Radical-based route to 2-(trifluoromethyl)-1,3,4-oxadiazoles and trifluoromethyl -substituted polycyclic 1,2,4-triazoles and dihydrofurans

Article abstract of DOI:10.1021/acs.orglett.5b00457

O-Ethyl S-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl xanthate was readily prepared on a large scale and shown to undergo very efficient intermolecular radical additions to unactivated alkenes. The products were further elaborated by exploiting both

Full text of DOI:10.1021/acs.orglett.5b00457

Letter
pubs.acs.org/OrgLett
Radical-Based Route to 2‑(Trifluoromethyl)-1,3,4-oxadiazoles and
Trifluoromethyl-Substituted Polycyclic 1,2,4-Triazoles and
Dihydrofurans
Ling Qin and Samir Z. Zard*
̀
Laboratoire de SyntheseOrganique, UMR 7652 CNRS/EcolePolytechnique Palaiseau 91128 Cedex, France
S
* Supporting Information
ABSTRACT: O-Ethyl S-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]methyl xanthate was readily prepared on a large scale and
shown to undergo very efficient intermolecular radical additions to unactivated alkenes. The products were further elaborated by
exploiting both radical and ionic processes to provide a variety of trifluoromethyl-substituted derivatives, including medicinally
relevant triazoles. In particular, the application of a radical allylation on the initial adducts leads to structures that are able to
undergo intramolecular [4 + 2] cycloaddition reactions.
he introduction of fluorine-bearing groups into hetero-
Taromatic structures has gained in intensity in recent years,
in view of the importance of organofluorine compounds for the
pharmaceutical and agrochemical industries as well as for
material science.1 The small atomic radius, high electro-
negativity, and low polarizability of the fluorine atom
profoundly alters the properties of the molecules to which it
Figure 1. Marketed drugs containing a 1,3,4-oxadiazole.
is attached such as lipophilicity, permeability, and metabolic
stability. The trifluoromethyl group, in particular, is the most
widespread moiety present in the various building blocks and
In previous work, we described the synthesis of various
fluorine-containing xanthates9 and demonstrated their use for
the generation and capture of the corresponding fluorine-
containing radicals through the reversible addition−transfer
process we discovered some years ago.10 We now describe a
simple, efficient route to O-ethyl S-[5-(trifluoromethyl)-1,3,4-
oxadiazol-2-yl]methyl xanthate 4, a convenient source of
(trifluoromethyl)oxadiazolylmethyl radical. As far as we know,
such a species (and 1,3,4-oxadiazolylmethyl radicals in general)
has not been hitherto exploited for the introduction of this
heteroaromatic moiety.
reagents that have so far been described.2
Owing to its metabolic profile and its ability to form
hydrogen bonds, the 1,3,4-oxadiazole nucleus is a popular
pharmacophore that is widely employed as a scaffold in
medicinal chemistry3 and present in marketed drugs such as
tiodazosin4 and nesapidil,5 both antihypertensive agents, as well
as furamizole,6 an antibiotic (Figure 1). 1,3,4-Oxadiazoles are
also well-known precursors of N-acylamidrazones and 1,2,4-
triazoles, the latter being in their own right important
heterocyclic building blocks for bioactive molecules.7 Fur-
thermore, 1,3,4-oxadiazoles can behave as electron-deficient
azadienes in inverse-electron-demand Diels−Alder reactions
and undergo tandem Diels−Alder/1,3-dipolar cycloaddition
processes to furnish polycyclic structures, and they have
therefore found application in several elegant total syntheses
of natural products.8
The desired xanthate 4 was readily prepared in three steps in
67% overall yield on up to 10-g scale (Scheme 1). Thus,
following the procedure of Balsells and co-workers,11 hydrazine
Received: February 12, 2015
Published: March 3, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00457
Org. Lett. 2015, 17, 1577−1580

Organic Letters
Letter
Scheme 1. Efficient Route to O-Ethyl S-[5-
Scheme 3. Further Transformations of the Adducts
(Trifluoromethyl)-1,3,4-oxadiazolyl-2-methyl] Xanthate
1 was converted into bishydrazide 2 via a one-pot reaction with
ethyl trifluoroacetate in acetonitrile and followed by simulta-
neous addition of chloroacetyl chloride and sodium hydroxide.
This compound was further dehydrated by treatment with
phosphorus oxychloride in acetonitrile to give (chloromethyl)-
oxadiazole 3. Finally, treatment with potassium O-ethyl
xanthate in acetone at 0 °C afforded the desired S-
(trifluoromethyl)oxadiazolylmethyl xanthate 4 as light yellow
solid (mp 51−52 °C).
Generally, aryl- and heteroarylmethyl radicals are poorly
reactive toward simple alkenes, unless the aromatic nucleus is
itself electron withdrawing or is substituted by electron-
withdrawing groups. This is because the resonance stabilization
decreases the reactivity of the radical, and this effect has to be
compensated by favorable polar factors, i.e., a matching
between the mildly electron-donating nature of the simple
alkene and a certain electrophilic character in the radical. Our
hope that the trifluoromethyl group would impart sufficient
electrophilicity to the radical to make its addition to the alkene
synthetically useful was realized in practice, as shown by the
examples in Scheme 2.
by a small amount of 9, which arises from a 1,5-hydrogen
translocation, prior to the cyclization step.13 Acetamide 10 is
the result of a radical Smiles rearrangement triggered by
regeneration of the radical from xanthate 5e,14 whereas the
formation compound 11 illustrates the possibility under certain
conditions of performing a second radical addition. The
complexity may also be further increased by allylation using
an allyl phenyl sulfone, as in the case of 12a,15 or by reaction
with derivative 13 to give alkylidenecyclobutane 12b. The latter
is an example of the use of fluoropyridyl derivatives of allylic
alcohols as radical allylating agents.16 In general, C−O bonds
are very difficult to cleave homolytically, and this recently
discovered process opens vast synthetic possibilities.
Scheme 2. Radical Additions of Xanthate 4 to Olefins
The purpose of the allylation leading to 12a and 12b was to
set up an arrangement that was capable of undergoing an
intramolecular cycloaddition.8 Indeed, upon heating in diphenyl
ether at 185 °C, the former was smoothly converted into
bicyclic dihydrofuran 14 (Scheme 4). Unfortunately, the
intermediate dipole could not be captured by vinyl acetate to
give 15 (see Scheme 5 for the mechanism), nor could a similar
cycloaddition leading logically to 16 be accomplished starting
with compound 12b, presumably because of the congested
nature of the alkene.
In contrast, oxadiazole 19, prepared by addition of xanthate 4
to imidazoledione 17 followed by radical allylation of adduct
18, was effectively converted into (trifluoromethyl)-
dihydrofuran 20. The trans fusion between the imidazolininone
and the cyclohexene rings is worthy of note.17 In a similar
fashion, unsaturated ester 22, obtained by radical addition and
1,2-aryl migration with concomitant elimination of a sulfonyl
radical, underwent cycloaddition to afford bicyclic tetrahy-
drofuran 23 in 63% yield (or 71% brsm). No dehydration of
the hemiketal took place in this case, despite the harsh reaction
conditions. The elimination of water is in all likelihood
The mildness of the experimental conditions typical of the
xanthate transfer translates into a tolerance for numerous useful
functional groups (e.g., the hydrazide in compound 5d).
Furthermore, the addition products can be simply reductively
dexanthylated by the Barton reagent system12 (examples 7a, 7b,
and 7d in Scheme 3) or modified and further enriched by a
number of transformations we have previously devised. For
instance, further treatment of adduct 5f with stoichiometric
quantities of lauroyl peroxide results in ring closure on the
nitrogen of the pyrimidine nitrogen (but interestingly not on
the oxadiazole nitrogen) to give spiro derivative 8 accompanied
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Organic Letters
Letter
either by protonation/deprotonation or, perhaps more likely,
via hemiketal 27 through loss of water.
Scheme 4. Synthesis of Trifluoromethyldihydrofurans
The trifluoromethyl-substituted oxadiazole ring is fairly
electron-deficient and readily undergoes attack by various
nucleophiles. The most interesting is the reaction with internal
amines.11 Thus, reductively dexanthylated product 7a was
readily transformed into bicyclic (trifluoromethyl)triazole 29a
in good yield via deprotection of Boc group by trifluoroacetic
acid in dichloromethane and neutralization by sodium
bicarbonate in methanol at room temperature (Scheme 6).
Scheme 6. Synthesis of (Trifluoromethyl)triazoles
Scheme 5. Mechanistic Rationale
Compound 29a bears some resemblance to the
(trifluoromethyl)triazole portion of stigaliptin 30, a promising
antidiabetes drug. We could even prepare the seven-membered
ring homologue 29b by a similar sequence starting with 7b, but
a higher reaction temperature was needed in the last step to
induce the more difficult formation of the azepine ring. In the
case of derivative 7d, we expected a structure such as tetrazine
29d or a derivative thereof, but we were disappointed to find
that deprotection of the hydrazine moiety and neutralization
with bicarbonate gave rise to a complex mixture with no readily
identifiable product.
Finally, we attempted to access the more substituted triazole
32 through conjugate addition of ammonia to the unsaturated
ester in compound 22 followed by intramolecular reaction with
the oxdiazole ring. Unfortunately, all we obtained was a modest
yield of the simple oxadiazole 31, where ammonia, acting as a
base, caused the migration of the olefin into conjugation with
the chlorophenyl ring. An attempt at the direct base-induced
cyclization of acetamide10 also failed to give the corresponding
triazole 34. Only methanolysis of the oxadiazole ring to give
ester 33 was observed.
prevented by the strain that would be generated in the fused
oxa-[3.3.0] structure. An attempt to capture the intermediate
dipole with diphenylacetylene also failed in this case. Instead of
the expected tricyclic compound 24, and despite the higher
reaction temperature, we only isolated compound 23, albeit in
somewhat lower yield than when it was heated alone.
A mechanistic rationale for these transformations, using
oxadiazole 12a as a typical substrate, is outlined in Scheme 5. A
[4 + 2] cycloaddition furnishes diazo intermediate 25, which
rapidly loses nitrogen at the high reaction temperature to give
dipole 26. In our limited study, this dipole failed to provide
structures of type 28 by a [3 + 2] cycloaddition with an external
dipolarophile. Instead, it was converted into dihydrofuran 14
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Letter
(5) Schlecker, R.; Thieme, P. C. Tetrahedron 1988, 44, 3289.
In summary, we have shown the myriad trifluoromethyl-
substituted structures that can be obtained through the
exploitation of the 2-(trifluoromethyl)-1,3,4-oxadiazolyl-5-
methyl radical. Such molecular architectures cannot be easily
obtained through ionic chemistry in view of the sensitivity of
the electrophilic oxadiazole ring to basic conditions and its
susceptibility to nucleophilic attack. The ability to rapidly
introduce alkenes or protected amines in positions suitable for
subsequent [4 + 2] cycloadditions or nucleophilic condensa-
tions with the oxadiazole nucleus is particularly noteworthy.
(6) (a) Hirao, I. Nippon Kagaku Zasshi 1967, 88, 574. (b) Ogata, M.;
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ASSOCIATED CONTENT
* Supporting Information
■
(9) Salomon, P.; Zard, S. Z. Org. Lett. 2014, 16, 1482.
S
(10) For reviews on the xanthate radical-transfer reaction, 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) Quiclet-Sire, B.; Zard,
S. Z. Pure Appl. Chem. 2011, 83, 519. (e) For an account of the
discovery of this process, see: Zard, S. Z. Aust. J. Chem. 2006, 59, 663.
(11) Balsells, J.; DiMichele, L.; Liu, J. C.; Kubryk, M.; Hansen, K.;
Armstrong, J. D. Org. Lett. 2005, 7, 1039.
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
■
(12) (a) Boivin, J.; Jrad, R.; Juge, S.; Nguyen, V. T. Org. Lett. 2003, 5,
1645. (b) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. Cs. Tetrahedron
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*E-mail: samir.zard@polytechnique.edu.
Notes
The authors declare no competing financial interest.
(13) Qin, L.; Liu, Z. B.; Zard, S. Z. Org. Lett. 2014, 16, 2966.
(14) Gheorghe, A.; Quiclet-Sire, B.; Vila, X.; Zard, S. Z. Org. Lett.
2005, 7, 1653.
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(16) Brioche, J.; Michalak, M.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett.
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ACKNOWLEDGMENTS
We thank EcolePolytechnique for scholarship to L.Q.
■
DEDICATION
■
This article is dedicated with respect and admiration to
Professor Iwao Ojima (Stony Brook University) on the
occasion of his 70th birthday.
(17) Han, S. Z.; Zard, S. Z. Org. Lett. 2014, 16, 5386.
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DOI: 10.1021/acs.orglett.5b00457
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