Stereoselective synthesis of electrophilic spirocyclopropanes in ionic liquids

Article abstract of DOI:10.1016/S0040-4039(00)01593-8

The reaction of β-oxosulfides of benzothiazole with Michael acceptors, in liquid tetrabutylammonium bromide and sodium bicarbonate as base, allows a stereoselective synthesis of spirocyclopropanes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01593-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8977–8980
Stereoselective synthesis of electrophilic spirocyclopropanes
in ionic liquids
Vincenzo Calo`, Angelo Nacci,* Luigi Lopez and Vito Luigi Lerario
Centro CNR ‘MISO’, Dipartimento di Chimica, Universita` di Bari, via Amendola 173-70126 Bari, Italy
Received 10 July 2000; revised 30 August 2000; accepted 14 September 2000
Abstract
The reaction of b-oxosulfides of benzothiazole with Michael acceptors, in liquid tetrabutylammonium
bromide and sodium bicarbonate as base, allows a stereoselective synthesis of spirocyclopropanes. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: cyclopropanation; stereocontrol; ionic liquids; benzothiazole; sulfides.
Cyclopropane derivatives have gained importance in the field of natural and non-natural
products for their insecticidal, cytostatic and antiinfective properties, such as those of the
antibiotic ciprofloxacin.1 A widely explored synthesis of electrophilic cyclopropanes involves a
cyclization reaction initiated by the conjugate addition of suitable nucleophiles, such as
a-halo,2–4 a-sulfide,5 a-sulfinate6 and a-sulfonate carbanions,7,8 to an electron-deficient alkene,
followed by expulsion of the leaving group (Scheme 1). However, this conceptually simple
synthetic methodology presents some drawbacks such as the use of toxic solvents, strong bases,
lack of stereoselectivity and easy ring cleavage of the electrophilic spirocyclopropanes by
nucleophiles.9
Scheme 1. LG=Br; Cl; SR; SOR, SO2R. R=CO2R; CN; COAr, EWG=CO2R; NO2; CN; COAr
* Corresponding author. Fax: +39-080-544-29-24; e-mail: nacci@chimica.uniba.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01593-8

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To circumvent some of these problems, in the first instance, we chose as pronucleophiles
b-ketosulfides of benzothiazole 1, which are easily deprotonated by weak bases,10 butyl acrylate
as the Michael acceptor and sodium acetate as the base in DMF or DMA as solvents (Scheme
2).
Scheme 2.
Although the S-benzothiazolyl group proved to be a good leaving group, the results were
disappointing as the reaction afforded a mixture of cyclopropane isomers 2 and the Michael
addition product 3, in low yield and these were difficult to isolate from the reaction medium.
Owing to our interest in the use of ionic liquids,11 we substituted DMF (harmful solvent) with
tetrabutylammonium bromide (TBAB) in the presence of sodium bicarbonate as base. Surpris-
ingly, in the reactions of cyclic and acyclic carbonyl sulfides of benzothiazole (5, 7, 9, 11, 13)
with butyl acrylate, we observed the formation, in one-step, of trans spiro or simple cyclo-
propanes (6, 8, 10, 12, 14) with good yields and a high degree of stereoselectivity (Scheme 3,
Table 1, runs 1–5).
Scheme 3.
Besides water and carbon dioxide, the Michael addition by-product (4) of the S-benzothia-
zolyl leaving group and acrylate was also formed. Therefore, the use of a mild base and the
formation of neutral by-products, may enable the survival of more reactive cyclopropanes
towards acidic or basic reagents. Different Michael acceptors, like methacrylate or enones (runs
6–7), may be successfully used to give trisubstituted and condensed cyclopropanes 15 and 16,
respectively, together with the corresponding, different by-products. In order to account for the
observed stereoselectivity, we believe that both steric interactions between the two carbonyl
groups and the high solvent polarity may influence the stereoselectivity of these
cyclopropanations.12,13
An additional merit of these reactions lies in the simple separation procedure14 of the reaction
products from the ionic liquid. Cyclopropanes are isolated by vacuum distillation or Soxhlet
extraction with hexane, thus allowing recycling of the ionic liquid. Work is in progress studying
the stereospecificity of cyclopropanations under these conditions.

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Table 1
Synthesis of cyclopropanes in TBABa
Acknowledgements
This work was in part financially supported by Ministero dell’Universita` e della Ricerca
Scientifica e Tecnologica, Rome, and the University of Bari (National Project: ‘‘Stereoselezione
in Sintesi Organica: Metodologie ed Applicazioni’’).
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14. Typical procedure: a Pyrex reaction flask was charged with tetrabutylammonium bromide (5 g) and heated at
110°C. To the stirred molten salt were added the lactone 9 (1.06 g, 4 mmol), butyl acrylate (1.54 g, 12 mmol) and
sodium bicarbonate (0.67 g, 8 mmol). After completion of the reaction, the mixture was extracted in a Soxhlet
apparatus with hexane for 1 h. After evaporation of the solvent, the residue was chromatographed on silica gel
(eluent, hexane/ethyl acetate 5:1) to give, besides 4, the spirocyclopropane 10 in a 70% yield as a pale yellow
1
liquid. H NMR (CDCl3) (l ppm): 0.88 (3H, t, J=7.4 Hz), 1.32 (1H, dd, J=6.5 4.0 Hz), 1.34 (2H, sextet, J=7.5
Hz), 1.57 (2H, quintet, J=7.5 Hz), 1.73 (1H, dd, J=8.7 4.0 Hz), 1.80–2.03 (4H, m), 2.50 (1H, dd, J=8.7 6.5 Hz),
4.05 (2H, t, J=6.3 Hz), 4.32–4.45 (2H, m).13C NMR (CDCl3) (l ppm): 13.5, 18.9, 22.9, 23.1, 24.2, 27.3, 29.1,
30.5, 64.8, 70.4, 169.9, 171.9. GC–MS (EI) m/z (%):171 (0.9, M+−55), 152 (29.8), 124 (100), 79 (23.0), 55 (31.0).
IR (liquid film) w=2961, 1719, 1460, 1402, 1349, 1298, 1263, 1153, 1078, 1018, 940, 802, 749 cm−1. The
stereochemistry of the spirocyclopropane 10 has been determined by performing a shift reagent experiment: upon
addition of 20 mol% of Eu(fod)3 the absorption of the cyclopropane protons at l=1.32 (HC), 1.73 (HB) and 2.50
(HA) shift to 2.07, 2.72 and 3.69 ppm, respectively. This indicates that HB and HA are both cis to the lactone
carbonyl.
.