Synthesis of Biphenylenes and Their π-Extended Derivatives

Article abstract of DOI:10.1055/s-0039-1690750

A series of biphenylenes and their π-extended derivatives are easily prepared through tert -butyllithium-mediated cyclization of suitable halobiaryls and haloteraryls, respectively. The reactions proceed via the corresponding arynyl intermediates at low temperature (up to -20 °C).

Full text of DOI:10.1055/s-0039-1690750

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
synpacts
A
en
M.-L. Pan, Y.-T. Wu
Synpacts
Synlett
Synthesis of Biphenylenes and Their -Extended Derivatives
R1
Ming-Lun Pan
Yao-Ting Wu*
Li
tBuLi
–100 to –30 °C
E
E+
R2
X
Department of Chemistry, National Cheng Kung University,
No. 1 Ta-Hsueh Rd., 70101 Tainan, Taiwan
ytwuchem@mail.ncku.edu.tw
Li
X = Br or I
E = H, Bpin,
I, CHO
Received: 10.09.2019
Accepted after revision: 30.10.2019
Published online: 19.11.2019
DOI: 10.1055/s-0039-1690750; Art ID: st-2019-p0479-sp
Abstract A series of biphenylenes and their -extended derivatives are
easily prepared through tert-butyllithium-mediated cyclization of suitable
halobiaryls and haloteraryls, respectively. The reactions proceed via the
corresponding arynyl intermediates at low temperature (up to –20 °C).
Key words arynes, biphenylenes, organolithiums, [3]phenylenes
Biphenylene is a tricyclic arene with reduced aromatici-
ty, and the first synthetic example was documented around
80 years ago.1 The importance of biphenylene and its higher
homologs in fundamental science is clearly described in re-
cent reviews.2 Recent studies have also revealed that bi-
phenylene-based arenes exhibit interesting optical proper-
Ming-Lun Pan (left) was born in Taipei (Taiwan) in 1990. He received
his B.Sc. and M.Sc. degrees in chemistry from National Cheng Kung Uni-
versity. He is currently pursuing his doctoral studies at the same univer-
sity under the supervision of Prof. Yao-Ting Wu. His research is focused
on the design and synthesis of biphenylene-based polyarenes.
Yao-Ting Wu (right) received his B.Sc. in chemistry from National
Cheng Kung University in 1995. After two years of military service, he
studied chemistry at the University of Göttingen and obtained his di-
ploma (Dipl.-Chem.) in 2000 and his Ph.D. (Dr. rer. nat.) in 2003 under
the supervision of Prof. Armin de Meijere. After postdoctoral studies at
the University of Zurich (2004–2005) with Prof. Jay S. Siegel, he joined
his alma mater as an assistant professor. He was promoted to full pro-
fessor in 2011. His research interests concern metal-catalyzed reac-
tions, aromatic chemistry and organic materials.
I
I
[2+2]
Cu2O
SiMe3
SiMe3
I
II
Co cat.
[(2+2)+2]
M
M
+
or
III
IV
M
ties3a,b and are potentially applicable as organic semicon-
ductors.3c Some synthetic methods for biphenylene have
been developed, with representative examples including
the copper-mediated Ullman reaction of 2,2′-diiodobiphe-
nyl (Scheme 1, method I),1,4 the cyclodimerization of ben-
zyne (method II),5 the oxidative cyclization of 2,2′-dimetal-
labiphenyl (M = Li, Zn) or 9-metallafluorene (M = Zn, Hg;
method III),6 and the cobalt-catalyzed cycloaddition of o-
dialkynylbenzene with an alkyne (i.e., the Vollhardt reac-
tion; method IV).7
O
Ph
O
Ph
O
O
+
V
O
Ph
Ph
Ph
O
R
R =
Si(iPr)3
Br
Ph
R
The aromatization of the Diels–Alder adduct, generated
from a 3,4-bis(methylene)cyclobutene derivative and 1,4-
naphthoquinone, produces a biphenylene-based oligoacene
(method V).3a Biphenylene-based linear and angular pol-
yarenes can also be generated by the palladium-catalyzed
Pd cat.
PPTS
O
O
VI
Scheme 1 Synthesis of biphenylenes and their derivatives using con-
ventional protocols
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M.-L. Pan, Y.-T. Wu
Synpacts
Synlett
influenced by the solvent, the temperature, and the organo-
lithium reagent used. Their mechanisms of formation are as
follows. On treatment with an organolithium reagent, the
starting material 1a undergoes successive lithiations to
yield 4-chloro-2-fluoro-2′,3-dilithiobiphenyl (7), which cy-
clizes to give 2-chloro-1-lithiobiphenylene (9) via 2′,3′-di-
dehydro-2-lithiobiphenyl species 8. The desired product 4a
is obtained by the protonation of 9. The formation of the
by-product 2a is rationalized by autometallation,14 as some
of the initially generated 2′-lithio-4-chloro-2-fluorobiphe-
I
X2
(HO)2B
X2
Pd cat.
+
Br
Br X1
X1
X1, X2 = Cl, F, OMe
X1
X2
Br
1) nBuLi
Br
I
X4
nBuLi
X4
X1
X2
Br
X3
2)
I
Br
X4
X
4 = F, Cl
X3 = Br, OTf
Scheme 2 Preparation of biphenyls as starting materials
R2
Cl
R2
Cl
R1
R1
Br
F
X
A
A
annulation of bromobenzene with 1,4-dihydro-1,4-dimeth-
yl-1,4-epoxynaphthalene, followed by aromatization under
acidic conditions (method VI).8,9
R1
R2
R1
R2
R1
1i (R1 = R2 = F)
4i (83%)
4j (76%)
4k (76%)
4l (95%)
Mild reaction conditions can prevent the possible de-
composition of biphenylene, which is an activated arene
because it contains a four-membered ring.2a,10 Following
this concept, we recently designed a synthetic protocol that
can be used to easily prepare a series of biphenylenes and
their higher homologs through the organolithium-mediat-
ed cyclization of halobiaryls and haloteraryls via the corre-
sponding arynyl intermediates at a low temperature.11 The
starting biphenyls are obtained through the Suzuki reac-
tions of haloarenes with arylboronic acids12 or through the
coupling reactions of lithioarenes with o-dihalobenzenes13
(Scheme 2).
The organolithium-mediated cyclization of 2′-bromo-4-
chloro-2-fluorobiphenyl (1a) generated 2-chlorobiphenyl-
ene (4a), accompanied by 4-chloro-2-fluorobiphenyl (2a)
and tert-butyl-substituted 4-chlorobiphenyl 3a as by-prod-
ucts (Scheme 3). The ratio of these compounds is strongly
1a (R1 = R2 = H, X = Br)
1b (R1 = R2 = Me, X = Br)
1c (R1 = R2 = OMe, X = I)
4a (86%)
4b (85%)
4c (65%)
1j (R1 = F, R2 = Cl)
1k (R1 = F, R2 = OMe)
1l (R1 = F, R2 = C≡CPh)
1m (R1 = R2 = Cl)
1d (R1 = H, R2 = OMe, X = Br) 4d (83%)
4m (52%)
1e (R1 = H, R2 = F, X = Br)
4e (79%)
R
F
F
I
Cl
Br
B
X
A
R
R
1n (R = F)
1o (R = Cl)
4n (77%)
4o (86%)
R2
R1
R2
R1
1f (R1 = R2 = H, X = Br)
1g (R1 = R2 = Me, X = Br)
1h (R1 = R2 = OMe, X = I)
4f (63%)
4g (71%)
4h (65%)
R1
R1
R2
F
Cl
Cl
Br
R2
A
F
Br
A
62%
12a (R1= Cl, R2 = H)
12b (R1 = OMe, R2 = F)
13a (59%)
13b (97%)
Cl
Cl
Cl
Cl
10
11
tBu
F
OMe
1) conditions
2) MeOH
F
F
F
+
+
Br
A
Cl
F
80%
OMe
Br
4a
Li
1a
2a
3a
14
15
auto-
metalation
F
tBuLi or
nBuLi
1) tBuLi
2) MeOH
MeOH
MeOH
Cl
tBuLi or
nBuLi
H
Cl Cl
E
Cl
THF
H
Cl
Cl
1) B
1o
1) A
6
Li
1a
2) EX
2) CuCN
TMBQ
54%
Li
Cl
F
tBuLi
Et2O
iPrO-Bpin
I2, or DMF
F
Li
4o-Bpin (71%)
4o-I (81%)
4o-CHO (80%)
Li
16
Li
9
Conditions A: 1) tBuLi (3 equiv), Et2O, toluene, –100 to –30 or –20 °C; 2) MeOH
Conditions B: 1) tBuLi (4 equiv), THF, toluene, –78 to –30 °C; 2) MeOH
5
7
8
Scheme 3 Synthesis of biphenylene 4a from biphenyl 1a and its mech-
Scheme 4 Preparation of biphenylenes and their -extended deriva-
anism of formation
tives
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
M.-L. Pan, Y.-T. Wu
Synpacts
Synlett
nyl (5) is immediately converted into 4-chloro-2-fluoro-3-
lithiobiphenyl (6) through the extraction of the most acidic
proton at the C-3 position in 5. This problem is resolved by
using diethyl ether as the solvent and tert-butyllithium as
the organolithium reagent, as well as by conducting the re-
action at a very low temperature (–100 °C). The formation
of by-product 3a can be reduced through treatment with a
suitable amount of tert-butyllithium. The highly selective
formation of 4a was achieved under the optimized condi-
tions (conditions A in Scheme 4) by conducting the reaction
using tert-butyllithium (3.0 equiv) at –100 °C first, then
adding the co-solvent toluene at –78 °C, and finally warm-
ing to –50 °C, resulting in excellent product distribution
(2a:3a:4a = 0:11:89 based on GC–MS analysis) and isolated
yields of 86% and 83% on scales of 1 mmol and 5 mmol, re-
spectively.
Scheme 4 reveals that suitable precursors for bi-
phenylenes can be 1,2,2′-trihalobiphenylenes or 4-substi-
tuted 2,2′-dihalobiphenyls, where the substituent is me-
thoxy, halogen, or phenylethynyl. Under the optimized con-
ditions (conditions A), these precursors can yield the
corresponding biphenylenes 4a–m in moderate to excellent
yields (52–95%). 2′-Bromo-3-halo-2-iodobiphenyls 1n and
1o are also ideal starting materials for the synthesis of 1-
halobiphenylenes 4n and 4o, respectively, but the cycliza-
tion must be performed in THF (conditions B). In contrast to
the aforementioned examples, 2′-bromo-4-(4-tolylsulfonyl-
oxy)-2-fluorobiphenyl, 2′-bromo-4-(trifluoromethylsulfo-
nyloxy)-2-fluorobiphenyl and 2,3,2′-tribromo-4-trimethyl-
silylbiphenyl cannot effectively generate the desired bi-
phenylenes (<10% yields). This protocol can also be applied
for the preparation of -extended benzobiphenylenes de-
rivatives 11 and 13 and dibenzobiphenylene 15 from the
corresponding biaryls. Bibiphenylene 16 can be straightfor-
wardly obtained in a yield of 54% from biphenyl 1a through
the copper-mediated dimerization of the intermediate 2-
chloro-1-lithiobiphenyl (9).15 One-pot syntheses of 1-sub-
stituted biphenylenes 4o-E can be performed through the
cyclization of biphenyl 1o under conditions B and subse-
quent treatment with an electrophilic reagent, including
isopropoxyboronic acid pinacol ester (iPrO-Bpin), iodine, or
DMF. Notably, 1,5-diiodobiphenylene, a useful building
block for the synthesis of biphenylene-fused polyarenes,
can be prepared in similar manner from 2,6,3′-tribromo-2′-
iodobiphenyl.16
Higher biphenylenyl homologs, such as linear
[3]phenylenes 18 and 20 and biphenyleno[2,3-b]biphenyl-
ene 22, can also be regioselectively generated from the cor-
responding teraryls through two independent cyclization
processes (Scheme 5). Hart and Saednya demonstrated that
R
R
Br
Br
F
F
Cl
Cl
C
Cl
Cl
18 (R= H, 81%)
18-Bpin (R = Bpin, 60%)
17
R
Br
F
Cl
C
Cl
Cl
Cl
F
Br
20 (R = H, 72%)
20-Bpin (R = Bpin, 55%)
R
19
R
R
Br
Br
F
F
Cl
Cl
C
21
Cl
Cl
22 (R = H, 70%)
22-Bpin (R = Bpin, 64%)
F
F
C
92%
Br
Br
F
F
24
23
Conditions C: 1) tBuLi (6 equiv), Et2O, toluene, –100 to –30 or –20 °C
2) MeOH or iPrO-Bpin
1) tBuLi (6.0 equiv)
THF, toluene
–110 to –30 °C
Cl
Cl
2) MeOH or I2
X
Br
Br F
27-R
27 (R = H, 60% from 25;
0% from 26)
27-I (R = I, 60% from 25)
Cl
R
Cl
25 (X = Br)
26 (X = F)
Scheme 5 Synthesis of [3]phenylenes and their -extended derivatives
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
M.-L. Pan, Y.-T. Wu
Synpacts
Synlett
the reaction of 1,3-dichlorobenzene with phenyllithium
yields 1,3-diphenylbenzene.17 Following this concept, 1,3-
diaryl-2,4,6-trifluorobenzene 23 can be efficiently convert-
ed into 5-fluoro[3]phenylene (24).
References and Notes
(1) Lothrop, W. C. J. Am. Chem. Soc. 1941, 63, 1187.
(2) For selected reviews on biphenylenes, see: (a) Takano, H.; Ito, T.;
Kanyiva, K. S.; Shibata, T. Eur. J. Org. Chem. 2019, 2871.
(b) Toyota, S. Science of Synthesis, Vol. 45b; Siegel, J. S.; Tobe, Y.,
Ed.; Thieme: Stuttgart, 2010, 855. (c) Miljanič, O. Š.; Vollhardt,
K. P. C. In Carbon-Rich Compounds: From Molecules to Materials;
Haley, M. M.; Tykwinski, R. R., Ed.; Wiley-VCH: Weinheim, 2006,
140.
(3) (a) Parkhurst, R. R.; Swager, T. M. J. Am. Chem. Soc. 2012, 134,
15351. (b) Fukazawa, A.; Oshima, H.; Shiota, Y.; Takahashi, S.;
Yoshizawa, K.; Yamaguchi, S. J. Am. Chem. Soc. 2013, 135, 1731.
(c) Wang, J.; Chu, M.; Fan, J.-X.; Lau, T.-K.; Ren, A.-M.; Lu, X.;
Miao, Q. J. Am. Chem. Soc. 2019, 141, 3589.
Angular [3]phenylene 27 can be prepared from teraryl
25, but not from 26 (Scheme 5), revealing that their o-di-
bromoaryl moieties should be regarded as arynes, rather
than o-dilithioarenes,18 after treatment with tert-butyllithi-
um. This reaction is strongly favored when THF is used as
the solvent and generates 27 and 27-I in yields of 60%.
Cyclodimerization of tetrahalo-substituted angular
[3]phenylene, i.e., 1,2,9,10-tetrahalobenzo[3,4]cyclobu-
ta[1,2-a]biphenylene, provides the possibility en route to
antikekulene (Scheme 6). Compound 29 could be a suitable
precursor for the synthetic approach. In our previous stud-
ies, an attempt was made to synthesize 29 by treating 27-I
with LDA (ca. 2.5 equiv) and chlorotrimethylsilane (3.0
equiv). However, 28 was furnished as the major product,
along with mono- and tris(trimethylsilyl)-substituted by-
products. The structure of 28 has been verified by X-ray
crystallography,19 but the details of the mechanism for its
formation remain unclear.20
(4) For a review, see: Nelson, T. D.; Crouch, R. D. Org. React. 2004,
63, 265.
(5) For selected examples, see: (a) Schlütter, F.; Nishiuchi, T.;
Enkelmann, V.; Müllen, K. Angew. Chem. Int. Ed. 2014, 53, 1538.
(b) Lu, J.; Zhang, J.; Shen, X.; Ho, D. M.; Pascal, R. A. Jr. J. Am.
Chem. Soc. 2002, 124, 8035. (c) Campbell, C. D.; Rees, C. W.
J. Chem. Soc. C 1969, 742.
(6) (a) Iyoda, M.; Kabir, S. M. H.; Vorashinga, A.; Kuwatani, Y.;
Yoshida, M. Tetrahedron Lett. 1998, 39, 5393. (b) Wittig, G.;
Herwig, W. Chem. Ber. 1954, 87, 1511. (c) Schaub, T.; Radius, U.
Tetrahedron Lett. 2005, 46, 8195. (d) Kabir, S. M. H.; Hasegawa,
M.; Kuwatani, Y.; Yoshida, M.; Matsuyama, H.; Iyoda, M. J. Chem.
Soc., Perkin Trans. 1 2001, 159.
I
LDA
(7) (a) Berris, B. C.; Lai, Y.-H.; Vollhardt, K. P. C. J. Chem. Soc., Chem.
Commun. 1982, 953. (b) Berris, B. C.; Hovakeemian, G. H.; Lai, Y.-
H.; Mestdagh, H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1985, 107,
5670.
SiMe3Cl
SiMe3
THF
–78 °C
Cl
I
Cl
Cl
Me3Si
28
Cl
27-I
30%
(8) Jin, Z.; Teo, Y. C.; Zulaybar, N. G.; Smith, M. D.; Xia, Y. J. Am.
Chem. Soc. 2017, 139, 1806.
(9) For other synthetic approaches reported recently, see: ref. 2b
and Nobusue, S.; Shimizu, A.; Hori, K.; Hisaki, I.; Miyata, M.;
Tobe, Y. Angew. Chem. Int. Ed. 2013, 52, 4184.
R1
R2
(10) (a) Gu, Z.; Boursalian, G. B.; Gandon, V.; Padilla, R.; Shen, H.;
Timofeeva, T. V.; Tongwa, P.; Vollhardt, K. P. C.; Yakovenko, A. A.
Angew. Chem. Int. Ed. 2011, 50, 9413. (b) Eisch, J. J.; Piotrowski,
A. M.; Han, K. I.; Krü ger, C.; Tsay, Y. H. Organometallics 1985, 4,
224.
Cl
SiMe3
29 (R1 or R2 = SiMe3)
I
Cl
antikekulene
(11) Wang, S.-L.; Pan, M.-L.; Su, W.-S.; Wu, Y.-T. Angew. Chem. Int. Ed.
2017, 56, 14694.
Scheme 6 Synthesis of angular [3]phenylenes 28
(12) For reviews, see: (a) Miyaura, N. In Metal-Catalyzed Cross-Cou-
pling Reactions; Diederich, F.; de Meijere, A., Ed.; Wiley-VCH:
New York, 2004, 41. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457.
(13) Leroux, F. R.; Bonnafoux, L.; Heiss, C.; Colobert, F.; Lanfranchi, D.
A. Adv. Synth. Catal. 2007, 349, 2705.
(14) (a) Bridges, A. J.; Patt, W. C.; Stickney, T. M. J. Org. Chem. 1990,
55, 773. (b) Coe, P. L.; Waring, A. J.; Yarwood, T. D. J. Chem. Soc.,
Perkin Trans. 1 1995, 2729.
(15) (a) Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. J. Am. Chem. Soc.
1981, 103, 7672. (b) Miyake, Y.; Wu, M.; Rahman, M. J.; Iyoda,
M. Chem. Commun. 2005, 411.
In summary, biphenylene and its derivatives can be eas-
ily and efficiently obtained at a low temperature through
the organolithium-mediated cyclization of halobiaryls or
haloterphenyls via an aryne intermediate. Biphenylene and
its derivatives presented in this article are useful building
blocks for biphenylene-fused polyarenes but are not ideal
precursors for antikekulene. Investigations on a suitable
synthetic approach to this ‘holy-grail’ compound are cur-
rently underway.
(16) Pan, M.-L.; Hung, H.-Y.; Wu, Y.-T. unpublished results.
(17) Saednya, A.; Hart, H. Synthesis 1996, 1455.
(18) (a) Durka, K.; Luliński, S.; Dąbrowski, M.; Serwatowski, J. Eur.
J. Org. Chem. 2014, 4562. (b) Hart, H.; Lai, C.-Y.; Nwokogu, G.;
Shamouilian, S.; Teuerstein, A.; Zlotogorski, C. J. Am. Chem. Soc.
1980, 102, 6649.
Funding Information
This work was supported by the Ministry of Science and Technology
of Taiwan (MOST 107-2113-M-006-013-MY3).
M
i
n
i
stryof
S
c
i
e
n
c
e
a
n
d
T
e
c
h
n
o
l
o
g
y
,
T
a
i
w
a
n
(M
O
S
T
1
0
7-2
1
1
3-M-0
0
6-0
1
3-M
Y
3)
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

E
M.-L. Pan, Y.-T. Wu
Synpacts
Synlett
(19) CCDC 11558654 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
(20) The iodine migration on an arene has been reported, see:
(a) Rausis, T.; Schlosser, M. Eur. J. Org. Chem. 2002, 3351.
(b) Heiss, C.; Marzi, E.; Schlosser, M. Eur. J. Org. Chem. 2003,
4625.
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E