Selective halogen-lithium exchange of 1,2-dihaloarenes for successive [2+4] cycloadditions of arynes and isobenzofurans

Article abstract of DOI:10.3390/molecules201019449

Successive [2+4] cycloadditions of arynes and isobenzofurans by site-selective halogen-lithium exchange of 1,2-dihaloarenes were developed, allowing the rapid construction of polycyclic compounds which serve as a useful synthetic intermediates for the preparation of various polyacene derivatives.

Full text of DOI:10.3390/molecules201019449

Molecules 2015, 20, 19449-19462; doi:10.3390/molecules201019449
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Selective Halogen-Lithium Exchange of 1,2-Dihaloarenes for
Successive [2+4] Cycloadditions of Arynes and Isobenzofurans
Shohei Eda and Toshiyuki Hamura *
Department of Applied Chemistry for Environment, School of Science and Technology,
Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan;
E-Mail: shoheie816@gmail.com
* Author to whom correspondence should be addressed; E-Mail: thamura@kwansei.ac.jp;
Tel./Fax: +81-79-565-7591.
Academic Editor: Hiroto Yoshida
Received: 1 October 2015 / Accepted: 20 October 2015 / Published: 23 October 2015
Abstract: Successive [2+4] cycloadditions of arynes and isobenzofurans by site-selective
halogen-lithium exchange of 1,2-dihaloarenes were developed, allowing the rapid construction
of polycyclic compounds which serve as a useful synthetic intermediates for the preparation
of various polyacene derivatives.
Keywords: aryne; isobenzofuran; [2+4] cycloaddition; 1,2-dihaloarenes; polyacene;
halogen-lithium exchange
1. Introduction
We previously reported dual annulations of dibromoisobenzofuran 1, a formal equivalent of
didehydroisobenzofuran A, via [2+4] cycloadditions of aryne [1–9] and isobenzofuran [10–23] (Scheme 1).
Selective bromine–lithium exchange from the starting two dibromides 2 and 3 enables the tandem generation
of arynes and dual cycloadditions with two different arynophiles (step 1 and step 2). Importantly, successive
process can be performed in one-pot by sequential addition of the arynophiles, affording various
functionalized polycyclic aromatic compounds [24–26].

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Scheme 1. Successive [2+4] cycloadditions of arynes and isobenzofurans.
This sequential cycloaddition, however, has a limitation in that the introduction of electron withdrawing
groups on the benzene ring in aryne precursor (e.g., 2b) is required to restrict the competitive formation
of the dual cycloadduct (Scheme 2). In fact, treatment of dibromobenzene 2a with n-BuLi in the presence
of dibromoisobenzofuran 1 gave cycloadduct 6a in 18% yield, accompanied by a sizable amount of
bis-cycloadduct 7a (25%). This result indicates that in addition to the generation of benzyne B, similar
reactivity of two dibromides 2a and 6a with n-BuLi caused the competitive generation of aryne D from
the initially formed cycloadduct 6a. In this case, excess amounts of the starting material 2a (5.0 equiv.)
improved the yields of the mono-cycloadduct 6a (42%) by selective generation of benzyne B. However,
it is not an essential solution, since existing of the large amount of the starting material 2a disturbed the
second [2+4] cycloaddition with 6a in a one-pot process.
Scheme 2. Previous study on the [2+4] cycloaddition of benzyne and dibromoisobenzofuran.
To expand the synthetic utility of this successive processes, we reexamined [2+4] cycloadditions of
aryne and isobenzofuran including the parent benzyne species B as an initial cycloaddition (vide supra).
The key to achieve this sequential process is search for a suitable aryne precursor to enable the selective
halogen-lithium exchange [27–30]. Along these lines, we select 1,2-dihaloarenes as an aryne precursor

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and expect that controlling the reactivity of the halogen would be possible by taking advantage of the
following two features: (1) utilization of the more electropositive halogen (type 1); or (2) tuning the
reactivity of halogen by the adjacent halogen (type 2) as shown in Scheme 3. The naive idea of the
second strategy is that the strong electron-withdrawing ability of the adjacent halogen might reinforce the
electrophilicity of the halogen atom, thus facilitating the halogen-lithium exchange. Importantly, these two
factors would allow for the site-selective halogen-lithium exchange among three halides, i.e., dihaloarene,
dihaloisobenzofuran, and dihalocycloadduct (Scheme 1), which leads to the tandem generation of arynes
and multiple cycloadditions with two or three different arynophiles. We report herein the positive
resolution of this scenario [31,32].
Scheme 3. Two strategies for selective halogen-lithium exchange of 1,2-dihaloarenes.
2. Results and Discussion
Table 1 shows initial model reaction for selective generation of benzyne species B. Upon
treatment of 1-bromo-2-iodobenzene (8a) with 1.2 equiv. of n-BuLi in the presence of 1.0 equiv of
5,6-dibromoisobenzofuran (1) in toluene at −78 °C, iodine–lithium exchange of 8a occurred cleanly.
The aryllithium intermediate, thus formed, underwent 1,2-elimination of LiBr to generate benzyne B,
which was trapped with 1 to give mono-cycloadduct 6a in 60% yield (entry 1). It is clear that the formation
of the bis-cycloadduct 7a via the bromine-lithium exchange of 6a was not fully but mainly suppressed
(9%) in comparison with the corresponding reaction of dibromide 2a used as a benzyne source. Same
reaction at higher reaction temperature (−15→25 °C) gave a better yield of the desired product 6a (78%),
and the bis-cycloadduct 7a was obtained only in 1% yield (entry 2). Using 1-chloro-2-iodobenzene (8b) as
a benzyne precursor again proved feasible with n-BuLi (toluene, −15→25 °C), affording 6a in 62% yield
(entry 4). Moreover, the corresponding reaction of iodide 8c having a fluorine atom at 2-position as
a leaving group gave moderate yield of 6a (entries 5–6). These results indicate that halogen-lithium
exchange selectively occurred at the more electropositive iodine atom in iodo-halides 8a–8c (Type 1 in
Scheme 3), smoothly generating (2-halo)phenyllithiums, respectively, whereas the dibromoisobenzofuran
1 and the dibromocycloadduct 6a almost untouched under these conditions [33–36]. As for the moderate
yield of the cycloadduct 6a in the reaction of the dihalides 8b and 8c, the lower leaving ability of halogen
(Cl and F) in comparison with bromine in aryllithium species would affect the elimination of lithium
halide and subsequent generation of benzyne B [37]. Based on these reaction outcomes, it is safe to say

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that use of 1,2-dihaloarenes 8a–8c possessing a more electropositive iodine atom is favored as a benzyne
precursor over the bromide 2a in terms of selectivity and yield.
Table 1. Initial model study.
Entry
X
Temp. (°C)
–78
Yield of 6a (%)
Yield of 7a (%) 1
1
2
3
4
5
6
8a: Br
8a: Br
8b: Cl
8b: Cl
8c: F
60
78
51
62
41
44
9
1
–15→25
–78
9
–15→25
–78
9
4
8c: F
–15→25
11
1 The cycloadduct 7a was obtained as a mixture of disastereomers (ds: 44/56~58/42).
Further study revealed that 5,6-dibromo-1,3-diphenylisobenzofuran (9a) was also a suitable reactive
partner, which cyclized with benzyne B, generated by treatment of iodobromide 8a with n-BuLi (toluene,
−15→25 °C), affording substituted epoxyanthracene 10 in 72% yield (Scheme 4).
Scheme 4. [2+4] cycloaddition of benzyne B and isobenzofuran 9a.
We next examined second [2+4] cycloaddition of aryne generated from the first cycloadduct.
To explore another mode of selective halogen-lithium exchange of 1,2-haloarenes, i.e., reactivity control
by adjacent halogen (type 2 in Scheme 3) [38,39], two different halogens were introduced to
isobenzofuran. Upon treatment of dibromide 10 with 1.3 equiv. of n-BuLi in the presence of 1.1 equiv.
of 5-bromo-6-chloro-1,3-diphenylisobenzofuran (9b) [40] (toluene, 25 °C), aryne E was selectively
generated and subsequent trapping with 9b gave mono-cycloadduct 11 in 54% yield as a mixture of
diastereomers (Scheme 5). In this case, bis-cycloadduct 12, caused by the generation of aryne F, was
produced in 16% yield. This observed site-selectivity in the bromine-lithium exchange among three bromides
9b, 10, and 11 was unexpected, because (2-chlorophenyl)lithium 14 was more thermodynamically stable
than (2-bromophenyl)lithium 15 by existing of a more electron withdrawing chlorine atom, which would

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suggest the favorable formation of aryne F over that of aryne E [41]. Aside from the unanticipated
site-selectivity in this bromine-lithium exchange, further introduction of fused ring onto the dual
cycloadduct 11 was realized by the third [2+4] cycloaddition of aryne F and isobenzofuran 9c by treatment
of 11 with n-BuLi under the similar conditions, affording polycyclic compound 13 in 66% yield, which
is expected to be suitably converted to substituted heptacenes [42–45].
Scheme 5. Mono-directional [2+4] cycloadditions of arynes.
Moreover, it is worth mentioning that 1,2,4,5-tetrabromobenzene (16) nicely worked as a reactive
platform [46–51], allowing bi-directional cycloadditions in an unsymmetrical manner (Scheme 6). The
essential point of this sequential process is using 5-bromo-6-chloro-1,3-diphenylisobenzofuran (9b)
to differentiate the reactivity of the two dihalogenated sites in the bis-aryne equivalent 17, which was
efficiently obtained by the first [2+4] cycloaddition of dibromobenzyne G and isobenofuran 9b. It is
notable that perfect site-selectivity was observed in the bromine-lithium exchange of 16, selectively
generating the dibromobenzyne G [52]. The cycloadduct 17, thus obtained, again underwent the
selective bromine-lithium exchange at the dibromo side in 17, as a related reaction of dibromide 10 and
isobenzofuran 9b (Scheme 5), generating the bromochlorobenzyne H, which was intercepted by 9c to
afford the unsymmetrical cycloadduct 11 in 65% yield, accompanied by a formation of dual cycloadduct
21 (20%). Although the observed selectivity in the reaction of 17 was moderate (11/21 = 3.2:1), use of
bis-aryne equivalent 17 with an unsymmetric form turned out to be indispensible to discriminate the
reactivity of the two dihalogenated sites in 17, because the corresponding reaction of the symmetrical
tetrabromide 20 resulted in the decreased selectivity in the formation of the desired mono-cycloadduct
21 and bis-cycloadduct 13 (21/13 = 1.5:1). Final [2+4] cycloaddition of aryne F, generated from the
bis-cycloadduct 11, with furan 18 under the above-mentioned conditions was satisfied, efficiently
affording the tris-cycloadduct 19 with a various synthetic opportunity for further introduction of fused
rings and/or functionalization.

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Scheme 6. Bi-directional [2+4] cycloadditions of arynes.
3. Experimental Section
General Information
All experiments dealing with air- and moisture-sensitive compounds were conducted under an
atmosphere of dry argon. Toluene (anhydrous; Wako Pure Chemical Industries, Ltd., Osaka, Japan) was
used as received. For thin-layer chromatography (TLC) analysis, Merck pre-coated plates (silica gel 60
F254, Art 5715, 0.25 mm, Merck Japan, Tokyo, Japan) were used. For flash column chromatography, silica
gel 60 N (spherical, neutral, 63–210 μm) from Kanto Chemical (Tokyo, Japan) was used. Silica gel
preparative TLC (PTLC) was performed on Merck silica gel 60 PF254 (Art 7747).
13
1H-NMR and C-NMR were measured on a JNM ECA-300 and a JNM ECX-500II spectrometer
(JEOL, Tokyo, Japan). Attenuated Total Reflectance Fourier Transformation Infrared (ATR-FTIR) spectra
were recorded on a FT/IR-4200 FT-IR Spectrometer (JASCO, Tokyo, Japan). High resolution mass
spectra were obtained with a JEOL JMS 700 spectrometer and a JEOL AccuTOF LC-plus JMS-T100LP.
Melting point (mp) determinations were performed by using a MP-S3 instrument (Yanako, Kyoto, Japan) or
a MPA100 Automated Melting Point System (OptiMelt, Sunnyvale, CA, USA) and are uncorrected.
Typical Procedure for [2+4] Cycloadditions of Aryne and Isobenzofuran: Synthesis of 2,3-Dibromo-9,10-
dihydro-9,10-epoxyanthracene (6a). To a mixture of 1-bromo-2-iodobenzene (8a, 70.0 mg, 0.247 mmol)
and isobenzofuran 1 (71.8 mg, 0.260 mmol) in toluene (2.0 mL) was added n-BuLi (1.60 M in n-hexane,
0.19 mL, 0.30 mmol) at −15 °C, and the reaction was warmed up to 25 °C. After 5 min, the reaction was
stopped by adding water. The products were extracted with EtOAc (×3), and the combined organic
extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by
PTLC (hexane/EtOAc = 8/2) to give 2,3-dibromo-9,10-dihydro-9,10-epoxyanthracene (6a, 67.9 mg,
78.1%) as a white solid and 2,3-dibromo-5,7,12,14-tetrahydro-5,14:7,12-diepoxypentacene (7a, 1.2 mg,
1.0%, ds: 17/83) as a mixture of diastereomers.

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1
Compound 6a: Mp 208.5–209.1 °C (hexane/CHCl3); H-NMR (CDCl3, δ) 6.01 (s, 2H), 7.06 (dd, 2H,
13
J1 = 3.1 Hz, J2 = 5.2 Hz), 7.33 (dd, 2H, J1 = 3.1 Hz, J2 = 5.2 Hz), 7.55 (s, 2H); C-NMR (CDCl3, δ)
82.0, 120.7, 121.6, 125.7, 126.5, 146.9, 149.2; IR (ATR) 3027, 1569, 1459, 1259, 1085, 953, 832,
762 cm−1; −HRMS (FAB) m/z 351.8925 (351.8922 calcd for C14H8Br2O, M+).
Compound 7a, less polar diastereomer: Rf 0.30 (hexane/CH2Cl2 = 4/6); Mp decomposed at 300 °C;
1H-NMR (CDCl3, δ) 5.90 (s, 2H), 5.95 (s, 2H), 7.00 (dd, 2H, J1 = 3.1 Hz, J2 = 5.5 Hz), 7.29 (dd, 2H,
J1 = 3.1 Hz, J2 = 5.5 Hz), 7.31 (s, 2H), 7.53 (s, 2H); 13C-NMR (CDCl3, δ) 81.9, 82.4, 114.2, 120.4, 121.6,
125.6, 126.0, 146.1, 147.8, 148.1, 149.2; IR (ATR) 3016, 1569, 1457, 1265, 1085, 949, 832, 772 cm−1;
−HRMS (FAB) m/z 468.9262 (468.9263 calcd for C22H13Br2O2, [M + H]+).
Compound 7a, more polar diastereomer: Rf 0.13 (hexane/CH2Cl2 = 4/6); Mp decomposed at 300 °C;
1H-NMR (CDCl3, δ) 5.90 (s, 2H), 5.96 (s, 2H), 6.97 (dd, 2H, J1 = 3.1 Hz, J2 = 5.2 Hz), 7.27 (dd, 2H,
J1 = 3.1 Hz, J2 = 5.2 Hz), 7.29 (s, 2H), 7.46 (s, 2H); 13C-NMR (CDCl3, δ) 82.0, 82.5, 113.9, 120.5, 121.5,
125.6, 125.9, 146.0, 147.9, 149.2; IR (ATR) 3010, 1573, 1457, 1271, 1086, 952, 836, 754 cm−1; −HRMS
(FAB) m/z 468.9256 (468.9263 calcd for C22H13Br2O2, [M + H]+).
2,3-Dibromo-9,10-diphenyl-9,10-epoxyanthracene (10). According to the procedure described for the
synthesis of cycloadduct 6a, 1-bromo-2-iodobenzene (8a, 112 mg, 0.396 mmol), isobenzofuran 9a (129 mg,
0.301 mmol) and n-BuLi (1.60 M in n-hexane, 0.25 mL, 0.40 mmol) gave, after purified by silica-gel flash
column chromatography (hexane/CH2Cl2/Et2O = 98/1/1→96/3/1), cycloadduct 10 (110 mg, 72.4%) as
a white solid.
1
Compound 10: Mp 167.6–168.5 °C (hexane/Et2O); H-NMR (CDCl3, δ) 7.08 (dd, 2H, J1 = 2.9 Hz,
J2 = 5.7 Hz), 7.38 (dd, 2H, J1 = 2.9 Hz, J2 = 5.7 Hz), 7.49–7.53 (m, 2H), 7.54 (s, 2H), 7.59–7.63 (m, 4H),
7.86–7.89 (m, 4H); 13C-NMR (CDCl3, δ) 90.2, 120.7, 121.8, 125.6, 126.4, 126.5, 128.7, 129.0, 133.9,
−
149.2, 151.6; IR (ATR) 3030, 1599, 1499, 1295, 1036, 992, 871, 741 cm−1; HRMS (DART) m/z
502.9644 (502.9646 calcd for C26H17Br2O, [M + H]+).
2-Bromo-3-chloro-5,7,12,14-tetraphenyl-5,14:7,12-diepoxypentacene (11). According to the procedure
described for the synthesis of cycloadduct 6a, cycloadduct 10 (75.6 mg, 0.150 mmol), isobenzofuran 9b
(63.2 mg, 0.165 mmol) and n-BuLi (1.60 M in n-hexane, 0.12 mL, 0.19 mmol) gave, after purification

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by silica-gel flash column chromatography (hexane/CH2Cl2/Et2O = 96/3/1→88/9/3), 2-bromo-3-chloro-
5,7,12,14-tetraphenyl-5,14:7,12-diepoxypentacene (11, 58.8 mg, 53.9%, ds. less polar/more polar =
46/54) and 2-bromo-3-chloro-5,7,12,14-tetraphenyl-5,14:7,12-diepoxy-pentacene (12, 23.7 mg, 15.9%)
as a mixture of diastereomers, respectively. The diastereomers of 11 were separated by PTLC
(hexane/toluene/CH2Cl2/Et2O = 82/10/6/2 X2), affording less polar 11 and more polar 11 as white solids.
Compound 11, less polar: Rf 0.38 (hexane/toluene/CH2Cl2/Et2O = 82/10/6/2, X2); Mp decomposed at
1
240 °C (MeOH/CHCl3); H-NMR (CDCl3, δ) 6.96 (dd, 2H, J1 = 2.9 Hz, J2 = 5.2 Hz), 7.27 (dd, 2H,
J1 = 2.9 Hz, J2 = 5.2 Hz), 7.29 (s, 1H), 7.33 (s, 2H), 7.44 (s, 1H), 7.46–7.51 (m, 4H), 7.56–7.60 (m, 8H),
7.77–7.79 (m, 4H), 7.83–7.86 (m, 4H); 13C-NMR (CDCl3, δ) 90.2, 90.3, 90.5, 113.7, 119.3, 120.4, 122.6,
125.6, 125.8, 126.4, 126.6, 128.4, 128.7, 128.9, 129.1, 131.5, 133.70, 133.73, 134.6, 148.26, 148.34,
149.9, 150.15, 150.17, 150.6, 151.3; IR (ATR) 3059, 1607, 1500, 1308, 1083, 986, 867, 744 cm−1;
−HRMS (ESI) m/z 749.0834 (749.0859 calcd for C46H28BrClNaO2, [M + Na]+).
Compound 11, more polar: Rf 0.28 (hexane/toluene/CH2Cl2/Et2O = 82/10/6/2, X2); Mp decomposed at
1
230 °C (MeOH/CHCl3); H-NMR (CDCl3, δ) 7.02 (dd, 2H, J1 = 2.9 Hz, J2 = 5.2 Hz), 7.30 (s, 2H),
7.32–7.35 (m, 3H), 7.43–7.49 (m, 5H), 7.52–7.57 (m, 8H), 7.75–7.77 (m, 4H), 7.81–7.84 (m, 4H);
13C-NMR (CDCl3, δ) 90.2, 90.3, 90.5, 113.49, 113.51, 119.3, 120.5, 122.7, 125.6, 125.7, 126.4, 126.5,
128.3, 128.7, 128.8, 129.0, 131.5, 133.7, 133.8, 134.6, 148.2, 148.3, 149.9, 150.0, 150.3, 150.8, 151.6;
−
IR (ATR) 3065, 1607, 1498, 1311, 1082, 989, 863, 746 cm−1; HRMS (ESI) m/z 749.0876 (749.0859
calcd for C46H28BrClNaO2, [M + Na]+).
Compound 12 (a mixture of four diastereomers): 1H-NMR (CDCl3, δ) 6.90–7.01 (m, 8H), 7.19–7.33 (m,
13
24H), 7.36–7.60 (m, 80H), 7.66–7.83 (m, 48H); C-NMR (CDCl3, δ) 90.0, 90.05, 90.07, 90.09, 90.11,
90.14, 90.17, 90.19, 90.36, 90.39, 90.46, 90.50, 113.3, 113.4, 113.47, 113.51, 113.7, 113.8, 119.2, 119.3,
119.5, 119.6, 120.08, 120.11, 120.2, 120.4, 122.4, 122.5, 122.7, 125.4, 125.5, 125.55, 125.62, 125.7,
125.8, 125.97, 126.00, 126.07, 126.12, 126.2, 126.3, 126.42, 126.44, 126.5, 126.57, 126.64, 126.7,
128.16, 128.21, 128.3, 128.4, 128.5, 128.59, 128.63, 128.66, 128.72, 128.8, 128.86, 128.90, 128.92,
129.00, 129.03, 131.4, 131.5, 131.58, 131.63, 133.68, 133.72, 133.76, 133.83, 133.87, 133.90, 134.3,
134.38, 134.44, 134.70, 134.73, 134.78, 134.80, 147.99, 148.03, 148.1, 148.2, 148.26, 148.30, 148.4,
148.9, 148.98, 149.02, 149.1, 149.2, 149.4, 149.49, 149.52, 149.70, 149.73, 149.78, 149.80, 149.86,
149.94, 149.96, 150.02, 150.2, 150.3, 150.35, 150.42, 150.5, 150.6, 151.18, 151.24, 151.37, 151.39; IR
−
(ATR) 3062, 1606, 1499, 1307, 1082, 983, 885, 748 cm−1; HRMS (ESI) m/z 1017.1756 (1017.1747
calcd for C66H40BrClNaO3, [M + Na]+).

Molecules 2015, 20
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5,7,9,14,16,18-Hexaphenyl-5,18:7,16:9,14-triepoxyheptacene (13). According to the procedure described
for the synthesis of cycloadduct 6a, cycloadduct 11 (more polar) (35.1 mg, 0.0482 mmol), isobenzofuran 9c
(14.7 mg, 0.0544 mmol) and n-BuLi (1.60 M in n-hexane, 0.040 mL, 0.064 mmol) gave, after purification
by silica-gel flash column chromatography (hexane/CH2Cl2/Et2O = 96/3/1→88/9/3), 5,7,9,14,16,18-
hexaphenyl-5,18:7,16:9,14-triepoxyheptacene (13) as a mixture of diastereomers (29.0 mg, 68.0%, ds. less
polar/more polar = 46/54). Those diastereomers were separated by PTLC (hexane/toluene/CH2Cl2/Et2O =
78/10/8/4, X4), affording less polar 13 and more polar 13 as white solids, respectively.
Compound 13 (less polar): Rf 0.55 (hexane/toluene/CH2Cl2/Et2O = 78/10/8/4, X4); Mp decomposed at
260 °C (MeOH/CHCl3); 1H-NMR (CDCl3, δ); 6.92 (dd, 4H, J1 = 2.9 Hz, J2 = 5.2 Hz), 7.22 (s, 4H), 7.23
(dd, 4H, J1 = 2.9 Hz, J2 = 5.2 Hz), 7.44–7.49 (m, 6H), 7.52–7.56 (m, 12H), 7.72–7.75 (m, 4H), 7.79–7.82
(m, 8H); 13C-NMR (CDCl3, δ) 90.4, 113.4, 120.3, 125.6, 126.5, 126.6, 128.2, 128.3, 128.8, 128.9, 134.6,
134.8, 149.2, 149.4, 150.1; IR (ATR) 3058, 1603, 1496, 1307, 974, 867, 747 cm−1; −HRMS (ESI) m/z
905.3020 (905.3032 calcd for C66H42NaO3, [M + Na]+).
Compound 13 (more polar): Rf 0.49 (hexane/toluene/CH2Cl2/Et2O = 78/10/8/4, X4); Mp decomposed at
1
250 °C (MeOH/CHCl3); H-NMR (CDCl3, δ) 6.94 (dd, 2H, J1 = 2.9 Hz, J2 = 5.2 Hz), 6.96 (dd, 2H,
J1 = 2.9 Hz, J2 = 5.2 Hz), 7.19 (s, 2H), 7.22–7.25 (m, 4H), 7.28 (s, 2H), 7.39–7.59 (m, 18H), 7.72–7.74
(m, 4H), 7.77–7.80 (m, 4H), 7.81–7.83 (m, 4H); 13C-NMR (CDCl3, δ) 90.37, 90.39, 90.5, 113.2, 113.5,
120.2, 120.3, 125.7, 125.8, 126.4, 126.5, 126.6, 128.11, 128.13, 128.3, 128.6, 128.8, 134.5, 134.8, 134.9,
149.0, 149.1, 149.3, 149.6, 149.9, 150.1; IR (ATR) 3063, 1602, 1497, 1308, 977, 869, 747 cm−1; −HRMS
(ESI) m/z 905.3028 (905.3032 calcd for C66H42NaO3, [M + Na]+).
2,3,6-Tribromo-7-chloro-9,10-diphenyl-9,10-epoxyanthracene (17). According to the procedure described
for the synthesis of cycloadduct 6a, 1,2,4,5-tetrabromobenzene (16, 1.54 g, 3.91 mmol), isobenzofuran 9b
(1.00 g, 2.61 mmol) and n-BuLi (1.60 M in n-hexane, 2.50 mL, 4.00 mmol) gave, after purification by
silica-gel flash column chromatography (hexane/CH2Cl2/Et2O = 96/3/1), 2,3,6-tribromo-7-chloro-9,10-
diphenyl-9,10-epoxyanthracene (17, 1.58 g, 98.1%) as a white solid.
1
Compound 17: Mp 247.2–248.0 °C (hexane/CHCl3); H-NMR (CDCl3, δ) 7.41 (s, 1H), 7.52–7.56
(m, 2H), 7.559 (s, 1H), 7.564 (s, 2H), 7.61–7.65 (m, 4H), 7.80–7.83 (m, 4H); 13C-NMR (CDCl3, δ) 89.8,
90.0, 120.1, 122.5, 122.9, 125.9, 126.3, 129.1, 129.2, 132.3, 132.89, 132.92, 149.5, 150.3, 150.37,
−
150.44; IR (ATR) 3017, 1601, 1499, 1288, 1089, 987, 887, 746 cm−1; HRMS (DART) m/z 614.8381
(614.8362 calcd for C26H15Br3ClO, [M + H]+).

Molecules 2015, 20
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2-Bromo-3-chloro-5,7,12,14-tetraphenyl-5,14:7,12-diepoxypentacene (11). According to the procedure
described for the synthesis of cycloadduct 6a, cycloadduct 17 (124 mg, 0.201 mmol), isobenzofuran 9c
(59.7 mg, 0.221 mmol) and n-BuLi (1.60 M in n-hexane, 0.15 mL, 0.24 mmol) gave, after purification
by silica-gel flash column chromatography (hexane/CH2Cl2/Et2O = 96/3/1→88/9/3), cycloadduct 11
(94.3 mg, 64.7%, ds. less polar/more polar = 52/48) and cycloadduct 13 as a mixture of diastereomers
(33.6 mg, 20.0%), respectively.
1,4-Dihydro-6,8,13,15-tetraphenyl-1,4:6,15:8,13-triepoxyhexacene (19). According to the procedure
described for the synthesis of cycloadduct 6a, cycloadduct 11 (less polar) (67.9 mg, 0.0933 mmol), furan 18
(65 mg, 0.96 mmol) and n-BuLi (1.63 M in n-hexane, 0.075 mL, 0.12 mmol) gave, after purification by
PTLC (hexane/CH2Cl2/acetone = 7/2/1), 1,4-dihydro-6,8,13,15-tetraphenyl-1,4:6,15:8,13-triepoxyhexacene
(19) as a mixture of diastereomers (42.3 mg, 66.6%).
Compound 19 (a mixture of two diastereomers): 1H-NMR (CDCl3, δ) 5.50 (s, 2H), 5.52 (s, 2H), 6.88 (s,
2H), 6.91 (s, 2H), 6.92–6.95 (m, 4H), 7.13 (s, 2H), 7.19 (s, 2H), 7.23 (dd, 2H, J1 = 2.9 Hz, J2 = 5.2 Hz),
7.26 (dd, 2H, J1 = 2.9 Hz, J2 = 5.2 Hz), 7.29 (s, 2H), 7.33 (s, 2H), 7.44–7.49 (m, 8H), 7.54–7.59 (m, 16H),
7.79–7.87 (m, 16H); 13C-NMR (CDCl3, δ) 82.2, 82.3, 90.47, 90.52, 113.40, 113.43, 113.6, 113.8, 120.2,
120.4, 125.6, 125.7, 126.5, 126.55, 126.60, 126.9, 128.3, 128.76, 128.81, 134.8, 134.9, 143.19, 143.22,
148.2, 148.3, 148.6, 148.8, 149.2, 149.5, 149.8, 150.0, 150.2; IR (ATR) 3062, 1602, 1499, 1308, 984,
848, 744, 700 cm−1; −HRMS (ESI) m/z 703.2233 (703.2249 calcd for C50H32NaO3, [M + Na]+).
2,3-Dibromo-5,7,12,14-tetraphenyl-5,14:7,12-diepoxypentacene (21). According to the procedure described
for the synthesis of cycloadduct 6a, 2,3,6,7-tetrabromo-9,10-diphenyl-9,10-epoxyanthracene (20, 110 mg,
0.166 mmol) and isobenzofuran 9c (49.5 mg, 0.183 mmol) and n-BuLi (1.63 M in n-hexane, 0.12 mL,
0.20 mmol) gave, after purification by silica-gel flash column chromatography (hexane/CH2Cl2/Et2O =
96/3/1→88/9/3), 2,3-dibromo-5,7,12,14-tetraphenyl-5,14:7,12-diepoxypentacene (21, 45.4 mg, 35.4%, ds.
less polar/more polar = 48/52) and 2,3-dibromo-5,7,12,14-tetraphenyl-5,14:7,12-diepoxypentacene (13)
as a mixture of diastereomers (35.0 mg, 23.9%), respectively.
Compound 21 (less polar): Rf 0.62 (hexane/toluene/CH2Cl2/Et2O = 82/10/6/2, X3); Mp decomposed at
1
250 °C (MeOH/CHCl3); H-NMR (CDCl3, δ) 6.96 (dd, 2H, J1 = 2.9 Hz, J2 = 5.2 Hz), 7.27 (dd, 2H,
J1 = 2.9 Hz, J2 = 5.2 Hz), 7.33 (s, 2H), 7.44 (s, 2H), 7.46–7.51 (m, 4H), 7.56–7.60 (m, 8H), 7.76–7.79
(m, 4H), 7.83–7.86 (m, 4H); 13C-NMR (CDCl3, δ) 90.2, 90.5, 113.7, 120.4, 121.7, 125.6, 125.8, 126.4,

Molecules 2015, 20
19459
126.6, 128.4, 128.7, 128.9, 129.0, 133.7, 134.6, 148.3, 149.9, 150.2, 151.4; IR (ATR) 3059, 1606, 1499,
1308, 1033, 984, 866, 743 cm−1; −HRMS (ESI) m/z 793.0333 (793.0354 calcd for C46H28Br2NaO2, [M + Na]+).
Compound 21 (more polar): Rf 0.52 (hexane/toluene/CH2Cl2/Et2O = 82/10/6/2, X3); Mp decomposed at
250 °C (MeOH/CHCl3); 1H-NMR (CDCl3, δ) 7.01 (dd, 2H, J1 = 2.9 Hz, J2 = 5.2 Hz), 7.31 (s, 2H), 7.33
(dd, 2H, J1 = 2.9 Hz, J2 = 5.2 Hz), 7.42–7.48 (m, 4H), 7.482 (s, 2H), 7.52–7.57 (m, 8H), 7.75–7.77
(m, 4H), 7.81–7.84 (m, 4H); 13C-NMR (CDCl3, δ) 90.2, 90.5, 113.5, 120.5, 121.7, 125.70, 125.74, 126.4,
126.6, 128.3, 128.7, 128.8, 129.0, 133.7, 134.7, 148.2, 150.0, 150.3, 151.7; IR (ATR) 3063, 1601, 1499,
1310, 1032, 983, 862, 745 cm−1; −HRMS (ESI) m/z 793.0361 (793.0354 calcd for C46H28Br2NaO2, [M + Na]+).
4. Conclusions
Site-selective halogen-lithium exchange of 1,2-dihaloarenes allowed for the successive generation
of benzynes and subsequent multiple [2+4] cycloadditions with various arynophiles to give highly
functionalized polycyclic compounds, which were amenable to selective transformation en route to
substituted polyacene derivatives. Further synthetic applications are under active investigation in
our laboratories.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/10/19449/s1.
Acknowledgments
This work was partially supported by the Grant-in-Aid for Scientific Research on Innovative
Areas 2707 Middle Molecular Strategy from MEXT, Japan, and ACT-C from the Japan Science and
Technology Agency.
Author Contributions
S.E. performed the experiments; S.E. and T.H. designed the experiments and wrote the paper.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Not available.
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