A novel and efficient synthesis of porphine

Article abstract of DOI:10.1016/j.tetlet.2006.10.010

meso-Tetra(n-hexyloxycarbonyl)porphyrin was found to be converted into porphine, the mother compound of porphyrins, in a 77% yield when heated in aqueous sulfuric acid at 180 °C over 30 min under an inert atmosphere. The observation demonstrates that the substituted porphyrin serves as a novel and useful precursor for porphine.

Full text of DOI:10.1016/j.tetlet.2006.10.010

Tetrahedron Letters 47 (2006) 8731–8732
A novel and efficient synthesis of porphine
a
a,
a
a
b
*
Saburo Neya, Jingshun Quan, Masayuki Hata, Tyuji Hoshino and Noriaki Funasaki
a
Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University,
Inage-Yayoi, Chiba 263-8522, Japan
Department of Physical Chemistry, Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8414, Japan
b
Received 3 September 2006; revised 26 September 2006; accepted 3 October 2006
Available online 20 October 2006
Abstract—meso-Tetra(n-hexyloxycarbonyl)porphyrin was found to be converted into porphine, the mother compound of porphy-
rins, in a 77% yield when heated in aqueous sulfuric acid at 180 °C over 30 min under an inert atmosphere. The observation dem-
onstrates that the substituted porphyrin serves as a novel and useful precursor for porphine.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
than 100 mg of porphine at one time. Taniguchi et al.
devised a sophisticated porphine synthesis from tripyr-
rane and 2,5-dihydroxymethylpyrrole in a 31% yield.
1
3
Heme is a vital pigment to constitute the essential com-
ponent of hemoprotein. Natural porphyrins are peri-
pherally substituted at the pyrrole rings, and the
porphyrin in hemoglobin and myoglobin is protopor-
phyrin. Complete removal of the peripheral chains of
porphyrins results in the most fundamental cyclic tetra-
pyrrole called porphine. Porphine serves not only as the
starting material of various porphyrin derivatives,1 but
also as a unique molecular tool to perturb the heme–glo-
bin interactions in protein. Neya et al. introduced iron
porphine into myoglobin and found that the smallest
heme was dynamically rotating around the iron–histi-
dine bond. Despite the simplest structure, the porphine
synthesis is difficult and the commercialized product is
Another rational approach to porphine is the initial
construction of substituted porphyrin followed by
the deletion of the side chains. The methodology is
advantageous over the direct porphine synthesis because
substituted porphyrins are simpler to prepare than
unsubstituted porphine. We have developed this strategy
and synthesized porphine in a 60–75% yield from
–3
4
14
meso-tetra(tert-butyl)porphyrin and b-tetra(tert-butyl)-
1
5
porphyrin.
5
Trova et al. have recently prepared new porphyrin deriv-
atives, that is, meso-tetra(alkoxycarbonyl)porphyrins with
carboxylate groups directly attached at the four meso-
6
7
fairly expensive. In view of the developing application
as well as the fundamental importance, the facile
porphine synthesis is to be explored.
1
6
bridges. The porphyrins are of interest because the
metal complexes exhibit a strong activity of superoxide
dismutase mimetics. The metal free compounds are
available from pyrrole and alkyl glyoxylate esters with
8
9
Fischer and Gleim and Rothemund first noted the
porphine formation in 1936. Their methods have been
improved by Eisner and Linstead and Krol with
the pyrrole derivatives containing a-methylene group
as the meso-carbon source for porphine. Neya et al.
reported a simple porphine synthesis with pyrrole and
1
7
the yields >6% under the Lindsey condition. The best
1
0
11
yield of 15% is reported for meso-tetra(n-hexyloxycar-
1
6
bonyl)porphyrin (1). We examined the conversion of
1 into porphine.
1
2
formalin. Neya’s reaction, though the yield is only
.9%, is easily carried out on a large scale to afford more
0
2. Results and discussion
The molecular structure of meso-tetra(alkoxycar-
bonyl)porphyrins implies that they may serve as precur-
sors for porphine if the meso-substituents are cleavable.
The removal of side chains was attempted under several
Keywords: Thermal decarboxylation; Aqueous sulfuric acid; meso-
Tetra(n-hexyloxycarbonyl)porphyrin; Porphine.
*
Corresponding author. Fax: +81 43 290 2927; e-mail: sneya@
p.chiba-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.010

8732
S. Neya et al. / Tetrahedron Letters 47 (2006) 8731–8732
CO2R
an ice bath, and the solution was diluted with water
600 ml). A saturating amount of sodium chloride was
(
added to the aqueous solution, and the precipitates of
the crude product were spun down. The precipitates
were washed with small amounts of water and methanol
with a centrifuge before being dried. The dry material
was purified on a silicagel column with chloroform.
The chloroform solution was evaporated down to leave
copper-colored fine crystals of porphine (76 mg, 77%
NH
N
N
H2SO4/H2O
o
NH
N
N
RO2C
CO2R
1
80 C, 30 min
HN
HN
CO R
R = n-hexyl
2
1
yield). Anal. Calcd. for C H N : C, 77.40; H, 4.55;
Scheme 1. Porphine synthesis from meso-tetra(n-hexyloxycarbonyl)-
porphyrin.
20 14
4
1
N, 18.05. Found: C, 77.59; H, 4.74; N, 17.67.
H
NMR (400 MHz, CDCl , d) 10.36 (s, 4H, meso-H),
3
9
.53 (s, 8H, pyrrole–H), À3.88 (br s, 2H, NH). MS:
14
+
conditions. Andrews et al. reported that the ester groups
in 1,4,5,8-tetramethyl-2,3,6,7-tetra(ethoxycarbony)por-
phyrin are removed to furnish 1,4,5,8-tetramethylpor-
phyrin when the former is heated at 290 °C over
m/z, 310 (M ). Visible absorption spectrum was identi-
cal with that reported previously.
1
20 min in glycerin containing sodium hydroxide.18
Acknowledgments
Application of the same condition to 1 under an inert
atmosphere was unsuccessful to cause intensive decom-
position. Shorter heating and/or lower temperature did
not improve the result. We consequently set out the
thermal decarboxylation of hydrolyzed 1 under acidic
condition. It is expected that hydrolysis of the ester
groups and subsequent decarboxylation will be carried
out in one-pot if hot aqueous sulfuric acid was used.
When we treated 1 with hydrated sulfuric acid under
the optimized condition, the Soret peak shifted from
This work was supported in grants-in-aid from Japan
Society for the Promotion of Science, No. 18590094
and ‘Initiatives for Attractive Education for Graduate
Schools’.
References and notes
1
. Ryppa, C.; Senge, M. O.; Hatcher, S. S.; Kleinpeter, E.;
Wacker, P.; Schilde, U.; Wiehe, A. Chem. Eur. J. 2005, 11,
3427–3442.
4
10 to 394 nm and the phyllo-type of visible spectrum
of porphine appeared to reflect the removal of the ester
side chains (Scheme 1). Water was indeed an essential
additive because no porphine was obtained in neat
sulfuric acid. After chromatographic purification, we
obtained crystalline porphine in a 77% yield. The yield
is comparable with or better than 65–75% reported for
2. Senge, M. O.; Richter, J. J. Porphyrins Phthalocyanines
004, 8, 934–953.
2
3
4
. Senge, M. O. Acc. Chem. Res. 2005, 38, 733–743.
. Sato, T.; Tanaka, N.; Neya, S.; Funasaki, N.; Iizuka, T.;
Shiro, Y. Biochim. Biophys. Acta 1992, 1121, 1–7.
. Neya, S.; Funasaki, N.; Sato, T.; Igarashi, N.; Tanaka, N.
J. Biol. Chem. 1993, 268, 8935–8942.
5
6
1
4,15
the previous porphine synthesis.
. Frank, B.; Noum, A. Angew. Chem., Int. Ed. Engl. 1995,
It has now turned out that the side chains in 1 are deleted
by using hot aqueous sulfuric acid to afford porphine.
The reaction is straightforward and the work-up is easy.
n-Hexylglyoxylate is readily accessible and gives 1 in a
good yield under a mild condition. These observations,
taken together, demonstrate that compound 1 is a novel
and promising precursor for porphine. In conclusion, we
have demonstrated that the initial construction of the
substituted porphyrins followed by side-chain removal
is a general instruction to the high-yielding synthesis
of porphine.
3
4, 1795–1811.
7. According to the Frontier Scientific Catalog in 2006, the
price for 5 mg of porphine, order code P310, is 103 US
dollars.
8
. Fischer, H.; Gleim, W. Liebigs Ann. Chem. 1936, 521, 157–
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1
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Porphyrin 1 (200 mg) was dissolved in sulfuric acid
(
40 ml), and water (8 ml) and anhydrous Na SO
2 4
1
(
4.0 g) were added. The solution was kept in an oil bath
at 180 °C over 20–30 min under argon until the efferves-
cence of CO due to the decarboxylation was over. The
2
17. Lindsey, J. S. In The Porphyrin Handbook; Academic
Press: New York, 2000; Vol. 1, pp 45–178.
18. Andrews, J. S.; Corwin, A. H.; Sharp, A. G. J. Am. Chem.
Soc. 1950, 72, 491–494.
dark green solution was changed into dark purple dur-
ing the incubation. Methanol (100 ml) and pyridine
(
120 ml) were added to the cooled reaction mixture on