Rhenium-catalyzed formation of bicyclo[3.3.1]nonene frameworks by a reaction of cyclic β-keto esters with terminal alkynes

Article abstract of DOI:10.1021/ol900772h

Treatment of cyclic βKeto esters with terminal alkynes in the presence of a catalytic amount of a rhenium complex, [ReBr(CO)₃(thf)] ₂, gave bicyclo[3.3.1]nonene derivatives. The reaction conditions and yields of the bicyclo[3.3.1]non

Full text of DOI:10.1021/ol900772h

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2535-2537
Rhenium-Catalyzed Formation of
Bicyclo[3.3.1]nonene Frameworks by a
Reaction of Cyclic ꢀ-Keto Esters with
Terminal Alkynes
Yoichiro Kuninobu,* Junya Morita, Mitsumi Nishi, Atsushi Kawata, and
Kazuhiko Takai*
DiVision of Chemistry and Biochemistry, Graduate School of Natural Science and
Technology, Okayama UniVersity, Tsushima, Kita-ku, Okayama 700-8530, Japan
kuninobu@cc.okayama-u.ac.jp; ktakai@cc.okayama-u.ac.jp
Received April 9, 2009
ABSTRACT
Treatment of cyclic ꢀ-keto esters with terminal alkynes in the presence of a catalytic amount of a rhenium complex, [ReBr(CO)3(thf)]2, gave
bicyclo[3.3.1]nonene derivatives. The reaction conditions and yields of the bicyclo[3.3.1]nonenes were improved by the sequential use of
tetrabutylammonium fluoride (TBAF) after the rhenium-catalyzed reactions.
Many bioactive compounds contain bicyclic skeletons. For
example, hyperforin,1 garsubellin A,2 and papuaforin A3 are
well-known natural products containing bicyclo[3.3.1]nonene
frameworks. Therefore, several studies on the construction
of bicyclo[3.3.1]nonene frameworks, such as hyperforin,4
garsubellin A,5 papuaforin A,6 and their derivatives have
been carried out.7 As an alternative synthetic route to
bicyclo[3.3.1]nonene derivatives, we investigated the syn-
thesis of bicyclo[3.3.1]nonene skeletons from six-membered
cyclic ꢀ-keto esters and terminal alkynes via the formation
of eight-membered unsaturated cyclic δ-keto esters (Figure
1).8 We report herein the synthesis of bicyclo[3.3.1]nonene
(1) (a) Gurevich, A. I.; Dobrynin, V. N.; Kolosov, M. N.; Popravko,
S. A.; Ryabova, I. D.; Chennov, B. K.; Derbentseva, N. A.; Aizenman,
B. E.; Garagulya, A. D. Antibiotiki 1971, 6, 510–513. (b) Bystrov, N. S.;
Chernov, B. K.; Dobrynin, V. N.; Kolosov, M. N. Tetrahedron Lett. 1975,
16, 2791–2794.
Figure
bicyclo[3.3.1]nonenes.
1
.
Proposed strategy for the retrosynthesis of
(2) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull.
1997, 45, 947.
(3) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J.
Nat. Prod. 2001, 64, 701–706.
(4) Nicolaou, K. C.; Carenzi, G. E. A.; Jeso, V. Angew. Chem., Int. Ed.
2005, 44, 3895–3899.
derivatives by rhenium-catalyzed insertion of alkynes into a
carbon-carbon single bond of cyclic ꢀ-keto esters and
successive intramolecular cyclization via the elimination of
ethanol.
Treatment of cyclic ꢀ-keto ester 1a with phenylacetylene
(2a) in the presence of a rhenium complex, [ReBr(CO)3-
(5) (a) Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943–1946. (b)
Usuda, H.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 3621–
3624. (c) Takagi, R.; Nerio, T.; Miwa, Y.; Matsumura, S.; Ohkata, K.
Tetrahedron Lett. 2004, 45, 7401–7405. (d) Kuramochi, A.; Usuda, H.;
Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
14200–14201.
(6) Kraus, G. A.; Jeon, I. Tetrahedron Lett. 2008, 49, 286–288.
10.1021/ol900772h CCC: $40.75
Published on Web 05/20/2009
 2009 American Chemical Society

(thf)]2, as a catalyst at 150 °C for 24 h gave the ring expanded
product 3, bicyclo[3.3.1]nonene derivative 4a, and alkeny-
lated product 5 in 16, 40, and 12% yields, respectively (eq
1).9,10 In this reaction, we considered that the bicyclic
compound 4a may be formed by intramolecular cyclization
of the eight-membered cyclic compound 3 via the elimination
of ethanol. To elucidate the hypothesis, 3 was treated with
[ReBr(CO)3(thf)]2 in toluene at 150 °C for 4 h (eq 2). As a
result, 4a was afforded in 56% yield. This result showed
that bicyclic compound 4a was produced from the eight-
membered product 3. However, 4a was not formed at 40
°C. Interestingly, by adding a catalytic amount of tetrabu-
tylammonium fluoride (TBAF) and molecular sieves 4A
(MS4A), the reaction was promoted dramatically; that is,
the reaction temperature could be decreased to 40 °C and
4a was produced in 95% yield (eq 2).11-15
Figure 2. X-ray crystal structure of bicycle[3.3.1]nonene derivative
4e. Hydrogen atoms are omitted for clarity.
than other carbon-carbon bonds of the bicyclo[3.3.1]nonene
framework (1.469(3) Å-1.569(4) Å).
When the reaction was carried out as a one-pot reaction
using MS4A in the first step and TBAF in the second step,
Table 1. Reactions between Cyclic ꢀ-Keto Ester 1a and
Alkynes 2a
The structure of bicyclic compound 4 was determined by
X-ray single crystal structure analysis (Figure 2). A single
crystal could be obtained using bicyclic compound 4e (Table
2, entry 5). The result shows that bicyclic compound 4e has
a bicyclo[3.3.1]nonene framework. In addition, the two
carbonyl and naphthyl groups are located at C1, C3, and C5
positions, respectively. The bond length between C4 and C5
is 1.350(3) Å, which is suitable for a double bond and shorter
(7) For the reviews of the synthesis of bicyclo[3.3.1]nonanes, see: (a)
Peters, J. A. Synthesis 1979, 321–336. (b) Butkus, E. Synlett 2001, 1827–
a 1a (1.0 equiv), 2 (1.0 equiv). b Isolated yield. c Step 2: 6 h. d Step 1:
toluene, 80 °C. Step 2: 80 °C, 2 h. e Step 1: 100 °C. Step 2: 80 °C, 2 h.
f Step 1: 80 °C. Step 2: 80 °C, 2 h.
1835
.
(8) We already reported on rhenium-catalyzed ring expansion reaction
by the insertion of alkynes into a carbon-carbon single bond of cyclic ꢀ-keto
esters. See: Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2006,
128, 11368–11369
.
(9) The formation reaction of 4a did not proceed using ReBr(CO)5,
RuH2(CO)(PPh3)3, Ru3(CO)12, AuCl3, PtCl2, and GaCl3.
the yield of bicyclo[3.3.1]nonene derivative 4a was improved
(Table 1, entry 1). Treatment of cyclic ꢀ-keto ester 1a with
phenylacetylene (2a) in the presence of a catalytic amount
of a rhenium complex, [ReBr(CO)3(thf)]2, and MS4A at 40
(10) This reactivity is in sharp contrast to the result that phenylacetylene
(2a) inserts into a C-H bond of ꢀ-keto ester 1a and yielded alkenylated
product 5 quantitatively. See: Kuninobu, Y.; Kawata, A.; Takai, K. Org.
Lett. 2005, 7, 4823–4825
.
2536
Org. Lett., Vol. 11, No. 12, 2009

°C for 24 h followed by the treatment of a catalytic amount
of TBAF at 40 °C for 4 h gave bicyclic compound 4a in
90% yield (Table 1, entry 1).16 Next, we investigated the
scope and limitations of alkynes. p-Methoxyphenylacetylene
(2b) also afforded bicyclo[3.3.1]nonene derivative 4b in 92%
yield (Table 1, entry 2). However, by using an alkyne bearing
an electron-withdrawing group, 2c, the yield of bicyclic
compound 4c was moderate (Table 1, entry 3). An aryl-
substitutedalkynebearingabrominealsoproducedbicyclo[3.3.1]nonene
derivative 4d in 92% yield without losing the bromine (Table
1, entry 4). Naphthyl acetylene 2e also provided bicyclic
compound 4e in 93% yield (Table 1, entry 5). In this reaction,
alkenyl- and alkyl-substituted alkynes 2f and 2g could also
be employed as substrates, and the corresponding bicyclo-
[3.3.1]nonene derivatives 4f and 4g were produced in 66%
and 79% yields, respectively (Table 1, entries 6 and 7).
However, in the case of trimethylsilylacetylene and diphe-
nylacetylene, the reaction did not proceed.
A proposed reaction mechanism for the formation of
bicyclo[3.3.1]nonene derivatives from the corresponding
eight-membered cyclic compounds 38 is as follows; (1)
isomerization of an olefin moiety and keto to enol form; and
(2) intramolecular Claisen-type reaction via the elimination
of ethanol.
Scheme 1. Proposed Mechanism for the Formation of
Bicyclo[3.3.1]nonene Derivatives 4
When an alkyne having a carbonyl group, 2h, was used,
a different reaction proceeded (eq 3). By the reaction of
cyclic ꢀ-keto ester 1a with alkyne 2h in the presence of a
catalytic amount of a rhenium complex, [ReBr(CO)3(thf)]2,
and MS4A in toluene at 80 °C for 24 h, bicyclic compound
6 was generated in 56% yield (eq 3). This reaction is likely
to proceed via the insertion of the acetylene moiety of 2h
into a carbon-carbon single bond of cyclic ꢀ-keto ester 1a
followed by intramolecular cyclization via the elimination
of water.
In summary, we have succeeded in the synthesis of
bicyclo[3.3.1]nonene derivatives in good to excellent yields
from cyclic ꢀ-keto esters and terminal alkynes. During the
formation of the bicyclo[3.3.1]nonene framework from an
eight-membered cyclic compound, TBAF plays a key role
to promote the reaction efficiently under mild conditions.
Since this reaction can be carried out as a one-pot reaction,
and the starting materials, cyclic ꢀ-keto esters and terminal
alkynes are easily available from chemical suppliers or by
preparation, the reaction will become a useful and efficient
method to synthesize bicyclo[3.3.1]nonene derivatives.
Next, we investigated using several cyclic ꢀ-keto esters.
Seven-membered cyclic ꢀ-keto ester 1b also provided the
corresponding bicyclic product 7 in 57% yield (eq 4).
However, cyclopentanone-2-carboxylic acid ethyl ester,
cyclooctanone-2-carboxylic acid ethyl ester, and 1,3-cyclo-
hexanedione did not react under the conditions.17
Acknowledgment. Financial support from the Ministry
of Education, Culture, Sports, Science, and Technology of
Japan is gratefully acknowledged.
(11) TheroleofTBAFisnotclear.However,1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) (20 mol %) also promoted the reaction and the corresponding
bicyclic compound 4a was formed in 16% yield. 1,4-Diazabicyclo[2.2.2]octane
(DABCO) gave bicyclic compound 4a in a trace amount. This result
indicates that TBAF works as a base. There have been several reports on
the use of TBAF as a base. See: (a) Gao, S.; Tseng, C.; Tsai, C. H.; Yao,
C.-F. Tetrahedron 2008, 64, 1955. (b) Okutani, M.; Mori, Y. J. Org. Chem.
2009, 74, 442–444.
Supporting Information Available: General experimental
procedure, characterization data for bicyclo[3.3.1]nonenes
4, 6, and 7, and data for X-ray crystal structure analysis of
4e. This material is available free of charge via the Internet
at http://pubs.acs.org.
(12) Several bases, such as NaOH, NaHCO3, Na2CO3, NEt3, and
pyridine, did not provide 4a at 80 °C.
(13) Other ammonium halides, nBu4NCl, nBu4NBr, and nBu4NI, did not
give 4a at 80 °C.
OL900772H
(14) nBu4NOH produced 4a in 56% yield.
(15) Several metal fluoride, such as KF, KF+18-crown-6, and CsF did
not promote the reaction at 80 °C.
(17) Cyclododecanone-2-carboxylic acid ethyl ester afforded a 2-pyra-
none derivative in 76% yield. For the synthesis of 2-pyranones from ꢀ-keto
esters and alkynes, see: Kuninobu, Y.; Kawata, A.; Nishi, M.; Takata, H.;
Takai, K. Chem. Commun. 2008, 6360–6362.
(16) By using a manganese complex, MnBr(CO)5 (5.0 mol %), as a
catalyst, 4a was formed in 57% yield (step 1: 80 °C, 24 h; step 2: 40 °C,
4 h).
Org. Lett., Vol. 11, No. 12, 2009
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