Access to 1,2-diketones by an unusual radical cascade

Article abstract of DOI:10.1039/c0cc04725b

An unusual radical fragmentation of an unstrained cyclohexane structure was observed leading to complex 1,2-diketones.

Full text of DOI:10.1039/c0cc04725b

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 3296–3298
www.rsc.org/chemcomm
COMMUNICATION
Access to 1,2-diketones by an unusual radical cascadewz
Rama Heng* and Samir Z. Zard*
Received 1st November 2010, Accepted 19th January 2011
DOI: 10.1039/c0cc04725b
An unusual radical fragmentation of an unstrained cyclohexane
structure was observed leading to complex 1,2-diketones.
In an earlier study directed at the synthesis of pleuromutilin 3,
we found that it was possible to construct the bridging eight-
membered ring by a radical cyclisation starting with xanthate
1 and leading to product 2 in fairly good yield (Scheme 1).1,2
Such 8-endo radical ring closures are quite rare,3 but could
nevertheless constitute an interesting approach to various
polycyclic terpenes containing a cyclooctane sub-unit. In this
respect, we examined the possibility of extending this route to
a model of the AB ring system found in taxol 4. While our
efforts towards this goal have not yet been successful, we
stumbled in the course of this work across a very unusual
radical cascade allowing a rapid access to complex 1,2-
diketones.
Xanthate 10a was prepared from 2-methyl-2-cyclohexenone
using standard reactions (Scheme 2).4 The sequence
5
furnished compound 10a as essentially one diastereoisomer,
Scheme 2 An unexpected fragmentation leading to a 1,2-diketone.
which proved to be the one with the undesired relative
stereochemistry. The trans- disposition of the allyl group and
the side-chain bearing the xanthate precludes any possibility of
cyclisation. However, before the relative stereochemistry of 10a
was unambiguously determined, we subjected the compound to
the cyclisation conditions, namely refluxing in chlorobenzene in
the presence of lauroyl peroxide as an initiator. We were
surprised to find that the reaction required stoichiometric
amounts of peroxide for complete consumption of the starting
material and, moreover, the product was unexpectedly diketone
11a, isolated in moderate yield (45%).
The most logical mechanistic rationale for this transformation
is outlined in Scheme 3. Attack by the radicals from the peroxide
on xanthate 10a generates radical 12a, which is well positioned to
abstract a tertiary hydrogen to form 13a.5 Fragmentation then
furnishes radical 14a, which ultimately evolves into diketone 11a.
The last step could proceed by electron transfer to the peroxide to
give the corresponding cation, followed by loss of a proton.
Alternatively disproportionation with radicals derived from the
decomposition of the peroxide would also result in the formation
of the diketone. Both pathways could in fact be operating since
neither excludes the other.
Scheme 1 Model 8-endo cyclisation in the synthesis of pleuromutilin.
`
Laboratoire de Synthese Organique, CNRS UMR 7652, Ecole
Polytechnique, F-91128 Palaiseau, France.
E-mail: heng@dcso.polytechnique.fr, zard@poly.polytechnique.fr;
Fax: +33 169335972; Tel: +33 169335971
w This communication is dedicated with respect to the memory of
Professor Heinz Viehe.
One of the remarkable features of this sequence is the
rupture of an unstrained carbon–carbon bond. Such
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c0cc04725b
c
3296 Chem. Commun., 2011, 47, 3296–3298
This journal is The Royal Society of Chemistry 2011

View Article Online
Scheme 5 Modification of the initial radical sequence.
Not unexpectedly, replacing the allyl or methallyl groups by
simpler appendages resulted in significantly improved yields
for the process. This is illustrated by the transformations of
derivatives 10c–g, which gave the corresponding fragmenta-
tion products 11c–g in yields ranging from 64 to 74%
(Scheme 4). Furthermore, by attaching a cyclopropyl side-
chain it was possible to modify the course of the reaction
and confirm the existence of an intramolecular hydrogen
abstraction step. Thus, substrate 10h furnished product 17,
as one geometrical isomer (presumably the E isomer shown,
but this was not unambiguously ascertained), through the
mechanistic pathway delineated in Scheme 5. Radical 12h
derived from 10h undergoes translocation and typical opening
of the cyclopropyl ring rather than the much more difficult
fragmentation of the cyclohexane moiety. This leads to
primary radical 16, which rapidly transfers a xanthate group
from the starting material 10h to give the observed product 17
and radical 12h to propagate the chain process.
Scheme 3 Mechanistic rationale for the formation of 1,2-diketones.
fragmentations are relatively rare,6 in contrast to instances
where the carbon–carbon bond is part of a strained ring, as
epitomised by the case of the cyclopropylmethyl radical.7 In
the present case, the fragmentation is favoured by the high
stability of radical 14a, due to its capto-dative nature, as well
as by the relative persistence of intermediate radical 13a, which
gives the presumably slow fragmentation step time to occur.
The extended lifetime of radical 13a is the result of the
reversibility of its reaction with the starting xanthate 10a
leading to xanthate 15a and starting radical 12a. More
generally, the reversible exchange of the xanthate group
increases the effective lifetime of most radicals in the medium
and often allows transformations that would be very difficult
to accomplish by other methods.2
Another interesting aspect is the survival of the delicate
skipped diene motif to the reaction conditions. In a related
example, compound 10b was converted into 11b in identical
yield (45%; Scheme 4). In both of these transformations, the
modest yield could be due to the competing intermolecular
addition of radicals 12a and 12b (not shown) derived from
xanthates 10a and 10b to the terminal alkene in the corres-
ponding fragmentation products 11a and 11b. Indeed, the
efficient intermolecular addition to alkenes, especially
unhindered terminal alkenes, is one of the hallmarks of the
xanthate transfer process.2
The complete scope of this new radical cascade, as well as its
synthetic implications, still remains to be ascertained, but the
present preliminary results reveal nevertheless an unusual and
rather counterintuitive approach to complex 1,2-diketones.
Such 1,2-diketones, which embody a very rich chemistry,
would be quite tedious to be obtained by more conventional
routes.
We thank Ecole Polytechnique for a scholarship to one of us
(R. H.).
Notes and references
1 E. Bacque, M. El Qacemi and S. Z. Zard, Org. Lett., 2004, 6, 3671.
´
2 For reviews of the xanthate transfer, see: S. Z. Zard, Angew. Chem.,
Int. Ed. Engl., 1997, 36, 672; S. Z. Zard, Xanthates and Related
Derivatives as Radical Precursors in Radicals in Organic Synthesis,
ed. P. Renaud and M. P. Sibi, Wiley-VCH, Weinheim, 2001, vol. 1,
pp. 90–108; B. Quiclet-Sire and S. Z. Zard, Top. Curr. Chem., 2006,
264, 201; B. Quiclet-Sire and S. Z. Zard, Chem.–Eur. J., 2006, 12,
6002.
3 A. Srikrishna, Unusual Radical Cyclizations in Radicals in Organic
Synthesis, ed. P. Renaud and M. P. Sibi, Wiley-VCH, Weinheim,
2001, vol. 2, pp. 151–187; B. Giese, B. Kopping, T. Gobel,
¨
J. Dickhaut, G. Thoma, K. J. Kulicke and F. Trach, Org. React.,
1995, 48, 301.
4 (a) F. A. Van-Catledge, D. W. Boerth and J. Kao, J. Org. Chem.,
1982, 47, 4096; (b) L. Baker and T. Minehan, J. Org. Chem., 2004,
69, 3957.
5 L. Feray, N. Kutznetsov and P. Renaud, Hydrogen Atom Abstraction
in Radicals in Organic Synthesis, ed. P. Renaud and M. P. Sibi,
Wiley-VCH, Weinheim, 2001, Vol. 2, pp. 246–278.
Scheme 4 Further examples of an unusual radical fragmentation.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3296–3298 3297

View Article Online
6 For recent examples, see: (a) F. M. Kessabi, T. Winkler, J. A. R.
Luft and K. N. Houk, Org. Lett., 2008, 10, 2255; (b) J. A. R. Luft,
T. Winkler, F. Murphy Kessabi and K. N. Houk, J. Org. Chem.,
2008, 73, 8175; (c) N. Cholleton, I. Gauthier-Gillaizeau, Y. Six and
S. Z. Zard, Chem. Commun., 2000, 535; See also: (d) I. J. Rosenstein,
Radical Fragmentation Reactions in Radicals in Organic Synthesis,
ed. P. Renaud and M. P. Sibi, Wiley-VCH, Weinheim, 2001, vol. 1,
pp. 50–71.
7 A. Gansauer and M. Pierobon, Radical Rearrangements of
¨
Cyclopropanes and Epoxides in Radicals in Organic Synthesis, ed.
P. Renaud and M. P. Sibi, Wiley-VCH, Weinheim, 2001,
vol. 2, pp. 207–220.
c
3298 Chem. Commun., 2011, 47, 3296–3298
This journal is The Royal Society of Chemistry 2011