Conclusiones: esbozos de un análisis coyuntural y estructural

In order to investigate the use of homochiral disulfides as catalysts for

enantioselective [3 + 2] annulation reactions of alkenes, as described by Singleton et al.,^ it was necessary to first prepare the reagents. Thus, in an attempt to produce the methylenecyclopropane 5 from the rhodium acetate catalysed carbene insertion reaction of dimethyl diazomalonate 32 with 1,1-dimethylallene 33 (Scheme 10),^^ the starting reagents were first prepared.

- V

Rh(II) acetate dimer, 80 °C

Scheme 10

1,1-Dimethylallene 33^^ was prepared in 11% overall yield from the chlorination of the alcohol 34, with subsequent reduction of the chloride 35 with lithium aluminium hydride to give the product allene (Scheme 11).^^ Although this reaction was low yielding, sufficient allene was prepared for the rhodium acetate catalysed carbene insertion.

L1A1H4

Dimethyl diazomalonate 32^^ was prepared in 24% yield from naphthalene 2- sulfonyl azide^® and dimethyl malonate (Scheme 12)/^ the azide had been previously prepared from the reaction of naphthalene 2-sulfonyl chloride with sodium azide.^^

.SO2N3

J U ,

The procedure for the preparation of the methylenecyclopropane 5 as described by Singleton et al. involves heating a mixture of 1,1-dimethylallene 33 (1.39 g, 20 mmol), dimethyl diazomalonate 32 (0.74 g, 4.7 mmol) and a catalytic amount of rhodium(II) acetate dimer (0.5 mol%) in a sealed pressure tube to 80 °C for 4 h.^^ The sealed tube was then cooled to -78 °C before being opened, and then the reaction mixture was poured into water and extracted with ether, dried over sodium sulfate and the solvent removed under reduced pressure. Reportedly, Singleton et at. were able to isolate the product 5 in 85% yield by flash-column chromatography. Since the authors state that extreme caution must be exercised with this reaction, because high pressures are developed due to a large volume of N2 evolved, it was decided that carrying out the

reaction in a steel autoclave would be a safer procedure. Therefore, a mixture of 1,1- dimethylallene 33 (2.8 g, 40 mmol), dimethyl diazomalonate 32 (1.5 g, 9.4 mmol) and rhodium(II) acetate dimer (0.5 mol%) was placed in a glass tube inside the Teflon liner of the autoclave under argon, and heated to 80 °C for 4 h. The pressure rose to

approximately 6 Bar during the reaction. The autoclave was then left to cool before being opened and the same work-up as described by Singleton et al. was then performed. However, as judged by NMR spectroscopic analysis of the crude material, no product methylenecyclopropane 5 had been formed.

This reaction was repeated several times and it was necessary to prepare more of the starting reagents. However, since the same negative results were obtained with the repeated reactions it was decided to try an alternative procedure for the preparation of 5, using a modified procedure described by Padwa et al?^ Thus, a mixture of 1,1-

dimethylallene 33 (1.39 g, 20.4 mmol), dimethyl diazomalonate 32 (0.74 g, 4.7 mmol) and rhodium(II) trifluoroacetate dimer (0.5 mol%) in 1,2-dichloroethane (b.p. 83 °C, 2 cm^) under argon, was heated under reflux for 2 The solvent was removed under reduced pressure and, as judged by NMR spectroscopy no product 5 was present in the crude product.

Since the starting reagent methylenecyclopropane 5 could not be produced by a safe method, it was decided to abandon this part of the project and concentrate on other work.

4.4 Summary

A variety of novel allylation procedures, potentially involving p-scission of a p- alkylthioalkyl radical to give a thiyl radical and a product acrylate, have been

investigated and the most successful of these radical-chain reactions involved the use of triphenylsilane to convert the electrophilic alkylthiyl radical into a nucleophilic silyl radical. The best yield of 19 Ph3SiCH2C(C02Et)=CH2 obtained was 46% and no change in the reaction conditions could improve this moderate yield. The low yields of the products of reactions A - C (Scheme 2) could be attributed to competing

polymerisation of the reaction product and/or the starting acrylate 12.

Many known and novel ethyl 3-alkylthioacrylates, RSCH=CH(C02Et) have been prepared as substrates for proposed novel vinylation reactions, in which a p-thioalkyl radical is a key intermediate of the proposed radical-chain reaction. However, no

significant amount of product alkene was formed in any reaction studied and therefore it has been concluded that one or more steps in the postulated mechanism must be slow.

The use of homochiral thiyl radicals as catalysts for enantioselective [3 + 2] annulation reactions of alkenes, which proceed via p-alkylthioalkyl radicals as key intermediates, was not investigated since the starting reagent methylenecyclopropane 5 could not be produced using a safe and mild procedure.

4.5 References

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3. B .P . Roberts, Adv. Free-Radical Chem., 1980, 6, 225.

4. A. G. Davies and B. P. Roberts, J. Chem. Soc. (B), 1971, 1830.

5. J. L. Kice, Sulfur-Centered Radicals, in Free Radicals, ed. J. K. Kochi, Wiley- Interscience, New York, vol. 2, ch. 24, 1973, pp.718 - 724.

6. (a) D. A. Singleton and K. M. Church, J. Org. Chem., 1990, 55, 4780. (b) D. A. Singleton, K. M. Church and M. J. Lucero, Tetrahedron Lett., 1990, 31, 5551. (c) D. A. Singleton, C. C. Huval, K. M. Church and E. S. Priestley, Tetrahedron Lett.,

1991, 32, 5765. (d) C. C. Huval andD. A. Singleton, J. Org. Chem., 1994, 59,

2020. (e) C. C. Huval and D. A. Singleton, Tetrahedron Lett., 1994, 35, 689. (f) C. C. Huval, K. M. Church andD. A. Singleton, Synlett, 1994, 273.

7. V. P. J. Marti, V. Paul and B. P. Roberts, J. Chem. Soc., Perkin Trans. 2, 1986, 481.

8. D. H. R. Barton and D. Crich, J. Chem. Soc., Perkin Trans. 1, 1986, 1613. 9. B. P. Roberts, Chem. Soc. Rev., 1999, 28, 25.

10. W. J. Croxall, J. O. Van Hook and R. Luckenbaugh, J. Am. Chem. Soc., 1949, 71,

2736.

11. F. Bohlmann and E. Bresinsky, Chem. Ber., 1964, 97, 2109.

12. W. J. Croxall, L. R. Freimiller and E. Y. Shropshire, J. Am. Chem. Soc., 1950, 72,

4275.

13. G. M. Brooke and M. A. Quasem, J. Chem. Soc., Perkin Trans. 1, 1973,429. 14. P. D. Halphen and T. C. Owen, J. Org. Chem., 1973, 38, 3507.

15. K. K. Khullar and L. Bauer, J. Org. Chem., 1971, 36, 3038. 16. K.-M. Kim and B. P. Roberts, J. Chem. Res., 1998, 132 (S).

17. P. Girard, N. Guillot, W. B. Motherwell, R. S. Hay-Motherwell and P. Potier, Tetrahedron, 1999, 55, 3573.

18. W. J. Bailey and C. R. Pfeifer, J. Org. Chem., 1955, 20, 95.

20. G. G. Hazen, L. M. Weinstock, R. Connell and F. W. Bollinger, Synth. Commun., 1981,11(12), 947.

21. M. Regitze, J. Hooker and A. Liedhegener, Org. Synth., 1973, Coll. Vol. 5., 179. 22. A. Padwa, S. M. Sheehan and C. S. Straub, J. Org. Chem., 1999, 64, 8648.

Chapter 5

Radical-Chain Redox Rearrangement of Cyclic Benzylidene Acetais