Chemoselective desulfurization-fluorination/bromination of carbonofluoridothioates for the O-trifluoromethylation and O-bromodifluoromethylation of alcohols

Article abstract of DOI:10.1007/s11426-021-1028-6

Herein, a method for synthesizing various alkyl trifluoromethyl and alkyl bromodifluoromethyl ethers using carbonofluoridothioates (R–OC(=S)F) as precursors has been described. Carbonofluoridothioates were obtained upon the reaction of an alcohol and S=CF₂ generated via the decomposition of an SCF₃ anion, and then selectively transformed into their corresponding trifluoromethyl and bromodifluoromethyl ethers upon changing the reaction conditions. This transformation has also been extended to the one-pot, two-step conversion of alcohols into alkyl trifluoromethyl ethers. A series of alkyl bromodifluoromethyl ethers has also been synthesized. These compounds open up a new avenue for the synthesis of a wide range of useful fluorinated products. In addition, this method is suitable for the late-stage introduction of trifluoromethyl ethers in complex small molecules. [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11426-021-1028-6

SCIENCE CHINA
Chemistry
•ARTICLES•
August 2021 Vol.64 No.8: 1372–1379
https://doi.org/10.1007/s11426-021-1028-6
Chemoselective desulfurization-fluorination/bromination of
carbonofluoridothioates for the O-trifluoromethylation and
O-bromodifluoromethylation of alcohols
Jie Liu1, Haonan Xiang1, Lvqi Jiang1* & Wenbin Yi1,2*
1School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China;
2Key Laboratory of Organofluorine Chemistry, Shanghai Institute Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received February 24, 2021; accepted May 24, 2021; published online July 13, 2021
Herein, a method for synthesizing various alkyl trifluoromethyl and alkyl bromodifluoromethyl ethers using carbono-
fluoridothioates (R–OC(=S)F) as precursors has been described. Carbonofluoridothioates were obtained upon the reaction of an
alcohol and S=CF2 generated via the decomposition of an SCF3 anion, and then selectively transformed into their corresponding
trifluoromethyl and bromodifluoromethyl ethers upon changing the reaction conditions. This transformation has also been
extended to the one-pot, two-step conversion of alcohols into alkyl trifluoromethyl ethers. A series of alkyl bromodifluoromethyl
ethers has also been synthesized. These compounds open up a new avenue for the synthesis of a wide range of useful fluorinated
products. In addition, this method is suitable for the late-stage introduction of trifluoromethyl ethers in complex small molecules.
carbonofluoridothioates, trifluoromethyl ethers, bromodifluoromethyl ethers, fluorination, alkyl
Citation:
Liu J, Xiang H, Jiang L, Yi W. Chemoselective desulfurization-fluorination/bromination of carbonofluoridothioates for the O-trifluoromethylation and
O-bromodifluoromethylation of alcohols. Sci China Chem, 2021, 64: 1372–1379, https://doi.org/10.1007/s11426-021-1028-6
1 Introduction
decomposition of trifluoromethoxide anions [15]. Therefore,
the development of an efficient synthesis of CF3O-contain-
ing compounds is highly desirable.
Substitution reactions that involve fluorine are crucial in
drug discovery and development because fluorine can
change the physicochemical properties of drug candidates
[1–7]. Among the fluorine-containing functional groups re-
ported to date, the trifluoromethoxy (–OCF3) group is be-
coming an increasingly common structural motif in
pharmaceutical agents because of its unique structural and
electronic properties. Many CF3O-containing compounds are
vital because they exhibit high lipophilicity and often show
enhanced in vivo uptake and transport in biological systems
[8–14]. However, few methods are used to prepare tri-
fluoromethyl ethers due to the limited number of tri-
fluoromethoxylation reagents available and the reversible
Over the past few decades, methods involving direct in-
troduction of an –OCF3 group have been developed. How-
ever, these approaches require stable CF3O-donor reagents,
which are challenging to be synthesized [16–25]. The tra-
ditional synthesis of trifluoromethyl ethers typically involves
the nucleophilic substitution of their corresponding tri-
chloromethyl ethers with fluoride [26–30]. Subsequently, the
deoxyfluorination of fluoroformates (Scheme 1a) [31,32]
and oxidative fluorodesulfurization of S-chlorine [33,34]/
methyl carbonodithioates [9,35–38] are the most widely used
procedures found in the literature (Scheme 1b, c). In addi-
tion, the preparation of fluoroformates (R–OC(=O)F) [31,32]
and carbonochloridothioates (R–OC(=S)Cl) [33,34] requires
harsh reaction conditions. The synthesis of xanthates (R–
*Corresponding authors (email: yiwb@njust.edu.cn; lvqi.jiang@njust.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021
chem.scichina.com link.springer.com

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Liu et al. Sci China Chem August (2021) Vol.64 No.8
Scheme 1 Indirect methods used to introduce the CF3O-group (color online).
OC(=S)SMe) [9,35–38] typically uses a two-step protocol
consisting of deprotonation, followed by alkylation with CS2
and MeI. These reactions are highly sensitive to the steric
and electronic properties of the substrates. Scheme 1 shows
that each traditional method has at least one major limitation
in terms of substrate scope, reaction conditions, precursor
synthesis, and the use of toxic reagents. Notably, most of
these synthetic methods have focused on the introduction of
a trifluoromethoxy group onto an aromatic substrate. The
introduction of a CF3O-group in unactivated alkyl alcohols
has rarely been reported and represents a significant chal-
lenge in this field.
Herein, we report a new method for synthesizing alkyl
trifluoromethyl ethers using carbonofluoridothioates (R–
OC(=S)F) as precursors, which can be simply obtained upon
the reaction of an alcohol with AgSCF3/KI [39]. This method
was conducted under mild reaction conditions. In addition,
the substrate scope was significantly increased compared
with the traditional methods. Surprisingly, both alkyl tri-
fluoromethyl and alkyl bromodifluoromethyl ethers can be
prepared in a highly regioselective manner upon simply
changing the reaction conditions. Moreover, we have also
demonstrated a one-pot method to synthesize alkyl tri-
fluoromethyl ethers, which can be applied to a variety of
biologically active substrates.
anions, which forms thiocarbonyl fluoride and fluoride anion
(Scheme 2a) [40–44], Qing and co-workers [39] reported
that treating an alcohol with AgSCF3 and KI led to the for-
mation of an R–OC(=S)F intermediate (2) (Scheme 2b). The
–OC(=S)F group is a good leaving group, which is suscep-
tible to nucleophilic attack. Qing et al. [39] and Xiao et al.
[45] reported the dehydroxytrifluoromethylthiolation of al-
cohols via R–OC(=S)F. However, the direct synthesis of
trifluoromethyl ethers from R–OC(=S)F via fluorination has
not been reported. Inspired by these studies on desulfuriza-
tion–fluorination [9,35–38], we propose that alkyl trifluoro-
methyl ethers can also be formed from carbono-
fluoridothioates. A positive halogen species (X+) will in-
itially attack the sulfur atom in R–OC(=S)F to activate the
C=S double bond, followed by nucleophilic fluorination by
the fluoride species to yield the corresponding tri-
fluoromethyl ether (Scheme 2c).
2 Results and discussion
Initially, O-(5-phenylpentyl) carbonofluoridothioate (2a)
was chosen as a model substrate to optimize the reaction
conditions. According to our reaction design, various fluor-
ide sources and positive halogen species were evaluated in
the reaction (Table 1, entries 1–9). The TBAH2F3 and NBL8
Due to the reversible decomposition of trifluoromethylthio

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Liu et al. Sci China Chem August (2021) Vol.64 No.8
Scheme 2 Reaction design (color online).
system was found to be better than the other systems studied
with 3a obtained in 45% yield (Table 1, entry 9). However,
the alkyl bromide was obtained as the major by-product and
a small amount of bromodifluoromethyl ether 4a was also
observed. To increase the yield of 3a, we investigated the use
of some additives (Table 1, entries 10 and 11). To our delight,
the yield of 3a was improved to 72% when conducting the
reaction in the presence of AgF, which may be beneficial for
removing the Br− as well as further increasing the con-
centration of F− [46]. Different reaction solvents were then
screened to improve the reaction efficiency and non-polar
aprotic solvents proved to be better in the reaction (Table 1,
entries 12–15). Among them, 1,2-dichloroethane (DCE)
exhibited the best performance giving the desired product in
85% yield (entry 12).
We compared the reactivity observed during the fluorina-
tion of 2a with TBAH2F3 and various oxidants with tradi-
tional precursors used to prepare trifluoromethyl ethers.
Table 1 (entries 16–18) shows our results were comparable to
their analogous reactions using traditional precursors, such
as –OC(=O)F, –OC(=S)SMe, and –OC(=S)Cl, which gen-
erally afforded lower yields than –OC(=S)F.
With the optimized reaction conditions in hand, we then
investigated the substrate scope in the reaction of primary
carbonofluoridothioates using the TBAH2F3/NBL8 system
(Scheme 3). Various alkyl carbonofluoridothioates were
successfully converted into their corresponding tri-
fluoromethyl ethers in moderate to good yield (3a–3m).
Substrates bearing aryl groups with both electron-donating
and electron-withdrawing substituents were successfully
used in the reaction. A wide range of functional groups in-
cluding ethoxy, aryl, tert-butyl, fluoro, chloro, bromo, and
iodo was tolerated in the reaction. Among them, the
–OC(=S)F group in long-chain alkyl carbonofluoridothioates
(2a, 2l, and 2m) exhibited better stability, which led to better
product yields. Multi-ring compounds including anthracene
(2j) and naphthalene (2k) were also good substrates and
exhibited good product yield.
Scheme 3 Synthesis of alkyl trifluoromethyl ethers using carbono-
fluoridothioates. Reaction conditions: 2(0.5 mmol), TBAH2F3 (5.0 equiv.),
NBL8 (4.0 equiv.), AgF (2.5 equiv.), dry DCE (3.0 mL), N2 atmosphere,
4 h, room temperature. All yields are those of the isolated product (color
online).
The small amount of R–OCF2Br product observed during
our optimization study (Table 1) aroused our interest. The
known approaches used to prepare R–OCF2Br compounds
include the pioneering work by Wakselman et al. [47], which
uses toxic difluorodibromomethane and a variety of phenol
precursors. Later, Gouverneur and co-workers [48] reported
the preparation of aryl-OCF2Br precursors from phenols
under harsh conditions using a multi-step synthesis. How-
ever, no method for the synthesis of alkyl bromodi-
fluoromethyl ethers has been reported to date to the best of
our knowledge. Considering the significance of the –OCF2Br
group in medicinal chemistry, we have successfully achieved
the selective bromodifluoromethoxylation of an alkane under
mild reaction conditions. Subsequently, we examined a range
of solvents, additives, and the ratio of the fluorinating re-
agent and oxidant to improve the conversion efficiency (for
details, see Supporting Information online). The reactions
conducted in acetonitrile gave higher product yields com-
pared with the other solvents studied, which may be due to
the solvent effect increasing the nucleophilicity of Br−. The
amount of TBAH2F3 and NBL8 used in the reaction was
crucial to achieving an efficient transformation. When an
additional bromine source was added, the primary carbono-
fluoridothioate was transformed into its corresponding alkyl
bromodifluoromethyl ether (4a) in 44% yield. The reaction
was slightly temperature-sensitive with the highest yield
(56%) obtained at 0 °C (entry 19).
Subsequently, we turned our attention to extending the
substrate scope in the reaction. Scheme 4 shows the sub-
strates that participate in the O-trifluoromethylation reaction

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Liu et al. Sci China Chem August (2021) Vol.64 No.8
Table 1 Optimization of the reaction conditions
Yield d) (%)
c)
Entry
F– source (equiv.)
Oxidant (equiv.)
Additive
Solvent
3a
n.d.
10
n.d.
25
20
15
15
40
45
72
50
85
20
25
75
n.d.
15
17
3
4a
n.d.
n.d.
n.d.
5
1
2
DAST(5)
none
none
none
none
none
none
none
none
none
none
AgF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
HF/Py(40)
NBS(4)
none
3
BAST(5)
4
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(5)
TBAH2F3(2)
NBS(4)
NCS(4)
NIS(4)
5
n.d
n.d
7
6
7
DBH(4)
NBL5(4)
NBL8(4)
NBL8(4)
NBL8(4)
NBL8(4)
NBL8(4)
NBL8(4)
NBL8(4)
NBL8(4)
NBL8(4)
NBL8(4)
NBL8(4)
8
5
9
5
10
11
12
13
14
15
Trace
5
KHF2
AgF
Trace
9
AgF
MeCN
THF
AgF
7
AgF
Hexane
DCE
Trace
n.d.
n.d.
n.d.
56
e)
16
AgF
f)
17
AgF
DCE
g)
18
AgF
DCE
h)
19
TBABr3
MeCN
a) Preparation of 2a: 1-naphthaleneethanol 1a (0.5 mmol) was reacted with AgSCF3 (1.5 equiv.) and KI (2.0 equiv.) in dry DCE (3.0 mL) at room
temperature under N2 atmosphere for 10 h. b) Reaction conditions: 2a (0.2 mmol), F– source (5.0 equiv.), oxidant (4.0 equiv.), additive (2.5 equiv.), solvent
(2.0 mL), N2 atmosphere, rt, 4 h. c) BAST=bis(2-methoxyethyl)aminosulfur trifluoride; TBAH2F3=tetra-n-butylammonium dihydrogen trifluoride. d) All
yields were determined using 19F NMR spectroscopy with PhCF3 as an internal standard. e) Ph–C5H10–OC(=O)F was used as the substrate. f) Ph–C5H10–
OC(=S)SMe was used as the substrate. g) Ph–C5H10–OC(=S)Cl was used as the substrate. h) Reaction conditions: TBAH2F3 (2.0 equiv.), NBL8 (4.0 equiv.),
dry TBABr3 (1.0 equiv.), distilled MeCN (2.0 mL), N2 atmosphere, 0 °C, 4 h.
were also suitable for the O-bromodifluoromethylation re-
action, predominately producing their corresponding alkyl
bromodifluoromethyl ethers in moderate yield. In addition,
the isolated yields were a little lower than those determined
using 19F nuclear magnetic resonance (19F NMR) spectro-
scopy. This can be attributed to the water used in the se-
paration process, which results in the decomposition of the
R–OCF2Br product at different degrees during high perfor-
mance liquid chromatography (HPLC). The mild reaction
conditions used for the synthesis of bromodifluoromethyl
ethers are tolerated by a series of functional groups, such as
tert-butyl (2c), iodo (2d), fluoro (2e), bromo (2f), chloro (2g
and 2h), and aryl (2i). Heterocycles, such as thiophene (2l),
are also tolerated in the reaction. Compared with the O-
trifluoromethylation reaction, the separation conditions were
not tolerated by substrates containing an alkoxy group such
as 4b, which can only be detected using 19F NMR spectro-
scopy.
Since some of the carbonofluoridothioate compounds were
decomposed during the separation process, we next sought to
directly convert alkyl alcohols into their corresponding alkyl
trifluoromethyl ethers without isolating the R–OC(=S)F in-
termediate. This one-pot desulfurization-fluorination reac-
tion applies to a variety of alcohol substrates (Scheme 5).

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Liu et al. Sci China Chem August (2021) Vol.64 No.8
Scheme 4 Substrate scope during the synthesis of alkyl bromodi-
fluoromethyl ethers using carbonofluoridothioates. Reaction conditions: 2
(0.5 mmol), TBAH2F3 (2.0 equiv.), NBL8 (4.0 equiv.), dry TBABr3 (1.0
equiv.), distilled MeCN (2.0 mL), N2 atmosphere, 4 h, 0 °C. All yields are
those of the isolated product. The yields obtained using 19F NMR spec-
troscopy with PhCF3 as an internal reference are reported in the parentheses
(color online).
The yields of 3a, 3l, and 3k did not decrease significantly
compared with those obtained during the fluorination of the
isolated –OC(=S)F intermediate. Alcohols bearing alkoxy
(2n, 2o, 2r, and 2t), cyano (2p), phthalimide (2q), and nitro
(2s) groups were well tolerated in the reaction, providing
their corresponding trifluoromethyl ethers (3) in 50%–60%
yield. Under the same optimal conditions, secondary alcohol
2u gave its corresponding product in a low 20% yield, which
may be due to its significant steric effect. Furthermore, in the
case of tertiary alcohols such as 2v, no R–OCF3 product was
detected. A limitation of this method was that no desired
product was observed by using benzyl alcohols and phenolic
compounds due to their steric effects.
Scheme 5 Direct conversion of R–OH to R–OCF3. Reaction conditions 1:
alcohol 1 (0.5 mmol), AgSCF3 (1.3 equiv.), KI (1.5 equiv.), DCE (2.0 mL),
N2 atmosphere, rt, 10 h. Reaction conditions 2: TBAH2F3 (5.0 equiv.),
NBL8 (4.0 equiv.), AgF (2.5 equiv.), dry DCE (2.0 mL), N2 atmosphere, rt,
4 h. All yields are those of the isolated product (color online).
To further illustrate the value of this protocol, a series of
molecules that have found applications in material sciences,
such as pyrene 2w in organic light-emitting diodes (OLEDs),
monomer 2z, and fluorescent material precursor 2ad, were
successfully used in the reaction and gave their corre-
sponding trifluoromethyl ethers in moderate yield. The
synthetic utility of this process was further highlighted by its
amenability to the late-stage trifluoromethoxylation of
biorelevant molecules. For example, Fmoc-glycinol, a pre-
cursor for anti-MSR1 antibodies, reacts to afford its CF3O-
analog (3x) in 36% yield. An intermediate of dapoxetine can
also be converted into its trifluoromethoxylated derivative
(3ac) in 45% yield. We then performed the late-stage func-
tionalization of several drugs with different structures (3y,
3aa, and 3ab) that are commercially available and used for
multiple purposes, including the treatment of Alzheimer’s
disease, acne, and gout.
The success of the one-pot O-trifluoromethylation of al-
cohols using AgSCF3, TBAH2F3, and NBL8 prompted us to
investigate the one-pot reaction of carbonofluoridothioates
using NaSO2CF3. Compared with AgSCF3, NaSO2CF3 is
cheaper and more stable, and can also produce SCF3 anions
under reductive conditions [43,44]. Therefore, we chose 1a
as a model substrate in this reaction (Scheme 6a). However,
trifluoromethyl ether 3a was produced in low yield (20%).
We speculated that the SCF3 anion was not easily formed and
decomposed in this system. Overall, this result demostrated
the potential of NaSO2CF3 for preparing trifluoromethyl
ethers from alcohols. However, the optimization of these

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Liu et al. Sci China Chem August (2021) Vol.64 No.8
Scheme 7 Control experiments (color online).
together with NBL8 (Scheme 7c). When only TBAH2F3 was
added as the fluorinating reagent, the fluorinated product
(3a) was not formed during the reaction (Scheme 7d). These
results suggest that most of the F atoms in the product ori-
ginate from TBAH2F3. However, TBAH2F3 alone does not
undergo the fluorination reaction and may require the pre-
sence of NBL8 to generate a cationic species.
Scheme 6 Synthesis of 3a using NaSO2CF3 and the transformation of
compound 4k (color online).
reaction conditions is currently underway in our laboratory.
In view of the previous work reported in the literature, we
believed that bromodifluoromethyl ethers (4) should have
unique versatility because the facile substitution of the bro-
mine atom can be exploited further. However, the direct
transformation of the bromodifluoromethoxy group has not
been reported to date. Herein, the utility of the bromodi-
fluoromethoxy group has been showcased using the facile
conversion of compound 4k into a series of valuable fluor-
ine-containing compounds, such as 1-(2-difluoro(phenoxy)-
methoxy)ethyl)naphthalene (5k) and 1-(2-(1,1-difluoro-2-
phenylethoxy)ethyl)naphthalene (6k). Furthermore, the
bromodifluoromethoxy group can be easily converted into
the trifluoromethoxy group via a Ag-mediated fluorination
reaction. Fluorination of 4k using KF/AgOTf, AgF, or
AgSbF6 gave trifluoromethyl ether 3k in 40%, 90%, and
63% yield, respectively, which demonstrates the potential of
this transformation to access medicinally important 18F-la-
beled motifs that are currently not accessible via conven-
tional methods.
Density functional theory (DFT) calculations offered a
preliminary insight into the mechanism of this transforma-
tion using 2k, fluoride (F−), and NBL8 (see Supporting In-
formation online for details). A proposed mechanism is
shown in Scheme 8. In the O-trifluoromethylation reaction
carried out in DCE, the electron-rich C=S bond in 2k can be
attacked by NBL8 to form an S–Br bond. The formation of
this bond weakens the C–S bond in 2k. Subsequent nu-
cleophilic attack by the fluoride ion at the electrophilic car-
bon atom forms a C–F bond to generate R–OCF2(SBr). The
increased C–S bond length observed from Int-1 to Int-2
results in Int-2 undergoing further electrophilic attack by
NBL8, which further weakens the C–S bond. Importantly,
the transition state for this reaction (TS-1) was concerted and
involved concomitant S–Br bond formation and C–S bond
cleavage with the generation of a difluoromethoxy cationic
intermediate (Int-3). Different from the previously proposed
mechanism involving a similar process [37], our calculations
show that the formation of Int-3 was not due to the nu-
cleophilic attack of F−. The conversion of Int-2 via transition
state TS-1 proceeds with an activation energy (ΔG‡) of
35.94DCE/34.87MeCN kcal/mol, which is consistent with the
rapid process. The bare –OCF2 cation is highly electrophilic
and is therefore trapped by F− to generate the final tri-
fluoromethoxylated product. Ag+ can preferentially remove
Br− via the precipitation of AgBr, which can selectively form
We performed a series of control experiments in order to
explore the fluorine source in the fluorination reaction
(Scheme 7). It was found that neither the addition of AgF nor
AgF/NBL8 led to the fluorination of O-(5-phenylpentyl)
carbonofluoridothioate 2a (Scheme 7a, b). However, 3a was
obtained in moderate yield (50%) when TBAH2F3 was added

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Liu et al. Sci China Chem August (2021) Vol.64 No.8
O-bromodifluoromethylation can be controlled by simply
changing the conditions using the same substrates. The O-
trifluoromethylation reaction was also feasible in a one-pot
process starting from alcohols. The late-stage O-tri-
fluoromethylation of small complex molecules has also been
proven to be efficient. Importantly, further derivatization of
the bromodifluoromethoxy group provides access to com-
pounds bearing difluoromethoxy and trifluoromethoxy
groups. DFT calculations indicate a mechanism involving
concerted S–Br bond formation and C–S bond cleavage in
this transformation. We believe that the presented metho-
dology will have wide application in pharmaceutical and
agrochemical research, and will open new avenues toward
innovation in organofluorine chemistry.
Acknowledgements This work was supported by the National Natural
Science Foundation of China (21776138, 22078161), the Fundamental
Research Funds for the Central Universities (30920021124, 30918011314),
the Natural Science Foundation of Jiangsu (BK20180476), the Postdoctoral
Science Foundation Funded Project (2019M661848), the Priority Academic
Program Development of Jiangsu Higher Education Institutions, and the
Center for Advanced Materials and Technology in Nanjing University of
Science and Technology.
Scheme 8 Proposed reaction mechanism (color online).
Conflict of interest The authors declare no conflict of interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
the R–OCF3 product. It is worth noting that the R–OCF2Br
product can be further fluorinated by AgF to form R–OCF3,
as shown in Scheme 7e, indicating that bromodifluoromethyl
ethers may also be an intermediate in the reaction. Although
path 2 cannot be excluded, we regard it to be less likely based
on our 19F NMR analysis. No obvious bromodifluoromethyl
ethers were detected during the formation of the R–OCF3
products.
For the O-bromodifluoromethylation reaction, the reaction
pathway is equivalent to the O-trifluoromethylation reaction.
However, the ratio of NBL8 and TBAH2F3 affects the se-
lectivity of the reaction in the MeCN system. In addition, the
increased polarity of the solvent can increase the nucleo-
philicity of Br−. The additional TBABr3 further increases the
nucleophilicity of Br−, reducing the probability of nucleo-
philic attack by F−, thereby increasing the selectivity of the
reaction toward the bromodifluoromethyl ether product.
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