Synthesis of novel functionalised zinc phthalocyanines applicable in photodynamic therapy

Article abstract of DOI:10.1002/(SICI)1099-0690(199912)1999:12<3441::AID-EJOC3441>3.0.CO;2-Y

The synthesis of several new phthalonitriles 3, 9, 14, 25, 33, and 36, functionalised with carboxyl groups, including two examples of amino acid derivatives is described. All new phthalonitriles were converted into their corresponding phthalocyaninatozinc compounds. The phthalocyanines, 2,3,9,10,16,17,23,24-octa(1-carboxyethyloxy)phthalocyaninatozinc (5), 2,9,16,23-tetra(2-amino-2-carboxyethyl)phthalocyaninatozinc (11), 2,9,16,23- tetra(1-carboxy-2-hydroxyethylaminocarbonyl)phthalocyaninatozinc (16), 1,8,15,22-tetra(carboxybutyl)phthalocyaninatozinc (27), 2,3,9,10,16,17,23,24- octa(carboxyalkyl)phthalocyaninatozinc (39), and the nonidentically substituted 9,10,16,17,23,24-hexa(carboxyalkyl)-2-[4-(N- succinimidyloxycarbonyl)butyl]phthaloyaninatozinc (41) are all sufficiently soluble in water. The nonidentically-substituted compounds are important due to their selective binding to tumor-selective antibodies. UV/Vis-spectroscopy was used to investigate the effect of more or less sterically-demanding substituents in the periphery of the phthalocyanines towards aggregation. The phototoxicity towards cancer cells of some of the new compounds was investigated in several in-vitro experiments.

Full text of DOI:10.1002/(SICI)1099-0690(199912)1999:12<3441::AID-EJOC3441>3.0.CO;2-Y

FULL PAPER
Synthesis of Novel Functionalised Zinc Phthalocyanines Applicable in
Photodynamic Therapy
Ulf Drechsler,[a] Mirjam Pfaff,[a] and Michael Hanack*[a]
Keywords: Zinc phthalocyanines / Tetra- and octa(carboxyalkyl)phthalocyaninatozinc compounds / Water soluble /
Photodynamic therapy
The synthesis of several new phthalonitriles 3, 9, 14, 25, 33, and
36, functionalised with carboxyl groups, including two
tically substituted 9,10,16,17,23,24-hexa(carboxyalkyl)-2-[4-(N-
succinimidyloxycarbonyl)butyl]phthaloyaninatozinc (41) are all
examples of amino acid derivatives is described. All new sufficiently soluble in water. The nonidentically-substituted
phthalonitriles were converted into their corresponding compounds are important due to their selective binding to
phthalocyaninatozinc compounds. The phthalocyanines, tumor-selective antibodies. UV/Vis-spectroscopy was used to
2,3,9,10,16,17,23,24-octa(1-carboxyethyloxy)phthalocyanin-
atozinc (5), 2,9,16,23-tetra(2-amino-2-carboxyethyl)phthalo- substituents in the periphery of the phthalocyanines towards
cyaninatozinc (11), 2,9,16,23-tetra(1-carboxy-2-hydroxyethyl- aggregation. The phototoxicity towards cancer cells of some of
aminocarbonyl)phthalocyaninatozinc (16), 1,8,15,22-tetra- the new compounds was investigated in several in-vitro
investigate the effect of more or less sterically-demanding
(carboxybutyl)phthalocyaninatozinc (27), 2,3,9,10,16,17,23,24- experiments.
octa(carboxyalkyl)phthalocyaninatozinc (39), and the noniden-
Recently, zinc phthalocyanines have found applications (1), the conversion into the diether 2 is obtained by treating
as sensitizers in the photodynamic therapy of cancer 1 with ethyl 2-bromopropionate in DMF in the presence of
(PDT).[1Ϫ4] To increase the selectivity of these thera- sodium methoxide.[12] Subsequent substitution of the bromo
peuticals, some targeting models, including the use of tumor groups by cyanide in a RosenmundϪvon Braun reaction
selective antibodies, have been developed.[5] The formation using cuprous cyanide,[13] affords the corresponding
of selective antibody-sensitizer conjugates follows two dif- phthalonitrile 3 in 50% yield. As depicted in Scheme 1, the
ferent strategies: the coordinative coupling of a biotinylated synthesis of the zinc phthalocyanine 5 is carried out in two
antibody and also biotinylated sensitizers to avidin, which steps. Heating the phthalonitrile 3 in n-pentanol with
is able to bind four molecules of biotin,[6] and the covalent zinc(II) acetate and catalytic amounts of DBU leads to the
linkage between antibody and sensitizer.[7Ϫ9] Both targeting phthalocyanine system 4 as a diastereomeric mixture. Under
models require sensitizers, which are sufficiently soluble in these conditions, a transesterification of the ester functions
water and which show only a weak tendency to form to the corresponding pentyl ester 4 is observed. After chro-
stacked aggregates.[10] Water solubility could be achieved by matographic purification, the ester phthalocyanine 4 is hy-
introducing carboxyl groups linked to the macrocyclic sys- drolysed to the carboxylic acid 5.
tem with more or less branched alkyl or alkoxy chains as
Compound 5 is highly soluble in polar organic solvents
spacers. Due to a certain steric demand, these spacers en- such as MeOH, DMF, or THF, and exhibits a good water
large the distance between two neighbouring macrocycles, solubility at pH Ն 6. The branched substituents in 5 lead to
which significantly lowers the tendency for aggregation. As an increased inter-ring distance between two neighbouring
isomeric mixtures show better photodynamic properties macrocycles, which significantly lowers their tendency to
there is no need to prepare isomerically pure compounds.[11] form stacked aggregates. This behaviour is indicated in the
In this paper we wish to report the synthesis of several new UV-spectrum of 5, which exhibits a highly resolved Q-band,
substituted zinc phthalocyanines, which fulfil the demands centered at 672 nm, assigned to the monomeric species. This
mentioned above.
absorption is accompanied by two transitions into excited
vibration states at 639.5 and 610.5 nm, respectively.
Synthesis of 2,3,9,10,16,17,23,24-Octa(1-carboxy-
ethyloxy)phthalocyaninatozinc (5)
Synthesis of Phthalocyaninatozinc Amino Acids 11
and 16
Scheme 1 shows the synthetic route to octasubstituted
zinc phthalocyanines. Starting from 4,5-dibromocatechol
To increase the water solubility of the compounds, we
decided to introduce amino acid moieties in the periphery
of the Pc macrocycles. The synthetic route to the target
compound 11 is shown in Scheme 2. Because of its substi-
tution pattern, 3,4-dihydroxyphenylalanine (DOPA, 6) is
used as starting material. To avoid undesired side reactions
[a]
Institut für Organische Chemie, Lehrstuhl II, Universität Tübin-
gen
Auf der Morgenstelle 18, D-72076 Tübingen, Germany.
Fax: (internat.) ϩ49 (0)7071/29-5244
E-mail: hanack@uni-tuebingen.de
Eur. J. Org. Chem. 1999, 3441Ϫ3453
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1212Ϫ3441 $ 17.50ϩ.50/0
3441

U. Drechsler, M. Pfaff, M. Hanack
FULL PAPER
Scheme 1. Synthesis of phthalocyanine 5 starting from 4,5-dibromocatechol (1)
during further reaction steps it is necessary to protect the shoulder at 667 nm. Changing the solvent to MeOH leads
amino function as well as the carboxyl group. In a first to a reduction of the absorption of the aggregated species
reaction step, the carboxyl group in 6 is esterified in excess and a simultaneous increase of the monomerЈs Q-band,
MeOH in the presence of trimethylsilyl chloride, giving the which is also shifted to higher wavelengths compared to the
corresponding methyl ester.[14] Subsequent treatment of the aqueous solution. These effects are further promoted when
amino group with di-tert-butyl dicarbonate leads to the the solvent is changed to DMF. These phenomena are read-
base-stable tert-butyl carbamate 7.[15] Compound 7 is con- ily explained by interactions between the solvent and the
verted into the corresponding bistriflate, 8, by treating it macrocycleЈs π-system: the driving forces for the stacking
with trifluoromethanesulfonic anhydride and triethylamine are hydrophobic in character, which means that in aqueous
in dichloromethane at Ϫ20°C.[16] The phthalonitrile deriva- solution no solvation of the phthalocyanine core could be
tive, 9, is obtaind by palladium-catalysed substitution of the expected. This effect is only partially compensated by the
triflate groups by cyanide in DMF at 60°C, using Zn(CN)2 excellent solvation of the peripheral amino acid functions.
as the cyanide source, tris(dibenzylideneacetone)dipallad- Changing the solvent to MeOH or DMF increases the solv-
ium [Pd2(dba)3] as the zerovalent metal species, and 1,1Ј- ation of the phthalocyanine core, finally leading to a higher
bis(diphenylphosphanyl)ferrocene (dppf) as a ligand in the amount of monomers in solution. The improved interaction
catalyst system.[17] The protected zinc phthalocyanine, 10, between solvent and π-system diminishes the distance be-
is obtained by heating the nitrile 9 in n-pentanol in the pres- tween the macrocycleЈs HOMO and LUMO, thereby pro-
ence of zinc(II) acetate and a catalytic amount of DBU at ducing a shift of the Q-band to higher wavelengths.
130°C. The Boc-protecting groups remain unchanged and
As depicted in Scheme 3, the synthetic route to the serine
the methyl ester groups are transesterified to the corre- substituted system 16 starts from 3,4-dibromobenzoyl chlo-
sponding pentyl esters under these conditions. After chrom- ride (12), which is reacted with O-tBu serine methyl ester to
atographic purification the amino groups are deprotected give the corresponding amide, 13, in 87% yield. Subsequent
with trifluoroacetic acid, followed by subsequent cleavage treatment of 13 with cuprous cyanide in DMF affords the
of the pentyl esters through alkaline hydrolysis. The phthalo- phthalonitrile, 14, in 30% yield. Heating phthalonitrile 14
cyanine tetraamino acid 11 is obtained as a mixture of dia- in the presence of Zn(OAc)2 and catalytic amounts of DBU
stereomeric and regioisomers in 75% yield. Compound 11 in n-pentanol leads to the protected phthalocyanine, 15, in
is slightly soluble in MeOH and DMF and exhibits excel- 17% yield as a diastereomeric and regioisomeric mixture.
lent water solubility, as expected. The aggregation behav- Cleavage of the protecting groups proceeds in two steps:
iour of tetraamino acid 11 in different solvents could be liberation of the hydroxyl functions by treatment of 15 with
monitored by UV-spectra. In aqueous solution the most in- trifluoroacetic acid, followed by alkaline hydrolysis afford-
tensive absorption band is assigned to the aggregated spec- ing the desired carboxylic acid 16 in 71% yield. Compound
ies, whereas the Q-band of the monomeric Pc appears as a 16 is slightly soluble in acetone, highly soluble in MeOH,
3442
Eur. J. Org. Chem. 1999, 3441Ϫ3453

Synthesis of Novel Functionalised Zinc Phthalocyanines Applicable in Photodynamic Therapy
FULL PAPER
Scheme 2. Synthetic route to phthalocyaninato zinc amino acid 11
and exhibits a good water solubility at a pH Ն 8. The UV-
spectrum of 16 shows the Q-band absorption of the mono-
meric species at 675 nm which is overlapped by the broad
absorption of a small amount of aggregated macrocycles,
centered at 634 nm.
Synthesis of 1,8,15,22-Tetra(4-carboxybutyl)-
phthalocyaninatozinc (27)
Depending on the arrangement of two neighbouring iso-
indoline subunits, substituents in the 1-position could
either be isolated, or arranged towards each other. Due to
steric hindrance, the substituents ordered towards each
other are pushed outside the plane of the macrocyclic sys-
tem, which enlarges the inter-ring distance between two
macrocycles. Because previously described synthetic meth-
ods are lenghty and low yielding,[18] we developed a more
suitable synthetic route. Considering the strong electron-
donating effect of phenolic hydroxyl groups, it is possible
to metallate the 3-position of suitably protected catechol
derivatives with n-butyllithium. The resulting phenyllith-
ium derivative could finally be alkylated with alkyl hal-
ides.[19] Scheme 4 shows the synthetic pathway to the de-
sired target compound, 27. The cyclohexylidene ketal rep-
Scheme 3. Synthesis of phthalocyanine 16
resents a sufficiently stable protecting group for the cat- hibits the presence of a carbonyl function, hence the de-
echol function towards organolithium compounds. As sired carboxyl function was masked as an ortho ester,[20]
shown in Scheme 4, the protected catechol, 19, is readily which is not attacked by strong nucleophiles. The ortho es-
metallated in 60% yield. The phenyllithium derivative pro- ter function in the resulting alkyl catechol, 20, is further
Eur. J. Org. Chem. 1999, 3441Ϫ3453
3443

U. Drechsler, M. Pfaff, M. Hanack
FULL PAPER
converted into the corresponding methyl ester in two steps; ester, has to be introduced. In order to avoid undesired in-
acid catalysed ring opening of the bicyclic system to the teractions between phthalocyanine and antibody,[22] this
dihydroxy ester 21, followed by subsequent reesterification anchor group is coupled to the phthalocyanine core by an
in MeOH to give the methyl ester, 22. During a further alkyl chain as spacer. These demands require nonident-
reaction step the ketal 22 is cleaved at room temperature ically-substituted phthalocyanines carrying the anchor-
using trifluoroacetic acid-water mixture (95:5). The free hy- spacer group as well as water solubility mediators. To pre-
droxyl groups in 23 are first converted into the correspond- pare these nonidentically-substituted phthalocyanines, 38a
ing ditriflate, 24, which is replaced by cyanide using and 38b, a suitable route is the statistical condensation of
Zn(CN)2 and a palladium-dppf catalyst to give the two different phthalonitriles in a specific ratio. The syn-
phthalonitrile derivative, 25, in high yields.[17] Treating thesis of the ester phthalonitriles, 33a and 33b, and the car-
phthalonitrile 25 with Zn(OAc)2 in n-pentanol and cata- boxyl phthalonitrile, 36, are illustrated in Schemes 5 and
lytic amounts of DBU at 130°C furnishes, after chromato- 6, respectively. Starting from 4,5-dibromocatechol (1) the
graphic purification, the corresponding zinc phthalocyan- protection of the catechol function as cyclohexylidene ketal
ine, 26, as a mixture of four constitutional isomers,[21] 28 is necessary to enable chromatographic purification in
which were not separated. Compound 26 is highly soluble further reaction steps. The dibromo compound, 28, is con-
in common organic solvents like hexane, chloroform, THF, verted into the unsaturated esters 29a or 29b by treating it
or MeOH. Alkaline hydrolysis finally leads to the tetracar- with ethyl acrylate or ethyl methacrylate, respectively, in a
boxylic acid, 27, which exhibits good water solubility. The Heck reaction with Pd(OAc)2 as catalyst.[23] Subsequent
UV-spectrum of 27 shows, as expected, a sharp Q-band at hydrogenation of the double bonds at atmospheric pressure
678 nm, accompanied by transitions into excited vibration using palladium on charcoal leads to the saturated esters
states, without any absorption of aggregated species.
30a and 30b, respectively. Cleavage of the ketal, followed
by triflate introduction, and finally, the substitution of the
triflate groups by cyanide leads to the desired nitriles 33a
and 33b, respectively. The phthalonitrile component carry-
ing the carboxyl function is prepared starting from 4-
iodophthalonitrile (34), which is alkenylated in a Heck reac-
tion with benzyl pent-4-enoate to the corresponding benzyl
ester, 35. In a subsequent hydrogenation at atmospheric
Synthesis of Nonidentically-Substituted
Phthalocyanines, 41
To enable a defined linkage of the phthalocyanine to the
antibody, a suitable anchor group, e.g. a succinimidyl active
Scheme 4. Synthesis of 27 starting from the protected catechol 19
3444
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Synthesis of Novel Functionalised Zinc Phthalocyanines Applicable in Photodynamic Therapy
FULL PAPER
Scheme 5. Synthesis of the phthalonitriles 33a and 33b
pressure using palladium on charcoal, hydrogenation of the cinimide (NHS). Finally, catalytic hydrogenation at atmos-
double bond and hydrogenolysis of the benzyl group pro- pheric pressure leads to the carboxylic acids 41a and 41b,
ceed simultaneously to give the phthalonitrile 36 in good respectively, with preservation of the active ester functions.
yields.
In-vitro Cytotoxicity Investigations
To investigate the phototoxicity towards cultivated T47d
human mammary carcinoma cells we exemplarily chose the
phthalocyanines 5, 11, 16, and 27 as sensitisers. All experi-
ments were run with an amount of 5·104 cells in phosphate
buffered saline (PBS). The phthalocyanine sensitisers were
dissolved in PBS containing 5% of DMSO, to give a con-
Scheme 6. Synthesis of 36
centration of 1 mg/mL, and were further dilluted to 10Ϫ1
,
As shown in Scheme 7, the statistical condensation[18][21] 10Ϫ2, and 10Ϫ3 mg/mL. Addition of these solutions to the
of the two different nitriles, 33a or 33b and 36, in a molar cell suspension finally lead to sensitiser concentrations of
ratio 6:1 is carried out in benzyl alcohol with Zn(OAc)2 and 0.5, 5·10Ϫ2, 5·10Ϫ3, and 5·10Ϫ4 mg/mL, respectively. The
catalytic amounts of DBU at 130°C. Benzyl alcohol was cell survival rate was determined four hours after ir-
chosen as solvent to convert the ester functions into the radiation with a fluence of 5 J·cmϪ2. A laser tuned to the
corresponding benzyl esters. The desired reaction products, absorption maximum of the corresponding phthalocyanine
in our case the symmetric compounds 37a or 37b, and the (approx. 675 nm) was used as the light emitting source. A
monocarboxyl complexes 38a or 38b, have to be separated certain amount of cells was removed and, after lysing using
from the mixture using column chromatography with gradi- a commercially available lysing solution, the content of
ent elution. In the case of the linearly substituted phthalo- ATP was measured by an ATP bioluminescence assay,
cyanines 37a and 38a, the use of CHCl3/EtOAc yields the which utilizes the ATP dependence of light emittance of the
symmetric phthalocyanine 37a as the first fraction. Chang- biooxidation of luciferine. The cell survival rate is deter-
ing the eluent to CHCl3/THF elutes monocarboxyl com- mined by the ratio of ATP content after irradiation com-
pound 38a as the second fraction. Separation of the pared to the nonirradiated sample.
branched systems 37b and 38b proceeds similarly; CHCl3/
Figure 1 shows the results for compound 27 compared
EtOAc gives 37b as the first fraction, and CHCl3/EtOAc/ to the survival rates of the similarily treated, nonirradiated
AcOH yields 38b, which has to be further purified in a se- sample, and a negative control which was treated in the
cond chromatographic step. As shown in Scheme 8, the same way (cells ϩ PBS ϩ DMSO ϩ irradiation) but without
symmetric octaesters 37a and 37b are hydrolysed in meth- addition of sensitiser. Due to a significantly lower aggre-
anolic NaOH to the corresponding octacarboxylic acids gation tendency, leading to higher singlet oxygen quantum
39a and 39b, respectively. The monocarboxyl phthalocyan- yields at lower concentrations, a maximum effectiveness at
ines 38a and 38b are converted into the corresponding ac- 5·10Ϫ2 mg/mL for compound 27 is observed. Further di-
tive esters 40a and 40b, respectively, with N-hydroxysuc- lution leads to absolute amounts of sensitisers which are
Eur. J. Org. Chem. 1999, 3441Ϫ3453
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U. Drechsler, M. Pfaff, M. Hanack
FULL PAPER
Scheme 7. Statistical condensation of 33 and 36
Scheme 8. Synthesis of the phthalocyanines 39, 40 and 41
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Eur. J. Org. Chem. 1999, 3441Ϫ3453

Synthesis of Novel Functionalised Zinc Phthalocyanines Applicable in Photodynamic Therapy
FULL PAPER
too low to be effective. In Figure 2 the results for compound
27 are compared with those for compound 5. It is obvious
Experimental Section
General: All melting points are uncorrected. Ϫ Commercially avail-
able starting compounds were directly used without further purifi-
cation. All reactions were carried out under nitrogen atmosphere
in degassed solvents, which were dried using conventional methods.
The following precursors were prepared according to literature pro-
cedures: 4,5-dibromocatechol,[24] N-tert-butyloxycarbonyl-(3,4-di-
cyanophenyl)alanine methyl ester,[17] 1O,2O-cyclohexylidene cat-
echol,[19] 4-iodophthalonitrile,[25] and 3-(hydroxymethyl)-3-methyl-
oxetane.[26] The compounds 2, 7, 8, 13, 18, 20, 21, 22, 23, 28, 29,
30, 31, and 35 were prepared as intermediates. It was not possible
to obtain mass spectra of carboxylic acids 5, 11, 27, 41a, and 41b
with the available methods (EI, FD, FAB). Because of the incom-
plete combustion of these compounds no elemental analysis can be
given. Ϫ FT-IR: Bruker IFS 48. Ϫ UV/Vis: Shimadzu UV-365. Ϫ
MS: Varian Mat 711 (EI, FD, FAB). Ϫ 1H-, 13C NMR: Bruker
that compound 5 shows no phototoxicity over the entire
concentration range, which is supposed to be the result of
a diminished singlet oxygen yield caused by the substitution
of the macrocycle by hetero atoms. Whereas the tetraamino
acid 11 showed only a poor phototoxicity, the serine deriva-
tive 16 exhibits even a dark toxicity, which was concluded
from the decrease of the cell amount under influence of
compound 16 without any irradiation.
1
ARX 250 (250 MHz and 62.9 MHz, for H and 13C, respectively).
The deuterated solvent was used as internal standard. Ϫ Elemental
Analyses: Carlo Erba Elemental Analyser 1104, 1106.
4,5-Bis[1-(ethyloxycarbonyl)ethyloxy]-1,2-dibromobenzene (2): To a
suspension of sodium methoxide (2.3 g, 41.8 mmol) in DMF
(20 mL) was added, dropwise, 4,5-dibromocatechol (5.6 g,
20.8 mmol) in DMF (20 mL) at 0°C. After stirring the mixture
for 1 h at 0°C, ethyl 2-bromopropionate (5.4 mL, 41.8 mmol) was
added. After the addition was complete, the mixture was stirred for
8Ϫ10 h at 120°C. The recooled mixture was poured into 150 mL
of ice water and the product was extracted three times with 100 mL
of ethyl acetate. The combined organic phases were dried with
Na2SO4 and the solvent was removed by rotary evaporation. Col-
umn chromatography of the residue on silica gel using chloroform
as eluent gave 2 (5.3 g, 54%) as a colourless oil. Ϫ 1H NMR
(CDCl3): δ ϭ 1.20 (t, J ϭ 7.08 Hz, 6 H, 2ϫCO2CH2CH3), 1.55 (d,
J ϭ 6.88 Hz, 6 H, 2ϫCH3), 4.14 (q, J ϭ 7.10 Hz, 4 H,
2ϫCO2CH2CH3), 4.72 (q, J ϭ 6.88 Hz, 2 H, 2ϫOCH), 7.08 (s, 2
H, aromatic H). Ϫ 13C NMR (CDCl3): δ ϭ 14.0 (CO2CH2CH3),
18.2 (CH3), 61.2 (CO2CH2CH3), 74.4 (OCH), 116.6 (aromatic
CBr), 122.1 (aromatic CH), 147.8 (aromatic COCH), 171.1 (CϭO).
Figure 1. Cell survival rates at different sensitiser concentrations.
a) Phthalocyanine 27, irradiated; b) Phthalocyanine 27, nonirradi-
ated; c) Negative control, irradiation without sensitiser
4,5-Bis[1-(ethyloxycarbonyl)ethyloxy]benzene-1,2-dicarbonitrile (3):
CuICN (3.6 g, 40.0 mmol) and 2 (5.3 g, 11.0 mmol) were dissolved
in DMF (20 mL). The mixture was stirred at 130°C for 4Ϫ5 h.
Figure 2. Comparison of different sensitisers. a) Phthalocyanine 27;
b) Phthalocyanine 5
After cooling the mixture to room temp.,
a solution of
FeCl3 · 6 H2O (11.9 g, 40.0 mmol) and 1 mL of concd. HCl in
20 mL of water was added and the resulting mixture was heated to
70°C for 15 min. The reaction mixture was cooled to room temp.
and poured into 200 mL of ice-water. The resulting mixture was
extracted three times with chloroform and the combined organic
phases were washed with 100 mL of dilute HCl, 100 mL of satu-
rated aqueous NaHCO3, and 100 mL of water and dried with
Na2SO4. After evaporation of the solvent, the residue was purified
Conclusion
We have developed novel synthetic routes to several
water-soluble zinc phthalocyanines, including carboxyl
groups and, for the first time, amino acid functions in the
periphery of the macrocycles. Due to a labelled anchor
group, some of the new compounds could selectively be
linked to tumor-selective antibodies. All new phthalocyan- by chromatography, on normal grade silica gel, using CHCl3/ethyl
acetate (5:1) as eluent to give 3 (2.0 g, 50.5%) as a colourless oil.
ines exhibit only weak tendencies to form stacked aggre-
gates in solution. These compounds should therefore be ex-
cellent sensitizers for singlet oxygen generation in the pho-
todynamic therapy of cancer. In-vitro investigations to
study the effectiveness of some of the new compounds
towards cancer cells were performed. In particular, the
weakly aggregated compound, 27, showed a good photo-
toxicity, whereas others exhibit an acute toxicity towards
the employed cells. Further investigations, involving tumor-
selective antibodies are in progress.
Ϫ IR (film): ν˜ ϭ 2990 cmϪ1, 2941, 2232, 1745, 1591, 1514, 1290,
1
1205, 1099. Ϫ H NMR (CDCl3): δ ϭ 1.24 (t, J ϭ 7.10 Hz, 6 H,
2ϫCO2CH2CH3), 1.65 (d, J ϭ 6.88 Hz, 6 H, 2ϫCH3), 4.19 (q, J ϭ
7.10 Hz, 4 H, 2ϫCO2CH2CH3), 4.86 (q, J ϭ 6.88 Hz, 2 H,
2ϫOCH), 7.12 (s, 2 H, aromatic H). Ϫ 13C NMR (CDCl3): δ ϭ
14.0 (CO2CH2CH3), 18.2 (CH3), 61.6 (CO2CH2CH3), 74.3 (OCH),
109.7 (CCN), 115.3 (CN), 120.2 (aromatic CH), 151.4 (aromatic
COCH), 170.2 (CϭO). Ϫ MS (EI) m/z: 360.2, [Mϩ] 287.1, 171.1.
Ϫ C18H20N2O6 (360.4): calcd. C 59.99, H 5.59, N 7.77; found C
59.80, H 5.50, N 8.03.
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U. Drechsler, M. Pfaff, M. Hanack
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N-(3,4-Dibromobenzoyl)-O-tert-butylserine Methyl Ester (13): A
solution of O-tert-butylserine methyl ester p-toluenesulfonyl salt
(3.5 g, 10.1 mmol), 3,4-dibromobenzoyl chloride (12) (3.0 g,
10.1 mmol), and dry pyridine (1.63 mL) in THF (60 mL) was
stirred under nitrogen at room temp. overnight. The resulting mix-
ture was poured into 200 mL of ice water and the product was
extracted three times with dichloromethane. The combined organic
layers were washed with water, dried with MgSO4, and the solvent
was evaporated. The residue was purified by column chromatogra-
phy on silica gel using CHCl3/ethyl acetate (2:1) as eluent to give
CH3), 1.54 (m, 4 H, 2ϫCH2), 1.76 (m, 2 H, CH2), 3.29 (t, J ϭ
6.70 Hz, 2 H, BrCH2), 3.78 (s, 6 H, 3ϫOCH2). Ϫ 13C NMR
(CDCl3): δ ϭ 14.3 (CH3), 21.8 (CH2), 30.0 [(OCH2)3CCH3], 32.3
(CH2), 33.4 (CH2), 35.4 (BrCH2), 72.3 (OCH2), 108.5
[CH2C(OCH2)3].
1,2-Di-O-Cyclohexylidene-3-[4-(4-methyl-2,6,7-trioxabicyclo[2.2.2]-
oct-1-yl)butyl]catechol (20): To a solution of 19 (6.6 g, 35.0 mmol)
in THF (40 mL) and diethyl ether (20 mL) was added, dropwise,
1.6  butyllithium in hexane (24.0 mL, 38.0 mmol) at Ϫ10°C. After
complete addition the mixture was stirred for 1 h at 0°C, and for
further 8 h at room temp. The mixture was recooled to Ϫ15°C and
18 (7.4 g, 28.0 mmol) in THF (10 mL) was added dropwise. The
mixture was stirred overnight at 0°C and 2Ϫ3 h at room temp.,
poured into 100 mL of ice water and extracted three times with
diethyl ether. The combined organic layers were dried with Na2SO4
and all volatile products were removed on a rotary evaporator. The
residue was purified by chromatography on silica gel with hexane/
ethyl acetate (9:1) as eluent, to give 20 (6.3 g, 60%) as a yellowish
oil, which was used directly without further characterisation.
13 (3.8 g, 86.5%) as a yellowish oil. Ϫ IR (film): ν˜ ϭ 3319 cmϪ1
2974, 2878, 1749, 1657, 1585, 1533, 1456, 1364, 1348, 1234, 1096.
1H NMR (CDCl3): δ ϭ 1.07 [s, 9 H, C(CH3)3], 3.60 (m, 1 H,
,
Ϫ
CH2OtBu), 3.70 (s, 3 H, CO2CH3), 3.81 (m, 1 H, CH2OtBu), 4.80
(m, 1 H, HNCH), 7.00 (d, J ϭ 8.20 Hz, 1 H, NH), 7.45 (m, 1 H,
aromatic H), 7.59 (d, J ϭ 8.10 Hz, 1 H, aromatic H), 7.98 (d, J ϭ
1.90 Hz, 1 H, aromatic H). Ϫ 13C NMR (CDCl3): δ ϭ 27.1
[C(CH3)3], 52.3 (CO2CH3), 53.3 (HNCH), 61.7 (CH2), 73.4
[C(CH3)3], 125.1 (CBr), 126.7 (aromatic CH), 128.5 (CBr), 132.4
(aromatic CH), 133.6 (aromatic CH), 134.4 (aromatic CCϭO),
164.7 (ArCONH), 170.6 (CϭO). Ϫ MS (EI) m/z: 438.0 [Mϩ ϩ 1],
262.9. Ϫ C15H19Br2NO4 (437.1): calcd. C 41.21, H 4.38, N 3.20;
Br, 36.56; found C 40.94, H 4.35, N 3.31, Br 36.62.
1,2-Di-O-Cyclohexylidene-3-{4-[2,2-bis(hydroxymethyl)propyl-
oxycarbonyl]butyl}catechol (21): To a solution of crude 20 (6.3 g,
16.8 mmol) in THF (50 mL) was added at, 0°C, a solution of
TsOHиH2O (650 mg, 3.4 mmol) in water (5 mL). After slow warm-
ing to room temp., the mixture was stirred for 3 h, poured into
150 mL of water and extracted three times with diethyl ether. The
combined organic phases were washed with saturated NaHCO3
and water, dried with Na2SO4, and the solvent was evaporated. The
residue was purified chromatographically on silica gel with chloro-
form/ethyl acetate (2:1) to give 21 (5.4 g, 80.5%) as a yellowish oil.
N-(3,4-Dicyanobenzoyl)-O-tert-butylserine Methyl Ester (14): The
same procedure as for the preparation of 3 was used. CuICN (3.4 g,
38.0 mmol), 13 (4.8 g, 10.9 mmol) and FeCl3 · 6 H2O (14.9 g,
55.0 mmol) gave, after column chromatography on silica gel using
CHCl3/ethyl acetate (2:1), 14 (1.1 g, 30%) as a colourless powder.
m.p. 108Ϫ109°C. Ϫ IR (KBr): ν˜ ϭ 3279 cmϪ1, 2976, 2241, 1745,
1734, 1649, 1437, 872. Ϫ 1H NMR (CDCl3): δ ϭ 1.12 [s, 9 H,
C(CH3)3], 3.67 (m, 1 H, CH2OtBu), 3.76 (s, 3 H, CO2CH3), 3.89
(m, 1 H, CH2OtBu), 4.85 (m, 1 H, HNCH), 7.07 (d, J ϭ 8.10 Hz,
1 H, NH), 7.90 (d, J ϭ 8.10 Hz, 1 H, aromatic H), 8.12 (m, 1 H,
aromatic H), 8.23 (d, J ϭ 1.20 Hz, 1 H, aromatic H). Ϫ 13C NMR
(CDCl3): δ ϭ 27.0 [C(CH3)3], 52.4 (CO2CH3), 53.5 (HNCH), 61.4
(CH2), 73.6 [C(CH3)3], 114.5 (CN), 114.6 (CN), 116.0 (CCN), 117.8
(CCN), 131.5 (aromatic CH), 132.4 (aromatic CH), 133.7 (aromatic
CH), 138.3 (aromatic CCϭO), 163.3 (ArCONH), 170.2 (CϭO). Ϫ
1
Ϫ H NMR (CDCl3): δ ϭ 0.80 (s, 3 H, CH3), 1.46 (m, 2 H, CH2
cyclohexyl ), 1.65 (m, 8 H, 4ϫCH2), 1.84 (m, 4 H, 2ϫCH2 cyclo-
hexyl), 2.36 (t, J ϭ 7.08 Hz, 2 H, CH2CO2CH2), 2.55 (t, J ϭ
7.10 Hz, 2 H, ArCH2), 2.98 (s, 2 H, 2ϫOH), 3.48 (s, 4 H,
2ϫCH2OH), 4.11 (s, 2 H, CH2CO2CH2), 6.60 (m, 3 H, aromatic
H). Ϫ 13C NMR (CDCl3): δ ϭ 16.7 (CH3), 23.1 (CH2), 24.4 (CH2),
24.5 (CH2 cyclohexyl), 28.7 (CH2), 28.8 (CH2 cyclohexyl), 34.0
(ArCH2), 35.1 (CH2 cyclohexyl), 40.6 [CH2C(CH2OH)2CH3], 66.3
(CH2OH), 67.2 (CH2CO2CH2), 106.2 [(O)2C(CH2)2], 117.7 (aro-
matic C), 120.5 (aromatic C), 121.6 (aromatic C), 122.9 (aromatic
CCH2), 145.4 (aromatic C), 146.8 (aromatic C), 174.5 (CϭO). Ϫ
MS (EI) m/z: 392.1 .[Mϩ] Ϫ C22H32O6 (392.5): calcd. C 67.32, H
8.22; found C 67.50, H, 8.23.
MS (EI) m/z: 330.1 [Mϩ], 299.0, 155.0, 127.0.
Ϫ
C17H19N3O4(329.4): calcd. C 62.00, H 5.81, N 12.76; found C
61.11, H 5.76, N 12.58.
1-(4-Bromobutyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane (18): To
a solution of 17 (13.5 g, 75.0 mmol) in dichloromethane (30 mL)
was added, dropwise, oxalyl chloride (8.6 mL, 100.0 mmol) at 0°C.
The resulting solution was stirred overnight at room temp. and all
volatile components were removed on a rotary evaporator. The resi-
due was redissolved in 15 mL of dichloromethane and added drop-
wise at 0°C to a solution of 3-(hydroxymethyl)-3-methyloxetane
(7.6 g, 75.0 mmol) and dry pyridine (6.0 mL, 75.0 mmol) in di-
chloromethane (15 mL). The reaction mixture was stirred at room
temp. for 4Ϫ6 h, evaporated, and the residue was filtered over a
short pad of silica gel pretreated with 10% triethylamine in di-
chloromethane. Evaporation to dryness gave a colourless oil, which
was directly converted without further characterisation. To a solu-
tion of the obtained oil in 50 mL of dichloromethane was added,
dropwise, at Ϫ15°C, freshly distilled borontrifluoride diethyl ether
(2.5 mL, 20.0 mmol). After stirring for 8 h at Ϫ15°C, triethylamine
(10 mL) was added and the resulting solution was poured into
150 mL of diethyl ether to precipitate the resulting borontrifluoride
triethylamine complex. The filtrate was eluted over a short pad
of silica gel, which had been pretreated with 10% triethylamine in
dichloromethane. Evaporation of the solvent gave 18 (14.9 g,
1,2-Di-O-Cyclohexylidene-3-[4-(methyloxycarbonyl)butyl]catechol
(22): A solution of 21 (5.4 g, 13.7 mmol) and sodium methoxide
(54 mg, 1.0 mmol) in MeOH (20 mL) was stirred at room temp. for
8 h. The solvent was removed in vacuo, and the residue was eluted
with chloroform over a short pad of silica gel to give 22 (3.8 g,
1
91%) as a yellowish oil. Ϫ H NMR (CDCl3): δ ϭ 1.48 (m, 2 H,
CH2 cyclohexyl), 1.65 (m, 8 H, CH2), 1.87 (m, 4 H, 2ϫCH2 cyclo-
hexyl), 2.32 (t, J ϭ 7.08 Hz, 2 H, CH2CO2CH3), 2.53 (t, J ϭ
7.10 Hz, 2 H, ArCH2), 3.63 (s, 3 H, CO2CH3), 6.60 (m, 3 H, aro-
matic H). Ϫ 13C NMR (CDCl3): δ ϭ 23.0 (CH2), 24.4 (CH2), 24.5
(CH2 cyclohexyl), 28.8 (CH2), 28.9 (CH2 cyclohexyl), 33.7
(ArCH2), 35.0 (CH2 cyclohexyl), 51.2 (CO2CH3), 106.0
[(CH2)2C(O)2 cyclohexyl], 117.5 (aromatic CH), 120.4 (aromatic
CH), 121.5 (aromatic CH), 122.9 (aromatic CCH2), 145.3 (aromatic
C), 146.7 (aromatic C), 173.8 (CϭO). Ϫ MS (EI) m/z: 304.1 [Mϩ].
Ϫ C18H24O4(304.4): C 71.03, H 7.95; found C 71.11, H 7.69.
3-[4-(Methyloxycarbonyl)butyl]catechol (23): Compound 22 (3.8 g,
12.5 mmol) was dissolved in trifluoroacetic acid (19 mL) and water
(1 mL). The solution was stirred at room temp. for 1 h, poured into
150 mL of ice water and the product was extracted three times with
1
81.5%) as a yellowish oil. Ϫ H NMR (CDCl3): δ ϭ 0.70 (s, 3 H,
3448
Eur. J. Org. Chem. 1999, 3441Ϫ3453

Synthesis of Novel Functionalised Zinc Phthalocyanines Applicable in Photodynamic Therapy
FULL PAPER
diethyl ether. The combined organic phases were washed with satu-
rated aqueous NaHCO3 and water, dried with Na2SO4, and the
der reflux overnight with azeotropic removal of the developed
water. After cooling to room temp., the solution was washed with
solvent was removed under reduced pressure. The residue was dried 100 mL of saturated aqueous NaHCO3 and 100 mL of water, dried
in vacuo to give 23 (1.6 g, 57%) as light brown oil. Ϫ 1H NMR
([D4]methanol): δ ϭ 1.60 (m, 4 H, CH2), 2.31 (t, J ϭ 7.10 Hz, 2
with Na2SO4, and the solvent was removed under vacuo. The resi-
due was recrystallised from EtOH/water (10:1) to give 28 (26.1 g,
H, CH2CO2CH3), 2.58 (t, J ϭ 7.20 Hz, 2 H, ArCH2), 3.61 (s, 3 H, 75%) as yellowish powder. m.p. 127Ϫ129°C. Ϫ 1H NMR (CDCl3):
CO2CH3), 4.79 (s, 2 H, 2ϫOH), 6.59 (m, 3 H, aromatic H). Ϫ 13C δ ϭ 1.46 (m, 2 H, CH2), 1.67 (m, 4 H, 2ϫCH2), 1.86 (m, 4 H,
NMR ([D4]methanol):
δ ϭ 24.4 (CH2), 29.1 (CH2), 29.2 2ϫCH2), 6.94 (s, 2 H, aromatic H).
(CH2CO2CH3), 33.4 (ArCH2), 50.7 (CH2CO2CH3), 112.5 (aro-
matic CH), 118.9 (aromatic CH), 120.6 (aromatic CH), 128.7 (aro-
matic CCH2), 142.9 (aromatic COH), 144.5 (aromatic COH), 174.8
(CϭO).
4,5-Bis[2-(ethyloxycarbonyl)ethenyl]-1,2-di-O-cyclohexylidene-
catechol (29a). ؊ General Procedure: A mixture of 28 (6.0 g,
17.0 mmol), K2CO3 (9.7 g, 70.0 mmol), tetrabutylammonium bro-
mide (8.0 g, 25.0 mmol), Pd(OAc)2 (225 mg, 1.0 mmol), and ethyl
acrylate (7.5 mL, 70.0 mmol) in DMF (30 mL) was heated to 90°C.
The mixture was stirred at this temperature until TLC-monitoring
indicated the complete conversion of 28 (5Ϫ6 h). After cooling to
room temp., the mixture was poured into 150 mL of dichlorometh-
ane and filtered over a short pad of silica gel. The filtrate was
washed with 0.1  HCl, water, saturated aqueous NaHCO3, and
water again, dried with MgSO4, and evaporated to dryness. The
1,2-Di-O-Bis(trifluoromethanesulfonyl)-3-[4-(methyloxycarbonyl)-
butyl]catechol (24). ؊ General Procedure: To a solution of trifluoro-
methanesulfonic anhydride (3.0 mL, 17.8 mmol) in dichlorometh-
ane (5 mL) were added 23 (1.6 g, 7.1 mmol) and triethylamine
(2.5 mL, 17.8 mmol) in dichloromethane (10 mL) at Ϫ20°C over a
1 h period. After slow warming to room temp. and stirring over-
night, the mixture was poured into 100 mL of ice-cold water. The
product was extracted three times with dichloromethane, the com- residue was purified by chromatography on silica gel using chloro-
bined organic phases were washed with water, dried with MgSO4,
and evaporated to dryness by rotary evaporation. The residue was
purified by chromatography on silica gel using hexane/ethyl acetate
form as eluent, to give 29a (5.9 g, 90%) as a yellowish oil. Ϫ IR
1
(film): ν˜ ϭ 2939 cmϪ1, 1717, 1630, 1609, 1491, 1167. Ϫ H NMR
(CDCl3): δ ϭ 1.31 (t, J ϭ 7.05 Hz, 6 H, 2ϫ CO2CH2CH3), 1.48
(2:1) as eluent to give 24 in 89% yield as yellowish oil. Ϫ IR (film): (m, 2 H, CH2), 1.71 (m, 4 H, 2ϫCH2), 1.88 (m, 4 H, 2ϫCH2), 4.23
1
ν˜ ϭ 2955 cmϪ1, 1740, 1431, 1225, 1138. Ϫ H NMR (CDCl3): δ ϭ
(q, J ϭ 7.03 Hz, 4 H, 2ϫCO2CH2CH3), 6.18 (d, J ϭ 15.6 Hz, 2 H,
1.65 (m, 4 H, 2ϫCH2), 2.30 (t, J ϭ 6.88 Hz, 2 H, CH2CO2CH3), 2ϫArCHCH), 6.92 (s, 2 H, aromatic H), 7.98 (d, J ϭ 15.6 Hz, 2
2.76 (t, J ϭ 7.38 Hz, 2 H, ArCH2), 3.60 (s, 3 H, CO2CH3), 7.30 H, 2ϫArCH). Ϫ 13C NMR (CDCl3): δ ϭ 14.3 (CO2CH2CH3), 23.1
(m, 3 H, aromatic H). Ϫ 13C NMR (CDCl3): δ ϭ 24.3 (CH2), 28.9 (CH2), 24.3 (CH2), 35.2 (CH2), 60.5 (CO2CH2CH3), 106.1
(CH2), 29.8 (CH2CO2CH3), 33.3 (ArCH2), 51.3 (CO2CH3), 118.4 [(O)2C(CH2)2], 119.4 (aromatic CH), 120.6 (ArCHCH), 128.8 (aro-
(q, JCF ϭ 314.5 Hz, CF3), 120.7 (aromatic CH), 129.1 (aromatic
matic CCH), 140.5 (aromatic C), 149.7 (ArCH), 166.6 (CϭO). Ϫ
CH), 130.3 (aromatic CH), 138.1 (aromatic CCH2), 138.8 (aromatic MS (EI) m/z: 386.2 [Mϩ]. Ϫ C22H26O6 (386.4): calcd. C 68.38, H
COTf), 141.0 (aromatic COTf), 173.5 (CϭO). Ϫ MS (EI) m/z: 6.78; found C 68.21, H 6.83.
489.0 [Mϩ ϩ 1]. Ϫ C14H14F6S2O8(488.4): calcd. C 34.43, H 2.89,
4,5-Bis[2-(ethyloxycarbonyl)ethyl]-1,2-di-O-cyclohexylidene-
catechol (30a). ؊ General Procedure: Compound 24a (5.9 g,
F 23.34, S 13.13; found C 34.66, H 2.82, F 24.04, S 13.11.
3-(4-Methyloxycarbonyl)butyl-1,2-benzenedicarbonitrile (25).
General Procedure: To a solution of tris(dibenzylideneacetone)di-
؊
15.3 mmol) was dissolved in EtOH (100 mL) and, after addition of
10% palladium on charcoal (200 mg), hydrogenated in a hydrogen-
palladium-chloroform adduct (260 mg, 0.25 mmol) and 1,1Ј-bis(di- ation apparatus at atmospheric pressure for 2 days. After complete
phenylphosphanyl)ferrocene (560 mg, 1.0 mmol) in DMF (15 mL) reaction, the catalyst was filtered off, the filtrate was evaporated,
was added 24 (3.0 g, 6.2 mmol) at room temp. The resulting solu-
tion was warmed to 90°C and Zn(CN)2 (870 mg, 7.4 mmol) was
added in small portions over a 3 h period. After complete addition,
and the residue was crystallised in the refrigerator. The title com-
pound 30a (5.6 g, 94%) was obtained as a yellowish powder. m.p.
69Ϫ71°C. Ϫ IR (KBr): ν˜ ϭ 2947 cmϪ1, 1730, 1499, 1367, 1285,
1
the mixture was stirred further for 3 h at 90°C. After cooling to 1248, 1177, 1094. Ϫ H NMR (CDCl3): δ ϭ 1.22 (t, J ϭ 7.08 Hz,
room temp., the solution was poured into 150 mL of ice water and
the product was extracted three times with dichloromethane. The
combined organic layers were washed with 0.1  HCl, water, satu-
6 H, 2ϫCO2CH2CH3), 1.45 (m, 2 H, CH2), 1.68 (m, 4 H, 2ϫCH2),
1.84 (m, 4 H, 2ϫCH2), 2.50 (t, J ϭ 7.80 Hz, 4 H, 2ϫArCH2CH2),
2.82 (t, J ϭ 7.90 Hz, 4 H, 2ϫArCH2), 4.11 (q, J ϭ 7.10 Hz, 4 H,
rated aqueous NaHCO3, and water again, dried with MgSO4, and 2ϫCO2CH2CH3), 6.52 (s, 2 H, aromatic H). Ϫ 13C NMR (CDCl3):
finally evaporated to dryness. The residue was purified by flash
chromatography on silica gel using hexane/ethyl acetate (2:1) as
δ
ϭ
14.2 (CO2CH2CH3), 23.1 (CH2), 24.5 (CH2), 27.5
(ArCH2CH2), 35.1 (CH2), 35.7 (ArCH2), 60.4 (CO2CH2CH3),
eluent to give 25 (1.2 g, 81%) as colourless needles. Ϫ m.p. 55°C. 108.8 [(O)2C(CH2)2], 118.4 (aromatic C), 130.5 (aromatic CH),
Ϫ IR (KBr): ν˜ ϭ 2951 cmϪ1, 2868, 2233, 1734, 1587, 1464, 1437,
1198. Ϫ 1H NMR (CDCl3): δ ϭ 1.68 (m, 4 H, 2ϫCH2), 2.34 (t,
J ϭ 6.88 Hz, 2 H, CH2CO2CH3), 2.89 (t, J ϭ 7.20 Hz, 2 H,
ArCH2), 3.64 (s, 3 H, CO2CH3), 7.60 (m, 3 H, aromatic H). Ϫ 13C
NMR (CDCl3): δ ϭ 24.3 (CH2), 29.9 (CH2), 33.5 (CH2CO2CH3),
34.4 (ArCH2), 51.6 (CO2CH3), 114.6 (aromatic CCN), 115.7 (CN),
116.4 (aromatic CCN), 131.2 (aromatic CH), 132.9 (aromatic CH),
133.7 (aromatic CH), 148.2 (aromatic CCH2), 173.6 (CϭO). Ϫ
C14H14N2O2(242.3): calcd. C 69.41, H 5.82, N 11.56; found C
69.73, H 5.69, N 11.67.
146.0 (aromatic CCH2), 172.8 (CϭO). Ϫ MS (EI) m/z: 390.2 [Mϩ].
Ϫ C22H30O6 (390.4): C 67.67, H 7.74; found C 68.17, H 8.16.
4,5-Bis[2-(ethyloxycarbonyl)ethyl]catechol (31a): The same pro-
cedure as for the preparation of 23 was used. Reaction of 30a
(5.6 g, 14.4 mmol), TFA (19 mL), and 1 mL of water gave 31a
(3.0 g, 78%) as light brown solid. m.p. 125Ϫ127°C. Ϫ 1H NMR
([D4]methanol): δ ϭ 1.21 (t, J ϭ 7.08 Hz, 6 H, 2ϫCO2CH2CH3),
2.51 (t, J ϭ 7.95 Hz, 4 H, 2ϫCH2CO2Et), 2.79 (t, J ϭ 7.95 Hz, 4
H, 2ϫArCH2), 4.09 (q, J ϭ 7.10 Hz, 4 H, 2ϫCO2CH2CH3), 4.86
(s, 2 H, 2ϫArOH), 6.57 (s, 2 H, aromatic H). Ϫ 13C NMR ([D4]me-
4,5-Dibromo-1,2-di-O-cyclohexylidenecatechol (28): A solution of 1
(23.6 g, 100 mmol), cyclohexanone (9.8 g, 100 mmol) and
TsOH · H2O (1.0 g, 5.2 mmol) in toluene (300 mL) was heated un-
thanol): δ ϭ 14.5 (CO2CH2CH3), 28.1 (CH2CO2Et), 36.8
(ArCH2CH2), 61.5 (CO2CH2CH3), 117.1 (aromatic CH), 130.7
(aromatic COH), 144.7 (aromatic CCH2), 174.8 (CϭO). Ϫ MS (EI)
Eur. J. Org. Chem. 1999, 3441Ϫ3453
3449

U. Drechsler, M. Pfaff, M. Hanack
m/z: 310.2 [Mϩ]. Ϫ C16H22O6 (310.3): calcd. C 61.92, H 7.15; found (m, 2 H, 2ϫCH), 4.03 (q, J ϭ 7.10 Hz, 4 H, 2ϫCO2CH2CH3),
FULL PAPER
C 62.11, H 7.22.
4.79 (s, 2 H, 2ϫArOH), 6.54 (s, 2 H, aromatic H). Ϫ 13C NMR
([D4]methanol): δ ϭ 14.4 (CO2CH2CH3), 17.4 (CHCH3), 36.9
(ArCH2), 42.6 (CH), 61.4 (CO2CH2CH3), 117.9 (aromatic CH),
129.9 (aromatic COH), 144.5 (aromatic CCH2), 178.0 (CϭO). Ϫ
MS (EI) m/z: 338.1 [Mϩ].
4,5-Bis[2-(ethyloxycarbonyl)ethyl]-1,2-bis(trifluoromethane-
sulfonyloxy)benzene (32a): The same procedure as for the prep-
aration of 24 was used. Reaction of 31a (3.0 g, 10.0 mmol), Tf2O
(3.9 mL, 23.0 mmol), and triethylamine (3.2 mL, 23.0 mmol) gave,
after chromatographic purification on silica gel using hexane/ethyl
acetate (2:1) as eluent, 32a (4.3 g, 75%) as a light-brown oil. Ϫ IR
4,5-Bis[2-(ethyloxycarbonyl)propyl]-1,2-bis(trifluoromethane-
sulfonyloxy)benzene (32b): Same procedure as for the preparation
of 32a. Yield 78% (2.75 g) as a yellowish oil. Ϫ IR (film): ν˜ ϭ
2984 cmϪ1, 1734, 1501, 1435, 1244, 1217. Ϫ 1H NMR (CDCl3):
δ ϭ 1.16 (m, 12 H, 2ϫCO2CH2CH3, 2ϫCHCH3), 2.71 (m, 4 H,
2ϫArCH2), 3.04 (m, 2 H, 2ϫCH), 4.04 (q, J ϭ 7.30 Hz, 4 H,
2ϫCO2CH2CH3), 7.21 (s, 2 H, aromatic H). Ϫ 13C NMR (CDCl3):
δ ϭ 13.9 (CO2CH2CH3), 17.3 (CHCH3), 35.7 (ArCH2), 40.3 (CH),
60.7 (CO2CH2CH3), 118.5 (q, JCF ϭ 320.9 Hz, CF3), 124.4 (aro-
matic CH), 138.2 (aromatic CSO3CF3), 140.5 (aromatic CCH2),
175.0 (CϭO). Ϫ MS (EI) m/z: 602.2 [Mϩ]. Ϫ C20H24F6S2O10
(602.5):calcd. C 39.87, H 4.01, F 18.92, S 10.64; found C 39.78, H
3.84, F 18.99, S 10.60.
(film): ν˜ ϭ 2986 cmϪ1, 1734, 1501, 1433, 1244, 1140, 1040. Ϫ H
1
NMR (CDCl3): δ ϭ 1.38 (t, J ϭ 7.10 Hz, 6 H, 2ϫCO2CH2CH3),
2.79 (t, J ϭ 7.95 Hz, 4 H, 2ϫCH2CO2Et), 3.18 (t, J ϭ 7.95 Hz, 4
H, 2ϫArCH2), 4.28 (q, J ϭ 7.10 Hz, 4 H, 2ϫCO2CH2CH3), 7.44
(s,
2 H, aromatic H). Ϫ δ ϭ 14.0
13C NMR (CDCl3):
(CO2CH2CH3), 26.9 (CH2CO2Et), 34.2 (ArCH2), 60.8
(CO2CH2CH3), 118.5 (q, JCF ϭ 320.7 Hz, CF3), 123.7 (aromatic
CH), 138.5 (aromatic CSO3CF3), 141.1 (aromatic CCH2), 171.8
(CϭO). Ϫ MS (EI) m/z: 574.1 [Mϩ]. Ϫ C18H20F6S2O10 (574.5):
calcd. C 37.63, H 3.51, F 19.84, S 11.16; found C 38.32, H 3.55, F
19.92, S 11.09.
4,5-Bis[2-(ethyloxycarbonyl)propyl]-1,2-benzenedicarbonitrile (33b):
Same procedure as for the preparation of 33a. Yield 75% (1.2 g) as
a yellowish oil. Ϫ IR (film): ν˜ ϭ 2982 cmϪ1, 2939, 2233, 1730, 1464,
4,5-Bis[2-(ethyloxycarbonyl)ethyl]-1,2-benzenedicarbonitrile (33a):
The same procedure as for the preparation of 25 was used. Reac-
tion of 32a (4.7 g, 8.2 mmol), Pd2(dba)3 (340 mg, 0.3 mmol), dppf
(730 mg, 1.3 mmol), and Zn(CN)2 (1.15 g, 9.8 mmol) gave, after
chromatographic purification on silica gel with hexane/ethyl acetate
(2:1), the nitrile 33a (2.0 g, 74%) as a white powder. m.p. 76°C. Ϫ
IR (KBr): ν˜ ϭ 2986 cmϪ1, 2239, 1730, 1288, 1205. Ϫ 1H NMR
(CDCl3): δ ϭ 1.22 (t, J ϭ 7.10 Hz, 6 H, 2ϫCO2CH2CH3), 2.63
(t, J ϭ 7.53 Hz, 4 H, 2ϫCH2CO2Et), 3.04 (t, J ϭ 7.50 Hz, 4 H,
2ϫArCH2CH2), 4.11 (q, J ϭ 7.10 Hz, 4 H, 2ϫCO2CH2CH3), 7.59
1
1182. Ϫ H NMR (CDCl3): δ ϭ 1.18 (m, 12 H, 2ϫCO2CH2CH3,
2ϫCHCH3), 2.69 (m, 4 H, 2ϫArCH2), 3.08 (m, 2 H, 2ϫCH), 4.05
(q, J ϭ 7.08 Hz, 4 H, 2ϫCO2CH2CH3), 7.55 (s, 2 H, aromatic H).
Ϫ
13C NMR (CDCl3): δ ϭ 13.9 (CO2CH2CH3), 17.5 (CHCH3),
35.8 (ArCH2), 40.2 (CH), 60.7 (CO2CH2CH3), 113.4 (aromatic
CCN), 115.3 (ArCN), 134.6 (aromatic CH), 144.7 (aromatic
CCH2), 174.6 (CϭO). Ϫ MS (EI) m/z: 356.1 [Mϩ]. Ϫ C20H24N2O4
(356.4): calcd. C 67.40, H 6.79, N 7.86; found C 67.59, H 6.70,
N 8.20.
(s,
2 H, aromatic H). Ϫ δ ϭ 14.0
13C NMR (CDCl3):
(CO2CH2CH3), 27.1 (CH2CO2Et), 33.7 (ArCH2), 60.9
(CO2CH2CH3), 113.6 (aromatic CCN), 115.3 (ArCN), 133.8 (aro-
matic CH), 145.3 (aromatic CCH2), 171.5 (CϭO). Ϫ MS (EI) m/z:
328.0 [Mϩ]. Ϫ C18H20N2O4 (328.4): calcd. C 65.84, H 6.14, N 8.53;
found C 65.65, H 6.10, N 8.36.
4-(4-Carboxybutyl)-1,2-benzenedicarbonitrile (36): A mixture of 4-
iodophthalonitrile (34) (2.0 g, 8.0 mmol), K2CO3 (2.8 g,
20.0 mmol), Bu4NBr (2.4 g, 8.0 mmol), benzyl penten-4-oate (2.8 g,
15.0 mmol), and Pd(OAc)2 (90 mg, 0.4 mmol) in DMF (25 mL) was
stirred for 6 h at 60°C. After cooling to room temp., the dark mix-
ture was poured into 100 mL of dichloromethane and filtered over
a short pad of silica gel. The filtrate was washed with 0.1  HCl,
water, saturated aqueous NaHCO3, and water again, dried with
Na2SO4, and evaporated. The residue was purified by chromatogra-
phy on silica gel using hexane/ethyl acetate (2:1) as eluent. The
benzyl ester, obtained after evaporation to dryness, was directly
used without further characterisation. The oily compound was dis-
solved in 100 mL of THF and, after addition of 10% palladium on
charcoal (200 mg), hydrogenated at atmospheric pressure until the
consumption of hydrogen was finished (10Ϫ12 h). After the cata-
lyst was filtered off, the filtrate was evaporated and the residue was
crystallised by addition of 50 mL of MeOH/water (2:1) and storing
in the refrigerator overnight. The title compound, 36 (730 mg,
40%), was obtained as a light brown solid. m.p. 111Ϫ113°C. Ϫ IR
(KBr): ν˜ ϭ 3040 cmϪ1, 2951, 2631, 2233, 1709, 1597, 1412, 1227.
4,5-Bis[2-(ethyloxycarbonyl)prop-1-enyl]-1,2-di-O-cyclohexylidene-
catechol (29b): The same procedure as for the preparation of 29a
was used. Reaction of 28 (7.0 g, 20.1 mmol), ethyl methacrylate
(10.3 mL, 83.0 mmol), K2CO3 (11.5 g, 83.0 mmol), Bu4NBr (9.4 g,
30.0 mmol), and Pd(OAc)2 (265 mg, 1.2 mmol) gave, after flash
chromatography on silica gel using chloroform as eluent, 29b (6.7 g,
81%) as yellowish oil. Ϫ IR (film): ν˜ ϭ 2941 cmϪ1, 1711, 1634,
1491, 1366, 1263, 1111. Ϫ MS (EI) m/z: 414.1 [Mϩ].
4,5-Bis[2-(ethyloxycarbonyl)propyl]-1,2-di-O-cyclohexylidene-
catechol (30b): The same procedure as for the preparation of 30a
was used. Yield 95% (6.0 g) as a colourless oil. Ϫ IR (film): ν˜ ϭ
1
2976 cmϪ1, 2939, 1732, 1497, 1366, 1283, 1165, 1096. Ϫ H NMR
(CDCl3): δ ϭ 1.16 (m, 12 H, 2ϫCO2CH2CH3, 2ϫCHCH3), 1.44
(m, 2 H, CH2 cyclohexyl), 1.67 (m, 4 H, 2ϫCH2 cyclohexyl), 1.81
(m, 4 H, 2ϫCH2 cyclohexyl), 2.55 (m, 4 H, 2ϫArCH2), 2.89 (m, 2
H, 2ϫCH), 4.05 (q, J ϭ 7.10 Hz, 4 H, 2ϫCO2CH2CH3), 6.48 (s, 2
H, aromatic H). Ϫ 13C NMR (CDCl3): δ ϭ 14.1 (CO2CH2CH3),
16.8 (CHCH3), 23.1 (CH2 cyclohexyl), 24.5 (CH2 cyclohexyl), 35.1
(CH2 cyclohexyl), 36.2 (ArCH2), 41.2 (CH), 60.2 (CO2CH2CH3),
109.6 [(O)2C(CH2)2], 118.3 (aromatic CH), 129.9 (aromatic CCH2),
145.8 (aromatic C), 176.2 (CϭO). Ϫ MS (EI) m/z: 418.1 [Mϩ]. Ϫ
C24H34O6 (418.5): calcd. C 68.88, H 8.19; found C 68.04, H, 8.06.
1
Ϫ H NMR ([D4]methanol): δ ϭ 1.66 (m, 4 H, 2ϫCH2), 2.32 (t,
J ϭ 7.10 Hz, 2 H, CH2CO2 H), 2.78 (t, J ϭ 7.10 Hz, 2 H, ArCH2),
7.69 (d, J ϭ 8.05 Hz, 1 H, aromatic H), 7.83 (s, 1 H, aromatic H),
7.85 (d, J ϭ 8.15 Hz, 1 H, aromatic H). Ϫ 13C NMR ([D4]me-
thanol): δ ϭ 24.0 (CH2), 29.7 (CH2), 33.1 (CH2CO2 H), 34.7
(ArCH2), 112.5 (aromatic CCN), 115.3 (ArCN), 115.4 (aromatic
CCN), 133.3 (aromatic CH), 133.4 (aromatic CH), 133.5 (aromatic
CH), 149.5 (aromatic CCH2), 178.8 (CϭO). Ϫ MS (EI) m/z: 228.0
[Mϩ]. Ϫ C13H12N2O2 (228.3): calcd. C 68.41, H 5.30, N 12.27;
found C 68.34, H 4.97, N 11.24.
4,5-Bis[2-(ethyloxycarbonyl)propyl]catechol (31b): Same procedure
as for the preparation of 31a. Yield 97% (2.0 g) as a light brown
oil. Ϫ IR (film): ν˜ ϭ 3404 cmϪ1, 2980, 2937, 1728, 1709, 1607,
1
1522, 1454, 1290, 1180. Ϫ H NMR ([D4]methanol): δ ϭ 1.13 (m, 2,3,9,10,16,17,23,24-Octa[1-(pentyloxycarbonyl)ethyloxy]phthalo-
12 H, 2ϫCO2CH2CH3, 2ϫCHCH3), 2.61 (m, 4 H, 2ϫArCH2), 2.78 cyaninatozinc (4). ؊ General Procedure: A solution of 3 (200 mg,
3450
Eur. J. Org. Chem. 1999, 3441Ϫ3453

Synthesis of Novel Functionalised Zinc Phthalocyanines Applicable in Photodynamic Therapy
FULL PAPER
0.6 mmol), Zn(OAc)2 · 2 H2O (100 mg), and catalytic amounts of preparation of 4 was used. Chromatography on silica gel using hex-
DBU in 1-pentanol (5 mL) was stirred at 130°C until TLC-moni- anes/THF (2:1) eluted undesired side products. Changing the eluent
toring indicated the absence of the dinitrile. After cooling to room to hexanes/THF (1:4) gave 15 (210 mg, 17%) as a dark green solid.
temp., the mixture was poured into 100 mL of MeOH/water (4:1),
the precipitate was centrifuged, and purified chromatographically
on silica gel using chloroform/ethyl acetate (4:1) as eluent. Drying
in vacuo gave 4 (75 mg, 27%) as a dark blue solid. Ϫ IR (KBr):
Ϫ IR (KBr): ν˜ ϭ 3312 cmϪ1, 2959, 2932, 1742, 1661, 1614, 1518,
1487, 1196, 1094. Ϫ 1H NMR ([D6]DMSO): δ ϭ 0.94 (t, J ϭ
6.67 Hz, 12 H, 4ϫCH3), 1.14 (m, 8 H, 4ϫCH2CH3), 1.41 [m, 44
H, 4ϫC(CH3)3, 4ϫCH2], 1.80 (m, 8 H, 4ϫCH2), 4.12Ϫ4.33 (m, 16
ν˜ ϭ 2959 cmϪ1, 2932, 1745, 1462, 1406, 1279, 1099. Ϫ UV/Vis H, 4ϫCO2CH2, 4ϫCH2OtBu), 5.04 (s, 4 H, 4ϫCH), 9.45Ϫ8.52 (m,
1
(THF): λmax ϭ 672 nm, 642, 607, 355. Ϫ H NMR ([D5]pyridine):
16 H, macrocyclic H, 4ϫNH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 13.9
(CH3), 21.8 (CH2CH3), 27.4 [C(CH3)3], 27.8 (CH2), 28.1 (CH2),
Due to the presence of different diasteomers, the signals are par-
tially split. δ ϭ 0.62 (m, 24 H, 8ϫCH3), 1.17 (m, 16 H, 8ϫCH2), 54.3 (CH), 61.7 (CO2CH2), 64.7 (CH2OtBu), 73.3 [C(CH3)3], 121.8
1.30 (m, 16 H, 8ϫCH2), 1.74 (m, 16 H, 8ϫCH2), 1.97 (m, 24 H, (macrocyclic CH), 128.4 (macrocyclic CH), 134.7 (macrocyclic C),
8ϫCH3), 4.36 (m, 16 H, 8ϫOCH2), 5.74 (m, 8 H, 8ϫCH), 9.49 (m, 137.0 (macrocyclic C), 139.1 (macrocyclic CCϭO), 151.2 (macro-
8 H, macrocyclic H). Ϫ 13C NMR ([D5]pyridine): δ ϭ 13.9 (CH3), cyclic C), 167.4 (HNCϭO), 171.0 (CϭO). Ϫ MS (FAB) m/z: 1606.3
18.8 (CH3), 22.4 (CH2), 28.1(CH2), 28.7 (CH2), 65.6 (OCH2), 75.0
(CH), 122.6 (macrocyclic C), 134.0 (macrocyclic C), 153.9 (macro-
cyclic C), 172.4 (CϭO).
[Mϩ]. Ϫ UV/Vis (CHCl3): λmax ϭ 682.0 nm, 614.0, 348.0. Ϫ
C84H108N12O16Zn (1607.2): calcd. C 62.77, H 6.77, N 10.46; found
Ϫ
MS (FAB) m/z: 1842.7 [Mϩ]. C 59.92, H 6.93, N 8.82.
ϪC96H128N8O24Zn (1843.5): calcd. C 62.55, H 7.00, N 6.08; found
C 63.12, H 7.08, N 6.68.
2,9,16,23-Tetra(1-carboxy-2-hydroxyethylaminocarbonyl)-
phthalocyaninatozinc (16): To
a
solution of 15 (100 mg,
0.062 mmol) in dry dichloromethane (5 mL) was added TFA
(1.5 mL) at 0°C. The reaction mixture was stirred for 16 h while
the solution was allowed to warm to room temp. All volatile com-
ponents were removed in vacuo and the residue was redissolved in
20 mL of MeOH containing NaOH (15 mg, 0.372 mmol). Stirring
was continued for further 16 h at room temp. The mixture was
poured into 50 mL of water and acidified with dillute HCl to pH 3.
The resulting precipitate was centrifuged, redissolved in 0.1 
NaOH and finally precipitated by addition of 0.1  HCl. Drying
in vacuo gave 16 (49 mg, 71%) as a dark green solid. Ϫ IR (KBr):
ν˜ ϭ 3263 cmϪ1, 2955, 2924, 2363, 1732, 1637, 1529, 1334, 1097. Ϫ
UV/Vis (MeOH): λmax (lg ε) ϭ 675.0 nm (4.83), 634.5 (4.54), 344.5
(4.64). Ϫ1H NMR ([D6]DMSO): δ ϭ 4.05 (d, J ϭ 3.79 Hz, 8 H,
4ϫCH2OH), 4.80 (m, 4 H, 4ϫCH), 9.59 (m, 16 H, macrocyclic H,
4ϫNH). Ϫ 13C NMR ([D6]DMSO): δ ϭ 56.4 (CH), 61.6 (CH2OH),
122.3 (macrocyclic CH), 122.4 (macrocyclic CH), 128.9 (macro-
cyclic CCϭO), 134.9 (macrocyclic C), 137.9 (macrocyclic C), 140.0
(macrocyclic CH), 152.8 (macrocyclic C), 167.2 (CϭO), 172.3 (Cϭ
O). Ϫ MS (MALDI, reflection mode, matrix 2,5-dihydroxybenzoic
acid, MeOH) m/z: 1101.1 [Mϩ]. Ϫ C48H36N12O16Zn (1102.3):
calcd. C 52.33, H 3.29, N 15.25; found C 49.06, H 3.87, N 13.52.
2,3,9,10,16,17,23,24-Octa(1-carboxyethyloxy)phthalocyani-
natozinc (5). ؊ General Procedure: To a solution of 4 (70 mg,
0.04 mmol) in MeOH (2 mL) was added 1  NaOH (0.5 mL). The
mixture was stirred overnight at room temp., acidified to pH 3 with
1  HCl, and the resulting precipitate centrifuged, washed with
water and acetone, and dried in vacuo to give 5 (50 mg, 96%) as a
dark blue solid. Ϫ IR (KBr): ν˜ ϭ 3431 cmϪ1, 2935, 1724, 1630,
1275, 1094, 1045. Ϫ UV/Vis (MeOH): λmax (lg ε) ϭ 672 nm (4.69),
1
640 (4.17), 611 (4.07), 354 (4.43). Ϫ H NMR ([D6]DMSO): δ ϭ
2.13 (m, 24 H, 8ϫCH3), 5.69 (m, 8 H, 8ϫCH), 8.85 (m, 8 H,
macrocyclic H).
2,9,16,23-Tetra[2-(tert-butyloxycarbonylamino)-2-(pentyloxycarb-
onyl)ethyl]phthalocyaninatozinc (10): The same procedure as for the
preparation of 4 was used. After chromatography on silica gel using
dichloromethane/EtOH (15:1) as eluent, 10 (97 mg, 27%) was ob-
tained as a dark green solid. Ϫ IR (KBr): ν˜ ϭ 3431 cmϪ1, 2959,
1740, 1718, 1491, 1167, 1092, 1053. Ϫ UV/Vis (THF): λmax
ϭ
673 nm, 644, 608, 347. Ϫ 1H NMR ([D5]pyridine): δ ϭ 0.65 (t, J ϭ
6.67 Hz, 12 H, 4ϫCH3), 1.14 (m, 16 H, 8ϫCH2), 1.44 [s, 36 H,
4ϫC(CH3)3], 1.61 (m, 8 H, 4ϫCH2), 4.08 (m, 8 H, 4ϫCH2), 4.32
(m, 8 H, 4ϫOCH2), 5.44 (m, 4 H, 4ϫCH), 8.36 (m, 4 H, macro-
cyclic H), 9.77 (m, 8 H, macrocyclic H). Ϫ 13C NMR ([D5]pyrid-
ine): δ ϭ 13.9 (CH3), 22.4 (CH2), 28.2 (CH2), 28.4 [OC(CH3)3],
28.6 (CH2), 39.0 (CH2), 56.8 (CH), 65.5 (OCH2), 78.9 [OC(CH3)3],
129.3, 131.5, 139.6, 148.5, 156.7 (macrocyclic C), 167.9 (CϭO),
173.2 (CϭO). Ϫ MS (FAB) m/z: 1606.3 [Mϩ]. ϪC84H108N12O16Zn
(1607.2): calcd. C 62.77, H 6.77, N 10.46; found C 62.20, H 6.50,
N 10.86.
1,8,15,22-Tetra[4-(pentyloxycarbonyl)butyl]phthalocyaninatozinc
(26): The same procedure as for the preparation of 4 was used.
Chromatographic workup on silica gel using chloroform/ethyl acet-
ate (8:1) as eluent gave 26 (160 mg, 31%) as a dark blue solid. Ϫ
IR (KBr): ν˜ ϭ 2955 cmϪ1, 2930, 1734, 1462, 1396, 1335, 1171. Ϫ
1
UV/Vis (THF): λmax ϭ 684 nm, 616, 348. Ϫ H NMR ([D5]pyrid-
ine): δ ϭ 0.70 (m, 12 H, 4ϫCH3), 1.11 (m, 16 H, 8ϫCH2), 1.45
(m,
8
H, 4ϫCH2), 2.67Ϫ2.21 (m, 24 H, 8ϫCH2,
2,9,16,23-Tetra(2-amino-2-carboxyethyl)phthalocyaninatozinc (11):
To a solution of 10 (60 mg, 0.04 mmol) in dichloromethane (5 mL)
was added TFA (1 mL). The resulting mixture was stirred for 1 h
at room temp. The mixture was poured into 30 mL of diethyl ether
and the resulting precipitate filtered off and redissolved in 3 mL of
MeOH. To this solution was added 0.1  NaOH (0.5 mL), and stir-
ring was continued for 10Ϫ12 h. After adjusting the pH to 7 using
0.1  HCl, and saturating the solution with NaCl, the product pre-
cipitated. The precipitate was centrifuged, washed with MeOH and
dried in vacuo to give 11 (28 mg, 75%) as a dark blue solid. Ϫ IR
(KBr): ν˜ ϭ 3425 cmϪ1, 3036, 2953, 1622, 1491, 1398, 1339, 1096.
Ϫ UV/Vis (MeOH): λmax (lg ε) ϭ 674 nm (4.31), 634 (4.30), 337
(4.40).
4ϫCH2CO2C5H11), 4.02 (m, 8 H, 4ϫCO2CH2), 4.67 (m, 8 H,
ArCH2), 8.11 (m, 8 H, macrocyclic H), 9.65 (m, 4 H, macrocyclic
H). Ϫ 13C NMR ([D5]pyridine): δ ϭ 14.0 (CH3), 22.4 (CH2), 25.1
(CH2), 28.2 (CH2), 28.6 (CH2), 31.4 (CH2), 33.7 (CH2), 34.7
(CH2CO2C5H11), 64.3 (CO2CH2), 121.2 (macrocyclic CH), 129.4
(macrocyclic CH), 139.8 (macrocyclic CH), 141.3 (macrocyclic C),
153.7 (macrocyclic C), 154.1 (macrocyclic C), 154.9 (macrocyclic
C), 173.6 (CϭO).
C72H88N8O8Zn (1258.9): calcd. C 68.69, H 7.05, N 8.90; found C
67.34, H 6.96, N 8.23.
Ϫ Ϫ
MS (FAB) m/z: 1257.6 [Mϩ].
1,8,15,22-Tetra(4-carboxybutyl)phthalocyaninatozinc (27): The
same procedure as for the preparation of 5b was used. Yield 89%
(70 mg) as a dark blue solid. Ϫ IR (KBr): ν˜ ϭ 3456 cmϪ1, 2932,
1707, 1659, 1406, 1331, 1113, 741. Ϫ UV/Vis (MeOH): λmax
(lg ε) ϭ 678 nm (4.83), 649 (4.16), 613 (4.15), 353 (4.35).
2,9,16,23-Tetra[2-tert-butyloxy-1-(pentyloxycarbonyl)ethylamino-
carbonyl]phthalocyaninatozinc (15): The same procedure as for the
Eur. J. Org. Chem. 1999, 3441Ϫ3453
3451

U. Drechsler, M. Pfaff, M. Hanack
FULL PAPER
2,3,9,10,16,17,23,24-Octa[2-(benzyloxycarbonyl)ethyl]phthalo-
cyaninatozinc (37a) and 9,10,16,17,23,24-hexa[2-(benzyloxycarbony-
l)ethyl]-2-[4-(N-succinimidyloxycarbonyl)butyl]phthalocyaninatozinc
with water and acetone, and dried in vacuo to give 41a (25 mg,
80%) as a dark green solid. Ϫ UV/Vis (MeOH): λmax (lg ε) ϭ
677 nm (4.62), 630 (4.18), 344 (4.41). Ϫ 1H NMR ([D6]DMSO):
δ ϭ 2.05 (s, 4 H, 2ϫCH2), 2.39 (br, 4 H, 2ϫCH2), 3.02 (m, 14 H,
6ϫCH2CO2 H, CH2CO2NH), 3.51 (m, 14 H, 7ϫArCH2), 8.06 (m,
(40a).
؊ General Procedure: A solution of 33a (540 mg,
1.60 mmol), 36 (62 mg, 0.27 mmol), Zn(OAc)2 · 2 H2O (100 mg,
0.47 mmol), and catalytic amounts of DBU in benzyl alcohol 1 H, macrocyclic H), 9.28 (m, 8 H, macrocyclic H).
(7 mL) was stirred overnight at 130°C. After cooling to room temp.
the mixture was poured into 100 mL of MeOH/water (4:1) and the
resulting precipitate was centrifuged. The residue was purified by
chromatography on silica gel using the following eluents: Chloro-
2,3,9,10,16,17,23,24-Octa[2-(benzyloxycarbonyl)propyl]phthalo-
cyaninatozinc (37b) and 9,10,16,17,23,24-hexa[2-(benzyloxycarb-
onyl)propyl]-2-[4-(N-succinimidyloxycarbonyl)butyl]phthalocyani-
natozinc (40b): The same procedure as for the preparation of 37a
form/ethyl acetate (8:1) gave 170 mg of the symmetrically substi-
and 40a was used. Column chromatography on silica gel using
tuted 37a as dark green solid. Changing the eluent to chloroform/
CHCl3/ethyl acetate (8:1) yielded 160 mg of 37b as first fraction.
THF (4:1) yielded a second fraction which was, after removal of
Changing the eluent to CHCl3/ethyl acetate/acetic acid (20:5:1)
the solvent, redissolved in 3 mL of THF. To this solution NHS
gave a second fraction which was further purified by a second chro-
(30 mg, 0.25 mmol), DMAP (10 mg, 0.08 mmol), and DCC (62 mg,
matography step using CHCl3/ethyl acetate/EtOH (16:4:1). Treat-
0.30 mmol) were added and the resulting solution was stirred at
ment of this fraction with NHS gave, after chromatography on sil-
room temp. overnight. The precipitate formed during this reaction
ica gel using CHCl3/ethyl acetate (8:1), 72 mg of 40b as a dark
was filtered off, the filtrate was evaporated and the residue was
blue solid.
further purified by chromatography on silica gel using CHCl3/ethyl
37b: IR (KBr): ν˜ ϭ 2934 cmϪ1, 1732, 1489, 1454, 1157, 1099. Ϫ
acetate (8:1) to yield 90 mg of 40a as dark green solid.
UV/Vis (CHCl3): λmax ϭ 683 nm, 616, 351. Ϫ 1H NMR ([D8]THF):
37a: IR (KBr): ν˜ ϭ 1732 cmϪ1, 1622, 1489, 1454, 1285, 1161, 1097.
δ ϭ 1.43 (m, 24 H, 8ϫCH3), 3.28 (m, 16 H, 8ϫArCH2), 3.80 (m,
Ϫ UV/Vis (THF): λ ϭ 682 nm, 654, 615, 350. Ϫ 1H NMR
8 H, 8ϫCH), 5.13 (s, 16 H, 8ϫCO2CH2), 7.15 (m, 40 H, aromatic
([D8]THF): δ ϭ 3.09 (t, J ϭ 8.07 Hz, 16 H, 8ϫCH2CO2Bzl), 3.54
H), 9.31 (s, 8 H, macrocyclic H). Ϫ 13C NMR ([D8]THF): δ ϭ 17.5
(t, J ϭ 8.05 Hz, 16 H, 8ϫArCH2), 5.27 (s, 16 H, 8ϫCO2CH2C6H5),
(CH3), 38.0 (ArCH2), 42.4 (CH), 65.9 (CO2CH2), 124.8 (macro-
7.34 (m, 40 H, aromatic H), 8.89 (s, 8 H, macrocyclic H). Ϫ 13C
cyclic CH), 128.4 (aromatic CH), 128.6 (aromatic CH), 128.9 (aro-
NMR ([D8]THF): δ ϭ 29.5 (CH2CO2Bzl), 36.2 (ArCH2), 66.7
matic CH), 137.4 (macrocyclic C), 138.2 (macrocyclic C), 140.8
(CO2CH2C6H5), 123.3 (macrocyclic CH), 128.6 (aromatic CH),
(aromatic C), 154.4 (macrocyclic CCH2), 175.9 (CϭO). Ϫ MS
128.9 (aromatic CH), 129.1 (aromatic CH), 137.7 (macrocyclic C),
(FAB) m/z: 1986.4 [Mϩ].
137.9 (macrocyclic C), 141.2 (aromatic CCH2), 153.4 (macrocyclic
40b: IR (KBr): ν˜ ϭ 2934 cmϪ1, 1730, 1452, 1159. Ϫ UV/Vis (THF):
CCH2), 172.9 (CϭO).
Ϫ Ϫ
MS (FD) m/z: 1874.0 [Mϩ].
λ
max ϭ 682 nm, 654, 615, 350. Ϫ 1H NMR ([D5]pyridine): δ ϭ 1.41
C112H96N8O16Zn (1875.4): calcd. C 71.73, H 5.16, N 5.97, found
C 71.76, H 4.78, N 6.33.
(m, 18 H, 6ϫCH3), 1.93 (m, 4 H, 2ϫCH2), 2.86 (s, 4 H, 2ϫCH2),
3.11 (m, 2 H, CH2CO2N), 3.44 (m, 14 H, 7ϫArCH2), 3.87 (m, 6
H, 6ϫCH), 5.28 (m, 12 H, 6ϫCO2CH2), 7.38 (m, 30 H, aromatic
H), 8.08 (m, 1 H, macrocyclic H), 9.77 (m, 8 H, macrocyclic H). Ϫ
13C NMR ([D5]pyridine): δ ϭ 17.5 (CH3), 24.8 (CH2), 26.1 (CH2),
31.0 (CH2), 37.6 (CH2), 41.8 (CH), 66.4 (CO2CH2), 124.7 (macro-
cyclic CH), 128.3 (aromatic CH), 128.7 (aromatic CH), 136.9 (aro-
matic C), 137.9 (macrocyclic C), 139.8 (macrocyclic CH), 140.7
(macrocyclic C), 154.6 (macrocyclic CCH2), 170.3 (CH2CO2N),
175.9 (CϭO), 176.0 (CH2CO2Bzl). Ϫ MS (FAB) m/z: 1832.4 [Mϩ].
40a: IR (KBr): ν˜ ϭ 1743 cmϪ1, 1680, 1664, 1454, 1161. Ϫ UV/Vis
1
(THF): λmax ϭ 677 nm, 648, 611, 350. Ϫ H NMR ([D5]pyridine):
δ ϭ 1.94 (m, 4 H, CH2CH2), 2.86 [s, 4 H, C(O)CH2CH2C(O)], 3.18
(m, 12 H, 6ϫCH2CO2Bzl), 3.62 (m, 2 H, CH2CO2N), 3.71 (m, 14
H, 7ϫArCH2), 5.30 (m, 12 H, 6ϫCO2CH2C6H5), 7.33 (m, 30 H,
aromatic H), 8.08 (m, 1 H, macrocyclic H), 9.72 (m, 8 H, macro-
cyclic H). Ϫ 13C NMR ([D5]pyridine): δ ϭ 24.9 (CH2), 26.0 (CH2),
26.1 (CH2), 29.0 (CH2CO2Bzl), 31.1 (CH2CO2N), 34.3 (ArCH2),
35.5 (ArCH2), 66.5 (CO2CH2C6H5), 121.2 (macrocyclic CH), 128.4
(aromatic CH), 128.6 (aromatic CH), 128.9 (aromatic CH), 137.0
(aromatic C), 137.7 (macrocyclic C), 139.3 (macrocyclic CH), 140.0
(macrocyclic C), 153.8 (macrocyclic CCH2), 169.5 (CH2CO2N),
170.4 (CϭO), 172.9 (CH2CO2Bzl). Ϫ MS (FD) m/z: 1747.3 [Mϩ].
Ϫ C101H87N9O16Zn (1748.2): calcd. C 69.39, H 5.02, N 7.21; found
C 69.65, H 5.18, N, 7.22.
2,3,9,10,16,17,23,24-Octa(2-carboxypropyl)phthalocyaninatozinc
(39b): The same procedure as for the preparation of 5b was used.
Yield 93% (60 mg) as a dark blue solid. Ϫ IR (KBr): ν˜ ϭ 3238 nm,
2930, 1709, 1462, 1342, 1109. Ϫ UV/Vis (MeOH): λmax (lg ε) ϭ
679 nm (4.73), 614 (3.92), 350 (4.32). Ϫ 1H NMR ([D6]DMSO):
δ ϭ 1.37 (m, 24 H, 8ϫCH3), 3.15 (m, 16 H, 8ϫArCH2), 3.60 (m,
8 H, 8ϫCH), 9.20 (s, 8 H, macrocyclic H).
2,3,9,10,16,17,23,24-Octa(2-carboxyethyl)phthalocyaninatozinc
9,10,16,17,23,24-Hexa(2-carboxypropyl)-2-[4-(N-succinimidyloxy-
carbonyl)butyl]phthalocyaninatozinc (41b): The same procedure as
for the preparation of 41a was used. Yield 75% (16 mg) as a dark
green solid. Ϫ UV/Vis (MeOH): λmax (lg ε) ϭ 679 nm (4.89), 613
(39a): The same procedure as for the preparation of 5b was used.
Yield 96% (60 mg) as dark blue solid. Ϫ IR (KBr): ν˜ ϭ 3429 cmϪ1
,
3038, 1711, 1641, 1205. Ϫ UV/Vis (MeOH): λmax (lg ε) ϭ 677 nm
1
(4.72), 631 (4.35), 343 (4.56). Ϫ H NMR ([D6]DMSO): δ ϭ 2.99
1
(4.20), 346 (4.70). Ϫ H NMR ([D6]DMSO): δ ϭ 1.15 (m, 18 H,
(t, 16 H, 8ϫCH2), 3.50 (br, 16 H, 8ϫArCH2), 9.18 (s, 8 H, macro-
cyclic H).
6ϫCH3), 2.08 (s, 4 H, CH2), 2.76 (m, 4 H, CH2), 2.95Ϫ3.80 (br, 16
H, CH2), 4.02 (m, 6 H, 6ϫCH), 7.26Ϫ9.21 (br, 9 H, macrocyclic
9,10,16,17,23,24-Hexa(2-carboxyethyl)-2-[4-(N-succinimidyloxy-
carbonyl)butyl]phthalocyaninatozinc (41a): General Procedure: To a
solution of 40a (50 mg, 0.025 mmol) in EtOH (5 mL) was added
10% Pd on charcoal (20 mg). The resulting mixture was hydrogen-
ated under atmospheric pressure until hydrogen consumption was
H).
Acknowledgments
finished (8Ϫ10 h). The mixture was diluted with 50 mL of EtOH We wish to thank PD Dr. Sepp Kaul and Bernd Bartik of the
and the catalyst was filtered off. The filtrate was acidified to pH 3
using 0.1  HCl, the resulting precipitate was centrifuged, washed
University Hospital, Heidelberg for their assistance in providing
and running the in-vitro experiments. We also thank Markus
3452
Eur. J. Org. Chem. 1999, 3441Ϫ3453

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