Catalytic One-Step Deoxytrifluoromethylation of Alcohols

Article abstract of DOI:10.1021/acs.joc.8b03072

A new bench-stable trifluoromethylation reagent, phenyl bromodifluoroacetate, converts readily available alcohols to trifluoromethanes in a Cu-catalyzed deoxytrifluoromethylation reaction. This reaction streamlines access to target biologically active molecules, and should be useful for a variety of medicinal, agricultural, and materials chemists.

Full text of DOI:10.1021/acs.joc.8b03072

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Article
Catalytic One-Step Deoxytrifluoromethylation of Alcohols
Francisco de Azambuja, Sydney M Lovrien, Patrick Ross, Brett R Ambler, and Ryan A. Altman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03072 • Publication Date (Web): 11 Jan 2019
Downloaded from http://pubs.acs.org on January 12, 2019
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Catalytic One-Step Deoxytrifluoromethylation of Alcohols
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Francisco de Azambuja,$ Sydney M. Lovrien, Patrick Ross, Brett R. Ambler,# Ryan A. Altman*
Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, United States
*raaltman@ku.edu
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TOC
• New Reagent
• One-Step Reaction
• Catalytic
O
Br
O
F
F
R
CF3
R
OH
cat. [CuI]
KF
Abstract
A new bench-stable trifluoromethylation reagent, phenyl bromodifluoroacetate, converts readily
available alcohols to trifluoromethanes in a Cu-catalyzed deoxytrifluoromethylation reaction. This reaction
streamlines access to target biologically active molecules, and should be useful for a variety of medicinal,
agricultural, and materials chemists.
Introduction
Methods for directly converting common functional groups to fluorinated motifs enable the rapid and
efficient discovery and development of new agrochemicals, materials, and pharmaceuticals.1 In particular,
protocols that employ simple reagents and mild reaction conditions can facilitate both late-stage
diversification of lead compounds and large-scale manufacture of chemicals. Given the ubiquity of alcohols
in bioactive compounds, materials, and synthetic intermediates, methods that directly convert alcohols to
useful fluorinated functional groups that alter physicochemical and biophysical properties of a parent
compound are highly valuable.2 This powerful strategy has been realized for converting alcohols to
monofluorinated analogs, which is an essential strategy to selectively and quickly incorporate fluorine into
molecules (Figure 1B, left).1a For these one-step deoxyfluorination reactions of alcohols, many benchmark
reagents are commercially available, and new methods are continuously being developed.3 However,
analogous one-pot deoxytrifluoromethylation protocols for transforming alcohols to trifluoromethanes,
another useful functional group for medicinal, agricultural and materials chemistries, remain extremely
limited.
Considering deoxyfluorination and deoxytrifluoromethylation reactions, intrinsic differences in stability
and reactivity of F and –CF3 render the latter reaction challenging. The deoxyfluorination strategy typically
–
relies on in situ activation of alcohols to generate more electrophilic intermediates, and subsequent
substitution by nucleophilic –F. Fluoride is a stable and small anion that can directly engage in nucleophilic
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–
substitutions, such as deoxyfluorination reactions. In contrast, CF3 is unstable, bulky, and decomposes
quickly in solution in the absence of a competent (usually sp2-hybridized) electrophile (Figure 1B, right).4
–
Because of this instability, CF3 does not react through pure nucleophilic substitution mechanisms, but
5
instead requires a transition metal to effectively generate a new C–CF3 bond.5 However, conditions for
activating alcohols have historically not been compatible with transition metal-catalyzed reactions. As such,
deoxytrifluoromethylation reactions of alcohols typically require multi-step transformations that
inefficiently manipulate oxidation states, require excess time and labor, generate excess waste, decrease
yields of desired products, and limit the use of functional groups that are sensitive to oxidation, reduction,
and/or strong nucleophiles.6 Herein, we describe the development of a new reagent that, in concert with a
Cu-based catalyst, enables the direct conversion of alcohols to trifluoromethanes under mild conditions.
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A) Conceptual Framework: Incorporation of Fluorine through
Readily Available Functional Groups
R
FG
R
(F)n
R
LG
FG = Functional Group
Readily Available
Fluorinated
Molecule
B) Deoxyfluorination vs. Deoxytrifluoromethylation
R
OH
F
F
F
F
R
CF3
R
F
R
LG
• Established Strategy
• [F–]: Efficient Nucleophile
• One-Step Reaction
• Many Reagents
• Underexplored Reaction
• [CF3–]: Poor Nucleophile
• Multi-Step Reaction
• No Reagents
C) This Work: Catalytic One-Step Deoxytrifluoromethylation
O
Cu cat.
O
[LG]
CF2Br
KF
Br
R
CF3
R
OH
R
O
New
Reagent
F
F
not isolated
(formed in-situ)
LG = Leaving Group
Figure 1: a) Methods that convert common functional groups to fluorinated motifs are valuable to discovery
and process chemists. b) While protocols that directly transform alcohols to alkyl fluorides are widely used,
analogous one-pot methods to access trifluoromethanes from alcohols are rare. c) Development of a new
reagent enables Cu-catalyzed deoxytrifluoromethylation.
Results and Discussion
To develop a one-step deoxytrifluoromethylation reaction, we aimed to develop a new reagent that
would convert an alcohol to a suitable leaving group for reaction with Cu–CF3 under mild conditions (Figure
1C). Among several alcohol-derived electrophiles, we focused on pioneering work of Chen and co-workers,7
who established the Cu-mediated C–O bond activation of bromodifluoroacetates, and the compatibility of
this system with Cu-mediated C–CF3 bond formation. Considering our previous work with
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bromodifluroacetates,8 we envisioned that a catalytic one-step deoxytrifluoromethylation reaction could be
achieved by designing a stable reagent that would convert the starting alcohol to the corresponding
bromodifluoroacetate derivative in situ, but that would not interfere with catalysis. We initially explored
commercially available bromodifluoroacetates (e.g. MeO2CCF2Br and NaO2CCF2Br) as
deoxytrifluoromethylation reagents; however, despite achieving catalytic turnover, thorough evaluation of
reaction conditions did not provide a suitable system for deoxytrifluoromethylation (Figure 2A). We
reasoned that water or an alcohol, generated from transesterification step, might adversely affect the final
Cu-catalyzed decarboxylative trifluoromethylation step. To test this hypothesis, Cu-catalyzed
trifluoromethylation of cinnamyl bromodifluoroacetate (3a) was conducted in the presence of an alcohol or
H2O (1 equiv.). Compared to the control reaction, addition of MeOH or H2O decreased the yield of
trifluoromethylated product (4a) from 75% to 19–24% (Figure 2B), thus confirming the incompatibility of
simple H2O and MeOH leaving groups (LG–H).
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Figure 2: Design of Deoxytrifluoromethylation Reagent Required Identification of Benign Leaving Group.
Subsequent efforts identified different LG–H that would not interfere with the Cu-catalyzed process
(Figure 2C). To identify such leaving groups (LG), we evaluated the effects of different additives (1.0
equiv.) on the conversion of cinnamyl bromodifluoroacetate 3a into trifluoromethyl products (Figure 2D).8a
In these reactions, succinimide did not decrease the yield of trifluoromethyl product 4a, while phenol and
trifluoroethanol slightly lowered the yields of 4a. Other N-based additives (e.g. 2-oxazolidinone, N-
tosylaniline, and N–H heterocycles), thiols, and other alcohols, negatively affected the Cu-catalyzed
process. Based on these additives, we prepared several bromodifluoroacetate (BDFA) -derived esters, and
tested them as reagents in the deoxytrifluoromethylation reaction of cinnamyl alcohol 2a using optimized
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conditions (Table 1). Under these conditions, commercially available NaO2CCF2Br (1a), MeO2CCF2Br
(1b), and EtO2CCF2Br (1c) still provided low yields of the desired product. Among the newly prepared
reagents, phenyl bromodifluoroacetate (PhBDFA, 1d) afforded the best compromise between availability,
stability, cost and yield of the desired cinnamyl trifluoromethane (4a). Substitutions on the phenyl ring of
the PhBDFA (1d) to perturb electronic character (1d–1g) or steric hindrance (1h) did not improve the
reaction. An exchange of the oxygen for the sulfur in compound 1i decreased the yield, which is consistent
with our additive based screening. Similarly, bromodifluoroacetamide 1j provided similar yields as
compared to the easier to synthesize bromodifluoroacetate esters. Moreover, reactions using 1j generated
significant quantities of side products deriving from the allylation of N-tosylaniline. In addition, the
bromodifluoroacylated succinimide was insufficiently stable for isolation, thus limiting the use of this
presumably useful leaving group. Ultimately, PhBDFA (1d) was selected as the most suitable reagent for
deoxytrifluoromethylation, given the inexpensive and readily available nature of phenol, and the reasonable
stability of the phenyl ester toward storage.9
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Table 1: Phenyl Bromodifluoroacetate (PhBDFA) Provided the Trifluoromethyl Product 4a in Higher Yield
than Other Bromodifluoroacylating Reagents
10 mol% CuI/DMEDA
O
50 mol% HO2CCF2Br
Br
Ph
[LG]
OH +
Ph
CF3
F
F
KF, DMF, 25 °C
2a (1 equiv.)
1a–j (2 equiv.)
4a
X
NaO
1a: 36%
Me
MeO
EtO
[LG] =
1b: 1%
1c: <1%
O
1d:
1e:
1f:
X = H
OMe
75%
71%
68%
76%
Ph
CF3
O
Me
S
N
Ts
1g:
1h: 17%
1i: 37%
1j: 64%
Using phenyl bromodifluoroacetate (PhBDFA, 1d), representative allylic (2a–2i), propargylic (5a–5f)
and benzylic (7a–7e) alcohols were trifluoromethylated in moderate to good yields (Tables 2–4). For
allylic8a and propargylic8c substrates, direct deoxytrifluoromethylation typically provided higher yields than
two-step protocols involving formation and purification of intermediate bromodifluoroacetic esters and
subsequent Cu-catalyzed decarboxylative trifluoromethylation. Notably, many allylic and propargylic
bromodifluoroacetates previously explored8a, c were unstable to basic conditions, silica gel, and cold storage
(slowly decomposing in the refrigerator for weeks). Therefore, the one-step protocol offered distinct
advantages by avoiding isolation of the instable intermediate bromodifluoroacetic esters. The direct
deoxytrifluoromethylation displayed good functional group tolerance, with cinnamyl derivatives 2a–2e
illustrating good compatibility with electron-donating, electron-withdrawing, and halogen functional
groups. In addition, the reaction tolerated non-cinnamyl substrates, such as allylic alcohol 2f. Endocyclic
alkenols, a structural unit present in several natural products, served as competent substrates, and delivered
4g–4h in good yields. As an example of such natural products, perillyl alcohol afforded trifluoromethyl
product 4i in 57% of yield. In addition, selected propargylic alcohols 5a–5f were also
deoxytrifluoromethylated to afford trifluoromethylallenes 6a–6f, bearing useful ester, amide, and chlorine
groups.10 In contrast to allylic and propargylic alcohols, benzyl alcohols 7a–7e were more challenging
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substrates, and required higher temperature to afford synthetically useful yields with electron-rich rings (7a–
7b). However, the reaction is compatible with a range of drug-like heterocycles, such as indole (7c),
pyrazole (7d), and indazole (7e).6e Together, these examples showcase the potential of this
deoxytrifluoromethylation reaction to provide valuable trifluoromethyl drug-like building-blocks from
simple alcohols in a single-step.
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Table 2: Phenyl Bromodifluoroacetate Enables Cu-catalyzed One-pot Deoxytrifluoromethylation of Allylic
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Alcoholsa
10 mol% CuI/DMEDA
O
50 mol% HO2CCF2Br
Br
+
OH
CF3
CF3
R
PhO
R
F
F
KF, DMF, 25 °C
2a–2i (1 equiv.)
4a–4i
1d (2 equiv.)
CF3
CF3
O2N
MeO
4a
4b
4c
One-pot yield: 75%b
Two-pot yield: 66%
One-pot yield: 75%
One-pot yield: 72%
Two-pot yield: 36%
Two-pot yield: 73%
Br
BnO
CF3
CF3
CF3
F
4d
4e
4f
One-pot yield: 64%
Two-pot yield: 39%
One-pot yield: 61%
Two-pot yield: 77%
One-pot yield: 81%
Two-pot yield: 57%
CF3
CF3
CF3
Me
4g
4h
4i
One-pot yield: 80%c
Two-pot yield: –
One-pot yield: 63%c
Two-pot yield: –
One-pot yield: 57%
Two-pot yield: –
a
Standard reaction conditions: 2a–2i (0.50 mmol), 1d (1.0 mmol), CuI (0.050 mmol), DMEDA (0.055
mmol), HO2CCF2Br (0.25 mmol), KF (1.0 mmol), DMF (1.0 mL), 25 °C. Yield of material after
b
chromatographic purification. For comparison, two-pot yields reported from reference 8a. Reaction
conducted on 5.0 mmol scale. c Yield determined by 19F NMR spectroscopy using α,α,α-trifluorotoluene as
an internal standard.
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Table 3: Phenyl Bromodifluoroacetate Enables Cu-catalyzed One-pot Deoxytrifluoromethylation of
Propargylic Alcoholsa
5
6
7
8
10 mol% CuI/phen
O
50 mol% HO2CCF2Br
Ar
OH
Br
PhO
+
Ar
F
F
KF, DMF, 50 °C
CF3
5a–5f (1 equiv.)
6a–6f
1d (2 equiv.)
9
OMe
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O2N
MeO2C
CF3
CF3
CF3
6a
6b
6c
One-pot yield: 69%
Two-pot yield: 68%
One-pot yield: 66%
Two-pot yield: 52%
One-pot yield: 70%
Two-pot yield: 46%
Boc
N
H
F3C
N
Cl
O
Cl
CF3
CF3
CF3
6d
6e
6f
One-pot yield: 41%
Two-pot yield: 34%
One-pot yield: 55%
Two-pot yield: 27%
One-pot yield: 65%
Two-pot yield: 67%
a Standard reaction conditions: 5a–5f (0.50 mmol), 1d (1.0 mmol), CuI (0.050 mmol), 1,10-phenanthroline
(0.055 mmol), HO2CCF2Br (0.25 mmol), KF (1.0 mmol), DMF (1.0 mL), 50 °C. Yield of material after
chromatographic purification. For comparison, two-pot yields reported from reference 8c.
Table 4: Phenyl Bromodifluoroacetate Enables Cu-catalyzed One-pot Deoxytrifluoromethylation of
Benzylic Alcoholsa
20 mol% CuI
O
40 mol% MeO2CCF2Br
Br
(Het)Ar
OH
(het)Ar
8a–8e
CF3
+
PhO
KF, KI
F
F
DMF:MeCN, 70 °C
7a–7e (1 equiv.)
1d (2 equiv.)
MeO
CF3
CF3
BnO
8a
8b
One-pot yield: 74%
Two-pot yield: 70%
One-pot yield: 62%
Two-pot yield: –
CF3
CF3
CF3
N
N
N
Ts
N
N
Ph
Me
8c
8d
8e
One-pot yield: 61%
Two-pot yield: –
One-pot yield: 49%
Two-pot yield: 73%
One-pot yield: 39%
Two-pot yield: –
a Standard reaction conditions: 7a–7e (0.50 mmol), 1d (1.0 mmol), CuI (0.10 mmol), MeO2CCF2Br (0.20
mmol), KI (0.12 mmol), KF (2.0 mmol), DMF (0.25 mL), MeCN (0.25 mL), 70 °C. For comparison, two-
pot yields reported from reference 8d.
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To further illustrate the potential impact of the catalytic one-step deoxytrifluoromethylation reaction,
we prepared trifluoromethylated intermediates 10 and 12 toward the syntheses of the COX-2-inhibitor L-
784-512,11 and a fluorinated analog of Tebufenpyrad,12 respectively. Previously, allyl trifluoromethane 10
was prepared in a one-pot two-step procedure in 74% yield employing chlorodifluoroacetic anhydride
[O(O2CCF2Cl)2] as the trifluoromethylating reagent; however, stoichiometric amounts of CuI were required
to suppress the formation of the corresponding allyl chloride side-product (Scheme 1A). In contrast, use of
PhBDFA (1d) as the trifluoromethylating reagent provided a similar yield with only a catalytic amount of
copper salt. A more insightful comparison involved the synthesis of trifluoroethyl pyrazole 12 (Scheme 1B).
The original route to this compound required four steps, including one final deoxygenation reaction with
excess of undesirable Bu3SnH (Route i).12a In a second preparation of 12, our previous two-step reaction
provided 12 in 60% yield (Route ii).8d Finally, when employing PhBDFA (1d), our catalytic conditions
afforded the desired product directly from the alcohol in 57% yield (Route iii). This operationally
straightforward one-step catalytic deoxytrifluoromethylation reaction provides direct access to a valuable
fluorinated product from a simple alcohol precursor, while avoiding inefficient redox manipulations,
chromatographic purifications, and generation of stoichiometric metallic byproducts. To further highlight
the utility of the reaction, we carried out the deoxytrifluomethylation of cinnamyl alcohol 2a in multigram
scale, as the scale up of related aromatic trifluoromethylation reactions using a related reagent
(MeO2CCF2Cl) has proved problematic.13 In our case, no loss in the yield was observed relative to the small
scales reactions, and 2.7 g of product was obtained in a single-reaction. In perspective, these examples
illustrate the streamlined synthetic routes enabled by the catalytic one-step deoxytrifluoromethylation
reaction, and its potential to be used in small multigram synthesis.
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A) PhBDFA (1d) Streamlines Synthesis of Key Intermediate 10 Under Catalytic Conditions en route to COX-2 Inhibitor in L-784,512
O
O
1) ClF2C
O
CF2Cl, DIPEA, DMF
SO2Me
5
2) KF, CuI (1 equiv.), 90 ºC
6
7
8
9
CF3
OH
Me
O
O
MeO2S
Me
Me
10
O
MeO2S
Two-pot yield: 74%
Br
F
9
O
CF3
PhO
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One-pot yield: 75%
F
F
F
L-784,512
(COX-2 Inhibitor)
1d (2 equiv.)
10 mol% CuI/DMEDA, BrCF2CO2H, KF
DMF, 25 °C
B) PhBDFA (1d) Affords Key Pyrazole 12 en route to Acaricidal Tebufenpyrad in One-Step Avoiding Redox Steps and Toxic Metal Reagents
S
S
HO
1) MnO2 (6 equiv.),
MeCN, 75%
Bu3SnH (4 equiv.)
AIBN (0.6 equiv.)
F3C
OPh
CF3
O
PhO
Cl
Route i
N
N
2) TMSCF3 (1.7 equiv.)
TBAFcat., THF, rt, 90%
PhMe, 80 ºC
75%
DMAP, MS 4A
PhMe, 60 ºC
61%
N
Overall Yield: 31%
(previous work)
N
O
Me
O
Me
O
20 mol% CuI
HO2CCF2Br
CF3
OH
CF2Br
O
BrCF2CO2Me (0.4 equiv)
(COCl)2, DMFcat.
Route ii
N
N
N
Overall Yield: 60%
(previous work)
N
N
KI (0.25 equiv), KF (2.0 equiv.)
DMF:MeCN (1:1)
70 °C, 24 h
Et3N, CH2Cl2
82%
O
N
Me
12
O
Me
11
O
Me
73%
O
Br
PhO
1d (2 equiv.)
Route iii
57% (1 step)
(this work)
F
F
20 mol% CuI, BrCF2CO2Me (0.4 equiv)
KI (0.25 equiv), KF (2.0 equiv.), DMF:MeCN (1:1)
40 ºC, 30 min then 70 °C, 24 h
C) One-Step Catalytic Deoxytrifluoromethylation Performs on a Multigram-Scale
10 mol% CuI / DMEDA
O
OH
CF3
+
Br
PhO
BrCF2CO2H, KF
DMF, 25 °C
F
F
2a
20 mmol
4a
1d
2 equiv.
75% (2.7 g)
Scheme 1: Catalytic One-Step Deoxytrifluoromethylation Reaction: (a–b) Shortens the Synthesis of Known
Intermediates to the Synthesis of COX-2 Inhibitor L-784,512 and a Fluorinated Analog of Tebufenpyrad;
(c) Is Equally Efficient on Multi-Gram Scale.
Several data support a mechanism involving a fast acylation/transesterification step prior to the Cu-
catalyzed decarboxylative trifluoromethylation reaction (Scheme 2A). Using time-course analysis, we
observed a quick acylation of cinnamyl alcohol 2a forming the corresponding bromodifluoroacetate 3a
during the first 15 min of the Cu-catalyzed reaction, reaching a maximum concentration at ~2 h, and then
converting to product 4a over the remaining course of the reaction (see SI for details). Further experiments
identified KF as the key component in facilitating formation of the thermodynamically favored ester 3a. In
contrast, excess BDFA, serving as a Brønsted acid, did not promote the transesterification step (Scheme
2B). Based on these results, relative to MeO2CCF2Br and other commercially available
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bromodifluoroacetates, the acylating ability of PhBDFA (1d) likely shifted the equilibrium of the
transesterification step, thus increasing the concentration of the key bromodifluoroacetate 3a, and
subsequently favoring the Cu-catalyzed trifluoromethylation (Scheme 2C). Such a facile acylation step
supports an overall deoxytrifluoromethylation mechanism involving conversion of the alcohol to a
bromodifluoracetate ester prior to a Cu-catalyzed decarboxylative trifluoromethylation, as previously
suggested (Scheme 2A).7, 8e, 14
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A) Proposed Mechanism
R
OH
KF
O
+
O
R
O
CF2Br
(fast)
3
+
PhOH
Br
PhO
F
F
LnCu–CF3
+KF
Cu-cycle
(slow)
–KBr
CO2
O
[LnCu]
O
CF2Br
R
CF3
B) KF Facilitates the In Situ Formation of the Active Ester 3a
O
Additive
O
Br
+
OH
Ph
PhO
Ph
O
CF2Br
DMF, 25 °C
F
F
2a
1d
3a
2 equiv.
No Additive
HO2CCF2Br
0%
0%
HO2CCF2Br + KF > 95% (GC yield)
KF > 95% (GC yield)
C) PhBDFA (1d) Increases Concentration of Active Ester 3a
O
MeO
CF2Br
+
O
k1
Ph
O
CF2Br
Ph
OH
k–1
2a
3a
Low Yield
+ MeOH
k1 ~ k–1
[Cu]
KF
O
Ph
CF3
O
4a
PhO
CF2Br
+
k2
Ph
O
CF2Br
High Yield
Ph
OH
k–2
2a
3a
+ PhOH
k2 >> k–2
D) PhBDFA (1d) Is Stable Under Reaction Conditions
O
O
10 mol% CuI/Ligand
O
Br
Br
+
PhO
PhO
PhO
CF3
HO2CCF2Br
KF, DMF
F
F
F F
Ligand
1d
2 equiv.
Phen
84%
82%
5%
8%
50 °C, 24 h
DMEDA
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Scheme 2: Control Experiments Suggest Rapid Formation of Bromodifluoroacetate 3a Prior to a Slow Cu-
catalyzed Decarboxylative Trifluoromethylation Reaction
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The ability of PhBDFA (1d) to serve as an effective trifluoromethylating reagent derived from its
aforementioned acylating ability in addition to its stability under the reaction conditions (Scheme 2).
Reagents previously used for trifluoromethylation of organic halides [RO2CCF2X (R = Na, Me, Et; X = Cl,
Br)] decompose under mild conditions (>40 °C in the presence of copper)14-15 to release difluorocarbene,
which polymerizes13 or reacts with alkenes or phenols.15b, 16 In contrast, minimal decomposition of the
PhBDFA (1d) was observed (>82% of 1d recovered) under the reaction conditions (Scheme 2D). Moreover,
the stability of PhBDFA (1d) discounted mechanisms involving initial outer-sphere thermal decomposition
of 1d to generate difluorocarbene, and subsequent formation of the Cu–CF3, which has been implicated in
trifluoromethylation reactions of organic halides.17 Overall, this analysis suggests that success of PhBDFA
(1d), compared to MeO2CCF2Br, relies on the inertness of the leaving group (Figure 2D), and from
equilibrium (Scheme 2C) and stability factors (Scheme 2D) of the newly designed reagent. Of note, the
optimized conditions utilize MeO2CCF2Br or HO2CCF2Br additives to help generate the active Cu–CF3
catalyst. Though these species serve as poor reagents for esterifying the alcohol substrate (Figure 2A), they
serve to convert the CuI precatalysts into the active Cu–CF3 species,8a and/or to regenerate Cu–CF3 that is
lost throughout the reaction.8d Further, as previously reported,14 the CuI/KF-mediated conversion of
MeO2CCF2Br or HO2CCF2Br to afford Cu–CF3 generates methyl iodide and CO2 as byproducts, which do
not inhibit the catalytic reaction in a similar fashion to H2O and MeOH, which would be generated by
transesterification.
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Conclusion
In summary, a catalytic one-step deoxytrifluoromethylation reaction of readily available alcohols was
developed using phenyl bromodifluoroacetate (1d, PhBDFA) as the key reagent. The new reaction provided
diverse trifluoromethyl compounds in good yields and tolerated many useful functional groups. Moreover,
its application to rapidly prepare intermediates in the synthesis of biologically active molecules illustrated
the potential impact of this reaction. Initial mechanistic analysis suggested that the success of 1d, in
comparison with commercially available bromodifluoroacetates, stems from both equilibrium and stability
factors, in addition to its inertness under the catalytic conditions. The deoxytrifluoromethylation reaction
complements the well-established deoxyfluorination reaction and opens up new possibilities to obtain
fluoroalkylated products from readily available functional groups. Further studies to expand this reaction
are undergoing in our lab.
Experimental Section
General Considerations
Unless otherwise noted, reactions were performed under an atmosphere of N2 using oven-dried
glassware. Trifluoromethylation reactions in 1-dram vials sealed with a PTFE-lined screw cap. Reactions
were setup inside a N2-filled glove box. All other reactions were performed in round-bottom flasks that were
sealed with rubber septa using oven-dried glassware and standard Schlenk techniques. High-quality
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laboratory-grade polypropylene and polyethylene syringes bearing stainless steel needles were used to
transfer air- and moisture-sensitive liquid reagents. Reactions were monitored by thin-layer 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, or iodine.
Purifications by column chromatography (SiO2) were conducted using an automated system or following
Still’s general procedure. 19F NMR Yields and isolated yields reported in the manuscript represent an
average of at least two independent runs. Yields reported in the supporting information refer to a single
experiment.
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Unless otherwise noted, reagents were purchased from commercial sources, and used as received.
Commercial anhydrous potassium fluoride (KF) was further dried in high-vacuum (~1.5 Torr, 185 ºC) for
18 h, and stored in the glovebox. N,N’-dimethylethylenediamine (DMEDA) was distilled under nitrogen
and stored in the glovebox. Anhydrous N,N-dimethylformamide (DMF), acetonitrile (CH3CN), 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.
Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear magnetic resonance (13C
NMR) spectra were recorded on Bruker AVIIIHD 400 spectrometer (400 and 100 MHz, respectively) or
Bruker AVIII 500 with CPDUL cryoprobe spectrometer (500 and 125 MHz, respectively). Chemical shifts
(δ) for protons are reported in parts per million (ppm) downfield from tetramethylsilane, and are referenced
to proton resonance of residual CHCl3 in the NMR solvent (CHCl3: δ = 7.26 ppm). Chemical shifts (δ) for
carbon are reported in ppm downfield from tetramethylsilane, and are referenced to the carbon resonances
of the solvent residual peak (CDCl3: δ = 77.16 ppm). Fluorine nuclear magnetic resonance (19F NMR)
spectra were recorded on a Bruker AVIIIHD 400 spectrometer (376 MHz). 19F NMR chemical shifts (δ) are
reported in ppm upfield from trichlorofluoromethane (0 ppm). 19F NMR yields were determined from the
crude mixtures using non-deuterated solvents and the relaxation delay time (D1) was set to 4 seconds to
ensure reproducible results. NMR data are represented as follows: chemical shift (ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, p = pentet, hept = heptet, m = multiplet), coupling constant in
Hertz (Hz), integration.
Exact mass spectra were recorded using (1) electrospray ion source (ESI), positive mode, and time-of-
flight (TOF) analyzer on a Waters LCT PremierTM mass spectrometer or (2) an atmospheric-pressure
chemical ionization (APCI) ion source and TOF analyzer on a Waters Q-Tof PremierTM mass spectrometer,
for which sample plus near mass internal exact mass standard were dissolved in hexane, and hexane or
PhMe/hexane were used as the ionization solvent. Mass calibration was carried out directly before the
measurement of the sample. Low-resolution mass spectra were recorded using an electron impact (EI) ion
source and a tandem quadrupole analyzer on a Waters Quattro Micro GC mass spectrometer, injected via a
gas chromatograph Agilent 6890N (GC/MS).
Quantitative gas chromatography (GC) analyses were recorded on an Agilent Technologies 7890A GC-
system with Flame Induced Detector (FID) and a HP-5 column (0.32 mm × 30 m, film: 0.25 μm). The
method used consisted of 70 ºC for 1 min, then 30 ºC/min to 250 ºC, and holding at 250 ºC for 1 min.
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Infrared spectra were measured using attenuated total reflection (ATR) at a Fourier Transform Infrared
Spectrometer. Uncorrected melting points were measured on Thomas Hoover Capillary Melting Point
apparatus.
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Preparation of Known Compounds
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N-4-toluenesulfonylaniline,18 (E)-3-(4-methoxyphenyl)prop-2-en-1-ol (2b),8a (E)-3-(4-fluorophenyl)prop-
2-en-1-ol (2d),8a (E)-3-(3-bromophenyl)prop-2-en-1-ol (2e),8a 3-(naphthalen-2-yl)prop-2-yn-1-ol (5a),8c 3-
(2-methoxy-5-nitrophenyl)prop-2-yn-1-ol (5b),8c methyl 3-(3-hydroxyprop-1-yn-1-yl)benzoate (5c) ,8c tert-
butyl 2-(3-hydroxyprop-1-yn-1-yl)-1H-indole-1-carboxylate (5d),8c 2,2,2-trifluoro-N-(4-(3-hydroxyprop-
1-yn-1-yl)phenyl)acetamide (5d),8c 3-(3,4-dichlorophenyl)prop-2-yn-1-ol (5e),8c (1-phenyl-1H-pyrazol-4-
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yl)methanol
(5f),8d
(1-methyl-1H-indazol-3-yl)methanol
(7e),19
(E)-2-methyl-3-(4-
(methylsulfonyl)phenyl)prop-2-en-1-ol11 (9) and (5-(furan-2-yl)-1-methyl-1H-pyrazol-3-yl)methanol
(11),12a were prepared according to previously literature reports. All compounds presented satisfactory
analysis coherent with characterization data published previously.
Synthesis of Aryl Bromodifluoroacetates
General Procedure A:
An oven-dried two-neck flask equipped with a stirring bar, a gas outlet attached to the Schlenk line and a
rubber septum under nitrogen was charged with bromodifluoroacetic acid (12.6 g, 72.0 mmol) and CH2Cl2
(150 mL). The resulting solution was cooled using an ice-water bath, and oxalyl chloride (5.7 mL, 66 mmol)
was added. Next, DMF (0.23 mL, 3.0 mmol) was added dropwise (caution: rapid evolution of noxious
gases). After stirring at low temperature for 10 min, the solution was stirred at room temperature until the
gas evolution ceased (~3 h). Next, the reaction mixture was cooled using an ice-water bath, and phenol (60.0
mmol) was added in one portion. After 10 min stirring at low temperature, Et3N (10.0 mL, 72.0 mmol) was
added, and the reaction was stirred for 30 min at low temperature, followed by stirring at room temperature
for ~16 h. The reaction was quenched with HCl(aq) 1 mol L-1 (25 mL) and transferred to a separation funnel.
The phases were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 25 mL). The combined
organic phases were washed with NaCl(sat) (1 x 25 mL), dried over anhydrous MgSO4, filtered, and
concentrated. Purification by flash column chromatography provided the desired product.
Phenyl 2-bromo-2,2-difluoroacetate (1d)
General procedure A was followed using phenol (5.64 g, 60.0 mmol), bromodifluoroacetic acid (12.6 g,
72.0 mmol), oxalyl chloride (5.7 mL, 66 mmol), DMF (0.23 mL, 3.0 mmol), CH2Cl2 (0.15 L), and Et3N
(10.0 mL, 72.0 mmol). Workup and chromatographic purification (100% hexanes) provided the title
compound as a colorless oil (10.7 g, 71%).
13
1H NMR (CDCl3, 400 MHz)  7.49 – 7.43 (m, 2H), 7.37 – 7.30 (m, 1H), 7.25 – 7.18 (m, 2H). C{1H}
NMR (CDCl3, 126 MHz)  158.1 (t, J = 32.3 Hz), 149.7, 130.0, 127.4, 120.6, 108.6 (t, J = 314.4 Hz). 19F
NMR (CDCl3, 376 MHz)  –61.6 (s, 2 F). IR (ATR) 3076, 1786, 1589, 1493, 1283, 1186, 1157, 1107, 945,
906, 839, 746, 704, 685 cm-1. HRMS (APCI, m/z): calcd for C8H5BrF2O2 [M]+ 249.9441, found 249.9433.
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4-Methoxyphenyl 2-bromo-2,2-difluoroacetate (1e)
General procedure A was followed using 4-methoxyphenol (1.24 g, 10.0 mmol), bromodifluoroacetic acid
(2.10 g, 12.0 mmol), oxalyl chloride (950 μL, 11.0 mmol), DMF (0.31 mL, 4.0 mmol), CH2Cl2 (0.030 L),
and Et3N (1.4 mL, 10 mmol). Workup and chromatographic purification (100% hexanes) provided the title
compound as a colorless oil (1.57 g, 56%).
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1H NMR (CDCl3, 400 MHz)  7.17 – 7.10 (m, 2H), 6.98 – 6.91 (m, 2H), 3.82 (s, 3H). C{1H} NMR
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(CDCl3, 126 MHz)  158.4 (t, J = 32.1 Hz), 158.3, 143.2, 121.4, 114.9, 108.7 (t, J = 314.8 Hz), 55.7. 19F
NMR (CDCl3, 376 MHz)  –61.5 (s, 2 F). IR (ATR) 3005, 2963, 2839, 1786, 1599, 1504, 1466, 1443,
1286, 1250, 1180, 1109, 1032, 947, 854, 812, 750, 692 cm-1. HRMS (APCI, m/z): calcd for C9H7BrF2O3
[M]+ 279.9547, found 279.9536.
[1,1'-biphenyl]-4-yl 2-bromo-2,2-difluoroacetate (1f)
General procedure A was followed using 4-phenylphenol (5.10 g, 30.0 mmol), bromodifluoroacetic acid
(3.90 g, 20.0 mmol), oxalyl chloride (2.1 mL, 24 mmol), DMF (0.62 mL, 8.0 mmol) CH2Cl2 (0.060 L), and
Et3N (5.6 mL, 40 mmol). Instead of the work up described in General Procedure A, the reaction solvent was
evaporated, and the crude mixture was washed with hexanes (100 mL). Next, a second filtration in SiO2 (10%
of EtOAc in hexanes) was performed to provide the title compound as a white solid (5.5 g, 84%),
contaminated with ~6% of 4-phenylphenol (estimated by 1H-NMR).
mp: 90 – 92 ºC (decomp.). 1H NMR (CDCl3, 400 MHz)  7.66 (d, J = 8.7 Hz, 2H), 7.61 – 7.56 (m, 2H),
7.46 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H). 13C{1H} NMR (CDCl3, 126 MHz)
 158.1 (t, J = 32.0 Hz), 149.1, 140.7, 139.9, 129.1, 128.7, 127.9, 127.3, 120.9, 108.6 (t, J = 314.3 Hz). 19F
NMR (CDCl3, 376 MHz)  –61.6 (s, 2 F). IR (ATR) 3040, 1794, 1518, 1485, 1217, 1199, 1107, 933, 862,
758, 685 cm-1. HRMS (APCI, m/z): calcd for C14H9BrF2O2 [M]+ 325.9754, found 325.9748.
4-(trifluoromethyl)phenyl 2-bromo-2,2-difluoroacetate (1g)
General procedure A was followed using 4-trifluoromethylphenol (1.62 g, 10.0 mmol), bromodifluoroacetic
acid (2.10 g, 12.0 mmol), oxalyl chloride (950 μL, 11.0 mmol), DMF (0.31 mL, 4.0 mmol), CH2Cl2 (0.030
L), and Et3N (1.4 mL, 10 mmol). Workup and a fast filtration in SiO2 (10% of EtOAc in hexanes) provided
the title compound as a colorless oil (1.36 g, 43%).
1H NMR (CDCl3, 400 MHz)  7.74 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H). 13C{1H} NMR (CDCl3,
126 MHz)  157.6 (t, J = 32.7 Hz), 152.0, 129.9 (q, J = 33.5 Hz), 127.5 (q, J = 3.6 Hz), 123.7 (q, J = 272.2
Hz), 121.3, 115.6, 108.3 (t, J = 314.3 Hz). 19F NMR (CDCl3, 376 MHz)  –61.9 (s, 2 F), –63.0 (s, 3 F). IR
(ATR) 1792, 1612, 1510, 1417, 1323, 1279, 1201, 1165, 1105, 1064, 1018, 941, 866, 812, 704 cm-1. HRMS
(APCI, m/z): calcd for C9H4BrF5O2 [M]+ 317.9315, found 317.9312.
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2,6-dimethylphenyl 2-bromo-2,2-difluoroacetate (1h)
General procedure A was followed using 2,6-dimethylphenol (1.83 g, 15.0 mmol), bromodifluoroacetic acid
(1.93 g, 11.0 mmol), oxalyl chloride (1.0 mL, 12 mmol), DMF (0.31 mL, 4.0 mmol) CH2Cl2 (0.030 L), and
Et3N (2.8 mL, 20 mmol). Workup and chromatographic purification (100% hexanes) provided the title
compound as a colorless oil (1.6 g, 52%).
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1H NMR (400 MHz, CDCl3) δ 7.16 – 7.08 (m, 3H), 2.22 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 198.5
(t, J = 31.88 Hz), 188.0, 171.0, 170.3, 168.3, 149.6 (t, J = 314.04 Hz), 57.2. 19F NMR (CDCl3, 376 MHz)
 –60.9 (s, 2 F). IR (ATR) 3047, 2927, 1786, 1475, 1286, 1167, 1147, 1111, 945, 841, 770, 700 cm-1.
HRMS (APCI, m/z): calcd for C10H9BrF2O2 [M]+ 277.9754, found 277.9743.
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S-phenyl 2-bromo-2,2-difluoroethanethioate (1i)
General procedure A was followed using 4-methoxyphenol (1.10 g, 10.0 mmol), bromodifluoroacetic acid
(2.10 g, 12.0 mmol), oxalyl chloride (950 μL, 11.0 mmol), DMF (0.31 mL, 4.0 mmol) CH2Cl2 (0.030 L),
and Et3N (1.7 mL, 12 mmol). Workup and chromatographic purification (100% hexanes) provided the title
compound as a colorless oil (0.4 g, 16%).
1H NMR (400 MHz, CDCl3) δ 7.67 – 7.39 (m, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 185.6 (t, J = 30.8
Hz), 134.8, 130.9, 130.0, 123.8, 113.2, (t, J = 319.7 Hz). 19F NMR (CDCl3, 376 MHz)  –59.5 (s, 2 F). IR
(ATR) 3065, 1712, 1479, 1442, 1192, 1144, 979, 815, 744, 687 cm-1. HRMS (APCI, m/z): calcd for
C8H5BrF2OS [M]+ 265.9213, found 265.9207.
2-bromo-2,2-difluoro-N-phenyl-N-tosylacetamide (1j)
General procedure A was followed using N-p-toluenesulfonylaniline18 (0.54 g, 2.2 mmol),
bromodifluoroacetic acid (0.35 g, 2.0 mmol), oxalyl chloride (0.18 mL, 2.1 mmol), DMF (5.0 μL, 0.1 mmol)
CH2Cl2 (4.0 mL), and Et3N (0.39 mL, 2.8 mmol). Workup and chromatographic purification (20% EtOAc
in hexanes) provided the title compound as a white solid (0.35 g, 43%).
mp: 136 – 138 ºC. 1H NMR (CDCl3, 400 MHz)  7.9 (d, J = 8.39 Hz, 2H), 7.6 – 7.5 (m, 1H), 7.5 – 7.4 (m,
13
2H), 7.4 (d, J = 8.66 Hz, 2H), 7.3 (d, J = 7.65 Hz, 2H), 2.5 (s, 3H). C{1H} NMR (CDCl3, 126 MHz) 
157.9 (t, J = 28.19 Hz), 146.4, 134.3, 133.4, 131.1, 131.0, 129.9, 129.9, 129.4, 110.6 (t, J = 319.13 Hz),
19
22.0. F NMR (CDCl3, 376 MHz)  –54.5 (s, 2 F). IR (ATR) 1720, 1361, 1166, 1117, 1084, 883, 398,
671, 572, 543 cm-1. HRMS (ESI, m/z): calcd for C15H12BrF2NO3S [M+Na]+ 425.9587, found 425.9557.
Initial Screening and Optimization of Reaction Conditions
Additive Screening Experiment
Experimental Procedure: A 1 dram vial sealed with PTFE septum under N2 was charged with cinnamyl
bromodifluoroacetate (3a) (58 mg, 0.20 mmol), KF (17 mg, 0.30 mmol), additive (0.20 mmol), DMF (0.10
mL), and a magnetic stir bar. The vial was placed on a pre-heated reaction block at 50 ºC, and an aliquot of
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the “Stock Solution of Activated Catalyst” (see infra) (0.10 mL) was transferred to the vial via syringe.
After heating at 50 ºC for 14 h, the vial was removed from the heating block and cooled to room temperature.
Next, the reaction mixture was diluted with EtOAc (2 mL), and dodecane (45 µL, 0.20 mmol) was injected
as an internal standard, and the reaction mixture was stirred at room temperature for 10 minutes to ensure
thorough mixing. An aliquot was taken from the vial, analyzed by GC-FID, and quantified using a standard
curve. Results are reported based on GC-FID yields.
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Experimental Procedure for the Preparation of “Stock Solution of Activated Catalyst”: CuI (57 mg, 0.30
mmol), NaO2CCF2Br (0.15 g, 0.75 mmol) and KF (87 mg, 1.5 mmol) were added to a 10 mL round bottom
flask. The flask was attached to a Schlenk line and evacuated and backfilled with N2 (3x). DMF (1.5 mL)
was injected and the mixture was heated in an oil bath at 50 °C for 10 min.
General Optimization
General Procedure B:
A 1 dram vial was charged with CuI (1.9 mg, 0.010 mmol), KF (12 mg, 0.20 mmol), DMEDA (1.2 µL,
0.011 mmol), 0.10 mL of a freshly prepared solution of bromodifluoroacetic acid (8.8 mg, 0.050 mmol) in
DMF (0.2 mL, final concentration = 0.25 mol L-1), and a magnetic stir bar. The reaction mixture was stirred
for 2–5 min at room temperate until a blue/purple suspension formed, and at 50 ºC until the color changed
to light yellow (~10 min). Next, the allylic alcohol (0.100 mmol) and phenyl bromodifluoroacetate (50.1
mg, 0.200 mmol) were dissolved in 0.1 mL of the bromodifluoroacetic solution in DMF, and the resulting
solution was added to the reaction. Subsequently, the reaction vial was sealed with a PTFE-lined screw cap,
and transferred out of the glove box. The sealed vial was placed on a pre-heated reaction block at 25 ºC and
stirred for 24–48 h. Next, the reaction mixture was diluted with EtOAc (~3.0 mL), and 0.100 mmol
naphthalene was added an internal standard, and the reaction mixture was stirred at room temperature for
10 minutes to ensure thorough mixing. An aliquot (130–150 μL) was taken from the vial, analyzed by GC-
FID, and quantified using a standard curve. Results are reported based on GC-FID yields. Alternatively (or
to double-check results), α,α,α-trifluorotoluene (12.3 µL, 0.100 mmol) was added as an internal standard,
and the reaction mixture was stirred at room temperature for 5 minutes to ensure thorough mixing. An
aliquot was taken from the vial for 19F NMR analysis. Results are reported based on 19F NMR yields.
Experimental Details and Characterization of Trifluoromethyl Compounds
Allyl Trifluoromethanes (Table 2)
General Procedure C:
A 1 dram vial was charged with CuI (9.5 mg, 0.050 mmol), KF (58 mg, 1.0 mmol), DMEDA (5.9 µL, 0.055
mmol), 0.30 mL of a freshly prepared solution of bromodifluoroacetic acid (44 mg, 0.25 mmol) in DMF
(1.00 mL, final concentration = 0.25 mol L-1), and a magnetic stir bar. The reaction mixture was stirred for
2–5 min at room temperate until a blue/purple suspension formed, and at 50 ºC until the color changed to
light yellow (~10 min). Next, the allylic alcohol (0.500 mmol) and phenyl bromodifluoroacetate (251 mg,
1.00 mmol) were dissolved in 0.70 mL of the bromodifluoroacetic acid solution in DMF, and the resulting
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solution was added to the reaction. Subsequently, the reaction vial was sealed with a PTFE-lined screw cap,
and transferred out of the glove box. The sealed vial was placed on a pre-heated reaction block at 25 ºC and
stirred for 36–48 h. Next, the reaction mixture was diluted with Et2O (~3.0 mL). α,α,α-Trifluorotoluene (30
µL, 0.25 mmol) was added as an internal standard, and the reaction mixture was stirred at room temperature
for 10 minutes to ensure thorough mixing. An aliquot was taken from the vial for 19F NMR analysis. After
determining the 19F NMR yield, the aliquot was recombined with the reaction mixture. Work up (Method
A or B, see Note 1 below) and purification of the crude mixture through flash column chromatography
provided the desired product (see Note 2).
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Note 1: Two methods for the isolation of the products were used:
Method A: The crude reaction was further diluted with 50 mL of Et2O, and sequentially washed with H2O
(3 x 10 mL), 1M NaOH (2 x 5 mL), H2O (1 x 10 mL) and NaCl(sat) (1 x 10 mL). The organic phase was
dried over Na2SO4, filtered and concentrated under reduced pressure (see Note 2).
Method B: Some non-polar products co-eluted with phenyl bromodifluoroacetate during the
chromatographic purification and required an alternative isolation procedure. The crude reaction was diluted
with THF (10 mL), 1M NaOH (0.5 mL) was added, and the mixture was stirred for 2 h at room temperature.
Next, the crude reaction was further diluted with 50 mL of Et2O, and sequentially washed with H2O (3 x 10
mL) and NaCl(sat) (1 x 10 mL). The organic phase was dried over Na2SO4, filtered and concentrated under
reduced pressure (see Note 2).
Note 2: Extra care was taken to isolate products of lower molecular weight due to volatility. For NMR
analysis of the crude reaction mixture, work up and purification using low boiling point solvents was
preferred (Et2O, CH2Cl2 or pentane). Solvent evaporation was done under pressure of ~60–100 Torr and
water-bath at 15–25 ºC.
(E)-(4,4,4-trifluorobut-1-en-1-yl)benzene (4a)
General procedure C was followed using (E)-3-phenylprop-2-en-1-ol (2a) (0.67 g, 5.0 mmol), phenyl
bromodifluoroacetate (1d) (2.5 g, 10 mmol), CuI (95 mg, 0.50 mmol), DMEDA (59 μL, 0.55 mmol),
bromodifluoroacetic acid (0.44 g, 2.5 mmol), KF (0.58 g, 10 mmol) and DMF (10.0 mL). The reaction was
stirred for 38 h. Work up according to Method A, except for the washing with 1M NaOH. Chromatographic
purification (pentane) afforded the title compound as a colorless oil (0.70 g, 75%) containing residual
CH2Cl2 (~0.14 g, estimated by 1H-NMR). Spectroscopic data agreed with the previous report.20
(E)-1-methoxy-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (4b)
General procedure C was followed using (E)-3-(4-methoxyphenyl)prop-2-en-1-ol (2b) (82 mg, 0.50 mmol),
phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), DMEDA (5.9 μL, 0.055
mmol), bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The
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reaction was stirred for 44 h. Work up (Method A) and chromatographic purification (0–5% Et2O in pentane)
afforded the title compound as a colorless oil (85 mg, 78%). Spectroscopic data agreed with the previous
report.8a
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(E)-1-nitro-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (4c)
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General procedure C was followed using (E)-3-(4-nitrophenyl)prop-2-en-1-ol (2c) (90 mg, 0.50 mmol),
phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), DMEDA (5.9 μL, 0.055
mmol), bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The
reaction was stirred for 39 h. Work up (Method A) and chromatographic purification (0–10% EtOAc in
hexanes) afforded the title compound as a yellow solid (83 mg, 72%). Spectroscopic data agreed with the
previous report.8a
(E)-1-fluoro-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (4d)
General procedure C was followed using (E)-3-(4-fluorophenyl)prop-2-en-1-ol8a (2d) (76 mg, 0.50 mmol
phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), DMEDA (5.9 μL, 0.055
mmol), bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The
reaction was stirred for 44 h. Work up (Method A) and chromatographic purification (pentane) afforded the
title compound as a colorless oil (66 mg, 64%). Spectroscopic data agreed with the previous report.8a
(E)-1-bromo-3-(4,4,4-trifluorobut-1-en-1-yl)benzene (4e)
General procedure C was followed using (E)-3-(3-bromophenyl)prop-2-en-1-ol8a (2e) (106 mg, 0.50 mmol),
phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), DMEDA (5.9 μL, 0.055
mmol), bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The
reaction was stirred for 44 h. Work up according to Method A, except for the washing with 1M NaOH.
Chromatographic purification (pentane) afforded the title compound as a colorless oil (81 mg, 61%).
Spectroscopic data agreed with the previous report.8a
(E)-(((5,5,5-trifluoropent-2-en-1-yl)oxy)methyl)benzene (4f)
General procedure C was followed using (Z)-4-(benzyloxy)but-2-en-1-ol (2f) (89 mg, 0.50 mmol), phenyl
bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), DMEDA (5.9 μL, 0.055 mmol),
bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The reaction was
stirred for 41 h. Work up (Method A) and chromatographic purification (0–5% Et2O in pentane or 0–5%
EtOAc in hexanes) afforded the title compound as a colorless oil (94 mg, 81%). Spectroscopic data agreed
with the previous report.8a
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1-(2,2,2-Trifluoroethyl)cyclopent-1-ene (4g)
General procedure C was followed using cyclopent-1-en-1-ylmethanol (2g) (49 mg, 0.50 mmol), phenyl
bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), DMEDA (5.9 μL, 0.055 mmol),
bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The reaction was
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stirred for 37 h. The product was too volatile for isolation. The yield was determined by F-NMR using
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α,α,α-trifluorotoluene. The identity of the product was confirmed by GC-MS analysis.
19F NMR (CDCl3, 376 MHz)  –65.9 (t, J = 11.5 Hz, 3F). GC-MS 150 (15), 67 (100).
1-(2,2,2-Trifluoroethyl)cyclohex-1-ene
General procedure C was followed using cyclohex-1-en-1-ylmethanol (2h) (49 mg, 0.50 mmol), phenyl
bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), DMEDA (5.9 μL, 0.055 mmol),
bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The reaction was
stirred for 37 h. Product was too volatile for isolation. Yield determined by 19F-NMR using α,α,α-
trifluorotoluene. The identity of the product was confirmed by GC-MS analysis.
19F NMR (CDCl3, 376 MHz)  –65.9 (t, J = 11.2 Hz, 3F). GC-MS 164 (50), 149 (45), 136 (35), 81 (100),
67 (65).
4-(prop-1-en-2-yl)-1-(2,2,2-trifluoroethyl)cyclohex-1-ene (4i)
General procedure C was followed using perillyl alcohol (2i) (76 mg, 0.50 mmol), phenyl
bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), DMEDA (5.9 μL, 0.055 mmol),
bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The reaction was
stirred for 42 h. Work up (Method B) and chromatographic purification (pentane) afforded the title
compound as a colorless oil (58 mg, 57%). Spectroscopic data agreed with the previous report.21
Allenyl Trifluoromethanes (Table 3)
General Procedure D:
A 1 dram vial was charged with CuI (9.5 mg, 0.050 mmol), KF (58 mg, 1.0 mmol), 1,10-phenantroline (9.9
mg, 0.055 mmol), 0.30 mL of a freshly prepared solution of bromodifluoroacetic acid (44 mg, 0.25 mmol)
in DMF (1.00 mL, final concentration = 0.25 mol L-1), and a magnetic stir bar. The reaction mixture was
stirred for 2–5 min at room temperate until a blue/purple suspension formed, and at 50 ºC until the color
changed to light yellow (~10 min). Next, the propargylic alcohol (0.500 mmol) and phenyl
bromodifluoroacetate (251 mg, 1.00 mmol) were dissolved in 0.70 mL of the bromodifluoroacetic acid
solution in DMF, and the resulting solution was added to the reaction. Subsequently, the reaction vial was
sealed with a PTFE-lined screw cap, and transferred out of the glove box. The sealed vial was placed on a
pre-heated reaction block at 50 ºC and stirred for 24–38 h. Next, the reaction mixture was diluted with Et2O
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(~3.0 mL). α,α,α-Trifluorotoluene (30 µL, 0.25 mmol) was added as an internal standard, and the reaction
mixture was stirred at room temperature for 10 minutes to ensure thorough mixing. An aliquot was taken
from the vial for 19F NMR analysis. After determining the 19F NMR yield, the aliquot was recombined with
the reaction mixture. The crude reaction was further diluted with 50 mL of Et2O, and sequentially washed
with H2O (3 x 10 mL), 1M NaOH (2 x 5 mL), H2O (1 x 10 mL) and NaCl(sat) (1 x 10 mL). The organic phase
was dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the crude mixture
through flash column chromatography provided the desired product
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2-(1,1,1-trifluorobuta-2,3-dien-2-yl)naphthalene (6a)
General procedure D was followed using 3-(naphthalen-2-yl)prop-2-yn-1-ol8c (5a) (91 mg, 0.50 mmol),
phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), 1,10-phenantroline (9.9
mg, 0.055 mmol), bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0
mL). The reaction was stirred for 37 h at 50 ºC. Work up and chromatographic purification (pentane)
afforded the title compound as a colorless oil (82 mg, 69%). Spectroscopic data agreed with the previous
report.8c
1-Methoxy-4-nitro-2-(1,1,1-trifluorobuta-2,3-dien-2-yl)benzene (6b)
General procedure D was followed using methyl 3-(3-hydroxyprop-1-yn-1-yl)benzoate8c (5b) (104 mg,
0.500 mmol), phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), 1,10-
phenantroline (9.9 mg, 0.055 mmol), bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol)
and DMF (1.0 mL). The reaction was stirred for 37 h at 50 ºC. Work up and chromatographic purification
(0–10% EtOAc in hexanes) afforded the title compound as a yellow oil (85 mg, 66%). Spectroscopic data
agreed with the previous report.8c
Methyl 3-(3-hydroxyprop-1-yn-1-yl)benzoate (6c)
General procedure D was followed using methyl 3-(3-hydroxyprop-1-yn-1-yl)benzoate8c (5c) (190 mg, 1.00
mmol), phenyl bromodifluoroacetate (1d) (0.50 g, 2.0 mmol), CuI (19 mg, 0.10 mmol), 1,10-phenantroline
(20 mg, 0.11 mmol), bromodifluoroacetic acid (88 mg, 0.50 mmol), KF (116 mg, 2.0 mmol) and DMF (2.0
mL). The reaction was stirred for 24 h at 50 ºC. Work up and chromatographic purification (0–10% EtOAc
in hexanes) afforded the title compound as a yellow oil (180 mg, 70%). Spectroscopic data agreed with the
previous report.8c
tert-Butyl 2-(1,1,1-trifluorobuta-2,3-dien-2-yl)-1H-indole-1-carboxylate (6d)
General procedure D was followed using tert-butyl 2-(3-hydroxyprop-1-yn-1-yl)-1H-indole-1-carboxylate8c
(5d) (108 mg, 40 mmol), phenyl bromodifluoroacetate (1d) (0.20 g, 0.80 mmol), CuI (7.7 mg, 0.040 mmol),
1,10-phenantroline (7.9 mg, 0.088 mmol), bromodifluoroacetic acid (35 mg, 0.20 mmol), KF (46 mg, 0.8
mmol) and DMF (0.80 mL). The reaction was stirred for 24 h at 50 ºC. Work up and chromatographic
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purification (0–10% EtOAc in hexanes) afforded the title compound as a yellow oil (53 mg, 41%).
Spectroscopic data agreed with the previous report.8c
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2,2,2-Trifluoro-N-(4-(1,1,1-trifluorobuta-2,3-dien-2-yl)phenyl)acetamide (6e)
General
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yl)phenyl)acetamide8c (6e) (122 mg, 0.500 mmol), phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol),
CuI (9.5 mg, 0.050 mmol), 1,10-phenantroline (9.9 mg, 0.055 mmol), bromodifluoroacetic acid (44 mg,
0.50 mmol), KF (58 mg, 1.0 mmol) and DMF (1.0 mL). The reaction was stirred for 24 h at 50 ºC. Work up
and chromatographic purification (0–20% EtOAc in hexanes) afforded the title compound still contaminated
with ~10% of phenol. After washing with 1M NaOH (3 x 5 mL), the pure product was obtained as an off-
white solid (81 mg, 55%). Spectroscopic data agreed with the previous report.8c
1,2-dichloro-4-(1,1,1-trifluorobuta-2,3-dien-2-yl)benzene (6f)
General procedure D was followed using 3-(3,4-dichlorophenyl)prop-2-yn-1-ol8c (5f) (122 mg, 0.500
mmol), phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol), 1,10-
phenantroline (9.9 mg, 0.055 mmol), bromodifluoroacetic acid (44 mg, 0.50 mmol), KF (58 mg, 1.0 mmol)
and DMF (1.0 mL). The reaction was stirred for 24 h at 50 ºC. Work up and chromatographic purification
(0–20% EtOAc in hexanes) afforded the title compound still contaminated with ~10% of phenol. After
washing with 1M NaOH (3 x 5 mL), the pure product was obtained as a yellow solid (99 mg, 67%).
Spectroscopic data agreed with the previous report.8c
Benzyl Trifluoromethanes (Table 4)
General Procedure E:
A 1 dram vial was charged with CuI (19 mg, 0.10 mmol), KF (0.12 mg, 2.0 mmol), KI (21 mg, 0.12 mmol),
and a magnetic stir bar. Next, the benzylic alcohol (0.500 mmol) and phenyl bromodifluoroacetate (251 mg,
1.00 mmol) were dissolved in DMF (0.25 mL) and MeCN (0.25 mL), and the resulting solution was added
to the reaction. Subsequently, the reaction vial was sealed with a PTFE-lined screw cap, and transferred out
of the glove box. The sealed vial was placed on a pre-heated reaction block at 40 ºC and stirred for 30 min.
Next, it was transferred to a second pre-heated reaction block at 70 ºC and stirred for 24 h. Next, the reaction
was cooled to room temperature, and diluted with Et2O (~3.0 mL). α,α,α-Trifluorotoluene (30 µL, 0.25
mmol) was added as an internal standard, and the reaction mixture was stirred at room temperature for 10
minutes to ensure thorough mixing. An aliquot was taken from the vial for 19F NMR analysis. After
determining the 19F NMR yield, the aliquot was recombined with the reaction mixture. The crude reaction
was further diluted with 50 mL of Et2O, and sequentially washed with H2O (3 x 10 mL), 1M NaOH (2 x 5
mL) or Na2CO3 (3 x 5 mL), H2O (1 x 10 mL) and NaCl(sat) (1 x 10 mL). The organic phase was dried over
Na2SO4, filtered and concentrated under reduced pressure. Purification of the crude mixture through flash
column chromatography provided the desired product
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2-(2,2,2-trifluoroethyl)naphthalene (8a)
General procedure E was followed using naphthalen-2-ylmethanol (7a) (79 mg, 0.500 mmol), phenyl
bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (19 mg, 0.10 mmol), methyl bromodifluoroacetate (38
mg, 0.20 mmol), KI (21 mg, 0.12 mmol), KF (0.12 g, 2.0 mmol) DMF (0.25 mL) and MeCN (0.25 mL).
The reaction was stirred for 24 h at 70 ºC. Work up and chromatographic purification (pentane) afforded
the product as a white solid (78 mg, 74%). Spectroscopic data agreed with the previous report.8d
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1-(benzyloxy)-2-methoxy-4-(2,2,2-trifluoroethyl)benzene (8b)
General procedure E was followed using (4-(benzyloxy)-3-methoxyphenyl)methanol (7b) (123 mg, 0.500
mmol), phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (19 mg, 0.10 mmol), methyl
bromodifluoroacetate (38 mg, 0.20 mmol), KI (21 mg, 0.12 mmol), KF (0.12 g, 2.0 mmol) DMF (0.25 mL)
and MeCN (0.25 mL). The reaction was stirred for 24 h at 70 ºC. Work up and chromatographic purification
(0–10% EtOAc in hexanes) afforded the product as a white solid (93 mg, 62%). Spectroscopic data agreed
with the previous report.22
1-Tosyl-3-(2,2,2-trifluoroethyl)-1H-indole (8c)
General procedure E was followed using (1-tosyl-1H-indol-3-yl)methanol23 (7c) (301 mg, 1.00 mmol),
phenyl bromodifluoroacetate (1d) (0.50 g, 2.0 mmol), CuI (38 mg, 0.20 mmol), methyl
bromodifluoroacetate (76 mg, 0.40 mmol), KI (42 mg, 0.25 mmol), KF (232 mg, 4.0 mmol), DMF (0.50
mL) and MeCN (0.50 mL). The reaction was stirred for 24 h at 70 ºC. Work up and chromatographic
purification (0–5% EtOAc in hexanes) afforded the product as a white solid (217 mg, 61%). Spectroscopic
data agreed with the previous report.24
(1-phenyl-1H-pyrazol-4-yl)methanol (8d)
General procedure E was followed using (1-phenyl-1H-pyrazol-4-yl)methanol8d (7d) (87 mg, 0.50 mmol),
phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (19 mg, 0.10 mmol), methyl
bromodifluoroacetate (38 mg, 0.20 mmol), KI (21 mg, 0.12 mmol), KF (0.12 g, 2.0 mmol), DMF (0.25 mL)
and MeCN (0.25 mL). Work up and chromatographic purification (10% EtOAc in hexanes) afforded the
title compound as a white solid (43 mg, 39%). Spectroscopic data agreed with the previous report 8d
1-Methyl-3-(2,2,2-trifluoroethyl)-1H-indazole (8e)
General procedure E was followed using (1-methyl-1H-indazol-3-yl)methanol19 (7e) (81 mg, 0.50 mmol),
phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (19 mg, 0.10 mmol), methyl
bromodifluoroacetate (38 mg, 0.20 mmol), KI (21 mg, 0.12 mmol), KF (0.12 g, 2.0 mmol), DMF (0.25 mL)
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and MeCN (0.25 mL). Work up and chromatographic purification (10% EtOAc in hexanes) afforded the
title compound as a light-yellow solid (43 mg, 39%).
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mp: 61 – 63 ºC. 1H NMR (CDCl3, 400 MHz)  7.71 (d, J = 8.2 Hz, 1H), 7.46 – 7.37 (m, 2H), 7.24 – 7.16
(m, 1H), 4.07 (s, 3H), 3.79 (q, J = 10.69 Hz, 2H). 13C{1H} NMR (CDCl3, 126 MHz)  141.1, 134.27 (q, J
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= 3.5 Hz), 126.7, 125.15 (q, J = 276.4 Hz), 123.2, 121.0, 120.3, 109.3, 35.6, 32.97 (q, J = 31.5 Hz). F
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NMR (CDCl3, 376 MHz)  –65.4 (t, J = 10.6 Hz). IR (ATR) 3065, 2978, 2939, 2854, 1618, 1504, 1348,
1256, 1092, 918, 736 cm-1. HRMS (ESI, m/z): calcd for C10H10F3N2 [M+H]+ 215.0796, found 215.0793.
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Synthetic Applications (Scheme 1)
(E)-1-(methylsulfonyl)-4-(4,4,4-trifluoro-2-methylbut-1-en-1-yl)benzene (10)
General procedure C was followed using (E)-2-methyl-3-(4-(methylsulfonyl)phenyl)prop-2-en-1-ol (9),11
(113 mg, 0.500 mmol), phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (9.5 mg, 0.050 mmol),
DMEDA (5.9 μL, 0.055 mmol), bromodifluoroacetic acid (44 mg, 0.25 mmol), KF (58 mg, 1.0 mmol) and
DMF (1.0 mL). The reaction was stirred for 44 h. Work up and chromatographic purification (0–30% EtOAc
in hexanes) afforded the title compound as a colorless oil (105 mg, 75%). Spectroscopic data agreed with
the previous report.11b
5-(furan-2-yl)-1-methyl-3-(2,2,2-trifluoroethyl)-1H-pyrazole (12)
General procedure E was followed using (5-(furan-2-yl)-1-methyl-1H-pyrazol-3-yl)methanol12a (11) (89
mg, 0.500 mmol), phenyl bromodifluoroacetate (1d) (0.25 g, 1.0 mmol), CuI (19 mg, 0.10 mmol), methyl
bromodifluoroacetate (38 mg, 0.20 mmol), KI (21 mg, 0.12 mmol), KF (0.12 g, 2.0 mmol), DMF (0.25 mL)
and MeCN (0.25 mL). Work up according to General Procedure E was done using Na2CO3 (3 x 5 mL),
because a decrease in the yield to 43% was observed when 1M NaOH was used. Chromatographic
purification (0–30% EtOAc in hexanes) afforded the title compound as a light yellow oil (67 mg, 57%).
Spectroscopic data agreed with the previous report.8d, 12a
Stability of the Phenyl Bromodifluoroacetate (1d)
The stability of phenyl bromodifluoroacetate (1d) was tested by storing it in 1-dram vials sealed with a
PTFE-lined screw cap under three distinct conditions, namely 1) on the bench, 2) in a desiccator, and 3) in
the freezer. The stability of the compound was evaluated by 1H- and 19F-NMR analysis (Figure S1 and S2),
as well as the deoxytrifluoromethylation reaction of cinnamyl alcohol (2a) (Scheme S1). The compound
was stable in all situations and showed no signs of decomposition by NMR. The reaction yields decreased
as the reagent aged. However, the reaction yields were still satisfactory even after 6–8 months. During this
work, the only decomposition pathway observed was the hydrolysis of the compound not properly protected
against residual moisture. No light sensitivity was observed.
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Mechanistic Experiments (Scheme 2)
Stability of Phenyl Bromodifluoroacetate (1d) Under Reaction Conditions
In the absence of alcohol, phenyl bromodifluoroacetate (1d) did not decompose when it was submitted to
the standard reaction conditions, with either DMEDA or Phen as ligands. Test reactions were setup
according to the General Procedure C (or D, if ligand was Phen), but the alcohol was not added. Both
reactions were stirred at 50 ºC for 24 hours, and then analyzed by 19F-NMR using α,α,α-trifluorotoluene as
standard.
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Study of the Formation of Putative “Active Ester Intermediate” In Situ
Experimental Procedure for Addition of KF in the Presence of BDFA: Inside the glovebox, a 1 dram vial
was charged with the cinnamyl alcohol (2a) (67 mg, 0.50 mmol) and phenyl bromodifluoroacetate (1d) (251
mg, 1.00 mmol), naphthalene (12.8 mg, 0.100 mmol), 1.00 mL of a freshly prepared solution of
bromodifluoroacetic acid (44 mg, 0.25 mmol) in DMF (1.00 mL, final concentration = 0.25 mol L-1), and a
magnetic stir bar. The reaction mixture was stirred for 60 min at 25 ºC. Next, KF (58 mg, 1.0 mmol) was
added, and the reaction mixture was kept stirring at 25 ºC. During the whole experiment, 50 µL aliquots
were taken every 15-25 min and quenched with a few drops of Et2O. The samples were analyzed using GC-
FID, and standard curves were used to calculated amount of each reaction component as a function of time.
Experimental Procedure for Addition of KF in the Absence of BDFA: Inside the glovebox, a 1 dram vial
was charged with the cinnamyl alcohol (2a) (67 mg, 0.50 mmol) and phenyl bromodifluoroacetate (1d) (251
mg, 1.00 mmol), naphthalene (12.8 mg, 0.100 mmol), 1.00 mL of DMF (1.00 mL, final concentration =
0.25 mol L-1), and a magnetic stir bar. The reaction mixture was stirred for 45 min at 25 ºC. Next, KF (58
mg, 1.0 mmol) was added, and the reaction mixture was kept stirring for another 60 min at 25 ºC. Next,
bromodifluoroacetic acid (44 mg, 0.25 mmol) was added, and the reaction mixture was kept stirring at 25
ºC. During the whole experiment, 50 µL aliquots were taken every 15–25 min and quenched with a few
drops of Et2O. The samples were analyzed using GC-FID, and standard curves were used to calculated
amount of each reaction component as a function of time.
Time-Course Analysis of the Reaction
Experimental Procedure: Inside the glovebox, deoxytrifluoromethylation reaction of cinnamyl alcohol 2a
was prepared according General Procedure C. Naphthalene (12.8 mg, 0.100 mmol) was used as the internal
standard. During the whole experiment, 50 µL aliquots were taken every 15–60 min and quenched with a
few drops of Et2O. The samples were analyzed using GC-FID, and standard curves were used to calculate
the amount of each reaction component as a function of time.
ASSOCIATED CONTENT
Supporting Information. Supplementary experiments and copy of NMR spectra.
AUTHOR INFORMATION
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Corresponding Author *E-mail: raaltman@ku.edu.
Present Address
$ Department of Chemistry, KU Leuven, Leuven (Heverlee), 3001, Belgium
# Department of Chemistry, University of Texas at Austin, Austin, Texas 78703, United States
The authors declare no competing financial interest.
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ORCID
Ryan A. Altman: 0000-0002-8724-1098
Francisco de Azambuja: 0000-0002-5537-5411
Patrick Ross: 0000-0003-1264-2273
ACKNOWLEDGMENTS
We thank the donors of the Herman Frasch Foundation for Chemical Research (701-HF12), the National
Science Foundation (CHE-1455163) for supporting this work. B.R.A. thanks the NIGMS Training Grant
on Dynamic Aspects of Chemical Biology (T32 GM08545) for a graduate traineeship. NMR
Instrumentation was provided by NIH Shared Instrumentation Grants S10OD016360 and S10RR024664,
NSF Major Research Instrumentation Grants 9977422 and 0320648, and NIH Center Grant P20GM103418.
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