Copper-catalyzed decarboxylative trifluoromethylation of propargyl bromodifluoroacetates

Article abstract of DOI:10.1055/s-0033-1339128

The development of efficient methods for accessing fluoA rinated functional groups is desirable. Herein, we report a two step method that utilizes catalytic copper for the decarboxylative trifluoromethylation of propargyl bromodifluoroacetates is described. This protocol affords a mixture of propargyl trifluoromethanes and trifluoromethyl allenes. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339128

1938▌
SPECIAL TOPIC
sCpeociapl tpopeicr-Catalyzed Decarboxylative Trifluoromethylation of Propargyl
Bromodifluoroacetates
Copper-Catalyzed Trifluoromethylation
Brett R. Ambler,a Santosh Peddi,b Ryan A. Altman*a
a
Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, KS 66045, USA
b
Department of Pharmacy, Birla Institute of Technology & Science, Pilani–Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal,
Hyderabad, 500078 Andhra Pradesh, India
Fax +1(785)8645326; E-mail: raaltman@ku.edu
Received: 28.02.2014; Accepted after revision: 05.05.2014
complexes have been reported (Scheme 2, eq 1–3).12 De-
Abstract: The development of efficient methods for accessing
pending upon the nature of the substrate and the Cu–CF3
fluorinated functional groups is desirable. Herein, we report a two-
species, two classes of products were obtained: propargyl
trifluoromethanes and trifluoromethyl allenes. Most com-
step method that utilizes catalytic copper for the decarboxylative tri-
fluoromethylation of propargyl bromodifluoroacetates is described.
This protocol affords a mixture of propargyl trifluoromethanes and monly, primary propargyl electrophiles yielded propargyl
trifluoromethyl allenes.
trifluoromethanes (Scheme 2, eq 1), whereas secondary
substrates provided trifluoromethyl allenes (Scheme 2, eq
2).12 Propargyl trifluoromethanes were also accessed from
secondary propargyl chlorides, however, the reaction pro-
ceeded via the initial formation of trifluoromethyl allene,
followed by a rearrangement that afforded a propargyl
trifluoromethane (Scheme 2, eq 3).12b In addition to these
copper-mediated reactions, an alternative copper-
catalyzed trifluoromethylation employed copper(I)
thiophene-2-carboxylate (CuTC) and trimethyl(trifluoro-
methyl)silane (TMS–CF3) with potassium fluoride (KF)
as an activator (Scheme 2, eq 4 and 5).13 The regioselec-
tivity of this transformation was dictated by the substrate,
with primary propargyl chlorides providing propargyl tri-
fluoromethanes (Scheme 2, eq 4), and secondary propar-
gyl chlorides affording trifluoromethyl allenes (Scheme 2,
eq 5).13
Key words: copper, catalysis, trifluoromethylation, decarboxyl-
ation, alkynes
The development of methods that enable the incorpora-
tion of the trifluoromethyl group into organic compounds
can impact agricultural chemistry,1 chemical biology,2
materials science,3 and medicinal chemistry.2 Among the
numerous approaches for trifluoromethylation,4 copper(0)
and copper salts are frequently employed to both generate
and harness reactive trifluoromethyl (CF3) complexes. In
recent years, improved methods have enabled the genera-
tion of copper–trifluoromethyl (Cu–CF3) species from
common starting materials, including R3Si–CF3,5 trifluo-
romethane (CHF3),6 halodifluoroacetates,7 and S-(trifluo-
romethyl)diarylsulfonium salts.8 In these reactions, Cu–
CF3 complexes typically display excellent functional
group compatibility, and can be used in the presence of
hard electrophiles such as aldehydes and ketones.6 Fur-
ther, these species tolerate high temperatures7b–f and the
presence of protic solvents, including water.9
Given these benefits, the reaction of Cu–CF3 species10
with activated electrophiles can provide trifluorometh-
anes under mild conditions. A range of allyl, benzyl,
propargyl and aromatic electrophiles react with Cu–CF3
complexes to provide trifluoromethane-containing prod-
ucts (Scheme 1).5–8 While the use of stoichiometric copper
enables a variety of important transformations,4 the prin-
ciples of green chemistry encourage the development of
trifluoromethylation reactions that only utilize catalytic
quantities of copper.11
In contrast, alternative electrophiles for nucleophilic sub-
stitution include propargyl halodifluoroacetates, which
undergo decarboxylative trifluoromethylation upon treat-
ment with stoichiometric copper(I) iodide (CuI).14 How-
ever, only a single example of this transformation exists,
which converts propargyl chlorodifluoroacetate into tri-
fluoromethyl allene (Scheme 2, eq 6).14 While this strate-
gy utilized decarboxylation as an effective method to
generate reactive fluorinated species, the use of stoichio-
CF3
TMSCF3 + X–
CF3
The conversion of propargyl electrophiles (bromides,
chlorides, mesylates, and trifluoroacetates) into trifluoro-
methanes represents one such transformation. Several
methods that utilize stoichiometric quantities of Cu–CF3
‘Cu CF3’
CHF3 + base
CF3
O
R1
•
R2
+ F–
CF2X
MO
SYNTHESIS 2014, 46, 1938–1946
Advanced online publication: 12.06.2014
DOI: 10.1055/s-0033-1339128; Art ID: ss-2014-c0147-st
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Generation of Cu–CF3 from various reagents enables the
synthesis of trifluoromethane-containing products
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

SPECIAL TOPIC
Copper-Catalyzed Trifluoromethylation
1939
(PPh3)3Cu–CF3
(1 equiv)
phenylpropynyl bromodifluoroacetate (1-Br) was ex-
plored. Promotion of the reaction with stoichiometric cop-
per provided a 57% yield of the trifluoromethylated
product with 2.6:1 regioselectivity (Table 1, entry 1). In
contrast, catalytic turnover was realized using just 10
mol% of copper(I) iodide, providing the trifluoromethyl-
ated product in 65% yield (Table 1, entry 2). Based on pre-
vious work in our laboratory,7a we hypothesized that the
addition of N,N′-dimethylethylenediamine (DMEDA),
and the use of an activation procedure might improve the
yield of product. While the use of DMEDA alone was det-
rimental to the reaction (Table 1, entry 3), possibly be-
cause of the uncatalyzed reaction of the amine with the
substrate, the employment of DMEDA, sodium bro-
mo(difluoro)acetate (NaO2CCF2Br) and an activation
procedure7a provided a 75% yield of the trifluoromethane-
containing product and a 2.7:1 ratio of 2A:2B (Table 1,
entry 4). Heating copper(I) iodide, DMEDA, potassium
fluoride and NaO2CCF2Br in N,N-dimethylformamide at
50 °C for 10 minutes prior to the addition of substrate may
facilitate the formation of an active (DMEDA)Cu–CF3
species (Scheme 4), and circumvent an induction period
during which the substrate could be destroyed via non-
productive pathways.
X
CF3
(1)
R
R
R
R
THF, 22 °C
(PPh3)3Cu–CF3
(1 equiv)
X
(2)
(3)
R
•
CF3
CF3
THF, 22 °C
(PPh3)3Cu–CF3
(1 equiv)
X
R
THF, 50 °C
R = aryl, alkyl X = Cl, Br, OMs, O2CCF3
CuTC (5 mol%)
Cl
Cl
CF3
(4)
(5)
R
R
TMS–CF3, KF
THF, 60 °C
CF3
CuTC (5 mol%)
R
R
•
TMS–CF3, KF
THF, 60 °C
R = aryl, alkyl
Table 1 Catalytic Decarboxylative Trifluoromethylation Improved
O
by DMEDA and an Activation Procedurea
CuI (1 equiv)
(6)
•
CF3
O
CF2Cl
KF, DMF, 100 °C
CF3
H
Ph
O
CuX, DMEDA
NaO2CCF2Br
Scheme 2 Methods for the conversion of propargyl electrophiles
2A
O
CF2Br
into trifluoromethanes
KF, DMF, 50 °C, 14 h
activation
CF3
Ph
1-Br
Ph
•
metric copper(I) iodide encourages the development of a
catalytic process.
2B
Entry
CuX
(mol%)
DMEDA Activationb Yield
In order to establish whether this strategy could be ex-
panded more generally to substituted propargyl
substrates, we subjected 3-phenylpropynyl chlorodifluo-
roacetate (1-Cl) to the previously reported conditions uti-
lizing stoichiometric copper(I) iodide.14 Interestingly, this
reaction provided a 1.7:1 mixture of propargyl (2A) and
allenyl (2B) products (Scheme 3). With the goal of devel-
oping a catalytic variant of the reaction, subjecting 1-Cl to
similar conditions with 10 mol% of copper(I) iodide pro-
vided a low yield of trifluoromethylated product (Scheme
3).
(mol%)
(%)c (A:B)d
1e
2
I (100)
I (10)
0
0
–
57 (2.6:1)
65 (3.3:1)
51 (3.6:1)
75 (2.7:1)
52 (2.7:1)
<5 (ND)
0 (–)
–
3
I (10)
10
10
10
0
–
4
I (10)
yes
yes
–
5
TC (10)
TC (5)
TC (5)
6f,g
7f,h
0
–
O
a Reactions were performed with 1-Br (0.20 mmol) and KF (0.40
mmol) in DMF (0.20 mL).
CF3
CuI
O
CF2Cl
CF3
+
b Activation involved heating CuI, DMEDA, NaO2CCF2Br and KF in
DMF for 10 minutes prior to injection of 1-Br.
c Combined yield of 2A and 2B as determined by 19F NMR spectro-
scopic analysis, using α,α,α-trifluorotoluene as an internal standard.
d Determined by 19F NMR spectroscopic analysis. ND = not deter-
mined.
KF, DMF
100 °C
Ph
Ph
Ph
•
2A
2B
1-Cl
100 mol% CuI:
10 mol% CuI:
30%
11%
18%
4%
Scheme 3 Decarboxylative trifluoromethylation provides a mixture
of products
e DMF (0.60 mL).
f KF (0.30 mmol), THF (1.2 mL), 20 h.
g TMSCF3 (0.30 mmol) was added to the reaction.
h 75% of 1-Br remained, as determined by 19F NMR spectroscopic
analysis.
Given the poor reactivity of chlorodifluoroacetates com-
pared to bromodifluoroacetates,7a,14 the reaction of 3-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1938–1946

1940
B. R. Ambler et al.
SPECIAL TOPIC
6).9 The present trifluoromethylation reaction was con-
ducted on an increased scale (7 mmol), and provided a
typical yield according to 19F NMR spectroscopy (Table
2, entry 9). In addition to aromatic substrates, an aliphatic
substrate also afforded a trifluoromethylated product in
moderate yield, and displayed distinct regioselectivity
compared to the aromatic substrates (Table 2, entry 10).
Based on the similarity of propargyl bromodifluoroace-
tates and cinnamyl bromodifluoroacetates, and the identi-
cal catalyst systems employed for decarboxylative
trifluoromethylation, it is anticipated that other functional
groups, including aryl bromides and triflates, thiophenes,
anilines, and phthalimides should also be tolerated under
the present reaction conditions.7a While attempts were
made to separate regioisomeric products, we were unable
to achieve sufficient separation via standard silica gel
chromatography to enable practical isolation of pure prod-
ucts.
CF3
Ph
O
2A
CF3
+
O
CF2Br
Ph
1-Br
Ph
•
O
2B
O
NaO
CF2Br
LnCu–CF3
LnCu
LnCuI
O
CF2Br
KF
KBr + CO2
KF
Scheme 4 Activation provides access into the proposed catalytic
cycle
Attempted optimization of several other parameters did
not lead to an improvement in the yield or selectivity. A
broad screen of N- and O-based ligands did not result in Table 2 Copper(I) Iodide/DMEDA-Catalyzed Reactions Tolerating
Important Functional Groupsa
increased yields or selectivity for the formation of 2A.
The regioselectivity of the reaction was not influenced
dramatically by temperature, and isomerization was not
CF3
CuI (10 mol%)
O
DMEDA (10 mol%)
R
NaO2CCF2Br (25 mol%)
observed upon prolonged heating. Incomplete conversion
of the starting material was observed at 8–10-hour time
points, therefore, an extended reaction time of 14 hours
was selected for the general reaction conditions. In addi-
tion, various control reactions were conducted to probe
the use of copper(I) thiophene-2-carboxylate as a catalyst
for the present reaction. This salt has been employed for
the regioselective conversion of propargyl chlorides into
propargyl trifluoromethanes.13 Treatment of 1-Br with
copper(I) thiophene-2-carboxylate provided a decreased
yield (52%) and a similar regiochemical outcome (2.7:1)
(Table 1, entry 5). Further, subjection of 1-Br to the exact
conditions that facilitated the conversion of propargyl
chlorides into trifluoromethanes [TMSCF3 (1.5 equiv)
and KF (1.5 equiv) in THF at 60 °C for 20 h] formed less
than 5% of the desired material, which demonstrates that
there are inherent differences in the reactivity of propargyl
chlorides and bromodifluoroacetates (Table 1, entry 6).
When the reaction was conducted in the absence of
TMSCF3, only 25% conversion of 1 occurred, which sug-
gests that decarboxylation does not occur under these con-
ditions (Table 1, entry 7). Based on the results in entries
5–7, we hypothesize that selection of an appropriate sol-
vent is critical for the present reaction.
4A
O
CF2Br
CF3
KF, DMF, 50 °C, 14 h
activation
R
3
R
•
4B
Entry
1
Product
Yield (%)b A:Bc
72 (77)
70 (78)
78 (83)
4.0:1 (3.5:1)
MeO
O2N
2
3
2.1:1 (2.3:1)
2.3:1 (2.6:1)
OMe
O
EtO
4
5
66 (70)
59 (62)
2.6:1 (2.9:1)
3.0:1 (2.9:1)
O
The copper(I) iodide/DMEDA-catalyzed trifluoromethyl-
ation of propargyl bromodifluoroacetates 3 tolerates
many useful and important functional groups. Electron-
donating aryl ethers provided trifluoromethane-contain-
ing products in moderate yields (Table 2, entries 1 and 2).
A variety of carbonyl-containing functional groups were
compatible with the reaction conditions, including: esters,
ketones, carbamates, and trifluoroacetamides (Table 2,
entries 3–6). In addition, the successful reaction of the tri-
fluoroacetamide gave the desired product, albeit in low
yield, which provides additional evidence that Cu–CF3
species tolerate protic functional groups (Table 2, entry
N
Boc
O
6
7
40 (44)
79 (84)
6.3:1 (3.4:1)
2.2:1 (2.5:1)
F3C
N
H
Cl
Cl
Synthesis 2014, 46, 1938–1946
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Copper-Catalyzed Trifluoromethylation
1941
Table 2 Copper(I) Iodide/DMEDA-Catalyzed Reactions Tolerating
Important Functional Groupsa (continued)
CF3
CuI (10 mol%)
Ar
Ar
O
CF3
DMEDA (10 mol%)
CuI (10 mol%)
6A
CF3
NaO2CCF2Br (25 mol%)
O
DMEDA (10 mol%)
R
NaO2CCF2Br (25 mol%)
O
CF2Br
4A
KF, DMF, 70 °C, 24 h
activation
O
CF2Br
Ar
CF3
KF, DMF, 50 °C, 14 h
activation
5
R
•
3
Ar = 3-O2NC6H4
R
•
6B
4B
41% (1.9:1)
Entry
8
Product
Yield (%)b A:Bc
Scheme 5 Copper-catalyzed decarboxylative trifluoromethylation
of secondary propargyl bromodifluoroacetates displays atypical reac-
tivity. The ratio of products represents an average of multiple runs
70 (73)
1.7:1 (1.8:1)
F3C
formed (Scheme 5). For the reactions of propargyl bro-
modifluoroacetates, both primary and secondary sub-
strates provided similar regiochemical outcomes, and
propargylic trifluoromethanes were observed as the major
product (Scheme 5). In contrast, previous copper-cata-
lyzed trifluoromethylation reactions of propargyl electro-
philes displayed substrate-dependent regioselectivity,
with primary electrophiles providing propargyl trifluoro-
methanes, and secondary electrophiles yielding trifluoro-
methyl allenes (Scheme 2, eq 4 and 5).13
9d
57 (77)
70 (69)
3.8:1 (2.2:1)
1:2.1 (1:1.6)
10
Ph
a Reactions were performed with substrates 3 (0.20 mmol), CuI (0.020
mmol), DMEDA (0.020 mmol), NaO2CCF2Br (0.050 mmol) and KF
(0.40 mmol) in DMF (0.20 mL) at 50 °C for 14 h following a 10-min-
ute activation period.
b Isolated yield of a purified mixture of regioisomers 4A and 4B; the
figure in parentheses represents the combined yield of 4A and 4B as
determined by 19F NMR spectroscopic analysis, using α,α,α-trifluoro-
toluene as an internal standard.
The present copper/DMEDA-based catalyst system dem-
onstrated unique chemoselectivity compared to other cop-
per-based catalyst systems. Several Cu–CF3 complexes
commonly react with aryl iodides under mild reaction
conditions to furnish trifluoromethylarenes.5,15 In order to
determine whether propargylic trifluoromethylation could
be achieved selectively in the presence of aryl iodides, an
exogenous aryl iodide was added to a standard decarbox-
ylative trifluoromethylation reaction.16 The addition of
one equivalent of aryl iodide 7 had no effect on the yield
or selectivity of the reaction (Scheme 6, eq 1). GC analy-
sis of the reaction revealed that 92% of the aryl iodide re-
mained unconsumed. In addition, less than 1% of
trifluoromethylarene 8 was observed, which demonstrates
c Ratio of regioisomers in the isolated material as determined by
1H NMR spectroscopic analysis; the ratio in parentheses represents
the ratio of isomers in the crude reaction mixture as determined by
19F NMR spectroscopic analysis.
d Reaction conducted on a 7 mmol scale.
Using the standard reaction conditions, a secondary
propargyl substrate was less reactive than primary sub-
strates, and provided a 16% yield of the trifluoromethyl-
ated product after 12 hours at 50 °C. However, under
more forcing conditions (70 °C, 24 h), both propargyl tri-
fluoromethane 6A and trifluoromethyl allene 6B were
I
CuI (10 mol%)
DMEDA (10 mol%)
NaO2CCF2Br (25 mol%)
I
CF3
(1)
O
CF3
O
CF2Br
CF3
+
+
+
+
Ph
•
KF, DMF, 50 °C, 14 h
activation
Ph
Ph
1-Br
7
2A
2B
7
8
100%
100%
–
57%
57%
23%
22%
–
92%
–
<1%
100%
O
O
CuI (10 mol%)
DMEDA (10 mol%)
NaO2CCF2Br (25 mol%)
CF3
CF3
CF2Br
•
+
(2)
KF, DMF, 50 °C, 14 h
activation
X
X
I
9
10/(4A–8)
10/(4B–8)
X = I (10)
X = CF3 (4–8)
54%
<1%
26%
<1%
Scheme 6 Propargylic trifluoromethylation is accomplished selectively in the presence of aryl iodides
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1938–1946

1942
B. R. Ambler et al.
SPECIAL TOPIC
tra were recorded on a Shimatzu GCMS-QP2010 SE mass spec-
trometer. High-resolution mass spectra were recorded on a Waters
LCT PremierTM mass spectrometer in the ESI mode.
the unique reactivity of this system. In order to confirm
that substrates containing aryl iodides were compatible
with the reaction conditions, 4-iodophenylpropynyl bro-
modifluoroacetate (9) was subjected to decarboxylative
trifluoromethylation. As expected, a good combined yield
(80%) of trifluoromethylated products 10A and 10B was
obtained with typical regioselectivity (2.1:1, Scheme 6, eq
2). Again, only trace amounts of aromatic trifluoromethyl
products 4A-8 and 4B-8 (see Table 2, entry 8) were ob-
served.
Propargyl Alcohols; Representative Procedure
An oven-dried 25 mL round-bottomed flask was charged with CuI
(76 mg, 0.40 mmol) and Pd(PPh3)2Cl2 (0.14 g, 0.20 mmol). The
flask was sealed and then evacuated and backfilled with N2 three
times. MeCN (0.010 L) and 4-iodoanisole (2.3 g, 0.010 mol) were
injected, and the suspension cooled to –10 °C. Et3N (6.3 mL, 45
mmol) was added dropwise, and the mixture was stirred for 10 min.
Propargyl alcohol (0.64 mL, 11 mmol) was injected dropwise, and
then the mixture was allowed to warm to 23 °C. After 4 h, the sol-
vent was removed in vacuo, and the crude mixture was dissolved in
EtOAc (60 mL). The solution was passed through a pad of silica,
which was washed with additional EtOAc (3 × 30 mL). Further
chromatographic purification (hexanes–EtOAc, 1:0→ 4:1) afforded
3-(4-methoxyphenyl)prop-2-yn-1-ol as a pale yellow solid (1.56 g,
96%).
In conclusion, a two-step, copper-catalyzed protocol en-
ables the conversion of propargyl bromodifluoroacetic es-
ters into a mixture of propargyl trifluoromethanes and
trifluoromethyl allenes. This decarboxylative strategy
utilizes the combination of bromo(difluoro)acetate and
potassium fluoride as an attractive system for trifluoro-
methylation that produces carbon dioxide as a benign,
easily separable by-product. For the copper-catalyzed tri-
fluoromethylation, the use of DMEDA as a ligand, and an
activation procedure, helped establish the catalyst system.
Ongoing work in our laboratory aims to develop more
selective and efficient catalyst systems for the current tri-
fluoromethylation reaction, as well as other related fluo-
roalkylation reactions.
Mp 69–70 °C (Lit.17 74–75 °C).
1H NMR (400 MHz, CDCl3): δ = 7.42–7.35 (m, 2 H), 6.89–6.81 (m,
2 H), 4.49 (d, J = 6.1 Hz, 2 H), 3.82 (s, 3 H), 1.64 (t, J = 6.1 Hz, 1 H).
Propargyl Bromodifluoroacetates; Representative Procedure
An oven-dried, single-neck round-bottomed flask (flask 1) was
charged with bromodifluoroacetic acid (0.74 g, 4.2 mmol), and the
system was attached to an N2 bubbler. CH2Cl2 (0.010 L) and DMF
(0.070 mL, 0.90 mmol) were injected, and then oxalyl chloride
(0.33 mL, 3.9 mmol) was added dropwise. In a separate oven-dried,
two-neck round-bottomed flask (flask 2), 3-(4-methoxyphe-
nyl)prop-2-yn-1-ol (0.49 g, 3.0 mmol), Et3N (0.84 mL, 6.0 mmol)
and CH2Cl2 (0.010 L) were combined, and the system was attached
to an N2 bubbler via a glass adapter. This solution was cooled to
0 °C, and then the solution in flask 1 was transferred into flask 2 via
cannula. The mixture was allowed to warm to 23 °C and stirred for
3 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with
1 M HCl (25 mL), H2O (25 mL), and brine (25 mL). The organic
solution was dried over anhydrous Na2SO4, filtered and the solvent
removed in vacuo. Chromatographic purification (hexanes–EtOAc,
19:1) afforded 3-(4-methoxyphenyl)prop-2-yn-1-yl 2-bromo-2,2-
difluoroacetate as a colorless oil (540 mg, 56%).
Unless otherwise noted, chemicals were purchased from commer-
cial sources and used without further purification. Potassium fluo-
ride (spray-dried) was ground into a fine powder with a mortar and
pestle and dried in a vacuum oven (180 °C) for a minimum of 24 h
prior to use. Dry solvents were used directly from a solvent purifi-
cation system, in which the solvent was dried by passage through
two columns of activated alumina under argon, or were purchased
from commercial sources in Sure-Seal® bottles. All reactions were
conducted under an atmosphere of dry N2 using oven-dried glass-
ware. Trifluoromethylation reactions were performed in resealable
15 mL test tubes sealed with PTFE septa, and all other reactions
were performed in round-bottomed flasks sealed with rubber septa.
Reactions were monitored by thin-layer chromatography using
Analtech UNIPLATETM Silica Gel HLF 250 micron glass plates
precoated with 230–400 mesh silica impregnated with a fluorescent
indicator (250 nm), visualizing with fluorescence quenching or
p-anisaldehyde solution. Flash column chromatography was per-
formed using a CombiFlash® RF–4x purification system. Silica gel
was purchased from Sorbent Technologies (cat. #30930M-25, 60 Å,
40–63 μm). Yields of products reported in the experimental section
refer to the isolated yield of a single experiment. 19F NMR yields re-
ported in tables were determined using α,α,α-trifluorotoluene (TFT)
as an internal standard, and represent the average of at least two in-
dependent runs. Uncorrected melting points were measured on a
Thomas Hoover Capillary Melting Point apparatus. Infrared spectra
were recorded using a Shimadzu FTIR-8400S Fourier Transform
Infrared Spectrometer. 1H NMR spectra were recorded on a Bruker
400 Avance spectrometer (400 MHz) or a Bruker 500 Avance spec-
trometer (500 MHz). 13C NMR spectra were recorded on a Bruker
500 Avance spectrometer (126 MHz). 19F NMR spectra were re-
corded on a Bruker 400 Avance spectrometer (376 MHz). Chemical
shifts (δ) for protons are reported in parts per million (ppm) down-
field from tetramethylsilane, and are referenced to the proton reso-
nance of residual CHCl3 in the NMR solvent (δ = 7.27 ppm).
Chemical shifts for carbon are reported in parts per million down-
field from tetramethylsilane, and are referenced to the carbon reso-
nances of the solvent peak (δ = 77.16 ppm). Chemical shifts for
fluorine are reported in parts per millions, and are referenced to
α,α,α-trifluorotoluene (δ = –63.72 ppm). Low-resolution mass spec-
IR (film): 3010, 2839, 1780, 1606, 1510, 1290, 1249, 1172, 1120,
1031, 946, 833, 709, 603 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.38 (m, 2 H), 6.91–6.79 (m,
2 H), 5.16 (s, 2 H), 3.83 (s, 3 H).
13C NMR (126 MHz, CDCl3): δ = 160.4, 159.2 (t, J = 31.9 Hz),
133.7, 114.1, 113.5, 108.6 (t, J = 314.4 Hz), 88.9, 79.1, 56.8, 55.4.
19F NMR (376 MHz, CDCl3): δ = –62.30 (s, 2 F).
HRMS (EI): m/z [M]+ calcd for C12H9BrF2O3: 317.9703; found:
317.9700.
Trifluoromethane-Containing Compounds; General Procedure
KF (23 mg, 0.40 mmol) was added to a resealable 15 mL test tube
and dried in a vacuum oven for a minimum of 24 h. The test tube
was removed from the oven, sealed with a PTFE septum, and cooled
under N2. CuI (3.8 mg, 0.020 mmol) and NaO2CCF2Br (9.8 mg,
0.050 mmol) were added, and the test tube was evacuated and back-
filled with N2 three times. DMEDA (2.2 μL, 0.020 mmol) and DMF
(0.20 mL) were injected into the test tube, which was placed into an
oil bath at 50 °C. The mixture was heated for 10 min, during which
bubbling was observed and the solution changed from teal/blue to
yellow. Next, propargyl bromodifluoroacetate (0.20 mmol) was in-
jected into the test tube, and heating was maintained for 14 h. The
mixture was diluted with EtOAc (3 mL), and TFT (24.6 μL, 0.200
mmol) was added as an internal standard. An aliquot was removed
and a 19F NMR spectrum was obtained. The aliquot was recom-
bined, and the mixture was diluted further with EtOAc (15 mL). The
Synthesis 2014, 46, 1938–1946
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Copper-Catalyzed Trifluoromethylation
1943
organic solution was washed with aq NH4Cl solution (10 mL) and
brine (10 mL), dried over anhydrous Na2SO4, filtered, and the sol-
vent was removed in vacuo. Chromatographic purification afforded
a mixture of propargyl trifluoromethane (A) and trifluoromethyl al-
4.33 (m, 4 H, A/B), 3.30 (q, J = 9.5 Hz, 2H, A), 1.41 (t, J = 7.1 Hz,
6 H, A/B).
13C NMR (126 MHz, CDCl3): δ = 208.71 (q, J = 4.0 Hz, B), 166.23
(B), 165.92 (A), 136.02 (A), 133.06 (A), 131.27 (B), 131.26 (q, J =
1.3 Hz, B), 130.94 (A), 129.85 (A), 129.79 (B), 129.39 (B), 128.94
(B), 128.59 (A), 128.44 (B), 124.24 (q, J = 277.4 Hz, A), 123.28 (q,
J = 273.9 Hz, B), 122.65 (A), 101.42 (q, J = 35.7 Hz, B), 84.23 (B),
83.56 (A), 78.59 (q, J = 5.1 Hz, A), 61.42 (A), 61.38 (B), 26.93 (q,
J = 34.9 Hz, A), 14.46 (A/B).
19F NMR (376 MHz, CDCl3): δ = –61.59 (t, J = 3.6 Hz, 3 F, B),
–67.51 (t, J = 10.0 Hz, 3 F, A).
MS (CI): m/z [M]+ calcd for C13H11F3O2: 256.1; found: 256.1.
1
lene (B). The ratio of regioisomers was determined by H NMR
spectroscopy (propargylic CH2/terminal CH2 of allene). Note: the
following numbering system is used for compounds 4: 4A/B-x,
where x is an integer referring to the specific entry in Table 2.
Compounds 4A/B-113,18
The general procedure was followed using 3-(4-methoxyphe-
nyl)prop-2-yn-1-yl 2-bromo-2,2-difluoroacetate (64 mg, 0.20
mmol), CuI (3.8 mg, 0.020 mmol), DMEDA (2.2 μL, 0.020 mmol),
NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40 mmol), with
DMF (0.20 mL) as solvent. Work-up and chromatographic purifica-
tion (hexanes–EtOAc, 1:0→49:1) afforded a mixture of regioiso-
mers as a yellow oil (31 mg, 72%). Analysis of the 1H NMR
spectrum revealed a 4.0:1 ratio of A/B.
Compounds 4A/B-4
The general procedure was followed using 3-(4-acetylphenyl)prop-
2-yn-1-yl 2-bromo-2,2-difluoroacetate (66 mg, 0.20 mmol), CuI
(3.8 mg, 0.020 mmol), DMEDA (2.2 μL, 0.020 mmol),
NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40 mmol), with
DMF (0.20 mL) as solvent. Work-up and chromatographic purifica-
tion (hexanes–EtOAc, 1:0→49:1) afforded a mixture of regioiso-
1H NMR (400 MHz, CDCl3): δ = 7.43–7.34 (m, 4 H, A/B), 6.94–
6.89 (m, 2 H, B), 6.88–6.82 (m, 2 H, A), 5.51 (q, J = 3.4 Hz, 2 H,
B), 3.83 (s, 3 H, B), 3.82 (s, 3 H, A), 3.26 (q, J = 9.6 Hz, 2 H, A).
19F NMR (376 MHz, EtOAc): δ = –61.76 (t, J = 3.6 Hz, 3 F, B),
–67.76 (t, J = 10.0 Hz, 3 F, A).
1
mers as a yellow oil (0.030 g, 66%). Analysis of the H NMR
spectrum revealed a 2.6:1 ratio of A/B.
IR (film): 3067, 2964, 2932, 2854, 1969, 1933, 1686, 1603, 1558,
1418, 1404, 1362, 1306, 1263, 1178, 1150, 1109, 1016, 957, 935,
906, 833, 717, 679, 628, 592 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.99–7.94 (m, 2 H, B), 7.94–7.89
(m, 2 H, A), 7.57–7.52 (m, 4 H, A/B), 5.64 (q, J = 3.3 Hz, 2 H, B),
3.32 (q, J = 9.5 Hz, 2 H, A), 2.62 (s, 3 H, B), 2.61 (s, 3 H, A).
13C NMR (126 MHz, CDCl3): δ = 209.23 (q, J = 3.9 Hz, B), 197.50
(B), 197.42 (A), 136.80 (A), 136.60 (B), 134.07 (B), 132.15 (A),
129.99 (A), 128.85 (B), 128.35 (A), 127.17 (q, J = 1.3 Hz, B),
127.08 (A), 124.13 (q, J = 277.4 Hz, A), 123.17 (q, J = 273.9 Hz,
B), 101.72 (B), 84.45 (B), 83.74 (A), 80.99 (q, J = 5.1 Hz, A), 27.03
(q, J = 35.0 Hz, A), 26.81 (A), 26.78 (B).
Compounds 4A/B-2
The general procedure was followed using 3-(2-methoxy-5-nitro-
phenyl)prop-2-yn-1-yl 2-bromo-2,2-difluoroacetate (73 mg, 0.20
mmol), CuI (3.8 mg, 0.020 mmol), DMEDA (2.2 μL, 0.020 mmol),
NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40 mmol), with
DMF (0.20 mL) as solvent. Work-up and chromatographic purifica-
tion (hexanes–EtOAc, 1:0→3:1) afforded a mixture of regioisomers
1
as a colorless solid (36 mg, 70%). Analysis of the H NMR spec-
trum revealed a 2.1:1 ratio of A/B.
Mp 76–81 °C.
IR (film): 3119, 3094, 2947, 2920, 2847, 1983, 1610, 1580, 1514,
1493, 1492, 1439, 1418, 1344, 1275, 1246, 1190, 1148, 1103, 1018,
968, 906, 891, 868, 833, 797, 750, 735, 694, 665, 638 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J = 2.8 Hz, 1 H, A), 8.28
(dd, J = 9.1, 2.8 Hz, 1 H, B), 8.24–8.20 (m, 2 H, A/B), 7.01 (d, J =
9.1 Hz, 1 H, B), 6.96 (d, J = 9.2 Hz, 1 H, A), 5.42 (q, J = 3.4 Hz, 2
H, B), 4.00 (s, 3 H, A), 3.96 (s, 3 H, B), 3.35 (q, J = 9.5 Hz, 2 H, A).
13C NMR (126 MHz, CDCl3): δ = 209.41 (q, J = 3.7 Hz, B), 164.97
(A), 162.43 (B), 141.23 (B), 141.09 (A), 129.59 (A), 126.67 (B),
126.51 (B), 126.21 (A), 124.10 (q, J = 277.0 Hz, A), 122.87 (q, J =
273.9 Hz, B), 119.90 (B), 112.56 (A), 110.98 (B), 110.48 (A), 95.74
(q, J = 37.2 Hz, B), 83.93 (q, J = 5.0 Hz, A), 82.19 (B), 78.61 (A),
56.79 (A), 56.58 (B), 27.15 (q, J = 34.9 Hz, A).
19F NMR (376 MHz, EtOAc): δ = –63.30 to –63.53 (m, 3 F, B),
–67.66 (t, J = 10.0 Hz, 3 F, A).
MS (CI): m/z [M]+ calcd for C12H9F3O: 226.1; found: 226.1.
Compounds 4A/B-5
The general procedure was followed using tert-butyl 3-[3-(2-bro-
mo-2,2-difluoroacetoxy)prop-1-yn-1-yl]-1H-indole-1-carboxylate
(86 mg, 0.20 mmol), CuI (3.8 mg, 0.020 mmol), DMEDA (2.2 μL,
0.020 mmol), NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40
mmol), with DMF (0.20 mL) as solvent. Work-up and chroma-
tographic purification (hexanes–EtOAc, 1:0→9:1) afforded a mix-
ture of regioisomers as a viscous orange oil (38 mg, 59%). Analysis
of the 1H NMR spectrum revealed a 3.0:1 ratio of A/B.
19F NMR (376 MHz, CDCl3): δ = –62.45 (t, J = 3.5 Hz, 3 F, B),
–67.35 (t, J = 9.9 Hz, 3 F, A).
MS (CI): m/z [M]+ calcd for C11H8F3NO3: 259.0; found: 259.0.
IR (film): 3159, 3055, 2980, 2932, 2851, 1740, 1558, 1475, 1454,
1420, 1375, 1357, 1308, 1279, 1234, 1256, 1234, 1111, 1049, 1032,
854, 831, 746, 729 cm–1.
Compounds 4A/B-3
1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.5 Hz, 1 H, B), 8.15
(d, J = 8.2 Hz, 1 H, A), 7.87 (dt, J = 8.0, 1.0 Hz, 1 H, B), 7.79 (s, 1
H, A), 7.73 (s, 1 H, B), 7.68–7.60 (m, 1 H, A), 7.37 (td, J = 7.8, 1.4
Hz, 2 H, A/B), 7.31 (td, J = 7.5, 1.1 Hz, 1 H, A), 7.29–7.24 (m, 1 H,
B), 5.69 (qd, J = 3.0, 0.9 Hz, 2 H, B), 3.37 (q, J = 9.6 Hz, 2 H, A),
1.70 (s, 9 H, B), 1.68 (s, 9 H, A).
13C NMR (126 MHz, CDCl3): δ = 208.94 (q, J = 3.7 Hz, B), 149.49
(B), 149.12 (A), 135.48 (B), 134.66 (A), 130.53 (A), 129.57 (A),
128.40 (B), 125.40 (A), 125.17 (B), 124.35 (q, J = 277.1 Hz, A),
124.21 (q, J = 1.3 Hz, B), 123.41 (A), 123.33 (q, J = 273.7 Hz, B),
123.07 (B), 120.07 (A), 119.93 (B), 115.46 (B), 115.40 (A), 107.96
(B), 102.44 (A), 95.70 (q, J = 36.1 Hz, B), 84.59 (A), 84.58 (A),
84.52 (B), 81.08 (q, J = 5.1 Hz, A), 76.64 (B), 28.30 (B), 28.28 (A),
27.20 (q, J = 34.8 Hz, A).
The general procedure was followed using ethyl 3-[3-(2-bromo-2,2-
difluoroacetoxy)prop-1-yn-1-yl]benzoate (72 mg, 0.20 mmol), CuI
(3.8 mg, 0.020 mmol), DMEDA (2.2 μL, 0.020 mmol),
NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40 mmol), with
DMF (0.20 mL) as solvent. Work-up and chromatographic purifica-
tion (hexanes–EtOAc, 1:0→49:1) afforded a mixture of regioiso-
1
mers as a pale green oil (0.040 g, 78%). Analysis of the H NMR
spectrum revealed a 2.3:1 ratio of A/B.
IR (film): 3067, 2984, 2932, 2854, 1971, 1720, 1472, 1367, 1298,
1256, 1231, 1173, 1148, 1111, 1084, 1026, 908, 872, 754 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.16–8.09 (m, 2 H, A/B), 8.05–
7.97 (m, 2 H, A/B), 7.66–7.60 (m, 2 H, A/B), 7.47 (t, J = 7.8 Hz, 1
H, B), 7.41 (t, J = 7.8 Hz, 1 H, A), 5.61 (q, J = 3.4 Hz, 2 H, B), 4.46–
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1938–1946

1944
B. R. Ambler et al.
SPECIAL TOPIC
19F NMR (376 MHz, CDCl3): δ = –63.41 (t, J = 3.5 Hz, 3 F, B),
–67.66 (t, J = 9.9 Hz, 3 F, A).
HRMS (ESI): m/z [2 M + Na]+ calcd for C34H32F6N2O4Na:
IR (film): 3063, 2934, 1971, 1927, 1618, 1406, 1366, 1329, 1281,
1267, 1151, 1130, 1105, 1068, 1018, 937, 906, 870, 843, 735, 723
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.67–7.53 (m, 8 H, A/B), 5.64 (q,
J = 3.4 Hz, 2 H, B), 3.31 (q, J = 9.5 Hz, 2 H, A).
13C NMR (126 MHz, CDCl3): δ = 209.04 (q, J = 4.1 Hz, B), 133.10
(q, J = 1.6 Hz, B), 132.27 (A), 130.64 (q, J = 32.7 Hz, A), 130.36
(q, J = 32.7 Hz, B), 127.41 (q, J = 1.6 Hz, B), 126.06 (q, J = 1.7 Hz,
A), 125.82 (q, J = 3.8 Hz, B), 125.42 (q, J = 3.9 Hz, A), 124.15 (q,
J = 278.6 Hz, A), 124.02 (q, J = 272.2 Hz, B), 123.93 (q, J = 271.8
Hz, A), 123.13 (q, J = 274.8 Hz, B), 101.33 (q, J = 35.0 Hz, B),
84.47 (B), 83.21 (A), 80.23 (q, J = 5.1 Hz, A), 26.96 (q, J = 34.9 Hz,
A).
669.2164; found: 669.2179 (2.2 ppm).
Compounds 4A/B-6
The general procedure was followed using 3-[4-(2,2,2-trifluoro-
acetamido)phenyl]prop-2-yn-1-yl 2-bromo-2,2-difluoroacetate (80
mg, 0.20 mmol), CuI (3.8 mg, 0.020 mmol), DMEDA (2.2 μL,
0.020 mmol), NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40
mmol), with DMF (0.20 mL) as solvent. Work-up and chromato-
graphic purification (hexanes–CH2Cl2, 1:0→1:1) afforded a mix-
ture of regioisomers as a colorless solid (24 mg, 40%). Analysis of
the 1H NMR spectrum revealed a 6.3:1 ratio of A/B.
19F NMR (376 MHz, EtOAc): δ = –61.50 (t, J = 3.5 Hz, 3 F, B),
–63.79 (3 F, B), –63.93 (3 F, A), –67.42 (t, J = 9.9 Hz, 3 F, A).
MS (CI): m/z [M]+ calcd for C11H6F6: 252.0; found: 252.0.
IR (film): 3300, 3202, 3136, 2964, 1705, 1607, 1547, 1512, 1410,
1366, 1281, 1246, 1202, 1155, 1107, 959, 906, 839, 727, 704, 654
cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.89 (s, 1 H, A), 7.83 (s, 1 H, B),
7.62–7.58 (m, 2 H, B), 7.58–7.54 (m, 2 H, A), 7.52–7.45 (m, 4 H,
A/B), 5.60 (q, J = 3.4 Hz, 2 H, B), 3.29 (q, J = 9.5 Hz, 2 H, A).
13C NMR (126 MHz, CDCl3): δ = 208.65 (q, J = 4.4 Hz, B), 154.89
(q, J = 37.5 Hz, B), 154.80 (q, J = 37.5 Hz, A), 135.38 (A), 135.00
(B), 133.10 (A), 128.16 (q, J = 1.5 Hz, B), 124.25 (q, J = 276.9 Hz,
A), 123.29 (q, J = 275.6 Hz, B), 120.71 (A), 120.32 (B), 120.25 (A),
120.18 (B), 115.70 (q, J = 288.8 Hz, B), 115.69 (q, J = 288.8 Hz,
A), 101.24 (q, J = 35.4 Hz, B), 84.25 (B), 83.51 (A), 78.48 (q, J =
5.0 Hz, A), 26.94 (q, J = 34.8 Hz, A).
Compounds 4A/B-913,18
The general procedure was followed using 3-(naphthalen-2-
yl)prop-2-yn-1-yl 2-bromo-2,2-difluoroacetate (2.4 g, 7.0 mmol),
CuI (130 mg, 0.70 mmol), DMEDA (75 μL, 0.70 mmol),
NaO2CCF2Br (0.35 g, 1.8 mmol), KF (0.81 g, 14 mmol), with DMF
(7.0 mL) as solvent. Work-up and chromatographic purification
(hexanes–EtOAc, 1:0→49:1) afforded a mixture of regioisomers as
1
a pale yellow solid (0.93 g, 57%). Analysis of the H NMR spec-
trum revealed a 3.8:1 ratio of A/B.
Mp 42–45 °C.
19F NMR (376 MHz, CDCl3): δ = –61.55 (t, J = 3.0 Hz, 3 F, B),
–67.35 (t, J = 9.5 Hz, 6 F, A), –76.69 (3 F, A/B).
MS (CI): m/z [M]+ calcd for C12H7F6NO: 295.0; found: 295.0.
1H NMR (400 MHz, CDCl3): δ = 8.00 (s, 1 H, A), 7.93 (s, 1 H, B),
7.88–7.77 (m, 6 H, A/B), 7.57–7.47 (m, 6 H, A/B), 5.63 (q, J = 3.3
Hz, 2 H, B), 3.34 (q, J = 9.6 Hz, 2 H, B).
19F NMR (376 MHz, CDCl3): δ = –61.30 (t, J = 3.6 Hz, 3 F, B),
–67.56 (t, J = 10.1 Hz, 3 F, A).
Compounds 4A/B-7
The general procedure was followed using 3-(3,4-dichlorophe-
nyl)prop-2-yn-1-yl 2-bromo-2,2-difluoroacetate (72 mg, 0.20
mmol), CuI (3.8 mg, 0.020 mmol), DMEDA (2.2 μL, 0.020 mmol),
NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40 mmol), with
DMF (0.20 mL) as solvent. Work-up and chromatographic purifica-
tion (hexanes) afforded a mixture of regioisomers as a pale yellow
Compounds 4A/B-10
The general procedure was followed using 5-phenylpent-2-yn-1-yl
2-bromo-2,2-difluoroacetate (63 mg, 0.20 mmol), CuI (3.8 mg,
0.020 mmol), DMEDA (2.2 μL, 0.020 mmol), NaO2CCF2Br (9.8
mg, 0.050 mmol), KF (23 mg, 0.40 mmol), with DMF (0.20 mL) as
solvent. Work-up and chromatographic purification (hexanes) af-
forded a mixture of regioisomers as a tan oil (0.030 g, 70%). Anal-
ysis of the 1H NMR spectrum revealed a 1:2.1 ratio of A/B.
1
oil (0.040 g, 79%). Analysis of the H NMR spectrum revealed a
2.2:1 ratio of A/B.
IR (film): 3074, 2928, 1973, 1533, 1475, 1466, 1364, 1352, 1281,
1254, 1178, 1151, 1130, 1111, 1034, 906, 881, 822 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 2.0 Hz, 1 H, A), 7.52
(d, J = 2.2 Hz, 1 H, B), 7.45 (d, J = 8.5 Hz, 1 H, B), 7.40 (d, J = 8.3
Hz, 1 H, A), 7.30–7.26 (m, 2 H, A/B), 5.63 (q, J = 3.3 Hz, 2 H, B),
3.28 (q, J = 9.5 Hz, 2 H, A).
13C NMR (126 MHz, CDCl3): δ = 208.60 (q, J = 3.9 Hz, B), 133.64
(A), 133.41 (A), 133.16 (B), 132.75 (A), 132.58 (B), 131.10 (A),
130.80 (B), 130.54 (A), 129.38 (B), 129.03 (q, J = 1.7 Hz, B),
126.30 (q, J = 1.7 Hz, B), 124.12 (q, J = 276.9 Hz, A), 123.02 (q,
J = 273.1 Hz, B), 122.18 (A), 100.59 (q, J = 35.2 Hz, B), 84.69 (B),
82.28 (A), 79.80 (q, J = 5.1 Hz, A), 26.92 (q, J = 34.9 Hz, A).
IR (film): 3088, 3065, 3030, 2932, 2862, 1985, 1954, 1605, 1497,
1454, 1366, 1333, 1281, 1261, 1200, 1157, 1115, 1055, 980, 908,
864, 744, 700 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.28 (m, 4 H, A/B), 7.26–
7.19 (m, 6 H, A/B), 5.18 (sext, J = 3.6 Hz, 2 H, B), 3.01 (qt, J = 9.7,
2.4 Hz, 2 H, A), 2.90–2.73 (m, 4 H, A/B), 2.54–2.41 (m, 4 H, A/B).
13C NMR (126 MHz, CDCl3): δ = 206.73 (q, J = 4.1 Hz, B), 140.80
(B), 140.54 (A), 128.59 (A/B), 128.56 (B), 128.52 (A), 126.48 (A),
126.35 (B), 124.53 (q, J = 277.8 Hz, A), 123.94 (q, J = 274.5 Hz,
B), 98.11 (q, J = 34.0 Hz, B), 84.28 (A), 82.54 (B), 69.21 (q, J = 5.1
Hz, A), 34.94 (A), 33.64 (B), 27.70 (B), 26.28 (q, J = 34.6 Hz, A),
20.99 (A).
19F NMR (376 MHz, EtOAc): δ = –61.59 (t, J = 3.6 Hz, 3 F, B),
–67.51 (t, J = 10.0 Hz, 3 F, A).
HRMS (ES): m/z [M]+ calcd for C10H5Cl2F3: 251.9720; found:
19F NMR (376 MHz, CDCl3): δ = –61.60 (t, J = 3.7 Hz, 3 F, B),
–67.54 (t, J = 10.0 Hz, 3 F, A).
251.9721 (0.3 ppm).
MS (CI): m/z [M]+ calcd for C12H11F3: 212.1; found: 212.1.
Compounds 4A/B-8
Compounds 6A/B
The general procedure was followed using 3-[4-(trifluorometh-
yl)phenyl]prop-2-yn-1-yl 2-bromo-2,2-difluoroacetate (71 mg,
0.20 mmol), CuI (3.8 mg, 0.020 mmol), DMEDA (2.2 μL, 0.020
mmol), NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40
mmol), with DMF (0.20 mL) as solvent. Work-up and chromato-
graphic purification (hexanes–EtOAc, 1:0→49:1) afforded a mix-
ture of regioisomers as a colorless oil (35 mg, 70%). Analysis of the
1H NMR spectrum revealed a 1.7:1 ratio of A/B.
The general procedure was followed using 4-(3-nitrophenyl)but-3-
yn-2-yl 2-bromo-2,2-difluoroacetate (5) (70 mg, 0.20 mmol), CuI
(3.8 mg, 0.020 mmol), DMEDA (2.2 μL, 0.020 mmol),
NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40 mmol), with
DMF (0.20 mL) as solvent. Work-up and chromatographic purifica-
tion (hexanes–EtOAc, 1:0→9:1) afforded a mixture of regioisomers
Synthesis 2014, 46, 1938–1946
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Copper-Catalyzed Trifluoromethylation
1945
as a yellow oil (0.020 g, 41%). Analysis of the 1H NMR spectrum
revealed a 1.6:1 ratio of A/B (single run).
References
(1) Theodoridis, G. Fluorine-Containing Agrochemicals: An
Overview of Recent Developments, In Fluorine and the
Environment: Agrochemicals, Archaeology, Green
Chemistry & Water; Tressaud, A., Ed.; Elsevier:
Amsterdam, 2006.
(2) (a) Fluorine in Pharmaceutical and Medicinal Chemistry:
From Biophysical Aspects to Clinical Applications;
Gouverneur, V.; Müller, K., Eds.; Imperial College Press:
London, 2012. (b) Fluorine in Medicinal Chemistry and
Chemical Biology; Ojima, I., Ed.; Blackwell Publishing Ltd:
West Sussex, 2009. (c) Bégué, J.-P.; Bonnet-Delpon, D.
Bioorganic and Medicinal Chemistry of Fluorine; John
Wiley & Sons: Hoboken, 2008.
IR (film): 3090, 2961, 2926, 2856, 1963, 1535, 1481, 1441, 1352,
1327, 1248, 1178, 1155, 1119, 980, 964, 926, 901, 806, 739, 710,
687 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.41–8.37 (m, 1 H, A), 8.32–8.24
(m, 2 H, A/B), 8.20–8.14 (m, 1 H, B), 7.85–7.80 (m, 1 H, A), 7.79–
7.73 (m, 1 H, B), 7.63–7.53 (m, 2 H, A/B), 6.08 (qt, J = 7.5, 3.1 Hz,
1 H, B), 4.43 (qq, J = 7.8, 2.5 Hz, 1 H, A), 1.97–1.93 (m, 6 H, A/B).
13C NMR (126 MHz, CDCl3): δ = 205.60 (q, J = 3.9 Hz, B), 148.66
(B), 148.47 (A), 135.54 (A), 134.62 (B), 132.72 (q, J = 1.8 Hz, B),
129.79 (B), 129.74 (A), 124.62 (A), 124.61 (B), 124.09 (q, J = 280.4
Hz, A), 124.00 (A), 123.07 (q, J = 274.8 Hz, B), 122.85 (A), 122.19
(q, J = 1.8 Hz, B), 100.12 (q, J = 35.3 Hz, B), 96.56 (B), 83.59 (A),
70.34 (q, J = 3.4 Hz, A), 43.30 (q, J = 31.8 Hz, A), 13.37 (B), 3.79
(A).
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(b) Dhara, M. G.; Banerjee, S. Prog. Polym. Sci. 2010, 35,
1022.
19F NMR (376 MHz, CDCl3): δ = –61.70 (s, 3 F, B), –71.74 (d, J =
7.5 Hz, 3 F, A).
MS (CI): m/z [M]+ calcd for C11H8F3NO2: 243.1; found: 243.1.
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Ritter, T. Angew. Chem. Int. Ed. 2013, 52, 8214. (b) Liu, H.;
Gu, Z.; Jiang, X. Adv. Synth. Catal. 2013, 355, 617. (c) Liu,
T.; Shen, Q. Eur. J. Org. Chem. 2012, 6679. (d) Studer, A.
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Y.; Ma, J.-A. Adv. Synth. Catal. 2010, 352, 2745.
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J. F. Angew. Chem. Int. Ed. 2011, 50, 3793. (b) Oishi, M.;
Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.
(c) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am.
Chem. Soc. 2008, 130, 8600.
Compounds 10A/B
The general procedure was followed using 3-(4-iodophenyl)prop-2-
yn-1-yl 2-bromo-2,2-difluoroacetate (9) (83 mg, 0.20 mmol), CuI
(3.8 mg, 0.020 mmol), DMEDA (2.2 μL, 0.020 mmol),
NaO2CCF2Br (9.8 mg, 0.050 mmol), KF (23 mg, 0.40 mmol), with
DMF (0.20 mL) as solvent. Work-up and chromatographic purifica-
tion (hexanes) afforded a mixture of regioisomers as an amorphous
1
tan solid (0.050 g, 80%). Analysis of the H NMR spectrum re-
vealed a 2.0:1 ratio of A/B.
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Adán, E. C.; Novák, P.; Grushin, V. V. J. Org. Chem. 2013,
78, 11126. (b) Zanardi, A.; Novikox, M. A.; Martin, E.;
Benet-Buchholz, J.; Grushin, V. V. J. Am. Chem. Soc. 2011,
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52, 11628. (c) Schareina, T.; Wu, X.-F.; Zapf, A.; Cotté, A.;
Gotta, M.; Beller, M. Top. Catal. 2012, 55, 426. (d) Li, Y.;
Chen, T.; Wang, H.; Zhang, R.; Jin, K.; Wang, X.; Duan, C.
Synlett 2011, 1713. (e) McReynolds, K. A.; Lewis, R. S.;
Ackerman, L. K. G.; Dubinina, G. G.; Brennessel, W. W.;
Vicic, D. A. J. Fluorine Chem. 2010, 131, 1108.
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1318.
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Y. J. Am. Chem. Soc. 2013, 135, 8436. (b) Lhu, L.; Liu, S.;
Douglas, J. T.; Altman, R. A. Chem. Eur. J. 2013, 19, 12800.
(c) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu,
Z.-J.; Gong, T.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133,
15300. (d) Kawai, H.; Furukawa, T.; Nomura, Y.;
Tokunaga, E.; Shibata, N. Org. Lett. 2011, 13, 3596.
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Gu, Y.-C.; Xiao, J.-C. Angew. Chem. Int. Ed. 2011, 50, 1896.
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Soc. 2013, 135, 17302.
IR (film): 3065, 2978, 1961, 1541, 1485, 1391, 1366, 1319, 1279,
1263, 1254, 1173, 1148, 1111, 1061, 1007, 935, 906, 868, 820, 743,
665 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.73–7.69 (m, 2 H, B), 7.69–7.64
(m, 2 H, A), 7.21–7.15 (m, 4 H, A/B), 5.56 (q, J = 3.4 Hz, 2 H, B),
3.27 (q, J = 9.5 Hz, 2 H, A).
13C NMR (126 MHz, CDCl3): δ = 208.50 (q, J = 4.0 Hz, B), 138.00
(B), 137.66 (A), 133.47 (A/B), 128.87 (q, J = 1.5 Hz, B), 124.18 (q,
J = 276.9 Hz, A), 123.19 (q, J = 273.6 Hz, B), 121.78 (A), 94.88
(A), 94.13 (B), 84.23 (A), 83.60 (B), 79.14 (q, J = 5.1 Hz, A), 26.99
(q, J = 34.9 Hz, A). Note: the terminal substituted carbon of allene
B could not be distinguished from the baseline [expected to be a
quartet (J ≈ 35 Hz) between δ = 102–100].
19F NMR (376 MHz, EtOAc): δ = –61.60 (t, J = 3.7 Hz, 3 F, B),
–67.54 (t, J = 10.0 Hz, 3 F, A).
MS (CI): m/z [M]+ calcd for C10H6F3I: 310.0; found: 310.0.
Acknowledgment
We thank the donors of the Herman Frasch Foundation for Chemi-
cal Research (701-HF12) and the American Chemical Society Pe-
troleum Research Fund (52073-DNI1) for financial support, and the
NIGMS Training Grant on Dynamic Aspects of Chemical Biology
(T32 GM08545) for a graduate traineeship (B.R.A.). Further finan-
cial assistance from the University of Kansas Office of the Provost,
Department of Medicinal Chemistry, and General Research Fund
(2301795) is gratefully acknowledged. Support for the NMR instru-
mentation was provided by NIH Shared Instrumentation Grant
# S10RR024664 and NSF Major Research Instrumentation Grant
# 0320648.
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Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunpfgIpi
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