Microwave-assisted synthesis of non-substituted tripyrrane, tetrapyrrane and pentapyrrane

Article abstract of DOI:10.1016/j.tetlet.2007.11.082

The microwave-assisted one-step condensation of aqueous formaldehyde with pyrrole was successfully applied for the preparation of non-substituted tri-, tetra- and pentapyrranes with reasonable yields. All three compounds are important precursors to advanced porphyrins and porphyrin analogs. The advantages of this method are short reaction times, clean reaction mixtures and work in the non-toxic and environment friendly solvent-water.

Full text of DOI:10.1016/j.tetlet.2007.11.082

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Tetrahedron Letters 49 (2008) 247–249
Microwave-assisted synthesis of non-substituted tripyrrane,
tetrapyrrane and pentapyrrane
Irena Saltsman and Zeev Gross*
Schulich Faculty of Chemistry, Technion, Israel Institute of Technology, Haifa 32000, Israel
Received 17 September 2007; revised 7 November 2007; accepted 14 November 2007
Available online 19 November 2007
Abstract—The microwave-assisted one-step condensation of aqueous formaldehyde with pyrrole was successfully applied for the
preparation of non-substituted tri-, tetra- and pentapyrranes with reasonable yields. All three compounds are important precursors
to advanced porphyrins and porphyrin analogs. The advantages of this method are short reaction times, clean reaction mixtures and
work in the non-toxic and environment friendly solvent—water.
Ó 2007 Elsevier Ltd. All rights reserved.
The most straightforward synthesis of symmetrically-
substituted porphyrinoids, such as triarylcorroles,
tetrarylporphyrins and expanded porphyrins, relies on
cyclocondensation of pyrrole and aldehydes. However,
there is also large demand for derivatives where non-
identical substituents occupy the methine bridges
between the pyrrole rings (called meso-carbon atoms),
as well as for porphyrinoids that are not meso-substi-
tuted. Efficient methods for the preparation of methyl-
ene-bridged oligopyrroles (called dipyrromethanes for
the simplest molecule, but tripyrrane, tetrapyrrane, etc.
for the other cases) are hence desirable, as these com-
pounds can be applied as precursors for the synthesis
We here report the microwave-assisted condensation of
aqueous formaldehyde with pyrrole as a very convenient
approach for the synthesis of non-substituted tri-, tetra-
1
2
and penta-pyrranes (Scheme 1). An open to air mix-
ture consisting of 5 mL of 1.4 M formalin (1) (6.2 mmol)
and 1.7 mL of (24.6 mmol) pyrrole (2) was heated in a
1
3
microwave oven (240 W power) for 40 s. The brownish
oil obtained from extraction of the reaction mixture by
dichloromethane was purified by column chromato-
graphy on silica gel (n-hexane/ethyl acetate = 17/3).
Single column chromatography was sufficient for
separating the desired components of the reaction in
reasonable yields: tripyrrane (3)—11%, tetrapyrrane
(4)—17% and pentapyrrane (5)—19%. The compounds
were found to be sensitive to light and air, but were
stable for extended periods when stored in a freezer
under an inert atmosphere.
1
–4
of many new derivatives.
Previous reports have
mainly focused on one-flask methods for the synthesis
5
–8
of meso-substituted oligopyrranes.
The procedures
usually involve acid-catalyzed condensation of an alde-
hyde with pyrrole, where the polymerization process
is suppressed by using a very large excess of pyrrole.
Unsubstituted dipyrromethane and tripyrrane (3) were
also reported and applied, but not any of the larger oligo-
Tetrapyrrane 4 is a potential precursor to the parent
(and still unknown) macrocyclic and aromatic corrole
6 (Scheme 2). Large efforts devoted to preparing 6 from
4 were not met with any real success: small amounts of
porphine (the parent porphyrin) and biliverdin-like
compounds were obtained instead. On the other hand,
oxidation of pentapyrrane 5 using p-chloranil resulted
in the formation of the meso-pyrrole-substituted por-
phine 7 (Scheme 3) as a single product in a respectable
47% yield. Compound 7 was recently obtained (and fully
characterized) in 7% yield from the condensation of 3
9
,10
mers.
One interesting outcome is that water was
found to be the best solvent for the preparation of
tripyrrane 3, as well as of its synthetic precursor 2,5-
bis(hydroxymethyl)pyrrole. Since water is also an ideal
solvent for microwave-assisted synthesis,11 we decided
to examine the utility of microwave irradiation with
regard to affecting the reaction between aqueous
formaldehyde and pyrrole.
1
4
with 2-formyl-pyrrole.
*
Corresponding author. Tel.: +972 4 829 3954; fax: +972 4 829
703; e-mail: chr10zg@tx.technion.ac.il
Microwave-assisted condensation of formalin and
pyrrole in aqueous solution is a very convenient
5
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.082

248
I. Saltsman, Z. Gross / Tetrahedron Letters 49 (2008) 247–249
Microwave irradiation
+
CH O (37% sol. in H O)
+
NH
HN
2
2
H O, 40 sec, 240 W
2
NH
NH
1
.4 M solution in water
1
2
3
, 11%
NH
NH HN
NH HN
+
NH
NH
HN
HN
4
, 17%
5, 19%
Scheme 1.
NH HN
NH HN
[
O]
[O]
NH HN
NH HN
N
N
4
NH
HN
[O]
6
NH HN
porphine, 3%
NH HN
O O
biliverdin-type structure
Scheme 2.
Gerardo Byk (Bar-Ilan University) for his assistance in
the experiment with the microwave synthesizer.
NH
[
O]
N
NH
NH
NH
HN
HN
NH
HN
N
References and notes
1
. Expanded, Contracted and Isomeric Porphyrins; Sessler, J.
L., Weghorn, S. J., Eds.; Pergamon: Oxford, 1997,
Chapter 2.
5
7, 47%
2
3
. Miyake, K.; Lash, T. D. Chem. Commun. 2004, 178–179.
. (a) Sessler, J. L.; Gebauer, A.; Kr a´ l, V.; Lynch, V. Inorg.
Chem. 1996, 35, 6636–6637; (b) Shevchuk, S. V.; Davis, J.
M.; Sessler, J. L. Tetrahedron Lett. 2001, 42, 2447–2450.
. Shimizu, S.; Taniguchi, R.; Osuka, A. Angew. Chem., Int.
Ed. 2005, 44, 2225–2229.
Scheme 3.
approach to the synthesis of oligopyrranes. The tetra-
pyrrane and pentapyrrane could not be oxidized to the
expected macrocyclic compounds, corrole and sapp-
hyrin, respectively, but rather to porphine and pyrrole-
substituted porphine. This apparently reflects the much
larger stability of (metal-free) porphyrins relative to
both the contracted and expanded analogs.
4
5
. (a) Ka, J.-W.; Cho, W.-S.; Lee, C.-H. Tetrahedron Lett.
2
000, 41, 8121–8125; (b) Ka, J.-W.; Lee, C.-H. Tetra-
hedron Lett. 2000, 41, 4609–4613.
6. Bri n˜ as, R. P.; Br u¨ ckner, C. Synlett 2001, 442–444.
7. Littler, B. J.; Miller, M. A.; Hung, C. H.; Wagner, R. W.;
O’Shea, D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem.
1
999, 64, 1391–1396.
. (a) Koszarna, B.; Gryko, D. T. J. Org. Chem. 2006, 71,
707–3717; (b) Koszarna, B.; Voloshchuk, R.; Gryko, D.
8
9
Acknowledgements
3
T. Synthesis 2007, 9, 1339–1342.
This research was supported by the Israel Science Foun-
dation, Grant No. 330/04 (Z.G.). The funding of I.S. by
the Center for Absorption in Science, Ministry of
Immigration, is also acknowledged. We thank Professor
. (a) Taniguchi, S.; Hasegawa, H.; Nishimura, M.; Taka-
hashi, M. Synlett 1999, 73–74; (b) Taniguchi, S.; Hasegawa,
H.; Yanagiya, S.; Tabeta, Y.; Nakano, Y.; Takahashi, M.
Tetrahedron 2001, 57, 2103–2108.

I. Saltsman, Z. Gross / Tetrahedron Letters 49 (2008) 247–249
249
1
0. Sobral, A. J. F. N.; Rebanda, N. G. C. L.; da Silva, M.;
Lampreia, S. H.; Silva, M. R.; Beja, A. M.; Paixao, J. A.;
Rocha Gonsalves, A. M. d’A. Tetrahedron Lett. 2003, 44,
b-pyrrole-H), 5.84 (m, 4H, b-pyrrole-H), 3.77 (s, 4H,
meso-H), 3.63 (m, 2H, meso-H); MS (MALDI-TOF): m/z
(%): 303.26 [M , 100%]. Compound 5: The pentapyrrane
À
3
971–3973.
1. Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563–
591.
was obtained as a yellowish oil (0.45 g, 19%). R
f
(silica,
n-hexane:ethyl acetate, 2:1) = 0.51; 300 MHz H NMR
(CDCl ): d = 7.68 (br s, 2H, NH), 7.48 (br s, 1H, NH),
1
1
1
2
3
2. For microwave-assisted syntheses of metallophthalo-
cyanines, see: Bahadoran, F.; Dialameh, S. J. Porphyrins
Phthalocyanines 2005, 9, 163–169.
3. A domestic microwave oven, model R-240F of the Sharp
company, was used for these experiments. The physical
data for the reaction products are as follows. Compound
7.43 (br s, 2H, NH), 6.55 (m, 2H, a-pyrrole-H), 6.08 (dd,
3
3
J (H, H) = 2.7 Hz, J (H, H) = 3.3 Hz, 2H, b-pyrrole-H),
3
5.92 (m, 2H, b-pyrrole-H), 5.83 (t, J (H, H) = 3.0 Hz,
3
1
2H, b-pyrrole-H), 5.80 (d, J (H, H) = 2.7 Hz, 2H,
3
b-pyrrole-H), 5.78 (d, J (H, H) = 2.7 Hz, 2H, b-pyr-
role-H), 3.74 (s, 4H, meso-H), 3.59 (s, 4H, meso-H); MS
À
3
: The tripyrrane was obtained as a colourless solid
(MALDI-TOF): m/z (%): 382.19 [M , 100%]. Com-
(
0.15 g, 11%). All physicochemical properties coincided
pounds 3, 4 and 5 were obtained in 9, 11 and 10% yields,
9
with literature data.
:1) = 0.55. Compound 4: The tetrapyrrane was obtained
as an amorphous solid (0.32 g, 17%). R (silica, n-
R
f
(silica, n-hexane:ethyl acetate,
respectively, when a Biotage microwave synthesizer (Bio-
TM
2
tage Initiator ) was used under the same conditions
f
(40 s and 240 W) used for the domestic microwave oven.
The temperature reached 60 °C and no significant
pressure developed.
1
hexane:ethyl acetate, 2:1) = 0.53; 300 MHz H NMR
CDCl ): d = 7.74 (br s, 2H, NH), 7.49 (br s, 2H, NH),
.55 (m, 2H, a-pyrrole-H), 6.10 (dd, J (H, H) = 3.0 Hz,
(
3
3
6
14. Saltsman, I.; Goldberg, I.; Balazs, Y.; Gross, Z. Tetra-
hedron Lett. 2007, 48, 239–244.
3
J (H, H) = 2.7 Hz, 2H, b-pyrrole-H), 5.94 (m, 2H,