CHART 1
Direct Synthesis of Magnesium Porphine via
1-Formyldipyrromethane
Dilek Kiper Dogutan, Marcin Ptaszek, and
Jonathan S. Lindsey*
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
method of synthesis and (2) extremely low solubility of the free
base porphine (1).
Methods for the synthesis of porphine span the past 70 years
(see the Supporting Information).4-16 The reactants employed
include pyrrole and formaldehyde,4,10 pyrrole-2-carboxalde-
hyde,52-(N,N-dimethylaminomethyl)pyrrole,6and2-hydroxymethyl-
pyrrole.7-9,11,12 The best method to date employs condensation
of 2-hydroxymethylpyrrole in an acidified biphasic mixture
followed by oxidation with DDQ, which has afforded 30 mg
of porphine in 15% yield.12 An alternative method entails
dealkylation of a tetra-tert-butylporphyrin or meso-tetrakis-
(hexyloxycarbonyl)porphyrin in the presence of strong acid,
which respectively affords porphine in 64-74%14 or 77%15
yield; however, this method obviously requires the preparation
of the porphyrin precursor. Porphine also can be prepared in
31% yield by the reaction of 5,10,15,17-tetrahydrotripyrrin and
2,5-bis(hydroxymethyl)pyrrole13 (or 2-hydroxymethylpyrrole16).
Thus, despite the structural simplicity of porphine, there
remains no method of satisfactory yield, scale, and ease of
implementation that enables the synthetic utility of porphine to
be unlocked. The low yields of macrocycle formation with
simple pyrrole compounds are mitigated by the easily available
starting materials; however, separation of the poorly soluble
porphine from the polymeric material in the crude reaction
mixture remains tedious. The use of more elaborate precursors
requires more synthetic effort than would seem warranted. Here
we report an efficient, concise, and practical method for
preparing Mg-1, which greatly facilitates access to this valuable
compound, and from which free base porphine (1) is readily
obtained.
ReceiVed March 14, 2007
The reaction of 1-formyldipyrromethane (100 mM) in toluene
at 115 °C containing DBU (10 mol equiv) and MgBr2 (3
mol equiv) in the presence of air affords the magnesium
chelate Mg(II) porphine in 30-40% yield. The advantages
of the new method include simplicity, high concentration,
chromatography-free purification, gram-scale synthesis, and
avoidance of the poorly soluble free base porphine. Mg(II)
porphine exhibits good solubility in common organic solvents
and is a valuable core scaffold for derivatization.
Porphine (1, Chart 1) is the simplest porphyrin and represents
the core macrocycle of naturally occurring and synthetic
porphyrins. Due to the presence of eight open â-pyrrole sites
and four open meso sites, porphine is a potential building block
for the elaboration of porphyrin derivatives. In this regard,
porphine undergoes selective monobromination at a â-position
to give 2-bromoporphine.1 On the other hand, Shi and Wheel-
house showed that the magnesium(II) chelate of porphine (Mg-
1) undergoes tetrabromination to give magnesium(II) meso-
tetrabromoporphine. Subsequent palladium-coupling reactions
afforded tetraaryl A4-tetraarylporphyrins, which included target
porphyrins that are not easily available by other routes (e.g.,
with heterocyclic substituents).2 Senge has shown that porphine
reacts with organolithium reagents to provide meso-substituted
A- or cis-A2-porphyrins, which also are difficult to synthesize
by other routes.3 These reports provide a glimmer of the possible
synthetic utility of porphine; however, the practical use of
porphine in synthetic chemistry has been thwarted by two vexing
and somewhat interrelated limitations: (1) lack of an efficient
1. Strategy and Survey. Our approach for the synthesis of
porphine, which has emerged from our prior studies of routes
(4) (a) Rothemund, P. J. Am. Chem. Soc. 1935, 57, 2010-2011. (b)
Rothemund, P. J. Am. Chem. Soc. 1936, 57, 625-627.
(5) Fischer, H.; Gleim, W. Liebigs Ann. 1936, 521, 157-160.
(6) (a) Eisner, U.; Linstead, R. P. J. Chem. Soc. 1955, 3742-3749. (b)
Egorova, G. D.; Solov’ev, K. N.; Shul’ga, A. M. J. Gen. Chem. (USSR)
1967, 37, 333-336.
(7) Krol, S. J. Org. Chem. 1959, 24, 2065-2067.
(8) Yalman, R. G. U.S. patent 3,579,533.
(9) Longo, F. R.; Thorne, E. J.; Adler, A. D.; Dym, S. J. Heterocycl.
Chem. 1975, 12, 1305-1309.
(10) Neya, S.; Yodo, H.; Funasaki, N. J. Heterocycl. Chem. 1993, 30,
549-550.
(11) Bonar-Law, R. P. J. Org. Chem. 1996, 61, 3623-3634.
(12) Ellis, P. E., Jr.; Langdale, W. A. J. Porphyrins Phthalocyanines
1997, 1, 305-307.
(13) Taniguchi, S.; Hasegawa, H.; Nishimura, M.; Takahashi, M. Synlett
1999, 73-74.
(14) (a) Neya, S.; Funasaki, N. Tetrahedron Lett. 2002, 43, 1057-1058.
(b) Neya, S.; Quan, J.; Hoshino, T.; Hata, M.; Funasaki, N. Tetrahedron
Lett. 2004, 45, 8629-8630.
(1) Schlo¨zer, R.; Fuhrhop, J.-H. Angew. Chem., Int. Ed. 1975, 14, 363.
(2) Shi, D.-F.; Wheelhouse, R. T. Tetrahedron Lett. 2002, 43, 9341-
9342.
(3) (a) Hatscher, S.; Senge, M. O. Tetrahedron Lett. 2003, 44, 157-
160. (b) Ryppa, C.; Senge, M. O.; Hatscher, S. S.; Kleinpeter, E.; Wacker,
P.; Schilde, U.; Wiehe, A. Chem. Eur. J. 2005, 11, 3427-3442.
(15) Neya, S.; Quan, J.; Hata, M.; Hoshino, T.; Funasaki, N. Tetrahedron
Lett. 2006, 47, 8731-8732.
(16) Saltsman, I.; Goldberg, I.; Balasz, Y.; Gross, Z. Tetrahedron Lett.
2007, 48, 239-244.
10.1021/jo070532z CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/23/2007
5008
J. Org. Chem. 2007, 72, 5008-5011