A new, practical access to amidyl radicals

Article abstract of DOI:10.1039/b405545d

Amidyl radicals are readily generated from N-allylsulfonimides by the action of a xanthate and a small amount of a peroxide as initiator. The process involves extrusion of sulfur dioxide from an N-amidosulfonyl radical by rupture of the nitrogen-sulfur bo

Full text of DOI:10.1039/b405545d

A new, practical access to amidyl radicals
Cécile Moutrille* and Samir Z. Zard
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, 91128 Palaiseau, France.
E-mail: zard@poly.polytechnique; Fax: +33(0)169333851; Tel: +33 (0)169334872
Received (in Cambridge, UK) 15th April 2004, Accepted 1st June 2004
First published as an Advance Article on the web 30th June 2004
Amidyl radicals are readily generated from N-allylsulfonimides
by the action of a xanthate and a small amount of a peroxide as
initiator. The process involves extrusion of sulfur dioxide from
an N-amidosulfonyl radical by rupture of the nitrogen-sulfur
bond; in some cases, the N-amidosulfonyl radical is prematurely
captured by the internal olefinic trap.
product was formed, which in fact turned out to be cyclic
sulfonamide 13a. It exhibited an NMR spectrum that was initially
misleading since it resembled that expected for the desired
compound, resulting from the amidyl radical cyclisation. The mass
spectrum, however, showed a molecular ion peak that was 64 units
higher than that calculated, indicating the presence of an SO2 motif,
and this was corroborated by the IR spectrum where peaks at 1360
and 1150 cm21 typical of sulfonamides were observed.
Clearly, the loss of sulfur dioxide represented by step B in the
mechanism delineated in Scheme 1 did not occur fast enough to
compete with cyclisation of the N-amidosulfonyl radical. The yield
of 13a, obtained as a single diastereoisomer, was a modest 36%. It
could be improved to 62% by using xanthate 10,8 which produces
a tertiary radical with a nucleophilic character and hence exhibits a
better reactivity towards the mildly electrophilic allylsulfonyl
group in the substrate. We therefore used this xanthate throughout
the rest of the study. Modification of the concentration from 0.3 M
(in 8a) to 0.6 M did not significantly alter the yield (58%).
Replacing the ethyl group on the nitrogen by the bulkier but
nevertheless primary phenethyl group caused a decrease in the
efficiency. Compound 13b was thus obtained in only 39% yield
from 8b under the same reaction conditions.
When substrate 14 was subjected to the same conditions, two
compounds 15 and 16 were formed, with the desired lactam
predominating (55%). Compound 17 produced a similar mixture of
N-sulfonylamide 18 (25%) and lactam 19 (51%). The slight change
in the geometric constraints in these two substrates is thus sufficient
to push the reaction in the desired direction.
In stark contrast to the above results, no complications were
observed from the premature cyclisation of the N-amidosulfonyl
radical when the ethyl group on the nitrogen was replaced by a
phenyl. Loss of sulfur dioxide is speeded up by the greater stability
We have developed over the past few years several processes for
the generation and capture of nitrogen centred radicals1,2 and
illustrated their potential for N–C bond formation by the total
synthesis of various complex alkaloids.3 We now describe yet
another process for the creation of amidyls, which does not involve
the use of organotin hydride but relies on the extrusion of sulfur
dioxide from N-amidosulfonyl radicals.
As outlined in Scheme 1, step A, N-amidosulfonyl radicals 2
could be produced by an addition–fragmentation sequence onto the
corresponding N-allylsulfonylamides 1.4 Loss of sulfur dioxide
would then furnish the desired amidyl radical, which would then
rapidly cyclise to give 4. As the source of the initial radicals, we
opted for a xanthate since the reversible transfer of a xanthate group
in the last propagation step D would not only introduce a useful
functionality into the product 5 but would also regenerate the first
radical to perpetuate the chain process.5
The very few earlier studies on N-amidosulfonyl radicals6
indicated that extrusion of sulfur dioxide (step B) is not a fast
process and could in fact prove to be problematic in our context.
The N-amidosulfonyl radicals could, for example, abstract a
hydrogen atom from the solvent or undergo addition to the internal
olefin. The former unwanted reaction could be curtailed by
choosing a solvent with poor hydrogen atom donating capability
and the latter could perhaps be overcome by the inherent
reversibility of the process.
We first prepared the typical substrates 8a and 8b, in 80 and 65%
yield respectively, by reacting the mixed anhydride 6, generated in
situ from commercially available cyclopentenecarboxylic acid and
isobutyl chloroformate in the presence of one equivalent of
triethylamine, with the lithium salt of N-ethyl- and N-phenethyl-
allylsulfonamide 7a and 7b.† The parent sulfonamides were
obtained by treating allylsulfonyl chloride7 with the requisite
amine. When compound 8a was subjected to the action of xanthate
9 and a sub-stoichiometric quantity of lauroyl peroxide, a major
Scheme 1 Chain reaction for the generation of amidyl radicals.
Scheme 2 Formation of cyclic N-sulfonylamides.
1848
C h e m . C o m m u n . , 2 0 0 4 , 1 8 4 8 – 1 8 4 9
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

of the nitrogen centred radical created in this case. Only lactam 21
(55%) was produced from allylsulfonamide 20, and substrate 22
gave rise to 2 : 3 mixture of epimeric lactams 23 and 24 in 57%
yield. This latter example contrasts with that of 14 which gave 16
as only one epimer. The presence of the aromatic ring allowed one
further twist in the radical sequence when the open chain precursor
25 was subjected to the same reaction conditions. The reaction
produced polycyclic derivative 28 in 58% yield. The “normal”
lactam 27 was not observed even though it could be formed during
the reaction but then converted into 28 through the reversible
exchange of the xanthate group. The presence of the xanthate group
is a powerful asset in view of the numerous possible further
transformations.4,5
In summary, these preliminary results demonstrate the potential
of this process for generating amidyl and perhaps other types of
nitrogen centred radicals. The precursors are readily available and
stable and the cyclisation can be easily incorporated into various
tandem sequences, thus opening a straightforward access to a
variety of complex structures. Further studies aimed at improving
the yield and extending the scope are under way.
We thank Rhodia for generous financial support to one of us
(CM), Dr Ghenwa Bouhadir for a preliminary experiment, and Drs
Jean-Marc Paris and François Metz of Rhodia for friendly
discussions.
Notes and references
†
Typical experimental procedure:
Synthesis of N-allylsulfonamides: Triethylamine (1–1.2 eq.) and isobutyl
chloroformate (1–1.2 eq.) were added to an ice cold solution of the
carboxylic acid (1 eq.) in dry THF (5.0 ml per mmole of acid) under an inert
atmosphere. In parallel, a solution of butyllithium in hexanes (1.25 M;
1.05–1.2 eq.) was added to a cold (278°C) solution of the allysulfonamide
(1.0 eq.) in dry THF (5.0 ml per mmole) under an inert atmosphere. After
15 minutes, the second solution was cannulated into the first. The resulting
mixture was allowed to warm to room temperature and then left stirring for
18 hours. Water and ether were then added and the layers separated. The
aqueous layer was further extracted with ether and the combined organic
layers combined, washed with brine, and dried over magnesium sulfate.
Filtration and evaporation gave a residue that was purified by flash
chromatography on silica (eluent: ether–petroleum ether mixtures) to give
the respective N-allylsulfonylamides.
Radical cyclisation: a solution of the N-allylsulfonylamide in 1,2-di-
chloroethane (0.5 M) and xanthate 10 (1.2 eq.) was refluxed for 15 minutes
under an inert atmosphere. Lauroyl peroxide was added in small portions
every 90 minutes (first 0.1 eq. then 0.05 eq.), until almost complete
disappearance of the starting material. Evaporation of the solvent and
purification of the residue by chromatography on silica gel (elutent: ether–
petroleum ether mixtures) gave the lactams and/or cyclic N-sulfonyl
lactams.
Scheme 3 Generation and cyclisation of amidyl radicals.
1 For a review, see: S. Z. Zard, Synlett, 1996, 1148.For more recent work,
see: J. Boivin, A.-M. Schiano, S. Z. Zard and H. Zhang, Tetrahedron
Lett., 1999, 40, 4531; F. Gagosz and S. Z. Zard, Synlett, 1999, 1978; F.
Gagosz, C. Moutrille and S. Z. Zard, Org. Lett., 2002, 4, 2707; D. Gennet,
S. Z. Zard and H. Zhang, Chem. Commun., 2003, 1870.
2 For recent work by other groups, see: L. El Kaim and C. Meyer, J. Org.
Chem., 1996, 61, 1556; X. Lin, D. Stien and S. M. Weinreb, Org. Lett.,
1999, 1, 637; X. Lin, D. Stien and S. M. Weinreb, Tetrahedron Lett.,
2000, 41, 2333.
3 J. Cassayre, F. Gagosz and S. Z. Zard, Angew. Chem. Int. Ed., 2002, 41,
1783; J. Cassayre and S. Z. Zard, J. Am. Chem. Soc., 1999, 121, 6072; X.
Hoang-Cong, B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 1999, 40,
2125.
4 For a review, see: F. Bertrand, F. Leguyader, L. Liguori, G. Ouvry, B.
Quiclet-Sire, S. Seguin and S. Z. Zard, C. R. Acad. Sci. Paris, 2001, II4,
547.
5 For general reviews 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, (Eds P. Renaud, M. P.
Sibi), Wiley-VCH, Weinheim, 2001, vol. 1, 90–108.
6 F. Montermini, E. Lacoˆte and M. Malacria, Org. Lett., 2004, 6, 921; M.
L. E. N. da Mata, W. B. Motherwell and F. Ujjainwalla, Tetrahedron
Lett., 1997, 38, 137; 141; P. Bougeard and M. D. Johnson, J. Organomet.
Chem., 1981, 206, 221; M. S. Kharasch and R. A. Mosher, J. Org. Chem.,
1952, 17, 453.
7 M. Adamczyk, Y.-Y. Chen, P. G. Mattingly, J. F. Moore and K. Shreder,
Tetrahedron, 1999, 55, 10899; P. Dauban and R. H. Dodd, Org. Lett.,
2000, 2, 2327.
Scheme 4 Generation and cyclisation of N-phenylamidyl radicals.
8 G. Binot, B. Quiclet-Sire, T. Saleh and S. Z. Zard, Synlett, 2003, 382.
C h e m . C o m m u n . , 2 0 0 4 , 1 8 4 8 – 1 8 4 9
1849