) Reviews: (a) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57, 5899-
5913. (b) Asao, N.; Yamamoto, Y. Bull, Chem. Soc. Jpn. 2000, 73, 1071-
1087. (c) Marek, I.; Normant, J. F. In Metal-catalyzed Cross-coupling
Reactions; Diederich, F., Stang, P. J., Ed; WILEY-VCH: Weinheim,
1998; pp 271-337.
(2) To alkenes: (a) Rodriguez, A.-L.; Bunlaksananusorn, T.; Knochel, P. Org.
Lett. 2000, 2, 3285-3287. To alkynes: (b) Koradin, C.; Rodriguez, A.-
L.; Knochel, P. Synlett 2000, 1452-1454. (c) Bertrand, M. T.; Courtois,
G.; Miginiac, L. Tetrahedron Lett. 1975, 36, 3147-3150. (d) Bertrand,
M. T.; Courtois, G.; Miginiac, L. Tetrahedron Lett. 1974, 23, 1945-
1948. (e) Schulte, K. E.; Rucker, G.; Feldkamp, J. Chem. Ber. 1972, 105,
24-33.
(3) (a) Nakamura, M.; Hatakeyama, T.; Hara, K.; Nakamura E. J. Am. Chem.
Soc. 2003, 125, 6362-6363. (b) Nakamura, M.; Hara, K.; Sakata, G.;
Nakamura, E. Org. Lett. 1999, 1, 1505-1507. (c) Nakamura, E.; Kubota,
K.; Sakata, G. J. Am. Chem. Soc. 1997, 119, 5457-5458. (d) Kubota, K.;
Nakamura, E. Angew. Chem., Int. Ed. Engl. 1997, 36, 2491-2493. (e)
Nakamura, E.; Kubota, K. Tetrahedron Lett. 1997, 38, 7099-7102.
(4) (a) Hirase, K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2002,
67, 970-973. (b) Arisawa, M.; Akamatsu, K.; Yamaguhi, M. Org. Lett.
2001, 3, 789-790. (c) Badanyan, Sh. O.; Chobanyan, Zh, A.; Tirakyan,
M. R.; Danielyan, A. O. Russ. J. Org. Chem. 1997, 33, 17-20 and
references therein.
a The reaction was carried out with 0.05-5 mol % of In(OTf)3 at 60-
140 °C for 4-18 h. See Supporting Information for details. b The alken-
ylation reaction can also be performed at 40-50 °C by use of 10 mol %
catalyst.
(5) Zinc, copper, and lanthanoid triflate did not promote the coupling reaction
under the same reaction conditions.
On the basis of the regio- and stereoselectivity of the reaction,
we propose the following catalytic mechanism (see also Figure 1):
An indium enolate, generated by the reaction between In(OTf)3
and â-dicarbonyl compound8 adds across the triple bond of
1-alkyne, and the resulting alkenyl indium is protonated by the
â-dicarbonyl compound to regenerate the indium enolate. The
higher reactivity of electron-rich alkynes suggests that coordination
of the indium atom to the alkyne is important in this carbometalation
process. The observed regioselectivity of the addition follows the
general rule of carbometalation of alkynes and alkenes, the origin
(6) The role of Et3N and n-BuLi is unknown at this time. A large amount of
uncharacterized side products formed without the bases.
(7) The In-catalyzed coupling reaction between ethyl 3-oxobutanoate 1 (R1
) CH3, R2 ) H) and an alkyne gave the corresponding R-alkylidene
compound due to transposition of the double bond after the C-C bond
formation.
(8) The alkyne substrates act as the trapping agent for TfOH and gives, upon
hydrolysis, a corresponding ketone, such as acetophenone.
(9) (a) Nakamura, E.; Miyachi, Y.; Koga, N.; Morokuma, K. J. Am. Chem.
Soc. 1992, 114, 6686-6692. (b) Nakamura, M.; Inoue, T.; Sato, A.;
Nakamura, E. Org. Lett. 2000, 2, 2193-2196.
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