Deconstructing the Catalytic, Vicinal Difluorination of Alkenes: HF-Free Synthesis and Structural Study of p-TolIF2

Article abstract of DOI:10.1021/acs.joc.7b01671

Recently, contemporaneous strategies to achieve the vicinal difluorination of alkenes via an I(I)/I(III) catalysis manifold were independently reported by this laboratory and by Jacobsen and co-workers. Both strategies proceed through a transient ArI(III)

Full text of DOI:10.1021/acs.joc.7b01671

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Article
Deconstructing the Catalytic, Vicinal Difluorination of
Alkenes: HF-Free Synthesis and Structural Study of p-TolIF2
Jérôme C Sarie, Christian Thiehoff, Richard J Mudd, Constantin G. Daniliuc, Gerald Kehr, and Ryan Gilmour
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01671 • Publication Date (Web): 28 Jul 2017
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The Journal of Organic Chemistry
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Deconstructing the Catalytic, Vicinal Difluorination of Alkenes: HF-
Free Synthesis and Structural Study of p-TolIF2
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Jérôme C. Sarie, Christian Thiehoff, Richard J. Mudd, Constantin G. Daniliuc,‡ Gerald Kehr, and Ryan
Gilmour*
Institute of Organic Chemistry, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany.
Supporting Information Placeholder
tion of the ArI(III)F2 intermediate. In contrast to Jacobsen’s pro-
cedure, whereby oxidation of the resorcinal catalyst by m-CPBA
proceeds via an ArIO intermediate, our approach relied on Select-
fluor® as the oxidant of choice.12 Whilst highly effective, this
oxidant raised a number of mechanistic questions regarding the
formation of p-TolI(III)F2, and the ultimate fate of the tetra-
fluoroborate counterion.
ABSTRACT: Recently, contemporaneous strategies to achieve
the vicinal difluorination of alkenes via an I(I)/I(III) catalysis
manifold were independently reported by this laboratory and by
Jacobsen and co-workers. Both strategies proceed through a tran-
sient ArI(III)F2 species generated by oxidation of the ArI catalyst.
Herein, an efficient synthesis of p-TolIF2 from p-TolI and Select-
fluor® is presented, together with a crystallographic and spectro-
scopic study. To mitigate safety concerns and simplify reaction
execution, an HF-free protocol was devised employing CsF as a
substitute fluoride source. The study provides insight into the
initial I(I) → I(III) oxidation stage of the catalytic protocol using
Selectfluor®.
Scheme 1. Organocatalytic, vicinal difluorination of alkenes
via a transient ArI(III)F2 intermediate.
Introduction
The vicinal difluoroethylene unit is synonymous with the fluorine
gauche effect; a reinforcing stereoelectronic phenomena that man-
ifests itself in a characteristic syn-clinal conformation with respect
to the F-C(sp3)-C(sp3)-F torsion angle (ϕ ≈ 60°).1,2 The effective-
ness of this motif in modulating structure and function has result-
ed in a rapid growth in the strategic installation of the vicinal
difluoroethylene group in catalysts and biomolecules.3 Despite
this, efficient catalysis-based strategies to install this moiety from
simple alkenes are rare; a problem that, although less pronounced,
is common to the vicinal dihalogenation of olefins generally.4
Whilst elegant strategies have been devised for olefin halogena-
tion, many of which are stereospecific,5 the deficiency of catalytic
vicinal difluorination protocols is conspicuous.6 The acuteness of
the problem is further augmented by the preeminence of fluorine
in pharmaceutical research and development.7
As part of a broader organo-fluorine program,8 this laboratory
recently reported a vicinal difluorination of alkenes catalyzed by
p-TolI proceeding via a proposed I(I)/I(III) cycle with HF•amine
as the fluoride source (Scheme 1).9 Contemporaneously, Jacobsen
and co-workers reported a similar transformation employing a
resorcinol-based catalyst.10 Common to both strategies is the in
situ generation of an ArI(III)F2 species from the corresponding
aryl iodide, thereby constituting a catalytic variant of Hara and
Yoneda’s stoichiometric transformation.11 These two catalytic
advances are highly complementary, differing both in terms of
substrate scope and mechanism.8 Perhaps most notable are differ-
ences in the initial oxidation I(I) → I(III) and subsequent genera-
Mechanistic delineation was, however, hampered by difficulties in
procuring this reagent from commercial sources. For the purposes
of this study, an important consideration was that the commercial
synthesis might not accurately resemble the conditions by which
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the species is produced in the catalysis protocol. Consequently, an
ultimately led to a set of conditions that allowed p-TolIF2 to be
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efficient synthetic route to p-TolI(III)F2 from p-TolI and Select-
fluor® was required to allow a structural study to be conducted. In
addition to providing valuable insight into the initial phase of the
catalytic process, this study would complement the existing data
on p-TolI(III)F2 and provide synthetic guidelines to prepare struc-
turally related reagents.13 It would also allow structural compari-
sons to be drawn between the title reagent and the popular 1-
fluoro-3,3-dimethyl-1,3-dihydro-1-λ3-benzo[d][1,2]iodoxole scaf-
fold.14
isolated in 91% yield (entry 10).
Attention was then focused on mitigating the safety risks associat-
ed with handling HF reagents. Consequently, Et3N•3HF was sub-
stituted by a variety of fluoride sources with the aim of identifying
a safer alternative. Tetrabutylammonium fluoride proved unsuita-
ble for this task, and decomposition of Selectfluor® was observed
1
by H NMR in this case (entry 11). In contrast, LiF gave an en-
couraging initial result and did not decompose the Selectfluor®
(23%, entry 12). This was significantly improved when switching
to the more soluble CsF (72%, entry 13).19 Moreover, the reaction
proceeded smoothly and cleanly, with side product formation
completely suppressed. Further optimization with CsF allowed
comparable isolated yields to be reached, thereby eliminating the
need to use Et3N•3HF for the preparation of p-TolIF2 (2) (62%
isolated yield, entry 14).
Since the discovery of ArI(III)F2 reagents over a century ago,15
a
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diverse arsenal of synthetic methods for their preparation have
been reported. These vary in operational complexity, and range
from direct fluorination with F2(g), through to multi-step sequences
often involving potentially hazardous reagents (e.g. Cl2/HF,
HgO/HF, XeF2, SF4).16 In 2005, Shreeve and co-workers reported
an operationally simple route to iodine(III) reagents utilizing Se-
lectfluor® (Scheme 1, lower).17 In addition to the direct oxidation
of iodoarenes, a convenient one-pot iodination/oxidation sequence
was also disclosed starting from a suitably functionalized arene
(mono-, 1,4-di, and 1,3,5-tri-alkylated), I2 and Selectfluor®.
Whilst combined yields are reported for the iodination/oxidation
sequences, data for the direct oxidation of iodoarenes by Select-
fluor® are not provided. This prompted us to streamline a general
route to p-TolIF2 with a view to investigating oxidation efficiency
and reagent formation within the framework of the catalytic pro-
tocol.
Table 1. Reaction optimization: Investigation of XF sources
and the identification of an HF-free protocol.a
Selectfluor®
(eq.)
Time Conversion
Results and Discussion
Entry
XF source
F- (eq.)
(h)
(%)
As a logical starting point for this study, the effect of external
fluoride additives was investigated to establish the ultimate source
of both fluorine atoms in reagent 2 (Table 1). In the original pro-
tocol reported by Shreeve and co-workers, p-TolI (1) was treated
with Selectfluor® in acetonitrile for 4 h at ambient temperature
prior to the addition of Et3N•3HF. As a control experiment, this
reaction was repeated, this time in the absence of the HF source,
and monitored by 1H NMR spectroscopy (entry 1). After 4 h, 26%
conversion was observed and two new aromatic species were
clearly identifiable (300 MHz, 299 K, d3-CH3CN). One set of
signals was attributed to p-TolIF2 (2) (δH 7.92 ppm and 7.45 ppm),
indicating that Selectfluor® can function as the source of both
fluorine atoms. The second species showed broad signals in the
1H NMR spectrum (δH 7.75 ppm and 7.24 ppm), indicative of a
fluxional process.18 Repeating the experiment and adding
Et3N•3HF (2 drops) after 4 h led to the complete disappearance of
the second species (entry 2). For completeness, the order of HF
addition was then investigated, and the reaction was performed
with the rigorous exclusion of light and moisture. A significant
increase in yield resulted when Et3N•3HF (2 drops) was added at
the beginning of the reaction (66%, entry 3). Again, the second
fluxional species observed in entry 1 was notably absent. Explor-
ing NFSI and N-fluoropyridinium tetrafluoroborate as oxidants
proved to be detrimental to reaction efficiency (see SI for full
details) and thus Selectfluor® was employed for the remainder of
the study. Extending the reaction time did not enhance efficiency
(59%, entry 4). Similarly, increasing the equivalents of Selectflu-
or® in the reaction mixture (2.6 to 5.0 eq.) did not significantly
improve the outcome (66%, entry 5). However, augmenting these
two parameters together led to an improved conversion of 80%
(entry 6). It is important to note that when isolated, the resulting
product p-TolIF2 (2) decomposed at ambient temperature. How-
ever, it remained stable under the reaction conditions for 22 h.
Modifying the number of equivalents of HF (entries 7-9) led to
small variations in conversion. Collectively, parameter variation
1
2
2.6
2.6
2.6
2.6
5.0
5.0
2.6
2.6
2.6
3.5
2.6
2.6
2.6
4.0
-
-
4
26
Et3N•3HF
Et3N•3HF
Et3N•3HF
Et3N•3HF
Et3N•3HF
Et3N•3HF
Et3N•3HF
Et3N•3HF
Et3N•3HF
TBAF•3H2O
LiF
2 drops
2 drops
2 drops
2 drops
2 drops
0.9
4
4
56b
66
59
66
80
49
63
54
91c
0
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4
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22
4
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2.3
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9
4.6
4
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14
3.7
22
8
5.0
5.0
8
23
72
62c
CsF
5.0
24
14
CsF
5.0
[a] All reactions were performed in a borosilicate NMR tube with d3-
CH3CN as solvent. Conversion determined by H NMR, based on the
1
consumption of p-TolI 1; [b] Et3N•3HF was added at the end of the
reaction in accordance with the literature protocol;17 [c] Yield (see SI).
These optimized conditions were then applied to a small collec-
tion of electronically modulated aryl iodides (Table 2). In contrast
to the parent p-CH3 system (62% isolated yield, 14 h), substrates
bearing electron-withdrawing para-substituents required extended
reaction times (48 h) and conversion was markedly reduced (en-
tries 1-3; 13%, 14% and 51% for p-NO2, p-CF3 and p-CO2Et,
respectively). The p-chloro system was subjected to the optimized
conditions and was smoothly oxidized to the corresponding ArIF2
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Figure 1. Monitoring the oxidation of p-TolI by Selectfluor® in
species (54% yield, entry 4). Gratifyingly, oxidation of electron
d3-CH3CN by 1H NMR spectroscopy.a
1
2
3
4
rich systems proved to be more efficient, and comparable to the
title compound (p-H, p-OBn and p-OMe; 80%, 75% and 89%
conversion, respectively. Entries 5, 7 and 8). Unfortunately, this
efficiency was offset by the intrinsic instability of the p-OBn and
p-OMe analogues towards isolation.
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9
Table 2. Exploring the effect of electronic modulation on the
oxidation of p-substituted aryl iodides using Selectfluor® and
CsF.
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Entry
R
NO2
CF3
CO2Et
Cl
ArIF2
2a
2b
2c
Time (h)
Conversion (%)a
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8
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6
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51
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80
74b
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89c
2d
2e
H
CH3
OBn
OMe
2
[a] All reactions were performed in a borosilicate NMR tube with d3-
CH3CN as solvent (300 MHz, 299 K); 40 mM for compound 1. A: Refer-
ence spectrum of p-TolIF2 (2). B: Reaction mixture 240 min (after addi-
tion of 2 drops of Et3N•3HF). C: Reaction mixture after 240 min (prior to
addition of 2 drops of Et3N•3HF). D: Reaction mixture after 130 min. E:
Reaction mixture 26 min. F: Reference p-TolI (1) (200 MHz, 299 K).
2f
2g
6
[a] All reactions were performed in a borosilicate NMR tube with d3-
CH3CN as solvent. Conversion determined by 1H NMR, based on the
consumption of ArI (1a-g); [b] Yield 62% (91% when using Et3N•3HF for
comparison); [c] Yield 76% when using Et3N•3HF.
Figure 2. Solution phase behavior of Selectfluor® and deriva-
tive 3 in d3-CH3CN by 1H NMR spectroscopy.a
Solution phase NMR investigation: To gain further insights into
the oxidation of p-TolI by Selectfluor®, the reaction was moni-
tored by 1H NMR spectroscopy over a period of 4 h in the absence
of the fluoride source (XF). In contrast to the literature report,17
disclosing the facile and quantitative generation of hypervalent
aryl iodine difluorides from the reaction of 2.0 eq. of Selectfluor®
with iodobenzene or iodotoluene, incomplete conversion after 4 h
using 2.6 eq. Selectfluor® was noted (N.B. Figure 1 depicts the
reaction with only 1.0 eq. Selectfluor®). Since our observation is
at variance with the literature, careful analysis of the NMR time
course was performed (Figure 1, Spectra A-F). As noted during
the optimization process (Table 1), the generation of two new
aromatic species was observed over this 4 h period. One can
clearly be identified as p-TolIF2 (2) [H 7.93, 7.45 ppm, Figure 1,
spectrum A], whilst the second has eluded isolation and unequiv-
ocal characterization [H 7.75, 7.24 ppm, Figure 1, spectra C and
D]. Since the formation of this unidentified species correlates with
the consumption of Selectfluor®, and is converted to 2 upon addi-
tion of a fluoride source, it is tempting to implicate a transient,
cationic complex of the type [p-TolI+F…R], where R may be NR3,
CH3CN or BF4- (Figure 1, spectra E to B).
1
In an attempt to provide substance to this conjecture, detailed H
[a] All reactions were performed in a borosilicate NMR tube with d3-
CH3CN as the solvent (300 MHz, 299 K). A: Spectrum of Selectfluor®
(200 MHz, 299 K). B: Mixture of p-TolI (1) and Selectfluor® after 240
min. C: Mixture of amine 3 and Selectfluor® after 240 min. D: Mixture of
p-TolI (1), Selectfluor® and CsF after 240 min. E: Spectrum of amine 3.
When p-TolI (1) and Selectfluor® were mixed in a NMR tube,
NMR analyses were performed on the mixture to glean an insight
into the solution phase behavior (Figures 1 and 2). To probe for
the involvement of a transient [p-TolI+F…R] complex, the reduced
product generated from Selectfluor® (3) was prepared according
to a literature procedure,20 and its H NMR spectrum recorded
1
(Figure 2, spectrum E). As a reference, spectrum A is that of Se-
new signals at H = 5.12, 3.70 and 3.56 ppm were observed (spec-
trum B). However, inspection of spectrum E indicates that these
lectfluor®.
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are not simply attributable to 3. Cognizant of an elegant study by
were found in the asymmetric unit cell, differing in the torsion
Laali and co-workers, who reported that Selectfluor® and chloro-
methylated DABCO generate symmetric tricationic dimers upon
mixing (80 °C),20 a 1:1 mixture of Selectfluor® and 3 was pre-
pared and investigated. However, at ambient temperature no
changes in chemical shifts were observed (spectrum C). These
observations are clearly at variance with the spectral signature of
the reaction mixture as shown in spectrum B prior to XF addition.
Although inconclusive, these experiments led us to gravitate to-
wards the notion of a fluxional [ArI+F…R] complex,21 as opposed
to a dimeric, tricationic species. It was envisaged that preliminary
validation for such a species could be obtained by simple addition
of a non-protic fluoride source, such as CsF. Indeed, when p-TolI
(1) and Selectfluor® were treated with CsF to produce p-TolIF2
(2), amine 3 was clearly visible (spectrum D) [(p-TolI (1) + Se-
lectfluor® + CsF  p-TolIF2 (2) + 3 + CsBF4)].
angle between the F-I-F moiety and the π-system.
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Figure 4. X-ray crystal structure of p-TolIF2 (2)
(CCDC1555065)a
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To describe the fluxional nature of the transient intermediate
[TolI+F…R], a series of nOe experiments were conducted (200
mM for compound 1) and are summarized in Scheme 2. Both
positive and negative effects were observed, thereby providing
evidence for dynamic exchange in solution (d3-CH3CN). The
negative nOe effects observed between the ortho- and meta-tolyl
hydrogens of TolIF+ and TolIF2, respectively, indicate a dynamic
equilibrium between both species that is observable on the NMR
time scale. This can be described as a simple fluoride exchange.
The positive nOe effects between the ortho-hydrogens of the
TolIF+ species and the NCH2 of the chloromethylated DABCO
donor confirm the proximity of these groups and support the tran-
sient [TolIF+··· DABCO] adduct depicted in Scheme 2 (lower).
[a] Two conformers (top-left, A and B) and extended structure viewed
along the a-axis (bottom-left) and b-axis (right) of the unit cell. Ellipsoids
are shown at the 50% probability level. Hydrogen atoms are omitted for
clarity in the extended structure. Intramolecular interactions below 3.5 Å
between iodine and fluorine are highlighted in orange.
A T-shape arrangement is observed, but distorted from the ex-
pected linear F-I-F geometry (conformer A = 170.8° and con-
former B = 173.3°). The IF2 unit is orientated neither parallel, nor
perpendicular with respect to the aromatic ring (conformer A = -
81.8° and conformer B = 61.5°): This is likely due to crystal pack-
ing effects between neighboring λ3-iodane species as observed in
the extended lattice. Short intermolecular F…F contacts involving
molecules of the same conformer (F1…F2 2.793 Å for conformer
A and F1…F2 2.874 Å for conformer B) are present in the packing
diagram. Consequently, the I-F distances show significant elonga-
tion (conformer A average = 2.012(3) Å; conformer B average =
2.015(3) Å).
Scheme 2. Solution phase analysis and evidence of dynamic
exchange by nOe investigations.
Conclusions
Reaction deconstruction is an intuitive component of the method
development process.24 Theoretical and/or experimental interroga-
tion of postulated reaction intermediates allows aspects of struc-
ture and reactivity to be systematically assessed, thereby inform-
ing rational design. Importantly, this process may provide rigor-
ous, independent support for the involvement and competence of
a postulated intermediate. In the context of our work on the cata-
lytic, vicinal difluorination of alkenes, success was contingent on
the formation of p-TolIF2 generated by in situ oxidation of p-TolI
using Selectfluor®. Although well-described in the literature,15-17
this species was never detected nor isolated during the reaction
development phase.9 It was envisaged that insight into the
I(I)→I(III) oxidation using Selectfluor®, and subsequent solution
phase behavior, would facilitate future reaction development. An
operationally simple route to p-TolIF2 was thus been developed
that substitutes potentially hazardous HF reagents by CsF, thereby
mitigating safety concerns. Whilst observing the oxidation by
NMR spectroscopy, a fluxional intermediate was determined that
exists in a dynamic exchange with p-TolIF2, prior to fluoride addi-
tion. Having discounted the possibility of bridged, dimeric, trica-
tionic systems, it was observed that this species readily converts
to p-TolIF2 upon addition of a non-protic fluoride source. This is
fully consistent with a mono-fluoride species [p-TolI+F….R],
where R is likely the reduced form of Selectfluor® (i.e. 3) and/or
Structural Characterization of p-TolIF2 (2): Whilst efforts to
isolate and characterize the postulated, cationic intermediate have
been thus far unsuccessful, it was possible to prepare colorless
needles of 2 that were suitable for X-ray analysis (CCDC
1555065, Figure 4).22,23 Two symmetry independent conformers
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Difluoro(p-tolyl)-λ3-iodane (2)
acetonitirile. Assessing the impact of this solution phase behavior
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2
3
4
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7
8
on catalysis is currently ongoing in our laboratories.
Prepared according to General Procedure 1. Reaction time: 14 h.
Yield = 160 mg, 62%.
Prepared according to General Procedure 2. Reaction time: 22 h.
Yield = 232 mg, 91%.
Experimental section
Colorless needles crystallized from 4 mL of CHCl3:n-hexane 1:3
at -18°C.
General information
1H NMR (300 MHz, d3-CH3CN) δ 7.92 (m, 2H), 7.44 (m, 2H),
2.45 (s, 3H). 19F NMR (282 MHz, d3-CH3CN) δ -174.4. 13C{1H}
NMR (75 MHz, d3-CH3CN) δ 143.9 (C), 132.9 (CH), 132.3 (CH,
t, 3JCF = 2.5 Hz), 122.9 (C, t, 2JCF = 12.1 Hz), 21.3 (CH3).
1H NMR (300 MHz, d-CHCl3) δ 7.84 (m, 2H), 7.39 (m, 2H), 2.47
(s, 3H). 19F NMR (282 MHz, d-CHCl3) δ -176.8. Data in agree-
ment with literature.17
All chemicals were reagent grade and used as supplied. Solvents
for extractions and chromatography were technical grade and
distilled prior to use. Analytical thin layer chromatography (TLC)
was performed on pre-coated Merck silica gel 60 F254 aluminum
sheets. Visualization was achieved using ultraviolet light (λ = 254
nm) or by dipping in potassium permanganate stain [KMnO4 (10
g), K2CO3 (65 g), and aqueous NaOH solution (1 mol•L-1, 15 mL)
in water (1 L)] followed by heating. Column chromatography was
carried out on VWR silica gel ZEOprep® 60 (230-400 mesh).
Concentration in vacuo was performed at ≈10 mbar and 35 °C,
drying at ≈10-2 mbar and ambient temperature unless stated oth-
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MS-EI-direct inlet: m/z (%) = 256.0 (32) [M]+, 237.0 (4) [M-F]+,
218.0 (98) [M-F2]+, 91.1 (100) [M-IF2]+.
Difluoro(4-methoxyphenyl)- λ3-iodane (2g)
1
erwise. H NMR, 19F NMR and 13C NMR spectra were recorded
Prepared according to General Procedure 2. Reaction time: 4 h.
Yield = 207 mg, 76%.
on Bruker AC 200 MHz or by the NMR service at the Institute of
Organic Chemistry (WWU Münster) on a Bruker AV 300 MHz, a
Bruker AV 400 MHz, Agilent VVMRS 500 MHz or an Agilent
DD2 600 MHz spectrometer at ambient temperature. Chemical
shifts δ are reported in ppm relative to the residual solvent. Cou-
pling constants J are reported in Hz. The multiplicities are report-
ed as: s = singlet, bs = broad singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. ESI accurate masses were measured by the
Mass Spectrometry department at the Institute of Organic Chem-
istry (WWU Münster) on a MicroTof (Bruker Daltronics, Bre-
men) with loop injection. Mass calibration was performed using
sodium formate cluster ions immediately followed by the sample
in a quasi-internal calibration. Mass spectra with direct inlet and
electron ionization (EI) were measured on a Triplequad TSQ 7000
(Thermo-Finnigan-MAT, Bremen).
Light yellow solid. Fast decomposition at ambient temperature,
light sensitive.
1H NMR (400 MHz, d3-CH3CN) δ 8.02 (m, 2H), 7.13 (m, 2H),
3.87 (s, 3H). 19F NMR (282 MHz, d3-CH3CN) δ -170.2. 13C{1H}
NMR (101 MHz, d3-CH3CN) δ 163.4 (C), 135.2 (CH, t, 2JCF = 1.7
Hz), 117.7 (CH), 117.1 (C, t, 3JCF = 13.7 Hz), 56.5 (CH3).
MS-EI-direct inlet: m/z (%) = 272.0 (4) [M]+, 234.0 (100) [M-
F2]+, 107.0 (7) [M-IF2]+.
Characterization data for Table 2:
Difluoro(4-nitrophenyl)-λ3-iodane (2a)25
1H NMR (200 MHz, d3-CH3CN) δ 8.41 (m, 2H), 8.17 (m, 2H).
General Procedure 1: (Selectfluor® and CsF)
Difluoro(4-(trifluoromethyl)phenyl)-λ3-iodane (2b)26
To a flame-dried Schlenk tube was added the iodoarene (1.0
mmol), Selectfluor® (1.41 g, 4.0 mmol, 4.0 eq.), CsF (760 mg, 5.0
mmol, 5.0 eq.) and dry acetonitrile (25 mL). The reaction mixture
was flushed with argon three times, wrapped in aluminum foil to
exclude light and stirred at room temperature for the indicated
time. The reaction mixture was then evaporated to dryness. To
this slurry was added a mixture of CHCl3:n-hexane (1:1) to dis-
solve the product (4 mL). The organic material was transferred by
syringe to a flame-dried Schlenk tube and the process was repeat-
ed 4 times. The solvent was evaporated to dryness at 0 °C (ice
bath), flushed with argon and then stored in a freezer (-18 °C).
1H NMR (600 MHz, d3-CH3CN) δ 8.14 (m, 2H), 7.93 (m, 2H). 19
F
NMR (564 MHz, d3-CH3CN) δ -63.6, -177.0. 13C{1H} NMR (151
MHz, d3-CH3CN) δ 133.6 (C, q, JFC = 33.0 Hz), 131.9 (CH, t, JFC
= 4.6 Hz), 129.0 (CH, q, JFC = 3.8 Hz), 128.5 (C, tm, JFC = 10.5
Hz), 124.5 (CF3, q, JFC = 271.9 Hz)
MS-EI-direct inlet: m/z (%) = 310.0 (8) [M]+, 272.0 (100) [M-
F2]+.
Ethyl 4-(difluoro-λ3-iodanyl)benzoate (2c)
1H NMR (400 MHz, d3-CH3CN) δ 8.20 (m, 2H), 8.06 (m, 2H),
4.38 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 19F NMR (282
MHz, d3-CH3CN) δ -176.9. 13C{1H} NMR (101 MHz, d3-CH3CN)
δ 165.8 (C), 134.4 (C), 132.7 (CH), 131.3 (CH, t, JFC = 4.2 Hz),
129.2 (C, t, JFC = 10.3 Hz), 62.5 (CH2), 14.4 (CH3).
General Procedure 2: (Selectfluor® and Et3N•3HF)
To a flame-dried Schlenk tube was added the iodoarene (1.0
mmol) and Selectfluor® (1.24 g, 3.5 mmol, 3.5 eq.) in dry acetoni-
trile (25 mL). The reaction mixture was flushed three times with
argon and Et3N•3HF (200 μL, 3.6 eq.) was added. The reaction
mixture was wrapped in aluminum foil to exclude light and stirred
at room temperature for the indicated time. The reaction mixture
was then evaporated to dryness. To this slurry was added a mix-
ture of CHCl3:n-hexane (1:3) to dissolve the product (4 mL). The
organic material was transferred by syringe to a flame-dried
Schlenk tube and the process was repeated 4 times. The solvent
was evaporated to dryness at 0 °C (ice bath), flushed with argon
and then stored in a freezer (-25 °C).
MS-EI-direct inlet: m/z (%) = 314.0 (4) [M]+, 231.0 (100) [M-
C2H5O]+.
Difluoro(4-chlorophenyl)-λ3-iodane (2d)25
1H NMR (200 MHz, d3-CH3CN) δ 7.97 (m, 2H), 7.64 (m, 2H).
MS-EI-direct inlet: m/z (%) = 275.9 (18) [M]+, 238.0 (100) [M-
F2]+.
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Page 6 of 7
(m, 2H), 5.04 (s, 2H); 13C{1H} NMR (101 MHz, d-CHCl3) δ
Difluoro(phenyl)-λ3-iodane (2e)17
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2
3
4
5
6
7
8
158.8 (C), 138.4 (CH), 136.6 (C), 128.8 (CH), 128.2 (CH), 127.6
(CH), 117.4 (CH), 83.2 (C), 70.2 (CH2). HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C13H11INaO+ 332.9753; Found 332.9751.
Analytical data in agreement with literature.27
1H NMR (200 MHz, d3-CH3CN) δ 8.03 (m, 2H), 7.63 (m, 3H).
Difluoro(4-(benzyloxy)phenyl)-λ3-iodane (2f)
1
Derived from reaction mixture (Table 2, entry 7): H NMR (200
ASSOCIATED CONTENT
Supporting Information
MHz, d3-CH3CN) δ 8.02 (m, 2H), 7.41 (m, 5H), 7.19 (m, 2H),
5.18 (s, 2H).
1H NMR (600 MHz, d-CHCl3) δ 7,91 (m, 2H), 7.40 (m, 5H), 7.14
(m, 2H), 5.15 (s, 2H). 19F NMR (564 MHz, d-CHCl3) δ -
173.3.13C{1H} NMR (151 MHz, d-CHCl3) δ 161.5 (C), 135.9
(CH), 132.9 (C), 129.9 (CH), 128.6 (CH), 127.6 (CH), 117.9
(CH), 115.0 (C, t, 3JFC= 13.2 Hz), 70.6 (CH2).
The Supporting Information is available free of charge on the
ACS Publications website. Experimental protocols, NMR spectra,
crystallographic data (pdf file).
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MS-EI-direct inlet: m/z (%) = 248.0 (2) [M]+, 91.1 (100) [M-
AUTHOR INFORMATION
C6H4F2IO]+.
Corresponding Author
Synthesis of 1-chloromethyl-1,4-diazabicyclo[2.2.2]octan-1-
ium chloride (4)20
ryan.gilmour@uni-muenster.de
Notes
A
round-bottom
flask
was
charged
with
1,4-
The authors declare no competing financial interests.
diazabicyclo[2.2.2]octane (1.0 g, 8.9 mmol, 1.0 eq.) dissolved in
dichloromethane (3 mL), and the mixture heated at reflux for 16
h. The resulting white precipitate was filtered, washed with di-
chloromethane and placed under vacuum to afford 1-
(chloromethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium chloride as a
white solid (1.6 g, 8.1 mmol, 91%).
1H NMR (300 MHz, D2O) δ 5.12 (s, 2H), 3.55 (m, 6H), 3.25 (m,
6H); 13C{1H} NMR (75 MHz, D2O) δ 68.2 (CH2), 51.2 (CH2),
43.9 (CH2).
‡ X-ray crystallographer
This manuscript is dedicated to Prof. Dr. Armido Studer on the
occasion of his 50th birthday.
ACKNOWLEDGMENT
We acknowledge generous financial support from the WWU
Münster, and the Deutsche Forschungsgemeinschaft (SFB 858,
and Excellence Cluster EXC 1003 “Cells in Motion – Cluster of
Excellence”). We are extremely grateful to Dr. Klaus Bergander
(WWU Münster) for assistance with NMR spectroscopy.
HRMS (ESI-TOF) m/z: [M-Cl]+ Calcd for C7H14N2Cl+ 161.0840;
Found 161.0815.
Synthesis of 1-chloromethyl-1,4-diazabicyclo[2.2.2]octan-1-
ium tetrafluoroborate (3)20
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To
a round-bottom flask was added 1-(chloromethyl)-1,4-
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eq.), NaBF4 (0.28 g, 2.5 mmol, 1.0 eq.) and water (5 mL). The
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white solid (0.61 g, 2.46 mmol, 98%).
1H NMR (400 MHz, D2O) δ 5.15 (s, 2H), 3.59 (m, 6H), 3.30 (m,
6H); 13C{1H} NMR (75 MHz, D2O) δ 68.2 (CH2), 51.2 (CH2),
-
43.9 (CH2); 19F NMR (282 MHz, D2O) δ -150.41, -150.46 (BF4 ).
- +
HRMS (ESI-TOF) m/z (%): [M-BF4 ] Calcd for C7H14N2Cl+
161.0840; Found 161.0814.
Synthesis of 1-benzyloxy-4-iodobenzene (5)
To a round-bottom flask was added 4-iodophenol (500 mg, 2.27
mmol, 1.0 eq.), benzyl bromide (297 μL, 2.50 mmol, 1.1 eq.),
potassium carbonate (627 mg, 4.54 mmol, 2.0 eq.) and dimethyl-
formamide (2 mL). The reaction mixture was stirred at ambient
temperature for 20 h before being poured into a saturated solution
of ammonium chloride (10 mL) and extracted with ethyl acetate
(3 x 5 mL). The combined organic layers were washed five times
with water (2 mL) and once with brine (2 mL), dried over magne-
sium sulfate, filtered and evaporated under vacuum. The resulting
material was purified by chromatography on silica gel (n-
pentane:dichloromethane 9:1) to afford 1-benzyloxy-4-
iodobenzene as a white solid (662 mg, 2.13 mmol, 94%). Rf: 0.2;
1H NMR (300 MHz, d-CHCl3) δ 7.55 (m, 2H), 7.39 (m, 5H), 6.76
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Graphical Abstract
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