Preparation of bis-Benzyne Precursor 2,5-bis(Trimethylsilyl)-1,4-Phenylene bis(Trifluoromethanesulfonate)

Full text of DOI:10.1080/00304948.2019.1651172

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
Preparation of bis-Benzyne Precursor
2,5-bis(Trimethylsilyl)-1,4-Phenylene
bis(Trifluoromethanesulfonate)
Casey A. Carpenter, Sarah E. Wegwerth & Christopher J. Douglas
To cite this article: Casey A. Carpenter, Sarah E. Wegwerth & Christopher J. Douglas
(2019): Preparation of bis-Benzyne Precursor 2,5-bis(Trimethylsilyl)-1,4-Phenylene
bis(Trifluoromethanesulfonate), Organic Preparations and Procedures International, DOI:
10.1080/00304948.2019.1651172
To link to this article: https://doi.org/10.1080/00304948.2019.1651172
Published online: 16 Aug 2019.
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Organic Preparations and Procedures International, 0:1–5, 2019
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1651172
OPPI BRIEF
Preparation of bis-Benzyne Precursor 2,5-
bis(Trimethylsilyl)-1,4-Phenylene
bis(Trifluoromethanesulfonate)
Casey A. Carpenter, Sarah E. Wegwerth, and
Christopher J. Douglas
Department of Chemistry, University of Minnesota–Minneapolis,
Minneapolis, Minnesota
Benzyne precursors are rapidly becoming well-used building-blocks for organic materi-
als.1 Our synthesis of conjugated oligoacene precursors by benzyne Diels-Alder reac-
tions created a need for a reliable preparation of a bis-benzyne precursor (BBPC) able
to form sequential benzyne intermediates. Kobayashi’s technique was avoided as it
requires organolithium reagents and low temperatures, which we found undesirable for
a large-scale synthesis.2–5 Alternatively, BBPC 6 was identified as a suitable precursor.
The literature lacked a detailed and efficient synthesis that was suitable for large scale,
so we optimized our own.6,7
Optimization of a route to prepare BBPC 6 (Scheme 1) was readily developed
drawing on several literature sources.7–9 In developing the route, key goals included
eliminating the need for chromatographic purification and utilizing reactions that can
easily be used on scale. Herein we report a detailed five-step synthetic route to bis-ben-
zyne precursor 2,5-bis(trimethylsilyl)-1,4-phenylenebis(trifluoromethanesulfonate)
6
from commercially available hydroquinone 1 in 21% over-all yield. Our work describes
a chromatography-free synthesis of 6 that should be suited for preparative, laboratory-
scale, synthesis.
Experimental Section
All reagents and solvents were of reagent grade and used without further purification
unless otherwise specified. All reactions were carried out using flame-dried glassware
under a nitrogen atmosphere unless aqueous solutions were employed as reagents.
Toluene, acetonitrile, pyridine, and trimethylsilylchloride (TMSCl) were dried by distil-
lation from CaH2 under nitrogen. All other chemicals were used as received unless
otherwise noted. Analytical thin layer chromatography (TLC) was carried out using
1
0.25 mm silica plates from Silicycle. Eluted plates were visualized with UV light. H
Received March 22, 2019; in final form May 14, 2019.
Address correspondence to Christopher J. Douglas, Department of Chemistry, University of
Minnesota–Minneapolis, 207 Pleasant Street SE, Minneapolis, MN 55455. E-mail: cdouglas@umn.edu
1

2
Douglas et al.
Scheme 1
NMR (500 MHz), 13C NMR (126 MHz), and 19F NMR (471 MHz) spectra were
obtained on Varian FT NMR or Bruker FT NMR instruments. NMR spectra were
1
reported as d values in ppm relative to TMS for H (0.00 ppm) and dimethyl sulfoxide
(2.50 ppm), and chloroform for 13C (77.16 ppm), and dimethyl sulfoxide (39.52 ppm).
Melting points were obtained on a Mel-Temp apparatus (Cambridge, MA) and are
uncorrected. Elemental analyses were performed by Atlantic Microlab, Inc.
(Norcross, GA).
2,5-Dibromohydroquinone (2)
In a 3-neck 250 mL round bottom flask equipped with an internal temperature probe, a
25-mL pressure-equilibrating addition funnel topped with a gas inlet adapter, and a gas
outlet line submerged in a solution of 1M sodium thiosulfate (ꢀ50 mL), hydroquinone
(5.50 g, 50.0 mmol, 1.00 eq.) was suspended in acetic acid (50 mL) at room temperature.
The internal temperature was monitored to ensure that the temperature did not exceed
35 ꢁC over the course of the reaction. The addition funnel was charged with a solution
of bromine (Safety Note: Along with standard good practice (eye protection, fume
hood, laboratory coat) the use of bromine requires impervious gloves and training for
the operator.) (5.2 mL, 100 mmol, 2.00 eq.) in acetic acid (5 mL), while positive nitro-
gen pressure was applied, at 2–3 bubbles per second in the sodium thiosulfate solution.
The bromine solution was added dropwise (1 drop/sec). Note: due to viscosity of the
bromine solution, it was necessary to vary the N2 pressure in order to deliver the full
volume over 30 minutes. Additional acetic acid (ꢀ 2 mL) was used to rinse the remain-
ing bromine into the funnel. Upon addition of approximately one-third the volume of
the bromine solution, the hydroquinone fully dissolved. Two hours after the complete
addition of bromine, an off-white precipitate formed. The reaction mixture was stirred
overnight. The precipitate was collected via vacuum filtration, washed with acetic acid
(5 mL) and DI water (50 mL) until colorless providing 2 (4.67 g, 35%, 17.5 mmol, 98%
1
pure by H NMR) as a colorless solid. Additional product precipitated by allowing the
filtrate to stand overnight at room temperature. However, this second crop of precipitate
contained a mixture of 2,5-dibromohydroquinone 2 and 2,3-dibromohydroquinone. The

bis-Benzyne Precursor
3
ratio of these products varied batch-to-batch, from ꢀ6:1 to ꢀ3:1, favoring 2. The 2,3-
dibromo-regioisomer was significantly more soluble in acetic acid at room temperature,
but co-precipitated with the desired regioisomer at lower temperatures. Purification by
flash-chromatography proved challenging due to lack of solubility for both products;
however, purity is imperative as the undesired regioisomer will generate persistent con-
taminants throughout subsequent reactions. A second crop of 2 could be achieved by
recrystallizing the regioisomeric mixtures obtained from the filtrate in hot methanol,
adding water as an anti-solvent until the mixture was turbid, yielding colorless crystals.
This method was only successful, however, if the starting mixture significantly favored
1
2 (ꢀ6:1). mp 187–190 ꢁC. H NMR (500 MHz, DMSO-d6) d 9.84 (s, 2H), 7.04 (s, 2H).
13C NMR (126 MHz, DMSO-d6) d 147.7, 119.9, 108.7. IR (KBr) 3277, 2921, 1617,
1424, 1196, 1060, 852 cmꢂ1
.
Anal. Calcd for C6H4Br2O2: C, 26.90; H, 1.51. Found: C, 26.91; H, 1.40.
((2,5-Dibromo-1,4-phenylene)bis(oxy))bis(trimethylsilane) (3)
To a flame-dried 25-mL flask under inert atmosphere, 2,5-dibromohydroquinone (2)
.
(4.0 g, 15 mmol, 1.00 eq.) and NaHSO4 SiO2 (80 mg; freshly prepared catalyst provides
best yields10) were added. The flask was evacuated and back-filled with nitrogen 3
times, then charged with dry acetonitrile (7.5 mL). While stirring at room temperature,
hexamethyldisilazane (HMDS) (3.5 mL, 16.8 mmol, 1.12 eq.) was added dropwise over
the course of 5 minutes. The reaction was stirred for an additional 5 minutes, then
diluted with dichloromethane (7.5 mL) and filtered. Concentrating the filtrate yielded
crude material as a light-yellow oil, which crystalized spontaneously. The product was
purified via recrystallization in hexanes yielding 3 (5.49 g, 89%, 13.4 mmol) of colorless
1
crystals. mp 63–66 ꢁC. H NMR (500 MHz, CDCl3) d 7.04 (s, 2H), 0.29 (s, 18H). 13C
NMR (126 MHz, CDCl3) d 147.4, 124.3, 114.1, 0.4. IR (film) 2959, 2898, 1055, 1476,
1254, 1210, 841 cmꢂ1
.
Anal. Calcd for C12H20Br2O2Si2: C, 34.96; H, 4.89. Found: C, 34.97; H, 4.78.
(2,5-bis((Trimethylsilyl)oxy)-1,4-phenylene)bis(trimethylsilane) (4)
An oven-dried 3-neck 250 mL flask was equipped with a large-stir bar, glass-stoppered
side arm, a septa-sealed side arm, and a reflux condenser. The round bottom flask was
then charged with 10 mL of freshly distilled toluene, followed by freshly cut elemental
sodium (1 g, 43.5 mmol, 4.00 eq., in several small blocks). The mixture was heated to
reflux at 130 ꢁC without stirring initially, which was a key step in the process to break
the sodium into sodium sand. The sodium blocks sat in refluxing toluene until the edges
and corners softened to rounded ends, then the mixture was stirred with a large stir-bar
at a high rate (500–700 rpm), achieving fine particulates of molten sodium. A high yield
was dependent on consistently stirring the molten sodium such that sodium droplets did
not agglomerate. While stirring, distilled trimethylsilyl chloride (1.6 mL, 13.1 mmol,
1.20 eq.) was added dropwise (1 drop/2 s), followed by a dropwise addition (1 drop/2 s)
of a solution of trimethylsilyl chloride (1.6 mL, 13.1 mmol, 1.20 eq.) and silyl ether (3)
(4.50 g, 10.9 mmol, 1.00 eq.) in toluene (8 mL). After silyl ether addition, the solution
turned blue. The reaction was refluxed for 1.5 hours then allowed to cool to room tem-
perature, then filtered under an inert atmosphere via a Schlenk filter. The sodium salts

4
Douglas et al.
were washed with fresh toluene (10 mL), followed by hexanes (10 mL). Combined fil-
trate and washes were concentrated to a crude yellow crystalline product. Crude product
3 was purified by dissolving in minimal CH2Cl2 in a suitable round bottom flask, then
sheeting with hexanes to form two layers. The flask was capped with a septum and vac-
uum (ꢀ40 torr) was applied via a 20 gauge needle, slowly evaporating the CH2Cl2
layer. This method formed large, block crystals, which were rinsed with cold hexanes
(pre-cooled in a –78 ꢁC bath). We note at this point that small amounts of by-products
persisting from formation of dibromohydroquinone 2 were removed during this recrys-
tallization. The filtrate was concentrated and the above crystallization repeated to grow
second and third crops of crystals, which were combined to yield 4 (3.52 g, 81%,
1
8.8 mmol) as colorless crystals, mp 123–126 ꢁC. Rf ¼ 0.47 (100% hexanes). H NMR
(500 MHz, CDCl3) d 6.76 (s, 2H), 0.29 (s, 18H), 0.24 (s, 18H). 13C NMR (126 MHz,
CDCl3) d 154.1, 131.7, 122.6, 0.8, –0.9. IR (film) 2955, 1450, 1339, 1254, 1205, 1106,
935, 837, 746 cmꢂ1
.
Anal. Calcd for C18H38O2Si4: C, 54.21; H, 9.60. Found: C, 53.94; H, 9.60.
2,5-bis(Trimethylsilyl)benzene-1,4-diol (5)
In a 100-mL oven-dried Schlenk tube, silyl ether 4 (2.36 g, 5.91 mmol, 1.00 eq.) and
KF (0.72 g, 12.41 mmol, 2.10 eq.) were quickly added, then the flask was evacuated
and back-filled with nitrogen 5 times. Deoxygenated methanol (65 mL, degassed by
bubbling N2 for 30 minutes) was charged to the flask and the solution was stirred at
25 ꢁC for 1.25 h. The reaction mixture was poured into ice-cold water (225 mL) and
extracted with CH2Cl2 (3 ꢃ 60 mL). The combined organic layers were washed with
brine (80 mL), dried over Na2SO4, filtered and concentrated to yield 5 (1.39 g, 93%,
5.48 mmol) as a tan solid, mp 178–183 ꢁC. Rf ¼ 0.16 (100% hexanes). 1H NMR
(500 MHz, CDCl3) d 6.67 (s, 2H), 4.46 (s, 2H), 0.29 (s, 18H). 13C NMR (126 MHz,
CDCl3) d 154.1, 128.1, 120.8, –0.9. IR (film) 3426, 2957, 1507, 1365, 1244, 1166,
1103, 836, 745 cmꢂ1. Elemental analysis was not attempted due to the instability of 5.
Compound 5 decomposes under ambient atmosphere and should be stored under an
inert atmosphere at low temperatures (–20 ꢁC). We recommend 5 be taken forward as
soon as possible.
2,5-bis(Trimethylsilyl)-1,4-phenylene bis(trifluoromethanesulfonate) (6)
In an oven-dried 100-mL Schlenk tube, hydroquinone 5 (1.27 g, 4.97 mmol, 1.00 eq.)
was dissolved in distilled pyridine (33 mL). The solution was then cooled to 0 ꢁC, and
while stirring triflic anhydride (2.1 mL, 12.40 mmol, 2.50 eq.) was added dropwise
(1 drop/s). Following complete addition, the solution was allowed to warm to room tem-
perature, then warmed to 50 ꢁC and maintained for 2 hours. The reaction mixture was
allowed to cool to room temperature and concentrated to yield a dark, viscous, oil. The
crude product was triturated with hexanes (5 mL ꢃ 4) at 50 ꢁC, collecting and combin-
ing the hexanes fractions, which were concentrated to yield 6 (2.2 g, 85%, 4.22 mmol)
as a colorless solid, mp 107–108 ꢁC. If necessary, 6 can be purified by recrystallization
1
from hexanes. Rf ¼ 0.69 (90% hexanes:10% EtOAc). H NMR (500 MHz, CDCl3) d
7.44 (s, 2H), 0.38 (s, 18H). 13C NMR (126 MHz, CDCl3) d 153.1, 137.4, 127.1 (q,

bis-Benzyne Precursor
5
J ¼ 1.8 Hz), 118.5 (q, J ¼ 320 Hz), ꢂ1.3. 19F NMR (471 MHz, CDCl3) d ꢂ76.90. IR
(film) 2961, 2904, 1421, 1339, 1218, 1141, 1080, 909, 844, 734 cmꢂ1
.
Anal. Calcd for C14H20F6O6S2Si2: C, 32.43; H, 3.89. Found: C, 32.49; H, 3.96.
Acknowledgments
The authors thank the donors of the American Chemical Society Petroleum Research
Fund for financial support (55606-ND1) and Dr. Letitia Yao for assistance with 19F-
decoupled 13C NMR spectroscopy.
ORCID
Christopher J. Douglas
http://orcid.org/0000-0002-1904-6135
References
1. S. Yoshida and T. Hosoya, Chem. Lett., 44, 1450 (2015).
2. Y. Himeshima, S. Takaaki, and H. Kobayashi, Chem. Lett., 12, 1211 (1983).
~
ꢀ
ꢀ
3. D. Pena, A. Cobas, D. Perez, and E. Guitian, Synthesis, 10, 1454 (2002).
4. S. M. Bronner and N. K. Garg, J. Org. Chem., 74, 8842 (2009).
5. Q. –C. Wu, B.-S. Li, C.-Q. Shi, Y.-X. Chen, Hecheng Huaxue, 15, 111 (2007)
6. S. E. Wegwerth, Studies into the Synthesis of Cyclacenes, Ph.D. Dissertation, University of
Minnesota - Twin Cities (2017), passim.
7. H. M. Duong, M. Bendikov, D. Steiger, Q. Zhang, G. Sonmez, J. Yamada, and F. Wudl,
Org. Lett., 5, 4433 (2003).
8. D. J. Atkinson, J. Sperry, and M. A. Brimble, Synthesis, 6, 911 (2010).
9. H. Bock, S. Nick, K. Z. Ruppert, Naturforsch, 50, 595 (1995).
10. M. S. Khalili, H. Ghafuri, S. Mojahedi-Jahromi, and M. M. Hashemi, Phosphorus Sulfur,
182, 175 (2007).