Facile synthesis of ortho-pyridyl-substituted corroles and molecular structures of analogous porphyrins

Article abstract of DOI:10.1016/j.tetlet.2008.04.113

The reactions of 5-(2-pyridyl)dipyrromethane with either pyridine-2-carboxaldehyde or pentafluorobenzaldehyde provided the expected corroles in 22-24% yields when performed according to the protocol perfected for such molecules, while porphyrins were the

Full text of DOI:10.1016/j.tetlet.2008.04.113

Tetrahedron Letters 49 (2008) 4163–4166
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Facile synthesis of ortho-pyridyl-substituted corroles and molecular
structures of analogous porphyrins
*
Irena Saltsman, Mark Botoshansky, Zeev Gross
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of 5-(2-pyridyl)dipyrromethane with either pyridine-2-carboxaldehyde or pentafluoro-
benzaldehyde provided the expected corroles in 22–24% yields when performed according to the protocol
perfected for such molecules, while porphyrins were the main products from reactions carried out in hot
propionic acid. The ortho-pyridyl-substituted porphyrins were characterized by X-ray crystallography,
thus revealing the first molecular structures of such molecules. The new corroles were transformed into
water-soluble derivatives via N-alkylation of the pyridyl groups, leading to the first ortho-pyridylium-
substituted corroles.
Received 19 March 2008
Revised 15 April 2008
Accepted 21 April 2008
Available online 24 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Porphyrins with para-pyridylium groups at their four meso-C
positions are the most intensively investigated in biochemical
and medicinal applications. On top of their extensive utilization
as photodynamic therapy (PDT) agents and as superoxide dismu-
tase (SOD) mimics,1,2 they were recently shown to bind to G-quad-
ruplex DNA, and the corresponding metal complexes were
disclosed as decomposition catalysts of peroxynitrite.3,4 The some-
what less commonly used ortho-pyridylium-substituted porphy-
rins are much more potent with regard to the last aspect;5 and
porphyrins with fewer than four pyridinium groups are often more
effective in various applications.6 Synthetic methodologies for the
preparation of porphyrin analogs with pyridinium groups are
much less developed and their potential has started to be uncov-
ered only recently. The latest examples are binding of para-pyr-
idylium-substituted corroles and porphyrazines to G-quadruplex
DNA, intercalation of the manganese complex of a bis-para-pyridy-
lium-substituted corrole into double-stranded DNA, and very effi-
cient catalytic decomposition of peroxynitrite by the latter.7,8 In
the only earlier example, comparison of analogous corrole and por-
phyrin derivatives with three remote ortho-pyridylium-substitu-
ents revealed that the former is more synthetically accessible
and more potent with regard to inhibition of endothelial cell pro-
liferation, tumor progression, and metastasis in an in vivo model
of cancer.9 This largely unexplored potential of corroles initiated
the present research which has focused on the synthesis of deriv-
atives with ortho-pyridylium-substituents. In addition to the suc-
cessful preparation of several such compounds, the first
molecular structures of porphyrins with fewer than four pyridyl
groups are reported.
The starting material for the new derivatives was 5-(2-pyr-
idyl)dipyrromethane (1),10 which was reacted with either pyr-
idine-2-carboxaldehyde (2) or pentafluorobenzaldehyde (3) by
two different synthetic approaches: that perfected by the research
group of Gryko for corroles ([aldehyde]/[1]/[TFA, 66 mM] = 1/2/4 in
CH2Cl2 at rt, followed by oxidation) and the propionic acid/reflux
method that is commonly used for porphyrins (Scheme 1: routes
a and b, respectively).11 The former methodology yielded only cor-
roles in quite respectable chemical yields: 24% of 4 and 22% of 5
from the reactions of 1 with 2 and 3, respectively.12,13 The struc-
ture of corrole 5, with ortho-pyridyl rings at C5 and C15 and one
pentafluorophenyl ring at the C10 position, reveals that no (or no
severe) scrambling occurred during the reaction.14 Very different
results were obtained when the same aldehydes were reacted with
1 according to route b: only small amounts of the same corroles
(3% of 4 from 2 and 5% of 5 from 3) were isolated, the major prod-
ucts were porphyrins (20% of 6 from 2 and 10% of 7 from 3), and
highly significant scrambling occurred in the reaction between 1
and 3.15,16 The meso-positions of the new porphyrin (7) produced
in the latter case are substituted with one C6F5 and three pyridyl
groups rather than two of each as would be expected from the
applied reagents.
The 1H NMR characteristics of corroles, 4 b-pyrrole doublets
with J coupling constants of 4.1–4.9 Hz,17 were clearly evident
for 4 and 5. The resonances of the ortho-pyridyl groups were signifi-
cantly broader, which may be attributed to the presence of various
atropoisomers (and equilibrium between them, vide infra) with
regard to the positioning of the nitrogen atoms above and below
the macrocyclic ring. Porphyrins 6 and 7 were also easily identified
by their 1H NMR spectra, displaying one singlet for all the b-pyrrole
H atoms of 6 and two doublets of 2H and one singlet of 4H for 7,
perfectly consistent with the symmetry of these compounds. The
corroles and porphyrins displayed similar electronic spectra, with
* Corresponding author. Tel.: +972 4 829 3954; fax: +972 4 829 5703.
E-mail address: chr10zg@tx.technion.ac.il (Z. Gross).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.113

4164
I. Saltsman et al. / Tetrahedron Letters 49 (2008) 4163–4166
F
NH
NH
F
F
F
F
or
+
N
N
CHO
CHO
3
2
1
1.
TFA, CH Cl
Et3N, DDQ
propionic acid
reflux
1.
2
2,
b
a
2. CH3I
2. CH3I
R'
R
10
10
N
HN
N
HN
15
R'
5
R
15
R'
R'
5
N
NH
NH HN
20
R'
Yield : 4, 24%
5, 22%
Yield: 6, 20% (+ 3% of 4)
7, 10% (+ 5% of 5)
4:
4a: R = R' =
R = R' =
6a: R = R' =
R = R' =
6:
+
+
N
N
N
N
CH3
CH3
F
F
F
F
R' =
N
F
F
5: R =
7: R =
F
R' =
R' =
N
F
F
F
F
F
F
F
F
F
R' =
5a: R =
F
7a: R =
+
+
N
N
CH3
F
F
F
CH3
Scheme 1.
Figure 1. ORTEP presentations with 50% probability thermal ellipsoids of the X-ray structures of porphyrins (a) 6 and (b) 7.

I. Saltsman et al. / Tetrahedron Letters 49 (2008) 4163–4166
4165
larger molar absorption coefficients (e) for the latter. More detailed
structural information was obtained for the porphyrins, which pro-
vided X-ray quality crystals.18
This work reports the successful synthesis of the first corroles
that carry ortho-pyridylium groups. These derivatives will be
applied in the near future in medicinal applications where corroles
have started to display significant advantages relative to other
metal-chelating agents.
The ORTEP drawings (Fig. 1) of 6 and 7 reveal that each of the
porphyrins crystallized in the form of one particular atropoisomer:
abab and aab, for 6 and 7, respectively, where a and b symbolize
the relative positioning of the ortho-pyridyl nitrogen atoms. The
macrocyclic framework in 6 is ruffled, with 18° dihedral angles
between the pyrrole subunits, and the four pyrrole nitrogen atoms
deviate by 0.05 Å above and below the mean plane of the N4 coor-
dination core. On the other hand, the ortho-pyridyl and pyrrole
rings are practically perpendicular (89.1°) and the greater than
4 Å distance between individual porphyrin molecules in the unit
cell clearly rules out intermolecular p–p interactions. The last
conclusion also holds for porphyrin 7, where the dihedral angle
between two neighboring macrocycles is 62°. This porphyrin is,
however, much more planar than 6: the four nitrogen atoms define
an almost perfect plane (with deviations of 0.001 Å and 0.02 Å for
the two different molecules) and the mean deviation of all the
atoms from the N4 plane does not exceed 0.05 Å.
Acknowledgments
This research was supported by the Israel Science Foundation,
Grant No. 330/04 (Z.G.). The funding of I.S. by the Center for
Absorption in Science, Ministry of Immigration, is also
acknowledged.
References and notes
1. (a) Bonnett, R. Chem. Soc. Rev. 1995, 24, 19; (b) Brown, S. B. Lancet Oncol. 2004,
5, 497.
2. Batinic´-Haberle, I.; Spasojevic´, I.; Hambright, P.; Benov, L.; Crumbliss, A. L.;
Fridorovich, I. Inorg. Chem. 1999, 38, 4011.
3. (a) Wheelhouse, R. T. J. Am. Chem. Soc. 1998, 120, 3261; (b) Shi, D. F. J. Med.
Chem. 2001, 44, 4509.
All four derivatives (4–7) were converted in >95% yield into the
respective N-methylpyridylium corroles and porphyrins (4a, 5a,
6a, and 7a) via their reaction with iodomethane.19 Close inspection
of the 1H NMR spectra of the corrole derivatives revealed that all
the possible atropoisomers were formed in the statistically pre-
dicted ratio: aaa, aab, and aba for the tris-pyridylium-substituted
4a, and aa and ab for the bis-pyridylium-substituted 5a,20 where
a and b represent opposite positioning of the N-methyl groups rel-
ative to the macrocycle plane. This information was deduced from
the number and relative integration of the resonances attributed to
the methyl groups, such as the 1:1 ratio of singlets at 4.13 and
4.15 ppm for 5a. For 4a, each isomer has two identical (on C5
and C15) and one different (on C10) methyl groups; and three such
2:1 pairs were evident in a 1:2:1 ratio for the aaa, aab, and aba
atropoisomers, respectively. The separation of atropoisomers was
successfully carried out by HPLC (Fig. 2a and b), but despite several
methods being applied for evaporation of the isolated fractions,
those of 4a isomerized back to the original distribution of atropoi-
somers. This previously noticed phenomenon (in related porphy-
rins)21,22 did not occur for 5a, whose atropoisomers were
successfully isolated in quite pure form (Fig. 2b).
4. Lee, J. B.; Hunt, J. A.; Groves, J. T. Bioorg. Med. Chem. Lett. 1997, 7, 2913–2918.
5. (a) Drel, V. R.; Pacher, P.; Vareniuk, I.; Pavlov, I.; Ilnytska, O.; Lyzogubov, V. V.;
Tibrewala, J.; Groves, J. T.; Obrosova, I. G. Eur. J. Pharm. 2007, 569, 48; (b)
Reboucas, J. S.; Spasojevic, I.; Tjahjono, D. H.; Richaud, A.; Mendez, F.; Benov, L.;
Batinic-Haberle, I. Dalton Trans. 2008, 1233.
6. (a) Goncßalves, D. P. N.; Ladame, S.; Balasubramanian, S.; Sanders, J. K. M. Org.
Biomol. Chem. 2006, 4, 3337; (b) Batinic´-Haberle, I.; Spasojevic´, I.; Stevens, R. D.;
ˇ
´
Bondurant, B.; Okado-Matsumoto, A.; Fridorovich, I.; Vujaškovic, Z.; Dewhirst,
M. W. Dalton Trans. 2006, 617.
7. (a) Goncßalves, D. P. N.; Rodriguez, R.; Balasubramanian, S.; Sanders, J. K. M.
Chem. Commun. 2006, 4685; (b) Fu, B.; Huang, J.; Ren, L.; Weng, X.; Zhou, Y.; Du,
Y.; Wu, X.; Zhou, X.; Yang, G. Chem. Commun. 2007, 3264.
8. Gershman, Z.; Goldberg, I.; Gross, Z. Angew. Chem., Int. Ed. 2007, 46, 4320.
9. Aviezer, D.; Cotton, S.; David, M.; Segev, A.; Khaselev, N.; Galili, N.; Gross, Z.;
Yayon, A. Cancer Res. 2000, 60, 2973.
10. Gryko, D.; Lindsey, J. S. J. Org. Chem. 2000, 65, 2249–2252.
11. Gryko, D. T.; Piechota, K. E. J. Porphyrins Phthalocyanines 2002, 6, 81–97.
12. Reaction conditions and purification: Compound
1 (0.4 mmol), appropriate
aldehyde (0.2 mmol), and trifluoroacetic acid (62 lL, 0.8 mmol) were dissolved
in CH2Cl2 (12 mL) at room temperature. Triethylamine (112 lL, 0.8 mmol) was
added after 1 h, followed by CH2Cl2 (308 mL) and DDQ (90 mg, 0.4 mmol), and
stirring was continued for a further 10 min prior to evaporation to dryness and
subsequent column chromatography on silica. The second band from the
mixture obtained from the reaction with
2 (eluted with ethyl acetate/n-
hexane, gradually increasing from 3:1 to 100% ethyl acetate and to 10%
methanol in ethyl acetate) provided a major fraction that contained corrole 4
and a few impurities. A second chromatographic treatment (from 3:1 ethyl
acetate/n-hexane to 3% n-hexane in ethyl acetate to 5% methanol in ethyl
acetate) provided pure 4 (25 mg, 24% yield), Rf (silica, ethyl acetate) = 0.24. The
second band (bluish-green colored) from the mixture obtained from the
reaction with 3 (eluted with ethyl acetate/n-hexane, from 1: 4 to 1: 2) provided
a
fraction that contained corrole 5. Final purification was achieved by
preparative thin-layer chromatography (silica plate, ethyl acetate/n-hexane,
3:4) to afford pure 5 (27 mg, 22% yield), Rf (silica, ethyl acetate/n-hexane,
2:3) = 0.81.
13. 5,10,15-Tris(2-pyridyl)corrole (4): MS (MALDI-TOF): m/z (%): 528.3 ([MÀH]À,
100%); 530.5 ([M+H]+, 100%). 1H NMR (500 MHz, C6D6): d 8.81 (br s, 2H), 8.79
(d, 3J(H,H) = 4.12 Hz, 2H), 8.67 (br s 1H), 8.65 (d, 3J(H,H) = 4.35 Hz, 2H), 8.44 (d,
3J(H,H) = 4.12 Hz, 2H), 8.23 (d, 3J(H,H) = 4.58 Hz, 2H), 8.04 (d, 3J(H,H) =
7.56 Hz, 2H), 7.91 (d, 3J(H,H) = 7.33 Hz, 1H), 7.34 (m, 3H), 6.92 (m, 3H). UV–
vis (ethyl acetate): kmax, nm (e  10À3) 418 (36.3), 582 (6.7), 614 (4.4). 10-
(Pentafluorophenyl)-5,15-bis(2-pyridyl)corrole (5). MS (MALDI-TOF): m/z (%):
617.0 ([MÀH]À, 100%); 619.2 ([M+H]+, 100%). 1H NMR (300 MHz, C6D6): d 8.74
(br s, 2H), 8.61 (d, 3J(H,H) = 4.12 Hz, 2H), 8.22 (d, 3J(H,H) = 4.67 Hz, 2H), 8.09 (d,
3J(H,H) = 7.96 Hz, 2H), 7.71 (d, 3J(H,H) = 4.94 Hz, 2H), 7.06 (m, 4H), 6.42 (m,
2H), À1.47 (br s, 3H). 19F (282 MHz, C6D6): d À138.36 (dd, 3J(F,F) = 25.3 Hz,
4J(F,F) = 5.6 Hz, 2F), À154.16 (t, 3J(F,F) = 22.6 Hz, 1F), À162.96 (td, 3J(F,F) =
25.4 Hz, 4J(F,F)=8.5 Hz, 2F). UV–vis (EtOAc): kmax, nm (e  10À3) 416 (48.5), 578
(10.3).
14. For factors affecting scrambling, see: Koszarna, B.; Gryko, D. J. Org. Chem. 2006,
71, 3707–3717.
15. Reaction conditions and purification: Samples of 1 (0.4 mmol) and appropriate
aldehyde (0.2 mmol) were dissolved in 10 mL of propionic acid, and the
reaction mixture was heated to reflux for 40 min. After evaporation of the
propionic acid, the residue was washed with hot water and neutralized with
NH4OH (25%). The solid material was separated by column chromatography on
silica. Separation of 4 and 6, formed in the reaction with 2, was achieved by
column chromatography (silica, ethyl acetate/n-hexane, 1:3 for 4 and 10% n-
hexane in ethyl acetate for 6). Pure 4 (5 mg, 5% yield) and 6 (25 mg, 20% yield)
were obtained by thin-layer chromatography (silica, ethyl acetate).
Figure 2. HPLC chromatograms of (a) the atropoisomeric mixtures of 4a and of (b)
the isolated atropoisomer of 5a.

4166
I. Saltsman et al. / Tetrahedron Letters 49 (2008) 4163–4166
Recrystallization of 6 (CHCl3/n-heptane) provided X-ray quality crystals. Rf
were stirred at room temperature overnight. A small amount of methanol and
a three fold excess of diethyl ether were added to the reaction mixtures.
Precipitated products were collected and washed with addition of portions of
diethyl ether.
(silica, methanol/ethyl acetate, 3:1) = 0.65. Partial separation between 5 and 7,
formed in the reaction with 3, was achieved by column chromatography (silica,
ethyl acetate/n-hexane, 1:3 for 5 and 2:1 for 7). Pure 5 (4 mg, 3% yield) and 7
(14 mg, 10% yield) were obtained by separation on preparative silica gel plates
(ethyl acetate/n-hexane, 3:4 for 5 and 4:1 for 7). Recrystallization of 7 (CH2Cl2/
n-hexane) provided X-ray quality crystals. Rf (silica, ethyl acetate) = 0.56.
16. 5,10,15,20-Tetrakis(2-pyridyl)porphyrin ( 6): MS (MALDI-TOF): m/z (%): 619.2
([M+H]+, 100%). 1H NMR ( 500 MHz, CDCl3): d 9.16 (d, 3J(H,H) = 7.50 Hz, 4H),
8.89 (s, 8H), 8.23 (d, 3J(H,H) = 7.5 Hz, 4H), 8.09 (m, 4H), 7.72 (m, 4H), À2.79 (s,
20. 5,10,15-Tris(N-methyl-2-pyridiniumyl)corrole (4a): This was obtained in 94%
yield as a mixture of three atropoisomers in a ratio of 50.1/22.7/21.0. Up to 6%
of products that were N-alkylated at the pyrrolic nitrogen atoms could be
separated by either column chromatography or HPLC. Rf silica = 0.46
(acetonitrile/H2O/KNO3(aq), 8:1:1). MS (MALDI-TOF) ES+ (CH3CN): m/z (%):
575 ([M+H]+, 10%), 560 (40%), 545 (100%), 287 ([M/2]+, 100%). 1H NMR
(300 MHz, CD3CN): d 9.19 (d, 3J(H,H) = 4.39 Hz, 2H), 9.11 (m, 3H), 8.69 (m, 6H),
8.56 (d, 3J(H,H) = 4.25 Hz, 2H), 8.54 (d, 3J(H,H) = 4.53 Hz, 2H), 8.39 (m, 3H), 8.31
(d, 3J(H,H) = 4.53 Hz, 2H), 4.21 (s, 2H), 4.18 (s, 2H), 4.16 (s, 1H), 4.09 s, 1H), 4.05 (s,
2H), 4.01 (s, 1H). UV–vis (acetonitrile): kmax, nm (e  10À3) 408 (8.0), 436 (8.2), 626
(3.3). 10-(Pentafluorophenyl)-5,15-bis(N-methyl-2-pyridiniumyl)corrole (5a): This
was obtained in 95% yield as a mixture of two atropoisomers in a 49.2/46.0 ratio. Up
to 4% of products that were N-alkylated at the pyrrolic nitrogen atoms could be
separated by either column chromatography or HPLC. Rf = 0.55 (acetonitrile/H2O/
KNO3(aq), 8:1:1). MS (MALDI-TOF) ES+ (CH3CN): m/z (%): 648.2 [M+H]+,
100%), 633.2 (85%), 324.1 ([M/2]+, 100%). 1H NMR (300 MHz, CD3CN): d 9.15 (d,
3J(H,H) = 4.16 Hz, 2H), 9.12 (d, 3J(H,H) = 6.46 Hz, 2H), 8.69 (m, 4H), 8.56 (d,
3J(H,H) = 4.74 Hz, 2H), 8.52 (d, 3J(H,H) = 4.22 Hz, 2H), 8.49 (d, 3J(H,H) = 4.67,
Hz, 2H), 8.31 (t, 3J(H,H) = 6.59 Hz, 2H), 4.15 (s, 3H), 4.13 (s, 3H). 19F ( 282 MHz,
CD3CN): d À141.01 (m, 2F), À158.21 (t, 3J(F,F) = 19.4 Hz, 1F), À165.01 (m, 2F).
UV–vis (acetonitrile): kmax, nm (e  10À3) 412 (4.8), 436 (5.1), 628 (2.3). A Waters
2996 HPLC system was used for HPLC separation of the atropoisomers utilizing a
2H). UV–vis (CH2Cl2): kmax
,
nm (e  10À3
) 414 (126.4), 512 (15.5). 5-
Pentafluorophenyl,10,15,20-tris(2-pyridyl)porphyrin ( 7): MS (MALDI-TOF): m/z
(%): 708.2 ([M+H]+, 100%). 1H NMR (500 MHz, C6D6): d 8.99 (d, 3J(H,H) =
4.81 Hz, 2H), 8.92 (s, 4H), 8.90 (m, 2H), 8.87 (m, 1H), 8.62 (d, 3J(H,H) = 4.81 Hz,
2H), 7.75 (m, 3H), 7.32 (m, 3H), 7.02 (m, 3H), À2.54 (s, 2H). 19F
(282 MHz, C6D6):
d
À137.91 (m, 2F), À152.97 (t, 3J(F,F) = 21.4 Hz, 1F),
À162.71 (m, 2F). UV–vis (CH2Cl2): kmax
,
nm (e  10À3
) 410 (100.2), 510
(12.7), 586 (4.5).
17. Balazs, Y. S.; Saltsman, I.; Mahammed, A.; Tkachenko, E.; Golubkov, G.; Levine,
J.; Gross, Z. . Magn. Reson. Chem. 2004, 42, 624–635.
18. The diffraction measurements were carried out on
a Nonius Kappa CCD
diffractometer, using graphite monochromated Mo Ka radiation (k = 0.7107 Å)
at ca. 110 K. Crystal data for 6:
C40H26N8; MW = 618.69; a = 14.918(3) Å;
b = 14.918(3) Å; c = 13.490(3) Å; V = 3002(1) Å3; tetragonal space group I-42d;
Z = 4; Dcalcd = 1.369 g/cm3; l(MoKa) = 0.084 mmÀ1; 2623 unique reflections;
R = 0.0424 (wR = 0.093) for 773 reflections with I P 2rI); R = 0.0878
TM
˚
(wR = 0.1139) for all unique data. Crystal data for 7:
C
41H22F5N7;
SymmetryPrep 300 A C18 5 lm packing column (size 19 Â 150 mm) at ambient
MW = 707.66; a = 26.899(5) Å; b = 10.829(2) Å; c = 11.590(2) Å; b = 99.93(3)°
V = 3325(1) Å3; monoclinic space group Pc; Z = 4; Dcalcd = 1.413 g/cm3;
l(MoKa) = 0.106 mmÀ1; 5677 unique reflections; R = 0.0914 (wR = 0.220) for
2719 reflections with I P 2rI); R = 0.1860 (wR = 0.2471) for all unique data.
The deposition numbers at the Cambridge Crystallographic Data Centre are
CCDC 682223 and 682224 for compounds 6 and 7, respectively.
temperature. Elution gradient at 5 mL/min: For 5a: 0–5–20–45 min, 80% A–70% A–
65% A–60% A; For 4a: 0–5–25–40 min 90%A–85% A–80% A. Solvent A: deionized
water, 20 mmol triethylamine, pH 2.7 adjusted with concentrated trifluoroacetic acid.
Solvent B: acetonitrile, HPLC grade. Injection volume: 200 lL.
21. Kaufmann, T.; Shamsai, B.; Song Lu, R.; Bau, R.; Miskelly, G. M. Inorg. Chem.
1995, 34, 5073–5079.
19. Corroles
4
and
5
were dissolved in
a
minimum volume of DMF, excess
22. Spasojevic´, I.; Menzeleev, R.; White, P. S.; Fridorovich, I. Inorg. Chem. 2002, 41,
iodomethane (100 equiv) was added to the solutions, and reaction mixtures
5874–5881.