Indium-catalyzed cycloisomerization of ω-alkynyl-β-ketoesters into six- to fifteen-membered rings

Article abstract of DOI:10.1002/anie.200702928

(Chemical Equation Presented) Many different sizes of rings available: Heating ω-alkynyl-β-ketoesters in the presence of In(NTf ₂)₃ (Tf=trifluoromethanesulfonyl) produces six- to fifteen-membered ring products in good yields. The reaction features low catalyst loading and moderately dilute conditions, and the formation of medium-sized rings is sometimes faster than that for the corresponding six-membered rings. A synthesis of (±)-muscone is also reported.

Full text of DOI:10.1002/anie.200702928

Communications
DOI: 10.1002/anie.200702928
Medium-Sized Rings
Indium-Catalyzed Cycloisomerization of w-Alkynyl-b-ketoesters into
Six- to Fifteen-Membered Rings**
Hayato Tsuji, Ken-ichi Yamagata, Yoshimitsu Itoh, Kohei Endo, Masaharu Nakamura, and
Eiichi Nakamura*
The ene reaction between an enol and an alkyne is an
established synthetic reaction with respect to its five-mem-
bered-ring-forming variant, known as the Conia reaction.[1,2]
Recent reports on transition-metal catalysis have described
several examples of the extension of the reaction to six- and
seven-membered carbocycles,[2a,f,i,3] yet it is entirely unknown
whether or not the reaction is applicable to the synthesis of
larger rings. Herein, we report that an indium salt catalyzes
the cycloisomerization of w-alkynyl-b-ketoesters to provide
an effective synthetic method of medium- to large-sized rings
(Scheme 1) based on a dual activation mechanism. Unusual
than that of smaller rings because of unfavorable entropy and
transannular interactions,[8] and the scope of the Conia and
related reactions has been limited likely for the same reasons.
To overcome these intrinsic mechanistic problems, we con-
sidered it necessary to find a powerful new reaction and
reagent to achieve this goal. In(OTf)3 was among the reagents
that we examined first as it is the most powerful catalyst for an
intermolecular version of the Conia reaction.[9] However, the
In(OTf)3-catalyzed reaction of w-alkynyl-b-ketoester 1s to
form a six-membered ring was rather slow and afforded the
desired product only in moderate yield even after 10 h at
1008C with 1 mol% catalyst (Table 1, entry 1).
Table 1: In-catalyzed cyclization reaction of unsubstituted w-alkynyl-b-
ketoesters.
Scheme 1. Indium-catalyzed cycloisomerization of w-alkynyl-b-ketoest-
ers. Tf=trifluoromethanesulfonyl.
and synthetically valuable features of the present reaction are
that it allows the formation of seven-to-fifteen-membered
rings under moderately dilute conditions and that some
medium-sized rings form readily, even more readily than a
six-membered ring. The reaction provided access to (Æ )-
muscone[4] as well as ring systems related to lignans.[5]
Entry[a] Substrate, s
X
Conditions Ring
size
Product Yield
(ratio) [%][b]
1
2
1s (n=0,
R2 =Et)
OTf 1 mol%,
0.1m
6
1b
58
1008C,
10 h
Medium-sized rings frequently appear in the structures of
1s (n=0,
R2 =Et)
NTf2 1 mol%,
0.1m
6
1b
90
natural products.[6] Their formation[7] is much more difficult
1008C,
10 h
NTf2 1 mol%,
0.1m
1008C, 2 h
NTf2 0.1 mol%,
0.1m
[*] Dr. H. Tsuji, K.-i. Yamagata, Dr. Y. Itoh, Dr. K. Endo,[+]
Prof. Dr. M. Nakamura,[$] Prof. Dr. E. Nakamura
Department of Chemistry, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5800-6889
E-mail: nakamura@chem.s.u-tokyo.ac.jp
[+] Present address:
3
4
2s (n=1,
R2 =Me)
7
7
2b+2c 98
(38:62)
2s (n=1,
R2 =Me)
2b+2c 81
(60:40)
1208C,
12 h
Department of Chemistry and Biochemistry
School of Advanced Science and Engineering, Waseda University
Ohkubo, Shinjuku, Tokyo 169-8555 (Japan)
5
3s (n=2,
R2 =Me)
NTf2 1 mol%,
0.1m
8
3c
51
1208C,
12 h
[$] Present address:
6
7
4s (n=3,
R2 =Et)
NTf2 1 mol%,
0.04m
1508C, 8 h
NTf2 2 mol%,
0.01m
9
4c
7
International ResearchCenter for Elements Science
Institute for Chemical Research, Kyoto University
Uji, Kyoto 611-0011 (Japan)
5s (n=9,
R2 =Me)
15
5b[c]
27
[**] We thank the Ministry of Education, Culture, Sports, Science and
Technology of Japan for financial support (18105004 to E.N.). Y.I.
thanks the Research Fellowship of the Japan Society for the
Promotion of Science (JSPS) for Young Scientists (18·9971).
1508C, 18 h
[a] The initial cyclization product a isomerized in situ to give b and/or c
and hence was not isolable. [b] Isolated yield. [c] The endo olefinic bond
had exclusively E geometry (Scheme 2).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
8060
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8060 –8062

Angewandte
Chemie
Screening of several indium salts indicated that 1 mol% of
[10]
In(NTf2)3
produces the desired six-membered ring com-
pound 1b in 90% yield in 10 h at 1008C (Table 1, entry 2).[11]
The product was obtained as a conjugated endo olefinic enone
1b (after in situ isomerization of the exo olefinic product 1a).
Interestingly, formation of the seven-membered ring from 2s
took place much faster than that of the six-membered ring
(complete in 2 h under the same conditions) and in a better
yield (98%; Table 1, entry 3). Even 0.1 mol% of In(NTf2)3
effectively catalyzed the reaction at 1208C to afford the
seven-membered-ring product in 81% yield. Formation of the
eight-membered ring from 3s took place more slowly and in a
lower yield (51%; Table 1, entry 5). The structure of 3c was
confirmed by X-ray structure analysis.[12] Formation of the
nine-membered ring from w-alkynyl-b-ketoester 4s was very
slow even at 1508C and gave the product 4c in 7% yield
(Table 1, entry 6).
Scheme 2. Synthesis of (Æ)-muscone through the fifteen-membered
ring product 5b. DMF=N,N-dimethylformamide.
product 8a was obtained as a keto/enol tautomeric mixture
(47:53). A crystalline dibenzocyclodecane 9a was obtained in
74% yield exclusively in its enol form and as a single
diastereomer (Table 2, entry 4). The stereochemistry of 9a
was confirmed by single-crystal X-ray structural analysis
Formation of the fifteen-membered-ring from 5s took
place in a 0.01m toluene solution to give the product 5b in
27% yield (Table 1, entry 7), while the formation of ten- and
eleven-membered rings from the methylene homologues of
4s was too slow to be useful. The
product 5b was transformed into
Table 2: In(NTf2)3-catalyzed cyclization reaction of substituted w-alkynyl-b-ketoesters.
(Æ)-muscone by hydrogenation fol-
lowed by decarboxylation
(Scheme 2).[4]
The method was found to be
useful for the synthesis of medium-
sized rings of some complexity at
concentrations of 0.04–0.1m in tolu-
ene with In(NTf2)3 (1 mol%) at
temperatures between 100 and
1508C (Table 2). Note that some
of the reactions were much faster
than that to form the six-membered
ring (compare with entry 2,
Table 1). Not unexpectedly, the
products were often obtained as a
mixture of keto/enol and double-
bond isomers. Phenylacetylenes 6s
and 7s gave the corresponding
benzo-fused eight- and nine-mem-
bered rings. Thus, 6s cyclized
quickly at 1008C in 2 h to afford
an isomeric mixture of benzocy-
clooctanone 6a (exclusively in its
keto form) and benzocyclooctenone
6b in 75% combined yield (Table 2,
entry 1). The formation of a nine-
membered ring from 7s took place
more slowly but with a comparable
yield of 71% to give an isomeric
mixture of 7a and 7b (each consist-
ing of isomers; see footnote for
entry 2, Table 2). The reaction of
8s quickly afforded a dibenzocy-
clooctane ring, a basic carbon skel-
eton of some lignans,[5] in 1 h in
Entry Substrate
Conditions
Ring size Product
(ratio)
Yield [%][a]
1
2
6s (n=1)
7s (n=2)
1 mol%, 0.1m
1008C, 2 h
1 mol%, 0.05m
1208C, 12 h
8
9
6a[b] +6b (23:77)
75
71
7a[c] +7b (15:85)
3
4
8s (n=0)
9s (n=2)
1 mol%, 0.05m
1008C, 1 h
1 mol%, 0.05m 10
1008C, 8 h
8
8a[d]
9a[e]
89
74
5
10s
1 mol%, 0.05m
1508C, 1.5 h
9
10a[f] +10b (85:15)
61
[a] Isolated yield. [b] Keto 100%. [c] Keto/enol=11:89. [d] Keto/enol=47:53; keto: major/minor=
90:10; enol: major/minor=94:6. The origin of the isomerism in the keto form is due to the central
chirality at the a-position of the ester moiety and the axial chirality of the biphenyl moiety. The enol form
does not have any central chirality, and the observed isomer may be due to the axial chirality at the
89% yield (Table 2, entry 3). The biphenyl and the butadiene moieties (see Figure 1). [e] Enol 100%. [f] Keto/enol=34:66.
Angew. Chem. Int. Ed. 2007, 46, 8060 –8062
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8061

Communications
Keywords: b-ketoesters · cyclization · indium ·
.
medium ring systems · muscone
[1] J. M. Conia, P. Le Perchec, Synthesis 1975, 1 – 19.
[2] a) J. J. Kennedy-Smith, S. T. Staben, F. D. Toste, J. Am. Chem.
Soc. 2004, 126, 4526 – 4527; b) S. T. Staben, J. J. Kennedy-Smith,
F. D. Toste, Angew. Chem. 2004, 116, 5464 – 5466; Angew. Chem.
Int. Ed. 2004, 43, 5350 – 5352; ; c) Q. Gao, B.-F. Zheng, J.-H. Li,
D. Yang, Org. Lett. 2005, 7, 2185 – 2188; d) Y. Kuninobu, A.
Kawata, K. Takai, Org. Lett. 2005, 7, 4823 – 4825; e) P. Cruciani,
R. Stammler, C. Aubert, M. Malacria, J. Org. Chem. 1996, 61,
2699 – 2708; f) O. Kitagawa, T. Suzuki, T. Inoue, Y. Watanabe, T.
Taguchi, J. Org. Chem. 1998, 63, 9470 – 9475; g) F. E. McDonald,
T. C. Olson, Tetrahedron Lett. 1997, 38, 7691 – 7692; h) D.
Bouyssi, N. Monteiro, G. Balme, Tetrahedron Lett. 1999, 40,
1297 – 1300; i) T. Lomberget, D. Bouyssi, G. Balme, Synthesis
2005, 311 – 329; j) B. K. Corkey, F. D. Toste, J. Am. Chem. Soc.
2005, 127, 17616 – 17617; k) E. Nakamura, G. Sakata, K. Kubota,
Tetrahedron Lett. 1998, 39, 2157 – 2158.
Figure 1. ORTEP drawing of the ten-membered ring product 9a (50%
probability for thermal ellipsoids). Hydrogen atoms except for those
on O3 and C20 are omitted for clarity. Selected bond lengths [Š]: 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).
(Figure 1).[12] A nine-membered ring compound 10p bearing
an N-p-toluenesulfonyl moiety was synthesized in 61% yield
from a ketoester 10s (Table 2, entry 11). The reaction
required the use of 10 mol% In(NTf2)3 to suppress the loss
of the ethoxycarbonyl group that occurred competitively in
the reaction under a lower (1 mol%) catalyst loading.
In conclusion, we have developed an In(NTf2)3-catalyzed
cycloisomerization of w-alkynyl-b-ketoesters that produces
six- to fifteen-membered all-carbon- or nitrogen-containing
rings through an intramolecular metalla ene reaction between
an indium enolate and an acetylenic bond. The reaction
features the following: 1) a relatively low catalyst loading,
2) good atom efficiency, 3) the requirement of only moder-
ately dilute reaction conditions, and 4) an anomalous relation-
ship between the ring size and the cyclization rate. The
efficiency of the present catalytic system is attributed to a dual
activation of both enolate and acetylenic moieties, as shown
by our previously reported computational transition-state
model of the intermolecular reaction; The indium enolate of a
1,3-dicarbonyl compound and an acetylene group forms a
well-ordered bicyclo[2.2.2]octane-type structure, which forces
the substituents on the reactants to point toward certain
restricted directions.[9d] We therefore consider that it is this
directionality that made the reaction suitable for the forma-
tion of medium-sized rings, thus allowing the reaction to take
place cleanly at a rather high concentration with a relatively
small amount of the catalyst for a rather wide range of
substrate variations.
[3] A. Ochida, H. Ito, M. Sawamura, J. Am. Chem. Soc. 2006, 128,
16486 – 16487.
[4] Y. Tanabe, N. Matsumoto, T. Higashi, T. Misaki, T. Itoh, M.
Yamamoto, K. Mitarai, Y. Nishii, Tetrahedron 2002, 58, 8269 –
8280, and references therein.
[5] For a recent review, see: J. Chang, J. Reiner, J. Xie, Chem. Rev.
2005, 105, 4581 – 4609.
[6] a) B. M. Fraga, Nat. Prod. Rep. 2003, 20, 392 – 413; b) D. J.
Faulkner, Nat. Prod. Rep. 1999, 16, 155 – 198.
[7] a) L. Yet, Chem. Rev. 2000, 100, 2963 – 3007; b) K. I. Booker-
Milburn, A. Sharpe, J. Chem. Soc. Perkin Trans. 1 1998, 983 –
1006; c) G. Molander, Acc. Chem. Res. 1998, 31, 603 – 609.
[8] a) G. Illuminati, L. Mandolini, Acc. Chem. Res. 1981, 14, 95 –
102; b) C. Galli, L. Mandolini, Eur. J. Org. Chem. 2000, 3117 –
3125.
[9] a) M. Nakamura, K. Endo, E. Nakamura, J. Am. Chem. Soc.
2003, 125, 13002 – 13003; b) M. Nakamura, K. Endo, E. Naka-
mura, Org. Lett. 2005, 7, 3279 – 3281; c) M. Nakamura, K. Endo,
E. Nakamura, Adv. Synth. Catal. 2005, 347, 1681 – 1686; d) K.
Endo, T. Hatakeyama, M. Nakamura, E. Nakamura, J. Am.
Chem. Soc. 2007, 129, 5264 – 5271.
[10] C. G. Frost, J. P. Hartley, D. Griffin, Tetrahedron Lett. 2002, 43,
4789 – 4791.
[11] Attempted five-membered-ring formation gave furan deriva-
tives due to an oxygen-centered cyclization reaction.
[12] CCDC-649749 (3c) and 649750 (9a) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: July 2, 2007
Published online: September 18, 2007
8062 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8060 –8062