Copper-Catalyzed Synthesis of Trifluoroethylarenes from Benzylic Bromodifluoroacetates

Article abstract of DOI:10.1021/acs.joc.5b01343

Trifluoroethylarenes are found in a variety of biologically active molecules, and strategies for accessing this substructure are important for developing therapeutic candidates and biological probes. Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic electrophiles; however, current catalytic methods do not effectively transform electron-deficient substrates and heterocycles. To address this gap, we report a Cu-catalyzed decarboxylative trifluoromethylation of benzylic bromodifluoroacetates. To account for the tolerance of sensitive functional groups, we propose an inner-sphere mechanism of decarboxylation.

Full text of DOI:10.1021/acs.joc.5b01343

Page 1 of 30
The Journal of Organic Chemistry
1
2
3
4
Copper-Catalyzed Synthesis of Trifluoroethylarenes from Benzylic Bromodifluoroacetates
5
6
7
Brett R. Ambler, Lingui Zhu†, Ryan A. Altman*
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United
States.
TABLE OF CONTENTS/ABSTRACT GRAPHIC
ABSTRACT
Trifluoroethylarenes are found in a variety of biologically active molecules, and strategies for
accessing this substructure are important for developing therapeutic candidates and biological probes.
Trifluoroethylarenes can be directly accessed via nucleophilic trifluoromethylation of benzylic
electrophiles; however, current catalytic methods do not effectively transform electronꢀdeficient
substrates and heterocycles. To address this gap, we report a Cuꢀcatalyzed decarboxylative
trifluoromethylation of benzylic bromodifluoroacetates. To account for the tolerance of sensitive
functional groups, we propose an innerꢀsphere mechanism of decarboxylation.
The trifluoromethyl group (CF3) is commonly utilized in medicinal chemistry, agricultural
chemistry and materials sciences to modulate the physical and biological properties of molecules.
1,2
Among trifluoromethylꢀcontaining substructures, trifluoroethyl(hetero)arenes represent an
important motif, with over 30,000 trifluoroethyl(hetero)arenes possessing documented biological
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 30
1
2
activity or being precursors to bioactive compounds.3 Thus, general strategies for preparing this
substructure are important for accessing biological probes and therapeutics. While several
approaches for preparing this group have been reported,4 one direct route involves the
trifluoromethylation of benzylic electrophiles; however, no general catalytic system can transform a
broad spectrum of (hetero)benzylic electrophiles. Current systems for benzylic trifluoromethylation
require either stoichiometric Cu (eq 1),4b,5 or exclusively transform electronꢀneutral (eq 2)6 or
electronꢀrich substrates (eq 3).7 Thus, a need remains for a catalytic system that can transform
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
electronꢀdeficient
benzylic
electrophiles
and
heterocyclic
derivatives
into
trifluoroethyl(hetero)arenes. Herein, we report such a general catalytic system that enables access to
a broad array of trifluoroethyl(hetero)arenes. Further, we propose a revised mechanism that accounts
for the expanded functional group tolerance.
Scheme 1. Trifluoromethylation of Benzylic Electrophiles Typically Requires Stoichiometric
Copper
ACS Paragon Plus Environment

Page 3 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
To address the aforementioned gap, we sought to develop a broadly applicable catalytic
method for converting benzylic electrophiles into trifluoroethyl(hetero)arenes. As a starting point for
this transformation, we considered Chen’s decarboxylative trifluoromethylation of benzyl
bromodifluoroacetates using stoichiometric Cu.5f Beneficial features of this early system included:
(1) facile access to substrates derived from simple benzylic alcohols, which are synthetically
accessible and already found in a wide variety of synthetic intermediates and building blocks; (2) the
formation of just CO2 and KBr as benign, easily separable byꢀproducts. However, this previous
transformation was not shown to convert a broad spectrum of substrates,5f potentially because the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
proposed mechanism invoked an outerꢀsphere decarboxylation that generated free CF3 (Scheme
2).5d–f If generated, this reactive intermediate would react with carbonylꢀbased functional groups via
1,2ꢀaddition and acidic functional groups via deprotonation, which would severely limit the
functional group compatibility of the transformation. However, we hypothesized that a catalytic
innerꢀsphere decarboxylation might generate the critical Cu–CF3 intermediate, which would enable
the conversion of substrates bearing sensitive carbonyl and acidic functional groups.
Scheme 2. Previously proposed mechanism involves generation of free –CF3
O
O
Ar
O
CF2Br
CuI
Ar
I
CuO
CF2Br (5)
+
+
O
CuO
CF2
CF2Br
F–
CuBr
–CF3
CO2
CF2
(6)
(7)
(8)
+
+
+
CuI
–CF3
Cu–CF3
Ar CF3
+
Cu–CF3
Ar
I
CuI
(9)
+
+
Beneficial Features:
• Easily Accessible Substrates
• Benign, Easily Separable Byproducts
Proposed Outer-sphere Decarboxylation:
• Free –CF3 in Solution → Poor FG Tolerance
Rational optimization of Chen’s CuIꢀmediated reaction provided a system capable of
transforming benzylic electrophiles with only catalytic quantities of Cu. Chen’s original reaction of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 30
1
2
1a with stoichiometric CuI provided trifluoroethylarene 2a in 71% yield;5f however, according to the
previous protocol, 1a was slowly added to the reaction mixture over 2 h, which can be labor intensive
and operationally challenging for small scale reactions.5f To explore a more userꢀfriendly protocol,
we charged the vessel with the full quantity of 1a at the outset of the reaction. Using stoichiometric
CuI, this procedure lowered the yield of 2a and formed benzylic bromide 3a as a side product (Table
1, entry 1). Given our aim of developing a Cuꢀcatalyzed process, we adapted conditions that
effectively catalyzed the decarboxylative trifluoromethylation of allylic bromodifluoroacetates (cat.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CuI,
N,N’ꢀdimethylethylenediamine,
NaO2CCF2Br,
DMF).8a
However,
benzylic
bromodifluoroacetates proved less reactive than their allylic counterparts, and optimization of our
previous catalyst system provided poor yields of 2a (entry 2), along with several side products,
generally in 2–10% yield (Bn–CF2CF3, Bn–I, Bn–F, Bn–Bn, and Bn–O2CCF3). Subsequent screening
of various Nꢀ, Oꢀ, and Pꢀbased ligands, and attempted modulation of reaction parameters did not
improve the transformation. Further, in many cases, addition of a chelating ligand impaired the
reaction. Thus, we pursued a system that did not employ a chelating ligand. Using a DMFꢀligated
system, and MeO2CCF2Br as an additive,5d a modest yield of 2a was observed, and benzylic bromide
3a was identified as the major sideꢀproduct (entry 3). The formation of 3a could be suppressed by
replacement of DMF with MeCN, but this change also afforded a less active system (entry 4). Based
on these observations, we hypothesized that the use of a DMF/MeCN solvent mixture would provide
an active system that would minimize the formation of 3a. Indeed, employment of a 1:1 mixture of
DMF/MeCN improved the yield of desired product 2a, and minimized formation of the benzylic
bromide sideꢀproduct 3a (entry 5).
Table 1. Solvent and I– Critical for Developing a Cu-catalyzed Reactiona
ACS Paragon Plus Environment

Page 5 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReactions were performed with 0.20 mmol of 1a, 0.080 mmol of QO2CCF2Br, 0.80 mmol of KF,
0.20 mL of solvent. Conversion and yield data were determined by GC/FID analysis, and represent
b
c
the average of a minimum of two independent experiments; 80 °C; No sideꢀproducts > 2% were
detected by GC/FID analysis.
In addition to the solvent, the presence of I– had a profound effect on the present reaction. In
previous reports of Cuꢀmediated trifluoromethylation of benzylic bromodifluoroacetates,
stoichiometric quantities of I– played an essential role in generating the desired products.5f In
contrast, a recent Cuꢀcatalyzed trifluoromethylation of allylic bromodifluoroacetates could occur in
the complete absence of I–.8a Thus, for the present system, the loading of I– merited investigation.
Addition of catalytic KI (45% total I–) provided the highest yield of desired product 2a, and
minimized formation of benzylic bromide 3a and other sideꢀproducts (< 2% by GC and 19F NMR
analysis; entry 6). In contrast, complete removal of I– from the system {[Cu(MeCN)4]PF6} decreased
the yield of trifluoroethylarene, and generated additional bromide 3a (entry 7). However, the
catalytic activity using [Cu(MeCN)4]PF6 could be restored by reintroducing 45% I– to the system
(entry 6 vs. entry 8). Further increase of the I– content beyond 45% decreased the yield of desired
product 2a (entry 9). In addition, removal of the MeO2CCF2Br additive from the system resulted in
decreased yield of 2a, and increased benzyl bromide 3a (entry 10). Ultimately, we selected a general
system that employed 20% CuI, 25% KI, 40% MeO2CCF2Br and superꢀstoichiometric KF in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 30
1
2
3
4
5
6
MeCN/DMF (1:1), which minimized the formation of sideꢀproducts (<2%) and provided good yield
of trifluoroethylarene 2a.
7
Table 2. Copper-catalyzed decarboxylative trifluoromethylation tolerates important functional
groups and heterocyclesa,b
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a0.25 mmol 1b–s, 0.050 mmol CuI, 0.063 mmol KI, 0.10 mmol MeO2CCF2Br, 1.0 mmol KF, 0.13
b
c
mL DMF, 0.13 mL MeCN; The yields represent the average of two independent experiments; 6.0
mmol scale, single experiment.
The present Cuꢀcatalyzed reaction tolerated a broad array of useful functional groups (Table
2), including: ethers (2b, 2e–f, 2l), a secondary amide (2c), a substituted aniline (2d), an aryl bromide
ACS Paragon Plus Environment

Page 7 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(2e), an alkene (2h), a mesylate (2j), esters (2k, 2n), and a ketone (2m). Substrates bearing
(pseudo)ortho substituents provided lower yields of products (2e–f, 2q–s), and a sterically hindered
2,6ꢀdisubstitued benzylic electrophile afforded product in modest yield (2g). The present reaction
also tolerated heterobenzylic substrates that incorporated N, O, and S atoms (2o–s). When the
reaction was conducted on gramꢀscale, the yield of the reaction was maintained (2b), which indicates
that this process would be useful for the preparation of larger quantities of target
trifluoroethyl(hetero)arene compounds.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The broad functional group compatibility implicates a metalꢀcentered decarboxylation that
does not involve solventꢀseparated reactive intermediates. If free in solution, –CF3 (pka = 27 in H2O)9
would react with sensitive functional groups. However, the tolerance of carbonyls (2k, 2m–o) and an
–
acidic amide (2c, pka ca. 13.8 in H2O),10 suggest that free CF3 must not exist in solution.4b
Additionally, in the reaction of 1m–n, 19F NMR spectra of the crude reaction mixtures did not show
products deriving from 1,2ꢀaddition or additionꢀelimination processes. Further, the reaction of 1a was
conducted in the presence of 2ꢀnaphthaldehyde (1.0 equiv) with minimal loss of yield (68%) and no
–
–
evidence of 1,2ꢀaddition of CF3 to the aldehyde, further discounting the existence of free CF3 in
solution.11 Thus, decarboxylation must be a process that either converts Cu–O2CCF2Br to Cu–CF3
directly at the metalꢀcenter, or that keeps reactive –CF3 within the solvent cage surrounding Cu. This
proposed mechanism likely explains the broad functional group compatibility of
bromodifluoroacetateꢀmediated trifluoromethylation reactions.8
Circumstantial evidence implicates that, as previously suggested,5f the present reaction may
involve in situ conversion of Bn–O2CCF2Br to a Bn–I intermediate prior to trifluoromethylation.
First, the catalytic system required I– for turnover, and added I– facilitated the transformation (vide
supra). Second, a steadyꢀstate concentration of Bn–I persisted throughout the course of the reaction,
and the experiment conducted with KI showed higher [Bn–I] than the experiment conducted without
KI.11 Third, the electronic nature of the arene ring noticeably perturbed the reactivity of the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 30
1
2
3
4
5
6
7
8
9
substrates, with electronꢀrich substrates (2b–f) providing higher yields than electronꢀneutral (2i–l)
and electronꢀdeficient substrates (2j–k). The latter trend may suggest that the benzylic position
develops cationic character at a transition state of the reaction, which may implicate a SN1ꢀ or SN2ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
like step in the mechanism. Based on these pathways, the more slowly reacting electronꢀdeficient
12
electrophiles may allow decomposition of Cu–CF3
to compete with productive
trifluoromethylation, thus providing decreased yields for the e–ꢀdeficient substrates. Combined, these
data fit a mechanism in which Bn–O2CCF2Br converts to Bn–I, prior to undergoing
trifluoromethylation (Figure 1). Further, the added I– may play an additional role by converting the
less reactive Bn–Br side product into a more active Bn–I electrophile. Regardless, the loading of I–
enabled optimal performance of the catalytic system, and for any given substrate, future users may
wish to optimize the loading of I–.
Figure 1. Iodide plays an essential role in benzylic trifluoromethylation
To illustrate the utility of this protocol, the Cuꢀcatalyzed decarboxylative
trifluoromethylation of benzylic bromodifluoroacetates was applied to an intermediate in the
synthesis of a fluorinated Tebufenpyrad analogue possessing acaricidal activity (Scheme 3). In a
previous report, alcohol 3 was transformed into fluorinated intermediate 5 through a 4ꢀstep procedure
ACS Paragon Plus Environment

Page 9 of 30
The Journal of Organic Chemistry
1
2
that employed stoichiometric Mn and Sn and afforded product in 31% overall yield.13 In contrast, the
present 2ꢀstep procedure converted 3 to 5 in 60% total yield utilizing catalytic Cu. Thus, the present
protocol demonstrated several desirable traits including: 1) improvement of overall yield of
trifluoroethylheteroarene; 2) avoidance of oxidation and reduction reactions; 3) decrease in time and
resource costs; 4) reduction of metalꢀcontaining waste products (stoichiometeric Mn and Sn vs.
catalytic Cu). These attractive features should be useful for both agricultural and medicinal chemists.
Scheme 3. Copper-catalyzed reaction improves access to target compounds
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In conclusion, two key features, solvent and I–, enabled a Cuꢀcatalyzed decarboxylative
trifluoromethylation of benzylic and heterobenzylic bromodifluoroacetates. This transformation
provided trifluoroethylarenes and heteroarenes from readily available alcohols through a simple and
robust twoꢀstep procedure. The protocol transformed a variety of benzylic bromodifluoroacetates,
including electronꢀdeficient and heterocyclic substrates, and substrates bearing carbonyl groups and
acidic protons. The expanded functional group compatibility is rationalized by a metalꢀcentered
–
decarboxylation event, which does not seem to generate free CF3 in solution. We envision that this
system will be useful for accessing biological probes, therapeutic agents, and agrochemicals.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 30
1
2
3
4
5
6
7
8
9
Ongoing work in our laboratory aims to use decarboxylative strategies to address related challenges
in synthetic organofluorine chemistry, such as the conversion of unactivated electrophiles to
trifluoromethanes.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
Unless otherwise noted, reactions were performed using ovenꢀdried glassware under an
atmosphere of dry N2. Trifluoromethylation reactions were performed in resealable 15 mL test tubes
sealed with PTFE septa. All other reactions were performed in roundꢀbottom flasks, which were
sealed with rubber septa. Stainless steel syringes were used to transfer airꢀ or moistureꢀsensitive
liquid reagents. Reactions were monitored by thinꢀlayer chromatography (TLC) on UNIPLATETM
Silica Gel HLF 250 micron glass plates precoated with 230–400 mesh silica impregnated with a
fluorescent indicator (250 nm), visualizing by quenching of fluorescence, KMnO4 solution, or pꢀ
anisaldehyde solution. Silica gel for chromatographic purifications was purchased from Sorbent
Technologies (cat. #30930Mꢀ25, 60 Å, 40–63 ꢁm).
Commercial reagents were purchased and used as received with the following exceptions.
Anhydrous potassium fluoride (KF) and potassium iodide (KI) were dried in a vacuumꢀoven at
200 °C for 24 h and stored in a N2 filled glovebox. Use of nonꢀanhydrous KF resulted in decreased
yields of desired products. In the absence of a glovebox, comparable yields were obtained by flameꢀ
drying KF and KI under vacuum, and using standard Schlenk techniques. Anhydrous N,N′ꢀ
dimethylformamide (DMF), acetonitrile (MeCN), methanol (MeOH), dichloromethane (DCM),
tetrahydrofuran (THF), and triethylamine (NEt3) were dispensed from a solvent purification system,
in which the solvent was dried by passage through two columns of activated alumina under argon.
Some benzylic alcohols were acquired by reduction of the corresponding aldehydes using NaBH4
(1.5 equiv) in anhydrous MeOH at 0 °C or the corresponding carboxylic acid using lithium aluminum
hydride (2.0 equiv) at 0 °C.
ACS Paragon Plus Environment

Page 11 of 30
The Journal of Organic Chemistry
1
2
Proton nuclear magnetic resonance (1H NMR) spectra were recorded at 400 or 500 MHz. Carbon
nuclear magnetic resonance (13C NMR) spectra were recorded at 101 or 126 MHz. Fluorine nuclear
magnetic resonance (19F NMR) spectra were recorded at 376 MHz. Chemical shifts (δ) for protons
are reported in parts per million (ppm) downfield from tetramethylsilane, and are referenced to the
proton resonance of residual CHCl3 in the NMR solvent (δ = 7.27 ppm). Chemical shifts (δ) for
carbon are reported in parts per million downfield from tetramethylsilane, and are referenced to the
carbon resonances of the solvent peak (δ = 77.16 ppm). Chemical shifts (δ) for fluorine are reported
in parts per millions, and are referenced to PhCF3 (δ = –63.72 ppm). NMR data are represented as
follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sept =
septet, m = multiplet), coupling constant in Hertz (Hz), and integration.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Exact mass determinations were obtained by the following methods; electron impact ionization
(EI) using a magnetic and electrostatic sector mass analyzer, electrospray ionization (ESI) using a
TOF mass analyzer, or atmosphericꢀpressure chemical ionization (APCI–hexane/PhMe) using a
QTOF mass analyzer, for which sample plus near mass internal exact mass standard were dissolved
in hexane, and hexane or PhMe/hexane were used as ionization solvent. Melting points were
uncorrected and measured on a Thomas Hoover Capillary Melting Point Apparatus.
General Procedure A
HO2CCF2Br (1.45 equiv) was added to a roundꢀbottom flask, which was sealed with a rubber septum
and attached to an oil bubbler. DCM and DMF were injected, and the solution was cooled to 0 °C.
Oxalyl chloride (1.4 equiv) was injected (caution: evolution of noxious gas), and after 5 min, the
mixture was allowed to warm to rt. After 2 h, the mixture was cooled to 0 °C, and a solution of
benzylic alcohol (1.0 equiv) and NEt3 (2–3 equiv) in DCM was added. The reaction was monitored
by TLC analysis, and after consumption of the benzylic alcohol (usually within 1–2 h), the reaction
was quenched with water, and the aqueous layer was extracted with DCM or EtOAc (4x). The
combined organic layers were washed with brine, dried over Na2SO4, and filtered. After the removal
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 30
1
2
3
4
5
6
of solvent, the residue was purified by flash column chromatography to afford bromodifluoroacetates
1a–s.
7
4-Methylbenzyl 2-bromo-2,2-difluoroacetate (1a)
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure A was followed using 4ꢀmethylbenzyl alcohol (1.5 g, 12 mmol). Workup and
chromatographic purification (hexanes) afforded the title compound as a colorless oil (2.9 g, 87%).
1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 5.33 (s, 2 H), 2.38
19
(s, 3 H). F NMR (376 MHz, CDCl3) δ –60.72 (s, 2 F). Spectroscopic data are consistent with the
previous report.5f
4-(Benzyloxy)benzyl 2-bromo-2,2-difluoroacetate (1b)
General Procedure A was followed using 4ꢀ(benzyloxy)benzyl alcohol (0.65 g, 3.0 mmol). Workup
and chromatographic purification (hexanes/EtOAc, 1:0→19:1) afforded the title compound as a
1
colorless solid (0.88 g, 79%). mp 64–65 °C. H NMR (400 MHz, CDCl3) δ 7.51–7.31 (m, 7 H), 7.01
(d, J = 8.4 Hz, 2 H), 5.31 (s, 2 H), 5.10 (s, 2 H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.7, 159.6 (t,
J = 31.6 Hz), 136.7, 130.8, 128.8, 128.3, 127.6, 125.9, 115.2, 108.9 (t, J = 314.5 Hz), 70.2, 69.9. 19F
NMR (376 MHz, CDCl3) δ –60.7 (s, 2 F). HRMS (EI): m/z [M]+ calcd for C16H13BrF2O3: 370.0016;
found: 370.0012 (1.1 ppm). IR (film): 2945, 2866, 1769, 1609, 1585, 1518, 1454, 1302, 1246, 1161,
1126, 1018, 955, 870, 814, 742, 706, 613 cm–1.
4-Pivalamidobenzyl 2-bromo-2,2-difluoroacetate (1c)
General Procedure A was followed using Nꢀ[4ꢀ(hydroxymethyl)phenyl] pivalamide (0.83 g, 4.0
mmol). Workup and chromatographic purification (hexanes/EtOAc, 1:0→25:4) afforded the title
1
compound as a yellow solid (1.2 g, 85%). mp 86–87 °C. H NMR (400 MHz, CDCl3) δ 7.61–7.56
13
(m, 2 H), 7.42 (s, 1 H), 7.39–7.34 (m, 2 H), 5.31 (s, 2 H), 1.32 (s, 9 H). C{1H} NMR (101 MHz,
CDCl3) δ 176.9, 159.5 (t, J = 31.4 Hz), 139.1, 129.9, 129.1, 120.2, 108.8 (t, J = 314.3 Hz), 69.6,
39.8, 27.7. 19F NMR (376 MHz, CDCl3) δ –60.8 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z [M+H]+
ACS Paragon Plus Environment

Page 13 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
calcd for C14H17BrF2NO3: 364.0360; found: 364.0362 (0.5 ppm). IR (film): 3292, 2975, 1771, 1655,
1599, 1520, 1460, 1294, 1157, 955, 820, 700, 604 cm–1.
7
3-(Dibenzylamino)benzyl 2-bromo-2,2-difluoroacetate (1d)
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure A was followed using [3ꢀ(dibenzylamino)phenyl]methanol (0.83 g, 4.0 mmol).
Workup and chromatographic purification (hexanes/EtOAc, 1:0→21:4) afforded the title compound
1
as a yellow solid (1.2 g, 85%). mp 67–68 °C. H NMR (400 MHz, CDCl3) δ 7.41–7.34 (m, 4 H),
7.33–7.25 (m, 6 H), 7.25–7.18 (m, 1 H), 6.80–6.72 (m, 3 H), 5.27 (s, 2 H), 4.71 (s, 4 H). 13C{1H}
NMR (101 MHz, CDCl3) δ 159.5 (t, J = 31.4 Hz), 149.6, 138.2, 134.6, 129.8, 128.9, 127.2, 126.7,
116.6, 113.1, 111.9, 108.8 (t, J = 314.3 Hz), 70.3, 54.3. 19F NMR (376 MHz, CDCl3) δ –60.7 (s, 2 F).
HRMS (APCI–hexane/PhMe): m/z [M]+ calcd for C23H20BrF2NO2: 459.0645; found: 459.0644 (0.2
ppm). IR (film): 3028, 2866, 1774, 1605, 1582, 1495, 1452, 1294, 1167, 1122, 953, 775, 733, 694
cm–1.
2-Bromo-3,4-dimethoxybenzyl 2-bromo-2,2-difluoroacetate (1e)
General Procedure A was followed using (2ꢀbromoꢀ3,4ꢀdimethoxyphenyl) methanol14 (0.94 g, 3.8
mmol). Workup and chromatographic purification (hexanes/EtOAc, 1:0→9:1) afforded the title
compound as a viscous, colorless oil [1.3 g, 83% (after correction for 10 mol% solvent impurity)]. 1H
NMR (400 MHz, CDCl3) δ 7.20 (d, J = 8.5 Hz, 1 H), 6.90 (d, J = 8.5 Hz, 1 H), 5.41 (s, 2 H), 3.90 (s,
13
3 H), 3.88 (s, 3 H). C{1H} NMR (126 MHz, CDCl3) δ 159.4 (t, J = 31.5 Hz), 154.6, 147.1, 126.5,
125.8, 120.2, 111.2, 108.8 (t, J = 314.4 Hz), 69.6, 60.7, 56.3. 19F NMR (376 MHz, CDCl3) δ –60.61
(s, 2 F). HRMS (APCI–hexane/PhMe): m/z [M]+ calcd for C11H10Br2F2O4: 401.8914; found:
401.8910 (1.0 ppm). IR (film): 2943, 2839, 1772, 1595, 1493, 1410, 1296, 1122, 1036, 941, 806,
750, 702 cm–1.
2-(Benzyloxy)benzyl 2-bromo-2,2-difluoroacetate (1f)
General Procedure A was followed using [2ꢀ(benzyloxy)phenyl]methanol (0.70 g, 3.3 mmol).
Workup and chromatographic purification (hexanes/EtOAc, 1:0→19:1) afforded the title compound
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 30
1
2
3
4
1
as a colorless solid (1.1 g, 88%). mp 45–46 °C. H NMR (400 MHz, CDCl3) δ 7.48 – 7.32 (m, 7 H),
5
6
13
7.05 – 6.97 (m, 2 H), 5.49 (s, 2 H), 5.16 (s, 2 H). C{1H} NMR (101 MHz, CDCl3) δ 159.6 (t, J =
7
31.3 Hz), 157.1, 136.7, 130.8, 130.5, 128.7, 128.2, 127.3, 122.3, 120.9, 112.1, 108.9 (t, J = 314.5
Hz), 70.2, 65.9. 19F NMR (376 MHz, CDCl3) δ –60.44 (s, 2 F). HRMS (EI): m/z [M]+ calcd for
C16H13BrF2O3: 370.0016; found: 370.0023 (1.9 ppm). IR (film): 3034, 1774, 1605, 1498, 1452, 1379,
1296, 1250, 1165, 1126, 1024, 949, 806, 754, 696 cm–1.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,4,6-Trimethylbenzyl 2-bromo-2,2-difluoroacetate (1g)
General Procedure A was followed using mesitylmethanol (0.60 g, 4.0 mmol). Workup and
chromatographic purification (hexanes/EtOAc, 1:0→19:1) afforded the title compound as a colorless
1
solid (1.1 g, 88%). mp 45–46 °C. H NMR (500 MHz, CDCl3) δ 6.92 (s, 2 H), 5.45 (s, 2 H), 2.39 (s,
13
6 H), 2.31 (s, 3 H). C{1H} NMR (126 MHz, CDCl3) δ 159.9 (t, J = 31.2 Hz), 139.7, 138.7, 129.4,
126.9, 108.9 (t, J = 314.7 Hz), 65.2, 21.2, 19.6. 19F NMR (376 MHz, CDCl3) δ –60.51 (s, 2 F).
HRMS (APCI–hexane/PhMe): m/z [M]+ calcd for C12H13BrF2O2: 306.0067; found: 306.0080 (4.2
ppm). IR (film): 3011, 2974, 2957, 2922, 2866, 1772, 1614, 1583, 1448, 1375, 1302, 1288, 1167,
1126, 1032, 951, 912, 851, 771, 700 cm–1.
(E)-4-Styrylbenzyl 2-bromo-2,2-difluoroacetate (1h)
General Procedure A was followed using (E)ꢀ(4ꢀstyrylphenyl) methanol15 (0.72 g, 3.4 mmol).
Workup and chromatographic purification (hexanes) afforded the title compound as a colorless solid
(1.1 g, 86%). mp 75–76 °C. 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.5 Hz, 4 H), 7.45–7.36 (m, 4
H), 7.34–7.28 (m, 1 H), 7.21–7.09 (m, 2 H), 5.38 (s, 2 H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.6
(t, J = 31.6 Hz), 138.5, 137.1, 132.6, 129.9, 129.2, 128.9, 128.1, 127.9, 127.0, 126.8, 108.9 (t, J =
314.4 Hz), 69.7. 19F NMR (376 MHz, CDCl3) δ –60.7 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z
[M]+ calcd for C17H13BrF2O2: 366.0067; found: 366.0055 (3.3 ppm). IR (film): 3026, 1772, 1514,
1448, 1383, 1296, 1165, 1126, 966, 949, 866, 818, 704, 690 cm–1.
Naphthalen-2-ylmethyl 2-bromo-2,2-difluoroacetate (1i)
ACS Paragon Plus Environment

Page 15 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
General Procedure A was followed using (naphthalenꢀ2ꢀyl)methanol (0.63 g, 4.0 mmol). Workup and
chromatographic purification (hexanes) afforded the title compound as a colorless solid (1.1 g, 88%).
m.p. 32–33 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.83 (m, 4 H), 7.58 – 7.53 (m, 2 H), 7.51 (d, J
= 8.7 Hz, 1 H), 5.54 (s, 2 H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.6 (t, J = 31.5 Hz), 133.6,
133.2, 130.9, 129.0, 128.4, 128.3, 127.9, 127.0, 126.8, 125.8, 108.9 (t, J = 315.0 Hz), 70.1. 19F NMR
(376 MHz, CDCl3) δ –60.68 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z [M]+ calcd for C13H9BrF2O2:
313.9754; found: 313.9763 (2.9 ppm). IR (film): 3056, 2964, 1774, 1508, 1375, 1296, 1171, 1124,
947, 854, 816, 750, 698 cm–1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-((Methylsulfonyl)oxy)benzyl 2-bromo-2,2-difluoroacetate (1j)
General Procedure A was followed using 4ꢀ(hydroxymethyl)phenyl methanesulfonate (1.4 g, 7.1
mmol). Workup and chromatographic purification (hexanes/EtOAc, 1:0→4:1) afforded the title
compound as a colorless solid (2.4 g, 95%). mp 48–49 °C. 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.47
(m, 2 H), 7.38 – 7.33 (m, 2 H), 5.38 (s, 2 H), 3.19 (s, 3 H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.4
(t, J = 31.7 Hz), 149.7, 132.9, 130.4, 122.6, 108.7 (t, J = 314.4 Hz), 68.7, 37.7. 19F NMR (376 MHz,
CDCl3) δ –60.79 (s, 2 F). HRMS (EI): m/z [M]+ calcd for C10H9BrF2O5S: 357.9322; found: 357.9329
(2.0 ppm). IR (film): 3033, 2941, 1774, 1606, 1506, 1456, 1420, 1371, 1298, 1178, 1153, 1122, 970,
872, 835, 710, 679 cm–1.
4-((2-Bromo-2,2-difluoroacetoxy)methyl)phenyl benzoate (1k)
General Procedure A was followed using 4ꢀ(hydroxymethyl)phenyl benzoate (0.57 g, 2.5 mmol).
Workup and chromatographic purification (hexanes/EtOAc, 1:0→9:1) afforded the title compound as
1
a colorless solid (0.79 g, 82%). mp 65–66 °C. H NMR (400 MHz, CDCl3) δ 8.27 – 8.18 (m, 2 H),
13
7.71 – 7.63 (m, 1 H), 7.58 – 7.46 (m, 4 H), 7.32 – 7.27 (m, 2 H), 5.39 (s, 2 H). C{1H} NMR (101
MHz, CDCl3) δ 165.1, 159.5 (t, J = 31.6 Hz), 151.7, 133.9, 131.2, 130.3, 130.1, 129.3, 128.8, 122.4,
19
108.8 (t, J = 314.3 Hz), 69.2. F NMR (376 MHz, CDCl3) δ –60.74 (s, 2 F). HRMS (EI): m/z [M]+
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 30
1
2
3
4
5
6
7
8
9
calcd for C16H11BrF2O4: 383.9809; found: 383.9810 (0.3 ppm). IR (film): 3065, 1776, 1740, 1601,
1510, 1452, 1379, 1298, 1265, 1204, 1123, 1061, 1024, 951, 876, 804, 706, 604 cm–1.
3-Phenoxybenzyl 2-bromo-2,2-difluoroacetate (1l)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure A was followed using (3ꢀphenoxyphenyl)methanol (0.69 g, 3.4 mmol). Workup
and chromatographic purification (hexanes/EtOAc, 1:0→19:1) afforded the title compound as a
colorless oil (0.99 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.34 (m, 3 H), 7.18 – 7.10 (m, 2 H),
7.07 – 7.00 (m, 4 H), 5.33 (s, 2 H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.5 (t, J = 31.6 Hz), 158.0,
156.7, 135.4, 130.4, 130.0, 123.9, 122.9, 119.5, 119.3, 118.3, 108.7 (t, J = 314.4 Hz), 69.2. 19F NMR
(376 MHz, CDCl3) δ –60.83 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z [M]+ calcd for
C15H11BrF2O3: 355.9860; found: 355.9845 (4.2 ppm). IR (film): 3065, 3040, 2964, 1778, 1585, 1489,
1448, 1377, 1301, 1259, 1213, 1173, 1122, 945, 874, 847, 777, 692, 604 cm–1.
3-Benzoylbenzyl 2-bromo-2,2-difluoroacetate (1m)
General Procedure A was followed using (3ꢀ(hydroxylmethyl)phenyl)(phenyl)methanone. Workup
and chromatographic purification (hexanes/EtOAc, 1:0→21:4) afforded the title compound as a pale
1
yellow oil (1.6 g, 88%). H NMR (400 MHz, CDCl3) δ 7.88 – 7.77 (m, 4 H), 7.67 – 7.59 (m, 2 H),
7.58 – 7.47 (m, 3 H), 5.43 (s, 2 H). 13C{1H} NMR (101 MHz, CDCl3) δ 196.1, 159.4 (t, J = 31.5 Hz),
138.3, 137.3, 133.9, 132.9, 132.3, 130.9, 130.2, 130.0, 129.1, 128.5, 108.7 (t, J = 314.3 Hz), 69.2. 19F
NMR (376 MHz, CDCl3) δ –60.81 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z [M+H]+ calcd for
C16H12BrF2O3: 368.9938; found: 368.9936 (0.5 ppm). IR (film): 3065, 3040, 2964, 1778, 1585, 1489,
1448, 1377, 1301, 1259, 1213, 1173, 1122, 945, 874, 847, 777, 692, 604 cm–1.
Methyl 4-((2-bromo-2,2-difluoroacetoxy)methyl)benzoate (1n)
General Procedure A was followed using methyl 4ꢀ(hydroxymethyl) benzoate (0.55 g, 3.3 mmol).
Workup and chromatographic purification (hexanes/EtOAc, 1:0→19:1) afforded the title compound
as a colorless oil (0.91 g, 85%). 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.9 Hz, 2 H), 7.47 (d, J =
8.0 Hz, 2 H), 5.41 (s, 2 H), 3.94 (s, 3 H). 13C{1H} NMR (101 MHz, CDCl3) δ 166.6, 159.4 (t, J =
ACS Paragon Plus Environment

Page 17 of 30
The Journal of Organic Chemistry
1
2
31.7 Hz), 138.3, 130.9, 130.2, 128.1, 108.6 (t, J = 314.2 Hz), 68.9, 52.4. 19F NMR (376 MHz,
CDCl3) δ –60.86 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z [M]+ calcd for C11H9BrF2O4: 321.9652;
found: 321.9639 (4.0 ppm). IR (film): 2955, 1778, 1724, 1616, 1437, 1379, 1283, 1171, 1111, 1020,
955, 847, 756, 708, 602 cm–1.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tert-butyl 3-((2-bromo-2,2-difluoroacetoxy)methyl)-1H-indole-1-carboxylate (1o)
General Procedure A was followed using tertꢀbutyl 3ꢀ(hydroxymethyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate (1.2
g, 3.0 mmol). Workup and chromatographic purification (hexanes/EtOAc, 1:0→9:1) afforded the
title compound as a colorless solid (0.91 g, 85%). mp 47–49 °C. 1H NMR (400 MHz, CDCl3) δ 8.18
(d, J = 8.3 Hz, 1 H), 7.77 (s, 1 H), 7.64 (dt, J = 7.8, 1.0 Hz, 1 H), 7.39 (ddd, J = 8.5, 7.2, 1.3 Hz, 1
H), 7.31 (td, J = 7.6, 1.1 Hz, 1 H), 5.54 (d, J = 0.7 Hz, 2 H), 1.69 (s, 9 H). 13C{1H} NMR (126 MHz,
CDCl3) δ 159.7 (t, J = 31.5 Hz), 149.5, 135.7, 128.9, 127.1, 125.2, 123.3, 119.2, 115.6, 113.3, 108.8
(t, J = 314.5 Hz), 84.5, 62.0, 28.3. 19F NMR (376 MHz, CDCl3) δ –60.7 (s, 2 F). HRMS (APCI–
hexane/PhMe): m/z [M]+ calcd for C16H16BrF2NO4: 403.0231; found: 403.0222 (2.2 ppm). IR (film):
3126, 3055, 2980, 2934, 1774, 1736, 1610, 1597, 1572, 1452, 1389, 1371, 1358, 1292, 1273, 1259,
1231, 1159, 1128, 1092, 1020, 945, 854, 768, 746, 704 cm–1.
(1-Phenyl-1H-pyrazol-4-yl)methyl 2-bromo-2,2-difluoroacetate (1p)
General Procedure A was followed using (1ꢀphenylꢀ1Hꢀpyrazolꢀ4ꢀyl)methanol16 (0.87 g, 5.0 mmol).
Workup and chromatographic purification (hexanes/EtOAc, 1:0→4:1) afforded the title compound as
1
a colorless solid (1.5 g, 89%). mp 60–61 °C. H NMR (400 MHz, CDCl3) δ 8.07 (s, 1 H), 7.81 (s, 1
13
H), 7.71 – 7.66 (m, 2 H), 7.51 – 7.44 (m, 2 H), 7.36 – 7.30 (m, 1 H), 5.36 (s, 2 H). C{1H} NMR
(101 MHz, CDCl3) δ 159.7 (t, J = 31.7 Hz), 141.7, 139.8, 129.7, 128.2, 127.2, 119.5, 116.0, 108.9 (t,
J = 314.5 Hz), 61.0. 19F NMR (376 MHz, CDCl3) δ –60.90 (s, 2 F). HRMS (ESI): m/z [M + H]+ calcd
for C12H10BrF2N2O2: 330.9781; found: 330.9788 (2.1 ppm). IR (film): 3057, 2970, 1774, 1514, 1489,
1375, 1292, 11689, 1122, 1067, 943, 887, 842, 771, 736, 692, 660 cm–1.
(2-Phenylfuran-3-yl)methyl 2-bromo-2,2-difluoroacetate (1q)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 30
1
2
General Procedure A was followed using (2ꢀphenylfuranꢀ3ꢀyl)methanol17 (0.52 g, 3.0 mmol).
3
4
5
6
1
Workup provided the title compound as a yellow oil (0.93 g, 93%). H NMR (400 MHz, CDCl3) δ
7
7.66 – 7.59 (m, 2 H), 7.51 – 7.45 (m, 3 H), 7.43 – 7.37 (m, 1 H), 6.61 (d, J = 1.9 Hz, 1 H), 5.40 (s, 2
H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.7 (t, J = 31.6 Hz), 153.4, 142.1, 129.9, 129.1, 128.7,
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
126.6, 113.56, 113.54, 108.8 (t, J = 314.6 Hz), 62.6. F NMR (376 MHz, CDCl3) δ –60.75 (s, 2 F).
HRMS (EI): m/z [M]+ calcd for C13H9BrF2O3: 329.9703; found: 329.9701 (0.6 ppm). IR (film): 3057,
2970, 1774, 1514, 1489, 1375, 1292, 11689, 1122, 1067, 943, 887, 842, 771, 736, 692, 660 cm–1.
Dibenzo[b,d]thiophen-4-ylmethyl 2-bromo-2,2-difluoroacetate (1r)
General Procedure A was followed using dibenzo[b,d]thiophenꢀ4ꢀylmethanol (1.2 g, 5.6 mmol).
Workup and chromatographic purification (hexanes) provided the title compound as a colorless solid
1
(1.9 g, 89%). mp 90–91 °C. H NMR (400 MHz, CDCl3) δ 8.22 – 8.15 (m, 2 H), 7.94 – 7.86 (m, 1
13
H), 7.57 – 7.47 (m, 4 H), 5.63 (s, 2 H). C{1H} NMR (101 MHz, CDCl3) δ 159.6 (t, J = 31.7 Hz),
139.24, 139.15, 136.6, 135.4, 127.7, 127.37, 127.33, 124.90, 124.86, 123.0, 122.6, 122.0, 108.7 (t, J
= 314.5 Hz), 68.7. 19F NMR (376 MHz, CDCl3) δ –60.52 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z
[M]+ calcd for C15H9BrF2O2S: 369.9475; found: 369.9471 (1.1 ppm). IR (film): 3064, 2931, 1778,
1585, 1443, 1408, 1298, 1180, 1136, 1047, 982, 941, 883, 827, 789, 746, 710, 669 cm–1.
(1-(Methylsulfonyl)-1H-indol-2-yl)methyl 2-bromo-2,2-difluoroacetate (1s)
General Procedure A was followed using [1ꢀ(methylsulfonyl)ꢀ1Hꢀindolꢀ2ꢀyl]methanol18 (1.1 g, 5.0
mmol). Workup and chromatographic purification (hexanes/EtOAc 1:0→9:1) provided the title
1
compound as a grey solid (1.1 g, 70%). mp 87–88 °C. H NMR (400 MHz, CDCl3) δ 8.05 (dt, J =
8.3, 1.0 Hz, 1 H), 7.66 – 7.61 (m, 1 H), 7.47 – 7.40 (m, 1 H), 7.38 – 7.31 (m, 1 H), 6.91 (s, 1 H), 5.69
(s, 2 H), 3.19 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.8 (t, J = 31.7 Hz), 137.2, 131.7, 128.3,
126.5, 124.3, 122.0, 114.8, 114.1, 108.7 (t, J = 314.3 Hz), 62.7, 41.1. 19F NMR (376 MHz, CDCl3) δ
–60.63 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z [M]+ calcd for C12H10BrF2NO4S: 380.9482;
ACS Paragon Plus Environment

Page 19 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
found: 380.9479 (0.8 ppm). IR (film): 3028, 1778, 1452, 1369, 1292, 1175, 1121, 964, 916, 823, 771,
748, 719, 685 cm–1.
7
(5-(Furan-2-yl)-1-methyl-1H-pyrazol-3-yl)methyl 2-bromo-2,2-difluoroacetate (3a)
HO2CCF2Br (0.27 g, 1.5 mmol) was added to a roundꢀbottom flask, which was sealed with a rubber
septum and attached to an oil bubbler. DCM (6.0 mL) and DMF (0.30 mL) were injected, and the
solution was cooled to –10 °C. Oxalyl chloride (0.13 mL, 1.5 mmol) was injected (caution: evolution
of noxious gas), and after 5 min, the mixture was allowed to warm to rt. After 2 h, the mixture was
cooled to –10 °C, and a solution of [5ꢀ(furanꢀ2ꢀyl)ꢀ1ꢀmethylꢀ1Hꢀpyrazolꢀ3ꢀyl]methanol13 (0.19 g, 1.0
mmol) and NEt3 (0.38 mL, 2.7 mmol) in DCM (1.5 mL) was added. After 2.5 h, the reaction was
quenched with water, and the aqueous layer was extracted with EtOAc (4 x 10 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and filtered. Chromatographic
purification (hexanes/EtOAc 1:0→3:2) provided the title compound as a yellow solid (0.29 g, 82%).
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
m.p. 39–40 °C. H NMR (400 MHz, CDCl3) δ 7.54 – 7.52 (m, 1 H), 6.59 (d, J = 3.4 Hz, 1 H), 6.57
(s, 1 H), 6.52 (dd, J = 3.4, 1.8 Hz, 1 H), 5.36 (s, 2 H), 4.05 (s, 3 H). 13C{1H} NMR (101 MHz,
CDCl3) δ 159.6 (t, J = 31.6 Hz), 144.4, 144.2, 143.1, 135.7, 111.7, 109.1, 108.8 (t, J = 314.9 Hz),
105.4, 63.5, 39.0. 19F NMR (376 MHz, CDCl3) δ –60.64 (s, 2 F). HRMS (APCI–hexane/PhMe): m/z
[M + Na]+ calcd for C11H9BrF2N2O3Na: 356.9662; found: 356.9648 (3.9 ppm). IR (film): 3128, 1776,
1531, 1475, 1448, 1362, 1302, 1163, 1124, 1011, 947, 903, 885, 800, 741, 702 cm–1.
General Procedure B (solid substrates)
An ovenꢀdried 15 mL screwꢀtop vial was sealed with a PTFE septum and cooled under an
atmosphere of dry N2. CuI (9.5 mg, 0.050 mmol) and (hetero)benzyl bromodifluoroacetate (0.25
mmol) were added to the vial, which was transferred into a N2ꢀfilled glovebox. Anhydrous KF (58.1
mg, 1.00 mmol) and anhydrous KI (10.4 mg, 0.0625 mmol) were added to the vial, which was sealed
with a PTFE septum and removed from the glovebox. MeCN (125 ꢁL), MeO2CCF2Br (11.0 ꢁL,
0.100 mmol) and DMF (125 ꢁL) were injected into the vial, which was placed in a preꢀheated hot
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 30
1
2
3
4
5
6
7
8
9
plate (70 °C) and stirred for 24 h. After cooling to room temperature, the mixture was diluted with
EtOAc or Et2O (25 mL). The mixture was washed with H2O (20 mL) and brine (20 mL). The organic
phase was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was
purified via silica gel chromatography to provide the corresponding trifluoroethyl(hetero)arene.
General Procedure C (liquid substrates)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
An ovenꢀdried 15 mL screwꢀtop vial was sealed with a PTFE septum and cooled under an
atmosphere of dry N2. CuI (9.5 mg, 0.050 mmol) was added to the vial, which was transferred into a
N2ꢀfilled glovebox. Anhydrous KF (58.1 mg, 1.00 mmol) and anhydrous KI (10.4 mg, 0.0625 mmol)
were added to the vial, which was sealed with a PTFE septum and removed from the glovebox.
MeCN (125 ꢁL), MeO2CCF2Br (11.0 ꢁL, 0.100 mmol), (hetero)benzyl bromodifluoroacetate (0.25
mmol), and DMF (125 ꢁL) were injected into the vial, which was placed in a preꢀheated hot plate (70
°C) and stirred for 24 h. After cooling to room temperature, the mixture was diluted with EtOAc or
Et2O (25 mL). The mixture was washed with H2O (20 mL) and brine (20 mL). The organic phase
was dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified via
silica gel chromatography to provide the corresponding trifluoroethyl(hetero)arene.
Synthesis of Trifluoroethyl(hetero)arenes
Each decarboxylative trifluoromethylation was run twice, and the yields in manuscript refer to the
average of two runs. The procedures described below represent one individual run. ArCH2CF2CF3
was observed as a minor sideꢀproduct (<2%) in many reactions, as evidenced by 19F NMR
spectroscopy (δ –85 (s, 3 F), –117 (t, J = 18 Hz, 2 F).
1-(Benzyloxy)-4-(2,2,2-trifluoroethyl)benzene (2b)
General Procedure B was followed using 1b (92.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/Et2O 39:1) afforded the title compound as a colorless solid (55.7 mg, 84%). mp
1
78–79 °C (lit.19 82–84 °C). H NMR (400 MHz, CDCl3) δ 7.48–7.39 (m, 4 H), 7.39–7.33 (m, 1 H),
7.27–7.21 (m, 2 H), 7.01–6.96 (m, 2 H), 5.09 (s, 2 H), 3.33 (q, J = 10.8 Hz, 2 H). 19F NMR (376
ACS Paragon Plus Environment

Page 21 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
MHz, CDCl3) δ –66.4 (3 F, t, J = 10.9 Hz). Spectroscopic data are consistent with the previous
report.19
7
Gram-scale Decarboxylative Trifluoromethylation: An ovenꢀdried 25 mL Schlenk flask was
sealed with a rubber septum and cooled under an atmosphere of dry N2. CuI (0.23 g, 1.2 mmol) was
added to the vial, which was transferred into a N2ꢀfilled glovebox. Anhydrous KF (1.4 g, 24 mmol)
and anhydrous KI (0.25 g, 1.5 mmol) were added to the flask, which was sealed with a rubber septum
and removed from the glovebox. The flask was attached to a Schlenk line, and remained open to an
atmosphere of dry N2 for the remainder of the reaction (CAUTION: CO2 (g) is generated during the
course of the reaction; therefore, the reaction should either be conducted in a pressureꢀrated vessel, or
open to an inert atmosphere). MeCN (3.0 mL), MeO2CCF2Br (0.26 mL, 2.4 mmol), 1b (2.2 g, 6.0
mmol), and DMF (3.0 mL) were injected into the flask, which was placed in a preꢀheated oil bath (70
°C) and stirred for 24 h. After cooling to room temperature, the mixture was diluted with EtOAc (75
mL). The mixture was washed with H2O (75 mL) and brine (75 mL). The organic phase was dried
over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified via silica gel
chromatography (hexanes/Et2O 39:1) to provide 2b as a colorless solid (1.4 g, 87%). The 1H and 19F
NMR spectrum were consistent with the data described above.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(4-(2,2,2-Trifluoroethyl)phenyl)pivalamide (2c)
General Procedure B was followed using 1c (91.0 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 1:0→9:1) afforded the title compound as a colorless solid (52.8 mg,
1
81%). mp 132–133 °C. H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2 H), 7.37 (s, 1 H), 7.25
13
(d, J = 8.3 Hz, 2 H), 3.33 (q, J = 10.8 Hz, 2 H), 1.32 (s, 9 H). C{1H} NMR (101 MHz, CDCl3) δ
176.8, 138.1, 130.8, 125.9 (q, J = 3.0 Hz), 125.8 (q, J = 276.7 Hz), 120.2, 39.76, 39.74 (q, J = 29.8
19
Hz), 27.7. F NMR (376 MHz, CDCl3) δ –65.65 (t, J = 10.8 Hz, 3 F). HRMS (EI): m/z [M]+ calcd
for C13H16F3NO: 259.1184; found: 259.1189 (1.9 ppm). IR (film): 3317, 2978, 2873, 1654, 1599,
1522, 1412, 1315, 1265, 1244, 1138, 1072, 905, 806, 698, 656 cm–1.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 30
1
2
3
4
N,N-Dibenzyl-3-(2,2,2-trifluoroethyl)aniline (2d)
5
6
7
8
General Procedure B was followed using 1d (115 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/DCM 1:0→17:3) afforded the title compound as a colorless oil (80.6 mg,
91%). 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.33 (m, 4 H), 7.32 – 7.25 (m, 6 H), 7.17 (t, J = 7.9 Hz,
1 H), 6.73 (dd, J = 8.4, 2.7 Hz, 1 H), 6.70 – 6.64 (m, 2 H), 4.68 (s, 4 H), 3.26 (q, J = 11.0 Hz, 2 H).
13C{1H} NMR (101 MHz, CDCl3) δ 149.6, 138.4, 131.2 (q, J = 2.8 Hz), 129.6, 128.8, 127.1, 126.8,
126.0 (q, J = 277.0 Hz), 118.6, 114.3, 112.3, 54.3, 40.7 (q, J = 29.5 Hz). 19F NMR (376 MHz,
CDCl3) δ –65.68 (t, J = 10.9 Hz, 3 F). HRMS (EI): m/z [M]+ calcd for C22H20F3N: 355.1548; found:
355.1561 (3.7 ppm). IR (film): 3061, 3030, 2922, 2860, 1605, 1582, 1499, 1452, 1358, 1259, 1132,
1078, 1028, 991, 964, 922, 777, 729, 696 cm–1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-Bromo-3,4-dimethoxy-1-(2,2,2-trifluoroethyl)benzene (2e)
General Procedure C was followed using 1e (101 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/DCM 1:0→17:3) afforded the title compound as a colorless oil (57.9 mg,
1
78%). H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.5 Hz, 1 H), 6.87 (d, J = 8.6 Hz, 1 H), 3.88 (s, 3
H), 3.86 (s, 3 H), 3.60 (q, J = 10.6 Hz, 2 H). 19F NMR (376 MHz, CDCl3) δ –65.48 (t, J = 10.5 Hz, 3
F). Spectroscopic data are consistent with the previous report.4a
1-(Benzyloxy)-2-(2,2,2-trifluoroethyl)benzene (2f)
General Procedure B was followed using 1f (92.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/DCM 1:0→19:1) afforded the title compound as a colorless oil (50.7 mg,
76%). 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.30 (m, 7 H), 7.07 – 6.93 (m, 2 H), 5.15 (s, 2 H), 3.57
13
(q, J = 11.0 Hz, 2 H). C{1H} NMR (101 MHz, CDCl3) δ 157.2, 137.0, 132.0, 129.6, 128.7, 128.1,
19
127.3, 126.3 (q, J = 277.3 Hz), 120.9, 119.3 (q, J = 2.8 Hz), 112.2, 70.3, 33.7 (q, J = 30.2 Hz). F
NMR (376 MHz, CDCl3) δ –65.34 (t, J = 10.9 Hz, 3 F). HRMS (EI): m/z [M]+ calcd for C15H13F3O:
266.0918; found: 266.0920 (0.8 ppm). IR (film): 3005, 2943, 1595, 1494, 1406, 1360, 1285, 1246,
1138, 1092, 1036, 947, 901, 806, 766, 681, 646 cm–1.
ACS Paragon Plus Environment

Page 23 of 30
The Journal of Organic Chemistry
1
2
3
4
1,3,5-Trimethyl-2-(2,2,2-trifluoroethyl)benzene (2g)
5
6
General Procedure C was followed using 1g (76.8 mg, 0.250 mmol). Workup and chromatographic
7
8
9
1
purification (hexanes) afforded the title compound as a colorless oil (22.4 mg, 46%). H NMR (400
13
MHz, CDCl3) δ 6.91 (s, 2 H), 3.48 (q, J = 10.8 Hz, 2 H), 2.35 (s, 6 H), 2.29 (s, 3 H). C{1H} NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(126 MHz, CDCl3) δ 138.3, 137.7, 129.4, 126.9 (q, J = 278.3 Hz), 125.6 (q, J = 2.47 Hz), 33.6 (q, J =
29.6 Hz), 21.0, 20.4 (q, J = 2.1 Hz). 19F NMR (376 MHz, CDCl3) δ –63.8 (t, J = 10.8 Hz, 3 F).
HRMS (EI): m/z [M]+ calcd for C11H13F3: 202.0969; found: 202.0978 (4.5 ppm). IR (film): 3007,
2964, 2926, 2868, 2856, 1614, 1481, 1450, 1427, 1381, 1352, 1306, 1248, 1202, 1130, 1099, 1026,
941, 910, 854, 833, 804, 735, 654 cm–1.
(E)-1-Styryl-4-(2,2,2-trifluoroethyl)benzene (2h)
General Procedure B was followed using 1h (91.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 1:0→9:1) afforded the title compound as a colorless solid (39.2 mg,
60%). mp 135–136 °C. 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.51 (m, 4 H), 7.41 (t, J = 7.5 Hz, 2 H),
13
7.36 – 7.29 (m, 3 H), 7.17 – 7.14 (m, 2 H), 3.40 (q, J = 10.8 Hz, 2 H). C{1H} NMR (101 MHz,
CDCl3) δ 137.4, 137.2, 130.6, 129.45 (q, J = 2.9 Hz), 129.41, 128.8, 128.0, 127.9, 126.8, 126.7,
125.9 (q, J = 276.9 Hz), 40.1 (q, J = 29.8 Hz). 19F NMR (376 MHz, CDCl3) δ –65.81 (t, J = 10.8 Hz,
3 F). HRMS (EI): m/z [M]+ calcd for C16H13F3: 262.0969; found: 262.0968 (0.4 ppm). IR (film):
3022, 1448, 1429, 1420, 1356, 1258, 1147, 1119, 1078, 964, 908, 820, 792, 754, 739, 692, 658 cm–1.
2-(2,2,2-Trifluoroethyl)naphthalene (2i)
General Procedure B was followed using 1i (78.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes) afforded the title compound as a colorless solid (42.3 mg, 81%). mp 51–53 °C.
1H NMR (400 MHz, CDCl3) δ 7.90 – 7.81 (m, 3 H), 7.79 (s, 1 H), 7.55 – 7.48 (m, 2 H), 7.42 (d, J =
8.4 Hz, 1 H), 3.55 (q, J = 10.8 Hz, 2 H). 19F NMR (376 MHz, CDCl3) δ –65.65 (t, J = 10.8 Hz, 3 F).
Spectroscopic data are consistent with the previous report.4b
4-(2,2,2-Trifluoroethyl)phenyl methanesulfonate (2j)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 30
1
2
3
4
General Procedure B was followed using 1j (89.8 mg, 0.250 mmol). Workup and chromatographic
5
6
purification (hexanes/DCM 1:0→2:3) afforded the title compound as a colorless solid (43.5 mg,
7
8
9
1
69%). mp 75–76 °C. H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.6 Hz, 2
H), 3.39 (q, J = 10.7 Hz, 2 H), 3.15 (s, 3 H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.1, 132.0, 129.6
(q, J = 3.0 Hz), 125.6 (q, J = 276.8 Hz), 122.4, 39.6 (q, J = 30.1 Hz), 37.5. 19F NMR (376 MHz,
CDCl3) δ –65.36 (t, J = 10.7 Hz, 3 F). HRMS (EI): m/z [M]+ calcd for C9H9F3O3S: 254.0225; found:
254.0229 (1.6 ppm). IR (film): 3031, 2945, 1608, 1502, 1456, 1421, 1361, 1302, 1177, 1153, 1132,
974, 876, 832, 707, 681 cm–1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(2,2,2-Trifluoroethyl)phenyl benzoate (2k)
General Procedure B was followed using 1k (96.3 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 1:0→19:1) afforded the title compound as a colorless solid (49.6 mg,
1
71%). mp 84–85 °C. H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 7.6 Hz, 2 H), 7.68 (t, J = 7.4 Hz, 1
H), 7.55 (t, J = 7.7 Hz, 2 H), 7.40 (d, J = 8.3 Hz, 2 H), 7.26 (d, J = 8.3 Hz, 2 H), 3.43 (q, J = 10.8 Hz,
19
2 H). F NMR (376 MHz, CDCl3) δ –66.37 (t, J = 10.8 Hz, 3 F). Spectroscopic data are consistent
with the previous report.20
1-Phenoxy-3-(2,2,2-trifluoroethyl)benzene (2l)
General Procedure C was followed using 1l (89.3 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/DCM 1:0→19:1) afforded the title compound as a colorless oil (41.9 mg,
67%). 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.29 (m, 3 H), 7.14 (t, J = 7.4 Hz, 1 H), 7.09 – 6.95 (m,
5 H), 3.35 (q, J = 10.8 Hz, 2 H). 19F NMR (376 MHz, CDCl3) δ –65.46 (t, J = 10.8 Hz, 3 F).
Spectroscopic data are consistent with the previous report.5l
Phenyl(3-(2,2,2-trifluoroethyl)phenyl)methanone (2m)
General Procedure C was followed using 1m (92.3 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/DCM 1:0→3:1) afforded the title compound as a colorless oil (40.9 mg, 62%).
1H NMR (400 MHz, CDCl3) δ 7.85 – 7.71 (m, 4 H), 7.62 (t, J = 7.4 Hz, 1 H), 7.57 – 7.45 (m, 4 H),
ACS Paragon Plus Environment

Page 25 of 30
The Journal of Organic Chemistry
1
2
3.45 (q, J = 10.7 Hz, 2 H). 13C{1H} NMR (101 MHz, CDCl3) δ 196.3, 138.2, 137.4, 134.2, 132.8,
131.8, 130.6 (q, J = 2.9 Hz), 130.2, 130.0, 128.8, 128.5, 125.7 (q, J = 276.9 Hz), 40.2 (q, J = 29.8
Hz). 19F NMR (376 MHz, CDCl3) δ –65.66 (t, J = 10.7 Hz, 3 F). HRMS (EI): m/z [M]+ calcd for
C15H11F3O: 264.0762; found: 264.0763 (0.4 ppm). IR (film): 3063, 3036, 2947, 1661, 1597, 1585,
1578, 1448, 1362, 1319, 1308, 1288, 1256, 1209, 1138, 1101, 1076, 986, 968, 932, 906, 870, 852,
813, 783, 714, 640, 602 cm–1.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 4-(2,2,2-trifluoroethyl)benzoate (2n)
General Procedure C was followed using 1n (80.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 1:0→9:1) afforded the title compound as a colorless oil [(29.5 mg, 51%
(after correction for 5 mol% ArCH2Br sideꢀproduct)]. 1H NMR (400 MHz, CDCl3) δ 8.07 – 8.02 (m,
2 H), 7.39 (d, J = 8.1 Hz, 2 H), 3.93 (s, 3 H), 3.44 (q, J = 10.7 Hz, 2 H). 19F NMR (376 MHz, CDCl3)
δ –65.58 (t, J = 10.7 Hz, 3 F). Spectroscopic data are consistent with the previous report.4b
Tert-butyl 3-(2,2,2-trifluoroethyl)-1H-indole-1-carboxylate (2o)
General Procedure B was followed using 1o (101 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc, 39:1) afforded the title compound as a colorless solid (58.1 mg, 78%).
m.p. 79–80 °C. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 6.7 Hz, 1 H), 7.61 (s, 1 H), 7.56 (d, J = 7.8
Hz, 1 H), 7.37 (ddd, J = 8.4, 7.2, 1.3 Hz, 1 H), 7.30 (ddd, J = 8.1, 7.3, 1.1 Hz, 1 H), 3.51 (qd, J =
10.6, 0.9 Hz, 2 H), 1.69 (s, 9 H). 13C{1H} NMR (126 MHz, CDCl3) δ 149.6, 135.4, 130.0, 125.93 (q,
J = 276.9 Hz), 125.92, 124.9, 123.0, 119.0, 115.5, 109.5 (q, J = 3.3 Hz), 84.2, 30.5 (q, J = 31.7 Hz),
19
28.3. F NMR (376 MHz, CDCl3) δ –65.57 (t, J = 10.7 Hz, 3 F). HRMS (EI): m/z [M]+ calcd for
C15H16F3NO2: 299.1133; found: 299.1122 (3.7 ppm). IR (film): 3057, 2982, 2934, 1736, 1452, 1375,
1350, 1277, 1259, 1229, 1153, 1138, 1101, 1016, 914, 856, 770, 744 cm–1.
1-Phenyl-4-(2,2,2-trifluoroethyl)-1H-pyrazole (2p)
General Procedure B was followed using 1p (82.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 1:0→9:1) afforded the title compound as a colorless solid (47.2 mg,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 30
1
2
83%). m.p. 45–46 °C. 1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1 H), 7.70 – 7.65 (m, 3 H), 7.49 – 7.42
(m, 2 H), 7.33 – 7.28 (m, 1 H), 3.36 (q, J = 10.7 Hz, 2 H). 13C{1H} NMR (126 MHz, CDCl3) δ 141.6,
140.0, 129.6, 127.0, 126.9, 125.7 (q, J = 276.2 Hz), 119.3, 111.8 (q, J = 3.3 Hz), 30.1 (q, J = 31.7
3
4
5
6
7
8
9
19
Hz). F NMR (376 MHz, CDCl3) δ –66.02 (t, J = 10.7 Hz, 3 F). HRMS (ESI): m/z [M + H]+ calcd
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
for C11H10F3N2: 227.0796; found: 227.0794 (0.9 ppm). IR (film): 3153, 3109, 3053, 2943, 1601,
1576, 1506, 1464, 1404, 1387, 1348, 1259, 1213, 1138, 1084, 1043, 1018, 955, 906, 862, 835, 808,
756, 692, 660 cm–1.
2-Phenyl-3-(2,2,2-trifluoroethyl)furan (2q)
General Procedure C was followed using 1q (82.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 1:0→19:1) afforded the title compound as a colorless oil (31.2 mg,
1
55%). H NMR (500 MHz, CDCl3) δ 7.61 – 7.57 (m, 2 H), 7.51 – 7.44 (m, 3 H), 7.41 – 7.36 (m, 1
H), 6.53 (s, 1 H), 3.45 (q, J = 10.5 Hz, 2 H). 13C{1H} NMR (126 MHz, CDCl3) δ 152.1, 142.0, 130.5,
128.9, 128.3, 126.8, 126.1 (q, J = 277.0 Hz), 113.5, 109.8 (q, J = 3.3 Hz), 31.3 (q, J = 31.0 Hz). 19F
NMR (376 MHz, CDCl3) δ –66.81 (t, J = 10.7 Hz, 3 F). HRMS (EI): m/z [M]+ calcd for C12H9F3O:
226.0605; found: 226.0597 (3.5 ppm). IR (film) 3055, 2937, 2856, 1599, 1487, 1447, 1433, 1362,
1298, 1273, 1254, 1140, 1105, 1082, 1053, 1032, 908, 887, 835, 764, 743, 692, 671, 650, 604 cm–1.
4-(2,2,2-Trifluoroethyl)dibenzo[b,d]thiophenes (2r)
General Procedure B was followed using 1r (92.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 1:0→19:1) afforded the title compound as a colorless solid (40.9 mg,
1
61%). mp 102–103 °C (lit.19 104–106 °C). H NMR (400 MHz, CDCl3) δ 8.21 – 8.13 (m, 2 H), 7.92
19
– 7.85 (m, 1 H), 7.54 – 7.42 (m, 4 H), 3.69 (q, J = 10.6 Hz, 2 H). F NMR (376 MHz, CDCl3) δ –
64.65 (t, J = 10.6 Hz, 3 F). Spectroscopic data are consistent with the previous report.19
1-(Methylsulfonyl)-2-(2,2,2-trifluoroethyl)-1H-indole (2s)
General Procedure B was followed using 1s (95.5 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 9:1→2:1) afforded the title compound as a colorless solid (42.6 mg,
ACS Paragon Plus Environment

Page 27 of 30
The Journal of Organic Chemistry
1
2
61%). m.p. 95–96 °C. 1H NMR (400 MHz, CDCl3) δ 8.03 – 7.99 (m, 1 H), 7.64 – 7.59 (m, 1 H), 7.41
(ddd, J = 8.4, 7.2, 1.4 Hz, 1 H), 7.34 (td, J = 7.5, 1.1 Hz, 1 H), 6.80 (s, 1 H), 4.04 (q, J = 10.2 Hz, 2
H), 3.13 (s, 3 H). 13C{1H} NMR (101 MHz, CDCl3) δ 136.8, 129.4 (q, J = 3.5 Hz), 129.0, 125.5,
125.2 (q, J = 277.1 Hz), 124.2, 121.3, 114.3, 113.1, 40.9, 32.8 (q, J = 31.7 Hz). 19F NMR (376 MHz,
CDCl3) δ –64.76 (t, J = 10.2 Hz, 3 F). HRMS (EI): m/z [M]+ calcd for C11H10F3NO2S: 277.0384;
found: 277.0382 (0.7 ppm). IR (film) 3022, 2934, 1452, 1366, 1331, 1304, 1275, 1254, 1234, 1175,
1153, 1082, 1057, 1022, 962, 924, 899, 818, 771, 748, 727, 665, 636, 554, 513 cm–1.
5-(Furan-2-yl)-1-methyl-3-(2,2,2-trifluoroethyl)-1H-pyrazole (5)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure B was followed using 3a (83.8 mg, 0.250 mmol). Workup and chromatographic
purification (hexanes/EtOAc 1:0→4:1) afforded the title compound as a yellow oil (42.6 mg, 73%).
1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 1.9, 0.8 Hz, 1 H), 6.57 (dd, J = 3.4, 0.8 Hz, 1 H), 6.51
(dd, J = 3.4, 1.8 Hz, 1 H), 6.48 (s, 1 H), 4.02 (s, 3 H), 3.45 (q, J = 10.8 Hz, 2 H). 19F NMR (376
MHz, CDCl3) δ –65.72 (t, J = 10.8 Hz). Spectroscopic data are consistent with the previous report.13
ACKNOWLEDGEMENT
We thank the donors of the American Chemical Society Petroleum Research Fund (5207–DNI1) and
the Herman Frasch Foundation for Chemical Research (701–HF12) for support of this research, and
the NIGMS Training Grant on Dynamic Aspects of Chemical Biology (T32 GM08545) for a
graduate traineeship (B. R. A.). Further financial support from the University of Kansas Office of the
Provost, Department of Medicinal Chemistry, and General Research Fund (2301795) is gratefully
acknowledged. We thank Aspira Scientific for generously donating HO2CCF2Br. Support for the
NMR instrumentation was provided by NSF Academic Research Infrastructure Grant No.
S10RR024664, and NSF Major Research Instrumentation Grant No. 0320648.
AUTHOR INFORMATION
Cooresponding Author
*Email: raaltman@ku.edu
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 30
1
2
3
4
Present Addresses
5
6
7
8
† Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, P. R. China.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Notes
The authors declare no competing financial interests.
ASSOCIATED CONTENT
Supporting Information: Supplementary experiments including timeꢀcourse analysis of benzylic
trifluoromethylation, as well as NMR spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
REFERENCES
(1) (a) Hiyama, T. Organofluorine Compounds: Chemistry and Applications; Springer: New York,
2000. (b) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity and Applications;
WileyꢀVCH: Weinheim, 2004. (c) Bégué, J. P.; BonnetꢀDelpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; WileyꢀVCH: Weinheim, 2008. (d) Ojima, I. Fluorine in Medicinal Chemistry
and Chemical Biology; WileyꢀBlackwell: Chichester, 2009. (e) Gouverneur, V.; Muller, K. Fluorine
in Pharmaceutical and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications;
Imperial College Press: London, 2012.
(2) (a) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432. (b) Müller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (c) Purse, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320. (d) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (e) Kirk, K. L. Org. Process Res.
Dev. 2008, 12, 305.
(3) The data from SciFinder were obtained March, 2015 by conducting a substructure search for
trifluoroethyl(hetero)arenes with accompanying biological studies.
ACS Paragon Plus Environment

Page 29 of 30
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(4) For discussions on strategies for the preparation of trifluoroethylarenes, see: (a) Qiao, Y.; Si, T.;
Yang, M.ꢀH.; Altman, R. A. J. Org. Chem. 2014, 79, 7122. (b) Kawai, H.; Furukawa, T.; Nomura,
Y.; Tokunaga, E.; Shibata, N. Org. Lett. 2011, 13, 3596.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) (a) Kobayashi, Y.; Yamamoto, K.; Kumadaki, I. Tetrahedron Lett. 1979, 20, 4071. (b)
Kondratenko, N. V.; Vechirko, E. P.; Yagupolskii, L. M. Synthesis 1980, 11, 932; (c) Urata, H.;
Fuchikami, T. Tetrahedron Lett. 1991, 32, 91. (d) Duan, J.ꢀX.; Su, D.ꢀB.; Chen, Q.ꢀJ. J. Fluorine
Chem. 1993, 61, 279. (e) Chen, Q.ꢀY.; Duan, J.ꢀX. J. Chem. Soc., Chem. Commun. 1993, 1389. (f)
Duan, J.ꢀX.; Chen, Q.ꢀY. J. Chem. Soc. Perkin Trans. 1 1994, 725. (g) Kim, J.; Shreeve, J. M. Org.
Biomol. Chem. 2004, 2, 2728. (h) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc.
2008, 130, 8600. (i) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A. Organometallics 2008, 27, 6233. (j)
Kremlev, M. M.; Mushta, A. I.; Tyrra, W.; Yagupolskii, Y. L.; Naumann, D.; Möeller, A. J. Fluorine
Chem. 2012, 133, 67. (k) Jiang, X.; Qing, F.ꢀL. Beilstein. J. Org. Chem. 2013, 9, 2862. (l) Zhu, L.;
Liu, S.; Douglas, J. T.; Altman, R. A. Chem. Eur. J. 2013, 19, 12800.
(6) Chen, Q.ꢀY.; Wu, S.ꢀW. J. Chem. Soc., Chem. Commun. 1989, 705.
(7) Miyake, Y.; Ota, S.ꢀi.; Shibata, M.; Nakajima, K.; Nishibayashi, Y. Org. Biomol. Chem. 2014, 12,
5594.
(8) (a) Ambler, B. R.; Altman, R. A. Org. Lett. 2013, 15, 5578. (b) Ambler, B. R.; Peddi, S.; Altman,
R. A. Synthesis 2014, 46, 1938. (c) Ambler, B. R.; Peddi, S.; Altman, R. A. Org. Lett. 2015, 17,
2506.
(9) Symons, E. A.; Clermont, M. J. J. Am. Chem. Soc. 1981, 103, 3127.
(10) pka of PhNHAc = 13.8 in H2O. Walter, W.; Voss, J. In The Chemistry of Amides; Patai, S., Ed.;
Interscience: London, 1970; ch. 8.
(11) See Supporting Information for experimental data.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 30 of 30
1
2
3
4
5
6
7
8
9
(12) (a) Footnote 7 in: Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832. (b) Zanardi,
A.; Novikov, M. A.; Martin, E.; BenetꢀBuchholz, J.; Grushin, V. V. J. Am. Chem. Soc. 2011, 133,
20901.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(13) Fustero, S.; Román, R.; SanzꢀCervera, J. F.; SimónꢀFuentes, A.; Bueno, J.; Villanova, S. J. Org.
Chem. 2008, 73, 8545.
(14) (a) Wiegand, S.; Schäfer, H. J. Tetrahedron 1995, 51, 5341. (b) Orito, K.; Miyazawa, M.;
Kanbayashi, R.; Tokuda, M.; Suginome, H. J. Org. Chem. 1999, 64, 6583.
(15) (a) Cui, X.; Li, J.; Liu, L.; Guo, Q. X. Chin. Chem. Lett. 2006, 18, 625. (b) Yang, J.ꢀS.; Lin, Y.ꢀ
D.; Chang, Y.ꢀH.; Wang, S.ꢀS. J. Org. Chem. 2005, 70, 6066.
(16) (a) Correa, A.; Bolm, C. Adv. Synth. Catal. 2007, 349, 2673. (b) de Oliveira, C. H. A.; Mairink,
L. M.; Pazini, F.; Liao, L. M.; de Oliveira, A. L.; Viegas, C.; de Oliveira, V.; Cunha, L. C.; Oliveira,
F. G. F.; Paz, J. L.; Eberlin, M. N.; Menegatti, R. Synth. Commun. 2013, 43, 1633. (c) Menozzi, G.;
Schenone, P.; Mosti, L. J. Heterocyclic Chem. 1993, 30, 997.
(17) (a) Kelly, A. R.; Kerrigan, M. H.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 4097. (b) Hojo, M.;
Ohkuma, M.; Ishibashi, N.; Hosomi, A. Tetrahedron Lett. 1993, 34, 5943.
(18) (a) Layek, M.; Lakshmi, U.; Kalita, D.; Barange, D. K.; Islam, A.; Mukkanti, K.; Pal, M.
Beilstein J. Org. Chem. 2009, 5, 46. (b) Shen, Z.; Lu, X. Adv. Syn. Catal. 2009, 351, 3107.
(19) Zhao, Y.; Hu, J. Angew. Chem. Int. Ed. 2012, 51, 1033.
(20) Xu, S.; Chen, H.ꢀH.; Dai, J.ꢀJ.; Xu, H.ꢀJ. Org. Lett. 2014, 16, 2306.
ACS Paragon Plus Environment