Electrophilic Trifluoromethyl- and Fluoroalkylselenolation of Organometallic Reagents

Article abstract of DOI:10.1002/ejoc.201601526

Fluoroalkylseleno groups are emerging groups that still suffer from a lack of efficient methods for introduction onto organic molecules. Herein, we describe an efficient method to perform reactions between in situ formed fluoroalkaneselenyl chlorides and organometallic reagents. With this strategy, various fluoroalkylselenolated molecules were easily obtained. Furthermore, the Hansch parameter of the CF₃Se group was determined for the first time.

Full text of DOI:10.1002/ejoc.201601526

DOI: 10.1002/ejoc.201601526
Communication
Trifluoromethylselenolation
Electrophilic Trifluoromethyl- and Fluoroalkylselenolation of
Organometallic Reagents
Quentin Glenadel,[a] Ermal Ismalaj,[a,b] and Thierry Billard*[a,b]
Abstract: Fluoroalkylseleno groups are emerging groups that chlorides and organometallic reagents. With this strategy, vari-
still suffer from a lack of efficient methods for introduction onto ous fluoroalkylselenolated molecules were easily obtained. Fur-
organic molecules. Herein, we describe an efficient method to thermore, the Hansch parameter of the CF3Se group was deter-
perform reactions between in situ formed fluoroalkaneselenyl mined for the first time.
Introduction
CF3Se moiety in one step. In this case, the preliminary synthesis
of selenylated compounds is not required. Recently, some nu-
cleophilic reactions with the trifluoromethylselenolate anion
(CF3Se–) were described.[10] However, all these methods were
based on the use of stoichiometric amounts of selenium metal
to form the CF3Se– species. In terms of an electrophilic ap-
proach, until recently, only a few examples were described that
involved the use of CF3SeCl.[11] This underdeveloped chemistry
can be explained not only by the difficulty to synthesize
CF3SeCl[12] but also by the high volatility and suspected toxicity
of this species.
Owing to the specific properties of the fluorine atom,[1] fluorin-
ated compounds have found growing interest in the last dec-
ades for a large panel of various applications.[2] With the aim to
modulate the properties of molecules, new fluorinated groups
have emerged. In particular, the association of fluoroalkyl moie-
ties with heteroatoms brings new electronic properties and
contributes to enhancing the lipophilicity of molecules. Such
specific properties are of particular interest in life sciences as
well as in material sciences.
Over the last years, the trifluoromethylsulfanyl group (CF3S)
has aroused great interest,[3] essentially because of its high lipo-
philicity (Hansch parameter πR = 1.44).[4] The trifluoromethyl-
selanyl group (CF3Se) is less known, although its electronic
Results and Discussion
properties are interesting (Hammett constants σp = 0.45, σm
=
0.44; Swain–Lupton constants F = 0.43, R = 0.02).[5] However, to
this day, its lipophilicity Hansch parameter is still unknown.
Organoselenium compounds can find some applications in
life sciences[6] and in drug design, as illustrated by the drug
ebselen,[7] and in materials science and nanotechnology.[8] Con-
sequently, the design of trifluoromethylselenolated molecules
may offer new substrates with specific properties.
To circumvent these drawbacks, we recently developed a one-
pot procedure, avoiding the isolation of CF3SeCl, to perform
electrophilic aromatic substitutions.[13] The strategy was based
on the oxidative chlorination of benzyl trifluoromethyl selenide
(1a), easily obtained from inexpensive nonmetallic potassium
selenocyanate.[14] This strategy was extended to other fluorin-
ated groups (starting from the corresponding benzyl fluoroalkyl
selenides), and then, various fluoroalkylselenolated aromatic
compounds were obtained in good yields. However, nonelec-
tron-rich aromatic substrates, such as benzene, gave low yields.
Furthermore, there was the possibility of some regioselectivity
issues with substituted aromatic compounds. To solve this low
reactivity and to favor regioselectivity, Grignard reagents were
envisaged (Table 1).
Despite such an interest, only a few methods for the synthe-
sis of trifluoromethyl selenides have been described in the liter-
ature. Indirect methods consisting of trifluoromethylate selenyl-
ated substrates were developed first.[9] However, the prelimi-
nary preparation of selenylated compounds can constitute a
major drawback. From a retrosynthetic point of view, direct
methods are more elegant, as they allow the addition of the
Because 1 equivalent of benzyl chloride was released during
the first step involving the preformation of CF3SeCl, 2 equiva-
lents of Grignard reagent 2a were required to obtained good
yields (Table 1, entries 1 and 2). A higher excess amount of 2a
did not improve the reaction (Table 1, entry 4). Because of the
exothermicity of the reaction, it appeared crucial to add 2a at
–78 °C (Table 1, entries 2 and 5) to avoid outgassing of highly
volatile CF3SeCl. With the optimal conditions in hand (Table 1,
entry 2), various Grignard reagents were engaged (Scheme 1).
[a] Institute of Chemistry and Biochemistry (ICBMS-UMR CNRS 5246)
Univ Lyon, Université Lyon 1, CNRS
43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
E-mail: Thierry.billard@univ-lyon1.fr
www.FMI-Lyon.fr
[b] CERMEP - in vivo imaging, Groupement Hospitalier Est
59 Bd Pinel, 69003 Lyon, France
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201601526.
Eur. J. Org. Chem. 2017, 530–533
530
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Reactivity of 1a with PhMgCl (2a).
Perfluoroalkylselenolated molecules were obtained in gener-
ally good yields in both the aromatic and aliphatic series. Com-
pound 3k with a long fluorinated chain was also synthesized
in satisfactory yield. Such a compound could be of interest in
materials science or as a surfactant. Molecule 3l bearing a func-
tional group was also obtained in satisfactory yield. This group
opens the way to possible postfunctionalization, as previously
demonstrated.[13,15]
Because alkynes constitute interesting building blocks for
further synthesis, this strategy was extended to terminal alk-
ynes through their lithium alkynides obtained after deprotona-
tion (Scheme 2).
Entry
SO2Cl2 [equiv.]
2a [equiv.]
T [°C]
Yield of 3a[a] [%]
1
2
3
4
5
1
1
2
1
1
1
2
2
2.5
2
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
0 to r.t.
36
84
46
75
38
[a] Yield was determined by 19F NMR spectroscopy by using PhOCF3 as an
internal standard.
Scheme 1. Trifluoromethylselenolation of Grignard reagents. Yields shown are
those of the isolated products; yields determined by 19F NMR spectroscopy
by using PhOCF3 as an internal standard are shown in parentheses.
In general, good yields were observed in both the aromatic
and aliphatic series. The reaction did not seem to be sensitive
to steric hindrance (see products 3d and 3e).
Because we already demonstrated the possible extrapolation
of this method to other fluoroalkylseleno groups,[13] higher
homologues of 1a were also examined under the same condi-
tions (Figure 1).
Scheme 2. Fluoroalkylselenolation of lithium alkynides. Yields shown are
those of the isolated products; yields determined by 19F NMR spectroscopy
by using PhOCF3 as an internal standard are shown in parentheses. RF
perfluorinated alkyl group.
=
Good results were obtained with both aromatic and aliphatic
alkynes. Similarly, extrapolation to higher homologues also led
to good yields.
Given that the Hansch–Leo parameter of the CF3Se group
was still unknown, we decided to determine it. Partition coeffi-
cients (P) between octanol and water for benzene and 3a were
then determined by the shake-flask method, which was fol-
lowed by UV titration (Figure 2).
Then, the Hansch–Leo parameter of the CF3Se group was
found to be 1.29 0.14. Consequently, the CF3Se group seems
to be less lipophilic than the CF3S group (πR = 1.44), which
could be interesting to modulate the physicochemical proper-
ties of designed molecules.
Figure 1. Fluoroalkylselenolation of Grignard reagents. Yields shown are those
of the isolated products; yields determined by 19F NMR spectroscopy by us-
ing PhOCF3 as an internal standard are shown in parentheses.
Eur. J. Org. Chem. 2017, 530–533
www.eurjoc.org
531
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Acknowledgments
This work was supported by the RADIOMI project (EU FP7- PEO-
PLE-2012-ITN-RADIOMI), the Centre National de la Recherche
Scientifique (CNRS), and the French Fluorine Network.
Keywords: Grignard reaction · Fluorine · Lipophilicity ·
Lithium · Selenium
[1] a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applica-
tions, Wiley-VCH, Weinheim, 2013; b) B. E. Smart, J. Fluorine Chem. 2001,
109, 3–11.
[2] a) A. Becker, Inventory of Industrial Fluoro-biochemicals, Eyrolles, Paris,
1996; b) T. Fujiwara, D. O'Hagan, J. Fluorine Chem. 2014, 167, 16–29; c)
E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell, J. Med.
Chem. 2015, 58, 8315–8359; d) W. K. Hagmann, J. Med. Chem. 2008, 51,
4359–4369; e) M. Hird, Chem. Soc. Rev. 2007, 36, 2070–2095; f) M. Pagli-
aro, R. Ciriminna, J. Mater. Chem. 2005, 15, 4981–4991; g) G. Theodoridis,
Advances in Fluorine Science Vol. 2 (Ed.: A. Tressaud), Elsevier, Amsterdam,
2006, pp. 121–175; h) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C.
Del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu, Chem.
Rev. 2014, 114, 2432–2506; i) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu,
J. L. Aceña, V. A. Soloshonok, K. Izawa, H. Liu, Chem. Rev. 2016, 116, 422–
518; j) P. Jeschke, Pest Manage. Sci. 2010, 66, 10–27; k) D. Chopra, T. N. G.
Row, CrystEngComm 2011, 13, 2175–2186; l) R. Berger, G. Resnati, P. Me-
trangolo, E. Weber, J. Hulliger, Chem. Soc. Rev. 2011, 40, 3496–3508.
[3] a) F. Toulgoat, S. Alazet, T. Billard, Eur. J. Org. Chem. 2014, 2415–2428; b)
X.-H. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 2015, 115, 731–764.
[4] A. Leo, C. Hansch, D. Elkins, Chem. Rev. 1971, 71, 525–616.
Figure 2. Log P (octanol/water) of CF3SePh and Hansch–Leo parameter πR of
the CF3Se group. πR = log P(CF3SePh) – log P(benzene).
Conclusions
To conclude, this method, based on the in situ formation of
fluoroalkaneselenyl chlorides from the corresponding benzyl
fluoroalkyl selenides, appears to be very efficient. The pre-
formed reagents could be treated with various organometallic
reagents to furnish a large panel of fluoroalkylselenolated com-
pounds. From a physicochemical point of view, these selenyl-
ated groups bring some moderation relative to their sulfur ana-
logues, as illustrated by the Hansch–Leo parameter of the CF3Se
group. Such a strategy should contribute to the introduction of
these new substituents in the toolbox of fluorine chemistry.
[5] C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165–195.
[6] a) R. Abdulah, K. Miyazaki, M. Nakazawa, H. Koyama, J. Trace Elem. Med.
Biol. 2005, 19, 141–150; b) M. Bodnar, P. Konieczka, J. Namiesnik, J. Envi-
ron. Sci. Health Part C: Environ. Carcinog. Ecotoxicol. Rev. 2012, 30, 225–
252; c) K. M. Brown, J. R. Arhur, Public Health Nutr. 2001, 4, 593–599; d)
G. F. Combs, W. P. Gray, Pharmacol. Ther. 1998, 79, 179–192; e) D. H.
Holben, A. M. Smith, J. Am. Dietet. Assoc. 1999, 99, 836–843; f) A. Kyriako-
poulos, D. Behne, Rev. Physiol. Biochem. Pharmacol. 2002, 145, 1–46; g)
J. Lu, A. Holmgren, J. Biol. Chem. 2009, 284, 723–727; h) M. P. Rayman,
Lancet 2000, 356, 233–241; i) L. A. Wessjohann, A. Schneider, M. Abbas,
W. Brandt, Biol. Chem. 2007, 388, 997–1006.
[7] a) N. Singh, A. L. Sharpley, U. E. Emir, C. Masaki, M. M. Herzallah, M. A.
Gluck, T. Sharp, C. J. Harmer, S. R. Vasudevan, P. J. Cowen, G. C. Churchill,
Neuropsychopharmacology 2016, 41, 1768–1778; b) E. D. Lynch, R. Gu, C.
Pierce, J. Kil, Hear. Res. 2005, 201, 81–89; c) S. Thangamani, W. Younis,
M. N. Seleem, Sci. Rep. 2015, 5, 11596.
[8] L. V. Romashov, V. P. Ananikov, Chem. Eur. J. 2013, 19, 17640–17660.
[9] a) P. Nikolaienko, M. Rueping, Chem. Eur. J. 2016, 22, 2620–2623; b) S.
Potash, S. Rozen, J. Org. Chem. 2014, 79, 11205–11208; c) P. Cherkupally,
P. Beier, Tetrahedron Lett. 2010, 51, 252–255; d) G. Blond, T. Billard, B. R.
Langlois, Tetrahedron Lett. 2001, 42, 2473–2475; e) S. Large, N. Roques,
B. R. Langlois, J. Org. Chem. 2000, 65, 8848–8856; f) T. Billard, S. Large,
B. R. Langlois, Tetrahedron Lett. 1997, 38, 65–68; g) T. Billard, B. R. Lan-
glois, Tetrahedron Lett. 1996, 37, 6865–6868; h) T. Billard, N. Roques, B. R.
Langlois, J. Org. Chem. 1999, 64, 3813–3820; i) T. Billard, B. R. Langlois,
S. Large, Phosphorus Sulfur Silicon Relat. Elem. 1998, 136, 521–524; j) J.-J.
Ma, W.-B. Yi, G.-P. Lu, C. Cai, Catal. Sci. Technol. 2016, 6, 417–421; k) C.
Pooput, W. R. Dolbier, M. Médebielle, J. Org. Chem. 2006, 71, 3564–3568;
l) C. Pooput, M. Medebielle, W. R. Dolbier, Org. Lett. 2004, 6, 301–303; m)
E. Magnier, E. Vit, C. Wakselman, Synlett 2001, 1260–1262.
[10] a) C. Wu, Y. Huang, Z. Chen, Z. Weng, Tetrahedron Lett. 2015, 56, 3838–
3841; b) Y. Wang, Y. You, Z. Weng, Org. Chem. Front. 2015, 2, 574–577; c)
Q. Lefebvre, R. Pluta, M. Rueping, Chem. Commun. 2015, 51, 4394–4397;
d) C. Hou, X. Lin, Y. Huang, Z. Chen, Z. Weng, Synthesis 2015, 47, 969–
975; e) M. Aufiero, T. Sperger, A. S. K. Tsang, F. Schoenebeck, Angew.
Chem. Int. Ed. 2015, 54, 10322–10326; Angew. Chem. 2015, 127, 10462–
10466; f) P. Zhu, X. He, X. Chen, Y. You, Y. Yuan, Z. Weng, Tetrahedron
2014, 70, 672–677; g) M. Rong, R. Huang, Y. You, Z. Weng, Tetrahedron
Experimental Section
Synthesis of [(Trifluoromethyl)selanyl]benzene (3a): A dried flask
equipped with a magnetic stirrer bar was charged with 1a
(0.5 mmol, 1.0 equiv.), and the flask was then flushed with nitrogen
several times. Sulfuryl chloride (0.5 mmol, 1.0 equiv.) and dry THF
(0.5 mL) were then added. The mixture was stirred at 23 °C until
complete formation of the CF3SeCl intermediate (15 min) and was
then cooled to –78 °C. Then, 2a (1.0 mmol, 2.0 equiv.) was added.
The resulting mixture was stirred at –78 °C for 30 min and was
then warmed to 23 °C until complete conversion of the CF3SeCl
intermediate (the conversion was monitored by 19F NMR spectro-
scopy with PhOCF3 as an internal standard). The mixture was then
partitioned between water and pentane, and the aqueous layer was
extracted with pentane. The combined organic layer was washed
with brine, dried with MgSO4, filtered, and concentrated to dryness.
The crude residue was purified by chromatography to afford prod-
1
uct 3a. H NMR (300 MHz, CDCl3): δ = 7.75 (m, 2 H), 7.47 (m, 1 H),
7.40 ppm (m, 2 H). 19F NMR (282 MHz, CDCl3): δ = –36.09 ppm (s,
3 F). In accordance with the literature data.[9h]
Eur. J. Org. Chem. 2017, 530–533
www.eurjoc.org
532
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
2014, 70, 8872–8878; h) C. Chen, L. Ouyang, Q. Lin, Y. Liu, C. Hou, Y.
Yuan, Z. Weng, Chem. Eur. J. 2014, 20, 657–661; i) C. Chen, C. Hou, Y.
Wang, T. S. A. Hor, Z. Weng, Org. Lett. 2014, 16, 524–527; j) N. V. Kondra-
tenko, A. A. Kolomeytsev, V. I. Popov, L. M. Yagupolskii, Synthesis 1985,
667–669; k) Q. Tian, Z. Weng, Chin. J. Chem. 2016, 34, 505–510.
[11] a) A. Haas, H.-W. Praas, Chem. Ber. 1992, 125, 571–579; b) V. G. Volosh-
chuk, L. M. Yagupol'skii, G. P. Syrova, V. P. Bystrov, Russ. J. Gen. Chem.
1967, 37, 105–108; c) L. M. Yagupol'skii, V. G. Voloshchuk, Russ. J. Gen.
Chem. 1966, 36, 173–174; d) L. M. Yagupol'skii, V. G. Voloshchuk, Russ. J.
Gen. Chem. 1967, 37, 1463–1465; e) L. M. Yagupol'skii, V. G. Voloshchuk,
Russ. J. Gen. Chem. 1968, 38, 2426–2429.
[12] a) J. W. Dale, H. J. Emeleus, R. N. Haszeldine, J. Chem. Soc. (Resumed)
1958, 2939–2945; b) N. N. Yarovenko, V. N. Shemanina, G. B. Gazieva,
Russ. J. Gen. Chem. 1959, 29, 924–927.
[13] Q. Glenadel, E. Ismalaj, T. Billard, J. Org. Chem. 2016, 81, 8268–8275.
[14] E. Magnier, C. Wakselman, Collect. Czech. Chem. Commun. 2002, 67,
1262–1266.
[15] E. Ismalaj, D. Le Bars, T. Billard, Angew. Chem. Int. Ed. 2016, 55, 4790–
4793; Angew. Chem. 2016, 128, 4868–4871.
Received: November 2, 2016
Eur. J. Org. Chem. 2017, 530–533
www.eurjoc.org
533
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim