Efficient formation of ring structures utilizing multisite activation by indium catalysis

Article abstract of DOI:10.1021/ja805657h

Lewis acidic indium(III) salts, in particular In(NTf₂) ₃, effect the conversion of α-(ω′-alkynyl)-β- ketoesters and ω-alkynyl-β-ketoesters to the corresponding cyclic products in a manner known as the Coniaene reaction. This reaction

Full text of DOI:10.1021/ja805657h

Published on Web 11/19/2008
Efficient Formation of Ring Structures Utilizing Multisite
Activation by Indium Catalysis
Yoshimitsu Itoh, Hayato Tsuji, Ken-ichi Yamagata, Kohei Endo, Iku Tanaka,
Masaharu Nakamura,† and Eiichi Nakamura*
Department of Chemistry, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received July 20, 2008; E-mail: nakamura@chem.s.u-tokyo.ac.jp
Abstract: Lewis acidic indium(III) salts, in particular In(NTf2)3, effect the conversion of R-(ω′-alkynyl)-ꢀ-
ketoesters and ω-alkynyl-ꢀ-ketoesters to the corresponding cyclic products in a manner known as the Conia-
ene reaction. This reaction can lead to the creation of five- to fifteen-membered-ring carbocycles and
heterocycles in good to excellent yields. The synthetic features of the reaction are a relatively low catalyst
loading, as low as 0.01 mol % in the best case, as well as no requirement of solvent for five-membered-
ring formation and the requirement of only moderately dilute reaction conditions for medium-sized-ring
formation. The high reactivity of indium salts is due to the double activation of the ꢀ-ketoester substrate
containing an acetylene function. The indium metal activates the ꢀ-ketoester moiety by the formation of an
indium enolate, and this indium metal electrophilically activates the alkyne moiety. Such a strong push-pull
activation of the substrate by a single metal circumvents the disadvantage of entropic and enthalpic factors
generally associated with the formation of medium- and large-sized rings. The reaction allows the ready
formation of a fifteen-membered-ring carbocycle, from which dl-muscone has been synthesized.
workers13 reported that gold catalysis enables the formation of
a seven-membered ring, and we reported that indium is useful
Introduction
Conia-ene cyclization of an alkyne bearing an enolizable
carbonyl group1 is a classic example of a thermal ene reaction
and has proved to be useful for the synthesis of five-membered
rings. The utility of this cyclization methodology has been
significantly expanded in recent years by the use of metal
catalysts, which has allowed the reaction to proceed at lower
temperatures and for a broader scope of substrates. A variety
of Lewis acidic main-group and transition-metal atoms have
been used in the recent examples.2-13 In spite of such advances,
the reaction has been a useful tool for five-membered-ring
formation as in the original thermal Conia reaction, except for
three cases2-4 of six-membered rings. Advances toward forma-
tion of larger rings were reported in 2007. Sawamura and co-
for the formation of a variety of seven- to fifteen-membered-
ring carbocyclic and heterocyclic compounds.14,15 This article
fully describes this indium-mediated Conia-ene-type reaction.
Four types of mechanisms have been suggested for the
reported metal-mediated Conia cyclization leading to five- to
seven-membered rings (Figure 1): (a) addition of a metal enolate
to the internal alkyne,3,4 (b) addition of an enol to a metal/
alkyne π complex,9,11 (c) ene-yne activation,5,6,12 and (d)
activation of the enol moiety and the alkyne by two different
metal atoms.8,10 A few years ago we discovered that indium(III)
tris(trifluoromethanesulfonate), In(OTf)3, is an extremely ef-
ficient catalyst for the intermolecular addition of a ꢀ-ketoester
to an unactivated alkyne.16 Theoretical calculations suggested
that this addition reaction involves a defined double-activation
mechanism where the indium metal electrophilically activates
the alkyne to which the ene part of the indium enolate adds
nucleophilically (Figure 2).16d We considered that this mech-
anism for the In(OTf)3-catalyzed reaction as applied to medium-
† Present address: International Research Center for Elements Science,
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011,
Japan.
(1) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1–19.
(2) For Zn-mediated reactions, see: Nakamura, E.; Sakata, G.; Kubota,
K. Tetrahedron Lett. 1998, 39, 2157–2158.
(3) For Ti-mediated reactions, see: Kitagawa, O.; Suzuki, T.; Inoue, T.;
Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998, 63, 9470–9475.
(4) For Sn-mediated reactions, see: Kitagawa, O.; Fujiwara, H.; Suzuki,
T.; Taguchi, T.; Shiro, M. J. Org. Chem. 2000, 65, 6819–6825.
(5) For Ni catalysis, see: Gao, Q.; Zheng, B.-F.; Li, J.-H.; Yang, D. Org.
Lett. 2005, 7, 2185–2188.
(11) For Au catalysis, see: (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste,
F. D. J. Am. Chem. Soc. 2004, 126, 4526–4527. (b) Staben, S. T.;
Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43,
5350–5352. (c) Pan, J.-H.; Yang, M.; Gao, Q.; Zhu, N.-Y.; Yang, D.
Synthesis 2007, 2539–2544.
(6) For Co catalysis, see: Cruciani, P.; Stammler, R.; Aubert, C.; Malacria,
M. J. Org. Chem. 1996, 61, 2699–2708.
(12) For Re catalysis, see: Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett.
2005, 7, 4823–4825.
(7) For Mo catalysis, see: McDonald, F. E.; Olson, T. C. Tetrahedron
Lett. 1997, 38, 7691–7692.
(13) Ochida, A.; Ito, H.; Sawamura, M. J. Am. Chem. Soc. 2006, 128,
16486–16487.
(8) For Cu catalysis, see: (a) Bouyssi, D.; Monteiro, N.; Balme, G.
Tetrahedron Lett. 1999, 40, 1297–1300. (b) Deng, C.-L.; Song, R.-J.;
Guo, S.-M.; Wang, Z.-Q.; Li, J.-H. Org. Lett. 2007, 9, 5111–5114.
(9) For Pd catalysis, see: Lomberget, T.; Bouyssi, D.; Balme, G. Synthesis
2005, 311–329.
(14) Tsuji, H.; Yamagata, K.-i.; Itoh, Y.; Endo, K.; Nakamura, M.;
Nakamura, E. Angew. Chem., Int. Ed. 2007, 46, 8060–8062.
(15) Hatakeyama and co-workers recently reported on the formation of five-
to seven-membered heterocyclic ring systems using In(OTf)3 catalysis:
Takahashi, K.; Midori, M.; Kawano, K.; Ishihara, J.; Hatakeyama, S.
Angew. Chem., Int. Ed. 2008, 47, 6244–6246.
(10) For enantioselective Pd catalysis, see: Corkey, B. K.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 17168–17169.
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2008 American Chemical Society
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A R T I C L E S
Itoh et al.
Figure 2. Schematic illustration of the calculated transition state for
intermolecular In(OTf)3-catalyzed addition of a 1,3-dicarbonyl compound
to acetylene.
First, we examined mode A and its efficacy for the formation
of five- to six-membered rings. We found that the reaction takes
place cleanly without solvent and at low catalyst loading [0.01
mol % of In(OTf)3] for five-membered-ring formation. The
substrate 1s gave the desired methylenecyclopentane compound
1a in 99% isolated yield (Table 1, entry 1) after 24 h with
stirring at 60 °C. An acid-sensitive allyl ester 2s and an aroyl
substrate 3s gave 2a and 3a in 93 and 78% yields, respectively
(entries 2 and 3). The use of a larger amount of the catalyst
resulted in the isomerization of the exo-methylene double bond
in the initial product to an internal position (data not shown).
The cyclization of iodoalkynyl compound 3s′ proceeded in
toluene at 40 °C to give the expected alkenyl iodide product
3a′ having exclusively E geometry in 91% yield (entry 4). This
stereoselectivity suggests that the addition of an indium enolate
intermediate to the Ct C triple bond occurs in a cis fashion, as
previously reported for the intermolecular valiant of the reaction
(see Figure 2).16 Six-membered-ring formation was completed
in 12 h in the presence of 1 mol % In(OTf)3 at 80 °C in toluene
(0.5 M) to give the six-membered-ring product 4a in 95%
isolated yield (entry 5). The use of In(NTf2)3 accelerates the
reaction to complete in 4 h to afford 4a in 98% isolated yield
(entry 6).
Figure 1. Proposed activation mechanisms in metal-mediated Conia-ene
cyclization.
sized-ring synthesis (Figure 1e) would overcome the entropic
and enthalpic problems associated with the formation of
medium-sized rings: a higher entropy barrier than for the
formation of three- to six-membered rings and an unfavorable
enthalpy barrier because of transannular interactions in the
formation of rings containing more than seven members.
Medium-sized rings are found in a number of biologically active
natural products,17,18 and their synthesis has long been a
challenge for synthetic chemists.19,20
Seven-membered-ring formation proceeded slowly. The reac-
tion of 5s in the presence of 1 mol % In(OTf)3 gave the product
5a in 40% yield (Table 2, entry 1) after 1 h at 150 °C in 0.1 M
toluene. Changing the counteranion (Cl, OTf, ONf,21 and
Results and Discussion
Cyclization of r-(ω′-Alkynyl)-ꢀ-ketoesters. The mode of
cyclization in most of the reported thermal and metal-mediated
Conia-ene reactions, i.e., cyclization of R-(ω′-alkynyl)-ꢀ-
ketoesters (mode A), is shown in eq 1; however, an alternative
cyclization mode using ω-alkynyl-ꢀ-ketoesters (mode B),8b,13
as shown in eq 2, appeared to us to be equally feasible. Both
modes A and B were examined in this study. First, we describe
the results of the conventional cyclization via mode A and its
use in the synthesis of five- to seven-membered rings. Second,
we describe the use of mode B for the formation of six- to
fifteen-membered rings.
(16) (a) Nakamura, M.; Endo, K.; Nakamura, E. J. Am. Chem. Soc. 2003,
125, 13002–13003. (b) Nakamura, M.; Endo, K.; Nakamura, E. Org.
Lett. 2005, 7, 3279–3281. (c) Nakamura, M.; Endo, K.; Nakamura,
E. AdV. Synth. Catal. 2005, 347, 1681–1686. (d) Endo, K.; Hatakeya-
ma, T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2007, 129,
5264–5271. (e) Tsuji, H.; Fujimoto, T.; Endo, K.; Nakamura, M.;
Nakamura, E. Org. Lett. 2008, 10, 1219–1221. (f) Fujimoto, T.; Endo,
K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008,
130, 4492–4496.
(17) For recent examples, see: (a) Fraga, B. M. Nat. Prod. Rep. 2003, 20,
392–413. (b) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155–198.
(18) For selected recent reviews, see: (a) Booker-Milburn, K. I.; Sharpe,
A. J. Chem. Soc., Perkin Trans 1 1998, 983–1006. (b) Molander, G.
Acc. Chem. Res. 1998, 31, 603–609. (c) Mehta, G.; Singh, V. Chem.
ReV. 1999, 99, 881–930. (d) Yet, L. Chem. ReV. 2000, 100, 2963–
3007.
(19) For reviews, see: (a) Winnik, M. A. Chem. ReV. 1981, 81, 491–524.
(b) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95–102.
(c) Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 3117–3125.
(20) One of the most famous medium-sized-ring formation reactions is ring-
closing metathesis. For recent reviews, see: (a) Maier, M. E. Angew.
Chem., Int. Ed. 2000, 39, 2073–2077. (b) Michaut, A.; Rodriguez, J.
Angew. Chem., Int. Ed. 2006, 45, 5740–5750. For examples, see: (c)
Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748–3759. (d)
Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760–3765.
(21) ONf (nonaflate) ) OSO2C4F9; see: Tsuchimoto, T.; Matsubayashi, H.;
Kaneko, M.; Shirakawa, E.; Kawakami, Y. Angew. Chem., Int. Ed.
2005, 44, 1336–1340.
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Efficient Formation of Ring Structures
A R T I C L E S
Table 1. Formation of Five- and Six-Membered Rings Using Indium Salts (Mode A)
entry
substrate
conditions
producta
yieldb
1
2
3
4
5
6
1s (n ) 1, X ) H, R1 ) Me, R2 ) Et)
2s (n ) 1, X ) H, R1 ) Me, R2 ) allyl)
3s (n ) 1, X ) H, R1 ) Ph, R2 ) Et)
3s′ (n ) 1, X ) I, R1 ) Ph, R2 ) Et)
4s (n ) 2, X ) H, R1 ) Me, R2 ) Me)
4s (n ) 2, X ) H, R1 ) Me, R2 ) Me)
In(OTf)3, 0.01 mol %, neat, 60 °C, 24 h
In(OTf)3, 0.01 mol %, neat, 60 °C, 36 h
In(OTf)3, 0.01 mol %, neat, 60 °C, 72 h
In(NTf2)3, 1 mol %, 0.5 M, 40 °C, 16 h
In(OTf)3, 1 mol %, 0.5 M, 80 °C, 12 h
In(NTf2)3, 1 mol %, 0.5 M, 80 °C, 4 h
1a (5)
2a (5)
3a (5)
3a′ (5)
4a (6)
4a (6)
99%
93%
78%
91%
95%
98%
a The number in parentheses is the number of members in the product ring. b Isolated yield.
Table 2. Seven-Membered-Ring Formation and Catalyst
Screening
Table 3. Seven-Membered-Ring Formation
entry
X
yielda
1
2
3
4
5
OTf
ONf
NTf2
NTf2
Cl
40%
67%
75%
93%b
0%
a NMR yield determined using bromoform as an internal standard.
b Isolated yield after 2 h.
NTf222) revealed that NTf2 is the best catalyst for this reaction,
giving a 93% yield after 2 h of reaction time (entry 4). Steric
bulkiness of the NTf2 group, which could prevent the deactiva-
tion of the indium metal by extra coordination, could account
for the high reactivity.23
In(NTf2)3 was found to be the catalyst of choice for seven-
membered-ring cyclization reactions (Table 3). We first focused
on bicyclo[5.3.0]decanes in view of the ubiquity of such rings
among sesquiterpenes. The cyclization of 2-methoxycarbonyl-
3-(hept-6-yl)cyclopentanone 6s, which was used as a diastere-
omeric mixture, afforded the cis-fused cyclization product 6a
as a single diastereomer in 81% yield (entry 1). The reaction
was slightly slower than that of the parent substrate 5s, reaching
completion after 14 h at 150 °C. Similarly, the corresponding
cyclohexanone 7s produced bicyclo[5.4.0]undecanone 7a in 84%
yield with high diastereoselectivity, namely, a 93:7 mixture of
cis and trans isomers (entry 2). The cis junction in these products
was determined by nuclear Overhauser effect (NOE) analysis
of their derivatives (see the Supporting Information). Cyclization
of an enyne substrate 8s afforded an intriguing cycloheptane
8a containing a conjugated diene structure in 91% yield (entry
3). The example in entry 4 illustrates the synthesis of a nitrogen-
containing seven-membered ring 9a (83% yield) from compound
9s, where the nitrogen atom is protected by a readily removable
2-nitrobenzenesulfonyl (Ns) group.24 Substrates bearing a sub-
stituent at the ꢀ position (R ) Et in 10s and R ) Ph in 11s)
gave 10a and 11a in 85 and 94% yields with 93:7 and 96:4
diastereomeric ratios, respectively (entries 5 and 6).
a The major diastereomer is shown. The ratio in parentheses refers to
the diastereomeric ratio. b Isolated yield.
The stereochemistry of the major diastereomer 11a was
determined by X-ray crystallography to have the R group
positioned cis to the ester group (Figure 3). The diastereose-
lectivity could be rationalized in terms of steric repulsion
between the R group and the methyl ketone, assuming that the
two hydrogen atoms occupy two diaxial positions (Figure 4).
Interestingly, the phenyl compound was as reactive (1 h, 150
°C) as the nonsubstituted compound 5s, while the ethyl
compound was much less reactive (36 h at 150 °C). This is
probably a result of the steric hindrance between the R group
and the ester moiety (see Figure 4, major pathway). Because of
(22) Frost, C. G.; Hartley, J. P.; Griffin, D. Tetrahedron Lett. 2002, 43,
4789–4791.
(23) No reaction took place in a coordinative solvent such as tetrahydrofuran
or dimethylformamide.
(24) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–359.
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A R T I C L E S
Itoh et al.
Figure 5. Schematic representations of eight-membered rings: (a) cyclooc-
tane; (b) 3-methylenecyclooctanone.
Figure 3. ORTEP drawing of the seven-membered-ring product 11a (50%
probability for thermal ellipsoids). Hydrogen atoms, except for H17, have
been omitted for clarity.
Figure 6. Schematic representations of transition states for eight-membered-
ring formation: (a) R- to R-cyclization (mode A); (b) γ- to R-cyclization
(mode B).
plified by a comparison of panels a and b of Figure 6, the latter
reactant will suffer less from the transannular steric interac-
tions.26
This idea was first tested on the formation of six- and seven-
membered rings (Table 4).27 The expected six-membered ring
12b was obtained from 12s in 90% yield exclusively in its enone
form (entry 1). Seven-membered-ring formation took place
much faster and in better yield than six-membered-ring forma-
tion under the same reaction conditions (entry 2). In the seven-
membered-ring formation reaction, the catalyst loading could
be reduced to 0.1 mol % and a good yield could still be obtained
(entry 3). The seven-membered ring was obtained as a mixture
of the double-bond isomers 13b and 13c, most likely because
of isomerization of the initial product 13a to 13b and then to
13c.
When the reaction was carried out using the substrate 14s,
the eight-membered-ring product 14c was obtained in 51% yield
(Table 5, entry 1). The structure was unambiguously determined
by single-crystal X-ray structure analysis (Figure 7). The product
was obtained as a double-bond isomer of the expected product
14a. The X-ray structure (Figure 7) shows that the transannular
steric interaction is effectively reduced as compared with that
in all-sp3-carbon cyclooctane (Figure 5). It is noteworthy that
the cyclization reaction took place in high yield in a 0.1 M
solution of toluene, a concentration considered unusually high
for medium-sized-ring formation.
Figure 4. Possible pathways leading to the major and minor diastereomers
in the cyclizations of 10s and 11s.
its flatness, the Ph group could avoid steric repulsion with the
ester group by rotational motion, while the Et group could not
since all of the carbon atoms are sp3-hybridized.
Cyclization of ω-Alkynyl-ꢀ-ketoesters. Despite the excellent
performance of In(NTf2)3 in the conversion of R-(ω′-alkynyl)-
ꢀ-ketoesters into five- to seven-membered rings, we could not
readily form an eight-membered ring by means of the mode A
cyclization (eq 3). We considered that transannular steric
interaction starts to interfere with the cyclization of an eight-
membered ring.
Cyclooctane25 is known to have several hydrogen atoms
pointing toward the inside of the ring, causing energetically
unfavorable transannular steric interactions (Figure 5). Replace-
ment of two sp3 carbon atoms (at the 1 and 3 positions, for
instance) by sp2 carbon atoms can reduce the ring strain.
Thus, we considered a strategy of cyclization that includes
sp2 carbon atoms in the ring structure involved in the transition
state for medium-sized-ring formation (Figure 6a,b). To this end,
we examined the reaction of ω-alkynyl-ꢀ-ketoesters. As exem-
Incorporation of an additional sp2 carbon center in the ring
system gave the corresponding eight-membered ring in even
higher yield. A substrate bearing a phenylacetylene moiety (15s)
gave the product in 75% yield (Table 5, entry 2). The substrate
16s is a more sp2-enriched compound and gave a dibenzocy-
clooctane structure in 89% yield (entry 3). The product 16a
(26) After our communication (ref 14), Li et al. (ref 8b) reported on a similar
strategy.
(27) The five-membered-ring formation gave a furan derivative because
of an oxygen-centered cyclization rather than the expected carbon-
centered cyclization.
(25) For stable conformations of medium-sized cycloalkanes, see: Dale, J.
Topics Stereochem. 1976, 9, 199–270.
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Efficient Formation of Ring Structures
A R T I C L E S
Table 4. Six- and Seven-Membered-Ring Formation Reaction Using ω-Alkynyl-ꢀ-ketoesters (Mode B)
entrya
substrate
conditions
productb
total yieldc
1
2
3
12s (n ) 0, R2 ) Et)
13s (n ) 1, R2 ) Me)
13s (n ) 1, R2 ) Me)
1 mol %, 0.1 M, 100 °C, 10 h
1 mol %, 0.1 M, 100 °C, 2 h
0.1 mol %, 0.1 M, 120 °C, 12 h
12b (6)
13b + 13c (7) (38: 62)
13b + 13c (7) (60: 40)
90%
98%
81%
a The initial cyclization product a isomerized in situ to b and/or c and hence could not be isolated. b The number in parentheses is the number of
members in the product ring. c Isolated yield.
Table 5. Eight-Membered-Ring Formation (Mode B)
Figure 7. ORTEP drawing of the eight-membered-ring product 14c (50%
probability for thermal ellipsoids). Selected bond lengths (Å): C(2)-C(3),
1.3596(19); C(2)-C(9), 1.4866(19); C(8)-C(9), 1.3358(19); C(9)-C(10),
1.5113(19).
a ketoester with a phenylene moiety, 18s, afforded benzo-fused
nine-membered-ring products 18a and 18b in 71% yield as a
mixture of double-bond isomers (entry 2).29 A substrate 19s
with an N-p-toluenesulfonyl (Ts) group afforded nine-membered-
ring heterocycles 19a and 19b in 61% yield (entry 3). The
optimum reaction conditions required 10 mol % of the In(NTf2)3
catalyst in order to avoid competitive loss of the ethoxycarbonyl
group, which became predominant in the reaction with a low
catalyst loading (i.e., slow cyclization). Similarly, substrate 20s
gave the expected ten-membered-ring product 20a in 74% yield
exclusively in its enol form and as a single diastereomer (eq
4). The stereochemistry of the crystalline dibenzocyclodecane
a Isolated yield. b Keto form 100%. c Keto/enol ) 47/53; keto major/
minor ) 90/10; enol major/minor ) 94/6.
20a was determined by single-crystal X-ray structural analysis
(Figure 8).
was obtained as a mixture of enol and keto tautomers, and the
latter involved diastereomers in a ratio of 90:10 because of the
existence of one central chirality at the R-position of the ester
moiety and another axial chirality of the biphenyl moiety. A
dibenzocyclooctane derivative is a core architecture in some
biologically active natural products, such as lignans.28
Formation of nine- and ten-membered rings was more
difficult. Cyclononane suffers greater transannular steric repul-
sion, and thus, the simple substrate 17s gave the nine-membered-
ring product in only 7% yield (Table 6, entry 1). Substrates
incorporating sp2 carbon atoms or an sp3 nitrogen atom were
effective, even for 9- and 10-membered-ring formation. Thus,
The indium-catalyzed cyclization methodology was found to
be applicable to the formation of a larger ring as well. Formation
(29) The cyclization of 18s did not proceed at all with AuCl(PPh3) (1 mol
%) and AgOTf (1 mol %) at room temperature in CH2Cl2 (0.4 M)
over 48 h, which was effective for five-membered-ring formation in
ref 11a. Even when the same reaction conditions as for In(NTf2)3 (0.05
M in toluene, 120 °C, 24 h) were used, the Au catalyst system could
not make the reaction proceed.
(28) For a recent review, see: Chang, J.; Reiner, J.; Xie, J. Chem. ReV.
2005, 105, 4581–4609.
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A R T I C L E S
Itoh et al.
Table 6. Nine-Membered-Ring Formation
Scheme 1
the system to overcome the entropy and enthalpy barriers
inherent in the formation of medium- to large-sized rings. The
second key issue is the study of the substrate structure. The
large difference between R-(ω′-alkynyl)-ꢀ-ketoesters and ω-alky-
nyl-ꢀ-ketoesters with respect to the ease of cyclization to form
the ring systems is quite remarkable.31 The former substrates
are the best for the five-membered rings, while the latter are
the best for the seven-membered rings, as studied for simple
methylene-tethered substrates. Of even greater interest is the
difference in the formation of eight-membered rings. The former
failed almost entirely, while the latter cyclized very well. With
careful design of substrates to reduce transannular steric
interactions, the latter type of substrate readily gave medium-
to large-sized rings. The overall features of the present cycliza-
tion strategy include the relatively low catalyst loading, as low
as 0.01 mol % in the best case, as well as the requirement of
no solvent for five-membered-ring formation and only moder-
ately dilute reaction conditions for medium-sized-ring formation.
As a result of the present demonstration of the high synthetic
potentials of indium(III) enolate chemistry, we expect that
further investigations into the use of indium metals in organic
chemistry will be worthwhile.
a Isolated yield. b Keto/enol ) 11/89. c Keto/enol ) 34/66.
Experimental Section
Typical Experimental Procedure for In(OTf)3-Catalyzed
Cycloisomerization (Mode A): Ethyl 1-(1-Oxoethyl)-2-methyl-
enecyclopentanecarboxylate (1a). A solution of In(OTf)3 in THF
(0.036 M, 2.75 mL, 0.10 µmol) was added to a dry vessel under
an argon atmosphere, and THF was removed in vacuo at 60 °C.
Substrate 1s (194.5 mg, 1.0 mmol) was added to the reaction vessel,
and the mixture was stirred at 60 °C for 24 h. The reaction mixture
was diluted with hexane and then filtered through a pad of Celite
and washed with hexane. The filtrate was concentrated in vacuo to
obtain an oily crude product. Flash column chromatography on silica
gel (eluent: 90/10 hexane/ethyl acetate) yielded the title compound
1a (192.1 mg, 99%) as a colorless oil. NMR spectra were in good
accordance with those in the literature.32
Figure 8. ORTEP drawing of the ten-membered-ring product 20a (50%
probability for thermal ellipsoids). Selected bond lengths (Å): C(1)-C(2),
1.4626(17); C(2)-C(3), 1.3587(18); C(2)-C(19), 1.4959(15); C(19)-C(20),
1.3208(18).
of a fifteen-membered ring from 21s took place in a 0.01 M
toluene solution to give the product 21a in 27% yield (Scheme
1). The product 21a was transformed into (()-muscone by
hydrogenation followed by decarboxylation.30
Typical Experimental Procedure for In(NTf2)3-Catalyzed
Cycloisomerization (Mode A): Methyl 1-(1-Oxoethyl)-2-meth-
ylenecycloheptanecarboxylate (5a). A dry reaction vessel was
charged with a solution of In(NTf2)3 in acetonitrile (0.05 M, 60
µL, 3.0 µmol). Acetonitrile was removed under vacuum (0.5 Torr)
at 60 °C for 1 h. After the reaction vessel was cooled to room
temperature, toluene (3 mL) and substrate 5s (63 mg, 0.30 mmol)
were added successively. The mixture was heated at 150 °C for
Conclusions
In this article, we have reported on an effective construction
of five- to fifteen-membered rings by Conia-ene-type cyclization
of R-(ω′-alkynyl)-ꢀ-ketoesters and ω-alkynyl-ꢀ-ketoesters. The
first key issue is the use of indium(III) catalysts, in particular
In(NTf2)3, which enable push-pull double activation of the
acetylenic triple bond, strongly organize the transition state of
the cyclization by means of multisite interactions, and allow
(31) Hatakeyama and co-workers (ref 15) reported the use of malonates
and internal alkynes as reactive substrates for In(OTf)3-catalyzed
Conia-ene-type cyclization.
(32) Boaventura, M. A.; Drouin, J.; Conia, J. M. Synthesis 1983, 801–
804.
(30) Tanabe, Y.; Matsumoto, N.; Higashi, T.; Misaki, T.; Itoh, T.;
Yamamoto, M.; Mitarai, K.; Nishii, Y. Tetrahedron 2002, 58, 8269–
8280, and references cited therein.
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17166 J. AM. CHEM. SOC. VOL. 130, NO. 50, 2008

Efficient Formation of Ring Structures
A R T I C L E S
2 h. The resulting mixture was cooled to room temperature and
then filtered through a thin pad of silica gel with elution of ether.
The organic solvent was removed in vacuo to yield the crude
product. Flash column chromatography on silica gel (eluent: 90/
Acknowledgment. We thank MEXT (KAKENHI for E.N.,
18105004) and the Global COE Program for Chemistry Innovation.
Y.I. thanks the Japan Society for the Promotion of Science (JSPS)
for a Research Fellowship for Young Scientists (18 ·9971).
1
10 hexane/ether) yielded the title compound as a colorless oil. H
NMR (500 MHz, CDCl3): δ 1.25-1.56 (m, 4H), 1.68-1.80 (m,
3H), 2.00-2.06 (m, 2H), 2.22 (s, 3H), 2.39-2.43 (m, 1H), 3.76
(s, 3H), 4.93 (s, 1H), 5.25 (s, 1H). 13C NMR (125 MHz, CDCl3):
δ 24.8, 27.1, 30.5, 30.8, 33.0, 35.6, 52.3, 69.7, 117.8, 147.1, 172.8,
204.5. FTIR (cm-1): 2928, 2858, 1744, 1710, 1630, 1446, 1434,
1355, 1233, 1202, 1183, 1140, 1050, 903. Anal. Calcd for C12H19O3:
C, 68.54; H, 8.63. Found: C, 68.45; H, 8.87.
Supporting Information Available: Experimental details and
CIF files. This material is available free of charge via the Internet
at http://pubs.acs.org.
JA805657H
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