Rational synthesis of tripyrranes

Article abstract of DOI:10.1021/jo900602z

(Chemical Equation Presented) The rational, chromatography-free synthesis of two regioisomeric 5,10-diaryltripyrranes from pyrrole and aromatic acids has been developed. The strategy is general and should be applicable to a broad range of acids. This meth

Full text of DOI:10.1021/jo900602z

pubs.acs.org/joc
meso-aryl substituents consists of an acid-catalyzed condensa-
Rational Synthesis of Tripyrranes
tion of aldehydes with pyrrole described by Dolphin4 and
Lee.10 Although one step, this procedure is associated with
many problems such as undesired formation of various oligo-
condensates and the necessity for long chromatographical
separation.4,10 This prompted us to develop an alternative
stepwise procedure but with easier overall purification.
ꢀ
ꢀ
Michaz Gaze˛zowski, Jaroszaw Jazwinski, Jan P. Lewtak, and
Daniel T. Gryko*
Institute of Organic Chemistry of the Polish Academy of
Sciences, Warsaw, Poland
The idea was to construct the tripyrrolic system via the
reaction of N-protected pyrrole-derived alcohols with pyrrole.
The sulfonyl group was chosen as a protecting group for the
following reasons: (1) stability under acidic conditions; (2) easy
removal under basic conditions; and (3) electron-withdrawing
effect that deactivates the pyrrole ring against electrophilic
aromatic substitution. Readily available N-mesylpyrrole (1)11
was chosen as a building block, which was acylated with mixed
anhydride,12 formed in situ from 4-methylbenzoic acid and
trifluoroacetic acid anhydride (TFAA), to afford ketone 2
(Scheme 1). Subsequent reduction with sodium borohydride
gave alcohol 3, which after condensation with pyrrole under
acidic conditions afforded bis-protected tripyrrane 4 in 94%
yield. The use of a standard concentration of KOH solution
(1.5%)13 as the deprotecting agent led only to the recovery of
the starting material. Thus 20% KOH/MeOH was applied
resulting in the formation of >50 colorful products and a
substantial amount of very polar black tar (Scheme 2).
Small amounts of products were formed and due to the
significant similarity of their chromatographical properties
only two of them were successfully isolated in the pure state
and analyzed. In addition one product that was not present in
the crude reaction mixture (it formed on silica gel) was isolated.
The strong absorption of visible light by these compounds
suggested that they formed by oxidation during or after
deprotection of tripyrrane 4. Unsubstituted tripyrrane 5 was
detected only in small amounts under these conditions. In light
of this observation, the deprotection reaction was carried out
under argon, affording tripyrrane 5in 99% yield as a mixture of
diastereomers (Scheme 2). The new method consists of five
steps giving tripyrrane 5 with an overall yield of 34% (only one
silica pad filtration was needed). The same synthesis was carried
out starting from N-tosylpyrrole, which resulted in tripyrrane 5
in even higher overall yield (77%) (see the Supporting Informa-
tion). Subsequently, the structures of the three dyes formed
during deprotection under air were studied. On the basis
of standard analyses, the red one was identified as tripyrrin-
1-one 7. Analogous compounds substituted at β positions
were studied by Falk and von Dobeneck and prepared
from pyrrole-2-carboxyaldehydes and dipyrrin-1(10H)-ones.14
daniel@icho.edu.pl
Received March 20, 2009
The rational, chromatography-free synthesis of two regioi-
someric 5,10-diaryltripyrranes from pyrrole and aromatic
acids has been developed. The strategy is general and
should be applicable to a broad range of acids. This
methodology was successfully applied to the synthesis of
monoprotected dipyrrane. The oxidation of N,N0-bis-me-
syltripyrrane under basic conditions led to the formation of
both known tripyrrin-1-one and unknown 1-methoxytri-
pyrrin;a fluorescent dye strongly absorbing green light.
Tripyrranes are popular building blocks in the construction
of various porphyrinoids. They were used in the synthesis of
porphyrins,1 hexaphyrins,2 sapphyrins,3,4 rubyrins,5 penta-
phyrins,6 N-fused [24]pentaphyrins,7 and texaphyrins.8 Re-
cently, we employed them in the synthesis of chlorins.9 The
most obvious method for the synthesis of tripyrranes bearing
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5610 J. Org. Chem. 2009, 74, 5610–5613
Published on Web 06/08/2009
DOI: 10.1021/jo900602z
r
2009 American Chemical Society

Gaze˛zowski et al.
JOCNote
SCHEME 1
SCHEME 2
Sessler and co-workers revealed that subjecting β-substituted
tripyrranes to Cu(OAc)2 resulted in the formation of tripyrrin-
1,5-dione copper complex.15 Recently Osuka and Furuta have
reported the formation of 14-benzoyltripyrrin-1-one as copper
complexes via oxidation of N-confused porphyrins.16 Further-
more, in 2003 Anderson found that the tripyrrin-1-one forms
during the oxidation step, which follows the condensation
reaction of TIPS-propynal with 3,4-diethylpyrrole.17
The second isolated product was not present in the original
reaction mixture; however, it was observed as a strong yellow
unpolar band during chromatography. This compound was
isolated in 13% yield. NMR data clearly confirmed its
structure as methoxydipyrrin 8 (Scheme 2). This compound
is probably formed from some unidentifiable precursor
during silica-catalyzed scrambling. The lack of stability of
dipyrranes on silica is well documented.18
At this point the structure of the third product remained
unclear. Taking the synthetic route employed into account,
together with using standard analytical methods two possi-
bilities (6 and 60) for the structure were identified (Figure 1).
Formation of compound 60 can be considered because,
although Friedel-Crafts reaction of pyrrole with aldehydes
mainly occurs at position 2, compounds substituted at posi-
tion 3 are also formed as minor products.19
Structure identification and signal assignments were
1
achieved by the use of H and 13C 1D NMR, 1D NOE
experiments, and 2D NMR techniques: COSY, LR-COSY
(long-range COSY, the measurement of which was opti-
mized for small coupling constants), 13C,1H-gHSQC, and
13C,1H-gHMBC. Initially, three pairs of 1H signals (two
doublets and two broad peaks) within the range of 6 to
7 ppm were identified by the use of the COSY spectrum. The
LR-COSY spectrum revealed the week coupling of the signal
1
ꢀ
(15) Sessler, J. L.; Gebauer, A.; Kral, V.; Lynch, V. Inorg. Chem. 1996,
35, 6636–6637.
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(17) Krivokapic, A.; Cowley, A. R.; Anderson, H. L. J. Org. Chem. 2003,
68, 1089–1096.
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(19) 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. 1999, 64, 1391–1396.
at 7.87 ppm with the signal at 6.47 ppm. The H NMR
spectrum with resolution enhancement (by Lorentzian-to-
Gauss transformation) allowed the detection of small split-
tings of the signals at 6.75 and 6.46 ppm (1.0 and 0.4 Hz,
respectively). These signals together with a signal at 7.87 ppm
were identified as being part of the same AMX spin system.
J. Org. Chem. Vol. 74, No. 15, 2009 5611

Gaze˛zowski et al.
JOCNote
FIGURE 1. 1H and 13C NMR chemical shifts of 6 (CDCl3 solution)
as well as an alternative structure 60 (atoms marked by asterisks in
the figure;see the explanation in the text).
FIGURE 2. Absorption of 6 (dotted line), 7 (solid line), and 8
(dashed line) as well as emission of 6 (bold line) in THF.
This was confirmed by the 13C,1H-gHMBC technique. By
carrying out NOE experiments, the signals of two Ar rings
(D and E) as well as the pyrrolic signals at 6.06, 6.20, 6.69,
and 6.75 ppm were identified. Hence, the presence of the
AMX and two AX systems in the spectrum together with
NOE findings argued the presence of A, B, and C rings in the
structure (Figure 1).
The signals of ring B bearing the methoxy group were
identified initially by 13C,1H-gHMBC experiment taking
into account the correlation between the methyl group and
the signal at 176.7 ppm. Then, the remaining assignments
were easily made by using 13C,1H-gHSQC and COSY data.
The positions of the methoxy group and both CH atoms in
ring B were established by a NOE experiment, in which a
NOE interaction between the signals 6.69 and 7.22 ppm (Ar),
and CH3 and 7.87 ppm, respectively, was observed. An
alternative structure of ring B (60) was excluded on the basis
of 13C chemical shifts of the quaternary and CH carbon
atoms (marked by asterisks in Figure 1). The first value
(147.8 ppm) suggests the vicinity of the N atom, whereas the
latter (119.4 ppm) indicates a larger distance from the
nitrogen.
of the chelated compound. Otherwise tripyrrins can only be
obtained as metal complexes. Our 1-methoxytripyrrin is the
first example of a nonsterically hindered tripyrrin stable as a
free base.
Both methoxytripyrrin 6 and tripyrrin-1-one 7 are red-
violet in solution. The most notable feature of their UV-vis
spectra is strong absorption of green light (Figure 2,
λmax (6)=545 nm, λmax (7)=534 nm). The visible band of
methoxytripyrrin 6 is both bathochromically and hyperchro-
mically shifted when compared to that of tripyrrin-1-one 7.
Weak absorption of lower energy light reported by Osuka for
14-benzoyltipyrrin-ones16 is absent in the spectrum of 7. In
contrast to compound 7, dye 6 is weakly fluorescent in
solution (λem (6)=579 nm) (Figure 2). The Stokes shift for
compound 6 is 1080 cm-1 (Figure 2).
Encouraged by the overall efficiency of the preparation of
tripyrrane 5, we decided to synthesize N-monoprotected
dipyrrane and regioisomeric tripyrrane in which one term-
inal pyrrole ring is linked at position 3 by the same metho-
dology. These types of tipyrranes (the potential building
block in the synthesis of porphyrinoids) was unknown until
now. N-Phenylsulfonylpyrrole 922 was acylated in position 3
(Scheme 3) to give ketone 10.23 Subsequent reduction gave
the corresponding alcohol, which was reacted with N-tosyl-
dipyrrane 11 (prepared via reaction of alcohol S3 with an
excess of pyrrole under acidic conditions, see the Supporting
Information) to give doubly protected “N-confused tripyr-
rane” 12 in 60% yield. Finally deprotection under basic
conditions gave tripyrrane 13 in 83% yield (Scheme 3).
In summary, we have developed a new rational procedure
toward tripyrranes via a five-step sequence of reactions from
N-mesylpyrrole or N-tosylpyrrole and carboxylic acids. Our
studies have clearly documented that [N-(mesyl)pyrrol-2-yl]-
(4-aryl)methanols are stable under acidic reaction conditions
and can selectively react with unsubstituted pyrrole. The
extraordinary ease with which all intermediates can be
prepared makes this protocol ideal for the generation
of a range of 5,10-diaryldipyrranes. This procedure offers
several advantages where the classical method cannot
be used or gives rise to an inseparable mixture of oligocon-
densates. The same strategy was used in the synthesis of
“confused tripyrrane”. Our results underline the instability
Since all 1H signals were identified either by COSY or LR-
COSY techniques, the assignment of the 13C signals by using
13C,1H-gHSQC and gHMBC data was straightforward.
Only the assignment of two quaternary carbon atoms of
the C ring, at 137.1 and 141.4 ppm, was ambiguous.
15N,1H-gHSQC measurement revealed one 15N signal at -
90.2 ppm (assuming CH3NO2=0 ppm), assigned to the A
ring. Such a chemical shift value suggests a pyridine-type
nitrogen atom. The signals of the remaining nitrogen atoms
were not detected, probably due to signal broadening.
All attempts to improve the yields of compounds 6 and 7
by using various oxidants like DDQ, p-chloranil, [bis(tri-
fluoroacetoxy)iodo]benzene (PIFA), CAN, and O2/Pd/C
failed. In all cases dyes 6 and 7 were formed in lower yields
or were not formed at all. Tripyrrins bearing substituents at
β-positions were intensively investigated by Broring.20,21 He
€
proved that the presence of tert-butyl groups at flanked
positions allows the stability of the free bases to match that
€
(20) (a) Broring, M.; Brandt, C. D. Chem. Commun. 2001, 499–500.
(b) Broring, M.; Brandt, C. D. J. Chem. Soc., Dalton Trans. 2002, 1391–
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1395. (c) Broring, M.; Prikhodovski, S.; Brandt, C. D.; Tejero, E. C.; Kohler,
S.; Pietzonka, C. Inorg. Chem. 2007, 46, 917–925. (d) Broring, M.;
€
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Prikhodovski, S.; Kohler, S. Acta Crystallogr. C 2007, 63, 68–70. (e) Broring,
M.; Prikhodovski, S.; Brandt, C. D.; Tejero, E. C. Chem.;Eur. J. 2007, 13,
396–406.
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1348.
5612 J. Org. Chem. Vol. 74, No. 15, 2009

Gaze˛zowski et al.
JOCNote
SCHEME 3
2H, J1=2.6 Hz, J2=10.2 Hz), 5.82 (d, 2H, J=8.6 Hz), 5.91 (d,
2H, J=3.3 Hz), 6.16-6.18 (m, 2H), 7.10 (s, br, 8H), 7.28 (d, br,
1H, J=8.7 Hz); 13C NMR (125 MHz, CDCl3, ppm) δ 21.0, 41.7,
41.9, 108.2, 110.4, 114.2, 122.5, 128.7, 129.2, 131.5,136.9, 137.1,
137.7; HRMS (EI) calcd for C30H31N3O4S2 [M+] 561.1756,
found 561.1740.
5,10-Bis(4-methylphenyl)tripyrrane (5). Method A: KOH
(179 mmol, 10 g) was added to a solution of tripyrrane 4 (8.0
mmol, 4.5 g) in dry methanol (50 mL) under argon. The reaction
mixture was stirred overnight and washed with water. The orga-
nic layer was dried (Na2SO4) and evaporated affording the pure
product as a foamy orange solid (3.21 g, 99%). Method B:
KOH (179 mmol, 10 g) was added to a solution of tripyrrane S4
(6.4 mmol, 4.6 g) in dry methanol (50 mL) under argon. The
reaction mixture was stirred for 20 h and water was added. After
extraction with CH2Cl2 the organic layer was dried (Na2SO4)
and evaporated affording the pure product as a foamy orange
solid (2.55 g, 99%). IR (KBr, νmax/cm-1) 510, 718, 760, 1027,
1090, 1424, 1511, 1560, 1700 (br), 2920, 3411; HRMS (EI) calcd
for C28H27N3 [M+] 405.2205, found 405.2219. Anal. Calcd for
C28H27N3: C, 82.93; H, 6.71; N, 10.36. Found: C, 82.69; H, 6.49;
N, 10.26. Other analytical data are consistent with literature
values.24
Tripyrrane 13. Tripyrrane 12 (2.71 mmol, 1.9 g) was dissolved
in dry methanol (100 mL), then KOH (0.36 mol, 20 g) was added
and the solution was stirred for 72 h under argon atmosphere.
Subsequently, the reaction mixture was evaporated, dissolved in
CH2Cl2, and washed with water. The organic layer was dried
and evaporated affording pure product as a pale pink solid (906
mg, 83%): IR (KBr, νmax/cm) 511, 717, 756, 1027, 1058, 1423,
1511, 2919, 3410 (br); 1H NMR (200 MHz, CDCl3, Me4Si, ppm)
δ 2.31 (s, 3H), 2.32 (s, 3H), 5.22 (s, 1H), 5.31 (s, 1H), 5.71(s, 1H),
5.72 (s, 1H), 5.83-5.86 (m, 1H), 6.04 (dd, 1H, J1= 2.4 Hz, J2=
4.2 Hz), 6.11 (m, 1H), 6.39-6.40 (m, 1H), 6.64 (dd, 1H, J1=2.6
Hz, J2=4.2 Hz), 6.68 (dd, 1H, J1=2.6 Hz, J2=4.8 Hz), 7.03-
7.13 (m, 8H), 7.69 (s, br, 1H), 7.89 (s, br, 1H), 7.97 (s, br, 1H);
13C NMR (50 MHz, CDCl3, ppm) δ 21.4, 43.3, 44.0, 106.9,
107.2, 107.4, 108.6, 109.0, 116.6, 117.2, 118.4, 126.4, 128.6 (2),
129.2 (2), 129.5, 131.8, 133.4, 135.2, 136.0, 136.6, 139.6, 141.7;
HRMS (EI) m/z calcd for C28H27N3 (M)+ 405.2205. Found:
405.2223. Anal. Calcd for C28H27N3: C, 82.93; H, 6.71; N,
10.36. Found: C, 82.63; H, 6.57; N, 10.16.
of tripyrranes toward even mild oxidants. Oxidation of meso-
substituted tripyrranes leads to their two oxidation pro-
ducts;tripyrrin-1-ones and 1-methoxytripyrrins. 1-Meth-
oxytripyrrins strongly absorb green light and they display
fluorescence.
Acknowledgment. We thank the Ministry of Science and
Higher Education (Project 3 T09A 12429) and the Volkswa-
gen Foundation for financial support and Patricia Fleming
and Dorota Gryko for amending the manuscript.
Experimental Section
1,17-Bis-N,N-methylosulfonylo-5,10-bis(4-methylphenyl)tri-
pyrrane (4). To a solution of 3 (20 mmol, 5.25 g) and pyrrole (9.5
mmol, 660 μL) in CH2Cl2 (100 mL) was added TFA (1.5 mmol,
115 μL). The reaction mixture was stirred at room temperature
for 72 h and washed with water. The organic layer was dried
(Na2SO4) and the solvent was evaporated in vacuo. The residue
was filtered through a silica pad affording the pure product as a
yellow-orange solid (5.0 g, 94%): 1H NMR (500 MHz, CDCl3,
Me4Si, ppm) δ 2.28 (s, 6H), 2.32 (s, 3H), 2.41 (s, 3H), 5.69 (dd,
Supporting Information Available: Full description of ex-
perimental procedures and analyses of compounds 2, 3, 6-12,
and S2-S4 and 1H NMR and 13C NMR spectra for compounds
2-13 and S2-S4. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Heo, P.-Y.; Shin, K.; Lee, C.-H. Tetrahedron Lett. 1996, 37,
197–200.
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