A convergent route to geminal difluorosulfides and to functionalized difluorothiochromans, a new family of organofluorine compounds

Article abstract of DOI:10.1021/ol5002939

The synthesis of the novel O-ethyl-S-(4-chlorophenylthio)difluoromethyl xanthate and its radical addition to various terminal alkenes are described. The geminal difluorosulfide adducts undergo closure onto the aromatic ring by further treatment with perox

Full text of DOI:10.1021/ol5002939

Letter
pubs.acs.org/OrgLett
A Convergent Route to Geminal Difluorosulfides and to
Functionalized Difluorothiochromans, a New Family of
Organofluorine Compounds
Pierre Salomon and Samir Z. Zard*
̀
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128 Palaiseau, Cedex, France
S
* Supporting Information
ABSTRACT: The synthesis of the novel O-ethyl-S-(4-chloro-
phenylthio)difluoromethyl xanthate and its radical addition to
various terminal alkenes are described. The geminal
difluorosulfide adducts undergo closure onto the aromatic
ring by further treatment with peroxide to furnish difluoro-
thiochromans, a new family of organofluorine compounds.
Scheme 1. Failed Attempt at the Synthesis of Xanthate 8a
luorine containing molecules, and especially aromatics,
Fheteroaormatics, and heterocycles, are of major importance
to the pharmaceutical and agrochemical industries and to
material sciences.1 The presence of fluorine atoms deeply
modifies the physical and chemical properties of molecules and
increases the metabolic stability in the case of biologically active
substances.2 Since organofluorine compounds have never been
found in animals3 and remain very rare in plants,4 they must be
obtained by synthesis. It is therefore not surprising that the
search for methods allowing the efficient introduction of
fluorine or fluorine containing groups has remained unabated
over many decades.
Essentially every type of reaction has been used to synthesize
organofluorine derivatives, and the literature on the subject is
indeed very extensive.5 However, while sulfur based fluorinated
synthons and reagents have become more popular in recent
times, in particular fluoroalkylsulfinate salts and fluoroalkyl-
sulfones,6 the use of fluorinated sulfides has remained relatively
limited so far.7
We and others have in the past applied the xanthate
reversible addition−transfer process8 to generate and capture
the various fluorine containing radicals 1−7 displayed in Figure
1.9 In order to expand the scope of this approach, we
considered preparing xanthate 8 as a possible convenient source
of arylthiodifluoromethyl radicals 9 (Figure 1). Such radicals
have been produced from the corresponding halides, but their
use in synthesis has remained limited.10
an iodide has been described.10b While this reaction, which is
probably not a simple SN2 process, is not very efficient, its
expediency compensates for its sluggishness and the moderate
yield. Unfortunately, the reaction of bromide 10 with
commercial potassium O-ethyl xanthate was not only also
sluggish, but further resulted in a complex mixture from which
ethyl sulfide 11 could be isolated in poor yield. This undesired
compound presumably arises through an ionic chain sequence,
whereby attack by the p-chlorophenylthiolate on the ethyl
group of xanthate 8a regenerates the same thiolate, along with
carbon oxysulfide and difluoromethanethione (difluoro-
thiophosgene). Since the desired xanthate 8a could not be
made by direct substitution, we resorted to the indirect route
depicted in Scheme 2. Thus, treatment of commercially
available sodium chlorodifluoroacetate with the sodium salt of
4-chlorothiophenol in refluxing dioxane resulted in the
replacement of the chlorine with the chlorothiophenyl
group.11 Acidification delivered the free carboxylic acid 12 in
68% yield. This unusual substitution possibly proceeds through
the reactive α-lactone 13. Exposure of carboxylic acid 12 to
oxalyl chloride effected a clean conversion into the correspond-
ing acid chloride, which was not purified but simply stirred with
In a first approach, we attempted a direct substitution of the
bromide in 10 by a xanthate (Scheme 1). The substitution by
Received: January 27, 2014
Published: February 14, 2014
Figure 1. Fluorinated radicals generated from xanthates.
© 2014 American Chemical Society
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Scheme 2. An Efficient Route to Xanthate 8a
Scheme 4. Further Transformations of the Radical Adducts
a suspension of potassium O-ethyl xanthate in hexane.
Subsequent irradiation of the reaction mixture with a 250 W
tungsten halogen lamp triggered a radical chain decarbonylation
reaction to give xanthate 8a as a beautifully crystalline solid in
excellent overall yield (94%), without isolation of the
intermediates (see Supporting Information).12 This sequence
was performed on a 15 g scale without significant loss in
efficiency.
With a convenient access to xanthate 8a in hand, we could
explore its addition to alkenes. As indicated by the examples in
Scheme 3, this fluorinated xanthate proved to be particularly
a
Scheme 3. Radical Addition of Xanthate 8a to Alkenes
fragmentation to give the two inseparable isomeric adducts 18
and 20 in a 2:1 ratio and in 80% combined isolated yield.
However, reduction of the mixture with the triethylammonium
salt of hypophosphorus acid14 furnished only the dexanthylated
derivative 21 in 60% yield. No trace of the product of direct
reduction of 18 was observed. Presumably, the slow reducing
hypophosphorus salt allows the corresponding carbon radical
17 time to rearrange into the most stable tertiary radical 19 via
common intermediate radical 16 before hydrogen atom
abstraction actually takes place.15
One obvious synthetic modification of the difluorosulfide
motif in the adducts is the thermal elimination of the
corresponding sulfoxide to introduce an alkene. Indeed,
reductive removal of the xanthate group in 14a, oxidation of
the resulting sulfide 22 to the sulfoxide, and thermolysis
furnished the expected N-(4,4-difluoro-3-butenyl)phthalimide
24. In line with earlier observations,10 the elimination of the
sulfoxide required a much higher temperature than that for
ordinary sulfoxides, but proceeded nevertheless in good yield.
What was surprising to us was the relatively low yield of the
reduction step. Reductive dexanthylations with tris(trimethyl-
silyl)silane (TTMSS) are usually nearly quantitative. In the
present case, a main side product was formed which turned out
to be difluorothiochroman 23 (∼10%).
While we have observed (and exploited) the radical closure
onto aromatic and heteroaromatic rings,16 it is very unusual
that a normally sluggish radical cyclization17 would be able to
compete with a relatively fast reducing agent such as TTMSS.18
Indeed, exposure of adduct 14a to a stoichiometric amount of
peroxide in the absence of an added hydrogen atom source
furnished difluorothiochroman 23a in 50% yield. It is
interesting that no significant side products resulting from an
ipso substitution via a radical Smiles rearrangement of the
sulfide were observed. Such rearrangements are well-known
with arylsulfonamides and can be exploited to accomplish
useful aryl transfer reactions.19
In the same manner, various other difluorothiochromans
were prepared starting with all the adducts 14 collected in
Scheme 3. The corresponding difluorothiochromans are
displayed in Scheme 5, and not unexpectedly, the same broad
tolerance to functional groups is exhibted in this second
a
Reaction in the presence of 1.2 equiv of camphorsulfonic acid.
effective, providing a generally high yield of the expected
adducts 14. Numerous groups are tolerated, including epoxide,
carbohydrate, urea, and pyrazole. In the case of addition to N-
allyl urea and to N-allyl-2,4-dimethylpyrazole, addition of
camphorsulfonic acid (CSA) neutralized the nucleophilic
nitrogens and prevented interference by unwanted ionic
reactions with the xanthate group.13 In its absence, the
reactions gave complex mixtures. We found it advantageous
in most examples to use the xanthate in slight excess (generally
1.5 equiv). The excess xanthate is easily recovered at the end.
The case of addition to (+)-sabinene 15 is interesting. As
depicted in Scheme 4, the addition is followed as expected by
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a
The second competition experiment was carried out on
adduct 14m derived by radical addition of 8a to N-allyl-N-
methanesulfonyl-4-methoxyaniline. The two competing path-
ways now are the formation of difluorothiochroman 23m or
indoline 26.21 Examination of the crude mixture from the
cyclization reaction indicated an 85:15 ratio in favor of the
former, which could be isolated in 35% yield. This is a
surprising outcome, since cases where the formation of a six-
membered ring is favored over a five-membered ring in a radical
cyclization are relatively rare.22 The underlying reasons in the
present case are not clear, and a more detailed study is
necessary to unravel the factors responsible for this preference.
Difluorothiochromans were hitherto unknown compounds as
far as we can tell, in contrast to thiochromans, which are fairly
common.23 Indeed, some members have some importance in
medicinal chemistry as indicated by the couple of examples
pictured in Figure 2. Tazarotene is a synthetic retinoid useful
Scheme 5. Synthesis of Difluorothiochromanes
Figure 2. Examples of biologically active thiochromans.
a
Reaction in the presence of 1.2 equiv of camphorsulfonic acid.
for the topical treatment of acne, psoriasis, and photoaging
(Tazorac/Zorac), and an orally effective formulation (Tazorac)
has been developed.24 Thiochroman CH4986399 is a non-
steroidal estrogen receptor down-regulator developed by
Kamakura Research Laboratories for the treatment of breast
cancer.25 Interestingly, the second compound contains a
perfluorobutyl residue capping the long alkyl side chain.
The effect of the two fluorines on the pharmacological profile
of biologically active thiochromans would be interesting to
examine. The trifluoromethanethiyl group (CF3S−) has one of
transformation. The moderate yields are in part due to
difficulties encountered during purification, especially with
nonpolar examples which tended to be contaminated with
coproducts derived from lauroyl peroxide.
In order to gauge the relative rate of cyclization onto the
aromatic ring, we performed two competition experiments. The
first involved examining the behavior of adduct 14l, obtained in
high yield by addition of 8a to 1-(4-methoxyphenyl)-pent-4-en-
1-one (Scheme 6). In this case, the intermediate radical can
cyclize on either of the two aromatic rings to give difluoro-
thiochroman 23l or tetralone 25.20 In the event, only the
former was obtained, with no trace of tetralone 25 visible in the
NMR of the crude reaction mixture.
the highest Hansch hydrophobicity parameter values (πR
=
1.44)26 and is often introduced to enhance lipophilicity and
other desirable properties in medicinal or agrochemical
substances. The cyclic difluorothiyl motif could have a similar
effect, in addition to increasing the metabolic stability because
the fluorine atoms are now part of the ring structure.
The convergence, flexibilty, experimental simplicity, and
tolerance for functional groups of the present approach should
open access to a large number of such thiochromans, as well as
to simpler structures such as difluorovinyl derivatives (e.g., 24),
which are also of much importance.
Scheme 6. Two Competition Experiments
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, full spectroscopic data, and copies of
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zard@poly.polytechnique.fr.
Notes
The authors declare no competing financial interest.
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Motherwell, W. B.; Rzepa, H. S. J. Chem. Soc., Chem. Commun. 1992,
942.
ACKNOWLEDGMENTS
■
This paper is dedicated with respect to the memory of
Professor Harry Wasserman (Yale University). We thank Ecole
Polytechnique for a scholarship to P.S.
́
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