Novel 1,3-Dipolar Cycloadditions of Cyclobutene Diester Epoxides to Polycyclic Aromatic Hydrocarbons [1]

Abstract. This paper announces the results of certain 1,3-dipolar cycloadditions to polycyclic aromatic hydrocarbons (PAHs). The 1,3-dipoles generated from cyclobutene diester epoxides thermally reacted with PAHs to give cycloadducts. This reaction demonstrated the remarkable ability of these 1,3-dipoles to disrupt an aromatic system by adding across specific ‘aromatic double bonds’. Similar products were prepared by “cross” oxadiazole (OD) coupling yielding the same geometry and stereochemistry as the cyclobutene diester epoxide derived products, but in inferior yields.

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Introduction. The 1,3-dipolar cycloaddition reaction is widely employed in organic synthesis for the preparation of heterocyclic structures.[2] Studies of the dipolar reaction with a variety of dipolarophiles have found that alkenes are particularly useful cycloaddition partners.[3] On the other hand, the ‘alkene bonds’ embedded in an aromatic ring are typically unreactive and such reactions have been scarcely reported in the literature. A literature search for dipolar cycloadditions to polycyclic aromatic hydrocarbons (PAHs) revealed the addition of nitrile oxides to PAHs and to acridine.[4,5,6,7] Ozone also cycloadds, in non-polar solvents, across the 1,2-positions of anthracene to form an ozonide whereas in polar solvents, a 9,10-adduct was formed.[8] Tetracyanoethylene oxide adds as a carbonyl ylid 1,3-dipole to benzene, phenanthrene and naphthalene[9] ‘olefins’ to yield tetracyanotetrahydrofurans. Further, cycloaddition of a carbonyl ylid generated in situ, gave a mixture of 1:1 and 2:1 adducts with anthracene.[10] Another rare literature example of naphthalene acting as a dienophile in a Diels-Alder cycloadditions is its reaction with dimethyl 1,2,4,5-s-tetrazine-3,6-dicarboxylate. Thus benzene and some other linearly annulated arenes have been recognized as dienophiles in the inverse electronic demand Diels-Alder reaction by adding across ‘aromatic double bonds’.[11]

For many years we have been interested in the synthetic use of 1,3-dipolar cycloadditions. Our research has yielded novel 1,3-dipole reagents embedded into polycyclic frameworks e.g. 2. Reactions of dipoles generated thermally from cyclobutene diester epoxides [12] (or aziridines) 1 with norbornenes 3 have proven to underpin a superior strategy for the synthesis of polyheteronorbornenes 4 (Scheme 1).[13]

In this paper we report our results on the 1,3-dipolar cycloadditions with PAHs. In order to investigate the reactivity cyclobutene diester epoxides, we have conducted a systematic study on the 1,3-dipolar cycloaddition reactions of the 1,4-dimethoxy-naphthonorbornadiene cyclobutane diester epoxide 5[14] with selected PAHs. The results, isolated yields and stereochemical outcomes are summarized in Scheme 2 (fragments which belong to the aromatic part are coloured blue). This reaction showed a high reactivity and remarkable ability of the 1,3-dipole generated from epoxide 5 to disrupt the aromatic systems by adding across ‘aromatic double bonds.

Epoxide 5 reacted with PAHs such as phenanthrene, phenanthroline and anthracene under 'melt' conditions. Initial experiments were simply done using excess PAH and adding the epoxide by spatula, mixing and melting on a hot air gun for a short time until the reaction mixture darkened somewhat (quite dark in the case of phenanthroline). The NMR spectra of the crude reaction mixtures all showed clear evidence of cycloadditions. In the phenanthroline and anthracene cases, there was clear evidence for two major but similar products for each forming approximately in 1:3 ratio, but for phenanthrene, there was one major product and only ~7 % of a second product. These additions were also conducted in dichloromethane (DCM) by heating at 120 ^oC for 2 hours in sealed glass tubes. It was found that these conditions gave the same products and ratios, but were more reproducible except for the case of phenanthroline where the 'melt' conditions proved superior. These reactions exhibited high site and stereo selectivities. In those reactions where two isomers (exo- and endo-) were obtained (Scheme 2), the endo- adduct was always the dominant product. (Through this manuscript, exo- and endo- stereochemistry are defined with respect to the heteroatom bridge). Thus anthracene and naphthalene[15] added across the 1,2- aromatic ring positions, while phenathrene and phenanthroline, benzo[f]quinoline[16] and benzo[h]quinoline[17] added across the 5,6- positions. Finally, 1,2-benzanthracene also added across the 5,6- positions[18] and acenapthylene at the 1,2- positions.

Reactions with biphenyl and flourene were unsuccessful, as well as reactions conducted under photochemical conditions in benzene solution.[14] While phenanthroline, benzo[f]- and benzo[h]quinoline were reactive, several other heterocyclic substrates tried in this study did not react or, if they did, led to thermally unstable products, viz., dibenzofuran, quinoline, isoquinoline, acridine, furan, thiophene and pyrrole. Some of the reactions depicted in Scheme 2 were also conducted photochemically. Reactions under photo-ACE conditions[14] (benzene or DCM, 300 nm, quartz tube, 3 hours) in a Rayonet photochemical reactor gave essentially the same products and isomer ratios as in the thermally conducted experiments. Although it is unusual for thermal and photochemical reactions to give the same products in the similar ratios, this observation was not further investigated. Similar stereochemical outcomes were observed previously in thermal and photochemical  reactions of epoxide 5 with norbornenes.[14]

Spectroscopic analysis. The elucidation of the stereochemistry of adducts 6-19 using ¹H NMR spectroscopy will be illustrated on the example of adduct 15. The endo- structure of 15 can be assigned by using standard 1D and 2D ¹H NMR spectroscopy (COSY and NOESY experiments). The ¹H NMR spectrum of 15 is shown in Figure 1. The methano proton resonances of the norbornane moiety occur as an AB pair (J=9.6 Hz) and resonate at 1.41 and 3.51 ppm. Due to the steric compression caused by the proximate oxygen atom, proton H₂ is shifted to lower field.[19] The two benzylic bridge protons H₃ and H₈ were assigned using 2D COSY and NOESY experiments, the most characteristic correlations being depicted in Figure 1. Endo- protons H₄ and H₇ were assigned by their W-couplings with the methano proton H₁ seen in the COSY spectrum (red lines, Figure 1). These geminal protons are also coupled to each other forming a typical AB pair (d 2.10 and 2.76, J=6.9 Hz). Furthermore, protons H₁, H₂, H₃, H₄, H₇ and H₈ are correlated in the NOESY spectrum. Protons H₅, H₆, H₉ and H₁₀ define a second group of characteristic signals. There are strong nOe correlations (see green arrows, Figure 1), but the lack of nOe correlations between endo- protons H₄ and H₇ and exo- protons H₅ and H₆ is the most diagnostic evidence for the endo- structure assignment of adduct 15. Olefinic protons H₉ and H₁₀ are positioned at lower magnetic field (d 5.94 and 6.52) as a coupled (J=10 Hz) pair. Proton H₉ is also coupled with exo- proton H₅, making a doublet of doublets (J=1.8 Hz). Methyl ester signals E₁ and E₂ (d 3.55 and 3.96) are assigned on the basis of a shift toward higher magnetic field due to the influence of the naphthalene ring, while the ether methoxy signals are little changed by the reaction.

After the initial 1,3-dipolar formation of the 1:1 endo- adduct 15, it was found that further reaction of epoxide 5 with 15 produced 2:1 adducts 20 and 21 (Scheme 3). In the initial experiment with an excess of anthracene, small amounts of 2:1 adducts were detected, while experiments with epoxide in excess (up to 4:1 ratio) gave larger quantities of these 2:1 adducts. The major product was the endo,endo- adduct 20 with a molar ratio of 5:1 with relation to the endo,exo- isomer.

Part 2. Oxadiazole couplings.

Mechanistically, the cycloaddition coupling of strained alkenes such as norbornenes with 2,4-bis-(trifluoromethyl)-1,3,4-oxadiazole (OD) 23[20], is proposed to involve a 1,3-dipolar intermediate related to 1,3-dipole 2 (Scheme 1). With this in mind, we anticipated that OD coupling could produce similar adducts with PAHs. Of course, a statistical mixture of products was expected, but we hoped for some selectivity. And indeed, the thermal coupling reaction of OD with the anthracene-norbornadiene adduct 22[21] in the presence of excess anthracene (in DCM, 140 oC, sealed tube, 16 hrs) produced a reaction mixture consisting of products 25 and 26 in 1:1 ratio (as estimated by ¹H-NMR analysis) and isolated in 25 % and 5 % yield, respectively (Scheme 4). Interestingly, we were unable to detect exo- isomer 27.

Spectroscopic evidence fully supported the structural assignement of 26 (Scheme 4). There is essentially no differences found in the aromatic moieties of the ¹H NMR spectra of adducts 26 and 15. The reaction mechanism proposed, involves initial formation of the isomeric 1:1 Diels-Alder adducts 30 and 31 (via transition states TS28 and TS29) (Scheme 5). These adducts can spontaneously eliminate dinitrogen to form 1,3-dipole 32, which then can react with anthracene to form product 26. The stereochemistry of the initially formed adducts 30 and 31 (not isolated or detected) will be lost in the dinitrogen elimination step and regardless of their stereochemistry,  and leads to the formation of single 1,3-dipole 32 (which was not isolated or spectroscopically detected). This reaction sequence is analogous to reactions conducted earlier in our laboratory when crossed OD products of norbornenes were prepared by the coupling reaction of two different olefins with OD.[22] Further support for the proposed mechanism was obtained from some control experiments viz., OD does not react with either anthracene or phenanthrene under the same reaction conditions (DCM, 145 ^oC for 5 days in a sealed glass tube). These control experiments indicate that these reactions are operating only at the dipole level and the OD addition to alkene 22 is the initial reaction step.

The ¹H-NMR spectrum of adduct 26 shows several unique ¹H-NMR signals in an unsymmetrical benzonorbornane setting with a characteristically  shielded ¹H of a methylene at d -0.47 ppm. The aromatic region is crowded but there are two vinyl ¹H multiplets at d 7.01 and d 5.68 ppm. Also, the ¹H-NMR spectrum has a striking ¹H proton as a doublet of multiplets at ~ d 3.6 ppm. The ¹³C-NMR spectrum shows 25 sp² and 11 sp³ carbons and the found mass of 626 further supports the assigned structure.

Analogously, the OD reaction with alkene 22 and phenantrene (in slight excess) produced a mixture of two products 25 and a crossed endo- adduct 33 in 6:1 ratio. When more phenanthrene was added to the reaction mixture, the ratio of 25 and 33 changed to 1:2. Again, this reaction produced stereoselectively only the endo- product 33, while the corresponding exo- isomer was not detected.

The ACE coupling methodology was further used for another entry to the geometrically similar type of products. Thus, alkene 22 was subjected to the Mitsudo reaction [23] to obtain the cyclobutene diester 34, that was then epoxidized to the cyclobutene diester epoxide 35 (Scheme 6). The thermal reaction of epoxide 35 with anthracene produced the same type of compound 36 as the previously mentioned OD product 26, but with different substituents at the bridgeheads of the oxanorbornane moiety. It is interesting to note that in both reactions, the endo- isomer was predominantly formed (> 10:1 ratio), and there were only traces of exo- product detected. This high stereoselectivity of the ACE reaction was not observed when epoxide 5 was reacted with PAHs. It could be rationalized in terms of different steric requirements of 1,3-dipole generated from epoxide 5 and 1,3-dipole 32 (different substituents at 1,3-positions). A reaction conducted in this manner significantly improved the yield of unsymmetrical product 36, over the OD reaction. The superiority of our ACE reactions is further seen in the much shorter reaction times required (and with no possibility of the formation of any OD symmetrical 2:1 product such as 25.

Conclusion. The 1,3-dipoles generated from cyclobutene diester epoxides thermally react with PAHs to give cycloadducts. In most of these reactions, exo/endo- mixtures were produced favoring endo- adducts. This reaction showed a very high reactivity and a remarkable ability of the 1,3-dipole to disrupt an aromatic system and add across ‘aromatic double bonds’. Similar products were prepared by “cross” oxadiazole coupling yielding the same geometry and stereochemical outcomes, however the OD reaction was inferior with respect to yields, reaction conditions and product mixture complexity.

Acknowledgements.  We are grateful to the Australian Research Council (ARC) for funding this research.

References. 

1. Preliminary results of this work were presented at The third Brisbane biological and organic chemistry symposium (BBOCS-3), The Queensland University of Technology, Brisbane, Australia, November 29, 2002, Margetić, D.; Warrener, R. N.; Butler, D. N., “1,3-Dipolar Cycloadditions to Polycyclic Aromatic Hydrocarbons”.

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3. Padwa, A. Ed. 1,3-Dipolar Cycloaddition Chemistry, Wiley, 1984.

4. a) Corsaro, A.; Librando, V.; Chiacchio, U.; Pistara, V. Tetrahedron 1996, 52(40), 13027; b) Librando, V.; Chiacchio, U.; Corsaro, A.; Gumina, G. Polycyclic Arom. Compds 1996, 11, 313.

5. Corsaro, A.; Chiacchio, U.; Librando, V.; Fisichella, S.; Pistara, V. Heterocycles 1997, 45(8), 1567.

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7. Corsaro, A.; Pistara V.; Rescifina, A.; Romeo, G.; Romeo, R.; Chiacchio, U. Arkivoc 2002, Part 8, 5.

8. Ogawa, T.; Mori, K.; Matsuri, M.; Sumiki, Y. Tetrahedron Lett. 1968, 24(6), 2551.

9. Linn, W. J.; Webster, O. W.; Benson, R. E. J. Am. Chem. Soc. 1965, 87(16), 3651; William, J.; Linn, W. J.; Benson, R. E. J. Am. Chem. Soc. 1965, 87(16), 3656.

10. Hojo, M.; Aihara, H.; Ito, H.; Hosomi, A. Tetrahedron Lett. 1996, 37(51), 9241.

11. Seitz, G.; Hoferichter, R. Archiv der Pharmazie (Weinheim) 1988, 321(12), 889; Seitz, G.; Hoferichter, R.; Mohr, R. Angew. Chem.  1987, 99(4), 345.

12. Warrener R. N.; Schultz, A. C.; Butler, D. N.; Wang, S.; Mahadevan, I. B.; Russell, R. A. Chem. Commun. 1997, 1023.

13. Warrener, R. N.; Butler, D. N.; Russell, R. A. Synlett 1998, 566; Butler, D. N.; Malpass, J. R.; Margetic, D.; Russell, R. A.; Sun, G.; Warrener, R. N. Synlett 1998, 588; Warrener, R. N.; Margetic, D.; Amarasekara, A. S.; Butler, D. N.; Mahadevan, I.; Russell, R. A. Org. Lett. 1999, 1, 199.

14. Margetic, D.; Russell, R. A.; Warrener, R. N. Org. Lett. 2000, 2, 4003. ACE reaction is the acronym for Alkene plus Cyclobutene Epoxide coupling.

15. Exo- adduct 19 was detected by NMR spectroscopy (in 10:1 ratio), but not isolated.

16. Products of benzo[f]quinoline additions were not isolated, ratios estimated by 1H-NMR spectroscopy.

17. Major adduct 12 isolated only

18. Complex mixture of regio-and stereo-isomers was produced, with 17 as a major product (~10:1 ratio) and the only one which we were able to isolate.

19. Proximity Effects: the Observation by ¹H NMR of Steric Compression of the Methano Bridge Protons of Polycyclic Norbornanes Possessing Adjacent Carbon, Oxygen and Nitrogen Bridges”, Margetic, D.; Johnston, M. R.; Warrener, R. N.; Butler, D. N., Article 37, The Fifth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-5), http://www.mdpi.org/ecsoc-5.htm, September 1-30, 2001, Editors: Oliver Kappe, Pedro Merino, Andreas Marzinzik, Helma Wennemers, Thomas Wirth, Jean-Jacques Vanden Eynde and Shu-Kun Lin, CD-ROM edition ISBN 3-906980-06-5 Published in 2001 by MDPI, Basel, Switzerland.

20. Brown, H. C.; Cheng, M. T.; Parcell, L. J.; Pilipovich, D. J. Org. Chem. 1961, 26, 4407.

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22. Warrener, R. N.; Margetic, D. M.; Tiekink, E. R. T.; Russell, R. A. Synlett 1997, 2, 196.

23. Mitsudo, T.; Naruse, H.; Kondo, T.; Ozaki, Y.; Watanabe, Y. Angew. Chemie, Int. Ed. Engl. 1994, 33, 580