Reductive Ring-Expansion of 1-Bromoalkyl-2-Oxocycloalkanecarboxylates at Silver Cathodes

Free-radical ring-expansion reactions are useful for the synthesis of a variety of organic compounds; these reactions are especially attractive for the preparation of large rings in natural products.¹  One such ring expansion, outlined by Dowd and Choi,² employs tri-n-butyltin hydride in the presence of 2,2′-azobis(2-methylpropionitrile), commonly referred to as AIBN, to cleave a carbon–halogen bond and to induce ring expansion.  These reagents are efficient, but are also environmentally dangerous.  To remove the need for these harmful chemicals, our laboratory (which has a long-standing interest in the reductive cleavage of organic halides) has previously utilized glassy carbon cathodes to initiate reductive ring expansion and has obtained modest yields—up to 26%—of the ring-expanded product.³  More recently, it has been discovered that silver cathodes have a catalytic ability to cleave carbon–halogen bonds.⁴   In the present work, we have explored the use of silver cathodes for reductive ring-expansion reactions of the subject compounds, and we have been able to achieve higher yields of ring-expanded products at less negative potentials than previously found through the use of glassy carbon electrodes.

                Figure 1 shows a cyclic voltammogram for the reduction of methyl 1-(bromomethyl)-2-oxocyclopentanecarboxylate (1) at a silver cathode in dimethylformamide (DMF) containing tetramethylammonium tetrafluoroborate (TMABF₄).  We attribute the first cathodic peak at approximately –0.4 V to reductive cleavage of the carbon–bromine bond, whereas the second cathodic peak at –1.4 V is due to reduction of the cyclopentanone moiety.  Interestingly, the first cathodic peak appears at a potential that is nearly 1 V more positive than that found with a glassy carbon electrode.  Two other substrates—methyl 1-(bromopropyl)-2-oxocyclopentanecarboxylate (2) and ethyl 1-(bromomethyl)-2-oxocyclohexanecarboxylate (3)—that have been studied exhibit similar electrochemical behavior (Figure 2).  

                Controlled-potential electrolyses have revealed that the electrochemically induced ring-expansion reaction occurs in a fashion similar to that of the original chemical reaction.  We have observed a one-electron reduction of 1that affords the desired ring-expanded product in high yield—up to 95%.  In addition to the ring-expanded product, side products (found by means of gas chromatography–mass-spectrometry) include a dehalogenated product and an unexpected side product that are shown in Figure 3.  Yields of the various products obtained from the three substrates mentioned in the preceding paragraph depend on the length of the haloalkane side-chain and on the size of the ring.

References

1.  Hierold, J.; Lupton, D. W. Org. Lett. 2012, 14, 3412–3415.

2.  Dowd, P.; Choi, S. C. Tetrahedron 1989, 45, 77–90.

3.  Mubarak, M. S.; Barker, W. E., IV, Peters, D. G. J. Electrochem. Soc. 2007, 154, F205–F210.   

4.  Isse, A. A.; Berzi, G.; Falciola, L.; Rossi, M.; Mussini, P. R.; Gennaro, A. Appl. Electrochem. 2009, 39, 2217–

     2225.