A new route to meso-formyl porphyrins

Article abstract of DOI:10.1021/jo049819b

Prior syntheses of porphyrins bearing meso-formyl groups have generally employed the Vilsmeier formylation of an acid-resistant copper or nickel porphyrin. A new approach for the synthesis of free base porphyrins bearing one or two (cis or trans) meso-for

Full text of DOI:10.1021/jo049819b

introducing a formyl group to a porphyrinic macrocycle
A New Rou te to m eso-F or m yl P or p h yr in s
entails Vilsmeier formylation.10 Vilsmeier formylation,
6,13
Arumugham Balakumar, Kannan Muthukumaran, and
J onathan S. Lindsey*
either with the traditional DMF/POCl3
or the more
recent HC(OMe)3/TFA or SnCl4,3 can only be carried out
with metalloporphyrins that are stable toward strong
acids (e.g., copper or nickel chelates). Hence, formylation
typically requires three steps: (1) insertion of copper into
a free base porphyrin, (2) formylation of the copper
chelate, and (3) demetalation of copper to give the free
base porphyrin bearing the formyl group. The removal
of copper generally requires strongly acidic conditions
such as TFA in H2SO4. The yield of the Vilsmeier
formylation is typically quite high (though mixtures of
polyformylated metalloporphyrins are known10,14,15). How-
ever, the requirement for a three-step procedure, use of
strong acid, and limited control over the site of formyla-
tion presents obvious limitations.
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
jlindsey@ncsu.edu
Received J anuary 31, 2004
Abstr a ct: Prior syntheses of porphyrins bearing meso-
formyl groups have generally employed the Vilsmeier formy-
lation of an acid-resistant copper or nickel porphyrin. A new
approach for the synthesis of free base porphyrins bearing
one or two (cis or trans) meso-formyl substituents entails
the use of a dipyrromethane bearing an acetal group at the
5-position, a dipyrromethane-1-carbinol bearing an acetal
group at the 5-position or carbinol position, or a dipyr-
romethane-1,9-dicarbinol bearing an acetal group at
a
There exists a need for a milder and more direct
procedure for preparing formyl porphyrins. Two routes
to porphyrins bearing distinct patterns of meso substit-
uents include (1) the self-condensation of a dipyr-
romethane-1-carbinol, affording trans-A2B2-porphyrins,16
and (2) the reaction of a dipyrromethane and a dipyr-
romethane-1,9-dicarbinol, affording porphyrins with up
to four different meso substituents (ABCD-porphyrins).17
We considered that the incorporation of a latent formyl
synthon in a dipyrromethane, dipyrromethane-1-carbinol,
or dipyrromethane-1,9-dicarbinol would enable a direct,
mild synthesis of formyl porphyrins. A recent paper by
Trova et al. outlined the condensation of a dipyr-
romethane bearing a 5-carboethoxy or 5-N,N-dimethy-
laminocarbonyl group with an aldehyde to give the
corresponding trans-A2B2-porphyrin.18 Such groups upon
further transformation could provide a complementary
entry into meso-formyl porphyrins. In this paper, we
describe the synthesis of four dipyrromethane or acyl-
dipyrromethane components, each bearing one or two
latent meso-formyl groups and explore their utility in
rational routes to porphyrins.
5-F or m ylp or p h yr in s. We initially examined the use
of a 5-(dithiolan-2-yl)dipyrromethane as a precursor to
porphyrins bearing a latent formyl group, but upon
porphyrin formation, the meso-dithiolane group was
partially lost, yielding a mixture of porphyrins (see
Supporting Information). While the origin of the frag-
mentation reaction was not clear, we turned to the use
of an acetal protecting group. The acid-catalyzed reaction
of glyoxal with neopentyl glycol provided a mixture of
carbinol position. Treatment of the resulting meso-acetal-
substituted free base porphyrin to gentle acidic hydrolysis
yields the corresponding meso-formyl porphyrin.
Formyl-substituted porphyrinic macrocycles provide
versatile intermediates and target molecules in bioor-
ganic and materials chemistry. Notable reactions of the
porphyrinic formyl group include classical reactions of
aldehydes (e.g., Wittig,1-3 Grignard,2,4 McMurry,5 Schiff’s
base,6-8 Knoevenagel7,9 10 as well as reaction with pyrrole
)
or a dipyrromethane leading to multi-porphyrinic archi-
tectures.11 The formyl group also has been exploited in
supramolecular chemistry wherein the oxygen of the
formyl group binds to the apical site on a neighboring
metalloporphyrin.12 Although a few formyl-porphyrinic
compounds occur naturally (e.g., chlorophyll b), most
must be synthesized de novo. The generic method for
(1) (a) Callot, H. J . Tetrahedron 1973, 29, 899-901. (b) Arnold, D.
P.; Gaete-Holmes, R.; J ohnson, A. W.; Smith, A. R. P.; Williams, G. A.
J . Chem. Soc., Perkin. Trans. 1 1978, 1660-1670. (c) Burrell, A. K.;
Officer, D. L. Synlett 1998, 1297-1307.
(2) Arnold, D. P.; J ohnson, A. W.; Mahendran, M. J . Chem. Soc.,
Perkin. Trans. 1 1978, 366-370.
(3) (a) Montforts, F.-P.; Scheurich, G.; Meier, A.; Haake, G.; Ho¨per,
F. Tetrahedron Lett. 1991, 32, 3477-3480. (b) Ando, A.; Yamazaki,
M.; Komura, M.; Sano, Y.; Hattori, N.; Omote, M.; Kumadaki, I.
Heterocycles 1999, 50, 913-918.
(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-
4418. (b) J aquinod, L.; Nurco, D. J .; Medforth, C. J .; Pandey, R. K.;
Forsyth, T. P.; Olmstead, M. M.; Smith, K. M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1013-1016.
(6) J ohnson, A. W.; Oldfield, D. J . Chem. Soc. C 1966, 794-798.
(7) Witte, L.; Fuhrhop, J .-H. Angew. Chem., Int. Ed. 1975, 14, 361-
363.
(8) (a) Ponomarev, G. V. Chem. Heterocycl. Compd. 1996, 32, 1263-
1280. (b) Ponomarev, G. V.; Morozova, Y. V.; Yashunsky, D. V. Chem.
Heterocycl. Compd. 2001, 37, 253-255.
(9) Schlo¨zer, R.; Fuhrhop, J .-H. Angew. Chem., Int. Ed. 1975, 14,
363.
(13) Inhoffen, H. H.; Fuhrhop, J .-H.; Voigt, H.; Brockmann H., J r.
J ustus Liebigs Ann. Chem. 1966, 695, 133-143.
(14) (a) Ponomarev. G. V.; Kirillova, G. V.; Maravin, G. B.; Babush-
kina, T. A.; Suboch, V. P. Chem. Heterocycl. Compd. 1979, 15, 622-
629. (b) Ponomarev, G. V.; Kirillova, G. V.; Maravin, G. B.; Babushkina,
T. A.; Suboch, V. P. Chem. Heterocycl. Compd. 630-633.
(15) (a) Smith, K. M., Bisset, G. M. F., Tabba, H. D. J . Chem. Soc.,
Perkin. Trans. 1 1982, 581-585. (b) Smith, K. M.; Bisset, G. M. F.;
Case, J . J .; Tabba, H. D. Tetrahedron Lett. 1980, 21, 3747-3750.
(16) Rao, P. D.; Littler, B. J .; Geier, G. R., III; Lindsey, J . S. J . Org.
Chem. 2000, 65, 1084-1092.
(10) Ponomarev, G. V. Chem. Heterocycl. Compd. 1994, 30, 1444-
1465.
(11) (a) Wasielewski, M. R.; J ohnson, D. G.; Niemczyk, M. P.; Gaines,
G. L., III; O’Neil, M. P.; Svec, W. A. J . Am. Chem. Soc. 1990, 112,
6482-6488. (b) J ohnson, D. G.; Niemczyk, M. P.; Minsek, D. W.;
Wiederrecht, G. P.; Svec, W. A.; Gaines, G. L., III; Wasielewski, M. R.
J . Am. Chem. Soc. 1993, 115, 5692-5701.
(12) Balaban, T. S.; Bhise, A. D.; Fischer, M.; Linke-Schaetzel, M.;
Roussel, C.; Vanthuyne, N. Angew. Chem., Int. Ed. 2003, 42, 2140-
2144.
(17) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J .; Lindsey, J . S. J .
Org. Chem. 2000, 65, 7323-7344.
(18) Trova, M. P.; Gauuan, P. J . F.; Pechulis, A. D.; Bubb, S. M.;
Bocckino, S. B.; Crapo, J . D.; Day, B. J . Bioorg. Med. Chem. 2003, 11,
2695-2707.
10.1021/jo049819b CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/22/2004
5112
J . Org. Chem. 2004, 69, 5112-5115

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-d iol
(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-Difor m ylp or p h yr in s. Two routes were investi-
gated for the synthesis of 5,15-diformylporphyrins. Each
route employs the self-condensation of the carbinol
derived from a 1-acyldipyrromethane. The routes differ
only in whether the acetal group is located at the
5-position or attached to the 1-acyl group of the 1-acyl-
dipyrromethane.
The route that employs a dipyrromethane-mono-
carbinol bearing the acetal at the 5-position begins with
dipyrromethane 2. Treatment of 2 under the standard
the monoacetal 119 and the bis-acetal. Our efforts to
isolate the monoacetal from the crude reaction mixture
by distillation provided the glyoxal monoacetal 1 in only
4% yield rather than the reported yield of 50%.19 Treat-
ment of 1 with excess pyrrole in the presence of InCl3
following a standard procedure20 afforded the acetal-
dipyrromethane 2 in 70% yield. Given the difficulty of
isolating pure 1 and the ease of isolation of 2, crude 1
(19) Blanc, A.; Hamedi-Sangsari, F.; Chastrette, F. J . U.S. Patent
4,835,320.
(20) Laha, J . K.; Dhanalekshmi, S.; Taniguchi, M.; Ambroise, A.;
Lindsey, J . S. Org. Process Res. Dev. 2003, 7, 799-812.
(21) Geier, G. R., III; Callinan, J . B.; Rao, P. D.; Lindsey, J . S. J .
Porphyrins Phthalocyanines 2001, 5, 810-823.
(22) Lindsey, J . S.; Brown, P. A.; Siesel, D. A. Tetrahedron 1989,
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
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).
SCHEME 4
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-Difor m ylp or p h yr in s. Acylation of 1-acyldipyr-
romethane 13 with benzoyl chloride by the standard
conditions for 1-acylation16 with pyridyl thioester 616
afforded the 1-acyldipyrromethane 7 in 72% yield. Re-
duction of 7 with NaBH4 and self-condensation16,21 of the
resulting dipyrromethane-monocarbinol 7-OH in the
presence of InCl3 followed by oxidation with DDQ gave
porphyrin 8 in 14% yield. Hydrolysis of the two acetal
groups in porphyrin 8 with CH2Cl2/TFA/H2O (10:1:1) gave
5,15-diformylporphyrin 9 in 90% yield (Scheme 2).
(23) Newman, M. S.; Chen, C. H. J . Org. Chem. 1973, 38, 1173-1177.
(24) Araki, M.; Sakata, S.; Takei, H.; Mukaiyama, T. Bull. Chem.
Soc. J pn. 1974, 47, 1777-1780.
(25) (a) Fenyo, D.; Chait, B. T.; J ohnson, T. E.; Lindsey, J . S. J .
Porphyrins Phthalocyanines 1997, 1, 93-99. (b) Srinivasan, N.; Haney,
C. A.; Lindsey, J . S.; Zhang, W.; Chait, B. T. J . Porphyrins Phthalo-
cyanines 1999, 3, 283-291.
5114 J . Org. Chem., Vol. 69, No. 15, 2004

procedure17 provided the 1,9-diacyldipyrromethane 16 in
57% yield. Reduction of 16 with NaBH4 gave the dipyr-
romethane-dicarbinol 16-d iol, which upon condensation
with dipyrromethane 2 in the presence of InCl3 followed
by oxidation with DDQ afforded porphyrin 17 in 17%
yield. Hydrolysis of the two acetal groups in porphyrin
17 in CH2Cl2/TFA/H2O (5:1:1) afforded the 5,10-di-
formylporphyrin 18 in 88% yield (Scheme 5).
(5,10-diformyl, 18). Each porphyrin gave the expected
molecule ion peak upon LD-MS analysis.
Con clu sion
Acetal-substituted dipyrromethane, dipyrromethane-
1-carbinol, and dipyrromethane-1,9-dicarbinol components
can be used in rational routes for forming porphyrins.
Gentle acid hydrolysis of the resulting meso-acetal por-
phyrins affords the corresponding meso-formyl porphy-
rins. The conversion of acetal-substituted dipyrromethane
species to free base porphyrins complements the tradi-
tional Vilsmeier formylation of metalloporphyrins.
Sp ectr oscop ic Ch a r a cter iza tion . Each porphyrin
1
was characterized by absorption spectroscopy, H NMR
spectroscopy, 13C NMR spectroscopy (except 9 and 15 due
to poor solubility), laser-desorption mass spectrometry
(LD-MS),25 and FAB-MS. The acetal-substituted porphy-
rins (4, 8, 14, 17) exhibited typical absorption spectra,
with the characteristic Soret band in the 416-419 nm
region. The corresponding formyl-porphyrins exhibited
red-shifted Soret bands. The magnitude of the shift
varied from 9 nm (one formyl, 5), to ∼12 nm (5,15-
diformyl, 9, 15), to 23 nm (5,10-diformyl, 18). The IR
spectra showed bands at 1672 cm-1 to 1674 cm-1 (one
formyl, 5; 5,15-diformyl, 15; 5,10-diformyl, 18) and at
1666 cm-1 (5,15-diformyl, 9). In each formyl-porphyrin,
the formyl proton resonated as a distinctive singlet at
12.3-12.5 ppm. The formyl carbon gave a resonance
at 195.13 ppm (one formyl, 5) and at 194.77 ppm
Ack n ow led gm en t. This work was supported by the
NIH (GM36238). Mass spectra were obtained at the
Mass Spectrometry Laboratory for Biotechnology at
North Carolina State University. Partial funding for the
facility was obtained from the North Carolina Biotech-
nology Center and the NSF.
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental section, including the synthesis of 5-(dithiolan-2-yl)-
dipyrromethane, and spectral data for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O049819B
J . Org. Chem, Vol. 69, No. 15, 2004 5115