Direct Trifluoromethylation of Alcohols Using a Hypervalent Iodosulfoximine Reagent

Article abstract of DOI:10.1002/chem.202005104

The direct trifluoromethylation of a variety of aliphatic alcohols using a hypervalent iodosulfoximine reagent afforded the corresponding ethers in moderate to good yields (14–72 %). Primary, secondary, and even tertiary alcohols, including examples derived from natural products, underwent this transformation in the presence of catalytic amounts of zinc bis(triflimide). Typical reaction conditions involved a neat mixture of 6.0 equivalents of the alcohol with 1.0 equivalent of the reagent, with the majority of reactions complete within 2 h with 2.5 mol % of the Lewis acid catalyst. Furthermore, experimental evidence was provided that the C?O bond-forming process occurred via the coordination of the alcohol to the iodine atom and subsequent reductive elimination.

Full text of DOI:10.1002/chem.202005104

Accepted Article
Accepted Article
Title: Direct Trifluoromethylation of Alcohols Using a Hypervalent
Iodosulfoximine Reagent
Authors: Antonio Togni, Jorna Kalim, Ewa Pietrasiak, Thibaut Duhail,
Elsa Anselmi, and Emmanuel Magnier
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202005104
Link to VoR: https://doi.org/10.1002/chem.202005104
01/2020

10.1002/chem.202005104
Chemistry - A European Journal
COMMUNICATION
Direct Trifluoromethylation of Alcohols Using a Hypervalent
Iodosulfoximine Reagent
Jorna Kalim, Thibaut Duhail, Ewa Pietrasiak, Elsa Anselmi, Emmanuel Magnier* and Antonio Togni*
(a) Approaches to Trifluoromethoxylated Compounds:
Abstract: The direct trifluoromethylation of a variety of aliphatic
CF3O
alcohols using a hypervalent iodosulfoximine reagent affords the
OH
OR'
OCF3
R''
R
R
R
R
or
CF3O
Step 1
Step 2
corresponding ethers in moderate to good yields (14-72%). Primary,
secondary and even tertiary alcohols, including examples derived
from natural products, undergo this transformation in the presence of
catalytic amounts of zinc bis(triflimide). Typical reaction conditions
involve a neat mixture of 6.0 equivalents of the alcohol with 1.0
equivalent of the reagent, with the majority of reactions complete
within 2 h with 2.5 mol-% of the Lewis acid catalyst. Furthermore, we
provide experimental evidence that the C–O bond-forming process
occurs via the coordination of the alcohol to the iodine atom and
subsequent reductive elimination.
R' = COF,
CS2Me, CCl3
R'' = H, SnBu3,
B(OH)2, C=CR
Challenges:
Challenges:
→ CF3O unstable towards fragmentation
→ Prefunctionalized starting material
→ Radical approach unselective
→ Harsh reaction conditions/toxic reagents (e.g. HF, SF4)
→ Multistep process
→ Limited functional group tolerence
(b) Electrophilic Trifluoromethylation
F3C
I
O
OH
OCF3
+
or
R
R
O
O
CF3
Togni II reagent (1)
Umemoto reagent
Challenges:
→ Low yields & high catalyst loadings with 1
→ In situ generation of unstable Umemoto
reagent
In the field of organofluorine chemistry, research efforts towards
accessing trifluoromethyl ethers (OCF3) has never moved faster
or more relentlessly than in the last decade. This is evidenced by
the emergence of five new trifluoromethoxylating reagents in the
past three years alone,[1–5] with several review articles appearing
alongside to keep up with the ever-growing body of synthetic
methodologies.[6–10] The pronounced interest in this group is due
to its high lipophilicity (Hansch parameter: p = +1.04)[11] relative to
CF3 and F, high electronegativity (Pauling’s electronegativity
(c) New Electrophilic Trifluoromethylation Reagent
This work
F3C
I
N
S
→ Low catalyst loadings
→ Short reaction times
→ Operationally simple
→ 34 substrates
OCF3
OH
+
CF3
R
R
O
→ Bio-relevant compounds
HYPISUL reagent (2)
Scheme 1. Synthetic approaches to accessing trifluoromethyl ethers.
scale:
c =
3.7),[12] good metabolic stability and unique
bond (Scheme 1a). Reagents which utilize trifluoromethoxide,
conformational properties.[13] The interest in new methodologies
is therefore rapidly increasing from an industrial perspective, as
marketed OCF3 containing pharmaceuticals and agrochemicals
remain sparse. However, facile access to such compounds is
often impeded by the lack of reagents capable of delivering this
functional group under mild conditions at a late-stage of a
synthetic sequence.
such
as
TASOCF3
(tris(dimethylamino)sulfonium
trifluoromethoxide),[14] TFMS (trifluoromethyl arylsulfonate)[4] and
TFBz (trifluoromethyl benzoate)[5] have been employed for the
synthesis of both aryl and alkyl trifluoromethyl ethers. TMSCF3
has also been employed for the silver-mediated oxidative
trifluoromethylation of alcohols.[15] Unfortunately, these
compounds have intrinsic limitations, including: 1) degradation of
the OCF3 fragment to fluorophosgene, 2) reagent synthesis from
toxic, gaseous or expensive chemicals, 3) often low yields, 4) the
requirement of several additives (including transition-metal
catalysts), and 5) need for pre-functionalized materials. In 2018
three radical trifluoromethoxylating reagents were reported; the
group of Ngai reported the use of benzimidazole[2] and
benzotriazole[3] based compounds, while one of our groups
reported a pyridine N-oxide reagent.[1] The major advantage of
these radical based reagents is the ability to functionalize
unactivated arenes under photoredox conditions. Thus far, this
method has not been extended beyond arenes, and is
encumbered firstly by the poor selectivity of the reagents
(resulting in mixtures of regioisomeric products), and the
requirement for large excess of starting material (5-10 eq.). A
much simpler and highly functional group tolerant method for
OCF3 formation is via the electrophilic trifluoromethylation of
alcohols; this direct approach is the most practically
straightforward. However, it is the least explored, with only two
reagents known in the literature that are capable of this
transformation. The first reagent, reported in 2007, is an O-
(trifluoromethyl)dibenzofuranium salt or “Umemoto’s reagent”
(Scheme 1b), which was successfully employed for the formation
of both aryl and alkyl trifluoromethyl ethers.[16] However, the use
Traditionally, trifluoromethyl ethers were accessed via de novo
synthesis under harsh reaction conditions using toxic, difficult to
handle chemicals, and pre-functionalized compounds, rendering
these methods limited in practicality and scope (Scheme 1a).[7]
Trifluoromethoxylated compounds are therefore often obtained
via multistep synthesis from expensive building blocks. Recently,
several mild reagents have emerged which employ either a
nucleophilic or radical pathway for the formation of the C–OCF3
J. Kalim, Prof. Dr. A. Togni
Swiss Federal Institute of Technology, ETH Zurich
Vladimir-Prelog-Weg 2, 8093 Zurich (Switzerland)
E-mail: atogni@ethz.ch
T. Duhail, Dr. E. Anselmi, Dr. E. Magnier
Université Paris-Saclay, UVSQ, CNRS, UMR 8180
Institut Lavoisier de Versailles, 78035 Versailles Cedex (France
E-mail: emmanuel.magnier@uvsq.fr
Dr. E. Pietrasiak
Pahong University of Science and Technology, Pahong 37673 (Republic of
Korea)
Dr. E. Anselmi
Université de Tours, Faculté des Sciences et Techniques, 37200 Tours
(France)
Supporting information for this article is given via a link at the end of the
document.
1
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of this compound is hampered firstly by the synthetic challenge of
preparing the reagent precursors, after which the oxonium salt is
generated in situ under photochemical conditions between -70
and -90 °C. In 2009, one of our groups reported the use of
Ph
OH
OCF3
I
N
S
O
reagent, catalyst
neat, 30 min
+
CF3
hypervalent iodine compound
1
(Scheme 1b) for the
3 eq. 3a
Entry Reagent
4a
5a
trifluoromethylation of primary and secondary alcohols using zinc
triflimide in either catalytic (usually requiring more than 30 mol-%)
or stoichiometric amounts.[17,18] Trifluoromethylation of triflimide
occurred as a competing reaction, requiring large excesses of
alcohol to be used (5-75 eq.) in order to achieve reasonable yields
(12-99%). Despite these advances, the generation of
trifluoromethyl ethers from alcohols as a fundamental synthetic
transformation remains hindered by impractical reaction
conditions. Newer methods that circumvent these issues are
highly desirable, thus highlighting the need for improved
conditions and reagents which the present study addresses.
Catalyst
(eq.)
Temperature
(°C)
Yield
Yield
4a (%)a
5a (%)a
1
2
3
2
2
2
Zn(NTf2)2, (0.25)
Zn(NTf2)2 (0.10)
Zn(NTf2)2, (0.025)
–
40
40
40
4
56
28
13
25
35
4
5
2
2
40
23
4
10
8
Zn(NTf2)2, (0.025)
Zn(NTf2)2, (0.025)
Zn(NTf2)2, (0.10)
Zn(NTf2)2, (0.025)
33
6b
2
23
46
11
7b
8
2
1
23
23
49
0
10
n.d.
F3C
I
O
F3C
I
N
S
Recently, we reported the synthesis and characterization of a new
electrophilic trifluoromethylating reagent which combines the
hypervalent iodine motif with a sulfoximine ligand (“HYPISUL”
reagent 2 in Scheme 1c).[19] HYPISUL is similarly reactive to the
parent Togni-type reagents in the trifluoromethylation of C-, S-
and P-nucleophiles. We anticipated that 2 could prove more
efficient in the trifluoromethylation of alcohols compared to 1 due
to the presence of a Lewis basic nitrogen atom which is likely to
coordinate to Lewis acidic species more readily. Herein, we report
the good reactivity of aliphatic alcohols with the HYPISUL reagent
catalyzed by zinc triflimide (2.5 to 20 mol-%); this is an
operationally simple setup which gives trifluoromethyl ethers in
relatively high yields, with comparatively minimal catalyst and
substrate loadings, within short reaction times. In particular, we
are able to demonstrate a broader substrate scope for the
trifluoromethylation of a variety of secondary and bio-relevant
CF3
O
O
1
2
Table 1. Optimization of reaction conditions for the trifluoromethylation of 3a
with 2. Yields are based on reagent 2 and determined by 19F NMR using
trifluoromethoxybenzene as an internal standard. [b] with 6.0 eq. of 3a.
in moderate yields after 30 min under neat reaction conditions.
The choice of Zn(NTf2)2 is advantageous due to the fact that it is
a minimally hygroscopic Lewis acid and thus ideal from a practical
point of view. The yield of 4a could be increased by lowering the
catalyst loading from 25 mol-% to 2.5 mol-% (Table 1, entries 1-
3), which supressed the formation of an N-alkylated side product
5a. We speculated that 5a is produced via the formation of an
intermediate carbocation species which then reacts with the
nitrogen of the sulfoximine moiety. This was tentatively verified by
using (R)-1-phenylethanol with 2, which gave 5a as a mixture of
diastereomers (see Supporting Information for details). Useful
yields with 2 could be obtained by decreasing the temperature to
23 °C (entry 5) and increasing the amount of substrate 3a to 6.0
equivalents to give 4a in 46% (entry 6). When we examined
compound 1 under the same reaction conditions, no product was
formed (entry 8), however by stirring the reaction at 40 °C for 3.5
h, 27% of 4a was obtained (see Supporting Information).
alcohols featuring various functional groups,
a significant
improvement to the former strategy using 1, as well as those
reported using other reagents. Previously, extensive
computational work has been dedicated to deciphering whether
reactions involving O- and N-centered nucleophiles with reagents
of type 1 occur via a radical, SN2 or reductive elimination type
pathway with contradictory findings.[20–22] Through a series of
control experiments, we provide strong evidence that the
mechanism for this reaction involves the coordination of the
alcohol substrate to the hypervalent iodine species, affording the
trifluoromethyl ether through a reductive elimination process.
With the optimized conditions in hand, we sought to examine and
broaden the substrate scope. Starting with aliphatic alcohols,
which are the least prone to side-product formation (Scheme 2,
3b to 3e), we found that using just 6.0 equivalents of the starting
material, an increased catalyst load of 10 mol-%, under neat
conditions gave yields between 44-68% in under 2 h. Benzylic
alcohols (3g to 3n) gave slightly lower yields due to the increased
likelihood of forming the N-alkylated side product, which was
We started our investigation using 1-phenylethanol (3a, Table 1)
as a model substrate in order to examine the possibility of
improving the yield of the electrophilic trifluoromethylation of
secondary alcohols. This substrate was chosen due to the fact
that in our previous work using 1, we found that benzylic alcohols
were particularly difficult to functionalize. Taking 3.0 equivalents
of 3a and 1.0 equivalent of 2, we investigated the use of various
Lewis acid catalysts (See Supporting Information for details) and
found Zn(NTf2)2 to be the optimal catalyst, giving 4a
2
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F3C
I
N
S
Zn(NTf2)2 (2.5 mol-% or 10 mol-%),
neat, CH2Cl2 or 1,2-dichloroethane
CF3
ROH
+
R
OCF3
O
6 eq. 3b-3ah
4b-4ah
1 eq. 2
Substrate scope
OCF3
OCF3
OCF3
Cl
OCF3
F3C
OCF3
R
OCF3
O2N
4g, R = H, 50%a 4k, R = I, 32%a
4h, R = F, 62%a 4l, R = CN, 47%
4e, 44% (26%)a
4b, 66%a
4c, 67%a
4d, 68%a
4f, 18%
4i, R = Cl, 29%a
4m, R = NO2, 40%
4j, R = Br, 33%
4n, R = CO2Me, 33%
Br
O
OCH3
OCF3
Br
OCF3
O
OCF3
OCF3
OCF3
OCF3
OCF3
S
4q, 65%b
4o, 65% (41%)a
4p, 49% (38%)a
4r, 30%
4s, (62%)
4u, 62%
4t, (65%)
OCF3
OCF3
OCH3
O
OCF3
OCF3
OCF3
OCF3
O
OCF3
OCF3
4x, 36%
4v, 72%
4w, 49% (38%)
4y, 55% (37%)
4z, 73% (24%)
4aa, 50% (25%)c
4ab, 14% (10%)c
4ac, 26%d
OCF3
O
OAc
OAc
F3CO
O
F3CO
O
Ph
AcO
O
O
O
OCF3
OAc
4ad, 39% (18%)c
4ae, 53% (18%)
4af, 17%d
4ag, 36%e
F3CO
4ah, 69% (49%)d
Scheme 2. Substrate scope of trifluoromethylation of aliphatic alcohols with 2. For all substrates which are oils no heating was required, in cases where the starting
material was a solid the reaction was conducted at the melting point of the compound if applicable or in solvent. Yields were based on reagent 2 and determined by
19F NMR analysis. Yields of isolated products are given in parenthesis. [a] 10 mol-% catalyst was used. [b] 20 mol-% catalyst was used. [c] reaction in 1,2-
dichloroethane (0.25 M in 2). [d] 10 mol-% catalyst was used, reaction in CH2Cl2 (0.13 M in 2). [e] 20 mol-% catalyst was used, reaction in CH2Cl2 (0.13 M in 2).
minimized by lowering the catalyst loading in most cases to 2.5
mol-%. This methodology is most amenable to benzylic alcohols
bearing electron-withdrawing groups; halides in o-, m- and p-
positions were all well tolerated (4h-4k, 4o, 4p) as well as nitrile
(4l), nitro (4m) and ester (4n) groups. Trifluoromethylation of an
alcohol bearing an α-methoxy group gave the product (4q) in
good yields (65%), however an α-carbonyl function (4r) was less
well tolerated (30% yield). We then turned our attention to
compounds containing synthetically useful motifs, such as
heteroarenes (3s and 3t), an alkyne (3u) and alkene (3e), which
proceeded to give the trifluoromethoxy-containing products in
good yields (44-65%). To our delight, secondary alcohols (3v-
3aa) gave moderate to good yields (36-73%) when using 2.5
mol-% catalyst in all cases, something that could not easily be
achieved using 1. Surprisingly, we found adamantanol (3ac) to be
a viable tertiary substrate, giving a 26% yield when employing 10
mol-% catalyst with CH2Cl2 as solvent. Furthermore, we were
pleased to find these reaction conditions amenable to biologically
relevant compounds such as borneol (3ad), (–)-8-phenylmenthol
(3ae), carbohydrate derivatives (3af and 3ag), and cholesterol
(3ah). Given that these substrates are often valuable, we could
reduce the amount of starting material used from 6.0 to 3.0
equivalents by increasing the reaction time, for example 4ah was
obtained in 69% yield with 6.0 equivalents after 3 d, upon reducing
the amount of 3ah to 3.0 equivalents and extending the reaction
period to 13 d, 72% of 4ah was formed.
selectivity was tested using 2-methoxy-2-phenylethanol and 2-
methoxy-1-phenylethanol; 75:25 selectivity was observed for
primary vs. secondary alcohol functionalization. Taking heptane-
1,6-diol, we found the reagent to have 56:40 chemoselectivity for
primary alcohols vs. secondary, further highlighting the good
reactivity of 2 with secondary alcohols. The chemoselectivity for
primary alcohols over tertiary gave 73:27 selectivity when using
3-(hydroxymethyl)-1-adamantol.
Intermolecular competition experiments
OCH3
OCF3
OCF3
OCH3
:
Ph
Ph
75:25 (62% yield)
Intramolecular competition experiments
OR1
OR1
OR2
OR2
A: R1 = H, R2 = CF3
B: R1 = CF3, R2 = H
C: R1 = CF3, R2 = CF3
A: R1 = H, R2 = CF3
B: R1 = CF3, R2 = H
A:B:C, 56:40:4 (77% yield)
A:B, 73:27 (24% yield)
Figure 1. Selectivity of reagent 2 for primary, secondary and tertiary alcohols. .
Yields were based on reagent 2 and determined by 19F NMR analysis.
Next, we sought to examine the inter- and intramolecular
selectivity of the reagent (Scheme 2). The intermolecular
3
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Finally, given the improved reactivity of reagent 2, we speculated
whether improved yields would also be observed for phenols
compared to that reported with 1.[17] However, taking phenol and
4-chlorophenol, poor selectivity for O-trifluoromethylation was
observed in both cases (11% and 16%, respectively) with C-
trifluoromethylated side-products observed by NMR spectroscopy.
I
NH
S
O
CF3
+
ROCF3
6
Zn(NTf2)2 = ZnX2
2
H+
reductive
elimination
R
In order to gain insight into why compound 2 out-performs 1 for
this transformation, DFT calculations were performed.
Investigating the natural charges on the carboxylate and
sulfoximine ligands, we found the lowest natural charge to be on
the nitrogen atom in 2, suggesting a stronger and thus more
favorable coordination of 2 with zinc triflimide. Based on our
previous findings,[17] we expected the reagents to form a 2:1
reagent·Zn adduct, DFT calculations on the optimized adducts
indicated that [ZnNTf2(2)2]NTf2 is thermodynamically favored
compared to [ZnNTf2(1)2]NTf2 by 6 kcal/mol in solution (see
Supporting Information for details). To further validate the
predicted stoichiometry, 19F NMR experiments were conducted,
which showed a downfield shift of the I–CF3 signal upon addition
of increasing amounts of Zn(NTf2)2 as a result of the increasing
iodonium character of 2.[23] Broadened signals were observed
upon addition of up to 0.50 eq. of the zinc catalyst, with sharpened
signals observed thereafter suggesting the likelihood of a 2:1
adduct.
O
[Zn(2)]X
[Zn]X
F3C
I
N
S
O
F3C
I
N
S
CF3
CF3
O
I
III
H
O
H+
R
ROH
[Zn]X
F3C
I
N
S
O
CF3
II
[Zn(OH)]X
R
F3C
I
N
S
I
N
S
CF3
+
CF3
R+
O
O
5
Scheme 3 Mechanistic proposal for the zinc catalyzed trifluoromethylation of
alcohols using reagent 2.
To probe the mechanism of this reaction we carried out selected
experiments which led us to conclude that a reductive elimination
pathway is operative. Firstly, we examined whether the reaction
involves radical intermediates, the reaction between 2 and 3h was
conducted in the presence of known radical acceptors (see
Supporting Information for further details). When using CBr4 and
styrene, the formation of product 4h was unimpeded, indicating
that this transformation occurs without the formation of radical
species. Using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as
a radical trap, product formation was completely inhibited due to
the oxidation of the alcohol substrate[24] and formation of the
corresponding hydroxylamine which is trifluoromethylated by 2,
as previously observed with Togni-type reagents.[25] Two possible
mechanistic pathways after formation of the 2:1 adduct (I) can
then be postulated.[17] The first, an SN2-type pathway, involves the
intermolecular attack of the nucleophile onto the CF3 moiety.
Alternatively, the nucleophile may coordinate to the iodine atom
to give the intermediate III; the trifluoromethoxy-containing
product is then formed after reductive elimination. To examine the
SN2-type pathway we carried out the reaction using the
corresponding alcoholate generated using NaH, the reagent and
catalyst were added after 10 mins of stirring, however no product
was formed, suggesting that an SN2 reaction is unlikely (see
Supporting Information, table 1). Additionally, taking a sterically
hindered nucleophile, diphenylmethanol (3ab), we found that the
corresponding trifluoromethyl ether was formed in moderate yield,
and the N-alkylated side-product, 5ab, was detected in 78% yield
by GCMS, (5ab was characterized by XRD, see Supporting
Information for details), further refuting an SN2 mechanism. The
formation of the side-products of type 5 is facilitated by the
coordination of the alcohol to the iodine atom in II (depicted in
Scheme 3), C–OH cleavage subsequently occurs due to the
proximity to the zinc(II) center which acts as a hydroxide
scavenger, giving the carbocationic R+ species. To validate this
hypothesis, we conducted an additional control
experiment taking iodosulfoximine 6 (Scheme 3) and 3a under the
standard reaction conditions. In this case the side-product was
not formed, hence coordination of the alcohol to the hypervalent
iodine center is essential. These experiments strongly support the
mechanistic pathway depicted in Scheme 3.
In conclusion, we describe the reactivity of reagent 2 with aliphatic
alcohols which gives trifluoromethyl ethers in an efficient and
atom-economic manner compared to many former strategies.
Using only 1.0 equivalent of 2 and minimal catalyst loadings (2.5
to 20 mol-%), a wide variety of trifluoromethyl ethers can be
accessed. The reaction shows high chemoselectivity, allowing for
the selective trifluoromethylation of alcohols in the presence of
many functional groups. We were particularly pleased to find that
the substrate scope could be expanded to a variety of secondary
alcohols and biologically relevant molecules. Finally, we provide
compelling experimental evidence that this reaction occurs
through a reductive elimination process. We anticipate this
method to be highly useful as a simple and practical method and
continue to explore the potential of reagent 2 in our labs.
Acknowledgements
This work was supported by a grant from the Swiss National
Science Foundation (Grant 200021E_175680/1) and the Agence
Nationale de la Recherche (ANR) with PRCI funding (ANR-17-
CE07-0048-01). J. K. would like to thank Sebastian Küng for help
with preparing starting materials. Dr. N. Trapp and Michael Solar
are thanked for their support with X-Ray Crystallography.
4
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COMMUNICATION
Keywords: Trifluoromethylation • Hypervalent Iodine •
Sulfoximines • Organofluorine Compounds •
Trifluoromethylethers
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10.1002/chem.202005104
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
R
OCF3
R
F3C
I
N
S
Zn cat.
OH
OCF3
+
2
CF3
CF3
32-65%
R
R
O
S
F3CO
65%
69%
→ Catalytic
→ Operationally simple
→ Broad Scope (34 examples)
→ Short reaction times
Trilfuoromethylethers made easy! An operationally simple
method using the new hypervalent iodosulfoximine reagent
alongside minimal amounts of a zinc catalyst, gives access to a
variety of different trifluoromethylethers, in under 2 hours for
most cases.
6
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