Electrophilic Hypervalent Trifluoromethylthio-Iodine(III) Reagent

Article abstract of DOI:10.1021/acs.orglett.0c00405

Herein we report the design and synthesis of hypervalent trifluoromethylthio-iodine(III) reagent 1 and the elucidation of its structure by NMR spectroscopy and X-ray crystallography. The trifluoromethylthiolation reactions of 1 with various nucleophiles were explored, and this compound was found to be a versatile electrophilic reagent for the transfer of a trifluoromethylthio group (-SCF₃). The hydrogen-bonding mode responsible for the activation of 1 by the solvent 1,1,1,3,3,3-hexafluoro-2-propanol was investigated both experimentally and computationally.

Full text of DOI:10.1021/acs.orglett.0c00405

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Electrophilic Hypervalent Trifluoromethylthio-Iodine(III) Reagent
Xiao-Guang Yang, Ke Zheng, and Chi Zhang*
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ABSTRACT: Herein we report the design and synthesis of
hypervalent trifluoromethylthio-iodine(III) reagent 1 and the
elucidation of its structure by NMR spectroscopy and X-ray
crystallography. The trifluoromethylthiolation reactions of 1 with
various nucleophiles were explored, and this compound was found
to be a versatile electrophilic reagent for the transfer of a
trifluoromethylthio group (−SCF3). The hydrogen-bonding mode
responsible for the activation of 1 by the solvent 1,1,1,3,3,3-
hexafluoro-2-propanol was investigated both experimentally and
computationally.
Scheme 1. (a) Representative Existing Electrophilic SCF3-
Transfer Reagents and (b) New SCF3-Transfer Reagent 1
ypervalent iodine reagents are multipurpose oxidizing
Hagents, and their effectiveness as functional-group-
transfer reagents is well-recognized.1 For example, chlorine
atoms and tosylate, cyano, and azide groups have been
introduced into organic molecules by means of ArICl2,2
Koser’s reagent,3 Zhdankin’s cyanoiodinane,4 and azidoiodi-
nane,5 respectively. In addition, fluorine atoms and various
fluorine-containing functional groups can also be efficiently
incorporated into organic molecules by using hypervalent
iodine(III) reagents. For example, ArIF2 and fluoro-benziodox-
ole can transfer a fluorine atom,6 Togni’s reagent and its
analogues can transfer a CF3 group,7 and perfluoroalkyl λ3-
iodane reagents can transfer their perfluoroalkyl groups.8
The trifluoromethylthiol group (−SCF3), a heteroatomic
fluorinated group, shows promise for medicinal chemistry
applications because it can enhance the lipophilicity and
metabolic stability of drugs as well as agrochemicals.9
Therefore, considerable effort has been devoted to the
development of SCF3-transfer reagents.10 In particular, the
research groups of Haas,11 Munavalli,12 Billard,13 Shen,14 and
Shibata15 have contributed greatly to this field with their
syntheses of novel electrophilic SCF3-transfer reagents, which
can be classified as N-based, O-based, or SO2CF3-based,
depending on their structures (Scheme 1a). Of particular
interest is Shibata’s reagent, a unique trifluoromethanesulfonyl
hypervalent iodonium ylide that acts as an efficient electro-
philic SCF3-transfer reagent in the presence of a copper(I)
catalyst. However, Shibata’s reagent does not contain an
I(III)−S bond, and the SCF3 group is generated by in situ
reduction of an SO2CF3 moiety with intramolecular
rearrangement.15a To the best of our knowledge, a hypervalent
iodine(III) reagent bearing an SCF3 group directly bonded to a
λ3-iodine atom remains unknown.14a,16 In this study, we
designed and synthesized the first N-acetylbenziodazole-based
hypervalent trifluoromethylthio-iodine(III) reagent (1, Scheme
1b) and explored its ability to act as an electrophilic SCF3-
transfer reagent.
In 2016, Schaefer and Zhang et al. showed that the
benziodoxole-based SCF3-transfer reagent would be unstable
on the basis of computational results.17 Therefore, we chose
the N-acetylbenziodazole skeleton, which has been less
investigated so far,18 and the specific reasons are as follows.
First, because intramolecular secondary I···O bonding is
Received: January 31, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00405
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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known to stabilize λ3-iodanes, we hypothesized that the
introduction of an acetyl group onto the benziodazole skeleton
would stabilize the reagent via a secondary bonding interaction
between the λ3-iodine atom and the carbonyl oxygen of the
acetyl group. Second, the mutual ligand interference (trans
influence) plays an important role in the stability of λ3-iodanes,
and a principle is developed in which a λ3-iodane with a strong
trans-influencing ligand and a moderate trans-influencing
ligand is stable.19 Suresh et al. used the molecular electrostatic
potential (MESP) minimum (Vmin) as a measure to quantify
the trans influence of ligands in λ3-iodanes.20 On the basis of
their work, we classified the SCF3 group and N-acetylbenza-
mido group (−N(PhCO)COMe) as moderate and strong
trans-influencing ligands, respectively, by density functional
theory (DFT) calculations. (See the SI for details.) In view of
the previously mentioned reasons, we speculated that the
combination of a SCF3 ligand and an N-acetylbenziodazole
skeleton would be favored and therefore tried to synthesize a
hypervalent trifluoromethylthio-iodine(III) reagent.
Figure 1. Single-crystal X-ray structure of 1.
typical of λ3-iodanes. The I1···O2 distance (2.966 Å) was
considerably shorter than the sum of the van der Waals radii of
the two atoms (3.50 Å),21 indicating the presence of secondary
bonding. Notably, this is the first observation of an I(III)−
SCF3 bond, which has a bond length of 2.566 Å.
With hypervalent trifluoromethylthio-iodine(III) reagent 1
in hand, we explored its synthetic utility for the trifluor-
omethylthiolation of nucleophiles (Scheme 3). We found that
Reagent 1 was readily synthesized via a three-step process
(Scheme 2). First, 2-iodobenzamide was acetylated to afford
Scheme 3. Direct Electrophilic Trifluoromethylthiolation of
a
Various Nucleophiles with 1
Scheme 2. Synthesis of Hypervalent Trifluoromethylthio-
iodine(III) Reagent 1
N-acetyl-2-iodobenzamide, which was allowed to react with t-
BuOCl to give hypervalent iodine(III) compound 2. A ligand
exchange reaction between 2 and AgSCF3 generated hyper-
valent trifluoromethylthio-iodine(III) reagent 1 as a colorless
1
solid in 75% overall yield. Reagent 1 was characterized by H,
13C, and 19F NMR spectroscopy and high-resolution mass
spectrometry. The 13C NMR chemical shift of the C−I ipso-
carbon (113.1 ppm) was in the typical region reported for
hypervalent iodine(III) compounds. The 19F NMR signal for
the I(III)-SCF3 moiety (−29.6 ppm) appeared at a markedly
lower field than the signals for N−SCF3 and O−SCF3
fragments (which range from −47.3 to −53.3 ppm), owing
to the strong deshielding effect of the λ3-iodine atom. It is
worth noting that 1 could be prepared on a large scale (25
mmol, 8.79 g) without diminishment of the yield.
Reagent 1 was air- and moisture-stable and could be stored
in a freezer (−20 °C) for at least 4 months without
decomposition. Thermogravimetry/differential thermal anal-
ysis showed that 1 decomposed at 137 °C to give a brown tar
(Figure S1). The reagent showed good solubility in common
organic solvents, including dichloromethane, chloroform, and
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP).
a
b
Isolated yields are reported. Reaction conditions, unless otherwise
noted: β-dicarbonyl compound (0.2 mmol), 1 (0.3 mmol), triethyl-
amine (0.22 mmol), MeCN (2 mL), rt. Substrate (0.2 mmol), 1
(0.24−0.30 mmol), HFIP (2 mL), rt. Reaction conditions, unless
otherwise noted: boronic acid (0.1 mmol), 1 (0.15 mmol), CuI (5
c
d
mmol %), 1,10-phenanthroline (10 mmol %), K2CO3 (0.2 mmol),
e
MeCN (2 mL), 65 °C. Substrate (0.2 mmol), 1 (0.24 mmol),
f
dichloromethane (2 mL), 0 °C. Sodium benzenesulfinate (0.3
g
mmol), 1 (0.2 mmol), HOAc (2 mL), rt. 1-Naphthanol (0.2 mmol),
h
1 (0.3 mmol), CHCl3 (2 mL), rt. Reaction was performed at 0 °C.
i
j
C2H5ONa (3.0 equiv) was used as a base. Reaction was performed at
rt.
cyclic and acyclic β-dicarbonyl compounds, including β-
ketoesters and a β-ketoamide, reacted with 1 in the presence
of a base under mild conditions to give the corresponding α-
trifluoromethylthiolated products (3a−f) in good to excellent
yield. Because SCF3-substituted arenes and heteroarenes are
important structural motifs in pharmaceuticals and agro-
chemicals,9a we also evaluated reactions of these types of
substrates and found that electron-rich arenes and hetero-
arenes (a pyrrole and an indole) could be transformed into the
corresponding trifluoromethylthiolated products (4a, 4b, 6a,
A single crystal of 1 was grown in dichloromethane/n-
hexane at room temperature, and X-ray crystallography showed
that the S1−I−N1 bond angle (169.33°) was <180° and that
the C1−I−S1 and C1−I−N1 bond angles (92.97 and 76.47°,
respectively) deviated from 90° (Figure 1). These results
demonstrate that 1 has a distorted T-shaped structure that is
B
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and 6b) by reaction with 1 in high to excellent yield.
Gratifyingly, even an unactivated arene could be efficiently
trifluoromethylthiolated: Compound 5 was obtained when the
corresponding aryl boronic acid was used as the substrate and
CuI was included as a catalyst. 1-Naphthanol was also a good
substrate, affording 4-trifluoromethylthiolated-1-naphthanol
(7) in a synthetically useful yield. The reaction of an enamine
with 1 afforded C(sp2)−H trifluoromethylthiolation product 8
in 74% yield when HFIP was used as a solvent. In addition,
trifluoromethylthiostyrenes 9a and 9b were obtained from the
corresponding styryl boronic acids in the presence of a catalytic
amount of CuI. Notably, this transformation was stereo-
specific: Only the E product was observed by 19F NMR
spectroscopy. Heteroatoms could also undergo trifluorome-
thylthiolation. Specifically, the SCF3 moiety could be efficiently
introduced onto the S (−2, +4), N, and Se atoms of p-
methoxybenzenethiol, sodium benzenesulfinate, diphenylme-
thanimine, 3-ethynylaniline, and phenylselenol upon reaction
with 1. It is worth noting that the reduction product N-acetyl-
2-iodobenzamide of 1 could be easily recovered (93%) after
the reactions to regenerate 1 by oxidation and ligand exchange.
Encouraged by the utility of 1 for the trifluoromethylth-
iolation of the arylthiol, we examined the reactivity of 1 with
three biologically relevant compounds bearing thiol groups
(Scheme 4). Both protected cysteine derivative 14 and 1-
Scheme 5. Trifluoromethylthiolation of Cysteine Residues
of Dipeptides
a
a
Isolated yields are reported. Reaction conditions, unless otherwise
noted: dipeptide (0.1 mmol), 1 (0.12 mmol), HFIP (2 mL), rt, 0.5 h.
b
Reaction time was 2 h.
Scheme 4. Trifluoromethylthiolation of Biologically
Relevant Thiol-Containing Compounds
dipeptides containing nonpolar natural amino acids (Ala, Gly,
Ile, Leu, Phe, and Val) with 1 in HFIP at room temperature
generated the corresponding trifluoromethyl disulfides in good
to high yield. This reaction showed excellent chemoselectivity;
cysteine residues could be selectively trifluoromethylthiolated
in the presence of other nucleophilic functional groups. For
example, dipeptides containing asparagine, proline, and
tryptophan residues all smoothly afforded the corresponding
dipeptides with trifluoromethylthiolated cysteine residues.
Notably, readily oxidized groups such as the methylthio
group of methionine, the hydroxyl group of serine, and the
phenolic group of tyrosine were also tolerated. Previous works
mainly focused on the trifluoromethylthioation of simple
thiols;25 as far as we know, this is the first systematic study on
the trifluoromethylthioation of cysteine-containing dipeptides.
As a strong hydrogen-bond donor,26 HFIP markedly
activates hypervalent iodine(III) reagents and existing SCF3-
transfer reagents via the hydrogen-bonding interaction.27 In
many of the reactions previously described, we observed that
using HFIP as a solvent facilitated the transfer of SCF3. To
gain insight into the mechanism by which HFIP activated 1, we
a
b
Isolated yield. Yield determined by 19F NMR spectroscopy with
PhCF3 as an internal standard.
thioglucose derivative 16 reacted with 1 under mild conditions
to give the corresponding trifluoromethyl disulfides in high
yield. It is worth noting that captopril, a widely used
antihypertension drug, was successfully trifluoromethylthio-
lated by using 1, affording the desired product 18 in 99% yield,
and the free carboxylic acid group did not hamper the reaction.
Previous literature has shown that trifluoromethyl disulfides
are valuable precursors to prepare biologically active
trifluoromethyl thiosulfonates.22
The modification of peptides and proteins is a powerful
strategy for modulating their biological functions,23 and
numerous methods for the modification of peptides or proteins
at cysteine residues have been reported.24 In this study, we
used the protocol described herein to carry out the
trifluoromethylthiolation of dipeptides at their cysteine
residues (Scheme 5). Specifically, the treatment of various
1
performed a H NMR spectroscopy study (Figure 2) and
1
density functional theory (DFT) calculations. The H NMR
spectrum of a 1:2 mixture of 1 and HFIP (Figure 2c) showed a
downfield shift of the OH signal of HFIP relative to that in the
absence of 1 (Figure 2a). The DFT calculations indicated that
HFIP formed hydrogen bonds with the two carbonyl oxygen
atoms of 1, and thus the nitrogen and sulfur atoms in the
hydrogen-bonded adduct were more electron-deficient than
those in isolated 1. (The charge distributions were −0.010 vs
0.191 and 0.117 vs 0.348, respectively; see the SI for details.)
On the basis of these experimental and theoretical results, we
reasoned that hydrogen bonding between 1 and HFIP
activated 1 by polarizing the hypervalent iodine bond. HFIP
may also have stabilized the trifluoromethylthio cation
(CF3S+).
C
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Tianjin 300071, China; orcid.org/0000-0001-9050-076X;
Email: zhangchi@nankai.edu.cn
Authors
Xiao-Guang Yang − State Key Laboratory of Elemento-Organic
Chemistry, Collaborative Innovation Center of Chemical
Science and Engineering, College of Chemistry, Nankai
University, Tianjin 300071, China
Ke Zheng − State Key Laboratory of Elemento-Organic
Chemistry, Collaborative Innovation Center of Chemical
Science and Engineering, College of Chemistry, Nankai
University, Tianjin 300071, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00405
Figure 2. 1H NMR spectra of (a) HFIP, (b) 1, and (c) a 1:2 mixture
of 1 and HFIP. The red arrow indicates the OH signal of interest,
which was deshielded in the adduct.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21472094, 21772096), the
National Key R&D Program of China (2017YFD020030202),
and The Tianjin Natural Science Foundation
(17JCYBJC20300).
In addition, we calculated the trifluoromethylthio-cation-
donating ability (Tt+DA) of 1 on the quantitative scale
established by Cheng and Xue’s group28 for electrophilic SCF3-
transfer reagents. This calculation revealed the Tt+DA value for
1 was 10.1 kcal·mol−1, confirming it to be a powerful
electrophilic SCF3-transfer reagent.
In conclusion, we designed and synthesized the first
hypervalent trifluoromethylthio-iodine(III) reagent 1. Reagent
1, which has a typical λ3-iodane structure, was characterized by
NMR spectroscopy and X-ray crystallography. We found that 1
could be used as an electrophilic SCF3-transfer reagent for the
trifluoromethylthiolation of various nucleophiles under mild
conditions. In particular, by using 1, we were able to
accomplish selective trifluoromethylthiolation of dipeptides at
cysteine residues with good tolerance for other functional
groups. Our findings reveal 1 to be an attractive tool for the
incorporation of SCF3 into molecules. Furthermore, we used
experimental and computational techniques to determine the
hydrogen-bonding mode by which HFIP activated 1. Further
study of the unique reactivity of 1 is underway in our
laboratory.
REFERENCES
■
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Experimental details, analytical data, and NMR spectra
(PDF)
Accession Codes
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crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
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(3) (a) Koser, G. F.; Rebrovic, L.; Wettach, R. H. Functionalization
of alkenes and alkynes with [hydroxy(tosyloxy)iodo]benzene. Bis-
(tosyloxy)alkanes, vinylaryliodonium tosylates, and alkynylaryliodo-
nium tosylates. J. Org. Chem. 1981, 46, 4324−4326. (b) Koser, G. F.
[Hydroxy(tosyloxy)iodo]benzene and closely related iodanes: the
second stage of development. Aldrichimica Acta 2002, 34, 89−102.
AUTHOR INFORMATION
Corresponding Author
■
Chi Zhang − State Key Laboratory of Elemento-Organic
Chemistry, Collaborative Innovation Center of Chemical Science
and Engineering, College of Chemistry, Nankai University,
D
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