Delocalized cationic azo dyes containing a thiazole moiety

Article abstract of DOI:10.1016/j.tet.2007.11.004

Several new delocalized cationic azo dyes incorporating a bathochromic thiazole moiety have been prepared in moderate to good yields. The synthesis involved the Knoevenagel condensation of an intermediate azo compound, bearing a terminal formyl group, with methylenic bases generated in situ from benzoazolium and quinolinium salts. All dyes display strong absorption around 700 nm and have shown negative solvatochromic behaviour.

Full text of DOI:10.1016/j.tet.2007.11.004

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 299e303
www.elsevier.com/locate/tet
Delocalized cationic azo dyes containing a thiazole moiety
Maria A. Salvador a, Lucinda V. Reis a, Paulo Almeida b, Paulo F. Santos a,
*
a Departamento de Qu´ımica, Centro de Qu´ımicadVila Real, Universidade de Tra´s-os-Montes e Alto Douro, 5001-801 Vila Real, Portugal
b Departamento de Qu´ımica and Unidade de I&D de Materiais Teˆxteis e Papeleiros, Universidade da Beira Interior, 6201-001 Covilh~a, Portugal
Received 14 September 2007; received in revised form 29 October 2007; accepted 1 November 2007
Available online 5 November 2007
Abstract
Several new delocalized cationic azo dyes incorporating a bathochromic thiazole moiety have been prepared in moderate to good yields. The
synthesis involved the Knoevenagel condensation of an intermediate azo compound, bearing a terminal formyl group, with methylenic bases
generated in situ from benzoazolium and quinolinium salts. All dyes display strong absorption around 700 nm and have shown negative
solvatochromic behaviour.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Cationic azo dyes; Thiazole; PDT; Solvatochromism
1. Introduction
Despite the enormous synthetic versatility of azo dyes,
which has turned them into the most widely used dye class,
they have scarcely been modified to display absorption in
the near-infrared5 and their aptitude as sensitizers for PDT
was rarely explored.6 So far, no delocalized cationic azo
dyes appear to have been studied with regard to their use for
PDT. Nevertheless cationic dyes have attracted great attention
as a new family of promising sensitizers since it was found
that cancer cells take up and retain them in a greater extent
than most normal cells.7
Photodynamic therapy (PDT) is an increasingly attractive
treatment for cancer and for a variety of diseases.1 It is based
on the use of photosensitizing drugs that acquire the desired
activity only when excited by light of the appropriate wave-
length. The activation of the sensitizer gives rise to lethal
reactive species, amongst which singlet oxygen is considered
to be main one,2 that destroy the cells circumscribed to the
region illuminated.
Hematoporphyrin derivatives have been the most widely
used drugs for clinical PDT. They present, however, several
limitations, which have led, in the last years, to a considerable
research effort directed towards other classes of photosensi-
tizers with improved characteristics.3 Any new photosensitizer
for PDT must fulfill several multidisciplinary requirements,
such as high quantum yield of the compound’s triplet state
and long triplet lifetime, because photochemical reactions pre-
dominantly occur in the excited state; efficient conversion of
ground-state triplet oxygen to cytotoxic singlet oxygen; and
strong absorption (3>105 Mꢀ1 cmꢀ1) within the photothera-
peutic window (600e1000 nm).4
Following our interest in the development of alternative
sensitizers for PDT,8 we addressed the synthesis of novel
delocalized cationic azo dyes displaying absorption in the
long-wavelength region.
2. Results and discussion
The bathochromic nature of the thiazole ring in azo dyes
was long established9 and it was used by Griffiths and
co-workers5a,b in one of the few successful approaches to
near-infrared absorbing azo dyes, mainly of the neutral type,
through the incorporation of a 4-chlorothiazole unit into the
chromophoric system. The bathochromism of chlorothiazoly-
lazo dyes, however, is somewhat hampered by a certain lack
of chemical stability.10
* Corresponding author. Tel.: þ351 259 350 257; fax: þ351 259 350 480.
E-mail address: psantos@utad.pt (P.F. Santos).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.004

300
M.A. Salvador et al. / Tetrahedron 64 (2008) 299e303
Table 1
Yield and vis spectral data of dyes 5aeh
The synthetic strategy pursued herein involved the forma-
tion of an intermediate azo dye incorporating a bathochromic
thiazole ring and a terminal formyl group to allow the exten-
sion of conjugation through condensation with an active meth-
ylene benzoazolium or quinolinium quaternary salt (Scheme
1). Thus, 2-aminothiazole-5-carbaldehyde11 (1) was diazo-
tized in nitrosylsulphuric acid to afford the diazonium salt 2,
which was subsequently coupled with N,N-diethylaniline to
afford 2-(4-diethylaminophenylazo)thiazole-5-carbaldehyde
(3). Knoevenagel condensation of the latter with the methyl-
enic bases generated in situ from benzoazolium and quinoli-
nium salts 4aeh in EtOH/pyridine gave the corresponding
dyes 5aeh in moderate to good yields. All delocalized
cationic azo dyes display intense absorption (log 3>5.6) above
ca. 650 nm (Table 1). Generally, a weak secondary band is
apparent around 430 nm.
Compound
Yield
(%)
lmax (nm) (log 3)
CH2Cl2
lmax (nm)
DMSO
lmax (nm)
MeOH
5a
5b
5c
5d
5e
5f
82
58
32
99
40
59
48
53
690 (5.73)
693 (5.82)
708 (5.70)
711 (5.78)
693 (5.61)
729 (5.90)
657 (5.71)
648 (5.75)
639
639
645
648
642
672
621
612
630
633
642
642
636
669
609
597
5g
5h
from CH2Cl2 to MeOH ranged from 48 to 69 nm, being more
pronounced for the 6-iodobenzothiazolium dye 5d (Fig. 1).
Azo dyes chiefly reveal positive solvatochromic behaviour;14
negative solvatochromism has been seldom referred.14,15
This synthetic methodology constitutes an interesting alter-
native to that traditionally employed in the synthesis of
The red shift promoted by the thiazole moiety is perceiv-
able when comparing the absorption of the intermediate azo
dye 3, having lmax (CH2Cl2) 549 nm, with that of 4-(4-diethyl-
aminophenylazo)benzaldehyde, for which has been reported
lmax 472 nm in the same solvent.5a
0.8
Methanol
Since delocalized cationic azo dyes are a border case of
polymethine dyes12 it is noteworthy that the maximum wave-
length of absorption of dyes 5 does not show the same order of
dependence neither from the basicity of the heteroaromatic
nuclei nor from the length of the p-conjugated system
observed for polymethine dyes, i.e., indole<benzothiazole<
benzoselenazole<quinoline<lepidine.13 The lepidine-derived
dye 5h, despite possessing a more extended conjugation than
the parent quinoline-based dye 5g, displays a value of lmax
inferior to that of 5g regardless of the solvent.
Not surprisingly, the length of the N-alkyl chain seems to
have a negligible influence on the lmax of the dyes, as illus-
trated for dyes 5a and 5b possessing, respectively, an N-ethyl
and N-hexyl pendent group.
Azo dyes 5 showed negative solvatochromism on passing
from CH2Cl2 to DMSO and from this to the even more polar
MeOH. The observed hypsochromic displacement of lmax
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
DMSO
Dichloromethane
300
400
500
600 700
Wavelength (nm)
800
900
1000
Figure 1. Absorption spectra of dye 5d in various solvents.
N
N
N
N
i
ii
OHC
NH2
OHC
N
OHC
N2
HSO4
S
S
S
S
1
2
3
NEt2
NEt2
Z
N
iii
R1
R3
+
Z
I
N
N
3
N
N
N
I
4a-h
N
R2
R1
R2
5a-g
a: Z = S, R1 = H, R2 = C2H5, R3 = CH3
N
S
b: Z = S, R1 = H, R2 = n-C6H13, R3 = CH3
c: Z = S, R1 = 5-I, R2 = C2H5, R3 = CH3
d: Z = S, R1 = 6-I, R2 = C2H5, R3 = CH3
e: Z = Se, R1 = H, R2 = C2H5, R3 = CH3
N
I
Et
NEt2
5h
f: Z = C(CH3)2, R1 = H, R2 = C2H5, R3 = CH3
g: Z = CH=CH, R1 = H, R2 = C2H5, R3 = CH3
h: Z = C(CH3)=CH, R1 = H, R2 = C2H5, R3 = H
Scheme 1. Reagents and conditions: (i) H2SO4, NaNO2, AcOH, ꢀ5 to 0 ꢁC; (ii) N,N-diethylaniline, H2SO4, H2O, 0 ꢁC to rt; (iii) EtOH, pyridine, 35 ꢁC to reflux.

M.A. Salvador et al. / Tetrahedron 64 (2008) 299e303
301
delocalized cationic azo dyes, which generally involves the
regioselective alkylation of disperse azo dyes.12
under reduced pressure to afford chromatographically pure
3. Yield: 55%. Dark-green crystals. Mp 140e143 ꢁC. Vis
(CH2Cl2) lmax (log 3) 549 nm (5.65). IR (KBr) nmax 2967
(w), 1661 (s), 1597 (s), 1543 (w), 1525 (w), 1509 (w), 1413
(w), 1382 (w), 1328 (s), 1306 (s), 1259 (s), 1228 (s), 1130
The photochemical evaluation of the dyes synthesized, with
prominence for the determination of the singlet oxygen gener-
ation ability, as well as the assessment of their potential pho-
totoxicity against selected cancer cells is currently the subject
of a separate study, the results of which shall be published
elsewhere.
1
(s), 1074 (s), 1007 (m), 826 (w), 700 (w) cmꢀ1. H NMR
(400.13 MHz, CDCl3) d 1.27 (t, 6H, J¼7.1 Hz, CH3), 3.51
(q, 4H, J¼7.1 Hz, CH2), 6.73 (d, 2H, J¼9.1 Hz, ArH ), 7.94
(d, 2H, J¼9.1 Hz, ArH ), 8.43 (s, 1H, ]CHN), 9.97 (s, 1H,
CHO). 13C NMR (100.61 MHz, CDCl3) d 12.7 (CH3), 45.3
(CH2), 111.8, 136.8, 142.8, 151.9, 153.2, 182.9, 184.4.
FABHRMS (3-NBA) calcd for C14H17N4OS [MþH]þ:
289.1123; found 289.1126.
3. Conclusions
The Knoevenagel condensation of 2-(4-diethylaminophenyl-
azo)thiazole-5-carbaldehyde (3) with methylenic bases gener-
ated in situ from benzoazolium and quinolinium salts was
used to prepare several new delocalized cationic azo dyes in
moderate to good yields. The synthesized dyes display strong
absorption around 700 nm and have shown negative solvato-
chromic behaviour.
4.3. Synthesis of quaternary ammonium salts 4
A solution of appropriate methylbenzoazole or methylqui-
noline (1.0 mmol) and 1-iodoethane or 1-iodohexane (3.0e
5.0 mmol) in CH3CN (25 mL) was heated at reflux for 5
days. After cooling, Et2O was added, the precipitated quater-
nary salt collected by filtration under reduced pressure, washed
several times with Et2O and dried under reduced pressure to
afford spectroscopically pure salts 4. The combined filtrates
were evaporated at reduced pressure and the remaining residue,
consisting mainly of unreacted starting materials, was heated at
reflux for another 5 days and worked up as described above.
The process was repeated until a suitable yield was achieved
(usually 2e3 times). The spectroscopic characterization of
salts 4a,b,eeh has been previously reported.16
4. Experimental
4.1. General
All reagents were of the highest purity available, obtained
from commercial suppliers and used as received. Solvents
were of analytical grade. 6-Iodo-2-methylbenzothiazole
(6b)8a and 2-aminothiazole-5-carbaldehyde (1)11 were pre-
pared as described in the literature. Reactions were monitored
by TLC using 0.25 mm aluminium-backed silica gel plates
(Merck 60 F254). Melting points were measured in open capil-
lary tubes in a Buchi 530 melting point apparatus and are
¨
4.3.1. 3-Ethyl-5-iodo-2-methylbenzothiazol-3-ium iodide (4c)
Yield: 61%. Yellowish solid. Mp 240e243 ꢁC (dec). IR
(KBr) nmax 3041 (w), 2975 (m), 2931 (w), 2905 (w), 1578
(m), 1561 (m), 1442 (s), 1414 (m), 1367 (m), 1330 (m),
uncorrected. FTIR spectra were recorded on a Mattson 5000
FT IR spectrophotometer. UV/vis spectra were performed on
a PerkineElmer Lambda 6 instrument. 1H and 13C NMR
1
spectra were recorded on a Brucker ARX 400 spectrometer.
¨
1200 (m), 1098 (w), 872 (w), 817 (s), 801 (w) cmꢀ1. H
Chemical shifts are reported with respect to the solvent or
TMS as internal standard. Mass spectra were determined on
a Micromass AutoSpec M spectrometer, operating at 70 eV.
A matrix of 3-nitrobenzyl alcohol (3-NBA) was used for
Fast Atom Bombardment High Resolution mass spectra.
NMR (400.13 MHz, DMSO-d6) d 1.42 (t, 3H, J¼7.3 Hz,
CH3), 3.19 (s, 3H, CH3), 4.74 (q, 2H, J¼7.3 Hz, CH2),
8.12 (dd, 1H, J¼1.3, 8.6 Hz, 6-CH ), 8.20 (d, 1H, J¼8.6 Hz,
7-CH ), 8.77 (d, 1H, J¼1.3 Hz, 4-CH ). FABHRMS (3-NBA)
calcd for C10H11NSI [M]þ: 303.9657; found 303.9659.
4.2. 2-(4-Diethylaminophenylazo)thiazole-5-
carbaldehyde (3)
4.3.2. 3-Ethyl-6-iodo-2-methylbenzothiazol-3-ium iodide (4d)
Yield: 78%. Dark-yellowish solid. Mp 269e272 ꢁC (dec).
IR (KBr) nmax 3044 (m), 2974 (w), 2937 (w), 1567 (m),
1511 (m), 1451 (s), 1384 (s), 1330 (s), 1266 (m), 1204 (w),
To stirred H2SO4 (7 mL) at 30 ꢁC was added NaNO2
(0.647 g, 9.38 mmol) and the mixture was heated at 65 ꢁC
until complete dissolution. The solution was then cooled in
an ice bath, CH3CO2H (4 mL) was added and the mixture
was left for 10 min. Following cooling to ꢀ5 ꢁC, 2-aminothi-
azole-5-carbaldehyde (1)11 (1.00 g, 7.81 mmol) was added por-
tionwise and the mixture stirred for 2 h 30 min at 5 ꢁC. The
resulting diazonium salt solution was added slowly to a stirred
suspension of N,N-diethylaniline (1.3 mL, 8.17 mmol) in
water (62 mL) and H2SO4 (1.2 mL). Once the addition was
completed, the reaction mixture was left at rt for 30 min and
then extracted with AcOEt. The combined organic layers
were dried over anhydrous Na2SO4 and the solvent removed
1
1098 (w), 802 (m) cmꢀ1. H NMR (400.13 MHz, DMSO-d6)
d 1.42 (t, 3H, J¼7.3 Hz, CH3), 3.18 (s, 3H, CH3), 4.72 (q,
2H, J¼7.3 Hz, CH2), 8.13 (d, 1H, J¼8.6 Hz, 4-CH ), 8.20
(d, 1H, J¼1.6, 8.9 Hz, 5-CH ), 8.85 (d, 1H, J¼1.6 Hz,
7-CH ). FABHRMS (3-NBA) calcd for C10H11NSI [M]þ:
303.9657; found 303.9659.
4.4. Synthesis of dyes 5: general procedure
A solution of the quaternary ammonium salt 4 (1.0 mmol)
and the intermediary azo dye 3 (1.0 mmol) in EtOH
(13.5 mL) containing pyridine (1.5 mL) was heated from

302
M.A. Salvador et al. / Tetrahedron 64 (2008) 299e303
35 ꢁC to reflux until complete consumption of the starting azo
dye (6e52 h). The heating rate was carefully controlled to
avoid the decomposition of 3. The reaction mixture was then
cooled in an ice bath and Et2O was added. The resulting
dark-blue solid was collected by filtration under reduced pres-
sure, washed several times with Et2O, redissolved in CHCl3
and washed with water. The organic layer, after being sepa-
rated by decantation, was dried over anhydrous NaSO4 and
the solvent evaporated to dryness. The resulting residue was
recrystallized from CHCl3/Et2O until a chromatographically
pure material was obtained (1e3 times).
ArH ), 8.08 (d, 1H, J¼8.3 Hz, ArH ), 8.19 (d, 1H, J¼8.3 Hz,
ArH ), 8.48 (d, 1H, J¼14.6 Hz, ]CHC), 8.56 (s, 1H,
]CHN), 8.69 (s, 1H, ArH ). 13C NMR (100.61 MHz, DMSO-
d6) d 12.4 (CH3), 13.9 (CH3), 44.2 (CH2), 44.7 (CH2), 95.3,
112.5, 113.0, 124.4, 125.6, 127.9, 133.3, 136.6, 139.6, 141.9,
142.2, 151.8, 153.1, 170.7, 181.6. FABHRMS (3-NBA) calcd
for C24H25N5S2I [M]þ: 574.0596; found 574.0599.
4.4.4. 3-Ethyl-2-{2-[2-(4-diethylaminophenylazo)thiazol-
5-yl]vinyl}-6-iodobenzothiazol-3-ium iodide (5d)
Yield: 99%. Dark-green solid. Mp 220 ꢁC (dec). IR (KBr)
nmax 2976 (w), 1585 (s), 1566 (m), 1541 (w), 1450 (w),
1286 (w), 1249 (s), 1235 (m), 1207 (w), 1124 (s), 1074 (m),
4.4.1. 3-Ethyl-2-{2-[2-(4-diethylaminophenylazo)thiazol-
5-yl]vinyl}benzothiazol-3-ium iodide (5a)
1
1030 (w), 1008 (w), 806 (w) cmꢀ1. H NMR (400.13 MHz,
Yield: 82%. Dark solid. Mp 215 ꢁC (dec). IR (KBr) nmax
2975 (w), 1594 (s), 1580 (s), 1541 (w), 1444 (w), 1418 (w),
1293 (w), 1253 (s), 1235 (s), 1207 (w), 1131 (s), 1119 (s), 1075
DMSO-d6) d 1.21 (t, 6H, J¼7.1 Hz, CH3), 1.42 (t, 3H,
J¼7.1 Hz, CH3), 3.60 (br q, 4H, CH2), 4.88 (br q, 2H, CH2),
6.97 (d, 2H, J¼9.2 Hz, ArH ), 7.70 (d, 1H, J¼15.4 Hz,
]CHC), 7.82 (d, 2H, J¼9.2 Hz, ArH ), 8.06 (d, 1H,
J¼8.8 Hz, ArH ), 8.17 (d, 1H, J¼8.8 Hz, ArH ), 8.51 (d, 1H,
J¼15.4 Hz, ]CHC), 8.56 (s, 1H, ]CHN), 8.86 (d,
1H, J¼1.4 Hz, ArH ). 13C NMR (100.61 MHz, DMSO-d6)
d 12.6 (CH3), 14.1 (CH3), 44.4 (CH2), 44.8 (CH2), 94.0,
112.7, 113.1, 118.0, 130.1, 132.4, 133.4, 137.8, 139.6, 140.5,
142.2, 152.0, 153.2, 170.3, 181.8. FABHRMS (3-NBA) calcd
for C24H25N5S2I [M]þ: 574.0596; found 574.0594.
(m), 1036 (w), 1007 (w), 792 (w) cmꢀ1
.
1H NMR
(400.13 MHz, DMSO-d6) d 1.20 (t, 6H, J¼6.9 Hz, CH3), 1.45
(t, 3H, J¼6.9 Hz, CH3), 3.57 (q, 4H, J¼6.9 Hz, CH2), 4.92
(q, 2H, J¼6.9 Hz, CH2), 6.93 (d, 2H, J¼9.3 Hz, ArH ), 7.70 (d,
1H, J¼15.4 Hz, ]CHC), 7.76e7.80 (m, 3H, ArH ), 7.86 (t, 1H,
J¼7.8 Hz, ArH ), 8.26 (d, 1H, J¼8.5 Hz, ArH ), 8.42e8.47 (m,
2H, ArHþ]CHC), 8.55(s, H, ]CHN). 13CNMR(100.61 MHz,
DMSO-d6) d 12.5 (CH3), 14.1 (CH3), 44.3 (CH2), 44.8 (CH2),
112.6, 113.4, 116.4, 124.4, 128.2, 128.3, 129.5, 133.4, 139.1,
140.8, 142.1, 151.7, 153.1, 170.2, 181.5. FABHRMS (3-NBA)
calcd for C24H26N5S2 [M]þ: 448.1630; found 448.1623.
4.4.5. 3-Ethyl-2-{2-[2-(4-diethylaminophenylazo)selenazol-
5-yl]vinyl}benzothiazol-3-ium iodide (5e)
Yield: 40%. Dark solid. Mp 193 ꢁC (dec). IR (KBr) nmax
2971 (w), 2927 (w), 1590 (s), 1541 (w), 1526 (w), 1441 (w),
1416 (w), 1296 (w), 1248 (s), 1231 (m), 1123 (s), 1071 (m),
4.4.2. 2-{2-[2-(4-Diethylaminophenylazo)thiazol-5-yl]-
vinyl}-3-hexylbenzothiazol-3-ium iodide (5b)
1
Yield: 58%. Dark solid. Mp 136 ꢁC (dec). IR (KBr) nmax
2925 (w), 2857 (w), 1593 (s), 1580 (s), 1538 (w), 1441 (w),
1416 (w), 1298 (w), 1253 (s), 1235 (s), 1127 (s), 1069 (s), 1005
1007 (w), 758 (w) cmꢀ1. H NMR (400.13 MHz, DMSO-d6)
d 1.20 (t, 6H, J¼7.0 Hz, CH3), 1.44 (t, 3H, J¼6.9 Hz, CH3),
3.59 (q, 4H, J¼7.0 Hz, CH2), 4.91 (q, 2H, J¼6.9 Hz, CH2),
6.97 (d, 2H, J¼9.4 Hz, ArH ), 7.69e7.74 (m, 2H, ArHþ]
CHC), 7.80e7.84 (m, 3H, ArH ), 8.25 (d, 1H, J¼8.7 Hz,
ArH ), 8.45 (d, 1H, J¼7.4 Hz, ArH ), 8.54e8.58 (m, 2H,
]CHCþ]CHN). 13C NMR (100.61 MHz, DMSO-d6)
d 12.6 (CH3), 14.1 (CH3), 44.9 (CH2), 45.3 (CH2), 112.7,
116.4, 118.1, 127.4, 128.0, 129.1, 130.3, 133.9, 140.9,
142.1, 142.3, 151.7, 153.2, 179.5, 181.5. FABHRMS (3-NBA)
calcd for C24H26N5S78Se [M]þ: 494.1082; found 494.1089;
calcd for C24H26N5S80Se [M]þ: 496.1074; found 496.1082.
1
(m), 882 (w), 793 (w) cmꢀ1. H NMR (400.13 MHz, DMSO-
d6) d 0.86 (t, 3H, J¼6.9 Hz, CH3), 1.21 (t, 6H, J¼6.9 Hz,
CH3), 1.25e1.36 (m, 4H, CH2), 1.40e1.46 (m, 2H, CH2),
1.80e1.88 (m, 2H, CH2), 3.59 (q, 4H, J¼6.9 Hz, CH2), 4.89
(t, 2H, J¼7.3 Hz, CH2), 6.95 (d, 2H, J¼9.0 Hz, ArH ), 7.69
(d, 1H, J¼15.3 Hz, ]CHC), 7.77e7.89 (m, 4H, ArH ), 8.26
(d, 1H, J¼8.5 Hz, ArH ), 8.43e8.47 (m, 2H, ArHþ]CHC),
8.55 (s, 1H, ]CHN). 13C NMR (100.61 MHz, DMSO-d6)
d 12.4 (CH3), 13.6 (CH3), 21.7 (CH2), 25.2 (CH2), 28.5
(CH2), 30.5 (CH2), 44.7 (CH2), 48.6 (CH2), 112.5, 113.4,
116.5, 124.2, 128.0, 128.2, 129.4, 133.3, 139.0, 141.0, 142.2,
151.5, 153.1, 170.4, 181.4. FABHRMS (3-NBA) calcd for
C28H34N5S2 [M]þ: 504.2256; found 504.2259.
4.4.6. 1-Ethyl-2-{2-[2-(4-diethylaminophenylazo)thiazol-
5-yl]vinyl}-3,3-dimethyl-3H-indolium iodide (5f)
Yield: 59%. Dark solid. Mp 221 ꢁC (dec). IR (KBr) nmax
2971 (w), 1604 (m), 1577 (s), 1536 (w), 1466 (w), 1302 (w),
1252 (s), 1229 (w), 1209 (w), 1147 (s), 1119 (s), 1089 (m),
4.4.3. 3-Ethyl-2-{2-[2-(4-diethylaminophenylazo)thiazol-
5-yl]vinyl}-5-iodobenzothiazol-3-ium iodide (5c)
1072 (m), 1042 (w), 1006 (w), 765 (w) cmꢀ1 1H NMR
.
Yield: 32%. Dark solid. Mp 208 ꢁC (dec). IR (KBr) nmax
2973 (w), 1588 (s), 1569 (m), 1523 (w), 1438 (w), 1411 (w),
1331 (w), 1296 (w), 1247 (s), 1125 (s), 1075 (m), 1008 (w),
793 (w) cmꢀ1. 1H NMR (400.13 MHz, DMSO-d6) d 1.20 (t, 6H,
J¼6.9 Hz, CH3), 1.41 (t, 3H, J¼7.0 Hz, CH3), 3.59 (br q, 4H,
CH2), 4.88 (br q, 2H, CH2), 6.96 (d, 2H, J¼8.6 Hz, ArH ),
7.67 (d, 1H, J¼14.6 Hz, ]CHC), 7.81 (d, 2H, J¼8.6 Hz,
(400.13 MHz, DMSO-d6) d 1.21 (t, 6H, J¼7.0 Hz, CH3),
1.43 (t, 3H, J¼7.1 Hz, CH3), 1.79 (s, 6H, CH3), 3.62 (q, 4H,
J¼7.0 Hz, CH2), 4.65 (q, 2H, J¼7.1 Hz, CH2), 7.00 (d, 2H,
J¼9.3 Hz, ArH ), 7.30 (d, 1H, J¼15.8 Hz, ]CHC), 7.61e
7.62 (m, 2H, ArH ), 7.83e7.92 (m, 4H, ArH ), 8.70 (d, 1H,
J¼15.8 Hz, ]CHC), 8.76 (s, 1H, ]CHN). 13C NMR
(100.61 MHz, DMSO-d6) d 13.2 (CH3), 14.2 (CH3), 26.1

M.A. Salvador et al. / Tetrahedron 64 (2008) 299e303
303
(CH3), 42.4 (CMe2), 45.6 (CH2), 52.5 (CH2), 112.7, 113.6,
115.4, 123.6, 129.6, 129.7, 134.8, 141.0, 143.2, 144.3, 144.6,
154.1, 155.0, 180.5, 183.5. FABHRMS (3-NBA) calcd for
C27H32N5S [M]þ: 458.2378; found 458.2376.
give 6a. Yellowish solid. Yield: 46%. Mp 83e85 ꢁC (lit.17
85.0e85.5 ꢁC). IR (KBr) nmax 3047 (w), 2960 (w), 1517
(m), 1433 (m), 1401 (m), 1379 (w), 1292 (w), 1168 (m),
1150 (m), 1065 (m), 882 (m), 794 (s) cmꢀ1 1H NMR
.
(400.13 MHz, CDCl3) d 2.83 (s, 3H, CH3), 7.54 (d, 1H,
J¼8.4 Hz, 7-CH ), 7.62 (dd, 1H, J¼1.6, 8.4 Hz, 6-CH ), 8.29
(d, 1H, J¼1.6 Hz, 4-CH ). TOFEIMS: 275 [M]þ.
4.4.7. 1-Ethyl-2-{2-[2-(4-diethylaminophenylazo)thiazol-
5-yl]vinyl}quinolinium iodide (5g)
Yield: 48%. Dark solid. Mp 207 ꢁC (dec). IR (KBr) nmax
2969 (w), 2929 (w), 1591 (s), 1521 (w), 1412 (w), 1347 (w),
1303 (w), 1254 (m), 1227 (m), 1130 (s), 1073 (m), 1008
Acknowledgements
(w), 968 (w) cmꢀ1 1H NMR (400.13 MHz, DMSO-d6)
.
ˆ
~
Fundac¸ao para a Ciencia e a Tecnologia (Portugal), POCI
2010 and FEDER are greatly acknowledged for the funding
of the Project ‘Azo Dyes for Photodynamic Therapy’ (POCI/
QUI/57913/2004).
d 1.20 (t, 6H, J¼7.0 Hz, CH3), 1.56 (t, 3H, J¼7.1 Hz, CH3),
3.56 (q, 4H, J¼7.0 Hz, CH2), 5.11 (q, 2H, J¼7.1 Hz, CH2),
6.89 (d, 2H, J¼9.3 Hz, ArH ), 7.51 (d, 1H, J¼15.4 Hz,
]CHC), 7.77 (d, 2H, J¼9.3 Hz, ArH ), 7.94 (t, 1H, J¼7.5 Hz,
ArH ), 8.17 (dt, 1H, J¼1.2, 8.1 Hz, ArH ), 8.34 (dd, 1H, J¼1.2,
8.1 Hz, ArH ), 8.41 (s, 1H, ]CHN), 8.48e8.55 (m, 3H,
ArHþ]CHC), 9.03 (d, 1H, J¼9.0 Hz, ]CHC). 13C NMR
(100.61 MHz, DMSO-d6) d 12.5 (CH3), 14.1 (CH3), 44.7
(CH2), 46.5 (CH2), 112.3, 118.8, 118.9, 120.8, 128.1, 128.9,
130.3, 134.3, 135.1, 137.9, 138.0, 141.9, 143.9, 149.7, 152.8,
154.1, 180.3. FABHRMS (3-NBA) calcd for C26H28N5S [M]þ:
442.2065; found 442.2062.
References and notes
1. (a) Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.; Kessel, D.;
Korbelik, M.; Moan, J.; Peng, Q. J. Natl. Cancer Inst. 1998, 90, 889e905;
(b) Detty, M. R.; Gibson, S. L.; Wagner, S. J. J. Med. Chem. 2004, 47,
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2. Niedre, M. J.; Patterson, M. S.; Wilson, B. C. Photochem. Photobiol.
2002, 75, 382e391.
3. (a) Diwu, Z.; Lown, J. W. Pharmacol. Ther. 1994, 63, 1e35; (b)
Wainwright, M. Chem. Soc. Rev. 1996, 25, 351e359; (c) Photodynamic
Tumour Therapy: 2nd and 3rd Generation Photosensitizers; Moser,
J. C., Ed.; Hardwood Academic: Amsterdam, 1998.
4.4.8. 1-Ethyl-4-{2-[2-(4-diethylaminophenylazo)thiazol-
5-yl]vinyl}quinolinium iodide (5h)
4. Jori, G. J. Photochem. Photobiol., B 1996, 36, 87e93.
5. (a) Bello, K. A.; Griffiths, J. J. Chem. Soc., Chem. Commun. 1986, 1639e
1640; (b) Griffiths, J.; Lee, W. J. Adv. Colour Sci. Technol. 2002, 5, 99e
102; (c) Hall, N.; Patel, P. GB Patent 2,237,804, 1991; (d) Gregory, P. Eur.
Patent 280,434, 1988; (e) Yasui, S.; Matsuoka, M.; Takao, M.; Kitao, T.
J. Soc. Dyers Colour. 1988, 104, 284e288.
Yield: 53%. Dark-purple crystals. Mp 223 ꢁC (dec). IR
(KBr) nmax 2974 (w), 2924 (w), 1586 (s), 1562 (m), 1534
(w), 1398 (w), 1328 (w), 1302 (w), 1247 (s), 1219 (w), 1133
1
(s), 1074 (m), 1004 (w), 825 (w), 756 (w) cmꢀ1. H NMR
(400.13 MHz, DMSO-d6) d 1.20 (t, 6H, J¼6.9 Hz, CH3), 1.59
(t, 3H, J¼7.1 Hz, CH3), 3.56 (q, 4H, J¼6.9 Hz, CH2), 5.01 (q,
2H, J¼7.1 Hz, CH2), 6.93 (d, 2H, J¼9.2 Hz, ArH ), 7.80 (d,
2H, J¼9.2 Hz, ArH ), 7.99e8.04 (m, 2H, ArHþ]CHC), 8.24
(t, 1H, J¼7.7 Hz, ArH ), 8.31 (s 1H, ]CHN), 8.40 (d, 1H, J¼
15.6 Hz, ]CHC), 8.45 (d, 1H, J¼6.4 Hz, ]CHC), 8.53 (d,
1H, J¼9.0 Hz, ArH ), 8.98 (d, 1H, J¼8.5 Hz, ArH ), 9.39 (d,
1H, J¼6.4 Hz, ]CHC). 13C NMR (100.61 MHz, DMSO-d6)
d 12.5 (CH3), 15.0 (CH3), 44.6 (CH2), 52.1 (CH2), 79.1, 112.2,
116.3, 118.9, 121.5, 126.4, 126.7, 129.1, 133.3, 135.0, 135.2,
137.5, 141.8, 147.0, 148.2, 151.6, 152.5, 179.3. FABHRMS
(3-NBA) calcd for C26H28N5S [M]þ: 442.2065; found 442.2066.
6. (a) Rajagopalan, R.; Cantrell, G. L.; Bujag, J. E.; Achilefu, S. I.; Dorshow,
R. B. U.S. Patent 72,763, 2003; (b) Rajagopalan, R.; Achilefu, S. I.;
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L. F. V. J. Photochem. Photobiol., A 2003, 160, 159e161; (c) Santos, P. F.;
Reis, L. V.; Almeida, P.; Serrano, J. P.; Oliveira, A. S.; Ferreira, L. F. V.
J. Photochem. Photobiol., A 2004, 163, 267e269.
9. Dickey, J. B.; Towne, E. B.; Bloom, M. S.; Moore, W. H.; Hill, H. M.;
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11. Frishberg, M. D. U.S. Patent 4,225,719, 1980.
4.5. 5-Iodo-2-methylbenzothiazole (6a)
12. Zollinger, H. Color Chemistry: Synthesis, Properties and Applications of
Organic Dyes and Pigments; VCH: Weinheim, 1991.
13. Matsuoka, M. Infrared Absorbing Dyes; Matsuoka, M., Ed.; Plenum: New
York, NY, 1990; pp 19e33.
To an ice-cooled mixture of 5-amino-2-methylbenzothi-
azole (1.00 g, 6.09 mmol), concd HCl (2.8 mL) and water
(2.8 mL) was added dropwise a solution of NaNO2 (0.772 g,
11.19 mmol) in water (3.6 mL) and, 30 min later, a solution
of KI (1.75 g, 10.54 mmol) in the same solvent (2 mL). After
stirring for 10 min, the reaction mixture was allowed to grad-
ually reach rt and then heated at 30e40 ꢁC for 15 min. The re-
sulting dark cake was dissolved in CH2Cl2 and washed with
5% aqueous NaHSO3 until a pale yellow colour was obtained.
The organic layer was dried over anhydrous Na2SO4, the sol-
vent removed under reduced pressure and the residue purified
by column chromatography (silica, CHCl3/n-hexane 1/1) to
14. Kim, J. J.; Funabiki, K.; Muramatsu, H.; Shibata, K.; Kim, S. H.;
Shiozaki, H.; Hartmann, H.; Matsui, M. J. Chem. Soc., Perkin Trans. 2
2001, 379e387 and references therein.
15. (a) Kim, J. J.; Funabiki, K.; Muramatsu, H.; Shibata, K.; Kim, S. H.;
Shiozaki, H.; Hartmann, H.; Matsui, M. Chem. Commun. 2000, 753e754;
(b) Allen, D. W.; Li, X. J. Chem. Soc., Perkin Trans. 2 1997, 1099e1103;
(c) Quast, H.; Schmitt, E. Liebigs Ann. Chem. 1970, 732, 43e63.
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Molecules 2002, 7, 320e330.
17. Gavryushin, A. Ph.D. Dissertation, Ludwig-Maximilians-Universitat,
¨
2006.