1154
LETTERS
SYNLETT
It appears that the formation of bicyclic compounds 3a and 3b and
cyclohexanones 3e-g, respectively from cyclic (entry 1 and 2) and
acyclic β-diketones (entry 5-7) proceeds more easily than formation of
1-acetylbicyclo[3.n.1]alkanones 3c-d from 2-acetyl cycloalkanone
precursors (entry 3 and 4). The low yields observed for 3c-d with
respect to the formation of 3a-b are due to competitive alkylation
pathways. For instance, the major product 5 (31%) observed from 2-
acetylcyclopentanone 2c resulted from two intermolecular alkylations,
while for 2d, the unexpected spiro compound 6 (16%) was obtained via
a C,C-dialkylation on the acyl substituent. Since monoalkylated
compound 7 is expected as the precursor of bridged bicyclic diketone 3d
and [5,5]spirodiketone 6 via an equilibrium mixture of enolates,
intramolecular alkylation of the sterically less demanding enolate of 7
competes favourably to obtain spiro compound 6. This eventuality does
not exist for symmetrical compounds 2a-b and 2e-g.
The isolation and characterization of disubstituted compounds 7, 8 and 9
3
proved that monosubstituted β-diketones 2 (R ≠ H) react as a twofold
9
carbon nucleophile. When 2e and 1a were subjected to conditions used
Scheme 2
for the alkylative annulation at 40°C for 1h, 8 was obtained in 53%
yield. Then, cyclisation of 8 was achieved with the same catalyst (40°C,
5h) to afford cleanly 3e in 69% yield. However, this two-step sequence
did not improve the overall yield.
direct access to medium-sized cyclic ketones. We are now extending the
scope of this reaction to azulane derivatives.
The modest yields observed rely on the stability of 1a in the presence of
5b
DBU under the reaction conditions. Indeed, the yields of bicyclic β-
Acknowledgements. We warmly thank Professor G. Buono, and Dr. A.
Heumann (University of Aix-Marseille III) for helpful comments and
correction of the manuscript.
diketones 3a and 3b are dramatically improved by introducing the DBU
progressively with a syringe pump during the reaction (entry 1-2). On
the other hand, diacetate 1a can be replaced with dicarbonate 1b
allowing the reaction to proceed under practically neutral conditions
with the generation of a catalytic amount of methylate ion as soon as π-
References and Notes
10
allyl palladium complex forms. Under these conditions, yields were
(1) Tsuji, J. Palladium Reagents and Catalysts, Innovations in
Organic Synthesis, Wiley: New York, 1995.
increased in a 15-20% range but higher temperatures are required (Table
2).
(2) Inoue, H.; Moritani, I.; Murahashi S.-I. Tetrahedron Lett., 1973,
121. Similar results using allylic 1,1-bisacetates were also
reported by X. Lu and Y. Huang Tetrahedron Lett., 1986, 27,
1615.
(3) Huang, Y.; Lu, X. Tetrahedron Lett., 1987, 28, 6219. See also
Jorand-Lebrun, C.; Fensterbank, L.; Malacria, M. Tetrahedron
Lett., 1995, 36, 6447.
(4) Huang, Y.; Lu, X. Tetrahedron Lett., 1988, 29, 5663.
(5) a) Gravel, D.; Benoît, S.; Kumanovic, S.; Sivaramakrishnan, H.
Tetrahedron Lett., 1992, 33, 1403. b) Gravel, D.; Benoît, S.;
Kumanovic, S.; Sivaramakrishnan, H. Tetrahedron Lett., 1992, 33,
1407.
The utility of the annulation process was demonstrated by the easy
transformation of bicyclic compounds 3a and 3c respectively to the
functionalized cycloheptanone 10 and cycloheptane 11 via a retro
Claisen fragmentation in the presence of NaOMe in MeOH at r.t.
(6) a) He, X. C.; Wang, B.; Bai, D. Tetrahedron Lett., 1998, 39, 411.
b) Kaneko, S.; Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron:
Asymmetry, 1997, 8, 829. c) Kozikowski, A. P.; Campiani, G.;
Aagaard, P.; McKinney, M. J. Chem. Soc., Chem. Commun. 1993,
860. d) Campiani, G.; San, L. Q.; Kozikowski, A. P.; Aagaard, P.;
McKinney, M. J. Org. Chem., 1993, 58, 7660.
Since two consecutive base-induced reactions are involved to obtain a
two-carbon atom ring expansion from cyclopentanones, the tandem
bicycloannulation/retro Claisen alkylation was examined in a one-pot
procedure. Thus, 2a was subjected to the palladium-catalyzed
annulation under the conditions described above. Then, acetonitrile was
replaced with methanol and the crude reaction mixture stirred with
NaOMe to afford 10 in 41% overall yield. The whole transformation
proceeds more efficiently than the stepwise process (28%) leading to 10.
(7) Tenaglia, A.; Kammerer, F. Synlett, 1996, 576.
(8) Typical procedure for the annulation : Pd(OAc) (9 mg, 0.04
2
mmol) and PPh (52 mg , 0.18 mmol) were stirred for 20 min at
3
r.t. in dry acetonitrile (3 mL). Diacetate 1a (212 mg, 1.2 mmol),
2a (114 mg , 1 mmol), and DBU (336 mg, 2.2 mmol) were
successively added. The mixture was stirred at 33°C until
complete consumption of diketone as monitored by TLC. After
usual work-up, flash chromatography over silica gel (petroleum
ether/AcOEt 2/ 1) afforded 71 mg (42%) of 3a.
In summary, the palladium catalyzed dialkylation of the readily
available monosubstituted β-diketones with bifunctional allylic reagents
1a or 1b opens
a new route for the construction of 4-
methylenecyclohexanone framework. Moreover access to functionalized
cycloheptanones is available by a retro-Claisen fragmentation. A simple
Selected analytical and spectroscopic data for 3a : m.p: 83-84°C;
-1
1
11
IR (KBr): 2940, 1730, 1700, 1450, 1420 cm ; H NMR
integrated one-pot process bicycloannulation/retro Claisen allows a