Synthesis of polycyclic aromatic iodides via ICI-induced intramolecular cyclization

Article abstract of DOI:10.1021/ol049161o

The reaction of 2-(arylethynyl)biphenyls with ICI at -78°C affords substituted polycyclic aromatic iodides in good to excellent yields. The aryl substituents can be either electron-donating or electron-withdrawing groups such as OMe, Me, CHO, CO₂Et or NO₂ groups. This chemistry has been successfully extended to systems containing a variety of polycyclic and heterocyclic rings.

Full text of DOI:10.1021/ol049161o

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2677-2680
Synthesis of Polycyclic Aromatic
Iodides via ICl-Induced Intramolecular
Cyclization
Tuanli Yao, Marino A. Campo, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received May 8, 2004
ABSTRACT
The reaction of 2-(arylethynyl)biphenyls with ICl at −78 °C affords substituted polycyclic aromatic iodides in good to excellent yields. The aryl
substituents can be either electron-donating or electron-withdrawing groups such as OMe, Me, CHO, CO Et or NO groups. This chemistry has
2
2
been successfully extended to systems containing a variety of polycyclic and heterocyclic rings.
Polycyclic aromatic iodides are very useful starting materials
in organic synthesis, particularly for palladium-catalyzed
annulation,1 cyclization,2 and carbonylation.3 They can also
be used as rigid molecular platforms critical to advances in
various areas of chemical research such as host-guest
chemistry,4 liquid crystal chemistry,5 and even biochemical
studies of synthetic peptides.6
p-alkoxy group on the phenylethynyl moiety was apparently
critical to the success of that methodology.
One possible approach to these compounds is electrophile-
induced, intramolecular acetylene cyclization. However, only
a very few iodonium-induced carbocyclization examples of
this type are known.7 Thus, Swager8 and Barluenga9 have
reported the electrophilic cyclization of acetylenic arenes
utilizing I(py)2BF4 (eq 1). Unfortunately, the presence of a
Recent success in the synthesis of iodides of benzo[b]-
thiophenes,10 benzofurans,11 isoquinolines and naph-
thyridines,12 isocoumarins and R-pyrones,13 furans,14 carbon-
(1) For reviews, see: (a) Larock, R. C. J. Organomet. Chem. 1999, 576,
111. (b) Larock, R. C. In Palladium-Catalyzed Annulation In PerspectiVes
in Organopalladium Chemistry for the XXI Century; Tsuji, J., Ed.; Elsevier
Press: Lausanne, Switzerland, 1999; pp 111-124. (c) Larock, R. C. Pure
Appl. Chem. 1999, 71, 1435. (d) Larock, R. C.; Doty, M. J.; Tian, Q.;
Zenner, J. M. J. Org. Chem. 1997, 62, 7536. (e) Larock, R. C.; Tian, Q. J.
Org. Chem. 1998, 63, 2002.
(4) (a) Cram, D. J. Nature 1992, 356, 29. (b) Schwartz, E. B.; Knobler,
C. B.; Cram, D. J. J. Am. Chem. Soc. 1992, 114, 10775. (c) Dijkstra, P. J.;
Skowronska-Ptasinska, M.; Reinhoudt, D. N.; Den Hertog, H. J.; Van
Eerden, J.; Harkema, S.; De Zeeuw, D. J. Org. Chem. 1987, 52, 4913.
(5) (a) Chandrasekhar, S. AdVances in Liquid Crystals; Academic
Press: New York, 1982; Vol. 5, p 47. (b) Chandrasekhar, S.; Ranganath,
G. S. Rep. Prog. Phys. 1990, 53, 57. (c) Praefcke, K.; Kohne, B.; Singer,
D. Angew. Chem., Int. Ed. Engl. 1990, 29, 177.
(6) (a) Veber, D. F.; Strachan, R. G.; Bergstrand, S. J.; Holly, F. W.;
Homnick, C. F.; Hirschmann, R.; Torchiana, M. L.; Saperstein, R. J. Am.
Chem. Soc. 1976, 98, 2367. (b) Tsang, K. Y.; Diaz, H.; Graciani, N.; Kelley,
J. W. J. Am. Chem. Soc. 1994, 116, 3988.
(2) Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons:
Chichester, 1999.
(3) (a) Campo, M. A.; Larock, R. C. Org. Lett. 2000, 2, 3675. (b) Arcadi,
A.; Cacchi, S.; Fabrizi, G.; Moro, L. Eur. J. Org. Chem. 1999, 1137. (c)
Cacchi, S.; Fabrizi, G.; Pace, P.; Marinelli, F. Synlett 1999, 5, 620. (d)
Arcadi, A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron 1994, 50,
437. (e) Arcadi, A.; Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F.
J. Org. Chem. 1996, 61, 9280. (f) Campo, M. A.; Larock, R. C. J. Org.
Chem. 2002, 67, 5616.
10.1021/ol049161o CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/03/2004

ates,15 pyrroles,16 â-lactams,17 indoles,18 naphthalenes,19
isochromenes,20 and phosphaisocoumarins21 by the electro-
philic cyclization of alkynes using ICl and I2 has prompted
us to try to develop a more general methodology for the
synthesis of polycyclic aromatic iodides. Herein, we report
a versatile method for the synthesis of polycyclic aromatic
iodides in high yields under mild reaction conditions using
simple arene-containing acetylenes and ICl. This chemistry
employs ICl, which is more economical and convenient to
handle than I(py)2BF4. Furthermore, the methodology we
report here can be extended to polycyclic aromatics contain-
ing a wide variety of organic functional groups such as OMe,
CO2Et, CHO and NO2 groups.
afforded the desired 10-iodophenanthrenes 4 and 6 in 98 and
99% yields, respectively (entries 2 and 3). The presence of
a modest electron-withdrawing group, like a p-CO2Et group
on the phenylethynyl moiety, as in 7, provided the cyclization
product 8 in a quantitative yield (entry 4). Surprisingly, even
the presence of a strong electron-withdrawing p-NO2 group
on the phenylethynyl moiety (9) afforded the corresponding
cyclization product 10 in a 57% yield, along with a 42%
combined yield of side products presumed to be 1,2-adducts
formed by ICl addition to the carbon-carbon triple bond
(entry 5). The p-alkoxy group on the phenylethynyl moiety,
which was critical to the success of Swager’s cyclization
methodology, is obviously not necessary in our chemistry.
However, the reaction of 2-(2-pyridinylethynyl)biphenyl and
2-(1-octynyl)biphenyl with ICl under our standard reaction
conditions failed to produce the desired phenanthrene
products. Thus, this methodology appears to be limited to
relatively electron-rich and conjugated biaryl acetylenes.
We initiated our iodocyclization studies by examining the
reaction of 2-(p-methoxyphenylethynyl)biphenyl (1) and ICl
(Table 1, entry 1). We first examined the reaction of 1 with
1.2 equiv of ICl in CH2Cl2 at room temperature. This reaction
afforded a mixture of the corresponding iodocyclization
product and a side-product, which is believed to be 10-iodo-
9-(3-iodo-4-methoxyphenyl)phenanthrene. Fortunately, when
the same reaction was carried out at -78 °C, the desired
10-iodo-9-(p-methoxyphenyl)phenanthrene (2) was the only
product formed in a 99% yield. Replacing ICl with I2 in this
reaction afforded a complex reaction mixture. Thus, our
standard reaction conditions employ 0.25 mmol of acetylene
and 1.2 equiv of ICl in CH2Cl2 at -78 °C.
Encouraged by our success with the above substrates, we
next investigated the iodocyclization of analogous acetylenes
in which various substituents are attached to the aromatic
ring undergoing attack during the cyclization. Treatment of
p-[(2-phenylethynyl)phenyl]benzaldehyde (11) with ICl un-
der our standard reaction conditions afforded cyclization
product 12 in a 71% yield. A 17% yield of products from
ICl addition to the alkyne was also obtained. Furthermore,
substrate 13 containing a strong electron-withdrawing p-NO2
group afforded the desired iodophenanthrene 14 in a 55%
yield, along with a 31% yield of ICl alkyne adducts (entry
7).
Employing this protocol in the reactions of 2-(p-tolyleth-
ynyl)biphenyl (3) and 2-(phenylethynyl)biphenyl (5) with ICl
(7) (a) Kitamura, T.; Takachi, T.; Kawasato, H.; Taniguchi, H. J. Chem.
Soc., Perkin Trans. 1 1992, 1969. (b) For similar Lewis acid-promoted
cyclization, see: Fu¨rstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264.
(8) (a) Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. J. Am. Chem.
Soc. 1997, 119, 4578. (b) Goldfinger, M. B.; Swager, T. M. J. Am. Chem.
Soc. 1994, 116, 7895.
(9) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez, J. M. Angew.
Chem., Int. Ed. 2003, 42, 2406.
(10) (a) Larock, R. C.; Yue, D. Tetrahedron Lett. 2001, 42, 6011. (b)
Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Flynn, B. L.;
Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651.
Interestingly, this iodocyclization chemistry can be suc-
cessfully extended to heterocyclic systems. For instance,
treatment of the benzofuran-containing acetylene 15 with ICl
afforded the cyclization product 16 in a 91% yield (entry
8), and 2-(2-thiophenylethynyl)biphenyl (17) afforded the
cyclization product 18 in a 96% yield (entry 9). Furthermore,
the isocoumarin-containing acetylene 19 also afforded the
expected cyclization product 20 in a 65% yield (entry 10).
(11) (a) Arcadi, A.; Cacchi, S.; Giancarlo, F.; Marinelli, F.; Moro, L.
Synlett 1999, 1432. (b) Arcadi, A.; Cacchi, S.; Di Giuseppe, S.; Fabrizi,
G.; Marinelli, F. Org. Lett. 2002, 4, 2409.
The regioselectivity in this iodocyclization chemistry has
also been investigated. The iodocyclization of the naphthalene-
containing acetylene 21 afforded approximately a 5:1 regio-
chemical mixture of 22 and 23 in an excellent overall yield
(entry 11). The predominant isomer is 22, which arises by
cyclization onto the 1-position of the naphthalene moiety.
Clearly, electronic effects favor cyclization to 22 over
cyclization to the less hindered 3-position of the naphthalene,
which affords 23. The double cyclization of diyne 24
afforded the desired cyclization product 25 in a 90% yield
(entry 12).
(12) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. Org. Lett. 2001, 3, 2973.
(b) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67, 3437.
(13) (a) Bellina, F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001,
57, 2857. (b) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.; Rossi, R.
Tetrahedron 2002, 58, 5023. (c) Yao, T.; Larock, R. C. Tetrahedron Lett.
2002, 43, 7401. (d) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina,
L. Tetrahedron 2003, 59, 2067. (e) Yao, T.; Larock, R. C. J. Org. Chem.
2003, 68, 5936.
(14) (a) Bew, S. P.; Knight, D. W. Chem. Commun. 1996, 1007. (b)
Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999, 40, 7193. (c) El-Taeb, G.
M. M.; Evans, A. B.; Jones, S.; Knight, D. W. Tetrahedron Lett. 2001, 42,
5945. (d) Rao, M. S.; Esho, N.; Sergeant, C.; Dembinski, R. J. Org. Chem.
2003, 68, 6788.
(15) Marshall, J. A.; Yanik, M. M. J. Org. Chem. 1999, 64, 3798.
(16) Knight, D. W.; Redfern, A. L.; Gilmore, J. Chem. Commun. 1998,
2207.
(17) Ren, X.-F.; Konaklieva, M. I.; Shi, H.; Dickey, S.; Lim, D. V.;
Gonzalez, J.; Turos, E. J. Org. Chem. 1998, 63, 8898.
(18) (a) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J, M. Angew.
Chem., Int. Ed. 2003, 42, 2406. (b) Yue, D.; Larock, R. C. Org. Lett. 2004,
6, 1037. (c) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539.
(19) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M.
Org. Lett. 2003, 5, 4121.
We propose a mechanism for this ICl-induced cyclization
chemistry that involves formation of an iodonium-complexed
acetylene, followed by electrophilic attack of this intermedi-
ate on the neighboring aromatic ring of the biaryl moiety in
a Friedel-Crafts type manner to generate the desired
polycyclic aromatic iodides.
(20) (a) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J.
M. J. Am. Chem. Soc. 2003, 125, 9028. (b) Yue, D.; Della Ca, N.; Larock,
R. C. Org. Lett. 2004, 6, 1581.
An interesting feature of this chemistry is the fact that the
polycyclic aromatic iodide products can be further elaborated
using a variety of palladium-catalyzed processes. For ex-
(21) Peng, A.-Y.; Ding, Y.-X. Org. Lett. 2004, 6, 1119.
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Org. Lett., Vol. 6, No. 16, 2004

Table 1. Synthesis of Polycyclic Aromatic Iodides via ICl-Induced Intramolecular Cyclizationa
a All reactions were run under the following conditions, unless otherwise specified: 0.25 mmol of the acetylene in 3 mL of CH2Cl2 was placed in a 4
dram vial under N2, and 1.2 equiv of ICl in 0.4 mL of CH2Cl2 was added at -78 °C and stirred for 1 h. b Yield determined by 1H NMR spectrocopy.
c Alkyne addition products were also observed in a 42% yield by 1H NMR spectroscopic analysis. d Alkyne addition products were also observed in a 17%
1
yield by H NMR spectroscopic analysis. e Alkyne addition products were isolated in a 31% yield.
ample, palladium-catalyzed Sonogashira coupling,22 alkyne
annulation,1d and cyclocarbonylation3a,f afford the corre-
sponding products 26-28 in 53, 83, and 98% yields,
respectively (Scheme 1).
Org. Lett., Vol. 6, No. 16, 2004
2679

functional groups as diverse as Me, OMe, CHO, CO2Et, and
NO2. It can be readily applied to the synthesis of polycyclic
aromatic hydrocarbons and heterocycles. Further work on
the scope and limitations of this methodology is presently
underway.
Scheme 1
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, and the National Science
Foundation for partial support of this research and Johnson
Matthey, Inc., and Kawaken Fine Chemicals Co., Ltd., for
donations of palladium catalysts.
Supporting Information Available: General experimen-
tal procedures and spectral data for the compounds listed in
Table 1 and Scheme 1. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL049161O
(22) For reviews, see: (a) Campbell, I. B. In The Sonogashira Cu-
Pd-Catalyzed Alkyne Coupling Reaction. Organocopper Reagents; Tayler,
R. T. K., Ed.; IRL Press: Oxford, UK, 1994; pp 217-235. (b) Sonogashira,
K.; Takahashi, S. Yuki Gosei Kagaku Kyokaishi 1993, 51, 1053. (c)
Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
In conclusion, an efficient synthesis of polycyclic aromatic
iodides has been developed. This methodology has been
successfully extended to aromatic products with organic
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