Trifluoromethylation of α-haloketones

Article abstract of DOI:10.1021/ja307783w

The C-X bond (X = Br, Cl) of α-haloketones is smoothly trifluoromethylated with the fluoroform-derived CuCF₃ reagent recently developed in our laboratories. This is the first nucleophilic α-trifluoromethylation reaction of carbonyl compounds and a rare example of CF₃-C(sp³) coupling. The transformation employs only low-cost chemicals and cleanly occurs in up to 99% yield at room temperature, thereby providing an unprecedentedly easy entry to valuable 2,2,2- trifluoroethylketones.

Full text of DOI:10.1021/ja307783w

Communication
pubs.acs.org/JACS
Trifluoromethylation of α‑Haloketones
Petr Novak, Anton Lishchynskyi, and Vladimir V. Grushin*
́
Institute of Chemical Research of Catalonia (ICIQ), Tarragona 43007, Spain
S
* Supporting Information
Scheme 1. Direct Cupration of Fluoroform6
ABSTRACT: The C−X bond (X = Br, Cl) of α-
haloketones is smoothly trifluoromethylated with the
fluoroform-derived CuCF3 reagent recently developed in
our laboratories. This is the first nucleophilic α-
trifluoromethylation reaction of carbonyl compounds and
a rare example of CF3−C(sp3) coupling. The trans-
formation employs only low-cost chemicals and cleanly
occurs in up to 99% yield at room temperature, thereby
providing an unprecedentedly easy entry to valuable 2,2,2-
trifluoroethylketones.
trifluoromethylation of aryl halides6 and boronic acids.7 Herein
we report a new reaction, nucleophilic trifluoromethylation of
α-haloketones with fluoroform-derived CuCF3. This trans-
formation (Scheme 2) is regiospecific for the substrate C−X (X
= Br, Cl) bond, readily occurring at room temperature and
affording 2,2,2-trifluoroethylketones in high yield.
Scheme 2. Trifluoromethylation of α-Haloketones with
Fluoroform-Derived CuCF3
rganic compounds bearing a CF3 group play an
O
important role in the production of agrochemicals,
pharmaceuticals, and specialty materials.1 The high demand
for new trifluoromethylation methods has led to considerable
progress in the area, especially in recent years.2 Nonetheless, no
large-scale industrial processes have emerged from this research
effort, mainly because of the prohibitively high cost of the CF3-
transferring reagents developed to date.
α-Trifluoromethylation of carbonyl compounds, “one of the
most important reactions not only in organofluorine chemistry
but also in medicinal chemistry”8 and “a central objective in the
field of chemical synthesis,”9 has been achieved by the radical
and electrophilic CF3 addition to enolates and silyl enol
ethers.2a,d−i,s,8−12 The highly sought-after, yet previously
unreported nucleophilic α-trifluoromethylation (Scheme 2)
cannot be performed with conventional CF3− synthons such as
CF3SiR3 because they bring about facile CF3-addition across the
CO bond.13
Trifluoromethane (CHF3, fluoroform, HFC-23), a side
product of Teflon manufacturing, is generated in the amount
of ca. 20 000−25 000 t per annum. While being nontoxic and
ozone-friendly, fluoroform (bp = −82 °C) has a tremendous
global warming potential, 11 700 times that of CO2 when
compared over a 100-year period.3 The long, 264-year
atmospheric lifetime of HFC-23 and a steady 5% annual
growth of its concentration in the atmosphere over the decades
pose a serious ecological danger. To address this threat, the
side-produced CHF3 should be either destroyed or used as a
feedstock for manufacturing fluorochemicals. The second of
these two options is vastly preferable, especially taking into
account the fact that HFC-23 is difficult and expensive to
incinerate.
Considering the above, fluoroform is the most attractive CF3
source for trifluoromethylation reactions. Efficient use of CHF3
in synthesis would allow production of useful materials from
this inevitably side-generated waste chemical that otherwise
must be destroyed in a costly process. Therefore, the
development of industrially feasible routes to valuable organo-
fluorine compounds from poorly reactive CHF3 is a critical task
of modern chemical research. However, only very limited
progress toward this goal has been made, thus far.3−5
We were pleased to find that 2-bromoacetophenone (1a)
6
readily reacted with CHF3-derived CuCF3 at room temper-
ature to give 2-trifluoromethylacetophenone (2a) in 75−80%
yield within 15 min. No CF3 addition to the carbonyl group13
was observed (19F NMR). It was noticed, however, that the just
produced 2a was unstable in the reaction medium, decaying at a
rate slower than, yet comparable with, that of its formation.
Attempts were made to avoid the decomposition by quenching
the mixture with H2O immediately after full conversion of 1a
was reached. This, however, did not solve the problem, as the
newly formed ketone continued to decompose even after the
addition of water. We reasoned that the lack of stability of 2a in
the reaction medium was likely due to HF elimination,10h
induced by the Et3N base present in the stabilized CuCF3
reagent.14 Indeed, buffering the reaction solution with nearly
pH-neutral TREAT HF15 provided stabilization to 2a, while
We have recently discovered a new reaction of direct
cupration of fluoroform (Scheme 1).2m,6 This reaction employs
only low-cost materials and readily occurs at room temperature
and atmospheric pressure to furnish CuCF3 in nearly
quantitative yield. The thus produced CuCF3, stabilized with
Et3N·3HF (TREAT HF), has been used for efficient
Received: August 6, 2012
© XXXX American Chemical Society
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Journal of the American Chemical Society
Communication
Table 1. Optimization of Trifluoromethylation of 1a
Scheme 3. Trifluoromethylation of α-Haloketones with
Fluoroform-Derived CuCF3 (19F NMR Yields; Isolated
Yields in Parentheses)
CuCF3
(equiv)
extra Et3N·3HF
(mol per mol CuCF3)
19F NMR yield
of 2a (%)
a
entry
method
1
2
3
1.3
1.3
1.3
1.3
1.3
1.2
1.0
0
79
85
77
87
96
90
85
0.10
0.13
0.20
0.20
0.20
0.20
A
A
A
B
B
B
b
4
5
6
7
a
Method A: extra Et3N·3HF was added immediately after mixing 1a
with stabilized CuCF3; Method B: extra Et3N·3HF was added to
stabilized CuCF3 prior to reaction with 1a. See the Supporting
b
Information for more details. 1 h at 0 °C.
not decomposing the CuCF3 reagent itself. Optimization of the
quantity of the stabilizer (Table 1) showed that the highest
yield of 96% (entry 5) could be obtained by adding 0.2 mol of
extra Et3N·3HF per mol of the stabilized CuCF3 reagent prior
to its use in the reaction.16 Under such conditions, full
conversion of 1a was achieved with only 1.3 equiv of the copper
reagent. Further lowering the amount of CuCF3 to 1.2 and 1.0
equiv (entries 6 and 7) resulted in lower yields of 90% and
85%, respectively.
Having optimized the reaction conditions, we investigated
the scope of the method (Scheme 3). The reactions were
performed in the presence of 0.2−0.3 mol of extra TREAT HF
per mol of CuCF3. The previously optimized amount of CuCF3
(1.3 equiv, see above) was used in all of the reactions of the α-
bromo ketones bearing aromatic and heterocyclic rings, except
for 1q·HBr (see below). Nonaromatic substrates and α-
chloroketones were trifluoromethylated with 1.5 equiv of
CuCF3. As can be seen from Scheme 3, the method has a
broad scope and exhibits high functional group tolerance. The
reaction affords RCOCH2CF3 for R = aryl (2a−p), heteroaryl
(2q−s), and alkyl (2t−w). Both electron-donating (2b, 2c, 2h,
2i, 2p) and -withdrawing (2e−g, 2j−l, 2m−o) substituents on
the aromatic ring are easily tolerated. Ortho-substituted
substrates react as smoothly to give the desired products 2h−
l in 84−98% yield. Remarkably, not only α-bromo but also α-
chloro derivatives could be trifluoromethylated in excellent
yield (2e, 2g, 2l), despite the fact that organocopper
compounds usually exhibit low reactivity toward Cl-electro-
philes. The starting material for the preparation of 2q was
hydrobromide 1q·HBr that, unlike 1q, is stable and
commercially available. The reaction of 1q·HBr with CuCF3
in amounts of 1.3, 2.0, and 3.0 equiv produced 2q in 29%, 62%,
and 66% 19F NMR yield, respectively. These results suggested
that the enhanced acidity of 1q·HBr prompted partial
decomposition of the CuCF3 reagent. The larger scale
trifluoromethylation of 1q·HBr with 2.5 equiv of CuCF3
furnished 2q in 52% isolated yield (Scheme 3).
and 2s were contaminated with ca. 5% of the corresponding
hydrodebromination side-product RCOCH3, whereas 2h
contained ca. 3−4% of unreacted 1h. In some instances (2b−
d, 2i, 2m, 2n, and 2p), the isolated yields slightly exceeded
those determined by 19F NMR in the parallel, lower-scale runs.
The difference, however, is within the ca. 5% error in the yield
determination by NMR. To demonstrate further scalability of
the method, 2-bromoacetylnaphthalene 1p was trifluoromethy-
lated on an 8 mmol scale. In this experiment, the desired
product 2p was isolated analytically pure as a white crystalline
solid in an amount of 1.83 g (96% yield).
Of the 23 trifluoromethylated compounds prepared in this
work (Scheme 3), 12 have not been previously reported. In
addition to full characterization of the new products by
conventional analytical and spectroscopic techniques, 2d, 2e,
and 2p were studied by single-crystal X-ray diffraction (Figure
1, Table 2). Interestingly, the geometry parameters within the
C(O)CH2CX3 moiety are virtually indistinguishable for X = F
(2e, this work) and for X = H17 (Table 2), even though the F-
atoms certainly play a role in the crystal packing. This structural
similarity might be yet another indication that the CF3 group
does not impose a positive charge on an adjacent atom.2m,18
Like any other synthetic protocol, our method is not without
limitations. For instance, while the thienyl ketone 2r was
formed quantitatively and isolated in 93% yield, the pyridine
(2q) and coumarin (2s) derivatives were obtained in noticeably
The α-trifluoromethylation reactions shown in Scheme 3
were performed on a 0.25 mmol scale for yield determination
by 19F NMR and on a 1−2 mmol scale for isolation of the
products 2a−e, 2g−j, and 2l−s. All isolated trifluoroethyl
ketones were spectroscopically (1H, 19F NMR) and analytically
pure (≥98%; often >99%), with the exception of 2h (96−97%
pure), 2m (95% pure), and 2s (95% pure). Both isolated 2m
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Journal of the American Chemical Society
Communication
also provide a number of advantages for potential larger scale
operations. In particular:
• Our reaction employs CuCF3 that is produced directly
from fluoroform, by far the cheapest and most readily
available and atom-economical CF3 source.
• In most instances, enolates and silyl enol ethers, the
substrates employed in the radical and electrophilic α-
trifluoromethylation reactions, should be premade using
a strong base, such as LDA.20 This adds to the cost and
puts additional limitations on functional groups that can
be present in the system. In contrast, our method utilizes
readily available, easily accessible, and inexpensive α-
haloketones that are used without any premodification.
• Although styrenes can be used directly in the recently
reported11 radical trifluoromethylation with costly
[Ph2SCF3]+ OTf−, the yields of the α-trifluoromethyl-
acetophenone products are only 20−40%.
Figure 1. ORTEP drawings of 2d (left) and 2p (right) with thermal
ellipsoids drawn to the 50% probability level.
Table 2. Selected Bond Distances (Å) and Bond Angles
(deg) of 2e and Its Fluorine-Free Analogue17
In conclusion, we have developed the first nucleophilic
trifluoromethylation of the C−X (X = Br, Cl) bond of α-
haloketones. The method employs only low-cost, readily
available chemicals, including fluoroform, by far the best and
cheapest CF3 source. The reaction is high-yielding, rapidly and
smoothly occurring at ambient temperature and exhibiting
unprecedented functional group tolerance. It is hoped that the
new method will find applications in the synthesis of
biologically active compounds and specialty materials.
X
C9−C8
C8−C7
C7−C4
C7−O1
C7−C8−C9
F
1.512(2)
1.516(4)
1.517(2)
1.511(4)
1.488(2)
1.500(4)
1.214(1)
1.215(3)
113.7(1)
114.0(2)
H
lower isolated yields (52−57%). Secondary halides of the type
RCOCH(R′)X (R′ = Me, X = Br; R′ = Ph, X = Cl) and α-
haloesters appeared poorly reactive toward CuCF3 under the
conditions used for the trifluoromethylation of 1a−w.
The detailed mechanism of the trifluoromethylation of α-
haloketones with CuCF3 remains to be elucidated. For that,
however, a better understanding of the structure of the CuCF3
species in solution is needed. These studies are currently in
progress in our laboratories. In the meantime, we propose that
coordination of the Cu-atom to the carbonyl and halide
facilitates substitution with the CF3 group, possibly as in the
reported19 Cu-catalyzed cross-coupling of alkylzinc reagents
with α-chloroketones.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full details of synthetic (PDF) and crystallographic studies
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
vgrushin@iciq.es
■
The utility of our method was further demonstrated by
performing a series of chemical modifications of a new ketone
2p. As shown in Scheme 4, the carbonyl group of 2p can be
Notes
The authors declare no competing financial interest.
Scheme 4. Examples of Synthetic Utility of 2p
ACKNOWLEDGMENTS
We thank Drs. Jordi Benet-Buchholz, Eduardo C. Escudero-
■
́
Adan
́
, Eddy Martin, and Marta Martınez Belmonte for single-
crystal X-ray diffraction studies. The ICIQ Foundation,
Consolider Ingenio 2010 (Grant CSD2006-0003), and The
Spanish Government (Grant CTQ2011-25418) are thankfully
acknowledged for support of this work.
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