Edge Article
Chemical Science
isolated precursors showed a good trend with calculated acti-
vation energies, allowing estimates of rearrangement tempera-
tures to be made before synthesis. Comparison of predictions
made by electronic structure calculations with experimental
activation energies for piperonyl 22a and literature examples
showed that the (U)M05-2X/6-31+G* method remained the most
accurate for assessing VCPR, but M06-2X/6-31G* calculations
were better for the aromatic-vinylcyclopropane rearrangement.
No single method stood out overall but the consistency in error
observed with (U)B3LYP/6-31G* calculations for both pathways,
meant that it came closest to a universal method for dealing
with the reaction manifold. There was no simple relationship
between the amount of HF-exchange and the accuracy of the
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Acknowledgements
1
We thank Dr Vipulkumar Patel (GSK, Flexible Discovery Unit) 16 (a) D. K. Lewis, D. J. Charney, B. L. Kalra, A.-M. Plate,
and the University of Strathclyde (studentship to D.O.), for
funding, the EPRSC National Mass Spectrometry Service Centre,
Swansea for accurate mass measurements, Craig Irving for help
M. H. Woodard, S. J. Cianciosi and J. E. Baldwin, J. Phys.
Chem. A, 1997, 101, 4097–4102; (b) W. R. Dolbier and
S. F. Sellers, J. Am. Chem. Soc., 1982, 104, 2494–2497.
with variable temperature NMR kinetic work and Dr Tell Tuttle 17 (a) L. A. Buttle and W. B. Motherwell, Tetrahedron Lett., 1994,
(
University of Strathclyde) and Dr Colin Edge (GSK, Department
35, 3995–3998; (b) F. Barth and C. O. Yang, Tetrahedron Lett.,
1991, 32, 5873–5876; (c) T. Taguchi, M. Kurishita, A. Shibuya
and K. Aso, Tetrahedron, 1997, 53, 9497–9508; (d) T. Mase,
I. N. Houpis, A. Akao, I. Dorziotis, K. Emerson, T. Hoang,
T. Iida, T. Itoh, K. Kamei, S. Kato, Y. Kato, M. Kawasaki,
F. Lang, J. Lee, J. Lynch, P. Maligres, A. Molina, T. Nemoto,
S. Okada, R. Reamer, J. Z. Song, D. Tschaen, T. Wada,
D. Zewge, R. P. Volante, P. J. Reider and K. Tomimoto,
J. Org. Chem., 2001, 66, 6775–6786; (e) P. E. Harrington,
L. Li and M. A. Tius, J. Org. Chem., 1999, 64, 4025–4029; (f)
C. Qing-Yun, J. Fluorine Chem., 1995, 72, 241–246; (g)
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of Platform Technology and Science) for helpful suggestions.
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