Copper-mediated trifluoromethylation of potassium alkynyltrifluoroborates with Langlois' reagent Dedicated to Professor Pierre Vogel on the occasion of his 70th birthday

Article abstract of DOI:10.1016/j.tet.2014.02.005

Synthesis of trifluoromethylated acetylenes by copper-mediated trifluoromethylation of potassium alkynyltrifluoroborates with CF₃ radicals generated from NaSO₂CF₃ and tert-butyl hydroperoxide (TBHP) is communicated. The trifluoromethylated acetylenes were obtained in good to moderate yields. The presented method tolerates a wide range of aromatic, heteroaromatic, and aliphatic potassium alkynyltrifluoroborates.

Full text of DOI:10.1016/j.tet.2014.02.005

Tetrahedron 70 (2014) 2118e2121
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Copper-mediated trifluoromethylation of potassium
alkynyltrifluoroborates with Langlois’ reagent
*
Srinivas Reddy Dubbaka , Shashidhar Nizalapur, Azmi Reddy Atthunuri, Manohar Salla,
Thresen Mathew
Department of Medicinal Chemistry, Albany Molecular Research Singapore Research Centre, Pte Ltd, 61 Science Park Road, #05-01 Galen,
Science Park II, Singapore 117525, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of trifluoromethylated acetylenes by copper-mediated trifluoromethylation of potassium al-
kynyltrifluoroborates with CF3 radicals generated from NaSO2CF3 and tert-butyl hydroperoxide (TBHP) is
communicated. The trifluoromethylated acetylenes were obtained in good to moderate yields. The
Received 17 December 2013
Received in revised form 20 January 2014
Accepted 3 February 2014
Available online 7 February 2014
presented method tolerates
a
wide range of aromatic, heteroaromatic, and aliphatic potassium
alkynyltrifluoroborates.
Ó 2014 Elsevier Ltd. All rights reserved.
Dedicated to Professor Pierre Vogel on the
occasion of his 70th birthday
Keywords:
Terminal alkynes
Trifluoromethylation
Potassium alkynyltrifluoroborates
Copper
Langlois’ reagent
1. Introduction
triflates. A trifluoromethyl group is also incorporated via electro-
þ
philic CF3 sources (Umemoto’s reagent,10 and Togni’s reagent11
)
Trifluoromethyl-substituted compounds are increasingly im-
portant structural motifs in pharmaceuticals, agrochemicals,
and organic materials due to their unique properties imparted by
the trifluoromethyl group, such as high electron density, steric
hindrance, and solubility.1 The importance of incorporation of
a trifluoromethyl group into aryl, alkenyl-, alkynyl motifs is evident
from their elaborate use in material and medicinal chemistry.2
The development of efficient methods for preparing tri-
fluoromethylated arenes, alkenes, and acetylenes has been a topic
of increasing importance in organic synthesis.3 The trifluoromethyl
group is incorporated into organic molecules by several methods,
including nucleophilic,4 electrophilic,5 or radical reactions.6
with aryl/heteroaryl boronic acids. Besides, oxidative coupling re-
actions also have been applied.12 Langlois reported of the use of
CF3SO2Na to generate CF3 radicals by the reaction with tert-butyl
hydroperoxide (TBHP), and its subsequent incorporation into aryl
and heteroaryl motifs.13 The latter method is further elaborated
into Cu-catalyzed/mediated reactions with boronic acids.14,15
Recently, groups of Buchwald,16 Wang,17 and others18 developed
Cu-catalyzed trifluoromethylation of unactivated olefins by
using Togni’s reagent. Pd-catalyzed cross-coupling is typically
employed in the synthesis of trifluoromethylated acetylenes.19,20
Direct CeH bond trifluoromethylation of terminal alkynes pro-
vides trifluoromethylated acetylenes in a straightforward fash-
ion.21e23 Research groups of Qing, Weng, and Fu made use of Cu in
catalytic/stoichiometric amounts in the trifluoromethylation of
terminal alkynes using Ruppert, Togni or Umemoto reagents. While
these methods deliver an equitable protocol to trifluoromethyl al-
kynes, they still require excess amounts of reagents and/or base
and high reaction temperatures, leaving behind a forcing need
for further development of methods towards competent
formation of such molecules. Recently, Huang and Weng
reported copper-catalyzed trifluoromethylation of potassium
Copper in catalytic/stoichiometric amounts is widely used in
nucleophilic, electrophilic, and radical reactions. A trifluoromethyl
-
group is installed by the reaction between a nucleophilic CF3
source (Ruppert reagent (CF3SiMe3),7 K[CF3B(OMe)3],8 CF3H,9
(FSO2CF2SO2Me, ClCF2CO2Me, CF3CO2Na, etc.)3e), and aryl halides/
* Corresponding author. Tel.: þ65 63950975; fax: þ65 63985511; e-mail address:
dubbaka.srinivasreddy@amriglobal.com (S.R. Dubbaka).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.005

S.R. Dubbaka et al. / Tetrahedron 70 (2014) 2118e2121
2119
alkynyltrifluoroborates with Togni’s reagent.24 However, Langlois’
Table 1
Copper-mediated
trifluoromethylation
of
aryl
and
aliphatic
reagent (NaSO2CF3) has not been explored as a trifluoromethylating
agent with potassium alkynyltrifluoroborates. Very recently, we
reported copper-mediated trifluoromethylation of potassium aryl-
and alkenyltrifluoroborates with Langlois’ reagent.25
alkynyltrifluoroboratesa,b
Herein we report the synthesis of trifluoromethylated acety-
lenes by the reaction of potassium alkynyltrifluoroborates with
Langlois’ reagent and TBHP in
fluoromethylation (Scheme 1).
a
copper-mediated tri-
Scheme 1. Cu-mediated trifluoromethylation of potassium alkynyltrifluoroborates
with Langlois’ reagent.
2. Results and discussion
The potassium alkynyltrifluoroborates 2aeo used in this
study were prepared from the corresponding acetylenes 1aeo
(Scheme 2). The acetylenes were deprotonated with n-BuLi in THF
at ꢀ78 ꢁC. After 60 min, addition of trimethoxyborane (1.5 equiv,
ꢀ30 ꢁC, 60 min), followed by KHF2 (6.0 equiv) in H2O resulted in
the formation of alkynyltrifluoroborates 2aeo in good yields
(Scheme 2) and their structures were confirmed by 1H, and 19F NMR
analyses.26 Interestingly, the triisopropylsilyl group was not re-
moved by KHF2 and compound 2m was obtained in 55% yield.
Furthermore, we prepared enyne trifluoroborate 2o in 50% yield.
a
Reaction conditions: Trifluoroborate (1.0 equiv, 0.25 mmol),
CuCl (1.0 equiv), NaHCO3 (1.0 equiv), NaSO2CF3 (3.0 equiv),
TBHP (5.0 equiv) in CH2Cl2/MeOH/H2O at 0 to 23 °C for 6-12 h.
b Isolated yield. c For volatile products, yields were determined by
19F NMR with 4-fluorobenzonitrile as an internal standard added
after the reaction.
desired trifluoromethylated product in poor yield (Table 1, 3j, 20%).
Our protocol also accommodates meta and ortho-substituted aryl
ethynyltrifluoroborate (2h, 2i) affording acceptable yields (Table 1,
3h, 60%; 3i, 61%). We also employed a heterocycle, 3-ethynyl thi-
ophenetrifluoroborate 2k that gave moderate yield (Table 1, 3k,
55%). Additionally, we tested aliphatic alkynyltrifluoroborates un-
der our reaction conditions to give the corresponding tri-
fluoromethylated products in good yield (Table 1, 3l, 61%; 3m, 42%;
3n, 50%). Under our reaction conditions, we could engage enyne
trifluoroborate (2m) for trifluoromethylation, whereby, 3m was
obtained in 50%. Usually, trifluoromethylated enynes are consid-
ered as quite valuable synthetic intermediates.27
Scheme 2. Preparation of alkynyltrifluoroborates 2aeo; for structures, see Table 1.
Based on the above observations, we envisioned that the CF3
radical generated from the reaction of TBHP with NaSO2CF3 oxi-
dizes Cu(I) to a Cu(II)- or Cu(III)-complex. The Cu(II)- or Cu(III)-
complex then undergoes transmetallation with the alkynyltri-
fluoroborate to form an alkynyleCu(II) or eCu(III) intermediate.
Reductive elimination then follows to produce the tri-
fluoromethylated product.28 Electron-withdrawing group results in
a slower transmetallation of potassium alkynyltrifluoroborate,
which might account for their poorer yields.14,15,25
In this study of preparing trifluoromethylated alkynes from
potassium alkynyltrifluoroborates, we directly applied the pre-
viously optimized conditions for the preparation of tri-
fluoromethylated arenes and alkenes, i.e., (trifluoroborate
(1.0 equiv, 0.25 mmol), CuCl (1.0 equiv), NaHCO3 (1.0 equiv),
NaSO2CF3 (3.0 equiv), TBHP (5.0 equiv) in CH2Cl2/MeOH/H2O at
0e23 ꢁC). Subsequently we explored the substrate scope of this
method. Aromatic, heteroaromatic, and aliphatic potassium alky-
nyltrifluoroborates were selected for the trifluoromethylation re-
action. We found that electron-rich substrates gave good yields in
most of the cases whereas electron-withdrawing substrates gave
only poor yield (Table 1). Ethynylarenetrifluoroborates bearing
electron-donating substituents (methoxy, methyl, ethyl, propyl,
butyl, and phenyl) underwent trifluoromethylation in good yields
(Table 1, 3b, 60%; 3c, 58%; 3d, 56%; 3e, 55%; 3f, 50%; 3g, 51%). Tri-
fluoromethylation of an electron-deficient substrate produced the
3. Conclusions
In summary, we report
a convenient Cu-mediated tri-
fluoromethylation of aryl-, heteroaryl, alkenyl, and aliphatic alky-
nyltrifluoroborates,29 using less expensive and stable CF3SO2Na as
,
the CF3 source by in situ generation of CF3 as the active tri-
fluoromethylating agent. The protocol is quite robust and the re-
actions work in water and CH2Cl2/MeOH at room temperature.

2120
S.R. Dubbaka et al. / Tetrahedron 70 (2014) 2118e2121
4. Experimental
4.3.1. (3,3,3-Trifluoroprop-1-ynyl)benzene
(3a).21a 1H
NMR
(400 MHz, DMSO-d6): d
ppm 7.32e7.19 (m, 5H); 19F NMR (400 MHz,
4.1. General information
DMSO-d6):
d
ppm ꢀ50.00 (s, 3F); GCeMS m/z 170 (Mþ).
1H NMR spectra, 19F NMR, and 13C NMR were recorded on Bruker
400 MHz or 300 MHz instruments in the solvents indicated;
chemical shifts are reported in units (parts per million) by assigning
CHCl3 resonance in the 1H spectrum as 7.26 ppm and CDCl3 reso-
nance in the 13C spectrum as 77.0 ppm. 19F NMR chemical shifts
were determined relative to CFCl3 as internal standard and are
measured proton decoupled. All coupling constants (J values) were
reported in Hertz (Hz). GC and GCeMS spectra were measured on
Shimadzu. Column chromatography was performed on silica gel
200e300 mesh on Combiflash. If not specially mentioned, all the
solvents and reagents were used as purchased and without further
purification.
4.3.2. 1-Methoxy-4-(3,3,3-trifluoroprop-1-ynyl)benzene (3b).21a 1H
NMR (400 MHz, CDCl3):
d
7.49 (d, J¼8.7 Hz, 2H), 6.89 (d, J¼9.0 Hz,
2H), 3.84 (s, 3H); 19F NMR (CDCl3, 282 MHz):
d
ꢀ49.41 (s, 3F);
GCeMS m/z 200 (Mþ).
4.3.3. 1-Methyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene
(3c).22 1H
NMR (400 MHz, CDCl3):
d
ppm 7.43 (d, J¼7.9 Hz, 2H), 7.20 (d,
J¼7.9 Hz, 2H), 2.39 (s, 3H); 19F NMR (377 MHz, CDCl3):
d ppm
ꢀ50.40 (s, 3F); GCeMS m/z 184 (Mþ).
4.3.4. 1-Ethyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene (3d).22 1H NMR
(400 MHz, CDCl3):
d
ppm 7.47 (d, J¼8.3 Hz, 2H), 7.22 (d, J¼8.2 Hz,
2H), 2.69 (q, J¼7.7 Hz, 2H), 1.24 (t, J¼7.8 Hz, 3H); 19F NMR (377 MHz,
4.2. General procedure for preparation of potassium alky-
nyltrifluoroborates (Scheme 2)
CDCl3):
d
ppm ꢀ49.57 (s, 3F); GCeMS m/z 198 (Mþ).
n-BuLi (4.70 mL,1.6 M in hexane, 7.57 mmol,1.0 equiv) was added
dropwise toa solution of acetylene (7.57 mmol,1.0 equiv)in 7.6 mL of
dry THF at ꢀ78 ꢁC under a nitrogen atmosphere. After 60 min at this
temperature, trimethylborate (1.10 g, 11.3 mmol, 1.5 equiv) was
added dropwise at ꢀ30 ꢁC. The mixture was stirred at this temper-
ature for 60 min and slowly allowed to warm to room temperature
within another 60 min. A saturated 4.5 M aqueous solution of po-
tassium hydrogen difluoride (KHF2) (10.1 mL, 45.3 mmol, 6.0 equiv)
was added at ꢀ20 ꢁC to the vigorously stirred solution. The resulting
mixture was continued to stir for 60 min at ꢀ20 ꢁC after which it was
allowed to warm to room temperature for 60 min. The solvent was
removed under reduced pressure, and the resulting white solid was
dried under high vacuum to remove water. The solid was washed
first with acetone and then with hot acetone. The solution was
concentrated to afford a white solid. The solid was dissolved in
minimum amount of hot acetone, precipitated by adding methyl
tert-butyl ether (MTBE), after which the solution was cooled to
ꢀ20 ꢁC to complete precipitation of the solid. The product was col-
lected as an off white solid 2aeo in 40e80% yield.
4.3.5. 1-Propyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene
NMR (400 MHz, CDCl3):
ppm 7.46 (d, J¼7.9 Hz, 2H), 7.20 (d,
(3e).22 1H
d
J¼7.9 Hz, 2H), 2.61 (t, J¼7.5 Hz, 2H), 1.66e1.61 (m, 2H), 0.95 (t,
J¼7.5 Hz, 3H); 19F NMR (377 MHz, CDCl3):
GCeMS m/z 212 (Mþ).
d
ppm ꢀ50.58 (s, 3F);
4.3.6. 1-Butyl-4-(3,3,3-trifluoroprop-1-ynyl)benzene (3f).24 1H NMR
(400 MHz, CDCl3):
ppm 7.45 (d, J¼7.9 Hz, 2H), 7.21 (d, J¼7.9 Hz,
d
2H), 2.73e2.53 (m, 2H), 1.61e1.58 (m, 2H), 1.35e1.31 (m, 2H), 0.95
(t, J¼7.5 Hz, 3H); 19F NMR (377 MHz, CDCl3):
d
ppm ꢀ50.77 (s, 3F).
GCeMS m/z 226 (Mþ).
4.3.7. 4-(3,3,3-Trifluoroprop-1-yn-1-yl)-1,10-biphenyl
(3g).21c 1H
NMR (400 MHz, CDCl3):
d ppm 7.68e7.55 (m, 6H), 7.48e7.43
(m, 2H), 7.41e7.38 (m, 1H); 19F NMR (377 MHz, CDCl3):
ꢀ49.69 (s, 3F); GCeMS m/z 246 (Mþ).
d ppm
4.3.8. 1-Methyl-3-(3,3,3-trifluoroprop-1-ynyl)benzene
(3h).22 1H
NMR (400 MHz, CDCl3):
d ppm 7.37e7.35 (m, 2H), 7.30e7.29 (m,
2H), 2.37 (s, 3H); 19F NMR (377 MHz, CDCl3):
d
ppm ꢀ49.73 (s, 3F);
(3i).22 1H
4.3. General procedure for copper-catalyzed tri-
fluoromethylation of potassium alkynyltrifluoroborates with
Langlois’ reagent (Table 1)
GCeMS m/z 184 (Mþ).
4.3.9. 1-Methyl-2-(3,3,3-trifluoroprop-1-ynyl)benzene
NMR (400 MHz, CDCl3):
d
ppm 7.50 (d, J¼6.8 Hz, 1H), 7.50 (d,
A mixture of the potassium alkynyltrifluoroborate (0.25 mmol,
1.0 equiv), CuCl (24.8 mg, 0.25 mmol, 1.0 equiv), NaSO2CF3 (117 mg,
0.75 mmol, 3.0 equiv), NaHCO3 (21.0 mg, 0.25 mmol, 3.0 equiv) in
CH2Cl2 (1.5 mL), MeOH (1.5 mL), and H2O (1.2 mL) was cooled to
J¼7.7 Hz, 1H), 7.32e7.19 (m, 1H), 7.17e7.12 (m, 1H), 2.49 (s, 3H); 19
F
NMR (377 MHz, CDCl3):
(Mþ).
d
ppm ꢀ49.70 (s, 3F); GCeMS m/z 184
0 ꢁC, and TBHP (70% solution in water, 172
ml, 5.0 equiv, 1.25 mmol)
4.3.10. Ethyl 4-(3,3,3-trifluoroprop-1-yn-1-yl)benzoate (3j).21a 1H
was added under vigorous stirring. The resulted reaction mixture
was stirred for 6e12 h at room temperature. The organic phase was
separated, the aqueous phase was extracted with CH2Cl2
(3ꢂ10 mL). The combined organic phases were dried over anhy-
drous Na2SO4, the solvent was removed at 1 atm and the residue
was purified by column chromatography on Combiflash with hex-
anes to afford desired compound.
The volatile products were not isolated (3n and 3o) and their
yields were determined only by 19F NMR of the reaction mixture.
For the compounds reported with 19F NMR yields, 4-
fluorobenzonitrile (0.25 mmol) was added as reference to the re-
action mixture, stirred for 5 min, an aliquot of the organic phase
was withdrawn for the 19F NMR measurement in CDCl3.
Analytical data of isolated products 3a,21a 3b,21a 3c,22 3d,22 3e,22
3f,24 3g,21c 3h,22 3i,22 3j,21 3k,21a 3l,22 and 3m23 are identical to
those given in literature. The purity of isolated products was de-
termined by GC and was >96%.
NMR (400 MHz, CDCl3):
d
ppm 8.12 (d, J¼7.9 Hz, 2H), 7.65 (d,
J¼7.9 Hz, 2H), 4.42 (q, J¼6.3 Hz, 2H), 1.45 (t, J¼6.3 Hz, 3H); 19F NMR
(377 MHz, CDCl3):
d
ppm ꢀ49.71 (s, 3F). GCeMS m/z 242 (Mþ).
4.3.11. 3-(3,3,3-Trifluoroprop-1-yn-1-yl)thiophene (3k).21a 1H NMR
(300 MHz, CDCl3):
d
ppm 7.58 (dd, J¼3.1, 1.5 Hz, 1H), 7.28 (dd, J¼5.3,
3.0 Hz, 1H), 7.17 (dd, J¼5.0 Hz, 1.1 Hz, 1H); 19F NMR (377 MHz,
CDCl3):
d
ppm ꢀ49.41 (s, 3F); GCeMS: 176 (Mþ).
4.3.12. (4,4,4-Trifluorobut-2-yn-1-yl)benzene
(3l).22 1H
NMR
(300 MHz, CDCl3): d ppm 7.38e7.31 (m, 2H), 7.32e7.27 (m, 3H), 3.73
(d, J¼3.6 Hz, 1H), 3.71 (d, J¼3.6 Hz, 1H); 19F NMR (377 MHz, CDCl3):
d
ppm ꢀ49.7 (s, 3F); GCeMS: 184 (Mþ).
4.3.13. Triisopropyl(3,3,3-trifluoroprop-1-yn-1-yl)silane (3m).23 1H
NMR (400 MHz, CDCl3):
ppm 1.25e1.05 (m, 3H), 1.10 (d, J¼6.0 Hz,
d

S.R. Dubbaka et al. / Tetrahedron 70 (2014) 2118e2121
2121
18H); 19F NMR (377 MHz, CDCl3):
d
ppm ꢀ50.48 (s, 3F); GCeMS:
ꢀ
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^
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28. There might other unforeseen reaction mechanisms exist.
29. We attempted to generate phenylethynylboronic acid (4a) from potassium
30
phenylethynyltrifluoroborate (2a) under basic reaction condition (Cs2CO3 in
THF/H2O or NaHCO3 in MeOH/H2O) at 60 ꢁC for 15e24 h. However, there was
no conversion from 2a to boronic acid 4a and when the reaction was kept for
longer time; protodeboronated phenylacetylene (1a) was observed.
30. Lennox, A. J. J.; Lloyd-Jones, G. C. J. Am. Chem. Soc. 2012, 134, 7431.
8. Khan, B. A.; Buba, A. E.; Gooßen, L. J. Chem.dEur. J. 2011, 17, 2689.