Fragmentation of nitrone triflates to 9-membered rings

Article abstract of DOI:10.1021/ol071049d

A new fragmentative rearrangement of nitrone derivatives to form 9-membered rings is reported. The fragmentations are triggered when nitrones are treated with triflic anhydride; a C-C bond antiperiplanar to the cleaving N-O bond is activated either by an oxygen lone pair or by an electron-rich aromatic ring. In the former case, further cyclization of the 9-membered intermediate leads to a rearranged condensed ring system, but when triggered by arenes, 9-membered ring amides are isolated.

Full text of DOI:10.1021/ol071049d

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3233-3236
Fragmentation of Nitrone Triflates to
9-Membered Rings
John A. Murphy,*,† Mohan Mahesh,† Gary McPheators,† R. Vijaya Anand,†
Thomas M. McGuire,† Robert Carling,‡ and Alan R. Kennedy†
WestCHEM, Department of Pure and Applied Chemistry, UniVersity of Strathclyde,
295 Cathedral Street, Glasgow G1 1XL, United Kingdom, and Merck, Sharp and
Dohme Ltd., Neuroscience Research Centre, Terlings Park, Harlow,
Essex CM20 2QR, United Kingdom
john.murphy@strath.ac.uk
Received May 5, 2007
ABSTRACT
A new fragmentative rearrangement of nitrone derivatives to form 9-membered rings is reported. The fragmentations are triggered when
nitrones are treated with triflic anhydride; a C C bond antiperiplanar to the cleaving N O bond is activated either by an oxygen lone pair or
−
−
by an electron-rich aromatic ring. In the former case, further cyclization of the 9-membered intermediate leads to a rearranged condensed ring
system, but when triggered by arenes, 9-membered ring amides are isolated.
Medium-sized rings are difficult to form by cyclization
processes, due to the inherent strains in the transition state
leading to formation of the ring and due to the entropic
difficulty of forming such rings from acyclic precursors. For
this reason, new routes to medium-sized rings are frequently
sought.1 The research undertaken in this paper was based
upon a new potential route to generate medium-sized rings
using rearrangements of nitrone triflates. The possibility of
using the fragmentation of an activated nitrone such as a
nitrone sulfonate 1, in approaches to the anti-tumor agent,
vinblastine 5 (X ) vindolinyl) is attractive, since this would
afford the product 4 with an amide in a 9-membered ring,
ripe for further elaboration toward vinblastine 5a or car-
bomethoxyvelbanamine 5b (Scheme 1).
derived from steroidal ketones gave product 6 that underwent
a migratory rearrangement to 9 that superficially resembled
a Beckmann rearrangement (Scheme 2), forming a new C-N
σ-bond in the process. However, in contrast to the Beckmann
reaction, both (Z)- and (E)-nitrone derivatives 6 afforded the
Scheme 1
Whereas rearragements of nitrones are known, they do not
include this type of fragmentative process. Thus, a number
of groups have studied2 rearrangements of sulfonylated
nitrones. Barton had shown2a that tosylation of nitrones
† University of Strathclyde.
‡ Merck, Sharp and Dohme Ltd.
(1) (a) Shiina, I. Chem. ReV. 2007, 107, 239. (b) Illuminati, G. G.;
Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
10.1021/ol071049d CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/25/2007

in 10, a concerted Beckmann-type process giving rise to the
very unstable vicinal dication 13 as an intermediate looks
very unattractive. On the other hand, formation of a
9-membered ring 11, driven by an electron-releasing X-
group, would afford macrocyclic amide 12 as product.
The alternative possibility, where reaction arises from an
adduct 14, features three processes that break C-C bonds,
one driven by electron-release from X, to afford 16, and two
driven by Y, to afford 15 and 17 respectively. The formation
of 16 depends on X being a much more effective electron-
pair donor than Y.
Scheme 2
For our studies, we chose nitrone triflates, where W ) Y
) OTf. With the known properties of the triflate anion as
an outstanding leaving group and as a very poor nucleophile,
the addition to molecule 10 to form 14 (analogous to that
proposed by Barton in conversion of 6 to 7) is made less
likely, while using triflate as the leaving group (W) in 10
maximizes the chance of fragmentation of 10 to 11. This
fragmentation should also benefit from stereoelectronic
advantages, as seen in the conversion of 1 to 2, where the
inter-ring bond that is targeted for cleavage is antiperiplanar
to the leaving group, assisting with the selectivity and
mildness of the reaction. Such stereoelectronic advantages
would apply optimally to functionalized nitrones (sp2 nitro-
gen), as here, rather than to amine derivatives (sp3 nitrogen)
bearing a leaving group. Nevertheless, the fragmentation
reaction to form the 9-membered ring might also occur from
adduct 14. Here the inter-ring bond targeted for cleavage
and the N-OTf bond have partial, but not optimal, overlap.
In terms of substrate design, such adduct formation could
be further discouraged by choosing ketone-derived nitrones
that are hindered on the R and R′-carbons.
identical product 9. This was attributed to the migration
occurring via a tetrahedral adduct of type 7, and possibly
being triggered during aqueous workup (i.e., X ) OH).
We proposed to test for an alternative and previously
unobserved reaction in which ring-fragmentation to a mac-
rocycle would occur. If such a fragmentation could be found,
it might subsequently be applied to synthesis of the 9-mem-
bered ring of vinca alkaloids, like vinblastine 5a through
rearrangement of compound 1 or analogues, where electron
release from the indoline might trigger the fragmentation.
We now report the first examples of such a fragmentative
rearrangement in this challenging setting of formation of
9-membered rings and examine the parameters where an
electron-rich aromatic ring or the lone pair of an oxygen
atom (X in structure 10, Scheme 3) are used to provide the
source of electronic push.
Scheme 3
Scheme 4
The first substrate, 22a, was prepared as in Scheme 4.
Alkylation of the known spirocyclohexanone 18 followed
by hydroxylation with 2-benzenesulfonyl-3-phenyloxazir-
idine 193 led to alcohol 20, which was converted directly to
The processes under consideration are shown in Scheme
3. First, if reaction arises from loss of the leaving group W
(2) (a) Barton, D. H. R.; Day, M. J.; Hesse, R. H.; Pechet, M. J. Chem.
Soc., Perkin Trans. 1 1975, 1764. (b) Cherest, M.; Lusinchi, X. Tetrahedron
1982, 38, 3471. (c) Prager, R. H.; Raner, K. D.; Ward, A. D. Aust. J. Chem.
1984, 37, 381. (d) Exner, O. Collect. Czech Chem. Commun. 1951, 16,
258.
(3) (a) Davis, F. A.; Vishwakarma, L. C.; Billmers, J. M.; Finn, J. J.
Org. Chem. 1984, 49, 3241. (b) Davis, F. A.; Sheppard, A. C. Tetrahedron
1989, 45, 5703.
3234
Org. Lett., Vol. 9, No. 17, 2007

bromide 21 which, on treatment with hydroxylamine, af-
forded nitrone 22a. Reaction with triflic anhydride led to a
single new rearranged product, 23, in 46% yield. This product
must arise by forming the nitrone triflate 22b as desired.
Loss of triflate anion and activation by the hydroxyl group
lone pair then cause ring-expansion to 9-membered ring-
containing intermediate 24. Clearly, this compound is highly
reactive and undergoes formation of enol 25, cyclization and
tautomerism to give observed product 23.
Treatment of ether 30 with hydroxylamine hydrochloride
gave the desired nitrone 314 as a diastereomeric mixture (ratio
2:1), which was separated by column chromatography.
The nitrone 31 (major isomer) was exposed to triflic
anhydride. In this case, a completely unexpected type of
rearranged product was obtained as an inseparable mixture
of diastereomers 32 (dr 1:1 from NMR) in 48% yield
(Scheme 5). The formation of the products 32 was confirmed
by spectroscopy and, following crystallization, by X-ray
crystallography.
A proposal for the formation of the rearranged product
32 is shown in Scheme 5. The nitrone 31 is transformed to
a reactive nitrone triflate 33. Attack by external nucleophile
X- to form 34 (or 3-membered ring formation by the adjacent
methoxy group behaving as an intramolecular nucleophile)
would permit loss of triflic acid (by a syn- or anti-
elimination) to afford the imine 35. Addition of nucleophile
H2O on workup, followed by loss of X- then produces the
isolated conjugated products 32. Why does nitrone 31 behave
in this anomalous way? Given the contrast with nitrone 22a,
the difference may be associated with the fused aromatic
ring. Certainly, the planarity of the aryl ring can facilitate
nucleophilic attack on the nitrone CdN bond. Formation of
the adduct can also ease crowding around the triflate group
in this case.
The formation of 23 happily shows that substrate 22 does
not follow the type of rearrangement observed by Barton et
al.,2a but instead proceeds by the desired fragmentation.
As mentioned above, the fragmentation reactions could
occur either directly from the nitrone triflates or from their
triflate adducts. In one substrate, nitrone 31, we saw possible
evidence of the intermediacy of an adduct. However, that
adduct led to an anomalous outcome. The synthetic route to
nitrone 31 is depicted in Scheme 5. R-Tetralone was
Scheme 5
The models that had been employed so far had used the
lone-pair of an oxygen directly bonded to the carbon R- to
the nitrone to trigger the fragmentation. We were more
interested to explore whether an electron-rich arene could
also drive this type of fragmentation.
The synthetic strategy designed for the synthesis of model
nitrone 43 is shown in Scheme 6. The alkene 36 was
epoxidized with m-CPBA to provide the epoxide 37 in 97%
yield. Subsequent ring-opening with an organocuprate de-
rived from 4-iodoanisole gave the alcohol 38 in 49% yield.
Oxidation with PDC in refluxing benzene afforded ketone
39, which was allylated using allyl bromide and KOtBu. The
allylated product 40 was formed in 89% yield. Ozonolysis
of 40 afforded aldehyde 41. Treatment with hydroxylamine
hydrochloride and NaOH gave the aldoxime 42 as a pair of
diastereomers in good yield. This was then reduced using
NaCNBH3 in the presence of methanolic HCl (pH 3) to give
the desired nitrone 43 in 19% yield from 41.
The successful formation of nitrone 43 led to an attempt
at ring fragmentation reaction. Thus, 43 was first exposed
to triflic anhydride, and then treated with water (Scheme 6).
It was heartening to see that the desired ring-expanded
product 44 was formed in 35% yield as a pair of diastereo-
isomers, resulting from geometric isomerism about the alkene
or, possibly, about the amide. It was clear that the product
converted into its hydrazone derivative 26 in 88% yield by
treatment with N,N-dimethylhydrazine in the presence of a
catalytic amount of acetic acid. Allylation with LDA and
allyl bromide gave product 27 in 87% yield. Hydrolysis of
the hydrazone proceeded smoothly to provide the allylated
ketone 28 in 72% yield, treatment of which with Davis’
oxaziridine3 19 provided the hydroxyketone 29 in 58% yield.
The hydroxyketone was converted into its methyl ether 30
in good yield.
1
was regioisomer 44 rather than 45 from 2D H,13C HSQC
1
1
and 2D H,1H COSY spectra. Thus, from the H NMR
spectrum, the vinyl protons resonating at δ 5.15-5.20 and
δ 5.25-5.27 ppm (correlating respectively with 13C signals
(4) We see this as likely resulting from oxime formation followed by
retro-Cope reaction. (a) Grigg, R.; Heaney, F.; Markandu, J.; Surendakumar,
S.; Thornton-Pett, M.; Warnock, W. J. Tetrahedron Lett. 1991, 47, 4007.
(b) Gravestock, M. B.; Knight, D. W.; Thornton, S. R. J. Chem. Soc., Chem.
Commun. 1993, 169.
Org. Lett., Vol. 9, No. 17, 2007
3235

future plans, and so we engaged in extensive optimization
studies. Happily, these steadily improved matters until an
easily repeatable 82% of indole 47 was obtained, providing
a launchpad for the exploration of more complex substrates
(Scheme 7).
Scheme 6
Scheme 7
In summary, we have reported the first examples of
fragmentative rearrangements of nitrone triflates, and have
focused on fragmentations that lead to 9-membered rings.
The application to the synthesis of the fused indole 47
complements the more widely used alkaloid rearrangements
of tertiary amine oxides,6 and opens a new avenue for the
preparation of stable macrocyclic amides.
Acknowledgment. We thank Merck Sharp and Dohme
Ltd. and the EPSRC for a CASE award (to T.M.M.), EPSRC
for funding, and the EPSRC Mass Spectrometry Centre,
Swansea, for mass spectra.
at δ 119.5 and δ 123.8 ppm), both coupled with protons H′′
in the range δ 1.8-2.3 ppm. By contrast, if 45 had been
produced, the vinyl proton would couple to protons H′, which
are expected to resonate considerably downfield of this value.
We then focused on the synthesis of the key indoline
nitrone 46; this was available by the approach of Gramain
et al.5 Initially, the rearrangement reaction of 46 did not
proceed in high yield, but this example was crucial to our
Supporting Information Available: Experimental pro-
cedures and spectra for obtained compounds; X-ray data for
32 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL071049D
(5) Mounir, N. B.; Dugat, D.; Gramain, J.-C.; Husson, H.-P. J. Org.
Chem. 1993, 58, 6457.
(6) Mangeney, P.; Andriamialisoa, R. Z.; Lallemand, J.-Y.; Langlois,
N.; Langlois, Y.; Potier, P. Tetrahedron 1979, 35, 2175.
3236
Org. Lett., Vol. 9, No. 17, 2007