1,2-(Bis)trifluoromethylation of Alkynes: A One-Step Reaction to Install an Underutilized Functional Group

Article abstract of DOI:10.1002/anie.201905247

Modifying the electronic properties of olefins is the quintessential approach to tuning alkene reactivity. In this context, the exploration of trifluoromethyl groups as divergent electronic modifiers has not been considered. In this work, we describe a copper-mediated 1,2-(bis)trifluoromethylation of acetylenes to create E-hexafluorobutenes (E-HFBs) under blue light in a single step. The reaction proceeds with high yield and E/Z selectivity. Since the alkyne captures two trifluoromethyl groups from each molecule of bpyCu(CF₃)₃, mechanistic studies were conducted to illuminate the role of the reactants. Interestingly, E-HFBs exhibit remarkable stability to standard olefin functionalization reactions in spite of the pendant trifluoromethyl groups. This finding has significant implications for medicine, agroscience, and materials.

Full text of DOI:10.1002/anie.201905247

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Accepted Article
Title: 1,2-(Bis)trifluoromethylation of Alkynes: A One-Step Reaction to
Install an Underutilized Functional Group
Authors: Shuo Guo, Deyaa AbuSalim, and Silas Cook
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1,2-(Bis)trifluoromethylation of Alkynes: A One-Step Reaction to
Install an Underutilized Functional Group
Shuo Guo, Deyaa I. AbuSalim and Silas P. Cook*
[9]
Abstract: Modifying the electronic properties of olefins represents the
quintessential approach to tuning alkene reactivity. In this context,
the exploration of trifluoromethyl groups as divergent electronic
modifiers has not been considered. Here, we describe a copper-
mediated 1,2-(bis)trifluoromethylation of acetylenes to create—in a
single step—E-hexafluorobutenes (E-HFBs). The reaction proceeds
with high yield and E/Z selectivity. Since the alkyne captures two
trifluoromethyl groups from each molecule of bpyCu(CF3)3,
mechanistic studies were conducted to illuminate the role of reactants.
Interestingly, E-HFBs exhibit remarkable stability to standard olefin
functionalization reactions in spite of the pendant trifluoromethyl
groups. This finding has significant implications for medicine,
agroscience, and materials.
Consequently, such copper complexes are more accurately
described, and spectroscopically observed,[10] as Cu(I)—which
has significant implications for reactivity.
Scheme 1. (a-c) Previous studies have established the capture of one
trifluoromethyl group from bpyCu(CF3)3; (d-e) the combination of persulfate and
light enable the capture of two trifluoromethyl groups from bpyCu(CF3)3.
The trifluoromethyl group, with its unique electronegativity,
hydrophobicity, metabolic stability, and bioavailability, has
permeated organic structures in the context of medicines,
agrochemicals, and organic materials.[1] While frequently
connected to aromatic systems, the trifluoromethyl group can also
be found appended to alkenes in many biologically active
molecules and organic functional materials.[2] Interestingly, olefins
bearing two trifluoromethyl groups remain rare but should
possess unique properties. The ability to introduce trifluoromethyl
groups into complex molecular architectures, however, presents
a difficult proposition—even with modern organic chemistry.
Synthesis of stereochemically defined E-hexafluorobutenes (E-
HFBs) requires multi-step synthesis, wherein the difficult-to-
append trifluoromethyl groups are added separately or through
the difunctionalization of hexafluoro-2-butyne—a gas at 25 ºC.[3]
For example, the treatment of trans-1,2-diiodoalkenes with
copper and FSO2CF2CO2Me leads to the formation of E-HFBs,[4]
and the treatment of arynes with a trifluoromethyl-ligated copper
produces ortho-bis(trifluoromethyl)benzenes.[5c] Obviously, the
direct difunctionalization of alkynes would offer advantages for
both step- and atom-economy.[5]
Trifluoromethyl-adorned copper systems have proven
robust, and numerous applications for aryl trifluoromethylation
have been developed.[6] As early as the 1980s, stable copper
complexes containing trifluoromethyl groups were synthesized
and studied.[7] In 2015, Grushin et al. reported bpyCu(CF3)3 and
related complexes that are bench-stable and easy to prepare.[8]
While some reports described similar copper systems as high-
valent Cu(III) complexes, theoretical work as early 1995 showed
that these structures possess filled 3d orbitals (i.e., d10), in part
due to the inversion of the ligand field caused by the CF3 ligands.
Several groups have demonstrated that the unique
reactivity of bpyCu(CF3)3 can be used for mono-
trifluoromethylation. For example, Li and co-workers developed
alkyl trifluoromethylation from halides or carboxylic acids
(Scheme 1a)[11] and, later, formed trifluoromethyl ketones from
aldehydes with bpyCu(CF3)3 (Scheme 1b).[12] Liu et al. and our
group disclosed benzylic C(sp3)−H trifluoromethylation that can
be employed for late-stage functionalization (Scheme 1c).[13]
Here, we describe the simultaneous introduction of two
trifluoromethyl groups across alkynes using bpyCu(CF3)3,
persulfate, and blue light to access E-HFBs (Scheme 1d). Under
irradiation, bpyCu(CF3)3 liberates one trifluoromethyl radical. We
found that the newly formed bpyCu(CF3)2(OSO3H) also liberates
a trifluoromethyl radical (Scheme 1e). The conditions provide a
tandem radical and inner sphere trifluoromethylation that we
harness for the synthesis of E-HFBs.
We have previously shown that UV light can homolyze
reagent 2 to form bpyCu(CF3)2 and trifluoromethyl radical.[13b] In
that study, the newly formed trifluoromethyl radical was quenched
with silane to prevent unwanted side reactions. Here, we
envisioned using this radical to add into an alkyne to generate a
vinylic radical that could recombine with copper to induce a
second trifluoromethylation. Interestingly, visible-light irradiation
(447 nm) of bpyCu(CF3)3/K2S2O8 in the presence of 4-
[*]
Shuo Guo, Deyaa I. AbuSalim and Prof. Dr. S. P. Cook
Department of Chemistry, Indiana University
800 East Kirkwood Avenue, Bloomington, IN 47405 (United States)
E-mail: sicook@indiana.edu
Supporting information for this article is given via a link at the end of
the document
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bromophenylacetylene (1a) produced the desired 1,2-
(bis)trifluoromethylation product (3a) in excellent yield (94%) and
stereoselectivity (E/Z = 15:1) (Table 1, entry 1). Since the ratio of
1a to 2 is 1:1, the reaction liberates two trifluoromethyl groups per
bpyCu(CF3)3. Surprisingly, lower efficiency was observed under
long UV (365 nm) irradiation (Table 1, entry 2).[13b] Interestingly,
aliphatic alkynes did not react under these conditions (vide infra).
While the optimal solvent system is comprised of acetonitrile and
methanol, other common solvent mixtures also work reasonably
well for the reaction (Table 1, entry 3, 4, 6-8). Although K2S2O8 is
not required for the reaction, the lack of oxidant significantly
decreased the yield (Table 1, entry 5). The supporting role of
K2S2O8 suggested a critical mechanistic switch that enables the
consumption of two trifluoromethyl groups (vida infra).
trifluoromethyl groups, E-HFBs are expected to be rather
electron-deficient. Conversely, near cancellation of their dipoles
might confer added stability. Remarkably, various attempts to
leverage the electronic deficiency of the E-HFB in 3c failed. For
example, E-HFBs fail to engage with Danishefsky diene[14] or
furan[15] but are also inert to a-diazo esters,[16] catalytic Rh
carbenes,[17] mCPBA,[18] and bromine—demonstrating that E-
HFBs are much more stable than the parent styrene.
Counterintuitively, the Os-catalyzed dihydroxylation of the E-HFB
proceeded in 78% yield to produce the vicinal diol (see SI). This
stability has significant implications for fields ranging from
medicinal chemistry to materials.
Table 2. Substrate Scope for 1,2-(Bis)trifluoromethylationa,b
Table 1. Effects of Pertinent Reaction Parametersa
a Unless otherwise noted, all the reactions were run with 1a (0.04 mmol) and 2
(0.04 mmol) in 0.7 mL of solvent for 1 h. b Yields of 3a were determined by 19
F
NMR spectroscopy with 1-fluoro-4-methylbenzene as the internal standard,
while the E/Z ratios were determined by 19F NMR spectroscopy of the crude
product mixtures. c Not detected by 19F NMR. bpy = 2,2'-bipyridine.
With near quantitative yield of E-HFBs, we sought to
examine the scope of various terminal alkynes (Table 2). Two
trifluoromethyl groups could be effectively incorporated across a
number of electronically and sterically differentiated aromatic
alkynes with high E selectivity. Moreover, the pronounced dipole
differences between the E and Z isomers allowed the separation
of both isomers by silica chromatography in all cases. Aromatic
bromides were tolerated under the reaction conditions with
positional insignificance (1a-c, Table 2). The reaction tolerated
aromatic alkynes bearing electron-donating substituents such as
tert-butyl (1i), methylthio (1j), and methoxy (1k) or electron-
withdrawing substituents (1a-h, 1p, 1q). Notably, if an aldehyde
is present, the reaction proceeds in high yield and produces the
acetal (1s). Overall, the reaction proved exceedingly mild,
tolerating numerous desirable functional groups such as Bpin
(1n), anilines (1r), thioethers (1j), mesyl (1o-p), and a ketone (1q).
Using these conditions, the tetra-trifluoromethylation of bis-alkyne
(1u) also proceeded with a good yield. Moreover, heteroaryl
acetylenes, such as 5-ethynylbenzofuran (1v), 1-(3-
ethynylphenyl)imidazole (1w), 4-pyridylacetylene (1x), and 5-
ethynyl-2-phenylpyrimidine (1y), function well in the reaction.
With general access to a wide range of E-HFBs, we sought
to explore the reactivity of this unusual olefin and add to the dearth
of known reactions of E-HFBs. With two antiparallel
a All reactions were with 1 (0.16 mmol) and 2 (0.16 mmol) in 2.8 mL of solvent
for 1 h. b The 19F NMR yield determined by 19F NMR spectroscopy with 1-fluoro-
4-methylbenzene as the internal standard, with the isolated yields given in
parentheses. The E/Z ratios were determined by 19F NMR spectroscopy of the
crude product mixtures.
Based on the remarkable scope developed in Table 2, we
thought this reaction might serve in the late-stage
functionalization of bioactive molecules. To that end, a variety of
alkyne-containing molecules were used to test whether this
chemistry can offer direct access to E-HFBs as a potentially new
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10.1002/anie.201905247
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functional group. We found the E-HFB functional group could be
easily installed in natural product scaffolds such as unnatural
amino acids (4), steroid structures (6), and tocopherol (7). An
alkyne-containing medicine with sensitive functionalities (5) could
also be converted to novel E-HFB structures.
Scheme 2. Late-Stage 1,2-(Bis)trifluoromethylation of Bioactive Moleculesa
We chose phenylacetylene and employed DFT to calculate
the relative Gibbs free energies for all intermediates and transition
states (see SI for computational details). The absorption of light
by 2 results in the formation of the triplet complex 32 that
elongates the axial Cu–CF3 bond (Figure 1). This system
decomposes into a trifluoromethyl radical and bpyCu(CF3)2 (I) —
which we used as our starting point for relative energies (Figure
1). The addition of the trifluoromethyl radical into the alkyne
proceeds with a transition state (I-TS) of 11.3 kcal/mol to produce
an allenyl radical II, which is –28.7 kcal/mol more stable than the
trifluoromethyl radical (Figure 2). The conjugated allenyl radical
explains the lack of reactivity for aliphatic alkynes. Allenyl radical
II recombines with the copper(II) species to form intermediate III
through a barrier (II-TS) of 12.8 kcal/mol, with III lower in energy
(–43.6 kcal/mol) than I. Intermediate III then undergoes reductive
elimination to form the 1,2-(bis)trifluoromethylated product IV and
Cu(I). This step (III-TS) has an energetic barrier of 15.9 kcal/mol
and was deemed rate-determining (Figure 2). Under these
reaction conditions, the homolysis of persulfate into two hydrogen
sulfate (or potassium sulfate) radicals was assumed. Consistent
with the reactions in Scheme 3, the binding of sulfate to copper
results in a 9.8 kcal/mol reduction in the Cu-CF3 bond-dissociation
energy (see SI for details). Moreover, the reductive elimination
now proceeds with a lower barrier (4.3 kcal/mol), thereby
changing the rate-determining step (RDS) to the radical addition
III-TS (11.3 kcal/mol). The change in RDS and lower overall
transition state energy explains the higher yield observed with
persulfate since it allows radical addition to vastly outcompete the
quench of the trifluoromethyl radical by solvent (see SI for more
details).
a All reactions were with alkyne substrate (0.16 mmol) and 2 (0.16 mmol) in
2.8 mL of solvent for 1 h.
To explore the role of oxidant and copper, a series of simple
mechanistic reactions were conducted. First, deuterated solvent
led to the detection of deuterated fluoroform (18% yield) under the
standard reaction conditions using 4-bromophenylacetylene (1a)
as substrate (Scheme 3A)—implying that quenching of
trifluoromethyl radical by solvent competes with our desired
reaction.[19] To further investigate the presence of trifluoromethyl
radicals, complex 2 was irradiated with blue light in the presence
of TEMPO (Scheme 3B). Interestingly, the trifluoromethyl ether of
TEMPO could be obtained in 300% yield with K2S2O8, but only
60% yield without—suggesting that K2S2O8 interacts directly with
copper to facilitate homolysis and generate trifluoromethyl radical.
This was further investigated under the standard reaction
conditions by varying the ratio of substrate 1a to Grushin’s
reagent 2 with and without the oxidant (Scheme 3C). While a ratio
of 1:1 without K2S2O8 provided low yield (32%), the yield could be
rescued (to 82%) by increasing the ratio to 1:3 (Scheme 3C).
These reactions suggest that copper complex 2 provides one
trifluoromethyl radical under blue light irradiation without K2S2O8
and, with K2S2O8, 2 offers all three trifluoromethyl groups. Since
these reactions revealed the critical role of K2S2O8 for the efficient
release of trifluoromethyl groups from 2, we turned to DFT to
better clarify these observations.
Scheme 3. Control Experiments
Figure 1. Computed geometries (uM06/LACVP**) and ∆Gsol energies for 2, 32,
and bipyCu (CF3)2. Bond lengths are measured in angstroms (Å).
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changes the RDS of these transformations. Such insights should
aid in the future design of reaction manifolds that employ
bpyCu(CF3)3. The reaction has excellent substrate scope and
functional-group compatibility providing the desired products in
high yields. The chemistry functions well for the late-stage
functionalization of alkynes in the presence of various functional
groups and heterocycles. Moreover, the E-HFBs demonstrate
remarkable chemical stability toward
a
range of olefin
functionalization reactions. Simple access to aromatic E-HFBs
provides exciting opportunities in medicinal chemistry,
agroscience and materials.
Acknowledgements
We acknowledge the NIH (GM121840). Eli Lilly & Co., and Amgen
supported this work through the Lilly Grantee Award and the
Amgen Young Investigator Award.
We would like to
acknowledge Mackenzie Fahey, Prof. Jeffrey Zaleski, and Prof.
Jeremy Smith for insightful discussions about the oxidation state
and photophysical properties of these copper complexes.
Figure
2.
Computed
∆Gsol
energies
(with
uM06/cc-pVTZ(-
f)−LACV3P**//uM06/LACVP**) for all intermediates and transition states along
the reaction pathway from I to IV.
Finally, we employed TDDFT[20] to examine the requisite
wavelength of light for the excitation of this system (see SI for
computational details). Interestingly, there exist several
transitions to the first excited state during the singlet-singlet
excitation (see SI), but the major transition promotes an electron
from the HOMO –1 to the LUMO +1 (Figure 3). This transition had
a calculated wavelength of 362 nm and results in the formation of
3I after intersystem crossing. We found that the first excited state
for the singlet-triplet excitation, however, results from promoting
an electron from the HOMO to the LUMO +1 with a calculated
wavelength of 486 nm. While this transition is spin-forbidden,
there exist several examples of populating a triplet system from a
singlet ground state.[21] Calculations suggest that UV irradiation
proceeds through a singlet-to-singlet excitation, followed by
intersystem crossing to a triplet prior to Cu–CF3 bond scission,
whereas blue light irradiation leads directly to a singlet-to-triplet
excitation. Further experiments will be needed to better
understand these properties.
Conflicts of Interest
The authors declair no conflicts of interest.
Keywords: Alkynes • Copper • Difunctionalization • Persulfate •
Trifluoromethylation
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
A copper-mediated
1,2-
Shuo Guo, Deyaa I. AbuSalim and Silas P.
Cook*
(bis)trifluoromethylation
of acetylenes enables
the preparation of E-
hexafluorobutenes (E-
HFBs)—in a single
step. The reaction
proceeds with high
yield and E/Z
Page No. – Page No.
1,2-(Bis)trifluoromethylation of Alkynes:
A One-Step Reaction to Install an
Underutilized Functional Group
selectivity. Significant
mechanistic work
explains the frontier
molecular orbital
behavior of the copper
complex and the role
of persulfate in this and
related reactions for
the first time.
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