ORGANIC LETTERS
Synthesis of Polycyclic Aromatic Iodides via ICl-Induced Intramolecular Cyclization
2004 Vol. 6, No. 16 2677-2680
Tuanli Yao, Marino A. Campo, and Richard C. Larock* Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
[email protected] 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, CO2Et or NO2 groups. This chemistry has 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 electrophileinduced, 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 (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. (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 Published on Web 07/03/2004
© 2004 American Chemical Society
Recent success in the synthesis of iodides of benzo[b]thiophenes,10 benzofurans,11 isoquinolines and naphthyridines,12 isocoumarins and R-pyrones,13 furans,14 carbon(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.
ates,15 pyrroles,16 β-lactams,17 indoles,18 naphthalenes,19 isochromenes,20 and phosphaisocoumarins21 by the electrophilic 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 containing a wide variety of organic functional groups such as OMe, CO2Et, CHO and NO2 groups. 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-iodo9-(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. Employing this protocol in the reactions of 2-(p-tolylethynyl)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. (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. (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. (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. (21) Peng, A.-Y.; Ding, Y.-X. Org. Lett. 2004, 6, 1119. 2678
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. 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 under 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). Interestingly, this iodocyclization chemistry can be successfully 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). The regioselectivity in this iodocyclization chemistry has also been investigated. The iodocyclization of the naphthalenecontaining acetylene 21 afforded approximately a 5:1 regiochemical 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). We propose a mechanism for this ICl-induced cyclization chemistry that involves formation of an iodonium-complexed acetylene, followed by electrophilic attack of this intermediate on the neighboring aromatic ring of the biaryl moiety in a Friedel-Crafts type manner to generate the desired polycyclic aromatic iodides. 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 exOrg. 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 CH Cl was placed in a 4 2 2 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% yield by 1H 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 correOrg. Lett., Vol. 6, No. 16, 2004
sponding products 26-28 in 53, 83, and 98% yields, respectively (Scheme 1). 2679
Scheme 1
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. 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 experimental 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
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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(22) For reviews, see: (a) Campbell, I. B. In The Sonogashira CuPd-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.
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