A Metal-Free Route to Heterocyclic Trifluoromethyl- and Fluoroalkylselenolated Molecules

Article abstract of DOI:10.1021/acs.orglett.7b03338

A metal-free methodology to easily synthesize various CF₃Se-containing heterocyclic compounds has been developed through intramolecular ring closures of alkynes promoted with CF₃SeCl. Moreover, this strategy has also been extended to other fluoroalkylselenyl groups.

Full text of DOI:10.1021/acs.orglett.7b03338

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Metal-Free Route to Heterocyclic Trifluoromethyl- and
Fluoroalkylselenolated Molecules
Quentin Glenadel, Ermal Ismalaj, and Thierry Billard*
Institute of Chemistry and Biochemistry (ICBMS UMR CNRS 5246), Univ Lyon, Universite
1918, 69622 Villeurbanne, France
́
Lyon 1, CNRS, 43 Bd du 11 novembre
S
* Supporting Information
ABSTRACT: A metal-free methodology to easily synthesize various CF3Se-containing heterocyclic compounds has been
developed through intramolecular ring closures of alkynes promoted with CF3SeCl. Moreover, this strategy has also been
extended to other fluoroalkylselenyl groups.
hese last decades, fluorinated compounds have received
mainly restricted to some simple and unsubstituted com-
pounds. Furthermore, these examples are essentially aromatic
compounds, and very few trifluoromethylselenolations of
nonaromatic elaborated heterocycles have been described.
Finally, most of these reactions generally require the use of a
metal.9,10
This relative underdevelopment of strategies to synthesize
trifluoromethylselenolated heterocycles, aromatic or nonaro-
matic, under metal-free conditions, is partly due to the lack of
efficient reagents to perform trifluoromethylselenolation
reactions.9 Ring closure of alkynes is a well-established method
to obtain heterocyclic structures.11 This strategy generally
requires the use of a Lewis acid or transition metal to favor the
cyclization. For instance, this has been recently described to
obtain trifluoromethylthiolated heterocyclic compounds in the
presence of an electrophilic trifluoromethylthiolating reagent
and a Lewis acid.12
Our group recently described an efficient method to generate
in situ the volatile CF3SeCl reagent to perform electrophilic
trifluoromethylselenolations.10g In particular, electrophilic
additions onto alkenes have been described. Because of the
high electrophilicity of this reagent, the use of a Lewis acid has
not been required.13 On the basis of these previous results, we
postulated that ortho-heteroatom-substituted alkynylaryl com-
pounds 1 could undergo electrophile-promoted nucleophilic
cyclizations with CF3SeCl under metal-free conditions.
We were delighted to observe the formation of the
corresponding trifluoromethylselenolated benzofuran 2a in
T
growing interest in various applications.1 Better resistance
to metabolism, increased lipophilicity, enhanced activity, and
modifications of physicochemical properties can partly explain
the positive effect of the fluorine atom in the life sciences.2
Variability of fluorinated substituents offers modulation of
properties depending on the targeted application. Hence, in
recent years combination of fluoroalkyl groups (in particular
CF3) with heteroatoms has been used to deliver specific
physicochemical properties to molecules. Thus, trifluorome-
thoxy (CF3O) and trifluoromethylsulfanyl (CF3S) moieties
have been largely studied, especially because of their high
lipophilicity.3 In contrast, the trifluoromethylselanyl group
(CF3Se) has experienced scarce interest to date. Nevertheless,
selenylated molecules have already found applications in the life
sciences4 and drug design.5 Furthermore, the CF3Se moiety
possesses interesting electronic (Hammett constants σp = 0.45,
σm = 0.44; Swain−Lupton constants F = 0.43, R = 0.02)6 and
lipophilicity (Hansch−Leo parameter πR = 1.29) properties.7
Consequently, this group is a valuable substituent for the
development of new molecules.
Heterocyclic molecules play an important role in the life
sciences and drug design.8 Indeed, numerous natural products
and bioactive molecules present at least one heterocyclic core.
Therefore, the design of trifluoromethylselenolated hetero-
cycles could be of interest in the development of new bioactive
molecules.
However, despite such an interest in these compounds,
synthetic strategies to achieve such molecules are still
underdeveloped and mainly restricted to a few heteroaromatic
scaffolds.9,10 Indeed, in the literature trifluoromethylselenola-
tions of heterocyclic molecules onto the heterocyclic part are
Received: October 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03338
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
good yield simply by adding CF3SeCl to 1-methoxy-2-(2-
phenylethynyl)benzene (1a) (Scheme 1). Benzothiophenes 2c
disfavors the 5-endo-dig cyclization relative to the chloride
anion opening facilitated by the more nucleophilic “benzylic”
position (Scheme 2). It is noteworthy that only one isomer of
3b was obtained, which is in accordance with the transient
formation of the episelenonium species. The exact config-
uration was not unambiguously determined, but we can
reasonably suppose that the E isomer was formed.
Scheme 1. Syntheses of Fluoroalkylselenolated Benzofurans
a
and Benzothiophenes
Encouraged by this outcome, we investigated the formation
of six-membered-ring heterocycles (Scheme 3). Generally,
Scheme 3. Syntheses of Fluoroalkylselenolated Six-
a
Membered-Ring Heterocycles
a
Yields shown are those of isolated products; yields determined by 19
F
NMR spectroscopy with PhOCF3 as an internal standard are shown in
b
parentheses. Not isolated; identified by 19F NMR spectroscopy and
GC−MS.
and 2d were also obtained following the same strategy.
Interestingly, this strategy was efficiently extended to other
fluoroalkylselenyl moieties (2e, 2f) that were not synthesizable
by previous methods described in the literature. Whereas both
benzothiophenes were obtained in good yields starting from
phenyl- or hexyl-substituted alkynes (1c, 1d), only benzofuran
2a was obtained in good yield. In the case of hexyl-substituted
alkyne 1b, only traces of the desired benzofuran 2b were
formed, with the major product being the adduct 3b (Scheme
2).
Such a surprising result could be potentially rationalized by a
kinetic competition. After reaction with CF3SeCl, an
episelenonium species is formed. From this intermediate, the
shorter C−O bond (compared with the C−S bond) kinetically
a
Yields shown are those of isolated products; yields determined by 19
F
NMR spectroscopy with PhOCF3 as an internal standard are shown in
parentheses. With 2 equiv of CF3SeCl.
b
satisfactory to excellent yields were obtained. Starting from the
corresponding methyl esters, various isocoumarins were easily
obtained (5a−f). This family of compounds presents
interesting pharmacological activities.14 Thus, trifluoromethyl-
selenolated derivatives were obtained (5a−c), but other
fluoroalkylselenyl moieties were also introduced (5d−f), in
particular the HCF2Se group, which can form hydrogen
bonds,15 and two moieties bearing a functional group
(SeCF2CO2Me and SeCF2SO2Ph), which can undergo further
post-transformations.10g,16 The 6-endo-dig cyclization was
confirmed by the single-crystal X-ray diffraction analysis of 5d
(Figure 1). A trifluoromethylselenolated isoquinoline (5g) was
also obtained in satisfactory yield using tert-butylimine as
a
Scheme 2. Reaction of CF3SeCl with 1b
a
Yields shown are those of isolated products; yields determined by 19
F
NMR spectroscopy with PhOCF3 as an internal standard are shown in
parentheses
Figure 1. Single-crystal X-ray structure of 5d.
B
DOI: 10.1021/acs.orglett.7b03338
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
starting material. In this case, 2 equiv of CF3SeCl was required
in order to obtain a satisfactory yield.
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, U.K.; fax: +44 1223 336033.
Unfortunately, the attempt to form isoquinolinone 7a from
the corresponding methyl amide afforded a complex mixture of
products. Nevertheless, such a structure is of interest since it is
found in IPI-549,17 an innovative selective phosphoinositide-3-
kinase (PI3K)-γ inhibitor18 in Phase 1 clinical evaluation in
subjects with advanced solid tumors.19 Consequently, the
synthesis of trifluoromethylselenolated isoquinolinones was
investigated through a multistep pathway (Scheme 4).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: thierry.billard@univ-lyon1.fr.
ORCID
Quentin Glenadel: 0000-0002-0687-0854
Ermal Ismalaj: 0000-0003-2015-2303
Thierry Billard: 0000-0002-2937-9523
Notes
Scheme 4. Synthesis of the Isoquinolinone Core
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the Centre National de la Recherche
Scientifique (CNRS), France, and the French Ministry of
Research for financial support. The French Fluorine Network
(GIS Fluor) is also acknowledged for its support. We thank Dr.
́
Erwann Jeanneau (Centre de Diffractometrie Henri Long-
chambon) for collecting the crystallographic data and solving
the structure of 5d.
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Experimental procedures and compound characterization
data (PDF)
Accession Codes
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D
DOI: 10.1021/acs.orglett.7b03338
Org. Lett. XXXX, XXX, XXX−XXX