Dibromoisobenzofuran as a formal equivalent of didehydroisobenzofuran: Reactive platform for expeditious assembly of polycycles

Article abstract of DOI:10.1021/ol4032792

Two-directional annulation of dibromoisobenzofuran, a formal equivalent to didehydroisobenzofuran, was developed. Importantly, selective bromine-lithium exchange allows the tandem generation of benzynes and dual cycloadditions with two different arynophiles. Also described is the application to the synthesis of a substituted pentacene.

Full text of DOI:10.1021/ol4032792

Letter
pubs.acs.org/OrgLett
Dibromoisobenzofuran as a Formal Equivalent of
Didehydroisobenzofuran: Reactive Platform for Expeditious
Assembly of Polycycles
Hiroshi Haneda,† Shohei Eda,† Masato Aratani,† and Toshiyuki Hamura*,†,‡
†Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337,
Japan
‡Japan Science and Technology Agency, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
ABSTRACT: Two-directional annulation of dibromoisobenzo-
furan, a formal equivalent to didehydroisobenzofuran, was
developed. Importantly, selective bromine−lithium exchange
allows the tandem generation of benzynes and dual cycloadditions
with two different arynophiles. Also described is the application to
the synthesis of a substituted pentacene.
sobenzofurans are 10π electron systems with quinoid
Scheme 2. Formal Use of Didehydroisobenzofuran by Dual
[2 + 4] Cycloadditions of Benzyne and Isobenzofuran
I
structures, which makes them useful intermediates for
various natural/unnatural product syntheses.1 Among various
possibilities, [4 + 2] cycloaddition with dienophiles is a reliable
method for the construction of a polycyclic structure.2
However, isobenzofuran I having no substituent at the C1
and C3 positions is unstable and regarded as a transient
intermediate with a few exceptions, which has limited the
availability of this attractive molecule.3,4
In our ongoing study on developing the synthetic utility of
the reactive molecules,5 we came up with an idea to use a
donor−acceptor molecule, having electron-donating and electron-
withdrawing moieties in one molecule, enabling the rapid
introduction of the fused rings onto the central core ring. In
particular, we are intrigued by the use of a formal equivalent to
didehydroisobenzofuran II, possessing a highly strained 1,2-
didehydroarene structure at the C5−C6 position in I, as it could
serve as a reactive platform for expeditious assembly of
polycycles by two directional annulations (Scheme 1).
Herein, we disclose dual annulations of dibromoisobenzofur-
an V, a formal equivalent of didehydroisobenzofuran II, via
successive [2 + 4] cycloadditions of benzyne6 and isobenzofur-
an (Scheme 2). Importantly, selective bromine−lithium
exchange from two dibromides IV and V enables the tandem
generation of benzynes and dual cycloadditions with two
different arynophiles (step 1 and step 2). The first [4 + 2]
cycloaddition of dibromoisobenzofuran V and benzyne A,
selectively generated from dibromobenzene IV, gives tetracyclic
compound VI, which, in turn, serves as a benzyne donor,
leading to the selective generation of benzyne B. Second [2 +
4] cycloaddition of benzyne B and isobenzofuran I gives
polycyclic compound VII.
The essential point of this integrated synthesis7 is isolability of
dibromoisobenzofuran V, which would provide great oppor-
tunities to use these potentially attractive molecules under
various reaction conditions.
Scheme 1. Two-Directional Annulations of
Didehydroisobenzofuran II
Scheme 3 shows the preparation of dibromoisobenzofuran.
Upon heating of epoxynaphthalene 1a8 with 3,6-di(2-pyridyl)-
1,2,4,5-tetrazine (2) in chloroform at 50 °C,3a the starting
Received: November 14, 2013
Published: December 5, 2013
© 2013 American Chemical Society
286
dx.doi.org/10.1021/ol4032792 | Org. Lett. 2014, 16, 286−289

Organic Letters
Letter
This successive process can be performed in one pot by
sequential addition of the arynophiles (Table 1). When the
Scheme 3. Preparation of Dibromoisobenzofuran
Table 1. One-Pot Dual [4 + 2] Cycloadditions
material was cleanly consumed. Purification by silica-gel column
chromatography under Ar atmosphere gave 3a in 60% yield as
white solids,9 which can be stored under Ar atmosphere in a
refrigerator for several months. Similarly, 5,6-dibromo-1,3-
diphenylisobenzofuran (3b) was prepared from epoxynaph-
thalene 1b.
Scheme 4 shows the initial model study for the first [4 + 2]
cycloaddition. When dibromobenzene 4 was treated with 1.0
Scheme 4. Initial Model Study on the Selective Generation
of Benzyne
a
b
c
equiv of n-BuLi in the presence of dibromoisobenzofuran 3a
(1.0 equiv, toluene, −15 → 25 °C), cycloadduct 5 was obtained
in 18% yield. A sizable amount of bis-cycloadduct 6 (25%) was
also produced. Although the difference in reactivity is not easily
expected, this result indicates the order of the reactivity among
the three dibromides, 4 ≈ 5 > 3a, which caused the competitive
second benzyne generation from monocycloadduct 5. In this
case, however, excess amounts of the starting material 4 (5.0
equiv) improved the yields of the monocycloadduct 5 (42%).
Further investigation revealed that introduction of the
electron-deficient fluoro group on the aromatic ring achieved
selective benzyne generation (Scheme 5). Upon treatment of
In toluene. In chlorobenzene. n-BuLi was used for the first
d e
cycloaddition. PhLi was used for the first cycloaddition. n-BuLi was
used for the second cycloaddition. PhLi was used for the second
cycloaddition.
f
above-mentioned first cycloaddition was conducted under the
same reaction conditions, the formation of the monocycload-
duct 8 was observed by TLC. The second arynophile, furan in
toluene, was added to the reaction mixture at −15 °C, to which
was slowly added n-BuLi and the temperature raised to 25 °C,
giving hexacycle 10 in 44% yield (entry 1). The dual reactions
with isobenzofuran 3b (the first arynophile) and isobenzofuran
3c (the second arynophile) also gave cycloadduct 11 (entry 2).
Similarly, the successive [2 + 4] cycloadditions with
isobenzofurans 3b and 3d gave the highly fluorinated
cycloadduct 12 in 62% yield (entry 3). The successive
processes also proved to be applicable to 1,2-dibromo-4,5-
dichlorobenzene (7b), selectively affording heptacycle 13 in
44% yield (entry 4).
Scheme 5. Successive [2 + 4] Cycloadditions of Benzyne and
Isobenzofuran
It is worth mentioning that 1,2,4,5-tetrabromobenzene (7c)
nicely worked as a reactive platform,10 allowing the 3-fold
cycloaditions in one pot (Scheme 6). The key of this process is
the selective bromine−lithium exchange of tetrabromobenzene
7c, cleanly generating the dibromobenzyne C, which was
Scheme 6. Two-Directional 3-Fold [4 + 2] Cycloadditions
1,2-dibromo-4,5-difluorobenzene (7a) with 1.1 equiv of PhLi in
the presence of 3a (1.2 equiv, toluene, −15 → 25 °C), 4,5-
difluorobenzyne was selectively generated to give monocy-
cloadduct 10 as almost the exclusive product in 66% yield. In
this case, PhLi was effective as a benzyne initiator in
comparison with n-BuLi (8: 49% yield). The cycloadduct 8,
thus obtained, can be used for the second cycloaddition:
treatment of 8 with 1.1 equiv of n-BuLi in the presence of furan
(2.7 equiv, toluene, −15 → 25 °C) gave the bis-cycloadduct 10
in 79% yield as a mixture of stereoisomers.
287
dx.doi.org/10.1021/ol4032792 | Org. Lett. 2014, 16, 286−289

Organic Letters
Letter
intercepted by 3b to afford the cycloadduct 14.11 The
tetrabromoarene 14, produced by the first cycloaddition, can
be viewed as a bis-aryne equivalent. Indeed, dual [2 + 4]
cycloadditions of bis-aryne D by treatment of 14 with n-BuLi in
the presence of furan gave bis-cycloadduct 15 as a mixture of
diastereomers. The stereochemistry of the bis-cycloadducts was
not determined. More importantly, the successive three ring
constructions could be carried out in one pot, affording the 3-
fold cycloadduct 15 with high synthetic utility.
REFERENCES
■
(1) (a) Patil, A. O.; Heeger, A. J.; Wudl, F. Chem. Rev. 1988, 88, 183.
(b) Roncali, J. Chem. Rev. 1997, 97, 173. (c) Friedrichsen, W. Adv.
Heterocyl. Chem. 1980, 26, 135. (d) Friedrichsen, W. Adv. Heterocyl.
Chem. 1999, 73, 1.
(2) For selective examples, see: (a) Binger, P.; Wedemann, P.;
Goddard, R.; Brinker, U. H. J. Org. Chem. 1996, 61, 6462. (b) Rodrigo,
R. Tetrahedron 1988, 44, 2093. (c) Wong, H. N. C. Acc. Chem. Res.
1989, 22, 145. (d) Man, Y.-M.; Mak, T. C. W.; Wong, H. N. C. J. Org.
Chem. 1990, 55, 3214. (e) Chan, S.-H.; Yick, C.-Y.; Wong, H. N. C.
Tetrahedron 2002, 58, 9413. (f) Rainbolt, J. E.; Miller, G. P. J. Org.
Chem. 2007, 72, 3020.
Scheme 7 shows one of the synthetic transformations of the
cycloadduct 15 into a substituted pentacene. When cycloadduct
(3) (a) Warrener, R. N. J. Am. Chem. Soc. 1971, 93, 2346.
(b) Warrener, R. N.; Shang, M.; Butler, D. N. Chem. Commun. 2001,
1550. (c) Sygula, A.; Sygula, R.; Rabideau, P. W. Org. Lett. 2006, 8,
5909. (d) Pei, B. J.; Chan, W. H.; Lee, A. W. M. Org. Lett. 2011, 13,
1774.
Scheme 7. Dual [4 + 2] Cycloaddition of Bis-isobenzofuran
into the Substituted Pentacene
(4) Recently, we developed one-pot synthetic method of 1,3-
diarylisobenzofurans by sequential reaction of methyl 2-formylben-
zoate with two identical or different aryl metal species; see: Hamura,
T.; Nakayama, R. Chem. Lett. 2013, 42, 1013.
(5) Hamura, T.; Chuda, Y.; Nakatsuji, Y.; Suzuki, K. Angew. Chem.,
Int. Ed. 2012, 51, 3368.
(6) For selected reviews on arynes, see: (a) Hoffmann, R. W.
Dehydrobenzene and Cycloalkynes; Academic Press: New York, 1967.
(b) Kessar, S. V. In Comprehensive Organic Synthesis; Trost, B. M., Ed.,
Pergamon: Oxford, U.K., 1991; Vol. 4, pp 483−515. (c) Pellissier, H.;
Santelli, M. Tetrahedron 2003, 59, 701. (d) Wenk, H. H.; Winkler, M.;
Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502. (e) Yoshida, H.;
Takaki, K. Synlett 2012, 23, 1725. (f) Bhunia, A.; Yetra, S.; Biju, R. A.
T. Chem. Soc. Rev. 2012, 41, 3140. (g) Dubrovskiy, A. V.; Markina, N.
A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191.
15 was heated in chloroform at 60 °C with tetrazine 2 and
dimethyl maleate, the dual [4 + 2] cycloadditions of bis-
isobenzofuran E12 occurred cleanly to give bis-cycloadduct 16
in 58% yield. Bis-isobenzofuran E is synthetically useful in that
the rapid introduction of the fused rings and/or functionaliza-
tion onto the isobenzofuran nucleus would be possible through
the dual cycloadditions. Subsequent acid catalyzed aromatiza-
tion cleanly occurred by treatment of 16 with H2SO4 in toluene
at 25 °C. Purification of the crude products by silica gel column
chromatography gave substituted pentacene 17 in 71% yield as
blue solids.13−15 The structure of 1713m was determined by X-
ray analysis.16
In summary, dual cycloadditions of didehydroisobenzofuran
equivalent with various arynophiles allowed rapid construction
of highly functionalized bis-cycloadducts, which were amenable
to selective transformation en route to substituted pentacene
derivatives. Further synthetic applications are under active
investigation in our laboratories.
(7) For integration of reactions, see: Suga, S.; Yamada, D.; Yoshida,
J.-i. Chem. Lett. 2010, 39, 404.
(8) For preparation, see the Supporting Information.
(9) It is important to protect isobenzofuran from oxygen. If not,
isobenzofuran 3a was gradually oxidized in solution to give 4,5-
dibromophthalaldehyde. Moreover, the parent isobenzofuran I was
purified by silica gel column chromatography under Ar atmosphere,
and a deoxygenated solution of I could be stored in a refrigerator for a
several hours. Stability and reactivity of 5,6-disubstituted isobenzofur-
ans are now in progress, which will be reported in a full paper.
(10) Tetrabromobenzene 7c can serve as a 1,4-benzdiyne equivalent.
For pioneering studies by Hart on the generation and trapping of 1,4-
benzdiyne equivalents, see: (a) Hart, H.; Ok, D. J. Org. Chem. 1986,
51, 979. (b) Hart, H.; Lai, C.-Y.; Nwokogu, G.; Shamouilian, S.;
Teuerstein, A.; Zlotogorski, C. J. Am. Chem. Soc. 1980, 102, 6649. For
other examples, see: (c) Chen, Y.-L.; Sun, J.-Q.; Wei, X.; Wong, W.-
W.; Lee, A. W. M. J. Org. Chem. 2004, 69, 7190. (d) Morton, G. E.;
Barrett, A. G. M. J. Org. Chem. 2005, 70, 3525. (e) Schuster, I. I.;
Cracium, L.; Ho, D. M.; Pascal, R. A., Jr. Tetrahedron 2002, 58, 8875.
(f) Duong, H. M.; Bendikov, M.; Steiger, D.; Zhang, Q.; Sonmez, G.;
Yamada, J.; Wudl, F. Org. Lett. 2003, 5, 4433. (g) Hamura, T.; Arisawa,
T.; Matsumoto, T.; Suzuki, K. Angew. Chem., Int. Ed. 2006, 45, 6842.
(11) This site selectivity in the bromine−lithium exchange is due to
the electron withdrawal of the four bromo atoms in 7c, which leads to
the selective generation of tribromophenyllithium. Subsequent
elimination of lithium bromide from this intermediate produced
dibromobenzyne C.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: thamura@kwansei.ac.jp.
Notes
(12) (a) Christopfel, W. C.; Miller, L. L. J. Org. Chem. 1986, 51,
4169. (b) Chiba, T.; Kenny, P. W.; Miller, L. L. J. Org. Chem. 1987, 52,
4327.
(13) For selected reports on synthesis of 6,13-disubstituted
pentacenes, see: (a) Anthony, J. E.; Brooks, J. S.; Eaton, D. L.;
Parkin, S. R. J. Am. Chem. Soc. 2001, 123, 9482. (b) Payne, M. M.;
Delcamp, J. H.; Parkin, S. R.; Anthony, J. E. Org. Lett. 2004, 6, 1609.
(c) Swartz, C. R.; Parkin, S. R.; Bullock, J. E.; Anthony, J. E.; Mayer, A.
C.; Malliaras, G. G. Org. Lett. 2005, 7, 3163. (d) Miao, Q.; Chi, X.;
Xiao, S.; Zeis, R.; Lefenfeld, M.; Siegrist, T.; Steigerwald, M. L.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research on Innovative Areas: “Organic Synthesis
Based on Reaction Integration” from MEXT, Japan, and ACT-
C from Japan Science and Technology Agency. We thank Prof.
Hidehiro Uekusa (Tokyo Institute of Technology) for X-ray
analysis.
288
dx.doi.org/10.1021/ol4032792 | Org. Lett. 2014, 16, 286−289

Organic Letters
Letter
Nuckolls, C. J. Am. Chem. Soc. 2006, 128, 1340. (e) Ono, K.; Totani,
H.; Hiei, T.; Yoshino, A.; Saito, K.; Eguchi, K.; Tomura, M.; Nishida,
J.; Yamashita, Y. Tetrahedron 2007, 63, 9699. (f) Palayangoda, S. S.;
Mondal, R.; Shah, B. K.; Neckers, D. C. J. Org. Chem. 2007, 72, 6584.
(g) Wang, Y.; Fu, N.; Chan, S.; Lee, H.; Wong, H. N. C. Tetrahedron
2007, 63, 8586. (h) Lehnherr, D.; McDonald, R.; Tykwinski, R. R. Org.
Lett. 2008, 10, 4163. (i) Lehnherr, D.; Murray, A. H.; McDonald, R.;
Ferguson, M. J.; Tykwinski, R. R. Chem.Eur. J. 2009, 15, 12580.
(j) Kaur, I.; Jia, W.; Kopreski, R. P.; Selvarasah, S.; Dokmeci, M. R.;
Pramanik, C.; McGruer, N. E.; Miller, G. P. J. Am. Chem. Soc. 2008,
130, 16274. (k) Wang, J.; Liu, K.; Liu, Y.; Song, C.; Shi, Z.; Peng, J.;
Zhang, H.; Cao, X. Org. Lett. 2009, 11, 2563. (l) Tang, M. L.; Oh, J.
H.; Reichardt, A. D.; Bao, Z. J. Am. Chem. Soc. 2009, 131, 3733.
(m) Li, S.; Zhou, L.; Nakajima, K.; Kanno, K.; Takahashi, T. Chem.
Asian J. 2010, 5, 1620.
(14) For selected reviews on pentacenes, see: (a) Bendikov, M.;
Wudl, F.; Perepichka, D. F. Chem. Rev. 2004, 104, 4891. (b) Anthony,
J. E. Chem. Rev. 2006, 106, 5028. (c) Anthony, J. E. Angew. Chem.
2008, 120, 460; Angew. Chem., Int. Ed. 2008, 47, 452. (d) Bettinger, H.
F. Pure Appl. Chem. 2010, 82, 905.
(15) Cycloadducts 11−13 could also be converted to the
corresponding 5,7,12,14-tetraphenylpentacene derivatives under the
suitable conditions. Experimental details and physical properties of
these compounds will be reported in due course.
(16) For details, see the Supporting Information.
289
dx.doi.org/10.1021/ol4032792 | Org. Lett. 2014, 16, 286−289