An Admix Approach to Determine Counter Anion Effects on Metal-Free Arylation Reactions with Diaryliodonium Salts

Article abstract of DOI:10.1021/acs.joc.7b01599

A method to determine the effect of counter anions in metal-free arylation reactions of diaryliodonium salts is described. This approach avoids the independent synthesis of individual diaryliodonium salts and potentially enables assessment of a large number of different counter anions, including those that are synthetically challenging to install. Diaryliodonium tosylate salts serve as a general precursor for this approach, and an azide arylation reaction was used to develop this strategy. Further optimization and representative scope of azide arylation is demonstrated in yields that range from 74-95% (89% average). The use of this method as a screening tool has also been validated with arylation reactions of three different nucleophiles employing diphenyliodonium tosylate.

Full text of DOI:10.1021/acs.joc.7b01599

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Article
An Admix Approach to Determine Counter Anion Effects on
Metal-Free Arylation Reactions with Diaryliodonium Salts
Thomas L. Seidl, and David Ross Stuart
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01599 • Publication Date (Web): 11 Aug 2017
Downloaded from http://pubs.acs.org on August 11, 2017
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An Admix Approach to Determine Counter Anion Effects on MetalꢀFree Arylation Reactions with
Diaryliodonium Salts
Thomas L. Seidl and David R. Stuart*
Department of Chemistry, Portland State University, Portland Oregon 97201, United States
dstuart@pdx.edu
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Abstract: A method to determine the effect of counter anions in metalꢀfree arylation reactions of
diaryliodonium salts is described. This approach avoids the independent synthesis of individual
diaryliodonium salts and potentially enables assessment of a large number of different counter
anions, including those that are synthetically challenging to install. Diaryliodonium tosylate salts
serve as a general precursor for this approach and an azide arylation reaction was used to
develop this strategy. Further optimization and representative scope of azide arylation is
demonstrated in yields that range from 74 – 95% (89% average). The use of this method as a
screening tool has also been validated with arylation reactions of three different nucleophiles
employing diphenyliodonium tosylate.
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Introduction
Reaction screening methods that reduce both time and material toward discovery are
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enabling tools for development of new chemical reactions and synthesis of complexꢀmolecule
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libraries. Empirical screening is a common and effective approach entrenched within organic
synthesis and is particularly important when mechanistic understanding of a reaction variable is
limited (e.g., solvent). However, synthesis of the reaction variable of interest is a major practical
hurdle to empirical screening and admixing primary components is an attractive approach to
circumvent synthesis. While admixing is common place for catalyst screening (metal salt and
1aꢀc,j,pꢀr
ligand),
it is rarely applied to screening potential reagents. Diaryliodonium salts are novel
arylation reagents and undergo reaction with a range of carbon and heteroatom nucleophiles
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under metalꢀfree conditions. The counter anion of these salts is reversibly displaced by
nucleophiles and often exerts a dramatic influence on reactivity; as such, it is a critical variable
for screening in reaction discovery and development efforts (eq 1). The optimal counter anion,
though, is typically determined by heuristic methods and the need to synthesize individual salts
for screening limits, in practice, the range of counter anions typically analyzed. The
development of a screening method that avoids the practical obstacle of salt synthesis by
admixing primary components (diaryliodonium and target anion) would facilitate a more
thorough investigation of the counter anion contribution in reactions of diaryliodonium salts.
Herein, we describe the development, validation, and application of a convenient approach for
such a screening protocol.
Results and Discussion
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We have analyzed 42 representative metalꢀfree arylation reactions with diaryliodonium
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salts published between 2011 and 2016 (Figure 1). In total, ten different counter anions were
screened within these reports and seven different counter anions were evaluated as “optimal”
for the given reaction, which corroborates the breadth of reactivity observed to result from
counter anions. The three most commonly screened counter anions in these reports were
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ꢀ
ꢀ
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triflate ( OTf), tetrafluoroborate ( BF ), and tosylate ( OTs), and we surmise that this is a direct
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result of wellꢀestablished methods to access these diaryliodonium salts.
Interestingly, 11 of
the literature reports did not describe counter anion screening studies and simply used
diaryliodonium triflates as the arylation reagent. On the other hand, our analysis found that
between two and five counter anions were typically screened in the majority of these reports
with three counter anions being the average and median. Given the importance of counter
anion screening indicated by this analysis but the relatively small number of anions assessed
(
typically three) in reaction development studies we sought to develop an efficient method to
elucidate counter anion effects and thereby address this disparity. Here, we demonstrate that
the effect of 13 different counter anions may be determined by combination of their sodium salts
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with a diaryliodonium tosylate in a nucleophile arylation reaction. The minimal synthetic effort
required by this approach facilitates multiꢀdimensional screening with other variables that are
amenable to high throughput screening. We have coupled this approach with elucidating
potential solvent and aryl group electronic effects on reaction outcome. Additionally, while we
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have utilized arylꢀazide coupling
as a platform for development, we have also
recapitulated literature results of counter anion screening studies in Bꢀ, Oꢀ, and Cꢀarylation
reactions with diphenyliodonium tosylate.
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Figure 1. Frequency of counter anions screened in reaction development studies for arylation
with diaryliodonium salts.
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This approach is supported by our recent finding that unsymmetrical
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aryl(auxiliary)iodonium tosylate salts readily exchange anions with an excess of NaX (X = Br , I ,
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TFA , OTF, PF , and BF ) salts under aqueous conditions when the auxiliary is 2,4,6ꢀ
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trimethoxyphenyl (TMP). We hypothesized that this facile exchange may be leveraged as an
in situ technique under nonꢀaqueous conditions to determine the effect of counter anions
without having to synthesize each iodonium salt and we envisioned that this may lead to a wider
range of anions routinely analyzed. Our approach consists of admixing an appropriate
aryl(TMP)iodonium tosylate with NaX for 15 minutes at room temperature prior to addition of the
nucleophile and adjustment of the reaction temperature (Scheme 1). In this way, we have
ꢀ
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analyzed 13 different anions: F , Cl , Br , TFA , TCA (trichloroacetate), OAc, OTf, TCM
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(trichloromesylate), OMs, OTs, BF , PF , and SbF ; and we prepared and used two
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electronically different aryl(TMP)iodonium tosylates 1aꢀOTs and 1bꢀOTs. Aryl azidation
with NaN as nucleophile was used to establish the feasibility for this approach in diglyme,
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which emerged from an initial solvent screen (Scheme 1). The results in Scheme 1 confirm
the success of this approach because they demonstrate a clear counter anion effect; a positive
and negative effect relative to tosylate is observed for 1aꢀOTs and a negative effect observed
for 1bꢀOTs. Selection of the optimal counter anion a priori is not currently possible and the
results from Scheme 1 illustrate that this approach provides insight into which anions are
problematic and which ones are worth pursuing further. The results also show several
interesting effects of the counter anion and its confluence with the electronic effects of the aryl
substituent to impact the yield of 2a and 2b (Scheme 1). First, the addition of NaX to these
reactions has a wideꢀranging influence on reaction yield (min of 0%; max of 70%). Second, as
expected, higher yields are obtained with 1b bearing an electron deficient aryl group relative to
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1
a with an electronꢀrich aryl group; this is consistent across the majority of counter anions
screened. Additionally, in general there was a larger variation in yield across the counter anions
for reactions of 1a than for 1b; that is, there was a larger “counter anion effect” for 1a. Third,
and perhaps most intriguing, is that five anions emerged from this study to provide similar yields
with electronꢀrich 1a and electronꢀdeficient 1b. Fluoride, chloride, acetate, mesylate, and
tosylate stood out in this regard and suggest that these less commonly used counter anions
may provide a general advantage over more commonly used anions (OTf, BF ) in the solvents
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tested. This strategy also provides a means to analyse the effect of counter anions that are
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difficult to install on diaryliodonium salts. For instance, we were unable to obtain pure acetate
or fluoride salts 1aꢀOAc and 1aꢀF, but found that addition of these anions as sodium acetate
and sodium fluoride to 1aꢀOTs, led to a small but positive counter anion effect.
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Scheme 1. Counter anion screening by admixing aryl(TMP)iodonium tosylate and NaX in a
a
metalꢀfree arylꢀazide coupling reaction.
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Conditions: 1ꢀOTs (0.1 mmol, 1 equiv.), NaX (0.4 mmol, 4 equiv.), solvent (1 mL), r.t., 15 min;
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NaN (0.2 mmol, 2 equiv.), 50 °C, 2 hours. Yield determined by GCMS vs bromomesitylene as
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ꢀ
ꢀ
an internal standard. TFA = trfluoroacetate, TCA = trichloroacetate, TCM = trichloromesylate
In order to probe our hypothesis that in situ anion exchange occurs when diaryliodonium
tosylates and sodium salts of potential counter anions are admixed, we directly compared the
yields of our screening protocol (1aꢀOTs + NaX and 1bꢀOTs + NaX) with those obtained from
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preꢀexchanged salts (1aꢀX and 1bꢀX; Scheme 2). We selected counter anions that led to a
range of yields and those that led to both similar and disparate yields of 2a and 2b for the same
ꢀ
ꢀ
counter anion (i.e., Cl and TFA , respectively). Overall, similar trends in yield were observed
when with preꢀexchanged salts (blue lines and circles, Scheme 2) and the admix approach (red
lines and circles, Scheme 2) were used, and several examples highlight this point. First, when
the screening experiment indicated a universally low yield (< 20%) of 2a and 2b (such as 1aꢀ
OTs and 1bꢀOTs with NaBr) the yield from the preꢀexchanged exchanged salts (1aꢀBr and 1bꢀ
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Br) was also low. Second, when the screening experiment indicated a moderate yield (~ 50%)
of both 2a and 2b (such as 1aꢀOTs and 1bꢀOTs + NaCl) the yield from the preꢀexchanged salt
(
1aꢀCl and 1bꢀCl) was similar. Third, the yields obtained for 2a and 2b in the screening
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experiment with NaTFA as the additive were 11 and 61%, respectively. This difference in yield
for 2a and 2b was also observed when the preꢀexchanged salts 1aꢀTFA and 1bꢀTFA were used
ꢀ
ꢀ
ꢀ
(
Scheme 2). The results with BF , OTf, and OTs as the counter anions and their effect on the
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yields of 2a and 2b with preꢀexchanged salts and with admixing warrants further discussion.
While the yields of 2b were uniformly high and similar for preꢀexchanged (1bꢀX) and admixed
(
(
1bꢀOTs + NaX) salts, there were distinct differences in yields of 2a for the 1a series of salts
Scheme 2). An important difference between the admixing experiment and that with the preꢀ
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exchanged salts is a fourꢀfold excess of the common ion X (from NaX). We assessed the effect
of added NaBF and NaOTf on reactions of 1aꢀBF and 1bꢀOTf (black ×, Scheme 2),
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respectively, and found that the yield was depressed to the same extent as the admixing
reaction when excess NaX was added to 1aꢀOTs; this may suggest a commonꢀion effect
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influencing the equilibrium in eq. 1. Indeed we have found that when the ratio of total azide:
total tosylate is varied the yield of 2a increases dramatically with ratios greater than 1 and
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decreases with fractional ratios. The observed trends from Scheme 2 with regard to the yields
of 2a support an anion exchange, but also suggest that due to the excess NaX required for the
admixing protocol, followꢀup experiments on the top two or three counter anions are strongly
suggested for further optimization studies.
Scheme 2. Comparison of preꢀexchanged diaryliodonium salts (1aꢀX and 1bꢀX, blue) with
diaryliodonium tosylates (1aꢀOTs and 1bꢀOTs) doped with NaX (red).
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These studies formed the basis of a highꢀyielding and metalꢀfree arylꢀazide coupling
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reaction (Scheme 4). Aryl azides are often prepared by metalꢀbased methods and very few
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methods employing diaryliodonium salts have been reported.
However, aryl azides represent
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attractive motifs because they are useful as moieties for bioconjugation, photoaffinity labels,
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and general precursors to other nitrogenꢀbased functional groups. Based on our initial lead
from the counter anion screening experiment (Scheme 1) and the studies with preꢀexchanged
salts (Scheme 2), we explored the influence of several variables to further optimize the yield of
aryl azide products 2 with 1ꢀOTs salts. The influence of the reaction temperature and
stoichiometry of added sodium azide were explored as key variables. We used a fullꢀfactorial
screening design at two levels to assess the main effects and interaction effects of these
variables. In this way the experimental space spanned 1 – 8 equivalents of sodium azide and
25 – 90 °C reaction temperature. All four combinations of the boundaries of the experimental
space were investigated as well as multiple runs of a center point (4.5 equivalents of sodium
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azide and 57.5 °C) to assess reproducibility of the yield.
The results of these experiments
revealed that temperature had a larger influence on yield of 2a than the stoichiometry of sodium
azide. A response surface on the temperatureꢀazide stoichiometry plane is included in the ESI
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and shows an increasing yield with both higher temperature and azide equivalents.
The
optimal conditions (> 90% yield) selected included 6.5 equivalents of sodium azide in diglyme at
65 °C for 2 hours. A representative scope of substrates is presented in Scheme 3 that
highlights the utility of this reaction. Both electronꢀrich and deficient aryl groups undergo
coupling in high yield (Scheme 3, 2a and 2b, respectively). Free hydroxyl groups are tolerated
under the reaction conditions (Scheme 3, 2c). Finally, the coupling of elaborate aryl groups that
warrant the use of an unsymmetrical aryl(auxiliary)iodonium salt are well tolerated (Scheme 3,
2d and 2e) as are heterocyclic pyridyl groups (Scheme 3, 2f).
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a
Scheme 3. Representative scope of aryl azide compounds synthesized.
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Conditions: 1ꢀOTs (0.1ꢀ0.5 mmol, 1 equiv.), NaN (0.65ꢀ3.25 mmol, 6.5 equiv.), diglyme (1ꢀ5
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mL), 65 °C, 2 hours. Reaction performed in acetonitrile as solvent.
We have validated this strategy beyond the reaction of aryl(TMP)iodonium salt
electrophiles and azide nucleophiles. Reaction discovery and development with iodonium salts
is often conducted with diphenyliodonium 3 and we have applied our admix approach as an
anion screening method to several previously reported reactions. We used 3ꢀOTs as
electrophile with three different nucleophiles (Bꢀ, Cꢀ, and Oꢀnucleophiles), that were reported in
three different solvents (MeOH, DMF, and toluene), and where three different counter anions
ꢀ
ꢀ
ꢀ
proved to be optimal ( OAc, PF , and BF ). In each case, our screening method recapitulated
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the literature results of counter anion screening with preꢀexchanged salts (Scheme 4). A recent
example of CꢀB bond formation reported Muñiz and coꢀworkers features anion activation of
13b
B (pin) as a means to a nucleophilic boron reagent.
The counter anion effect reported by
2
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Muñiz was dramatic in which acetate acts as an “onꢀswitch” for the reaction; no conversion was
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ꢀ
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ꢀ
reported for OTf, Cl , or PF counter anions tested (Scheme 4a). We observed a similar effect
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when 3ꢀOTs was used and NaOTf, NaCl, NaPF , and NaOAc were admixed in MeOH prior to
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ꢀ
ꢀ
addition of B (pin) . Given our previous observation that OTs/ OAc exchange may not be
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operative, this result indicates that a counter anion effect may still be probed by this method and
is particularly relevant for difficult to prepare diaryliodonium salts. Ackermann and coꢀworkers
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have reported the metalꢀfree arylation of indoles with diphenyliodonium salts in DMF.
Six
counter anions were screened in the original report, and all except bromide provided highꢀyield
of product 5 (Scheme 4b). We have used 3ꢀOTs to screen the same six counter anions and the
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ꢀ
results show that similar yields are obtained (Scheme 4b). Specifically, addition of TFA and
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PF improve the yield relative to OTs alone whereas addition of BF and OTf lead to similar
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ꢀ
ꢀ
yields as OTs and addition of Br results in no product 5 detected by GCMS. Third, we explored
t
the CꢀO coupling reaction of 3ꢀOTs with benzoic acid/KO Bu in toluene at 100 °C that has been
22
ꢀ
ꢀ
ꢀ
ꢀ
reported by Olofsson and coꢀworkers (Scheme 4c). In the original work, Br , OTf, OTs, and
ꢀ
BF were screened with BF providing the highest yield of product. Notably, like the original
4
4
ꢀ
report, the use of Br does provide a low, but measurable, yield of product 6. We have obtained
ꢀ
ꢀ
ꢀ
similar results with Br , OTs, and BF . However, the relative yield of 6 that we obtained from
4
ꢀ
our screening experiment with OTf was significantly lower than Olofsson’s result and may point
ꢀ
to the common ion effect of OTf in this case as well; the common ion effect may also have a
nucleophile dependence.
Scheme 4. Comparison of relative yields for literature (blue) and screening (red) result in a) CꢀB
bond formation; b) CꢀC bond formation; c) CꢀO bond formation.
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Conclusion
We have described a straightforward and practical method to efficiently assess the effect
of counter anions in metalꢀfree arylation reactions by admixing diaryliodonium tosylate with
sodium salts of target anions. This method permits screening a wide variety of counter anions
including those that are challenging to install in diaryliodonium salts (i.e., acetate and fluoride).
We are continue to explore the extent to which in situ anion exchange occurs for different
anions by NMR spectroscopy. A byꢀproduct of the development of this strategy was a highꢀ
yielding method to synthesize aryl azides, which are useful moieties in diverse science
disciplines. The method was also validated on several literature examples that include CꢀB, Cꢀ
C, and CꢀO coupling reactions. In a broader sense, the demonstration of this approach may
engender related studies of other salt reagents wherein either anion or cation may be screened
by admixing, such as reactions of aryl diazo compounds and organotrifluoroborates.
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Experimental Section
General Considerations. Commercially available reagents and solvents were used
8e
23
without further purification unless otherwise stated. Compounds 1aꢀfꢀOTs, 1a,bꢀTFA, and
0
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0
8b
3
were prepared by literature procedures. All other materials were prepared as described in
1
detail below. Crude reaction mixtures were analyzed by H NMR spectroscopy, gas
chromatography mass spectrometry (GCMS), and thinꢀlayer chromatography (TLC). Crude
materials were purified by flash column chromatography on silica gel unless otherwise stated.
1
13
1
19
1
H, C{ H} , and F{ H} NMR spectra were recorded in CDCl or DMSOꢀd (referenced to
3
6
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 recorded as solutions in DCM or CDCl3. High
resolution mass spectrometry (HRMS) data was obtained by electrospray ionization (ESI) with
an ion trap mass analyzer or electron impact (EI, 70 eV). Melting points are reported as
uncorrected.
8e
General procedure for anion exchange from aryl(TMP)iodonium tosylates (A).
Aryl(TMP)iodonium tosylate (~ 1 g, 1 equiv) is added to 50 mL boiling water. If the iodonium
salt does not dissolve after boiling for 1ꢀ2 minutes, then methanol is added in small portions until
the material is dissolved. While still hot, a salt containing the target anion is added in excess.
The exact amount required depends on the exchange salt and the iodonium salt and an excess
of 10 or more equivalents is recommended. The resulting solution is allowed to naturally cool to
ambient temperature, before chilling further in an iceꢀbath. The precipitate is isolated by suction
filtration and the filter cake washed by slurry filtration with water (3 x 30 mL). The cake is dried
under suction for 10 – 20 min and then washed by slurry filtration with ethyl ether (3 x 30 mL).
The sample is finally dried under high vacuum to remove residual solvent. If product is
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suspected in the aqueous wash then it may be recovered by extraction with dichloromethane or
ethyl acetate.
Compound 1aꢀBr: Prepared from 1aꢀOTs according to procedure A on 2 mmol scale,
10
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17
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53
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57
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59
60
using potassium bromide (12 g, 10 equiv.) and obtained in 95% yield (1.138 g) as a white
1
powder. H NMR (600 MHz, DMSO-d & CD OD) δ 7.81 (d, J = 7.0 Hz, 2H), 7.43 (d, J = 7.0 Hz,
6
3
13
1
2H), 6.39 (s, 2H), 3.92 (s, 6H), 3.83 (s, 3H), 1.24 (s, 9H). C{ H} NMR (151 MHz, DMSO-d &
6
CD OD) δ 165.6 , 159.3 , 153.9 , 133.9 , 128.3 , 114.7 , 91.9 , 90.3 , 57.2, 56.1, 34.7, 30.73.
3
ꢀ1
+
FTIR: 3051, 2953, 2868, 2841, 1576, 1458, 1409, 1207, 1121, 814 cm . HRMS (ESI ):
+
3
+
Calculated for C H IO [M ꢀ Br] : 427.0765; Found: 427.0768. Mp 195 – 196 ˚C.
19
24
Compound 1aꢀCl: Prepared from 1aꢀOTs according to procedure A on 2 mmol scale,
using sodium chloride (12.6 g, 100 equiv.) and obtained in 94% (0.873 g) yield as a white
1
powder. H NMR (600 MHz, DMSO-d & CD OD) δ 7.81 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.6 Hz,
6
3
13
1
2
H), 6.40 (s, 2H), 3.92 (s, 6H), 3.84 (s, 3H), 1.23 (s, 9H). C{ H} NMR (151 MHz, DMSO-d &
6
CD OD) δ 166.6, 159.9, 155.0, 134.4, 128.7, 113.4, 92.0, 88.0, 57.1, 56.0, 34.9, 30.7. FTꢀIR:
3
ꢀ1
+
3
068, 3004, 2955, 2901, 2868, 1586, 1410, 1231, 1119, 1059, 810, 670 cm . HRMS (ESI ):
+
3
+
Calculated for C H IO [M ꢀ Cl] : 427.0765, Found: 427.0759. Mp 205 – 206 ˚C.
19
24
Compound 1aꢀOTf: Prepared from 1aꢀOTs according to procedure A on 2 mmol scale,
using sodium triflate (5.0 g, 29 equiv.) and obtained in 92% (1.06 g, 1.8 mmol) yield as a white
1
powder. H NMR (400 MHz, DMSO-d ) δ 7.84 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 6.48
6
13
1
(
s, 2H), 3.96 (d, J = 5.8 Hz, 6H), 3.87 (d, J = 4.7 Hz, 3H), 1.25 (s, 9H). C{ H} NMR (101 MHz,
DMSO-d ) δ 166.1 , 159.3 , 154.7 , 134.2 , 128.7 , 120.7 (q, JC - F = 322.5 Hz), 112.5 , 92.0 ,
6
19
1
86.9, 57.3, 56.1, 34.8, 30.7 . F{ H} NMR (376 MHz, DMSOꢀd ) δ (ppm): −77.7. FTꢀIR: 3070,
6
ꢀ1
+
2
955, 2870, 2847, 1580, 1471, 1415, 1243, 1210, 1125, 1026, 814, 635 cm . HRMS (ESI ):
+
3
+
Calculated for C H IO [M ꢀ OTf] : 427.0765, Found: 427.0765. Mp 78 – 79 ˚C.
19
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Compound 1aꢀBF : Prepared from 1aꢀOTs according to procedure A on 2 mmol scale,
4
using sodium tetrafluoroborate (22 g, 95 equiv.) and obtained in 91% yield (0.930 g, 1.81 mmol)
1
as a white powder. H NMR (400 MHz, DMSOꢀd ) δ 7.85 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6
6
13
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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7
8
9
0
Hz, 2H), 6.48 (s, 2H), 3.97 (s, 6H), 3.88 (s, 3H), 1.25 (s, 9H). C{ H} NMR (101 MHz, DMSOꢀ
19
1
d6) δ 166.6, 159.9, 155.2, 134.7, 129.2, 113.0, 92.5, 87.4, 57.8, 56.6, 35.3, 31.2. F[ H} NMR
(
376 MHz, DMSOꢀd ) δ (ppm): −148.3. FTꢀIR: 3022, 2903, 2870, 1579, 1462, 1347, 1232,
6
ꢀ1
+
+
+
1
126, 1050, 995, 808, 665cm . HRMS (ESI ): Calculated for C H IO [M – BF ] : 427.0765,
19 24 3 4
Found: 427.0747. Mp 156 – 157 ˚C.
Compound 1bꢀBr: Prepared from 1bꢀOTs according to procedure A on 2 mmol scale,
using potassium bromide (12 g, 100 equiv.) and obtained in 85% yield (0.930 g, 1.81 mmol) as
1
a white powder. H NMR (600 MHz, DMSOꢀd ) δ 8.27 – 7.79 (m, 4H), 6.49 (s, 2H), 3.97 (s, 6H),
6
13
1
3.89 – 3.52 (m, 6H). C{ H} NMR (151 MHz, DMSOꢀd ) δ 166.9, 165.6, 159.9, 135.1, 132.7,
6
132.3, 121.4, 92.6, 87.3, 57.8, 56.6, 53.1. FTꢀIR: 3086, 2988, 2972, 2901, 1721, 1579, 1279,
ꢀ1
+
+
+
1
121 cm . HRMS (ESI ): Calculated for C H IO [M ꢀ Br] : 429.0193; Found 429.0167. Mp
17 18 5
1
59 – 160 ˚C.
Compound 1bꢀCl: Prepared from 1bꢀOTs according to procedure A on 3.25 mmol
scale, using sodium chloride (14 g, 74 equiv.) and obtained in 94 % yield (1.42 g) as a white
1
powder. H NMR (400 MHz, DMSOꢀd and CD OD) δ 8.03 – 7.83 (m, 4H), 6.37 (s, 2H), 3.90 (s,
6
3
13
1
6
H), 3.82 (s, 3H), 3.82 (s, 3H). C{ H} NMR (101 MHz, DMSOꢀd & CD OD) δ 166.4, 165.0,
6 3
159.4, 134.0, 132.1, 131.2, 121.1, 91.4, 87.3, 56.4, 55.3, 51.7. FTꢀIR: 3071, 2988, 2971, 2944,
ꢀ1
+
+
+
2
901, 1733, 1577, 1280, 1116, 748 cm . HRMS (ESI ): Calculated for C H IO [M ꢀ Cl] :
17 18 5
4
29.0193; Found 429.0170. Mp 164 – 165 ˚C.
Compound 1bꢀOTf: Prepared from 1bꢀOTs by procedure A on 1 mmol scale, using
1
sodium triflate (3 g, 17.5 equiv) and obtained in 84 % yield as a white powder. H NMR (400
MHz, DMSOꢀd ) δ 8.05 (d, J = 8.6 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H), 6.49 (s, 2H), 3.95 (s, 6H),
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.88 (s, 3H), 3.86 (s, 3H). C{ H} NMR (101 MHz, DMSOꢀd ) δ 166.4 , 165.1 , 159.4 , 134.6 ,
6
19
1
1
32.2 , 131.8 , 120.8, 120.7 (q, JC-F = 322.4 Hz), 92.1 , 86.8 , 57.3 , 56.2 , 52.6. F{ H} NMR
(
376 MHz, DMSOꢀd ) δ ꢀ77.7 (s). FTIR: 3107, 2950, 2849, 1732, 1576, 1464, 1352, 1275,
6
ꢀ
1
+
+
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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46
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48
49
50
51
52
53
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59
60
1229, 1159, 1029, 816, 665 cm . HRMS (ESI ): Calculated for C H IO [M – OTf] : 429.0193;
17 18 5
Found 429.0191. Mp 120 – 122 ˚C (decomposition).
Compound 1bꢀBF : Prepared from 1bꢀOTs by procedure A on 2 mmol scale, using
4
sodium tetrafluoroborate (11 g, 50 equiv) and obtained in 77 % yield (0.8079 g) as a white
.
1
powder. The filtrate was not extracted to recover more product. H NMR (400 MHz, DMSOꢀd6
13
1
and CD OD) δ 8.61 – 7.78 (m, 4H), 6.49 (s, 2H), 4.01 (s, 6H), 3.92 – 3.78 (m, 6H).
C{ H}
3
NMR (101 MHz, DMSOꢀd and CD OD) δ 166.9, 165.6, 159.9, 135.1, 132.7, 132.3, 121.4, 92.6,
6
3
19
1
87.3, 57.8, 56.6, 53.1.
F{ H} NMR (376 MHz, DMSOꢀd and CD OD) δ ꢀ148.30 (s). FTꢀIR:
6 3
ꢀ1
+
3089, 2988, 2971, 2901, 1716, 1578, 1549, 1277, 1159, 1115, 1066, 642 cm . HRMS (ESI ):
+
5
+
Calculated for C H IO [M – BF ] : 429.0193; Found 429.0186. Mp 152 – 153 °C.
17
18
4
General procedure for determining the effect of counter anion by admixing (B).
Aryl(TMP)iodonium tosylate (0.1 mmol, 1eq) and is added to a vial with a magnetic stirbar. A
sodium salt with the desired anion is added (0.4 mmol, 4 equ), followed by 1 mL of anhydrous
diglyme. The mixture is vigorously stirred at room temperature for 15 min. Sodium azide (2
mmol, 2 equiv) is added and the mixture is stirred at 50 °C for two hours and then removed from
heat and diluted with 1 mL of aqueous sodium bicarbonate solution. Upon addition of (10 ꢁL,
~1 eq) of internal standard (bromo mesitylene), the reaction is extracted with ethyl acetate,
filtered through a celite plug and analyzed by GC/MS.
General procedure for aryl azidation with pre-exchanged diaryliodonium salts (C).
Aryl(TMP)iodonium salt (0.1 mmol, 1eq) is added to a vial with a magnetic stirbar. Sodium
azide (0.2 mmol, 2 equiv. or 0.65, 6.5 equiv.) is added, followed by 1 mL anhydrous diglyme.
The solution is stirred at 50 °C or 65 °C for two hours, removed from heat and diluted with 1 mL
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of aqueous bicarbonate solution and extracted with ethyl acetate. The reaction is either
analyzed by GCMS (with 10 ꢁL of bromo mesitylene as internal standard) or purified by flash
column chromatography.
0
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Compound 2a: Prepared according to procedure C on 0.5 mmol scale (6.5 equivalents
of sodium azide and heating at 65 °C) and obtained in 94% (0.0818 g, 0.47 mmol) yield as a
pale yellow oil. The crude product was adsorbed onto silica and purified by column
chromatography using hexanes as the eluent. The characterization data agree with previously
24 1
reported values. H NMR (400 MHz, CDCl ) δ 7.31 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz,
3
13
1
2H), 1.27 (s, 9H).
C{ H} NMR (101 MHz, CDCl ) δ 147.9, 137.2, 126.6, 119.0, 34.5, 31.3
3
ppm.
Compound 2b: Prepared according to procedure C on 0.1 mmol scale with the following
deviations: i) the crude reaction was extracted with pentane and purified by column
chromatography on silica using 5% ethyl ether followed by 10% ethyl ether in pentane. The
product was obtained in 95% (0.0167 g, 0.095 mmol) yield as a pale yellow solid. The
25 1
characterization data agree with previously reported values. H NMR (600 MHz, CDCl ) δ 8.03
3
1
3
1
(
d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 3.91 (s, 1H).
66.3, 144.8, 131.4, 126.7, 118.8, 52.2 ppm.
Compound 2c: Prepared according to procedure C on 0.1 mmol scale with the following
C{ H} NMR (151 MHz, CDCl ) δ
3
1
deviations: i) acetonitrile was used as the solvent, ii) the crude reaction was extracted with ethyl
ether and purified by column chromatography on silica using ethyl ether in hexanes (1:1) to
followed by neat ethyl ether. The product was obtained in 86% (0.014 g, 0.086 mmol) yield as a
26 1
colorless oil. The characterization data agree with previously reported values. H NMR (600
MHz, CDCl ) δ 7.21 (d, J = 7.6 Hz, 2H), 6.98 (d, J = 7.4 Hz, 2H), 3.84 (t, J = 6.4 Hz, 2H), 2.84 (t,
3
13
1
J = 6.4 Hz, 2H), 1.70 (s, 1H). C{ H} NMR (101 MHz, CDCl ) δ 138.3, 135.5, 130.5, 119.2,
3
65.9, 38.6 ppm.
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Compound 2d: Prepared according to procedure C on 0.5 mmol scale and obtained in
1
9
3% (0.0828 g, 0.465 mmol) yield as a yellow solid. H NMR (400 MHz, CDCl ) δ 7.64 (d, J =
3
13
1
2
.4 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.17 (dd, J = 8.3, 2.4 Hz, 1H), 2.57 (s, 3H). C{ H} NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(101 MHz, CDCl ) δ 149.7, 139.3, 134.1, 130.0, 123.4, 115.2, 20.0. FTꢀIR: 3081, 2988, 2938,
3
ꢀ
1
+
2901, 2110, 1527, 1303, 1338, 1066, 907, 872, 729 cm . HRMS (ESI ) Calculated for
+
2
+
C H N O [M ꢀ H] : 178.0491; Found 178.0507. Mp 67 ꢀ 68 ˚C.
7
6
4
Compound 2e: Prepared according to procedure C on 0.5 mmol scale and obtained in
1
9
2% (0.172 g, 0.462 mmol) yield. H NMR (400 MHz, CDCl ) δ 7.55 (d, J = 8.5 Hz, 1H), 7.17 (d,
3
13
1
J = 2.7 Hz, 1H), 7.01 (t, J = 1.8 Hz, 1H), 6.91 – 6.85 (m, 3H), 5.04 (s, 2H). C{ H} NMR (101
MHz, CDCl ) δ 159.1, 140.0, 137.0, 135.6, 133.9, 121.9, 120.0, 119.2, 117.2, 114.0, 69.4. FTꢀ
3
ꢀ1
+
IR: 3095, 3055, 2920, 2842, 2115, 2075, 1590, 1572, 1299, 1057, 804, 662 cm . HRMS (ESI )
+
Calculated for C H BrCl N O [M ꢀ H] : 370.9228; Found 370.9250. Mp 98 ꢀ 99˚C
13
8
2
3
Compound 2f: Prepared according procedure C on 0.1 mmol scale with the following
deviations: i) acetonitrile was used as the solvent. The crude product was purified by column
chromatography on silica using 10% ethyl ether in hexanes. The product was obtained in 74%
1
(
0.0114 g, 0.074 mmol) yield as a yellow solid. H NMR (400 MHz, CDCl ) δ 8.14 (dd, J = 2.1,
3
13
1
1
.5 Hz, 1H), 7.45 – 7.25 (m, 2H). C{ H} NMR (101 MHz, CDCl ) δ 147.1, 140.7, 136.4, 128.9,
3
ꢀ1
+
1
25.0. FTꢀIR: 3086, 3055, 2131, 2099, 1455, 1299, 824, 565 cm . HRMS (ESI ) Calculated for
+
C H ClN [M ꢀ H] : 154.0046 Found 154.0066. Mp 39 ˚C.
5
3
4
Acknowledgments
We acknowledge Portland State University for financial support of this work. Florian Guillot is
thanked for NMR titration experiments. Rory Gallagher is thanked for acquisition of selected
melting point data.
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Supporting Information. Complete references, details of optimization, and NMR ( H, C{ H},
19
1
F{ H}) spectra for all new compounds.
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ESI for details.
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