An expedient route to dihydrothiazines, a virtually unknown class of heterocycles

Article abstract of DOI:10.1021/ol402973q

Upon heating at 180-200 C in diphenyl ether, S-(4-oximinoalkyl)xanthates with a secondary isopropyl or isobutyl group on the oxygen undergo a Chugaev elimination followed by ring closure onto the oxime to give dihydrothiazines, a virtually unknown class of heterocycles.

Full text of DOI:10.1021/ol402973q

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
An Expedient Route to Dihydrothiazines,
a Virtually Unknown Class of Heterocycles
ꢀ
Beatrice Quiclet-Sire* and Samir Z. Zard*
ꢁ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128
Palaiseau Cedex, France
beatrice.sire@polytechnique.edu; zard@poly.polytechnique.fr
Received October 16, 2013
ABSTRACT
Upon heating at 180À200 °C in diphenyl ether, S-(4-oximinoalkyl)xanthates with a secondary isopropyl or isobutyl group on the oxygen undergo a
Chugaev elimination followed by ring closure onto the oxime to give dihydrothiazines, a virtually unknown class of heterocycles.
Heterocycles and heteroaromatics constitute the back-
bone of the majority of medicinally useful compounds.1
The search for practical synthetic routes to new or rare
Scheme 1
heterocyclic structures hence remains a worthwhile endea-
vor. From this perspective, radical reactions remain grossly
underutilized despite their immense potential for creating
new structures. While we have, over the years, exploited
the unique power of the degenerative radical additionÀ
transfer of xanthates2 for the creation of new carbonÀ
carbon bonds to construct or to modify heterocyclic and
heteroaromatic derivatives,3 we have only seldom taken
advantage of the presence of the xanthate group in
the adducts to access sulfur containing heterocycles.
Indeed, the degenerative xanthate addition allows the
bringing together of various functional groups, which
precursorstodienes4.4 Inthecasewherethe radical adduct
can then be made to react not only just with each other
is derived from a 2-fluoroarylketone, heating with potas-
sium carbonate provides an unusually short route to 2,3-
dihydrothieno[2,3-b]thiopyran-4-ones 5, a rare class of
sulfur heterocycles.5 We also accidentally discovered an
expedient synthesis of dithietanones 7 by the action of
TiCl4 on adducts 6 derived from vinyl pivalate.6 Dithieta-
nones also represent a rare family of sulfur com-
pounds, and preliminary work indicates them to be useful
but also with the xanthate under suitable conditions.
Our main contributions in the latter respect are sum-
marized in Scheme 1.
We have, in particular, established a practical access to
dihydrothiophene S,S-dioxides 3, which are convenient
(1) (a) Ward, R. A.; Kettle, J. G. J. Med. Chem. 2011, 54, 4670. (b)
Pitt, W. R.; Parry, D. M.; Perry, B. G.; Groom, C. R. J. Med. Chem.
2009, 52, 2952. (c) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem.
2009, 52, 6752.
(2) For reviews on the xanthate radical addition-transfer process, see:
(a) Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672. (b) Quiclet-Sire, B.;
Zard, S. Z. Chem.;Eur. J. 2006, 12, 6002. (c) Quiclet-Sire, B.; Zard, S. Z.
Top. Curr. Chem. 2006, 264, 201. (d) Zard, S. Z. Aust. J. Chem. 2006, 59,
663. (e) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205. (f) Quiclet-Sire, B.;
Zard, S. Z. Pure Appl. Chem. 2011, 83, 519.
(4) Lusinchi, M.; Stanbury, T.; Zard, S. Z. Chem. Commun. 2002,
1532.
(5) (a) Boutillier, P.; Quiclet-Sire, B.; Zafar, S. N.; Zard, S. Z.
Tetrahedron: Asymmetry 2010, 21, 1649. (b) Boivin, J.; Boutillier, P.;
Zard, S. Z. Tetrahedron Lett. 1999, 40, 2529.
(3) For a review, see: El Qacemi, M.; Petit, L.; Quiclet-Sire, B.; Zard,
S. Z. Org. Biomol. Chem. 2012, 10, 5707.
(6) Quiclet-Sire, B.; Sanchez-Jimenez, G.; Zard, S. Z. Chem. Com-
mun. 2003, 1408.
r
10.1021/ol402973q
XXXX American Chemical Society

A solution to this difficulty presented itself in the guise of
the Chugaev elimination (Scheme3, routeB). Thisclassical
reaction is seldom applied in synthesis, but then usually as
a method for generating alkenes from alcohols by thermo-
lysis of the corresponding S-methyl xanthates. Xanthates
derived from tertiary alcohols decompose under very mild
conditions, often at, and sometimes even below, room tem-
perature. Indeed, it is usually difficult to handle xanthates
prepared from tertiary alcohols. Xanthates derived from
secondary alcohols start decomposing at temperatures
around 150 °C whereas those made from primary alcohols
require drastic temperatures in excess of 200 °C and are not
normally useful precursors of alkenes. The methanethiol
coproduced in the process is discarded or destroyed be-
cause of its stench.
Scheme 2
precursors of thioaldehydes. In continuation of our
work on xanthates, we have now discovered an expedient
route to the virtually unknown dihydrothiazines 8
(Scheme 2).
In contrast to dihydrooxazines 9, their oxygen analogs,
which are well-known and popular among medicinal
chemists,7 dihydrothiazines are extremely rare heterocyclic
compounds. Indeed, only the parent compound 8a has
been reported.8,9 This substance was discovered serendipi-
tously when nitrone 10 was irradiated with UV light
(Scheme 2), whichcaused its isomerization intooxaziridine
11.8 This compound is unstable and spontaneously
collapses into dihydrothiazine 8a and benzophenone.
Despite its mechanistic elegance, this approach cannot
be easily generalized because of the major difficulties
associated with the synthesis of substituted nitrone
precursors.
Scheme 4
Our initial synthetic plan, outlined in Scheme 3 (route
A), relied on the ready accessibility of adducts 2, which
appeared to be logical precursors to dihydrothiazines 8 via
the corresponding activated oxime derivatives. However,
our attempts at implementing what looked like a trivial
sequence were frustratedbycompetition from a Beckmann
rearrangement upon conversion of oximes 12 into the
corresponding mesylate 13. We could not therefore
reach the desired intermediate thiol 14, which we hoped
would evolve spontaneously into dihydrothiazines 8
under the mildly basic conditions used to cleave the
xanthate group. Introduction of a poorer ester type
leaving group on the oxime, such as an acetate (e.g.,
15), would alleviate complications from the Beckmann
rearrangement but would raise the problem of how to
accomplish selective cleavage of the xanthate to form the
required thiol acetate 16.
In our case, the thiol is the valuable product, and by
starting with a xanthate derived from a simple secondary
alcohol such as 17, thermolysis would lead to the forma-
tion of a volatile alkene and leave behind the desired thiol
16. To test this approach, compound 21a was prepared by
addition of xanthate 18a to 1-octene and the ketone group
in the resulting adduct 19a was converted into its oxime
acetate 21a using standard reactions (Scheme 4). We were
pleasantly surprised tofindthatheatingasolutionof 21a in
diphenyl ether at 180 °C for 120 min resulted in a reason-
ably clean reaction to give directly dihydrothiazine 22a in
45% yield. Even more interesting, a blank experiment on
free oxime 20a also furnished dihydrothiazine 22a in a
slightly higher yield (67%). It is clearly not necessary to go
through the acetate, and this results in a very significant
simplification of the synthesis.
Scheme 3
(7) For a recent review on six-membered ring cyclic oxime ethers, see:
Sukhorukov, A. Y.; Ioffe, S. L. Chem. Rev. 2011, 111, 5004.
(8) (a) Leyshon, W. M.; Wilson, D. A. J. Chem. Soc., Perkin Trans. 1
1975, 1925. (b) Leyshon, W. M.; Wilson, D. A. J. Chem. Soc., Perkin
Trans. 1 1975, 1929.
(9) Benzothiazines are more robust substances and are better docu-
mented: (a) Grant, R. D.; Moody, C. J.; Rees, C. W.; Tsoi, S. C. J. Chem.
Soc., Chem. Commun. 1982, 884. (b) Gairns, R. S.; Grant, R. D.; Moody,
C. J.; Rees, C. W.; Tsoi, S. C. J. Chem. Soc., Perkin Trans. 1 1986, 491. (c)
Jones, S.; Kennewell, P. D.; Westwood, R.; Sammes, P. G. J. Chem. Soc.,
Chem. Commun. 1990, 498. (d) Shimazu, H.; Ikedo, K.; Hamada, K.;
Ozawa, M.; Matsumoto, H.; Kamata, K.; Nakamura, H.; Ji, M.;
Kataoka, T.; Hori, M. J. Chem. Soc., Perkin Trans. 1 1991, 1733. (e)
King, J. F.; Yuyitung, G.; Gill, M. S.; Stewart, J. C.; Payne, N. C. Can. J.
Chem. 1998, 76, 164. (f) Piatek, A.; Chapuis, C.; Jurczak, J. Helv. Chim.
Acta 2002, 85, 1973.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 5
Scheme 6
A plausible mechanism for this transformation is de-
picted in Scheme 5. Chugaev fragmentation of xanthate 20
leads to thiol 23, which can then proceed to dihydrothia-
zine 22 by ring closure of protonated oxime intermediate
24. Alternatively, reversible cyclization onto to the carbon
of the oxime first takes place to give hydroxylamine 25
followed by formation of bicyclic intermediate 26, which
should rapidly collapse into the same dihydrothiazine 22.
These two mechanistic variants are not mutually exclusive
and could operate simultaneously under the reaction
conditions. We did not observe a clear dependence on
the initial geometry of the oxime, suggesting at least an
equilibration between the E and Z isomers. Furthermore,
we found that the main side product in these reactions is
dihydrothiophene 27 and/or the isomeric exoalkylidene
tetrahydrothiophene, with the double bond outside the
ring (not shown). Such compounds could be observed in
the NMR of the crude reaction mixtures once the diphenyl
ether solvent was removed and, in a few cases, could even
be isolated (see for example compound 27i in Scheme 8).
With an expedient route to this family of heterocycles in
hand, we explored its scope. Despite the somewhat drastic
conditions, many functional groups are tolerated as in-
dicated by the examples displayed in Schemes 6À9 (in all
these schemes, DLP is lauroyl peroxide). The yields are
generally moderate, partly because of the competitive
formation of dihydrothiophenes in 10À35% yield and
because of the relative fragility of the dihydrothiazines to
chromatographic purification. In some instances, deacti-
vation of the silica with triethylamine proved beneficial.
In our initial experiments, O-isobutyl xanthates such
as 18aÀc were used, as they were available from
another study (Scheme 6); however, we soon switched to
O-isopropyl xanthates (e.g., 18d), since these could be
thermolyzed at similar temperatures, do not introduce a
cumbersome extra chiral center, and exhibit simpler NMR
spectra. The reaction leading to dihydrothiazines could
also be accomplished starting with aliphatic ketones (e.g.,
18b), and even adducts prepared from relatively complex
alkenes such as 2-allyl-3,7-dimethyl xanthine underwent
the expected transformation (example 22d in Scheme 6).
Two further examples using relatively complex alkenes
are displayed in Scheme 7. The first, 22g, results from
addition to a steroid alkene, whereasthe second, 22h, arises
from a glucose derived alkene. Both of these dihydrothia-
zines, and especially the latter, would be exceedingly
difficult to access by more conventional routes. In the case
of ketone 19h, a precursor of 22h, the radical addition gave
two separable epimers and only the major epimer was
processed further. It is nevertheless remarkable that the
carbohydrate derivative reasonably withstood the ther-
mally harsh experimental conditions. This is due to the
fact that the heating is done under strictly neutral condi-
tions. Most of the material loss is caused by the unwanted
formation of the dihydrothiophene side product and par-
tial destruction of the dihydrothiazine on silica during
purification rather than through decomposition during
thermolysis.
One feature of this approach is the fact that the ketone
can be present on the alkene partner and not necessarily on
the xanthate, as illustrated by the two examples depicted in
Scheme8. Startingfrom 1-(p-methoxyphenyl)-buten-4-ene
29a leads to dihydrothiazine 22i in a rather disappointingly
low yield, with the major side product being dihydrothio-
phene 27i, isolated in this case in 37% yield. A better out-
comewasobservedwith2-allyl-cyclopentanone29b, which
furnished the corresponding dihydrothiazine 22j in 38%
yield. The reason underlying the difference in efficiency
between the two reactions is not clear at the moment.
The possibility of having the ketone in either the
xanthate or the alkene partner reflects the high degree of
flexibility of this approach. This versatility is further
increased by the important observation that the radical
Org. Lett., Vol. XX, No. XX, XXXX
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Scheme 7
Scheme 9
22l and 22m respectively are pictured in the same scheme.
In the case of the latter, the intermediate adduct 20m was
contaminated with a small amount of the inseparable
reduced material 31, so that the corrected yield (35%) of
dihydrothiazine 22m is slightly higher.
Scheme 8
These preliminary results demonstrate the viability of
our approach to this virtually unknown class of hetero-
cyclic compounds. While the yields are mostly modest and
much optimization work remains to be done, this route
nevertheless offers tremendous versatility. It is convergent,
is concise, and tolerates a broad range of functional
groups. The chemical reactivity of dihydrothiazines and
their potential in medicinal chemistry can now be more
conveniently and systematically studied.
Acknowledgment. We dedicate this paper with respect
ꢀ
to the memory of Professor Serge David (Universite Paris
XI, Orsay).
addition of the xanthate can be accomplished on the
preformed oxime. This avoids problems of regioselectivity
in the formation of the oxime intermediate when both the
alkene and xanthate partners bear a ketone group. Thus
xanthyl ketone 18c could be added efficiently to the oxime
of 2-allylcyclohexanone 30a to give adduct 21k, which
furnished dihydrothiazine 22k in 52% yield (Scheme 9).
Two other examples of additions to allyl substituted
oximes 30a and 30b leading ultimately to dihydrothiazines
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data, and copies of 1H and 13
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX