Novel crowned-porphyrin ligands. Synthesis and conformational studies

Article abstract of DOI:10.1016/j.tet.2006.01.029

Three new macromolecules - a cryptand, a bis-macrocycle, and a tris-macrocycle - have been synthesized as chelating ligands for cation binding. They result from the surprisingly simple reaction of various bis-functionalized meso-aryl porphyrins with a dia

Full text of DOI:10.1016/j.tet.2006.01.029

Tetrahedron 62 (2006) 3056–3064
Novel crowned-porphyrin ligands. Synthesis
and conformational studies
b
b
Zakaria Halime,a,c Mohammed Lachkar,c, Niki Matsouki, Georgios Charalambidis,
*
Massimo di Vaira,d Athanassios G. Coutsolelosb, and Bernard Boitrel
a,
*
*
a
´ ´
Institut de Chimie, Universite de Rennes1, UMR CNRS 6509, Organometalliques et Catalyse,
´
Chimie et Electrochimie Moleculaire, 35042 Rennes Cedex, France
bLaboratory of BioInorganic Chemistry, Chemistry Department, University of Crete, PO Box 1470, 714 09 Heraklion, Crete, Greece
c
´ ´ ´ ´ ´
Laboratoire d’Ingenierie des Materiaux Organometalliques et Moleculaires (LIMOM), Faculte des Sciences Dhar El Mehraz,
´
`
Universite Sidi Mohammed Ben Abdellah, B.P. 1796 (Atlas), 30000 Fes, Morocco
dChemistry Department, University of Florence, 50019 Sesto Fiorentino, Firenze, Italy
Received 14 December 2005; revised 6 January 2006; accepted 10 January 2006
Abstract—Three new macromolecules—a cryptand, a bis-macrocycle, and a tris-macrocycle—have been synthesized as chelating ligands
for cation binding. They result from the surprisingly simple reaction of various bis-functionalized meso-aryl porphyrins with a diaza-crown
ether coupled one to each other through either one or several urea linkage(s). Indeed, the latter induces some additional rigidity in comparison
with the usual amide linkage found in such macromolecules. Various strategies are reported to optimize the yield of the reaction towards the
formation of a cofacial singly-linked crown-porphyrin, which is the most promising ligand to stabilize large cations such as bismuth(III) as
the angle between the two macrocycles can vary.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
explained this non coordination of gadolinium presumably
because of a para-pyridyl residue on two meso positions of
the porphyrin, which can directly interact with the
lanthanide cation, a competitive interaction to the metall-
ation process. In the second example, the bis-crowned
porphyrin was not flexible enough to be distorted and hence
to allow the entry of the bismuth cation inside the cavity.
However, as these three elements exhibit different radii,9
our goal was to design a rigid but still flexible family of
molecules, which could adapt its size to the desired cation.10
This is the reason why we have investigated the synthesis of
singly-linked crown porphyrins.
In our on-going research program dedicated to the
coordination of various cations of medical interests, we
have been studying for almost a decade different types of
macromolecular architectures.1 Among these cations, one
can cite gadolinium, yttrium, bismuth, or europium. The
first one is obviously known to be efficient in the design of
new imaging agents2 where the last one is commonly
employed for the preparation of luminescent molecules.3
The second and third elements are either already clinically
used in b-radiotherapy4 or evaluated for a-radiotherapy,5
respectively. An example of these chelating molecules is the
cofacial cyclam-strapped porphyrins, which have proved to
be efficient for the coordination of two transition metals as
iron and cobalt.6 However, such edifices are likely too rigid
to be efficient chelators of larger cations such as gadolinium,
europium or bismuth. Indeed, neither the former nor the
latter are stabilized in single-crowned7 or bis-crowned
porphyrins,8 respectively. In the first case, we have
2. Results and discussion
The reaction of 1,4,10,13-tetraoxa-7,16-diaza-cyclooctade-
cane (Kryptofix-2,2 or diaza-18-crown-6 ether) on a 5,15-o-
diamido picket porphyrin or on a 5,15-o-diaminophenyl
porphyrin usually leads to the formation of a macromolecule
in which the two different macrocycles appear to be in a
cofacial geometry as in macrotricycle 1.11 Indeed, in the
latter, the diaza-crown ether being bis-linked on the
porphyrin, cannot escape from its apical position, as it can
in compound 2. However, when the bonds between the two
Keywords: Porphyrin; Crown-ether; Cofacial; Chelation; Cation binding.
*
Corresponding authors. Tel.: C 212 71 55 674 (M.L.); Tel.: C30 2810
393601; fax: C30 2810 393636 (A.G.C.); tel.: C33 2 2323 5856; fax:
C33 2 2323 5637 (B.B.); e-mail addresses: mlachkar@caramail.com;
coutsole@chemistry.uoc.gr; bernard.boitrel@univ-rennes1.fr
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.029

Z. Halime et al. / Tetrahedron 62 (2006) 3056–3064
3057
macrocyles are very short as in the case of a urea bond,12 we
noticed that the system was not sufficiently flexible to
coordinate metal cations bulkier than zinc for instance. To
obtain flexible systems, we required the crown-ether motif
to be able—more or less—to move away from the porphyrin
according to the cation to stabilize, hence the target
molecule 2. Such a compound should exist as two different
isomers (endo and exo) but owing to the urea bond, the
cofacial geometry is expected to be favored. Moreover, if
one considers that the crown-ether is attached by the meso
positions 5 and 15, it is obvious that the steric hindrance
induced by the two other meso positions, namely 10 and 20
can influence the approach of the cage by the cation and also
the position of the strapped crown-ether. Accordingly, we
studied various aromatic groups (Scheme 1) such as 2,4,6-
trimethylphenyl (mesityl, compounds labeled a) or 3,5-
dimethoxyphenyl (compounds labeled b). Indeed, in the
case of the dimesityl porphyrin, the two ortho positions of
the aromatic rings in the positions 10 and 20 being
substituted by a methyl group, the crown ether is expected
to be less mobile than in the other series with methoxy
groups in meta positions. This detail will be discussed vide
infra. Actually, by choosing the experimental conditions, we
could optimize the reaction towards the preparation of 1 or
2, concomitantly with the synthesis of the tris-macrocycle 3
and the macrotetracycle 4. Obviously, to avoid unambi-
guously the synthesis of the macrotricyclic crown-porphyrin
1, the unique procedure would consist in protecting one
amino function of both the porphyrin and the crown-ether.
But in regard with the facility of the synthetic path of
Scheme 1, we preferred to vary the experimental procedure
(method B vs method A, see Section 4.2) to obtain
compound 2. Additionally, in the mesityl series a, we
have also investigated an alternative procedure that consists
in working with a singly reduced porphyrin such as 5aNO2.
In literature, this type of selectivity has already been
achieved either by reducing13 only one nitro group of a 2,6-
dinitro-mesophenyl group or by acylating only one amino
function after reduction of the two nitro functions.14
Theoretically, in a typical synthesis, 1 should be the single
product of the reaction but is also the less attractive.
Practically, the three other compounds exhibit more
sophisticated structures. For instance, in compound 2, two
structural criterions have to be considered. The first deals
with the ‘face-to-face’ spatial arrangement of the two
macrocycles. As already mentioned, the urea bond itself
should maintain this cofacial geometry. Moreover, this is
verified by proton NMR spectroscopy, since we can carry
O
O
N
O
NH2
O
O
Et3N, Diphosgene,
NH
N
Ar
diaza-18-crown-6 ether
N
Ar
NH
X
HN
N
N
NH
HN
O
HN
1
Ar
N
Ar
5αα
O
O
NH
O
O
N
O
NH
Ar
N
NH
X
HN
N
Ar
Ar
N
NH
HN
N
2
Ar
HN
O
NH2
N
O
O
O
N
O
O
O
O
O
O
N
N
O
NH
NH
Ar
N
Ar
HN
O
NH2
NH
HN
N
N
NH
HN
Ar
N
Ar
3
4
Scheme 1. General synthesis of crowned porphyrins from an a-5,15-bis-(2-amino-phenyl)porphyrin or from an a-5-(2-amino-phenyl)-a-15-(2-nitro-
phenyl)porphyrin. Compounds are labelled as follow: series a: ArZ2,4,6-trimethyl-phenyl, series b: ArZ3,5-dimethoxy-phenyl. When XZNO2, NO2 is
added at the end of the name. Note that two methods can be used for this reaction.

3058
Z. Halime et al. / Tetrahedron 62 (2006) 3056–3064
out a reliable comparison with compound 1 for which we
know precisely the conformation. For instance, in 1b, the
fingerprint of the crown-ether is composed of 3 singlets
integrating for 8 protons each at 2.56, 1.94 and 0.49 ppm. In
the case of 2b, the NMR signature becomes 6 broad singlets
of 4 protons in the range 2.68–1.43 ppm. In the latter
compound, signals upfield shifted as in compound 1b do not
exist anymore, which testifies well to the larger distance
—at least for some protons— of the crown-ether to the cone
of anisotropy of the porphyrin. However, it is difficult to
investigate if the crown-ether motif is still above the
porphyrin or presumably slightly off-centered. In the 2,4,6-
trimethyl-phenyl series a, a similar conclusion is drawn with
signals at 2.60, 2.07 and 1.56 ppm for 1a and signals
between 2.88 and 1.97 ppm for 2aNO2.
justify a ‘curved’ conformation of the crown-ether.
Conversely, in conformation (c3), the fact that the crown-
ether is pinched between the two porphyrins could be
induced by the urea linkage itself, as in compound 2b in
which a relaxed face-to-face conformation is observed.
Hence, we propose this ‘Z-shape’ structure in solution for
compound 3b.
Finally, the fourth isolated compound is the macrotetracycle
4b. Although related somehow to the coreceptor molecules
reported by Lehn and co-workers,15 4b is different as the
two porphyrin units are not expected to be cofacial. Indeed,
in this compound, the two porphyrinic units are attached via
a urea linkage, which act as a hinge, and the angle between
the two porphyrins is actually imposed by the crown-ether,
which acts as a spacer. The chemical shifts of the protons
from the crown-ether are 3.80, 2.15, and 0.89 ppm. In light
of the structure of 4b, these chemical shifts are expected as
they are more down-field shifted than in 2b, one of them
being almost the same (0.89 ppm in 4b vs 0.49 ppm in 2b).
According to these data, it can be predicted that the angle
between the porphyrin(s) and the crown-ether is larger in 4b
than it is in 2b. But obviously, 4b should be more flexible
than 2b.
But the most intriguing observation resulting from the
comparison of the various NMR data consists in the
signature of the crown-ether obtained in the case of
the bis-porphyrin compound 3b. Indeed, one can easily
conceive various spatial arrangements in solution for this
type of compound (Fig. 1). The most probable is depicted in
representation (c1) with no specific conformation of the
crown-ether moiety and the two porphyrin units most distant
one from the other. Yet, this conformation is not consistent
at all with the chemical shifts of the protons from the crown-
ether, which resonate as broad singlets of 8 protons each at
1.82, 1.13, and K0.46 ppm. Theses chemical shifts show
that all the protons of the crown-ether in 3b are more
shielded than they are in 1b. More particularly, 8 of them are
more upfield-shifted of 1 ppm (K0.46 ppm) relatively to the
8 most shielded protons in 1b (0.49 ppm). This observation
implies that 3b has to exist in a conformation in which the
crown-ether motif undergoes the additive effect of the two
porphyrin rings. Such possible conformations are rep-
resented in (c2) and (c3) (Fig. 1). However, the confor-
mation (c2) is difficult to explain as there is no argument to
As already mentioned, to optimise the formation of
compounds 2 relatively to compounds 1, we have employed
two different approaches. The first one that we have
described consists in modifying the experimental procedure.
For instance, when method B (see Section 4) is applied
instead of method A, the yield of isolated compound 2b
rises up from 5 to 48% yield, mostly at the expense of
compounds 1b and 3b, the yield of compound 4b increasing
from 3 to 11%. Actually, these two experimental procedures
differ mainly by the fact that in method B, both reagents, the
activated porphyrin and the crown-ether are added together.
The second approach, increasing the yield of 2a consists in
Ar
N
NH
HN
N
Ar
Ar
NH
N
NH
O
HN
N
H2N
Ar
Ar
N
NH
N
N
NH
O
HN
N
H2N
O
Ar
HN
O
O
NH2
O
O
O
N
O
O
O
O
O
O
O
N
N
O
N
O
O
NH
NH
NH
Ar
Ar
Ar
N
N
N
NH2
NH2
NH2
NH
NH
NH
HN
HN
HN
N
N
N
Ar
Ar
Ar
(c1)
Figure 1. Various possible conformations (c1–c3) of tris-macrocycle 3.
(c2)
(c3)

Z. Halime et al. / Tetrahedron 62 (2006) 3056–3064
3059
Ar
6
TFA
Ar
CHO
+
NH
HN
N
H
excess
NO2
1. TFA
2. DDQ
NO2
Ar
SnCl2/HCl
N
NH
HN
+
6
CHO
N
CH2Cl2
Ar
O2N
7
2 atropisomers
NH2
NH2
Ar
Ar
N
N
NH
NH
Ar
HN
HN
+
N
N
Ar
O2N
H2N
8
8NO2
2 atropisomers
2 atropisomers
Scheme 2. Synthesis of the two porphyrinic building-blocks. For compounds labelling, use convention of Scheme 1. When ArZ2,4,6-trimethyl-phenyl, the
reduction step leading to 8 was performed at 0 8C.
inhibiting the reactivity of one of the anilines of the
porphyrin. Therefore, we have performed a partial reduction
of the nitro groups of 7a to obtain 8aNO2 (Scheme 2), and
then, after a separation of the two atropisomers, obtained the
5aNO2aa atropisomer (Scheme 1). Hence, following the
same procedure applied for the diamino counterparts, it is
obvious that the formation of either 1a or 4a becomes
impossible, thereby controlling the reaction towards the
exclusive formation of 2a and 3a. However, when the
reaction was performed with 5aNO2aa, it should be noted
that compound 3a was not obtained either, or only as
negligible traces. This observation demonstrates that
working with a mono-nitro mono-amino tetraaryl porphyrin
represents an efficient alternative for the almost exclusive
synthesis of bis-macrocycles 2.
the steric hindrance of the two ortho positions (Fig. 2b).
According to the distances of atoms from the mean
porphyrin plane, the distortion may be chiefly described in
terms of a saddled conformation, in view of the alternate
Incidentally, in compounds 2, if one considers that the
2-amino (or nitro) aryl groups are on the 5 and 15 meso
positions, the substitution of the two other meso aryl groups
may have some influence on the conformation of the
compound. For example, in the mesityl series (compounds
a), it could be probed if the two methyl groups in ortho
position generate a steric hindrance with the crown-ether or
not. Again, this is confirmed by comparing the proton NMR
data of 2a with 2b. For instance, the chemical shifts of the
protons from the crown-ether in 2a are slightly larger than
their analogues in 2b but the difference is not really
significant. Therefore, we can assume that the conformation
is not strongly affected by the nature of the two meso aryl
groups in positions 10 and 20. Additionally, it should be
pointed out that any possible distortion of the porphyrin
could influence the geometry of the various compounds.
Actually, consideration of the X-ray structure of 7aaa, that
could be determined (Fig. 2), reveals that there is indeed a
slight distortion of the porphyrin cycle, presumably due to
Figure 2. Ball and stick representation of the X-ray structure of the
atropisomer aa of 7a; (a) perspective view, (b) apical view with distances
˚
in A of each atom to the mean plane of the porphyrin.

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Z. Halime et al. / Tetrahedron 62 (2006) 3056–3064
tilting of adjacent pyrrolic units and meso carbons.
However, the distortion is not purely saddled as it also
exhibits some ruffling, since the Ca–N–N–Ca torsion angles
between two diametrically opposed pyrroles are equal to
2.41 and 8.618.
additional 1 h. The solvent was removed under vacuum and
the residue was purified by silica gel chromatography. The
compound 4b was eluted with CH2Cl2 and obtained in 3%
yield (9 mg), compound 3b was eluted with 0.2% methanol/
CH2Cl2 and obtained in 15% yield (22 mg), compound 1b
was eluted with 0.8% methanol/ CH2Cl2 and obtained in
55% yield (97 mg) and compound 2b was eluted with 2%
methanol/CH2Cl2 and obtained in 5% yield (8.4 mg).
3. Conclusion
According to two different approaches, we have shown that
with a simple and unique reaction, we can synthesize four
macromolecules, all of them incorporating at least one
porphyrin unit as well as one crown-ether moiety. Whereas
one of the two described methods allows the preponderant
formation of both the bis-macrocycle and the macrotetra-
cycle, an alternative approach is also proposed to optimize
the synthesis of the bis-macrocycle versus the macrotetra-
cycle. Among these four ligands, three of them should
exhibit very different properties towards the binding of
various cations from groups 13 and 15 or lanthanides. These
three macromolecules differ both by the shape and the size
of the cavity resulting from the assembly of several
macrocycles either by one or two link(s). Coordination
studies of these novel bis-macrocycle, tris-macrocycle, and
macrotetracycle will be reported elsewhere.
Method B. In a two neck round bottom flask equipped with a
stir bar and a gas inlet, 5baa (120 mg, 0.16 mmol) was
charged with dry THF (10 mL) and Et3N (0.1 mL). The
reaction mixture was cooled to 0 8C then diphosgene
(7.2 mL, 59 mmol) was added. After 1 h, the resulting
reaction mixture of activated porphyrin was charged in a
10 mL syringe as well as a solution of diaza-18-crown-6
ether (46 mg, 0.18 mmol) in dichloromethane (10 mL).
These two solutions were added dropwise over 2 h with a
syringe pump to a solution of THF (400 mL) and NEt3
(0.1 mL). The mixture was stirred for an additional 1 h. The
solvent was removed under vacuum and the residue was
purified by chromatography column. Compound 4b was
eluted with CH2Cl2 and obtained in 11% yield (33 mg),
compound 3b was eluted with 0.2% methanol/CH2Cl2 and
obtained in 13% yield (19 mg), compound 1b was eluted
with 0.8% methanol/CH2Cl2 and obtained in 20% yield
(35 mg), and compound 2b was eluted with 2% methanol/
CH2Cl2 and obtained in 46% yield (77 mg). As far as
concern the series of a derivatives, the yields are identical
via method A or B with those of series b.
4. Experimental
4.1. General considerations
1H (500.13, 300.13 MHz) NMR spectra were recorded on
Bruker Avance spectrometers and referenced to the residual
protonated solvent. Mass spectra were performed on a MS/
MS ZABSpec TOF spectrometer at the University of
Rennes I (C.R.M.P.O.). UV–vis spectra were recorded on
a Varian Cary 1E and an Uvikon XL spectrometers. Infrared
spectra were recorded on Bruker IFS 66 and 28 spectro-
meters. All solvents (ACS for analysis) were purchased
from Carlo Erba. THF was distilled from potassium metal
whereas methanol was distilled from magnesium turnings.
CH2Cl2 was used as received. Triethylamine was distilled
from CaH2. The starting materials were generally used as
received (Acros, Aldrich) without any further purification.
All reactions were performed under an argon atmosphere
and monitored by TLC (silica, CH2Cl2/MeOH). Column
flash chromatography was performed on silica gel (Merck
TLC-Kieselgel 60H, 15 mm). Elemental analyses were
obtained on an EA 1108 Fisons Instruments.
4.2.1. 1,4,10,13-Tetraoxa-7,16-diaza-cyclooctadecane-
7,16-dicarboxylic acid {2,20-[10,20-bis-(2,4,6-trimethyl-
phenyl)-porphyrin-a-5,15-diyl]-diphenyl}-diamide 1a.
1H NMR (500 MHz, CDCl3): dZ8.82 (d, JZ4.5 Hz, 4H,
bpyr), 8.69 (d, JZ4.5 Hz, 4H, bpyr), 8.60 (d, JZ7 Hz, 2H,
aro), 8.04 (d, JZ7.5 Hz, 2H, aro), 7.73 (t, JZ7.5 Hz, 2H,
aro), 7.52 (t, J1Z7 Hz, 2H, aro), 7.37 (s, 2H, aro), 7.24 (s,
2H, aro), 5.96 (s, 2H, NHCO), 2.65 (s, 6H, –CH3), 2.60 (s,
8H, –CH2–), 2.11 (s, 6H, –CH3), 2.07 (s, 8H, –CH2–), 1.64
(s, 6H, –CH3), 1.56 (s, 8H, –CH2–), K2.23 (s, 2H, NHpyr).
13C NMR (125 MHz, CDCl3): dZ157.0, 141.5, 140.1,
138.9, 138.3, 138.1, 133.9, 130.3, 129.7, 128.4, 128.2,
120.8, 120.0, 118.6, 114.0, 69.2, 50.3, 30.1, 22.1, 22.0, 21.8.
HRMS (ESC) Calcd for C64H66N8O6Na (MCNa)C
1065.5003. Found, 1065.5006. UV–vis (CH2Cl2) l nm
(10K33, dm3 molK1 cmK1): 420 (329.3), 516 (23.6), 550
(7.4), 591 (7.2), 647 (3.9).
4.2.2. 1,4,10,13-Tetraoxa-7,16-diaza-cyclooctadecane-
7,16-dicarboxylic acid {2,20-[10,20-bis-(3,5-dimethoxy-
phenyl)-porphyrin-a-5,15-diyl]-diphenyl}-diamide 1b.
1H NMR (500 MHz, CDCl3): dZ8.98 (d, JZ4.5 Hz, 4H,
bpyr), 8.88 (d, JZ4.5 Hz, 4H, bpyr), 8.54 (dd, J1Z7.5 Hz,
J2Z1.5 Hz, 2H, aro), 7.96 (d, JZ8 Hz, 2H, aro), 7.80 (td,
J1Z8 Hz, J2Z1 Hz, 2H, aro), 7.60 (td, J1Z7.5 Hz, J2Z
1 Hz, 2H, aro), 7.53 (s, 2H, aro), 7.15 (s, 2H, aro), 6.92 (t,
JZ2 Hz, 2H, aro), 5.80 (s, 2H, NHCO), 4.12 (s, 6H,
–OCH3), 3.92 (s, 6H, –OCH3), 2.56 (s, 8H, –CH2–), 1.94 (s,
8H, –CH2–), 0.49 (br s, 8H, –CH2–), K2.51 (s, 2H, NHpyr).
13C NMR (125 MHz, CDCl3): dZ159.1, 156.5, 155.4,
148.6, 147.5, 146.4, 142.2, 140.9, 133.5, 131.3, 129.4,
122.2, 121.7, 114.3, 113.8, 99.9, 69.3, 55.6, 49.7. HRMS
4.2. General synthetic paths
The two following procedures were performed to graft a
crown ether on the porphyrin: method A optimises the yield
of 1b and method B, the yield of 2b.
Method A. In a two neck round bottom flask equipped with a
stir bar and a gas inlet, 5baa (120 mg, 0.16 mmol) was
charged with dry THF (10 mL) and Et3N (0.1 mL). The
mixture was cooled to 0 8C then, diphosgene (9.6 mL,
79 mmol) was added. After 1 h, diaza-18-crown-6 ether
(46 mg, 0.18 mmol) in 10 mL of dry CH2Cl2 was added
dropwise over 30 min and the mixture was stirred for an

Z. Halime et al. / Tetrahedron 62 (2006) 3056–3064
3061
(ESC) Calcd for C62H62N8O10Na (MCNa)C 1101.4486.
Found, 1101.4495. UV–vis (CH2Cl2) l nm (10K33,
dm3 molK1 cmK1): 418 (301.3), 516 (17.1), 551 (5.5), 589
(5.4), 646 (2.6).
8.51 (d, JZ4.5 Hz, 4H, bpyr), 8.34 (d, JZ8 Hz, 2H, aro),
7.86 (d, JZ7.5 Hz, 2H, aro), 7.77 (d, JZ7.5 Hz, 2H, aro),
7.63 (t, JZ8 Hz, 2H, aro), 7.57 (t, JZ7.5 Hz, 2H, aro), 7.27
(m, 2H, aro), 7.24 (s, 4H, aro), 7.19 (s, 4H, aro), 7.14–7.08
(m, 4H, aro), 6.88 (s, 2H, NHCO), 3.60 (br s, 4H, NH2), 2.62
(s, 12H, –CH3), 1.76 (s, 12H, –CH3), 1.58 (s, 8H, –CH2–),
1.38 (m, 8H, –CH2–), 1.29 (s, 12H, –CH3), K1.02 (br s, 8H,
–CH2–), K2.80 (s, 4H, NHpyr). 13C NMR (125 MHz,
CDCl3): dZ158.1, 153.5, 145.3, 139.0, 138.7, 138.2, 136.9,
136.6, 135.2, 130.5, 129.7, 128.4, 124.1, 120.8, 119.7,
119.3, 116.2, 114.0, 71.5, 69.8, 68.8, 50.7, 46.8, 22.5, 22.1,
21.7. HRMS (ESC) Calcd for C114H111N14O6 (MCH)C
1771.8811. Found, 1771.8813. UV–vis (CH2Cl2) l nm
(10K33, dm3 molK1 cmK1): 418 (512.3), 515 (40.3), 547
(19.8), 592 (19.1), 647 (12.5).
4.2.3. 1,4,10,13-Tetraoxa-7,16-diaza-cyclooctadecane-7-
carboxylic acid {2-[a-15-(2-nitro-phenyl)-10,20-bis-
(2,4,6-trimethyl-phenyl)-porphyrin-a-5-yl]-phenyl}-
amide 2aNO2. A mixture of porphyrin 5aNO2aa (31 mg,
41 mmol), triethylamine (11 mL, 82mmol) and carbonic acid
ditrichloromethyl ester (triphosgene) (4 mg, 13.6 mmol) in
dry CH2Cl2 (20 mL) was stirred for 1 h under argon at room
temperature. This mixture was added dropwise, over 2 h
with a syringe pump to a solution of diaza-18-crown-6 ether
(11 mg, 41 mmol) in dry CH2Cl2 (10 mL). The mixture was
stirred for an additional 1 h. The solvent was removed under
vacuum and the residue was purified by chromatography
column. The desired compound 2aNO2 was eluted with 1%
4.2.6. 1,4,10,13-Tetraoxa-7,16-diaza-cyclooctadecane-
7,16-dicarboxylic acid bis-{2-[a-15-(2-amino-phenyl)-
10,20-bis-(3,5-dimethoxy-phenyl)-porphyrin-a-5-yl]-
phenyl}-diamide 3b. 1H NMR (500 MHz, CDCl3): dZ8.87
(d, JZ4.8 Hz, 4H, bpyr), 8.82 (d, JZ4.8 Hz, 4H, bpyr),
8.79 (d, JZ4.8 Hz, 4H, bpyr), 8.65 (d, JZ4.8 Hz, 4H,
bpyr), 8.38 (d, JZ8.1 Hz, 2H, aro), 7.85 (d, JZ7.2 Hz, 2H,
aro), 7.79 (d, JZ7.2 Hz, 2H, aro), 7.68 (t, JZ7 Hz, 2H, aro),
7.62 (t, JZ7.8 Hz, 2H, aro), 7.26 (m, 6H, aro), 7.17 (m, 6H,
aro), 7.08 (d, JZ7.8 Hz, 2H, aro), 6.87 (br s, 4H, aro), 6.78
(br s, 2H, NHCO), 3.93 (s, 12H, –OCH3), 3.90 (s, 12H,
–OCH3), 3.53 (br s, 4H, NH2), 1.82 (br s, 8H, –CH2–), 1.13
(br s, 8H, –CH2–), K0.46 (br s, 8H, –CH2–), K2.93 (s, 4H,
NHpyr). 13C NMR (125 MHz, CDCl3): dZ158.8, 146.8,
140.5, 134.9, 130.7, 129.9, 120.7, 119.3, 117.5, 114.3,
113.7, 99.9, 68.4, 67.5, 55.6, 48.9. HRMS (ESC) Calcd for
C110H102N14O14Na (MCNa)C 1865.7598. Found,
1865.7577. UV–vis (CH2Cl2) l nm (10K33, dm3 molK1
cmK1): 418 (523.5), 514 (33.4), 549 (9.6), 589 (10.2),
645 (4.7).
1
methanol/CH2Cl2 and obtained in 88% yield (38 mg). H
NMR (500 MHz, CDCl3): dZ8.83 (d, JZ4.5 Hz, 2H,
bpyr), 8.69–8.62 (m, 4H, bpyr and 1H, aro), 8.59 (d, JZ
4.5 Hz, 2H, bpyr), 8.43 (dd, J1Z8 Hz, J2Z1.5 Hz, 1H, aro),
8.23 (dd, J1Z7 Hz, J2Z1.5 Hz, 1H, aro), 7.99–7.92 (m, 3H,
aro), 7.74 (td, J1Z8 Hz, J2Z1.5 Hz, 1H, aro), 7.69 (s, 1H,
NHCO), 7.34 (td, J1Z7.5 Hz, J2Z1 Hz, 1H, aro), 7.30 (s,
2H, aro), 7.28 (s, 2H, aro), 5.00 (br s, 1H, NH), 2.88 (br s,
4H, –CH2–), 2.63 (s, 6H, –CH3), 2.38 (br s, 12H, –CH2–),
1.97 (br s, 8H, –CH2–), 1.85 (s, 6H, –CH3), 1.82 (s, 6H,
–CH3), K2.51 (s, 2H, NHpyr). 13C NMR (125 MHz,
CDCl3): dZ157.3, 152.2, 141.6, 139.7, 139.2, 138.5,
138.2, 137.4, 136.6, 135.5, 131.5, 130.1, 129.9, 129.8,
128.4, 128.3, 124.3, 120.8, 119.4, 119.2, 116.0, 114.0, 71.5,
69.8, 68.7, 49.1, 47.0, 22.2, 22.0, 21.9. HRMS (ESC) Calcd
for C63H67N8O7 (MCH)C 1047.5132. Found, 1047.5131.
UV–vis (CH2Cl2) l nm (10K33, dm3 molK1 cmK1): 420
(261.8), 516 (15.6), 549 (5.4), 592 (4.9), 648 (2.6).
4.2.4. 1,4,10,13-Tetraoxa-7,16-diaza-cyclooctadecane-7-
carboxylic acid {2-[a-15-(2-amino-phenyl)-10,20-bis-
(3,5-dimethoxy-phenyl)-porphyrin-a-5-yl]-phenyl}-
4.2.7. 1,3-Bis-{2-[1,4,10,13-tetraoxa-7,16-diaza-cyclo-
octadecane-7,16-dicarboxylic acid bis-{2-[2-{10,20-bis-
(3,5-dimethoxy-phenyl)}-a-15-phenyl]-amide}-porphy-
1
1
amide 2b. H NMR (500 MHz, CDCl3): dZ9.06 (d, JZ
rin-a-5,50-diyl]-diphenyl}-urea 4b. H NMR (500 MHz,
4.5 Hz, 2H, bpyr), 9.04 (d, JZ4.5 Hz, 2H, bpyr), 8.98 (d,
JZ5 Hz, 2H, bpyr), 8.93 (d, JZ5 Hz, 2H, bpyr), 8.59 (d,
JZ9 Hz, 1H, aro), 7.99 (d, JZ7.5 Hz, 1H, aro), 7.87 (d, JZ
7.5 Hz, 1H, aro), 7.78 (t, JZ6.5 Hz, 1H, aro), 7.64 (t, JZ
7.5 Hz, 1H, aro), 7.38 (m, 5H, aro), 7.19 (m, 3H, aro and
NHCO), 6.93 (t, JZ2.5 Hz, 2H, aro), 4.03 (s, 6H, –OCH3),
4.01 (s, 1H, NH), 3.97 (s, 6H, –OCH3), 2.68 (br s, 4H,
–CH2–), 2.52 (br s, 4H, –CH2–), 2.36 (br s, 4H, –CH2–),
1.96 (br s, 4H, –CH2–), 1.61 (br s, 4H, –CH2–), 1.43 (br s,
4H, –CH2–), K2.75 (s, 2H, NHpyr). 13C NMR (125 MHz,
CDCl3): dZ159.1, 150.2, 140.6, 134.9, 131.6, 129.7, 121.0,
119.8, 117.7, 114.6, 113.7, 111.5, 99.9, 95.9, 70.3, 68.4,
64.1, 55.6, 48.5, 46.6. HRMS (ESC) Calcd for C61H65N8O9
(MCH)C 1053.4874. Found, 1053.4867. UV–vis (CH2Cl2)
l nm (10K33, dm3 molK1 cmK1): 419 (215.3), 512 (14.7),
548 (4.3), 588 (4.4), 646 (2.3).
CDCl3): dZ8.73 (d, JZ4.2 Hz, 4H, bpyr), 8.67 (d, JZ
5.1 Hz, 4H, bpyr), 8.65 (d, JZ5.1 Hz, 4H, bpyr), 8.60 (d,
JZ4.2 Hz, 4H, bpyr), 8.51 (d, JZ8.2 Hz, 2H, aro), 8.43 (d,
JZ8.2 Hz, 2H, aro), 7.84 (t, JZ8.4 Hz, 2H, aro), 7.71 (m,
4H, aro), 7.61 (d, JZ7.5 Hz, 2H, aro), 7.40 (t, JZ7.5 Hz,
2H, aro), 7.30 (t, JZ7.5 Hz, 2H, aro), 7.16 (s, 4H, aro), 6.98
(s, 4H, aro), 6.81 (s, 4H, aro), 6.77 (s, 2H, NHCO), 5.69 (s,
2H, NHCO), 3.87 (s, 12H, –OCH3), 3.78 (s, 12H, –OCH3),
3.80 (br s, 8H, –CH2–), 2.15 (br s, 8H, –CH2–), 0.89 (br s,
8H, –CH2–), K3.25 (s, 2H, NHpyr). 13C NMR (125 MHz,
CDCl3): dZ158.9, 140.0, 139.3, 129.6, 129.2, 128.1, 127.5,
126.2, 125.4, 124.6, 121.2, 115.2, 105.5, 55.8, 52.8, 29.7.
HRMS (ESC) Calcd for C111H100N14O15Na (MCNa)C
1891.7390. Found, 1891.7372. UV–vis (CH2Cl2) l nm
(10K33, dm3 molK1 cmK1): 422 (435.5), 515 (24.4), 550
(8.7), 589 (8.8), 646 (4.7).
4.2.5. 1,4,10,13-Tetraoxa-7,16-diaza-cyclooctadecane-
7,16-dicarboxylic acid bis-{2-[a-15-(2-amino-phenyl)-
10,20-bis-(2,4,6-trimethyl-phenyl)-porphyrin-a-5-yl]-
phenyl}-diamide 3a. 1H NMR (500 MHz, CDCl3): dZ8.76
(d, JZ4.5 Hz, 4H, bpyr), 8.59 (d, JZ4.5 Hz, 8H, bpyr),
4.2.8. a-5,15-Bis-(2-aminophenyl)-10,20-bis-(2,4,6-tri-
methyl-phenyl)-porphyrin 5aaa and a-5-b-15-(2-amino-
phenyl)-10,20-bis-(2,4,6-trimethyl-phenyl)-porphyrin
5aab. The two atropisomers of 7a (200 mg, 0.25 mmol)
were dissolved in CH2Cl2 (50 mL) in a 250 mL round flask.

3062
Z. Halime et al. / Tetrahedron 62 (2006) 3056–3064
SnCl2$2H2O (0.95 g, 5 mmol) and concentrated hydro-
chloric acid (50 mL) were added and the resulting green
mixture was stirred for 12 h at room temperature; then
cautiously neutralized at 0 8C with concentrated aqueous
ammonia. CH2Cl2 (100 mL) was added and the organic
layer was washed with aqueous NaHCO3 (3!100 mL) and
brine (2!100 mL). The organic layer was dried (MgSO4),
concentrated and the residue was chromatographed on a
silica gel column. The 5aab atropisomer was eluted with
CH2Cl2 and obtained in 62% yield (114 mg) where 5aaa
atropisomer was eluted with 0.5% ethanol/CH2Cl2 and
obtained in 34% yield (61 mg). 5aaa. 1H NMR (500 MHz,
CDCl3): dZ8.84 (d, JZ5 Hz, 4H, bpyr), 8.69 (d, JZ5 Hz,
4H, bpyr), 7.92 (dd, J1Z7.2 Hz, J2Z1.5 Hz, 2H, aro), 7.59
(td, J1Z8 Hz, J2Z1.5 Hz, 2H, aro), 7.28 (s, 2H, aro), 7.27
(s, 2H, aro), 7.17 (td, J1Z7.5 Hz, J2Z1.5 Hz, 2H, aro), 7.11
(dd, J1Z7.2 Hz, J2Z1.5 Hz, 2H, aro), 3.54 (s, 4H, NH2),
2.63 (s, 6H, –CH3), 1.88 (s, 6H, –CH3), 1.80 (s, 6H, –CH3),
K2.58 (s, 2H, NHpyr). 13C NMR (125 MHz, CDCl3): dZ
147.3, 139.7, 138.5, 138.1, 135.2, 131.7, 130.9, 130.0,
128.3, 127.4, 118.7, 117.9, 115.7, 115.5, 22.1, 22.0, 21.9.
HRMS (ESC) Calcd for C50H45N6Na (MCNa)C 751.3525.
Found, 751.3518. UV–vis (CH2Cl2) l nm (10K33,
dm3 molK1 cmK1): 418 (362.7), 514 (22.4), 550 (6.7), 588
759.3447. Found, 759.3446. UV–vis (CH2Cl2) l nm (10K33,
dm3 molK1 cmK1): 419 (343.8), 515 (24.0), 549 (7.7), 591
(7.5), 647 (3.6).
4.2.10. a-5-(2-Aminophenyl)-b-15-(2-nitrophenyl)-
10,20-bis-(2,4,6-trimethyl-phenyl)-porphyrin 5aNO2ab.
To a solution of porphyrin 7aab (287 mg, 0.36 mmol) in
CHCl3 (680 mL) was added concentrated hydrochloric acid
(1.43 mL, 14.4 mmol). This was followed by addition of
SnCl2$2H2O (410 mg, 2.16 mmol), and the reaction mixture
was stirred was stirred at 0 8C and monitored by TLC. After
stirring for 4 h, concentrated aqueous ammonia (7 mL), was
added to the reaction mixture, and then the mixture was
washed with aqueous NaHCO3 (3!100 mL) and brine (2!
100 mL). The organic layer was dried (MgSO4), concen-
trated and the residue was chromatographed on a silica gel
column. Compound 5aNO2ab was eluted with CH2Cl2/
1
hexane 6:4 and obtained in 21% yield (57 mg). H NMR
(500 MHz, CDCl3): dZ8.84 (d, JZ5 Hz, 2H, bpyr), 8.69
(m, 4H, bpyr), 8.59 (d, JZ4.5 Hz, 2H, bpyr), 8.47 (dd, J1Z
8 Hz, J2Z1 Hz, 1H, aro), 8.21 (dd, J1Z7.5 Hz, J2Z1.5 Hz,
1H, aro), 7.98–7.91 (m, 2H, aro), 7.89 (dd, J1Z7.5 Hz, J2Z
1 Hz, 1H, aro), 7.60 (td, J1Z8 Hz, J2Z1 Hz, 1H, aro), 7.28
(s, 2H, aro), 7.27 (s, 2H, aro), 7.17 (t, JZ7.5 Hz, 1H, aro),
7.12 (d, JZ8 Hz, 1H, aro), 3.60 (s, 2H, NH2), 2.63 (s, 6H,
–CH3), 1.85 (s, 12H, –CH3), K2.54 (s, 2H, NHpyr). 13C
NMR (125 MHz, CDCl3): dZ152.0, 147.1, 139.2, 138.3,
138.1, 137.4, 137.0, 135.2, 131.7, 131.1, 130.9, 130.2,
130.1, 130.0, 128.3, 128.1, 127.4, 124.4, 119.1, 118.0,
116.0, 115.6, 114.0, 22.1, 21.9. HRMS (ESC) Calcd for
C50H43N6O2 (MCH)C 759.3447. Found, 759.3446. UV–vis
(CH2Cl2) l nm (10K33, dm3 molK1 cmK1): 419 (343.8),
515 (24.0), 549 (7.7), 591 (7.5), 647 (3.6).
1
(6.8), 649 (3.4). 5aab. H NMR (500 MHz, CDCl3): dZ
8.84 (d, JZ5 Hz, 4H, bpyr), 8.69 (d, JZ5 Hz, 4H, bpyr),
7.85 (dd, J1Z7.5 Hz, J2Z1.5 Hz, 2H, aro), 7.59 (td, J1Z
8.2 Hz, J2Z1.5 Hz, 2H, aro), 7.28 (s, 4H, aro), 7.15 (t, JZ
7.5 Hz, 2H, aro), 7.12 (d, JZ8.2 Hz, 2H, aro), 3.60 (s, 4H,
NH2), 2.63 (s, 6H, –CH3), 1.84 (s, 12H, –CH3), K2.58 (s,
2H, NHpyr). 13C NMR (125 MHz, CDCl3): dZ147.2,
139.8, 138.2, 135.2, 131.5, 130.7, 130.0, 128.2, 118.6,
117.8, 115.6, 115.5, 22.1, 21.9. HRMS (ESC) Calcd for
C50H45N6Na (MCNa)C 751.3525. Found, 751.3518.
UV–vis (CH2Cl2) l nm (10K33, dm3 molK1 cmK1): 418
(362.7), 514 (22.4), 550 (6.7), 588 (6.8), 649 (3.4).
4.2.11.
a-5,15-Bis-(2-aminophenyl)-10,20-bis-(3,5-
dimethoxy-phenyl)-porphyrin 5baa and a-5-b-15-bis-
(2-aminophenyl)-10,20-bis-(3,5-dimethoxy-phenyl)-por-
phyrin 5bab. In a 250 mL beaker, the two atropisomers of
7b (1 g, 1.2 mmol) were dissolved in concentrated
hydrochloric acid (100 mL) at room temperature and
SnCl2$2H2O (2.17 g, 9.6 mmol) was added. The resulting
green mixture was stirred for 2 days, then cautiously
neutralized at 0 8C with aqueous potassium hydroxide.
Ethyl acetate (100 mL) was added and the mixture stirred
for 1 h. The ethyl acetate layer was separated and the
aqueous layer extracted several times with ethyl acetate.
The organic layer was concentrated and the residue was
chromatographed on a silica gel column. The 5bab
atropisomer was eluted with CH2Cl2 and obtained in
38% yield (348 mg), where the 5baa atropisomer was
eluted with 0.4% methanol/CH2Cl2 and obtained in 40%
4.2.9. a-5-(2-Aminophenyl)-a-15-(2-nitrophenyl)-10,20-
bis-(2,4,6-trimethyl-phenyl)-porphyrin 5aNO2aa. To a
solution of porphyrin 7aaa (110 mg, 0.14 mmol) in CH2Cl2
(280 mL) was added concentrated hydrochloric acid
(0.55 mL, 5.6 mmol). This was followed by addition of
SnCl2$2H2O (0.16 g, 0.84 mmol), and the reaction mixture
was stirred at 0 8C and monitored by TLC. After stirring for
9 h, concentrated aqueous ammonia (3 mL), was added to
the reaction mixture, and then the mixture was washed with
aqueous NaHCO3 (3!100 mL) and brine (2!100 mL).
The organic layer was dried (MgSO4), concentrated and the
residue was chromatographed on a silica gel column.
Compound 5aNO2aa was eluted with CH2Cl2 and obtained
1
in 65% yield (69 mg). H NMR (500 MHz, CDCl3): dZ
1
8.87 (d, JZ5 Hz, 2H, bpyr), 8.72 (d, JZ5 Hz, 2H, bpyr),
8.70 (d, JZ4.5 Hz, 2H, bpyr), 8.60 (d, JZ4.5 Hz, 2H,
bpyr), 8.46 (d, JZ8 Hz, 1H, aro), 8.27 (d, JZ7 Hz, 1H,
aro), 7.95 (m, 2H, aro), 7.91 (d, JZ7.5 Hz, 1H, aro), 7.61 (t,
JZ7.5 Hz, 1H, aro), 7.31 (s, 2H, aro), 7.29 (s, 2H, aro), 7.18
(t, JZ7.5 Hz, 1H, aro), 7.13 (d, JZ7.5 Hz, 1H, aro), 3.61 (s,
2H, NH2), 2.64 (s, 6H, –CH3), 1.91 (s, 6H, –CH3), 1.83 (s,
6H, –CH3), K2.52 (s, 2H, NHpyr). 13C NMR (125 MHz,
CDCl3): dZ152.0, 147.1, 139.8, 138.4, 138.2, 137.4, 137.0,
135.0, 131.7, 131.2, 131.1, 130.3, 130.2, 128.3, 128.1,
127.0, 124.9, 124.5, 119.1, 117.8, 116.0, 115.5, 114.0, 22.2,
22.0, 21.9. HRMS (ESC) Calcd for C50H43N6O2 (MCH)C
yield (367 mg). 5baa. H NMR (500 MHz, CDCl3): dZ
8.97 (d, JZ4.5 Hz, 4H, bpyr), 8.91 (d, JZ4.5 Hz, 4H,
bpyr), 7.91 (dd, J1Z7.5 Hz, J2Z1.5 Hz, 2H, aro), 7.63 (td,
J1Z8 Hz, J2Z1.5 Hz, 2H, aro), 7.40 (d, JZ2.5 Hz, 4H,
aro), 7.20 (t, JZ7.5 Hz, 2H, aro), 7.14 (d, JZ8 Hz, 2H,
aro), 6.91 (t, JZ2 Hz, 2H, aro), 3.97 (s, 12H, –OCH3), 3.53
(s, 4H, NH2), K2.73 (s, 2H, NHpyr). 13C NMR (125 MHz,
CDCl3): dZ164.7, 150.1, 140.9, 139.2, 137.5, 135.6,
133.2, 130.7, 128.6, 126.6, 123.9, 123.1, 122.2, 121.9.
HRMS (ESC) Calcd for C48H40N6O4Na (MCNa)C
787.3008. Found, 787.2982. UV–vis (CH2Cl2) l nm
(10K33, dm3 molK1 cmK1): 420 (337.6), 514 (21.9), 549

Z. Halime et al. / Tetrahedron 62 (2006) 3056–3064
3063
(5.2), 588 (5.9), 646 (2.3). 5bab. 1H NMR (500 MHz,
CDCl3): dZ8.97 (d, JZ4.5 Hz, 4H, bpyr), 8.91 (d, JZ
4.5 Hz, 4H, bpyr), 7.88 (dd, J1Z7.5 Hz, J2Z1.5 Hz, 2H,
aro), 7.64 (td, J1Z8 Hz, J2Z1.5 Hz, 2H, aro), 7.41 (d, JZ
2.5 Hz, 4H, aro), 7.20 (t, JZ7.5 Hz, 2H, aro), 7.15 (d, JZ
8 Hz, 2H, aro), 6.92 (t, JZ2 Hz, 2H, aro), 3.98 (s, 12H,
–OCH3), 3.58 (s, 4H, NH2), K2.72 (s, 2H, NHpyr). 13C
NMR (125 MHz, CDCl3): dZ164.2, 149.7, 140.9, 139.1,
137.5, 135.6, 133.3, 130.5, 128.6, 126.6, 123.9, 123.0,
122.2, 121.7. HRMS (ESC) Calcd for C48H40N6O4Na
(MCNa)C 787.3008. Found, 787.2982. UV–vis (CH2Cl2)
l nm (10K33, dm3 molK1 cmK1): 420 (337.6), 514 (21.9),
549 (5.2), 588 (5.9), 646 (2.3).
4.2.14. a-5,15-Bis-(2-nitro-phenyl)-10,20-bis-(2,4,6-tri-
methyl-phenyl)-porphyrin 7aaa and a-5-b-15-(2-nitro-
phenyl)-10,20-bis-(2,4,6-trimethyl-phenyl)-porphyrin
7aab. A solution of 6a (2 g, 7.6 mmol) and 2-nitro-
benzaldehyde (1.15 g, 7.6 mmol) in CH2Cl2 (780 mL)
was degassed by argon bubbling for 15 mL, and then
trifluoroacetic acid (1.11 mL, 14.5 mmol) was added. The
solution was stirred for 30 mL at room temperature, then,
DDQ (1.9 g, 8.4 mmol) was added and the mixture was
stirred for an additional 1 h. The reaction mixture was
poured onto a pad of alumina and eluted with CH2Cl2
until the eluting solution was pale brown. Removal of
the solvent under reduced pressure gave 7a (2
atropisomers: aa and ab) in 20% yield (220 mg). The
mixture of the two atropisomers was chromatographed on
a silica gel column. The 7aab atropisomer was eluted
with CH2Cl2/hexane 1:1 and obtained in 13% yield
(143 mg), where 7aaa atropisomer was eluted with
CH2Cl2/hexane 3:2 and obtained in 7% yield (77 mg).
7aaa. 1H NMR (500 MHz, CDCl3): dZ8.67 (d, JZ
4.5 Hz, 4H, bpyr), 8.58 (d, JZ4.5 Hz, 4H, bpyr), 8.47
(dd, J1Z8 Hz, J2Z1.5 Hz, 2H, aro), 8.21 (dd, J1Z
7.5 Hz, J2Z1.5 Hz, 2H, aro), 7.97 (td, J1Z8 Hz, J2Z
1.5 Hz, 2H, aro), 7.92 (td, J1Z7.5 Hz, J2Z1.5 Hz, 2H,
aro), 7.29 (s, 2H, aro), 7.26 (s, 2H, aro), 2.62 (s, 6H,
–CH3), 1.87 (s, 6H, –CH3), 1.82 (s, 6H, –CH3), K2.50
(s, 2H, NHpyr). 13C NMR (125 MHz, CDCl3): dZ152.0,
140.2, 139.5, 138.4, 138.3, 137.4, 136.9, 131.3, 131.0,
130.5, 129.9, 128.4, 128.0, 124.5, 119.5, 114.4, 22.3,
22.0, 21.8. HRMS (ESC) Calcd for C50H41N6O4 (MC
H)C 789.3189. Found, 789.3164. UV–vis (CH2Cl2) l nm
(10K33, dm3 molK1 cmK1): 419 (333.6), 516 (18.7), 550
(6.1), 592 (5.7), 649 (2.9). 7aab. 1H NMR (500 MHz,
CDCl3): dZ8.65 (d, JZ4.5 Hz, 4H, bpyr), 8.57 (d, JZ
4.5 Hz, 4H, bpyr), 8.46 (dd, J1Z8 Hz, J2Z1.5 Hz, 2H,
aro), 8.23 (dd, J1Z7.5 Hz, J2Z1.5 Hz, 2H, aro), 7.95 (td,
J1Z8 Hz, J2Z1.5 Hz, 2H, aro), 7.94 (td, J1Z7.5 Hz,
J2Z1.5 Hz, 2H, aro), 7.26 (s, 4H, aro), 2.61 (s, 6H,
–CH3), 1.83 (s, 12H, –CH3), K2.52 (s, 2H, NHpyr). 13C
NMR (125 MHz, CDCl3): dZ152.0, 139.8, 138.4, 138.2,
137.4, 136.9, 131.4, 130.8, 130.4, 129.9, 128.2, 124.6,
119.0, 114.1, 22.1, 21.9. HRMS (ESC) Calcd for
C50H41N6O4 (MCH)C 789.3189. Found, 789.3164.
UV–vis (CH2Cl2) l nm (10K33, dm3 molK1 cmK1): 419
(333.6), 516 (18.7), 550 (6.1), 592 (5.7), 649 (2.9).
4.2.12. 2-[(1H-Pyrrol-2-yl)-(2,4,6-trimethyl-phenyl)-
methyl]-1H-pyrrole 6a. A solution of 2,4,6-trimethyl-
benzaldehyde (2.65 mL, 18 mmol) and pyrrole (50 mL,
720 mmol) was degassed by argon bubbling for 15 min.
Trifluoroacetic acid (138 mL, 1.8 mmol) was then added and
the solution was stirred under argon at room temperature for
an additional hour and then quenched with triethylamine
(0.4 mL). The mixture was diluted with toluene (150 mL)
then washed with brine (2!100 mL) and dried (MgSO4).
The solvent was removed under reduced pressure and then
the unreacted pyrrole was removed by vacuum distillation at
room temperature. The residue was dissolved in CH2Cl2 and
filtered through a short pad of silica using CH2Cl2 as the
eluent. Evaporation of the solvent under reduced pressure
resulted in a brown solid. This solid was washed with
cyclohexane and then with hexane, giving a pale yellow
solid, which was collected by filtration (1.85 g). Yield: 70%.
1H NMR (500 MHz, CDCl3): dZ7.95 (br s, 2H, NHpyr),
6.87 (s, 2H, Ar), 6.67 (br s, 2H, pyr), 6.18 (m, 2H, pyr), 6.02
(br s, 2H, pyr), 5.93 (s, 1H, meso), 2.27 (s, 3H, –CH3), 2.06
(s, 6H, –CH3). 13C NMR (125 MHz, CDCl3): dZ138.0,
137.0, 135.0, 131.7, 130.8, 116.6, 109.1, 106.9, 38.8, 21.2,
21.0. HRMS (ESC) Calcd for C18H20N2 (M%)C 264.1626.
Found, 264.1615.
4.2.13. 2-[(1H-Pyrrol-2-yl)-(3,5-dimethoxy-phenyl)-
methyl]-1H-pyrrole 6b. A solution of 3,5-dimethoxy-
benzaldehyde (3 g, 18 mmol) and pyrrole (50 mL,
720 mmol) was degassed by argon bubbling for 15 mL,
then trifluoroacetic acid (138 mL, 1.8 mmol) was added.
After 1 h, the reaction mixture was neutralized with Et3N
(0.44 mL, 3.2 mmol). The unreacted pyrrole was removed
by vacuum distillation and the mixture was diluted with
toluene and washed with aqueous 10% NaCl (2!100 mL).
The organic phase was dried with MgSO4, filtered and the
solvent removed under vacuum. Finally, the residue was
chromatographed on a silica gel column and eluted with
(hexane/ethyl acetate/triethylamine; 80:20:1). The expected
compound was recrystallized with (hexane/ethyl acetate;
98:2) at 0 8C, washed with hexane (100 mL), and obtained
in 71% yield (3.6 g). 1H NMR (200 MHz, CDCl3): dZ7.94
(br s, 2H, NHpyr), 6.71 (q, JZ4.5 Hz, 2H, pyr), 6.41–6.38
(m, 3H, Ar), 6.18 (q, JZ3.1 Hz, 2H, pyr), 5.98 (br s, 2H,
pyr), 5.43 (s, 1H, meso), 3.76 (s, 6H, –OCH3). 13C NMR
(125 MHz, CDCl3): dZ118.8, 108.1, 105.7, 109.3, 108.0,
45.2, 55.5. HRMS (ESC) Calcd for C17H18N2O2 (M%)C
282.1368. Found, 282.1371.
4.2.15.
5,15-Bis-(2-nitrophenyl)-10,20-bis-(3,5-
dimethoxy-phenyl)-porphyrin 7b. A solution of 6b
(3 g, 10.6 mmol) and 2-nitro-benzaldehyde (1.6 g,
10.6 mmol) in dry CH2Cl2 (1.1 L) was degassed by
argon bubbling for 15 mL, then trifluoroacetic acid
(787 mL, 10.6 mmol) was added. The solution was stirred
for 12 h at room temperature, then, DDQ (2.4 mg,
10.6 mmol) was added and the mixture was stirred for
an additional 1 h, and neutralized with Et3N (440 mL,
10.6 mmol). The solvent was removed under vacuum, and
the expected compound was recrystallized with a
minimum of CH2Cl2 at 0 8C, and finally washed with
CH2Cl2 (500 mL) and methanol (500 mL). Compound 7b
(2 atropisomers: aa and bb) was obtained in 30% yield
(1.3 g). HRMS (ESC) Calcd for C48H37N6O8 (MCH)C
825.2672. Found, 825.2660.

3064
Z. Halime et al. / Tetrahedron 62 (2006) 3056–3064
4.2.16. X-ray crystallographic studies. 7aaa: crystal
data: formula C50H40N6O4$C6H14, MwZ875.05, mono-
References and notes
˚
clinic, space group P21/n, aZ14.054(7) A, bZ
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Acknowledgements
Both research teams acknowledge Platon bilateral program
for financial support to N.K. and Z.H., also part of the
project is co-funded by the European Social Fund and
National resources (G.C.). We gratefully acknowledge La
´
Ligue contre le cancer, Region Bretagne, and the CNRS for
financial support. We are particularly indebted to the
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´
ˆ
Comite des Cotes-d’Armor de La Ligue contre le cancer
for his generous help to Z.H.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2006.
01.029. Complete NMR spectra (1D and 2D) of new
compounds described in this work.
¨ ¨
Refinement; University of Gottingen: Gottingen, Germany,
1986.