Reaction of 4-methoxy-4-(1-methylethenyl)-2-cyclobutenone derivatives with 2-lithiopropene and α-lithiostyrene: Synthesis of eight-membered ring carbocycles

Article abstract of DOI:10.1016/S0040-4039(00)01173-4

2-Alkyl- or phenyl-substituted 4-methoxy-4-(1-methylethenyl)-2-cyclobutenones react with 2-lithiopropene or α-lithiostyrene to produce 4-methoxy-2,4-cyclooctadienones in moderate yield, accompanied by varying amounts of 4-methoxy-4-(1-methylethenyl)-2-cyclohexenones. The reaction is general for 2-alkyl substituted 4-methoxy-4-(1-methylethenyl)-2-cyclobutenones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01173-4

Tetrahedron Letters 41 (2000) 7111±7114
Reaction of 4-methoxy-4-(1-methylethenyl)-2-cyclobutenone
derivatives with 2-lithiopropene and a-lithiostyrene: synthesis
of eight-membered ring carbocycles
Metin Zora,* Ilkay Koyuncu and Baris Yucel
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 3 April 2000; revised 3 July 2000; accepted 12 July 2000
Abstract
2-Alkyl- or phenyl-substituted 4-methoxy-4-(1-methylethenyl)-2-cyclobutenones react with 2-lithiopropene
or a-lithiostyrene to produce 4-methoxy-2,4-cyclooctadienones in moderate yield, accompanied by varying
amounts of 4-methoxy-4-(1-methylethenyl)-2-cyclohexenones. The reaction is general for 2-alkyl substituted
4-methoxy-4-(1-methylethenyl)-2-cyclobutenones. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: cyclooctadienones; cyclohexenones; cyclobutenones; eight-membered rings; cycloadditions.
Recently, the construction of eight-membered ring compounds has attracted considerable
attention since they constitute common structural cores of a large number of biologically important
compounds.1 Among the numerous methods available, ring enlargement of small ring
compounds occupies an important position.2 For this purpose, squaric acid is a fascinating C4-
synthon with four-membered ring strain to drive reactions. The ready availability of numerous
cyclobutenediones and cyclobutenones from squaric acid has opened the way to development of
the syntheses of highly functionalized ring systems.3 In this regard, the syntheses of polyquinanes
from squarate esters have been intensively studied by the Paquette research group.4 6 They have
shown that the reaction of cyclobutenedione 1 with 2-lithiopropene a€orded 5,5-fused ring
carbocycle 5 as a major product (Scheme 1).4 Although 5,5-fused ring formation proceeds via
eight-membered ring intermediates such as 2 and 3, no eight-membered structure has been
observed as an end product in these reactions, due to a spontaneous transannular ring closure of
3 to 5 via intramolecular aldol reaction.4 6
A new synthetic route to eight-membered ring carbocycles can be realized if the reaction
sequence in Scheme 1 is stopped at the stage of eight-membered ring intermediate 3. This may be
achieved by replacing the lithium enolate moiety of 3 by an enol ether, i.e. by forming the stable
* Corresponding author. Fax: +90-312-210 1280; e-mail: zora@metu.edu.tr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01173-4

7112
Scheme 1.
derivatives of general structure 4 by alternative reaction processes. As part of a program to
develop a new cycloaddition reaction for the preparation of carbocyclic eight-membered rings, we
have investigated the reaction of cyclobutenones 6 with vinyllithiums 7, which a€orded cyclo-
octadienones 8, accompanied by varying amounts of cyclohexenones 9, or 5,5-fused ring carbocycles
10 (Scheme 2). We herein report the preliminary results of our study.
Scheme 2. Compound 6: (A) R1=Me; (B) R1=Bu; (C) R1=Ph; (D) R1=i-PrO; Compound 7: (A) R2=Me; (B) R2
=Ph; compounds 8, 9 and 10: see footnote a in Table 1
The starting cyclobutenones 6 were readily prepared from the corresponding cyclobutene-
diones 117 according to known literature procedures (Scheme 3). Addition of 2-lithiopropene
(7A)4 to cyclobutenedione 11 led to formation of cyclobutenone 12,7 which was then methylated
by using iodomethane and silver oxide to a€ord the cyclobutenone 6.8
Scheme 3. Compounds 6, 11 and 12: (A) R1=Me; (B) R1=Bu; (C) R1=Ph; (D) R1=i-PrO. Yields: 12A: 70%; 12B:
84%; 12C: 72%; 12D: 78%; 6A: 56%; 6B: 67%; 6C: 44%; 6D: 70%
As depicted in Scheme 2, cyclobutenone derivatives (6A±D)7 were reacted with equimolar
amounts of 2-lithiopropene (7A)4 or a-lithiostyrene (7B)4 at ^78ꢀC in THF under argon for 3
hours. Upon further stirring the mixture at room temperature overnight, followed by hydrolysis,
the products were isolated by column chromatography. The results are summarized in Table 1.
The reaction of 6A with 7A produced the cyclooctadienone derivative 8A (Entry A).9 A complication
in this reaction was the formation of the cyclohexenone derivative 9A as a mixture of two
diastereomers.10 A similar trend was observed in the reaction of cyclobutenone 6B with 7A, where
cyclooctadienone 8B and cyclohexenones 9B were obtained (Entry B). However, the reaction

7113
Table 1
Reaction of cyclobutenones 6 with vinyllithiums 7
between 6C and 7A revealed a complex reaction mixture; only the cyclooctadienone 8C could be
isolated (Entry C). The reaction of a-lithiostyrene (7B) with cyclobutenones 6A and 6B produced
the expected cyclooctadienones 8D and 8E, respectively, without formation of any cyclohexenones
such as 9D and 9E (Entries D and E). These results imply that both processes, cyclooctadienone-
and cyclohexenone-forming reaction, or one of them can be operative depending upon the
substitution pattern of starting cyclobutenones 6 and vinyllithiums 7. Interestingly, the reaction
of 6D with 7A led to a formation of two diastereomers of 5,5-fused ring carbocycle 10F;5 none of
the expected cyclooctadienone 8F and cyclohexenone diastereomers 9F were observed (Entry F).
Formation of the diastereomeric 5,5-fused ring carbocycles 10F may not actually represent a
di€erent reactivity pattern, since they are secondary products of the reaction and result from the
initially formed cyclooctadienone 8F by a transannular ring closure, as in the case of conversion
of 3 to 5 as shown in Scheme 1.6 For instance, compound 8A yields 10A when subjected to acidic
hydrolysis. Apparently, the substituent at the 2-position of cyclooctadienone 8 (i.e. R1) controls
whether transannular cyclization to 10 occurs. As can be seen in Table 1, cyclooctadienone
formation is general for 2-alkyl or phenyl substituted cyclobutenones (6A±C).
Scheme 4. R1 and R2 for compounds 6 and 7: see Scheme 2; compounds 8±15: see footnote a in Table 1

7114
The mechanism proposed for the formation of products 8 and 9 is outlined in Scheme 4.11 It
®rst involves the addition of vinyllithium 7 to cyclobutenone 6, leading to a mixture of cis- and
trans-divinyl substituted cyclobutenes 11 and 12.11 Cyclobutene 11 undergoes anionic oxy-Cope
rearrangement to give 13. However, cyclobutene 12 experiences a conrotatory electrocyclic ring
opening to a€ord 14, which yields the enolates 13 and 15 by 8p and 6p electrocyclization,
respectively.10,11 Hydrolysis of 13 and 15 produces the compounds 8 and 9. As noted before, the
substitution pattern of the reactants determines the reaction pathway leading to formation of 8
and/or 9.
In summary, we have developed a new method for the synthesis of cyclooctadienones. Further
investigation of the mechanism, scope and limitations of this process is currently under investigation,
as well as delineation of the factors which in¯uence cyclooctadienone versus cyclohexenone and
cyclooctadienone versus 5,5-fused ring formation.
Acknowledgements
We thank the Scienti®c and Technical Research Council of Turkey (TBAG-1433), State
Planning Organization of Turkey (DPT-98K122490), and Research Board of Middle East
Technical University (AFP-98-01-03-06) for support of this research.
References
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Machrouhi, F. J. Org. Chem. 1999, 64, 4119±4123. (b) Takahashi, T.; Sun, W.-H.; Liu, Y.; Nakajima, K.; Kotora,
M. Organometallics 1998, 17, 3841±3843. (c) Wender, P. A.; Nuss, J. M.; Smith, D. B.; Suarez-Sobrino, A.;
Vagberg, J.; Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908±4809. (d) Wender, P. A.; Ihle, N. C. J. Am.
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1242±1253. (c) See also Refs. 4±6 and 9.