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Synthesis of 5,15-diarylporphyrins via orthoesters condensation with aryldipyrromethanes
Tetrahedron Letters 52 (2011) 3175–3178
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Synthesis of 5,15-diarylporphyrins via orthoesters condensation with aryldipyrromethanes Zahra Abada a,b, Laurent Ferrié b, Bernardin Akagah a, Anh Tuan Lormier a, Bruno Figadère b,⇑ a b
Alpha-Chimica, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry, France UMR CNRS 8076, University Paris-Sud, Laboratoire de Pharmacognosie, UFR de Pharmacie, Châtenay-Malabry F-92296, France
a r t i c l e
i n f o
Article history: Received 24 February 2011 Revised 5 April 2011 Accepted 6 April 2011 Available online 12 April 2011
a b s t r a c t General access to 5,15-diarylporphyrins in two steps is described. Generalization of this approach to tetra-substituted porphyrins allows the reproducible preparation of compounds, in some cases with high yields for porphyrins, which can be used in photodynamic therapy (PDT) in cancer today. Ó 2011 Published by Elsevier Ltd.
Keywords: Condensation Symmetry Acid catalysis Photosensitizers Anticancer
The general access to 5,15-diarylporphyrins follows usually the well known two step procedure,1–3 however giving low yields and tedious chromatography purifications: namely, preparation of dipyrromethane4 (an air and moisture sensitive compound5) then condensation with an aromatic aldehyde followed by DDQ oxidation (Fig. 1). Recently, Banfi et al. has studied the comparative activity of tetra-arylporphyrins and 5,15-diarylporphyrins in PDT.2,3 The study has shown that (i) 5,15-diarylporphyrins were more active and (ii) the crucial importance of hydroxyl groups on the aryl substituents, both for the solubility concerns and for the photo-toxicity was observed.3 Indeed, in the treatment of cancer, photodynamic therapy (PDT) has become an attractive alternative approach.6,7 PDT uses a tumor-localizing photosensitizing agent, usually a porphyrin, that absorbs visible light and in presence of oxygen generates cytotoxic reactive oxygen species (ROS). It is well admitted that the produced singlet oxygen (1O2) is responsible for cell death.8 To this date only two compounds have been approved for PDT cancer treatment: porfimer (photofrin) is derived from hematoporphyrin,9 and foscan (m-THPC or 5,10,15,20-terakis(m-hydroxyphenyl)chlorin) is a chlorin, a second generation porphyrin derivative that shows an interesting photo-toxicity against cancerous cell lines (Fig. 2).10
It is important to note that verteporfin, a 1:1 mixture of photosensitizing porphyrins isomers, has been approved for the treat-
HCHO
N H
N H
Ar
N H
1) ArCHO 2)DDQ
N
N H N
NH Ar
Figure 1. Preparation of 5,15-diarylporphyrins in the literature.
HO
OH
HO N
N H
O
HN
NH
N
N
N
HO
H N
O HO
⇑ Corresponding author. E-mail address: bruno.fi[email protected] (B. Figadère). 0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2011.04.028
O Photofrin
2
HO
OH
Figure 2. Photofrin and foscan.
Foscan
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O
O HO
O HO
O
Table 1 Preparation of aryldipyrromethanes 2a–i from pyrrole and aldehydes 1a–i
O
O N HN
NH
HN
NH
N
MeO
N
+
N
HO
O
O HO
Entry
Aldehyde
TFA (equiv)
Yield (%)
1 2 3 4 5 6 7 8 9
PhCHO 1a 3-Br-PhCHO 1b 2-Br-PhCHO 1c 2,3,4,5,6-F6-PhCHO 1d 2,6-Cl2-PhCHO 1e 2-NaphthylCHO 1f 3-IndolylCHO 1g 4-NO2-PhCHO 1h 3,4,5-(OMe)3-PhCHO 1i
0.1 0.5 0.5 0.1 0.1 0.1 0.1 0.5 0.5
2a: 89 2b: 80 2c: 74 2d: 62 2e: 70 2f: 72 2g: 75 2h: 70 2i: 71
MeO O
O Figure 3. Verteporfin.
R1 ArCHO N H
NH
RC(OMe)3
N H
then air
2a-i R R = H: 3a-i R = CH3: 4a R = Ph: 5a
N
N R1
R1
N H H N
R
Figure 4. Our strategy for the synthesis of 5,15-diarylporphyrins 3a-I, 4a, 5a.
ment of abnormal blood vessels in the eyes associated with macular degeneration (Fig. 3). It would be interesting to compare the activity of symmetric 5,15-diarylporphyrins (A2 symmetry) with the activity of tetraarylporphyrins of several symmetries (A2B2, A2BC, etc.). This requires having a better access to 5,15-diarylporphyrins in term of yield, purification procedure and access to starting materials. Our strategy for the preparation of 5,15-diarylporphyrins relies on the condensation of aryldipyrromethanes with orthoesters, giving directly the desired porphyrin after air oxidation (Fig. 4). It is important to note that to our best knowledge, the condensation of phenyldipyrromethane with methyl orthoformate has been reported once, giving the expected porphyrins in low yields.11 Some other examples started from dicarboxyl–dipyrromethane and after in situ decarboxylation, the formation of porphyrin took place with trimethyl orthoformate.12 These strategies present the advantage of producing the expected porphyrins directly after condensation and treatment with air without the drawback of preparing the unstable dipyrromethane, using DDQ for the oxidation step, or performing tedious chromatography purifications.11 In this letter we report an improved preparation of 5,15-diarylporphyrins in two steps and the preparation of A2B2 tetra-substituted porphyrins, following the same strategy. Yields were moderate to good, and a wide variety of porphyrins were thus obtained. The aryldipyrromethanes 2a–i were easily prepared through the well-known Lindsey et al. procedure4 from the corresponding aromatic aldehydes 1a–i and pyrrole in the presence of a catalytic amount of trifluoroacetic acid (TFA), in yields ranging from 62% to 89% (Table 1). The reactions were performed in the presence of a large excess of pyrrole (200 equiv) with 1 equiv of aldehyde 1a–i
under nitrogen and with TFA (0.1–0.5 equiv). After work-up, excess of pyrrole was distilled off and the crude residue purified by flash column chromatography on silica gel (with 8/2/1 cyclohexane/ EtOAc/NEt3 as eluent), affording the air and moisture stable aryldipyrromethanes 2a–i. Then we studied the condensation of compounds 2a–i with methyl orthoformate (72 equiv) under acid activation, as reported.11 In our hands the use of an excess of trichloroacetic acid did not allow us to obtain the desired 5,15-diphenylporphyrin 3a with the reported yield (14%), albeit in trace amount or around 1% isolated yield, depending on the experiment (Table 2, entry 1). As it was reported,11a preparation of 5,15-diphenylporphyrin 3a was hardly reproducible under these reaction conditions. We thus decided to study the influence of the acid used (Table 2, entries 2–7) and found that higher yields were obtained in the presence of trifluoroacetic acid (TFA), better Brønsted acid tested, or Lewis acids such as magnesium bromide (MgBr2) and trifluoroborate etherate (BF3OEt2). Finally, with 38 equiv of TFA, 5,15-diphenylporphyrin 3a was obtained in a moderate but reproducible 36% isolated yield (Table 2, entry 7).13 With lower amounts of TFA (10 or 23 equiv), yields remain moderate (21% and 27%, respectively). So far as evidenced by 1H NMR and MS analysis, no N-confused porphyrin was formed under these reaction conditions. Indeed, it is worth noting that the remaining mass balance was mainly due to polymeric material, since besides the expected porphyrin a minor product was formed (isolated in 6% yield and separated by flash chromatography), which corresponds to 10-formyl5,15-diphenyl porphyrin 7a.14a Then 5,15-diarylporphyrins 3b–i were prepared according to the reaction conditions described above (Table 3), by treatment of the aryldipyrromethanes 2b–i with methyl orthoformate (72 equiv) in dichloromethane under nitrogen and in the dark. TFA (38 equiv) in dichloromethane was added at room temperature in 30 min. After 4 h of stirring, pyridine was added and stirring was maintained 17 h, prior bubbling air for 15 min and stirring for 4 h. Solvent was evaporated off under vacuum and the residue was purified by flash chromatography on silica gel (CH2Cl2/cyclohexane = 70:30 as eluent). Most of the 5,15-diarylporphyrins were obtained with yields ranging from 4% to 9% (Table 3, entries 2, 3, 5–8). However most of the remaining mass balances were again due to polymerization, since flash chromatographies on silica gel afforded
Table 2 Preparation of 5,15-diphenylporphyrin 3a from 2a and methyl orthoformate Entry
Acid
(equiv)
3a (%)
1 2 3 4 5 6 7
CCl3COOH CH3SO3H BF3OEt2 MgBr2 CF3COOH CF3COOH CF3COOH
(23) (23) (23) (23) (10) (23) (38)
1 9 4 8 21 27 36
Z. Abada et al. / Tetrahedron Letters 52 (2011) 3175–3178 Table 3 Preparation of 5,15-diarylporphyrins 3a–i and tetra-substituted porphyrins 4a and 5a Entry
Aryldipyrrromethane (Ar)
Ortho ester
Porphyrin: yield (%)
1 2 3 4 5 6 7 8 9 10 11
2a (Ph) 2b (3-Br-Ph) 2c (2-Br-Ph) 2d (2,3,4,5,6-F6-Ph) 2e (2,6-Cl2-Ph) 2f (2-naphthyl) 2g (3-indolyl) 2h (4-NO2-Ph) 2i (3,4,5-(OMe)3-Ph) 2a (Ph) 2a (Ph)
HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 CH3C(OMe)3 PhC(OMe) 3
3a: 36 3b: 10 3c: 9 3d: 5 3e: 6 3f: 17 3g: 4 3h: traces 3i: 43 4a: 27 5a: 20
easily the expected products. Minor compounds, which were not the N-confused porphyrins, were sometimes characterized such as 10-formyl-5,15-bis(3-bromophenyl)porphyrin 7b.14b Higher yields were however obtained for 5,15-bis-(2-naphthyl)porphyrin 3f (17%, Table 3, entry 6) and for 5,15-bis-(3,4,5-trimethoxyphenyl)porphyrin 3i (43%, Table 3, entry 9). Thus the presence of an electron-withdrawing group, such as 4-nitro or a halogen atom, seems to have a deleterious effect on the course of the reaction, whereas electron-donor groups give higher yields. Steric hindrance (substitution at the 2 and 6 positions of the phenyl group) is also responsible for lower yields in the expected porphyrins.15 Then, generalization of the reaction was studied by using methyl orthoacetate and methyl orthobenzoate with phenyldipyrromethane 2a. In both cases, the expected A2B2 and A4 tetrasubstituted porphyrins were obtained in moderate but reproducible yields (27% for 4a16 and 20% for 5a, Table 3 entries 10 and 11). Finally, with 5,15-diarylporphyrins 3a–i in hands, it is interesting to note that tetra-arylporphyrins could also be obtained in a four step procedure by addition of 10 equiv of aryllithium and oxidation by DDQ,17,18 followed by a second addition of aryllithium and DDQ oxidation. For instance, tetra-substituted tetrakis-phenyl porphyrin 5a was obtained in 47% yield from 6a and 15% overall yield (from benzaldehyde), through the triarylporphyrine intermediate 6a, which was obtained in 97% yield from 3a (Fig. 5).19 In conclusion, this study shows that 5,15-diarylporphyrins can be prepared from aryldipyrromethanes by condensation with methyl orthoformate in the presence of trifluoroacetic acid. Yields were low to moderate, but the purification step was straightfor-
N H N
N H N
PhLi then DDQ 97%
N H N
N H N 6a
3a
PhLi then DDQ
47%
N H N
N H N 5a
Figure 5. Preparation of tetra-substituted porphyrin 5a.
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ward since the desired porphyrins were easily separated from polymeric materials and secondary compounds (e.g., 10-formyl5,15-diarylporphyrin). Electron-withdrawing substituents on the phenyl ring of the aryldipyrromethanes (e.g., halogen, nitro group) gave lower yields as well as indolyl moiety. Extension of this methodology to the condensation of aryldipyrromethanes with methyl orthoacetate and methyl orthobenzoate allowed us to prepare the corresponding 5,10,15,20-tetra-substituted porphyrins in acceptable yields. Finally, double addition of aryllithium reagents on 5,15-diarylporphyrins gave an easy access to 5,10,15,20-tetraarylporphyrines with A4 symmetry in reasonable yields and easy chromatographic purifications. This study has thus allowed us to prepare 13 porphyrins (most are new ones) that will be tested in due course in PDT. Acknowledgments Thanks are due to K. Leblanc for her help in chromatography analyses, and for mass spectrometry analyses. We wish to thank J. C. Jullian (Châtenay-Malabry) and J. F. Gallard (ICSN, Gif sur Yvette, France) for NMR experiments. Supplementary data Supplementary data (1H NMR spectra of compounds 3a–i, 4a, 5a, 6a, 7a,b) associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.04.028. References and notes 1. (a) Manka, J. S.; Lawrence, D. S. Tetrahedron Lett. 1989, 30, 6989–6992; (b) Gariboldi, M. B.; Ravizza, R.; Baranyai, P.; Caruzo, E.; Banfi, S.; Meschini, S.; Monti, E. Bioorg. Med. Chem. 2009, 17, 2009–2016; (c) Lecas-Nawrocka, A.; Boitrel, B.; Rose, E. Tetrahedron Lett. 1992, 33, 481. 2. Banfi, S.; Caruso, E.; Caprioli, S.; Mazzagatti, L.; Canti, G.; Ravizza, R.; Gariboldi, M.; Monti, E. Bioorg. Med. Chem. 2004, 12, 4853–4860. 3. Banfi, S.; Caruso, E.; Buccafuni, L.; Murano, R.; Monti, E.; Gariboldi, M.; Papa, E.; Gramatica, P. J. Med. Chem. 2006, 49, 3293–3304. 4. Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391–1396. 5. Laha, J. K.; Dhanaleski, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S. Org. Process Rev. Dev. 2003, 7, 799–812. 6. (a) O’Connor, A. E.; Gallagher, W. M.; Byrne, A. T. Photochem. Photobiol. 2009, 85, 1053–1074; (b) Maisch, T. Mini-Rev. Med. Chem. 2009, 9, 974–983. 7. Sharman, W. M.; Allen, C. M.; van Lier, J. E. Drug Discovery Today 1999, 4, 507– 517. 8. (a) Jimenez-Banzo, A.; Sagrista, M. L.; Mora, M.; Nonell, S. Free Radical Biol. Med. 2008, 44, 1926–1934; (b) Juzeniene, A.; Moan, J. Photodiagn. Photodyn. Ther. 2007, 7, 3–11; (c) Kral, V.; Kralova, J.; Kaplanek, R.; Briza, T.; Martasek, P. Physiol. Res. 2006, 55, S3–S26. 9. (a) Byrne, C. J.; Cooper, M. A.; Cowled, P. A.; Johnson, R. A. W.; MacKenzie, L.; Marshallsay, L. V.; Morris, I. K.; Muldoon, C. A.; Raftery, M. J.; Yin, S. S.; Waerd, A. D. Aust. J. Chem. 2004, 57, 1091–1102; (b) Vogeser, M.; Schaffer, M.; Egeler, E.; Spohrer, U. Clin. Biochem. 2005, 38, 73–78. and references cited therein. 10. (a) Bonnett, R.; White, R. D.; Winfield, U. J.; Berenbaum, M. C. Biochem. J. 1989, 261, 277–280; (b) Bonnett, R.; Charlesworth, P.; Djelal, B. D.; MacGarvey, D. J.; Truscott, T. G. J. Chem. Soc., Perkin Trans. 2 1999, 325–328; (c) Serra, A. C.; Pineiro, M.; d’A Rocha Gonsalves, A. M.; Abrantes, M.; Laranjo, M.; Santos, A. C.; Botelho, M. F. J. Photochem. Photobiol., B-Biol. 2008, 92, 59–65. and references cited therein. 11. (a) Boyle, W.; Bruckner, C.; Posakony, J.; James, B. R.; Dolphin, D. Org. Synth. 1998, 76, 287–293; (b) Fox, S.; Hudson, R.; Boyle, R. W. Tetrahedron Lett. 2003, 44, 1183–1185. 12. (a) Collman, J. P.; Chong, A. O.; Jameson, G. B.; Oakley, R. T.; Rose, E.; Schmittou, E. R.; Ibers, J. A. J. Am. Chem. Soc. 1981, 103, 516–533; (b) Lecas, A.; Levisalles, J.; Renko, Z.; Rose, E. Tetrahedron Lett. 1984, 25, 1563–1566; (c) Boitrel, B.; Lecas, A.; Renko, Z.; Rose, E. Chem. Commun. 1985, 1820–1821; (d) Boitrel, B.; Lecas, A.; Renko, Z.; Rose, E. New J. Chem. 1989, 13, 73–99. 13. 5,15-Diphenylporphyrin 3a:11 following general procedure from 5phenyldipyrromethane (121.5 mg, 0.55 mmol) and trimethyl orthoformate gave expected porphyrin 3a as purple solid (45.6 mg, 36%), C32H22N4. 1H (CDCl3, 400 MHz) d 3.11 (br s, 2H, 2NH), 7.81 (m, 6H, m,p-Ph H), 8.29 (m, 4H, o-Ph H), 9.09 (d, 3J = 4.5 Hz, 4H, b H), 9.40 (d, 3J = 4.5 Hz, 4H, b H), 10.33 (s, 2H, H-meso). 13C (CDCl3, 100 MHz) d 147.2 (C); 145.2 (C), 141.4 (C), 134.8 (CH), 131.6 (CH), 131.0 (CH), 127.7 (CH), 126.9 (CH), 119. (C), 105.3 (CH meso). UV– vis (nm): 400, 499, 533, 573. HRMS (ESI): MH+, found 463.1907. C32H22N4 requires 462.1918. Rf (cyclohexane/AcOEt: 7/3) 0.58.
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14. (a) 10-Formyl-5,15-diphenylporphyrin 7a: As a purple solid (9.4 mg, 6%), C31H22N4O. 1H (CDCl3, 400 MHz) d 2.53 (br s, 2H, 2NH), 7.82 (m, 6H, m,pPh-H), 8.18 (dd, J = 0.9 Hz, J = 7.2 Hz, 4H, o-Ph-H), 8.86 (d, J = 4.5 Hz, 2H, b-Hd), 9.03 (d, J = 5.1 Hz, 2H, b-Hb), 9.22 (d, J = 4.5 Hz, 2H, b-Hc), 10.03 (d, J = 4.5 Hz, 2H, b-Ha), 10.28 (s, 1H, Hmeso), 12.53 (s, 1H, CHO). 13C (CDCl3, 100 MHz) d 195.2 (CHO), 141.2 (C), 134.4 (CH), 131.6 (CH), 131.5 (CH), 128.1 (CH), 126.9 (CH), 122.2 (C), 109.9 (CH), 108.1 (C). UV–vis (nm): 424, 521, 560, 593, 648 in CHCl3. IR (cm 1): 3020, 2165, 1975, 1665, 1215, 1050, 745. LRMS (ESI): 491 (MH+). Rf (cyclohexane/AcOEt: 7/3) 0.49; (b) 10-Formyl-5,15-bis(3bromophenyl)porphyrin 7b: As a purple solid (68 mg, 6%), C33H20Br2N4O. 1H (CDCl3, 400 MHz) d 2.58 (br s, 2H, 2NH), 7.67 (t, J = 7.8 Hz, 2H, Ph-H), 8.00 (d, J = 8.1 Hz, 2H, Ph-H), 8.13 (d, J = 6.9 Hz, 2H, Ph-H), 8.37 (s, 2H, Ph-H), 8.88 (d, J = 4.2 Hz, 2H, b-Hd), 9.04 (d, J = 4.8 Hz, 2H, b-Hb), 9.31 (d, J = 4.2 Hz, 2H, b-Hc), 10.09 (d, J = 4.5 Hz, 2H, b-Ha), 10.28 (s, 1H, Hmeso), 12.59 (s, 1H, CHO). 13C (CDCl3, 75 MHz) d 195.1 (CHO), 174.4, 160.1, 143.2, 136.9, 132.9, 131.4, 128.4, 121.4, 110.1. UV–vis (nm): 424, 521, 560, 593, 648 in CHCl3. LRMS (APCI): 649 (MH+). Rf (cyclohexane/AcOEt: 8/2) 0.56. 15. (a) 5,15-Bis(3-bromophenyl)porphyrin 3b: Following general procedure from 5(3-bromophenyl)dipyrromethane (1.1 g, 3.59 mmol) and trimethyl orthoformate gave expected porphyrin 3b as purple solid (109 mg, 10%), 1 C32H20Br2N4. H (CDCl3, 300 MHz) d 2.25 (br s, 2H, 2NH), 7.6 (t, J = 7.8 Hz, 2H), 7.83 (ddd, J = 1.9 Hz, J = 2.0 Hz, J = 8.1 Hz, 2H), 8.15 (dd, J = 7.4 Hz, J = 0.9 Hz, 2H, PhH), 8.32 (s, 2H, PhH), 8.88 (d, J = 4.6 Hz, 4H, b H), 9.37 (d, J = 4.7 Hz, 4H, b H), 10.36 (s, 2H, CH meso). 13C (pyridinD5, 500 MHz) d 137.7, 135.1, 133.8, 132.8, 132.6, 131.4, 131.2, 129.2, 106.4, 103.3, 79.7. UV–vis (nm): 394, 502, 536, 575, 629. HRMS (ESI): MH+ found, 619.0137. C32H21N4Br2 requires 619.0127. Rf (cyclohexane/AcOEt: 8/2) 0.71. (b) 5,15-Bis(2bromophenyl)porphyrin 3c: Following general procedure from 5-(2bromophenyl)dipyrromethane (300 mg, 1.00 mmol) and trimethyl orthoformate gave expected porphyrin 3c as purple solid (28.3 mg, 9%), C32H20Br2N4.1H (CDCl3, 400 MHz) d 3.11 (br s, 2H, NH), 7.72 (m, 4H, Ph-H), 8.07 (m, 2H, Ph-H), 8.19 (dd, J = 2.3 Hz, J = 7.2 Hz, 1H, CH–CBr), 8.23 (dd, J = 1.9 Hz, J = 7.2 Hz, 1H, Ph-H), 8.90 (d, J = 4.2 Hz, 4H, b H), 9.37 (d, J = 4.2 Hz, 4H, b H), 10.29 (s, 2H, CH meso). 13C (CDCl3, 75 MHz) d 135.4 (CH), 135.3 (CH), 132.2 (CH), 131.8 (CH), 130.5 (C), 130.0 (CH), 127.9 (C), 127.6 (C), 126.0 (CH), 105.4 (CHmeso), 90.1 (C–Br). HRMS (ESI): MH+ found, 619.0125. C32H21N4Br2 requires 619.0127. UV–vis (nm): 407, 503, 532, 575, 630. Rf (cyclohexane/ AcOEt: 7/3) 0.62; (c) 5,15-Bispentafluorphenyl-porphyrin 3d: Following general procedure from 5-pentafluoro-dipyrromethane (3.25 g, 10,4 mmol) and trimethyl orthoformate gave expected porphyrin 3d as dark purple solid (172 mg, 5%), C32H12F10N4. 1H (CDCl3, 300 MHz) d 3.24 (br s, 2H, 2NH), 9.00 (d, J = 4.7 Hz, 4H), 9.49 (d, J = 4.8 Hz, 4H), 10.39 (s, 2H, CH meso). UV–vis (nm): 405, 503, 537, 575, 630. HRMS (ESI): MH+ found, 643.0984. C32H13F10N4 requires 643.0978. Rf (cyclohexane/AcOEt: 7/3) 0.73; (d) 5,15-Bis(2,6dichlorophenyl)porphyrin 3e: Following general procedure from 5-bis(2,6dichlorophenyl)dipyrromethane (500 mg, 1.72 mmol) and trimethyl orthoformate gave expected porphyrin 3e as purple solid (63 mg, 8%), C32H18Cl4N4. 1H (CDCl3, 300 MHz) d 3.10 (br s, 2H, 2NH), 7.83 (m, 6H, Ph H), 8.87 (d, J = 4.7 Hz, 4H, b H), 9.38 (d, J = 4.8 Hz, 4H, b H), 10.29 (s, 2H, CH meso). UV–vis (nm): 407, 502, 533, 581, 631. HRMS (ESI): MH+ found, 601.0321. C32H19Cl4N4 requires 600.9726. Rf (cyclohexane/AcOEt: 7/3) 0.58; (e) 5,15-Bisnaphthylporphyrin 3f: Following general procedure from 5naphtyldipyrromethane (300 mg, 1.10 mmol) and trimethyl orthoformate gave expected porphyrin 3f as purple solid (51.7 mg, 17%), C40H26N4. 1H (CDCl3, 300 MHz) d 3.01 (br s, 2H, NH), 7.76 (m, 4H, CHAR), 8.14 (m, 2H, CHAR), 8.24 (d, J = 8.6 Hz, 2H, CHAR), 8.47 (d, J = 8.4 Hz, 2H, CHAR), 8.74 (s, 2H, CHAR), 9.11 (d, J = 4.6 Hz, 2H, b H), 9.41 (d, J = 4.6 Hz, 2H, b H), 10.34 (s, 2H, CH meso). 13 C (CDCl3, 500 MHz) d 147.5, 147.5, 145.4 (4C), 144.9 (4C),139.0 (2C),134.0 (2CH), 132.9, 132.9 (2C), 132.5 (2C), 131.7 (4CH), 131.2 (4CH), 128.5 (2CH), 128.1 (2CH), 126.9 (2CH), 126.9 (2CH), 126.2 (2CH), 119.1 (2C), 118.3 (2C), 105.4 (CH). UV–vis (nm): 410, 506, 541, 578, 633. HRMS (ESI): MH+ found, 563.2226. C40H27N4 requires 563.2230. Rf (cyclohexane/AcOEt: 7/3) 0.63; (f) 5,15-Bis(3-indolyl)porpohyrin 3g: Following general procedure from 5-(3indolyl)dipyrromethane (1 g, 3.83 mmol) and trimethyl orthoformate gave
16.
17. 18.
19.
20. 21. 22.
expected porphyrin 3g as red purple solid (25 mg, 3%), C36H24N6. 1H (CDCl3, 300 MHz) d 3.41 (br s, 2H, NH), 7.52 (m, 4H), 7.72 (m, 2H), 7.79 (m,2H), 8.06 (d, J = 2.1 Hz, 1H), 8.88 (brs,1H), 9.27 (d, J = 4.5 Hz, 2H, b H), 9.37 (d, J = 4.5 Hz, 2H, b H), 9.49 (m, 4H, b H), 10.25 (s, 1H), 10.32 (s, 2H, CH meso). 13C (CDCl3, 500 MHz) d 139.1 (C), 131.7 (CH), 131.6 (CH), 131.1 (CH), 131.0 (CH), 128.6 (CH), 122.9 (CH), 120.9 (CH), 120.6, 111.3 (CH), 107.3 (C), 104.5 (CH), 103.4 (CH). UV–vis (nm): 407, 501, 536, 574, 630. HRMS (ESI): MH+ found, 541.1069. C36H25N6 requires 541.2136. Rf (cyclohexane/AcOEt: 7/3) 0.29; (g) 5,15Di(3,4,5-trimethoxyphenyl)-porphyrin 3i:3,20 following general procedure from 5-(3,4,5-trimehtoxypheny) dipyrromethane (300 mg, 0.96 mmol) and trimethyl orthoformate gave expected porphyrin 3i as dark red purple solid (133.7 mg, 43%), C38H34N4O6. 1H (CDCl3, 300 MHz) d 3,11 (br s, 2H, NH), 3.99 (s, 12H, m-CH3O), 4.18 (s, 6H, p-CH3O), 7,51 (s, 4H, o-Ph H), 9.16 (d, J = 4.5 Hz, 4H, b H,), 9.38(d, J = 4.5 Hz, 4H, b H,), 10.30 (s, 2H, H meso). 13C (CDCl3, 75 MHz) d 151.7 (C), 147.1 (C), 145.3 (C), 137.9 (C), 136.9 (C), 131.7 (CH), 131.0 (CH), 118.9 (C), 112.9(CH), 105.4 (CH meso), 61.3 (OMe), 56.4 (OMe). UV–vis (nm): 411, 445, 504, 539, 580, 630. HRMS (ESI): MH+ found, 643.2538. C38H34N4O6 requires 643.2794. Rf (cyclohexane/AcOEt: 7/3) 0.33. 5,15-Dimethyl-10,20-diphenylporphyrin 4a: Following general procedure from 5-phenydipyrromethane (100 mg, 0.96 mmol) and trimethyl orthoacetate gave expected porphyrin as dark purple solid (29.8 mg, 27%), C34H26N4. 1H (CDCl3, 300 MHz) d 2.56 (s, 2H, 2NH), 4.6 (s, 6H, 2CH3), 7.78 (m, 6H, m,p-PhH), 8.20 (m, 4H, o-PhH), 8.85 (d, J = 4.8 Hz,4H, b H), 9.44 (d, J = 4.8 Hz, 4H, b H). 13C (CDCl3, 75 MHz) d 154.6 (C), 147.0 (C), 129.0 (CH), 128.9 (CH), 128.5 (CH), 128.3 (CH), 101.1 (CH), 29.7 (CH3). 13C (CDCl3, 500 MHz) d 154.6 (C), 147.0 (C), 142.7 (C), 134.5, 131.6, 129.0 (CH), 128.9 (CH), 128.5 (CH), 128.3 (CH), 127.6 (CH), 126.6, 119.2, 116.5, 113.8 (C), 101.1 (CH), 29.7 (CH3). HRMS (ESI): MH+ found, 491.2227. C34H27N4 requires 491.2229. UV–vis (nm): 423, 518, 554, 597, 654. Rf (cyclohexane/AcOEt: 7/3) 0.61. Feng, X. D.; Senge, M. O. Tetrahedron 2000, 56, 587–590. (a) Takanami, T.; Matsumoto, J.; Kumagai, Y.; Sawaizumi, A.; Suda, K. Tetrahedron Lett. 2009, 50, 68–70; (b) Takanami, T.; Wakita, A.; Sawaizumi, A.; Iso, K.; Onodera, H.; Suda, K. Org. Lett. 2008, 10, 685–687. (a) 5,10,15-Triphenylporphyrin 6a:18,20,21 In a dry flask, under positive pressure of nitrogen, containing diphenylporphyrin 3a (15 mg, 0.032 mmol, 1 equiv) in 1.3 mL of dry tetrahydrofurane, PhLi (1.4 mL, 0.24 mmol, 7.5 mmol, 1.8 M in Bu2O) was added slowly with a syringe at 78 °C. The mixture became black red and was stirred at 78 °C for 2 h. The bath was removed to allow the temperature rising. After 1 h at room temperature H2O was added at 0 °C, the solution was stirred 10 min, DDQ was added and the green mixture became dark red. Stirring was maintained for 30 min then the reaction mixture was poured into brine and extracted with dichloromethane. The crude product was purified by column chromatography (cyclohexane/AcOEt 9/1) to give the expected triphenylporphyrin 6a as a red purple solid (16.8 mg, 97%), C38H26N4. 1 H (CDCl3, 400 MHz) d 2.95 (br s, 2H, NH), 7.81 (m, 9H, m,p-PhH), 8.26 (m, 6H, o-PhH), 8.91 (m, 4H, b H), 9.04 (d, J = 4.5 Hz, 2H, b H), 9.33 (d, J = 4.5 Hz, 2H, b H), 10.21 (s, 1H, CH meso). 13C (CDCl3, 100 MHz) d 142.6 (C), 141.8 (C), 134.6 (2CH), 134,5 (CH), 132.4 (CH), 131.5 (CH), 131.4 (CH), 131.3 (CH), 130.7 (CH), 130.0 (CH), 128.3 (CH), 127.7 (2CH), 126.8 (2CH), 126,5 (CH), 120.6 (C), 119.6 (C), 104.8 (CH meso). HRMS (ESI): MH+ found, 539.2208. C38H27N4 requires 539.2230. UV–vis (nm): 414, 440, 509, 543, 583, 640. Rf (cyclohexane/AcOEt: 9/ 1) 0.60; (b) Tetrakisphenylporphyrin 5a:22 Following previous procedure above from triphenylporphyrin 6a the expected tetraphenylporphyrin 5a was obtained as dark purple solid (46 mg, 47%), C44H30N4. 1H (CDCl3, 300 MHz) d 2.76 (br s, 2H, NH), 7.75 (m, 12H, m,p-Ph-H), 8.24 (m, 8H, o-Ph-H), 8.84 (s, 8H, b H). 13C (CDCl3, 75 MHz) d 145.7 (C), 142.2 (C), 134.0 (CH), 130.5 (CH), 127.5 (CH), 126.0 (CH), 119.5 (C). HRMS (ESI): MH+ found, 615.2559. C44H31N4 requires 615.2543. UV–vis (nm): 423, 516, 551, 591, 649. Rf (cyclohexane/ AcOEt: 9/1) 0.63. Senge, M. O.; Shaker, Y. M.; Pintea, M.; Ryppa, C.; Hatscher, S. S.; Ryan, A.; Sergeeva, Y. Eur. J. Org. Chem. 2010, 2, 237–258. Senge, M. O. Acc. Chem. Res. 2005, 38, 733–743. Lindsey, J. S.; Hsu, H. C.; Schreiman, I. C. Tetrahedron Lett. 1986, 27, 4969–4970.
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 5,15-diarylporphyrins via orthoesters condensation with aryldipyrromethanes Zahra Abada a,b, Laurent Ferrié b, Bernardin Akagah a, Anh Tuan Lormier a, Bruno Figadère b,⇑ a b
Alpha-Chimica, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry, France UMR CNRS 8076, University Paris-Sud, Laboratoire de Pharmacognosie, UFR de Pharmacie, Châtenay-Malabry F-92296, France
a r t i c l e
i n f o
Article history: Received 24 February 2011 Revised 5 April 2011 Accepted 6 April 2011 Available online 12 April 2011
a b s t r a c t General access to 5,15-diarylporphyrins in two steps is described. Generalization of this approach to tetra-substituted porphyrins allows the reproducible preparation of compounds, in some cases with high yields for porphyrins, which can be used in photodynamic therapy (PDT) in cancer today. Ó 2011 Published by Elsevier Ltd.
Keywords: Condensation Symmetry Acid catalysis Photosensitizers Anticancer
The general access to 5,15-diarylporphyrins follows usually the well known two step procedure,1–3 however giving low yields and tedious chromatography purifications: namely, preparation of dipyrromethane4 (an air and moisture sensitive compound5) then condensation with an aromatic aldehyde followed by DDQ oxidation (Fig. 1). Recently, Banfi et al. has studied the comparative activity of tetra-arylporphyrins and 5,15-diarylporphyrins in PDT.2,3 The study has shown that (i) 5,15-diarylporphyrins were more active and (ii) the crucial importance of hydroxyl groups on the aryl substituents, both for the solubility concerns and for the photo-toxicity was observed.3 Indeed, in the treatment of cancer, photodynamic therapy (PDT) has become an attractive alternative approach.6,7 PDT uses a tumor-localizing photosensitizing agent, usually a porphyrin, that absorbs visible light and in presence of oxygen generates cytotoxic reactive oxygen species (ROS). It is well admitted that the produced singlet oxygen (1O2) is responsible for cell death.8 To this date only two compounds have been approved for PDT cancer treatment: porfimer (photofrin) is derived from hematoporphyrin,9 and foscan (m-THPC or 5,10,15,20-terakis(m-hydroxyphenyl)chlorin) is a chlorin, a second generation porphyrin derivative that shows an interesting photo-toxicity against cancerous cell lines (Fig. 2).10
It is important to note that verteporfin, a 1:1 mixture of photosensitizing porphyrins isomers, has been approved for the treat-
HCHO
N H
N H
Ar
N H
1) ArCHO 2)DDQ
N
N H N
NH Ar
Figure 1. Preparation of 5,15-diarylporphyrins in the literature.
HO
OH
HO N
N H
O
HN
NH
N
N
N
HO
H N
O HO
⇑ Corresponding author. E-mail address: bruno.fi[email protected] (B. Figadère). 0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2011.04.028
O Photofrin
2
HO
OH
Figure 2. Photofrin and foscan.
Foscan
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Z. Abada et al. / Tetrahedron Letters 52 (2011) 3175–3178
O
O HO
O HO
O
Table 1 Preparation of aryldipyrromethanes 2a–i from pyrrole and aldehydes 1a–i
O
O N HN
NH
HN
NH
N
MeO
N
+
N
HO
O
O HO
Entry
Aldehyde
TFA (equiv)
Yield (%)
1 2 3 4 5 6 7 8 9
PhCHO 1a 3-Br-PhCHO 1b 2-Br-PhCHO 1c 2,3,4,5,6-F6-PhCHO 1d 2,6-Cl2-PhCHO 1e 2-NaphthylCHO 1f 3-IndolylCHO 1g 4-NO2-PhCHO 1h 3,4,5-(OMe)3-PhCHO 1i
0.1 0.5 0.5 0.1 0.1 0.1 0.1 0.5 0.5
2a: 89 2b: 80 2c: 74 2d: 62 2e: 70 2f: 72 2g: 75 2h: 70 2i: 71
MeO O
O Figure 3. Verteporfin.
R1 ArCHO N H
NH
RC(OMe)3
N H
then air
2a-i R R = H: 3a-i R = CH3: 4a R = Ph: 5a
N
N R1
R1
N H H N
R
Figure 4. Our strategy for the synthesis of 5,15-diarylporphyrins 3a-I, 4a, 5a.
ment of abnormal blood vessels in the eyes associated with macular degeneration (Fig. 3). It would be interesting to compare the activity of symmetric 5,15-diarylporphyrins (A2 symmetry) with the activity of tetraarylporphyrins of several symmetries (A2B2, A2BC, etc.). This requires having a better access to 5,15-diarylporphyrins in term of yield, purification procedure and access to starting materials. Our strategy for the preparation of 5,15-diarylporphyrins relies on the condensation of aryldipyrromethanes with orthoesters, giving directly the desired porphyrin after air oxidation (Fig. 4). It is important to note that to our best knowledge, the condensation of phenyldipyrromethane with methyl orthoformate has been reported once, giving the expected porphyrins in low yields.11 Some other examples started from dicarboxyl–dipyrromethane and after in situ decarboxylation, the formation of porphyrin took place with trimethyl orthoformate.12 These strategies present the advantage of producing the expected porphyrins directly after condensation and treatment with air without the drawback of preparing the unstable dipyrromethane, using DDQ for the oxidation step, or performing tedious chromatography purifications.11 In this letter we report an improved preparation of 5,15-diarylporphyrins in two steps and the preparation of A2B2 tetra-substituted porphyrins, following the same strategy. Yields were moderate to good, and a wide variety of porphyrins were thus obtained. The aryldipyrromethanes 2a–i were easily prepared through the well-known Lindsey et al. procedure4 from the corresponding aromatic aldehydes 1a–i and pyrrole in the presence of a catalytic amount of trifluoroacetic acid (TFA), in yields ranging from 62% to 89% (Table 1). The reactions were performed in the presence of a large excess of pyrrole (200 equiv) with 1 equiv of aldehyde 1a–i
under nitrogen and with TFA (0.1–0.5 equiv). After work-up, excess of pyrrole was distilled off and the crude residue purified by flash column chromatography on silica gel (with 8/2/1 cyclohexane/ EtOAc/NEt3 as eluent), affording the air and moisture stable aryldipyrromethanes 2a–i. Then we studied the condensation of compounds 2a–i with methyl orthoformate (72 equiv) under acid activation, as reported.11 In our hands the use of an excess of trichloroacetic acid did not allow us to obtain the desired 5,15-diphenylporphyrin 3a with the reported yield (14%), albeit in trace amount or around 1% isolated yield, depending on the experiment (Table 2, entry 1). As it was reported,11a preparation of 5,15-diphenylporphyrin 3a was hardly reproducible under these reaction conditions. We thus decided to study the influence of the acid used (Table 2, entries 2–7) and found that higher yields were obtained in the presence of trifluoroacetic acid (TFA), better Brønsted acid tested, or Lewis acids such as magnesium bromide (MgBr2) and trifluoroborate etherate (BF3OEt2). Finally, with 38 equiv of TFA, 5,15-diphenylporphyrin 3a was obtained in a moderate but reproducible 36% isolated yield (Table 2, entry 7).13 With lower amounts of TFA (10 or 23 equiv), yields remain moderate (21% and 27%, respectively). So far as evidenced by 1H NMR and MS analysis, no N-confused porphyrin was formed under these reaction conditions. Indeed, it is worth noting that the remaining mass balance was mainly due to polymeric material, since besides the expected porphyrin a minor product was formed (isolated in 6% yield and separated by flash chromatography), which corresponds to 10-formyl5,15-diphenyl porphyrin 7a.14a Then 5,15-diarylporphyrins 3b–i were prepared according to the reaction conditions described above (Table 3), by treatment of the aryldipyrromethanes 2b–i with methyl orthoformate (72 equiv) in dichloromethane under nitrogen and in the dark. TFA (38 equiv) in dichloromethane was added at room temperature in 30 min. After 4 h of stirring, pyridine was added and stirring was maintained 17 h, prior bubbling air for 15 min and stirring for 4 h. Solvent was evaporated off under vacuum and the residue was purified by flash chromatography on silica gel (CH2Cl2/cyclohexane = 70:30 as eluent). Most of the 5,15-diarylporphyrins were obtained with yields ranging from 4% to 9% (Table 3, entries 2, 3, 5–8). However most of the remaining mass balances were again due to polymerization, since flash chromatographies on silica gel afforded
Table 2 Preparation of 5,15-diphenylporphyrin 3a from 2a and methyl orthoformate Entry
Acid
(equiv)
3a (%)
1 2 3 4 5 6 7
CCl3COOH CH3SO3H BF3OEt2 MgBr2 CF3COOH CF3COOH CF3COOH
(23) (23) (23) (23) (10) (23) (38)
1 9 4 8 21 27 36
Z. Abada et al. / Tetrahedron Letters 52 (2011) 3175–3178 Table 3 Preparation of 5,15-diarylporphyrins 3a–i and tetra-substituted porphyrins 4a and 5a Entry
Aryldipyrrromethane (Ar)
Ortho ester
Porphyrin: yield (%)
1 2 3 4 5 6 7 8 9 10 11
2a (Ph) 2b (3-Br-Ph) 2c (2-Br-Ph) 2d (2,3,4,5,6-F6-Ph) 2e (2,6-Cl2-Ph) 2f (2-naphthyl) 2g (3-indolyl) 2h (4-NO2-Ph) 2i (3,4,5-(OMe)3-Ph) 2a (Ph) 2a (Ph)
HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 HC(OMe)3 CH3C(OMe)3 PhC(OMe) 3
3a: 36 3b: 10 3c: 9 3d: 5 3e: 6 3f: 17 3g: 4 3h: traces 3i: 43 4a: 27 5a: 20
easily the expected products. Minor compounds, which were not the N-confused porphyrins, were sometimes characterized such as 10-formyl-5,15-bis(3-bromophenyl)porphyrin 7b.14b Higher yields were however obtained for 5,15-bis-(2-naphthyl)porphyrin 3f (17%, Table 3, entry 6) and for 5,15-bis-(3,4,5-trimethoxyphenyl)porphyrin 3i (43%, Table 3, entry 9). Thus the presence of an electron-withdrawing group, such as 4-nitro or a halogen atom, seems to have a deleterious effect on the course of the reaction, whereas electron-donor groups give higher yields. Steric hindrance (substitution at the 2 and 6 positions of the phenyl group) is also responsible for lower yields in the expected porphyrins.15 Then, generalization of the reaction was studied by using methyl orthoacetate and methyl orthobenzoate with phenyldipyrromethane 2a. In both cases, the expected A2B2 and A4 tetrasubstituted porphyrins were obtained in moderate but reproducible yields (27% for 4a16 and 20% for 5a, Table 3 entries 10 and 11). Finally, with 5,15-diarylporphyrins 3a–i in hands, it is interesting to note that tetra-arylporphyrins could also be obtained in a four step procedure by addition of 10 equiv of aryllithium and oxidation by DDQ,17,18 followed by a second addition of aryllithium and DDQ oxidation. For instance, tetra-substituted tetrakis-phenyl porphyrin 5a was obtained in 47% yield from 6a and 15% overall yield (from benzaldehyde), through the triarylporphyrine intermediate 6a, which was obtained in 97% yield from 3a (Fig. 5).19 In conclusion, this study shows that 5,15-diarylporphyrins can be prepared from aryldipyrromethanes by condensation with methyl orthoformate in the presence of trifluoroacetic acid. Yields were low to moderate, but the purification step was straightfor-
N H N
N H N
PhLi then DDQ 97%
N H N
N H N 6a
3a
PhLi then DDQ
47%
N H N
N H N 5a
Figure 5. Preparation of tetra-substituted porphyrin 5a.
3177
ward since the desired porphyrins were easily separated from polymeric materials and secondary compounds (e.g., 10-formyl5,15-diarylporphyrin). Electron-withdrawing substituents on the phenyl ring of the aryldipyrromethanes (e.g., halogen, nitro group) gave lower yields as well as indolyl moiety. Extension of this methodology to the condensation of aryldipyrromethanes with methyl orthoacetate and methyl orthobenzoate allowed us to prepare the corresponding 5,10,15,20-tetra-substituted porphyrins in acceptable yields. Finally, double addition of aryllithium reagents on 5,15-diarylporphyrins gave an easy access to 5,10,15,20-tetraarylporphyrines with A4 symmetry in reasonable yields and easy chromatographic purifications. This study has thus allowed us to prepare 13 porphyrins (most are new ones) that will be tested in due course in PDT. Acknowledgments Thanks are due to K. Leblanc for her help in chromatography analyses, and for mass spectrometry analyses. We wish to thank J. C. Jullian (Châtenay-Malabry) and J. F. Gallard (ICSN, Gif sur Yvette, France) for NMR experiments. Supplementary data Supplementary data (1H NMR spectra of compounds 3a–i, 4a, 5a, 6a, 7a,b) associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2011.04.028. References and notes 1. (a) Manka, J. S.; Lawrence, D. S. Tetrahedron Lett. 1989, 30, 6989–6992; (b) Gariboldi, M. B.; Ravizza, R.; Baranyai, P.; Caruzo, E.; Banfi, S.; Meschini, S.; Monti, E. Bioorg. Med. Chem. 2009, 17, 2009–2016; (c) Lecas-Nawrocka, A.; Boitrel, B.; Rose, E. Tetrahedron Lett. 1992, 33, 481. 2. Banfi, S.; Caruso, E.; Caprioli, S.; Mazzagatti, L.; Canti, G.; Ravizza, R.; Gariboldi, M.; Monti, E. Bioorg. Med. Chem. 2004, 12, 4853–4860. 3. Banfi, S.; Caruso, E.; Buccafuni, L.; Murano, R.; Monti, E.; Gariboldi, M.; Papa, E.; Gramatica, P. J. Med. Chem. 2006, 49, 3293–3304. 4. Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391–1396. 5. Laha, J. K.; Dhanaleski, S.; Taniguchi, M.; Ambroise, A.; Lindsey, J. S. Org. Process Rev. Dev. 2003, 7, 799–812. 6. (a) O’Connor, A. E.; Gallagher, W. M.; Byrne, A. T. Photochem. Photobiol. 2009, 85, 1053–1074; (b) Maisch, T. Mini-Rev. Med. Chem. 2009, 9, 974–983. 7. Sharman, W. M.; Allen, C. M.; van Lier, J. E. Drug Discovery Today 1999, 4, 507– 517. 8. (a) Jimenez-Banzo, A.; Sagrista, M. L.; Mora, M.; Nonell, S. Free Radical Biol. Med. 2008, 44, 1926–1934; (b) Juzeniene, A.; Moan, J. Photodiagn. Photodyn. Ther. 2007, 7, 3–11; (c) Kral, V.; Kralova, J.; Kaplanek, R.; Briza, T.; Martasek, P. Physiol. Res. 2006, 55, S3–S26. 9. (a) Byrne, C. J.; Cooper, M. A.; Cowled, P. A.; Johnson, R. A. W.; MacKenzie, L.; Marshallsay, L. V.; Morris, I. K.; Muldoon, C. A.; Raftery, M. J.; Yin, S. S.; Waerd, A. D. Aust. J. Chem. 2004, 57, 1091–1102; (b) Vogeser, M.; Schaffer, M.; Egeler, E.; Spohrer, U. Clin. Biochem. 2005, 38, 73–78. and references cited therein. 10. (a) Bonnett, R.; White, R. D.; Winfield, U. J.; Berenbaum, M. C. Biochem. J. 1989, 261, 277–280; (b) Bonnett, R.; Charlesworth, P.; Djelal, B. D.; MacGarvey, D. J.; Truscott, T. G. J. Chem. Soc., Perkin Trans. 2 1999, 325–328; (c) Serra, A. C.; Pineiro, M.; d’A Rocha Gonsalves, A. M.; Abrantes, M.; Laranjo, M.; Santos, A. C.; Botelho, M. F. J. Photochem. Photobiol., B-Biol. 2008, 92, 59–65. and references cited therein. 11. (a) Boyle, W.; Bruckner, C.; Posakony, J.; James, B. R.; Dolphin, D. Org. Synth. 1998, 76, 287–293; (b) Fox, S.; Hudson, R.; Boyle, R. W. Tetrahedron Lett. 2003, 44, 1183–1185. 12. (a) Collman, J. P.; Chong, A. O.; Jameson, G. B.; Oakley, R. T.; Rose, E.; Schmittou, E. R.; Ibers, J. A. J. Am. Chem. Soc. 1981, 103, 516–533; (b) Lecas, A.; Levisalles, J.; Renko, Z.; Rose, E. Tetrahedron Lett. 1984, 25, 1563–1566; (c) Boitrel, B.; Lecas, A.; Renko, Z.; Rose, E. Chem. Commun. 1985, 1820–1821; (d) Boitrel, B.; Lecas, A.; Renko, Z.; Rose, E. New J. Chem. 1989, 13, 73–99. 13. 5,15-Diphenylporphyrin 3a:11 following general procedure from 5phenyldipyrromethane (121.5 mg, 0.55 mmol) and trimethyl orthoformate gave expected porphyrin 3a as purple solid (45.6 mg, 36%), C32H22N4. 1H (CDCl3, 400 MHz) d 3.11 (br s, 2H, 2NH), 7.81 (m, 6H, m,p-Ph H), 8.29 (m, 4H, o-Ph H), 9.09 (d, 3J = 4.5 Hz, 4H, b H), 9.40 (d, 3J = 4.5 Hz, 4H, b H), 10.33 (s, 2H, H-meso). 13C (CDCl3, 100 MHz) d 147.2 (C); 145.2 (C), 141.4 (C), 134.8 (CH), 131.6 (CH), 131.0 (CH), 127.7 (CH), 126.9 (CH), 119. (C), 105.3 (CH meso). UV– vis (nm): 400, 499, 533, 573. HRMS (ESI): MH+, found 463.1907. C32H22N4 requires 462.1918. Rf (cyclohexane/AcOEt: 7/3) 0.58.
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14. (a) 10-Formyl-5,15-diphenylporphyrin 7a: As a purple solid (9.4 mg, 6%), C31H22N4O. 1H (CDCl3, 400 MHz) d 2.53 (br s, 2H, 2NH), 7.82 (m, 6H, m,pPh-H), 8.18 (dd, J = 0.9 Hz, J = 7.2 Hz, 4H, o-Ph-H), 8.86 (d, J = 4.5 Hz, 2H, b-Hd), 9.03 (d, J = 5.1 Hz, 2H, b-Hb), 9.22 (d, J = 4.5 Hz, 2H, b-Hc), 10.03 (d, J = 4.5 Hz, 2H, b-Ha), 10.28 (s, 1H, Hmeso), 12.53 (s, 1H, CHO). 13C (CDCl3, 100 MHz) d 195.2 (CHO), 141.2 (C), 134.4 (CH), 131.6 (CH), 131.5 (CH), 128.1 (CH), 126.9 (CH), 122.2 (C), 109.9 (CH), 108.1 (C). UV–vis (nm): 424, 521, 560, 593, 648 in CHCl3. IR (cm 1): 3020, 2165, 1975, 1665, 1215, 1050, 745. LRMS (ESI): 491 (MH+). Rf (cyclohexane/AcOEt: 7/3) 0.49; (b) 10-Formyl-5,15-bis(3bromophenyl)porphyrin 7b: As a purple solid (68 mg, 6%), C33H20Br2N4O. 1H (CDCl3, 400 MHz) d 2.58 (br s, 2H, 2NH), 7.67 (t, J = 7.8 Hz, 2H, Ph-H), 8.00 (d, J = 8.1 Hz, 2H, Ph-H), 8.13 (d, J = 6.9 Hz, 2H, Ph-H), 8.37 (s, 2H, Ph-H), 8.88 (d, J = 4.2 Hz, 2H, b-Hd), 9.04 (d, J = 4.8 Hz, 2H, b-Hb), 9.31 (d, J = 4.2 Hz, 2H, b-Hc), 10.09 (d, J = 4.5 Hz, 2H, b-Ha), 10.28 (s, 1H, Hmeso), 12.59 (s, 1H, CHO). 13C (CDCl3, 75 MHz) d 195.1 (CHO), 174.4, 160.1, 143.2, 136.9, 132.9, 131.4, 128.4, 121.4, 110.1. UV–vis (nm): 424, 521, 560, 593, 648 in CHCl3. LRMS (APCI): 649 (MH+). Rf (cyclohexane/AcOEt: 8/2) 0.56. 15. (a) 5,15-Bis(3-bromophenyl)porphyrin 3b: Following general procedure from 5(3-bromophenyl)dipyrromethane (1.1 g, 3.59 mmol) and trimethyl orthoformate gave expected porphyrin 3b as purple solid (109 mg, 10%), 1 C32H20Br2N4. H (CDCl3, 300 MHz) d 2.25 (br s, 2H, 2NH), 7.6 (t, J = 7.8 Hz, 2H), 7.83 (ddd, J = 1.9 Hz, J = 2.0 Hz, J = 8.1 Hz, 2H), 8.15 (dd, J = 7.4 Hz, J = 0.9 Hz, 2H, PhH), 8.32 (s, 2H, PhH), 8.88 (d, J = 4.6 Hz, 4H, b H), 9.37 (d, J = 4.7 Hz, 4H, b H), 10.36 (s, 2H, CH meso). 13C (pyridinD5, 500 MHz) d 137.7, 135.1, 133.8, 132.8, 132.6, 131.4, 131.2, 129.2, 106.4, 103.3, 79.7. UV–vis (nm): 394, 502, 536, 575, 629. HRMS (ESI): MH+ found, 619.0137. C32H21N4Br2 requires 619.0127. Rf (cyclohexane/AcOEt: 8/2) 0.71. (b) 5,15-Bis(2bromophenyl)porphyrin 3c: Following general procedure from 5-(2bromophenyl)dipyrromethane (300 mg, 1.00 mmol) and trimethyl orthoformate gave expected porphyrin 3c as purple solid (28.3 mg, 9%), C32H20Br2N4.1H (CDCl3, 400 MHz) d 3.11 (br s, 2H, NH), 7.72 (m, 4H, Ph-H), 8.07 (m, 2H, Ph-H), 8.19 (dd, J = 2.3 Hz, J = 7.2 Hz, 1H, CH–CBr), 8.23 (dd, J = 1.9 Hz, J = 7.2 Hz, 1H, Ph-H), 8.90 (d, J = 4.2 Hz, 4H, b H), 9.37 (d, J = 4.2 Hz, 4H, b H), 10.29 (s, 2H, CH meso). 13C (CDCl3, 75 MHz) d 135.4 (CH), 135.3 (CH), 132.2 (CH), 131.8 (CH), 130.5 (C), 130.0 (CH), 127.9 (C), 127.6 (C), 126.0 (CH), 105.4 (CHmeso), 90.1 (C–Br). HRMS (ESI): MH+ found, 619.0125. C32H21N4Br2 requires 619.0127. UV–vis (nm): 407, 503, 532, 575, 630. Rf (cyclohexane/ AcOEt: 7/3) 0.62; (c) 5,15-Bispentafluorphenyl-porphyrin 3d: Following general procedure from 5-pentafluoro-dipyrromethane (3.25 g, 10,4 mmol) and trimethyl orthoformate gave expected porphyrin 3d as dark purple solid (172 mg, 5%), C32H12F10N4. 1H (CDCl3, 300 MHz) d 3.24 (br s, 2H, 2NH), 9.00 (d, J = 4.7 Hz, 4H), 9.49 (d, J = 4.8 Hz, 4H), 10.39 (s, 2H, CH meso). UV–vis (nm): 405, 503, 537, 575, 630. HRMS (ESI): MH+ found, 643.0984. C32H13F10N4 requires 643.0978. Rf (cyclohexane/AcOEt: 7/3) 0.73; (d) 5,15-Bis(2,6dichlorophenyl)porphyrin 3e: Following general procedure from 5-bis(2,6dichlorophenyl)dipyrromethane (500 mg, 1.72 mmol) and trimethyl orthoformate gave expected porphyrin 3e as purple solid (63 mg, 8%), C32H18Cl4N4. 1H (CDCl3, 300 MHz) d 3.10 (br s, 2H, 2NH), 7.83 (m, 6H, Ph H), 8.87 (d, J = 4.7 Hz, 4H, b H), 9.38 (d, J = 4.8 Hz, 4H, b H), 10.29 (s, 2H, CH meso). UV–vis (nm): 407, 502, 533, 581, 631. HRMS (ESI): MH+ found, 601.0321. C32H19Cl4N4 requires 600.9726. Rf (cyclohexane/AcOEt: 7/3) 0.58; (e) 5,15-Bisnaphthylporphyrin 3f: Following general procedure from 5naphtyldipyrromethane (300 mg, 1.10 mmol) and trimethyl orthoformate gave expected porphyrin 3f as purple solid (51.7 mg, 17%), C40H26N4. 1H (CDCl3, 300 MHz) d 3.01 (br s, 2H, NH), 7.76 (m, 4H, CHAR), 8.14 (m, 2H, CHAR), 8.24 (d, J = 8.6 Hz, 2H, CHAR), 8.47 (d, J = 8.4 Hz, 2H, CHAR), 8.74 (s, 2H, CHAR), 9.11 (d, J = 4.6 Hz, 2H, b H), 9.41 (d, J = 4.6 Hz, 2H, b H), 10.34 (s, 2H, CH meso). 13 C (CDCl3, 500 MHz) d 147.5, 147.5, 145.4 (4C), 144.9 (4C),139.0 (2C),134.0 (2CH), 132.9, 132.9 (2C), 132.5 (2C), 131.7 (4CH), 131.2 (4CH), 128.5 (2CH), 128.1 (2CH), 126.9 (2CH), 126.9 (2CH), 126.2 (2CH), 119.1 (2C), 118.3 (2C), 105.4 (CH). UV–vis (nm): 410, 506, 541, 578, 633. HRMS (ESI): MH+ found, 563.2226. C40H27N4 requires 563.2230. Rf (cyclohexane/AcOEt: 7/3) 0.63; (f) 5,15-Bis(3-indolyl)porpohyrin 3g: Following general procedure from 5-(3indolyl)dipyrromethane (1 g, 3.83 mmol) and trimethyl orthoformate gave
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expected porphyrin 3g as red purple solid (25 mg, 3%), C36H24N6. 1H (CDCl3, 300 MHz) d 3.41 (br s, 2H, NH), 7.52 (m, 4H), 7.72 (m, 2H), 7.79 (m,2H), 8.06 (d, J = 2.1 Hz, 1H), 8.88 (brs,1H), 9.27 (d, J = 4.5 Hz, 2H, b H), 9.37 (d, J = 4.5 Hz, 2H, b H), 9.49 (m, 4H, b H), 10.25 (s, 1H), 10.32 (s, 2H, CH meso). 13C (CDCl3, 500 MHz) d 139.1 (C), 131.7 (CH), 131.6 (CH), 131.1 (CH), 131.0 (CH), 128.6 (CH), 122.9 (CH), 120.9 (CH), 120.6, 111.3 (CH), 107.3 (C), 104.5 (CH), 103.4 (CH). UV–vis (nm): 407, 501, 536, 574, 630. HRMS (ESI): MH+ found, 541.1069. C36H25N6 requires 541.2136. Rf (cyclohexane/AcOEt: 7/3) 0.29; (g) 5,15Di(3,4,5-trimethoxyphenyl)-porphyrin 3i:3,20 following general procedure from 5-(3,4,5-trimehtoxypheny) dipyrromethane (300 mg, 0.96 mmol) and trimethyl orthoformate gave expected porphyrin 3i as dark red purple solid (133.7 mg, 43%), C38H34N4O6. 1H (CDCl3, 300 MHz) d 3,11 (br s, 2H, NH), 3.99 (s, 12H, m-CH3O), 4.18 (s, 6H, p-CH3O), 7,51 (s, 4H, o-Ph H), 9.16 (d, J = 4.5 Hz, 4H, b H,), 9.38(d, J = 4.5 Hz, 4H, b H,), 10.30 (s, 2H, H meso). 13C (CDCl3, 75 MHz) d 151.7 (C), 147.1 (C), 145.3 (C), 137.9 (C), 136.9 (C), 131.7 (CH), 131.0 (CH), 118.9 (C), 112.9(CH), 105.4 (CH meso), 61.3 (OMe), 56.4 (OMe). UV–vis (nm): 411, 445, 504, 539, 580, 630. HRMS (ESI): MH+ found, 643.2538. C38H34N4O6 requires 643.2794. Rf (cyclohexane/AcOEt: 7/3) 0.33. 5,15-Dimethyl-10,20-diphenylporphyrin 4a: Following general procedure from 5-phenydipyrromethane (100 mg, 0.96 mmol) and trimethyl orthoacetate gave expected porphyrin as dark purple solid (29.8 mg, 27%), C34H26N4. 1H (CDCl3, 300 MHz) d 2.56 (s, 2H, 2NH), 4.6 (s, 6H, 2CH3), 7.78 (m, 6H, m,p-PhH), 8.20 (m, 4H, o-PhH), 8.85 (d, J = 4.8 Hz,4H, b H), 9.44 (d, J = 4.8 Hz, 4H, b H). 13C (CDCl3, 75 MHz) d 154.6 (C), 147.0 (C), 129.0 (CH), 128.9 (CH), 128.5 (CH), 128.3 (CH), 101.1 (CH), 29.7 (CH3). 13C (CDCl3, 500 MHz) d 154.6 (C), 147.0 (C), 142.7 (C), 134.5, 131.6, 129.0 (CH), 128.9 (CH), 128.5 (CH), 128.3 (CH), 127.6 (CH), 126.6, 119.2, 116.5, 113.8 (C), 101.1 (CH), 29.7 (CH3). HRMS (ESI): MH+ found, 491.2227. C34H27N4 requires 491.2229. UV–vis (nm): 423, 518, 554, 597, 654. Rf (cyclohexane/AcOEt: 7/3) 0.61. Feng, X. D.; Senge, M. O. Tetrahedron 2000, 56, 587–590. (a) Takanami, T.; Matsumoto, J.; Kumagai, Y.; Sawaizumi, A.; Suda, K. Tetrahedron Lett. 2009, 50, 68–70; (b) Takanami, T.; Wakita, A.; Sawaizumi, A.; Iso, K.; Onodera, H.; Suda, K. Org. Lett. 2008, 10, 685–687. (a) 5,10,15-Triphenylporphyrin 6a:18,20,21 In a dry flask, under positive pressure of nitrogen, containing diphenylporphyrin 3a (15 mg, 0.032 mmol, 1 equiv) in 1.3 mL of dry tetrahydrofurane, PhLi (1.4 mL, 0.24 mmol, 7.5 mmol, 1.8 M in Bu2O) was added slowly with a syringe at 78 °C. The mixture became black red and was stirred at 78 °C for 2 h. The bath was removed to allow the temperature rising. After 1 h at room temperature H2O was added at 0 °C, the solution was stirred 10 min, DDQ was added and the green mixture became dark red. Stirring was maintained for 30 min then the reaction mixture was poured into brine and extracted with dichloromethane. The crude product was purified by column chromatography (cyclohexane/AcOEt 9/1) to give the expected triphenylporphyrin 6a as a red purple solid (16.8 mg, 97%), C38H26N4. 1 H (CDCl3, 400 MHz) d 2.95 (br s, 2H, NH), 7.81 (m, 9H, m,p-PhH), 8.26 (m, 6H, o-PhH), 8.91 (m, 4H, b H), 9.04 (d, J = 4.5 Hz, 2H, b H), 9.33 (d, J = 4.5 Hz, 2H, b H), 10.21 (s, 1H, CH meso). 13C (CDCl3, 100 MHz) d 142.6 (C), 141.8 (C), 134.6 (2CH), 134,5 (CH), 132.4 (CH), 131.5 (CH), 131.4 (CH), 131.3 (CH), 130.7 (CH), 130.0 (CH), 128.3 (CH), 127.7 (2CH), 126.8 (2CH), 126,5 (CH), 120.6 (C), 119.6 (C), 104.8 (CH meso). HRMS (ESI): MH+ found, 539.2208. C38H27N4 requires 539.2230. UV–vis (nm): 414, 440, 509, 543, 583, 640. Rf (cyclohexane/AcOEt: 9/ 1) 0.60; (b) Tetrakisphenylporphyrin 5a:22 Following previous procedure above from triphenylporphyrin 6a the expected tetraphenylporphyrin 5a was obtained as dark purple solid (46 mg, 47%), C44H30N4. 1H (CDCl3, 300 MHz) d 2.76 (br s, 2H, NH), 7.75 (m, 12H, m,p-Ph-H), 8.24 (m, 8H, o-Ph-H), 8.84 (s, 8H, b H). 13C (CDCl3, 75 MHz) d 145.7 (C), 142.2 (C), 134.0 (CH), 130.5 (CH), 127.5 (CH), 126.0 (CH), 119.5 (C). HRMS (ESI): MH+ found, 615.2559. C44H31N4 requires 615.2543. UV–vis (nm): 423, 516, 551, 591, 649. Rf (cyclohexane/ AcOEt: 9/1) 0.63. Senge, M. O.; Shaker, Y. M.; Pintea, M.; Ryppa, C.; Hatscher, S. S.; Ryan, A.; Sergeeva, Y. Eur. J. Org. Chem. 2010, 2, 237–258. Senge, M. O. Acc. Chem. Res. 2005, 38, 733–743. Lindsey, J. S.; Hsu, H. C.; Schreiman, I. C. Tetrahedron Lett. 1986, 27, 4969–4970.