A general strategy to spiro[4.n]alk-2-ene-1,6-diones and spiro[5.n]alk- 2-ene-1,7-diones via intramolecular acylation of α-sulfinyl carbanions

Article abstract of DOI:10.1016/S0040-4039(99)01897-3

A convenient and general synthetic method for spiro[4.n]alk-2-ene-1,6- diones and spiro[5.n]alk-2-ene-1,7-diones, which involves the intramolecular acylation of an α-sulfinyl carbanion, is described.

Full text of DOI:10.1016/S0040-4039(99)01897-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 377–380
A general strategy to spiro[4.n]alk-2-ene-1,6-diones and
spiro[5.n]alk-2-ene-1,7-diones via intramolecular acylation of
α-sulfinyl carbanions1
Manat Pohmakotr,∗ Tanasri Bunlaksananusorn and Patoomratana Tuchinda
Department of Chemistry, Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
Received 7 September 1999; accepted 6 October 1999
Abstract
A convenient and general synthetic method for spiro[4.n]alk-2-ene-1,6-diones and spiro[5.n]alk-2-ene-1,7-
diones, which involves the intramolecular acylation of an α-sulfinyl carbanion, is described. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: acylation; annulation; carbanions; spiro compounds; sulfoxides.
Spirocarbocyclic systems are of interest because they are commonly found as subunits of many natural
products. Synthetic methods directed to these classes of compounds have been extensively developed.2
In contrast to other procedures that are described for obtaining spirocarbocyclic compounds, there are
very few general methods available for the synthesis of spiro[4.n]alkane-1,6-diones and spiro[5.n]alkane-
1,7-diones.3 In the course of our studies on the intramolecular acylation of sulfinyl carbanions for the
preparation of cyclopentenone and cyclohexenone derivatives,4 we investigated a general route for the
construction of spiro[4.n]alk-2-ene-1,6-diones and spiro[5.n]alk-2-ene-1,7-diones. These compounds are
highly functionalized intermediates, which may be useful for further synthetic conversions.
Starting from readily available cyclic β-ketoesters 1a–c, the sulfoxides 2 or 3 could be obtained in good
overall yields by a simple base-catalyzed alkylation using 1,3-dibromopropane or 1,4-dibromobutane
(NaH/DMF, room temperature, overnight) followed by treatment of the resulting bromides with a
tetrahydrofuran solution of thiophenol and triethylamine, at 0°C to room temperature overnight, and
then oxidation of the resulting sulfides with sodium metaperiodate in aqueous methanol at 0°C. Having
considered the structures of the sulfoxides 2 and 3, it was found that the difference in acidities of the
protons alpha to the carbonyl and to the sulfinyl groups should allow selective deprotonation by an
appropriate base. As shown in Scheme 1, effective cyclization of the sulfoxides 2 and 3 to the desired
spiro-diones 7 and 8 required the protection of the carbonyl group in order to avoid the competitive
∗
Corresponding author. Tel: 066-02-2461358-74, ext. 1508; fax: 066-02-2477050; e-mail: scmpk@mahidol.ac.th
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01897-3

378
proton abstraction. We therefore planned to protect the carbonyl group as its enolate anion 4 before the
α-sulfinyl carbanion 5 was generated. Intramolecular acylation of α-sulfinyl carbanion 5 was expected
to provide the dienolate 6 and then the spiro-diones 7 and 8 after acidic workup. Initially, cyclisation of
the sulfoxide 2a was attempted by employing lithium diisopropylamide (LDA) as a base.
Scheme 1.
Thus, treatment of the sulfoxide 2a with LDA (4.0 equiv.) in tetrahydrofuran at −78°C for 1 h and
at 0°C for 2 h afforded a complex mixture of unidentified products. The reaction in the presence of
hexamethylphosphoramide (HMPA) under the same conditions gave similar results. These unsatisfactory
results might be due to low selectivity for the deprotonation of protons alpha to the keto and sulfinyl
groups of the sulfoxide 2a by the LDA and incomplete formation of the enolate anion 4 before formation
of the α-sulfinyl carbanion 5. On the other hand, treatment of the sulfoxide 3a under the same reaction
conditions afforded the expected spiro-dione 8a in 46% yield as a diastereomeric mixture after radial
chromatography. Cyclisation of the sulfoxide 3b under these conditions provided, however, a low yield
(20% yield) of the spiro-dione 8b along with a complex mixture of products. These unsatisfactory
results led us to use a less reactive base such as lithium hexamethyldisilazide (LiHMDS). As expected,
when the sulfoxide 2a was subjected to reaction with 4–4.5 equivalents of LiHMDS in THF in the
presence of HMPA at −78°C to room temperature overnight, followed by quenching the reaction mixture
with glacial acetic acid, the spiro-dione 7a was isolated in 83% yield as a diastereomeric mixture.
Cyclization of the other sulfoxides of types 2 and 3 was investigated and found to proceed smoothly
to give the corresponding spiro[4.n]dione 7 and spiro[5.n]dione 8 in moderate to good yields. The results
are summarized in Table 1. It is worthy to note that under the standard conditions, the 8-membered
ketosulfoxide 2c provided the desired spiro-dione 7c in 40–45% yield along with the ring-expansion
product 13 in 45% yield (Table 1, entry 3). Compound 13 resulted presumably from the intramolecular

379
Table 1
Preparation of the starting sulfoxides 2 and 3, spiro-diones 7 and 8 and spiro-endiones 9 and 10
nucleophilic addition of the initially formed α-sulfinyl carbanion 11 to the carbonyl group of the
cyclooctanone moiety followed by ring-expansion of the resulting β-alkoxyester 12 (Scheme 2).
Scheme 2.
Finally, conversion of the spiro-diones 7 and 8 into the corresponding spiro[4.n]alk-2-ene-1,6-diones 9
and spiro[5.n]alk-2-ene-1,7-diones 10 could be accomplished in good yields by refluxing in dry toluene
in the presence of calcium carbonate for 10 h as summarized in Table 1. Similarly, compound 13 could
be converted into compound 14 in 78% yield as the (E)-isomer under the same conditions.
To demonstrate the synthetic utility of our spiroannulation reaction, the spiro-ketosulfoxides 7b and
7c were transformed into phenylthio-substituted spiro-dienones 15a and 15b in moderate yields by
performing the Pummerer rearrangement using trifluoroacetic anhydride in acetonitrile in the presence
of a catalytic amount of methanesulfonic acid (0°C, 2 h) (Scheme 3).5 This type of highly functionalized
spiro compound may be useful in organic synthesis.
In summary, we have developed a general and facile approach for the construction of spiro[4.n]alk-2-
ene-1,6-diones 9 and spiro[5.n]alk-2-ene-1,7-diones 10 starting from simple cyclic β-ketoesters. These
types of spiro compound appear to be valuable intermediates in organic synthesis.

380
Scheme 3.
Acknowledgements
We thank the Institutional Strengthening Program, Faculty of Science, Mahidol University, for provi-
ding a research scholarship to T.B.
References
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