carried out in refluxing chlorobenzene; in octane, the major
compound was the corresponding acetamide 10c-e. Thus,
in contrast to the tert-butyl substituted radical 6a, where the
Smiles rearrangement is faster than reduction with octane,
radicals 6c-e, possessing a smaller group on the nitrogen,
underwent the 4-exo addition less rapidly than hydrogen
abstraction from the solvent, which must proceed at com-
parable rates for radicals 6a and 6c-e.
Scheme 2. Smiles Rearrangement through a Spiroazetidinone
Further compelling evidence for the intermediacy of a
spiroazetidinone and amidyl radicals 7 and 8 emerged when
we examined the extension to benzene derivatives. Xanthate
12 was prepared by reaction of 2-chloroaniline with tert-
butyl trichloroacetimidate in the presence of BF3‚OEt2,4
followed by chloroacetylation and displacement of the
chlorine with potassium O-ethyl xanthate. We expected 12
to be less reactive than the analogous pyridine derivative
3a, but our worries proved unfounded. Exposure of 12 to
lauroyl peroxide in refluxing octane also produced a good
yield (73%) of the rearranged product 13. Unexpectedly,
under the same conditions, toluidine analogue 14 furnished
the rearranged dimer 16 in 55% yield, along with the product
of direct reduction 15 (23%). Dimer 16 can only arise from
coupling of benzylic radicals 18, themselves derived by an
internal 1,6 hydrogen atom abstraction by the intermediate
amidyl radical 17 (Scheme 3). We had found that a clean
formation of dimers is possible in the xanthate transfer
process when a stabilized radical is generated,5 and this has
profound mechanistic implications which set the xanthate
transfer apart from other Kharasch-type reactions. Replacing
the methyl with a trifluoromethyl group blocked the hydrogen
abstraction step and the “normal” product 20 was now
obtained in 46% yield from xanthate 19.
A further interesting observation arose when we examined
the case of xanthate 22a, with two chlorine atoms in the
ortho positions. The substitution step itself from the chloride
precursor 21a proved problematic, and we had to switch to
the corresponding neopentyl xanthate. We have in the past
resorted to the more robust O-neopentyl xanthates in difficult
cases.6 The sluggish substitution reflects the severe steric
congestion and the consequent conformational restrictions
in that part of the molecule. When xanthate 22a was
subjected to the action of the peroxide in refluxing octane
(0.1 M), the Smiles product 23a was formed, accompanied
this time by the unexpected symmetrical diarylethane 24 in
a 75:25 ratio as determined by NMR. The isolated yield of
23a was 55%, but the rather nonpolar 24 could not be
obtained completely pure because of contamination by
residues from lauroyl peroxide. No dichloroacetanilide 25a,
the product of simple reduction of the xanthate, was
observed.
but we are not aware of any report claiming a radical Smiles
rearrangement proceeding through a four-membered ring. In
the present case, steric repulsion between the chlorine atom
and the bulky tert-butyl group hinders the desired ring closure
of radical 6a into 9a. The tert-butyl group further compresses
the radical terminus toward the pyridine ring and favors an
otherwise difficult 4-exo-cyclization, as a prelude to the
unusual Smiles rearrangement. As depicted in Scheme 2, a
reactive amidyl radical 8a is generated which abstracts a
hydrogen atom from the medium but which can also undergo
a number of undesired side reactions accounting for the
modest yield of 5a. The yield of amide 5a increased to 71%
when chlorobenzene was replaced with octane, a solvent with
better hydrogen atom donating ability. The choice of octane
is important because it behaves as a good hydrogen atom
donor toward the reactive amidyl radical 8a but as poor
hydrogen atom donor toward the less electrophilic initial
radical 6a, thus giving the latter enough lifetime to undergo
the Smiles rearrangement. Otherwise, premature reduction
of 6a would result in the generation of uninteresting amide
10a. In the same manner, xanthate 3b furnished the corre-
sponding rearranged amide 5b in 71% yield.
The importance of the steric bulk of the tert-butyl group
was revealed by studying the behavior of xanthates 3c-e
under similar conditions. For instance, in the case of 3c with
a comparatively small methyl group on the nitrogen, the
Smiles rearrangement was not observed. The corresponding
azaoxindole 4c now became the major product and could
be isolated in 39% yield, along with smaller amounts of the
reduced acetamide 10c (9%). The higher analogues 3d and
3e, with moderately bulky isopropyl and cyclohexyl groups,
gave a mixture of all three compounds 4d, 5d, and 10d in
18, 31, and 9% yield and 4e (traces), 5e, and 10e in 42 and
10% yield, respectively. These series of experiments were
The formation of compound 24 can, logically, only arise
through the dimerization of radical 28, itself generated by
loss of tert-butyl isocyanate either by rupture of the azeti-
(4) Anderson, J. C.; Cran, J. W.; King, N. P. Tetrahedron Lett. 2002,
21, 3849-3852.
(5) For a mechanistic discussion, see: Tournier, L.; Zard, S. Z.
Tetrahedron Lett. 2005, 46, 455-459.
(3) (a) Studer, A. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 44-60. (b) Studer,
A.; Bossart, M. Tetrahedon 2001, 57, 9649-9667.
(6) See for example: Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc.
1996, 118, 9190-9191.
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Org. Lett., Vol. 7, No. 17, 2005
Bacque, Eric
