Letter Cite This: Org. Lett. XXXX, XXX, XXX-XXX
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Investigation of Iodonium Trifluoroborate Zwitterions as Bifunctional Arene Reagents Raphael̈ Robidas, Vincent Guérin, Laurent Provençal, Marco Echeverria, and Claude Y. Legault* University of Sherbrooke, Department of Chemistry, Centre in Green Chemistry and Catalysis, 2500 boul. de l’Université, Sherbrooke, Québec 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 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. ypervalent iodine reagents have greatly impacted the field of oxidative chemistry over the past 25 years.1 They have 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
H
Instead of restraining their role to benzyne precursors, we envisioned that such species could serve as high-value bifunctional 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 Scheme 1. Diarylodonium Salts and Their Zwitterionic Variants
Figure 1. Diarylodonium salts and their zwitterionic variants.
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 requirement for such a reagent to exist. The impressive functionalization potential of this group would furnish the advantageous bifunctional (nucleophile/electrophile) character desired.12 This is not a trivial assumption; a very recent report of Zhdankin and Yoshimura has described pseudocyclic arylbenziodoxaboroles (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
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 aryliodonium 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 structurally characterized. For example, zwitterion 2a has been commonly used as a benzyne precursor. The bonding description of 2a is a matter of debate, as it is considered to be an intermediate between the zwitterionic and covalent benziodoxole forms.10 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. © XXXX American Chemical Society
Received: October 23, 2017
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DOI: 10.1021/acs.orglett.7b03307 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters corresponding boronic acids. They were obtained in quantitative yields from 5a13 and 5b, respectively (eq 1).
Table 1. Synthesis of Reagents 4a and 4b
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 previously 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).
a
entry
R
T (°C)
time (h)
yield (%)a
1 2 3 4 5 6
H (6a)
20 20 40 20 20 20
4 20 17 48 4 20
77 84 86 84 75 81
F (6b)
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 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.
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. B
DOI: 10.1021/acs.orglett.7b03307 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Arylation of Phenolates Using 4a and 4ba
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, 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 reactivity, 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 diaryliodonium 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 organotrifluoroborate 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 temperature, 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 arylation 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. cReaction performed at 50 °C. d Reaction performed at 65 °C. b
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-trimethylphenolate 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 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Foundation for Innovation (CFI), the FRQNT Centre in Green Chemistry and Catalysis (CGCC), and the Université de Sherbrooke. R.R. is grateful to NSERC for an Undergraduate Student Research Award (USRA).
The functionalization potential of products 9 was exemplified with two representative reactions, shown in Scheme 5.
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Scheme 5. Examples of Synthetic Applications of 9a
The formation of phenol 11 by oxidation of the C−B bond, and the formation of the boronic acid 12 by hydrolysis of the trifluoroborate group were found to yield almost quantitative yields of the desired products. The hydrolysis could be used as a workup procedure 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 structural 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 communication 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.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03307. Experimental procedures and NMR spectra for all new compounds; full Gaussian reference; Cartesian coordinates; electronic and zero-point vibrational energies (PDF) 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
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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REFERENCES
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Claude Y. Legault: 0000-0002-0730-0263 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Science and Engineering Research Council (NSERC) of Canada, the Canada D
DOI: 10.1021/acs.orglett.7b03307 Org. Lett. XXXX, XXX, XXX−XXX
