Synthesis and characterizations of meso-disubstituted asymmetric porphycenes

Tetrahedron Letters 54 (2013) 5727–5729

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Synthesis and characterizations of meso-disubstituted asymmetric porphycenes Masatsugu Taneda a, Akihiro Tanaka a,b, Hisashi Shimakoshi a, Atsushi Ikegami a, Koichi Hashimoto a, Masaaki Abe a,⇑, Yoshio Hisaeda a,c,⇑ a b c

Department of Chemistry and Biochemistry, Graduate School of Engineering, Kyushu University, 744 Moto-oka, Nishi-ku, Fukuoka 819-0395, Japan Synthesis Research Department, Chemical Research Laboratory, Nissan Chemical Industries, Ltd, Funabashi 274-8507, Japan Center for Molecular Systems (CMS), Kyushu University, 744 Moto-oka, Nishi-ku, Fukuoka 819-0395, Japan

a r t i c l e

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Article history: Received 16 July 2013 Revised 3 August 2013 Accepted 6 August 2013 Available online 13 August 2013 Keywords: Asymmetric porphycenes meso-Substitution Acetoxylation Nitration Optical properties

a b s t r a c t A post-synthetic method has been developed to synthesize novel asymmetric porphycenes bearing two different substituents on the meso-positions. Nitration of 9-acetoxy-2,7,12,17-tetra-n-propylporphycene with AgNO3 in CH3COOH/CH2Cl2 occurs regioselectively at the 19-position of the macrocycle to give 9-acetoxy-19-nitro-2,7,12,17-tetra-n-propylporphycene (3a) which was readily converted to 9-acetoxy-19-amino-2,7,12,17-tetra-n-propylporphycene (4a) by the reduction with SnCl2 in pyridine. Ó 2013 Elsevier Ltd. All rights reserved.

Porphycene, which is a constitutional isomer of porphyrin and first synthesized by Vogel et al.,1 displays remarkably stronger Qbands in the absorption spectra than porphyrin owing to the lower symmetry of the porphycene (D2h) relative to porphyrin (D4h).2 Due to their ability to absorb red light and to photosensitize the formation of a singlet oxygen, the porphycenes are promising candidates as photosensitizers for photodynamic therapy (PDT).3 In order to control their photophysical and other properties, insertions of functionalities into the periphery of the porphycene macrocycle are essential. To date, various synthetic methodologies are available to modify the pyrrole-b positions4,5 and, to a more reduced number of literatures, the meso-positions.4 The most of the latter ever reported are limited to 9-substituted, asymmetric porphycenes appending single substituents such as acetoxy, nitro, amino, hydroxy, and other groups.6–10 These 9-substituted porphycenes are known to be eminent precursors for many derivatives for photophysical,7 electrochemical,8 and biomedical/ pharmaceutical studies,9 and also provide good models to examine tautomeric proton-transfer dynamics.10 Synthetic studies on porphycene meso-functionalization to introduce two or more functionalities are apparently rare.11

This Letter reports the preparation of new asymmetric porphycenes bearing two different functional groups at the meso-positions, starting from a prototype of the porphycenes 2,7,12,17-tetra-npropylporphycene (1).1 The new meso-disubstituted asymmetric porphycenes are shown in Figure 1. Compounds 9-acetoxy-19-nitro-2,7,12,17-tetra-n-propylporphycene (3a) and 10-acetoxy-19-nitro-2,7,12,17-tetra-n-propylporphycene (3b) involve the acetoxy and nitro groups attached to the mutually opposite meso positions in the trans (9-/19-) and cis (10-/19-) topologies, respectively, while compounds 9-acetoxy-19-amino-2,7,12,17-tetra-n-propylporphycene (4a) and 10acetoxy-19-amino-2,7,12,17-tetra-n-propylporphycene (4b) are

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⇑ Corresponding authors. Tel./fax: +81 92 802 2827. E-mail addresses: [email protected] (M. Abe), yhisatcm@mail. cstm.kyushu-u.ac.jp (Y. Hisaeda). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.08.026

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Figure 1. Chemical structures of meso-disubstituted asymmetric porphycenes.

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also isomeric with respect to the acetoxy and amino groups. Synthetic routes to new asymmetric meso-disubstituted porphycenes are outlined in Scheme 1. We have found that the nitration of 9acetoxy-2,7,12,17-tetra-n-propylporphycene (2)7d,8a with AgNO3 occurs in a regioselective manner to give compound 3a as a main product. In contrast, an alternate reaction, for example, the acetoxylation of 9-nitro-2,7,12,17-tetra-n-propylporphycene (5), was not regioselective to give two isomeric products 3a and 3b as a 1:1 mixture. Optical properties of these compounds are also reported herein. In order to access the new meso-disubstituted porphycenes, two different approaches were examined (Scheme 1). In one route, compound 2,7d,8a which was prepared from 1 according to the literature method (step i), was reacted with an excess amount of AgNO3 in CH3COOH–CH2Cl2 at 50 °C for 20 min to give a main product which afterward proved to be trans compound 3a (step ii).12 MALDI-TOF-MS of this compound provided an evidence of an insertion of a single nitro group to the macrocycle (m/z = 582.28 corresponding to [M+H]+). The attachment of the nitro group at the meso positions (rather than the pyrrole rings) was unequivocally determined by 1H NMR spectroscopy. 1H NMR spectrum of this product (CDCl3) showed the presence of two equallypopulated singlets assigned to the meso protons (d 9.10 and 9.86), indicating that the single nitro group was introduced at either 19or 20-C site; if the nitro group was attached to the pyrrole rings, a doublet peak due to the meso protons must be observed. This signal pattern also ruled out the formation of an additional possible isomer with two different functionalities located at one side of the meso positions (9-acetoxy-10-nitro isomer; Supplementary Fig. S1). A DFT calculation on the precursor 2 at the UB3LYP/631G(d,p) level (Fig. S2) revealed that the HOMO locates more largely at the 19-C site than the other meso carbons (10- and 20-C). This computational result indicates that the electrophilic nitration of 2 favors insertion of the nitro group at 19-C to give 3a. Attempts to characterize the substituent location by 2D NMR techniques such as HMBC and HMQC13 were unsuccessful due to very neighboring resonances of the 1H and 13C NMR spectra. Chemical reduction of the 19-nitro group in 3a with SnCl2
2H2O in pyridine at 90 °C gave 4a in 59% yield after purification (step iii).14 In the alternate route, the acetoxylation of 9-nitro-2,7,12,17tetra-n-propylporphycene (5),7d which was obtained from 1 (step

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iv), was examined. Unlike the above reactions, the acetoxylation of 5 with Pb(CH3COO)4 in dry THF was found to give two major products, 3a and its isomeric counterpart 3b, as a 1:1 mixture (step v).15 1H NMR spectrum of this mixture (CDCl3) gave diagnostic singlets assigned to the meso protons at d 9.84 and 9.94 (1:1 ratio). Equal distribution of the acetoxy group at both carbon sites was again rationalized by the DFT calculation on 5 (Fig. S3), which revealed a nearly equivalent population of the vacant orbitals at 19- and 20-C in the LUMO level. This does not contradict the current observation that acetoxylation of 5 yields both isomers. Although the LUMO also spreads on the pyrrole-b positions, steric hindrance of the n-propyl group and the hydrogen atom on the pyrrole ring reduces the reactivity. Subsequent reduction of this mixture with SnCl2
2H2O gave a mixture of aminated products 4a and 4b accordingly (step vi).15 We note that these geometric isomers, 4a/4b and also their precursors 3a/3b, were not separated by recrystallization and by flash column chromatography. Absorption and luminescent properties were studied for selected porphycenes. The absorption spectra are shown in Figure 2, and the absorption data are summarized in Table S1 (the Supplementary data). As shown in Figure 2a, a marginal effect was seen for the acetoxylation and nitration. In contrast, effects of amination at the porphycene meso group on the absorption spectra are profound,6a,7e,f,10a as shown in Figure 2b, in which red-shift of the Q-bands and a split of the Soret band are observed for 9-amino2,7,12,17-tetra-n-propylporphycene (7). We find here that this amination-induced red-shift of the Q-band is more significant for the trans isomer 4a than the cis counterpart4b,16 clearly indicating a remarkable impact of the substituent location on electronic structures of the meso-disubstituted porphycenes. The substituted porphycenes obtained in this work were weakly fluorescent in the red and near-IR region, among which compound 4a emits in the lowest energy region, kem = 740 nm (CH2Cl2; Fig. S4). In conclusion, this study provides a new post-modification method to functionalize meso-carbon atoms in the porphycene macrocycle to yield a unique set of meso-disubstituted asymmetric porphycenes. A regioselective nitration at the 19-C site (one of the meso-carbons) of the 9-acetoxy 2,7,12,17-tetra-n-propylporphycene, our new finding based on the 1H NMR spectroscopy and DFT calculations, will lead to the synthesis of more elaborate derivatives of meso-substituted porphycenes in which their electronic

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Scheme 1. Synthetic routes. Reagents and conditions: (i) Pb(CH3COO)4 (7 equiv), dry THF–CH2Cl2, reflux, 10 min, 30%; (ii) AgNO3 (21 equiv), CH3COOH–CH2Cl2 (1:1, v/v), 50 °C, 20 min, 83%, (iii) SnCl2
2H2O (9 equiv), pyridine, 90 °C, 30 min, 59%; (iv) AgNO3 (20 equiv), CH3COOH, 60 °C, 15 min, 85%; (v) Pb(CH3COO)4 (8 equiv), dry THF, reflux, 40 min, 48%; (vi) the same conditions as those of step (iii).

M. Taneda et al. / Tetrahedron Letters 54 (2013) 5727–5729

3. 4. 5.

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10. Figure 2. Absorption spectra of meso-substituted porphycenes and 1 in CH2Cl2 at room temperature. Panel (a): 1 (dashed-dotted), 2 (dotted), 5 (dashed), and 3a (solid). Panel (b): 1 (dashed-dotted), 7 (dotted), a calculated spectrum of 4b (dashed), and 4a (solid).

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and photophysical properties could be tuned in a desired direction. In particular, absorption and fluorescence properties in the near-IR region are very attractive for future applications such as PDT, biomedical sensing, and night-vision-readable displays.17 Acknowledgements This work was supported by a research fund from the Nissan Chemical Industries, Ltd, Grants-in-Aid for Scientific Research on Innovative Areas ‘Molecular Activation’ (No. 25105537) and ‘Coordination Programming’ (No. 24108730), Grants-in-Aid for Scientific Research (A) (No. 21245016) and (B) (No. 25288031), and the Global COE Program ‘Science for Future Molecular Systems’ from MEXT. The authors thank Professor Hiroyuki Furuta (Kyushu University) for measurements of the NIR spectra.

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Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.tetlet.2013.08.026. References and notes 1. Vogel, E.; Köcher, M.; Schmickler, H.; Lex, J. Angew. Chem., Int. Ed. Engl. 1986, 25, 257–259. 2. (a) Vogel, E.; Balci, M.; Pramod, K.; Koch, P.; Lex, J.; Ermer, O. Angew. Chem., Int. Ed. Engl. 1987, 26, 928–931; (b) Gisselbrecht, J. P.; Gross, M.; Koecher, M.; Lausmann, M.; Vogel, E. J. Am. Chem. Soc. 1990, 112, 8618–8620; (c) Bernard, C.; Gisselbrecht, J. P.; Gross, M.; Vogel, E.; Lausmann, M. Inorg. Chem. 1994, 33,

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2393–2401; (d) D’Souza, F.; Boulas, P.; Aukauloo, A. M.; Guilard, R.; Kisters, M.; Vogel, E.; Kadish, K. M. J. Phys. Chem. 1994, 98, 11885–11891; (e) D’Souza, F.; Boulas, P. L.; Kisters, M.; Sambrotta, L.; Aukauloo, A. M.; Guilard, R.; Kadish, K. M. Inorg. Chem. 1996, 35, 5743–5746. Stockert, J. C. Curr. Med. Chem. 2007, 14, 997–1026. Sánchez-García, D.; Sessler, J. L. Chem. Soc. Rev. 2008, 37, 215–232. (a) Shimakoshi, H.; Sasaki, K.; Iseki, Y.; Hisaeda, Y. J. Porphyrins Phthalocyanines 2012, 16, 530–536; (b) Shimakoshi, H.; Baba, T.; Iseki, Y.; Aritome, I.; Endo, A.; Adachi, C.; Hisaeda, Y. Chem. Commun. 2008, 2882–2884; (c) Matsuo, T.; Ito, K.; Nakashima, Y.; Hisaeda, Y.; Hayashi, T. J. Inorg. Biochem. 2008, 102, 166–173; (d) Shimakoshi, H.; Baba, T.; Iseki, Y.; Endo, A.; Adachi, C.; Watanabe, M.; Hisaeda, Y. Tetrahedron Lett. 2008, 49, 6198–6201; (e) Baba, T.; Shimakoshi, H.; Hisaeda, Y. Tetrahedron Lett. 2004, 45, 5973–5975. (a) Vogel, E. Koch, P.A. Rahbar, A. Cross, A.D. Cytopharm. Inc. USA. 92US364(9212636), 39. 6–8-1992. WO. 1-29-1992.; (b) Vogel, E. Benninghaus, T. Richert, C. Müllar, M. Cross, A.D. Cytopharm. Inc. USA. 92-US4624(9300087), 76. 7-1-1993. WO. 6-5-1992.; (c) Vogel, E. Müllar, M. Halpern, O. Cross, A.D. Cytopharm. Inc. USA. 96-US4177(9631452), 30. 10-10-1996. WO. 4-4-1996.; (d) Vogel, E. Müllar, M. Halpern, O. Cross, A. D. Cytopharm. Inc. USA. 96US4176(9631451), 36. 10-10-1996. WO. 4–4-1996.; (e) Vogel, E. Müllar, M. Halpern, O. Cross, A.D. Cytopharm. Inc. USA. 97-US17918(9815271), 62. 4-161998. WO. 10-9-1997. (a) Szeimies, R.-M.; Karrer, S.; Abels, C.; Steinbach, P.; Fickweiler, S.; Messmann, H.; Baumler, W.; Landthaler, M. J. Photochem. Photobiol., B 1996, 34, 67–72; (b) Braslavsky, S. E.; Müller, M.; Mártire, D. O.; Pörting, S.; Bertolotti, S. G.; Chakravorti, S.; Koç-Weier, G.; Knipp, B.; Schaffner, K. J. Photochem. Photobiol., B 1997, 40, 191–198; (c) Polo, L.; Segalla, A.; Bertoloni, G.; Jori, G.; Schaffner, K.; Reddi, E. J. Photochem. Photobiol., B 2000, 59, 152–158; (d) Gil, M.; Jasny, J.; Vogel, E.; Waluk, J. Chem. Phys. Lett. 2000, 323, 534–541; (e) Arad, O.; Rubio, N.; Sánchez-García, D.; Borrell, J. I.; Nonell, S. J. Porphyrins Phthalocyanines 2009, 13, 376–381; (f) Lan, Z.; Nonell, S.; Barbatti, M. J. Phys. Chem. A 2012, 116, 3366– 3376. (a) Okawara, T.; Abe, M.; Shimakoshi, H.; Hisaeda, Y. Bull. Chem. Soc. Jpn. 2011, 84, 718–728; (b) Okawara, T.; Abe, M.; Shimakoshi, H.; Hisaeda, Y. Res. Chem. Intermed. 2013, 39, 161–176. (a) Segalla, A.; Fedeli, F.; Reddi, E.; Jori, G.; Cross, A. Int. J. Cancer 1997, 72, 329– 336; (b) Scherer, K.; Abels, C.; Baumler, W.; Ackermann, G. Arch. Dermatol. Res. 2004, 295, 535–541. (a) Fita, P.; Pszona, M.; Orzanowska, G.; Slnchez-García, D.; Nonell, S.; Vauthey, E.; Waluk, J. Chem. Eur. J. 2012, 18, 13160–13167; (b) Abdel-Latif, M. K.; Kuhn, O. Theor. Chem. Acc. 2011, 128, 307–316. Czerski, I.; Listkowski, A.; Nawrocki, J.; Urbanska, N.; Piwonskia, H.; Sokołowski, A.; Pietraszkiewicz, O.; Pietraszkiewicz, M.; Waluk, J. J. Porphyrins Phthalocyanines 2012, 16, 589–602. Compound 2 (53 mg, 0.099 mmol) was reacted with AgNO3 (354 mg, 0.208 mmol) in a mixture of CH3COOH (50 mL) and CH2Cl2 (50 mL) at 50 °C for 24 min. After the solution was cooled to room temperature, the solution was washed with water (50 mL  3). The organic layer was dried over MgSO4, concentrated, and the residue was purified by column chromatography on a silica gel by eluting with a 1:1 mixture (v/v) of CH2Cl2 and n-hexane. After evaporation of the solvent, the residue was recrystallized from CH2Cl2/nhexane to afford 3a (38 mg, 0.065 mmol, 66%) as a purple powder. Anal. Calcd for C34H39N5O4
1/4(CH2Cl2): C, 68.23; H, 6.60; N, 11.62. Found: C, 68.53; H, 6.64; N, 11.83. 1H NMR (CDCl3, 298 K, 500 MHz) d 1.30–1.41 (m, 12H, CH2CH3), 2.29–2.39 (m, 8H, CH2CH3), 2.86 (s, 3H, –C(O)CH3), 3.51 (br, 2H, NH), 3.63–3.89 (m, 8H, PyCH2), 9.10 (s, 1H, 10-H), 9.13 (s, 2H, 13-H, 16-H), 9.14 (s, 1H, 6-H), 9.21 (s, 1H, 3-H), 9.86 (s, 1H, 20-H). UV/vis (CH2Cl2): k/nm (e/M 1 cm 1) 375 (99 100), 568 (26 300), 607 (32 700) 639 (33 100). MALDI-TOF-MAS: m/ z = 582.28; calcd for [M+H]+: m/z = 582.31. Okawara, T.; Hashimoto, K.; Abe, M.; Shimakoshi, H.; Hisaeda, Y. Chem. Commun. 2012, 5413–5415. Compound 3a (38 mg, 0.065 mmol) and SnCl2
2H2O (117 mg, 0.52 mmol) were added to pyridine (4 mL), then the solution was refluxed for 30 min. After the solution was cooled to room temperature, the solution was purified by column chromatography on a silica gel by eluting with a 20:20:1 mixture (v/v) of CH2Cl2, n-hexane, and triethylamine. Recrystallization of the residue from CH2Cl2/n-hexane afforded 4a (23 mg, 0.041 mmol, 63%) as a purple powder. Anal. Calcd for C34H41N5O2: C, 74.02; H, 7.49; N, 12.69. Found: C, 73.72; H, 7.49; N, 12.75. 1H NMR (CDCl3, 298 K, 500 MHz) d 1.30–1.39 (m, 12H, CH2CH3), 2.30–2.40 (m, 8H, CH2CH3), 2.82 (s, 3H, –C(O)CH3), 3.49 (br, 2H, NH), 3.72–3.86 (m, 8H, pyrrole CH2), 5.14 (br, 2H, NH2), 8.51 (s, 1H, 10-H), 8.92 (s, 1H, 16-H), 8.94 (s, 1H, 6-H), 8.99 (s, 1H, 3-H), 9.01 (s, 1H, 13-H), 9.16 (s, 1H, 20-H). UV/vis (CH2Cl2): k/nm (e/M 1 cm 1) 369 (96 500), 402 (71 400), 560 (24 000), 676 (29 100) 716 (17 200). MALDI-TOF-MAS: m/z = 552.38; calcd for [M+H]+: m/ z = 552.33. See the Supplementary data for details in the synthetic procedures and characterizations. The UV/vis spectrum of 4b was calculated by using spectra of pure 4a and of a 1:1 mixture of 4a and 4b, which were obtained via the independent synthetic routes (Scheme 1). The spectrum of 3b was obtained similarly (Table S1). (a) Won, D. H.; Toganoh, M.; Terada, Y.; Fukatsu, S.; Uno, H.; Furuta, H. Angew. Chem., Int. Ed. 2008, 47, 5438–5441; (b) Qian, B. G.; Zhong, Z.; Luo, M.; Yu, D.; Zhiqiang, Z.; Wang, Z. Y.; Ma, D. Adv. Mater. 2009, 21, 111–116.