A New Route to meso-Formyl Porphyrins introducing a formyl group to a porphyrinic macrocycle

entails Vilsmeier formylation.10 Vilsmeier formylation,

Arumugham Balakumar, Kannan Muthukumaran, and either with the traditional DMF/POCl36,13 or the more
Jonathan S. Lindsey* recent HC(OMe)3/TFA or SnCl4,3 can only be carried out
Department of Chemistry, North Carolina State University, with metalloporphyrins that are stable toward strong
Raleigh, North Carolina 27695-8204 acids (e.g., copper or nickel chelates). Hence, formylation
jlindsey@ncsu.edu
typically requires three steps: (1) insertion of copper into
a free base porphyrin, (2) formylation of the copper
Received January 31, 2004 chelate, and (3) demetalation of copper to give the free
base porphyrin bearing the formyl group. The removal
Abstract: Prior syntheses of porphyrins bearing meso-
of copper generally requires strongly acidic conditions
formyl groups have generally employed the Vilsmeier formy-
lation of an acid-resistant copper or nickel porphyrin. A new such as TFA in H2SO4. The yield of the Vilsmeier
approach for the synthesis of free base porphyrins bearing formylation is typically quite high (though mixtures of
one or two (cis or trans) meso-formyl substituents entails polyformylated metalloporphyrins are known10,14,15). How-
the use of a dipyrromethane bearing an acetal group at the ever, the requirement for a three-step procedure, use of
5-position, a dipyrromethane-1-carbinol bearing an acetal strong acid, and limited control over the site of formyla-
group at the 5-position or carbinol position, or a dipyr- tion presents obvious limitations.
romethane-1,9-dicarbinol bearing an acetal group at a There exists a need for a milder and more direct
carbinol position. Treatment of the resulting meso-acetal- procedure for preparing formyl porphyrins. Two routes
substituted free base porphyrin to gentle acidic hydrolysis to porphyrins bearing distinct patterns of meso substit-
yields the corresponding meso-formyl porphyrin. uents include (1) the self-condensation of a dipyr-
romethane-1-carbinol, affording trans-A2B2-porphyrins,16
Formyl-substituted porphyrinic macrocycles provide and (2) the reaction of a dipyrromethane and a dipyr-
versatile intermediates and target molecules in bioor- romethane-1,9-dicarbinol, affording porphyrins with up
ganic and materials chemistry. Notable reactions of the to four different meso substituents (ABCD-porphyrins).17
porphyrinic formyl group include classical reactions of We considered that the incorporation of a latent formyl
aldehydes (e.g., Wittig,1-3 Grignard,2,4 McMurry,5 Schiff’s synthon in a dipyrromethane, dipyrromethane-1-carbinol,
base,6-8 Knoevenagel7,9)10 as well as reaction with pyrrole or dipyrromethane-1,9-dicarbinol would enable a direct,
or a dipyrromethane leading to multi-porphyrinic archi- mild synthesis of formyl porphyrins. A recent paper by
tectures.11 The formyl group also has been exploited in Trova et al. outlined the condensation of a dipyr-
supramolecular chemistry wherein the oxygen of the romethane bearing a 5-carboethoxy or 5-N,N-dimethy-
formyl group binds to the apical site on a neighboring laminocarbonyl group with an aldehyde to give the
metalloporphyrin.12 Although a few formyl-porphyrinic corresponding trans-A2B2-porphyrin.18 Such groups upon
compounds occur naturally (e.g., chlorophyll b), most further transformation could provide a complementary
must be synthesized de novo. The generic method for entry into meso-formyl porphyrins. In this paper, we
describe the synthesis of four dipyrromethane or acyl-
(1) (a) Callot, H. J. Tetrahedron 1973, 29, 899-901. (b) Arnold, D. dipyrromethane components, each bearing one or two
P.; Gaete-Holmes, R.; Johnson, A. W.; Smith, A. R. P.; Williams, G. A. latent meso-formyl groups and explore their utility in
J. Chem. Soc., Perkin. Trans. 1 1978, 1660-1670. (c) Burrell, A. K.; rational routes to porphyrins.
Officer, D. L. Synlett 1998, 1297-1307.
(2) Arnold, D. P.; Johnson, A. W.; Mahendran, M. J. Chem. Soc., 5-Formylporphyrins. We initially examined the use
Perkin. Trans. 1 1978, 366-370. of a 5-(dithiolan-2-yl)dipyrromethane as a precursor to
(3) (a) Montforts, F.-P.; Scheurich, G.; Meier, A.; Haake, G.; Höper,
F. Tetrahedron Lett. 1991, 32, 3477-3480. (b) Ando, A.; Yamazaki,
porphyrins bearing a latent formyl group, but upon
M.; Komura, M.; Sano, Y.; Hattori, N.; Omote, M.; Kumadaki, I. porphyrin formation, the meso-dithiolane group was
Heterocycles 1999, 50, 913-918. partially lost, yielding a mixture of porphyrins (see
(4) Runge, S.; Senge, M. O. Tetrahedron 1999, 55, 10375-10390.
(5) (a) Vicente, M. G. H.; Smith, K. M. J. Org. Chem. 1991, 56, 4407- Supporting Information). While the origin of the frag-
4418. (b) Jaquinod, L.; Nurco, D. J.; Medforth, C. J.; Pandey, R. K.; mentation reaction was not clear, we turned to the use
Forsyth, T. P.; Olmstead, M. M.; Smith, K. M. Angew. Chem., Int. Ed. of an acetal protecting group. The acid-catalyzed reaction
Engl. 1996, 35, 1013-1016.
(6) Johnson, A. W.; Oldfield, D. J. Chem. Soc. C 1966, 794-798. of glyoxal with neopentyl glycol provided a mixture of
(7) Witte, L.; Fuhrhop, J.-H. Angew. Chem., Int. Ed. 1975, 14, 361-
363. (13) Inhoffen, H. H.; Fuhrhop, J.-H.; Voigt, H.; Brockmann H., Jr.
(8) (a) Ponomarev, G. V. Chem. Heterocycl. Compd. 1996, 32, 1263- Justus Liebigs Ann. Chem. 1966, 695, 133-143.
1280. (b) Ponomarev, G. V.; Morozova, Y. V.; Yashunsky, D. V. Chem. (14) (a) Ponomarev. G. V.; Kirillova, G. V.; Maravin, G. B.; Babush-
Heterocycl. Compd. 2001, 37, 253-255. kina, T. A.; Suboch, V. P. Chem. Heterocycl. Compd. 1979, 15, 622-
(9) Schlözer, R.; Fuhrhop, J.-H. Angew. Chem., Int. Ed. 1975, 14, 629. (b) Ponomarev, G. V.; Kirillova, G. V.; Maravin, G. B.; Babushkina,
363. T. A.; Suboch, V. P. Chem. Heterocycl. Compd. 630-633.
(10) Ponomarev, G. V. Chem. Heterocycl. Compd. 1994, 30, 1444- (15) (a) Smith, K. M., Bisset, G. M. F., Tabba, H. D. J. Chem. Soc.,
1465. Perkin. Trans. 1 1982, 581-585. (b) Smith, K. M.; Bisset, G. M. F.;
(11) (a) Wasielewski, M. R.; Johnson, D. G.; Niemczyk, M. P.; Gaines, Case, J. J.; Tabba, H. D. Tetrahedron Lett. 1980, 21, 3747-3750.
G. L., III; O’Neil, M. P.; Svec, W. A. J. Am. Chem. Soc. 1990, 112, (16) Rao, P. D.; Littler, B. J.; Geier, G. R., III; Lindsey, J. S. J. Org.
6482-6488. (b) Johnson, D. G.; Niemczyk, M. P.; Minsek, D. W.; Chem. 2000, 65, 1084-1092.
Wiederrecht, G. P.; Svec, W. A.; Gaines, G. L., III; Wasielewski, M. R. (17) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J.
J. Am. Chem. Soc. 1993, 115, 5692-5701. Org. Chem. 2000, 65, 7323-7344.
(12) Balaban, T. S.; Bhise, A. D.; Fischer, M.; Linke-Schaetzel, M.; (18) Trova, M. P.; Gauuan, P. J. F.; Pechulis, A. D.; Bubb, S. M.;
Roussel, C.; Vanthuyne, N. Angew. Chem., Int. Ed. 2003, 42, 2140- Bocckino, S. B.; Crapo, J. D.; Day, B. J. Bioorg. Med. Chem. 2003, 11,
2144. 2695-2707.

10.1021/jo049819b CCC: $27.50 © 2004 American Chemical Society

5112 J. Org. Chem. 2004, 69, 5112-5115 Published on Web 06/22/2004
SCHEME 1 SCHEME 2

was employed directly in the dipyrromethane-forming

reaction. In this manner, 2 was obtained from glyoxal in
32% overall yield.
The condensation of dipyrromethane 2 with 3-diol
(prepared by the NaBH4 reduction of 1,9-diacyldipyr-
romethane 317) was carried out in the standard man-
ner17,21 in the presence of InCl3 followed by oxidation with
DDQ. Acetal-porphyrin 4 was obtained cleanly in 13%
yield. Hydrolysis of the acetal in porphyrin 4 was carried
out using a biphasic mixture of CH2Cl2, TFA, and water
(10:1:1)22 at room temperature to afford meso-formyl
porphyrin 5 in 92% yield. Metalation of 5 with
Zn(OAc)2‚2H2O gave the zinc porphyrin Zn-5 in 92% yield
(Scheme 1).
5,15-Diformylporphyrins. Two routes were investi-
gated for the synthesis of 5,15-diformylporphyrins. Each
the monoacetal 119 and the bis-acetal. Our efforts to route employs the self-condensation of the carbinol
isolate the monoacetal from the crude reaction mixture derived from a 1-acyldipyrromethane. The routes differ
by distillation provided the glyoxal monoacetal 1 in only only in whether the acetal group is located at the
4% yield rather than the reported yield of 50%.19 Treat- 5-position or attached to the 1-acyl group of the 1-acyl-
ment of 1 with excess pyrrole in the presence of InCl3 dipyrromethane.
following a standard procedure20 afforded the acetal- The route that employs a dipyrromethane-mono-
dipyrromethane 2 in 70% yield. Given the difficulty of carbinol bearing the acetal at the 5-position begins with
isolating pure 1 and the ease of isolation of 2, crude 1 dipyrromethane 2. Treatment of 2 under the standard

(19) Blanc, A.; Hamedi-Sangsari, F.; Chastrette, F. J. U.S. Patent (21) Geier, G. R., III; Callinan, J. B.; Rao, P. D.; Lindsey, J. S. J.
4,835,320. Porphyrins Phthalocyanines 2001, 5, 810-823.
(20) Laha, J. K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.; (22) Lindsey, J. S.; Brown, P. A.; Siesel, D. A. Tetrahedron 1989,
Lindsey, J. S. Org. Process Res. Dev. 2003, 7, 799-812. 45, 4845-4866.

J. Org. Chem, Vol. 69, No. 15, 2004 5113

SCHEME 3 SCHEME 5

The route that employs a dipyrromethane-mono-

carbinol bearing the acetal at the 1-carbinol position
requires the synthesis of an appropriate acetal-containing
SCHEME 4 Mukaiyama reagent. The reaction of glyoxylic acid mono-
hydrate with neopentyl glycol in the presence of Am-
berlyst-15 ion-exchange resin (as described for homolo-
gous compounds)23 provided a mixture of the desired
acetal-acid 10 and an acetal-ester byproduct. Hydrolysis
of the mixture with 20% aqueous NaOH afforded 10 in
73% yield. The Mukaiyama reaction24 of 10 with 2,2′-
dipyridyl disulfide and Ph3P provided pyridyl thioester
11, which proved to be difficult to purify. The crude
reaction mixture containing 11 was used in the next step.
Thus, acylation of 5-phenyldipyrromethane (12)20 in the
standard manner16 with the crude 11 afforded the 1-acyl-
dipyrromethane 13 in 64% yield (Scheme 3).
Reduction of 13 with NaBH4 gave the dipyrromethane-
monocarbinol 13-OH, which upon self-condensation16,21
in the presence of InCl3 followed by oxidation with DDQ
provided porphyrin 14 in 21% yield. Hydrolysis of the
two acetal groups in porphyrin 14 in CH2Cl2/TFA/H2O
(5:1:1) afforded the 5,15-diformylporphyrin 15 in 83%
yield (Scheme 4).
5,10-Diformylporphyrins. Acylation of 1-acyldipyr-
conditions for 1-acylation16 with pyridyl thioester 616
romethane 13 with benzoyl chloride by the standard
afforded the 1-acyldipyrromethane 7 in 72% yield. Re-
duction of 7 with NaBH4 and self-condensation16,21 of the
(23) Newman, M. S.; Chen, C. H. J. Org. Chem. 1973, 38, 1173-1177.
resulting dipyrromethane-monocarbinol 7-OH in the (24) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull. Chem.
presence of InCl3 followed by oxidation with DDQ gave Soc. Jpn. 1974, 47, 1777-1780.
porphyrin 8 in 14% yield. Hydrolysis of the two acetal (25) (a) Fenyo, D.; Chait, B. T.; Johnson, T. E.; Lindsey, J. S. J.
Porphyrins Phthalocyanines 1997, 1, 93-99. (b) Srinivasan, N.; Haney,
groups in porphyrin 8 with CH2Cl2/TFA/H2O (10:1:1) gave C. A.; Lindsey, J. S.; Zhang, W.; Chait, B. T. J. Porphyrins Phthalo-
5,15-diformylporphyrin 9 in 90% yield (Scheme 2). cyanines 1999, 3, 283-291.

5114 J. Org. Chem., Vol. 69, No. 15, 2004

procedure17 provided the 1,9-diacyldipyrromethane 16 in (5,10-diformyl, 18). Each porphyrin gave the expected
57% yield. Reduction of 16 with NaBH4 gave the dipyr- molecule ion peak upon LD-MS analysis.
romethane-dicarbinol 16-diol, which upon condensation
with dipyrromethane 2 in the presence of InCl3 followed Conclusion
by oxidation with DDQ afforded porphyrin 17 in 17% Acetal-substituted dipyrromethane, dipyrromethane-
yield. Hydrolysis of the two acetal groups in porphyrin 1-carbinol, and dipyrromethane-1,9-dicarbinol components
17 in CH2Cl2/TFA/H2O (5:1:1) afforded the 5,10-di- can be used in rational routes for forming porphyrins.
formylporphyrin 18 in 88% yield (Scheme 5). Gentle acid hydrolysis of the resulting meso-acetal por-
Spectroscopic Characterization. Each porphyrin phyrins affords the corresponding meso-formyl porphy-
was characterized by absorption spectroscopy, 1H NMR rins. The conversion of acetal-substituted dipyrromethane
spectroscopy, 13C NMR spectroscopy (except 9 and 15 due species to free base porphyrins complements the tradi-
to poor solubility), laser-desorption mass spectrometry tional Vilsmeier formylation of metalloporphyrins.
(LD-MS),25 and FAB-MS. The acetal-substituted porphy-
rins (4, 8, 14, 17) exhibited typical absorption spectra, Acknowledgment. This work was supported by the
with the characteristic Soret band in the 416-419 nm NIH (GM36238). Mass spectra were obtained at the
region. The corresponding formyl-porphyrins exhibited Mass Spectrometry Laboratory for Biotechnology at
red-shifted Soret bands. The magnitude of the shift North Carolina State University. Partial funding for the
facility was obtained from the North Carolina Biotech-
varied from 9 nm (one formyl, 5), to ∼12 nm (5,15-
nology Center and the NSF.
diformyl, 9, 15), to 23 nm (5,10-diformyl, 18). The IR
spectra showed bands at 1672 cm-1 to 1674 cm-1 (one Supporting Information Available: Complete experi-
formyl, 5; 5,15-diformyl, 15; 5,10-diformyl, 18) and at mental section, including the synthesis of 5-(dithiolan-2-yl)-
1666 cm-1 (5,15-diformyl, 9). In each formyl-porphyrin, dipyrromethane, and spectral data for selected compounds.
the formyl proton resonated as a distinctive singlet at This material is available free of charge via the Internet at
http://pubs.acs.org.
12.3-12.5 ppm. The formyl carbon gave a resonance
at 195.13 ppm (one formyl, 5) and at 194.77 ppm JO049819B

J. Org. Chem, Vol. 69, No. 15, 2004 5115