Heterocyclic aromatic amide protecting groups for aryl and phthalocyaninesulfonic acids

Article abstract of DOI:10.1139/v98-219

Pyrroles, indole, imidazole, and a pyrazole were treated with 3,4-dibromobenzenesulfonyl chloride to form 3,4-dibromobenzenesulfonamides. The 1-(3,4-dibromophenylsulfonyl)pyrrole and 1-(3,4-dibromophenylsulfonyl)indole were stable to CuCN in DMF to produce 1-(3,4-dicyanophenylsulfonyl)pyrrole and 1-(3,4-dicyanophenylsulfonyl)indole, which upon treatment with ammonia in 2-N,N-dimethylaminoethanol gave the protected phthalocyanine-2,9,16,23-tetrasulfonamides. Base cleavage of these sulfonamides yielded the free acids. A mixed condensation of 4,5-diheptylphthalonitrile and 1-(3,4-dicyanophenylsulfonyl)pyrrole gave 9,10,16,17,23,24-hexakis(1-heptyl)-2-(1-pyrrolylsulfonyl)phthalocyanine. Cleavage of the latter yielded the lithium salt of the monosulfonic acid.

Full text of DOI:10.1139/v98-219

138
Heterocyclic aromatic amide protecting groups
for aryl and phthalocyaninesulfonic acids
Zhaopeng Li, Johan van Lier, and Clifford C. Leznoff
Abstract: Pyrroles, indole, imidazole, and a pyrazole were treated with 3,4-dibromobenzenesulfonyl chloride to form
3,4-dibromobenzenesulfonamides. The 1-(3,4-dibromophenylsulfonyl)pyrrole and 1-(3,4-dibromophenylsulfonyl)indole
were stable to CuCN in DMF to produce 1-(3,4-dicyanophenylsulfonyl)pyrrole and 1-(3,4-dicyanophenylsulfonyl)indole,
which upon treatment with ammonia in 2-N,N-dimethylaminoethanol gave the protected phthalocyanine-2,9,16,23-
tetrasulfonamides. Base cleavage of these sulfonamides yielded the free acids. A mixed condensation of
4,5-diheptylphthalonitrile and 1-(3,4-dicyanophenylsulfonyl)pyrrole gave 9,10,16,17,23,24-hexakis(1-heptyl)-2-(1-
pyrrolylsulfonyl)phthalocyanine. Cleavage of the latter yielded the lithium salt of the monosulfonic acid.
Key words: sulfonic acid blocking groups, phthalocyanine sulfonic acids, 1-(3,4-dicyanophenylsulfonyl)pyrrole,
1-(3,4-dicyanophenylsulfonyl)indole.
Résumé : La réaction du chlorure de 3,4-dibromobenzènesulfonyle avec des pyrroles, l’indole, l’imidazole et un pyra-
zole conduit à la formation de 3,4-dibromobenzènesulfonamides. Le 1-(3,4-dibromophénylsulfonyl)pyrrole et du
1-(3,4-dibromophénylsulfonyl)indole ont été soumis à l’action du CuCN dans le DMF pour produire du 1-(3,4-dicyano-
phénylsulfonyl)pyrrole et du 1-(3,4-dicyanophénylsulfonyl)indole qui, par traitement avec de l’ammoniac dans le
2-N,N-diméthylaminoéthanol conduit aux phtalocyanine-2,9,16,23-tétrasulfonamides protégés. Le clivage basique de ces
sulfonamides conduit aux acides libres. Une condensation mixte du 4,5-diheptylphtalonitrile et du 1-(3,4-dicyano-
phénylsulfonyl)pyrrole conduit à la 9,10,16,17,23,24-hexakis(1-heptyl)-2-(1-pyrrolylsulfonyl)phtalocyanine. Le clivage
de cette dernière fournit le sel de lithium de l’acide monosulfonique.
Mots clés : acide sulfonique comme agents bloqueurs, acides phtalocyanine sulfoniques, 1-(3,4-dicyanophényl-
sulfonyl)pyrrole, 1-(3,4-dicyanophénylsulfonyl)indole.
[Traduit par la Rédaction] Li et al. 145
to recover the free amines is not a trivial operation, but a
large number of sophisticated procedures (17) have been
Phthalocyanine (Pc) sulfonic acids have potential as
photodynamic therapy (PDT) agents of cancer tumours (1,
2). Although phthalocyanine -2,9,16,23-tetrasulfonic acid is
commercially available as a mixture of isomers, it has been
shown that phthalocyanine-2-sulfonic acid and phthalocyanine-
2,9-disulfonic acid are more effective for direct cell kill (3–9).
Unfortunately, only small samples obtained by high-perfor-
mance liquid chromatography (HPLC) of these unsymmetri-
cal phthalocyanine sulfonic acids (6–8) were available for
PDT studies (9, 10). Some recent attempts at preparing
mono sulfonated Pcs by the oxidation of sulfides (11) or
trisulfonated Pcs (12, 13) via subphthalocyanines (14, 15)
gave Pcs in low yield.
One roadblock in the development of a rich variety of
readily available sulfonated Pcs is the paucity of suitable
blocking groups or precursors of sulfonic acids. Sulfona-
mides are common compounds made from sulfonyl chlo-
rides and amines, and sulfonamides are widely used as
blocking groups of amines. Cleavage (16) of sulfonamides
used to accomplish this task, often requiring harsh condi-
tions such as the use of concentrated acid and high tempera-
tures (18), or reducing agents (19). In most of these
procedures little attention is paid to the sulfonic acid residue
remaining after the cleavage, and indeed, the sulfonic acid
group is often transformed in the process (17–19). The re-
cent description of a neopentyl ester group as a blocking
group (20) of sulfonic acid seemed interesting to us but
early experiments indicated it to be unsuitable for phthalo-
cyanine synthesis.
Aryl sulfonyl chlorides have been used as blocking groups
of five-membered ring aromatic amines such as imidazole,
(21, 22), pyrrole (23), and indole (24), and these were
cleaved under a variety of conditions, liberating both the
amine and recovered sulfonic acids, and hence we directed
our attention to the use of these five-membered heterocyclic
amines as blocking groups of aryl sulfonic acids. It proved
to be essential to develop an aryl sulfonic acid blocking
group that was stable to both phthalonitrile and phthalo-
Received July 15, 1998.
Z. Li and C.C. Leznoff.1 Department of Chemistry, York University, Toronto, ON M3J 1P3 Canada.
J. van Lier. MRC Group in the Radiation Sciences, Faculty of Medicine, Université de Sherbrooke, PQ J1N 5N4, Canada.
1Author to whom correspondence may be addressed. Telephone: (416) 736-2100, ext. 33838. Fax: (416) 736-5936.
e-mail: leznoff@yorku.ca
Can. J. Chem. 77: 138–145 (1999)
© 1999 NRC Canada

Li et al.
139
Scheme 1.
cyanine formation and yet could be cleaved under conditions
in which the sulfonic acid groups remained intact.
Br
Br
Br
Br
HO3S
Chlorosulfonation of 1,2-dibromobenzene (1) readily gave
3,4-dibromobenzenesulfonyl chloride (2) (25). Solov’eva et
al. (25) described the synthesis of a wide variety of
N,N-dialkyl-3,4-dibromobenzenesulfonamides for use in
phthalonitrile and phthalocyanine synthesis, but these sul-
fonamides are not readily cleaved to the free acids. We first
decided to try to see if aryl groups such as diphenylamine
(3) used in making N,N-diphenylbenzenesulfonamide would
be useful in phthalocyanine synthesis and at the same time
compare that analog with a series of heteroarylbenzene-
sulfonamides derived from pyrrole (4), 2-ethylpyrrole (5),
3,5-dimethylpyrazole (6), imidazole (7), and indole (8).
Treatment of sulfonyl chloride 2 with 3 in refluxing
CHCl3 and pyridine (py) afforded 3,4-dibromo-N,N-di-
phenylbenzenesulfonamide (9) in high yield. On the other
hand, pyrroles 4 and 5 were first treated with NaH in tetra-
hydrofuran (THF) to form the sodium derivatives, which
1
15
B -
ClSO3H
Br
Br
R2NH, MH
Br
Br
MCO3, or py
ClO2S
R2NO2S
2
3 R = Ph
9 R = Ph
10 R2 =
4 R2 =
5 R2 =
then reacted with
2 at room temperature to give
1-(3,4-dibromophenylsulfonyl)pyrrole (10), 1-(3,4-dibromo-
phenylsulfonyl)-2-ethylpyrrole (11), and 1-(3,4-dibro-
mophenylsulphonyl)-3,5-dimethylpyrazole (12) in 50, 3, and
84% yields, respectively. The reaction of imidazole (7) and
indole (8) with base in CHCl3 likewise gave 1-(3,4-dibro-
mophenylsulfonyl)imidazole (13) and 1-(3,4- dibromophenyl-
sulfonyl)indole (14) in 34 and 50% yields, respectively
(Scheme 1). The low yield of 11 precluded further work on
this compound, although we had envisioned that the ethyl
group of 5 would afford enhanced solubility to the subse-
quent phthalonitrile and phthalocyanine.
At this point it was important to test the stability of
sulfonamides 9, 10, and 12–14 to the conditions of (i) the
Rosenmund – von Braun reaction (CuCN, 200°C, DMF)
(26), (ii) phthalocyanine formation (MOR or NH3), and
(iii) sulfonamide cleavage. Sulfonamides 9, 10, 13, and 14
were stable to the Rosemund – von Braun reaction, but 12
was not and was abandoned for further consideration. Sul-
fonamides 9, 10, and 14 were stable to NaOCH3 at room
temperature and NH3 in 2-N,N-dimethylaminoethanol (DMAE),
possible methods for use in phthalocyanine formation but 13
did not survive these conditions (Table 1) and was dropped
as a potential candidate for Pc formation. Sulfonamides 10
and 14 were solvolyzed by NaOCH3 in refluxing methanol
to give 3,4-dibromophenylsulfonic acid (15) (27), but again
12 and 13 gave 15 simply upon stirring at room temperature
as above (Table 1). All sulfonamides were stable to concen-
trated HCl at room temperature. Thus, only sulfonamides 9,
10, and 14 were suitable substrates for development for
phthalocyanine synthesis.
11 R2 =
Et
Me
Et
Me
N
N
6 R2 =
12 R2 =
Me
Me
N
N
7 R2 =
8 R2 =
13 R2 =
14 R2 =
Since we had already shown that 10 and 14 are cleaved by
metal alkoxides at refluxing methanol conditions, we treated
′
′′ ′′′
17 and 18 with NH3 in DMAE to form N,N ,N ,N -
tetrakis-(1-pyrrolyl)phthalocyanine-2,9,16,23-tetrasulfonamide (20)
and N,N ,N ,N -tetrakis-(1-indolyl) phthalocyanine-2,9, 16,23-
tetrasulfonamide (21) in 33 and 42% yields, respectively.
Under similar conditions to the formation of 21 and 22, but
with the addition of Zn(OAc)2, 17 and 18 were converted di-
′
′′ ′′′
′
′′ ′′′
rectly to N,N ,N ,N -tetrakis- (1-pyrrolyl)phthalocyanine-2,9,16,
′
′′ ′′′
23-tetrasulfonamide zinc(II) (22) and N,N ,N ,N -tetrakis-
(1-indolyl)phthalocyanine-2, 9,16, 23-tetrasulfonamide zinc(II)
(23) in 32 and 68% yields, respectively (Scheme 2).
As expected Pc 19 proved to be resistant to solvolysis, but
Pc sulfonamides 20 and 21 were readily converted to phtha-
locyanine-2,9,16,23-tetrasulfonic acid (24) by treatment with
lithium 2-N,N-dimethylaminoethoxide in DMAE (for 20) or
lithium methoxide in THF–MeOH for 21 (Scheme 2).
Early experiments towards the synthesis of a phthalo-
cyanine monosulfonic acid via a mixed condensation of 17
and phthalonitrile gave insoluble residues difficult to sepa-
rate by chromatography. To increase the solubility of the
The dibromosulfonamides 9, 10, and 14 were readily con-
verted via CuCN in DMF to 3,4-dicyano-N,N-diphenylben-
zenesulfonamide (16), 1-(3,4-dicyanophenylsulfonyl)pyrrole
(17), and 1-(3,4-dicyanophenylsulfonyl)indole (18) in 29, 43,
and 45% yields, respectively (Scheme 2). The N,N-diphenyl-
′
′
′′ ′′ ′′′ ′′′
sulfonamide 16 readily formed N,N,N ,N ,N ,N ,N ,N -
octaphenylphthalocyanine-2,9,16,23-tetrasulfonamide (19) in
50% yield when treated with lithium in DMAE at 70°C (28).
© 1999 NRC Canada

140
Can. J. Chem. Vol. 77, 1999
Table 1. Synthesis of 3,4-dibromosulfonamides and their stability to bases and the Rosenmund – von Braun
reaction.
Stability at 20°C
NH3
Method
(base/solvent)
Compound
Yield (%)
NaOMe
CuCN–DMFa
9
10
12
13
14
py/CHCl3
NaH/THF
NaH/THF
Na2CO3/CHCl3
65
50
84
34
57
Stable
Stable
Stable
Stable
Unstable
Stable
Stable
Stable
—
—
Stable
Stableb
Unstable
Unstable
Stableb
c
d
NaOH/CH2Cl2
aRefluxed.
bUnstable in refluxing MeOH.
cWith MeOH.
dBu4NHSO4 phase transfer reagent.
phthalocyanine product, 17 was condensed with 4,5-
diheptylphthalonitrile (25) (29), as for the formation of 22,
to give 9,10,16,17,23,24-hexakis(1-heptyl)phthalocyanine-
2-(N-pyrrolyl)sulfonamide (26) in 14.7% yield. Treatment of
26 with Zn(OAc)2 in DMF readily afforded 9,10,16,17, 23,
24-hexakis(1-heptyl)phthalocyanine-2-(N-pyrrolyl)sulfonamide
zinc(II) (27) in 86% yield. Hydrolysis of 27 with lithium
methoxide in methanol afforded lithium 9,10,16,17,23,24-
hexakis(1-heptyl)phthalocyanine-2-sulfonate zinc(II) (28) in
85% yield (Scheme 3).
Spectral data of all new compounds were consistent with
their structures (see Experimental). Pcs 19–23 exhibited
multiplets in their NMR spectra, consistent with the fact that
they exist as mixtures of isomers. Mass spectra of all sul-
fonamides exhibited ions showing loss of SO2 and peaks
representing both fragments (30).
(NMR) spectroscopy was performed at 295–300 K unless
otherwise noted, using a Bruker ARX 400 high-field Fourier
transform instrument. Chemical shifts are reported in parts
per million relative to a tetramethylsilane (TMS) internal
standard.
3,4-Dibromobenzenesulfonyl chloride (2)
To a flask containing 1,2-dibromobenzene (1) (20 g,
88.47 mmol) and dry CHCl3 (120 mL), which was cooled to
ca. –10°C by an ice–NaCl bath, was added chlorosulfonic
acid (30 g) over 20 min. The light brown solution was stirred
at room temperature for 20 h. The reaction mixture turned
red during this period. The solution was refluxed for 1 h. Af-
ter cooling to room temperature, the vigorously stirred reac-
tion mixture was poured onto crushed ice (200 g). The
aqueous and organic layers were separated. The former was
washed with CH2Cl2 (100 × 2 mL). The combined organic
layer was washed with aqueous NaHCO3 (10%, 150 mL)
followed by water until pH neutral. After drying over
MgSO4, and evaporating the solvent, vacuum distillation af-
forded a colourless solid product (120–125°C/5 mmHg
(1 mmHg = 133.3 Pa), 22.7 g, 85%), mp 31–33°C (lit. (27)
We have demonstrated that indole and pyrrole moieties
can be successfully used to form sulfonamides as blocking
groups in the synthesis of phthalocyanine sulfonic acids.
1
mp 34°C); H NMR (CDCl3) δ: 8.28 (d, J = 1.8, 1H, H4),
All organic solvents were dried by appropriate methods
and distilled before use. All reagents were freshly distilled,
or were recrystrallized and then dried under reduced pres-
sure, before use. Unless otherwise noted, magnetic stirring
methods under an inert atmosphere (Matheson High Purity
argon) were utilized during distillation or reaction processes,
and round-bottom glass vessels chosen such that the quantity
of reagents and solvent did not exceed half of the available
volume. Water-cooled condensers were used if reaction pro-
cesses were held near, or at, reflux conditions. Melting
points were determined using a Kofler hot-stage melting
point apparatus and are reported uncorrected. Infrared spec-
troscopy was performed on either a Pye Unicam SP3-2000
or a Perkin Elmer 1310 infrared spectrophotometer and
FTIR spectroscopy was performed on a Unicam Matheson
3000 FTIR spectrometer, using samples prepared as KBr
discs unless otherwise noted. Mass spectral analyses were
performed by Dr. B. Khouw (York University, Toronto, On-
tario), Dr. R. Smith (McMaster University, Hamilton, On-
tario), and Dr. R.N. Cerny (Midwest Center for Mass
Spectrometry, University of Nebraska–Lincoln, Lincoln, Ne-
braska). HRMS were preformed by Dr. R. Smith (McMaster
University, Hamilton, Ontario). Nuclear magnetic resonance
7.91 (d, J = 8.4, 1H, H6), 7.85 (dd, J1 = 1.8, J2 = 8.4, 1H,
H5).
3,4-Dibromo-N,N-diphenylbenzenesulfonamide (9)
To a solution of 3,4-dibromobenzenesulfonyl chloride (2)
(1.0 g, 3.2 mmol) in dry CHCl3 (10 mL) were added
diphenylamine (3) (0.7 g, 3.0 mmol) and pyridine (0.5 mL).
The solution was refluxed for 14 h, and cooled at room tem-
perature, washed with aqueous HCl (5%, 10 mL) and water
until neutral. After drying over MgSO4 and evaporating the
solvent, the crude product was recrystallized from ethanol to
give colourless crystalline needles (0.9 g, 65%), mp
160–161°C; IR (KBr cm–1): 1957, 1886, 1589, 1449, 1446,
1351; 1H NMR (CDCl3) δ: 7.93 (d, J = 2.0, 1H), 7.74 (d, J =
8.0, 1H), 7.45 (dd, J1 = 8.0, J2 = 2.0, 1H), 7.31 (m, 10H);
MS (m/z, relative intensity): 469 (M+, 15), 467 (M+, 30), 465
(M+, 14), 167 (100). Anal. calcd. for C18H13NBr2NO2S: C
46.25, H 2.78, N 3.00; found: C 46.41, H 2.66, N 2.96.
1-(3,4-Dibromophenylsulfonyl)pyrrole) (10)
To freshly distilled pyrrole (4) (220 mg, 30 mmol) in dry
THF (5 mL), cooled to 0°C, was added NaH (300 mg, 60%
© 1999 NRC Canada

Li et al.
141
Scheme 2.
Br
Br
CN
CN
CuCN
DMF
R2NO2S
9 R = Ph
R2NO2S
16 R = Ph
10 R2 =
14 R2 =
17 R2 =
18 R2 =
R2NO2S
X
N
N
N
N
N
N
N
N
N
SO2NR 2
X
M
N
N
M
N
N
R2NO2S
X
N
N
N
SO2NR 2
X
19 R = Ph
20 R2 =
M = 2H
24 X = SO3H M = 2H
M = 2H
21 R2 =
22 R2 =
M = 2H
M = Zn
M = Zn
23 R2 =
oil dispersion). 3,4-Dibromobenzenesulfonyl chloride (2)
(1.0 g, 3.2 mmol) was added over 30 min. under Ar. After
stirring at room temperature for 6 h, the brown reaction mix-
ture was carefully poured into a saturated NH4Cl solution
(30 mL) placed in an ice bath. Ether (30 mL) was added and
the aqueous layer was washed with ether (20 mL). The com-
bined organic layer was washed with saturated NH4Cl until
neutral. After drying over MgSO4 and evaporating the sol-
vent, the crude product was recrystallized from ethanol to
give colourless crystalline needles (545 mg, 50%), mp
141–142°C; IR (KBr cm–1): 3075 (s, ArH), 1375 (s, SO2N),
(m, 2H), 6.36 (m, 2H); MS (m/z, relative intensity): 367
(M+, 50), 365 (M+, 95), 363 (M+, 50), 299 (90), 235 (100).
Anal. calcd. for C10H7NBr2: C 32.88, H 1.92, N 3.84; found:
C 33.72, H 1.87, N 3.91.
1-(3,4-Dibromophenylsulphonyl)-2-ethylpyrrole (11)
The crude product, obtained as described for 10 but using
2-ethylpyrrole (5), recrystallized from ethanol to give in 3%
yield fine colourless crystals 78–79°C; IR (KBr cm–1): 3074
(s, ArH), 1372 (s, SO2N), 1180 (s, SO2N); 1H NMR (CDCl3)
δ: 8.14 (d, J = 1.6, 1H), 8.03 (d, J = 7.8, 1H), 7.73 (dd, J1 =
1.6, J2 = 7.8, 1H), 7.41 (d, 1.7, 1H), 6.31 (t, 1H) (6.12 bs,
1H); 2.71 (q, J = 7.3, 2H), 1.24 (t, J = 7.3, 3H); MS (m/z,
1
1186 (s, SO2N); H NMR (CDCl3) δ: 8.10 (d, J = 2.0, 1H),
7.77 (d, J = 8.4, 1H), 7.63 (dd, J1 = 8.4, J2 = 2.0, 1H), 7.16
© 1999 NRC Canada

142
Can. J. Chem. Vol. 77, 1999
Scheme 3.
CN
CN
C7H15
C7H15
CN
CN
+
NO2S
17
25
C7H15 C7H15
N
N
N
C7H15
C7H15
1) NH3/DMAE
N
M
N
N
2) Zn(OAc)2
3) LiOMe
X
N
N
C7H15 C7H15
26 M = 2H
27 M = Zn
28 M = Zn
X =
NO2S
NO2S
X =
X =
SO3Li
relative intensity): 393 (M+, 75), 379 (70), 315 (67), 299
(70), 80 (100). Anal. calcd. for C12H11Br2NO2S: C 36.64, H
2.80, N 3.56; found: C 37.27, H 2.74, N 3.52.
J = 8.0, 1H), 7.73 (dd, J1 = 8.0, J2 = 2.0, 1H), 7.32 (brs,
1H); 7.16 (brs, 1H); MS (m/z, relative intensity): 366 (M+,
95) 299 (100), 235 (100). Anal. calcd. for C9H6Br2N2O2S: C
29.51, H 1.64, N 7.65; found: C 29.61, H 1.46, N 7.61.
1-(3,4-Dibromophenylsulphonyl)-3,5-dimethylpyrazole
(12)
1-(3,4-Dibromophenylsulfonyl)indole (14)
The crude product, obtained as described for 10 but using
3,5-dimethylpyrazole (6), was recrystallized from ethanol
twice to give 0.98 g of 12 in 84% yield, mp 145–147°C; IR
(KBr cm–1): 3082 (s, ArH), 1374 (s, SO2N), 1188 (s, SO2N);
1H NMR (CDCl3) δ: 8.19 (d, J = 1.5, 1H), 7.75 (m, 2H),
Ground NaOH (2.0 g) was mixed with tetrabutylam-
monium hydrogen sulfate (140 mg) in CH2Cl2 (30 mL). The
reaction flask was cooled by a salt–ice bath to 0–4°C after
which indole (8) (1.85 g, 15.8 mmol) was added. Sulfonyl
chloride (7) (5.0 g, 15.0 mmol) was added over 30 min. and
stirred for an additional 30 min. in the ice bath. The solution
was stirred at room temperature for 20 h, washed with HCl
(10%, 20 mL) and with water until neutral. After drying
over MgSO4 and evaporating the solvent, the crude product
was chromographed with 20% ethyl acetate – hexane to give
14 as a fine, colourless crystals (3.1 g, 50% mp) 125–126°C;
1
5.94 (s, H), 2.51 (s, 3H), 2.22 (s, 31H); MS (m/z, relative
intensity): 394 (M+, 10), 328 (100), 299 (30), 250 (40), 236
(50). Anal. calcd. for C11H10Br2N2O2S: C 33.50, H 2.54, N
7.11; found: C 33.72, H 2.30, N 7.14.
1-(3,4-Dibromophenylsulfonyl)imidazole (13)
1
IR (KBr cm–1): 3140, 3081 (s, ArH), 1376 (s, SO2N); H
To a solution of (3) (1.0 g, 3.2 mmol) in a mixture of
chloroform (5 mL) and methanol (1 mL) was added imida-
zole (7) in chloroform (2 mL) and Na2CO3 (1.0 g). The mix-
ture was stirred at room temperature for 22 h, filtered, and
the filtrate was washed with HCl (10%, 20 mL) and water
until neutral. After drying over MgSO4 and evaporating the
solvent, the crude product was chromatographed with 40%
ethyl acetate – hexane to give pure 13 as fine, colourless
crystals (320 mg, 34%), mp 119–120°C; IR (KBr cm–1):
NMR (CDCl3) δ: 8.13 (d, J = 2.0, 1H), 7.99 (d, J = 8.0, 1H),
7.66 (m, 2H), 7.56 (m, 2H), 7.37 (m, 1H); 7.29 (m, 1H),
6.74 (d, J = 4.0, 1H); MS (m/z, relative intensity): 417 (M+,
45), 415 (M+, 88) 413 (M+, 43) 116 (100). Anal. calcd. for
C14H9Br2NO2S: C 40.68, H 2.18, N 3.39; found: C 40.79, H
1.95, N 3.37.
3,4-Dibromobenzenesulfonic acid (15)
Compound 13 (50 mg, 0.14 mmol) was dissolved in meth-
anol (5 mL) and NaOMe (40 mg, 0.74 mmol) was added.
1
1938 (m), 1768 (m), 1564 (s), 1464 (s), 1381 (s, SO2N); H
NMR (CDCl3) δ: 8.19 (d, J = 2.0, 1H), 8.04 (s, 1H), 7.85 (d,
© 1999 NRC Canada

Li et al.
143
The reaction solution was stirred at room temperature for
20 h. The solvent was evaporated. The residue was dissolved
in water (50 mL) and washed with ether (10 mL) followed
by neutralization with aqueous HCl (36%). The solvent was
evaporated, the residue recrystallized from water, and the
product was further purified by ion-exchange resin (Dowex
50X8-400). Recrystallization from EtOH (80%) afforded
pale, yellow needles of 15 (26 mg, 60%), mp 64–66°C (lit.
(5 g) and aqueous HCl (10 mL, 4 M). The precipitate was
collected by filtration, and the crude product was purified
using flash chromatography with 5% THF–CH2Cl2 as eluent
to give a dark blue, fine powder of 19 (11 mg, 11%), mp
>310°C. IR (KBr cm–1): 1394, 1164 (s, SO2N); UV-vis
(THF) (λmax): 698, 664, 636, 604, 344, 238; 1H NMR
(pyridine-d5): 8.91 (s) 8.46 (s), 7.85 (m), 7.37 (m), 6.96 (s);
MS (FAB+, m/z relative intensity): 1438 (M+). Anal. calcd.
for C80H54N12O8S4: C 66.76, H 3.75, N 11.68; found: C
66.95, H 3.66, N 10.82.
1
(27) mp 66.5–67.5°C); H NMR (D2O) δ: 7.99 (s, 1H), 7.74
(d, 1H), 7.52 (dd, 1H). In a similar manner 12 gave 15 in
69% yield, while 10 and 14 were cleaved in methanol at re-
flux to give 15 in 72 and 57% yield, respectively.
2,9,16,23-Tetrakis(1-pyrrolysulfonyl)phthalocyanine (20)
Compound 17 (200 mg, 0.78 mmol) was dissolved in
N,N-dimethylaminoethanol (DMAE) (2 mL). As ammonia
gas was bubbled through, the reaction mixture was heated to
100–110°C (sand bath) for 1 h and then refluxed for 4 h.
The reaction mixture was cooled to room temperature, the
solvent evaporated, and water (10 mL) was added to the re-
sulting sticky solution. The blue precipitate was collected by
filtration or centrifugation and purified by flash chromatog-
raphy using 5% THF–CH2Cl2 as eluent to give in the first
fraction phthalocyanine 20 as dark blue crystals (66 mg,
33%), mp >310°C; IR (KBr cm–1): 3141 (m, ArH), 1374 (s,
SO2N), 1191 (s, SO2N); UV-vis (THF), (λmax): 696, 662,
3,4-Dicyano-N,N-diphenylbenzenesulfonamide (16)
To a solution of 9 (1.80 g, 3.87 mmol) in dry DMF
(20 mL) was added CuCN (1.80 g, 20 mmol). The reaction
solution was gently refluxed for 6 h, cooled to room temper-
ature, and CH2Cl2 (200 mL) was added. A fine insoluble
powder precipitated overnight. The crude product was puri-
fied by chromatography with 30% ethyl acetate – hexane as
eluent to give colourless, scaly crystals (395 mg, 29%), mp
185–187°C; IR (KBr cm–1): 3091 (s, ArH), 2235, (s, CN),
1
1360 (s, SO2N), 1186 (s, SO2N); H NMR (CDCl3) δ: 7.90
(s, 1H), 7.82 (d, J = 8.0, 1H), 7.76 (d, J = 8.0), 7.19 (m,
5H), 7.07 (m, 5H); MS (m/z, relative intensity): 359 (M+,
60), 168 (100). Anal. calcd. for C20H13N3O2S: C 66.85, H
3.62, N 11.70; found: C 66.36 H 3.33, N 11.56.
1
634, 608, 394, 348; H NMR (THF-d8) δ: 9.40, 9.38, 8.45
(m, 4H, H3), 7.79 (m, 4H, H4), 6.95, 5.87 (m, 8H, H1), 6.93
(m, 8H, H2), 664 (m, 4H, H5); MS (FAB+, m/z, relative in-
tensity): 1030 (M+). Anal. calcd. for C48H130N12O8S4: C
55.92, H 2.91, N 16.31; found: C 55.80, H 2.90, N 15.78.
1-(3,4-Dicyanophenylsulfonyl)pyrrole (17)
In a manner identical to that of 16, 10 gave a crude prod-
uct 17, which on flash chromatography with 30% ethyl ace-
tate – hexanes as eluents yielded fine, colourless crystals
(43%), mp 155–157°C; IR (KBr cm–1): 2235 (s, CN), 1388,
2,9,16,23-Tetrakis(1-indolylsulfonyl)phthalocyanine (21)
As for 20, but from 18, phthalocyanine 21 was obtained
as dark, blue crystals in 42% yield, mp >310°C; IR
(KBr cm–1): 1387 (s, SO2N) 1173 (s, SO2N); UV-vis (THF)
1
1287 (s, SO2N); H NMR (CDCl3) δ: 8.22 (d, J = 1.2, 1H),
1
8.17 (dd, J1 = 1.2, J2 = 8.2, 1H), 7.97 (d, J = 8.2, 1H), 7.16
(d, J = 1.8, 2H), 6.41 (d, J = 1.8, 2H); MS (m/z, relative in-
tensity): 257 (M+, 100), 193 (70). Anal. calcd. for
C12H7N3O2S: C 56.03, H 2.72, N 16.34; found: C 56.17 H
2.62, N 16.34.
(λmax): 698, 666, 634, 612, 346, 248; H NMR (CDCl3) δ:
9.56 (m, br), 8.88 (m, br), 8.70 (m, br), 8.54 (m), 8.14 (m),
8.03 (m), 7.67(m), 7.55 (m), 7.01 (m), 6.92 (m); MS (FAB+,
m/z, relative intensity): 1230 (M+, 40), 671 (70), 539 (100).
Anal. calcd. for C64H38N12O8S4: C 62.44, H, 3.09, N 13.66;
found: C 62.85, H 3.32, N 13.27.
1-(3,4-Dicyanophenylsulfonyl)indole (18)
As for 16 above, 14 gave a crude product, which on puri-
fication by flash chromatography with 30% ethyl acetate –
hexane as eluents, yielded pale yellow, fine crystals (45%),
mp 171–173°C; IR (KBr cm–1): 3110 (s, ArH), 2242 (s,
2,9,16,23-Tetrakis(1-pyrrolylsulfonyl)phthalocyanine
zinc(II) (22)
Compound 17 (200 mg, 0.78 mmol) was dissolved in
2-N,N-dimethylaminoethanol (DMAE) (2 mL) containing
anhydrous Zn(OAc)2 (200 mg). The reaction mixture was
heated to 100–110°C (sand bath) and kept at that tempera-
ture for 1 h while ammonia gas was bubbled through it. The
solution was refluxed for 4 h and cooled to room tempera-
ture. The solvent was evaporated and water (10 mL) was
added to the resulting sticky solution. The blue precipitate
was collected by filtration or centrifugation and purified by
flash column chromatography using 50% THF–CH2Cl2 as
eluent to give in the first fraction 22 as dark crystals (68 mg,
32%), mp >310°C; IR (KBr cm–1): 1371 (m, SO2N) 1167 (s,
1
CN), 1391 (s, SO2N); H NMR (CDCl3) δ: 8.25 (s, 1H, H1),
8.17 (dd, J1 = 1.6, J2 = 8.5, 1H, H3), 7.96 (d, J = 8.5, 1H,
H2), 7.88 (d, J = 8.0, 1H, H4), 7.58 (d, J = 7.7, 1H, H7), 7.51
(d, J = 3.5, 1H, H9), 7.40 (t, J1 = 8.0, J2 = 7.3, 1H, H5), 7.32
(t, J1 = 7.3, J2 = 8.0, 1H, H6), 6.79 (d, J = 3.5, 1H, H8); MS
(m/z, relative intensity): 3.07 (M+, 53), 116 (52), 105 (100).
Anal. calcd. for C16H9N3O2S: C 62.54, H 2.93, N 1368;
found: C 62.95, H 2.81, N 13.62.
′′ ′′
N,N,N′,N′,N ,N ,N“,N“-Octaphenylphthalocyanine-
1
SO2N); UV-vis (THF) (λmax): 672, 610, 350, 242; H NMR
2,9,16,23-tetrasulfonamide (19)
Small pieces of metal lithium (30 mg, 4.3 mmol) were
dissolved in DMAE (2 mL) to which 16 (100 mg,
0.28 mmol) was added. The reaction solution was stirred at
60–70°C (oil bath) for 20 h, cooled to room temperature,
and the sticky blue solution was poured into a mixture of ice
(THF-d8) δ: 9.73 (br), 7.36–8.66 (m, br), 6.59–6.90 (m, br).
MS (FAB+, m/z, relative intensity): 1093 (M+ + 1250), 964
(20), 625 (52) 558 (100). Anal. calcd. for
C48H128N12O8S4Zn: C 52.70, H 2.56, N 15.37; found: C
52.29, H 2.80, N 14.46.
© 1999 NRC Canada

144
Can. J. Chem. Vol. 77, 1999
tained two spots, which was rechromatrographed later. The
second fraction was a mixture of multisulfonate Pcs (8.7 mg).
The first fraction was separated by column chromatography
using 50% CH2Cl2–hexanes to give 26 (4.5 mg, 4.7%), mp
>310°C; IR (KBr cm–1): 1337 (m, SO2N), 1167 (s, SO2N);
2,9,16,23-Tetrakis(1-indolylsulfonyl)phthalocyanine
zinc(II) (23)
As for 22, 18 yielded a crude product which was purified
by flash chromatography by using 40% THF–benzene as
eluent to give 23 as dark blue crystals (68%), mp >310°C;
IR (KBr cm–1): 1376 (m, SO2N), 1173 (s, SO2N); UV-vis
1
UV-vis (THF) (λmax): 714, 692, 686, 656; H NMR (CDCl3)
1
δ: 9.54 (s, 1H), 9.03 (s, 1H), 8.71 (m 3H), 8.50 (m, 2H), 8.25
(d, J = 7.6, 1H), 7.69 (s, 1H), 7.57 (s, Py-H, 2H), 6.42 (s,
Py-H, 2H), 3.15 (m, 12H), 1.49 (m, 78H); MS (FAB+ m/z):
1232 (M+ + 1). Anal. calcd. for C78H105N9O2S: C 76.04, H
8.53, N 10.24; found: C 76.62, H 8.85, N 9.52.
(THF) (λmax): 676, 610, 360, 244; H NMR (CDCl3) δ: 9.79
(m), 9.12 (m), 8.68 (m), 8.31 (m), 8.04 (m), 7.60 (m), 7.17
(m), 6.86 (m), 6.62 (m); MS (FAB+, m/z, relative intensity):
1293 (M+, 60), 1113 (50), 919 (100). Anal. calcd. for
C64H36N12O8S4Zn: C 59.40, H 2.78, N 12.99; found: C
59.19; H 3.09, N 12.65.
9,10,16,17,23,24-Hexakis-(1-heptyl)-2-
(1-pyrrolylsulfonyl)-phthalocyanine zinc(II) (27)
Phthalocyanine-2,9,16,23-tetrasulfonic acid (24)
Metal-free Pc 26 (10 mg, 0.008 mmol) was dissolved in a
mixture of toluene (3 mL) and DMF (3 mL) to which anhy-
drous Zn(OAc)2 was added. The reaction solution was
refluxed for 24 h, the solvent evaporated, and the residue
washed with water (10 mL × 2) and methanol (10 mL × 2).
After drying under vacuum, the crude product was purified
by column chromatography using 5% THF–CH2Cl2 as eluent
to give 27 as a dark blue powder (9 mg, 86%), mp >310°C;
IR (KBr cm–1): 1339, 1166 (s, SO2N); UV-vis (THF) (λmax):
Method A
Small pieces of metal lithium (400 mg, 58 mmol) were
dissolved in DMAE (20 mL) and 20 (100 mg, 0.097 mmol)
was added. The solution was stirred at 60–70°C for 30 h. An
aliquot was taken and added to a mixture of water and
CH2Cl2. The organic solution appeared colourless. The reac-
tion mixture was cooled to room temperature, water was
added, and the solvent was reduced to half volume under
vacuum. After acetone (15 mL) was added, the precipitates
were separated by centrifugation and washed with aqueous
HCl (36%, 5 × 3 mL). Drying under high vacuum gave a
dark blue powder of 24 (25, 31) (70 mg, 86%), mp >310°C;
IR (KBr cm–1): 3400 (s, SO3H), 1472 (s, SO3H); UV-vis
1
692, 666, 634, 604, 354; H NMR (C6D6) δ: 9.96 (br, 1H),
9.10–8.12 (m, 8H), 7.45 (py-H, 2H), 6.13 (py-H, 2H), 3.15
(m, 12H), 1.70 (m, 60H), 1.01(m, 18H); MS (FAB+, m/z,
relative intensity): 1295 (M+ + 1, 100), 736 (60). Anal.
calcd. for C78H103N9O2SZn: C 72.33, H 7.96, N 9.74; found:
C 72.12, H 8.21, N 9.14.
1
(MeOH) (λmax): 692, 656; H NMR (DMSO-d6) δ: 10.19 (br,
4H), 9.71 (br, 4H), 9.53 (m, 4H), 8.60 (m, 4H); MS
(electrospray, m/z): 834.13 (M + 1 – H)–, 753.50 (M + 1 –
H-SO3H)–, 416.11 (M – 2H)2–, 277.07 (M – 3H)3–, 250.19
(M + 1 – SO3H-3H)3–, 207.49 (M – 4H)4–.
Lithium 9,10,16,17,23,24-hexakis-(1-
heptyl)phthalocyanine-2-sulfonate zinc(II) (28)
To a solution of lithium (40 mg) in MeOH (2 mL) was
added 27 (17 mg). The solution was refluxed for 24 h, the
solvent evaporated, and the crude product purified by col-
umn chromatography (Si-gel, 70–230 mesh) using 40%
EtOAc–hexanes and methanol as eluents to give 28 as a dark
blue fine powder (14 mg, 85%), mp >310°C; IR (KBr cm–1):
1110 (s, SO3Li). UV-vis (THF) (λmax): 676, 616, 346, 240
Method B
Small pieces of metal lithium (40 mg, 5.8 mmol) were
dissolved in a mixture of methanol (2 mL) and THF (2 mL)
to which 21 (20 mg) was added. The solution was refluxed
for 20 h. TLC with 5% THF–CH2Cl2 as eluent showed that
the starting material had disappeared. The solvent was evap-
orated and the residue was washed with aqueous HCl (36%,
5 × 3 mL) to give a product identical with that from method
A (23 mg, 84%).
1
(0.47); H NMR (DMSO-d6) δ: 9.60 (br, 1H), 9.31 (d, J =
8.0, 1H), 9.15 (m, 6H), 8.42 (d, J = 8.0, 1H), 1.94 (m, 6H),
1.38 (m, 60H), 0.92 (m, br, 18H); MS (FAB+, m/z, relative
intensity): 1251 (M+, 100).
9,10,16,17,23,24-Hexakis-(1-heptyl)-2-(1-
pyrrolylsulfonyl)phthalocyanine (26)
Acknowledgement
We are grateful to the Natural Sciences and Engineering
Research Council of Canada for financial support of this re-
search.
Excess 4,5-diheptylphthalonitrile (25) (29), prepared by
our previously described method (32), (200 mg, 0.69 mmol)
and 17 (20 mg, 0.078 mmol) were dissolved in DMAE
(3 mL). As ammonia gas was bubbled through, the reaction
mixture was heated to 100–110°C (sand bath). After 1 h, the
solution was raised to reflux temperatures and refluxed for
20 h. The reaction mixture was cooled to room temperature,
ice (5 g) was added to the resulting sticky solution, and the
precipitates were separated by centrifugation followed by se-
quential washing with water (10 × 2 mL) and methanol (10
× 2 mL). The blue precipitate was collected by filtration or
centrifugation and purified by flash column chromatography
using CH2Cl2 as eluent. After evaporation of the solvent, the
residue was rechromatographed with 10% EtOAc–hexanes
and then 5% THF–CH2Cl2 as eluents. The first fraction con-
1. R.W. Boyle and D. Dolphin. Photochem. Photobiol. 64, 469
(1996); T.J. Dougherty. Photochem. Photobiol. 58, 895 (1993).
2. A.M. Fisher, A.L. Murphree, and C.J. Gamer. Lasers Surg.
Med. 17, 2 (1995).
3. C.J. Byrne, L.V. Marshallsay, S.Y. Sek, and A.P. Ward. In
Photodynamic therapy of neoplastic disease. Edited by D.
Kessel. CRC press, Boca Raton. 1990. pp. 133–144.
4. (a) J.D. Spikes. Photochem Photobiol. 43, 691 (1986); (b) J.E.
van Lier. In Photodynamic therapy of neoplastic disease.
© 1999 NRC Canada

Li et al.
Edited by D. Kessel. CRC Press, Boca Raton. 1990.
145
B. Nyasse, L. Grehn, and U. Ragnarsson. J. Chem. Soc. Chem.
pp. 279–290.
Commun. 1017 (1997).
5. W.S. Chan, J.F. Marshall, R. Svensen, J. Bedwell, and I.R.
Hart. Cancer Res. 50, 4533 (1990).
6. N. Brasseur, H. Ali, R. Langlois, and J.E. van Lier.
Photochem. Photobiol. 46, 739 (1987).
7. B. Paquette, H. Ali, R. Langlois, and J.E. van Lier.
Photochem. Photobiol. 47, 215 (1988).
20. J.C. Roberts, H. Gao, A. Gopalsamy, A. Kongsjahju, and R.J.
Patch. Tetrahedron Lett. 38, 355 (1997).
21. J.J. Plattner, P.A. Marcotte, H.D. Kleinert, H.H. Stein, J. Greer,
G. Bolis, A.K.L. Fung, B.A. Bopp, J.R. Luly, H.L. Sham. D.J.
Kempf, S.H. Rosenberg, J.F. Dullaria, B. De, I. Merits, and
T.J. Perun. J. Med. Chem. 31, 2277 (1988).
8. H. Ali, R. Langlois, J.R. Wagner, N. Brasseur, B. Paquette,
and J.E. van Lier. Photochem. Photobiol. 47, 713 (1988).
9. P. Margaron, P. Madarnas, R. Ouellet, and J.E. van Lier.
Anticancer Res. 16, 613 (1996).
10. W.-S. Chan, N. Brasseur, C. La Madeleine, and J.E. van Lier.
Anticancer Res. 16, 1998 (1996).
11. S.V. Kudrevich, H. Ali, and J.E. van Lier. J. Chem. Soc.
Perkin Trans. 1, 2767 (1994).
12. S.V. Kudrevich, S. Gilbert, and J.E. van Lier. J. Med. Chem.
40, 3897 (1997).
22. R.J. Sundberg. J. Heterocyclic Chem. 14, 517 (1977).
23. (a) E.P. Papadopoulos and N.F. Haidar. Tetrahedron Lett. 1721
(1968); (b) M. Kakushima, P. Hamel, R. Frenette, and J.
Rokach. J. Org. Chem. 48, 3214 (1983); (c) H.J. Gogan, R.
McDonald, and L.G. Edwards. Can. J. Chem. 63, 896 (1985).
24. (a) V.D. Illi. Synthesis, 136 (1979); (b) D.M. Ketcha and G.W.
Gribble. J. Org. Chem. 50, 5451 (1985); J.-Y Mérour, B.
Malapel, and E. Desarbe. Synth. Commun. 26, 3267 (1996).
25. L.I. Solov’eva, S.A. Mikhalenko, E.V. Chernykh, and E.A.
Luk’yanets. Zh. Obshch. Khim. 52, 90 (1982).
13. S.V. Kudrevich, N. Brasseur, C. La Madeleine, S. Gilbert, and
J.E. van Lier. J. Med. Chem. 40, 3897 (1997).
14. N. Kobayashi, R. Kondo, S. Nakajima, and T. Osa. J. Am.
Chem. Soc. 112, 9640 (1990).
15. A. Weitemeyer, H. Kliesch, and D. Wöhrle. J. Org. Chem. 60,
4900 (1995); J. Rauschnabel and M. Hanack. Tetrahedron Lett.
36, 1629 (1995).
26. (a) Ellis and Romney-Alexander. Chem. Rev. 87, 779 (1987);
(b) M. Hu, N. Brasseur, S.Z. Yildiz, J.E. van Lier, and C.C.
Leznoff. J. Med. Chem. 41, 1789 (1998).
27. (a) C. Goslich. Ann. 186, 148 (1877); (b) L. Spiegelberg. Ann.
197, 257 (1879).
28. C.C. Leznoff, M. Hu, and K.J.M. Nolan. J. Chem. Soc. Chem.
Commun. 1245 (1996).
16. S. Searles and S. Nukina. Chem. Rev. 59, 1077 (1959).
17. E. Vedejs and S. Lin. J. Org. Chem. 59, 1602 (1994); C.
Goulaouic-Dubois, A. Guggisberg, and M. Hesse. J. Org.
Chem. 60, 5969 (1995).
18. J.E. Richmond and T.J. Atkins. J. Am. Chem. Soc. 96, 2268
(1974); R.C. Roemmele and H. Rapoport. J. Org. Chem. 53,
2367 (1988).
29. H. Mishi, N. Azuma, and K. Kitahara. J. Heterocycl. Chem.
29, 475 (1992).
30. V.M. Negrimousky, V.M. Derkacheva, E.A. Luk’yanets, A.
Weitemeyer, D. Wöhrle, and G. Schneider. Phosphorus Sulfur
Silicon Relat. Elem. 104, 161 (1995).
31. R.P. Linstead and F.T. Weiss. J. Chem. Soc. 2975 (1950).
32. D.S. Terekhov, K.J.M. Nolan, C.R. McArthur, and C.C.
Leznoff. J. Org. Chem. 61, 3034 (1996).
19. S. Ji, L.B. Gorther, A. Waring, A. Battisti, S. Bank, W.D.
Closson, and P. Wriede. J. Am. Chem. Soc. 89, 5311 (1967);
© 1999 NRC Canada