Unsymmetrical Aryl(2,4,6-trimethoxyphenyl)iodonium Salts: One-Pot Synthesis, Scope, Stability, and Synthetic Studies

Article abstract of DOI:10.1021/acs.joc.5b02833

Diaryliodonium salts have recently attracted significant attention as metal-free-arylation reagents in organic synthesis, and efficient access to these salts is critical for advancement of their use in reaction discovery and development. The trimethoxybenzene-derived auxiliary is a promising component of unsymmetrical variants, yet access remains limited. Here, a one-pot synthesis of aryl(2,4,6-trimethoxyphenyl)iodonium salts from aryl iodides, m-CPBA, p-toluenesulfonic acid, and trimethoxybenzene is described. Optimization of the reaction conditions for this one-pot synthesis was enabled by the method of multivariate analysis. The reaction is fast (<1 h), provides a high yield of product (>85% average), and has broad substrate scope (>25 examples) including elaborate aryl iodides. The utility of these reagents is demonstrated in moderate to high yielding arylation reactions with C-, N-, O-, and S-nucleophiles including the synthesis of a liquid crystal molecule.

Full text of DOI:10.1021/acs.joc.5b02833

Article
pubs.acs.org/joc
Unsymmetrical Aryl(2,4,6-trimethoxyphenyl)iodonium Salts: One-Pot
Synthesis, Scope, Stability, and Synthetic Studies
Thomas L. Seidl, Sunil K. Sundalam, Brennen McCullough, and David R. Stuart*
Department of Chemistry, Portland State University, Portland, Oregon 97201, United States
S
* Supporting Information
ABSTRACT: Diaryliodonium salts have recently attracted
significant attention as metal-free-arylation reagents in organic
synthesis, and efficient access to these salts is critical for
advancement of their use in reaction discovery and develop-
ment. The trimethoxybenzene-derived auxiliary is a promising
component of unsymmetrical variants, yet access remains
limited. Here, a one-pot synthesis of aryl(2,4,6-trimethoxy-
phenyl)iodonium salts from aryl iodides, m-CPBA, p-toluene-
sulfonic acid, and trimethoxybenzene is described. Optimiza-
tion of the reaction conditions for this one-pot synthesis was
enabled by the method of multivariate analysis. The reaction is
fast (<1 h), provides a high yield of product (>85% average),
and has broad substrate scope (>25 examples) including elaborate aryl iodides. The utility of these reagents is demonstrated in
moderate to high yielding arylation reactions with C-, N-, O-, and S-nucleophiles including the synthesis of a liquid crystal
molecule.
transfer of elaborate arenes in late-stage coupling reactions.
While electron-rich auxiliaries derived from anisole (An),3,5
mesitylene (Mes),7,8 and trimethoxybenzene (TMB)18,19 are
promising (Scheme 1b), the general use of such auxiliaries is
scarce in new metal-free methodology.20
Efficient one-pot protocols to access diaryliodonium salts
from aryl iodides continue to be developed21−27 in light of
growing interest in metal-free arylation reactions of these
reagents. In many cases a two-stage, one-pot approach has been
adopted wherein the iodide moiety is oxidized under acidic
conditions in the first stage and the auxiliary is introduced in a
second stage (eq 1). The integration of two stages into a single
INTRODUCTION
■
Diaryliodonium salts are novel reagents for metal-free-arylation
reactions in contemporary organic synthesis.1−12 A renewal of
interest in these salts is prompted by their good bench stability,
low toxicity, and arylation reactivity that parallel transition
metal catalysts.13−17 Unsymmetrical aryl(auxiliary)iodonium
salts are especially attractive in arylation chemistry because
they are inherently less wasteful than their symmetrical
counterparts. Specifically, a recoverable and potentially reusable
auxiliary iodide is coproduced when an unsymmetrical salt
reacts with a nucleophile, whereas half of the arylation reagent
is potentially lost as aryl iodide with a symmetrical diary-
liodonium salt (Scheme 1a). This is particularly relevant to the
Scheme 1. Diaryliodonium Salts As Arylation Reagents
reaction vessel reduces waste and improves efficiency28,29 but
presents challenges in optimization as several variables must be
integrated within the experimental space. In this approach to
diaryliodonium salts, halogenatated solvents, such as dichloro-
methane (DCM) and trifluoroethanol (TFE), are common
place in combination with m-CPBA as the oxidant and a
sulfonic acid, such as triflic or tosic acid, in the first stage. While
the former acid is more common, the latter is more attractive
from a cost and safety perspective.30 This general approach
Received: December 14, 2015
© XXXX American Chemical Society
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works well to introduce An- and Mes-auxiliaries in the second
stage (Scheme 1b, left and center).
Scheme 2. Synthetic Strategy for a One-Pot Approach to
Aryl(2,4,6-trimethoxyphenyl)iodonium Salts
Despite a report of the trimethoxybenzene (TMB)-derived
auxiliary (Scheme 1b, right) in a metal-free arylation of a
malonate derivative with a diaryliodonium salt over a decade
ago31 there has been very little research activity into the
potential of this spectator group.32 Recently, in addition to
malonate, this auxiliary has been investigated as a general
spectator in chemoselective phenylation reactions of aniline and
phenoxide nucleophiles with phenyl(2,4,6-trimethoxyphenyl)-
iodonium triflate18 and fluoride nucleophiles with aryl(2,4,6-
trimethoxyphenyl)iodonium tosylates for applications in
positron emission tomography (PET) imaging.19 Indeed, in
the former the TMB-auxiliary provided higher levels of phenyl
transfer selectivity than both An- and Mes-auxiliaries.18 In both
of these reports,18,19 and others,33−35 the TMB auxiliary was
introduced into diaryliodonium salts by reaction with hyper-
valent (diacetoxy)iodo arenes that were prepared in a separate
step; the direct installation through a one-pot synthesis with
aryl iodides is exceedingly rare.26 We posit that the dearth of
available methods to access aryl(2,4,6-trimethoxyphenyl)-
iodonium salts has limited their broad adoption as reagents
for metal-free arylation reactions. Moreover, improved
synthetic methods with high functional group compatibility
may lead to applications of elaborate aryl(2,4,6-trimethoxy-
phenyl)iodonium salts in late-stage metal-free coupling
reactions.
Herein, we describe our approach to a one-pot synthesis of
aryl(2,4,6-trimethoxyphenyl)iodonium salts from aryl iodides.
Reaction optimization was enabled by chemometric methods.36
The one-pot reaction occurs in relatively short reaction time
(<1 h total), provides a high yield of product (>85% average
isolated yield), and has good functional group tolerance.
Moreover, we highlight the utility of these reagents with C-, N-,
O-, and S-nucleophiles, including the metal-free synthesis of a
liquid crystal molecule. We also provide insight into the
contribution of counteranion identity and aryl group electronic
effects on the light and thermal stability of this nascent class of
arylating reagent.
the reaction outcome: solvent, concentration, bath temperature,
time of each stage, and stoichiometry of trimethoxybenzene
(Scheme 2b). The identity of the solvent was first considered
because a single solvent throughout the entire reaction will
minimize unnecessary manipulation of the reaction system and
waste associated with a solvent switch; acetonitrile emerged as a
promising solvent. We turned our attention to a chemometric-
based optimization of the other reaction variables.
A model reaction was used for optimization, and the
1
response (yield) was determined by analysis of the crude H
NMR spectrum against DMF as an internal standard. Aryl
iodide 1 was selected as the model substrate, as we anticipated
that iodo-oxidation would be a challenging step (eq 2).40
A
RESULTS AND DISCUSSION
■
Chemical reactions of organic compounds are complex systems
comprised of many known and unknown variables. Moreover,
the interaction of these variables presents a significant challenge
to the development of new reactions. Multivariate analysis
provides a systematic approach to reaction optimization
wherein both the influence of individual variables and the
interaction of variables may be determined.37−39 We have
leveraged this approach in the development of our one-pot
synthesis of aryl(2,4,6-trimethoxyphenyl)iodonium salts.
These studies were initiated by identifying promising leads
for each “stage” of a one-pot reaction from aryl iodides
(Scheme 2a). This was critical, as simply adding TMB-H to
standard22 one-pot reactions failed to provide appreciable
quantities of aryl(2,4,6-trimethoxyphenyl)iodonium tosylate.
Specifically, we surmised that electron-rich 1,3,5-trimethox-
ybenzene is incompatible with a strong acid (TfOH) under
oxidizing conditions. The lead precedent for oxidation of aryl
iodide produces a [hydroxy(tosyloxy)iodo]arene under more
mild acidic conditions (TsOH);40 the lead precedent for ligand
exchange intercepts this intermediate to yield the aryl(2,4,6-
trimethoxyphenyl)iodonium salt (Scheme 2a).19,35 Several
variables were identified that we anticipated would influence
Placket−Burmann design41 was used to assess the most
influential continuous variables (concentration, temperature,
time, and stoichiometry of TMB-H).42 The same temperature
was used for each stage as a practical consideration. This
preliminary design revealed that the stoichiometry of
trimethoxybenzene was optimal at 1 mol equiv; excess
trimethoxybenzene was detrimental to the yield of 2 in this
specific system.
Optimization was continued with a two-level factorial design
focusing on the four remaining variables: concentration of 1,
time of Stage 1, time of Stage 2, and reaction bath temperature
(Figure 1a). The actual and coded values for the variable ranges
used in this design are shown in Figure 1a and represent the
volume of the experimental space. Experiments for all
combinations of the coded values (24 = 16 experiments)
were performed, and an equation that correlates the response
(yield) to the variables was obtained.42 The β-coefficients of
each variable of the model equation are listed in Figure 1a, and
their relative magnitude indicates the relative influence of the
corresponding variable on the yield of 2. Notably, the
magnitude of the coefficient for the time of Stage 2 was small
(∼ −0.7) and, therefore, had little influence on the yield of 2.
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ature−concentration plane indicate that high yields (>70%) of
2 may be obtained with a broad range of combinations of
concentration and temperature. This insight reveals both
optimal conditions and synthetic flexibility in implementation
of this method with other (perhaps more sensitive) substrates
(vide infra).
The central composite design that yielded the response
surface plots and the corresponding model equation was
obtained with 26 experiments. This is substantially more time
and material efficient than the >600 experiments that would be
required to assess all combinations of the same four variables
on five different levels (54 = 625). Moreover, the depth of
knowledge gained through these studies is deeper than typically
obtained by one-variable-at-a-time (OVAT) optimization
methods. Subsequently, the utility of the model was confirmed
for its ability to predict the yield of 2 at experimental conditions
not used to build the model (0.2 mmol scale) and for
preparative reactions (5 mmol scale) at the optimal conditions.
First, the experimentally obtained yield and the predicted yield
for the center point are in much better agreement when
curvature is taken into account with the central composite
design (compare 70% and 74%, respectively) versus the 2-level
factorial design (vide supra). Three additional points on the
response surface in Figure 2 were selected to confirm the
predictive ability of the model (Table 1). In each case good
Figure 1. Results of a two level factorial design with 1. Notes: (a)
based on eq 2 with TMB-H set to 1 equiv; (b) predicted yield of 2
(blue) and experimental yield of 2 (red).
Moreover, it was found to be statistically insignificant in the
model equation.42 We further concluded from these data that
the concentration of 1 (A) and time of Stage 1 (B) had similar
moderate influence on the reaction outcome and that
temperature (D) was the most influential variable on the
yield of 2 (Figure 1a). Further, we were able to observe
interaction effects between variables with this design and
positive minor effects were noted between concentration and
time of Stage 1 (AB) as well as concentration and temperature
(AD; Figure 1a). Factorial designs on two levels are inherently
linear and do not assess possible curvature in the response due
to individual variables. Therefore, in addition to the extreme
points (all coded variables “−1” or “+1”) we probed the model
by examining the center point (all coded variables “0”) of the
experimental space (Figure 1b). The experimental conditions
for the “center point” are 0.55 M in 1, 16 min for Stage 1, 16
min for Stage 2, and 53 °C. The experimentally observed
(70%) and predicted (45%) yields for the center-point differ
dramatically, thus suggesting curvature in the response.
The factorial design was augmented with 10 additional
experiments, in a central composite design, in order to assess
the expected curvature in the response.42 Several surface plots
were obtained from this design, and a sample is shown in
Figure 2 that verifies curvature, in this case with respect to
concentration and temperature. Excellent yields (>90%) are
predicted by this model at both high temperature and
concentration. Additionally, the contour lines on the temper-
a
Table 1. Model Confirmation for Composite Design
[1]
(M)
temp
(°C)
predicted yield
Experimental yield
b
c
entry
( 10%)
(%)
d
1
2
3
1.0
0.8
0.5
77
70
60
92
95
88
95 1 (93 2)
93
89
4
1
a
Conditions (based on eq 2): [Stage 1] 1 (0.2 mmol), m-CPBA (0.2
mmol, 1 equiv), TsOH·H2O (0.2 mmol, 1 equiv), MeCN (see table
for concentration), temperature (see table), 30 min; [Stage 2]
b
trimethoxybenzene (0.2 mmol, 1 equiv), 5 min. Error of the model
c
equation. 1H NMR yield vs DMF as internal standard, average of 3
d
runs. Isolated yield on 5 mmol scale of 1, average of 3 runs.
agreement was obtained between the predicted and exper-
imental yields. Notably, on preparative scale, excellent yield
(93%) was obtained at the conditions of the highest
experimental yield (1.0 M and 77 °C, entry 1, Table 1).
The scope of the reaction is presented in Chart 1. While the
reaction optimization was carried out on a single aryl iodide 1,
the resulting conditions were generally applied to aryl iodides
having diverse electronic and steric effects. In total 25 different
examples were examined and the yield of aryl(2,4,6-trimethoxy-
phenyl)iodonium tosylates range between 66% and 96% (>85%
average) indicating that the optimal reaction conditions may be
broadly applied with success. Electron-donating and -with-
drawing substituents are tolerated on the aryl iodide in the
ortho-, meta-, and para-positions. Even sensitive functional
groups, such as benzyl bromide and an unprotected hydroxyl
moiety, may be included on aryl iodides. It is interesting to note
that when these specific examples were initially investigated
under the optimal conditions, low yields and evidence of
oxidative decomposition were observed. However, intimate
knowledge of the influence of reaction variables, such as
temperature and concentration (Figure 2), obtained from
multivariate analysis prompted us to explore slightly modified
conditions. When the reaction of these substrates was
conducted at low temperature (rt) and high concentration (1
Figure 2. Surface plot obtained from central composite design with 1.
Notes: Conditions: [Stage 1] 1 (0.2 mmol), m-CPBA (0.2 mmol, 1
equiv), TsOH·H2O (0.2 mmol, 1 equiv), MeCN (y-axis), temperature
(x-axis), 30 min; [Stage 2] trimethoxybenzene (0.2 mmol, 1 equiv), 5
min. Black squares are confirmation points (Table 2; 0.2 mmol scale).
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Chart 1. Scope of Aryl(auxiliary)iodonium Tosylate Salts Obtained in This Work
a
Conditions: [Stage 1] aryl iodide (5 mmol), m-CPBA (5 mmol, 1 equiv), TsOH·H2O (5 mmol, 1 equiv), MeCN (5 mL), 77 °C, 30 min; [Stage 2]
b
c
d
trimethoxybenzene (5 mmol, 1 equiv), 5 min. Reaction conducted at room temperature. 10 mmol scale of aryl iodide. 30 mmol scale of aryl
iodide. 1 mmol scale of aryl iodide. 20 mmol scale of aryl iodide.
e
f
M), a good yield of product is obtained (5, 85%; 7, 87%; and 8,
86%; Chart 1). The rapid identification of alternate reaction
conditions was enabled by the multivariate approach taken in
optimization of the reaction conditions. Iodonium salt products
19−29 bear polysubstituted or elaborate aryl groups and are
obtained in moderate to high yield. These examples underscore
the importance of unsymmetrical aryl(auxiliary)iodonium salts
as the symmetric salts would be more expensive to prepare and
more wasteful in subsequent arylation chemistry. Our method
may also be used to introduce other auxiliaries including
mesityl, 2-thienyl, and anisyl (11, 12, and 13 respectively) in
high yield. Moreover, similar to several other aryliodonium salts
syntheses, this reaction does not require chromatographic
purification of the products; analytically pure material was
isolated by filtration after trituration with ether. All compounds
were characterized by spectroscopic and spectrometric analysis.
Our scope studies have focused primarily on the synthesis of
diaryliodonium tosylate salts (Chart 1). The counteranion is,
however, an important structural feature of these reagents, and
specifically, the ability to introduce or vary the counteranion is a
critical screening element in reaction development with
hypervalent iodonium salts. It is possible to incorporate
counteranion exchange into this method, and this is described
here in two ways (Scheme 3). In the first approach, which is
appropriate when a variety of different counteranions for a
single iodonium moiety are desired, the tosylate readily
exchanges with several counteranions under aqueous conditions
in high yield as demonstrated for 14-OTs (Scheme 3b).43,44 In
the second approach, a third stage was appended to the
standard one-pot protocol (Scheme 3a). Two examples
highlight this strategy, and the isolated yields of the bromide
salts are similar to those previously obtained for the tosylate
Scheme 3. Counteranion Exchange
a
Conditions: 14-OTs (2 mmol, 1 equiv), alkali salt (see table), H2O
b
(∼50 mL), 100 °C to room temperature. Conditions: [Stage 1] aryl
iodide (5 mmol), m-CPBA (5 mmol, 1 equiv), TsOH·H2O (5 mmol, 1
equiv), MeCN (5 mL), 77 °C, 30 min; [Stage 2] trimethoxybenzene
(5 mmol, 1 equiv), 5 min; [Stage 3] KBr (50 mmol, 10 equiv), H2O
(∼100 mL), 100 °C to room temperature.
salts in two stages (compare Chart 1, 23 and 26 and Scheme
3a). Collectively, these two strategies introduce diverse
counteranions into aryl(2,4,6-trimethoxyphenyl)iodonium
salts that influence reactivity and stability (vide infra).
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In light of our interest in exploring and developing the
synthetic utility of these reagents, we have investigated their
bench stability over the course of this study. We have found
that the relative light and thermal stability of these reagents
depends on the electronic effects of the aryl group and the
identity of the counteranion as shown in Figure 3. When
in case 1 did not exceed the oil bath temperature of 77 °C, and
the max temperature observed was 76 °C which occurred
during Stage 1. The internal reaction temperature in case 2
decreased to a minimum of 8 °C at the beginning of Stage 1
during dissolution of the reactants in acetonitrile and increased
to a maximum of 24 °C over the course of Stage 1. The
maximum internal temperature observed in case 2, which was
31 °C, occurred after addition of TMB-H, and the internal
temperature decreased to ∼25 °C over 10 min. The
temperature−time plots for these reactions are provided in
the Supporting Information. The diverse examples presented in
Chart 1 were obtained on a 1−30 mmol scale without incident,
and in these two specific cases on the 20 mmol scale, no “run-
away” exothermic event was observed. However, we urge
extreme caution on scale-up of these reactions given the
unknown energetics of reaction intermediates and products that
depend on electronic effects of aryl groups and counteranion
identity.
We have provided representative synthetic applications of
aryl(2,4,6-trimethoxyphenyl)iodonium salts to complement the
efficiency of the one-pot synthesis described here (Scheme 4).
Figure 3. Light and thermal stability studies. a Notes: temperature of
exothermic onset peak. b No exothermic onset peak noted below 200
°C. c Left-hand vial left open to ambient room and sun light; right-
hand vial kept in the dark as a control.
a
Scheme 4. Synthetic Applications
exposed to ambient light, even for 1 day, diaryliodonium salts
bearing more electron-rich aryl groups discolor more than their
electron-deficient counterparts (compare 14-PF6 vs 22-PF6 or
14-OTs vs 22-OTs; Figure 3). Also, salts with more weakly
coordinating counteranions discolor more than those with
stronger coordinating counteranions (compare 14-PF6 vs 14-
OTs or 22-PF6 vs 22-OTs; Figure 3).45 After 30 days of
ambient light exposure some salts appeared as brown oils.42 All
of the salts prepared in this study appear to be thermally stable
at room temperature. However, we looked for evidence of
exothermic events when heated in the solid state by differential
scanning calorimetry (DSC) analysis.42,46 This behavior was
also dependent on aryl electronic effects and counteranion
identity. Analogous to light stability, iodonium salts with PF6
counteranions appeared less thermally stable than those with
OTs counteranions as evidenced by exothermic onset peaks at
lower temperature (compare 22-PF6 vs 22-OTs or 14-PF6 vs
14-OTs Figure 3). Aryl electronic effects appeared to have the
opposite effect in which iodonium salts with more electron-rich
aryl groups were more thermally stable, i.e., higher exothermic
onset temperature (compare 22-PF6 vs 14-PF6; Figure 3).
These data are in agreement with the decomposition or melting
temperatures of these salts observed during melting point
measurements (Figure 3). On the basis of these observations,
we have found that storage of these reagents in a cool and dark
place will retain the initial color and free-flowing appearance of
these salts for all counteranions that we have investigated.
The exothermic onset peaks observed in the solid-state DSC
analysis prompted us to assess the potential of such exothermic
activity under the reaction conditions.47 The internal reaction
temperature was monitored for two select cases: (1) the
synthesis of 2, bearing an electron-withdrawing substituent, in a
77 °C oil bath, and (2) the synthesis of 4, bearing an electron-
donating substituent, at ambient room temperature. Both
reactions were carried out on 20 mmol scale. Interestingly,
under the reaction conditions, the internal reaction temperature
a
Conditions: (with β-keto ester nucleophile) 14-OTf (1.33 equiv),
NaH (1.33 equiv), ethyl 2-oxocyclohexane-1-carboxylate (1 equiv),
DMF (0.25 M), 0 °C; (with sodium azide) 10-OTs or 14-OTf (1
equiv), NaN3 (1.4 equiv), dioxane/H2O (70:30; 0.25 M), 80 °C, 2−65
h; (with phenol nucleophile) 14-OTf or 4-Br (1.2 equiv), 4-
fluorophenol (1 equiv), KOtBu (1.1 equiv), toluene (0.3 M), 40 °C;
(with sodium sulfinate nucleophile) 14-OTf (1.1 equiv), sodium
phenyl sulfinate (1 equiv), DMF (0.5 M), 90 °C; (with alkoxide
nucleophile) 1-octanol (2 equiv), NaH (1.5 equiv), 29-Br (1 equiv),
TBME (0.2 M), 50 °C, 1 h.
Moreover, these examples contribute to a small, but important,
body of literature that has begun to establish unsymmetrical
aryl(2,4,6-trimethoxyphenyl)iodonium salts as synthetically
useful metal-free arylation reagents.31,48,18,19,49 Several high-
lights from these examples are worth noting. First, the
compatibility of these electrophilic aryl reagents with four
different nucleophiles including C-, N-, O-, and S-nucleophiles
has been demonstrated in synthetically useful yields ranging
from 55% to 85% (Scheme 4a). Specifically, enolate,31 azide,50
phenoxide,51 and sulfinate52 nuclophiles react with 4-Br, 10-
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dure. All other materials were prepared as described in detail below.
Crude reaction mixtures were analyzed by 1H NMR spectroscopy and
thin-layer chromatography (TLC) on silica gel (60 Å F-254) TLC
plates and visualized by UV irradiation. Crude material was purified by
flash column chromatography on silica gel unless otherwise stated. 1H,
13C, 19F NMR spectra were recorded in CDCl3 or DMSO-d6
(referenced to tetramethylsilane) on a 400 or 600 MHz spectrometer
at 298 K unless otherwise stated. The following notation is used: br,
broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,
doublet of doublets. FTIR spectra were obtained from solutions in
DCM or CDCl3. High resolution mass spectrometry (HRMS) data
were obtained by electrospray ionization (ESI) with an ion trap mass
analyzer or electron impact (EI, 70 eV). Melting points are reported as
uncorrected.
General Procedure for the Synthesis of Aryl(2,4,6-
trimethoxyphenyl)iodonium Tosylates (2−29) . Aryl iodide (5
mmol, 1 equiv) and acetonitrile (5 mL) were added to a 50 mL round-
bottom flask, equipped with a magnetic stir bar. Toluenesulfonic acid
(5.05 mmol, 1.01 equiv) was added in one portion, followed by one
portion of m-CPBA (5.05 mmol, 1.01 equiv). After attaching a reflux
condenser, the reaction was lowered into an oil bath set to 77 °C and
stirred vigorously. After 30 min, the reflux condenser was removed in
order to add 1,3,5-trimethoxybenzene (5.05 mmol, 1.01 equiv) in one
portion and stirring was continued at 77 °C for 5 min. The reaction
was removed from heat and concentrated under reduced pressure. The
crude residue was triturated with diethyl ether. The precipitate was
isolated by vacuum filtration and washed by slurry filtration with
diethyl ether (3 × 20 mL). After drying under high vacuum the
diaryliodonium salt was obtained in analytically pure form.
OTs, and 14-OTf chemoselectively at the aryl group. Second,
the examples in Scheme 4a involve formal nucleophilic addition
to electron-rich arenes (σp = −0.01, −0.17, −0.20 for Ph, Me,
and t-Bu, respectively)53 which remain a current challenge with
unsymmetrical aryl(mesityl)iodonium salts.8,18 Third, while
each of the examples in Scheme 4a bears the TMB-derived
auxiliary we have demonstrated that three different counter-
anions (Br, OTf, OTs) are compatible in these nucleophile
arylation reactions. However, we also emphasize that these
results were obtained from unoptimized combinations of a
counteranion and the TMB-auxiliary and, therefore, demon-
strate the breadth of possible counteranions used with this
auxiliary. Fourth, we have demonstrated that 14-OTf reacts
with four diverse nucleophiles under mild and straightforward
conditions to yield four diverse biphenyl derivatives in
moderate (55%) to high (80%) yield. This result, together
with the one-pot synthesis, points toward aryl(2,4,6-trimethoxy-
phenyl)iodonium salts as potential reagents for late-stage
diversification reactions.54−56 Finally, we have demonstrated
the utility of these reagents in the synthesis of a liquid crystal
nematic mesogen 8OCB 36 which is used in optical devices
(Scheme 4b).57 In this case octanol is arylated under basic
conditions8 with unsymmetrical 29-Br to yield 36 in 70% yield.
We are continuing to explore the synthetic utility of these
reagents with carbon and heteroatom nucleophiles.
CONCLUSIONS
Compound 2. Prepared according to the general procedure above
■
on 5 mmol scale and obtained in 93% yield (2.798 g) as a pale yellow
The optimization and scope of a one-pot synthesis to access a
diverse range of aryl(2,4,6-trimethoxyphenyl)iodonium tosylate
salts was described. The chemometric-based optimization
yielded general conditions and insight into the experimental
space. Under the optimal conditions, this reaction proceeds in a
short reaction time (<1 h), at high concentration (1 M), in
equal stoichiometry of all reactants, and in generally high yield
(85% average). Anion metathesis with these salts may be
accomplished in two different ways and leads to diaryliodonium
bromide, iodide, trifluoroacetate, triflate, hexafluorophosphate,
and tetrafluoroborate salts in high yield. The general stability of
these reagents was assessed and point toward the utility of these
compounds as thermally stable reagents at room temperature
that should be stored away from light. Preliminary synthetic
application of these reagents was highlighted with C-, N-, O-,
and S-nucleophiles and in the synthesis of a liquid crystal
molecule via metal-free C−O coupling; we are actively pursuing
new synthetic directions with these reagents. Collectively, the
method described here is inexpensive, operationally simple,
scalable, and broad in scope; these points, in combination with
the facile anion exchange chemistry, should increase the
accessibility of unsymmetrical aryl(2,4,6-trimethoxyphenyl)-
iodonium salts for discovery and development of metal-free
arylation reactions. Moreover, the ability to vary both aryl
electronic density and counteranion identity and insight into
thermal and light stability thereof may provide new inspiration
for previously inaccessible compounds that have applications
beyond organic synthesis.
1
powder. H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 8.4 Hz, 2H),
7.96 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.8 Hz,
2H), 6.49 (s, 2H), 3.95 (s, 6H), 3.88 (s, 3H), 3.86 (s, 3H), 2.28 (s,
3H). 13C NMR (101 MHz, DMSO-d6) δ 166.3, 165.1, 159.4, 145.5,
137.6, 134.5, 132.0, 131.7, 128.0, 125.4, 121.0, 92.1, 86.7, 57.3, 56.1,
52.6, 20.7. FT-IR: 3041, 2949, 2842, 1721, 1646, 1582, 1457, 1343,
+
1282, 1186, 1034, 816 cm−1. HRMS (ESI+): calculated for C17H18IO5
[M − OTs]+, 429.0193; observed, 429.0167. Melting point: 169−175
°C.
Compound 3. Prepared according to the general procedure above
on 5 mmol scale and obtained in 93% yield (2.520 g) as a white
1
powder. H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 7.5 Hz, 2H),
7.64−7.38 (m, 5H), 7.10 (d, J = 7.5 Hz, 2H), 6.47 (s, 2H), 3.94 (s,
6H), 3.86 (s, 3H), 2.27 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
166.1, 159.3, 145.5, 137.6, 134.2, 131.4(2), 131.3(6), 128.0, 125.4,
116.0, 92.0, 87.0, 57.2, 56.1, 20.7. FT-IR: 3041, 2949, 2842, 2842,
1721, 1646, 1582, 1457, 1343, 1282, 1186, 1034, 816 cm−1. HRMS
+
(ESI+): calculated for C15H16IO3 [M − OTs]+, 371.0139; observed,
371.0121. Melting point: decomposed 167 °C.
Compound 4. Prepared according to the general procedure above
on 10 mmol scale and obtained in 96% yield (5.353 g) as an off-white
powder. 1H NMR (400 MHz, DMSO-d6) δ 7.83−7.75 (m, 2H), 7.52−
7.45 (m, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.45
(s, 2H), 3.94 (s, 6H), 3.86 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H). 13C
NMR (101 MHz, DMSO-d6) δ 166.0, 159.3, 145.5, 141.8, 137.6,
134.3, 132.0, 128.0, 125.4, 112.4, 91.9, 87.2, 57.2, 56.1, 20.7 (one
carbon signal unaccounted for due to overlapping methyl signals). FT-
IR: 3023, 1642, 1585, 1458, 1414, 1207, 1185, 1035, 816 cm−1. HRMS
+
(ESI+): calculated for C16H18IO3 [M − OTs]+, 385.0295; observed,
385.0265. Melting point: decomposed 168 °C.
Compound 5. Prepared according to the general procedure above
with the exception of running both stages at room temperature. The 5
EXPERIMENTAL SECTION
1
mmol scale reaction yielded 85% (2.621 g) as a white powder. H
■
NMR (400 MHz, DMSO-d6) δ 7.92−7.87 (m, 2H), 7.54−7.44 (m,
4H), 7.10 (d, J = 7.8 Hz, 2H), 6.45 (s, 2H), 4.70 (s, 2H), 3.94 (s, 6H),
3.86 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.0,
159.2, 145.4, 141.5, 137.6, 134.6, 132.0, 128.0, 125.4, 115.8, 91.9, 87.7,
57.2, 56.1, 32.7, 20.7. FT-IR: 3090, 3033, 2978, 2945, 2844, 1643,
1583, 1413, 1186, 815, 682, 565 cm−1. HRMS (ESI+): calculated for
General Considerations. Commercially available reagents and
solvents were used without further purification unless otherwise stated.
m-CPBA was obtained from a commercial source, dried, and assayed
by iodometric titration before use according to literature procedures.58
4′-Iodo-[1,1′-biphenyl]-4-carbonitrile59 and 2-(4-iodobenzyl)-
isoindoline-1,3-dione60 were prepared according to literature proce-
F
DOI: 10.1021/acs.joc.5b02833
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
C16H17BrIO3 [M − OTs]+, 462.9400; observed, 462.9383. Melting
(s, 6H), 2.28 (s, 6H), 1.23 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ
154.6, 145.4, 142.8, 141.4, 137.5, 134.1, 129.6, 128.8, 127.9, 125.4,
122.6, 111.0, 34.7, 30.6, 26.2, 20.7, 20.4. FT-IR: 3090, 3062, 3039,
2965, 2871, 2843, 1640, 1393, 1214, 1187, 816 cm−1. HRMS (ESI+):
calculated for C19H24I+ [M − OTs]+, 379.0917; observed, 379.0895.
Melting point: decomposed 175 °C.
Compound 12. Prepared according to the general procedure above
on 5 mmol scale with the following deviation: (i) in Stage 2, thiophene
was used in place of TMB. The product was obtained in 71% yield
(1.186 g) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.20−
8.13 (m, 2H), 8.11−8.05 (m, 1H), 7.99−7.92 (m, 1H), 7.57−7.44 (m,
4H), 7.17−7.07 (m, 3H), 2.28 (s, 3H), 1.23 (s, 9H). 13C NMR (101
MHz, DMSO-d6) δ 154.9, 145.1, 140.2, 137.8, 137.0, 134.3, 129.4,
128.6, 128.0, 125.4, 115.8, 100.7, 34.7, 30.6, 20.7. FT-IR: 3094, 3059,
2962, 2927, 2867, 1652, 1392, 1214, 1188, 1032, 816 cm−1. HRMS
(ESI+): calculated for C14H16IS+ [M − OTs]+, 343.0012; observed,
342.9998. Melting point: 125−136 °C.
point: decomposed 157 °C.
Compound 6. Prepared according to the general procedure above
on 5 mmol scale and obtained in 90% yield (3.164 g) as a white
1
powder. H NMR (400 MHz, DMSO-d6) δ 7.95−7.79 (m, 6H), 7.49
(d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H),
6.44 (s, 2H), 4.81 (s, 2H), 3.94 (s, 6H), 3.85 (s, 3H), 2.27 (s, 3H). 13C
NMR (101 MHz, DMSO-d6) δ 167.6, 166.1, 159.3, 145.5, 140.3,
137.6, 134.5, 131.4, 130.2, 129.1, 128.0, 125.4, 123.2, 114.6, 91.9, 87.1,
57.2, 56.0, 40.2, 20.7. FT-IR: 3021, 2968, 2842, 1700, 1643, 1392,
1229, 1184, 788, 729 cm−1. HRMS (ESI+): calculated for
+
C24H21INO5 [M − OTs]+, 530.0459; observed, 530.0438. Melting
point: decomposed 172 °C.
Compound 7. Prepared according to the general procedure above
on 5 mmol scale with the following deviations: (i) Stage 1 was run at
ambient temperature; (ii) Stage 2 was run at ambient temperature;
(iii) Stage 2 reaction progress was assessed by TLC, and Stage 2
reaction time was 1 h. The product was isolated in 87% yield (2.49 g)
as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.4
Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.10 (d, J
= 7.9 Hz, 2H), 6.45 (s, 2H), 5.50−5.25 (br. s, 1H), 4.52 (s, 2H), 3.94
(s, 6H), 3.85 (s, 3H), 2.27 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
166.0, 159.2, 146.5, 145.4, 137.6, 134.1, 129.1, 128.0, 125.4, 113.6,
91.9, 87.2, 61.9, 57.2, 56.0, 20.7. FT-IR: 3410, 3080, 3033, 2995, 2918,
2852, 1644, 1572, 1443, 1412, 1340, 1040, 821 cm−1. HRMS (ESI+):
calculated for C16H18IO4+ [M − OTs]+, 401.0244; observed, 401.0219.
Melting point: 184−186 °C.
Compound 13. Prepared according to the general procedure above
on 5 mmol scale with the following deviations: (i) in Stage 2, anisole
was used in place of TMB; (ii) Stage 2 reaction time was 1 h and
reaction progress was assessed by TLC; (iii) the solvent was not
removed from the crude reaction and instead was immediately
triturated with ethyl ether. The product was filtered and washed
according to the general procedure and obtained in 84% yield (2.250
1
g) as a white powder. H NMR (400 MHz, DMSO-d6) δ 8.24−8.17
(m, 2H), 8.16−8.10 (m, 2H), 7.56−7.51 (m, 2H), 7.50−7.45 (m, 2H),
7.12 (d, J = 7.9 Hz, 2H), 7.06−7.01 (m, 2H), 3.77 (s, 3H), 2.28 (s,
3H), 1.23 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 161.7, 154.7,
145.5, 137.6, 137.2, 134.6, 128.5, 128.0, 125.5, 117.2, 113.5, 105.4,
55.6, 34.7, 30.6, 20.7. FT-IR: 3091, 3061, 3050, 2963, 2902, 2869,
2840, 1395, 1254, 1184, 817 cm−1. HRMS (ESI+): calculated for
C17H20IO+ [M − OTs]+, 367.0553; observed, 367.0528. Melting
point: 177−180 °C.
Compound 8. Prepared according to the general procedure above
on 5 mmol scale with the following deviations: (i) Stage 1 was run at
ambient temperature; (ii) Stage 2 was run at ambient temperature;
(iii) Stage 2 reaction progress was assessed by TLC, and Stage 2
reaction time was 35 min. The product was obtained in 86% yield
1
(2.504 g) as a white powder. H NMR (400 MHz, DMSO-d6) δ 7.82
(d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H),
7.11 (d, J = 7.9 Hz, 2H), 6.45 (s, 2H), 4.68 (s, 1H), 3.94 (s, 6H), 3.85
(s, 3H), 3.58 (t, J = 6.6 Hz, 2H), 2.72 (t, J = 6.6 Hz, 2H), 2.27 (s,
3H).13C NMR (101 MHz, DMSO-d6) δ 166.0, 159.3, 145.4, 143.9,
137.7, 134.1, 132.0, 128.0, 125.4, 112.9, 91.9, 87.1, 61.4, 57.2, 56.1,
38.8, 20.7. FT-IR: 3424, 3083, 3030, 2948, 2906, 1640, 1577, 1339,
Compound 14. Prepared according to the general procedure above
on 10 mmol scale and obtained in 90% yield (5.533 g) as an off-white
1
powder. H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.6 Hz, 2H),
7.74 (d, J = 8.6 Hz, 2H), 7.70−7.62 (m, 2H), 7.56−7.32 (m, 5H), 7.10
(d, J = 7.9 Hz, 2H), 6.49 (s, 2H), 3.97 (s, 6H), 3.88 (s, 3H), 2.27 (s,
3H). 13C NMR (101 MHz, DMSO-d6) δ 166.1, 159.3, 145.6, 143.1,
138.1, 137.5, 134.8, 129.5, 129.0, 128.5, 128.0, 126.9, 125.4, 114.5,
92.0, 87.0, 57.3, 56.1, 20.7. FT-IR: 3089, 3068,2967, 2943, 2878, 2839,
1646, 1586, 1468, 1339, 1209, 1033, 816, 765, 684 cm−1. HRMS
+
1218, 1177, 1033, 562 cm−1. HRMS (ESI+): calculated for C17H20IO4
[M − OTs]+, 415.0401; observed, 415.0382. Melting point: 181−184
°C.
+
Compound 9. Prepared according to the general procedure above
on 5 mmol scale and obtained in 77% yield (2.251 g) as a white
powder. H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 8.4 Hz, 2H),
(ESI+): calculated for C21H20IO3 [M − OTs]+, 447.0452; observed,
447.0431. Melting point: 162−164 °C.
1
Compound 15. Prepared according to the general procedure above
on 30 mmol scale and obtained in 90% yield (16.527 g) as a white
7.47 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 7.8 Hz,
2H), 6.46 (s, 2H), 3.95 (s, 6H), 3.86 (s, 3H), 2.90 (septet, J = 6.8 Hz,
1H), 2.28 (s, 3H), 1.16 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz,
DMSO-d6): δ 166.0, 159.3, 152.3, 145.7, 137.5, 134.4, 129.6, 127.9,
125.4, 112.6, 91.9, 87.0, 57.2, 56.1, 33.1, 23.4, 20.7. FT-IR: 3090, 3059,
3032, 2961, 2867, 2840, 1651, 1583, 1412, 1213, 1186, 815 cm−1.
1
powder. H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 8.2 Hz, 2H),
7.82 (d, J = 8.4 Hz, 2H), 7.52−7.43 (m, 2H), 7.11 (d, J = 7.8 Hz, 2H),
6.50 (s, 2H), 3.96 (s, 6H), 3.89 (s, 3H), 2.29 (s, 3H). 13C NMR (101
MHz, DMSO-d6) δ 166.4, 159.4, 145.5, 137.6, 135.0, 131.3 (q, JC−F
=
32.4 Hz), 128.1 (q, JC−F = 3.5 Hz), 128.0, 125.4, 123.4 (q, JC−F = 272.8
Hz), 120.3 (br. s), 92.1, 87.0, 57.3, 56.2, 20.7. 19F NMR (376 MHz,
DMSO-d6) δ −61.6. FT-IR: 3090, 2979, 2847, 1467, 1644, 1584, 2949,
1414, 1210, 1182, 1034, 816 cm−1. HRMS (ESI+): calculated for
+
HRMS (ESI+): calculated for C18H22IO3 [M − OTs]+, 413.0608;
observed, 413.0587. Melting point: 149−152 °C.
Compound 10. Prepared according to the general procedure above
on 10 mmol scale and obtained in 93% yield (5.570 g) as a white
powder. 1H NMR (400 MHz, DMSO-d6) δ 7.87−7.80 (m, 2H), 7.53−
7.44 (m, 4H), 7.10 (d, J = 7.8 Hz, 2H), 6.47 (s, 2H), 3.96 (s, 6H), 3.87
(s, 3H), 2.28 (s, 3H), 1.23 (s, 9H). 13C NMR (101 MHz, DMSO) δ
166.0, 159.3, 154.5, 145.6, 137.5, 134.1, 128.5, 128.0, 125.4, 112.6,
91.9, 87.0, 57.3, 56.1, 34.7, 30.6, 20.7. FT-IR: 3071, 2953, 2867, 2840,
1036, 1634, 1583, 1467, 1412, 1208, 1125, 815 cm−1. HRMS (ESI+):
calculated for C19H24IO3+ [M − OTs]+, 427.0765; observed, 427.0746.
Melting point: 190−192 °C.
+
C16H15F3IO3 [M − OTs]+, 439.0013; observed, 438.9989. Melting
point: 167−170 °C.
Compound 16. Prepared according to the general procedure above
on 5 mmol scale and obtained in 90% yield (2.656 g) as a pale yellow
powder. 1H NMR (400 MHz, DMSO-d6) δ 8.27−8.11 (m, 4H), 7.50−
7.43 (m, 2H), 7.14−7.05 (m, 2H), 6.50 (s, 2H), 3.95 (s, 6H), 3.88 (s,
3H), 2.28 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.4, 159.4,
149.0, 145.5, 137.6, 135.4, 128.0, 125.9, 125.4, 122.3, 92.1, 87.1, 57.3,
56.2, 20.7. FT-IR: 3094, 3058, 3017, 2981, 2946, 2846, 1643, 1583,
1527, 1468, 1346, 1346, 1210, 1034, 848, 816 cm−1. HRMS (ESI+):
Compound 11. Prepared according to the general procedure above
on 5 mmol scale with the following deviations: (i) in Stage 2,
mesitylene was added in place of TMB; (ii) Stage 2 reaction time was
6 h and reaction progress was monitored by TLC. The product was
obtained in 84% yield (2.303 g) as a white powder. H NMR (400
MHz, DMSO-d6) δ 7.88 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H),
7.46 (d, J = 8.1 Hz, 2H), 7.19 (s, 2H), 7.09 (d, J = 7.9 Hz, 2H), 2.60
+
calculated for C15H15INO5 [M − OTs]+, 415.9989; observed,
415.9963. Melting point: 158−165 °C.
Compound 17. Prepared according to the general procedure above
on 1 mmol scale and obtained in 75% yield (0.428 g) as a pink
powder. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (dd (appears as
triplet), J = 1.5 Hz, 1H), 8.22−8.17 (m, 1H), 8.10−8.03 (m, 1H), 7.65
1
G
DOI: 10.1021/acs.joc.5b02833
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(dd (appears as triplet), J = 8.0 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.11
(d, J = 7.9 Hz, 2H), 6.48 (s, 2H), 3.95 (s, 6H), 3.88 (s, 3H), 2.29 (s,
3H). 13C NMR (101 MHz, DMSO-d6) δ 166.3, 159.3, 145.4, 138.8,
137.6, 137.3, 135.2, 132.2, 128.0, 125.4, 116.9, 116.1, 113.6, 92.0, 87.1,
57.3, 56.1, 20.7. FT-IR: 3088, 2946, 2846, 2232, 1647, 1583, 1468,
1413, 1229, 1187, 1035, 785 cm−1. HRMS (ESI+): calculated for
8.06 (dd, J = 8.2, 1.9 Hz, 1H), 7.60−7.53 (m, 1H), 7.49−7.41 (m,
2H), 7.10 (d, J = 7.8 Hz, 2H), 6.48 (s, 2H), 3.96 (s, 6H), 3.88 (s, 3H),
2.51 (s, 3), 2.28 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.3,
159.3, 149.3, 145.5, 138.1, 137.6, 136.5, 135.4, 129.7, 128.0, 125.4,
112.5, 92.1, 87.3, 57.3, 56.1, 20.7, 19.3. FT-IR: 3079, 2975, 2942, 2841,
1581, 1455, 1411, 1272, 1161, 1024 cm1. HRMS (ESI+): calculated for
+
+
C16H15INO3 [M − OTs]+, 396.0091; observed, 396.0076. Melting
C16H17INO5 [M − OTs]+, 430.0146; observed, 430.0116. Melting
point: 175−178 °C.
point: decomposed 113 °C.
Compound 18. Prepared according to the general procedure above
on 5 mmol scale and obtained in 86% yield (2.395 g) as a white
Compound 24. Prepared according to the general procedure above
on 10 mmol scale and obtained in 95% yield (5.715 g) as a pale yellow
1
1
powder. H NMR (400 MHz, DMSO-d6) δ 7.88−7.82 (m, 1H), 7.72
powder. H NMR (400 MHz, DMSO-d6) δ 8.58 (dd, J = 9.1, 4.7 Hz,
(d, J = 7.9 Hz, 1H), 7.55−7.40 (m, 4H), 7.11 (d, J = 7.9 Hz, 2H), 6.48
(s, 2H), 3.95 (s, 6H), 3.88 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 166.3, 161.7 (d, JC−F = 251.9 Hz), 159.4, 145.5, 137.7,
133.2 (d, JC−F = 7.8 Hz), 130.3 (d, JC−F = 3.2 Hz), 128.0, 125.4 121.2
(d, JC−F = 24.6 Hz), 118.7 (d, JC−F = 20.8 Hz), 115.6 (d, JC−F = 7.4
Hz), 92.0, 87.2, 57.3, 56.1, 20.7. 19F NMR (376 MHz, DMSO-d6) δ
−108.1. FT-IR: 3086, 2945, 2845, 1650, 1581, 1468, 1414, 1344, 1209,
1H), 7.83−7.71 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.15−7.06 (m,
3H), 6.62 (s, 2H), 3.97 (s, 3H), 3.93 (s, 6H), 2.29 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 167.8, 165.7 (d, JC−F = 262.8 Hz), 160.3,
145.4, 143.0 (d, JC−F = 2.9 Hz), 137.7, 130.2 (d, JC−F = 10.2 Hz),
128.0, 125.4, 119.5 (d, JC−F = 23.6 Hz), 118.9 (d, JC−F = 27.7 Hz),
110.8 (d, JC−F = 7.8 Hz), 92.5, 84.6, 57.5, 56.4, 20.7. 19F NMR (376
MHz, DMSO-d6) δ −98.1. FT-IR: 3090, 2949, 2847, 2847, 1643,
1582, 1525, 1460, 1347, 1347, 1212, 1187, 1034, 869 cm−1. HRMS
+
1035 cm−1. HRMS (ESI+): calculated for C15H15FIO3 [M − OTs]+,
+
389.0044; observed, 389.0021. Melting point: 181−182 °C.
Compound 19. Prepared according to the general procedure above
on 5 mmol scale and obtained in 89% yield (2.532 g) as a white
(ESI+): calculated for C15H14FINO5 [M − OTs]+, 433.9895;
observed, 433.9876. Melting point: 173−174 °C.
Compound 25. Prepared according to the general procedure above
on 5 mmol scale and obtained in 85% yield (2.750 g) as a white
powder. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.95 (s, 2H),
7.49 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 6.47 (s, 2H), 3.95
(s, 6H), 3.86 (s, 3H), 2.27 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
166.4, 159.5, 145.2, 140.4, 138.0, 135.9−135.5 (m), 131.1, 130.6−
1
powder. H NMR (400 MHz, DMSO-d6) δ 7.55 (s, 2H), 7.47 (d, J =
8.0 Hz, 2H), 7.21 (s, 1H), 7.10 (d, J = 7.9 Hz, 2H), 6.46 (s, 2H), 3.95
(s, 6H), 3.86 (s, 3H), 2.32−2.22 (m, 9H). 13C NMR (101 MHz,
DMSO-d6) δ 166.0, 159.3, 145.6, 141.0, 137.5, 132.9, 131.6, 128.0,
125.4, 115.6, 92.0, 86.7, 57.2, 56.1, 20.7, 20.5. FT-IR: 3086, 3054,
3010, 2976, 2945, 2916, 2840, 1582, 1413, 1207, 1189, 1034, 815
130.3 (m), 129.1 (q, JC−F = 33.1 Hz), 128.2, 125.5, 122.7 (q, JC−F
=
+
cm−1. HRMS (ESI+): calculated for C17H20IO3 [M − OTs]+,
273.1 Hz), 120.1, 92.2, 87.6, 57.1, 56.2, 20.8. 19F NMR (376 MHz,
399.0452; observed, 399.0434. Melting point: 166−168 °C.
DMSO-d6) δ −61.4. FT-IR: 3032, 2942, 2847, 1643, 1590, 1457, 1407,
+
Compound 20. Prepared according to the general procedure above
on 5 mmol scale with the following deviations: (i) the reaction was
removed from the heat bath for 10 min before starting Stage 2; (ii)
Stage 2 was run for 10 min at room temperature. The product was
obtained in 81% yield (2.478 g) as a light pink powder. 1H NMR (400
MHz, DMSO-d6) δ 7.95 (d, J = 1.8 Hz, 2H), 7.83 (s, 1H), 7.48 (d, J =
8.0 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.50 (s, 2H), 3.97 (s, 6H), 3.89
(s, 3H), 2.29 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.5, 159.4,
145.3, 137.7, 135.5, 132.1, 131.4, 128.0, 125.4, 116.6, 92.1, 87.3, 57.3,
56.2, 20.7. FT-IR: 3067, 3037, 2980, 2959, 2939, 2839, 1646, 1587,
1409, 1211, 1188, 816, 795, 657, 563 cm−1. HRMS (ESI+): calculated
1212, 1072, 1037 cm−1. HRMS (ESI+): calculated for C16H14ClF3IO3
[M − OTs]+, 472.9623; observed, 472.9594. Melting point: 168−170
°C.
Compound 26. Prepared according to the general procedure above
on 1 mmol scale and obtained in 85% yield (0.4933 g) as a white
1
powder. H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 2.2 Hz, 1H),
8.38 (dd, J = 8.5, 2.3 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.0
Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.47 (s, 2H), 3.96 (s, 6H), 3.88 (s,
3H), 2.29 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.3, 159.2,
153.5, 152.6, 145.3, 145.1, 137.7, 128.0, 127.4, 125.4, 113.8, 92.0, 87.2,
57.3, 56.1, 20.7. FT-IR: 3035, 2943, 2847, 1581, 1455, 1413, 1301,
1210, 1186, 1031, 815 cm−1. HRMS (ESI+): calculated for
+
for C15H14Cl2IO3 [M − OTs]+, 438.9359; observed, 438.9342.
+
Melting point: 193−196 °C.
C14H14ClINO3 [M − OTs]+, 405.9701; observed, 405.9684. Melting
Compound 21. Prepared according to the general procedure above
on 1 mmol scale and obtained in 67% yield (0.397 g) as a white
point: decomposed 165 °C.
Compound 27. The precursor aryl iodide (S1) was prepared
powder. H NMR (400 MHz, DMSO) δ 7.98−7.96 (m, 1H), 7.76−
according to a literature procedure8 on 10 mmol scale and obtained in
1
1
7.72 (m, 1H), 7.50−7.39 (m, 3H), 7.10 (d, J = 7.8 Hz, 2H), 6.47 (s,
2H), 3.95 (s, 6H), 3.87 (s, 3H), 2.33 (s, 3H), 2.28 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 166.2, 159.3, 145.5, 139.7, 137.6, 134.8,
133.7, 133.6, 132.8, 128.0, 125.4, 112.8, 92.0, 87.2, 57.3, 56.1, 20.7,
19.4. FT-IR: 3093, 2945, 2845, 1649, 1582, 1467, 1414, 1186, 1211,
51% yield (2.349 g) as a white solid. H NMR (400 MHz, CDCl3) δ
7.83 (d, J = 2.2 Hz, 1H), 7.52 (dd, J = 17.0, 2.3 Hz, 1H), 7.31 (d, J =
8.4 Hz, 1H), 7.02 (d (appears as a triplet), J = 1.8 Hz, 1H), 6.90 (d, J =
1.8 Hz, 2H), 5.01 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 159.1,
138.5, 137.5, 137.3, 135.5, 134.2, 121.9, 121.9, 113.9, 92.7, 69.0. FTIR:
+
1033 cm1. HRMS (ESI+): calculated for C16H17ClIO3 [M − OTs]+,
3053, 1573, 1265 cm−1 HRMS (AP+): calculated for
.
418.9905; observed, 418.9877. Melting point: 176−178 °C.
Compound 22. Prepared according to the general procedure above
on 20 mmol scale and obtained in 90% yield (11.258 g) as a white
[C13H8BrCl2IO]+, 455.8180; observed, 455.8203. Melting point:
123−125 °C. Rf : 0.20 in 100% hexanes. 27: Prepared according to
the general procedure above on 5 mmol scale and obtained in 92%
yield (2.871 g) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ
7.98 (d, J = 2.1 Hz, 1H), 7.86−7.74 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H),
7.20 (t, J = 1.7 Hz, 1H), 7.14−7.06 (m, 4H), 6.45 (s, 2H), 5.19 (s,
2H), 3.92 (s, 6H), 3.88 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 166.2, 159.2, 159.1, 145.5, 138.4, 137.6, 135.5, 135.4,
134.6, 134.4, 128.0, 126.1, 125.4, 121.0, 114.7, 114.0, 91.9, 87.1, 69.0,
57.2, 56.1, 20.7. FT-IR: 3033, 2945, 2845, 1640, 1580, 1413, 1212,
1
powder. H NMR (400 MHz, DMSO) δ 8.36 (dd, J = 6.6, 1.8 Hz,
1H), 8.27−8.18 (m, 1H), 7.66−7.56 (m, 1H), 7.47 (d, J = 8.1 Hz,
2H), 7.11 (d, J = 7.9 Hz, 2H), 6.50 (s, 2H), 3.96 (s, 6H), 3.89 (s, 3H),
2.29 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.4, 160.3 (d, JC−F
= 259.6 Hz), 159.3, 145.4, 141.5 (d, JC−F = 9.9 Hz), 137.7, 133.3 (d,
JC−F = 4.6 Hz), 128.0, 125.4, 121.4 (q, JC−F = 267.6 Hz), 120.7 (d, JC−F
= 21.8 Hz), 118.8 (dq, JC−F = 33.3, 13.3 Hz), 110.5 (d, JC−F = 3.7 Hz),
92.1, 87.5, 57.3, 56.2, 20.7. 19F NMR (376 MHz, DMSO-d6) δ −60.4
(d, J = 12.5 Hz), −110.5 (q, J = 12.5 Hz). FT-IR: 3091, 3063, 3034,
2947, 2886, 2886, 2846, 1469, 1345, 1229, 1210, 1033, 816, 682, 665,
+
1186, 815, 680 cm−1. HRMS (ESI+): calculated for C22H19BrCl2IO4
[M − OTs]+, 622.8883; observed, 622.8856. Melting point:
decomposed 180 °C.
+
566 cm−1. HRMS (ESI+): calculated for C16H14F4IO3 [M − OTs]+,
Compound 28. The precursor aryl iodide (S2) was prepared
456.9918; observed, 456.9895. Melting point: 133−136 °C.
Compound 23. Prepared according to the general procedure above
on 10 mmol scale and obtained in 95% yield (5.715 g) as a white
according to the literature procedure8 on 10 mmol scale and obtained
1
in 77% yield (2.915 g) as a colorless liquid. H NMR (400 MHz,
CDCl3) δ 7.64−7.56 (m, 2H), 7.04−7.02 (m, 3H), 6.91−6.89 (m,
1H), 6.74−6.70 (m, 1H), 4.09 (t, J = 6.7 Hz, 2H), 3.02 (t, J = 6.7 Hz,
1
powder. H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.8 Hz, 1H),
H
DOI: 10.1021/acs.joc.5b02833
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2H). 13C NMR (101 MHz, CDCl3) δ 154.9 (d, JC−F = 2.4 Hz), 152.7
(d, JC−F = 241.3 Hz), 137.6, 137.5, 131.0, 121.0 (d, JC−F = 19.1 Hz),
116.7 (d, JC−F = 22.5 Hz), 116.2, 114.0 (d, JC−F = 6.7 Hz), 91.9, 69.0,
35.1. 19F NMR (376 MHz, CDCl3) δ −126.1. FTIR: 3024, 2253, 1499,
1202, 909 cm−1. HRMS (EI): calculated for C14H11ClFIO, 375.9527;
observed, 375.9516. Rf : 0.26 in 100% hexanes. 28: Prepared according
to the general procedure above on 5 mmol scale and obtained in 93%
yield (2.586 g) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ
7.86 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.4 Hz,
2H), 7.28 (t, J = 9.1 Hz, 1H), 7.15−7.06 (m, 3H), 6.93−6.85 (m, 1H),
6.46 (s, 2H), 4.18 (t, J = 6.5 Hz, 2H), 3.95 (s, 6H), 3.86 (s, 3H), 3.04
(t, J = 6.4 Hz, 2H), 2.28 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
166.0, 159.3, 154.8 (d, JC−F = 2.1 Hz), 151.7 (d, JC−F = 238.8 Hz),
145.6, 142.4, 137.5, 134.3, 132.1, 128.0, 125.4, 119.6 (d, JC−F = 19.0
Hz), 117.1 (d, JC−F = 22.3 Hz), 115.8, 114.9 (d, JC−F = 6.9 Hz), 113.5,
92.0, 87.0, 68.3, 57.2, 56.1, 34.19, 20.7. 19F NMR (376 MHz, DMSO-
d6) δ −127.1. FT-IR: 3092, 3059, 2960, 2927, 2867, 1657, 1394, 1214,
Compound 14-O2CCF3. Prepared according to the general anion
exchange procedure above on 1 mmol scale, using sodium
trifluoroacetate (2.758 g, 20 mmol, 20 equiv) and obtained in 86%
1
yield (0.481 g) as an off-white to light brown powder. H NMR (400
MHz, DMSO-d6) δ 7.99 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H),
7.67 (d, J = 7.4 Hz, 2H), 7.53−7.35 (m, 3H), 6.47 (s, 2H), 3.97 (s,
6H), 3.87 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.1, 159.5,
158.1 (q, JC−F = 30.9 Hz), 143.1, 138.2, 134.8, 129.5, 129.1, 128.5,
126.9, 117.2 (q, JC−F = 300.4 Hz), 114.9, 92.0, 87.4, 57.2, 56.0. 19F
NMR (376 MHz, DMSO-d6) δ −73.4. FT-IR: 3061, 2946, 2843, 1681,
1583, 1414, 1230, 1160, 1026, 803 cm−1. HRMS (ESI+): calculated for
C21H20IO3+ [M − CF3COO]+, 447.0452; observed, 447.0431. Melting
point: 175−177 °C.
Compound 14-OTf. Prepared according to the general anion
exchange procedure above on 2 mmol scale with sodium triflate (6.99
g, 40.6 mmol, 20 equiv) and obtained in 90% yield (1.094 g) as an off-
white to light brown powder. 1H NMR (400 MHz, DMSO-d6) δ 8.01
(d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H),
7.59−7.38 (m, 3H), 6.50 (s, 2H), 3.99 (s, 6H), 3.89 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 166.2, 159.4, 143.2, 138.1, 134.9, 129.6,
129.1, 128.5, 126.9, 120.7 (q, JC−F = 322.3 Hz), 114.5, 92.0, 87.0, 57.3,
56.1. 19F NMR (376 MHz, DMSO) δ −77.7. FT-IR: 3090, 3063, 2944,
2883, 2846, 1578, 1457, 1415, 1259, 1162, 1027, 815 cm−1. HRMS
+
1187, 816 cm−1. HRMS (ESI+): calculated for C23H22ClFIO4 [M −
OTs]+, 543.0230; observed, 543.0206. Melting point: 128−130 °C.
Compound 29. Prepared according to the general procedure above
on 5 mmol scale and obtained in 92% yield (2.931g) as a white
1
powder. H NMR (400 MHz, DMSO-d6) δ 8.06−7.78 (m, 8H), 7.47
(d, J = 8.1 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 6.49 (s, 2H), 3.97 (s,
6H), 3.88 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
167.6, 166.1, 159.2, 145.6, 140.3, 137.5, 134.5(3), 134.5(0), 134.2,
131.4, 130.1, 127.9, 125.4, 123.2, 114.4, 91.9, 87.0, 57.2, 56.0, 20.7. FT-
IR: 3089, 3056, 2980, 2946, 2839, 2227, 1645, 1582, 1413, 1164, 815.
+
(ESI+): calculated for C21H20IO3 [M − OTf]+, 447.0452; observed,
447.0471. Melting point: decomposed 93 °C.
Compound 14-PF6 . Prepared according to the general anion
exchange procedure above on 1 mmol scale with potassium
hexafluorophosphate (3.821 g, 20.8 mmol, 20.8 equiv) and obtained
in 90% yield (0.556 g) as an off-white to light brown powder. 1H NMR
(400 MHz, DMSO-d6) δ 8.04 (d, J = 7.9 Hz, 2H), 7.76 (d, J = 7.9 Hz,
2H), 7.67 (d, J = 7.1 Hz, 2H), 7.59−7.36 (m, 3H), 6.51 (s, 2H), 4.00
(s, 6H), 3.90 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.2, 159.4,
143.2, 138.2, 134.9, 129.6, 129.1, 128.5, 126.9, 114.5, 92.0, 87.0, 57.3,
56.1. 19F NMR (376 MHz, DMSO-d6) δ −70.1 (d, JF‑P = 711.5 Hz).
FT-IR: 3109, 1636, 2949, 1583, 2848, 3065, 1473, 1415, 1231, 1163,
+
HRMS (ESI+): calculated for C22H19INO3 [M − OTs]+, 472.0404;
observed, 472.0375. Melting point: 174−179 °C.
General Procedure for Anion Exchange of 14-OTs to 14-X
(Scheme 3a), 4-OTs to 4-Br, 22-OTs to 22-PF6, and 29-OTs to
29-Br. Reactions were carried out on 1−2.5 mmol scale of 14-OTs,
22-OTs, or 29-OTs as indicated below. 14-OTs, 22-OTs, or 29-OTs
(1 equiv) was added to 50 mL of boiling water. If the iodonium salt
did not dissolve after boiling for 1−2 min, then methanol was added
portionwise until the solution had a homogeneous appearance. While
the mixture was still hot, a salt containing the target anion was added
in excess (10−100 equiv). The resulting solution was left to cool to
ambient temperature, before chilling further in an ice-bath. The
mixture was suction filtered, and the filter cake was washed by slurry
filtration with water (3 × 30 mL). The cake was dried under suction
for 10−20 min and then washed by slurry filtration with diethyl ether
(3 × 30 mL). The sample was finally dried under high vacuum to
remove residual solvent. If a low yield is obtained and the iodonium
salt is suspected to remain in the aqueous filtrate, then it may be
extracted with a suitable solvent such as dichloromethane or ethyl
acetate.
+
1065, 843 cm−1. HRMS (ESI+): calculated for C21H20IO3 [M −
PF6]+, 447.0452; observed, 447.0425. Melting point: decomposed 127
°C.
Compound 14-BF4 . Prepared according to the general anion
exchange procedure above on 1 mmol scale, using sodium
tetrafluoroborate (11.438 g, 104 mmol, 104 equiv) and obtained in
1
96% yield (0.532 g) as an off-white to light brown powder. H NMR
(400 MHz, DMSO-d6) δ 7.99 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.4 Hz,
2H), 7.67 (d, J = 7.5 Hz, 2H), 7.53−7.38 (m, 3H), 6.49 (s, 2H), 3.97
(s, 6H), 3.88 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.2, 159.4,
143.2, 138.1, 134.9, 129.6, 129.1, 128.6, 126.9, 114.5, 92.0, 87.0, 57.3,
56.1. 19F NMR (376 MHz, DMSO-d6) δ −148.3. FT-IR: 3088, 3061,
2945, 2845, 1625, 1582, 1472, 1413, 1230, 1034, 817 cm−1. HRMS
Compound 14-Br. Prepared according to the general anion
exchange procedure above on 2.5 mmol scale, using potassium
bromide (6.00 g, 50 mmol, 20 equiv) and obtained in 96% yield (1.28
g) as an off-white to light brown powder. 1H NMR (400 MHz,
DMSO-d6) δ 8.00−7.95 (m, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.68−7.63
(m, 2H), 7.53−7.37 (m, 3H), 6.45 (s, 2H), 3.95 (s, 6H), 3.87 (s, 3H).
13C NMR (101 MHz, DMSO-d6) δ 165.6, 159.2, 142.6, 138.3, 134.6,
+
(ESI+): calculated for C21H20IO3 [M − BF4]+, 447.0452; observed,
447.0427. Melting point: 160−162 °C.
Compound 4-Br. Prepared according to the general anion exchange
procedure above on 1 mmol scale using potassium bromide (12.5 g,
10.5 mmol, 10.5 equiv) and obtained in 85% yield (0.395 g) as a white
1
powder. H NMR (600 MHz, DMSO-d6) δ 7.77 (d, J = 8.3 Hz, 2H),
7.22 (d, J = 8.3 Hz, 2H), 6.42 (s, 2H), 3.92 (s, 6H), 3.85 (s, 3H), 2.30
(s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 165.5, 159.1, 141.1, 134.0,
131.7, 114.4, 91.8, 90.0, 57.1, 56.0, 20.7. FT-IR: 3014, 2966, 2933,
1580, 1464, 1227, 1032, 808 cm−1. HRMS (ESI+): calculated for
129.3, 129.0, 128.3, 126.8, 116.5, 91.9, 89.9, 57.2, 56.0. FT-IR: 3072,
2944, 2836, 1636, 1587, 1467, 1338, 1232, 1158, 1033, 824 cm−1.
+
HRMS (ESI+): calculated for C21H20IO3 [M − Br]+, 447.0452;
+
C16H18IO3 [M − Br]+, 385.0295; observed, 385.0324. Mp 192−193
observed, 447.0423. Melting point: 193−195 °C.
Compound 14-I. Prepared according to the general anion exchange
procedure above on 1 mmol scale, using potassium iodide (1.765 g, 11
mmol, 11 equiv) and obtained in 95% yield (0.544 g) as an off-white
°C.
Compound 22-PF6 . Prepared according to the general anion
exchange procedure above on 1 mmol scale and obtained in 61% yield
(0.365 g) as a white powder. 1H NMR (600 MHz, DMSO-d6) δ 8.39−
8.35 (m, 1H), 8.26−8.18 (m, 1H), 7.68−7.54 (m, 1H), 6.49 (s, 2H),
3.96 (s, 6H), 3.88 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 166.7,
160.6 (dd, J = 260.1, 1.8 Hz), 159.6, 141.7 (d, JC−F = 9.6 Hz), 133.6,
(d, JC−F = 3.9 Hz), 121.54 (q, J = 273.1 Hz), 120.9 (d, J = 21.8 Hz),
119.2 (dq, J = 33.2, 13.2 Hz), 110.5 (d, J = 3.7 Hz), 92.2, 87.5, 57.4,
56.2. 19F NMR (376 MHz, DMSO-d6) δ −60.6 (d, J = 12.5 Hz), −70.2
(d, JP‑F = 711.3 Hz), −110.3 (q, J = 12.5 Hz). FT-IR: 3116, 3064,
1
to light brown powder. H NMR (400 MHz, DMSO-d6) δ 8.03−7.95
(m, 2H), 7.77−7.70 (m, 2H), 7.70−7.62 (m, 2H), 7.54−7.39 (m, 3H),
6.47 (s, 2H), 3.97 (s, 6H), 3.88 (s, 3H). 13C NMR (101 MHz, DMSO-
d6) δ 165.8, 159.2, 142.8, 138.2, 134.8, 129.4, 129.0, 128.4, 126.8,
115.6, 92.0, 88.6, 57.3, 56.1. FT-IR: 3055, 3036, 2970, 2833, 1645,
1585, 1468, 1229, 1162, 1030, 808 cm−1. HRMS (ESI+): calculated for
+
C21H20IO3 [M − I]+, 447.0452; observed, 447.0422. Melting point:
164−165 °C.
I
DOI: 10.1021/acs.joc.5b02833
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The Journal of Organic Chemistry
Article
2952, 2952, 2848, 1414, 1311, 1163, 845 cm1. HRMS (ESI+):
Compound 31. Prepared according to literature procedure50 on 0.5
mmol scale of 10-OTs and obtained in 63% yield (0.0613 g) as a pale
+
calculated for C16H14F4IO3 [M − PF6]+, 456.9889; observed,
1
yellow oil. H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 8.7 Hz, 2H),
456.9895. Melting point: decomposed 126 °C.
6.95 (d, J = 8.8 Hz, 2H), 1.30 (s, 9H). 13C NMR (151 MHz, CDCl3) δ
148.0, 137.1, 126.7, 118.6, 34.4, 31.3. The spectral data were consistent
with those previously reported.61
Compound 29-Br. Prepared according to the general anion
exchange procedure above on 1.9 mmol scale, using potassium
bromide (4.5 g, 36 mmol, 19 equiv) and obtained in 91% yield (1.733
Compound 32. Prepared according to literature procedure50 on 0.5
mmol scale of 14-OTf and obtained in 72% yield (0.0706 g) as a pale
yellow solid. 1H NMR (600 MHz, CDCl3) δ 7.59−7.49 (m, 4H), 7.41
(t, J = 7.7 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 8.2 Hz, 2H).
13C NMR (151 MHz, CDCl3) δ 140.2, 139.2, 138.0, 129.0, 128.5,
127.4, 126.9, 119.4. The spectral data were consistent with those
previously reported.62
1
g) as a white powder. H NMR (400 MHz, DMSO-d6) δ 8.11−7.69
(m, 8H), 6.45 (s, 2H), 3.96 (s, 6H), 3.87 (s, 3H). 13C NMR (101
MHz, DMSO-d6) δ 165.6, 159.2, 142.8, 140.4, 134.6, 132.9, 129.6,
127.8, 118.7, 118.6, 110.9, 91.9, 90.9, 57.2, 56.0. FT-IR: 3089, 3056,
2980, 2946, 2839, 2227, 1645, 1582, 1413, 1164, 815 cm−1. HRMS
+
(ESI+): calculated for C22H19INO3 [M − Br]+, 472.0404; observed,
472.0375. Melting point: 175−176 °C.
Compound 33. Prepared according to literature procedure51 on
0.34 mmol scale of 4-Br and obtained in 85% yield (0.0586 g) as a
Representative Procedure for One-Pot Synthesis of Aryl-
(2,4,6-trimethoxyphenyl)iodonium Bromides (Scheme 3b).
Compound 23-Br. 4-Methyl-3-nitro iodobenzene (1.33 g, 5.1 mmol,
1 equiv) and acetonitrile (5 mL) were added to a 250 mL round-
bottom flask, equipped with a stir bar. Toluenesulfonic acid
monohydrate (0.965 g, 5.1 mmol, 1.0 equiv) was added in one
portion, followed by one portion of m-CPBA (1.09 g, 5.1 mmol, 1.0
equiv). After a reflux condenser was attached, the reaction was lowered
into a heat bath set to 77 °C and stirred vigorously. After 30 min, the
reflux condenser was removed in order to add 1,3,5-trimethoxy-
benzene (0.858 g, 5.1 mmol, 1.0 equiv) in one portion and stirring was
continued at 77 °C for 5 min. The reaction was removed from heat,
and 100 mL of water were added. The mixture was brought to near
boiling until dissolved, and KBr (6.0 g, 50 mmol, 10 equiv) was added.
After stirring for 2 min the solution was removed from heat and
allowed to cool to ambient temperature, before chilling further in an
ice−water bath. The mixture was suction filtered, and the filter cake
was washed by slurry filtration with water (3 × 30 mL). The cake was
dried under suction for 10−20 min and then washed by slurry
filtration with ethyl ether (3 × 30 mL). The sample was finally dried
under high vacuum to remove trace solvent. If iodonium salt is
suspected to remain in the aqueous filtrate, then it may be extracted
with a suitable solvent such as dichloromethane or ethyl acetate. After
drying under high vacuum, 23-Br was obtained in 82% yield (2.112 g,
4.2 mmol) as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.51
(d, J = 1.7 Hz, 1H), 8.06 (dd, J = 8.2, 1.8 Hz, 1H), 7.54 (d, J = 8.4 Hz,
1H), 6.44 (s, 2H), 3.95 (s, 6H), 3.87 (s, 3H), 2.51 (d, J = 6.7 Hz, 3H).
13C NMR (101 MHz, DMSO-d6) δ 165.7, 159.1, 149.1, 138.0, 135.8,
1
colorless liquid. H NMR (400 MHz, CDCl3) δ 7.14−7.11 (m, 2H),
7.02−6.92 (m, 4H), 6.88−6.86 (m, 2H), 2.32 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 158.56 (d, JC−F = 241.0 Hz), 155.2, 153.4 (d, JC−F
=
2.4 Hz), 132.8, 130.2, 119.9 (d, JC−F = 8.2 Hz), 118.5, 116.15 (d, JC−F
= 23.2 Hz), 20.7. 19F NMR (376 MHz, CDCl3) δ 120.79. The spectral
data were consistent with those previously reported.63
Compound 34. Prepared according to literature procedure51 on 1.0
mmol scale of 14-OTf and obtained in 80% (0.213 g) as a white solid.
1H NMR (400 MHz, CDCl3) δ 7.58−7.52 (m, 4H), 7.45−7.39 (m,
2H), 7.35−7.30 (m, J = 5.9, 4.7, 2.3 Hz, 1H), 7.09−6.99 (m, 6H). 13C
NMR (101 MHz, CDCl3) δ 160.1, 157.7, 157.3, 152.8, 140.5, 136.2,
128.6 (d, JC−F = 33.3 Hz), 127.0, 126.8, 120.6 (d, JC−F = 8.2 Hz),
118.4, 116.3 (d, JC−F = 23.2 Hz). 19F NMR (376 MHz, CDCl3) δ
−119.9. FT-IR: 1500, 1265, 1214 cm−1. HRMS (EI): calculated for
C18H13FO, 264.0950; observed, 264.0942. Melting point: 76−78 °C.
Rf : 0.6 in 100% hexane.
Compound 35. Prepared according to literature procedure52 on 1.0
mmol scale of 14-OTf and obtained in 78% yield (0.235 g) as a white
1
powder. H NMR (400 MHz, CDCl3) δ 8.03−7.95 (m, 4H), 7.73−
7.67 (m, 2H), 7.60−7.36 (m, 8H). 13C NMR (101 MHz, CDCl3) δ
146.2, 141.8, 140.1, 139.2, 133.2, 129.3, 129.1, 128.6, 128.2, 127.9,
127.6, 127.3. FT-IR: 1637, 1265, 1158 cm−1. HRMS (ESI+): calculated
for C18H15O2S+ [M + H]+, 295.0793; observed, 295.0763. Melting
point: 142.8−147 °C. Rf : 0.20 in 20% diethyl ether/hexane.
Compound 36. Prepared according to literature procedure8 on 1
mmol scale of 29-Br and obtained in 70% yield after purification
(0.215 g) as a white powder. The crude product was purified by
column chromatography with silica gel and gradient elution (hexane,
1% ethyl ether, 2% ethyl ether). Mixed fractions were again
chromatographed according to the same procedure for a combined
135.0, 129.4, 116.2, 91.9, 91.8, 57.2, 56.0, 19.3. FT-IR: 3079, 2975,
2942, 2841, 1581, 1524, 1455, 1411, 1342, 1272, 1161, 1024, 815
+
cm−1. HRMS (ESI+): calculated for C16H17INO5 [M − Br]+,
430.0146; observed, 430.0125. Melting point: 166−167 °C.
1
70% yield of 33. H NMR (400 MHz, CDCl3) δ 7.68−7.55 (m, 4H),
Compound 26-Br. Prepared analogously to the representative one-
pot procedure above on 5 mmol scale and isolated in 74% yield (2.298
g), as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d,
J = 2.2 Hz, 1H), 8.36 (dd, J = 8.5, 2.4 Hz, 1H), 7.60 (d, J = 8.5 Hz,
1H), 6.44 (s, 2H), 3.96 (s, 6H), 3.88 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 165.6, 159.0, 153.2, 151.8, 144.7, 127.0, 117.7, 92.1, 91.9,
57.2, 56.1. FT-IR: 3075, 3039, 2971, 2942, 2842, 1582, 1454, 1412,
1342, 1161, 817, 731 cm−1. HRMS (ESI+): calculated for
7.53−7.43 (m, 2H), 7.02−6.91 (m, 2H), 3.98 (t, J = 6.6 Hz, 2H),
1.88−1.70 (m, 2H), 1.52−1.21 (m, 10H), 0.89 (t, J = 6.9 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 159.9, 145.2, 132.6, 131.2, 128.3, 127.0,
119.1, 115.1, 110.0, 68.2, 31.9, 29.4, 29.2(9), 29.2(8), 26.1, 22.7, 14.2.
The spectral data were consistent with those previously reported.64
ASSOCIATED CONTENT
■
+
C14H14ClINO3 [M − Br]+, 405.9701; observed, 405.9684. Melting
S
* Supporting Information
point: 161−163 °C.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02833.
Procedures for Synthetic Applications (Scheme 4). Literature
procedures were applied to 4-Br, 10-OTs, 14-OTf, and 29-Br on
0.34−1 mmol scale.
Additional details of multivariate experimental designs,
Compound 30. Prepared according to literature procedure31 on 0.4
mmol scale of 14-OTf and obtained in 55% yield (0.070 g) as a white
qualitative light stability studies, DSC, in situ temperature
1
monitoring of reactions, and H, 13C, 19F NMR spectra
1
solid. H NMR (400 MHz, CDCl3) δ 7.59 (dt, J = 8.9, 2.0 Hz, 4H),
of all new compounds (PDF)
7.46−7.39 (m, 2H), 7.37−7.28 (m, 3H), 4.31−4.19 (m, 2H), 2.88−
2.76 (m, 1H), 2.66−2.54 (m, 2H), 2.37 (ddd, J = 10.5, 6.9, 3.1 Hz,
1H), 2.09−1.94 (m, 1H), 1.93−1.72 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 206.6, 171.2, 140.6, 140.4, 135.8,
128.8, 128.2, 127.4, 127.1, 127.1, 66.2, 61.8, 40.9, 35.4, 27.7, 22.3, 14.0.
FT-IR: 3054, 2985, 1713, 1265, 1133 cm−1. HRMS (ESI+): calculated
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dstuart@pdx.edu.
+
for C21H23O3 [M + H]+, 323.1647; observed, 323.1619. Melting
Notes
point: 131−132 °C. Rf : 0.22 in 15% diethyl ether/hexane.
The authors declare no competing financial interest.
J
DOI: 10.1021/acs.joc.5b02833
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(26) Dohi, T.; Yamaoka, N.; Itani, I.; Kita, Y. Aust. J. Chem. 2013, 64,
529−535.
ACKNOWLEDGMENTS
■
We acknowledge Portland State University and the donors of
the American Chemical Society Petroleum Research Fund
(PRF DNI1 #54405) for support of this research. For the
acquisition of select high-resolution mass spectra, we acknowl-
edge the Biomolecular Mass Spectrometry Core of the
Environmental Health Sciences Core Center at Oregon State
University which is supported, in part, by Award Number
P30ES000210 from the National Institute of Environmental
Health Science (NIEHS), National Institute of Health (NIH).
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the NIEHS or
NIH. Mr. Justin Tran is thanked for early experimental
assistance, Dr. Alexander Sandtorv is thanked for insightful
comments on multivariate analysis and Dr. Jim Tung is
acknowledged for collection of DSC data.
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