Trifluoromethyl Nonaflate: A Practical Trifluoromethoxylating Reagent and its Application to the Regio- and Stereoselective Synthesis of Trifluoromethoxylated Alkenes

Article abstract of DOI:10.1002/anie.202104975

The trifluoromethoxy group has elicited much interest among drug and agrochemical discovery teams because of its unique properties. We developed trifluoromethyl nonafluorobutanesulfonate (nonaflate), TFNf, an easy-to-handle, bench-stable, reactive, and scalable trifluoromethoxylating reagent. TFNf is easily and safely prepared in a simple process in large scale and the nonaflyl part of TFNf can easily be recovered as nonaflyl fluoride after usage and recycled. The synthetic potency of TFNf was showcased with the underexplored synthesis of various trifluoromethoxylated alkenes, through a high regio- and stereoselective hydro(halo)trifluoromethoxylation of alkyne derivatives such as haloalkynes, alkynyl esters, and alkynyl sulfones. The synthetic merits of TFNf were further underscored with a high-yielding and smooth nucleophilic trifluoromethoxylation of alkyl triflates/bromides and primary/secondary alcohols.

Full text of DOI:10.1002/anie.202104975

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Trifluoromethyl Nonaflate: A New and Practical
Trifluoromethoxylating Reagent and its Application to the Regio-
and Stereoselective Synthesis of Trifluoromethoxylated Alkenes
Authors: Gerald Hammond, Zhichao Lu, Tatsuya Kumon, and Teruo
Umemoto
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202104975
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10.1002/anie.202104975
Angewandte Chemie International Edition
RESEARCH ARTICLE
Trifluoromethyl Nonaflate: A New and Practical
Trifluoromethoxylating Reagent and its Application to the Regio-
and Stereoselective Synthesis of Trifluoromethoxylated Alkenes
Zhichao Lu,[a] Tatsuya Kumon,[b] Gerald B. Hammond,*[a] and Teruo Umemoto*[a]
[a]
Dr. Z. Lu, Dr. T. Umemoto, and Prof. G. B. Hammond
Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States
E-mail: gb.hammond@louisville.edu; teruo.umemoto@louisville.edu.
Dr. T. Kumon
[b]
Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: The trifluoromethoxy group has elicited much interest
among drug and agrochemical discovery teams because of its unique
properties. We developed trifluoromethyl nonafluorobutanesulfonate
(nonaflate), TFNf, an easy-to-handle, bench-stable, reactive, and
scalable trifluoromethoxylating reagent. TFNf is easily and safely
prepared in a simple process in large scale and the nonaflyl part of
TFNf can easily be recovered as nonaflyl fluoride after usage and
recycled. The synthetic potency of TFNf was showcased with the
underexplored synthesis of various trifluoromethoxylated alkenes,
and aryl trifluoromethyl ethers.[11] However, the high volatility of
TFMT (bp 19 oC) is a serious disadvantage.
a) Easy-to-handle nucleophilic trifluoromethoxylation reagents
O
O
S
OCF3
OCF3
OCF3
O
R
O2N
NO2
TFBz (2018)
DNTFB (2010)
TFMS (2016)
H
through
a
high
regio-
and
stereoselective
O
OCF3
n
C4F9
S
OCF3
N
hydro(halo)trifluoromethoxylation of alkyne derivatives such as
haloalkynes, alkynyl esters and alkynyl sulfones. The synthetic merits
of TFNf were further underscored with a high yielding and smooth
nucleophilic trifluoromethoxylation of alkyl triflates/bromides and
primary/secondary alcohols.
R
O
TFNf (this work)
TFBO (2020)
safe, easy preparation,
bench-stable, reactive
b) Nucleophilic trifluoromethoxylation reactions
Previous works:
The trifluoromethoxy (CF3O) group has become a prominent
motif in pharmaceuticals, agrochemicals, and organic materials
because of its distinctive properties,[1] chiefly among them, its high
lipophilicity and electron-withdrawing effect, which improve the
permeability and metabolic stability of organic compounds
considerably.[2] Despite its potential, current methods for the
syntheses of the trifluoromethyl ether motif, either through indirect
or direct trifluoromethoxylation leave room for improvement.
Indirect trifluoromethoxylation, such as trifluoromethylation of
Alkyl
R
X
Alkyl OCF3
trilfuoromethoxylation
R
E
E = electrophile
OCF3
Ar
X
Ar-OCF3 Ar = (hetero)aryl
This work:
Trifluoromethoxylation of alkynes: synthesis of trifluoromethoxylated alkenes
R1
R1
alcohols
or
phenols,[3]
fluorodecarboxylation
of
TFNf AgF
R2
R3
R2 = Cl, SO2R, CO2R
R3 = H, Cl, Br, I
R3
aryloxydifluoroacetic acids,[4] fluorodesulfurization of xanthates,[5]
deoxofluorination of aryl fluoroformates with SF4,[6] and
chlorination/fluorination of anisoles with Cl2/HF[7] suffer from long
steps for their preparation, use of toxic, explosive, or expensive
reagents, poor substrate scope, or harsh reaction conditions. In
theory, direct trifluoromethoxylation is the ideal method for the
preparation of trifluoromethyl ether-containing compounds but
despite the tremendous effort devoted to the development of
nucleophilic trifluoromethoxylation reagents, the reported
nucleophilic trifluoromethoxylating reagents have shortcomings.
F3CO
- NfF
R2
good to excellent yields (50 examples)
high functional group compatibility
excellent regio/stereo-selectivity
Scheme 1. Trifluoromethyl Nonaflate (TFNf) as
a New Nucleophilic
Trifluoromethoxylation Reagent and Its Application
To address these issues, easy-to-handle nucleophilic
trifluoromethoxylating reagents such as 2,4-
dinitro(trifluoromethoxy)benzene (DNTFB),[12] trifluoromethyl
arylsulfonates (TFMS),[13] trifluoromethyl benzoate (TFBz)[14] and
(E)-O-trifluoromethyl-benzaldoximes (TFBO)[15] were developed
(Scheme 1a). These reagents have been explored[16] in the
reactions with alkyl derivatives,[11b,11c,11g,11k,12,13b,13e-h,14-15,17]
olefins,[11f,13i,18] and (hetero)aromatic substrates.[11a,11h,13c,19]
However, trifluoromethoxylation of alkynes has been scarcely
Among
earlier
reports,
sulfurane
and
its
oxide,
(CF3)2S(O)n(OCF3)2 (n
=
0, 1), converted phenols to
(trifluoromethoxy)benzenes via nucleophilic attack of the CF3O
moiety.[8] However, the preparation of sulfuranes required a
special technique that used very toxic and explosive
compounds.[9] More recently, trifluoromethyl triflate (TFMT)[10] was
employed as a nucleophilic reagent with fluoride to prepare alkyl
reported to date[20] except for
a
reactive benzyne
1
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10.1002/anie.202104975
Angewandte Chemie International Edition
RESEARCH ARTICLE
species[11c,14](Scheme 1b) (during our manuscript’s first review
process, a paper on dibromotrifluoromethoxylation of terminal
F
F
F
F
F
F
NfOK
n-Bu4NCl
40 oC, 0.5 h
alkynes with TFMS appeared.[21]
Despite their effectiveness
)
rt. 2 h
S+
S+
CF3
1
S+
NfO-
Cl-
OTf-
yield:95%
yield: 97%
CF3
in
straightforward
CF3
(Nf=n-C4F9SO2)
3
trifluoromethoxylation reactions, DNTFB showed low reactivity
and very limited scope; TFMS and TFBO were prepared with
Togni’s reagent, whose suspected explosiveness raises safety
concerns in large-scale synthesis; and the synthesis of TFBz
required stringent reaction conditions because of the hygroscopic
nature of the reagents required for its preparation as well as the
generation of toxic fluorophosgene during the reaction. Recently,
it was reported that R4NOCF3[17] was prepared by the reaction of
CF3OCH3 with tertiary amines. But CF3OCH3 is a gas and the
resulting hygroscopic CF3O- ammonium salts showed low
reactivity. Also, AgOCF3 generated from triphosgene and AgF,[22]
was reported, but triphosgene is hazardous; the reaction scope
was narrow too. In sum, the search for a safe, practical, and
versatile trifluoromethoxylating agent is still an unmet challenge.
2
O
S
Thermolysis
146-155 oC
n
C4F9
OCF3
O
neat 3
yield: 90%
29 g
(TFNf)
a colorless, odorless
liquid (bp: 87-89 oC)
29 g TFNf
Scheme 2. Preparation of TFNf
Since
2,3,7,8-tetrafluoro-S-
(trifluoromethyl)dibenzothiophenium nonaflate 3c also exhibited a
low decomposition point (156.9 C), we chose to prepare TFNf
o
We
are
now
pleased
to
introduce
trifluoromethyl
by thermolysis of nonaflate 3c (Scheme 3). Indeed, TFNf was
prepared smoothly and in high yield by thermolysis of neat 3c,
which was prepared from the corresponding triflate[24-25] using
simple anion exchange steps analogous to 3 (see SI).
nonafluorobutanesulfonate (nonaflate) (TFNf), an easy-to-
prepare, easy-to-handle, stable yet reactive, and scalable
trifluoromethoxylating agent whose nonaflyl part can be easily
recovered after use and recycled. The synthetic potency of TFNf
was underscored with the synthesis of various new
F
F
trifluoromethoxylated alkenes through
a highly regio- and
Thermolysis
stereoselective hydro(halo)trifluoromethoxylation of alkyne
derivatives in addition to high-yield preparation of CF3O-
compounds from alkyl halides and alcohols.
TFNf
F
F
140-160 oC
yield: 89%
S+
NfO-
CF3
Although there have been two reports[23] on the synthesis of
TFNf, these methods are cumbersome and not suitable for scale-
up preparation. One method needed dangerous F2 and FCl,[23a]
neat 3c
Scheme 3. Thermolysis of tetrafluoro analog 3c
n
and the other was haunted by expensive C4F9SO3Ag, gaseous
CF3I, low yield as well as difficult purification from solvent
(benzene).[23b] Consequently, the application of TFNf, especially
as a trifluoromethoxylation reagent, has never been reported. Our
new method for TFNf preparation is safe, easy, efficient, and
scalable (for details, see Supporting Information, SI). As shown in
Thus, the whole process of preparing TFNf in high yield from
1 encompassed a simple reaction setup and an easy workup
procedure (just filtration for the first two steps and distillation for
the last step). It should be noted that Umemoto reagent II (1) is
commercially available and can be prepared effectively in large
scale, in one-pot and using a water-washing workup process.[24]
TFNf is an odorless, thermally stable, and non-flammable liquid
with a boiling point 87-89 oC; this convenient boiling point allows
for easy distillation in the production process as well as its
handling, storage, and transportation. TFNf can withstand a 3 M
HCl solution for 150 hours without decomposition and 40% of
TFNf was still intact after being treated with 3M KOH solution for
150 hours (see SI). In sum, the preparation of TFNf does not
employ any explosive chemicals or toxic gaseous chemicals and
is purifiable by simple distillation. Therefore, our process can be
carried out in large scale in industrial settings without safety or
separation concerns. These properties are in sharp contrast to the
previously reported trifluoromethoxylating agents that use
explosive or toxic chemicals in their productions and had to be
purified by costly column chromatography. Moreover, the nonaflyl
fluoride (NfF), generated from the TFNf activation by fluoride, can
be easily recovered by simple pipetting from acetonitrile after the
reaction is complete (see SI, section 2.3). This easy and
economically advantageous recovery is due to the poor solubility
of NfF in acetonitrile and its spontaneous partition from the
reaction mixture. The recovered NfF can be reused for the
synthesis of TFNf through hydrolysis and anion exchange
reaction with 2 (see SI, section 2.3). The significant merits of TFNf
Scheme
2,
starting
from
2,8-difluoro-S-
(trifluoromethyl)dibenzothiophenium triflate 1 (Umemoto reagent
II),[24] TFNf reagent was prepared in high yield following two
simple anion exchange steps and subsequent thermolysis of neat
nonaflate 3. TFNf was easily collected in a condenser vessel from
the thermolysis reaction. The easy and effective thermolysis of
nonaflate 3 was possible because of its low melting and
o
decomposition point (133-135 C), compared to triflate 1, which
has a high decomposition point of 204 oC. This unique property of
3 was further underscored by thermolysis of methanesulfonate 3a
-
-
(CH3SO3 counter-anion) and benzenesulfonate 3b (PhSO3
counter-anion). These provided poor thermolysis outcomes (see
SI, section 2.1c, d for details).
2
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10.1002/anie.202104975
Angewandte Chemie International Edition
RESEARCH ARTICLE
(i.e. smooth thermolysis of nonaflate 3, suitable boiling point of
TFNf for easy separation and handling, and easy recovery of NfF
from organic solvent) are brought about by the unique properties
of the perfluoroalkyl chain in TFNf, namely its very low surface
energies, low intermolecular interaction, and water and oil-
repulsion effect.[26]
Using TFNf, in conjunction with AgF, for the
trifluoromethoxylation of alkynes, we discovered that simple
alkynes were too inert and thus alkyne derivatives were explored
(see SI). We found that haloalkynes afforded satisfactory results.
The reaction with 1-iodooctyne furnished 11% of the expected
Entry
Deviation
Yield
Yield
(5, %)b
(5’, %)b
1
no
84
86
4
5
2
0.3 mL CH3CN as solvent
0.3 mL DME as solvent
0.3 mL DMF as solvent
1.5 eq AgF
14
3
3
4
54
81
78
61
76
75
42
78
58
73
81
71
61
88
27
6
5
6
2.5 eq AgF
9
hydrotrifluoromethoxylation
product
along
with
iodotrifluoromethoxylation and iodofluorination by-products (48%
and 25%, respectively). These iodo by-products implied that
additional intermolecular reactions occurred due to the presence
of reactive iodoalkynes. The reaction with 1-bromooctyne
afforded 75% yield of the expected product, but 24% of the
hydrofluorination by-product was also found (see SI). The best
result was obtained with 1-chloroalkynes.1-Chlorooctyne was
then selected as a model substrate for the reaction optimization
(Table 1). AgF was an excellent activator and it played a dual role
in that F- activated TFNf and Ag+ activated the alkyne triple bond.
The reaction was conducted in a sealed ampoule to inhibit the
decomposition of the CF3O- to fluorophosgene and fluoride anion,
which is detrimental to the reaction.[13h,16a,27] To our delight, 86%
7
2 eq TFNf
15
8
8
activation at rt for 3h
no activation at rt
rt for 48 h, no heating
rt for 2 h, then heating to 80 oC
no additive
9
6
10
11
12
13c
14c
15d
16e
17f
1
20
6
0.5 eq TMAI as additive
0.5 eq TMACl as additive
0.5 eq TBABr as additive
0.5 eq TOABr as additive
0.2 mmol 4
5
8
of hydrotrifluoromethoxylation product
5 was found when
5
acetonitrile was used as solvent (entry 2). However,
hydrofluorination also occurred and formed 6 as a side product
(14%). Less polar solvents gave low conversion of the starting
material (entry 3). More polar solvents, on the other hand,
converted more starting material but also produced more
hydrofluorination side product (entry 4). This phenomenon could
be explained by the solubility of AgF in different solvents as more
AgF dissolved in polar solvents and hence promoted the reaction.
The polar solvents also increased the fluoride concentration in the
reaction, which then competed with the CF3O- to generate more
side product 5’. A CH3CN/DME solvent system proved beneficial
(entry 1 vs entries 2 and 3) and a AgF/TFNf ratio screening led to
the optimal amount of both reagents (entries 5, 6 and 7). The
activation time at room temperature was critical because too long
or short activation times impaired the reaction outcome (entries 8,
9). Heating was still required after activation (entries 10, 11).
Additives played a key role: The reaction yield decreased
dramatically without them. Various quaternary ammonium salt
additives improved the AgF solubility and helped to stabilize the
CF3O-.[13h,17] The reaction yield was further improved when 0.2
mmol of chloroalkyne 4 was employed, due to scale merit (entry
17). After thorough reaction condition screenings (see SI for more
details), we found that reacting 0.2 mmol of chloroalkyne 4 with 2
equiv of AgF, 3.0 equiv of TFNf, and 0.5 equiv of TMABr in 1:2
(v/v) CH3CN/DME in a sealed ampoule gave the best yield of the
desired product 5.
12
7
aConditions: Unless otherwise noted, reactions were conducted as follows: A 2-
mL amber ampoule was loaded with 4 (0.1 mmol), tetramethylammonium
bromide (TMABr) (additive) (0.5 equiv), AgF (2 equiv) and 0.3 mL mixed solvent
(CH3CN/DME = 1/2) sequentially. TFNf (3 equiv) was then added and the
ampoule was sealed immediately. The reaction was activated (stirred) at rt for
1h and then stirred at 65 oC for 48h. bYields were determined by GC. cTMAI,
TMACl: tetramethylammonium iodide, chloride. dTBABr: tetrabutylammonium
bromide. eTOABr: tetraoctylammonium bromide. fOptimized condition.
With the optimized reaction conditions in hand, we explored the reaction scope
of this hydrotrifluoromethoxylation. As shown in
Table 2 Table 2, all reactions gave regio- and stereoselective
hydrotrifluoromethoxylation products in good to excellent yields.
Chloroalkynes with diverse functionalities such as esters (5a-5f,
5t-5w, 5y, 5z, 5aa, 5cc, 5dd), ethers (5k-5q, 5bb), nitro (5e),
nitriles (5j, 5dd), aldehyde (5p), ketones (5m, 5bb), amides (5r,
5s, 5y, 5z, 5aa), sulfonates (5g, 5h), and sulfonamides (5i, 5cc)
were well-tolerated using our protocol. Acceptable to high yields
were also obtained with heterocyclic substrates including pyridine
(5t), thiazole (5u), furan (5v), thiophene (5w), triazole (5x),
pyrrolidine (5y), and piperidine (5z). Impressively, some
“vulnerable” substituents such as 2-tetrahydropyranyl (5k) and
cyclopropyl (5o) proved to be suitable substrates. These results
underscored the mild conditions and excellent functional group
tolerance of our methodology. The absolute configuration of the
double bond was determined to be cis by single-crystal X-ray
diffraction analysis of 5s.[28] We then explored late-stage regio-
and stereoselective hydrotrifluoromethoxylation of natural
products (5aa, 5bb) and biologically active molecule derivatives
(5cc, 5dd). Both hydrotrifluoromethoxylation reactions of L-
phenylalanine and estrone derivatives proceeded smoothly to
provide the corresponding 5aa and 5bb in good isolated yields.
Table 1. Reaction Condition Optimization for Hydrotrifluoromethoxylation of
Chloroalkynesa
OCF3
F
AgF
Cl
Cl
n-C4F9SO2OCF3
n-Hex
Cl
n-Hex
n-Hex
solvent
4
(TFNf)
5
5'
3
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10.1002/anie.202104975
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RESEARCH ARTICLE
Our protocol provides an easy-to-use synthetic tool for the
modification of drug molecules. For example, we obtained a
derivative of Probenecid (5cc) in 73% yield. Probenecid is a
prototypical uricosuric agent used to treat patients with renal
hydrotrifluoromethoxylation protocol is suitable for the late-stage,
protecting-group-free modification of biologically interesting
molecules. In addition, we prepared 5d on a gram scale under
standard reaction conditions in 82% isolated yield, which
demonstrated both the scalability and practicality of this method.
It should also be noted that the chlorine atoms on the double
bonds of these products are potential versatile handles for further
functionalization through transition metal-catalysed coupling
reactions.
impairment. On the other hand,
a
Febuxostat-tethered
chloroalkyne was converted to the hydrotrifluoromethoxylated
product in 77% yield. Febuxostat is a xanthine oxidase inhibitor
for the treatment of gout. It possesses various functionalities like
ester, nitrile, ether, and a thiazole ring which remained intact using
our mild protocol. These examples further demonstrate that our
Table 2. Substrates Scope of Hydrotrifluoromethoxylation of Chloroalkynesa,b
H
2 eq AgF, 0.5 eq TMABr
R
NfOCF3
3 eq
R
Cl
NfF
Cl
OCF3
5a 5z 5aa 5dd
ACN/DME = 0.1 mL/0.2 mL,
rt, 2 h, then 65 oC for 48 h
4a-4z,4aa-4dd
0.2 mmol
-
,
-
a. chloroalkynes with various functionalities
H
H
O
O
H
H
O
H
5a
5b
5c
5d
Cl
n = 1
n = 2
n = 3
n = 4
, 80%
, 85%
, 82%
, 81%
TsO
Cl
MsO
Cl
9
O
Cl
EtO
Cl
O
Cl
n
OCF3
61%
OCF3
OCF3
OCF3
, 64%
OCF3
O2N
O
H
c
5e
5f
5g,
5h
, 80%
, 78%
O
O
O
O
H
H
H
H
H
O
O
BnO
Cl
NC
Cl
OCF3
Cl
O
Cl
N
Cl
Cl
Ms
OCF3
OCF3
5l, 91%
OCF3
OCF3
OCF3
5m, 71%
5i, 90%
5j, 61%
5k, 67%
5n, 85%
H
O
OHC
OCF3
O
OCF3
Cl
OCF3
H
H
Cl
O
O
N
O
Cl
OCF3
Cl
O
O
Cl
OCF3
H
NPhthH
5o, 80%
5p, 88%
5q, 82%
5r, 60%
5s, 82%
b. chloroalkynes with heterocyclic substituents
O
H
O
H
O
H
N
O
Cl
O
Cl
O
Cl
S
O
OCF3
OCF3
N
OCF3
X-ray of 5s
Br
5t, 57%
5u, 71%
5v, 85%
H
O
O
H
O
H
O
H
N
N
N
Cl
Cl
OCF3
O
Cl
O
Cl
OCF3
OCF3
5x, 65%
BocN
NBoc
OCF3
S
5w
, 87%
5y, 81%
5z, 78%
c. chloroalkyne tethered natrural products and drugs
O
H
F3CO
Cl
O
NC
O
H
Cl
OCF3
H
S
O
O
H
O
Bn
O
O
Cl
H
N
S
H
H
N
NHBoc
OCF3
O
O
Cl
O
from Probenecid
5cc
from Febuxostat
5dd
from L-Phenylalanine
5aa
from estrone
5bb
OCF3
, 61%
, 69%
, 73%
, 77 %
aReaction Conditions: Unless otherwise noted, reactions were conducted as follows: Starting material 4 (0.2 mmol), TMABr (0.5 equiv), AgF (2 equiv), and 0.3 mL
mixed solvent (CH3CN/DME = 1/2) were added to a 2-mL amber ampoule sequentially. TFNf (3 equiv) was then added and the ampoule was sealed immediately.
The reaction mixture was stirred at rt for 2h and then stirred at 65 oC for 48h. bIsolated yields. c82% isolated yield was obtained when 1.01 g of 4d was applied.
4
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10.1002/anie.202104975
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RESEARCH ARTICLE
1 eq AgF,
1.2 eq NBS
Our hydrotrifluoromethoxylation protocol also works with
alkynyl sulfones. As shown in Table 3, various alkynyl sulfones
OCF3
R2
R1
O
O
S
R1
S
NfOCF3
4 eq
O
O
0.15 mL ACN
0 oC, 18 h
R2
Br
(7a-7e)
can
be
converted
to
the
corresponding
6
8
hydrotrifluoromethoxylation products in good yields and high
regio- and stereoselectivity. The Z-configuration of the products
was determined by observation of the NOE interactions between
the CH3 group and the proton as shown by the double-headed
arrow in 7a (see SI for more details).
0.2 mmol
Br
OCF3
O
8a, X = Br, 74%c,
E/Z = 11/1
8aa, X = Cl, 70%d
Ph
OCF3
O
OCF3
S
S
O
Ts
O
Br
Br
X
8ab, X = I, 18%e
8c,79%
E/Z = 11/1
8b, 82%
E/Z = 11/1
Table 3. Hydrotrifluoromethoxylation of Alkynyl Sulfonesa,b
1.5 eq AgF,
O
OCF3
R2
O
F3CO
0.2 eq TMABr
R1
O
R1
S
R2
CF3ONf
3 eq
OCF3
O
S
OCF3
OCF3
Br
O
O
S
O
0.1 mL ACN,
S
O
6
S
S
Cl
0
oC 30 min,
7
O
O
Br
0.2 mmol
Br
Br
then rt for 18 h
8d, 67%
8e, 65%
8f,81%
E/Z = 11/1
E/Z = 12/1
E/Z = 11/1
Br
OCF3
OCF3
OCF3
O
O
O
OCF3
OCF3
S
O
OCF3
S
S
Ts
CH3
CH3
CH3
Ts
O
O
Ts
n-Hex
H
H
H
Br
8g, 85%f
Br
8h, 61%f
Br
8i, 78%f
7a, 68%
7b, 78%
7c, 75%
F3CO
E/Z = 5/1
E/Z = 12/1
E/Z >20/1
OCF3
CH3
OCF3
CH3
O
O
Br
S
S
S
OCF3
O
O
Ts
Cl
H
H
7d, 65%
7e, 64%
Br
8j, 65%f
aReaction Conditions: Reactions were conducted as follows: Starting material 6
(0.2 mmol), TMABr (0.2 equiv), AgF (1.5 equiv), and 0.1 mL CH3CN were added
to a 1-mL amber ampoule sequentially. TFNf (3 equiv) was then added and the
ampoule was sealed immediately. The reaction mixture was stirred at 0 oC for
0.5 hour and then stirred at rt for 18 hours. bIsolated yields.
E/Z = 19/1
X-ray of (E)-8j
OCF3
OCF3
OCF3
Ts
Ts
Ts
O
O
OBz
OMs
We also found that alkynyl sulfones easily underwent
halotrifluoromethoxylation when an electrophilic halogenating
reagent was added with our protocol. The reaction delivered the
Br
Br
Br
8k, 64%f
8m, 64%f
8l, 56%f
E/Z = 12/1
E/Z = 9/1
E/Z = 10/1
aReaction Conditions: Unless otherwise noted, reactions were conducted as
follows: Starting material 6 (0.2 mmol), AgF (1 equiv), NBS (1.2 equiv) and 0.15
mL CH3CN were added to a 1-mL amber ampoule sequentially. TFNf (4 equiv)
was then added and the ampoule was sealed immediately. The reaction mixture
was stirred at 0 oC for 18 hours. bIsolated yields. c72% isolated yield was
tetrasubstituted
alkene,
a
highly
functionalized
trifluoromethoxylated alkene tethered with a halogen, which could
be further converted to other trifluoromethoxylated derivatives by
coupling reactions. As shown in Table 4, all reactions gave highly
regio- and stereoselective bromotrifluoromethoxylated alkenes in
good to excellent yields, with E-configuration as the major product.
Alkynyl sulfones with diverse functionalities such as esters (8l),
ethers (8k), sulfonates (8m), and halide (8j) were well-tolerated
with our protocol. Chlorotrifluoromethoxylated alkene (8aa) and
Iodotrifluoromethoxylated alkene (8ab) could also be obtained
when trichloroisocyanuric acid or N-iodosuccinimide was used as
the halogenating reagent instead of N-bromosuccinimide.
Various aryl sulfones with different substituents on the aromatic
ring (8a-8f) were screened and all showed good yields. Alkynyl
sulfones with either aryl (8g) or alkyl (8a-8f, 8h-8m) substituents
(R2) worked well with our protocol. It should be noted that
substrates with “vulnerable” substituents such as cyclopropyl (8i)
and 2-tetrahydropyranyl (8k) are also compatible with our
halotrifluoromethoxylation protocol. When the reaction with 6a
was scaled up to 3 mmol, a good isolated yield (72%) was
obtained. The absolute configuration of the major product was
determined by single-crystal X-ray diffraction analysis of 8j as a
E-configuration.[29]
obtained when
3
mmol (583 mg) of 6a was applied. d1.2 equiv
trichloroisocyanuric acid was applied instead of NBS. e1.2 equiv N-
iodosuccinimide was applied instead of NBS. fThe reaction mixture was stirred
at 0 oC for 1 hour and then stirred at rt for 18 hours.
We found that alkynyl ester substrates also work with our
bromotrifluoromethoxylation protocol. As shown in the equations
and 2, alkynoates 9a and 9b can be converted to
bromotrifluoromethoxylated alkenoate 10a and 10b respectively
1
in good yields.
1 eq AgF,
1.2 eq NBS
O
O
OCF3
eq 1
eq 2
NfOCF3
4 eq
O
O
O
0.15 mL ACN
0 oC 1 h, then rt 18 h
Br
9a
10a
, 77% (NMR)
0.2 mmol
1.2 eq AgF,
1.2 eq NBS
O
O
OCF3
NfOCF3
4 eq
O
0.15 mL ACN
oC 1 h, then rt 18 h
n-Hex
0.2 mmol
Br
10b
9b
0
, 71%
To gain an insight on the reaction mechanism, we monitored
the reaction between TFNf and AgF by 19F NMR spectroscopy. It
showed that AgOCF3 (–27.5 ppm) and NfF were generated in the
reaction (see SI), which confirmed that AgOCF3 was generated in
situ during the reaction. Cationic silver species are well-known
effective catalysts for the electrophilic activation of alkynes
towards nucleophiles,[30] so it is not unrealistic to expect that the
alkyne moiety coordinates with the silver cation to form π-complex
Table 4. Halotrifluoromethoxylation of Alkynyl Sulfonesa,b
5
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10.1002/anie.202104975
Angewandte Chemie International Edition
RESEARCH ARTICLE
A, which is subsequently converted to the corresponding vinyl-
by smooth thermolysis of 3 at large scale. In addition, the nonaflyl
portion of TFNf can easily be recovered and recycled. The
significant merits of TFNf are brought about by the fluorine effect
of the long perfluoroalkyl chain of TFNf. The high synthetic
potential of TFNf was demonstrated with the regio- and
stereoselective hydro(halo)trifluoromethoxylation of various
alkyne derivatives. This synthetic protocol is characterized by
wide functional group compatibility, good yields, and accessible
gram-scale synthesis, all of which may elicit broader applications
in pharmaceutical and agrochemical research and development.
Other trifluoromethoxylation reactions, including nucleophilic
silver intermediate
B
by trans-addition of AgOCF3.
Protonation/halogenation of the vinyl-silver intermediate B by
moisture/halogenating reagent yielded trifluoromethoxylated
alkene as the product, plus silver oxide as a black precipitate
observed in the reaction (Scheme 4).[30a] The protonation process
was further proved by adding D2O to the reaction (see SI). We
ascribed the high regio- and stereoselectivity of the product to the
back-side attack of trifluoromethoxide anion (A to B)[30a] with the
electron-withdrawing R2 group serving as an activating and regio-
directing group for the weakly nucleophilic CF3O anion.[30a]
substitution
of
alkyl
(pseudo)halides
and
one-pot
CD3CN
trifluoromethoxylation of primary/secondary alcohols via triflates,
were effectively achieved with TFNf. Further applications and
commercialization of this reagent are currently underway in our
laboratory.
-27.5 ppm in 19F NMR
AgF
AgOCF3
Ag+
TFNf
R1
H/X
R2
R1
F3CO
Ag
R2
H2O/X+
F3CO
5
Ag+
R1
R2
R1
R2
AgOH
Ag2O
R2 = Cl, SO2R,
CO2R
A
B
AgOCF3
Acknowledgements
Scheme 4. Plausible Mechanism for the Regio- and Stereoselective
We are grateful to the National Institutes of Health for financial
support (R01GM121660). Support for the acquisition of the
Bruker Venture D8 diffractometer through the Major Scientific
Research Equipment Fund from the President of Indiana
University and the Office of the Vice President for Research and
Dr. Maren Pink’s X-ray help are gratefully acknowledged.
Hydrotrifluoromethoxylation of Alkynes Derivatives
To demonstrate the synthetic prowess of TFNf, we carried the
synthesis of trifluoromethyl ethers under various protocols
(Scheme 5). The AgF-activated TFNf converted benzyl bromide
and alkyl triflate to the alkyl trifluoromethyl ethers 11 and 14 in
excellent yields. Furthermore, TFNf was an excellent vehicle for
the one-pot synthesis of trifluoromethyl ethers 12 and 13 from
primary and secondary alcohols in high yields. We also compared
our reagent with TFMS (TsOCF3 was used in this case) in the
hydrotrifluoromethoxylation of chloroalkyne 4d and alkynyl
sulfone 6a, our TFNf showed slightly better yields than TFMS in
both reactions (see SI, section 6 for details).
Keywords: Trifluoromethoxylating reagent, Chloroalkynes,
Alkynyl esters, Alkynyl sulfones, Hydrotrifluoromethoxylation,
halotrifluoromethoxylation, Trifluoromethoxylated alkenes
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o
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6
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10.1002/anie.202104975
Angewandte Chemie International Edition
RESEARCH ARTICLE
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7
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RESEARCH ARTICLE
Entry for the Table of Contents
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o
Trifluoromethyl nonaflate (TFNf), an odorless liquid (bp 87-89 C), was developed as an easy-to-handle, bench-stable, and reactive
trifluoromethoxylating reagent which can be easily and safely prepared in large scale. The synthetic potency of TFNf was demonstrated
with the underexplored synthesis of various trifluoromethoxylated alkenes, through a highly regio- and stereoselective direct
hydro(halo)trifluoromethoxylation of various alkyne derivatives. The reactions showed wide functional group compatibility, good yields,
and gram-scale synthesis.
8
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