A Practical Synthesis of Meso-monosubstituted, β-Unsubstituted Porphyrins

Article abstract of DOI:10.1021/ol0265867

(Matrix Presented) A simple straightforward synthesis for meso-monosubstituted, β-unsubstituted porphyrins is reported. Porphyrins of this type are easily prepared by condensation of dipyrromethane, pyrrole-2-carbaldehyde, and the desired aromatic or aliphatic aldehyde. The method can be used for a variety of functional groups with yields between 2 and 12%. In most cases, the 5,15-disubstituted porphyrin is obtained as a second product but can be removed easily.

Full text of DOI:10.1021/ol0265867

ORGANIC
LETTERS
2
002
Vol. 4, No. 22
807-3809
A Practical Synthesis of
Meso-monosubstituted, â-Unsubstituted
Porphyrins
3
†
Arno Wiehe, Claudia Ryppa, and Mathias O. Senge*
Institut f u¨ r Chemie, Organische Chemie, Freie UniVersit a¨ t Berlin, Takustr. 3,
D-14195 Berlin, Germany
mosenge@chemie.fu-berlin.de
Received July 23, 2002
ABSTRACT
A simple straightforward synthesis for meso-monosubstituted, â-unsubstituted porphyrins is reported. Porphyrins of this type are easily
prepared by condensation of dipyrromethane, pyrrole-2-carbaldehyde, and the desired aromatic or aliphatic aldehyde. The method can be
used for a variety of functional groups with yields between 2 and 12%. In most cases, the 5,15-disubstituted porphyrin is obtained as a second
product but can be removed easily.
In the past few decades, enormous progress has been made
in synthetic porphyrin chemistry. Today, porphyrins with
substituents (3 or 4) in the meso positions, regardless of
whether the substituents are identical or different (Figure 1).
And even the parent porphyrin without any substituents
1
nearly all sorts of substitution patterns are accessible. The
synthetic strategies applied comprise direct methods such as
condensations of pyrrole (or pyrrolic derivatives such as
5
(porphine 1) is now accessible in high yield.
2
dipyrromethanes) with various aldehydes or total syntheses.
Alternatively, modifications of existing porphyrins utilize
3
either electrophilic (e.g., formylation, halogenation, nitration)
4
or nucleophilic (e.g., organolithium chemistry) aromatic
substitution reactions. These methods provide convenient
access to porphyrins with four (6), three (5), or two
†
Permanent address: Biolitec AG, Winzerlaer Str. 2a, D-07745 Jena,
Germany.
(
1) Kadish, K. M., Smith, K. M., Guilard, R., Eds. The Porphyrin
Handbook; Academic Press: San Diego, 2000; Vol. 1.
2) (a) Lindsey, J. S. In The Porphyrin Handbook; Kadish, K. M., Smith,
K. M., Guilard, R., Eds.; Academic Press: San Diego, 2000; Vol. 1, pp
5-118. (b) Smith, K. M. In The Porphyrin Handbook; Kadish, K. M.,
Smith, K. M., Guilard, R., Eds.; Academic Press: San Diego, 2000; Vol.
, pp 119-148.
3) Jaquinod, L. In The Porphyrin Handbook; Kadish, K. M., Smith, K.
(
Figure 1. Types of meso-substituted porphyrins.
4
1
(
M., Guilard, R., Eds.; Academic Press: San Diego, 2000; Vol. 1, pp 201-
Nevertheless, several blank spots remain on the map of
synthetic porphyrin chemistry. One of these is the synthesis
2
37.
(4) (a) Senge, M. O.; Kalisch, W. W.; Bischoff, I. Chem. Eur. J. 2000,
6
, 2721-2738. (b) Feng, X.; Bischoff, I.; Senge, M. O. J. Org. Chem. 2001,
6
6, 8693-8700.
(5) Neya, S.; Funasaki, N. Tetrahedron Lett. 2002, 43, 1057-1058.
1
0.1021/ol0265867 CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/03/2002

of porphyrins with only one substituent, e.g., meso-mono-
substituted, â-unsubstituted porphyrins (2). Though there are
a number of occurrences where porphyrins of this type are
referred to in previous studies, their synthesis either relied
on the tedious monofunctionalization6 of porphyrin 1 or they
are described as byproducts for which synthesis and/or
Table 1. Products and Yields after Purification for the
Condensation Reaction of Pyrrole-2-carbaldehyde and
Dipyrromethane with Various Aldehydes
,7
8
characterization often remain unclear. Examples include
6
mononitrated and monobrominated porphyrin, (5-formylpor-
7
8a
phyrinato)copper(II), and tert-butyl- and indolizine-
9
8b
substituted porphyrins among others. Yields for the latter
are typically e1%. To date, no practical synthesis for
compounds of type 2 exists.
Yet, porphyrins of this type are of special interest because
they offer the intriguing possibility of introducing additional
substituents into the three other meso positions in a step-
10
by-step procedure, thereby opening the way to a rational
synthesis of ABCD-tetrasubstituted porphyrins and to com-
binatorial porphyrin libraries. Moreover, in many physico-
chemical investigations, for example, in perturbation studies,
meso-monosubstituted porphyrins are highly valuable refer-
ence compounds.11
In principle, compounds of type 2 are accessible by
9
condensation of a bilane with a suitable aldehyde. However,
as bilane is highly unstable and difficult to prepare, the need
exists for a synthesis that circumvents the use of bilane by
utilization of simpler building blocks. One possible compo-
nent to build porphyrins with unsubstituted meso positions
is pyrrole-2-carbaldehyde 7, which originally was used by
Fischer in one of the first syntheses of porphine.1 Another
component that accounts for an unsubstituted meso position
in the final porphyrin is dipyrromethane 8, which is relatively
2
1
3
stable and can easily be prepared in large quantities. Thus,
we planned to use a combination of 7 and 8 as an
“
equivalent” for the bilane, wherein the deactivating effect
of the formyl group in 7 favors a reaction with 8 over self-
condensation (Scheme 1).
Indeed, condensation of 2 equiv of 7 with 8 and benzalde-
hyde afforded the desired 5-phenylporphyrin 9a in 5% yield.
Scheme 1
We tested this method with a series of aldehydes and found
that it tolerates aldehydes with a variety of functional groups,
including those amenable for use in subsequent C-C-
coupling reactions (e.g., 10 or 11), for the preparation of
hydrophilic porphyrins (e.g., 14-16 after deprotection of the
methyl ether) for medicinal applications (or 17 and 18 for
1
9
in vivo F NMR), and for superstructured porphyrins (12
or 13 and related amino compounds) (Table 1).
(
6) (a) Drach, J. E.; Longo, F. R. J. Org. Chem. 1974, 39, 3282-3284.
Callot, H. J.; Schaeffer, E. J. Chem. Res., Synop. 1978, 51. (b) Nudy, L.
R.; Coffey, J. C.; Longo, F. R. J. Heterocycl. Chem. 1982, 19, 1589-1590.
Nudy, L. R.; Hutchinson, H. G.; Schieber, C.; Longo, F. R. Tetrahedron
1
984, 40, 2359-2363. Nudy, L. R.; Schieber, C.; Longo, F. R.; Agarwala,
V. S. Heterocycles 1987, 26, 1797-1803.
3808
Org. Lett., Vol. 4, No. 22, 2002

Generally, both aliphatic and aromatic aldehydes may be
used in this reaction. The yields of the monosubstituted
porphyrins 9a-20a vary between 2 and 12%, which is quite
satisfactory given the low yields often observed in porphyrin
syntheses employing condensation reactions and the inac-
cessibility of the target porphyrins by other methods. The
simple filtration of the crude reaction mixture through a short
silica column is sufficient for purification, while the others
require a standard column chromatographic separation.14
In conclusion, we have developed a simple and straight-
forward method that provides the first systematic access to
meso-monosubstituted, â-unsubstituted porphyrins. Currently,
we are expanding the methodology described herein and
using the monosubstituted porphyrins as precursors in the
development of a rational synthesis of 5,10- (3) and 5,15-
disubstituted porphyrins (4).
5,15-disubstituted porphyrin (b in Table 1), which in most
cases is obtained as a second product, can easily be separated
from the monosubstituted porphyrin by column chromatog-
raphy.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (Heisenberg Fellowship Se543/3-2 and Grant
Se543/5-1), the Biolitec AG, and the Fonds der Chemischen
Industrie for their support.
In practical terms, the yields and relative formation of
mono- versus disubstituted product observed for the indi-
vidual reactions do not depend so much on the electronic
effects of the substituents but on the solubility of the
monosubstituted product versus that of the disubstituted
porphyrin. In most cases, the disubstituted porphyrin is much
less soluble than the monosubstituted porphyrin and thus is
either simply retained on the chromatography column or
easily separated. For example, for compounds 16a and 19a,
OL0265867
(
14) For example, the synthesis of 5-(4-methoxyphenyl)-porphyrin 14a
is as follows: 380 mg (4.00 mmol) of 7, 300 mg (2.06 mmol) of 8, and
.25 mL (2.06 mmol) of 4-methoxybenzaldehyde were dissolved in 1 L of
0
dry dichloromethane under argon. To this solution was added 70 µL (0.9
mmol) of TFA, and the reaction mixture was shielded from ambient light
and stirred for 16 h in the dark. After this time, 1.3 g (5.73 mmol) of DDQ
suspended in about 100 mL of dry dichloromethane was added and the
mixture stirred for another 60 min. Then, 1.5 mL of triethylamine was added
and the reaction mixture concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel using 2:1 v/v dichloro-
methane/hexane as the eluent. Recrystallization from dichloromethane/
methanol afforded 99 mg (0.24 mmol, 12%) of 5-(4-methoxyphenyl)-
(
7) Schloezer, R.; Fuhrhop, J.-H. Angew. Chem. 1975, 87, 388-389.
(8) (a) Song, X.-Z.; Jentzen, W.; Jaquinod, L.; Khoury, R. G.; Medforth,
C. J.; Jia, S.-L.; Ma, J.-G.; Smith, K. M.; Shelnutt, J. A. Inorg. Chem. 1998,
3
7, 2117-2128. (b) Cavaleiro, J. A. S.; Neves, M. G. P. M.; Medforth, C.
J.; Smith, K. M. Heterocycles 1994, 37, 213-218. Silva, A. M. G.; Tom e´ ,
A. C.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S. Tetrahedron Lett. 2000,
1
porphyrin 14a as purple crystals: mp 286 °C; H NMR (500 MHz, CDCl3)
4
1, 3065-3068.
9) Matsumoto, K.; Ogasawara, A.; Kimura, S.; Hayashi, N.; Machiguchi,
δ 10.29 (2H, s, 10, 20-Cmeso-H), 10.21 (1H, s, 15-Cmeso-H), 9.46 (2H, AB,
3
3
(
J ) 4.4 Hz, 12,18-Câ-H), 9.44 (2H, AB, J ) 4.4 Hz, 13,17-Câ-H), 9.39
3
3
T. Heterocycles 1998, 48, 861-864.
(2H, AB, J ) 4.5 Hz, 2,8-Câ-H), 9.11 (2H, AB, J ) 4.5 Hz, 3,7-Câ-H),
3 3
(
10) Senge, M. O.; Bischoff, I. Eur. J. Org. Chem. 2001, 1735-1751.
8.16 (2H, AB, J ) 8.6 Hz, Aro-H), 7.32 (2H, AB, J ) 8.6 Hz, Arm-H),
13
(11) Kuz’mitskii, V. A.; Gael, V. I.; Mazurenko, A. S. Zh. Fiz. Khim.
4.11 (3H, s, CH3), -3.60 ppm (2H, br s, NH); C NMR (125 MHz, CDCl3)
δ 159.49 (C28), 135.79 (C26, C30), 134.05 (C25), ∼131 (C2, C3, C7, C8,
C12, C13, C17, C18), 119.42 (C5), 112.39 (C27, C29), 104.59 (C10, C20),
103.36 (C15), 55.61 ppm (C31); MS (EI, 310 °C, 80 eV) m/z (%) 416
1
995, 69, 276-281. do Monte, S. A.; Braga, M. Chem. Phys. Lett. 1998,
2
90, 136-142. Shediac, R.; Gray, M. H. B.; Uyeda, H. T.; Johnson, R. C.;
Hupp, D. T.; Angiolillo, P. J.; Therien, M. J. J. Am. Chem. Soc. 2000, 122,
•
+
+
+
2+
7
017-7033.
12) Fischer, H.; Gleim, W. Justus Liebigs Ann. Chem. 1935, 521, 157-
60.
13) Lee, C.-H.; Lindsey, J. S. Tetrahedron 1994, 50, 11427-11440.
(100) [M] , 401 (4) [M - CH3] , 385 (1) [M - OCH3] , 208 (13) [M] ;
(
UV-vis (CH2Cl2) λmax (lg ꢀ) 405 nm (5.13), 499 (4.11), 539 (3.60), 575
(3.64), 628 (3.12); HRMS (EI) [C27H20N4O [M ]] calcd 416.16371, found
+
1
(
416.16522.
Org. Lett., Vol. 4, No. 22, 2002
3809