Synthesis of meso-substituted porphyrins carrying carboranes and oligo(ethylene glycol) units for potential applications in boron neutron capture therapy

Article abstract of DOI:10.1039/b209534c

Selective delivery of ¹⁰B to tumours is one of the major remaining problems in boron neutron capture therapy (BNCT) of cancer. Porphyrins are selectively accumulated in tumours. Thus two series of carborane-carrying porphyrins were constructed, with additional functionality for attachment of uncharged potentially water-solubilising polyethers 3-(1,2-Dicarbaclosododecaboran(12)-1-ylmethoxy)benzaldehyde was prepared by protection of the aldehyde of 3-(prop-2-ynyloxy)benzaldehyde as a dithioacetal, treatment with decaborane(14) and deprotection. Condensation with a 3-nitrophenyldipyrromethane gave a separable mixture of meso-(3-nitrophenyl)-meso-(3-carboranylmethoxyphenyl)porphyrins, resulting from extensive scrambling at the porphyrinogen stage. Similarly, condensation of 3-(1,2-dicarbaclosododecaboran(12)-1-yl)benzaldehyde with this dipyrromethane gave an analogous mixture of meso-(3-nitrophenyl)-meso-(3-carboranylpheneyl)porphyrins. In this second series, the two regioisomeric bis(nitrophenyl)bis(carboranylphenyl)porphyrins could only be distinguished by X-ray crystallography, their NMR spectra being identical. The nitro groups of the mono(nitrophenyl)porphyrins and the bis(nitrophenyl)-porphyrins were reduced to the corresponding amines with tin(II) chloride and the monoamines were coupled with a ω-methoxy poly(ethylene glycol) chloroformate of mean MW 600 to give the MeOPEGylated tricarboranyl porphyrins.

Full text of DOI:10.1039/b209534c

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Synthesis of meso-substituted porphyrins carrying carboranes and
oligo(ethylene glycol) units for potential applications in boron
neutron capture therapy†
Christophe Frixa,a Mary F. Mahon,b Andrew S. Thompsona and Michael D. Threadgill*a
a Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath,
UK BA2 7AY. E-mail: m.d.threadgill@bath.ac.uk; Fax: ϩ44 1225 386114;
Tel: ϩ44 1225 386840
b X-Ray Crystallographic Unit, Department of Chemistry, University of Bath, Claverton Down,
Bath, UK BA2 7AY
Received 1st October 2002, Accepted 11th November 2002
First published as an Advance Article on the web 19th December 2002
Selective delivery of 10B to tumours is one of the major remaining problems in boron neutron capture therapy
(BNCT) of cancer. Porphyrins are selectively accumulated in tumours. Thus two series of carborane-carrying
porphyrins were constructed, with additional functionality for attachment of uncharged potentially water-
solubilising polyethers. 3-(1,2-Dicarbaclosododecaboran(12)-1-ylmethoxy)benzaldehyde was prepared by
protection of the aldehyde of 3-(prop-2-ynyloxy)benzaldehyde as a dithioacetal, treatment with decaborane(14) and
deprotection. Condensation with a 3-nitrophenyldipyrromethane gave a separable mixture of meso-(3-nitrophenyl)-
meso-(3-carboranylmethoxyphenyl)porphyrins, resulting from extensive scrambling at the porphyrinogen stage.
Similarly, condensation of 3-(1,2-dicarbaclosododecaboran(12)-1-yl)benzaldehyde with this dipyrromethane gave
an analogous mixture of meso-(3-nitrophenyl)-meso-(3-carboranylphenyl)porphyrins. In this second series, the two
regioisomeric bis(nitrophenyl)bis(carboranylphenyl)porphyrins could only be distinguished by X-ray crystallography,
their NMR spectra being identical. The nitro groups of the mono(nitrophenyl)porphyrins and the bis(nitrophenyl)-
porphyrins were reduced to the corresponding amines with tin() chloride and the monoamines were coupled with
a ω-methoxy poly(ethylene glycol) chloroformate of mean MW 600 to give the MeOPEGylated tricarboranyl
porphyrins.
were β-substituted meso-free derivatives of haem, such as
Introduction
BOPP 19 and VCDP 210 (Fig. 1). In these compounds, the
Boron neutron capture therapy (BNCT) is under active investi-
lipophilicity of the closocarboranes and the porphyrin ring is
counteracted by formation of salts of the carboxylic acids to
aid water-solubility; in the latter, the carborane cages have also
gation for the treatment of various cancers, notably gliomas
and melanomas.1 When the 10B isotope is irradiated with slow
7
(‘thermal’) neutrons, an [n,α] reaction ensues, giving Li and
been degraded to the anionic nido clusters. Later, synthetic
4He nuclei with kinetic energy (2.31 MeV). With this energy, the
and biological studies were reported11 on a meso-tetraphenyl-
α-particle has a range of ca. one cell diameter in biological
porphyrin with nido-carboranes linked to the phenyls though
tissue and damage is limited to the cell containing the boron.
amides (3, Fig. 2). More recently, ether linkages between the
Early clinical failures of BNCT were attributed2 to inadequate
carboranylmethyl unit and the phenyl of the TPP were used by
concentrations of 10B in the tumour tissue or to lack of selectiv-
Miura et al.12 in carborane–porphyrin constructs 4; in these, the
ity of disposition of 10B, leading to damage to normal tissue.
water-solubility is provided by eight carboxylates and
Thus one of the remaining major issues in BNCT is the devel-
unwanted photosensitisation was suppressed by metallation.
opment of water-soluble boron-containing drugs that are
This group have also reported13 analogous constructs 5 in
selectively taken up or retained by tumours. Carboranes have
which four nidocarboranes are linked through ethers to TPP;
these lack the β-acetic acids of 4. In general, the boron-carrying
TPP derivatives present less problems of toxicity than the haem
derivatives and have been most successful in biodistribution
studies in vivo. However, all of these carborane–porphyrin
constructs rely on their anionic nature for solubility in water;
been linked inter alia to nucleosides3 and to nitroimidazoles4,5
in attempts to target boron selectively to tumours.
The selective accumulation of porphyrins in tumours was first
observed in the 1940s.6 However, the first porphyrins carrying
multiple borons (meso-tetrakis(closo-1,2-dicarbadodecaboran-
(12)ylmethyl)- and meso-tetrakis(nido-1,2-dicarbaundecaboran-
this may adversely influence their intracellular biodistribution
(12)ylmethyl)- porphyrins) were synthesised in the late 1970s
(accumulation near polyanionic DNA is optimum for
by Haushalter and Rudolph7 as catalysts for reversible multi-
BNCT14). Thus we sought to pursue other, non-ionic
electron reductions. The use of porphyrins as boron carriers
approaches to solubilising carborane–TPP constructs.
for BNCT arose from the photodynamic therapy studies of
Our principal synthetic targets were the porphyrins 6 and 7
Dougherty8 in 1983. Since then, several groups have prepared
(Fig. 3), which carry multiple carboranes and one poly(ethylene
porphyrins carrying clusters of boron and have evaluated them
glycol) unit. The carboranes are attached either through an
in the context of BNCT. The early boron-carrying porphyrins
ether linkage or through a direct carbon–carbon bond between
the carborane and the phenyl of the TPP. The ω-methoxyPEG
is designed as a non-ionic non-toxic water-solubilising group15
† Electronic supplementary information (ESI) available: experimental
details for the synthesis of compounds 12–15, 31 and 32. See http://
www.rsc.org/suppdata/ob/b2/b209534c/
for these constructs and, for ease of synthesis,16 we chose to
attach it via a carbamate to the carboranyl TPP.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Fig. 1 Structures of anionic β-linked carboranylporphyrins BOPP 1 and VCPP 2, as reported by Fairchild et al.9 and Miura et al.10.
Fig. 2 Structures of anionic meso-linked carboranylporphyrins 3–5, as reported by Kahl et al.11 and Miura et al.12,13
.
to approach the 4-substituted TPP derivatives (Scheme 1). As a
model for the assembly of porphyrins carrying nitrophenyl and
alkoxyphenyl meso-substituents by the Lindsey 2 ϩ 2 route,17
condensation of the 4-nitrophenyldipyrromethane 8 with
4-methoxybenzaldehyde 9 was investigated. Condensation of
4-nitrobenzaldehyde 7 with excess pyrrole in the presence of
trifluoroacetic acid gave the dipyrromethane 8 in high yield.
This compound was remarkably stable to storage, unlike many
other dipyrromethanes, remaining essentially undecomposed
after 3 months at 4 ЊC. Condensation with 4-methoxybenzalde-
hyde 9 in the presence of boron trifluoride as a Lewis acid,
followed by oxidation of the mixture of porphyrinogens with
DDQ, gave the correct di(4-methoxyphenyl)di(4-nitrophenyl)-
porphyrin 10 in 40% yield with little scrambling of the sub-
stituted arenes around the porphyrin core. Scrambling often
occurs in condensations of dipyrromethanes with aldehydes,
owing to the establishment of equilibria between acidolytic
cleavage reactions and re-condensations.18 In the light of this
excellent yield of 10, the process was extended to the assembly
of the analogous ether-linked carborane–porphyrin 16. The
1,2-dicarbaclosododecaborane(12) (“carborane”) structure is
most conveniently prepared by reaction of a terminal alkyne
with decaborane(14) in the presence of a Lewis base, such as
acetonitrile. The anion of 4-hydroxybenzaldehyde 11 was alkyl-
Fig. 3 Structures of target neutral carboranylporphyrins 6,7, carrying
polyethers.
Results and discussion
Thus the first targets were the tris(carboranylmethoxy)-
porphyrin monoamines and the corresponding bis(carboranyl-
methoxy)porphyrin diamines. Initial experiments were designed
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
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Scheme 1 Syntheses of 5,15-bis(4-nitrophenyl)-10,20-bis(4-methoxyphenyl)porphyrin 10 and 5,15-bis(4-nitrophenyl)-10,20-bis[4-(carboranyl-
methoxy)phenyl]porphyrin 16. Reagents and conditions: i, pyrrole (70 equiv.), CF3CO2H, CH2Cl2, Ar, 87%; ii, BF3.OEt2, CHCl3; iii, DDQ, CHCl3,
40% (10), 0.5% (16); iv, NaOEt, BrCH2C≡CH, EtOH, reflux, 70%; v, HSCH2CH2SH, BF3ؒOEt2, CH2Cl2, 83%; vi, B10H14, dry MeCN, reflux, 47%; vii,
Hg(ClO4)2ؒH2O, THF, 76%.
ated with propargyl bromide, giving the ether 12 in good yield.
Many functional groups are sensitive to decaborane(14),5,19
since it is a Lewis acid and a powerful reducing agent. Alde-
hydes and acetals are amongst these sensitive groups, so the
aldehyde function was protected as the dithioacetal 13. Now the
carborane 14 could be constructed in the relatively good yield
of 47%. Rapid deprotection, catalysed by Hg2ϩ, gave the
required 4-(carboranylmethoxy)benzaldehyde 15. Surprisingly,
in contrast to the good yield and low scrambling achieved
for the model compound 10, condensation of the (4-nitro-
phenyl)dipyrromethane 8 with 15 under a variety of conditions
resulted in extensive scrambling and formation of only a trace
(0.5%) of the target dicarborane–porphyrin 16; indeed, this
material was only formed in sufficient amount for character-
isation by HRMS.
Rationalising that electronic effects from the para-sub-
stituents may be responsible for instability of the intermediate
polypyrranes and thus for the very low yield of 16, the effect of
moving the nitro and carboranylmethoxy groups to the posi-
tions meta to the point of attachment to the porphyrin was
investigated (Scheme 2). Meta-substituents may also decrease
the potential for π-stacking of the target carboraneporphyrins
and contribute to their solubility. Using methods analogous
to those for the preparation of the para-substituted series, 3-
hydroxybenzaldehyde 16 was propargylated and the aldehyde
17 was protected as the dithioacetal 18. The carborane 19 was
constructed in the very good yield of 58%, under the usual
conditions (B10H14, boiling MeCN) and the aldehyde 20 was
revealed by treatment with mercury() perchlorate. Similarly,
condensation of 3-nitrobenzaldehyde 21 with excess pyrrole
gave the (3-nitrophenyl)dipyrromethane 22 in high yield. Now,
condensation of 22 with 20 in the presence of boron trifluoride
gave a mixture of porphyrins in good total yield. Thus the
scrambling observed with the para-series was maintained in the
meta-series but the yield was greatly enhanced. Careful chrom-
atography allowed the isolation of five porphyrins from the
product mixture; the sixth (and most polar) was identified as
the 5,10,15,20-tetrakis(3-nitrophenyl)porphyrin 28 only by
chromatographic comparison with an authentic sample. The
first porphyrin (2% yield) to be eluted was readily identified as
the 5,10,15,20-tetrakis(3-carboranylmethoxyphenyl)porphyrin
23 by NMR spectroscopy. As expected, the carborane 2-H
signal was observed at δ 4.17 and the carborane B–H signals
1
appeared as a broad 1 : 1 : 1 : 1 quartet at δ 2.6 with JB–H
1
150 Hz. The H and 13C NMR spectra also reflected the high
symmetry of this porphyrin. The 5-(3-nitrophenyl)-10,15,20-
tris(3-carboranylmethoxyphenyl)porphyrin 24 was then isolated
in 14% yield; this was also converted to its zinc complex 29. The
two regioisomeric bis(carboranylmethoxyphenyl)bis(nitro-
phenyl)porphyrins 25 and 26 were separable by very careful and
repeated chromatography.
Identification of these compounds was achieved by consid-
eration of their symmetries with respect to their 1H NMR spec-
tra. The presence of two orthogonal planes of symmetry in
25 suggests that the porphyrin β-protons are in only two
magnetic environments, either adjacent to a meso-nitrophenyl
or a meso-carboranylmethoxyphenyl group. Fortunately, in this
case, the two types of meso-substituent are electronically sig-
nificantly different and the two sets of signals are distinct, form-
ing two doublets at δ 8.76 and δ 8.89 (J 4.9 Hz). Assuming free
rotation about the porphyrin–phenyl bond, porphyrin 26 has
only one plane of symmetry (in addition to the porphyrin
plane) and thus its β-protons would be expected to resonate in
four magnetically inequivalent groups. In practice, these are
observed as doublets (J 4.9 Hz) at δ 8.77 and δ 8.97 and singlets
at δ 8.79 and δ 8.87. Porphyrins 25 and 26 were each formed
in 9% yield. Finally, the mono(carboranylmethoxyphenyl)tris-
(nitrophenyl)porphyrin 27 was isolated in 2% yield.
Carborane–porphyrins 23–27 have an ether link between the
carborane and the tumour-targeting porphyrin core; such a link
may possibly be metabolically labile. Thus analogous por-
phyrins 7 with the carboranes directly linked by carbon–carbon
bonds to the porphyrin core were investigated. We have
previously reported the direct coupling of 1,2-dicarbacloso-
dodecaboran(12)-1-yl copper() with a TPP–zinc complex
carrying iodine in the para position of one of the phenyl rings.20
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
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Scheme 2 Syntheses of ether-linked meso-(3-nitrophenyl)-meso-[3-(carboranylmethoxy)phenyl]porphyrins. Reagents and conditions: i, NaOEt,
BrCH2C≡CH, EtOH, reflux, 78%; ii, HSCH2CH2SH, BF3ؒOEt2, CH2Cl2, 55%; iii, B10H14, dry MeCN, reflux, 58%; iv, Hg(ClO4)2ؒH2O, THF, 81%;
v, pyrrole (70 equiv.), CF3CO2H, CH2Cl2, Ar, 74%; v, BF3ؒOEt2, CH2Cl2; vii, DDQ, CH2Cl2, 2% (23), 14% (24), 9% (25), 9% (26), 2% (27);
viii, Zn(OAc)2, AcOH, reflux, 71%.
However, this process gave a coupling yield of only 8% after
12 d in boiling bis(2-methoxyethyl)ether; thus a similar coup-
ling with a tris(iodophenyl)porphyrin is likely to give <0.1%
overall yield, even under these highly forcing conditions. Lack-
ing a suitable methodology for this direct attachment of the
boron cages after the assembly of the porphyrin macrocycle, a
route involving condensation of a carboranylbenzaldehyde
40 (1%) and a mixture of the regioisomeric dinitro dicarboranyl
porphyrins 38 and 39. The latter mixture was separated by
repeated chromatography, giving the 5,15-bis(4-nitrophenyl)
compound 38 in 10% yield and the 5,10-bis(4-nitrophenyl)
isomer 39 (9%), giving a total isolated yield of carboranylpor-
phyrins of 40%, in addition to identification of a trace of the
tetra(nitrophenyl)porphyrin 28 in the crude product mixture.
As in the ether-linked series, the tetracarborane 36, the
mononitro tricarboranyl porphyrin 37 and the trinitro mono-
with
a nitrophenyldipyrromethane was again employed.
Sonogashira coupling of trimethylsilylethyne with 3-bromo-
benzaldehyde 30 gave the protected intermediate 31 in good
yield but deprotection was more troublesome, affording the
required 3-ethynylbenzaldehyde 32 in moderate yield through
treatment with potassium carbonate in methanol, as shown in
Scheme 3. Other deprotection systems were less effective. As
with the ether-linked series above, it was necessary to protect
the aldehyde function as a dithioacetal during the construction
of the carborane. Thus the dithioacetal 33, carrying the alkyne,
was converted to the corresponding carborane 34 efficiently
using decaborane(14) in boiling acetonitrile. As before, depro-
tection was achieved with mercury() perchlorate in wet tetra-
hydrofuran, giving the 3-carboranylbenzaldehyde 35. 2 ϩ 2
Cyclocondensations of 35 with the nitrophenyldipyrromethane
22 were investigated, using boron trifluoride or trifluoroacetic
acid as catalysts. The optimum yield of porphyrins was achieved
with the former catalyst but at the expense of extensive scram-
bling. The reaction was optimised by variation of the concen-
tration and of the reaction time for the initial equilibrating
condensations before the mixed porphyrinogens were oxidised
to porphyrins, terminating the equilibration. Chromatography
allowed the isolation of the expected range of porphyrins: the
tetracarboranylporphyrin 36 (2%), the mononitro tricarboranyl
porphyrin 37 (18%), the trinitro monocarboranyl porphyrin
1
carboranyl porphyrin 40 were readily characterised by H and
13C NMR spectroscopy, although it was notable that the effects
of the 3-nitrophenyl and 3-carboranylphenyl meso-substituents
on the chemical shifts of the adjacent β-protons were identical.
For 37, the 2,3,7,8,12,13,17,18-protons resonated as one singlet
at δ 8.80 and in the spectrum of 40, the corresponding singlet
was at δ 8.81. Since the regiochemical assignment of the ether-
linked analogues 25 and 26 above was based on the differences
in electronic effect of the two types of meso-substituent and the
corresponding effects are apparently identical in the directly
linked series here, it could be predicted that regioisomeric
1
assignment of 38 and 39 would be challenging. Indeed the H
spectra of these compounds were identical and superimposable.
Moreover, the 13C spectra were very similar and could not be
used predictively.
A crystal of the less-polar regioisomer was grown by slow
evaporation from a solution in a chloroform–hexane mixture.
X-Ray analysis confirmed that the structure was the sym-
metrical 5,15-bis(3-nitrophenyl)-10,20-bis(3-carboranylphen-
yl)porphyrin 38. The structure of 38 was notable in several
respects. Firstly, it is the first report of the structure of a metal-
free carbon-linked carboranylporphyrin; a previous report21
was of a structure where the carborane was linked to the
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
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Scheme 3 Syntheses of directly linked meso-(3-nitrophenyl)-meso-(3-carboranyl)phenylporphyrins. Reagents and conditions: i, Et3N, Pd(OAc)2,
PPh3, Me3SiC≡CH, reflux, 72%; ii, K2CO3, MeOH, 58%; iii, HSCH2CH2SH, BF3ؒOEt2, CH2Cl2, 52%; iv, B10H14, dry MeCN, reflux, 57%;
v, Hg(ClO4)2ؒH2O, THF, 97%; vi, BF3ؒOEt2, CH2Cl2; vii, DDQ, CH2Cl2, 2% (36), 18% (37), 10% (38), 9% (39), 1% (40).
meso-phenyl through a CH2 and the porphyrin contained a
central zinc. Both of these features will affect the rigidity and
thus the conformation of the molecule. Clearly, whereas
Vicente et al.21 observed intermolecular co-ordination of a
B–H hydrogen to the zinc of an adjacent porphyrin, such co-
ordination is unavailable to porphyrin 38. Secondly, the crystal
contains two different atropisomers of 38. Approximately 80%
of the molecules have the α,α,β,β conformation shown in Fig. 4,
C(10)–C(31) is ϩ170.2Њ, C(2)–C(1)–C(10)–C(31) is Ϫ9.3Њ and
C(2)–C(1)–C(10)–C(9) is ϩ172.9Њ. By contrast, near the carbo-
ranylphenyl meso position, the dihedral angle N(1)–C(4)–C(5)–
C(6) is ϩ2.2Њ, N(1)–C(4)–C(5)–C(21) is Ϫ179.7Њ, C(3)–C(4)–
C(5)–C(6) is Ϫ177.0Њ, C(3)–C(4)–C(5)–C(21) is ϩ1.2Њ and
N(2)–C(6)–C(5)–C(4) is ϩ1.6Њ. Fourthly, the phenyl rings, as
expected, are not in the plane of the porphyrin. The dihedral
angle between the porphyrin and the carborane-carrying phenyl
ring is illustrated by the C(1)–C(10)–C(31)–C(36) angle which is
ϩ71.2Њ. The corresponding angle at the meso position carrying
the nitrophenyl unit is C(6)–C(5)–C(21)–C(26), which is
ϩ84.4Њ. Thus the substituent on the phenyl has an effect on this
twist angle. Fifthly, the carborane is ordered with respect to
the orientation of its C–H bond. The dihedral angle to this
carborane C–H, C(34)–C(33)–C(41)–C(42), is ϩ36.8Њ.
The observation of atropisomers in the crystal helps rational-
isation of phenomena in the 1H NMR spectra. As noted above,
the highly symmetrical tetracarborane–porphyrin 36 gives a
sharp 1H NMR spectrum in CDCl3 at 20 ЊC, in which the
2,3,7,8,12,13,17,18-protons gave a singlet at δ 8.80, suggesting
either that only one atropisomer is present (presumably the least
crowded α,β,α,β,atropisomer) or that the atropisomers of this
compound are in rapid equilibrium at this temperature. This
contrasts markedly with the NMR spectrum reported by Vice-
nte et al.21 for this compound in the same solvent. These
authors report multiple signals for these protons and suggest
that the presence of slowly interconverting atropisomers may be
responsible; they also report coalescence of these signals at 50
ЊC. However, in the proton NMR spectrum of 38, it was notable
that the resonances for the phenyl rings bearing the nitro groups
were sharp at 25 ЊC, whereas those for the carborane-carrying
phenyls were markedly broader. These signals sharpened upon
heating to 50 ЊC, indicating the presence of slowly interconvert-
ing atropisomers at the lower temperature. Atropisomers are
well known in the cases of porphyrins carrying ortho-substitu-
ents on the meso-phenyl rings.22 Such atropisomers are separ-
able and do not usually interconvert at room temperature,
requiring >100 ЊC for rapid equilibration. Atropisomers from
meta-substituted meso-phenylporphyrins normally interconvert
much more rapidly,23 as there would be much less steric clash
between the substituent and the adjacent porphyrin β-proton
Fig. 4 Crystal structure of 5,15-bis(3-nitrophenyl)-10,20-bis(3-carb-
oranylphenyl)porphyrin 38.
whereas 20% have the α,α,α,β conformation where the α-carbo-
rane is flanked by two α-nitro substituents (Fig. 5). No mole-
cules have both carboranes on the same face. Thirdly, in the
major atropisomer, the porphyrin ring is deformed out of plane
in the regions of the carboranylphenyl substituents but not in
the other meso regions bearing the nitrophenyl groups. For
example, near the carboranylphenyl meso position, the dihedral
angle N(2)–C(9)–C(10)–C(1) is Ϫ3.9Њ, N(2)–C(9)–C(10)–C(31)
is ϩ173.0Њ, C(8)–C(9)–C(10)–C(31) is Ϫ6.2Њ, C(8)–C(9)–C(10)–
C(1) is ϩ176.0Њ, N(1)–C(1)–C(10)–C(9) is Ϫ7.7Њ, N(1)–C(1)–
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
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Fig. 5 Structures of the α,α,β,β and α,α,α,β atropisomers of 5,15-bis(3-nitrophenyl)-10,20-bis(3-carboranylphenyl)porphyrin 38.
during rotation about the porphyrin–phenyl bond. However,
the carborane represents a locally very bulky substituent and
this may lead to a higher energy barrier to rotation between
atropisomers than is normal for meta substitution.
To provide a point of attachment for the poly(ethylene
glycol) units, the nitro groups of the nitrophenyl carboranyl
porphyrins were reduced to amines. 5-(4-Nitrophenyl)-
10,15,20-triphenylporphyrin 41 was synthesised by nitration of
meso-tetraphenylporphyrin and, as shown in Scheme 4, was
reduced to the corresponding amine 42 with tin() chloride in
boiling hydrochloric acid, as previously reported by us.20,24 This
process also successfully reduced the nitro groups of the bis-
(4-nitrophenyl)bis(4-methoxyphenyl)porphyrin 10 to give the
diamine 43 in moderate yield. However, this process was
ineffective for the carborane-bearing porphyrins, largely owing
to their limited solubility in aqueous media. However, reduction
of the mono(nitrophenyl) tris(carboranylmethoxyphenyl) por-
phyrin 24 with the same reductant in acetic acid was successful
in giving the required monoamine 44 in 72% yield. A similar
reaction converted the mono(nitrophenyl)tris(carboranyl-
phenyl)porphyrin 37 to the analogous amine 47. An alternative
reduction, a transfer hydrogenation with cyclohexene in the
presence of Raney nickel, only afforded a 14% yield of 44.
Owing to the difficulty in separating individual dinitro regio-
isomers from the pairs 25/26 and 38/39, the nitro to amine
reductions were carried out on equimolar mixtures of isomers.
After reduction with tin() chloride in hydrochloric acid by
prolonged treatment at ambient temperature, the symmetrical
diamine 45 could be separated readily by chromatography from
its less symmetrical isomer 46. Similarly, the product mixture
from 38/39 was separated to give the required diamines 48 and
49 in high yields.
Fig. 6 Part of the FAB negative ion mass spectrum of mono-
(MeOPEG) tricarboranyl porphyrin 52. The individual clusters
correspond to the pseudomolecular ions of the different MeOPEG
oligomers present whereas the envelope of each individual cluster
corresponds to the statistical distribution of the 11B and 10B isotopes
present at natural abundance.
the individual clusters correspond to the different MeOPEG
oligomers present whereas the envelope of each individual
cluster corresponds to the statistical distribution of the 11B and
10B isotopes present at natural abundance. Surprisingly, the
individual oligomers of 51 and 52 were separable by thin layer
chromatography on silica gel (Fig. 7); selected oligomers of 51
Since we have previously noted that the amines of meso-(4-
aminophenyl)porphyrins are relatively weak nucleophiles,24 the
formation of the carbamate link between the aminophenyl-
porphyrins and the PEG unit was tested in a model system
(Scheme 4). Poly(ethylene glycol) monomethyl ether of mean
MW 550 Da (MeOPEG550) was selected as a suitable polyether
mono-alcohol and was converted to the corresponding chloro-
formate by treatment16 with phosgene in dichloromethane.
Whereas the meso-(4-aminophenyl)porphyrin 42 required pro-
longed treatment with “active” esters to achieve efficient acyl-
ation,24 the MeOPEG550 chloroformate reacted rapidly with
this amine to give the MeOPEGylated derivative 50 in excellent
yield, after chromatography to separate it from excess poly-
ether. Similar high yields were obtained in couplings of the
MeOPEG550 chloroformate with 44 (giving 51) and 45 (giving
52). Considerable difficulty was experienced in separating 51
and 52 from excess polyether. The FAB mass spectra of 50–52
showed the expected distribution of pseudomolecular ions corre-
sponding to the mixture of MeOPEG oligomers present. Fig. 6
illustrates part of the FAB negative ion mass spectrum of 52;
Fig. 7 Thin layer chromatogram (silica gel, ethyl acetate) of the
mono(MeOPEG) tricarboranyl porphyrin 52. Each spot corresponds
to an individual oligomer of the MeOPEG unit. n refers to the number
of oxyethylene units in the oligomers (MeO(CH2CH2O)nCOHNPh)-
(carboranylphenyl)3porphyrin.
were characterised by mass spectrometry. Straightforward
chromatographic separation of PEG oligomers (of more than
five repeating OCH2CH2 units) is unusual and this observation
may point to a potential method for fractionating PEG deriv-
atives into individual oligomers. In contrast, the reactions of
the diamines 43, 45, 48 and 49 gave rise to intractable mixtures
of MeOPEGylated porphyrins and unreacted MeOPEG
derivatives.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
311

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Scheme 4 Reduction of meso-(nitrophenyl)porphyrins and attachment of the polyether units. Reagents and conditions: i, SnCl2, aq. HCl, 65 ЊC, 84%
(42), 56% (43); ii, SnCl2, AcOH, 72% (44), 39% (47); iii, Raney Ni, cyclohexene, MeOH, 14%; iv, SnCl2, aq. HCl, 76% (45), 76% (46), 80% (48), 72%
(49); v, Et3N, MeO(CH2CH2O)∼12COCl, 4-dimethylaminopyridine, CHCl3, 99% (50), 96% (51), 90% (52).
Conclusions
Experimental
NMR spectra were recorded on samples in CDCl3, unless
otherwise stated. Mass spectra were obtained by fast atom
bombardment (FAB) in the positive ion mode, unless otherwise
stated. The stationary phase for chromatography was silica
gel; column chromatography of porphyrins was performed at
atmospheric pressure. Melting points are uncorrected. Solu-
tions in organic solvents were dried with MgSO4. Solvents were
evaporated under reduced pressure. Experiments were con-
ducted at ambient temperature, unless otherwise stated. The
brine was saturated. The pyrrole was distilled from potassium
hydroxide pellets under argon.†
In this paper, we report the synthesis of two porphyrins 51 and
52 carrying methoxyPEG units and three carboranes, these
compounds having potential for the selective delivery of boron
to tumours for use in BNCT. Although the additional aqueous
solubility conferred by the MeOPEG was very limited, these
compounds are currently under investigation for their boron-
delivering properties in experimental BNCT models. In the
synthesis of these constructs, several meso-(aminophenyl)-
meso-(carboranylphenyl) porphyrins were made available;
these compounds have the amino functions available for
attachment of alternative solubilising groups or tissue-targeting
entities. Useful conformational and structural information for
carboranylporphyrins is given by the first reported crystal
structure of a metal-free carborane–porphyrin. We are actively
pursuing these developments.
Di(pyrrol-2-yl)(4-nitrophenyl)methane 8
Trifluoroacetic acid (230 mg, 2.0 mmol) in dichloromethane
(4.6 cm3) was added to 4-nitrobenzaldehyde 7 (3.20 g, 20 mmol)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
312

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in pyrrole (freshly distilled under argon) (94 g, 1.4 mol) under
Ar and the mixture was stirred for 20 min. Evaporation and
recrystallisation (aq. methanol) gave 8 (4.65 g, 87%) as a pale
yellow solid: mp 158–160 ЊC (lit.25 mp 159–160 ЊC); δH 5.59
(1 H, m, methine-H), 5.87 (2 H, m, 2 × pyrrole 3-H), 6.18 (2 H,
q, J 2.9 Hz, 2 × pyrrole 4-H), 6.75 (2 H, m, 2 × pyrrole 5-H),
7.37 (2 H, d, J 8.6 Hz, Ph 2,6-H2), 8.01 (2 H, br s, 2 × NH),
8.17 (2 H, d, J 8.6 Hz, Ph 3,5-H2); m/z 267 (M ϩ H), 201
(M-pyrrole), 145 (M–C6H4NO2).
4-H), 7.15 (2 H, m, Ph 2,6-H2), 7.22 (1 H, t, J 7.8 Hz, Ph 5-H);
δC 40.0, 55.5, 55.9, 75.5, 78.3, 114.2, 114.4, 121.0, 129.3, 142.1,
12
157.4; m/z (EIϩ) 238.0291 (M C12H12O134S132S1 requires
12
238.0287), 237.0357 (M 13C1 C11H12O132S2 requires 237.0363),
236.0328 (M 12C12H12O132S2 requires 236.0330).
1-[3-(4,5-Dihydro-1,3-dithiol-2-yl)phenoxymethyl]-1,2-di-
carbaclosododecaborane(12) 19
Decaborane(14) (5.0 g, 41 mmol) in dry acetonitrile (100 cm3)
was stirred under argon for 4 h before 18 (10.0 g, 42 mmol) in
dry acetonitrile (10 cm3) was added. The mixture was boiled
under reflux for 3 d. Evaporation and chromatography
(hexane–chloroform 3 : 2) gave 19 (8.34 g, 58%) as a white
powder: mp 122–123 ЊC; δH 1.4–3.2 (10 H, br q, JB–H 150 Hz,
B10H10), 3.35 (2 H, m) and 3.49 (2 H, m) (dithiole 4,5-H4), 4.09
(1 H, br s, carborane 2-H), 4.40 (2 H, d, J 4.1 Hz, OCH2), 6.73
(1 H, m, Ph 4-H), 7.05 (1 H, t, J 1.9 Hz, Ph 2-H), 7.14 (1 H, m,
Ph 6-H), 4.22 (1 H, td, J 7.8, 4.1 Hz, Ph 6-H); δC 40.3, 55.8,
57.7, 69.0, 71.3, 113.9, 114.1, 122.1, 129.6, 142.4, 156.8; m/z
5,15-Bis(4-methoxyphenyl)-10,20-bis(4-nitrophenyl)-21H,23H-
porphine 10
Boron trifluoride diethyl etherate (2.5 cm3, 20 mg cmϪ3 in
chloroform, 140 µmol) was added to 8 (118 mg, 440 µmol) and
4-methoxybenzaldehyde 9 (63 mg, 460 µmol) in chloroform
(44 cm3) and the mixture was stirred for 2 h. 2,3-Dichloro-5,6-
dicyanobenzoquinone (100 mg, 440 µmol) was added and the
mixture was stirred for 6 h. Evaporation and chromatography
(hexane–dichloromethane 1 : 2) gave 10 (68 mg, 40%) as a dark
purple powder: mp >350 ЊC; (Found: C, 70.30; H, 4.37; N,
10.50. C46H32N6O6.H2O requires C, 70.58; H, 4.37; N, 10.73%);
δH Ϫ2.78 (2 H, s, 21,23-H2), 4.11 (6 H, s, 2 × OCH3), 7.31 (4 H,
d, J 8.5 Hz, 2 × MeOAr 3,5-H2), 8.12 (4 H, d, J 8.5 Hz, 2 ×
MeOAr 2,6-H2), 8.40 (4 H, d, J 8.5 Hz, 2 × O2NAr 2,6-H2), 8.65
(4 H, d, J 8.5 Hz, 2 × O2NAr 3,5-H2), 8.75 (4 H, d, J 4.6 Hz,
2,8,12,18-H4), 8.94 (4 H, d, J 4.6 Hz, 3,7,13,17-H4); m/z 765
(M ϩ H).
11
(EIϩ) 356.2057 (M C12H22 B10O1S2 requires 356.2042),
355.2083 (M C12H2211B910B1O1S2 requires 355.2079), 354.2115
(M C12H2211B810B2O1S2 requires 354.2115) 353.2145 (M
C12H2211B710B3O1S2 requires 353.2145), 352.2172 (M C12H22-
11B610B4O1S2 requires 352.2189).
3-(1,2-Dicarbaclosododecaboran(12)-1-ylmethoxy)benzaldehyde
20
Dithiole 19 (4.90 g, 13.9 mmol) was stirred with mercury()
perchlorate hydrate (12.2 g, 31 mmol) in tetrahydrofuran (115
cm3) for 10 min. The suspension was filtered. The evaporation
residue, in dichloromethane, was washed with aq. sodium
carbonate, water and brine and was dried. Evaporation gave 20
(3.14 g, 81%) as a white powder: mp 101–103 ЊC; (Found: C,
43.30; H, 6.41. C10H18B10O2 requires C, 43.15; H, 6.52%);
δH 1.4–3.2 (10 H, br q, JB–H 150 Hz, B10H10), 4.08 (1 H, br s,
carborane 2-H), 4.49 (2 H, s, CH2), 7.16 (1 H, m, 4-H), 7.33
(1 H, dd, J 2.7, 1.2 Hz, 2-H), 7.50 (1 H, m, 5-H), 7.56 (1 H, dd,
J 7.4, 1.2 Hz, 6-H); δC 57.9, 69.3, 71.0, 112.4, 121.7, 125.3,
130.5, 137.8, 157.3, 191.1; m/z (EIϩ) 11B/10B cluster centred at
278 (M).
5,15-Bis[4-(1,2-dicarbaclosododecaborane(12)-1-ylmethoxy-
phenyl)]-10,20-bis(4-nitrophenyl)-21H,23H-porphine 16
Boron trifluoride diethyl etherate (0.9 cm3, 20 mg. cmϪ3 in
chloroform, 120 µmol) was added to 8 (93 mg, 350 µmol) and 15
(108 mg, 350 µmol) in chloroform (35 cm3). The solution was
stirred for 80 min before 2,3-dichloro-5,6-dicyanobenzoqui-
none (80 mg, 350 µmol) was added. The mixture was stirred for
a further 90 min. Evaporation and chromatography (hexane–
dichloromethane 1 : 2) gave 16 (2 mg, 0.5%) as a purple powder:
12
11
m/z 1053.6002 (M ϩ H 13C1 C49H53
B
10B1N6O6 requires
19
1053.5957), 1052.5990 (M ϩ H 13C1 C49H53
requires 1052.5994), 1051.5981 (M ϩ H C50H53
requires 1051.5960), 1050.6031 (M ϩ H C50H53
requires 1050.6000), 1049.6081 (M ϩ H C50H53
requires 1049.6033), 1047.6070 (M ϩ H C50H53
requires 1047.6106), 1046.6094 (M ϩ H C50H53
requires 1046.6142), 1045.3132 (M ϩ H C50H53
B
B
B
B
B
B
B
10B2N6O6
10B2N6O6
10B3N6O6
10B4N6O6
10B6N6O6
10B7N6O6
10B8N6O6
12
11
18
18
17
16
14
13
12
12
11
11
11
11
11
11
12
12
Di(pyrrol-2-yl)(3-nitrophenyl)methane 22
12
3-Nitrobenzaldehyde was treated with pyrrole and trifluoro-
acetic acid, as for the synthesis of 8, to give 22 (5.96 g, 74%) as a
pale yellow solid: mp 124–127 ЊC; δH 5.58 (1 H, m, methine-H),
5.87 (2 H, m, 2 × pyrrole 3-H), 6.17 (2 H, m, 2 × pyrrole 4-H),
6.75 (2 H, m, 2 × pyrrole 5-H), 7.48 (1 H, t, J 7.8 Hz, Ph 5-H),
7.55 (1 H, d, J 7.8 Hz, Ph 6-H), 8.00 (2 H, br s, 2 × NH), 8.11
(2 H, m, Ph 2,4-H2); m/z 267 (M ϩ H), 201 (M Ϫ pyrrole), 145
(M Ϫ C6H4NO2).
12
12
requires 1045.6179).
3-(Prop-2-ynyloxy)benzaldehyde 17
Sodium (2.40 g, 100 mmol) was stirred in dry ethanol (200 cm3)
for 30 min. 3-Hydroxybenzaldehyde 16 (12.2 g, 100 mmol), was
added, followed by 3-bromopropyne (16.4 g, 80% w/v in
toluene, 110 mmol). The mixture stirred for 18 h, then filtered.
The evaporation residue, in chloroform, was washed with water
and brine. Drying, evaporation and chromatography (hexane–
chloroform 1 : 1) gave 17 (12.6 g, 78%) as a pale yellow oil (lit.26
oil): δH 2.55 (1 H, d, J 2.4 Hz, C≡CH), 4.77 (2 H, d, J 2.4 Hz,
CH2O), 7.24–7.52 (4 H, m, Ar 2,4,5,6-H4), 9.99 (1 H, s, CHO);
m/z (EIϩ) 159 (M).
5,10,15,20-Tetrakis[3-(1,2-dicarbaclosododecaboran(12)-1-
ylmethoxy)phenyl]-21H,23H-porphine 23, 5-(3-nitrophenyl)-
10,15,20-tris[3-(1,2-dicarbaclosododecaboran(12)-1-ylmeth-
oxy)phenyl]-21H,23H-porphine 24, 5,15-bis(3-nitrophenyl)-
10,20-bis[3-(1,2-dicarbaclosododecaboran(12)-1-ylmethoxy)-
phenyl]-21H,23H-porphine 25, 5,10-bis(3-nitrophenyl)-15,20-
bis[3-(1,2-dicarbaclosododecaboran(12)-1-ylmethoxy)phenyl]-
21H,23H-porphine 26 and 5,10,15-tris(3-nitrophenyl)-20-[3-(1,2-
dicarbaclosododecaboran(12)-1-ylmethoxy)phenyl]-21H,23H-
porphine 27
2-[3-(Prop-2-ynyloxy)phenyl]-4,5-dihydro-1,3-dithiole 18
Boron trifluoride diethyl etherate (9.4 cm3, 77 mmol) was added
to 17 (12.3 g, 77 mmol) and ethane-1,2-dithiol (14.5 g, 154
mmol) in dry dichloromethane (390 cm3) at 0 ЊC and the
mixture was stirred at 20 ЊC for 16 h. Evaporation and chrom-
Dipyrromethane 22 (1.30 g, 4.9 mmol) and aldehyde 20 (1.35 g,
4.9 mmol) in dry dichloromethane (490 cm3) were bubbled with
argon before boron trifluoride diethyl etherate (70 mg, 500
µmol) was added. The mixture was stirred for 1.5 h before 2,3-
dichloro-5,6-dicyanobenzoquinone (1.23 g, 5.4 mmol) was
added. The mixture was stirred for 2 h, washed with water and
brine. Drying, evaporation and chromatography (hexane–
atography (hexane–dichloromethane 3 : 1
2 : 1) gave 18 (10.1
g, 55%) as a colourless oil: δH 2.53 (1 H, d, J 2.6 Hz, C≡CH),
3.32 (2 H, m) and 3.46 (2 H, m) (dithiole 4,5-H4), 4.68 (2 H, d,
J 2.6 Hz, CH2O), 5.60 (1 H, s, dithiole 2-H), 6.86 (1 H, m, Ph
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
313

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chloroform–dichloromethane 3 : 1 : 1
2 : 3 : 3) gave 23
zinc() acetate dihydrate (154 mg, 700 µmol) in acetic acid
(35 mg, 2%) as a purple solid: mp >350 ЊC (decomp.); δH Ϫ2.86
(2 H, s, 21,23-H2), 2.6 (10 H, br q, JB–H 150 Hz, B10H10), 4.17
(4 H, br s, 4 × carborane 2-H), 4.61 (8 H, s, 4 × CH2), 7.29 (4 H,
m, 4 × Ph 4-H), 7.68 (8 H, m, 4 × Ph 2,5-H2), 7.90 (4 H, d, J 6.6
Hz, 4 × Ph 6-H), 8.84 (8 H, s, 2,3,7,8,12,13,17,18-H8); δC 58.2,
69.7, 71.7, 114.5, 119.5, 121.3, 128.2, 129.3, 131.5, 143.9, 155.6;
m/z 1304 (M ϩ H). Further elution gave 24 (268 mg, 14%) as a
purple solid: mp >350 ЊC (decomp.); δH (50 ЊC) Ϫ2.79 (2 H, s,
21,23-H2), 1.6–3.2 (10 H, br m, B10H10), 4.12 (3 H, br s, 3 ×
carborane 2-H), 4.61 (6 H, s, 3 × CH2), 7.29 (3 H, m, Ph10,15,20
4-H3), 7.68 (6 H, m, Ph10,15,20 2,5-H6), 7.90 (3 H, d, J 7.2 Hz,
Ph10,15,20 6-H3), 7.94 (1 H, t, J 7.9 Hz, Ph5 5-H), 8.52 (1 H, d,
J 7.9 Hz, Ph5 6-H), 8.67 (1 H, m, Ph5 4-H), 8.72 (2 H, d, J 4.9
Hz, 2,8-H2), 8.83 (4 H, s, 12,13,17,18-H4), 8.86 (2 H, d, J 4.9 Hz,
3,7-H2), 9.04 (1 H, s, Ph5 2-H); δC 57.7, 69.2, 71.2, 114.0, 116.7,
119.3, 120.8, 122.8, 128.0, 128.3, 128.5, 129.3, 131.5, 139.4,
(3 cm3) under argon for 30 min. The mixture was added
to aqueous sodium hydroxide (2 M) and was extracted with
chloroform. The extract was washed with water and brine. Dry-
ing, evaporation, chromatography (chloroform–hexane 1 : 1
4 : 1) and drying at 160 ЊC under reduced pressure (3 torr) for 3
h gave 29 (60 mg, 71%) as a bright pink–purple glass: δH 2.4 (30
H, br q, J 145 Hz, 3 × B10H10), 4.15 (3 H, br s, 3 × carborane 2-
H), 4.61 (6 H, m, 3 × OCH2), 7.28 (3 H, m, 3 × Ph10,15,20 4-H),
7.68 (6 H, m, 3 × Ph10,15,20 2,5-H2), 7.92 (3 H, m, 3 × Ph10,15,20 6-
H), 7.95 (1 H, m, Ph5 5-H), 8.54 (1 H, m, Ph5 6-H), 8.67 (1 H,
m, Ph5 4-H), 8.83 (2 H, d, J 4.8 Hz, 2,8-H2), 8.94 (4 H, s,
12,13,17,18-H4), 8.96 (2 H, d, J 4.8 Hz, 3,7-H2), 9.03 (1 H, s,
Ph5 2-H); δC 57.7, 69.2, 71.2, 113.9, 117.7, 120.3, 120.4, 120.6,
127.3, 127.6, 127.9, 128.7, 128.8, 131.2, 131.9, 132.0, 132.2,
139.2, 143.9, 144.0, 146.5, 149.3, 149.7, 149.8, 149.9, 155.0;
11
m/z 1242.7146 (M ϩ H C53H64
1242.7105), 1241.7179 (M
B
10B4N5O566Zn requires
26
11
143.2, 143.3, 146.7, 155.1; m/z 1179.7940 (M ϩ H C53H66-
ϩ
H
C53H64
B
10B5N5O566Zn
25
11
11
B
10B3N5O5 requires 1179.7964), 1178.7943 (M
ϩ
H
requires 1241.7141), 1240.7198 (M ϩ H C53H64
B
10B6-
27
24
11
11
C53H66
C53H66
C53H66
H C53H66
C53H66
B
B
B
10B4N5O5 requires 1178.8001), 1177.8007 (M ϩ H
N5O566Zn requires 1240.7177), 1239.7189 (M ϩ H C53H64
-
26
25
24
11
11
10B5N5O5 requires 1177.8037), 1176.8033 (M ϩ H
10B6N5O5 requires 1176.8073), 1175.8068 (M ϩ
B2310B7N5O566Zn requires 1239.7214), 1238.7225 (M ϩ H
11
C53H64
B
10B8N5O566Zn requires 1238.7250), 1237.7241 (M ϩ
22
11
11
B
10B7N5O5 requires 1175.8110), 1174.8107 (M ϩ H
H C53H64
ϩ H C53H64
(M
B
10B9N5O566Zn requires 1237.7286), 1236.7279 (M
23
21
11
11
10
B
10B8N5O5 requires 1174.8146). Further elution gave
B
B N5O566Zn requires 1236.7278), 1235.7272
22
20
10
11
10
25 (230 mg, 9%) as a purple solid: mp >350 ЊC (decomp.);
δH Ϫ2.85 (2 H, s, 21,23-H2), 1.6–3.2 (10 H, br m, B10H10), 4.18
(2 H, br s, 2 × carborane 2-H), 4.62 (4 H, s, 2 × CH2), 7.30 (2 H,
m, Ph10,20 4-H2), 7.69 (4 H, m, Ph10,20 2,5-H4), 7.91 (2 H, m, Ph10,20
6-H2), 7.98 (2 H, t, J 7.3 Hz, Ph5,15 5-H2), 8.55 (2 H, d, J 7.3 Hz,
Ph5,15 6-H2), 8.70 (2 H, m, Ph5,15 4-H2), 8.76 (4 H, d, J 4.9 Hz,
2,8,12,18-H4), 8.89 (4 H, d, J 4.9 Hz, 3,7,13,17-H4), 9.07 (2 H, s,
Ph5,15 2-H2); δC 58.2, 69.7, 71.7, 114.6, 117.7, 120.1, 121.3,
ϩ
H
C53H64
B
B N5O566Zn requires 1235.7314),
19 11
11 10
1234.7348 (M
ϩ
H
C53H64
B
B N5O566Zn requires
18 12
1234.7395).
2-(3-Ethynylphenyl)-4,5-dihydro-1,3-dithiole 33
Aldehyde 32 (1.95 g, 15 mmol) and 1,2-ethanedithiol (2.5 cm3,
30 mmol) in dry dichloromethane (80 cm3) were stirred with
boron trifluoride diethyl etherate (1.85 cm3, 15 mmol) at 0 ЊC
for 30 min and at 20 ЊC for 1 h. The mixture was washed with
water and brine and dried. Evaporation and chromatography
123.4, 128.0, 128.5, 129.0, 131.1, 139.8, 143.6, 143.7, 147.2,
155.3; m/z 1052.5951 (M ϩ H C50H53
1052.5924), 1051.5991 (M ϩ H C50H53
11
B
B
10B1N6O6 requires
10B2N6O6 requires
19
11
18
(chloroform–hexane 1 : 6
1 : 4) gave 33 (1.60 g, 52%) as a
1051.5960). Further elution gave 26 (230 mg, 9%) as a purple
solid: mp >350 ЊC (decomp.); δH Ϫ2.84 (2 H, s, 21,23-H2), 1.6–
3.2 (10 H, br m, B10H10), 4.18 (2 H, br s, 2 × carborane 2-H),
4.62 (4 H, s, 2 × CH2), 7.31 (2 H, m, Ph10,20 4-H2), 7.71 (4 H, m,
Ph10,20 2,5-H4), 7.93 (2 H, m, Ph10,20 6-H2), 7.97 (2 H, t, J 7.9 Hz,
Ph5,15 5-H2), 8.55 (2 H, m, Ph5,15 6-H2), 8.70 (2 H, d,J 7.9 Hz
Ph5,15 4-H2), 8.77 (2 H, d, J 4.9 Hz) and 8.79 (2 H, s) (2,8,12,18-
H4), 8.87 (2 H, s) and 8.97 (2 H, d, J 4.9 Hz) (3,7,13,17-H4), 9.08
(2 H, s, Ph5,15 2-H2); δC 57.7, 69.2, 71.1, 114.1, 117.0, 119.8,
120.8, 122.9, 127.6, 127.9, 128.5, 128.9, 131.5, 139.4, 143.1,
colourless oil: δH 3.17 (1 H, s, C≡CH), 3.32 (2 H, m) and 3.47
(2 H, m) (dithiole 4,5-H4), 5.57 (1 H, s, dithiole 2-H), 7.25 (1 H,
t, J 7.8 Hz, Ph 5-H), 7.37 (1 H, ddd, J 7.8, 1.6, 1.2 Hz, Ph 4-H),
7.49 (1 H, ddd, J 7.8, 1.6, 1.2 Hz, Ph 6-H), 7.65 (1 H, dd, J 1.6,
1.2 Hz, Ph 2-H); m/z (EIϩ) 206 (M).
1-[3-(4,5-Dihydro-1,3-dithiol-2-yl)phenyl]-1,2-dicarbacloso-
dodecaborane(12) 34
Alkyne 33 was treated with decaborane(14) and acetonitrile, as
for the synthesis of 19 except that the chromatographic eluant
146.7, 155.1; m/z 1053.5996 (M ϩ H 13C1 C49H53
B
10B1N6O6
12
11
19
requires 1053.5957), 1052.5995 (M ϩ H 13C1 C49H53 B18-
12
11
was chloroform–hexane 2 : 3
1 : 1, to give 34 (57%) as a white
10B2N6O6 requires 1052.5994), 1051.5980 (M ϩ H 12C50H53 B18-
11
glass: δH 2.4 (10 H, br q, JB–H 150 Hz, B10H10), 3.37 (2 H, m) and
3.50 (2 H, m) (dithiole 4,5-H4), 3.96 (1 H, br s, carborane 2-H),
5.57 (1 H, s, dithiole 2-H), 7.27 (1 H, t, J 7.8 Hz, Ph 5-H), 7.38
(1 H, m, Ph 4-H), 7.54 (1 H, d, J 7.8 Hz, Ph 6-H), 7.62 (1 H, m,
Ph 2-H); δC 40.8, 56.0, 60.5, 76.5, 127.3, 127.4, 129.2, 129.8,
133.8, 141.9; m/z (EIϩ) 11B/10B cluster centred at 324 (M).
10B2N6O6 requires 1051.5960), 1050.6084 (M ϩ H 13C1 C49H53-
12
11
B
10B4N6O6 requires 1050.6066). Further elution gave 27 (30
16
mg, 2%) as a purple solid: mp >350 ЊC (decomp.); δH Ϫ2.84 (2
H, s, 21,23-H2), 1.5–3.2 (10 H, br m, B10H10), 4.18 (1 H, br s,
carborane 2-H), 4.62 (2 H, s, OCH2), 7.31 (2 H, dd, J 8.4, 2.2
Hz, carboraneAr 4-H), 7.70 (2 H, m, carboraneAr 2,5-H2), 7.92
(1 H, br m, carboraneAr 6-H), 7.98 (3 H, t, J 7.9 Hz, 3 × O2NAr
5-H), 8.55 (3 H, m, 3 × O2NAr 6-H), 8.71 (3 H, m, 3 × O2NAr
3-(1,2-Dicarbaclosododecaboran(12)-1-yl)benzaldehyde 35
Dithiole 34 was treated with mercury() perchlorate hydrate, as
for the synthesis of 20 except that the reaction time was 5 min,
to give 35 (97%) as a white powder: mp 105–107 ЊC, δH 2.3
(10 H, br q, JB–H 150 Hz, B10H10), 4.05 (1 H, br s, carborane
2-H), 7.56 (1 H, t, J 7.8 Hz, Ph 5-H), 7.78 (1 H, m, Ph 4-H), 7.91
(1 H, m, Ph 6-H), 7.96 (1 H, m, Ph 2-H); δC 59.8, 75.0, 127.3,
129.5, 131.1, 133.0, 134.5, 136.4, 190.4.
4-H), 8.77 (2 H, d,
(3,7,8,12,13,17-H6), 8.90 (2 H, d, J 4.9 Hz, 2,18-H2), 9.08 (3 H,
s, 3 × O2NAr 2-H) δC 57.8, 69.4, 71.2, 114.4, 117.8, 120.4, 121.1,
J 4.8 Hz) and 8.80 (4 H, s)
123.2, 127.9, 128.5, 131.3, 139.7, 143.4, 147.1, 155.1; m/z
11
924.3969 (M
ϩ
H
C47H40 B10N7O7 requires 924.3920),
923.3972 (M ϩ H C47H4011B910B1N7O7 requires 923.3956),
922.3962 (M ϩ H C47H4011B810B2N7O7 requires 922.3992),
921.4068 (M ϩ H C47H4011B710B3N7O7 requires 921.4029),
920.3998 (M ϩ H C47H4011B610B4N7O7 requires 920.4065).
5,10,15,20-Tetrakis[3-(1,2-dicarbaclosododecaboran(12)-1-yl)-
phenyl]-21H,23H-porphine 36, 5-(3-nitrophenyl)-10,15,20-tris-
[3-(1,2-dicarbaclosododecaboran(12)-1-yl)phenyl]-21H,23H-por-
phine 37, 5,15-bis(3-nitrophenyl)-10,20-bis[3-(1,2-dicarbacloso-
dodecaboran(12)-1-yl)phenyl]-21H,23H-porphine 38, 5,10-bis(3-
nitrophenyl)-15,20-bis[3-(1,2-dicarbaclosododecaboran(12)-1-yl)-
5-(3-Nitrophenyl)-10,15,20-tris[3-(1,2-dicarbaclosododeca-
boran(12)-1-ylmethoxyphenyl)]-21H,23H-porphinatozinc(II) 29
Porphyrin 24 (80 mg, 68 µmol) was boiled under reflux with
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
314

View Article Online
phenyl]-21H,23H-porphine 39 and 5,10,15-tris(3-nitrophenyl)-
20-[3-(1,2-dicarbaclosododecaboran(12)-1-yl)phenyl]-21H,23H-
porphine 40
4-H3), 8.81 (8 H, s, 2,3,7,8,12,13,17,18-H8), 9.08 (3 H, s, 3 ×
O2NAr 2-H); m/z 893.3917 (M ϩ H 13C1 C45H3811B810B2N7O6
12
12
requires 893.3920), 892.3904 (M ϩ H C46H3811B810B2N7O6
12
requires 892.3887), 891.3905 (M ϩ H C46H3811B710B3N7O6
12
Compounds 22 (2.09 g, 8.4 mmol) and 35 (2.26 g, 8.4 mmol) in
dry dichloromethane (845 cm3) were bubbled with argon before
boron trifluoride diethyl etherate (0.17 cm3, 1.4 mmol) was
added. The mixture was stirred for 2.5 h. 2,3-Dichloro-5,6-
dicyanobenzoquinone (2.11 g, 9.3 mmol) was added and the
mixture was stirred for 16 h. The organic layer was washed with
water and brine and was dried. Chromatography (hexane–
requires 891.3923), 890.3962 (M ϩ H C46H3811B610B4N7O6
12
requires 890.3959), 889.3981 (M ϩ H C46H3811B510B5N7O6
requires 889.3996).
5,15-Bis(4-aminophenyl)-10,20-bis(4-methoxyphenyl)-21H,23H-
porphine 43
Porphyrin 10 (10 mg, 13 µmol) was heated with tin() chloride
hydrate (15.0 mg, 78 µmol) in hydrochloric acid (9 M, 60 cm3)
for 4 h at 65 ЊC. Water (100 cm3) was added and the pH was
adjusted to 8 with aqueous ammonia (35%) before extraction
with chloroform (120 cm3). Drying and evaporation gave
43 (5.0 mg, 56%) as a purple solid: mp >350 ЊC (decomp.);
δH Ϫ2.74 (2 H, s, 21,23-H2), 0.91 (4 H, s, 2 × Ar–NH2), 4.10
(6 H, s, 2 × OCH3), 7.07 (4 H, d, J 8.5 Hz, 2 × H2NAr 3,5-H2),
7.32 (4 H, d, J 8.5 Hz, 2 × MeOAr 3,5-H2), 8.00 (4 H, d, J 8.5
Hz, 2 × H2NAr 2,6-H2), 8.12 (4 H, d, J 8.5 Hz, 2 × MeOAr
2,6-H2), 8.85 (4 H, d, J 4.9 Hz, 2,8,12,18-H4), 8.92 (4 H, d, J 4.9
chloroform–dichloromethane 3 : 1 : 1
4 : 5 : 5) gave 36
(50 mg, 2%) as a purple solid: mp >350 ЊC (decomp.); δH Ϫ2.87
(2 H, s, 21,23-H2), 1.3–3.6 (40 H, br m, 4 × B10H10), 4.19 (4 H, s,
4 × carborane 2-H), 7.75 (4 H, br t, J 7.9 Hz, 4 × Ph 5-H), 7.94
(4 H, d, J 7.9 Hz, 4 × Ph 4-H), 8.28 (4 H, m, 4 × Ph 6-H), 8.34
(4 H, m, 4 × Ph 2-H), 8.80 (8 H, s, 2,3,7,8,12,13,17,18-H8); δC
60.1, 76.5, 118.9, 127.0, 127.4, 131.3, 132.5, 133.3, 135.7, 142.5;
m/z 11B/10B cluster centred at 1184 (M ϩ H). Further elution
gave 37 (507 mg, 18%) as a purple solid: mp >350 ЊC (decomp.);
δH Ϫ2.86 (2 H, s, 21,23-H2), 1.5–3.5 (30 H, br m, 3 × B10H10),
4.19 (3 H, s, 3 × carborane 2-H), 7.78 (3 H, br t, J 7.9 Hz,
Ph10,15,20 5-H3), 7.94 (3 H, br d, J 7.9 Hz, Ph10,15,20 4-H3), 7.99
(1 H, m, Ph5 5-H), 8.26 (3 H, m, Ph10,15,20 6-H3), 8.34 (3 H, s,
Ph10,15,20 2-H3), 8.57 (1 H, m, Ph5 6-H), 8.71 (1 H, m, Ph5 4-H),
8.80 (8 H, s, 2,3,7,8,12,13,17,18-H8), 9.08 (1 H, m, Ph5 2-H);
δC 59.9, 77.0, 117.2, 118.8, 122.9 (NO2Ph 4-C), 126.7, 127.2,
Hz, 3,7,13,17-H4); m/z 706.3014 (M ϩ H 13C1 C45H37N6O2
12
requires 706.3012), 705.2959 (M ϩ H C46H37N6O2 requires
705.2978).
5-(3-Aminophenyl)-10,15,20-tris[3-(1,2-dicarbaclosododeca-
borane(12)-1-ylmethoxy)phenyl]-21H,23H-porphine 44
127.6, 128.0, 131.1, 132.1, 133.1, 135.4, 139.5, 142.0, 143.1,
11
10B2N5O2 requires
10B3N5O2 requires
Method A. Porphyrin 24 (156 mg, 137 µmol) was stirred with
tin() chloride hydrate (550 mg, 2.9 mmol) in acetic acid (140
cm3) for 7 d. The evaporation residue was stirred with aqueous
sodium hydroxide (2 M) and chloroform. The organic layer was
washed with aqueous sodium hydroxide (2 M), water and brine
and was dried. Evaporation and chromatography (chloroform
chloroform–ethyl acetate 99 : 1) gave 44 (110 mg, 72%) as a
purple solid: mp >350 ЊC (decomp.); δH Ϫ2.86 (2 H, s, 21,23-
H2), 1.6–3.2 (30 H, br m, B10H10), 3.96 (2 H, s, NH2), 4.17 (3 H,
br s, 3 × carborane 2-H), 4.61 (6 H, s, 3 × CH2), 7.11 (1 H, dd,
J 1.2, 7.2 Hz, Ph5 4-H), 7.28 (3 H, m, Ph10,15,20 4-H3), 7.52 (2 H,
m, Ph5 2,5-H2), 7.60 (1 H, d, J 7.2 Hz, Ph5 6-H), 7.69 (6 H, m,
Ph10,15,20 2,5-H6), 7.91 (3 H, d, J 6.6 Hz, Ph10,15,20 6-H3), 8.81
(6 H, m, 2,8,12,13,17,18-H4), 8.96 (2 H, d, J 4.9 Hz, 3,7-H2);
δC 58.2, 69.6, 71.7, 114.4, 114.8, 119.1, 119.3, 121.2, 122.2,
126.2, 127.7, 128.2, 129.4, 131.5, 143.0, 144.0, 144.8, 155.6.
146.7; m/z 1090.7656 (M ϩ H C50H60
1090.7611), 1089.7669 (M ϩ H C50H60
B
B
C50H60
28
11
27
11
11
1089.7648), 1088.7690 (M
ϩ
H
B
B
10B4N5O2
10B5N5O2
26
requires 1088.7684), 1087.7700 (M ϩ H C50H60
requires 1087.7720), 1086.7725 (M ϩ H C50H60
O2 requires 1086.7757), 1085.7750 (M ϩ H C50H60
25
11
B
10B6N5-
24
11
B
10B7N5O2
23
requires 1085.7793). Further elution gave 38 (422 mg, 10%) as a
purple solid: mp >350 ЊC (decomp.); δH (50 ЊC) Ϫ2.77 (2 H, s,
21,23-H2), 1.5–3.5 (20 H, br m, 2 × B10H10), 4.16 (2 H, s, 2 ×
carborane 2-H), 7.76 (2 H, br t, J 7.3 Hz, Ph10,20 5-H2), 7.95 (2
H, d, J 7.3 Hz, Ph10,20 4-H2), 7.98 (2 H, d, J 8.5 Hz, Ph5,15 5-H2),
8.26 (2 H, d, J 7.3 Hz, Ph10,20 6-H2), 8.34 (2 H, s, Ph10,20 2-H2),
8.54 (2 H, m, Ph5,15 6-H2), 8.69 (2 H, d, J 8.5 Hz, Ph5,15 4-H2),
8.78 (8 H, s, 2,3,7,8,12,13,17,18-H8), 9.06 (2 H, s, Ph5,15 2-H2); δC
60.3, 76.4, 117.5, 119.2, 123.1, 127.0, 127.4, 127.9, 128.1, 131.8,
132.5, 133.1, 135.4, 139.7, 141.8, 143.0, 146.8; m/z 993.5777
12
11
(M
ϩ
H
13C1 C47H49
B
10B1N6O4 requires 993.5746),
19
11
Method B. Porphyrin 24 (59 mg, 52 µmol) was stirred with
Raney nickel (50 mg) in methanol (16 cm3) and cyclohexene
(24 cm3) for 30 h and filtered. Evaporation, chromatography
12
992.5739 (M ϩ H C48H49
990.5747 (M ϩ H C48H49
987.5856 (M ϩ H C48H49
B
10B1N6O4 requires 992.5713),
10B3N6O4 requires 990.5785),
10B6N6O4 requires 987.5894).
19
17
14
12
11
11
B
B
12
(chloroform
chloroform–ethyl acetate 99 : 1) and drying at
Further elution gave 39 (380 mg, 9%) as a purple solid: mp
>350 ЊC (decomp.); δH Ϫ2.84 (2 H, s, 21,23-H2), 1.5–3.5 (40 H,
br m, 2 × B10H10), 4.19 (2 H, s, 2 × carborane 2-H), 7.77 (2 H,
m, Ph15,20 5-H2), 7.98 (2 H, d, J 7.3 Hz, Ph15,20 4-H2), 8.01
(2 H, d, J 8.5 Hz, Ph5,10 5-H2), 8.29 (2 H, br s, Ph15,20 6-H2), 8.34
(2 H, s, Ph15,20 2-H2), 8.55 (2 H, m, Ph5,10 6-H2), 8.70 (2 H, d,
J 8.5 Hz, Ph5,10 4-H2), 8.81 (8 H, s, 2,3,7,8,12,13,17,18-H8), 9.09
(2 H, s, Ph5,10 2-H2); δC 60.4, 76.5, 117.9, 119.6, 123.5, 127.3,
127.7, 128.1, 128.5, 131.9, 132.7, 133.6, 135.9, 139.9, 142.5,
120 ЊC under reduced pressure (3 torr) for 4 h gave 44 (8 mg,
14%) as a bright purple solid with properties as above.
5,15-Bis(3-aminophenyl)-10,20-bis[3-(1,2-dicarbaclosododeca-
borane(12)-1-yl-methoxyphenyl]-21H,23H-porphine 45 and
5,10-bis(3-aminophenyl)-15,20-bis[3-(1,2-dicarbaclosododeca-
borane(12)-1-yl-methoxyphenyl]-21H,23H-porphine 46
An equimolar mixture of 25 and 26 (89 mg, 85 µmol) was
stirred vigorously with tin() chloride hydrate (484 mg,
2.5 mmol) in hydrochloric acid (9 M, 2 cm3) for 7 d. The
mixture was poured into aqueous sodium hydroxide (2 M,
200 cm3) and was extracted with chloroform. The extract was
washed with aqueous sodium hydroxide (2 M), water and brine.
Drying, evaporation and chromatography (chloroform
chloroform–ethyl acetate 12 : 1) gave 45 (from 25) (31 mg, 76%)
as a purple glass: δH Ϫ2.85 (2 H, s, 21,23-H2), 1.5–3.1 (20 H, br
m, 2 × B10H10), 3.92 (4 H, s, 2 × NH2), 4.14 (2 H, br s, 2 ×
carborane 2-H), 4.58 (4 H, s, 2 × OCH2), 7.09 (2 H, ddd, J 8.2,
2.4, 1.0 Hz, 2 × Ph5,15 4-H), 7.28 (2 H, m, 2 × Ph10,20 4-H), 7.50
(4 H, m, 2 × Ph5,15 2,5-H2), 7.59 (2 H, d, J 7.5 Hz, 2 × Ph5,15
6-H), 7.66 (4 H, m, 2 × Ph10,20 2,5-H2), 7.91 (2 H, d, J 7.5 Hz,
12
11
11
11
11
11
11
11
143.5, 147.2; m/z 993.5741 (M ϩ H 13C1 C47H49
B
19
B
19
B
18
B
17
B
16
B
15
B
14
10B1N6O4
10B1N6O4
10B2N6O4
10B3N6O4
10B4N6O4
10B5N6O4
10B6N6O4
12
requires 993.5746), 992.5762 (M ϩ H C48H49
12
requires 992.5713), 991.5756 (M ϩ H C48H49
12
requires 991.5749), 990.5771 (M ϩ H C48H49
12
requires 990.5785), 989.5801 (M ϩ H C48H49
12
requires 989.5822), 988.5838 (M ϩ H C48H49
12
requires 988.5858), 987.5877 (M ϩ H C48H49
requires 987.5894). Further elution gave 40 (30 mg, 1%) as a
purple solid: mp >350 ЊC (decomp.); δH Ϫ2.84 (2 H, s, 21,23-
H2), 1.4–3.6 (10 H, br m, B10H10), 4.19 (1 H, s, carborane 2-H),
7.79 (1 H, m, Ph20 5-H), 7.99 (4 H, m, Ph20 4-H and Ph5,10,15
5-H3), 8.28 (1 H, br m, Ph20 6-H), 8.34 (1 H, s, Ph20 2-H), 8.56
(3 H, m, Ph5,10,15 6-H3), 8.71 (3 H, dt, J 1.1, 8.4 Hz, Ph5,10,15
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
315

View Article Online
2 × Ph10,20 6-H), 8.79 (4 H, d, J 4.6 Hz, 2,8,12,18-H4), 8.94 (2 H,
d, J 4.6 Hz, 3,7,13,17-H4); δC 57.7, 69.1, 71.2, 113.8, 114.3,
118.5, 120.3, 120.7, 121.7, 125.7, 127.2, 127.6, 128.9,
131.0, 142.6, 143.7, 144.3, 155.0; m/z 993.6485 (M ϩ H
glass: δH Ϫ2.85 (2 H, s, 21,23-H2), 1.6–3.6 (20 H, m, 2 × B10H10),
3.95 (4 H, s, 2 × NH2), 4.19 (2 H, s, 2 × carborane 2-H), 7.10
(2 H, ddd, J 8.1, 2.2, 1.1 Hz, Ph5,10 4-H2), 7.51 (4 H, br m, Ph5,10
2,5-H4), 7.60 (2 H, m, Ph5,10 6-H2), 7.72 (1 H, t, J 7.4 Hz, Ph15
5-H), 7.73 (1 H, t, J 7.4 Hz, Ph20 5-H), 7.91 (2 H, d, J 7.4 Hz,
Ph15,20 4-H2), 8.26 (2 H, m, Ph15,20 6-H2), 8.32 (2 H, s, Ph15,20
2-H2), 8.69 (1 H, d, J 5.0 Hz) and 8.71 (1 H, d, J 5.0 Hz)
(3,12-H2), 8.75 (2 H, s, 7,8-H2), 8.96 (2 H, s, 17,18-H2), 8.99
(2 H, d, J 5.0 Hz, 2,13-H2); δC 60.4, 76.6, 114.8, 118.1, 121.4,
122.2, 126.2, 127.1, 127.5, 127.7, 131.5, 132.4, 133.5, 136.0,
13C1 C49H57
B
B
10BN6O2 requires 993.6473), 992.6491 (M ϩ H
10B2N6O2 requires 992.6510), 991.6484 (M ϩ
12
11
11
19
13C1 C49H57
12
18
H 12C50H57
B
10B2N6O2 requires 991.6477), 990.6504 (M ϩ H
11
18
12
12
12
11
11
11
C H57
B
B
B
10B3N6O2 requires 990.6513), 989.6511 (M ϩ H
10B4N6O2 requires 989.6549), 988.6535 (M ϩ H
10B5N6O2 requires 988.6586). Further elution gave
50
17
16
15
C H57
50
C H57
50
12
46 (from 26) (31 mg, 76%) as a purple glass: δH Ϫ2.85 (2 H, s,
21,23-H2), 1.6–3.1 (20 H, br m, B10H10), 3.95 (4 H, s, NH2), 4.17
(2 H, br s, 2 × carborane 2-H2), 4.60 (4 H, s, 2 × OCH2), 7.11
(2 H, m, 2 × Ph5,10 4-H), 7.28 (2 H, m, 2 × Ph15,20 4-H), 7.51 (4 H,
m, 2 × Ph5,10 2,5-H2), 7.61 (2 H, d, J 7.0 Hz, Ph5,10 6-H), 7.67
(4 H, m, 2 × Ph15,20 2,5-H2), 7.91 (2 H, d, J 7.0 Hz, 2 × Ph15,20 6-H),
8.80 (4 H, m, 12,13,17,18-H4), 8.95 (2 H, m, 2,3,7,8-H4); δC 58.2,
69.6, 71.7, 114.3, 114.8, 118.8, 121.0, 121.2, 122.2, 126.2, 127.7,
128.1, 129.4, 131.5, 143.1, 144.2, 144.8, 155.6; m/z 992.6495
143.0, 143.1, 144.7; m/z 933.6219 (M ϩ H 13C1 C47H53-
11
11
12
B
B
10B1N6 requires 933.6263), 932.6251 (M ϩ H 13C1 C47H53-
19
10B2N6 requires 932.6299), 931.6334 (M ϩ H 13C1 C47-
12
18
11
H53
B
10B3N6 requires 931.6335), 930.6336 (M
ϩ
H
17
12
11
C H53
C H53
C H53
B
B
B
10B3N6 requires 930.6302), 929.6325 (M ϩ H
48
17
16
15
12
12
11
11
10B4N6 requires 929.6338), 928.6343 (M ϩ H
48
10B5N6 requires 928.6374).
48
5-[3-(MeOPEG550carbonylamino)phenyl]-10,15,20-triphenyl-
21H,23H-porphine 50
12
11
(M ϩ H 13C1 C49H57
B
10B2N6O2 requires 992.6510), 991.6486
18
12
11
11
(M ϩ H C50H57
B
B
10B2N6O2 requires 991.6477), 990.6506
10B3N6O2 requires 990.6513), 989.6517
18
17
Dry triethylamine (42 mg, 420 µmol) was added to porphyrin
4224 (130 mg, 210 µmol) and 4-dimethylaminopyridine (3.5 mg)
in dry chloroform (12 cm3) under argon, followed by
MePEG550 chloroformate (258 mg, 420 µmol, derived from
polyethylene glycol 550 monomethyl ether by treatment with
phosgene16). The mixture was stirred for 2.5 h, then diluted
with chloroform to 300 cm3and washed with aqueous sodium
hydroxide (2 M), water and brine. Drying, evaporation, chrom-
12
(M ϩ H C50H57
(M ϩ H 12C50H57
B
10B4N6O2 requires 989.6549).
11
16
5-(3-Aminophenyl)-10,15,20-tris[3-(1,2-dicarbaclosododeca-
boran(12)-1-yl)phenyl]-21H,23H-porphine 47
Porphyrin 37 (159 mg, 146 µmol) was stirred with tin()
chloride hydrate (554 mg, 2.9 mmol) in acetic acid (140 cm3) for
8 d. The evaporation residue, in chloroform, was washed with
aqueous sodium hydrogen carbonate (2 M) (2 (), water and
brine and was dried. Chromatography (chloroform–hexane 1 : 1
chloroform) gave 47 (60 mg, 39%) as a bright purple solid:
mp >350 ЊC (decomp.); δH (50 ЊC) Ϫ2.79 (2 H, s, 21,23-H2), 1.4–
3.2 (10 H, br q, JB–H 145 Hz, B10H10), 3.95 (2 H, br s, NH2), 4.15
(1 H, br s, carborane 2-H), 7.10 (1 H, m, Ph5 4-H), 7.52 (2 H, m,
Ph5 2,5-H2), 7.59 (1 H, m, Ph5 6-H), 7.73 (3 H, t, J 7.7 Hz,
Ph10,15,20 5-H3), 7.92 (3 H, d, J 7.7 Hz, Ph10,15,20 4-H3), 8.24 (3 H,
s, Ph10,15,20 6-H3), 8.33 (3 H, s, Ph10,15,20 2-H3), 8.70 (2 H, m,
2,8-H2), 8.74 (4 H, s, 12,13,17,18-H6), 9.00 (2 H, d, J 4.8 Hz,
3,7-H2); δC 60.1, 76.3, 114.7, 118.3, 118.5, 121.6, 122.0, 126.0,
atography (chloroform
ethyl acetate–methanol 9 : 1) and
drying at 180 ЊC under reduced pressure (3 torr) for 3 h gave 50
(250 mg, 99%) as a bright purple wax: δH Ϫ2.78 (2 H, s, 21,23-
H2), 3.35 (3 H, s, CH3O), 3.54–3.78 (m, (OCH2CH2)n), 4.47
(2 H, m, CH2O2C), 7.77 (9 H, m, 3 × Ph10,15,20 3,4,5-H3), 7.82
(2 H, d, J 8.2 Hz, Ph5 3,5-H2), 8.15 (2 H, d, J 8.2 Hz, Ph5 2,6-
H2), 8.22 (6 H, m, 3 × Ph10,15,20 2,6-H2), 8.84 (6 H, m,
2,8,12,13,17,18-H6), 8.88 (2 H, d, J 4.9 Hz, 3,7-H2); m/z 1282
(M ϩ Na, n = 13, 14%), 1238 (M ϩ Na, n = 12, 22%), 1194
(M ϩ Na, n = 11, 30%), 1150 (M ϩ Na, n = 10, 37%), 1106
(M ϩ Na, n = 9, 30%), 1062 (M ϩ Na, n = 8, 22%), 1018 (M ϩ
Na, n = 7, 20%), 974 (M ϩ Na, n = 6, 12%).
127.4, 127.6, 131.0, 132.4, 133.4, 135.7, 142.6, 142.7, 144.7; m/z
11
1060.7899 (M ϩ H C50H62
1059.7960 (M ϩ H C50H62
1058.7955 (M ϩ H C50H62
1057.7989 (M ϩ H C50H62
B
B
B
B
B
10B2N5 requires 1060.7869),
10B3N5 requires 1059.7906),
10B4N5 requires 1058.7942),
10B5N5 requires 1057.7978),
10B6N5 requires 1056.8015),
5-[3-(MeOPEG550carbonylamino)phenyl]-10,15,20-tris[3-(1,2-
dicarbacloso-dodecaboran(12)-1-ylmethoxy)phenyl]-21H,23H-
porphine 51
28
27
26
25
24
11
11
11
11
Porphyrin 44 was treated with MePEG550 chloroformate, as
for the synthesis of 50 except that the chromatographic eluant
1056.8024 (M ϩ H C50H62
11
1055.8060 (M ϩ H C50H62
B
10B7N5 requires 1055.8051).
23
was chloroform
ethyl acetate, to give 51 (96%) as a bright
purple wax: δH Ϫ2.86 (2 H, s, 21,23-H2), 1.5–3.2 (30 H, br m,
3 × B10H10), 3.4–4.0 (m, (OCH2CH2)nOMe), 4.18 (3 H, br s, 3 ×
carborane 2-H), 4.61 (6 H, m, 3 × OCH2), 7.60–7.72 (8 H, m,
3 × Ph10,15,20 2,5-H2 and Ph5 5,6-H2), 7.84–7.91 (4 H, m, 3 ×
Ph10,15,20 6-H and Ph5 4-H), 8.30 (1 H, br s, Ph5 2-H), 8.82 (6 H,
m, 2,8,12,13,17,18-H4), 8.90 (2 H, d, J 4.6 Hz, 3,7-H2); δC 58.2,
59.3 (OCH3), 64.5, 69.6, 70.6–70.9 ((OCH2CH2)n), 71.7, 110.1,
114.4, 119.2, 119.3, 121.2, 124.9, 127.5, 128.2, 129.3, 144.0,
155.6; m/z cluster centred at 1911 (M ϩ H, n = 16, 0.5%), cluster
centred at 1867 (M ϩ H, n = 15, 0.7%), cluster centred at 1823
(M ϩ H, n = 14, 1.2%), cluster centred at 1779 (M ϩ H, n = 13,
1.5%), cluster centred at 1735 (M ϩ H, n = 12, 2.5%), cluster
5,15-Bis(3-aminophenyl)-10,20-bis[3-(1,2-dicarbaclosododeca-
boran(12)-1-yl)phenyl]-21H,23H-porphine 48 and 5,10-bis(3-
aminophenyl)-15,20-bis[3-(1,2-dicarbaclosododecaboran(12)-1-
yl)phenyl]-21H,23H-porphine 49
An equimolar mixture of 38 and 39 was treated with tin()
chloride hydrate, as for the synthesis of 45 and 46. Chromato-
graphy (chloroform
chloroform–ethyl acetate 16 : 1) gave 48
(80%) as a purple glass: δH (CDCl3/(CD3)2SO) 19:1) Ϫ2.90 (2 H,
s, 21,23-H2), 1.5–3.5 (20 H, m, 2 × B10H10), 4.61 (4 H, s,
2 × NH2), 5.04 (2 H, s, 2 × carborane 2-H), 7.11 (2 H, m, Ph5,15
4-H2), 7.48 (4 H, br m, Ph5,15 2,5-H4), 7.52 (2 H, br s, Ph5,15
6-H2), 7.66 (2 H, t, J 7.4 Hz, Ph10,20 5-H2), 7.98 (2 H, d, J 7.4 Hz,
Ph10,20 4-H2), 8.26 (2 H, d, J 7.4 Hz, Ph10,20 6-H2), 8.38 (2 H, s,
Ph10,20 2-H2), 8.74 (4 H, br s, 2,8,12,18-H4), 9.00 (4 H, d, J 4.6
centred at 1690 (M ϩ H, n = 11, 4.2%), 1694.1044 (M ϩ H
11
C77H114
C77H114
C77H114
B
B
B
10BN5O16 requires 1694.1088), 1689.1268 (M ϩ H
10B6N5O16 requires 1689.1270), 1688.1320 (M ϩ H
10B7N5O16 requires 1688.1306), cluster centred at
29
24
23
11
11
12
11
Hz, 3,7,13,17-H4); m/z 932.6319 (M ϩ H 13C1 C47H53 B18-
10B2N6 requires 932.6299), 931.6332 (M ϩ H 13C1 C47H53-
1647 (M ϩ H, n = 10, 4%), cluster centred at 1603 (M ϩ H, n =
9, 3.5%), cluster centred at 1559 (M ϩ H, n = 8, 3.7%), cluster
centred at 1514 (M ϩ H, n = 7, 2.7%), cluster centred at 1471
(M ϩ H, n = 6, 2%), cluster centred at 1425 (M ϩ H, n = 5,
1.2%), cluster centred at 1381 (M ϩ H, n = 4, 1%), 59
(CH3OCH2CH2, 100%).
12
11
11
B
10B3N6 requires 931.6335), 930.6338 (M ϩ H 12C48H53 B17-
17
10B3N6 requires 930.6302), 929.6360 (M ϩ H 12C48H53
B
16
B
15
B
14
10B4N6
10B5N6
10B6N6
11
12
11
11
requires 929.6338), 928.6383 (M ϩ H C48H53
requires 928.6374), 927.6378 (M ϩ H C48H53
12
requires 927.6411). Further elution gave 49 (72%) as a purple
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
316

View Article Online
2 A. H. Soloway, R. L. Wright and J. R. Messner, J. Pharmacol. Exp.
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5-[3-(MeOPEG550carbonylamino)phenyl]-10,15,20-tris[3-(1,2-
dicarbacloso-dodecaboran(12)-1-yl)phenyl]-21H,23H-porphine
52
Porphyrin 47 was treated with MePEG550 chloroformate, as
for the synthesis of 50 except that the chromatographic eluant
was chloroform
chloroform–acetone (2 : 3), to give 52 (90%)
as a bright purple wax: δH Ϫ2.80 (2 H, s, 21,23-H2), 1.6–3.2 (30
H, m, 3 × B10H10), 3.4–4.0 (m, (OCH2CH2)nOMe), 4.21 (3 H, s,
3 × carborane 2-H), 4.60 (6 H, m, 3 × OCH2), 7.10 (1 H, m, Ph5
4-H), 7.52 (2 H, m, Ph5 2,5-H2), 7.59 (1 H, m, Ph5 6-H), 7.73
(3 H, t, J 7.7 Hz, Ph10,15,20 5-H3), 7.92 (3 H, d, J 7.7 Hz, Ph10,15,20
4-H3), 8.24 (3 H, s, Ph10,15,20 6-H3), 8.33 (3 H, s, Ph10,15,20 2-H3),
8.70 (2 H, m, 2,8-H2), 8.74 (4 H, s, 12,13,17,18-H4), 9.00 (2 H, d,
J 4.8 Hz, 3,7-H2); m/z 1687 (M ϩ H, n = 12, 0.6%), 1643 (M ϩ
H, n = 11, 1.4%), 1598 (M ϩ H, n = 10, 1.6%), 1556 (M ϩ H, n =
9, 1.7%), 1511 (M ϩ H, n = 8, 2%), 1467 (M ϩ H, n = 7, 1.7%),
1423 (M ϩ H, n = 6, 1.2%), 1378 (M ϩ H, n = 5, 0.9%), 1333
(M ϩ H, n = 4, 0.4%), 59 (CH3OCH2CH2, 100%).
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Crystal structure determination of compound 38
A crystal of 38 was grown by slow evaporation of a solution in
chloroform/hexane.
Crystal data. C48H48B20N6O4, M = 989.12, wavelength =
0.71073 Å, monoclinic, space group P21/n, a = 14.5870(2), b =
7.0000(1), c = 27.8680(4)Å, U = 2748.01(7) Å3, Z = 2, Dc = 1.195
Mg mϪ3, µ = 0.070 mmϪ1, F(000) = 1020, crystal size 0.13 × 0.13
× 0.08 mm. A hemisphere of data (36917 reflections) were
collected on a Nonius(kappaCCD diffractometer at 150 K, of
which 5373 were unique, [R(int) = 0.0687] and 1863 observed
with I>2σ(I ). Data were treated for Lorentz and polarisation
but not for absorption. All non-hydrogen atoms were treated
anisotropically in the final least squares cycles. Hydrogen atoms
were included at calculated positions with the exception of H1
(attached to N1), which was located and refined at a distance of
0.89 Å from the parent atom. Final residuals R1 and wR2 were
0.0757 and 0.2287, respectively, with max peak/hole in the
difference Fourier map of 0.624 and Ϫ0.309 eÅϪ3. Structural
solution was effected using SHELXS-8627 and refinement
completed using SHELXL-97.28 Fig. 4 was produced using
ORTEX.29 CCDC 195567. See http://www.rsc.org/suppdata/ob/
b2/b209534c/ for crystallographic files in CIF or other elec-
tronic format.
13 M. Miura, G. M. Morris, P. L. Micca, D. T. Lombardo,
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Acknowledgements
The authors thank Dr S. J. Black, Mr R. R. Hartell and
Mr D. Wood (University of Bath) for the NMR spectra and
Mr C. Cryer (University of Bath) for the mass spectra. We are
particularly grateful to Dr H. Patel (Harvard University) and
Professor J. W. Hopewell (University of Oxford) for helpful
discussions on BNCT. CF held a University of Bath Research
Bursary.
25 B. J. Littler, M. A. Miller, C.-H. Hung, R. W. Wagner, D. F. O’Shea,
P. D. Boyle and J. S. Lindsey, J. Org. Chem., 1999, 64, 1391.
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45, 4466.
27 G. M. Sheldrick, Acta Cryst., 1990, A46, 467.
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 6 – 3 1 7
317