Copper catalyzed oxidative coupling reactions for trifluoromethylselenolations-synthesis of R-SeCF3 compounds using air stable tetramethylammonium trifluoromethylselenate

Article abstract of DOI:10.1039/c4cc10212f

The aerobic, room-temperature coupling of tetramethylammonium trifluoromethylselenate with readily available boronic acids, boronic esters, and terminal alkynes has been developed. The method permits direct access to valuable trifluoromethylselenoarenes and alkynes under mild conditions. A convenient one-pot reaction, a scale up procedure as well as an extension to perfluoroalkylselenates are also presented to further demonstrate the synthetic utility of this reaction.

Full text of DOI:10.1039/c4cc10212f

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Copper catalyzed oxidative coupling reactions
for trifluoromethylselenolations – synthesis of
R-SeCF3 compounds using air stable
Cite this:DOI: 10.1039/c4cc10212f
Received 21st December 2014,
Accepted 4th February 2015
tetramethylammonium trifluoromethylselenate†
Quentin Lefebvre,‡ Roman Pluta‡ and Magnus Rueping*
DOI: 10.1039/c4cc10212f
www.rsc.org/chemcomm
The aerobic, room-temperature coupling of tetramethylammonium Trifluoromethylselenolated compounds are usually prepared by
trifluoromethylselenate with readily available boronic acids, boronic trifluoromethylation of electrophilic sources of selenium, but this
esters, and terminal alkynes has been developed. The method permits requires the preparation of the corresponding diselenide or sele-
direct access to valuable trifluoromethylselenoarenes and alkynes nium chloride.4 Another more modular approach would be the
under mild conditions. A convenient one-pot reaction, a scale up direct formation of the C–SeCF3 bond. In principle, (F3CSe)2 and
procedure as well as an extension to perfluoroalkylselenates are also F3CSeCl could serve as electrophilic reagents, and F3CSeH as a
presented to further demonstrate the synthetic utility of this reaction. nucleophilic reagent. These reagents have boiling points of 72 1C,
31 1C, and À14.5 1C, respectively, as well as high toxicity, making
Fluorine is the most electronegative element and plays an impor- their use cumbersome. Therefore, MSeCF3 salts, where M is a metal,
tant role in contemporary chemical research and development. have been investigated, and the coupling of copper derivatives with
Fluorinated groups can be found on the market in blockbuster alkyl and aryl halides has been reported in 1985 by Yagupolskii, and
drugs and highly effective agrochemicals and also have applica- revised very recently by Weng and co-workers.5 This approach is
tions in material sciences.1 Compounds possessing fluorinated restricted to the metal used.
moieties have gained increased attention during the past few
Based on Naumann’s work,6 we identified tetramethyl-
years, as their strong lipophilic and electron-withdrawing abilities ammonium trifluoromethylselenate ([Me4N]SeCF3) as a promis-
allow modulation of their physicochemical properties (i.e., logP, ing reagent, readily prepared from red selenium and the
pKa, solubility). This often leads to enhanced bioactivity and Ruppert–Prakash reagent (TMSCF3). The chemistry of this
bioavailability compared to parent non-fluorinated compounds. reagent has not been well established. Therefore, we decided
Therefore, methods for the introduction of these groups into to evaluate the reactivity and stability of [Me4N]SeCF3 and to
organic molecules are of great interest for pharmaceutical and apply it for the challenging introduction of the SeCF3 group
agrochemical industries as well as material sciences.
into different molecules.
Selenium is an essential element in nature, as a vital part of
antioxidant enzymes.2 Organoselenium compounds are even more
easily oxidized compared to their sulfur counterparts, leading to a
richer hypervalent chemistry.3 The odor of selenols and disele-
nides partially prevented the in-depth investigation of methodo-
logies for preparing selenium-containing molecules. In particular
the production of trifluoromethylatedselenoethers still represents
a challenge, even though these compounds might have promising
properties.
Table 1 Optimization of the trifluoromethylselenolation of terminal alkynes
Entry
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
Standard conditionsa
No air (Ar atmosphere)
O2 atmosphere
No copper
No ligand
10 mol% Cu(OTf)2
2 equiv. Cs2CO3
93
o1
94
Therefore, we decided to develop a mild, safe and odor-
free method for the synthesis of fluorinated selenoethers.
nr
9
o5
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52074 Aachen, Germany. E-mail: magnus.rueping@rwth-aachen.de;
Fax: +49 241-809-2127
33
a
Standard conditions: alkyne 1a (0.10 mmol), [Me4N]SeCF3 (0.11 mmol),
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc10212f
Cu(OTf)2 (0.10 mmol) and bipyridine (0.11 mmol) in THF (1 mL) were
b
stirred at RT for 18 h. Full optimization table in the ESI. Yields were
‡ Q. L. and R. P. contributed equally to this work.
determined by 19F NMR analysis with PhCF3 as the internal standard.
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Alkynes are versatile building blocks in organic and polymer bpy or dtbpy as ligand for both Cu(I) and Cu(II) mediated
chemistry, and a wide range of metal-catalyzed methods are reactions provided similar results. That was unexpected as it
known for their functionalization.7 Despite numerous reports was shown by Weng that these ligands tend to form respectively
on the functionalization of selenoalkynes,8 trifluoromethyl- dimeric or monomeric copper(I) complexes with the SeCF3
selenoalkynes are virtually unknown.3i Oxidative coupling of anion in the solid state.5c These results point to an oxygen-
alkynes with heteronucleophiles is challenging due to the promoted Cu(III) intermediate.9
competitive Glaser coupling. However, encouraging preliminary
The scope of this reaction proved to be very general, as
results lead us to investigate the trifluoromethylselenolation of aromatic and heteroaromatic alkynes 1a–i gave excellent yields
alkynes using [Me4N]SeCF3. To our delight, the reaction pro- of the cross-coupling products 2a–i, disregarding the substitu-
ceeded smoothly under aerobic, copper(II)-mediated conditions, tion pattern (Table 2). Aliphatic alkynes 1j–l were also suitable
with THF being the solvent of choice. However, various other substrates, although giving the expected products 2j–l in lower
solvents could also be used (Table 1, full optimization table in the yields due to incomplete conversion. However, this oxidative
ESI†). The reaction can be performed under air or under oxygen coupling represents the first procedure for the introduction of
with equal success. Low conversion was observed under an argon the SeCF3 moiety into alkynes.10
atmosphere or in the absence of a ligand (Table 1, entries 2
With these encouraging results in hand, we wondered
and 5). Using substoichiometric amounts of copper did not result whether this methodology could be applied to the coupling with
in full conversion of starting materials. Interestingly, using either boronic acid 3a (Table 3, full optimization table in the ESI†).11 To
our delight, we found that these Chan–Lam-type conditions gave
the corresponding trifluoromethylselenoarene 4a in good yield.
Table 2 Reaction scope for terminal alkynes
This time, DMF was the solvent of choice, and once again,
although the reaction worked best under an oxygen atmosphere,
the product was obtained in comparable yield under air (Table 3,
entries 3 and 1). Addition of base or molecular sieves did not
improve the yield (Table 3, entries 7 and 8).
We also investigated different nucleophiles (see ESI†) and
realized that next to boronic acid 3a, boron pinacol ester 5a and
boronic acid neopentyl glycol ester 6a gave similar results with
over 80% yield, whereas MIDA and DEAM boronates 7a and 8a
as well as organotin reagent 10a were inferior, with low to
moderate yields. On the other hand, no desired product was
observed if potassium trifluoroborate 9a was used. Given the
range of substrates, we believe this methodology which does
not require aromatic halides as starting materials, or the use of
a glove-box, poisonous gases or high temperatures will be
widely applicable.12
With the optimized conditions in hand, we examined the
scope of this reaction (Table 4). Both electron-rich and electron
deficient aromatic boronic acids and pinacol esters took part in
Table 3 Optimization of the trifluoromethylselenolation of boronic acids
Entry
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Standard conditionsa
No air (Ar atmosphere)
O2 atmosphere
No copper
88
20
90
nr
26
7
No ligand
10 mol% Cu(OTf)2
2 equiv. Cs2CO3
4 Å MS
67
81
a
Standard conditions: boronic acid 1a (0.10 mmol), [Me4N]SeCF3
Reaction conditions: alkyne 1 (0.10 mmol), [Me4N]SeCF3 (0.11 mmol), (0.11 mmol), Cu(OTf)2 (0.10 mmol) and bipyridine (0.11 mmol) in DMF
Cu(OTf)2 (0.10 mmol) and bipyridine (0.11 mmol) in THF (1 mL) were (1 mL) were stirred at RT for 18 h. Full optimization table in the ESI. b Yields
stirred at RT for 18 h. Yield of isolated products.
were determined by 19F NMR analysis with PhCF3 as internal standard.
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Table 4 Reaction scope for boronic acids and boronic pinacol esters
Scheme 1 One-pot procedure. Yields of isolated products.
After reaction completion and standard work-up, we could
isolate the trifluoromethylselenolated products 2a and 4a in
56% and 80% yield, respectively (Scheme 1). A similar experiment
was conducted using the perfluoroethyl analogue, providing the
corresponding products 11a and 12a in good yields. Therefore,
this methodology is expected to be applicable for the synthesis of
a wide range of selenoethers. As a proof of synthetic usefulness,
oxidation of 4a to the corresponding selenoxide proceeded
uneventfully in 86% yield (see ESI†).
In summary, we have developed a new oxidative trifluoro-
methylselenolation of boron derivatives and alkynes. This reaction
proceeds in various solvents, under air, and at room temperature,
and tolerates a wide range of substrates, thus possibly making it
valuable for late-stage functionalization of complex organic mole-
cules. Next to the use of air and moisture stable tetramethyl-
ammonium trifluoromethylselenate ([Me4N]SeCF3), the reaction
can also be performed starting from selenium and TMSCF3.
Furthermore, the scale up of the reaction as well as the introduc-
tion of perfluoroalkylselenate groups has been demonstrated.
Thus the development of such a practical methodology will
provide new classes of compounds relevant for pharmaceutical
and agrochemical industries as well as material sciences.
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a
b
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