Synthesis of Phenolic Compounds by Trapping Arynes with a Hydroxy Surrogate

Trapping of arynes with various nucleophiles provides a range of heteroatom-functionalized arene derivatives, but the corresponding reaction with water does not provide phenol derivatives. Silver trifluroacetate (AgO2CCF3) can nicely solve this problem. It was found that in typical organic solvent, AgO2CCF3 readily reacts with arynes to generate trifluoroacetoxy organosilver arene intermediate, which, upon treating with silica gel, provides phenolic products. This protocol can be extended to the synthesis of α-halofunctionalized phenol derivatives by simply adding NBS (N-bromosuccinimides) or NIS (N-iodosuccinimides) to the reaction along with silver trifluroacetate, which provided α-bromo or α-iodophenol derivatives in good yield. However, the similar reactions with NCS (N-chlorosuccinimides) afforded only the protonated product instead of the expected α-chlorophenols derivatives. Interestingly, substrates containing silyl substituents on 1,3-diynes resulted in α-halotrifluoroacetates rather than their hydrolyzed product. Additionally, trapping the same arynes with other oxygen-based nucleophiles containing silver counter cation, along with NXS (N-halosuccinimides), generated α-halooxyfunctionalized products.

It would be highly desirable if we could expand the aryne trapping reaction to directly install a phenolic hydroxyl group on arene scaffolds, as this is an important functionality in large number of compounds, including natural products and pharmaceuticals [23,24]. In search of suitable reagents that can behave like a water surrogate under the given reaction conditions, we refer to a clue suggested by our previous nucleophile trapping study [21,25] of arynes, formed from various tetraynes (1), where nucleophiles (F − , F3C − , CF3S − ) associated with a silver counter cation, including silver trifluroacetate (AgO2CCF3), and provided excellent yields of the corresponding adducts (Scheme 1). Surprisingly, for the similar reaction with silver trifluoroacetate, the protonation of the initially formed putative intermediate 2 did not lead to the expected trifluoroacetate 3, instead, its deacetylated phenolic product 4 was obtained after purification [21]. Scheme 1. Trapping reactions of an in situ generated aryne intermediate with various nucleophiles with a silver counter cation.

Results and Discussion
On the basis of this initial observation, we carried out a systematic study of aryne trapping reactions with AgO2CCF3 as a water surrogate to prepare a variety of highly functionalized arene products containing a free phenolic hydroxyl group, and, herein, we report the results.
First, reactions with both symmetrical and unsymmetrical tetrayne substrates of varying substituents were screened to optimize conditions that produce formal water addition products (Table 1). It was quickly identified that the reaction with 1.5 equivalents of AgO2CCF3 in toluene at 90 °C, followed by purification on silica gel, afforded the phenolic products in good yields. Oxygen-tethered symmetrical tetrayne 1a with butyl substituents provided a mixture of ortho-and meta-OH adducts o-4a and m-4a in a 1.3:1 ratio (Entry 1). The reaction of all-carbon tethered substrate 1b with a gem-dicarboxylate moiety in place of the oxygen tether afforded a similar result, but with slightly improved selectivity and yield (87%) of o-4b and m-4b (Entry 2) [26]. Replacing the butyl groups with trimethylsilyl groups afforded only a single isomer o-4c (Entry 3) [21,[27][28][29][30][31][32][33][34][35][36][37]. Although the tether was also changed from oxygen in 1a to tosylated nitrogen in 1c, we believe this change has negligible impact on the selectivity. As expected, an ynamide-tethered unsymmetrical tetrayne with triethylsilyl substituents 1d afforded only the ortho isomer o-4d in 66% yield (Entry 4). A complete switch in regioselectivity was observed when a tosylated nitrogen tethered symmetrical bis-1,3-diyne with phenyl substituents was used, which provided in a majority m-4e along with o-4e in a 6.6:1 ratio (entry 5). This switch in regioselectivity can be explained in terms of the charge-controlled model [30], where the electron withdrawing phenyl group creates a more positive character on the farther carbon of the aryne. This allows the nucleophile to attack the meta carbon more preferably. This clearly indicates that, not the tether, but the substituents at the terminal carbon of the 1,3-diyne moieties are the main controlling elements for the selectivity [38]. With this result in hand, we envisioned that the putative organosilver intermediate 2 might be captured by suitable electrophiles to generate α-functionalized phenol derivatives. To test the viability of this hypothesis, the reaction was run with N-halosuccinimides under otherwise identical conditions, and the results are summarized in Table 2. When substrate 1a was treated with AgO2CCF3 (1.5 equiv.) and NBS (2.0 equiv.), a mixture of α-bromophenol derivatives o-5a-Br and m-5a-Br were obtained in 69% yield with a 1.6:1 ratio (Entry 1). Similarly, with NIS instead of NBS, the corresponding α-iodophenol derivatives o-5a-I and m-5a-I were isolated in 67% yield with a 1.8:1 ratio (Entry 2). Substrate 1b furnished the bromophenol derivatives in 63% yield with an expected selectivity of 1.4:1 [26]. N-Tosylamide tethered substrate 1f containing n-hexyl substituents provided bromo and iodophenol derivatives o-5f-Br/m-5f-Br and o-5a-I/m-5a-I in 83% and 88% yield with a 1.8 and 2.6 ratio, respectively (Entries 5 and 6). Tetrayne 1e containing phenyl substituents was found to be less efficient and provided a mixture of o-5e-Br and m-5e-Br in only 36% yield (Entry 4).
While exploring the scope of the direct synthesis of α-halophenol derivatives, we found that the silyl substituent ortho to the trifluoroacetate moiety interferes with its hydrolysis when halogen was incorporated. Thus, the reaction of 1g afforded single regioisomer o-6g-CF 3 as a major product along with expected phenolic product o-5g-Br in 10% yield (Entry 1) ( Table 3). This is in stark contrast to the formation of o-4c and o-4d, which are derived from their precursors via complete hydrolysis of the corresponding trifluoroacetates. Based on this observation, we further explored the 1,2-oxyhalogenation to form oxygen-masked form of halophenol derivatives ( Table 3). The reaction of substrate 1c in the presence of silver acetate and NBS provided single regioisomer o-6c-CH 3 along with phenolic product o-5c-Br in a 1:2.2 ratio (Entry 2). Unexpectedly, however, the reaction of 1c with AgO2CCF3 and NIS afforded a mixture of iodotrifluoroacetates o-6c and m-6c in a 6.2:1 ratio devoid of hydrolyzed product (Entry 3). Substrates 1a and 1f upon treating with silver triflate and NBS afforded a mixture of bromotriflates o-6a/m-6a (2.6:1) and o-6f/m-6f (4.8:1) in 82% and 94% yield, respectively (Entries 4 and 5) [39]. The reaction of 1f with silver benzoate and NBS provided a mixture of α-bromobenzoates o-6f-Br and m-6f-Br in 30% yield with a 2:1 ratio (Entry 6), but, with NCS, not even traces of the expected chloride-trapped product were obtained, instead only protonated products o-6f-H and m-6f-H were isolated in 76% yield with a 2.1:1 ratio (Entry 7).

General Information
Reactions were carried out in oven-dried glassware unless otherwise noted. Compounds were purchased from Aldrich, Acros, TCI America, or Oakwood Chemicals, unless otherwise noted. Toluene, acetonitrile, and dichloromethane were distilled over calcium hydride (CaH2) under a nitrogen atmosphere. THF was distilled over sodium-benzophenone ketyl under a nitrogen atmosphere. Column chromatography was performed using silica gel 60 Å (32−63 mesh), purchased from Silicycle Inc. (Quebec, QC, Canada). Analytical thin layer chromatography (TLC) was performed on 0.25 mm E. Merck precoated silica gel 60 (particle size 0.040−0.063 mm). Yields refer to chromatographically and spectroscopically pure compounds unless otherwise stated. 1 H-NMR and 13 C-NMR spectra were recorded on a Bruker AV-500 spectrometer (Bruker BioSpin Corporation, Billerica, MA, USA). 19 F-NMR spectrum was recorded in Varian Mercury-Vx-300 spectrometer (Palo Alto, CA, USA). 1 H-NMR chemical shifts (δ) are reported in parts per million (ppm) downfield of TMS and are referenced relative to the residual proteated solvent peak (CDCl3 (7.26 ppm)). 13 C chemical shifts (δ) are reported in parts per million downfield of TMS and are referenced to the carbon resonance of the solvent (CDCl3 (77.2 ppm)). Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), sext (sextet), or m (multiplet). 1 H-NMR signals that fall within a ca. 0.3-ppm range are generally reported as a multiplet, with a range of chemical shift values corresponding to the peak or center of the peak. Coupling constants, J, are reported in Hz (Hertz). Electrospray ionization (ESI) mass spectra were recorded on a Waters Micromass Q-Tof Ultima (Waters Corporation, Milford, MA, USA) at the University of Illinois at Urbana-Champaign. Electron impact (EI) mass spectra and Chemical Ionization (CI) mass spectra were obtained using a Micromass 70-VSE (Waters Corporation, Milford, MA, USA) at the University of Illinois at Urbana-Champaign.

General Procedure for the Mono-Functionalization (GPM)
In a glove box, a mixture of a substrate (0.1 mmol, 1.0 equiv.) and a nucleophile (0.15 mmol, 1.5 equiv.) in dry toluene (3 mL) was taken into a Schlenk tube. The reaction mixture was stirred at 90 °C for 5 h, unless otherwise noted. After completion, the reaction mixture was transferred to a round-bottom flask, concentrated and loaded on silica gel column for chromatographic purification, using ethyl acetate-hexane mixture as the eluent.

Conclusions
In conclusion, we developed a formal hydration method of arynes generated from hexadehydro Diels-Alder reaction. While direct use of water does not efficiently trap the in situ generated arynes to generate phenolic products, silver trifluroacetate (AgO2CCF3) can behave as an effective water surrogate in these reactions. This is probably due to the improved miscibility and reactivity of AgO2CCF3 with arynes, compared to water, to generate the corresponding trifluoroacetoxy organosilver arene intermediates, and, upon treating, with silica gel, these intermediates readily undergo protonolysis of their carbon-silver bonds and hydrolysis of the trifluoroacetyl groups. This protocol can be extended to the synthesis of α-halofunctionalized phenol derivatives by simply adding NBS or NIS to the reaction along with silver trifluroacetate, which provided α-bromo or α-iodophenol derivatives in good yield. Interestingly, the similar reactions with NCS afforded only the corresponding protonated products instead of the expected α-chlorophenols derivatives. Unexpectedly, reactions of substrates containing trialkylsilyl substituents on 1,3-diynes provided α-halotrifluoroacetates rather than their hydrolyzed products. Trapping the same arynes with other oxygen-based nucleophiles containing a silver counter cation, along with NXS, generated α-halooxyfunctionalized products in good yields.

Acknowledgments
Financial support from UIC (LAS AFS) and the National Science Foundation (CHE 1361620) is greatly acknowledged. We are grateful to Furong Sun of the University of Illinois at Urbana-Champaign for high resolution mass spectrometry data.

Author Contributions
D.L. designed the research and wrote the paper. R.K. and S.G. performed the bench work for synthesizing starting materials and products. Everyone contributed to the analysis of the spectra. Y.X. carried out the computational study. All authors read and approved the final manuscript.

Conflicts of Interest
The authors declare no conflict of interest.