Indium-catalyzed [1 + n] annulation reaction between β-ketoester and αω-diyne

Article abstract of DOI:10.1021/ol9003542

A catalytic amount of ln(NTf₂)₃ effects the inter- and intramolecular addition of a β-ketoester to an a,αω-diyne to produce a 1, 3- dimethylenecycloalkane derivative in a single step. This [1 + n] annulation reaction shows good funct

Full text of DOI:10.1021/ol9003542

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1845-1847
Indium-Catalyzed [1 + n] Annulation
Reaction between ꢀ-Ketoester and
r,ω-Diyne
Hayato Tsuji,* Iku Tanaka, Kohei Endo,† Ken-ichi Yamagata,
Masaharu Nakamura,‡ and Eiichi Nakamura*
Department of Chemistry, School of Science, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received February 18, 2009
ABSTRACT
A catalytic amount of In(NTf2)3 effects the inter- and intramolecular addition of a ꢀ-ketoester to an r,ω-diyne to produce a 1,3-
dimethylenecycloalkane derivative in a single step. This [1 + n] annulation reaction shows good functional group tolerance and allows the
synthesis of five- to seven-membered carbo- and heterocyclic as well as spirocyclic structures in moderate to excellent yields.
Construction of ring systems through a quick assembly of
multiple components continues to attract the interest of our
group1 and other researchers.2,3 Focusing on the addition of
metal enolates to unactivated alkenes4 and alkynes,5 we
recently found that indium salts catalyzed the inter-6 and
intramolecular addition reactions7 of a 1,3-dicarbonyl com-
pound to an unactivated alkyne.8,9 The efficiency of these
reactions was found to be very high, particularly for the
intramolecular reaction, which has been cross-checked
independently by Hatakeyama.8 Therefore, we conjectured
† Present address: Department of Chemistry and Biochemistry, School
of Advanced Science and Engineering, Waseda University, Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan.
‡ Present address: International Research Center for Elements Science
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011,
Japan.
(5) (a) Nakamura, M.; Liang, C.; Nakamura, E. Org. Lett. 2004, 6, 2015–
2017. (b) Nakamura, M.; Fujimoto, T.; Endo, K.; Nakamura, E. Org. Lett.
2004, 6, 4837–4840.
(1) (a) Nakamura, E.; Yamago, S. Acc. Chem. Res. 2002, 35, 867–877.
(b) Tsuji, H.; Yamagata, K.-i.; Fujimoto, T.; Nakamura, E. J. Am. Chem.
Soc. 2008, 130, 7792–7793. See also ref 3.
(6) (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.; Hatakeyama, 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.
(2) For reviews, see: (a) Lautens, M.; Kulte, W.; Tam, W. Chem. ReV.
1996, 96, 49–92. (b) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471–
1499. (c) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003,
4101–4111
(3) Kuninobu, Y.; Nishi, M.; Yudha, S. S.; Takai, K. Org. Lett. 2008,
10, 3009–3011
.
.
(4) (a) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed. Engl. 1997,
36, 2491–2493. (b) Lorthiois, E.; Marek, I.; Normant, J. F. J. Org. Chem.
1998, 63, 566–574. (c) Rodriguez, A. L.; Bunlaksananusorn, T.; Knochel,
P. Org. Lett. 2000, 2, 3285–3287. (d) Pei, T.; Widenhoefer, R. A. J. Am.
Chem. Soc. 2001, 123, 11290–11291. (e) Yao, X.; Li, C.-J. J. Am. Chem.
Soc. 2004, 126, 6884–6885. (f) Nakamura, M.; Hatakeyama, T.; Hara, K.;
Nakamura, E. J. Am. Chem. Soc. 2003, 125, 6362–6363. (g) Nakamura,
M.; Hatakeyama, T.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 11820–
(7) (a) Tsuji, H.; Yamagata, K.-i.; Itoh, Y.; Endo, K.; Nakamura, M.;
Nakamura, E. Angew. Chem., Int. Ed. 2007, 46, 8060–8062. (b) Itoh, Y.;
Tsuji, H.; Yamagata, K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura,
E. J. Am. Chem. Soc. 2008, 130, 17161–17167.
(8) Takahashi, K.; Midori, M.; Kawano, K.; Ishihara, J.; Hatakeyama,
S. Angew. Chem., Int. Ed. 2008, 47, 6244–6246
.
(9) An example of inter- and intramolecular addition of a ꢀ-dicarbonyl
moiety to an alkyne catalyzed by a Re complex: Kuninobu, Y.; Kawata,
11825
.
A.; Takai, K. Org. Lett. 2005, 7, 4823–4825.
10.1021/ol9003542 CCC: $40.75
Published on Web 03/24/2009
2009 American Chemical Society

that it is possible to apply this indium catalysis to the one-
pot [1 + n] synthesis of carbocyclic and heterocyclic rings.
Herein, we report that the In(NTf2)3-catalyzed reaction of
ꢀ-ketoesters and R,ω-diynes takes place smoothly to afford
the expected [1 + n] annulation products, 1,3-dimethyl-
enecycloalkane derivatives (Scheme 1). This reaction, usually
Table 1. Reaction of ꢀ-Ketoesters with 1,6-Heptadiynea
Scheme 1
carried out in a 0.2 M toluene solution with 1 mol % of
catalyst loading at 150 °C, gives an excellent yield and
produces five- and six-membered rings with a simple
structure and a moderate yield in the synthesis of seven-
membered rings and of five- and six-membered rings with a
relatively complex structure.
a The data were obtained from reactions on a 0.2 mmol scale unless
otherwise noted. b Isolated yield. c The reaction time and yield in parentheses
are for the 1 g scale reaction.
A typical procedure for the formation of six-membered
rings as performed on a gram scale is as follows. A mixture
of ethyl acetoacetate 1a (1.06 g) and 1,6-heptadiyne 2a (0.86
g) in toluene (38 mL) was heated at 150 °C for a period of
3 h in the presence of 1 mol % of In(NTf2)3, which was
found to be the most effective catalyst for intermolecular
cyclization in our previous studies.7 After being cooled to
ambient temperature, the resulting mixture was passed
through a pad of Celite to remove the catalyst. After
evaporation, bulb-to-bulb distillation afforded 1.41 g of the
product 3aa (90% yield, Table 1, entry 1, in parentheses).
When this reaction was carried out on a 0.5 mmol scale,
and the resulting mixture was purified using silica gel column
chromatography, the expected 1,3-dimethylenecyclohexane
product 3aa was obtained in a 98% isolated yield (Table 1,
entry 1). The structure of the product was fully characterized
from the NMR spectra, mass spectrometry data, and elemen-
tal analysis.
Other examples of the reaction of ꢀ-ketoesters with 1,6-
heptadiyne 2a are shown in Table 1. Benzyl and allyl acetates
that may be moderately acid-sensitive gave the cyclized
products in 97% (2 h) and 90% yields (12 h), respectively
(entries 2 and 3). We can ascribe the lower reactivity of the
allyl acetate 1c compared to 1a and 1b to the competitive
coordination of the alkene moiety of the allyl group and the
alkyne to the indium atom. The reactions of benzoyl- and
cinnamoylacetate, which produced some uncharacterizable
side products, afforded the cyclized products in lower yields
(entries 4 and 5). Other active methylene compounds, such
as ꢀ-ketoamide and malonic ester, did not participate well
in the reaction. ꢀ-Diketone (2,4-pentanedione) gave the
corresponding six-membered ring product in a high yield as
a mixture of 1,3-dimethylenecyclohexane and its olefin
isomer, a 1-methyl-5-methylenecyclohex-1-ene derivative
(see the Supporting Information).
Next, we examined the reactions of ethyl acetoacetate 1a
with various other R,ω-diynes 2b-i (Table 2). The formation
of the simplest five-membered ring by the reaction with 1,5-
hexadiyne was performed at 100 °C to obtain a 1,3-
dimethylenecyclopentane product 3ab in a 79% isolated yield
(72 h, entry 1). We did not detect any of the initial
monoaddition product (i.e., without cyclization), as opposed
to the case of the seven-membered ring formation (vide
infra), where the second intramolecular cyclization was found
to be slow. The 1,2-diethynylbenzene afforded an indane
derivative 3ac in a 30% yield (at 100 °C after 48 h, entry
2). When these reactions were performed at 150 °C, the yield
of the desired product decreased (28% and trace amounts of
3ab and 3ac, respectively), while the amount of unidentified
product increased. Such a reactivity in the formation of five
membered-rings is presumably due to the ring strain of the
resulting dimethylenecyclopentane products.
In agreement with the results shown in Table 1, the
synthesis of six-membered rings took place in higher yields.
Thus, an R,R-dipropargyl malonate 2d afforded the expected
cyclized product 3ad in 78% yield (entry 3) and the
dipropargyl ether 2e gave the dimethylenetetrahydropyrane
derivative 3ae in a 70% yield (entry 4). The reaction of
2-nitrobenzensulfonyl (Ns)10 dipropargylamine 2f was com-
plete after 8 h at 150 °C and gave the cyclic amine 3af in
90% yield (entry 5). The reaction with 2,7-dibromo-9,9′-
(10) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–359.
Org. Lett., Vol. 11, No. 8, 2009
1846

1,7-octadiyne (2h) took place slowly in a lower yield (entry
7) and produced an inseparable mixture of a 1,3-dimethyl-
enecycloheptane 3ah and its olefin isomer, the 1-methyl-6-
methylenecyclohept-1-ene derivative, 3ah′ in 30% and 15%
yields, respectively. The uncyclized monoaddition product
(as an R-alkylydene compound 4,5b see the Supporting
Information) also formed in a 10% yield, indicating that the
intramolecular addition is slow. The reaction of 2,2′-
diethynylbiphenyl 2i took place much faster than 1,7-
octadiyne (2h) to afford dibenzocycloheptane 3ai in a 71%
yield (entry 8) either because of the higher reactivity of the
arylacetylene structure or because of the lower degree of
freedom of the starting material. Attempts to form rings larger
than eight-membered rings have so far been unsuccessful.
The single-crystal X-ray structure of the spirofluorene
compound 3ag is shown in Figure 1. The 1,3-dimethylenecy-
Table 2. Reaction of Ethyl Acetoacetate with R,ω-Diynes
Figure 1. ORTEP drawing of the spirocyclic compound 3ag (50%
probability for thermal ellipsoids). Hydrogen atoms are omitted for
clarity.
clohexane moiety is in a chair conformation, which places
the ester group flanked by the two exo-methylene groups.
In summary, we have shown that In(NTf2)3 catalyzes the
double addition of a ꢀ-ketoester to an R,ω-diyne to promote
the [1 + n] cyclization reaction. This reaction produces
densely functionalized cyclic compounds with minimal effort
and, hence, will be useful in further synthetic applications.
Acknowledgment. This research was supported by KAK-
ENHI provided by MEXT/JSPS (to E.N., Grant No.
18105004) and the Global COE Program for Chemistry
Innovation through Cooperation of Science and Engineering.
a Isolated yield. b Reaction temperature was 100 °C. c exo-Olefin (3ah):
endo-olefin (3ah′) ) 2:1. The R-alkynylidene compound was also obtained
in 10% yield. See the Supporting Information. d Concentration was 0.05
M.
Supporting Information Available: Detailed experimen-
tal procedure and properties of compounds. CIF file of
compound 3ag. This material is available free of charge via
the Internet at http://pubs.acs.org.
dipropargylfluorene 2g required a longer reaction time and
afforded a structurally intriguing spirofluorene compound 3ag
in 57% yield (entry 8). Note that the bromine atoms in the
starting material survived the reaction conditions, and the
dibromide product may serve as a useful starting material
for further development of organoelectronic materials.11
Seven-membered ring formation by the reaction of 1a with
OL9003542
(11) For a recent example, see: Tsuji, H.; Mitsui, C.; Ilies, L.; Sato, Y.;
Nakamura, E. J. Am. Chem. Soc. 2007, 129, 11902–11903.
Org. Lett., Vol. 11, No. 8, 2009
1847