Single-step synthesis of cyclooctadienone derivatives by reaction of alkenylcyclobutenones with alkenyllithiums: Enhanced reactivity of 8π cyclization by acetylating the intermediary lithium tetraenolate

Article abstract of DOI:10.1246/cl.2002.1042

Various functionalized cyclooctadienones are accessible in high yields by the reaction of alkenylcyclobutenones with alkenyllithiums.

Full text of DOI:10.1246/cl.2002.1042

1042
Chemistry Letters 2002
Single-Step Synthesis of Cyclooctadienone Derivatives by Reaction of Alkenylcyclobutenones
with Alkenyllithiums: Enhanced Reactivity of 8ꢀ Cyclization
by Acetylating the Intermediary Lithium Tetraenolate
Toshiyuki Hamura, Nobuyuki Kawano, Shinsuke Tsuji, Takashi Matsumoto, and Keisuke Suzukiꢀ
Department of Chemistry, Tokyo Institute of Technology and CREST, Japan Science and Technology Corporation (JST),
O-okayama, Meguro-ku, Tokyo 152-8551
(Received July 8, 2002; CL-020566)
Various functionalized cyclooctadienones are accessible in
high yields by the reaction of alkenylcyclobutenones with
alkenyllithiums.
We recently reported an approach to eight-membered
carbocycles via ring expansion of dienylbenzocyclobutene or
dienylcyclobutene derivatives (eq 1),1;2 which could be formally
categorized as [4 þ 4] processes.
Reported herein is an alternative synthetic access to
cyclooctadienone derivatives,3 which could be viewed as a
Scheme 1.
[4 þ 2 þ 2] process4 as shown in eq 2. The process relies on the
tetraene, among which the former step is facile, being already
complete at À78 ꢁC.
ability of dichlorocyclobutenone derivatives 1 to accept two
alkenyl anions, same or different, and subsequent consecutive
electrocyclic ring opening and ring closure.
The procedure was applicable also to cyclobutenone 6 with a
2-buten-2-yl group. Treatment of 6 with 2-propenyllithium at
À78 ꢁC followed by gradual warming to 25 ꢁC brought about a
slow, but smooth conversion to ketone 7 in 78% yield. It is notable
that ketone 7 was formed as a single isomer having a trans
relationship of two methyl groups as evidenced by X-ray
analysis.7
Thus, the SN20 reaction of dichloride 15 by 2-propenyllithium
gave the alkenylated acetal 2, which was hydrolyzed to furnish
ketone 3,6 ready for accepting the second alkenyl group.
We found that, furthermore, the formation of the eight-
membered rings was facilitated by acetylating the intermediary
lithium tetraenolates. Thus, ketone 6 was treated with 2-
propenyllithium at À78 ꢁC, and the temperature raised to 0 ꢁC.
At this stage, Ac2O was added, the temperature further raised to
25 ꢁC, where only 3 h (cf. eq 4) was required to obtain the
cyclooctatriene 9 as the sole product in 91% yield (Scheme 2).
Relevant to the origin of this enhanced reactivity by
acetylation, the following data are noted. (1) If the reaction was
quenched after the addition of Ac2O at 0 ꢁC, the main product was
tetraene 10, which was gradually converted to cyclooctatriene 9.
(2) If Ac2O was added at À78 ꢁC, the overall process proceeded
more slowly, giving cyclooctatriene 9 in 56% yield along with
cyclobutene 8 in 34% yield (entry 2). (3) Compound 8 was stable
at room temperature, and was composed solely of the trans isomer
Upon treatment with 2-propenyllithium, generated from
CH2=C(CH3)Br and t-C4H9Li, (1.3 mol. amt. and 2.6 mol. amt.
to 3, respectively, in Et2O, À78 ꢁC), ketone 3 was quickly
consumed, and direct warming of the resulting lithium alkoxide,
gratifyingly, yielded the ring-enlarged product 5 in 82% yield
(Scheme 1, entry 1). By contrast, when the above reaction was
immediately quenched with H2O at À78 ꢁC (entry 2), the only
product was the ring-opened ketone 4 in 84% yield. These results
gave us a mechanistic insight that the process is comprised of two
consecutive electrocyclic reactions, (1) ring opening of the
dialkenylcyclobutene, and (2) subsequent closure of the resulting
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
1043
Table 1.a
Scheme 2.
with respect to two alkenyl groups, as shown by NOE study.
These results are consistent with a mechanistic proposal
summarized in Scheme 3. There exists a seemingly opposite
tendency in the relative reactivities of the alkoxide vs the acetate
in the two electrocyclic processes: The initial ring opening of the
four-membered ring is faster with the lithium alkoxide 11,
whereas the subsequent 8ꢀ ring closure of tetraene is faster with
acetate 10 than the corresponding lithium alkoxide 12.8
In summary, the present [4 þ 2 þ 2] approach to the
cyclooctenone derivatives starting from cyclobutenes and dienes
should find utility in natural product synthesis, and further studies
are currently underway in our laboratories.
Scheme 3.
References and Notes
This finding was not only mechanistically interesting, but
allowed us to establish a rapid, high-yielding synthetic protocol
for constructing eight-membered ring compounds. Indeed, when
cyclobutenone 14, having a butyl group on the four-membered
ring, was treated with 2-propenyllithium (À78 ! 0 ꢁC) followed
by Ac2O (0 ! 25 ꢁC), the ring expansion occurred to give eight-
membered compound 16 in 83% yield (entry 1, Table 1). Under a
similar set of conditions with acetylation, reaction of 3 with cis-2-
butenyllithium and cyclopentenyllithium proceeded smoothly to
give cyclooctatrienes 17 and 18 in 88% and 91% yield,
respectively (entries 2 and 3). Alkenylcyclobutenone 15, with a
cyclic alkenyl moiety, was also a good substrate for the clean ring
expansion (entry 4).
Compounds 16–19 were hydrolyzed by either of two
procedures, (1) K2CO3, MeOH, 0 ! 25 ꢁC, 2–3 h (for 16 and
17), or (2) 2 M NaOH, MeOH, 0 ꢁC, 1 h (for 18 and 19)9 to give the
corresponding ketones 20–23 in high yields, respectively.
Compounds 21 and 22 were solely or mainly composed of the
cis isomers with respect to the relation of vicinal dialkyl groups as
evidenced by X-ray analysis.10
1
2
3
T. Hamura, S. Tsuji, T. Matsumoto, and K. Suzuki, Chem Lett., 2002, 280.
T. Hamura, S. Tsuji, T. Matsumoto, and K. Suzuki, Chem Lett., 2002, 750.
For the difficulty in forming eight-membered rings, and the strain inherent in such
medium rings, see: a) G. Mehta and V. Singh, Chem. Rev., 99, 881 (1999). b) N. A.
Petasis and M. A. Patane, Tetrahedron, 48, 5757 (1992).
4
5
For related [4 þ 2 þ 2] approaches, see: a) L. A. Paquette and J. Tae, Tetrahedron
Lett., 38, 3151 (1997). b) L. A. Paquette and T. M. Morwick, J. Am. Chem. Soc.,
119, 1230 (1997). c) M. Zora, I. Koyuncu, and B. Yucel, Tetrahedron Lett., 41,
7111 (2000).
a) R. L. Danheiser and H. Sard, Tetrahedron Lett., 24, 23 (1983). b) R. L.
Danheiser and S. Savariar, Tetrahedron Lett., 28, 3299 (1987). c) R. L. Danheiser,
S. Savariar, and D. D. Cha, Org. Synth., Coll. Vol. VIII, 82 (1993). d) A. Hassner
and J. L. Dillon, Jr., J. Org. Chem., 48, 3382 (1983).
6
7
T. Hamura, M. Kakinuma, S. Tsuji, T. Matsumoto, and K. Suzuki, Chem. Lett.,
2002, 748.
We thank Ms. Sachiyo Kubo, this department, for X-ray analysis. Crystal-
lographic data reported in this paper have been deposited with Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC-192410.
Copies of the data can be obtained free of charge on application to CCDC, 12
Unions Road, Cambridge, CB2 1EZ, UK (fax: (+44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
8For a related precedent, see: K. C. Nicolaou, N. A. Petasis, R. E. Zipkin, and J.
Uenishi, J. Am. Chem. Soc., 104, 5555 (1982).
9
Hydrolysis of compounds 18 and 19 with K2CO3 in MeOH gave lower yields of
products.
10 The stereochemistry of 23 is currently under study, which will be reported in a full
paper.