Synthesis of phenolic compounds by trapping arynes with a hydroxy surrogate

Article abstract of DOI:10.3390/molecules200915862

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.

Full text of DOI:10.3390/molecules200915862

Molecules 2015, 20, 15862-15880; doi:10.3390/molecules200915862
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Synthesis of Phenolic Compounds by Trapping Arynes with
a Hydroxy Surrogate
Rajdip Karmakar 1, Sourav Ghorai 1, Yuanzhi Xia 2 and Daesung Lee 1,*
1
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago,
IL 60607, USA; E-Mails: rkarma2@uic.edu (R.K.); sghora2@uic.edu (S.G.)
2
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035,
Zhejiang, China; E-Mail: xyz@wzu.edu.cn
* Author to whom correspondence should be addressed; E-Mail: dsunglee@uic.edu;
Tel.: +1-312-996-5189; Fax: +1-312-996-0431.
Academic Editor: Hiroto Yoshida
Received: 6 August 2015 / Accepted: 24 August 2015 / Published: 31 August 2015
Abstract: 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.
Keywords: aryne; bis-functionalization; halophenol; silver trifluoroacetate; regioselectivity

Molecules 2015, 20
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1. Introduction
A variety of trapping reactions of arynes [1–8] have been reported on the basis of their highly
electrophilic nature [9]. In contrast, a brief screening of literature readily identifies the lack of the
examples of aryne trapping with water under traditional aryne formation conditions [10–16] or under
the conditions of the hexadehydro Diels-Alder reaction [17–20]. Although, in theory, water should be
a suitable nucleophile to react with arynes similar to alcohols and carboxylic acids [21,22], the lack of
successful trapping of arynes with water might be the consequence of the immiscibility of water with
the transient arynes generated in organic solvent, typically CH2Cl2 or toluene.
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.
2. 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

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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) [21,27–37]. 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].
Table 1. Trapping reactions of various aryne intermediate to form phenolic products.
Entry Diyne
R
Products Ratio a
Yield (%) b
1
1a
1b
Bu
75
2
Bu
87
3
4
5
1c
1d
1e
SiMe3
SiEt3
Ph
66
66
69
a The ratio was determined with the isolated product. b Isolated yield after SiO2 chromatography.

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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.
Table 2. 1,2-Bis functionalization to form α-halophenol derivatives.
Entry Diyne
R
Products Ratio a
Yield (%) b
1
69
1a
Bu
2
67
63
3
1b
Bu
4
5
83
88
1f
Hex
6
1e
Ph
36
a The ratio was determined with the isolated product. b Isolated yield after SiO2 chromatography.
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

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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-CF3 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-CH3 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).
Table 3. 1,2-Bis functionalization to form oxygen-masked α-halophenol derivatives.
Entry Diyne
R
Products Ratio a
Yield (%) b
1
2
1g
1c
SiEt3
82
SiMe3
SiMe3
52
65
3
1c

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Table 3. Cont.
Entry Diyne
R
Products Ratio a
Yield (%) b
4
1a
1f
Bu
82
5
6
Hex
Hex
94
30
1f
7
76
a The ratio was determined with the isolated product. b Isolated yield after SiO2 chromatography.
3. Experimental Section
3.1. 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
1
13
pure compounds unless otherwise stated. H-NMR and C-NMR spectra were recorded on a Bruker
AV-500 spectrometer (Bruker BioSpin Corporation, Billerica, MA, USA). 19F-NMR spectrum was
1
recorded in Varian Mercury-Vx-300 spectrometer (Palo Alto, CA, USA). H-NMR chemical shifts (δ)
are reported in parts per million (ppm) downfield of TMS and are referenced relative to the residual
13
proteated solvent peak (CDCl3 (7.26 ppm)). 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),
1
or m (multiplet). 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.

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3.2. Experimental Details
3.2.1. 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.
3.2.2. General Procedure for the Bis-Functionalization (GPB)
In a glove box, a mixture of a substrate (0.1 mmol, 1.0 equiv.) and a nucleophile (0.15 mmol,
1.5 equiv.) and an electrophile (0.2 mmol, 2.0 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 subjected to column
chromatography, using ethyl acetate-hexane mixture as the eluent, to get pure products.
3.2.3. Characterization Data of the Products
o-4a: This compound was prepared using GPM as an inseparable mixture of isomers (o/m = 1.3:1) in
1
75% overall yield after column chromatographic purification. H-NMR (CDCl3, 500 MHz): δ (major
isomer) 6.58 (s, 1H), 5.07–5.04 (m, 4H), 4.76 (s, 1H), 2.78 (t, 2H, J = 8.0 Hz), 2.45 (t, 2H, J = 7.0 Hz),
1.64–1.36 (m, 8H), 0.97–0.92 (m, 6H); 13C-NMR (CDCl3, 125 MHz): δ (major isomer) 153.1, 137.1,
134.0, 129.6, 118.2, 107.4, 97.5, 76.6, 74.1, 74.0, 31.7, 30.9, 27.8, 22.9, 21.9, 19.2, 14.0, 13.6; HRMS
(ESI) calcd for C18H25O2 [M + H]+ 273.1849, found 273.1850.
Bu
Bu
MeO2C
MeO2C
OH
o-4b: This compound was formed through GPM at 120 °C (overnight) in an inseparable mixture of
1
two isomers with 66% overall yield after purification by column chromatography. H-NMR (CDCl3,
500 MHz): δ (major isomer) 6.55 (s, 1H), 4.71 (s, 1H), 3.75 (s, 6H), 3.57 (s, 2H), 3.51 (s, 2H), 2.73
(t, 2H, J = 7.8 Hz), 2.46 (t, 2H, J = 7.0 Hz), 1.62–1.32 (m, 8H), 0.99–0.89 (m, 6H); 13C-NMR (CDCl3,

Molecules 2015, 20
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125 MHz): δ (all discernible signals for both isomers) 172.3, 172.1, 152.8, 150.7, 145.9, 144.8, 137.7,
134.6, 129.2, 122.7, 120.8, 114.2, 112.2, 110.6, 110.0, 97.4, 95.8, 59.8, 59.6, 53.0, 53.0, 41.3, 40.8,
40.4, 37.3, 34.0, 32.9, 31.7, 31.1, 31.0, 28.0, 22.9, 22.6, 22.0, 19.3, 14.0, 13.95, 13.6; HRMS (ESI)
calcd for C23H31O5 [M + H]+ 387.2166, found 387.2162.
o-4c: This compound was prepared using GPM. only single isomer was isolated in 66% after
purification using column chromatography. 1H-NMR (CDCl3, 500 MHz) δ 7.77–7.74 (m, 2H), 7.33–7.30
(m, 2H), 6.49 (s, 1H), 5.28 (s, 1H), 4.55 (s, 4H), 2.41 (s, 3H), 0.41 ( s, 9H), 0.25 (s, 9H); 13C-NMR (CDCl3,
125 MHz): δ 160.57, 143.7, 138.3, 133.9, 132.8, 129.8, 127.6, 125.4, 124.8, 109.8, 103.4, 103.0, 54.3,
53.8, 21.5, 1.1, −0.3; HRMS (ESI) calcd for C23H32NO3SSi2 [M + H]+ 458.1636, found 458.1624.
o-4d: This compound was prepared using GPM and isolated in 66% yield as a single isomer after
1
column chromatographic purification. H-NMR (CDCl3, 500 MHz): δ 7.73–7.69 (m, 2H), 7.28–7.24
(m, 2H), 7.02 (s, 1H), 5.09 (s, 1H), 3.88 (t, 2H, J = 10 Hz), 2.92 (t, 2H, J = 10 Hz), 2.39 (s, 3H),
13
1.03–0.91 (m, 24H), 0.67–0.57 (m, 6H); C-NMR (CDCl3, 125 MHz): δ 161.6, 144.3, 143.5, 134.0,
129.8, 128.6, 127.3, 126.7, 117.2, 104.8, 102.3, 99.9, 49.9, 27.9, 21.6, 7.7, 7.4, 4.7, 4.3; HRMS (ESI)
calcd for C29H44NO3SSi2 [M + H]+ 542.2575, found 542.2571.
o-4e: This compound was produced through GPM with other isomer with 69% overall yield after
purification by column chromatography. 1H-NMR (CDCl3, 500 MHz): δ (major isomer) 7.83–7.80 (m,
2H), 7.59–7.55 (m, 2H) 7.43–7.28 (m, 10H), 6.74 (s, 1H), 5.74 (s, 1H), 4.79 (m, 2H), 4.69 (m, 2H),
2.41 (s, 3H); 13C-NMR (CDCl3, 125 MHz): δ (major isomer) 150.6, 145.6, 143.8, 141.8, 139.5, 133.8,
131.3, 130.0, 129.1, 128.3, 128.2 128.0, 127.8, 127.6, 123.2, 121.8, 115.8, 109.0, 95.0, 85.8, 54.7,
52.3, 21.5; HRMS (ESI) calcd for C29H24NO3S [M + H]+ 466.1471, found 466.1469.

Molecules 2015, 20
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o-5a-Br: This compound was prepared using GPB and isolated in 42% yield after purification by
1
column chromatography. H-NMR (CDCl3, 500 MHz): δ 5.45 (s, 1H), 5.17–5.15 (m, 2H), 5.07–5.04
(m, 2H), 2.86–2.81 (m, 2H), 2.44 (t, 2H, J = 6.8 Hz), 1.62–1.36 (m, 8H), 0.95 (t, 3H, J = 7.3 Hz), 0.94
13
(t, 3H, J = 7.3 Hz); C-NMR (CDCl3, 125 MHz): δ 149.4, 136.7, 134.3, 131.6, 117.6, 103.0, 98.2,
76.1, 75.5, 75.4, 31.5, 30.8, 28.8, 22.8, 21.9, 19.3, 14.0, 13.6.
m-5a-Br: This compound was prepared using GPB and isolated in 27% yield after purification by
1
column chromatography. H-NMR (CDCl3, 500 MHz): δ 5.77 (s, 1H), 5.14 (m, 2H), 5.09 (m, 2H),
13
2.92 (t, 2H, J = 8.1 Hz), 2.44 (t, 2H, J = 6.9 Hz), 1.61–1.40 (m, 8H), 0.99–0.92 (m, 6H); C-NMR
(CDCl3, 125 MHz): δ 145.9, 144.1, 143.5, 122.9, 111.2, 110.3, 96.3, 76.1, 74.5, 72.8, 34.8, 31.3, 30.9,
22.8, 21.9, 19.2, 13.9, 13.6; HRMS (ESI) calcd for C18H22BrO2 [M − H]+ 349.0803, found 349.0800.
o-5a-I: This compound was prepared using GPB and isolated in 43% yield after separation using
column chromatography. 1H-NMR (CDCl3, 500 MHz): δ 5.23–5.20 (m, 3H), 4.99–4.96 (m, 2H), 2.85
(t, 2H, J = 7.7 Hz), 2.44 (t, 2H, J = 6.9 Hz), 1.62–1.36 (m, 8H), 0.98–0.92 (m, 6H); 13C-NMR (CDCl3,
125 MHz): δ 151.8, 140.8, 134.1, 130.4, 118.7, 98.5, 78.6, 78.3, 76.0, 75.9, 31.5, 30.8, 29.2, 22.8,
21.9, 19.3, 14.0, 13.6; HRMS (ESI) calcd for C18H22IO2 [M − H]+ 397.0664, found 397.0660.

Molecules 2015, 20
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Bu
Bu
I
O
OH
m-5a-I: This compound was prepared using method B and isolated in 24% yield after column
chromatographic separation. 1H-NMR (CDCl3, 500 MHz): δ 5.61 (s, 1H), 5.14–5.12 (m, 2H), 5.11–5.09
(m, 2H), 2.99–2.94 (m, 2H), 2.45 (t, 2H, J = 6.5 Hz), 1.62–1.41 (m, 8H), 1.01–0.91 (m, 6H); 13C-NMR
(CDCl3, 125 MHz): δ 148.2, 147.4, 144.8, 122.1, 109.8, 96.2, 92.0, 76.3, 74.4, 73.0, 39.6, 31.3, 30.9,
22.9, 21.9, 19.2, 13.9, 13.6; HRMS (ESI) calcd for C18H24IO2 [M + H]+ 399.0815, found 399.0803.
o-5b-Br: This compound was prepared using GPB at 120 °C (overnight) and isolated in 63% yield
1
after column chromatographic purification. H-NMR (CDCl3, 500 MHz): δ 5.38 (s, 1H), 3.77 (s, 6H),
3.68 (s, 2H), 3.58 (s, 2H), 2.80 (t, 2H, J = 8.0 Hz), 2.46 (t, 2H, J = 7.0 Hz), 1.64–1.34 (m, 8H), 0.96
13
(t, 3H, J = 7.5 Hz), 0.93 (t, 3H, J = 8.0 Hz); C-NMR (CDCl3, 125 MHz): δ 171.9, 149.1, 137.1,
134.7, 131.1, 120.2, 106.6, 98.2, 76.7, 53.1, 42.6, 41.5, 31.5, 30.9, 29.0, 22.8, 22.0, 19.4, 14.0, 13.6;
HRMS (ESI) calcd for C23H30BrO5 [M + H]+ 465.1271, found 465.1184.
o-5e-Br: This compound was prepared using GPB and isolated in inseparable mix with 36% overall
yield after isolation using column chromatography. 1H-NMR (CDCl3, 500 MHz): δ 7.85–7.82 (m, 2H),
7.48–7.42 (m, 3H), 7.37–7.33 (m, 2H), 7.31–7.27 (m, 3H), 7.26–7.22 (m, 2H), 7.11–7.08 (m, 2H), 5.94
(s, 1H), 4.79–4.76 (m, 2H), 4.74–4.71 (m, 2H), 2.43 (s, 3H); 13C-NMR (CDCl3, 125 MHz): δ (all
discernible signals for both isomers) 148.0, 147.9, 147.6, 147.3, 145.3, 143.9, 143.9, 139.9, 139.3,
138.1, 136.4, 133.8, 131.3, 130.0, 129.6, 129.4, 129.4, 129.2, 129.0, 128.9, 128.8, 128.6 , 128.4, 128.3,
128.3, 128.2, 128.0, 127.9, 127.8, 127.6, 122.8, 122.6, 122.3, 122.1, 111.7, 111.0, 96.0, 84.9, 54.5,
53.4, 52.5, 52.3, 21.5; HRMS (ESI) calcd for C29H23BrNO3S [M + H]+ 544.0577, found 544.0576.

Molecules 2015, 20
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o-5f-Br: This compound was prepared using GPB and isolated in 61% yield after purification by column
1
chromatography. H-NMR (CDCl3, 500 MHz): δ 7.79–7.76 (m, 2H), 734–7.31 (m, 2H), 5.41 (s, 1H),
4.67–4.64 (m, 2H), 4.56–4.54 (m, 2H), 2.79–2.74 (m, 2H), 2.44 (t, 2H, J = 7.0 Hz), 2.41 (s, 3H), 1.64–1.57
(m, 2H), 1.54–1.42 (m, 4H), 1.38–1.25 (m, 10 H), 0.92 (m, 3H), 0.90–0.85 (m, 3H); 13C-NMR (CDCl3,
125 MHz): δ 149.7, 143.7, 133.9, 133.7, 132.1, 131.2, 129.9, 127.6, 119.1, 104.2, 99.3, 75.6, 55.7,
55.0, 31.7, 31.4, 29.4, 29.12, 29.09, 28.7, 28.6, 22.6, 21.5, 19.6, 14.1; HRMS (ESI) calcd for
C29H39BrNO3S [M + H]+ 560.1829, found 560.1829.
m-5f-Br: This compound was prepared using method GPB and isolated in 22% yield after purification
1
by column chromatography. H-NMR (CDCl3, 500 MHz): δ 7.79–7.76 (m, 2H), 7.33–7.30 (m, 2H),
5.74 (s, 1H), 4.60 (s, 4H), 2.88–2.83 (m, 2H), 2.46–2.42 (m, 2H), 2.41 (s, 3H), 1.63–1.54 (t, 3H),
13
1.53–1.42 (m, 3H), 1.41–1.27 (m, 10H), 0.94–0.86 (m, 6H); C-NMR (CDCl3, 125 MHz): δ 146.5,
144.6, 143.7, 140.0, 133.9, 129.9, 127.6, 120.2, 111.8, 111.4, 97.3, 75.6, 54.5, 52.4, 35.2, 31.6, 31.4,
29.4, 29.0, 28.8, 28.6, 22.6, 21.5, 19.6, 14.1; HRMS (ESI) calcd for C29H39BrNO3S [M + H]+
560.1829, found 560.1829.
o-5f-I: This compound was prepared using GPB and isolated in 64% yield after purification by column
chromatography. 1H-NMR (CDCl3, 500 MHz): δ 7.80–7.76 (m, 2H), 7.34–7.31 (m, 2H), 5.19 (s, 1H),
4.71–4.69 (m, 2H), 4.50–4.47 (m, 2H), 2.81–2.76 (m, 2H), 2.44 (t, 2H, J = 7.0 Hz), 2.41 (s, 3H),
1.64–1.42 (m, 6H), 1.38–1.24 (m, 10H), 0.92 (t, 3H, J = 6.8 Hz), 0.89–0.85 (m, 3H); 13C-NMR
(CDCl3, 125 MHz): δ 152.2, 143.7, 137.8, 133.9, 131.0, 130.9, 130.0, 129.9, 127.6, 120.1, 99.6, 80.3,
75.5, 59.1, 55.4, 31.7, 31.4, 29.7, 29.5, 29.4, 29.1, 28.7, 28.6, 22.6, 21.5, 19.6, 14.1; HRMS (ESI)
calcd for C29H39INO3S [M + H]+ 608.1690, found 608.1694.

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m-5f-I: This compound was isolated in 24% yield using GPB after column chromatographic separation.
1H-NMR (CDCl3, 500 MHz): δ 7.79–7.76 (m, 2H), 7.33–7.30 (m, 2H), 5.58 (s, 1H), 4.63–4.59 (m,
4H), 2.92–2.87 (m, 2H), 2.44 (t, 2H, J = 7.2 Hz), 2.40 (s, 3H), 1.63–1.29 (m, 16H), 0.94–0.87 (m, 6H);
13C-NMR (CDCl3, 125 MHz): δ 148.9, 147.9, 143.7, 141.3, 133.9, 129.9, 127.6, 119.3, 111.2, 97.2,
91.3, 75.8, 54.5, 52.7, 40.1, 31.5, 31.4, 29.4, 29.0, 28.8, 28.6, 22.6, 21.5, 19.6, 14.1; HRMS (ESI)
calcd for C29H39INO3S [M + H]+ 608.1690, found 608.1692.
SiEt3
SiEt3
TsN
OCOCF3
Br
o-6g-CF3: This compound was prepared using GPB and isolated in 72% yield after column
1
chromatographic purification. H-NMR (CDCl3, 500 MHz): δ 7.78–7.75 (m, 2H), 7.36–7.32 (m, 2H),
4.79–4.58 (m, 4H), 2.42 (s, 3H), 1.08–0.95 (m, 12H), 0.91–0.86 (m, 12H), 0.71 (q, 6H, J = 7.9 Hz);
13C-NMR (CDCl3, 125 MHz): δ 156.2 (C=O), 155.8 (C=O), 155.5 (C=O), 155.1 (C=O), 151.0, 144.1,
141.3, 140.2, 133.5, 133.1, 130.0, 127.6, 124.5, 115.6 (CF3), 113.4(CF3), 111.2, 104.8, 102.3, 56.2, 55.4,
21.5, 7.4, 7.3, 4.1, 4.0; HRMS (ESI) calcd for C31H42BrF3NO4SSi2 [M + H]+ 716.1503, found 716.1504.
o-5g-Br: This compound was isolated in 10% after column chromatographic purification in GPB.
1H-NMR (CDCl3, 500 MHz): δ 7.77–7.74 (m, 2H), 7.34–7.31 (m, 2H), 5.64 (s, 1H), 4.64–4.58 (m, 4H),
2.41 (s, 3H), 1.07–0.95 (m, 15H), 0.94–0.89 (m, 9H), 0.69 (q, 6H, J = 6.9 Hz). HRMS (ESI) calcd for
C29H43BrNO3SSi2 [M + H]+ 620.1680, found 620.1669.

Molecules 2015, 20
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o-6d-CH3: This compound was prepared using GPB and isolated in 16% yield after purification by
1
column chromatography. H-NMR (CDCl3, 500 MHz): δ 7.79–7.76 (m, 2H), 7.36–7.33 (m, 2H),
4.8–4.53 (m, 4H), 2.43 (s, 3H), 2.31 (s, 3H), 0.36 (s, 9H), 0.25 (s, 9H); 13C-NMR (CDCl3, 125 MHz):
δ 169.0, 151.8, 144.0, 139.5, 139.2, 135.8, 133.6, 130.0, 127.5, 123.6, 112.7, 105.8, 101.7, 56.1, 55.1,
21.5, 21.3, 0.7, −0.4; HRMS (ESI) calcd for C25H33BrNO4SSi2 [M + H]+ 578.0847, found 578.0846.
o-5d-Br: This compound was prepared using GPB and isolated in 36% yield after purification by column
1
chromatography. H-NMR (CDCl3, 500 MHz): δ 7.79–7.76 (m, 2H), 7.35–7.32 (m, 2H), 5.66 (s, 1H),
4.66–4.64 (m, 2H), 4.58–4.56 (m, 2H), 2.42 (s, 3H), 0.38 (s, 9H), 0.25 (s, 9H); 13C-NMR (CDCl3,
125 MHz): δ 155.9, 143.8, 137.9, 133.8, 133.5, 129.9, 127.5, 127.5, 123.5, 105.8, 104.1, 102.2, 56.0,
55.0, 21.5, 1.1, −0.4; HRMS (ESI) calcd for C23H31BrNO3SSi2 [M + H]+ 536.0741, found 536.0740.
o-6d: This compound was prepared using GPB and isolated in 48% yield after purification by column
1
chromatography. H-NMR (CDCl3, 500 MHz): δ 7.80–7.77 (m, 2H), 7.37–7.34 (m, 2H), 4.86–4.68
13
(m, 2H), 4.63–4.49 (m, 2H), 2.43 (s, 3H), 0.36 (s, 9H), 0.26 (s, 9H); C-NMR (CDCl3, 125 MHz): δ
156.0 (C=O), 155.7 (C=O), 152.9, 144.7, 144.1, 139.7, 134.7, 133.6, 130.1, 127.5, 125.2, 118.0 (CF3),
115.7 (CF3), 113.5 (CF3), 107.2, 101.2, 86.4, 59.7, 55.4, 21.5, 0.6, −0.5; HRMS (ESI) calcd for
C25H30F3INO4SSi2 [M + H]+ 680.0425, found 680.0433.

Molecules 2015, 20
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o-6a: This compound was prepared using method GPB in an inseparable mixture of two isomers
(2.7:1) with 83% overall yield after column chromatography purification. 1H-NMR (CDCl3, 500 MHz):
δ (major isomer) 5.22–5.20 (m, 2H), 5.11–5.09 (m, 2H), 2.94–2.90 (m, 2H), 2.46 (t, 2H, J = 6.5 Hz),
1.64–1.36 (m, 8H), 0.98–0.92 (m, 6H); 13C-NMR (CDCl3, 500 MHz): δ (all discernible signals for
both isomers) 146.7, 144.6, 143.9, 142.8, 139.8, 139.6, 139.4, 130.9, 130.1, 129.9, 129.7, 129.6, 128.2,
128.1, 127.9, 126.0, 125.6, 119.9, 118.8, 118.6, 117.4, 116.8, 108.9, 100.7, 100.4, 75.8, 75.3, 74.5,
72.8, 35.1, 35.1, 31.6, 31.0, 30.6, 30.6, 29.8, 22.8, 22.7, 21.9, 19.3, 19.2, 13.8, 13.7, 13.5; HRMS (ESI)
calcd for C19H21BrF3O4S [M − H]+ 481.0296, found 481.0305.
o-6f: This compound was prepared using GPB and isolated in 78% yield after purification by column
chromatography. 1H-NMR (CDCl3, 500 MHz): δ 7.80–7.76 (m, 2H), 7.36–7.33 (m, 2H), 4.71 (s, 2H),
4.60 (s, 2H), 2.87–2.83 (m, 2H), 2.46 (t, 2H, J = 7.0 Hz), 2.42 (s, 3H), 1.65–1.42 (m, 6H), 1.38–1.25
(m, 10H), 0.95–0.91 (m, 3H), 0.90–0.86 (m, 3H); 13C-NMR (CDCl3, 125 MHz): δ 144.1, 144.1, 141.0,
139.7, 136.9, 133.6, 130.0, 127.5, 122.4 (CF3), 120.4, 119.8 (CF3), 117.3 (CF3), 110.5, 101.9, 74.8,
56.0, 55.1, 31.4, 31.3, 30.2, 29.4, 29.3, 28.6, 28.5, 22.6, 22.5, 21.5, 19.7, 14.1, 14.0; HRMS (ESI)
calcd for C30H38BrF3NO5S2 [M + H]+ 692.1321, found 692.1309.
m-6f: This compound was isolated as minor isomer in an inseparable mix with previous compound
with 16% yield after purification using column chromatography. 1H-NMR (CDCl3, 500 MHz): δ 7.78–7.75
(m, 2H), 7.35–7.32 (m, 2H), 4.73 (s, 2H), 4.61 (s, 2H), 2.96–2.91 (m, 2H), 2.48 (t, 2H, J = 7.1 Hz),
2.41 (s, 3H), 1.65–1.28 (m, 16H), 0.95–0.86 (m, 6H); HRMS (ESI) calcd for C30H38BrF3NO5S2
[M + H]+ 692.1321, found 692.1306.

Molecules 2015, 20
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o-6f-Br: This compound was formed by GPB in an inseparable mixture of two isomers (ratio 2:1) with
30% overall yield after column chromatography. 1H-NMR (CDCl3, 500 MHz): δ (major isomer) 8.22–8.19
(m, 2H), 7.81–7.77 (m, 2H), 7.57–7.51 (m, 3H), 7.37–7.33 (m, 2H), 4.65–4.62 (m, 2H), 4.59–4.54
(m, 2H), 2.56–2.38 (m, 7H), 1.66–1.18 (m, 16H) , 0.96–0.87 (m, 6H); 13C-NMR (CDCl3, 125 MHz): δ
(all discernible signals for both isomers) 164.0, 163.3, 146.4, 145.89, 143.92, 143.84, 139.8, 138.9,
137.4, 135.4, 135.4, 134.5, 134.2, 134.0, 133.64, 130.6, 130.5, 130.3, 130.0, 129.96, 128.9, 128.8,
128.7, 127.6, 127.5, 119.2, 117.8, 111.0, 100.3, 99.6, 75.6, 75.3, 55.8, 55.2, 54.4, 52.7, 35.2, 31.6,
31.4, 31.3, 29.7, 29.5, 29.3, 29.2, 28.9, 28.7, 28.6, 22.6, 22.5, 21.5, 19.7, 19.6, 14.1, 14.0; HRMS (ESI)
calcd for C36H43BrNO4S [M + H]+ 664.2091, found 664.2079.
o-6f-H: This compound was isolated in 24.5% using GPB after purification by column chromatography.
1H-NMR (CDCl3, 500 MHz): δ 8.17–8.13 (m, 2H), 7.78–7.74 (m, 2H), 7.69–7.64 (m, 1H), 7.56–7.50
(m, 2H), 7.34–7.29 (m, 2H), 6.94 (s, 1H), 4.66 (s, 2H), 4.57 (s, 2H), 2.75–2.68 (m, 2H), 2.50–2.44
(m, 2H), 2.41 (s, 3H), 1.66–1.53 (m, 4H), 1.52–1.44 (m, 2H), 1.39–1.24 (m, 10H), 0.97–0.91 (m, 3H),
13
0.90–0.85 (m, 3H); C-NMR (CDCl3, 125 MHz) δ 164.1, 146.6, 144.4, 143.7, 141.0, 134.0, 133.9,
130.3, 129.9, 128.8, 128.7, 127.6, 125.8, 121.2, 116.4, 98.8, 75.6, 54.5, 52.4, 34.2, 31.7, 31.4, 30.5,
29.7, 29.1, 28.8, 28.6, 22.6, 22.6, 21.5, 19.6, 14.1; HRMS (ESI) calcd for C36H44NO4S [M + H]+
586.2986, found 586.2990.
m-6f-H: This compound was prepared using GPB and isolated in 51.5% yield (with 85% purity) after
purification by column chromatography. 1H-NMR (CDCl3, 500 MHz): δ 8.18–8.15 (m, 2H), 7.80–7.76

Molecules 2015, 20
15877
(m, 2H), 7.67–7.62 (m, 1H), 7.54–7.49 (m, 2H), 7.35–7.30 (m, 2H), 6.88 (s, 1H), 4.64 (s, 2H), 4.62
(s, 2H), 2.69–2.64 (m, 2H), 2.49–2.44 (m, 2H), 2.42 (s, 3H), 1.65–1.57 (m, 2H), 1.54–1.42 (m, 4H),
13
1.38–1.17 (m, 10 H), 0.94–0.90 (m, 3H), 0.81–0.76 (m, 3H); C-NMR (CDCl3, 125 MHz): δ 165.2,
148.8, 143.7, 136.6, 136.5, 134.0, 133.8, 133.7, 130.1, 129.9, 129.2, 128.7, 127.6, 120.4, 116.1, 99.6,
75.8, 54.2, 54.1, 31.5, 31.4, 29.6, 29.3, 28.8, 28.7, 28.6, 22.6, 22.5, 21.5, 19.6, 14.1, 14.0.
4. 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.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/09/15862/s1.
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.

Molecules 2015, 20
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the ortho-addition of triflate.
Sample Availability: Samples of the compounds are not available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).