Lead structures for applications in photodynamic therapy. Part 2: Synthetic studies for photo-triggered release systems of bioconjugate porphyrin photosensitizers

Article abstract of DOI:10.1016/j.tet.2009.06.037

Photodynamic therapy (PDT) selectivity and specificity can be improved by binding the photosensitizers to target receptors. One approach is to cross-link porphyrins to a biological target receptor via the photocleavable o-nitrobenzyl linker, where a contr

Full text of DOI:10.1016/j.tet.2009.06.037

Tetrahedron 65 (2009) 7064–7078
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Lead structures for applications in photodynamic therapy. Part 2: Synthetic
studies for photo-triggered release systems of bioconjugate porphyrin
photosensitizers
,c,
Mohd Bakri Bakar a, Michael Oelgemo¨ller b, Mathias O. Senge a
*
a School of Chemistry, SFI Tetrapyrrole Laboratory, Trinity College Dublin, Dublin 2, Ireland
b School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Queensland 4811, Australia
c Institute for Molecular Medicine, Medicinal Chemistry, Trinity Centre for Health Sciences, Trinity College Dublin, St. James’s Hospital, Dublin 8, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
Photodynamic therapy (PDT) selectivity and specificity can be improved by binding the photosensitizers
to target receptors. One approach is to cross-link porphyrins to a biological target receptor via the
photocleavable o-nitrobenzyl linker, where a controlled released of the porphyrin can be monitored upon
irradiation. The synthetic pathways involved esterification of a porphyrin–carboxylic acid and a unit
containing the o-nitrobenzyl alcohol moiety and the bioconjugate. Reactions of a model porphyrin and
o-nitrobenzyl alcohol using the carbonyl activating carbodiimide reagent DCC gave a stable N-acyl urea
porphyrin, whereas use of EDAC (1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride) gave
the desired compounds. Further studies were carried out on the attachment of carbohydrates (i.e., po-
tentially receptor binding ligands) through such a linker to porphyrins. Preliminary irradiation experi-
ments of such a compound show that upon UV irradiation (350 nm) for 80 min, approximately 50% of the
porphyrin was cleaved to release the carboxylic acid porphyrin photosensitizer indicating the utility of
such systems as photosensitizers delivery systems.
Received 18 March 2009
Received in revised form 15 May 2009
Accepted 11 June 2009
Available online 17 June 2009
Keywords:
Porphyrins
Carbodiimide
O-Nitrobenzyl
Photodynamic therapy
Tetrapyrroles
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
through increasing the target/non-target tissue ratio. This can result
in a reduction of the effective photosensitizer dose and its toxicity.
Photodynamic therapy (PDT) is a treatment modality based on
photoactive substances of photosensitizers that localize preferen-
tially in tumor cells. Irradiation of the target tissues with the ap-
propriate wavelength of light activates the production of highly
reactive oxygen and leads to a series of phototoxic reactions that
cause selective death of tumor cells. Remarkable advancements
have been made in recent decades to improve the efficiency of three
PDT basic components: light, oxygen and photosensitizers; along
with increased understanding of their biomedical and biophysical
function.1 Studies have been conducted to treat a variety of malig-
nant and premalignant cancer conditions including head and neck
cancer, lung cancer, mesothelioma, Barrett’s esophagus, prostate
and brain tumors.2 The main advantage of PDT lies in it being a se-
lective cancer treatment due to enrichment of the localized photo-
sensitizers in the tissue and the directing of light to the affected
tissue. The selectivity of PDT can be increased through targeted
delivery of the photosensitizers to its site of action. Thus, side-ef-
fects are minimized and the therapeutic window is widened
In addition, the exact localization of a photosensitizer is important
because the active singlet oxygen has a short life time of about
0.01 ms with a range of action of about 0.01–0.02 m
m.3
Targeted delivery systems employing various carriers have been
developed especially using hydrophobic photosensitizers.4 Common
carriers can be divided into three classes: (i) soluble carrier, such as
monoclonal antibodies, emulsions or polymers5; (ii) particulate
carriers of liposomes, nanoparticles or microspheres6 and (iii) the
target specific recognition7 of carbohydrates,8 lectins, oligonucleo-
tides, epidermal growth factors, peptides, hormones, vitamins or
lipoproteins. While the targeted photosensitizers delivery are ca-
pable of attaining site-specific delivery, a major concern is to control
the release kinetics of the photosensitizers in a predictable manner
and to deliver them at a pre-determined rate. One area of interest is
the development of photosensitizer release systems that can be
triggered externally.9 For example, a photochemically triggered re-
lease system can be achieved through photocleavage of specific
bonds in a pro-drug molecular system. This offers more control and
specificity as the light beam can be turned on and off (temporal
control) and light can be focused at particular sites (spatial control).
Our approach is to link porphyrin photosensitizers to ligand
* Corresponding author.
E-mail address: sengem@tcd.ie (M.O. Senge).
molecules and subsequently attempt a photo-release of the
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.037

M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
7065
porphyrin photosensitizers in targeted tumor tissue. The construc-
tion of photocleavable porphyrin-conjugate systems will enhance the
specific targeting of photosensitizers and localize their activation at
defined effector places. In addition, tumor necrosis or induced apo-
ptosis that contribute to cell death require light activation.10 Thus,
photocleavable linkers would be most advantageous. We proposed
earlier to utilize the photolabile spirobisdithianes and trithiane as
such linker groups, however the strategy had its limits due to in-
stability of the porphyrin systems towards photocleavage under
ambient conditions.11
Recently, photolabile o-nitrobenzyl linkers were utilized to de-
sign light-triggered anticancer pro-drugs which released the tegafur
drug from porphyrins upon photolysis.12 o-Nitrobenzyl linkers have
advantages due to their compatibility with a variety of functional
groups, ease of synthesis, stability under ambient light, clean
cleavage and fast fragmentation upon photoirradiation.13 In the
present work, we develop the necessary synthetic methodologies
for the construction of labile systems for porphyrin photosensitizers
based on the o-nitrobenzyl linker group and selected bioconjugates.
Another method that enables the introduction of ester func-
tional groups is to condense a mixture of pyrrole and the appro-
priately substituted benzaldehyde in a particular ratio.19 This
condensation reaction leads to the synthesis of a tetrasubstituted
compound (16) and ester porphyrin (17) (Scheme 2). Addition of
zinc acetate as a metal template during the condensation process
can facilitate the reaction, thus increasing the yield of the con-
densed products.20 The free base porphyrin can be obtained sub-
sequently under acidic conditions.
All of the ester porphyrins were further converted to function-
alised carboxylic acids porphyrins via base-hydrolysis using NaOH–
EtOH19 and afforded compounds 18–27 in high yields.
2.3. Esterification of porphyrins
The esterification of carboxylic acid porphyrins is often ach-
ieved using acylation21 or carbodiimide coupling techniques.22
However, the carbodiimide coupling offers
a more feasible
method as it requires simple and moderate conditions. We have
investigated several preliminary esterification reactions between
carboxylic acid porphyrins 7, 9, 28,22c 2922d and 2-nitro-
benzylalcohol as the model linker using primarily N,N0-dicyclo-
hexylcarbodiimide (DCC). However, the reactions tend to undergo
rearrangement to form stable N-acylisourea species (30–33) in-
stead of the reactive intermediates of o-acylisourea. A similar
rearrangement was observed in crown ether macrocycles23 and it
has been suggested that this process occurs via a four-membered
transition state (Scheme 3).
A crystal structure of compound 30 clearly shows the N-acyli-
sourea substitution pattern (Fig. 1). Meanwhile, under optimized
conditions (5 equiv DCC, 1 equiv DMAP, 5 equiv nitrobenzylalcohol),
we managed to obtain the respective nitrobenzyl-derivative of por-
phyrins (34–35) in moderate yields (Scheme 4). To overcome the
problem of low yields it is necessary to stabilize the intermediate
o-acylisourea using additive of N-hydroxysuccinimide (NHS) or
1-hydroxybenzotriazole (HOBt).24 The additive acts as the intermediate
nucleophile which converts the o-acylisourea to an activated ester
containing nucleophile, thus preventing the rearrangement.
Further esterifications were carried out using 1-ethyl-3-
2. Results and discussion
2.1. Synthetic rational
Although various approaches to porphyrin functionalization
have been established, esterification reactions have been mainly
utilized in attempts to attach porphyrin moieties to bioconjugates
via linker groups. Two synthetic pathways were chosen to syn-
thesize the target compounds: (i) esterification of porphyrin-car-
boxylic acids with o-nitrobenzyl alcohol containing systems and
the appropriate bioconjugate and (ii) the coupling of hydroxyl
porphyrins with selected bioconjugates (Scheme 1).
O
(a)
Linker
Porphyrin
Porphyrin
COOH + HO
C
Linker
O
Bioconjugate
Bioconjugate
O
O
(3-dimethylaminopropyl)carbodiimide
hydrochloride
(EDAC)
(b)
Porphyrin
Linker
COOH + HO
Porphyrin
C
which has high solubility in water and organic solvents such as
CH2Cl2, THF, DMF and is easy to use. These reactions proceeded
efficiently and gave the target compounds (34–43) in high yield
(Scheme 5).
Linker
OH
Protecting Group
Scheme 1. Synthetic rationale.
These approaches require the presence of bioconjugates reactive
2.4. Porphyrin-linked carbohydrates
towards the phenolic functional group. The latter method is de-
veloped through employing protecting group synthons, which later
can be deprotected to obtain the active porphyrin, and provides
convenient visual experimental monitoring due to associated color
changes of the porphyrins. Individual syntheses will be discussed
for the specific target compounds.
Porphyrins with carbohydrate moieties have been reported as
efficient photosensitiser candidates for PDT.25 Not only do they
alter the amphiphilicity of the photosensitizers, but they also ex-
hibit specific membrane interactions, thus resulting in specific
targeting of tumor cells.26 Therefore, a model compound of por-
phyrin-linker-bioconjugate was prepared by reaction of carboxylic
acid porphyrin (29) with (3-hydroxymethyl-4-nitrophenyl)-
2.2. Starting materials- carboxylic acid porphyrins
2,3,4,6-tetra-O-acetyl-b-D
-galactopyranoside27 to yield the target
A direct route to obtain carboxylic acid porphyrins is through
hydrolysis of ester-type porphyrins. Several known methods are
available. One of these is the use of palladium-catalysed Suzuki14 and
Heck15 coupling reactions using halogenated porphyrin precursors.
Hence, the initial step involved bromination16 at the meso- or
compound 44 in 76% yield (Scheme 6).
2.5. Protecting group method
The synthesis of a nitrobenzyl analog containing an active
phenolic group started with the protection of the phenolic group of
5-hydroxy-2-nitrobenzaldehyde using the acid-sensitive protect-
ing group, 2-methoxyethoxymethyl (MEM) ether, giving 45.28
Further reduction with sodium borohydride at room temperature
gave the respective nitrobenzyl alcohol 46 in quantitative yield. The
esterification process with EDAC carbodiimide was employed using
b-position of several free base porphyrins (1-6) which were acces-
sible through standard condensation17 or RLi-alkylation pro-
cedures.18 Consequently, Suzuki and Heck coupling reactions were
carried out using methylester-boronic acid or -vinyl derivatives.
These afforded a range of ester porphyrins in good yields (7–15)
(Scheme 2).

7066
M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
CO Me
2
COOH
1
R
R
B(OH)
O
2
NH
N
N
NH
N
N
K PO
NH
N
N
3
4
NaOH
EtOH
3
1
Br
+
2
R
1
R
2
R
R
R
Pd(PPh)
HN
2
3
HN
HN
MeO
3
3
R
R
1
1
1
1
2
3
18 (93%)
19 (93%)
20 (77%)
R
R
R
R
= R = Phenyl, R = Hexyl
1
7 (82%)
8 (94%)
9 (98%)
2
3
= R = 3-MeO-Phenyl, R = Hexyl
2
2
3
= R = Phenyl, R = H
= R = Phenyl, R = Br
3
1
3
2
1
3
2
2
3
R
R
= R = Phenyl,
= 4-CO Me-Phenyl 10 (94%)
2
R
R
= R = Phenyl,
= 4-CO OH-Phenyl 21 (81%)
4
2
CO Me
2
COOH
1
R
B(OH)
2
NH
N
N
HN
2
NH
N
N
HN
2
K PO
NH
N
N
HN
2
3
4
NaOH
EtOH
3
1
Br
+
3
R
1
R
3
R
R
R
Pd(PPh)
3
O
OMe
3
R
R
R
1
1
2
3
R
R
= R = Phenyl, R = Hexyl 1
11 (84%)
22 (94%)
2
3
3
= R = 3,5-di-t-Butyl-Phenyl, R = Br 5
R
= 3-MeO C-Phenyl 12 (77%)
R
= 3-HOOC-Phenyl 23 (89%)
2
R
R
R
HO C
2
MeO C
2
B(OH)
Br
2
NH
N
N
NH
N
NH
N
N
NaOH
EtOH
K PO
R
3
4
R
R
R
+
R
R
HN
N
HN
Pd(PPh)
3
HN
MeO
O
R
R
R
24 (82%)
13 (52%)
R = 3,5-di-t-Butyl-Phenyl 6 (96%)
CO Me
2
COOH
1
R
NH
N
N
HN
2
NH
N
N
HN
2
K PO
NH
N
HN
2
3
4
NaOH
EtOH
3
1
+
Br
3
R
1
R
3
R
R
R
CO Me
2
Pd(PPh)
3
N
R
R
R
1
1
2
3
R
R
= R = Phenyl, R = Hexyl 1
= R = 3-MeO-Phenyl, R = Hexyl 2
14 (55%)
15 (60%)
25 (93%)
26 (98%)
2
3
1
1
1
R
R
R
1
R -CHO
NN
NN
Zn
N
NN
Zn
N
Zn(OAc)
2
NaOH
EtOH
1
2
2
1
1
1
R
+
R
+
Zn
R
R
R
R
2
N
H
R -CHO
DDQ, NEt
N
N
N
N
3
1
1
1
R
R
R
1
R
R
= 3,5-di-t-Butyl-phenyl
= 4-CO Me-Phenyl
2
2
2
2
16 (12%)
R = 4-CO Me-Phenyl 17 (10%)
2
R
= 4-CO H-Phenyl 27 (82%)
2
Scheme 2. Entry to carboxylic acid porphyrins.
18 to give 47. Deprotection of the MEM group was carried out under
neutral conditions to avoid adverse reactions from the acidic con-
ditions. Heating of 47 using ethylene glycol29 led to the formation of
48 due to nucleophilic attack of a hydroxyl group in ethylene glycol
at the reactive benzylic carbon. The resulting product was esterified
with the carboxylic acid porphyrin 49 and gave the bisporphyrin 50
in 93% yield (Scheme 7).
Subsequently, we decided to use trifluoroacetic acid (TFA)30 as
a deprotection reagent for cases where the porphyrin core is re-
quired to be metallated to avoid unnecessary protonation.

M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
7067
a function of time. It was observed that, upon irradiation for 80 min,
approximately 50% of the porphyrin 29 was photocleaved. The
cleavage product was identified as porphyrin 29 [MS (ESþ): m/z
¼995.6233 (MþH)þ]. The mechanism of o-nitrobenzyl alcohol ester
derivatives involves photoinduced intramolecular hydrogen ab-
straction and a redox rearrangement that form o-quinonoid in-
termediates, followed by releasing of the carboxylic acid and
formation of nitrosobenzaldehyde.32 o-Nitroso benzaldehyde may
further react to form secondary products via azobenzene-2,20-di-
carboxylic acid that acts as an internal filter, hence slowing the de-
sired photoreaction.33 Two approaches may be used to further
increase its photoefficiency: (i) introduction of an additional o-nitro
group to increase hydrogen abstraction of the excited nitro group and
HN
NH
N
O
N
O
O
N
N
R
O-
R
O
R
O
N-acylisourea
O-acylisourea
HN
O
(ii) introduction of an a-substitutent to the chromophore to enhance
its efficiency for hydrogen abstraction. Both approaches require ad-
ditional synthetic steps and are currently under investigation.
O
N
COOH
3. Conclusion
NH
N
N
The results reported demonstrate that it is possible to synthesize
compounds containing the required structural motifs for photo-
cleavage. In addition, we could show the photolability of the target
material. Although the deprotection is still not optimal, subsequent
work will focus on improving the efficiency of the labile linker
couplings and will target various bioconjugates to fulfill the poten-
tial of increased binding affinity to targeted cell receptors. Pending
its success, this methodology will pave the way towards improved
localization of photosensitizers in PDT and their controlled release.
NH
N
N
R1 DCC/ DMAP
R3
R1
R3
HN
HN
R2
R2
18 R1 = R2 = Phenyl, R3 = Hexyl
30 (30%)
31 (39%)
32 (27%)
33 (52%)l
19 R1 = R2 = Phenyl, R3 = H
28 R1 = R2 = R3 = Phenyl
29 R1 = R2 = R3 = 3,5-di-t-butyl-Phenyl
Scheme 3. Formation of N-acylisourea porphyrins.
4. Experimental
4.1. General information
1H NMR and 13C NMR spectra were recorded on a Bruker DPX
400 (400.13 MHz for 1H NMR and 100.61 MHz for 13C NMR) and/or
Bruker AV 600 (600.13 MHz for 1H NMR and 150.90 MHz for 13C
NMR) instrument. Chemical shifts are reported in ppm referenced
to tetramethylsilane set at 0.00 ppm. High resolution mass spec-
trometry were measured on a Micromass/Waters Corp., USA liquid
chromatography time-of-flight spectrometer equipped with an
electrospray source. UV–vis measurements were performed on
a Shimadzu MultiSpec-1501. Melting points were acquired on
a Stuart SMP10 melting point apparatus and are uncorrected. Thin
layer chromatography (TLC) was performed on silica gel 60F254
(Merck) pre-coated aluminum sheets. Flash chromatography was
carried out using Fluka Silica Gel 60 (230–400 mesh). Anhydrous
THF distilled over sodium/benzophenone and dichloromethane
dried over P2O5 were used. All commercial chemicals were supplied
by Aldrich and used without further purification.
Figure 1. View of the molecular structure of 30 in the crystal. Hydrogen atoms have
been omitted for clarity; thermal ellipsoids are drawn for 50% occupancy.
4.2. Bromination of porphyrins
Porphyrin 47 was metallated with zinc acetate to give 51 which
after further treatment with excess TFA, the reaction progressed
smoothly to eliminate the MEM-group and demetallate the por-
phyrin moiety yielding 52 in 81% (Scheme 8). This compound opens
an entry for the attachment of diverse functional groups due to the
presence of the phenolic group. However, an attempt to attach folic
acid as a targeted bioconjugate31 did not proceed as planned.
Therefore, further investigation will be carried out on the optimi-
zation of their reactivity and will be reported later.
The porphyrin was dissolved in chloroform and a few drops of
pyridine were added. The solution was then cooled to 0 ꢀC. N-
Bromosuccinimide (1.1 equiv) was added and the mixture was
stirred (TLC monitoring) followed by evaporation of the solvent in
vacuo and purification via column chromatography.
4.2.1. 5-Bromo-15-hexyl-10,20-diphenylporphyrin (1)
A
solution of 5-hexyl-10,20-diphenylporphyrin18d (0.40 g,
0.73 mmol), pyridine (0.3 mL) and N-bromosuccinimide (0.14 g,
0.81 mmol) was dissolved in chloroform (150 mL) and stirred for
30 min. The title compound was purified by column chromato-
graphy on silica gel with n-hexane/dichloromethane (2:1, v/v) to
yield 1 0.46 g (0.29 mmol, 99%) as a purple solid: mp >310 ꢀC;
Rf¼0.75 (SiO2, CH2Cl2/C6H14, 1:1, v/v); 1H NMR (400 MHz, CDCl3,
2.6. Irradiation experiments
A solution of 44 was irradiated with long wavelength UV light
(centered at 350 nm) and the photofragmentation reaction was
monitored by HPLC. The conversion of 44 to 29 was followed as

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M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
NO2
O
HN
O
O
N
O
COOH
NO2
DCC /
DMAP
NH
N
N
NH
N
N
NH
N
N
OH
R1
R1
R1
R3
R3
+
R3
+
HN
HN
HN
R2
R2
R2
28 R1 = R2 = R3 = Phenyl
34 (27%)
35 (38%)
32 (69%)
33 (43%)
29 R1 = R2 = R3 = 3,5-di-t-butyl-Phenyl
Scheme 4. Synthesis of nitrobenzyl porphyrins.
TMS):
d
¼ꢁ2.72 (s, 2H, NH), 0.92 (t, J¼7.0 Hz, 3H, –CH3), 1.34–1.40
J¼1.8 Hz, 1H, phenyl-H), 8.82 (d, J¼1.8 Hz, 1H,
5H,
-H), 8.94 (d, J¼4.8 Hz, 1H,
-H); 13C NMR (100 MHz, CDCl3):
¼29.73, 31.96, 35.06, 120.94, 121.35, 129.12, 129.73, 140.96, 141.38,
b-H), 8.89–8.94 (m,
(m, 2H, –CH2), 1.44–1.51 (m, 2H, –CH2), 1.73–1.79 (m, 2H, –CH2),
2.43–2.51 (m, 2H, –CH2), 4.84 (t, J¼8.1 Hz, 2H, –CH2), 7.73–7.80 (m,
b
b
d
6H, phenyl-H), 8.16 (d, J¼6.4 Hz, 4H, phenyl-H), 8.84 (s, 4H,
b
-H),
-H); 13C NMR
¼13.74, 22.29, 29.79, 31.44, 35.08, 38.36, 101.47,
119.76, 121.25, 126.40, 127.39, 130.48, 131.54, 141.59 ppm; UV–vis
148.71, 148.90 ppm; UV–vis (CH2Cl2): lmax (log
3)¼423 (5.10), 520
9.37 (d, J¼4.7 Hz, 2H,
(100 MHz, CDCl3):
b-H), 9.58 (d, J¼4.7 Hz, 2H,
b
(3.64), 554 (2.64), 598 (3.48), 654 (3.62); HRMS (ESþ)
d
[C76H94N4Br1]: calcd for [MþH]þ 1141.6662, found 1141.6544.
(CH2Cl2): lmax (log
3
)¼420 (5.21), 520 (3.90), 554 (2.64), 598 (3.48),
4.3. Synthesis of porphyrin ester
654 (3.62); HRMS (ESþ) [C38H33N4Br]: calcd for [MþH]þ 625.1953,
found 625.1967.
4.3.1. Method A: Suzuki cross coupling approach
To a stirred slurry of K3PO4 (40 equiv) in anhydrous THF were
added bromoporphyrin (1 equiv), boronic acid (20 equiv), and
Pd(PPh3)4 (0.2 equiv). The reaction was heated to reflux at 85 ꢀC for
18 h and shielded from light. The solvent was evaporated after
completion and the residue was dissolved in CH2Cl2. This mixture
was washed with saturated NaHCO3, H2O, and brine followed by
drying over Na2SO4. The organic solvent was evaporated and the
crude product was purifed by column chromatography.
4.2.2. 5-Bromo-15-hexyl-10,20-bis(3-methoxyphenyl)
porphyrin (2)
A solution of 5-hexyl-10,20-bis(3-methoxyphenyl) porphyrin18d
(0.50 g, 0.82 mmol), pyridine (0.3 mL) and N-bromosuccinimide
(0.16 g, 0.91 mmol) was dissolved in chloroform (150 mL) and stir-
red for 30 min. The title compound was purified by column chro-
matography on silica gel with n-hexane/dichloromethane (1:1, v/v)
to yield 0.54 g of 2 (0.37 mmol, 95%) as a purple solid: mp¼225 ꢀC;
Rf¼0.36 (SiO2, CH2Cl2/C6H14, 1:1, v/v); 1H NMR (400 MHz, CDCl3,
4.3.2. 5-(4-Methoxycarbonylphenyl)-15-hexyl-10,20-
diphenylporphyrin (7)
TMS):
d
¼ꢁ2.71 (s, 2H, NH), 0.91 (t, J¼7.4 Hz, 3H, –CH3),1.35–1.40 (m,
2H, –CH2), 1.46–1.50 (m, 2H, –CH2), 1.73–1.78 (m, 2H, –CH2), 2.44–
2.52 (m, 2H, –CH2), 3.99 (s, 6H, –OCH3), 4.87 (t, J¼7.7 Hz, 2H, –CH2),
7.34 (dd, J1¼1.8 Hz, J2¼1.8 Hz, 2H, phenyl-H), 7.64 (t, J¼8.1 Hz, 2H,
K3PO4 (1.36 g, 6.39 mmol), 5-bromo-15-hexyl-10,20-diphenyl-
porphyrin 1 (0.2 g, 0.32 mmol), 4-methoxy carbonylphenylboronic
acid (0.58 g, 3.20 mmol) and Pd(PPh3)4 (0.04 g, 0.03 mmol) were
reactedinanhydrous THF(70 mL) followingmethodA (Section4.3.1).
The title compound was purifed by column chromatography on silica
gel with n-hexane/dichloromethane (1:1, v/v) and yielded 7 (0.29 g,
0.20 mmol, 82%) as a purple solid: mp >310 ꢀC; Rf¼0.60 (SiO2, EtOAc/
phenyl-H), 7.75–7.78 (m, 4H, phenyl-H), 8.89 (d, J¼4.4 Hz, 4H,
b
-H),
-H); 13C NMR
¼22.73, 29.76, 30.25, 31.91, 35.52, 38.82, 55.54,
101.92, 113.63, 119.94, 120.50, 121.70, 127.53, 129.60, 143.36,
9.37 (d, J¼4.8 Hz, 2H,
(100 MHz, CDCl3):
b-H), 9.58 (d, J¼4.8 Hz, 2H,
b
d
157.95 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼421 (5.50), 520 (4.25),
n-hexane,1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.67 (s, 2H,
554 (4.00), 598 (3.78), 654 (3.70); HRMS (ESþ) [C40H37N4O2Br]:
NH), 0.96 (t, J¼7.0 Hz, 3H, –CH3), 1.38–1.43 (m, 2H, –CH2), 1.49–1.53
(m, 2H, –CH2),1.75–1.82 (m, 2H, –CH2), 2.50–2.57 (m, 2H, –CH2), 4.13
(s, 3H, –OCH3), 4.91 (t, J¼8.2 Hz, 2H, –CH2), 7.75–7.81 (m, 6H, phenyl-
H), 8.23 (d, J¼7.6 Hz, 4H, phenyl-H), 8.32 (d, J¼7.6 Hz, 2H, phenyl-H),
calcd for [MþH]þ 685.2178, found 685.2166.
4.2.3. 2-Bromo-5,10,15,20-tetrakis(3,5-di-tert-butyl-
phenyl)porphyrin (6)
8.45 (d, J¼7.6 Hz, 2H, phenyl-H), 8.79 (d, J¼4.7 Hz, 2H,
b
-H), 8.85 (d,
-H), 9.44 (d, J¼4.7 Hz, 2H,
¼13.79, 22.34, 29.84, 31.50, 35.13,
38.49, 52.04, 117.34, 119.39, 120.83, 127.34, 127.56, 129.05, 134.20,
A
solution of 5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)por-
J¼4.7 Hz, 2H,
b
-H), 8.93(d, J¼4.7 Hz,2H,
b
b-
phyrin22d (0.20 g, 0.19 mmol), pyridine (0.5 mL) and N-bromo-
succinimide (0.04 g, 0.21 mmol) was dissolved in chloroform
(100 mL) and stirred for 1 h. The title compound was purified by
column chromatography on silica gel with n-hexane/dichloro-
methane (1:1, v/v) to yield 6 (0.21 g, 0.24 mmol, 96%) as a purple
solid: mp >310 ꢀC; Rf¼0.75 (SiO2, CH2Cl2/C6H14, 1:1, v/v); 1H NMR
H); 13C NMR (100 MHz, CDCl3):
d
141.90,146.62,166.99 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼419 (5.52),
517 (3.20), 551 (3.91), 593 (3.76), 649 (3.83); HRMS (ESþ)
[C46H41N4O2]: calcd for [MþH]þ 681.3230, found 681.3256.
(400 MHz, CDCl3, TMS):
d
¼ꢁ2.79 (s, 2H, NH),1.50 (s,18H, –C(CH3)3),
4.3.3. 5-(4-Methoxycarbonylphenyl)-15-hexyl-10,20-bis-
(3-methoxyphenyl)porphyrin (8)
1.52 (s, 54H, C(CH3)3), 7.78 (t, J¼1.8 Hz, 3H, phenyl-H), 7.80 (t,
J¼1.8 Hz, 1H, phenyl-H), 7.92 (d, J¼1.8 Hz, 1H, phenyl-H), 7.93 (d,
J¼1.8 Hz, 1H, phenyl-H), 8.03 (t, J¼1.8 Hz, 1H, phenyl-H), 8.04
(d, J¼1.8 Hz, 1H, phenyl-H), 8.06 (t, J¼1.8 Hz, 3H, phenyl-H), 8.09 (d,
K3PO4 (3.10 g, 14.59 mmol), 5-bromo-15-hexyl-10,20-bis(3-
methoxyphenyl)-porphyrin
2 (0.50 g, 0.73 mmol), 4-methoxy-
carbonylphenylboronic acid (1.31 g, 7.29 mmol) and Pd(PPh3)4

M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
7069
NO2
O
R
AcO
O
OAc
O
NH
N
N
O
O
COOH
HO
+
R
OAc
OAc
OH
HN
O2N
NO2
R
EDAC /
DMAP
N
N
N
N
N
N
M
N
R1
R = 3,5-di-t-butyl-Phenyl
OH
R3
R1
+
EDAC/ DMAP
R3
M
N
29
R2
R2
OAc
AcO
18 R1 = R2 = Phenyl, R3 = Hexyl; M = 2H
36 (81%)
37 (83%)
38 (81%)
34 (73%)
35 (86%)
19 R1 = R2 = 3-MeO-Phenyl, R3 = Hexyl; M = 2H
27 R1 = R2 = R3 = 3,5-di-t-butyl-Phenyl; M = Zn(II)
28 R1 = R2 = R3 = Phenyl; M = 2H
OAc
AcO
O
R
29 R1 = R2 = R3 = 3,5-di-t-butyl-Phenyl; M = 2H
O
NH
N
N
O
O
R
O
NO2
NO2
HN
COOH
O
R
44 (76%)
Scheme 6. Synthesis of porphyrin-linked glucose derivatives.
NO2
EDAC /
NH
N
NH
N
N
DMAP
R1
OH
R4
R1
R3
+
N
HN
HN
R2
J2¼2.0 Hz, 2H, phenyl-H), 7.64 (t, J¼8.3 Hz, 2H, phenyl-H), 7.79 (t,
J¼7.8 Hz, 4H, phenyl-H), 8.27 (d, J¼7.8 Hz, 2H, phenyl-H), 8.42 (d,
R2
39 R4 = Hexyl (81%)
40 R4 = 3-CO2-o-
nitrobenzylphenyl (63%)
22 R1 = R2 = Phenyl, R3 = Hexyl
27 R1 = R2 = 3,5-di-t-butyl-Phenyl,
J¼8.3 Hz, 2H, phenyl-H), 8.73 (d, J¼4.8 Hz, 2H,
b-H), 8.86 (d,
R
3 = 3-COOH -Phenyl
J¼4.9 Hz, 2H,
b
-H), 8.96 (d, J¼4.4 Hz, 2H, -H), 9.46 (d, J¼4.9 Hz, 2H,
b
b
-H); 13C NMR (100 MHz, CDCl3):
d
¼14.20, 22.75, 30.29, 31.94,
O2N
35.60, 38.94, 52.45, 55.54, 113.55, 117.75, 119.53, 120.46, 121.28,
127.49, 127.63, 127.98, 129.48, 134.60, 143.64, 147.01, 157.93,
O
O
167.40 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼419 (5.34), 516 (4.26),
COOH
551 (4.06), 593 (3.98), 650 (3.94); HRMS (ESþ) [C48H45N4O4]: calcd
for [MþH]þ 741.3441, found 741.3441.
NO2
EDAC /
DMAP
NH
N
N
NH
N
N
4.3.4. 5-(4-Methoxycarbonylphenyl)-10,20-diphenylporphyrin (9)
K3PO4 (1.57 g, 7.38 mmol), 5-bromo-10,20-diphenylporphyrin15a
(0.20 g, 0.37 mmol), 4-methoxy carbonylphenyl boronic acid (0.66 g,
3.69 mmol) and Pd(PPh3)4 (0.04 g, 0.04 mmol) were reacted in an-
hydrous THF (70 mL) according to method A (Section 4.3.1). The title
compound was purifed by column chromatography on silica gel with
n-hexane/dichloromethane (1:2, v/v) and yielded 0.22 g of 9
(0.13 mmol, 98%) as a purple solid: mp >310 ꢀC; Rf¼0.42 (SiO2,
R1
OH
R3
R1
R3
+
HN
HN
R2
R2
25 R1 = R2 = Phenyl, R3 = Hexyl
41 (81%)
42 (83%)
26 R1 = R2 = 3-MeO-Phenyl, R3 = Hexyl
O2N
CH2Cl2/C6H14, 2:1, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d¼ꢁ3.02 (s,
O
2H, NH), 4.11 (s, 3H, –OCH3), 7.77–7.80 (m, 6H, phenyl-H), 8.24 (dd,
J1¼2.3 Hz, J2¼1.8 Hz, 4H, phenyl-H), 8.31 (d, J¼8.2 Hz, 2H, phenyl-H),
R
R
COOH
O
8.42 (d, J¼4.7 Hz, 2H, phenyl-H), 8.42 (d, J¼4.7 Hz, 2H,
b-H), 8.92 (d,
NH
N
NH
N
N
NO2
J¼4.7 Hz, 2H,
-H), 10.20 (s, 1H, meso-H); 13C NMR (100 MHz, CDCl3):
52.02, 65.46, 104.75, 118.54, 119.44, 126.44, 127.37, 129.14, 130.62,
b-H), 9.03 (d, J¼4.7 Hz, 2H,
b-H), 9.32 (d, J¼4.7 Hz, 2H,
R
EDAC /
DMAP
R
R
R
N
HN
HN
OH
b
d¼14.86,
+
R
134.25,141.19,147.02,166.93 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼413
R
(5.57), 509 (4.04), 542 (3.60), 584 (3.64), 638 (3.30); HRMS (ESþ)
43 (68%)
24 R = 3,5-di-t-butyl-Phenyl
[C40H29N4O2]: calcd for [MþH]þ 597.2291, found 597.2285.
Scheme 5. Synthesis of nitrobenzyl porphyrins via EDAC-carbodiimide coupling
reactions.
4.3.5. 5,15-Bis(4-methoxycarbonylphenyl)-10,20-
(0.08 g, 0.07 mmol) were reacted in anhydrous THF (80 mL) fol-
lowing method A (Section 4.3.1). The title compound was purifed by
column chromatography on silica gel with n-hexane/dichloro-
methane (1:2, v/v) and yielded 8 (0.41 g, 0.30 mmol, 63%) as a pur-
ple solid: mp¼210 ꢀC; Rf¼0.36 (SiO2, EtOAc/n-hexane, 1:3, v/v); 1H
di-phenylporphyrin (10)
K3PO4 (2.74 g, 12.90 mmol), 5,15-dibromo-10,20-diphenylpor-
phyrin15a (0.20 g, 0.32 mmol), 4-methoxycarbonylphenylboronic
acid (1.16 g, 6.44 mmol) and Pd(PPh3)4 (0.07 g, 0.06 mmol) were
reacted in anhydrous THF (70 mL) following procedure A (Section
4.3.1). The crude mixture was purified by column chromatography
on silica gel with n-hexane/dichloromethane (1:1, v/v) and yielded
10 (0.24 g, 94%) as a purple solid: mp >310 ꢀC; Rf¼0.38 (SiO2,
NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.73 (s, 2H, NH), 0.92 (t, J¼7.4 Hz,
3H, –CH3), 1.36–1.42 (m, 2H, –CH2), 1.47–1.54 (m, 2H, –CH2), 1.76–
1.84 (m, 2H, –CH2), 2.50–2.58 (m, 2H, –CH2), 3.99 (s, 6H, –OCH3), 4.10
(s, 3H, –OCH3), 4.98 (t, J¼7.8 Hz, 2H, –CH2), 7.37 (dd, J1¼2.4 Hz,
CH2Cl2/C6H14,1:1 v/v); 1H NMR (400 MHz, CDCl3, TMS):
d¼ꢁ2.80 (s,

7070
M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
H3CO
R1
R1
NH
O
NO2
O
NO2
O
CHO
O
OH
N
NaBH4
H3CO
NH
N
N
EDAC/ DMAP
R3
O
O
R3
+
OH
O
NO2
N
HN
HN
O
O
R2
R2
H3CO
R1 = R2 = Phenyl, R3 = Hexyl 18
47 (83%)
45
46
Ph
Ph
N
Ni
R1
N
Ph
N
O
O
N
OH
Ph
O
NH
N
HO
O
O
N
N
N
EDAC/ DMAP
R3
47 +
OH
+
Ni
OH
Ph
140 °C
O
N
HN
R2
R1 = R2 = Phenyl, R3 = Hexyl 48 (92%)
N
O
R1
N
Ph
49
HN
NH
R2
N
50 (93%)
R3
Scheme 7. Ethylene glycol deprotection method.
H3CO
H3CO
R1
O
R1
Zn
O
O
O
NH N
N HN
N
N
N
O
Zn(OAc)2
O
R3
R3
O
NO2
O
NO2
TFA
N
R2
R2
51 (94%)
R1
R1 = R2 = Phenyl, R3 = Hexyl 47
H2N
N
HO
O
N
HN
NH N
N HN
H
R3
N
N
O
O
NO2
H
N
OH
O
R2
O
52 (71%)
Folic Acid, DCC
DMSO/Pyridine
R1
O
O
NH N
N HN
O
R3
O
NO2
R2
Scheme 8. Synthesis of porphyrin-linked folic acid.
2H, NH), 4.10 (s, 6H, –OCH3), 7.64 (d, J¼8.2 Hz, 6H, phenyl-H), 7.72–
7.78 (m, 4H, phenyl-H), 8.09 (d, J¼8.8 Hz, 2H, phenyl-H), 8.18 (d,
J¼7.6 Hz, 2H, phenyl-H), 8.31 (d, J¼8.2 Hz, 2H, phenyl-H), 8.42 (d,
2H, NH), 0.93 (t, J¼7.3 Hz, 3H, –CH3), 1.36–1.42 (m, 2H, –CH2), 1.47–
1.54 (m, 2H, –CH2),1.76–1.84 (m, 2H, –CH2), 2.50–2.58 (m, 2H, –CH2),
3.98 (s, 3H, –OCH3), 4.98 (t, J¼8.0 Hz, 2H, –CH2), 7.75–7.80 (m, 6H,
phenyl-H), 7.82 (t, J¼7.7 Hz, 1H, phenyl-H), 8.21 (d, J¼6.2 Hz, 4H,
phenyl-H), 8.37 (d, J¼7.7 Hz, 1H, phenyl-H), 8.46 (d, J¼7.7 Hz,
J¼7.6 Hz, 2H, phenyl-H), 8.80 (d, J¼4.7 Hz, 4H,
b
-H), 8.86 (d,
¼51.82, 118.51,
120.17, 126.33, 126.80, 127.49, 129.76, 134.13, 141.45, 143.88, 146.48,
J¼4.7 Hz, 4H,
b d
-H); 13C NMR (100 MHz, CDCl3):
1H, phenyl-H), 8.73 (d, J¼4.8 Hz, 2H,
H), 8.89 (s, 1H, phenyl-H), 8.92 (d, J¼4.8 Hz, 2H,
-H); 13C NMR (100 MHz, CDCl3):
d
b
-H), 8.82 (d, J¼4.4 Hz, 2H,
-H), 9.47 (d,
¼14.20, 22.75,
b-
166.37, 166.89 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼419 (5.43), 515
b
(4.04), 550 (3.62), 592 (3.45), 648 (3.45); HRMS (ESþ)
J¼4.8 Hz, 2H,
b
[C48H34N4O4]: calcd for [MþH]þ 731.2658, found 731.2620.
30.28, 31.93, 35.61, 38.93, 52.37,117.77,119.76,121.14,126.67,126.93,
127.74, 128.89, 128.99, 134.52, 134.90, 138.54, 142.36, 142.47,
4.3.6. 5-Hexyl-15-(3-methoxycarbonylphenyl)-10,20-
diphenylporphyrin (11)
167.39 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼418 (5.14), 516 (4.08),
551 (3.93), 593 (3.88), 651 (3.89); HRMS (ESþ) [C46H41N4O2]: calcd
K3PO4 (1.36 g, 6.39 mmol), 5-hexyl-15-bromo-10,20-diphe-
nylporphyrin 1 (0.20 g, 0.32 mmol), 3-methoxycarbonylphenylboronic
acid (0.58 g, 3.20 mmol), and Pd(PPh3)4 (0.03 g, 0.03 mmol) were
reacted in anhydrous THF (70 mL) according to method A (Section
4.3.1). The title compound was isolated by column chromatography
on silica gel with n-hexane/dichloromethane (1:1, v/v) to give 0.18 g
of 11 (0.12 mmol, 84%) as a purple solid: mp >310 ꢀC; Rf¼0.77 (SiO2,
for [MþH]þ 681.3230, found 681.3238.
4.3.7. 5,15-Bis(3-methoxycarbonylphenyl)-10,20-bis(3,5-di-tert-
butylphenyl)porphyrin (12)
K3PO4 (1.01 g, 4.74 mmol), 5,15-dibromo-10,20-bis(3,5-di-tert-
butylphenyl)-porphyrin15b (0.10 g, 0.12 mmol), 3-methoxycarbonyl-
phenylboronic acid (0.43 g, 2.47 mmol) and Pd(PPh3)4 (0.03 g,
0.02 mmol)wereheatedtorefluxinanhydrousTHF(50 mL)following
EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.71 (s,

M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
7071
method A (Section 4.3.1). The title compound was isolated by column
chromatography on silica gel with n-hexane/dichloromethane (1:2,
v/v) to yield 0.09 g of 12 (0.09 mmol, 77%) as a purple solid:
(dd, J1¼4.8 Hz, J2¼4.8 Hz, 4H,
b
-H), 9.40 (t, J¼4.4 Hz, 4H,
b
-H), 10.20
(d, J¼15.8 Hz,1H, ]CH); 13C NMR (100 MHz, CDCl3):
¼14.16, 22.71,
d
30.25, 31.89, 35.49, 38.81, 52.08, 111.19 m 120.59, 122.73, 130.31,
mp¼260 ꢀC; Rf¼0.56 (SiO2, CH2Cl2/C6H14
,
1:1, v/v); 1H NMR
142.18, 145.98, 166.86 ppm; UV–vis (CH2Cl2): lmax (log
3)¼426
(400 MHz, CDCl3, TMS):
d
¼ꢁ2.76 (s, 2H, NH), 1.51 (s, 36H, –(CH3)3),
(5.11), 526 (3.97), 565 (3.96), 600 (3.79), 654 (3.79); HRMS (ESþ)
3.96 (s, 6H, –OCH3), 7.79 (d, J¼8.8 Hz, 2H, phenyl-H), 7.83 (d, J¼7.6 Hz,
2H, phenyl-H), 8.06 (d, J¼1.8 Hz, 4H, phenyl-H), 8.39 (d, J¼7.6 Hz, 2H,
phenyl-H), 8.45 (d, J¼7.6 Hz, 2H, phenyl-H), 8.75 (d, J¼4.7 Hz, 4H,
[C42H39N4O2]: calcd for [MþH]þ 631.3073, found 631.3062.
4.3.11. 5-Hexyl-15-(2-methoxycarbonylethenyl)-10,20-bis-
(3-methoxyphenyl)porphyrin (15)
phenyl-H and
CDCl3):
126.39, 128.30, 128.56, 129.52, 134.33, 137.93, 140.50, 142.25, 148.37,
b
-H), 8.89 (d, J¼4.6 Hz, 6H,
b
-H); 13C NMR (100 MHz,
d
¼13.70, 22.26, 29.27, 31.39, 34.61, 51.91,118.11,120.68,121.44,
Methyl acrylate (0.66 mL, 7.26 mmol) was added to a solution of
5-bromo-15-hexyl-10,20-bis(3-methoxyphenyl)porphyrin 2 (0.10 g,
0.15 mmol), palladium acetate (6.59 mg, 0.03 mmol), di-tert-
butylbiphenylphosphine (22.42 mg, 0.08 mmol) and K2CO3
(24.85 mg, 0.18 mmol) in dry DMF (10 mL) and dry toluene (10 mL),
followed by heating for 15 h (see 4.3.9). The mixture was purifed by
column chromatography on silica gel with n-hexane/dichloro-
methane (1:4, v/v) and yielded 0.06 g (0.04 mmol, 55%) of 15 as
a purple solid: mp¼275 ꢀC; Rf¼0.65 (SiO2, EtOAc/C6H14,1:3, v/v); 1H
166.91 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼421 (5.20), 517 (3.86), 553
(3.68), 595 (3.64), 654 (3.90); HRMS (ESþ) [C64H66N4O4]: calcd for
[MþH]þ 955.5162, found 955.5205.
4.3.8. 2-(4-Methoxycarbonylphenyl)-5,10,15,20-tetrakis-(3,5-di-
tert-butylphenyl)porphyrin (13)
K3PO4 (0.37 g, 1.75 mmol), 2-bromo-5,10,15,20-tetrakis(3,5-di-
tert-butylphenyl)porphyrin
6
(0.10 g, 0.09 mmol), 4-methoxy-
NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.43 (s, 2H, NH), 0.96 (t, J¼7.6 Hz,
carbonylphenylboronic acid (0.16 g, 0.88 mmol) and Pd(PPh3)4
(0.01 g, 0.01 mmol) were reacted in anhydrous THF (50 mL)
according to method A (Section 4.3.1). The product was purifed by
column chromatography on silica gel with n-hexane/dichloro-
methane (1:1, v/v) to yield 0.04 g of 7 (0.05 mmol, 52%) as a purple
solid: mp >310 ꢀC; Rf¼0.57 (SiO2, EtOAc/C6H14, 1:5 v/v); 1H NMR
3H, –CH3), 1.34–1.40 (m, 2H, –CH2), 1.44–1.50 (m, 2H, –CH2), 1.73–
1.81 (m, 2H, –CH2), 2.45–2.53 (m, 2H, –CH2), 3.99 (s, 6H, –OCH3),
4.04 (s, 3H, –OCH3), 4.90 (t, J¼7.6 Hz, 2H, –CH2), 6.80 (d, J¼15.8 Hz,
1H, –CH]), 7.34 (dd, J1¼2.3 Hz, J2¼2.3 Hz, 2H, phenyl-H), 7.65 (t,
J¼8.2 Hz, 2H, phenyl-H), 7.77 (t, J¼7.6 Hz, 4H, phenyl-H), 8.89 (dd,
J1¼4.7 Hz, J2¼4.7 Hz, 4H,
b
-H), 9.39 (q, J¼4.7 Hz, 4H,
b-H), 10.21 (d,
(400 MHz, CDCl3, TMS):
d
¼ꢁ2.54 (s, 2H, NH),1.35 (s,18H, –C(CH3)3),
J¼15.8 Hz, 1H, ]CH); 13C NMR (100 MHz, CDCl3):
d¼13.73, 22.28,
1.53 (s, 54H, –C(CH3)3), 3.94 (s, 3H, –OCH3), 7.24 (s, 1H, phenyl-H),
7.47 (d, J¼8.0 Hz, 2H, phenyl-H), 7.80–7.82 (m, 7H, phenyl-H), 8.08
(dd, J1¼1.8 Hz, J1¼1.4 Hz, 4H, phenyl-H), 8.15 (d, J¼1.4 Hz, 2H, phe-
29.80, 31.45, 35.03, 38.37, 51.64, 55.09, 110.75, 113.17, 119.84, 119.98,
122.28, 129.85, 131.89, 143.04, 145.54, 157.50, 166.42 ppm; UV–vis
(CH2Cl2): lmax (log
3
)¼427 (5.23), 526 (4.01), 566 (4.00), 5.99 (3.79),
nyl-H), 8.71–8.75 (m, 2H,
(100 MHz, CDCl3):
121.29, 122.19, 127.01, 128.55, 129.77, 130.66, 140.20, 141.42, 141.59,
b-H), 8.87 (m, 5H,
b
-H); 13C NMR
657 (3.81); HRMS (ESþ) [C44H42N4O4]: calcd for [MþH]þ 691.3284,
d
¼29.73, 31.94, 35.06, 52.02, 53.44, 121.01,
found 691.3293.
148.64, 148.66, 167.15 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼426
4.3.12. Method C: condensation approach
(5.43), 5.22 (4.00), 559 (3.56), 598 (3.08), 655 (3.51); HRMS (ESþ)
To a mixture of aldehyde (4 equiv) and Zn(OAc)2 (1 equiv) in
propionic acid, pyrrole (4 equiv) was added at 100 ꢀC over the
course of 1 h under vigorous stirring. The resulting dark solution
was heated to reflux for further a 4 h and then cooled to room
temperature. The solvent was evaporated and the solid residue was
filtered through silica gel and all product containing fractions were
collected. The volume was reduced to 100 mL and pyridine and
excess DDQ were added. The resulting mixture was heated at reflux
for 1 h. The solution was cooled to room temperature and evapo-
rated to give a black-purple crude product followed by column
chromatography on silica gel.
[C84H100N4O2]: calcd for [MþH]þ 1197.7930, found 1197.7880.
4.3.9. Method B: Heck coupling approach
Bromoporphyrin (1 equiv), palladium acetate (0.2 equiv) di-tert-
butylbiphenylphosphine (0.5 equiv) and K2CO3 (1.2 equiv) were
added to a Schlenk tube and dried under vacuum. The vessel was
filled with argon, followed by addition of dry DMF, dry toluene, and
the vinyl reagent (50-fold excess). The mixture was then degassed
via three freeze-pump-thaw cycles before the vessel was purged
with argon again to ensure the reaction mixture was free of oxygen.
The Schlenk flask was sealed and heated to 105 ꢀC and the mixture
was stirred for 15 h. The progress of reaction was monitored by TLC
and, upon completion, the mixture was diluted with toluene and
washed with water. The organic layer was separated, dried over
MgSO4 and the residue was purified by column chromatography.
4.3.13. [5,10,15-Tris(3,5-di-tert-butylphenyl)-20-(4-
methoxycarbonylphenyl)porphyrinato]zinc(II) (17)
4-Carboxylmethylbenzaldehyde (0.25 g, 1.53 mmol), 3,5-di-
tert-butylbenzaldehyde (1.00 g, 4.58 mmol), Zn(OAc)2 (0.34 g,
1.53 mmol) and pyrrole (0.42 mL, 6.12 mmol) were reacted in
propionic acid (30 mL) following method C (Section 4.3.11). The
solution volume was reduced to 100 mL and pyridine (0.5 mL) and
DDQ (0.5 g) were added. The title compound was purifed by col-
umn chromatography on silica gel with n-hexane/dichloro-
methane (1:1 v/v) gave a red solid of 17 as the second fraction
4.3.10. 5-Hexyl-15-(2-methoxycarbonylethenyl)-10,20-
diphenylporphyrin (14)
Methyl acrylate (0.72 mL, 7.97 mmol) was added to the solution
of 5-bromo-15-hexyl-10,20-diphenylporphyrin 1 (0.10 g, 0.16 mmol),
palladium acetate (7.22 mg, 0.03 mmol), di-tert-butylbiphenyl-
phosphine (24.59 mg, 0.08 mmol) and K2CO3 (27.33 mg,
0.20 mmol) in dry DMF (10 mL) and dry toluene (10 mL), followed
by heating for 15 h (see Section 4.3.9). The title compound was
purifed by column chromatography on silica gel with n-hexane/
dichloromethane (1:2, v/v) and yielded 0.06 g (0.04 mmol, 60%)
of 14 as a purple solid: mp >310 ꢀC; Rf¼0.61 (SiO2, EtOAc/C6H14,1:3,
(0.16 g, 0.17 mmol, 10%): mp >310 ꢀC; Rf¼0.44 (SiO2, EtOAc/C6H14
,
1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼1.53 (s, 54H, –C-
(CH3)3), 4.03 (s, 3H, –OCH3), 7.80 (d, J¼1.76 Hz, 3H, phenyl-H), 8.10
(s, 6H, phenyl-H), 8.31 (d, J¼8.2 Hz, 2H, phenyl-H), 8.36 (d,
J¼8.2 Hz, 2H, phenyl-H), 8.89 (d, J¼4.7 Hz, 2H,
b
-H), 9.02 (d,
¼31.34, 34.62,
J¼5.3 Hz, 6H,
b d
-H); 13C NMR (100 MHz, CDCl3):
51.91, 118.69, 120.42, 122.22, 127.29, 128.71, 129.25, 130.83, 131.83,
131.98, 141.30, 147.59, 148.14, 149.03, 149.96, 150.16, 166.99 ppm;
v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.44 (s, 2H, NH), 0.90 (t,
J¼7.4 Hz, 3H, –CH3), 1.33–1.39 (m, 2H, –CH2), 1.46–1.49 (m, 2H,
–CH2),1.73–1.80 (m, 2H, –CH2), 2.45–2.53 (m, 2H, –CH2), 4.04 (s, 3H,
–OCH3), 4.91 (t, J¼7.7 Hz, 2H, –CH2), 6.79 (d, J¼15.8 Hz, 1H, –CH]),
7.73–7.80 (m, 6H, phenyl-H), 8.16 (d, J¼6.2 Hz, 4H, phenyl-H), 8.83
UV–vis (CH2Cl2): lmax (log
3
)¼423 (5.34), 549 (4.87), 589 (4.77);
HRMS (ESþ) [C70H78O2N4Zn]: calcd for [M] 1070.5416, found
1070.5425. The first fraction contained [5,10,15,20-tetrakis(3,5-di-

7072
M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
tert-butylphenyl) porphyrinato]zinc(II) 1634 (0.198 g, 0.22 mmol,
12%) as a red solid.
(0.11 g, 0.06 mmol, 77%): mp >310 ꢀC; Rf¼0.29 (SiO2, EtOAc/C6H14
,
1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ3.30 (s, 2H, NH),
7.54–7.72 (m, 6H, phenyl-H), 8.02–8.04 (m, 6H, phenyl-H), 8.17 (d,
J¼7.5 Hz, 2H, phenyl-H), 8.68 (d, J¼14.0 Hz, 4H, -H), 8.82 (s, 2H,
H), 9.17 (s, 2H,
-H), 10.05 (s, 1H, meso-H); 13C NMR (100 MHz,
CDCl3):
¼30.73, 31.44, 32.04, 97.03, 107.36, 109.48, 113.21, 118.70,
120.88, 122.17, 122.44, 129.86, 130.22, 133.87, 136.62, 144.02, 147.48,
4.4. Hydrolysis of porphyrin esters
b
b-
b
4.4.1. General method
d
A solution of porphyrin in THF, was mixed with ethanol and 2 M
NaOH and the suspension was heated to reflux (TLC monitor) before
being cooled to room temperature. The mixture was acidified with
aqueousHCl(1 M)andextractedwithchloroform. Theorganicextract
waswashed withsaturatedsodiumbicarbonateaqueous solutionand
dried over anhydrous sodium sulfate. The solvent was then removed
under reduced pressure before undergo further purification.
Spectroscopic data for porphyrin 21 in accordance with previous
literature.19b
175.96 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼413 (5.27), 509 (4.23),
542 (4.04), 582 (4.04), 636 (3.95); HRMS (ESþ) [C39H27N4O2]: calcd
for [MþH]þ 583.2134, found 583.2134.
4.4.5. 5-(3-Carboxyphenyl)-15-hexyl-10,20-diphenyl
porphyrin (22)
5-(3-Methoxycarbonylphenyl)-15-hexyl-10,20-diphenylporphyrin
11 (0.14 g, 0.21 mmol) was heated to reflux in THF (20 mL), ethanol
(30 mL) and 2 M NaOH (30 mL) for 2 h. Filtration through a plug of
silica gel eluting with (CH2Cl2/EtOAc¼5:1) followed by evaporation of
the solvent gave a purple solid of 22 (0.13 g, 0.09 mmol, 94%): mp
>310 ꢀC; Rf¼0.24 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz,
4.4.2. 5-(4-Carboxyphenyl)-15-hexyl-10,20-diphenyl
porphyrin (18)
5-(4-Methoxycarbonylphenyl)-15-hexyl-10,20-diphenyl-porphy-
rin 7 (0.10 g, 0.15 mmol) was heated to reflux in THF (20 mL), ethanol
(25 mL) and 2 M NaOH (50 mL) for 2 h. Filtration through a plug of
silica gel eluting with (CH2Cl2/EtOAc¼5:1) followed by evaporation of
the solvent gave a purple solid of 18 (0.09 g, 0.06 mmol, 93%): mp
>310 ꢀC; Rf¼0.24 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz,
CDCl3, TMS):
d
¼ꢁ2.78 (s, 2H, NH), 0.88 (t, J¼7.3 Hz, 3H, –CH3),1.31–1.34
(m, 2H, –CH2), 1.42–1.48 (m, 2H, –CH2), 1.73–1.79 (m, 2H, –CH2), 2.45–
2.53 (m, 2H, –CH2), 4.96 (t, J¼7.8 Hz, 2H, –CH2), 7.67–7.72 (m, 6H,
phenyl-H), 7.76 (t, J¼7.7 Hz, 1H, phenyl-H), 8.13 (d, J¼6.8 Hz, 4H, phe-
nyl-H), 8.27 (d, J¼6.8 Hz, 1H, phenyl-H), 8.49 (d, J¼7.8 Hz, 1H, phenyl-
CDCl3, TMS):
d
¼ꢁ2.67 (s, 2H, NH), 0.96 (t, J¼7.0 Hz, 3H, –CH3), 1.20–
H), 8.72 (d, J¼4.9 Hz, 4H,
b
-H), 8.85 (d, J¼4.9 Hz, 2H,
b-H), 8.93 (s, 1H,
1.24 (m, 2H, –CH2), 1.58–1.64 (m, 2H, –CH2), 1.74–1.80 (m, 2H, –CH2),
2.51–2.56 (m, 2H, –CH2), 5.17 (t, J¼8.2 Hz, 2H, –CH2), 7.85–80.00 (m,
6H, phenyl-H), 8.08 (d, J¼7.6 Hz, 4H, phenyl-H), 8.28 (d, J¼7.6 Hz, 2H,
phenyl-H), 9.43 (d, J¼4.9 Hz, 2H,
b
-H); 13C NMR (100 MHz, CDCl3):
d
¼13.67, 20.72, 22.24, 27.72, 31.43, 33.84, 35.11, 38.42, 65.93, 67.48,
117.88, 119.15, 120.44, 124.41, 125.04, 126.14, 127.19, 128.65, 134.01,
134.97, 137.58, 143.92, 144.32, 151.09, 168.86 ppm; UV–vis (CH2Cl2):
phenyl-H), 8.40(d, J¼7.6 Hz,4H, phenyl-H),8.52(d,J¼4.7 Hz,2H,
b
-H),
-H), 9.21 (d,
¼13.74, 22.29, 27.75,
8.87 (d, J¼4.7 Hz, 2H,
b
-H), 8.96 (d, J¼4.7 Hz, 2H,
b
lmax (log
3
)¼418 (5.31), 517 (4.30), 550 (4.18), 595 (4.00), 651 (4.00);
J¼4.7 Hz, 2H,
b
-H); 13C NMR (100 MHz, CDCl3):
d
HRMS (ESþ)[C45H39N4O2]: calcd for [MþH]þ 667.3073, found 667.3072.
29.03, 29.75, 31.46, 34.03, 34.85, 38.29, 99.86, 118.41, 119.68, 122.80,
125.13, 126.13, 127.30, 128.41, 130.92, 134.09, 135.11, 141.02, 143.86,
4.4.6. 5,15-Bis(3-carboxyphenyl)-10,20-bis(3,5-di-tert-
148.96 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼419 (5.26), 518 (4.60), 552
butylphenyl)porphyrin (23)
(4.54), 594 (4.49), 647 (4.47); HRMS (ESþ) [C45H39N4O2]: calcd for
5,15-Bis(3-methoxycarbonylphenyl)-10,20-bis(3,5-di-tert-butyl-
phenyl) porphyrin 12 (0.02 g, 0.02 mmol) was heated to reflux in
THF (10 mL), ethanol (20 mL) and 2 M NaOH (20 mL) for 5 h. Fil-
tration through a plug of silica gel eluting with (CH2Cl2/EtOAc¼5:1)
followed by evaporation of the solvent gave a purple solid of 23
(16.5 mg, 0.02 mmol, 89%): mp >310 ꢀC; Rf¼0.23 (SiO2, EtOAc/
[MþH]þ 667.3073, found 667.3068.
4.4.3. 5-(4-Carboxyphenyl)-15-hexyl-10,20-bis(3-methoxy-
phenyl)porphyrin (19)
5-(4-Methoxycarbonylphenyl)-15-hexyl-10,20-bis(3-methoxy-
phenyl)porphyrin 8 (0.18 g, 0.24 mmol) was heated to reflux in THF
(15 mL), ethanol (30 mL) and 2 M NaOH (30 mL) for 5 h. Filtration
through a plug of silica gel eluting with (CH2Cl2/EtOAc¼5:1) and
evaporation of the solvent gave a purple solid of 19 (0.16 g,
0.11 mmol, 93%): mp >310 ꢀC; Rf¼0.13 (SiO2, EtOAc/C6H14, 1:3, v/v);
C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.83 (s, 2H,
NH), 1.50 (s, 36H, –(CH3)3), 7.29 (s, 2H, phenyl-H), 7.90–7.95 (m, 6H,
phenyl-H), 8.04 (t, J¼4.0 Hz, 2H, phenyl-H), 8.44 (dd, J1¼1.5 Hz,
J2¼3.4 Hz, 4H, phenyl-H), 9.07 (d, J¼4.7 Hz, 4H,
b
-H), 9.37 (d,
¼31.30, 32.11,
44.65, 119.20, 123.74, 124.41, 126.65, 127.58, 128.40, 129.64, 132.20,
J¼4.6 Hz, 4H,
b d
-H); 13C NMR (100 MHz, CDCl3):
1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ3.07 (s, 2H, NH), 0.95 (t,
J¼7.4 Hz, 3H, –CH3), 1.34–1.38 (m, 2H, –CH2), 1.40–1.46 (m, 2H,
–CH2), 1.70–1.76 (m, 2H, –CH2), 2.38–2.47 (m, 2H, –CH2), 3.98 (s, 6H,
–OCH3), 5.00 (t, J¼7.8 Hz, 2H, –CH2), 7.37 (d, J¼7.8 Hz, 2H, phenyl-
H), 7.72 (t, J¼8.2 Hz, 2H, phenyl-H), 7.85 (t, J¼7.8 Hz, 4H, phenyl-H),
8.14 (d, J¼7.8 Hz, 2H, phenyl-H), 8.47 (d, J¼8.3 Hz, 2H, phenyl-H),
140.66,142.23, 149.45,165.85 ppm; UV–vis (CH2Cl2): lmax (log
3)¼408
(5.11), 503 (4.61), 573 (4.58), 598 (4.54), 652 (4.54); HRMS (ESþ)
[C62H63N4O4]: calcd for [MþH]þ 927.4849, found 927.4872.
4.4.7. 2-(4-Carboxyphenyl)-5,10,15,20-tetrakis(3,5-di-tert-
butylphenyl)porphyrin (24)
8.73 (d, J¼4.8 Hz, 2H,
J¼4.4 Hz, 2H, -H), 9.12 (d, J¼4.9 Hz, 2H,
CDCl3):
b-H), 8.86 (d, J¼4.9 Hz, 2H,
b-H), 8.90 (d,
b
b
-H); 13C NMR (100 MHz,
2-(4-Methoxycar-bonylphenyl)-5,10,15,20-tetrakis(3,5-di-tert-butyl-
phenyl)-porphyrin 13 (0.03 g, 0.03 mmol) was heated to reflux in THF
(5 mL), ethanol (10 mL) and 2 M NaOH (10 mL) for 5 h. Filtration
through a plug of silica gel eluting with CH2Cl2 followed by evap-
oration of the solvent gave a purple solid of 24 (0.03 g, 0.03 mmol,
82%): mp >310 ꢀC; Rf¼0.28 (SiO2, EtOAc/C6H14, 1:5, v/v); 1H NMR
d
¼14.22, 21.29, 22.76, 25.66, 29.52, 30.42, 31.90, 34.33,
38.80, 54.47, 68.08, 112.45, 118.58, 119.61, 125.62, 126.27, 126.57,
128.13, 134.69, 135.87, 142.77, 144.64, 151.62, 156.87, 176.39 ppm;
UV–vis (CH2Cl2): lmax (log
3
)¼420 (5.27), 516 (4.35), 551 (4.13), 593
(4.08), 648 (4.08); HRMS (ESþ) [C47H43N4O4]: calcd for [MþH]þ
727.3284, found 727.3256.
(400 MHz, CDCl3, TMS):
d
¼ꢁ2.77 (s, 2H, NH), 1.22 (s, 48H,
–C(CH3)3), 1.22 (s, 24H, –C(CH3)3), 7.52 (s, 2H, phenyl-H), 7.79 (s, 1H,
phenyl-H), 7.89 (s, 5H, phenyl-H), 8.06 (s, 2H, phenyl-H), 8.42 (br s,
2H, phenyl-H), 8.73 (d, J¼1.8 Hz, 2H, phenyl-H), 8.81 (d, J¼1.8 Hz,
4.4.4. 5-(4-Carboxyphenyl)-10,20-diphenylporphyrin (20)
5-(4-Methoxycarbonylphenyl)-10,20-diphenylpor-phyrin 9 (0.15 g,
0.09 mmol) was heated to reflux in THF, ethanol (40 mL) and 2 M
NaOH (95 mL) for 11 h. Filtration through a plug of silica gel eluting
with (CH2Cl2/EtOAc¼5:1) and evaporation of the solvent followed
by recrystallization from MeOH/H2O gave a purple solid of 20
2H, phenyl-H), 8.85 (d, J¼4.8 Hz, 5H,
b-H), 8.95 (s, 2H, b
-H); 13C
NMR (100 MHz, CDCl3):
121.50, 122.19, 127.01, 128.55, 129.77, 130.65, 141.59, 148.67,
167.15 ppm; UV–vis (CH2Cl2): lmax (log
)¼426 (5.25), 523 (4.20),
d¼29.73, 31.94, 35.06, 52.02, 53.46, 121.01,
3

M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
7073
560 (4.04), 598 (3.90), 653 (3.95); HRMS (ESþ) [C83H98N4O2]: calcd
nitrobenzylalcohol in THF was added at room temperature. The
mixture was heated to reflux for 18 h and diluted with THF before
being extracted with a solution of aq NH4Cl. The organic solvent
was washed with brine and dried over Na2SO4 followed by evap-
oration of the solvent under reduced pressure and purification by
column chromatography.
for [MþH]þ 1183.7768, found 1183.7727.
4.4.8. 5-(2-Carboxyethenyl)-15-hexyl-10,20-diphenylpor-
phyrin (25)
5-Hexyl-15-(2-methoxycarbonylethenyl)-10,20-diphenylporphyrin
14 (0.03 g, 0.02 mmol) was heated to reflux in THF (5 mL), ethanol
(10 mL) and 2 M NaOH (10 mL) for 3 h. Filtration through a plug of
silica gel eluting with (CH2Cl2/EtOAc¼5:1) followed by evaporation
of the solvent gave a purple solid of 25 (0.03 g, 0.02 mmol, 93%): mp
>310 ꢀC; Rf¼0.19 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz,
4.5.2. 5-(4-Dicyclohexylureacarbonylphenyl)-15-hexyl-10,20-
diphenylporphyrin (30)
5-(4-Carboxyphenyl)-15-hexyl-10,20-diphenylporphyrin18 (0.03 g,
0.04 mmol), DCC (9.3 mg, 0.04 mmol), DMAP (4.84 mg, 0.04 mmol)
and 2-nitrobenzylalcohol (34.4 mg, 0.03 mmol) were heated to
reflux for 18 h in THF (10 mL) according to method A (Section 4.5.1).
Purification on silica gel (n-hexane/dichloromethane¼1:2, v/v)
yielded the intermediate product of title compound as a purple solid
CDCl3, TMS):
d
¼ꢁ2.40 (s, 2H, NH), 0.93 (t, J¼7.4 Hz, 3H, –CH3), 1.35–
1.38 (m, 2H, –CH2),1.40–1.55 (m, 2H, –CH2),1.70–1.79 (m, 2H, –CH2),
2.14–2.50 (m, 2H, –CH2), 5.09 (t, J¼7.7 Hz, 2H, –CH2), 6.83 (d,
J¼15.8 Hz, 1H, –CH]), 7.90–7.94 (m, 6H, phenyl-H), 8.26
(d, J¼6.2 Hz, 4H, phenyl-H), 8.80 (d, J¼4.7 Hz, 4H,
b
-H), 8.96 (d,
-H),10.16 (d, J¼15.8 Hz,1H,
¼13.65, 22.20, 24.19, 29.21,
29.73, 31.33, 38.28, 55.02, 94.26, 106.61, 126.31, 127.60, 127.99,
(11.7 mg, 0.01 mmol, 30%): mp >310 ꢀC; Rf¼0.37 (SiO2, EtOAc/C6H14
,
J¼5.3 Hz, 2H,
b
-H), 9.71 (t, J¼4.4 Hz, 2H,
b
1:3, v/v); 1HNMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.71 (s, 2H, NH), 0.89–
]CH); 13C NMR (100 MHz, CDCl3):
d
0.93 (m, 2H, –CH2), 0.96 (t, J¼14.6 Hz, 3H, –CH3), 1.16–1.20 (m, 2H,
–CH2), 1.38–1.45 (m, 4H, –CH2), 1.51–1.56 (m, 2H, –CH2), 1.61–1.65
(m, 2H, –CH2), 1.73–1.78 (m, 4H, –CH2), 1.84 (t, J¼15.2 Hz, 2H, –CH2),
1.92–1.94 (m, 4H, –CH2), 2.05–2.07 (m, 2H, –CH2), 2.16–2.25 (m, 2H,
–CH2), 2.54–2.61 (m, 2H, –CH2), 3.71–3.78 (m,1H, –N–CH), 4.38–4.45
(m,1H, –CON–CH), 5.04 (t, J¼8.2 Hz, 2H, –CH2), 6.31 (d, J¼7.0 Hz,1H,
–NH), 7.81 (t, J¼7.6 Hz, 6H, phenyl-H), 7.98 (d, J¼7.6 Hz, 2H, phenyl-
H), 8.24 (d, 4H, J¼6.4 Hz, phenyl-H), 8.28 (d, J¼7.6 Hz, 2H, phenyl-H),
128.58, 133.66, 141.27 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼426
(5.26), 527 (3.78), 569 (3.86), 601 (3.30), 654 (3.48); HRMS (ESþ)
[C41H37N4O2]: calcd for [MþH]þ 617.2917, found 617.2901.
4.4.9. 5-(2-Carboxyethenyl)-15-hexyl-10,20-bis(3-methoxy-
phenyl)porphyrin (26)
5-Hexyl-15-(2-methoxycarbonylethenyl)-10,20-bis(3-methoxy-
phenyl)porphyrin 15 (0.06 g, 0.08 mmol) was heated to reflux inTHF
(5 mL), ethanol (10 mL) and 2 M NaOH (10 mL) for 3 h. Filtration
through a plug of silica gel eluting with (CH2Cl2/EtOAc¼5:1) followed
by evaporation of the solvent gave a purple solid of 26 (0.05 g,
0.03 mmol, 88%): mp¼197 ꢀC; Rf¼0.19 (SiO2, EtOAc/C6H14, 1:3, v/v);
8.76 (d, J¼4.7 Hz, 2H,
J¼4.7 Hz, 2H, -H), 9.52 (d, J¼4.7 Hz, 2H,
CDCl3):
¼13.73, 22.29, 24.19, 25.98, 30.47, 31.47, 35.16, 38.50, 49.49,
57.07, 62.05, 119.35, 120.82, 124.86, 126.23, 127.31, 134.04, 141.85,
b
-H), 8.84 (d, J¼4.7 Hz, 2H,
b-H), 8.95 (d,
b
b
-H); 13C NMR (100 MHz,
d
144.44, 154.05 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼419 (5.31), 517
(3.94), 551 (3.64), 594 (4.51), 653 (3.75); HRMS (ESþ) [C58H61N6O2]:
1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.43 (s, 2H, NH), 0.98 (t,
calcd for [MþH]þ 873.4856, found 873.4874.
J¼7.6 Hz, 3H, –CH3),1.27–1.33 (m, 2H, –CH2),1.55–1.60 (m, 2H, –CH2),
1.84–1.88 (m, 2H, –CH2), 2.52 (m, 2H, –CH2), 4.06 (s, 6H, –OCH3), 5.12
(t, J¼7.6 Hz, 2H, –CH2), 6.85 (d, J¼15.8 Hz, 1H, –CH]), 7.48(d, J¼8.2 Hz,
2H, phenyl-H), 7.75 (t, J¼8.2 Hz, 2H, phenyl-H), 7.84 (t, J¼7.6 Hz, 4H,
4.5.3. 5-(4-Dicyclohexylureacarbonylphenyl)-10,20-di-
phenylporphyrin (31)
5-(4-Carboxyphenyl)-10,20-diphenylporphyrin 19 (0.05 g, 0.09
mmol), DCC (17.7 mg, 0.09 mmol), DMAP (9.25 mg, 0.09 mmol) and
2-nitrobenzylalcohol (65.6 mg, 0.43 mmol) wereheatedtoreflux for
18 h in THF (10 mL) according to method A (Section 4.5.1). Purifi-
cation on silica gel (n-hexane/dichloromethane¼1:2, v/v) yielded
the intermediate product of 31 as a purple solid (26.4 mg,
0.02 mmol, 39%): mp >310 ꢀC; Rf¼0.32 (SiO2, EtOAc/C6H14, 1:3,
phenyl-H), 8.94(d,J¼13.4 Hz, 4H,
b
-H), 9.72 (d, J¼4.7 Hz, 2H,
b-H), 9.91
(d, J¼4.7 Hz, 2H,
b
-H), 10.20 (d, J¼15.8 Hz, 1H, ]CH); 13C NMR
(100 MHz, CDCl3):
d¼14.17, 21.25, 22.72, 25.63, 29.47, 31.80, 34.28,
38.67, 54.39, 55.56, 67.99,112.28,118.90,119.78,120.45,126.77,128.30,
135.81, 142.64, 143.25, 151.57, 156.81 ppm; UV–vis (CH2Cl2): lmax
(log
3
)¼427 (5.33), 525 (4.32), 571 (4.32), 599 (4.18), 654 (4.15); HRMS
(ESþ) [C43H41N4O4]: calcd for [MþH]þ 677.3128, found 677.3121.
v/v); 1H NMR (400 MHz, CDCl3, TMS):
d¼ꢁ3.01 (s, 2H, NH),
0.87–0.92 (m, 2H, –CH2), 1.13–1.21 (m, 2H, –CH2), 1.37–1.47 (m,
4H, –CH2), 1.59–1.67 (m, 2H, –CH2), 1.74–1.77 (m, 2H, –CH2),
1.89–1.95 (m, 4H, –CH2), 2.04–2.07 (m, 2H, –CH2), 2.15–2.24 (m,
2H, –CH2), 3.71–3.75 (m, 1H, –N–CH), 4.39–4.45 (m, 1H, –CON–
CH), 6.33 (d, J¼7.0 Hz, 1H, –NH), 7.79 (t, J¼7.6 Hz, 6H, phenyl-H),
7.97 (d, J¼7.6 Hz, 2H, phenyl-H), 8.24 (d, 4H, J¼6.4 Hz, phenyl-
4.4.10. [5-(4-Carboxyphenyl)-10,15,20-tris(3,5-di-tert-
butylphenyl)porphyrinato]zinc(II) (27)
[5,10,15-Tris(3,5-di-tert-butylphenyl)-20(4-methoxycarbonyl-phenyl)-
porphyrinato]zinc(II) 17 (0.12 g, 0.13 mmol) was heated to reflux in
THF (5 mL), ethanol (20 mL) and 2 M NaOH (20 mL) for 5 h. Filtra-
tion through a plug of silica gel eluting with CH2Cl2 followed by
evaporation of the solvent yielded a purple solid of 27 (0.10 g,
0.10 mmol, 82%): mp >310 ꢀC; Rf¼0.32 (SiO2, EtOAc/C6H14,1:3, v/v);
H), 8.28 (d, J¼7.6 Hz, 2H, phenyl-H), 8.82 (d, J¼4.7 Hz, 2H,
8.92 (d, J¼4.7 Hz, 2H, -H), 9.02 (d, J¼4.7 Hz, 2H, -H), 9.31 (d,
J¼4.7 Hz, 2H,
-H), 10.19 (s, 1H, meso-H); 13C NMR (100 MHz,
CDCl3):
¼24.48, 26.01, 29.31, 30.51, 32.25, 57.07, 104.77, 118.46,
119.45, 124.77, 126.47, 127.40, 134.27, 135.93, 141.20, 144.92,
154.08, 167.36, 170.77 ppm; UV–vis (CH2Cl2): lmax (log
b-H),
b
b
b
1H NMR (400 MHz, CDCl3, TMS):
18H, –C(CH3)3), 7.68 (s, 1H, phenyl-H), 7.78 (s, 2H, phenyl-H), 8.01
(s, 4H, phenyl-H), 8.08 (s, 2H, phenyl-H), 8.44 (s, 2H, phenyl-H), 8.97
d
¼1.40 (s, 36H, –C(CH3)3), 1.52 (s,
d
3)¼413
(s, 2H, phenyl-H), 8.97 (s, 8H,
b
-H); 13C NMR (100 MHz, CDCl3):
(5.29), 509 (3.87), 542 (3.04), 586 (3.11), 654 (2.90); HRMS
d
¼31.23, 34.49, 120.22, 122.07, 128.14, 129.18, 131.08, 131.70, 134.06,
(ESþ) [C52H49N6O2]: calcd for [MþH]þ 789.3917, found 789.3934.
141.30, 147.98, 149.23, 149.87, 149.92 ppm; UV–vis (CH2Cl2): lmax
(log
3
)¼423 (5.11), 551 (4.86), 589 (4.78); HRMS (ESþ)
4.5.4. 5-(4-(o-Nitrobenzylcarboxy)phenyl)-10,15,20-
triphenylporphyrin (34)
[C69H77N4O2Zn]: calcd for [MþH]þ 1056.526, found 1056.530.
5-(4-Carboxyphenyl)-10,15,20-triphenylporphyrin21c (0.02 g, 0.03
mmol), DCC (34.88 mg, 0.15 mmol), DMAP (18.15 mg, 0.15 mmol) and
2-nitrobenzylalcohol (0.17 g, 0.15 mmol) were heated to reflux for
18 h in THF (10 mL) according to method A (Section 4.5.1). The crude
product was purified on silica gel (n-hexane/dichloromethane¼2:1,
v/v) and the first fraction corresponds to the title compound of 5-(4-
4.5. Esterification of carboxylic acid porphyrins
4.5.1. Method A: DCC carbodiimide reagent approach
To a solution of porphyrin, N,N-dicyclohexylcarbodiimide (DCC)
and dimethylamino-pyridine (DMAP) in dry THF, a solution of 2-

7074
M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
(o-nitrobenzyl carboxy)phenyl)-10,15,20-triphenylporphyrin 34 as
a purple solid (6.6 mg, 0.01 mmol, 27%): mp >310 ꢀC; Rf¼0.69 (SiO2,
J¼7.0 Hz, 2H, phenyl-H), 8.12 (dd, J1¼1.8 Hz, J2¼1.8 Hz, 6H, phenyl-
H), 8.34 (d, J¼7.0 Hz, 2H, phenyl-H), 8.82 (d, 2H, -H), 8.95 (s, 6H,
H); 13C NMR (100 MHz, CDCl3):
34.61, 62.10, 117.43, 120.58, 121.18, 124.57, 128.04, 129.47, 133.69,
136.33, 140.67, 148.32, 154.08, 165.73 ppm; UV–vis (CH2Cl2): lmax
b
b-
EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d¼ꢁ2.80 (s,
d
¼24.30, 25.96, 29.27, 31.30, 32.28,
2H, NH), 5.95 (s, 2H, –OCH2), 7.55 (t, J¼8.2 Hz, 1H, phenyl-H), 7.72 (d,
J¼2.8 Hz, 1H, phenyl-H), 7.76 (t, J¼7.3 Hz, 9H, phenyl-H), 7.86 (d,
J¼7.0 Hz, 1H, phenyl-H), 8.18 (s, 1H, phenyl-H), 8.19–8.21 (m, 6H,
phenyl-H), 8.32 (d, J¼8.2 Hz, 2H, phenyl-H), 8.47 (d, J¼8.2 Hz, 2H,
(log
3
)¼421 (5.33), 518 (3.64), 554 (3.20), 596 (2.60), 655 (3.64);
HRMS (ESþ) [C82H101N6O2]: calcd for [MþH]þ 1201.799, found
1201.804. Alternatively compound 35 was prepared via method B
(Section 4.5.6). 5-(4-Carboxyphenyl)-10,15,20-tris(3,5-di-tert-butyl-
phenyl)porphyrin21d (0.02 g, 0.02 mmol), EDAC (7.66 mg,
0.04 mmol), DMAP (4.88 mg, 0.04 mmol) and 2-nitrobenzylalcohol
(12.4 mg, 0.08 mmol) were stirred for 18 h in DCM (10 mL)
according to method B (Section 4.5.6). Purification on silica gel (n-
hexane/dichloromethane¼1:2, v/v) yielded 35 as a purple solid
(19.5 mg, 0.02 mmol, 86%).
phenyl-H), 8.79 (d, J¼4.7 Hz, 2H,
NMR (100 MHz, CDCl3):
119.97, 124.79, 126.29, 127.67, 131.93, 133.49, 134.11, 141.57, 147.17,
b
-H), 8.84 (t, J¼5.2 Hz, 6H,
b C
-H); 13
d
¼13.70, 22.27, 29.27, 31.49, 63.25, 117.84,
147.28, 165.73 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼419 (5.15), 516
(4.59), 551 (4.51), 597 (4.48), 649 (4.54); HRMS (ESþ) [C52H36N5O4]:
calcd for [MþH]þ 794.2767, found 794.2781. The second fraction
corresponds to the intermediate product of 5-(4-dicyclohexylurea-
carbonylphenyl)-10,15,20-triphenyl porphyrin 32 as a purple solid
(13.7 mg, 0.12 mmol, 52%): mp >310 ꢀC; Rf¼0.52 (SiO2, EtOAc/C6H14
,
1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.83 (s, 2H, NH), 0.82–
4.5.6. Method B: EDAC carbodiimide reagent approach
0.88 (m, 2H, –CH2), 1.13–1.19 (m, 2H, –CH2), 1.34–1.43 (m, 4H, –CH2),
1.58–1.64 (m, 2H, –CH2), 1.67–1.75 (m, 2H, –CH2), 1.83–1.90 (m, 4H,
–CH2), 1.98–2.03 (m, 2H, –CH2), 2.11–2.18 (m, 2H, –CH2), 3.67–3.75
(m, 1H, –N–CH), 4.34–4.40 (m, 1H, CON–CH), 6.30 (d, 1H, –NH), 7.75
(d, J¼6.4 Hz, 9H, phenyl-H), 7.95 (d, J¼7.0 Hz, 2H, phenyl-H), 8.20 (d,
6H, J¼7.0 Hz, phenyl-H), 8.26 (d, J¼7.0 Hz, 2H, phenyl-H), 8.77 (s, 2H,
To a solution of porphyrin (1 equiv), 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride (EDAC) (2 equiv) and
dimethylaminopyridine, (DMAP) (2 equiv) in dry DCM, a solution of
2-nitrobenzylalcohol (4 equiv) in DCM were added at rt. The mix-
ture was stirred at rt for 18 h. Upon completion, the solution was
diluted with DCM and extracted with a solution of aqueous NH4Cl.
The mixture was washed with brine and dried over Na2SO4, fol-
lowed by evaporation of the solvent to give the crude product and
purification by column chromatography.
b-H), 8.83 (s, 6H,
b
-H); 13C NMR (100 MHz, CDCl3):
d¼29.27, 32.21,
62.09, 124.57, 126.30, 127.37, 128.04, 129.51, 133.69, 134.12, 141.57,
167.54 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼418 (5.16), 515 (3.95), 550
(3.75), 0.022 (3.64), 0.026 (3.72); HRMS (ESþ) [C58H53N6O2]: calcd for
[MþH]þ 865.423, found 865.4211. Alternatively compound 34 was
4.5.7. 5-Hexyl-15-(4-(o-nitrobenzylcarboxy)phenyl)-10,20-
diphenylporphyrin (36)
prepared via method
B (Section 4.5.6). 5-(4-Carboxyphenyl)-
10,15,20-triphenylporphyrin 28 (0.02 g, 0.03 mmol), EDAC (5.83 mg,
0.03 mmol), DMAP (3.71 mg, 0.03 mmol) and 2-nitrobenzylalcohol
(4.66 mg, 0.03 mmol) were stirred for 18 h in DCM (10 mL) at rt.
Purification on silica gel (n-hexane/dichloromethane¼1:2, v/v)
yielded 34 as a purple solid (17.6 mg, 0.01 mmol, 73%).
5-Hexyl-15-(4-carboxyphenyl)-10,20-diphenylporphyrin 18 (0.02 g,
0.03 mmol), EDAC (11.5 mg, 0.06 mmol), DMAP (7.31 mg,
0.06 mmol) and 2-nitrobenzylalcohol (18.6 mg, 0.12 mmol) were
stirred for 18 h in DCM (10 mL) at rt according to method B (Section
4.5.6). Purification on silica gel (n-hexane/dichloromethane¼1:2,
v/v) yielded 36 as a purple solid (13.0 mg, 0.01 mmol, 81%): mp
>310 ꢀC; Rf¼0.75 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz,
4.5.5. 5,10,15-Tris(3,5-di-tert-butylphenyl)-20-(4-(o-nitrobenzyl-
carboxy)phenyl)porphyrin (35)
CDCl3, TMS):
d¼ꢁ2.75 (s, 2H, NH), 0.92 (t, J¼7.3 Hz, 3H, –CH3), 1.39–
5-(4-Carboxyphenyl)-10,15,20-tris(3,5-di-tert-butylphenyl)por-
phyrin21d (0.02 g, 0.02 mmol), DCC (23.25 mg, 0.10 mmol), DMAP
(12.10 mg, 0.10 mmol) and 2-nitrobenzylalcohol (0.11 g, 0.10 mmol)
were heated to reflux for 18 h in THF (10 mL) according to method
A (Section 4.5.1). The crude product was purified on silica gel
(n-hexane/dichloromethane¼2:1, v/v) and the first fraction corre-
sponds to the title compound 35 as purple solid (8.6 mg, 0.01 mmol
38%): mp >310 ꢀC; Rf¼0.48 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR
1.41 (m, 2H, –CH2), 1.45–1.47 (m, 2H, –CH2), 1.74–1.82 (m, 2H, –CH2),
2.50–2.65 (m, 2H, –CH2), 5.01 (t, J¼8.0 Hz, 2H, –CH2), 5.95 (s, 2H,
–OCH2), 7.50 (t, J¼8.2 Hz, 1H, phenyl-H), 7.56 (d, J¼2.8 Hz, 1H,
phenyl-H), 7.72–7.76 (m, J¼7.3 Hz, 6H, phenyl-H), 7.86 (d, J¼7.0 Hz,
1H, phenyl-H), 8.18 (dd, J1¼1.8 Hz, J2¼1.1 Hz, 4H, phenyl-H), 8.24 (s,
1H, phenyl-H), 8.29 (d, J¼8.4 Hz, 2H, phenyl-H), 8.45 (d, J¼8.4 Hz,
2H, phenyl-H), 8.72 (d, J¼4.8 Hz, 2H,
H), 8.89 (d, J¼4.8 Hz, 2H, -H), 9.48 (d, J¼4.8 Hz, 2H,
(100 MHz, CDCl3):
b
-H), 8.79 (d, J¼4.8 Hz, 2H,
b-
b
b
-H); 13C NMR
(400 MHz, CDCl3, TMS):
d¼ꢁ2.71 (s, 2H, NH), 1.52 (s, 54H,
d
¼14.14, 22.71, 29.38, 30.05, 30.28, 31.46, 31.95,
–C(CH3)3), 5.96 (s, 2H, –OCH2), 7.55 (t, J¼7.6 Hz, 1H, phenyl-H), 7.73
(d, J¼8.1 Hz, 1H, phenyl-H), 7.76 (s, 3H, phenyl-H), 7.86 (d, J¼7.9 Hz,
1H, phenyl-H), 8.08 (t, J¼7.9 Hz, 6H, phenyl-H), 8.20 (d, J¼8.1 Hz,
1H, phenyl-H), 8.35 (d, J¼8.2 Hz, 2H, phenyl-H), 8.48 (d, J¼8.2 Hz,
34.96, 63.68, 124.18, 124.40, 125.25, 126.66, 127.76, 127.97, 128.85,
128.93, 129.16, 130.93, 133.94, 134.74, 142.28, 151.22, 151.85 ppm;
UV–vis (CH2Cl2): lmax (log
3
)¼419 (5.48), 516 (4.48), 551 (4.37), 592
(4.33), 651 (4.29); HRMS (ESþ) [C52H44N5O4]: calcd for [MþH]þ
2H, phenyl-H), 8.79 (d, J¼4.7 Hz, 2H,
NMR (100 MHz, CDCl3):
120.62, 121.22, 127.63, 128.66, 129.40, 134.25, 140.68, 148.32,
165.79 ppm; UV–vis (CH2Cl2): lmax (log
b-H), 8.91 (s, 6H,
b
-H); 13C
802.3393, found 802.3401.
d¼13.72, 22.28, 29.28, 31.30, 34.61, 63.23,
4.5.8. 5-Hexyl-10,20-bis(3-methoxyphenyl)-15-(4-
(o-nitrobenzylcarboxy)phenyl)-porphyrin (37)
3
)¼422 (5.16), 518 (4.66),
571 (4.65), 599 (4.61), 651 (4.65); HRMS (ESþ) [C76H84N5O4]: calcd
for [MþH]þ 1130.6523, found 1130.6526. The second fraction cor-
responds to the intermediate product of 5-(4-di-cyclohexylurea-
carbonyl phenyl)-10,15,20-tris(3,5-di-tert-butylphenyl) porphyrin
33 as a purple solid (10.3 mg, 0.01 mmol, 43%): mp >310 ꢀC;
Rf¼0.46 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3,
5-(3-carboxyphenyl)-15-hexyl-10,20-bis(3-methoxyphenyl)-
porphyrin 19 (0.02 g, 0.03 mmol), EDAC (10.54 mg, 0.06 mmol),
DMAP (6.71 mg, 0.06 mmol) and 2-nitrobenzylalcohol (17.06 mg,
0.11 mmol) were stirred for 18 h in DCM (10 mL) at rt according to
method B (Section 4.5.6). Purification on silica gel (n-hexane/
dichloromethane¼1:1, v/v) yielded 37 as a purple solid (19.6 mg,
0.02 mmol, 83%): mp¼227 ꢀC; Rf¼0.38 (SiO2, EtOAc/C6H14,1:3, v/v);
TMS):
d
¼ꢁ2.69 (s, 2H, NH), 0.87–0.95 (m, 2H, –CH2), 1.15–1.20 (m,
2H, –CH2), 1.41–1.46 (m, 4H, –CH2), 1.52 (s, 54H, –C(CH3)3), 1.79–
1.82 (m, 2H, –CH2), 1.94–1.98 (m, 4H, –CH2), 2.05–2.08 (m, 2H,
–CH2), 2.15–2.24 (m, 2H, –CH2), 2.52–2.58 (m, 2H, –CH2), 3.74 (d,
J¼7.6 Hz, 1H, –N–CH), 4.45 (t, J¼11.7 Hz, 1H, CON–CH), 6.23
(d, J¼6.4 Hz, 1H, –NH), 7.85 (d, J¼1.8 Hz, 3H, phenyl-H), 8.00 (d,
1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.84 (s, 2H, NH), 0.92 (t,
J¼7.3 Hz, 3H, –CH3), 1.36–1.39 (m, 2H, –CH2), 1.49–1.52 (m, 2H,
–CH2), 1.57–1.62 (m, 2H, –CH2), 1.77–1.85 (m, 2H, –CH2), 3.98 (s, 6H,
–OCH3), 4.99 (t, J¼7.7 Hz, 2H, –CH2), 5.93 (s, 2H, –OCH2), 7.33 (d,
J¼8.1 Hz, 2H, phenyl-H), 7.53 (t, J¼7.7 Hz, 1H, phenyl-H), 7.58 (t,

M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
7075
J¼8.0 Hz, 2H, phenyl-H), 7.72 (t, J¼7.36 Hz, 1H, phenyl-H), 7.78 (t,
J¼7.7 Hz, 4H, phenyl-H), 7.83 (d, J¼7.7 Hz, 1H, phenyl-H), 8.17 (d,
J¼8.1 Hz, 1H, phenyl-H), 8.29 (d, J¼8.4 Hz, 2H, phenyl-H), 8.46 (d,
0.23 mmol) were stirred for 18 h in DCM (10 mL) according to
method B (Section 4.5.6). Purification on silica gel (n-hexane/
dichloromethane¼1:1, v/v) yielded the title compound 40 as
a purple solid (8.30 mg, 0.01 mmol, 58%): mp >310 ꢀC; Rf¼0.48
(SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
J¼8.4 Hz, 2H, phenyl-H), 8.73 (d, J¼4.8 Hz, 2H,
b
-H), 8.85 (d,
-H), 9.46 (d, J¼4.8 Hz, 2H,
¼14.18, 22.74, 29.72, 30.33,
J¼4.8 Hz, 2H,
b
-H), 8.95 (d, J¼4.8 Hz, 2H,
b
b
-H); 13C NMR (100 MHz, CDCl3):
d
d
¼ꢁ2.76 (s, 2H, NH), 1.51 (s, 36H, –C(CH3)3), 5.85 (s, 4H, –OCH2),
31.93, 35.62, 38.96, 55.55, 62.42, 63.69, 113.56, 117.52, 119.58,
120.50, 121.37, 124.96, 127.51, 128.41, 128.94, 129.81, 132.37, 133.94,
134.76, 136.82, 143.54, 147.50, 157.94, 166.24 ppm; UV–vis (CH2Cl2):
7.42 (t, J¼7.3 Hz, 2H, phenyl-H), 7.57 (t, J¼7.7 Hz, 2H, phenyl-H),
7.69 (d, J¼7.7 Hz, 2H, phenyl-H), 7.79 (s, 2H, phenyl-H), 7.87 (t,
J¼7.7 Hz, 2H, phenyl-H), 8.08 (d, J¼9.6 Hz, 6H, phenyl-H), 8.44 (d,
J¼8.1 Hz, 2H, phenyl-H), 8.51 (d, J¼8.51 Hz, 2H, phenyl-H), 8.77 (s,
lmax (log
3
)¼419 (5.31), 514 (4.26), 550 (4.15), 578 (4.30), 654 (4.45);
HRMS (ESþ) [C54H47N5O6]: calcd for [MþH]þ 862.3605, found
2H, phenyl-H), 8.78 (s, 2H,
(s, 2H, d
b
-H), 8.90 (d, J¼4.76 Hz, 4H,
b
-H), 8.94
862.3610.
b
-H); 13C NMR (100 MHz, CDCl3):
¼27.85, 29.71, 31.73,
35.07, 36.21, 52.29, 59.42, 63.64, 118.38, 121.16, 122.00, 125.12,
126.55, 128.39, 129.59, 132.28, 133.85, 137.62, 138.83, 140.91,
142.92, 147.53, 148.86, 151.63, 166.17, 170.95 ppm; UV–vis (CH2Cl2):
4.5.9. [5,10,15-Tris(3,5-di-tert-butylphenyl)-20-(4-(o-nitrobenzyl-
carboxy)phenyl)porphyrinato]zinc(II) (38)
[5-(4-Carboxyphenyl)-10,15,20-tris(3,5-di-tert-butyl-phenyl)por-
phyrinato]zinc(II) 27 (0.02 g, 0.02 mmol), EDAC (7.21 mg,
0.04 mmol), DMAP (4.59 mg, 0.04 mmol) and 2-nitrobenzylalcohol
(11.5 mg, 0.08 mmol) were stirred for 18 h in DCM (10 mL) at rt
according to method B (Section 4.5.6). Purification on silica gel (n-
hexane/dichloromethane¼1:2, v/v) yielded 38 as a purple solid
(19.4 mg, 0.02 mmol, 81%): mp >310 ꢀC; Rf¼0.65 (SiO2, EtOAc/
lmax (log
3
)¼420 (5.30), 514 (4.53), 545 (4.48), 577 (4.53), 652
(4.51); HRMS (ESþ) [C76H73N6O8]: calcd for [MþH]þ 1197.5490,
found 1197.5450.
4.5.12. 5-Hexyl-15-(2-o-nitrobenzylcarboxyethenyl)-10,20-
diphenylporphyrin (41)
5-(2-Carboxyethenyl)-15-hexyl-10,20-diphenylporphyrin 25 (0.01 g,
0.02 mmol), EDAC (6.21 mg, 0.03 mmol), DMAP (3.95 mg,
0.03 mmol) and 2-nitrobenzylalcohol (10.05 mg, 0.06 mmol) were
stirred for 18 h in DCM (10 mL) according to method B (Section
4.5.6). Purification on silica gel (n-hexane/dichloromethane¼1:2,
v/v) yielded 41 as a purple solid (9.88 mg, 0.01 mmol, 81%): mp
>310 ꢀC; Rf¼0.53 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz,
C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼1.52 (s, 54H,
–C(CH3)3), 5.91 (s, 2H, –OCH2), 7.52 (t, J¼8.4 Hz, 1H, phenyl-H), 7.73
(t, J¼8.4 Hz, 1H, phenyl-H), 7.78–7.80 (m, 3H, phenyl-H), 7.83 (d,
J¼8.0 Hz, 1H, phenyl-H), 8.08–8.09 (m, 6H, phenyl-H), 8.18 (dd,
J1¼1.8 Hz, J2¼1.8 Hz, 1H, phenyl-H), 8.35 (d, J¼8.2 Hz, 2H, phenyl-
H), 8.48 (d, J¼8.2 Hz, 2H, phenyl-H), 8.89 (d, J¼4.7 Hz, 2H,
b-H), 8.91
¼22.71, 29.72, 31.77,
(s, 6H,
b
-H); 13C NMR (100 MHz, CDCl3):
d
CDCl3, TMS):
d¼ꢁ2.39 (s, 2H, NH), 0.88 (t, J¼7.3 Hz, 3H, –CH3), 1.35–
35.07, 63.60, 118.90, 120.87, 122.70, 125.21, 127.93, 128.90, 129.61,
132.43, 133.91, 134.57, 141.73, 148.61, 149.41, 150.41, 166.26 ppm;
1.38 (m, 2H, –CH2),1.46–1.49 (m, 2H, –CH2),1.73–1.79 (m, 2H, –CH2),
2.45–2.53 (m, 2H, –CH2), 4.93 (t, J¼7.6 Hz, 2H, –CH2), 5.88 (s, 2H,
–OCH2), 6.86 (d, J¼15.8 Hz,1H, –CH]), 7.53 (t, J¼8.2 Hz, 2H, phenyl-
H), 7.70 (d, J¼7.6 Hz, 1H, phenyl-H), 7.77 (m, 6H, phenyl-H), 7.83 (d,
J¼7.6 Hz, 1H, phenyl-H), 8.16 (dd, J1¼7.6 Hz, J2¼7.0 Hz, 4H, phenyl-
UV–vis (CH2Cl2): lmax (log
3
)¼423 (5.29), 549 (4.65), 650 (4.54);
HRMS (ESþ) [C76H81N5O4Zn]: calcd for [M] 1191.5580, found
1191.5614.
H), 8.84 (dd, J1¼4.7 Hz, J2¼4.7 Hz, 4H,
b-H), 9.41 (t, J¼4.7 Hz, 4H,
b-
4.5.10. 5-Hexyl-15-(30-(o-nitrobenzylcarboxy)phenyl)-10,20-
diphenylporphyrin (39)
H), 10.27 (d, J¼15.8 Hz, 1H, ]CH–); 13C NMR (100 MHz, CDCl3):
d
¼13.71, 22.27, 29.27, 29.81, 31.43, 35.07, 38.38, 62.09, 62.89,120.33,
5-(3-Carboxyphenyl)-15-hexyl-10,20-diphenylporphyrin
22
122.62,124.56,126.29,127.45,128.04,128.70,129.50,133.97,136.32,
(0.02 g, 0.03 mmol), EDAC (11.5 mg, 0.06 mmol), DMAP (7.31 mg,
0.06 mmol) and 2-nitrobenzylalcohol (18.6 mg, 0.12 mmol) were
stirred for 18 h in DCM (10 mL) according to method B (Section
4.5.6). Purification on silica gel (n-hexane/dichloromethane¼1:1,
v/v) yielded 39 as a purple solid (16.8 mg, 0.01 mmol, 70%): mp
>310 ꢀC; Rf¼0.60 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz,
141.65, 146.65 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼427 (5.46), 526
(4.62), 572 (4.66), 599 (4.56), 653 (4.56); HRMS (ESþ) [C48H42N5O4]:
calcd for [MþH]þ 752.3231, found 752.3237.
4.5.13. 5-Hexyl-10,20-bis(3-methoxyphenyl)-15-(2-o-nitro-
benzylcarboxyethenyl)porphyrin (42)
CDCl3, TMS):
d¼ꢁ2.74 (s, 2H, NH), 0.92 (t, J¼7.3 Hz, 3H, –CH3),
5-(2-Carboxyethenyl)-15-hexyl-10,20-bis(3-methoxyphenyl)-
porphyrin 26 (0.02 g, 0.03 mmol), EDAC (10.54 mg, 0.05 mmol),
DMAP (6.71 mg, 0.05 mmol) and 2-nitrobenzylalcohol (17.06 mg,
0.10 mmol) were stirred for 18 h in DCM (10 mL) according to
method B (Section 4.5.6). Purification on silica gel (n-hexane/
dichloromethane¼1:2, v/v) yielded 42 as a purple solid (19.67 mg,
0.02 mmol, 83%): mp >310 ꢀC; Rf¼0.36 (SiO2, EtOAc/C6H14, 1:3, v/
1.35–1.49 (m, 2H, –CH2), 1.46–1.50 (m, 2H, –CH2), 1.78–1.84 (m,
2H, –CH2), 2.50–2.58 (m, 2H, –CH2), 5.00 (t, J¼8.0 Hz, 2H, –CH2),
5.83 (s, 2H, –OCH2), 7.38 (t, J¼8.4 Hz, 1H, phenyl-H), 7.52 (t,
J¼7.7 Hz, 1H, phenyl-H), 7.65 (d, J¼7.7 Hz, 1H, phenyl-H), 7.76 (m,
6H, phenyl-H), 7.85 (t, J¼7.7 Hz, 1H, phenyl-H), 8.06 (d, J¼8.4 Hz,
1H, phenyl-H), 8.19 (d, J¼6.2 Hz, 4H, phenyl-H), 8.41 (d, J¼7.7 Hz,
1H, phenyl-H), 8.49 (d, J¼7.7 Hz, 1H, phenyl-H), 8.72 (d, J¼4.8 Hz,
v); 1H NMR (400 MHz, CDCl3, TMS):
d¼ꢁ2.41 (s, 2H, NH), 0.90 (t,
2H,
H and
CDCl3):
b
-H), 8.80 (d, J¼4.8 Hz, 2H,
b
-H), 8.91 (t, J¼2.2 Hz, 3H, phenyl-
J¼7.3 Hz, 3H, –CH3), 1.33–1.39 (m, 2H, –CH2), 1.46–1.50 (m, 2H,
–CH2), 1.74–1.82 (m, 2H, –CH2), 2.46–2.54 (m, 2H, –CH2), 4.13 (t,
J¼7.6 Hz, 2H, –CH2), 4.94 (s, 6H, –OCH3), 5.89 (s, 2H, –OCH2), 6.86 (d,
J¼15.8 Hz, 1H, –CH]), 7.33 (d, J¼8.4 Hz, 2H, phenyl-H), 7.45 (t,
J¼8.0 Hz, 2H, phenyl-H), 7.53 (t, J¼7.7 Hz, 1H, phenyl-H), 7.64
(t, J¼7.7 Hz, 4H, phenyl-H), 7.83 (d, J¼7.7 Hz, 1H, phenyl-H), 8.07 (d,
J¼8.1 Hz, 1H, phenyl-H), 8.17 (d, J¼8.0 Hz, 1H, phenyl-H), 8.88 (dd,
b
-H), 9.48 (d, J¼4.8 Hz, 2H,
b
-H); 13C NMR (100 MHz,
d
¼14.18, 22.74, 29.45, 29.74, 30.28, 31.93, 35.63, 38.95,
63.60, 117.46, 119.80, 121.24, 125.08, 126.67, 127.13, 127.75, 128.30,
129.19, 133.84, 134.90, 138.91, 142.30, 147.44, 166.17 ppm; UV–vis
(CH2Cl2): lmax (log
3
)¼418 (5.48), 516 (4.47), 551 (4.36), 594 (4.32),
650 (4.33); HRMS (ESþ) [C52H44N5O4]: calcd for [MþH]þ 802.3393,
found 802.3380.
J1¼4.4 Hz, J2¼4.4 Hz, 4H,
b
-H), 9.41 (s, 4H,
b
-H), 10.26 (d, J¼15.8 Hz,
1H, ]CH–); 13C NMR (100 MHz, CDCl3):
d
¼14.15, 22.70, 28.22,
4.5.11. 5,15-Bis(3,5-di-tert-butylphenyl)-10,20-bis-
(3-(o-nitrobenzylcarboxy)phenyl)porphyrin (40)
31.89, 35.50, 38.88, 55.54, 62.59, 110.58, 117.86, 120.43, 126.31,
128.86, 134.15, 143.43, 144.59, 147.96, 165.63, 169.68 ppm; UV–vis
5,15-Bis(3,5-di-tert-butylphenyl)-10,20-bis(3-carboxyphenyl)-
porphyrin 23 (0.01 g, 0.01 mmol), EDAC (10.91 mg, 0.11 mmol),
DMAP (6.94 mg, 0.11 mmol) and 2-nitrobenzylalcohol (17.63 mg,
(CH2Cl2): lmax (log
3
)¼426 (5.26), 527 (3.72), 575 (4.79), 600 (4.75),
652 (4.75); HRMS (ESþ) [C50H46N5O4]: calcd for [MþH]þ 812.3455,
found 812.3448.

7076
M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
4.5.14. 5,10,15,20-Tetrakis(3,5-di-tert-butylphenyl)-2-(4-
(o-nitrobenzylcarboxy)phenyl)porphyrin (43)
–CH2OH), 5.24 (s, 2H, –OCH2O), 6.88 (dd, J1¼2.4 Hz, J2¼2.3 Hz,
1H, phenyl-H), 7.30 (s,1H, phenyl-H), 7.95 (d, J¼9.36 Hz,1H, phenyl-
2-(4-Carboxyphenyl)-5,10,15,20-tetrakis(3,5-di-tert-butyl-phenyl)-
porphyrin 24 (0.01 g, 0.01 mmol), EDAC (3.24 mg, 0.02 mmol), DMAP
(2.06 mg, 0.02 mmol) and 2-nitrobenzylalcohol (5.24 mg,
0.03 mmol) were stirred for 18 h in DCM (10 mL) according to
method B (Section 4.5.6). Purification on silica gel (n-hexane/
dichloromethane¼1:1, v/v) yielded 43 as a purple solid (7.57 mg,
0.01 mmol, 68%): mp >310 ꢀC; Rf¼0.82 (SiO2, EtOAc/C6H14, 1:3,
H), 13C NMR (100 MHz, CDCl3):
d¼58.27, 61.34, 67.57, 70.89, 92.61,
113.78, 114.57, 127.00, 139.81, 140.69, 161.16 ppm; HRMS (ESþ)
[C11H15NO6]: calcd for [MþNa]þ 280.0797, found 280.0800.
4.7.2. 5-Hexyl-15-(4-(o-nitro-p-methoxyethoxymethyl
benzylcarboxy)phenyl)-10,20-diphenylporphyrin (47)
5-(4-Carboxyphenyl)-15-hexyl-10,20-diphenylporphyrin 18 (0.05 g,
0.08 mmol), EDAC (28.8 mg, 0.15 mmol), DMAP (18.3 mg,
0.15 mmol) and 5-(methoxyethoxymethyl)-2-nitrophenylmethanol
46 (77.2 mg, 0.30 mmol) were stirred for 18 h in DCM (10 mL). The
solution was diluted with DCM and extracted with a solution of
aqueous NH4Cl. The mixture was washed with brine and dried over
Na2SO4, followed by evaporation of the solvent to give the crude
product. Purification on silica gel (n-hexane/dichloromethane¼1:2,
v/v) yielded 47 as a purple solid (19.67 mg, 0.02 mmol, 83%): mp
>310 ꢀC; Rf¼0.36 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz,
v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.56 (s, 2H, –NH), 1.50 (s,
72H, –C(CH3)3), 5.81 (s, 2H, –OCH2), 7.34 (t, J¼1.8 Hz, 1H, phenyl-
H), 7.50 (d, J¼8.0 Hz, 1H, phenyl-H), 7.68–7.70 (m, 4H, phenyl-H),
7.75–7.78 (m, 4H, phenyl-H), 7.82 (d, J¼1.8 Hz, 2H, phenyl-H),
7.85 (d, J¼8.4 Hz, 1H, phenyl-H), 8.06 (dd, J1¼1.8 Hz, J2¼1.8 Hz,
4H, phenyl-H), 8.12 (d, J¼1.8 Hz, 2H, phenyl-H), 8.18 (d, J¼8.1 Hz,
1H, phenyl-H), 8.71 (d, J¼4.8 Hz, 1H,
(m, 1H,
-H), 8.85 (d, J¼3.6 Hz, 2H,
NMR (100 MHz, CDCl3):
b
-H), 8.74 (s, 1H, -H), 8.82
b
b
b
-H), 8.90 (m, 2H, b
-H); 13C
d
¼14.20, 23.91, 29.43, 30.05, 32.76,
34.88, 37.11, 121.01, 128.70, 129.60, 130.04, 130.68, 133.80, 139.99,
CDCl3, TMS):
d¼ꢁ2.72 (s, 2H, NH), 0.93 (t, J¼6.8 Hz, 3H, –CH3), 1.36–
147.99, 148.64, 148.82, 165.90 ppm; UV–vis (CH2Cl2): lmax
1.41 (m, 2H, –CH2),1.47–1.54 (m, 2H, –CH2), 1.76–1.83 (m, 2H, –CH2),
2.50–2.58 (m, 2H, –CH2), 3.31 (s, 3H, –OCH3), 3.53 (t, J¼3.9 Hz, 2H,
–OCH2), 3.82 (t, J¼3.9 Hz, 2H, –CH2OCH3), 4.96 (t, J¼8.8 Hz, 2H,
–CH2), 5.34 (s, 2H, –OCH2), 5.92 (s, 2H, –OCH2O), 7.09 (dd, J1¼2.0 Hz,
J2¼2.0 Hz, 1H, phenyl-H), 7.43 (d, J¼1.96 Hz, 1H, phenyl-H), 7.74–
7.80 (m, 6H, phenyl-H), 8.20 (s, 1H, phenyl-H), 8.22 (d, J¼5.8 Hz, 4H,
phenyl-H), 8.33 (d, J¼7.8 Hz, 2H, phenyl-H), 8.49 (d, J¼7.8 Hz, 2H,
(log
3
)¼426 (5.23), 525 (4.23), 576 (4.30), 601 (4.28), 653 (4.33);
HRMS (ESþ) [C90H104N5O4]: calcd for [MþH]þ 1318.8090, found
1318.8030.
4.6. Synthesis of porphyrin bioconjugates
4.6.1. 5,10,15-Tris(3,5-di-tert-butylphenyl)-20-(40-(o-nitro-p-
phenyl-H), 8.77 (d, J¼4.9 Hz, 2H,
8.92 (d, J¼4.9 Hz, 2H, -H), 9.46 (d, J¼4.9 Hz, 2H,
(100 MHz, CDCl3):
58.64, 62.14, 62.70, 63.42, 67.88, 71.02, 93.03, 114.35, 115.67, 117.07,
119.40, 120.90, 126.23, 127.32, 127.71, 128.45, 134.04, 140.65, 141.83,
147.08, 159.69, 161.23, 165.68, 169.89 ppm; UV–vis (CH2Cl2): lmax
b
-H), 8.84 (d, J¼4.9 Hz, 2H,
b-H),
(20,30,40,60-tetra-O-acetyl-
b-
D-galactopyrano-side)benzyl)carboxy)-
b
b
-H); 13C NMR
phenyl)-porphyrin (44)
d
¼13.73, 22.29, 29.28, 29.83, 31.47, 35.17, 38.50,
5-(Carboxyphenyl)-10,15,20-tris(3,5-di-tert-butylphenyl)porphyrin
29 (0.08 g, 0.08 mmol), EDAC (30.8 mg, 0.16 mmol), DMAP(19.6 mg,
0.16 mmol) and 5-((aceto-glucose)-2-nitrophenyl)methanol (0.16 g,
0.32 mmol) were stirred for 18 h in DCM (15 mL). The solution was
diluted with DCM and extracted with a solution of aqueous NH4Cl. The
mixture was washed with brine and dried over Na2SO4, followed by
evaporation of the solvent to give the crude product. Purification on
silica gel (n-hexane/dichloromethane¼1:1, v/v) yielded 44 as a purple
solid (90.3 mg, 0.02 mmol, 76%): mp >310 ꢀC; Rf¼0.32 (SiO2, EtOAc/
(log
3
)¼418 (5.16), 516 (3.90), 551 (3.65), 594 (3.58), 653 (3.78);
HRMS (ESþ) [C56H52N5O7]: calcd for [MþH]þ 906.3867, found
906.3899.
4.7.3. 5-Hexyl-15-(hydroxyethylcarboxyphenyl)-10,20-
diphenylporphyrin (48)
C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d¼ꢁ2.71 (s, 2H, NH),
5-Hexyl-15-(40-(o-nitro-p-(methoxyethoxymethyl)benzylcarboxy)-
phenyl)-10,20-di-phenylporphyrin 47 (0.05 g, 0.06 mmol) was dis-
solved in a small amount of THF. Ethylene glycol (10 mL) was added
to the solution and was heated at 140 ꢀC for 5 h (TLC monitor). The
reaction was cooled to room temperature and was washed with
saturated aqueous sodium bicarbonate and brine. The solution was
dried over anhydrous magnesium sulfate and the solvent evapo-
rated under reduced pressure to yield 48 as a purple solid (64.7 mg,
0.05 mmol, 92%): mp >310 ꢀC; Rf¼0.44 (SiO2, EtOAc/C6H14, 1:3, v/
1.52 (s, 54H, –C(CH3)3),1.83 (s, 3H, –COCH3),1.99 (s, 3H, –COCH3),2.06(s,
6H, –COCH3), 3.90–3.93 (m, 1H, –CH), 4.16 (d, J¼10.5 Hz, 1H, –CH), 4.28
(dd, J1¼5.0 Hz, J2¼5.0 Hz, 1H, –CH), 5.15–5.20 (m, 1H, –CH), 5.30–5.33
(m, 3H, –CH and –CH2CO), 5.97 (s, 2H, –OCH2), 7.10 (dd, J1¼2.2 Hz,
J2¼2.2 Hz, 1H, phenyl-H), 7.42 (d, J¼2.28 Hz, 1H, phenyl-H), 7.79 (s, 3H,
phenyl-H), 8.07 (s, 6H, phenyl-H), 8.27 (d, J¼9.0 Hz, 1H, phenyl-H), 8.38
(d, J¼8.0 Hz, 2H, phenyl-H), 8.49 (d, J¼8.0 Hz, 2H, phenyl-H), 8.79 (d,
J¼4.5 Hz, 2H,
b-H), 8.91 (s, 6H, b
-H); 13C NMR (100 MHz, CDCl3):
¼31.77, 35.08, 61.70, 63.74, 67.83, 70.94, 72.44, 98.08, 115.68, 116.81,
d
v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.75 (s, 2H, NH), 0.91 (t,
117.64, 121.10, 121.70, 122.05, 128.07, 128.61, 129.83, 134.83, 135.68,
141.14, 142.42, 148.25, 160.48, 169.23, 170.11, 170.43 ppm; UV–vis
J¼7.0 Hz, 3H, –CH3), 1.34–1.40 (m, 2H, –CH2), 1.46–1.53 (m, 2H,
–CH2), 1.76–1.83 (m, 2H, –CH2), 2.49–2.55 (m, 2H, –CH2), 4.09 (s, 2H,
–OCH2), 4.64 (t, J¼4.0 Hz, 2H, –CH2OH), 5.00 (t, J¼8.2 Hz, 2H, –CH2),
7.72–7.80 (m, 6H, phenyl-H), 8.18 (d, J¼6.4 Hz, 4H, phenyl-H), 8.27
(d, J¼8.2 Hz, 2H, phenyl-H), 8.43 (d, J¼8.2 Hz, 2H, phenyl-H), 8.71
(CH2Cl2): lmax (log
3
)¼421 (5.18), 518 (3.81), 553 (3.60), 593 (3.41), 667
(3.75); HRMS (ESþ) [C90H102N5O14]: calcd for [MþH]þ 1476.7420, found
1476.7410.
(d, J¼5.3 Hz, 2H,
2H,
-H), 9.47 (d, J¼4.7 Hz, 2H,
¼14.17, 22.74, 30.29, 31.94, 35.64, 38.95, 61.63, 66.98, 93.50,114.94,
116.54, 117.59, 119.83, 121.33, 127.87, 128.92, 134.78, 142.30, 147.34,
b
-H), 8.79 (d, J¼4.7 Hz, 2H,
b
-H), 8.90 (d, J¼5.2 Hz,
4.7. Protecting group approach
b
b
-H); 13C NMR (100 MHz, CDCl3):
d
4.7.1. 5-(Methoxyethoxymethyl)-2-nitrophenylmethanol (46)
5-(Methoxyethoxymethyl)-2-nitrobenzaldehyde28 45 (0.62 g,
2.44 mmol) was dissolved in THF (50 mL) and the solution was
cooled to 0 ꢀC. Sodium borohydride (92 mg, 2.44 mmol) was added
and the mixture was stirred for 2 h. The mixture was filtered
through silica gel and the solvent was evaporated in vacuo to yield
the title compound 46 as a yellow solid (0.62 g, 0.16 mmol, 98%):
mp 98–101 ꢀC; Rf¼0.29 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR
167.24 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼418 (5.17), 517 (2.30),
551 (3.45), 594 (3.28), 650 (3.38); HRMS (ESþ) [C47H43N4O3]: calcd
for [MþH]þ 711.3335, found 711.3354.
4.7.4. [5-(4-(Ethoxycarbonylphenyl-)-15-hexyl-10,20-
diphenylporphyrin)-carboxyethenyl)-10,15,20-triphenyl-
porphyrinato]nickel(II) (50)
(400 MHz, CDCl3, TMS):
d
¼3.22 (s, 3H, –OCH3), 3.22–3.46 (m, 2H,
5-(2-Carboxyethenyl)-10,15,20-triphenylporphyrinato]nickel(II)21d
49 (0.01 g, 0.02 mmol), EDAC (2.88 mg, 0.03 mmol), DMAP (1.83 mg,
–CH2O), 3.71–3.41 (m, 2H, –OCH2), 4.11 (br s, 1H, –OH), 4.84 (s, 2H,

M.B. Bakar et al. / Tetrahedron 65 (2009) 7064–7078
7077
0.03 mmol) and 5-hexyl-15-(hydroxyethylcarboxyphenyl)-10,20-
diphenylporphyrin 48 (11 mg, 0.02 mmol) were stirred for 18 h in
DCM (10 mL). The solution was diluted with DCM and extracted
with a solution of aqueous NH4Cl. The mixture was washed with
brine and dried over Na2SO4, followed by evaporation of the solvent
to give the crude product. Purification on silica gel (n-hexane/
dichloromethane¼1:2, v/v) yielded the title compound as a purple
solid (19.0 mg, 0.03 mmol, 93%): mp >310 ꢀC; Rf¼0.15 (SiO2, EtOAc/
>310 ꢀC; Rf¼0.28 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz,
CDCl3, TMS):
d¼ꢁ2.62 (s, 2H, NH), 0.93 (t, J¼7.0 Hz, 3H, –CH3), 1.34–
1.42 (m, 2H, –CH2),1.45–1.53 (m, 2H, –CH2),1.75–1.83 (m, 2H, –CH2),
2.49–2.57 (m, 2H, –CH2), 4.98 (t, J¼7.6 Hz, 2H, –CH2), 5.86 (s, 2H,
–OCH2), 6.63 (dd, J1¼2.8 Hz, J2¼2.5 Hz, 1H, phenyl-H), 7.03 (s, 1H,
phenyl-H), 7.71–7.77 (m, 6H, phenyl-H), 8.10 (dd, J1¼2.0 Hz,
J2¼1.8 Hz, 1H, phenyl-H), 8.17–8.19 (m, 4H, phenyl-H), 8.26 (d,
J¼8.2 Hz, 2H, phenyl-H), 8.42 (d, J¼7.6 Hz, 2H, phenyl-H), 8.71 (d,
C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
d
¼ꢁ2.78 (s, 2H,
J¼4.6 Hz, 2H,
-H), 9.46 (d, J¼4.7 Hz, 2H,
¼14.17, 20.78, 22.74, 29.40, 31.96, 35.65, 38.96, 62.58, 114.89,
121.09, 126.69, 127.79, 128.18, 128.39, 129.71, 134.77, 142.27, 148.73,
b
-H), 8.79 (d, J¼4.7 Hz, 2H,
b
-H), 8.90 (d, J¼4.7 Hz, 2H,
NH), 0.97 (t, J¼7.3 Hz, 3H, –CH3), 1.63–1.65 (m, 2H, –CH2), 1.74–1.79
(m, 2H, –CH2), 1.94–1.97 (m, 2H, –CH2), 2.51–2.55 (m, 2H, –CH2),
4.52–4.56 (m, 4H, –CH2), 5.00 (t, J¼7.6 Hz, 2H, –CH2), 6.41 (d,
J¼15.2 Hz, 1H, –CH]C), 7.50–7.52 (m, 6H, phenyl-H), 7.68–7.77 (m,
9H, phenyl-H), 7.86 (d, J¼7.0 Hz, 4H, phenyl-H), 7.91 (d, J¼8.2 Hz,
2H, phenyl-H), 8.13 (d, J¼6.44 Hz, 4H, phenyl-H), 8.25 (d,
J¼8.2 Hz, 2H, phenyl-H), 8.48 (d, J¼8.2 Hz, 2H, phenyl-H), 8.57 (d,
b
d
b
-H); 13C NMR (100 MHz, CDCl3):
161.26, 169.54 ppm; UV–vis (CH2Cl2): lmax (log
3
)¼419 (5.45), 517
(4.06), 551 (3.69), 594 (3.56), 650 (3.68); HRMS (ESþ) [C52H44N5O5]:
calcd for [MþH]þ 818.3342, found 818.3313.
J¼4.7 Hz, 2H,
b
-H), 8.63 (d, J¼4.7 Hz, 2H,
b
-H), 8.66 (d, J¼4.7 Hz, 2H,
4.8. Irradiation experiment
b
-H), 8.69 (d, J¼4.7 Hz, 2H,
b
-H), 8.77 (d, J¼5.2 Hz, 2H,
b
-H), 8.87 (d,
A 50
m
M solution of 5,10,15-tris(3,5-di-tert-butylphenyl)-20-(40-
-galacto pyrano-side)benzyl)-
J¼4.7 Hz, 2H,
b
-H), 9.39 (d, J¼4.7 Hz, 2H, -H), 9.46 (d, J¼4.7 Hz, 2H,
b
-H), 9.98 (d, J¼15.8 Hz, 1H, ]CHCO); 13C NMR (100 MHz, CDCl3):
(o-nitro-p-(20,30,40,60-tetra-O-acetyl-
b-D
b
d¼14.18, 20.76, 22.74, 23.35, 23.79, 25.01, 25.64, 29.11, 29.46, 29.74,
carboxy)phenyl)-porphyrin 44 in 2% water/98% acetone was placed
in a quartz cuvette. Irradiation was performed using a photochem-
ical chamber reactor (Rayonet Model RMR-600) with 350ꢂ25 nm
30.29, 31.94, 35.64, 38.94, 62.80, 63.15, 68.01, 73.55, 91.21, 109.33,
117.62, 119.54, 119.79, 120.48, 121.27, 126.62, 126.95, 126.99, 129.15,
130.74, 131.38, 132.32, 132.76, 133.49, 133.52, 134.46, 134.67, 140.16,
141.52, 142.17, 142.83, 144.79, 147.30, 166.15, 166.75 ppm; UV–vis
UV lamps. Aliquots of 20 mL were removed at different time in-
tervals of irradiation and analyzed by analytical HPLC (detection
UV: 350 nm) using a nucleosile 5u Si 100A (250ꢃ4.00 mm) column
and eluting with a mixture of n-Hexane/ethyl acetate (50:50) at
a flow rate of 1.5 mL/min.
(CH2Cl2): lmax (log
3
)¼420 (5.11), 523 (4.41), 546 (4.41), 597 (4.40),
653 (4.45); HRMS (ESþ) [C88H67NiN8O4]: calcd for [MþH]þ
1357.4639, found 1357.4669.
4.7.5. [5-Hexyl-15-(3-o-nitro-p-(methoxyethoxymethyl)-
Acknowledgements
benzylcarboxyphenyl)10,20-diphenylporphyrinato]-zinc(II) (51)
5-Hexyl-15-(4-(o-nitro-p-(methoxyethoxy-methyl)benzylcarboxy-
phenyl)-10,20-di-phenylporphyrin 47 (0.10 g, 0.11 mmol) was dis-
solved in CHCl3 (30 mL). Two drops of TFA were added, followed by
zinc(II)oxide (26.9 mg, 0.33 mmol). The solution was stirred for 18 h
and filtered. The solvent was evaporated and subjected to column
chromatography (SiO2, n-hexane/dichloromethane¼1:2, v/v) and gave
the 51 as a purple solid (100.24 mg, 0.10 mmol, 94%): mp >310 ꢀC;
Rf¼0.32 (SiO2, EtOAc/C6H14, 1:3, v/v); 1H NMR (400 MHz, CDCl3, TMS):
This work was generously supported by a Science Foundation
Ireland Research Professorship Award (SFI 04/RP1/B482), the
Health Research Board (HRB TRA2007/11), and by the Universiti
Teknologi Malaysia.
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d
¼0.93 (t, J¼7.0 Hz, 3H, –CH3), 1.38–1.42 (m, 2H, –CH2), 1.46–1.52 (m,
2H, –CH2), 1.76–1.83 (m, 2H, –CH2), 2.50–2.58 (m, 2H, –CH2), 3.15 (s,
3H, –OCH3), 3.35 (t, J¼4.1 Hz, 2H, –OCH2), 3.39 (t, J¼4.1 Hz, 2H,
–CH2OCH3), 4.97 (t, J¼8.2 Hz, 2H, –CH2), 5.24 (s, 2H, –OCH2), 5.85 (s,
2H, –OCH2O), 7.03 (d, J¼2.9 Hz, 1H, phenyl-H), 7.36 (d, J¼2.4 Hz, 1H,
phenyl-H), 7.72–7.78 (m, 6H, phenyl-H), 8.16 (s, 1H, phenyl-H), 8.18 (d,
J¼5.8 Hz, 4H, phenyl-H), 8.29 (d, J¼7.6 Hz, 2H, phenyl-H), 8.42 (d,
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2H, -H), 9.53 (d, J¼4.6 Hz, 2H,
-H), 8.97 (d, J¼4.6 Hz, 2H,
NMR (100 MHz, CDCl3):
38.76, 58.48, 62.10, 62.66, 63.32, 67.72, 70.85, 92.88, 114.22, 114.58,
115.31, 118.12, 120.31, 121.78, 127.08, 127.45, 128.18, 128.63, 130.78,
134.17, 135.05, 140.55, 142.36, 147.94, 149.32, 149.74, 159.67, 161.10,
b
-H), 8.89 (d, J¼4.7 Hz,
b
b
b
-H); 13C
d
¼13.74, 22.31, 29.27, 29.98, 31.49, 35.43,
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4.7.6. 5-Hexyl-15-(40-(o-nitro-p-hydroxybenzyl-carboxy)-phenyl)-
10,20-diphenylporphyrin (52)
A solution of [5-hexyl-15-(3-o-nitro-p-(methoxyethoxymethyl)-
benzyl carboxyphenyl)-10,20-diphenylporphyrinato]zinc(II) 51
(0.06 g, 0.06 mmol) in CH2Cl2 (3.30 mL) was treated with trifluoro-
acetic acid (3.30 mL), stirred at rt for 7 h and concentrated. The
solution was neutralized with aqueous-KOH and extracted with
CH2Cl2. The organic phase was dried over Na2SO4, filtered and
the solvent was removed under reduced pressure to yield the
title compound 52 as a purple solid (34.8 mg, 0.03 mmol, 71%): mp

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