Investigation of Iodonium Trifluoroborate Zwitterions as Bifunctional Arene Reagents

Article abstract of DOI:10.1021/acs.orglett.7b03307

The synthesis of a new family of iodonium zwitterions, in which the formal anion is a trifluoroborate moiety, is reported. These reagents present very good stability and have high resistance toward benzyne formation. Their structures were confirmed by X-ray crystallographic analysis and were further investigated using DFT calculations. QTAIM analysis supports an ionic, noncovalent, I⁺···BF₃^- interaction, in accordance with a true zwitterionic nature. Preliminary results of synthetic applications, the arylation of phenolates and trifluoroborate group functionalization, are reported.

Full text of DOI:10.1021/acs.orglett.7b03307

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Investigation of Iodonium Trifluoroborate Zwitterions as
Bifunctional Arene Reagents
Raphael Robidas, Vincent Guerin, Laurent Provenca̧ l, Marco Echeverria, and Claude Y. Legault*
́
̈
University of Sherbrooke, Department of Chemistry, Centre in Green Chemistry and Catalysis, 2500 boul. de l’Universite,
Sherbrooke, Quebec J1K 2R1, Canada
́
́
S
* Supporting Information
ABSTRACT: The synthesis of a new family of iodonium zwitterions,
in which the formal anion is a trifluoroborate moiety, is reported. These
reagents present very good stability and have high resistance toward
benzyne formation. Their structures were confirmed by X-ray crystallo-
graphic analysis and were further investigated using DFT calculations.
QTAIM analysis supports an ionic, noncovalent, I+···BF3 interaction,
−
in accordance with a true zwitterionic nature. Preliminary results of syn-
thetic applications, the arylation of phenolates and trifluoroborate group
functionalization, are reported.
Instead of restraining their role to benzyne precursors, we
ypervalent iodine reagents have greatly impacted the field
1
Hof oxidative chemistry over the past 25 years. They have envisioned that such species could serve as high-value bifunc-
tional arene reagents. They would give access to enhanced
synthetic strategies, by rapidly exploiting both the electro- and
nucleophilic groups (Scheme 1). An anionic moiety conferring a
received a lot of attention due to the wide diversity of synthetic
transformations they can promote.2 They are highly valued,
as they tend to be considered as nontoxic and eco-friendly
alternatives for many heavy-metal oxidants.3 In particular,
diaryliodonium salts (Figure 1, 1) are being actively studied
Scheme 1. Diarylodonium Salts and Their Zwitterionic
Variants
Figure 1. Diarylodonium salts and their zwitterionic variants.
due to their huge synthetic potential.4 They have been used, for
example, as photoacid generators (PAGs) in polymer science,5
and as benzyne precursors.6 They have been investigated as
haloarene surrogates in the field of transition-metal-catalyzed
coupling chemistry.7 Due to the hyperfugacity of the arylio-
donium group, they have had a huge impact as electrophilic
arylation reagents.8 They support numerous substitution
patterns and react with a wide variety of nucleophiles. These
salts will have variable solubility in organic solvents, depending
on the nature of the counterion, potentially limiting their
application in some methodologies. Interestingly, only a
few examples of neutral, iodonium zwitterion (2) variants
have been reported.9 And very few examples have been struc-
turally characterized. For example, zwitterion 2a has been
commonly used as a benzyne precursor. The bonding descrip-
tion of 2a is a matter of debate, as it is considered to be an
intermediate between the zwitterionic and covalent benzio-
doxole forms.10
nucleophilic character to C1 carbon is required to achieve this
feat. The challenge is to have such an anionic group, without
spontaneously releasing the free benzyne. We postulated that
−
the trifluoroborate moiety (X− = BF3 ), due to its efficient
negative charge dispersion capability, could fill the require-
ment for such a reagent to exist. The impressive functionalization
potential of this group would furnish the advantageous bifunc-
tional (nucleophile/electrophile) character desired.12
This is not a trivial assumption; a very recent report of
Zhdankin and Yoshimura has described pseudocyclic arylben-
ziodoxaboroles (3) as very efficient, water-promoted, benzyne
precursors.6a In this preliminary communication, we report
the viability of our hypothesis and the synthesis of the first
iodonium trifluoroborate zwitterions (4). We also report their
structural characterization, as well as preliminary synthetic
applications.
For the proof of concept, we used the organotrifluoroborate
salts 6a and 6b, due to the commercial availability of their
There are very few reports of the use of these zwitterions as
electrophilic reagents.9c11 It thus seems that this family of formally
neutral iodonium species has been greatly underexploited.
Received: October 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03307
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Letter
corresponding boronic acids. They were obtained in quantitative
yields from 5a13 and 5b, respectively (eq 1).
Table 1. Synthesis of Reagents 4a and 4b
a
entry
R
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
H (6a)
20
20
40
20
20
20
4
20
17
48
4
77
84
86
84
75
81
Our strategy relied on the oxidation of 6a and 6b in the
presence of an aromatic nucleophile to access the desired
zwitterions in one simple step. Having compound 6a in hand,
we evaluated its stability toward Selectfluor, an oxidant pre-
viously used in hypervalent iodine chemistry. The stability
of intermediate 7 was uncertain, as it could rapidly lead to
benzyne formation and degradation, or instead be isolable
(Scheme 2).
F (6b)
20
a
Isolated yields.
Scheme 2. Oxidation Strategy of 6a
Figure 2. X-ray crystal structures of 4a.
Gratifyingly, when 6a was submitted to oxidation by
Selectfluor, the zwitterion 4c, resulting from the addition of 6a
on proposed intermediate 7 (not observed experimentally),
was obtained. By adjusting the stoichiometry of Selectfluor in
accordance to this result, zwitterion 4c was obtained in 81% yield
(eq 2). Zwitterion 4c was found to be a stable white solid,
Figure 3. X-ray crystal structure of 4b.
Two different conformations were observed in the crystal
asymmetric unit of 4a: the bottom conformation presents distant
(2.80 Å, 3.12 Å) I···F interactions, while the top conformation
presents an even weaker I+···BF3− internal interaction (3.19 Å).
The two conformations were optimized separately using DFT
calculations, and a marginal free energy difference (0.5 kcal/mol)
was measured, in favor of the bottom structure.14 QTAIM15
proving the accessibility of these new species. The result also
demonstrates that the right reactivity range is obtained using
organotrifluoroborate salts as nucleophiles.
With this very promising result in hand, we then reacted
6a and 6b with Selectfluor in the presence of potassium
aryltrifluoroborate 8. The latter was expected to be less sterically
hindered and more nucleophilic than the trifluoroborate salts 6a
and 6b. Consequently 8 should react faster with intermediate 7.
The results are summarized in Table 1.
The desired zwitterions 4a and 4b were obtained and proved
to be analytically pure in very good yields following simple
liquid−liquid extraction. We were delighted to observe the
complete selectivity of the addition of 8 in all attempts, with
zwitterion 4c not being observed in any cases. Longer reaction
times did provide a slight increase in yield. As in the case of 4c,
compounds 4a and 4b are stable crystalline solids. It was
hence possible to confirm their structures by X-ray diffraction
analysis.13 They are illustrated in Figures 2 and 3.
−
analysis of I+···BF3 interactions in both conformations further
support weak, mostly ionic bonding contributions.
Only one conformation was observed in the X-ray crystal
structure of 4b. This conformation was found to be the global
minimum by DFT calculations. A much shorter I···F interaction
(2.65 Å) was observed, mostly due to the repulsion incurred by
the presence of the fluorine atom at C6. Despite the shorter I−F
distance, QTAIM analysis did show a similar, mostly ionic,
I+···BF3− interaction. These structural and computational results
support the truly zwitterionic nature of these new species.
In analogy to 4c, these compounds are not air and moisture
sensitive and appear to be indefinitely stable at room temperature.
B
DOI: 10.1021/acs.orglett.7b03307
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Letter
a
They are soluble in numerous solvents (THF, CH2Cl2, CHCl3,
ClCH2CH2Cl, MeCN) and are also stable indefinitely in solution
at room temperature. The UV spectra of 4a and 4b show a
slightly red-shifted second absorbance band, down to 320 nm,
Scheme 4. Arylation of Phenolates Using 4a and 4b
compared to Ph2I+PF6 .14 The thermal stability of 4b in solution
−
was investigated. It was found to be stable in THF up to 70 °C,
at which point it would promote solvent polymerization
and degrade completely over the course of 6 h into unidentified
products. As this degradation could originate from solvent reac-
tivity, we evaluated the stability again in two, less coordinating,
solvents: 1,2-dichloroethane and acetonitrile. No degradation
was observed in either solvent after heating a solution of 4b at
70 °C for 6 h. We then investigated their synthetic potential in
electrophilic arylation reactions with nucleophiles. This has been
a major and highly useful area of research involving diary-
liodonium salts.4 It is not trivial to predict if the presence of a
nucleophile would lead to the desired coupling product, or
benzyne generation (Scheme 3). However, if arylation occurs, it
Scheme 3. Concept of Arylation of Nucleophiles Using 4a−b
has been demonstrated that it would be favored on the least
electron-rich arene. By having the para-methoxy-phenyl group
on 4a and 4b, C−Nu bond formation with the arene bearing the
trifluoroborate group is expected.16 With the right choice of
nucleophile counterion, then the corresponding organotrifluoro-
borate salts (9), polyvalent reagents,12 would be obtained.
We selected phenolate nucleophiles for a proof of concept, as the
resulting ortho-phenoxy products would be building blocks of great
interest in medicinal chemistry.17 They could also serve to rapidly
access dibenzofuran derivatives through a Pschorr-type cyclization,
recently reported by Baran and co-workers.18 The results of the
arylations are presented in Scheme 4. THF was selected as the ideal
solvent, as it provided sufficient solubility of both the phenolates
and zwitterions. Since the reaction was sluggish at room temper-
ature, mild heating (40−65 °C) was thus used. Furthermore, to
favor the bimolecular process, we performed the reactions at fairly
high concentrations (0.65 M). Under these optimized conditions,
we were delighted to observe that the addition of potassium
phenolate salts was clean and efficient, affording the desired
potassium organotrifluoroborate salts (9) in excellent yields.
The method does not require a large excess of the nucleophile to
furnish complete conversion. Both zwitterions were as proficient to
promote the arylation, 4b being slightly more reactive. The aryla-
tion proceeds with exquisite selectivity, as we did not detect the
presence of compound 6a or 6b in the crude mixtures. Purification
is usually performed by precipitation with CHCl3 or CH2Cl2, and
trituration yielded the trifluoroborate salts. We have found that
purification was challenging in some cases (e.g., 9h), as they were
even soluble in these solvents, atypical for such salts. This could be
rationalized by their larger sizes. In such cases, precipitation at
low temperature, or in Et2O/Hexanes, was necessary for the
purification.14 Interestingly, we found that the products obtained
from 4b were typically much easier to precipitate and purify and
a
Isolated yields; see Supporting Information for purification details.
Reaction performed at 40 °C. Reaction performed at 50 °C.
Reaction performed at 65 °C.
b
c
d
tend to furnish higher yields. The method supports a wide range of
substituents at various positions.
It is noteworthy that a phenolate possessing an unprotected
alcohol could furnish the product 9i in fair yield. We have found
that steric hindrance of the nucleophile seems to have a more
pronounced effect on reactivity than what is typically observed in
classic diarylodonium salt chemistry. The most striking example
is illustrated in eq 3. Reaction of potassium 2,4,6-trimethylphe-
nolate with 4b did not result in any arylation product.
Instead, precipitation after a reaction time of 16 h only
furnished a low yield of the trifluoroborate salt 10. Formation
of this product can be rationalized by SET from the phenolate
to 4b, followed by elimination of 4-iodoanisole and hydrogen
abstraction by the resulting aryl radical. Similar side products
were observed for the formation of product 9l. Fortunately,
in this case, a shorter reaction time at higher temperature reduced
this undesired process. These results do put into perspective the
possible competing ionic and radical reactions in this method.
C
DOI: 10.1021/acs.orglett.7b03307
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Letter
The functionalization potential of products 9 was exem-
plified with two representative reactions, shown in Scheme 5.
Foundation for Innovation (CFI), the FRQNT Centre in Green
́
Chemistry and Catalysis (CGCC), and the Universite de
Sherbrooke. R.R. is grateful to NSERC for an Undergraduate
Student Research Award (USRA).
Scheme 5. Examples of Synthetic Applications of 9a
REFERENCES
■
(1) (a) Zhdankin, V. V. Hypervalent iodine chemistry: preparation,
structure, and synthetic applications of polyvalent iodine compounds; Wiley:
Chichester, U.K., 2013. (b) Tohma, H.; Kita, Y. In Hypervalent Iodine
Chemistry; Wirth, T., Ed.; Springer: Berlin, 2003; p 209. (c) Zhdankin, V.
V.; Stang, P. J. Chem. Rev. 2002, 102, 2523. (d) Moriarty, R. M.; Prakash,
O. Org. React. 2001, 57, 327. (e) Varvoglis, A. Hypervalent Iodine in
Organic Synthesis; Academic Press: San Diego, 1997.
The formation of phenol 11 by oxidation of the C−B bond, and the
formation of the boronic acid 12 by hydrolysis of the trifluoro-
borate group were found to yield almost quantitative yields of the
desired products. The hydrolysis could be used as a workup proce-
dure following the arylation reaction, in the event that a final product
cannot be purified by precipitation. One could also imagine
developing rapid, one-pot, procedures involving such reactions.
In conclusion, we have demonstrated the synthesis of novel
iodonium trifluoroborate zwitterions and investigated their struc-
tural and chemical properties. Additionally, we have explored the
first aspect of their reactivity through the arylation of phenolate
derivatives. The o-aryloxy trifluoroborate salts obtained are
highly useful synthetic intermediates that will find numerous
synthetic applications. The results presented in this communi-
cation are just a first glimpse at the overall impressive potential
for these novel reagents. The ease with which the arylation of
phenolates is performed could be exploited to react with peptides
for the synthesis of new BF3K-based radiotracers.19 Furthermore,
in light of our recent investigations on the Lewis acidity of
diaryliodonium salts,20 they could prove to be mild neutral Lewis
acids with unique properties. Our group is currently exploring
their use in novel metal-free and transition-metal catalyzed
synthetic methods, and the results will be reported in due course.
(2) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328−3435.
(3) Yusubov, M. S.; Zhdankin, V. V. Resource-Efficient Technol. 2015, 1,
49−67.
(4) Merritt, E.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052−
9070.
(5) (a) Crivello, J. V. J. Polym. Sci., Part A: Polym. Chem. 1999, 37,
4241−4254. (b) Crivello, J. V.; Lam, J. H. W. Macromolecules 1977, 10,
1307−1315.
(6) (a) Zhdankin, V.; Yoshimura, A.; Fuchs, J.; Middleton, K.;
Maskaev, A.; Rohde, G.; Saito, A.; Postnikov, P.; Yusubov, M.; Nemykin,
V. Chem. - Eur. J. 2017, DOI: 10.1002/chem.201704393. (b) Kitamura,
T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu, N.; Meng, Z.; Fujiwara,
Y. J. Am. Chem. Soc. 1999, 121 (50), 11674−11679. (c) Bachofner, H. E.;
Beringer, F. M.; Meites, L. J. Am. Chem. Soc. 1958, 80, 4274−4278.
(7) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924−1935.
(8) (a) Fananas
́
-Mastral, M. Synthesis 2017, 49, 1905−1930. (b) Aradi,
h, B. L.; Tolnai, G. L.; Novak, Z. Synlett 2016, 27, 1456−1485.
(9) (a) Kaszynski, P.; Ringstrand, B. Angew. Chem., Int. Ed. 2015, 54,
̃
K.; Tot
́
́
́
6576−6581. (b) Mei, H.; DesMarteau, D. D. J. Fluorine Chem. 2014,
160, 12−15. (c) Justik, M. W.; Protasiewicz, J. D.; Updegraff, J. B.
Tetrahedron Lett. 2009, 50, 6072−6075. (d) DesMarteau, D. D.;
Pennington, W. T.; Montanari, V.; Thomas, B. H. J. Fluorine Chem.
2003, 122, 57−61. (e) Spyroudis, S.; Varvoglis, A. J. Chem. Soc., Perkin
Trans. 1 1984, 1, 35−37. (f) Page, S. W.; Mazzola, E. P.; Mighell, A. D.;
Himes, V. L.; Hubbard, C. R. J. Am. Chem. Soc. 1979, 101, 5858−5860.
(g) Beringer, F. M.; Huang, S. J. J. Org. Chem. 1964, 29, 445−448.
(h) Beringer, F. M.; Lillien, I. J. Am. Chem. Soc. 1960, 82, 725−731.
(10) Batchelor, R. J.; Birchall, T.; Sawyer, J. F. Inorg. Chem. 1986, 25,
1415−1420.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03307.
(11) (a) Yusubov, M. S.; Yusubova, R. Y.; Nemykin, V. N.; Zhdankin,
V. V. J. Org. Chem. 2013, 78, 3767−3773. (b) Scherrer, R. A.; Beatty, H.
R. J. Org. Chem. 1980, 45, 2127−2131.
Experimental procedures and NMR spectra for all new
compounds; full Gaussian reference; Cartesian coordinates;
electronic and zero-point vibrational energies (PDF)
(12) (a) Synthesis and Application of Organoboron Compounds;
Fernan
Springer International Publishing: Cham, 2015; Vol. 49. (b) Molander,
G. A.; Jean-Gerard, L. Org. React. 2013, DOI: 10.1002/
́
dez, E., Whiting, A., Eds.; Topics in Organometallic Chemistry;
Accession Codes
CCDC 1584267 and 1584269 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
0471264180.or079.01. (c) Darses, S.; Genet, J.-P. Chem. Rev. 2008,
108, 288−325. (d) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40,
275−286.
(13) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed.
2008, 47, 2876−2879.
(14) See Supporting Information for details.
(15) Bader, R. F. W. Atoms in Molecules: A Quantum Theory; Oxford
University Press: Oxford, U.K., 1990.
(16) (a) Malmgren, J.; Santoro, S.; Jalalian, N.; Himo, F.; Olofsson, B.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: claude.legault@usherbrooke.ca.
ORCID
Chem. - Eur. J. 2013, 19, 10334−10342. (b) Pinto de Magalhaes, H.;
̃
Luthi, H. P.; Togni, A. Org. Lett. 2012, 14, 3830−3833.
̈
(17) Schneider, P.; Schneider, G. Angew. Chem., Int. Ed. 2017, 56,
7971−7974.
Claude Y. Legault: 0000-0002-0730-0263
Notes
(18) Lockner, J. W.; Dixon, D. D.; Risgaard, R.; Baran, P. S. Org. Lett.
2011, 13, 5628−5631.
The authors declare no competing financial interest.
(19) Perrin, D. M. Acc. Chem. Res. 2016, 49, 1333−1343.
(20) Labattut, A.; Tremblay, P.-L.; Moutounet, O.; Legault, C. Y. J. Org.
Chem. 2017, DOI: 10.1021/acs.joc.7b01616.
ACKNOWLEDGMENTS
This work was supported by the National Science and
Engineering Research Council (NSERC) of Canada, the Canada
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DOI: 10.1021/acs.orglett.7b03307
Org. Lett. XXXX, XXX, XXX−XXX